Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[C:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:6]=[CH:5][C:4]=1[OH:16])#[N:2].Cl.N1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:19]([C:21]12[CH2:7][CH2:8][C:3]([C:4]([O:16][C:4]3[CH:5]=[CH:6][C:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:8]([C:9]#[N:10])[C:3]=3[C:1]#[N:2])=[O:16])([CH2:19][CH2:20]1)[CH2:23][CH2:22]2)[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCc1ccc(O)c(C#N)c1C#N
Reactant: c1ccncc1
Agent: Cl
Product: CCCCCc1ccc(OC(=O)C23CCC(CCCCC)(CC2)CC3)c(C#N)c1C#N

Procedure:
25 mmoles of 4-pentylbicyclo(2,2,2)octane-1-carboxylic acid are warmed to the reflux temperature with 40 ml of thionyl chloride for 30 minutes. The acid chloride formed was freed from excess thionyl chloride. The acid chloride thus obtained was now added dropwise to a solution of 25 mmoles of 2,3-dicyano-4-pentylphenol (m.p. 142° C.) in 100 ml of pyridine at 80° C. When the reaction had ended, the mixture was poured into excess dilute hydrochloric acid and extracted with methylene chloride. The crude product obtained from the extract by evaporation was recrystallized. The resulting title compound of this example is monotropically nematic (K 84.0 N (36.1) I) and has a negative DCA.
Reaction SMILES: B.C1COCC1.[Br:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C:15]([CH3:19])([CH3:18])[C:16]#[N:17]>C1COCC1>[Br:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C:15]([CH3:19])([CH3:18])[CH2:16][NH2:17]
Reactant: CC(C)(C#N)c1ccc(F)cc1Br
Agent: B
Solvent: C1CCOC1
Product: CC(C)(CN)c1ccc(F)cc1Br
Yield: 98.5 %

Procedure:
Add borane-THF complex (2 M in THF, 10 mL, 20 mmol) to a stirred solution of 2-(2-bromo-4-fluoro-phenyl)-2-methyl-propionitrile (0.8 g, 3.30 mmol) in 10 mL of THF at 0° C. Stir the mixture at 0° C. to RT over the weekend. Quench the reaction with diluted ammonium hydroxide. Extract the product with chloroform. Dry the organic phase over sodium sulfate and concentrate to give the title compound (0.8 g, 99%). MS (ES) m/z 246/248 [M+1]+.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([CH2:11][CH2:12][C:13]3[CH:22]=[C:21]4[C:16]([CH:17]=[CH:18][CH:19]=[N:20]4)=[CH:15][C:14]=3[O:23][CH3:24])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H][H]>CO.[C].[Pd]>[O:4]1[C:5]2([CH2:6][CH2:7][N:8]([CH2:11][CH2:12][C:13]3[CH:22]=[C:21]4[C:16]([CH2:17][CH2:18][CH2:19][NH:20]4)=[CH:15][C:14]=3[O:23][CH3:24])[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: COc1cc2cccnc2cc1CCN1CCC2(CC1)OCCO2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1cc2c(cc1CCN1CCC3(CC1)OCCO3)NCCC2
Reaction time: 10 h
Yield: 101.9 %

Procedure:
445 mg of 7-(2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)ethyl)-6-methoxyquinoline was dissolved in 10 ml of methanol. Thereafter, 100 mg of 10% palladium carbon was added to the reaction solution. The obtained mixture was stirred for 6 hours under a 4 kg/cm2 of hydrogen atmosphere. Palladium carbon was removed by filtration, followed by concentration under a reduced pressure. The reaction solution was stirred under the same conditions for 10 hours 3 times, followed by concentration under a reduced pressure. A saturated sodium bicarbonate aqueous solution was added to the residue, followed by extraction with chloroform. The extract was dried over magnesium sulfate and then concentrated under a reduced pressure, so as to obtain 459 mg of 7-(2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)ethyl)-6-methoxy-1,2,3,4-tetrahydroquinoline. This compound was used in the following reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][S:6][CH:7]=1.[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:2][C:3]1[N:4]=[CH:5][S:6][CH:7]=1)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8]
Reactant: CCCCCCCCCCCCO
Reactant: COc1cscn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCOc1cscn1
Temperature: 130 °C
Yield: 55.1 %

