Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[O:13][C:12](=O)[NH:11][C:10](=[O:15])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:16][NH2:17].C>CO>[CH3:16][N:17]1[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[CH:9][C:10](=[O:15])[NH:11][C:12]1=[O:13]
Reactant: CN
Reactant: O=c1cc(-c2cccc(F)c2)oc(=O)[nH]1
Agent: C
Solvent: CO
Product: Cn1c(-c2cccc(F)c2)cc(=O)[nH]c1=O
Yield: 54 %

Procedure:
To 490 mg (2.36 mM) of 6-m-fluorophenyl-1,3-oxazine-2,4-dione of Preparation IIa(1) is added 30.0 ml of a 40 percent aq. CH3NH2 solution. The reaction solution is heated at reflux for 18 hours. The solution is cooled and evaporated to dryness, under vacuum, to yield an amber solid. The solid is dissolved in CH3OH (hot), treated with darco, filtered and the CH3OH filtrate is evaporated to a white solid. The solid is recrystallized from H2O to yield 280 mg (54 percent) (m.p.: 192-194) of 1-N-methyl-6-m-fluorophenyl-2,4-pyrimidine-dione.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=2)=[N:6][CH:7]=1.[CH3:25][C:26]1([NH2:30])[CH2:29][O:28][CH2:27]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:30][C:26]3([CH3:25])[CH2:29][O:28][CH2:27]3)=[O:22])=[CH:18][N:17]=2)=[N:6][CH:7]=1
Reactant: CC1(N)COC1
Reactant: Cn1nnc(-c2ccc(F)cn2)c1COc1ccc(C(=O)O)cn1
Product: Cn1nnc(-c2ccc(F)cn2)c1COc1ccc(C(=O)NC2(C)COC2)cn1
Yield: 91 %

Procedure:
As described for example 35b, 6-[5-(5-fluoro-pyridin-2-yl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-nicotinic acid (80 mg, 0.24 mmol) was converted, using 3-methyl-3-oxetanamine instead of 4-aminotetrahydropyran, to the title compound (88 mg, 91%) which was obtained as a white solid. MS: m/e=399.2 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:6]2.Cl.N1C=CC=CC=1>>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([S:12](=[O:14])(=[O:15])[NH2:13])=[CH:6]2
Reactant: COc1ccc2[nH]c(S(N)(=O)=O)cc2c1
Agent: Cl
Solvent: c1ccncc1
Product: NS(=O)(=O)c1cc2cc(O)ccc2[nH]1
Temperature: 190 °C
Yield: 102.8 %

Procedure:
5-Methoxy-2-sulfamoyl-1H-indole (2.5 gm, 11 mmol) was mixed with pyridine hydrochloride (7.5 gm) and heated neat at 190° C. for 30 minutes. The reaction was cooled to 140° C. and poured onto ice water (25 gm). The mixture was extracted with ethyl acetate (3×100 ml), washed with water (2×50 ml), brine (2×25 ml) and dried (MgSO4). The ethyl acetate was removed under vacuum to yield a brown solid 2.4 gm. The solid was flash chromatographed using silica gel with 95/5 (V/V) chloroform-methanol. The isolated compound was crystallized using chloroform-methanol 95/5 (V/V) to yield a white solid; 628 mg., m.p. 220°-221° C. (dec).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:13][CH2:14][C:15](Cl)=[O:16].Cl>ClCCCl>[Cl:13][CH2:14][C:15]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[F:8])=[O:16]
Reactant: O=C(Cl)CCl
Reactant: Fc1cccc(F)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(CCl)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
Into the solution of 1,3-difluorobenzene in 1,2-dicholoroethane (DCE) was added anhydrous aluminium chloride (1.2 molar equivalent of 1,3-difluorobenzene) at 25-30° C. and stirred for 30 minutes. The reaction mixture was then cooled to 0° C. and chloroacetyl chloride (1.1 molar equivalent of 1,3-difluorobenzene), in DCE, was then added into it over a period of 30-60 min keeping the reaction temperature below 20° C. After the addition was over, the reaction mixture was stirred at 25-30° C. for 5-7 hours. The reaction mixture was then diluted with DCE and poured into dil. hydrochloric acid (5%) at 0-5° C. The mixture was then extracted with DCE. The combined organic layer was washed successively with 5% aq. sodium bicarbonate solution and water. Evaporating DCE from the organic layer under reduced pressure gave an oil which on triturating with n-Hexane gave the title compound as white crystalline material (Yield 75% of theory).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[N:6]([CH3:31])[C:7]3[C:12]([N:13]=2)=[C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:10]=[C:9]([N:20]2[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[N:22]=[C:21]2[CH2:29][CH3:30])[N:8]=3)[CH2:2]1.[O:32]1[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:29]([C:21]1[N:20]([C:9]2[N:8]=[C:7]3[C:12]([N:13]=[C:5]([CH:3]4[CH2:2][N:1]([CH:35]5[CH2:36][CH2:37][O:32][CH2:33][CH2:34]5)[CH2:4]4)[N:6]3[CH3:31])=[C:11]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:10]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=1)[CH3:30]
Reactant: O=C1CCOCC1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3CNC3)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3CN(C4CCOCC4)C3)n(C)c2n1
Reaction time: 16 h

