Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:30]=[CH:29][C:12]([CH2:13][N:14]2[CH:18]=[C:17]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:26][CH2:27][CH3:28])=[N:15]2)=[CH:11][C:10]=1[O:31][CH3:32])C1C=CC=CC=1.C(O)C>[C].[Pd].O1CCCC1>[CH2:27]([O:26][C:16]1[C:17]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:18][N:14]([CH2:13][C:12]2[CH:29]=[CH:30][C:9]([OH:8])=[C:10]([O:31][CH3:32])[CH:11]=2)[N:15]=1)[CH3:28]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3ccccc3)c(OC)c2)nc1OCC
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CCc1cn(Cc2ccc(O)c(OC)c2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
A mixture of ethyl 3-[1-(4-benzyloxy-3-methoxybenzyl)-3-ethoxy-1H-pyrazol-4-yl]propionate (2.92 g), 5% palladium-carbon (6.00 g), ethanol (20 ml), and tetrahydrofuran (20 ml) was stirred at room temperature for one hour under a hydrogen atmosphere. After removal of the catalyst by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-ethoxy-1-(4-hydroxy-3-methoxybenzyl)-1H-pyrazol-4-yl]propionate (2.04 g, yield: 89%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH3:23])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)(=[O:12])=[O:11])=O.O.[NH2:25][NH2:26]>C(O)C>[N:25](=[CH:1][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH3:23])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[NH2:26]
Reactant: NN
Reactant: CN(c1ccccc1C=O)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Solvent: CCO
Solvent: O
Product: CN(c1ccccc1C=NN)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
A solution of N-(2-formylphenyl)-N-methyl-4-(trifluoromethyl)benzenesulfonamide (0.40 g, 1.2 mmol) in ethanol (13 mL) is treated with hydrazine monohydrate (69 □L, 1.6 mmol). The reaction is stirred at rt overnight. The reaction is concentrated, taken up in ether-hexane, filtered and evaporated. An 87% yield (0.37 g) of N{2-[hydrazonomethyl]phenyl}-N-methyl-4-(trifluoromethyl)benzenesulfonamide is obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:36]=[CH:35][CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:32]=[CH:31][C:17]([C:18]([N:20]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[CH:16][CH:15]=1)=[O:12].[OH-].[Na+].[C:39](OC(=O)C)(=[O:41])[CH3:40]>S(=O)(=O)(O)O>[C:39]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:36]=[CH:35][CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:32]=[CH:31][C:17]([C:18]([N:20]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[CH:16][CH:15]=1)=[O:12])(=[O:41])[CH3:40]
Reactant: NCCCCCCOc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)NCCCCCCOc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1-{4-[2-(6-aminohexyloxy)benzoylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.70 g), acetic anhydride (20 ml) and two drops of conc. sulfuric acid is stirred at room temperature for 3 hours. To the reaction mixture is added aqueous 2N aqueous sodium hydroxide solution under ice-cooling and the mixture is extracted with chloroform. The organic layer is washed successively with water and saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; chloroform:methanol=200:1), and recrystallized from methanol/diethyl ether to give 1-{4-[2-(6-acetylaminohexyloxy)benzoylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.60 g) as colorless needles, m.p. 171°-172° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[S:6][C:5]2[CH:7]=[C:8]3[S:12][C:11]([CH3:14])([CH3:13])[S:10][C:9]3=[CH:15][C:4]=2[S:3]1.[CH2:17]([Li])[CH2:18][CH2:19][CH3:20].C[O:23][C:24]([C:26]1[C:36]2[O:37][C:38]([CH3:41])([CH3:40])[O:39][C:35]=2[CH:34]=[C:28]2[O:29][C:30]([CH3:33])([CH3:32])[O:31][C:27]=12)=O>C1COCC1>[CH3:13][C:11]1([CH3:14])[S:10][C:9]2[C:15]([C:24]([C:17]3[C:5]4[S:6][C:2]([CH3:16])([CH3:1])[S:3][C:4]=4[CH:20]=[C:19]4[S:12][C:11]([CH3:13])([CH3:14])[S:10][C:18]=34)([C:26]3[C:27]4[O:31][C:30]([CH3:32])([CH3:33])[O:29][C:28]=4[CH:34]=[C:35]4[O:39][C:38]([CH3:40])([CH3:41])[O:37][C:36]=34)[OH:23])=[C:4]3[S:3][C:2]([CH3:16])([CH3:1])[S:6][C:5]3=[CH:7][C:8]=2[S:12]1
Reactant: [Li]CCCC
Reactant: COC(=O)c1c2c(cc3c1OC(C)(C)O3)OC(C)(C)O2
Reactant: CC1(C)Sc2cc3c(cc2S1)SC(C)(C)S3
Solvent: C1CCOC1
Product: CC1(C)Oc2cc3c(c(C(O)(c4c5c(cc6c4SC(C)(C)S6)SC(C)(C)S5)c4c5c(cc6c4SC(C)(C)S6)SC(C)(C)S5)c2O1)OC(C)(C)O3
Reaction time: 1 h
Yield: 44 %

