Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:11][CH3:12])=[N:4][C:5]([O:8][CH2:9][CH3:10])=[CH:6][CH:7]=1.[C:13]([OH:17])(=O)[CH2:14]O>>[CH2:9]([O:8][C:5]1[N:4]=[C:3]2[N:11]([CH3:12])[C:14]([CH2:13][OH:17])=[N:1][C:2]2=[CH:7][CH:6]=1)[CH3:10]
Reactant: O=C(O)CO
Reactant: CCOc1ccc(N)c(NC)n1
Product: CCOc1ccc2nc(CO)n(C)c2n1
Yield: 62.2 %

Procedure:
A procedure similar to that described in Preparation 43 was repeated, except that 4.15 g 3-amino-6-ethoxy-2-methylaminopyridine (prepared as described in Preparation 97), and 5.66 g of glycolic acid were used, and that the product was purified by column chromatography through silica gel, using a 10:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 3.20 g of the title compound, melting at 161° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O.O>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:17][C:16]2[CH:19]=[CH:20][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1ccc(O)cc1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C=CCc1ccc(OCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Allylphenol, (6.14 g, 0.046 moles), 4-methoxybenzyl chloride, (6.3 ml, 0.046 moles), potassium carbonate (8.3 g, 0.06 moles) and a catalytic amount of potassium iodide were mixed together in about 200 ml acetone, and heated to reflux, with stirring. The reaction was allowed to proceed overnight, then cooled to room temperature and diluted with about 100 ml water. The product was extracted into ethyl acetate (3 times, 300 ml each time), and then dried over magnesium sulfate/potassium carbonate, filtered and concentrated in vacuo to yield the title compound as a light yellow solid, m.p. 59-61° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])[C:5]([Cl:17])=[CH:4][N:3]=1.[S:18]([NH2:28])(=[O:27])([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)=[O:19].N>C(O)CCC>[S:18]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]#[N:16])[C:5]([Cl:17])=[CH:4][N:3]=2)=[CH:22][CH:21]=1)(=[O:19])(=[O:27])[NH2:28]
Reactant: N#Cc1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Agent: N
Solvent: CCCCO
Product: N#Cc1ccccc1Nc1nc(Nc2ccc(S(N)(=O)=O)cc2)ncc1Cl
Temperature: 25 °C
Yield: 10.6 %

Procedure:
2,5-Dichloro4-(2-cyanoanilino)pyrimidine (265 mg, 1.00 mmol) was dissolved in n-butanol (1 ml) and sulphanilamide (207 mg, 1.20 mmol) was added. The resulting suspension was heated at reflux for 2 hours and allowed to cool to ambient temperature. The reaction mixture was then basified using methanolic ammonia and evaporated onto silica. The residue was purified by column chromatography eluting with 0–15% 2.0M methanolic ammonia solution in dichloromethane to afford a solid product (42.6 mg). NMR (303.1K): 7.09 (2H, s), 7.41–7.59 (5H, m), 7.65 (1H, d), 7.74–7.86 (1H, m), 7.94 (1H, d 8.25 (1H, s), 9.46 (1H, s), 9.78 (1H, s); MS (M+H)+: 401, 403.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[C@@H:3]1[CH2:18][C:19](O)=[O:20].[Si:22]([O:29][CH2:30][CH2:31][N:32]1[C:40]2[CH2:39][CH2:38][CH2:37][CH:36]([NH2:41])[C:35]=2[CH:34]=[N:33]1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[Si:22]([O:29][CH2:30][CH2:31][N:32]1[C:40]2[CH2:39][CH2:38][CH2:37][CH:36]([NH:41][C:19](=[O:20])[CH2:18][C@@H:3]3[C:2](=[O:1])[NH:7][CH2:6][CH2:5][N:4]3[S:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:15])=[CH:16][CH:17]=3)(=[O:10])=[O:9])[C:35]=2[CH:34]=[N:33]1)([C:25]([CH3:28])([CH3:26])[CH3:27])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)OCCn1ncc2c1CCCC2N
Reactant: Cc1ccc(S(=O)(=O)N2CCNC(=O)[C@H]2CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CCNC(=O)[C@H]2CC(=O)NC2CCCc3c2cnn3CCO[Si](C)(C)C(C)(C)C)cc1

