Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[O:12][CH3:13].[C-:14]#[N:15].[Na+]>CCO>[CH3:13][O:12][C:4]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=1[CH2:2][C:14]#[N:15]
Reactant: COc1ccc([N+](=O)[O-])cc1CBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Product: COc1ccc([N+](=O)[O-])cc1CC#N

Procedure:
2-Bromomethyl-1-methoxy-4-nitro-benzene (25 g) was dissolved in warm EtOH (45 mL) and stirred while slowly adding a solution of NaCN (6.0 g in 12 mL H2O) at 70° C. After the addition was complete, the reaction was stirred at 70° C. for 90 min. The inorganic solid, which separated on cooling, was collected and washed well with CH3CN. The CH3CN filtrate was filtered again giving further inorganic solid, and again washed with CH3CN. The final CH3CN filtrate was evaporated giving a red-brown solid. This solid was triturated with CH2Cl2 until the washings were colorless. Evaporation of the CH2Cl2 filtrate gave (2-methoxy-5-nitrophenyl)-acetonitrile as a red-brown solid, which was used without further purification.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:14][CH2:15]Br)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:18][C:19]1[CH:33]=[CH:32][C:22]2[C:23]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[N:24][O:25][C:21]=2[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.C1(C)C=CC=CC=1.O>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:14][CH2:15][N:29]3[CH2:28][CH2:27][CH:26]([C:23]4[C:22]5[CH:32]=[CH:33][C:19]([F:18])=[CH:20][C:21]=5[O:25][N:24]=4)[CH2:31][CH2:30]3)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(=O)N1CCc2c(sc(C)c2CCBr)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1CCc2c(sc(C)c2CCN2CCC(c3noc4cc(F)ccc34)CC2)C1
Temperature: 50 °C
Reaction time: 7 h

Procedure:
A mixture of 5.9 g of 6-acetyl-3-(2-bromoethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine, 5 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride, 6.7 g of potassium carbonate and 3.2 g of potassium iodide in 50 ml of dimethylformamide and 50 ml of toluene was stirred at 50° C. for 7 hours and poured into water. The toluene layer was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on a silica gel and crystallized from isopropyl ether. The resulting crystals were recrystallized from acetonitrile to give 6-acetyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine, m.p. 70°-75° C.
Reaction SMILES: O[CH2:2][CH:3]1[O:7][C:6]2[CH:8]=[CH:9][C:10]([C:13](=[O:15])[CH3:14])=[C:11]([OH:12])[C:5]=2[CH:4]1[CH2:16][CH2:17][CH3:18].[SH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:33])[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:22][CH:21]=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[O:33]=[C:26]([C:23]1[CH:22]=[CH:21][C:20]([S:19][CH2:2][CH:3]2[O:7][C:6]3[CH:8]=[CH:9][C:10]([C:13](=[O:15])[CH3:14])=[C:11]([OH:12])[C:5]=3[CH:4]2[CH2:16][CH2:17][CH3:18])=[CH:25][CH:24]=1)[CH2:27][CH2:28][C:29](=[O:30])[O:31][CH3:32]
Reactant: COC(=O)CCC(=O)c1ccc(S)cc1
Reactant: CCCC1c2c(ccc(C(C)=O)c2O)OC1CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Product: CCCC1c2c(ccc(C(C)=O)c2O)OC1CSc1ccc(C(=O)CCC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound of Example 15 (1.4 g, 5.59 mmoles, 1 equivalent) and methyl 4-mercapto-γ-oxobenzenebutanoate (1.4 g) was taken up in 30 ml THF. This mixture was added dropwise to a 0° solution of 1.2 equivalent DEAD, (1.1 ml) and 1.2 equivalent (1.76 g) in 40 ml THF. The reaction mixture was stirred cold 30 minutes, then warmed to room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, purified on a column of silica gel using 10/1 toluene/ethyl acetate to afford the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](OS(C2C=CC(C)=CC=2)(=O)=O)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:29][CH2:30][C:31]#[CH:32]>CCCCCCC.C(Cl)Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:32]#[C:31][CH2:30][CH2:29][CH2:28][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#CCCCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Oc2nn(Cc3ccccc3)c3ccccc23)cc1
Solvent: CCCCCCC
Solvent: ClCCl
Product: C(#Cc1nn(Cc2ccccc2)c2ccccc12)CCCc1ccccc1

