Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]2[CH2:13][CH2:12][N:11](CC=C)[CH2:10]2)[N:4]=1.CN1C(=O)CC(=O)N(C)C1=O>ClCCl.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>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]2[CH2:13][CH2:12][NH:11][CH2:10]2)[N:4]=1
Reactant: C=CCN1CCC(c2cccc(OC)n2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Solvent: ClCCl
Product: COc1cccc(C2CCNC2)n1
Temperature: 40 °C
Yield: 84 %

Procedure:
To a solution of 2-methoxy-6-[1-(prop-2-en-1-yl)pyrrolidin-3-yl]pyridine a1-55 (218 mg, 1 mmol, 1 eq) in dichloromethane (3 ml) are added 1,3-dimethylbarbituric acid (470 mg, 3 mmol, 3 eq) and Pd(PPh3)4 (20 mg) and the mixture is warmed overnight at 40° C. The reaction mixture is loaded on an ion exchange acidic resin cartridge, washed with methanol (2×50 ml) and then released with a 1M solution of ammonia in methanol (20 ml) to afford 150 mg of crude 2-methoxy-6-(pyrrolidin-3-yl)pyridine a1-59 that is used in the next step without any further purification.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:14][OH:15]>C(O)C.C(O)(=O)C.ClCCl>[C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=[N:14][OH:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(c2ccccc2)CC1
Reactant: NO
Solvent: CC(=O)O
Solvent: CCO
Solvent: ClCCl
Product: ON=C1CCC(c2ccccc2)CC1

Procedure:
To a stirred solution of 4-phenylcyclohexanone (5 g) in ethanol (100 ml) and acetic acid (16.4 ml) was added aqueous hydroxylamine (50%, 4.5 ml). The reaction was heated at reflux for 16 h, before being allowed to cool, and diluted with dichloromethane (100 ml). The reaction was washed with aqueous sodium bicarbonate (sat, 2×50 ml), the organic layer dried over magnesium sulphate (2 g) and the solvent removed in vacuo to yield a white solid. This was purified by flash chromatography (silica, eluent 50% ethyl acetate/hexane), to yield the title compound as a white solid (5.1 g).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:11][N:10]([CH2:12][C:13]2[CH:14]=[C:15]3[C:23](=[CH:24][CH:25]=2)[C:22]2[O:21][N:20]=[C:19]([C:26]([O:28]C)=[O:27])[C:18]=2[CH2:17][CH2:16]3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.O>[C:1]([O:5][C:6]([CH:8]1[CH2:11][N:10]([CH2:12][C:13]2[CH:14]=[C:15]3[C:23](=[CH:24][CH:25]=2)[C:22]2[O:21][N:20]=[C:19]([C:26]([OH:28])=[O:27])[C:18]=2[CH2:17][CH2:16]3)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1noc2c1CCc1cc(CN3CC(C(=O)OC(C)(C)C)C3)ccc1-2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc3c(c2)CCc2c(C(=O)O)noc2-3)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 120.2 %

