Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:30]([NH2:32])=[O:31])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=4)[CH:21]=3)[NH:16][N:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].C([O-])([O-])=O.[K+].[K+].[OH:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>CN(C=O)C>[F:29][C:25]1[CH:24]=[C:23]([C:20]2[CH:21]=[C:22]3[C:17](=[C:18]([C:30]([NH2:32])=[O:31])[CH:19]=2)[NH:16][N:15]=[C:14]3[CH:11]2[CH2:12][CH2:13][N:8]([S:5]([CH2:4][CH2:3][CH2:2][N:43]3[CH2:44][CH2:45][CH:40]([OH:39])[CH2:41][CH2:42]3)(=[O:7])=[O:6])[CH2:9][CH2:10]2)[CH:28]=[CH:27][CH:26]=1
Reactant: OC1CCNCC1
Reactant: NC(=O)c1cc(-c2cccc(F)c2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)n[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2cccc(F)c2)cc2c(C3CCN(S(=O)(=O)CCCN4CCC(O)CC4)CC3)n[nH]c12
Yield: 26.6 %

Procedure:
The title compound was prepared according to the general procedure of Example 38b. Thus, 3-{1-[(3-Chloropropyl)sulfonyl]-4-piperidinyl}-5-(3-fluorophenyl)-1H-indazole-7-carboxamide (Example 38a) (0.222 mmol) in DMF (4 mL) was reacted with K2CO3 (61 mg, 0.444 mmol) and 4-hydroxy piperidine (112 mg, 1.11 mmol) to afford the title compound (32.07 mg, 27% for 2 steps).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[C:11]([F:30])=[CH:12][C:13]([F:29])=[C:14]([C@:16]3([CH3:28])[C:22]([F:24])([F:23])[C:21]([CH3:26])([CH3:25])[O:20][CH2:19][C:18](=O)[NH:17]3)[CH:15]=2)[CH:5]=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[C:11]([F:30])=[CH:12][C:13]([F:29])=[C:14]([C@:16]3([CH3:28])[C:22]([F:24])([F:23])[C:21]([CH3:26])([CH3:25])[O:20][CH2:19][C:18](=[S:40])[NH:17]3)[CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OCC(=O)N[C@](C)(c2cc(C#Cc3cccc(Cl)c3)c(F)cc2F)C1(F)F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: CC1(C)OCC(=S)N[C@](C)(c2cc(C#Cc3cccc(Cl)c3)c(F)cc2F)C1(F)F
Yield: 83.1 %

