Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3]1.C(N(CC)C(C)C)(C)C.Cl[S:18]([C:21]1[CH:22]=[C:23]([C:27]2[C:36]([CH3:38])([CH3:37])[CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[C:32]([C:39]([O:41][CH3:42])=[O:40])[CH:33]=3)[N:28]=2)[CH:24]=[CH:25][CH:26]=1)(=[O:20])=[O:19]>ClCCl>[CH3:37][C:36]1([CH3:38])[CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:39]([O:41][CH3:42])=[O:40])[CH:33]=2)[N:28]=[C:27]1[C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([S:18](=[O:20])(=[O:19])[NH:7][CH:4]2[CH2:5][CH2:6][N:2]([CH3:1])[CH2:3]2)[CH:22]=1
Reactant: CN1CCC(N)C1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)Cl)c1)=N2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)NC3CCN(C)C3)c1)=N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.6 %

Procedure:
To a stirred solution of 1-methylpyrrolidin-3-amine (52 mg, 0.52 mmol) and N,N-diisopropylethylamine (112 mg, 0.86 mmol) in dichloromethane (4 mL) was added methyl 2-(3-(chlorosulfonyl)phenyl)-3,3-dimethyl-3,4-dihydroquinoline-6-carboxylate (170 mg, 0.43 mmol) portionwise. The resultant yellow solution was stirred for 3 h at room temperature. The mixture was purified on preparative Thin layer chromatography to afford 152 mg of methyl 3,3-dimethyl-2-(3-(N-(1-methylpyrrolidin-3-yl)sulfamoyl)phenyl)-3,4-dihydroquinoline-6-carboxylate, which was used directly.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=2)[C:10](OC)=[O:11])[N:5]=[N:4][N:3]=1.O.[BH4-].[Li+].O1CCCC1>CCOCC.CO>[CH3:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH2:10][OH:11])[CH:14]=[C:15]([C:17]([F:19])([F:18])[F:20])[CH:16]=2)[N:5]=[N:4][N:3]=1
Reactant: COC(=O)c1cc(-n2nnnc2C)cc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1nnnn1-c1cc(CO)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
Methyl 3-(5-methyltetrazol-1-yl)-5-(trifluoromethyl)benzoate (1.56 g, 5.5 mmol) was dissolved in ether (20 ml) and cooled in ice. Water (98 ml, 98 mg, 5.5 mmol) then lithium borohydride (131 mg, 6 mmol) were added and the mixture was stirred at room temperature for 1 hour. Tetrahydrofuran (10 ml) was added and the mixture was stirred at room temperature for 1 hour. Methanol (5 ml) was added and the solvent was evaporated under reduced pressure. Saturated aqueous sodium hydrogen carbonate (20 ml) and water (10 ml) were added and the mixture was extracted with dichloromethane (10×10 ml). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by MPLC on silica gel, eluting with ethyl acetatelhexane (50:50 increasing to 100:0) to give 3-(5-methyltetrazol-1-yl)-5-(trifluoromethyl)phenylmethanol as a colorless oil (1.00 g, 70%), 1H (CDCl 3) δ 7.84 (1H, s), 7.75 (1H, s), 7.67 (1H, s), 4.92 (2H, s), 2.67 (3H, s), and 1.86 (1H, br s). m/z 259 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9](O)=[O:10])=[CH:4][CH:3]=1.S(Cl)([Cl:16])=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([Cl:16])=[O:10])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C(=O)O)c1ccc(Cl)cc1
Solvent: ClCCl
Product: CC(C)(C(=O)Cl)c1ccc(Cl)cc1
Temperature: 40 °C

