Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([C:11]([O:13][CH3:14])=[O:12])#[C:6][C:7]([O:9][CH3:10])=[O:8]>CN(C=O)C>[NH:1]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([C:11]([O:13][CH3:14])=[O:12])[N:3]=[N:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)C#CC(=O)OC
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1nn[nH]c1C(=O)OC

Procedure:
To a stirred suspension of sodium azide (5.03 g, 77.39 mmol) in DMF (120 mL) was added dropwise at 0° C. over 30 min, a solution of dimethyl acetylene-dicarboxylate (10.0 g, 70.36 mmol) in DMF (100 mL). After 30 min the solvent was removed in vacuo at 30° C. to leave a light purple-brown solid. The solid was washed twice with ether and taken up in water (100 mL). The aqueous solution was acidified with conc. HCl to pH 2. The aqueous layer was first extracted with ether (100 mL) and then with chloroform (100 mL). The combined organic layers were evaporated to give a light red colored solid: 128-130° C. The solid was washed with hot hexane and crystallized from benzene: Yield 11.0 g (85%); 1H NMR (CDCl3) δ 4.00 (s, 6H), 11.87 (br s, 1H, NH).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:28]=[CH:27][C:21]2[C:22](=[O:26])[CH2:23][CH2:24][O:25][C:20]=2[C:19]=1[CH2:29][CH2:30][CH3:31].OC1C=CC2C(=O)CCOC=2C=1CCC.COC(=O)CCC1C=CC=CC=1CCCCCI.[OH-].[Na+]>CO>[O:26]=[C:22]1[C:21]2[CH:27]=[CH:28][C:18]([O:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[CH2:5][CH2:4][C:3]([OH:32])=[O:2])=[C:19]([CH2:29][CH2:30][CH3:31])[C:20]=2[O:25][CH2:24][CH2:23]1
Reactant: CCCc1c(OCCCCCc2ccccc2CCC(=O)OC)ccc2c1OCCC2=O
Agent: CCCc1c(O)ccc2c1OCCC2=O
Agent: COC(=O)CCc1ccccc1CCCCCI
Agent: [Na+]
Solvent: CO
Product: CCCc1c(OCCCCCc2ccccc2CCC(=O)O)ccc2c1OCCC2=O
Yield: 67.5 %

Procedure:
Using the procedure of example 4, 2-[5-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]pentyl]benzenepropanoic acid methyl ester was prepared, in 67.5% yield, starting from 0.35 g (1.69 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one and 0.54 g (1.5 mmol) of 2-(5-iodopentyl)benzenepropanoic acid methyl ester. A 0.5 g (1.14 mmol) sample of this ester was treated with 20 mL of methanol and 3 mL of aqueous 1N sodium hydroxide. The mixture was stirred and refluxed for 2.5 hr and then the solvent was removed in vacuo. The residue was diluted with water, acidified, and worked-up with ether in the usual manner. The product was recrystallized from hexane-ethyl acetate giving 2-[5-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]pentyl]benzenepropanoic acid as a colorless solid, mp 94°-96° C., in 58.2% overall yield.
Reaction SMILES: Br.[NH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][N:7]([CH2:13][CH2:14][CH3:15])[CH2:8]2.C(=O)(O)[O-].[K+].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[C:26](Cl)=[O:27].C1C2C(=CC=CC=2)CCN1>C1C=CC=CC=1>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[C:26]([NH:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][N:7]([CH2:13][CH2:14][CH3:15])[CH2:8]2)=[O:27]
Reactant: CCCN1CCc2c(N)cccc2C1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Agent: Br
Agent: O=C([O-])O
Agent: [K+]
Solvent: c1ccccc1
Product: CCCN1CCc2c(cccc2NC(=O)c2ccc(OC)c(OC)c2)C1

