Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[F:38])=[C:4]([C:9]2[C:10]3[CH:19]=[CH:18][N:17]([S:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)(=[O:22])=[O:21])[C:11]=3[C:12](=[O:16])[N:13]([CH3:15])[CH:14]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].C(O)(=O)C.[N:43]([O-])=O.[Na+]>C(OCC)(=O)C.O>[F:38][C:32]1[CH:33]=[C:34]([F:37])[CH:35]=[CH:36][C:31]=1[O:30][C:3]1[C:2]2[N:1]=[N:43][NH:8][C:7]=2[CH:6]=[CH:5][C:4]=1[C:9]1[C:10]2[CH:19]=[CH:18][N:17]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=3)(=[O:21])=[O:22])[C:11]=2[C:12](=[O:16])[N:13]([CH3:15])[CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ccc(N)c(N)c4Oc4ccc(F)cc4F)cn(C)c(=O)c32)cc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ccc5[nH]nnc5c4Oc4ccc(F)cc4F)cn(C)c(=O)c32)cc1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
A solution of 4-[3,4-diamino-2-(2,4-difluorophenoxyl)phenyl]-6-methyl-1-[(4-methylphenyl)sulfonyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (0.040 g, 0.074 mmol) in acetic acid (0.1 mL, 3 mmol) was treated with water (0.37 mL, 21 mmol) followed by sodium nitrite (0.026 g, 0.37 mmol) and stirred at 20° C. for 30 min. The reaction mixture was diluted with ethyl acetate and water. The organic layer was washed with saturated sodium bicarbonate (2×) and brine, dried with magnesium sulfate, filtered, and concentrated to give the desired product (32 mg, 78%) as a crude brown residue that was used immediately without further purification. LCMS calculated for C27H20F2N5O4S (M+H)+: m/z=548.1. found: 548.1.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:6][C:5](=[O:15])[CH:4]=1)[CH3:2].[OH-].[Na+].[I:18]I>O>[CH2:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:6][C:5](=[O:15])[C:4]=1[I:18])[CH3:2]
Reactant: CCc1cc(=O)[nH]c(-c2ccccc2)n1
Reactant: II
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1nc(-c2ccccc2)[nH]c(=O)c1I
Temperature: 50 °C
Yield: 94.5 %

Procedure:
A mixture of 8.18 g (40.9 mmol) of 6-ethyl-2-phenyl-4(3H)-pyrimidinone, 1.68 g (42.0 mmol) of sodium hydroxide, 10.42 g (41.0 mmol) of iodine and 50 mL of water was heated at 50° C. for 4 h. The mixture was cooled and filtered. The white solid collected was dried in a vacuum oven to leave 12.60 g (75%) of 6-ethyl-5-iodo-2-phenyl-4(3H)-pyrimidinone. 1H-NMR (d6-DMSO)δ1.25(3H,t), 2.85(2H,q), 7.50(3H,m), 8.15(2H,m).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=O)(C)(C)C.N[C@H](C(O)=O)CC(C)C.FC(F)(F)C(O)=O.C(OC([NH:40][C@H:41]([C:49]([OH:51])=[O:50])[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=O)(C)(C)C.CC(N=C=NC(C)C)C>C(N(C(C)C)CC)(C)C.C(Cl)Cl>[NH2:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12].[NH2:40][C@H:41]([C:49]([OH:51])=[O:50])[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)C[C@H](N)C(=O)O
Agent: CC(C)N=C=NC(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 2 h

