Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[C:11](=[O:32])[CH:10]([CH3:33])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:34](Br)[CH:35]=C.[Li+].[CH3:39][Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH2:33]([C:10]1([CH3:39])[CH2:9][C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C@@H:13]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[N:12]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=2[O:30][CH3:31])[C:11]1=[O:32])[CH:34]=[CH2:35]
Reactant: COc1ccc(CN2C(=O)C(C)C[C@H](c3cccc(Cl)c3)[C@H]2c2ccc(Cl)cc2)c(OC)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: C=CCBr
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(Cc2ccc(OC)cc2OC)C1=O
Temperature: 40 °C
Yield: 141.8 %

Procedure:
A solution of (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2,4-dimethoxybenzyl)-3-methylpiperidin-2-one (Example 71, Step B, mixture of C-3 diastereomers) (117.0 g, 242 mmol) in anhydrous THF (966 mL) was degassed by bubbling argon through the solution for 20 minutes. Allyl bromide (105 mL, 1208 mmol) was added followed by the addition of LHMDS (725 mL, 725 mmol) over 20 minutes. The reaction mixture was heated at 40° C. under argon for 5 hours. The reaction mixture was cooled to rt. and the reaction was quenched by the addition of sat. aqueous NH4Cl (500 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (2×1 L) and the organics were pooled, washed with sat. aq. NaCl solution (1 L), dried (MgSO4), filtered and concentrated in vacuo to provide a red oil (180 g). Purification using the Biotage system (Charlotte, N.C.) with a 1.5 kg SiO2 column and eluting with 10-30% EtOAc/hexanes provided the title compound as a very pale yellow oil as a 3.7:1 mixture of (3S):(3R) diastereomers.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[CH:23][N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4C3CCCCO3)=[CH:14][CH:13]=[CH:12][N:11]=2)=[C:7]([F:31])[CH:6]=[CH:5][C:4]=1[NH:32][S:33]([N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)(=[O:35])=[O:34]>>[N:24]1[C:16]([C:15]2[C:10]([NH:9][C:8]3[C:3]([F:2])=[C:4]([NH:32][S:33]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)(=[O:34])=[O:35])[CH:5]=[CH:6][C:7]=3[F:31])=[N:11][CH:12]=[CH:13][CH:14]=2)=[C:17]2[C:21]([NH:20][CH:19]=[N:18]2)=[N:22][CH:23]=1
Reactant: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)N1CCOCC1
Agent: Cl
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3[nH]cnc23)c1F)N1CCOCC1
Reaction time: 2 h
Yield: 94 %

Procedure:
1M aqueous hydrochloric acid solution was added into the N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)morpholine-4-sulfonamide (12 mg, 0.020 mmol) prepared at Step 10 and stirred for 2 hours. After the reaction, the reactant was washed with an aqueous solution of sodium hydrogen carbonate and salt water. After extraction with ethylacetate, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 9 mg of the target compound, N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)morpholine-4-sulfonamide (percentage yield: 94%), was obtained.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[C:14]([F:37])[CH:15]=[C:16]([S:17][C:18]3[CH:27]=[CH:26][C:25]4[C@H:24]([CH2:28][NH:29]C(OC(C)(C)C)=O)[CH2:23][CH2:22][CH2:21][C:20]=4[CH:19]=3)[C:11]=2[N:10]=[CH:9]1)=O)(C)(C)C.ClC1C=CC=C(C(OO)=O)C=1.C(OC(N1C2C=C(F)C=C(S(C3C=CC4C(CNC(OC(C)(C)C)=O)CCCC=4C=3)(=O)=O)C=2N=C1)=O)(C)(C)C>>[F:37][C:14]1[CH:15]=[C:16]([S:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]([CH2:28][NH2:29])[CH2:23][CH2:22][CH2:21]3)[C:11]2[N:10]=[CH:9][NH:8][C:12]=2[CH:13]=1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CCCc2cc(Sc3cc(F)cc4c3ncn4C(=O)OC(C)(C)C)ccc21
Agent: CC(C)(C)OC(=O)NCC1CCCc2cc(S(=O)(=O)c3cc(F)cc4c3ncn4C(=O)OC(C)(C)C)ccc21
Agent: O=C(OO)c1cccc(Cl)c1
Product: NCC1CCCc2cc(Sc3cc(F)cc4[nH]cnc34)ccc21