Procedure:
The reaction of (R)-5-[5-(3-chloro-phenylethynyl)-2,4-difluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-one (622 mg, 1.14 mmol) with Lawesson's reagent (572 mg, 1.41 mmol) in 1,4-dioxane (40 ml) yielded the (R)-5-[5-(3-chloro-phenylethynyl)-2,4-difluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-thione (432 mg, 67% yield) as a light brown gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[I:11]I>C(#N)C>[I:11][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[O:9][CH3:10]
Reactant: COc1ccc(OC)cc1
Reactant: II
Solvent: CC#N
Product: COc1ccc(OC)c(I)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Following the procedure from a previous publication (0. V. Branytska et al., J. Org. Chem., 68, 9510-12 (2003)), a 350 ml heavy wall pressure vessel fitted with a stir bar was charged with p-dimethoxybenzene (20.00 g, 144.7 mmol), iodine (18.37 g, 72.37 mmol), oxidation catalyst H5PV2Mo10O40.34H2O (T. Onoda et al., U.S. Pat. No. 4,146,574 (Mar. 27, 1979)) (3.40 g, 1.45 mmol), and acetonitrile (1.8 M). The vessel was degassed via the freeze-pump-thaw method (2 times) and warmed to room temperature prior to being backfilled with oxygen (2 atm), heated to 80° C., and stirred for 12 hr. The crude reaction mixture was filtered to remove spent catalyst, then water (100 ml) was added and the product extracted into ethyl acetate (100 ml). The organic layer was washed with sodium thiosulfate (aq) and excess water. The organic layer was dried over MgSO4, filtered, and then concentrated by rotary evaporation. Ethanol (100 ml) was added to this crude material in which a white precipitate formed and was filtered via suction filtration yielding 1 as a byproduct. The supernate was concentrated via rotary evaporation and the resulting red oil distilled yielding starting material ˜60° C. at 50 mtorr and product 8 (29.2 g, 76%) at ˜115° C. at 50 mtorr as a clear oil. 1H NMR (300 MHz, CDCl3): δ 7.32 (d, 1H, J=2.94 Hz), 6.84 (dd, 1H, J=5.99 Hz), 6.73 (d, 1H, J=8.95 Hz), 3.81 (s, 3H), 3.73 (s, 3H). 13C NMR (60 MHz, acetone-d6): δ 154.78, 153.10, 125.09, 115.01, 112.21, 85.95, 56.76, 55.75.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][N:18]([CH2:22][C@@H:23]2[C@@H:30]3[C@@H:26]([O:27]C(C)(C)[O:29]3)[C@H:25]([N:33]3[C:37]4[N:38]=[CH:39][N:40]=[C:41]([NH:42]CC5C=CC(OC)=CC=5OC)[C:36]=4[CH:35]=[CH:34]3)[O:24]2)[CH:19]([CH3:21])[CH3:20])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>FC(F)(F)C(O)=O.O>[NH2:42][C:41]1[C:36]2[CH:35]=[CH:34][N:33]([C@@H:25]3[O:24][C@H:23]([CH2:22][N:18]([CH:19]([CH3:20])[CH3:21])[CH2:17][CH2:16][CH2:15][NH:14][C:12]([NH:11][C:8]4[CH:7]=[CH:6][C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:10][CH:9]=4)=[O:13])[C@@H:30]([OH:29])[C@H:26]3[OH:27])[C:37]=2[N:38]=[CH:39][N:40]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(CCCNC(=O)Nc3ccc(C(C)(C)C)cc3)C(C)C)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N(CCCNC(=O)Nc1ccc(C(C)(C)C)cc1)C[C@H]1O[C@@H](n2ccc3c(N)ncnc32)[C@H](O)[C@@H]1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46.7 %

