Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[C:11]([CH2:12][NH2:13])=[CH:10][CH:9]=[C:8]([C:14]([F:17])([F:16])[F:15])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1N=CN([C:23]([N:25]2C=N[CH:27]=[CH:26]2)=[O:24])C=1.NC1C2[O:37][CH2:38][C:39](=[O:41])[NH:40][C:35]=2[CH:34]=[CH:33][CH:32]=1>C1COCC1.CN(C=O)C>[O:41]=[C:39]1[NH:40][C:35]2[CH:34]=[CH:33][CH:32]=[C:26]([NH:25][C:23]([NH:13][CH2:12][C:11]3[C:6]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[N:7][C:8]([C:14]([F:17])([F:15])[F:16])=[CH:9][CH:10]=3)=[O:24])[C:27]=2[O:37][CH2:38]1
Reactant: NCc1ccc(C(F)(F)F)nc1N1CCCC1
Reactant: Nc1cccc2c1OCC(=O)N2
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C1COc2c(cccc2NC(=O)NCc2ccc(C(F)(F)F)nc2N2CCCC2)N1
Temperature: 100 °C
Yield: 24 %

Procedure:
To a solution of 2-(1-pyrrolidinyl)-6-(trifluoromethyl)-3-aminomethyl-pyridine 29e (0.58 g, 2.3 mmol) in THF (25 mL) was added CDI (2.1 mol eq, 0.77 g) and the mixture was heated for 5 h. The reaction mixture was evaporated, water was added and the aqueous phase was extracted with EtOAc (3×20 mL). The recombined organic phases were anhydrified over Na2SO4 and evaporated at reduced pressure. The oil obtained (0.51 g, 1.52 mmol) was dissolved in DMF (20 mL) and the bicyclic amine 1f was added (0.8 mol eq, 0.20 g), then the mixture obtained was heated at 100° C. overnight. The solvent was removed at reduced pressure and the residue was purified by chromatography (1:1 EtoAc:Petroleum ether) to obtain the product as a white solid (0.12 g, 24% Yield). 1HNMR (DMSO, 400 MHz) δ 1.89 (m, 4H), 3.56 (m, 4H), 4.41 (d, 2H, J=6), 4.61 8s, 2H), 6.46 (dd, 1H, J=2), 6.80 (t, 1H, J=8), 7.12 (d, 1H, J=8), 7.25 (t, 1H), 7.70 (m, 2H), 8.17 (bs, 1H), 10.66 (bs, 1H). [M+1] 436.03 (C20H20F3N5O3 requires 435.40).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][Cl:11].[N+:12]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19]([C:24](O)=[O:25])=[CH:18]2)([O-:14])=[O:13].CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:11][CH2:10][CH2:9][C:3]1[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=1[NH:1][C:24]([C:19]1[NH:20][C:21]2[C:17]([CH:18]=1)=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:23][CH:22]=2)=[O:25]
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: Nc1cc(O)ccc1CCCl
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cc(O)ccc1CCCl)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Yield: 14 %

