Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.NN.[CH3:4][O:5][C:6](=[O:39])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:25])[CH:23]=3)[NH:18][C:17]=2[CH2:26][CH2:27][N:28]2C(=O)C3[C:30](=CC=CC=3)[C:29]2=[O:38])=[CH:9][CH:8]=1.C(OC(=O)C)(=O)C.O>CC(O)C>[CH3:4][O:5][C:6](=[O:39])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:25])[CH:23]=3)[NH:18][C:17]=2[CH2:26][CH2:27][NH:28][C:29](=[O:38])[CH3:30])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(OCCc2c(CCN3C(=O)c4ccccc4C3=O)[nH]c3ccc(Cl)cc23)cc1
Agent: NN
Solvent: O
Solvent: CC(C)O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1ccc(OCCc2c(CCNC(C)=O)[nH]c3ccc(Cl)cc23)cc1
Temperature: 70 °C

Procedure:
Hydrazine hydrate (174 g, 3 mol) was added in one portion to a stirred suspension of 4-(2-{5-Chloro-2-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoic acid methyl ester (503 g, 1.0 mol) in 5.7 L 2-propanol. The suspension was warmed to 82 C for 3.5 h. HPLC analysis showed remaining starting material was less than 1%. The reaction mixture was allowed to cool to 70° C. and filtered at this temperature. Pyridine (1 L) was added to the filtrate, and the 2-propanol was distilled in vacuo (40C, 50 mmHg). The concentrate was charged to a 12 L 4-neck flask equipped with mechanical stirrer. The mixture was cooled to 5° C. under stirring. Acetic anhydride (113 g, 1.1 mol) was added dropwise maintaining an internal temperature below 10 C. The mixture was stirred for 0.5 h after complete acetic anhydride addition. HPLC analysis showed less 1% of amine remaining. Water (5 L) was added and the resulting suspension was stirred for 12 h at rt. The solid was collected by filtration and washed with water (3×500 mL). The product was dried in a vacuum oven at 50C to an LOD of <1%. 1H-NMR (300 MHz, DMSO−d6): δ1.78 (s, 3H), 2.87 (t, J=7 Hz, 2H), 3.10 (t, J=7 Hz, 2H), 3.36 (t, J=7 Hz, 2H), 3.80 (s, 3H), 4.16 (t, J=7 Hz, 2H), 6.98-7.03 (m, 3H), 7.26 (d, J=9 Hz, 1H), 7.57 (d, J=2 Hz, 1H), 7.88 (d, J=9 Hz, 2H), 8.00 (t, J=6 Hz, 1H), 10.90 (s, 1H) ppm
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[C:14]3[C:13]([C:24]([CH3:27])([CH3:26])[CH3:25])=[N:12][NH:11][C:10]=3[C:9]2=[O:28])=[CH:4][CH:3]=1.[O:29]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(C1C=C(C(C)C)C=C(C(C)C)C=1C1C=CC=CC=1P)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(O)CCC>[C:24]([C:13]1[C:14]2[CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([C:31]4[CH:32]=[CH:33][O:29][CH:30]=4)=[CH:7][CH:6]=3)[C:9](=[O:28])[C:10]=2[NH:11][N:12]=1)([CH3:25])([CH3:26])[CH3:27]
Reactant: OB(O)c1ccoc1
Reactant: COc1ccccc1C1c2c(C(C)(C)C)n[nH]c2C(=O)N1c1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCCCO
Product: COc1ccccc1C1c2c(C(C)(C)C)n[nH]c2C(=O)N1c1ccc(-c2ccoc2)cc1
Yield: 62 %

