Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[F:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:30])=[C:25]([CH:29]=1)[C:26](Cl)=[O:27]>>[F:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:30])=[C:25]([CH:29]=1)[C:26]([NH:19][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)=[CH:7][C:2]=1[CH3:1])=[O:27]
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Reactant: Cc1ccc(F)cc1C(=O)Cl
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1cc(F)ccc1C

Procedure:
The title compound was prepared in a manner substantially the same as Example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 5-fluoro-2-methyl-benzoyl chloride (from Alfa Aesar). LCMS: RT=1.56 minutes, MS: 396 (M+H).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[CH:23]=[CH2:24]>C(O)C>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:17][CH2:18][N:19]([CH2:24][CH2:23][C:22]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:21]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: C1=Cc2ccccc2C(=C2CCNCC2)c2ccccc21
Reactant: C=CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)CCN1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1

Procedure:
A mixture of 4.00 g of 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine, 2.1 ml of ethyl acrylate and 20 ml of ethanol was refluxed for 1 hr and concentrated to give 5.35 g of colorless liquid. The liquid was purified by column chromatography on silica gel (eluent: chloroform) to give 5.3 g of colorless solid, which was recrystallized from n-hexane to give colorless crystals, mp 66°-67° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:7]1([NH:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]([CH3:32])=[C:17]([NH:19][C:20](=[O:31])[C:21]3[CH:26]=[C:25](F)[CH:24]=[CH:23][C:22]=3[N+:28]([O-:30])=[O:29])[CH:18]=2)=[O:12])[CH2:9][CH2:8]1>>[CH:7]1([NH:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]([CH3:32])=[C:17]([NH:19][C:20](=[O:31])[C:21]3[CH:26]=[C:25]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:24]=[CH:23][C:22]=3[N+:28]([O-:30])=[O:29])[CH:18]=2)=[O:12])[CH2:9][CH2:8]1
Reactant: C1CCNCC1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]

Procedure:
Using an analogous procedure to that described paragraph (A) in the portion of Example 13 which is concerned with the preparation of starting materials piperidine was reacted with N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-fluoro-2-nitrobenzamide to give N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-nitro-5-piperidin-1-ylbenzamide; NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.68 (m, 2H), 1.60 (m, 6H), 2.30 (s, 3H), 2.82 (m, 1H), 3.52 (m, 4H), 7.02 (m, 2H), 7.27 (d, 1H), 7.55 (d, 1H), 7.96 (s, 1H), 8.02 (d, 1H), 8.39 (s, 1H), 9.95 (s, 1H); Mass Spectrum: M+H+ 423.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16](=[O:31])[N:17]3[C:22](=[C:23]([C:25](O)=[O:26])[CH:24]=2)[C:21]2[S:28][CH:29]=[CH:30][C:20]=2[CH:19]=[CH:18]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)Cl.CN(C=O)C.[CH2:41]([NH:43][CH2:44][CH2:45][O:46][CH3:47])[CH3:42]>C1(C)C=CC=CC=1.O1CCOCC1.C(N(CC)CC)C>[CH2:41]([N:43]([CH2:44][CH2:45][O:46][CH3:47])[C:25]([C:23]1[CH:24]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][CH:11]=2)[C:16](=[O:31])[N:17]2[C:22]=1[C:21]1[S:28][CH:29]=[CH:30][C:20]=1[CH:19]=[CH:18]2)=[O:26])[CH3:42]
Reactant: CCNCCOC
Reactant: O=C(O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3ccsc3c12
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCN(CCOC)C(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3ccsc3c12

Procedure:
From 8-[p-(benzyloxy)phenyl]-7-oxo-7H-thieno[2,3-a]quinolizine-10-carboxylic acid with SOCl2 and DMF in toluene. Then treatment with triethylamine and ethyl-(2-methoxy-ethyl)-amine in dioxan.
Reaction SMILES: Cl.[O:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C@H:3]1[C:12]([OH:14])=[O:13]>>[O:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C@H:3]1[C:12]([O:14][CH2:5][CH:6]([CH3:11])[CH3:7])=[O:13]
Reactant: O=C(O)[C@@H]1CCc2ccccc2O1
Agent: Cl
Product: CC(C)COC(=O)[C@@H]1CCc2ccccc2O1

