Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:23]=[C:5]2[C:6]([NH:10][C:11]3[C:12]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=2)[NH2:34])[CH2:27][CH2:26]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:22][N:17]([C:12]1[C:11]([NH:10][C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:34][C:33]4[CH:35]=[CH:36][CH:37]=[C:31]([N:28]5[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]5)[CH:32]=4)[N:23]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:16][CH:15]=[CH:14][N:13]=1)[S:18]([CH3:21])(=[O:20])=[O:19]
Reactant: CN1CCN(c2cccc(N)c2)CC1
Reactant: CN(c1ncccc1Nc1cccn2nc(Cl)nc12)S(C)(=O)=O
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2cccc(Nc3nc4c(Nc5cccnc5N(C)S(C)(=O)=O)cccn4n3)c2)CC1

Procedure:
N-(3-Amino-pyridin-2-yl)-N-methyl-methanesulfonamide was prepared from N-methyl-N-(3-nitro-pyridin-2-yl)-methanesulfonamide (6.20 g, 26.8 mmol)(prepared as described in J. Med. Chem., 2007, 50, 3431) via hydrogenation using a Paar apparatus with 10% Palladium on Carbon (50% Wet)(5:45:50, Palladium:carbon black:Water, 5.71 g, 2.68 mmol) and Hydrogen (50 psi) in 2:1 ethyl acetate:methanol (150 mL). The mixture was shaken on a Paar apparatus until adsorption of hydrogen ceased. The mixture was degassed, backflushed with nitrogen, filtered through a plug of diatomaceous earth and rinsed with dichloromethane. The filtrate was evaporated under reduced pressure. Product isolated as brown solid (5.15 g, 95%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.85 (dd, J=3.7, 2.5 Hz, 1H), 7.10-7.08 (m, 2H), 4.24 (br s, 2H), 3.23 (s, 3H), 3.08 (s, 3H). MS=202 (MH)+. 111b) N-[3-(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-pyridin-2-yl]-N-methyl-methanesulfonamide was prepared from N-(3-amino-pyridin-2-yl)-N-methyl-methanesulfonamide (238.0 mg, 1.183 mmol) and 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (250.0 mg, 1.075 mmol) in a manner analogous to Example 2d. Product isolated as a pale yellow foam (0.185 g, 48%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.18-8.15 (m, 1H), 8.11 (d, J=6.8 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.50 (s, 1H), 7.32-7.25 (m, 1H), 7.17 (d, J=7.5 Hz, 1H), 6.93 (t, J=7.3 Hz, 1H), 3.31 (s, 3H), 3.07 (s, 3H). MS=353, 355 (MH)+. 111c) N-Methyl-N-(3-{2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino}-pyridin-2-yl)-methanesulfonamide was prepared from N-[3-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-pyridin-2-yl]-N-methyl-methanesulfonamide (75.0 mg, 0.212 mmol) and 3-(4-methylpiperazin-1-yl)aniline (45.0 mg, 0.235 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (23.0 mg, 0.0421 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a brown foam (0.017 g, 16%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.11-8.06 (m, 2H), 7.78 (d, J=7.5 Hz, 1H), 7.52 (s, 1H), 7.28-7.19 (m, 3H), 7.12 (d, J=7.5 Hz, 1H), 7.06 (d, J=7.9 Hz, 1H), 6.84 (s, 1H), 6.78-6.73 (m, 1H), 6.57 (d, J=8.0 Hz, 1H), 3.32 (s, 3H), 3.29-3.24 (m, 4H), 3.09 (s, 3H), 2.62-2.57 (m, 4H), 2.36 (s, 3H). MS=518 (MH)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH2:3][C:4](Cl)=[O:5].Cl.[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[C:20]([C:22]3[CH:31]=[C:30]4[C:25]([CH2:26][CH2:27][NH:28][CH2:29]4)=[CH:24][CH:23]=3)[N:19]=[C:18]([NH2:32])[N:17]=2)[CH2:12][CH2:11]1>>[CH3:1][CH:2]([CH3:7])[CH2:3][C:4]([N:28]1[CH2:27][CH2:26][C:25]2[C:30](=[CH:31][C:22]([C:20]3[CH:21]=[C:16]([N:13]4[CH2:12][CH2:11][N:10]([CH3:9])[CH2:15][CH2:14]4)[N:17]=[C:18]([NH2:32])[N:19]=3)=[CH:23][CH:24]=2)[CH2:29]1)=[O:5]
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: CC(C)CC(=O)Cl
Agent: Cl
Product: CC(C)CC(=O)N1CCc2ccc(-c3cc(N4CCN(C)CC4)nc(N)n3)cc2C1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 2 starting from 3-methylbutanoyl chloride (Aldrich, Cat. #157422) and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=409.2.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([CH3:17])=[N:7][O:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)=[O:4].[OH-].[Li+]>CO.O>[Br:16][C:13]1[CH:12]=[CH:11][C:10]([C:9]2[O:8][N:7]=[C:6]([CH3:17])[C:5]=2[C:3]([OH:4])=[O:2])=[CH:15][CH:14]=1
Reactant: COC(=O)c1c(C)noc1-c1ccc(Br)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1noc(-c2ccc(Br)cc2)c1C(=O)O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carboxylic acid methyl ester (39 mmol) in MeOH (50 mL) and H2O (10 mL) was treated with lithium hydroxide (2 g, 48 mmol) and the reaction was stirred at 60° C. for 1 hour. The mixture was acidified, and standard workup provided the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=[O:18])=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([CH3:19])=[CH:8]2.C(N(CC)CC)C.CS(C)=O>O>[CH3:19][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[C:10]([CH:17]=[O:18])[C:11]3[C:16]([C:3]=2[CH:2]=[O:1])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:8]=1
Reactant: Cc1ccc2c(CO)c3ccccc3c(C=O)c2c1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc2c(C=O)c3ccccc3c(C=O)c2c1
Reaction time: 1 h

