Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:18][N:7]2[C:8]3[CH:9]=[C:10]([C:15]([OH:17])=O)[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:19])[NH:4][CH2:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:33][C:34]1[O:38][N:37]=[C:36]([NH2:39])[CH:35]=1.N1(C2CCCCCCCCCC2)CCCN=CCCCCC1>C1COCC1>[CH3:20][C:2]1([CH3:1])[CH2:18][N:7]2[C:8]3[CH:9]=[C:10]([C:15]([NH:39][C:36]4[CH:35]=[C:34]([CH3:33])[O:38][N:37]=4)=[O:17])[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:19])[NH:4][CH2:3]1
Reactant: Cc1cc(N)no1
Reactant: CC1(C)CNC(=O)c2cc3ccc(C(=O)O)cc3n2C1
Agent: C1=NCCCN(C2CCCCCCCCCC2)CCCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)c2ccc3cc4n(c3c2)CC(C)(C)CNC4=O)no1
Temperature: 55 °C
Reaction time: 0.17 h
Yield: 60.6 %

Procedure:
To a solution of 4,4-dimethyl-1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxylic acid (100 mg, 0.37 mmol) in THF (2 mL) is added 1,1′-carbonyldiimidazole (149 mg, 0.92 mmol). The reaction mixture is heated at 55° C. for 1 h. The mixture is cooled to room temperature and 5-methyl-3-aminoisoxazole (144 mg, 1.47 mmol) is added. After stifling 10 min, 1,8-diazabicycloundec-7-ene (0.14 mL, 0.92 mmol) is added and the reaction is heated at 60° C. for 16 h. After cooling to room temperature, the solvent is evaporated and the residue is purified by preparative HPLC using 10-85% acetonitrile/water with 0.1% TFA to afford the title compound (79 mg, 61%). LCMS (ESMS): m/z 353.45 (M+H+).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([O:14][CH3:15])(=[O:13])[C:9](OC)=[O:10]>O([Ti](OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1)C1C=CC=CC=1>[C:8]([O:14][C:15]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)(=[O:13])[C:9]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:10]
Reactant: Oc1ccccc1
Reactant: COC(=O)C(=O)OC
Agent: c1ccc(O[Ti](Oc2ccccc2)(Oc2ccccc2)Oc2ccccc2)cc1
Product: O=C(Oc1ccccc1)C(=O)Oc1ccccc1
Temperature: 190 °C

Procedure:
A solution comprising 54.1% by weight of phenol, 45.3% by weight of dimethyl oxalate and 0.5% by weight of tetraphenoxytitanium was fed into the twelfth step from the top of a first fifty-plate Oldershaw-type reactive distillation column provided with a one liter bottom flask and having an inner diameter of 32 mm, at a flow rate of 600 ml/hr, and the bottom flask was heated by a mantle heater to a temperature of 190° C., while withdrawing a resultant vapor fraction from the top portion of the first column at a reflux ratio of 2 and condensing the withdrawn vapor fraction by a cooler, to transesterify dimethyl oxalate with phenol and to produce diphenyl oxalate.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([C:21]2[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=2)=[O:20])[CH2:15][CH2:14]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(OCCO)C.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>[OH:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([C:24]3[CH:23]=[CH:22][C:21]([C:19]([N:16]4[CH2:15][CH2:14][CH:13]([CH3:12])[CH2:18][CH2:17]4)=[O:20])=[CH:26][CH:25]=3)[S:3][C:4]=2[CH:10]=1
Reactant: CC1CCN(C(=O)c2ccc(B(O)O)cc2)CC1
Reactant: Oc1ccc2nc(Br)sc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCCO
Product: CC1CCN(C(=O)c2ccc(-c3nc4ccc(O)cc4s3)cc2)CC1
Temperature: 115 °C
Reaction time: 2 h
Yield: 20.1 %

