Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[NH2:26])=[CH:21][CH:20]=3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH2:9]1[C:10]2[C:15](=[CH:14][C:13]([O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([NH2:26])=[O:27])=[CH:21][CH:20]=3)=[CH:12][CH:11]=2)[CH2:16][CH2:17][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Oc3ccc(C(N)=O)cc3)ccc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCNC3)cc1
Reaction time: 24 h
Yield: 71.1 %

Procedure:
Combine 6-(4-Carbamoyl-phenoxy)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (4.0 g, 10.83 mmol), CH2Cl2 (100 ml), and TFA (25 ml) at room temperature. After the reaction stirred for 24 hours followed by the addition of 1M K2CO3 (aq), extract the product out of the aqueous layer with several washings of ethyl acetate/THF. Concentrate the organic phase under reduced pressure and add to 2, 10 g SCX Columns pre-treated with 5% AcOH/MeOH. After several washings of the SCX Columns with MeOH, the elute the product using 1N NH3-MeOH solution to afford 2.00 g, 7.7 mmol (71% yield) of the title compound as a white foam: 1H NMR (500 MHz, DMSO); 2.9-3.1 (2H, m), 3.10-3.25 (1H, m), 3.3-3.5 (2H, m), 4.1-4.3 (2H, m), 7.0-7.2 (3H, m), 7.2-7.4 (1H, m), 7.4-7.6 (1H, m), 8.0-8.1 (1H, m), 8.2-8.4 (1H, m), 8.5-8.65 (1H, m), 9.2-9.4 (2H, m); MS m/z 269 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])=[C:4]([NH:8][C:9]([C@@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)=O)[CH:5]=[CH:6][CH:7]=1.C(O)(=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]2[N:24]([CH2:25][CH2:26][CH2:27][O:28][CH3:29])[C:9]([C@@H:11]3[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]3)=[N:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: COCCCNc1c(Cl)cccc1NC(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COCCCn1c([C@@H]2CCCN(C(=O)OC(C)(C)C)C2)nc2cccc(Cl)c21

Procedure:
(R)-tert-Butyl 3-(3-chloro-2-(3-methoxypropylamino)phenylcarbamoyl)piperidine-1-carboxylate (30C) (crude material, 2.23 mmol max) was added to a 50 mL round-bottomed flask equipped for stirring under nitrogen. Glacial acetic acid (10 mL) was then added and the resultant solution was stirred at 70° C. under nitrogen for 16 hr. Analysis of the reaction mixture at this time by LC/MS indicated that the reaction was complete. The reaction solution was then concentrated in-vacuo to give a brownish oil. Toluene (30 mL) was added and the subsequent solution was concentrated in vacuo. This dissolution in toluene and re-concentration was repeated three times to remove any trace quantities of acetic acid affording (R)-tert-butyl 3-(7-chloro-1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate (30D) as a brown oil. This oil was then purified by preparative LC/MS (25-85% CH3CN in H2O) to afford the title compound 30D as a tan oil (0.233 mmol, 0.095 g, 10% yield over 3-steps). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.39 (s, 9H) 1.46-1.60 (m, 1H) 1.72-1.96 (m, 2H) 1.97-2.12 (m, 3H) 2.77-2.92 (m, 1H) 3.02-3.15 (m, 2H) 3.24 (s, 3H) 3.29-3.40 (m, 2H) 3.93-4.02 (m, 1H) 4.12 (br. s., 1H) 4.51-4.59 (m, 2H) 7.20 (t, J=7.83 Hz, 1H) 7.28 (d, J=7.83 Hz, 1H) 7.58 (d, J=7.83 Hz, 1H) ESI-MS: m/z 408.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14](S(C4C=CC=CC=4)(=O)=O)[C:15]([C:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]=4)=[CH:16][C:9]=23)[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1.O>[F:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]=4)=[CH:16][C:9]=23)[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(-c4cccc(F)n4)ccnc3n2S(=O)(=O)c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(-c4cccc(F)n4)ccnc3[nH]2)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of Example 309D (3.0 g, 5.61 mmol) in 1,4-dioxane (50 mL) was treated with a solution of sodium hydroxide (0.673 g, 16.83 mmol) in water (10 mL). The resulting mixture was stirred at 80° C. overnight. Most solvent was evaporated. The solids were filtered, washed with water/ethyl acetate/ether, and vacuum oven-dried to give the title compound. MS (ESI+) m/z 395.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:25])[C:10]2[N:15]=[C:14]3[S:16][C:17]([NH:19][C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])=[N:18][C:13]3=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl:26][C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=1[N:37]=[C:38]=[O:39]>CN(C)C=O.C(OCC)(=O)C>[Cl:26][C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=1[NH:37][C:38]([NH:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:25])[C:10]2[N:15]=[C:14]3[S:16][C:17]([NH:19][C:20]([CH:22]4[CH2:23][CH2:24]4)=[O:21])=[N:18][C:13]3=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8])=[O:39]
Reactant: CN(c1ccc(F)c(N)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(c1ccc(F)c(NC(=O)Nc2ccc(C(F)(F)F)cc2Cl)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 63.5 %

