Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([CH3:18])=[N:4][O:5][C:6]=1[C:7]1([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:9][CH2:8]1.[CH3:19][C:20]1([CH3:27])[C:24]([CH3:26])([CH3:25])[O:23][BH:22][O:21]1.C(N(CC)CC)C>CC#N.CC#N.Cl[Pd]Cl.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.O1CCOCC1>[CH3:18][C:3]1[C:2]([B:22]2[O:23][C:24]([CH3:26])([CH3:25])[C:20]([CH3:27])([CH3:19])[O:21]2)=[C:6]([C:7]2([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:9][CH2:8]2)[O:5][N:4]=1
Reactant: Cc1noc(C2(NC(=O)OC(C)(C)C)CC2)c1Br
Reactant: CC1(C)OBOC1(C)C
Agent: Cl[Pd]Cl
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1noc(C2(NC(=O)OC(C)(C)C)CC2)c1B1OC(C)(C)C(C)(C)O1
Temperature: 100 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a 50 mL round bottom flask containing tert-butyl 1-(4-bromo-3-methylisoxazol-5-yl)cyclopropylcarbamate (0.219 g, 0.621 mmol) was added dichlorobis(acetonitrile)palladium(II) (0.0025 g, 9.64 μmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (0.0134 g, 0.033 mmol), followed by anhydrous 1,4-dioxane (0.40 mL). The reaction vessel was evacuated and purged with N2 (g) (3×). To the flask was added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.153 mL, 1.056 mmol) and triethylamine (0.294 mL, 2.113 mmol) sequentially. The reaction vessel was evacuated and purged with N2 (g) again, then heated to 100° C. The reaction mixture became heterogeneous and was judged complete within 1 h by LC-MS. The heterogeneous mixture was cooled to room temperature, dilute with EtOAc and the mixture was filtered over a plug of Celite. The filter cake was rinsed with EtOAc (3×) and the filtrate was concentrated to give a yellow oil, that crystallized upon standing under vacuum. The product tert-butyl 1-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazol-5-yl)cyclopropylcarbamate (0.226 g, 0.620 mmol, 100% yield) was used without further purification. LC/MS m/z 365 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][NH:16][C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)=[O:18])[CH2:11][CH2:10]2)[N:4]=1.[C:30](Cl)(=O)[C:31](Cl)=O.C[N:37]([CH3:40])C=O>ClCCl>[C:17]([C:19]1[CH:20]=[C:21]([C:31]2[CH:30]=[CH:7][CH:8]=[CH:3][C:2]=2[F:1])[C:22]2[O:24][C:23]([C:22]3[CH:26]=[CH:27][C:19]([C:17]([NH:16][CH2:15][CH:12]4[CH2:11][CH2:10][N:9]([C:5]5[N:4]=[C:3]([C:2]([F:29])([F:28])[F:1])[CH:8]=[CH:7][N:6]=5)[CH2:14][CH2:13]4)=[O:18])=[CH:20][CH:21]=3)=[N:37][C:40]=2[CH:27]=1)#[N:16]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(C(=O)NCC2CCN(c3nccc(C(F)(F)F)n3)CC2)cc1
Reactant: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1cc(-c2ccccc2F)c2oc(-c3ccc(C(=O)NCC4CCN(c5nccc(C(F)(F)F)n5)CC4)cc3)nc2c1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 14 %

