Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][C:16]2[C:24]3[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=3[NH:18][CH:17]=2)[CH2:9][CH2:8]1.CN(C)[CH:27]=[O:28]>>[CH3:6][N:7]1[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][C:16]2[C:24]3[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=3[NH:18][C:17]=2[CH:27]=[O:28])[CH2:11][CH2:12]1
Reactant: CN(C)C=O
Reactant: CN1CCN(CCCc2c[nH]c3c2CCCC3)CC1
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCN(CCCc2c(C=O)[nH]c3c2CCCC3)CC1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
POCl3 (1.8 mL, 18.9 mmol) was added dropwise to N,N-dimethylformamide(DMF, 3.8 mL, 51.6 mmol) at −5° C. The mixture was then allowed to come to room temperature and then stirred for 30 minutes after which it was again cooled to −5° C. A solution of 3-[3-(4-methylpiperazin-1-yl)-propyl]-4,5,6,7-tetrahydro-1H-indole (4.5 g, 17.2 mmol) in DMF (9 mL) was added dropwise. The mixture was again allowed to come to room temperature and then stirred at that temperature overnight. The reaction was then quenched with ice, followed by 10 N NaOH to adjust the pH to 10-11. After stirring at room temperature for 1 hr, the reaction was extracted with ethyl acetate (EtOAc), the organic layer separated, washed with brine, dried and concentrated to give 3.1 g (62%) of 3-[3-(4-methylpiperazin-1-yl)-propyl]-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:31][C:32]1[CH:33]=[N:34][NH:35][CH:36]=1)[C:23]1[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:23]1[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)[CH2:31][C:32]1[CH:33]=[N:34][N:35]([CH2:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[CH:36]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClCCc1ccccn1
Reactant: COc1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: COc1ccc(N(Cc2cnn(CCc3ccccn3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 56.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-[(pyrazol-4-yl)methyl]-N-(6-methoxypyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.70 g) and 2-(2-chloroethyl)pyridine (0.42 g) as starting materials, 5-benzyloxy-N-(6-methoxypyridin-3-yl)-N-({1-[2-(2-pyridyl)ethyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.45 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 139, 5-hydroxy-N-(6-methoxypyridin-3-yl)-N-({1-[2-(2-pyridyl)ethyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide dihydrochloride (0.31 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12]CC)=[N:10][C:9](N)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.N1C=CC=CC=1.[FH:22].N([O-])=O.[Na+].C([O-])(O)=O.[Na+].[Al+3].[Cl-].[Cl-].[Cl-]>O>[Cl:1][C:2]1[C:11]([OH:12])=[N:10][C:9]([F:22])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: F
Reactant: CCOc1nc(N)c2ncccc2c1Cl
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Al+3]
Solvent: O
Solvent: c1ccncc1
Product: Oc1nc(F)c2ncccc2c1Cl
Temperature: 0 °C
Yield: 88 %

Procedure:
To a 25 mL round bottom flask was added 5-chloro-6-ethoxy-1,7-naphthyridin-8-amine (1.03 mmol), followed by hydrogen fluoride pyridine (5 mL). The solution was cooled to 0° C., then sodium nitrite (1.23 mmol) was added in portions. The mixture was warmed to room temperature over a period of 1 h. The reaction was then neutralized with saturated NaHCO3 and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The resultant crude residue was dissolved in dichloroethane (50 mL), then AlCl3 (820 mg, 6.18 mmol) was added in one portion. The mixture was refluxed for 2 h under Ar. The solution was allowed to cool to room temperature, then diluted with water. The aqueous phase was extracted with ethyl acetate, the organic layer was washed with brine then dried over Na2SO4. The solvent was concentrated to yield 5-chloro-8-fluoro-1,7-naphthyridin-6-ol (180 mg, 88%) as a pale yellow solid. LC/MS m/z 199 [M+H].
Reaction SMILES: C([Al](CC(C)C)CC(C)C)C(C)C.CC(O)C.[Cl:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[C:22](=[O:25])[CH2:23][Cl:24].Cl>C1(C)C=CC=CC=1.C1C=C2C=CC(O)=C(C3C4C(=CC=CC=4)C=CC=3O)C2=CC=1.O.CCCCCC>[Cl:24][CH2:23][C@@H:22]([C:21]1[CH:26]=[CH:27][CH:28]=[C:19]([Cl:18])[CH:20]=1)[OH:25]
Reactant: O=C(CCl)c1cccc(Cl)c1
Agent: CC(C)C[Al](CC(C)C)CC(C)C
Agent: Cl
Agent: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Solvent: Cc1ccccc1
Solvent: CC(C)O
Solvent: O
Product: O[C@@H](CCl)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 120.9 %

