Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)[CH:2]=[CH2:3].ClC1C=C(C=CC=1)C(OO)=[O:17]>ClCCl>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:1][CH:2]2[CH2:3][O:17]2)=[CH:5][CH:6]=1
Reactant: C=CCc1ccc(OC)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(CC2CO2)cc1

Procedure:
To a stirring solution of 4-allylanisole (3.1 g, 20.9 mmol) in 50 mL dichloromethane was added 3-chloroperoxybenzoic acid (80%, 6.7 g, 31.4 mmol) at room temperature. TLC (20:1 hexanes/ethyl acetate) showed no remaining allyl after 3 h. The precipitate was removed via filtration and washed with hexanes. The filtrate was purified on 40 g silica eluting with 0 to 10% ethyl acetate/hexanes to give the product. NMR CDCl3) d (1H, 2.55 ppm), m (2H, 2.7-2.8 ppm), dd (1H, 2.85 ppm), m (1H, 3.1 ppm), s (3H, 3.75 ppm), d (2H, 6.85 ppm), d (2H, 7.15 ppm).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH3:13][O:14][CH2:15][CH2:16][N:17]1[C:25]2[C:20](=[CH:21][C:22]([CH2:26][NH:27][S:28]([C:31]3[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=3)(=[O:30])=[O:29])=[CH:23][CH:24]=2)[CH:19]=[N:18]1>>[Cl:8][C:7]1[C:2]([N:27]([CH2:26][C:22]2[CH:21]=[C:20]3[C:25](=[CH:24][CH:23]=2)[N:17]([CH2:16][CH2:15][O:14][CH3:13])[N:18]=[CH:19]3)[S:28]([C:31]2[CH:32]=[CH:33][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:39][CH:40]=2)(=[O:30])=[O:29])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: COCCn1ncc2cc(CNS(=O)(=O)c3ccc(C(=O)OC)cc3)ccc21
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Product: COCCn1ncc2cc(CN(c3ncc(C(F)(F)F)cc3Cl)S(=O)(=O)c3ccc(C(=O)OC)cc3)ccc21

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 2,3-dichloro-5-(trifluoromethyl)pyridine and methyl 4-(N-((1-(2-methoxyethyl)-1H-indazol-5-yl)methyl)sulfamoyl)benzoate (step-3 of Example 20).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:32][C:31]2[CH:30]=[CH:29][C:28]([N:25]3[CH2:24][CH2:23][N:22]([CH3:21])[CH2:27][CH2:26]3)=[CH:34][CH:33]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CN1CCN(c2ccc(NC(=O)c3cc([N+](=O)[O-])c(Sc4c(Cl)cncc4Cl)s3)cc2)CC1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 4-(4-methylpiperazin-1-yl)aniline (19.0 mg, 0.12 mmol). The title compound was obtained as a solid (10.0 mg, 19% yield). MS m/z: 524.00, 526.00 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:14][C:15]([Cl:22])([Cl:21])[CH2:16][O:17][C:18](Cl)=[O:19]>CCOCC>[Cl:14][C:15]([Cl:22])([Cl:21])[CH2:16][O:17][C:18]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)=[O:19]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: C1CNCCN1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(OCC(Cl)(Cl)Cl)N1CCNCC1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of 0.5 mol of piperazine and 0.5 mol of triethylamine in ether is added dropwise 0.25 mol of 2,2,2-trichloroethylchloroformate. The reaction mixture is stirred for 1-6 hours at room temperature (ca. 25° C.) and is then worked up with aqueous weak basic solution to give 1-(2,2,2-trichloroethoxycarbonyl)piperazine. This is reacted with p-nitrobenzenesulfonyl chloride in a non-polar solvent, e.g., tetrahydrofuran, to give 1-(p-nitrobenzenesulfonyl)-4-(2,2,2-trichloroethoxycarbonyl)piperazine.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][C:8](=O)[N:7]([CH2:12][C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14])[C:6]=2[C:5]([CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:8]1[N:7]([CH2:12][C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14])[C:6]2[C:5]([CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]=2[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCC(CC)c1ccc(Cl)c2[nH]c(=O)n(CC(=O)OC(C)C)c12
Product: CCC(CC)c1ccc(Cl)c2nc(Cl)n(CC(=O)OC(C)C)c12
Temperature: 100 °C
Reaction time: 72 h
Yield: 92 %

