Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:36][O:37][CH3:38])[C:4]([CH3:35])=[C:5]([C:26]([O:28][CH2:29][O:30][C:31](=[O:34])[CH2:32][CH3:33])=[O:27])[CH:6]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:7]=1[C:8]([O:10]COC(=O)CC)=[O:9]>C(OC(C)C)(C)C.O>[CH3:1][C:2]1[N:3]([CH2:36][O:37][CH3:38])[C:4]([CH3:35])=[C:5]([C:26]([O:28][CH2:29][O:30][C:31](=[O:34])[CH2:32][CH3:33])=[O:27])[C@@H:6]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: CCC(=O)OCOC(=O)C1=C(C)N(COC)C(C)=C(C(=O)OCOC(=O)CC)C1c1cccc([N+](=O)[O-])c1
Solvent: CC(C)OC(C)C
Solvent: O
Product: CCC(=O)OCOC(=O)C1=C(C)N(COC)C(C)=C(C(=O)O)[C@@H]1c1cccc([N+](=O)[O-])c1
Reaction time: 8 h
Yield: 69.2 %

Procedure:
In 20 ml of isopropyl ether saturated with water was dissolved 267 mg of bis(propionyloxymethyl) 1,4-dihydro -2,6-dimethyl-1-methoxymethyl-4-(3-nitrophenyl) -3,5-pyridinedicarboxylate obtained in Example 12, and 50 mg of Lipase B was added thereto, followed by stirring at 0° to 5° C. for 8 hours. Any insoluble matter was removed by filtration and washed with dichloromethane. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate/hexane=1/2) to obtain 155 mg (yield: 71%) of (S)-1,4-dihydro-2,6-dimethyl-1-methoxymethyl-4-(3-nitrophenyl)-5-propionyloxymethoxycarbonyl -3-pyridinecarboxylic acid as a pale yellow crystal.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]([C@@H:18]1[CH2:20][O:19]1)[CH2:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[F:17])([CH3:4])([CH3:3])[CH3:2].[CH2:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][NH:23]1>>[C:1]([O:5][C:6](=[O:21])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[F:17])[C@@H:18]([OH:19])[CH2:20][N:23]1[CH2:24][CH2:25][C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:22]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cc(F)ccc1F)[C@@H]1CO1
Reactant: c1ccc2c(c1)CCNC2
Product: CC(C)(C)OC(=O)N[C@H](Cc1cc(F)ccc1F)[C@@H](O)CN1CCc2ccccc2C1

Procedure:
Using general procedure 1 and purification method D with [(1R)-1-{(2R)-oxiran-2-yl}-2-(2,5-difluoro-phenyl)-ethyl]carbamic acid tert-butylester (0.385 g, 1.3 mmol) and 1,2,3,4,-tetrahydro-isoquinoline (0.200 mL, 1.50 mmol) gives the title compound.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1([CH:13]2[CH2:18][CH2:17][C:16]([NH:19][CH:20]=O)=[CH:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.P(Cl)(Cl)(Cl)=O>C(O)(C)(C)C>[N+:19]([C:16]1[CH2:17][CH2:18][CH:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:14][CH:15]=1)#[C-:20]
Reactant: O=CNC1=CCC(c2ccccc2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O=P(Cl)(Cl)Cl
Product: [C-]#[N+]C1=CCC(c2ccccc2)CC1
Reaction time: 2 h

Procedure:
Potassium tert-butoxide (34.3 g, 306 mmol) was added portionwise to a solution of 4-phenyl-1-formamidocyclohexene (13.6 g, 68 mmol) (Biiorg. Med. Chem; 8; 6; 2000; 1343) in tert-butanol (150 ml), and the mixture stirred for 2 hours, with sufficient heating to ensure solution. Phosphorous oxychloride (7.82 g, 51 mmol) was added dropwise, with cooling of the reaction vessel, and once additon was complete, the reaction was stirred at room temperature for 24 hours. TLC analysis showed starting material remaining, so additional potassium tert-butoxide (3.8 g, 34 mmol) and phosphorous oxychloride (1.57 ml, 17 mmol) were added, and the reaction stirred for a further 45 minutes. The mixture was concentrated under reduced pressure, the residue poured into brine (500 ml) and extracted with dichloromethane (100 ml, 3×50 ml). The combined organic solutions were washed with water (100 ml), brine (200 ml), dried (Na2SO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using hexane:ethyl acetate (90:10) as eluant to afford the title compound, 5.8 g.
Reaction SMILES: [F:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([C@@H:9]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C@H:10]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH3:19])[CH2:14][CH2:13]2)[CH3:11])=[O:8])[CH2:3]1.[C:28](O)(=[O:30])[CH3:29].C(N(CC)C(C)C)(C)C.C1C=NC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[C:23]([O:22][C:21](=[O:27])[NH:20][C@H:9]([C:7]([N:4]1[CH2:5][CH2:6][C@H:2]([F:1])[CH2:3]1)=[O:8])[C@H:10]([CH:12]1[CH2:17][CH2:16][CH:15]([N:18]([C:28](=[O:30])[CH3:29])[CH3:19])[CH2:14][CH2:13]1)[CH3:11])([CH3:26])([CH3:25])[CH3:24]
Reactant: CNC1CCC([C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N2CC[C@H](F)C2)CC1
Reactant: CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(C)C1CCC([C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N2CC[C@H](F)C2)CC1

