Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.C([O-])([O-])=O.[K+].[K+].[N:19]1([CH2:24][CH2:25][N:26]([CH2:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[C:27](=[O:33])[CH2:28][CH2:29][CH2:30][CH2:31]Cl)[CH2:23][CH2:22][CH2:21][CH2:20]1>CN(C)C=O>[N:19]1([CH2:24][CH2:25][N:26]([CH2:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[C:27]([CH2:28][CH2:29][CH2:30][CH2:31][O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]3)=[O:33])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Reactant: O=C(CCCCCl)N(CCN1CCCC1)CC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CCCCOc1ccc2[nH]c(=O)ccc2c1)N(CCN1CCCC1)CC1CCCCC1
Yield: 10.3 %

Procedure:
To 50 ml of dimethylformamide are added 1.73 g of 6-hydroxycarbostyril, 1.8 g of K2CO3 and 0.5 g of KI. To this mixture being stirred at 60°-70° C. is dropwise added 4.2 g of N-[2-(1-pyrrolidinyl)ethyl]-N-(5-chloropentanoyl)-cyclohexylmethylamine. Then, the mixture is stirred for 4 hours at the same temperature. The solvent is removed by evaporation. The residue is dissolved in 200 ml of chloroform and the solution is washed with diluted hydrochloric acid, a 1% aqueous sodium hydroxide solution and water in this order, and dried with anhydrous magnesium sulfate. The desiccant is removed by filtration and the filtrate is concentrated. The residue is purified by means of a silica gel column chromatography (eluent; chloroform:methanol=20:1) and recrystallized from diethyl ether to obtain 0.5 g of 6-[4-{N-[2-(1-pyrrolidinyl)ethyl]-N-cyclohexylmethylaminocarbonyl}butoxy]carbostyril.
Reaction SMILES: [CH:1]1([C:6]2[CH:18]=[CH:17][C:9]([C:10]([O:12]C(C)(C)C)=[O:11])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[CH:17][CH:18]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)c1ccc(C2CCCC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc(C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
To a solution of tert-butyl 4-cyclopentylbenzoate (350 mg, 1.42 mmol) in dichloromethane (10 mL) was added 2,2,2-trifluoroacetic acid (2 mL). After stirring at room temperature for 0.5 hour, the mixture was concentrated to give 4-cyclopentylbenzoic acid (200 mg, 74%) as a white solid. LRMS (M+H+) m/z: calcd 190.10. found 190. 1H NMR (300 MHz, CD3OD): δ 12.78 (br, 1H), 7.86 (d, J=8.1 Hz, 2H), 7.37 (d, J=8.1 Hz, 2H), 3.10-3.01 (m, 1H), 2.05-2.01 (m, 2H), 1.78-1.65 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:11][CH:12]([C:14]([OH:16])=[O:15])[CH2:13][C:9]=2[C:8]2[CH2:7][CH:6]([CH2:17][CH2:18][CH3:19])[CH:5]([OH:20])[C:4]=2[C:3]=1[CH3:21].S(=O)(=O)(O)O>CC(C)=O.O.[O-2].[O-2].[O-2].[Cr+6]>[CH3:1][C:2]1[C:10]2[O:11][CH:12]([C:14]([OH:16])=[O:15])[CH2:13][C:9]=2[C:8]2[CH2:7][CH:6]([CH2:17][CH2:18][CH3:19])[C:5](=[O:20])[C:4]=2[C:3]=1[CH3:21]
Reactant: CCCC1Cc2c3c(c(C)c(C)c2C1O)OC(C(=O)O)C3
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: CC(C)=O
Solvent: O
Product: CCCC1Cc2c3c(c(C)c(C)c2C1=O)OC(C(=O)O)C3

