Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:8][C:9]([O-:11])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[Na+].[Br:13][C:14]1[C:15]([CH3:21])=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[Br:13][C:14]1[C:15]([CH3:21])=[C:16]([NH:17][C:9](=[O:11])[CH2:8][C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: Cc1c(N)cccc1Br
Reactant: O=C([O-])Cc1ncccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(Br)cccc1NC(=O)Cc1ncccc1F
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 60.6 %

Procedure:
A mixture of sodium 2-(3-fluoropyridin-2-yl)acetate (1.847 g, 10.37 mmol), 3-bromo-2-methylaniline (1.41 mL, 11.4 mmol), DIEA (5.4 mL, 31.1 mmol) and HATU (4.73 g, 12.4 mmol) in DMF (30 mL) was stirred at room temperature for 1.25 h. The mixture was diluted with EtOAc and washed twice with 10% aqueous LiCl, then with brine. The combined aqueous layers were extracted with EtOAc, and the combined organic phases were dried and concentrated. The residue was dissolved in hot EtOAc, allowed to cool, and the resulting white solid collected by filtration and washed with 60% EtOAc-hexanes. The combined filtrates were concentrated and the residue was recrystallized twice using the same procedure. The residue from concentration of the final filtrate was purified by column chromatography on silica gel, eluting with EtOAc-hexanes, to provide a solid which was combined with the recrystallized batches to provide N-(3-bromo-2-methylphenyl)-2-(3-fluoropyridin-2-yl)acetamide as a white solid (2.03 g, 61% yield). Mass spectrum m/z 323, 325 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH3:11])=[CH:4][CH:3]=1.C([Li])(C)(C)C.I[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20][CH:19]=1>C1COCC1.CCOCC.[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>[CH2:8]([C:5]1[CH:6]=[CH:7][C:2]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20][CH:19]=2)=[CH:3][CH:4]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCc1ccc(Br)cc1
Reactant: CCOC(=O)CCc1ccc(I)cc1
Agent: [Pd]
Agent: [Li]C(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCc1ccc(-c2ccc(CCC(=O)OCC)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a stirred solution of 3.20 g (15.0 mmol) of 1-bromo-4-butylbenzene (Aldrich Chemical Company #33,576-2) at -78° C. under argon was added, dropwise over 30 min, 18.0 mL (30.6 mmol, 1.7M in pentane) of t-butyllithium solution. The resulting light yellow solution was warmed to 0° C. and stirred for 1 h. To this solution was added 3.4 g (25 mmol) of thrice-fused zinc chloride in 20 mL of THF. The resulting slurry was stirred for 30 min and then a solution of 2.0 g (6.5 mmol) of 4-iodobenzenepropanoic acid, ethyl ester (Example 43, Part B) and 0.4 g (0.35 mmol) of tetrakis(triphenylphosphine)-palladium(0) in 5 mL of THF was added. The reaction was stirred for 16 h, diluted with ether and washed once with 10% citric acid. The organic phase was dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel (5×20 cm column) eluted with 1:1 hexanes/dichloromethane gave title compound as a colorless oil, 1.79 g , 91% yield.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:8][CH:7]=1.[OH-].[K+].Cl>O.C(O)C>[CH2:13]([O:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:4][C:3]([OH:29])=[O:2])=[CH:11][CH:10]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCOc1ccc(OCC(=O)OC)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCCCOc1ccc(OCC(=O)O)cc1
Reaction time: 18 h
Yield: 57.9 %

Procedure:
A mixture of 24.5 g of 4-Hexadecyloxyphenoxyacetic acid methyl ester 10.14 g of potassium hydroxide in 10 ml of water and 250 ml ethyl alcohol is refluxed for 3 hours then allowed to stand at 50° for 18 hours. The mixture is poured into dilute hydrochloric acid and extracted with chloroform. The organic layer is evaporated to a residue which is crystallized from hexane:carbon tetrachloride to give 13.7 g of the desired product as a white solid, m.p. 125°-127° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH2:37][CH2:38]O)[CH:30]=2)=[CH:24][CH:23]=1)[C:9]1[C:10]([CH3:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:59]N1C(=O)CCC1=O>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH2:37][CH2:38][Br:59])[CH:30]=2)=[CH:24][CH:23]=1)[C:9]1[C:10]([CH3:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCO)c2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCBr)c2)cc1
Yield: 63 %