Procedure:
To a solution of 1.25 g. of 10-(hydroxymethyl)-2-methyl-9-anthraldehyde in a mixture of 14 ml. of triethylamine and 20 ml. of dry dimethylsulfoxide is added a solution of 4.80 g. of sulfur trioxide pyridine complex in 20 ml. of dry dimethylsulfoxide. The reaction mixture is stirred for one hour and then poured into 200 ml. of water. The solid is collected and washed with water, giving 1.18 g. of the desired product as orange crystals, mp. 150°-152° C.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[O:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.C([Li])CCC.[N+:18]([C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=1)([O-:20])=[O:19].[Cl-].[NH4+]>CCOCC.O1CCCC1>[Cl:1][C:2]1[S:3][C:4]([C:21]2([N+:18]([O-:20])=[O:19])[CH:22]=[CH:23][C:24]([CH2:25][OH:26])=[CH:27][CH2:28]2)=[CH:5][C:6]=1[O:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: Clc1sccc1OC1CCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=[N+]([O-])C1(c2cc(OC3CCCC3)c(Cl)s2)C=CC(CO)=CC1
Temperature: -78 °C
Reaction time: 4 h
Yield: 98.2 %

Procedure:
To a solution of 2-chloro-3-cyclopentyloxythiophene (2.15 g, 10.6 mmol) in ether (27 mL) was added n-butyllithium (2.5 N in hexanes, 4.4 mL, 11 mmol) dropwise at −78° C. under argon. The mixture was allowed to reach 20-25° C. and stirred for 4 hours. After cooling back to −78° C., a solution of p-nitrobenzaldehyde (1.56 g, 10.3 mmol) in tetrahydrofuran (27 mL) was added dropwise. The mixture was stirred at −78° C. for 1 hour. Saturated ammonium chloride was added at −78° C. and the mixture was allowed to reach about 10° C. The crude product was extracted with ethyl acetate, washed with water, brine, dried (Na2SO4), and concentrated to dryness to give 4-(5-chloro-4-cyclopentyloxythien-2-yl)-(4-nitrophenyl)methanol (3.6 g), and was directly used in the next step.
Reaction SMILES: [C:1]([CH:4]([CH3:31])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][CH2:16][CH3:17])[CH:10]=[C:9]2[CH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][C:20]=1[O:29][CH3:30])([OH:3])=O.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH3:30][O:29][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:19]=1[CH2:18][C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([CH2:5][CH:4]([CH3:31])[C:1]([N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[O:3])[CH:7]=2)[N:11]([CH2:15][CH2:16][CH3:17])[CH:10]=1)[C:23]([O:25][CH3:26])=[O:24]
Reactant: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(CC(C)C(=O)O)ccc21
Reactant: C1CCNC1
Product: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(CC(C)C(=O)N3CCCC3)ccc21