Procedure:
2,2,6,6-Tetramethylbenzo[1,2-d:4,5-d']bis(1,3)dithiole (2.86 g, 10 mmol; prepared according to WO-91/12024) was dissolved in anhydrous THF (75 mL) and cooled to -70° C. n-Butyllithium (4.4 mL, 2.5M in hexane) was added. The reaction mixture was allowed to reach ambient temperature. 4-Methoxycarbonyl-2,2,6,6-tetramethylbenzo[1,2-d:4,5-d']-bis-(1,3)-dioxole (1.4 g, 5 mmol) was added as a solid. After 1 hour, the mixture was quenched with saturated aqueous NaH2PO4. The aqueous phase was discarded and the organic layer evaporated. The residue was dissolved in dichloromethane, washed with water and dried (Na2SO4). The product was purified by column chromatography (dichloromethane:heptane, 1:1) giving 1.8 g (44%) of pure product.
Reaction SMILES: [S:1]1[C:5]2=[N:6][CH:7]=[CH:8][N:9]=[C:4]2[C:3]([NH:10][CH2:11][CH2:12][CH2:13][NH2:14])=[N:2]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([CH:29]=O)=[CH:25][CH:24]=2)=[CH:19][CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[S:1]1[C:5]2=[N:6][CH:7]=[CH:8][N:9]=[C:4]2[C:3]([NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:29][C:26]2[CH:25]=[CH:24][C:23]([C:20]3[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)=[CH:28][CH:27]=2)=[N:2]1
Reactant: NCCCNc1nsc2nccnc12
Reactant: COc1ccc(-c2ccc(C=O)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc(-c2ccc(CNCCCNc3nsc4nccnc34)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.6 %

Procedure:
N1-(Isothiazolo[5,4-b]pyrazin-3-yl)propane-1,3-diamine (410 mg, 1.96 mmol) and 4′-methoxybiphenyl-4-carbaldehyde (410 mg, 1.96 mmol) were combined in 1,2-dichloroethane (8 mL) and treated with sodium triacetoxyborohydride (506 mg, 2.35 mmol). The mixture was shaken at room temperature for 3 h. The reaction was diluted with methylene chloride, quenched with water and the layers were separated. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography, on silica gel, eluting with methylene chloride:methanol to yield N1-(isothiazolo[5,4-b]pyrazin-3-yl)-N3-((4′-methoxybiphenyl-4-yl)methyl)propane-1,3-diamine (100 mg) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): 8.79 (d, 1H), 8.72 (d, 1H), 7.90 (t, 1H), 7.54 (m, 4H), 7.40 (d, 2H), 6.98 (d, 2H), 3.82 (s, 2H), 3.80 (s, 3H), 3.48 (t, 2H), 2.70 (m, 3H), 1.85 ppm (m, 2H). MW=405 confirmed by LC-MS, tr=9.59 min (Method Y) MH+=404-406.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([Cl:10])=[CH:8][C:7](N)=[CH:6][C:5]=1[Cl:12].N([O-])=[O:15].[Na+].O>Cl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([OH:15])=[CH:6][C:5]=1[Cl:12]
Reactant: O=N[O-]
Reactant: COC(=O)c1c(Cl)cc(N)cc1Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)c1c(Cl)cc(O)cc1Cl
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
4-Amino-2,6-dichlorobenzoic acid methyl ester (0.5 g) was suspended in 20% HCl (25 mL) and stirred for 30 min then cooled to 0-5° C. After slow addition of NaNO2 (188 mg), the mixture was stirred for 30 min at that temperature and added to boiling water (50 mL). The mixture was then refluxed for 2 h, allowed to cool to room temperature and extracted with AcOEt, dried (MgSO4), filtered and evaporated. The residue was purified by preparative TLC (silica gel; eluent: CH2Cl2) to give 2,6-dichloro-4-hydroxybenzoic acid methyl ester (275 mg).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.O.C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc2c(c1)CCCC2
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc2ccccc2c1
Yield: 67 %

