Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:20])[NH:10][CH2:11][C:12]([CH3:19])([CH3:18])[C:13]([O:15]CC)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>>[CH2:1]([NH:8][C:9](=[O:20])[NH:10][CH2:11][C:12]([CH3:18])([CH3:19])[C:13]([OH:15])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)CNC(=O)NCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC(C)(CNC(=O)NCc1ccccc1)C(=O)O
Yield: 50.7 %

Procedure:
According to the procedure described in the synthesis method of Compound VI-1, ethyl 3-(3-benzylureido)-2,2-dimethylpropanoate (Compound V-4) (840 mg, 3.0 mmol) was reacted with lithium hydroxide monohydrate (151 mg, 3.6 mmol) to obtain the title compound (381 mg, 50.7%).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=1.[CH3:15][N:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17](Cl)=[O:18].N12CCN(CC1)CC2>O1CCCC1>[N+:12]([C:5]1[CH:6]=[C:7]([C:8]([F:11])([F:9])[F:10])[C:2]([O:1][C:17](=[O:18])[N:16]([CH3:15])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:3][CH:4]=1)([O-:14])=[O:13]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: O=[N+]([O-])c1cnc(O)c(C(F)(F)F)c1
Agent: C1CN2CCN1CC2
Solvent: C1CCOC1
Product: CN(C(=O)Oc1ncc([N+](=O)[O-])cc1C(F)(F)F)c1ccccc1
Yield: 93.2 %

Procedure:
A solution of 2-hydroxy-5-nitro-3-(trifluoromethyl)pyridine (0.36 g, 1.73 mmol), N-methyl-N-phenylcarbamoyl chloride (0.44 g, 2.59 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.29 g, 2.59 mmol) in tetrahydrofuran (15 ml) was stirred at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (15:85)) yielding the title compound (0.55 g, 92% yield) as an orange solid.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:31][OH:32])([N:7]1[CH:11]=[C:10]([C:12]2[C:24]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([OH:29])([C:25]([F:28])([F:27])[F:26])[C:16]=3[CH:15]=[C:14]([CH3:30])[CH:13]=2)[CH:9]=[N:8]1)[C:4](O)=[O:5].C(O)C.O.C(=O)([O-])O.[Na+]>O1CCCC1>[OH:5][CH2:4][C:3]([N:7]1[CH:11]=[C:10]([C:12]2[C:24]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([OH:29])([C:25]([F:28])([F:26])[F:27])[C:16]=3[CH:15]=[C:14]([CH3:30])[CH:13]=2)[CH:9]=[N:8]1)([CH2:31][OH:32])[CH2:2][OH:1]
Reactant: Cc1cc(-c2cnn(C(CO)(CO)C(=O)O)c2)c2c(c1)C(O)(C(F)(F)F)c1ccccc1-2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(-c2cnn(C(CO)(CO)CO)c2)c2c(c1)C(O)(C(F)(F)F)c1ccccc1-2
Reaction time: 5 h
Yield: 83.9 %

Procedure:
To a solution of an optically active form (15.5 g) of 3-hydroxy-2-hydroxymethyl-2-[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propionic acid in tetrahydrofuran (31 ml) was added dropwise at room temperature a 1.09M solution (127 ml) of borane-tetrahydrofuran complex in tetrahydrofuran, and the mixture was stirred for 5 hr. To the reaction mixture was added dropwise ethanol (15 ml) at room temperature and the mixture was stirred at 75° C. for 1 hr. To this mixture were added water (90 ml) and saturated aqueous sodium hydrogen carbonate (150 ml), and the mixture was extracted twice with ethyl acetate (150 ml, 75 ml). The combined organic layer was successively washed once with saturated aqueous sodium hydrogen carbonate (75 ml), twice with water (75 ml) and once with saturated brine (75 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. To a solution of the obtained residue in ethanol (45 ml) was added sodium borohydride (1.3 g) at room temperature, and the mixture was stirred for 1 hr. To the reaction mixture was added 1N hydrochloric acid (150 ml), and the mixture was extracted with ethyl acetate (150 ml). The separated aqueous layer was extracted again with ethyl acetate (75 ml). The combined organic layer was successively washed with water (75 ml), saturated aqueous sodium hydrogen carbonate (75 ml), water (75 ml) and saturated brine (75 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform/methanol=20/1 to 10/1) to give the title compound (12.6 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@H:4]([NH:15]C(OC(C)(C)C)=O)[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1.FC(F)(F)C(O)=O>>[CH3:1][O:2][C:3](=[O:23])[C@H:4]([NH2:15])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1
Reactant: COC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Reaction time: 2 h

