Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[CH:8][N:9]=[CH:10][CH:11]=2)[O:6][CH2:5]1.ClC1C=CC=C(C(OO)=[O:21])C=1>C(Cl)Cl>[CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[CH:8][N+:9]([O-:21])=[CH:10][CH:11]=2)[O:6][CH2:5]1
Reactant: CON=C1COc2cnccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CON=C1COc2c[n+]([O-])ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of furo[2,3-c]pyridin-3(2H)-one O-methyl oxime (5.35 mmol) (A.2.4.4) in 15 mL DCM was added 3-chloroperbenzoic acid (16.0 mmol). The mixture was stirred at RT overnight, diluted with 20 mL DCM and extracted with sat. aq. NaHCO3 solution (2×), with sat. aq. Na2S2O3 solution (2×) and brine. The combined organic layers were dried over MgSO4 and concentrated in vacuo to give the desired product as yellow solid;
Reaction SMILES: C(OC([N:8]1[C:12]2=[C:13](Cl)[N:14]=[CH:15][C:16]([C:17]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])=[C:11]2[C:10]([CH3:26])=[CH:9]1)=O)(C)(C)C.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32]>C(OCC)C>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([NH:32][C:13]2[N:14]=[CH:15][C:16]([C:17]([N:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)=[O:18])=[C:11]3[C:10]([CH3:26])=[CH:9][NH:8][C:12]=23)[CH:33]=[CH:34][CH:35]=1
Reactant: Cc1cn(C(=O)OC(C)(C)C)c2c(Cl)ncc(C(=O)N3CCCCC3)c12
Reactant: COc1cccc(N)c1
Solvent: CCOCC
Product: COc1cccc(Nc2ncc(C(=O)N3CCCCC3)c3c(C)c[nH]c23)c1

Procedure:
Prepared in a similar manner to Example 4(d) from 7-chloro-3-methyl-4-(1-piperidin-1-yl-methanoyl)-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester (90 mg) and using 3-methoxyaniline (54 ul) instead of 3-bromoaniline and heating for 15 rather than 30 minutes. Isolated by MDAP rather than trituration with diethyl ether to give 1-[7-(3-methoxy-phenylamino)-3-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl]-1-piperidin-1-yl-methanone (65 mg).
Reaction SMILES: [ClH:1].Cl.[CH:3]([N:16]1[C@@H:21](C)[CH2:20][N:19]([CH2:23][C:24]([OH:26])=[O:25])[C@H:18]([CH3:27])[CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.Cl.C(N1[C@H](C)CN(CC(O)=O)[C@@H](C)C1)(C1C=CC=CC=1)C1C=CC=CC=1>>[ClH:1].[ClH:1].[CH:3]([N:16]1[CH2:21][CH2:20][N:19]([CH2:23][C:24]([OH:26])=[O:25])[C@H:18]([CH3:27])[CH2:17]1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C[C@@H]1CN(C(c2ccccc2)c2ccccc2)[C@@H](C)CN1CC(=O)O
Agent: C[C@@H]1CN(CC(=O)O)[C@@H](C)CN1C(c1ccccc1)c1ccccc1
Agent: Cl
Product: C[C@@H]1CN(C(c2ccccc2)c2ccccc2)CCN1CC(=O)O

Procedure:
a mixture of 2-((2R,5S)-4-benzhydryl-2,5-dimethylpiperazin-1-yl)acetic acid dihydrochloride and 2-((2S,5R)-4-benzhydryl-2,5-dimethylpiperazin-1-yl)acetic acid dihydrochloride MS (ESI, pos. ion) m/z: 339 (M+1).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:18]([F:19])=[C:17]([O:20][CH3:21])[C:12]([C:13]([O:15]C)=[O:14])=[C:11]([O:22][CH3:23])[C:10]=1[F:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl>C(O)C>[CH2:1]([NH:8][C:9]1[C:10]([F:24])=[C:11]([O:22][CH3:23])[C:12]([C:13]([OH:15])=[O:14])=[C:17]([O:20][CH3:21])[C:18]=1[F:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1c(OC)c(F)c(NCc2ccccc2)c(F)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1c(F)c(NCc2ccccc2)c(F)c(OC)c1C(=O)O
Temperature: 10 °C
Reaction time: 1.5 h
Yield: 84.3 %