Procedure:
2-(2-Amino-4-hydroxyphenyl)ethyl chloride was coupled with 5-nitroindole-2-carboxylic acid with EDCI at 0-50° C., preferably at room temperature, in DMF to give 4-(2-chloroethyl)-3-(5-nitroindole-2-carboxamido)phenol in 14% yield. Subsequent catalytic hydrogenation of 4-(2-chloroethyl)-3-(5-nitroindole-2-carboxamido)phenol at 0-50° C., preferably at room temperature, with 5% Pd-C in THF gave an amine which was directly reacted with at 0-50° C., preferably at room temperature, benzoic acid mustard (p-N,N-bis(2-chloroethyl)aminobenzoic acid) and EDCI to give the desired compound 4-(2-chloroethyl)-3-[[5-(4-bis-(2-chloroethyl)amino)benzamido]indole-2-carboxamido]phenol in 24% yield. Reaction of 4-(2-chloroethyl)-3-[[5-(4-bis-(2-chloroethyl)amino)benzamido]indole-2-carboxamido]phenol at 0-50° C., preferably at 5° C., with 4-nitrobenzyl chloroformate and triethylamine gave the prodrug 4-(2-chloroethyl)-O-(4-nitrobenzylcabonato)-3-[[5-(4-bis-(2-chloroethyl)amino)benzamido]indole-2-carboxamido]phenol in 13% yield, after purification by silica gel column chromatography. The structures of all the compounds prepared were confirmed using IR, 1H-NMR (1H and 13C) spectroscopy, and FAB mass spectrometry including accurate mass measurements.
Reaction SMILES: [CH2:1]([O:8][O:9]CC1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].S(=O)(=O)(O)[OH:19]>C(Cl)(Cl)Cl.CO>[CH:7]1[C:2]([C:1]([O:8][OH:9])=[O:19])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(O)O
Reactant: c1ccc(COOCc2ccccc2)cc1
Agent: [Na]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(OO)c1ccccc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
19 g (78 mmol) of dibenzyl peroxide are dissolved in 125 ml of chloroform at −5° C. 2.2 g (94 mmol) of sodium dissolved in 50 ml of methanol under a stream of nitrogen are added dropwise. After stirring for 30 minutes at −5° C., ice-cold water is added and the medium is acidified with aqueous 2N sulfuric acid solution. Extraction with dichloromethane is performed and the organic phase is then dried over magnesium sulfate, filtered and concentrated. 9 g of perbenzoic acid are obtained in the form of a white solid in a yield of 83%.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH:10]([NH:17][C:18]1[C:27]2[C:22](=[C:23]([C:36](=[O:38])[NH2:37])[CH:24]=[C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:26]=2)[N:21]=[CH:20][N:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C)(C)(C)C.C1COCC1.Cl>O1CCOCC1>[CH2:29]([O:28][C:25]1[CH:26]=[C:27]2[C:22](=[C:23]([C:36]([NH2:37])=[O:38])[CH:24]=1)[N:21]=[CH:20][N:19]=[C:18]2[NH:17][CH:10]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:9][NH:7][CH3:6])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CN(CC(Nc1ncnc2c(C(N)=O)cc(OCc3ccccc3)cc12)c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CNCC(Nc1ncnc2c(C(N)=O)cc(OCc3ccccc3)cc12)c1ccccc1
Reaction time: 8 h
Yield: 78 %

Procedure:
A scintillation vial equipped with a stir bar was charged with [2-(6-benzyloxy-8-carbamoyl-quinazolin-4-ylamino)-2-phenyl-ethyl]-methyl-carbamic acid tert-butyl ester (81 mg, 0.15 mmol) and THF, (3 mL). Then, 4 M HCl in dioxane, (3 mL) was added at RT and the mixture was stirred overnight. After 18 h, a white precipitate had formed and LCMS indicated consumption of SM. The mixture was diluted with Et2O (30 mL) and the precipitate was filtered through a filter paper and washed with Et2O, (30 mL). The solid was dried under vacuum. Amount obtained: 50 mg, 0.12 mmol, 78% yield. LCMS (ESI) 428 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][C@H:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1.C1CCN2C(=NCCC2)CC1>>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([N:22]2[CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][C@H:17]2[CH3:16])[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1c(N2CCN(C(=O)OC(C)(C)C)C[C@H]2C)nc2cc(F)cc(F)c2c1Cl

Procedure:
Prepared according to Procedure G using 2,4-dichloro-5,7-difluoro-3-methylquinoline (1.00 g, 4.10 mmol) and (R)-tert-butyl 3-methylpiperazine-1-carboxylate and using DBU (1.0 eq) as a base to give (R)-tert-butyl 4-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)-3-methylpiperazine-1-carboxylate. Mass Spectrum (ESI) m/e=412.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18](F)=[C:17]([F:23])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2].[C:25]1([CH:31]2[CH2:36][NH:35][CH2:34][CH2:33][NH:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CS(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:35]4[CH2:34][CH2:33][NH:32][CH:31]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:36]4)=[C:17]([F:23])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2]
Reactant: c1ccc(C2CNCCN2)cc1
Reactant: CCOC(=O)c1cn(C)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1cn(C)c2nc3c(F)c(N4CCNC(c5ccccc5)C4)c(F)cc3cc2c1=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 78.1 %

