Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([CH3:18])([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:10]=2)[N:7]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH2:15]([O:14][C:12]([C:11]([C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:7][N:6]2[CH:8]=1)([CH3:18])[CH3:17])=[O:13])[CH3:16]
Reactant: C1CNCCN1
Reactant: CCOC(=O)C(C)(C)c1cn2nc(Cl)ccc2n1
Product: CCOC(=O)C(C)(C)c1cn2nc(N3CCNCC3)ccc2n1
Yield: 100 %

Procedure:
Using ethyl 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate (2.00 g) and piperazine (19.7 g), and by a reaction at 100° C. in the same manner as in Example 196 (1), 1-[2-(1-ethoxycarbonyl-1-methylethyl)-6-imidazo[1,2-b]pyridazinyl]piperazine (2.37 g) was obtained as an oil.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)(=[O:13])=[O:12].Cl[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][N:22]=1>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([CH:14]1[CH2:19][CH2:18][N:17]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][N:22]=2)[CH2:16][CH2:15]1)(=[O:12])=[O:13]
Reactant: O=S(=O)(c1ccc2ccccc2c1)C1CCNCC1
Reactant: Clc1nccc2ccccc12
Product: O=S(=O)(c1ccc2ccccc2c1)C1CCN(c2nccc3ccccc23)CC1
Yield: 73.6 %

Procedure:
Using the procedure from Example 7A, Step 7E, 4-(2-naphthylsulfonyl)piperidine (130 mg, 0.51 mmol) was reacted with 1-chloroisoquinoline (164 mg, 1.0 mmol) to afford the title compound (151 mg), a white solid, in 31% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:13]=[C:14]([C:18]([C:20]3[C:28]4[CH:27]=[N:26][CH:25]=[N:24][C:23]=4[N:22]([CH:29]([CH3:33])[C:30](O)=[O:31])[CH:21]=3)=[O:19])[CH:15]=[N:16][CH:17]=2)=[O:10])=[CH:4][CH:3]=1.[CH3:34][NH2:35]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:13]=[C:14]([C:18]([C:20]3[C:28]4[CH:27]=[N:26][CH:25]=[N:24][C:23]=4[N:22]([CH:29]([CH3:33])[C:30]([NH:35][CH3:34])=[O:31])[CH:21]=3)=[O:19])[CH:15]=[N:16][CH:17]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CN
Reactant: CC(C(=O)O)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cc3)c2)c2cncnc21
Product: CNC(=O)C(C)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cc3)c2)c2cncnc21

Procedure:
The title compound was prepared according to the method described for Example 34 at 50° C. using 2-{5-[(5-{[(4-chlorophenyl)acetyl]amino}pyridin-3-yl)carbonyl]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}propanoic acid (Example 354) and methylamine. Purification was accomplished by preparative HPLC (method 1) to afford the title compound.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2([C:28]3[CH:33]=[CH:32][C:31]([S:34][CH3:35])=[CH:30][CH:29]=3)[CH2:10][CH2:9][CH2:8][N:7]3[C:11]([C:14]4[CH:19]=[CH:18][C:17]([C:20]5[O:24][C:23]([CH3:25])=[N:22][CH:21]=5)=[C:16]([O:26][CH3:27])[CH:15]=4)=[N:12][N:13]=[C:6]23)[CH2:3][CH2:2]1.[OH2:36].[OH2:37].O.O.O.O.[Mg+2].C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=O>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([CH2:4][C:5]2([C:28]3[CH:33]=[CH:32][C:31]([S:34]([CH3:35])(=[O:37])=[O:36])=[CH:30][CH:29]=3)[CH2:10][CH2:9][CH2:8][N:7]3[C:11]([C:14]4[CH:19]=[CH:18][C:17]([C:20]5[O:24][C:23]([CH3:25])=[N:22][CH:21]=5)=[C:16]([O:26][CH3:27])[CH:15]=4)=[N:12][N:13]=[C:6]23)[CH2:3][CH2:2]1
Reactant: COc1cc(-c2nnc3n2CCCC3(CC2CC2)c2ccc(SC)cc2)ccc1-c1cnc(C)o1
Reactant: O
Agent: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(-c2nnc3n2CCCC3(CC2CC2)c2ccc(S(C)(=O)=O)cc2)ccc1-c1cnc(C)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.3 %

