Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1([C:14]([O:16]C)=[O:15])[CH2:13][CH2:12]1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1([C:14]([OH:16])=[O:15])[CH2:12][CH2:13]1)[CH3:9])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1(CN(C)C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(CC1(C(=O)O)CC1)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
Methyl 1-{[(tert-butoxycarbonyl)(methyl)amino]methyl}cyclopropanecarboxylate was dissolved in methanol (6.8 mL) and water (5.8 mL) and treated with 10M sodium hydroxide (0.98 mL, 9.82 mmol). The solution was heated at 50° C. After 30 minutes, the reaction was cooled with an ice bath and quenched into a cold (ice bath temperature) mixture of 1N hydrogen chloride (19.6 mL) and saturated sodium chloride (19.6 mL). The product was extracted with ethyl acetate (3 times). The organic solution was dried over anhydrous sodium sulfate and filtered. Concentration of the organic solution gave the title compound (680 mg, 94% yield) which was used crude in the next step.
Reaction SMILES: [CH2:1]([N:5]1[C:6](=[O:40])[NH:7][C:8](=[O:39])/[C:9]/1=[CH:10]/[C:11]1[N:15]=[C:14]([CH2:16][CH2:17][CH2:18][CH3:19])[N:13]([C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:12]=1)[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].I[CH2:48][CH2:49][CH2:50][CH3:51]>CN(C=O)C.CCOCC>[CH2:1]([N:5]1[C:6](=[O:40])[N:7]([CH2:48][CH2:49][CH2:50][CH3:51])[C:8](=[O:39])/[C:9]/1=[CH:10]/[C:11]1[N:15]=[C:14]([CH2:16][CH2:17][CH2:18][CH3:19])[N:13]([C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(/C=C2/C(=O)NC(=O)N2CCCC)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCc1nc(/C=C2/C(=O)N(CCCC)C(=O)N2CCCC)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 16 h

Procedure:
To a solution of Z-1-butyl-5-[[2-butyl-3-(triphenylmethyl)-3H-imidazol-5-yl]methylene]-2,4-imidazolidinedione (1.20 g, 2.26 mmol) in DMF (5 mL) was added K2CO3 (1.56 g, 11.3 mmol) and then 1-iodobutane (0.344 mL, 3.02 mmol). The mixture was stirred for 16 hours and then diluted with ether and washed with water and brine. After drying over MgSO4 the product was isolated by chromatography on silica eluting with 80% petroleum ether 20% ethyl acetate.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]2=[CH:9][N:10]=[C:11]([CH3:12])[N:7]2[N:6]=[CH:5][N:4]=1.[CH:13]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)=O.[C:24](=[O:27])([O-])[O-].[Na+].[Na+]>C(O)C.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>[CH3:5][N:6]1[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH:24]=[O:27])=[CH:17][CH:16]=2)=[C:3]([C:9]2[N:10]=[C:11]([CH3:12])[N:7]3[C:8]=2[C:3]([NH:2][CH3:1])=[N:4][CH:5]=[N:6]3)[CH:8]=[N:7]1
Reactant: CNc1ncnn2c(C)ncc12
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CCO
Product: CNc1ncnn2c(C)nc(-c3cnn(C)c3-c3ccc(C=O)cc3)c12
Yield: 141.6 %

