Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH:11]([OH:20])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:21]=O.OS(O)(=O)=O>C(O)(=O)C>[C:5]1([CH2:4][CH2:3][CH:2]2[CH:11]([CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[O:20][CH2:21][O:1]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: OC(CCc1ccccc1)C(O)CCc1ccccc1
Reactant: C=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: c1ccc(CCC2OCOC2CCc2ccccc2)cc1

Procedure:
The resultant compound of Example 149 was treated with paraformaldehyde and H2SO4 in acetic acid according to the procedure of Hough, et. al. (J. Chem. Soc., 1952, 1525) to provide the desired compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[CH:20]=[C:19]([C:21]([OH:23])=O)[O:18][N:17]=2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:55][CH:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>CN(C=O)C>[O:59]1[CH2:60][CH2:61][CH:56]([NH:55][C:21]([C:19]2[O:18][N:17]=[C:16]([O:15][CH2:14][C:9]3[N:10]([CH3:13])[N:11]=[N:12][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:20]=2)=[O:23])[CH2:57][CH2:58]1
Reactant: NC1CCOCC1
Reactant: Cn1nnc(-c2ccc(F)cc2)c1COc1cc(C(=O)O)on1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nnc(-c2ccc(F)cc2)c1COc1cc(C(=O)NC2CCOCC2)on1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
To a solution of 3-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-isoxazole-5-carboxylic acid (40 mg, 0.13 mmol) and TBTU (64.6 mg, 0.20 mmol) in DMF (2.0 mL) was added DIPEA (106.9 μL, 0.63 mmol). Then 4-aminotetrahydropyran (14 mg, 0.14 mmol) was added and the mixture was stirred at room temperature under Ar for 1 h. The mixture was then evaporated and purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (35 mg, 70%) as a white solid. MS: m/e=402.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17]CC)=[O:16])=[CH:7][C:6]=2[CH:20]=1.[OH-].[Na+]>C1COCC1.C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)[C:5]2[O:10][CH:9]([C:11]([F:12])([F:14])[F:13])[C:8]([C:15]([OH:17])=[O:16])=[CH:7][C:6]=2[CH:20]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(-c3ccc(Cl)cc3)c2OC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)C1=Cc2cc(Cl)cc(-c3ccc(Cl)cc3)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.7 %

Procedure:
The ester from Step 1 (0.500 g, 1.20 mmol) was dissolved in a solution of THF:ethanol:water (7:2:1; 10 mL), treated with sodium hydroxide (0.48 mL, 1.20 mmol of a 2.5 N solution), and stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue was dissolved in water (10 mL). Diethyl ether (10 mL) was added and the mixture acidified with concentrated HCl. The organic layer was separated, and the aqueous phase was extracted with diethyl ether (2×10 mL). The combined extracts were dried over MgSO4, filtered, and evaporated to yield a white solid, which was recrystallized in diethyl ether-hexane to afford the title compound as a white solid (0.40 g, 86%): mp 205.5–207.3° C. 1H NMR (CDCl3/300 MHz) 7.81 (s, 1H), 7.42(s, 4H), 7.34 (d, 1H, J=2.4 Hz), 7.25 (s, 1H), 5.69 (q, 1H, J=6.8 Hz). FABLRMS m/z 387 (M−H) ESHRMS m/z 386.9788 (M−H, Calc'd. 386.980259). Anal. Calc'd. for C17H9Cl2F3O3: C, 52.47; H, 2.33; Cl, 18.22. Found: C, 52.38; H, 2.47; Cl, 18.20.
Reaction SMILES: [Br:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:11]([CH2:12][CH2:13][CH2:14][CH3:15])=[N:10][N:9]([C:16]3[CH:21]=[C:20]([C:22]([O:24]C)=O)[CH:19]=[CH:18][C:17]=3[Cl:26])[C:8]2=[O:27])=[C:4]([F:30])[CH:3]=1.C(Cl)Cl.CO>C(N)CCC>[Br:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:11]([CH2:12][CH2:13][CH2:14][CH3:15])=[N:10][N:9]([C:16]3[CH:21]=[C:20]([C:22](=[O:24])[NH:7][CH2:6][CH2:5][CH2:4][CH3:3])[CH:19]=[CH:18][C:17]=3[Cl:26])[C:8]2=[O:27])=[C:4]([F:30])[CH:3]=1
Reactant: CCCCc1nn(-c2cc(C(=O)OC)ccc2Cl)c(=O)n1Cc1ccc(Br)cc1F
Solvent: ClCCl
Solvent: CO
Solvent: CCCCN
Product: CCCCNC(=O)c1ccc(Cl)c(-n2nc(CCCC)n(Cc3ccc(Br)cc3F)c2=O)c1