Procedure:
To a mixture of 5-(4-bromophenyl)-3-t-butyl-4-(2-methoxyphenyl)-4,5-dihydro-1H-pyrrolo[3,4-c]pyrazol-6-one (0.10 g, 0.23 mmol), 3-furylboronic acid (0.038 g, 0.34 mmol), tripotassium phosphate (0.096 g, 0.45 mmol) and butanol (1 mL), (2′,4′,6′-tri-isopropylbiphenyl-2-yl)phosphine (0.009 g, 0.02 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.004 g, 0.004 mmol) were added under a nitrogen atmosphere, and the mixture was stirred under reflux for 3 hr. The reaction mixture was purified by silica gel column chromatography (ethyl acetate/n-hexane). The fraction was concentrated under reduced pressure and the precipitate was collected by filtration to give 3-t-butyl-5-(4-fur-3-ylphenyl)-4-(2-methoxyphenyl)-4,5-dihydro-1H-pyrrolo[3,4-c]pyrazol-6-one (0.061 g, 63%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11]([N:13]1[CH2:17][C@@H:16]([CH3:18])[CH2:15][C@H:14]1[C:19]1[NH:20][C:21]([C:24]2[CH:29]=[C:28]3[CH2:30][O:31][C:32]4[CH:59]=[C:58]5[C:35]([CH:36]=[CH:37][C:38]6[N:42]=[C:41]([C@@H:43]7[CH2:47][C@H:46]([CH2:48][O:49][CH3:50])[CH2:45][N:44]7C(OC(C)(C)C)=O)[NH:40][C:39]=65)=[CH:34][C:33]=4[C:27]3=[CH:26][CH:25]=2)=[CH:22][N:23]=1)=[O:12])[C@@H:7]([CH2:9][CH3:10])[CH3:8])=[O:4].[CH3:60][O:61][C@H:62]([CH3:72])[C@H:63]([NH:67][C:68]([O:70][CH3:71])=[O:69])[C:64]([OH:66])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>Cl.CCO.CN(C=O)C>[CH3:71][O:70][C:68]([NH:67][C@H:63]([C:64]([N:44]1[CH2:45][C@@H:46]([CH2:48][O:49][CH3:50])[CH2:47][C@H:43]1[C:41]1[NH:40][C:39]2[C:58]3[C:35]([CH:36]=[CH:37][C:38]=2[N:42]=1)=[CH:34][C:33]1[C:27]2[C:28]([CH2:30][O:31][C:32]=1[CH:59]=3)=[CH:29][C:24]([C:21]1[NH:20][C:19]([C@@H:14]3[CH2:15][C@H:16]([CH3:18])[CH2:17][N:13]3[C:11](=[O:12])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[C@H:7]([CH3:8])[CH2:9][CH3:10])=[N:23][CH:22]=1)=[CH:25][CH:26]=2)=[O:66])[C@H:62]([CH3:72])[O:61][CH3:60])=[O:69]
Reactant: CC[C@@H](C)[C@H](NC(=O)OC)C(=O)N1C[C@@H](C)C[C@H]1c1ncc(-c2ccc3c(c2)COc2cc4c(ccc5nc([C@@H]6C[C@H](COC)CN6C(=O)OC(C)(C)C)[nH]c54)cc2-3)[nH]1
Reactant: COC(=O)N[C@H](C(=O)O)[C@@H](C)OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CN1CCOCC1
Product: CC[C@@H](C)[C@H](NC(=O)OC)C(=O)N1C[C@@H](C)C[C@H]1c1ncc(-c2ccc3c(c2)COc2cc4c(ccc5nc([C@@H]6C[C@H](COC)CN6C(=O)[C@@H](NC(=O)OC)[C@H](C)OC)[nH]c54)cc2-3)[nH]1
Reaction time: 3 h
Yield: 80.5 %

