Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([C:28]1[CH:33]=[CH:32][C:31]([CH:34]2[CH2:39][CH2:38][CH:37]([CH:40]3[CH2:45][CH2:44][CH:43]([CH:46]=O)[CH2:42][CH2:41]3)[CH2:36][CH2:35]2)=[CH:30][CH:29]=1)[CH2:26][CH3:27]>ClCCl>[Br:2][C:1]([Br:5])=[CH:46][CH:43]1[CH2:42][CH2:41][CH:40]([CH:37]2[CH2:38][CH2:39][CH:34]([C:31]3[CH:30]=[CH:29][C:28]([CH2:25][CH2:26][CH3:27])=[CH:33][CH:32]=3)[CH2:35][CH2:36]2)[CH2:45][CH2:44]1
Reactant: CCCc1ccc(C2CCC(C3CCC(C=O)CC3)CC2)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCc1ccc(C2CCC(C3CCC(C=C(Br)Br)CC3)CC2)cc1
Reaction time: 0.5 h

Procedure:
34.0 g (0.10 mol) of carbon tetrabromide are initially introduced in 120 ml of dichloromethane, and 53.7 g (0.21 mol) of triphenylphosphine are added in portions. When the addition is complete, the mixture is stirred for 30 min, and a suspension of 16.0 g (51.2 mmol) of 4′-(4-propylphenyl)bicyclohexyl-4-carbaldehyde in 45 ml of dichloromethane is slowly added. The mixture is stirred for 22 h, and the precipitate is filtered off. The filtrate is concentrated to completion, and the residue is purified by column chromatography (SiO2, n-heptane). 4-(2,2-Dibromovinyl)-4′-(4-propylphenyl)bicyclohexyl is obtained as a colourless solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)=[N:8][C:9]([NH2:14])=[N:10][C:11]=1[S:12][CH3:13])=[CH2:5])C.Cl>C1COCC1>[NH2:14][C:9]1[N:8]=[C:7]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[C:6]([C:4](=[O:3])[CH3:5])=[C:11]([S:12][CH3:13])[N:10]=1
Reactant: C=C(OCC)c1c(SC)nc(N)nc1-c1ccco1
Agent: Cl
Solvent: C1CCOC1
Product: CSc1nc(N)nc(-c2ccco2)c1C(C)=O
Reaction time: 43 h
Yield: 33.2 %

Procedure:
To a stirred solution of 670 mg (2,42 mmol) 5-(1-ethoxy-vinyl)-4-furan-2-yl-6-methylsulfanyl-pyrimidin-2-ylamine in 18 ml THF was added 2.00 ml (2.00 mmol) 1M hydrochloric acid and stirring continued for 43 hours at room temperature. The reaction mixture was partitioned between ethyl acetate and sodium bicarbonate solution and the layers separated. The organic phase was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was triturated in ethyl acetate/ether to afford 200 mg (33%) 1-(2-amino-4-furan-2-yl-6-methylsulfanyl-pyrimidin-5-yl)-ethanone as a light brown crystalline solid. EI-MS m/e (%): 249 (M+, 14), 234 (38), 221 (100), 206 (20), 43 (30).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[N:24]=1.[C:25](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:25])[C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[N:24]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1Nc2cnc(Cl)nc2N(CCCc2ccccc2)CC1(F)F
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)C(F)(F)CN(CCCc2ccccc2)c2nc(Cl)ncc21
Reaction time: 4 h
Yield: 95.4 %

