Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=O)[CH3:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[H-].[Na+].[CH2:16](Br)[CH2:17]CC.O>CN(C)C=O>[CH2:11]([NH:10][C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1)[CH2:12][CH2:16][CH3:17]
Reactant: CC(=O)Nc1ccc(C(C)C)cc1
Reactant: CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCNc1ccc(C(C)C)cc1
Reaction time: 8 h

Procedure:
To a solution of N-(4-isopropylphenyl)acetamide (1.8 g) in dimethylformamide (18 mL) was added, under ice-cooling, 60% sodium hydride (0.44 g). Further, butyl bromide (1.4 mL) was added and the mixture was stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed, dried and concentrated under reduced pressure. 4N Hydrochloric acid (13 mL) was added to the residue and the mixture was refluxed for 7 hr. Water was added to the reaction mixture followed by neutralization and the mixture was extracted with ethyl acetate. The organic layer was washed, dried and concentrated under reduced pressure to give butyl(4-isopropylphenyl)amine (1.8 g).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([C:15]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]2[CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:16])([OH:14])[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[CH:27]1([CH:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:25][CH2:26][N:17]2[C:15]([C:11]2([OH:14])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:16])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: O=C(N1CCc2ccccc2C1C1CCCCC1)C1(O)CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=C(N1CCc2ccccc2C1C1CCCCC1)C1(O)CCNCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.4 %

Procedure:
1-benzyl-4-[(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]piperidin-4-ol (220 mg) was dissolved in MeOH (12 mL), and 20% palladium hydroxide-supported activated carbon (360 mg) was added thereto, followed by stirring under a hydrogen atmosphere, at room temperature and normal pressure, for 15 hours. Thereafter, the catalyst was separated through celite. The solvent was evaporated to obtain 4-[(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]piperidin-4-ol (154 mg).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.C1COCC1.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[C:21]([O:27][CH3:28])[CH:20]=1>C1(C)C=CC=CC=1>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[OH:24])=[C:21]([O:27][CH3:28])[CH:20]=1
Reactant: COc1cc(Cl)ccc1C=O
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1cc(Cl)ccc1C(O)c1cccnc1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 26.8 %

Procedure:
Toluene (3.5 mL) was added to a 3-necked flask and cooled to −60° C. n-BuLi (1.3 mL, 2.5M in hexanes) was added. A solution of 3-bromopyridine (0.3 mL, 3 mmol) in toluene (1.2 mL) was added dropwise to maintain internal temperature <−50° C. The resulting slurry was then stirred for 30 minutes at −60° C. THF (1.2 mL) was added dropwise, and the mixture was stirred for an additional 15 minutes. 4-Chloro-2-methoxy-benzaldehyde (561 mg, 3.3 mmol) was added and the mixture was allowed to warm to room temperature. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with 7:3 hexanes/ethyl acetate to provide 201 mg (27%) of the title compound. MS (ESI) m/e 250 (M+H)+.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.F[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=1[C:21]([F:24])([F:23])[F:22].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:2]([C:3]1[CH:11]=[CH:10][C:8]([O:9][C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=2[C:21]([F:22])([F:24])[F:23])=[C:5]([O:6][CH3:7])[CH:4]=1)=[O:1]
Reactant: COc1cc(C=O)ccc1O
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1Oc1ccc(C#N)cc1C(F)(F)F
Temperature: 80 °C