Procedure:
tert-butyl (2S,4S)-2-[9-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-L-alloisoleucyl]-4-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate (105 mg, 0.13 mmol) in 1.25 N HCl in EtOH (3 mL) was heated to 50° C. for 3 h and then concentrated under reduced pressure. The crude residue was treated with (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (35 mg, 0.18 mmol), HATU (59 mg, 0.16 mmol) and DMF (1.3 mL), then N-methylmorpholine (0.043 mL, 0.39 mmol) was added dropwise. After 3 hr, the mixture was quenched with 1N HCl (0.100 mL) and then purified by HPLC to afford methyl {(2S,3R)-1-[(2S,4S)-2-(5-{2-[(2S,4S)-1-[N-(methoxycarbonyl)-O-methyl-L-allothreonyl]-4-(methoxymethyl)pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl}carbamate (92 mg, 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].O.[NH2:12][NH2:13]>CN(C)C1C=CN=CC=1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:12][NH2:13])=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: NN
Agent: CN(C)c1ccncc1
Solvent: CCO
Solvent: O
Product: NNC(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
A mixture of 3-chlorobenzoic acid. (0.5 g, 3.19 mmol), 1,3-diccyclohexylcarbodiimide (0.72 g, 3.51 mmol), 4-dimethylaminopyridine (0.04 g, 0.32 mmol) in ethanol was stirred at ambient temperature for 1.5 hour. The white solid was filtered off and the filtrate diluted with dichloromethane (100 mL). The organic solution was washed with 1 N sodium hydrogen sulfate (100 mL), saturated sodium bicarbonate (100 mL), water (100 mL) and brine (100 mL). The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The crude residue was dissolved in ethanol (15 mL) and treated with hydrazine monohydrate (0.46 mL, 9.58 mmol). The resulting clear solution was stirred overnight at ambient temperature. The reaction mixture was then concentrated to dryness in vacuo. Silica gel chromatography of the residue, using 3% methanol in dichloromethane, afforded 0.29 g (53%) of 3-chlorobenzhydrazide as a white solid.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]2[O:21][CH2:20][CH2:19][O:18]2)[CH:12]=1)[C:6](OCC)=[O:7])C.[Cl-].[Ca+2].[Cl-].C(O)C.[BH4-].[Na+]>O>[O:18]1[CH2:19][CH2:20][O:21][CH:17]1[C:13]1[CH:12]=[C:11]([CH:5]([CH2:6][OH:7])[CH2:4][OH:3])[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1cccc(C2OCCO2)c1
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: OCC(CO)c1cccc(C2OCCO2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52 %

Procedure:
To a mixture of 2.01 g of diethyl[3-(1,3-dioxolan-2-yl)phenyl]malonate, 2.89 g of calcium chloride, and 50 ml of ethanol was added 2.47 g of sodium borohydride under ice-cooling, followed by stirring at the same temperature for 2 hours and at room temperature for 4 hours. To the reaction solution was added 10 ml of water at room temperature, followed by stirring for 30 minutes. The insoluble material was separated by filtration using Celite, and the filtrate was concentrated under reduced pressure to obtain 0.76 g of 2-[3-(1,3-dioxolan-2-yl)phenyl]propane-1,3-diol as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([C@H:13]2[CH2:38][O:37][C:16]3=[CH:17][C:18]4[CH2:19][C@@H:20]([C:34](O)=[O:35])[N:21]([C@H:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:26][CH3:27])[CH2:22][C:23]=4[CH:24]=[C:15]3[O:14]2)[CH:10]=[CH:11][CH:12]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.Cl.C[O:67][C:68](=[O:86])[C@@H:69]([NH2:85])[CH2:70][C:71]1[CH:76]=[CH:75][C:74]([C:77]2[CH:82]=[CH:81][N:80]=[C:79]([CH3:83])[C:78]=2[CH3:84])=[CH:73][CH:72]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([C@H:13]2[CH2:38][O:37][C:16]3=[CH:17][C:18]4[CH2:19][C@@H:20]([C:34]([NH:85][C@@H:69]([CH2:70][C:71]5[CH:76]=[CH:75][C:74]([C:77]6[CH:82]=[CH:81][N:80]=[C:79]([CH3:83])[C:78]=6[CH3:84])=[CH:73][CH:72]=5)[C:68]([OH:67])=[O:86])=[O:35])[N:21]([C@H:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:26][CH3:27])[CH2:22][C:23]=4[CH:24]=[C:15]3[O:14]2)[CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccnc(C)c2C)cc1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1cccc(OCc2ccc(Cl)c(Cl)c2)c1)O3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccnc(C)c2C)cc1)C(=O)O)OC[C@H](c1cccc(OCc2ccc(Cl)c(Cl)c2)c1)O3
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 56.4 %

