Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:10][CH3:11])[C:5]([NH2:9])=[N:6][C:7]=1[Cl:8].[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[S:20](Cl)(=[O:22])=[O:21]>>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[S:20]([NH:9][C:5]1[C:4]([O:10][CH3:11])=[N:3][C:2]([Cl:1])=[C:7]([Cl:8])[N:6]=1)(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: COc1nc(Cl)c(Cl)nc1N
Product: COc1nc(Cl)c(Cl)nc1NS(=O)(=O)c1ccc(Cl)cc1Cl

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 5,6-dichloro-3-methoxy-2-pyrazinamine (0.1 g) and 2,4-dichlorobenzenesulphonyl chloride (0.15 g). Yield 0.076 g.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][CH2:6][C:7]#[CH:8])(=O)=O.[C:16]1([C:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH:27]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[C:16]1([C:22]2[CH2:27][CH2:26][N:25]([CH2:8][CH2:7][C:6]#[CH:5])[CH2:24][CH:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: C#CCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCCN1CC=C(c2ccccc2)CC1

Procedure:
A solution of 3-butynyl tosylate (25.0 g, 0.11 mol), 4-phenyl-1,2,3,6-tetrahydropyridine (21.8 g, 0.11 mol) and sodium bicarbonate (10.3 g, 0.12 mol) in 300 mL of dimethylformamide is heated at 80° C. for 18 hours. The solvent is removed under reduced pressure, and the residue is partitioned between 200 mL of dichloromethane and 200 mL of water. The aqueous layer is extracted with 100 mL of dichloromethane and the combined organic layers are dried (sodium sulfate), and the solvent is removed in vacuo. The residue is chromatographed (silica 9el, 25% ethyl acetate/75% hexane) to give the title compound as a yellow solid; mp 36.5°-37.5° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][OH:8].[H-].[Na+].[N+:11]([C:14]1[CH:15]=[N:16][CH:17]=[C:18]([N+]([O-])=O)[CH:19]=1)([O-:13])=[O:12]>CN(C=O)C.O.[Cl-].[Na+].O>[N+:11]([C:14]1[CH:19]=[C:18]([O:8][CH2:7][C@@H:3]2[CH2:4][CH2:5][CH2:6][N:2]2[CH3:1])[CH:17]=[N:16][CH:15]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cncc([N+](=O)[O-])c1
Reactant: CN1CCCC1CO
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCC[C@H]1COc1cncc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7.6 %

Procedure:
1-Methylpyrrolidinylmethanol (0.46 ml, 3.9 mmol) was added to a suspension of NaH in DMF at room temperature. After stirring at room temperature for 30 minutes, 3,5-dinitro-pyridine (0.34 g, 4 mmol) was added, and the mixture was allowed to stir at room temperature for 16 hours. The mixture was diluted with 1:1 water/brine, and the aqueous solution was extracted with ether. The combined ether layers were dried over MgSO4, filtered and concentrated. The residue was chromatographed, eluting with CH2Cl2 : methanol (10:0.5) to afford 70 mg of the title compound. MS (DCI/NH3) m/e: 238 (M+1). 1H NMR (CDCl3, 300MHz) δ: 9.06 (m, 1H), 8.62 (d, 1H), 7.97 (m, 1H), 4.07 (m, 2H), 3.50 (s, 3H), 3.13 (m, 1H), 2.73 (m, 1H), 2.35 (m, 1H), 2.05 (m, 1H), 1.82 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28].Br[CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=1>>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:12][CH2:13][N:14]([CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=3)[CH2:15][CH2:16]1)[CH2:10][C:9]2=[O:28]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Reactant: COc1cccc(CCBr)c1
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCc3cccc(OC)c3)CC1)O2
Yield: 83.1 %

