Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]([N+:14]([O-])=O)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])([O-:3])=[O:2].O>CCO>[NH2:14][C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=1
Reactant: CCOC(=O)Cc1c([N+](=O)[O-])cc([N+](=O)[O-])c2ccccc12
Solvent: O
Solvent: CCO
Product: CCOC(=O)Cc1c([N+](=O)[O-])cc(N)c2ccccc12
Reaction time: 0.5 h
Yield: 11.1 %

Procedure:
Na2S (60%, 4.27 g, 32.87 mmol) was added to a refluxing solution of ethyl (2,4-dinitronaphthalen-1-yl)acetate (10.0 g, 32.87 mmol) in EtOH (200 mL) and stirred for 0.5 h. The mixture was poured into water (200 mL), concentrated and extracted with AcOEt (300 mL). The organic layer was washed with H2O (100 mL) and saturated aqueous NaCl (50 mL). The each aqueous layer was extracted with AcOEt (100 mL). The combined organic layer was washed with saturated aqueous NaCl (50 mL), dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography (20% AcOEt-Petroleum ether) afforded ethyl (4-amino-2-nitronaphthalen-1-yl)acetate (1.0 g, 11%) as a dark purple solid. M.p. 93-100° C. (decomp.); 1H NMR (CDCl3, 500 MHz) δ 8.08 (d, 8.0, 1H), 7.86 (d, 7.5, 1H), 7.66 (t, 7.0, 1H), 7.62 (t, 7.0, 1H), 7.20 (s, 1H), 4.40 (brs, 2H), 4.26 (s, 2H), 4.20 (q, 7.0, 2H), 1.26 (t, 7.0, 3H); IR (neat) 3459, 3379, 3255, 2980, 1728, 1634, 1590, 1515, 1466, 1439, 1368, 1337, 1249, 1200, 1156, 1027, 841, 756 cm−1. FABMS (NBA) m/z 274 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]=[C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:21][C:22]([O:24]CC)=[O:23])[N:17]=3)[O:13][N:12]=2)[CH2:7][CH2:6]1.[OH-].[Na+]>>[Br:1][C:2]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]=[C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:21][C:22]([OH:24])=[O:23])[N:17]=3)[O:13][N:12]=2)[CH2:7][CH2:6]1
Reactant: CCOC(=O)Cn1ccc(-c2nc(N3CCC(Oc4cc(F)ccc4Br)CC3)no2)n1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cn1ccc(-c2nc(N3CCC(Oc4cc(F)ccc4Br)CC3)no2)n1

Procedure:
The title compound was prepared in a similar manner as described in Example 7 (step 5) from ethyl (3-{3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,2,4-oxadiazol-5-yl}-1H-pyrazol-1-yl)acetate and aqueous NaOH. 1H NMR (500 MHz, acetone-d6): δ7.97 (s, 1H), 7.62 (t, 1H), 7.12 (d, 1H), 6.94 (s, 1H), 6.75 (s, 1H), 5.22 (s, 2H), 4.91 (s, 1H), 3.82-3.75 (m, 2H), 3.63-3.57 (m, 2H), 2.16-2.07 (m, 2H), 1.94 (s, 2H). MS: m/z 466, 468 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:7]2=[CH:8][C:9]3[CH2:10][CH2:11][C:12]4[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=4[C:14]=3[N:6]2[CH2:5][CH2:4][N:3]=1.[BH4-].[Na+].[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25]>C(O)C.O>[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25].[CH3:1][CH:2]1[C:7]2=[CH:8][C:9]3[CH2:10][CH2:11][C:12]4[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=4[C:14]=3[N:6]2[CH2:5][CH2:4][NH:3]1
Reactant: CC1=NCCn2c1cc1c2-c2ccccc2CC1
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1NCCn2c1cc1c2-c2ccccc2CC1
Yield: 24 %

