Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:26]2[O:30][CH:29]=[N:28][CH:27]=2)[N:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][N:18]=[C:17](S(C)(=O)=O)[N:16]=3)=[CH:11][C:10]2=[O:25])=[CH:4][C:3]=1[F:31].[O:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1>CC(N(C)C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:26]2[O:30][CH:29]=[N:28][CH:27]=2)[N:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:38][CH:35]4[CH2:36][CH2:37][O:32][CH2:33][CH2:34]4)[N:16]=3)=[CH:11][C:10]2=[O:25])=[CH:4][C:3]=1[F:31]
Reactant: CS(=O)(=O)c1nccc(-c2ccn(C(c3ccc(Cl)c(F)c3)c3cnco3)c(=O)c2)n1
Reactant: NC1CCOCC1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=c1cc(-c2ccnc(NC3CCOCC3)n2)ccn1C(c1ccc(Cl)c(F)c1)c1cnco1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
A microwave tube was charged with a solution of 1-((4-chloro-3-fluorophenyl)(oxazol-5-yl)methyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one (53 mg, 0.12 mmol) in DMA (1.2 mL). Tetrahydro-2H-pyran-4-amine (35 mg, 0.35 mmol) was added neat by syringe. The reaction was put into a microwave apparatus and heated to 120° C. After 1 hour, the solution was diluted to 30 mL with ethyl acetate and washed with a water/brine mixture (4×30 mL). The organics were isolated, dried (MgSO4), filtered and concentrated. TLC in ethyl acetate showed complete loss of starting material and a new spot of nearly the same rf. The crude product was loaded onto a Biotage 12M column with ethyl acetate and eluted. Product containing fractions were pooled and concentrated to an oil, 1-((4-chloro-3-fluorophenyl)(oxazol-5-yl)methyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (20 mg, 36%). 1H NMR (400 MHz, CDCl3) δ 8.40 (d, 1H), 7.98 (s, 1H), 7.56 (s, 1H), 7.43 (dd, 1H), 7.31 (d, 1H), 7.22 (br s, 1H), 7.08 (s, 1H), 7.00 (m, 2H), 6.90 (s, 1H), 6.83 (dd, 1H), 5.20 (br d, 1H), 4.11 (m, 1H), 4.01 (m 2H), 3.55 (m, 2H), 2.06 (m, 2H), 1.58 (m, 2H); m/z (APCI-pos) M+1=483.0.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH2:30]([O:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH:35]=O)[CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:35][C:34]4[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=4[O:32][CH2:30][CH3:31])[CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOc1ccccc1C=O
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2ccccc2OCC)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 100.1 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylate (300 mg) and 2-ethoxybenzaldehyde (570 mg) in 1,2-dichloroethane (10 ml) was added sodium triacetoxyborohydride (402 mg), and the mixture was stirred under nitrogen atmosphere at room temperature for 5 days. Then, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was unified with silica gel column chromatography (hexane:ethyl acetate=3:1) to give methyl 7-(4-butoxyethoxyphenyl)-1-(2-ethoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylate (402 mg) as yellow oil.