Procedure:
A solution of vanillin (1.65 g, 10.86 mmol) and 4-fluoro-3-trifluoromethyl-benzonitrile (10.26 mmol) in DMF (15 mL) was treated with K2CO3 (2.83 g, 21.72 mmol), and the mixture was heated in an oil bath at 80° C. for 12 h. The reaction was cooled to RT and partitioned between EtOAc and H2O. The organic phase was washed with water (3×), dried over Na2SO4 and concentrated in vacuo. Silica gel chromatography (EtOAc/hexanes) afforded the title compound. 1H NMR (400 Hz, CDCl3) δ 10.00 (s, 1H), 8.00 (m, 1H), 7.68 (dd, 1H), 7.58-7.53 (m, 2H), 7.29 (d, 1H), 6.75 (d, 1H), 3.83 (s, 3H); LC/MS (m/z) [M+1]+ 322.1 (calculated for C16H11F3NO3, 322.06).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:19])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:20][C:21]1[N:22]=[CH:23][N:24](COCC[Si](C)(C)C)[C:25]=1[C:26](O)=[O:27]>>[Cl:20][C:21]1[N:22]=[CH:23][NH:24][C:25]=1[C:26]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[CH:17][CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)[C:4]=1[F:19])=[O:27]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Reactant: N#Cc1cccc(Oc2c(Cl)ccc(CN)c2F)c1
Product: N#Cc1cccc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Yield: 69.1 %

Procedure:
The previously described 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}benzonitrile (0.28 mmol) and 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.055 g, 0.20 mmol) were employed in a similar process described herein to prepare the title compound (0.056 g, 69%) as a white solid after deprotection and purification by Reverse-Phase HPLC (water:acetonitrile with 0.1% TFA). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.73 (s, 1H) 7.42-7.55 (m, 2H) 7.29-7.42 (m, 2H) 7.17-7.27 (m, 2H) 4.65 (s, 2H). ES-LCMS: m/z 405.0, 407.0 (M+1).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[C:10]([CH3:14])=[N:11][N:12]([CH3:13])[C:5]=12)([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:23])C=1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH:1]([C:4]1[CH:9]=[CH:8][N+:7]([O-:23])=[C:6]2[C:10]([CH3:14])=[N:11][N:12]([CH3:13])[C:5]=12)([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1nn(C)c2c(C(C)C)ccnc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1nn(C)c2c(C(C)C)cc[n+]([O-])c12
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To 7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine (prepared in the previous step, 2.50 g, 13.22 mmol) in 100 mL of chloroform was added 77% MCPBA (5.91 g, 26.44 mmol) at 0° C. The resulting solution was stirred at 90° C. for 3 hours. After cooling, it was neutralized with aq NaHCO3 and extracted with DCM thoroughly. The combined organic phases were then washed with water, brine and concentrated. Column chromatography using 5% 7N NH3 in MeOH/DCM as eluant afforded the title compound as a white solid. Spectroscopic data: 1H-NMR (300 MHz, CDCl3): δ ppm 1.37 (d, J=6.73 Hz, 6 H), 2.83 (s, 3 H), 3.60 (hept, J=6.73 Hz, 1 H), 4.21 (s, 3 H), 6.78 (d, J=6.30 Hz, 1 H), 8.01 (d, J=6.30 Hz 1 H).
Reaction SMILES: ClCCl.[NH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[N:10]1[S:11][N:12]=[C:13]2[CH:18]=[C:17]([C:19](OC)=[O:20])[CH:16]=[CH:15][C:14]=12>C1(C)C=CC=CC=1>[N:10]1[S:11][N:12]=[C:13]2[CH:18]=[C:17]([C:19]([N:4]3[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]3)=[O:20])[CH:16]=[CH:15][C:14]=12
Reactant: COC(=O)c1ccc2nsnc2c1
Reactant: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(c1ccc2nsnc2c1)N1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
Trimethylaluninum (2M in toluene; 3.0 mL, 6.0 mmol) was diluted into 30 mL dichloromethane to which piperidine (0.55 g, 6.5 mmol) and methyl benzo-2,1,3-thiadiazole-5-carboxylate (1.16 g, 6.00 mmol) were added. The reaction was stirred at room temperature for 2 hours and concentrated to one-half the volume by rotary evaporation. Dry toluene (25 mL) was added and the reaction solution was heated to 80° C. for 1 hour. Additional piperidine (about 0.2 g) was added and the temperature was increased to 100° C. for 1 hour. The solution was allowed to cool to room temperature and stirred overnight, at which time it was quenched with 10% citric acid and hydrochloric acid. The solution was diluted with ethyl acetate and sequentially washed with 10% citric acid, saturated sodium hydrogen phosphate and saturated sodium chloride, and subsequently dried over anhydrous sodium sulfate. The solution was concentrated onto silica and product was eluted with hexane/ethyl acetate (3:1). Purification by distillation in a kugelrohr at 180° C. and 0.5 mmHg yielded 1-(benzo-2,1,3-thiadiazole-5-ylcarbonyl)piperidine, 1 (1.29 g, 87%) as a pale yellow oil. IR: 2920, 2855, 1633, 1478, 1439, 1280, 1223, 1001, 816, and 748 cm−1. 1H NMR (500 MHz): δ8.06 (1H, d, J=9.1 Hz); 8.02 (1H, s); 7.63 (1H, t, J=9.0 and 1.5 Hz); 3.77 (2H, br s); 3.40 (2H, br s); 1.72 (4H, br s); and 1.57 ppm (2H, br s).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:29])[C@:14]([CH3:28])([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.N1C=CC=CC=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[OH:22][C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@@:14]([CH3:28])([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:13](=[O:29])[C:12]=1[C:7]1[NH:6][C:5]2[CH:30]=[CH:31][C:2]([NH:1][S:39]([CH3:38])(=[O:41])=[O:40])=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1
Reactant: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Yield: 64.7 %

