Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C=[C:10]1[C:15](=[O:16])[CH:14]=[CH:13][C:12]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11]1)C.Cl[CH2:30][Cl:31]>>[Cl:31][C:30]1[CH:10]=[CH:11][C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:13][C:14]=1[CH:15]=[O:16]
Reactant: CN(C)C=C1CC(c2ccccc2)(c2ccccc2)C=CC1=O
Reactant: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: O=CC1=C(Cl)C=CC(c2ccccc2)(c2ccccc2)C1
Temperature: 20 °C

Procedure:
0.193 cm3 of phosphorus oxychloride is added to a solution of 0.607 g of 6-dimethylaminomethylene-4,4-diphenylcyclohex-2-enone in 15 cm3 of dichloromethane. The mixture is heated to the reflux temperature and refluxing is maintained for about 3 hours. After cooling to a temperature in the region of 20° C., the solution is concentrated to dryness under reduced pressure (13 kPa). The residue is dissolved in 20 cm3 of tetrahydrofuran and 20 cm3 of water are added in a single portion. The mixture is refluxed for about 24 hours. After cooling to a temperature in the region of 20° C., the mixture is concentrated to dryness under reduced pressure (13 kPa). The residue is taken up in 10 cm3 of ethyl acetate. The solution is washed three times with 30 cm3 of water and then dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (13 kPa). 0.6 g of 2-chloro-5,5-diphenylcyclohexa-1,3-dienecarbaldehyde is thus obtained in the form of an orange-coloured resin, which is used without further modification in subsequent syntheses and the characteristics of which are as follows:
Reaction SMILES: F[B-](F)(F)F.[CH3:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=[C:15]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[O+]=1.[PH3:32]>C(O)CCC>[CH3:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=[C:15]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[P:32]=1
Reactant: P
Reactant: Cc1ccccc1-c1cc(-c2ccccc2)cc(-c2ccccc2C)[o+]1
Agent: F[B-](F)(F)F
Solvent: CCCCO
Product: Cc1ccccc1-c1cc(-c2ccccc2)cc(-c2ccccc2C)p1

Procedure:
The reaction was carried out twice using 15 g (35 mmol) each time of 2,6-bis(2-methylphenyl)-4-phenylpyrylium tetrafluoroborate in 150 ml of n-butanol. The two autoclave products obtained after the reaction with PH3 were combined and evaporated to about 50 ml under reduced pressure at about 80° C. The solid which precipitated was filtered off with suction, washed with n-pentane and subsequently dissolved in toluene. The toluene solution was then washed with water until the aqueous phase was neutral. After removal of the solvent, the residue was suspended in methanol, and dichloromethane was then added until the solid had completely dissolved. The resulting solution was evaporated under reduced pressure at about 40° C. until a solid precipitated. The solid was filtered off with suction, washed with a little n-pentane and subsequently dried in a high vacuum. Yield: 15.6 g (63%) of white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:5]([F:15])[CH:4]=1.Cl.[C:17]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH:28][C:29](O)=[O:30])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([C:21]1[CH:22]=[CH:23][C:24]([CH:27]=[CH:28][C:29]([NH:1][CH2:2][C:3]2[CH:8]=[C:7]([CH3:9])[C:6]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:5]([F:15])[CH:4]=2)=[O:30])=[CH:25][CH:26]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: Cc1cc(CN)cc(F)c1NS(C)(=O)=O
Reactant: CC(C)(C)c1ccc(C=CC(=O)O)cc1
Agent: Cl
Product: Cc1cc(CNC(=O)C=Cc2ccc(C(C)(C)C)cc2)cc(F)c1NS(C)(=O)=O
Yield: 96 %

Procedure:
N-(4-Aminomethyl-2-fluoro-6-methyl-phenyl)-methanesulfonamide, and HCl salt (100 mg, 0.35 mmol) were reacted with 3-(4-t-butyl-phenyl)-acrylic acid following the general procedure to give a white solid (140 mg, 96%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[NH:11]1[C:19]2[C:14](=[CH:15][C:16]([CH:20]=O)=[CH:17][CH:18]=2)[CH:13]=[N:12]1.N1CCCCC1>CCO>[NH:11]1[C:19]2[C:14](=[CH:15][C:16](/[CH:20]=[C:3]3/[C:2](=[O:10])[NH:1][C:9]4[C:4]/3=[CH:5][CH:6]=[CH:7][CH:8]=4)=[CH:17][CH:18]=2)[CH:13]=[N:12]1
Reactant: O=C1Cc2ccccc2N1
Reactant: O=Cc1ccc2[nH]ncc2c1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2ccccc2/C1=C\c1ccc2[nH]ncc2c1
Temperature: 90 °C
Yield: 7.7 %