Procedure:
To a mixture of 8-(cyclopropylmethyl)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-8-[4-(methylsulfanyl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine (86.0 mg) in DMF (1 mL) was added monoperoxyphthalic acid magnesium salt hexahydrate (87.4 mg) at 0° C., and the mixture was stirred at room temperature for 2 hr. Monoperoxyphthalic acid magnesium salt hexahydrate (87.4 mg) was added to the reaction mixture at room temperature, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, the mixture was washed with aqueous sodium thiosulfate solution (1M) and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (27.8 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[S:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:2]=12.S(Cl)([Cl:15])=O>>[N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[S:7][C:8]([C:10]([Cl:15])=[O:12])=[CH:9][C:2]=12
Reactant: O=C(O)c1cc2nccnc2s1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc2nccnc2s1
Yield: 100 %

Procedure:
A solution of thieno[2,3-b]pyrazine-6-carboxylic acid (400 mg, 2.220 mmol) in thionyl chloride (1.6 mL, 22.20 mmol) was heated to 80° C. for 2 h. Concentrated to dryness and coevaporated with toluene to give thieno[2,3-b]pyrazine-6-carbonyl chloride 63 (441 mg, 100%).
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][C:7](=[CH:9][CH:10]=[O:11])[CH3:8])[CH3:3].CC(=CCC/C(=C/C=O)/C)C.CC(=CCC/C(=C\C=O)/C)C>>[CH3:1][C:2](=[CH:4][CH2:5][CH2:6][CH:7]([CH2:9][CH:10]=[O:11])[CH3:8])[CH3:3]
Reactant: CC(C)=CCCC(C)=CC=O
Agent: CC(C)=CCC/C(C)=C/C=O
Agent: CC(C)=CCC/C(C)=C\C=O
Product: CC(C)=CCCC(C)CC=O

Procedure:
A-2) asymmetrically hydrogenating citral containing geranial and neral at a molar ratio of from 90:10 to 10:90 to thereby obtain an optically active citronellal,
Reaction SMILES: C1([C@@H](N[C:14]([CH3:28])=[CH:15][C:16]([O:18][C@@H:19]([C:24]([Cl:27])([Cl:26])[Cl:25])[CH:20]=[C:21]([CH3:23])[CH3:22])=[O:17])C)C2C(=CC=CC=2)C=CC=1.Cl.[O:30]1CCCC1>>[C:16]([O:18][C@@H:19]([C:24]([Cl:27])([Cl:26])[Cl:25])[CH:20]=[C:21]([CH3:23])[CH3:22])(=[O:17])[CH2:15][C:14]([CH3:28])=[O:30]
Reactant: C1CCOC1
Reactant: CC(C)=C[C@@H](OC(=O)C=C(C)N[C@@H](C)c1cccc2ccccc12)C(Cl)(Cl)Cl
Agent: Cl
Product: CC(=O)CC(=O)O[C@H](C=C(C)C)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 62 h
Yield: 85 %

