Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([F:18])=[CH:4][C:5]([F:17])=[C:6](/[C:8](=[N:10]/[S@@:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])/[CH3:9])[CH:7]=1.Br[C:20]([F:27])([F:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[CH2:24]([O:23][C:21](=[O:22])[C:20]([F:27])([F:26])[C@@:8]([C:6]1[CH:7]=[C:2]([Br:1])[C:3]([F:18])=[CH:4][C:5]=1[F:17])([NH:10][S@@:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])[CH3:9])[CH3:25]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: C/C(=N\[S@](=O)C(C)(C)C)c1cc(Br)c(F)cc1F
Product: CCOC(=O)C(F)(F)[C@](C)(N[S@](=O)C(C)(C)C)c1cc(Br)c(F)cc1F

Procedure:
Starting from (R)-2-methyl-propane-2-sulfinic acid [1-(5-bromo-2,4-difluoro-phenyl)-eth-(E)-ylidene]-amide (intermediate A2.2) and ethyl 2-bromo-2,2-difluoroacetate, the product (R)-3-(5-bromo-2,4-difluoro-phenyl)-2,2-difluoro-3-((R)-2-methyl-propane-2-sulfinylamino)-butyric acid ethyl ester was obtained as an orange oil. MS: m/z=462.1 [M+H]+ and 464.1 [M+2+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@@H:8]([CH3:13])/[C:9](/[NH2:12])=[N:10]/[OH:11])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23]>C(Cl)Cl>[C:22]([O:11]/[N:10]=[C:9](\[NH2:12])/[C@@H:8]([NH:7][C:6](=[O:14])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH3:13])(=[O:24])[CH3:23]
Reactant: C[C@H](NC(=O)OC(C)(C)C)/C(N)=N/O
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)O/N=C(\N)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
To a mixture of tert-butyl[(1S,2Z)-2-amino-2-(hydroxyimino)-1-methylethyl]carbamate (Step 3, 100 mg, 0.5 mmol) in methylene chloride (2 mL) cooled at 0° C. was added triethylamine (0.10 mL, 0.74 mmol). To the mixture was then added acetyl chloride (42 mg, 0.54 mmol) dropwise and the reaction was warmed to room temperature. After stirring at room temperature for 1 h, the reaction was concentrated. The residue was dissolved in dichloromethane (DCM), washed with water and brine, dried over MgSO4, filtered and concentrated to afford the desired crude product (100 mg, 82.8%) which was directly used in the next step reaction without further purification. 1H-NMR (300 MHz, DMSO-d6): 6.90 (d, J=9.0 Hz, 1H), 6.22 (s, 2H), 4.05 (m, 1H), 2.01 (s, 3H), 1.36 (s, 9H), 1.20 (d, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:8][CH:9]=1)(=O)[CH3:2].C([O-])(=O)C.[Na+].[Cl-].[OH:22][NH3+:23]>C(O)C.O>[OH:22][N:23]=[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:8][CH:9]=1)[CH3:2]
Reactant: [NH3+]O
Reactant: COC(=O)COc1ccc(C(C)=O)cn1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)COc1ccc(C(C)=NO)cn1
Yield: 43.8 %

Procedure:
To a solution of methyl 2-((5-acetylpyridin-2-yl)oxy)acetate (1.23 gm, 0.059 mole) in ethanol (10 mL), a solution of sodium acetate (0.942 gm, 0.0117 mole) and hydroxylammonium chloride (1.2 gm, 0.0117 mole) in water (5 ml) was added and the reaction mixture was refluxed for 1 h. The reaction mixture was coiled to room temperature and solvent was evapourated in vacuum. The residue was diluted with ice cold water and solid seperated was filtered, washed with water and dried over P2O5 under vacuum to yield 1.15 gm (88%) of title product as off white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+:20]>>[OH:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1.[Na+:20]
Reactant: CC(C(=O)O)c1ccc(-c2ccccc2)c(O)c1
Agent: [Na+]
Agent: [OH-]
Product: CC(C(=O)[O-])c1ccc(-c2ccccc2)c(O)c1