Procedure:
2-Bromo-6-hydroxybenzothiazole (400 mg, 1.74 mmol), 4-(4-methylpiperidine-1-carbonyl)phenylboronic acid (472 mg, 1.91 mmol), potassium phosphate (848 mg, 6.96 mmol) and tetrakis(triphenylphosphine)palladium (60 mg, 0.05 mmol) were dissolved in a mixture of 1.3.5 mL 2-ethoxyethanol and 1.5 mL water. The mixture was stirred at 115° C. under argon for 2 h. The reaction mixture was let to reach room temperature then activated-carbon was added and stirred for 20 min. The mixture was filtered, the solid was washed with ethanol and the combined filtrates were evaporated. The residue was purified by column chromatography (Kieselgel 60) with chloroform as the eluent. The crude product was triturated with Et2O, collected and air dried, affording the title compound (122 mg, 0.35 mmol, 20%).
Reaction SMILES: [CH3:1][C:2]1([CH3:41])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16]C(=O)[N:14]([CH2:18][CH2:19][C:20]4[CH:40]=[CH:39][C:23]([O:24][CH2:25][CH2:26][O:27][CH2:28][C:29]5[CH:30]=[C:31]([NH:35][C:36]([NH2:38])=[O:37])[CH:32]=[CH:33][CH:34]=5)=[CH:22][CH:21]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.CC1(C)OC2C=CC([C@H]3OC(=O)N(CCC4C=CC(OCCOCC5C=C(NC(=N)OC(=N)N)C=CC=5)=CC=4)C3)=CC=2CO1.O([Si](C)(C)C)[K]>C1COCC1>[CH3:1][C:2]1([CH3:41])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12]([OH:16])[CH2:13][NH:14][CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:24][CH2:25][CH2:26][O:27][CH2:28][C:29]4[CH:30]=[C:31]([NH:35][C:36]([NH2:38])=[O:37])[CH:32]=[CH:33][CH:34]=4)=[CH:39][CH:40]=3)=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCOCc5cccc(NC(N)=O)c5)cc4)C(=O)O3)ccc2O1
Agent: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCOCc5cccc(NC(=N)OC(=N)N)c5)cc4)C(=O)O3)ccc2O1
Agent: C[Si](C)(C)O[K]
Solvent: C1CCOC1
Product: CC1(C)OCc2cc([C@@H](O)CNCCc3ccc(OCCOCc4cccc(NC(N)=O)c4)cc3)ccc2O1
Temperature: 75 °C

Procedure:
The mixture of N-(3-{[2-(4-{2-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethoxy]methyl}phenyl)urea and N-(3-{[2-(4-{2-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethoxy]methyl}phenyl)dicarbonimidic diamide (135 mg) in THF (2 mL) was treated with KOSiMe3 (123 mg) and the resulting solution was heated at 75° C. under nitrogen for 1.5 h. The reaction mixture was then quenched with MeOH and concentrated in vacuo. The residue was taken up in EtOAc, washed with water, dried (MgSO4) and concentrated in vacuo. The residue was purified by HPLC to give N-[3-({2-[4-(2-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}ethyl)phenoxy]ethoxy}methyl)phenyl]urea (12 mg). LCMS RT=2.47 min and N-[3-([2-[4-(2-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}ethyl)phenoxy]ethoxy}methyl)phenyl]dicarbonimidic diamide (6 mg). LCMS RT=2.58 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:14][C:13](=O)[CH2:12][N:11]3[C:7](=[N:8][C:9]([CH2:16][O:17][CH3:18])=[N:10]3)[C:6]=2[CH:19]=1.ClC1C=CC2NC(=O)C[N:30]3[C:26](=[N:27][C:28](COC)=[N:29]3)C=2C=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:14]=[C:13]([N:29]3[CH:28]=[N:27][CH:26]=[N:30]3)[CH2:12][N:11]3[C:7]([C:6]=2[CH:19]=1)=[N:8][C:9]([CH2:16][O:17][CH3:18])=[N:10]3
Reactant: COCc1nc2n(n1)CC(=O)Nc1ccc(Br)cc1-2
Reactant: COCc1nc2n(n1)CC(=O)Nc1ccc(Cl)cc1-2
Product: COCc1nc2n(n1)CC(n1cncn1)=Nc1ccc(Br)cc1-2
Yield: 79 %