Reaction SMILES: [CH:1]1([C:5]([NH:7][C@H:8]([C:24]([NH:26][CH:27]([P:35](=[O:38])([OH:37])[OH:36])[CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:25])[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=[O:6])[CH2:4][CH2:3][CH2:2]1.[C:39]1([CH2:45][O:46][C:47]([NH:49][CH2:50][CH2:51][CH2:52][CH2:53][C@H:54](O)[C:55]([N:57]2[CH2:71][CH2:70][CH2:69][C@H:58]2[C:59]([O:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)=[O:60])=[O:56])=[O:48])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[C:39]1([CH2:45][O:46][C:47]([NH:49][CH2:50][CH2:51][CH2:52][CH2:53][C@H:54]([O:38][P:35]([CH:27]([NH:26][C:24](=[O:25])[C@@H:8]([NH:7][C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)=[O:6])[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])[CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([OH:37])=[O:36])[C:55]([N:57]2[CH2:71][CH2:70][CH2:69][C@H:58]2[C:59]([O:61][CH2:62][C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)=[O:60])=[O:56])=[O:48])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(NCCCC[C@H](NC(=O)C1CCC1)C(=O)NC(Cc1ccccc1)P(=O)(O)O)OCc1ccccc1
Reactant: O=C(NCCCC[C@H](O)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: O=C(NCCCC[C@H](NC(=O)C1CCC1)C(=O)NC(Cc1ccccc1)P(=O)(O)O[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[1-[[N2 -(Cyclobutylcarbonyl)-N6 -[(phenylmethoxy) carbonyl]-L-lysyl]amino]-2-phenylethyl]phosphonic acid (500 mg., 0.91 mmole) is dissolved in pyridine (10 ml.) with 1-[(S)-6-[[(phenylmethoxy)carbonyl]amino]-2-hydroxy-1-oxohexyl]-L-proline, phenylmethyl ester (426 mg., 0.91 mmole). Dicyclohexylcarbodiimide (224 mg., 1.09 mmole) is added and the mixture is stirred at room temperature overnight. It is then concentrated in vacuo and partitioned between ethyl acetate and 5% potassium bisulfate after filtering to remove dicyclohexyl urea. The ethyl acetate layer is washed with brine, dried over sodium sulfate, and concentrated to give 1-[(S)-6-[[(phenylmethoxy)carbonyl]amino]-2-[[[1-[[(S)-6-[[(phenylmethoxy)carbonyl]amino]-2-[(cyclobutylcarbonyl)amino]-1-oxohexyl]amino]-2-phenylethyl]hydroxyphosphinyl]oxy]-1-oxohexyl]-L-proline, phenylmethyl ester as a crude oil. TLC (silica gel; dichloromethane:methanol:acetic acid, 20:1:1) Rf =0.33.
Reaction SMILES: Cl.[NH2:2][CH2:3][C@@H:4]1[O:8][C:7](=[O:9])[N:6]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH:19]=[O:20])[CH:14]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:13]3)[CH2:5]1.C(N(CC)CC)C.[C:32](SCC)(=[S:34])[CH3:33]>CO>[CH3:22][C:21]([CH:14]1[CH2:13][C:12]2[C:16](=[CH:17][CH:18]=[C:10]([N:6]3[CH2:5][C@H:4]([CH2:3][NH:2][C:32](=[S:34])[CH3:33])[O:8][C:7]3=[O:9])[CH:11]=2)[N:15]1[CH:19]=[O:20])([CH3:24])[CH3:23]
Reactant: CC(C)(C)C1Cc2cc(N3C[C@H](CN)OC3=O)ccc2N1C=O
Reactant: CCSC(C)=S
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(=S)NC[C@H]1CN(c2ccc3c(c2)CC(C(C)(C)C)N3C=O)C(=O)O1
Yield: 45.6 %

Procedure:
The amine hydrochloride salt (200 mg, 0.566 mmol) prepared in Step 12 is stirred in a mixture of methanol (4 ml) and triethylamine (0.234 ml, 1.683 mmol). To this solution is added ethyl dithioacetate (0.08 ml, 0.70 mmol) and the mixture heated to reflux for 2 hours then allowed to cool. The precipitate is filtered to afford the thioamide as white needles (97 mg, 46%): mp 219-221° C. Anal: Calcd. for C19H25N3O3S: C, 60.78; H, 6.71; N, 11.19. Found: C, 60.63; H, 6.80; N, 11.12.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.C(O)(C(F)(F)F)=O>O1CCCC1.[Ru]>[F:14][C:2]([F:1])([F:13])[CH:3]1[CH2:12][CH2:11][CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[NH:4]1
Reactant: FC(F)(F)c1ccc2ccccc2n1
Agent: [Ru]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)C1CCC2CCCCC2N1

Procedure:
15 g (0.076 mol) of 2-(Trifluoromethyl)quinoline [prepared from quinoline-2-carboxylic acid according to M. S. Raasch, J. Org. Chem. 27, 1406 (1962)] were hydrogenated in 100 ml of tetrahydrofuran on 2.5 g of ruthenium on alumina (about 10% RU content) at 180° C. for 8 h at an H2 pressure of 80-100 bar in a 0.3 1 V4A autoclave. After filtration, the THF was stripped off and the crude product was fractionated in a water pump vacuum by means of a microdistillation apparatus. B.p.16 (main fraction): 88° C. Yield: 12.5 g (0.061 mol) (80% of theory) The product was obtained as a diastereomer mixture. 19F--NMR: δ=+0.65 ppm(d, JH-F =7.1 Hz)(according to integral about 88%) 19F--NMR: δ=+0.90 ppm(d, JH-F =7.1 Hz)(according to integral about 12%) (against external CF3COOH).
