Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1]([OH:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].C(NCC)C.[C:14]([P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])(=[O:16])[CH3:15]>>[CH2:3]([O:2][P:1]([C:14]([P:17](=[O:24])([O:18][CH2:19][CH3:20])[O:21][CH2:22][CH3:23])([OH:16])[CH3:15])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:4]
Reactant: CCOP(=O)(OCC)C(C)=O
Reactant: CCOP(O)OCC
Solvent: CCNCC
Product: CCOP(=O)(OCC)C(C)(O)P(=O)(OCC)OCC

Procedure:
Diethyl hydrogen phosphite (1.0 mole) and diethyl amine (1.0 mole) were combined in a round bottom flask. Diethyl acetylphosphonate (1.0 mole) was added dropwise, with stirring. The reaction mixture was maintained at a temperature of about 75° C. for an additional 2 hours after all of the diethyl acetyl phosphonate was added. The resulting mixture was distilled under reduced pressure to yield tetraethyl 1-hydroxyethylidene bisphosphonic acid as a pale yellowish liquid which crystallized at -15° C. into small needle-shaped crystals.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:12])[NH:7]2.[H-].[Na+].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1>CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:12])[N:7]2[CH2:21][C:20]1[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=c1ccc2c(Br)cccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)ccc3c(Br)cccc32)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 106.6 %

Procedure:
To a solution of 5-bromoquinolin-2(1H)-one (0.84 g, 2.29 mmol) in DMF (20 mL) at room temperature was added sodium hydride (0.57 g, 14.22 mmol) and 4-methoxybenzyl chloride (1.24 mL, 9.10 mmol). Upon completion of addition, the reaction mixture was stirred at room temperature for 2 d, and then heat to 75° C. where it stirred for 2 h. After cooling to room temperature, the reaction mixture was quenched with water, and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue was purified by flash chromatography (0 to 30% ethyl acetate:hexanes) to afford the title compound (0.84 g, 40% yield) as a white powder. LCMS, [M+H]+=344.0. 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J=9.8 Hz, 1H), 7.44 (dd, J=6.6, 2.2 Hz, 1H), 7.28-7.23 (m, 3H), 7.14 (d, J=8.2 Hz, 1H), 6.89 (d, J=9.8 Hz, 1H), 6.83 (d, J=8.6 Hz, 2H), 5.5 (s, 2H), 3.76 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[O:11]1[C:15]2([CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)[O:14][CH2:13][CH2:12]1>CCOCC>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([C:18]2([OH:21])[CH2:19][CH2:20][C:15]3([O:14][CH2:13][CH2:12][O:11]3)[CH2:16][CH2:17]2)=[CH:3][C:4]=1[CH3:10]
Reactant: COc1ncc(Br)cc1C
Reactant: O=C1CCC2(CC1)OCCO2
Solvent: CCOCC
Product: COc1ncc(C2(O)CCC3(CC2)OCCO3)cc1C

Procedure:
The title compound was prepared as a white solid from 5-bromo-2-methoxy-3-methyl-pyridine (Alfa Aesar) and 1,4-dioxa-spiro[4.5]decan-8-one in ether using the procedure described in Step A of Example 1.
Reaction SMILES: [CH2:1]([O:8][P:9]([O:19][CH2:20][O:21][C:22](=[O:39])[N:23]([CH:36]1[CH2:38][CH2:37]1)[C:24](=[O:35])[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([N+:32]([O-])=O)[CH:26]=1)([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+]>CO.C1COCC1.[Zn]>[CH2:12]([O:11][P:9]([O:19][CH2:20][O:21][C:22](=[O:39])[N:23]([C:24](=[O:35])[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([NH2:32])[CH:26]=1)[CH:36]1[CH2:38][CH2:37]1)([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1ccc(C(=O)N(C(=O)OCOP(=O)(OCc2ccccc2)OCc2ccccc2)C2CC2)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)N(C(=O)OCOP(=O)(OCc2ccccc2)OCc2ccccc2)C2CC2)cc1N
Reaction time: 3 h
Yield: 97.2 %

