Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][CH:2]([CH2:6][C:7]([OH:9])=[O:8])[C:3]([OH:5])=[O:4].C(OC([NH:17][C:18](=[NH:48])[C:19]1[S:23][C:22]([S:24][CH3:25])=[C:21]([S:26]([C:29]2[CH:30]=[C:31]([C:35]3[C:40]([CH3:41])=[CH:39][CH:38]=[CH:37][C:36]=3[CH2:42]OS(C)(=O)=O)[CH:32]=[CH:33][CH:34]=2)(=[O:28])=[O:27])[CH:20]=1)=O)(C)(C)C.C(N(CC)CC)C.C(Cl)(Cl)Cl.[F:60][C:61]([F:66])([F:65])[C:62]([OH:64])=[O:63]>ClCCl>[F:60][C:61]([F:66])([F:65])[C:62]([OH:64])=[O:63].[C:18]([C:19]1[S:23][C:22]([S:24][CH3:25])=[C:21]([S:26]([C:29]2[CH:30]=[C:31]([C:35]3[C:40]([CH3:41])=[CH:39][CH:38]=[CH:37][C:36]=3[CH2:42][S:1][CH:2]([CH2:6][C:7]([OH:9])=[O:8])[C:3]([OH:5])=[O:4])[CH:32]=[CH:33][CH:34]=2)(=[O:27])=[O:28])[CH:20]=1)(=[NH:17])[NH2:48]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2COS(C)(=O)=O)c1
Reactant: O=C(O)CC(S)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2CSC(CC(=O)O)C(=O)O)c1
Reaction time: 2 h
Yield: 42 %

Procedure:
2-Mercapto-succinic acid (0.004 g, 0.028 mmol) was added to a solution of methanesulfonic acid 3′-[5-(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-ylmethyl ester (0.017 g, 0.028 mmol) [example 214, step a] and triethylamine (0.009 g, 0.084 mmol) in dichloromethane [0.5 mL] at 40° C., stirred for 2 hours and then evaporated. The crude reaction was dissolved in a solution of dichloromethane/trifluoroacetic acid (1/1) [2 mL] and stirred for 1 hour. The reaction mixture was evaporated and purified via reverse-phase HPLC [acetonitrile/water (0.01% TFA)] to give the title compound (0.005 g, 42%) as a solid. 1H-NMR (MeOD): δ 8.31 (s, 1H), 8.06 (t, 1H, J=8.0 Hz), 7.83 (d, 1H, J=16.8 Hz), 7.70 (q, 1H, J=6.8 Hz), 7.57 (t, 1H, J=7.2 Hz), 7.29–7.21 (m, 3H), 3.60–3.48 (m, 1H), 3.54 (s, 3H), 3.37–3.34 (m, 1H), 2.70 (s, 3H), 2.68–2.57 (m, 1H), 2.31–2.14 (m, 1H), 1.97 (s, 3H). ESI-MS (m/z): Calcd. for C24H24N2O6S4: 564.05; found: 565.1.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH3:15])[C:10](=[O:16])[CH2:9]1)=O)(C)(C)C.[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20]>ClCCl>[CH2:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C:10]1=[O:16])[CH3:15].[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20]
Reactant: CCN1CCN(C(=O)OC(C)(C)C)CC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN1CCNCC1=O
Reaction time: 2 h

Procedure:
1-tert-Butoxycarbonyl-4-ethyl-3-oxopiperazine (5.9 g) was dissolved in dichloromethane (100 ml), cooled in an ice-bath, and trifluoroacetic acid (145 ml) added. The mixture was stirred at the same temperature for 2 hours. Solvent was evaporated to yield 1-ethyl-2-oxopiperazine product as a salt with 3 moles of trifluoroacetic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][N:5]([CH3:18])[C:6]=1[C:7]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=1[O:16][CH3:17].[OH-].[Na+].CCOC(C)=O>CCO>[F:1][C:2]1[CH:3]=[N:4][N:5]([CH3:18])[C:6]=1[C:7]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:8]=1[O:16][CH3:17]
Reactant: COc1ccc([N+](=O)[O-])cc1-c1c(F)cnn1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(N)cc1-c1c(F)cnn1C
Temperature: 50 °C
Yield: 47 %

