Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[S:12][C:13]=1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([CH:23]([CH3:25])[CH3:24])=[N:21][N:22]=2)[N:19]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH:26]2[CH2:31][CH2:30][N:29]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:28][CH2:27]2)[S:12][C:13]=1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([CH:23]([CH3:25])[CH3:24])=[N:21][N:22]=2)[N:19]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)c1nnc2ccc(-c3sc(C4CCNCC4)nc3-c3ccc(F)cc3F)nn12
Solvent: ClCCl
Product: CC(C)c1nnc2ccc(-c3sc(C4CCN(S(C)(=O)=O)CC4)nc3-c3ccc(F)cc3F)nn12
Temperature: 2 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
A mixture of 4-(2,4-difluorophenyl)-5-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-2-(piperidin-4-yl)thiazole (0.25 g, 0.57 mmol, Example #Q.1.1), TEA (0.32 mL, 2.3 mmol) and DCM (5 mL) was cooled to about 0-4° C. Methanesulfonyl chloride (0.044 mL, 0.57 mmol) was added. The reaction mixture was stirred at about 04° C. for about 1 h. The reaction was quenched with saturated aqueous Na2CO3 solution. The aqueous layer was extracted with DCM (200 mL). The organic layer was dried over Na2SO4, decanted, and concentrated. The crude product was purified by RP-HPLC (Table 1, Method e) to give the title compound (0.14 g, 48%): LC/MS (Table 1, Method a) Rt=2.49 min; MS m/z: 519.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][CH2:14][CH2:15]I)[C:10](=[O:17])[C@@H:9]([CH2:18][C:19]#[N:20])[O:8][C@H:7]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[C:6]=2[CH:31]=1.[CH3:32][C:33]1[NH:34][CH:35]=[CH:36][N:37]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][CH2:14][CH2:15][N:34]3[CH:35]=[CH:36][N:37]=[C:33]3[CH3:32])[C:10](=[O:17])[C@@H:9]([CH2:18][C:19]#[N:20])[O:8][C@H:7]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[C:6]=2[CH:31]=1
Reactant: Cc1ncc[nH]1
Reactant: N#CC[C@H]1O[C@H](c2cccc3ccccc23)c2cc(Cl)ccc2N(CCCCI)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nccn1CCCCN1C(=O)[C@@H](CC#N)O[C@H](c2cccc3ccccc23)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 47.3 %

Procedure:
Trans-7-chloro-5-(1 -naphthyl)-1 -(4-iodobutyl)-2-oxo-1,2,3,5-tetrahydro-4,1 -benzoxazepine-3-acetonitrile (575 mg, 1.06 mmol), 2-methylimidazole (87 mg, 1.06 mmol) and potassium carbonate (146 mg, 1.06 mmol) were dissolved in DMF (5 ml) and the resulting solution stirred at 25° C. for 72 hours. Ethyl acetate was added and the solution washed with water (4×). The organic layer was dried (MgSO4), concentrated under reduced pressure and purified by flash column chromatography (ethyl acetate/diethylamine 95:5) to give the title compound (250 mg, 47%) as a colorless foam.
Reaction SMILES: C(NCC[C:6]1[C:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:10]=2[CH:9]=[CH:8][CH:7]=1)=O.P(Cl)(Cl)(Cl)=O.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH2:33][CH3:34])(=[O:32])=[O:31])=[CH:26][C:25]=1[C:35]1[NH:36][CH:37]=[CH:38][CH:39]=1.[BH4-].[Na+]>ClCCCl.O.CO>[C:6]1([N:36]([CH2:37][C:37]2[NH:36][C:35]([C:25]3[CH:26]=[C:27]([S:30]([CH2:33][CH3:34])(=[O:31])=[O:32])[CH:28]=[CH:29][C:24]=3[O:23][CH3:22])=[CH:39][CH:38]=2)[CH2:35][CH3:25])[C:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: CCS(=O)(=O)c1ccc(OC)c(-c2ccc[nH]2)c1
Reactant: O=CNCCc1cccc2c1CCCCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCCl
Product: CCN(Cc1ccc(-c2cc(S(=O)(=O)CC)ccc2OC)[nH]1)c1cccc2c1CCCCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 207.2 %