Procedure:
5-Amino-2-n-propyl-1,2,3,4-tetrahydroisoquinoline hydrobromide (10 g) prepared as in Example 5 was suspended in dry benzene (100 ml) and 0.5 g dry potassium bicarbonate was added. A 0.1 mole excess of 3,4-dimethoxybenzoyl chloride was dissolved in dry benzene (100 ml) and this solution was added to the solution of the tetrahydroisoquinoline. The mixture was refluxed for 5 days. The precipitate formed at the end of this period was collected by filtration and washed with 10% sodium carbonate solution followed by water. The washings were discarded and the remaining solid was purified by recrystallization from ethanol to yield 6.7 g of 5-(3,4-dimethoxybenzamido)-2-n-propyl-1,2,3,4-tetrahydroisoquinoline as a white powder, m.p. 146°-147° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=4[Cl:26])[CH2:15][CH2:14]3)=[O:12])=[N:9][N:10]=2)[CH:7]=1.[CH3:27][N:28](C=O)C>C(=O)(O)[O-].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:26][C:20]1[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=1[CH:16]1[CH2:17][CH2:18][N:13]([C:11]([C:8]2[N:6]3[CH:7]=[C:2]([C:27]#[N:28])[CH:3]=[CH:4][C:5]3=[N:10][N:9]=2)=[O:12])[CH2:14][CH2:15]1
Reactant: O=C(c1nnc2ccc(Br)cn12)N1CCC(c2cc(F)ccc2Cl)CC1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: N#Cc1ccc2nnc(C(=O)N3CCC(c4cc(F)ccc4Cl)CC3)n2c1
Temperature: 130 °C
Yield: 26.1 %

Procedure:
A solution of (6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(2-chloro-5-fluorophenyl)piperidin-1-yl)methanone (50 mg, 0.21 mmol) in DMF (2.0 mL) zinc cyanide (48 mg, 0.41 mmol) was sparged with Ar for 20 min. To the solution was added Pd(PPh3)4 (13 mg, 0.011 mmol) and the vessel was sealed and heated to 130° C. with microwaves for 30 min. The mixture was diluted with saturated sodium bicarbonate solution (10 mL) and extracted with EtOAc (4×30 mL). The combined organic extracts were concentrated to dryness under reduced pressure. The resulting residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0% to 50% EtOAc in hexanes) and freeze dried to give 3-(4-(2-chloro-5-fluorophenyl)piperidine-1-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrile as a white solid (21 mg, 54%): mp 211-214° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.52-9.50 (m, 1H), 8.13 (dd, J=9.5, 1.0 Hz, 1H), 7.81 (dd, J=9.5, 1.5 Hz, 1H), 7.50 (dd, J=9.0, 5.5 Hz, 1H), 7.28 (dd, J=10.5, 3.5 Hz, 1H), 7.16-7.11 (m, 1H), 5.16-5.11 (m, 1H), 4.78-4.71 (m, 1H), 3.46-3.30 (m, 2H, overlaps with H2O), 3.11-3.01 (m, 1H), 1.99-1.70 (m, 4H); ESI MS m/z 384 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][O:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[I:17][C:18]1[CH:19]=[C:20]([CH2:24][NH2:25])[CH:21]=[CH:22][CH:23]=1>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][O:13][CH2:12]2)=[C:4]([NH:25][CH2:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([I:17])[CH:19]=2)[N:3]=1
Reactant: NCc1cccc(I)c1
Reactant: Clc1nc(Cl)c2ncn(C3CCOC3)c2n1
Solvent: CCCCO
Product: Clc1nc(NCc2cccc(I)c2)c2ncn(C3CCOC3)c2n1
Yield: 53188.9 %

Procedure:
The operation is carried out as in Stage 2 of Example 2 starting from 133 mg of the product obtained in Stage 1 of Example 2 and 2 ml of butanol and using 0.2 mg of 3-iodo-benzenemethanamine (1.1 eq) in place of the benzylamine. In this way 208 mg of expected product is obtained in the form of white crystals.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:13])=[CH:7][CH:6]=1)[CH3:4].C[O-].[Na+].[CH2:26](Br)[CH:27]=[CH2:28]>O>[CH2:28]([O:1][N:2]=[C:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([NH:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:13])=[CH:9][CH:10]=1)[CH3:4])[CH:27]=[CH2:26]
Reactant: CC(=NO)c1ccc(NC(=O)NCC(=O)OC(C)(C)C)cc1
Reactant: C=CCBr
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: C=CCON=C(C)c1ccc(NC(=O)NCC(=O)OC(C)(C)C)cc1