Procedure:
A mixture of 4.0 g (34.7 mmol) of 4-methoxythiazole (9), 12.8 g (68.7 mmol) of dodecanol, 0.7 g (3.7 mmol) of p-toluenesulfonic acid monohydrate, and 75 mL of toluene was heated at 130° C. for 24 hours. The mixture was cooled to room temperature and purified by flash chromatography (silica gel, 5.5×30 cm, methylene chloride). The resulting oily solid was recrystallized from 20 mL of cold pentane to give 5.15 g (55% yield) of 4-dodecyloxythiazole (10) as a colorless solid. 1H NMR (500 MHz) δ 8.58 (d, 1H, J=2.3 Hz), 6.13 (d, 1H, J=2.3 Hz), 4.13 (t, 2H, J=6.6 Hz), 1.83 (m, 2H), 1.49-1.28 (m, 18H), 0.90 (t, 3H, J=7.0).
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]([CH2:38][C:39]3[CH:48]=[C:47]([CH3:49])[C:42]4[NH:43][C:44](=[O:46])[O:45][C:41]=4[CH:40]=3)[C:21]([N:23]3[CH2:28][CH2:27][CH:26]([N:29]4[CH2:33][CH2:32][CH2:31][C@H:30]4[C:34]([O:36]C)=[O:35])[CH2:25][CH2:24]3)=[O:22])=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:50]=[CH:51][CH:52]=[CH:53][C:6]=2[NH:5]1>O.C1COCC1>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C@H:20]([CH2:38][C:39]3[CH:48]=[C:47]([CH3:49])[C:42]4[NH:43][C:44](=[O:46])[O:45][C:41]=4[CH:40]=3)[C:21]([N:23]3[CH2:24][CH2:25][CH:26]([N:29]4[CH2:33][CH2:32][CH2:31][C@H:30]4[C:34]([OH:36])=[O:35])[CH2:27][CH2:28]3)=[O:22])=[O:18])[CH2:15][CH2:16]2)[CH2:9][CH2:8][C:7]2[CH:50]=[CH:51][CH:52]=[CH:53][C:6]=2[NH:5]1
Reactant: COC(=O)[C@@H]1CCCN1C1CCN(C(=O)[C@@H](Cc2cc(C)c3[nH]c(=O)oc3c2)OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC[C@H]3C(=O)O)CC2)cc2oc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 66 h

Procedure:
A solution of 17 mg (0.71 mmol) LiOH in 3 mL water was added to a solution of 200 mg (0.29 mmol) (R)-2-[4-((S)-2-methoxycarbonyl-pyrrolidin-1-yl)-piperidin-1-yl]-1-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 9 mL THF and the reaction mixture was stirred for 66 h at RT. The solvents were eliminated in a nitrogen current and the residue was purified by HPLC. The fractions containing the product were combined and lyophilised.
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]2[N:6]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]3[O:19][C:18](=[O:20])[N:17]([CH3:21])[N:16]=3)=[N:8][C:4]=2[CH:3]=1.[NH2:28][C:29]1[N:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.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>[NH2:28][C:29]1[N:34]=[CH:33][C:32]([C:2]2[CH:27]=[CH:26][C:5]3[N:6]([C:22]([CH3:23])([CH3:25])[CH3:24])[C:7]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[C:15]4[O:19][C:18](=[O:20])[N:17]([CH3:21])[N:16]=4)=[N:8][C:4]=3[CH:3]=2)=[CH:31][N:30]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Cn1nc(-c2ccccc2-c2nc3cc(Br)ccc3n2C(C)(C)C)oc1=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+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1nc(-c2ccccc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)oc1=O
Temperature: 110 °C
Yield: 25.3 %