Procedure:
(E)-3-{4-Oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (169 mg, 0.500 mmol, Intermediate 1, hydrochloride salt) was alkylated using 1-(2-bromo-ethyl)-3-methoxy-benzene (0.16 ml, 1.5 mmol) as described in Example 56, Step A, giving (E)-3-{1′-[2-(3-methoxy-phenyl)-ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (181 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([F:12])[CH:3]=1.CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>>[Br:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([N:8]=[CH:15][N:16]([CH3:18])[CH3:17])=[O:7])=[C:4]([F:12])[CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1cc(C(N)=O)c(F)cc1Br
Product: Cc1cc(C(=O)N=CN(C)C)c(F)cc1Br
Yield: 95 %

Procedure:
A solution of 4-bromo-2-fluoro-5-methylbenzamide (20 g, 86 mmol) in N,N-dimethyl-formamide dimethylacetal (200 mL) was stirred at 100° C. under nitrogen for 3 h. The resulting mixture was concentrated and dried to give the desired product (24.6 g, 95% yield) as a yellow oil, which was used in the next step without further purification. MS (ESI) m/z 287.0 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][O:11][CH3:12])=[CH:4][C:3]=1[C:13](=O)[CH3:14].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25]>CN(C)C=O>[CH:26]1([C:24]([C:23]2[O:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][O:11][CH3:12])=[CH:4][C:3]=3[C:13]=2[CH3:14])=[O:25])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(CBr)C1CCCCC1
Reactant: COCCOc1ccc(O)c(C(C)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1ccc2oc(C(=O)C3CCCCC3)c(C)c2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.8 %

Procedure:
1-[2-Hydroxy-5-(2-methoxyethoxy)phenyl]ethanone (7.0 g) synthesized in the above-mentioned (1) was dissolved in N,N-dimethylformamide (140 mL). Potassium carbonate (13.8 g) and 2-bromo-1-cyclohexylethanone (8.9 g) synthesized in Example A51(1) were added to the reaction mixture at room temperature, and the mixture was stirred for 15 hr. The reaction mixture was filtered through celite, water (200 mL) was added, and the mixture was extracted with diethyl ether (100 mL×2). The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide solution (100 mL), DBU (5.3 mL) was added at room temperature, and the mixture was stirred at 100° C. for 1 hr. The reaction mixture was allowed to cool to room temperature, 1N hydrochloric acid (100 mL) was added, and the mixture was extracted with diethyl ether (100 mL×2). The extract was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:20, volume ratio) to give the title object compound (10.3 g, 98%) as a pale-yellow oil.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C@@:3]([O:8][Si](C)(C)C)([CH3:7])[C:4](Cl)=[O:5].[Cl:15][C:16]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18].N1C=CC=CC=1>C(Cl)Cl>[Cl:15][C:16]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:17]=1[NH:18][C:4](=[O:5])[C@:3]([OH:8])([CH3:7])[C:2]([F:14])([F:13])[F:1]
Reactant: C[C@@](O[Si](C)(C)C)(C(=O)Cl)C(F)(F)F
Reactant: Cc1cccc(N)c1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cccc(NC(=O)[C@@](C)(O)C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.1 %

Procedure:
A solution of (S)-3,3,3-trifluoro-2-trimethylsilyoxy-2-methylpropanoyl chloride (prepared from (R)-(+)-2-Hydroxy-2-methyl-3,3,3-trifluoropropanoic acid (Method 3) as described in J Med. Chem., 1999, 42, 2741-2746)(17.4 g, 70 mmol) in DCM (50 ml) was added to a stirred mixture of 2-chloro-3-methyl-aniline (WO 9741846; 8.25 g, 141.6 mmol) and pyridine (7.1 ml, 87.5 mmol) in DCM (100 ml). The resultant mixture was stirred at ambient temperature for 24 hours, washed with 1 M hydrochloric acid, saturated sodium hydrogen carbonate solution and brine, dried and evaporated. The residue was dissolved in methanol (150 ml), treated with 2 M hydrochloric acid (130 ml) and the mixture stirred at ambient temperature for 18 hour. The methanol was evaporated, the aqueous layer was extracted with EtOAc (2×75 ml), the EtOAc extracts were combined and washed with saturated sodium hydrogen carbonate solution and brine, dried and evaporated. The residue was chromatographed on silica with DCM as eluent to give the title compound as a solid (13.6 g, 48.4 mmol). NMR (CDCl3): 1.75 (s, 3H), 2.4 (s, 3H), 3.75 (s, 1H), 7.05 (d, 1H), 7.2 (dd, 1H), 8.2 (d, 1H), 8.85 (brs, 1H); m/z 280.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:14][CH:15]1[CH2:17][CH2:16]1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH:15]1([CH2:14][O:12][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]3)[CH2:17][CH2:16]1
Reactant: Cc1ccc2cccc(O)c2n1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc2cccc(OCC3CC3)c2n1
Temperature: 25 °C
Yield: 98.5 %