Procedure:
5-Bromo-1-methyl-1H-pyrazol-4-yl)-N,7-dimethylimidazo[5,1-f][1,2,4]triazin-4-amine (1.18 g, 3.66 mmol), (4-formylphenyl)boronic acid (604 mg, 4.03 mmol), tetrakis(triphenylphosphine)palladium(0) (423 mg, 0.366 mmol) and sodium carbonate (776 mg, 7.32 mmol) were combined in ethanol (20 mL), and the reaction mixture was heated at reflux for 18 hours. After cooling, solvent was removed in vacuo, and the residue was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification via silica gel chromatography (Gradient: 0% to 100% [18:1:1 ethyl acetate/methanol/triethylamine] in heptane) provided the crude product (900 mg), which was taken directly to the next step. LCMS m/z 348.2 (M+1). 1H NMR (400 MHz, CD3OD), product peaks only: δ 2.57 (s, 3H), 2.82 (s, 3H), 3.95 (s, 3H), 7.51 (br d, J=8.2 Hz, 2H), 7.75 (s, 1H), 7.78 (s, 1H), 7.92 (br d, J=8.5 Hz, 2H), 9.98 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:13])=[C:4]([C:8]([I:12])=[CH:9][C:10]=1[I:11])[C:5]([OH:7])=[O:6].[Cl:14][CH2:15][C:16](Cl)=[O:17]>CC(N(C)C)=O>[Cl:14][CH2:15][C:16]([NH:1][C:2]1[C:3]([I:13])=[C:4]([C:8]([I:12])=[CH:9][C:10]=1[I:11])[C:5]([OH:7])=[O:6])=[O:17]
Reactant: Nc1c(I)cc(I)c(C(=O)O)c1I
Reactant: O=C(Cl)CCl
Solvent: CC(=O)N(C)C
Product: O=C(CCl)Nc1c(I)cc(I)c(C(=O)O)c1I
Yield: 78.9 %

Procedure:
According to the procedure described in Example 1, a suspension of 103 g of 3-amino-2,4,6-triiodobenzoic acid (Beil. XIV, 414) (0.2 mol) in 200 ml of DMA is added to 24.8 g of chloroacetyl chloride (0.22 mol). 93.27 g of 3-[(2-chloroacetyl)amino]-2,4,6-triiodobenzoic acid are obtained (0.158 mol).
Reaction SMILES: Cl[C:2]1C=C(Cl)[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[OH:27])=[N:13][C:14]=1[CH2:15][CH3:16].[CH3:30][N:31]([CH3:42])[C:32]1[N:37]=CC(B(O)O)=C(C)[CH:33]=1>>[CH3:30][N:31]([CH3:42])[C:32]1[N:37]=[CH:2][C:3]([C:9]2[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][C@@H:19]3[OH:27])=[N:13][C:14]=2[CH2:15][CH3:16])=[C:4]([CH3:5])[CH:33]=1
Reactant: Cc1cc(N(C)C)ncc1B(O)O
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: CCc1nc(-c2cnc(N(C)C)cc2C)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 6-(dimethylamino)-4-methylpyridin-3-ylboronic acid and making non-critical variations provided the title compound as a light yellow amorphous solid. IR (diffuse reflectance) 3448, 2962, 2954, 2933, 1611, 1567, 1520, 1482, 1392, 1376, 1174, 1160, 1046, 741, 737 cm−1; OAMS supporting ions at: ESI+ 418.3; MS (EI) m/z 417 (M+); HRMS (FAB) calcd for C25H31N5O+H1 418.2607, found 418.2611. Anal. Calcd for C25H31N5O: C, 71.91; H, 7.48; N, 16.77. Found: C, 71.59; H, 7.57; N, 16.40.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([CH2:11][CH2:12][CH:13](C(OCC)=O)C(OCC)=O)=[C:5]([N:24]2[CH:28]=[CH:27][CH:26]=[CH:25]2)[CH:4]=1.[OH-:29].[Na+].[CH2:31]([OH:33])[CH3:32]>>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([CH2:11][CH2:12][C:13]([O:33][CH2:31][CH3:32])=[O:29])=[C:5]([N:24]2[CH:25]=[CH:26][CH:27]=[CH:28]2)[CH:4]=1
Reactant: CCOC(=O)C(CCc1cc(OC)c(OC)cc1-n1cccc1)C(=O)OCC
Reactant: CCO
Reactant: [OH-]
Agent: [Na+]
Product: CCOC(=O)CCc1cc(OC)c(OC)cc1-n1cccc1
Temperature: 150 °C

