Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])[C:5]([NH2:8])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:27]2[CH:41]=[CH:40][C:30]([O:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:29][CH:28]=2)O1>>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=1[CH2:10][O:9][C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:27]2[CH:41]=[CH:40][C:30]([O:31][CH2:32][CH2:33][N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[CH:29][CH:28]=2)[CH:3]=1
Reactant: Nc1ncc(Br)cc1OCc1c(Cl)cccc1Cl
Reactant: CC1(C)OB(c2ccc(OCCN3CCOCC3)cc2)OC1(C)C
Product: Nc1ncc(-c2ccc(OCCN3CCOCC3)cc2)cc1OCc1c(Cl)cccc1Cl

Procedure:
3-(2,6-Dichloro-benzyloxy)-5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-2-ylamine was prepared from 5-bromo-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine (example I(a)) and 4{2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-ethyl}-morpholine (prepared in part 1) following procedure 3 as a white solid.
Reaction SMILES: [CH:1]1([CH:4]([C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=2)O)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[CH3:20][S:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:31]=1[NH:30][CH:29]=[CH:28]2>ClCCl>[CH:1]1([CH:4]([C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=2)[C:28]2[C:27]3[C:31](=[C:23]([CH2:22][S:21][CH3:20])[CH:24]=[CH:25][CH:26]=3)[NH:30][CH:29]=2)[CH2:3][CH2:2]1
Reactant: OC(c1ccc(F)cc1)C1CC1
Reactant: CSCc1cccc2cc[nH]c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSCc1cccc2c(C(c3ccc(F)cc3)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
188 mg (1.13 mmol) of cyclopropyl(4-fluorophenyl)methanol and 0.10 ml (1.35 mmol) of trifluoroacetic acid were added to 200 mg (1.13 mmol) of the compound from Example 8A in 13 ml of dichloromethane. The reaction mixture was stirred at RT for 15 min, the solvent was removed in vacuo, and the crude product was then purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 267 mg (73% of theory) of the title compound were obtained.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][C:8]=1[CH3:16])(=O)=O.[CH3:19][S:20]([NH2:23])(=[O:22])=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C(OCC)(=O)C>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([NH:23][S:20]([CH3:19])(=[O:22])=[O:21])=[C:8]([CH3:16])[CH:9]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Reactant: CS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(=O)c1ccc(NS(C)(=O)=O)c(C)c1
Reaction time: 0.17 h
Yield: 34.3 %

Procedure:
A test tube for microwave was charged with tris(dibenzylidenacetone)dipalladium (0) chloroform adduct (205 mg, 0.20 mmol), 9,9-dimethyl-9H-xanthene-4,5-diyl)bis[diphenylphosphine] (345 mg, 0.60 mmol), 4-acetyl-2-methylphenyl trifluoromethanesulfonate (1.41 g, 5.0 mmol), methanesulfonamide (570 mg, 6.0 mmol), cesium carbonate (1.63 g, 7.0 mmol) and 1,4-dioxane (5 ml). The mixture was subjected to microwave irradiation at 120° C. with stirring for 10 minutes. Then, it was filterd off and the filtrate was concentrated under reduced pressure to furnish the crude residue which was applied to a silica gel chromatography column and eluted with a volume mixture of hexane:ethyl acetate (2/1) to give 390 mg (34% yield) of the title compound as a yellow solid.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([S:16]([OH:19])(=[O:18])=[O:17])[CH:10]=[CH:9]2.Cl.[BrH:21]>O>[Br:21][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([S:16]([OH:19])(=[O:18])=[O:17])[CH:10]=[CH:9]2
Reactant: Nc1ccc2cc(S(=O)(=O)O)ccc2c1
Reactant: Br
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=S(=O)(O)c1ccc2cc(Br)ccc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 22 %

