Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C)C)(C)C.Br[CH2:11][CH2:12][O:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].Cl.[O:25]=[C:26]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])[CH:39]=2)[O:34][C:28]2([CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH2:27]1.CO>CN(C=O)C.ClCCl.C(OCC)(=O)C.O>[CH3:45][S:42]([NH:41][C:38]1[CH:39]=[C:40]2[C:35](=[CH:36][CH:37]=1)[O:34][C:28]1([CH2:29][CH2:30][N:31]([CH2:11][CH2:12][O:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:32][CH2:33]1)[CH2:27][C:26]2=[O:25])(=[O:43])=[O:44]
Reactant: CC(C)(C)OC(=O)NCCOCCBr
Reactant: CS(=O)(=O)Nc1ccc2c(c1)C(=O)CC1(CCNCC1)O2
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCOCCN1CCC2(CC1)CC(=O)c1cc(NS(C)(=O)=O)ccc1O2
Temperature: 25 °C
Yield: 134.9 %

Procedure:
A solution of N,N-diisopropylethylamine (1.3 mL, 7.5 mmol), tert-butyl 2-(2-bromoethoxy)ethyl-carbamate (4, 0.59 g, 2.2 mmol), and N-(4-oxospiro[chroman-2,4′-piperidine]-6-yl)methanesulfon-amide hydrochloride (11, 0.5 g, 1.4 mmol) in 10 mL of anhydrous DMF was stirred at 60-65° C. After ˜24 hours TLC (silica gel, 10% methanol in dichloromethane, UV visualization) showed almost complete disappearance of starting amine 11 (Rf=0.02−0.06) and appearance of one major new product (Rf=0.35-0.45). The reaction was allowed to cool to room temperature and 10 mL of water was added. The resulting mixture was transferred to a separatory funnel with the aid of ethyl acetate and the layers were separated. The aqueous layer was extracted with 20 mL of ethyl acetate. The organic extracts were combined, washed successively with 10 mL portions of water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure on a rotary evaporator followed by high vacuum to provide 0.94 g of orange-brown oil.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH2:13]([N:15]1[C:21]2[N:22]=[CH:23][C:24]([CH2:26][CH2:27][OH:28])=[CH:25][C:20]=2[C:19](=[O:29])[N:18]([CH3:30])[C:17]2[CH:31]=[CH:32][C:33]([F:35])=[N:34][C:16]1=2)[CH3:14].O[C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]=[CH:39][CH:38]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[CH2:13]([N:15]1[C:21]2[N:22]=[CH:23][C:24]([CH2:26][CH2:27][O:28][C:37]3[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[N:40]=[CH:39][CH:38]=3)=[CH:25][C:20]=2[C:19](=[O:29])[N:18]([CH3:30])[C:17]2[CH:31]=[CH:32][C:33]([F:35])=[N:34][C:16]1=2)[CH3:14]
Reactant: CCN1c2ncc(CCO)cc2C(=O)N(C)c2ccc(F)nc21
Reactant: Oc1ccnc2ccccc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCN1c2ncc(CCOc3ccnc4ccccc34)cc2C(=O)N(C)c2ccc(F)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.5 %

Procedure:
Diethyl azodicarboxylate (DEAD) (14.3 mL, 91.0 mmol) was added drop-wise to a solution of 5,11-dihydro-11-ethyl-2-fluoro-8-(2-hydroxyethyl)-5-methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (19.2 g, 60.7 mmol), 4-hydroxyquinoline (13.2 g, 91.0 mmol) and Ph3P (23.9 g, 91.0 mmol) in THF (300 mL) at room temperature. The mixture was stirred at room temperature for 1 h then was concentrated under reduced pressure. The residue was purified by flash chromatography (EtOAc:MeOH; 95:5) to give the title compound (17.9 g, 67% yield) as a white solid: MS (ESI) m/z 444 (M)+.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20]Cl)=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:4][CH2:3]1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:4][CH2:3]1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCl
Reactant: C1CCNC1
Product: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCN1CCCC1