Procedure:
A mixture of methyl 7-((3-(tert-butoxycarbonyl)azetidin-1-yl)methyl)-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxylate (Preparation 45D, 95 mg, 0.238 mmol) and lithium hydroxide monohydrate (12.01 mg, 0.286 mmol) in THF (3 mL) and water (1.500 mL) was allowed to stir at room temperature overnight. The THF was evaporated and the residue diluted with 5 ml of water. The pH was adjusted to 5-6 and extracted with ethyl acetate six times. The organic layers were combined, dried over sodium sulfate and concentrated to afford 110 mg of product (HPLC purity 75-80%). The compound had an HPLC ret. time=0.67/2.0 min. (condition E); MS:(M+H)=385.3.
Reaction SMILES: C(=O)([O-])[O-].[Ba+2].O.[CH3:7][CH2:8][CH2:9][CH2:10][CH:11]1[C:46](=[O:47])[O:45][CH:44]([CH:48]([CH:50]([OH:58])[CH2:51][CH2:52][CH2:53][NH:54][C:55]([NH2:57])=[NH:56])[CH3:49])[CH:43]([CH3:59])[CH:42]=[C:41]([CH3:60])[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]([OH:61])[CH2:35][CH:34]([OH:62])[CH2:33][CH:32]([OH:63])[CH2:31][CH:30]([OH:64])[CH2:29][CH:28]([OH:65])[CH:27]([O:66][C@H:67]2[O:71][C@H:70]([CH2:72][OH:73])[C@@H:69]([OH:74])[C@@H:68]2[OH:75])[CH:26]=[C:25]([CH3:76])[CH:24]([OH:77])[CH2:23][CH2:22][CH2:21][CH:20]([OH:78])[CH2:19][CH2:18][CH2:17][CH:16]([OH:79])[CH2:15][CH2:14][CH:13]([CH3:80])[CH:12]1[OH:81].S([O-])([O-])(=O)=O.[Cl:87]([OH:91])(=[O:90])(=[O:89])=[O:88]>CO>[CH3:7][CH2:8][CH2:9][CH2:10][CH:11]1[C:46](=[O:47])[O:45][CH:44]([CH:48]([CH:50]([OH:58])[CH2:51][CH2:52][CH2:53][NH:54][C:55]([NH2:57])=[NH:56])[CH3:49])[CH:43]([CH3:59])[CH:42]=[C:41]([CH3:60])[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]([OH:61])[CH2:35][CH:34]([OH:62])[CH2:33][CH:32]([OH:63])[CH2:31][CH:30]([OH:64])[CH2:29][CH:28]([OH:65])[CH:27]([O:66][C@H:67]2[O:71][C@H:70]([CH2:72][OH:73])[C@@H:69]([OH:74])[C@@H:68]2[OH:75])[CH:26]=[C:25]([CH3:76])[CH:24]([OH:77])[CH2:23][CH2:22][CH2:21][CH:20]([OH:78])[CH2:19][CH2:18][CH2:17][CH:16]([OH:79])[CH2:15][CH2:14][CH:13]([CH3:80])[CH:12]1[OH:81].[Cl:87]([O-:91])(=[O:90])(=[O:89])=[O:88]
Reactant: [O-][Cl+3]([O-])([O-])O
Agent: CCCCC1C(=O)OC(C(C)C(O)CCCNC(=N)N)C(C)/C=C(\C)CCCCC(O)CC(O)CC(O)CC(O)CC(O)C(O[C@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)/C=C(\C)C(O)CCCC(O)CCCC(O)CCC(C)C1O
Agent: CCCCC1C(=O)OC(C(C)C(O)CCCNC(=N)N)C(C)C=C(C)CCCCC(O)CC(O)CC(O)CC(O)CC(O)C(O[C@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)C=C(C)C(O)CCCC(O)CCCC(O)CCC(C)C1O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CO
Product: [O-][Cl+3]([O-])([O-])[O-]
Reaction time: 0.33 h

Procedure:
0.087 g (0.444 millimoles) of barium carbonate is dissolved in 8.87 ml of a 0.1 N aqueous perchloric acid solution under slight warming whereupon water is removed in vacuo. The residue is taken up in 10 ml of methanol and added to a suspension of 1.0 g (0.887 millimoles) of primycin sulfate in 80 ml of methanol. The reaction mixture is heated to boiling for 20 minutes under stirring. The primycin perchlorate thus formed remains in the solution and the barium sulfate is precipitated. The hot solution is filtered over Celite and the solid is thoroughly washed on the filter with 10 ml of a 2:1 mixture of acetone and water. Thus 0.94 g of white primycin perchlorate is obtained, yield 88.7%. Mp.: 170°-171° C., /α/D25 =+20°.
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[CH:5]=[C:6]([S:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]2[CH2:20][C:21]([O:23]C)=[O:22])(=[O:13])=[O:12])[CH:7]=[CH:8][C:9]=1[Cl:10]>CO.O>[Cl:3][C:4]1[CH:5]=[C:6]([S:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]2[CH2:20][C:21]([OH:23])=[O:22])(=[O:12])=[O:13])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: COC(=O)CC1CCCCN1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CC1CCCCN1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 16 h

Procedure:
Lithium hydroxide (0.75 mg, 18 mmol) was added to a cooled solution of methyl 2-(1-(3,4-dichlorophenylsulfonyl)piperidin-2-yl)acetate (2.1 g, 6 mmol) in methanol (20 ml) and water (20 ml), and stirring was carried out for 16 h at room temperature (TLC monitoring). The solvent was removed using a rotary evaporator and the residue was taken up in water. The aqueous phase was washed with ethyl acetate and then acidified with 1 M HCl, and the product was extracted with ethyl acetate, and the organic phase was then washed with saturated NaCl solution. The organic phase was dried over sodium sulfate and concentrated to dryness. Yield: 2.9 g (98%)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[I:9]N1C(=O)CCC1=O.S(=O)(=O)(O)O.O>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([I:9])[CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: Oc1ccc(Br)cc1I

