Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S([N:11]1[C:23]2[CH:22]=[CH:21][C:20]([N:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:26]4[CH:33]=[CH:34][CH:35]=[N:36][C:25]3=4)=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)(C1C=CC(C)=CC=1)(=O)=O.[OH-].[Na+]>C1COCC1.C(O)C.O>[CH:22]1[C:23]2[NH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[CH:19]=[C:20]([N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]3[CH:33]=[CH:34][CH:35]=[N:36][C:25]2=3)[CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)n2c3ccccc3c3cc(-n4c5ccccc5c5cccnc54)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: c1ccc2c(c1)[nH]c1ccc(-n3c4ccccc4c4cccnc43)cc12
Temperature: 25 °C
Yield: 70.9 %

Procedure:
A mixture solution of 9-(9-tosyl-carbazol-3-yl)-pyrido[2,3-b]indole (9.9 g, 20.30 mmol) and NaOH (8.12 g, 203 mmol) in THF (100 mL), ethanol (50 mL) and water (50 mL) was refluxed over weekend. After cooling to room temperature, the white solid was obtained by filtration, and washed successively with water, ethanol, DCM and ethanol to yield the 9-(9H-carbazol-3-yl)-9H-pyrido[2,3-b]indole (4.8 g).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:11]([NH2:13])=O>>[N:1]1[C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4](=[O:6])[NH:13][CH:11]=1
Reactant: NC=O
Reactant: Nc1ncccc1C(=O)O
Product: O=c1[nH]cnc2ncccc12
Yield: 70 %

Procedure:
2-aminonicotinic acid (1.381 g, 10 mM) and formamide (2.70 g, 60 mM) are heated at 165-170° C. for 2 h by means of an oil bath. The reaction mixture is cooled and the resulting solid recrystallized from water to give about 1.030 g of title compound (70% yield). mp 255-8° C.
Reaction SMILES: Cl.[F:2][CH:3]([F:32])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25].[CH2:33]([N:35]([CH2:39][CH3:40])[C:36](Cl)=[O:37])[CH3:34]>>[CH2:33]([N:35]([CH2:39][CH3:40])[C:36]([N:29]1[CH2:28][CH2:27][N:26]([C:24]([C:6]2[N:5]([CH2:4][CH:3]([F:2])[F:32])[C:13]3[C:8]([CH:7]=2)=[CH:9][C:10]([O:14][CH:15]2[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]2)=[CH:11][CH:12]=3)=[O:25])[CH2:31][CH2:30]1)=[O:37])[CH3:34]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCNCC2)n3CC(F)F)CC1
Reactant: CCN(CC)C(=O)Cl
Agent: Cl
Product: CCN(CC)C(=O)N1CCN(C(=O)c2cc3cc(OC4CCN(C(C)C)CC4)ccc3n2CC(F)F)CC1