Procedure:
To a slurry solution of 143 mg (0.5 mmol) of (S)-1,1′-bi-2-naphthol in 10 ml of toluene was added 0.5 ml (0.5 mmol) of a 1.0 M hexane solution of triisobutylaluminum at room temperature, and the mixture was stirred at room temperature for 30 minutes. Thereto 1.52 ml (20 mmol) of 2-propanol was added and the mixture was stirred at room temperature for 30 minutes. Thereto 1.89 g (10 mmol) of m-chlorophenacyl chloride was added and the mixture was stirred further at 50° C. for 4 hours. To the mixture were added 2 ml of 1N hydrochloric acid and 20 ml of water to conduct hydrolysis. The mixture was extracted with ethyl acetate and concentrated to obtain 2.310 g of an oily product. The obtained oil was analyzed by HPLC.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([F:11])[C:8](F)=[CH:7][C:6]=1[F:13])[CH3:2].C(N(CC)CC)C.[C:22]([O:26][C:27](=[O:34])[NH:28][CH:29]1[CH2:33][CH2:32][NH:31][CH2:30]1)([CH3:25])([CH3:24])[CH3:23]>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([CH:33]2[CH2:32][NH:31][CH2:30][CH:29]2[NH:28][C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:34])=[CH:7][C:6]=1[F:13])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: CCOC(=O)c1cc(F)c(F)cc1F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1cc(F)c(C2CNCC2NC(=O)OC(C)(C)C)cc1F
Reaction time: 45 h

Procedure:
To a solution of 2,4,5-trifluorobenzoic acid ethyl ester (Example 1e, 14.8 g, 72.4 mmol) in acetonitrile (225 mL) is added triethylamine (65 mL, 466 mmol) and pyrrolidin-3-ylcarbamic acid tert-butyl ester (16.07 g, 86.2 mmol). After 45 hours, the reaction mixture is diluted with ethyl acetate and washed with saturated NaHCO3, water, and brine. The organic layer is dried over MgSO4, filtered, and the filtrate is concentrated to afford an oil. The resulting residue is purified by flash chromatography (1:5 ethyl acetate/hexanes) to afford the title compound. MS (ES, M+1) m/z 371, mp 98-100° C.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:36]=[CH:35][C:18]([CH2:19][NH:20][O:21][C@H:22]4[C@H:27]([O:28][CH3:29])[C@H:26]([O:30][CH3:31])[C@@H:25]([O:32][CH3:33])[C@H:24]([CH3:34])[O:23]4)=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[C:39]1(=[O:45])[O:44][C:42](=[O:43])[CH2:41][CH2:40]1>N1C=CC=CC=1.CCOC(C)=O>[F:38][C:2]([F:1])([F:37])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:36]=[CH:35][C:18]([CH2:19][N:20]([O:21][C@H:22]4[C@H:27]([O:28][CH3:29])[C@H:26]([O:30][CH3:31])[C@@H:25]([O:32][CH3:33])[C@H:24]([CH3:34])[O:23]4)[C:39](=[O:45])[CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: CO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](ONCc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)[C@@H]1OC
Reactant: O=C1CCC(=O)O1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](ON(Cc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)C(=O)CCC(=O)O)[C@@H]1OC
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 39 %