Procedure:
A mixture of 4-(8-(azetidin-3-yl)-2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-9H-purin-6-yl)morpholine 680 (100 mg, 0.24 mmol), tetrahydropyran-4-one (34 mg, 0.33 mmol) and 4 Å powdered molecular sieves (130 mg) in DCE (3 mL) was stirred for 5.5 h before the addition of sodium triacetoxyborohydride (101 mg, 0.48 mmol). The resulting mixture was allowed to stir for 16 h at r.t, then filtered through Celite®, washing with DCM. The filtrate was washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-30%) followed by Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH. The resulting solid was triturated with EtOAc affording 747 as a white powder (37 mg, 31%). LCMS (method I): RT 2.46 min, [M+H]+ 503.1. 1H NMR (CDCl3, 400 MHz): δ 8.01-7.97 (1 H, m), 7.75-7.74 (1 H, m), 7.26 (2 H, s), 4.37 (4 H, s), 4.02-3.80 (9 H, m), 3.70 (3 H, s), 3.51-3.37 (4 H, m), 3.34 (2 H, q, J=7.48 Hz), 2.41-2.33 (1 H, m), 1.77-1.66 (3 H, m), 1.43 (4 H, t, J=7.47 Hz)
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:20][C:21]1[C:26]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)=[CH:25][CH:24]=[CH:23][N:22]=1.[F:34][C:35]1[CH:36]=[C:37]([CH2:41]O)[CH:38]=[CH:39][CH:40]=1>C1COCC1>[F:34][C:35]1[CH:36]=[C:37]([CH:38]=[CH:39][CH:40]=1)[CH2:41][O:33][C:30]1[CH:31]=[CH:32][C:27]([C:26]2[C:21]([NH2:20])=[N:22][CH:23]=[CH:24][CH:25]=2)=[CH:28][CH:29]=1
Reactant: Nc1ncccc1-c1ccc(O)cc1
Reactant: OCc1cccc(F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1ncccc1-c1ccc(OCc2cccc(F)c2)cc1
Reaction time: 8 h