Procedure:
To a solution of (bis(benzyloxy)phosphoryloxy)methyl-cyclopropyl(4-methyl-3-nitrobenzoyl)carbamate (0.53 g, 1.0 mmol) in MeOH/THF (1:1, 50 mL) under nitrogen were added ammonium chloride (0.79 g, 14.8 mmol) and zinc (0.75 g, 11.5 mmol). After 3 h, the precipitate was filtered, and the filtrate was concentrated in vacuo, diluted with EtOAc and washed with water (2×), brine successively, dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound as a colorless oil (0.51 g, 100% yield). (M+H)+=525.19.
Reaction SMILES: [OH:1][C:2]1([CH2:8][C@H:9]2[CH2:14][CH2:13][C@H:12](OS(C)(=O)=O)[CH2:11][N:10]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[N-:27]=[N+:28]=[N-:29].[Na+]>CN(C)C=O>[N:27]([C@H:12]1[CH2:11][N:10]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@@H:9]([CH2:8][C:2]2([OH:1])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]2)[CH2:14][CH2:13]1)=[N+:28]=[N-:29]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](OS(C)(=O)=O)CC[C@@H]1CC1(O)CCOCC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](N=[N+]=[N-])CC[C@@H]1CC1(O)CCOCC1
Temperature: 80 °C
Reaction time: 24 h
Yield: 82.5 %

Procedure:
To a stirred solution of tert-butyl trans-2-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]-5-[(methylsulfonyl)oxy]piperidine-1-carboxylate (673 mg, 1.71 mmol, step 3 of Example 2) in N,N-dimethylformamide (4 mL) was added sodium azide (334 mg, 5.13 mmol) at room temperature and the mixture was stirred at 80° C. for 24 h. After cooling, the mixture was quenched with water (50 mL), and extracted with ethyl acetate (50 mL×4). The combined organic layer was washed with water (50 mL×4), brine (30 mL), dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (2:1) to give 480 mg (82%) of the title compound as a white crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.[CH:11]1([N:14]2[C:18]([C:19]3[N:24]=[C:23]([NH2:25])[CH:22]=[CH:21][CH:20]=3)=[CH:17][N:16]=[CH:15]2)[CH2:13][CH2:12]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:25][C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([C:18]3[N:14]([CH:11]4[CH2:13][CH2:12]4)[CH:15]=[N:16][CH:17]=3)[N:24]=2)=[O:10])[CH:3]=1
Reactant: Nc1cccc(-c2cncn2C2CC2)n1
Reactant: O=C(O)c1cc(Cl)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(Nc1cccc(-c2cncn2C2CC2)n1)c1cc(Cl)ccn1
Yield: 47.1 %

