Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:13][C:14]1[CH:20]=[C:19]([C:21]#[C:22][CH2:23][O:24][CH3:25])[CH:18]=[CH:17][C:15]=1[NH2:16].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:11][C:10]1[C:2]([NH:16][C:15]2[CH:17]=[CH:18][C:19]([C:21]#[C:22][CH2:23][O:24][CH3:25])=[CH:20][C:14]=2[F:13])=[C:3]([CH:7]=[CH:8][C:9]=1[F:12])[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccc(F)c(F)c1F
Reactant: COCC#Cc1ccc(N)c(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COCC#Cc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1

Procedure:
2,3,4-Trifluorobenzoic acid and the product of Example 5, Step A, 2-fluoro-4-(3-methoxy-1-propynyl)aniline, were reacted in the presence of LiHMDS solution in THF by the general procedure of Example 1. After workup, followed by purification by chromatography on silica gel (10% EtOAc/hexanes as eluant), 3,4-difluoro-2-[[2-fluoro-4-(3-methoxy-1-propynyl)phenyl]amino]-benzoic acid was isolated (62%) as a pale yellow solid; mp (EtOAc/hexanes) 221-223° C. 1H NMR [400 MHz, (CD3)2SO] δ 13.60 (br s, 1 H), 9.27 (br s, 1 H), 7.85-7.79 (m, 1 H,), 7.36 (dd, J=12.0, 1.8 Hz, 1 H), 7.20 (dd, J=8.3, 1.5 Hz, 1 H), 7.18-7.11 (m, 1 H), 6.96 (td, 8.8, 5.5 Hz, 1 H), 4.31 (s, 2 H), 3.32 (s, 3 H). Anal Calcd for C17 H12F3NO3: C, 60.9; H, 3.6; N, 4.2. Found C, 61.4; H, 3.6; N, 4.2.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[CH:15][C:14]3[C:13]([C:17]([NH:19][CH2:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[O:18])=[C:12]([Cl:27])[CH:11]=[CH:10][C:9]=3[N:8]=2)[CH2:3]1.Cl[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].C(N(CC)CC)C>C(#N)C>[Cl:27][C:12]1[C:13]([C:17]([NH:19][CH2:20][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)=[O:18])=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:4]1[CH2:5][CH2:6][C@H:2]([NH:1][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:3]1)[CH:16]=[CH:15]2
Reactant: CCOC(=O)CCl
Reactant: N[C@H]1CCN(c2ccc3c(C(=O)NCC4CCCCC4)c(Cl)ccc3n2)C1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CN[C@H]1CCN(c2ccc3c(C(=O)NCC4CCCCC4)c(Cl)ccc3n2)C1
Temperature: 25 °C

Procedure:
A stirred solution of 2-[(3S)-3-Amino-1-pyrrolidinyl]-6-chloro-N-(cyclohexylmethyl)-5-quinolinecarboxamide (prepared as in Example 44) (450 mg), ethyl chloroacetate (0.21 mL) and triethylamine (0.33 mL) in acetonitrile (3 mL) was heated at 100° C. in a microwave for 1 hour after which it was cooled to room temperature and concentrated. Purification by chromatography (SiO2, dichloromethane:methanol:ammonia in methanol (7 M) 96:3:1 as eluant) gave the subtitle compound as a solid (490 mg).
Reaction SMILES: Br[C:2]1[C:3]([O:28][CH3:29])=[C:4]([CH:10]([NH:12][C:13]2[N:21]=[CH:20][N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][N:17]3C2CCCCO2)[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[F:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[N:35][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl.O>CO.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.O1CCOCC1>[Cl:9][C:6]1[C:7]([CH3:8])=[C:2]([C:33]2[CH:34]=[N:35][CH:36]=[C:31]([F:30])[CH:32]=2)[C:3]([O:28][CH3:29])=[C:4]([CH:10]([NH:12][C:13]2[N:21]=[CH:20][N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][NH:17]3)[CH3:11])[CH:5]=1
Reactant: OB(O)c1cncc(F)c1
Reactant: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(C)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1-c1cncc(F)c1
Temperature: 100 °C