Procedure:
(R)-4-[5-(tert-Butoxycarbonylamino-methyl)-5,6,7,8-tetrahydro-naphthalen-2-ylsulfanyl]-6-fluoro-benzoimidazole-1-carboxylic acid tert-butyl ester was treated with metachloroperbenzoic acid using the procedure of step 8 of Example 15. The resulting 4-[5-(tert-Butoxycarbonylamino-methyl)-5,6,7,8-tetrahydro-naphthalene-2-sulfonyl]-6-fluoro-benzoimidazole-1-carboxylic acid tert-butyl ester was deprotected following the procedure of step 10 of Example 15 to give C-[6-(6-Fluoro-1H-benzoimidazol-4-ylsulfanyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-methylamine, M+H=360.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2.C([O-])([O-])=O.[K+].[K+].[CH3:28][C:29](C)=O>>[CH2:28]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[O:8][CH:7]([C:13]([F:16])([F:14])[F:15])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2)[CH3:29]
Reactant: CCOC(=O)C1=Cc2cc(O)cc(C)c2OC1C(F)(F)F
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C1=Cc2cc(OCC)cc(C)c2OC1C(F)(F)F
Temperature: 55 °C
Yield: 98 %

Procedure:
The ethyl 6-hydroxy-8-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Example 613b, Step 2 (0.2 g, 0.66 mmole) and K2CO3 (0.48 g, 3.44 mmole) was suspended in acetone (7.5 mL). lodoethane (1.03 g, 6.60 mmole) was added and heated to 55° C. for 3 hrs. The contents were filtered through a plug of celite and washed with acetone. The solution was concentrated in vacuo to give an orange solid (0.22 g, 98%). GCMS m/z 330.0 (M+). LCMS m/z 331.0 (M+H). 1H NMR (CDCl3/400 MHz) 7.62 (s, 1H), 6.71 (s, 1H), 6.55 (s, 1H), 5.65 (q, 1H, J=7.0 Hz), 4.28 (m, 2H), 3.93 (m, 2H), 2.19 (s, 3H), 1.33 (m, 6H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[N:7][C:8]=2[Cl:12])[N:3]=1.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>COC(O)C>[CH2:21]([NH:28][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[N:7][C:8]=2[Cl:12])[N:3]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(-c2cc3nc(Cl)ccc3c(Cl)n2)cc1
Agent: COC(C)O
Product: COc1ccc(-c2cc3nc(NCc4ccccc4)ccc3c(Cl)n2)cc1
Temperature: 80 °C
Reaction time: 72 h
Yield: 30.5 %

