Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.Cl.[NH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:27])([CH3:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)c1ccc(CCN)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)C(C)(C)c1ccc(CCNC(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 68 %

Procedure:
9.6 g. 4-Chlorobenzoyl chloride are added dropwise to a solution of 14.1 g ethyl 2-[4-(2-aminoethyl)-phenyl]-2-methylpropionate hydrochloride in 90 ml anhydrous pyridine at 5°-10° C. The reaction mixture is kept at 10° C. for 90 minutes, then allowed to warm up to ambient temperature and subsequently heated to 45° C. for 10 minutes. A part thereof remains undissolved. The reaction mixture is stirred into 750 ml. ice water, filtered with suction and the filter cake then washed. There are obtained 13.2 g (68% of theory) ethyl 2-{4-[2-(4-chlorobenzamido)-ethyl]-phenyl}-2-methylpropionate which, after recrystallization from isopropanol, melts at 108°-109° C.
Reaction SMILES: [H-].[Na+].C([O:5][CH2:6][CH3:7])=O.[C:8]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:23])=[C:16]2[C:21]=1[C:20](=[O:22])C[CH2:18][CH2:17]2)(=[O:10])[CH3:9].[Cl-].[Na+]>C(COC)OC.C(O)C>[C:8]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:23])=[C:16]2[C:21]=1[C:20](=[O:22])[C:7](=[CH:6][OH:5])[CH2:18][CH2:17]2)(=[O:10])[CH3:9]
Reactant: CC(=O)Nc1ccc(Cl)c2c1C(=O)CCC2
Reactant: CCOC=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CC(=O)Nc1ccc(Cl)c2c1C(=O)C(=CO)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
960 mg of 60% aqueous solution of sodium hydride was added to 8 ml of ethyl formate under ice-cooling, and 5 minutes after the mixture was cooled to room temperature, a solution of 1.43 gm of 8-acetylamino-5-chloro-1-tetralone dissolved in 30 ml of dimethoxyethane was slowly added. After the addition of 0.06 ml of ethanol, the mixture was stirred for 30 minutes. The reaction mixture was poured into 300 ml of 14% aqueous solution of sodium chloride, extracted with ethyl acetate, washed with 10% aqueous solution of citric acid and saturated brine, and dried over anhydrous sodium sulfate. After concentration, ether was added to the residue to collect the precipitate of 1.30 gm of the title compound the by filtration.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:29](Cl)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C@@H:19]([NH:21][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: C[C@H](N)[C@@H](Cc1ccccc1)Oc1ccc2c(cnn2-c2ccc(F)cc2)c1
Product: C[C@H](NC(=O)C(C)(C)C)[C@@H](Cc1ccccc1)Oc1ccc2c(cnn2-c2ccc(F)cc2)c1

Procedure:
Prepared as described in Example 1 using (2S,3R)-3-[1-(4-fluorophenyl)indazol-5-yl]oxy-4-phenyl-butan-2-amine (60 mg, 0.16 mmol) and pivaloyl chloride (0.078 mL, 0.64 mmol). Yield 53 mg (72%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=[O:6].Cl[CH2:12][C:13]([O:15][CH3:16])=[O:14].C[O-].[Na+].CO>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:6][CH:12]2[C:13]([O:15][CH3:16])=[O:14])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: COC(=O)CCl
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1OC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3,4-dichlorobenzaldehyde (51.0 g) and methyl chloroacetate (51 mL) in methanol (500 mL) was added 28% sodium methoxide/methanol (68 mL) solution under ice-cooling, and the mixture was stirred at room temperature overnight. The resultant product was collected by filtration, and washed with distilled water to give the title compound (90.9 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][C:8]([O:10]CC)=[O:9])=[CH:5][C:4]2[O:13][CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17](=[O:18])[C:3]1=2.[OH-].[Na+].Cl>C(O)C.O>[CH3:1][N:2]1[C:6]([CH2:7][C:8]([OH:10])=[O:9])=[CH:5][C:4]2[O:13][CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17](=[O:18])[C:3]1=2
Reactant: CCOC(=O)Cc1cc2c(n1C)C(=O)c1ccccc1CO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1c(CC(=O)O)cc2c1C(=O)c1ccccc1CO2
Yield: 57 %