Procedure:
To of 4-{[({1-[4-(trifluoromethyl)pyrimidin-2-yl]piperidin-4-yl}methyl)amino]carbonyl}benzoic acid (INTERMEDIATE 25, 100 mg) in 4 ml of dichloromethane was slowly added oxalyl chloride (600 μl, 2M in dichloromethane) followed by dimethylformamide (10 □l). The mixture was stirred for 15 min to completely dissolve the carboxylic acid. The solution was then concentrated in vacuo and redissolved in 35 ml of dioxane. To the resultant acyl chloride was added 5-amino-2′-fluoro-6-hydroxybiphenyl-3-carbonitrile (INTERMEDIATE 24, 59 mg). The mixture was heated at 80° C. for 1 h, and then cooled to room temperature. The dioxane was removed in vacuo, and to the residue was added 45 ml of toluene and 46 mg of p-toluenesulfonic acid monohydrate (46 mg). The solution was heated to 140° C. and stirred at this temperature for 15 h. The reaction mixture was then cooled to room temperature, and the solvent was removed in vacuo. The residue was purified via column chromatography using a Biotage Horizon, 40 M column, eluting with 1 column volume of 100% hexanes followed by a gradient of 0 to 50% ethyl acetate in hexanes over 10 column volumes, followed by 100% ethyl acetate for 4 column volumes to provide the title compound (20 mg, 14%). Mass spectrum (ESI) 601.2 (M+2). 1H NMR (500 MHz, CDCl3): δ 8.48 (d, J=4.8 Hz, 1H), 8.31 (d, J=8.2 Hz, 2H), 8.12 (s, 1H), 7.93 (d, J=8.4 Hz, 2H), 7.80 (s, 1H), 7.65 (t, J=5.7 Hz, 1H), 7.54 (m, 1H), 7.37 (t, J=7.6 Hz, 1H), 7.32 (t, J=9.7 Hz, 1H), 6.73 (d, J=4.8 Hz, 1H), 6.30 (bs, 1H), 4.87 (d, J=13.5 Hz, 2H), 3.44 (t, J=6.5 Hz, 2H), 2.94 (t, J=13.5 Hz, 2H), 2.01 (m, 1H), 1.90, (d, J=13.0 Hz, 2H), 1.31 (qd, J=12.5 Hz, 3.9 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:22][CH2:23][N:24]3[C@H:29]4[CH2:30][CH2:31][C@@H:25]3[CH2:26][CH:27]([N:32]3[C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=5[N:34]=[C:33]3[CH3:41])[CH2:28]4)[CH2:13][CH2:12][N:11]([C:14]([C:16]3([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:42][C:43]([CH3:48])([CH3:47])[C:44](Cl)=[O:45].CCN(C(C)C)C(C)C>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:22][CH2:23][N:24]3[C@H:25]4[CH2:31][CH2:30][C@@H:29]3[CH2:28][CH:27]([N:32]3[C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=5[N:34]=[C:33]3[CH3:41])[CH2:26]4)[CH2:13][CH2:12][N:11]([C:14]([C:16]3([NH:21][C:44](=[O:45])[C:43]([CH3:48])([CH3:47])[CH3:42])[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)C2(N)CCCC2)CC1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)C2(NC(=O)C(C)(C)C)CCCC2)CC1
Yield: 53.7 %

Procedure:
N-{1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]cyclopentyl}-2,2-dimethylpropanamide was obtained from treating 1,1-dimethylethyl {1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]cyclopentyl}carbamate (0.627 g, 0.95 mmol) with HCl as outlined in the procedure for Example 890 to form 1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]cyclopentanamine (0.528 g, 99%). 1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]cyclopentanamine (0.050 g, 0.09 mmol), 2,2-Dimethyl-propionyl chloride (0.011 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in Example 890 to give the title compound, N-{1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]cyclopentyl}-2,2-dimethylpropanamide (0.031 g, 54%) as an oil. ES-LCMS m/z 642 (M+1).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:29])[C:11]2[CH:16]=[C:15]([N+:17]([O-])=O)[C:14]([NH:20][CH3:21])=[C:13]([F:22])[C:12]=2[N:23]2[CH2:27][CH2:26][C@@H:25]([F:28])[CH2:24]2)[CH2:5][CH2:4]1.CO>[Pd].C1COCC1>[F:31][C:2]([F:1])([F:30])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:29])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH:20][CH3:21])=[C:13]([F:22])[C:12]=2[N:23]2[CH2:27][CH2:26][C@@H:25]([F:28])[CH2:24]2)[CH2:5][CH2:4]1
Reactant: CNc1c([N+](=O)[O-])cc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(N2CC[C@@H](F)C2)c1F
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CNc1c(N)cc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(N2CC[C@@H](F)C2)c1F

