Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH:5](OC(=O)C)[C:6]1[CH:18]=[C:17]2[C:9]([C:10]3[CH:11]=[C:12]([Br:20])[CH:13]=[CH:14][C:15]=3[C:16]2=[O:19])=[CH:8][CH:7]=1)(=O)C.C[O-].[Na+].P([O-])([O-])([O-])=O>CO.C1COCC1.C(OCC)(=O)C>[Br:20][C:12]1[CH:13]=[CH:14][C:15]2[C:16](=[O:19])[C:17]3[C:9]([C:10]=2[CH:11]=1)=[CH:8][CH:7]=[C:6]([CH:5]=[O:4])[CH:18]=3
Reactant: CC(=O)OC(OC(C)=O)c1ccc2c(c1)C(=O)c1ccc(Br)cc1-2
Agent: C[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)C(=O)c1ccc(Br)cc1-2
Temperature: 25 °C
Reaction time: 22.5 h
Yield: 105.4 %

Procedure:
7-Diacetoxymethyl-3-bromo-9-fluorenone (61.1 mg) was suspended in methanol (4.4 ml) and THF (1.0 ml). To this suspension was added 0.054M NaOMe (0.56 ml). The reaction mixture was stirred at room temperature for 22.5 hours. It was then neutralized with 0.2M pH 7 phosphate buffer. The THF and methanol were removed under reduced pressure. Reaction mixture was then diluted with ethyl acetate, washed with water and brine, dried and evaporated gave the crude product (47.5 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([I:8])=[CH:6][N:5]=[C:4](N)[CH:3]=1.[C:10](O)(C(F)(F)F)=[O:11].N(OC(C)(C)C)=O>CO>[Cl:1][C:2]1[C:7]([I:8])=[CH:6][N:5]=[C:4]([O:11][CH3:10])[CH:3]=1
Reactant: Nc1cc(Cl)c(I)cn1
Reactant: O=C(O)C(F)(F)F
Agent: CC(C)(C)ON=O
Solvent: CO
Product: COc1cc(Cl)c(I)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.5 %

Procedure:
To a solution of 4-chloro-5-iodo-pyridin-2-ylamine (64.2 g, 0.25 mol) in methanol (1.1 L) and TFA (93.7 mL, 1.26 mol) was added tert-butyl nitrite (150 mL, 1.26 mol) so as to maintain temperature less than 3° C. The resultant mixture was stirred at RT for 1 h then allowed to warm to RT and stirred for 16 h. The reaction was quenched by the careful addition of water then concentrated in vacuo to ¼ volume. The resultant residue was treated with water (1 L) and the precipitate formed collected by filtration and dried in vacuo at 35° C. to give the title compound (62.3 g, 92%). Contains 16% impurity. 1H NMR 400 MHz (DMSO-d) δ: 8.56 (1H, s), 7.20 (1H, s), 3.86 (3H, s).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[CH:20]=[CH:19][C:18]3[N:17]([CH3:21])[C:16]4[CH2:22][CH:23]5[NH:27][CH:26]([C:15]=4[C:14]=3[C:13]=2C(OC(C)(C)C)=O)[CH2:25][CH2:24]5)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O>>[F:36][C:2]([F:1])([F:35])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[C:16]2[CH2:22][CH:23]4[NH:27][CH:26]([C:15]3=2)[CH2:25][CH2:24]4)(=[O:10])=[O:11])=[CH:5][CH:4]=1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4ccc(C(F)(F)F)cc4)ccc31)C1CCC(C2)N1
Solvent: O=C(O)C(F)(F)F
Product: Cn1c2c(c3cc(S(=O)(=O)c4ccc(C(F)(F)F)cc4)ccc31)C1CCC(C2)N1
Yield: 95 %