Procedure:
Ethyl 5,10-dihydro-1-methyl-10-oxo-1H-[2]benzoxepino[4,3-b]pyrrole-2-acetate (196 mg, 0.66 mmol) is dissolved in ethanol and 2.5 N aqueous sodium hydroxide (2 ml, 5 mmol) is added dropwise at reflux under nitrogen. The reaction is heated for an additional ten minutes, then the solution is cooled and diluted with water (5 ml). The resulting mixture is acidified with 2.5 N aqueous HCl (3 ml). The product separates as an oil, then solidifies on scratching. The solid is filtered, washed with water and dried to give 160 ml crude product. The product is recrystallized from ethanol to give 102 mg of 5,10-dihydro-1-methyl-10-oxo-1H-[2]benzoxepino[4,3-b]pyrrole-2-acetic acid, M.P. 114°-116° (dec).
Reaction SMILES: [CH3:1][CH:2]1[C:7](=O)[CH:6]2[CH2:9][CH2:10][N:3]1[CH2:4][CH2:5]2.[CH3:11][O:12][C:13]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:14]=1[CH2:15][NH2:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[CH3:11][O:12][C:13]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:14]=1[CH2:15][NH:16][CH:7]1[CH:6]2[CH2:9][CH2:10][N:3]([CH2:4][CH2:5]2)[CH:2]1[CH3:1]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: CC1C(=O)C2CCN1CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ccc(CNC2C3CCN(CC3)C2C)c(OC)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2-Methyl-1-aza-bicyclo[2.2.2]octan-3-one (500 mg, 3.59 mmol) and 2,4-dimethoxybenzyl amine (1.2 g, 7.18 mmol) were dissolved in anhydrous 1,2-dichloroethane (10 ml). Sodium triacetoxyborohydride (1.1 g, 5.0 mmol) followed by glacial acetic acid (0.21 ml, 3.59 mmol) and the resultant foamy suspension was stirred at ambient temperature for 12 hours. The reaction was quenched by the addition of 1M NaOH, and the layers were separated. The aqueous phase was extracted further with ethyl acetate. The organic portions were combined, dried (Na2SO4), filtered and concentrated in vacuo. The crude reaction mixture was purified by chromatography [eluent gradient: 10-30% MeOH/Et3N (9:1) in EtOAc) to give pure (2,4-dimethoxy-benzyl)-(2-methyl-1-aza-bicyclo[2.2.2]oct-3-yl)-amine.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1/[CH:13]=[CH:14]/[C:15]1[O:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1.[CH2:24]([NH:27][CH2:28][CH2:29][CH3:30])[CH2:25][CH3:26].Cl>>[CH2:24]([N:27]([CH2:28][CH2:29][CH3:30])[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1/[CH:13]=[CH:14]/[C:15]1[O:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1)[CH2:25][CH3:26]
Reactant: CCCNCCC
Reactant: ClCCCCOc1ccccc1/C=C/c1nc2ccccc2o1
Agent: Cl
Product: CCCN(CCC)CCCCOc1ccccc1/C=C/c1nc2ccccc2o1
Yield: 30 %

Procedure:
The procedure of Example 18 was followed starting with (D) of Example 18 (2.5 g, 7.6 mmol) and using dipropylamine in place of dibutylamine to produce 0.90 g (30% yield) of the named compound as the HCl salt, mp 150°-152° C. IR(KBR): 1600 cm-1. MS: 393(MH+). 1H NMR (CDCl3): δ 8.09-6.87 (m, 10H), 4.01 (t, J=5.4 Hz, 2H), 3.02 (m, 6H), 1.95 (m, 8H), 0.99 (m, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([C:15]1([CH2:30][CH3:31])[CH2:20][CH2:19][C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][CH2:16]1)[CH3:14].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH2:13]([C:15]1([CH2:30][CH3:31])[CH2:20][CH2:19][C:18]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])=[CH:17][CH2:16]1)[CH3:14]
Reactant: CCC1(CC)CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COc1ccc(Br)c([N+](=O)[O-])c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CCC1(CC)CC=C(c2ccc(OC)cc2[N+](=O)[O-])CC1
Temperature: 25 °C