Procedure:
Tetralin (1,2,3,4-tetrahydronaphthalene) reacts quantitatively) with water under the standard condition to give 22% benzene, 6% toluene, 67% naphthalene, and the rest to gases. The exit gas composition was 77% H2, 19% CO2, 3% CO, and 2% CH4. By raising the reaction temperature to 550° C., the yield of benzene increases to 49%, while the amount of naphthalene decreases to 10%.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.[OH:16][C@@H:17]([C@H:19]1[CH2:23][N:22]([C@@H:24]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH3:25])[C:21](=[O:34])[CH2:20]1)[CH3:18].[Cl:35][C:36]1[N:41]=[C:40](S(C)(=O)=O)[C:39]2[N:46]([CH3:49])[CH:47]=[N:48][C:38]=2[CH:37]=1>CN(C=O)C>[Cl:35][C:36]1[N:41]=[C:40]([O:16][C@@H:17]([C@H:19]2[CH2:23][N:22]([C@@H:24]([C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)[CH3:25])[C:21](=[O:34])[CH2:20]2)[CH3:18])[C:39]2[N:46]([CH3:49])[CH:47]=[N:48][C:38]=2[CH:37]=1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)O)CC2=O)cc1
Reactant: Cn1cnc2cc(Cl)nc(S(C)(=O)=O)c21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(Cl)cc4ncn(C)c34)CC2=O)cc1
Temperature: 25 °C
Reaction time: 0.3 h

Procedure:
A solution of NaHMDS in THF (1.0 M, 1.05 mL, 1.05 mmol) was added to a solution of (R)-4-((R)-1-hydroxyethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 1.04 (277 mg, 1.05 mmol) in DMF (14 mL) at room temperature. After 18 minutes, a suspension of 6-chloro-3-methyl-4-(methylsulfonyl)-3H-imidazo[4,5-c]pyridine 2.04 (237 mg, 0.967 mmol) in DMF (4 mL) was added and mixture stirred at room temperature. After 40 minutes, LC/MS indicated full conversion to desired product. Reaction mixture was quenched with 15 mL of water, poured into 30 mL of water and extracted with ethyl acetate (3×50 mL). Combined organics were washed with 50% Brine (2×50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to a residue. This residue was purified by silica gel column chromatography (0-10% methanol in dichloromethane) to yield (R)-4-((R)-1-(6-chloro-3-methyl-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 2.05.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([O:4][C:5]([NH:7][C@H:8]1[CH2:12][CH2:11][N:10](C(OCC2C=CC=CC=2)=O)[CH2:9]1)=[O:6])[CH3:3].[H][H]>CO.[Pd]>[CH3:3][C:2]([CH3:23])([O:4][C:5]([NH:7][C@H:8]1[CH2:12][CH2:11][NH:10][CH2:9]1)=[O:6])[CH3:1]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CCNC1
Yield: 98.2 %

Procedure:
A solution of 17.7 g (55.2 mmol) of (S)-3-[[(1,1-dimethylethoxy)carbonyl]amino]-1-pyrrolidinecarboxylic acid, phenylmethyl ester, in 400 ml of methanol was treated with 2.0 g of 20% palladium on carbon and shaken in an atmosphere of hydrogen at temperatures of 22°-26.5° and pressures of 45-50.5 psi for one hour. The solvent was removed in vacuo to give 10.1 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][C@H:5]1[CH2:9][CH2:8][C@@H:7](O)[CH2:6]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:32]>C(Cl)Cl>[Br:32][C@H:7]1[CH2:8][CH2:9][C@H:5]([CH2:4][C:3]([O:2][CH3:1])=[O:11])[CH2:6]1
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)C[C@H]1CC[C@@H](O)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C[C@H]1CC[C@H](Br)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
To (1S,3R)-(3-hydroxy-cyclopentyl)acetic acid methyl ester (2.0 g, 12.6 mmol) in 10 mL of DCM at 0° C. was added PPh3 (3.49 g, 13.3 mmol, 1.05 eq.), followed by CBr4 (4.41 g, 13.3 mmol, 1.05 eq.) slowly. The mixture was stirred at room temperature overnight. The reaction mixture was filtered through a thin layer silica gel and the filtrate was concentrated down. The residue was purified by silica gel chromatography with (15% EtOAc in hexanes) to provide 1.96 g of methyl 2-((1R,3S)-3-bromocyclopentyl)acetate 101.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1Br.[C:14]([Cu])#[N:15].[C-:17]#[N:18].[Na+]>CN(C)C=O.O>[F:12][C:4]1[C:5]([O:10][CH3:11])=[C:6]([O:8][CH3:9])[CH:7]=[C:2]([C:17]#[N:18])[C:3]=1[C:14]#[N:15]
Reactant: COc1cc(Br)c(Br)c(F)c1OC
Reactant: [C-]#N
Reactant: N#C[Cu]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C#N)c(C#N)c(F)c1OC
Yield: 45.8 %