Procedure:
A suspension of 3-ethoxycarbonyl-7,8,9-trifluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (1.8 g) and (RS)-2-phenylpiperazine (3.2 g) in dimethyl sulphoxide (30 cc) is heated to a temperature in the region of 100° C. with stirring for 1 hour and a half. The solution obtained, at approximately 100° C., is poured with stirring into a mixture of water (150 cc) and ice (50 g). The suspension obtained is extracted at approximately 20° C. with trichloromethane (3×40 cc). The combined organic extracts are washed with water (2×50 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 kPa) at approximately 50° C. The solid obtained is recrystallized in a mixture of dimethylformamide (40 cc) and ethanol (40 cc). (RS)-3-Ethoxycarbonyl-7,9-difluoro-1-methyl-4-oxo-8-(3-phenyl-1-piperazinyl)-1,4-dihydrobenzo[b][1,8]naphthyridine (2 g) is obtained in the form of a yellow solid, m.p. 216° C.
Reaction SMILES: P(C1C=CC=CC=1)(C)C.FC(F)(F)S(O[C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]=1[Cl:26])(=O)=O.[C:29](#[N:32])[CH:30]=[CH2:31].C(N(CC)CC)C>CC([O-])=O.CC([O-])=O.[Pd+2].C(#N)C>[Cl:26][C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[CH:25][C:16]=1/[CH:31]=[CH:30]/[C:29]#[N:32]
Reactant: O=S(=O)(Oc1ccc2ccccc2c1Cl)C(F)(F)F
Reactant: C=CC#N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CP(C)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#C/C=C/c1ccc2ccccc2c1Cl
Yield: 34.9 %

Procedure:
Pd(OAc)2 (3 mol %, 11 mg), PMe2Ph (5 mol %, 11 mg), 1-chloronaphthalen-2-yl trifluoromethanesulfonate (500 mg, 1.61 mmol), acrylonitrile (103 mg, 1.93 mmoli), triethylamine (242 mg, 2.4 mmol) and 15 mL of acetonitrile were added to a microvawe vial and the mixture was irradiated by MW at 120° C. for 1 h. At the conclusion of the reaction, the solvent was evaporated under reduced pressure and the residue was treated with dichloromethane and washed with water; the organic layer was filtered through a pad of silica gel with copious washings, concentrated, and purified by flash chromatography on silica gel eluted with petroleum ether/ethyl acetate (93:7) to give (2E)-3-(1-chloronaphthalen-2-yl)prop-2-enenitrile as colourless oil (120 mg, 35% yield).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:18][C:19]([O:21]CC)=[O:20])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.[OH-].[Na+].Cl>O>[C:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:18][C:19]([OH:21])=[O:20])[C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)Cn1ncc(-c2ccccc2)c1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)Cn1ncc(-c2ccccc2)c1-c1ccccc1
Yield: 93.4 %

Procedure:
Twelve grams (0.04 mol) of ethyl 4,5-diphenyl-1-H-pyrazole-1-acetate of example 1 was refluxed in 40 mL of water, 40 mL of ethanol and 5 mL of 35% aqueous sodium hydroxide for 1.5 hours. The ethanol was stripped off, water was added, and the slurry was acidified with excess 6N HCl. The resulting precipitate was filtered off and rinsed with water to yield 10.4 g of free acid, mp 169°-170° C.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])[CH:10]=2)[NH:5][C:4]1=[O:31].[NH2:32][C:33]1[CH:34]=[C:35]([OH:39])[CH:36]=[CH:37][CH:38]=1>C1COCC1>[OH:39][C:35]1[CH:34]=[C:33]([NH:32][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([C:23]5[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=5)=[O:22])[CH:17]=[CH:18][CH:19]=4)=[O:13])[CH:10]=3)[NH:5][C:4]2=[O:31])[CH:38]=[CH:37][CH:36]=1
Reactant: Nc1cccc(O)c1
Reactant: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)C(=CO)C(=O)N3)c1
Solvent: C1CCOC1
Product: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)C(=CNc2cccc(O)c2)C(=O)N3)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 79.2 %