Procedure:
Into a microwave vial was added N-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (0.046 g, 0.096 mmol), (5-fluoropyridin-3-yl)boronic acid (0.020 g, 0.14 mmol), 10% sodium carbonate solution (0.23 mL, 0.23 mmol), 1,4-dioxane (0.9 mL) and tetrakis(triphenylphosphine)palladium(0) (0.011 g, 0.0096 mmol). The mixture was bubbled with N2 for 5 min and then heated at 100° C. for 2 hours. The cooled reaction was treated directly with 6.0 M hydrogen chloride in water (0.2 mL, 1 mmol) at room temperature for ˜30 min. The mixture was diluted with MeOH, filtered and purified on Prep LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C20H19ClFN6O (M+H)+: m/z=413.1. found: 413.1.
Reaction SMILES: [C:1]([C:3](=[C:9](SC)[S:10][CH3:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[NH:14]([C:16]1[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:20]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:19]=[C:18]([C:34]([F:37])([F:36])[F:35])[N:17]=1)[NH2:15]>CO>[NH2:2][C:1]1[N:14]([C:16]2[C:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[C:20]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:19]=[C:18]([C:34]([F:37])([F:36])[F:35])[N:17]=2)[N:15]=[C:9]([S:10][CH3:11])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: NNc1nc(C(F)(F)F)nc(-c2ccccc2)c1-c1ccccc1
Reactant: CCOC(=O)C(C#N)=C(SC)SC
Solvent: CO
Product: CCOC(=O)c1c(SC)nn(-c2nc(C(F)(F)F)nc(-c3ccccc3)c2-c2ccccc2)c1N

Procedure:
Ethyl 2-cyano-3,3-bis(methylthio)acrylate (0.3 g, 1.36 mmol) was heated with 4-hydrazino-5,6-diphenyl-2-(trifluoromethyl)pyrimidine (0.15 g, 0.45 mmol) in methanol (6 ml) overnight at 60-65° C. The solid that separated out from the reaction mixture was filtered and washed with isopropylalcohol (5 ml), to furnish the required compound. 1H-NMR (DMSO-d6) δ: 1.22-1.25 (t, 3H), 3.16 (s, 3H), 4.11-4.17 (q, 2H), 4.36 (br, 2H, D2O exchangeable), 7.12 (d, 2H), 7.25-7.35 (m, 7H), 7.69 (d, 1H). MS m/z: 500.1 (M++1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][CH2:6][CH:7]([OH:10])[CH2:8][OH:9])[CH3:2].[C:12]([Si:16](Cl)([CH3:18])[CH3:17])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([O:3][C:4](=[O:11])[CH2:5][CH2:6][CH:7]([OH:10])[CH2:8][O:9][Si:16]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:18])[CH3:17])[CH3:2]
Reactant: CCOC(=O)CCC(O)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCC(O)CO[Si](C)(C)C(C)(C)C
Reaction time: 18 h