Procedure:
Using 3.9 g of N-(trans-4-methylcyclohexyl)-4-(2-chloroethoxy)-3-methoxycinnamamide (Example 138) and 18 ml of pyrrolidine, a reaction similar to that conducted in Example 142 was carried out. As a result, 2.68 g of N-(trans-4-methylcyclohexyl)-4-[2-(1-pyrrolidinyl)ethoxy]-3-methoxycinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](I)=[CH:4][N:3]=1.CC(C)([O-])C.[Na+].C1OCCOCCOCCOCCOCCOC1.[C:57](=[NH:70])([C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>CN(C)C=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([N:70]=[C:57]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)=[CH:4][N:3]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: COc1cc(-c2csc3c(I)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: [Pd]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Solvent: CN(C)C=O
Product: COc1cc(-c2csc3c(N=C(c4ccccc4)c4ccccc4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 95 °C
Yield: 64.8 %

Procedure:
A mixture of N-[4-(4-amino-7-iodothieno[3,2-c]pyridin-3-yl)-2-methoxyphenyl]-1-methyl-1H-indole-2-carboxamide (4.03 g, 7.72 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.283 g, 0.31 mmol, 9,9-dimethyl-4-5-bis(diphenylphosphino)xanthene (0.536 g, 0.93 mmol), sodium tert-butoxide (1.00 g, 10.42 mmol), 18-crown-6 (2.75 g, 10.42 mmol), and benzophenone imine (1.16 mL, 6.9 mmol) were combined in N,N-dimethylformamide (100 mL), and the solution was heated at 95° C. for 12 h. The reaction mixture was cooled to ambient temperature and concentrated. The residue was diluted with brine (100 mL) and extracted with methanol/dichloromethane (1:33, 3×150 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated. Purification of the residue by flash column chromatography on silica gel which had been deactivated with triethylamine (10% by volume of silica gel used), using a gradient of ethyl acetate/heptane (1:3 to 4:1) as the mobile phase afforded the title compound (2.71 g, 4.47 mmol) as a yellow foam: MS: (MH)+ 608; LCMS (Conditions a), Rt 2.27 min.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(O[C@H:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:13][O:12][CH2:11]1)(=O)=O>CS(C)=O.O>[N:1]([C@H:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:13][O:12][CH2:11]1)=[N+:2]=[N-:3]
Reactant: CS(=O)(=O)O[C@@H]1COC[C@@H]1c1ccc(F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=N[C@@H]1COC[C@@H]1c1ccc(F)cc1
Reaction time: 4 h
Yield: 93.3 %

Procedure:
Sodium azide (30 g, 0.46 mol, 3.0 eq) was added under vigorous stirring to a mixture of compound (3S*,4S*)-4-(4-fluorophenyl)tetrahydrofuran-3-yl methanesulfonate (Preparation 60, 40 g, 0.15 mol, 1 eq) in dimethylsulfoxide (200 mL). The mixture was stirred on a water bath at 80 C for 4 h, cooled, diluted with water (700 mL), and extracted with ether (3×300 mL). The combined organic layer was washed with water (300 mL) and the saturated sodium chloride solution, dried over sodium sulfate, and rotary evaporated in the absence of vacuum at a bath temperature of 70° C. The residue was evaporated in water-aspirator vacuum at a bath temperature of 70° C. to give title compound (29.6 g, 0.14 mol, 94%).
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:8]([NH2:11])(=[O:10])=[O:9])=[C:5]([Br:7])[N:6]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1>[Br:7][C:5]1[N:6]=[C:2]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[S:3][C:4]=1[S:8]([NH2:11])(=[O:10])=[O:9]
Reactant: NS(=O)(=O)c1sc(Br)nc1Br
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: NS(=O)(=O)c1sc(N2CCOCC2)nc1Br
Yield: 43.8 %