Procedure:
5,6,10,11-Tetrahydro-8-methylbenzo[g]pyrazino[1,2-a]indole (0.6 g) was dissolved in a mixture of 25 ml of ethanol and 2.5 ml of water under argon. The solution was treated portionwise with 0.3 g of sodium borohydride while stirring and stirred at room temperature overnight. Thereafter, the solvent was removed in a vacuum, the residue was taken up in 50 ml of methylene chloride and washed with 50 ml of 10% ammonia solution. The phases were separated and the aqueous phase was extracted twice with 20 ml of methylene chloride each time. The organic phases were combined, dried with MgSO4 and freed from solvent. The crude product, 0.5 g of brown solid, was dissolved in a 20-fold amount of ethanol and treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There was obtained 0.2 g (24%) of 5,6,8,9,10,11-hexahydro-8-methylbenzo[g]pyrazino[1,2-a]indole fumarate (1:1); m.pt.: 181°-184° C. (dec.).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[C:30]([O:33][C:34]([C:37](Cl)=[O:38])([CH3:36])[CH3:35])(=[O:32])[CH3:31].CO>C(Cl)Cl>[C:30]([O:33][C:34]([CH3:36])([CH3:35])[C:37](=[O:38])[N:10]1[CH2:11][CH2:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@H:9]1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=1)(=[O:32])[CH3:31]
Reactant: FC(F)(F)c1ccc([C@H]2NCCc3ccccc32)cc1
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: CC(=O)OC(C)(C)C(=O)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (R)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (207 mg, 747 μmol, example 30 (step 1) and DIEA (130 μL, 747 μmol) in DCM (2.5 mL) was added 1-chlorocarbonyl-1-methylethyl acetate (119 μL, 821 μmol). The mixture was stirred at RT for 3 h. Then, 1-chlorocarbonyl-1-methylethyl acetate (50 μL) was added and the mixture was stirred at RT for 16 h. MeOH (1 mL) was added and the mixture was filtered. The filtrate was purified by preparative HPLC (0%-100% MeCN 0.1% TFA/water 0.1% TFA) to give the title compound in a solution of H2O 0.1% TFA and MeCN 0.1% TFA. The solvent was removed and saturated NaHCO3 (5 mL) was added. The mixture was extracted with EtOAc (2×30 mL). The combined organic extracts were dried over MgSO4, concentrated, and dried in vacuo to give the title compound as a white solid. MS (ESI, positive ion) m/z: 406 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH:17][C:18]([CH3:25])=[CH:19][C:20](OCC)=[O:21])=[S:16])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[Na]>C(O)(C)C.CN(C)C=O>[Cl:1][C:2]1[CH:13]=[CH:12][C:11]([N:14]2[C:20](=[O:21])[CH:19]=[C:18]([CH3:25])[NH:17][C:15]2=[S:16])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CCOC(=O)C=C(C)NC(=S)Nc1ccc(Cl)c(C(=O)OC(C)C)c1
Agent: [Na]
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: Cc1cc(=O)n(-c2ccc(Cl)c(C(=O)OC(C)C)c2)c(=S)[nH]1

Procedure:
using isopropyl 2-chloro-5-{3-[2-(ethoxycarbonyl)-1-methylvinyl]thioureido}-benzoate with sodium isopropylate in an isopropanol/dimethylformamide mixture there is obtained isopropyl 2-chloro-5-[3,6-dihydro-4-methyl-6-oxo-2-thioxo-1(2H)-pyrimidinyl]-benzoate,
Reaction SMILES: [ClH:1].[OH:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[O:8][C:7]=2[CH:6]=[C:5]([O:18][CH2:19][CH:20]2[CH2:22][O:21]2)[CH:4]=1>C(OCC)(=O)C>[Cl:1][CH2:22][CH:20]([OH:21])[CH2:19][O:18][C:5]1[CH:4]=[C:3]([OH:2])[C:16]2[C:15](=[O:17])[C:14]3[C:9]([O:8][C:7]=2[CH:6]=1)=[CH:10][CH:11]=[CH:12][CH:13]=3
Reactant: O=c1c2ccccc2oc2cc(OCC3CO3)cc(O)c12
Reactant: Cl
Solvent: CCOC(C)=O
Product: O=c1c2ccccc2oc2cc(OCC(O)CCl)cc(O)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.1 %

