Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:53]/[O:54][CH2:55][C:56]([O:58][CH:59]([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)=[O:57])/[C:27]([NH:29][CH:30]2[C:51](=[O:52])[N:32]3[C:33]([C:39]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=4)=[O:40])=[C:34]([CH2:37]Cl)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:72][C:73]1[S:74][C:75]2[CH:76]=[N:77][CH:78]=[CH:79][C:80]=2[N:81]=1.SC1SC2C=CN=CC=2N=1>>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:53]/[O:54][CH2:55][C:56]([O:58][CH:59]([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)=[O:57])/[C:27]([NH:29][CH:30]2[C:51](=[O:52])[N:32]3[C:33]([C:39]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=4)=[O:40])=[C:34]([CH2:37][S:72][C:73]4[S:74][C:75]5[CH:76]=[N:77][CH:78]=[CH:79][C:80]=5[N:81]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3C(NC(=O)/C(=N\OCC(=O)OC(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Reactant: Sc1nc2ccncc2s1
Agent: Sc1nc2cnccc2s1
Product: COc1ccc(COC(=O)C2=C(CSc3nc4ccncc4s3)CS[C@@H]3C(NC(=O)/C(=N\OCC(=O)OC(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Yield: 75.2 %

Procedure:
Using 301 mg of p-methoxybenzyl 7-{(Z)-2-(2-tritylaminothiazol-4-yl)-2-diphenylmethoxycarbonylmethoxyiminoacetamido}-3-chloromethyl-3-cephem-4-carboxylate and 60 mg of 2-mercaptothiazolo[5,4-c]pyridine in place of p-methoxybenzyl 7-{(Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetamido}-3-chloromethyl-3-cephem-4-carboxylate and 2-mercaptothiazolo[4,5-c]pyridine, respectively, the reaction and purification were carried out in the same manner as in Example 1(a) to obtain 256 mg of the title compound in a yield of 75%.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:6]=1)[CH2:3][OH:4].[C:18]1([CH:24]2[CH2:26][CH:25]2[C:27](O)=[O:28])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:2]([NH:1][C:27]([CH:25]2[CH2:26][CH:24]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:28])[CH2:3][OH:4])=[CH:6][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: O=C(O)C1CC1c1ccccc1
Reactant: N[C@@H](CO)c1ccc(F)c(N2CCOCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC(CO)c1ccc(F)c(N2CCOCC2)c1)C1CC1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
A mixture of (R)-2-amino-2-(4-fluoro-3-morpholin-4-yl-phenyl)-ethanol (0.1 mmol), 2-phenyl-cyclopropanecarboxylic acid (0.1 mmol), EDAC.HCl (0.2 mmol), DMAP (0.1 mmol), triethylamine (0.4 mmol) in dichloromethane (2 mL) was stirred at room temperature overnight. The reaction mixture was purified by flash chromatography with 3% methanol in ethyl acetate to give the desired product (27 mg) as a solid.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:15][CH:16]([CH2:20][CH:21]=[CH2:22])[C:17](Cl)=[O:18]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:2]1([CH2:1][O:8][C:17](=[O:18])[CH:16]([CH3:15])[CH2:20][CH:21]=[CH2:22])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCC(C)C(=O)Cl
Reactant: OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCC(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.3 %

Procedure:
To a 0° C. solution of 23.8 g of benzyl alcohol, 0.05 g of 4-(dimethylamino)pyridine, 18.3 g of pyridine and 250 ml of methylene chloride is added, dropwise, a solution of 29.5 g of racemic 2-methyl-4-pentenoyl chloride in 50 ml of methylene chloride. The mixture is stirred at room temperature for 4 hours, followed by successive washing with 2N hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride. The organic layer is dried and concentrated in vacuo. The residue is purified by Kugelrohr distillation to give 35.2 g of the desired product as a colorless oil; bp 70°-75° C. at 0.10 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[O:9])=[C:6]([CH3:19])[CH:5]=[C:4](Cl)[N:3]=1.Cl.[CH3:22][C@@H:23]1[CH2:28][O:27][CH2:26][CH2:25][NH:24]1.CN1C(=O)CCC1>CCOC(C)=O>[Cl:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[O:9])=[C:6]([CH3:19])[CH:5]=[C:4]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][C@H:23]2[CH3:22])[N:3]=1
Reactant: Cc1cc(Cl)nc(Cl)c1C(=O)NCc1ccc(F)cc1
Reactant: C[C@@H]1COCCN1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1cc(N2CCOC[C@H]2C)nc(Cl)c1C(=O)NCc1ccc(F)cc1
Temperature: 180 °C
Yield: 19.3 %