Procedure:
The product of step A was subjected to Boc-deprotection with TFA following the procedure of Example 28, step B to give 2-(4-trifluoromethylphenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole (100 mg, 95%) as an off-white solid: 1H NMR (CDCl3, 300 MHz) δ 8.03-8.11 (m, 3H), 7.11-7.62 (m, 3H), 7.26-7.30 (m, 1H), 4.74-4.75 (m, 1H), 4.22 (br s, 1H), 3.56 (s, 3H), 3.26-3.31 (m, 1H), 2.56-2.62 (m, 1H), 1.99-2.28 (m, 3H), 1.59-1.64 (m, 1H).
Reaction SMILES: [CH2:1]([N:3]([CH2:36][CH3:37])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[F:69][C:70]1[CH:76]=[CH:75][C:73]([NH2:74])=[CH:72][CH:71]=1>CN(C=O)C>[CH2:36]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([NH:74][C:73]2[CH:75]=[CH:76][C:70]([F:69])=[CH:71][CH:72]=2)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:37]
Reactant: Nc1ccc(F)cc1
Reactant: CCN(CC)CCCNc1nc(-c2cccc(C(=O)O)c2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNc1nc(-c2cccc(C(=O)Nc3ccc(F)cc3)c2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.5 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]benzoic acid (30 mg, 0.06 mmol) in DMF (0.5 mL) were added HBTU (27 mg, 0.072 mmol), triethylamine (16.9 uL, 0.12 mmol) and 4-fluoroaniline (8.64 uL, 0.09 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (20 mg, 55.5%). LC-MS m/z 601 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([S:13](Cl)(=[O:15])=[O:14])[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([OH:23])=[O:22]>>[C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:12]=[CH:11][CH:10]=[C:9]([S:13]([NH:17][C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=2)[C:21]([OH:23])=[O:22])(=[O:15])=[O:14])[CH:8]=1
Reactant: Nc1cccc(C(=O)O)c1
Reactant: O=S(=O)(Cl)c1cccc(-c2ccccc2)c1
Product: O=C(O)c1cccc(NS(=O)(=O)c2cccc(-c3ccccc3)c2)c1
Yield: 100 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, with 3-phenylbenzenesulfonylchloride (13.9 mg, 0.055 mmol) and 3-aminobenzoic acid (6.9 mg, 0.050 mmol). The title compound was obtained in 100% yield (17.7 mg). MS (ESI+) calcd mass for C19H15NO4S 353.072179, found 353.071899.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][N:12]1[C@@H:28]2[CH2:29][C:17]3[CH:18]=[CH:19][C:20]([O:31][CH3:32])=[C:21]4[O:22][C@H:23]5[C@@H:24]([OH:30])[CH:25]=[CH:26][C@@H:27]2[C@:15]5([C:16]=34)[CH2:14][CH2:13]1.CCN(CC)CC>C(Cl)Cl>[CH3:11][N:12]1[C@@H:28]2[CH2:29][C:17]3[CH:18]=[CH:19][C:20]([O:31][CH3:32])=[C:21]4[O:22][C@H:23]5[C:24]([CH:25]=[CH:26][C@@H:27]2[C@:15]5([C:16]=34)[CH2:14][CH2:13]1)=[O:30]
Reactant: COc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c3c1O[C@H]1C(=O)C=C[C@H]4[C@@H](C2)N(C)CC[C@]314
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 126.5 %

Procedure:
To a solution of dimethylsulfoxide (16.53 g, 0.21 mole) in CH2Cl2 (80 ml) at -78° C. was added dropwise a solution of oxalyl chloride (13.01 g, 0.10 mole) in CH2Cl2 (50 ml) over a period of 40 min. After stirring for 10 min., a solution of codeine (20.33 g, 0.068 mole) in CH2Cl2 (100 ml) was added over 50 min. while keeping the reaction mixture at -78°C. After stirring at -78° C. for 2 hr., Et3N (50 ml) was added, followed by CH2Cl2 (100 ml). The reaction mixture was allowed to warm-up to room temperature, washed with water (6×150 ml), dried over anhydrous Na2SO4 and evaporated to dryness in vacuo to give codeinone (25.57 g). IR (KBr)(v, cm-1): 1668 (s, sharp, --C=C--C=O); NMR (δH)(CDCl3): 6.67 (1, d, J, 8.2, 2-H), 6.62 (1, d, J, 10.2, 8-H), 6.59 (1, d, J, 8.2, 1-H), 6.07 (1, dd, J, 10.2 & 2.9, 7-H), 4.68 (1, s, 5-H), 3.85 (3, s, OCH3), 3.45-3.35 (1, m, 9-H), 3.25-3.17 (1, m, 14-H), 3.10 (1, d, J, 18.5, 10-Hβ), 2.61 (1, dm, J, 11.9, 16-He), 2.45 (3, s, NCH3), 2.30 (1, dd, J, 18.5 & 5.5, 10-Hα), 2.30 (1, td, J, 11.9 & 3.7, 16-Ha), 2.06 (1, td, J, 12.0 & 4.8, 15-Ha), 1.85 (1, dm, J, 12.5, 15-He).
Reaction SMILES: C1([Se][C:8]2([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)C=CC=CC=1.OO>ClCCl>[O:12]1[C:11]2([CH2:16][CH2:17][C:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:9][CH2:10]2)[O:15][CH2:14][CH2:13]1
Reactant: CCOC(=O)C1([Se]c2ccccc2)CCC2(CC1)OCCO2
Agent: OO
Solvent: ClCCl
Product: CCOC(=O)C1=CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.6 %