Procedure:
N-Formyl-N-(benzocycloheptan-1-yl)ethylamine (0.39 g, 1.81 mmol) was treated with phosphorus oxychloride (0.17 ml, 1.81 mmol) at room temperature under argon. After 30 minutes, 1,2-dichloroethane (1.2 ml) was added at 0° C. followed by a solution of 2-(2-methoxy-5-ethylsulfonylphenyl)-1H-pyrrole (0.4 g, 1.51 mmol) in 1,2-dichloroethane (4 ml). The mixture was allowed to warm to room temperature and stirred for 16 h at 25° C. and then for 6 h at 40° C. Sodium borohydride (0.55 g, 14.5 mmol) was then added at 0° C., and the reaction mixture was warmed to room temperature and stirred for 3 h. Water (2.4 ml) and then methanol (2.4 ml) were added dropwise. More water (30 ml) was added and the borane complex was extracted with dichloromethane (3×30 ml). The combined organics were dried (Na2SO4) and evaporated to an oil which was then treated with methanol (4.8 ml) and conc. HCl (2.4 ml) at room temperature for 16 h. The mixture was diluted with water (25 ml) and basified with 40% aqueous NaOH. Extraction into dichloromethane (3×30 ml), followed by drying (Na2SO4) and evaporation of the organic extracts gave an orange oil (0.73 g). The crude material was purified by chromatography on silica eluting with ethyl acetate (20-50%)--hexane, to give the title compound as an orange oil (0.31 g, 44%)
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:4][N:3]=1.[C:19](Cl)(=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[CH3:1][C:2]1[N:6]=[C:5]([C:7]2[S:11][C:10]([NH:12][C:19](=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[N:9][C:8]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:4][N:3]=1
Reactant: CCCCCC(=O)Cl
Reactant: Cc1noc(-c2sc(N)nc2-c2ccccc2)n1
Product: CCCCCC(=O)Nc1nc(-c2ccccc2)c(-c2nc(C)no2)s1

Procedure:
Prepared from 5-(3-methyl-[1,2,4]oxadiazol-5-yl)-4-phenyl-thiazol-2-ylamine and hexanoyl chloride.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:7][CH:6]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([O:17]C)[C:10]=3[CH:9]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C@H:20]([OH:33])[CH2:21][O:22][C:23]1[C:28]2[CH:29]=[C:30]([CH3:32])[O:31][C:27]=2[CH:26]=[CH:25][CH:24]=1.C([S-])C.[Na+]>CN(C=O)C>[CH3:1][C:2]1([CH3:34])[CH2:7][CH:6]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:10]=3[CH:9]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C@H:20]([OH:33])[CH2:21][O:22][C:23]1[C:28]2[CH:29]=[C:30]([CH3:32])[O:31][C:27]=2[CH:26]=[CH:25][CH:24]=1
Reactant: COc1cccc2sc(C3CCN(C[C@H](O)COc4cccc5oc(C)cc45)C(C)(C)C3)cc12
Agent: CC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(OC[C@@H](O)CN3CCC(c4cc5c(O)cccc5s4)CC3(C)C)cccc2o1
Yield: 37.9 %

Procedure:
A solution of (2S)-(+)-3-[2,2-dimethyl-4-(4-methoxybenzo[b]thiophen-2-yl)piperidin-1-yl]-1-(2-methylbenzofuran-4-yl)oxy-2-propanol (0.750 g, 1.56 mmol) and sodium ethanethiolate (2.10 g, 25.0 mmol) in DMF (26 mL) was heated at 90° C. for 14 h and concentrated under reduced pressure. The residue was then diluted with 50 mL of brine and extracted with CH2Cl2 (3×50 mL). The organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography [0 to 6% (2.0 M NH3 in MeOH)/CH2Cl2]. The residual DMF was removed as an azeotrope with xylenes and re-run through a column of silica gel [3.5% (2.0 M NH3 in MeOH)/CH2Cl2] to give the title compound as an off-white foam (0.2751 g, 37%). IR (KBr) 3593, 2969, 2936, 1281, 1085 cm−1. Ion Spray MS 466.2 (M+H)+; 464.3 (M−H)−. [α]D=55.26 (c 0.5791, MeOH). C27H31NO4S.0.2CH2Cl2
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[N+:17]([O-])=O)[O:5][CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].O.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27]([OH:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1.[H][H]>CO.[Pd]>[C:21]1([CH3:31])[CH:22]=[CH:23][C:24]([S:27]([OH:30])(=[O:28])=[O:29])=[CH:25][CH:26]=1.[NH2:17][C:16]1[CH:15]=[CH:14][C:4]([O:5][CH2:6][C:7]([O:9][C:10]([CH3:12])([CH3:13])[CH3:11])=[O:8])=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cc(OCC(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: Cc1cc(OCC(=O)OC(C)(C)C)ccc1N
Yield: 45.8 %