Procedure:
A solution of 4-chloro-pyridine-2-carboxylic acid (141 mg, 0.895 mmol), 6-(3-cyclopropyl-3H-imidazol-4-yl)-pyridin-2-ylamine (150 mg, 0.750 mmol), (2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (342 g, 0.899 mmol), and N-methylmorpholine (250 μL, 2.70 mmol) in N,N-dimethylformamide was stirred at room temperature for 12 hours. The solvent was removed under reduced pressure, the residue suspended in acetonitrile, and the solid isolated by filtration, washed with water (80 mL), acetonitrile (80 mL) and diethyl ether (80 mL), and dried under reduced pressure to afford 4-chloro-N-(6-(1-cyclopropyl-1H-imidazol-5-yl)pyridin-2-yl)picolinamide as a white powder (120 mg, 47% yield). M+1=340.1
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([OH:12])[CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[CH3:21]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:20][CH3:21])=[C:7]([OH:12])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(O)c(O)c1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCC)c(O)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
5 g (27.2 mmol) of 3,4-Dihydroxy-benzoic acid ethyl ester was dissolved in 100 ml DMF and 3.75 g (27.2 mmol) of potassium carbonate was added. The solution was cooled to 0° C. and a solution of 2.96 g (27.2 mmol) ethyl bromide in 10 ml DMF was added dropwise. The solution was stirred for 16 h at room temperature (RT). The solvent was removed under reduced pressure. The residue was taken-up in ethyl acetate and the solution was washed three times with water and twice with saturated aqueous sodium chloride. The organic phase was dried with magnesium sulphate, filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with ethyl acetate/n-heptane (1/4).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([O:7][C:8](=[O:39])[CH:9]([NH:23][C:24]([C:26]1([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)=[CH:13][CH:12]=1)[CH3:6].CCN(CC)CC>C(Cl)Cl>[CH2:5]([O:7][C:8](=[O:39])[CH:9]([NH:23][C:24]([C:26]1([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27][CH2:28][CH2:29][CH2:30]1)=[O:25])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:1](=[O:3])[CH3:2])[CH2:18]2)=[CH:15][CH:16]=1)[CH3:6]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C(Cc1ccc(C2CCCNC2)cc1)NC(=O)C1(NC(=O)OC(C)(C)C)CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Cc1ccc(C2CCCN(C(C)=O)C2)cc1)NC(=O)C1(NC(=O)OC(C)(C)C)CCCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Acetyl chloride (50 mL, 0.70 mmol) is added slowly to a solution of 2-[(1-tert-butoxycarbonylamino-cyclopentanecarbonyl)-amino]-3-[4-(piperidin-3-yl)-phenyl]-propionic acid ethyl ester (277 mg, 0.57 mmol) and 11 mL (0.79 mmol) of Et3N in 2 mL of CH2Cl2. The reaction mixture is stirred at 0° C. for 2 h, and then partitioned between saturated aqueous NaHCO3 solution and CH2Cl2. The organic phase is washed with brine, dried over MgSO4, filtered, and concentrated. The residue is purified by chromatography on silica gel (EtOAc) to furnish 2-[(1-tert-butoxycarbonylamino-cyclopentanecarbonyl)-amino]-3-[4-(1-acetyl-piperidin-3-yl)-phenyl]-propionic acid ethyl ester; 1H NMR (300 MHz, CDCl3) δ7.00-7.15 (m, 4 H), 4.80-4.90 (m, 1 H), 4.70 (br t, 2 H), 4.15 (q, 2 H), 3.00-3.15 (m, 3 H), 2.45-2.70 (m, 2 H), 2.12, 2.08 (s each, 3 H) 1.95-2.40 (m, 6 H), 1.50-1.95 (m, 8 H), 1.40 (s, 9 H), 1.20 (t, 3 H).
Reaction SMILES: Cl.O1CCOCC1.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([CH:21]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:22][CH2:23][N:24]2[CH2:31][CH:30]3[CH:26]([CH2:27][N:28]([C:32]([C:34]4[C:35]([CH3:41])=[N:36][CH:37]=[N:38][C:39]=4[CH3:40])=[O:33])[CH2:29]3)[CH2:25]2)[CH2:17][CH2:16]1)=[O:14])(C)(C)C.ClC(OC)=O>C(Cl)Cl>[CH3:8][O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([CH:21]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:22][CH2:23][N:24]2[CH2:25][CH:26]3[CH:30]([CH2:29][N:28]([C:32]([C:34]4[C:35]([CH3:41])=[N:36][CH:37]=[N:38][C:39]=4[CH3:40])=[O:33])[CH2:27]3)[CH2:31]2)[CH2:17][CH2:16]1)=[O:14]
Reactant: Cc1ncnc(C)c1C(=O)N1CC2CN(CCC(c3ccccc3)C3CCN(C(=O)OC(C)(C)C)CC3)CC2C1
Agent: COC(=O)Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)N1CCC(C(CCN2CC3CN(C(=O)c4c(C)ncnc4C)CC3C2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
HCl-dioxane (1 mL, 4.0 M) was added to 78a (Ar1=Ph, Ar2=4,6-dimethyl-pyrimidin-5-yl, 40 mg, 0.073 mmol). The mixture was stirred at RT for 90 min. The solvent was removed, and the residue was dried in vacuo. Methyl chloroformate (8 μL, 0.10 mmol) was added to a solution of the residue from the deprotection, TEA (16 μL, 0.11 mmol) in DCM (0.5 mL) maintained at 0° C. The reaction mixture was stirred and warmed to RT. The crude product was purified on a preparative TLC plate developed with a 45:55 mixture of DCM and DCM/MeOH/NH4OH (60/10/1) to afford 0.004 g (11%) of V-7.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:9][C:10]([O:13][CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[CH:11][CH:12]=1)(=O)=O.[C:30]([C@:32]1([OH:40])[CH:37]2[CH2:38][CH2:39][N:34]([CH2:35][CH2:36]2)[CH2:33]1)#[CH:31].C(N(CC)CC)C>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.CN(C)C=O>[CH2:21]([C:8]1[C:7]([C:31]#[C:30][C@:32]2([OH:40])[CH:37]3[CH2:38][CH2:39][N:34]([CH2:35][CH2:36]3)[CH2:33]2)=[CH:12][CH:11]=[C:10]([O:13][CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[N:9]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=S(=O)(Oc1ccc(OCC2CCCCO2)nc1Cc1ccccc1)C(F)(F)F
Reactant: C#C[C@@]1(O)CN2CCC1CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O[C@]1(C#Cc2ccc(OCC3CCCCO3)nc2Cc2ccccc2)CN2CCC1CC2
Temperature: 90 °C
Reaction time: 3 h
Yield: 71.1 %

