Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1([F:46])[CH2:11][CH:10]1[C:12]([NH:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20](C1CCCCO1)[N:19]=[C:18]2[C:30]1[NH:34][C:33]2[CH:35]=[CH:36][C:37]([N:39]3[CH2:44][CH2:43][O:42][CH:41]([CH3:45])[CH2:40]3)=[CH:38][C:32]=2[N:31]=1)=[O:13]>C(Cl)Cl>[F:46][C:9]1([F:8])[CH2:11][CH:10]1[C:12]([NH:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[C:18]2[C:30]1[NH:34][C:33]2[CH:35]=[CH:36][C:37]([N:39]3[CH2:44][CH2:43][O:42][CH:41]([CH3:45])[CH2:40]3)=[CH:38][C:32]=2[N:31]=1)=[O:13]
Reactant: CC1CN(c2ccc3[nH]c(-c4nn(C5CCCCO5)c5ccc(NC(=O)C6CC6(F)F)cc45)nc3c2)CCO1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1CN(c2ccc3[nH]c(-c4n[nH]c5ccc(NC(=O)C6CC6(F)F)cc45)nc3c2)CCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
TFA (0.215 mL, 2.80 mmol) was added to solution of 2,2-difluoro-N-(3-(5-(2-methylmorpholino)-1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropanecarboxamide (15 mg, 0.028 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred overnight at room temperature, and then the solvent was removed in vacuo. Purification by flash chromatography (5% CH3OH/CH2Cl2) afforded the title compound (9 mg) as a solid. 1H NMR: (400 MHz, CD3OD): δ 8.44 (d, 1H, J=0.8 Hz), 7.64 (dd, 1H, J=1.6 and 8.8 Hz), 7.58-7.54 (m, 2H), 7.17 (d, 1H, J=1.6 Hz), 7.04 (dd, 1H, J=2.0 and 8.8 Hz), 3.99 (m, 1H), 3.82 (m, 2H), 3.52 (m, 1H), 3.44 (m, 1H), 2.84-2.70 (m, 2H), 2.47 (m, 1H), 2.12 (m, 1H), 1.85 (m, 1H), 1.24 (d, 3H, J=6.0 Hz); ESI-MS [M+H]+: 453.1.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8]Br)(=[O:5])[C:2]([CH3:4])=[O:3].[NH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1>O1CCCC1>[CH2:7]([O:6][C:1](=[O:5])[C:2](=[O:3])[CH2:4][N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)[CH3:8]
Reactant: c1ccc2c(c1)CCCN2
Reactant: CC(=O)C(=O)OCCBr
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)CN1CCCc2ccccc21
Reaction time: 24 h
Yield: 111.1 %

Procedure:
Add bromoethyl pyruvate (40 mL, 0.29 mol) to a solution of 1,2,3,4-tetrahydroquinoline (75.5 mL, 0.59 mol) in tetrahydrofuran (300 mL) dropwise over 30 minutes. Stir for 24 hours, filter the reaction mixture, rinse the filter cake well with tetrahydrofuran (100 mL), and concentrate the filtrate under reduced pressure to provide the desired compound as a red oil (79.7 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[CH:3]=1.[CH:10]1([C:13]#[N:14])[CH2:12][CH2:11]1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][C:10]1([C:13]#[N:14])[CH2:12][CH2:11]1
Reactant: BrCc1cccc(Br)c1
Reactant: N#CC1CC1
Product: N#CC1(Cc2cccc(Br)c2)CC1

Procedure:
Prepared according to the procedure described in Example 240, Step 1, using 1-bromo-3-bromomethyl-benzene and cyclopropanecarbonitrile.
Reaction SMILES: C([O-])(=O)C.[Na+].Br.Br.[CH2:8]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[CH2:9][CH3:10].[C:17]([N:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C([BH3-])#N.[Na+]>CO>[C:20]([O:19][C:17]([N:24]1[CH2:29][CH2:28][CH:27]([N:14]2[CH2:15][CH2:16][N:11]([CH2:8][CH2:9][CH3:10])[CH2:12][CH2:13]2)[CH2:26][CH2:25]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCCN1CCNCC1
Agent: Br
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Solvent: CO
Product: CCCN1CCN(C2CCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 56 %

