Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16](Cl)[N:15]=[C:14]([NH:19][CH3:20])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:21]([NH2:24])([CH3:23])[CH3:22]>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([NH:24][CH:21]([CH3:23])[CH3:22])[N:15]=[C:14]([NH:19][CH3:20])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CNc1nc(Cl)cc(NS(=O)(=O)c2ccc(N)cc2)n1
Reactant: CC(C)N
Solvent: CCO
Product: CNc1nc(NC(C)C)cc(NS(=O)(=O)c2ccc(N)cc2)n1
Yield: 35.7 %

Procedure:
0.314 g (0.001 mol) of 4-amino-N-(6-chloro-2-methylamino-pyrimidin-4-yl)-benzenesulfonamide and 8.6 ml (0.1 mol) of isopropylamine were stirred in 15 ml of ethanol in an autoclave at 130° C. for 3 hours. The reaction mixture was freed from solvent, the residue was suspended in 8 ml of ethanol and treated in an ultra sound bath for 15 minutes. The precipitate was filtered off, dissolved in 10 ml of 0.1N NaOH and filtered. The filtrate was adjusted to pH 6 with 0.1N HCl. The precipitate was filtered off under suction, washed with water and dried. There was obtained 0.12 g (36%) of 4-amino-N-(6-isopropylamino-2-methylamino-pyrimidin-4-yl)-benzenesulfonamide as beige crystals; m.p. 240° C. (dec.).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH2:13][NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1([C:24]([NH:26][CH2:27][CH:28]=[CH2:29])=[O:25])C=CN=C1.C(N(CC)C(C)C)(C)C>C(#N)C>[C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH2:13][N:14]([C:24](=[O:25])[NH:26][CH2:27][CH:28]=[CH2:29])[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CNCc1ccc(C(=O)OC(C)(C)C)s1
Reactant: C=CCNC(=O)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C=CCNC(=O)N(Cc1ccc(C(=O)OC(C)(C)C)s1)CC(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
5-{[(2-Methylpropyl)amino]methyl}thiophene-2-carboxylic acid tert-butyl ester (0.55 g, 2.0 mmol) obtained in Example 24, step 1 and N-(1H-imidazol-1-ylcarbonyl)-allylamine (0.49 g, 3.2 mmol) obtained in step 1 were dissolved in acetonitrile (20 ml), N,N-diisopropylethylamine (0.56 mL, 3.2 mmol) was added, and the mixture was stirred at 60° C. overnight. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by column chromatography (hexane/ethyl acetate) to give the title compound (0.72 g, 2.0 mmol).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([N:13]1[CH:17]=[CH:16]N=C1)=[S:12].[Cl:18][C:19]1[CH:24]=[CH:23][C:22](CCN)=[CH:21][CH:20]=1>CN(C)C=O>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:16][CH2:17][NH:13][C:11]([NH:10][C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[S:12])=[CH:21][CH:20]=1
Reactant: S=C(Nc1nc2ccccc2s1)n1ccnc1
Reactant: NCCc1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: S=C(NCCc1ccc(Cl)cc1)Nc1nc2ccccc2s1
Temperature: 25 °C
Yield: 64 %