Procedure:
A dipeptide of L-leucine and L-phenylalanine was prepared using the above described resin. N-(tert-butyloxycarbonyl)-L-leucine was coupled using the procedure of Example 1. Amino acid analysis of this resin showed a leucine content of 0.75 meq/g. When treated with 45% trifluoroacetic acid to deprotect and cap the residual sulfide as in Example 1, the leucine content dropped to 0.49 meq/g. A sample of this resin (0.994 g, 0.49 mmol) was washed twice with a solution of 10% diisopropyl ethylamine in methylene chloride, followed by three washes with methylene chloride to neutralize the resin. The resin was coupled with N(tert-butyloxycarbonyl)-L-phenylalanine by suspending the resin in 10 ml methylene chloride and adding 464 mg (1.75 mmol) N-(tert-butyloxycarbonyl)-L-phenylalanine and 0.27 ml (235 mg, 1.86 mmol) N,N-diisopropylcarbodiimide. After shaking for two hours, the resin was washed three times with methylene chloride and dried under vacuum. Amino acid analysis showed the leucine content to be 0.40 meq/g and the phenylalanine content to be 0.40 meq/g.
Reaction SMILES: C([N:8]1[CH2:13][C:12]([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=2)=[C:11]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:37])[CH2:10][CH2:9]1)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[Cl:44]C(OC(Cl)C)=O>ClCCCl>[ClH:44].[F:25][C:23]([F:24])([F:26])[C:21]1[CH:22]=[C:17]([CH:18]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:20]=1)[CH2:16][O:15][CH2:14][C:12]1[CH2:13][NH:8][CH2:9][CH2:10][C:11]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH3:37]
Reactant: Cc1ccccc1C1=C(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CN(Cc2ccccc2)CC1
Reactant: CC(Cl)OC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Product: Cc1ccccc1C1=C(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CNCC1
Product: Cl
Temperature: 50 °C

Procedure:
A mixture of 1-benzyl-5-(3,5-bis-trifluoromethyl-benzyloxymethyl)-4-o-tolyl-1,2,3,6-tetrahydro-pyridine (76 mg, 0.15 mmol), potassium carbonate (20 mg, 0.15 mmol) and 1-chloroethyl chloroformate (23 mg, 0.16 mmol) in 3 ml of 1,2-dichloroethane was heated at 50° C. for 3 h. The mixture was filtered and concentrated in vacuo. The residue was dissolved in 2 ml of methanol and heated at reflux over night. Evaporation of the solvent in vacuo was followed by flash column chromatography to give the free base of the title compound. Dissolution in a 2 M solution of hydrochloric acid in diethyl ether and concentration in vacuo gave 57 mg (84%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:24]3[C:15](=[CH:16][C:17]4[O:22][CH2:21][CH2:20][O:19][C:18]=4[CH:23]=3)[O:14][CH2:13]1)[C:5](=[O:12])[N:6]2[CH3:11].[CH:25]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][CH2:26]1>ClCCl.N1C=CC=CC=1>[CH3:11][N:6]1[C:7]2[C:3](=[C:2]([NH:1][C:29]([CH:25]3[CH2:28][CH2:27][CH2:26]3)=[O:30])[CH:10]=[CH:9][CH:8]=2)[C:4]2([C:24]3[C:15](=[CH:16][C:17]4[O:22][CH2:21][CH2:20][O:19][C:18]=4[CH:23]=3)[O:14][CH2:13]2)[C:5]1=[O:12]
Reactant: O=C(Cl)C1CCC1
Reactant: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(N)cccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(NC(=O)C3CCC3)cccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.1 %

Procedure:
To a solution of 4′-amino-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (700 mg, 1.72 mmol) in dichloromethane (50 mL) and pyridine (5 mL) was added cyclobutanecarbonyl chloride (0.17 mL, 1.48 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 18 h, diluted with dichloromethane (150 mL), washed sequentially with water, 10% w/v hydrochloric acid, water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography and eluted with ethyl acetate/hexanes (1/3) to afford N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)cyclobutanecarboxamide (0.50 g, 71%): mp 234-236° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.32-7.26 (m, 1H), 7.11-7.08 (m, 1H), 6.94-6.91 (m, 1H), 6.43 (s, 1H), 6.17 (s, 1H), 4.68 (ABq, 2H), 4.13-4.05 (m, 4H), 3.15 (s, 3H), 2.96-2.90 (m, 1H), 2.05-1.64 (m, 6H); 13C NMR (75 MHz, DMSO-d6) δ 176.6, 173.5, 155.1, 144.6, 144.3, 138.3, 134.6, 129.5, 125.3, 120.8, 119.4, 112.0, 106.8, 98.8, 78.2, 64.6, 64.0, 57.1, 27.1, 25.0, 24.9, 17.9; MS (ES+) m/z 406.9 (M+1).
Reaction SMILES: [ClH:1].[NH:2]1[C:6]2[CH2:7][CH2:8][C@@H:9]([C:11]([OH:13])=O)[CH2:10][C:5]=2[N:4]=[CH:3]1.S(Cl)([Cl:16])=O.[CH2:18]([CH2:21]OC)OC>>[NH:2]1[C:6]2[CH2:7][CH2:8][C@@H:9]([C:11]([Cl:16])=[O:13])[CH2:10][C:5]=2[N:4]=[CH:3]1.[ClH:1].[CH3:3][N:2]1[C:18]2[C:21](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:11]([C@@H:9]2[CH2:8][CH2:7][C:6]3[NH:2][CH:3]=[N:4][C:5]=3[CH2:10]2)=[O:13])=[CH:6]1
Reactant: O=C(O)[C@@H]1CCc2[nH]cnc2C1
Reactant: COCCOC
Reactant: O=S(Cl)Cl
Agent: Cl
Product: Cn1cc(C(=O)[C@@H]2CCc3[nH]cnc3C2)c2ccccc21
Product: O=C(Cl)[C@@H]1CCc2[nH]cnc2C1
Temperature: -40 °C
Reaction time: 3 h
Yield: 78.8 %