Reaction SMILES: C1CO[CH:20]2[CH:3]([CH2:4][C:5]34O[C@H:6]3[C:7](=[CH2:30])[C@@H:8]3[C@@H:17]([C@@:18]4([CH3:24])[C@@H:19]2[CH3:23])[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][C@:11]3([F:29])OCC[O:25][CH:12]32)[O:2]1.[Mg].[CH3:33]I>C1C=CC=CC=1.C(OCC)C>[F:29][C@@H:11]1[CH2:10][C@H:9]2[C@H:8]3[C@H:17]([CH2:16][CH2:15][C@:13]2([CH3:14])[C:12]1=[O:25])[C@:18]1([CH3:24])[C:5](=[CH:4][C:3](=[O:2])[CH2:20][C@H:19]1[CH3:23])[C@H:6]([CH3:33])[C:7]3=[CH2:30]
Reactant: C=C1[C@@H]2[C@H](CC[C@]3(C)C4OCCO[C@@]4(F)C[C@@H]23)[C@@]2(C)[C@H](C)C3OCCOC3CC23O[C@@H]13
Reactant: CI
Agent: [Mg]
Solvent: CCOCC
Solvent: c1ccccc1
Product: C=C1[C@@H](C)C2=CC(=O)C[C@@H](C)[C@]2(C)[C@H]2CC[C@]3(C)C(=O)[C@H](F)C[C@H]3[C@H]12
Reaction time: 3 h
Yield: 80.5 %

Procedure:
3,17-bis(ethylenedioxy)-5,6α-epoxy-16α-fluoro-1β-methyl-7-methylenandrostane (431 mg) in benzene solution (40 ml), is added to a Grignard mixture prepared from magnesium (122 mg) and methyl iodide (710 mg) in diethylether (10 ml). Solvent is removed until the boiling point reaches ~78° C. Heating is then continued for a further 3 hrs. Ice and saturated ammonium chloride solution are added, the product extracted with ethyl acetate and the organic layer is evaporated in vacuo after having washed and dried it. The residue is dissolved in a 2:1 mixture of acetic acid and water (10 ml) and the solution heated for about 6 hrs at 40°-50° C. Then water is added and the product extracted with ethyl acetate. The organic layer is washed with sodium bicarbonate solution, dried and evaporated in vacuo. The residue is submitted to column chromatography thus giving pure 16α-fluoro-1β,6β-dimethyl-7-methylenandrost-4-ene-3,17-dione (275 mg).