Procedure:
A stirred suspension of 4,5-dimethyl-6-hydroxy-7-propyl-1,2,7,8-tetrahydro-6H-indeno[5,4-b]furan-2-carboxylic acid (5.0 g., 0.017 mole) in acetone (250 ml.) is treated over a ten minute period with an oxidizing reagent prepared from chromium trioxide (2.5 g. and concentrated sulfuric acid (2.2 ml.) in water (18 ml.). The acetone solution is decanted from the precipitated chromium salts and poured into water (700 ml.) affording 4,5-dimethyl-6-oxo-7-propyl-1,2,7,8-tetrahydro-6H-indeno-[5,4-b]furan-2-carboxylic acid which melts at 161°C. after recrystallization from butyl chloride.
Reaction SMILES: [OH-].[K+].[CH2:3]([NH:7][C:8]1[CH:13]=[C:12]2[O:14][CH2:15][O:16][C:11]2=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18])[CH2:4][CH2:5][CH3:6].[OH:20][CH2:21][CH:22](CO)[OH:23]>>[OH:20][CH:21]([CH2:22][OH:23])[CH2:15][O:14][C:12]1[CH:13]=[C:8]([NH:7][CH2:3][CH2:4][CH2:5][CH3:6])[C:9]([N+:17]([O-:19])=[O:18])=[CH:10][C:11]=1[OH:16]
Reactant: CCCCNc1cc2c(cc1[N+](=O)[O-])OCO2
Reactant: OCC(O)CO
Agent: [K+]
Agent: [OH-]
Product: CCCCNc1cc(OCC(O)CO)c(O)cc1[N+](=O)[O-]

Procedure:
0.128 mol (8.5 g) of 85% pure potassium hydroxide pellets is dissolved in 70 ml of double-distilled glycerol on a boiling water bath. 2-n-butylamino-4,5-methylenedioxy-1-nitrobenzene, prepared according to Example 4, is added with stirring.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[O:13][CH3:14].CC1(C)C(C)(C)OB([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[F:30])O1>>[Br:1][C:2]1[CH:7]=[C:6]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[F:30])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[O:13][CH3:14]
Reactant: CC1(C)OB(c2ccc(F)cc2F)OC1(C)C
Reactant: COc1c(Br)cc(I)cc1C(C)(C)C
Product: COc1c(Br)cc(-c2ccc(F)cc2F)cc1C(C)(C)C

Procedure:
The product from Example 1 Part A (0.185 g, 0.501 mmol) and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,5-difluorobenzene (0.120 g, 0.501 mmol) were reacted in the same manner as Example 1 Part B for 16 hours. The crude product was purified on an Isco 12 g silica cartridge eluting with 5% ethyl acetate in hexane to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1>CN(C)C=O>[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:3]2[C:4](=[O:15])[C:5]3[C@@H:6]4[C:11]([CH3:12])([CH3:13])[C@@:9]([CH3:14])([CH2:8][CH2:7]4)[C:10]=3[N:2]2[CH3:1])=[CH:19][CH:18]=1
Reactant: Cn1[nH]c(=O)c2c1[C@]1(C)CC[C@H]2C1(C)C
Reactant: Fc1ccc(CBr)cc1
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1Cc1ccc(F)cc1)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 40.4 %

Procedure:
A mixture of (4S,7R)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 19; 100 mg, 0.49 mmol) and 4-fluoro-benzyl bromide (60 μL, 0.48 mmol) in N,N-dimethylformamide (5 mL) was heated at 100° C. overnight. The reaction mixture was evaporated and the residue was purified using a Biotage 40S system, eluting with 0-1% methanol/chloroform, followed by drying under high vacuum to give (4S,7R)-2-(4-fluoro-benzyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (61 mg, 41%) as a white solid. APCI-MS (M+H) 315.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].C(=O)([O-])[O-].[K+].[K+].[C:20]([C:22]1[CH:23]=[C:24]([S:29]([NH:32][C:33]2[S:37][N:36]=[CH:35][N:34]=2)(=[O:31])=[O:30])[CH:25]=[CH:26][C:27]=1F)#[N:21].Cl>CS(C)=O.C(OCC)(=O)C>[C:20]([C:22]1[CH:23]=[C:24]([S:29]([NH:32][C:33]2[S:37][N:36]=[CH:35][N:34]=2)(=[O:31])=[O:30])[CH:25]=[CH:26][C:27]=1[O:13][C:3]1[CH:4]=[CH:5][C:6]([O:8][C:9]([F:11])([F:12])[F:10])=[CH:7][C:2]=1[I:1])#[N:21]
Reactant: Oc1ccc(OC(F)(F)F)cc1I
Reactant: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1Oc1ccc(OC(F)(F)F)cc1I