Procedure:
A scintillation vial was charged with indolin-2-one (67 mg, 0.500 mmol), 1H-indazole-5-carbaldehyde (73 mg, 0.550 mmol), piperidine (5.0 uL, 0.076 mmol) and EtOH (2 mL). The reaction was then heated to 90° C. for 2 hrs. The EtOH was removed and the product purified by preparatory reverse-phase HPLC to give 10 mg, 7.6% of the title compound. 1H NMR (400 MHz, CD3OD) δ 8.20-8.18 (m, 2H), 7.89 (s, 1H), 7.76 (d, J=7.9 Hz, 1H), 7.71-7.67 (m, 2H), 7.24 (t, J=7.4 Hz, 1H), 6.93 (d, J=7.7 Hz, 1H), 6.90 (t, J=7.5 Hz, 1H); MS ESI 262.0 [M+H]+, calcd for [C16H11IN3O+H]+ 262.10.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:16][C:17]([F:37])([F:36])[C:18]1[CH:19]=[C:20]([S:24]([N:27]2[CH2:31][C@@H:30]3[C@@H:32]([NH2:35])[CH2:33][CH2:34][C@@H:29]3[CH2:28]2)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1.F[C:39](F)(F)C1C=C(S(N2C[C@H]3[C@H](N)CC[C@H]3C2)(=O)=O)C=CC=1>>[CH3:12][N:8]([C@@H:9]([CH:10]([CH3:11])[CH3:39])[C:13](=[O:15])[NH:35][C@@H:32]1[C@@H:30]2[C@@H:29]([CH2:28][N:27]([S:24]([C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:16])([F:36])[F:37])[CH:19]=3)(=[O:25])=[O:26])[CH2:31]2)[CH2:34][CH2:33]1)[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@@H]21
Reactant: N[C@@H]1CC[C@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]21
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Product: CC(C)[C@@H](C(=O)N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@@H]21)N(C)C(=O)OC(C)(C)C

Procedure:
The title compound was prepared by substituting N-(tert-butoxycarbonyl)-N-methyl-L-valine for (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid and (3aR,4S,6aS)-2-(3-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine from Step D of Example 252 for (3aS,4R,6aR)-2-(3-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 266: 1H NMR (500 MHz, pyridine-d5, temperature 90° C.) δ ppm 8.30-8.32 (bs, 1H), 8.14 (d, J=7.8 Hz, 1H), 7.84 (d, J=7.8 Hz, 1H), 7.64 (t, J=7.8 Hz, 1H), 7.58-7.69 (bs, 1H), 4.32 (d, J=9.5 Hz, 1H), 4.03-4.12 (m, 1H), 3.68 (dd, J=10.2, 3.3 Hz, 1H), 3.27-3.31 (m, 1H), 3.08-3.16 (m, 2H), 3.00 (s, 3H), 2.53-2.61 (m, 1H), 2.46-2.53 (m, 1H), 2.33-2.43 (m, 1H), 1.85-1.93 (m, 1H), 1.77-1.85 (m, 1H), 1.47-1.54 (m, 1H), 1.45 (s, 9H), 1.21-1.30 (m, 1H), 0.97 (d, J=6.5 Hz, 3H), 0.86 (d, J=6.7 Hz, 3H); MS (ESI+) m/z 570 (M+Na)+.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[CH:8]=[N:9][C:10]2[C:15]([C:16]=1[Cl:17])=[CH:14][CH:13]=[CH:12][C:11]=2[O:18][CH3:19])=[O:6])[CH:2]=[CH2:3].[CH2:20]([C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24])[CH3:21]>O1CCOCC1>[ClH:17].[CH2:1]([NH:4][C:5]([C:7]1[CH:8]=[N:9][C:10]2[C:15]([C:16]=1[NH:24][C:23]1[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=1[CH2:20][CH3:21])=[CH:14][CH:13]=[CH:12][C:11]=2[O:18][CH3:19])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCNC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: CCc1ccccc1N
Solvent: C1COCCO1
Product: C=CCNC(=O)c1cnc2c(OC)cccc2c1Nc1ccccc1CC
Product: Cl