Procedure:
To a sealed vial is added 5-[2-(5-bromo-1-tert-butyl-1H-benzimidazol-2-yl)-phenyl]-3-methyl-3H-[1,3,4]oxadiazol-2-one (92 mg, 0.215 mmol) in DMF (3 mL), followed by the addition of 2-aminopyrimidine-5-boronic acid pinacol ester (57 mg, 0.258 mmol), tetrakis(triphenylphosphine)palladium(0) (25 mg, 0.022 mmol) and 2M aq. Na2CO3 (0.45 ml, 0.9 mmol). The reaction mixture is heated under Argon at 110° C. for 3 hours. The residue is diluted with EtOAc (20 mL), washed with brine, dried under anhydrous Na2SO4, filtered and concentrated. The residue is purified by silica gel flash column chromatography with 0-4% 7M NH3 in MeOH/CH2Cl2 as the eluent to afford the title compound (24 mg, 25%) as a off-white solid. LCMS (ESMS): m/z 442.43 (M++1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[C:17]([OH:26])[C:16]([Br:27])=[CH:15][CH:14]=1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[NH2:12][C:13]1[C:18]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[C:17]([O:26][S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[C:16]([Br:27])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)c1c(N)ccc(Br)c1O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Oc2c(Br)ccc(N)c2C(=O)OC(C)(C)C)cc1
Reaction time: 1 h
Yield: 80.2 %

Procedure:
4-Methylbenzenesulfonyl chloride (2.26 g) was added to a solution of tert-butyl 6-amino-3-bromo-2-hydroxybenzoate (Intermediate 51, 2.85 g), DMAP (1.21 g), and triethylamine (1.5 g) in DCM (40 mL) and left at room temperature for 1 hour. The resulting solution was washed with water, filtered through a phase separator and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-15% to give tert-butyl 6-amino-3-bromo-2-(4-methylbenzenesulfonyloxyl)benzoate (3.51 g) as an off-white solid.
Reaction SMILES: [C:1]([CH2:3][N:4]([CH2:9][CH2:10][C:11]#[N:12])[CH2:5][CH2:6][CH2:7][OH:8])#N.N>>[OH:8][CH2:7][CH2:6][CH2:5][N:4]1[CH2:9][CH2:10][CH2:11][NH:12][CH2:1][CH2:3]1
Reactant: N#CCCN(CC#N)CCCO
Agent: N
Product: OCCCN1CCCNCC1

Procedure:
hydrogenating the cyanomethyl-(2-cyano-ethyl)-(3-hydroxy-propyl)-amine in the presence of a hydrogenation catalyst and ammonia to form 1-(3-hydroxy-propyl)-1,4-diazepane;
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH:20]=[C:19]3[C:15]([CH2:16][CH2:17][NH:18]3)=[CH:14][CH:13]=2)=[O:11])=[CH:5][CH:4]=1)#[N:2].[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([O:32][CH3:33])=[C:26]([S:28](Cl)(=[O:30])=[O:29])[CH:27]=1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([C:12]2[CH:20]=[C:19]3[C:15]([CH2:16][CH2:17][N:18]3[S:28]([C:26]3[CH:27]=[C:22]([Cl:21])[CH:23]=[CH:24][C:25]=3[O:32][CH3:33])(=[O:29])=[O:30])=[CH:14][CH:13]=2)=[O:11])=[CH:7][CH:8]=1)#[N:2]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Reactant: N#Cc1ccc(NC(=O)c2ccc3c(c2)NCC3)cc1
Product: COc1ccc(Cl)cc1S(=O)(=O)N1CCc2ccc(C(=O)Nc3ccc(C#N)cc3)cc21

Procedure:
1-(5-Chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid [4-(1H-tetrazol-5-yl)-phenyl]-amide, MS (ISP), m/e=509.1 (M−H), was prepared in analogy to example 13, steps 1 to 4. Step 1 was performed using 4-amino-benzonitrile and yielded 1H-indole-6-carboxylic acid (4-cyano-phenyl)-amide which was reduced to 2,3-dihydro-1H-indole-6-carboxylic acid (4-cyano-phenyl)-amide in step 2. This was coupled with 5-chloro-2-methoxy benzenesulfonyl chloride in step 3, yielding 1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid (4-cyano-phenyl)-amide, which was converted to 1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid [4-(1H-tetrazol-5-yl)-phenyl]-amide by reaction with ammonium azide in step 4.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][CH2:10][CH2:11][Cl:12])=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:13])[CH2:9][CH2:10][CH2:11][Cl:12])=[CH:6][CH:7]=1
Reactant: O=C(CCCCl)c1ccc(Br)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(CCCCl)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a solution of 1-(4-bromophenyl)-4-chlorobutan-1-one (1.00 g, 3.83 mmol) in methanol (20 mL) was added sodium borohydride (260 mg, 7.66 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hour. 1M HCl was added and the mixture was stirred for 15 minutes. Solvents were removed and the residue was extracted with ethyl acetate (10 mL×2). The combined organic layer were washed with brine, dried and concentrated to give target compound (1 g, 99%) as a light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH2:13][NH2:14])[CH2:6]2.[C:15]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[OH-].[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH2:13][NH:14][CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[CH2:6]2
Reactant: COc1cc2c(cc1OC)[C@@H](CN)C2
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)[C@@H](CNC1CCCC1)C2
Reaction time: 4 h

