Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[CH2:19]([O:21][C:22](=[O:35])[CH:23]([O:32][CH2:33][CH3:34])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)[CH3:20].[CH2:36]([O:43][C:44]1[CH:49]=[CH:48][C:47]([CH2:50][CH2:51]O)=[CH:46][CH:45]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:19]([O:21][C:22](=[O:35])[CH:23]([O:32][CH2:33][CH3:34])[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][CH2:51][CH2:50][C:47]2[CH:48]=[CH:49][C:44]([O:43][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:45][CH:46]=2)=[CH:29][CH:30]=1)[CH3:20]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Reactant: OCCc1ccc(OCc2ccccc2)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccc(OCCc2ccc(OCc3ccccc3)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
Azodicarbonyl dipiperidine (7.5 g; 30 mmole) was added to 2-ethoxy-3-(4-hydroxyphenyl)propanoic acid ethyl ester (described in Example 20b) (7 g; 30 mmole), 2-(4-benzyloxyphenyl)ethanol (6.8 g; 30 mmole) and triphenylphosphine (7.8 g; 30 mmole) dissolved i dichloromethane. After stirring at room temperature overnight the solvent was evaporated in vacuo and diethyl ether was added. The solid material was filtered off after 1 hour and the filtrate was evaporated in vacuo. Purification by chromatography on silica gel using ethyl acetate:dichloromethane as eluant gave 10 g (yield 75%) of 3-{4-[2-(4-benzyloxyphenyl)ethoxy]phenyl}-2-ethoxypropanoic acid ethyl ester.
Reaction SMILES: [C:1]1(=[O:26])[N:5]([CH:6]2[C:19](=[O:20])[N:8]3[CH:9]([C:15]([O:17][CH3:18])=[O:16])[C:10]([CH3:14])([CH3:13])[S:11](=[O:12])[C@H:7]23)[C:4](=[O:21])[C:3]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:2]12.[Cl:27]N(C)S(C1C=CC(C)=CC=1)(=O)=O>C(Cl)(Cl)(Cl)Cl>[CH3:13][C:10](=[CH2:14])[CH:9]([N:8]1[C:19](=[O:20])[CH:6]([N:5]2[C:4](=[O:21])[C:3]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:2]3[C:1]2=[O:26])[CH:7]1[S:11]([Cl:27])=[O:12])[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)C1N2C(=O)C(N3C(=O)c4ccccc4C3=O)[C@H]2S(=O)C1(C)C
Reactant: Cc1ccc(S(=O)(=O)N(C)Cl)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(C)C(C(=O)OC)N1C(=O)C(N2C(=O)c3ccccc3C2=O)C1S(=O)Cl
Temperature: 25 °C

Procedure:
To 300 ml of carbon tetrachloride were added 3.7 g. (10 mmole) of methyl 6-phthalimido-2,2-dimethylpenam-3-carboxylate-1-oxide and 2.2 g. (10 mmol.) of N-chloro-N-methyl-p-toluenesulfonamide. The mixture was heated at reflux for 90 minutes. The reaction mixture then was cooled to room temperature, washed with water and brine, dried over magnesium sulfate, and divided into two equal portions.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][N:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH:6]2[CH2:5][CH2:4]1.Cl[C:14]1[C:18]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:17]=2[O:16][N:15]=1>>[Cl:23][C:21]1[CH:20]=[CH:19][C:18]2[C:14]([N:10]3[CH2:9][CH2:8][N:7]4[CH2:12][CH:3]([CH2:2][OH:1])[CH2:4][CH2:5][CH:6]4[CH2:11]3)=[N:15][O:16][C:17]=2[CH:22]=1
Reactant: OCC1CCC2CNCCN2C1
Reactant: Clc1ccc2c(Cl)noc2c1
Product: OCC1CCC2CN(c3noc4cc(Cl)ccc34)CCN2C1
Yield: 53.8 %