Procedure:
2-(2-hydroxy-4-biphenylyl)propionic acid was mixed with an equivalent amount of aqueous sodium hydroxide. The mixture was evaporated to dryness to give sodium 2-(2-hydroxy-4-biphenylyl)propionate, 230 (decomposed)° C.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:13][C:12]3[C:7](=[C:8]([CH3:21])[CH:9]=[C:10]([CH2:14][CH:15]4[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]4)[CH:11]=3)[C:6]2=[O:22])[CH2:3][CH2:2]1.[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[CH:1]1([CH2:4][N:5]2[CH2:13][C:12]3[C:7](=[C:8]([CH3:21])[CH:9]=[C:10]([CH2:14][CH:15]4[CH2:20][CH2:19][N:18]([CH2:27][C:26]5[CH:29]=[CH:30][CH:31]=[C:24]([F:23])[CH:25]=5)[CH2:17][CH2:16]4)[CH:11]=3)[C:6]2=[O:22])[CH2:2][CH2:3]1
Reactant: O=Cc1cccc(F)c1
Reactant: Cc1cc(CC2CCNCC2)cc2c1C(=O)N(CC1CC1)C2
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(CC2CCN(Cc3cccc(F)c3)CC2)cc2c1C(=O)N(CC1CC1)C2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-Cyclopropylmethyl-7-methyl-5-piperidin-4-ylmethyl-2,3-dihydro-isoindol-1-one (30 mg, 0.110 mmol) in methanol (2 mL) was slowly added acetic acid (1 mL). After stirring at room temperature for 5 minutes, 3-Fluoro-benzaldehyde (12.8 μL, 0.121 mmol) and sodium cyanoborohydride (8 μL, 0.111 mmol) were added dropwisely. The mixture stirred at room temperature for 2 hours and was neutralized with saturated sodium bicarbonate (10 mL). The aqueous mixture was extracted with dichloromethane and the organics were dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (10-40% ethyl acetate in hexanes) provided the title compound as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.70-7.23 (m, 1H), 7.09-7.03 (m, 3H), 6.97-6.92 (m, 2H), 4.41 (s, 2H), 3.48-3.44 (m, 4H), 2.88-2.85 (d, 2H), 2.71 (s, 3M), 2.60-2.57 (d, 2H), 1.93 (t, 2H), 1.64-1.50 (m, 3H), 1.36-1.28 (m, 2H), 1.04 (m, 1H), 0.60-0.55 (m, 2H), 0.34-0.32 (m, 2H)
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[C:3]=1[S:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:17][CH:16]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:41]2)=CC=1>O1CCOCC1>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[C:3]=1[S:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[S:41])[NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:17][CH:16]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(NCc1ccc(F)cc1)c1ccc(CSc2c(Cl)ccc3c2CCNCC3)cc1
Solvent: C1COCCO1
Product: Fc1ccc(CNC(=S)c2ccc(CSc3c(Cl)ccc4c3CCNCC4)cc2)cc1
Temperature: 25 °C

Procedure:
Combine 7-chloro-6-[4-(4-fluorobenzylcarbamoyl)-benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine (23 mg, 0.05 mmol) with 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's reagent) (23 mg, 0.05 mmol) in anhydrous 1,4-dioxane (1 mL) in a sealed tube and heat at 100° C. for 2 h Cool the reaction mixture to room temperature, concentrate in vacuo and purify the residue by SCX chromatography to obtain 7-chloro-6-[4-(4-fluorobenzylthiocarbamoyl)-benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:13])=[CH:4][C:5](F)=[C:6]([NH:8][C:9]([NH2:11])=[S:10])[CH:7]=1.[H-].[Na+]>CN1C(=O)CCC1>[Br:1][C:2]1[C:3]([F:13])=[CH:4][C:5]2[S:10][C:9]([NH2:11])=[N:8][C:6]=2[CH:7]=1
Reactant: NC(=S)Nc1cc(Br)c(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Nc1nc2cc(Br)c(F)cc2s1
Temperature: 130 °C
Yield: 52 %

