Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18]([OH:20])=O)[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1)[CH2:22][CH2:23][CH2:24][CH3:25].Cl.CN(C)CCCN=C=NCC>C(Cl)(Cl)Cl>[CH2:21]([C:26]1[CH:27]=[CH:28][C:29]([NH:30][C:18]([C@@H:17]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:20])=[CH:31][CH:32]=1)[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCCCCc1ccc(NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)cc1
Reaction time: 8 h

Procedure:
To a stirred solution of (S)—N-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (10.0 g, 36.1 mmol) and 4-pentylaniline (4.91 g, 30.1 mmol) in chloroform (150 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (6.92 g, 36.1 mmol). The reaction was allowed to proceed overnight and then washed with aqueous sodium bicarbonate solution, dried (sodium sulfate) and concentrated to afford crude product as an off-white, foamy solid. This material was used in the next step without further purification.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[N:15]=[C:14]([Cl:16])[N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[C@@H:17]2[O:21][C@H:20]([CH2:22][O:23][C:24]([NH:26][CH3:27])=[O:25])[C@@H:19]([OH:28])[C@H:18]2[OH:29])[CH2:2]1.[CH:30]1(N)[CH2:34]C[CH2:32][CH2:31]1.CN>>[O:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[N:15]=[C:14]([Cl:16])[N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[C@@H:17]2[O:21][C@H:20]([CH2:22][O:23][C:24]([NH:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:34]3)=[O:25])[C@@H:19]([OH:28])[C@H:18]2[OH:29])[CH2:2]1
Reactant: CNC(=O)OC[C@H]1O[C@@H](n2cnc3c(N[C@@H]4CCOC4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: NC1CCCC1
Agent: CN
Product: O=C(NC1CCCC1)OC[C@H]1O[C@@H](n2cnc3c(N[C@@H]4CCOC4)nc(Cl)nc32)[C@H](O)[C@@H]1O

Procedure:
This compound was prepared in a manner similar to that of 13 substituting cyclopentyl amine for methyl amine.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)(C)(C)C.C(Cl)[Cl:23].[ClH:25]>O1CCOCC1>[ClH:23].[ClH:25].[N:18]1[CH:19]=[CH:20][C:15]([O:14][C@H:11]2[CH2:10][CH2:9][C@H:8]([NH2:7])[CH2:13][CH2:12]2)=[CH:16][CH:17]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Oc2ccncc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CC[C@H](Oc2ccncc2)CC1
Reaction time: 2 h

Procedure:
A mixture of tert-butyl[trans-4-(pyridin-4-yloxy)cyclohexyl]carbamate in a solution of methylene chloride (1 mL) and 4.0 M of hydrogen chloride in 1,4-dioxane (2 mL) was stirred at r.t for 2 hours. The mixture was concentrated to yield 45% of trans-4-(pyridin-4-yloxy)cyclohexanamine dihydrochloride (2-step).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([OH:21])[C:16](=[NH:20])[O:17]CC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:22]1CCC[CH2:23]1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]1[O:21][C:23](=[O:22])[NH:17][C:16]1=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: CCOC(=N)C(O)c1ccccc1OCc1ccccc1
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C(c2ccccc2OCc2ccccc2)O1

Procedure:
By the procedure Method A of Example 12, ethyl 1-(2-benzyloxyphenyl)-1-hydroxymethanecarboximidate (13 g.) in 350 ml. of tetrahydrofuran was converted to toluene recrystallized 5-(2-benzyloxyphenyl)oxazolidine-2,4-dione (7.23 g., 55%; m.p. 191°-193° C.; m/e 283)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12]CC)=O)=[CH:7][C:6]=2[CH:15]=1.Cl[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10](=[O:12])[C:22]3[CH:17]=[CH:3][CH:2]=[CH:15][C:21]=3[N:20]3[CH2:7][CH2:8][O:9][CH2:18][CH2:19]3)=[CH:7][C:6]=2[CH:15]=1
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2o1
Reactant: Clc1ccncc1
Solvent: C1CCOC1
Product: O=C(c1cc2cc(Cl)ccc2o1)c1ccccc1N1CCOCC1
Reaction time: 16 h