Procedure:
An aqueous ethyl acetate 1M-HCl (3 mL) was added to 1-hydroxy-3-(oxiran-2-ylmethoxy)-9H-xanthen-9-one (30 mg, 0.11 mmol) prepared in Step 2 of Example 2, followed by stirring at room temperature for 30 minutes, and the reaction solvent was removed under reduced pressure. Ether was added to the residue, followed by sonication, and the solvent was removed to give the title compound (32 mg, 94.1%) as a red solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([O:15][C@H:16]2[CH2:20][NH:19][C@H:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17]2)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][CH:9]=[C:8]([O:13][CH3:14])[CH:7]=2.[CH3:25][C:26]([CH3:44])([CH3:43])[C@@H:27]([C:40](O)=[O:41])[NH:28][C:29]([O:31][C@@H:32]1[CH2:34][C@H:33]1[CH2:35][CH2:36][CH2:37][CH:38]=[CH2:39])=[O:30].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH3:25][C:26]([CH3:44])([CH3:43])[C@@H:27]([C:40]([N:19]1[CH2:20][C@H:16]([O:15][C:4]2[C:3]([Cl:2])=[N:12][C:11]3[C:6](=[CH:7][C:8]([O:13][CH3:14])=[CH:9][CH:10]=3)[N:5]=2)[CH2:17][C@H:18]1[C:21]([O:23][CH3:24])=[O:22])=[O:41])[NH:28][C:29]([O:31][C@@H:32]1[CH2:34][C@H:33]1[CH2:35][CH2:36][CH2:37][CH:38]=[CH2:39])=[O:30]
Reactant: C=CCCC[C@@H]1C[C@H]1OC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: COC(=O)[C@@H]1C[C@@H](Oc2nc3cc(OC)ccc3nc2Cl)CN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCCC[C@@H]1C[C@H]1OC(=O)N[C@H](C(=O)N1C[C@H](Oc2nc3cc(OC)ccc3nc2Cl)C[C@H]1C(=O)OC)C(C)(C)C
Temperature: 20 °C
Reaction time: 5 h
Yield: 96 %

Procedure:
A solution (0.2 M) of methyl (4R)-4-[(3-chloro-7-methoxyquinoxalin-2-yl)oxy]-L-prolinate hydrochloride in DMF was treated with 3-methyl-N-({[(1R,2R)-2-pent-4-en-1-ylcyclopropyl]oxy}carbonyl)-L-valine (1.1 eq), DIEA (5 eq) and HATU (1.2 eq). The resulting mixture was stirred at 20° C. for 5 h, then diluted with EtOAc. The organic layer was separated and washed with aqueous HCl (1 N), saturated aqueous NaHCO3 and brine. The dried organic phase was concentrated under reduced pressure to give a residue that was purified by flash chromatography (eluent 10-30% EtOAc/petroleum ether) to furnish the title compound (96%) as an oil. MS (ES+) m/z 604 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[C:20]([C:25](OC)=[O:26])[CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C.C1COCC1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[C:20]([CH2:25][OH:26])[CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(-c2cnc(C3CCCN3C(=O)OC(C)(C)C)[nH]2)ccc1Br
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(Br)c(CO)c2)[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 105.5 %

Procedure:
To the solution of 2-[5-(4-Bromo-3-methoxycarbonyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 0.44 mmol) in THF (4 ml) at −78° C. was added DIBAL-H THF solution (3.33 ml, 3.33 mmol). The mixture was warmed to 25° C. and stirred for 5 hours. The mixture was cooled to 0° C. and quenched with 2.0 N NaOH solution until PH=11. The mixture was extracted with EtOAc. The organic phase was washed with water and brine, and was dried with sodium sulfate. Concentration gave 2-[5-(4-bromo-3-hydroxymethyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (196 mg). m/z: 421.9 (M+H)+, 420.2 (M−H)−.
Reaction SMILES: C[O:2][C:3]1[N:8]=[C:7]([O:9]C)[C:6]([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[CH:5][N:4]=1.[ClH:16]>O1CCOCC1>[ClH:16].[S:12]1[CH:13]=[CH:14][N:15]=[C:11]1[C:6]1[C:7](=[O:9])[NH:8][C:3](=[O:2])[NH:4][CH:5]=1
Reactant: COc1ncc(-c2nccs2)c(OC)n1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1[nH]cc(-c2nccs2)c(=O)[nH]1
Reaction time: 1 h