Procedure:
N-{5-[(3-Amino-4-fluorophenyl)(methyl)amino][1,3]thiazolo[5,4-b]pyridin-2-yl}cyclopropanecarboxamide (120 mg, 0.34 mmol) produced in Example 1(x) was dissolved in N,N-dimethylformamide (1.5 mL), 2-chloro-1-isocyanato-4-(trifluoromethyl)benzene (62 μL, 0.40 mmol) was added, and the mixture was stirred at room temperature 6 hr. The reaction mixture was diluted with ethyl acetate (10 mL), and washed successively with saturated aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=50/50→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (125 mg, 64%) as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#N)=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH3:11]CN(C(C)C)C(C)C>C(O)CCC>[NH:5]1[C:6]2[CH:7]=[CH:8][CH:11]=[N:1][C:2]=2[N:3]=[CH:4]1
Reactant: CCN(C(C)C)C(C)C
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CCCCO
Product: c1cnc2nc[nH]c2c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A mixture of 4-amino-6-chloropyrimidine-5-carbonitrile (B) (1.0 eqv.), C-5 (1.0 eqv.) and DIEA (3.0 eqv.) in n-butanol was stirred at 110° C. for overnight. The reaction was monitored by TLC, after completion of reaction the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using 0 to 10% gradient of MeOH in DCM as eluent to give C-6.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]3=[O:24])[CH2:8][CH2:7]2)[N:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4][N:3]1[C@H:31]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:32]([O:34]C)=[O:33].[OH-].[Li+].CO>O>[O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]3=[O:24])[CH2:8][CH2:7]2)[N:5]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:4][N:3]1[C@H:31]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:32]([OH:34])=[O:33]
Reactant: COC(=O)[C@@H](c1ccccc1)N1CN(c2ccccc2)C2(CCN(CCCn3c(=O)[nH]c4ccccc43)CC2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)[C@@H](c1ccccc1)N1CN(c2ccccc2)C2(CCN(CCCn3c(=O)[nH]c4ccccc43)CC2)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 20.6 %

Procedure:
A solution of (R)-methyl 2-(4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetate (105 mg, 0.189 mmol, 1 equiv) and lithium hydroxide (15.9 mg, 0.38 mmol, 2.0 equiv) in a 3:1 mixture of methanol and water (5 ml t/v) was stirred at ambient temperature for 24 hrs. The reaction was concentrated in vacuo and purified using preparatory high performance liquid chromatography. The combined pure fractions were lyophilized to afford the acetate salt of the title compound as a white solid (21 mg, 20%); 1H NMR (400 MHz, DMSO-d6): δ 1.57-1.66 (m, 2H), 1.87-1.91 (m, 2H); 2.79-2.85 (m, 4H); 3.27-3.42 (bs, 4H); 3.85 (t, 2H, J=6.8 Hz); 4.11 (d, 1H, J=4.8 Hz); 4.91 (d, 1H, J=4.8 Hz); 5.71 (s, 1H); 6.76-6.82 (m, 3H); 6.97-6.98 (m, 3H); 7.17-7.23 (m, 3H); 7.35-7.43 (m, 5H); 10.83 (s, 1H); 12.5 (bs, 1H); MS for C31H33ClN5O4 540.01 (M+H)+.
Reaction SMILES: [I:1][C:2]1[C:10]([NH2:11])=[C:9]([I:12])[CH:8]=[C:7]([I:13])[C:3]=1[C:4]([OH:6])=[O:5].C1(=O)[N:18]([CH2:19][CH2:20][C:21](Cl)=[O:22])C(=O)C2=CC=CC=C12>>[I:1][C:2]1[C:10]([NH:11][C:21](=[O:22])[CH2:20][CH2:19][NH2:18])=[C:9]([I:12])[CH:8]=[C:7]([I:13])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(Cl)CCN1C(=O)c2ccccc2C1=O
Reactant: Nc1c(I)cc(I)c(C(=O)O)c1I
Product: NCCC(=O)Nc1c(I)cc(I)c(C(=O)O)c1I