Procedure:
A mixture of isopropyl [4-chloro-7-(1-ethylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]acetate (14.5 g, 42.8 mmol) and phosphorus oxychloride (60 mL) was stirred at 100° C. for 3 days. After cooling, phosphorus oxychloride was evaporated in vacuo. The residue was poured into ice-cold saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate (×2). The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 5-15% ethyl acetate/n-hexane gradient mixture to give the title compound (14.1 g, 39.5 mmol, 92%) as an oil.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:28]([CH3:29])[C:27](=[O:30])[N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:25](=[O:39])[C:24]=2[CH3:40])=[C:19]([CH3:41])[CH:18]=1>N1C=CC=CC=1>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:28]([CH3:29])[C:27](=[O:30])[N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:25](=[O:39])[C:24]=2[CH3:40])=[C:19]([CH3:41])[CH:18]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cc(O)ccc1-c1c(C)c(=O)n(COCC[Si](C)(C)C)c(=O)n1C
Solvent: c1ccncc1
Product: Cc1cc(OS(=O)(=O)C(F)(F)F)ccc1-c1c(C)c(=O)n(COCC[Si](C)(C)C)c(=O)n1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoromethanesulfonic anhydride (1.3 g, 4.6 mmol) was slowly added to a 0° C. solution of C5 (600 mg, 1.6 mmol) in pyridine (15 mL), and the reaction mixture was stirred at room temperature for 3 hours. After solvent had been removed under reduced pressure, the residue was purified by silica gel chromatography (Gradient: 5% to 17% ethyl acetate in petroleum ether) to afford the product as a yellow oil. Yield: 790 mg, 1.55 mmol, 97%. 1H NMR (400 MHz, CDCl3) δ 7.27-7.33 (m, 2H), 7.21-7.25 (m, 1H), 5.50 (AB quartet, JAB=9.2 Hz, ΔνAB=4.1 Hz, 2H), 3.73-3.79 (m, 2H), 3.02 (s, 3H), 2.26 (br s, 3H), 1.63 (s, 3H), 1.00-1.06 (m, 2H), 0.03 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](O)=[O:10])=[C:4]([F:12])[CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:19][NH2:20]>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:20][CH3:19])=[O:10])=[C:4]([F:12])[CH:3]=1
Reactant: O=C(O)Cc1ccc(Br)cc1F
Reactant: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CNC(=O)Cc1ccc(Br)cc1F
Reaction time: 2 h
Yield: 23.5 %

Procedure:
A solution of 2-(4-bromo-2-fluorophenyl)acetic acid (10.56 mmol) in dichloromethane (20 mL) was treated with oxalyl chloride (31.7 mmol) and dimethylformamide (0.106 mmol). Effervescense was observed for fifteen minutes. When the bubbling had ceased, the reaction was concentrated to dryness in vacuo. The resulting oil was dissolved with dichloromethane and was concentrated to dryness in vacuo. The material was then diluted with tetrahydrofuran (20 mL) and was treated with methanamine (31.7 mmol) dropwise. Effervescense was again observed. A precipitate formed as the reaction was stirred over a two hour period. The contents of the reaction were concentrated to dryness in vacuo and were then dissolved in a minimal amount of methanol. Ethyl acetate was then added to this solution until a solid precipitated. The precipitate was collected by vacuum filtration. In a similar manner, two additional crops were collected from the mother liquor. The resulting solids were combined and triturated with dichloromethane. Purification of the solid by silica gel chromatography (0-5% methanol/dichloromethane) afforded the title compound as a white solid (610 mg, 22% yield). MS(ES)+ m/e 246.0/247.8 [M+H]+ (bromide isotope pattern).
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[C:11]([CH3:13])[C:8]([C:9]#[N:10])=[C:7]([SH:14])[N:6]=1)[CH:2]([CH3:4])[CH3:3].Br[CH2:16][C:17]([NH2:19])=[O:18].[O-]CC.[Na+]>CN(C=O)C.O>[NH2:10][C:9]1[C:8]2[C:7](=[N:6][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:12][C:11]=2[CH3:13])[S:14][C:16]=1[C:17]([NH2:19])=[O:18]
Reactant: Cc1cc(CC(C)C)nc(S)c1C#N
Reactant: NC(=O)CBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(CC(C)C)nc2sc(C(N)=O)c(N)c12
Temperature: 70 °C