Procedure:
To a solution of ethyl 8-(phenylselanyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate (14.00 g, 38.00 mmol) in dichloromethane (100 mL) was added 30% hydrogen peroxide solution (11.6 mL, 380.0 mmol). The reaction mixture was stirred at ambient temperature for 16 h then diluted with dichloromethane (100 mL), washed with saturated sodium hydrogencarbonate (100 mL), saturated ammonium chloride (3×75 mL), and brine (3×75 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was purified by column chromatography with ethyl acetate in hexanes (10%) to afford the title compound as a colorless liquid (6.10 g, 76%): 1H NMR (300 MHz, CDCl3) δ 6.82 (m, 1H), 4.11 (dd, J=7.1 Hz, 2H), 3.92 (s, 4H), 2.49-2.43 (m, 2H), 2.34-2.29 (m, 2H), 1.76-1.65 (m, 4H), 1.21 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH:1]1([CH2:4][S:5]([CH2:8][C@H:9]([NH:27][C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[O:29])[C:10](=[O:26])[NH:11][C@H:12]([CH:15]([OH:25])[C:16]2[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[O:18][N:17]=2)[CH2:13][CH3:14])(=[O:7])=[O:6])[CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH:1]1([CH2:4][S:5]([CH2:8][C@H:9]([NH:27][C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[O:29])[C:10](=[O:26])[NH:11][C@H:12]([C:15]([C:16]2[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[O:18][N:17]=2)=[O:25])[CH2:13][CH3:14])(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: CC[C@H](NC(=O)[C@H](CS(=O)(=O)CC1CC1)NC(=O)N1CCOCC1)C(O)c1noc(C(F)(F)F)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC[C@H](NC(=O)[C@H](CS(=O)(=O)CC1CC1)NC(=O)N1CCOCC1)C(=O)c1noc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 2.4 %

Procedure:
A solution of morpholine-4-carboxylic acid ((R)-2-cyclopropylmethanesulfonyl-1-{(S)-1-[hydroxy-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-methyl]-propylcarbamoyl}-ethyl)-amide (370 mg, 0.70 mmol) in methylene chloride (10 mL) was treated with Dess Martin periodinane (298 mg, 0.70 mmol) and stirred at room temperature for 3 hours. The reaction mixture was washed with an aqueous solution of Na2S2O3 (0.26M), saturated aqueous bicarbonate solution and water, dried over Na2SO4 and the solvent evaporated under reduced pressure. The crude was subjected to flash chromatography eluting with a mixture of ethyl acetate and heptane. It was then further subjected to preparative HPLC (using Gilson 215 liquid handler, and MonoChrom 10 microns C18 column—PN0504—100×212 from MetaChem), eluting with a mixture of acetonitrile and water, going from 10% to 100% acetonitrile in water to give morpholine-4-carboxylic acid {(R)-2-cyclopropylmethanesulfonyl-1-[(S)-1-(5-trifluoromethyl-1,2,4-oxadiazole-3-carbonyl)-propylcarbamoyl]-ethyl}-amide as a white solid (9 mg). 1H NMR (CDCl3): 7.87 (d, J=6 Hz, 1H), 5.99 (d, J=6 Hz, 1H), 5.16 (m, 1H), 4.87 (m, 1H), 3.74-3.66 (m, 5H), 3.44-3.36 (m, 5H), 3.14 (d, J=7 Hz, 2H), 2.20-2.02 (m, 1H), 1.98-1.78 (m, 1H), 1.21 (m, 1H), 1.02 (t, J=7 Hz, 3H), 0.82-0.70 (m, 2H), 0.57-0.40 (m, 2H). MS: 526 (MH+)
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=O)=[CH:9][CH:8]=1.[C:17]([O-])([O-])=[O:18].[K+].[K+].[OH-].[Na+]>CN(C=O)C>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([C:13](=[CH:14][OH:16])[CH:17]=[O:18])=[CH:11][CH:12]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)Cc1ccc(Br)cc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=CC(=CO)c1ccc(Br)cc1
Temperature: 75 °C
Reaction time: 0.08 h
Yield: 99 %

