Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23](O)=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:26]1([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=2)[CH2:28][CH2:27]1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:22][C:23]([N:29]([CH:26]2[CH2:27][CH2:28]2)[CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=2)=[O:24])(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: COc1ccc(CNC2CC2)cc1OC
Product: COc1ccc(CN(C(=O)CN(c2ccc(C)cc2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)C2CC2)cc1OC

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with cyclopropyl-(3,4-dimethoxy-benzyl)-amine
Reaction SMILES: C1(C2C=CC=CC=2)C=CC=C(N2C=C(C([Cl:14])=O)N=C2)C=1.[F:21][C:22]1[C:27]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([N:34]3[CH:38]=[C:37]([C:39](O)=[O:40])[N:36]=[CH:35]3)[CH:29]=2)=[C:26]([O:42][CH3:43])[CH:25]=[CH:24][CH:23]=1>>[F:21][C:22]1[C:27]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([N:34]3[CH:38]=[C:37]([C:39]([Cl:14])=[O:40])[N:36]=[CH:35]3)[CH:29]=2)=[C:26]([O:42][CH3:43])[CH:25]=[CH:24][CH:23]=1
Reactant: COc1cccc(F)c1-c1cccc(-n2cnc(C(=O)O)c2)c1
Reactant: O=C(Cl)c1cn(-c2cccc(-c3ccccc3)c2)cn1
Product: COc1cccc(F)c1-c1cccc(-n2cnc(C(=O)Cl)c2)c1

Procedure:
This compound is prepared analogously to 11a from 10g.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11](Cl)=[CH:10][C:9]=2[CH3:15])=[CH:4][CH:3]=1.[C:16]([O:20][CH2:21][CH3:22])(=[O:19])[NH:17][NH2:18]>C(O)CCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH:18][NH:17][C:16]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][C:9]=2[CH3:15])=[CH:4][CH:3]=1
Reactant: CCOC(=O)NN
Reactant: Cc1cc(Cl)nnc1-c1ccc(Br)cc1
Solvent: CCCCO
Product: CCOC(=O)NNc1cc(C)c(-c2ccc(Br)cc2)nn1
Temperature: 25 °C

Procedure:
A mixture of 8.49 g. of 6-(p-bromophenyl)-5-methyl-3-chloropyridazine and 6.25 g. of ethyl carbazate in 100 ml. of n-butyl alcohol is prepared. This solution is stirred and heated at reflux temperature for 4 hours. The reaction mixture is cooled to room temperature and the solvent removed on a rotating evaporator. Water is added to the residue and the resulting solid filtered, washed with water, ether and dried. The product is recrystallized from ethanol to yield the product, m.p. 178°-179° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[Cl:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][C:14]=1[F:15])[NH2:11]>CC(C)=O>[Cl:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][C:14]=1[F:15])[NH:11][C:4](=[O:5])[CH2:3][CH2:2][Cl:1]
Reactant: O=C(Cl)CCCl
Reactant: Nc1ccc(F)c(Cl)c1
Solvent: CC(C)=O
Product: O=C(CCCl)Nc1ccc(F)c(Cl)c1
Temperature: 20 °C
Reaction time: 0.58 h
Yield: 74.5 %

