Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](O)=[O:24])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Cl.[NH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>O1CCCC1.C(#N)C>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][C:23]([NH:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[O:24])=[CH:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: COC(=O)CN
Reactant: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCC(=O)O)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CC#N
Product: COC(=O)CNC(=O)CCc1ccc(-c2ccc(CCN3CCC[C@H]3C)cc2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-3-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)propanoic acid (40 mg, 0.119 mmol), methyl 2-aminoacetate hydrochloride (19.35 mg, 0.154 mmol), and TEA (0.050 mL, 0.356 mmol) in tetrahydrofuran (1 mL) and acetonitrile (1 mL) was added HATU (54.1 mg, 0.142 mmol). The reaction was stirred at 60° C. for 2 h. The mixture was added 1M HCl and purified by HPLC to give the title compound. LCMS m/z=409.1 [M+H]+; 1H NMR (400 MHz, CD3CN) δ ppm 1.27 (d, J=6.8 Hz, 0.3H), 1.46 (d, J=6.5 Hz, 2.7H), 1.70-1.82 (m, 1H), 2.01-2.12 (m, 2H), 2.23-2.33 (m, 1H), 2.56 (t, J=7.7 Hz, 2H), 2.96 (t, J=7.8 Hz, 2H), 3.07-3.21 (m, 4H), 3.36-3.47 (m, 1H), 3.49-3.61 (m, 1H), 3.69 (s, 3H), 3.73-3.83 (m, 1H), 3.90 (d, 6.0 Hz, 2H), 6.80 (s, 1H), 7.34 (d, J=8.1 Hz, 2H), 7.38 (d, J=8.1 Hz, 2H), 7.57 (d, J=8.1 Hz, 2H), 7.63 (d, J=8.2 Hz, 2H).
Reaction SMILES: Cl[Si:2]([NH:5][C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])[CH3:3].[C:10]1([CH:16]([K])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[C:6]([NH:5][Si:2]([CH3:4])([CH3:3])[CH:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: [K]C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)N[Si](C)(C)Cl
Solvent: C1CCOC1
Product: CC(C)(C)N[Si](C)(C)C(c1ccccc1)c1ccccc1

Procedure:
To a solution of 4.1 g (24.7 mmol) of ClSiMe2NHCMe3 in 80 mL of THF were added 3.735 g (18.1 mmol) of solid diphenylmethyl potassium. The orange color of the diphenylmethyl potassium disappeared instantly and precipitate formed rapidly. The reaction mixture was stirred for several days. The solvent was removed under reduced pressure and the residue was extracted with hexane and the solvent was removed under reduced pressure. The yellow liquid product was subjected to vacuum pumping to remove the excess ClSiMe2NHCMe3. The yield was 4.786 g, 88.9 percent.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26](=O)[NH2:27])=[CH:22][CH:21]=2)=[O:17])=[CH:11][CH:10]=1)[CH3:7]>CN(C=O)C>[CH2:6]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]#[N:27])=[CH:24][CH:25]=2)=[O:17])=[CH:13][CH:14]=1)[CH3:7]
Reactant: CCOc1ccc(CC(=O)OCc2ccc(C(N)=O)cc2)cc1
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOc1ccc(CC(=O)OCc2ccc(C#N)cc2)cc1

Procedure:
65 g of POCl3 is added dropwise at 50° and while stirring to a solution, in 500 ml of DMF, of 31.3 g of p-carbamoylbenzyl p-ethoxyphenylacetate (obtainable by esterification). After stirring for a further hour, the mixture is poured onto ice and worked up in a customary manner to give p-cyanobenzyl p-ethoxyphenylacetate, m.p. 59°, c.p. -40°.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]([S:6]([OH:9])(=[O:8])=[O:7])[CH3:5].[OH2:10]>O1CCOCC1>[S:6]([CH:4]([CH3:5])[CH2:3][CH2:2][O:1][S:6]([CH:4]([CH2:3][CH2:2][OH:1])[CH3:5])(=[O:7])=[O:10])([OH:9])(=[O:8])=[O:7]
Reactant: CC(CCO)S(=O)(=O)O
Reactant: O
Solvent: C1COCCO1
Product: CC(CCOS(=O)(=O)C(C)CCO)S(=O)(=O)O