Procedure:
Cool to 4° C. phosphorous oxychloride (2.34 mL, 26.0 mmol) in a 100 mL flask. To this, add 5 mL of DMF and stir mixture for 5 min. Remove the flask from the cooling bath and heat at 75° C. Add (4-bromophenyl)acetic acid (2.00 g, 9.30 mmol) in one portion with an additional 5 mL of DMF and stir the mixture at 75° C. under Ar for 16 h. Pour the mixture into ice and neutralize by slow addition of K2CO3. Heat the solution at 75° C. and make strongly basic by the addition of 50% aq. NaOH resulting in an oil. Extract the oil from the aq. phase with 2×70 mL of CH2Cl2, dry with MgSO4, filter and concentrate to give 2.10 g, 99% of 2-(4-bromo-phenyl)-3-hydroxy-propenal.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][S:20]([C:23]1[CH:37]=[CH:36][C:26]([CH2:27][NH:28][CH2:29][CH:30]([OH:35])[CH2:31][CH2:32][CH2:33][CH3:34])=[CH:25][CH:24]=1)(=[O:22])=[O:21].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C1COCC1.C(N(CC)CC)C.C(#N)C>[C:1]([C:9]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:10]=1[C:11]([N:28]([CH2:29][CH:30]([OH:35])[CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][C:26]1[CH:25]=[CH:24][C:23]([S:20]([CH3:19])(=[O:22])=[O:21])=[CH:37][CH:36]=1)=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCC(O)CNCc1ccc(S(C)(=O)=O)cc1
Reactant: O=C(O)c1ccc(Br)cc1C(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCC(O)CN(Cc1ccc(S(C)(=O)=O)cc1)C(=O)c1ccc(Br)cc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 68.5 %

Procedure:
[Step 1] To a solution (20 ml) of 2-benzoyl-4-bromobenzoic acid (2.0 g) in THF were added 1-(4-methanesulfonylbenzylamino)hexan-2-ol (1.9 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.9 g), 1-hydroxy-1H-benzotriazole monohydrate (1.0 g), acetonitrile (20 ml) and triethylamine (5 ml) at room temperature. The mixture was stirred at room temperature for 12 hrs. and concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with water, 1N-hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-hexane:ethyl acetate=1:1) to give 2-benzoyl-4-bromo-N-(2-hydroxyhexyl)-N-(4-methanesulfonylbenzyl) benzamide (2.57 g).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:37]([NH:39][S:40]([N:43]([CH3:45])[CH3:44])(=[O:42])=[O:41])=[O:38])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:23]4[CH2:28][C@H:27]([CH3:29])[NH:26][C@H:25]([CH3:30])[CH2:24]4)=[O:22])=[CH:18][C:17]4[CH:31]=[C:32]([O:35][CH3:36])[CH:33]=[CH:34][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C=O.[C:48]([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:37]([NH:39][S:40]([N:43]([CH3:44])[CH3:45])(=[O:41])=[O:42])=[O:38])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:23]4[CH2:24][C@H:25]([CH3:30])[N:26]([CH3:48])[C@H:27]([CH3:29])[CH2:28]4)=[O:22])=[CH:18][C:17]4[CH:31]=[C:32]([O:35][CH3:36])[CH:33]=[CH:34][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [BH3-]C#N
Reactant: COc1ccc2c(c1)C=C(C(=O)N1C[C@@H](C)N[C@@H](C)C1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)N(C)C)cc21
Agent: C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1)C=C(C(=O)N1C[C@@H](C)N(C)[C@@H](C)C1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)N(C)C)cc21
Temperature: 60 °C
Yield: 81.9 %