Procedure:
A solution of 1-[(2-benzothiazolyl)thiocarbamoyl] imidazole (1.04 g, 4 mmol) and 2-(4-chlorophenyl)ethylamine (0.63 g, 4 mmol) in N,N-dimethylformamide (15 mL) was stirred at 100° C. for 1 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 0.89 g (64%) of the title product:
Reaction SMILES: [ClH:1].[F:2][C:3]1[C:11]2[NH:10][C:9](=[O:12])[N:8]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:7]=2[CH:6]=[C:5]([CH3:19])[C:4]=1[F:20].C(N(C(C)C)CC)(C)C.[O:30]1[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[ClH:1].[F:2][C:3]1[C:11]2[NH:10][C:9](=[O:12])[N:8]([CH:13]3[CH2:14][CH2:15][N:16]([CH:33]4[CH2:34][CH2:35][O:30][CH2:31][CH2:32]4)[CH2:17][CH2:18]3)[C:7]=2[CH:6]=[C:5]([CH3:19])[C:4]=1[F:20]
Reactant: Cc1cc2c([nH]c(=O)n2C2CCNCC2)c(F)c1F
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc2c([nH]c(=O)n2C2CCN(C3CCOCC3)CC2)c(F)c1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4,5-Difluoro-6-methyl-1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one hydrochloride D23 (120 mg) was dissolved in dichloromethane (5 ml) and diisopropylethylamine (0.2 ml, 1.2 mmol), tetrahydro-4H-pyran-4-one (0.2 ml, 2.0 mmol) and sodium triacetoxyborohydride (250 mg, 1.2 mmol) were added and the mixture stirred at room temperature for 4 h. The mixture was partitioned with water/MDC at pH9. Drying (MgSO4), evaporation, and crystallisation of the residue from diethyl ether, washing with dichloromethane gave the title compound free base, which was converted to the hydrochloride. Trituration with diethyl ether gave 35 mg of hydrochloride salt. MH+=352,
Reaction SMILES: [O:1]=[O+][O-].[C:4]1([CH3:21])[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=CC)[C:12]=1[OH:20]>C(OCC)(=O)C.C(O)(=O)C>[OH:20][C:12]1[C:11]([S:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH3:21])=[CH:16][CH:15]=[CH:14][C:13]=1[CH:17]=[O:1]
Reactant: CC=Cc1cccc(Sc2ccccc2C)c1O
Reactant: O=[O+][O-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1ccccc1Sc1cccc(C=O)c1O

Procedure:
Ozone gas was introduced into a solution of 2-(o-tolylthio)-6-(1-propenyl)phenol (24.3 g) in a mixture of ethyl acetate (200 ml) and acetic acid (5 ml) at 3° C. for 1.5 hours. The excess of ozone was removed by air-bubbling and further decomposed with aqueous sodium hydrogen sulfite. The resultant organic layer was separated, washed with aqueous sodium hydrogen sulfite and water in turn, dried and then evaporated under reduced pressure. The oily residue was crystallized with ethanol to give yellow needles of 2-hydroxy-3-(o-tolylthio)benzaldehyde (12.2 g), mp. 42°-43° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:9]1[C:10]([F:28])=[C:11]([C:16]2[C:17]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[C:18]([SH:21])[NH:19][N:20]=2)[C:12]([F:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:43][CH2:44]Br>CN(C=O)C>[CH2:29]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([C:16]2[C:17]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[C:18]3[S:21][CH2:43][CH2:44][N:19]3[N:20]=2)[C:10]=1[F:28])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCCBr
Reactant: Fc1ccc(N(Cc2ccccc2)Cc2ccccc2)c(F)c1-c1n[nH]c(S)c1-c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc(N(Cc2ccccc2)Cc2ccccc2)c(F)c1-c1nn2c(c1-c1ccncc1)SCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.5 %

Procedure:
5-(3-Dibenzylamino-2,6-difluoro-phenyl)-4-pyridin-4-yl-2H-pyrazole-3-thiol (1.26 g, 2.6 mmol) was dissolved in dry DMF (33 mL) under nitrogen atmosphere. Solid potassium carbonate (1.8 g, 13 mmol, 5 eq) was added followed by 1,2-dibromoethane (0.252 mL, 2.86 mmol, 1.1 eq) and the suspension was stirred at room temperature for 4 hours. DMF was then removed under reduced pressure and the residue was partitioned between saturated aqueous NaHCO3 and ethyl acetate. The organic phase was washed with brine, dried over Na2SO4 and evaporated to dryness. 537 mg of dibenzyl-[2,4-difluoro-3-(7-pyridin-4-yl-2,3-dihydro-pyrazolo[5,1-b]thiazol-6-yl)-phenyl]-amine were obtained as white solid (47% over 2 steps).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]2([OH:27])[C:15]3=[N:16][CH:17]=[CH:18][C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:14]3[C:13](=[O:26])[O:12]2)[N:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C)C=O>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([C:11]([C:15]2[N:16]=[CH:17][CH:18]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]=2[C:13]([O:26][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:12])=[O:27])[N:6]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc(OC)nc(C2(O)OC(=O)c3c(-c4ccccc4)ccnc32)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(C(=O)c2nccc(-c3ccccc3)c2C(=O)OCc2ccccc2)n1
Temperature: 0 °C
Yield: 81.6 %