Procedure:
To a solution of the material prepared in Step C (0.020 g, 0.052 mmol) in DMF (1 mL) was added acetic acid (0.003 mL, 0.06 mmol), N,N-diisopropylethylamine (0.045 mL, 0.26 mmol), HOAT (0.095 mL of a 0.6 M DMF solution, 0.095 mmol), and HATU (0.022 g, 0.095 mmol). After 3 h at ambient temperature the reaction was diluted with 100 mL of ethyl acetate and washed with 0.5 M aqueous sodium bicarbonate. The organic layer was washed with brine, dried (magnesium sulfate), and concentrated in vacuo. Purification by reverse phase liquid chromatography (20%-60% acetonitrile in water gradient) afforded the title compound as a white solid. LC/MS 450.3 (M+Na).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23](Br)[CH:22]=3)[C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)[CH:22]=3)[C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2cccc(Br)c2)[C@H](c2ccccc2)C1
Reactant: C1CCNC1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2cccc(N3CCCC3)c2)[C@H](c2ccccc2)C1

Procedure:
The title compound, MS: m/e=547.2 (M+), was prepared in accordance with the general method of example 10 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[4-(3-bromo-phenyl)-3-phenyl-piperidin-1-yl]-methanone and pyrrolidine.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][N:8]=1.[BH4-].[Na+]>C(O)C>[C:1]1([CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:8]=[CH:9][C:10]([CH2:11][OH:12])=[CH:13][CH:14]=1
Reactant: Cc1ccccc1-c1ccc(C=O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccccc1-c1ccc(CO)cn1
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 1.070 g (5.43 mmol) of 6-o-tolylnicotinaldehyde in 19 mL of ethanol at 0-5° C., was added 287 mg (7.5 mmol, 1.4 eq.) of sodium borohydride. After 2 h, the reaction mixture was quenched with saturated sodium bicarbonate solution and, after 30 min, partitioned between dichloromethane and brine. The organic extract was dried over magnesium sulfate and concentrated to give the indicated product as a colorless oil, 1.08 g, 100% yield.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[F:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>>[F:20][C:21]1[CH:26]=[C:25]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[CH:18][NH:17][N:16]=3)[N:3]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Reactant: OB(O)c1cccc(F)c1
Product: COc1ccc2c(-c3cccc(F)c3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3-fluoro-phenylboronic acid to give [1-(3-fluoro-phenyl)-6-methoxy-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 335(MH+).
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([C:21](OC2C=CC([N+]([O-])=O)=CC=2)=[O:22])[C:6](=[O:33])[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[C:4]=1[CH3:44])#[N:2].[NH2:45][CH2:46][CH2:47][OH:48]>C(#N)C>[C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([C:21]([NH:45][CH2:46][CH2:47][OH:48])=[O:22])[C:6](=[O:33])[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:42])([F:43])[F:41])[CH:35]=2)[C:4]=1[CH3:44])#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: NCCO
Solvent: CC#N
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)NCCO)C(=O)N1c1cccc(C(F)(F)F)c1

