Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[N:9]2[CH:4]([O:5][CH2:6][CH:7]=[CH:8]2)[CH2:3][CH:2]1[CH2:10][OH:11]>CCl.O=[Mn]=O>[N:1]1[N:9]2[C:4]([O:5][CH2:6][CH2:7][CH2:8]2)=[CH:3][C:2]=1[CH:10]=[O:11]
Reactant: OCC1CC2OCC=CN2N1
Agent: O=[Mn]=O
Agent: CCl
Product: O=Cc1cc2n(n1)CCCO2
Yield: 104.7 %

Procedure:
To the stirred solution of 2,3-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-2-yl-methanol (2.08 g, 13.5 mmol) in 60 ml of CH3Cl was added 9.38 g of MnO2. The suspension was refluxed for 2 hour under a nitrogen atmosphere. The reaction mixture was filtered through a pad of Celite. The filtrate was concentrated to give yellow oil. The product was purified by chromatography. 2.15 g of the product was obtained (78%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24][CH2:25][OH:26]>C(N(CC)CC)C>[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24][CH2:25][O:26][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCc1cccs1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCc2cccs2)cc1
Temperature: 45 °C
Reaction time: 4 h

Procedure:
4-toluenesulfonyl chloride (162 g), toluene (363.3 g) and 2-(2-Thienyl)ethanol (104 g) are combined. Triethylamine (93 g) is added maintaining the temperature lower than 45° C. After 4 hrs, the mixture is washed with aqueous phosphoric acid, aqueous sodium hydroxide and then water. The organic phase is distilled off under vacuum. Isopropanol (314 g) and heptanes (365.9 g) are added. The batch is crystallized by cooling and isolated at −15° C. The crystals are filtered and washed with heptanes (175 mL). The crystals are then dried under vacuum at room temperature until a melting point of 30° C. is obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:26])=[C:5]([C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][OH:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[F:27][C:28]([F:38])([F:37])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]=O)[CH:30]=1>>[CH3:1][C:2]1[NH:3][C:4]([CH3:26])=[C:5]([C:20]([O:22][CH:23]([CH3:24])[CH3:25])=[O:21])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18](=[CH:35][C:31]3[CH:32]=[CH:33][CH:34]=[C:29]([C:28]([F:27])([F:37])[F:38])[CH:30]=3)=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(NO)c1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Agent: COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(/[N+]([O-])=C/c2cccc(C(F)(F)F)c2)c1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc([N+]([O-])=Cc2cccc(C(F)(F)F)c2)c1

Procedure:
The reaction of hydroxylamine 82 (0.71 g, 2 mmol) with α,α,α-trifluoro-m-tolualdehyde (60) (0.348 g, 2 mmol) afforded, after workup, a light yellow solid. The crude product was recrystallized from ether/petroleum ether to obtain 0.80 g (1.55 mmol. 78%) of 85 as a white crystalline solid: mp 127°-129° C.; IR (CH2Cl2) 3440, 2980, 1698, 1624, 1558, 1475, 1332, 1300, 1215, 1100, 1018, 810 cm-1 ; 1H NMR (CDCl3) δ 1.14 (d, J=6.2 Hz, 3H), 1.26 (d, J=6.2 Hz, 3H), 2.29 (s, 6H), 3.65 (s, 3H), 4.97 (septet, J=6.2 Hz, 1H), 5.08 (s, 1H), 6.47 (br s, 1H), 7.28-8.76 (m, 9H); 13C NMR (CDCl3) δ 19.48, 21.99, 22.22, 39.98, 51.15, 67.31, 102.99, 103.70, 119.43, 121.55, 125.52, 125.55, 127.22, 128.56, 129.28, 130.43, 131.46, 131.92, 133.40, 144.79, 145.33, 148.92, 149.91, 167.01, 168.03. Anal. Calcd for C27H27N2O5F3 : C, 62.79; H, 5.23. Found: C, 62.68; H, 5.02.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@:13]([CH2:23][OH:24])([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:12][C@@H:11]([N:25]2[CH:32]=[CH:31][C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@@H:10]1[OH:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>ClCCl.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][C@@H:9]1[C@@:13]([CH2:23][O:24][S:40]([C:37]2[CH:38]=[CH:39][C:34]([CH3:44])=[CH:35][CH:36]=2)(=[O:42])=[O:41])([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:12][C@@H:11]([N:25]2[CH:32]=[CH:31][C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@@H:10]1[O:33][S:40]([C:37]1[CH:38]=[CH:39][C:34]([CH3:44])=[CH:35][CH:36]=1)(=[O:42])=[O:41])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=c1ccn([C@@H]2O[C@](CO)(COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H]2O)c(=O)[nH]1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@]2(COCc3ccccc3)O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](OS(=O)(=O)c3ccc(C)cc3)[C@@H]2OCc2ccccc2)cc1
Reaction time: 2 h
Yield: 78 %