Procedure:
The sub-title compound is prepared in analogy to procedure 6b from (R)—N-(trans-4-trifluoromethyl-cyclohexyl)-2-[3-fluoro-pyrrolidinyl]-3-fluoro-4-methylamino-5-nitro-benzoic acid amide (230 mg, 0.51 mmol), Pd/C (20 mg), MeOH (15 mL), THF (5 mL) and 3 bar H2-atmosphere. Yield: 215 mg.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([NH:14][NH2:15])=O)=[CH:10][CH:9]=2)[CH:2]=1.I.CS[C:21](=[NH:34])[NH:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=1>N1C=CC=CC=1>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:21]2[NH:34][C:12]([C:11]3[CH:16]=[CH:17][C:8]([O:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[CH:9][CH:10]=3)=[N:14][N:15]=2)=[CH:24][C:25]=1[C:30]([F:31])([F:32])[F:33]
Reactant: CSC(=N)Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: NNC(=O)c1ccc(Oc2cccnc2)cc1
Agent: I
Solvent: c1ccncc1
Product: FC(F)(F)c1cc(Nc2nnc(-c3ccc(Oc4cccnc4)cc3)[nH]2)ccc1Cl
Yield: 12.7 %

Procedure:
4-(pyridine-3-yloxy)benzohydrazide (2.33 g, 10.2 mmol) was dissolved in ca. 70 mL of anhydrous pyridine and S-methyl N-[4-chloro-3-(trifluoromethyl)phenyl]isothiourea hydroiodide (4.04 g, 10.2 mmol) was added. The reaction mixture was refluxed for 18 hrs under Ar. The pyridine was removed in vacuo and the resulting residue was purified by silica gel chromatography using EtOAc as eluent to give the title product (0.56 g) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12](=[CH2:31])[O:11][C@H:10]1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH3:48])=[CH:42][CH:41]=2)[CH:33]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:49]CCCCC.ICI>C(OCC)C.C([Zn]CC)C.O.C(=O)(O)[O-].[Na+]>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12]2([CH2:49][CH2:31]2)[O:11][C@H:10]1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH3:48])=[CH:42][CH:41]=2)[CH:33]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCC
Reactant: C=C1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCC)cc3)c2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: CC[Zn]CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ICI
Solvent: CCOCC
Product: CCOc1ccc(Cc2cc([C@@H]3OC4(CC4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
To a solution of (2S,3S,4R,5S)-3,4,5-tris-benzyloxy-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-methylene-tetrahydro-pyran (150 mg, 0.22 mmole) in dry diethyl ether (3 mL), 1.0M diethylzinc in hexane (1.2 mL, 1.2 mmole), diiodomethane (0.1 mL, 1.2 mmole) was added at room temperature and stirred at 40° C. in sealed vessel for 8 hours. The reaction mixture was diluted with water (20 mL) and saturated aqueous sodium bicarbonate (3 ml) and extracted with DCM (2×30 mL). The crude product was purified by silica gel column chromatography (2% ethyl acetate in hexane) to furnish 105 mg of (5S,6S,7R,8S)-6,7,8-tris-benzyloxy-5-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-4-oxa-spiro[2.5]octane.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][CH2:6][NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2].[Li+].[CH3:22][Si]([N-][Si](C)(C)C)(C)C.CI>CN(C=O)C>[CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][CH2:6][N:7]([CH3:22])[C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:2]
Reactant: CCOC(CCNC(=O)OCc1ccccc1)OCC
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(CCN(C)C(=O)OCc1ccccc1)OCC
Reaction time: 0.08 h