Procedure:
By the method of Example 7, the alcohol-amine title product of Example 6 (203 mg, 1.19 mmol) and 3,6-dichlorobenzo[d]isoxazole were converted into present title product (206 mg, 53.8% yield) isolated as a pale yellow amorphous solid. In this product the 7-and 9a-hydrogen substitutents are trans. TLC Rf (methylene chloride/methanol=9:1 in volume; potassium permanganate spray): 0.41. 13CNMR (CDCl3) delta 164.2, 160.6, 136.1, 123.3, 122.8, 114.9, 110.8, 65.9, 60.2, 58.7, 54.1, 53.4, 48.0, 39.0, 28.8, 26.7.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][N:6]=[C:5]([CH3:11])[CH:4]=1.C([Li])CCC.CN(C)[C:19](=[O:21])[CH3:20].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][N:6]=[C:5]([CH2:11][C:19](=[O:21])[CH3:20])[CH:4]=1
Reactant: CC(=O)N(C)C
Reactant: COc1cnc(C)cc1OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cnc(CC(C)=O)cc1OC
Temperature: 0 °C

Procedure:
To a stirred solution of 4,5-dimethoxy-2-methylpyridine (2.92 g) in tetrahydrofuran (30 ml) was added a solution of n-butyllithium in n-hexane (1.63M, 14 ml) dropwise at −50° C. under a nitrogen atmosphere, and the mixture was warmed to 0° C. The mixture was cooled to −50° C., and N,N-dimethylacetamide (2.31 ml) was added dropwise. Then the mixture was warmed to room temperature, poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate (100 ml×4). The combined organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 100 g, n-hexane:ethyl acetate=1:1) to give 1-(4,5-dimethoxypyridin-2-yl)propan-2-one (1.59 g).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1(=[O:15])[O:10][C:8](=[O:9])[C:7]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:6]12.[CH2:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17]>Cl>[CH2:16]([C:18]1[CH:23]=[CH:22][C:21]([C:8]([C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[C:5]([OH:10])=[O:15])=[O:9])=[CH:20][CH:19]=1)[CH3:17]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCc1ccc(C(=O)c2ccccc2C(=O)O)cc1

Procedure:
aluminum chloride (270 g) was added in portions to a stirred mixture of phthalic anhydride (270 g) and ethyl benzene (1125 ml). After 4 hours the mixture was poured onto ice and concentrated hydrochloric acid (450 ml) was added. Excess ethylbenzene was removed by steam distillation, and the residual solution was cooled and filtered so as to afford 2-(4-ethylbenzoyl)benzoic acid.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][O:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[N:31][CH:30]=1>>[CH3:26][O:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:8](=[O:9])[CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH:13]=[N:12]2)[CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:31][CH:30]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: Cc1ccccc1Oc1cnn(C(CC2CCCC2)C(=O)O)c(=O)c1
Product: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3ccccc3C)cc2=O)nc1
Yield: 32 %

Procedure:
Using the method described in Example 66, 3-cyclopentyl-2-(6-oxo-4-o-tolyloxy-6H-pyridazin-1-yl)-propionic acid (Intermediate 41) and 6-amino-nicotinic acid methyl ester afforded 6-[3-cyclopentyl-2-(6-oxo-4-o-tolyloxy-6H-pyridazin-1-yl)-propionylamino]-nicotinic acid methyl ester as a yellow solid (230 mg, 32%); ESI-LRMS m/e calcd for C26H28N4O5 [M+] 477, found 477 [M+H+]. 1H-NMR (300 MHz, DMSO-d6) δ ppm 0.95-1.25 (m, 1H) 1.31-1.81 (m, 8H) 1.85-2.07 (m, 1H) 2.16 (s, 3H) 2.21-2.41 (m, 1H) 3.85 (s, 3H) 5.51-5.60 (m, 1H) 5.58 (d, J=2.8 Hz, 1H) 7.22 (dd, J=7.5, 1.5 Hz, 1H) 7.24-7.38 (m, 2H) 7.38-7.45 (m, 1H) 8.11 (d, J=8.8 Hz, 1H) 8.19 (d, J=2.8 Hz, 1H) 8.27 (dd, J=8.8, 2.4 Hz, 1H) 8.87 (d, J=2.4 Hz, 1H) 11.39 (s, 1H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[NH2:10][C:11]1[N:15]([CH3:16])[N:14]=[C:13]([C:17]2[C:22]([Cl:23])=[CH:21][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][C:18]=2[Cl:28])[CH:12]=1>O>[NH2:10][C:11]1[N:15]([CH3:16])[N:14]=[C:13]([C:17]2[C:22]([Cl:23])=[CH:21][C:20]([C:24]([F:25])([F:27])[F:26])=[CH:19][C:18]=2[Cl:28])[C:12]=1[N+:1]([O-:4])=[O:2]
Reactant: Cn1nc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1N
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cn1nc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c([N+](=O)[O-])c1N
Reaction time: 0.17 h