Procedure:
A solution of 4,5-dihydroxy-pentanoic acid ethyl ester, (7 g, 43.2 mmol) and 4-dimethylaminopyridine (0.2 g, 1.73 mmol) in dichloromethane (145 mL) at room temperature under nitrogen is treated with tert-butyl-dimethyl-silyl chloride (7.8 g, 51.85 mmol) and triethylamine (6.9 mL, 47.52 mmol) and stirred 18 h. The mixture is diluted with dichloromethane (100 mL), washed with water (100 mL), saturated ammonium chloride solution, and brine. The solution is filtered and concentrated in vacuo to yield the title compound, 11.85 g (99%), as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][C:12]([CH2:20][CH2:21][CH2:22]O)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]([C:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:25])[N:10]=1.C([N:34](CC)CC)C.S(Cl)(C)(=O)=O.C([O-])(O)=O.[Na+].[N-]=[N+]=[N-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.[Cl-].[Na+].O.CCOC(C)=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][C:12]([CH2:20][CH2:21][CH2:22][NH2:34])([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:11]([C:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:25])[N:10]=1
Reactant: CCN(CC)CC
Reactant: O=C(N1CCOCC1)N1N=C(c2cc(F)ccc2F)CC1(CCCO)c1ccccc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: NCCCC1(c2ccccc2)CC(c2cc(F)ccc2F)=NN1C(=O)N1CCOCC1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
To 268 mg (0.62 mmol) of 7-6 in CH2Cl2 was added 175 μL (1.24 mmol) of triethylamine and 75 mL (0.93 mmol) of mesyl chloride. After stirring for 1 h, the mixture was dumped into a separatory funnel with saturated NaHCO3, extracted twice with CH2Cl2, washed with water, and dried over Na2SO4. The residue was dissolved in DMF, 82 mg (1.24 mmol) of sodium azide was added, and the reaction was heated for 4 h at 65° C. After cooling to rt, the mixture was dumped into brine, extracted twice with EtOAc, and then washed with brine. The organic layer was dried over Na2SO4, concentrated, redissolved in THF and 205 mg (0.78 mmol) of triphenylphosphine was added. After stirring for 15 h, 1 mL of water was added and the mixture was heated at 65° C. for 1 h. The reaction was worked up with EtOAc and brine, dried over Na2SO4, concentrated, and purified by column chromatography on silica gel with CH2Cl2/MeOH/TEA to provide 7-7 as a white solid. Data for 7-7: 1HNMR (500 MHz, CDCl3) δ 7.5 (m, 1H), 7.4-7.2 (m, 5H), 7.1-7.0 (m, 2H), 3.8-3.6 (m, 4H), 3.6 (m, 4H), 3.5 (m, 1H), 3.4 (m, 1H), 2.9-2.8 (m, 3H), 2.2 (m, 1H), 1.6 (m, 2H) ppm. HRMS (ES) calc'd M+Na for C23H26F2N4O2: 429.2097. Found: 429.2097.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[N:20][N:21]([CH:23]2[CH2:28][CH2:27][CH2:26][N:25]([CH3:29])[CH2:24]2)[CH:22]=1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([F:46])[C:32]=1[OH:47]>>[Cl:30][C:31]1[CH:36]=[C:35]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:5]3[NH:17][C:18]2[CH:19]=[N:20][N:21]([CH:23]3[CH2:28][CH2:27][CH2:26][N:25]([CH3:29])[CH2:24]3)[CH:22]=2)[CH:34]=[C:33]([F:46])[C:32]=1[OH:47]
Reactant: CN1CCCC(n2cc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CN1CCCC(n2cc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(F)c(O)c(Cl)c5)cc34)cn2)C1
Yield: 73.7 %