Procedure:
A mixture of 2,4-dibromothiazole-5-sulfonamide (0.515 g, 1.60 mmol), morpholine (0.153 mL, 1.76 mmol), THF (4.22 mL) and cesium carbonate (1.56 g, 4.80 mmol) in a sealed tube was heated to 80 degrees for 4 hours. The cooled reaction was concentrated in vacuo and the residue was taken up in ethyl acetate (50 mL) and water (25 mL). The layers were separated and the organic layer was washed with water (15 mL), dried and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/DCM=0/100→50/50) to give 230 mg (44% yield) of the title compound as a white solid. LC/MS (FA) ES+ 328, 330. 1H NMR (400 MHz, DMSO-d6) δ: 7.76 (s, 2H), 3.69-3.66 (m, 4H), 3.43-3.40 (m, 4H).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:14]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:12]2[N:11]3[CH2:19][CH2:20][N:21]([C:26]4[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[C:29]([C:36](=[O:38])[CH3:37])=[CH:28][N:27]=4)[CH:22]([CH:23]([CH3:25])[CH3:24])[C:10]3=[CH:9][C:8]=2[CH:7]=1)(=O)C.[Li+].[Cl-].[CH2:41]1COCC1.C[Mg]Cl.[NH4+].[Cl-]>C1COCC1.O>[OH:4][CH2:5][C:6]1[C:14]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:12]2[N:11]3[CH2:19][CH2:20][N:21]([C:26]4[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[C:29]([C:36]([OH:38])([CH3:41])[CH3:37])=[CH:28][N:27]=4)[CH:22]([CH:23]([CH3:25])[CH3:24])[C:10]3=[CH:9][C:8]=2[CH:7]=1
Reactant: CC(=O)OCc1cc2cc3n(c2cc1S(C)(=O)=O)CCN(c1ncc(C(C)=O)c(C(F)(F)F)n1)C3C(C)C
Reactant: C1CCOC1
Agent: C[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Product: CC(C)C1c2cc3cc(CO)c(S(C)(=O)=O)cc3n2CCN1c1ncc(C(C)(C)O)c(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (2-(5-acetyl-4-(trifluoromethyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydropyrazino[1,2-a]indol-8-yl)methyl acetate (37 mg, 67 μmol) in dry THF (2 mL) was added LaCl3.2 LiCl THF solution (0.12 mL, 70 μmol). The resulting mixture was stirred for 20 min at rt. The reaction mixture was cooled down to 0° C., MeMgCl in THF solution (3.0 M, 0.15 mL) was added slowly and the reaction mixture was allowed to stir at the same temperature for 0.5 h. Sat. aq. NH4Cl (1 mL) and water (2 mL) were added. The aqueous layer was extracted with EtOAc (4×10 mL). Combined organic phases were dried (Na2SO4) and concentrated. The crude residue was purified by silica chromatography and SFC separation to give isomers of 2-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)propan-2-ol.
Reaction SMILES: N[C:2]1[S:3][C:4]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[N+]([O-])(OC(C)(C)C)=O.O.CCOC(C)=O>C1COCC1>[F:18][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([F:19])[C:12]=1[C:4]1[S:3][CH:2]=[N:6][C:5]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1nc(N)sc1-c1c(F)cccc1F
Agent: CC(C)(C)O[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ncsc1-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of ethyl 2-amino-5-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylate in THF was slowly added dropwise tert-butyl nitrate under heating under reflux. After completion of dropwise addition, it was further stirred at the same temperature for 4 hours. The reaction mixture was cooled to room temperature, followed by addition of water and extraction with EtOAc. The organic layer was washed with brine, dried, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:EtOAc=9:1-7:3) to obtain ethyl 5-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylate as a yellow oily substance.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:11]3[CH:12]=[CH:13][N:14]=[C:10]3[CH:9]=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[N:7]=2)[CH:3]=[N:2]1.[CH3:27]C1NN=CC=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:27][C:5]1[C:4]([C:6]2[N:11]3[CH:12]=[CH:13][N:14]=[C:10]3[CH:9]=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[N:7]=2)=[CH:3][NH:2][N:1]=1
Reactant: Cc1[nH]ncc1B1OC(C)(C)C(C)(C)O1
Reactant: c1cn2c(-c3cn[nH]c3)nc(-c3ccc(N4CCOCC4)cc3)cc2n1
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: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1n[nH]cc1-c1nc(-c2ccc(N3CCOCC3)cc2)cc2nccn12
Temperature: 100 °C
Yield: 48.1 %