Procedure:
A solution of ethyl 5-chlorobenzofuran-2-carboxylate (350 mg, 1.56 mmol) in THF (10 ml) is added at −70° C. to a THF solution of lithiated 4-chloropyridine (1.8 mmol prepared according to G. Quéguiner et al., Synthesis 1986, 886-891). The mixture is allowed to reach room temperature within 16 hours before quenching with acetic acid. The product is extracted with chloroform. Drying and chromatography on silicagel gives the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[C:10]([O:14][C:15]([N:17]([CH:21]=[C:22]1[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[C:24]([NH2:25])[CH2:23]1)[CH:18]([CH3:20])[CH3:19])=[O:16])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([O:14][C:15]([N:17]([CH:21]=[C:22]1[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[C:24]([NH:25][C:6]2[C:5]([F:9])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:23]1)[CH:18]([CH3:20])[CH3:19])=[O:16])([CH3:11])([CH3:12])[CH3:13]
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: COC1=CC=C(N)CC1=CN(C(=O)OC(C)(C)C)C(C)C
Product: COC1=CC=C(Nc2nc(Cl)ncc2F)CC1=CN(C(=O)OC(C)(C)C)C(C)C

Procedure:
In like manner to the preparation of 2-chloro-5-fluoro-N4-(3-methyloxycarbonyl-4-methoxyphenyl)-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 3-(N-tert-butoxycarbonyl-N-iso-propylaminomethylene)-4-methoxy-aniline were reacted to produce N4-(3-(N-tert-butoxycarbonyl-N-iso-propylaminomethylene)-4-methoxyphenyl)-2-chloro-5-fluoro-4-pyrimidineamine R940320. 1H NMR (DMSO-d6): δ 10.01 (1H, s), 8.34 (1H, d, J=3.6 Hz), 7.52 (2H, m), 7.08 (1H, d, J=8.7 Hz), 4.33 (3H, m), 3.90 (3H, s), 1.50-1.30 (9H, m), 1.18 (6H, d, J=6.9 Hz); purity 95%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:27])[CH:10]=[CH:11][N:12]2[C:17]=1[CH:16]=[CH:15][C:14]([O:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[F:26])=[N:13]2.[CH3:28][CH2:29][CH2:30]C[Sn](/C=C/C)(CCCC)CCCC>>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[O:18][C:14]1[CH:15]=[CH:16][C:17]2[N:12]([CH:11]=[CH:10][C:9](=[O:27])[C:8]=2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2/[CH:28]=[CH:29]/[CH3:30])[N:13]=1
Reactant: O=c1ccn2nc(Oc3ccc(F)cc3F)ccc2c1-c1ccccc1Br
Reactant: C/C=C/[Sn](CCCC)(CCCC)CCCC
Product: C/C=C/c1ccccc1-c1c(=O)ccn2nc(Oc3ccc(F)cc3F)ccc12

Procedure:
The title compound was prepared from 5-(2-bromophenyl)-2-(2,4-difluorophenoxy)-6H-pyrido[1,2-b]pyridazin-6-one as described in Example-7 using tri-N-butyl(1-propenyl)tin in place of tri-N-butyl (vinyl)tin. 50/50 mixture of cis and trans.
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:5])[CH3:4].Br[CH2:15][C:16]1[S:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1>CN(C)C=O.C(OCC)(=O)C>[S:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=[C:16]1[CH2:15][O:13][C:10]1[CH:11]=[CH:12][C:7]([NH:6][C:3](=[O:5])[CH3:4])=[CH:8][CH:9]=1
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: BrCc1nc2ccccc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(OCc2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 83.7 %