Procedure:
2,5-Dichloro-7-(4-methoxyphenyl)-[1,6]naphthyridine (147 mg, 0.48 mmol) and benzyl amine (0.055 mL, 0.5 mmol) were combined in methoxyethanol (2 mL) and stirred at 80° C. for 72 hours. The crude reaction mixture was concentrated, and column chromatography afforded benzyl-[5-chloro-7-(4-methoxyphenyl)-[1,6]naphthyridin-2-yl]-amine (55 mg, 30%).
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:18]C(=O)OC(C)(C)C)[C:4]([N:6]([CH3:17])[C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1)=[O:5].[ClH:26].CCOCC>CO>[ClH:26].[NH2:18][C@@H:3]([CH2:2][OH:1])[C:4]([N:6]([CH3:17])[C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1)=[O:5]
Reactant: CN(C(=O)[C@H](CO)NC(=O)OC(C)(C)C)[C@@H]1CCCc2ccccc21
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CN(C(=O)[C@@H](N)CO)[C@@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1,1-dimethylethyl [(1S)-1-(hydroxymethyl)-2-[methyl[(1R)-1,2,3,4-tetrahydro-1-naphthalenyl]amino]-2-oxoethyl]carbamate (1.11 g, 3.19 mmol) (i.e. the product of Example 17, Step A) in methanol (15 mL) was added a 2 M solution of hydrogen chloride in ether (15 mL, 30 mmol), and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo and the resulting residue was dissolved in methanol and concentrated in vacuo again. The residue was dried in high vacuum to give 750 mg of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[C:26](=[O:56])[N:27]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[N:28]([CH2:31][C@H:32]([O:34][C:35](=[O:49])[C@@H:36]([NH:38]C(OCC3C=CC=CC=3)=O)[CH3:37])[CH3:33])[C:29]=2[CH3:30])=[O:24])=[CH:18][C:17]=1[F:57]>CCOC(C)=O.CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[C:26](=[O:56])[N:27]([C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[N:28]([CH2:31][C@H:32]([O:34][C:35](=[O:49])[C@@H:36]([NH2:38])[CH3:37])[CH3:33])[C:29]=2[CH3:30])=[O:24])=[CH:18][C:17]=1[F:57]
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)c4c(C)n(C[C@@H](C)OC(=O)[C@H](C)NC(=O)OCc5ccccc5)n(-c5ccccc5)c4=O)cc3F)c2cc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4c(C)n(C[C@@H](C)OC(=O)[C@H](C)N)n(-c5ccccc5)c4=O)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (S)—((R)-1-(4-(4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl-carbamoyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydropyrazol-1-yl)propan-2-yl)2-(benzyloxy-carbonylamino)propanoate (200 mg, 0.257 mmol) in a mixture of EtOAc (15 mL) and MeOH (10 mL) was added catalytic amount of Pd/C (10%, ˜55% w/w water content, 20 mg) under N2 atmosphere. The suspension was degassed under vacuum and then purged with H2. The reaction mixture was stirred at rt for 20 minutes under H2 balloon. The mixture was filtered and the residue was washed with MeOH (5 mL×3). The filtrate used for the next step immediately.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([NH2:10])=[CH:4][CH:3]=1.[CH3:11][N:12]1[C:16]([CH3:17])=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:14]=[N:13]1>>[CH3:11][N:12]1[C:16]([CH3:17])=[C:15]([C:2]2[N:7]=[C:6]([O:8][CH3:9])[C:5]([NH2:10])=[CH:4][CH:3]=2)[CH:14]=[N:13]1
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cnn1C
Reactant: COc1nc(Br)ccc1N
Product: COc1nc(-c2cnn(C)c2C)ccc1N

Procedure:
The title compound was prepared according to the method described for Preparation 158 using 6-bromo-2-methoxypyridin-3-amine and 1,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. The crude residue was purified using silica gel column chromatography eluting with 1-10% MeOH/aqueous ammonia (10/1) in DCM.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4](I)[CH:3]=1.[C:10]1(B2OC(C)(C)C(C)(C)O2)[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.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>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=2)[CH:3]=1
Reactant: CC1(C)OB(C2=CCCCC2)OC1(C)C
Reactant: Nc1ccc(Br)cc1I
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: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Nc1ccc(Br)cc1C1=CCCCC1
Temperature: 80 °C
Reaction time: 5 h
Yield: 86.9 %