Procedure:
A mixture of the above nitrile (1.00 g, 4.85 mmol), bromoacetamide (0.67 g, 4.85 mmol), and sodium ethoxide (0.68 g, 10 mmol) in DMF (20 mL) was heated at 70° C. for 1 h before it was allowed to cool to room temperature. The resulting mixture was diluted with water, filtrated and the precipitates washed with EtOH providing the title compound (0.5 g, 39%).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]#[N:32])=[CH:21][CH:20]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:42](Cl)(=[O:47])[CH2:43][CH2:44][CH2:45][CH3:46].N>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([C:11]1([N:17]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]#[N:32])=[CH:23][CH:24]=2)[C:42](=[O:47])[CH2:43][CH2:44][CH2:45][CH3:46])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCC(=O)Cl
Reactant: N#Cc1ccccc1-c1ccc(CNC2(C(=O)OCc3ccccc3)CCCCC2)cc1
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)C1(C(=O)OCc2ccccc2)CCCCC1
Reaction time: 1 h

Procedure:
A solution of 2.9 g (6.8 mmol) of N-(1-benzyloxycarbonylcyclohexyl)-N-(2'-cyanobiphenyl-4-ylmethyl)-amine and 4.4 ml (26 mmol) of Hunig base in 50 ml of ethyl acetate is treated with 1.1 g (9 mmol) of pentanoyl chloride, and the mixture is heated to reflux for 24 hours. After cooling, the reaction mixture is treated with 20 ml of aqueous ammonia solution (2N) and stirred for 1 hour. The organic phase is separated, washed in succession with 2 N-hydrochloric acid, saturated sodium hydrogencarbonate solution and brine, dried and evaporated. The N-(1-benzyloxycarbonylcyclohexyl)-N-(2'-cyanobiphenyl-4-ylmethyl)-N-pentanoyl-amine is thus obtained in the form of a brown oil [Rf : 0.44 (toluene/methanol=19:1)], which is used for further reactions in crude form.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[N:8][OH:9])[NH2:7])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[C:18]([C:22]1[N:26]2[CH2:27][CH2:28][CH:29]([C:31](OC)=O)[CH2:30][C:25]2=[N:24][N:23]=1)([CH3:21])([CH3:20])[CH3:19].C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[C:18]([C:22]1[N:26]2[CH2:27][CH2:28][CH:29]([C:31]3[O:9][N:8]=[C:6]([C:5]4[CH:10]=[CH:11][C:2]([F:1])=[CH:3][CH:4]=4)[N:7]=3)[CH2:30][C:25]2=[N:24][N:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)C1CCn2c(nnc2C(C)(C)C)C1
Reactant: NC(=NO)c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)c1nnc2n1CCC(c1nc(-c3ccc(F)cc3)no1)C2
Yield: 50.4 %