Procedure:
The title compound was prepared in analogy to example 51, from [1-(2,2-difluoro-ethyl)-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone hydrochloride and N,N-diethylcarbamoyl chloride. Off-white solid. MS (m/z): 534.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#N.[CH2:11](I)[CH3:12].[CH:14]1([NH:20][OH:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[N+:20]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[O-:21]
Reactant: ONC1CCCCC1
Reactant: CCI
Reactant: N#Cc1ccc(O)cc1F
Product: CCOc1ccc(C=[N+]([O-])C2CCCCC2)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in Example 29 using 2-fluoro-4-hydroxybenzonitrile, ethyl iodide and N-cyclohexylhydroxylamine. The title compound was isolated in 58.8% overall yield as slightly yellowish crystals, m.p. 112.7° C. (Rf=0.17 on a silica gel plate using hexanes/ethyl acetate, 4:1, v:v, as the eluant).
Reaction SMILES: [CH:1]1([C@@H:7]([NH:25][CH2:26][C:27]2[C:32]([N+:33]([O-])=O)=[CH:31][N:30]=[C:29]([O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:28]=2)[CH2:8][CH2:9][C:10]([N:12]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:13][C:14]2[NH:18][N:17]=[N:16][N:15]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:43]#[C:44]Br>C(O)C.C1COCC1.[Pd]>[NH2:43][C:44]1[N:25]([C@H:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:8][CH2:9][C:10]([N:12]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:13][C:14]2[NH:18][N:17]=[N:16][N:15]=2)=[O:11])[CH2:26][C:27]2[CH:28]=[C:29]([O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:30]=[CH:31][C:32]=2[N:33]=1
Reactant: N#CBr
Reactant: O=C(CC[C@H](NCc1cc(Oc2ccccc2)ncc1[N+](=O)[O-])C1CCCCC1)N(Cc1nnn[nH]1)C1CCCCC1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: NC1=Nc2cnc(Oc3ccccc3)cc2CN1[C@@H](CCC(=O)N(Cc1nnn[nH]1)C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(S),N-dicyclohexy-4-[(5-nitro-2-phenoxy-pyridin-4-ylmethyl)-amino]-N-(1H-tetrazol-5-ylmethyl)-butyramide (0.75 g, 1.3 mmole) in ethanol (30 mL) and THF (20 mL) was added palladium on carbon (10%, 0.48 g). The reaction mixture was hydrogenated for 1 hour at 20 psi. The reaction mixture was then filtered. Cyanogen bromide (3 M in dichloromethane, 0.65 ml, 1.9 mmole) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the resulting residue was purified by reverse phase HPLC to yield 4-{[4-(2-amino-6-phenoxy-4H-pyrido[3,4-d]pyrimidin-3-yl)-4-(S),N-dicyclohexyl-N-(1H-tetrazol-5-ylmethyl)-butyramide as a white solid, as its corresponding TFA salt.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].[ClH:14].[NH:15]1[CH2:20][CH2:19][CH:18]=[C:17]([C:21]([O:23][CH3:24])=[O:22])[CH2:16]1.Cl>CO.CC(C)=O>[ClH:14].[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:15]2[CH2:20][CH2:19][CH:18]=[C:17]([C:21]([O:23][CH3:24])=[O:22])[CH2:16]2)=[CH:4][CH:3]=1
Reactant: COC(=O)C1=CCCNC1
Reactant: O=Cc1ccc(O)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Product: COC(=O)C1=CCCN(Cc2ccc(O)cc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 65.8 %

Procedure:
4-Hydroxybenzaldehyde (1.34 g.) and sodium cyanoborohydride (0.7 g.) were added to a solution of methyl 1,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride (3.1 g.) in methanol (30 ml.). The mixture was stirred for 3 days at 25° C., evaporated and water (30 ml.) added to the residue followed by concentrated hydrochloric acid to pH 1. This mixture was extracted with ether (2×20 ml.) and the extracts discarded. The aqueous phase was basified to pH 9 with 10% w/v sodium carbonate solution and then extracted with ether (2×30 ml.). The combined extracts were dried (MgSO4) and evaporated. The oil obtained was dissolved in acetone and treated with a slight excess of ethereal hydrogen chloride. The solid which was precipitated was collected by filtration to give methyl 1-(4-hydroxybenzyl)-1,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride (2.05 g.). A portion was recrystallised from methanol and acetone to give pure material of m.p. 212°-214° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([C:7]([OH:9])=O)[N:6]=1.C(Cl)(=O)C(Cl)=O.[N:21]1C(C)=CC=[CH:23][C:22]=1[CH3:28].C(N)(C)C>ClCCl.CN(C)C=O>[Cl:1][C:2]1[S:3][C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([C:7](=[O:9])[NH:21][CH:22]([CH3:28])[CH3:23])[N:6]=1
Reactant: Cc1cccc(C)n1
Reactant: CCOC(=O)c1sc(Cl)nc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(C)N
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(Cl)nc1C(=O)NC(C)C
Temperature: 45 °C
Yield: 97.2 %

