Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[S:10])=[CH:4][CH:3]=1.[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30].C(N(CC)CC)C>C(Cl)Cl>[C:19]([C:16]1[CH:15]=[CH:14][C:13]([C:12]([NH:11][C:9](=[S:10])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][Br:24])=[CH:3][CH:4]=2)=[O:23])=[CH:18][CH:17]=1)([CH3:20])([CH3:22])[CH3:21]
Reactant: O=C(Cl)CCCCBr
Reactant: CC(C)(C)c1ccc(C(=O)NC(=S)Nc2ccc(N)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C(=O)NC(=S)Nc2ccc(NC(=O)CCCCBr)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.3 %

Procedure:
Thiourea 4 (6 g, 18.3 mmol, 1 equiv.) was stirred in CH2Cl2 (110 mL) under N2 atmosphere. 5-Bromovaleryl chloride (3.65 g, 18.3 mmol, 1 equiv.) was added, followed by triethylamine (2.51 mL, 18.3 mmol, 1 equiv.). The beige suspension was stirred at rt for 4 h and diluted with CH2Cl2 (50 mL). The organic solution was washed with 1 M aqueous hydrochloric acid (1×50 mL), 10% aqueous sodium hydroxide (1×50 mL), and saturated brine (1×50 mL). The organic phase was dried over MgSO4 and concentrated in vacuo. The resulting brown foam was purified by flash chromatography on silica (50% ethyl acetate/petroleum ether) to give 5-bromo-pentanoic acid {4-[3-(4-tert-butyl-benzoyl)-thioureido]-phenyl}-amide (intermediate JH140) (6.76 g, 77%) as a yellow powder.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18]>N1C=CC=CC=1>[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([N:9]1[C:10](=[O:12])[CH2:11][N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]1=[O:13])=[O:18]
Reactant: O=C1CN(c2ccccc2)C(=O)N1
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: c1ccncc1
Product: O=C1CN(c2ccccc2)C(=O)N1C(=O)c1ccccc1Cl
Yield: 13 %

Procedure:
In a similar manner to Example 8, 560 mg (3.18 mmol) of 1-phenyl-imidazolidin-2,4-dione were reacted with 560 mg (3.22 mmol) of 2-chlorobenzoyl chloride. After completion of the reaction, pyridine was distilled off under reduced pressure, and the resultant residue was subjected to extraction with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and with saturated saline. The thus-washed organic layer was dried over anhydrous magnesium sulfate, and the solvent was then distilled off. The resultant residue was purified by column chromatography on silica gel (developing solvent: methylene chloride) and subjected to crystallization from n-hexane/ethyl acetate to obtain 130 mg (yield: 12.9%) of the title compound.
Reaction SMILES: Br[CH:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:3]([NH:5][C:6]1[S:7][C:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:9][N:10]=1)=[O:4].[CH3:25][NH:26][CH3:27]>CN(C)C=O>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][C:8]1[S:7][C:6]([NH:5][C:3](=[O:4])[CH:2]([N:26]([CH3:27])[CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:10][CH:9]=1
Reactant: CNC
Reactant: O=C(Nc1ncc(Cc2ccccc2Cl)s1)C(Br)c1ccccc1
Solvent: CN(C)C=O
Product: CN(C)C(C(=O)Nc1ncc(Cc2ccccc2Cl)s1)c1ccccc1