Procedure:
Add 4-fluorobenzamidoxime (4.61 g, 29.93 mmol) to a 1M solution of potassium t-butoxide (27.6 mL, 27.63 mmol) in tetrahydrofuran. Add methyl 3-tert-butyl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-7-carboxylate (6.07 g, 23.02 mmol) and stir overnight at room temperature. Dissolve the reaction in a 1:1 mixture of 50% saturated aqueous sodium bicarbonate and ethyl acetate. Separate layers and extract the aqueous layer with additional ethyl acetate. Wash the combined organic layers with brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the resulting residue by flash chromatography (silica gel), eluting with first 25-100% ethyl acetate:hexane and then 5% methanol in ethyl acetate. Recrystallize from dichloromethane and hexane to afford the title compound as a white solid (3.96 g). Mass spectrum (m/z): 342 (M+1).
Reaction SMILES: C1(C[O:8][C:9](=[O:51])[CH2:10][N:11]([C:23]2[CH:28]=[C:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:26]=[C:25]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH:24]=2)[CH2:12][C:13](=[O:22])[O:14]CC2C=CC=CC=2)C=CC=CC=1.[H][H]>[Pd]>[C:9]([CH2:10][N:11]([C:23]1[CH:28]=[C:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:26]=[C:25]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH:24]=1)[CH2:12][C:13]([OH:22])=[O:14])([OH:51])=[O:8]
Reactant: CCCCCCCCCCOc1cc(OCCCCCCCCCC)cc(N(CC(=O)OCc2ccccc2)CC(=O)OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Product: CCCCCCCCCCOc1cc(OCCCCCCCCCC)cc(N(CC(=O)O)CC(=O)O)c1
Yield: 74.8 %

Procedure:
A mixture of 10.2 g (0.0145 mol) of N-[3,5-bis(decyloxy)phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycine phenylmethyl ester and 1.5 g of 10% palladium on charcoal in 500 ml of THFwas shaken in a hydrogen atmosphere at room temperature for 7 hours. The catalyst was removed by filtration and the filtrate was concentrated underreduced pressure to a solid which was recrystallized from acetonitrile to give 5.66 g (75% yield, mp 110°-114°) of N-(carboxymethyl)-N-[3,5-bis(decyloxy)phenyl]glycine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][C:18]([O:27][CH:28]([CH3:30])[CH3:29])=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=3)[CH:15]2[OH:31])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:15](=[O:31])[C:16]3[C:21](=[CH:20][C:19]([N+:24]([O-:26])=[O:25])=[C:18]([O:27][CH:28]([CH3:29])[CH3:30])[CH:17]=3)[C:22]2=[O:23])[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)Oc1cc2c(cc1[N+](=O)[O-])C(=O)N(C1CCN(C(=O)OC(C)(C)C)CC1)C2O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1cc2c(cc1[N+](=O)[O-])C(=O)N(C1CCN(C(=O)OC(C)(C)C)CC1)C2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the solution of 4-(1-hydroxy-6-isopropoxy-5-nitro-3-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester from the previous step (173.9 mg, 0.4 mmol) in DMF (4 mL) is added pyridinum dichromate (286.5 mg, 0.8 mmol) in one portion. After stirring at room temperature for 2 h, the reaction mixture is poured into 25 mL of water and the product is extracted with EtOAc. The organic extracts are dried over Na2SO4, filtered and concentrated in vacuo to give crude 4-(5-isopropoxy-6-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester, which is directly used in the next step without further purification.
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][C:32]=1[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]O>ClCCl.C(OCC)C.CCCCC>[Br:1][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][C:32]1[CH:33]=[CH:34][C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:31]=1
Reactant: BrBr
Reactant: OCCCCCc1ccc2ccccc2c1
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCC
Solvent: CCOCC
Product: BrCCCCCc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Bromine (a 2M solution in dichloromethane; 955 mg, 5.97 mmol) was added to a solution of 1,2-bis (diphenyl)phosphinoethane (1.16 g, 2.99 mmol) in dichloromethane (15 ml) at 0°. A solution of 5-(2-napthyl)pentan-1-ol (513 mg, 2.39 mmol) in dichloromethane (5 ml) was added to the 0° solution. The solution was warmed to room temperature and stirred for 1.5 hours. The solution was diluted with ethyl ether/pentane (1:3), filtered through a thin pad of celite and the solvent evaporated. The resulting oil was purified by flash chromatography (hexane) giving the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:12]([CH2:15][CH3:16])[C:13]#[N:14])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:17](=O)([O:23]C(C)(C)C)[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].[BH4-].[Na+]>CO>[Cl:1][C:2]1[C:3]([CH:12]([CH2:15][CH3:16])[CH2:13][NH:14][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: CCC(C#N)c1ncc(C(F)(F)F)cc1Cl
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC(CNC(=O)OC(C)(C)C)c1ncc(C(F)(F)F)cc1Cl
Reaction time: 3 h