Procedure:
To a solution of 1.0 g (0.0028 mole) of 2-chloro-7,7-difluoro-9-(3-phenyl-propyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-281) in 20 mL of dimethylformamide was added 1.4 g (0.0042 mole) of cesium carbonate, followed by 0.53 mL (0.0084 mole) of iodomethane. After stirring four hours, the mixture filtered and then concentrated under reduced pressure. Ice water and dichloromethane were added. The mixture was extracted with dichloromethane twice. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 0.98 g of 2-chloro-7,7-difluoro-5-methyl-9-(3-phenyl-propyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-281) as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]2[CH:20]=[C:19]([N:21]=[N+]=[N-])[N:18]=[CH:17][N:16]=2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][C:15]2[CH:20]=[C:19]([NH2:21])[N:18]=[CH:17][N:16]=2)=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cc2cc(N=[N+]=[N-])ncn2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(Cc2cc(N)ncn2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A suspension of [4-(6-azido-pyrimidin-4-ylmethyl)-phenyl]-carbamic acid tert-butyl ester (870 mg, 2.66 mmol) and 10% Pd/C (174 mg) in MeOH (35 mL) is stirred for 1.5 h at rt and a hydrogen atmosphere. The reaction mixture is filtered through a plug of celite (washing the filter cake with copious amounts of MeOH). The filtrate is concentrated in vacuo to afford the title compound as a beige solid: ES-MS: 301.1 [M+H]+; single peak at tR=6.25 min (System 2).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7](Br)[S:8][C:9]=1[C:10]1[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=1)=[O:4].[CH3:18][NH:19][CH3:20]>>[CH3:18][N:19]([CH3:20])[C:7]1[S:8][C:9]([C:10]2[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=2)=[C:5]([C:3]([OH:2])=[O:4])[N:6]=1
Reactant: COC(=O)c1nc(Br)sc1-c1cccc(C)c1
Reactant: CNC
Product: Cc1cccc(-c2sc(N(C)C)nc2C(=O)O)c1

Procedure:
prepared by reaction of 2-bromo-5-m-tolyl-thiazole-4-carboxylic acid methyl ester with dimethylamine. LC-MS: tR=0.85 min; [M+H]+=263.1.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2([C:25]#[N:26])[CH2:24][CH2:23][C:18]3(OCC[O:19]3)[CH2:17][CH2:16]2)=[N:13][CH:14]=1>>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2([C:25]#[N:26])[CH2:16][CH2:17][C:18](=[O:19])[CH2:23][CH2:24]2)=[N:13][CH:14]=1
Reactant: N#CC1(c2ccc(Br)cn2)CCC2(CC1)OCCO2
Solvent: O=C(O)C(F)(F)F
Product: N#CC1(c2ccc(Br)cn2)CCC(=O)CC1
Reaction time: 22 h
Yield: 94.7 %

Procedure:
Trifluoroacetic acid (4.1 ml) was added to 8-(5-bromopyridin-2-yl)-1,4-dioxaspiro[4,5]decane-8-carbonitrile (3.4 g) described in Reference Example 82 at room temperature, and stirred at the same temperature for 22 hours. After completion of the reaction, the solvent and trifluoroacetic acid were evaporated and the resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 1-(5-bromopyridin-2-yl)-4-oxocyclohexanecarbonitrile (2.78 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)Cl)=[CH:5][CH:4]=1.[C:21]([NH:24][CH2:25][C:26](=[S:28])[NH2:27])(=[O:23])[CH3:22]>C(O)C>[C:21]([NH:24][CH2:25][C:26]1[S:28][C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:27]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)NCC(N)=S
Reactant: COc1ccc(C(=O)C(Cl)c2ccc(OC)cc2)cc1
Solvent: CCO
Product: COc1ccc(-c2nc(CNC(C)=O)sc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Yield: 33.2 %

Procedure:
A mixture of 1,2-bis(4-methoxyphenyl)-2-chloroethanone (5.99 g) and 2-(acetylamino)ethanethioamide (3.00 g) in ethanol (30 ml) was refluxed for 2 hours. After allowing to cool to room temperature, the solvent was evaporated in vacuo, and the residue was dissolved in chloroform (200 ml) and aqueous solution of sodium hydrogencarbonate (200 ml). The separated organic layer was washed with water and brine, dried over magnesium sulfate and treated with activated charcoal. After filtration, the filtrate was evaporated in vacuo. The resulting residue was dissolved in diethyl ether, added ethanol solution of hydrogen chloride, and the resulting precipitate was collected by filtration. The resulting crude compound was recrystallized with ethanol (10 ml). And the resulting crystal was collected by filtration, washed with ethanol and diethyl ether, and dried to give 2-acetylaminomethyl-4,5-bis(4-methoxyphenyl)thiazole (2.52 g).
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:9](SC)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:27][NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CO>ClCCl>[C:21]([O:20][C:18]([N:10]1[C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[C:9]1[N:28]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:27])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CNCc1ccccc1
Reactant: CSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CO
Product: CN(Cc1ccccc1)C1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1C(=O)OC(C)(C)C
Temperature: 95 °C
Yield: 22.9 %