Procedure:
2-Bromo-N-[5-(2-chloro-benzyl)-thiazol-2-yl]-2-phenyl-acetamide (42 mg, 0.10 mmol) was dissolved in 0.5 mL of N,N-dimethylformamide containing dimethylamine (90.2 mg, 2.00 mmol). The reaction vessel was sealed and then subjected to microwave irradiation for 5 minutes at 80° C. The crude mixture was evaporated to dryness and purified by reverse-phase preparative liquid chromatography (13 mg, 0.034, 34%). ESI-MS m/z calc. 385.1, found 386.0 (M+1)+ Retention time 2.40 minutes.
Reaction SMILES: [CH3:1][C@H:2]([NH2:7])[C:3]([CH3:6])([CH3:5])[CH3:4].[C:8]([O-])(O)=[O:9].[Na+].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[N:7]([C@@H:2]([CH3:1])[C:3]([CH3:6])([CH3:5])[CH3:4])=[C:8]=[O:9]
Reactant: O=C([O-])O
Reactant: C[C@H](N)C(C)(C)C
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H](N=C=O)C(C)(C)C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
To a solution of (S)-1,2,2-trimethylpropylamine (626 mg, 6.2 mmol) in methylene chloride (20 mL) and satd aq NaHCO3 (20 mL) was added triphosgene (607 mg, 2.05 mmol) at 0° C. The mixture was stirred for 15 min. The organic phase was separated, dried and concentrated to give (S)-3-isocyanato-2,2-dimethyl-butane (845 mg, 90%). 1H NMR (CDCl3): 0.90 (s, 9H), 1.21 (m, 3H), 3.31 (m, 1H).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7](Br)=[CH:8][N:9]=1)(=[O:3])[CH3:2].[OH:11][C:12]1[C:13]([SH:18])=[N:14][CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([S:18][C:13]2[C:12]([OH:11])=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: Oc1cccnc1S
Reactant: CC(=O)Nc1ncc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncc(Sc2ncccc2O)s1
Temperature: 90 °C
Yield: 110.3 %

Procedure:
A mixture of 2-acetylamino-5-bromothiazole (1.8 g), 3-hydroxy-2-mercaptopyridine (1.3 g) and potassium carbonate (2.0 g) in N,N-dimethylformamide (40 ml) was heated at 90° C. for 3.5 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was triturated with water. The mixture was extracted with a mixture of tetrahydrofuran and ethyl acetate (1:1), washed with aqueous saturated sodium chloride and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 150 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 2-acetylamino-5-(3-hydroxypyridin-2-ylthio)thiazole (2.4 g, yield: 89.9%). mp: 236°-238° C. (dec.) IR (Nujol): 3175, 1690, 1565, 1300 cm-1
Reaction SMILES: [C:1](/[C:3](=[CH:8]\[C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH2:18][CH2:19][Cl:20])=[CH:11][C:10]=1[N+:21]([O-])=O)/[C:4]([O:6][CH3:7])=[O:5])#[N:2]>C(O)(=O)C.[Fe]>[NH2:2][C:1]1[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][C:9]2[C:10](=[CH:11][C:12]([O:17][CH2:18][CH2:19][Cl:20])=[C:13]([O:15][CH3:16])[CH:14]=2)[N:21]=1
Reactant: COC(=O)/C(C#N)=C/c1cc(OC)c(OCCCl)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: COC(=O)c1cc2cc(OC)c(OCCCl)cc2nc1N
Yield: 83 %

Procedure:
To methyl (2E)-2-cyano-3-[4-(2-chloroethoxy)-5-methoxy-2-nitrophenyl]-2-propenoate (19.3 g, 56.6 mmol) in 250 mL of acetic acid is added portionwise 12.0 g (215.0 mmol) of iron. The mixture is heated at reflux for 20 minutes, cooled slightly and filtered washing with ethyl acetate. The filtrate is concentrated in vacuo and water is added to the residue. The resulting yellow solid is collected by filtration washing with water to provide 14.6 g of methyl 2-amino-7-[2-chloroethoxy]-6-methoxy-3-quinolinecarboxylate. An analytical sample is obtained by stirring a portion of the product with a mixture of methanol and aqueous ammonium hydroxide. The undissolved solids are removed by filtration. Upon standing solids appeared in the filtrate and are collected to provide methyl 2-amino-7-[2-chloroethoxy]-6-methoxy-3-quinolinecarboxylate as light yellow crystals, mp 145–157° C.
Reaction SMILES: [Cl:1][C:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12](Cl)(=[O:14])=[O:13])=[CH:3][Cl:4].O.[NH3:17]>C(Cl)Cl>[Cl:1][C:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH2:17])(=[O:14])=[O:13])=[CH:3][Cl:4]
Reactant: N
Reactant: O=S(=O)(Cl)c1ccccc1OC(Cl)=CCl
Solvent: O
Solvent: ClCCl
Product: NS(=O)(=O)c1ccccc1OC(Cl)=CCl
Reaction time: 6 h