Procedure:
189 g of 2-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]butanenitrile (0.758 mol), 331 g (1.51 mol) of diterbutyl carbonate, 198 g (0.834 mol) of nickel chloride (II)-hexahydrate are stirred in 2 L of methanol at room temperature. 200.6 g (5.31 mol) of sodium borohydride are added portionwise. After 3 hours of stirring, the reaction mixture is filtered over Supercel, 2 L of ethyl acetate are added, followed by 1.5 L of an aqueous solution of sodium bicarbonate.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].CCN(C(C)C)C(C)C.[C:15]([O:19][C:20]([N:22]1[CH2:27][C@@H:26]2[CH2:28][C@H:23]1[CH2:24][NH:25]2)=[O:21])([CH3:18])([CH3:17])[CH3:16]>C(Cl)Cl>[C:15]([O:19][C:20]([N:22]1[CH2:27][C@@H:26]2[CH2:28][C@H:23]1[CH2:24][N:25]2[S:2]([CH3:1])(=[O:4])=[O:3])=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2S(C)(=O)=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Methanesulfonyl chloride (120 μL, 1.55 mmol) and DIPEA (187 μL, 1.07 mmol) were added to a solution of (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (200 mg, 1.01 mmol) in DCM (20 mL) and the reaction mixture stirred at ambient temperature for 17 h, then partitioned between EtOAc and water. The organic layer was separated and washed with brine, then dried (MgSO4) and concentrated in vacuo to give (1S,4S)-5-methanesulfonyl-2,5-diazabicyclo[2.2.1]-heptane-2-carboxylic acid tert-butyl ester. TFA (3 mL) was added to a solution of (1S,4S)-5-methanesulfonyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester in DCM (10 mL) and the mixture stirred at ambient temperature for 30 min. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g); the cartridge was washed with MeOH before the desired product was eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo to afford the title compound as a white solid (170 mg, 96%). 1H NMR (CDCl3, 400 MHz) δ 4.37 (d, J=2.0 Hz, 1 H); 3.83 (d, J=2.0 Hz, 1 H); 3.41 (dd, J=9.2, 2.19 Hz, 1 H); 3.25 (d, J=9.2 Hz, 1 H); 3.20 (d, J=10.3 Hz, 1 H); 3.01 (dd, J=10.3, 2.14 Hz, 1 H); 2.89 (s, 3 H); and 1.79 (bs, 2 H)
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]1[C:16]1[CH:46]=[C:45]([F:47])[CH:44]=[CH:43][C:17]=1[CH2:18][NH:19][C:20]([C:22]1[N:23]=[C:24]2[N:29]([C:30](=[O:40])[C:31]=1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:28][CH2:27][O:26][C:25]2([CH3:42])[CH3:41])=[O:21])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(O)=O.[Na+]>O1CCCC1>[F:47][C:45]1[CH:44]=[CH:43][C:17]([CH2:18][NH:19][C:20]([C:22]2[N:23]=[C:24]3[N:29]([C:30](=[O:40])[C:31]=2[O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:28][CH2:27][O:26][C:25]3([CH3:42])[CH3:41])=[O:21])=[C:16]([N:11]2[C:12](=[O:15])[CH2:13][CH2:14][C@@H:10]2[CH2:9][OH:8])[CH:46]=1
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1N1C(=O)CC[C@@H]1CO[Si](C)(C)C(C)(C)C)c(OCc1ccccc1)c2=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1N1C(=O)CC[C@@H]1CO)c(OCc1ccccc1)c2=O
Temperature: 23 °C
Reaction time: 3 h
Yield: 72.7 %