Procedure:
To 2.8 g of concentrated nitric acid was added dropwise 3.7 g of concentrated sulfuric acid at room temperature, followed by stirring for 10 minutes to obtain a mixed acid solution. A 0.5 g quantity of 5-amino-3-(2,6-dichloro-4-trifluoromethylphenyl)-1-methylpyrazole (13) was added in small portions to the solution at 60° C., and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was added to water, the resulting mixture was extracted with ether, and the aqueous layer was made weakly alkaline with a saturated sodium carbonate aqueous solution and then extracted with ethyl acetate, followed by washing with brine and drying over anhydrous magnesium sulfate. Removal of the solvent gave 0.2 g of the desired compound in the form of orange crystals (yield 35.1%), m.p. 107°-108° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:16]3[CH2:15][CH2:14][NH:13][CH2:12][C:11]=3[C:10](=[O:17])[O:9][C:7]=2[CH:8]=1.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:16]3[CH2:15][CH2:14][N:13]([CH2:24][C:23]4[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:28])[F:29])=[CH:27][CH:26]=4)[CH2:12][C:11]=3[C:10](=[O:17])[O:9][C:7]=2[CH:8]=1
Reactant: COc1ccc2c3c(c(=O)oc2c1)CNCC3
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Product: COc1ccc2c3c(c(=O)oc2c1)CN(Cc1ccc(C(F)(F)F)cc1)CC3
Yield: 70 %

Procedure:
Prepared by the procedure of Example 3 from 8-methoxy-1,2,3,4-tetrahydro-chromeno[3,4-c]pyridin-5-one and 4-trifluoromethylbenzaldehyde. Yield 70%; mp 203°-206° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[CH3:33])[CH2:5][CH:6]([CH2:10][C:11](=[O:29])[N:12]1[CH2:17][CH2:16][CH:15]([N:18]2[CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][C:19]2=[O:28])[CH2:14][CH2:13]1)[C:7](O)=[O:8].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)C(C)C)C.[N:75]1([CH:81]2[CH2:86][CH2:85][NH:84][CH2:83][CH2:82]2)[CH2:80][CH2:79][CH2:78][CH2:77][CH2:76]1>O.C1COCC1>[N:75]1([CH:81]2[CH2:86][CH2:85][N:84]([C:7](=[O:8])[CH:6]([CH2:5][C:4]3[CH:30]=[CH:31][C:32]([CH3:33])=[C:2]([CH3:1])[CH:3]=3)[CH2:10][C:11]([N:12]3[CH2:17][CH2:16][CH:15]([N:18]4[CH2:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[NH:20][C:19]4=[O:28])[CH2:14][CH2:13]3)=[O:29])[CH2:83][CH2:82]2)[CH2:80][CH2:79][CH2:78][CH2:77][CH2:76]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: Cc1ccc(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)O)cc1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCCCC3)CC2)cc1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 0.9 g (2.0 mmol) 2-(3,4-dimethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butanoic acid, 0.71 g (2.2 mmol) TBTU, 0.28 g (2.1 mmol) HOBt, 0.39 mL (2.2 mmol) ethyldiisopropylamine, 45 mL THF and 5 mL water was stirred for 10 min at RT, combined with 0.37 g (2.1 mmol) [1,4′]bipiperidinyl and stirred for a further 4 h. The reaction mixture was evaporated down under reduced pressure, the residue was combined with saturated NaHCO3 solution and extracted three times with DCM/MeOH (95:5). The combined organic phases were dried, evaporated down under reduced pressure and purified by chromatography over silica gel. The product fractions were evaporated down under reduced pressure, the residue was triturated with diisopropylether and suction filtered.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:35]=[N:34][N:33]([CH:36]([CH3:38])[CH3:37])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][N:23]([C:26]([CH:28]3[CH2:32][CH2:31][NH:30][CH2:29]3)=[O:27])[CH2:24][CH:25]=2)[CH:19]=1)=[O:13].C=O.[BH3-][C:42]#N.[Na+]>CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:35]=[N:34][N:33]([CH:36]([CH3:38])[CH3:37])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][N:23]([C:26]([CH:28]3[CH2:32][CH2:31][N:30]([CH3:42])[CH2:29]3)=[O:27])[CH2:24][CH:25]=2)[CH:19]=1)=[O:13]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C(=O)C4CCNC4)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C(=O)C4CCN(C)C4)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 30 %