Procedure:
In 50 ml of ethanol was dissolved 3.1 g of diethyl (2-(4,5-dimethoxy-2-(1-pyrrolyl)phenyl)ethyl)malonate, and 5.0 ml of 35% sodium hydroxide was added to the solution, followed by heating under reflux for 3 hours. The solvent was removed under reduced pressure, and water was added to the residue. The residue was made acidic with concentrated hydrochloric acid and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to yield pale brown powder. The powder was heated at 150° C. for 10 minutes, allowed to cool, and purified by silica gel column chromatography (chloroform-methanol) to obtain 2.1 g of pale brown powder. Recrystallization from chloroform-ethyl ether gave the title compound as a colorless crystal.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13](=[O:15])[CH3:14].[Br:18]CC(C1C=C(Cl)C=CC=1Cl)=O>>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=[CH:5][C:4]=1[C:13](=[O:15])[CH2:14][Br:18]
Reactant: O=C(CBr)c1cc(Cl)ccc1Cl
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1C(F)(F)F
Product: O=C(CBr)c1ccc(C(F)(F)F)cc1C(F)(F)F
Yield: 63 %

Procedure:
This compound was prepared from 1-[2,4-bis(trifluoromethyl)phenyl]ethanone (5.0 g, 19.52 mmol) in the manner described for 2-bromo-1-(2,5-dichlorophenyl)ethanone, affording 4.12 g (63%) of a white solid. 1H-NMR (DMSO-d6) δ 8.28 to 8.16 (m, 3H), 4.98 (s, 2H);
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([S:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)[N:16]=2)[CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:36].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([C:27]([F:29])([F:30])[F:28])=[O:36])=[CH:22][CH:21]=3)[N:16]=2)[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(Cn2nc(-c3nc(-c4ccc(SC(F)(F)F)cc4)no3)cc2C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(Cn2nc(-c3nc(-c4ccc(S(=O)C(F)(F)F)cc4)no3)cc2C)cc1

Procedure:
To a mechanically stirred solution of 5-[5-methyl-1-(4-methylbenzyl)-1H-pyrazol-3-yl]-3-{4-[(trifluoromethyl)sulfanyl]phenyl}-1,2,4-oxadiazole (Example 105, 570 mg, 1.32 mmol) in dichloromethane (215 mL) was added 3-chloroperoxybenzoic acid (408 mg, 1.66 mmol) at a temperature of 0° C. The reaction mixture was stirred over night at the same temperature. Then saturated aqueous sodium bicarbonate solution (80 mL) was added, and the mixture was extracted with dichloromethane (3×30 mL). The combined organic extracts were dried over anhydrous sodium sulfate. After filtration and evaporation of the solvent, the title compound was obtained as a white solid after purification by MPLC (silica, cyclohexane/ethyl acetate 4:1) (346 mg, 59%): 1H NMR (400 MHz, DMSO-d6) 8.38 (d, 2H), 8.11 (d, 2H), 7.18 (d, 2H), 7.12 (d, 2H), 6.92 (s, 1H), 5.43 (s, 2H), 2.32 (s, 3H), 2.27 (s, 3H); ES-MS m/z 447, HPLC RT (Method E) 2.44 min.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([NH:8][C:9]2[S:10][C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Li+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([N:14]1[C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[N:19][C:11]=2[S:10][C:9]1=[N:8][C:7]1[CH:20]=[CH:21][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=c1nc(Nc2ccc([N+](=O)[O-])cc2)sc2ncccc12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Li+]
Product: O=c1c2cccnc2sc(=Nc2ccc([N+](=O)[O-])cc2)n1Cc1ccccc1
Yield: 75.1 %

Procedure:
The reaction procedure of Example 11 was followed except that 901 mg (3.0 mmol) of 2-(4-nitroanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 30 mg of lithium hydride and 616 mg of benzyl bromide were used. The resulting residue was then purified through silica gel column chromatography (eluant: chloroform) to obtain 880 mg of 3-benzyl-2,3-dihydro-2-[(4-nitrophenyl)imino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one (75%, recrystallized from a mixture of ether and hexane).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[N:3]=1.F[C:18]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=1[N+:26]([O-:28])=[O:27]>>[CH3:25][O:24][C:22]1[CH:21]=[CH:20][C:19]([N+:26]([O-:28])=[O:27])=[C:18]([N:14]2[CH2:13][CH2:12][C:11](=[CH:10][C:9]#[C:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[N:3]=3)[CH2:16][CH2:15]2)[CH:23]=1
Reactant: COc1ccc([N+](=O)[O-])c(F)c1
Reactant: Cc1cccc(C#CC=C2CCNCC2)n1
Product: COc1ccc([N+](=O)[O-])c(N2CCC(=CC#Cc3cccc(C)n3)CC2)c1
Yield: 48.2 %