Procedure:
A mixture of 428 mg of 2-benzyl-6-[(tetrahydro-4H-pyran-2-yl)methyloxy]-3-pyridyl trifluoromethanesulfonate, 180 mg of (3R)-3-ethynyl-3-quinuclidinol, 57.3 mg of tetrakis(triphenylphosphine)palladium(0), 1.9 mg of cuprous iodide, 415 μl of triethylamine and 5 ml of N,N-dimethylformamide was stirred at 90° C. for 3 hours in a nitrogen atmosphere. NH-silica gel was added to the reaction solution, and the solvent was removed. The residue was subjected to NH-silica gel column chromatography using 3% methanol/ethyl acetate, to give 305 mg of the target compound.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[K+].[Mn]([O-])(=O)(=O)=[O:16].[K+].C(O)CO>O>[OH:16][C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC(C)c1ccc(C(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: CC(C)(O)c1ccc(C(=O)O)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
4-Isopropylbenzoic acid (5.0 g, 30.5 mmol) was dissolved in a solution of potassium hydroxide (4.1 g, 2 mL, 73.1 mmol) in water (125 mL). To the reaction mixture was added a solution of potassium permanganate (9.6 g, 60.9 mmol) in water (125 mL). The combined mixture was allowed to stir at 60° C. for 2 hours. The reaction mixture was cooled to 0° C. and treated with ethylene glycol (100 μL) and cooled to 0° C. The solid were removed by filtration and the filtrate was acidified to pH 1 by addition of 6 N HCl solution. The solid was removed by filtration, and the filtrate was extracted with diethyl ether (3×200 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to provide 4-(1-hydroxy-1-methyl-ethyl)benzoic acid (5.1 g, 93%) as a white solid. ESI-MS m/z calc. 180.1. Found 181.2 (M+1)+; Retention time: 0.6 minutes (3 min run). 1H NMR (400 MHz, MeOD) δ 8.00-7.95 (m, 2H), 7.61-7.56 (m, 2H), 2.64 (s, 1H), 1.54 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:22]1[CH2:27][CH2:26][CH:25]([N:28]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[NH:30][C:29]2=[O:37])[CH2:24][CH2:23]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C(C)=CC=CC=1>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[CH2:13][CH2:12][CH:11]([N:22]3[CH2:23][CH2:24][CH:25]([N:28]4[C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=5[NH:30][C:29]4=[O:37])[CH2:26][CH2:27]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)CC1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: O=c1[nH]c2ccccc2n1C1CCN(C2CCC(c3ccc(F)cc3)(c3ccc(F)cc3)CC2)CC1