Procedure:
2-(4-chlorophenyl)-2-methyl propionyl chloride was prepared as follows: To a flask containing 2-(4-chlorophenyl)-2-methyl propionic acid (15.0 g, 75.6 mmol) was added thionyl chloride (approx. 6 mL). Dichloromethane (20 mL) was then added before adding an additional portion of thionyl chloride (approx. 12 mL). The reaction was allowed to heat to 40° C. for two hours before cooling to room temperature and concentrating in vacuo (azeotroping with tetrahydrofuran). The resulting acid chloride was used in the following acylation step without further purification or characterization.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][O:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[C:10]([O:18][CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:9]=2)=[CH:2]1.C(=O)([O-])[O-].[K+].[K+]>CO>[S:1]1[CH:5]=[CH:4][C:3]([CH2:6][O:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[C:10]([O:18][CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:9]=2)=[CH:2]1
Reactant: COC(=O)c1ccc(OCc2ccsc2)cc1OCOCC[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C[Si](C)(C)CCOCOc1cc(OCc2ccsc2)ccc1C(=O)O
Yield: 51.7 %

Procedure:
A mixture of methyl 4-(3-thienylmethoxy)-2-(2-trimethylsilylethoxy)methoxybenzoate (12.1 g) and aqueous potassium carbonate solution (50 mL; 10% w/v) in methanol (200 mL) is heated at reflux for 7 hours. It is then concentrated in vacuo and the residue is treated with water (200 mL) and acidified to pH 1 by treatment with hydrochloric acid (1 N), and the resulting solid is quickly filtered off and is then washed with water. The white solid is then azeotroped with cyclohexane in a Dean-Stark apparatus until no more water is removed. The solid is filtered off, to give 4-(3-thienylmethoxy)-2-(2-trimethylsilylethoxy)methoxybenzoic acid (6.03 g), in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:65]1[C:69]([C:70]2[CH:71]=[C:72]([NH2:76])[CH:73]=[CH:74][CH:75]=2)=[N:68][N:67]=[N:66]1>C(Cl)Cl>[NH:68]1[C:69]([C:70]2[CH:71]=[C:72]([NH:76][C:28]([CH:9]3[CH:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=4[F:31])[C:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]3)=[O:29])[CH:73]=[CH:74][CH:75]=2)=[N:65][N:66]=[N:67]1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2cccc(-c3nnn[nH]3)c2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.172 mmol) in methylene chloride (10 mL), HATU (Aldrich, 130 mg, 0.344 mmol) was added followed by the addition of DIPEA (90 uL, 0.52 mmol) and 3-(1H-tetrazol-5-yl)-phenylamine (Alfa, 55 mg, 0.344 mmol). The mixture was stirred at rt for 2 hrs. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on a reverse phase HPLC (24 g column, eluent, 30% EtOAc/methylene chloride) to give a yellow solid. 21 mg.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([F:21])[CH:15]=2)[C@H:10]2[CH2:22][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])[CH3:2].[CH3:23][S:24]([NH:27][C:28]1[CH:43]=[CH:42][C:31]2[NH:32][C:33]([CH2:38][C:39](O)=[O:40])=[N:34][S:35](=[O:37])(=[O:36])[C:30]=2[CH:29]=1)(=[O:26])=[O:25].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.Cl>CN(C)C=O>[CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([F:21])[CH:15]=2)[C:39](=[O:40])[CH2:38][C:33]2[NH:32][C:31]3[CH:42]=[CH:43][C:28]([NH:27][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:29][C:30]=3[S:35](=[O:36])(=[O:37])[N:34]=2)[C@H:10]2[CH2:22][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCc1ccc(C)c(F)c1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N(Cc1ccc(C)c(F)c1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (1S,2R,3S,4R)-3-(3-fluoro-4-methyl-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (92 mg, 0.30 mmol), (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1g, 100 mg, 0.30 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (60 mg, 0.315 mmol) in N,N-dimethylformamide (4.0 mL) was added N-methylmorpholine (0.07 mL, 0.63 mmol). After stirring at 25° C. for 3 h, the mixture was poured into a 1.0 M aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with saturated aqueous brine solution, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude product, (1S,2R,3S,4R)-3-{(3-fluoro-4-methyl-benzyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester, as an orange oil. The crude product was used in the next step without further purification. LC-MS (ESI) calcd for C28H33FN4O7S2 620.18. found 621.4 [M+H+].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]([O:19][CH3:20])=[O:18].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](B(O)O)[CH:30]=1>CN(C=O)C.O.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>[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:6]=[C:5]3[C:17]([O:19][CH3:20])=[O:18])[CH:30]=1
Reactant: COC(=O)c1nn(C2CCCCO2)c2ccc(Br)cc12
Reactant: OB(O)c1cccnc1
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: CN(C)C=O
Solvent: O
Product: COC(=O)c1nn(C2CCCCO2)c2ccc(-c3cccnc3)cc12
Temperature: 90 °C
Yield: 90 %