Procedure:
To a stirred solution of 2-chloro-5 (ethoxycarbonyl)-1,3-thiazole-4-carboxylic acid (Intermediate 7, 1.0 g, 4.2 mmol) in dry dichloromethane (20 mL) was added oxalyl chloride (0.73 mL, 8.4 mmol) and 2 drops of dry dimethylformamide. The reaction mixture was refluxed to 45° C. for 1½ h. The reaction mixture was cooled to room temperature, and then evaporated to dryness under reduced pressure. The residue was dissolved in dry dichloromethane (20 mL) and cooled to 0° C., then 2,6-lutidine (0.493 mL, 4.237 mmol) was added followed by addition of isopropyl amine (0.360 mL, 4.237 mmol). After completion of the reaction, the reaction mixture was concentrated to dryness and the residue was extracted with ethyl acetate (2×50 mL). The organic layer was washed with 1 N hydrochloric acid (1×50 mL), then dried over anhydrous sodium sulfate and concentrated under vacuum to afford 1.13 g (96%) of the title compound as a thick syrup. NMR: 1.26 (d, 6H), 1.38 (t, 3H), 4.24 (m, 1H), 4.40 (q, 2H), 7.51 (br s, 1H).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:17][NH:18][CH3:19])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(CC)CC.[C:35](Cl)([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36].O>C(Cl)Cl>[Si:1]([O:8][CH:9]1[CH2:10][CH2:11][CH:12]([CH2:15][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:17][N:18]([CH3:19])[C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:36])[CH2:13][CH2:14]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CNC[C@H](CC1CCC(O[Si](C)(C)C(C)(C)C)CC1)NC(=O)OC(C)(C)C
Reactant: O=C(Cl)OCc1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C[C@H](CC1CCC(O[Si](C)(C)C(C)(C)C)CC1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.2 %

Procedure:
To a solution of (S)-tert-butyl 1-(4-(tert-butyldimethylsilyloxy)cyclohexyl)-3-(methylamino)propan-2-ylcarbamate (57 g, 0.142 mol) and Et3N (28.8 g, 0.285 mol) in CH2Cl2 (600 mL) was added CbzCl (26.6 g, 0.156 mol) at −20° C., which was allowed to stir for 1 h at rt. The reaction mixture was treated with water (200 mL) and extracted with CH2Cl2 (3×100 mL). The organic layer was dried over Na2SO4 and evaporated. The residue was separated on a silica column to give the pure isomer (S)-tert-butyl 1-(4-(tert-butyldimethylsilyloxy)cyclohexyl)-3-(N-methyl-N-(benzyloxycarbonyl)amino)propan-2-ylcarbamate (5.5 g) and a fraction with a mixture isomers (33 g, total yield 51%). Mixture isomer: 1H NMR (CDCl3, 400 MHz) δ 0.02 (d, 6H), 0.88 (s, 9H), 1.16-1.29 (m, 5H), 1.41 (d, 9H), 1.60 (m, 51H), 1.83 (m, 1H), 2.95 (t, 3H), 3.00-3.40 (m, 1H), 3.49 (m, 1H), 3.89 (m, 2H), 5.11 (s, 2H), 7.34 (m, 5H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[S:6][C:7]([F:10])=[CH:8][CH:9]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:17]([NH:20][CH2:21][CH:22]=[CH2:23])[CH:18]=[CH2:19]>C(#N)C.C(OCC)(=O)C.O>[CH2:17]([N:20]([CH2:21][CH:22]=[CH2:23])[CH2:2][C:3]([C:5]1[S:6][C:7]([F:10])=[CH:8][CH:9]=1)=[O:4])[CH:18]=[CH2:19]
Reactant: C=CCNCC=C
Reactant: O=C(CBr)c1ccc(F)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C=CCN(CC=C)CC(=O)c1ccc(F)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.4 %

Procedure:
To a stirred solution of 2-bromo-1-(5-fluorothiophen-2-yl)ethanone (13.28 g, 59.53 mmol) in acetonitrile (298 mL) at 0° C. under nitrogen is added potassium carbonate (10.70 g, 77.39 mmol) and diallylamine (9.54 mL, 77.39 mmol). The mixture is allowed to slowly warm to room temperature with stirring over 16 hours then diluted with ethyl acetate (500 mL) and water (200 mL). The phases are separated and the aqueous phase extracted twice with ethyl acetate (100 mL). The combined organic extracts are dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel chromatography eluting with hexanes/ethyl acetate (9:1) to give the title compound (12.45 g, 87%) as a yellow oil. ES/MS (m/e): 240 (M+H).
Reaction SMILES: OC1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=CC=1.S(=O)(=O)(O)O.[CH3:23]C(=C)C>C1(C)C=CC=CC=1>[OH:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[C:8]([CH3:9])([CH3:10])[CH2:5][C:6]2([CH3:7])[CH3:23]
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CC1(C)CC(C)(C)c2cc(O)ccc21