Procedure:
As described for example 4e) 9-bromo-2-methoxymethyl-6H-1,3,3a,6-tetraaza-benzo[e]azulen-5-one (12.5 g, 38.7 mmol), instead of 9-chloro-2-methoxymethyl-6H-1,3,3a,6-tetraaza-benzo[e]azulen-5-one, was converted to the title compound (11.4 g, 79%) which was obtained as a light yellow solid. MS: m/e=373.0/375.1 [M+H]+.
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][CH2:8][C@@H:9]([N:11]1[CH2:16][CH2:15][N:14]2[C:17](=[O:27])[C:18]([N:21]3[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]3)=[CH:19][CH:20]=[C:13]2[C:12]1=[O:28])[CH3:10].F[C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:31]=1[S:39]([F:44])([F:43])([F:42])([F:41])[F:40]>O1CCCC1.O>[CH3:26][C:24]1[N:23]=[CH:22][N:21]([C:18]2[C:17](=[O:27])[N:14]3[CH2:15][CH2:16][N:11]([C@@H:9]([CH3:10])[CH2:8][O:7][C:30]4[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:31]=4[S:39]([F:42])([F:43])([F:44])([F:40])[F:41])[C:12](=[O:28])[C:13]3=[CH:20][CH:19]=2)[CH:25]=1
Reactant: O=[N+]([O-])c1ccc(F)c(S(F)(F)(F)(F)F)c1
Reactant: Cc1cn(-c2ccc3n(c2=O)CCN([C@@H](C)CO)C3=O)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cn(-c2ccc3n(c2=O)CCN([C@@H](C)COc2ccc([N+](=O)[O-])cc2S(F)(F)(F)(F)F)C3=O)cn1
Reaction time: 0.17 h

Procedure:
A solution of potassium tert-butoxide in tetrahydrofuran (1 M, 1.97 mL, 1.97 mmol) was added to a slurry of 2-[(2S)-1-hydroxypropan-2-yl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione (C54) (541 mg, 1.79 mmol) in tetrahydrofuran (6 mL), and the mixture was allowed to stir for 10 minutes. A solution of 1-fluoro-4-nitro-2-(pentafluoro-λ6-sulfanyl)benzene (P15) (478 mg, 1.79 mmol) in tetrahydrofuran (4 mL) was added, and the reaction mixture was stirred at room temperature for 18 hours. At that point, it was diluted with water and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Eluents: ethyl acetate, then 10% methanol in ethyl acetate) afforded the product as a yellow foam. Yield: 695 mg, 1.26 mmol, 70%. LCMS m/z 550.2 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.53 (d, J=7.1 Hz, 3H), 2.34 (d, J=1.0 Hz, 3H), 3.73-3.85 (m, 2H), 4.30-4.47 (m, 4H), 4.99-5.08 (m, 1H), 7.16-7.21 (m, 2H), 7.28 (d, J=7.7 Hz, 1H), 7.52 (d, J=7.7 Hz, 1H), 8.40 (dd, J=9.2, 2.7 Hz, 1H), 8.44 (br s, 1H), 8.71 (d, J=2.6 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:24][CH:23]=[C:22]([C:25](O)=[O:26])[C:21]=1[CH3:28])/[C:12](=[O:18])[NH:13]2.[N:29]1([CH2:34][C@@H:35]2[CH2:40][CH2:39][CH2:38][NH:37][CH2:36]2)[CH2:33][CH2:32][CH2:31][CH2:30]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:24][CH:23]=[C:22]([C:25]([N:37]3[CH2:38][CH2:39][CH2:40][C@@H:35]([CH2:34][N:29]4[CH2:30][CH2:31][CH2:32][CH2:33]4)[CH2:36]3)=[O:26])[C:21]=1[CH3:28])/[C:12](=[O:18])[NH:13]2
Reactant: Cc1c(C(=O)O)c[nH]c1/C=C1\C(=O)Nc2cccc(-c3c(F)cccc3F)c21
Reactant: C1CNC[C@H](CN2CCCC2)C1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: C1CCOC1
Product: Cc1c(C(=O)N2CCC[C@@H](CN3CCCC3)C2)c[nH]c1/C=C1\C(=O)Nc2cccc(-c3c(F)cccc3F)c21
Yield: 69.9 %