Procedure:
A mixture of 10 g of 4,4-bis(p-fluorophenyl)cyclohexanone, 6.6 g of 1-(4-piperidyl)-2-benzimidazolinone, 0.2 g of p-toluenesulfonic acid and 80 ml of xylene is stirred under reflux for 34 hours, the water formed being removed. The xylene is then removed under reduced pressure, and to the residue is added 200 ml of methanol and 10 ml of water. To the resulting mixture is added dropwise 15 g of sodium borohydride at about 20° C with cooling. After the addition is complete, the mixture is stirred under reflux for 3 hours. The reaction mixture is concentrated completely under reduced pressure, water is added to the residue, and the aqueous mixture is extracted with chloroform. The extract is washed with water and dried over sodium sulfate, and the solvent is removed. The residual viscous oil is purified by column chromatography using methylene chloride and then a mixture of methylene chloride and methanol (9:1) as an eluent. Thus is obtained 1-[1-(4,4-bis(p-fluorophenyl)cyclohexyl)-4-piperidyl]- 2-benzimidazolinone as colorless crystals, melting at 235°-238° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][NH2:7].[CH2:8]([N:10]1[C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][CH:17]=2)=[CH:13][C:12]([C:24]2[CH:25]=[C:26]([C:30]([NH:33][S:34]([CH2:37][C:38]([F:41])([F:40])[F:39])(=[O:36])=[O:35])([CH3:32])[CH3:31])[CH:27]=[CH:28][CH:29]=2)=[N:11]1)[CH3:9]>CN(C=O)C>[CH2:8]([N:10]1[C:14]([O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][NH:7][CH2:6][CH:2]3[CH2:3][CH2:4][CH2:5][O:1]3)=[CH:20][CH:21]=2)=[CH:13][C:12]([C:24]2[CH:25]=[C:26]([C:30]([NH:33][S:34]([CH2:37][C:38]([F:41])([F:39])[F:40])(=[O:35])=[O:36])([CH3:32])[CH3:31])[CH:27]=[CH:28][CH:29]=2)=[N:11]1)[CH3:9]
Reactant: NCC1CCCO1
Reactant: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)cc1Oc1ccc(C=O)cc1
Solvent: CN(C)C=O
Product: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)cc1Oc1ccc(CNCC2CCCO2)cc1
Temperature: 22 °C
Reaction time: 16 h

Procedure:
1-(tetrahydrofuran-2-yl)methanamine (12.3 mgs, 0.121 mmol, 1.2 equiv) followed by Si-bound cyanoborohydride (322 mg, 0.303 mmol, 3.0 equiv, 0.94 mmol/g) were added to N-(2-{3-[1-ethyl-5-(4-formylphenoxy)-1H-pyrazol-3-yl]phenyl}propan-2-yl)-2,2,2-trifluoroethanesulfonamide (50.0 mg, 0.101 mmol, 1 equiv) stirring in DMF (with 0.05% acetic acid v:v, 0.5 mL). The resulting mixture was stirred at 22° C. for 16 hours then filtered through a 0.45 micron nylon syringe filter and flushed with methanol. The filtrate was purified by reversed phase HPLC (0-95% acetonitrile:water with 0.025% TFA v:v). Pure fractions were identified, combined, basified with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The drying agent was filtered away and the filtrate was concentrated in vacuo to give N-(2-{3-[1-ethyl-5-(4-{[(tetrahydrofuran-2-ylmethyl)amino]methyl}phenoxy)-1H-pyrazol-3-yl]phenyl}propan-2-yl)-2,2,2-trifluoroethanesulfonamide. Calc'd (M+1) 581.2. Found: 581.2
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:5][CH:4]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:26][C:27]1[CH:28]=[C:29]([S:36](Cl)(=[O:38])=[O:37])[CH:30]=[CH:31][C:32]=1[N+:33]([O-:35])=[O:34]>C1COCC1>[F:26][C:27]1[CH:28]=[C:29]([S:36]([N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][CH:14]=2)[C:9]2[S:10][CH:11]=[CH:12][N:13]=2)(=[O:37])=[O:38])[CH:30]=[CH:31][C:32]=1[N+:33]([O-:35])=[O:34]
Reactant: COc1ccc(CNc2nccs2)cc1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc([N+](=O)[O-])c(F)c2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.8 %