Procedure:
114 g (0.5 mol) of 2,2-bis-(4-hydroxyphenyl)-propane, 6 ml of concentrated sulphuric acid and 90 g (1.6 mol) of isobutylene are stirred in an autoclave for 6 hours at 180° C. After cooling, the reaction product is taken up in 150 ml of toluene and washed with 10 % by weight aqueous sodium hydrogen carbonate solution to remove the catalyst. The toluene solution is then distilled to remove the solvent and the residue of 176.9 g is subsequently subjected to fractional distillation, giving 20.6 g (22 % of the theoretical) of 5-hydroxy-1,1,3,3-tetramethyl indane.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)[C:14]3[CH:13]=[C:12](Cl)[N:11]=[C:10]([F:23])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:24][C:25]1[C:30](B(O)O)=[CH:29][CH:28]=[CH:27][N:26]=1.[CH3:34][C:35]1[CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH:38]=[CH:37][N:36]=1>>[F:23][C:10]1[C:9]2[O:8][C:5]3[C:4]([C@:15]4([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]4)[C:14]=2[CH:13]=[C:12]([C:39]2[CH:38]=[CH:37][N:36]=[C:35]([CH3:34])[CH:40]=2)[N:11]=1)=[CH:3][C:2]([C:30]1[C:25]([F:24])=[N:26][CH:27]=[CH:28][CH:29]=1)=[CH:7][CH:6]=3
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: NC1=N[C@]2(COC1)c1cc(Br)ccc1Oc1c2cc(Cl)nc1F
Reactant: OB(O)c1cccnc1F
Product: Cc1cc(-c2cc3c(c(F)n2)Oc2ccc(-c4cccnc4F)cc2[C@@]32COCC(N)=N2)ccn1

Procedure:
The titled compound was synthesized by steps analogous to those described in method A1 above, but using (Intermediate 17B), 2-fluoropyridin-3-ylboronic acid and 2-methylpyridine-4-boronic acid pinacol ester.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:9]([OH:10])[CH:8]=[CH:7][S:6]1)=[O:4].S(Cl)(Cl)(=O)=O.C(N(CC)CC)C.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[OH:10])=[O:4]
Reactant: COC(=O)C1SC=CC1O
Agent: Cl
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1sccc1O
Reaction time: 2 h
Yield: 82 %

Procedure:
80 parts of 3-hydroxy-dihydrothiophene-2-carboxylic acid methyl ester are dissolved in 250 parts by volume of methylene chloride. 67.5 parts of sulfuryl chloride in 100 parts by volume of methylene chloride are added in the course of one hour at from 0° to 5° C., whilst passing nitrogen into the mixture. The mixture is then stirred for 2 hours at from 0° to 5° C. 50 parts of triethylamine are then added at from 0° to 5° C. and the pH is brought to 7.5 with more triethylamine. The mixture is stirred for 2 hours at 0° C. and is then brought to pH 5 by means of 10 percent strength by weight hydrochloric acid. The mixture is separated into its phases and the organic phase is washed with twice 100 parts by volume of saturated sodium chloride solution, dried, concentrated and distilled. 65 parts (82% of theory) of 3-hydroxy-thiophene-2-carboxylic acid methyl ester of boiling point 68°-73° C./0.4 mbar and melting point 42°-43° C. are obtained.
Reaction SMILES: [C:1]([C:11]([C:14]([C:17]([C:20]([C:23]([C:26]([CH2:29][CH2:30][SH:31])([F:28])[F:27])([F:25])[F:24])([F:22])[F:21])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])([C:3]([F:6])([F:5])[F:4])[F:2].C[O-].[Na+].[CH2:35]1[O:37][CH:36]1[CH2:38][OH:39].Cl>O.CO>[C:1]([C:11]([C:14]([C:17]([C:20]([C:23]([C:26]([CH2:29][CH2:30][S:31][CH2:35][CH:36]([CH2:38][OH:39])[OH:37])([F:27])[F:28])([F:24])[F:25])([F:21])[F:22])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])([C:3]([F:6])([F:5])[F:4])[F:2]
Reactant: OCC1CO1
Reactant: FC(F)(F)C(F)(C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCS
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCC(O)CSCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 500 ml reaction flask is charged with 50 g (0.094 mole) of (CF3)2CF(CF2)6C2H4SH, 5.1 g (0.094 mole) of sodium methoxide and 100 ml of methanol. To this is slowly added glycidol while maintaining the temperature at 25°C with an ice bath. After addition is completed, the reaction mixture is stirred for 3 hours, and then there is added 150 ml of water and enough concentrated hydrochloric acid to neutralize the base. Extraction with 1,1,2-trichloro-1,2,2-trifluoroethane and evaporation of solvent affords 53 g of (CF3)2CF(CF2)6C2H4SCH2CH(OH)CH2OH, m.p. 92°-95°.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]#[N:12])[CH:8]=2)[NH:3]1.[H][H]>CO.O=[Pt]=O>[NH2:12][CH2:11][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2](=[O:1])[CH2:10]2
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CO
Product: NCc1ccc2c(c1)CC(=O)N2