Procedure:
A mixture of intermediate 59 (0.4 g, 0.00109 mol), N-methylbenzylamine (0.42 mL, 0.00326 mol) and MeOH (0.1 mL) is heated at 95° C. for 2 days. The reaction mixture is cooled to RT, dichloromethane is added and the mixture is purified by chromatography on silica gel; gradient elution with heptane:EtOAc (80:20-75:25) gives 110 mg of the product 81. 1H NMR (CDCl3) δ 7.50-7.20 (m, 6H), 7.10-6.90 (m, 7H), 6.90-6.75 (m, 2H), 5.52 (q, 2H), 4.84 (d, 1H), 4.52 (d, 1H), 2.97 (s, 3H), 1.45 (s, 9H); MS: m/z 442 (M++1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]2[O:9][C:8](S)=[N:7][C:6]=2[CH:11]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>[N+](C)([O-])=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]2[O:9][C:8]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:7][C:6]=2[CH:11]=1
Reactant: C1CNCCN1
Reactant: Cc1cc(C)c2oc(S)nc2c1
Solvent: C[N+](=O)[O-]
Product: Cc1cc(C)c2oc(N3CCNCC3)nc2c1

Procedure:
A 50 mg portion of 5,7-dimethyl-2-mercaptobenzoxazole was dissolved in 5 ml of nitromethane, and the solution was mixed with 240 mg of piperazine and heated under reflux for 12 hours. The solvent was concentrated under a reduced pressure, and the residual oily matter was mixed with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate, and then the solvent was evaporated under a reduced pressure. Thereafter, the thus obtained mixture was purified by a silica gel column chromatography (chloroform:methanol=20:1) to obtain the title compound (35 mg) in white color.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[NH:22]1[CH:26]=[N:25][C:24]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)=[N:23]1>>[N:30]1[CH:29]=[CH:28][C:27]([C:24]2[N:25]=[CH:26][N:22]([C:2]3[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]4[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=4)[N:3]=3)[N:23]=2)=[CH:32][CH:31]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1
Reactant: c1cc(-c2nc[nH]n2)ccn1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-n3cnc(-c4ccncc4)n3)n2)cc1

Procedure:
The title compound was prepared from 2-chloro-4-trifluoromethyl-6-(4-trifluoromethylphenyl)-pyrimidine (example A.2) (0.16 g, 0.5 mmol) and 4-(1H-[1,2,4]-triazol-3-yl)-pyridine [CAS-No. 14803-99-7] (0.075 g, 0.51 mmol) according to the general procedure IVa. Obtained as a white solid (0.096 g, 44%). MS (ISP) 437.3 [(M+H)+]; mp 248° C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:11]([CH3:12])=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[CH3:13].[Cl:14][C:15]1[N:16]=[C:17](Cl)[C:18]2[N:23]([CH3:24])[CH:22]=[CH:21][C:19]=2[N:20]=1>CN1C(=O)CCC1.O>[Cl:14][C:15]1[N:16]=[C:17]([O:3][C:4]2[C:5]([CH3:13])=[CH:6][C:7]([C:8]#[N:9])=[CH:10][C:11]=2[CH3:12])[C:18]2[N:23]([CH3:24])[CH:22]=[CH:21][C:19]=2[N:20]=1
Reactant: Cc1cc(C#N)cc(C)c1O
Reactant: Cn1ccc2nc(Cl)nc(Cl)c21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc(C#N)cc(C)c1Oc1nc(Cl)nc2ccn(C)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
To a stirred solution of NaH (42.1 mg, 1.05 mmol) in dry NMP (2.5 mL) was added 4-hydroxy-3,5-dimethylbenzonitrile (154.7 mg, 1.05 mmol) and stirred at room temperature for 30 min under argon. The reaction mixture was added to a solution of 2,4-dichloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (211.3 mg, 1.05 mmol) in dry NMP (2.7 mL) and heated at 160° C. for 16 h. After completion of the reaction, the resulting mixture was diluted with water and washed with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (3:1-1:1), to give the product as a light yellow solid (294 mg, 85%).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:15][N:16]=[C:17]([C:23](=[O:30])[CH:24]([S:26][CH2:27][CH2:28]O)C)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:13]=[CH2:14]>C1(C)C=CC=CC=1>[O:30]1[C:23]([C:17](=[N:16][O:15][CH2:12][CH:13]=[CH2:14])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:24][S:26][CH2:27][CH2:28]1
Reactant: C=CCON=C(C(=O)OCC)C(=O)C(C)SCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C=CCON=C(C(=O)OCC)C1=CSCCO1
Yield: 76.4 %