Procedure:
A solution of sodium nitrite (2.7 g) in water (5 ml) was added during 2 hours to a stirred mixture of 6-amino-2-naphthalene-sulphonic acid (8.8 g), dilute aqueous hydrochloric acid (2.8% weight/volume, 20 ml) and water (15 ml) which had been cooled to 0° C. The mixture was stirred at 0° C. for 30 minutes and poured onto a stirred suspension of cuprous bromide (5.34 g) in dilute aqueous hydrobromic acid (2.8%, 20 ml). The mixture was stored at ambient temperature for 18 hours. The mixture was evaporated to give 6-bromo-2-naphthalenesulphonic acid which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][O:8][C:9]2=O)([O-:3])=[O:2].[CH3:15][NH2:16].CO>>[CH3:15][N:16]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])[C:9]1=[O:8]
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Reactant: CN
Solvent: CO
Product: Cn1ccc2c([N+](=O)[O-])cccc2c1=O

Procedure:
5-Nitro-isochromen-1-one (1.2 g, 0.0063 mol) and 40% aqueous methylamine (10 mL, 0.09 mol) were refluxed in methanol (40 mL, 1 mol) for 1 hour. The solvents were removed and the residue was diluted with CH2Cl2/MeOH (95:5 v/v, 100 mL), washed with brine (20 mL×2). The CH2Cl2 layer was dried over Na2SO4, purified via flash chromatography (40 g of silica gel, 0-50% EtOAc/Hexanes) to give a yellow solid. MS m/z (M+H) 204.8.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([F:12])([F:11])[O:7][C:6]=2[C:5]([F:13])=[CH:4][CH:3]=1.C(O[B:18]1[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]1)(C)C.[NH4+].[Cl-].Cl>O1CCCC1.C(OCC)(=O)C>[CH3:25][C:20]1([CH3:26])[C:21]([CH3:24])([CH3:23])[O:22][B:18]([C:2]2[C:10]3[O:9][C:8]([F:12])([F:11])[O:7][C:6]=3[C:5]([F:13])=[CH:4][CH:3]=2)[O:19]1
Reactant: Fc1ccc(Br)c2c1OC(F)(F)O2
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2ccc(F)c3c2OC(F)(F)O3)OC1(C)C
Temperature: -5 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
4-Bromo-2,2,7-trifluorobenzo[d][1,3]dioxole (2.0 g, 7.8 mmol) was dissolved in dry tetrahydrofuran (12 ml), cooled to −5° C. and treated in portions with isopropylmagnesium lithium chloride complex (1.3 M; 6.3 mL, 8.2 mmol). The mixture was stirred for 2 h at 5 to 15° C., treated with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.6 g, 8.4 mmol) and stirred for 2 h at 10 to 20° C. The mixture was treated with saturated NH4Cl (5 mL), stirred for 10 min and then shaken with 1 M HCl (10 mL) and ethyl acetate (75 mL). The organic phase was washed with saturated NaCl (10 mL), dried (Na2SO4) and evaporated to give the title compound as a white solid (2.3 g, 98%): 1H NMR (400 MHz, CDCl3) δ 7.41 (dd, J=8.7, 5.3 Hz, 1H), 6.88 (dd, J=9.5, 8.8 Hz, 1H), 1.36 (s, 12H); 19F NMR (376 MHz, CDCl3) δ −49.07, −131.31; EIMS m/z 302.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH:11]1([C@@H:14]([NH2:16])[CH3:15])[CH2:13][CH2:12]1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([NH:16][C@H:14]([CH:11]2[CH2:13][CH2:12]2)[CH3:15])=[O:10])=[N:6][CH:7]=1
Reactant: C[C@H](N)C1CC1
Reactant: O=C(O)c1cnc(Cl)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)c1cnc(Cl)cn1)C1CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 79.8 %