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(1-(pyrrolidine-3-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.) in methanol was added formalin (5 equiv.) stirred it at room temperature for 10 min. Then NaBH3CN (1 equiv.) was added to it Resulting reaction mixture was stirred at room temperature for 1 h. After completion of reaction, solvent was removed under reduced pressure and water was added to it. Extraction was carried out using 10% MeOH/DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired compound (30% yield). LCMS: 532.35 (M+1)+; HPLC: 89.75% (@ 254 nm) (Rt; 7.188); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (s, 1H), 8.84 (bs, 1H), 8.30 (s, 1H), 7.84 (d, 1H, J=10 Hz), 6.91 (bs, 1H), 5.89 (s, 1H), 5.21 (m, 1H), 4.38 (d, 2H, J=4.4 Hz), 4.29 (bs, 1H), 4.21 (bs, 1H), 3.70 (bs, 2H), 2.76 (m, 2H), 2.66 (bs, 1H), 2.43 (m, 1H), 2.32 (m, 1H), 2.22 (s, 3H), 2.20 (s, 3H), 2.12 (s, 3H), 2.00-1.94 (m, 4H), 1.50 (d, 6H, J=6.8 Hz).
Reaction SMILES: [CH:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=O)[CH:15]=3)[CH2:10][CH2:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH3:53][CH:54]([CH3:57])[CH2:55][NH2:56]>C(Cl)Cl.O>[CH:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH:56][CH2:55][CH:54]([CH3:57])[CH3:53])=[O:19])[CH:15]=3)[CH2:10][CH2:9][N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)CN
Reactant: O=C(O)c1ccc2c(c1)C(C1CCCCC1)=NCC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)CNC(=O)c1ccc2c(c1)C(C1CCCCC1)=NCC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-cyclohexyl-3,4-dihydroisoquinoline-7-carboxylic acid (1.15 g) was dissolved in methylene chloride (15 mL). O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (2.03 g), N,N-diisopropylethylamine (1.55 mL), and 2-methyl-1-propanamine (0.87 mL) were added thereto, followed by stirring at room temperature for 18 hours. Then, water was added to the mixture, followed by extraction with chloroform. The extract was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (chloroform-MeOH) to obtain 1-cyclohexyl-N-isobutyl-3,4-dihydroisoquinoline-7-carboxamide (700 mg).
Reaction SMILES: [CH:1]1([N:4]([CH:16]2[CH2:19][O:18][CH2:17]2)[CH:5]2[CH2:10][CH2:9][CH:8]([C:11](OCC)=[O:12])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH:1]1([N:4]([CH:16]2[CH2:19][O:18][CH2:17]2)[CH:5]2[CH2:6][CH2:7][CH:8]([CH2:11][OH:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)C1CCC(N(C2CC2)C2COC2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCC1CCC(N(C2CC2)C2COC2)CC1
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 329B (1.2 g) in tetrahydrofuran (20 mL) was added lithium aluminum hydride (0.681 g). The mixture was stirred overnight. 2N aqueous NaOH solution was added dropwise to the reaction mixture. The mixture was then diluted with ethyl acetate (300 mL) and washed with water, brine and dried over Na2SO4. Filtration and evaporation of the solvent gave the title compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:13][CH2:14][CH2:15][Cl:16].C1(O)C=CC=CC=1>COCCOC>[Cl:16][CH2:15][CH2:14][CH2:13][O:9][C:6]1[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1
Reactant: CSc1ccc(O)cc1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: Oc1ccccc1
Product: CSc1ccc(OCCCCl)cc1
Yield: 32 %