Procedure:
To a solution of the product from step (a) (4.18 g) in methanol (250 ml) under argon was added p-toluenesulphonic acid monohydrate (2.99 g) followed by 10% Pd on C (1.8 g). The argon was replaced by hydrogen and the reaction mixture was stirred under a blanket of hydrogen for 6 hours. The catalyst was filtered off through a pad of diatomaceous earth and washed with methanol. The blue-coloured filtrate and washings were evaporated to near dryness and excess ether was added. On storage overnight at -10° C. a solid crystallised which was collected, washed with ether and dried to give t-butyl 4-amino-3-methylphenoxyacetate, p-toluenesulphonate salt (2.93 g) as an off-white solid: NMR Spectrum (DMSO-d6) 1.42 (9H, s), 2.28 (3H, s), 2.30 (3H, s), 4.63 (2H, s), 6.82 (1H, dd), 6.88 (1H, d), 7.12 (2H, d), 7.24 (1H, d), 7.48 (2H, d), 9.50 (3H, br s); Mass Spectrum m/Z 260 (M+Na)+.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].[C:20](=O)([O-])[O-].[K+].[K+].IC.O>CN(C=O)C>[F:19][C:2]([F:1])([F:18])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:11][CH:12]=2)[N:7]([CH3:20])[CH:6]=1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: O=C(c1c[nH]c2cc(C(F)(F)F)ccc12)C(F)(F)F
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc(C(=O)C(F)(F)F)c2ccc(C(F)(F)F)cc21
Reaction time: 2 h
Yield: 93 %

Procedure:
To a mixture of 2,2,2-trifluoro-1-[6-(trifluoromethyl)-1H-indol-3-yl]ethanone (200 mg, 0.71 mmol) and potassium carbonate (246 mg, 1.8 mmol) in DMF (2 mL) was added iodomethane (0.067 mL, 1.1 mmol) at room temperature. After stirring at the same temperature for 2 hours, the mixture was poured into water, and the aqueous phase was extracted with EtOAc (ethyl acetate)-hexane (2:1, twice). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (4:1 (v/v)) to give 195 mg (93% yield) of the title compound as a pale brown solid:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]2[CH2:18][CH2:17]2)[CH3:15])[C:11]([Cl:19])=[CH:10][C:9]=1[NH2:20])(C)(C)C.C(O[C:27](=[O:39])[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][N:34]=[C:33]([C:37]#[N:38])[CH:32]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:19][C:11]1[C:12]([N:14]([CH:16]2[CH2:17][CH2:18]2)[CH3:15])=[CH:13][C:8]2[N:7]=[C:29]([C:31]3[CH:36]=[CH:35][N:34]=[C:33]([C:37]#[N:38])[CH:32]=3)[CH2:28][C:27](=[O:39])[NH:20][C:9]=2[CH:10]=1
Reactant: CN(c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl)C1CC1
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(c1cc2c(cc1Cl)NC(=O)CC(c1ccnc(C#N)c1)=N2)C1CC1

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(cyclopropyl-methyl-amino)-phenyl]-carbamic acid tert.-butyl ester (Example J11) (150 mg, 0.5 mmol) and 3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acid tert.-butyl ester (Example K3) (150 mg, 0.61 mmol) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (69 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[CH:5]2.[Li]CCCC.CON(C)[C:30](=[O:34])[CH2:31][CH2:32][CH3:33]>C1COCC1>[Si:15]([O:14][CH2:13][CH2:12][C:6]1[N:7]([CH3:11])[C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([C:30](=[O:34])[CH2:31][CH2:32][CH3:33])=[CH:10][CH:9]=2)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CCCC(=O)N(C)OC
Reactant: Cn1c(CCO[Si](C)(C)C(C)(C)C)cc2cc(Br)ccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC(=O)c1ccc2c(c1)cc(CCO[Si](C)(C)C(C)(C)C)n2C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 68.1 %