Procedure:
To a stirred solution of 1-(3,5-di-O-benzyl-4-C-hydroxymethyl-β-D-ribofuranosyl)uracil 41 (3.55 g, 7.81 mmol) in dichloromethane (50 cm3) were added DMAP (3.82 g) and p-toluenesulphonyl chloride (4.47 g, 23.5 mmol) at room temperature. Stirring was continued for 2 h, and dichloromethane (100 cm3) was added. The reaction mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate (2×75 cm3) and dried (Na2SO4). The organic phase was evaporated under reduced pressure and the residue was purified by silica gel column chromatography using dichloromethane/methanol (99.5:0.5, v/v) as eluent to give nuceloside 75 (4.65 g, 78%) as a white solid material. δH (CDCl3) 8.49 (1H, br s, NH), 7.67 (1H, d, J 8.3, 6-H), 7.51-7.03 (18H, m, Bn, Ts), 6.0 (1H, d, J 7.6, 1′-H), 5.05 (1H, m, 2′-H), 4.91 (2H, m, 5-H, Bn), 4.56 (2H, m, Bn), 4.42 (1H, d, J 10.4, Bn), 4.31 (1H, d, J 4.9, 3′-H), 4.05 (2H, m, 1″-H), 3.75-3.64 (2H, m, 5′-H), 2.41 (3H, s, CH3), 2.34 (3H, s, CH3 ), δc (CDCl3) 162.2 (C-4), 149.5 (C-2), 146.0, 145.3 (Ts), 139.0 (C-6), 136.7, 131.9, 130.0, 129.9, 128.9, 128.7, 128.5, 128.4, 128.3, 128.2, 128.0, 127.6 (Bn, Ts) 102.7 (C-5), 85.5 (1′-C), 84.4 (4′-C), 79.2, 78.3, 75.1, 74.3, 72.4, 69.1 (Bn, 3′-C, 2′-C, 5′-C, 1″-C), 21.7, 21.6 (Ts). FAB-MS m/z 763. Found: C 61.2; H, 4.4; N, 3.3; C38H38N2 O11S2 requires C, 59.8; H 5.0; N, 3.6.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[C:16]([O:18][CH3:19])=[O:17])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:20]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([CH2:15][Br:20])[CH:12]=[CH:11][C:10]=1[C:16]([O:18][CH3:19])=[O:17])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(C)cc1S(=O)(=O)NC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1S(=O)(=O)NC(C)(C)C
Yield: 59.9 %