Procedure:
This product was prepared from toluene-4-sulfonic acid 1-benzyl-1H-indazol-3-yl ester and pent-4-ynyl-benzene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/DCM 1:1; yield (87.5 mg, 50%); δH (CDCl3): 7.92 (d, J=8.11 Hz, 1H), 7.4-7.19 (m, 8H), 7.15-7.08 (m, 5H), 5.5 (s, 2H), 2.76 (t, J=7.16 Hz, 2H), 2.4 (t, J=7.15 Hz, 2H), 1.91 (p, J=7.21 Hz, 2H); LCMS m/z: 350.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+].[N+:15]([C:18]1[CH:19]=[N:20][C:21]2[C:26]([C:27]=1[NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:25][CH:24]=[CH:23][CH:22]=2)([O-])=O.ClCCl>O.[Br-].[Br-].C([N+]1C=CC(C2C=C[N+](CCCCCCCC)=CC=2)=CC=1)CCCCCCC>[NH2:15][C:18]1[CH:19]=[N:20][C:21]2[C:26]([C:27]=1[NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:25][CH:24]=[CH:23][CH:22]=2
Reactant: CCOC(=O)CCCCCNc1c([N+](=O)[O-])cnc2ccccc12
Agent: CCCCCCCC[n+]1ccc(-c2cc[n+](CCCCCCCC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CCCCCNc1c(N)cnc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
A solution of sodium hydrosulfite (73.55 g, 422.4 mmol) and potassium carbonate (65.9 g, 476 mmol) in water (200 mL) was stirred for 15 minutes. A mixture of ethyl 6-(3-nitroquinolin-4-ylamino)hexanoate (40.0 g, 121 mmol, prepared as described in Parts A and B of Example 6), 1,1′-di-n-octyl-4,4′-bipyridinium dibromide (0.65 g, 1.2 mmol), dichloromethane (200 mL), and water (40 mL) was added over a period of five minutes, and the reaction was stirred overnight at ambient temperature. Water (100 mL) was added; the organic layer was separated and washed with water (3×150 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide 25.15 g of ethyl 6-[(3-aminoquinolin-4-yl)amino]hexanoate. The product was mixed with material from another run.
Reaction SMILES: [CH3:1][C:2]([OH:12])([CH2:5][CH2:6][C:7]([CH3:11])=[C:8]([CH3:10])[CH3:9])[C:3]#[CH:4].[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[CH3:1][C:2]([OH:12])([CH2:5][CH2:6][C:7]([CH3:11])=[C:8]([CH3:10])[CH3:9])[CH2:3][CH3:4]
Reactant: C#CC(C)(O)CCC(C)=C(C)C
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Product: CCC(C)(O)CCC(C)=C(C)C
Temperature: 45 °C

Procedure:
383.0 g of 3,6,7-trimethyl-6-octen-1-in-3-ol and 0.3 g of Lindlar catalyst (5% Pd+3.5% Pb on CaCO3) are put in an autoclave and heated under nitrogen to a temperature of 45° C. Nitrogen is exchanged by hydrogen (H2) and the reaction mixture put at an absolute pressure of 2 bar. After the calculated amount of hydrogen has been consumed the reaction mixture is filtered and distilled (2 mbar, 115° C.) to obtain 3,6,7-trimethyl-6-octen-3-ol (=compound of formula (Ia)).
Reaction SMILES: CC1C=CC(S(OCC2CC3C=CC=C(C4C=CC=CC=4)C=3O2)(=O)=O)=CC=1.[N-]=[N+]=[N-].[Na+].[C:32]1([C:38]2[C:46]3[O:45][CH:44]([CH2:47][N:48]=[N+]=[N-])[CH2:43][C:42]=3[CH:41]=[CH:40][CH:39]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[N-]=[N+]=[N-]>[Pd]>[C:32]1([C:38]2[C:46]3[O:45][CH:44]([CH2:47][NH2:48])[CH2:43][C:42]=3[CH:41]=[CH:40][CH:39]=2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: [N-]=[N+]=NCC1Cc2cccc(-c3ccccc3)c2O1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccccc4)c3O2)cc1
Agent: [N-]=[N+]=[N-]
Product: NCC1Cc2cccc(-c3ccccc3)c2O1
Yield: 65 %