Procedure:
A solution of the N-[4-(1-hydroxyiminoethyl)phenyl]-N'-tertbutoxycarbonylmethylurea in 25% methanolic sodium methoxide (1.0 equivalent) is treated at room temperature with 1.1 equivalent of allyl bromide. The reaction mixture is stirred until the temperature falls to about 20° C. The reaction mixture is then poured into cold water and extracted with diethyl ether. The ether solution is dried over MgSO4 and filtered, and the solvent is removed by rotary evaporator to yield the product N-[4-(1-allyloxyiminoethyl)phenyl]-N'-tert-butoxycarbonylmethylurea.
Reaction SMILES: Cl[C:2]1[C:3](=[O:19])[N:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:20][O-:21].[Na+].O>CO>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:11]=[C:2]([O:21][CH3:20])[C:3]2=[O:19])=[CH:13][CH:14]=1
Reactant: O=c1c(Cl)nc2ccccc2n1-c1ccc(Cl)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1nc2ccccc2n(-c2ccc(Cl)cc2)c1=O
Yield: 67.3 %

Procedure:
A solution of 3-chloro-1-(4-chlorophenyl)-1,2-dihydroquinoxalin-2-one (7.7 g) and sodium methoxide (2.0 g) in methanol (70 ml) was refluxed for 4 hours. Water was added and the product was extracted into chloroform. Evaporation of the solvent followed by crystallization from ethanol gave the title compound (5.1 g) mp 245°-247° C.
Reaction SMILES: [NH:1]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C@H:2]([C:12](O)=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].CN1CCOCC1.ClC(OCC)=O.[BH4-].[Na+].OS([O-])(=O)=O.[K+]>C1COCC1.CO>[C:7]([O:6][C:5](=[O:11])[CH2:4][CH2:3][C@H:2]([NH:1][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:12][OH:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCOC(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CO
Product: CC(C)(C)OC(=O)CC[C@@H](CO)NC(=O)OCc1ccccc1
Reaction time: 0.33 h

Procedure:
In analogy to G. Kokotos (Synthesis 1990, 299), a solution of 5.00 g (14.8 mmol) of Z-Glu(OtBu)-OH in 74.0 ml of THF was treated at −10° C. with 1.63 ml (14.8 mmol) of 4-methylmorpholine, 1.41 ml (14.8 mmol) of ethyl chloroformate. After 10 min 1.682 g (44.5 mmol) of natriumborohydrid was added in one portion. Methanol (148 ml) was then added dropwise over a period of 25 min at 0° C. The solution was stirred 20 min, and then neutralized with a 10% KHSO4 solution. The organic solvents are evaporated under reduced pressure and the obtained residue is poured on a 10% KHSO4 extracted with EtOAc (3×). The organic phases were washed with aqueous 10% KHSO4, 10% NaCl, dried over Na2SO4 and evaporated to yield 5.16 g (quantitative) of the titled compound as yellow oil. MS: 324.18 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:15][CH2:14][N:13]([C:16]2[C:17]3[CH:24]=[CH:23][NH:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:12][C:9]21[CH2:11][CH2:10]2)=O)(C)(C)C.Cl[C:26]1[C:27]2C=CNC=2N=CN=1.C(OC(N1CCNCC21CCCC2)=O)(C)(C)C>>[CH2:11]1[C:9]2([CH2:12][N:13]([C:16]3[C:17]4[CH:24]=[CH:23][NH:22][C:18]=4[N:19]=[CH:20][N:21]=3)[CH2:14][CH2:15][NH:8]2)[CH2:27][CH2:26][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Reactant: Clc1ncnc2[nH]ccc12
Agent: CC(C)(C)OC(=O)N1CCNCC12CCCC2
Product: c1nc(N2CCNC3(CCCC3)C2)c2cc[nH]c2n1

Procedure:
Prepared in a sequence similar to the sequence described for intermediates 1 and 2, starting from 4-chloro-7H-pyrrolo[2,3-d]pyrimidine and 6,9-diaza-spiro[4.5]decane-6-carboxylic acid tert-butyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:15])=[C:7](C(O)=O)[CH:8]=[N:9]2)=[N:4][CH:3]=1.N1C2C(=CC=CC=2)C=CC=1>CC(C)=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:15])=[CH:7][CH:8]=[N:9]2)=[N:4][CH:3]=1
Reactant: O=C(O)c1cnc2cc(Br)cnc2c1O
Solvent: c1ccc2ncccc2c1
Solvent: CC(C)=O
Product: Oc1ccnc2cc(Br)cnc12
Yield: 88.9 %