Procedure:
Using a similar procedure to that described in Example 49, part g, except starting from methyl 4-[5-(2-carboxypropyl)-1-propylindol-3-ylmethyl]-3-methoxybenzoate, and using pyrrolidine instead of pentylamine, methyl 3-methoxy-4-[5-(2-methyl-3-pyrrolidino-3-oxopropyl)-1-propylindol-3-ylmethyl]benzoate was obtained (60%) as a colorless glass; partial NMR (250 MHz, DMSO-d6): 0.78(t, 3H, CH2CH3), 0.98(d, 3H, CH(CH3)), 1.4-1.8 (complex m, 6H), 2.6(m, 1H), 2.83(m, 4H), 3.3(complex m, 2H), 3.83(s, 3H, OCH3), 3.92(s, 3H, OCH3).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C@@H:8]1[CH2:10][C@H:9]1[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[Br:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br>CN(C=O)C>[Br:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][O:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]2[CH2:10][C@H:8]2[NH:7][C:6](=[O:18])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:12][CH:13]=1
Reactant: BrCc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(OCc2cccc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.2 %

Procedure:
To a solution of tert-butyl-(trans)-2-(4-hydroxyphenyl)cyclopropylcarbamate (Intermediate N, 5 g, 20.0 mmol), K2CO3 (6.8 g, 50.0 mmol) in dry DMF (10 vols) was added 3-Bromo benzyl bromide (5 g, 20.0 mmol) and stirred at RT for 16 h. After completion, the reaction mixture was poured into ice water (150 mL) and extracted with EtOAc (2×75 mL). The combined extracts were washed with water (100 mL), brine (100 mL), dried over anhydrous Na2SO4, filtered and evaporated. The crude residue was purified by flash chromatography to give (tert-butyl (trans)-2-(4-(3-bromobenzyloxy)phenyl)cyclopropylcarbamate (5.2 g, 62%) as a white solid. The crude was carried to next step without further purification.
Reaction SMILES: [CH2:1]([N:4]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:29])C=1.S([O-])(O)=O.[Na+]>ClCCl>[CH2:14]([O:13][C:11]([N:4]([CH2:1][CH:2]1[O:29][CH2:3]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCN(C(=O)OCc1ccccc1)c1ccccc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N(CC1CO1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 37.7 %

Procedure:
Under nitrogen, to a solution of N-allyl-N-phenyl-benzyloxycarbonylamine (5.5 g) in dichloromethane (50 ml) was added m-chloroperbenzoic acid (3.9 g) at 5° C., and the mixture was stirred at room temperature for 3 days. The resulting mixture was poured into aqueous sodium hydrogensulfite and extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=10:1 to 5:1) to give 1-(N-benzyloxycarbonyl-N-phenylamino)-2,3-epoxypropane (2.2 g).
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][OH:5].C(N(CC)CC)C.[C:14]12([C:24](Cl)=[O:25])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2>C1COCC1.C(OCC)(=O)C>[C:14]12([C:24]([O:5][CH2:4][CH:3]=[C:2]([CH3:6])[CH3:1])=[O:25])[CH2:21][CH:20]3[CH2:19][CH:18]([CH2:17][CH:16]([CH2:22]3)[CH2:15]1)[CH2:23]2
Reactant: CC(C)=CCO
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)=CCOC(=O)C12CC3CC(CC(C3)C1)C2
Yield: 78.9 %