Procedure:
At ambient temperature, 2.9 g (15 mmol) of {[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}amine and 1.3 mL (15 mmol/1 eq.) of cyclopentanone are mixed into 60 mL of dichloromethane. There are then added 4.8 g (22.5 mmol/1.5 eq.) of sodium triacetoxyborohydride and then 0.86 mL (15 mmol/1 eq.) of acetic acid, and stirring is carried out at ambient temperature for 4 hours. 90 mL of 1N sodium hydroxide solution are then poured in; extraction with two 120 mL quantities of ether is then carried out. The combined organic phases are washed with 90 mL of water and then with 90 mL of saturated aqueous sodium chloride solution and are then dried over magnesium sulphate. After filtration and concentration, the desired product is collected.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[O:8]=[C:9]1[N:15]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C@@H:25]([C:38](O)=[O:39])[CH2:26][C:27]3[CH:36]=[C:35]([CH3:37])[C:30]4[NH:31][C:32](=[O:34])[O:33][C:29]=4[CH:28]=3)=[O:23])[CH2:18][CH2:17]2)[CH2:14][CH2:13][C:12]2[CH:41]=[CH:42][CH:43]=[CH:44][C:11]=2[NH:10]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[O:8]=[C:9]1[N:15]([CH:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C@H:25]([CH2:26][C:27]3[CH:36]=[C:35]([CH3:37])[C:30]4[NH:31][C:32](=[O:34])[O:33][C:29]=4[CH:28]=3)[C:38](=[O:39])[N:1]3[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]3)=[O:23])[CH2:20][CH2:21]2)[CH2:14][CH2:13][C:12]2[CH:41]=[CH:42][CH:43]=[CH:44][C:11]=2[NH:10]1
Reactant: O=C1CCNCC1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc2oc(=O)[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(=O)CC2)cc2oc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
200 mg (1.30 mmol) piperidin-4-one (used as the hydrate of the hydrochloride salt) were added to a solution of 500 mg (0.98 mmol) (R)-1-carboxy-2-(4-methyl-2-oxo-2,3-dihydrobenz-oxazol-6-yl)-ethyl 4-(2-oxo-1,2,4,5,-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 350 mg (1.09 mmol) TBTU, 300 μL (2.15 mmol) triethylamine in 10 mL DMF and the reaction mixture was stirred for 4 h at RT. The reaction solution was evaporated down i. vac., the residue was taken up in DCM, the organic phase was washed with saturated NaHCO3 solution and dried on Na2SO4. After the desiccant and solvent had been eliminated the residue was purified by chromatography (silica gel, gradient DCM/MeOH 20:1 to DCM/MeOH 10:1). The fractions containing the product were concentrated by evaporation, the residue was stirred with DIPE, suction filtered and dried.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:13])=[CH:7][C:8](=[O:12])[S:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:21]([O:23][C:24](=[O:29])[CH2:25][N:26]=[C:27]=[O:28])[CH3:22].Cl>ClCCl>[CH2:21]([O:23][C:24](=[O:29])[CH2:25][NH:26][C:27]([C:7]1[C:8](=[O:12])[S:9][C:10]2[C:5]([C:6]=1[OH:13])=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=2)=[O:28])[CH3:22]
Reactant: CCOC(=O)CN=C=O
Reactant: O=c1cc(O)c2ccc(F)cc2s1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)c1c(O)c2ccc(F)cc2sc1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.1 %