Procedure:
In a RBF fitted with a reflux condenser, 7-bromo-4-hydroxy-1,5-naphthyridine-3-carboxylic acid (1 g, 4 mmol) was added in portions over 10 minutes to stirred refluxing quinoline (50 mL), and the resulting mixture was refluxed for 1 h. The mixture was cooled and diluted with acetone. The precipitate was filtered, washed with water and dried to give 0.8 g of a grey-brown powder. The product was reprecipitated from aq. NaOH with glacial acetic acid to give a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:44])[NH:14][CH2:15][C:16]([N:18]2[CH:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[CH:21]([C:30]([N:32]([CH2:35][CH3:36])[CH2:33][CH3:34])=[O:31])[CH2:20][CH:19]2[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:17])[CH:9]=[CH:10][CH:11]=1)=[O:5])C.[OH-].[K+]>O.CO>[C:40]([O:39][C:37]([CH:19]1[CH2:20][CH:21]([C:30]([N:32]([CH2:33][CH3:34])[CH2:35][CH3:36])=[O:31])[CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[N:18]1[C:16](=[O:17])[CH2:15][NH:14][C:13](=[O:44])[NH:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[C:4]([OH:5])=[O:3])=[O:38])([CH3:42])([CH3:43])[CH3:41]
Reactant: CCOC(=O)c1cccc(NC(=O)NCC(=O)N2C(C(=O)OC(C)(C)C)CC(C(=O)N(CC)CC)C2c2ccccc2F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCN(CC)C(=O)C1CC(C(=O)OC(C)(C)C)N(C(=O)CNC(=O)Nc2cccc(C(=O)O)c2)C1c1ccccc1F
Yield: 29.9 %

Procedure:
A The reaction is carried out in a way analogous to that described in Example 3, but from 1.75 g of tert-butyl (2RS,4SR,5SR)-1-{2-[3-(3-(ethoxycarbonyl)phenyl)ureido]acetyl}-4-diethylaminocarbonyl-5-(2-fluorophenyl)pyrrolidine-2-carboxylate and 2.8 cm3 of a normal aqueous potassium hydroxide solution in a mixture of 15 cm3 of distilled water and 65 cm3 of methanol. After treatment, there is obtained 0.50 g of (2RS,4SR,5SR)-3-{3-[2-(2-tert-butoxycarbonyl-4-diethylaminocarbonyl-5-(2-fluorophenyl)-1-pyrrolidinyl)-2-oxoethyl]ureido}-benzoic acid, melting at 150° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:13]O)[C:9]([F:12])([F:11])[F:10])=[C:4]([OH:15])[CH:3]=1.C(OC(=O)C)(=O)C.C(N(CC)CC)C>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]([C:9]([F:10])([F:11])[F:12])=[N:13][O:15][C:4]=2[CH:3]=1
Reactant: ON=C(c1ccc(Br)cc1O)C(F)(F)F
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: FC(F)(F)c1noc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 1.8 %

Procedure:
To a flask containing 1-(4-bromo-2-hydroxy-phenyl)-2,2,2-trifluoro-ethanone oxime (2.64 g, 9.29 mmol) was added acetic anhydride (14 mL) and the reaction mixture stirred for 18 h at rt. The reaction mixture was concentrated and taken up in toluene and again concentrated to yield the acylated intermediate. This intermediate was dissolved in pyridine (15 mL) and triethylamine (3.2 mL) and heated at 112° C. for 4.5 h. The reaction mixture was concentrated and the residue was taken up in toluene and again concentrated the residue was then partitioned between EtOAc (25 mL) and HCl (1 N aq., 25 mL). The layers were separated and the organic layer washed with HCl (1 N aq., 25 mL). The combined water layers were then extracted with EtOAc (25 mL×2) and the combined organic layers were washed with brine (15 mL), dried (Na2SO4) and concentrated. The crude material was purified (FCC) to yield the title compound (44 mg, 17%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH:13](=[N:1]/[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2)\[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1cccc2ccc(O)cc12
Reactant: O=Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Oc1ccc2cccc(/N=C/c3ccccc3)c2c1
Temperature: 25 °C
Yield: 98.4 %