Procedure:
A solution of 50 mg (0.10 mmol) of 4-(4-bromo-2-fluorobenzyl)-5-n-butyl-2-[2-chloro-5-(methoxycarbonyl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step D) in 1 mL of n-butylamine was stirred overnight at 65° C. and then evaporated in vacuo. The residue was flash chromatographed on 15 cc of silica gel (gradient elution with 1-5% MeOH in CH2Cl2) to yield 41 mg (76%) of colorless, glassy solid, mp 114°-116° C.; homogeneous by TLC (95:5 CH2Cl2 --MeOH); mass spectrum (FAB) M/e 537, 539 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[F:17][C:18]([F:30])([F:29])[O:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>>[F:17][C:18]([F:29])([F:30])[O:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:23]
Reactant: O=C(Cl)c1ccccc1OC(F)(F)F
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3ccccc3OC(F)(F)F)c2)CC1

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and 2-(trifluoromethoxy)benzoyl chloride (37 μL, 0.229 mmol) and mixing for 24 h, 49.8 mg (>100%) of the title compound were recovered.
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH3:36])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:24][CH2:23]2)[C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH3:37][N:38](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.CO>[CH2:1]([N:3]([CH2:35][CH3:36])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:24][CH2:23]2)[C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([NH:38][CH3:37])=[O:18])=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCN(CC)C(=O)c1ccc(C(c2cccc(C(=O)O)c2)N2CCN(Cc3ccccc3)CC2)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1ccc(C(c2cccc(C(=O)NC)c2)N2CCN(Cc3ccccc3)CC2)cc1
Reaction time: 0.5 h

Procedure:
To a solution INTERMEDIATE 9 (0.120 mg, 0.25 mmol)) in 2 ml of DMF was added HATU (0.132 mg, 0.35 mmol) and diisopropylethylamine (173 μL, 0.99 mmol). The reaction was stirred for 30 minutes, after which was added (250 μL, 0.50 mmol) of 2 N HNCH3 in MeOH and the stirring continued over night. The reaction was concentrated and partitioned between a saturated solution of NaHCO3 and ethyl acetate. The organic layer was separated and the aqueous layer extracted 5 times with ethyl acetate. The organic layers were dried (MgSO4), filtered and concentrated to yield COMPOUND 3. 1H NMR (400 NM, CD3OD): δ 1.07 (m, 3H), 1.21 (m, 3H), 2.32 (m, 2H), 2.90 (s, 3H), 3.02 (m, 2H), 3.24 (m, 4H), 3.40 (m, 2H), 3.50 (m, 2H), 4.34 (s, 2H), 4.55 (s, 1H), 7.33 (d, J=8.2 Hz, 2 H), 7.41 (m, 1H), 7.48 (m, 5H), 7.56 (d, J=8.2 Hz, 2H), 7.63 (m, 2H), 7.93 (m, 1H)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].[C:13](Cl)(=O)C>CO>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([O:7][CH3:13])=[O:6]
Reactant: CC(=O)Cl
Reactant: COc1ccc(C(=O)O)cc1N
Solvent: CO
Product: COC(=O)c1ccc(OC)c(N)c1
Temperature: 25 °C
Yield: 88.4 %