Procedure:
A solution of 2-methylquinolin-8-ol (10.0 g, 62.82 mmol), (bromomethyl)cyclopropane (17.0 g, 125.6 mmol), and K2CO3 (17.80 g, 128.8 mmol) in acetone (50 mL) in a sealed flask was stirred at 88° C. for 2 days. After cooling to ambient temperature, the acetone was removed under reduced pressure. DCM (100 mL) and water (50 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (DCM) to give 8-(cyclopropylmethoxy)-2-methylquinoline (13.2 g, 98.5%) as a solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4]/[CH:5]=[CH:6]/[C:7]([NH:9][C:10]1[CH:11]=[C:12]2[C:25]([NH:26][C:27]3[CH:28]=[CH:29][C:30]([F:34])=[C:31]([Cl:33])[CH:32]=3)=[N:24][CH:23]=[N:22][C:13]2=[CH:14][C:15]=1[O:16][C@@H:17]1[CH2:21][O:20][CH2:19][CH2:18]1)=[O:8])[CH3:3].[C:35]([OH:47])(=[O:46])[CH2:36][C:37]([CH2:42][C:43]([OH:45])=[O:44])([C:39]([OH:41])=[O:40])[OH:38]>C(O)C>[CH3:1][N:2]([CH2:4]/[CH:5]=[CH:6]/[C:7]([NH:9][C:10]1[CH:11]=[C:12]2[C:25]([NH:26][C:27]3[CH:28]=[CH:29][C:30]([F:34])=[C:31]([Cl:33])[CH:32]=3)=[N:24][CH:23]=[N:22][C:13]2=[CH:14][C:15]=1[O:16][C@@H:17]1[CH2:21][O:20][CH2:19][CH2:18]1)=[O:8])[CH3:3].[C:35]([O-:47])(=[O:46])[CH2:36][C:37]([CH2:42][C:43]([O-:45])=[O:44])([C:39]([O-:41])=[O:40])[OH:38]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: CN(C)C/C=C/C(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1O[C@H]1CCOC1
Solvent: CCO
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Temperature: 25 °C

Procedure:
Ethanol (2 ml) was added to 100 mg (0.205 mmol) afatinib free base and the light yellow solution was stirred at room temperature. A solution of 39.4 mg (0.205 mmol) citric acid in 0.5 ml ethanol was added over the course of 2 min. Another 0.5 ml ethanol was added. Precipitation was observed and the mixture was stirred for 15 min. The solid was filtered, washed with 0.5 ml ethanol and dried on rotary evaporator at 50° C. for 2 h to give 80 mg (57%) of a light yellow solid.
Reaction SMILES: C([CH:4]1[N:9](N=O)[CH2:8][C:7]2[CH:12]=[CH:13][S:14][C:6]=2[CH:5]1O)(O)=O.[OH-].[Na+]>Cl>[S:14]1[C:6]2[CH:5]=[CH:4][N:9]=[CH:8][C:7]=2[CH:12]=[CH:13]1
Reactant: O=NN1Cc2ccsc2C(O)C1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: c1cc2sccc2cn1