Procedure:
0.24 g of sodium hydride (as a 60% w/w dispersion in mineral oil) were added to a solution of 133.9 mg of 4-acetamidophenol in 2.7 ml of dimethylformamide, followed by the addition of a solution of 205.6 mg of 2-bromomethylbenzothiazole in 2 ml of dimethylformamide. The resulting mixture was stirred at room temperature for 7 hours, after which the reaction mixture was diluted with ethyl acetate, washed with water, tried over sodium sulfate and the solvent removed by evaporation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 1:2 by volume mixture of hexane and ethyl acetate as the eluent, to give 221.1 mg (yield 84%) of the title compound as a solid having a melting point of 168 to 170° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=O)[CH2:7][CH:6]2[CH2:15][CH2:16][NH:17][CH3:18].[Na]>C(O)CCC>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[N:9]([CH3:13])[CH:8]3[CH2:7][CH:6]([CH2:15][CH2:16][N:17]3[CH3:18])[C:5]=2[CH:4]=1
Reactant: CNCCC1CC(=O)N(C)c2ccc(OC)cc21
Agent: [Na]
Solvent: CCCCO
Product: COc1ccc2c(c1)C1CCN(C)C(C1)N2C
Yield: 52.3 %

Procedure:
To a stirred solution of 4.50 g of 3,4-dihydro-6-methoxy-1-methyl-4-[2-(methylamino)ethyl]-2(1H)-quinolinone in 450 ml of refluxing n-butanol was added, incrementally over a period of 1.5 hours, 27.0 g of sodium. The resulting mixture was stirred at reflux until all of the sodium was consumed, and then it was cooled, and diluted with water. The aqueous phase was separated and extracted with ethyl acetate. The combined organic layers were washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered, and concentrated. The concentrate was purified by means of column chromatography on silica gel (elution with triethylamine/methanol/ethyl acetate) followed by recrystallization from diethyl ether-pentane to afford 2.20 g (52%) of 1,2,3,4,5,6-hexahydro-8-methoxy-1,3-dimethyl-2,6-methano-1,3-benzodiazocine, m.p. 72°-73.5° C.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]([NH:14][C:15]([C:17]1[C:25]2[C:20](=[N:21][CH:22]=[C:23]([C:26]3[C:34]4[C:29](=[CH:30][C:31]([F:35])=[CH:32][CH:33]=4)[N:28]([CH3:36])[N:27]=3)[N:24]=2)[NH:19][CH:18]=1)=[O:16])([CH3:13])[CH3:12])(C(C)(C)C)(C)C>Cl.O1CCOCC1>[F:35][C:31]1[CH:30]=[C:29]2[C:34]([C:26]([C:23]3[N:24]=[C:25]4[C:17]([C:15]([NH:14][C:11]([CH3:13])([CH2:10][CH2:9][OH:8])[CH3:12])=[O:16])=[CH:18][NH:19][C:20]4=[N:21][CH:22]=3)=[N:27][N:28]2[CH3:36])=[CH:33][CH:32]=1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)CCO[Si](C)(C)C(C)(C)C)c3n2)c2ccc(F)cc21
Agent: Cl
Solvent: C1COCCO1
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)CCO)c3n2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 27 %

Procedure:
N-(4-(tert-butyldimethylsilyloxy)-2-methylbutan-2-yl)-2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (70 mg, 0.140 mmol) was dissolved in 30 mL of a saturated solution of HCl (g) in dioxane and the solution was stirred at room temperature for one hour. The solvent was evaporated at 40° C. under reduced pressure and the residue was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 38% acetonitrile/62% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 42% acetonitrile/58% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-N-(4-hydroxy-2-methylbutan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (15 mg, 27.6%) as a yellow solid. MS: (M+H)+=397; 1H NMR (300 MHz, DMSO): δ 12.84 (s, 1H), 9.10 (s, 1H), 8.55-8.50 (m, 1H), 8.40 (s, 1H), 7.89 (s, 1H), 7.73-7.69 (m, 1H), 7.22-7.16 (m, 1H), 7.42 (t, 2H, J=4.6 Hz), 4.17 (s, 3H), 3.61-3.55 (m, 2H), 2.13-2.09 (m, 2H), 1.25 (s, 6H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=O)[NH:3][C:2]1=O.C([N:16]1C=C[N:18]=[C:17]1CCN)C1C=CC=CC=1>>[NH:1]1[CH:6]=[C:5]2[C:4]([N:16]=[CH:17][NH:18]2)=[N:3][CH2:2]1
Reactant: O=C1CCNC(=O)N1
Reactant: NCCc1nccn1Cc1ccccc1
Product: C1=c2[nH]cnc2=NCN1