Procedure:
To a solution of N-(4-methoxybenzyl)thiazol-2-amine (1 g, 4.577 mmol) in THF (30 mL) was added LiHMDS (1.58 g, 9.09 mmol, Aldrich) at −78° C. and the reaction mixture was stirred at 25° C. for 15 min. Afterward, 3-fluoro-4-nitrobenzene-1-sulfonyl chloride (2.17 g, 9.09 mmol) dissolved in THF was added to the above mixture at −78° C. and reaction mixture was stirred at 25° C. for 1 h. The reaction mixture was cooled to 0° C. and quenched with ice water (70 mL). The organic compound was extracted with EtOAc, washed with water, dried over sodium sulfate and concentrated to get the crude material which was purified by silica gel column chromatography using a gradient of 0-40% EtOAc in hexanes as the eluent to afford 1.1 g of 3-fluoro-N-(4-methoxybenzyl)-4-nitro-N-(thiazol-2-yl)benzenesulfonamide as light yellow solid in 57.8% yield. 1H-NMR (400 MHz, DMSO): δ 8.12 (t, J=18.8 Hz, 1H), 8.09-8.07 (m, 1H), 7.84 (d, J=8.8 Hz, 1H), 7.49-7.53 (dd, 2H), 7.22-7.32 (m, 2H), 6.88-6.98 (m, 2H), 5.07 (s, 2H), 3.71 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[CH:24][C:23]=2B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:28][CH3:29])=[CH:26][C:27]=2[C:2]2[C:3]3[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][CH2:19]1
Reactant: CCOC(=O)c1c(C)[nH]c2c(Cl)ncnc12
Reactant: CCc1ccc(OCC2CC2)c(B2OC(C)(C)C(C)(C)O2)c1
Product: CCOC(=O)c1c(C)[nH]c2c(-c3cc(CC)ccc3OCC3CC3)ncnc12

Procedure:
Starting from ethyl 4-chloro-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example A4) and 2-(2-cyclopropylmethoxy-5-ethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example B.c14) the title compound is obtained as pale yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6])#[CH:2].Br.Br[CH:12]([C:14]1[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]2[C:23]=1[O:22][C:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[CH:20][C:19]2=[O:30])[CH3:13]>>[C:1]([C:3]1[CH:4]=[C:5]([NH:6][CH:12]([C:14]2[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]3[C:23]=2[O:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:20][C:19]3=[O:30])[CH3:13])[CH:7]=[CH:8][CH:9]=1)#[CH:2]
Reactant: C#Cc1cccc(N)c1
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Agent: Br
Product: C#Cc1cccc(NC(C)c2cc(C(=O)N(C)C)cc3c(=O)cc(N4CCOCC4)oc23)c1
Yield: 64.8 %

Procedure:
3-ethynylaniline (0.083 mL, 0.73 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (0.09 g, 0.18 mmol) using an analogous procedure to the one described in Example 3.03 to give 8-(1-(3-ethynylphenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (52 mg, 64%) as a white solid. Mass Spectrum: M+H+ 446.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[F:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH:21]([NH2:25])[CH2:20][CH2:19]2>>[F:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH:21]([NH:25][C:8]1[CH:7]=[CH:6][C:5]3[C:4]([NH2:1])=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=1)[CH2:20][CH2:19]2
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: NC1CCc2cc(F)ccc21
Product: Nc1cccc2nc(NC3CCc4cc(F)ccc43)ccc12

Procedure:
The title compound, light yellow foam, MS: m/e=294.1 (M+H+), was prepared in accordance with the general method of example 16 from 5-nitro-2-chloroquinoline (example 16, CAS 13067-94-2) and commercially available (RS)-5-fluoro-indane-1-ylamine.
Reaction SMILES: [P:1](Cl)([Cl:7])([S:3][CH2:4][CH2:5][CH3:6])=[O:2].[CH2:9]([OH:11])[CH3:10].C(N(CC)CC)C>C(Cl)Cl>[P:1]([Cl:7])([S:3][CH2:4][CH2:5][CH3:6])([O:11][CH2:9][CH3:10])=[O:2]
Reactant: CCCSP(=O)(Cl)Cl
Reactant: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCSP(=O)(Cl)OCC
Temperature: -10 °C
Reaction time: 2 h

Procedure:
S-Propyl dichlorothiophosphate (3.1 grams; 0.016 mole) was charged into a 300 ml glass reaction flask equipped with a mechanical stirrer. Methylene chloride (80 ml) was added and the solution was cooled to a temperature of -10° C. A solution of ethanol (0.737 grams; 0.016 mole) and triethylamine (1.62 grams; 0.016 mole) was then added dropwise with stirring while maintaining the temperature of the reaction mixture at about -5° C. After the addition was completed the reaction mixture was allowed to warm to room temperature and stirring was continued for a period of two hours to yield the desired product O-ethyl S-propyl chlorothiophosphate in solution.