Procedure:
A solution of 3-chloropropionyl chloride (127 g) in acetone (200 cc) is added with stirring in the course of 35 minutes to a solution, at a temperature in the region of 55°) C., of 3-chloro-4-fluoroaniline (291 g) in acetone (500 cc), and the mixture is maintained at this temperature for 2 hours. After cooling to approximately 20° C., the insoluble matter is removed by filtration and washed with acetone (2×200 cc). The combined filtrate and washings are poured with stirring into water (2 liters) and ice (1 kg). The temperature is allowed to rise to approximately 20° C. and the product is extracted with dichloromethane (4×500 cc). The combined organic extracts are washed with water (3×500 cc), dried over magnesium sulphate, stirred for 15 minutes with Norit vegetable charcoal (6 g), filtered through diatomaceous silica for filtration and concentrated under reduced pressure (2.7 kPa) at 50° C. The solid obtained is recrystallized in a mixture of cyclohexane (133 cc) and isopropyl ether (67 cc). 3'-Chloro-4'-fluoro-3-chloropropionanilide (176 g) is obtained in the form of a beige solid, m.p. 94° C., which is used without further treatment for the subsequent steps.
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@H:10]([C:11](=[O:19])[N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[O:9][C:8]([C:20]([O:22]C)=[O:21])=[CH:7][C@H:6]1[N:24]=[N+]=[N-])(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>O1CCCC1.O>[C:1]([NH:4][C@H:5]1[C@H:10]([C:11](=[O:19])[N:12]([CH2:13][CH2:14][CH3:15])[CH2:16][CH2:17][CH3:18])[O:9][C:8]([C:20]([OH:22])=[O:21])=[CH:7][C@H:6]1[NH2:24])(=[O:3])[CH3:2]
Reactant: CCCN(CCC)C(=O)[C@@H]1OC(C(=O)OC)=C[C@@H](N=[N+]=[N-])[C@H]1NC(C)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCCN(CCC)C(=O)[C@@H]1OC(C(=O)O)=C[C@@H](N)[C@H]1NC(C)=O
Reaction time: 21 h
Yield: 38.4 %

Procedure:
To a stirred solution of (4R,5R,6R)-5-acetylamino-4-azido-6-(dipropylcarbamoyl)-5,6-dihydro-4H-pyran-2-carboxylic acid, methyl ester (500 mg) in tetrahydrofuran (6 ml) under nitrogen was added triphenylphosphine (428 mg). After 3.5 hours at 23° C. water (1 ml) was added adn the solution was stirred for a further 21 hours. Triethylamine (1 ml) was added and stirring was continued for a further 7 hours after which the solvents were removed in vacuo. The resulting liquid was redissolved in ethyl acetate, was dried over anhydrous magnesium sulphate, and the solvent was evaporated in vacuo to leave a yellow solid. The solid was chromatographed over silica (Merck 9385, 45 g) using medium pressure (ca 4 psi) and chloroform/methanol (15:1, v/v) as eluant. Appropriate fractions were combined and the solvent was evaporated in vacuo to afford a white solid which was suspended in water (5 ml) containing triethylamine (2 ml) and was stirred at 50° C. for 1.5 hours. The solvents were removed in vacuo to afford the title compound as a white solid (171 mg). 1H NMR (250MHz, D6 -DMSO) 8.4 (1H, broad s), 5.7 (1H, d, J=1.5Hz), 5.1 (1H, d, J=4Hz), 4.4 (1H, broad s), 3.95 (1H, broad s), 2.95-3.86 (6H, m), 2.0 (3H, s), 1.6 (4H, m), 0.94+0.99 (6H, two t, J=7.5Hz). Mass spec. (low resolution): MH+ =328. Mass analysis: C15H25N3O5. 1.5 H2O Required: C, 50.79; H, 7.90; N, 11.85. Found: C, 50.87; H, 8.04; N, 11.54.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[Cl:16][C:17]1(Cl)[CH2:22][O:21][CH2:20][CH2:19][O:18]1>>[C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:19](=[O:18])[CH2:20][O:21][CH2:22][CH2:17][Cl:16])=[CH:15][CH:14]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Reactant: ClC1(Cl)COCCO1
Product: O=C(COCCCl)Nc1ccc(C(=O)c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of 1.60 g (8.12 mmol) of 4-aminobenzophenone and 1.11 g of 2-chlorodioxene (contains 6% of 2,2-dichlorodioxane) is heated at 80° C. with stirring for 24 hours, giving 2.6 g of N-(4-benzoylphenyl)-2-(2-chloroethoxy)acetamide as brown oil. ESI 318.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH:4]=[C:5]([C:11]([CH2:13][O:14][CH2:15][CH2:16][N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27])=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH2:32]([O:34][C:35](=[O:40])/[CH:36]=[C:37](\[NH2:39])/[CH3:38])[CH3:33]>CC(O)C>[Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH:4]1[C:36]([C:35]([O:34][CH2:32][CH3:33])=[O:40])=[C:37]([CH3:38])[NH:39][C:11]([CH2:13][O:14][CH2:15][CH2:16][N:17]2[C:21](=[O:22])[C:20]3[C:19](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18]2=[O:27])=[C:5]1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(=Cc1ccccc1Cl)C(=O)COCCN1C(=O)c2ccccc2C1=O
Reactant: CCOC(=O)/C=C(/C)N
Solvent: CC(C)O
Product: CCOC(=O)C1=C(C)NC(COCCN2C(=O)c3ccccc3C2=O)=C(C(=O)OCC)C1c1ccccc1Cl
Temperature: 15 °C
Reaction time: 20 h