Procedure:
A well homogenised mixture of the Compound of Example 3 (20 mg, 0.93 mmol) and 2-fluoro-4-methoxynitrobenzene (21.3 mg, 0.12 mmol) was stirred at 120° C. for 0.5 h. The reaction crude was purified by flash chromatography (EtOAc—Petroleum Ether 1:1) affording the title product (21 mg).
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][OH:5].C(Cl)CCl.CCN(CC)CC.[OH:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][C:29](O)=[O:30])=[CH:22][CH:21]=1>C1COCC1.CN(C1C=CN=CC=1)C>[OH:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][CH2:28][C:29]([O:5][CH2:4][CH2:3][Si:2]([CH3:7])([CH3:6])[CH3:1])=[O:30])=[CH:24][CH:25]=1
Reactant: O=C(O)CCCc1ccc(O)cc1
Reactant: C[Si](C)(C)CCO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOC(=O)CCCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.6 %

Procedure:
To a stirred solution of 2-(trimethylsilyl) ethanol (0.56 mL, 3.91 mmol) in THF (1 mL) at rt under nitrogen, was added 4-DMAP (113 mg, 0.92 mmol) followed by EDC (177 mg, 0.92 mmol). After about 1 minute Et3N (170 μL, 1.22 mmol) was added, drop-wise followed by 4-(4-hydroxyphenyl)butanoic acid (150 mg, 0.83 mmol) in THF (4 mL) and the mixture stirred at rt for 18 hours. The mixture was then partitioned between Et2O (25 mL) and aqueous HCl (2M, 30 mL) and the layers separated. The aqueous layer was re-extracted with Et2O (20 mL) and the combined organic layer washed with brine (50 mL), dried (MgSO4) and concentrated under vacuum to give a ‘chalk-white’ milky oil. Purification by SPE (silica, 5 g Cartridge) eluting with cyclohexane:EtOAc (gradient 25:1 to 1:2) afforded the title compound (55 mg).
Reaction SMILES: [F:1][CH:2]([F:17])[CH2:3][NH:4][CH:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:19]1[N:24]=[C:23]([NH:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]2[NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[C:22]([Cl:37])=[CH:21][N:20]=1>>[Cl:37][C:22]1[C:23]([NH:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]2[NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[N:24][C:19]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][CH:5]([NH:4][CH2:3][CH:2]([F:17])[F:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:20][CH:21]=1
Reactant: Nc1ccc2c(c1)CCC(NCC(F)F)CC2
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Product: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Nc2ccc3c(c2)CCC(NCC(F)F)CC3)ncc1Cl
Yield: 61 %

Procedure:
In an analogous procedure to Example 651, part c, N*7*-(2,2-Difluoro-ethyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine was combined with N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide to yield N-((1R,2R)-2-{5-Chloro-2-[7-(2,2-difluoro-ethylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-methanesulfonamide (69.11 mg, 61% yield) as a beige foam. 1H-NMR (CDCl3) δ 7.91 (s, 1H), 7.24 (m, 2H), 7.05 (d, J=7.7 Hz, 1H), 6.85 (s, 1H), 5.83 (m, 1H), 5.39 (m, 2H), 3.86 (m, 1H), 3.23 (m, 1H), 3.02 (m, 2H), 2.78 (m, 2H), 2.68 (m, 2H), 2.20 (br s, 2H), 2.07 (br s, 2H), 1.82 (br s, 2H), 1.36 (m, 7H). LC/MS (ESI+)=542 (M+H).
Reaction SMILES: Br[C:2]12[CH:10]3[CH2:11][CH:7]([CH:8]=[CH:9]3)[CH:6]1S[N:4]([C:12](C)(C)C)[C:3]2=[O:16].[S:17](Cl)(Cl)(=[O:19])=[O:18].[Cl:22]CCl>>[Cl:22][CH2:12][N:4]1[C:3](=[O:16])[C:2]2[CH:10]3[CH2:11][CH:7]([C:6]=2[S:17]1(=[O:19])=[O:18])[CH2:8][CH2:9]3
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(C)(C)N1SC2C3C=CC(C3)C2(Br)C1=O
Reactant: ClCCl
Product: O=C1C2=C(C3CCC2C3)S(=O)(=O)N1CCl
Reaction time: 2 h
Yield: 81 %