Procedure:
After dissolving the 1,2-dibromo-3-fluoro-4,5-dimethoxybenzene (40 g, 0.127 mol) in dimethylformamide (300 ml), CuCN (34.1 g, 0.381 mol) was added at room temperature while stirring and the mixture was stirred at 150° C. for 4 hours. After cooling on ice, a solution of sodium cyanide (44 g) in water (600 ml) was added and the mixture was stirred at room temperature for 10 minutes, after which extraction was performed with ethyl acetate (500 ml×3) and then after washing the combined organic layers with brine (500 ml) and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (white crystals 12.0 g, 46%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:14]([NH:15][C@H:16]([CH:21]4[CH2:23][CH2:22]4)[C:17]([F:20])([F:19])[F:18])=[N:13][CH:12]=[C:11]([C:24]#[N:25])[C:7]=3[NH:8][C:9]=2[CH:10]=1.C(=O)([O-])[O-:27].[K+].[K+].CS(C)=O.OO>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:14]([NH:15][C@H:16]([CH:21]4[CH2:22][CH2:23]4)[C:17]([F:18])([F:20])[F:19])=[N:13][CH:12]=[C:11]([C:24]([NH2:25])=[O:27])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: N#Cc1cnc(N[C@H](C2CC2)C(F)(F)F)c2c1[nH]c1cc(Cl)ccc12
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: NC(=O)c1cnc(N[C@H](C2CC2)C(F)(F)F)c2c1[nH]c1cc(Cl)ccc12
Temperature: 80 °C

Procedure:
7-Chloro-1-{[(1R)-1-cyclopropyl-2,2,2-trifluoroethyl]amino}-5H-pyrido[4,3-b]indole-4-carbonitrile (4.48 g, 12.3 mmol) and potassium carbonate (8.49 g, 61.4 mmol) were placed in a flask. DMSO (246 ml) and 30% hydrogen peroxide (12.55 ml, 123 mmol) were added and the solution heated at 80° C. for 2 h. Additional 30% hydrogen peroxide (12.55 mL, 123 mmol) and potassium carbonate (8.49 g, 61.4 mmol) were added. The resultant mixture was heated to 80° C. for 2 h, cooled to room temperature, and diluted with EtOAc. The mixture was washed with water and brine, dried (magnesium sulfate), concentrated, and purified by flash chromatography to give the title compound. 1H NMR (600 MHz, CD3SOCD3) δ 11.81 (s, 1H); 8.54 (s, 1H); 8.50 (d, 1H); 7.96 (br s, 1H); 7.80 (d, 1H); 7.33 (br s, 1H); 7.30 (dd, 1H); 7.07 (d, 1H); 4.86 (m, 1H); 1.59 (m, 1H); 0.76 (m, 1H); 0.64 (m, 1H); 0.54 (m, 1H); 0.33 (m, 1H). LRMS (APCI) calc'd for (C17H14ClF3N4O) [M+H]+, 383.1. found 383.0.
Reaction SMILES: C(OC(=O)COC1C=C(C)C(SC2C=CC(C[NH:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=CC=2C)=CC=1C)C.[CH2:36]([O:38][C:39](=[O:62])[CH2:40][O:41][C:42]1[C:51]2[CH2:50][CH2:49][CH2:48][CH2:47][C:46]=2[C:45]([S:52][C:53]2[CH:58]=[CH:57][C:56]([CH:59]=O)=[CH:55][C:54]=2[Cl:61])=[CH:44][CH:43]=1)[CH3:37]>>[CH2:36]([O:38][C:39](=[O:62])[CH2:40][O:41][C:42]1[C:51]2[CH2:50][CH2:49][CH2:48][CH2:47][C:46]=2[C:45]([S:52][C:53]2[CH:58]=[CH:57][C:56]([CH2:59][NH:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:25][CH:24]=3)=[CH:55][C:54]=2[Cl:61])=[CH:44][CH:43]=1)[CH3:37]
Reactant: CCOC(=O)COc1ccc(Sc2ccc(C=O)cc2Cl)c2c1CCCC2
Reactant: CCOC(=O)COc1cc(C)c(Sc2ccc(CNc3ccc(C(F)(F)F)cc3)cc2C)cc1C
Product: CCOC(=O)COc1ccc(Sc2ccc(CNc3ccc(C(F)(F)F)cc3)cc2Cl)c2c1CCCC2