Procedure:
A solution of (R)-2-(3-oxo-1-tosylpiperazin-2-yl)acetic acid (624 mg, 2.0 mmol), 1-(2-(tert-butyldimethylsilyloxy)ethyl)-4,5,6,7-tetrahydro-1H-indazol-4-amine (649 mg, 2.2 mmol), HOBt (297 mg, 2.2 mmol) and EDCI (422 mg, 2.2 mmol) in 1.2 mL of DMF was stirred overnight at room temperature. After quenching with Sat. NaHCO3 solution, the reaction mixture was extracted with EtOAc. The combined organic phase was washed brine, dried over Na2SO4, and evaporated in vaco. Flash chromatography (SiO2, EtOAc/MeOH=100:4 to 100:8 to 100:10 to 100:15) gave the title compound as a white solid. MS: 590.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([O:18][CH:19]2[CH2:23][CH2:22][NH:21][CH2:20]2)[CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][C:12](=[O:32])[N:13]2[C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:31].C=O.[C:35]([BH3-])#N.[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([O:18][CH:19]2[CH2:23][CH2:22][N:21]([CH3:35])[CH2:20]2)[CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][C:12](=[O:32])[N:13]2[C:24]1[C:25]([Cl:31])=[CH:26][CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: O=C1CCc2c(-c3ccccc3Cl)cc(OC3CCNC3)cc2N1c1c(Cl)cccc1Cl
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCC(Oc2cc(-c3ccccc3Cl)c3c(c2)N(c2c(Cl)cccc2Cl)C(=O)CC3)C1
Reaction time: 48 h

Procedure:
To a solution of 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-(pyrrolidin-3-yloxy)-3,4-dihydroquinolin-2(1H)-one (0.046 g) in 5 mL of methanol was added formaldehyde (50 μL) and sodium cyanoborohydride (0.012 g). The reaction mixture was stirred for 48 h, then washed with 1N HCl (5 mL), extracted with 5×5 mL of ethyl acetate, washed with brine (5 mL), dried with sodium sulfate, and concentrated. Purification was achieved by preparative thin layer chromatography eluting with 10% ethanol/dichloromethane to yield product. Mass spectrum (ESI) 501.1 (M+1). 1H NMR (500 MHz, CDCl3): δ 7.50-7.48 (m, 3H), 7.36-7.30 (m, 4H) 6.38 (s, 1H), 5.85 (s, 1H), 4.66 (m, 1H), 2.87-2.65 (m, 8H), 2.36 (s, 3H), 2.18-2.15 m, 1H), 1.94-1.91 (m, 1H).
Reaction SMILES: [Cl:1][CH:2]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:3]([N:5]1[CH2:14][C:13]2[CH:12]=[N:11][C:10]3[NH:15][N:16]=[CH:17][C:9]=3[C:8]=2[CH2:7][CH2:6]1)=[O:4].[Br:24]N1C(=O)CCC1=O>ClCCl>[Br:24][C:17]1[C:9]2[C:8]3[CH2:7][CH2:6][N:5]([C:3](=[O:4])[CH:2]([Cl:1])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:14][C:13]=3[CH:12]=[N:11][C:10]=2[NH:15][N:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(C(Cl)c1ccccc1)N1CCc2c(cnc3[nH]ncc23)C1
Solvent: ClCCl
Product: O=C(C(Cl)c1ccccc1)N1CCc2c(cnc3[nH]nc(Br)c23)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.1 %