Procedure:
4-(4-(5-Chloroimidazo[1,2-c]pyrimidin-7-yl)phenyl) morpholine (Example 113, Step D) (0.120 g, 0.381 mmol), 5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.119 g, 0.572 mmol) and potassium carbonate (0.158 g, 1.144 mmol) were suspended in a mixture of DME (5 mL) and water (2 mL) and de-gassed with Ar(g). Tetrakis(triphenylphosphine)palladium (0) (0.0220 g, 0.0191 mmol) was added and the reaction sealed and heated at 100° C. for 4 hours. The reaction mixture was diluted with water and filtered. The solids were washed with acetone and dried under high vacuum to afford 4-(4-(5-(3-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-7-yl)phenyl)morpholine (0.0660 g, 0.1831 mmol, 48.0% yield). MS (apci) m/z=361.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:34])[CH2:9][C:10]([C:12]2[C:13](O)=[C:14]([CH:22]3[CH2:26][CH2:25][N:24]([CH3:27])[CH:23]3[CH2:28][O:29]C(=O)C)[C:15]([O:20][CH3:21])=[CH:16][C:17]=2[O:18][CH3:19])=[O:11])=[C:4]([Cl:35])[CH:3]=1.C([O-])(O)=O.[Na+]>Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:34][C:13]3[C:12]([C:10](=[O:11])[CH:9]=2)=[C:17]([O:18][CH3:19])[CH:16]=[C:15]([O:20][CH3:21])[C:14]=3[C@@H:22]2[CH2:26][CH2:25][N:24]([CH3:27])[C@H:23]2[CH2:28][OH:29])=[C:4]([Cl:35])[CH:3]=1
Reactant: COc1cc(OC)c(C2CCN(C)C2COC(C)=O)c(O)c1C(=O)CC(=O)c1ccc(Br)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc(OC)c2c(=O)cc(-c3ccc(Br)cc3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CO
Reaction time: 3 h

Procedure:
To a solution of n-BuLi (15% solution in hexane, 4.23 mL, 10 mmol) in THF (25 mL), maintained at 0° C. under nitrogen atmosphere, hexamethyldisilazane (2.1 mL, 10 mmol) was added dropwise and stirred for 15 min. To this, a solution of the compound of example (32)(2.8 g, 5 mmol) in THF (25 mL) was added drop wise, maintaining the temperature at 0° C. After the addition, the reaction was allowed to warm to room temperature and stirred for 2.5 hrs. The reaction mixture was acidified with dilute HCl, and basified with 10% sodium bicarbonate to pH 8-9. The aqueous layer was extracted with chloroform (3×50 mL). The organic layer was washed with water (25 mL), brine (25 mL) and dried over anhydrous Na2SO4. The organic layer was concentrated under reduced pressure and dried under vacuum to yield acetic acid 3-{3-[3-(4-bromo-2-chloro-phenyl)-3-oxo-propionyl]-2-hydroxy-4,6-dimethoxy-phenyl}-1-methyl-pyrrolidin-2-ylmethyl ester as a brown solid (2.65 g). This ester was dissolved in conc. HCl (20 mL) and stirred for 3 hrs. to effect cyclisation. At the end of 3 hrs, the reaction mixture was basified with solid NaHCO3 to pH 8-9. The aqueous layer was extracted with chloroform (50×3 mL) and washed with water (25 mL) and brine (25 mL). The organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure and dried over vacuum. The residue was purified by column chromatography with 3% methanol in chloroform and 0.01% ammonia as eluent to yield the compound, (+)-trans-2-(4-bromo-2-chloro-phenyl)-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-dimethoxy-chromen-4-one, as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[C:31]([NH2:35])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([NH:35][C:14]([C:7]1([CH3:17])[CH2:6][CH2:5][C:4]2[C:9](=[C:10]([CH3:13])[C:11]([CH3:12])=[C:2]([OH:1])[C:3]=2[CH3:18])[O:8]1)=[O:16])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)N
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NC(C)(C)C)O2
Yield: 20.5 %