Procedure:
A solution of 17.5 g of 2-(1,2-dichlorovinyloxy)phenylsulfonyl-chloride in 150 ml of methylenechloride is added slowly to a mixture of 30 ml of methylene chloride, 50 ml of water and 50 ml of 30% aqueous ammonia. The reaction mixture is stirred for 6 hours at a temperature of 20°-25° C. The organic phase is washed with water, dried over sodium sulfate and evaporated to a volume of 40 ml. The crystallised 2-(1,2-dichlorovinyloxy)phenylsulfonamide is separated and dried. Yield: 12.5 g, m.p. 147°-149° C.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=O.ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.[ClH:33].Cl.[S:35]1[CH:39]=[C:38]([CH2:40][C@@H:41]([C:43]([N:45]2[CH2:52][CH2:51][CH2:50][C@H:46]2[C:47]([NH2:49])=[O:48])=[O:44])[NH2:42])[N:37]=[CH:36]1.C(N(CC)CC)C>CN(C)C=O>[ClH:33].[ClH:33].[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:42][C@H:41]([C:43]([N:45]1[CH2:52][CH2:51][CH2:50][C@H:46]1[C:47]([NH2:49])=[O:48])=[O:44])[CH2:40][C:38]1[N:37]=[CH:36][S:35][CH:39]=1)=[O:9]
Reactant: NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)Cc1cscn1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1cscn1)NC(=O)[C@@H]1CCC(=O)N1
Reaction time: 2 h

Procedure:
L-Pyroglutamic acid (1.76 g, 13.64 mmol) and N-hydroxysuccinimide (1.73 g, 15 mmol) were dissolved in N,N-dimethylformamide (50 ml). To this solution was added the solution of DCC (3.09 g, 15 mmol) in N,N-dimethylformamide (10 ml) under ice-cooling and the resulting mixture was stirred for 2 h at, the same temperature. 3-(4-thiazolyl)-L-alanyl-L-prolineamide dihydrochloride (4) (6.67 g, 15 mmol) and triethylamine (4.6 ml. 33 mmol) were added successively to the solution and the reaction mixture was stirred overnight. After the precipitation which appeared was filtered off, to the filtrate was added sodium hydrogencarbonate aq. to adjust pH 8. The reaction mixture was subjected to gel filtration column chromatography (MCI gel CHP-20P, 200 ml, aq. MeOH) to give the compound (I-1) (2.54 g, 49%).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH2:9][C:10]([O:12]N1C(=O)CCC1=O)=O)=[O:7])([CH3:4])[CH3:3].[NH2:20][CH2:21][CH:22]([OH:25])[CH2:23][OH:24]>CN(C=O)C>[C:6]([NH:8][CH2:9][C:10]([NH:20][CH2:21][CH:22]([OH:25])[CH2:23][OH:24])=[O:12])([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7]
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Reactant: NCC(O)CO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)NCC(O)CO
Reaction time: 18 h
Yield: 98 %

Procedure:
10.00 g (36.73 mmol) Boc-Gly-Osu (Bachem) was dissolved together with 3.35 g (36.77 mmol) 1-amino-2,3-propanediol in 50 ml DMF and stirred for 18 h. The product was purified by flash chromatography (CH2Cl2 /MeOH; 95:5 v/v). 8.94 g (98%) 19 was obtained as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[CH:9]([CH2:10][C:11](=[O:15])[NH:12][N:13]=3)[CH2:8][CH2:7][C:6]=2[CH:16]=1.[CH2:17](Br)[CH2:18][CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:17]([N:13]1[CH:14]2[CH:9]([CH2:8][CH2:7][C:6]3[CH:16]=[C:2]([NH2:1])[CH:3]=[CH:4][C:5]=32)[CH2:10][C:11](=[O:15])[NH:12]1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCBr
Reactant: Nc1ccc2c(c1)CCC1CC(=O)NN=C21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCN1NC(=O)CC2CCc3cc(N)ccc3C21