Procedure:
Treatment of oxazole 1 with n-BuLi, followed by an alkylation reaction, and a deprotection reaction with TFA affords 2-(oxazol-2-yl)ethanamine 3. Amine 3 can be coupled with dihydropurine 4 to give compound 6.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1>Cl.O>[F:13][C:12]([F:15])([F:14])[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][CH:3]=[C:2]2[NH:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1
Reactant: FC(F)(F)c1cccc2c(Cl)ccnc12
Reactant: Nc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: O
Product: O=C(O)c1ccc(Nc2ccnc3c(C(F)(F)F)cccc23)cc1
Temperature: 90 °C
Yield: 96.6 %

Procedure:
23.16 Grams (0.1 mole) of 4-chloro-8-trifluoromethyl quinoline were dissolved in 22 milliliters of concentrated hydrochloric acid and 150 milliliters of water and the solution was added in a stream to a vigorously stirred solution of 13.7 grams (0.1 mole) of p-aminobenzoic acid in 150 milliliters of water at 60° C. The mixture was heated at 90° C. for 2 hours, cooled, and the solid collected and recrystallized from ethanol to give 32.1 grams (83%) of the title compound as the hydrochloride monohydrate, melting point 262°-265° C.(d).
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[CH3:7][C:8]1[C:9]([C:30]([NH2:32])=[O:31])=[N:10][C:11]([C:15]2[CH:20]=[CH:19][C:18]([B:21]3[O:25]C(C)(C)C(C)(C)[O:22]3)=[CH:17][CH:16]=2)=[C:12]([CH3:14])[N:13]=1.Cl>C1COCC1.O>[C:30]([C:9]1[N:10]=[C:11]([C:15]2[CH:16]=[CH:17][C:18]([B:21]([OH:25])[OH:22])=[CH:19][CH:20]=2)[C:12]([CH3:14])=[N:13][C:8]=1[CH3:7])(=[O:31])[NH2:32]
Reactant: Cc1nc(C)c(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)nc1C(N)=O
Agent: Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(C)c(-c2ccc(B(O)O)cc2)nc1C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
Sodium periodate (19.64 g, 91.81 mmol) was added in one portion to 3,5-dimethyl-6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carboxamide (Intermediate 7-6; 10.81 g, 30.60 mmol) in THF (320 mL) and water (80 mL) and the resulting cloudy suspension was stirred at ambient temperature for 30 minutes. 1M hydrochloric acid (21.42 mL, 21.42 mmol) was added and the resulting suspension was stirred at ambient temperature for 17 hours. The reaction mixture was evaporated and diluted with water (100 mL) and the precipitate was collected by filtration, washed with water (400 mL) and dried under vacuum at 65° C. over 4 hours to afford 4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)phenylboronic acid (7.13 g, 86%) as a white solid, which was used without further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6])=[CH2:2].C[Si](Cl)(C)C.[CH2:16](O)[CH2:17][OH:18]>C(=O)(O)[O-].[Na+]>[CH2:17]1[O:18][CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[CH:1]=[CH2:2])[O:6][CH2:16]1
Reactant: C=Cc1ccccc1C=O
Reactant: OCCO
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: C=Cc1ccccc1C1OCCO1
Reaction time: 16 h