Procedure:
Treatment of (±)-(7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.40 g, 1.06 mmol) with sodium azide (0.17 g, 2.65 mmol) generally according to the procedure described for Intermediate 98 provided (±)-(7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl azide. Treatment of the azide with palladium on carbon (0.025 g, 10 wt. %) generally according to the procedure described for Example 1 afforded 0.181 g (65%) of (±)-1-(7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine as a white solid, hydrochloride salt. mp >200° C. (dec); Anal. calcd. for C15H15NOHCl.0.2H2O: C, 67.90; H, 6.23; N, 5.2 Found: C, 67.69; H, 6.16; N, 5.3.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16](O)=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.F[B-](F)(F)F.N1(O[C+](N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.[NH2:53][CH:54]([C:57]1[CH:58]=[N:59][CH:60]=[CH:61][CH:62]=1)[CH2:55][OH:56]>CN(C=O)C.O>[F:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:2]([F:1])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:53][CH:54]([C:57]3[CH:58]=[N:59][CH:60]=[CH:61][CH:62]=3)[CH2:55][OH:56])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)O
Reactant: NC(CO)c1cccnc1
Agent: CN(C)[C+](On1nnc2ccccc21)N(C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(CO)c1cccnc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
150 mg (0.47 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid, 227 mg (0.71 mmol) of (benzotriazol-1-yloxy)bisdimethylaminomethylium fluoroborate (TBTU) and 238 mg (2.36 mmol) of 4-methylmorpholine were initially charged in 3 ml of DMF. After 10 min at RT, 98 mg (0.71 mmol) of 2-amino-2-(pyridin-3-yl)ethanol were added and the mixture was stirred at room temperature overnight. About 25 ml of water were added to the reaction solution and the precipitate formed was stirred for another 30 min, filtered off, washed thoroughly with water and dried under high vacuum overnight. The crude product was purified by silica gel chromatography (mobile phase: dichloromethane:methanol gradient). The product fractions were concentrated and stirred with acetonitrile. The solid obtained was filtered off and dried. This gave 40 mg of the target compound (20% of theory, purity 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][CH:10]([CH3:18])[C:11]([O:16]C)=[CH:12][C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1.Cl(O)(=O)(=O)=O.[CH2:34](Cl)Cl>>[Cl:1][C:2]1[CH:24]=[C:23]([C:25]([F:27])([F:26])[F:28])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][CH:10]([CH3:18])[C:11](=[O:16])[CH2:12][C:13]([O:15][CH3:34])=[O:14])=[CH:7][CH:6]=1
Reactant: ClCCl
Reactant: COC(=CC(=O)O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1
Agent: [O-][Cl+3]([O-])([O-])O
Product: COC(=O)CC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of the methyl ester of 4-[4-(2-chloro-4-trifluoromethylphenoxy)phenoxy]-3-methoxy-2-pentenoic acid (0.5 g), 35% aqueous perchloric acid (5 ml.) and methylene dichloride (5 ml.) is stirred at RT for 4 days. Then the sollution is extracted with methylene dichloride. The residue is purified by prep. thin layer chromatography using 20% ethyl acetate/hexane to yield methyl 4-[4-(2-chloro-4-trifluoromethylphenoxy)phenoxy]-3-oxopentanoate.
Reaction SMILES: [CH3:1][N:2]([C:9]([C:11]1[C:12]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:13][O:14][C:15]=1[CH2:16][C:17]1[N:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH3:26])[N:18]=1)=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O:37]O)(C)(C)C>C(#N)C.[CH-]=O.[CH-]=O.[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Co].[Co+2]>[CH3:1][N:2]([C:9]([C:11]1[C:12]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:13][O:14][C:15]=1[C:16]([C:17]1[N:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH3:26])[N:18]=1)=[O:37])=[O:10])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1cc(OC)nc(Cc2onc(-c3ccccc3)c2C(=O)N(C)c2ccccc2)n1
Reactant: CC(C)(C)OO
Agent: [Co+2]
Agent: [Co]
Agent: [C-]#[O+]
Solvent: CC#N
Product: COc1cc(OC)nc(C(=O)c2onc(-c3ccccc3)c2C(=O)N(C)c2ccccc2)n1
Reaction time: 48 h

