Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][N:11]([CH3:28])[CH2:12][CH:13]([OH:27])[CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[C:1]([O:27][CH:13]([CH2:12][N:11]([CH3:10])[CH3:28])[CH:14]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CC(O)C(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CN(C)CC(OC(=O)c1ccccc1)C(c1ccccc1)c1ccccc1
Reaction time: 4 h
Yield: 99 %

Procedure:
Benzoyl chloride (1 49g) was added to 3-dimethylamino-1,1-diphenyl-propan-2-ol (2,55g) in dry pyridine (10 ml.) and the solution allowed to stand for 4 hours. Pyridine was removed by evaporation and the residue dissolved in dilute hydrochloric acid and ether. Basification of the acid extract and isolation through ether in the usual manner gave 2-benzoyloxy-3-dimethylamino-1,1-diphenyl-propane (3.47g . 99%), m.p. 90°- 91°.
Reaction SMILES: [C:1]1([P:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:9][CH2:10][NH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[CH:18](=[N:11][CH2:10][CH2:9][CH2:8][P:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCCCP(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccc1
Solvent: CCO
Product: C(=NCCCP(c1ccccc1)c1ccccc1)c1ccccc1
Yield: 96.2 %

Procedure:
Under argon, a solution of 3-diphenylphosphino-propylamine (631.2 mg, 2.6 mmol) and benzaldehyde (278.1 mg, 2.6 mmol) in ethanol (15 mL) was heated at 65° C. (oil bath) for 4 h. Then, the solvent was removed in-vacuo to give the desired product (>98% by 1H-NMR) as a white solid (822.3 mg, 2.5 mmol, 96%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][N:3]=1.[C:8](Cl)(=[O:11])[CH:9]=[CH2:10].C(N(CC)CC)C.N1C=CC=N1>C1C=CC=CC=1>[C:8]([N:3]1[C:2]([CH3:1])=[CH:6][C:5]([CH3:7])=[N:4]1)(=[O:11])[CH:9]=[CH2:10]
Reactant: Cc1cc(C)[nH]n1
Reactant: C=CC(=O)Cl
Agent: c1cn[nH]c1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=CC(=O)n1nc(C)cc1C
Temperature: 10 °C
Reaction time: 4 h