Procedure:
0.5 g of 7-(4,6-dimethoxypyrimidin-2-yl)-7-hydroxy-4-phenylfuro[3,4-b]pyridin-5(7H)one was dissolved in 10 ml of N,N-dimethylformamide, and 0.2 g of potassium carbonate was added thereto. Then, the reaction solution was stirred sufficiently. 0.23 g of benzyl bromide was added dropwise to the reaction solution at room temperature, and the reaction solution was stirred for one day. The reaction solution was poured into ice water and extracted with ethyl acetate. The extract was sufficiently washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting crude crystals were washed with isopropyl ether to obtain 0.5 g (yield 80%) of the desired compound. m.p.: 124°-126° C.
Reaction SMILES: [NH2:1][C:2]([CH3:9])([CH:6]([CH3:8])[CH3:7])[C:3]([NH2:5])=[O:4].[S:10]1[C:14]2=[N:15][C:16]3[C:22](=[O:23])[O:21][C:19](=[O:20])[C:17]=3[CH:18]=[C:13]2[CH:12]=[CH:11]1.N#N>C1COCC1>[C:3]([C:2]([NH:1][C:22]([C:16]1[N:15]=[C:14]2[S:10][CH:11]=[CH:12][C:13]2=[CH:18][C:17]=1[C:19]([OH:21])=[O:20])=[O:23])([CH3:9])[CH:6]([CH3:8])[CH3:7])(=[O:4])[NH2:5]
Reactant: O=C1OC(=O)c2nc3sccc3cc21
Reactant: CC(C)C(C)(N)C(N)=O
Agent: N#N
Solvent: C1CCOC1
Product: CC(C)C(C)(NC(=O)c1nc2sccc2cc1C(=O)O)C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
2-Amino-2,3-dimethylbutyramide (9.84 g, 0.076 mol) is added to a stirred suspension of thieno[2,3-b]pyridine-5,6-dicarboxylic acid anhydride (14.8 g, 0.072 mol) in THF under an inert atmosphere of N2 at room temperature. The dark solution is stirred at room temperature overnight and the resulting solid filtered off, washed with THF and air dried to give 17.35 g (72%) of 6-[(1-carbamoyl-1,2-dimethylpropyl)carbamoyl]thieno[2,3-b]pyridine-5-carboxylic acid.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:6][N+:7]1[C:12](Cl)=[CH:11][C:10]([NH:14][CH3:15])=[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:8]=1.O.[H][H]>[Ni].C(N(CC)CC)C>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:6][N+:7]1[CH:12]=[CH:11][C:10]([NH:14][CH3:15])=[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:8]=1
Reactant: CNc1cc(Cl)[n+](C)nc1-c1ccccc1
Reactant: [H][H]
Agent: [Ni]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCN(CC)CC
Solvent: O
Product: CNc1cc[n+](C)nc1-c1ccccc1
Reaction time: 24 h

Procedure:
15 parts of 1-methyl-3-phenyl-4-methylamino-6-chloropyridazinium perchlorate, 100 parts of water, 5 parts of triethylamine and about 2 parts of Raney nickel are treated at room temperature in a shaking apparatus with hydrogen at atmospheric pressure. After 24 hours the reaction mixture is suction filtered, the residue is boiled with 200 parts of methanol and filtered and the filtrate is concentrated and cooled. 10.3 parts (76.6% of theory) of 1-methyl-3-phenyl-4-methylaminopyridazinium perchlorate is obtained; C12H14O4N3Cl, melting point 155° to 157°C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[NH:13][CH3:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6].O.N.[CH:17](O)=O>>[CH3:14][N:13]1[C:12]2[CH:11]=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][C:2]=2[N:1]=[CH:17]1
Reactant: CCOC(=O)c1ccc(NC)c(N)c1
Reactant: O=CO
Agent: N
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)ncn2C