Procedure:
A mixture of 5-chloropyrazine-2-carboxylic acid (0.5 g, 3 mmol), (1S)-1-cyclopropylethanamine (0.30 g, 3.5 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (1.8 g, 4.7 mmol) and N,N-diisopropylethylamine (1.6 mL, 9.5 mmol) in methylene chloride (5 mL) was stirred at room temperature overnight (22 h.). The mixture was concentrated under reduced pressure. The residue was was purified by flash chromatography on a silica gel column with methanol in dichloromethylene (0-5%) to afford the desired product (0.54 g). LCMS (M+H)+: m/z=226.1.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[F:7])=[O:5].[CH2:16]([O:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23]([CH3:31])=[CH:24][C:25]([CH3:30])([CH3:29])[O:26]2)=[CH:21][C:20]=1[C:32](=O)[CH2:33][CH3:34])[CH3:17]>>[CH2:16]([O:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23]([CH3:31])=[CH:24][C:25]([CH3:30])([CH3:29])[O:26]2)=[CH:21][C:20]=1/[C:32](/[CH2:33][CH3:34])=[C:6](/[F:7])\[C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH3:17]
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: CCOc1cc2c(cc1C(=O)CC)C(C)=CC(C)(C)O2
Product: CCOC(=O)/C(F)=C(/CC)c1cc2c(cc1OCC)OC(C)(C)C=C2C

Procedure:
Following General Procedure K, triethyl-2-fluoro-2-phosphonoacetate (993 mg, 4.11 mmol) and 1-(7-ethoxy-4-methyl-2,2-dimethyl-2H-chromen-6-yl)-propan-1-one (Compound 60, 225 mg, 0.82 mmol) were reacted to give the title compound as a colorless oil after purification by flash chromatography (silica gel, 5% ethyl acetate in hexanes).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH2:22])(C)(C)C.[Cl:24][C:25]1[CH:26]=[C:27]([C:31]2OC(C)(C)O[C:33](=[O:39])[CH:32]=2)[CH:28]=[CH:29][CH:30]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:24][C:25]1[CH:26]=[C:27]([C:31]2[CH2:32][C:33](=[O:39])[NH:22][C:9]3[CH:10]=[C:11]([C:14]#[C:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:12]=[CH:13][C:8]=3[N:7]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(Cl)c2)O1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(Cl)c2)=Nc2ccc(C#Cc3ccccc3)cc2N1

Procedure:
Prepared from (2-amino-4-phenylethynyl-phenyl)-carbamic acid tert.-butyl ester (Example G2) and 6-(3-chloro-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J6) according to the general procedure K. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as an orange solid (155 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14].[OH-].[K+].[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1.O>CS(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[N:11]([CH2:25][C:24]1[CH:27]=[CH:28][C:21]([O:20][CH3:19])=[CH:22][CH:23]=1)[C:12](=[O:16])[CH:13]([CH3:14])[CH3:15]
Reactant: COc1ccc(CCl)cc1
Reactant: COc1cc(NC(=O)C(C)C)c(Br)cc1C
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CN(C(=O)C(C)C)c2cc(OC)c(C)cc2Br)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 89.9 %