Procedure:
4-Fluoro-5-(2-methoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole (205 mg, 0.817 mmol) in EtOH (25 mL) was treated with Sn(II) chloride dihydrate (626.3 mg, 2.45 mmol) and heated to 50° C. for 12 hours. The reaction was allowed to cool to room temperature and 10% NaOH (100 ml) was added. EtOAc (50 ml) was added and the organic layer was separated. The aqueous layer was extracted with EtOAc (2×50 mL) and the organics combined, dried over Na2SO4, filtered, and the solvent removed under reduced pressure. The residue was dissolved in DMSO (5 ml), and purified by preparative HPLC to afford 85 mg (47%) of 3-(4-fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine as a light brown oil. LCMS m/z (%)=222 (M+H, 100). 1H NMR (400 MHz, CDCl3) δ: 7.38 (d, JH,F=4.8 Hz, 1H), 6.86 (d, J=8.8 Hz, 1H), 6.79 (dd, J1=8.8 Hz, J2=2.8 Hz, 1H), 6.64 (d, J=2.8 Hz, 1H), 3.75 (s, 3H), 3.69 (s, 3H), 3.21 (s, 2H). 19F NMR (376 MHz, CDCl3) δ: −175.50 (d, JH,F=5.3 Hz, 1F).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH3:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[CH3:28])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: Cc1ccccc1B(O)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(-c2ccccc2C)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), 2-methylphenylboronic acid (1.0 g), triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (1.0 g) in methylene chloride (15 mL) was added copper(II) acetate (1.0 g), and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate. The insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.12 g, 10%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7](=[O:10])[CH2:8]Br)=[CH:5][CH:4]=1.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.[K]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7](=[O:10])[CH2:8][N:17]2[C:13](=[O:23])[C:14]3[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:16]2=[O:18])=[CH:5][CH:4]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-methoxyphenacyl bromide (5.78 g, 25.23 mmol) in DMF (20 mL) was added potassium phthalimide (5.00 g, 26.99 mmol) and the reaction stirred at rt for 18 h. The reaction mixture was partitioned between dichloromethane (200 mL) and water (100 mL). The layers were separated and the aqueous layer extracted with dichloromethane (3×50 mL). The combined organics were washed with sodium hydroxide (2M, 50 mL), water (50 mL) and brine (50 mL) and dried (MgSO4). Filtration, then concentration in vacuo gave an off white solid. Trituration with diethyl ether followed by collection by filtration gave the title compound as a white solid. δH (CDCl3): 3.86 (3H, s), 5.15 (2H, s), 7.09 (2H, d), 7.81–8.01 (4H, m), 8.05 (2H, d).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([CH:19]([CH3:21])[CH3:20])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[F:22][C:23]([F:37])([F:36])[C:24]1([C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)[N:26]=[N:25]1>>[CH:19]([N:12]1[C:13]2[N:14]=[CH:15][N:16]=[CH:17][C:18]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:31](=[O:32])[C:30]3[CH:34]=[CH:35][C:27]([C:24]4([C:23]([F:37])([F:36])[F:22])[N:26]=[N:25]4)=[CH:28][CH:29]=3)[CH:7]=[N:6][CH:5]=2)=[O:9])=[CH:11]1)([CH3:21])[CH3:20]
Reactant: O=C(O)c1ccc(C2(C(F)(F)F)N=N2)cc1
Reactant: CC(C)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Product: CC(C)n1cc(C(=O)c2cncc(NC(=O)c3ccc(C4(C(F)(F)F)N=N4)cc3)c2)c2cncnc21

