Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2C2C=CC(C([O-])=O)=CC=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]([CH3:13])[CH2:11][CH3:12].[OH-:29].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([OH:29])=[CH:16][CH:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]([CH3:13])[CH2:11][CH3:12]
Reactant: CCC(C)COc1ccc(-c2ccccc2-c2ccc(C(=O)[O-])cc2)cc1Br
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: CCC(C)COc1ccc(-c2ccc(O)cc2)cc1Br

Procedure:
A mixture of 3'-bromo-4'-(2-methylbutyloxy)-4-biphenylylbenzoate (4.8 g) from step (IV), a 40% aqueous solution (3.2 g) of NaOH and ethanol (100 ml) was heated under reflux for 3 hours, followed by distilling off ethanol, adding toluene, acidifying with 6N hydrochloric acid, heating to dissolve insolubles, separating the solution layer, washing with water, further washing with an aqueous solution of sodium hydrogen sulfite, washing with water to make the solution neutral, drying, distilling off toluene and recrystallizing the residue from n-heptane to obtain 3'-bromo-4'-(2-methylbutyloxy)-4-hydroxybiphenyl (3.0 g). M.p.: 75°~76.5° C.
Reaction SMILES: [CH2:1]1[C:6]2[C:7]3[N:8]([CH:19]=[N:20][N:21]=3)[C:9]3[CH:17]=[CH:16][C:15](=[O:18])[CH2:14][C:10]=3[N:11]3[CH:12]=[CH:13][C:4]([C:5]=23)=[CH:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:29][CH:30]1[CH2:32][CH2:31]1>CN(C)C=O>[CH:30]1([CH2:29][CH:14]2[C:10]3[N:11]4[CH:12]=[CH:13][C:4]5[C:5]4=[C:6]([CH2:1][CH2:2][CH:3]=5)[C:7]4[N:8]([CH:19]=[N:20][N:21]=4)[C:9]=3[CH:17]=[CH:16][C:15]2=[O:18])[CH2:32][CH2:31]1
Reactant: O=C1C=CC2=C(C1)n1ccc3c1=C(CCC=3)c1nncn12
Reactant: ClCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1C=CC2=C(C1CC1CC1)n1ccc3c1=C(CCC=3)c1nncn12
Temperature: 95 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
1,2-Dihydrobenzo[b]pyrrolo[3,2,1-jk][1,2,4]triazolo[4,3-d][1,4]benzodiazepin-8(7H)-one (5.2 g) was dissolved in dimethylformamide (150 ml). Potassium carbonate (0.5 g) was added, followed by (chloromethyl)cyclopropane (2.1 ml). The mixture was stirred at 95° C. overnight, filtered, and evaporated under reduced pressure. The residue was purified by high performance liquid chromatography (1% methanol/dichloromethane) to yield 3.4 g (54.8%) of product. Recrystallization from pentane/ether gave the analytical sample, mp 99° C.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:2][C:3]#[CH:4].Br[C:14]1[N:18]([CH3:19])[N:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21]>CCN(CC)CC.CCOC(C)=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:19][N:18]1[C:14]([C:4]#[C:3][CH2:2][CH2:1][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[N:17]1
Reactant: C#CCCNC(=O)OC(C)(C)C
Reactant: Cn1ncc([N+](=O)[O-])c1Br
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cn1ncc([N+](=O)[O-])c1C#CCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 78.5 %