Procedure:
A solution of dl-8-amino-4,4a,5,6-tetrahydro-2H-benzo(h)-cinnolin-3-one (3 g) and n-butyl-bromide (5.7 g) in acetone (75 ml) is heated at reflux temperature in the presence of fine powdered potassium carbonate (5 g). The mixture is filtered, the acetone is evaporated and the residue is partitioned between water and ethyl acetate. The usual work-up affords a crude compound (3.9 g) which is crystallized from methanol to yield dl-1-n-butyl-8-amino-4,4a,5,6-tetrahydro-2H-benzo(h)-cinnolin-3-one m.p. 141°-142° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16](=[O:18])[CH3:17])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[Br:19]Br.O>C(Cl)Cl>[Br:19][CH2:17][C:16]([C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=1)=[O:18]
Reactant: CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: BrBr
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1cc(C(=O)CBr)cc(C(C)(C)C)c1O

Procedure:
20.6 g (83 mmol) of 1-(3,5-di-tert.-butyl-4-hydroxy-phenyl)ethanone were dissolved in 50 ml of methylene chloride with stirring and heated to boiling, and 14.4 g (90 mmol) of bromine were added dropwise in the course of 15 minutes. The mixture was then heated under reflux for a further 2 hours and cooled, 50 ml of water were added, and the organic phase was separated and dried over sodium sulfate. After removing the solvent under reduced pressure, the solid residue was recrystallized from methylcyclohexane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[N:13]=[C:14]([C:28]([OH:30])=O)[N:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[CH:16]=2)=[O:10])=[C:4]([CH3:31])[CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:44][CH2:45][CH2:46][OH:47].[Cl-].[Na+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[N:13]=[C:14]([C:28]([NH:44][CH2:45][CH2:46][OH:47])=[O:30])[N:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:20][CH:19]=3)[CH:16]=2)=[O:10])=[C:4]([CH3:31])[CH:3]=1
Reactant: NCCO
Reactant: Cc1cc(Cl)ccc1NC(=O)Nc1cn(Cc2ccc(C(F)(F)F)cc2)c(C(=O)O)n1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Cl)ccc1NC(=O)Nc1cn(Cc2ccc(C(F)(F)F)cc2)c(C(=O)NCCO)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1.81 g (4 mmol) of 4-({[(4-chloro-2-methylphenyl)amino]carbonyl}amino)-1-[4-(trifluoromethyl)benzyl]-1H-imidazole-2-carboxylic acid (Example 20A) are dissolved in 16 ml of absolute DMF, and 1.94 g (12 mmol) of N,N-carbonyldiimidazole are added. The reaction mixture is stirred at RT for 1.5 h and, after addition of 144 μl of water, stirred at RT for 10 min. Then 366 mg (6 mmol) of 2-aminoethanol are added, and the mixture is stirred at RT for 1 h. The reaction mixture is mixed with saturated sodium chloride solution and extracted twice with ethyl acetate. The combined extracts are washed once each with 10% strength citric acid, saturated sodium bicarbonate solution, water and saturated sodium chloride solution, dried with magnesium sulphate and concentrated in vacuo. The residue from evaporation is purified by chromatography on silica gel with dichloromethane/methanol as eluent.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([N:18]2[CH:22]=[N:21][N:20]=[CH:19]2)=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].[CH3:23][Si](C=[N+]=[N-])(C)C>CO.CCCCCC>[CH3:23][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:11]([N:18]2[CH:22]=[N:21][N:20]=[CH:19]2)[C:12]([C:14]([F:17])([F:15])[F:16])=[CH:13][C:5]=1[NH:4][C:1](=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(C(F)(F)F)c(-n2cnnc2)cc1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCCCCC
Product: COC(=O)c1cc(-n2cnnc2)c(C(F)(F)F)cc1NC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
A solution of 1.3 g (4.14 mmol) of 2-acetylamino-5-[1,2,4]triazol-4-yl-4-trifluoromethyl-benzoic acid in 15 ml of methanol is treated dropwise with 3.1 ml (6.21 mmol) of a 2M solution of trimethylsilyl diazomethane in hexane. The mixture is stirred for 1 hour at room temperature and another 1.5 ml (3.00 mmol) of a solution of trimethylsilyl diazomethane in hexane (2M) is added. After 1 hour, the reaction is quenched by adding glacial acetic acid until no more gas evolution is observed. The mixture is concentrated in vacuo and the residue taken up in ethyl acetate, washed with water, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, gradient 100% ethyl acetate to ethyl acetate/methanol 9:1) afforded 456 mg (34%) of 2-acetylamino-5-[1,2,4]triazol-4-yl-4-trifluoromethyl-benzoic acid methyl ester as yellow crystals, m.p. 180-184° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>CO.O>[CH:25]1([NH:28][C:21]([C:17]2[S:16][C:15](/[CH:14]=[CH:13]/[C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)=[N:9][O:10][C:11]=3[CH3:24])=[N:19][C:18]=2[CH3:20])=[O:23])[CH2:27][CH2:26]1
Reactant: Cc1nc(/C=C/c2c(-c3ccc(F)cn3)noc2C)sc1C(=O)O
Reactant: NC1CC1
Solvent: CO
Solvent: O
Product: Cc1nc(/C=C/c2c(-c3ccc(F)cn3)noc2C)sc1C(=O)NC1CC1
Yield: 52 %