Procedure:
p-Toluenesulfonic acid (0.40 g.) was added to a solution of ethyl 2-allyloxyimino-4-(2-hydroxyethylthio)-3-oxovalerate (4.30 g.) in toluene (43 ml.), and refluxed under heating for 20 minutes while removing the produced water. After cooling, ethyl acetate (10 ml.) was added to the resultant solution and washed with water (40 ml.) twice. The solution was dried over magnesium sulfate and concentrated in vacuo to give oily residue (3.3 g.). The residue was subjected to column chromatography on silica gel and eluted with chloroform. The eluate was concentrated in vacuo to give ethyl 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-allyloxyiminoacetate (2.92 g.).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([OH:8])[CH2:5][O:6][CH3:7].I[CH2:10][C:11]([O-:13])=[O:12].[Na+].[H-].[Na+].O>O1CCCC1>[CH3:1][O:2][CH2:3][CH:4]([O:8][CH2:10][C:11]([OH:13])=[O:12])[CH2:5][O:6][CH3:7]
Reactant: COCC(O)COC
Reactant: O=C([O-])CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCC(COC)OCC(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38.6 %

Procedure:
A solution of 1,3-dimethoxy-2-propanol (361.5 mg, Tyger) in tetrahydrofuran (4 ml) was added with sodium iodoacetate (624.6 mg, Spectrum), and successively added with sodium hydride (198 mg, Wako Pure Chemical Industries) as several portions at 0° C., and the mixture was stirred at the same temperature for 30 minutes, and then further stirred at room temperature for 15.5 hours. The reaction mixture was cooled again to 0° C., and then carefully added with water and then with chloroform, and the organic layer was separated. The aqueous layer was acidified (pH 4) with 1 N hydrochloric acid, and extracted three times with chloroform, and the combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure to obtain the title compound (206.5 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].[Br:19]N1C(=O)CCC1=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:19][C:15]1[CH:16]=[CH:17][C:12]([NH:11][CH2:10][C:4]2[CH:5]=[N:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)=[N:13][C:14]=1[F:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ncc(CNc2cccc(F)n2)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ncc(CNc2ccc(Br)c(F)n2)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.2 %

Procedure:
To (5-fluoro-6-methoxy-pyridin-3-ylmethyl)-(6-fluoro-pyridin-2-yl)-amine (58, 3.21 g, 12.8 mmol) in 100 mL of acetonitrile, N-bromosuccinimide (2.30 g, 12.9 mmol) in 30 mL of acetonitrile was added slowly at room temperature. The reaction was stirred at room temperature for 4 hours, then poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with 20% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (59, 3.60 g).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.[H-].[Na+].[CH2:17](Br)[CH:18]([CH3:20])[CH3:19]>CN(C=O)C>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:4]=2[CH:3]=1
Reactant: CC(C)CBr
Reactant: Brc1ccc2c(c1)[nH]c1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Cn1c2ccccc2c2ccc(Br)cc21
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 88.4 %

Procedure:
2-bromo-9H-carbazole (4.1 g, 16.74 mmol) was dissolved in DMF. To the stirred solution was slowly added NaH (1.8 g, 75.5 mmol) in 3 portions. Isobutylbromide (4.8 mL, 43.2 mmol) was added to the stirred slurry and after waiting for 20 minute, warmed up to 60° C. for 4 h. Reaction mixture was cooled to room temperature and carefully quenched with drop wise addition of saturated NH4Cl solution. Content was then partitioned in brine and ethylacetate. Organic layer was dried over anhydrous Na2SO4 and evaporated under vacuum. The crude product was flashed over silica gel with 10% ethylacetate/hexane. Final product (4.45 g, 14.8 mmol) was isolated as white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH:15]=[CH:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=2)=[CH:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Rh]>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:25][CH:26]=2)=[CH:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(C=Cc2cccnc2OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Rh]
Solvent: CCO
Product: O=C(O)c1ccc(CCc2cccnc2OCc2ccccc2)cc1
Yield: 51.7 %