Procedure:
To 4.92 g (16.2 mmol) of N-α-t-BOC-D-tryptophan in 100 mL of DMF was added 2.46 g (17.8 mmol) of potassium carbonate followed by 2.41 g (17.0 mmol) of iodomethane, and the mixture was stirred overnight at 24° C. under an atmosphere of nitrogen. The reaction mixture was diluted with water, and extracted three times with ethyl acetate. The combined organics were washed five times with 500 mL of water and once with brine, dried over MgSO4 and concentrated to give 4.67 g of a white solid. To the crude (R)-2-tert-butoxycarbonylamino-3-(1H-indol-3-yl)-propionic acid methyl ester was added 15 mL of cold trifluoroacetic acid at about 0° C. and the mixture was stirred for about 2 h. The mixture was concentrated and the residue was diluted with 1N NaOH and extracted three times with ethyl acetate. The combined organic extracts were washed with brine and dried over Na2SO4 to give (R)-2-amino-3-(1H-indol-3-yl)-propionic acid methyl ester as an orange oil in quantitative yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:10]=1[CH:11]=O)=[O:5])[CH3:2].O.[NH2:28][NH2:29]>C(O)(=O)C.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:9]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[C:10]=1[CH:11]=[N:28][NH2:29])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(-c2ccccc2Cl)n(-c2ccc(Cl)cc2)c1C=O
Reactant: NN
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)c1nc(-c2ccccc2Cl)n(-c2ccc(Cl)cc2)c1C=NN
Temperature: 25 °C

Procedure:
A solution of 1-(4-chloro-phenyl)-2-(2-chloro-phenyl)-5-formyl-1H-imidazole-4-carboxylic acid ethyl ester (I-2e, 102 mg, 0.26 mmol), aqueous hydrazine hydrate (50% solution, 0.6 mmol) and glacial acetic acid (1 drop) was heated under reflux in toluene (3 ml) for 18 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The residue was partitioned between CH2Cl2 and sat'd aq. NaHCO3. The organic solution was dried and concentrated in vacuo. Purification using 2 mm chromatotron plates and a solvent gradient of 1:1 EtOAc/hexanes to 100% EtOAc provided the desired product I-2f (Rf=0.8, 100% EtOAc, 62 mg): +APCI MS (M+1) 403.1; 1H NMR (CD2Cl2) δ 1.40 (3H, t), 4.37 (2H, q), 5.60 (2H, br s), 7.10–7.14 (2H, m), 7.21–7.25 (3H, m), 7.29–7.33 (3H, m), 8.40 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:18])=[CH:4][C:5](=[O:17])[N:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=2)[CH:7]=1.OC1C=CNC(=O)C=1.CS(O[CH:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]1)(=O)=O.CS(OC1CCN(C2N=CC(CCC)=CN=2)CC1)(=O)=O>>[Cl:1][C:2]1[C:3]([O:18][CH:32]2[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]2)=[CH:4][C:5](=[O:17])[N:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: N#Cc1ccc(-n2cc(Cl)c(O)cc2=O)cc1F
Agent: CCCc1cnc(N2CCC(OS(C)(=O)=O)CC2)nc1
Agent: O=c1cc(O)cc[nH]1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(C#N)c(F)c3)cc2Cl)CC1