Procedure:
A solution of tert-butyl 3-butyn-1-ylcarbamate (123 mg, 0.728 mmol) in NEt3 (4 mL) was treated with 5-bromo-1-methyl-4-nitro-1H-pyrazole (100 mg, 0.485 mmol) and copper(I) bromide dimethyl sulfide complex (10 mg, 0.049 mmol). The mixture was degassed four times by evacuating and refilling with nitrogen gas before tetrakis(triphenylphosphine)-palladium(0) (28 mg, 0.024 mmol) was added. Degassing was repeated twice and the reaction mixture was stirred at room temperature for 20 hr. More tert-butyl 3-butyn-1-ylcarbamate (123 mg, 0.728 mmol) and copper(I) bromide dimethyl sulfide complex (10 mg, 0.049 mmol) were added and the mixture was degassed three times. Tetrakis(triphenylphosphine)palladium(0) (28 mg, 0.024 mmol) was added and the reaction mixture was stirred at room temperature for 48 hr. The mixture was diluted with EtOAc (100 mL) and washed with water (20 mL) and brine (20 mL). The organic layer was separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification of the residue via silica gel column chromatography (30-40% EtOAc/isohexane) gave tert-butyl 4-(1-methyl-4-nitro-1H-pyrazol-5-yl)but-3-ynylcarbamate as a yellow oil (112 mg, 78%). 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 5.03 (s, 1H), 3.94 (s, 3H), 3.46 (q, J=6.4 Hz, 2H), 2.79 (t, J=6.4 Hz, 2H), 1.67-1.27 (m, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.Cl.[CH3:13][O:14][NH2:15]>N1C=CC=CC=1>[CH3:13][O:14][N:15]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: CON
Reactant: O=C1CCc2cc(Br)ccc21
Agent: Cl
Solvent: c1ccncc1
Product: CON=C1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-Bromo-1-indanone and O-methylhydroxylamine hydrochloride were combined in pyridine and stirred at ambient temperature for 16 hours. The mixture was concentrated under reduced pressure and the residue was suspended in diethyl ether. The suspension was filtered and the filter cake was washed with diethyl ether. The filtrate was washed with water, 1N HCl, water, and concentrated to provide the title compound. 1H NMR (300 MHz, d6-DMSO) 7.63 (m, 2H), 7.48 (m, 2H), 3.90 (s, 3H), 3.00 (m, 2H), 2.80 (m, 2H); MS (DCI/NH3) m/e 240 (M+H)+.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[NH:9]1[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10]1>C1COCC1>[Br:8][C:13]1[NH:9][CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc[nH]c1
Solvent: C1CCOC1
Product: COC(=O)c1c[nH]c(Br)c1
Temperature: 23 °C
Reaction time: 1.5 h
Yield: 67.1 %

Procedure:
NBS (Aldrich; 1.201 g, 6.75 mmol) was added in one portion to a solution of methyl 1H-pyrrole-3-carboxylate (Aldrich; 0.844 g, 6.75 mmol) in THF (10 mL), and the resulting solution was stirred at 23° C. for 1.5 h. THF was removed in vacuo, and the residue was taken up in DCM (50 mL) and washed with 10:1 water/sat. aq. NaHCO3 (50 mL). The organic layer was separated, and the aq. layer was extracted with DCM (2×40 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated onto silica gel. Chromatographic purification (silica gel, 0-50% EtOAc/hexanes) furnished methyl 5-bromo-1H-pyrrole-3-carboxylate (924.2 mg, 4.53 mmol, 67% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.41 (1H, br. s.), 7.36 (1H, dd, J=2.9, 1.8 Hz), 6.60 (1H, dd, J=2.5, 1.8 Hz), 3.81 (3H, s). m/z (ESI, +ve) 203.9/205.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13](F)=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:21][NH2:22]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13]([NH:22][CH3:21])=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: O=C(Nc1cccc(Cl)n1)c1ccc(F)c([N+](=O)[O-])c1
Product: CNc1ccc(C(=O)Nc2cccc(Cl)n2)cc1[N+](=O)[O-]

Procedure:
Prepared analogously to example 316a from N-(6-chloro-pyridin-2-yl)-4-fluoro-3-nitro-benzamide and methylamine.
Reaction SMILES: [Cl:1][C:2]1[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:3]=1[CH2:4][NH:5][C:6](=[O:40])[N:7]([CH:9]([CH2:25][O:26][CH2:27][CH:28]([OH:39])[CH2:29][O:30][P:31]([O:36]CC)([O:33]CC)=[O:32])[CH2:10][O:11][C:12](=[O:24])[NH:13][C:14]1[N:15]=[CH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:8].[Si](I)(C)(C)C>C(#N)C>[Cl:1][C:2]1[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:3]=1[CH2:4][NH:5][C:6](=[O:40])[N:7]([CH:9]([CH2:25][O:26][CH2:27][CH:28]([OH:39])[CH2:29][O:30][P:31]([OH:36])([OH:33])=[O:32])[CH2:10][O:11][C:12](=[O:24])[NH:13][C:14]1[N:15]=[CH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:8]
Reactant: CCOP(=O)(OCC)OCC(O)COCC(COC(=O)Nc1cc2ccccc2cn1)N(C)C(=O)NCc1cccc(F)c1Cl
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: CN(C(=O)NCc1cccc(F)c1Cl)C(COCC(O)COP(=O)(O)O)COC(=O)Nc1cc2ccccc2cn1
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 72 %