Procedure:
The aqueous phase of the hydrolysis reaction was acidified to pH of 2.0 with conc. HCl forming a white precipitate of (S)-chroman-2-carboxylic acid. The S-acid was extracted into toluene, and the phases were separated. The organic layer was placed in a vessel suitable for acid catalyzed esterification. Sulfuric acid was added to the vessel, and the mixture was heated to reflux. Water was removed by azeotropic distillation. The conversion of the acid to the ester was followed by GC analysis. Isobutyl (S)-chroman-2-carboxylate was thereby formed. Upon completion of the esterification, the sulfuric acid catalyst used in the reaction was removed by washing the reaction product with saturated sodium carbonate, and the S-carboxylate product was azeotropically dried again.
Reaction SMILES: F[C:2]1[C:3]([CH:16]=[O:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[NH:18]1[CH:22]=[CH:21][CH:20]=[N:19]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:12][C:9]1([CH3:13])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]2[CH:4]=[C:3]([CH:16]=[O:17])[C:2]([N:18]3[CH:22]=[CH:21][CH:20]=[N:19]3)=[CH:11][C:10]1=2
Reactant: c1cn[nH]c1
Reactant: CC1(C)CCC(C)(C)c2cc(C=O)c(F)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC1(C)CCC(C)(C)c2cc(-n3cccn3)c(C=O)cc21
Temperature: 25 °C
Yield: 42.3 %

Procedure:
A solution of 0.200 g (0.845 mmol) of 3-fluoro-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthaldehyde, 0.058 g (0.854 mmol) of pyrazole, and 0.130 g (0.939 mmol) of potassium carbonate in 2 mL dimethylsulfoxide was heated to 95° C. for 18 hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The product was purified on flash chromatography on silica gel (5% ethyl acetate/hexane) to afford 0.101 g (42%) of 5,5,8,8-tetramethyl-3-pyrazol-1-yl-5,6,7,8-tetrahydro-2-naphthaldehyde. (mp=95.7-97.6).
Reaction SMILES: [C:1]([O:5][C:6]([C@@:8]1([CH2:23][CH2:24][CH2:25][OH:26])[CH:12]([F:13])[C:11](=[O:14])[N:10]([C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C.O.C(=O)(O)[O-].[Na+]>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([C@@:8]1([CH2:23][CH2:24][CH2:25][O:26][S:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:35])=[O:34])[CH:12]([F:13])[C:11](=[O:14])[N:10]([C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](c1ccccc1)N1C[C@@](CCCO)(C(=O)OC(C)(C)C)C(F)C1=O
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](c1ccccc1)N1C[C@@](CCCOS(=O)(=O)c2ccccc2)(C(=O)OC(C)(C)C)C(F)C1=O
Temperature: 25 °C
Reaction time: 12.5 h

Procedure:
(3S)-4-Fluoro-3-(3-hydroxy-1-propyl)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (12.20 g) was dissolved in dichloromethane (400 mL). Benzenesulfonyl chloride (9.06 mL), triethylamine (10.7 mL), and 4-dimethylaminopyridine (2.04 g) were added under ice-cooling, and the mixture was stirred at room temperature for 12.5 hours. Saturated sodium bicarbonate water was added to the reaction solution, and the mixture was stirred for 30 minutes, followed by extraction with dichloromethane. The organic layer was sequentially washed with a 10% citric acid solution and brine, dried over anhydrous sodium sulfate, and filtered. Thereafter, the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=8:2→1:1) to give 11.7 g of the title compound as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[CH:19]1[CH2:24][CH2:23][CH:22]([CH:25]2[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]2)[CH2:21][CH2:20]1.[H-].[Na+].O.[C:35]1(C)[CH:40]=CC=C[CH:36]=1>BrCCC.CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[CH:19]1[CH2:24][CH2:23][CH:22]([CH:25]2[CH2:26][CH2:27][CH:28]([O:31][CH2:36][CH2:35][CH3:40])[CH2:29][CH2:30]2)[CH2:21][CH2:20]1
Reactant: CCCCCC1CCC(c2ccc(C3CCC(C4CCC(O)CC4)CC3)c(F)c2)CC1
Reactant: Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCCBr
Solvent: O
Product: CCCCCC1CCC(c2ccc(C3CCC(C4CCC(OCCC)CC4)CC3)c(F)c2)CC1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
The compound (15) (8.2 g), dimethyl sulfoxide (40 ml) and sodium hydride (1.0 g) were put in a reaction vessel under a nitrogen atmosphere, and heated to 60° C. The stirring was continued for 1 hour, and then a dimethyl sulfoxide solution in which 1-bromopropane (16) (2.6 g) was dissolved in dimethyl sulfoxide (5 ml) was added dropwise thereto, and the mixture was heated to 120° C. The stirring was continued for 2 hours, and then the mixture was cooled slowly to room temperature, and water (200 ml) and toluene (200 ml) were added and mixed thereto. The mixture was then allowed to stand until it had separated into two phases, the organic and aqueous phases, and an extractive operation to an organic phase was carried out. The organic phase was fractionated, and washed sequentially with water and a saturated aqueous solution of sodium hydrogencarbonate and brine, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was purified with a fractional operation by means of column chromatography using toluene as an eluent and silica gel as a stationary phase powder, and further purified by means of recrystallization from a mixed solvent of heptane and Solmix (heptane: Solmix=1:1 by volume) and dried, giving 2.8 g of 4-[2-fluoro-4-(4-pentyl-cyclohexyl)-phenyl]-4′-propoxybicyclohexane (No. 54). The yield based on the compound (12) was 31.4%.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][N:6]1[N:10]=[N:9][C:8](/[CH:11]=[C:12]2\[CH2:13][N:14]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:16][CH:17]\2O)=[N:7]1)=[O:4].[C:38]([OH:41])(=[S:40])[CH3:39].C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C>ClCCl.O.C1(C)C=CC=CC=1>[C:38]([S:40][CH:17]1[CH2:16][CH2:15][N:14]([C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:13]/[C:12]/1=[CH:11]\[C:8]1[N:9]=[N:10][N:6]([CH2:5][C:3]([O:2][CH3:1])=[O:4])[N:7]=1)(=[O:41])[CH3:39]
Reactant: COC(=O)Cn1nnc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2O)n1
Reactant: CC(O)=S
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)Cn1nnc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2SC(C)=O)n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 58.4 %