Procedure:
The crude product from Example 72C and triphenylphosphine (0.730 g, 2.78 mmoles) in anhydrous DMF (5 mL) at 0° C. were treated with N-bromosuccinimide (0.396 g, 2.24 mmoles). Reaction mixed at 0° C. for 30 minutes. Reaction diluted with ethyl acetate, washed with H2O (2×), brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 30% ethyl acetate:hexanes) to provide the title compound (0.214 g, 63%). MS (ESI+) m/z 609 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([C:16]([OH:18])=O)[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[Cl:52][C:53]1[CH:54]=[CH:55][C:56]2[NH:65][CH2:64][C:63]3[CH:62]=[N:61][N:60]([CH3:66])[C:59]=3[NH:58][C:57]=2[CH:67]=1>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH:10]1[CH2:11][CH2:12][CH:13]([C:16]([N:65]2[CH2:64][C:63]3[CH:62]=[N:61][N:60]([CH3:66])[C:59]=3[NH:58][C:57]3[CH:67]=[C:53]([Cl:52])[CH:54]=[CH:55][C:56]2=3)=[O:18])[CH2:14][CH2:15]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC1CCC(C(=O)O)CC1
Reactant: Cn1ncc2c1Nc1cc(Cl)ccc1NC2
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc2c1Nc1cc(Cl)ccc1N(C(=O)C1CCC(CNC(=O)OC(C)(C)C)CC1)C2
Temperature: 25 °C
Yield: 90.8 %

Procedure:
A solution of 4-(tert-butoxycarbonylamino-methyl)-cyclohexanecarboxylic acid from Example E9 (510 mg, 2.0 mmol) in dichloromethane (25 ml) at room temperature was treated with DIEA (0.70 ml, 4.0 mmol), PyBrop (2.40 g, 5.1 mmol), and 6-chloro-3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E1 (422 mg, 1.8 mmol) and the resulting solution was heated at reflux for 20 h and allowed to cool to room temperature. The solution was diluted with dichloromethane, washed with brine and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant EtOAc) to yield the title compound (775 mg, 91%).
Reaction SMILES: Cl.[CH:2]12[CH2:7][CH:6]1[CH2:5][NH:4][CH2:3]2.CC(C)=O.[C-]#N.[K+].CN(C)[C:17]1([C:22]#[N:23])[CH2:21]CC[CH2:18]1>O>[CH:2]12[CH2:7][CH:6]1[CH2:5][N:4]([C:17]([CH3:21])([CH3:18])[C:22]#[N:23])[CH2:3]2
Reactant: C1NCC2CC12
Reactant: CN(C)C1(C#N)CCCC1
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C#N)N1CC2CC2C1
Yield: 84 %