Procedure:
A flask was charged with 2.6 g (0.03 mol) of 3-methyl-2-buten-1-ol, 3.1 g (0.025 mol) of triethylamine and 20 ml of THF to prepare a solution. While stirring the solution, a solution of 5.0 g (0.025 mol) of 1-adamantanecarbonyl chloride in 40 ml of THF was added dropwise over 1 hour, followed by stirring further for 5 hours. After salts formed were removed by filtration from the reaction mixture, the filtrate was concentrated. The thus-obtained crude product was dissolved in 70 ml of ethyl acetate, and the solution was washed each 3 times with a 5% aqueous solution of sodium hydrogencarbonate and saturated saline and dried over magnesium sulfate. The solvent was then distilled off to obtain 4.9 g of 3-methyl-2-butenyl 1-adamantanecarboxylate [the formula (61)].
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[N:6]=1.[F:16][C:17]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[CH:19][C:18]=1[C:32]1[CH:33]=[N:34][C:35]([NH2:38])=[N:36][CH:37]=1>>[NH2:38][C:35]1[N:36]=[CH:37][C:32]([C:18]2[CH:19]=[CH:20][C:21]([C:2]3[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=3[O:4][C:5]3[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[N:6]=3)=[CH:22][C:17]=2[F:16])=[CH:33][N:34]=1
Reactant: Nc1nccc(Oc2ccccc2Br)n1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Nc1ncc(-c2ccc(-c3ccccc3Oc3ccnc(N)n3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 4-(2-bromophenoxy)pyrimidin-2-amine and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C20H15FN6O, 374.13; m/z found, 375.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.46 (s, 2H), 7.98-7.94 (d, J=5.8, 1H), 7.53-7.49 (d, J=7.6, 1H), 7.49-7.42 (m, 2H), 7.41-7.36 (m, 1H), 7.36-7.32 (d, J=8.2, 1H), 7.32-7.27 (m, 1H), 7.26-7.14 (d, J=8.0, 1H), 6.13-6.04 (d, J=5.8, 1H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:30]#[C:31][CH2:32]OS(C)(=O)=O)[CH:28]=4)[N:23]=[CH:22][N:21]=3)[CH2:16][CH2:15]2)=[O:13])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH2:38]([NH:40][CH2:41][CH3:42])[CH3:39]>CC#N>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:30]#[C:31][CH2:32][N:40]([CH2:41][CH3:42])[CH2:38][CH3:39])[CH:28]=4)[N:23]=[CH:22][N:21]=3)[CH2:16][CH2:15]2)=[O:13])=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(NC(=O)N2CCC(c3ncnc4ccc(C#CCOS(C)(=O)=O)cc34)CC2)cc1
Reactant: CCNCC
Solvent: CC#N
Product: CCN(CC)CC#Cc1ccc2ncnc(C3CCN(C(=O)Nc4ccc(OC(C)C)cc4)CC3)c2c1
Temperature: 25 °C
Yield: 78.9 %

Procedure:
A solution of methanesulfonic acid 3-{4-[1-(4-isopropoxy-phenylcarbamoyl)-piperidin-4-yl]-quinazolin-6-yl}-prop-2-ynyl ester (180.0 mg, 345 μmol), as prepared in the previous step, in CH3CN (0.5 mL) was treated with diethylamine (79 μL, 759 μmol) very rapidly by syringe in 1 portion with stirring at rt, and the pale yellow solution was allowed to stir at rt for 2 h. Purification of the crude reaction with a flash silica column (1:2 hex/acetone) afforded the title compound as an off-white foam (136 mg, 79%). 1H-NMR (300 MHz, CDCl3) δ 9.22 (s, 1H), 8.21 (d, 1H), 7.99 (d, 1H), 7.88 (dd, 1H), 7.25 (m, 2H), 6.84 (m, 2H), 6.38 (br s, 1H), 4.48 (heptet, 1H), 4.32-4.22 (m, 2H), 3.78-3.65 (m, 1H), 3.70 (s, 2H), 3.16 (td, 2H), 2.68 (q, 4H), 2.21-1.94 (m, 4H), 1.31 (d, 6H), 1.15 (t, 6H). LC/MS (ESI): calcd mass 499.3, found 500.5 (MH)+. A select fraction of this material was submitted for combustion analysis: Anal. Calcd for C30H37N5O2.0.18 water: C, 71.65; H, 7.49; N, 13.93. Found: C, 71.7; H, 7.55; N, 13.92.
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[I:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17]([NH:19][NH2:20])=[O:18].C(N(CC)CC)C>C1COCC1>[I:13][C:14]1[CH:15]=[C:16]([C:17]2[O:18][C:6](=[O:7])[NH:20][N:19]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: NNC(=O)c1cccc(I)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=c1[nH]nc(-c2cccc(I)c2)o1
Temperature: 25 °C