Procedure:
A small screw cap test tube was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-phenyl]-amide (as prepared in Example 1, 30 mg, 0.072 mmol) and THF (1 mL). To the resulting solution was added 3-aminophenol (11.8 mg, 0.1082 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 79% (29 mg, 0.057 mmol) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][CH3:23])[C:17]([OH:19])=O)[C:10](=[O:24])[CH:9]=2)[CH:7]=1.[NH2:27][C:28]1[CH:36]=[C:35]2[C:31]([C:32](=[O:37])[NH:33][NH:34]2)=[CH:30][CH:29]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][CH3:23])[C:17]([NH:27][C:28]3[CH:36]=[C:35]4[C:31]([C:32](=[O:37])[NH:33][NH:34]4)=[CH:30][CH:29]=3)=[O:19])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: COCCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: Nc1ccc2c(=O)[nH][nH]c2c1
Product: COCCC(C(=O)Nc1ccc2c(=O)[nH][nH]c2c1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
150 mg (377 μmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoic acid (racemate) and 65 mg (438 μmol, 1.1 eq.) of 6-amino-1H-indazol-3(2H)-one were reacted according to General Method 1. The crude product was purified by flash chromatography (silica gel 50, dichloromethane/methanol mixtures). Yield: 105 mg (52% of theory)
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:30])=[CH:11][C:12](N)=[N:13][C:14]=1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][O:27][CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N([O-])=O.[Na+].[OH-:35].[Na+].[CH3:37]I>O>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][O:27][CH3:28])=[N:13][C:12]([O:35][CH3:37])=[CH:11][C:10]=1[CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCOCCCCCCCCCCc1nc(N)cc(C)c1OCc1ccccc1
Reactant: [OH-]
Reactant: CI
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COCOCCCCCCCCCCc1nc(OC)cc(C)c1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution at 0° C. containing 65 mg (0.16 mmol) of 5-(benzyloxy)-6-(10-(methoxymethoxy)decyl)-4-methylpyridin-2-amine in 2 mL of water-50% aqueous H3PO2 1:1 were added 17 mg (0.24 mmol) of sodium nitrite. The reaction mixture was stirred at 0° C. for 30 min and then at 23° C. for 16 h. The reaction mixture was neutralized (pH˜7) with aqueous NaOH and stirred for two hours. The reaction mixture was poured into 50 mL of water and extracted with two 40-mL portions of DCM. The combined organic layer was dried (MgSO4) and concentrated under diminished pressure. The residue was dissolved into 5 mL of anhydrous DCM. To the solution were added 100 μL (1.60 mmol) of methyl iodide followed by 66 mg (0.24 mmol) of Ag2CO3. The reaction mixture was stirred overnight at 23° C. and protected from light. The reaction mixture was filtered and the filtrate was concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (8×1 cm). Elution with 3:1 hexanes-ethyl acetate afforded the expected product as colorless oil: yield 18 mg (26%); silica gel TLC Rf 0.55 (4:1 hexanes-ethyl acetate) 1H NMR (CDCl3) δ 1.24-1.24 (m, 12H), 1.56 (quint, 2H, J=7.6 Hz), 1.70 (quint, 2H, J=7.6 Hz), 2.22 (s, 3H), 2.70 (dd, 2H, J=7.6, 7.6 Hz), 3.34 (s, 3H), 3.49 (t, 2H, J=6.8 Hz), 3.86 (s, 3H), 4.60 (s, 2H), 4.74 (s, 2H), 6.37 (s, 1H) and 7.33-7.44 (m, 5H); 13C NMR (CDCl3) δ 16.36, 26.19, 28.65, 29.42, 29.52, 29.54, 29.58, 29.65, 29.73, 31.77, 53.30, 55.05, 67.86, 75.31, 96.36, 108.75, 127.77, 128.07, 128.07, 128.53, 128.53, 137.29, 143.29, 146.62, 152.34 and 159.44; mass spectrum (APCI+), m/z 430.2965 (M+H) (C16H29N2O2 requires 430.2957).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[S:4][N:3]=1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:9](=[O:10])[O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:4][N:3]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1cc(N)sn1
Solvent: c1ccncc1
Product: Cc1cc(NC(=O)Oc2ccccc2)sn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
3-Methylisothiazol-5-amine (156 mg, 1.04 mmol) in pyridine (1.2 mL) was mixed with phenyl chloroformate (260 μL, 2.07 mmol) under cooling with ice and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and after addition of water, extracted with chloroform twice, and the organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1 (v/v)) to give the title compound as a pale yellow solid (173 mg, yield 71%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][NH:8][N:7]=1.[CH3:11][N:12]=[C:13]=[O:14]>>[CH3:11][NH:12][C:13]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][NH:8][N:7]=1)=[O:14]
Reactant: NCCSCc1cc[nH]n1
Reactant: CN=C=O
Product: CNC(=O)NCCSCc1cc[nH]n1