Reaction SMILES: S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[C:16]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:20])[C@H:17]([CH3:19])O.N1C(C)=CC=CC=1C.[CH2:37]([O:40][NH2:41])[CH:38]=[CH2:39].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:22]([O:21][C:16](=[O:20])[C@@H:17]([CH3:19])[NH:41][O:40][CH2:37][CH:38]=[CH2:39])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C=CCON
Reactant: C[C@H](O)C(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: C=CCON[C@H](C)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
A solution of triflic anhydride (10.86 g, 38.5 mmol) in dry CH2Cl2 (20 mL) was added dropwise to a solution of benzyl (S)-lactate (1a) (6.31 g, 35 mmol) in dry CH2Cl2 (100 mL) with cooling (−68˜−72° C.) and stirring. After 5˜7 min, a solution of 2,6-lutidine (4.31 g, 40.3 mmol) in dry CH2Cl2 (15 mL) was added dropwise at the same temperature and the reaction mixture was stirred for 30 min at −68˜−72° C. A solution of O-allylhydroxylamine (4.55 g, 77 mmol) in dry CH2Cl2 (15 mL) was added dropwise to the prepared solution of the alkylating reagent with cooling (−68˜−72° C.) and stirring. The reaction mixture was stirred for 15 min at ca. −72° C. and then was allowed to warm up to RT. After stirring for 15 h at RT, the reaction mixture was thoroughly shaken with sat. aqueous NaHCO3 (200 mL) and dried over MgSO4. After removal of the solvent, the residue was purified by dry flash chromatography (Silica Gel 60H for TLC, 10% EtOAc-hexanes) to afford 8.20 g (99.6%) of the product 2a as a pale yellowish oil. 1H NMR (100 MHz) in CDCl3+1 drop of D2O (J, Hz): δ 1.28 (3H, d, 3J=7.1, MeCH), 3.82 (1H, q, 3J=7.1, MeCH), 4.22 (2H, dt, 3J=5.7, 4J=1.2, OCH2CH═CH2), 5.16-5.37 (2H, m, CH═CH2), 5.23 (2H, CH2Ph), 5.76-6.15 (1H, m, 3J=5.7, 3Jcis=9.9, 3Jtrans=17.1, CH═CH2), 7.38 (5H, Ph). 13C (100 MHz) in CDCl3: δ 14.81, 59.09, 66.63, 75.22, 117.53, 128.06, 128.24, 128.56, 134.37, 135.84, 174.01. IR (film), cm−1: 3264, 1740, 1456, 1208, 1170. Anal. Calcd for C13H17NO3: C, 66.4; H, 7.3; N, 5.95. Found: C, 66.3; H, 7.4; N, 6.15%.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.[C:18]([O:22][C:23]([N:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1[CH2:34][NH:35][CH:36]1[C:45]2[N:44]=[CH:43][CH:42]=[CH:41][C:40]=2[CH2:39][CH2:38][CH2:37]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:17]=[CH:16][C:13]([CH2:14][N:35]([CH2:34][C:26]2[N:25]([C:23]([O:22][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:24])[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[N:27]=2)[CH:36]2[C:45]3[N:44]=[CH:43][CH:42]=[CH:41][C:40]=3[CH2:39][CH2:38][CH2:37]2)=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(-c2nc3ccccc3[nH]2)cc1
Reactant: CC(C)(C)OC(=O)n1c(CNC2CCCc3cccnc32)nc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1c(CN(Cc2ccc(-c3nc4ccccc4[nH]3)cc2)C2CCCc3cccnc32)nc2ccccc21
Temperature: 60 °C
Reaction time: 3 h
Yield: 32.1 %

Procedure:
Using General Procedure B: To a solution 4-(benzimidazol-2-yl)-benzaldehyde (39 mg, 0.175 mmol) and (1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (60 mg, 0.16 mmol) in THF (2 mL) was added acetic acid (90 μL) and sodium triacetoxyborohydride (68 mg, 0.32 mmol) and the mixture stirred at 60° C. for 3 h. Purification of the crude product by radial chromatography on silica gel (0.7% MeOH/0.5% NH4OH/CH2Cl2) afforded the desired [4-(1H-benzimidazol-2-yl)-benzyl]-(N-tert-butoxycarbonylbenzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amine (30 mg, 39%) as a flaky white solid. 