Procedure:
A solution of 24 g of the nitroso derivative obtained in Example 2 in 200 cc 6 N hydrochlorid acid is heated at 60° C. for 2 hours. Gas is evolved, and russet fumes are formed. After cooling, the brown reaction medium is made basic with aqueous sodium hydroxide and is then extracted with methylene chloride. The organic extracts are washed with water, dried over sodium sulfate, decolorized with carbon black, filtered through talc and evaporated to dryness. Vacuum distillation of the residue gives 6.5 g (overall yield, from the starting material of the formula (IV): 43%) thieno[3,2-c]pyridine which crystallizes on cooling. M.p. <50° C.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][S:15](=[O:18])[CH2:14][CH2:13]2)[C:9]2[C:4](=[N:5][C:6]([N:20]3[CH2:25][CH2:24][S:23](=[O:26])[CH2:22][CH2:21]3)=[C:7]([Cl:19])[N:8]=2)[N:3]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[Cl:19][C:7]1[N:8]=[C:9]2[C:4](=[N:5][C:6]=1[N:20]1[CH2:25][CH2:24][S:23](=[O:26])[CH2:22][CH2:21]1)[N:3]=[C:2]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[N:11]=[C:10]2[N:12]1[CH2:17][CH2:16][S:15](=[O:18])[CH2:14][CH2:13]1
Reactant: C1CNCCN1
Reactant: O=S1CCN(c2nc3nc(Cl)nc(N4CCS(=O)CC4)c3nc2Cl)CC1
Product: O=S1CCN(c2nc3nc(N4CCNCC4)nc(N4CCS(=O)CC4)c3nc2Cl)CC1

Procedure:
This compound was prepared analogous to Example 1 from 2,6-dichloro-4,7-bis-(1-oxido-thiomorpholino)pteridine and piperazine.
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]2([CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:31][CH2:30][C:29]5[C:24](=[CH:25][CH:26]=[C:27]([O:32][CH2:33][C@@H:34]6[CH2:38][CH2:37][CH2:36][O:35]6)[CH:28]=5)[C:23]4=[O:39])=[CH:18][C:17]=3F)[CH2:12]2)[CH2:9]1)=O)(C)(C)C.[O:41]1CCC[C@H:42]1COC1C=C2C(=CC=1)C(=O)OCC2.C(OC(N1CC2(CCN(C3C=CC(N)=CC=3F)C2)C1)=O)(C)(C)C>>[CH2:9]1[C:10]2([CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][CH:26]=[C:27]([O:32][CH2:33][C@@H:34]6[CH2:38][CH2:37][CH2:36][O:35]6)[CH:28]=5)[C:23]4=[O:39])=[CH:18][C:17]=3[O:41][CH3:42])[CH2:12]2)[CH2:11][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CC2(CCN(c3ccc(N4CCc5cc(OC[C@@H]6CCCO6)ccc5C4=O)cc3F)C2)C1
Reactant: O=C1OCCc2cc(OC[C@@H]3CCCO3)ccc21
Agent: CC(C)(C)OC(=O)N1CC2(CCN(c3ccc(N)cc3F)C2)C1
Product: COc1cc(-n2ccc3cc(OC[C@@H]4CCCO4)ccc3c2=O)ccc1N1CCC2(CNC2)C1