Procedure:
A solution of 100 mg of N-methyl 3-phenyl-5-(4,6-dimethoxy-2-pyrimidinylmethyl)-4-isoxazolecarboxanilide, 20 mg of dicobalt octacarbonyl, and 1 ml of t-butylhydroperoxide, in 60 ml of acetonitrile is refluxed for 48 hours. An additional 1 ml of t-butylhydroperoxide is added after 12 hrs and 24 hrs. Thin layer chromatography after 48 hrs indicates the presence of starting material and the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3[N:18]([CH3:19])[C:17]([CH3:20])=[N:16][CH:15]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:21][CH3:22])[C:3]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1.O1CCOCC1>[O-2].[O-2].[Mn+4].C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[N:18]([CH3:19])[C:17]([CH3:20])=[N:16][CH:15]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([O:21][CH3:22])[C:3]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:31])[F:33])=[CH:28][CH:29]=1
Reactant: COc1nc2ccc(C(O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COc1nc2ccc(C(=O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
To a flask containing (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)methanol (1.68 g, 3.53. mmol, Intermediate 60: step a) was added 1,4-dioxane (75 mL) and THF (10 mL) which produced a suspension at room temperature. Warming the suspension to 45° C. formed a homogeneous solution. Manganese dioxide (1.5 g, 17.25 mmol) was introduced and the mixture was heated to 80° C. After 60 minutes, the mixture was filtered through a Celite® pad, rinsing with THF. The filtrate was then concentrated to dryness. Tituration with Et2O provided the title compound as a white powder.
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][C:10]#[N:11])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[O:12]1[C:17]2[CH:18]=[CH:19][C:20]([CH:22]=O)=[CH:21][C:16]=2[O:15][CH2:14][CH2:13]1.N1CCCCC1.C(O)(=O)C>CC(O)C>[C:10]([CH2:9][CH2:8][O:7][C:1](=[O:6])[C:2](=[CH:22][C:20]1[CH:19]=[CH:18][C:17]2[O:12][CH2:13][CH2:14][O:15][C:16]=2[CH:21]=1)[C:3](=[O:4])[CH3:5])#[N:11]
Reactant: CC(=O)CC(=O)OCCC#N
Reactant: O=Cc1ccc2c(c1)OCCO2
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC(=O)C(=Cc1ccc2c(c1)OCCO2)C(=O)OCCC#N
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 2-cyanoethyl acetoacetate (5.00 g, 32.2 mmol), 1,4-benzodioxan-6-carboxaldehyde (5.29 g, 32.2 mmol), piperidine (137 mg, 1.61 mmol) and acetic acid (97 mg, 1.6 mmol) in 70 ml of 2-propanol was stirred at r.t. for 48 hrs. After evaporation of solvent, the product was purified by chromatography (SiO2, AcOEt: Hexane, 60:10). 2-[(3,4-Ethylenedioxyphenyl)methylene]-3-oxobutanoic acid 2-cyanoethyl ester was obtained as a yellowish oil (2.64 g, 27% yield).
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4]C=1.[CH3:26][C:27]1[C:28]2[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=2[S:30][C:31]=1[CH:32]=O>>[Cl:25][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[N:10]=[N:9][C:8]([C:1]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1)=[C:17]2[C:18]1[CH:19]=[C:20]([NH:24][CH2:32][C:31]2[S:30][C:29]3[CH:34]=[CH:35][CH:36]=[CH:37][C:28]=3[C:27]=2[CH3:26])[CH:21]=[CH:22][CH:23]=1
Reactant: Cc1c(C=O)sc2ccccc12
Reactant: Nc1cccc(-c2c(Cc3ccccc3)nnc3c(Cl)cccc23)c1
Product: Cc1c(CNc2cccc(-c3c(-c4ccccc4)nnc4c(Cl)cccc34)c2)sc2ccccc12