Procedure:
A 1 L 3-necked round bottomed flask equipped with a nitrogen inlet, stirbar, addition funnel and thermocouple was charged with 3-amino-4-methoxy benzoic acid (50 g, 0.299 mol) and methanol (300 mL). The system was cooled to 0 C and acetyl chloride (30 mL, 0.42 mol) was added dropwise. The system was warmed to room temperature, the addition funnel was replaced with a reflux condenser, and was heated to reflux for 1.5 h. The reaction mixture was cooled to room temperature, quenched with saturated aqueous NaHCO3, and extracted with ethyl acetate. The organic extract was washed with brine, dried with Na2SO4 and concentrated in vacuo to give methyl 3-amino-4-methoxybenzoate as a dark solid (47.9 g, 88%). 1H NMR (400 MHz, CD3OD) δ 7.40 (t, J=268 Hz, 1H), 7.37 (t, J=2.0 Hz, 1H), 6.86 (d, J=8.8 Hz, 1H), 3.98 (s, 3H), 3.81 (s, 3H) ppm. ES-HRMS m/z 182.0826 (M+H calcd for C9H12ClNO3 requires 182.0812).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4([C:26]([F:29])([F:28])[F:27])[CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[N:13]=2)=[N:7]1.[C:33]([CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)#[N:34]>>[CH3:11][C:10]1[N:6]([CH2:5][C:4]2[CH:3]=[C:2]([N:38]3[CH2:39][CH2:40][CH:35]([C:33]#[N:34])[CH2:36][CH2:37]3)[CH:32]=[CH:31][CH:30]=2)[N:7]=[C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4([C:26]([F:29])([F:28])[F:27])[CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[N:13]=2)[CH:9]=1
Reactant: N#CC1CCNCC1
Reactant: Cc1cc(-c2nc(-c3ccc(C4(C(F)(F)F)CC4)cc3)no2)nn1Cc1cccc(Br)c1
Product: Cc1cc(-c2nc(-c3ccc(C4(C(F)(F)F)CC4)cc3)no2)nn1Cc1cccc(N2CCC(C#N)CC2)c1

Procedure:
Analogously to the process described in Example 9, 50 mg (0.099 mmol) of the compound from Example 2A and 22 mg (0.199 mmol) of 4-cyanopiperidine were used to obtain 23 mg (43% of theory) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:11](=[O:12])[CH:10]2[C:5](=[C:6]3[N:16]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][C:18]=4[O:25][CH3:26])[N:14]=[C:7]3[C:8](=[O:13])[CH2:9]2)[CH:4]=[N:3]1.[OH:28]O>C(O)(=O)C.O.N>[CH3:1][C:2]1([CH3:27])[C:11](=[O:12])[CH:10]2[C:5](=[C:6]3[N:16]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([S:23]([CH3:24])=[O:28])=[CH:19][C:18]=4[O:25][CH3:26])[N:14]=[C:7]3[C:8](=[O:13])[CH2:9]2)[CH:4]=[N:3]1
Reactant: OO
Reactant: COc1cc(SC)ccc1C1=NC2=C3C=NC(C)(C)C(=O)C3CC(=O)C2=N1
Agent: N
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(S(C)=O)ccc1C1=NC2=C3C=NC(C)(C)C(=O)C3CC(=O)C2=N1
Reaction time: 50 h

Procedure:
5.1 gm of 7,7-dimethyl-2-(2-methoxy-4-methylmercapto-phenyl)-5H,7H-imidazo[4,5-h]isoquinoline-4,6-dione were reacted in 100 ml of 70% acetic acid with 1.7 gm of 30% hydrogen peroxide, and the mixture was allowed to stand for 50 hours at room temperature (the first 3 hours while stirring). After 18 and again after 26 hours 1.3 gm of 30% hydrogen peroxide were added. The reaction mixture was then diluted with water, and ammonia was added until alkaline reaction. The precipitate was suction-filtered off and the filtrate was extracted twice with chloroform. The combined chloroform phases were evaporated, and the evaporation residue was combined with the precipitate. The thus obtained product was purified on a silicagel column (eluant: chloroform/acetone 19:1).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:38])[CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][NH:19][C:20]([C:22]3[CH:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[O:24][C:23]=3[C:34]([F:37])([F:36])[F:35])=[O:21])[CH:14]=2)[CH:9]=1.O.Cl>C1COCC1>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:25]2[O:24][C:23]([C:34]([F:36])([F:35])[F:37])=[C:22]([C:20]([NH:19][CH2:18][C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[CH:9]=[C:8]([O:7][CH2:6][C:5]([OH:38])=[O:4])[CH:17]=[CH:16]4)=[O:21])[CH:26]=2)=[CH:32][CH:31]=1
Reactant: COC(=O)COc1ccc2cc(CNC(=O)c3cc(-c4ccc(Cl)cc4)oc3C(F)(F)F)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)COc1ccc2cc(CNC(=O)c3cc(-c4ccc(Cl)cc4)oc3C(F)(F)F)ccc2c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 91.9 %