Procedure:
The sulfide (1.05 g, 3 mmol) in dichloromethane (100 mL) was treated with sulfuryl chloride (0.66 g, 5 mmol) and stirred for 2 hr. The resulting yellow solution was diluted with MDC (100 mL), washed with saturated NaHCO3 solution, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (33% MDC in hexanes) to give 0.66 g (81%) of 2-chloromethyl-4,5,6,7-tetrahydro-4,7-methano-1,2-benzisothiazol-3(2H)-one 1,1-dioxide.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:13]2[C:8](=[C:9]([N:22](CC3C=CC=CC=3)[S:23]([CH3:26])(=[O:25])=[O:24])[C:10]([O:14]CC3C=CC=CC=3)=[CH:11][CH:12]=2)[CH2:7][CH2:6][CH:5]=1.B(Br)(Br)[Br:35]>C(Cl)Cl>[BrH:35].[NH2:2][CH2:3][C:4]1[C:13]2[C:8](=[C:9]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[C:10]([OH:14])=[CH:11][CH:12]=2)[CH2:7][CH2:6][CH:5]=1
Reactant: BrB(Br)Br
Reactant: CS(=O)(=O)N(Cc1ccccc1)c1c(OCc2ccccc2)ccc2c1CCC=C2CN
Agent: Cl
Solvent: ClCCl
Product: Br
Product: CS(=O)(=O)Nc1c(O)ccc2c1CCC=C2CN

Procedure:
The dibenzyl compound of Example 32 is treated with BBr3 in CH2Cl2 to yield 1-aminomethyl-3,4-dihydro-6-hydroxy-5-methanesulfonylamino naphthalene HBr.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]1(O)[CH2:14][CH2:13][CH2:12]1.S(=O)(=O)(O)O.[H][H]>C(O)C.[Pd]>[CH:11]1([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C:2]([F:17])([F:1])[F:16])[CH2:12][CH2:13][CH2:14]1
Reactant: [H][H]
Reactant: OC1(c2cnccc2OCC(F)(F)F)CCC1
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CCO
Product: FC(F)(F)COc1ccncc1C1CCC1
Temperature: 50 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
To a solution of 1-[4-(2,2,2-Trifluoro-ethoxy)-pyridin-3-yl]-cyclobutanol (Example 108b, 3.88 g, 15.7 mmol) in ethanol (50 ml) under argon atmosphere was added sulfuric acid 97% (4.62 g, 2.51 ml, 47.1 mmol) and palladium(0) on charcoal 10% (384 mg, 3.61 mmol). The reaction vessel was pressurized with hydrogen to 2.5 bar and stirred at 50° C. for 18 hours. The reaction mixture was cooled down to room temperature, filtered through a pad of Celite and the filter cake was washed twice with ethanol. The filtrate was evaporated down to dryness, the residue was dissolved in ethylacetate and extracted with an 2.0M aqueous solution of sodium carbonate. The organic phase was collected and the aqueous phase was back-extracted with ethylacetate. The organic phases were combined, dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a dichloromethane/methanol gradient to yield the title compound (3.05 g, 84%) as yellow oil. MS (ESI, m/z): 232.6 (M+H+).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C[C:6]([O:8][C:9]([CH3:11])=[O:10])=O.CC1[S:17][C:16]([C:18](O)=O)=[CH:15][CH:14]=1.OS(O)(=O)=O>CO>[CH3:18][C:16]1[S:17][C:11]([C:9]([O:8][CH3:6])=[O:10])=[CH:14][C:15]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(C(=O)O)s1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1cc([N+](=O)[O-])c(C)s1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Fuming nitric acid (3 eq.) was added dropwise to Ac2O (5 eq.) at −20° C., then 5-methyl-2-thiophenecarboxylic acid (1 eq.) was added portion-wise and the mixture placed in an ice bath. After stirring at 0° C. for 1.5 h the reaction mixture was poured into ice, and when the ice was molten the precipitate was filtered off (66%). To a 1M solution of the latter in MeOH, conc. H2SO4 (1.4 eq.) was added at RT. The mixture was stirred overnight at reflux. All volatiles were evaporated i. vac., then the residual material was mixed with water and the resulting solution extracted with EtOAc; the organic layer was washed with sat. NaHCO3 and brine, dried over Na2SO4 and concentrated (98%). 1H-NMR (400 MHz, CDCl3, 300 K, δ) 8.21 (1H, s), 3.93 (s, 3H), 2.85 (s, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:43])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH3:41])[C:36]=2[CH3:42])[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:41][C:37]1[C:36]([CH3:42])=[C:35]([C:31]2[CH:30]=[C:29]([C:27]3[CH2:26][C:25](=[O:43])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:21])([F:23])[F:22])[C:12]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)[CH:40]=[CH:39][N:38]=1
Reactant: Cc1nccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)c1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nccc(-c2cccc(C3=Nc4cc(OCC(F)(F)F)c(C(F)(F)F)cc4NC(=O)C3)c2)c1C