Procedure:
42 g (0.50 mol) sodium acetate were added in portions to 73 g (0.25 mol) N-propylpiperazine dihydrobromide in 1 l methanol at 40° C. Subsequently, this was cooled to 0° C. and 50 g (0.25 mol) Boc-4-piperidon and 16 g (0.25 mol) sodium cyanoborohydride, in portions, were added, one after the other. Everything was then stirred at room temperature for 16 h. The reaction mixture was concentrated in a vacuum and then distributed between ethyl acetate and 1M NaOH. The organic phase was separated, washed with 1M NaOH, H2O and conc. NaCl solution, dried and concentrated in a vacuum. The residue was chromatographically purified over silica gel (mobile phase: MeOH/CH2Cl2=1/15). 43.6 g of the product were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[C:12]1([C:18]2[O:22][N:21]=[CH:20][C:19]=2[CH2:23][CH2:24][C:25](O)=[O:26])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[N:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:25](=[O:26])[CH2:24][CH2:23][C:19]3[CH:20]=[N:21][O:22][C:18]=3[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1cnoc1-c1ccccc1
Reactant: Nc1ccc2ncccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCc1cnoc1-c1ccccc1)Nc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
A mixture of 6-aminoquinoline (0.38 g), 3-(5-phenyl-4-isoxazolyl)propionic acid (0.56 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.46 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.60 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-(6-quinolyl)-3-(5-phenyl-4-isoxazolyl)propionamide (0.79 g, yield 89%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 170–171° C.
Reaction SMILES: [C-:1]#[N:2].[Na+].[NH2:4][C:5]1[C:14]([CH3:15])=[CH:13][C:12](Br)=[CH:11][C:6]=1[C:7]([NH:9][CH3:10])=[O:8].O=O.C1(OC)C=CC=CC=1>[Cu]I.[Cu](I)I.O>[NH2:4][C:5]1[C:14]([CH3:15])=[CH:13][C:12]([C:1]#[N:2])=[CH:11][C:6]=1[C:7]([NH:9][CH3:10])=[O:8]
Reactant: [C-]#N
Reactant: CNC(=O)c1cc(Br)cc(C)c1N
Agent: I[Cu]I
Agent: [Cu]I
Agent: O=O
Solvent: O
Solvent: COc1ccccc1
Product: CNC(=O)c1cc(C#N)cc(C)c1N
Temperature: 155 °C
Reaction time: 3 h

Procedure:
A 100-mL, four-necked flask equipped with a magnetic stirrer, thermocouple and condenser was charged with copper(I) iodide (0.88 g, 4.6 mmol), powdered sodium cyanide (1.87 g, 37.0 mmol, 97% purity), 2-amino-5-bromo-N,3-dimethylbenzamide (prepared by the method of Reference Example 1) (7.50 g, 30.9 mmol), oxygen-free 4-methoxypyridine (0.505 g, 4.6 mmol) and oxygen-free anisole (15 mL) under a nitrogen atmosphere in a glovebox. The reaction mixture was heated at about 155° C. for 12 h and then allowed to cool to room temperature overnight. The solid reaction mixture was then heated at 155° C., and then more copper iodide (0.588 g. 4.6 mmol) was added. After about 3 h, more anisole (15 mL) and powdered sodium cyanide (0.779 g, 15.4 mmol) were added to the reaction mixture, the mixture was cooled to 110° C., and then water (30 mL) was added. The reaction mixture was taken out of the glovebox, allowed to cool to room temperature and filtered. The solid collected was washed with water (3×15 mL) and toluene (2×15 mL), and then dried in a vacuum-oven at 55° C. to give the title compound as an off-white solid (5.22 g).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][NH:22][C:23](=O)[CH3:24])=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O>C(#N)C>[CH3:24][C:23]1[C:14]2=[C:13]3[C:18](=[CH:17][CH:16]=[C:15]2[O:19][CH2:20][CH2:21][N:22]=1)[N:10]([S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])[CH:11]=[CH:12]3
Reactant: CC(=O)NCCOc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CC1=NCCOc2ccc3c(ccn3S(=O)(=O)c3ccccc3)c21
Temperature: 25 °C
Yield: 104.9 %

Procedure:
To N-(2-{[1-(phenylsulfonyl)-1H-indol-5-yl]oxy}ethyl)acetamide (Intermediate 25, 5.0 g, 14 mmol) in acetonitrile (7.5 L) was phosphoryl chloride (100 mL) added and the reaction mixture was heated at reflux overnight. The reaction mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure to give the crude material of the title compound (5.0 g). A small amount of the crude material was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound (12 mg). MS m/z 341 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[C:17]([F:18])=[C:16]([NH2:19])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2].N1C=CC=CC=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[C:17]([F:18])=[C:16]([NH:19][S:28]([CH3:27])(=[O:30])=[O:29])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCCN(C)C(=O)c1cc(N)c(F)c(C(=O)OCC)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCN(C)C(=O)c1cc(NS(C)(=O)=O)c(F)c(C(=O)OCC)c1
Temperature: 0 °C
Reaction time: 48 h
Yield: 75.1 %