Procedure:
N-acrylyl-3,5-dimethyl pyrazole was prepared by reacting 3,5-dimethylpyrazole with acrylyl chloride in the presence of triethylamine. 19.2 grams (0.2 mole) of 3,5-dimethylpyrazole and 20.2 grams (0.2 mole) of triethylamine were dissolved in 125 milliliters of benzene and the solution put into a dropping funnel. The acrylyl chloride, 18.1 grams (0.2 mole) was dissolved in 25 milliliters of benzene and this solution put into a flask equipped for stirring and cooled at 10°C. The pyrazole solution was then added to the acrylyl chloride solution over a period of 45 minutes with constant stirring. Temperature of the reaction mix was held at 8°C. to 15°C. throughout the addition. Following the addition, the reaction mix was allowed to warm to room temperature and let stand for 4 hours. The mix was then filtered to remove triethylamine-hydrochloric acid salt which was formed in the reaction. The filtrate was heated to evaporate off volatiles, leaving 24.5 grams of an amber-colored liquid residue. The residue was then cooled to about 0°C. and 12.1 grams of a white crystalline precipitate was filtered out. After standing 16 hours at about 0°C., 2.5 more grams of crystalline solid was filtered out. The solids were combined and twice recrystallized from a solution of 18 milliliters of methanol and 2 milliliters of water to yield 9.4 grams of a crystalline solid having a melting point of 36°-37°C. The nuclear magnetic resonance (NMR) spectra of the solid conformed with that of the expected product.
Reaction SMILES: C(N)(=O)C.Br[C:6]1[CH:7]=[CH:8][C:9]([N+:12]([O-:14])=[O:13])=[N:10][CH:11]=1.[CH3:15][S:16]([NH2:19])(=[O:18])=[O:17].C(=O)([O-])[O-].[K+].[K+].Cl>O>[N+:12]([C:9]1[N:10]=[CH:11][C:6]([NH:19][S:16]([CH3:15])(=[O:18])=[O:17])=[CH:7][CH:8]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CS(N)(=O)=O
Agent: CC(N)=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Product: CS(=O)(=O)Nc1ccc([N+](=O)[O-])nc1
Temperature: 145 °C
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
A solution of molten acetamide (2.36 g, 40.0 mmol) heated to 90° C. was treated with a mixture of 5-bromo-2-nitropyridine (2.0 g, 9.85 mmol), methanesulfonamide (2.81 g, 29.55 mmol), and potassium carbonate (3.43 g, 24.8 mmol). The resulting mixture was quickly brought to 145° C. The resulting solution was stirred at 145° C. for 30 min. At this time, the reaction was cooled to 25° C. and then was treated with water (8 mL). This solution was cooled to 0° C. and then was treated with a 1N aqueous hydrochloric acid solution until the pH of the solution was adjusted to pH=8. The precipitate which resulted was removed by filtration. The filtrate was adjusted to pH=4 by the addition of a 1N aqueous hydrochloric acid solution. The resulting precipitate was collected and dried in vacuo to afford N-(6-nitro-pyridin-3-yl)-methanesulfonamide (1.46 g, 68%) as a white solid: mp 187–189° C.; (ES)−-HRMS m/e calcd for C6H7N3O4S (M−H)− 216.0084, found 216.0085.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][CH2:5][C:6]([NH:8][C@H:9]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-])=O)[CH:24]=2)=[CH:19][CH:18]=1)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:7]>CCO.[Pd]>[NH2:29][C:25]1[CH:24]=[C:23]([C:20]2[CH:19]=[CH:18][C:17]([CH2:16][C@@H:9]([NH:8][C:6](=[O:7])[CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:32])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:22][CH:21]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc([N+](=O)[O-])c2)cc1)NC(=O)CCC(=O)OC
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(N)c2)cc1)NC(=O)CCC(=O)OC
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 91.6 %

Procedure:
A suspension of (R)-ethyl 3-(4-methoxy-4-oxobutanamido)-4-(3′-nitrobiphenyl-4-yl)butanoate (123 mg, 0.278 mmol) and Pd/C (59.2 mg, 0.028 mmol) in EtOH (2 ml) is allowed to stir under hydrogen at room temperature for 5.5 hours. The reaction mixture is filtered, and the solution is concentrated to give (R)-ethyl 4-(3′-aminobiphenyl-4-yl)-3-(4-methoxy-4-oxobutanamido)butanoate (105 mg); HPLC retention time=0.84 minutes (condition B); MS (m+1)=413.1; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.28 (t, J=7.2 Hz, 3 H) 2.41-2.65 (m, 6 H) 2.85-3.00 (m, 2 H) 3.67 (s, 3 H) 4.11-4.22 (m, 2 H) 4.46-4.54 (m, 1 H) 6.31 (br d, J=8.8 Hz, 1 H) 6.71-6.74 (m, 1 H) 6.95-7.02 (m, 2 H) 7.21-7.25 (m, 3 H) 7.48-7.50 (m, 2 H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[C:30]([Cl:35])[CH:29]=3)=[C:20]([C:36]([F:39])([F:38])[F:37])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.Cl>C(O)C>[ClH:35].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[C:30]([Cl:35])[CH:29]=2)=[C:20]([C:36]([F:39])([F:38])[F:37])[CH:19]=1)([CH2:13][OH:12])[CH2:9][OH:10]
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(OCCCc3ccc(F)c(Cl)c3)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: Cl
Solvent: CCO
Product: NC(CO)(CO)CCc1ccc(OCCCc2ccc(F)c(Cl)c2)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 170.5 %