Procedure:
The same procedure is used as for Compound I, using 2,4,6-triiodo-3-amino-benzoic acid as iodo starting material and β-phthalimidopropionic acid chloride.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C@H:10]([CH2:13][OH:14])[O:9][C:8]=2[CH:15]=1)([O-:3])=[O:2].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.O>N1C=CC=CC=1>[CH3:26][C:16]1[CH:21]=[CH:20][C:19]([S:22]([O:14][CH2:13][C@@H:10]2[O:9][C:8]3[CH:15]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=3[O:12][CH2:11]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)O[C@@H](CO)CO2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc([N+](=O)[O-])cc3O2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
A 5 L three necked flask equipped with a mechanical stirrer and thermocouple is changed with [(2S)-7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl]methanol (210.4 g, 0.996 mol) and anhydrous pyridine (600 mL). The flask is immersed in an ice/brine bath to achieve an internal temperature of 0-1° C. To this is added a solution of p-toluenesulfonyl chloride (220.0 g, 1.15 mol) is dissolved in pyridine (200 mL) over 30 min. The bath is allowed to expire, and the mixture is stirred for 18 h at room temperature. Water (1600 mL) is added at a constant rate over 45 min. The resulting suspension is stirred for 1 h, and then the precipitate is collected by vacuum filtration onto a medium porosity fritted funnel. The filter cake is washed with water (1600 mL) and suction dried under nitrogen to give [(2R)-7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (356.8 g, 98%) as a tan powder; m.p. 138° C. LCMS (Standard Method): 2.78 min, 388 (M+Na)+. 1H NMR (300 MHz, DMSO-d6) δ7.79-7.72 (m, 3H), 7.49-7.42 (m, 3H), 7.06 (d, J=8.8 Hz, 1H), 4.59-4.55 (m, 1H), 4.41 (dd, J=2.6, 11.6 Hz, 2H), 4.22 (dd, J=6.3, 11.5 Hz, 1H), 4.12 (dd, J=6.8, 11.7 Hz, 1H), 2.38 (s, 3H).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)(=[O:4])=[O:3].[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18][NH2:19]>C1COCC1>[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18][NH:19][C:10](=[O:11])[C:9]1[CH:13]=[CH:14][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: CN(C)CCN
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)c1ccc(NS(C)(=O)=O)cc1

Procedure:
In a three-neck flask equipped with mechanical stirrer, cooled in ice bath under nitrogen atmosphere, place a solution of 4.67 g (0.02 mole) of 4-[(methylsulfonyl)amino]benzoyl chloride in 30 ml of anhydrous THF. Add dropwise a solution of 1.77 g (0.02 mole) of N,N-dimethylethylenediamine in 10 ml of anhydrous THF; white solid precipitate forms immediately. Stir the mixture at ice temperature for one-half hour and at room temperature for one-half hour. Collect the solid by filtration, wash with dichloromethane, and recrystallize from methanol ether mixture to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:12]=1[C:13]#[N:14]>CS(C)=O>[C:2]1([NH:1][C:11]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:12]=2[C:13]#[N:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1c(F)cccc1-c1ccccc1
Reactant: Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#Cc1c(Nc2ccccc2)cccc1-c1ccccc1
Temperature: 25 °C