Procedure:
To a solution of (E)-3-{[2-(methoxycarbonylmethyl)-2H-tetrazol-5-yl]methylidene}-1-(triphenylmethyl)piperidin-4-ol (1.5 g) in a mixed solvent of dichloromethane (30 ml) and toluene (30 ml) was added thioacetic acid (2.2 ml) and N,N-dimethylformamide dineopentyl acetal (8.5 ml). After the mixture was stirred at 50° C. for 2 hours, it was cooled, water and dichloromethane were added and the layers were separated. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The extract was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using hexane, ethyl acetate, and dichloromethane (2:1:1) as an eluent to afford (E)-4-(acetylsulfanyl)-3-{[2-(methoxycarbonylmethyl)-2H-tetrazol-5-yl]methylidene}-1-(triphenylmethyl)piperidine (containing impurity, gross amount: 880 mg, gross yield: 58.4%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.Br[CH2:17][CH2:18][OH:19].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:17][CH2:18][OH:19])[CH2:12][CH2:11]1
Reactant: OCCBr
Reactant: COc1ccccc1N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccccc1N1CCN(CCO)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
A mixture of 2.29 g (10 mmol) 1-(2-methoxy-phenyl)-piperazine hydrochloride, 7.1 mL (100 mmol) 2-bromo-ethanol, 5.52 g (40 mmol) potassium carbonate and 100 mL acetonitrile is stirred at 60° C. overnight. Filtration and concentration in vacuum yields the crude product which is purified via column chromatography over silica gel eluting with dichloromethane/ammonia-saturated methanol 98:2.
Reaction SMILES: Br[C:2]1[C:3]([NH:31][C@@H:32]2[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33]2)=[N:4][C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[C:6]([C:8](=[O:10])[NH2:9])[N:7]=1.[N:44]1C=CC=C[CH:45]=1>>[C:8]([C:6]1[N:7]=[C:2]([C:45]#[N:44])[C:3]([NH:31][C@@H:32]2[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33]2)=[N:4][C:5]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][CH:21]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1)(=[O:10])[NH2:9]
Reactant: c1ccncc1
Reactant: CN1CCN(C2CCN(c3ccc(Nc4nc(N[C@@H]5CCN(C(=O)OC(C)(C)C)C5)c(Br)nc4C(N)=O)cc3)CC2)CC1
Product: CN1CCN(C2CCN(c3ccc(Nc4nc(N[C@@H]5CCN(C(=O)OC(C)(C)C)C5)c(C#N)nc4C(N)=O)cc3)CC2)CC1
Reaction time: 3 h