Procedure:
7-Fluoro-4-hydroxy-thiochromen-2-one (2.0 g, 10.2 mmol) was dissolved in a mixture of triethylamine (1.7 mL, 12.23 mmol) and dichloromethane (50 mL). Isocyanato-acetic acid ethyl ester (1.4 mL, 12.23 mmol) was added to the solution and the reaction stirred overnight (18 h) at ambient temperature. The reaction mixture was acidified to pH 3 using 1N HCl and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, and the crude residue purified by silica gel chromatography (10%-40% ethyl acetate in hexanes) to provide [(7-fluoro-4-hydroxy-2-oxo-2H-thiochromene-3-carbonyl)-amino]-acetic acid ethyl ester (900 mg, 30%). MS ESI(−) m/e: 324.117 (M−1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C(OO)(=[O:14])C>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[CH:3]=[N+:4]([O-:14])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Brc1cnc2ccccc2c1
Reactant: CC(=O)OO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: [O-][n+]1cc(Br)cc2ccccc21
Reaction time: 12 h

Procedure:
To a solution of 3-bromo-quinoline (1.0 eq.) in CH2Cl2 (0.2M) was added peracetic acid (2.0 eq.). The mixture was stirred for 12 h, poured in saturated aqueous NaHCO3 and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. Crystallization from CH2Cl2:Hex afforded the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[O:21])[C:10]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=3[O:36][CH:37]([CH3:39])[CH3:38])=[N:9]2)=[CH:4][CH:3]=1.[CH2:40]1[O:43][CH:41]1[CH3:42]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:22]3[CH2:23][CH2:24][N:25]([CH2:40][CH:41]([OH:43])[CH3:42])[CH2:26][CH2:27]3)=[O:21])[C:10]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=3[O:36][CH:37]([CH3:39])[CH3:38])=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(C2=NC(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)N2CCNCC2)c(OC(C)C)c1
Reactant: CC1CO1
Solvent: CO
Product: COc1ccc(C2=NC(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)N2CCN(CC(C)O)CC2)c(OC(C)C)c1

Procedure:
The compound was prepared by the treatment of [4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-piperazin-1-yl-methanone (example 10 g) with propylene oxide in methanol for 7 h at 45° C. in a sealed tube. HR-MS (ES, m/z) calculated for C33H38N4O4Cl2[(M+H)+]625.2343, observed 625.2350.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1O>>[C:1]([O:7][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[Cl:8])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5]
Reactant: C#CCCC(=O)O
Reactant: Oc1ccccc1Cl
Product: C#CCCC(=O)Oc1ccccc1Cl
Yield: 87.1 %

Procedure:
According to the protocol described in Example 235(B), the reaction between pent-4-ynoic acid (590 mg, 6.0 mmol) and 2-chlorophenol (771 mg, 6.0 mmol) afforded 1.09 g of 2-chlorophenyl pent-4-ynoate (Yield: 87%) as colorless-oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]([F:32])=[CH:16][C:17]3[N:21]=[C:20]([CH2:22][C:23]([O:25]CC)=O)[N:19]([CH:28]4[CH2:30][CH2:29]4)[C:18]=3[CH:31]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+:34].[OH-].[NH4+]>C(O)C>[C:23]([CH2:22][C:20]1[N:19]([CH:28]2[CH2:30][CH2:29]2)[C:18]2[CH:31]=[C:14]([N:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:13][CH2:12]3)[C:15]([F:32])=[CH:16][C:17]=2[N:21]=1)(=[O:25])[NH2:34]
Reactant: [NH4+]
Reactant: CCOC(=O)Cc1nc2cc(F)c(N3CCN(C(=O)OC(C)(C)C)CC3)cc2n1C1CC1
Agent: [Cl-]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2cc3c(cc2F)nc(CC(N)=O)n3C2CC2)CC1
Reaction time: 18 h
Yield: 53.2 %