Procedure:
Diisopropylazadicarboxylate (1.19 mL) was added dropwise to a solution of triphenylphosphine (1585 mg), 4-(2-aminopyridin-3-yl)phenol (750 mg) and (3-fluorophenyl)methanol (0.434 mL) in THF (dry) (15 mL) at room temperature and the mixture was stirred overnight and concentrated in vacuo. The residue was purified by column chromatography (1st; NH-silica gel, eluted with EtOAc in hexane, 2nd; silica gel, eluted with EtOAc in hexane) to give the title compound (210 mg) as a white powder.
Reaction SMILES: [CH2:1]([S:8][CH:9]([S:39]CC1C=CC=CC=1)[C@H:10]([C@@H:19]([C@@H:28]([CH2:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)O)[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[O:11]CC1C=CC=CC=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.II.N1C=CN=C1.[C:73]1([CH3:79])[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1.C(#N)C>>[CH2:79]([O:11][C@H:10]1[C@H:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:28]([CH2:30][O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[S:39][CH:9]1[S:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1
Reactant: O[C@H](COCc1ccccc1)[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)C(SCc1ccccc1)SCc1ccccc1
Reactant: Cc1ccccc1
Agent: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: c1ccc(COC[C@@H]2SC(SCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
To a solution of 4 (13.0 g, 20 mmol) in dry 2:1 toluene/acetonitrile (200 mL) were added triphenylphosphine (15.7 g, 60 mmol), iodine (12.7 g, 50 mmol) and imidazole (5.44 g, 80 mmol). The reaction mixture was stirred at 90° C. for 24 hours after which time the solution was evaporated to dryness. The crude product was purified by silica gel chromatography (cyclohexane/EtOAc, 4:1) to afford benzyl 2,3,5-tri-O-benzyl-1,4-dithio-L-Xylofuranoside as a syrup (5, 9.0 g, 72%). MS 543 (M+H)+.
Reaction SMILES: C(N(C(C)C)C(C)C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[F:28][C:29]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=1[C:37]1[CH:41]=[C:40]([CH2:42][CH2:43][C@@:44]([CH3:52])([S:48]([CH3:51])(=[O:50])=[O:49])[C:45](O)=[O:46])[O:39][N:38]=1.[O:53]1[CH2:58][CH2:57][CH2:56][CH2:55][CH:54]1[O:59][NH2:60]>CN(C1C=CN=CC=1)C.C(OCC)(=O)C.O>[F:28][C:29]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=1[C:37]1[CH:41]=[C:40]([CH2:42][CH2:43][C@@:44]([CH3:52])([S:48]([CH3:51])(=[O:49])=[O:50])[C:45]([NH:60][O:59][CH:54]2[CH2:55][CH2:56][CH2:57][CH2:58][O:53]2)=[O:46])[O:39][N:38]=1
Reactant: COc1cccc(-c2cc(CC[C@](C)(C(=O)O)S(C)(=O)=O)on2)c1F
Reactant: NOC1CCCCO1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(-c2cc(CC[C@](C)(C(=O)NOC3CCCCO3)S(C)(=O)=O)on2)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.4 %

Procedure:
N,N-Dimethy-4-aminopyridine (0.04 g, 0.3 mmol, 0.3 equiv), N-ethyl-N-isopropylpropan-2-amine (0.89 mL, 5.2 mmol, 4.5 equiv), T3P® (50% w/w solution in ethyl acetate, 2.7 mL, 4.5 mmol, 4.0 equiv), and (2R)-4-[3-(2-fluoro-3-methoxyphenyl)isoxazol-5-yl]-2-methyl-2-(methylsulfonyl)butanoic acid (0.42 g, 1.1 mmol, 1.0 equiv) were allowed to stir at room temperature for 30 min. A solution of O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.15 g, 1.2 mmol, 1.2 equiv) in ethyl acetate (12 mL) was added, and the reaction was allowed to stir overnight (18 h) at room temperature. Water (40 mL) was added, and the mixture was extracted with ethyl acetate (2×50 mL). The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (25 g silica gel column, 0-100% gradient ethyl acetate in hexanes) to provide (2R)-4-[3-(2-fluoro-3-methoxyphenyl)isoxazol-5-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide as a tan solid (0.23 g, 42%). MS (LCMS) m/z 469.1 (M−1).
Reaction SMILES: [CH3:1][C:2]1([CH2:6][OH:7])[CH2:5][O:4][CH2:3]1.[H-].[Na+].[N+](C1C=CC([O:19][C:20]([N:22]2[CH2:26][C@@H:25]([N:27]([CH2:40][C:41]3[CH:46]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:44]=[C:43]([C:51]([F:54])([F:53])[F:52])[CH:42]=3)[C:28]3[N:33]=[CH:32][C:31]([C:34]4[CH:35]=[N:36][N:37]([CH3:39])[CH:38]=4)=[CH:30][N:29]=3)[CH2:24][C@H:23]2[CH2:55][CH3:56])=O)=CC=1)([O-])=O>C1COCC1>[CH3:1][C:2]1([CH2:6][O:7][C:20]([N:22]2[CH2:26][C@@H:25]([N:27]([CH2:40][C:41]3[CH:42]=[C:43]([C:51]([F:52])([F:53])[F:54])[CH:44]=[C:45]([C:47]([F:48])([F:49])[F:50])[CH:46]=3)[C:28]3[N:29]=[CH:30][C:31]([C:34]4[CH:35]=[N:36][N:37]([CH3:39])[CH:38]=4)=[CH:32][N:33]=3)[CH2:24][C@H:23]2[CH2:55][CH3:56])=[O:19])[CH2:5][O:4][CH2:3]1
Reactant: CC1(CO)COC1
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1C(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1C(=O)OCC1(C)COC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
To a mixture of 3-methyl-3-oxetanemethanol (0.202 mmol; 20.6 mg) and sodium hydride (60% oil dispersion in mineral oil, 0.202 mmol; 8.1 mg) in THF (0.5 mL) is added a solution of (2R,4S)-4-{(3,5-bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidine-1-carboxylic acid 4-nitro-phenyl ester (0.101 mmol; 67 mg) in THF (0.5 mL). The reaction mixture is stirred for 1 hour at room temperature, then quenched with saturated aqueous ammonium chloride. The product is extracted three times with EtOAc. The combined organic layer is washed with brine, dried over Na2SO4, filtered, concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: n-hexane/EtOAc), followed by another silica gel column chromatography (eluent: dichloromethane/methanol) to give (2R,4S)-4-{(3,5-Bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidine-1-carboxylic acid 3-methyl-oxetan-3-ylmethyl ester (40.7 mg, 64%); ESI-MS m/z: 626 [M+1]+, Retention time 2.19 min (condition A).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[N:3]=1.[O:21]=[C:22]1[NH:26][C:25]2[CH:27]=[CH:28][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:30][C:24]=2[NH:23]1>>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([C:28]3[CH:29]=[CH:30][C:24]4[NH:23][C:22](=[O:21])[NH:26][C:25]=4[CH:27]=3)[N:7]=[C:6]3[N:8]([CH3:11])[N:9]=[CH:10][C:5]=23)[CH:18]=[CH:17][CH:16]=1
Reactant: CC1(C)OB(c2ccc3[nH]c(=O)[nH]c3c2)OC1(C)C
Reactant: COc1cccc(Nc2nc(Cl)nc3c2cnn3C)c1
Product: COc1cccc(Nc2nc(-c3ccc4[nH]c(=O)[nH]c4c3)nc3c2cnn3C)c1