Procedure:
0.3 G of N-(2-propenyl)-4-chloro-8-methoxyquinoline-3-carboxamide and 0.26 g of o-ethylaniline were dissolved in 20 ml of dioxane, and the reaction mixture was refluxed for five hours. After dioxane was distilled off, the residue was recrystallized from ethanol and n-hexane to give 0.2 g of N-(2-propenyl)-4-[(2-ethylphenyl)amino]-8-methoxyquinoline-3-carboxamide hydrochloride in the form of yellow powder. mp. 222° to 223° C. (decomposed)
Reaction SMILES: CS(O[CH:6]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)[CH2:7][N:8]1[C:16]2[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[C:10]2[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]1=2)(=O)=O.[N-:29]=[N+:30]=[N-:31].[Na+]>CN(C=O)C.O>[N:29]([CH:6]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)[CH2:7][N:8]1[C:16]2[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[C:10]2[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]1=2)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc2c(c1)c1c(n2CC(OS(C)(=O)=O)c2ccncc2)CCN(C)C1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CC(N=[N+]=[N-])c2ccncc2)CCN(C)C1
Temperature: 100 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
To a solution of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(pyridin-4-yl)ethyl methanesulfonate (900 mg, 2.18 mmol) in DMF (10 mL) was added sodium azide (212.5 mg, 3.2 mmol) and the reaction mixture was stirred at 100° C. for 1 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 5-(2-azido-2-(pyridin-4-yl)ethyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (650 mg). The resulting racemate was purified and resolved by chiral preparative HPLC. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.8 (d, 2H), 8.0 (d, 2H), 7.31 (d, 1H), 7.3 (s, 1H), 7.04 (d, 1H), 5.45 (m, 1H), 4.7 (d, 1H), 4.59 (t, 1H), 4.4 (m, 2H), 3.9 (d, 1H), 3.6 (m, 1H), 3.4 (m, 1H), 3.2 (m, 1H), 3.1 (s, 3H), 2.4 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]#[N:38])[CH:32]=2)[CH:9]2[CH2:14][CH2:13][N:12]([CH:15]([CH3:29])[CH2:16][CH2:17][NH:18][C:19]([C:21]3[C:22]([CH3:28])=[N:23][CH:24]=[N:25][C:26]=3[CH3:27])=[O:20])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[C:39](Cl)(Cl)=[O:40].[Cl-].[NH4+].CC[N:47](C(C)C)C(C)C>C1(C)C=CC=CC=1>[C:37]([C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[CH2:30][N:8]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:39]([NH2:47])=[O:40])=[CH:7][CH:6]=1)[CH:9]1[CH2:14][CH2:13][N:12]([CH:15]([CH3:29])[CH2:16][CH2:17][NH:18][C:19]([C:21]2[C:26]([CH3:27])=[N:25][CH:24]=[N:23][C:22]=2[CH3:28])=[O:20])[CH2:11][CH2:10]1)#[N:38]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(N)cc2)CC1
Reactant: O=C(Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(NC(N)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 41.5 %