1H NMR (CDCl3) δ 1.72 (s, 10H), 1.97 (m, 2H), 2.26 (m, 1H), 2.73 (m, 2H), 3.80 (d, 1H, J=15.0 Hz), 4.00 (d, 1H, J=15.0 Hz), 4.35 (m, 1H), 4.71 (s, 2H), 7.00 (m, 1H), 7.14 (m, 2H), 7.24 (m, 3H), 7.33 (d, 2H, J=7.2 Hz), 7.47 (br, 1H), 7.53 (d, 1H, J=7.2 Hz), 7.63 (d, 1H, J=7.8 Hz), 7.67 (d, 2H, J=7.8 Hz), 7.79 (br, 1H), 8.39 (d, 1H, J=3.5 Hz), 9.92 (br, 1H (NH)).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.[CH3:32][O:33][C:34](=[O:45])[C:35]1[CH:40]=[CH:39][C:38]([CH2:41][NH2:42])=[CH:37][C:36]=1[O:43][CH3:44].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH3:32][O:33][C:34](=[O:45])[C:35]1[CH:40]=[CH:39][C:38]([CH2:41][NH:42][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]2)=[O:29])=[CH:37][C:36]=1[O:43][CH3:44]
Reactant: COC(=O)c1ccc(CN)cc1OC
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(CNC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1OC
Yield: 104 %

Procedure:
In a manner similar to the method described in Example 379, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (64 mg, 0.137 mmol) and 4-aminomethyl-2-methoxy-benzoic acid methyl ester (55 mg, 0.282 mmol) in N,N-dimethyl formamide (5 mL) were reacted with DIPEA (111.3 mg, 0.861 mmol), HOBt (38.8 mg, 0.287 mmol) and HBTU (107.6 mg, 0.284 mmol) at room temperature to give rac-4-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-2-methoxy-benzoic acid methyl ester (91.8 mg, ˜100%). HRMS (ES+) m/z Calcd C33H33Cl2F2N3O4+H [(M+H): 644.1889. Found: 644.1885.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O-:13])=O)[C:6]([O:8]CC)=[O:7])C.[Cl:14][C:15]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][CH2:19][NH:20]2.C(O)C.[OH-].[Na+]>O>[Cl:14][C:15]1[C:16]2=[C:21]3[N:20]([CH2:19][CH2:18][CH2:17]2)[CH:4]=[C:5]([C:6]([OH:8])=[O:7])[C:11](=[O:13])[C:22]3=[C:23]([Cl:25])[CH:24]=1
Reactant: Clc1cc(Cl)c2c(c1)NCCC2
Reactant: CCOC=C(C(=O)[O-])C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cn2c3c(c(Cl)cc(Cl)c3c1=O)CCC2
Temperature: 140 °C
Yield: 67.8 %

Procedure:
3.1 g of ethyl ethoxymethylenemalonate was added to 2.7 g of 5,7-dichloro-1,2,3,4-tetrahydroquinoline and the mixture was heated on an oil bath at 110° C. during which time distillation of ethanol was observed. After heating the mixture at the same temperature as above for 30 minutes, 30 g of polyphosphoric acid was added thereto followed by heating at 140° C. for 30 minutes. After completion of the reaction, the reaction mixture was poured into 100 ml of water and the resulting mixture was rendered neutral with a 40% aqueous sodium hydroxide solution to precipitate light brown crystals. Without further purification the crystals were mixed with 100 ml of a 10% aqueous sodium hydroxide solution and the mixture was heat-refluxed for 40 minutes during which time the crystals were dissolved to form a uniform solution. The solution was treated with activated carbon while hot and filtered. The filtrate was allowed to cool and adjusted to a pH of 2 to obtain 2.7 g of 8,10-dichloro-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid as light yellow crystals having a melting point of 300° to 304° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1.C(N(CC)C(C)C)(C)C.[NH2:25][C@@H:26]([CH2:39][CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)[CH2:27][N:28]1[C:36](=[O:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]1=[O:38].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:25][C@H:26]([CH2:27][N:28]2[C:36](=[O:37])[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]2=[O:38])[CH2:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)=[O:9])=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1