Procedure:
(3S,8S)-3-[3-(3,4-Dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid (25 mg), EDCI (10 mg), HOBT (8 mg) and (S)-2-amino-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester dihydrochloride (15 mg) were taken up in 1 mL of anhydrous DCM and stirred for 5 minutes. The reaction mixture was cooled to 0° C. and DIEA (21 mg) was added and reaction was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was loaded onto a silica gel column (1:3 EtOAc:hexanes to 4% MeOH in 1:1 EtOAc:hexanes) to get purified (S)-2-{[(3S,8S)-3-[3-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester (23 mg). This was hydrolysed according to General Procedure B to give the title compound (20 mg). LCMS (m/z): 857.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH2:14][NH2:15])=[CH:12][C:11]([C:16]([F:19])([F:18])[F:17])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[F:20][C:21]1[CH:22]=[C:23]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH2:29][O:30][CH3:31]>C(Cl)Cl.O>[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH2:14][NH:15][C:33]([NH:32][C:23]3[CH:24]=[CH:25][C:26]([O:27][CH2:28][CH2:29][O:30][CH3:31])=[C:21]([F:20])[CH:22]=3)=[O:34])=[CH:12][C:11]([C:16]([F:17])([F:18])[F:19])=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COCCOc1ccc(NC(=O)Oc2ccccc2)cc1F
Reactant: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: COCCOc1ccc(NC(=O)NCc2cc(C(F)(F)F)nn2-c2cccc(Cl)c2)cc1F
Reaction time: 16 h
Yield: 53.4 %

Procedure:
To a stirred solution of (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine hydrochloride (102 mg, 0.327 mmol, 1.0 eq.) in DCM (5.0 mL) was added TEA (1.36 mL, 0.981 mmol, 3.0 eq) followed by phenyl 3-fluoro-4-(2-methoxyethoxy)phenylcarbamate (100 mg, 0.327 mmol, 1.0 eq.) at RT and stirred for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL). The organic layer was washed with water (10 mL) and brine (5 mL), dried over anhydrous Na2SO4, and the solvent evaporated under vacuum. The crude product obtained was purified by neutral alumina column chromatography using MeOH/CHCl3 (1:9) as eluent to yield 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(3-fluoro-4-(2-methoxyethoxy)-phenyl)urea (example A18) (85 mg, 53%) as a white solid (TLC system: MeOH/CHCl3 (1:9), Rf: 0.5).
Reaction SMILES: [C:1]([N:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[C:14]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][C:18]([S:24]([N:27](CC1C=CC(OC)=CC=1OC)[C:28]1[S:29][CH:30]=[CH:31][N:32]=1)(=[O:26])=[O:25])=[CH:19]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CO>[C:1]([N:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[C:14]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][C:18]([S:24]([NH:27][C:28]1[S:29][CH:30]=[CH:31][N:32]=1)(=[O:26])=[O:25])=[CH:19]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(C4CCCN4C(=O)c4ccccc4)cccc3c2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCCC1c1cccc2cc(S(=O)(=O)Nc3nccs3)ccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5-(1-benzoylpyrrolidin-2-yl)-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)naphthalene-2-sulfonamide (0.040 g, 0.065 mmol) was dissolved in DCM and TFA (0.1 mL, 1.298 mmol) was added. The reaction was stirred for 15 minutes at room temperature. The reaction was diluted with methanol and concentrated. The material was triturated in diethyl ether, filtered, and the solids were washed with diethyl ether. The solids were collected and vacuum dried overnight to afford 5-(1-benzoylpyrrolidin-2-yl)-N-(thiazol-2-yl)naphthalene-2-sulfonamide as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=12.79 (br. s., 1H), 8.48 (s, 1H), 8.38 (d, J=8.8 Hz, 1H), 8.11-7.95 (m, 1H), 7.87 (d, J=9.3 Hz, 1H), 7.75-7.57 (m, 4H), 7.49 (br. s., 3H), 7.26 (br. s., 1H), 7.17-6.96 (m, 1H), 6.84 (d, J=4.2 Hz, 1H), 5.94 (br. s., 1H), 3.90 (br. s., 1H), 3.58 (br. s., 1H), 2.70-2.58 (m, 1H), 1.89 (br. s., 2H), 1.74 (br. s., 1H). m/z (ESI) 464.2 (M+H)+.
Reaction SMILES: C(OC1C=NC(C2C=CC=CC=2C(N[C@H]2CCC[C@@H]2NC2C=NC(C(F)(F)F)=CN=2)=O)=NC=1)C.Cl.[F:36][C:37]1[C:38]([NH:47][C@H:48]2[CH2:52][CH2:51][CH2:50][C@@H:49]2[NH2:53])=[N:39][CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1.[F:54][C:55]1[CH:56]=[CH:57][C:58]([C:64]2[N:69]=[CH:68][CH:67]=[CH:66][N:65]=2)=[C:59]([CH:63]=1)[C:60](O)=[O:61]>>[F:54][C:55]1[CH:56]=[CH:57][C:58]([C:64]2[N:65]=[CH:66][CH:67]=[CH:68][N:69]=2)=[C:59]([CH:63]=1)[C:60]([NH:53][C@H:49]1[CH2:50][CH2:51][CH2:52][C@@H:48]1[NH:47][C:38]1[C:37]([F:36])=[CH:42][C:41]([C:43]([F:46])([F:44])[F:45])=[CH:40][N:39]=1)=[O:61]
Reactant: N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1F
Reactant: O=C(O)c1cc(F)ccc1-c1ncccn1
Agent: CCOc1cnc(-c2ccccc2C(=O)N[C@H]2CCC[C@@H]2Nc2cnc(C(F)(F)F)cn2)nc1
Agent: Cl
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1F)c1cc(F)ccc1-c1ncccn1