Procedure:
Following the amide coupling procedure described in protocol A, 500 mg 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.00 mmol), 355 mg CDI (2.20 mmol) and 160 mg t-butylamine (2.20 mmol) produced 125.1 mg of N-tert-butyl-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide as a white crystalline solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH:16]([C:20]([OH:22])=O)[CH2:15]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[NH2:30][CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=1)=[O:33]>C(Cl)Cl.CN(C=O)C.O>[CH3:41][O:40][C:36]1[CH:35]=[C:34]([C:32](=[O:33])[CH2:31][NH:30][C:20]([CH:16]2[O:17][CH2:18][CH2:19][N:14]([CH2:13][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:15]2)=[O:22])[CH:39]=[CH:38][CH:37]=1
Reactant: COc1cccc(C(=O)CN)c1
Reactant: O=C(O)C1CN(Cc2ccccc2)CCO1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)CNC(=O)C2CN(Cc3ccccc3)CCO2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
Oxalyl chloride (1.139 mL, 13.02 mmol) was added to a suspension of 4-(phenylmethyl)-2-morpholinecarboxylic acid (2.237 g, 8.68 mmol) and DMF (0.034 mL, 0.434 mmol) in CH2Cl2 (80 mL) at 0° C., and the resulting mixture was stirred at 25° C. for 2 hours. The mixture was concentrated, and the resulting residue was dissolved in CH2Cl2 (80 mL). The resulting brown solution was added to a suspension of triethylamine (3.63 mL, 26.0 mmol) and 2-amino-1-[3-(methyloxy)phenyl]ethanone (1.75 g, 8.68 mmol) in CH2Cl2 at 0° C., and the reaction mixture was stirred at 25° C. for 3 hours. Water (150 mL) was added to the reaction mixture, and the resulting mixture was extracted with CH2Cl2 (3×100 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. Purification by silica gel chromatography eluting with EtOAc in PE from 0% to 50% afforded the title compound (1.6 g) as an orange oil. LC-MS (ES) m/z=369 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([C:17](=[O:21])[CH2:18][CH2:19]Cl)[C:4]=2[CH:3]=1.ClC1C=CC2SC3C(=CC=CC=3)NC=2C=1.ClCCC(Cl)=O.ClC1C=CC2SC3C(=CC=CC=3)N(C(=O)CCCl)C=2C=1.OO.[NH:65]1[CH:69]=[CH:68][N:67]=[CH:66]1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([C:17](=[O:21])[CH2:18][CH2:19][N:65]3[CH:69]=[CH:68][N:67]=[CH:66]3)[C:4]=2[CH:3]=1
Reactant: c1c[nH]cn1
Reactant: O=C(CCCl)N1c2ccccc2S(=O)c2ccc(Cl)cc21
Agent: Clc1ccc2c(c1)Nc1ccccc1S2
Agent: O=C(CCCl)N1c2ccccc2Sc2ccc(Cl)cc21
Agent: O=C(Cl)CCCl
Solvent: c1ccccc1
Product: O=C(CCn1ccnc1)N1c2ccccc2S(=O)c2ccc(Cl)cc21
Reaction time: 0.5 h

Procedure:
A mixture of 68 g (0.2 mole) of 2-chloro-10-(3-chloropropionyl)-phenothiazine-5-oxide [obtainable by boiling 2-chlorophenothiazine with 3-chloropropionyl chloride in benzene for 12 hours and oxidizing the resulting 2-chloro-10-(3-chloropropionyl)-phenothiazine (melting point 110°-112°) with H2O2 ] and 68 g (1 mole) of imidazole is stirred at 110°-115° for 30 minutes. Working up in the customary manner gives 2-chloro-10-[3-(imidazol-1-yl)-propionyl]-phenothiazine-5-oxide, melting point 148°-149°. Hydrochloride, melting point 222°-223°.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:16](OC1C=CC(C(C2C=CC=CC=2)=O)=CC=1)[CH:17]=[CH2:18]>>[CH2:18]([C:15]1[CH:14]=[C:5]([CH:4]=[CH:3][C:2]=1[OH:1])[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7])[CH:17]=[CH2:16]
Reactant: C=CCOc1ccc(C(=O)c2ccccc2)cc1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Product: C=CCc1cc(C(=O)c2ccccc2)ccc1O
Yield: 46.2 %