Procedure:
According to the General Procedure 1, 4-nitrophenyl (6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate (80.0 mg, 0.128 mmol; Example 6A) was reacted with 2-aminoethanol (23.4 mg, 0.384 mmol) in acetonitrile (1 ml) to give the target compound (27 mg, 39% of theory).
Reaction SMILES: [C:1]([O:5][C:6](=[O:54])[NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[NH:16][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][C:29]([C:32]5[NH:33][C:34]([CH:37]6[CH2:41][CH2:40][CH2:39][N:38]6[C:42](=[O:52])[CH:43]([NH:47][C:48]([O:50][CH3:51])=[O:49])[CH:44]([CH3:46])[CH3:45])=[N:35][CH:36]=5)=[CH:28][CH:27]=4)=[CH:22][CH:21]=3)=[CH:18][N:19]=2)[C:9]1=[O:53])(C)(C)C.COC(=O)N[CH:59](C(N1CCCC1C1NC(C2C=CC(C3C=CC(C4NC(CN5CCCC(N)C5=O)=NC=4)=CC=3)=CC=2)=CN=1)=O)[CH:60](C)C>>[CH3:1][O:5][C:6](=[O:54])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]2[N:10]([CH:14]([C:15]3[NH:16][C:17]([C:20]4[CH:21]=[CH:22][C:23]([C:26]5[CH:31]=[CH:30][C:29]([C:32]6[NH:33][C:34]([CH:37]7[CH2:41][CH2:40][CH2:39][N:38]7[C:42](=[O:52])[CH:43]([NH:47][C:48]([O:50][CH3:51])=[O:49])[CH:44]([CH3:45])[CH3:46])=[N:35][CH:36]=6)=[CH:28][CH:27]=5)=[CH:24][CH:25]=4)=[CH:18][N:19]=3)[CH2:59][CH2:60]2)[C:9]1=[O:53]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(CN5CCCC(N)C5=O)[nH]4)cc3)cc2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(CN5CCCC(NC(=O)OC(C)(C)C)C5=O)[nH]4)cc3)cc2)[nH]1)C(C)C
Product: COC(=O)NC1CCC2CCC(c3ncc(-c4ccc(-c5ccc(-c6cnc(C7CCCN7C(=O)C(NC(=O)OC)C(C)C)[nH]6)cc5)cc4)[nH]3)N2C1=O

Procedure:
{3-[5-(4′-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-5-oxo-octahydro-indolizin-6-yl}-carbamic acid methyl ester was prepared following method 804 followed by method 805, substituting {3-[5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-5-oxo-octahydro-indolizin-6-yl}-carbamic acid tert-butyl ester for {1-[5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-ylmethyl]-2-oxo-piperidin-3-yl}-carbamic acid tert-butyl ester in method 804, and substituting {1-[2-(5-{4′-[2-(6-Amino-5-oxo-octahydro-indolizin-3-yl)-3H-imidazol-4-yl]-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester for {1-[2-(5-{4′-[2-(3-amino-2-oxo-piperidin-1-ylmethyl)-3H-imidazol-4-yl]-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester in method 805. C39H46N8O6 calculated 722.4 observed [M+1]+ 723.4; rt=1.62 min. 1H (DMSO-d6): δ=8.10 (m, 1H), 7.90 (m, 8H), 7.31 (m, 2H), 5.12 (m, 2H), 4.11 (m, 2H), 3.84 (m 2H), 3.74 (m, 1H), 3.53 (s, 6H), 2.38 (m, 2H), 2.14 (m, 3H), 2.05 (m, 5H), 1.82 (m 3H), 0.81 (dd, J=8.8 Hz, J=17.6 Hz, 6H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[O:14]1[CH2:19]C[O:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.ClCCl.O>[C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:7][C:2]([CH2:19][O:14][CH2:15][CH2:16][OH:17])=[CH:3][CH:4]=1
Reactant: C1COCCO1
Reactant: Clc1ccc(-c2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: ClCCl
Product: OCCOCc1ccc(-c2ccccc2)cc1
Temperature: 100 °C
Reaction time: 13 h
Yield: 38 %

Procedure:
To a mixture of 4-chlorobiphenyl (15 mg, 79.5 μmol) and 1,4-dioxane (1.5 ml) were added water (0.15 ml), cesium carbonate (117 mg, 358 μmol), sodium (2-hydroxyethoxy)methyl trifluoroborate (19.7 mg, 119 mol), palladium (II) acetate (5.37 mg, 23.9 μmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (19.6 mg, 47.7 μmol). Then, the reaction mixture was stirred at 100° C. (external temperature) for 13 hours. After the reaction mixture was cooled at room temperature, water and dichloromethane were added to the mixture, followed by filtration using Celite. The separated organic layer was washed with an aqueous saturated sodium chloride solution. The organic layer was separated, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=1:1 NH silica gel) to obtain the title compound (6.8 mg, 30 μmol, 38%).
Reaction SMILES: C(OC(=O)[C@@H:5]([CH2:25][S:26][CH3:27])[NH:6][C:7](=[O:24])[C@@H:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH:9][C:10](OC(C)(C)C)=[O:11])C.Cl>C(OCC)(=O)C>[CH2:17]([C@H:8]1[NH:9][C:10](=[O:11])[C@@H:5]([CH2:25][S:26][CH3:27])[NH:6][C:7]1=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)[C@@H](CSC)NC(=O)[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CSC[C@H]1NC(=O)[C@@H](Cc2ccccc2)NC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 30.3 %