Procedure:
1 N NaOH (324 μL, 0.32 mmol) was added under nitrogen to a solution at room temperature of [6-({[5-(4-chloro-phenyl)-2-trifluoromethyl-furan-3-carbonyl]-amino}-methyl)-naphthalen-2-yloxy]-acetic acid methyl ester (140 mg, 0.27 mmol), prepared in the previous step, in 15 mL of THF plus 8 mL of water. After the addition the reaction was stirred at room temperature for 7 h. The reaction was acidified with 1 N HCl and then concentrated under reduced pressure to remove the THF. The solid present was collected by filtration and dried under reduced pressure to give the title compound (125 mg, 91%) as an off-white solid, mp 194-196° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[S:8])[NH:6][CH:7]=1.[CH3:9][C:10](C)([O-:12])[CH3:11].[K+].C(C1OC1)I>CN(C=O)C>[O:12]1[CH2:11][CH:10]1[CH2:9][S:8][C:5]1[N:6]=[CH:7][C:2]([Cl:1])=[CH:3][N:4]=1
Reactant: S=c1ncc(Cl)c[nH]1
Reactant: CC(C)(C)[O-]
Agent: ICC1CO1
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cnc(SCC2CO2)nc1
Yield: 29 %

Procedure:
A mixture of 5-chloropyrimidine-2-thione (6.9 mmol) and potassium tert-butoxide (6.9 mmol) was stirred together in anhydrous DMF (40 ml) for 5 min before epiiodohydrin (6.9 mmol) was added. The mixture was stirred at 80° C. for 7 h while small portions of potassium tert-butoxide were added from time to time to maintain a strong basic solution. The solvent was then removed at reduced pressure, the residue triturated with water (50 ml), the insoluble material extracted with chloroform and the dried (MgSO4) chloroform solution evaporated leaving the oily sulfide, yield 29%. This material was chromatographically homogenous and was identified by its spectroscopic properties. 1H NMR (CDCl3): δ2.6-3.4 (5H, m), 8.50 (H-4, H-6).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([CH3:13])[CH:5]=[C:6]2[CH2:11][CH2:10][O:9][C:8](=[O:12])[C:7]=12.[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>C(O)C>[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:2]2[N:3]=[C:4]([CH3:13])[CH:5]=[C:6]3[CH2:11][CH2:10][O:9][C:8](=[O:12])[C:7]=23)=[CH:17][CH:16]=1
Reactant: Cc1cc2c(c(Cl)n1)C(=O)OCC2
Reactant: Nc1ccc(F)cc1
Solvent: CCO
Product: Cc1cc2c(c(Nc3ccc(F)cc3)n1)C(=O)OCC2
Temperature: 80 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
8-chloro-6-methyl-3,4-dihydro-pyrano[3,4-c]pyridine-1-on (200 mg, 1.012 mmol) was dissolved in 5 mL of ethanol and then added with 4-fluoroaniline (224.9 mg, 2.024 mmol) and stirred at 80° C. overnight. The mixture was concentrated under reduced pressure. A silica gel column chromatography (20% EtOAc/Hexane) was performed on the resulting residue and 250 mg (90%) of 8-(4-fluoro-phenylamino)-6-methyl-3,4-dihydro-pyrano[3,4-c]pyridine-1-on was obtained in pale yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([C:15]#[N:16])([O:13][CH3:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Ni]>[NH2:16][CH2:15][C:10]1([O:13][CH3:14])[CH2:11][CH2:12][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9]1
Reactant: COC1(C#N)CCN(Cc2ccccc2)C1
Agent: [Ni]
Product: COC1(CN)CCN(Cc2ccccc2)C1

Procedure:
The solution of 26.5 g (0.11 mol, 93% proof) 1-benzyl-3-cyano-3-methoxypyrrolidine in 300 ml methanole is hydrogenated at 15 g Raney-Ni at 60° C./100 bar H2. The catalyst is removed by filtration, the methanol is removed in vacuo, and the residue is destilled.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6](Br)[N:7]=1.[CH3:11][S:12]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)(=[O:14])=[O:13].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([S:12]([CH3:11])(=[O:14])=[O:13])[CH:20]=2)[N:7]=1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cn1cc(Br)nc(N)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2cccc(S(C)(=O)=O)c2)nc(N)c1=O
Yield: 17.9 %