Procedure:
5-[4-(2,6-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (114 mg, 0.3 mmol) was coupled with (R)-3-pyrrolidin-1-ylmethyl-piperidine (99 mg, 2 eq.), HOBt (1 eq.), EDC (1.5 eq.) and TEA (3 drops) in THF (1 mL) and aceonitrile (1 mL) at rt for overnight to give 111.3 mg (70%) of the titled compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:25][CH:26]2[CH2:31][O:30]C(C3C=CC=CC=3)[O:28][CH2:27]2)[N:12]=1.O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:25][CH:26]([CH2:27][OH:28])[CH2:31][OH:30])[N:12]=1
Reactant: O=S(=O)(Nc1cc(OC2COC(c3ccccc3)OC2)nc(SCc2cccc(F)c2F)n1)N1CCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CO
Product: O=S(=O)(Nc1cc(OC(CO)CO)nc(SCc2cccc(F)c2F)n1)N1CCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[(2-phenyl-1,3-dioxan-5-yl)oxy]-4-pyrimidinyl]-1-azetidinesulfonamide (the product of step iv) (220 mg) in methanol (5 ml)/water (0.1 ml) was added pyridinium p-toluenesulfonate (20 mg) and the mixture was stirred at ambient temperature for 1.5 hour, then at reflux for 20 hour. The reaction mixture was evaporated, suspended in water and extracted with ethyl acetate (×2). The combined organic layers were dried with magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography on silica gel using a 98:2 mixture of methylene chloride and methanol as eluent to give the title compound as a white solid. Yield: 120 mg
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([N:6]=[C:7](Cl)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:17](#[N:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Al](Br)(Br)Br>ClC1C=CC(Cl)=CC=1>[Cl:1][C:2]1[CH:16]=[C:15]2[C:5](=[CH:4][CH:3]=1)[N:6]=[C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[N:24]=[C:17]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClC(=Nc1ccc(Cl)cc1)c1ccccc1
Reactant: N#Cc1ccccc1
Agent: Br[Al](Br)Br
Solvent: Clc1ccc(Cl)cc1
Product: Clc1ccc2nc(-c3ccccc3)nc(-c3ccccc3)c2c1
Yield: 69 %