Procedure:
To a mixture of 4-bromo-2-iodo-phenylamine (2.00 g, 6.71 mmol), 2-cyclohex-1-enyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1.40 g, 6.71 mmol) and Pd(PPh3)4 (388 mg, 0.336 mmol) in 40 mL of 1,4-dioxane was added 2.0 M aq Na2CO3 solution (26.8 mL, 53.7 mmol). After stirring at 80° C. for 5 h under Ar, the reaction was cooled to room temperature (RT). The mixture was treated with EtOAc (100 mL), washed with H2O (3×30 mL) and brine (20 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (10-20% EtOAc/hexane) to give 1.47 g (87%) of the title compound as a light brown oil. Mass spectrum (ESI, m/z): Calcd. for C12H14BrN, 252.0 (M+H). found 252.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[S:20][C:19]([C:21]([O:23]C)=O)=[N:18][N:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1.[N:26]1([CH2:31][CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH2:30][CH2:29][CH2:28][CH2:27]1.C[Al](C)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:25])[C:6]([S:10]([N:13]([CH3:14])[CH2:15][C:16]2[S:20][C:19]([C:21]([N:37]3[CH2:36][CH2:35][N:34]([CH2:33][CH2:32][CH2:31][N:26]4[CH2:27][CH2:28][CH2:29][CH2:30]4)[CH2:39][CH2:38]3)=[O:23])=[N:18][N:17]=2)(=[O:12])=[O:11])=[C:7]([CH3:9])[CH:8]=1
Reactant: COC(=O)c1nnc(CN(C)S(=O)(=O)c2c(C)cc(OC)cc2C)s1
Reactant: C1CCN(CCCN2CCNCC2)C1
Agent: C[Al](C)C
Solvent: C1CCOC1
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N3CCN(CCCN4CCCC4)CC3)s2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BK using methyl 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,3,4-thiadiazole-2-carboxylate (200 mg, 0.50 mmol), 1-(3-pyrrolidin-1-ylpropyl)piperazine (118 mg, 0.60 mmol), THF (10 mL) and trimethylaluminium (2.0 M in toluene, 0.55 mL). The crude product was purified by FCC, eluting with 0-2% MeOH in DCM to afford the title compound as a white solid.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.N([O-])=O.[Na+].[ClH:18]>C(O)(=O)C.O>[Cl:18][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1
Reactant: Cl
Reactant: Nc1ccccc1Sc1ncc[nH]1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Clc1ccccc1Sc1ncc[nH]1
Reaction time: 0.17 h
Yield: 79 %

Procedure:
To a solution of 5.6 g (29.3 mmoles) of the product from Example 32 in 50 ml of 3N hydrochloric acid and 50 ml of glacial acetic acid (cooled in an ice bath), was added dropwise over 20 minutes, a solution of 2.0 g (29.3 mmoles) of sodium nitrite in 8 ml of water. After stirring for 10 minutes, the mixture was added to a cold solution of 8.7 g (80 mmoles) cuprous chloride in 80 ml of 6N hydrochloric acid. After stirring at room temperature for 5 hours, the mixture was concentrated and the residue made alkaline with ammonium hydroxide. The product was extracted with dichloromethane which was washed with saturated sodium chloride, dried and concentrated. The residue was dissolved in hot dichloromethane and filtered through silica gel using dichloromethane/ethyl acetate (1:1 by volume) as the eluent. The fractions containing the product were concentrated to give 4.9 g (79%) of the product which was crystallized from dichloromethane to give colorless rods, mp 138°-141° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:23]([N:25]2[C@H:34]([CH2:35][N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:24])=[C:8]([C:10]2[N:11]3[C:15](=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:17]=2)[CH2:14][C@@H:13]([OH:22])[CH2:12]3)[CH:9]=1.[CH2:42](Br)[CH:43]=[CH2:44]>C1COCC1>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:23]([N:25]2[C@H:34]([CH2:35][N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:24])=[C:8]([C:10]2[N:11]3[C:15](=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:17]=2)[CH2:14][C@@H:13]([O:22][CH2:44][CH:43]=[CH2:42])[CH2:12]3)[CH:9]=1
Reactant: C=CCBr
Reactant: COC(=O)c1cc(-c2cc(F)ccc2C(=O)N2Cc3ccccc3C[C@H]2CN2CCOCC2)n2c1C[C@@H](O)C2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCO[C@@H]1Cc2c(C(=O)OC)cc(-c3cc(F)ccc3C(=O)N3Cc4ccccc4C[C@H]3CN3CCOCC3)n2C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 62 mg (1.54 mmol) of sodium hydride in 8 mL of anhydrous THF cooled to 0° C. there is added a solution of the compound of Step B (820 mg; 1.54 mmol) in THF (6 mL). The suspension is stirred for 15 minutes at 0° C. There is subsequently added 0.15 mL (1.69 mmol) of allyl bromide, dropwise. The reaction mixture is stirred for 5 hours at ambient temperature, and then hydrolysed with a saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic phase is dried over MgSO4, filtered and concentrated to dryness. The oil so obtained is purified by flash chromatography (gradient: dichloromethane/ammoniacal methanol) to yield the title product in solid form.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:11][C@@H:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@H:13]2[F:25])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[S:34](Cl)(=[O:36])=[O:35]>>[ClH:26].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[S:34]([NH:1][C:2]1[CH:3]=[C:4]([O:11][C@@H:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]2[F:25])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1)(=[O:36])=[O:35]
Reactant: O=S(=O)(Cl)c1cc(F)ccc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Oc2cc(N)cc3ccoc23)[C@H](F)C1
Product: Cl
Product: O=S(=O)(Nc1cc(O[C@@H]2CCNC[C@H]2F)c2occc2c1)c1cc(F)ccc1Cl