Procedure:
To a solution of the product of Example 39-6 (310 g, 0.705 mol) and pyridine (167.6 g, 2.12 mol) in dichloromethane (1645 mL) at 18-20° C. was added methanesulfonyl chloride (121.1 g, 1.06 mol) over 45 minutes. The solution was mixed at RT for 16 h then quenched with 1 M HCl (2000 mL). The layers were separated and the organic layer was concentrated under vacuum. The product was crystallized from ethyl acetate/heptane (1/1, 8 volumes) to give the title compound (236.0 g, 65%).
Reaction SMILES: [C:1](/[N:3]=[C:4](\OC1C=CC=CC=1)/[N:5]1[CH2:10][CH2:9][C@H:8]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][C:20]=3[CH3:27])[CH2:15][CH2:14]2)=[O:12])[C@@H:7]([C:28]([O:30][CH3:31])=[O:29])[CH2:6]1)#[N:2].C(#N)C.[NH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>>[C:1](/[N:3]=[C:4](\[N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)/[N:5]1[CH2:10][CH2:9][C@H:8]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][C:20]=3[CH3:27])[CH2:15][CH2:14]2)=[O:12])[C@@H:7]([C:28]([O:30][CH3:31])=[O:29])[CH2:6]1)#[N:2]
Reactant: C1CCNCC1
Reactant: COC(=O)[C@H]1CN(/C(=N/C#N)Oc2ccccc2)CC[C@@H]1C(=O)N1CCN(c2ccc(C#N)cc2C)CC1
Solvent: CC#N
Product: COC(=O)[C@H]1CN(/C(=N/C#N)N2CCCCC2)CC[C@@H]1C(=O)N1CCN(c2ccc(C#N)cc2C)CC1

Procedure:
To a stirred solution of methyl (3R,4S)-1-[(Z)-(cyanoimino)(phenoxy)methyl]-4-[4-(4-cyano-2-methylphenyl)piperazin-1-yl]carbonylpiperidine-3-carboxylate (52 mg, 0.00010 mol) in acetonitrile (2.006 mL, 0.03840 mol) was added piperidine (0.200 mL, 0.00202 mol). The reaction mixture refluxed(oil bath at 85 deg). Upon completion reaction mixture concentrated in vacuum. The residue was purified by combiflash using 0-5% methanol/dichloromethane to give the product (53.3 mg, 98% in yield). MS (ESI): (M+H)+=506.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]2=[N:21]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N>C1COCC1.CO.[Ni]>[NH2:21][CH:12]1[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13]1
Reactant: CC1(C)CC(=NO)c2cc(OCc3ccccc3)ccc2O1
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)CC(N)c2cc(OCc3ccccc3)ccc2O1