Procedure:
Compound 61-4 (740 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (520 mg) as a white powder.
Reaction SMILES: Cl.O1CCOCC1.CN(C)S([N:13]1[CH:17]=[CH:16][C:15]([C:18]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=2)([NH:20]S(C(C)(C)C)=O)[CH3:19])=[N:14]1)(=O)=O>CO>[Cl:33][C:29]1[CH:28]=[C:27]([C:18]([NH2:20])([C:15]2[CH:16]=[CH:17][NH:13][N:14]=2)[CH3:19])[CH:32]=[CH:31][CH:30]=1
Reactant: CN(C)S(=O)(=O)n1ccc(C(C)(NS(=O)C(C)(C)C)c2cccc(Cl)c2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(N)(c1cccc(Cl)c1)c1cc[nH]n1
Temperature: 80 °C
Reaction time: 18 h
Yield: 85.4 %

Procedure:
Hydrochloric acid 4 M in dioxane (19.79 mL, 79.15 mmol) was added to a solution of 3-[1-(3-chloro-phenyl)-1-(2-methyl-propane-2-sulfinylamino)-ethyl]-pyrazole-1-sulfonic acid dimethylamide (2.29 g, 5.28 mmol) in MeOH (5 mL) and the mixture was stirred at 80° C. in a sealed tube for 18 hours. The solvent was evaporated in vacuo. The residue was poured into NaHCO3 (aq. sat. solution) and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo to yield rac-1-(3-chloro-phenyl)-1-(1H-pyrazol-3-yl)-ethylamine (1 g, 86% yield) as a pale yellow solid which was used in the next step without further purification.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][C:14]([NH:16][C@@H:17]([CH2:20][C:21]1[NH:25][CH:24]=[N:23][CH:22]=1)[CH2:18][OH:19])=[O:15])=O)C1C=CC=CC=1>[Pd].CO.O>[NH2:11][CH2:12][CH2:13][C:14]([NH:16][C@@H:17]([CH2:20][C:21]1[NH:25][CH:24]=[N:23][CH:22]=1)[CH2:18][OH:19])=[O:15]
Reactant: O=C(CCNC(=O)OCc1ccccc1)N[C@H](CO)Cc1cnc[nH]1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: NCCC(=O)N[C@H](CO)Cc1cnc[nH]1
Temperature: 40 °C
Yield: 56.5 %

Procedure:
A round-bottom flask under inert atmosphere is loaded with 26 g of the oily product from Example 3, and 100 g of a 1:1 methanol/water mixture. The mixture is stirred to complete dissolution, then added with 2.6 g of 10% Pd/C. A washing cycle is carried out under nitrogen-vacuum, then the mixture is heated to 40° C. and hydrogen is slowly bubbled therein until complete disappearance of the starting product. The mixture is cooled to 30° C. and the catalyst is filtered off through a celite pad, washing twice with a methanol-water mixture. The solvent is evaporated off and the residue is repeatedly taken up with isobutanol and evaporated to obtain 9 g of a white solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[I-].C[N+]1C=CN([C:26]([N:28]2[CH2:33][CH2:32][CH2:31][CH:30]([CH3:34])[CH2:29]2)=[O:27])C=1>>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:26]([N:28]3[CH2:33][CH2:32][CH2:31][CH:30]([CH3:34])[CH2:29]3)=[O:27])=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: CC1CCCN(C(=O)n2cc[n+](C)c2)C1
Agent: [I-]
Product: CC1CCCN(C(=O)Oc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)C1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 1-methyl-3-(3-methyl-piperidine-1-carbonyl)-3H-imidazol-1-ium iodide. The crude product was purified by flash chromatography using a Quad flash 25 (ethyl acetate/heptane (1:6), (75%, white crystals). HPLC-MS m/z=381.1 (M+1), Rt: 5.4 min.
Reaction SMILES: N#N.C(NC(C)C)(C)C.CC1CCCO1.[Li]CCCC.[CH2:21]([N:28]1[CH2:32][CH2:31][CH2:30][C:29]1=[O:33])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[C:34](OCC)(=[O:39])[CH2:35][CH:36]([CH3:38])[CH3:37]>CCCCCCC>[CH2:21]([N:28]1[CH2:32][CH2:31][C@@H:30]([C:34](=[O:39])[CH2:35][CH:36]([CH3:38])[CH3:37])[C:29]1=[O:33])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)CC(C)C
Reactant: O=C1CCCN1Cc1ccccc1
Agent: N#N
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CC1CCCO1
Solvent: CCCCCCC
Product: CC(C)CC(=O)[C@@H]1CCN(Cc2ccccc2)C1=O
Temperature: -10 °C
Yield: 22635 %