Procedure:
To a solution of N-(2-bromo-5-methoxy-4-methyl-phenyl)-isobutyramide (6.83 g) in DMSO (40 mL) was added powder KOH (2.68 g, 47.7 mmol) and 4-methoxybenzyl chloride (7.5 g, 47.7 mmol) under argon. The mixture was stirred at room temperature for 17 hours. Water (30 mL) was added and the mixture extracted with EtOAc, washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:EtOAc/10:1 t0 3:1) to give 8.72 g of N-(2-bromo-5-methoxy-4-methyl-phenyl)-N-(4-methoxy-benzyl)-isobutyramide (90%). 1H NMR (300 MHz, CDCl3, ppm): δ: 1.00 (d, J=7.03 Hz, 3 H), 1.13 (d, J=6.45 Hz, 3 H), 2.17 (s, 3 H), 2.28 (m, 1 H), 3.48 (s, 3 H), 3.78 (s, 3 H), 3.84 (d, J=14.07 Hz, 1 H), 5.62 (d, J=14.07 Hz, 1 H), 6.06 (s, 1 H), 6.78–6.81 (m, 2 H), 7.10–7.13 (m, 2 H), 7.38 (s, 1 H).
Reaction SMILES: ClC(OC(Cl)C)=O.C([N:15]1[CH2:24][CH2:23][C:22]2[C:21]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[N:20][C:19]([CH2:36][O:37][CH3:38])=[N:18][C:17]=2[CH2:16]1)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C>ClCCCl>[F:35][C:32]([F:33])([F:34])[C:29]1[CH:30]=[CH:31][C:26]([NH:25][C:21]2[C:22]3[CH2:23][CH2:24][NH:15][CH2:16][C:17]=3[N:18]=[C:19]([CH2:36][O:37][CH3:38])[N:20]=2)=[CH:27][CH:28]=1
Reactant: COCc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(Cc1ccccc1)C2
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCNC2
Temperature: 60 °C
Reaction time: 2 h

Procedure:
1-Chloroethyl chloroformate (543 mg, 3.8 mmol) was added dropwise to a mixture of 7-benzyl-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2-(methoxymethyl)pyrido[3,4-d]pyrimidin-4-amine from Example 31 (820 mg, 1.9 mmol) and diisopropylethyl amine (490 mg, 3.8 mmol) in 1,2-dichloroethane (5 mL, anhydrous) at room temperature. After addition, the reaction mixture was stirred at 60° C. for 2 h under nitrogen. Solvent was removed in vacuo, residue was dissolved in methanol (10 mL) and was stirred at 60° C. for 1 hr. Solvent was removed in vacuo, residue was dissolved in ethyl acetate and was washed with saturated aqueous sodium bicarbonate, brine and dried over sodium sulfate. Solvent was removed in vacuo and light orange oily residue which was usd directly in the next step.
Reaction SMILES: C([O:3][C:4]1[C:9]([C:10]2[S:14][C:13]([CH2:15][NH:16][C:17]([C:19]3[NH:20][CH:21]=[C:22]([C:24](=[O:34])[C:25]4[C:30]([F:31])=[CH:29][C:28]([F:32])=[CH:27][C:26]=4[F:33])[CH:23]=3)=[O:18])=[N:12][N:11]=2)=[CH:8][CH:7]=[CH:6][N:5]=1)C.Cl>O1CCOCC1>[O:3]=[C:4]1[C:9]([C:10]2[S:14][C:13]([CH2:15][NH:16][C:17]([C:19]3[NH:20][CH:21]=[C:22]([C:24](=[O:34])[C:25]4[C:26]([F:33])=[CH:27][C:28]([F:32])=[CH:29][C:30]=4[F:31])[CH:23]=3)=[O:18])=[N:12][N:11]=2)=[CH:8][CH:7]=[CH:6][NH:5]1
Reactant: CCOc1ncccc1-c1nnc(CNC(=O)c2cc(C(=O)c3c(F)cc(F)cc3F)c[nH]2)s1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NCc1nnc(-c2ccc[nH]c2=O)s1)c1cc(C(=O)c2c(F)cc(F)cc2F)c[nH]1
Temperature: 25 °C
Reaction time: 7 h
Yield: 98.8 %