Procedure:
To a solution of (5-Bromo-2,4-difluoro-phenyl)-thiourea (0.75 g, 2.80 mmol) in NMP (5.0 mL) was added NaH (0.17 g, 4.21 mmol, 60% dispersion in oil) portion wise. The reaction mixture was then heated at 130° C. for 2 h. The reaction mixture was then poured onto crushed ice and extracted with EtOAc (3×50 mL). The combined organics was evaporated to get the crude residue that was purified over silica gel (100-200 M, 12% EtOAc-Hexane) to obtain the desired compound (0.36 g, 52%). 1H-NMR (400 MHz, DMSO-d6): δ 7.57 (d, J=6.40 Hz, 1H), 7.66 (br s, 2H) and 7.79 (d, 8.80 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[O:11][CH3:12].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20].[Al+3].[Cl-].[Cl-].[Cl-].Cl>C(Cl)Cl>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([C:7]1[CH:8]=[C:3]([O:2][CH3:1])[C:4]([O:11][CH3:12])=[CH:5][C:6]=1[O:9][CH3:10])=[O:20]
Reactant: O=C(Cl)CCCCCBr
Reactant: COc1ccc(OC)c(OC)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(OC)c(C(=O)CCCCCBr)cc1OC
Temperature: -10 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
6 ml (40 mmol) of 1,2,4-trimethoxybenzene are introduced into 80 ml of dry CH2Cl2 and the mixture is cooled to −10° C. with stirring. 6-Bromohexanoyl chloride (6.2 ml, 40 mmol) dissolved in 20 ml of CH2Cl2 is then added dropwise. AlCl3 (5.6 g, 42 mmol) is progressively introduced in small portions into the reaction mixture. The reaction is maintained with stirring for 8 h with a return to ambient temperature. The reaction mixture is then poured onto ice (200 ml) and acidified to pH 1 using HCl. The mixture is stirred until it returns to ambient temperature, 1 h. After evaporation of the CH2Cl2, the mixture is extracted with AcOEt, and the organic phases are separated, dried over MgSO4, filtered and evaporated. The residue is subjected to flash chromatography over SiO2 with a gradient of pure heptane to heptane-AcOEt 50-50. The pure fractions are evaporated to obtain 13.6 g (yield=99%) of crystals. TLC SiO2 (heptane-ACOEt 70-30) Rf=0.5; 1H NMR (CDCl3): 7.41 (s, 1H), 6.50 (s, 1H), 3.95 (s, 3H), 3.91 (s, 3H), 3.87 (s, 3H), 3.43 (t, 2H, J=6.76 Hz), 2.98 (t, 2H, J=6.32 Hz), 1.91 (m, 2H), 1.71 (m, 2H), 1.51 (m, 2H).
Reaction SMILES: Cl[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[O:3].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH3:44])[CH:37]=[C:38]([O:42]C)[C:39]=1[O:40][CH3:41].Cl>ClCCCl>[OH:42][C:38]1[C:39]([O:40][CH3:41])=[C:34]([O:33][CH3:32])[CH:35]=[C:36]([CH3:44])[C:37]=1[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[O:3]
Reactant: COc1cc(C)cc(OC)c1OC
Reactant: COC(=O)CCCCCCCCCCCCCCCCCCCCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COC(=O)CCCCCCCCCCCCCCCCCCCCC(=O)c1c(C)cc(OC)c(OC)c1O
Temperature: 0 °C