Procedure:
116.7 g of ethyl 2-(o-chlorobenzylidene)-4-(2-phthalimidoethoxy)acetoacetate was dissolved in 120 ml of 2-propanol at 80° C. 31.2 g of ethyl-3-aminocrotonate was added and the mixture was heated at the same temperature for 16 hours. The mixture was evaporated to dryness. The residue was dissolved in 180 ml of glacial acetic acid at 80° C. The mixture was cooled to 15° C. and stirred at the same temperature for 20 hours. The solid was filtered off and washed with 92 ml of glacial acetic acid. The solid was dissolved in 75 ml of ethanol at 80° C. The solution was cooled to 20° C. and the suspension was agitated for 2 h. The solid was filtered off, washed with 25 ml of ethanol. The wet product was recrystallized from 60 ml of ethyl acetate.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:34])=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[CH:17]=[C:16]4[C:31](O)=[O:32])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[NH2:35][CH:36]1[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1>[C:45]([O:44][C:42]([N:39]1[CH2:40][CH2:41][CH:36]([NH:35][C:31]([C:16]2[C:15]3[C:20](=[CH:21][CH:22]=[C:13]([C:11]4[CH:12]=[C:7]([C:5](=[O:6])[NH:4][CH:1]5[CH2:2][CH2:3]5)[CH:8]=[CH:9][C:10]=4[CH3:34])[CH:14]=3)[C:19](=[O:23])[N:18]([CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[CH:17]=2)=[O:32])[CH2:37][CH2:38]1)=[O:43])([CH3:48])([CH3:46])[CH3:47]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccncc3)cc(C(=O)O)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccncc3)cc(C(=O)NC3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of the product of Example 54 step iii) (0.1 g), 4-amino-N-boc-piperadine (0.05 g) and N,N-diisopropylethylamine (0.25 mL) in tetrahydrofuran (10 mL) was added HATU (0.16 g) and the mixture stirred at room temperature for 3 hours. The reaction mixture was then concentrated to dryness and the crude product purified HPLC to give the sub-title compound (0.09 g).
Reaction SMILES: [C:1]([CH:3]=[CH:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([NH:11]C(=O)OC(C)(C)C)[CH2:6]1)#[N:2].[ClH:19].O1CCOCC1>C(Cl)Cl>[ClH:19].[NH2:11][CH:7]1[CH2:8][CH2:9][CH2:10][CH:5]([CH:4]=[CH:3][C:1]#[N:2])[CH2:6]1
Reactant: CC(C)(C)OC(=O)NC1CCCC(C=CC#N)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: N#CC=CC1CCCC(N)C1

Procedure:
tert-Butyl {3-[2-cyanovinyl]cyclohexyl}carbamate was treated with 4.0 M hydrogen chloride in dioxane (1.6 mL, 6.6 mmol) in methylene chloride (2 mL) at room temperature for 2 h. The mixture was stripped to dryness to give the desired product as a mixture of cis- and trans-isomers. LCMS calculated for C9H15N2 (M+H)+: m/z=151.1. Found: 151.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])(CC)C.[CH2:14]([CH:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)[CH2:15][CH2:16][CH2:17][CH3:18].[Cl-].[NH4+]>C1(C)C=CC=CC=1.C1COCC1.C1CCCCC1.CCCCCC>[F:1][C:2]1[C:3]([F:8])=[CH:4][CH:5]=[CH:6][C:7]=1[C:22]1([OH:25])[CH2:21][CH2:20][CH:19]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:24][CH2:23]1
Reactant: Fc1ccccc1F
Reactant: CCCCCC1CCC(=O)CC1
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCCCC1CCC(O)(c2cccc(F)c2F)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 115.9 %