Procedure:
Example 267 was prepared according to procedures described in Example 173 Step C substituting 4-(5-chloro-4-hydroxy-2-oxopyridin-1(2H)-yl)-2-fluorobenzonitrile (prepared according to the procedure described in Step B of Example 263) for 4-hydroxypyridin-2(1H)-one and substituting tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (prepared according to the procedure described in Step C of Example 1) for 1-(5-propylpyrimidin-2-yl)piperidin-4-yl methanesulfonate except that the crude product was purified by flash chromatography (SiO2, 0 to 100% EtOAc in CH2Cl2). 1H NMR (400 MHz, CDCl3) δ ppm 7.77 (t, J=7.53 Hz, 1 H), 7.37-7.46 (m, 2 H), 7.30-7.36 (m, 1 H), 6.00 (s, 1 H), 4.54-4.68 (m, 1 H), 3.58-3.71 (m, 2 H), 3.40-3.56 (m, 2 H), 1.93-2.07 (m, 2 H), 1.78-1.93 (m, 2 H), 1.49 (s, 9 H). MS (ESI) 392 (M−56+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9](=O)[CH:8]([CH3:13])[CH2:7]1)=[O:5])[CH3:2].[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([NH:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]([CH3:13])[CH2:7]1)=[O:5])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CCOC(=O)C1CCC(=O)C(C)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCOC(=O)C1CCC(NCc2ccccc2)C(C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture comprising 3-methyl-4-oxo-cyclohexanecarboxylic acid ethyl ester (1.00 g, 5.43 mmol) and benzylamine (0.58 g, 5.43 mmol) in DCE (50 mL) is treated with sodium triacetoxyborohydride (2.30 g, 10.9 mmol) and stirred at RT for 2 hours. The mixture is partitioned between DCM and water and the organic portion is separated, dried (MgSO4) and concentrated in vacuo. Purification by chromatography on silica eluting with iso-hexane: EtOAc (4:1 increasing to 1:1) affords the title compound. 1H NMR (400 MHz, DMSO-d6) δ 7.32 (4H, m), 7.20 (1H, m) 4.04 (2H, q), 3.72 (2H, m), 2.50-1.30 (9H, m), 1.19 (4H, m), 0.89 (3H, d).
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[O:7][C:8]1[N:16]=[CH:15][C:14]([F:17])=[CH:13][C:9]=1[C:10]([OH:12])=O)[CH3:2].Cl.[NH2:22][CH:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:30](=[O:36])[C:31]([CH3:35])([CH3:34])[CH2:32][OH:33])[CH2:25][CH2:24]1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH2:1]([S:3][C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[O:7][C:8]1[N:16]=[CH:15][C:14]([F:17])=[CH:13][C:9]=1[C:10]([NH:22][C@H:23]1[CH2:24][CH2:25][C@H:26]([NH:29][C:30](=[O:36])[C:31]([CH3:34])([CH3:35])[CH2:32][OH:33])[CH2:27][CH2:28]1)=[O:12])[CH3:2]
Reactant: CCSc1cccc(Oc2ncc(F)cc2C(=O)O)c1
Reactant: CC(C)(CO)C(=O)NC1CCC(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@H](NC(=O)C(C)(C)CO)CC2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2-(3-Ethylsulfanyl-phenoxy)-5-fluoro-nicotinic acid (150 mg, 0.51 mmol) was added to a solution of N-(4-amino-cyclohexyl)-3-hydroxy-2,2-dimethyl-propionamide hydrochloride (80:20 cis:trans, 135 mg, 0.54 mmol) and triethylamine (0.21 ml, 1.5 mmol) in dimethylformamide (3 ml) under nitrogen at room temperature. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (108 mg, 0.56 mmol) followed by 1-hydroxybenzotriazole (76 mg, 0.56 mmol) were then added and the reaction was stirred at room temperature for 20 h. The mixture was concentrated under reduced pressure, partitioned between ethyl acetate (20 ml) and water (20 ml) and the organic phase was removed, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on a silica gel eluting with a solvent gradient of dichloromethane:methanol (95:5) and the product was purified by preparative HPLC to give two products.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C.O>[CH2:17]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To a stirring solution of 1-(4-hydroxyphenyl)ethanone (5 g, 36 mmol) in Acetonitrile 50 mL was added potassium carbonate (9.9 g, 72 mmol) and benzyl bromide (7.5 g, 44 mmol) and stirred at RT for overnight, reaction mass was diluted with water and extracted with ethyl acetate, organic layer was given water and brine washes, dried over Na2SO4, evaporation under reduced pressure yields titled compound as white solid (7 g Yield: 84.1%): 1H NMR (300 MHz, CDCl3): δ 7.85-7.88 (d, 2H), 7.25-7.37 (m, 5H), 6.92-6.95 (d, 2H), 5.06 (s, 2H), 2.48 (s, 3H).
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:14]3[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=3[O:12][N:11]=2)[CH2:6][CH2:5]1.[F:21][C:22]1[CH:36]=[CH:35][C:25]2[C:26]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[N:27][O:28][C:24]=2[CH:23]=1.[ClH:37]>C(O)(C)C.C(O)C>[ClH:37].[ClH:37].[F:19][C:17]1[CH:16]=[CH:15][C:14]2[C:10]([CH:7]3[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:20][N:32]4[CH2:31][CH2:30][CH:29]([C:26]5[C:25]6[CH:35]=[CH:36][C:22]([F:21])=[CH:23][C:24]=6[O:28][N:27]=5)[CH2:34][CH2:33]4)[CH2:5][CH2:6]3)=[N:11][O:12][C:13]=2[CH:18]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: Fc1ccc2c(C3CCN(CC4CO4)CC3)noc2c1
Agent: Cl
Solvent: CC(C)O
Solvent: CCO
Product: OC(CN1CCC(c2noc3cc(F)ccc23)CC1)CN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 65 °C
Reaction time: 16 h