Procedure:
Charge a 5 L, 3-neck round bottom flask equipped with a magnetic stirrer, thermal couple, addition funnel and N2 inlet with diisopropylamine (176 mL, 1265 mmoles) and 2-methyltetrahydrofuran (500 mL). Cool the solution to ˜−10° C. (salt/ice bath) with stirring and add a solution of n-BuLi (2.5 M in hexanes, 504 mL, 1259 mmoles) drop wise while maintaining a temperature at or below 0° C. Rinse the addition funnel with 2-methyltetrahydrofuran (25 mL). Stir the solution for about 15 min, at ˜−5° C. Add a solution of N-benzyl-2-pyrrolidinone (100.8 g, 575 2 mmoles), ethyl isovalerate (90 g, 690 mmoles) in 2-Me-THF (500 mL) drop wise at a rate to maintain a temperature at or below 5° C. to provide a yellow slurry. Stir the reaction mixture about 1 hour at −5° C., add heptane (1 L) drop wise, and stir for an additional 1 hr. at −5° C. Collect the solid by filtration through a medium fritted funnel, wash with a 1:1 solution of 2-methyltetrahydrofuran/heptane (250 mL) followed by heptane (250 mL) and air dry until the solid becomes powder-like. Place the yellow solid into a 5 L, 3-neck round bottom flask equipped with a magnetic stirrer and add MTBE (1 L) and 10% citric acid (1 L). Stir the mixture for about 1 hour at room temperature to provide a homogeneous mixture. Separate the layers and wash the organic layer with H2O (2×500 mL), followed by brine (500 mL). Dry over Na2SO4, filter and concentrate to give the crude intermediate (128 g) as an orange oil. A Kuegelrohr distillation removes the major impurity from the crude material to yield the desired intermediate as a dark orange oil (117.4 g, 452.7 mmoles, 78.7% yield). 1H NMR (300 MHz, CDCl3) δ 7.38-7.16 (m, 5H), 4.55-4.35 (m, 2H), 3.62 (dd, 1H, J=5.86, 9.37 Hz), 3.38-3.14 (m, 2H), 2.92-2.8 (m, 1H), 2.64-2.42 (m, 2H), 2.28-2.11 (m, 1H), 2.08-1.93 (m, 1H), 0.96 (d, 3H, J=7.03 Hz) 0.93 (d, 3H, J=7.04 Hz). GC/MS=260 (M+1).
Reaction SMILES: O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(=[N:28][C:29]1([CH2:36][C:37]#[CH:38])[CH2:33][CH2:32][N:31]([CH3:34])[C:30]1=[O:35])(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[NH2:28][C:29]1([CH2:36][C:37]#[CH:38])[CH2:33][CH2:32][N:31]([CH3:34])[C:30]1=[O:35]
Reactant: C#CCC1(N=C(c2ccccc2)c2ccccc2)CCN(C)C1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: C1CCOC1
Product: C#CCC1(N)CCN(C)C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 107.2 %