Procedure:
A mixture of 4-bromo-3-nitroanisole (2 g, 8.62 mmol), 2-(4,4-diethylcyclohex-1-enyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (2.7 g, 10.3 mmol) prepared in Example (6c), tripotassium phosphate (2.7 g, 13.0 mmol) and 1,2-dimethoxyethane (20 mL) was stirred at room temperature under a nitrogen atmosphere, and then tetrakis(triphenylphosphine)palladium(0) (0.5 g, 0.43 mmol) was added. The mixture was then stirred at an external temperature of 80° C. for 26 hours.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[C:22]2[N:26]([C@H:27]3[CH2:31][CH2:30][NH:29][CH2:28]3)[CH:25]=[N:24][N:23]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:32][C:33]([CH3:35])=O.[BH3-]C#N.[Na+]>CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[C:22]2[N:26]([C@H:27]3[CH2:31][CH2:30][N:29]([CH:33]([CH3:35])[CH3:32])[CH2:28]3)[CH:25]=[N:24][N:23]=2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-c2nncn2[C@H]2CCNC2)cc1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)N1CC[C@H](n2cnnc2-c2cc(Cl)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled solution of 4-tert-butyl-N-[4-chloro-2-((S)-4-pyrrolidin-3-yl-4H-[1,2,4]triazol-3-yl)-phenyl]-benzenesulfonamide (200 mg, 0.43 mmol) in MeOH (5 MI) was added acetone (0.048 mL, 0.65 mmol) and then NaCNBH3 (0.054 g, 0.86 mmol). The reaction mixture was stirred at room temperature for 2 h, evaporated to dryness, adsorbed onto silica gel, and purified by automated normal-phase chromatography (50% MeOH in EtOAc) and then preparative HPLC (20→95% CH3CN in H2O with 0.1% TFA). The pure fractions were combined and lyophilized to obtain title compound as a powder: MS (ES) M+H expected 502.0, found 502.1.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[S:14])[CH:5]=[C:6]([CH3:13])[O:7]2.C(=O)([O-])[O-].[K+].[K+].[CH:21](I)([CH3:23])[CH3:22].CN(C=O)C>O>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH:21]([CH3:23])[CH3:22])[CH:9]=[C:8]2[C:3]=1[C:4](=[S:14])[CH:5]=[C:6]([CH3:13])[O:7]2
Reactant: CC(C)I
Reactant: Cc1cc(=S)c2c(O)cc(O)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(=S)c2c(O)cc(OC(C)C)cc2o1
Yield: 88.3 %

Procedure:
6.88 g of 5,7-dihydroxy-2-methylthiochromone (30.35 mmol), 12.56 g of potassium carbonate (91.05 mmol), 6.07 ml of isopropyl iodide (60.70 mmol) and 150 ml DMF were stirred at 60° C. for 30 minutes. After addition of water, the reaction solution was extracted twice with ethyl acetate, and the organic layer was washed with saturated NaCl water and was then dried over sodium sulfate anhydride. The solvent was distilled off under reduced pressure, and the crude product was purified by flash column chromatography (hexane : ethyl acetate=4 : 1), to give 6.71 g of 5-hydroxy-7-isopropoxy-2-methylthiochromone (83% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]([NH:19][C:20](=[O:29])[C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])=[O:18])[CH:5]=[C:6]([Cl:15])[C:7]=1[O:8][C:9]([F:14])([F:13])[CH:10]([Cl:12])[Cl:11].[OH-].[K+].I[CH3:33]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]([N:19]([CH3:33])[C:20](=[O:29])[C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])=[O:18])[CH:5]=[C:6]([Cl:15])[C:7]=1[O:8][C:9]([F:13])([F:14])[CH:10]([Cl:11])[Cl:12]
Reactant: O=C(NC(=O)c1c(F)cccc1F)Nc1cc(Cl)c(OC(F)(F)C(Cl)Cl)c(Cl)c1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CN(C(=O)Nc1cc(Cl)c(OC(F)(F)C(Cl)Cl)c(Cl)c1)C(=O)c1c(F)cccc1F

Procedure:
N-(((3,5-Dichloro-4-(2,2-dichloro-1,1-difluoroethoxy)phenyl)amino)carbonyl)-2,6-difluorobenzamide (9.9 g, 0.02 mole) and KOH (1.4 g, 87 percent purity, 0.02 mole) were added to 50 ml dimethylformamide with stirring, giving a clear solution. Iodomethane (3.2 g, 0.022 mole) was added and the resulting solution was stirred at room temperature for about 24 hours. The precipitated product was collected by suction filtration and dried. The product was purified by recrystallization from isopropanol. The purified product was a white solid melting at 153°-155° C. NMR spectral features support the structural assignment.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:36])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=5)=[CH:25][C:24]=4[F:35])[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[F:35][C:24]1[CH:25]=[C:26]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH:27]=[CH:28][C:23]=1[C:20]1([C:17]2[N:13]3[CH2:14][CH2:15][S:16][C:10]([CH2:9][OH:8])([CH3:36])[CH2:11][C:12]3=[N:19][N:18]=2)[CH2:22][CH2:21]1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5cccnc5)cc4F)CC3)n2CCS1
Agent: Cl
Solvent: CO
Product: CC1(CO)Cc2nnc(C3(c4ccc(-c5cccnc5)cc4F)CC3)n2CCS1
Yield: 55.1 %