Procedure:
To solution of 5-bromo-2-(2-(tert-butyldimethylsilyloxy)ethyl)-1-methyl-1H-indole (9.963 g, 27.04 mmol) in THF (100 mL) at −78° C. was added solution of n-BuLi (2.5M hexanes, 13.0 mL, 32.50 mmol) dropwise over 10 min. Reaction was stirred at −78° C. for 10 min before solution of N-methoxy-N-methylbutyramide (4.30 g, 32.78 mmol) in THF (10 mL) was added dropwise. Reaction was stirred at −78° C. for 15 min and then quenched with NH4Cl (aqueous saturated, 30 mL). Once ambient temperature was reached in the reaction mixture product was extracted with EtOAc (2×100 mL). Combined organics were washed with NaCl (aqueous saturated) and dried over Na2SO4. Upon solvent removal residue was purified by column chromatography using EtOAc/hexanes (gradient 0-30%) to afford 1-(2-(2-(tert-butyldimethylsilyloxy)ethyl)-1-methyl-1H-indol-5-yl)butan-1-one (6.620 g, 68%) as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[C:13]1[N:18]=[CH:17][C:16]([CH2:19][C:20]#[N:21])=[CH:15][CH:14]=1.B.C1COCC1>C1COCC1>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[C:13]1[N:18]=[CH:17][C:16]([CH2:19][CH2:20][NH2:21])=[CH:15][CH:14]=1
Reactant: COc1ccc2nccc(-c3ccc(CC#N)cn3)c2n1
Agent: B
Solvent: C1CCOC1
Product: COc1ccc2nccc(-c3ccc(CCN)cn3)c2n1
Reaction time: 24 h

Procedure:
To a stirred solution of [6-(6-methoxy[1,5]naphthyridin-4-yl)pyridin-3-yl]acetonitrile (0.26 g, 0.94 mmole), in THF (20 mL) at RT was added 1M BH3.THF (5 mL, 5.0 mmole). After 24 h, H2O (10 mL) wash added dropwise to the reaction solution followed by 1M HCl (10 mL). After 1 h, the reaction solution was made basic by addition of 6M NaOH (2 mL). The reaction contents were concentrated under vacuum and extracted with EtOAc (3×50 mL). The organic phase was dried over Na2SO4 and concentrated under vacuum affording the crude title compound as light orange solid which was used directly without further purification: LC-MS (ES) m/e 281 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH2:11][C:12]([CH2:15]Cl)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH2:11][C:12]([CH:15]=[CH2:18])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1CC(CCl)=NC=C1OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CC1=NC=C(OCc2ccccc2)C(=O)C1
Reaction time: 3 h
Yield: 66.2 %

Procedure:
A solution of 5-benzyloxy-2-chloromethyl-4-pyridone (10.0 g) and triphenylphosphine (10.5 g) in N,N-dimethylformamide (50 ml) was stirred for 5 hours at 90°-100° C. The resulting mixture was poured into ethyl acetate (800 ml). The precipitate was collected by filtration, washed with ethyl acetate and dissolved in dichloromethane (500 ml). To the solution were added water (300 ml) and 38% aqueous formaldehyde (100 ml). The mixture was adjusted to pH 10-10.5 with potassium carbonate. After being stirred for 3 hours at 35°-40° C., the organic layer was separated, washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The product was isolated by column chromatography on silica gel with ethyl acetate as an eluent to give 5-benzyloxy-2-vinyl-4-pyridone (6.02 g) .
Reaction SMILES: FC1C=C(C2C=C(F)C=CC=2OC)C=CC=1C(N[S:11]([C:14]1[C:15]([C:20]([F:23])([F:22])[F:21])=[N:16][N:17]([CH3:19])[CH:18]=1)(=[O:13])=[O:12])C.[Cl:33][C:34]1[CH:35]=[C:36]([C:42]2[CH:47]=[CH:46][C:45]([C@H:48]([NH2:50])[CH3:49])=[C:44]([O:51][CH3:52])[CH:43]=2)[C:37]([O:40][CH3:41])=[N:38][CH:39]=1>>[Cl:33][C:34]1[CH:35]=[C:36]([C:42]2[CH:47]=[CH:46][C:45]([C@H:48]([NH:50][S:11]([C:14]3[C:15]([C:20]([F:23])([F:21])[F:22])=[N:16][N:17]([CH3:19])[CH:18]=3)(=[O:13])=[O:12])[CH3:49])=[C:44]([O:51][CH3:52])[CH:43]=2)[C:37]([O:40][CH3:41])=[N:38][CH:39]=1
Reactant: COc1ccc(F)cc1-c1ccc(C(C)NS(=O)(=O)c2cn(C)nc2C(F)(F)F)c(F)c1
Reactant: COc1cc(-c2cc(Cl)cnc2OC)ccc1[C@@H](C)N
Product: COc1cc(-c2cc(Cl)cnc2OC)ccc1[C@@H](C)NS(=O)(=O)c1cn(C)nc1C(F)(F)F