Procedure:
4-Bromophenol (51.9 g, 0.30 mol) and N-iodosuccinimide (67.5 g, 0.30 mol) were combined in acetic acid (360 mL). The mixture was stirred briefly, treated with concentrated sulfuric acid (5 mL, 0.09 mol) and stirred at about 22° C. overnight. The mixture was poured into water (about 800 mL) with stirring to precipitate the product. The suspension was stirred for about 1 hour and filtered. The wet cake was washed with water (50 mL, 2×) and dried under reduced pressure at about 50° C. (80.9 g, 90%). MS-DEI (M+H)+ m/z at 298; 1H NMR (CDCl3 at 400 MHz) δ 5.28 (s,1H), 6.86 (d, 1H), 7.33 (dd, 1H), 7.75 (d, 1H); 13C NMR (CDCl3 at 100 MHz) δ 86.0, 112.8, 116.0, 132.7, 139.4, 153.7.
Reaction SMILES: CS(C)=O.[C:5]([N:15]1[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]1)([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].C(N(CC)CC)C>C(Cl)Cl>[C:5]([N:15]1[CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH2:20]1)([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Yield: 73403.4 %

Procedure:
To a cooled solution (-78° C.) of oxalyl chloride (freshly distilled, 18.2 mL, 0.21 mol, 1.5 eq) in methylene chloride (1400 mL) under nitrogen was added freshly distilled dimethylsulfoxide (29.6 mL, 0.42 mol, 3.0 eq). The solution was stirred for 10 min after which a methylene chloride solution (150 mL) of 1-carbobenzyloxypiperidin-4-ol (described in example 87b) (32.76 g, 0.139 mmol) was added via cannula transfer. The solution was maintained at -78° C. for 30 min Triethylamine (116 mL, 0.83 mol, 6.0 eq) was added and the reaction warmed to room temperature over 1.5 h. Once at room temperature, the reaction was quenched with 3N HCl (400 mL). The organic phase was washed with 3N HCl (2×400 mL), 2.5N NaOH (2×400 mL) and saturated brine (1×400 mL). The methylene chloride phase was dried over anhydrous magnesium sulfate, filtered over 100 g of silica gel, and reduced to an oil. The procedure resulted in 23.8 g (73%) of the title compound which did not require any additional purification. 1H NMR (CDCl3, 300 MHz) 7.34 (m, 5H), 5.18 (s, 2H), 3.80 (t, J=6.2 Hz, 4H), 2.46 (br t, 4H) MS (CI, CH4) m/z 234 (M+1,39), 262 (M+29,10), 91 (100).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[C:6]([CH2:11][CH2:12][CH2:13][NH:14][C:15]([CH:17]3[CH2:19][CH2:18]3)=[O:16])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH2:2]1>C(O)C.[Pt]>[O:1]1[C:10]2[C:5](=[C:6]([CH2:11][CH2:12][CH2:13][NH:14][C:15]([CH:17]3[CH2:18][CH2:19]3)=[O:16])[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NCCCc1cccc2c1C=CCO2)C1CC1
Agent: [Pt]
Solvent: CCO
Product: O=C(NCCCc1cccc2c1CCCO2)C1CC1
Yield: 73.1 %

Procedure:
A solution of cyclopropanecarboxylic acid [3-(2H-chromen-5-yl)-propyl]-amide (76 mg) in ethanol (5 ml) was hydrogenated over platinum (5% on carbon, 10 mg) for 16 h. The catalyst was filtered off and the filtrate evaporated. The residue was purified by column chromatography on silica. Elution with hexane/ethyl acetate 2:1 gave the title compound as a colourless solid (56 mg)
Reaction SMILES: [CH3:1]/[C:2](/[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])=[CH:3]/[CH2:4]O.P(Br)(Br)[Br:13]>C(OCC)C>[Br:13][CH2:4]/[CH:3]=[C:2](/[CH3:1])\[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10]
Reactant: CC(C)=CCC/C(C)=C\CO
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: CC(C)=CCC/C(C)=C\CBr
Reaction time: 0.5 h