Procedure:
By heating a mixture of 4.05 g of (R)-4,5,6,7-tetrahydro-1H-benzimidazole-5-carboxylic acid monohydrochloride (99.4% e.e.), 120 ml of dimethoxyethane and 5.47 g of thionyl chloride at 70° C. for 2 hours, (R)-4,5,6,7-tetrahydro-1H-benzimidazole-5-carbonyl chloride was synthesized, and the solvent was evaporated under a reduced pressure. A 80 ml portion of toluene was added to the residue and again evaporated under a reduced pressure, and the residue was mixed with 120 ml of toluene and 5.24 g of 1-methyl-1H-indole and cooled to −40° C. in an atmosphere of nitrogen. A 30 ml portion of 1.0 mol/l toluene solution of ethylaluminum sesquichloride was slowly added to this liquid and stirred at −40° C. for 3 hours, and 10 ml of tetrahydrofuran was added thereto after the stirring. This liquid was slowly dispersed in 160 ml of water cooled at 0° C., and after removing the organic layer, the water layer was washed with 40 ml of toluene and extracted by adding 80 ml of 2-butanone and 50 ml of 20% sodium hydroxide aqueous solution thereto. The water layer was washed with 40 ml of 2-butanone, and the organic layers were combined and washed twice with 20 ml of 10% brine and then with 4 ml of water. A 40 ml portion of ethanol was added to the thus obtained organic layer and evaporated under a reduced pressure, and 40 ml of ethanol was again added to the residue and evaporated under a reduced pressure. A 120 ml portion of a mixed solvent of ethanol and ethyl acetate (1:3) was added to the residue, and this was heated at 70° C. for 1 hour by adding 5 ml ethyl acetate solution of 4 mol/l hydrogen chloride and then slowly cooled to 0° C. The precipitated crystals were filtered, and the crystals were washed with an ethanol-ethyl acetate mixed solvent and then dried in vacuo at 50° C., thereby obtaining 4.98 g of (−)-(R)-5-[(1-methyl-1H-indol-3-yl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole monohydrochloride (yield 78.8%, 99.5% e.e.). FAB-MS (m/z): 280 [M+H+]
Reaction SMILES: [N:1]1C=C[CH:4]=[CH:3][CH:2]=1.[CH:7]([SiH:10]([CH:26]([CH3:28])[CH3:27])[C:11]1[CH:25]=[CH:24][C:14]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:16])=[CH:13][CH:12]=1)([CH3:9])[CH3:8].C(CCO)#N.C(N(CC)CC)C>C(Cl)(Cl)Cl.O>[C:2]([CH2:3][CH2:4][O:22][C:21](=[O:23])[CH2:20][CH2:19][CH2:18][NH:17][C:15](=[O:16])[C:14]1[CH:13]=[CH:12][C:11]([SiH:10]([CH:7]([CH3:9])[CH3:8])[CH:26]([CH3:28])[CH3:27])=[CH:25][CH:24]=1)#[N:1]
Reactant: CC(C)[SiH](c1ccc(C(=O)NCCCC(=O)O)cc1)C(C)C
Reactant: c1ccncc1
Agent: N#CCCO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)[SiH](c1ccc(C(=O)NCCCC(=O)OCCC#N)cc1)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
A condensing agent of N,N-bis (2-oxo-3-oxazolidinyl)-phosphnic acid chloride BOP-Cl (1.5 g, 6.1 mmol) was added to pyridine solution (20 mL) dissolving 4-[4-(diisopropylsilanyl)benzoylamino]butanoic acid (3) (1.3 g, 4.1 mmol), 2-cyanoethanol (548 μL, 8.1 mmol) and triethylamine (828 μL, 6.1 mmol). The resulting mixture was stirred for 3 hours at a room temperature and mixed with water (5 mL). Five minutes later, it was diluted with chloroform (200 mL) and extracted three times with 5 wt % aqueous solution (150 ml) of sodium hydrogen carbonate. An organic layer was collected and dehydrated with anhydrous sodium sulfate and filtered so that the resulting solvent was distilled out under a reduced pressure. The resulting crude product was then purified by silica gel column chromatography. After eluted with chloroform having 0-3% methanol gradient, the solvent was distilled out to give a desired product (1.2 g, 79%). Its NMR data are as follows:
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]2[C:10]([NH:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=[CH:7][N:6]2[C:18]=1[CH3:19].S(Cl)([Cl:22])=O.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:22][CH2:2][C:3]1[N:4]=[C:5]2[C:10]([NH:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=[CH:7][N:6]2[C:18]=1[CH3:19]
Reactant: Cc1c(CO)nc2c(NC(=O)C(C)(C)C)cccn12
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(CCl)nc2c(NC(=O)C(C)(C)C)cccn12
Reaction time: 2 h
Yield: 91.3 %