Procedure:
To a solution of Isoquinolin-3-yl-carbamic acid 2-[3-(2-chloro-3-fluoro-benzyl)-1-methyl-ureido]-3-[3-(diethoxy-phosphoryloxy)-2-hydroxy-propoxy]-propyl ester (0.60 g, 0.895 mmol) in acetonitrile (30 mL) was added TMSI (1.43 g, 7.16 mmol) dropwise at 0° C. After stirring at 0° C. for 4.5 h, the reaction was quenched with EtOH. The solvent was removed, and the resulting residue was purified on RP-HPLC using a mixture of acetonitrile and H2O (0.1% TFA buffer) to give isoquinolin-3-yl-carbamic acid 2-[3-(2-chloro-3-fluoro-benzyl)-1-methyl-ureido]-3-(2-hydroxy-3-phosphonooxy-propoxy)-propyl ester (396 mg, 73%). LRMS [M−H]+m/z 613.5
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH:9]=[CH:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([NH:20][C:21]4[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=4[C:23]([OH:25])=O)=[CH:17][CH:18]=3)[N:13]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][O:31]3)[N:12]=2)[CH:3]=1.[CH:36]1([C:39]#[C:40][CH2:41][NH2:42])[CH2:38][CH2:37]1>>[CH:36]1([C:39]#[C:40][CH2:41][NH:42][C:23](=[O:25])[C:22]2[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=2[NH:20][C:16]2[CH:15]=[C:14]3[C:19]([C:11]([CH:10]=[CH:9][C:4]4[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=4)=[N:12][N:13]3[CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][O:31]3)=[CH:18][CH:17]=2)[CH2:38][CH2:37]1
Reactant: NCC#CC1CC1
Reactant: Cc1cc(C)nc(C=Cc2nn(C3CCCCO3)c3cc(Nc4ccccc4C(=O)O)ccc23)c1
Product: Cc1cc(C)nc(C=Cc2nn(C3CCCCO3)c3cc(Nc4ccccc4C(=O)NCC#CC4CC4)ccc23)c1

Procedure:
Was prepared in a similar manner to that described for Example 6 above, except using 2-[3-[2-(4,6-dimethyl-pyridin-2-yl)-vinyl]-1-(tetrahydro-pyran-2-yl)-1H-indazol-6-ylamino]-benzoic acid E and 3-Cyclopropyl-prop-2-ynylamine. 1H NMR (CDCl3): δ 9.51 (1H, s), 7.97 (1H, d, J=8.7 Hz), 7.81 (1H, d, J=16.6 Hz), 7.51–7.42 (3H, m), 7.34–7.29 (2H, m), 7.16 (1H, s), 7.11 (1H, dd, J=9.0,1.9 Hz), 6.85 (1H, s), 6.81 (1H, dt, J=7.2, 1.1 Hz), 6.23 (1H, t, J=7.2 Hz), 5.61 (1H, dd, J=9.0, 2.6 Hz), 4.17 (2H, dd, J=5.3, 2.3 Hz), 4.07–4.00 (1H, m), 3.75–3.66 (1H, m), 2.63–2.50 (1H, m), 2.54 (3H, s), 2.32 (3H, s), 2.20–2.02 (2H, m), 1.79–1.62 (3H, m), 1.29–1.19 (1H, m), 0.77–0.67 (4H, m).
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:29]=[CH:28][C:8]([C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[O:20][CH:19]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17][C:16]=3[CH:27]=2)=[O:10])=[C:7]([F:30])[CH:6]=1.C(N(CC)CC)C.Cl[C:39]([O:41][CH3:42])=[O:40]>CN(C)C1C=CN=CC=1.ClCCl>[F:30][C:7]1[CH:6]=[C:5]([CH:4]=[N:3][NH:2][C:39]([O:41][CH3:42])=[O:40])[CH:29]=[CH:28][C:8]=1[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]2[O:20][CH:19]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17][C:16]=2[CH:27]=1)=[O:10]
Reactant: CCOC(=O)CC1CCc2cc(NC(=O)c3ccc(C=NN)cc3F)ccc2O1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC1CCc2cc(NC(=O)c3ccc(C=NNC(=O)OC)cc3F)ccc2O1

