Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([NH:12][C:13]3[CH:17]=[N:16][N:15]([CH3:18])[C:14]=3[C:19]([OH:21])=O)=[O:11])[C:7]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[N:6][CH:5]=2)[CH2:3][CH2:2]1.Cl.[CH3:30][NH:31][O:32][CH3:33]>>[CH3:33][O:32][N:31]([CH3:30])[C:19]([C:14]1[N:15]([CH3:18])[N:16]=[CH:17][C:13]=1[NH:12][C:10]([C:8]1[C:7]([NH:22][C:23]2[CH:24]=[N:25][CH:26]=[N:27][CH:28]=2)=[N:6][CH:5]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[N:9]=1)=[O:11])=[O:21]
Reactant: Cn1ncc(NC(=O)c2nc(C3CC3)cnc2Nc2cncnc2)c1C(=O)O
Reactant: CNOC
Agent: Cl
Product: CON(C)C(=O)c1c(NC(=O)c2nc(C3CC3)cnc2Nc2cncnc2)cnn1C

Procedure:
The product was obtained starting from 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-2-methyl-2H-pyrazole-3-carboxylic acid (50 mg, 131 μmol; example 236, step 3) and N,O-dimethylhydroxylamine hydrochloride (14 mg, 145 μmol) according to the method described in example 64, step 6 after purification by preparative HPLC using an acetonitrile/water gradient as yellow foam (47 mg, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([N+]([O-])=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9].[N+]([O-])([O-])=O.[Na+].[ClH:26]>CN(C)C=O.O>[Cl:1][C:2]1[CH:17]=[C:16]([Cl:26])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1cccc(Oc2ccc([N+](=O)[O-])cc2Cl)c1
Reactant: Cl
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cccc(Oc2ccc(Cl)cc2Cl)c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
The product (10 g) from paragraph (a) was dissolved in dimethyl formamide (150 ml), cooled to 5°-10° C. and concentrated hydrochloric acid (40 ml) added dropwise, the temperature being kept at 10°-15° C. The mixture was then kept at 5° C. while sodium nitrate (5.2 g) in water (20 ml) was added dropwise with stirring over a period of 30 minutes. The solution so prepared was added dropwise to a solution of cuprous chloride (19 g) in concentrated hydrochloric acid (150 ml) kept at 10° C., giving a thick green suspension. When addition was complete, the mixture was left to stand overnight and then heated to 60° C. for 30 minutes. The white solid was filtered off, dried, and recrystallised from petroleum (100°-120° C.) to give 3(2,4-dichlorophenoxy)benzoic acid (5.1 g) with a melting point of 143°-144° C. This compound was used as starting material for compound no 19 of Table 1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(OC([NH:31][CH2:32][CH2:33][C:34](O)=[O:35])=O)(C)(C)C>>[NH2:31][CH2:32][CH2:33][C:34]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=3)[N:9]=2)[CH:3]=1)=[O:35]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: Nc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Product: NCCC(=O)Nc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 24 was coupled to 3-tert-butoxycarbonylamino-propionic acid by procedure K. The resulting product was deprotected by procedure G. LC-MS showed the product had the expected M+H+ of 377. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.6 (d, 1H) 8.4 (d, 1H) 8.1 (s, 1H) 7.8 (d, 1H) 7.5 (t 3H), 7.2 (d, 1H), 7.1 (d, 2H), 6.7 (d 2H), 3.6 (d, 2H), 3.1 (d, 2H), 2.8 (d, 2H), 2.5 (d, 2H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([Br:20])=[CH:9][N:8]=1)(=O)=O.Cl.[OH:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(CC)CC)C>CN(C)C=O>[CH2:13]([C:11]1[C:10]([Br:20])=[CH:9][N:8]=[C:7]([N:28]2[CH2:29][CH2:30][CH:25]([OH:24])[CH2:26][CH2:27]2)[CH:12]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(Oc1cc(Cc2ccccc2)c(Br)cn1)C(F)(F)F
Reactant: OC1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: OC1CCN(c2cc(Cc3ccccc3)c(Br)cn2)CC1
Reaction time: 3 h
Yield: 56 %