Procedure:
Sulfoalkylating agent, obtainable by heating 4-hydroxy butane-2-sulfonic acid or 3-methyl-1,3-propane sultone to a temperature in the region of from 80° to 180° C. in the presence of water in an amount of from 1 to 4 moles per mol of 4-hydroxy-butane-2-sulfonic acid or 3-methyl-1,3-propane sultone, and characterized by the following 13C-NMR-shifts (ppm, relative to TMS=0, in the presence of dioxane): 15.4; 31.7; 34.4; 53.6; 60.0 and 68.5.
Reaction SMILES: C(=O)=[N:2][S:3](Cl)(=[O:5])=[O:4].[CH:8]([C:11]1[CH:16]=[C:15]([S:17][C:18]#[N:19])[CH:14]=[C:13]([CH:20]([CH3:22])[CH3:21])[C:12]=1[OH:23])([CH3:10])[CH3:9]>C1(C)C=CC=CC=1>[CH:8]([C:11]1[CH:16]=[C:15]([S:17][C:18]#[N:19])[CH:14]=[C:13]([CH:20]([CH3:22])[CH3:21])[C:12]=1[O:23][S:3](=[O:4])(=[O:5])[NH2:2])([CH3:10])[CH3:9]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)c1cc(SC#N)cc(C(C)C)c1O
Solvent: Cc1ccccc1
Product: CC(C)c1cc(SC#N)cc(C(C)C)c1OS(N)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.5 %

Procedure:
N-Chlorosulfonyl isocyanate (1.02 mL, 11.7 mmol) was added to a warm solution of 2,6-diisopropyl-4-thiocyanato-phenol (2.5 g, 10.6 mmol) in 150 mL toluene. The resulting solution was heated to reflux for 6 hours and then cooled to room temperature and stirred overnight. The reaction was concentrated in vacuo and the residue was quenched with ice water and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give 1.75 g of sulfamic acid 2,6-diisopropyl-4-thiocyanato-phenyl ester as a white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.Cl[C:22]([O:24][CH:25]([Cl:27])[CH3:26])=[O:23].CN1CCOCC1>ClCCl>[Cl:27][CH:25]([O:24][C:22]([NH:2][CH2:3][C:4]1([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=[O:23])[CH3:26]
Reactant: NCC1(CC(=O)OCc2ccccc2)CCCCC1
Reactant: CC(Cl)OC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(Cl)OC(=O)NCC1(CC(=O)OCc2ccccc2)CCCCC1
Temperature: 15 °C
Yield: 100.6 %

Procedure:
In a 5-liter, 3-neck, round bottom flask, stirred mechanically and under nitrogen, was added dichloromethane (1.5 L), compound (6) (1.85 mol) and l-chloroethyl chloroformate (258 g, 1.81 mol). The resulting solution was cooled to 15° C. and N-methylmorpholine (396 mL, 3.60 mol) was added slowly, with cooling, over a one hour period. The resulting turbid solution was stirred for 30 min, after which 1H-NMR analysis showed the reaction to be complete. The reaction mixture was washed with water (2×2 L) and brine (1 L) and dried over sodium sulfate. Evaporation of the solvent afforded the title compound (9) as an orange oil (670 g, 98% yield). 1HNMR (CDCl3, 400 MHz): 1.33–1.53 (m, 10H), 1.75 (d, 3H), 2.33 (s, 2H), 3.18 (d, 2H), 5.09 (s, 2H), 5.58 (t, 1H), 6.53 (q, 1H), 7.29–7.33 (m, 5H).
Reaction SMILES: [C:1]1([CH2:6][OH:7])([CH2:4][OH:5])[CH2:3][CH2:2]1.[CH3:8][S:9](Cl)(=[O:11])=[O:10]>C(Cl)Cl>[CH3:8][S:9]([O:5][CH2:4][C:1]1([CH2:6][OH:7])[CH2:3][CH2:2]1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1(CO)CC1
Solvent: ClCCl
Product: CS(=O)(=O)OCC1(CO)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of cyclopropane-1,1-diyldimethanol (0.1 g, 0.98 mmol) in DCM (5 mL) was added TEA (0.15 g, 1.44 mmol). Methanesulfonyl chloride (0.11 g, 0.98 mmol) was added dropwise at 0° C. The reaction was stirred at room temperature for 2 h. The mixture was partitioned between DCM and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product which was used without purification.
Reaction SMILES: [CH3:1][CH:2]1[NH:6][CH2:5][C:4]2([CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2)[S:3]1.C1(N=C=NC2CCCCC2)CCCCC1.[C:28](O)(=[O:31])[CH2:29][CH3:30]>ClCCl>[CH3:1][CH:2]1[N:6]([C:28](=[O:31])[CH2:29][CH3:30])[CH2:5][C:4]2([CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2)[S:3]1
Reactant: CC1NCC2(CCN(C)CC2)S1
Reactant: CCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCC(=O)N1CC2(CCN(C)CC2)SC1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.7 %