Procedure:
To a solution of (R)-3-methyl-1-trichloromethylbut-2-en-1-yl (S)-3-[N-(1-(1-naphthyl)ethyl)amino]but-2-enoate (10 g, 0.023 mole) in tetrahydrofuran (200 ml) at room temperature was added, in one portion, 0.5 N aqueous hydrochloric acid (250 ml, 0.125 mole). Upon addition of the acid, a white precipitate formed immediately, then slowly disappeared. The mixture was stirred at room temperature for a total of 62 hours and then extracted three times with 200 ml of hexane, after which the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The pale yellow oily residue was distilled to yield (R)-1-trichloromethyl-3-methyl-2-butenyl acetoacetate (5.57 g, 85% yield); bp, 90°-92° C. (0.05 mmHg); [α]D25 =+13.00° (CHCl3).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH:15]=[CH2:16])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[Br:25][C:26]1[CH:27]=[CH:28][C:29]([CH:32]=[O:33])=[N:30][CH:31]=1.C(N(CC)CC)C>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C>[Br:25][C:26]1[CH:27]=[CH:28][C:29]([C:32](=[O:33])[CH2:16][CH2:15][C:14](=[O:17])[CH:13]([C:10]2[CH:9]=[CH:8][C:7]([S:4]([CH:1]3[CH2:3][CH2:2]3)(=[O:6])=[O:5])=[CH:12][CH:11]=2)[CH2:18][CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[N:30][CH:31]=1
Reactant: O=Cc1ccc(Br)cn1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(CCC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1)c1ccc(Br)cn1
Temperature: 25 °C
Yield: 84.1 %

Procedure:
To a solution of 4-[4-(cyclopropylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (1.00 g) in ethanol (10 mL) were added 5-bromopyridine-2-carbaldehyde (640 mg), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (85 mg) and triethylamine (175 μL), and the mixture was stirred with heating under reflux overnight. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (1.29 g, yield 84%) was obtained as a yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (3:2, volume ratio). MS: 536 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:26])[CH2:9][CH2:10][CH2:11][N:12]2[CH2:16][CH2:15][C:14]3([C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]([OH:25])[CH2:17]3)[CH2:13]2)=[CH:4][CH:3]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28].[OH-].[Na+]>N1C=CC=CC=1>[C:27]([O:25][CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]2([CH2:15][CH2:16][N:12]([CH2:11][CH2:10][CH2:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[O:26])[CH2:13]2)[CH2:17]1)(=[O:29])[CH3:28]
Reactant: O=C(CCCN1CCC2(CC(O)c3ccccc32)C1)c1ccc(F)cc1
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CC(=O)OC1CC2(CCN(CCCC(=O)c3ccc(F)cc3)C2)c2ccccc21

Procedure:
7.5 g of p-fluoro-4-(3-hydroxyspiro[indan-1,3'-pyrrolidin]-1'-yl)butyrophenone are stirred at room temperature with 15 cc of pyridine and 15 cc of acetic anhydride for 18 hours. The mixture is then poured on ice, is rendered alkaline with 2 N caustic soda solution and is extracted thrice with 50 cc of ether. The ether phase is washed with water, dried over sodium sulphate and concentrated by evaporation. The oily residue is converted into the hydrogen furmarate, which is recrystallized from ethanol/ether. The hydrogen fumarate of the title compound has a M.P. of 154°-156°.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Cl.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:13]1([N:12]2[CH2:2][CH2:3][C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1
Reactant: ClCCc1ccccc1CCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: c1ccc(N2CCc3ccccc3C2)cc1
Yield: 29.7 %

Procedure:
A mixture of 2-(2-chloroethyl)benzyl chloride (19 g), aniline (9.3 g), and triethylamine (22.22 g,) in chloroform (80 ml) was heated at reflux for 6 hrs. The reaction mixture was cooled and washed with 2M sodium hydroxide solution (3×100 ml). The chloroform layer was dried (magnesium sulphate) and evaporated in vacuo. The residue was distilled in vacuo to afford 2-phenyl-1,2,3,4-tetrahydroisoquinoline (6.2 g. b.pt. 112°-113°/0.08-0.1 mmHg) characterised by its nmr spectrum.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([NH2:21])=[CH:17][CH:16]=1.[C:22]1([CH3:31])[CH:27]=[CH:26][C:25]([C:28](Cl)=[O:29])=[CH:24][CH:23]=1>>[CH3:31][C:22]1[CH:27]=[CH:26][C:25]([C:28]([NH:21][C:18]2[N:19]=[N:20][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:16][CH:17]=2)=[O:29])=[CH:24][CH:23]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(N)nn1
Reactant: Cc1ccc(C(=O)Cl)cc1
Product: Cc1ccc(C(=O)Nc2ccc(OCc3c(-c4ccccc4)noc3C)nn2)cc1
Yield: 80 %