Procedure:
A stirred mixture of 1-(2,3-epoxypropyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (1.19 g, 4.3 mmol) and 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (0.95 g, 4.3 mmol) in isopropyl alcohol (50 ml) was heated at reflux for 1 hour, then stirred at 65° C. for 16 hours. The solvent was removed on a rotary evaporator. The solid residues were purified by flash chromatography over a silica gel column (SiO2, 35 g; eluted with methylene chloride, DCM, and CH3OH in DCM). The product thus obtained, weighed 2.55 g. This material was dissolved in ethanol and was treated with a solution of HCl (1M in ether). The salt collected weighed 2.35 g, m.p. >270° C. dec.
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].Br[CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:4]([CH:17]1[CH2:22][CH2:21][CH2:20][N:19]([CH2:24][CH2:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCCNC1
Reactant: COc1ccc(CCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(CCCN2CCCC(C(C(N)=O)(c3ccccc3)c3ccccc3)C2)cc1

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)piperidine (0.26 g), 1-bromo-3-(4-methoxyphenyl)propane (0.23 g), anhydrous potassium carbonate (0.3 g) and acetonitrile (10 ml) was heated under reflux for 16 hours. The mixture was partitioned between dichloromethane (30 ml) and 10% aqueous sodium carbonate (30 ml), the layers separated, and the aqueous layer extracted with dichloromethane (2×30 ml). The dichloromethane extracts were combined, dried (MgSO4) and concentrated in vacuo to give a solid which was recrystallised from ethanol to give the title compound, yield 0.19 g, m.p. 180°-182° C.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH3:11])=[CH:8][CH:9]=2)[N:4]([CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])[N:3]=1.C([Mg]Cl)(C)C.[CH2:22]([Sn:26]([CH2:32][CH2:33][CH2:34][CH3:35])([CH2:28][CH2:29][CH2:30][CH3:31])Cl)[CH2:23][CH2:24][CH3:25]>C1COCC1>[CH3:15][N:14]([CH3:16])[CH2:13][CH2:12][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=2)[C:2]([Sn:26]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:22][CH2:23][CH2:24][CH3:25])=[N:3]1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1ccc2c(I)nn(CCN(C)C)c2c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(CCN(C)C)c2cc(C)ccc12
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 203.1 %

