Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.Cl.N1C=CC=CC=1.[C:16]1([NH:22][C:23]([N:25]2[C:33]3[C:28](=[CH:29][C:30]([NH2:34])=[CH:31][CH:32]=3)[CH:27]=[CH:26]2)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN1CCCC1=O>[C:16]1([NH:22][C:23]([N:25]2[C:33]3[C:28](=[CH:29][C:30]([NH:34][C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=4)=[CH:31][CH:32]=3)[CH:27]=[CH:26]2)=[O:24])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1ccc2c(ccn2C(=O)Nc2ccccc2)c1
Reactant: Nc1cc(Cl)ccn1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN1CCCC1=O
Product: Nc1cc(Nc2ccc3c(ccn3C(=O)Nc3ccccc3)c2)ccn1
Temperature: 100 °C
Reaction time: 6.5 h
Yield: 104 %

Procedure:
2-Amino-4-chloropyridine (500 mg, 0.446 mmol) was dissolved in N-methylpyrrolidone (5.0 ml); pyridine hydrochloride (750 mg) and 5-aminoindole-1-carboxylic acid phenylamide (408 mg, 1.62 mmol) was added thereto; the reaction mixture was stirred at 100° C. for 6.5 hours. After cooling to room temperature, the reaction mixture was partitioned between saturated aqueous solution of sodium hydrogencarbonate and ethyl acetate; the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia NH, hexane-ethyl acetate-methanol system). The obtained pale yellow oil was solidified with diethyl ether; and the crystals were suspended in diethyl ether, filtered off, washed with diethyl ether, and dried to yield the title compound (188 mg, 0.464 mmol, 35.7%) as pale yellow crystals.
Reaction SMILES: [CH3:1][N:2]1C[CH2:6][O:5][CH2:4][CH2:3]1.[F:8][C:9]([F:35])([F:34])[C:10]1[N:14]2[N:15]=[C:16]([N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=4)[CH2:21][CH2:20]3)[CH:17]=[CH:18][C:13]2=[N:12][N:11]=1.ClC1N=C(OC)N=C(OC)N=1.COCCNC>CN(C=O)C>[CH3:6][O:5][CH2:4][CH2:3][N:2]([CH3:1])[C:29](=[O:30])[C:28]1[CH:32]=[CH:33][C:25]([CH:22]2[CH2:21][CH2:20][N:19]([C:16]3[CH:17]=[CH:18][C:13]4[N:14]([C:10]([C:9]([F:34])([F:8])[F:35])=[N:11][N:12]=4)[N:15]=3)[CH2:24][CH2:23]2)=[CH:26][CH:27]=1
Reactant: O=C(O)c1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Reactant: CN1CCOCC1
Agent: CNCCOC
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CN(C)C=O
Product: COCCN(C)C(=O)c1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.4 %

Procedure:
4-Methylmorpholine (17.56 mL, 159.70 mmol) was added dropwise to 4-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]benzoic acid (25 g, 63.88 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (13.46 g, 76.66 mmol) suspended in DMF (250 mL) at 0° C. The resulting suspension was stirred for 10 minutes, then 2-methoxy-N-methylethanamine (5.69 g, 63.88 mmol) was added and the mixture warmed to ambient temperature and stirred for 16 hours. The reaction mixture was concentrated and diluted with DCM (1000 mL) and washed with water (500 mL). The aqueous phase was re-extracted with DCM (500 mL), then the combined organics were washed with saturated NaHCO3 (500 mL) and saturated brine (250 mL), and dried over MgSO4, filtered and evaporated to afford crude product. The crude product was triturated with ether, and the resulting solid was collected by filtration and dried under vacuum, then purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford N-(2-methoxyethyl)-N-methyl-4-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]benzamide (23.45 g, 79%) as a solid.
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.CN(C)CCC(N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1)=O.[CH3:87][C@H:88]1[O:93][C@@H:92]([CH3:94])[CH2:91][N:90]([CH2:95][C:96]([OH:98])=O)[CH2:89]1>>[CH3:94][C@H:92]1[CH2:91][N:90]([CH2:95][C:96]([NH:1][C@:2]23[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]2[C@@H:4]2[C@@:17]([CH3:20])([CH2:18][CH2:19]3)[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5]2)=[O:98])[CH2:89][C@@H:88]([CH3:87])[O:93]1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: C[C@@H]1CN(CC(=O)O)C[C@H](C)O1
Agent: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)CN3C[C@@H](C)O[C@@H](C)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 43 %