Procedure:
In 60 ml of 1,2-dichloroethane is dissolved 8 g of methyl 21-chloroformylheneicosanoate, followed by addition of 5.5 g of aluminum chloride. The mixture is stirred. Then, under ice-cooling and stirring in a nitrogen stream, a solution of 5.67 g of 3,4,5-trimethoxytoluene in 1,2-dichloroethane (13 ml) is added dropwise. The mixture is stirred for 48 hours, after which 1.3 g of aluminum chloride is added. The mixture is stirred at room temperature for 16 hours and further at 35° C.-38° C. for 40 minutes. To this reaction mixture are added ice-water and 3N-HCl, followed by extraction with chloroform. The extract is washed with water, a saturated aqueous solution of sodium hydrogen carbonate and water in that order. After drying, the solvent is distilled off under reduced pressure and the residue is chromatographed on silica gel. The fractions containing the desired compound are pooled and recrystallized from methanol. The above procedure yields methyl 21-(2-hydroxy-3,4-dimethoxy-6-methylbenzoyl)heneicosanoate as colorless needles. m.p. 73°-74° C. NMR(δ, in deuteriochloroform): 1.24(36H, b, CH2), 2.27(2H,t,CH2COO), 2.42(3H, s, nuclear CH3), 2.86(2H, t,COCH2), 3.64(3H,s,COOCH3), 3.84(3H,s,OCH3), 3.87(3H,s,OCH3), 6.22(1H,s,nuclear H).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[CH2:7]([O:9][C:10]([C@@H:12]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:13][C@H:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15](O)=[O:16])=[O:11])[CH3:8]>C(Cl)Cl>[CH2:7]([O:9][C:10]([C@@H:12]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:13][C@H:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15]([Cl:4])=[O:16])=[O:11])[CH3:8]
Reactant: CCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The starting material is prepared as follows: 4.0 g of trans-2,4-dibenzyl glutaric anhydride is refluxed in 40 ml of ethanol:toluene (3:2) overnight. The reaction mixture is concentrated to yield 4-ethoxycarbonyl-(R*,R*) -2,4-dibenzylbutyric acid as an oil. Oxalyl chloride (3.5 ml) is added to the solution of 4.5 g of 4-ethoxycarbonyl-(R*,R*)-2,4-dibenzylbutyric acid in 10 ml of methylene chloride. The mixture is stirred at room temperature overnight and evaporated to yield 4-ethoxycarbonyl-(R*,R*)-2,4-dibenzylbutyryl chloride, which is used as such without further purification.
Reaction SMILES: [C:1]([NH:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11]([CH3:16])[CH:10]=[C:9]([CH3:17])[N:8]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[H-].[Na+].CS(O[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:36]([CH3:37])=[CH:35][CH:34]=[C:33]2[C:38]#[N:39])=[CH:28][CH:27]=1)(=O)=O>CN(C)C=O>[C:1]([N:6]([C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11]([CH3:16])[CH:10]=[C:9]([CH3:17])[N:8]=1)[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:36]([CH3:37])=[CH:35][CH:34]=[C:33]2[C:38]#[N:39])=[CH:28][CH:27]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Nc1nc(C)cc(C)c1[N+](=O)[O-]
Reactant: Cc1ccc(C#N)n1-c1ccc(COS(C)(=O)=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC(=O)N(Cc1ccc(-n2c(C)ccc2C#N)cc1)c1nc(C)cc(C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.7 %

Procedure:
To a solution of 2-butyrylamino-4,6-dimethyl-3-nitropyridine (2.49 g) in dimethylformamide (12.5 ml) was added sodium hydride (441 mg) in an ice-water bath. The mixture was stirred at room temperature for an hour, and a solution of 1-(4-methanesulfonyloxymethylphenyl)-5-methylpyrrole-2-carbonitrile (3.05 g) in dimethylformamide (15 ml) was dropwise therein. The reaction mixture was stirred at room temperature for 5.5 hours and was stood overnight. The separated oil was extracted with ethyl acetate. The extract were washed with brine, dried, and concentrated in vacuo. The residue was purified by flash column chromatography eluted by n-hexane/ethyl acetate (1/1) to give 2-[N-butyryl-N-[4-(2-cyano-5-methyl-1-pyrrolyl)benzyl]amino]-4,6-dimethyl-3-nitropyridine (2.75 g) as oil.
Reaction SMILES: O[C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>>[NH:15]([C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1cc2ccccc2cc1O
Agent: Cl
Product: O=C(O)c1cc2ccccc2cc1Nc1ccccc1
Temperature: 170 °C
Reaction time: 16 h
Yield: 6.8 %