Procedure:
The title compound (583 mg, 84%) was prepared from 3-azabicyclo[3.1.0]hexane hydrochloride (550 mg, 4.6 mmol) [Pestic. Chem: Hum. Welfar Environ., Proc, Int, Congr. Pestic. Che., 5th, 1982, 1,159-64, 1983], acetone (267 mg, 4.6 mmol) and potassium cyanide (300 mg, 4.6 mmol) in water (2.5 ml) in a similar manner to that described in D1. 1H NMR (CDCl3) δ: 0.40 (1H, m), 0.58 (1H, m), 1.43 (8H, m), 2.64 (2H, m), 3.10 (2H, d, J=8 Hz).
Reaction SMILES: [CH2:1]([N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=O.C([Li])CCC.Cl[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35]>O1CCCC1.O>[CH2:37]([O:36][C:34](=[O:35])[C:11]1[C:12]([F:15])=[CH:13][CH:14]=[C:9]([N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]=1[F:16])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Fc1ccc(N(Cc2ccccc2)Cc2ccccc2)c(F)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)=O
Product: O=C(OCc1ccccc1)c1c(F)ccc(N(Cc2ccccc2)Cc2ccccc2)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To dibenzyl-(2,4-difluoro-phenyl)-amine (3.097 g, 10.02 mmol) in tetrahydrofuran (45 mL), under nitrogen atmosphere, cooled at −78° C. acetone/dry in ice bath, n-butyllithium (1.6 M in hexane, 6.88 mL, 11.02 mmol) was added slowly. The reaction was stirred for 1 hour, benzyl chloroformate (1.54 mL, 11.02 mmol) was added and the reaction was allowed to warm to room temperature during 2 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 5% ethyl acetate in hexane grading to 10% acetate to provide the title compound as colourless oil (4.0 g, 90%).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].C(N(C(C)C)C(C)C)C.[CH:17]1([CH2:20][CH2:21][O:22][C:23]2[CH:50]=[CH:49][C:26]([C:27]([NH:29][CH:30]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][C:45]([F:48])([F:47])[F:46])=[CH:40][CH:39]=3)[C:31]([NH:33]CCO)=[O:32])=[O:28])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1>C(Cl)Cl.C1COCC1>[C:5]([O:4][CH2:1][CH2:2][NH:33][C:31](=[O:32])[CH:30]([NH:29][C:27](=[O:28])[C:26]1[CH:25]=[CH:24][C:23]([O:22][CH2:21][CH2:20][CH:17]2[CH2:18][CH2:19]2)=[CH:50][CH:49]=1)[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][C:45]([F:48])([F:46])[F:47])=[CH:40][CH:39]=1)(=[O:7])[CH3:6]
Reactant: O=C(NC(Cc1ccc(OC(F)(F)F)cc1)C(=O)NCCO)c1ccc(OCCC2CC2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)OCCNC(=O)C(Cc1ccc(OC(F)(F)F)cc1)NC(=O)c1ccc(OCCC2CC2)cc1
Temperature: 25 °C
Reaction time: 65 h
Yield: 52 %

Procedure:
Acetic anhydride (50 μL, 0.526 mmol) and N-ethyl-N,N-diisopropylamine (84 μL, 0.479 mmol) were added to a methylene chloride:THF (1:1, V/V, 4 mL) solution of 4-(2-cyclopropylethoxy)-N-{2-[(2-hydroxyethyl)amino]-2-oxo-1-[4-(trifluoromethoxy)benzyl]ethyl}benzamide (116 mg, 0.239 mmol) prepared in Example 4. The mixture was stirred at room temperature for 65 hours. The reaction solution was evaporated, and the residue was purified by thin layer chromatography for separation (ethyl acetate, developed once) to give 65 mg of the title compound (white powder, yield: 52%).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][S:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]O)=[CH:20][CH:19]=1.[H+].[B-:27]([F:31])([F:30])([F:29])[F:28]>C(Cl)Cl>[F:28][B-:27]([F:31])([F:30])[F:29].[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([S+:7]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([Cl:17])=[CH:19][CH:20]=2)[CH2:6][C:5]2[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: OCc1ccc(Cl)cc1
Reactant: Clc1ccc(CSc2ccc(Cl)cc2)cc1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: ClCCl
Product: Clc1ccc(C[S+](Cc2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Yield: 77.4 %