Procedure:
The title compound was prepared according to the method described for preparing compound 21.5, using compound 22.4 as the starting material. 1H NMR (300 MHz) (CDCl3) δ 7.38 (2H, d, J=8.6 Hz); 7.34 (1H, d, J=8.6 Hz); 7.33 (1H, s); 6.99 (1H, dd, J=1.5, 7.9 Hz); 6.58 (3H, d, J=7.1 Hz); 6.49 (1H, d, J=8.2 Hz); 4.67 (2H, s); 4.37 (1H, brt); 4.28 (2H, q, J=7.2 Hz); 4.28 (2H, d, J=4.5 Hz); 2.78-2.74 (4H, m); 1.74-1.72 (4H, m); 1.31 (3H, t, J=7.1 Hz).
Reaction SMILES: S([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])(C(F)(F)F)(=O)=O.[CH2:16]([NH:23][CH2:24][CH2:25]O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:16]([N:23]([S:9]([C:12]([F:15])([F:14])[F:13])(=[O:10])=[O:8])[CH2:24][CH2:25][O:8][S:9]([C:12]([F:13])([F:14])[F:15])(=[O:10])=[O:11])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: OCCNCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(OCCN(Cc1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.1 %

Procedure:
Triflic anhydride (11.18 g, 6.5 ml, 39 mmol) dissolved in 90 ml of DCM was added drop by drop to a well stirred solution of N-benzyl ethanol amine (2 g, 13.2 mmol) and diisopropylethyl amine (5.1 g, 6.9 ml, 39.7 mmol) in dichloromethane (160 ml) at 0° C. and stirred at room temperature for 1 h under nitrogen atmosphere. The reaction mixture was quenched with water and extracted with dichloromethane. Organic layer was washed with water and dried under sodium sulfate. Solvent evaporation under reduced pressure afforded 500 mg of the title compound as a an oil
Reaction SMILES: [O:1]=[S:2]1(=[O:27])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]2[CH:7]=[C:6]([CH:16]([CH2:20][CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:17]([OH:19])=O)[CH:5]=[CH:4][C:3]1=2.[CH3:28][N:29]1[CH:33]=[CH:32][C:31]([NH2:34])=[N:30]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1>CN(C)C=O.C(OCC)(=O)C>[O:1]=[S:2]1(=[O:27])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]2[CH:7]=[C:6]([CH:16]([CH2:20][CH:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[C:17]([NH:34][C:31]3[CH:32]=[CH:33][N:29]([CH3:28])[N:30]=3)=[O:19])[CH:5]=[CH:4][C:3]1=2
Reactant: Cn1ccc(N)n1
Reactant: O=C(O)C(CC1CCOCC1)c1ccc2c(c1)Nc1ccccc1S2(=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: Cn1ccc(NC(=O)C(CC2CCOCC2)c2ccc3c(c2)Nc2ccccc2S3(=O)=O)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
600 mg of 2-(5,5-dioxo-5,10-dihydrophenothiazin-2-yl)-3-(tetrahydropyran-4-yl)propionic acid, 120 mg of commercially available 1-methyl-1H-pyrazole-3-amine and 729 μl of N,N-diisopropylethylamine are dissolved in 5 ml of dimethylformamide. 561 mg of HATU and 200 mg of HOAT are added, and the mixture is stirred at room temperature for two hours. The reaction mixture is then diluted by addition of 200 ml of ethyl acetate and washed three times with in each case 50 ml of water and saturated sodium chloride solution. The organic phase is dried over MgSO4, and the solvent is then removed under reduced pressure. The residue is purified by RP-HPLC. This gives 200 mg of 2-(5,5-dioxo-5,10-dihydrophenothiazin-2-yl)-N-(11-methyl-1H-pyrazol-3-yl)-3-(tetrahydropyran-4-yl)propionamide as a colorless lyophilisate.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1.Br[C:16]1[CH:17]=[C:18]([CH:36]=[CH:37][C:38]=1[CH3:39])[C:19]([NH:21][C:22]1[CH:23]=[N:24][C:25]([N:28]2[CH2:33][CH:32]([CH3:34])[O:31][CH:30]([CH3:35])[CH2:29]2)=[CH:26][CH:27]=1)=[O:20].C([O-])([O-])=O.[Na+].[Na+].COCCOC>CCOC(C)=O.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>[CH3:34][C@H:32]1[CH2:33][N:28]([C:25]2[N:24]=[CH:23][C:22]([NH:21][C:19]([C:18]3[C:17]([CH3:16])=[C:39]([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:5][CH:6]=4)[CH:38]=[CH:37][CH:36]=3)=[O:20])=[CH:27][CH:26]=2)[CH2:29][C@@H:30]([CH3:35])[O:31]1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Cc1ccc(C(=O)Nc2ccc(N3CC(C)OC(C)C3)nc2)cc1Br
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: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(N3C[C@@H](C)O[C@@H](C)C3)nc2)cccc1-c1ccc(OC(F)(F)F)cc1
Temperature: 130 °C
Yield: 61 %