Procedure:
A solution of 3-amino-5-bromo-1-methylpyrazin-2-one (81.0 mg, 0.4 mmol), (3-methylsulfonylphenyl)boronic acid (120.0 mg, 0.6 mmol), Cs2CO3 (391.0 mg, 1.2 mmol), Pd(PPh3)4 (20.0 mg, 0.017 mmol) in dioxane (20.0 mL) and water (2.0 mL) was stirred at 95° C. for 12 h under N2. The mixture was concentrated and purified by silica gel chromatography (PE: EA=3:2) to give the title compound (20.0 mg, 18%). 1H NMR (DMSO-d6 400 MHz): δ 8.35 (s, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.73 (s, 1H), 7.66 (t, J=8.0 Hz, 1H), 6.93 (brs, 2H), 3.50 (s, 3H), 3.24 (s, 3H). LCMS (M+H)+ 280.
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:5]=[C:6]([OH:20])[C:7]2[C:16]([CH:17]=1)=[CH:15][C:14]1[C:9](=[CH:10][C:11]([C:18]#[N:19])=[CH:12][CH:13]=1)[CH:8]=2)=[O:3].C(N(CC)CC)C.O1CCCC1.[P:33](=[O:49])(Cl)([S:44][CH2:45][CH2:46][CH3:47])[O:34][C:35]1[C:40]([Cl:41])=[CH:39][C:38]([Cl:42])=[CH:37][C:36]=1[CH3:43]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[P:33](=[O:49])([S:44][CH2:45][CH2:46][CH3:47])([O:20][C:6]1[C:7]2[C:16](=[CH:15][C:14]3[C:9]([CH:8]=2)=[CH:10][C:11]([C:18]#[N:19])=[CH:12][CH:13]=3)[CH:17]=[C:4]([S:2]([CH3:1])=[O:3])[CH:5]=1)[O:34][C:35]1[C:40]([Cl:41])=[CH:39][C:38]([Cl:42])=[CH:37][C:36]=1[CH3:43]
Reactant: CCCSP(=O)(Cl)Oc1c(C)cc(Cl)cc1Cl
Reactant: CS(=O)c1cc(O)c2cc3cc(C#N)ccc3cc2c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCSP(=O)(Oc1c(C)cc(Cl)cc1Cl)Oc1cc(S(C)=O)cc2cc3ccc(C#N)cc3cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Methylsulfinyl-7-cyano-1-anthrol (0.01 mole), triethylamine (0.01 mole), tetrahydrofuran (25 ml) and toluene (25 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The mixture is cooled to a temperature of about 0° C. and O-(2-methyl-4,6-dichlorophenyl) S-propyl phosphorochloridothioate (0.01 mole) dissolved in toluene (25 ml) is added with stirring over a period of about 30 minutes. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 16 hours. After this time the reaction mixture is filtered to remove triethylamine hydrochloride. The filtrate is then washed with water, dried over anhydrous magnesium sulfate and stripped of solvents leaving a residue. This residue is subjected to flash chromatography using ethyl acetate as the eluant to yield the desired product O-(2-methyl-4,6-dichlorophenyl) O-(3-methylsulfinyl-7-cyano-1-anthryl) S-propyl phosphorothioate.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:4][CH:5]=[CH:6][C:7](=[O:10])[C:8]=1[OH:9].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[OH:1][CH2:2][C:3]1[O:4][CH:5]=[CH:6][C:7](=[O:10])[C:8]=1[O:9][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: O=c1ccoc(CO)c1O
Product: O=c1ccoc(CO)c1OCc1ccccc1