Procedure:
A solution of 54.8 g (192 mmol) of N-tert-butyl-2-methoxycarbonyl-5-methylbenzenesulfonamide in 420 ml of tetrachloromethane is heated at reflux for 6-8 h under a nitrogen protective-gas atmosphere, following addition of 36 g (202 mmol) of N-bromosuccinimide and 0.5 g of azobisisobutyronitrile (AIBN) with simultaneous irradiation with a daylight lamp. The solution is then filtered and then washed in succession with sodium disulphide solution, sodium hydrogen carbonate solution and water, dried over Na2SO4 and evaporated to dryness i.v. Crystallization of the residue from diisopropyl ether/ethyl acetate yields 41.9 g (57%) of N-tert-butyl-5-bromomethyl-2-methoxycarbonylbenzenesulfonamide of mp. 88°-90° C.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:14]=[CH:13][O:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:23][CH2:24][OH:25].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([N:8]([CH2:9][C:10]1[CH:14]=[CH:13][O:12][CH:11]=1)[CH2:23][CH2:24][OH:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCBr
Reactant: c1ccc(CNCc2ccoc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: OCCN(Cc1ccccc1)Cc1ccoc1

Procedure:
N-Benzyl-3-furylmethylamine (12 g, 64 mmol), triethylamine (18 ml, 130 mmol) and 2-bromoethanol (8.0 g, 64 mmol) were stirred at 60° C. to 70° C. for 16 hours in anhydrous N,N-dimethylformamide (120 ml). The reaction solution was mixed with ethyl acetate, washed with water and saturated brine and then dried with anhydrous magnesium sulfate. The solvent was removed by evaporation from the organic layer under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 7.1 g (31 mmol, 48% in yield) of the title compound.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([C:10]2[N:15]=[C:14]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[C:13]([CH3:21])=[CH:12][N:11]=2)[N:8]=[CH:7][C:6]=1[CH2:22][NH2:23])[CH2:2][CH2:3][CH3:4].[NH:24]1[C:28]([CH2:29][C:30](O)=[O:31])=[CH:27][N:26]=[CH:25]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([C:10]2[N:15]=[C:14]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[C:13]([CH3:21])=[CH:12][N:11]=2)[N:8]=[CH:7][C:6]=1[CH2:22][NH:23][C:30](=[O:31])[CH2:29][C:28]1[NH:24][CH:25]=[N:26][CH:27]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)Cc1cnc[nH]1
Reactant: CCCCc1c(CN)cnn1-c1ncc(C)c(-c2cccs2)n1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCCCc1c(CNC(=O)Cc2cnc[nH]2)cnn1-c1ncc(C)c(-c2cccs2)n1

Procedure:
A mixture of (5-butyl-1-(5-methyl-4-(thiophen-2-yl)pyrimidin-2-yl)-1H-pyrazol-4-yl)methanamine and 2-(1H-imidazol-5-yl)acetic acid in 1:1 molar ratio was treated with EDC (1 equiv.), HOBT (1 equiv.) and N-methylmorpholine (2 equiv.) in methylene chloride (at a concentration of 0.5 M) at room temperature overnight (20 hours). Upon completion, an additional methylene chloride was added and the resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The crude material was purified by column chromatography using 10% CH3OH/CH2Cl2 as the eluent to give the title compound 34. 1H NMR (400 MHz, CD3OD) δ 8.79 (s 1H), 8.34 (t, J=5.48 Hz, 1H), 8.10 (s 1H), 7.94 (s 1H), 7.93 (s 1H), 7.62 (s 1H), 7.33 (D, J=4.69 Hz, 1H), 7.10 (s 1H), 4.18 (D, J=5.48 Hz, 2H), 3.49 (s 3H), 3.11 (t, J=7.83 Hz, 2H), 2.60 (s 3H), 1.40 (quint, J=7.43 Hz, 2H), 1.24 (sex, J=7.83 Hz, 2H), 0.77 (t, J=7.43 Hz, 3H). LCMS (ES+) m/z 436 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6](=[S:15])[N:7]([CH3:14])[CH2:8][CH:9]([CH2:11][CH2:12]Cl)[O:10][C:4]=2[CH:3]=1.[CH3:18][NH:19][CH3:20]>C(O)C.Cl>[ClH:1].[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6](=[S:15])[N:7]([CH3:14])[CH2:8][CH:9]([CH2:11][CH2:12][N:19]([CH3:20])[CH3:18])[O:10][C:4]=2[CH:3]=1
Reactant: CN1CC(CCCl)Oc2cc(Cl)ccc2C1=S
Reactant: CNC
Agent: Cl
Solvent: CCO
Product: CN(C)CCC1CN(C)C(=S)c2ccc(Cl)cc2O1