Procedure:
A mixture of 4-(trifluoromethoxy)phenylboronic acid (254 mg, 1.24 mmol), 3-bromo-N-[6-(2,6-dimethyl-morpholin-4-yl)-pyridin-3-yl]-4-methyl-benzamide 5 (250 mg, 0.62 mmol), Pd(PPh3)4 (36 mg, 0.03 mmol), Na2CO3 (2.0M aqueous solution, 1.23 mL, 2.4 mmol) and DME (4.5 mL) in a sealed tube was heated at 130° C. overnight. The reaction mixture was diluted with EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine and concentrated to give the crude product which was then purified by preparative mass triggered HPLC (C18 column, eluted with CH3CN—H2O containing 0.05% TFA) to give N-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-methyl-4′-(trifluoromethoxy)biphenyl-3-carboxamide (183.5 mg, 61.1% yield). LC-MS m/z: 486.2 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)[O:5][CH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.[OH-].[K+]>C(O)C.O>[Cl:19][C:14]1[CH:13]=[C:12]([CH:4]([O:5][CH:6]2[CH2:11][CH2:10][O:9][CH2:8][CH2:7]2)[C:3]([OH:20])=[O:2])[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: COC(=O)C(OC1CCOCC1)c1ccc(Cl)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C(OC1CCOCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.3 %

Procedure:
A solution of rac-(3,4-dichloro-phenyl)-[(tetrahydro-pyran-4-yl)oxy]-acetic acid methyl ester (598 mg, 1.87 mmol) in ethanol (15 mL) was treated with a solution of potassium hydroxide (262 mg, 4.68 mmol) and water (2 mL) and the mixture was allowed to stir at 25° C. After 3 h, the reaction was diluted with water (10 mL) and the ethanol was removed in vacuo. The aqueous layer was then acidified to pH 2 with 1N hydrochloric acid and extracted with dichloromethane (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated under reduced pressure. The reaction product was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 95/5 chloroform/methanol plus 1% acetic acid) to afford rac-(3,4-dichloro-phenyl)-[(tetrahydro-pyran-4-yl)oxy]-acetic acid (544 mg, 95% yield) as a clear colorless oil: EI-HRMS m/e calcd for C13H14Cl2O4 (M+) 304.0269, found 304.0259.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][NH:11][C:12]3[CH:18]=[CH:17][N:16]=[CH:15][C:13]=3[N:14]=2)=[CH:5][CH:4]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([Cl:27])=[O:26])[CH:20]=1>>[ClH:27].[C:25]([N:11]1[C:12]2[CH:18]=[CH:17][N:16]=[CH:15][C:13]=2[N:14]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=2)[NH:10]1)(=[O:26])[C:21]1[CH:22]=[CH:23][CH:24]=[N:19][CH:20]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: Oc1ccc(C2=Nc3cnccc3NN2)cc1
Agent: Cl
Product: O=C(c1cccnc1)N1NC(c2ccc(O)cc2)=Nc2cnccc21
Yield: 79 %

Procedure:
2.75 g (0.01 moles) of 3-(p-hydroxyphenyl)-1,2-dihydropyrido[3,4-e]-as-triazine hydrochloride are reacted with pyridine-3-carbonyl chloride as described in Example 2 to obtain 1-nicotinoyl-3-(p-hydroxyphenyl)-1,2-dihydropyrido[3,4-e]-as-triazine hydrochloride with a yield of 79%; m.p.: 212°-213° C.