Procedure:
The title compound was prepared from [2-{3-[3-(2,3-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M129) (0.32 g, 0.51 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (180 mg, 69%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[OH:7][C@H:8]([CH2:21][CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[C@H:9]([CH3:20])[O:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.I[C:30]1[C:31]([O:36][CH3:37])=[N:32][CH:33]=[CH:34][CH:35]=1>C(O)C.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>[CH3:37][O:36][C:31]1[C:30]([C:14]2[CH:15]=[CH:16][C:11]([O:10][C@@H:9]([CH3:20])[C@H:8]([OH:7])[CH2:21][CH2:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[CH:12][CH:13]=2)=[CH:35][CH:34]=[CH:33][N:32]=1
Reactant: COc1ncccc1I
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
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: CCO
Product: COc1ncccc1-c1ccc(O[C@@H](C)[C@H](O)CCc2cccnc2)cc1
Temperature: 25 °C

Procedure:
Prepared according to the method described in Example 21b) from 2M aqueous sodium carbonate (2.0 ml), (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (Example 21a), 0.508 g), 3-iodo-2-methoxypyridine (0.730 g, J. Org. Chem., 1988 53(12), 2740), and tetrakis(triphenylphosphine)palladium(0) (0.216 g) in ethanol (10 ml). The mixture was heated at reflux for 6 hours. After cooling to room temperature the mixture was concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with ethyl acetate to give an oil, which was further purified by normal phase HPLC eluting with 2-propanol:dichloromethane (3:97) to give the title compound as an oil.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:12][CH2:13][CH2:14][CH:15]([C:20]1[CH:25]=[CH:24][C:23]([B:26]2[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]2)=[C:22]([Cl:35])[CH:21]=1)[C:16]([O:18][CH3:19])=[O:17]>C1COCC1>[Cl:35][C:22]1[CH:21]=[C:20]([C:15]2([C:16]([O:18][CH3:19])=[O:17])[CH2:14][CH2:13][CH2:12]2)[CH:25]=[CH:24][C:23]=1[B:26]1[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]1
Reactant: COC(=O)C(CCCBr)c1ccc(B2OC(C)(C)C(C)(C)O2)c(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)c(Cl)c2)CCC1
Temperature: 0 °C
Reaction time: 12 h
Yield: 98.6 %

Procedure:
Lithium bis(trimethylsilyl)amide (0.872 mL, 0.87 mmol) was added dropwise to methyl 5-bromo-2-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pentanoate (Intermediate 7-3; 342 mg, 0.79 mmol) in THF (10 mL) cooled to 0° C. under nitrogen the reaction and was stirred at 0° C. for 12 hours. The reaction mixture was quenched with saturated NH4Cl (50 mL) and was diluted with EtOAc (75 mL). The organic layer was separated and re-extracted with EtOAc (75 mL). The combined organics were washed with saturated brine (50 mL), dried (MgSO4), filtered and concentrated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 1-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutanecarboxylate (273 mg, 98%) as a colourless gum.