Procedure:
As described for example 71d, 2-{(E)-2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-vinyl}-4-methyl-thiazole-5-carboxylic acid (69 mg, 0.2 mmol) was converted, using cyclopropylamine instead of isopropylamine, to the title compound (40 mg, 52%) which was obtained as a white solid after trituration from methanol/water. MS: m/e=385.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.Cl.[Cl:19][C:20]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:21]=1[NH2:22]>>[Cl:19][C:20]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:21]=1[NH:22][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: COc1ccc(Cl)c(N)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cnccn2)n1
Agent: Cl
Product: COc1ccc(Cl)c(Nc2cc(C(F)(F)F)nc(-c3cnccn3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.192 mmol) and 2-chloro-5-methoxyaniline hydrochloride (56 mg, 0.288 mmol) similar to Example 76 and isolated as a tan solid (41 mg, 56%). 1H NMR (CDCl3): 9.75 (d, J=1.2 Hz, 1H), 8.79 (dd, J=1.7, 2.6 Hz, 1H), 8.73 (d, J=2.4 Hz, 1H), 7.70 (s, 1H), 7.52 (s, 1H), 7.40 (d, J=9.3 Hz, 1H), 7.04 (s, 1H), 6.78 (dd, J=2.9, 8.9 Hz, 1H), 3.89 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[N:10][NH:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:13]C1C=C(C=CC=1)C#N>>[Cl:13][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[N:10][NH:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccc(-c2nn[nH]n2)c1
Reactant: N#Cc1cccc(Cl)c1
Product: Clc1cccc(-c2nn[nH]n2)c1

Procedure:
Following the procedure in COMPOUND 3 for the synthesis of intermediate 5-(3-bromophenyl)-2H-tetrazole, 3-chlorobenzonitrile (1.88 g, 13.67 mmol) was employed to obtain 5-(3-chlorophenyl)-2H-tetrazole.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[C:4]1([CH2:14][N:15]2[CH:19]=[C:18]([C:20](OCC)=[O:21])[C:17]([C:25](OCC)=[O:26])=[CH:16]2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1>C(O)C>[CH3:1][N:2]1[C:25](=[O:26])[C:17]2=[CH:16][N:15]([CH2:14][C:4]3[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[CH:7]=[CH:6][CH:5]=3)[CH:19]=[C:18]2[C:20](=[O:21])[NH:3]1
Reactant: CNN
Reactant: CCOC(=O)c1cn(Cc2cccc3ccccc23)cc1C(=O)OCC
Solvent: CCO
Product: Cn1[nH]c(=O)c2cn(Cc3cccc4ccccc34)cc2c1=O
Temperature: 200 °C

Procedure:
Methyl hydrazine (0.55 ml) was added to a solution of diethyl 1-(1-naphthalenylmethyl)pyrrole-3,4-dicarboxylate (1.00 g) in ethanol (10 ml). The mixture was heated at 200° C. in a sealed tube for 3 days. The mixture was evaporated and the residue was purified by column chromatography, eluting with ethyl acetate:methanol (19:1). The resulting solid was suspended in ethyl acetate (25 ml), heated to reflux, and allowed to cool to ambient temperature. The title compound (0.105 g) was collected by filtration.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:14]([O-])=O)=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:3]=1[NH2:14]
Reactant: Cc1cccc(-c2ccccc2)c1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(-c2ccccc2)c1N