Procedure:
To a mixture of tert-butyl (3R)-3-{[3-bromo-5-carbamoyl-6-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazin-2-yl]amino}pyrrolidine-1-carboxylate (500 mg) and pyridine (3 mL) was added cuprous cyanide (88 mg), followed by reacting at 140° C. for 3 hours. The reactant was left to be cooled, and then subjected to liquid separation by the addition of a mixed solvent of chloroform:methanol:28% aqueous ammonia (100:10:1) and a saturated aqueous sodium hydrogen carbonate solution. To the organic phase was added silica gel, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-200:10:1) to obtain tert-butyl (3R)-3-{[5-carbamoyl-3-cyano-6-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazin-2-yl]amino}pyrrolidine-1-carboxylate (Preparation Example 317 a:154 mg), which is a low-polarity product, as a yellow amorphous substance and tert-butyl (3R)-3-{[3,5-dicarbamoyl-6-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazin-2-yl]amino}pyrrolidine-1-carboxylate (Preparation Example 317 b:130 mg), which is a high-polarity substance, as a brown amorphous substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[NH2:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([Br:26])[C:19]=1O>C(OCC)C.N1C=CC=CC=1.C(Cl)Cl.CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([O:7][C:19]1[C:18]([NH:17][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:2]([F:1])[CH:3]=2)=[CH:23][C:22]([O:24][CH3:25])=[CH:21][C:20]=1[Br:26])=[O:6]
Reactant: COc1ccc(C(=O)O)cc1F
Reactant: COc1cc(N)c(O)c(Br)c1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COc1cc(Br)c(OC(=O)c2ccc(OC)c(F)c2)c(NC(=O)c2ccc(OC)c(F)c2)c1
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
A mixture of 3-fluoro-4-methoxybenzoic acid (39.0 g, 229 mmol), thionyl chloride (100 mL), and N,N-dimethylformamide (0.5 mL) was refluxed for 1 h. The volatiles were removed under vacuum. The solids were taken in benzene (twice) and the volatiles were removed under vacuum. The residue was dissolved in CH2Cl2 (100 mL) and added into a cold (0° C.) mixture (mechanically stirred) of 2-amino-6-bromo-4-methoxyphenol (20.0 g, 91.7 mmol) and CH2Cl2 (150 mL). Anhydrous pyridine (37.0 mL, 468.5 mmol) was added dropwise into the new mixture. During the pyridine addition a precipitate was formed. The mixture was stirred for 30 min and then ethyl ether (250 mL) was added. The precipitated solids were filtered off and washed with ethyl ether. The solids were taken in water and stirred for 20 min. The solids were then filtered off and dried to give an off-white solid (46.5 g, 97% yield, m.p. 184-186° C.); MS m/e 520 (M−H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[S:7](N)([NH2:10])(=[O:9])=[O:8]>O1CCOCC1>[N:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: NS(N)(=O)=O
Reactant: C1COCCN1
Solvent: C1COCCO1
Product: NS(=O)(=O)N1CCOCC1

Procedure:
Morpholine (5 ml) and sulfamide (11 g) in 1,4-dioxane (100 ml) were heated at reflux for 48 h. The solvent was evaporated under reduced pressure and the resulting solid partitioned between EtOAc and water. The organic phase was collected and the aqueous phase was further extracted with EtOAc (×4). The combined organic extracts were dried (MgSO4) and the solvent removed in vacuo. The solid residue was triturated with Et2O and filtered to give the subtitle compound as a white crystallin solid. Yield: 2.1 g.
Reaction SMILES: [C:1]([C:3]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:4]=1[O:5][CH2:6][CH:7]([O:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([OH:10])=[O:9])#[N:2].N1C=C[CH:30]=[CH:29][CH:28]=1.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH2:30]([O:9][C:8](=[O:10])[CH:7]([O:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][O:5][C:4]1[CH:19]=[CH:20][C:21]([C:23]([F:24])([F:25])[F:26])=[CH:22][C:3]=1[C:1]#[N:2])[CH:29]=[CH2:28]
Reactant: N#Cc1cc(C(F)(F)F)ccc1OCC(Oc1ccccc1Cl)C(=O)O
Reactant: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: C=CCOC(=O)C(COc1ccc(C(F)(F)F)cc1C#N)Oc1ccccc1Cl
Reaction time: 3 h