Procedure:
To a suspension of 2-iodo-4-(trifluoromethoxy)phenol (Preparation 226, 600 mg, 1.97 mmol) and potassium carbonate (1125 mg, 8.14 mmol) in Dimethylsulfoxide (10 mL) was added 3-cyano-4-fluoro-N-[1,2,4]thiadiazol-5-yl-benzenesulfonamide (Preparation 65). The reaction was heated to 80° C. under N2 for 7 hours before the addition of ethyl acetate (20 mL) and 3M aqueous HCl solution (30 mL). The organic layer was collected, washed with brine (20 mL), dried over sodium sulphate and concentrated in vacuo. The residue was triturated in dichloromethane and filtered to afford 965 mg of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=2[C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][C:30]2=[O:36])[CH:26]=[CH:27][CH:28]=1.Cl>C(O)(C)C>[CH3:15][CH:14]([NH:13][C:11](=[O:12])[C:10]1[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=1[NH:8][C:6]1[C:5]([CH3:21])=[CH:4][N:3]=[C:2]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][C:30]3=[O:36])[CH:24]=2)[N:7]=1)[CH3:16]
Reactant: Cc1cnc(Cl)nc1Nc1ccccc1C(=O)NC(C)C
Reactant: CN1CCN(c2cccc(N)c2)C(=O)C1
Agent: Cl
Solvent: CC(C)O
Product: Cc1cnc(Nc2cccc(N3CCN(C)CC3=O)c2)nc1Nc1ccccc1C(=O)NC(C)C
Temperature: 25 °C
Yield: 27.1 %

Procedure:
2-[(2-Chloro-5-methyl-4-pyrimidinyl)amino]-N-(1-methylethyl)benzamide (103 mg, 0.337 mmol) and 1-(3-aminophenyl)-4-methyl-2-piperazinone (68.8 mg, 0.335 mmol) were stirred at 95° C. overnight in isopropanol (10 mL) with 12 N HCl (0.056 mL, 0.673 mmol). The reaction was cooled to room temperature and the solid was filtered off and washed with isopropanol. The solid was chromatographed using reverse phase HPLC eluting with 5-30% acetonitrile containing 0.1% formic acid to give a white solid (43 mg, 27%) after lyophilization of the combined HPLC fractions. MS: M(C26H31N7O2)=473.57, (M+H)+=473.8.
Reaction SMILES: C(OC(=O)N[C@H](C(=O)[NH:13][C@H:14]([B:19]1[O:27][C@H:26]2[C@:21]([CH3:31])([C@H:22]3[CH2:28][C@@H:24]([CH2:25]2)[C:23]3([CH3:30])[CH3:29])[O:20]1)[CH2:15][CH:16]([CH3:18])[CH3:17])C(C)C)(C)(C)C.[C:34]([NH:41][C@H:42]([C:47]([OH:49])=O)[CH2:43][CH:44]([CH3:46])[CH3:45])([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>>[C:37]([O:36][C:34](=[O:35])[NH:41][C@H:42]([C:47](=[O:49])[NH:13][C@H:14]([B:19]1[O:27][C@H:26]2[C@:21]([CH3:31])([C@H:22]3[CH2:28][C@@H:24]([CH2:25]2)[C:23]3([CH3:29])[CH3:30])[O:20]1)[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:43][CH:44]([CH3:45])[CH3:46])([CH3:38])([CH3:39])[CH3:40]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1

Procedure:
The title compound is prepared as described for {(S)-2-Methyl-1-[(R)-3-methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-butylcarbamoyl]-propyl}-carbamic acid tert-butyl ester (example 1 (c)) but using Boc-L-leucine.
Reaction SMILES: [C:1]([NH2:4])(=[S:3])[CH3:2].Br[CH:6]([C:12](OCC)=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8]>C1(C)C=CC=CC=1>[CH2:10]([O:9][C:7]([C:6]1[S:3][C:1]([CH3:2])=[N:4][C:12]=1[OH:13])=[O:8])[CH3:11]
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: CC(N)=S
Solvent: Cc1ccccc1
Product: CCOC(=O)c1sc(C)nc1O
Temperature: 25 °C
Yield: 25.7 %