Procedure:
A mixture of 6.0 g (19.2 mmol) 2,6-dichloro-N-(4-fluorobenzyl)-4-methyl-pyridine-3-carboxylic amide (synthesized according to the methods described in section a) of example 2), 3.9 g (28.7 mmol) (R)-3-methylmorpholine hydrochloride, 13.0 ml (76.6 mmol) and NMP (18.4 ml) was heated in the MW to 180° C. for 16 h. After cooling to RT the mixture was partiotionated between EtOAc and a 2M aq. NaOH sol. The organic layer was separated, dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 1:1) provided 1.4 g (3.7 mmol, 20%) 2-chloro-N-(4-fluorobenzyl)-4-methyl-6-[(3R)-3-methylmorpholino]-pyridine-3-carboxylic amide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[CH3:9][O:10][C:11](=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[CH:19])[CH:13]=1>C(N(CC)CC)C.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.[Cu]I>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:19]#[C:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([C:11]([O:10][CH3:9])=[O:20])[CH:13]=2)[N:3]=1
Reactant: C#Cc1cccc(C(=O)OC)c1
Reactant: Brc1cccc(Br)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(C#Cc2cccc(Br)n2)c1
Reaction time: 1 h
Yield: 23.8 %

Procedure:
A solution of 15.1 g of 2,6-dibromopyridine in 500 ml of triethylamine is mixed under ice cooling with 10.2 g of 3-ethinylbenzoic acid methyl ester, 1.1 g of bis-(triphenylphosphine)-palladium(II) chloride and 150 mg of copper(I) iodide and the mixture is stirred for 1 hour. Then, the ice bath is removed and it is stirred for 48 hours at room temperature. The precipitate is filtered off, the filtrate is evaporated to dryness, mixed with water and shaken out with ethyl acetate. The organic phase is dried on sodium sulfate, concentrated by evaporation and the residue is chromatographed on silica gel with hexane/0-12% ethyl acetate. 4.8 g of 2-bromo-6-[2-(3-methoxycarbonyiphenyl)-ethinyl]-pyridine of melting point 12°-126° C. is obtained.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:6]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[NH:29][C:28]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=5)=[N:27][N:26]=4)[CH2:21][CH2:20]3)=[CH:14][CH:13]=1)=[N:7]2.[NH2:42][NH2:43]>O1CCOCC1>[NH:42]([C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:6]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[NH:29][C:28]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=5)=[N:27][N:26]=4)[CH2:21][CH2:20]3)=[CH:14][CH:13]=1)=[N:7]2)[NH2:43]
Reactant: Clc1nccc2nc(-c3ccc(CN4CCC(c5nnc(-c6ccccn6)[nH]5)CC4)cc3)c(-c3ccccc3)cc12
Reactant: NN
Solvent: C1COCCO1
Product: NNc1nccc2nc(-c3ccc(CN4CCC(c5nnc(-c6ccccn6)[nH]5)CC4)cc3)c(-c3ccccc3)cc12
Temperature: 100 °C

Procedure:
To a stirred solution of 9-2 (5 g, 8.9 mMol) in anhydrous 1,4-dioxane (20 mL) was added hydrazine (5.9 mL, 188.1 mMol). The solution was heated to 100° C. in a microwave reactor for 5 minutes. The solvent was removed in vacuo and was dried azeotropically with toluene three times. The crude solid was triturated with a saturated NaHCO3 solution for 20 minutes. The suspension was filtered and washed with copious amounts of water. The solid was dried azeotropically with toluene three times to yield 9-3 as a tan solid. LC/MS (M+1) calculated: 554.6; observed: 554.2
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([O:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=3)[CH:10]=2)=[O:8])=[CH:5][N:4]=[CH:3]1.[CH3:28][Mg+].[Br-]>C1COCC1>[OH:8][C:7]([C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([O:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[CH:10]=1)([C:6]1[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=1)[CH3:28]
Reactant: Cn1cncc1C(=O)c1ccc(C#N)c(Oc2ccc3ccccc3c2)c1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: Cn1cncc1C(C)(O)c1ccc(C#N)c(Oc2ccc3ccccc3c2)c1
Temperature: 25 °C