Procedure:
Aniline (0.168 g, 1.8 mmol) was dissolved in dimethyl sulfoxide (3 mL) and stirred under argon at room temperature. Sodium hydride (0.0043 g, 1.8 mmol) was added and a deep purple color developed while the mixture was stirred at room temperature for 1 hour. The mixture was cooled to 0° C. in an ice bath and the product of example 12a above, 2-fluoro-6-phenylbenzonitrile, (0.295 g, 1.5 mmol) dissolved in dimethyl sulfoxide (2 mL) was added and the mixture stirred at room temperature overnight. The solvent was evaporated in vacuo, and the residue was partitioned between ethyl acetate and water. The organic phase was washed with water (5×), brine (1×) dried over anhydrous Na2SO4 filtered, and evaporated to give the crude product which was then chromatographed on silica gel eluted with 0-30% CH2Cl2 in hexane to give the title compound as a white amorphous solid. ES (+) MS m/e=271 (MH+)
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](=[O:5])[CH3:4].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br-].[CH2:19]([C:21]([C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([CH3:37])[CH:31]=1)([C:24]1[S:25][CH:26]=[C:27]([CH3:29])[CH:28]=1)[CH2:22][CH3:23])[CH3:20].C1COCC1>C1COCC1.CCOC(C)=O>[CH2:19]([C:21]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:4][C:3](=[O:5])[C:2]([CH3:7])([CH3:6])[CH3:1])=[C:32]([CH3:37])[CH:31]=1)([C:24]1[S:25][CH:26]=[C:27]([CH3:29])[CH:28]=1)[CH2:22][CH3:23])[CH3:20]
Reactant: CCC(CC)(c1ccc(C)c(C)c1)c1cc(C)cs1
Reactant: CC(=O)C(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(CCC(=O)C(C)(C)C)c(C)c1)c1cc(C)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a 0° C. solution of {4-[1-ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenyl}-methanol (6 g,) in THF (50 ml) is treated with PBr3 (2.2 ml, 23.3 mmol) and warmed to RT. After stirring for 2 h, the mixture is partitioned between EtOAc and brine. The organic layer is MgSO4 dried, concentrated, and dissolved in anhydrous THF (30 ml) to give a solution of {4-[1-ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenyl}-methane bromide. Separately, a solution of 3,3-dimethyl-butan-2-one (5.3 ml, 42.4 mmol) in THF (15 ml) is treated with LiHMDS (42.4 ml, 42.4 mmol, 1M in THF) at −70° C. for 1 h. This solution is transferred (via cannula) into a −70° C. solution of {4-[1-ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenyl}-methanebromide/THF. The mixture is warmed to RT and stirred for 1 h. The reaction is diluted with EtOAc and washed with 0.2 N HCl until the aq layer is pH 2. The organic layer is concentrated to give the title compound (6.2 g, 79%).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][N:10]2[C:19](OC2C=CC([N+]([O-])=O)=CC=2)=[O:20])=[CH:5][CH:4]=1.[NH2:33][C:34]1[CH:35]=[N:36][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:38][CH:39]=1.[H-].[Na+].O>CC#N>[F:31][C:2]([F:1])([F:32])[C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][N:10]2[C:19]([NH:33][C:34]2[CH:35]=[N:36][C:37]([C:40]([F:43])([F:41])[F:42])=[CH:38][CH:39]=2)=[O:20])=[CH:7][CH:8]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc(C(F)(F)F)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C(Nc1ccc(C(F)(F)F)nc1)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-4-nitrophenyl 1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (70 mg, 158 example 88) in MeCN (0.5 mL) was added 3-amino-6-(trifluoromethyl)pyridine (77 mg, 475 μmol). The resulting mixture was then subjected to a microwave irradiation at 150° C. for 15 min and at 180° C. for 15 min. Then, sodium hydride, 60% dispersion in mineral oil (18 mg, 475 μmol) was added and the mixture was stirred at RT for overnight. Then, H2O (0.5 mL) was added and the solvents were removed. The residue was then dissolved in a solution of MeOH and DMSO (1:1. 1.0 mL). The solution mixture was purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give the desired product, which was then dissolved in MeOH (1.0 mL). The solution was then washed through PL-HCO3 MP resin (polymerlabs, 200 mg/6 mL tube) and the resin was washed with MeOH (2×0.5 mL). The combined washings were then concentrated and dried under vacuum to give the title compound as a yellow solid. MS (ESI, positive ion) m/z: 466 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18](O)=[O:19])=[C:13]([C:15](=[O:17])[NH2:16])[N:14]=[C:7]3[C:6]=2[CH:21]=1.[NH2:23][CH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[O:19])=[C:13]([C:15]([NH2:16])=[O:17])[N:14]=[C:7]3[C:6]=2[CH:21]=1
Reactant: NC1CCOCC1
Reactant: NC(=O)c1nc2n(c1C(=O)O)CCOc1cc(F)c(Br)cc1-2
Product: NC(=O)c1nc2n(c1C(=O)NC1CCOCC1)CCOc1cc(F)c(Br)cc1-2

Procedure:
10-Bromo-2-carbamoyl-9-fluoro-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylic acid (55 mg) was reacted with 4-aminotetrahydropyran similar to as described in Example 2 to produce crude 10-bromo-9-fluoro-N3-tetrahydropyran-4-yl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide which was then reacted with 2-Methyl-3-butyne-ol similar to as described in Procedure E to afford 12.5 mg of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-N3-tetrahydropyran-4-yl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following reverse phase hplc purification. MS (Q1) 457 (M)+. 1H NMR (400 MHz, DMSO) δ 11.42 (d, J=11.5 Hz, 1H), 8.60 (d, J=8.4 Hz, 1H), 8.38 (s, 1H), 7.88 (s, 1H), 7.01 (d, J=10.6 Hz, 1H), 5.47 (s, 1H), 5.08-4.94 (m, 2H), 4.60-4.49 (m, 2H), 4.10-3.92 (m, 1H), 3.91-3.79 (m, 2H), 3.54-3.43 (m, 2H), 1.93-1.80 (m, 2H), 1.49 (s, 6H), 1.48-1.42 (m, 1H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](Cl)=[O:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N:17]1[CH:22]=CC=C[CH:18]=1.CNC>ClCCl>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:15])[N:17]([CH3:22])[CH3:18])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: c1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cl)CC1
Agent: CNC
Solvent: ClCCl
Product: CN(C)C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 70 %