Procedure:
To a solution of N-{4-[1-(4-trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]-benzyl}-O-((2S,3R,4R,5S,6S)-3,4,5-trimethoxy-6-methyl-tetrahydropyran-2-yl)-hydroxylamine (3; 140 mg, 0.26 mmol) in pyridine (5 mL) was added succinic anhydride (large excess), and the mixture stirred at room temperature for 3.5 h. The mixture was diluted with EtOAc and washed with 1 N HCl. The aqueous fraction was extracted with EtOAc (2×). The organic fractions were combined, washed with brine, dried with anhydrous MgSO4 and evaporated at room temperature under vacuum. The resulting crude material was purified by silica gel chromatography (eluting with 80% EtOAc in Hexane going to 100% EtOAc over a short gradient). The title product (64 mg, 39%) was isolated as a white solid: mp 61-75° C.; 1H NMR (300 MHz, CDCl3) δ 8.63 (s, 1H), 8.16 (d, J=8.3 Hz, 2H), 7.93-7.68 (m, 2H), 7.40 (d, J=8.4 Hz, 4H), 5.40-5.10 (m, 2H), 4.76 (d, J=16.1 Hz, 1H), 3.73-3.25 (m, 13H), 3.15 (dd, J=9.1, 7.9 Hz, 1H), 3.04-2.60 (m, 4H), 1.27 (dd, J=9.8, 4.3 Hz, 3H); ESIMS m/z 639 (M+H), 638 (M+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3]/[C:4](/[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[C:5](\[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)/[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:8][CH:7]=1.[H][H]>[Pd].C(O)(=O)C>[Cl:1][CH2:2][CH2:3][CH:4]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:5]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:10][CH:11]=1
Reactant: ClCC/C(=C(\c1ccccc1)c1ccc(OCCN2CCCC2)cc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: ClCCC(c1ccccc1)C(c1ccccc1)c1ccc(OCCN2CCCC2)cc1

Procedure:
(RR, SS)-isomers: A mixture containing 43.2 g of (Z)-4-chloro-1,2-diphenyl-1-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-1-butene, 4 g of 5% palladium-on-charcoal and 800 ml of glacial acetic acid is stirred under hydrogen atmosphere at 75° C. until one equivalent of hydrogen is consumed, about 6 h. The solvent is evaporated and the evaporation residue is dissolved in toluene. The toluene solution is washed first with 2 M sodium hydroxide solution and then with water, after which the solution is dried over sodium sulfate. Finally the solvent is evaporated leaving the product as an oil at quantitative yield.
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:19][C:20]1[C:24]([CH3:25])=[C:23]([NH2:26])[O:22][N:21]=1>O1CCCC1>[CH3:19][C:20]1[C:24]([CH3:25])=[C:23]([NH:26][CH:8]=[C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[O:22][N:21]=1
Reactant: O=C1Nc2ccccc2/C1=C/O
Reactant: Cc1noc(N)c1C
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: Cc1noc(NC=C2C(=O)Nc3ccccc32)c1C