Procedure:
30 g of 6-benzyloxy-2,2-dimethylchroman-4-one oxime were dissolved in 900 ml of THF/methanol (1:1), treated with 25 ml of aqueous ammonia and hydrogenated in a shaking duck using Raney Ni. The catalyst was then filtered off with suction, the filtrate was concentrated in vacuo, the residue was dissolved in EA, dried and concentrated, and the residue was crystallized using petroleum ether, 22.9 g, m.p. 86-88° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.[CH:37]([N:40]1[CH2:45][CH2:44][C:43](=O)[CH2:42][CH2:41]1)([CH3:39])[CH3:38].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[C:25]1([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:23][NH:22][C:5]2[N:4]=[C:3]([CH2:2][NH:1][CH:43]3[CH2:44][CH2:45][N:40]([CH:37]([CH3:39])[CH3:38])[CH2:41][CH2:42]3)[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Reactant: CC(C)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNC4CCN(C(C)C)CC4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.1 %

Procedure:
(2R,3R,4S,5R)-2-{2-(Aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 1) (310 mg, 0.63 mmol) was dissolved (using gentle heating) in dry tetrahydrofuran (20 ml). The resulting solution was cooled to room temperature and, with stirring, treated with a solution of 1-isopropyl-4-piperidinone (90 mg, 0.63 mmol) and acetic acid (45 mg) in dry tetrahydrofuran (5 ml). The mixture was stirred for 1 hr, sodium triacetoxyborohydride (200 mg, 0.94 mmol) added and stirring continued for a further 18 hr. The solvent was then removed under reduced pressure and the residue partitioned between a saturated aqueous solution of sodium hydrogen carbonate and ethyl acetate. The organic phase was separated and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol:ammonia (90:10:0.5) changing to dichloromethane:methanol:ammonia (85:15:0.75) to afford the title compound as a foam (140 mg). MS: 616 (MH+).
Reaction SMILES: [Br:1]Br.[Br:3][C:4]1[CH:13]=[CH:12][C:7]2[S:8][CH:9]=[C:10]([CH3:11])[C:6]=2[CH:5]=1>C(Cl)(Cl)Cl>[Br:1][C:9]1[S:8][C:7]2[CH:12]=[CH:13][C:4]([Br:3])=[CH:5][C:6]=2[C:10]=1[CH3:11]
Reactant: Cc1csc2ccc(Br)cc12
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: Cc1c(Br)sc2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.1 %

Procedure:
A solution of bromine (3.20 g) in chloroform (10 ml) was added dropwise to a stirred solution of 5-bromo-3-methylbenzo[b]-thiophene (4.54 g) in chloroform (40 ml) and the solution was stirred at room temperature for 1.5 hours. It was then washed with dilute sodium hydroxide solution, water and dried (Na2SO4). Evaporation of the solvent gave a solid which was crystallised from petrol (b.p. 80°-100°) to give 2,5-dibromo-3-methylbenzo[b]-thiophene (5.45 g), m.p. 118°-122°.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:23]=[C:22]([O:24][CH3:25])[C:13]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])=[C:12]([O:26][CH3:27])[CH:11]=1.[C:28](O)(=[O:32])[C:29]([CH3:31])=[CH2:30].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C=CC(O)=CC=1)O>C1(C)C=CC=CC=1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[C:12]([O:26][CH3:27])[C:13]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:28](=[O:32])[C:29]([CH3:31])=[CH2:30])=[C:22]([O:24][CH3:25])[CH:23]=1
Reactant: C=C(C)C(=O)O
Reactant: COc1cc(-c2nc3ccccc3s2)cc(OC)c1OCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Oc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)OCCCCCCOc1c(OC)cc(-c2nc3ccccc3s2)cc1OC
Yield: 67 %