Procedure:
A mixture of 8-amino-2-naphthol 1 (8.2 g, 52 mmol), benzaldehyde (16 mL, 156 mmol) and sodium sulfate (41.3 g, 291 mmol) in THF (100 mL) was stirred at reflux over night. The mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (hexane ethyl acetate/triethyl amine 75/23/2) to give 12.65 g of impure (E)-8-(benzylideneamino) naphthalen-2-ol (2) which was used in the next step without further purification.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][N:9]=1)=[O:4].[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1>C(#N)C>[N:10]1([CH2:2][C:3]([C:5]2[S:6][CH:7]=[CH:8][N:9]=2)=[O:4])[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: O=C(CBr)c1nccs1
Reactant: c1c[nH]cn1
Solvent: CC#N
Product: O=C(Cn1ccnc1)c1nccs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-bromo-1-(thiazol-2-yl)ethanone (2.5 g; 12 mmol), acetonitrile (70 ml) and imidazole (1.65 g; 24 mmol) was stirred at ambient temperature for 1 hour. The mixture was evaporated to dryness and the residue partitioned between dichloromethane and water. The organic phase was separated, washed with saturated brine and evaporated to give 2-(imidazol-1-yl)-1-(thiazol-2-yl)-ethanone as a brown solid (1.17 g; 50%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(N(CC)CC)C.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>ClCCl.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([N:18]1[CH2:19][CH2:20][N:21]([S:38]([C:35]2[CH:36]=[CH:37][C:32]([CH3:42])=[CH:33][CH:34]=2)(=[O:40])=[O:39])[CH2:22][CH2:23]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@@H](N1CCNCC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)N2CCN([C@H](C)[C@](O)(Cn3cncn3)c3ccc(F)cc3F)CC2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 35.5 %

Procedure:
To a mixture of piperazinyl compound 2 (146 mg, 0.43 mmol) and triethylamine in dichloromethane (5 ml) was added p-toluenesulphonyl chloride (51 mg, 0.45 mmol) in dichloromethane (1 ml) at 0° C. The reaction mixture was stirred at 0° C. for 15 minutes and 2 h at room temperature. Then the reaction mixture was diluted with chloroform (15 ml), washed with water, brine and dried over sodium sulphate. The solvent was removed under reduced pressure and the resulting product was purified on a column of silica gel (CHCl3 /MeOH; 98:2 ) to give the title compound as a colorless solid (75 mg, 16%).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[NH:15][C:16]([NH:18][CH2:19][CH3:20])=[S:17]>C(Cl)Cl>[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[N:15]1[C:2](=[O:3])[C:1](=[O:5])[N:18]([CH2:19][CH3:20])[C:16]1=[S:17]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCNC(=S)Nc1c(C)cccc1C
Solvent: ClCCl
Product: CCN1C(=O)C(=O)N(c2c(C)cccc2C)C1=S
Yield: 45.7 %

Procedure:
Oxalyl chloride (7.62 g; 0.06 mol) was added dropwise to the stirring solution of N-(2,6-dimethylphenyl)-N′-ethylthiourea (10.4 g; 0.05 mol) in methylene chloride (200 mL). The mixture was heated at reflux for 1 hour then evaporated to dryness. Ethanol (100 mL) was added and the mixture was heated at reflux for 1 hour then evaporated to dryness. The residue was dissolved in ethyl acetate (300 mL) and washed with 2N hydrochloric acid (500 mL) then with water (300 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was crystallized from ether/hexane to give 6.0 g of 1-(2,6-Dimethylphenyl)-3-ethyl-2-thioxo-4,5-imidazolidinedione, m.p. 103–105° C. Mass spectrum; FAB (M+H)+ m/z 263. 1H-NMR (DMSO-d6; 300 MHz): δ 7.31–7.27 (m, 1H), 7.18 (d, 2H), 3.94 (q, 2H), 2.08 (s, 6H), and 1.25 ppm (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([CH2:8][CH2:9][O:10][C:11]([CH2:13][NH:14][CH2:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=2[NH2:26])=[O:12])=[O:7])=[CH:4][CH:3]=1.[N:29]1([C:34]([C:36]2[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=2)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:8][CH2:9][O:10][C:11]([CH2:13][NH:14][CH2:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=2[NH:26][CH2:40][C:39]2[CH:38]=[CH:37][C:36]([C:34]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:35])=[CH:43][CH:42]=2)=[O:12])=[O:7])=[CH:27][CH:28]=1
Reactant: O=Cc1ccc(C(=O)N2CCCC2)cc1
Reactant: COC(=O)c1ccc(CNCC(=O)OCCC(=O)c2ccc(Cl)cc2)c(N)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1ccc(CNCC(=O)OCCC(=O)c2ccc(Cl)cc2)c(NCc2ccc(C(=O)N3CCCC3)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
120 mg (0.30 mmol) of methyl 4-[((4-chlorobenzoyl)ethoxycarbonylmethylamino)methyl]-3-aminobenzoate and 66 mg (0.33 mmol) of 4-(1-pyrrolidinecarbonyl)benzaldehyde were dissolved in 10 ml of dichloromethane. 0.034 ml (0.6 mmol) of acetic acid was added to the solution, and they were stirred at room temperature for 30 minutes. 158 mg (0.75 mmol) of sodium triacetoxyborohydride was added to the obtained mixture, and they were stirred at room temperature overnight. After the treatment with dichloromethane as the extracting solvent by an ordinary method, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:27])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15](OC4C=CC=CC=4)[C:14]3=[O:26])[CH:7]=2)[CH2:3][CH2:2]1.[C:28]1([SH:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[CH:1]1([NH:4][C:5](=[O:27])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([S:34][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:14]3=[O:26])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Sc1ccccc1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(Oc2ccccc2)c1=O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(Sc2ccccc2)c1=O
Temperature: 120 °C