Procedure:
To a solution of 2-chloro-1-(8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7(6H)-yl)-2-phenylethanone (0.340 g, 1.04 mmol) in dichloromethane (20 mL) was added N-bromosuccinimide (NBS, 0.195 g, 1.09 mmol). The reaction mixture was stirred for 16 hours at room temperature. During the reaction a yellow solid crashed out. The reaction was quenched by addition of aqueous NaHCO3. The aqueous layer was extracted with EtOAc (2×200 mL). The combined organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure to give crude 1-(1-bromo-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7(6H)-yl)-2-chloro-2-phenylethanone as a pale yellow solid (0.38 g, 90%). 1H NMR (400 MHz, DMSO-d6) δ11.08 (brs, 1H), 8.43 (s, 1H), 7.52-7.39 (m, 5H), 6.52 (s, 1H), 4.80 (m, 2H), 3.85 (m, 2H), 3.28 (m, 2H); LCMS [M+H]: 405. The product was used in the next step without any further purification.
Reaction SMILES: C([O:8][C:9]([NH:11][C:12]12[CH2:19][C:16]([C:20]([O:22]C)=O)([CH2:17][CH2:18]1)[CH2:15][CH2:14][CH2:13]2)=O)C1C=CC=CC=1.[Li+].[BH4-].N#N.[CH2:28]1COCC1>>[OH:22][CH2:20][C:16]12[CH2:19][C:12]([NH:11][C:9](=[O:8])[CH3:28])([CH2:18][CH2:17]1)[CH2:13][CH2:14][CH2:15]2
Reactant: C1CCOC1
Reactant: COC(=O)C12CCCC(NC(=O)OCc3ccccc3)(CC1)C2
Agent: N#N
Agent: [BH4-]
Agent: [Li+]
Product: CC(=O)NC12CCCC(CO)(CC1)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a stirred solution of methyl 5-(benzyloxycarbonylamino)bicyclo[3.2.1]octane-1-carboxylate (1.0 g, 3.15 mmol) in THF (20 mL) at 0° C. was added LiBH4 (2M in THF, 3 mL, 6 mmol) dropwise under N2. After stirring at 0° C. for 30 min, the reaction was allowed to warm up to room temperature overnight. The reaction was quenched with Sat. NH4Cl and resulting mixture was extracted with ethyl acetate (3×20 mL). Combined organic phase was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford a residue, which was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=3/1) to give 750 mg (81%) of the title compound, N-(5-(hydroxymethyl)bicyclo[3.2.1]octan-1-yl)acetamide as a colorless oil. ESI-MS m/z: 290 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[Cl:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:31]2[CH2:30][CH2:29][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([Cl:21])[CH:23]=3)[CH2:33][CH2:32]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(OC)ccc2nc1OC
Reactant: Clc1cccc(N2CCNCC2)c1
Product: COc1ccc2nc(OC)c(NC(=O)N3CCN(c4cccc(Cl)c4)CC3)nc2c1
Yield: 85 %

Procedure:
Ethyl N-(2,6-dimethoxyquinoxalin-3-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 64 to obtain the titled compound (yield, 85%). 1H NMR (300 MHz, CDCl3): δ 3.21-3.32 (m, 4H), 3.75-3.88 (m, 6H), 4.10-4.13 (m, 4H), 6.80-6.90 (m, 4H), 7.14-7.29 (m, 3H), 7.63-7.66 (m, 1H).
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[Cl:17][C:18]1[CH:19]=[C:20]([S:24]([N:27]2[CH2:43][CH2:42][C:30]3([N:34]=[C:33]([CH:35]4[CH2:40][CH2:39][CH2:38][NH:37][CH2:36]4)[NH:32][C:31]3=[O:41])[CH2:29][CH2:28]2)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1>ClCCl>[Cl:17][C:18]1[CH:19]=[C:20]([S:24]([N:27]2[CH2:43][CH2:42][C:30]3([N:34]=[C:33]([CH:35]4[CH2:40][CH2:39][CH2:38][N:37]([C:7]([N:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)=[O:8])[CH2:36]4)[NH:32][C:31]3=[O:41])[CH2:29][CH2:28]2)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1
Reactant: O=C(Cl)N1CCCCC1
Reactant: O=C1NC(C2CCCNC2)=NC12CCN(S(=O)(=O)c1cccc(Cl)c1)CC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N1CCCCC1)N1CCCC(C2=NC3(CCN(S(=O)(=O)c4cccc(Cl)c4)CC3)C(=O)N2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.1 %

Procedure:
TEA (1.143 mmol, 3 eq) and piperidine-1-carbonyl chloride (0.457 mmol, 1.2 eq) were sequentially added to a mixed solution of 8-(3-chloro-benzenesulfonyl)-2-piperidin-3-yl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one trifluoroacetate (200 mg, 0.38 mmol) in dichloromethane (3 ml). The resulting mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The resulting residue was purified by HPLC to give 8-(3-chloro-benzenesulfonyl)-2-[1-(piperidine-1-carbonyl)-piperidin-3-yl]-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (30 mg, yield 15%).
Reaction SMILES: [C:1]1([C:10]#[N:11])[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2.I[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([O:23][CH2:24][O:25][CH3:26])[CH:14]=1.C([O-])(=O)C.[K+].O>CN1CCCC1=O>[C:10]([C:1]1[CH:2]=[C:3]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([O:23][CH2:24][O:25][CH3:26])[CH:14]=2)[N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2)#[N:11]
Reactant: COCOc1cc(I)ccc1C(=O)OC
Reactant: N#Cc1ccn2ccccc12
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COCOc1cc(-c2cc(C#N)c3ccccn23)ccc1C(=O)OC
Temperature: 100 °C
Reaction time: 1 h
Yield: 35.9 %