Procedure:
To a solution of 2-Oxo-2,3-dihydro-1H-indole-5-carbonitrile (1.3 g) in methanol (30 ml) was added 10% PtO2 (0.200 g). This was shaken under 44 psi hydrogen over night. The catalyst was removed by filtration, and the mixture was dried over Na2SO4. The solution was concentrated to give a yellow solid, (1.1 g). MW 162; MS (m/e) 162 (M+).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:26][C@@H:25]2[C@:20]([CH3:31])([CH2:21][CH2:22][C@H:23]([O:27][CH2:28][CH2:29][OH:30])[CH2:24]2)[C@@H:19]2[C@@H:3]1[C@H:4]1[C@:16]([CH3:33])([C@@H:17]([OH:32])[CH2:18]2)[C@@H:7]([C@H:8]([CH3:15])[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:6][CH2:5]1.[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[OH:1][C@@H:2]1[CH2:26][C@H:25]2[C@:20]([CH3:31])([CH2:21][CH2:22][C@H:23]([O:27][CH2:28][CH2:29][O:30][S:40]([C:37]3[CH:38]=[CH:39][C:34]([CH3:44])=[CH:35][CH:36]=3)(=[O:42])=[O:41])[CH2:24]2)[C@@H:19]2[C@@H:3]1[C@H:4]1[C@:16]([CH3:33])([C@@H:17]([OH:32])[CH2:18]2)[C@@H:7]([C@H:8]([CH3:15])[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:6][CH2:5]1
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@H]4C[C@@H](OCCO)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@@H](OCCOS(=O)(=O)c5ccc(C)cc5)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reaction time: 8 h

Procedure:
The compound of Example 1B (1.50 g, 3.2 mmol) was dissolved in 15 ml of chloroform and 15 ml of pyridine; p-toluenesulfonyl chloride (920 mg, 4.83 mmol) was added, and the mixture was stirred overnight. Chloroform (250 ml) was added, the resultant solution was washed with 5% HCI solution and sat. Na2SO4. After solvent removal in vacuo, the crude product was purified by column chromatography on silica gel (40%->60% ethyl acetate/hexanes. The yield of the title compound was 1.40 g (71%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[Cl:27])[C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]#[N:23])=[CH:17][CH:16]=2)=[CH:12][CH:13]=1)=[O:6].[OH2:28].[NH2:29]O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[Cl:27])[C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22](=[NH:29])[NH:23][OH:28])=[CH:17][CH:16]=2)=[CH:12][CH:13]=1)=[O:6]
Reactant: O
Reactant: N#CCc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cn2)cc1
Reactant: NO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N=C(Cc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cn2)cc1)NO