Procedure:
Following general procedure F, {6-Bromo-4-[1-(1-methylpiperidin-3-yl)-1H-pyrazol-4-ylamino]quinolin-3-yl}(cyclopropyl)methanone (58 mg, 0.120 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (49 mg, 0.180 mmol) to afford the desired product (46 mg, 74%) as a yellow-green solid: 1H NMR (500 MHz, DMSO-d6) δ 10.86 (s, 1H), 9.08 (s, 1H), 8.24 (d, J=2.1 Hz, 1H), 8.04 (dd, J=8.8, 2.1 Hz, 1H), 7.93-7.83 (m, 2H), 7.43 (s, 1H), 7.39-7.30 (m, 2H), 4.19-4.12 (m, 1H), 2.95-2.81 (m, 3H), 2.29-2.15 (s, 5H), 2.01-1.89 (m, 4H), 1.02-0.92 (m, 4H).; ESI MS m/z 520 [C28H27ClFN5O2+H]+; HPLC 98.6% (AUC), tR=10.16 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([O:20][C:21]4[N:26]=[CH:25][N:24]=[C:23]([CH2:27][N:28]5[CH2:33][CH2:32][CH:31]([C:34]([O:36]C)=[O:35])[CH2:30][CH2:29]5)[CH:22]=4)=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)=[O:10])=[CH:4][C:3]=1[C:38]([F:41])([F:40])[F:39]>C1COCC1.O.[Li+].[OH-]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([O:20][C:21]4[N:26]=[CH:25][N:24]=[C:23]([CH2:27][N:28]5[CH2:33][CH2:32][CH:31]([C:34]([OH:36])=[O:35])[CH2:30][CH2:29]5)[CH:22]=4)=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)=[O:10])=[CH:4][C:3]=1[C:38]([F:41])([F:39])[F:40]
Reactant: COC(=O)C1CCN(Cc2cc(Oc3ccc4c(ccn4C(=O)Nc4ccc(F)c(C(F)(F)F)c4)c3)ncn2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CCN(Cc2cc(Oc3ccc4c(ccn4C(=O)Nc4ccc(F)c(C(F)(F)F)c4)c3)ncn2)CC1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of methyl 1-((6-(1-(4-fluoro-3-(trifluoromethyl)phenylcarbamoyl)-1H-indol-5-yloxy)pyrimidin-4-yl)methyl)piperidine-4-carboxylate (0.13 g, 0.228 mmol) in 40 mL of THF/H2O (3:1), 2 M aq LiOH solution (0.23 mL) is added. The mixture is stirred at rt for 3.5 h before being concentrated and purified by semi-prep HPLC (12-48% CAN/H2O with 0.1% TFA) to give the title compound. MS (ESI) m/z 558.1 (M+1); 1H NMR (400 MHz, DMSO-d5) δ ppm 10.43 (s, 1H), 9.93-10.12 (m, 1H), 8.88 (s, 1H), 8.32 (d, J=9.1 Hz, 1H), 8.08-8.17 (m, 2H), 7.96-8.06 (m, 1H), 7.58 (t, J=9.9 Hz, 1H), 7.52 (d, J=2.5 Hz, 1H), 7.25 (br. S., 1H), 7.17 (dd, J=9.0, 2.4 Hz, 1H), 6.83 (d, J=3.5 Hz, 1H), 4.39-4.60 (m, 2H), 3.45-3.57 (m, 2H), 2.98-3.17 (m, 2H), 1.95-2.14 (m, 3H), 1.73-1.91 (m, 2H)
Reaction SMILES: [Cl:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:6]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[CH:3]=1
Reactant: FC(F)(F)c1cc(Cl)[nH]n1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1nc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a suspension of 5-chloro-3-(trifluoromethyl)-1H-pyrazole (i.e. the product of Example 10, Step C) (2.1 g, 12.3 mmol) and potassium carbonate (3.6 g, 26.0 mmol) in 20 mL of N,N-dimethylformamide was added ethyl bromoacetate (2.1 mL, 18.8 mmol), and the resulting mixture was stirred at room temperature for 12 h. The resulting mixture was diluted with ethyl acetate, washed with water, and dried (MgSO4). The reaction mixture was concentrated in vacuo and further purified by medium-pressure liquid chromatography using 0-50% of ethyl acetate in hexanes as eluant to give 940 mg of the title compound as an oil.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:18]=[CH:19][C:20]([N:22]([O:24][CH3:25])[CH3:23])=[O:21])[CH:16]=2)[CH:11]=[CH:10]1>C1COCC1>[CH3:25][O:24][N:22]([CH3:23])[C:20]([CH:19]1[CH2:2][CH:18]1[C:15]1[CH:16]=[C:17]2[C:12]([CH:11]=[CH:10][NH:9]2)=[CH:13][CH:14]=1)=[O:21]
Reactant: C[S+](C)(C)=O
Reactant: CON(C)C(=O)C=Cc1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CON(C)C(=O)C1CC1c1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.8 %

Procedure:
Trimethylsulfoxonium iodide (2.20 g, 10.00 mmol) was added to a suspension of sodium hydride (60% dispersion in oil, 0.40 g, 10.00 mmol) in anhydrous THF and stirred at room temperature for 1 h. 3-(1H-Indol-6-yl)-N-methoxy-N-methylacrylamide (0.90 g, 3.90 mmol) was dissolved in anhydrous THF and added dropwise to the cloudy white suspension. The mixture was stirred for 16 h at room temperature. The reaction was quenched with a solution of saturated ammonium chloride. Water was added and the solution was extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give 2-(1H-indol-6-yl)-cyclopropanecarboxylic acid methoxy-methyl-amide as a yellowish solid (0.96 g, 100%). LC-MS: MH+: 245.12, 72% AP.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[NH2:9].[CH:11](OCC)=[O:12]>>[CH3:1][N:2]([CH3:10])[C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[NH:9][CH:11]=[O:12]
Reactant: CCOC=O
Reactant: CN(C)[C@@H]1CCCC[C@H]1N
Product: CN(C)[C@@H]1CCCC[C@H]1NC=O
Yield: 85 %