Procedure:
To a stirred suspension of 13 g of 2-hydroxymethyl-3-methyl-8-pivaloylaminoimidazo[1,2-a]pyridine in 500 ml of dry dichloromethane is added dropwise a solution of 6.5 g thionyl chloride in 50 ml dry dichloromethane at 0–5° C. to give a clear yellow solution. After 2 h the reaction mixture is hydrolysed by adding 200 ml saturated sodium bicarbonate solution under cooling. The resulting mixture is transferred to a separatory funnel and shaken vigorously. The organic layer is separated, washed with water and dried over anhydrous sodium sulfate. The solvent is removed in vacuo to give 12.7 g (92%) of the title compound (m.p. 168° C.).
Reaction SMILES: [C:1]([S:5](/[N:7]=[C:8](/[C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=1)\[CH2:9][CH2:10][C:11]([CH3:17])([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[O:6])([CH3:4])([CH3:3])[CH3:2].[CH3:26][Mg]Br.C(OCC)C>C(Cl)Cl>[C:1]([S:5]([NH:7][C@@:8]([C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=1)([CH3:26])[CH2:9][CH2:10][C:11]([CH3:16])([CH3:17])[C:12]([O:14][CH3:15])=[O:13])=[O:6])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[Mg]Br
Reactant: COC(=O)C(C)(C)CC/C(=N\S(=O)C(C)(C)C)c1cc(F)cc(F)c1
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)C(C)(C)CC[C@](C)(NS(=O)C(C)(C)C)c1cc(F)cc(F)c1
Reaction time: 0.25 h

Procedure:
To a solution of methyl (5E)-5-[(tert-butylsulfinyl)imino]-5-(3,5-difluorophenyl)-2,2-dimethylpentanoate (342 mg, 0.920 mmol) in CH2Cl2 (6 mL) at 0° C., was added dropwise over five minutes methyl magnesium bromide as a 3M solution in diethyl ether (0.61 mL, 1.83 mmol). After 15 minutes the reaction was determined to be complete by LCMS analysis. The reaction was quenched by the dropwise addition of 1M HCl (5 mL), followed by 5 mL of water. The aqueous layer was extracted once with CH2Cl2 (10 mL) and the organics were combined and washed once with brine (15 mL). The organics were dried over sodium sulfate, filtered and concentrated in vacuo to give a residue that was purified by silica gel chromatography, eluting with a gradient of EtOAc:Hexanes—10:90 to 55:45, to give the title compound. MS: m/z=390 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][NH2:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=O)[C:26](=[N:34]O)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:21][CH:20]=1>N1C=CC=CC=1>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[NH:17][C:16]([C:13]3[CH:12]=[CH:11][C:10]([N:7]4[CH2:6][CH2:5][N:4]([CH2:3][CH2:2][OH:1])[CH2:9][CH2:8]4)=[CH:15][CH:14]=3)=[N:34][C:26]=2[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)C(=NO)C(=O)c1ccc(Cl)cc1
Reactant: NCc1ccc(N2CCN(CCO)CC2)cc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1nc(-c2ccc(N3CCN(CCO)CC3)cc2)[nH]c1-c1ccc(Cl)cc1