Procedure:
A solution of 9.8 g (0.04 mole) of 8-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepine-5(4H)-thione in 50 ml of absolute ethanol and 10 ml of a 40% aqueous solution of dimethylamine were mixed and heated in a steel bomb at 100° C. for 16 hr. The ethanol was evaporated under reduced pressure and the residue dissolved in chloroform and partitioned with 10% sodium hydroxide solution. The chloroform layer was evaporated under reduced pressure to give an amorphous solid. The solid was dissolved in 6N hydrochloric acid and the solution washed with ethyl acetate. The aqueous layer was basified with 50% sodium hydroxide and extracted with ethyl acetate. The ethyl acetate layer was evaporated under reduced pressure to give a viscous oil comprised substantially of the free base of the title compound which was dissolved in absolute ethanol and reacted with ethereal hydrogen chloride. The hydrochloride salt was recrystallized from ethanol to give 30 g (25%) product, m.p. 196°-199° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH:16]=O.CO[Na].Cl>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH:9]=[CH:16][C:12]2[O:11][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccco1
Reactant: CC(=O)c1ccc(Br)cc1
Agent: CO[Na]
Agent: Cl
Solvent: CO
Product: O=C(C=Cc1ccco1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
To a solution of 4-bromophenylethanone (112.6 g, 570 mmol) and furan-2-carbaldehyde (58.5 g, 610 mmol) in methanol (1.5 L) was added CH3ONa (31 g, 570 mmol) over 10 min and the reaction solution was stirred at room temperature overnight. The reaction mixture was neutralized with conc. HCl to pH=7, and the solvent was removed under reduced pressure. To the resultant residue was added EA and water. The aqueous layer was extracted with EA for 3 times. The combined layers were washed with brine, dried over MgSO4, concentrated and purified by silica gel column chromatography (PE (petroleum ether): EA (ethyl acetate)=10:1) to afford 1-(4-bromophenyl)-3-(furan-2-yl)prop-2-en-1-one (5A) as a yellow solid (90.2 g, 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:21]=1)=[O:19]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18](=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:21]=1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Reactant: O=C(CBr)c1cccc(OCc2ccccc2)c1
Product: CCOC(=O)n1c(C(=O)c2cccc(OCc3ccccc3)c2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 2-bromo-3′-(benzyloxy)acetophenone (T. Fujii, M. Ohba, M. Tsuchida, K. Saito, Y. Hirano, and J. Sakaguchi, Chem.Pharm.Bull., 1986, 34, 496-507).
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[O:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:31]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)=O)=[CH:30][C:25]=2[O:24][CH2:23]1.O>C1COCC1>[O:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:31]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)=[CH:9][C:10]#[N:11])=[CH:30][C:25]=2[O:24][CH2:23]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1ccc(C(=O)c2ccc3c(c2)OCO3)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=CC#N)c2ccc3c(c2)OCO3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
To a solution of cyanomethylphosphonic acid diethyl ester (3.0 mL, 18.7 mmol) in anhydrous THF (20 mL) was added lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 18.7 mL, 18.7 mmol) at 0° C. and stirred for 30 min at room temperature followed by addition of benzo[1,3]dioxol-5-yl-(4-methoxy-phenyl)-methanone (2.40 g crude, HPLC purity 93%, 9.4 mmol) in THF (15 mL) and refluxed for 3 hours. The reaction mixture was poured into water (80 mL), extracted with CH2Cl2 (2×60 mL). The combined organic phases were washed with brine (60 mL), dried over MgSO4, and purified via flash column chromatography (EtOAc, Hexane) to give 3-benzo[1,3]dioxol-5-yl-3-(4-methoxy-phenyl)-acrylonitrile as an oil (1.98 g, 76% yield): 1H NMR (DMSO-d6) δ 3.79 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 6.10-6.13 (ms, 6H, 2CH2 and 2CH), 6.70-7.33 (m, 14H, Ar); 13C NMR (DMSO-d6) δ 55.3, 55.4, 93.0, 93.2, 101.6, 101.8, 107.8, 108.2, 108.3, 109.3, 113.9, 114.1, 118.6, 118.7, 123.6, 123.8, 129.3, 129.9, 130.4, 130.8, 130.9, 132.4, 147.3, 147.8, 148.4, 149.3, 160.3, 160.9, 161.0, 161.1. LC/MS showed desired peak at 280 for (M+1)+1 positive ion mass.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)=[C:4]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:3]=1.O.O.Cl[Sn]Cl>CO>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)=[C:4]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(Cl)cc2C2CCCCC2)cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: Nc1ccc(Oc2ccc(Cl)cc2C2CCCCC2)cc1