Procedure:
A mixture of 550 mg of 4-benzyl-5-bromo-2-pyridyl trifluoromethanesulfonate (Production Example 1), 600 mg of 4-hydroxypiperidine hydrochloride, 1 ml of triethylamine and 2 ml of N,N-dimethylformamide was heated under stirring for 3 hours in an oil bath kept at 100° C. in a nitrogen atmosphere. After cooling as it was, the reaction mixture was extracted with ethyl acetate/water. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to silica gel column chromatography and eluted with 50% ethyl acetate/hexane, to give 270 mg of the target compound.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.[C:16]([C:18]1[C:23]2[N:24]=[C:25]([C:27]3[S:28][CH:29]=[C:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[N:31]=3)[O:26][C:22]=2[C:21](F)=[C:20]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:19]=1[CH3:44])#[N:17]>CS(C)=O>[C:16]([C:18]1[C:23]2[N:24]=[C:25]([C:27]3[S:28][CH:29]=[C:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[N:31]=3)[O:26][C:22]=2[C:21]([N:5]2[CH2:6][CH2:7][C@H:3]([N:2]([CH3:8])[CH3:1])[CH2:4]2)=[C:20]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:19]=1[CH3:44])#[N:17]
Reactant: CCOC(=O)c1csc(-c2nc3c(C#N)c(C)c(-c4ccccc4)c(F)c3o2)n1
Reactant: CN(C)[C@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOC(=O)c1csc(-c2nc3c(C#N)c(C)c(-c4ccccc4)c(N4CC[C@H](N(C)C)C4)c3o2)n1
Temperature: 100 °C
Reaction time: 3 h
Yield: 66.3 %

Procedure:
(3S)-3-(Dimethylamino)pyrrolidine (91.6 μl, 0.722 mmol) and triethylamine (101 μl, 0.722 mmol) were added to a dimethyl sulfoxide (2 ml) solution of ethyl 2-(4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazol-2-yl)-1,3-thiazole-4-carboxylate (I-197) (147 mg, 0.361 mmol), followed by stirring in an oil bath at 100° C. for 3 hours. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in chloroform (100 ml) and washed with water (50 ml) and saturated brine (50 ml). After drying over anhydrous sodium sulfate and concentration, the resulting residue was purified by silica gel column chromatography (eluent, chloroform:methanol=100:1→100:3), and the obtained yellow solid was purified in slurry with isopropanol (3 ml) to obtain the entitled compound (120 mg, 66.3%) as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([NH:17][NH2:18])=[O:16])=[CH:13][N:12]3[CH:19]=[CH:20][N:21]=[C:11]3[C:10]=2[Cl:22])=[C:4]([F:23])[CH:3]=1.[C:24](=S)=[S:25].[OH-].[K+].Cl>C(O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]3[O:16][C:24]([SH:25])=[N:18][N:17]=3)=[CH:13][N:12]3[CH:19]=[CH:20][N:21]=[C:11]3[C:10]=2[Cl:22])=[C:4]([F:23])[CH:3]=1
Reactant: NNC(=O)c1cn2ccnc2c(Cl)c1Nc1ccc(Br)cc1F
Reactant: S=C=S
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Fc1cc(Br)ccc1Nc1c(-c2nnc(S)o2)cn2ccnc2c1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 29.7 %