Procedure:
To a solution of thioacetamide (17.2 g, 0.229 mol) in toluene (130 mL) was added diethyl bromomalonate (55.0 g, 0.230 mol) and the mixture heated at reflux for 3 h. The reaction mixture was cooled to RT, filtered through Celite, then concentrated in vacuo. The resultant solid was triturated with hexane to give the title compound as a yellow solid (11.0 g, 26%).
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[CH3:14][Si](C=[N+]=[N-])(C)C>>[CH3:14][O:5][C:4](=[O:6])[CH2:3][CH:2]([NH2:1])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1
Reactant: NC(CC(=O)O)c1cccc(Br)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Product: COC(=O)CC(N)c1cccc(Br)c1
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
To a solution of 3-amino-3-(3-bromo-phenyl)-propionic acid (1.0 g, 4.1 mmol) in methanol-toluene (100 mL; 1:1 solution) at room temperature is added trimethylsilyl diazomethane (2.0 M solution in hexanes, 20 mL, 40 mmol). After 30 min, excess trimethylsilyl diazomethane is quenched by addition of glacial acetic acid (5 mL). Concentration in vacuo affords of 3-amino-3-(3-bromo-phenyl)-propionic acid methyl ester (1.0 g, 95%) as a colorless liquid which solidifies upon standing.
Reaction SMILES: O.[OH-].[Li+].[OH:4][C:5]([C:8]1[N:9]=[C:10]([CH2:54][O:55][CH3:56])[N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[N:34]([C:35]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[N:33]=[N:32][N:31]=3)=[CH:20][CH:19]=2)[C:12]=1[C:13]([O:15][CH3:16])=[O:14])([CH3:7])[CH3:6].[C:57](=[O:59])=[O:58]>O.O1CCOCC1>[OH:4][C:5]([C:8]1[N:9]=[C:10]([CH2:54][O:55][CH3:56])[N:11]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[N:34]([C:35]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)([C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)[N:33]=[N:32][N:31]=3)=[CH:22][CH:23]=2)[C:12]=1[C:13]([O:15][CH2:16][O:58][C:57](=[O:59])[C:5]([CH3:8])([CH3:7])[CH3:6])=[O:14])([CH3:6])[CH3:7]
Reactant: O=C=O
Reactant: COCc1nc(C(C)(C)O)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COCc1nc(C(C)(C)O)c(C(=O)OCOC(=O)C(C)(C)C)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 41.9 mg of lithium hydroxide monohydrate in 15 ml of water was added, whilst ice-cooling, to a solution of 0.75 g of methyl 4-(1-hydroxy-1-methylethyl)-2-methoxymethyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in Example 82(a)] in 15 ml of dioxane, and the mixture was stirred at room temperature overnight. At the end of this time, a small quantity of dry ice was added to the reaction solution, and the dioxane was removed by distillation under reduced pressure. The residue was then dissolved in a small quantity of an aqueous solution of sodium chloride and ethyl acetate. The ethyl acetate layer was separated, washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was dried in vacuo at 50° C. for 1 hour. 0.25 g of potassium carbonate were then added to a solution of the resulting residue in 10 ml of N,N-dimethylacetamide, and the mixture was cooled with ice-water. A solution of 0.31 ml of pivaloyloxymethyl chloride in 3 ml of N,N-dimethylacetamide was then added dropwise to the mixture, which was then stirred at 70° C. for 1.5 hours. At the end of this time, water and ethyl acetate were added to the reaction solution. The ethyl acetate layer was separated, washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 0.79 g of the title compound as a foam-like solid.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7]([OH:17])[CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:18]([O:20][C:21]([C:23]1([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][C:35](B4OC(C)(C)C(C)(C)O4)=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)[CH2:25][CH2:24]1)=[O:22])[CH3:19]>>[CH2:18]([O:20][C:21]([C:23]1([C:26]2[CH:27]=[CH:28][C:29]([C:32]3[CH:33]=[CH:34][C:35]([C:2]4[S:3][CH:4]=[CH:5][C:6]=4[CH:7]([OH:17])[CH2:8][CH2:9][CH2:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:36][CH:37]=3)=[CH:30][CH:31]=2)[CH2:25][CH2:24]1)=[O:22])[CH3:19]
Reactant: OC(CCCc1ccccc1)c1ccsc1Br
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4sccc4C(O)CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 5, Step 2, using the following starting materials: 1-(2-bromo-thiophen-3-yl)-4-phenyl-butan-1-ol (Enantiomer B) and 1-[4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH2:19][CH2:20][CH3:21])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].C(=O)([O-])[O-].[K+].[K+].Cl[C:31]1[CH:32]=[C:33]([C:38]([N+:41]([O-:43])=[O:42])=[CH:39][N:40]=1)[C:34]([O:36][CH3:37])=[O:35].Cl>CN(C)C=O.O>[F:1][C:2]([F:22])([F:23])[C:3]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:31]2[CH:32]=[C:33]([C:38]([N+:41]([O-:43])=[O:42])=[CH:39][N:40]=2)[C:34]([O:36][CH3:37])=[O:35])=[C:14]([CH2:19][CH2:20][CH3:21])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:6])([F:5])[F:7]
Reactant: COC(=O)c1cc(Cl)ncc1[N+](=O)[O-]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1cc(C(=O)OC)c([N+](=O)[O-])cn1
Yield: 72.7 %