Procedure:
A mixture of 3-hydroxy-2-naphthoic acid (Aldrich cat. # H4600-7) (376 g, 2.0 mol) and aniline (376 ml, 4.1 mol) was heated at 170° C. with stirring under nitrogen for 16 hours. The resulting mixture, when hot, was poured into 1N HCl (2.5 ml), heated to 100° C., and stirred at this temperature for 5 minutes. The mixture, when hot, was filtrated and the solid was washed with 0.2N HCl (600 ml). The wet material was boiled and mechanically stirred with 0.5N sodium carbonate solution (6.0 ml) for 10 minutes, cooled and filtered. The reddish filtrate was treated dropwise with 5N HCl with stirring to ~pH 7. The resulting yellow precipitate was collected, washed with small amount of water and crystallized from ethanol (400 ml) to give 3-anilino-2-naphthoic acid (36 g, 7%). Rf 0.6 (silica gel, EM Art. 5715, 20% methanol/chloroform). MS (EI): m/z 264 (M).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([C:25]([OH:28])([CH3:27])[CH3:26])=[CH:6][CH:5]=1.[CH3:29]I>CN(C)C=O.O>[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([C:25]([O:28][CH3:29])([CH3:26])[CH3:27])=[CH:6][CH:5]=1
Reactant: CC(C)(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(C)(C)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reaction time: 0.08 h
Yield: 85.8 %

Procedure:
Sodium hydride (60% in oil, 17.5 mg, 0.438 mmol) was added to a stirred solution of 2-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-2-ol (150 mg, 0.365 mmol) in N,N-dimethylformamide (1.5 mL) at room temperature. After stirring 5 min, methyl iodide (77.7 mg, 0.548 mmol) was added to the mixture, and the mixture was stirred at room temperature for 4 hr. The mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-40% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/diisopropyl ether to give the title compound as a colorless crystal (133 mg, 0.313 mmol, 86%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[S:9][C:8]([OH:10])=[N:7][C:6]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=O.[NH2:16][C:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=1>COCCOC>[CH2:14]([O:13][C:11]([C:6]1[N:7]=[C:8]([OH:10])[S:9][C:5]=1[C:3]1[N:16]=[C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]2[CH:2]=1)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1nc(O)sc1C(=O)CBr
Reactant: Cc1cccnc1N
Solvent: COCCOC
Product: CCOC(=O)c1nc(O)sc1-c1cn2cccc(C)c2n1
Yield: 58 %

Procedure:
A solution of ethyl 5-(2-bromoacetyl)-2-hydroxy-4-thiazolecarboxylate (2.94 g) and 2-amino-3-methylpyridine (3.24 g) in 1,2-dimethoxyethane (100 ml) was refluxed for 1.5 hours. The reaction mixture was evaporated in vacuo. To the residue was added a mixture of ethyl acetate and water, and the resulting mixture was acidified to pH 0.8 with 10% hydrochloric acid. The separated aqueous layer was adjusted to pH 7.5 with 20% potassium carbonate and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was triturated with diethyl ether and recrystallized from a mixture of ethyl acetate and tetrahydrofuran to give 2-(4-ethoxycarbonyl-2-hydroxy-5-thiazolyl)-8-methylimidazo[1,2-a]pyridine (1.76 g). mp 240°-242° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]=1[CH:20]([CH2:25][CH2:26][CH3:27])[C:21]([O:23]C)=[O:22].[O-2].[Li+].[Li+].Cl>O1CCOCC1.O>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:3]=1[CH:20]([CH2:25][CH2:26][CH3:27])[C:21]([OH:23])=[O:22]
Reactant: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccccc1)CCC3
Agent: Cl
Agent: [Li+]
Agent: [O-2]
Solvent: O
Solvent: C1COCCO1
Product: CCCC(C(=O)O)c1c(C)nc2sc3c(c2c1-c1ccccc1)CCC3
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 47.8 %