Procedure:
Dissolve 5-amino-6-fluoro-N-methyl-N-propyl-isophthalamic acid ethyl ester (0.162 g, 0.58 mmol) in dichloromethane (1.5 mL). Cool to 0° C. Add pyridine (51.2 μL, 0.63 mmol) and methanesulfonyl chloride (44.5 μL, 0.58 mmol) to the solution. Allow the reaction to warm to room temperature and stir for 2 days. Quench with water (10 mL) and extract with dichloromethane (2×30 mL). Combine the organic layers and wash with saturated aqueous sodium chloride (20 mL), dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 40:60 ethyl acetate:dichloromethane) to give the title compound as a solid (157 mg, 76%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][C:10](=[O:18])[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10](=[O:18])[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CC(=O)NN1c1ncccc1Cl
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(=O)[nH]n1-c1ncccc1Cl
Yield: 15.7 %

Procedure:
To a suspension of ethyl 2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolidinecarboxylate (i.e. product of Example 12, Step A) (27 g, 100 mmol) stirred in dry acetonitrile (200 mL) was added sulfuric acid (20 g, 200 mmol) in one portion. The reaction mixture thinned to form a pale green, nearly clear solution before thickening again to form a pale yellow suspension. Potassium persulfate (33 g, 120 mmol) was added in one portion, and then the reaction mixture was heated at gentle reflux for 3.5 hours. After cooling using an ice bath, a precipitate of white solid was removed by filtration and discarded. The filtrate was diluted with water (400 mL) and then extracted three times with ethyl ether (700 mL total). Concentration of the combined ether extracts to a reduced volume (75 mL) caused precipitation of an off-white solid (3.75 g), which was collected by filtration. The ether mother liquor was further concentrated to yield a second crop of an off-white precipitate (4.2 g), which was also collected by filtration. An off-white solid also precipitated from the aqueous phase; this solid (4.5 g) was collected by filtration to provide a combined total of 12.45 g of the title compound.
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([OH:14])=[C:11]([CH:13]=1)[NH2:12].C(=O)(O)[O-].[Na+]>ClCCl.[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[O:14][CH2:2][C:3](=[O:4])[NH:12][C:11]=2[CH:13]=1
Reactant: Nc1cc(Cl)ccc1O
Reactant: O=C(Cl)CCl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1COc2ccc(Cl)cc2N1
Yield: 93 %

Procedure:
Chloroacetyl chloride (2.39 ml) in dichloromethane (25 ml) was added to a mixture of 5-chloro-2-hydroxyaniline (3.59 g), triethyl benzylammonium chloride (5.7 g) and sodium bicarbonate (8.4 g) in dichloromethane (100 ml) at 0°C. After the addition the mixture was heated to reflux for 4 hours, then cooled and concentrated. The residue was treated with water and the resultant solid washed with ether to give 6-chloro-benzo[1,4]oxazin-3-one (4.2 g, 93% yield) as a buff coloured solid; 1H NMR (270 Mz): 3.2(1H,brd), 4.42(2H,s), 6.8-7.0(3H,m) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:18]2(O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:8][C:9]=1[NH:10]C(OC(C)(C)C)=O)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=2)=[CH:8][C:9]=1[NH2:10])=[O:4]
Reactant: COC(=O)c1sc(C2(O)CCCCC2)cc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1sc(C2=CCCCC2)cc1N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
To a solution of 3-tert-butoxycarbonylamino-5-(1-hydroxy-cyclohexyl)-thiophene-2-carboxylic acid methyl ester (68 g, 0.192 mol) in 400 mL of dichloromethane at 0° C. (ice bath) was added trifluoroacetic acid (400 mL). The mixture was stirred for 30 min at 0° C. and followed by TLC. After completion, the reaction mixture was evaporated to dryness and partitioned between ethyl acetate and saturated water solution of NaHCO3. The organic layer was separated, dried (Na2SO4) and concentrated. The residue was triturated in 4.4 volume of hexane for 30 min. Then filtered and washed with cold hexane. Dried in the vacuum oven to afford 35 g (76%) of 3-Amino-5-cyclohex-1-enyl-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([C:21]([O:23]CC)=[O:22])=[C:12]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:13][C:7]=2[N:6]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:5]1=[O:30].O>CO.O1CCCC1>[CH3:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([C:21]([OH:23])=[O:22])=[C:12]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:13][C:7]=2[N:6]([CH2:26][CH:27]([CH3:28])[CH3:29])[C:5]1=[O:30]
Reactant: CCOC(=O)c1c(Cc2ccccc2)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(C(=O)O)c(Cc3ccccc3)sc21
Temperature: 50 °C
Reaction time: 16 h
Yield: 71.7 %