Procedure:
A solution of the compound (517 mg, 1.0 mmol) obtained in Example 15-1) and 4 M hydrochloric acid (1,4-dioxane solution, 2 mL) in methanol (2 mL) was stirred at room temperature for 15 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (226 mg, 84%) as a colorless solid.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29]>>[C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:28]([O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:29])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CSc1nc(-c2cccc(N)c2)c2c(N)c(C(=O)NC(C)(C)C)sc2n1
Reactant: O=C(Cl)Oc1ccccc1
Product: CSc1nc(-c2cccc(NC(=O)Oc3ccccc3)c2)c2c(N)c(C(=O)NC(C)(C)C)sc2n1
Reaction time: 0.5 h

Procedure:
The reaction of tert-butyl 5-amino-2-methylthio-4-(3-aminophenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 9e, 100 mg) with phenyl chloroformate (324 μl) was performed using the methods described in example 15. The title compound was purified by HPLC using a Luna C-18 column with the following gradient: CH3CN/10% aq. CH3CN=10/90 to 90/10 (v/v) in 30 min. The title compound was then lyophilized from a mixture of 1,4-dioxane and H2O.
Reaction SMILES: [C:1]([OH:8])(=O)/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].Br[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.O>O1CCCC1>[C:18]1([C:1](=[O:8])[CH:2]=[CH:3][C:4]([OH:6])=[O:5])[C:19]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)/C=C\C(=O)O
Reactant: Brc1cccc2ccccc12
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C=CC(=O)c1cccc2ccccc12
Temperature: 78 °C
Reaction time: 0.08 h
Yield: 30 %

Procedure:
5.88 g(60 mmol) of dry maleic acid was dissolved in 100 ml of dry tetrahydrofuran and the mixture was cooled down to 78° C. 4.14 g(20 mmol) of 1-bromonaphthalene was dissolved in 100 ml of dry tetrahydrofuran and 13.8 ml of 1.6N n-butyllithium-hexane solution was added thereto at 78° C. This reaction solution was stirred for 5 minutes and then it was added to the dry maleic acid solution prepared in advance using cannula. The resulting mixture was stirred for 10 minutes, and water was added thereto to stop the reaction. The solvent was removed under reduced pressure, and the residue was acidified by 1N aqueous hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with water and aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and subjected to column chromatography(eluent: ethyl acetate/hexane=2/1, v/v) to give 1.35 g(6.0 mmol; Yield 30%) of the title compound.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]CC)=O)=[CH:15][CH:14]=1.[NH2:35][C:36]1[NH:37][CH2:38][CH2:39][CH2:40][N:41]=1>C(Cl)Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH2:22][C:23](=[O:25])[NH:35][C:36]2[NH:41][CH2:40][CH2:39][CH2:38][N:37]=2)=[CH:17][CH:18]=1
Reactant: CCOC(=O)CCCOc1ccc(C[C@H](Nc2nc3ccccc3s2)C(=O)OC(C)(C)C)cc1
Reactant: NC1=NCCCN1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)NC2=NCCCN2)cc1)Nc1nc2ccccc2s1
Reaction time: 24 h
Yield: 28.2 %

Procedure:
The ester 7-2 (80 mg) is mixed with 2-amino-1,4,5,6-tetrahydropyrimidine (40 mg) in 5 ml of CH2Cl2 and agitation is carried out at ambient temperature for 24 hours. After evaporating under reduced pressure, purifying the dry extract obtained by chromatography eluting with a CH2Cl2/MeOH mixture (100/0→90/10), 25 mg of the expected product 7-3 is obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.Br[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([O:18][CH3:19])[CH:12]=1)=O.[OH-].[NH4+]>C(O)C>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:1]=[C:2]3[N:6]([CH:8]=2)[CH:5]=[CH:4][S:3]3)=[CH:12][C:13]=1[O:18][CH3:19]
Reactant: Nc1nccs1
Reactant: COc1cc(C(=O)CBr)ccc1F
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(-c2cn3ccsc3n2)ccc1F
Reaction time: 18 h
Yield: 65.8 %