Procedure:
To a stirred solution of intermediate 166, (R)-N-(2-(2-((tert-butyldimethylsilyloxy)methyl)-5-oxopyrrolidin 1-yl)-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.10 g, 0.150 mmol) in tetrahydrofuran (5 mL) at 23° C. was added a solution of tetrabutylammonium fluoride (1M in tetrahydrofuran) (180 μL, 0.18 mmol). The reaction mixture was stirred at 23° C. for 3 h. NaHCO3 (1N in H2O, 30 mL) was then added and the organic material was extracted with ethyl acetate (2×25 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified on a Biotage system using a silica gel column with ethyl acetate/Hexanes (1:1) to ethyl acetate 100% as eluent to afford the title compound (0.060 g, 73% yield): 1HNMR 400 MHz (MeOD) δ (ppm): 7.55 (1H, dd, (t), 6.6 Hz), 7.43 (2H, m), 7.13 (1H, dd, J=9.5, 2.4 Hz), 7.03 (1H, m), 5.26 (2H, s), 4.57 (1H, m), 4.32 (2H, m), 4.08 (2H, t, J=5.0 Hz), 7.03 (2H, t, J=5.0 Hz), 3.53 (2H, m), 2.69–2.56 (2H, m), 2.38 (1H, m), 2.22 (1H, m), 1.62 (6H, s). LCMS (M+H)+ m/z 551.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:35]([NH2:37])=[O:36])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH:28][C:29](=[O:34])[CH2:30][CH2:31][CH2:32][CH3:33])[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].CC1(C)C(C)(C)OB(C2C=C([CH2:52][NH:53]C(=O)CCCC)C=CC=2)O1>>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:35]([NH2:37])=[O:36])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH:28][C:29]([C:30]5[N:53]([CH3:52])[CH:33]=[CH:32][CH:31]=5)=[O:34])[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCCCC(=O)NCc1cccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)c1
Reactant: CCCCC(=O)NCc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNC(=O)c5cccn5C)c4)cc23)CC1

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(pentanoylamino)methyl]phenyl}-1H-indole-7-carboxamide substituting 1-methyl-N-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-1H-pyrrole-2-carboxamide (49 mg, 0.144 mmol) for N-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}pentanamide. Compound was purified by Gilson Preparatory HPLC to give the title compound.
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([N:23]([CH3:25])[CH3:24])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)C=CC=CC=1.[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[C:37]1[CH2:38][CH2:39][NH:40][CH2:41][CH:42]=1>O1CCOCC1>[CH3:24][N:23]([CH3:25])[C:14]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:15][CH2:16][CH:11]([CH2:10][NH:9][C:8]([N:40]2[CH2:39][CH:38]=[C:37]([C:31]3[C:30]4[C:34](=[CH:35][CH:36]=[C:28]([F:27])[CH:29]=4)[NH:33][CH:32]=3)[CH2:42][CH2:41]2)=[O:7])[CH2:12][CH2:13]1
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: CN(C)C1(c2ccccc2)CCC(CNC(=O)Oc2ccccc2)CC1
Solvent: C1COCCO1
Product: CN(C)C1(c2ccccc2)CCC(CNC(=O)N2CC=C(c3c[nH]c4ccc(F)cc34)CC2)CC1
Yield: 15.1 %

Procedure:
The diastereoisomer mixture of (4-dimethylamino-4-phenylcyclohexylmethyl)-carbamic acid phenyl ester (700 mg, 1.98 mmole) was added to a solution of 5-fluoro-3-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole (428.2 mg, 1.98 mmole) in dioxane (10 ml). The reaction mixture was then boiled under reflux for 12 hours. The reaction mixture was slightly cloudy at RT. The reaction mixture was worked up by distilling off the solvent. The residue contained, apart from phenol, also the two diastereoisomers of 4-(5-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide. The diastereoisomers were separated and purified by flash chromatography on silica gel (50 g). Methanol/EE (1:1; 1000 ml) was used as eluent. The non-polar diastereoisomer of 4-(5-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexyl-methyl)-amide (300 mg, pale yellow, m.p. 105°-109° C., 32%) and the polar diastereoisomer of 4-(5-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide (142 mg, 15%) were thereby obtained in pure form.