Procedure:
The title compound was prepared according to the procedure described for Example 84 starting from tert-butyl trans-4-[(5-amino-1-benzofuran-7-yl)oxy]-3-fluoropiperidine-1-carboxylate (Intermediate 53) and 2-chloro-5-fluorobenzenesulfonyl chloride. Yield: 34 mg (18%), HPLC purity=100%, m/z=443 (M+H)+, 1H NMR (270 MHz, methanol-d4) δ ppm 2.11-2.36 (m, 2H) 3.15-3.58 (m, 3H) 3.63-3.81 (m, 1H) 4.77-4.98 (m, 1H) 5.00-5.24 (m, 1H) 6.75 (d, J=2.23 Hz, 1H) 6.85 (d, J=1.98 Hz, 1H) 7.05 (d, J=1.98 Hz, 1H) 7.09-7.20 (m, 1H) 7.42 (dd, J=8.66, 2.47 Hz, 1H) 7.72 (d, J=2.23 Hz, 1H) 7.97-8.06 (m, 1H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.CC(OC([N:52]1[C:60]2[C:55](=[CH:56][CH:57]=[C:58]([NH:61][C:62](=[O:70])[CH2:63][CH2:64][O:65][C:66]([CH3:69])([CH3:68])[CH3:67])[CH:59]=2)[CH:54]=[C:53]1[C:71](O)=[O:72])=O)(C)C.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:71]([C:53]2[NH:52][C:60]3[C:55]([CH:54]=2)=[CH:56][CH:57]=[C:58]([NH:61][C:62](=[O:70])[CH2:63][CH2:64][O:65][C:66]([CH3:68])([CH3:67])[CH3:69])[CH:59]=3)=[O:72])=[C:28]([F:44])[C:29]=1[O:34][C:35]1[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: CC(C)(C)OCCC(=O)Nc1ccc2cc(C(=O)O)n(C(=O)OC(C)(C)C)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OCCC(=O)Nc1ccc2cc(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
HATU (0.090 g, 0.237 mmol) was added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.0491 g, 0.158 mmol), 1-{[(1,1-dimethylethyl)oxy]carbonyl}-6-({3-[(1,1-dimethylethyl)oxy]propanoyl}amino)-1H-indole-2-carboxylic acid (0.048 g, 0.158 mmol) and diisopropylethylamine (0.041 mL, 0.237 mmol) in DMF (1 mL). The mixture was stirred at room temperature overnight. The reaction mixture was extracted with ethyl acetate and water. The organic layer was washed with water, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (hexane:ethyl acetate) to give the title compound (0.055 g, 58%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.47 (s, 1H), 9.81 (s, 1H), 8.89 (t, 1H), 7.94 (s, 1H), 7.78 (s, 1H), 7.39-7.53 (m, 4H), 7.36 (t, 1H), 7.03-7.12 (m, 2H), 4.52 (d, 2H), 3.57 (t, 2H), 2.36-2.49 (m, 2H), 1.10 (s, 9H). ES MS: m/z 597 (M+1).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([CH:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1.Br[CH2:26][N:27]1[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]2[C:28]1=[O:37].C(O)(=O)C>CN(C)C=O.O>[Cl:3][C:4]1[C:5]([C:14]([CH2:26][N:27]2[C:31](=[O:32])[C:30]3[C:29](=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:28]2=[O:37])([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ncc(C(F)(F)F)cc1Cl
Reactant: O=C1c2ccccc2C(=O)N1CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)C(CN1C(=O)c2ccccc2C1=O)(C(=O)OCC)c1ncc(C(F)(F)F)cc1Cl
Reaction time: 0.25 h