Procedure:
During a 45 minute period 3-methyl-2-nitro-[1,1'-biphenyl] (25.4 g, 0.119 mole) was added portionwise at 30° to a stirred solution of stannous chloride (107.5 g, 0.476 mole) and 150 ml of concentrated hydrochloric acid in enough ethanol to produce a solution. After complete addition the mixture was heated at reflux for 17 hours. The mixture was cooled and made basic (pH 9-10) with 4N aqueous sodium hydroxide, producing a white precipitate. The precipitate was collected by filtration and partitioned between water and methylene chloride. The organic phase was separated, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated to give 3-methyl-[1,1'-biphenyl]-2-amine as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[C:15]#[N:16])[CH2:7][CH:6]3[CH2:21][O:22][CH2:23][CH2:24][N:5]3[C:4]=2[N:3]=1.S(=O)(=O)(O)[OH:26]>C(OCC)(=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[C:15]([NH2:16])=[O:26])[CH2:7][CH:6]3[CH2:21][O:22][CH2:23][CH2:24][N:5]3[C:4]=2[N:3]=1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccccc1CN1CC2COCCN2c2nc(Cl)ncc21
Solvent: CCOC(C)=O
Product: NC(=O)c1ccccc1CN1CC2COCCN2c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
2-((2-Chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)methyl)benzonitrile (PREPARATION x17, 140 mg, 0.410 mmol) was dissolved in concentrated sulfuric acid (1 mL) and was stirred overnight at room temperature. Following reaction, the mixture was diluted with ethyl acetate and was washed with aqueous saturated NaHCO3 (2×15 mL) and brine (2×5 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The product was purified by LC/MS using a gradient of 20-45% CH3CN (with 0.035% TFA) in H2O (with 0.05% TFA). The pure fractions were combined and lyophilized to afford the title compound as a white solid (147 mg, 99%). 1H NMR (400 MHz, DMSO-d6) δ 2.91-3.05 (m, 2 H), 3.10-3.19 (m, 1 H), 3.22-3.29 (m, 1 H), 3.44-3.49 (m, 1 H), 3.63-3.73 (m, 1 H), 3.81-3.99 (m, 2 H), 4.21-4.29 (m, 1 H), 4.36-4.61 (m, 2 H), 7.19-7.24 (m, 1 H), 7.30-7.50 (m, 5 H), 7.78-7.87 (m, 1 H). ESI-MS m/z [M+H]+ calc'd for C17H18ClN5O2, 360.11; found 360.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[CH2:21][CH2:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[S:23]([CH:22]=[CH2:21])(=[O:25])=[O:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
L-Proline t-butyl ester (6.9 g 0.04 mole) and triethylamine (14 ml, 0.1 mole) are dissolved in 200 ml of dichloromethane and stirred in an ice bath while 2-chloroethanesulfonyl chloride (8.2 g, 0.05 mole) in 100 ml of dichloromethane is added over 20 minutes. After stirring 2 hours, the mixture is washed with 5% potassium bisulfate solution, saturated sodium bicarbonate solution and brine, then evaporated in vacuo. The semi-solid residue is chromatographed on 350 ml. silica gel using 1:1 ethyl acetate/hexane as eluant. The main fraction, comprising N-(vinylsulfonyl)-L-proline t-butyl ester is crystallized from ether/hexane, m.p. 84°-87° (7.1 g, 68%).
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7](=[O:15])[CH2:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1.CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>>[CH3:18][N:19]([CH3:21])[CH:20]=[C:8]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[C:7]([C:6]1[CH:5]=[CH:4][O:3][C:2]=1[CH3:1])=[O:15]
Reactant: COC(OC)N(C)C
Reactant: Cc1occc1C(=O)Cc1cccnc1
Product: Cc1occc1C(=O)C(=CN(C)C)c1cccnc1
Temperature: 100 °C
Yield: 48.8 %

Procedure:
A mixture of 1-(2-methyl-3-furanyl)-2-(3-pyridinyl)ethanone (1207 mg, 6 mmol) in N,N-dimethylformamide dimethyl acetal (797 μl, 6.00 mmol) was heated at 100° C. for 2 hours. The mixture was cooled to room temperature and the solvent was evaporated. The residue was partitioned between ethyl acetate and water. The organic phase was separated, washed with water and brine, dried and evaporated to give the title compound as an orange oil (750 mg, 49%). LC/MS [M+H]+=257.