Procedure:
A solution of N,N-carbonyldiimidazole (800 mg, 5.0 mmol) in 5 mL of dry THF was added dropwise to an ice-cold solution of the product from Step A (1.048 g, 4.0 mmol) and triethylamine (0.60 mL, 4.0 mmol) in 12 mL of dry THF. The resultant mixture was allowed to warm to room temperature overnight, and was then concentrated under reduced pressure. The residue was partitioned between diethyl ether and water, and the ether layer was washed sequentially with 5% aqueous hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated aqueous brine, dried (magnesium sulfate), and concentrated under reduced pressure to afford a white powder. Recrystallization from ethyl acetate-hexanes afforded the title compound as a fluffy white solid. LC/MS 289.2 (M+1).
Reaction SMILES: [OH-].[Na+].Cl.Cl.[CH:5]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:7])[CH3:6].[CH:14]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)=[O:15]>O.C1(C)C=CC=CC=1>[CH:5]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:24]=[CH:23][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=2)=[O:15])[CH2:10][CH2:9]1)([CH3:7])[CH3:6]
Reactant: O=Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)N1CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 101 %

Procedure:
A solution of NaOH (24.0 g, 0.600 mol) in de-ionized H2O (240 mL) and toluene (60 mL) at 0° C. was treated with isopropyl piperazine dihydrochloride salt (39.0 g, 194 mmol). The resulting biphasic solution was stirred at 0° C. for 30 min. A solution of 4-formyl-benzoyl chloride in toluene was added in a slow stream via an addition funnel over 1 h, with vigorous mechanical agitation. The mixture was allowed to warm to room temperature over 16 h, then cooled to 0° C., and the pH adjusted to 10 with 1 N NaOH. The phases were separated and the aqueous layer was extracted with toluene (2×200 mL). The organic layers were combined, washed with brine (200 mL), and concentrated to yield 4-(4-isopropyl-piperazine-1-carbonyl)-benzaldehyde (52.5 g, mass balance 101%) as a pale, yellow-brown oil. The oil was dissolved in EtOH (600 mL) and, with vigorous mechanical agitation, was treated with a solution of NaHSO3 (23.1 g, 222 mmol) in de-ionized H2O (50 mL) which was added via an addition funnel over 30 min. The resulting mixture was stirred at room temperature for 48 h, and then cooled to 0° C. Methyl-tert-butyl ether (500 mL) was added and the resulting the slurry was stirred for 30 min. The precipitate was collected by suction filtration through a medium porosity glass frit, washed with cold EtOH/EtOAc (5:1, 3×60 mL). The solids were dried under vacuum for 2 h, then at 40° C. in a vacuum oven for 16 h to yield the title compound as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C@H:10]([OH:18])[CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH3:17])[CH:7]=[CH:8][CH:9]=1.[O:19]1[CH:24]=[CH:23][CH2:22][CH2:21][CH2:20]1>Cl>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:10]([O:18][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][O:19]2)[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH3:17])[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc([C@H](O)C[C@H]2CCCN2C)c1
Reactant: C1=COCCC1
Agent: Cl
Product: COc1cccc(C(CC2CCCN2C)OC2CCCCO2)c1

Procedure:
0.3 g of (R*,R*)-1-(3-methoxyphenyl)-2-(1-methyl-2-pyrrolidinyl)-ethanol-hydrochloride, one drop of etheral hydrochloric acid and 3.5 ml of 3.4-dihydro-2H-pyran are stirred for 24 hours at room temperature and subsequently concentrated to 0.39 g of the oily hydrochloride of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][N:14]=1.ClC1C=CC(C(NC2C=CC(I)=C(C)C=2)=O)=CN=1>>[C:1]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:13]([Cl:12])=[N:14][CH:15]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: CC(C)(C)c1ccnc(N)n1
Agent: Cc1cc(NC(=O)c2ccc(Cl)nc2)ccc1I
Product: CC(C)(C)c1ccnc(NC(=O)c2ccc(Cl)nc2)n1

Procedure:
N-(4-tert-Butyl-pyrimidin-2-yl)-6-chloro-nicotinamide was prepared from 4-tert-butyl-pyrimidin-2-ylamine (prepared as described in J. Org. Chem. 1977, 221) and 6-chloronicotinoyl chloride following a procedure similar to the one described in the synthesis of 6-chloro-N-(4-iodo-3-methyl-phenyl)-nicotinamide, above. The product was isolated after silica gel purification with 20-40% EtOAc in hexanes gradient followed by suspension in hexanes and filtration. HRMS m/z calcd for C14H15N4OCl [M+H]+: 291.1007. Found: 291.1007.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13](Br)[CH:14]=[CH2:15]>>[CH2:15]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11])[CH:14]=[CH2:13]
Reactant: C=CCBr
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Product: C=CCOc1ccc(C=O)cc1[N+](=O)[O-]