Procedure:
A mixture of 13-cyclohexyl-N-[(dimethylamino)sulfonyl]-6-[(cis-3,5-dimethyl-1-piperazinyl)carbonyl]-3-methoxy-7H-indolo[2,1-a][2]benzazepine-10-carboxamide (42 mg, 0.066 mmol), zinc chloride (27.4 mg, 0.20 mmol), paraformaldehyde (6.0 mg, 0.20 mmol), and sodium cyanoborohydride (12.7 mg, 0.20 mmol) in MeOH was heated at 60° C. for 2 hrs. The mixture was quenched with 0.5 mL of NaOH (1N). The solution was extracted with ethyl acetate and the extract washed with dilute sodium bicarbonate (2×), brine (3×), and then dried (Na2SO4). The extract was concentrated and the crude product purified on the Shimadzu preparative liquid chromatograph. The product containing fraction was concentrated on a Speed Vac® to leave, the titled compound as a yellow solid (35 mg, 82%). ESI-MS m/z 648 (MH+); 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 0.77-1.58 (m, 10 H) 1.69-2.19 (m, 6 H) 2.76-2.91 (m, 4 H) 3.01 (s, 6 H) 3.12-3.38 (m, 5 H) 3.91 (s, 3 H) 4.33-4.49 (m, 2 H) 5.07-5.22 (m, 1 H) 6.99 (s, 1 H) 7.08 (d, J=2.44 Hz, 1 H) 7.16 (dd, J=8.70, 2.59 Hz, 1 H) 7.56 (t, J=9.31 Hz, 2 H) 7.93 (d, J=8.55 Hz, 1 H) 8.11 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[C:4]=1B(O)O.Br[C:17]1[CH:22]=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:20]=[C:19]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[C:4]=1[C:17]1[CH:18]=[C:19]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:20]=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:22]=1
Reactant: COc1cc(OC)c(B(O)O)c(OC)c1
Reactant: CCOC(=O)c1cc(Br)cc(C(=O)OCC)n1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2c(OC)cc(OC)cc2OC)cc(C(=O)OCC)n1
Temperature: 95 °C

Procedure:
2,4,6-trimethoxyphenylboronic acid (2.12 g, 10.0 mmol) and diethyl 4-bromopyridine-2,6-dicarboxylate (3.33 g, 11.0 mmol) were dissolved in dry DMF (50 mL). Caesium carbonate (4.56 g, 14.0 mmol) and tetrakis(triphenylphosphine)-palladium(0) (0.23 g, 0.20 mmol) were added, and the mixture was deaerated with argon. The mixture was heated at 95° C. for 48 h. The mixture was allowed to cool to room temperature and filtered. The filtrate was concentrated in vacuo, the residue was dissolved in chloroform (60 mL) and washed with 10% aq. citric acid and water, dried over Na2SO4 and concentrated. Purification was performed on silica gel (eluent petroleum ether bp 40-60° C.; ethyl acetate 5:3→2:5, v/v). Yield was 2.09 g (54%). 1H NMR (CDCl3): δ 1.45 (6H, t, J 7.1); 3.74 (6H, s); 3.90 (3H, s); 4.49 (4H, q, J 7.1); 6.22 (2H, s); 8.28 (2H, s). IR (film)/cm−1 1743, 1610 (C═O); 1339, 1238, 1128 (C—O). ESI-MS: [M+H]+ 390.19 calc. for C20H24NO7+ 390.15.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21](=[O:23])[CH3:22]>CC(C)=O>[O:23]=[C:21]([CH3:22])[CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[CH:7][C:8](=[O:12])[O:9][C:10]=2[CH:11]=1
Reactant: CC(=O)CCl
Reactant: O=c1ccc2ccc(O)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1ccc2ccc(=O)oc2c1
Temperature: 0 °C
Yield: 96.2 %