Procedure:
A solution of 2-(3-iodo-6-methyl-1H-indazol-1-yl)-N,N-dimethylethanamine (450 mg, 1.4 mmol) in 20 mL of dry THF was cooled to −20° C. under nitrogen atmosphere, isopropylmagnesium chloride (1.4 mL, 2.8 mmol, 2 M in THF) was added and stirred for 15 min at −20° C. Then tributylchlorostannane (0.8 mL, 2.8 mmol) was added and allowed to warm to room temperature. The reaction was cooled in an ice bath and quenched with saturated ammonium chloride solution, extracted with ethyl acetate (3×30 mL), combined organics dried with sodium sulfate and concentrated to give 1.4 g of crude N,N-dimethyl-2-(6-methyl-3-(tributylstannyl)-1H-indazol-1-yl)ethanamine as an oil which was used in the next step directly without further purification.
Reaction SMILES: [O-:1][O-:2].[Na+].[Na+].Cl[C:6]([O:8][C:9]([C:12]#[N:13])([CH3:11])[CH3:10])=[O:7]>O>[C:6]([O:1][O:2][C:6]([O:8][C:9]([C:12]#[N:13])([CH3:11])[CH3:10])=[O:7])([O:8][C:9]([C:12]#[N:13])([CH3:11])[CH3:10])=[O:7]
Reactant: CC(C)(C#N)OC(=O)Cl
Reactant: [O-][O-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C#N)OC(=O)OOC(=O)OC(C)(C)C#N
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 63 %

Procedure:
Into a 500 ml round bottom flask equipped with a thermometer, a dropping funnel and a Teflon blade stirrer were added a solution of 50 weight percent sodium hydroxide (41.9 grams, 0.52 mole) and 84 grams of distilled water. The solution was cooled to 15° C. by an ice bath and 50% hydrogen peroxide (18.4 grams, 0.27 mole) was added slowly through the dropping funnel. A sodium peroxide slurry formed immediately. The sodium peroxide slurry was transferred slowly into a 500 ml four-necked round bottom reactor flask containing 82.1 grams (0.5 mole) of the 1-cyano-1-methylethyl chloroformate of Example 1. The reactor flask was equipped with a Teflon blade stirrer, a bottom stopcock, a vent, a sodium peroxide slurry inlet and a thermometer. The temperature within the reactor flask was maintained at about 15° C. or less by spraying ice water on the outside of the flask. On completing the addition of the sodium peroxide slurry, 50 ml of distilled water was added to the reactor flask with stirring and a solid material precipitated immediately. The stirring was continued for 90 minutes. Thereafter, the solid precipitate (43.5 grams, 63% yield) was recovered by filtration, washed twice with distilled water and once with 2-propanol. The product was a white solid having a melting point of 58°-59° C. Identification of the product as di(1-cyano-1-methylethyl)peroxydicarbonate was confirmed by infrared and NMR spectroscopy. Iodometric titration of the product gave a percarbonate assay of 93%.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[N:5][N:6]=1.C([O:17][CH:18]=[CH:19][C:20](OCC)=O)C>>[CH2:8]([S:7][C:4]1[S:3][C:2]2=[N:1][CH:20]=[CH:19][C:18](=[O:17])[N:6]2[N:5]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCSc1nnc(N)s1
Reactant: CCOC=CC(=O)OCC
Product: CCCCCCCSc1nn2c(=O)ccnc2s1
Reaction time: 0.5 h
Yield: 51.2 %

Procedure:
A mixture of 20.1 g of 2-amino-5-heptylthio-1,3,4-thiadiazole, 20.0 g of ethyl 3-ethoxypropenoate and 23 g of polyphosphoric acid was heated to 130°~140° C. and stirred for 30 minutes. The residue obtained by the same procedure as in Preparation Example 13 was purified by silica gel column chromatography using an ethyl acetate/toluene mixture as an eluent. Thus 12.6 g of 2-heptylthio-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. Yield 51%.
Reaction SMILES: C(Cl)CCl.[NH2:5][C:6]1[N:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]([OH:16])=O)=[CH:8][CH:7]=1.[CH3:17][N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([CH2:27][NH:28][CH3:29])=[CH:19]1.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:5][C:6]1[N:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([N:28]([CH3:29])[CH2:27][C:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]([CH3:17])[CH:19]=2)=[O:16])=[CH:8][CH:7]=1
Reactant: CNCc1cn(C)c2ccccc12
Reactant: Nc1ccc(C=CC(=O)O)cn1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(Cc1cn(C)c2ccccc12)C(=O)/C=C/c1ccc(N)nc1
Reaction time: 8 h
Yield: 54.4 %