Procedure:
To a solution of 4,6-dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-amino-phenyl)-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (see EXAMPLE 154) (54 mg, 0.10 mmol) in toluene (1 mL) was added phosgene (20% in toluene, 82 μL, 0.15 mmol) and the resultant slurry was stirred at room temperature for 3.5 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in DMF (1 mL). To the solution were added ammonium chloride (28 mg, 0.53 mmol) and DIPEA (110 μL, 0.64 mmol) and the mixture was stirred at room temperature for 25 hours. Standard work-up and purification afforded COMPOUND 159 as a white solid (23 mg, 39%). 1H NMR (CDCl3) δ0.90-1.10 (m, 5H), 1.54 (d, 1H, J=13.5 Hz), 1.74-1.83 (m, 3H), 2.17 (t, 1H, J=11.1 Hz), 2.50 (s, 6H), 2.56 (t, 1H, J=11.1 Hz), 2.73-2.84 (m, 3H), 3.31 (m, 1H), 3.56 (m, 1H), 3.82-3.89 (m, 1H), 3.89 (s, 2H), 4.72 (s, 2H), 6.51 (d, 2H, J=8.1 Hz), 6.58 (s, 1H), 7.05 (d, 2H, J=8.1 Hz), 7.41-7.56 (m, 4H), 8.62 (br s, 1H), 8.85 (s, 1H). 13C NMR (CDCl3) δ 13.44, 21.94, 29.21, 30.42, 30.73, 40.05, 43.58, 48.57, 51.99, 53.45, 56.55, 60.24, 112.55, 117.73, 118.98, 125.26, 128.41, 129.36, 129.93, 130.67, 130.88, 131.02, 141.60, 145.94, 157.52, 157.75, 163.11, 166.29. ES-MS m/z 555 (M+H). Anal. Calcd. for C31H38N8O2.0.8CH2Cl2: C, 61.34; H, 6.41; N, 18.00. Found. C, 61.52; H, 6.49; N, 17.93.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.N[CH:13]([CH2:21][NH:22][C:23]1[C:28]([CH2:29][CH3:30])=[C:27]([N:31]2[CH2:36][CH2:35][CH:34]([C:37]3[CH:46]=[CH:45][C:44]4[CH2:43][CH2:42][CH2:41][NH:40][C:39]=4[N:38]=3)[CH2:33][CH2:32]2)[N:26]=[CH:25][N:24]=1)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>ClCCl.N1C=CC=CC=1>[CH2:29]([C:28]1[C:23]([NH:22][CH2:21][CH:13]([C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])=[N:24][CH:25]=[N:26][C:27]=1[N:31]1[CH2:36][CH2:35][CH:34]([C:37]2[CH:46]=[CH:45][C:44]3[CH2:43][CH2:42][CH2:41][NH:40][C:39]=3[N:38]=2)[CH2:33][CH2:32]1)[CH3:30]
Reactant: CCc1c(NCC(N)C(=O)OC(C)(C)C)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1c(NCC(C(=O)OC(C)(C)C)C(=O)c2ccc(OC)cc2)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
40 mg (0.233 mmoles) of 4-methoxy-benzoyl chloride in solution in 3 ml of dichloromethane is added to a mixture of 112.5 mg (0.233 mmoles) of tert-butyl 2-amino-3-{5-ethyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-piperidin-1-yl]-pyrimidin-4-ylamino}-propionate in solution in 6 ml of dichloromethane and 650 μl of pyridine. The reaction mixture is stirred at ambient temperature for 1 hour. Then, the solvent is evaporated off under reduced pressure (2 kPa) and the residue is chromatographed on silica gel with the following eluent: ethyl acetate-dichloromethane (50-50), ethyl acetate-dichloromethane/methanol (95/5) 50-50 then finishing with ethyl acetate-dichloromethane/methanol (9/1) 50-50. 98 mg of expected product is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][CH2:11][C:12]2[O:16][C:15]([C:17]3[CH:27]=[CH:26][C:20]([C:21](OCC)=[O:22])=[CH:19][CH:18]=3)=[CH:14][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[C-]#[N:29].[K+]>CO.N>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][CH2:11][C:12]2[O:16][C:15]([C:17]3[CH:27]=[CH:26][C:20]([C:21]([NH2:29])=[O:22])=[CH:19][CH:18]=3)=[CH:14][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: CCOC(=O)c1ccc(-c2ccc(CNCCc3cccc(F)c3)o2)cc1
Agent: N
Agent: [K+]
Solvent: CO
Product: NC(=O)c1ccc(-c2ccc(CNCCc3cccc(F)c3)o2)cc1
Temperature: 125 °C
Reaction time: 8 h
Yield: 3.3 %