Procedure:
A mixture of N-tert-butoxycarbonyl-D-phenylalanyl-S-methyl-D-cysteine ethyl ester (0.41 g), ethyl acetate (10 ml), and saturated solution of hydrogen chloride in ethyl acetate (10 ml) was stirred for 4 hours at room temperature. After removal of the solvent, the residue was dissolved in ethanol (10 ml) and saturated ammonia in ethanol (10 ml) was added to the solution. The resulting mixture was stirred for 17 hours at room temperature and the solvent was evaporated off. Recrystallization from acetic acid gave (3R,6S)-3-benzyl-6-methylthiomethylpiperazine-2,5-dione (0.08 g).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH2:6]([O:13][C:14]1[CH:15]=C(C=[CH:20][CH:21]=1)C=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH:3]([C:2]1[CH:1]=[CH:20][CH:21]=[C:14]([O:13][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:15]=1)=[CH2:4]
Reactant: [Li]CCCC
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1cccc(OCc2ccccc2)c1
Reaction time: 0.17 h

Procedure:
To a solution of methyltriphenylphosphonium bromide (51 g, 143 mmol) in tetrahydrofuran (500 mL) under argon at -20° C. was added butyllithium (56 mL, 140 mmol) over 20 minutes. The reaction was stirred for 10 minutes, then 3-benzyloxybenzaldehyde (29 g, 137 mmol) in tetrahydrofuran (60 mL) was added over 15 minutes. The reaction was stirred for 6.5 hours and left to stand overnight. The solvent was decanted off and the residue dissolved in dichloromethane (100 mL) and extracted with a heptane/diethyl ether mixture (9:1) until all the product was removed. The combined organics were filtered through silica and the solvent removed in vacuo to give the product as a clear oil, 122 mmol, 89%.
Reaction SMILES: C([O:4][CH2:5][CH:6]1[O:11][C:10](=[O:12])[CH:9]([C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[N+:21]([O-:23])=[O:22])[C:8](=[O:25])[CH2:7]1)(=O)C.[OH-].[Na+].Cl>C(O)C>[OH:4][CH2:5][CH:6]1[O:11][C:10](=[O:12])[CH:9]([C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[N+:21]([O-:23])=[O:22])[C:8](=[O:25])[CH2:7]1
Reactant: CC(=O)OCC1CC(=O)C(C(=O)c2ccc(Cl)cc2[N+](=O)[O-])C(=O)O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1CC(CO)OC(=O)C1C(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 67 %

Procedure:
To 10 ml of ethanol was dissolved 1.50 g (4.1 mmole) of 6-acetoxymethyl-3-(4-chloro-2-nitrobenzoyl)-tetrahydropyran-2,4-dione, then 8.0 ml of 1N aqueous solution of sodium hydroxide was added thereto to react for 1 hour at room temperature. The solution for the reaction was poured into ice water, acidified with diluted hydrochloric acid, then extracted with chloroform. The organic solvent layer extracted was washed with water and saturated brine in turn, dried with magnesium sulfate, and the solvent therein was distilled. The resulting crystals were washed with methanol, then 0.90 g of the objective product was obtained in whitish crystals. The melting point thereof was from 135° to 137° C.
Reaction SMILES: [C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].CCC([O-])(C)C.[Na+].[F:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[C:22](F)[C:21]=1[F:30].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+].[Cl-].[Na+]>C1(C)C=CC=CC=1.O>[F:30][C:21]1[C:20]([F:19])=[CH:25][CH:24]=[C:23]([N+:26]([O-:28])=[O:27])[C:22]=1[CH:2]([C:3](=[O:4])[CH3:5])[C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Agent: CCC(C)(C)[O-]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)C(C(=O)OC(C)(C)C)c1c([N+](=O)[O-])ccc(F)c1F
Temperature: 70 °C