Procedure:
Prepared according to the procedure for 2-(5-Ethoxypyrimidin-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 135) from (1S,2S)-1-N-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 34: 200 mg, 0.76 mmol) and 5-fluoro-2-(pyrimidin-2-yl)benzoic acid (CAS number 1293284-57-7; 166 mg, 0.76 mmol) except after the reaction was complete it was concentrated in vacuo and the residue was purified by reverse phase column chromatography (C18 silica, 0-100% water (0.05% ammonia)/methanol), then by column chromatography (silica, 0-50% ethyl acetate/petrol) and then triturated with DCM/petrol to afford the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:14].O.C1C=C(Cl)C=C(C(OO)=O)C=1>CC(C)=O>[CH2:1]([N:8]1[CH2:12][CH:11]2[O:14][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=CCN(Cc2ccccc2)C1
Reactant: O=S(=O)(O)O
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: CC(C)=O
Product: c1ccc(CN2CC3OC3C2)cc1
Yield: 97 %

Procedure:
To a solution of 15.9 g (0.1 mol) of 1-benzyl-3-pyrroline, 12.0 g (0.12 mol) of 98% sulfuric acid, 15.0 g of water, and 60.0 g of acetone in a round flask reactor, 31.1 g (0.13 mol) of 70% m-CPBA (m-chloroperbenzoic acid produced by Tokyo Chemical Industry Co., Ltd.) was added with stirring and allowed to react for 10 hours at room temperature without irradiation by lamps. After completion, acetone was evaporated under reduced pressure, neutralized by NaOH (aq), and extracted with toluene and water. After the solvent was evaporated under reduced pressure, 17.0 g of 1-benzyl-3,4-epoxypyrrolidine (yield 97.0%) was obtained.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9](#[N:12])[CH:10]=[CH2:11].CC(N=NC(C#N)(C)C)(C#N)C.P([O-])([O-])([O-])=O.[Ca+2].[Ca+2].[Ca+2].P([O-])([O-])([O-])=O>O>[CH:1]([CH:11]=[CH:10][C:9]#[N:12])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: C=CC#N
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=P([O-])([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: N#CC=CC=Cc1ccccc1