Procedure:
As described for example 18, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-ylamine (280 mg, 1 mmol) was converted, using p-toluoyl chloride instead of methoxyacetyl chloride, to the title compound (320 mg, 80%) which was obtained as a white solid. MS: m/e=401.3 [M+H]−.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:6])[CH2:3][OH:4].CCN(CC)CC.O.CCOCC>CS(C)=O>[CH3:1][C@@H:2]([C@@H:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:6])[CH:3]=[O:4]
Reactant: C[C@H](CO)[C@H](C)OCc1ccccc1
Solvent: O
Solvent: CS(C)=O
Solvent: CCOCC
Product: C[C@H](C=O)[C@H](C)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
The Py.SO3 complex (4.09 g, 25.67 mmol, 6.0 eq.) was added in portions at 0° C. to a solution of (2R,3S)-2-methyl-3-benzyloxybutanol (13) (830 mg, 4.28 mmol) and Et3N (2.86 g, 3.93 ml, 28.25 mmol, 6.6 eq.) in DMSO (14 ml). The reaction mixture is stirred at 0° C. for 3.5 hours, and then at room temperature for 2 hours, and then it was divided between water and ether. The aqueous layer was extracted with ether. The combined ether extracts were washed with 1M HCl, waters saturated NaHCO3, brine, and they were dried over Na2SO4 and evaporated in order to obtain crude (2S,3S)-2-methyl-3-benzyloxybutyraldehyde which was used directly for the next reaction without purification. 1H NMR (250 MHz, CDCl3) δ 9.73 (d, J=2.4 Hz, 1H); 4.63 (d, J=11.7 Hz, 1H); 4.44 (d, J=11.7 Hz, 1H); 3.81 (quintuplet, J=6.4 Hz, 1H); 2.57 (quintuplet-d, J=7.0; 2.4 Hz, 1H); 1.25 (d, J=6.2 Hz, 3H); 1.09 (d, J=7.1 Hz, 3H).
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:16])[C:5]=2[CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:26]=[C:27]4[C:32](=[CH:33][CH:34]=3)[N:31]=[C:30]([C:35]([O:37]C)=[O:36])[CH:29]=[CH:28]4)=[CH:21][CH:20]=2)[CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+].Cl>CO>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[C:10]([Cl:16])=[CH:11][CH:12]=[CH:13][C:14]=3[Cl:15])[C:5]=2[CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:26]=[C:27]4[C:32](=[CH:33][CH:34]=3)[N:31]=[C:30]([C:35]([OH:37])=[O:36])[CH:29]=[CH:28]4)=[CH:23][CH:24]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)cc3)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)cc3)ccc2n1
Temperature: 120 °C
Yield: 89 %

Procedure:
To a solution of methyl 6-[4-({[5-cyclopropyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (58 mg, 0.11 mmol) in 2:1 tetrahydrofuran:methanol (1.5 mL) was added 1 N sodium hydroxide (0.18 mL, 0.18 mmol). The solution was heated in a microwave reactor at 120° C. for 500 seconds. The solution was concentrated and water was added followed by 1 N hydrochloric acid (0.18 mL, 0.18 mmol). The solution was extracted twice with ethyl acetate and the combined organic layers were washed with brine and concentrated to afford 6-[4-({[5-cyclopropyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylic acid (52 mg, 92%). 1H-NMR (400 MHz, DMSO-d6) δ 13.36 (br s, 1H), 8.53 (d, J=9 Hz, 1H), 8.27 (s, 1H), 8.17-8.08 (m, 3H), 7.73 (d, J=9 Hz, 2H), 7.62-7.51 (m, 3H), 6.95 (d, J=9 Hz, 2H), 4.93 (s, 2H), 2.49-2.43 (m, 1H), 1.20-1.10 (m, 4H). HRMS (ESI) C29H20Cl2N2O4 calculated: 531.0873 [M+H]+, found: 531.0873 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12](=[O:14])[CH3:13])(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: NS(=O)(=O)c1cccc(Br)c1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NS(=O)(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.3 %