Procedure:
Methyl 4-(benzylamino)-3,5-difluoro-2,6-dimethoxybenzoate (24.0 g) was dissolved in ethanol (75 mL) and the solution stirred and cooled to 10° C. under a nitrogen atmosphere. Sodium hydroxide, 50% aqueous solution (12.5 g, 156 mmol) was added dropwise over 10 minutes at 10° C.–15° C. followed by ethanol (10 mL). The solution was stirred at 15° C.–25° C. A thick precipitate formed. Stirring was continued for a total of 2 hours at 15° C.–25° C. The mixture was heated to 50° C.–55° C. where it was held for 1.5 hours. The mixture was allowed to cool to room temperature and held overnight. Water (100 mL) was added and the resulting solution cooled in an ice bath and acidified with 37% HCl (13.5 mL) to pH 2. The mixture was extracted with toluene (100 mL) and methyl tert-butyl ether (100 mL) and the organic extract washed with water (10 mL) and concentrated to an oil. This was triturated with toluene (20 mL) to give crystals which were collected and vacuum dried at 45° C. to give 4-(benzylamino)-3,5-difluoro-2,6-dimethoxybenzoic acid (19.4 g, 60 mmol): mp: 85° C.–86° C. (decomposition with gas evolution).
Reaction SMILES: [H-].[Na+].[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([OH:30])[C:26]([O:28][CH3:29])=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:32]1[N:37]=[CH:36][N:35]=[C:34]2[N:38]([C:41]3[CH:42]=[C:43]([CH:46]=[CH:47][C:48]=3[CH3:49])[C:44]#[N:45])[N:39]=[CH:40][C:33]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O.CCOC(C)=O>[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([O:30][C:32]1[N:37]=[CH:36][N:35]=[C:34]2[N:38]([C:41]3[CH:42]=[C:43]([C:44]#[N:45])[CH:46]=[CH:47][C:48]=3[CH3:49])[N:39]=[CH:40][C:33]=12)[C:26]([O:28][CH3:29])=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1ccc(C#N)cc1-n1ncc2c(Cl)ncnc21
Reactant: COC(=O)[C@@H](O)COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@H](COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ncnc2c1cnn2-c1cc(C#N)ccc1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 26.4 %

Procedure:
Sodium hydride (108 mg, 2.69 mmol) was added to (S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxypropanoate (795 mg, 1.97 mmol) (Intermediate AB3) in anhydrous THF (20 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 3-(4-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-4-methylbenzonitrile (Intermediate AM2) (484 mg, 1.79 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was neutralised with 1M citric acid and the reaction mixture diluted with water (10 mL) and EtOAc (30 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×30 mL). The combined organics were washed with saturated brine (75 mL),dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 30 to 50% Et2O in isohexane to afford the product (300 mg, 26.3%). m/z (ES+) (M+H)+=636.5; HPLC tR=3.65 min.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:11]1[C:12]2[CH:19]=[CH:18][NH:17][C:13]=2[N:14]=[CH:15][N:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]1([C:11]2[C:12]3[CH:19]=[CH:18][NH:17][C:13]=3[N:14]=[CH:15][N:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: c1ccc(-c2ncnc3[nH]ccc23)cc1
Temperature: 150 °C