Procedure:
To a solution of indolizine-1-carbonitrile (0.20 g) in N-methylpyrrolidone (5 mL) were added methyl 4-iodo-2-methoxymethoxybenzoate (0.5 g), dichlorobis (triphenylphosphine) palladium (II) (0.05 g), potassium acetate (0.28 g) and water (0.05 mL), and the mixture was stirred at 100° C. for 1 hour. After cooling to room temperature, to the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=100/0-0/100) to give methyl 4-(1-cyanoindolizine-3-yl)-2-methoxymethoxybenzoate (0.17 g). To a mixed solution of the obtained compound (0.17 g) in tetrahydrofuran (4.5 mL), ethanol (1.5 mL) and water (1.5 mL) was added lithium hydroxide monohydrate (0.10 g), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 2 mol/L hydrochloric acid (1.5 mL), and the mixture was stirred at 50° C. overnight. After cooling to room temperature, to the reaction mixture was added water. The precipitated solid was collected by filtration, washed with water and n-hexanc, and dried under reduced pressure at 50° C. to give the title compound (0.11 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[CH:12]3)[CH:5]=[N:4][CH:3]=1.[N:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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:18]1[CH:23]=[CH:22][C:21]([C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=3)[NH:14][CH:13]=[CH:12]4)[CH:5]=[N:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: OB(O)c1ccncc1
Reactant: Clc1cncc(Nc2ccc3[nH]ccc3c2)n1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: c1cc(-c2cncc(Nc3ccc4[nH]ccc4c3)n2)ccn1
Yield: 31.1 %

Procedure:
A mixture of N-(6-chloro-pyrazin-2-yl)-1H-indol-5-amine (0.030 g, 0.123 mmol), pyridine-4-boronic acid (0.018 g, 0.147 mmol), sodium carbonate (0.067 g, 0.615 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.007 g, 0.006 mmol) in DME:water (3:2, 5 mL) was heated at reflux for 20 h. The reaction mixture was concentrated under reduced pressure and the residue obtained was extracted with dichloromethane. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (5% methanol in CH2Cl2 as eluent) to yield N-(6-pyridin-4-ylpyrazin-2-yl)-1H-indol-5-amine (0.011 g, 31%) as a yellow solid. 1H NMR (CD3OD) δ 8.70-8.68 (d, J=6.17 Hz, 2H), 8.47 (s, 1H), 8.15 (s, 1H), 8.14 (d, J=1.50 Hz, 2H) 7.96 (d, J=1.70 Hz, 1H), 7.45-7.43 (d, J=8.64 Hz, 1H), 7.37-7.35 (dd, J=10.46, 1.83 Hz, 1H), 7.29-7.28 (d, J=3.06 Hz, 1H), 6.49-6.48 (d, J=3.02 Hz, 1H); MS (API-ES/Positive); m/z: 288 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=[O:16].Cl.C(O)(=O)C.[NH3:26]>[Cu]I>[NH2:26][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=[O:16]
Reactant: Cc1cc(Br)c2cnn(-c3cccc(C(=O)O)c3)c2c1
Reactant: N
Agent: [Cu]I
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cc(N)c2cnn(-c3cccc(C(=O)O)c3)c2c1
Temperature: 20 °C
Reaction time: 48 h