Procedure:
tert-Butyl acetoacetate (3.852 g) was added to a stirred mixture of sodium tert-pentoxide (2.804 g) in toluene (26 ml) at 40° C. The mixture was heated to 70° C. and 1,2,3-trifluoro-4-nitrobenzene (2.00 g) added. The mixture was maintained at 70° C. for 3 hours. The mixture was cooled to 25° C. and 20% w/w sulphuric acid added to adjust the mixture to pH 1. Sodium bicarbonate was added to bring the mixture to pH 5. Water (5 ml) and saturated sodium chloride (5 ml) was added. The lower aqueous layer was discarded and the organic layer is washed successively with water (7 ml), water (7 ml), 2.3% w/w aqueous sodium bicarbonate solution (2.75 ml) and then water (6 ml). The organic layer was distilled under reduced pressure (50 mbar), to leave a solution of tert-butyl 2-(2,3-difluoro-6-nitrophenyl)-3-oxobutanoate in toluene.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][CH:12]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:19]1[O:28][C:27]2[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][C:21]=2[O:20]1>C(O)CCC>[O:28]1[C:27]2[CH:26]=[CH:25][C:23]([NH:24][C:2]3[C:3]4[CH:10]=[C:9]([C:11]5[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][CH:12]=5)[NH:8][C:4]=4[N:5]=[CH:6][N:7]=3)=[CH:22][C:21]=2[O:20][CH2:19]1
Reactant: OCc1ccc(-c2cc3c(Cl)ncnc3[nH]2)cc1
Reactant: Nc1ccc2c(c1)OCO2
Solvent: CCCCO
Product: OCc1ccc(-c2cc3c(Nc4ccc5c(c4)OCO5)ncnc3[nH]2)cc1
Temperature: 115 °C
Reaction time: 16 h

Procedure:
A mixture of 1.5 g (5.8 mmol) of [4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-phenyl]-methanol and 1.58 g (11.5 mmol) 3,4-methylendioxy-aniline in 30 ml n-butanol is stirred for 16 h at 115° C. under N2-atmosphere. After cooling to ambient temperature, the title compound can be filtered off and washed with n-butanol; MS-ES+: (M+H)+=361; HPLC (conditions see Examples 67-78) tR=8.7 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]2[C:16]3[CH2:17][C:18]([CH3:27])([CH3:26])[O:19][C:20]=3[C:21]([C:23](O)=[O:24])=[CH:22][C:12]=2[N:11]=1.S(Cl)(Cl)=O.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][N+:34]=1[O-:43].CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]2[C:16]3[CH2:17][C:18]([CH3:27])([CH3:26])[O:19][C:20]=3[C:21]([C:23]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([C:39]([F:40])([F:42])[F:41])=[CH:35][N+:34]=3[O-:43])=[O:24])=[CH:22][C:12]=2[N:11]=1
Reactant: Nc1ccc(C(F)(F)F)c[n+]1[O-]
Reactant: Cn1c(Nc2c(F)cccc2Cl)nc2cc(C(=O)O)c3c(c21)CC(C)(C)O3
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: Cn1c(Nc2c(F)cccc2Cl)nc2cc(C(=O)Nc3ccc(C(F)(F)F)c[n+]3[O-])c3c(c21)CC(C)(C)O3
Yield: 10.6 %

Procedure:
The title compound was prepared following the procedure described for Example-108 using 2-((2-chloro-6-fluorophenyl)amino)-1,7,7-trimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylic acid (Intermediate-49, 0.100 g, 0.2564 mmol), thionyl chloride (2.0 mL), 2-amino-5-(trifluoromethyl)pyridine 1-oxide (Intermediate-41, 0.0835 g, 0.5128 mmol), THF (5.0 mL) and DIPEA (2 mL). The obtained crude product was purified by column chromatography on basic alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.015 g of the desired product. 1HNMR (DMSO-d6): δ 1.60 (s, 6H), 3.49 (s, 2H), 3.53 (s, 3H), 7.02 (m, 1H), 7.18-7.36 (m, 3H), 7.80 (d, J=9.9 Hz, 1H), 8.64 (d, J=8.7 Hz, 1H), 8.95 (s, 1H), 10.56 (s, 1H), 12.21 (s, 1H); MS [M+H]+: 550.08.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN([C:43](N(C)C)=[N+:44]1[C:52]2[C:47](=[N:48][CH:49]=[CH:50]C=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.CN1CCNCC1>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([N:48]5[CH2:47][CH2:52][N:44]([CH3:43])[CH2:50][CH2:49]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: CN1CCNCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.08 h
Yield: 81.2 %

Procedure:
A mixture of 0.045 g (0.1 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (I-22), 0.042 g (0.110 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.052 ml (0.300 mmole) of ethyldiisopropyl amine and 1.0 mL of dimethylformamide was stirred for 5 minutes and then 0.015 g (0.15 mmole) 1-methyl-piperazine was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluting with water-acetonitrile (gradient, 0:100-80:20) to give 0.043 g of 9-cyclopentyl-7,7-difluoro-2-[2-methoxy-4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (I-128) as a white solid.