Procedure:
Citric acid monohydrate (10.39 g, 49.46 mmol) was added to a solution of 3-(benzhydrylidene-amino)-1-methyl-3-prop-2-ynyl-pyrrolidin-2-one (6.26 g, 19.79 mmol) (which may be prepared as described in Description 2) in THF (150 mL) and the reaction was stirred at room temperature for 18 hours. A colourless solid precipitated out. The solvent was evaporated to give a gummy white solid. This was triturated with Et2O and the solid was washed with further Et2O. The solid was suspended in water/MeOH and purified by SCX (70 g Silca), eluting with water/MeOH, MeOH and finally 0.5M NH3 in MeOH. Fractions containing product were evaporated to afford 3-amino-1-methyl-3-prop-2-ynyl-pyrrolidin-2-one (3.23 g, 21.223 mmol) as a pale yellow oil;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([F:12])=[C:7]([CH:11]=1)[CH2:8][C:9]#[N:10].[O-]CC.[Na+].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[F:12][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][C:7]=1[C:8](=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]#[N:10]
Reactant: O=Cc1ccccc1
Reactant: COc1ccc(F)c(CC#N)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(F)c(C(C#N)=Cc2ccccc2)c1
Temperature: 25 °C

Procedure:
To a solution of 5-methoxy-2-fluorobenzylcyanide (8 g, 48.4 mmol) in 200 ml ethanol was added sodium ethoxide 21% in ethanol (19.89 ml, 53.3 mmol) and benzaldehyde (4.92 ml, 48.4 mmol). The reaction mixture was stirred at room temperature over night and concentrated to ½ volume, filtered and washed with small amount of ether, and dried under high vacuum to obtain yellow crystals.
Reaction SMILES: [P:1](Cl)([S:5][CH2:6][CH3:7])([O:3][CH3:4])=[O:2].[Br:9][C:10]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]2[C:11]=1[CH2:12][CH2:13][C:14]2=[O:20].C(N(CC)CC)C>C1(C)C=CC=CC=1>[P:1]([O:19][C:16]1[CH:17]=[CH:18][C:10]([Br:9])=[C:11]2[C:15]=1[C:14](=[O:20])[CH2:13][CH2:12]2)([S:5][CH2:6][CH3:7])([O:3][CH3:4])=[O:2]
Reactant: CCSP(=O)(Cl)OC
Reactant: O=C1CCc2c(Br)ccc(O)c21
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCSP(=O)(OC)Oc1ccc(Br)c2c1C(=O)CC2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
O-Methyl S-ethyl chlorothiophosphate (0.015 mole) dissolved in dry toluene (80) is charged into a glass reaction vessel equipped with a stirrer, thermometer and gas inlet tube. The solution is cooled to about 0° C. and a solution of 4-bromo-7-hydroxyindan-1-one (0.015 mole) and triethylamine (0.0175 mole) in toluene (20 ml) is slowly added with stirring. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 8 hours. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed solution is then dried and is stripped of solvent leaving a residue. This residue is chromatographed through a 200 ml clay column using ethyl acetate and hexane mixtures as the eluant. Ten separate fractions each containing increasing percentages of ethyl acetate are collected and analyzed by IR for the product. The appropriate fractions are then combined stripped of solvent and subjected to vacuum to yield the desired product O-methyl S-ethyl O-(4-bromoindan-1-on-7-yl) thiophosphate.
Reaction SMILES: [NH2:1][C:2]1[C:13]([Br:14])=[CH:12][C:5]([C:6]([N:8]([CH2:10][CH3:11])[CH3:9])=[O:7])=[CH:4][N:3]=1.Cl[CH2:16][CH:17]=O.C(=O)([O-])O.[Na+]>C(O)C>[Br:14][C:13]1[C:2]2[N:3]([CH:16]=[CH:17][N:1]=2)[CH:4]=[C:5]([C:6]([N:8]([CH2:10][CH3:11])[CH3:9])=[O:7])[CH:12]=1
Reactant: O=CCCl
Reactant: CCN(C)C(=O)c1cnc(N)c(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCN(C)C(=O)c1cc(Br)c2nccn2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
6-Amino-5-bromo-N-ethyl-N-methylnicotinamide (250 mg, 0.97 mmol) obtained in Step 1 of Example 170 was dissolved in ethanol (2.5 mL), and a 50% aqueous chloroacetaldehyde solution was added thereto, and the mixture was stirred overnight under reflux. After the mixture was left to cool to room temperature, an aqueous sodium hydrogen carbonate solution was added thereto, and the mixture was extracted with a chloroform/isopropanol (6/1) mixed solution. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=98/2) to give 8-bromo-N-ethyl-N-methylimidazo[1,2-a]pyridine-6-carboxamide (65 mg, 0.23 mmol, yield: 24%).
Reaction SMILES: I[C:2]1[C:3]([NH:12][C@H:13]2[C@@H:17]3[O:18][C:19]([CH3:22])([CH3:21])[O:20][C@@H:16]3[C@@H:15]([CH2:23][OH:24])[CH2:14]2)=[N:4][C:5]([S:10][CH3:11])=[N:6][C:7]=1[O:8][CH3:9].[S:25]1[C:33]2[CH:32]=[CH:31][N:30]=[CH:29][C:28]=2[N:27]=[CH:26]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:9][O:8][C:7]1[N:6]=[C:5]([S:10][CH3:11])[N:4]=[C:3]([NH:12][C@H:13]2[C@@H:17]3[O:18][C:19]([CH3:22])([CH3:21])[O:20][C@@H:16]3[C@@H:15]([CH2:23][OH:24])[CH2:14]2)[C:2]=1[C:26]1[S:25][C:33]2[CH:32]=[CH:31][N:30]=[CH:29][C:28]=2[N:27]=1
Reactant: c1cc2scnc2cn1
Reactant: COc1nc(SC)nc(N[C@@H]2C[C@H](CO)[C@H]3OC(C)(C)O[C@H]32)c1I
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1nc(SC)nc(N[C@@H]2C[C@H](CO)[C@H]3OC(C)(C)O[C@H]32)c1-c1nc2cnccc2s1
Temperature: 100 °C