Procedure:
A mixture of 2-vinylbenzaldehyde (2.9 g, 22 mmol) and trimethylsilyl chloride (11 ml) in ethylene glycol (95 ml) was stirred for 16 h, diluted with saturated sodium bicarbonate solution, extracted with ether, dried over sodium sulphate and evaporated to afford a colourless oil (2.7 g), MS (+EI) 176 (M+), 1H NMR (CDCl3) 7.57 (1H, m), 7.53 (1H, dd, J1.5, 7.5 Hz), 7.36-7.30 (2H, m), 7.14 (1H, dd, J11, 17.4 Hz), 6.04 (1H, s) 5.69 (1H, dd, J1.3, 17.4 Hz), 5.34 (1H, dd, J1.3, 11.0 Hz), 4.18-4.04 (2H, m), 3.77-3.65 (2H, m).
Reaction SMILES: Br.Cl[C:3]1[N:8]2[CH:9]=[C:10]([CH3:12])[N:11]=[C:7]2[CH:6]=[CH:5][CH:4]=1.Cl.[SH-:14].[Na+]>>[SH:14][C:3]1[N:8]2[CH:9]=[C:10]([CH3:12])[N:11]=[C:7]2[CH:6]=[CH:5][CH:4]=1
Reactant: [SH-]
Reactant: Cc1cn2c(Cl)cccc2n1
Agent: Br
Agent: Cl
Agent: [Na+]
Product: Cc1cn2c(S)cccc2n1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
In a nitrogen atmosphere, 17.33 g (70 mmol) of 5-chloro-2-methylimidazo[1,2-a]pyridine hydrobromide was added to 70 ml of a sodium hydrosulfide solution at room temperature, followed by stirring at 90° C. for 24 hours. After the reaction mixture was cooled, concentrated hydrochloric acid was added until the reaction mixture's pH became 3-4. The resulting precipitate was collected by filtration, washed with water and dried to yield 12.32 g (quant, yellow powder) of the desired product.
Reaction SMILES: [OH-:1].[Na+].[C:3]([CH2:6][CH2:7][S:8][CH:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[C:19]([C:20]#[N:21])[C:14]=2[CH2:13][O:12][C:11]2[CH:22]=[CH:23][C:24]([O:26][CH2:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][C:32]([Cl:38])=[CH:33][CH:34]=4)[N:29]=3)=[CH:25][C:10]1=2)([OH:5])=[O:4].O>C(O)C>[C:20]([C:19]1[C:14]2[CH2:13][O:12][C:11]3[CH:22]=[CH:23][C:24]([O:26][CH2:27][C:28]4[CH:37]=[CH:36][C:35]5[C:30](=[CH:31][C:32]([Cl:38])=[CH:33][CH:34]=5)[N:29]=4)=[CH:25][C:10]=3[CH:9]([S:8][CH2:7][CH2:6][C:3]([OH:5])=[O:4])[C:15]=2[CH:16]=[CH:17][CH:18]=1)(=[O:1])[NH2:21]
Reactant: N#Cc1cccc2c1COc1ccc(OCc3ccc4ccc(Cl)cc4n3)cc1C2SCCC(=O)O
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=O)c1cccc2c1COc1ccc(OCc3ccc4ccc(Cl)cc4n3)cc1C2SCCC(=O)O