Procedure:
A suspension of rhodium on alumina (5%, 0.1 g) in ethanol (20 ml) was flushed well with argon. A solution of the methyl 4-[2-(2-benzyloxypyrid-3-yl)ethenyl]benzoate (1.0 g, 2.9 mmol) in ethanol (60 ml) was added. The reaction was transferred to a manometer under an atmosphere of hydrogen and the reaction was stirred at ambient temperature until 1.4 equivalents hydrogen had been taken up. The reaction mixture was filtered and evaporated and the residue subjected to chromatography on SiO2 (CH2Cl2 /hexane) to give 4-[2-(2-benzyloxypyrid-3-yl)ethyl]benzoic acid (0.5 g, 49%).
Reaction SMILES: [CH2:1]([C@H:8]([NH:33][C:34](=[O:44])[O:35][C@@H:36]1[C@H:43]2[C@H:39]([O:40][CH2:41][CH2:42]2)[O:38][CH2:37]1)[C@H:9]([OH:32])[CH2:10][N:11]([CH2:23][C:24]([CH3:31])([CH3:30])[CH2:25][CH2:26][CH2:27][C:28]#[N:29])[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH3:22])[CH:16]=1)(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Ni]>[NH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C:24]([CH3:31])([CH3:30])[CH2:23][N:11]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH3:22])[CH:16]=1)(=[O:14])=[O:13])[CH2:10][C@@H:9]([OH:32])[C@@H:8]([NH:33][C:34](=[O:44])[O:35][C@@H:36]1[C@H:43]2[C@H:39]([O:40][CH2:41][CH2:42]2)[O:38][CH2:37]1)[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNc1cccc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)CC(C)(C)CCCC#N)c1
Agent: [Ni]
Product: CNc1cccc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)CC(C)(C)CCCCN)c1
Yield: 70.8 %

Procedure:
A mixture of 0.18 g (0.29 mmol) of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-[(1S,2R)-1-benzyl-3-((5-cyano-2,2-dimethylpentyl)[3-(methylamino)phenyl]sulfonylamino)-2-hydroxypropyl]carbamate (obtained via a protocol directely analogous to Example (Compound 245)) and approximately 50 mg of Raney nickel (washed with water and then MeOH) in 40 mL of 2M NH3/MeOH was subjected to hydrogenation at 40 psi. After 1.5 hours the vessel was purged with nitrogen, catalyst removed by filtration through celite and the filtrate concentrated to dryness in vacuo. The residue was subjected to flash chromatography (SiO2, 9:1 CH2Cl2, 2M NH3 in MeOH) to afford 0.13 g (72%) of the desired amine as a white foam.
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]([CH:18]([CH3:20])[CH3:19])[C@H:12]([OH:17])[C:13]([F:16])([F:15])[F:14])C1C=CC=CC=1>C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[NH2:10][C@@H:11]([CH:18]([CH3:20])[CH3:19])[C@H:12]([OH:17])[C:13]([F:14])([F:15])[F:16]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)[C@H](O)C(F)(F)F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)[C@H](N)[C@H](O)C(F)(F)F
Temperature: 25 °C
Reaction time: 7 h
Yield: 101.4 %

Procedure:
N-[(1S,2S)-3,3,3,-trifluoro-2-hydroxy-1-(isopropyl)propyl]-carbamic acid benzyl ester (740 g, 2.42 mol) obtained in Example 5 was dissolved in ethyl acetate (1500 ml), and thereto was added 20% palladium hydroxide (30 g), and the mixture was stirred at room temperature for 7 hours under hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give the desired compound (420 g, yield:quantitative) as an oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH2:3][CH:4]([OH:6])[CH3:5].[C:8](Cl)(=[O:12])[C:9]([Cl:11])=[O:10]>>[C:9]([Cl:11])(=[O:10])[C:8]([O:6][CH:4]([CH2:3][CH:2]([CH3:7])[CH3:1])[CH3:5])=[O:12]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)CC(C)O
Product: CC(C)CC(C)OC(=O)C(=O)Cl
Yield: 88.2 %