Procedure:
The title compound was prepared in 43% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except [(2R,6S)-2,6-dimethylmorpholin-4-yl]acetic acid was used instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 685.6 (M+H)+, 2.48 min (method 6). 1H NMR (500 MHz, 1:1 CDCl3:MeOD) δ=7.92 (d, J=8.2 Hz, 2H), 7.20 (d, J=8.2 Hz, 2H), 5.29 (dd, J=1.5, 6.1 Hz, 1H), 4.75 (d, J=1.2 Hz, 1H), 3.89 (dd, J=6.3, 9.0 Hz, 2H), 3.64 (br. s., 1H), 3.24 (br. s., 2H), 2.69-2.49 (m, 4H), 2.39 (dd, J=8.1, 12.4 Hz, 1H), 2.13 (dd, J=6.4, 17.1 Hz, 1H), 1.93-1.76 (m, 3H), 1.74 (br. s., 1H), 1.72 (s, 3H), 1.70-1.66 (m, 1H), 1.60-1.42 (m, 8H), 1.42-1.30 (m, 3H), 1.25 (d, J=3.1 Hz, 3H), 1.24 (d, J=2.7 Hz, 3H), 1.18-1.11 (m, 2H), 1.08 (s, 3H), 1.03 (s, 3H), 1.01 (s, 3H), 0.95 (s, 3H), 0.94 (s, 3H).
Reaction SMILES: [CH2:1]([NH:8][C:9]([N:11]1[C@H:16]2[CH2:17][N:18]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34](F)[N:33]=3)[C:19](=[O:30])[C@H:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]=3[F:29])[N:15]2[C:14](=[O:39])[CH2:13][N:12]1[CH2:40][CH:41]=[CH2:42])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:43]1[CH2:46][CH:45]([N:47]2[CH2:52][CH2:51][N:50]([CH3:53])[C@@H:49]([CH3:54])[CH2:48]2)[CH2:44]1>N1C=CC=CC=1>[CH2:1]([NH:8][C:9]([N:11]1[C@H:16]2[CH2:17][N:18]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([N:43]4[CH2:46][CH:45]([N:47]5[CH2:52][CH2:51][N:50]([CH3:53])[C@@H:49]([CH3:54])[CH2:48]5)[CH2:44]4)[N:33]=3)[C:19](=[O:30])[C@H:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]=3[F:29])[N:15]2[C:14](=[O:39])[CH2:13][N:12]1[CH2:40][CH:41]=[CH2:42])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCN1CC(=O)N2[C@@H](Cc3ccc(O)cc3F)C(=O)N(Cc3cccc(F)n3)C[C@@H]2N1C(=O)NCc1ccccc1
Reactant: C[C@H]1CN(C2CNC2)CCN1C
Solvent: c1ccncc1
Product: C=CCN1CC(=O)N2[C@@H](Cc3ccc(O)cc3F)C(=O)N(Cc3cccc(N4CC(N5CCN(C)[C@@H](C)C5)C4)n3)C[C@@H]2N1C(=O)NCc1ccccc1
Temperature: 25 °C
Yield: 58.2 %