Procedure:
6-(2-Fluoro-4-{1-oxo-6-[(S)-1-(tetrahydro-furan-2-yl)methoxy]-3,4-dihydro-1H-isoquinolin-2-yl}-phenyl)-2,6-diaza-spiro[3.4]octane-2-carboxylic acid tert-butyl ester Reaction of 6-[(S)-1-(Tetrahydro-furan-2-yl)methoxy]-isochroman-1-one with 6-(4-Amino-2-fluoro-phenyl)-2,6-diaza-spiro[3.4]octane-2-carboxylic acid tert-butyl ester by method AC resulted in the desired product with the molecular weight 551, 66 (C31H38FN3O5); MS (ESI): 552 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([CH2:12][CH2:13][CH3:14])[CH2:10][OH:11])[C:5]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)=[O:24])=[CH:18][C:17]=2[O:34]CC2C=CC=CC=2)=[C:4]([CH3:42])[N:3]=1>CCOC(C)=O.[Pd]>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([CH2:12][CH2:13][CH3:14])[CH2:10][OH:11])[C:5]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)=[O:24])=[CH:18][C:17]=2[OH:34])=[C:4]([CH3:42])[N:3]=1
Reactant: CCC[C@@H](CO)Nc1nc(N)nc(C)c1Cc1ccc(CC(=O)OCC2CCN(C)CC2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC[C@@H](CO)Nc1nc(N)nc(C)c1Cc1ccc(CC(=O)OCC2CCN(C)CC2)cc1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The product from step (ii) (100 mg) was dissolved in EtOAc (10 mL) and Pd/C (73.9 mg) in EtOAc (1 mL) was added and the reaction stirred under hydrogen (4 bar) at rt for 16 h. The catalyst was filtered off and the solvents were evaporated. The crude product was purified by RPHPLC to give the title compound as a white solid, 22 mg.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([C@H:14]1[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH2:24][N:25]4[CH2:30][CH2:29][CH:28]([O:31][CH3:32])[CH2:27][CH2:26]4)[CH:20]=3)[CH2:15]1)[CH2:7][CH2:6]2.C1(S)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([C@H:14]1[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH2:24][N:25]4[CH2:26][CH2:27][CH:28]([O:31][CH3:32])[CH2:29][CH2:30]4)[CH:20]=3)[CH2:15]1)[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCN([C@H]1CCc3cc(CN4CCC(OC)CC4)ccc3C1)C2=O
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COC1CCN(Cc2ccc3c(c2)CC[C@H](N2CCc4cc(O)ccc4C2=O)C3)CC1
Temperature: 210 °C

Procedure:
A mixture of 6-methoxy-2-[(S)-6-(4-methoxypiperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-2-yl]-3,4-dihydro-2H-isoquinolin-1-one (0.59 g), NMP (2 ml), thiophenol (150 mg) and potassium carbonate (235 mg) was heated to 210° C. in a microwave reactor for 40 minutes. The cooled reaction mixture was purified by chromatography on silica gel (eluent: 9:1 dichloromethane/methanol). The product was thus obtained with the molecular weight of 420.56 (C26H32N2O3); MS (ESI): 421 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=1.Cl[CH:19]([C:25]([CH3:27])=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)C>[F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:25]([CH3:27])[N:12]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: Nc1ncccc1OCc1c(F)cccc1F
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12
Yield: 41.6 %

Procedure:
170 g of 3-[(2,6-difluorobenzyl)oxy]pyridine-2-amine (Example 4A; 719 mmol, 1 equivalent) were initially charged in 3800 ml of ethanol, and 151 g of powdered molecular sieve 3 Å and 623 g of ethyl 2-chloroacetoacetate (3.6 mol, 5 equivalents) were added. The resulting reaction mixture was heated under reflux for 24 h and then filtered off through kieselguhr and concentrated under reduced pressure. After relatively long standing (48 h) at RT, a solid precipitated out. This solid was filtered off, three times suspended in a little isopropanol and in each case filtered off again and finally washed with diethyl ether. This gave 60.8 g (23.4% of theory) of the title compound. The combined mother liquor of the filtration steps was chromatographed on silica gel using cyclohexane/diethyl ether as mobile phase. This gave a further 46.5 g (18.2% of theory; total yield: 41.6% of theory) of the title compound.
Reaction SMILES: [OH:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[N:4]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[N:3]=1.[H-].[Na+].I[CH3:28].O>CN(C=O)C>[CH3:28][O:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[N:4]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[N:3]=1
Reactant: CI
Reactant: COc1ccc(-c2nc(O)nn2-c2ccc(S(N)(=O)=O)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(OC)nn2-c2ccc(S(N)(=O)=O)cc2)cc1
Reaction time: 3 h
Yield: 75 %