Procedure:
4-[4-(2-Hydroxyethyl)piperazin-1-yl]phenylmethylamine and tert-butyl 3-(4-chlorophenyl)-2-hydroxyimino-3-oxopropionate are dissolved in pyridine, and the solution is treated in the same manner as in Starting Material Synthetic Example 170 to give the objective tert-butyl 5-(4-chlorophenyl)-2-{4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}imidazole-4-carboxylate.
Reaction SMILES: [C:1]12([CH:11](I)[C:12]([OH:14])=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:16][NH2:17]>O1CCCC1>[C:1]12([CH:11]([NH:17][CH3:16])[C:12]([OH:14])=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(O)C(I)C12CC3CC(CC(C3)C1)C2
Reactant: CN
Solvent: C1CCOC1
Product: CNC(C(=O)O)C12CC3CC(CC(C3)C1)C2

Procedure:
Adamantan-1-yl-iodo-acetic acid (7.86 g, 24.55 mmol, P. A. Krasutskii. et. Al.;J. Org. Chem. USSR (Engl. Trans.); 1985; 1327-1332) is refluxed with 100 mL of 2M methylamine in tetrahydrofuran for 18 hours. The solvent is evaporated in vacuo, and the residue treated with water. The pH is adjusted to 6 and the resulting solid collected and dried to give 2.16 g of the title compound as a white solid. MS: m/z 224.2 (M+1).
Reaction SMILES: O.[C:2]1([CH2:8][C:9](=O)[C:10]([O-:12])=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].Cl.[Cl:16][C:17]1[CH:18]=[C:19]([NH:24][NH2:25])[CH:20]=[CH:21][C:22]=1[Cl:23].C(O)C>O>[Cl:16][C:17]1[CH:18]=[C:19]([NH:24][N:25]=[C:9]([CH2:8][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]([OH:12])=[O:11])[CH:20]=[CH:21][C:22]=1[Cl:23]
Reactant: O=C([O-])C(=O)Cc1ccccc1
Reactant: NNc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)C(Cc1ccccc1)=NNc1ccc(Cl)c(Cl)c1

Procedure:
Add 21.0 g of sodium β-phenylpyruvate monohydrate and 21.3 g of 3,4-dichlorophenylhydrazine hydrochloride to 300 ml of ethanol and reflux the resulting mixture for 30 minutes. Cool, add water, collect and dry the solid to yield phenylpyruvic acid 3,4-dichlorophenylhydrazone, m.p. 166°-167°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15]Br)=[CH:11][C:10]=2[F:17])[CH:5]=[CH:6][C:7]=1[Cl:8].[C-:18]#[N:19].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:18]#[N:19])=[CH:11][C:10]=2[F:17])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Fc1cc(CBr)ccc1-c1ccc(Cl)c(Cl)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CCc1ccc(-c2ccc(Cl)c(Cl)c2)c(F)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
3′,4′-dichloro-2-fluoro-4-bromomethyl-biphenyl (35.0 g, 0.105 mol) and sodium cyanide (5.4 g, 0.110 mol) were dissolved in a mixture of ethanol (228 ml) and water (25 ml), then heated at 50° C. for 3 hours. The solution was concentrated under vacuum and the residue was suspended in ethanol/water 1/1 v/v (35 ml) and cooled at 0-5° C. for 30 minutes. The obtained solid is filtered and dried at 40° C. under vacuum. The crude product was suspended in ethanol (56 ml) at 20 to 25° C. for 30 minutes, filtered and dried at 40° C. under vacuum. The compound 3′,4′-dichloro-2-fluoro-4-cyanomethyl-biphenyl was obtained as a light brown powder (16.8 g, 57% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.S(O)(O)(=O)=O.[CH3:15][O:16][C:17](=[NH:19])[NH2:18].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH:19][C:17](=[NH:18])[O:16][CH3:15])[N:3]=1
Reactant: COC(=N)N
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=N)Nc1nc(Cl)cc(Cl)n1
Temperature: 110 °C
Reaction time: 10 h
Yield: 142.6 %