Procedure:
A mixture of phenylboronic acid (1.59 g, 13.0 mmol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.00 g, 6.51 mmol), sodium carbonate (1.38 g, 13.0 mmol), PdCl2(dppf) (113 mg, 0.138 mmol) in dioxane (20 mL) and water (5 mL) was purged with argon gas for 10 minutes and then heated by microwave irradiation at 150° C. for 1 hour. Brine was added to the reaction mixture and the organic layer was separated. The aqueous layer was then extracted with ethyl acetate (×3) and the organic layers were combined and dried with sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was then purified by silica chromatography eluting with 10-80% ethyl acetatehexane to afford 4-phenyl-7H-pyrrolo[2,3-d]pyrimidine as a light brown solid. LRMS (ESI) calc'd for C12H9N3 [M]+: 195, found 195.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:12][N+:13]2[CH:18]=[CH:17][C:16]([C:19]3[S:20][CH2:21][C:22](=[O:25])[NH:23][N:24]=3)=[CH:15][CH:14]=2)=[O:11])=[CH:6][CH:5]=1.[BH4-].[Na+]>CO.O>[OH:11][CH:10]([C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:9][CH:8]=1)[CH2:12][N:13]1[CH2:18][CH2:17][C:16]([C:19]2[S:20][CH2:21][C:22](=[O:25])[NH:23][N:24]=2)=[CH:15][CH2:14]1
Reactant: COc1ccc(C(=O)C[n+]2ccc(C3=NNC(=O)CS3)cc2)cc1
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(C(O)CN2CC=C(C3=NNC(=O)CS3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
1-[(4-Methoxyphenyl)carbonylmethyl]-4-(4H,6H-1,3,4-thiadiazin-5-one-2-yl)pyridinium bromide (3.84 g, 9.09 mmol) was dissolved in methanol-water (1:1 v/v %) (50 ml), gradually added with sodium borohydride (3.43 g, 90.9 mmol) under ice cooling and then stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was added with dichloromethane, then washed with water and dried over anhydrous magnesium sulfate. The solvent was removed to obtain the titled compound (2.44 g) as white crystals.
Reaction SMILES: N.[Li].[C:3]([O:7][C:8]([N:10]1[CH2:14][C@H:13]([O:15]CC2C=CC=CC=2)[CH2:12][C@H:11]1[CH2:23][CH3:24])=[O:9])([CH3:6])([CH3:5])[CH3:4].C(O)(C)(C)C>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:14][C@H:13]([OH:15])[CH2:12][C@H:11]1[CH2:23][CH3:24])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC[C@@H]1C[C@@H](OCc2ccccc2)CN1C(=O)OC(C)(C)C
Agent: N
Agent: [Li]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CC[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
In a flask purged with ammonia gas, about 150 mL of liquid ammonia is collected with ammonia condenser at −78° C. To the liquid ammonia is added portion wise lithium metal (116 mmol; 805 mg) at the same temperature. To the deep blue solution is added a solution of (2R,4R)-4-benzyloxy-2-ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (29.1 mmol; 8.90 g) and tert-butanol (58.2 mmol; 4.31 g) in THF (30 mL). After stirring for 2 hours, the reaction mixture is quenched with MeOH, and then warmed to ambient temperature. The mixture is diluted with water, then aqueous 1M HCl is added to reach pH 8-9. The product is extracted three times with EtOAc. The combined organic layer is washed with brine, dried over MgSO4, filtered, concentrated under reduced pressure to give (2R,4R)-4-hydroxy-2-ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (6.25 g, 99.8%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=3[O:24][CH2:25][CH3:26])[CH:11]=[C:10]([C:27]([F:30])([F:29])[F:28])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:31]([NH:35][S:36]([C:39]1[S:40][C:41](B2OC(C)(C)C(C)(C)O2)=[CH:42][CH:43]=1)(=[O:38])=[O:37])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([NH:35][S:36]([C:39]1[S:40][C:41]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:9]=[C:10]([C:27]([F:28])([F:29])[F:30])[CH:11]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][C:15]=4[O:24][CH2:25][CH3:26])[N:13]=3)[CH:3]=2)=[CH:42][CH:43]=1)(=[O:37])=[O:38])([CH3:34])([CH3:32])[CH3:33]
Reactant: CCOc1cc(C(F)(F)F)ccc1-c1cc(C(F)(F)F)nc(-c2cccc(Br)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Product: CCOc1cc(C(F)(F)F)ccc1-c1cc(C(F)(F)F)nc(-c2cccc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1

Procedure:
N-tert-Butyl-5-{3-[6-(2-ethoxy-4-trifluoromethyl-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide was prepared from 2-(3-bromophenyl)-4-(2-ethoxy-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example E.108) (0.185 g, 0.41 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-sulfonamide (example F.1) (0.17 g, 0.49 mmol) according to the general procedure VI. Obtained as an off-white foam (0.18 g), which was subsequently deprotected.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].Cl[C:14]([O:17]C(Cl)=O)(Cl)Cl>O1CCOCC1>[N:1]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12])=[C:14]=[O:17]
Reactant: COC(=O)c1ccc(N)c(C)c1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc(N=C=O)c(C)c1
Reaction time: 5 h

Procedure:
1.50 g (9.08 mmol) methyl 4-amino-3-methyl-benzoate are dissolved in 250 ml dioxane combined with 1.3 ml (10.7 mmol) trichloromethyl-chloroformate and refluxed for 5. 5 hours with stirring. Then the mixture is evaporated down i. vac. and the residue is further reacted without any more purification.
Reaction SMILES: Br[CH:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4].[Na].[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCOCC>CN(C=O)C>[CH2:9]([O:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4])=[CH:21][CH:22]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)C(C)Br
Agent: [Na]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1ccc(OCc2ccccc2)cc1
Temperature: 80 °C