Procedure:
6-Chloro-N-(3-methoxyphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine 6 was reacted with 2-oxo-2,3-dihydro-1H-benzoimidazole-5-boronic acid pinacol ester using General Procedure A. Purification on silica yielded 115. NMR: (CDCl3): 3.84 (s, CH3), 4.01 (s, CH3), 6.72 (dd, H, ArH, J=2.1, 8.28), 7.04 (d, H, ArH, J=8.2), 7.35 (t, H, ArH, J=8), 7.47 (d, H, ArH, J=8), 7.72 (s, H, NH), 8.06 (s, H, NH), 8.18 (dd, H, ArH, J=1.4, 8.3), 8.25 (s, H, NH), 10.03 (s, H, ArH), 10.81 (s, H, ArH), 10.86 (s, H, ArH). MS: (ESI+) MH+=388.21
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[CH2:10](Cl)[CH:11]=[CH2:12].[OH-].[Na+]>>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][CH2:12][CH:11]=[CH2:10]
Reactant: C=CCCl
Reactant: Cc1cccc(C)c1N
Agent: [Na+]
Agent: [OH-]
Product: C=CCNc1c(C)cccc1C

Procedure:
2,6-Dimethylaniline (12.1 g, 0.1 mole) and allyl chloride (3.8 g, 0.05 mole) were mixed and heated over a steam bath using an efficient reflux condenser for 8 hours, then treated with aqueous caustic soda solution, extracted with ether, the ethereal layer worked up and the residue distilled to give 2,6-dimethylphenyl allylamine, b.p. 5355°/0.3 mm) (6.0 g, 75%).
Reaction SMILES: [OH-].[Na+].O.CO.[OH:6][CH:7]([CH2:14][C:15](=[O:40])/[CH:16]=[CH:17]/[C:18]1[C:19]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][N:21]2[C:30]=1[CH:31]([CH3:33])[CH3:32])[CH2:8][C:9]([O:11]CC)=[O:10]>C(O)(=O)C>[OH:6][CH:7]([CH2:14][C:15](=[O:40])/[CH:16]=[CH:17]/[C:18]1[C:19]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][N:21]2[C:30]=1[CH:31]([CH3:33])[CH3:32])[CH2:8][C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)CC(O)CC(=O)/C=C/c1c(-c2ccccc2)c2c3ccccc3ccn2c1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)c1c(/C=C/C(=O)CC(O)CC(=O)O)c(-c2ccccc2)c2c3ccccc3ccn12
Temperature: 25 °C
Reaction time: 5 h
Yield: 37 %