Procedure:
45.9 g (0.25 mol) of 2,4,6-trichloropyrimidine, 30.8 g (0.125 mol) of O-methyl-isourea sulphate and 51.8 g (0.375 mol) of ground potassium carbonate are suspended in 800 ml of toluene and stirred at 110° C. for 10 hours. After cooling, the crystalline solid is filtered off with suction, stirred with water for 15 minutes and again filtered off with suction. 39.4 g of N-(4,6-dichloro-pyrimidin-2-yl)-O-methylisourea are obtained (GC purity 98%: 38.6 g; yield: 69 of theory), melting point 178° C.
Reaction SMILES: [CH:1]1([C:7]2[NH:11][C:10](=[O:12])[C:9]3([CH2:17][CH2:16][N:15]([S:18]([CH:21]=[CH2:22])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[C:30](OS(C(F)(F)F)(=O)=O)[CH:29]=[CH:28][CH:27]=2.C(N(CC)CC)C>O1CCOCC1>[CH:1]1([C:7]2[NH:11][C:10](=[O:12])[C:9]3([CH2:17][CH2:16][N:15]([S:18](/[CH:21]=[CH:22]/[C:30]4[CH:29]=[CH:28][CH:27]=[C:26]5[C:31]=4[CH:32]=[C:24]([CH3:23])[NH:25]5)(=[O:20])=[O:19])[CH2:14][CH2:13]3)[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1cc2c(OS(=O)(=O)C(F)(F)F)cccc2[nH]1
Reactant: C=CS(=O)(=O)N1CCC2(CC1)N=C(C1CCCCC1)NC2=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1cc2c(/C=C/S(=O)(=O)N3CCC4(CC3)N=C(C3CCCCC3)NC4=O)cccc2[nH]1
Temperature: 100 °C
Reaction time: 18 h
Yield: 13.8 %

Procedure:
A mixture of 2-cyclohexyl-8-ethenesulfonyl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (100 mg, 0.307 mmol), trifluoro-methanesulfonic acid 2-methyl-1H-indol-4-yl ester (129 mg, 0.462 mmol), tetrakistriphenylphosphine palladium(0) (35 mg, 30.2 μmol) and triethylamine (130 μL, 0.933 mmol) in 1,4-dioxane (1.5 ml) was heated with stirring at 100° C. for 18 hours. The reaction mixture was cooled, and then quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 2-cyclohexyl-8-[(E)-2-(2-methyl-1H-indol-4-yl)-ethenesulfonyl]-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (19.3 mg, 14%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[O:8])[CH:2]=1.[CH3:9][C:10](=[N:14]O)[C:11](=O)[CH3:12].[ClH:16].C(OCC)(=O)C>>[Cl:16][CH2:9][C:10]1[N:14]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[O:8][C:11]=1[CH3:12]
Reactant: CC(=O)C(C)=NO
Reactant: O=Cc1cccnc1
Reactant: Cl
Solvent: CCOC(C)=O
Product: Cc1oc(-c2cccnc2)nc1CCl
Temperature: 25 °C
Reaction time: 72 h
Yield: 19 %

Procedure:
A mixture of pyridine-3-carbaldehyde (26.26 g), 2,3-butanedione-2-oxime (24.77 g) and 4N hydrogenchloride-ethyl acetate solution (300 mL) was stirred at room temperature for 3 days. The reaction mixture was concentrated, and the obtained crystals were washed with diethyl ether. To the crystals was added tetrahydrofuran (250 mL), and a solution of thionyl chloride (43.78 g) in tetrahydrofuran (50 mL) was further added. The mixture was heated under reflux for 3 hrs. The reaction mixture was concentrated and ethyl acetate was added to the residue. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 3-(4-chloromethyl-5-methyl-1,3-oxazol-2-yl)pyridine as colorless crystals (9.48 g, 19%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 87-88° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[H][H]>CO.O=[Pt]=O>[ClH:1].[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Cc1c(Cl)cnc(N)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CO
Product: Cc1c(Cl)cnc(N)c1N
Product: Cl
Yield: 193.3 %

Procedure:
The material from Step 1 (1.0 g) was dissolved in MeOH (300 ml) and PtO2 (40 mg) was added. The mixture was subjected to hydrogen (50 psi) in a Parr shaker for 3.5 h, then filtered through Celite and to the filtrate was added conc. HCl (1 ml) before concentrating to yield 5-chloro-4-methyl-pyridine-2,3-diamine hydrochloride (1 g). NMR (CDCl3) δ 7.39 (s, 1H), 2.29 (s, 3H).