Procedure:
A 42 g (0.25 mole) portion of methyl 2-bromopropionate was added to 0.25 mole of the sodium salt of p-benzyloxyphenol (prepared from 13.5 g sodium methoxide and 50 g p-benzyloxyphenoxy) in 70 cc of DMF. The reaction mixture was heated at approximately 80° C. for 14.5 hours. The cooled reaction mixture was then poured into 1 liter ice-water. The product was isolated by ether extraction and was crystallized from methanol to give 45.2 g methyl 2-(4-benzyloxyphenoxy)propanoate, m.p. 38°-42°.
Reaction SMILES: C1C2C(C(O)=O)C3C(=CC=CC=3)C=2C=CC=1.Cl.CO.[Na].ClCC(N)=O.[CH3:26][O:27][C:28]([C:30]1(O)[C:42]2[CH:41]=[C:40](F)[CH:39]=[CH:38][C:37]=2[C:36]2[C:31]1=[CH:32][C:33](F)=[CH:34][CH:35]=2)=[O:29].[OH-].[Na+]>CO>[CH3:26][O:27][C:28]([CH:30]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=2[C:37]2[C:42]1=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:29]
Reactant: COC(=O)C1(O)c2cc(F)ccc2-c2ccc(F)cc21
Agent: Cl
Agent: NC(=O)CCl
Agent: O=C(O)C1c2ccccc2-c2ccccc21
Solvent: CO
Product: COC(=O)C1c2ccccc2-c2ccccc21
Reaction time: 0.25 h

Procedure:
9H-fluoren-9-carboxylic acid methyl ester (19), which was prepared by refluxing 9H-fluoren-9-carboxylic acid (Aldrich Chemical, Inc.) in HCl/MeOH, (10.0 g, 44.6 mmol) was added to a solution of sodium (1.2 eq, 53.5 mmol, 1.23 g) in 100 mL methanol. After 15 min., 2-chloroacetamide (1.1 eq, 49.1 mmol, 4.59 g) was added and the mixture was allowed to stir at room temperature under nitrogen for two (2) days. The reaction mixture was poured into 400 mL of cold 2.5% w/v aqueous sodium hydroxide and the insoluble material was removed by filtration. The filtrate was chilled and acidified with concentrated hydrochloric acid to precipitate the spiro-succinimide which was collected and air dried to provide 6.7 g (60%). Recrystallization from methanol gave purified (20), 4.28 g (39%). m.p. 237°-239° C. Calc. %C 77.09, %H 4.45, %N 5.62: meas. %C 77.17, %H 4.55, %N 5.58.
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[CH:10]=[CH:11][C:12]([F:21])=[C:13]([CH:20]=1)[CH2:14][NH:15][S:16]([CH3:19])(=[O:18])=[O:17].[CH3:22][Si:23]([C:26]#[CH:27])([CH3:25])[CH3:24]>O1CCCC1.[Br-].[Zn+2].[Br-].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:21][C:12]1[CH:11]=[CH:10][C:9]([C:27]#[C:26][Si:23]([CH3:25])([CH3:24])[CH3:22])=[CH:20][C:13]=1[CH2:14][NH:15][S:16]([CH3:19])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)NCc1cc(Br)ccc1F
Reactant: C#C[Si](C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(F)c(CNS(C)(=O)=O)c1
Temperature: 60 °C
Yield: 73.5 %

Procedure:
Dissolve zinc (II) bromide (313 mg, 1.20 mmol) in tetrahydrofuran (2.5 mL) and treat with triethylamine (0.64 mL, 4.80 mmol). After 4 min add N-(5-bromo-2-fluorobenzyl)methanesulfonamide (282 mg, 1.00 mmol), (prepared as described in PREPARATION 35), trimethylsilylacetylene (0.30 mL, 2.12 mmol), and tetrakis(triphenylphosphine)palladium (0) (58 mg, 0.050 mmol) to the reddish solution. Heat to 60° C. in a sealed tube overnight, cool to room temperature and filter through diatomaceous earth with ethyl acetate. Concentrate the filtrate and purify the residue by silica gel chromatography, eluting with 75:25 hexanes:ethyl acetate, to give the title compound as a white crystalline solid (220 mg, 74%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[CH:12]=[C:13]([CH:18]=[C:19]([NH:21][C:22]3[CH:27]=[N:26][CH:25]=[CH:24][N:23]=3)[N:20]=2)[C:14](OC)=[O:15])[CH3:9])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[CH:12]=[C:13]([CH2:14][OH:15])[CH:18]=[C:19]([NH:21][C:22]3[CH:27]=[N:26][CH:25]=[CH:24][N:23]=3)[N:20]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(Nc2cnccn2)nc(N[C@@H](C)c2ccc(F)cc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](Nc1cc(CO)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 65 %