Procedure:
To a solution of methyl 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylate (CXVII) (7.0 g, 20.6 mmol) in DMF (80 mL) and water (16 mL) was added K3PO4 (6.56 g, 30.9 mmol), pyridin-3-ylboronic acid (CXXXI) (2.79 g, 22.7 mmol), Pd(PPh3)4 (1.19 g, 1.03 mmol) and. The solution was purged with argon and heated at 90° C. for 3 h. The solution was cooled to room temperature and then concentrated under reduced pressure. The residue was dissolved in DCM and washed with water, dried over MgSO4, filtered and then evaporated under vacuum. The residue was purified on a silica gel column (100% DCM→1.5:98.5 MeOH:DCM) to give methyl 5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylate (CXXXIX) as an orange oil which solidified at rt (6.28 g, 18.6 mmol, 90% yield). ESIMS found for C19H19N3O3 m/z 338.0 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[O:21][C:20]([NH:22][CH2:23][C:24]5[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=5)=[N:19][N:18]=4)[CH:15]=3)[N:10]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:9]=2)[CH:5]=[N:4][CH:3]=1.[F:42][C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[F:42][C:43]1[CH:48]=[CH:47][C:46]([C:2]2[N:7]=[C:6]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]5[O:21][C:20]([NH:22][CH2:23][C:24]6[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=6)=[N:19][N:18]=5)[CH:15]=4)[N:10]([S:32]([C:35]4[CH:36]=[CH:37][C:38]([CH3:39])=[CH:40][CH:41]=4)(=[O:34])=[O:33])[CH:9]=3)[CH:5]=[N:4][CH:3]=2)=[CH:45][CH:44]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cncc(Cl)n3)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cncc(-c5ccc(F)cc5)n3)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Yield: 36.3 %

Procedure:
To a solution of 5-(3-(6-chloropyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (500 mg, 0.853 mmol) and 4-fluorophenylboronic acid (143.5 mg, 1.02 mmol) in 1,4-dioxane/H2O (3:1, 15 mL), was added K2CO3 (235.5 mg, 1.71 mmol) and Pd(PPh3)4 (49 mg, 0.0427 mmol). The reaction was heated at reflux for 24 h then quenched with H2O and extracted with EtOAc. The organic layer was dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 50% EtOAc in Hex) to give 5-(3-(6-(4-fluorophenyl)pyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (200 mg, 36.5%). MS (ESI, pos. ion) m/z: 647.1 (M+1); 1H-NMR (400 MHz DMSO-d6): δ 12.11 (s, 1H), 9.18 (s, 1H), 9.08-8.98 (m, 2H), 8.52 (d, J=2.8 Hz, 1H), 8.36-8.33 (m, 2H), 8.14-8.03 (m, 1H), 7.74 (d, J=8 Hz, 1H), 7.65-7.55 (m, 2H), 7.46-7.7.28 (m, 4H), 6.92-6.88 (m, 2H), 4.41 (m, 2H), 3.73 (s, 3H), 2.24 (s, 3H).
Reaction SMILES: [CH2:1]=[O:2].[N:3]1[C:10]([NH2:11])=[N:9][C:7]([NH2:8])=[N:6][C:4]=1[NH2:5]>>[CH2:1]([NH:5][C:4]1[N:6]=[C:7]([NH2:8])[N:9]=[C:10]([NH2:11])[N:3]=1)[OH:2]
Reactant: Nc1nc(N)nc(N)n1
Reactant: C=O
Product: Nc1nc(N)nc(NCO)n1