Procedure:
To a solution of methyl [2-methyl-4-phenyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate (0.111 g; 0.292 mmol) in dioxane (4 mL) and water (1 mL) was added a 1N lithium oxide solution (1.8 mL; 1.80 mmol). The reaction mixture was heated at 60° C. for 3 h and 1N lithium oxide solution (0.9 mL; 0.90 mmol) was added again. After 2.5 h at 60° C., the reaction mixture was acidified with 1N HCl (pH˜2) and partially concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate/heptane to afford 0.051 g (48%) of the title compound as a white powder.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH:22]=O)=[CH:14][CH:13]=2)[CH2:4][CH2:3]1.[CH3:24][C:25]1[CH:26]=[C:27]([NH2:32])[C:28]([NH2:31])=[CH:29][CH:30]=1>>[CH3:24][C:25]1[CH:30]=[CH:29][C:28]2[NH:31][C:22]([C:15]3[C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:12]([O:11][CH2:10][CH2:9][CH2:8][N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:13][CH:14]=3)=[N:32][C:27]=2[CH:26]=1
Reactant: Cc1ccc(N)c(N)c1
Reactant: CN1CCN(CCCOc2ccc(C=O)c3ccccc23)CC1
Product: Cc1ccc2[nH]c(-c3ccc(OCCCN4CCN(C)CC4)c4ccccc34)nc2c1

Procedure:
This compound was prepared by the method described in Example 1, using 4-[3-(4-methyl-piperazin-1-yl)-propoxy]-naphthalene-1-carbaldehyde (63 mg, 0.20 mmol, 1.0 equiv), 4-methyl-benzene-1,2-diamine (24 mg, 0.20 mmol, 1.0 equiv), and Na2S2O5 (49 mg, 0.26 mmol, 1.3 equiv) in General Procedure 3. The desired product was isolated from the reaction mixture using Method 1 and was subsequently re-purified by Method 2 to afford 54.6 mg (66%) of the title compound. MS (electrospray): mass calculated for C26H30N4O, 414.24; m/z found, 415.62 [M+H]+. 1H NMR (400 MHz, CD3OD): 8.48 (d, J=8.0 Hz, 1H), 8.10 (d, J=8.4 Hz, 1H), 8.0 (d, J=8.2 Hz, 1H), 7.78-7.65 (m, 4H), 7.50 (d, J=8.4 Hz, 1H), 7.21 (d, J=8.2 Hz, 1H), 4.43 (t, J=6.0 Hz, 2H), 3.40 (br s, 4H), 3.30-3.00 (m, 6H), 2.88 (s, 3H), 2.59 (s, 3H), 2.36-2.30 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]#[N:9])=[C:5]([NH2:7])[N:6]=1.CN(C)C=O.[SH2:15]>C(N(CC)CC)C>[CH3:1][C:2]1[S:3][C:4]([C:8](=[S:15])[NH2:9])=[C:5]([NH2:7])[N:6]=1
Reactant: Cc1nc(N)c(C#N)s1
Reactant: S
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(N)c(C(N)=S)s1
Yield: 58 %

Procedure:
5.5 parts of 2-methyl-4-amino-5-cyano-thiazole in 50 parts of dimethylformamide and 10 parts of triethylamine are reacted with 3 parts of hydrogen sulfide as described in Example 1(a). 4.0 parts of 2-methyl-4-amino-5-thiocarbamoylthiazole (58% of theory) of melting point 209°-213° C. are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([CH3:14])[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]([N:17]1[C:29]2[CH:28]=[CH:27][C:26]([CH2:30][NH2:31])=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH3:16]>>[CH2:15]([N:17]1[C:29]2[CH:28]=[CH:27][C:26]([CH2:30][NH:31][C:11](=[O:13])[CH:10]([CH3:14])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH3:16]
Reactant: CCn1c2ccccc2c2cc(CN)ccc21
Reactant: CC(CNC(=O)OC(C)(C)C)C(=O)O
Product: CCn1c2ccccc2c2cc(CNC(=O)C(C)CNC(=O)OC(C)(C)C)ccc21

Procedure:
Using 3-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid and (9-ethyl-9H-carbazol-3-yl)methanamine, and by the reaction and purification in the same manner as in the method described in Step 1 of Example 36, tert-butyl (3-(((9-ethyl-9H-carbazol-3-yl)methyl)amino)-2-methyl-3-oxopropyl)carbamate was obtained.