Procedure:
The named compound is prepared by substituting 3,4-dimethyl-isoxazol-5-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.100 gms.) is reacted with 0.1388 gms. 3,4-dimethyl-isoxazol-5-ylamine by refluxing in tetrahydrofuran (2.7 mL).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:11]=2)=[C:4]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[O:33][CH3:34])[CH:3]=1.[Cl-].C[Zn+].[CH3:38]N1CCN(C)C1=O.C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:4]2[CH:3]=[C:2]([CH3:38])[N:7]=[N:6][C:5]=2[N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:18])([F:17])[F:19])[CH:13]=[C:12]([S:20]([CH3:23])(=[O:21])=[O:22])[CH:11]=2)=[C:27]([O:33][CH3:34])[CH:28]=1
Reactant: CN1CCN(C)C1=O
Reactant: COc1cc(F)ccc1-c1cc(Cl)nnc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Agent: C[Zn+]
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(F)ccc1-c1cc(C)nnc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a solution of N-[6-chloro-4-(4-fluoro-2-methoxy-phenyl)-pyridazin-3-yl]-3-methanesulfonyl-N-methyl-5-trifluoromethyl-benzamide (100 mg, 193 mmol, example 1) in tetrahydrofuran (2 mL) was added methylzinc chloride (2M solution in tetrahydrofuran, 145 μL, 290 mmol) and 1,3-dimethyl-2-imidazolidinone (400 μL, CAS RN 80-73-9) and PEPPSI-IPr (2.62 mg, 3.86 μmol, CAS RN 905459-27-0). The reaction mixture was stirred at 60° C. for 5 hours, poured on 10% aqueous sodium bicarbonate solution (30 mL) and ethyl acetate (30 mL) and the layers were separated. The aqueous layer was extracted a second time with ethyl acetate (30 mL). The organic layers were washed with brine (30 mL), dried over magnesium sulfate, filtered and concentrated under vacuum. The compound was purified by silica gel chromatography on a 20 g column using an MPLC (Flashmaster) system eluting with a gradient of n-heptane:ethyl acetate (100:0 to 0:100). Light brown solid (70 mg, 72.9%). MS (ESI+): m/z=498.110 ([M+H]+).
Reaction SMILES: [C:1]1([C:9]([CH2:11][C:12]2[CH:19]=[CH:18][C:15]([O:16][CH3:17])=[CH:14][CH:13]=2)=O)[CH:8]=[CH:7][C:4]([O:5][CH3:6])=[CH:3][CH:2]=1.[CH3:20][NH:21][CH3:22].C1(C)C=CC=CC=1>C(OCC)C.[Ti](Cl)(Cl)(Cl)Cl>[CH3:6][O:5][C:4]1[CH:7]=[CH:8][C:1]([C:9](=[CH:11][C:12]2[CH:19]=[CH:18][C:15]([O:16][CH3:17])=[CH:14][CH:13]=2)[N:21]([CH3:22])[CH3:20])=[CH:2][CH:3]=1
Reactant: COc1ccc(CC(=O)c2ccc(OC)cc2)cc1
Reactant: CNC
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1ccc(C=C(c2ccc(OC)cc2)N(C)C)cc1

Procedure:
A solution of 307.56 g. of desoxyanisoin in three liters of diethyl ether was cooled to about 0° C. by means of an external ice/alcohol bath. Under a nitrogen atmosphere, 441 ml. of dimethylamine were added to the solution with stirring. A solution of 79 ml. of titanium tetrachloride in 500 ml. of toluene was then added to the reaction mixture over a 90 minute period at such a rate to keep the temperature below 5° C. The reaction was then allowed to stir overnight at room temperature. The reaction was filtered and the precipitate was washed with two liters of diethyl ether. The ether filtrate and wash were combined and evaporated in vacuo. The residue was crystallized from ether/Skelly B to provide 272.2 g. of the desired title intermediate, m.p. about 67°-69° C.
Reaction SMILES: [CH3:1][C:2]([C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)([CH3:15])[CH2:3][N:4]1C(=O)C2=CC=CC=C2C1=O.CO.O.NN>C(Cl)(Cl)Cl>[CH3:15][C:2]([C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)([CH3:1])[CH2:3][NH2:4]
Reactant: CC(C)(CN1C(=O)c2ccccc2C1=O)c1ccc([N+](=O)[O-])cc1
Agent: NN
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)(CN)c1ccc([N+](=O)[O-])cc1
Yield: 78 %

Procedure:
To a mixture of the compound (152 mg) obtained in Example 179, methanol (10 ml) and chloroform (10 ml), hydrazine monohydrate (0.05 ml) was added and heated under reflux for 24 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure; following addition of 2 N HCl, the mixture was washed with ethyl acetate. Then, the aqueous layer was made alkaline with a 2 N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure to give 71 mg of the titled compound (yield, 78%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[NH:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:13]=1[CH:14]=[C:15]([C:18]#[N:19])[C:16]#[N:17]>>[NH2:19][CH2:18][C:15]1[C:16]([NH2:17])=[N:7][C:6]([C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=2)=[N:8][C:14]=1[C:13]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:12]=1[Cl:11]
Reactant: Cc1ccc(C(=N)N)cc1
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Product: Cc1ccc(-c2nc(N)c(CN)c(-c3ccc(Cl)cc3Cl)n2)cc1