Procedure:
1-(4-(tert-butyl)phenyl)-3-(3-((((3aR,4R,6R,6aR)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(isopropyl)amino)propyl)urea (1.07 g, 1.39 mmol) was dissolved in a mixture of trifluoroacetic acid (25 mL) and water (2.5 mL) which had been cooled at 0° C. and the resulting solution was stirred at 0° C. for 30 minutes, then warmed to room temperature. After 4 h, the reaction was found to be complete by HPLC. The reaction mixture was concentrated in vacuo and the residue was taken up in 25 mL MeOH (white slurry) and concentrated. This process was repeated three times and the resultant residue was placed under high vacuum. The material was taken up in 100 mL 10% MeOH/CH2Cl2 and washed with two 75 mL portions of sat NaHCO3 and 50 mL 1% aq Na2CO3. The organic phase was dried over Na2SO4, filtered and concentrated to yield a glass/solid. The crude material was purified by flash chromatography (100 g silica gel, 5-10% 7N NH3 in CH3OH/CH2Cl2) to yield the title compound (0.35 g, 46%) as a colorless glass: MS (ESI+) for C28H41N7O4 m/z 540.3 (M+H)+; (ESI−) for C28H41N7O4 m/z 538.3 (M−H)−, m/z 584.4 (M+HCO2)−; HPLC purity 98% (ret. time 2.86 min); 1H NMR (400 MHz, d4-MeOH) ppm 8.05 (s, 1H), 7.27 (d, J=3.73 Hz, 1H), 7.24 (m, 2H), 7.18 (m, 2H), 6.63 (d, J=3.73 Hz, 1H), 6.15 (d, J=4.77 Hz, 1H), 4.46 (t, J=5.08 Hz, 1H), 4.18 (t, J=5.39 Hz, 1H), 4.11 (m, 1H), 3.22 (m, 2H), 3.07 (m, 1H), 2.85 (m, 1H), 2.72 (m, 1H), 2.60 (t, J=6.43 Hz, 2H), 1.68 (m, 2H), 1.28 (s, 9H), 1.05 (d, J=6.63 Hz, 3H), 1.01 (d, J=6.43 Hz, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.[Cl:26][CH2:27][CH2:28][N:29]([CH3:40])[C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[C:35](=O)[O:34][CH2:33]2.Cl>C(COC)OC>[Cl:26][CH2:27][CH2:28][N:29]([CH3:40])[C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[C:35](=[C:3]1[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]1=[O:10])[O:34][CH2:33]2
Reactant: O=C1Cc2ccccc2N1
Reactant: CN(CCCl)c1ccc2c(c1)COC2=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: COCCOC
Solvent: C1CCOC1
Product: CN(CCCl)c1ccc2c(c1)COC2=C1C(=O)Nc2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
To a stirred solution of oxindole (0.739 g, 5.55 mmol) in anhydrous dimethoxyethane (10 ml) under nitrogen was added 1.0M LiHMDS/THF solution (14.0 ml, 14.0 mmol). The mixture was stirred at room temperature for 10 minutes, and 5-[(2-chloro-ethyl)-methyl-amino]-3H-isobenzofuran-1-one (1.0 g, 4.4 mmol) was added. The mixture was stirred at room temperature for 3 hours and was then poured into 1M HCl aqueous solution (300 ml) with stirring. The resulting mixture was heated at 40° C. for 30 minutes. The solid was filtered, washed with water and dried under vacuum to afford 3-{5-[(2-chloro-ethyl)-methyl-amino]-3H-isobenzofuran-1-ylidene}-1,3-dihydro-indol-2-one as a yellow solid (1.20 g, 79%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[C:25]([C:26](OCC)=[O:27])=[C:24]([C:31]4[C:36]([F:37])=[CH:35][CH:34]=[C:33]([F:38])[C:32]=4[F:39])[NH:23][C:22]4[NH:40][N:41]=[C:42]([C:43]5[S:44][CH:45]=[CH:46][CH:47]=5)[C:21]3=4)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(=O)(O)[O-].[Na+]>C1(C)C(C)=CC=CC=1>[N:11]1([C:14]2[CH:19]=[C:18]3[C:17](=[CH:16][CH:15]=2)[C:20]2=[C:21]4[C:42]([C:43]5[S:44][CH:45]=[CH:46][CH:47]=5)=[N:41][NH:40][C:22]4=[N:23][C:24]([C:31]4[C:36]([F:37])=[CH:35][CH:34]=[C:33]([F:38])[C:32]=4[F:39])=[C:25]2[C:26]3=[O:27])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CCOC(=O)C1=C(c2c(F)ccc(F)c2F)Nc2[nH]nc(-c3cccs3)c2C1c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: O=C1c2cc(N3CCNCC3)ccc2-c2c1c(-c1c(F)ccc(F)c1F)nc1[nH]nc(-c3cccs3)c21
Reaction time: 36 h
Yield: 3.2 %

Procedure:
10 g of polyphosphoric acid is added to a solution of 2 g (3 mmol) of ethyl 4-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)-3-(thiophen-2-yl)-6-(2,3,6-trifluorophenyl)-4,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carboxylate in xylene (20 ml). The reaction mixture is carried at 160° C. for 36 hours. After returning to room temperature, the reaction medium is poured over crushed ice. Saturated sodium bicarbonate solution is added until the reaction medium is neutralized and then the product is extracted with ethyl acetate. The organic phases are combined, dried on magnesium sulfate and concentrated. The residue is purified by silica gel chromatography (eluent: 88:12 dichloromethane/methanol) to yield 50 mg (3%) of 8-(piperazin-1-yl)-1-(thiophen-2-yl)-5-(2,3,6-trifluorophenyl)indeno[1,2-d]pyrazolo[3,4-b]pyridin-6(3H)-one in the form of a pinkish solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH2:13][NH:14][CH3:15])[CH2:6]2.Br[CH2:17][CH2:18][CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH2:13][N:14]([CH3:15])[CH2:17][CH2:18][CH2:19][N:20]1[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]1=[O:30])[CH2:6]2
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: CNC[C@H]1Cc2cc(OC)c(OC)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc2c(cc1OC)[C@@H](CN(C)CCCN1C(=O)c3ccccc3C1=O)C2
Yield: 96.4 %