Procedure:
The nitro intermediate (10 mmol) obtained above was dissolved in MeOH (20 mL), and treated with SnCl2.2H2O (50 mmol), according to General Procedure I. The reaction mixture was heated under reflux until completion, as indicated by TLC or HPLC. The solvent was removed in vacuuo and the residue was treated with 4.0 N aqueous NaOH to pH ˜8. The residue was extracted with EtOAc (2×50 mL), washed with 1.0 N aqueous NaOH, brine and dried over sodium sulfate. The solvent was removed in vacuuo to afford the desired 4-(4-chloro-2-cyclohexylphenoxy) aniline, which was used directly for further transformation without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[CH:2]1.Br[C:13]1[CH:14]=[CH:15][C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[C:17]([CH:20]=1)[C:18]#[N:19].CC(C)([O-])C.[Na+].N[C@@H]1CCCC[C@H]1N>CN(C=O)C.CCOC(C)=O.CCCCCC>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:16]1[CH:15]=[CH:14][C:13]([N:1]2[CH:5]=[CH:4][C:3]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=3)=[CH:2]2)=[CH:20][C:17]=1[C:18]#[N:19]
Reactant: c1ccc(-c2cc[nH]c2)nc1
Reactant: N#Cc1cc(Br)ccc1-c1ccccn1
Agent: CC(C)(C)[O-]
Agent: N[C@@H]1CCCC[C@H]1N
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cc(-n2ccc(-c3ccccn3)c2)ccc1-c1ccccn1
Temperature: 140 °C
Yield: 24.8 %

Procedure:
2-(1H-Pyrrol-3-yl)pyridine (300 mg, 2.0 mmol), 5-bromo-2-pyridin-2-ylbenzonitrile (538.7 g, 2.0 mmol), sodium tert-butoxide (384 mg, 4.0 mmol) and trans-1,2 diaminocyclohexane (23 mg, 0.2 mmol) were combined in DMF (10 mL) under argon. The reaction mixture was heated at 140° C. overnight. The reaction mixture was allowed to cool to ambient temperature. TLC analysis showed no starting material present. The reaction mixture was diluted with EtOAc (100 mL), and washed with H2O (3×100 mL), brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford a dark oil. The crude product was purified by column chromatography eluting with 5.5:4.5 EtOAc:Hexane to afford 2-pyridin-2-yl-5-(3-pyridin-2-yl-1H-pyrrol-1-yl)benzonitrile (160 mg, 27% yield) as a yellow solid. 1H NMR (CDCl3, 300 MHz) δ 8.73-8.74 (d, 1H), 8.48-8.49 (d, 1H), 8.14-8.15 (d, 1H), 7.98-8.01 (m, 3H), 7.92-7.94 (d, 1H), 7.86-7.88 (d, 1H), 7.79-7.81 (t, 1H), 7.47-7.53 (m, 2H), 7.22-7.24 (m, 1H), 6.94-6.95 (m, 1H). MS 323.4 (M++H).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[N:6]=1.[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:5]1[N:6]=[C:2]([N:17]2[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]2)[S:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1ccccc1-c1csc(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccccc3Cl)cs2)CC1
Yield: 67 %