Procedure:
Compound 6 (467 mg, 1.00 mmol), thiazolo[4,5-c]pyridine (272 mg, 2.00 mmol), CuI (67.0 mg, 0.350 mmol), cesium carbonate (1.95 mg, 6.00 mmol) and Pd(Ph3P)4 (231 mg, 0.200 mmol) were combined and suspended in DMF (10 mL). The reaction was degassed and heated to 100° C. for a 1 h. The reaction mixture was cooled to room temperature, extracted twice with ethyl acetate. The combined organics were washed with water, brine, dried (MgSO4), filtered and concentrated. The residue was then purified by column chromatrography on silica gel (MeOH/DCM) to give the title compound. LCMS 1.90 min, 476 (M+H)
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([S:10]([O-:12])=[O:11])[CH:7]=[CH:8][CH:9]=1.[Na+].Br[C:17]1[CH:25]=[CH:24][C:23]2[N:22]([CH3:26])[C:21]3[CH2:27][CH:28]4[NH:32][CH:31]([C:20]=3[C:19]=2[C:18]=1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30][CH2:29]4>>[F:14][C:2]([F:1])([F:13])[O:3][C:4]1[CH:5]=[C:6]([S:10]([C:17]2[CH:25]=[CH:24][C:23]3[N:22]([CH3:26])[C:21]4[CH2:27][CH:28]5[NH:32][CH:31]([C:20]=4[C:19]=3[C:18]=2[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30][CH2:29]5)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(Br)ccc31)C1CCC(C2)N1
Reactant: O=S([O-])c1cccc(OC(F)(F)F)c1
Agent: [Na+]
Product: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4cccc(OC(F)(F)F)c4)ccc31)C1CCC(C2)N1
Yield: 32 %