Procedure:
The title compound, MS: m/e=358.2 (M+), was prepared from 4-methylbenzamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:4].[NH2:25][C@@H:26]([C:28]([OH:30])=[O:29])[CH3:27].C[O-].[Na+].CO>>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][C@H:26]([CH3:27])[C:28]([OH:30])=[O:29])=[O:4])[N:6]=1)#[N:24]
Reactant: C[C@@H](N)C(=O)O
Reactant: COC(=O)c1nc(C#N)c2c(Oc3ccccc3)cccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C[C@@H](NC(=O)c1nc(C#N)c2c(Oc3ccccc3)cccc2c1O)C(=O)O
Temperature: 25 °C
Yield: 79.5 %

Procedure:
A mixture of 1-cyano-4-hydroxy-8-phenoxy-isoquinoline-3-carboxylic acid methyl ester (95 mg, 0.30 mmole), D-Alanine (529 mg, 5.94 mmole) and 0.5 M sodium methoxide/methanol (11.3 mL) was refluxed for three days before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (25 mL) and extracted with dichloromethane (3×30 mL). The remaining aqueous layer was acidified to pH=3 with 1N HCl (8 mL). The white suspension was extracted with ethyl acetate (30 mL) and dichloromethane (30 mL). The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo to give the title compound as a white solid (90 mg): 1H NMR (DMSO-d6, 200 MHz): δ=13.52 (bs, 1H), 9.15 (br s, 1H), 8.30 (d, 1H), 8.10 (m, 1H), 7.67 (t, J=8 Hz, 1H), 7.42 (m, 2H), 7.17 (m, 3H), 4.83 (q, 1H), 1.68 (d, J=7.0 Hz, 3H)); MS: (+) m/z 378.29 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12]([CH2:14][NH2:15])[OH:13]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:15][CH2:14][CH2:12][OH:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Product: O=S(=O)(NCCO)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-bromo-benzenesulfonyl chloride (1.00 g, 3.92 mmol) in methylene chloride (25 mL) was added N,N-dimethylaminopyridine (0.608 g, 4.98 mmol). The reaction mixture was cooled to 0° C., and ethanolamine (0.287 g, 4.70 mmol) was added dropwise. After stirring for 30 minutes, the reaction mixture was quenched with water (15 mL). The resulting mixture was extracted with methylene chloride (3×25 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Purification using silica gel chromatography (100-200 mesh, 10-15% ethyl acetate-hexane) provided 4-bromo-N-(2-hydroxy-ethyl)-benzenesulfonamide. MS calcd. for C8H11BrNO3S [(M+H)+] 281, obsd. 282.2.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5](=O)[C:6]2[S:7][CH2:8][C:9](=[O:14])[N:10]([CH3:13])[C:11]=2[N:12]=1)[CH3:2].P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:5]1[C:6]2[S:7][CH2:8][C:9](=[O:14])[N:10]([CH3:13])[C:11]=2[N:12]=[C:3]([CH2:1][CH3:2])[N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1nc2c(c(=O)[nH]1)SCC(=O)N2C
Product: CCc1nc(Cl)c2c(n1)N(C)C(=O)CS2
Yield: 83 %