Procedure:
To a stirred solution of 2,8-dimethyl-1-thia-3,8-diaza-spiro[4.5]decane (Example 1) (0.86 g, 4.62 mmol) in dichloromethane (90 ml) at room temperature was added dicyclohexylcarbodiimide (DCC) (1.28 g, 6.2 mmol) followed by addition of propionic acid (0.41 ml, 5.5 mmol). The resulting solution was stirred at room temperature overnight. During the reaction a white solid precipitated. After filtration the solvent was evaporated and the crude product was purified by flash chromatography (silica, CH2Cl2/MeOH/NH4OH 90/10/1) to give the title compound (0.5 g) as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 5.51, 5.19 (2q, J=6.15 and J=6.22 Hz, 1H, CHCH3), 4.63, 3.74 (2d, J=11.88 and J=11.57 Hz, 1H, CHHNCO), 3.44, 3.08 (2d, J=11.55 and J=12.09 Hz, 1H, CHHNCO), 2.8-2.6 (m, 2H), 2.5-2.2 (m, 7H, CH2, CH2CH3, NCH3), 2.2-2.0 (m, 1H), 2.0-1.8 (m, 3H) 1.52, 1.48 (2d, J=6.30 and J=6.18 Hz, 3H, CH3—CH), 1.19-1.12 (m, 3H, CH3) ppm; 13C NMR (CDCl3, 300 MHz) δ 171.6 (C), 57.5, 57.2 (CH), 55.5 (C), 54.7, 54.3 (CH2), 53.2, 53.0 (CH2), 46.3 (CH3), 38.4, 37.7 (CH2), 37.0, 36.4 (CH2), 28.8, 26.8 (CH2), 25.6, 23.6 (CH3), 9.6, 9.4 (CH3) ppm.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:31]([CH3:32])=[CH:30][C:15]2[N:16]=[C:17]([C:19]3[CH:27]=[C:26]4[C:22]([C:23]([CH3:29])=[N:24][N:25]4[CH3:28])=[CH:21][CH:20]=3)[S:18][C:14]=2[C:13]=1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CCO>[C:1]([O:5][C@@H:6]([C:12]1[C:31]([CH3:32])=[CH:30][C:15]2[N:16]=[C:17]([C:19]3[CH:27]=[C:26]4[C:22]([C:23]([CH3:29])=[N:24][N:25]4[CH3:28])=[CH:21][CH:20]=3)[S:18][C:14]=2[C:13]=1[C:33]1[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(C)nn(C)c4c3)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc2nc(-c3ccc4c(C)nn(C)c4c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 50 °C

Procedure:
To a vial was dissolved (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(1,3-dimethyl-1H-indazol-6-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (100 mg, 0.178 mmol) in THF (4 mL) and EtOH (2 mL). 1M NaOH (2 mL) was added, and the mixture was heated to 50° C. overnight. The reaction was cooled to 23° C., and filtered (0.45 micron teflon syringe filter). The filtrate was purified by reverse phase HPLC, eluting with 5-100% acetonitrile in H2O with 0.1% TFA to give the desired product. LCMS-ESI+: calc'd for C29H29ClN3O3S: 534.1 (M+H+); Found: 534.2 (M+H+). 1H NMR (400 MHz, CD3OD): δ 8.04 (s, 1H), 7.77 (s, 1H), 7.70 (q, J=8.7 Hz, 3H), 7.57 (d, J=6.1 Hz, 3H), 5.25 (s, 1H), 3.98 (s, 3H), 2.59 (s, 3H), 2.51 (s, 3H), 0.97 (s, 9H).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[N:14][OH:15])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([I:12])[C:7]=2F)[CH2:3][CH2:2]1.N12CCCN=C1CCCCC2>O1CCCC1>[CH:1]1([NH:4][C:5]2[C:6]3[CH:11]=[CH:10][CH:9]=[C:8]([I:12])[C:7]=3[O:15][N:14]=2)[CH2:3][CH2:2]1
Reactant: ON=C(NC1CC1)c1cccc(I)c1F
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Ic1cccc2c(NC3CC3)noc12
Temperature: 150 °C
Yield: 66.2 %