Procedure:
By the procedure of Example 24, 3-[(2-aminoethyl)thiomethyl]pyrazole is reacted with methyl isocyanate to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([N+:31]([O-])=O)[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[C:9]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[CH2:16][CH2:15]2)=[O:13])[N:8]=[CH:7][N:6]=1>O1CCCC1.[OH-].[Pd+2].[OH-].[C]>[NH2:31][C:29]1[CH:28]=[CH:27][C:3]([O:4][C:5]2[CH:10]=[C:9]([NH:11][C:12]([N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]4)[CH2:16][CH2:15]3)=[O:13])[N:8]=[CH:7][N:6]=2)=[C:2]([F:1])[CH:30]=1
Reactant: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc([N+](=O)[O-])cc4F)ncn3)CC2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4F)ncn3)CC2)CC1
Reaction time: 8 h
Yield: 100.8 %

Procedure:
4-(2-Fluoro-4-nitrophenoxy)-6-{[4-(1-methylpiperazin-4-yl)piperidin-1-yl]carbonylamino}pyrimidine (104 mg) was dissolved in tetrahydrofuran (15 ml). After adding 20% palladium hydroxide-carbon (70 mg), the mixture was stirred overnight under a hydrogen atmosphere. The catalyst was filtered and washed with tetrahydrofuran. The filtrate and the washings were combined and concentrated under reduced pressure, and the resultant residue was dried under reduced pressure to provide the title compound (98 mg, quantitative) as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)=[CH:5][CH:4]=1.[CH2:24](I)[CH2:25][CH2:26][CH3:27]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH2:24][CH2:25][CH2:26][CH3:27])=[CH:7][CH:8]=1
Reactant: COc1ccc(NCCCOc2ccc3ccccc3c2)cc1
Reactant: CCCCI
Solvent: CC(C)=O
Product: CCCCN(CCCOc1ccc2ccccc2c1)c1ccc(OC)cc1

Procedure:
A mixture of N-(4-methoxyphenyl)-(3-(naphthalen-2-yloxy)propyl)amine (0.5 gm, 0.002 mole) and butyl iodide(1 ml, 0.003 mole) was taken in dry acetone (40 ml). It was refluxed for 12 hrs and the progress of reaction checked by TLC. Reaction mixture was filtered and the filtrate was concentrated to get oily compound which was further crystallized by benzene hexane mixture to get N-(4-methoxyphenyl)-N-butyl-(3-(naphthalen-2-yloxy) propyl) amine crystallized yellow solid, m.p. 127° C., (yield 0.78 gm, 98%).
Reaction SMILES: C1(N2C(=O)C3=CNC4C=[CH:15][C:16]([N:19]5[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]5)=NC=4C3=N2)C=CC=CC=1.F[C:28]1[CH:37]=[CH:36][C:35]2[NH:34][CH:33]=[C:32]3[C:38](=[O:47])[N:39]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=4)[N:40]=[C:31]3[C:30]=2[N:29]=1.CN1CCCNCC1.N1CCNCC1>>[CH3:24][N:19]1[CH2:16][CH2:15][CH2:23][N:22]([C:28]2[CH:37]=[CH:36][C:35]3[NH:34][CH:33]=[C:32]4[C:38](=[O:47])[N:39]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=5)[N:40]=[C:31]4[C:30]=3[N:29]=2)[CH2:21][CH2:20]1
Reactant: O=c1c2c[nH]c3ccc(N4CCNCC4)nc3c-2nn1-c1ccccc1
Reactant: O=c1c2c[nH]c3ccc(F)nc3c-2nn1-c1ccccn1
Agent: C1CNCCN1
Agent: CN1CCCNCC1
Product: CN1CCCN(c2ccc3[nH]cc4c(=O)n(-c5ccccn5)nc-4c3n2)CC1