Procedure:
A solution of 1-Boc-4-(chlorocarbonyl)piperazine (300 mg, 1.22 mmol), pyridine (288.4 mg, 3 equiv) (Preparation B-12-A), and dimethylamine (1.83 mmol, 1.5 equiv) in dichloromethane was refluxed overnight. The solution was quenched by the dropwise addition of water. The organic layer was separated, dried over anhydrous Na2SO4, and evaporated in vacuo. The residue was purified by flash chromatography to give the title compound as a solid (˜70% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:23](=[O:35])CC3C4C(=CC=CC=4)N(C)C=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([N:43]=C=O)=[CH:39][CH:38]=1>>[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:23]([NH:22][C@@H:17]2[CH2:18][CH2:19][CH2:20][CH2:21][C@H:16]2[NH:15][C@H:11]2[CH2:12][CH2:13][CH2:14][N:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)[CH2:10]2)=[O:35])=[CH:39][CH:38]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Cn1cc(CC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c2ccccc21
Product: N#Cc1ccc(N2CCC[C@H](N[C@@H]3CCCC[C@H]3NC(=O)Nc3ccc(Cl)cc3)C2)cc1

Procedure:
1-(4-Chlorophenyl)-3-((1R,2R)-2-((S)-1-(4-cyanophenyl)piperidin-3-ylamino)cyclohexyl)urea was synthesized using 4-((S)-3-((1R,2R)-2-aminocyclohexylamino)piperidin-1-yl)benzonitrile (from intermediate D, Example 10) (60 mg, 0.2 mmol) and 1-chloro-4-isocyanatobenzene (30.9 mg, 0.2 mmol) according to General Procedure G to give 25 mg (27.5%) of white solid. Anal. Calcd. for C25H30ClN5O m/z 451.2, found: 452.2 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.66 (bs, 1H), 7.43 (d, J=8.8 Hz, 4H), 7.26 (d, J=8.8 Hz, 2H), 6.95 (m, 2H), 6.13 (s, 1H), 3.80 (m, 2H), 3.3 (m, 1H), 2.79 (bs, 1H), 2.4 (m, 1H), 1.91 (m, 3H), 1.64 (m, 4H), 1.48 (m, 1H), 1.23 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([OH:9])=[C:4]([N+:10]([O-])=O)[CH:3]=1>C(O)(=O)C.O.[Fe]>[NH2:10][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[CH:6][C:5]=1[OH:9]
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1O
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc(Cl)c(Cl)cc1O
Temperature: 50 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a stirred solution of 4,5-dichloro-2-nitrophenol (15 g, 72 mmol) in acetic acid (150 mL) and water (450 mL), iron powder (16 g, 285 mmol) was added in portions. The resulting mixture was stirred at 50° C. for 2 h. The mixture was allowed to cool to room temperature, filtered, and the cake was rinsed with ethyl acetate. The filtrate was extracted with ethyl acetate. The organic layer was washed with water, NaHCO3 (aq.) and brine, dried over Na2SO4 and concentrated in vacuo to afford the desired product (10 g, 78%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5](O)=[O:6].Cl.C[N:15](C)CCCN=C=NCC.ON1C(=O)CCC1=O.N>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5]([NH2:15])=[O:6]
Reactant: O=C(O)c1cc(F)c(F)c(F)c1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.8 %

Procedure:
3,4,5-Trifluorobenzoic acid (1.00 g) was dissolved in N,N-dimethylformamide (15 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.31 g) and N-hydroxysuccinimide (785 mg) were added thereto at 0° C. The mixture was stirred at room temperature for 3 hr. 28% Aqueous ammonia solution (2 mL) was added to the mixture at 0° C. and the mixture was stirred at room temperature for 30 min. Water was added to the mixture and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate-hexane=1:2→3:1) and recrystallized from a mixed solvent of isopropylether and hexane to give the title compound as colorless crystals (yield: 734 mg).