Reactant: Cn1nccc1-c1cc(C(=O)O)sc1Cl
Reactant: N[C@@H](CC1CCCCC1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1nccc1-c1cc(C(=O)N[C@@H](CC2CCCCC2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.2 %

Procedure:
To a solution of 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (150 mg, 0.62 mmol) [Prepared in Example 95], N,N-diisopropylethylamine (0.54 ml, 3.10 mmol) and 2-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione (200 mg, 0.62 mmol) [Prepared according to the procedure of Preparation 6, except substituting 3-cyclohexyl-N-{[(1,1-dimethylethyl)oxy]carbonyl}-L-alanine (5 g, 18.4 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (347 mg, 0.74 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 45% EtOAc in hexanes) yielding 5-chloro-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (168 mg, 0.33 mmol, 53% yield) as a clear oil: LCMS (ES) m/e 511, 513 (M, M+2)+.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[CH:10][C:9]([CH2:17][CH2:18][CH:19]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][CH:22]1[CH2:27][NH:26][CH2:25][CH2:24][N:23]1[C:28]1[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:21][CH:22]1[CH2:27][N:26]([CH2:19][CH2:18][CH2:17][C:9]2[CH:10]=[C:11]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH2:25][CH2:24][N:23]1[C:28]1[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=1
Reactant: Cc1cccc(N2CCNCC2C)c1
Reactant: O=CCCc1cc(-c2cccs2)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(N2CCN(CCCc3cc(-c4cccs4)n(-c4ccccc4)n3)CC2C)c1

Procedure:
55 mg (79%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)-propanal (40 mg, 0.142 mmol), 2-methyl-1-m-tolylpiperazine (27 mg, 0.142 mmol), DIPEA (0.040 mL, 0.213 mmol) and NaBH(OAc)3 (90 mg, 0.573 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.C(O[CH:12]=[C:13]([CH3:16])[CH:14]=O)C>C(O)(=O)C>[CH3:16][C:13]1[CH:12]=[N:1][C:2]2[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]=2[CH:14]=1
Reactant: CCOC=C(C)C=O
Reactant: NC1=CC(=O)CCC1
Solvent: CC(=O)O
Product: Cc1cnc2c(c1)C(=O)CCC2
Temperature: 0 °C

Procedure:
A mixture of 3-aminocyclohex-2-enone (24.1g, 0.22m) and 3-ethoxy-2-methylacrolein (27.7g, 0.24m) in glacial acetic acid (55 ml.) was heated at reflux for 24 hours, cooled to 0° C and filtered. The solid (5g.) was recrystallised from ethanol as colourless needles m.p. 253° and identified di(2-methylprop-2-enalyl)amine.
Reaction SMILES: C[OH:2].[C:3]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[C:21]([OH:22])=[C:20]([O:23][CH3:24])[C:19]([O:25][CH3:26])=[CH:18][C:17]=1[CH3:27])(=[O:5])[CH3:4].N1C=CC=CC=1>O=O.C1C=C(C=NCCN=CC2C([O-])=CC=CC=2)C([O-])=CC=1.[Co+2]>[C:3]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[C:21](=[O:22])[C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[C:18](=[O:2])[C:17]=1[CH3:27])(=[O:5])[CH3:4]
Reactant: COc1cc(C)c(CCCCCCCCCOC(C)=O)c(O)c1OC
Reactant: CO
Agent: [Co+2]
Agent: O=O
Agent: [O-]c1ccccc1C=NCCN=Cc1ccccc1[O-]
Solvent: c1ccncc1
Product: COC1=C(OC)C(=O)C(CCCCCCCCCOC(C)=O)=C(C)C1=O

Procedure:
To a methanol solution (30 ml) of 6-(9-acetoxynonyl)-2,3-dimethoxy-5-methylphenol (1.1 g) are added pyridine (0.3 ml) and bis(salicylidene)ethylenediiminocobalt(II) (14 mg), followed by stirring in oxygen streams at atmospheric temperature and pressure for 72 hours. The reaction product is isolated as in Example 7 and recrystallized from hexane. The above procedure yields 6-(9-acetoxynonyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone as orange-yellow needles melting at 30° C.