Procedure:
The preparation of 4-phenylquinazolines from an N-benzylideneaniline type of Schiff base that is formed from aniline and benzaldehyde, as shown in the reaction between p-chloro-(α-chlorobenzylidene)aniline and benzonitrile in 1,4-dichlorobenzene at 140° C. in the presence of AlBr3 that afforded 69% of 6-chloro-2,4-diphenylquinazoline [23], and the reaction between N-[o-(triphenylphosphoranylideneamino)benzylidene]-p-toluidine and p-nitrobenzaldehyde when refluxed in xylene for 12 hours that gave 70% of 6-methyl-4-p-nitrophenyl-2-phenylquinazoline [24]. The latter reaction would afford dihydroquinazolines as well if other benzaldehydes rather than p-nitrobenzaldehyde are used. In addition, the reaction between 3,4-diphenyl-1,2,4-oxadiazol-5(4H)-one and benzylideneaniline also afforded 2,4-diphenylquinazoline [25];
Reaction SMILES: [CH3:1][N:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[NH:3]1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>ClCCl>[CH3:1][N:2]1[N:3]=[C:4]([Cl:9])[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[NH:7]1
Reactant: CN1N=C(Cl)C=C(Cl)N1
Reactant: C1COCCN1
Solvent: ClCCl
Product: CN1N=C(Cl)C=C(N2CCOCC2)N1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
2-Methyl-4,6-dichlorotriazine (256 mmol) is dissolved in dichloromethane (200 mL) and chilled to −78° C. in an inert atmosphere. Morpholine (550 mol) dissolved in dichloromethane (100 mL) is added slowly. The reaction is allowed to warm to room temperature while stirring overnight. The organic layer is washed with saturated ammonium chloride (2×100 mL), dried with sodium sulfate, and evaporated to give 2-methyl-4-chloro-6-morpholino-triazine.
Reaction SMILES: C1C(N=NC2C=CC(N/N=[C:21]3/[C:22](S([O-])(=O)=O)=[CH:23][C:24]4[C:29]([C:30]/3=[O:31])=[CH:28][C:27](N)=C(S([O-])(=O)=O)[CH:25]=4)=C3C=2C=CC(S([O-])=O)=C3)=CC=C(S([O-])(=O)=O)C=1.[Na+].[Na+].[Na+].[Na+].O[CH2:53]C(CO)O.[CH2:58]([OH:64])[CH2:59][O:60][CH2:61][CH2:62]O>O>[CH2:30]([O:31][CH2:62][CH2:61][O:60][CH2:59][CH2:58][OH:64])[CH2:29][CH2:28][CH3:27].[CH3:25][CH:24]([CH2:29][C:30]([OH:31])([C:21]#[CH:22])[CH3:53])[CH3:23]
Reactant: OCCOCCO
Reactant: Nc1cc2c(cc1S(=O)(=O)[O-])C=C(S(=O)(=O)[O-])/C(=N/Nc1ccc(N=Nc3ccc(S(=O)(=O)[O-])cc3)c3ccc(S(=O)[O-])cc13)C2=O
Reactant: OCC(O)CO
Agent: [Na+]
Solvent: O
Product: C#CC(C)(O)CC(C)C
Product: CCCCOCCOCCO
Reaction time: 2 h

Procedure:
A solution containing 2.00 g Food Black 2 (C.I. Food Black 2), 0.08 g LM pectin (Product Name: LM-104AS, The Copenhagen Pectin Factory Ltd.), 5.00 g of glycerol, 5.00 g of diethylene glycol, 8.00 g diethylene glycol mono-n-butyl ether, 0.80 g of Surfynol 465, and 79.12 g of ultrapure water was prepared. The solution was stirred for 2 hours and then filtered through a 5 μm stainless steel mesh.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:10]=[C:11]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=3)[C:12]([C:15]([NH2:17])=[O:16])=[N:13][CH:14]=2)[CH2:4][CH2:3]1.C(Cl)(Cl)[Cl:30].ClN1C(=O)CCC1=O>C(#N)C>[Cl:30][C:14]1[N:13]=[C:12]([C:15]([NH2:17])=[O:16])[C:11]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:26])=[O:27])[CH:20]=2)=[N:10][C:9]=1[NH:8][C@H:5]1[CH2:4][CH2:3][C@H:2]([OH:1])[CH2:7][CH2:6]1
Reactant: ClC(Cl)Cl
Reactant: CS(=O)(=O)c1cccc(Nc2nc(N[C@H]3CC[C@H](O)CC3)cnc2C(N)=O)c1
Agent: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CS(=O)(=O)c1cccc(Nc2nc(N[C@H]3CC[C@H](O)CC3)c(Cl)nc2C(N)=O)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (Example 111) (298 mg), chloroform (40 mL) and acetonitrile (10 mL), N-chlorosuccinimide (108 mg) was added and stirred at 70° C. for 8 hours. After the reaction liquid was cooled, silica gel was added, and the solvent was distilled off, followed by purification by silica gel column chromatography (eluent; chloroform:methanol=10:0 to 10:1). The resulting crude product was solidified from chloroform and collected by filtration. The resulting solid was heated with ethyl acetate and washed with ethyl acetate to give 6-chloro-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (189 mg) as a white solid.
Reaction SMILES: [N+](C1C=CC(C[O:11][C:12]([C:14]2[N:15]3[CH:18]([CH:19]([CH3:31])[C:20]=2[S:21][CH:22]2[CH2:26][CH:25]([CH2:27][N:28]=[N+]=[N-])[O:24][CH2:23]2)[CH:17]([CH:32]([OH:34])[CH3:33])[C:16]3=[O:35])=[O:13])=CC=1)([O-])=O.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>[Pd].O1CCOCC1>[NH2:28][CH2:27][CH:25]1[O:24][CH2:23][CH:22]([S:21][C:20]2[CH:19]([CH3:31])[CH:18]3[N:15]([C:16](=[O:35])[CH:17]3[CH:32]([OH:34])[CH3:33])[C:14]=2[C:12]([OH:13])=[O:11])[CH2:26]1
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(CN=[N+]=[N-])C3)C(C)C12
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(O)C1C(=O)N2C(C(=O)O)=C(SC3COC(CN)C3)C(C)C12
Yield: 29.5 %