Procedure:
To a solution of 7-hydroxycoumarin (1.62 g, 10 mmol) in acetone (20 ml) were added potassium carbonate (5.53 g, 40 mmol) and chloroacetone (1.38 g, 15 mmol). The resulting mixture was refluxed for 4 h. (monitored by TLC). Evaporation of the solvent gave a residue which was poured into ice water (50 ml). The resulting solid was collected and crystallized from ethyl acetate to afford 7-(2-oxopropoxy)-2H-1-benzopyran-2-one (3a) (2.10 g, 96.1%) as a white needle crystal. mp: 165°-167° C.; IR(KBr) νmax : 1709, 1620; UV(CHCl3) λmax (log ε): 308 (4.14), 244 (3.52); 1H-NMR (CDCl3): δ2.31 (s, 3H, CH3), 4.65 (s, 2H, OCH2), 6.29 (d, 1H, 3-H), 6.76 (d, 1H, 8-H), 6.88 (dd, 1H, 6-H), 7.42 (d, 1H, 5-H), 7.65 (d, 1H, 4-H). Anal. Calcd for C12H10O4 : C, 66.05; H, 4.62. Found: C, 65.98; H, 4.61.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH:6]=[CH:5]2.C([Li])CCC.[B:19](OC(C)C)([O:24]C(C)C)[O:20]C(C)C.Cl>O1CCCC1>[CH3:12][C:7]1([CH3:13])[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([B:19]([OH:24])[OH:20])[CH:3]=2)[O:8]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC1(C)C=Cc2cc(Br)ccc2O1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)C=Cc2cc(B(O)O)ccc2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a solution of 6-bromo-2,2-dimethyl-2H-chromene (18 g) in tetrahydrofuran (150 mL) was added butyllithium (53 mL, 1.6 M hexane solution) at −78° C. under an argon atmosphere, and the mixture was stirred for 30 min. Triisopropyl borate (21 mL) was added, and the mixture was stirred for 3 hr while allowing to warm to room temperature. 1 M hydrochloric acid (150 mL) was added to the reaction mixture, and the mixture was stirred for 2 hr and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography to give the title compound (13 g, 82%) as colorless crystals.
Reaction SMILES: [C:1]1([CH2:7][O:8][CH:9]2[C:14](=[O:15])[CH2:13][CH2:12][N:11](CC3C=CC=CC=3)[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClCCl.[C:26](Cl)(=[O:30])[O:27][CH2:28][CH3:29]>C(N(CC)CC)C>[O:15]=[C:14]1[CH2:13][CH2:12][N:11]([C:26]([O:27][CH2:28][CH3:29])=[O:30])[CH2:10][CH:9]1[O:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)Cl
Reactant: O=C1CCN(Cc2ccccc2)CC1OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC(=O)C(OCc2ccccc2)C1
Reaction time: 6.3 h
Yield: 86.5 %

Procedure:
To a stirred mixture of 10 parts of 3-(phenylmethoxy)-1-(phenylmethyl)-4-piperidinone and 65 parts of dichloromethane were added dropwise 5 parts of ethyl carbonochloridate at room temperature. After stirring for 6.30 hours at reflux, there were added 5 parts of N,N-diethylethanamine. Upon completion, stirring at reflux was continued for 24 hours. The reaction mixture was washed successively with water, a diluted hydrochloric acid solution and again with water, dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 8.1 parts (86.5%) of ethyl 4-oxo-3-(phenylmethoxy)-1-piperidinecarboxylate as an oily residue (intermediate 47).
Reaction SMILES: [NH2:1][C@H:2]([C:10](O)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.B(F)(F)F.CCOCC.CSC.B.[OH-].[Na+]>O1CCCC1.O.O1CCCC1>[NH2:1][CH:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:10][OH:11]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: B
Agent: FB(F)F
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: NC(CO)Cc1ccccc1
Reaction time: 7 h
Yield: 76.6 %

Procedure:
A dry, 12-liter glass reaction vessel equipped as described in Example 1 was charged with 1.17 kilograms (7.1 moles) of phenylalanine and 3 liters of tetrahydrofuran. Using the procedure described in Example 1, boron trifluoride diethyl etherate (0.96 liter, 7.8 moles) was added followed by 0.78 liter (7.8 moles) of borane-dimethyl sulfide at reflux. The addition took 7 hours and heating was then continued for an additional 3 hours following the addition. The reaction mixture was then hydrolyzed with 0.75 liter of tetrahydrofuran/water followed by 4 liters of 6N aqueous sodium hydroxide solution. The product was isolated as described in Example 1 giving 822 grams (77% yield) of 2-amino-3-phenyl-1-propanol, bp 110°-111°C at 0.10 mm, as a clear, colorless oil which crystallized in the receiver, mp 65°-66°C. The purity by perchloric acid titration was only 93%. The impure amino alcohol was dissolved in 6 liters of tetrahydrofuran and anhydrous hydrogen chloride was added to precipitate the hydrochloride salt which was collected and dried in a vacuum oven giving 940 grams of 2-amino-3-phenyl-1-propanol hydrochloride, mp 147°-151°C, purity by perchloric acid titration: 100%.
Reaction SMILES: Br[CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:15][CH2:16][CH2:17][CH2:18][OH:19].C(=O)([O-])[O-].[Na+].[Na+]>>[C:3]1([CH:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:19][CH2:18][CH2:17][CH2:16][Br:15])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OCCCBr
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: BrCCCOC(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
A mixture of 12.3 g (50 mmole) of bromodiphenylmethane, 8.3 g (60 mmole) of 3-bromopropanol and 6.3 g (60 mmole) of sodium carbonate was heated at 120°-130° C. for 10 hours and then left overnight at room temperature. The mixture was extracted with ether and washed with water. The ethereal extract was dried on sodium sulfate. Evaporation of the ether yielded an oil, which was purified by distillation.