Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][CH2:7][C:8]1[C:9]([Cl:27])=[C:10]2[CH:16]=[CH:15][N:14]([S:17]([C:20]3[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:11]2=[N:12][CH:13]=1.Cl.C([O-])(O)=O.[Na+].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1COCC1.CC(C)=O.CCOC(C)=O.O>[Cl:27][C:9]1[C:8]([CH2:7][CH2:6][CH:2]=[O:1])=[CH:13][N:12]=[C:11]2[N:14]([S:17]([C:20]3[CH:21]=[CH:22][C:23]([CH3:24])=[CH:25][CH:26]=3)(=[O:19])=[O:18])[CH:15]=[CH:16][C:10]=12
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)c(CCC4OCCO4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)c(CCC=O)cnc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
To a solution of 5-(2-(1,3-dioxolan-2-yl)ethyl)-4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine (0.520 g, 1.28 mmol) in THF (4.2 mL) was added aqueous HCl (6 M, 0.639 mL, 3.83 mmol). The reaction mixture was stirred at ambient temperature for about 2 h and was heated to about 50° C. for about 1 h. The reaction was cooled to ambient temperature and water (0.64 mL) was added and the reaction stirred for about 16 h. The pH was adjusted to about 7 with saturated aqueous NaHCO3 and EtOAc (about 10 mL) was added. The layers were separated and the aqueous phase was extracted with EtOAc (10 mL). The combined organics were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Acetone (12 mL) and pyridinium p-toluenesulfonate (0.096 g, 0.383 mmol) were added. The reaction was heated at reflux for about 2 h. The reaction was cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0-50% EtOAc in DCM to give 3-(4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)propanal (0.44 g, 84%, 90% purity) as an off white foam: LC/MS (Table 1, Method b) Rt=2.50 min; MS m/z: 363 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[C:8]1([CH3:15])[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=1.[Mg].[Cl-].[NH4+]>CCOCC>[Br:1][C:2]1[C:3]([C:11]2[CH:12]=[CH:13][C:8]([CH3:15])=[CH:9][CH:10]=2)=[N:4][CH:5]=[N:6][CH:7]=1
Reactant: Brc1cncnc1
Reactant: Cc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: Cc1ccc(-c2ncncc2Br)cc1
Reaction time: 8 h

Procedure:
To a solution of 5-bromopyrimidine (15.9 g, 0.1 mmol) in ether (200 ml) was added a Grignard reagent (prepared from p-tolyl bromide (20.52 g, 0.12 mmol), magnesium (2.92 g, 0.1 mmol) and ether (100 ml) dropwise at room temperature during 10 minutes. After the addition, the resulting suspension was heated under reflux for 1 hour and allowed to stand overnight. The reaction mixture was treated with aqueous ammonium chloride and then the ether layers were collected. The aqueous layers were extracted with methylene chloride and the extracts were combined with the ether layers and concentrated to dryness. The residue was purified by column chromatography on silica gel and then dissolved in acetone (100 ml). To the acetone solution was added a solution of potassium permanganate in acetone until red color disappeared, manganese dioxide was removed from the reaction mixture by filtration. The filtrate was concentrated to dryness and the residue was purified by column chromatography on silica gel. Recrystallization from hexane afforded colorless needles (12.8 g, 51%), m.p. 81°-82° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[C:13]([CH:18]([CH3:20])[CH3:19])=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1.[C:21]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[CH:27][CH:26]=1)(=[O:23])[CH3:22]>C(O)C>[CH:18]([C:13]1=[N:14][NH:15][C:16](=[O:17])/[C:12]/1=[C:4]1\[NH:5][C:6]2[C:11]([C:2]([S:31][C:28]3[CH:27]=[CH:26][C:25]([NH:24][C:21](=[O:23])[CH3:22])=[CH:30][CH:29]=3)=[CH:3]\1)=[CH:10][CH:9]=[CH:8][CH:7]=2)([CH3:20])[CH3:19]
Reactant: CC(=O)Nc1ccc(S)cc1
Reactant: CC(C)C1=NNC(=O)/C1=C1/C=C(Cl)c2ccccc2N1
Solvent: CCO
Product: CC(=O)Nc1ccc(SC2=C/C(=C3/C(=O)NN=C3C(C)C)Nc3ccccc32)cc1
Temperature: 180 °C