Procedure:
1,2-Difluorobenzene (29) (60.5 g) and THF (500 ml) were put in a reaction vessel under a nitrogen atmosphere, and cooled to −73° C. s-Butyllithium (1.06 M, in a n-hexane and cyclohexane solution; 500.0 ml) was added dropwise thereto in the temperature range of −74° C. to −65° C., and the mixture was stirred for another 2 hours. Subsequently, 4-pentylcyclohexanone (40) (89.2 g) in a THF (200 ml) solution was added dropwise thereto in the temperature range of −76° C. to −65° C., and the stirring was continued for another 20 hours while the mixture was allowed to return to 25° C. Then, the reaction mixture was poured into a vessel containing ammonium chloride (55.1 g) and ice-water (1,000 ml), and mixed. Toluene (1500 ml) was added thereto and the mixture was allowed to separate into organic and aqueous phases, and then an extractive operation was carried out. The organic phase was fractionated, and washed sequentially with water and a saturated aqueous solution of sodium hydrogencarbonate and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, giving 173.5 g of 1-(2,3-difluoropheyl)-4-pentylcyclohexanol (41). The compound (41) was pale-yellow oil.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:7]=12.[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][OH:19])=[CH:16][CH:15]=1>>[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][O:19][C:2]2[N:3]=[N:4][CH:5]=[C:6]3[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:7]=23)=[CH:16][CH:15]=1
Reactant: OCc1ccc(F)cc1
Reactant: Cc1[nH]c2c(Cl)nncc2c1C
Product: Cc1[nH]c2c(OCc3ccc(F)cc3)nncc2c1C
Yield: 29.8 %

Procedure:
The title compound was prepared as pale yellow crystals in 29.8% yield in a similar procedure to that described in Referential Example 79 by using 7-chloro-2,3-dimethylpyrrolo[2,3-d]pyridazine and 4-fluorobenzyl alcohol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Br[CH2:23][CH2:24][F:25]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:23][CH2:24][F:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(CCF)CC1
Temperature: 25 °C

Procedure:
Charge a reaction vessel with N-tert-butoxycarbonylpiperazine (1.600 g, 8.590 mmol), potassium carbonate (3.56 g, 25.77 mmol), sodium iodide (catalytic) (10 mg, 66.7 μmol), 1,4-dioxane (20 mL), and 1-bromo-2-fluoroethane (704.0 μL 9.45 mmol). Heat the mixture with stirring at reflux temperature overnight. Upon reaction completion, cool to room temperature and concentrate under reduced pressure. Partition the resulting residue with ethyl acetate and water. Separate the organic layer and dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to afford pure 4-(2-fluoro-ethyl)-piperazine-1-carboxylic acid tert-butyl ester. GC-MS m/z 232 (M).
Reaction SMILES: [CH3:1][N:2]([C@@H:10]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[Br:16][C:17]1[C:18](F)=[C:19]2[C:25]([NH:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1.CC#N.O>CCCCO.O>[Br:16][C:17]1[C:18]([N:12]2[CH2:13][CH2:14][CH2:15][C@@H:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7])[CH2:11]2)=[C:19]2[C:25]([NH:26][C:27](=[O:31])[CH:28]([CH3:29])[CH3:30])=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCCNC1
Reactant: CC(C)C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Solvent: CCCCO
Solvent: O
Solvent: CC#N
Product: CC(C)C(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](N(C)C(=O)OC(C)(C)C)C3)c12
Temperature: 160 °C
Yield: 13.2 %