Procedure:
To a solution of 3,4-dichloro-N-[6-(4-cyanomethylphenoxy)pyridin-3-yl]benzamide (700 mg, 1.76 mmol) in ethanol (30 mL) were added water (2 mL), hydroxylamine (420 mg, 12.71 mmol) and potassium carbonate (1.76 g, 12.73 mmol). Under argon, the resulting solution was stirred under reflux for 4 hours. The resulting reaction solution was concentrated under reduced pressure. To the residue was added water, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=10:1), to thereby yield 510 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[C:29]([NH:30][S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])=[CH:28][CH:27]=[C:26]([F:37])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[CH:15]=[C:14](I)[N:13]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:10]2=[N:11][CH:12]=1)=[O:5].[CH3:38][N:39]1[C:47]2[C:42](=[CH:43][C:44](B(O)O)=[CH:45][CH:46]=2)[CH:41]=[CH:40]1.C([O-])([O-])=O.[K+].[K+].CC#N.O>CCOC(C)=O.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>[F:1][C:2]1[C:29]([NH:30][S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])=[CH:28][CH:27]=[C:26]([F:37])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[CH:15]=[C:14]([C:44]3[CH:43]=[C:42]4[C:47](=[CH:46][CH:45]=3)[N:39]([CH3:38])[CH:40]=[CH:41]4)[N:13]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:10]2=[N:11][CH:12]=1)=[O:5]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3c(c2)cc(I)n3S(=O)(=O)c2ccccc2)c1F
Reactant: Cn1ccc2cc(B(O)O)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3c(c2)cc(-c2ccc4c(ccn4C)c2)n3S(=O)(=O)c2ccccc2)c1F
Temperature: 160 °C
Yield: 70 %

Procedure:
A mixture of 2,6-difluoro-N-(2-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (27 mg, 40 mmol, 1.0 eq.), 1-methyl-1H-indol-5-ylboronic acid (1.5 eq.), K2CO3 (20 eq.) and Pd(PPh3)4 (0.05 eq.) were taken up in 4:1 MeCN/water (0.7 mL) and heated to 160° C. for 15 minutes under microwave irradiation. The mixture was diluted with 1:1 EtOAc/water (6 mL), filtered through GF/F paper, and the layers were separated. The organic layer was dried over MgSO4, filtered, and concentrated to afford 2,6-difluoro-N-(2-(1-methyl-1H-indol-5-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (19 mg, 70%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@H:13]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14]2=[O:19])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[N:20]1([C:24]([C:26]2[CH:31]=[CH:30][C:29](F)=[C:28]([Cl:33])[CH:27]=2)=[O:25])[CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+].C[Si](C=[N+]=[N-])(C)C>CC(N(C)C)=O.C(O)(=O)C.CO>[N:20]1([C:24]([C:26]2[CH:31]=[CH:30][C:29]([O:1][C:2]3[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@H:13]4[CH2:17][CH2:16][N:15]([CH3:18])[C:14]4=[O:19])[CH:11]=3)[C:5]([O:7][CH3:8])=[O:6])=[C:28]([Cl:33])[CH:27]=2)=[O:25])[CH2:23][CH2:22][CH2:21]1
Reactant: COC(=O)c1cc(O)cc(O[C@H]2CCN(C)C2=O)c1
Reactant: O=C(c1ccc(F)c(Cl)c1)N1CCC1
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)N(C)C
Solvent: CC(=O)O
Product: COC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)cc2Cl)cc(O[C@H]2CCN(C)C2=O)c1
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A mixture of methyl 3-hydroxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-benzoate (Intermediate 8) (265 mg, 1 mmol), azetidin-1-yl-(3-chloro-4-fluoro-phenyl)methanone (CAS no. 863454-79-9) (320 mg, 1.5 mmol) and potassium carbonate (276 mg, 2.0 mmol) in DMA (10 mL) was stirred at 120° C. for 16 hours. The solution was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL), washed with water (3×20 mL), dried (MgSO4), filtered and the solvent removed under reduced pressure. The combined aqueous extracts were acidified with 2N hydrochloric acid, extracted with a mixture of ethyl acetate and DCM (1:1, 3×20 mL), washed with brine, dried (MgSO4), filtered and the solvent removed under reduced pressure. The residue from this was dissolved in THF (2 mL) and methanol (1 mL) and treated with 2M (trimethylsilyl)diazomethane (0.240 mL, 0.48 mmol) and stirred for 30 minutes. The solution was treated with acetic acid (1 drop), evaporated under reduced pressure. This residue was combined with that from the initial ethyl acetate extraction and purified by flash chromatography on silica eluting with 20-100% ethyl acetate in isohexane to afford the product (380 mg, 83%). m/z 459 (M+H)+