Procedure:
Formaldehyde reacts with melamine to form methylol melamine: ##STR2## Polymerization of melamine and formaldehyde is inhibited by keeping the solution at an alkaline pH, by keeping the temperature and concentration of reactants somewhat low, and by the inclusion of methanol in the formalin solution (formalin solutions typically include about 15% methanol to inhibit polymerization of formaldehyde molecules).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[C:8]([O:10]C)[CH:7]=[CH:6][C:5]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[BrH:18]>>[BrH:18].[BrH:18].[OH:10][C:8]1[CH:7]=[CH:6][C:5]([N:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)=[C:4]([O:3][CH3:2])[CH:9]=1
Reactant: COc1ccc(N2CCNCC2)c(OC)c1
Agent: Br
Agent: Cl
Product: COc1cc(O)ccc1N1CCNCC1

Procedure:
A mixture of 1-(2,4-dimethoxyphenyl) piperazine hydrochloride (3.1 g, 13.9 mmol) in 30 mL of approximately 40% aqueous hydrogen bromide was heated at reflux for 30 hours and then the volatiles were removed in vacuo. Recrystallization of the residue from methanol gave 1-(4-hydroxy-2-methoxyphenyl)piperazine dihydrobromide (4.6 g, 12.4 mmol), m.p. >280° C.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]([NH:19][C:20](N)=[O:21])=[O:18].C(N(C(C)C)CC)(C)C.C([O-])(=O)CCC([O-])=O>N1C=CC=CC=1>[N:6]12[CH2:11][CH2:10][CH:9]([CH2:8][CH2:7]1)[CH:4]([NH:3][C:20]([NH:19][C:17]([C:13]1[O:12][CH:16]=[CH:15][CH:14]=1)=[O:18])=[O:21])[CH2:5]2
Reactant: NC(=O)NC(=O)c1ccco1
Reactant: NC1CN2CCC1CC2
Agent: Cl
Agent: O=C([O-])CCC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC(=O)c1ccco1)NC1CN2CCC1CC2

Procedure:
The above compound was prepared, following the procedure of Example 14b, from 3-aminoquinuclidine dihydrochloride (1.0 g, 5 mmol), 2-furoylurea (0.77 g, 5 mmol), and diisopropylethylamine (1.3 g, 10 mmol) in pyridine (20 ml). The product (0.58 g) was converted to the 1:1 succinate mp 156°-159° C.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.CS(Cl)(=O)=O.[NH2:15][C:16]1[N:21]=[C:20]([NH2:22])[N:19]=[C:18]([C:23]2[C:24]([F:33])=[CH:25][C:26]3[C:31]([CH:32]=2)=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:17]=1>N1C=CC=CC=1>[NH2:22][C:20]1[N:21]=[C:16]([NH:15][C:1](=[O:9])[C:2]2[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=2)[N:17]=[C:18]([C:23]2[C:24]([F:33])=[CH:25][C:26]3[C:31]([CH:32]=2)=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:19]=1
Reactant: O=C(O)c1cccnc1
Reactant: Nc1nc(N)nc(-c2cc3ccccc3cc2F)n1
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: Nc1nc(NC(=O)c2cccnc2)nc(-c2cc3ccccc3cc2F)n1