Procedure:
Ethyl 3-amino-4-methylaminobenzoate (24.1 g, 124 mmol) in the Step 1-1-3 was dissolved in formic acid (200 ml), and the solution was heated under reflux for 2 hours. After being cooled by ice, the solution was neutralized with a 25% ammonia water. The solution was subjected to extraction with chloroform, and the extract was dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (chloroform:methanol=20:1) to give the title compound (26.1 g, quantitative) as a light-purple powder.
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:12][CH:13]1[CH2:18][CH2:17][CH:16]([CH2:19][C:20](O)=[O:21])[CH2:15][CH2:14]1>>[CH3:12][CH:13]1[CH2:18][CH2:17][CH:16]([CH2:19][C:20]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[CH:4]=[CH:3][CH:2]=[N:1]3)=[O:21])[CH2:15][CH2:14]1
Reactant: CC1CCC(CC(=O)O)CC1
Reactant: Nc1cccc2ncccc12
Product: CC1CCC(CC(=O)Nc2cccc3ncccc23)CC1
Yield: 17.2 %

Procedure:
Prepared according to the method of example 18, using 5-quinolinamine (250 mg) and 4-methyl-cyclohexaneacetic acid (270 mg). Purification (HPLC, Symmetry—0.1% aqueous trifluoroacetic acid/acetonitrile) followed by recrystallisation from methanol/ethyl acetate gave the title compound as a colourless solid (84 mg).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[S:11][C:12]2[C:18]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=2[N:14]=1.[H-].[Na+].[CH3:29]I>CN(C=O)C>[CH3:26][O:25][C:15]1[C:13]2[N:14]=[C:10]([C:2]3[N:3]([CH3:29])[C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[N:1]=3)[S:11][C:12]=2[C:18]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:17][CH:16]=1
Reactant: CI
Reactant: COc1ccc(N2CCOCC2)c2sc(-c3nc4ccccc4[nH]3)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4ccccc4n3C)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
0.05 g of 2-(1H-Benzoimidazol-2-yl)-4-methoxy-7-morpholin-4-yl-benzothiazole (0.14 mmol) were dissolved in dry DMF (2.0 ml) and treated with 0.005 g NaH (65% in oil, 0.14 mmol) at 0° C. After stirring at ambient temperature for 1 h, 25 μl MeI (0.4 mmol) was added and the reaction mixture was stirred for 16 h. The suspension was filtered and the residue on the filter dried in vacuo. One obtained 0.042 g of 4-methoxy-2-(1-methyl-1H-benzoimidazol-2-yl)-7-morpholin-4-yl-benzothiazole (81%) as a yellow solid; M.p.: 283–285° C.
Reaction SMILES: [N:1]1([CH:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH2:10][O:9][C:8]3[CH:17]=[CH:18][C:19]([C:21]([O:23]C)=[O:22])=[CH:20][C:7]2=3)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[K+].Cl>CO.O1CCCC1>[N:1]1([CH:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH2:10][O:9][C:8]3[CH:17]=[CH:18][C:19]([C:21]([OH:23])=[O:22])=[CH:20][C:7]2=3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)c1ccc2c(c1)C(n1ccnc1)c1ccccc1CO2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2c(c1)C(n1ccnc1)c1ccccc1CO2
Temperature: 70 °C

Procedure:
Dissolve 3.1 gm of the ester of Step A in a mixture of 60 ml of methanol and 60 ml of tetrahydrofuran. Add 60 ml of 5% aqueous potassium hydroxide and heat the mixture at 70° C. under a nitrogen atmosphere for 5 hours. Pour the mixture onto ice and acidify to pH 5 with concentrated hydrochloric acid. Separate the solids by filtration. Wash with cold water and dry at 60° C. under vacuum for 2 hours to obtain the title product (m.p. 244°-255° C. dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21]([C:23]#[C:24][C:25]3[CH:26]=[N:27][NH:28][CH:29]=3)[S:22][C:13]=12.Cl.Cl[CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21]([C:23]#[C:24][C:25]3[CH:29]=[N:28][N:27]([CH2:32][CH2:33][N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[CH:26]=3)[S:22][C:13]=12
Reactant: ClCCN1CCOCC1
Reactant: COc1cc(Nc2c(C#N)cnc3cc(C#Cc4cn[nH]c4)sc23)c(Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Nc2c(C#N)cnc3cc(C#Cc4cnn(CCN5CCOCC5)c4)sc23)c(Cl)cc1Cl
Temperature: 50 °C
Yield: 69.5 %