Procedure:
76 parts by weight of styrene, 24 parts by weight of acrylonitrile, and 120 parts of deionized water are mixed. To the mixture, 0.17 parts by weight of azobisisobutylonitrile (AIBN), 0.4 parts by weight of t-dodecyl mercaptan chain transfer agent, and 0.5 parts by weight of tricalciumphosphate are added. The mixture is suspension polymerized at 75° C. for 5 hours, and a styrene-acrylonitrile (SAN) copolymer resin is obtained. The resultant copolymer is washed, dehydrated and dried to obtain SAN copolymer resin having a weight average molecular weight of 150,000 g/mol in powder form.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C=O.[BH3-][C:14]#N.[Na+].C(O)(=O)C>CC#N.CCOCC>[CH3:14][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCCN2
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOCC
Solvent: CC(=O)O
Product: CN1CCCc2ccccc21
Reaction time: 0.5 h

Procedure:
1,2,3,4-tetrahydroquinoline (2.0 g, 0.0015 mol) and formaldehyde (12 ml of 38% aqueous, 0.015 mol) were combined in 60 ml CH3CN. NaBH3CN (2.85 g) and then, over a 10 minute period, glacial acetic acid (1.50 ml) were added and the mixture stirred 2 hours, at which time additional acetic acid (0.5 ml) was added. After stirring an additional 30 minutes, the reaction mixture was poured into 200 ml ether, washed 3×30 ml IN NaOH, dried (K2CO3) and stripped in vacuo to yield title product, 2.27 g.
Reaction SMILES: O1CCCC1.[C:6]([C:8]1[C:9]([NH2:14])=[N:10][CH:11]=[CH:12][CH:13]=1)#[CH:7].[F:15][C:16]1[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=1)[O:19][C:20]1[N:25]=[CH:24][C:23]([CH2:26][C:27](Cl)=[N:28][OH:29])=[CH:22][CH:21]=1.C(N(CC)CC)C>O>[F:15][C:16]1[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=1)[O:19][C:20]1[N:25]=[CH:24][C:23]([CH2:26][C:27]2[CH:7]=[C:6]([C:8]3[C:9]([NH2:14])=[N:10][CH:11]=[CH:12][CH:13]=3)[O:29][N:28]=2)=[CH:22][CH:21]=1
Reactant: C#Cc1cccnc1N
Reactant: ON=C(Cl)Cc1ccc(Oc2cccc(F)c2)nc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: Nc1ncccc1-c1cc(Cc2ccc(Oc3cccc(F)c3)nc2)no1
Temperature: 50 °C
Reaction time: 3 h
Yield: 53.6 %

Procedure:
To a tetrahydrofuran (4 mL) solution of 3-ethynyl-pyridin-2-ylamine (20 mg, 0.17 mmol) described in Manufacturing Example 1-2-3 and (6-(3-fluoro-phenoxy)-pyridin-3-yl)-acetohydroximoyl chloride (95 mg, 0.34 mmol) described in Manufacturing Example 71-1-4 was added triethylamine (47 mL, 0.34 mmol), which was stirred for 3 hours at 50° C. under nitrogen atmosphere. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the filtrate was purified by NH silica gel column chromatography (ethyl acetate:methanol=20:1) and further purified by reverse-phase high-performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoracetic acid) to obtain the title compound (33 mg, 33%) as a ditrifluoracetic acid salt.
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][NH:11][C:12](=[O:39])[CH2:13][CH2:14][C:15]([CH3:38])=[CH:16][CH2:17][C:18]1[C:19]([O:31]CC[Si](C)(C)C)=[C:20]2[C:24](=[C:25]([CH3:29])[C:26]=1[O:27][CH3:28])[CH2:23][O:22][C:21]2=[O:30])(=[O:8])[O:5]CC)C.C[Si](Br)(C)C.N1C(C)=CC=CC=1C>C(#N)C>[OH:31][C:19]1[C:18]([CH2:17][CH:16]=[C:15]([CH3:38])[CH2:14][CH2:13][C:12]([NH:11][CH2:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5])=[O:39])=[C:26]([O:27][CH3:28])[C:25]([CH3:29])=[C:24]2[C:20]=1[C:21](=[O:30])[O:22][CH2:23]2
Reactant: CCOP(=O)(CCNC(=O)CCC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)OCC
Agent: C[Si](C)(C)Br
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Product: COc1c(C)c2c(c(O)c1CC=C(C)CCC(=O)NCCP(=O)(O)O)C(=O)OC2
Reaction time: 8 h
Yield: 21.5 %