Procedure:
The title compound is prepared by the procedure of Example 18 using 2.8 g of product from Example 45, 0.60 g of 10% palladium/carbon, 27 ml of sodium phosphate buffer (pH 7) and 82 ml of dioxane to give 0.562 g of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][C:15]3[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=4)[S:20][C:14]=3[C:13]2=[O:29])[CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].[N:30]1([CH2:35][CH2:36][NH2:37])[CH2:34][CH2:33][CH2:32][CH2:31]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][C:15]3[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=4)[S:20][C:14]=3[C:13]2=[O:29])[CH:9]=[CH:8][C:4]=1[C:5]([NH:37][CH2:36][CH2:35][N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:6]
Reactant: NCCN1CCCC1
Reactant: COc1ccc(-c2cc3c(s2)C(=O)N(c2ccc(C(=O)O)c(OC)c2)CC3)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(-c2cc3c(s2)C(=O)N(c2ccc(C(=O)NCCN4CCCC4)c(OC)c2)CC3)cc1
Yield: 5.1 %

Procedure:
Suspend 2-methoxy-4-[2-(4-methoxy-phenyl)-7-oxo-4,7-dihydro-5H-thieno[2,3-c]pyridin-6-yl]-benzoic acid (0.1451 g, 0.35 mmol) in DMF (5 mL) and add 2-pyrrolidin-1-yl-ethylamine (45 mg, 0.39 mmol), EDCI (81 mg, 0.42 mmol), HOBt (57 mg, 0.42 mmol) and Et3N (0.15 mL, 1.06 mmol). Stir the reaction at RT overnight. Dilute with EtOAc (100 mL), wash with water (2×30 mL), and dry over Na2SO4. Purify the crude material by silica gel chromatography, eluting with 2% NH3—H2O, 50% CH3OH/EtOAc to give 9 mg (5%) of the title compound. LC-MS/ES m/z 506.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:23]([F:26])([F:25])[F:24])=[CH:11][C:12]=2[S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[CH:4][CH:3]=1.[Br:27]Br.C([O-])(=O)C.[Na+].O>C(O)(=O)C.BrBr>[Br:27][C:11]1[C:12]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)(=[O:14])=[O:15])=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[NH:9][C:10]=1[C:23]([F:25])([F:24])[F:26]
Reactant: BrBr
Reactant: O=S(=O)(c1ccc(Cl)cc1)c1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=S(=O)(c1ccc(Cl)cc1)c1c(-c2ccc(Cl)cc2)[nH]c(C(F)(F)F)c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
A solution of 2-(p-chlorophenyl)-3-[(p-chlorophenyl)sulfonyl]-5-(trifluoromethyl)pyrrole (2.15 g, 5.12 mmol), bromine (0.29 mL, 5.63 mmol) and sodium acetate (0.46 g, 5.63 mmol) in acetic acid is stirred at room temperature for 4 hours, treated with additional bromine (3 drops), stirred overnight at room temperature and poured into water. The resultant aqueous mixture is filtered to obtain a solid. Flash column chromatography of the solid using silica gel and a 1:5 ethyl acetate/hexanes solution gives the title product as a white solid (1.88 g, mp >230° C.).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>C(O)C>[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])=[CH:20][CH:19]=1
Reactant: Nc1ccc(Br)cc1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Solvent: CCO
Product: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1ccc(Br)cc1
Yield: 44.4 %