Procedure:
The title compound was prepared by the method outlined for 2-hydroxymethyl-3-benzyloxy-6-methyl-pyran-4(1B)-one, using 7.1 g (50 mmol, 1 eq.) of 2-hydroxymethyl-3-hydroxy-pyran-4(1 H)-one and 9.5 g benzyl bromide (55 mmol, 1.1 eq.) to yield the crude product as an organe oil. Further purification by column chromatography on silica gel (eluant: 10% CH3OH/90% CHCl3) furnished the pure product (9.4 g, 81%) as a bright yellow oil. (Looker and Clifton (1986).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([NH:7][C:8]2[S:9][C:10]3[N:18]=[CH:17][CH:16]=[CH:15][C:11]=3[C:12](=[O:14])[N:13]=2)=[CH:5][CH:4]=1.[H-].[Li+].[CH2:23](I)[CH2:24][CH3:25]>>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([N:7]=[C:8]2[N:13]([CH2:23][CH2:24][CH3:25])[C:12](=[O:14])[C:11]3[CH:15]=[CH:16][CH:17]=[N:18][C:10]=3[S:9]2)=[CH:5][CH:4]=1
Reactant: CCCI
Reactant: COc1ccc(Nc2nc(=O)c3cccnc3s2)cc1
Agent: [H-]
Agent: [Li+]
Product: CCCn1c(=Nc2ccc(OC)cc2)sc2ncccc2c1=O

Procedure:
The reaction procedure of Example 11 was followed except that 428 mg of 2-(4-methoxyanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 14 mg of lithium hydride and 0.15 ml of propyl iodide were used. As a result, 227 mg of 2-[(4-methoxyphenyl)imino]-3-propyl-2,3-dihydro-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained as a low polarity substance, and 78 mg of 2-[N-(4-methoxyphenyl)-N-propylamino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained as a high polarity substance.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:9][C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[C:15]([OH:19])=[C:14]([CH3:20])[CH:13]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:29][OH:30].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:9]/[C:10](/[C:12]2[CH:17]=[C:16]([CH3:18])[C:15]([OH:19])=[C:14]([CH3:20])[CH:13]=2)=[N:29]\[OH:30])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1ccccc1C(CC(=O)c1cc(C)c(O)c(C)c1)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1cc(C)c(O)c(C)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 151, step 3, 3-(4-bromo-phenyl)-1-(4-hydroxy-3,5-dimethyl-phenyl)-3-o-tolyl-propan-1-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing less than 10% of the corresponding Z isomer as an off-white solid, MS (ESI+): m/z=436.2 [M−H]−.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12].[OH-].[K+].CCOCC>CN(C)C(=O)C.CO.C1(C)C=CC=CC=1>[C:11]([CH:13]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])[C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: CCOC(=O)CC#N
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Solvent: CO
Product: CCOC(=O)C(C#N)c1ccccc1[N+](=O)[O-]
Yield: 73.2 %

Procedure:
A mixture of 2-chloronitrobenzene (47.2 g, 0.300 mole) and ethyl cyanoacetate (40 ml, 0.38 mol) in N,N-dimethylacetamide (DMA, 250 ml) was treated at once with potassium hydroxide pellets (120 g, 2.14 mole). The mixture was mechanically stirred and heated for ten minutes at 110°-120° C. (caution: minimal heat application may be needed, exothermic reaction) then poured into ice-cold dilute hydrochloric acid. Ether extractive workup gave an oil. The oil was passed through silica gel eluting with toluene to provide a yellow oil, which was dissolved in 100 ml methanol then chilled. The solid was filtered to afford ethyl cyano-2-nitrophenylacetate as a yellow solid (51.4 g, 73.2%) mp 57°-61° C. (literature 59°-60° C.).
Reaction SMILES: C(OC(=O)[NH:10][C:11]1([CH3:23])[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:13][CH2:12]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)(C)C.[Pd]>[CH3:23][C:11]1([NH2:10])[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:13][CH2:12]1
Reactant: CC1(NC(=O)OCc2ccccc2)CCN(c2ccccn2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(C)O
Product: CC1(N)CCN(c2ccccn2)CC1
Temperature: 150 °C

Procedure:
To a stirred solution of (4-methyl-3,4,5,6-tetrahydro-2H-(1,2′)bipyridinyl-4-yl)-carbamic acid benzyl ester (0.06 g, 0.185 mmol) in isopropanol (1.8 mL) at room temperature was added ammonium formate (0.047 g, 0.75 mmol) and 5 mg of 10% Pd/C under nitrogen. The reaction mixture was heated under microwave conditions at 150° C. for 30 minutes, cooled, filtered through Celite and concentrated under reduced pressure to provide the titled compound. MS (CI) m/z 192 (M+1).