Procedure:
40 ml of a 1N-sodium hydroxide aqueous solution was added to 0.85 g of the compound 11-(2-carboxyethylthio)-2-(7-chloroquinolin-2-yl)methoxy-7-cyano-6,11-dihydrodibenz[b,e]oxepine obtained in Example 15 dissolved in 10 ml of ethanol and the mixture was refluxed under heating for 2 hours. After completion of the reaction, water was added to the residue obtained by removing the solvent, the mixture was adjusted to about pH 3 with 1N-hydrochloric acid and crystals precipitated were dissolved in ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and condensed. The resulting residue was applied to silica gel column chromatography to obtain 0.25 g of the title compound as slightly yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[N:10]=[N:9]1>C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[N:10]=[N:9]1
Reactant: CCOC(=O)c1cn(-c2ccccc2F)nn1
Solvent: O
Solvent: CCO
Product: O=C(O)c1cn(-c2ccccc2F)nn1
Temperature: 60 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
Ethyl 1-(2-fluorophenyl)-1H-1,2,3-triazole-4-carboxylate (110 mg) was dissolved in ethanol (3 ml)-water (2 ml)-1M aqueous sodium hydroxide solution (1 ml) and the mixture was stirred at 60° C. for 12 hr. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water, neutralized (pH: 2) with 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (92 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[N:7]=[C:8](SC)[C:9]3[C:10](=[CH:12][S:13][CH:14]=3)[NH:11][C:5]=2[CH:4]=1.O.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[N:7]=[C:8]([N:24]3[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]3)[C:9]3[C:10](=[CH:12][S:13][CH:14]=3)[NH:11][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)Nc1cscc1C(SC)=N2
Reactant: CN1CCNCC1
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2c(c1)Nc1cscc1C(N1CCN(C)CC1)=N2

Procedure:
A solution of 6-methoxy-10-(methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine in excess N-methylpiperazine and glacial acetic acid is heated at reflux for 2 days. The solution is poured into water and the product is collected.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[N:5]=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19](=[O:21])[CH3:20])[CH:13]=1>CCOC(C)=O.[Pd]>[NH2:8][C:6]1[N:5]=[CH:4][C:3]([O:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19](=[O:21])[CH3:20])[CH:13]=2)=[C:2]([CH3:1])[CH:7]=1
Reactant: CC(=O)Nc1cc(Oc2cnc([N+](=O)[O-])cc2C)ccn1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cc(Oc2cnc(N)cc2C)ccn1
Yield: 99.2 %

Procedure:
A solution of N-(4-((4-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)acetamide (0.36 g, 1.249 mmol) in EtOAc (15 mL) was treated with 10% Pd/C (50% w/w water, 0.133 g, 0.125 mmol) and hydrogenated (1 atm) overnight. The solids were removed via filtration through diatomaceous earth, washed with EtOAc and the filtrate was concentrated to dryness to afford N-(4-((6-amino-4-methylpyridin-3-yl)oxy)pyridin-2-yl)acetamide (320 mg, 99%). 1H NMR (400 MHz, DMSO-d6): δ 10.47 (s, 1H), 8.11 (d, J=5.7 Hz, 1H), 7.66 (s, 1H), 7.55 (d, J=2.4 Hz, 1H), 6.55 (dd, J=5.7, 2.4 Hz, 1H), 6.37 (s, 1H), 5.88 (s, 2H), 2.02 (s, 3H), 1.93 (s, 3H); MS (ESI) m/z: 259.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl.O>[F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH2:4][N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C1CCNC1
Reactant: O=Cc1ccc(O)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Oc1ccc(CN2CCCC2)c(F)c1
Reaction time: 0.33 h
Yield: 93.9 %