Procedure:
436 mg (1.0 mmol) of the amidine from Example 69, 0.3 ml triethylamine, and 20 mg 4-dimethylaminopyridine were dissolved in 29 ml dichloromethane followed by addition of 104 mg (1.1 mmol) methyl chloroformate at 0° C. After stirring overnight at room temperature a white precipitate of the title compound had been formed. It was filtered with suction and washed successively with water and with ether. Yield: 0.35 g (77%) of a pale yellow powder, m.p. 202-204° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[CH3:14][O:15][C:16]1[CH:21]=[C:20]([C:22]2[NH:26][C:25]([CH3:27])=[N:24][N:23]=2)[CH:19]=[CH:18][C:17]=1[NH2:28]>C(#N)C>[Cl:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4]([NH:6][C:7]([NH:28][C:17]1[CH:18]=[CH:19][C:20]([C:22]2[NH:26][C:25]([CH3:27])=[N:24][N:23]=2)=[CH:21][C:16]=1[O:15][CH3:14])=[O:8])=[O:5]
Reactant: COc1cc(-c2nnc(C)[nH]2)ccc1N
Reactant: O=C=NC(=O)c1ccc(F)cc1Cl
Solvent: CC#N
Product: COc1cc(-c2nnc(C)[nH]2)ccc1NC(=O)NC(=O)c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The solution of equivalent amounts of 2-chloro-4-fluorobenzoyl isocyanate was added dropwise to the solution of 35 mg of 2-methoxy-4-(5-methyl-4H-[1,2,4]triazol-3-yl)phenylamine in 3 ml of acetonitrile and the mixture was stirred at room temperature for 30 minutes. The solid was then filtered off with suction, stirred with t-butyl methyl ether, filtered off with suction and dried under reduced pressure.
Reaction SMILES: [Br:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][C:5]1[O:6][C:7]([CH3:25])=[C:8]([CH3:24])[C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:13]=1)=[O:11].Cl[S:31]([C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[C:36]([OH:43])[CH:35]=1)(=[O:33])=[O:32]>>[Br:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][C:5]1[O:6][C:7]([CH3:25])=[C:8]([CH3:24])[C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][S:31]([C:34]2[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[C:36]([OH:43])[CH:35]=2)(=[O:33])=[O:32])=[C:14]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:13]=1)=[O:11]
Reactant: Cc1oc(Cc2ccccc2Br)c(C(=O)c2ccc(O)c(C3CCCC3)c2)c1C
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Product: Cc1oc(Cc2ccccc2Br)c(C(=O)c2ccc(OS(=O)(=O)c3ccc(C(=O)O)c(O)c3)c(C3CCCC3)c2)c1C
Yield: 68.3 %

Procedure:
The title compound was prepared according to the procedure in Example 4 using [2-(2-bromo-benzyl)-4,5-dimethyl-furan-3-yl]-(3-cyclopentyl-4-hydroxy-phenyl)-methanone (0.516 g, 1.14 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.540 g, 2.28 nmmol). Purification on 2% H3PO4/MeOH treated silica gel, eluting with a 15 & 25% EtOAc/hexane step gradient gave 0.509 g (68%) of the title compound as a brown solid, mp 72-82° C. 1H NMR (DMSO-d6) δ1.25-1.34 (m, 2H), 1.50-1.55 (m, 2H), 1.62-1.74 (m, 4H), 1.77 (s, 3H), 2.15 (s, 3H), 2.95 (quintet, 1H), 3.88 (s, 2H), 7.10-7.15 (m, 2H), 7.20 (d, 1H), 7.27 (t, 1H), 7.35-7.37 (m, 2H), 7.48-7.58 (m, 3H), 7.96 (dd, 1H). IR (KBr) 3400,2950, 1690, 1390 and 1190 cm−1. mass spectrum (−ESI) m/z 651 (M−H). Anal. Calcd. for C32H29BrO8S.0.4H2O: C, 58.17; H, 4.55; N, 0.00. Found: C, 58.20; H, 4.55; N, 0.03.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].II.C([C:13]1([N:19]2[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)#N>O1CCCC1.BrCCBr>[C:2]1([C:13]2([N:19]3[CH2:20][CH2:21][CH:22]([OH:25])[CH2:23][CH2:24]3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CC1(N2CCC(O)CC2)CCCCC1
Reactant: Brc1ccccc1
Agent: II
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: OC1CCN(C2(c3ccccc3)CCCCC2)CC1
Reaction time: 17 h