Procedure:
A mixture of N-cyclopropyl-4-methyl-3-(2-oxo-3-phenoxy-1(2H)-pyrazinyl)-benzamide (Example 116, 55 mg), benzenethiol (0.1 mL) and THF (1 mL) was heated under an atmosphere of nitrogen within a microwave for 90 minutes at 120° C. Purification by preparative HPLC (Gemini column, 0.1% ammonia:acetonitrile eluent) afforded the title compound as a solid (32 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21]([OH:23])=O)[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.Cl.[OH:26][CH:27]1[CH2:30][NH:29][CH2:28]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21]([N:29]4[CH2:30][CH:27]([OH:26])[CH2:28]4)=[O:23])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: OC1CNC1
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)O)n(C)n1
Agent: Cl
Product: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)N2CC(O)C2)n(C)n1
Yield: 17 %

Procedure:
As described for example 55, 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (100 mg, 0.3 mmol) was converted, using 3-hydroxyazetidine hydrochloride instead of 2-amino-2-methyl-1-propanol, to the title compound (20 mg, 17%) which was obtained as a colorless gum. MS: m/e=387.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:48]([F:49])=[CH:47][CH:46]=[C:45]([F:50])[C:4]=2[S:5][C:6]=1[C:7]([N:9]([CH2:25][C:26]1[CH:31]=[C:30]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([C:38](=[O:42])N(C)C)[CH:33]=2)[CH:29]=[CH:28][C:27]=1[O:43][CH3:44])[CH:10]1[CH2:15][CH2:14][CH:13]([N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12][CH2:11]1)=[O:8].[CH3:51][Mg]Br>C1COCC1>[C:19]([O:18][C:17](=[O:23])[N:16]([CH:13]1[CH2:12][CH2:11][CH:10]([N:9]([CH2:25][C:26]2[CH:31]=[C:30]([C:32]3[CH:37]=[CH:36][N:35]=[C:34]([C:38](=[O:42])[CH3:51])[CH:33]=3)[CH:29]=[CH:28][C:27]=2[O:43][CH3:44])[C:7]([C:6]2[S:5][C:4]3[C:45]([F:50])=[CH:46][CH:47]=[C:48]([F:49])[C:3]=3[C:2]=2[Cl:1])=[O:8])[CH2:15][CH2:14]1)[CH3:24])([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1ccc(-c2ccnc(C(=O)N(C)C)c2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: COc1ccc(-c2ccnc(C(C)=O)c2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reaction time: 1 h

Procedure:
To a solution of dimethyl amide 163 (50 mg, 0.07 mmol) in dry THF (3 ml) at 0° C. was added a 3M solution of methyl magnesium bromide (0.18 ml, 0.55 mmol) in THF. After 1 h, the completed reaction was quenched with 1.2 M HCl, basified and extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered, reduced in vacuo and purified by chromatography with 70% EtOAc in heptane to give the title compound.