Procedure:
A mixture of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(1H-pyrazol-4-ylethynyl)thieno[3,2-b]pyridine-6-carbonitrile (57 mg, 0.13 mmol), 4-(2-chloroethyl)morpholine hydrochloride (24 mg, 0.13 mmol), and cesium carbonate (42 mg, 0.13 mmol) in 1 mL of dimethylformamide is heated at 50° C. overnight. The mixture is cooled to room temperature and then added to water. The resulting precipitate is collected by filtration. The collected solid is purified by flash column chromatography, eluting with 1:7 methanol:ethyl acetate to provide 50 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{[1-(2-morpholin-4-ylethyl)-1H-pyrazol-4-yl]ethynyl}thieno[3,2-b]pyridine-6-carbonitrile as a yellow solid, mp greater than 200° C.; 1H NMR (DMSO-d6) δ 2.44 (br s, 4H), 2.62 (t, 2H), 3.53 (br s, 4H), 3.81 (s, 3H), 4.23 (br s, 2H), 6.77 (s, 1H), 7.57 (s, 1H), 7.71 (s, 1H), 7.80 (br, 1H), 8.24 (br, 1H), 8.37 (s, 1H), 13.36 (br s, 1H); MS 553.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@@H:8]([CH2:12][NH2:13])[CH2:7]1.[C:18]1([C:24]2[O:25][C:26]([CH3:33])=[C:27]([CH2:29][C:30](O)=[O:31])[N:28]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@@H:8]([CH2:12][NH:13][C:30](=[O:31])[CH2:29][C:27]2[N:28]=[C:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:25][C:26]=2[CH3:33])[CH2:7]1
Reactant: Cc1oc(-c2ccccc2)nc1CC(=O)O
Reactant: NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: Cc1oc(-c2ccccc2)nc1CC(=O)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 48.5 %

Procedure:
Example 54 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 9 (0.055 g) and 2-phenyl-5-methyl-4-oxazolylacetic acid (0.050 g) to give the title compound (0.046 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH:5](O)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.S(Cl)([Cl:19])=O>C(Cl)Cl.N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH:5]([Cl:19])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1
Reactant: OC(c1ccc(Cl)cc1)c1cccc(Br)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Clc1ccc(C(Cl)c2cccc(Br)c2)cc1
Reaction time: 8 h
Yield: 103 %

Procedure:
A solution of the above benzhydryl alcohol (13.0 g, 43 mmol) in 100 mL of methylene chloride and 5 mL of pyridine was stirred at room temperature during dropwise addition of 4.7 mL (64 mmol) of thionyl chloride in 20 mL of methylene chloride. After stirring overnight, the reaction solution was washed with two 60 mL portions of 1M hydrochloric acid and 50 mL of water and dried over magnesium sulfate. Evaporation of the solvent gave 14.0 g of 3-bromo-4'-chlorobenzhydryl chloride as a pale yellow oil. A portion was purified by chromatography on silica gel with hexane to give a colorless oil. Calc. for C13H9BrCl2 : C, 49.41; H, 2,87; Br, 25.28; Cl, 22.44. Found: C, 49.50; H, 2.82; Br, 25.27; Cl, 22.48.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:11]2[CH:12]=[N:13][NH:14][C:15](=O)[C:10]=2[N:9]=1.O=P(Cl)(Cl)[Cl:27]>>[Cl:27][C:15]1[N:14]=[N:13][CH:12]=[C:11]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:9][C:10]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]ncc2c1nc(-c1ccccc1Cl)n2-c1ccc(Cl)cc1
Product: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(Cl)nncc32)cc1
Temperature: 25 °C