Procedure:
55 g (0.15 Mol) of the acid obtained in Example 2 are dissolved in 120 ml of toluene. Then 2 ml of pyridine and 40 ml of thionyl chloride are added thereto. This mixture is stirred for 3 hours at 80°. Then the solvents are distilled off under reduced pressure and the remaining oil (56 g) is dissolved in 200 ml of toluene. To this solution is added dropwise, at a temperature of 5°-15°, first 12.5 g of allyl alcohol, then 28 g of triethylamine. This reaction mixture is stirred overnight at room temperature and then added with 50 ml of water. The organic phase is separated, dried over sodium sulfate, filtered and then evaporated to dryness. The residue represents 57.8 g of a dark oil, which is dissolved in toluene and cleaned by chromatography over an alumina oxide column. After evaporation of the toluene and distillation, there remains 54 g of the allyl ester as a clear oil, b.p. 165° /0.01 torr.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([OH:13])=[O:12].C(O)CO.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([SH:29])=[CH:25][CH:24]=1.Cl>O.C(OCC)(=O)C.CC(O)C>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([OH:13])=[O:12])=[CH:25][CH:24]=1
Reactant: COc1ccc(S)cc1
Reactant: O=C(O)c1cccc(I)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Solvent: O
Product: COc1ccc(Sc2cccc(C(=O)O)c2)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 84.9 %

Procedure:
Cu(I) iodide (10 mg, 0.05 mmol), potassium carbonate (414 mg, 3.0 mmol) and 3-iodobenzoic acid (248 mg, 1.0 mmol) were charged into a screw-capped test tube with Teflon-lining. The tube was evacuated and backfilled with argon (3 cycles). 2-Propanol (1.0 mL, bench grade solvent without degassing and pre-drying), ethylene glycol (111 μL, 2.0 mmol, bench grade solvent) and 4-methoxythiophenol (123 μL, 1.0 mmol) were added by syringes at room temperature. The tube was heated to 80° C. and stirred for 24 hours. The reaction mixture was then allowed to reach room temperature. Ethyl acetate (˜5 mL), water (˜10 mL) and dil. HCl were added to reach pH 3-4. The reaction mixture was extracted with ethyl acetate (2×10 mL) and CH2Cl2 (2×10 mL). The combined organic phase was passed through a short pad of silica (0.5 cm diameter×1 cm height). Solvent was removed and the yellow residue was redissolved in minimum amount of CH2Cl2. Hexane was added slowly and the solution was stand overnight at room temperature. White crystal was obtained as the titled product (221 mg, 85% yield). Rf=0.2 (hexane/ethyl acetate=2/1) (Note: same Rf value as the starting material). Melting point; 121-123° C. 1H NMR (CDCl3, 300 MHz) δ 10.68 (brs, 1 H), 7.86 (s, 1 H), 7.82 (dt, 1 H, J=1.8 Hz, 6.6 Hz), 7.42 (dt, 2 H, J=2.1 Hz, 8.7 Hz), 7.28-7.31 (m, 2 H), 6.90 (dt, 2 H, J=2.1 Hz, 8.7 Hz), 3.83 (s, 3 H). 13C NMR (CDCl3, 75 MHz) δ 172.0, 160.3, 140.3, 136.1, 132.8, 130.2, 129.2, 129.1, 127.4, 123.1, 55.7. IR (neat, cm−1) 2964 (broad), 2943, 2902, 2875, 2856, 2840, 2813, 2360, 2342, 1688. MS (EI) m/z (relative intensity) 260 (100). Anal. Cald. for C14H12O3S, Cald. C: 64.60, H: 4.65; Found C: 64.52, H: 4.68.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[N:19]3[N:20]=[C:21]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][N:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)=[CH:26][CH:25]=4)[N:22]=[C:18]3[CH:17]=[CH:16][CH:15]=2)[CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[NH2:7][C:8]1[CH:9]=[C:10]([C:14]2[N:19]3[N:20]=[C:21]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][N:33]5[CH2:34][CH2:35][CH2:36][CH2:37]5)=[CH:26][CH:25]=4)[N:22]=[C:18]3[CH:17]=[CH:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Reaction time: 2 h

Procedure:
(3-{2-[4-(2-Pyrrolidin-1-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-phenyl)-carbamic acid tert-butyl ester (1.39 g, 2.71 mmol) was dissolved in dichloromethane (10 ml). Trifluoroacetic acid (10 ml) was added and the reaction mixture stirred for 2 hours. Neutralisation was performed by adding saturated aqueous sodium hydrogencarbonate. The aqueous phase was extracted twice with dichloromethane, and the combined organics washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the desired compound. Yield 830 mg, 74%. 50 mg was purified by preparatory LCMS.