Procedure:
To bromobenzene (4.1 ml) and magnesium turnings (4 g) in 200 ml dry tetrahydrofuran under nitrogen was added a crystal of iodine and 10 drops of 1,2-dibromoethane. After small bubbles began to form, the reaction was stirred and heated to reflux for 4 hours. After cooling to room temperature 1-(1-cyanocyclohexyl)-4-hydroxypiperidine (2 g) was added. After 17 hours, the reaction was filtered, 120 ml saturated ammonium chloride was added and the mixture was extracted with ethyl ether. The ether layer was dried and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluted with the appropriate mixture of methanol and chloroform to yield pure 1-(1-phenylcyclohexyl)-4-hydroxypiperidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=O)=[O:25])[CH:19]=3)=[CH:16][CH:17]=2)=[CH:11][C:10]([C:28]([NH2:31])([CH3:30])[CH3:29])=[N:9]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:39][CH2:40][CH2:41][CH2:42]Br>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])=[O:25])[CH:19]=3)=[CH:16][CH:17]=2)=[CH:11][C:10]([C:28]([CH3:29])([N:31]2[CH2:42][CH2:41][CH2:40][CH2:39]2)[CH3:30])=[N:9]1
Reactant: CC(C)(N)c1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2ccccc2Cl)n1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CS(=O)c1cccc(-c2ccc(-c3cc(C(C)(C)N4CCCC4)nn3-c3ccccc3Cl)s2)c1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of the 2-[1-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]propan-2-amine (142 mg, 0.3 mmol), K2CO3 (83 mg, 0.6 mmol), 1,4-dibromobutane (0.1 mL, 0.7 mmol) and anhydrous EtOH was stirred at 100° C. in a sealed vial for 18 h. The solvent was removed in vacuo, and the residue was purified by flash chromatography (0-40% 20% MeOH/DCM) to give the title compound as a pale-yellow solid. 1HNMR (CDCl3): Et 8.03 (m, 1H), 7.86-7.83 (m, 1H), 7.74-7.71 (m, 1H), 7.61-7.47 (m, 5H), 7.23 (d, 1H), 6.93 (s, 1H), 6.83 (d, 1H), 3.68 (m, 2H), 3.08 (s, 3H), 2.17 (m, 2H), 2.04 (s, 6H), 1.83 (m, 2H). MS(ES): 526 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[NH:22][C@@:16]2([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:17][C@H:18]3[C:23]([O:25]C(C)(C)C)=[O:24])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Cl:38]CCl.Cl>C(OCC)C>[ClH:38].[F:37][C:2]([F:1])([F:36])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[NH:22][C@@:16]2([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:17][C@H:18]3[C:23]([OH:25])=[O:24])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: ClCCl
Agent: Cl
Solvent: CCOCC
Product: O=C(O)[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
A mixture of (1R*,2R*,5S*,6R*)-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(tert-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octane (Example 25; 20 mg, 0.04 mmol), dichloromethane (1 ml) and 1M HCl in diethyl ether (0.5 ml) was kept at room temperature for 2 weeks. The white solid was filtered off, washed with a 1:1 mixture dichloromethane:diethyl ether to give the title compound (11 mg).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]2[N:8]([C:12]3[CH:17]=[CH:16][C:15]4[O:18][CH2:19][O:20][C:14]=4[CH:13]=3)[C:9](=[O:11])[NH:10][C:5]2=[CH:4][CH:3]=1.[OH-].[K+].[CH2:23](Br)[CH:24]=[CH2:25]>CC(C)=O>[F:1][C:2]1[N:7]=[C:6]2[N:8]([C:12]3[CH:17]=[CH:16][C:15]4[O:18][CH2:19][O:20][C:14]=4[CH:13]=3)[C:9](=[O:11])[N:10]([CH2:25][CH:24]=[CH2:23])[C:5]2=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2ccc(F)nc2n1-c1ccc2c(c1)OCO2
Reactant: C=CCBr
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: C=CCn1c(=O)n(-c2ccc3c(c2)OCO3)c2nc(F)ccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Treat a suspension of 1.4 g. (0.005 mole) of the imidazopyridine product of Step D in 80 ml. of acetone with 560 mg. (0.01 mole) of powdered potassium hydroxide. Stir at room temperature for 20 minutes and add 1.21 g. (0.01 mole) of allyl bromide. Continue stirring overnight. Concentrate the reaction mixture to one-half volume and dilute with 75 ml. of water. Separate the solid product by filtration and crystalize from ethanol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24]O)=[C:12]2[O:26][CH2:27][CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:36])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24][Cl:36])=[C:12]2[O:26][CH2:27][CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)Cn1c(CO)c(OCCCC(F)(F)F)c2cc(OCc3ccccc3)ccc2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)Cn1c(CCl)c(OCCCC(F)(F)F)c2cc(OCc3ccccc3)ccc2c1=O
Yield: 88.2 %