Procedure:
A solution of the trans 2-(dimethylamino)cyclohexylamine prepared as in Procedure VIII (5.12 g.; 0.036 mole) and 100 ml. of ethyl formate (distilled over K2CO3) was reluxed for 17 hours and evaporated. The titled product (A) was distilled at 0.1 mm, b.p. 104°, 5.2 g. (85% yield). ir NH 3280, 3040; CH 2930, 2860; N-alkyl 2770; C=O 1670; amide II 1540; other 1450, 1385. nmr in CDCl3 (100 MHz) was in accord. Mass spectrum M+ 170.
Reaction SMILES: C(C1C=CC(C(Cl)=O)=CC=1)C.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[C:29]([F:34])[CH:28]=1.[CH2:35]([C:37]1[CH:42]=[CH:41][C:40]([C:43]([N:45]=[C:46]=[S:47])=[O:44])=[CH:39][CH:38]=1)[CH3:36]>C1(C)C=CC=CC=1.C(O)C>[CH2:35]([C:37]1[CH:38]=[CH:39][C:40]([C:43]([N:45]=[C:46]=[S:47])=[O:44])=[CH:41][CH:42]=1)[CH3:36].[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH:31][C:46]([NH:45][C:43](=[O:44])[C:40]2[CH:41]=[CH:42][C:37]([CH2:35][CH3:36])=[CH:38][CH:39]=2)=[S:47])=[C:29]([F:34])[CH:28]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: CCc1ccc(C(=O)Cl)cc1
Agent: CCc1ccc(C(=O)N=C=S)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
4-Ethyl-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-ethyl-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-ethyl-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (69 mg, yield 87%).
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH2:9][C:10]3[CH:21]=[CH:20][C:13]4[N:14]=[C:15](S(C)=O)[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[NH2:24][C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]1[OH:31].CCN(C(C)C)C(C)C.O>CC(N(C)C)=O>[Br:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH2:9][C:10]3[CH:21]=[CH:20][C:13]4[N:14]=[C:15]([NH:24][C@@H:25]5[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]5[OH:31])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cc(Br)ccc43)cc2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: O
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(Br)ccc43)cc2s1
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 114.4 %

Procedure:
To a suspension of 6-((5-bromo-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (655 mg, 1.6 mmol) and (1R,2R)-2-aminocyclohexanol (558 mg, 4.8 mmol) in anhydrous DMA (3.0 mL) was added DIEA (842 μL, 4.8 mmol). The mixture was heated in a sealed tube at 110° C. for 18 h. The mixture was cooled to rt and added dropwise to a stirred solution of water causing a precipitate to form. After stirring for 10 min, the solid was collected by filtration to afford (1R,2R)-2-((6-((5-bromo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (837 mg) as a tan solid. The material was used in the next step without further purification. 1H NMR (300 MHz, DMSO-d6) δ 8.46 (s, 1H), 7.97 (d, J=7.5 Hz, 1H), 7.85 (d, J=1.7 Hz, 1H), 7.65 (s, 1H), 7.54 (d, J=8.5 Hz, 1H), 7.26-7.39 (m, 2H), 7.19 (m, 1H), 5.47 (s, 2H), 4.74 (d, J=5.1 Hz, 1H), 3.51 (m, 1H), 3.32 (m, 1H), 2.01 (m, 1H), 1.87 (m, 1H), 1.55-1.67 (m, 2H), 1.13-1.32 (m, 4H); LCMS (ESI) m/z 457, 459 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:26])[CH:3]=1.[O:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32]>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:29]5[CH2:30][CH2:31][O:27][C:28]5=[O:32])=[CH:3][C:4]=4[CH3:26])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: Cc1cc(Br)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C)CC1
Reactant: O=C1NCCO1
Product: Cc1cc(N2CCOC2=O)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C)CC1
Yield: 88.9 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methylphenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (347 mg) described in Preparation Example 130 and oxazolidin-2-one (109 mg), the title compound (313 mg) was obtained.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[C:6]([CH2:12][CH2:13][CH3:14])[C:5]=1[OH:15])(=[O:3])[CH3:2].[NH2:16][C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1>C(#N)C>[C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH:16][C:17]2[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=2)=[C:6]([CH2:12][CH2:13][CH3:14])[C:5]=1[OH:15])(=[O:3])[CH3:2]
Reactant: CCCc1c(CCl)ccc(C(C)=O)c1O
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CC#N
Product: CCCc1c(CNc2ccc(C(=O)OCC)cc2)ccc(C(C)=O)c1O