Procedure:
The title compound was prepared from [3-(3-benzyl-8-chlorocinnolin-4-yl)phenyl]amine and 3-methyl-benzo[b]thiophene-2-carbaldehyde according to the procedure of Step 5 Example 6. MS (ES) m/z 492.2.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C@H:11]2[CH2:16][CH2:15][C@H:14]([CH:17]=[CH2:18])[CH2:13][CH2:12]2)[CH:8]=[C:7]([F:19])[C:3]=1[C:4](O)=O.ClCCCl.S(Cl)(Cl)=O.[N:28]1C=CC=CC=1>>[F:1][C:2]1[CH:10]=[C:9]([C@H:11]2[CH2:16][CH2:15][C@H:14]([CH:17]=[CH2:18])[CH2:13][CH2:12]2)[CH:8]=[C:7]([F:19])[C:3]=1[C:4]#[N:28]
Reactant: C=C[C@H]1CC[C@H](c2cc(F)c(C(=O)O)c(F)c2)CC1
Reactant: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Product: C=C[C@H]1CC[C@H](c2cc(F)c(C#N)c(F)c2)CC1
Temperature: 25 °C

Procedure:
To 20 g of 2,6-difluoro-4-(trans-4-vinylcyclohexyl) benzoic acid were then added 120 ml of 1,2-dichloroethane, 16 g of thionyl chloride and few drops of pyridine. The reaction mixture was then heated under reflux for 6 hours. The reaction mixture was then allowed to cool to room temperature. The solvents and excess thionyl chloride were distilled off under reduced pressure. To the residue was then added 150 ml of dichloromethane. The residue solution was then cooled to a temperature of 10° C. or lower. Ammonia was then introduced into the solution with stirring at a rate such that the liquid temperature was kept at 20° C. or lower. When heat generation was terminated, the solvents were then distilled off under reduced pressure. To the residue was then added 150 ml of N,N-dimethylformamide. The residue solution was then cooled to a temperature of 10° C. or lower. To the solution was then added dropwise 26.5 g of phosphorus oxychloride at a rate such that the liquid temperature was kept at 10° C. or lower. The temperature of the reaction solution was then returned to room temperature. The solution was then poured onto crushed ice. The resulting crystal was then filtered. The crystal thus obtained was washed with water, and then dried under reduced pressure. The crystal was then purified through silica gel column chromatography (solvent: toluene) to obtain 2,6-difluoro-4-(trans-4-vinylcyclohexyl)benzonitrile. The product was then recrystallized from ethanol to obtain 12.1 g of a purified product. The compound thus obtained had a melting point of 39° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9](S(C)(=O)=O)[N:8]=[C:7]([Cl:15])[N:6]=1)=[O:4].[NH3:16]>O1CCOCC1.CO>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([NH2:16])[N:8]=[C:7]([Cl:15])[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(S(C)(=O)=O)nc(Cl)n1
Reactant: N
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1cc(N)nc(Cl)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
2-Chloro-6-methanesulfonylpyrimidine-4-carboxylic acid methyl ester (3.7 g, 14.75 mmol) was dissolved in dioxane and 7N ammonia in methanol was added. The reaction mixture was stirred at room temperature for 3 hours, concentrated under vacuum, and the residue partitioned between ethyl acetate and water. The organic phase was dried and concentrated. The product was purified by column chromatography to provide 6-amino-2-chloropyrimidine-4-carboxylic acid methyl ester (2.35 g, 85% yield): 1H NMR (DMSO-d6): δ 7.6 (br s, 1H), 7.00 (s, 1H), 3.84 (s, 3H), 3.33 (s, 3H).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:34][O:35][C:36]([C:38]1[O:39][C:40]([CH3:45])=[C:41]([CH2:43]O)[CH:42]=1)=[O:37].[Br:46][C:47]1[CH:52]=[CH:51][C:50]([SH:53])=[CH:49][CH:48]=1>O1CCCC1>[CH3:34][O:35][C:36]([C:38]1[O:39][C:40]([CH3:45])=[C:41]([CH2:43][S:53][C:50]2[CH:51]=[CH:52][C:47]([Br:46])=[CH:48][CH:49]=2)[CH:42]=1)=[O:37]
Reactant: COC(=O)c1cc(CO)c(C)o1
Reactant: Sc1ccc(Br)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(CSc2ccc(Br)cc2)c(C)o1