Procedure:
The title compound was prepared according to the method described for Example 34 starting from (5-aminopyridin-3-yl)(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Preparation 95) and 4-[3-(trifluoromethyl)-3H-diaziren-3-yl]benzoic acid to afford the title compound as a white solid in 4% yield, 2 mg. LCMS (system 3): Rt=3.64 min; m/z 494 [M+H]+.
Reaction SMILES: O=[C:2]([CH2:8][C:9](=O)[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:17][CH:18]([N:20]1[C:24]([NH2:25])=[CH:23][CH:22]=[N:21]1)[CH3:19]>C1C=CC=CC=1>[CH3:17][CH:18]([N:20]1[C:24]2[N:25]=[C:9]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)[CH:8]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:23]=2[CH:22]=[N:21]1)[CH3:19]
Reactant: CCOC(=O)C(=O)CC(=O)c1ccncc1
Reactant: CC(C)n1nccc1N
Solvent: c1ccccc1
Product: CCOC(=O)c1cc(-c2ccncc2)nc2c1cnn2C(C)C
Temperature: 62 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
To a suspension of ethyl 2,4-dioxo-4-(4-pyridinyl)butanoate (442 mg, 1.997 mmol) in benzene (5 mL) was added 1-(1-methylethyl)-1H-pyrazol-5-amine (250 mg, 1.997 mmol), and the reaction mixture was stirred at 62° C. overnight. The reaction mixture was concentrated in vacuo and the residue was purified using column chromatography (Silica gel, 0 to 100% EtOAc/hexanes) to give 270 mg (43%) of product. LCMS E-S (M+H)=311.3 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.54 (t, J=7.2 Hz, 3H), 1.68 (d, J=6.6 Hz, 6H), 4.58 (q, J=7.1 Hz, 2H), 5.41-5.60 (m, 1H), 8.04-8.19 (m, 2H), 8.29 (s, 1H), 8.44-8.55 (m, 2H), 8.76-8.91 (m, 1H).
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.[CH:11]1([CH2:14][N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][N:22]=3)[C:17]([C:24](Cl)=[O:25])=[CH:16]2)[CH2:13][CH2:12]1.C(OCC)(=O)C>C1COCC1.O>[N:8]1[CH:9]=[CH:10][C:5]([CH2:4][NH:3][C:24]([C:17]2[C:18]3[C:23](=[N:22][CH:21]=[CH:20][CH:19]=3)[N:15]([CH2:14][CH:11]3[CH2:13][CH2:12]3)[CH:16]=2)=[O:25])=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1cn(CC2CC2)c2ncccc12
Reactant: NCc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NCc1ccncc1)c1cn(CC2CC2)c2ncccc12
Temperature: 10 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (60%, 1.14 g) is suspended in 21 mL of THF. While stirring at about 10° C., a solution of 0.93 g of 4-aminomethylpyridine (8.6 mmoles) in 21 mL of THF is added dropwise. After about 15 minutes, the previously prepared solution of 1-cyclopropylmethyl-7-azaindole-3-carboxylic acid chloride is added dropwise to the reaction mixture. Subsequently, the whole is refluxed for 3 hours. After cooling, the reaction mixture is mixed with 36 mL of ethyl acetate and 36 mL of water. The phases are separated and the organic phase is washed with water. The solvent is distilled off and the residue recrystallized from ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[OH:12].[CH3:13][C:14](=[CH2:27])[CH2:15][S:16][C:17]1[CH:22]=[C:21](F)[CH:20]=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[CH:4][C:3]=1[O:12][C:21]1[CH:20]=[CH:19][C:18]([N+:24]([O-:26])=[O:25])=[C:17]([S:16][CH2:15][C:14]([CH3:27])=[CH2:13])[CH:22]=1
Reactant: C=C(C)CSc1cc(F)ccc1[N+](=O)[O-]
Reactant: Oc1ccc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)CSc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 3 h
Yield: 66.6 %

Procedure:
A mixture of 1.85 g (0.00939 mole) of 2-chloro-4-trifluoromethylphenol (Example 1, Part A), 2.1 g (0.0093 mole) of 2-(2-methyl-2-propenylthio)-4-fluoronitrobenzene (Part A), and 1.3 g (0.0094 mole) of potassium carbonate in 25 ml of dimethyl formamide was stirred at 60° C. for three hours. The mixture was poured into water and extracted with chloroform. The chloroform extract was washed with water and dried over anhydrous magnesium sulfate. After filtration, the chloroform was evaporated under reduced pressure. The residue was subjected to a hagh vacuum, leaving 2.5 g of 3-(2-methyl-2-propenylthio)-4-nitrophenyl 2-chloro-4-trifluoromethylphenyl ether as an oil.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[C:16]=2[CH:30]=[O:31])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(#N)C.CCOCC>ClCCl>[N:11]1([C:15]2[N:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[C:16]=2[CH:30]=[O:31])[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2c(C=O)c3cccnc3n2-c2ccccc2)CC1
Solvent: CC#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=Cc1c(N2CCCNCC2)n(-c2ccccc2)c2ncccc12
Temperature: 25 °C
Reaction time: 22 h
Yield: 113.2 %