Procedure:
1M Sodium hydroxide solution (7.5 ml) was added to a stirred solution of ethyl 1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-phenylmethyl-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylate (1.50 g) in methanol (7.5 ml) and tetrahydrofuran (15 ml). After 16 hours, further 1M sodium hydroxide solution (7.5 ml) was added and the solution was stirred at 50° C. for a further 8 hours. Water (100 ml) was added and the solution was washed with ether (100 ml). The aqueous phase was acidified by addition of concentrated hydrochloric acid and then extracted with ethyl acetate (2×100 ml). Undissolved solid in the organic extracts was filtered and dried in vacuo at 50° C. to give the title compound (1.00 g).
Reaction SMILES: [Br:1]Br.[N+:3]([CH:6]=[C:7]1[NH:12][CH2:11][CH2:10][CH2:9][S:8]1)([O-:5])=[O:4]>C(Cl)Cl.O>[Br:1][C:6]([N+:3]([O-:5])=[O:4])=[C:7]1[NH:12][CH2:11][CH2:10][CH2:9][S:8]1
Reactant: BrBr
Reactant: O=[N+]([O-])C=C1NCCCS1
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])C(Br)=C1NCCCS1

Procedure:
A solution of 3.2 g of bromine in 10 ml of methylene chloride was added dropwise to a solution of 3.2 g of 1A in 50 ml of water, the temperature being held at 5°-10°. The mixture was then stirred for 45 minutes when 200 ml of methylene chloride was added to dissolve the solid material. The organic phase was separated, washed with water, dried (Na2SO4) and concentrated under reduced pressure to give a yellow solid. This was washed with ether to give 2A as a yellow solid, m.p. 122° (with decomposition).
Reaction SMILES: O=[C:2]([CH2:8][C:9](=[O:14])[CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl.[CH3:16][O:17][NH2:18]>C(O)C>[CH3:16][O:17][N:18]=[C:2]([CH2:8][C:9](=[O:14])[CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CON
Reactant: CCCCC(=O)CC(=O)C(=O)OCC
Agent: Cl
Solvent: CCO
Product: CCCCC(=O)CC(=NOC)C(=O)OCC
Temperature: 25 °C
Reaction time: 15 h
Yield: 72.5 %

Procedure:
To an ethanol (100 ml) solution of ethyl 2,4-dioxooctanoate (20 g) (K. Seki et al., Chem. Pharm. Bull., 32, 1568(1984)) was added, under ice-cooling, methoxyamine hydrochloride (8.4 g), and the mixture was stirred for one hour, then it was stirred for further 15 hours at room temperature. The reaction mixture was concentrated under reduced pressure, to which was added a saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with ether. The extract solution was dried over anhydrous sodium sulfate, then the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel to afford the title compound as a colorless oil (16.6 g, 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[CH:12]1([C:18]2[NH:19][CH:20]=[C:21]([CH3:23])[N:22]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(#N)C>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N:19]2[CH:20]=[C:21]([CH3:23])[N:22]=[C:18]2[CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: Cc1c[nH]c(C2CCCCC2)n1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cn(-c2cc(Cl)ccc2[N+](=O)[O-])c(C2CCCCC2)n1