Procedure:
Diisopropylazodicarboxylate (1.27 g, 6.3 mmoles) was added to a solution of triphenylphosphine (1.65 g, 6.3 mmoles) in tetrahydrofuran (15 ml) with stirring and cooling in an ice/water bath. A solution of 4-hydroxymethyl-5-methyl-furan-2-carboxylic acid methyl ester (16) (536 mg, 3.15 mmoles) and 4-bromo-thiophenol (584 mg, 3.09 mmoles) in tetrahydrofuran (5 ml) was added and the mixture stirred for 30 minutes at 0° C. then 72 hours at room temperature. The solvent was evaporated and the residue extracted with heptane then diethyl ether. The extracts were combined and evaporated to give a yellow oil which was purified by flash chromatography using heptane/ethyl acetate 9:1 v/v as eluent. This gave compound 150 (600 mg) as a white solid. LC/MS System A; Rt=4.12 mins.
Reaction SMILES: [N:1]([CH:4]([C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)[CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=2[C:8]2[CH2:16][N:17]([CH3:20])[CH2:18][CH2:19][C:7]1=2)=[N+]=[N-].[Cl-].[NH4+]>CCO.O.[Zn]>[CH3:20][N:17]1[CH2:18][CH2:19][C:7]2[N:6]([CH2:5][CH:4]([C:21]3[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=3)[NH2:1])[C:14]3[CH:13]=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=3[C:8]=2[CH2:16]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(N=[N+]=[N-])c2ccncc2)CCN(C)C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CC(N)c2ccncc2)CCN(C)C1
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 54 %

Procedure:
To a solution of 5-(2-azido-2-(pyridin-4-yl)ethyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (2.4 g, 6.93 mmol) in EtOH-water (25-2.5 mL) were added zinc dust (1.8 g, 27.7 mmol) and ammonium chloride (1.5 g, 27.74 mmol) and the reaction mixture stirred at 80° C. for 45 min. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was basified with aq. ammonia and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and evaporated to yield 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(pyridin-4-yl)ethanamine (1.2 g). 1H NMR (CDCl3, freebase) δ (ppm): 8.56 (d, 2H), 7.28 (d, 2H), 7.21 (m, 2H), 7.00 (d, 1H), 4.48 (t, 1H), 4.08 (m, 2H), 3.65 (q, 2H), 2.83 (m, 2H), 2.72 (m, 1H), 2.56 (m, 1H), 2.53 (s, 3H), 2.44 (s, 3H). Separation by chiral HPLC provided enantiomers 27a and 27b.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[H-].[Na+].Br[CH2:22][CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O>[Si:25]([O:24][CH2:23][CH2:22][O:1][CH2:2][C@@H:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](COCCO[Si](C)(C)C(C)(C)C)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 15.2 %

Procedure:
To a 0° C. solution of (S)-tert-butyl (1-hydroxy-3-phenylpropan-2-yl)carbamate (Alfa Aesar, 500 mg, 1.99 mmol) in DMF (13.0 mL) was added NaH (60% in mineral oil, 119 mg, 2.98 mmol). The resulting reaction mixture was stirred at 0° C. for 15 min and then (2-bromoethoxy)(tert-butyl)dimethylsilane (512 μL, 2.39 mmol) was added. The reaction mixture was stirred at 0° C. for 2 h and then at room temperature for 3 h. The mixture was poured into a separatory funnel containing EtOAc and sat. aq. NH4Cl. The aqueous layer was extracted with EtOAc (3×), and the combined organics were washed with sat. NaCl, dried over Na2SO4, filtered and concentrated in vacuo. The crude oil was purified using flash chromatography (40 g column, gradient from 0% to 40% EtOAc/hexanes over 14 min) to give the title compound (124 mg, 15%) as a colorless oil. MS (ESI+) m/z 310.1 (M+H−Boc)+.