Procedure:
3-Bromobenzenesulfonamide (470 mg, 2.0 mmol) was dissolved in pyridine (1 mL). To this solution was added DMAP (7.3 mg, 0.060 mmol) and then acetic anhydride (570 μL, 6.0 mmol). The reaction was stirred for 3 h at room temperature during which time the reaction changed from a yellow solution to a clear solution. The solution was diluted with ethyl acetate, and then washed with aqueous NH4Cl solution (×3) and water. The organic layer was dried over MgSO4 and concentrated. The resulting oil was triturated with hexanes and the precipitate was collected by filtration to obtain N-(3-bromophenylsulfonyl)-acetamide as a shiny white solid (280 mg, 51%). 1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.01 (t, J=1.8 Hz, 1H), 7.96-7.90 (m, 2H), 7.61 (t, J=8.0 Hz, 1H), 1.95 (s, 3H); HPLC ret. time 1.06 min; ESI-MS 278.1 m/z (MH+).
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[NH:10][C:11](=S)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.O>C(OCCO)C>[N:1]1[C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[N:10]=[C:11]([NH:17][CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: S=C1Nc2ccccc2Nc2ncccc21
Reactant: NCc1cccnc1
Solvent: CCOCCO
Solvent: O
Product: c1cncc(CNC2=Nc3ccccc3Nc3ncccc32)c1
Yield: 52.8 %

Procedure:
A solution of 0.5 g (2.2 mmol) of 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-thione [(European Published Patent Application EP-393,604); C.A. 114, 143455] in 10 mL 2-ethoxyethanol was treated with 0.24 mL (10.8 mmol) of 3-(aminomethyl)pyridine and heated at reflux for 2 days. The mixture was poured into H2O and extracted with EtOAc. The EtOAc was washed three times with H2O, then saturated NaHCO3 solution and saturated NaCl solution. Drying over MgSO4 and removal of the solvent under reduced pressure left the crude product. Chromatography on silica gel, eluting with a gradient of CH2Cl2 /hexane (90/10) to CH2Cl2 /MeOH (94/6) gave 0.35 g (53% yield) of the product as a yellow solid, mp 192-194° C. The structure was confirmed by NMR and mass spectroscopy. (m+H)+ =302.
Reaction SMILES: [NH2:1][C:2]1[C:11](I)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:13][CH3:14])[CH:3]=1.[C:15]([Zn]C#N)#[N:16].O.CO>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOCC>[NH2:1][C:2]1[C:11]([C:15]#[N:16])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:13][CH3:14])[CH:3]=1
Reactant: N#C[Zn]C#N
Reactant: COC(=O)c1cc(I)c(N)cc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(C#N)c(N)cc1OC
Temperature: 80 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
A solution of methyl 4-amino-5-iodo-2-methoxybenzoate (intermediate 128; 5 g, 16.28 mmol) and dicyanozinc (1.5 g, 12.77 mmol) in dimethylformamide (50 mL) in a slenck vessel was degasified with nitrogen. Then tetrakis (1 g, 0.87 mmol) was added and the reaction mixture was stirred at 80° C. for 2 hours. Water was added into the reaction mixture and the crude was extracted with ethyl acetate, the organic layer was washed with brine, dried and the solvent was removed under reduced pressure. The crude obtained was treated with methanol and ether to obtain the title compound as a yellow solid (76%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(O[CH:12]=[C:13]([C:19]#[N:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])C.C(C(=CNC1C=CC(CCCC)=CN=1)C(OCC)=O)#N>>[C:19]([C:13](=[CH:12][NH:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:20]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: Nc1ncccc1Cl
Agent: CCCCc1ccc(NC=C(C#N)C(=O)OCC)nc1
Product: CCOC(=O)C(C#N)=CNc1ncccc1Cl
Yield: 44 %

