Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[NH2:11])([O-:3])=[O:2].C([O-])(O)=O.[Na+].Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19].O>C(#N)C.ClCCl>[CH2:21]([O:20][C:18](=[O:19])[NH:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([NH2:11])[CH:6]=1)[CH3:22]
Reactant: Nc1ccc([N+](=O)[O-])c(N)c1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: CCOC(=O)Nc1ccc([N+](=O)[O-])c(N)c1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
To a solution of 4-nitro-benzene-1,3-diamine (1.6 g) in acetonitrile (20 mL) was added NaHCO3 (1 g) and ethyl chloroformate (1.0 mL). The mixture was heated at 75° C. with stirring overnight. Cooled to ambient temperature, the mixture was diluted by water and extracted twice with ethyl acetate. Combined organics were dried over Na2SO4, filtered, and concentrated to give crude yellow solid. Trituration from dichloromethane afforded (3-amino-4-nitro-phenyl)-carbamic acid ethyl ester: 1H NMR (400 MHz, CD3OD) 7.9 (d, 1H), 7.3 (s, 1H), 6.5 (d, 1H), 4.2 (q, 2H), 1.3 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:25][C@@H:26]2[C@@H:31]3[CH2:32][C@@H:28]([CH:29]=[CH:30]3)[C@@H:27]2[C:33]([NH2:35])=[O:34])=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=3[CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH2:36]1[O:39][C@@H:37]1[CH3:38]>CO>[Cl:1][C:2]1[C:3]([NH:25][C@@H:26]2[C@@H:31]3[CH2:32][C@@H:28]([CH:29]=[CH:30]3)[C@@H:27]2[C:33]([NH2:35])=[O:34])=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=3[CH:19]3[CH2:20][CH2:21][N:22]([CH2:36][C@@H:37]([OH:39])[CH3:38])[CH2:23][CH2:24]3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(-c2nc3c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)c(Cl)cnc3[nH]2)c(C2CCNCC2)c1
Reactant: C[C@@H]1CO1
Solvent: CO
Product: COc1ccc(-c2nc3c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)c(Cl)cnc3[nH]2)c(C2CCN(C[C@H](C)O)CC2)c1
Yield: 16.3 %

Procedure:
(1S,2S,3R,4R)-3-[6-Chloro-2-(4-methoxy-2-piperidin-4-yl-phenyl)-3H-imidazo[4,5-b]pyridine-7-ylamino]-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (Compound XXX) (60 mg, 0.1 mmol) was stirred with (R)-propylene oxide (8.0 mg, 1.0 mmol) in methanol (5 mL) in a sealed tube overnight. The reaction was concentrated and the product purified by reverse phase chromatography (Gilson). Desired fractions were collected, combined, and neutralized by partitioning between dichloromethane and saturated sodium bicarbonate solution. The organic layer was separated, dried (magnesium sulfate) and concentrated to afford the title compound as a white solid 9 mg, 10%). 1H NMR (d-chloroform): 13.83 (br s, 1H), 7.89 (s, 1H), 7.66 (d, J=8 Hz, 1H), 7.07 (s, 1H), 6.97 (d, J=8 Hz, 1H), 6.32-6.28 (m, 3H), 5.62 (m, 1H), 5.22 (m, 2H), 3.95 (s, 3H), 3.87 (m, 1H), 3.70 (m, 1H), 3.15 (s, 1H), 3.07 (m, 1H), 2.93 (m, 2H), 2.74 (d, J=7 Hz, 1H), 2.36 (m, 4H), 1.99 (m, 3H), 1.76 (m, 3H), 1.28 (s, 1H), 1.18 (d, J=5 Hz, 3H). MS: 551.18 (M+H). HPLC retention time: 1.99 minutes (G Method).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:26][CH:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1)[C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH2:19][CH2:20][CH2:21][O:22]C(=O)C)[CH:14]=[CH:15][CH:16]=1.O1CCOCC1.[OH-].[Na+].Cl>O.CO>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:26][CH:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1)[C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH2:19][CH2:20][CH2:21][OH:22])[CH:14]=[CH:15][CH:16]=1