Procedure:
4-(3-Methyl-3H-imidazole-4-carbonyl)-2-(naphthalen-2-yloxy)-benzonitrile (0.109 g, 0.308 mmol) was dissolved in anhydrous THF (5 mL) and a 3.0 M solution of MeMgBr (0.35 mL, 1.05 mmol) was added and stirred at RT. The reaction was quenched with NH4Cl after 1 h, concentrated, diluted with EtOAc, washed with satd. NaHCO3 solution, water, brine, dried (MgSO4) and concentrated to give the title compound. FT/ICR MS (M+1)=370.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1.F[C:16]1[CH:17]=[C:18]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:20][CH:21]=1.O>CS(C)=O>[Cl:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[O:14][C:16]1[CH:17]=[C:18]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:20][CH:21]=1
Reactant: Oc1cccc(Cl)c1
Reactant: O=[N+]([O-])c1cccc(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1cccc(Oc2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of potassium t-butoxide (12.3 g) in DMSO (100 mL) was added at once 3-chlorophenol (12.86 g). The resulting solution was stirred for 5 minutes at room temperature, then 3-fluoronitrobenzene (12.70 g) was added all at once. The resulting dark mixture was heated at 120° C. for 12 hours, cooled to room temperature then poured into water (700 mL). The resulting mixture was extracted with ether (2×200 mL). The organic fraction was washed with 2N NaOH (100 mL), then with water (100 mL). After drying (MgSO4), the solvent was evaporated and the resulting dark oil was distilled to give 3-(3-chlorophenoxy)nitrobenzene as a yellow oil, b.p. 135-140° C. at 0.05 mm
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([Si:7]([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:8][CH3:9])=[CH:4][C:3]=1[CH2:14][OH:15].C(N(CC)CC)C.[C:23](Cl)(=[O:35])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[C:23]([O:15][CH2:14][C:3]1[CH:4]=[C:5]([Si:7]([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:8][CH3:9])[O:6][C:2]=1[CH3:1])(=[O:35])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: CC[Si](CC)(CC)c1cc(CO)c(C)o1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(=O)OCc1cc([Si](CC)(CC)CC)oc1C
Temperature: 25 °C

Procedure:
To a stirred solution of 5-methyl-2-triethylsilyl-4-furylmethanol (208 mg. 0.92 mmol) and triethylamine (121 mg, 1.20 mmol) in tetrahydrofutan (10 ml) at 0 degrees under argon was added lauroyl chloride 302 mg, 1.38 mmol). This solution was allowed to warm gradually to room temperature and quenched with a 10% aqueous HCl solution. The organics were extracted into hexanes and the combined fractions were washed with a saturated aqueous solution of sodium bicarbonate, H2O and brine. Evaporation of the dried (magnesium sulfate) extracts gave an oil which was purified by filtration through silica using 2% ethyl ether/hexanes to give the title compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[CH2:4][CH2:5][O:6][C:7]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2].ClCCl.CO.N>C(OCC)(=O)C>[NH2:18][C:15]1[CH:16]=[CH:17][C:7]([O:6][CH2:5][CH2:4][N:3]([CH2:21][CH3:22])[CH2:1][CH3:2])=[C:8]([CH:14]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1OCCN(CC)CC
Agent: N
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(N)ccc1OCCN(CC)CC

Procedure:
Prepared analogously to Example 3.1.b. from 0.30 g ethyl 2-(2-diethylaminoethoxy)-5-nitrobenzoate in ethyl acetate. Yield: 0.27 g (100% of theory); C15H24N2O3 (M=280.37); calc.: molecular ion peak (M+H)+: 281; found: molecular ion peak (M+H)+: 281; Rf value: 0.40 (silica gel, dichloromethane/methanol/ammonia (39:1:0.1)).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[C:2]#[CH:3].C([Li])CCC.[CH3:12][O:13][C:14]1[C:21]([O:22][CH3:23])=[C:20]([O:24][CH3:25])[CH:19]=[CH:18][C:15]=1[CH:16]=[O:17].[Cl-].[NH4+]>O1CCCC1>[OH:17][CH:16]([C:15]1[CH:18]=[CH:19][C:20]([O:24][CH3:25])=[C:21]([O:22][CH3:23])[C:14]=1[O:13][CH3:12])[C:3]#[C:2][C:1]([O:5][CH3:6])=[O:4]
Reactant: COc1ccc(C=O)c(OC)c1OC
Reactant: C#CC(=O)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)C#CC(O)c1ccc(OC)c(OC)c1OC
Reaction time: 0.17 h