Procedure:
(R)-tert-Butyl methyl(piperidin-3-yl)carbamate (471 mg, 2.20 mmol; Example E) was added to a suspension of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide (220 mg, 0.733 mmol) in n-BuOH (2.5 mL). The resulting mixture was heated in a sealed tube at 160° C. for 24 hours. The cooled mixture was diluted with water (40 mL) and extracted with EtOAc (3×20 mL). The combined organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 15-90% CH3CN/water, 25CV) to give (R)-tert-butyl 1-(5-bromo-3-isobutyramido-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-yl(methyl)carbamate (48 mg, 13% yield) as a solid. LCMS (APCI+) m/z 494.1, 497.1 (M+H)+, Retention time=4.18 minutes.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][C:12]2([C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[N:15]=[CH:14]2)[CH2:11][CH2:10][N:9]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[CH2:1]([CH:8]1[CH2:13][C:12]2([C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[NH:15][CH2:14]2)[CH2:11][CH2:10][N:9]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(C=Nc3ccc(Cl)cc32)CC1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC2(CNc3ccc(Cl)cc32)CC1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tert-butyl 2′-benzyl-5-chlorospiro[indole-3,4′-piperidine]-1′-carboxylate (200 mg, 0.49 mmol) was dissolved in dichloromethane (5 mL) and then sodium triacetoxy borohydride (206 mg, 0.97 mmol) was added followed by acetic acid (0.5 mL). The resulting mixture was stirred for 2 h at ambient temperature at which time it was quenched by the addition of saturated sodium bicarbonate solution. The mixture was diluted with EtOAc and then washed twice with water and once with brine. The organic layer was dried over magnesium sulfate, filtered and concentrated to give tert-butyl 2′-benzyl-5-chlorospiro[indoline-3,4′-piperidine]-1′-carboxylate. The material thus obtained was used without further purification (185 mg, 92%). LCMS (APCI+) m/z 311.1; Rt=4.32 min.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])=[C:4]([CH3:17])[CH:3]=1.[Br:18][C:19]1[CH:24]=[CH:23][C:22](I)=[C:21]([CH3:26])[CH:20]=1>>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:16]=[CH:15][C:5]([CH2:6][O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])=[C:4]([CH3:17])[CH:3]=2)=[C:21]([CH3:26])[CH:20]=1
Reactant: Cc1cc(Br)ccc1I
Reactant: Cc1cc(Br)ccc1CO[Si](C)(C)C(C)(C)C
Product: Cc1cc(-c2ccc(Br)cc2C)ccc1CO[Si](C)(C)C(C)(C)C
Yield: 34 %

Procedure:
In accordance with Example 19-(2), but using [(4-bromo-2-methylbenzyl)oxy](tert-butyl)dimethylsilane instead of tert-butyl 5-(benzyloxy)-2-{[1-(5-bromopyridin-2-yl)piperidin-4-yl]methyl}-6-methylpyrimidine-4-carboxylate, and 4-bromo-1-iodo-2-methylbenzene instead of tert-butyl[(4-iodobenzyl)oxy]dimethylsilane, the title compound (yield 34%) was afforded as a yellow oil.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]([OH:15])(=[O:14])[C:7]1[CH:12]=[CH:11][N+:10]([O-])=[CH:9][CH:8]=1>>[Cl:3][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][N:10]=1)[C:6]([OH:15])=[O:14]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(O)c1cc[n+]([O-])cc1
Product: O=C(O)c1ccnc(Cl)c1
Temperature: 120 °C
Reaction time: 7 h

Procedure:
Phosphorus oxychloride (220.7 g) was added to isonicotinic acid N-oxide (50.064 g), and the mixture was stirred on an oil bath at 120° C. for 7 hours. The reaction mixture was slowly poured into ice water with vigorously stirring to precipitate light yellow crystals. The mixture was adjusted to approximately pH 4 with 4N NaOH aqueous solution. The resulting crystals were filtered out, washed with water, and dried by vacuum heating (60° C.) to obtain the above-captioned compound ([9]-(92)-467) (37.845 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:41]1([CH2:47][CH2:48][CH2:49][NH2:50])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@H:13]([C:14](=[O:15])[NH:50][CH2:49][CH2:48][CH2:47][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:11])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: NCCCc1ccccc1
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)C(=O)NCCCc1ccccc1