Reactant: CC(=O)OCCCC=Cc1cccc(C(OC2CCN(C)CC2)c2nc3ccccc3s2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: CN1CCC(OC(c2cccc(C=CCCCO)c2)c2nc3ccccc3s2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Acetic acid 5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-enyl ester (150 mg) in a mixture of water (1 mL), 1,4-dioxane (1 mL) and methanol (1 mL) is added 1N sodium hydroxide solution (0.6 mL). The reaction mixture is stirred at room temperature for 2 hours. After neutralization to pH 7 with addition of 1N hydrochloric acid, the reaction mixture is extracted with dichloromethane. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane/methanol/ammonia from 95/5/0.5 to 90/10/1) to afford 5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-en-1-ol.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[NH2:11])([O-])=O.[Na+].[CH2:13]([N:15]([CH2:20][CH3:21])[CH2:16][C:17]([O-])=[O:18])[CH3:14].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)CC)C>C(#N)C.C(O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[C:8]([NH:10][C:17](=[O:18])[CH2:16][N:15]([CH2:20][CH3:21])[CH2:13][CH3:14])[CH:7]=[CH:6][C:5]=1[NH2:11]
Reactant: Nc1ccc(N)c([N+](=O)[O-])c1
Reactant: CCN(CC)CC(=O)[O-]
Agent: [Pd]
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCN(CC)CC(=O)Nc1ccc(N)c(N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Nitrobenzene-1,4-diamine (1.55 g, 10.1 mmol), N,N-diethylglycine sodium salt (1.61 g, 10.6 mmol) and DEPBT (3.02 g, 10.0 mmol) were suspended in acetonitrile (75 mL). Triethylamine (2.8 mL, 20.0 mmol) was added and the solution stirred overnight at room temperature. The brown precipitate which was formed was filtered and discarded. The filtrate was concentrated and the residue partitioned between EA and saturated aqueous sodium bicarbonate. The organic phase was washed with water and then with brine, dried over sodium sulfate, and the solvent removed under reduced pressure. The residue was dissolved in ethanol (50 mL) and hydrogenated at atmospheric pressure with 10% palladium on charcoal (1.0 g, 0.9 mmol) at room temperature overnight. Filtration and concentration under reduced pressure gave N-(3,4-diaminophenyl)-2-(diethylamino)acetamide as a light brown semi-solid, which solidified and turned blue on standing.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])(=[O:5])=[O:4].C1C[O:22][CH2:21]C1.C([Li])(CC)C.CCCCCC>O.CN(C)C=O>[CH3:1][N:2]([CH3:18])[S:3]([N:6]1[C:10]([CH:21]=[O:22])=[CH:9][N:8]=[C:7]1[Si:11]([C:14]([CH3:15])([CH3:17])[CH3:16])([CH3:13])[CH3:12])(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)n1ccnc1[Si](C)(C)C(C)(C)C
Reactant: C1CCOC1
Agent: [Li]C(C)CC
Solvent: CCCCCC
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)n1c(C=O)cnc1[Si](C)(C)C(C)(C)C
Temperature: -20 °C
Reaction time: 1 h

Procedure:
1-Dimethylsulfamoyl-2-t-butyldimethylsilyl imidazole (3) (5.0 g, 17.3 mmol) was added to 100 mL of THF. The solution was cooled to −20° C. A solution of secondary butyl lithium (s-BuLi) in hexane (1.3M, 14.6 mL, 19 mmol) was added dropwise to the reaction flask. Upon completion the reaction was stirred for 1 h at −20° C. 8 mL of dimethylformamide (DMF) was added to the reaction and then stirred at rt for 3.5 h. The reaction was diluted with water and the organic layer separated. The organic phase was washed with brine and then dried over sodium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure. Column chromatography (20% ethyl acetate/hexane) afforded a light yellow oil. Upon cooling the product solidifies to give yellow crystals of 1-dimethylsulfamoyl-2-t-butyldimethylsilyl-5-imidazolecarboxaldehyde (4).