Procedure:
A mixture of sodium hydroxide (120 mg), water (2 ml), methanol (10 ml) and ethyl (E)-3-hydroxy-7-(3-isopropyl-1-phenylpyrrolo[2,1-a]isoquinolin-2-yl)-5-oxohept-6-enoate (230 mg; prepared as described in Example 4) was stirred under an argon atmosphere at the ambient temperature for 5 hours. Water (10 ml) was added and the solution was acidified to pH 5 by treatment with glacial acetic acid. The milky solution was extracted with diethyl ether (4×50 ml) and the combined extracts were dried over magnesium sulphate and evaporated, to give (E-3-hydroxy-7-(3-isopropyl-1-phenylpyrrolo[2,1-a]isoquinolin-2-yl)-5-oxohept-6-enoic acid, (80 mg) in the form of a buff foam, m.p. 95°-100° C. [Elemental analysis: C 76.7; H, 6.57; N, 3.02%; Calculated: C, 76.2; H, 6.16; N, 3.2%. N.M.R. (in CDCl3 and D2O): 1.56 (6H, d, J=7 Hz), 2.54 (2H, d, J=7 Hz), 2.55 (2H, d, J=7 Hz), 3.76 (1H, septet, J=7 Hz), 4.42 (1H, quintet, J=7 Hz), 5.68 (1H, d, J=16 Hz), 6.75 (1H, d, J=8 Hz), 7.03-7.57 (9H, m), 7.84 (1H, d, J=8 Hz), 7.86 (1H, d, J=16 Hz)].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15](/[CH:19]=[CH:20]/[C:21]2[C:29]3[C:24](=[CH:25][C:26]([CH:30]=O)=[CH:27][CH:28]=3)[NH:23][N:22]=2)[CH:14]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=[CH:30][C:26]1[CH:25]=[C:24]2[C:29]([C:21](/[CH:20]=[CH:19]/[C:15]3[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=3)=[N:22][NH:23]2)=[CH:28][CH:27]=1
Reactant: O=Cc1ccc2c(/C=C/c3cccnc3)n[nH]c2c1
Reactant: COc1ccc2c(c1)CC(=O)N2
Product: COc1ccc2c(c1)C(=Cc1ccc3c(/C=C/c4cccnc4)n[nH]c3c1)C(=O)N2
Yield: 67.2 %

Procedure:
The title compound (53 mg, 67%) was synthesized as an orange red solid according to the method described for Example A67 (oil temp 75° C., reflux 90 min) using 5-methyoxyoxindole (32.6 mg, 0.2 mmol) and (E)-3-(2-(pyridin-3-yl)vinyl)-1H-indazole-6-carbaldehyde (49.8 mg, 0.2 mmol). 1H NMR indicated 4:1 mixture of E/Z isomers. 1H NMR (400 MHz, DMSO-d6) δ 13.50 (br. s, 1H, NH), 10.44 (s, 1H, NH), 8.91 (d, 1H), 8.48 (d, J=4.8 Hz, 1H), 8.36 (d, J=8.4 Hz, 1H), 8.20 (d, J=7.6 Hz, 1H), 7.92 (s, 1H), 7.79 (s, 1H), 7.73 (d, J=16.8 Hz, 1H), 7.59 (d, J=16.4 Hz, 1H), 7.54 (d, J=8.8 Hz, 1H), 7.43 (dd, J=8.0 Hz, 5.2 Hz, 1H), 7.19 (d, 1H), 6.86 (dd, J=8.4 Hz, 2.0 Hz, 1H), 6.81 (d, J=8.4 Hz, 1H), 3.78 (s, 3H); MS ESI 395.2 [M+H]+, calcd for [C24H18N4O2+H]+ 395.1.
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[C:4]([CH2:6][C:7]([OH:9])=O)#[N:5].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:22]1([CH2:28][CH2:29][C:30]2[NH:31][C:32]3[C:38](C(O)=O)=[CH:37][CH:36]=[CH:35][C:33]=3[N:34]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl.C(=O)(O)[O-].[Na+]>O1CCCC1.C(#N)C.C(N(CC)CC)C>[C:22]1([CH2:28][CH2:29][C:30]2[NH:34][C:33]3[C:35]([C:7](=[O:9])[CH2:6][C:4]#[N:5])=[CH:36][CH:37]=[CH:38][C:32]=3[N:31]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)c1cccc2nc(CCc3ccccc3)[nH]c12
Reactant: N#CCC(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#CCC(=O)c1cccc2nc(CCc3ccccc3)[nH]c12
Temperature: 25 °C
Reaction time: 23 h
Yield: 47.4 %