Procedure:
A mixture of 5.00 g (21.5 mmol) 4-chloro-6-nitro-quinoline-3-carbonitrile, 200 ml ethanol, and 4.42 g (25.8 mmol) p-bromoaniline was heated to reflux under N2 for 3 hours. Removed heat and added saturated sodium bicarbonate until basic. Stripped solvents and azeotroped with ethanol. Slurried residue with hexane, collected solids, and air dried. Washed with water and dried in vacuo. Boiled in 1.4 liters ethyl acetate, and without completely dissolving all solids, stirred with Darco, and filtered. Stripped solvent and dried in vacuo, giving 3.524 g of yellow solid: mass spectrum (electrospray m/e): M+H=369, 370.9.
Reaction SMILES: C(OC([NH:11][C:12](C)([CH3:29])[CH2:13][NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]([CH3:28])[CH2:23][C:24](=[O:27])[NH:25][N:26]=2)=[CH:17][CH:16]=1)=O)C1C=CC=CC=1.NC1C=[CH:36][C:35]([C:38]2C(C)CC(=O)NN=2)=[CH:34]C=1.C(=O)CC.C([BH3-])#N.[Na+].[C:54]([OH:57])(=[O:56])C>>[C:35]([O:57][C:54]([NH:11][CH:12]([CH3:29])[CH2:13][NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]([CH3:28])[CH2:23][C:24](=[O:27])[NH:25][N:26]=2)=[CH:17][CH:16]=1)=[O:56])([CH3:38])([CH3:36])[CH3:34]
Reactant: CC1CC(=O)NN=C1c1ccc(NCC(C)(C)NC(=O)OCc2ccccc2)cc1
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: CC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCC=O
Product: CC(CNc1ccc(C2=NNC(=O)CC2C)cc1)NC(=O)OC(C)(C)C

Procedure:
The same operation as in Example 1, (1-c) was carried out by using 6-(4-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone (2.03 g), 2-butoxycarbonylamino)propanal (2.09 g), acetic acid (0.6 g) and sodium cyanoborohydride (0.33 g), to obtain 6-[4-(2-t-butoxycarbonylaminopropylamino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone (2.89 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:13])=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.[H][H]>FC(F)(F)C(O)=O.[Pd]>[CH3:1][O:2][C:3]1[C:4]([CH3:13])=[N:5][C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1
Reactant: COc1cc2ccccc2nc1C
Reactant: [H][H]
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(nc1C)CCCC2
Yield: 99.6 %

Procedure:
A mixture of 3-methoxy-2-methylquinoline (0.081 mol) in trifluoro-acetic acid (150 ml) was hydrogenated at room temperature under a 3-4 bar pressure for 48 hours with palladium on activated carbon (2 g) as a catalyst. After uptake of hydrogen (2 equiv.), the catalyst was filtered through celite and washed with H2O. The filtrate was basified with a concentrated NH4OH solution and extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated, yielding 14.3 g (quant.) of 5,6,7,8-tetrahydro-3-methoxy-2-methylquinoline (interm. 13).