Procedure:
Analogously to Method F, 25 g of 4-hydroxy-3-nitrobenzaldehyde and 25.1 ml of allyl bromide are reacted. The title compound is obtained as a slightly yellowish solid. Rf=0.30 (1:2 EtOAc-heptane). Rt=4.00.
Reaction SMILES: C[O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2=[N:13][CH:14]=[C:15]([C:18]([O:20]CC)=[O:19])[C:16](=[O:17])[N:5]2[CH:4]=1>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>[OH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2=[N:13][CH:14]=[C:15]([C:18]([OH:20])=[O:19])[C:16](=[O:17])[N:5]2[CH:4]=1
Reactant: CCOC(=O)c1cnc2c3ccccc3c(OC)cn2c1=O
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Product: O=C(O)c1cnc2c3ccccc3c(O)cn2c1=O

Procedure:
A suspension of ethyl 7-methoxy-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylate (240 mg., 0.83 mmole) in a mixture of acetic (4 ml.) and 37% hydrochloric (2 ml.) acids was refluxed for 2 hours. The mixture was flash evaporated to dryness, diluted with water and the precipitated solid collected and crystallized from acetic acid with charcoal treatment to give straw needles of the title acid, m.p. 273°-276°.
Reaction SMILES: [NH2:1][NH2:2].O[C:4]1[C:5]([OH:10])=[N:6][CH:7]=[CH:8][CH:9]=1>COCCOC>[NH:1]([C:9]1[CH:8]=[CH:7][NH:6][C:5](=[O:10])[CH:4]=1)[NH2:2]
Reactant: Oc1cccnc1O
Reactant: NN
Solvent: COCCOC
Product: NNc1cc[nH]c(=O)c1
Temperature: 25 °C
Yield: 78 %

Procedure:
To a solution of hydrazine (8 mL) in DME (40 mL) was added dihydroxypyridine (2.00 g, 18 mmol) and the reaction heated at reflux overnight. The solution was cooled to rt, and the solids removed by filtration. The filtrate was concentrated and the resulting solid crystallized from hot EtOH to afford 4-hydrazinylpyridin-2(1H)-one (1.75 g, 78% yield). LC-MS (ESI) m/z 126 (M+H)+.
Reaction SMILES: S(S([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+].[CH2:17]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29]([NH:38][CH2:39][CH:40]3[CH2:44][O:43][C:42]([CH3:46])([CH3:45])[O:41]3)=[C:30]([N+:35]([O-])=O)[CH:31]=[N:32]2)=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O.ClCCl.CC[N+]1C=CC(C2C=C[N+](CC)=CC=2)=CC=1.[Br-].[Br-]>[CH2:17]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29]([NH:38][CH2:39][CH:40]3[CH2:44][O:43][C:42]([CH3:46])([CH3:45])[O:41]3)=[C:30]([NH2:35])[CH:31]=[N:32]2)=[CH:27][CH:26]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC1(C)OCC(CNc2c([N+](=O)[O-])cnc3cc(OCc4ccccc4)ccc23)O1
Agent: CC[n+]1ccc(-c2cc[n+](CC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])S(=O)(=O)[O-]
Solvent: O
Solvent: ClCCl
Product: CC1(C)OCC(CNc2c(N)cnc3cc(OCc4ccccc4)ccc23)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A solution of sodium dithionate (85% pure, 135.07 g, 659.42 mmol) and potassium carbonate (101.27 g, 732.73 mmol) in water (450 mL) was added dropwise to a mechanically stirred mixture of ethyl viologen dibromide (1.1 g, 2.93 mmol) and (7-benzyloxy-3-nitro-quinolin-4-yl)[(2,2-dimethyl[1,3]dioxolan-4-yl)methyl]amine (60.0 g, 146.54 mmol) in dichloromethane (500 mL) and water (50 mL). The reaction mixture was stirred at ambient temperature overnight and then diluted with water (600 mL) and stirred for an additional 10 minutes. The organic phase was separated and the aqueous layer was reextracted with dichloromethane (400 mL). The combined organic layers were washed with water (800 mL) and brine (800 mL), dried over sodium sulfate, and concentrated under reduced pressure to afford 55.60 g of 7-benzyloxy-N4-[(2,2-dimethyl[1,3]dioxolan-4-yl)methyl]quinoline-3,4-diamine as a brown foam.