Procedure:
A solution of 3.4 ml (40 mmol) of methyl propiolate in 30 ml of tetrahydrofuran was treated at -78° under argon with 25 ml of n-butyllithium (1.6M in hexane). The mixture was stirred at -78° for 10 minutes and then a solution of 7.85 g (40 mmol) of 2,3,4-trimethoxybenzaldehyde in 40 ml of tetrahydrofuran was added within 10 minutes. The reaction mixture was brought to room temperature, stirred for 15 minutes and treated with 60 ml of saturated ammonium chloride solution. The aqueous phase was extracted twice with ether. The combined organic phases were washed in succession with saturated sodium chloride solution and with water, dried over sodium sulphate and concentrated. The residue was purified by flash chromatography on 500 g of silica gel (elution agent methylene chloride/ethyl acetate 9:1). There was obtained methyl 4-hydroxy-4-(2,3,4 -trimethoxyphenyl)-2-butynoate as a red oil.
Reaction SMILES: [OH:1][C:2]1[N:11]=[C:10]([N:12]([NH2:18])C(OCC)=O)[C:9]2[C:4](=[C:5]([CH3:20])[C:6]([CH3:19])=[CH:7][CH:8]=2)[N:3]=1.CN(C)[CH:23]=[O:24]>>[CH3:20][C:5]1[C:4]2[NH:3][C:2](=[O:1])[N:11]3[C:23](=[O:24])[NH:18][N:12]=[C:10]3[C:9]=2[CH:8]=[CH:7][C:6]=1[CH3:19]
Reactant: CN(C)C=O
Reactant: CCOC(=O)N(N)c1nc(O)nc2c(C)c(C)ccc12
Product: Cc1ccc2c([nH]c(=O)n3c(=O)[nH]nc23)c1C
Temperature: 25 °C

Procedure:
3.88 g (0.012 mol) of ethyl 2-hydroxy-7,8-dimethylquinazoline-4-yl-carbazate in 220 ml of dimethylformamide were boiled under reflux for 2 hrs. The reaction mixture was cooled to room temperature and then poured on to ice-water. The precipitate was filtered off and dried in a vacuum. There were obtained white crystals which were recrystallized from dimethylformamide. Yield: 1.62 g (50%) of 7,8-dimethyl-2,3,5,6-tetrahydro-1,2,4-triazolo[4,3-c]quinazoline-3,5-dione as yellowish crystals; m.p. 380°-382° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14](I)[CH:13]=2)=[O:10])=[CH:4][C:3]=1[O:19][CH3:20].O[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](NC2C=CC=CC=2I)=O)=[CH:24][C:23]=1OC>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:29]#[C:28][C:25]2[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=2)=[O:10])=[CH:4][C:3]=1[O:19][CH3:20]
Reactant: COc1cc(CC(=O)Nc2cccc(I)c2)ccc1O
Reactant: COc1cc(CC(=O)Nc2ccccc2I)ccc1O
Product: COc1cc(CC(=O)Nc2ccccc2C#Cc2ccccc2)ccc1O

Procedure:
Instead of Intermediate 1 in Example 36, 4-hydroxy-N-(2-iodophenyl)-3-methoxyphenylacetamide is treated in a similar manner to Example 36 to give the desired compound.
Reaction SMILES: [C:1]1([C:7]2[O:8][CH2:9][C:10](=[O:13])[NH:11][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[CH:15]1[CH2:19][CH2:18][O:17][CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[C:1]1([C:7]2[O:8][CH2:9][C:10](=[O:13])[N:11]([CH:15]3[CH2:19][CH2:18][O:17][CH2:16]3)[N:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1COC(c2ccccc2)=NN1
Reactant: OC1CCOC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C1COC(c2ccccc2)=NN1C1CCOC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.8 %