Procedure:
To a solution of 4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenol (1.68 g, 4.86 mmol) in N,N-dimethylformamide (30 mL), potassium carbonate (1.34 g) and methyl 2-chloro-5-nitroisonicotinate (1.58 g) were added, and the resultant mixture was stirred in an oil bath with the oil temperature at 80° C. After completion of the reaction, the reaction solution was neutralized by adding 2 mol/L of hydrochloric acid, added with water, and extracted with ethyl acetate. Subsequently, the organic layer was washed with brine, dried using anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified using thin-layer silica-gel column chromatography (hexane/ethyl acetate) and the title compound (1.86 g, yield 73%) was obtained as a colorless oil.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1B(O)O>>[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(F)cc4F)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (49 mg, 58%), MS (ISP) m/z=338.5 [(M+H)+], mp 237° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 2,4-difluoro-phenylboronic acid (51.3 mg, 0.325 mmol).
Reaction SMILES: Cl.[F:2][C:3]([F:16])([F:15])[CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([CH:12]([NH2:14])[CH3:13])=[CH:8][CH:7]=1.[NH2:17][C:18]1[C:19]([C:24](O)=[O:25])=[N:20][CH:21]=[CH:22][CH:23]=1>>[NH2:17][C:18]1[C:19]([C:24]([NH:14][CH:12]([C:9]2[CH:10]=[N:11][C:6]([O:5][CH2:4][C:3]([F:2])([F:15])[F:16])=[CH:7][CH:8]=2)[CH3:13])=[O:25])=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cccnc1C(=O)O
Reactant: CC(N)c1ccc(OCC(F)(F)F)nc1
Agent: Cl
Product: CC(NC(=O)c1ncccc1N)c1ccc(OCC(F)(F)F)nc1
Yield: 74 %

Procedure:
The title compound is prepared in 74% yield (98 mg, a white solid) from (−)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (100 mg, 0.39 mmol, Amine-1, single enantiomer) and 3-aminopicolinic acid (54 mg, 0.39 mmol) by the similar manner in Step-1 of Example-8.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[S:12][C:11]([NH2:14])=[N:10][C:9]=2[C:8]([O:15][CH3:16])=[CH:7][CH:6]=1)=[O:4].[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>>[CH3:1][O:2][C:3]([C:5]1[C:13]2[S:12][C:11]([NH:14][C:22](=[O:23])[C:21]3[CH:25]=[CH:26][C:18]([F:17])=[CH:19][CH:20]=3)=[N:10][C:9]=2[C:8]([O:15][CH3:16])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(OC)c2nc(N)sc12
Reactant: O=C(Cl)c1ccc(F)cc1
Product: COC(=O)c1ccc(OC)c2nc(NC(=O)c3ccc(F)cc3)sc12