Procedure:
(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-isopropyl-1H-pyrazol-5(4H)-one (0.029 g, 0.089 mmol) was dissolved in ethanol (1 mL) and 4-acetamidothiophenol (0.016 g, 0.094 mmol) was added. The reaction mixture was heated to 180° C. using a microwave reactor for 30 minutes. The mixture was then concentrated and purified by LC-MS to give Example 19. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.96 (d, J=6.82 Hz, 6H) 2.13 (s, 3H) 2.53 (bs, 1H) 6.65 (s, 1H) 7.68-7.70 (m, 3H) 7.86-7.97 (m, 3H) 8.02 (s, 1H) 8.20 (d, J=8.34 Hz, 1H) 10.43 (s, 1H); ESI-MS: m/z calc'd for C23H22N4O2S 418.51. found 419.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[CH:11])=[CH:6][CH:5]=1)[CH3:2].[Br:12][C:13]1[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=1.C(NC(C)C)(C)C.CCOC(C)=O>C1COCC1.[Cu]I>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:11]#[C:10][C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)=[CH:15][CH:14]=1
Reactant: Brc1ccc(I)cc1
Reactant: C#Cc1ccc(OCC)cc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOc1ccc(C#Cc2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 1.60 g (11.0 mmol) 4-ethoxyphenylacetylene in 40 mL THF are added 3.10 g (11.0 mmol) 1-bromo-4-iodo-benzene under argon, followed by 0.18 g (0.22 mmol) Pd(dppf)Cl2CH2Cl2 as catalyst, 0.04 g (0.22 mmol) copper(I)iodide and 3.10 mL (21.9 mmol) diisopropylamine as base. The mixture is stirred at rt for 3 h. After that time, EtOAc is added and the organic layer is washed with ammonia (5%, 2×) and water (1×). The organic layer is separated, dried over magnesium sulphate and the solvent is evaporated. The residue is purified by column chromatography (silicia gel; PE:EtOAc 9:1) to yield the desired product.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[C:8]([C:9]([O:11]CC)=[O:10])=[C:7]([CH2:14][CH3:15])[C:6]([C:16]([O:18]CC)=[O:17])=[C:5]([C:21]([F:24])([F:23])[F:22])[N:4]=1.CO.[OH-].[K+]>O>[F:25][CH:2]([F:1])[C:3]1[N:4]=[C:5]([C:21]([F:24])([F:22])[F:23])[C:6]([C:16]([OH:18])=[O:17])=[C:7]([CH2:14][CH3:15])[C:8]=1[C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1CC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1c(C(=O)O)c(C(F)F)nc(C(F)(F)F)c1C(=O)O
Yield: 52.3 %

Procedure:
A 1-liter flask is charged with 60 g (0.163 mole) of the product of Example 12 and 200 ml of methyl alcohol. In another flask, 150 ml of water and 21.52 g (0.326 mole) of potassium hydroxide are combined. The aqueous KOH is poured into the 1-liter flask and the mixture is heated to reflux overnight. The reaction mixture is cooled and extracted once with ethyl ether. The aqueous layer is acidified with concentrated hydrochloric acid and extracted with ethyl ether. The organics are dried on anhydrous magnesium sulfate, filtered, and concentrated to yield 26.72 g (52%) of the desired product, m.p. 237°-239° C.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][C:7]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11][C:8]=3[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[Cl:29][C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[Cl:29][C:30]([N:1]1[C:10]2[C:5](=[CH:6][C:7]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11][C:8]=3[CH:9]=2)[CH2:4][CH2:3][CH2:2]1)=[O:32]
Reactant: CC(C)(C)OC(=O)N1CCc2cc3c(cc2CC1)NCCC3
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCc2cc3c(cc2CC1)N(C(=O)Cl)CCC3
Reaction time: 3 h
Yield: 193.6 %