Procedure:
To a solution of 6-benzyloxy-3-hydroxymethyl-2-isobutyl-4-(4,4,4-trifluorobutoxy)-1(2H)-isoquinolinone (3.80 g, 8 mmol) in toluene (30 mL) was added thionyl chloride (1.2 mL, 16 mmol). The obtained mixture was refluxed under heating for 2 h. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 6-benzyloxy-3-chloromethyl-2-isobutyl-4-(4,4,4-trifluorobutoxy)-1(2H)-isoquinolinone (3.4 g, 88.8%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][CH:15]=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19]CC)=O)[C:9]2=[O:27])=[CH:5][CH:4]=1>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[C:9](=[O:27])[C:10]3[N:14]=[CH:15][C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:17]([OH:19])[C:11]=3[CH:12]=[CH:13]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(=CNc1cccn(Cc2ccc(OC)cc2)c1=O)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCOC(=O)c1cnc2c(=O)n(Cc3ccc(OC)cc3)ccc2c1O
Reaction time: 0.5 h

Procedure:
Dowtherm A (50 ml) was heated to 250° C. in a 500 ml a 3-neck rbf equipped with a temperature probe, a stir bar and a reflux condenser. Diethyl 2-((1-(4-methoxybenzyl)-2-oxo-1,2-dihydropyridin-3-ylamino)methylene)malonate (5.00 g, 12.5 mmol) was added in one portion. The mixture was stirred for 30 mins and then was rapidly cooled down using a stream of nitrogen. At around 140° C., a solid started to crash out. Once at RT, the mixture was diluted with hexanes (100 ml) and was allowed to stand overnight. The precipitate that formed was collected by suction filtration, washed with ether and dried to give ethyl 7-(4-methoxybenzyl)-4-hydroxy-8-oxo-7,8-dihydro-1,7-naphthyridine-3-carboxylate as a yellow solid. MS (M+H)+ 355.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:22]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:35][C:36]1[CH:50]=[CH:49][C:39]([C:40]([NH:42][CH:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)=[O:41])=[CH:38][CH:37]=1>C(O)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:35][C:36]4[CH:37]=[CH:38][C:39]([C:40]([NH:42][CH:43]5[CH2:48][CH2:47][O:46][CH2:45][CH2:44]5)=[O:41])=[CH:49][CH:50]=4)=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCCC2)c2nc(Cl)ncc21
Reactant: Nc1ccc(C(=O)NC2CCOCC2)cc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CC(C)O
Solvent: O
Product: CN1C(=O)C(F)(F)CN(C2CCCCC2)c2nc(Nc3ccc(C(=O)NC4CCOCC4)cc3)ncc21
Yield: 54.1 %

Procedure:
A mixture of 0.0562 g (0.18 mmole) 2-chloro-9-cyclohexyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-246), 0.0514 g (0.27 mmole) of toluenesulfonic acid monohydrate, 0.0396 g (0.18 mmole) of 4-amino-N-(tetrahydro-pyran-4-yl)-benzamide and 1 mL of isopropanol was heated in a sealed vessel at 140 degrees for 16.5 hours, cooled and concentrated under reduced pressure. The residue taken up in ethyl acetate and washed successively with 50 mL of saturated aqueous sodium bicarbonate, 50 mL of water, 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from acetonitrile to give 0.0501 g of 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(tetrahydro-pyran-4-yl)-benzamide (I-263) as a white solid.