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=CC=1.[NH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]([N:50]2[CH2:55][CH2:54][N:53]([CH2:56][CH3:57])[CH2:52][CH2:51]2)=[O:49])=[CH:44][CH:43]=1.C(N1CCN(C2C=C(F)C(N)=C(F)C=2)CC1)C.[C:75](Cl)(Cl)=[S:76]>>[CH2:56]([N:53]1[CH2:52][CH2:51][N:50]([C:48]([C:45]2[CH:44]=[CH:43][C:42]([NH:41][C:75]([N:27]3[C:17]4[N:18]=[C:19]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[N:20]=[C:15]([C:12]5[CH:11]=[N:10][C:9]([NH2:8])=[N:14][CH:13]=5)[C:16]=4[CH2:29][CH2:28]3)=[S:76])=[CH:47][CH:46]=2)=[O:49])[CH2:55][CH2:54]1)[CH3:57]
Reactant: S=C(Cl)Cl
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: CCN1CCN(C(=O)c2ccc(N)cc2)CC1
Agent: CCN1CCN(c2cc(F)c(N)c(F)c2)CC1
Product: CCN1CCN(C(=O)c2ccc(NC(=S)N3CCc4c(-c5cnc(N)nc5)nc(N5CCOCC5)nc43)cc2)CC1
Yield: 62 %

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (80.9 mg) and (4-amino-phenyl)-(4-ethyl-piperazin-1-yl)-methanone (42 mg) obtained in Step B in Example 1-D-103 instead of 4-(4-ethyl-piperazin-1-yl)-2,6-difluoro-phenylamine, and thiophosgene (22.9 μl) instead of triphosgene, in the same manner as Step D in Example 1-D-18, 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carbothioic acid [4-(4-ethyl-piperazine-1-carbonyl)-phenyl]-amide was obtained as a crude product. The PMB groups were removed according to Deprotection method 3, to obtain the desired compound (D-232) as a colorless solid (54.1 mg, 62%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][OH:11].I(C1C=CC=CC=1C(O)=O)(=O)=O>C(OCC)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH:10]=[O:11]
Reactant: OCc1cc2ccccc2[nH]1
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CCOC(C)=O
Product: O=Cc1cc2ccccc2[nH]1
Temperature: 80 °C
Reaction time: 16 h
Yield: 50.7 %

Procedure:
A mixture of (1H-indol-2-yl)methanol (8.00 g, 54.4 mmol) and 2-iodoxybenzoic acid (“IBX”) (40.0 g, 0.163 mol) in ethyl acetate (200 mL) was stirred at 80° C. for 16 hours. The solid was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether/ethyl acetate (50:1) to give 1H-indole-2-carbaldehyde (4.0 g, 50% yield) as a solid. LCMS (ESI) m/z: 146.1 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][C:5]1[S:6][C:7]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:9]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>>[C:26]([O:1][CH2:2][CH2:3][S:4][C:5]1[S:6][C:7]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[N:9]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(-c2nc(SCCO)sc2-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2nc(SCCOC(C)=O)sc2-c2ccc(OC)cc2)cc1

Procedure:
5.0 g of 2-(2-hydroxyethylthio)-4,5-bis-(p-methoxyphenyl)-thiazole are suspended in 50 ml of acetic anhydride and, while stirring, the suspension is heated to the boil and refluxed for 15 minutes. The product is concentrated to dryness by evaporation under reduced pressure, two 30 ml portions of xylene are added, with concentration by evaporation being carried out again after each addition to remove traces of acetic anhydride, and the residue is dried under reduced pressure. 2-(2-Acetoxyethylthio)-4,5-bis-(p-methoxyphenyl)-thiazole is obtained in the form of an oil, Rf =0.33 (silica gel toluene/ethyl acetate 10:1), IR-spectrum: νC=O =1730 cm-1 (CCl4).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH:5]=[C:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2.[C:24]([Cu])#[N:25].CCOC(C)=O>CN1CCCC1=O.[Cu]I>[CH:17]1[C:8]2[CH2:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:6](=[CH:5][C:4]3[CH:21]=[C:22]([CH:23]=[CH:2][CH:3]=3)[C:24]#[N:25])[C:7]=2[CH:20]=[CH:19][CH:18]=1