Procedure:
To a solution of 3.83 g of t-butyl 1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate in 40 ml of dichloromethane were added 1.3 ml of pyridine and 1.29 g of triphosgene under ice-cooling, followed by stirring for 3 hours. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed with water and an aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. To the residue was added hexane, followed by stirring, and the solid was collected by filtration and dried to obtain 3.07 g of t-butyl 1-(chlorocarbonyl)-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[N:37](S(C4C=CC(C)=CC=4)(=O)=O)[C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH2:21][NH:22][CH:23]5[CH2:28][CH2:27][CH:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25][CH2:24]5)=[C:15]4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:48][CH3:49].[OH-].[K+]>>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[NH:37][C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH2:21][NH:22][CH:23]5[CH2:24][CH2:25][CH:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:27][CH2:28]5)=[C:15]4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:48][CH3:49]
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(CNC4CCC(NC(=O)OC(C)(C)C)CC4)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(nc1OC)c(-c1cc3c(CNC4CCC(NC(=O)OC(C)(C)C)CC4)ccnc3[nH]1)cn2C
Yield: 79.5 %

Procedure:
The product is prepared by following the procedure described in example 34 stage (k), starting with 0.235 g of tert-butyl (4-{[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]-amino}cyclohexyl)carbamate instead of the cyclopropyl-[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]amine used in example 34 stage (k) and 1.36 cm3 of 5N potassium hydroxide. 0.145 g of tert-butyl (4-{[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]amino}-cyclohexyl)carbamate is obtained with the following characteristics:
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]([CH3:14])[C:9]([C@@H:11]([NH2:13])[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH2:15][C:16]1[C:21]([C:22]#[N:23])=[C:20](Cl)[N:19]=[CH:18][N:17]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:15][C:16]1[C:21]([C:22]#[N:23])=[C:20]([NH:13][C@H:11]([C:9]2[N:8]([CH3:14])[C:7]3[C:2]([Br:1])=[CH:3][CH:4]=[CH:5][C:6]=3[N:10]=2)[CH3:12])[N:19]=[CH:18][N:17]=1
Reactant: C[C@H](N)c1nc2cccc(Br)c2n1C
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2cccc(Br)c2n1C
Temperature: 90 °C
Yield: 72.3 %

Procedure:
A mixture of (S)-1-(7-bromo-1-methyl-1H-benzoimidazol-2-yl)ethylamine (1 g, 3.9 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (0.64 g, 4.1 mmol) and DIPEA (2.1 mL, 4.1 mmol) in IPA (7.8 mL) was heated for 16 h at 90° C. After cooling to RT, the reaction mixture was filtered and the solid washed with MeOH and DCM to afford 421 as a cream solid (1.05 g, 72%). LCMS (Method K): RT 3.27 min [M+H]+ 372 (for 79Br) 1H NMR (DMSO-d6, 400 MHz): δ 8.07 (1H, s), 7.79 (1H, d, J=7.5 Hz), 7.63 (1H, d, J=8.0 Hz), 7.41 (1H, d, J=4.0 Hz), 7.32 (2H, bs), 7.11 (1H, dd, J=8.0, 8.0 Hz), 5.70 (1H, dq, J=7.5, 7.0 Hz), 4.01 (3H, s), 1.60 (3H, d, J=7.0 Hz)
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH2:28])[C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)=[C:12]([O:26][CH3:27])[CH:11]=2)=[CH:6][CH:7]=1.[CH:29](OCC)(OCC)OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C(O)C.C(OCC)(=O)C>[I:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]4[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=4)=[C:12]([O:26][CH3:27])[CH:11]=3)[CH:29]=[N:28][C:4]=2[CH:3]=1
Reactant: COc1ccc(COc2ccc(CNc3ccc(I)cc3N)cc2OC)cn1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(COc2ccc(Cn3cnc4cc(I)ccc43)cc2OC)cn1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 91 %