Procedure:
2,4-bis(methyloxy)-5-(1,3-thiazol-2-yl)pyrimidine (Prep25, 294 mg, 1.225 mmol) was suspended in 4M HCl solution in 1,4-dioxane (25 ml) to give a white suspension. After 1 h at 90° C., the solvent was evaporated. 306.8 mg of the title compound were isolated as a white solid.
Reaction SMILES: [CH2:1]([O:8][N:9]=[CH:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19](=[N:24][O:25][CH3:26])[C:20]([O:22]C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][NH2:28].O>CO>[CH3:27][NH:28][C:20](=[O:22])[C:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][O:11][CH:10]=[N:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[N:24][O:25][CH3:26]
Reactant: CON=C(C(=O)OC)c1ccccc1COC=NOCc1ccccc1
Reactant: CN
Solvent: O
Solvent: CO
Product: CNC(=O)C(=NOC)c1ccccc1COC=NOCc1ccccc1
Reaction time: 24 h
Yield: 90 %

Procedure:
Methyl 2-(2-benzyloxyiminomethyloxymethylphenyl)-2-methoxyiminoacetate) (compound No. 2) (200 mg. 0.6 mmol) was dissolved into 8 ml of methanol, an aqueous solution of 40% methylamine (230 mg, 2.9 mmol) was added thereto. After stirring for 1 day, water was added to the reaction solution, methanol was removed by evaporation, and there was extracted with ethyl acetate. The organic layer was rinsed with water and dried. After removing the solvent by evaporation, the residue was purified with silica gel chromatography to obtain 0.18 g of N-methyl 2-(2-benzyloxyiminomethyloxymethylphenyl)-2-methoxyiminoacetamide (Compound No. 3; yield: 90%). The proton NMR spectrum of the compound is 2.81 s (3H); 3.89 s (3H); 4.91 s (2H); 5.00 s (2H); 6.52 s (1H): 6.82 bd(1H); 7.15-7.21 m (1H); 7.23-7.47 m (8H) (solvent: CDCl3).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.Cl.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1>>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:3][C:4]=1[CH3:9]
Reactant: Cc1cc(N)ccc1O
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Cl
Product: COc1cc2ncnc(Nc3ccc(O)c(C)c3)c2cc1OC
Yield: 100.4 %

Procedure:
An analogous reaction to that described in example 17, but starting with 4-amino-2-methylphenol (6.98 g, 56.7 mmol) and 4-chloro-6,7-dimethoxyquinazoline hydrochloride (14.79 g, 56.7 mmol), yielded 4-(4-hydroxy-3-methylanilino)-6,7-dimethoxyquinazoline (17.72 g, 90% yield) as a white solid:
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11]O)[OH:10])O)O)O.C(OS(C1C=CC=CC=1)(=O)=O)CCCCCCCCCCC.[Na].C1(C)C=CC=CC=1.[ClH:43]>[Cl-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.O>[Cl:43][CH2:11][C:9]1[O:10][C:3]([CH:2]=[O:1])=[CH:5][CH:7]=1
Reactant: Cl
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: CCCCCCCCCCCCOS(=O)(=O)c1ccccc1
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1ccc(CCl)o1
Reaction time: 5 h

Procedure:
To the same three-necked flask as in Example 1 were added 5 g (0.028 mole) of a commercially available D-(+)-galactose and two kinds of surface active agent, i.e., 89.6 mg (0.00028 mole) of cetyltrimethylammonium chloride and 97.6 mg (0.00028 mole) of sodium laurylbenzenesulfonate. Then, 30 ml of toluene was added thereto and the mixture was stirred to make a suspension. Thereafter, about 6 ml of 35% aqueous hydrochloric acid was added dropwise from a dropping funnel over about 1 hour. A slight excess of hydrogen chloride was then slowly passed therethrough at 50° C. over 3 hours with stirring. After stirring was continued for a further 5 hours, the reaction solution was diluted with a little water and filtered through Celite while being washed with toluene. The toluene layer was neutralized, dried and concentrated to obtain about 1.9 g (theoretical yield 4.01 g) of 5-chloromethylfurfural as a crude product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:20][C@H:12]2[CH2:13][N:14]([CH2:16][C:17](O)=[O:18])[CH2:15][C@@:11]2([C:21]([N:23]2[CH2:32][CH2:31][C:30]3[N:29]=[CH:28][C:27]([C:33]([F:36])([F:35])[F:34])=[CH:26][C:25]=3[CH2:24]2)=[O:22])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:37][NH:38][CH3:39].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]1[CH2:20][C@H:12]2[CH2:13][N:14]([CH2:16][C:17]([N:38]([CH3:39])[CH3:37])=[O:18])[CH2:15][C@@:11]2([C:21]([N:23]2[CH2:32][CH2:31][C:30]3[N:29]=[CH:28][C:27]([C:33]([F:36])([F:35])[F:34])=[CH:26][C:25]=3[CH2:24]2)=[O:22])[CH2:10]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]2CN(CC(=O)O)C[C@@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)CN1C[C@@H]2C[C@@H](NC(=O)OC(C)(C)C)C[C@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1