Procedure:
A solution of 6.8 g. of 4-acetyl-3-hydroxy-2propylbenzyl chloride and 14.9 g. of ethyl 4-aminobenzoate in 200 ml. of acetonitrile was heated to reflux for 48 hours. An additional 9.9 g. of ethyl 4aminobenzoate were added and the reaction was refluxed an additional 120 hours. The reaction mixture was cooled and concentrated in vacuo. The residue was dissolved in methylene chloride. The organic solution was washed first with a saturated sodium carbonate solution and then with water. The organic solution was then dried over sodium sulfate and evaporated to dryness. Chromatography of the residue afforded 7.4 g. of the desired title product. NMR.
Reaction SMILES: [CH3:1][N:2]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:3]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[CH:4]1[C:10](O)=[O:11].Cl.CN(C)CCCN=C=NCC.[OH:46][N:47]1C2C=CC=CC=2N=N1.NO>CN(C=O)C.C(OCC)(=O)C>[OH:46][NH:47][C:10]([C@@H:4]1[C@H:3]([N:2]([CH3:1])[S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=3)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C@@H:8]2[CH2:9][C@H:5]1[CH2:6][CH2:7]2)=[O:11]
Reactant: CN(C1C2CCC(C2)C1C(=O)O)S(=O)(=O)c1ccc(OCc2ccc3ccccc3c2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN([C@@H]1[C@H]2CC[C@H](C2)[C@@H]1C(=O)NO)S(=O)(=O)c1ccc(OCc2ccc3ccccc3c2)cc1
Reaction time: 20 h
Yield: 50 %

Procedure:
To a solution of 3-{methyl-[4-(naphthalen-2-ylmethoxy)-benzenesulfonyl]-amino}-bicyclo[2.2.1]heptane-2-carboxylic acid (125 mg, 0.268 mmol) in DMF (1 mL) were added 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (103 mg, 0.536 mmol), 1-hydroxybenzotriazole (72.5 mg, 0.536 mmol) and hydroxylamine (50% in water, 82 μL, 1.34 mmol) at room temperature. The mixture was stirred for 20 h, diluted with ethyl acetate (5 mL), and washed with water (3×3 mL) and brine (3 mL). The organic layer was concentrated and the residue was purified by RP-HPLC to give (1R,2S,3R,4S)-N-hydroxy-3-(methyl{[4-(2-naphthylmethoxy)phenyl]sulfonyl}amino)bicyclo[2.2.1]heptane-2-carboxamide (50% yield). MS (ESI) [M+H] 481.2
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH2:10])=[O:9].[CH2:15]([NH:17][CH2:18][CH:19]([OH:30])[CH2:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1)[CH3:16].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C>[C:26]([C:25]1[CH:28]=[CH:29][C:22]([O:21][CH2:20][CH:19]([OH:30])[CH2:18][N:17]([CH2:15][CH3:16])[CH2:2][CH2:3][CH2:4][S:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([NH2:10])=[O:9])=[CH:23][CH:24]=1)#[N:27]
Reactant: NC(=O)c1ccccc1SCCCCl
Reactant: CCNCC(O)COc1ccc(C#N)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCN(CCCSc1ccccc1C(N)=O)CC(O)COc1ccc(C#N)cc1

Procedure:
5.5 g 2-(3- chloropropylthio)benzamide, 5.3 g of 4-[3-(ethylamino) -2-hydroxypropoxy]- benzonitrile, 6.6 g potassium carbonate and 7.2 g sodiumiodide were mixed in 100 ml of acetonitrile and heated to reflux for two days. The mixture was filtered and evaporated and the residue was dissolved in 1 M sulphuric acid. The acidic water layer was then washed twice with ether, alkalized with 10 M sodiumhydroxide and extracted with dichlormethane. The organic layer was dried over sodiumsulphate, treated with active carbon, filtered and evaporated. The residue, 8.7 g, was separated by column chromatography. Yield: 4.5 g of the title compound.