Procedure:
A mixture of N-cyclopropyl-2-fluoro-N′-hydroxy-3-iodobenzimidamide (preparation 22f, 2.15 g, 8.1 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.30 mL, 8.7 mmol) in tetrahydrofuran (13 mL) was heated at 150° C. for 150 minutes in Biotage Initiator Microwave Synthesizer. Then, the mixture was cooled to ambient temperature and evaporated. The residue was partitioned between water and ethyl acetate and the organic layer was washed with brine, dried (MgSO4) and evaporated. The crude residue was purified by flash chromatography (3:1 hexanes/ethyl acetate) to give the title compound (1.61 g, 68%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.Cl[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][C:28]2[N:29]=[C:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:31][C:32]=2[CH3:33])=[N:24][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:33][C:32]1[O:31][C:30]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[N:29][C:28]=1[CH2:27][O:26][C:23]1[N:24]=[CH:25][C:20]([CH2:19][O:1][C:2]2[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:3]=2)=[CH:21][CH:22]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cn1
Reactant: COC(=O)Cc1cn(-c2ccccc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)nc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 77.3 %

Procedure:
A mixture of methyl (3-hydroxy-1-phenyl-1H-pyrazol-4-yl)acetate (406 mg), 5-chloromethyl-2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine (551 mg), potassium carbonate (484 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 4 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give methyl [3-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethoxy]-1-phenyl-1H-pyrazol-4-yl]acetate (690 mg, yield 77%), which was then recrystallized from ethyl acetate-hexane. melting point: 96–97° C.
Reaction SMILES: [C:1]1([C:6]([OH:8])=O)[CH2:5][CH2:4][CH2:3][CH:2]=1.[CH:9]1[CH2:13][CH2:12][CH2:11][CH:10]=1>S([O-])([O-])(=O)=O.[NH4+].[NH4+]>[C:1]12[CH2:5][CH2:4][CH2:3][C:2]=1[C@@H:13]1[C@@H:9]([CH2:10][CH2:11][CH2:12]1)[C:6]2=[O:8]
Reactant: O=C(O)C1=CCCC1
Reactant: C1=CCCC1
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Product: O=C1C2=C(CCC2)[C@H]2CCC[C@@H]12
Temperature: 30 °C
Reaction time: 4 h

Procedure:
A stirred suspension of 1-cyclopentene carboxylic acid (11.2 g, 100 mmol) and cyclopentene (13.6 g, 200 mmol) was added slowly to stirring polyphosphoric acid (Aldrich, 300 g) at 60° C. in a 250 mL flask. The reaction mixture was stirred at 70–80° C. for 4 hours under nitrogen. The dark brown reaction mixture was cooled to 30° C. and poured on 300 g of ice and vigorously stirred in a cooling bath. The brown mass was then neutralized with a saturated solution of ammonium sulfate (200 ml). The resulting mixture was then extracted with Et2O (5×200 mL). The combined organic layers were washed successively with water, saturated sodium bicarbonate solution and water. The washed organic extract was then dried over anhydrous MgSO4 and concentrated in vacuo. The residue was distilled at 130–135° C. at 4 mmHg to yield 3.5 g, 25%, about 90% purity. This product was chromatographed on silica gel using hexane and ethyl acetate as eluent to obtain pure cis-tricyclo [6.3.0.03,7] undec-1(8)-en-2-one. 1H-NMR (CDCl3): δ 3.2 (m, 1 H), 3.1 (m, 1 H), 2.5 (m, 2 H), 2.4 (m, 4 H), 1.9 (m, 1 H), 1.6 (m, 4 H), 1.3 (m, 1 H).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18]>ClCCl>[C:3]1([CH2:2][CH2:1][NH:9][C:17](=[O:19])[CH3:18])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NCCc1ccccc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.5 %