Procedure:
A solution of 4-(3-formyl-1-phenyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (330 mg, 0.786 mmol) in dichloromethane (20 mL) is treated with trifluoroacetic acid (0.60 mL, 6.04 mmol). The resulting solution is allowed to stir at room temperature for 22 hours before treating the reaction with a further aliquot of trifluoroacetic acid (0.60 mL, 6.04 mmol). After stirring for a further 18 hours, the reaction mixture is evaporated to give a gooey red oil. Trituration of the crude product salt with acetonitrile and ether gives 285 mg of 2-[1,4]diazepan-1-yl-1-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde; trifluoro-acetic acid salt as a pink solid (84% yield). LC/MS: retention time 2.25 min, m/e 321 (M+H). 1H NMR (300 MHz, DMSO-d6): 10.15 (1H, s), 8.60 (2H, br.s), 8.36 (1H, dd), 8.08 (1H, dd), 7.63-7.48 (5H, m), 7.22 (1H, dd), 3.63-3.48 (4H, m), 3.11-2.95 (4H, m), 1.81 (2H, m).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].[OH-:11].[K+].Cl>O>[O:11]=[C:2]1[CH:3]=[C:4]([C:5]([OH:7])=[O:6])[CH:8]=[CH:9][NH:10]1
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=C(O)c1cc[nH]c(=O)c1
Yield: 98.9 %

Procedure:
To a stirred solution of 2-chloroisonicotinic acid (15 g, 1.0 eq) in 200 mL water at 0° C. was added KOH (40 g, 7.5 eq). Then the reaction mixture was heated to reflux for 36 h., cooled, and 3 N HCl (aq) was added to pH=1˜3. The precipitate was collected by filtration and washed with water to give the product as a white solid (13.1 g, 99% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.80 (brs, 2H), 7.47 (d, J=6.4 Hz, 1H), 6.79 (s, 1H), 6.50 (dd, J=6.8 Hz, 1.6 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:13])(/[C:8](/[CH2:11][CH3:12])=[CH:9]/[CH3:10])[C:3](OCC)=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][C:2]([CH3:13])(/[C:8](/[CH2:11][CH3:12])=[CH:9]/[CH3:10])[CH2:3][OH:4]
Reactant: C/C=C(\CC)C(C)(C)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C/C=C(\CC)C(C)(C)CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.8 %

Procedure:
Ethyl (E)-2,2-dimethyl-3-ethyl-3-pentenoate 23 (35.58 g, 193 mmol) is added dropwise to a suspension of lithium aluminium hydride (12.1 g, 320 mmol) in 81 ml of THF. The mixture is refluxed for 3 h, stirred for 16 h at r.t. and quenched with ice. The precipitate is filtered off by suction, washed several times with diethyl ether and hydrolyzed with 1 M hydrochloric acid. The aqueous solution is extracted with diethyl ether (3×100 ml). The combined etheral extracts are dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by vacuum distillation affords the title compound 24 (15.87 g, 58%) as a colourless liquid (b.p. 105-106° C./30 mbar). 13C-NMR (100 MHz, CDCl3): δ=145.2; 120.5; 69.7; 42.0; 24.0; 20.0; 14.2; 13.6
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([OH:11])[CH2:3][CH2:2]1.[Cl:12][C:13]1[CH:18]=[N:17][CH:16]=[C:15](Cl)[N:14]=1>O1CCOCC1.ClCCl>[Cl:12][C:13]1[CH:18]=[N:17][CH:16]=[C:15]([O:11][CH:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[O:1][CH2:2][CH2:3]2)[N:14]=1
Reactant: OC1CCOc2ccccc21
Reactant: Clc1cncc(Cl)n1
Solvent: ClCCl
Solvent: C1COCCO1
Product: Clc1cncc(OC2CCOc3ccccc32)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
K-t-BuO (1.28 g, 11.42 mmol) was added to a stirred solution of 4-chromanol (1.81 g, 12.0 mmol) in dioxane (30 mL) at 0° C. (ice-bath). After being stirred for 5 min at room temperature, the mixture was chilled to 0° C. (ice-bath) and 2,6-dichloropyrazine (1.49 g, 10.0 mmol) was added. The reaction mixture was stirred at room temperature for 15 min and diluted with dichloromethane. Filtration and concentration in vacuo furnished an orange thick oil which was purified by chromatography on silica gel (15×4 cm) using n-hexane/ethyl acetate (8:2) as eluent. This furnished 1.87 g (71%) of the title compound as a colorless oil. HRMS m/z calcd for C13H11ClN2O2 (M)+ 262.0509, found 262.0520. Anal. (C13H11ClN2O2) C, H, N.
Reaction SMILES: Cl.CO[C:4](=[NH:9])[CH2:5][CH:6]1[CH2:8][CH2:7]1.[CH3:10][C:11]1([CH3:19])[O:16][C:15](=[O:17])[CH2:14][C:13](=[O:18])[O:12]1.C(N(CC)CC)C>C(Cl)(Cl)Cl.ClCCl>[NH2:9][C:4](=[C:14]1[C:15](=[O:17])[O:16][C:11]([CH3:19])([CH3:10])[O:12][C:13]1=[O:18])[CH2:5][CH:6]1[CH2:7][CH2:8]1
Reactant: COC(=N)CC1CC1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC1(C)OC(=O)C(=C(N)CC2CC2)C(=O)O1
Yield: 8.6 %