Procedure:
To a solution of 2-fluoro-4-hydroxybenzaldehyde (0.42 g, 3.00 mmol) in DCM (15 mL) was added pyrrolidine (0.26 g, 3.60 mmol). After stirring for 20 min, sodium triacetoxyborohydride (0.76 g, 3.60 mmol) was added and the reaction mixture was stirred overnight. The mixture was then diluted with DCM and transferred to a separatory funnel. Water was added, basified to pH 9-10 with a 0.1 M solution of NaOH and extracted 6 times with DCM. The organic layer was dried (phase separator) and concentrated in vacuo. There was obtained 0.55 g (94%) of 31A as a solid. 1H NMR (500 MHz, CDCl3): δ 1.85 (s, 4H), 2.70 (s, 4H), 3.60 (s, 2H), 6.25 (m, 2H), 7.00 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:3]=1[CH2:4][N:5]1[C:13](=[O:14])[N:12](C(OC(C)(C)C)=O)[C:11]2[C:6]1=[N:7][C:8]([N:22]1[C:26]3[CH:27]=[C:28]([C:31]#[N:32])[CH:29]=[CH:30][C:25]=3[N:24]=[CH:23]1)=[N:9][CH:10]=2>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:37][C:33]1[CH:34]=[CH:35][CH:36]=[C:2]([F:1])[C:3]=1[CH2:4][N:5]1[C:13](=[O:14])[NH:12][C:11]2[C:6]1=[N:7][C:8]([N:22]1[C:26]3[CH:27]=[C:28]([C:31]#[N:32])[CH:29]=[CH:30][C:25]=3[N:24]=[CH:23]1)=[N:9][CH:10]=2
Reactant: CC(C)(C)OC(=O)n1c(=O)n(Cc2c(F)cccc2F)c2nc(-n3cnc4ccc(C#N)cc43)ncc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc2ncn(-c3ncc4[nH]c(=O)n(Cc5c(F)cccc5F)c4n3)c2c1
Reaction time: 1 h

Procedure:
A 1:1 solution of TFA/DCM (10 mL) was added to tert-Butyl 9-(2,6-difluorobenzyl)-2-(6-cyano-1H-benzo[d]imidazol-1-yl)-8-oxo-8,9-dihydropurine-7-carboxylate (60) and stirred for 1 hr. The solvents were removed en vacuo and the resulting solid was triturated with Et2O, and suspended in 6N HCl. Removal of solvents and trituration with Et2O of the resulting solid gave the titled compound (61) (68 mg) as a HCl salt, MH+=404, 1H NMR (d6-DMSO) δ 11.8 (s, 1H), 9.2 (s, 1H), 8.8 (s, 1H), 8.0 (s, 1H), 7.9 (d, 1H), 7.8 (broad s, 1H), 7.4 (d, 1H), 7.4 (quintet, 1H), 7.1 (m, 2H), 5.2 (s, 2H) ppm, 19F NMR δ −114.3 (m).
Reaction SMILES: C[O:2][C:3](=[O:40])[CH2:4][CH2:5][NH:6][C:7](=[O:39])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[C:15]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[C:16]2[S:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=3)[N:20]=2)=[CH:10][CH:9]=1.[OH-].[Na+]>CO.C1COCC1>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([C:15]([C:16]2[S:17][CH:18]=[C:19]([C:21]3[CH:22]=[CH:23][C:24]([O:27][C:28]([F:30])([F:29])[F:31])=[CH:25][CH:26]=3)[N:20]=2)=[CH:14][C:11]2[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:40])=[O:2])=[O:39])=[CH:13][CH:12]=2)=[CH:33][CH:34]=1
Reactant: COC(=O)CCNC(=O)c1ccc(C=C(c2ccc(Cl)cc2)c2nc(-c3ccc(OC(F)(F)F)cc3)cs2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCNC(=O)c1ccc(C=C(c2ccc(Cl)cc2)c2nc(-c3ccc(OC(F)(F)F)cc3)cs2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.9 %

Procedure:
3-(4-{2-(4-Chlorophenyl)-2-[4-(4-trifluoromethoxyphenyl)thiazol-2-yl]vinyl}benzoylamino)propionic acid methyl ester (14 mg) was dissolved in methanol (5 mL) and 1 N sodium hydroxide (72 μL, 3 equivalents) and 5 drops THF were added and the resulting mixture was stirred at room temperature for 1 hour. More 1 N sodium hydroxide (72 μL, 3 equivalents) and 5 drops THF were added and the resulting mixture was stirred at room temperature for 1 hour and at 50° C. for 1 hour. The mixture was concentrated in vacuo and the residue was added water (5 mL) and 1 N hydrochloric acid was added to pH 2. The solid was filtered off, washed with water and dried in vacuo to afford 6 mg (4%) of the title compound.