Procedure:
After phenethylamine (37.8 ml, 0.3mol) and triethylamine (42 ml, 0.3mol) were dissolved in dichloromethane (200 ml), acetyl chloride (20.7 ml, 0.3mol) was dropwise added thereto, while maintaining the reaction temperature below 0° C. The resulting solution was stirred for 10 minutes at room temperature, washed with water dried over anhydrous magnesium sulfate, and concentrated in vacuo to give 45.8 g of the titled compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[C:32]1([CH:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:39][NH2:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:29])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([NH:40][CH2:39][CH:38]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[O:24])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: NCC(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(NCC(c1ccccc1)c1ccccc1)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2,2-diphenylethylamine as in General Procedure 10 to give the title compound. LCMS: m/z=626.99 (M+H+); retention time=1.06 minutes.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]2[C:11](=[O:13])[N:10]([C:14]3[C:19]([F:20])=[CH:18][C:17]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][C:15]=3[F:27])[C:9](=[O:28])[C:8]=2[C:7]([O:29][CH2:30][CH3:31])=[C:6]2[CH:32]=[CH:33][CH:34]=[CH:35][C:5]=12)[CH3:2].[BH4-].[Na+]>C1COCC1.CO>[CH2:30]([O:29][C:7]1[C:8]2[C:9](=[O:28])[N:10]([C:14]3[C:15]([F:27])=[CH:16][C:17]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][C:19]=3[F:20])[CH:11]([OH:13])[C:12]=2[C:4]([O:3][CH2:1][CH3:2])=[C:5]2[CH:35]=[CH:34][CH:33]=[CH:32][C:6]=12)[CH3:31]
Reactant: CCOC(=O)Cc1cc(F)c(N2C(=O)c3c(c(OCC)c4ccccc4c3OCC)C2=O)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)Cc1cc(F)c(N2C(=O)c3c(c(OCC)c4ccccc4c3OCC)C2O)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98 %

Procedure:
To a stirred solution of ethyl {4-[4,9-bis(ethyloxy)-1,3-dioxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl]-3,5-difluorophenyl}acetate (0.240 g, 0.50 mmol) in THF (10 ml) and methanol (5 ml) was added sodium borohydride (0.019 g, 0.50 mmol) slowly under an argon atmosphere. This was stirred at room temperature for 15 minutes, and then a further 0.057 g (1.50 mmol) of sodium borohydride was added to drive the reaction to completion. After 1.5 hours the reaction was evaporated and quenched with an aqueous solution of ammonium chloride. This was extracted ×2 with ethyl acetate (25 ml) and the combined extracts washed with brine. The organics layer was then dried over magnesium sulphate, filtered and evaporated to give the title compound as a yellow oily solid (0.240 g, 0.49 mmol) LC/MS: Rt=3.42 and 3.46, [MH]+ 486.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[F:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([F:28])[C:19]=1[CH:20]=O>O1CCCC1.C(OCC)(=O)C>[F:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([F:28])[C:19]=1/[CH:20]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COc1cc(F)c(C=O)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1c(F)cc(OC)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.1 %

Procedure:
A solution of ethyl diethylphosphonoacetate (2.34 g, 10.4 mmol) and 60% sodium hydride (0.38 g, 9.50 mmol) in tetrahydrofuran (40 mL) was stirred under ice-cooling for 10 min. Thereto was added 2,6-difluoro-4-methoxybenzaldehyde (1.5 g, 8.71 mmol) and the mixture was stirred for 4 hr while allowing to warm to room temperature. The reaction solution was diluted with ethyl acetate, washed successively with aqueous citric acid solution, water and aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=1:10-1:5) to give the title compound (1.1 g, yield 52%) as colorless needles.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[C:15]([CH3:16])=[N:14][C:13]2[O:12][CH:11]([CH2:17][CH2:18]Cl)[CH2:10][N:9]([CH3:20])[C:8](=[O:21])[C:7]=2[CH:6]=1.CO.[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28]>C(O)(C)C>[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28].[Cl:4][C:5]1[C:15]([CH3:16])=[N:14][C:13]2[O:12][CH:11]([CH2:17][CH2:18][N:2]([CH3:3])[CH3:1])[CH2:10][N:9]([CH3:20])[C:8](=[O:21])[C:7]=2[CH:6]=1
Reactant: CNC
Reactant: Cc1nc2c(cc1Cl)C(=O)N(C)CC(CCCl)O2
Agent: O=C(O)/C=C/C(=O)O
Solvent: CC(C)O
Solvent: CO
Product: Cc1nc2c(cc1Cl)C(=O)N(C)CC(CCN(C)C)O2
Reaction time: 48 h