Procedure:
A suspension of 3-(4-bromo-6-methyl-1H-indazol-1-yl)benzoic acid (1450.5 g, 4.38 mol) and copper (I) iodide (42.47 g, 0.22 mol, 5 mol %) in aqueous ammonia (0.88 sg, 13.5 L) was heated in a sealed pressure vessel until a pressure of 7 Bar±0.3 Bar was generated (contents temperature ˜78° C.). Stirring was continued for a period of ca. 2 days. The reaction mixture was cooled to 20° C. and then charged in to a Controlled Lab Reactor fitted with a 5M HCl scrubber. The solution was heated at reflux to remove excess ammonia by gradually raising the contents temperature to >90° C.—end point pH 7.87. The reaction mixture was then cooled to 60±3° C. and acetic acid (725 mL, 12.7 mol) was added slowly to form a precipitate—end point pH=5.68. The batch was cooled to 5±3° C. and stirred for 825 minutes. The slurry was filtered and washed with water (3×4.5 L). The solid was dried in vacuo at 50° C. to afford the title compound (1112.3 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:19][CH2:20][CH3:21])[CH:16]=3)[CH:11]([C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[CH:10]2[C:31]([O:33]C)=[O:32])=[C:5]([O:35][CH2:36][O:37][CH3:38])[CH:4]=1.[OH-].[Na+]>C(O)(C)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:19][CH2:20][CH3:21])[CH:16]=3)[CH:11]([C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[CH:10]2[C:31]([OH:33])=[O:32])=[C:5]([O:35][CH2:36][O:37][CH3:38])[CH:4]=1
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCOC)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCOC)C(C(=O)O)C2c1ccc2c(c1)OCO2
Yield: 85 %

Procedure:
A solution of methyl (1RS,2RS,3RS)-3-(4-methoxy-2-methoxymethoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (2.42 g, 4.6 mmol) in isopropyl alcohol (30 ml) with aqueous NaOH (8 ml of 5N solution) was refluxed for 4 h. The resultant mixture was partitioned between EtO Ac and 3N HCl. The organic extract was washed with H2O then brine, dried (Na2 SO4) and solvent removed in vacuo to afford the title compound as a colorless oil (1.98 g, 84%).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[C:10](Cl)(=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>>[CH2:1]([N:5]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNCCCC
Reactant: CCCCCCCC(=O)Cl
Product: CCCCCCCCN(CCCC)CCCC

Procedure:
N,N-dibutyloctylamine was prepared from dibutylamine and octanoyl chloride by a method similar to that in Example 14.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22]([C:24]2[C:29]([NH:30][C:31](=[O:41])[C:32]3[CH:37]=[CH:36][C:35]([S:38][CH3:39])=[CH:34][C:33]=3O)=[CH:28][CH:27]=[CH:26][N:25]=2)=[O:23])=[N:19][CH:20]=1>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22]([C:24]2[C:29]([NH:30][C:31](=[O:41])[C:32]3[CH:33]=[CH:34][C:35]([S:38][CH3:39])=[CH:36][C:37]=3[O:13][CH2:12][CH:10]3[CH2:11][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]3)=[CH:28][CH:27]=[CH:26][N:25]=2)=[O:23])=[N:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Reactant: CSc1ccc(C(=O)Nc2cccnc2C(=O)Nc2ccc(Cl)cn2)c(O)c1
Product: CSc1ccc(C(=O)Nc2cccnc2C(=O)Nc2ccc(Cl)cn2)c(OCC2CN(C(=O)OC(C)(C)C)C2)c1
Yield: 78 %

Procedure:
Using a procedure analogous to Example 38-D, 1-t-butoxycarbonyl-3-hydroxymethylazetidine and N-(5-chloro-pyridin-2-yl)-3-[2-hydroxy-4-(methylthio)benzoylamino]-pyridine-2-carboxamide gave the title compound as a white solid (1.1 g, 78%).
Reaction SMILES: [O:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:18]=[C:17]([C:19](O)=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1)[CH3:2].Cl.[OH:23][C:24]1[C:33]([N:34]([CH3:36])[CH3:35])=[CH:32][CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][NH:28][CH2:29]2>>[O:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:18]=[C:17]([C:19]([N:28]3[CH2:27][CH2:26][C:25]4[C:30](=[CH:31][CH:32]=[C:33]([N:34]([CH3:36])[CH3:35])[C:24]=4[OH:23])[CH2:29]3)=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: COc1cccc(-c2nc(C(=O)O)c3ccccc3n2)c1
Reactant: CN(C)c1ccc2c(c1O)CCNC2
Agent: Cl
Product: COc1cccc(-c2nc(C(=O)N3CCc4c(ccc(N(C)C)c4O)C3)c3ccccc3n2)c1
Yield: 10 %