Procedure:
5.3 g (25.5 mmoles) of 1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methyl-methanamine and 6.8 g (25.5 mmoles) of 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione are dissolved in 230 mL of acetone. 13 g (95 mmoles, 3.7 eq.) of potassium carbonate are added to the resulting solution. The mixture is then heated at reflux for 24 hours. After returning to ambient temperature, the potassium carbonate is filtered off and the filtrate is evaporated to dryness. The residue is taken up in water and extracted with dichloromethane. The organic phase is dried over MgSO4, filtered and evaporated to dryness. 9.7 g of expected product are obtained in the form of a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH:8](OS(C1C=CC(C)=CC=1)(=O)=O)[CH3:9].[CH3:23][N:24]1[C:29]([C:30]([F:33])([F:32])[F:31])=[CH:28][C:27](=[O:34])[N:26]([C:35]2[CH:40]=[C:39]([NH2:41])[C:38]([Cl:42])=[CH:37][C:36]=2[F:43])[C:25]1=[O:44].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH:8]([NH:41][C:39]1[CH:40]=[C:35]([N:26]2[C:27](=[O:34])[CH:28]=[C:29]([C:30]([F:32])([F:33])[F:31])[N:24]([CH3:23])[C:25]2=[O:44])[C:36]([F:43])=[CH:37][C:38]=1[Cl:42])[CH3:9]
Reactant: COC(=O)CCNC(=O)C(C)OS(=O)(=O)c1ccc(C)cc1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(N)c(Cl)cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)CCNC(=O)C(C)Nc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 38.7 %

Procedure:
3-[2-(Toluene-4-sulfonyloxy)-propionylamino]propionic acid methyl ester (307 mg) was dissolved in acetonitrile (5 mL). After addition of 1-methyl-3-(5-amino-4-chloro-2-fluorophenyl)-6-trifluoromethyl-1H-pyrimidin-2,4-dione (300 mg) and potassium carbonate (135 mg), the reaction mixture was heated for 6 hours under reflux without cooling. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL). Thus obtained organic layer was dried with magnesium sulfate and concentrated. The concentrate was purified by silica gel column chromatography to give the target compound (170 mg).
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20]>CN(C=O)C.O>[Si:22]([C@@:3]1([OH:4])[C@@H:5]([CH2:6][O:7][Si:22]([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23])[O:8][C@@H:1]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:2]1)([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23]
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cn([C@H]2C[C@@](O)([Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of thymidine (5.00 g, 20.64 mmol) and imidiazole (9.0 g, 132.1 mmol) in anhydrous DMF (11 mL), a solution of TBSCl (9.96 g, 66.05 mmol) in DMF (11 mL) was added dropwise, and the mixture was stirred at room temperature overnight under a N2 atmosphere. After the mixture was diluted with water (100 mL), the formed precipitate was filtered and dissolved in ethyl ether (125 mL). The ether solution was washed twice with water (25 mL each) and once with brine (25 mL), dried over Na2SO4, and concentrated under reduced pressure to a waxy solid, which was re-crystallized from hexane/ethyl either (10:1) to yield 3′,5′-O-bis-tert-butyldimethylsilyl-thymidine dT.04 (10.64 g, 90%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([OH:12])([CH2:10][CH3:11])[C:4]#[C:5][Si](C)(C)C.[H-].[Na+].[N+:17]([C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1)([O-:19])=[O:18]>CN(C=O)C>[N+:17]([C:20]1[CH:21]=[CH:22][C:23]([C:24]([O:12][C:3]([CH2:10][CH3:11])([C:2]([F:14])([F:13])[F:1])[C:4]#[CH:5])=[O:25])=[CH:27][CH:28]=1)([O-:19])=[O:18]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CCC(O)(C#C[Si](C)(C)C)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CC(CC)(OC(=O)c1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reaction time: 0.42 h