Procedure:
A mixture of 4-bromo-2-hydroxyacetophenone (0.460 g, 2.0 mmol), titanium tetraethoxide (1.0 g, 4.0 mmol) and (R)-2-methyl-2-propanesulfinamide (0.266 g, 2.2 mmol) in dichloromethane (3.0 ml) was heated in a microwave oven at 120° C. for 15 min. The mixture was cooled in ice and added to a stirred mixture of sodium borohydride (0.30 g, 8.0 mmol) in tetrahydrofuran (50 ml). This mixture was stirred for 1 h at ambient temperature, treated with brine (30 ml) and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and the solvent evaporated The residue was flash chromatographed on silica gel eluting with 3:1 heptane/ethyl acetate to give (R)-2-methyl-propane-2-sulfinic acid [1-(4-bromo-2-methoxy-phenyl)-ethyl]-amide. A mixture of (R)-2-methyl-propane-2-sulfinic acid [1-(4-bromo-2-methoxy-phenyl)-ethyl]-amide (0.130 g, 0.4 mmol), 5-chloro-2-methoxy-pyridine-3-boronic acid (0.150 g, 0.8 mmol), tetrakis(triphenylphosphine)palladium (0) (0.025 g, 0.02 mmol), 2M aqueous sodium carbonate solution (2 ml), toluene (1 ml) and ethanol (1 ml) was heated in a microwave oven at 120° C. for 15 min. The mixture was partitioned between ethyl acetate and dilute aqueous sodium carbonate solution. The organic layer was dried over anhydrous sodium sulfate, the solvent evaporated and the residue dissolved in methanol. This solution was treated with 2M hydrogen chloride in diethyl ether solution. After standing for 2 hours, the mixture was poured onto an SCX column, washed with methanol and then eluted with 1M ammonia in methanol solution. The solvent was evaporated and the residue flash chromatographed on silica gel eluting with 98:2 ethyl acetate/2M ammonia in methanol to give (R)-1-[4-(5-chloro-2-methoxy-pyridin-3-yl)-2-methoxy-phenyl]-ethylamine. The title compound was prepared in a similar manner to 1-methyl-3-trifluoromethyl-1H-pyrazole-4-sulfonic acid [1-(3,5′-difluoro-2′-methoxy-biphenyl-4-yl)-ethyl]-amide (Example 30) using (R)-1-[4-(5-chloro-2-methoxy-pyridin-3-yl)-2-methoxy-phenyl]-ethylamine instead of 1-(3,5′-difluoro-2′-methoxy-biphenyl-4-yl)-ethylamine. MS (ESI) m/z: 505.0 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[C:8]([Cl:32])=[C:9]([C:28]([Cl:31])=[CH:29][CH:30]=1)[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[C:17]2[N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)[CH3:6])=[O:4].C(N(CC)CC)C.[S:40](Cl)([CH3:43])(=[O:42])=[O:41]>ClCCl>[Cl:32][C:8]1[C:7]([N:5]([C:3](=[O:4])[CH2:2][NH:1][S:40]([CH3:43])(=[O:42])=[O:41])[CH3:6])=[CH:30][CH:29]=[C:28]([Cl:31])[C:9]=1[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[C:17]2[N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: Cc1cc(-n2ccnc2)c2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)c2n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(-n2ccnc2)c2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNS(C)(=O)=O)c3Cl)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a stirred solution of 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-4-(imidazol-1-yl)-2-methylquinoline (80 mg) and triethylamine (22.4 mg) in dichloromethane (1 ml) was dropwise added mesyl chloride (21.4 mg) under ice-cooling, and the mixture was stirred for 15 minutes at the same temperature and for 2 hours at ambient temperature. The mixture was washed with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform:methanol, 10:1, v/v) to give 8-[2,6-dichloro-3-[N-(mesylglycyl)-N-methylamino]benzyloxy]-4-(imidazol-1-yl)-2-methylquinoline (70 mg) as colorless amorphous.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=[O:22])=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:34](=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.O>O1CCCC1.ClCCl>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH:18]([CH:34]([OH:41])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:17]2=[O:22])=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(N2CCCCC2=O)sc1C(=O)NCc1ccccc1
Reactant: O=Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: Cc1nc(N2CCCC(C(O)c3ccccc3)C2=O)sc1C(=O)NCc1ccccc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 3 %