Procedure:
Nicotinic acid (0.58 gram) was dissolved in 10 ml of pyridine, 0.27 gram of methanesulfonyl chloride was added thereto, the mixture was heated to reflux for thirty minutes, 0.5 gram of 2,4-diamino-6-(2-fluoro-3-naphthyl)-s-triazine was added, and the mixture was heated to reflux for four hours. After the reaction was completed, pyridine was evaporated, water was added to the residue, the resulting separated mass was subjected to a column chromatography using 100 grams of silica gel, and eluted with ethyl acetate-benzene (9:1) to afford 2-amino-4-nicotinoylamino-6-(2-fluoro-3-naphthyl)-s-triazine, colourless crystals, melting point 230° to 235° C. (with decomposition). The yield was 0.35 gram.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([O:11][CH2:12][CH2:13][Cl:14])=[CH:8][C:9]=1C)=[O:4].COC(C1SC(OCCCl)=C(C)C=1)=O>CO.O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([O:11][CH2:12][CH2:13][Cl:14])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1sc(OCCCl)cc1C
Agent: COC(=O)c1cc(C)c(OCCCl)s1
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(OCCCl)s1

Procedure:
3-Methyl-5-(2-chloro-1-ethoxy)-thiophene-2-carboxylic acid methyl ester, melting point (MeOH/H2O) 47°-50° C. (86%), and 4-Methyl-5-(2-chloro-1-ethoxy)-thiophene-2-carboxylic acid methyl ester, melting point (petroleum ether) 75° C. (90%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][N:6]=1)=[O:4].[CH3:14][C:15](C)([O-])[CH3:16].[K+]>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH:15]([CH3:16])[CH3:14])[N:6]=1)=[O:4]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)c1n[nH]c2ccccc12
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1nn(C(C)C)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
To a solution of indazole-3-carboxylic acid methyl ester (40.7 g, 231 mmol) in anhydrous tetrahydrofuran (700 mL) cooled in an ice bath was added slowly solid potassium tert-butoxide (28.3 g, 252 mmol). The mixture was stirred at the same temperature for 1 hr prior to the addition of 2-iododopropane (34.4 mL, 367 mmol). The final mixture was stirred for 12 h at ambient temperature, and refluxed for 12 h. After cooling to room temperature, the mixture was filtered, and the collected solid was rinsed with tetrahydrofuran (100 mL). The filtrates were combined, and concentrated to dryness under reduced pressure, affording crude 1-isopropyl-1H-indazole-3-carboxylic acid methyl ester (49.7 g) as a pale yellow oil. The crude material was purified by flash silica gel chromatography eluting with hexane/ethyl acetate (9/1 to 3/1) to yield 1-isopropyl-1H-indazole-3-carboxylic acid methyl ester (43 g, 197 mmol, >99% pure). 1H-NMR (CD3OD, 300 MHz): δ (ppm) 8.1-8.0 (1H, d), 7.6 (1H, d), 7.4 (1H, t), 7.2 (1H, t), 5.0 (1H, quin), 3.9 (s, 3H), 1.5 (6H, d).
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[C:16]([C:18]2[N:22]=[C:21](C(Cl)(Cl)Cl)[O:20][N:19]=2)[CH:15]=[C:14]([CH3:27])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]1[O:12][N:11]=[C:10]([CH3:13])[CH:9]=1.[CH3:28][O-:29].[Na+].CO>CN(C)C=O.O>[CH3:1][C:2]1[CH:17]=[C:16]([C:18]2[N:22]=[C:21]([O:29][CH3:28])[O:20][N:19]=2)[CH:15]=[C:14]([CH3:27])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]1[O:12][N:11]=[C:10]([CH3:13])[CH:9]=1
Reactant: Cc1cc(CCCOc2c(C)cc(-c3noc(C(Cl)(Cl)Cl)n3)cc2C)on1
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: COc1nc(-c2cc(C)c(OCCCc3cc(C)no3)c(C)c2)no1
Temperature: 25 °C
Reaction time: 0.38 h