Procedure:
The 6,7-dihydro-2-ethyl-8-methyl-3H-pyrimido- ]5,4-b][1,4]thiazine-4,7-dione of Example 115 (2.7 g, 12.04 mmole) was suspended in approximately 150 ml of phosphorus oxychloride and refluxed for about 20 hours. The solution was concentrated in vacuo and the excess phosphorus oxychloride was decomposed with the careful addition of ice and water. The aqueous solution was neutralized with the cautious addition of concentrated ammonium hydroxide, followed by the addition of sodium bicarbonate. The aqueous solution was extracted numerous times with chloroform; the extracts were combined, washed well with water, then brine, dried over magnesium sulfate, filtered and evaporated in vacuo to provide 2.4 g (83%) of an off-white solid. The structural assignment was confirmed by infrared and nuclear magnetic resonance spectral analyses.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH:14]1[CH2:22][OH:23].[F:24][C:25]1[C:30](=[O:31])[NH:29][C:28]([CH2:32][C:33]([O-])=[O:34])=[N:27][C:26]=1[N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.[Na+].O>CN(C=O)C.N1C=CC=CC=1.ClCCl>[F:24][C:25]1[C:30](=[O:31])[NH:29][C:28]([CH2:32][C:33]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH:14]2[CH2:22][OH:23])=[O:34])=[N:27][C:26]=1[N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)c(F)c(=O)[nH]1
Reactant: OCC1Cc2ccccc2N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: O=C(Cc1nc(N2CCOCC2)c(F)c(=O)[nH]1)N1c2ccccc2CC1CO
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.2 %

Procedure:
198 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 105 mg of (−)-(2,3-dihydro-1H-indol-2-yl)methanol (reference example 8a) are added to a solution of 207 mg of sodium (5-fluoro-4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetate in 6 ml of DMF and 6 ml of pyridine. The reaction medium is stirred at ambient temperature for 18 hours and then a mixture of water and dichloromethane is added. After settling out, the organic phase is dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue obtained is purified on a silica column, eluent: 95/05 dichloromethane/methanol, so as to give 77 mg of 5-fluoro-2-[2-((+)-2-hydroxymethyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one, the characteristics of which are the following:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:38][C:39]([F:52])([F:51])[C:40]1[CH:41]=[C:42]([CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1)[NH2:43]>>[CH3:1][O:2][C:3](=[O:37])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[C:25]([C:33]([F:34])([F:35])[F:36])[CH:24]=2)[CH:12]=[C:13]([NH:43][C:42]2[CH:44]=[C:45]([C:47]([F:48])([F:49])[F:50])[CH:46]=[C:40]([C:39]([F:38])([F:51])[F:52])[CH:41]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:7])[CH3:8]
Reactant: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: COC(=O)C(CC(C)C)c1cc(Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 47 %

Procedure:
The title compound was prepared in 47% yield from 4-methyl-2-(5-trifluoromethanesulfonyloxy-3′,5′-bis-trifluoromethyl-biphenyl-3-yl)-pentanoic acid methyl ester and 3,5-bis-trifluoromethyl-aniline under the conditions described in Example 37, step (b).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8](=[NH:10])[N:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([F:25])=[C:20]([CH:24]=1)[C:21](Cl)=[O:22].C(N(CC)CC)C>C1COCC1.CCOC(C)=O>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:21](=[O:22])[C:20]2[CH:24]=[C:16]([Cl:15])[CH:17]=[CH:18][C:19]=2[F:25])/[N:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Cn1cc(C(C)(C)C)sc1=N
Reactant: O=C(Cl)c1cc(Cl)ccc1F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)Cn1cc(C(C)(C)C)s/c1=N\C(=O)c1cc(Cl)ccc1F

Procedure:
5-tert-Butyl-3-isobutylthiazol-2(3H)-imine (Example 16A, 1.5 g, 7.1 mmol) was dissolved in 10 mL of THF. 5-Chloro-2-fluorobenzoyl chloride (1.4 g, 7.1 mmol) was added then triethylamine (3 mL, 21.6 mmol) and the mixture stirred at room temperature for 3 hours. The reaction was diluted with EtOAc, washed with water, brine, dried over MgSO4, filtered and concentrated under reduced pressure. Purification by flash chromatography using a gradient from 0 to 40% EtOAc in hexanes afforded the title compound. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 0.98 (d, J=6.74 Hz, 6H) 1.36 (s, 9H) 2.19-2.39 (m, 1H) 4.01 (d, J=7.14 Hz, 2H) 6.63 (s, 1H) 7.05 (dd, J=10.31, 8.72 Hz, 1H) 7.35 (ddd, J=8.73, 3.97, 2.78 Hz, 1H) 8.10 (dd, J=6.74, 2.78 Hz, 1H). MS (DCI/NH3) m/z 369.2 (M+H)+.