Procedure:
A solution of 4-(methylthio)phenol (10.0 g, 0.071 mole) in 150 ml. of 1,2-dimethoxyethane is added to a slurry of a 57% dispersion of sodium hydride (3.0 g., 0.071 mole) in mineral oil (previously washed with hexane to remove the mineral oil) in 100 ml. of 1,2-dimethoxyethane. After the initial reaction is complete, 1-bromo-3-chloropropane (12.63 g., 0.08 mole) is added in one portion. The resulting mixture is stirred and refluxed for a period of 68 hrs., cooled and then concentrated under reduced pressure. Residual material (oil) is dissolved in ether and washed with water. The ether solution (after drying over magnesium sulfate) is concentrated under reduced pressure to provide 14.6 g. of an oil containing approximately 25% starting phenol according to NMR spectra. Distillation of the oil under reduced pressure affords, after a forerun of 4-(methylmercapto)phenol, 5.0 g. (32% yield) of 1-chloro-3-[4-(methylthio)phenoxy]propane, b.p. 150°-152° C. at 27 mm Hg.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:19]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH2:18][C@@:17]2([CH3:26])[CH:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:27])[CH2:3]1.[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[C:30]([C:38]([N:40]2[CH2:47][CH2:46][CH2:45][C@H:41]2[C:42](O)=[O:43])=[O:39])[N:29]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[OH:1][C@@H:2]1[C@@H:19]([N:20]2[CH2:21][CH2:22][N:23]([C:42]([C@@H:41]3[CH2:45][CH2:46][CH2:47][N:40]3[C:38]([C:30]3[N:29]=[CH:28][C:37]4[C:32]([CH:31]=3)=[CH:33][CH:34]=[CH:35][CH:36]=4)=[O:39])=[O:43])[CH2:24][CH2:25]2)[CH2:18][C@@:17]2([CH3:26])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:27])[CH2:3]1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)c1cc2ccccc2cn1
Reactant: C[C@]12C[C@H](N3CCNCC3)[C@@H](O)CC1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@]12C[C@H](N3CCN(C(=O)[C@@H]4CCCN4C(=O)c4cc5ccccc5cn4)CC3)[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 8 h

Procedure:
To a solution of compound 23 (356 mg, 0.95 mmol) in anhydrous DMF (5 mL) at room temperature under an atmosphere of argon were added 1-(isoquinolin-3-ylcarbonyl)-L-proline (335 mg, 1.2 mmol), PyBOP (647 mg, 1.2 mmol), HOBt (168 mg, 1.2 mmol), and DIPEA (662 μL, 3.8 mmol). The solution was subsequently stirred overnight at room temperature. The resulting solution was then poured into water and extracted with EtOAc (2×30 mL), washed with brine, dried with MgSO4 and evaporated to dryness. Purification by two successive flash chromatography procedures using (DCM/MeOH: 95:5) and (Hexanes/Acetone: 1:1) respectively yielded 302 mg (50%) of compound 43. 1H NMR (CDCl3) δ: 0.84 and 0.86 (2s, 18-CH3), 0.89 and 0.90 (2s, 19-CH3), 0.70-2.30 (residual CH and CH2), 2.35-2.85 (broad m, 2×CH2N, 16β-CH and 2α-CH), 3.10-4.27 (broad m, 2×CH2NCO, CH2N of proline, and 3β-CH), 5.10 and 5.88 (2m, NCHCO of proline), 7.58 (m, CH of quinoline), 7.76 (m, CH of quinoline), 7.84 (t, J=8.3 Hz, CH of quinoline), 7.98 (t, J=8.7 Hz, CH of quinoline), 8.02 and 8.12 (2d, J=8.6 Hz, CH of quinoline), 8.21 and 8.24 (2d, J=8.9 Hz, CH of quinoline).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH3:19])[C:13]([CH3:18])([CH3:17])[C:14](O)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[N:22](C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.N>C1COCC1>[NH2:22][C:14](=[O:15])[C:13]([CH3:18])([CH3:17])[C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:19]
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(C)(C)C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: N
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCCl
Product: C[C@@H](NC(=O)OCc1ccccc1)C(C)(C)C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.6 %