Procedure:
5.2 g (19.4 mmol) of 4-chlorophenyl 4-chlorobenzyl sulfide, 4.14 g (29.0 mmol) of 4-chlorobenzyl alcohol and 14.15 g (87 mmol) of hydrogen tetrafluoroborate (54% in diethyl ether) in 20 ml of methylene chloride are reacted as in Example 6(a) to give 7.23 g (77.4% of theory) of 4-chlorophenylbis(4-chlorobenzyl)sulfonium tetrafluoroborate in the form of white-beige crystals of melting point 147°-148° C.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([N:20]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([F:31])[CH:27]=3)[N:22]=[CH:21]2)[C:9]([NH:11][C:12]2[S:13][C:14]([C:17]([OH:19])=O)=[CH:15][N:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:56][CH2:57][N:58](CC)[CH2:59][CH3:60]>CN(C=O)C>[CH:1]1([CH2:7][CH:8]([N:20]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([F:31])[CH:27]=3)[N:22]=[CH:21]2)[C:9]([NH:11][C:12]2[S:13][C:14]([C:17]([N:58]([CH2:59][CH3:60])[CH2:57][CH3:56])=[O:19])=[CH:15][N:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cnc(NC(=O)C(CC2CCCCC2)n2cnc3ccc(F)cc3c2=O)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1cnc(NC(=O)C(CC2CCCCC2)n2cnc3ccc(F)cc3c2=O)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of Compound 143 (0.1 g, 0.225 mmol) and HBTU (256 mg, 0.675 mmol) was dissolved in anhydrous DMF (1 mL) and Et3N (0.125 mL, 0.9 mmol) and stirred for 30 min. To this solution was added Et2N (0.028 mL, 0.270 mmol) and the mixture was stirred at RT overnight. The reaction was poured onto ice to crash out the crude product. The product was purified via preparative HPLC. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.88-1.25 (m, 12H) 1.48-1.81 (m, 5H) 2.00-2.13 (m, 1H) 2.21-2.36 (m, 1H) 3.46 (s, 4H) 5.80 (dd, J=11.87, 4.80 Hz, 1H) 7.73-7.92 (m, 4H) 8.52 (s, 1H). [M+H] calc'd for C25H30FN5O3S, 500; found, 500.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([N:14]2[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15]2)=[O:13])[CH2:11][CH2:10]1.CC(C)=O>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([N:14]2[CH2:18][CH2:17][C:16](=[O:19])[CH2:15]2)=[O:13])[CH2:11][CH2:10]1
Reactant: O=C(N1CCC(O)C1)C1(c2ccc(Cl)cc2Cl)CC1
Solvent: CC(C)=O
Solvent: O
Product: O=C1CCN(C(=O)C2(c3ccc(Cl)cc3Cl)CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solutin of 1-{[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl}pyrrolidin-3-ol (3.05 g, 0.0102 mol) in acetone (50 mL, 0.7 mol) was added Jone's oxidant in water (8.00 M, 2.54 mL) at 0 degrees celsius and the resulting solution was stirred at rt for 1 hour. The mixture was filetered through celite and the filtrate was concentrated. The resulting residue was dissolved in AcOEt, washed with water and brine successively, dried with MgSO4, and concentrated in-vauo. The crude product was purified by Combiflash eluting with 40% AcOEt in hexanes.
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([F:17])=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]=[CH:10]2)#[N:2].[BH4-].[Na+]>>[C:1]([CH2:3][O:4][C:5]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([F:17])=[C:11]2[C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10]2)#[N:2]
Reactant: COc1cc(F)c2c(c1OCC#N)CCC=C2
Agent: [BH4-]
Agent: [Na+]
Product: COc1cc(F)c2c(c1OCC#N)CCCC2
Yield: 65.4 %

Procedure:
The product from Example 68 (2.5 g) was reduced with sodium borohydride (1.3 g) using the procedure of Example 2 to afford the product (1.65 g) in 66% yield.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([N+:18]([O-:20])=[O:19])=[CH:13][CH:14]=2)[CH2:9]1)=[O:5])C.[OH-].[Na+].Cl>C(O)C>[C:4]([CH2:6][CH2:7][N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([N+:18]([O-:20])=[O:19])=[CH:13][CH:14]=2)[CH2:9]1)([OH:5])=[O:3]
Reactant: CCOC(=O)CCN1CCc2ccc([N+](=O)[O-])cc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCN1CCc2ccc([N+](=O)[O-])cc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.51 g of 2-(2-(ethoxycarbonyl)ethyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline was dissolved in 100 ml of ethanol, and 13.0 ml of 2N aqueous solution of sodium hydroxide was added to the solution. The solution was stirred overnight at room temperature. Dilute hydrochloric acid was added dropwise to the resulting solution to acidify the solution, and the solution was concentrated under reduced pressure, and dissolved in anhydrous ethanol. The insoluble content was separated by filtration, and the solvent was distilled off to obtain crude crystals of 2-(2-carboxyethyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline. The crystals, with no further purification, were dissolved in 20 ml of DMF, and the solution was neutralized by adding 1.8 ml of triethylamine. To this solution were added 1.93 g of benzylalcohol, 3.42 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, and 1.93 g of 1-hydroxybenzotriazol, and the solution was stirred overnight at room temperature. The resulting solution was extracted with ethyl acetate, washed with water, saturated aqueous solution of sodium bicarbonate, and saturated aqueous solution of sodium chloride, and dried with anhydrous sodium sulfate. After separating the desiccant by filtration, the filtrate was purified by silica gel column chromatography to obtain 1.60 g of 2-(2-benzyloxycarbonylethyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline, which was an oily product (yield: 49%).
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])(=O)=O.[F:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([N:29]3[CH2:33][CH2:32][CH2:31][C@H:30]3[CH2:34]O)=[N:27][N:28]=2)[CH:25]=1.CCN(CC)CC.N>CO.C(Cl)Cl.CN(C=O)C>[F:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([N:29]3[CH2:33][CH2:32][CH2:31][C@H:30]3[CH2:34][O:6][Si:7]([CH:8]([CH3:9])[CH3:10])([CH:11]([CH3:12])[CH3:13])[CH:14]([CH3:15])[CH3:16])=[N:27][N:28]=2)[CH:25]=1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: OC[C@@H]1CCCN1c1nnc2ccc(F)cn12
Agent: N
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: CC(C)[Si](OC[C@@H]1CCCN1c1nnc2ccc(F)cn12)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.5 %