Procedure:
To N-{[5-(2-ethoxypyridin-3-yl)-1,3,4-thiadiazol-2-yl]methyl}-4-(2,4,6-trifluorobenzoyl)-1H-pyrrole-2-carboxamide (example 16) (102 mg, 021 mmol) was added 3 mL of 4M hydrogen chloride in 1,4-dioxane and the resulting suspension was stirred at rt for 7 hr. The reaction mixture was concentrated. The residue was triturated from dichloromethane to give the title compound (95 mg).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[NH:25]1[C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([NH2:34])[C:28]=2[CH:27]=[N:26]1>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:34][C:29]3[CH:30]=[CH:31][CH:32]=[C:33]4[C:28]=3[CH:27]=[N:26][NH:25]4)=[O:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Reactant: Nc1cccc2[nH]ncc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2cccc3[nH]ncc23)ncn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 6-((cyclopropylmethyl)(propyl)amino)pyrimidine-4-carboxylic acid (Intermediate 21, 230 mg; 0.98 mmol) in DCM (5 ml) was treated with polymer-supported Mukaiyama reagent (400 mg) and triethylamine (0.41 ml; 2.9 mmol) followed by 1H-indazol-4-amine (Key Organics, 150 mg; 1.12 mmol). After stirring at RT for 72 hours the mixture was filtered and washed with saturated sodium bicarbonate solution. The organic phase was passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.O.C(=O)([O-])[O-].[Na+].[Na+].Br[C:19]1[CH:27]=[C:26]2[C:22]([C:23]([NH:36][C:37](=[O:41])[CH2:38][CH2:39][CH3:40])=[N:24][N:25]2[CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])=[CH:21][CH:20]=1>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>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:19]1[CH:27]=[C:26]2[C:22]([C:23]([NH:36][C:37](=[O:41])[CH2:38][CH2:39][CH3:40])=[N:24][N:25]2[CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:33])[CH3:34])=[CH:21][CH:20]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Br)ccc12
Reactant: OB(O)c1ccccc1Cl
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: O
Solvent: C1COCCO1
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccccc3Cl)ccc12
Yield: 92.9 %

Procedure:
853 mg of 2-chlorophenylboronic acid, 30 cm3 of water, 964 mg of sodium carbonate and 252 mg of tetrakis(triphenylphosphine)palladium are added to 1 g of N-[6-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, prepared as described in Example 51, in 60 μm3 of dioxane. The reaction medium is then refluxed for 18 hours and filtered through a sinter funnel packed with Celite, and then concentrated to dryness under reduced pressure (2 kPa; 50° C.). The residue is taken up in 70 cm3 of ethyl acetate and the organic phase is washed with 2×30 cm3 of distilled water and then with 30 cm3 of saturated aqueous sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 45° C.). The residue obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a cyclohexane/ethyl acetate mixture (90/10 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); 1 g of N-[6-(2-chlorophenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide are obtained in the form of a yellow wax.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([S:38]([O:41][CH2:42][C:43](O)=[O:44])(=[O:40])=[O:39])[CH:33]=[CH:34][C:35]=1[O:36][CH3:37].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl.Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:43](=[O:44])[CH2:42][O:41][S:38]([C:32]1[CH:33]=[CH:34][C:35]([O:36][CH3:37])=[C:30]([O:29][CH3:28])[CH:31]=1)(=[O:40])=[O:39]
Reactant: COc1ccc(S(=O)(=O)OCC(=O)O)cc1OC
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)OCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 62 %

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (30 mg, 0.071 mmol), 2-(3,4-dimethoxyphenyl-sulfonyloxy)acetic acid (39.4 mg, 0.143 mmol), DMAP (8.72 mg, 0.071 mmol), and EDC (20.53 mg, 0.107 mmol) were dissolved in DCM (2 ml). The reaction was stirred at RT for 1.5 hours. The reaction mixture was diluted with HCl 1N and extracted with DCM. The organic phase was washed with HCl 1N, Na2CO3 sat and brine, dried over Na2SO4 and concentrated under vacuum. The crude product was triturated in EtOH to give (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(3,4-dimethoxyphenylsulfonyloxy)acetoxy)-ethyl)pyridine 1-oxide (30 mg, 0.044 mmol, 61.9% yield).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[Br:10][C:11]1[N:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=1.[OH-].[K+]>CO>[Br:10][C:11]1[N:16]=[CH:15][C:14]([CH:17]([C:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:1][CH:2]=2)[OH:18])=[CH:13][CH:12]=1
Reactant: c1cnc2[nH]ccc2c1
Reactant: O=Cc1ccc(Br)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: OC(c1ccc(Br)nc1)c1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.5 %