Procedure:
To a 50 mL sealed tube was added ethyl 4-[5-({[2-(3-fluorophenyl)ethyl]amino}methyl)-2-furanyl]benzoate (100 mg, 0.27 mmol, Example X-1), 2.0 M MeOH/NH3 (20 mL), and KCN (30 mg). The reaction mixture was stirred at 125° C. overnight. The crude mixture was purified on RP-preparative HPLC to give 3 mg of 4-[5-({[2-(3-fluorophenyl)ethyl]amino}methyl)-2-furanyl]benzamide. (M+1) 339.23, 1.42 min (LC/MS method A)
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[S:52][C:18]2[N:19]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([C:44]4[C:45]([C:50]#[N:51])=[CH:46][CH:47]=[CH:48][CH:49]=4)=[CH:40][CH:39]=3)[C:20](=[O:36])[N:21]([CH2:24][C:25]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=3[F:35])=[O:26])[C:22](=[O:23])[C:17]=2[CH:16]=1)[CH3:14]>C(Cl)(Cl)Cl>[CH2:13]([C:15]1[S:52][C:18]2[N:19]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=4[C:50]4[NH:3][C:4](=[O:7])[O:5][N:51]=4)=[CH:40][CH:39]=3)[C:20](=[O:36])[N:21]([CH2:24][C:25]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=3[F:35])=[O:26])[C:22](=[O:23])[C:17]=2[CH:16]=1)[CH3:14]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3F)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3F)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 7.6 %

Procedure:
A mixture of hydroxylammonium chloride (1 g), sodium hydrogencarbonate (1.5 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[6-ethyl-3-[2-(2-fluoro-4-methoxyphenyl)-2-oxoethyl]-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (1 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC and dissolved in methylene chloride (20 mL). N,N′-Carbonyldiimidazole (0.11 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.096 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by preparative HPLC to give the title compound as a colorless amorphous solid (0.084 g, 8%).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=2)[O:3]1.[C:21](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O.ClCCl>[CH3:21][N:15]([C:12]1[CH:11]=[CH:10][C:9]([B:4]2[O:3][C:2]([CH3:20])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:14][CH:13]=1)[S:16]([CH3:19])(=[O:18])=[O:17]
Reactant: CC1(C)OB(c2ccc(NS(C)(=O)=O)cc2)OC1(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: ClCCl
Solvent: CC(C)=O
Product: CN(c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of N-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamide (0.50 g, 1.7 mmol) and potassium carbonate (0.28 g, 2.0 mmol) in acetone (10 mL) was added methyl iodide (0.12 mL, 2.0 mmol). The mixture was stirred at room temperature for 18 hours under an atmosphere of nitrogen then diluted with dichloromethane (20 mL), filtered through a plug of diatomaceous earth, rinsed with dichloromethane and evaporated. The material was subjected to high vacuum for 18 hours. N-Methyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamide was isolated as a yellow solid (0.50 g, 95%) and was used without further purification. 1H NMR (400 MHz, CDCl3, δ, ppm): 7.83 (d, J=7.9 Hz, 2H), 7.39 (d, J=7.8 Hz, 2H), 3.34 (s, 3H), 2.82 (s, 3H), 1.34 (s, 12H). MS=312 (MH)+. 62b) N-[4-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-phenyl]-N-methyl-methanesulfonamide was prepared from 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (300.0 mg, 1.408 mmol) and N-methyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamide (500.0 mg, 1.607 mmol) in a manner analogous to Step 2c. The reaction product was isolated as an off-white solid (0.33 g, 73%). MP=245-247° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.55 (d, J=5.8 Hz, 1H), 8.12 (d, J=7.5 Hz, 2H), 7.72 (d, J=7.1, 1H), 7.52 (d, J=7.2 Hz, 2H), 6.98 (t, J=6.2 Hz, 1H), 6.11 (s, 2H), 3.29 (s, 3H), 2.98 (s, 3H). MS=318 (MH)+. 62c) N-Methyl-N-(4-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-phenyl)-methanesulfonamide was prepared from N-[4-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-phenyl]-N-methyl-methanesulfonamide (75.0 mg, 0.236 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (70.0 mg, 0.274 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (26.0 mg, 0.0476 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a tan solid (0.027 g, 23%). MP=205-206° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.41 (d, J=6.5 Hz, 1H), 8.04 (d, J=7.7 Hz, 2H), 7.57-7.46 (m, 5H), 6.99-6.91 (m, 3H), 6.66 (s, 1H), 3.38 (s, 3H), 3.19-3.14 (m, 4H), 2.90 (s, 3H), 2.62-2.57 (m, 4H), 2.36 (s, 3H). MS=492 (MH)+.
Reaction SMILES: [CH2:1]([S:3]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)(=[O:5])=[O:4])[CH3:2].[C:16]([OH:20])(=[O:19])[CH:17]=[CH2:18].C(OC(=O)C)(=O)C>C(O)(=O)C>[CH2:1]([S:3]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH2:18][CH2:17][C:16]([OH:20])=[O:19])(=[O:5])=[O:4])[CH3:2]
Reactant: C=CC(=O)O
Reactant: CCS(=O)(=O)Nc1ccc2[nH]ccc2c1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCS(=O)(=O)Nc1ccc2[nH]cc(CCC(=O)O)c2c1
Yield: 99.4 %