Procedure:
A solution of 6-(4-benzothiazol-2-yl-2,6-dimethoxy-phenoxy)hexan-1-ol (1.10 g, 0.0038 mol), methacrylic acid (1.30 g, 0.015 mol) of p-toluenesulfonic acid (0.10 g, 0.0005 mol), hydroquinone (0.10 g, 0.0009 mol) and toluene (50 cm3) was heated under reflux for 48 hours in a Dean and Stark apparatus to remove water continuously and then allowed to cool. The solvent was removed under reduced pressure and the residue dissolved into diethyl ether (100 cm3). The resultant solution was washed with water (20 cm3), dried (Na2SO4), filtered and then evaporated down under slightly reduced pressure. The residue was recrystallised from methanol to yield 1.16 g (67.1%) of the desired product. A small amount of 2,6-di-tert-butyl-4-methylphenol was added to act as an inhibitor to prevent spontaneous polymerisation.
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+].[CH:39]1([NH2:44])[CH2:43][CH2:42][CH2:41][CH2:40]1>CN(C=O)C>[CH:39]1([NH:44][CH2:2][CH2:3][CH2:4][S:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[C:22]4[C:17](=[C:18]([C:30]([NH2:32])=[O:31])[CH:19]=[C:20]([C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=5)[CH:21]=4)[NH:16][N:15]=3)[CH2:10][CH2:9]2)(=[O:7])=[O:6])[CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: NC1CCCC1
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)CCCNC4CCCC4)CC3)n[nH]c12
Yield: 6.8 %

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 cyclopentyl amine (110 uL, 1.11 mmol) to afford the title compound (8 mg, 7% for 2 steps).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:9][C@H:5]2[O:6][CH2:7][CH2:8][C@@:4]2([C:10]([N:12]2[CH2:17][C:16]3[CH:18]=[C:19]([C:22]([F:25])([F:24])[F:23])[CH:20]=[CH:21][C:15]=3[O:14][CH2:13]2)=[O:11])[CH2:3]1.[CH3:26][O:27][C@H:28]1[C:33](=O)[CH2:32][CH2:31][O:30][CH2:29]1>>[CH3:26][O:27][C@H:28]1[C@@H:33]([NH:1][C@@H:2]2[CH2:9][C@H:5]3[O:6][CH2:7][CH2:8][C@@:4]3([C:10]([N:12]3[CH2:17][C:16]4[CH:18]=[C:19]([C:22]([F:25])([F:24])[F:23])[CH:20]=[CH:21][C:15]=4[O:14][CH2:13]3)=[O:11])[CH2:3]2)[CH2:32][CH2:31][O:30][CH2:29]1
Reactant: CO[C@@H]1COCCC1=O
Reactant: N[C@@H]1C[C@H]2OCC[C@@]2(C(=O)N2COc3ccc(C(F)(F)F)cc3C2)C1
Product: CO[C@@H]1COCC[C@@H]1N[C@@H]1C[C@H]2OCC[C@@]2(C(=O)N2COc3ccc(C(F)(F)F)cc3C2)C1

Procedure:
The title compound was prepared from the reaction of the product of Step E and (R)-3-methoxydihydro-2H-pyran-4(3H)-one (Intermediate 1) following the procedure described in Example 1, Step H. 1H NMR (CHLOROFORM-d) δ: 7.42 (d, J=8.6 Hz, 1H), 7.36 (br. s., 1H), 6.95 (d, J=8.1 Hz, 1H), 5.43 (br. s., 2H), 4.96-5.11 (m, 1H), 4.82 (br. s., 2H), 3.84-4.15 (m, 3H), 3.68 (d, J=7.1 Hz, 1H), 3.55 (br. s., 1H), 3.32-3.45 (m, 4H), 3.20-3.32 (m, 2H), 2.69-2.84 (m, 1H), 2.39 (br. s., 1H), 2.12-2.25 (m, 2H), 1.99-2.12 (m, 1H), 1.78-1.99 (m, 1H), 1.46-1.78 (m, 4H). Calculated for C23H29F3N2O5: 471.2 (M+1). found: 471.2.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]([OH:11])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4][C:5]#[CH:6].N1C=CN=C1.[CH3:18][Si:19]([CH3:22])([CH3:21])Cl.C(=O)(O)[O-].[Na+]>CCCCCC.CN(C)C=O>[F:1][CH:2]([F:12])[C:3]([O:11][Si:19]([CH3:22])([CH3:21])[CH3:18])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4][C:5]#[CH:6]
Reactant: C[Si](C)(C)Cl
Reactant: C#CCC(O)(CCCC)C(F)F
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: C#CCC(CCCC)(O[Si](C)(C)C)C(F)F
Temperature: 0 °C