Procedure:
A solution of phenylmethyl [3,3-bis(ethyloxy)propyl]carbamate (4.17 g, 14.8 mmol, J. Med. Chem. 1998 41, 3919-3922) in anhydrous DMF (15 mL) under nitrogen at ambient temperature was treated LiHMDS (1.0 M in THF, 17.8 mL, 17.8 mmol). After stirring 5 min., methyl iodide (1.11 mL, 17.8 mmol) was added. After stirring an additional 15 min., the reaction mixture was quenched by addition of saturated brine, water and Et2O. After separation of the phases, the aqueous layer was back-extracted with Et2O. The combined organic phases were washed with brine, dried over anhydrous MgSO4, filtered, evaporated in vacuo and purified on silica gel eluting with 25% EtOAc in Hexanes to provide the product as an oil: 1H NMR (CDCl3) δ 7.28-7.38 (5H, m), 5.12 (2H, s), 4.45-4.56 (1H, m), 3.29-3.68 (6H, m), 2.92 (3H, s), 1.81-1.90 (2H, m), 1.11-1.23 (6H, m); ES+ MS: 318 (M+Na+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:12]=[C:11]([NH2:34])[CH:10]=1.Br[CH2:37][C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39].CN(C)[C:50]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][C:58]=2N(C)C)C=CC=1.[I-].[Na+]>C(#N)C.CN(C=O)C>[C:42]1([CH2:41][O:40][C:38](=[O:39])[CH2:37][N:34]([C:11]2[CH:10]=[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:35])[CH:14]=[C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:12]=2)[CH2:4][C:3](=[O:2])[O:35][CH2:50][C:59]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(N)cc(OCCCCC(=O)OC)c1
Reactant: O=C(CBr)OCc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCCC(=O)OC)cc(N(CC(=O)OCc2ccccc2)CC(=O)OCc2ccccc2)c1
Yield: 120.5 %

Procedure:
A mixture of 6.77 g (13.8 mmol) of 5-[3-amino-5-(octadecyloxy)phenoxy]pentanoic acid methyl ester, 6.6 ml (41.3 mmol) of benzyl bromoacetate, 7.4 g (34.4 mmol) of 1,8-bis(dimethylamino)naphthalene and 0.6 g (3.9 mmol) of sodium iodide in 150 ml of acetonitrile and 50 ml of DMF was stirred at reflux under an argon atmosphere for 48 hours. The reaction mixture was concentrated at reduced pressure to remove the solvents and ethyl acetate was added to the residue. The extract was washed with 0.5N HCl, with NaHCO3 solution, dried and concentrated at reduced pressure to an oil. Purification by HPLC using 20% ethyl acetate-hexane gave 6.55 g (60% yield, mp 48°-50°) of N-[3-(octadecyloxy)-5-[(5-methoxy-5-oxopentyl)oxy]phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycine phenylmethyl ester.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[NH:9][C:8]2=[O:18])[CH2:3][CH2:2]1.[Cl:19][C:20]1[C:28]2[NH:27][N:26]=[CH:25][C:24]=2[C:23]2[CH2:29][N:30]([CH2:55][C:56]([CH3:59])([CH3:58])[CH3:57])[C:31](=[O:54])[C@H:32]([CH2:34][C:35](=[O:53])N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)[CH2:33][C:22]=2[CH:21]=1>>[Cl:19][C:20]1[C:28]2[NH:27][N:26]=[CH:25][C:24]=2[C:23]2[CH2:29][N:30]([CH2:55][C:56]([CH3:59])([CH3:58])[CH3:57])[C:31](=[O:54])[C@H:32]([CH2:34][C:35](=[O:53])[N:1]3[CH2:2][CH2:3][CH:4]([N:7]4[CH:11]=[C:10]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=5)[NH:9][C:8]4=[O:18])[CH2:5][CH2:6]3)[CH2:33][C:22]=2[CH:21]=1
Reactant: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Reactant: O=c1[nH]c(-c2ccccn2)cn1C1CCNCC1
Product: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(n3cc(-c4ccccn4)[nH]c3=O)CC2)C1=O
Yield: 37 %