Procedure:
To a stirred suspension of 4-iodo-N1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)benzene-1,2-diamine in ethanol (100 mL) was added triethyl orthoformate (4.45 g, 30.03 mmol) and p-toluenesulfonic acid monohydrate (0.075 g, 0.39 mmol). As the resulting mixture was warmed to reflux, the solids gradually dissolved to provide an orange solution. After 45 min, the reaction mixture was allowed to cool to room temperature, resulting in the formation of a precipitate. Water (250 mL) was added to the mixture, and the solids were isolated by filtration. The moist solids were dissolved in ethyl acetate (250 mL), and this solution was washed with brine, dried over magnesium sulfate, filtered, and concentrated to provide 5.99 g (91%) of 5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole as a tan solid.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][C:8]([N:16]1[N:20]=[N:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]([NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:29][C@H:30]([OH:46])[C@@H:31]([NH:39]C(=O)C(F)(F)F)[CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:23][CH:22]=2)=[N:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9]>CO>[CH3:9][C:8]([N:16]1[N:20]=[N:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]([NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:29][C@H:30]([OH:46])[C@@H:31]([NH2:39])[CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:23][CH:22]=2)=[N:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:7]
Reactant: CC(C)(C)OC(=O)NN(Cc1ccc(-c2nnn(C(C)(C)c3ccccc3)n2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)NN(Cc1ccc(-c2nnn(C(C)(C)c3ccccc3)n2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Reaction time: 15 h

Procedure:
28 ml of a 1N K2CO3 solution are added dropwise, at 70° C., to 1.9 g (2.8 mmol) of 1-{4-[2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-phenyl}-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-(trifluoroacetyl)amino-6-phenyl-2-azahexane in 29 ml of methanol and the mixture is stirred for 15 hours. After cooling and concentration by evaporation, methylene chloride and water and added; the aqueous phase is separated off and extracted with methylene chloride. The organic phases are washed with water, dried (Na2SO4) and concentrated by evaporation to yield the title compound: HPLC20-100 : tRet =15.1; FAB MS (M+H)+ =469.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([O:10][CH3:11])=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1.[I:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[N+:22]([O-:24])=[O:23])[NH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[I:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[N+:22]([O-:24])=[O:23])[N:15]([CH2:2][C:3]2[C:4]([O:10][CH3:11])=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=2)[N:14]=1
Reactant: COc1nc(C)ccc1CBr
Reactant: O=[N+]([O-])c1cccc2[nH]nc(I)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc(C)ccc1Cn1nc(I)c2c([N+](=O)[O-])cccc21
Yield: 101.9 %

Procedure:
A mixture of 3-(bromomethyl)-2-methoxy-6-methylpyridine (500 mg, 2.314 mmol) and 3-iodo-4-nitro-1H-indazole (668.8 mg, 2.314 mmol) (prepared as in Example 1, step E) was dissolved in dry N,N-dimethylformamide (11.6 mL) with stirring under an atmosphere of nitrogen. Potassium carbonate (479.7 mg, 3.471 mmol) was added and the mixture was stirred at ambient temperature for 16 hours. The mixture was diluted with water (50 mL) and extracted into ethyl acetate. The combined organic extracts were washed with brine and dried over sodium sulfate. The solution was filtered and concentrated under reduced pressure to give 3-iodo-1-((2-methoxy-6-methylpyridin-3-yl)methyl)-4-nitro-1H-indazole (1.0 g) which was used without purification.
Reaction SMILES: C([NH:8][C@H:9]1[CH2:13][CH2:12][C@@H:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:10]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>>[NH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([C@@H:11]2[CH2:12][CH2:13][C@H:9]([NH2:8])[CH2:10]2)=[CH:15]1
Reactant: c1ccc(CN[C@H]2CC[C@@H](c3c[nH]c4ccccc34)C2)cc1
Agent: O=C[O-]
Agent: [NH4+]
Product: N[C@H]1CC[C@@H](c2c[nH]c3ccccc23)C1
Yield: 89.2 %