Procedure:
A mixture of 1H-Pyrrolo[2,3-b]pyridine (1, 1.2 g, 0.010 mol), 6-bromo-pyridine-3-carbaldehyde (88, 1.8 g, 0.0097 mol), and potassium hydroxide (1.8 g, 0.032 mol) in methanol (25 mL) was stirred at room temperature overnight. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with methanol in dichloromethane to provide the compound as a white solid (89, 1.4 g, 45%), or may be used as mixture of 89 and 90 in Step 2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH3:10].[Br:11]N1C(=O)CCC1=O>ClC(Cl)C.CC(N=NC(C#N)(C)C)(C#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][Br:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(Br)c(C)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC(Cl)Cl
Product: COc1ccc(Br)c(CBr)c1
Yield: 64 %

Procedure:
To a solution of 2-bromo-5-methoxytoluene (50 g, 0.25 mol) in dichloroethane (375 ml), N-bromosuccinimide (48.8 g, 0.275 mol) and AIBN (1.36 g) were added and the reaction was refluxed for 4 h. The cooled solution was filtered and the solvent was evaporated to give a weight of 44.8 g crude 1-Bromo-2-bromomethyl-4-methoxy-benzene (64% yield).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1.O[CH2:35][CH2:36][C@@H:37]([NH:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C:38]([O:40][CH:41]1[CH2:45][CH2:44][CH2:43][CH2:42]1)=[O:39]>C(Cl)Cl>[Br:1][CH2:35][CH2:36][C@@H:37]([NH:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C:38]([O:40][CH:41]1[CH2:45][CH2:44][CH2:43][CH2:42]1)=[O:39]
Reactant: CC(C)(C)OC(=O)N[C@H](CCO)C(=O)OC1CCCC1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](CCBr)C(=O)OC1CCCC1
Reaction time: 0.08 h
Yield: 83.7 %

Procedure:
To a slurry of N-bromo succinimide (1.86 g, 10.4 mmol) in DCM (16.2 ml) was added a solution of triphenyl phosphine (2.56 g, 9.74 mmol) in DCM (7.2 ml). The solution was stirred for a further 5 minutes after addition. Pyridine (338 μl, 4.18 mmol) was added, followed by a solution of cyclopentyl(2R)-4-hydroxy-2-[(tert-butoxycarbonyl)amino]butanoate (1.0 g, 3.48 mmol) in DCM (8.8 ml). The solution was stirred for 18 hrs, concentrated in vacuo and the residual solvent azeotroped with toluene (3×16 ml). The residue was triturated with diethyl ether (10 ml) and ethyl acetate:heptane (1:9, 2×10 ml). The combined ether and heptane solutions was concentrated onto silica and purified by column chromatography using ethyl acetate/heptane (1:9-2:8) to provide 1.02 g (84% yield) of title compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([CH2:16][NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[C:31]([O:35][C:36](=[O:39])[CH2:37]Cl)([CH3:34])([CH3:33])[CH3:32].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[C:31]([O:35][C:36](=[O:39])[CH2:37][N:17]([CH2:16][C:14]1[S:15][C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=2)=[CH:12][CH:13]=1)[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([F:30])([F:28])[F:29])(=[O:20])=[O:19])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)CCl
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CNS(=O)(=O)c3ccccc3C(F)(F)F)s2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)CN(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)S(=O)(=O)c1ccccc1C(F)(F)F

Procedure:
In analogy to example 10, step 3, N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-trifluoromethyl-benzenesulfonamide (example 27, step 1) was reacted with tert-butylchloroacetate and cesium carbonate in N,N-dimethylacetamide to give [[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-(2-trifluoromethyl-benzenesulfonyl)-amino]-acetic acid tert-butyl ester as a light yellow oil. MS: 606.6 ([M+NH4]+)