Procedure:
EDC (0.35 g, 1.89 mmole) was added to a solution of 3-(6-aminopyridin-3-yl)acrylic acid (0.31 g. 1.89 mmole), 1-methyl-3-(methylaminomethyl)-1H-indole (0.30 g, 1.72 mmole), HOBt 1H2O (0.24 g, 1.89 mmole) and diisopropylethylamine (0.60 mL, 3.44 mmole) in DMF (20 mL) at RT. The reaction was stirred overnight, then was concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine and dried over Na2SO4. Flash chromatography on silica gel (5% MeOHWCHCl3) gave the title compound (0.30 g, 55%) as a light yellow solid: MS (ES) m/e 321 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH3:22]>>[C:15]1([CH2:14][N:11]2[CH2:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH2:22])=[CH:3][CH:4]=3)[CH2:9][CH2:10]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OC1(c2ccc(Br)cc2)CCN(Cc2ccccc2)CC1
Reactant: N
Product: Nc1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Temperature: 180 °C

Procedure:
A mixture of 4-(4-bromophenyl)-1-(phenylmethyl)-4-piperidinol (0.23 mole) and Cu2O (2 g) in aqueous ammonia (500 ml) was stirred at 180° C. for twelve hours. The mixture was cooled, extracted with DCM and washed with water. The organic layer was dried, filtered off and evaporated, yielding 60 g of 4-[1,2,3,6-tetrahydro-1-(phenylmethyl)-4-pyridinyl]benzenamine.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21][CH3:22])[CH:17]=2)[CH:12]([C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][O:31][C:25]=3[CH:24]=2)[CH:11]1[C:32]([O:34][CH3:35])=[O:33].[H-].[Na+].Br[CH2:39][CH2:40][CH2:41][OH:42]>CN(C=O)C>[OH:42][CH2:41][CH2:40][CH2:39][O:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21][CH3:22])[CH:17]=2)[CH:12]([C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][O:31][C:25]=3[CH:24]=2)[CH:11]1[C:32]([O:34][CH3:35])=[O:33]
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1O)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Reactant: OCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCCCO)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64.5 %

Procedure:
Methyl(1RS,2RS,3RS)-3-(2-Hydroxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylate (0.14 g, 0.29 mmol) in dry DMF (1 ml) was added to NaH (9mg, 0.38 mmol) in a small volume of dry DMF. The mixture was stirred at ambient temperature for 20 min. then 3-bromopropan-1-ol (37 μl, 0.41 mmol) was added. After stirring for 1 h. the product was partitioned between 3M aqueous HCl and ethyl acetate. The organic layer was washed with water then brine, then dried (MgSO4 anhyd.) filtered and evaporated to give an oil. The product was purified by column chromatography to provide methyl(1RS,2RS,3RS)-3-[2-(3-Hydroxyprop-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (0.1 g, 65%)(1H-NMR indicated some epimerization had occurred at C-2). This material was used without further purification. Methyl(1RS,2RS,3RS)-3-[2-(3-Hydroxyprop-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylate (0.04 g, 0.075 mmol) was dissolved in methanol (2 ml) and aqueous potassium hydroxide added (2M, 0.22 ml, 0.44 mmol). The mixture was stirred under reflux overnight then cooled, diluted with water, acidified with 3M aqueous hydrochloric acid and extracted with ethyl acetate. The organic extract was washed with water and brine, dried (MgSO4 anhydrous), filtered and evaporated to give an oil. The product was purified by chromatography on silica-gel (eluant: ethyl acetate/hexane/3% acetic acid) to give 12 mg of free acid which was convened to its dicyclohexylamine salt.