Procedure:
To a solution of (R)-3-(((benzyloxy)carbonyl)amino)-2,2-dimethylbutanoic acid (9.0 g, 33.9 mmol) in THF (100 mL) under N2 atmosphere DIPEA (17.77 mL, 102 mmol) was added followed by addition of HOBT (5.19 g, 33.9 mmol) and EDC (6.50 g, 33.9 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 1 h. Then freshly prepared saturated ammonia in THF 50 mL (50 mL of THF, ammonia gas was purged at −40° C. for 20 min) was poured into the above reaction mixture at −20° C. and slowly allowed reaction mass temperature to 25° C. and stirred for further 12 h. Upon completion of the reaction, it was quenched with water (250 mL) and extracted into ethyl acetate (2×200 mL). The combined organic layer was washed with brine solution, dried over anhydrous sodium sulphate, concentrated under reduced pressure to obtain pale brown oil. This crude product was purified by column chromatography using 60-120 silica gel, by eluted with ethyl acetate:hexane (40:60) to yield (R)-benzyl (4-amino-3,3-dimethyl-4-oxobutan-2-yl)carbamate (4.8 g, 46.5%) as pale yellow oil. 1HNMR (400 MHz, CDCl3) δ ppm: 7.36-7.35 (d, J=4.4 Hz, 5H), 5.104 (s, 2H), 3.75-3.67 (t, J=16, 18.4 Hz, 1H), 1.25-1.24 (d, J=5.2 Hz, 6H), 1.18-1.17 (d, J=6.8 Hz, 3H). HPLC purity: Column: Sunfire C18 (4.6×150 mm, 3.5 μm), Buffer: 0.05% TFA in H2O (pH 2.5, adjusted with ammonia), Solvent A: Buffer: CH3CN (95:5). Solvent B: Buffer: CH3CN (5:95). Time: 0-10, 12-100, 15-100 min, Flow: 1.0 mL/min Retention Time: 7.408: Purity: 93.74%. Chiral HPLC purity: Column: CHIRALPAK AD-H (250×4.6 mm) 5 micron, Mobile Phase: 0.2% DEA in hexane:ethanol (50:50). Flow: 1.0 mL/min: Retention Time: 6.036. Purity: 100%. LCMS Purity: Column: Ascentis C18 (5×2.1 mm-2.7 μm). Mobile Phase A: 2% ACN −98% H2O-10 mM NH4COOH. Mobile Phase B: 98% ACN −2% H2O-10 mM NH4COOH. Flow: 1.0 mL/min. Retention Time: 1.785 Min. Purity: 99.9% (m/z=265.2 M+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[C:4]([Cl:14])[CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH:19]=O>CO>[Cl:14][C:4]1[CH:3]=[C:2]([N:1]=[CH:19][C:18]2[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:16]([F:15])[CH:17]=2)[CH:7]=[C:6]([Cl:8])[C:5]=1[N:9]=[CH:10][N:11]([CH3:12])[CH3:13]
Reactant: COc1ccc(C=O)cc1F
Reactant: CN(C)C=Nc1c(Cl)cc(N)cc1Cl
Solvent: CO
Product: COc1ccc(C=Nc2cc(Cl)c(N=CN(C)C)c(Cl)c2)cc1F
Temperature: 5 °C

Procedure:
A 7.0 g. amount of N'-(4-amino-2,6-dichlorophenyl)-N,N-dimethylformamidine and 4.6 g. of 3-fluoro-p-anisaldehyde are each dissolved separately in 25 ml. of warm methanol and then combined. The mixture is cooled at 5° C. The crystallized product is collected and washed with ether to provide 8.2 g. of the product of the Example as yellow crystals, m.p. 139°-141° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:35])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28](I)[CH:27]=[CH:26][C:25]=3[O:31][CH2:32][CH2:33][OH:34])[C:5]2=[CH:4][CH:3]=1.[CH3:36][Si:37]([C:40]#[CH:41])([CH3:39])[CH3:38].CCN(CC)CC>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:35])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([C:41]#[C:40][Si:37]([CH3:39])([CH3:38])[CH3:36])[CH:27]=[CH:26][C:25]=3[O:31][CH2:32][CH2:33][OH:34])[C:5]2=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(I)ccc2OCCO)N1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1ccc(OCCO)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1
Temperature: 76 °C

Procedure:
To a solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-iodo-2-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (6.05 g, 9.71 mmol) prepared in example 190c in DMF (80 mL) were added trimethylsilylacetylene (10 mL), CuI (40 mg), Et3N (50 mL), PdCl2(Ph3P)2 (Aldrich, 205 mg, 0.29 mmol) were added. The mixture was purged with nitrogen and heated at 76° C. for 1.5 h, then cooled to room temperature. The mixture was poured into water, extracted with EtOAc several times. The extracts were combined and dried with sodium sulfate and dried to give a foam. The foam was purified by chromatography to give the title compound as a light yellow solid. Yield 3.28 g, 57%.