Procedure:
The product of Example 12 (627 mg, 1.46 mmol) was added to a freshly prepared solution of sodium methoxide in methanol (1.5 equivalents sodium in 5 mL methanol) in dry dimethylformamide (3-5 mL) and the mixture was stirred at room temperature for 15-30 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate (3x). The combined organic extracts were washed with water, brine, dried (MgSO4) and concentrated in vacuo. The crude residue (0.64 g) was purified by chromatography (Silica Gel 60, first with 2% methanol in methylene chloride followed by 5% ethyl acetate in methylene chloride) to give pure title compound (308 rag) as a colorless oil which crystallized from methanol, mp 64.5°-65.5° C. (white solid).
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[C:11]3[C:17]2[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH:22]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].CO>[CH:1]1([O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[C:11]3[CH:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CC=C(c2c[nH]c3ccc(OC4CCCCC4)cc23)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCC(c2c[nH]c3ccc(OC4CCCCC4)cc23)CC1
Reaction time: 8 h

Procedure:
Palladium on carbon (10%, 31 mg) was added to a solution of 5-cyclohexyloxy-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4c, 48.4 mg, 0.16 mmol) in methanol (5 mL) and the mixture was stirred under an atmosphere of hydrogen for 8 h. Removal of the catalyst by filtration through celite and silica (20% 2M methanolic ammonia in dichloromethane) yielded 5-cyclohexyloxy-3-(1-methyl-4-piperidinyl)-1H-indole (quantitative, HRMS-FAB+ for C20H28N2O: calculated MH+: 313.22800; found MH+ : 313.23083).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C(N(CC)CC)C.[CH:13]1([C:16](Cl)=[O:17])[CH2:15][CH2:14]1>C(Cl)Cl>[CH3:5][O:4][N:3]([CH3:2])[C:16]([CH:13]1[CH2:15][CH2:14]1)=[O:17]
Reactant: CNOC
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C1CC1
Reaction time: 1 h
Yield: 61.4 %

Procedure:
N,O-dimethyl-hydroxylamine HCl (40 g, 410 mmol) was suspended under nitrogen in DCM (400 mL) and cooled in ice. Triethylamine (63 mL, 451 mmol) was added slowly, then cyclopropanecarbonyl chloride (41 mL, 451 mmol) was added slowly. Stirring without cooling was continued for 1 h. Extraction: 2×DCM, 1×1 N HCl, 1×NaCl. Distillation: 75° C./20 mbar. One obtained 32.5 g (61%) of a colorless oil.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[NH2:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][CH:11]=1>CS(C)=O>[NH2:9][C:10]1[CH:11]=[CH:12][C:13]([C@@H:16]2[CH2:4][C@H:17]2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:15]=1
Reactant: CCOC(=O)/C=C/c1ccc(N)cc1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(N)cc1
Reaction time: 8 h

Procedure:
To a suspension of sodium hydride (36 mg, 0.89 mmol) in DMSO (2 mL) was added the solid trimethyl sulfoxonium iodide (185 mg, 1.05 mmol). The mixture was stirred for 25 min before a solution of ethyl (E)-3-(4-aminophenyl)prop-2-enoate (100 mg, 0.52 mmol) in DMSO (2 mL) was added quickly at RT. The mixture was left to stir overnight. The bulk mixture was quenched with NH4Cl (sat.) and the mixture diluted with water and EtOAc. The layers were separated and the aqueous layer extracted into EtOAc (3×30 mL). The organic fractions were combined, dried with brine then MgSO4 and the solvent removed. Flash chromatography on silica gel, eluting with 20-50% ethyl acetate gradient in n-heptane, gave ethyl (1R,2R)-2-(4-aminophenyl)cyclopropanecarboxylate, 70 mg. 1H NMR (400 MHz, CDCl3) δ 6.96-6.89 (m, 2H), 6.68-6.61 (m, 2H), 4.17 (q, J=7.1 Hz, 2H), 2.44 (ddd, J=9.2, 6.6, 4.2 Hz, 1H), 1.80 (ddd, J=8.4, 5.2, 4.2 Hz, 1H), 1.53 (ddd, J=9.2, 5.2, 4.5 Hz, 1H), 1.28 (t, J=7.1 Hz, 3H), 1.24 (ddd, J=8.3, 6.6, 4.5 Hz, 1H).