Procedure:
To a mixed solution of (6S,9aS)-N-benzyl-6-((2-fluoro-4-hydroxyphenyl)methyl)-8-((6-fluoropyridin-2-yl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide (4.00 g 6.94 mmol) described in Production Example 1-1-6 and pyridine (100 mL) was added (2S)-4-(azetidin-3-yl)-1,2-dimethylpiperazine (2.35 g, 13.9 mmol) described in Production Example 4-3 at room temperature. The resultant mixture was stirred under reflux for 6 hours and 50 minutes. The reaction mixture was cooled to room temperature, and then concentrated under a reduced pressure. The resultant residue was purified by silica gel column chromatography (methanol), and then purified by NH silica gel column chromatography (ethyl acetate:methanol=20:1) to give the title compound (2.93 g, yield: 58%).
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][CH2:13][CH2:14]O)=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:6]1(=[O:23])=[O:22])([CH3:4])([CH3:3])[CH3:2].CC1C=CC(S([Cl:34])(=O)=O)=CC=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][CH2:13][CH2:14][Cl:34])=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:6]1(=[O:23])=[O:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1C(=O)C(NCCCO)=C(c2ccccc2)S1(=O)=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)N1C(=O)C(NCCCCl)=C(c2ccccc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
A mixture of 2-tert-butyl-4-[(3-hydroxypropyl)amino]-5-phenylisothiazol-3(2H)-one 1,1-dioxide (Example 49) (0.14 g, 0.42 mmol 4-methylbenzenesulfonyl chloride (0.089 mg, 0.46 mmol) and TEA (0.065 ml, 0.46 mmol) in DCM (2 ml) was stirred at rt for 2 h, after which more TEA (0.065 ml, 0.46 mmol) and cat. DMAP were added. After a further 18 h more 4-methylbenzenesulfonyl chloride (0.16 mg, 0.84 mmol), TEA (0.059 ml, 0.42 mmol) and DMAP (0.052 g, 0.42 mmol) were added. After 5 h the reaction mixture was warmed to reflux for 18 h and evaporated to dryness. The residue was purified by silica gel column chromatography (Horizons Biotage) using 10% EtOAc in hexane as eluent to give the title compound (0.097 g, 64%). 1H NMR (500 MHz, CDCl3): δ 7.56-7.50 (m, 2H), 7.50-7.44 (m, 3H), 5.32 (t, 1H), 3.35 (t, 2H), 3.08 (q, 2H), 1.80-1.72 (m, 11H); 13C NMR (125 MHz, CDCl3): δ 159.8, 135.0, 131.8, 130.0, 128.9, 124.9, 107.8, 61.8, 41.7, 41.3, 32.0, 27.8; Mass Spectrum: M+H+ 357.
Reaction SMILES: [C:1]1([CH2:11][C:12]#N)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:14]I.[H-].[Na+].OS(O)(=O)=O.C[N:24]([CH:26]=O)C>C(OCC)(=O)C>[CH3:14][C:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)([CH3:12])[C:26]#[N:24]
Reactant: N#CCc1cccc2ccccc12
Reactant: CI
Reactant: CN(C)C=O
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C#N)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 16.7 g (100 mmol) of 1-naphthylacetonitrile in 200 m of DMF and 15 ml (240 mmol) of methyl iodide is mixed at 0° C. with 10.4 g (260 mmol) of sodium hydride (addition within 2.5 hours). The batch is stirred for 3 hours at 0° C. and for 18 hours at 25° C. It is mixed with ice and ethyl acetate. The organic phase is acidified with 10% H2SO4, washed three times with water, dried (Na2SO4) and concentrated by evaporation in a vacuum. A large-scale purification is carried out by bulb tube distillation (boiling range 60–130° C.) in an oil pump vacuum; yield: 18.8 g.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][NH:4][CH2:3]1.[C:8]([N:15]1[CH2:18][C:17](=O)[CH2:16]1)([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.CC(O)=O>[C:11]([O:10][C:8]([N:15]1[CH2:18][CH:17]([N:4]2[CH2:5][CH2:6][NH:7][C:2](=[O:1])[CH2:3]2)[CH2:16]1)=[O:9])([CH3:14])([CH3:12])[CH3:13]
Reactant: O=C1CNCCN1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC(N2CCNC(=O)C2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
To a mixture of 3-oxopiperazine 4a (490 mg, 4.89 mmol) and N-Boc-azetidin-3-one 1a (922 mg, 5.38 mmol) in 1,2-dichloroethane (10 mL) and HOAc (0.5 mL) was added Na(OAc)3BH (1141, 5.38 mmol). The reaction was stirred at room temperature overnight. Additional 1a (335 mg, 1.96 mmol) and Na(OAc)3BH (415 mg, 1.96 mmol) was added. The reaction was stirred for another 24 h before it was quenched with aq. NaHCO3. The resulting mixture was extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated. Purification by column chromatography (silica gel, 4% MeOH/CH2Cl2) gave intermediate 4b as white solid (860 mg).
Reaction SMILES: Cl[CH:2](Cl)[C:3]1[N:4]([CH3:11])[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][N:7]=1.S(=O)(=O)(O)[OH:14].[OH-].[Na+]>>[CH:2]([C:3]1[N:4]([CH3:11])[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][N:7]=1)=[O:14]
Reactant: Cn1c([N+](=O)[O-])cnc1C(Cl)Cl
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cn1c([N+](=O)[O-])cnc1C=O