Procedure:
A solution of 5-ethanesulfonylamino-1H-indole (8.0 g, 36 mmol), acrylic acid (5.15 g, 71 mmol), and acetic anhydride (7.3 g, 71 mmol) in 35 mL of acetic acid was heated at 90° C. for 20 h. The volatile materials were removed under high vacuum at 90° C. The remaining residue was dissolved in 1N NaOH and subsequently acidified to pH 1 with concentrated HCl. The aqueous solution was then extracted with five portions of ethyl acetate. The organic extracts were combined, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to yield 3-(5-ethanesulfonylamino-1H-indol-3-yl)propanoic acid (10.6 g of crude material). NMR and mass spectral analysis indicated the presence of the desired product. No attempt was made to purify this material; it was immediately subjected to reduction as described below.
Reaction SMILES: [NH:1]1[C:13]2[C:4]([S:5][CH:6]=[C:7]3[CH:12]=[CH:11][N:10]=[CH:9][C:8]3=2)=[N:3][S:2]1.[CH3:14][I:15]>CC(C)=O>[I-:15].[CH3:14][N:10]1[CH:11]=[CH:12][C:7]2=[CH:6][S:5][C:4]3[C:13](=[NH+:1][S:2][N:3]=3)[C:8]2=[CH:9]1
Reactant: C1=c2ccncc2=C2NSN=C2S1
Reactant: CI
Solvent: CC(C)=O
Product: CN1C=CC2=CSc3ns[nH+]c3C2=C1
Product: [I-]

Procedure:
A solution of [1,2,5]thiadiazolo[3',4':2,3]thiopyrano[4,5-c]pyridine (100 mg, 0.5 mmol) and methyliodide (1.5 mmol) in acetone (10 ml) was stirred at room temperature overnight. The precipitate was collected by filtration to give the wanted product in 120 mg (70%) yield.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[CH:20]1([C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:24])[CH2:22][CH2:21]1>>[CH:20]1([C:23]([N:25]2[CH2:30][CH2:29][N:28]([C:17]([C:15]3[CH:16]=[C:11]([C:5]4[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=4[CH3:10])[CH:12]=[N:13][CH:14]=3)=[O:19])[CH2:27][CH2:26]2)=[O:24])[CH2:21][CH2:22]1
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Reactant: O=C(C1CC1)N1CCNCC1
Product: CCc1cc(-c2cncc(C(=O)N3CCN(C(=O)C4CC4)CC3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and 4-cyclopropanecarbonyl-piperazine to afford the title compound. MS: m/e=395 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10])=[O:4].[S:16]1C=CC=C1CC([O-])=O.[K+].[CH3:26][C:27](C)=[O:28]>CCCCCC>[C:27]([S:16][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10])=[O:4])(=[O:28])[CH3:26]
Reactant: CC(C)=O
Reactant: O=C([O-])Cc1cccs1
Reactant: COC(=O)c1cccc(NC(=O)CCl)c1
Agent: [K+]
Solvent: CCCCCC
Product: COC(=O)c1cccc(NC(=O)CSC(C)=O)c1

Procedure:
A mixture of methyl 3-(2-chloroacetamido)-benzoate (16 g., 0.07 mole) and potassium thiolacetate (7.1 g., 0.065 mole) in 150 ml. of acetone is refluxed for 4.5 hr. After cooling, the reaction mixture is filtered and the filtrate concentrated under reduced pressure. The residual solid thus obtained is slurried with n-hexane to afford an 86% yield of crude product. Crystallization of the crude product from ethyl acetate-n-hexane affords analytically pure METHYL 3-[2-(ACETYLTHIO)ACETAMIDO]BENZOATE, m.p. 117.5°-119.5° C.