Procedure:
1 g (7 mmol) 2-Cyclopropyl-acetimidic acid methyl ester hydrochloride, 963 mg (7 mmol) 2,2-dimethyl-[1,3]dioxane-4,6-dione and 1.07 ml (8 mmol) triethylamine were heated under reflux in 7 ml chloroform for 14 h. The mixture was diluted with dichloromethane, washed neutral with brine/ice water 1/1 and the organic layer was dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by flash chromatography (silica gel, heptane/AcOEt) to give 128 mg (0.6 mmol, 9%) of the title compound as yellow crystals.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:14][CH2:15]OS(C)(=O)=O)=[CH:10][CH:11]=2)[C:6]([CH2:21][C:22]([N:24]2[C@H:29]([C:30](=[O:41])[NH:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=3[F:40])[CH2:28][C@@H:27]3[C@H:25]2[CH2:26]3)=[O:23])=[CH:5]1)(=[O:3])[NH2:2].[CH3:42][NH:43][CH3:44]>CCO>[Cl:39][C:35]1[C:34]([F:40])=[C:33]([CH:38]=[CH:37][CH:36]=1)[CH2:32][NH:31][C:30]([C@@H:29]1[CH2:28][C@@H:27]2[C@@H:25]([CH2:26]2)[N:24]1[C:22](=[O:23])[CH2:21][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH2:15][N:43]([CH3:44])[CH3:42])[CH:8]=2)[N:4]([C:1]([NH2:2])=[O:3])[CH:5]=1)=[O:41]
Reactant: CNC
Reactant: CS(=O)(=O)OCCOc1ccc2c(c1)c(CC(=O)N1[C@@H]3C[C@@H]3C[C@H]1C(=O)NCc1cccc(Cl)c1F)cn2C(N)=O
Solvent: CCO
Product: CN(C)CCOc1ccc2c(c1)c(CC(=O)N1[C@@H]3C[C@@H]3C[C@H]1C(=O)NCc1cccc(Cl)c1F)cn2C(N)=O
Temperature: 70 °C

Procedure:
Methanesulfonic acid 2-(1-carbamoyl-3-{2-[(1R,3S,5R)-3-(3-chloro-2-fluoro-benzylcarbamoyl)-2-aza-bicyclo[3.1.0]hex-2-yl]-2-oxo-ethyl}-1H-indol-5-yloxy)-ethyl ester in a solution of dimethylamine 5.6 M in EtOH (1 mL) was sealed in a microwave vial and heated at 70° C. for 2 h (Emrys Optimizer; personal chemistry). The reaction mixture was quenched by addition of saturated aqueous NaHCO3, extracted with EtOAc, dried (Na2SO4) and evaporated in vacuo. Then crude residue was purified by catch-release (SCX Tosic Acid-1 g from Silicycle; eluent MeOH (10 mL) to 2M ammonia in MeOH (10 mL)) to give the desired material which was precipitated in Et2O. MS (UPLC/MS): 556.5/558.5 [M+H]+, 600.4/602.5 [M+HCOO]−; tR (HPLC conditions f): 1.46 min.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]2[C:27]([NH:28][C:29](=[O:36])[CH2:30][CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:26][N:25]=[C:24]3[N:37]([S:40]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)(=[O:42])=[O:41])[CH:38]=[CH:39][C:23]=23)[CH2:17][CH2:16]1)=O)(C)(C)C.[C:49](#[N:52])[CH:50]=[CH2:51]>C(Cl)Cl>[C:43]1([S:40]([N:37]2[C:24]3=[N:25][CH:26]=[C:27]([NH:28][C:29](=[O:36])[CH2:30][CH:31]4[CH2:32][CH2:33][CH2:34][CH2:35]4)[C:22]([NH:21][CH:18]4[CH2:19][CH2:20][N:15]([CH2:51][CH2:50][C:49]#[N:52])[CH2:16][CH2:17]4)=[C:23]3[CH:39]=[CH:38]2)(=[O:41])=[O:42])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2c(NC(=O)CC3CCCC3)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Reactant: C=CC#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CCCN1CCC(Nc2c(NC(=O)CC3CCCC3)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 158 %