Procedure:
210 parts of 2-dichloromethyl-1-methyl-5-nitroimidazole are stirred in 800 parts by volume of 10 percent strength by weight sulfuric acid for 2 hours at 100° C. The mixture is then neutralized with 550 parts of 6N sodium hydroxide solution, with intense cooling, and the resulting solution is extracted with 4 times 500 parts by volume of methylene chloride. The combined extracts are dried. 126 parts (82% of theory) of 2-formyl-1-methyl-5-nitroimidazole of melting point 93° C. (after recrystallization from toluene) are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:16][C:17]=1[CH3:18])[CH2:6][OH:7].Cl[C:26]1[C:31]([C:32]#[N:33])=[CH:30][CH:29]=[CH:28][N:27]=1.CN(C)C=O.[H-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:16][C:17]=1[CH3:18])[CH2:6][O:7][C:26]1[N:27]=[CH:28][CH:29]=[CH:30][C:31]=1[C:32]#[N:33]
Reactant: COc1cc(CO)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: N#Cc1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(COc2ncccc2C#N)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 90 %

Procedure:
To a mixture of 3-methoxy-4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyl alcohol (4.00 g), 2-chloro-3-cyanopyridine (1.62 g) and N,N-dimethylformamide (40 mL) was added sodium hydride (60%, oil, 515 mg) under ice-cooling. The reaction mixture was stirred at room temperature for 15 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained crystals were recrystallized from ethyl acetate-hexane to give 2-[3-methoxy-4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]nicotinonitrile as pale-yellow crystals (4.50 g, 90%). melting point: 117-118° C.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[CH2:8][CH2:9][C@@H:10]([NH2:11])[C:4]2=[N:3][CH:2]=1.[F:16][C:17]1[CH:31]=[CH:30][C:20]([C:21]([NH:23][C:24]2([C:27](O)=[O:28])[CH2:26][CH2:25]2)=[O:22])=[CH:19][CH:18]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH:1]1[N:5]2[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[CH2:8][CH2:9][C@@H:10]([NH:11][C:27]([C:24]3([NH:23][C:21](=[O:22])[C:20]4[CH:30]=[CH:31][C:17]([F:16])=[CH:18][CH:19]=4)[CH2:26][CH2:25]3)=[O:28])[C:4]2=[N:3][CH:2]=1
Reactant: N[C@@H]1CCc2ccccc2-n2ccnc21
Reactant: O=C(NC1(C(=O)O)CC1)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1(C(=O)N[C@@H]2CCc3ccccc3-n3ccnc32)CC1)c1ccc(F)cc1
Yield: 67.5 %

Procedure:
Combine (4R)-5,6-dihydro-4H-imidazo[1,2-a][1]benzazepin-4-amine (95.0 mg, 0.48 mmol), 1-[(4-fluorobenzoyl)amino]cyclopropanecarboxylic acid (128.0 mg, 0.57 mmol), and O—-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (218.0 mg, 0.57 mmol) in N,N-dimethylformamide (4 mL). Add diisopropylethylamine (0.21 mL, 1.19 mmol) and stir the reaction for approximately 16 hours at ambient temperature under nitrogen. Dilute the reaction with ethyl acetate, wash with saturated sodium bicarbonate and brine, dry over sodium sulfate, and concentrate the organic layer under reduced pressure. Purify the residue by flash chromatography (3% ammonia (2M) solution in methanol/dichloromethane) to give the title compound (131.0 mg, 68%): MS (m/z): 405 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[C@H:18]1[CH2:23][C@@H:22]([NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:21](=[O:35])[C@@H:20]([CH3:36])[CH2:19]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:37](O)[CH2:38][OH:39].B(F)(F)F.CCOCC>C1COCC1.CCOC(C)=O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[C@@H:18]1[CH2:19][C@H:20]([CH3:36])[C:21]2([O:39][CH2:38][CH2:37][O:35]2)[C@H:22]([NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCO
Reactant: C[C@H]1C[C@@H](c2ccncc2NC(=O)OCc2ccccc2)C[C@@H](NC(=O)OCc2ccccc2)C1=O
Agent: FB(F)F
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@H]1C[C@@H](c2ccncc2NC(=O)OCc2ccccc2)C[C@@H](NC(=O)OCc2ccccc2)C12OCCO2
Temperature: 100 °C
Yield: 100 %