Reactant: Brc1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Reactant: N#C[Cu]
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: N#Cc1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Reaction time: 1 h
Yield: 71.5 %

Procedure:
Purge a solution of 5-(3-bromo-benzylidene)-10,11-dihydro-5H-dibenzo-[a,d]cycloheptene (4.2 g, 11.6 mmol) in N-methylpyrrolidinone (80 mL) with nitrogen for 10 minutes. Add CuI (6.7 g, 35 mmol) and CuCN (3.1 g, 35 mmol) and heat to 130° C. After 1 hour, cool the reaction to ambient temperature and shake with aqueous FeCl3 (200 mL) and EtOAc (200 mL). Wash the organic layer with water, dry with MgSO4 and concentrate to obtain 6.4 g crude product. Purify on silica gel using EtOAc/hexane to obtain 2.55 g (71%) title compound as a white solid, mp 115.7° C. 1H NMR (CDCl3) δ 3.02 (br d, 2H), 3.40 (br d, 2H), 6.77 (s, 1H), 6.93 (dd, 1H), 7.02-7.49 (m,11H); MS (EI) 307. HPLC shows 98% purity.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([S:8][S:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([CH3:17])[CH:11]=2)[CH:5]=[CH:4][C:3]=1[OH:18].[C:19]([O:23][C:24](=[O:27])[CH2:25]Br)([CH3:22])([CH3:21])[CH3:20].[H-].[Na+]>CN(C=O)C.CCOCC>[C:19]([O:23][C:24](=[O:27])[CH2:25][O:16][C:13]1[CH:14]=[CH:15][C:10]([S:9][S:8][C:6]2[CH:5]=[CH:4][C:3]([O:18][CH2:25][C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:27])=[C:2]([CH3:1])[CH:7]=2)=[CH:11][C:12]=1[CH3:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1cc(SSc2ccc(O)c(C)c2)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1cc(SSc2ccc(OCC(=O)OC(C)(C)C)c(C)c2)ccc1OCC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To an ice cooled solution of 4.75 g (17.06 mmol) 4,4′-dithio-bis-(2-methyl-phenol) and 5.55 ml (37.6 mmol) bromo-acetic acid tert-butyl ester in 50 ml DMF was added 204 mg (85.3 mmol) sodium hydride (55% in oil). The reaction mixture was stirred over night at RT and then it was taken up in ether, washed with 1N HCl and water. The crude product was purified by chromatography over silica gel with AcOEt/heptane 1:4 providing 3.4 g pure [4-(4-tert-butoxycarbonylmethoxy-3-methyl-phenyldisulfanyl)-2-methyl-phenoxy]-acetic acid tert-butyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([C:14]([N:16]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20])=[O:15])=[N:9]2)=[C:4]([C:25]([N:27]2[C@H:36]([CH2:37][OH:38])[CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28]2)=[O:26])[CH:3]=1.[Si:39](Cl)([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40].N1C=CN=C1>C(Cl)Cl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([C:14]([N:16]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20])=[O:15])=[N:9]2)=[C:4]([C:25]([N:27]2[C@H:36]([CH2:37][O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28]2)=[O:26])[CH:3]=1
Reactant: CCCCN(CCCC)C(=O)c1cc(C)n(-c2ccc(Br)cc2C(=O)N2Cc3ccccc3C[C@H]2CO)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CCCCN(CCCC)C(=O)c1cc(C)n(-c2ccc(Br)cc2C(=O)N2Cc3ccccc3C[C@H]2CO[Si](C)(C)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.9 %

Procedure:
To a solution of (S)-1-(4-bromo-2-(3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N,N-dibutyl-5-methyl-1H-pyrazole-3-carboxamide (3.0 g, 5.2 mmol) in DCM (30 mL) were added TBDMS-chloride (0.93 g, 6.2 mmol), imidazole (0.70 g, 10.3 mmol) followed by stirring at RT for 5 h. The reaction mixture was diluted with water, extracted with EtOAc (100 mL×2), twice. The combined organic layers were washed with water (100 mL), brine (50 mL), dried over sodium sulphate and concentrated invacuo. The residue was purified on silica gel (100-200 mesh) to afford the title compound as a liquid 3.0 g (83%). Rf=0.66 (50% EtOAc in hexane); 1H NMR (400 MHz, DMSO-d6): δ 8.00-7.40 (m, 3H), 7.30-6.60 (m, 4H), 6.55-6.20 (m, 1H), 5.00-4.10 (m, 2H), 4.10-2.40 (m, 6H), 2.40-2.00 (m, 6H), 1.60-0.50 (m, 23H), 0.20-−0.40 (m, 6H); LC-MS: m/z 695.3 (M+H).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][CH2:27][S:28]([CH3:30])=[O:29])/[C:9]1=[O:31])=O)(C)(C)C.[F:32][C:33]1[CH:34]=[CH:35][C:36]([CH3:48])=[C:37]([CH:39]=[N:40][C:41]([O:43][Si](C)(C)C)=[CH2:42])[CH:38]=1>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:31])[C:10]3([CH:18]([C:19]4[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=4[O:26][CH2:27][S:28]([CH3:30])=[O:29])[CH2:42][C:41](=[O:43])[NH:40][CH:39]3[C:37]3[CH:38]=[C:33]([F:32])[CH:34]=[CH:35][C:36]=3[CH3:48])[C:11]2=[CH:12][CH:13]=1
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Reactant: CS(=O)COc1ccc(Cl)cc1/C=C1\C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)ccc21
Solvent: Cc1ccccc1
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCS(C)=O)C12C(=O)Nc1cc(Cl)ccc12
Yield: 9.7 %

Procedure:
In a manner similar to the method described in Example 10d, E/Z-6-chloro-3-(5-chloro-2-methanesulfinylmethoxy-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (400 mg, 0.83 mmol) was reacted with 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (5 mmol) in toluene to give the title compound as a white solid (45 mg).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:39])=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][O:24][C:25]3[CH:38]=[CH:37][C:28]4[C@H:29]([CH2:32][C:33]([O:35]C)=[O:34])[CH2:30][O:31][C:27]=4[CH:26]=3)[CH:18]=2)[C:5]([CH3:16])=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13].CO.[OH-].[Na+].Cl>O.O1CCCC1>[F:1][C:2]1[C:3]([CH3:39])=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][O:24][C:25]3[CH:38]=[CH:37][C:28]4[C@H:29]([CH2:32][C:33]([OH:35])=[O:34])[CH2:30][O:31][C:27]=4[CH:26]=3)[CH:18]=2)[C:5]([CH3:16])=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OCCCS(C)(=O)=O)c(F)c4C)c3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(OCCCS(C)(=O)=O)c(F)c(C)c1-c1cccc(COc2ccc3c(c2)OC[C@H]3CC(=O)O)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 61.8 %

Procedure:
To a solution of methyl [(3S)-6-({3′-fluoro-2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetate (0.418 g, 0.740 mmol) in a mixed solvent of methanol (4 mL) and tetrahydrofuran (8 mL) was added 2 M aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was diluted with water, acidified with 1 M hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=50:50-100:0), and the obtained crystals were recrystallized from hexane-ethyl acetate to give the title compound (0.248 g, yield 62%) as colorless crystals.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[S:21][C:20]([NH:23][C:24]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=4)=[O:25])=[N:19][C:18]=3[C:17]([O:33][CH3:34])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:35].CO>>[ClH:35].[CH3:34][O:33][C:17]1[C:18]2[N:19]=[C:20]([NH:23][C:24](=[O:25])[C:26]3[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=3)[S:21][C:22]=2[C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:15][CH:16]=1
Reactant: COc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)c2sc(NC(=O)c3ccnc(C)c3)nc12