Procedure:
500 mg of 4-[3-hydroxy-5-(4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide prepared in the above Example 16, was dissolved in 10 ml of DMF and then 1.05 eq of NaH was slowly added thereto. Afterwards 1.5 eq of iodomethane was added to the mixture and then stirred for 3 hours at the same temperature. When the reaction was completed, the resultant was poured into 100 ml of cold water to form precipitate. The precipitate was filtered and then washed with 100 ml of cold ether and 100 ml of cold water (1× each) to give 385 mg (yield 75%) of the titled compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][C:13](=[O:19])[NH:14]3)=[CH:6][CH:5]=1.[N:22]1([CH2:27][CH2:28][NH:29][C:30]([C:32]2[C:36]([CH3:37])=[C:35]([CH:38]=O)[NH:34][C:33]=2[CH3:40])=[O:31])[CH:26]=[CH:25][N:24]=[N:23]1>C(O)C.N1CCCCC1>[N:22]1([CH2:27][CH2:28][NH:29][C:30]([C:32]2[C:36]([CH3:37])=[C:35]([CH:38]=[C:12]3[C:11]4[C:15](=[CH:16][CH:17]=[CH:18][C:10]=4[C:7]4[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:9][CH:8]=4)[NH:14][C:13]3=[O:19])[NH:34][C:33]=2[CH3:40])=[O:31])[CH:26]=[CH:25][N:24]=[N:23]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCn1ccnn1
Reactant: O=C1Cc2c(cccc2-c2ccc(OC(F)(F)F)cc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(OC(F)(F)F)cc4)c32)c(C)c1C(=O)NCCn1ccnn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 37 %

Procedure:
To a solution of 4-(4-trifluoromethoxy-phenyl)-1,3-dihydro-indol-2-one (73.3 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)amide (67.9 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2,4-dimethyl-5-[2-oxo-4-(4-trifluoromethoxy-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-ylethyl)amide as a yellow solid (49.6 mg, 37%).
Reaction SMILES: C(OC([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=O)(C)(C)C.CCOCC.[ClH:32]>CCOC(C)=O>[ClH:32].[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:21])[CH3:22])[CH:17]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc2ccc(O[Si](C)(C)C(C)(C)C)cc12
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2cccc(N)c2c1
Reaction time: 1 h

Procedure:
A solution of 1-(tert-butoxycarbonylamino)-7-(tert-butyldimethylsilyloxy)naphthalene, as described above in Step B, (5.00 g, 13.4 mmol) in EtOAc (240 mL) and Et2O (60 mL) at ambient temperature was saturated with HCl (g). After 1 hour, the mixture was concentrated in vacuo to yield the desired product as a pale solid.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[N:5]1[C:10]2[NH:11][C:12]3[CH:20]=[CH:19][N:18]=[CH:17][C:13]=3[CH2:14][C:15](=[O:16])[C:9]=2[CH:8]=[CH:7][CH:6]=1>O.C(O)(=O)C>[N:5]1[C:10]2[NH:11][C:12]3[CH:20]=[CH:19][N:18]=[CH:17][C:13]=3[C:14](=[N:1][OH:3])[C:15](=[O:16])[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: O=C1Cc2cnccc2Nc2ncccc21
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1c(=NO)c2cnccc2[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of sodium nitrite (0.259 g, 3.75 mmol) in water (1.0 mL) was added dropwise to a solution of 6,11-dihydro-5H-dipyrido[2,3-b:3′,4′-f]azepin-5-one (0.330 g, 1.56 mmol, Intermediate D-6) dissolved in acetic acid (6.0 mL). The mixture was stirred at room temperature for 90 minutes at which time a precipitate had formed. The yellow mixture was reduced to about half original volume in vacuo, and then diluted with 20 mL water and stirred for 30 minutes. A thick precipitate formed which was collected by suction filtration, washed with water and then dried in a vacuum oven at 50° C. overnight. The desired product was obtained as a yellow powder (224 mg, 60%). (2 peaks, ˜2:1 ratio of oxime isomers). 1H NMR (DMSO-d6, ˜2:1 mixture of oxime isomers): δ 12.55 & 12.32 (bs, 1H), 11.41 & 11.18 (bs, 1H), 8.67 (m, 2H), 8.54-8.25 (m, 2H), 7.56 (m, 1H), 7.27 (m, 1H). LC/MS: 241 (M+H)+
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O>>[F:20][C:21]1[CH:22]=[C:23]([CH2:24][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)[CH:26]=[CH:27][CH:28]=1
Reactant: O=Cc1cccc(F)c1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: Fc1cccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-fluorobenzaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 21 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(3-fluorophenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.