Procedure:
To 70 ml of freshly collected dimethylamine was added 5.0 g (0.017 mole) of 7-chloro-2-(2-chloroethyl)-2,3-dihydro-4,8-dimethylpyrido[3,2-f]-1,4-oxazepin-5(4H)-one and 5 ml of methanol. The reaction flask was sealed tightly and left standing at room temperature for 2 days. The reaction flask was cooled and opened and the solvent evaporated in a stream of air. The residue was taken up in 100 ml of methylene chloride and the solution was washed with 3×50 ml of 1N sodium hydroxide, dried over sodium sulfate, filtered and concentrated by rotary evaporation. The residual oil was treated with 2 equivalents of fumaric acid in isopropyl alcohol which yielded 5.3 g (59%) of white analytically pure crystals, m.p. 153°-56° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[NH2:24])[C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][N:10]2[CH:18]=[CH:19][CH:20]=[C:9]2[CH2:8]1)=[O:6].[Cl:25][C:26]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29].C(N(C(C)C)CC)(C)C>ClCCl>[CH:20]1[CH:19]=[CH:18][N:10]2[CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:7]([C:5]([C:4]3[CH:21]=[CH:22][C:23]([NH:24][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][C:33]([Cl:35])=[CH:34][C:26]=4[Cl:25])=[C:2]([CH3:1])[CH:3]=3)=[O:6])[CH2:8][C:9]=12
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1NC(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.1 %

Procedure:
A mixture of 0.40 g of 10,11-dihydro-10-(3-methyl-4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 0.40 g of 2,4-dichlorobenzoyl chloride and 0.75 g of diisopropylethylamine in 50 ml of dichloromethane is stirred at room temperature for 16 hours. The mixture is washed with water, dried (MgSO4) and the solution passed through a thin pad of hydrous magnesium silicate. The filtrate is concentrated and hexane added to give crystals. Recrystallization from dichloromethane-hexane gives 0.52 g of crystals, m.p. 213°-215° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[N:3]1[C:9]1[N:13]2[CH:14]=[C:15]([O:18][C@H:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:22]([NH2:29])[CH2:21][CH2:20]3)[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1.ClC(Cl)(Cl)C[O:33][C:34](=O)[NH:35][C:36]1[N:37]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([CH2:51][OH:52])[CH:46]=2)[N:38]=[C:39]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:40]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:41]([C:39]1[CH:40]=[C:36]([NH:35][C:34]([NH:29][C@@H:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C@H:19]([O:18][C:15]3[CH:16]=[CH:17][C:12]4[N:13]([C:9]([N:3]5[C@H:2]([CH3:1])[CH2:7][CH2:6][CH2:5][C@@H:4]5[CH3:8])=[N:10][N:11]=4)[CH:14]=3)[CH2:20][CH2:21]2)=[O:33])[N:37]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([CH2:51][OH:52])[CH:46]=2)[N:38]=1)([CH3:44])([CH3:42])[CH3:43]
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(CO)c2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(CO)c4)c4ccccc43)cn12
Temperature: 80 °C
Reaction time: 7 h
Yield: 144.5 %

Procedure:
A mixture of Intermediate 96c (150 mg, 0.38 mmol), Intermediate 29c (161 mg, 0.38 mmol) and DIPEA (133 μL, 0.77 mmol) in dioxane (4 mL) was stirred at 80° C. for 7 hours. After cooling, the reaction mixture was partitioned between water and DCM. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 1-10% MeOH in DCM to afford the title compound (364 mg, 95%) as a glassy white solid %). LCMS (Method 4): Rt 3.50 min, m/z 663 [MH+].