Procedure:
3.75 g 4-Chloro-2-fluoro-nitrobenzene, 3.4 g 2-Cyclohexyl-4-methyl-imidazole, 50 ml acetonitrile and 5 ml triethylamine were heated 6 hours at 60° C. The solvent was distilled off followed by extraction with 100 ml ethylacetate and 2 times 50 ml water. The organic layer was distilled off and the residue chromatographed on silica gel with 5% MeOH/CH2Cl2.
Reaction SMILES: C([O:5][C:6](=[O:35])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=2)[C:10]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:9]1[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>>[CH:21]1([C:10]2[C:11]3[C:16](=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=3)[N:8]([CH2:7][C:6]([OH:35])=[O:5])[C:9]=2[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(OC)cc3)n(CC(=O)OC(C)(C)C)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(OC)cc3)n(CC(=O)O)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
A solution (0.4 M) of methyl 1-(2-tert-butoxy-2-oxoethyl)-3-cyclohexyl-2-(4-methoxyphenyl)-1H-indole-6-carboxylate (from Step 2) in a 1:1 mixture of CH2Cl2/TFA was stirred at 25° C. for 4 h. The mixture was concentrated and the residue was triturated with Et2O to afford the title compound (95%) as a solid. 1H NMR (300 MHz, DMSO-d6, 300K) δ 1.13-1.36 (m, 3H), 1.62-1.95 (m, 7H), 2.56-2.67 (m, 1H), 3.86 (s, 3H), 3.89 (s, 3H), 4.74 (s, 2H), 7.12 (d, J 8.6, 2H), 7.28 (d, J 8.6, 2H), 7.69 (dd, J 8.5, 1.2, 1H), 7.86 (d, J 8.5, 1H), 8.02 (d, J 1.2, 1H), 12.98 (bs, 1H).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6](Br)[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:3].[C:27]([NH:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)(=[O:29])[CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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>[C:27]([NH:30][C:31]1[CH:36]=[C:35]([C:6]2[CH:7]=[C:8]3[C:12](=[C:4]([C:2]([NH2:1])=[O:3])[CH:5]=2)[NH:11][N:10]=[C:9]3[CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:34]=[CH:33][CH:32]=1)(=[O:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc(-c2cc(C(N)=O)c3[nH]nc(C4CCN(C(=O)OC(C)(C)C)CC4)c3c2)c1

Procedure:
Following the general procedure of Example 66, a mixture of 1,1-dimethylethyl 4-[7-(aminocarbonyl)-5-bromo-1H-indazol-3-yl]-1-piperidinecarboxylate (Intermediate 5) (30 mg, 0.07 mmols), [3-(acetylamino)phenyl]boronic acid (38 mg, 0.21 mmols), cesium carbonate (150 mg), and Pd(PPh3)4 (10 mg) in dioxane/water (3/1, 4 mL) were reacted to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[S:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)C(C)C)C.[CH3:33][O:34][CH2:35]Cl.O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:13]([CH2:33][O:34][CH3:35])[S:14]([C:17]3[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=3)(=[O:16])=[O:15])[S:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2nc(-c3cccc(Br)c3)cs2)cc1
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COCN(c1nc(-c2cccc(Br)c2)cs1)S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 0.72 g of N-[4-(3-bromo-phenyl)-thiazol-2-yl]-4-methyl-benzenesulfonamide and 0.6 ml of ethyidiiso-propylamine in 10 ml of methylene chloride was cooled to 0° C. and, after the addition of 0.13 ml of chloromethyl methyl ether, stirred at 0° C. for 2 h. Thereafter, the mixture was treated with 40 ml of water and extracted with methylene chloride. The organic phase was dried with magnesium sulphate and concentrated. After chromatography on 60 g of Kieselgel 60 with ethyl acetate/hexane (1:3) as the eluent the product-containing fractions were concentrated. 0.64 g of colorless N-[4-(3-bromo-phenyl)-thiazol-2-yl]-N-methoxymethyl-4-methyl-benzenesulfonamide, obtained in amorphous form, was processed without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:35])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:34])[CH:14]([C:24]2[CH:29]=[CH:28][C:27]([O:30]COC)=[CH:26][CH:25]=2)[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][CH3:17])=[CH:8][CH:7]=1.Cl.C([O-])(O)=O.[Na+]>CO.CCOC(C)=O.O>[CH3:35][N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:34])[CH:14]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][CH3:17])=[CH:10][CH:11]=1
Reactant: CC=C(c1ccccc1)C(C(=O)Nc1ccc(OCCN(C)C)cc1)c1ccc(OCOC)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC=C(c1ccccc1)C(C(=O)Nc1ccc(OCCN(C)C)cc1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
To a solution of 3b (30 mg, 0.0632 mmol) in MeOH (1 ml) was added 3N HCl in AcOEt (0.5 ml) under ice cooling, and the mixture was stirred at room temperature for 1 h. A solution of NaHCO3 (139 mg) in H2O was poured into the reaction mixture under ice cooling, and the whole was extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4, and then concentrated. The residue was crystallized with Et2O to give 8 (67%). 8: colorless powder; 1H-NMR (CD3OD) δ 1.53 (3H, dd, J=1.4, 6.8 Hz), 2.35 (6H, s), 2.77 (2H, t, J=5.4 Hz), 4.06 (2H, t, J=5.4 Hz), 4.64 (1H, brt), 5.53 (2H, dq, J=1.5, 6.8 Hz), 6.74 (2H, d, J=8.6 Hz), 6.85 (2H, d, J=9.2 Hz), 7.18-7.22 (5H, m), 7.27-7.32 (4H, m). HRMS calcd for C27H31N2O3 [M+H]+: 431.2335. Found: 431.2348.