Procedure:
Ethyl 6-[4-(tert-butoxycarbonyl)-1-piperazinyl]-1-cyclopropyl-5-fluoro-2-benzimidazoleacetate (4.5 g, 10 mmol) is dissolved in ethanol (100 ml) and treated with ammonium chloride (5.35 g, 100 mmol) and 25 percent ammonium hydroxide solution (50 ml). The suspension obtained is stirred at 50° for 18 hours and thereafter evaporated under reduced pressure. The residue is suspended in ethyl acetate (150 ml) and the insoluble ammonium chloride is filtered off. The filtrate is concentrated to a volume of 50 ml and then chromatographed on silica gel (eluent: ethyl acetate/methanol 9:1). The product is recrystallized from ethyl acetate/n-hexane. There are obtained 2.22 g (53%) of tert-butyl 4-[2-(carbamoylmethyl)-1-cyclopropyl-5-fluoro-6-benzimidazolyl]-1-piperazinecarboxylate with a m.p. of 219°-220°.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:14]([C:19](=O)[CH3:20])[C:15]([O:17][CH3:18])=[O:16].[NH2:22][C:23]([CH3:33])=[CH:24][C:25](=[O:32])[CH2:26][CH2:27][CH:28]1[CH2:31][CH2:30][CH2:29]1>C(O)C>[CH:28]1([CH2:27][CH2:26][C:25]([C:24]2[CH:13]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[O:3][C:2]([CH3:1])=[CH:11][C:10]4=[O:12])[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:19]([CH3:20])[NH:22][C:23]=2[CH3:33])=[O:32])[CH2:29][CH2:30][CH2:31]1
Reactant: COC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(C)=O
Reactant: CC(N)=CC(=O)CCC1CCC1
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)CCC2CCC2)C1c1cccc2c(=O)cc(C)oc12

Procedure:
50 mg (0.175 mmol) of methyl 2-[(2-methyl-4-oxo-4H-chromen-8-yl)methylene]-3-oxobutanoate are dissolved with 38 mg (0.227 mmol) of 5-amino-1-cyclobutylhex-4-en-3-one in 3 ml of ethanol and heated under reflux under argon for 24 h. The reaction mixture is purified by preparative HPLC. Concentration of the fractions results in 43 mg (56% of theory) of the title compound as a white solid.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10](OS(C(F)(F)F)(=O)=O)[C:9]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[CH:8][N:7]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:37][Si:38]([C:41]#[CH:42])([CH3:40])[CH3:39]>C(#N)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([C:42]#[C:41][Si:38]([CH3:40])([CH3:39])[CH3:37])[C:9]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[CH:8][N:7]=1)(=[O:3])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: COc1ccc(COc2cnc(COC(C)=O)cc2OS(=O)(=O)C(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(COc2cnc(COC(C)=O)cc2C#C[Si](C)(C)C)cc1
Temperature: 45 °C

Procedure:
(5-({[4-(Methyloxy)phenyl]methyl}oxy)-4-{[(trifluoromethyl)sulfonyl]oxy}-2-pyridinyl)methyl acetate (for a synthesis see WO2004058144 Example 60(d)) (10 g, 23 mmol) was dissolved in acetonitrile (400 ml) and triethylamine (65 ml) and copper (I) iodide (0.44 g, 2.3 mmol) were added. The mixture was degassed and placed under a blanket of argon. Trimethylsilylacetylene (10 ml, 69 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.645 g, 0.9 mmol) were added and the mixture heated to 45° C. for 18 h. The mixture was then allowed to cool and filtered. The filtrate was evaporated to dryness and the residue partitioned between ethyl acetate and water. The organic layer was separated and dried (sodium sulphate).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.F[C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[C:18](=[O:26])[NH:19][CH:20]=[N:21]2>>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([O:1][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[C:18](=[O:26])[NH:19][CH:20]=[N:21]3)[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=c1[nH]cnc2cccc(F)c12
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc3nc[nH]c(=O)c23)CC1
Yield: 103 %

Procedure:
Thus, tert-butyl 4-hydroxypiperidine-1-carboxylate (0.33 g) was reacted with 5-fluoro-3,4-dihydroquinazolin-4-one (0.18 g) to give 5-(1-tert-butoxycarbonylpiperidin-4-yloxy)-3,4-dihydroquinazolin-4-one (0.39 g); NMR Spectrum: (CDCl3) 1.5 (s, 9H), 1.9–2.0 (m, 4H), 3.52 (m, 2H), 3.7 (m, 2H), 4.72 (m, 1H), 6.95 (d, 1H), 7.32 (d, 1H), 7.65 (m, 1H), 7.95 (s, 1H), 10.22 (br s, 1H); Mass Spectrum: M+H+ 346;