Procedure:
A solution of 2-bromo-4-(2-chlorophenyl)-1,3-thiazole (4.48 g, 16.3 mmol), tert-butyl piperazine-1-carboxylate (6.08 g, 32.6 mmol) and potassium carbonate (2.26 g, 16.3 mmol) in dimethylformamide (50 ml) was stirred at 120° C. for 15 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 4.15 g (66.9%) of the desired product as a solid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)=[O:4].[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH3:26])=[O:25])=[CH:20][CH:19]=1.[H-].[Li+]>O1CCCC1.C(OC)(C)(C)C>[F:1][C:2]([F:15])([F:16])[C:3]([OH:4])([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:12])([F:13])[F:14])[CH:6]=1)[CH2:26][C:24]([C:21]1[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=1)=[O:25]
Reactant: CC(=O)c1ccc(C)cc1
Reactant: O=C(c1cccc(C(F)(F)F)c1)C(F)(F)F
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: Cc1ccc(C(=O)CC(O)(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc1
Yield: 97.2 %

Procedure:
A solution of 2,2,2-trifluoro-1-[3-(trifluoromethyl)-phenyl]ethanone (3.0 g), 4-methylacetophenone (1.1 g) and lithium hydride (0.13 g) in tetrahydrofuran (30 mL) was stirred for 3 hours at 60° C. After the reaction solution was diluted with t-butylmethylether, the solution was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was then purified by silica gel chromatography to yield 4,4,4-trifluoro-3-hydroxy-1-(4-methylphenyl)-3-[3-(trifluoromethyl)phenyl]butan-1-one (3.0 g).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[C:34]([N:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1)(=[O:37])[CH2:35][CH3:36]
Reactant: CCC(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CCCNC4)c[nH]c23)cc1F
Agent: Cl
Product: CCC(=O)N1CCC[C@H](NC(=O)c2c[nH]c3c(-c4cc(F)c(OC)cc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (S)-piperidin-3-ylamide hydrochloride (example A168) and propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[F:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:9]2[CH2:10][CH2:11][C:6]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:27][CH:28]=3)(=[O:22])=[O:21])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)=[CH:18][CH:17]=1
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(F)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(F)cc3)CC2)cc1

Procedure:
1-(4-Fluoro-benzyl)-4-(4-butoxy-bezenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from 1-(4-Fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester (4.77 g, 10 mmol) dissolved in THF:methanol 3:1 and 10N NaOH (10 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 3.5 g (79%); off white solid; mp 114° C.; MS: 450 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]([CH2:39][CH3:40])[CH2:4][C:5]1([C:11]([NH:13][C:14]2[C:15]([S:24]C(C3(CC(CC)CC)CCCCC3)=O)=[CH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:2].[OH-].[K+].O>CO.O1CCCC1>[SH:24][C:15]1[C:14]([NH:13][C:11]([C:5]2([CH2:4][CH:3]([CH2:39][CH3:40])[CH2:1][CH3:2])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]2)=[O:12])=[CH:23][C:22]2[C:17]([CH:16]=1)=[CH:18][CH:19]=[CH:20][CH:21]=2
Reactant: CCC(CC)CC1(C(=O)Nc2cc3ccccc3cc2SC(=O)C2(CC(CC)CC)CCCCC2)CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCC(CC)CC1(C(=O)Nc2cc3ccccc3cc2S)CCCCC1
Reaction time: 1 h

Procedure:
The crude product obtained in step A) is dissolved in a mixture of methanol and tetra-hydrofuran (1:1). Then 3.5 mol equivalents of potassium hydroxide are added at room temperature and the mixture is stirred for 1 hour. Then water is added and the mixture is washed with n-hexane. The aqueous layer is then acidified by addition of KHSO4 and extracted with chloroform. The combined extracts are washed with water and brine, dried (Na2SO4) and concentrated to obtain 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid (3-mercapto-naphthalen-2-yl)-amide.