Procedure:
Title compound was prepared from 1-(piperidin-4-yl)-4-(pyridine-2-yl)-1H-imidazol-2(3H)-one in a manner analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Material was obtained as white solid in 37% yield. MS m/e (M+H)+=590.2. 1H NMR (500 MHz, DMSO-D6): δ=13.54 (s, 1H), 10.69 (d, 1H), 8.45 (s, 1H), 8.37 (s, 1H), 7.74 (s, 1H), 7.54 (d, J=8.24, 1H), 7.33 (d, J=4.88, 1H), 7.25 (s, 1H), 7.15 (dd, J1=6.71, J2=5.19, 1H), 5.37 (d, J=17.09, 1H), 4.63 (d, J=15.87, 1H), 4.50 (s, 1H), 4.12 (m, 2H), 3.87 (m, 1H), 3.56 (dd, J1=28.69, J2=13.43, 1H), 3.18 (t, J=13.73, 1H), 3.10 (d, J=14.65, 1H), 3.01 (m, 2H), 2.88 (t, J=15.26, 1H), 2.66 (m, 1H), 2.35 (d, J=14.95, 1H), 1.84 (m, 3H), 1.57 (m, 1H), 0.73 (d, J=16.17, 9H).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])(=[O:4])=[O:3].CCN(C(C)C)C(C)C.[NH:28]1[CH2:33][CH2:32][S:31](=[O:35])(=[O:34])[CH2:30][CH2:29]1.[NH4+].[Cl-]>C(Cl)Cl>[CH3:11][O:10][C:8](=[O:9])[C:7]1[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=[C:5]([S:2]([N:28]2[CH2:33][CH2:32][S:31](=[O:35])(=[O:34])[CH2:30][CH2:29]2)(=[O:4])=[O:3])[CH:6]=1
Reactant: O=S1(=O)CCNCC1
Reactant: COC(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)N2CCS(=O)(=O)CC2)c1

Procedure:
To a solution of methyl 3-(chlorosulfonyl)-5-(trifluoromethyl)benzoate (1 g, 3.3 mmol, Buttpark Ltd.) and DIPEA (641 mg, 866 μL, 4.96 mmol) in CH2Cl2 (4 mL) was added dropwise a solution of thiomorpholine 1,1-dioxide (447 mg, 3.3 mmol, CAS RN 39093-93-1) in CH2Cl2 (4.00 mL). After 90 minutes the suspension was poured on saturated aqueous NH4Cl solution and CH2Cl2 and the layers were separated. The aqueous layer was extracted twice with CH2Cl2. The organic layers were dried over MgSO4, filtered and evaporated. The compound was purified by silica gel chromatography on a 50 g column using an MPLC (Flasmaster) system eluting with a gradient of n-heptane:EtOAc (100:0 to 80:20). Light brown solid (0.99 g; 74%). MS (ESI): m/z=419.05 [M+NH4]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:28](O)=[O:29])=[CH:5][C:6]2[N:10]=[C:9]([NH:11][C:12]3[S:13][C:14]4[CH:20]=[C:19]([O:21][C:22]([F:25])([F:24])[F:23])[CH:18]=[CH:17][C:15]=4[N:16]=3)[N:8]([CH3:26])[C:7]=2[CH:27]=1.[NH2:31][CH2:32][CH:33]([OH:35])[CH3:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[OH:35][CH:33]([CH3:34])[CH2:32][NH:31][C:28]([C:4]1[C:3]([O:2][CH3:1])=[CH:27][C:7]2[N:8]([CH3:26])[C:9]([NH:11][C:12]3[S:13][C:14]4[CH:20]=[C:19]([O:21][C:22]([F:23])([F:25])[F:24])[CH:18]=[CH:17][C:15]=4[N:16]=3)=[N:10][C:6]=2[CH:5]=1)=[O:29]
Reactant: COc1cc2c(cc1C(=O)O)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Reactant: CC(O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1C(=O)NCC(C)O)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 66.1 %