Procedure:
To a solution of (2-{6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoylamino}-ethyl)-phosphonic acid diethyl ester (36.6 mg, 0.063 mmol) in acetonitrile (1 mL) was added TMSBr (81 μL, 0.63 mmol) followed by 2,6-lutidine (73 μL, 0.63 mmol). The reaction was allowed to proceed overnight when it was completed as judged by LCMS. The reaction mixture was quenched with MeOH and concentrated to dryness. The residue was purified by preparative reverse-phase HPLC to afford 5.8 mg (29%) of desired product as a white solid. 1H NMR (300 MHz, CD3OD) δ 1.80 (s, 3H), 2.14 (m, 5H), 2.25 (m, 4H), 3.35 (m, 2H), 3.38-3.38 (m, 2H), 3.75 (s, 3H), 5.23 (s, 3H) ppm; 31P (121.4 MHz, CD3OD) δ 26.03 ppm; MS (m/z) 426 [M−H]−, 428 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[C:12](=[O:29])[NH:13][C:14](=[O:28])[C:15]=1[C:16]1[CH:17]=[C:18]2[C:23]3=[C:24]([CH2:26][CH2:27][N:22]3[CH2:21][CH2:20][CH2:19]2)[CH:25]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[C:12](=[O:29])[NH:13][C:14](=[O:28])[C:15]=1[C:16]1[CH:17]=[C:18]2[C:23]3=[C:24]([CH:26]=[CH:27][N:22]3[CH2:21][CH2:20][CH2:19]2)[CH:25]=1
Reactant: O=C1NC(=O)C(c2c[nH]c3ccc(Br)cc23)=C1c1cc2c3c(c1)CCN3CCC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1NC(=O)C(c2c[nH]c3ccc(Br)cc23)=C1c1cc2c3c(ccn3CCC2)c1
Reaction time: 0.5 h
Yield: 85.5 %

Procedure:
A solution of 3-(5-bromo-1H-indol-3-yl)-4-(1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)-pyrrole-2,5-dione (300 mg, 0.668 mmol) in anhydrous tetrahydrofuran (15 ml) at room temperature was treated with 2,3-dichloro-5,6-dicyano-p-benzoquinone (182 mg, 0.802 mmol) and stirred for 30 minutes. The reaction was treated with 10% aqueous sodium sulfite (40 ml) and diluted with water (50 ml) and ethyl acetate (50 ml). The aqueous layer was removed and the organic layer was washed with saturated aqueous sodium bicarbonate (50 ml) then water (2×50 ml). The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by flash column chromatography (SiO2, 1% methanol to 10% methanol in dichloromethane) to provide 3-(5-bromo-1H-indol-3-yl)-4-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)-pyrrole-2,5-dione as an orange solid (255 mg). 400 MHz 1H NMR (DMSO-d6) δ: 11.94 (s, 1H), 10.95 (s, 1H), 7.99 (s, 1H), 7.45 (d, J=1.6 Hz, 1H), 7.33 (m, 2H), 7.08 (dd, J=6.8 and 1.6 Hz, 1H), 6.81 (d, J=1.6 Hz, 1H), 6.34 (d, J=2.8 Hz, 1H), 6.20 (d, J=2.0 Hz, 2H), 4.17 (m, 2H), 2.75 (m, 2H), 2.12 (m, 2H); LCMS: 446 and 448 [M+H].