Procedure:
Intermediate 3 was coupled with the product of Example 27, step B following the procedure of Example 27, step C. The crude material was purified by flash column chromatography (SiO2, 7:3 hexane/ethyl acetate) to give tert-butyl 2-(3-trifluoromethoxyphenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (110 mg, 32%) as an off-white solid: 1H NMR (CDCl3, 300 MHz): δ 8.18 (s, 1H), 7.87 (d, J=7.8 Hz, 1H), 7.81 (s, 1H), 7.67 (dd, J=8.6, 1.4 Hz, 1H), 7.50 (t, J=8.1 Hz, 1H), 7.29-7.38 (m, 2H), 5.13-5.40 (m, 1H), 4.49-4.84 (m, 1H), 3.61 (s, 3H), 3.20-3.52 (m, 1H), 2.50 (d, J=16.2 Hz, 1H), 2.12-2.41 (m, 2H), 1.86-2.00 (m, 1H), 1.58-1.68 (m, 1H), 1.37 (br s, 9H).
Reaction SMILES: [CH2:1]([C:3]([O:32][Si](CC)(CC)CC)([CH2:30][CH3:31])[CH2:4][CH2:5]/[CH:6]=[C:7](/[C:9]1[S:13][C:12]([CH2:14][O:15][C:16]2[CH:17]=[C:18]([C:26]([O:28][CH3:29])=[O:27])[C:19](=[CH:24][CH:25]=2)[C:20]([O:22][CH3:23])=[O:21])=[CH:11][CH:10]=1)\[CH3:8])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([C:3]([OH:32])([CH2:30][CH3:31])[CH2:4][CH2:5]/[CH:6]=[C:7](/[C:9]1[S:13][C:12]([CH2:14][O:15][C:16]2[CH:17]=[C:18]([C:26]([O:28][CH3:29])=[O:27])[C:19](=[CH:24][CH:25]=2)[C:20]([O:22][CH3:23])=[O:21])=[CH:11][CH:10]=1)\[CH3:8])[CH3:2]
Reactant: CCC(CC)(CC/C=C(\C)c1ccc(COc2ccc(C(=O)OC)c(C(=O)OC)c2)s1)O[Si](CC)(CC)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(O)(CC)CC/C=C(\C)c1ccc(COc2ccc(C(=O)OC)c(C(=O)OC)c2)s1
Temperature: 60 °C

Procedure:
750 mg (1.3 mmol) of dimethyl 4-[5-((E)-5-ethyl-1-methyl-5-triethylsilanyloxyhept-1-enyl)-2-thienylmethoxy]phthalate are dissolved in 30 mL of THF. 2.6 mL (2.6 mmol) of a 1.0 M tetrabutylammonium fluoride solution are added and the reaction medium is heated at 60° C. for 3 hours. After treatment with ammonium chloride solution and extraction with ethyl acetate, the organic phases are combined, dried and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica. A yellow oil is obtained (m=355 mg; Y=59%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([O:23][CH3:24])=[CH:20][CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[F:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH:30]=[C:29]2[C@@H:35]1[CH2:39][CH2:38][C@H:37]([NH2:40])[CH2:36]1.[OH-].[Na+]>CS(C)=O>[F:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH:30]=[C:29]2[C@@H:35]1[CH2:39][CH2:38][C@H:37]([NH:40][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([O:23][CH3:24])=[CH:20][CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)[CH2:36]1
Reactant: COc1cccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Reactant: N[C@H]1CC[C@@H](c2c[nH]c3ccc(F)cc23)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1cccc2c1O[C@@H](CN[C@H]1CC[C@@H](c3c[nH]c4ccc(F)cc34)C1)CO2
Temperature: 80 °C
Yield: 45.9 %

Procedure:
A mixture of [(2R)-8-methoxy-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzene-sulfonate (0.5 g, 1.42 mmole) and cis-3-(5-fluoro-1H-indol-3-yl)-cyclopentyl-amine (0.24 g, 1.1 mmol) in anhydrous DMSO (10 mL) was heated at 80° C. for 30 h. The cooled reaction mixture was poured into 1 N aqueous NaOH (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), then were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 0.5 g of crude product. Flash chromatography on silica gel (10% MeOH/ethyl acetate) afforded 0.2 g (48%) of the title compound as a thick oil, which was converted to its hydrochloride salt (0.195 g): MS (ESI) m/z 397 [M+H]+.