Procedure:
To a stirred solution of 3-(trifluoromethyl)-1-(trimethylsilyl)pent-1-yn-3-ol (10.5 g, 46.9 mmol) in DMF (140 mL), sodium hydride (60% in oil, 1.9 g, 46.9 mmol) was added portionwise. After 25 min stirring, a solution of 4-nitrobenzoyl chloride (8.7 g, 46.9 mmol) in 50 mL DMF was added slowly. The reaction mixture was then stirred at room temperature for 2 hours. The reaction mixture was quenched with pH 7 buffer 25% NH4OAc aq solution (500 mL) and the product was extracted with diethyl ether (4×), washed with water (3×) and brine, dried over MgSO4, filtered and concentrated. The crude residue obtained was purified by column chromatography (Ethyl acetate/hexanes, 15:85). 1H NMR (400 MHz, acetone-d6): 8.45 (d, 2H), 8.27 (d, 2H), 3.69 (s, 1H), 2.60-2.40 (m, 2H), 1.16 (t, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH:24]3[CH2:26][CH2:25]3)=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10].[C:27]([N:30]1[CH2:34][CH2:33][NH:32][C:31]1=[O:35])(=[O:29])[CH3:28]>>[C:27]([N:30]1[CH2:34][CH2:33][N:32]([C:2]2[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=2[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH:24]4[CH2:26][CH2:25]4)=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])[C:31]1=[O:35])(=[O:29])[CH3:28]
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Cl)cc2Br)CC1
Reactant: CC(=O)N1CCNC1=O
Product: CC(=O)N1CCN(c2cc(Cl)ccc2C(=O)N2CCN(c3ncc(C4CC4)cc3C)CC2)C1=O
Yield: 61.4 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 12 and using (2-bromo-4-chlorophenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (1.91 g) described in Preparation Example 195 and 1-acetyl-2-imidazolidinone (0.563 g), the title compound (1.3 g) was obtained.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[O:15]1[C:19]2([CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]2)[O:18][CH2:17][CH2:16]1.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[CH2:26]([NH:33][CH:22]1[CH2:23][CH2:24][C:19]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:20][CH2:21]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc(CNC2CCC3(CC2)OCCO3)cc1
Reaction time: 2 h
Yield: 101.1 %

Procedure:
Na(OAc)3BH 2.03 g (9.6 mmol) was added to a solution of 1,4-dioxa-spiro[4.5]decan-8-one 1.0 g (6.4 mmol) and benzylamine 0.69 g (6.4 mmol) in CH2Cl2 (20 ml) under nitrogen as inert gas and stirring was performed for 2 h at RT. After the addition of CH2Cl2 (80 ml), the organic phase was washed with aqueous saturated NaHCO3 solution. After drying of the separated organic phases over Na2SO4 and filtration, the solvent was removed by distillation and the product benzyl-(1,4-dioxa-spiro[4.5]dec-8-yl)-amine 1.6 g (100% of theoretical) was obtained.
Reaction SMILES: [F:1][C:2]1([F:33])[CH2:6][N:5](CC2C=CC=C(C(F)(F)F)C=2)[C@@H:4]([C:18]([NH:20][C@H:21]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[CH3:22])=[O:19])[CH2:3]1>CO.Cl.[Pd]>[F:33][C:2]1([F:1])[CH2:6][NH:5][C@@H:4]([C:18]([NH:20][C@H:21]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[CH3:22])=[O:19])[CH2:3]1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CC(F)(F)CN2Cc2cccc(C(F)(F)F)c2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CC(F)(F)CN2)cc1
Reaction time: 3 h
Yield: 136.9 %

Procedure:
A suspension of methyl 4-((S)-1-((R)-4,4-difluoro-1-(3-(trifluoromethyl)benzyl)pyrrolidine-2-carboxamido)ethyl)benzoate (D164) (33 mg) and 10% w Pd/C (5 mg) in MeOH (5 ml) and 1M HCl (0.5 ml) was stirred under a constant current of H2 for 3 hrs. Catalyst was filtered off and solvent evaporated to afford a residue which was triturated with cHex and filtered to afford the title compound (D165) (30 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[CH:8][C:7]=1[N+:18]([O-])=O>C(O)C.[Pd]>[CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[CH:8][C:7]=1[NH2:18]
Reactant: COCOCc1c([N+](=O)[O-])cc(OC)c(OC)c1OC
Agent: [Pd]
Solvent: CCO
Product: COCOCc1c(N)cc(OC)c(OC)c1OC
Yield: 89.2 %