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid and 3-phenylpropylamine (41 uL) according to Method A to give the title compound (48 mg). 1H-NMR (400 MHz, CD3OD) d 7.79 (s, 1H), 7.40 (d, J=8.5 Hz, 1H), 7.26-7.13 (m, 10H), 6.99 (d, J=8.5 Hz, 1H), 4.72 (s, 2H), 4.52 (t, J=6.8 Hz, 1H), 4.25 (dd, J=5.3 Hz, J=9.2 Hz, 1H), 3.18 (m, 1H), 3.09-2.92 (m, 4H), 2.77 (dd, J=9.5 Hz, J=13.5 Hz, 1H), 2.50 (t, J=7.7 Hz, 2H), 1.69 (m, 2H), 1.34 (s, 9H); IR (KBr) 3302, 2926, 1736, 1686, 1646 cm−1; HRMS m/z 647.2823 (calc. of monoisotopic mass for C35H41N3O9 gives 647.2823).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH:19]4[CH2:24][C:23]([CH3:26])([CH3:25])[NH:22][C:21]([CH3:28])([CH3:27])[CH2:20]4)[N:13]=3)=[CH:8][NH:9]2)=[CH:5][CH:4]=1.[H-].[Na+].CN(C=O)C.Br[CH2:37][C:38]#[N:39]>C1COCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH:19]4[CH2:24][C:23]([CH3:26])([CH3:25])[NH:22][C:21]([CH3:28])([CH3:27])[CH2:20]4)[N:13]=3)=[CH:8][N:9]2[CH2:37][C:38]#[N:39])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)c[nH]c2c1
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc2c(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)cn(CC#N)c2c1
Reaction time: 0.25 h

Procedure:
A solution of [4-(6-Methoxy-1H-indol-3-yl)-pyrimidin-2-yl]-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine (150 mg, 0.40 mmol) in 2 ml of THF was added to a suspension of sodium hydride (55.3 mg, 1.38 mmol, 60% mineral dispersion) in 2 ml of THF. 0.1 ml of DMF was added and stirring was continued for 15 minutes. Bromoacetonitrile (51.9 mg, 0.43 mmol) was then added and the solution was stirred for 5 hours. The solvent was removed and the residue was purified by flash chromatography on silicagel (EtOAc/MeOH/ammonia:5/1/0.05) to give the title compound. Yield: 142 mg (88%).
Reaction SMILES: OS([O-])(=O)=O.[Na+].O.[OH-].[Na+].[CH3:10][C@H:11]1[CH2:16][C@@H:15]([OH:17])[C@H:14]([C:18]([CH3:20])=[CH2:19])[CH2:13][CH2:12]1.OO.S([O-])([O-])=[O:24].[Na+].[Na+]>OP(O)(O)=O.O.C1(C)C=CC=CC=1>[CH3:10][C@H:11]1[CH2:16][C@@H:15]([OH:17])[C@H:14]([C:18]2([CH3:20])[O:24][CH2:19]2)[CH2:13][CH2:12]1
Reactant: C=C(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Reactant: O=S([O-])[O-]
Agent: O=P(O)(O)O
Agent: O=S(=O)([O-])O
Agent: OO
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@@H]1CC[C@@H](C2(C)CO2)[C@H](O)C1
Yield: 160.4 %

Procedure:
Into a 500 mL 4 necked flask equipped with a stirrer and a reflux condenser, NaWO4·2H2O (6.60 g, 0.02 mol), NaHSO4·H2O (6.90 g, 0.05 mol), [(Oct)3MeN]Cl (4.04 g, 0.01 mol), 85% H3PO4 (0.98 g, 0.0085 mol), toluene (77 g) and water (10 g) were charged. After adjusting pH of the solution to 4.0 with a 20% NaOH aqueous solution (5.8 g), L-isopulegol (77.1 g, 0.5 mol) was added thereto, and a 30% H2O2 aqueous solution (85 g, 0.75 mol) was added drop-wise at a temperature in a range of 35 to 40° C. for 1.5 hours with stirring. After the reaction mixture was stirred at 40° C. for further 10 hours, a 20% sodium sulfite aqueous solution (161 g, 0.26 mol) was added drop-wise to the reaction liquid at 40° C. or lower with stirring. After left for standing, an organic layer was separated, and the resulting organic layer was washed twice with water (100 g), and then the solvent was distilled off under reduced pressure to obtain a crude epoxide (83.8 g). The epoxide was distilled with a Claisen distiller to obtain 71.0 g of isopulegol epoxide (GC purity: 95.6%, boiling point: 93° C./533 Pa). Yield was 83% based on isopulegol.