Procedure:
To a mixture of 2-aminothiazole (0.976 g, 9.74 mmol) and 2-bromo-1-(4-fluoro-3-methoxy-phenyl)-ethanone (2.4 g, 9.74 mmol) was added absolute ethanol (100 ml). The reaction was allowed to reflux with vigorous stirring for 18 hours (checked by HPLC). The reaction mixture was reduced to half its original volume in vacuo. The remaining liquid was poured onto ice and the solution made basic by the addition of ammonium hydroxide solution (30%), until pH is 8. The mixture was extracted with ethyl acetate (2×100 ml). The combined extracts were washed with water (100 ml) and saturated aqueous sodium chloride solution (100 ml). The organic phase was dried with sodium sulfate, filtered and concentrated in vacuo, to give an orange solid. Purification by flash chromatography (gradient 25%-50% ethyl actetate in hexanes) afforded the title product as a pale yellow solid (1.59 g, 66%). 400 MHz 1H NMR (DMSO-d6) δ 8.26 (s, 1H), 7.95 (d, J=2.3 Hz, 1H), 7.61 (dd, J=8.6, 2.0 Hz, 1H), 7.39 (ddd, J=8.2, 4.3, 2.0 Hz, 1H); 7.28 (d, J=4.7 Hz, 1H), 7.22 (dd, J=11.3, 8.2 Hz, 1H), 3.91 (s, 3H). LCMS: 249 [M+H].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[F:16])[O:5][Si](C(C)(C)C)(C)C.[Li]CCCC.[CH3:22][N:23]([CH2:25][CH:26]1[C:33](=[O:34])[CH2:32][CH2:31][C:28]2([CH2:30][CH2:29]2)[CH2:27]1)[CH3:24]>C1COCC1.CCCCCC>[CH3:24][N:23]([CH2:25][CH:26]1[C:33]([C:2]2[CH:3]=[C:4]([OH:5])[CH:13]=[CH:14][C:15]=2[F:16])([OH:34])[CH2:32][CH2:31][C:28]2([CH2:30][CH2:29]2)[CH2:27]1)[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(F)c(Br)c1
Reactant: CN(C)CC1CC2(CCC1=O)CC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN(C)CC1CC2(CC2)CCC1(O)c1cc(O)ccc1F
Temperature: -78 °C
Reaction time: 2 h
Yield: 36.1 %

Procedure:
Cool a solution of (3-bromo-4-fluoro-phenoxy)-tert-butyl-dimethyl-silane (472 mg, 1.547 mmol) in THF (40 mL) to −78° C. under N2. Then add dropwise a solution of n-BuLi (0.63 mL, 1.547 mmol) in hexane via syringe to the reaction solution. After being stirred at −78° C. for 2 hour, add dropwise a solution of 5-Dimethylaminomethyl-spiro[2.5]octan-6-one (70 mg, 0.387 mmol) in THF (1 mL) to the reaction mixture and stir the mixture at −78° C. for additional 2 hours. Quench the reaction with 20 mL of diluted HCl (2N), and stir at ambient temperature for 2 hours. Basify the resultant mixture with K2CO3 to pH=9, and extract with EtOAc (30 mL×2). The combined organic layers are washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. Purify the residue by silica gel chromatography (CH2Cl2 to CH2Cl2:MeOH=10:1) to afford 5-dimethylaminomethyl-6-(2-fluoro-5-hydroxy-phenyl)-spiro[2.5]octan-6-ol as white solid (41 mg, yield: 36.3%). MS (m/z): 294 (M+1).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH2:17][CH2:18][S:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].S(Cl)(Cl)=O.[CH3:30]O>>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH2:17][CH2:18][S:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:30])=[O:24])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: CO
Reactant: CC(C)(C)c1cc(SCCSCCCC(=O)O)cc(C(C)(C)C)c1O
Solvent: O=S(Cl)Cl
Product: COC(=O)CCCSCCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
The title compound was prepared according to the method of Example 8 from the title compound of Example 14 (6.5 g) and thionyl chloride (10 ml) in methyl alcohol (75 ml).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9](NC1CCN(C2SC=CN=2)CC1)=[O:10].Cl.[NH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:32]=[C:33]([CH:38]=[C:39]([Cl:41])[N:40]=2)[C:34]([O:36][CH3:37])=[O:35])[CH2:27][CH2:26]1>>[Cl:41][C:39]1[CH:38]=[C:33]([CH:32]=[C:31]([N:28]2[CH2:27][CH2:26][CH:25]([NH:24][C:9]([C:3]3[NH:4][C:5]([CH3:8])=[C:6]([Cl:7])[C:2]=3[Cl:1])=[O:10])[CH2:30][CH2:29]2)[N:40]=1)[C:34]([O:36][CH3:37])=[O:35]
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3nccs3)CC2)c(Cl)c1Cl
Reactant: COC(=O)c1cc(Cl)nc(N2CCC(N)CC2)c1
Agent: Cl
Product: COC(=O)c1cc(Cl)nc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)c1

Procedure:
The title compound was prepared in a manner analogous to Example 18 starting from 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 3) and methyl 2-(4-aminopiperidin-1-yl)-6-chloroisonicotinate hydrochloride salt (Intermediate 93).