Procedure:
4-hydroxybenzophenone (25 g) was converted to 4-allyloxybenzophenone (29.2 g, yellow solid) by the procedure of Example 23. Claisen rearrangement using that procedure gave 13.5 g (47%) of desired 3-allyl-4-hydroxybenzophenone, the balance being recovered. Finally, acylation of 3-allyl-4-hydroxybenzophenone (5.9 G) according to general procedure of Example 1 produced 6.9 g (86%) of product as yellow solid.
Reaction SMILES: [F:1][C:2]1([F:34])[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:33]=[CH:32][C:22]([C:23]([NH:25]C4CCOCC4)=[O:24])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:8]=2)[CH2:3]1.[O:35]1[CH2:40][CH2:39][CH:38]([CH2:41]N)[CH2:37][CH2:36]1>>[F:1][C:2]1([F:34])[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:20]=[CH:21][C:22]([C:23]([NH:25][CH2:41][CH:38]4[CH2:39][CH2:40][O:35][CH2:36][CH2:37]4)=[O:24])=[CH:32][CH:33]=3)(=[O:17])=[O:18])[CH:8]=2)[CH2:3]1
Reactant: O=C(NC1CCOCC1)c1ccc(S(=O)(=O)n2cc(C3CCC(F)(F)C3)c3ccccc32)cc1
Reactant: NCC1CCOCC1
Product: O=C(NCC1CCOCC1)c1ccc(S(=O)(=O)n2cc(C3CCC(F)(F)C3)c3ccccc32)cc1
Yield: 100 %

Procedure:
Using a similar procedure as for 4-[3-(3,3-Difluoro-cyclopentyl)-indole-1-sulfonyl]-N-(tetrahydro-pyran-4-yl)-benzamide using C-(Tetrahydro-pyran-4-yl)-methylamine in place of Tetrahydro-pyran-4-ylamine to give 4-[3-(3,3-Difluoro-cyclopentyl)-indole-1-sulfonyl]-N-(tetrahydro-pyran-4-ylmethyl)-benzamide (280 mg, 100% yield). Mass Spectrum (m/e): 503.98 (MH+).
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:37]([CH3:38])=[CH:36][C:18]2[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:23]=3)[S:21][C:17]=2[C:16]=1Br)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cl:40][C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=1.C([O-])([O-])=O.[K+].[K+]>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>[C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:37]([CH3:38])=[CH:36][C:18]2[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:23]=3)[S:21][C:17]=2[C:16]=1[C:44]1[CH:45]=[CH:46][C:41]([Cl:40])=[CH:42][CH:43]=1)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Cc1cc2nc(-c3cccc(OCc4ccccc4)c3)sc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
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: [K+]
Solvent: C1COCCO1
Product: Cc1cc2nc(-c3cccc(OCc4ccccc4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 120 °C
Yield: 97.8 %

Procedure:
The mixture of (S)-2-(2-(3-(benzyloxy)phenyl)-7-bromo-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (100 mg, 0.164 mmol), 4-chlorophenylboronic acid (38 mg, 0.246 mmol), 2N K2CO3 (400 μL), Pd(PPh3)4 (18 mg, 0.016 mmol) in dioxane in sealed tube was heated at 120° C. After the reaction is finished, the reaction mixture was washed by sat. NaHCO3, extracted by EtOAc, the organic phase was dried over MgSO4, filtered, concentrated down and purified by silica gel column (0-50% EtOAc in Hexanes) to give the product (103 mg, 97%). LCMS-ESI+: calc'd for C38H40ClNO4S: 642.2 (M+H+); Found: 642.3 (M+H+).