Procedure:
100 mg of methyl (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinate was dissolved in 1 ml of tetrahydrofuran, 20 mg of lithium aluminum hydride was added by small portions, and the mixture was stirred at room temperature for 6 hours. The reaction solution was diluted with tetrahydrofuran, and then cooled to 0° C., and 25 μl of water, 25 μl of 2N sodium hydroxide aqueous solution, and further 75 μl of water were added, and the reaction mixture was dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 60 mg of the objective compound as pale yellow powder.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)([O-:3])=[O:2].[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][O:13][C:10]1[CH:9]=[CH:8][C:7]([O:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=1
Reactant: O=[N+]([O-])c1ccccc1Oc1ccc(O)cc1
Reactant: Fc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1Oc1ccc(OCc2ccccc2F)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 95.8 %

Procedure:
To a solution of 4-(2-nitrophenoxy)phenol (462 mg, 2.0 mmol) in N,N-dimethylformamide (20 ml) were added 2-fluorobenzyl bromide (400 mg, 2.1 mmol), potassium iodide (40 mg, 0.24 mmol) and potassium carbonate (300 mg, 2.2 mmol), followed by stirring at 50° C. for 4 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution and dried. The solvent was evaporated under reduced pressure to give 1-[4-(2-fluorobenzyloxy)phenoxy]-2-nitrobenzene (0.65 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18]1[CH:26]=O>>[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18]1[CH:26]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[NH:11][C:10]1=[O:16]
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Reactant: O=Cc1cc2ccccc2[nH]1
Product: O=C1Nc2cccc(-c3ccncc3)c2C1=Cc1cc2ccccc2[nH]1

Procedure:
4-Pyridin-4-yl-1,3-dihydroindol-2-one was condensed with 1H-indole-2-carbaldehyde to give the title compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH2:3][CH2:4][OH:5].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>C(Cl)Cl.N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:5][CH2:4][CH2:3][C:2]([F:7])([F:6])[F:1])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCC(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 68 %

Procedure:
To a solution of 3,3,3-trifluoropropan-1-ol (5.0 g, 43.8 mmol) in CH2Cl2 (25 mL) and pyridine (25 mL) was added 4-(dimethylamino)pyridine (0.27 g, 2.2 mmol) followed by p-toluenesulfonyl chloride (8.4 g, 43.8 mmol). The mixture was allowed to stir at ambient temperature for 72 h then was quenched with 5% aqueous HCl (20 mL). The layers were separated and the aqueous phase was extracted with CH2Cl2 (3×7 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 75% hexanes in EtOAc) afforded the title compound (8.0 g, 29.8 mmol, 68% yield). MS (DCI/NH3) m/z 286 (M+NH4)+.
Reaction SMILES: Cl.CN.C([O-])(=O)C.[Na+].[C:9]([BH3-])#[N:10].[Na+].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>CO>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([NH:10][CH3:9])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: CN
Agent: Cl
Solvent: CO
Product: CNC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Powdered molecular seives (3 Å, 5.2 g), methylamine hydrochloride (16.96 g, 251 mmol), anhydrous sodium acetate (41.21 g, 502 mmol), and 95% sodium cyanoborohydride (3.99 g, 60 mmol) were added sequentially to a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester in methanol (400 mL) at 0° C., and the mixture was allowed to warm to 25° C. over several hours. After 18 hours at 25°C., the reaction mixture was filtered thru Celite®, the solids washed with methanol and ethyl acetate, and the filtrate concentrated. The residue was dissolved in ethyl acetate and the resulting solution washed twice with 2N NaOH, once with brine, dried and concentrated to an oil (12.79 g, 119%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH2:36][C@@H:37]5CCCO5)[CH:31]=[C:30]([F:42])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].O1CC[CH2:48][C@H:47]1[CH2:51]N>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH2:36][CH2:37][CH:47]([CH3:51])[CH3:48])[CH:31]=[C:30]([F:42])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNC[C@@H]5CCCO5)c4)cc23)CC1
Reactant: NC[C@@H]1CCCO1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNCCC(C)C)c4)cc23)CC1
Yield: 49.4 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate, substituting 3-methyl-1-butanamine (45 mg, 0.525 mmol) for 1-[(2S)-tetrahydro-2-furanyl]methanamine to afford 27.6 mg of the title compound (49.4%).