Procedure:
2-Phenyl-4H-1,3,4-oxadiazine-5(6H)-one (0.30 g) synthesized according to Receuil des Travaux chimiques des Pays Bas, 1929, 48, 417, 3-hydroxy tetrahydrofuran (0.30 g) and triphenyl phosphine (0.89 g) were dissolved in tetrahydrofuran (10 ml). Under ice-cooling, 40% diethyl azodicarboxylate/toluene solution (0.59 g) diluted with tetrahydrofuran (3 ml) was added thereto, followed by stirring overnight at room temperature. The reaction solution was evaporated and purified by Cromatorex NH silica gel chromatography (hexane/ethyl acetate system), to give the title compound (0.15 g, 36%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[CH:11]=[C:12]4[C:16](=[C:17]([C:19]([NH2:21])=[O:20])[CH:18]=3)[NH:15][CH:14]=[C:13]4[CH:22]3[CH2:27][CH2:26][N:25]([S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])[CH2:24][CH2:23]3)=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[CH:33](=O)[CH3:34].C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[CH2:33]([N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:10]3[CH:11]=[C:12]4[C:16](=[C:17]([C:19]([NH2:21])=[O:20])[CH:18]=3)[NH:15][CH:14]=[C:13]4[CH:22]3[CH2:27][CH2:26][N:25]([S:28]([CH2:31][CH3:32])(=[O:29])=[O:30])[CH2:24][CH2:23]3)[CH:5]=2)[CH2:1]1)[CH3:34]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc5c(c4)CNC5)cc23)CC1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CCN1Cc2ccc(-c3cc(C(N)=O)c4[nH]cc(C5CCN(S(=O)(=O)CC)CC5)c4c3)cc2C1
Yield: 38.8 %

Procedure:
To a solution of 5-(2,3-dihydro-1H-isoindol-5-yl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (20 mg, 0.044 mmol) in MeOH (1 mL), was added acetaldehyde (6 mg, 0.133 mmol), sodium cyanoborohydride (6 mg, 0.088 mmol) and zinc chloride (6 mg, 0.044 mmol). The resultant mixture was heated in a microwave for 30 min at 100° C. Mixture was then concentrated, filtered and purified by Gilson Preparatory HPLC to give 8.2 mg of the title compound.
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[C:10]=1[F:16])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[O:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[N:23]1[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=[N:24]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:4]([O:3][C:1](=[O:2])[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:27]2[N:23]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][O:17]3)[N:24]=[CH:25][CH:26]=2)[C:10]=1[F:16])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: CC(C)(C)OC(=O)Nc1cccc(Br)c1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)Nc1cccc(-c2ccnn2C2CCCCO2)c1F
Reaction time: 0.5 h
Yield: 152.5 %

Procedure:
In a microwave tube N-Boc-3-bromo-2-fluoro-aniline (300 mg, 1.034 mmol) was dissolved in a 9:1 DME/H2O mixture (12 mL) and argon was bubbled through the solution for 10 minutes. 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (prepared as described in WO2010/010154) (576 mg, 2.071 mmol, 2 eq) was then added, followed by cesium carbonate (1.0 g, 3 eq) and Pd(dppf)Cl2.CH2Cl2 (84 mg, 14.6 mmol, 0.1 eq) and the reaction mixture was irradiated at 100° C. for 30 minutes. A further addition of 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1 eq) was made and a second microwave cycle was performed at 100° C. for 30 min. The mixture was then filtered over a Celite pad, which was washed with AcOEt. The filtrate was washed with water and brine, dried over Na2SO4 and evaporated to dryness. The crude was purified by chromatography on silica gel (Hex/AcOEt 8:2) to give 570 mg of {2-Fluoro-3-[2-(tetrahydro-pyran-2-yl)-2H-pyrazol-3-yl]-phenyl}-carbamic acid tert-butyl ester contaminated by N-tetrahydropyranyl-pyrazole (NMR title about 57%). HPLC (254 nm): Rt: 6.82 min; 1H NMR (DMSO-d6) Shift: 9.09 (s, 1H), 7.72 (t, J=7.6 Hz, 1H), 7.62 (d, J=1.8 Hz, 1H), 7.22-7.29 (m, 1H), 7.16-7.22 (m, 1H), 6.42-6.45 (m, 1H), 5.09-5.15 (m, 1H), 3.86-3.95 (m, 1H), 3.35-3.46 (m, 1H), 1.51-1.73 (many m, 6H), 1.48 (s, 9H); HRMS (ESI) calcd for C19H25FN3O3 [M+H]+ 362.1875. found 362.1874.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-])=O)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:23]#[N:24])[CH:6]=[CH:7][CH:8]=1.NN>[Pd].C(O)C>[NH2:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]([C:23]#[N:24])=[C:10]2[NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cccc(Nc2c(C#N)cnc3ccc([N+](=O)[O-])cc23)c1
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: COc1cccc(Nc2c(C#N)cnc3ccc(N)cc23)c1
Reaction time: 1.5 h
Yield: 96.2 %