Procedure:
A solution the product from Step A (37 mg, 0.072 mmol), dimethylamine (0.0433 mL, 0.0866 mmol, 2 M in THF), EDAC (18 mg, 0.0938 mmol), HOBt (19.51 mg, 0.144 mmol) and DIPEA (0.0252 mL, 0.144 mmol) in DMF (3 mL) was stirred at rt over the weekend. The reaction was quenched by addition of brine, extracted with EtOAc, dried over Na2SO4 and purified by CombiFlash (eluent: 8% methanol in DCM) to give the product as a yellowish gel. 1H-NMR (400 MHz, CDCl3): δ 1.29-1.43 (m, 9H), 1.75-2.09 (m, 4H), 2.20-2.35 (m, 1H), 2.55-2.71 (m, 3H), 2.86-3.00 (m, 4H), 3.05-3.22 (m, 6H), 3.60-3.93 (m, 2H), 4.25 (d, J=5.6 Hz, 1H), 4.59-4.92 (m, 3H), 7.70 (s, 1H), 8.70 (s, 1H); LC/MS: C26H36F3N5O4: m/z 540.3 (M+H).
Reaction SMILES: ClCl.[C:3]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][N:10]=[C:9]2[NH:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=1)(=[O:5])[CH3:4].C(Cl)[Cl:26]>C(O)C>[Cl:26][CH2:4][C:3]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][N:10]=[C:9]2[NH:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=1)=[O:5]
Reactant: CC(=O)c1ccc2ncnc(Nc3ccc(F)c(Cl)c3)c2c1
Reactant: ClCCl
Agent: ClCl
Solvent: CCO
Product: O=C(CCl)c1ccc2ncnc(Nc3ccc(F)c(Cl)c3)c2c1
Temperature: 22.5 °C
Reaction time: 1 h

Procedure:
Chlorine gas was led into a stirred mixture of 6-acetyl-4-(3-chloro-4-fluoroanilino)quinazoline (0.11 g), methylene chloride (40 ml) and ethanol (60 ml) and the mixture was cooled to a temperature in the range 20 to 25° C. After 10 minutes the supply of chlorine was stopped and the reaction mixture was stirred at ambient temperature for 1 hour. The mixture was evaporated to give 6-(2chloroacetyl)-4-(3-chloro-4-fluoroanilino)quinazoline (0.114 g) which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:17](=[O:20])[CH:18]=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:15]C)[CH:10]=3.B(Br)(Br)Br.[OH-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:17](=[O:20])[CH:18]=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:15])[CH:10]=3
Reactant: COc1cc2c(=O)ccn3c4cc(Br)ccc4c(c1)c23
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=c1ccn2c3cc(Br)ccc3c3cc(O)cc1c32
Yield: 61.1 %