Procedure:
This compound was prepared in the same manner as for Intermediate 20, using cis-benzyl-3-(1H-indol-3-yl)-cyclopentylamine (1.3 g, 4.48 mmol) and ammonium formate (1.6 g, 25.3 mmol) to afford 0.8 g (90%) of the desired product as a thick oil which solidified upon standing: MS (ESI) m/z 201 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:19]([CH3:20])=[CH:18][C:5]([O:6][CH2:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[C:4]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)(=[O:24])=[O:23])[CH:3]=1.[CH3:31][CH:32]1[CH2:34][O:33]1>N1C=CC=CC=1>[OH:33][CH:32]([CH3:34])[CH2:31][N:21]([S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)(=[O:23])=[O:24])[C:4]1[CH:3]=[C:2]([CH3:1])[C:19]([CH3:20])=[CH:18][C:5]=1[O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(COc2cc(C)c(C)cc2NS(=O)(=O)c2ccccn2)cc1
Reactant: CC1CO1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(COc2cc(C)c(C)cc2N(CC(C)O)S(=O)(=O)c2ccccn2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
680 mg of methyl 4-({4,5-dimethyl-2-[(pyridin-2-ylsulfonyl)amino]phenoxy}methyl)benzoate was dissolved in 6.45 mL of pyridine, and 1.13 mL of 2-methyloxirane was added thereto, followed by stirring at 80° C. overnight in a sealed tube. The reaction liquid was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=100:1 to 99:1) to obtain 466 mg of methyl 4-({2-[(2-hydroxypropyl)(pyridin-2-ylsulfonyl)amino]-4,5-dimethylphenoxy}methyl)benzoate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Br[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCOCC1>[CH2:12]([S:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[NH2:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1cccc(S)c1
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1cccc(SCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
To a stirring suspension of 25 grams (0.20 mole; M.W. 125.19) of 3-aminothiophenol in 200 ml. of 5N NaOH was added dropwise a solution of 34.2 grams of α-bromotoluene (0.20 mole; M.W. 171.04) dissolved in 100 ml. of 1,4-dioxane. The addition required about 30 minutes. The reaction mixture was stirred at room temperature for 2 hours and then extracted with two 500 ml. portions of ethyl ether. The extracts were combined, dried over Na2SO4, and evaporated to yield 41.0 grams of m-benzylthioaniline.
Reaction SMILES: [C:1]1([CH3:24])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([C:15]4[CH:16]=[C:17]([CH2:21][OH:22])[CH:18]=[CH:19][CH:20]=4)=[CH:11][N:10]3[CH:23]=2)=[CH:3][CH:2]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([O:22][CH2:21][C:17]2[CH:16]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]4[N:10]([CH:23]=[C:7]([C:4]5[CH:3]=[CH:2][C:1]([CH3:24])=[CH:6][CH:5]=5)[N:8]=4)[CH:11]=3)[CH:20]=[CH:19][CH:18]=2)=[CH:28][CH:27]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: Cc1ccc(-c2cn3cc(-c4cccc(CO)c4)ccc3n2)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccc(-c2cn3cc(-c4cccc(COc5ccc(Cl)cc5)c4)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.2 %