Procedure:
Using 2-amino-4-methoxy-benzothiazole-7-carboxylic acid methyl ester and 4-fluoro-benzoyl chloride the title compound was obtained as a white solid (91% yield), MS: m/e=361.1 (M+H+).
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9][C:4]=2[CH:3]=[C:2]1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[H-].[Na+].[CH3:24]I>C1COCC1>[CH3:24][N:1]1[C:5]2[CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9][C:4]=2[CH:3]=[C:2]1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CI
Reactant: CCOC(=O)c1cc2c([nH]1)CN(C(=O)OC(C)(C)C)CC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(n1C)CN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-tert-butyl 2-ethyl 1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridine-2,6-dicarboxylate (1.0 eq) in dry THF was added NaH (1.2 eq) at 0° C. and reaction mixture was stirred at room temperature for 30 min. Methyl iodide (6.0 eq.) was added and stirred further at room temperature for 3 hrs. Reaction mixture was quenched with water and extracted with dichloromethane, over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the desired 6-tert-butyl 2-ethyl 1-methyl-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridine-2,6-dicarboxylate.
Reaction SMILES: [ClH:1].[NH:2]([CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([OH:15])=O)[CH2:9][CH2:8]1)[C:3]([NH2:5])=[NH:4].[C:16]([O:25][CH2:26][CH3:27])(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[NH2:19].N1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>O>[ClH:1].[CH2:26]([O:25][C:16]([C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH:19][C:13]([C@H:10]1[CH2:9][CH2:8][C@H:7]([CH2:6][NH:2][C:3]([NH2:5])=[NH:4])[CH2:12][CH2:11]1)=[O:15])=[O:24])[CH3:27]
Reactant: N=C(N)NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CCOC(=O)c1ccccc1N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)c1ccccc1NC(=O)[C@H]1CC[C@H](CNC(=N)N)CC1

Procedure:
Trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride (10.0 g, 0.042 mole) (which is prepared by the method as disclosed in Japanese Patent First Publication No. 19694/1977, C.A., 87, 53269x) and ethyl anthranilate (10.4 g, 0.063 mole) are added to pyridine (50 ml), and the mixture is stirred for a while, and thereto is added dicyclohexylcarbodiimide (13 g, 0.063 mole), and the mixture is stirred at room temperature for 72 hours. After the completion of the reaction, water (30 ml) is added to the reaction mixture, and the mixture is stirred for 30 minutes, and the undissolved materials are filtered off. The filtrate is concentrated to dryness. The resulting residue is washed with ethyl acetate (300 ml) and recrystallized from water to give the title compound (6.74 g) as white crystals. m.p. 92°-95° C.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.[NH3:13]>>[N:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([NH2:13])=[O:2])=[CH:7][CH:8]=1
Reactant: N
Reactant: COC(=O)CCc1ccncc1
Product: NC(=O)CCc1ccncc1
Temperature: 25 °C
Reaction time: 65 h

Procedure:
The crude ester was dissolved in 250 mL of 7.1M methanolic ammonia solution and was stirred at room temperature for 65 hours. After the solvent and excess ammonia were removed by distillation under reduced pressure. The residue was dissolved in 150 mL of 1N HCl and extracted with dichloromethane to remove residual triphenylphosphine oxide. The aqueous phase was basified with 40 mL of 4N NaOH and then was extracted with ethyl acetate (5×300 mL). The dried (Na2SO4) extracts were evaporated to furnish 6 g of the amide. The aqueous layer was concentrated to dryness and triturated with tetrahydrofuran (4×100 mL) and evaporation of the tetrahydrofuran extracts yielded an additional 5 g of amide. The combined crude products were dried, triturated with ether and the solids were filtered to yield 10.7 g of 4-pyridinpPropanamide, mp 164°-166° C.