Procedure:
The title compound (m.p. 139.5°-141.5°, 44% yield) was prepared from 2-amino-3 -chloropyridine and ethyl ethoxymethylenecyanoacetate in a manner similar to that described for the preparation of ethyl 2-cyano-3-(5-n-butyl-2-pyridylamino)acrylate in Preparation D3 of U.S. Pat. No. 4,122,274.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)/[C:6](=[C:17](/[NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]([CH3:42])[C:32](=[O:41])[CH2:33][N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)=[CH:27][CH:26]=2)\[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)/[C:5]1=[O:43])(=O)C.C([O-])([O-])=O.[K+].[K+]>CO>[CH3:42][N:31]([C:28]1[CH:27]=[CH:26][C:25]([NH:24]/[C:17](/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:6]2\[C:5](=[O:43])[NH:4][C:12]3[C:7]\2=[N:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)=[CH:30][CH:29]=1)[C:32](=[O:41])[CH2:33][N:34]1[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]1
Reactant: COC(=O)c1cnc2c(c1)N(C(C)=O)C(=O)/C2=C(\Nc1ccc(N(C)C(=O)CN2CCN(C)CC2)cc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1cnc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(C)C(=O)CN2CCN(C)CC2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Step-3: A mixture of (Z)-methyl 1-acetyl-3-(((4-(N-methyl-2-(4-methylpiperazin-1-yl)acetamido)phenyl)amino)(phenyl)methylene)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-6-carboxylate (6 mg, 0.0103 mmol), K2CO3 (1.42 mg, 0.0103 mmol) in MeOH (2 mL) was stirred for 2 h at room temperature. The crude product was concentrated and purified by preparative TLC to afford (Z)-methyl 3-(((4-(N-methyl-2-(4-methylpiperazin-1-yl)acetamido)phenyl)amino)(phenyl)methylene)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-6-carboxylate. MS (ES+): m/z 541.3 (MH)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9](Cl)[N:10]=1)[C:5]([OH:7])=[O:6].Cl.[CH3:13][OH:14]>[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:14][CH3:13])[N:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Reactant: CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(C(=O)O)cc(Cl)n1
Temperature: 34 °C
Reaction time: 8 h

Procedure:
To a solution of 2,6-dichloroisonicotinic acid (200 g, 1.04 mol) in methanol (3 L), 32% aq. NaOH (770 mL) is added. The stirred mixture becomes warm (34° C.) and is then heated to 70° C. for 4 h before it is cooled to rt. The mixture is neutralised by adding 32% aq. HCl (100 mL) and 25% aq. HCl (700 mL). The mixture is stirred at rt overnight. The white precipitate that forms is collected, washed with methanol and dried. The filtrate is evaporated and the residue is suspended in water (200 mL). The resulting mixture is heated to 60° C. Solid material is collected, washed with water and dried. The combined crops give 2-chloro-6-methoxy-isonicotinic acid (183 g) as a white solid; LC-MS: tR=0.80 min, [M+1]+=187.93.
Reaction SMILES: [CH:1]1([NH2:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(C(C)C)CC)(C)C.[C:32]([C:34]1[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[C:36]([CH3:43])[CH:35]=1)#[N:33]>ClCCl>[C:32]([C:34]1[CH:42]=[CH:41][C:37]([C:38]([NH:8][CH:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:39])=[C:36]([CH3:43])[CH:35]=1)#[N:33]
Reactant: NC1CCCCCC1
Reactant: Cc1cc(C#N)ccc1C(=O)O
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1cc(C#N)ccc1C(=O)NC1CCCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.2 %

Procedure:
Add cycloheptylamine (0.83 mL, 6.5 mmol), HOBT (838 mg, 6.2 mmol), EDC (1.2 g, 6.2 mmol) and diisopropylethylamine (3.2 mL, 18.6 mmol) to a solution of 4-cyano-2-methyl-benzoic acid (1 g, 6.2 mmol) in dichloromethane (20 mL) at room temperature under a nitrogen atmosphere. Stir the mixture for 16 h at room temperature. Wash the mixture with water (20 mL), separate and concentrate the organic layer in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (19:1 to 3:2 gradient) to obtain the desired intermediate (830 mg, 52%). MS (ES+) m/z: 257.3 (M+H)+.