Procedure:
Triisopropylsilyl trifluoromethanesulfonate (327 mg, 1.06 mmol) was added to a solution of Intermediate 28a (210 mg, 0.89 mmol) and Et3N (135 mg, 1.33 mmol) in a DMF (3 mL) and the mixture stirred at RT for 1 h. The reaction mixture was applied to an SCX-2 cartridge (25 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-10% [2M NH3 in MeOH] in DCM, gave the title compound (110 mg, 31%). LCMS (Method 1): Rt 4.45 min, m/z 393 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[CH:15]([NH:18][NH:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:17])[CH3:16].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([N:18]([CH:15]([CH3:17])[CH3:16])[NH:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:8]
Reactant: N#Cc1ccc(OCC(=O)O)c(Br)c1
Reactant: CC(C)NNC(=O)c1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(C#N)cc1Br
Yield: 28.1 %

Procedure:
A solution of (2-bromo-4-cyano-phenoxy)-acetic acid (910 mg, 3.5 mmol) and benzoic acid N′-isopropyl-hydrazide (749 mg, 4.2 mmol) in DMF (20 ml) was treated with diisopropylethyl amine (1.52 mL, 8.75 mmol) and PyBroP (2.45 g, 5.25 mmol) at room temperature overnight. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-30% ethyl acetate/hexanes gradient to afford the product as a white solid (410 mg, 0.9849 mmol, 28%).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][N:14]=2)=[CH:7][CH:6]=1)([O-])=O.C(O)C.[OH-].[K+]>[Fe].C(Cl)(Cl)Cl.O>[NH2:2][C:5]1[CH:6]=[CH:7][C:8]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][N:14]=2)=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(C=Cc2ccncn2)cc1
Agent: [Fe]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: Nc1ccc(C=Cc2ccncn2)cc1
Temperature: 65 °C
Reaction time: 2 h
Yield: 42.4 %

Procedure:
Hydrochloric acid (100 ml of 4N) is added dropwise to a mixture of 4-[2-(p-nitrophenyl)ethenyl]pyrimidine (28 g), ethanol (250 ml) and iron fillings (28 g). The reaction temperature is increased to 65° C., and the mixture is stirred at that temperature for two hours. Water is added, followed by an aqueous 30% potassium hydroxide solution (200 ml), and chloroform (1 liter). The mixture is filtered through celite, and the chloroform layer is separated, dried over sodium sulfate and then concentrated. Addition of ether gives 4-[2-(p-aminophenyl)ethenyl]pyrimidine (10.3 g), m.p. 227°-230° C., which is used as the starting compound without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH2:54][CH2:55][O:56][CH3:57])=[CH:48][CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>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.O>[CH3:57][O:56][CH2:55][CH2:54][CH2:53][O:52][C:49]1[CH:50]=[CH:51][C:46]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:12])(=[O:13])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)=[CH:47][CH:48]=1
Reactant: COCCCOc1ccc(OB([O-])[O-])cc1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COCCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.4 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) was added toluene/ethanol/water (10/1/1, 19.2 ml) and then were added 4-(3-methoxypropoxy)phenyl borate (145 mg) and potassium carbonate (175 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (27 mg), and the mixture was refluxed for 14 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1) and recrystallized from ethanol to give 7-[4-(3-methoxypropoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 102) (190 mg).