Procedure:
A stirred solution of 51.4 grams of (Z)-3,7-dimethyl-2,6-octadien-1-ol in 400 milliliters of dry ethyl ether, protected from light, is treated with 29.8 grams of phosphorous tribromide, dropwise, over a 1/2 hour period. The mixture is refluxed for about 2.5 hours, then cooled, poured on ice water and extracted with ether. The ethereal extract is washed with sodium bicarbonate, then with water and dried over sodium sulfate. Solvent is removed under reduced pressure to yield (Z)-1-bromo-3,7-dimethyl-2,6-octadiene.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O>>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: COc1ccccc1B(O)O
Product: COc1ccc2c(-c3ccccc3OC)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 2-methoxy-phenylboronic acid to give [1-(2-methoxy-phenyl)-6-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 361(MH+).
Reaction SMILES: [CH2:1]([C@:3]12[CH2:27][CH2:26][C@:25]([C:29]([F:32])([F:31])[F:30])([OH:28])[CH2:24][C@@H:4]1[CH2:5][CH2:6][CH2:7][C:8]1[C:9]2=[CH:10][C:11]2[CH:12]=[N:13][N:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:15]=2[CH:16]=1)[CH3:2].[H-].[Na+].Br[CH2:36][C:37]([O:39]CC1C=CC=CC=1)=[O:38].[OH-].[Li+]>C(O)(=O)C.O.C1COCC1>[CH2:1]([C@:3]12[CH2:27][CH2:26][C@@:25]([O:28][CH2:36][C:37]([OH:39])=[O:38])([C:29]([F:32])([F:31])[F:30])[CH2:24][C@@H:4]1[CH2:5][CH2:6][CH2:7][C:8]1[C:9]2=[CH:10][C:11]2[CH:12]=[N:13][N:14]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[C:15]=2[CH:16]=1)[CH3:2]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CC[C@]12CC[C@@](O)(C(F)(F)F)C[C@@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Agent: [H-]
Agent: [Li+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC[C@]12CC[C@@](OCC(=O)O)(C(F)(F)F)C[C@@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Temperature: 25 °C
Yield: 10.8 %

Procedure:
A flask with stir bar and nitrogen line was charged with (3S,4aS,12bS)-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-ol (11, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.15 g, 0.336 mmol), THF (3 mL) and sodium hydride (60 wt % in oil, 0.027 g, 0.672 mmol) then warmed to about 65° C. for about 15 min. The mixture was cooled to rt then benzyl 2-bromoacetate (0.096 g, 0.420 mmol) was added and the mixture was stirred for about 20 min. Benzyl 2-bromoacetate (0.096 g, 0.420 mmol) was added to the mixture then after about 20 min sodium hydride (60 wt % in oil, 0.027 g, 0.672 mmol) and another portion of benzyl 2-bromoacetate (385 mg, 1.68 mmol). The mixture was transferred to a microwave vial then it was heated in a microwave at about 130° C. for about 20 min. Water (1 mL) and lithium hydroxide (200 mg, 8.33 mmol) were added then the mixture was heated in microwave at about 130° C. for about 20 min. Acetic acid (1.5 mL) was added then the reaction mixture was purified without further manipulation in one portion by preparative reverse phase HPLC using a Hypersil HS C18 column (250 mm×21.2 mm, 8 μm particle size) with a gradient of 15-100% MeCN in 0.05 N aq. ammonium acetate pH 4.5 buffer. Product fractions were concentrated under reduced pressure then the material was suspended in water (˜3 mL), collected by filtration then dried to yield 2-(((3S,4aS,12bS)-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-yl)oxy)acetic acid (18.3 mg, 10.80%); LC/MS, method 2, Rt=2.60 min, MS m/z 505 (M+H)+. 1H NMR (400 MHz, DMSO) δ 12.72 (s, 1H), 8.26 (s, 1H), 7.83 (s, 1H), 7.82-7.78 (m, 2H), 7.57 (s, 1H), 7.43-7.37 (m, 2H), 4.21 (s, 2H), 3.27-3.20 (m, 1H), 2.96-2.91 (m, 1H), 2.31-2.09 (m, 3H), 2.08-1.98 (m, 2H), 1.89-1.76 (m, 4H), 1.70-1.61 (m, 3H), 1.40-1.29 (m, 1H), 0.44 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:25])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[NH:6][C:5]1=[O:24])[CH:2]=[CH2:3].I[C:27]1[CH:32]=[N:31][CH:30]=[CH:29][N:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(CCN(C)C)C>O1CCOCC1.[Cu]I>[CH2:1]([C@@:4]1([CH3:25])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C:27]2[CH:32]=[N:31][CH:30]=[CH:29][N:28]=2)[C:5]1=[O:24])[CH:2]=[CH2:3]
Reactant: Ic1cnccn1
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)NC1=O
Agent: [Cu]I
Agent: CN(C)CCN(C)C
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(c2cnccn2)C1=O
Temperature: 110 °C
Reaction time: 15 h