Procedure:
325 mg of 10% palladium on carbon was added to a round bottom flask under N2 and covered with 165 ml ethanol. Added 3.29 g (10.3 mmol) 4-[(3-methoxyphenyl)-amino]-6-nitro-3-quinolinecarbonitrile and 800μl anhydrous hydrazine and heated mixture to reflux. At 1.5 hours, filtered hot through celite, stripped solvent and dried in vacuo, giving 2.876 g of yellow solid: mass spectrum (electrospray m/e): M+H=291.2.
Reaction SMILES: [CH:1]([CH:4]([CH2:10][CH2:11][C:12](=[O:14])[CH3:13])[CH:5]=[CH:6][C:7](=[O:9])[CH3:8])([CH3:3])[CH3:2].C>[Pd].C(OCC)(=O)C>[CH:1]([CH:4]([CH2:5][CH2:6][C:7](=[O:9])[CH3:8])[CH2:10][CH2:11][C:12](=[O:14])[CH3:13])([CH3:3])[CH3:2]
Reactant: CC(=O)C=CC(CCC(C)=O)C(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)CCC(CCC(C)=O)C(C)C

Procedure:
1.96 g (10 mM) of 5-isopropyl-non-3-ene-2,8-dione, prepared according to the method described in paragraph a) of example 2, in 20 ethyl acetate were reduced by catalytic hydrogenation in the presence of 0.196 g of palladium at 10 % over charcoal. After filtration and evaporation of the volatile portions, a residue was obtained which by fractional distillation gave 1.77 g (89 %), of the desired dione; B.p. 80°/0.001 Torr; d420 = 0.9292; nD20 = 1.4501
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].C(N)(C)(C)C.[Cl:10][CH2:11][CH2:12][CH2:13][CH2:14][S:15](Cl)(=[O:17])=[O:16]>>[Cl:10][CH2:11][CH2:12][CH2:13][CH2:14][S:15]([NH:4][CH2:1][CH2:2][CH3:3])(=[O:17])=[O:16]
Reactant: CCCN
Reactant: O=S(=O)(Cl)CCCCCl
Solvent: CC(C)(C)N
Product: CCCNS(=O)(=O)CCCCCl
Yield: 88 %

Procedure:
This was prepared in an analogous manner to that disclosed for Intermediate 41, using n-propylamine (commercially available, for example, from Aldrich) instead of t-butylamine, and 4-chloro-1-butanesulfonyl chloride (prepared according to White, E. H.; Lim, H. M. J. Org. Chem. 52, 1987, 11, 2162-2166) instead of 3-chloropropane sulfonyl chloride. Yield 88%. LCMS RT=2.54 min, ES+ve m/z 214 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([OH:15])=[N:6][O:7][C:8]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3][CH2:2]1.[C:16]([O:20][C:21]([NH:23][CH2:24][CH2:25]O)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([NH:23][CH2:24][CH2:25][O:15][C:5]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[C:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[O:7][N:6]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: Oc1noc(-c2ccccc2)c1C1CC1
Reactant: CC(C)(C)OC(=O)NCCO
Product: CC(C)(C)OC(=O)NCCOc1noc(-c2ccccc2)c1C1CC1
Yield: 73 %

Procedure:
4-Cyclopropyl-3-hydroxy-5-phenylisoxazole (0.2 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.18 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 9(a) to obtain the title compound (0.25 g, 74%) as a colorless powder.