Procedure:
Trifluoroacetic acid (2 ml) was added to a solution of 4-[1-benzenesulfonyl-5-(2-cyclopentyl-acetylamino)-1H-pyrrolo[2,3-b]pyridin-4-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (0.421 g, 0.724 mmol) in CH2Cl2 (10 ml) at 25° C. The reaction mixture was stirred at 25° C. for 30 min, then was concentrated under reduced pressure. The residue was partitioned between half-saturated NaHCO3 (100 ml) and EtOAc (2×100 ml) and the combined organic layers were dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was dissolved in DMF (8 ml) at 25° C. Acrylonitrile (1.0 ml, 0.200 mmol) was added and the reaction mixture was stirred at 25° C. for 18 h, then was concentrated under reduced pressure. The residue was partitioned between water (100 ml) and EtOAc (2×100 ml). The combined organic layers were dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient: 0 to 7% CH3OH in CH2Cl2) afforded N-{1-benzenesulfonyl-4-[1-(2-cyano-ethyl)-piperidin-4-ylamino]-1H-pyrrolo[2,3-b]pyridin-5-yl}-2-cyclopentyl-acetamide (0.169 g, 63%) as a white foam. LCMS (Method G, ESI): RT=0.70 min, m+H=535.4. This material was used in the next step below without additional characterization.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12]([C:17](OCC)=[O:18])=[CH:11]3)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>O1CCCC1>[Br:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12]([CH2:17][OH:18])=[CH:11]3)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2cc(OCc3ccc(Br)cc3)ccc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1cc2cc(OCc3ccc(Br)cc3)ccc2[nH]1
Reaction time: 1 h
Yield: 82.2 %

Procedure:
To a solution of the ethyl 5-[(4-bromobenzyl)oxy]-1H-indole-2-carboxylate (300 mg, 0.802 mmol) obtained in the above 1) in tetrahydrofuran (4 ml) was added lithium aluminum hydride (60.8 mg, 1.60 mmol) at 0° C., and the mixture was stirred for 1 hour. Ethyl acetate was added to the reaction solution, the mixture was washed with 1N hydrochloric acid and an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After the solvent was concentrated under reduced pressure, the resulting residue was purified by alumina column chromatography (developing solvent: ethyl acetate), and converted into powders with isopropyl ether and hexane to obtain the titled compound (219 mg).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([Cl:15])([F:14])[F:13])[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[CH2:25]([NH:27][CH3:28])[CH3:26]>CN(C=O)C>[Cl:15][C:12]([F:14])([F:13])[C:6]1[N:5]=[C:4]([C:16]([F:17])([F:19])[F:18])[C:3]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:2]([N:27]([CH2:25][CH3:26])[CH3:28])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CCNC
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1N(C)CC
Yield: 86.3 %

Procedure:
This compound was prepared as described in Example 37: 5.0 g (0.013 mol) of product of Example 28, 1.54 g (0.026 mol) of N-ethylmethylamine in 30 ml of DMF were reacted at room temperature for 16 hours affording a residue which was kugelrohr distilled at 80 Pa, pot temperature 104° C., to give 4.7 g of oil. Purification by HPLC using 5% ethyl acetate/cyclohexane as eluting solvent afforded 4.0 g of oil which was purified by kugelrohr distillation at 67 Pa, pot temperature 107° C., to give 3.85 g (70.7%) of product as a yellow solid; mp 33°-35° C.