Procedure:
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one (Example 71, Step D) (100 mg, 0.27 mmol), 2-iodopyrazine (170 μL, 0.80 mmol) and cesium carbonate (220 mg, 0.67 mmol) were dissolved in 2.7 mL of 1,4-dioxane. The reaction vessel was flushed with argon, copper (I) iodide (5.1 mg, 27 μmol) and TMEDA (11 μL, 80 μmol) were added, and the reaction mixture was allowed to stir at 110° C. for 15 hours. The reaction mixture was cooled to room temperature, quenched with water and extracted (2×EtOAc). The combined organic layers were washed with sat. aq. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (0 to 50% EtOAc/hexanes) provided the title compound as a colorless solid.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][C:12]([O:17][C:18](=[O:24])NCCCC)([C:15]#[CH:16])[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:25]1CCOCC1>>[CH2:2]([N:9]1[CH2:10][CH2:11][C:12]2([O:17][C:18](=[O:24])[O:25][C:15]2=[CH2:16])[CH2:13][CH2:14]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C1COCCO1
Reactant: C#CC1(OC(=O)NCCCC)CCN(Cc2ccccc2)CC1
Agent: Cl
Product: C=C1OC(=O)OC12CCN(Cc1ccccc1)CC2
Reaction time: 8 h
Yield: 80.6 %

Procedure:
Dry gaseous hydrogen chloride is introduced at 20° to 50° C. during 2.5 to 3 hours into a solution containing 31.4 g of 1-benzyl-4-butylcarbamoyloxy-4-ethynylpiperidine in 157 ml of anhydrous dioxane. After standing overnight the reaction mixture is evaporated in a water bath of 40° to 50° C. temperature under reduced pressure. After adding 200 ml of water to the evaporation residue the base is liberated by sodium hydrogen carbonate. After filtration the solid precipitate is washed to chloride-free with water and dried. The crude product obtained is recrystallized from n-hexane under clarifying by activated carbon to give the title compound in 80.6% yield, m.p.: 65°-67° C.
Reaction SMILES: [CH3:1][C:2]([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[CH2:3].[S-:9][C:10]#[N:11].[Na+]>>[C:2]([N:11]=[C:10]=[S:9])([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:1])[CH3:3]
Reactant: C=C(C)CC(C)(C)C
Reactant: N#C[S-]
Agent: [Na+]
Product: CC(C)(C)CC(C)(C)N=C=S

Procedure:
The t-octylisothiocyanate was prepared from the reaction of diisobutylene and sodium thiocyanate as follows:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][N:17]3[CH:21]=[N:20][CH:19]=[N:18]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[C:25]([F:30])[CH:24]=1.Cl>CN(C=O)C.C(O)(C)C>[ClH:1].[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][N:17]4[CH:21]=[N:20][CH:19]=[N:18]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[C:25]([F:30])[CH:24]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: COc1cc2c(Cl)ccnc2cc1OCCn1cncn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ccnc2cc1OCCn1cncn1
Temperature: 150 °C
Yield: 20.2 %

Procedure:
A solution 2 4-chloro-6-methoxy-7-(2-([1,2,4]-triazol-1-yl)ethoxy)quinoline (203 mg, 0.66 mmol), (prepared as described for the starting material in Example 38), and 4-chloro-2-fluoroaniline (74 μl, 0.66 mmol) in DMF (10 ml) containing 5M hydrogen chloride in isopropanol (0.4 ml) was heated at 150° C. for 8 hours. The volatiles were removed by evaporation and the residue was partitioned between water and methylene chloride. The aqueous layer was adjusted to pH9 with I M sodium hydroxide. The organic layer was washed with brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was dissolved in methylene chloride/methanol and 2M ethereal hydrogen chloride (1 ml) was added. After removal of the volatiles by evaporation, the residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-([1,2,4]-triazol-1-yl)ethoxy)quinoline hydrochloride (60 mg, 17%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([S:7][CH2:8][CH2:9][CH2:10][C:11]#[N:12])=[CH:3][CH:2]=1>B.O1CCCC1>[N:1]1[CH:6]=[CH:5][C:4]([S:7][CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[CH:3][CH:2]=1
Reactant: N#CCCCSc1ccncc1
Agent: B
Solvent: C1CCOC1
Product: NCCCCSc1ccncc1
Reaction time: 72 h
Yield: 86 %