Procedure:
In this example the product was prepared in two synthetic steps. In the first step 4-methyl-2-pentanol was reacted with 50% molar excess of oxalyl chloride. Upon completion of the reaction the excess oxalyl chloride was stripped from the product at reduced pressure to produce 4-methyl-2-pentyl chlorooxalate having an assay of 96.2% and in a corrected yield of 88.2%. In the second step 4-methyl-2-pentyl chlorooxalate was reacted with 3-hydroxy-1,1-dimethylbutyl hydroperoxide in the presence of pyridine to yield the product as described below:
Reaction SMILES: OS(O)(=O)=O.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][NH:13][C:12]([CH2:19]Br)(CBr)[CH:11]=2.[OH-:21].[Na+]>O>[Cl:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([CH:19]=[O:21])[N:13]=[CH:14]2)=[CH:9][CH:8]=1
Reactant: Clc1ccc2c(c1)=CNC(CBr)(CBr)C=2
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=Cc1cc2ccc(Cl)cc2cn1
Temperature: 150 °C

Procedure:
A 20 mL of 80% H2SO4 is added 7-chloro-3,3-dibromomethyl isoquinoline (0.69 g, 2.06 mmol) is heated to 150° C. for 16 hours. The solution is then cooled to ambient temperatures and diluted with 40 mL of H2O. The resulting solution is basified to pH=11 with 1N NaOH. The aqueous solution is extracted with CH2Cl2. The organic solution is washed with H2O and a saturated NaCl solution. The organic layer is dried over MgSO4, filtered and concentrated to give the product as an oil (0.25 g, 1.3 mmol). 1H NMR (CDCl3, 300 MHz) δ10.0 (s, 1H), 9.30 (s, 1H), 8.36 (s, 1H), 8.07 (s, 1H), 7.95 (d, 1H), 7.78 (d, 1H). MS (EI): m/z 191, 193 (M+), Cl pattern.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][NH:5][CH:4]([CH2:7][N:8]([CH2:24][C:25]([CH3:33])=[CH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:9]([C:11]2[CH:21]=[C:20]([O:22][CH3:23])[C:14]3[O:15][C:16]([CH3:19])([CH3:18])[O:17][C:13]=3[CH:12]=2)=[O:10])[CH2:3]1.[O:34]1[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1.C(O)(=O)C.C([BH3-])#N.[Na+].Cl>>[OH:1][CH:2]1[CH2:6][N:5]([CH:37]2[CH2:38][CH2:39][O:34][CH2:35][CH2:36]2)[CH:4]([CH2:7][N:8]([CH2:24][C:25]([CH3:33])=[CH:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:9]([C:11]2[CH:21]=[C:20]([O:22][CH3:23])[C:14]3[O:15][C:16]([CH3:19])([CH3:18])[O:17][C:13]=3[CH:12]=2)=[O:10])[CH2:3]1
Reactant: COc1cc(C(=O)N(CC(C)=Cc2ccccc2)CC2CC(O)CN2)cc2c1OC(C)(C)O2
Reactant: O=C1CCOCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(C(=O)N(CC(C)=Cc2ccccc2)CC2CC(O)CN2C2CCOCC2)cc2c1OC(C)(C)O2
Yield: 69.2 %

Procedure:
Experimental condition analogous to Example 14 were used with 7-methoxy-2,2-dimethyl-benzo[1,3]dioxole-5-carboxylic acid (4-hydroxy-pyrrolidin-2-ylmethyl)-(2-methyl-3-phenyl-allyl)-amide 0.16 g (0.35 mmol), tetrahydro-4H-pyrane-4-one 0.042 g (0.42 mmol), acetic acid 0.03 ml (0.53 mmol) and sodium cyanoborohydride 0.026 g (0. 42 mmol). After transforming the free base to HCl salt, 130 mg of white solid was obtained. Yield: 65%.