Procedure:
A solution of 2-(2-chloro-phenyl)-1-(4-chloro-phenyl)-1,5-dihydro-imidazo[4,5-d]pyridazin-4-one (I-2g, 22 mg, 0.062 mmol) in POCl3 (3 ml) was heated under reflux for 2.5 hours. The reaction mixture was cooled to room temperature and the solvent was removed under vacuum. The residue was dissolved in toluene and again concentrated. This procedure was repeated twice. The residue was then taken up in CH2Cl2, and H2O was added. The pH of the aqueous solution was adjusted via addition of sat'd aq NaHCO3 until the pH was neutral (˜7). The CH2Cl2 layer was separated and the aqueous solution was extracted with CH2Cl2 (3×). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give I-2h as a pale yellow oil (22 mg): +APCI MS (M+1) 375.0/377.0; 1H NMR (CDCl3) δ 7.18–7.23 (2H, m), 7.35–7.48 (5H, m), 7.56–7.60 (1H, m), 9.22 (1H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>CO.[Ni]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][C:13](=[O:16])[CH2:14][CH2:15]2)=[CH:6][CH:5]=1
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Ni]
Solvent: CO
Product: Nc1ccc(N2CCC(=O)CC2)cc1
Yield: 90.5 %

Procedure:
A solution of 1-(4-nitrophenyl)-4-piperidone (400 mg, 1.8 mmol) in methanol (5 μL) was hydrogenated over Raney nickel (0.08 g) at atmospheric pressure for 3 hours at r.t. The mixture was filtered through Celite and the filtrate evaporated to dryness to obtain 1-(4-aminophenyl)-4-piperidone (310 mg, 89%) as a semisolid.
Reaction SMILES: C([CH:4]1[O:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[CH2:6][O:5]1)=CC.C1(CO)C([CH2:21][OH:22])=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.CCOCC>COCCOC>[CH3:21][O:22][CH:4]1[O:5][CH2:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][O:10]1
Reactant: CC=CC1OCc2ccccc2CO1
Reactant: OCc1ccccc1CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COCCOC
Solvent: CCOCC
Product: COC1OCc2ccccc2CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
A method for synthesizing 3-(1-propenyl)-1,5-dihydro-3H-2,4-benzodioxepine is illustrated in Scheme 3. 1,2-Benzenedimethanol (500 mg, 3.62 mmol) and p-toluenesulfonic acid (172 mg, 0.9 mmol) were dissolved in 2 mL of dry DME and triethylortoformate (0.396 mL, 3.62 mmol) was added. The solution was stirred at rt. and under argon for 1 h. Ether (20 mL) was added and the organic layer washed with a saturated solution of NaHCO3 and water, then dried (Na2SO4). The solvent was evaporated giving crude 3-methoxy-1,5-dihydro-3H-2,4 benzodioxepine as a colorless oil (526 mg, 89%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])[N:6]=[C:5]2[N:19]1[CH2:23][CH2:22][C@@H:21]([NH:24]C(=O)OC(C)(C)C)[CH2:20]1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:24][C@@H:21]1[CH2:22][CH2:23][N:19]([C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=3)[N:8]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[N:6]=2)[CH2:20]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2nc(-c3ccccc3O)nc3ccc(F)cc23)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CCN(c2nc(-c3ccccc3O)nc3ccc(F)cc23)C1

Procedure:
To a solution of tert-butyl(R)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-ylcarbamate (480 mg, 1.11 mmol) in CH2Cl2 (10 mL) was added TFA (4 mL). The reaction was stirred for an hour, diluted with 10 mL CH2Cl2, and neutralized with a saturated aqueous NaHCO3 solution. The aqueous layer was extracted twice with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 3-20% EtOAc/CH2Cl2 gave 2-(4-((R)-3-aminopyrrolidin-1-yl)-6-fluoroquinazolin-2-yl)phenol. LC/MS: m/z 325.5 (M+H)+ at 1.26 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).