Procedure:
The title compound was prepared following the procedure described for 6a using 5b and 4-methyl-[1,4]-diazepane instead of 5a and piperazine respectively. 1H-NMR (DMSO-d6) δ (ppm): 2.04 (2H, m), 2.35 (3H, s), 2.60 (2H, m), 2.76 (2H, m), 3.76 (2H, d, J=6.32 Hz), 3.98 (2H, t, J=4.67 Hz), 6.96 (1H, d, J=9.36 Hz), 7.25 (1H, ddd, J=7.14, 4.55, 0.82 Hz), 7.82 (1H, d, J=9.34 Hz), 7.92 (1H, m), 8.30 (1H, dt, J=8.24, 0.82 Hz), 8.49 (1H, m), 8.52 (1H, s). m/z 376.4 (MH+).
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.Cl.[CH:12]12[O:19][CH:16]([CH2:17][CH2:18]1)[CH2:15][NH:14][CH2:13]2.[OH-].[Na+]>O>[C:2]([N:14]1[CH2:13][CH:12]2[O:19][CH:16]([CH2:17][CH2:18]2)[CH2:15]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: C1CC2CNCC1O2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(c1cccnc1)N1CC2CCC(C1)O2
Reaction time: 2 h
Yield: 45.8 %

Procedure:
Nicotinoyl chloride hydrochloride (17.81 grams, 0.1 mole) was slowly added to a mixture of 8-oxa-3-azabicyclo(3.2.1) octane hydrochloride (15 grams, 0.1 mole) and sodium hydroxide (15 grams) in 300 ml of water, at 10° C. After the addition of nicotinoyl chloride hydrochloride, the reaction mixture was stirred for 2 hours and then left overnight at room temperature. The product was extracted from the reaction mixture with diethyl ether and the extract treated with DARCO G60 (activated carbon). After the removal of ether, the product was obtained as a clear liquid (10 grams, 46% yield) which crystallized. The product 3-nicotinoyl-8-oxa-3-azabicyclo(3.2.1)octane was recrystallized from a blend of about 30% petroleum ether (boiling point 30°-60° C.) and 70% diethyl ether (v/v) to white crystals having a melting point of 48°-49.5° C.
Reaction SMILES: [CH:1]([N:4]1[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:6]2[CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=[CH:15][C:5]1=2)([CH3:3])[CH3:2].Cl[C:20]1[N:25]=[C:24]([NH:26][CH:27]2[CH:32]3[CH2:33][CH:29]([CH:30]=[CH:31]3)[CH:28]2[C:34]([NH2:36])=[O:35])[C:23]([Cl:37])=[CH:22][N:21]=1>>[Cl:37][C:23]1[C:24]([NH:26][CH:27]2[CH:32]3[CH2:33][CH:29]([CH:30]=[CH:31]3)[CH:28]2[C:34]([NH2:36])=[O:35])=[N:25][C:20]([NH:16][C:13]2[CH:14]=[CH:15][C:5]3[N:4]([CH:1]([CH3:3])[CH3:2])[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:6]=3[CH:12]=2)=[N:21][CH:22]=1
Reactant: NC(=O)C1C2C=CC(C2)C1Nc1nc(Cl)ncc1Cl
Reactant: CC(C)N1C(=O)CCCc2cc([N+](=O)[O-])ccc21
Product: CC(C)N1C(=O)CCCc2cc(Nc3ncc(Cl)c(NC4C5C=CC(C5)C4C(N)=O)n3)ccc21
Yield: 57 %

Procedure:
In an analogous procedure to Example 651, part c, 1-isopropyl-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one was combined with 3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide to yield 3-[5-Chloro-2-(1-isopropyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (55.01 mg, 57% yield) as a white powder. 1H-NMR (DMSO-d6) δ 9.35 (s, 1H), 7.77 (m, 2H), 7.62 (m, 2H), 7.27 (m, 1H), 7.12 (d, J=8.5 Hz, 1H), 6.36 (s, 1H), 6.24 (s, 1H), 4.60 (m, 1H), 4.15 (m, 1H), 2.88 (s, 1H), 2.87 (s, 1H), 2.64 (m, 1H), 2.55 (m, 1H), 2.10 (m, 4H), 1.82 (m, 1H), 1.41 (d, J=8.3 Hz, 1H), 1.32 (d, J=6.6 Hz, 3H), 0.99 (d, J=6.8 Hz, 3H). LC/MS (ESI+)=481 (M+H). MP=260° C.