Procedure:
A solution of 11.5 g. of 4-difluoromethyl-4-hydroxy-1-octyne and 11.32 g. of imidazole in 45 ml. of dimethylformamide is cooled in an ice bath under nitrogen. A 10.3 ml. portion of trimethylchlorosilane is added using a syringe over a 15 minute period. The mixture is stirred in the ice bath for one hour and then overnight at room temperature. The solution is diluted with hexane and then poured into saturated aqueous sodium bicarbonate solution. The hexane solution is separated, washed with aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate and the solvents are evaporated to dryness giving the desired product as a colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1/[CH:11]=[CH:12]/[CH:13]=O.[N:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N+:16]=[N-:17].[Na].[Cl-].[NH4+]>C(O)C.CCO.CCO>[N:15](/[C:18](=[CH:13]/[CH:12]=[CH:11]/[C:4]1[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])/[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N+:16]=[N-:17]
Reactant: COc1cccc(OC)c1/C=C/C=O
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)/C(=C\C=C\c1c(OC)cccc1OC)N=[N+]=[N-]
Temperature: -10 °C

Procedure:
Add dropwise, while stirring, a solution of 37 g (192 mmol) of (2E)-3-(2,6-dimethoxyphenyl)acrylaldehyde and 85.7 g (664 mmol) of ethyl 2-azidoacetate in 200 mL of absolute ethanol EtOH to a solution of 15.5 g (673 mmol) of sodium in 500 mL of absolute EtOH cooled to −10° C. and kept under argon, maintaining the temperature at −10° C. After stirring at −10° C. for 3 h, stir the reaction mixture for 15 h at RT, then pour into 600 mL of an aqueous solution of ammonium chloride (NH4Cl) at 30 wt. %. After filtration on a frit and rinsing with 2×200 mL of water, take up the precipitate in 600 mL of DCM, dry over Na2SO4 and concentrate under reduced pressure, which leads to 42 g of ethyl (2E,4E)-2-azido-5-(2,6-dimethoxyphenyl)penta-2,4-dienoate in the form of a yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[CH2:19][CH2:20][CH2:21][CH2:22][OH:23].[CH3:24][S:25](O)(=[O:27])=[O:26].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[CH2:19][CH2:20][CH2:21][CH2:22][O:23][S:25]([CH3:24])(=[O:27])=[O:26]
Reactant: O=c1c(CCCCO)c(O)c2cccnc2n1-c1ccccc1
Reactant: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CS(=O)(=O)OCCCCc1c(O)c2cccnc2n(-c2ccccc2)c1=O
Temperature: 55 °C

Procedure:
4-Hydroxy-3-(4-hydroxybutyl)-1-phenyl-1,8- naphthyridin-2(1H)-one (10 g.) was dissolved, with stirring, in Eaton's Reagent (10% P2O5 in methanesulfonic acid; 50 ml.) under a nitrogen atmosphere. The solution was heated to 55° C. where it was held for 31/2 hr. It was then cooled and poured into a water/ice mixture. After stirring for several hours, the aqueous mixture was extracted (3x) with ethyl acetate (250 ml. each). The organic extract was separated, dried (Na2SO4), filtered and evaporated. The residue was stirred with a small volume of cold isopropanol and filtered to yield a brown solid, the mono-mesylate, which was used without further purification in Example 7.