Procedure:
Triethylamine (5.2 mL) and magnesium chloride (4.3 g) were added to dry acetonitrile (30 mL) solution of cyanoacetic acid (1.6 g), and the mixture was vigorously stirred at room temperature for 23 hours under an atmosphere of argon. Next, a catalytically effective amount of N,N-dimethylaminopyridine and 1,1′-carbonyldiimidazole (1.34 g) were added to anhydrous tetrahydrofuran (20 mL) suspension of 2-(2-phenylethyl)benzimidazole-4-carboxylic acid (2.0 g) obtained in Reference Example 3, and the mixture was stirred for 2.5 hours under an atmosphere of argon. The reaction solution was added to the previously prepared cyanoacetic acid suspension of magnesium salt while cooling in an ice bath, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ice water (30 mL) and, at the same temperature, adjusted to pH 1 with 4 N hydrochloric acid. At the same temperature, this was adjusted to pH 9 with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) and the desired fraction was concentrated to obtain the title compound as colorless crystal (1.03 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH:6]([CH2:8][OH:9])[CH2:5][CH2:4][O:3]1.N1C=CC=CC=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:9][CH2:8][CH:6]2[CH2:5][CH2:4][O:3][C:2]([CH3:10])([CH3:1])[CH2:7]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C)CC(CO)CCO1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CCOC(C)(C)C2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (2,2-dimethyltetrahydro-2H-pyran-4-yl)methanol (1 g, 6.93 mmol) in DCM (5 mL) and pyridine (5 mL, 61.8 mmol) was added para-toluenesulfonyl chloride (1.586 g, 8.32 mmol) and DMAP (0.042 g, 0.347 mmol). The mixture was stirred for 18 hr at ambient temperature. The reaction mixture was concentrated in vacuo and the resulting resulting residue was diluted with water and DCM. The separated organic layer was washed with 0.2N aqueous HCl (1×), 1N aqueous HCl (2×), brine, dried over sodium sulfate, filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2, 40 g, EtOAc/hexane=0/100 to 50/50; 25 min] providing (R/S)-(2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate as a colorless oil. Yield: 2.05 g. LCMS (m/z): 299.1 [M+H]+; Retention time=0.96 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:21]2[C:16](=[CH:17][C:18]([S:22]([N:25]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=3[O:40][CH3:41])[C:26]3[S:30][N:29]=[CH:28][N:27]=3)(=[O:24])=[O:23])=[CH:19][CH:20]=2)[NH:15][CH2:14][CH2:13]1.[H-].[Na+].I[CH3:45]>CN(C=O)C.O.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:5]=[CH:4][C:3]=1[N:12]1[C:21]2[C:16](=[CH:17][C:18]([S:22]([N:25]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=3[O:40][CH3:41])[C:26]3[S:30][N:29]=[CH:28][N:27]=3)(=[O:24])=[O:23])=[CH:19][CH:20]=2)[N:15]([CH3:45])[CH2:14][CH2:13]1
Reactant: CI
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(c2)NCCN3c2ccc(C(F)(F)F)cc2Cl)c(OC)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(c2)N(C)CCN3c2ccc(C(F)(F)F)cc2Cl)c(OC)c1
Temperature: 70 °C
Reaction time: 0.67 h

Procedure:
A solution of 1-(2-chloro-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)-1,2,3,4-tetrahydroquinoxaline-6-sulfonamide (INTERMEDIATE V, 0.045 g, 0.072 mmol) in DMF (0.719 mL) was treated with sodium hydride (4.31 mg, 0.108 mmol) to afford a dark brown solution. Iodomethane (6.74 μL, 0.108 mmol) was added dropwise to give a light-yellow solution. The reaction was stirred for 40 minutes. Additional iodomethane (6.74 μL, 0.108 mmol) was added and the reaction was heated to 70° C. and stirred for one hour. The mixture was diluted with water and a small amount of brine (to break up an emulsion) then extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The material was purified via silica gel chromatography (12 g column, gradient elution 0 to 50% EtOAc:Heptane) to afford 1-(2-chloro-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-4-methyl-N-(1,2,4-thiadiazol-5-yl)-1,2,3,4-tetrahydroquinoxaline-6-sulfonamide as a white solid. m/z (ESI) 639.8 (M+H)+.