Procedure:
Reaction of 2-(3-methoxylphenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-dimethylamino-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 50 (10% yield) as a brown solid. 1H NMR (300 MHz, CDCl3) δ 2.64 and 2.68 (2s, 6H), 2.87 and 3.09 (2t, 2H), 3.60 and 4.21 (2t, 2H), 3.94 and 3.97 (2s, 3H), 4.50 and 5.09 (2s, 2H), 6.34 and 6.82 (2d, 1H), 6.95-7.16 (m, 2H), 7.42-7.49 (m, 1H), 7.55-7.65 (m, 1H), 7.90-8.06 (m, 2H), 8.13-8.29 (m, 3H); MS (ESI) m/z 455 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:9][NH:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1([CH2:9][N:10]([C:19]2[C:20]([N+:24]([O-:26])=[O:25])=[CH:21][N:22]=[C:17]([Cl:16])[N:18]=2)[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(CNC2CCCC2)CCC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C1(CN(c2nc(Cl)ncc2[N+](=O)[O-])C2CCCC2)CCC1

Procedure:
Reaction of 1-cyclopentylaminomethyl-cyclobutanecarboxylic acid methyl ester with 2,4-dichloro-5-nitropyrimidine and K2CO3 in acetone gave 1-{[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-methyl}-cyclobutanecarboxylic acid methyl ester
Reaction SMILES: [H-].[Na+].Cl[C:4]1[O:5][C:6]([C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:8]=1.[CH3:23][C:24]1[NH:25][CH:26]=[CH:27][N:28]=1>CN(C)C=O>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2[N:8]=[C:4]([N:25]3[CH:26]=[CH:27][N:28]=[C:24]3[CH3:23])[O:5][C:6]=2[C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:11]=1
Reactant: CCOC(=O)C(=O)c1oc(Cl)nc1-c1ccc(Cl)cc1
Reactant: Cc1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1oc(-n2ccnc2C)nc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.8 %

Procedure:
Sodium hydride(oil, 60%, 710 mg) was gradually added to a mixture of ethyl 2-(2-chloro-4-[4-chlorophenyl)-5-oxazolyl]-2-oxoacetate(4.63 g), 2-methylimidazole(1.45 g) and N,N-dimethylformamide(50 ml) at 0° C. After stirring for 1 hour at room temperature, the reaction mixture was poured into ice water to give ethyl 2-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]-2-oxoacetate(3.12 g, 59%). This was recrystallized from ethyl acetate-hexane to give colorless prisms. mp 126-127° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.O.ON1C2C=CC=CC=2N=N1.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[CH2:28][CH2:29][NH2:30].Cl.CN(C)CCCN=C=NCC>C(#N)C>[NH2:1][C:2]1[C:3]([C:9]([NH:30][CH2:29][CH2:28][C:24]2[S:23][CH:27]=[CH:26][CH:25]=2)=[O:11])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: Nc1ncc(Br)nc1C(=O)O
Reactant: NCCc1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: Nc1ncc(Br)nc1C(=O)NCCc1cccs1
Temperature: 25 °C
Yield: 66.4 %

Procedure:
A solution of 3-amino-6-bromopyrazine-2-carboxylic acid (0.50 g, 2.3 mmol; described in: Ellingson, R. C.; Henry, R. L. J. Am. Chem. Soc. 1949, 2798-2800), 1-hydroxybenzotriazole hydrate (0.41 g, 2.7 mmol) in acetonitrile (5 mL) were added to a stirred solution of 2-thien-2-ylethanamine (0.32 g, 2.5 mmol) in acetonitrile (5 mL) followed by addition of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.52 g, 2.7 mmol) and acetonitrile (1.5 mL). The resulting mixture was stirred at room temperature over night and the solvent was evaporated. The residue was re-crystallized from acetonitrile and subsequently from methanol to give 0.5 g (66% yield) of the title compound: 1H NMR DMSO-d6, 400 MHz) δ 8.73 (t, J=6 Hz, 1H), 8.34 (s, 1H), 7.71 (br s, 2H), 7.34 (dd, J=5, 1 Hz, 1H), 6.95 (d, J=3 Hz, 1H), 6.91 (m, 1H), 3.50 (q, J=7 Hz, 2H), 3.05 (t, J=7 Hz, 2H); MS (ES) m/z 327 and 329 (M++1).