Procedure:
(+/−)-Benzyl ((1R,3S,5R)-5-(3-((benzoxycarbonyl)amino) pyridin-4-yl)-3-methyl-2-oxocyclohexyl)carbamate (1.0 equiv.) was dissolved in dry THF (0.20 M) under nitrogen and ETHYLENE GLYCOL (8.0 equiv.) was added followed by BF3.OEt2 (1.4 equiv.). The solution was microwave vial and heated at 100° C. for 60 mins. The solution was diluted with EtOAc and washed with sat. sodium bicarbonate, water, brine, dried over sodium sulfate and concentrated. The crude material was purified by ISCO chromatography to afford (+/−)-benzyl ((6R,8R,10S)-8-(3-((benzoxycarbonyl)amino)pyridin-4-yl)-10-methyl-1,4-dioxaspiro[4.5]decan-6-yl)carbamate in 100% yield. LC/MS (m/z)=532.2 (MH+), Rt=0.81 min.
Reaction SMILES: C(O)C(N)(CO)CO.[Cl-:9].[Cl-].[Cl-].[Cr+3:12].[CH3:13][Si:14]([CH:17]([Li:22])[Si:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:15]>C(OCC)C>[CH3:13][Si:14]([CH:17]([Cr+2:12])[Si:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:15].[Cl-:9].[Li+:22]
Reactant: [Cr+3]
Reactant: [Li]C([Si](C)(C)C)[Si](C)(C)C
Agent: NC(CO)(CO)CO
Agent: [Cl-]
Solvent: CCOCC
Product: C[Si](C)(C)C([Cr+2])[Si](C)(C)C
Product: [Li+]
Reaction time: 2 h

Procedure:
Tris[bis(trimethylsilyl)methyl chromium(III) was synthesized according to the method described in J. Chem. Soc. Dalton, 734 (1977) as follows. 0.48 g (3.03 mmol) of anhydrous chromium trichloride (a product of Nakalai Tesque Inc.) was put into a 100 ml flask the inner atmosphere of which had previously been replaced by nitrogen gas, and 50 ml of diethyl ether was then added to the flask to prepare a slurry. After cooling the flask with a dry ice-alcohol bath, 17. 1 ml (9.09 mmol) of a diethyl ether solution of bis(trimethylsilyl)methyl lithium synthesized in (1) above was added dropwise to the flask over 1 hour. After completion of the dropwise addition, temperature of the reaction solution was returned to room temperature and the solution was stirred for 2 hours. Precipitate of lithium chloride was formed. Solvent was completely removed under reduced pressure to obtain a dark green bulk. 80 ml of hexane was added to the bulk to dissolve the bulk therein, and after centrifugal separation, only a supernatant liquid was collected. Chromium concentration in the solution was measured and was found to be 0.0538 mol/liter, 2.80 g/liter.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:3]=1.C(N1CCNCC1)C.C(=O)([O-])[O-:29].[K+].[K+]>CN(C)C=O>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:4]2[NH:3][C:2](=[O:29])[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[CH:13][CH:14]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(-c2cc3ccccc3c(Cl)n2)cc1
Agent: CCN1CCNCC1
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc3ccccc3c(=O)[nH]2)cc1
Yield: 123 %

Procedure:
A mixture of 1-chloro-3-(4-methoxyphenyl)isoquinoline (0.89 g), N-ethylpiperazine (0.86 g) and potassium carbonate (1.10 g) was heated in dimethylformamide (20 ml) at 90° C. for 12 hr. The reaction mixture was evaporated, water was added to the resulting residue, and then it was extracted with ethyl acetate. The resulting organic layer was washed with water and brine, dried over magnesium sulfate, and then the solvent was romoved. The resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give the title compound as a pale brown oil (1.02 g, yield; 88%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.O=S(Cl)Cl.[Cl:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19].C(Cl)(Cl)Cl>C1C=CC=CC=1>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[Cl:16])=[O:6]
Reactant: Nc1ccccc1Cl
Reactant: Nc1ccc(Br)cc1C(=O)O
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: Nc1ccc(Br)cc1C(=O)Nc1ccccc1Cl
Yield: 19.7 %