Agent: Cl
Solvent: CO
Product: COc1ccc(C2CCNCC2)c2sc(NC(=O)c3ccnc(C)c3)nc12
Yield: 57 %

Procedure:
0.15 g (0.31 mMol) 4-{4-methoxy-2-[(2-methyl-pyridine-4-carbonyl)-amino]-benzothiazol-7-yl}-piperidine-1-carboxylic acid tert-butyl ester were dissolved in 4 ml 2.5 M HCl/MeOH and heated to reflux for 1.5 h. The reaction mixture was concentrated in vacuo and taken up in 5 ml isopropanol. The suspension formed was filtered and the material on the filter was washed with diethyl ether and dried in vacuo. One obtained 80 mg (57%) N-(4-methoxy-7-piperidin-4-yl-benzothiazol-2-yl)-2-methyl-isonicotinamide hydrochloride (1:2) as a white solid. F.p.: 272-277° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].[F:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([C:36](O)=[O:37])=[CH:28][CH:27]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[CH2:20]([O:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][CH:2]([NH:1][C:36]([C:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:26]([F:25])=[CH:27][CH:28]=1)=[O:37])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4])[C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: CC(C)(C)COc1cccc(CC(N)C(O)c2cccc(Cl)c2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)COc1cccc(CC(NC(=O)c2ccc(F)c3ccccc23)C(O)c2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
To a solution of (1RS,2SR)-2-amino-3-[3-(neopentyloxy)phenyl]-1-(3-chlorophenyl)-1-propanol (0.30 g, 0.86 mmol) in N,N-dimethylformamide (5 ml) were added 4-fluoronaphthalene-1-carboxylic acid (0.17 g, 0.90 mmol) and 1-hydroxybenzotriazole monohydrate (0.138 g, 0.90 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.173 g, 0.90 mmol) was finally added. The mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) to give N-[(1RS,2SR)-1-[3-(neopentyloxy)benzyl]-2-(3-chlorophenyl)-2-hydroxyethyl]-4-fluoro-1-naphthamide (0.354 g, 79%) as colorless crystals.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[N:6]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:5]=1[CH3:26].[I-].[Na+].[C:29]1(=[O:39])[NH:33][C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]12.[K]>CN(C=O)C>[C:29]1(=[O:39])[N:33]([CH2:2][CH2:3][C:4]2[CH:8]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=3)[N:6]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:5]=2[CH3:26])[C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]12
Reactant: Cc1c(CCBr)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [I-]
Agent: [K]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(CCN2C(=O)c3ccccc3C2=O)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(2-bromoethyl)-1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulphonyl)phenyl]-1H-pyrrole (0.80 mmol) in dry DMF (10 mL) was added sodium iodide (0.80 mmol) and the resulting mixture was stirred at r.t. for 30 min. Potassium phthalimide (0.90 mmol) was then added, and the reaction mixture was heated at 70° C. for 14 h. After cooling the mixture was poured onto crushed ice and extracted with CH2Cl2. The organic phase was thoroughly washed with water to remove the DMF excess, dried and concentrated under reduced pressure. The residue, purified by flash-chromatography (EtOAc/hexane 1:1 v/v), gave the expected compound as an oil which crystallizes on standing. Yellowish needles from EtOAc Mp 198-201° C. (yield 70%) 1H-NMR (CDCl3) δ ppm: 2.04 (s, 3H), 2.86 (t, 2H, J=7.5), 2.98 (s, 3H), 3.88 (t, 2H, J=7.6), 6.42 (s, 1H), 7.07 (m, 6H), 7.61-7.74 (m, 4H), 7.81-7.85 (m, 2H).