Procedure:
A solution of 2-methoxymethoxymethyl-1-nitro-3,4,5-trimethoxy-benzene (6.03 g, 21 mmol) in ethanol (150 ml) was catalytically hydrogenated over 5% palladium on carbon (3 g) at 50 psi for 2 hours. The catalyst was removed by filtration through a pad of Celite, and the filtered catalyst was washed with ethanol. The combined filtrate and the washings are concentrated in vacuo to dryness, and the product was purified by column chromatography (SiO2, 4×25 cm, CHCl3) to give 4.82 g of 2-methoxymethoxymethyl-3,4,5-trimethoxyaniline (89.7%) as a syrup. 1H-NMR (CDCL3): δ3.42 (3H, s, CH2OMe), 3.77, 3.80, and 3.87 (each 3H, s, 3×OMe), 4.63 and 4.66 (each 2H, s, 2×CH2), 6.05 (1H, s, H-6). Analyses: Calculated for C12H19NO5 : C, 56.02; H, 7.44; N, 5.44. Found: C, 56.47; H, 7.05; N, 5.48.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:10][CH:9]2[CH:4]([CH:5]3[CH2:11][CH:8]2[O:7][NH:6]3)[O:3]1>[Pd].CO>[NH2:6][C@H:5]1[C@@H:4]2[O:3][C:2]([CH3:1])([CH3:12])[O:10][C@@H:9]2[C@@H:8]([OH:7])[CH2:11]1
Reactant: CC1(C)OC2C3CC(ON3)C2O1
Agent: [Pd]
Solvent: CO
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](O)C[C@H]2N
Temperature: 20 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
Under a pressurized hydrogen atmosphere (3 atm), a suspension of 4,4-dimethyl-3,5,8-trioxa-9-aza-tricyclo[5.2.1.02,6]decane (16.7 g, 97.55 mmol, 1.00 equiv.), 10% palladium on carbon (1.67 g), and methanol (250 mL) was stirred at about 20° C. for about 60 minutes. After filtering the solution, the resulting filtrate was concentrated in vacuo to give the title product as a white solid (16.8 g; yield=99%). MS: m/z=174 (MH)+.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12](=O)[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)=[CH:6][CH:5]=1.I.[NH:30]1[CH2:36][CH2:35][CH2:34][CH2:33][N:32]=[C:31]1[NH:37][NH2:38]>C(O)(C)C>[NH:32]1[CH2:33][CH2:34][CH2:35][CH2:36][N:30]=[C:31]1[NH:37][N:38]=[C:12]([CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1)[CH:11]=[CH:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][C:2]([F:28])([F:27])[F:1])=[CH:5][CH:6]=1
Reactant: O=C(C=Cc1ccc(OC(F)(F)F)cc1)C=Cc1ccc(OC(F)(F)F)cc1
Reactant: NNC1=NCCCCN1
Agent: I
Solvent: CC(C)O
Product: FC(F)(F)Oc1ccc(C=CC(C=Cc2ccc(OC(F)(F)F)cc2)=NNC2=NCCCCN2)cc1
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 74.2 %

Procedure:
A mixture of 1,5-bis[p-(trifluoromethoxy)phenyl]-1,4-pentadien-3-one (4.0 g; 0.01 mole), 4,5,6,7-tetrahydro-1H-1,3-diazepine-2-ylhydrazine hydroiodide (2.6 g; 0.01 mole) and isopropyl alcohol (25 ml) is heated at reflux for 2 to 3 hours. The reaction mixture is then cooled to -15° C., and the precipitated material is isolated by filtration and washed with ether. The isolated material is mixed with ether and saturated sodium carbonate solution and the mixture stirred for about 15 minutes. The ether layer is then separated, dried, and concentrated to afford 3.8 g (75%) of title product, a bright yellow solid, m.p. 184.5°-185.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21](OCC)=[O:22])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:27][C:28]1([CH2:33][OH:34])[CH2:32][CH2:31][CH2:30][CH2:29]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21]([NH:27][C:28]4([CH2:33][OH:34])[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:22])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: NC1(CO)CCCC1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Product: Cn1c(=O)c(C(=O)NC2(CO)CCCC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 47 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (18 mg, 0.050 mmol) described in example 92 and (1-aminocyclopentyl)methanol (76 mg, 0.66 mmol) was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[1-(hydroxymethyl)cyclopentyl]-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide(10 mg, 48% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.56 (br s, 1H), 8.55 (s, 1 H), 7.37 (s, 1 H), 7.17-7.14 (m, 2 H), 7.04-6.99 (m, 2 H), 4.12 (s, 2 H), 3.78 (s, 2 H), 3.56 (s, 3 H), 1.98-1.68 (m, 8 H); MS m/z 424 (M−1).