Procedure:
Prepared according to Procedure A using 2-amino-5-bromobenzoic acid (5.0 g, 23.1 mmol) and SOCl2 (7.0 mL, 95.9 mmol) in benzene (50 mL), followed by 2-chloroaniline (7.3 mL, 69.3 mmol) and CHCl3 (50 mL). The product was purified by two chromatographies in CH2Cl2 to provide 1.48 g of a yellow orange solid (20%). 1H NMR (CDCl2) δ: 8.36 (dd, J=1.2, 8.2 Hz, 1H); 8.20 (br s, 1H); 7.62 (d, J=2.1 Hz, 1H); 7.42 (dd, J=1.3, 8.0 Hz, 1H); 7.34 (dd, J=2.2, 8.8 Hz, 1H); 7.28-7.33 (m, 1H); 7.09 (dt, J=1.4, 7.7 Hz, 1H); 6.62 (d, J=8.7 Hz, 1H); 5.57 (br s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:13][C:14]2[O:18][CH:17]=[C:16]([C:19](O)=[O:20])[CH:15]=2)[CH3:12])(=[O:10])=[O:9])=[C:4]([CH2:22][CH3:23])[CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[N:36]1([CH2:41][C:42]2[CH:43]=[C:44]([CH2:48][NH2:49])[CH:45]=[CH:46][CH:47]=2)[CH2:40][CH2:39][CH2:38][CH2:37]1>ClCCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:13][C:14]2[O:18][CH:17]=[C:16]([C:19]([NH:49][CH2:48][C:44]3[CH:45]=[CH:46][CH:47]=[C:42]([CH2:41][N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)[CH:43]=3)=[O:20])[CH:15]=2)[CH3:12])(=[O:9])=[O:10])=[C:4]([CH2:22][CH3:23])[CH:3]=1
Reactant: CCc1cc(Br)ccc1S(=O)(=O)N(C)Cc1cc(C(=O)O)co1
Reactant: NCc1cccc(CN2CCCC2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: CCc1cc(Br)ccc1S(=O)(=O)N(C)Cc1cc(C(=O)NCc2cccc(CN3CCCC3)c2)co1

Procedure:
The title compound was prepared according to general procedure AA using 5-({[(4-bromo-2-ethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (40 mg, 0.10 mmol), CDI (32 mg, 0.2 mmol) and 1-[3-(pyrrolidin-1-ylmethyl)phenyl]methanamine (57 mg, 0.3 mmol) in DCE (2 mL). The crude product was purified using prep method A.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].N1C=CC=CC=1.[CH2:16]([O:18][CH:19]=[CH:20][C:21](Cl)=[O:22])[CH3:17].Cl>C1COCC1.O>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][C:21](=[O:22])/[CH:20]=[CH:19]/[O:18][CH2:16][CH3:17]
Reactant: CCOC=CC(=O)Cl
Reactant: Cc1cccc(Cl)c1N
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: CCO/C=C/C(=O)Nc1c(C)cccc1Cl
Temperature: 20 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
To a cold stirring solution of 2-chloro-6-methylaniline (59.5 g 0.42 mol) and pyridine (68 ml, 0.63 mol) in THF (600 mL) was added 3-ethoxyacryloyl chloride (84.7 g, 0.63 mol) slowly keeping the temp at 0-5° C. The mixture was then warmed and stirred for 2 h. at 20° C. Hydrochloric acid (1N, 115 mL) was added at 0-10° C. The mixture was diluted with water (310 mL) and the resulting solution was concentrated under vacuum to a thick slurry. The slurry was diluted with toluene (275 mL) and stirred for 15 min. at 20-22° C. then 1 h. at 0° C. The solid was collected by vacuum filtration, washed with water (2×75 mL) and dried to give 74.1 g (73.6% yield) of (E)-N-(2-chloro-6-methylphenyl)-3-ethoxyacrylamide). 1H NMR (400 Hz, DMSO-d6) δ 1.26 (t, 3H, J=7 Hz), 2.15 (s, 3H), 3.94 (q, 2H, J=7 Hz), 5.58 (d, 1H, J=12.4 Hz), 7.10-7.27 (m, 2H, J=7.5 Hz), 7.27-7.37 (d, 1H, J=7.5 Hz), 7.45 (d, 1H, J=12.4 Hz), 9.28 (s, 1H); 13C NMR (100 MHz, CDCl3) δ: 14.57, 18.96, 67.17, 97.99, 126.80, 127.44, 129.07, 131.32, 132.89, 138.25, 161.09, 165.36.