Procedure:
A solution of 14.35 g of 4-(4-pyridylthio)butanenitrile in 280 ml of 1 Molar borane in tetrahydrofuran was stirred over night at room temperature. The excess reagent was quenched by the careful addition of 100 ml of methanol. The reaction mixture was evaporated to dryness, diluted with 200 ml of methanol, evaporated, diluted with 100 ml of 6N hydrochloric acid and allowed to stand at room temperature for 72 hours. The resulting mixture was made strongly basic with 50% sodium hydroxide and was extracted with 4×150 ml of dichloromethane. The combined organic layers were dried over potassium carbonate, evaporated, and the residue was distilled to give 12.62 g (86%) of 4-(4-pyridylthio)butanamine, bp 180° C./0.1 mm.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([Cl:12])[C:9]([Cl:11])=[CH:10][C:4]=2[N:3]=1.Cl.[Cl:14][C:15]1[C:16]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[N:17][CH:18]=[CH:19][CH:20]=1.C(N(CC)C(C)C)(C)C>>[Cl:14][C:15]1[C:16]([N:21]2[CH2:22][CH2:23][N:24]([C:2]3[NH:6][C:5]4[CH:7]=[C:8]([Cl:12])[C:9]([Cl:11])=[CH:10][C:4]=4[N:3]=3)[CH2:25][CH2:26]2)=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: Clc1cccnc1N1CCNCC1
Reactant: Clc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cc2nc(N3CCN(c4ncccc4Cl)CC3)[nH]c2cc1Cl

Procedure:
The 2,5,6-trichloro-1H-benzoimidazole (0.110 g, 0.5 mmol, Example 25b), 1-(3-chloropyridin-2-yl)piperazine hydrochloride (0.234 g, 1 mmol, Example 3b) and N,N-diisopropylethylamine (0.35 mL, 2 mmol, Aldrich) were reacted under the conditions of Example 3c to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 382 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([CH2:24][N:25]2[CH2:29][CH2:28][CH:27]([O:30][CH3:31])[CH2:26]2)[CH2:20][CH2:19]1.[Cl:32][C:33]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[C:35]([Cl:48])[C:34]=1[OH:49].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C@H:18]2[CH2:19][CH2:20][C@H:21]([CH2:24][N:25]4[CH2:29][CH2:28][CH:27]([O:30][CH3:31])[CH2:26]4)[CH2:22][CH2:23]2)=[CH:3][C:2]([C:37]2[CH:38]=[C:33]([Cl:32])[C:34]([OH:49])=[C:35]([Cl:48])[CH:36]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: COC1CCN(C[C@H]2CC[C@H](Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)CC2)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC1CCN(C[C@H]2CC[C@H](Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)cc34)CC2)C1
Temperature: 80 °C

Procedure:
To a suspension of (6-bromo-4-((trans-4-((3-methoxypyrrolidin-1-yl)methyl)cyclohexyl)amino)quinolin-3-yl)(cyclopropyl)methanone (49 mg, 0.10 mmol), 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (43 mg, 0.15 mmol) and Pd(dppf)Cl2 (11 mg, 0.015 mmol) in dioxane (4 mL) was added Cs2CO3 (1.0 M in H2O, 0.4 mL, 0.4 mmol). N2 gas was bubbled through the reaction mixture and the mixture was then heated at 80° C. for 2 h. The solution was allowed to cool to room temperature, then directly subjected to column chromatography (silica, 0-20% methanol/dichloromethane). The resultant residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated to afford the desired product (30.6 mg, 54%) as a yellow solid. 1H NMR (500 MHz, MeOD+TFA-d) δ 9.36 (br s, 1H), 8.47 (br s, 1H), 8.27 (dd, J=8.7, 1.8 Hz, 1H), 7.98 (d, J=8.7 Hz, 1H), 7.75-7.71 (s, 2H), 4.53-4.49 (br s, 1H), 4.19 (d, J=18.9 Hz, 1H), 3.85-3.74 (m, 2H), 3.35 (s, 3H), 3.28-3.26 (m, 1H), 3.25-3.12 (m, 3H), 2.84 (br s, 1H), 2.45-2.29 (m, 3H), 2.20-1.97 (m, 4H), 1.80-1.73 (m, 2H), 1.37-1.18 (m, 6H). ESI MS m/z 568 [C31H35Cl2N3O3+H]+; HPLC>99% (AUC), tR=11.42 min.