Procedure:
200 mg of [3-(2-p-tolylimidazo[1,2-a]pyridin-6-yl)phenyl]methanol (Example 3) are dissolved in 20 ml of dry tetrahydrofuran, 123 mg of p-chlorophenol, 193 mg of tributylphosphine and 210 mg of 1,1′-azodicarbonyldipiperidine are added thereto and the mixture is left to stir at ambient temperature for 16 h. The solvent is evaporated off under reduced pressure. The residue is taken up with 10 ml of ethyl acetate, the precipitate is removed, the filtrate is concentrated and the residue is purified by chromatography. The solid obtained is taken up with petroleum ether and the precipitate is recovered by filtration and dried under reduced pressure. 52 mg of compound are obtained. Mp=182-184° C. 1H NMR (DMSO-d6, δ in ppm): 2.32 (s, 3H); 5.17 (s, 2H); 7.06 (d, J=7 Hz, 2H); 7.23 (d, J=7.2 Hz, 2H); 7.32 (d, J=7.3 Hz, 2H); from 7.40 to 7.80 (m, 6H); 7.84 (m, J=7.8 Hz, 2H); 8.32 (s, 1H); 8.86 (m, 1H). M+H=425.
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:24])([F:23])[C:5]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)([OH:10])[C:6]([F:9])([F:8])[F:7].C(N(CC)CC)C.[Cl:32][C:33]1[C:38]([S:39](Cl)(=[O:41])=[O:40])=[CH:37][CH:36]=[C:35]([Cl:43])[N:34]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:32][C:33]1[C:38]([S:39]([N:20]2[CH2:21][CH2:22][N:17]([C:14]3[CH:13]=[CH:12][C:11]([C:5]([OH:10])([C:6]([F:9])([F:8])[F:7])[C:4]([F:3])([F:23])[F:24])=[CH:16][CH:15]=3)[CH2:18][CH2:19]2)(=[O:41])=[O:40])=[CH:37][CH:36]=[C:35]([Cl:43])[N:34]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1Cl
Reactant: OC(c1ccc(N2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(Cl)nc1Cl)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
To a 20-mL vial was added 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol dihydrochloride (0.40 g, 1.0 mmol, Example 91), CH2Cl2 (8 mL), and triethylamine (0.70 mL, 5.0 mmol). To this solution was added 2,6-dichloropyridine-3-sulfonyl chloride (0.30 g, 1.2 mmol, Organic Process Research and Development 2009, 875). After stirring overnight at room temperature, saturated aqueous sodium bicarbonate and CH2Cl2 were added to the reaction mixture. After stirring for 5 min, the solution was transferred onto a phase separation cartridge (Radleys Discovery Technologies, Essex, UK) with the organic phase being collected and passed through a plug of Na2SO4. The collected solution was purified by silica gel chromatography (0 to 70% EtOAc in hexanes) to afford 2-(4-(4-((2,6-dichloropyridin-3-yl)sulfonyl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.43 g) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]([CH3:12])=[CH:11][C:7]=2[C:6]([CH:13]=[O:14])=[CH:5][CH:4]=1.S(=O)(=O)([OH:17])N.Cl([O-])=O.[Na+]>CC(C)=O.O>[CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]([CH3:12])=[CH:11][C:7]=2[C:6]([C:13]([OH:17])=[O:14])=[CH:5][CH:4]=1
Reactant: NS(=O)(=O)O
Reactant: COc1ccc(C=O)c2cc(C)oc12
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(C(=O)O)c2cc(C)oc12
Temperature: 0 °C

Procedure:
To a well stirred solution of 7-methoxy-2-methylbenzo[b]furan-4-carboxaldehyde (from step 3) (4.0 g, 21.05 mmol) in acetone (40.0 mL) was added a solution of sulphamic acid (2.4 g, 25.26 mmol) in water (10.0 mL) followed by addition of a solution of sodium chlorite (2.8 g, 31.57 mmol) at 5-10° C. Ice cold water (250 mL) was added to reaction mixture and the product separated was filtered and dried at 60-70° C. to give intermediate-4 (3.2 g) as white solid.