Procedure:
6-Methoxy-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylic acid (2-hydroxy-propyl)-amide (56 mg) was prepared by following General Procedure F starting from 6-methoxy-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (75 mg), 1-amino-2-propanol (14 mg), HBTU (78 mg), and DIEA (45 uL). LC/MS: m/z 496.6. 1H NMR (DMSO-d6, 400 MHz): δ 12.27 (s, 1H), 8.32 (t, 1H), 8.16 (s, 1H), 7.90 (s, 1H), 7.71 (d, 1H), 7.35 (d, 1H), 7.26 (s, 1H), 4.85 (d, 1H), 4.00 (s, 3H), 3.85-3.76 (m, 1H), 3.64 (s, 3H), 3.43-3.34 (m, 1H), 3.24-3.14 (m, 1H), 1.10 (d, 3H).
Reaction SMILES: [CH:1]1([CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([CH2:16][NH:17][C:18](=[O:47])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:46])[CH2:26][C:27]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:11]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:48]([I:50])[CH3:49]>>[I-:50].[CH:1]1([CH2:9][N+:10]2([CH2:48][CH3:49])[CH2:15][CH2:14][CH2:13][CH:12]([CH2:16][NH:17][C:18](=[O:47])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:46])[CH2:26][C:27]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: CCI
Reactant: O=C(CCCCCNC(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1)NCC1CCCN(CC2CCCCCCC2)C1
Product: CC[N+]1(CC2CCCCCCC2)CCCC(CNC(=O)CCCCCNC(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Product: [I-]

Procedure:
The title compound was prepared by a method similar to Example 130, using N-(6-{(1-cyclooctylmethyl-3-piperidyl)methyl}amino-6-oxohexyl)-3,3,3-triphenylpropanamide and ethyl iodide. The compound was obtained as a pale yellow solid.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].C([OH:10])C.N1[CH:16]=[CH:15]C=CC=1>C(Cl)Cl>[C:2](=[O:10])([O:3][CH2:15][CH3:16])[O:4][CH:5]([Cl:7])[CH3:6]
Reactant: c1ccncc1
Reactant: CC(Cl)OC(=O)Cl
Reactant: CCO
Solvent: ClCCl
Product: CCOC(=O)OC(C)Cl

Procedure:
The title compound was prepared according to the procedure as described in Example 26 step 1 using a solution of 1-chloroethyl chloroformate (10 g, 69.9 mmol) in DCM (200 mL), a mixture of ethanol (4.5 mL, 77.2 mmol) and pyridine (6.8 mL, 84.5 mmol) in DCM (50 mL). The title compound was obtained as colorless oil (9.32 g, 87.7%) and was used in the next step without further purification. The title compound was characterized by 1H NMR as shown below:
Reaction SMILES: [CH3:1][CH:2]([SH:4])[CH3:3].F[C:6]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].C(N(CC)CC)C>CN(C=O)C>[CH:2]([S:4][C:6]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])([CH3:3])[CH3:1]
Reactant: CC(C)S
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)Sc1ccc([N+](=O)[O-])cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
Isopropylthiol (3.06 mL, 32.8 mmol) was added to a solution of 2-fluoro-5-nitrobenzoic acid (5.06 g, 27.3 mmol) and triethylamine (8.4 mL, 60.3 mmol) in DMF (86 mL). The reaction mixture was stirred overnight at rt and then most of the DMF was removed in vacuo. The residual solution was poured into ice water (500 mL) and the resulting yellow solid was isolated by filtration to give 16A (6.5 g, 100%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[C:16]([F:17])=[CH:15][C:12]([C:13]#[N:14])=[C:11]([NH:18][C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:20]=2)[CH:10]=1.CC[OH:32]>CS(C)=O.[OH-].[Na+].OO>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[C:16]([F:17])=[CH:15][C:12]([C:13]([NH2:14])=[O:32])=[C:11]([NH:18][C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:20]=2)[CH:10]=1
Reactant: CCO
Reactant: N#Cc1cc(F)c(N[C@@H]2CCCC[C@@H]2N)cc1Nc1cc(-c2ccccc2)no1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: NC(=O)c1cc(F)c(N[C@@H]2CCCC[C@@H]2N)cc1Nc1cc(-c2ccccc2)no1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-((1R,2S)-2-aminocyclohexylamino)-5-fluoro-2-(3-phenylisoxazol-5-ylamino)benzonitrile in EtOH (1 mL) and DMSO (0.5 mL), 1N aq. NaOH (0.5 mL) and H2O2 (50% aq., 0.5 mL) were added. After being stirred at room temperature for 1 h, the mixture was concentrated in vacuo. The residue was acidified with HOAc (0.5 mL), and then was purified by HPLC to give the titled compound (33 mg). MS 410.3 (M+H); UV 204.7, 246.1, 287.8 nm.