Procedure:
To a solution of N-benzyl-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamide (0.25 g, 0.76 mmol) in anhydrous tetrahydrofuran (10 mL) at −78° C. was added lithium bis(trimethylsilyl)amide in tetrahydrofuran (0.83 mL, 0.83 mmol) dropwise. The reaction mixture was stirred at −78° C. for 5 minutes, followed by the dropwise addition of benzaldehyde (0.077 mL, 0.76 mmol). The resulting mixture was slowly warmed to −30° C. over 30 minutes, followed by the addition of water (5 mL) and extraction with dichloromethane (3×10 mL). The combined organic solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (ethyl acetate/hexanes (1/1)) to afford the title compound as a white solid (0.010 g, 3%): mp 74-75° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.42-7.22 (m, 10H), 6.01 (t, J=5.5 Hz, 1H), 5.63 (d, J=2.5 Hz, 1H), 4.57 (d, J=5.5 Hz, 2H), 4.38-4.30 (m, 1H), 3.91-3.81 (m, 1H), 2.88-2.82 (m, 1H), 2.63 (s, 3H), 2.09-1.51 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 171.7, 162.6, 152.0, 141.4, 137.9, 128.8, 128.6, 128.4, 127.9, 127.7, 127.5, 125.8, 119.7, 72.7, 49.8, 48.0, 44.1, 21.6, 19.4, 17.3; MS (ES+) m/z 436.2 (M+1).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[F:12][C:13]([F:34])([F:33])[C:14]1[CH:27]=[CH:26][C:25]2[S:24][C:23]3[C:18]4=[C:19]([C:28](=[O:32])[NH:29][C:30](=[O:31])[N:17]4[C:16]=2[CH:15]=1)[CH:20]=[CH:21][CH:22]=3>CO>[F:34][C:13]([F:33])([F:12])[C:14]1[CH:27]=[CH:26][C:25]2[S:24](=[O:9])[C:23]3[C:18]4=[C:19]([C:28](=[O:32])[NH:29][C:30](=[O:31])[N:17]4[C:16]=2[CH:15]=1)[CH:20]=[CH:21][CH:22]=3
Reactant: O=c1[nH]c(=O)n2c3c(cccc13)Sc1ccc(C(F)(F)F)cc1-2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Product: O=c1[nH]c(=O)n2c3c(cccc13)S(=O)c1ccc(C(F)(F)F)cc1-2

Procedure:
m-Chloroperbenzoic acid (1.9 g., 0.011 mol.) was added portion-wise to a cold (0-5°), stirred solution of 3.36 g. (0.01 mol.) of 10-trifluoromethyl-1H-pyrimido[5,4,3-kl]phenothiazine-1,3(2H)-dione in 35 ml. of absolute methanol. The reaction mixture was stirred in the cold for one hour, then an additional four hours at ambient temperature. The reaction mixture was chilled and the precipitated product was collected by filtration and washed with ice-cold methanol to give the title compound, m.p. 302-304° (methanol).