Procedure:
9-bromo-2-methoxy-4H-pyrido[3,2,1-jk]carbazole-4-one (650 mg) produced in Example 116 was suspended in anhydrous methylene chloride (50 ml), and a solution of boron tribromide in methylene chloride (1M, 12 ml) was added dropwise at room temperature. The mixture was heated under reflux for 14 hours, and the reaction mixture was poured into 1N aqueous solution of sodium hydroxide (100 ml), and the crystals precipitated were recovered by filtration. The thus obtained crude crystals were washed with ethanol and ether in succession to obtain the title compound (380 mg, 61%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[S:12][C:11]2[C@@H:10]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3=[O:19])[C@H:9]([OH:20])[C:8]([CH3:22])([CH3:21])[O:7][C:6]=2[CH:5]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CN(C=O)C>[CH2:23]([O:20][C@@H:9]1[C:8]([CH3:22])([CH3:21])[O:7][C:6]2[CH:5]=[C:4]([Br:3])[S:12][C:11]=2[C@H:10]1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[O:19])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC1(C)Oc2cc(Br)sc2[C@@H](N2CCCCC2=O)[C@@H]1O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)Oc2cc(Br)sc2[C@@H](N2CCCCC2=O)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in mineral oil, 0.47 g, 11.7 mmol) was added to a solution of trans-2-bromo-5,6-dihydro-6-hydroxy-5,5-dimethyl-7-(2-oxopiperidin-1-yl)-7H-thieno-[3,2-b]pyran (4.0 g, 11.1 mmol) in DMF (50 mL) at 0° C. and stirred at rt for 30 min. Benzylbromide (1.45 mL, 12.2 mmol) was added to the resultant solution and stirred at rt for 2 h. The solution was poured into water (200 mL) and extracted into dichloromethane. The organic phase was washed several times with water and dried over magnesium sulfate. The solvent was evaporated in vacuo, and the residue was purified by flash chromatography using 2% methanol in dichloromethane as the eluant. The product was recrystallized from dichloromethane/hexane to give a colorless solid, 3.87 g (77%); mp 146°-147° C.; IR(KBr): 1634 and 1570 cm-1 ; MS: m/z 450 (MH+); 1H NMR(CDCl 3): 1.32 (s, 3H), 1.50 (s, 3H), 1.53-1.77 (m, 4H), 2.37-2.45 (m, 2H), 2.87 (m, 1H), 3.08 (m, 1H), 3.69 (d, J=8.6 Hz, 1H), 4.60 (d, J=11.8 Hz, 1H), 4.73 (d, J=11.8 Hz, 1H), 5.90 (bs, 1H), 6.54 (s, 1H) and 7.26-7.37 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[P:49]([O:61][CH2:62]Cl)([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50]>CN(C)C=O>[C:52]([O:51][P:49]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])([O:61][CH2:62][O:36][C:35](=[O:37])[C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:42])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]2)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=1)=[O:50])([CH3:55])([CH3:54])[CH3:53]
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: CC(C)(C)OP(=O)(OCCl)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)OCOP(=O)(OC(C)(C)C)OC(C)(C)C)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reaction time: 3 h
Yield: 70.7 %

Procedure:
To a solution of chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1, 200.0 mg, 0.324 mmol) in dimethylformamide (8 mL) was added cesium carbonate (529 mg, 1.62 mmol). The mixture was stirred for ˜20 min before di-tert-butyl chloromethyl phosphate (TCI, 236 mg, 0.9912 mmol) in dimethylformamide (1 mL) was added. The reaction mixture was allowed to stirr at room temperature for 3 h before it was partitioned between ethyl acetate and water, washed with water and dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash chromatography (hexane/ethyl acetate, 85/15 to 5/95) to give chiral 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid di-tert-butoxy-phosphoryloxymethyl ester as a white solid (192 mg, 70% yield). LCMS (ES+) m/z calcd. for C40H49Cl2F2N3O8P [(M+H)+]: 838, found: 838.
Reaction SMILES: Br[CH2:2][C:3]1[S:4][C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1.[CH3:11][O:12][P:13]([O:16]C)[O:14][CH3:15]>>[CH3:11][O:12][P:13]([CH2:2][C:3]1[S:4][C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1)([O:14][CH3:15])=[O:16]
Reactant: O=[N+]([O-])c1ccc(CBr)s1
Reactant: COP(OC)OC
Product: COP(=O)(Cc1ccc([N+](=O)[O-])s1)OC

Procedure:
2-Bromomethyl-5-nitrothiophene and trimethylphosphite ((CH3O)3 P) were treated in the same manner as in Reference Example 43 to yield 2-dimethoxyphosphorylmethyl-5-nitrothiophene as an oil.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[N:13][CH:14]=2)=[CH:5][CH:4]=1.Br[CH2:24][CH2:25][C:26]#[N:27]>>[F:22][C:2]([F:1])([F:21])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:20][CH2:19][N:18]([CH2:24][CH2:25][C:26]#[N:27])[CH2:17][CH2:16]3)=[N:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: N#CCCBr
Reactant: FC(F)(F)c1ccc(-c2ccc(N3CCNCC3)nc2)cc1
Product: N#CCCN1CCN(c2ccc(-c3ccc(C(F)(F)F)cc3)cn2)CC1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 55, starting from 4-(5-(4-trifluoromethylphenyl)pyridin-2-yl)piperazine and 3-bromopropionitrile.