Procedure:
To a suspension of 60% sodium hydride (0.65 g) in dry dimethylformamide (20 ml) at 0° C. was added a solution of diethyl 2-(3-chloro-5-trifluoromethyl-2-pyridyl)malonate (5 g) in dry dimethylformamide (10 ml) and the mixture was stirred for 15 minutes. A solution of N-bromomethylphthalimide (3.55 g) in dry dimethylformamide (10 ml) was added dropwise and the mixture was warmed with stirring to 22° C. over 18 hours. Glacial acetic acid (1 ml) was added and the mixture was poured into cold water (500 ml). The aqueous solution was extracted with diethyl ether (3×150 ml) and the combined extract was water washed (3×100 ml). The organic extract was dried (MgSO4) and evaporated to give a crude product. Trituration with diethyl ether/light petroleum (b.p. 40-60° C.) (1:1) gave the title compound, m.p. 159-61° C.
Reaction SMILES: CO[CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]2[CH:18]=[C:19]([CH2:23][S:24]([NH2:27])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:11]=1.ClC1N=CN=C(N[C:36]2[CH:37]=[C:38](CS(N)(=O)=O)[CH:39]=[CH:40][CH:41]=2)N=1.C1(CCC2CCCN2)C=CC=CC=1>>[C:36]1([CH2:8][CH2:9][CH:4]2[CH2:3][CH2:7][CH2:6][N:5]2[C:10]2[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]3[CH:18]=[C:19]([CH2:23][S:24]([NH2:27])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=3)[N:11]=2)[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: COCC1CCCCN1c1ncnc(Nc2cccc(CS(N)(=O)=O)c2)n1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Agent: c1ccc(CCC2CCCN2)cc1
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCCC3CCc3ccccc3)n2)c1

Procedure:
B27 was prepared following the procedure reported for B4 using A1 and rac-2-(2-phenylethyl)pyrrolidine and obtained as a white crystalline solid; yield: 140 mg (35%). MS (ES) C22H26N6O2S requires: 438. found: 439 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[CH:18][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:20][CH:21]=3)[N:16]([CH3:27])[N:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[Cl:28]C(OC(Cl)C)=O>C(Cl)Cl>[ClH:28].[CH3:27][N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:26])[F:25])[CH:18]=2)[C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:15]1
Reactant: Cn1nc(C2CCN(Cc3ccccc3)CC2)c2ccc(C(F)(F)F)cc21
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: Cl
Product: Cn1nc(C2CCNCC2)c2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
To the 3-(1-benzyl-piperidin-4-yl)-1-methyl-6-trifluoromethyl-1H-indazole (1.41 g, 3.78 mmol) in DCM (20 mL) was added 1-chloroethyl chloroformate (0.49 mL, 4.50 mmol). The resulting solution was stirred at room temperature overnight when the volitiles were removed in vacuo. The residue was taken un in methanol (20 mL) and the resulting solution was heated at reflux for 1 hour. The mixture was cooled to room temperature and the solution was evaporated. The residue was taken up in EtOAc and the solid product was collected by filtration yielding 1.03 g (86%) of the HCl salt as a white solid.