Procedure:
7-(4-Bromo-2-fluoro-phenylamino)-8-chloro-imidazo[1,2-a]pyridine-6-carboxylic acid hydrazide (50 mg, 0.13 mmol) was suspended in ethanol (2.5 mL) and cooled to 0° C. Carbon disulfide (22 mg, 0.29 mmol) was added, followed by powdered potassium hydroxide (7 mg, 0.13 mmol). The reaction mixture was stirred under N2 for 1 hour at 0° C. and then for 30 minutes at room temperature. The reaction mixture was then brought to reflux and stirred under N2 for 5 days. The reaction mixture was diluted with water and acidified to pH 1-2 with aqueous 1 M HCl. This mixture was then extracted with ethyl acetate (2×). The combined organic layers were washed with saturated aqueous NaHCO3, saturated aqueous NaCl, dried over Na2SO4 and concentrated. Purification of the crude product was achieved by flash column chromatography (gradient of dichloromethane to 15:1 dichloromethane/methanol) and then trituration with diethyl ether and dichloromethane to yield the desired product (17 mg, 31%) as a yellow solid. MS ESI (+) m/z 440, 442 (M+, Cl, Br pattern) detected. 1H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.16 (s, 1H), 8.08 (br s, 1H), 7.73 (s, 1H), 7.49 (d, 1H), 7.15 (d, 1H), 6.59 (t, 1H). 19F (376 MHz, DMSO-d6)−128.7 (s).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:26]=[CH:25][C:11]([CH2:12][S:13][C:14]3[N:19]([CH3:20])[C:18]4[NH:21][CH:22]=[CH:23][C:17]=4[C:16](=[O:24])[N:15]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:31]I>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:26]=[CH:25][C:11]([CH2:12][S:13][C:14]3[N:19]([CH3:20])[C:18]4[N:21]([CH3:31])[CH:22]=[CH:23][C:17]=4[C:16](=[O:24])[N:15]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:27][CH:28]=1
Reactant: CI
Reactant: Cn1c(SCc2ccc(C(=O)c3ccc(Cl)cc3)cc2)nc(=O)c2cc[nH]c21
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cn1ccc2c(=O)nc(SCc3ccc(C(=O)c4ccc(Cl)cc4)cc3)n(C)c21
Reaction time: 0.33 h
Yield: 44.1 %

Procedure:
Under argon gas, 2-[4-(4-chlorobenzoyl) benzyl]thio-1-methyl-7H-pyrrolo(2,3-d]pyrimidin-4-one (103 mg) was dissolved in anhydrous DMSO (20 ml) with warming. Then, at room temperature, 60% sodium hydride-oil (11 mg) was added and the mixture was stirred for 20 minutes. Then, methyl iodide (42.6 mg) was added and the mixture was further stirred overnight. The reaction mixture was diluted with water (200 ml) and the resulting precipitate was collected by filtration, dried, and purified by flash column chromatography (silica gel; chloroform-ethanol: chloroform=1:49) to provide the title compound (47 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[F:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:27]([C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)(=[O:29])=[O:28])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: O=S(=O)(Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1)c1ccc(F)cc1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 2) and 4-fluorobenzene-1-sulfonyl chloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]([OH:13])=[O:12])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14]CCCCCC=CCCC.CI>C1C=CC=CC=1>[CH3:14][O:12][C:11](=[O:13])[CH2:10][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH3:9]
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: CCCC=CCCCCCC
Solvent: CI
Solvent: c1ccccc1
Product: COC(=O)CN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 86.4 %

Procedure:
To a solution of N-t-butoxycarbonyl-sarcosine (50 g; 0.264 mol) in 700 ml of benzene was added 1,8-diazabicyclo 5.4.0!-undec-7-ene (DBU; 40.19 g, 0.264 mol) in one portion. To the above clear solution added 74.94 g (0.528 mol) of methyl iodide in one portion and the resulting clear solution was allowed to reflux for 7 hours. After adding additional methyl iodide (16 ml), the reaction mixture was refluxed with stirring and then cooled to room temperature, and stirred overnight. The reaction mixture was filtered, the residue washed with ether, and the combined filtrate was washed with water, a saturated sodium bicarbonate solution, and then brine. The resulting organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford 46.38 g (86.4%) of N-t-butoxycarbonyl-sarcosine methyl ester as a yellow oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].[Cl:8][C:9]1[N:14]=[C:13](S(C)(=O)=O)[N:12]=[C:11]([NH:19][CH:20]([CH3:22])[CH3:21])[C:10]=1[C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:30]>CN(C=O)C>[Cl:8][C:9]1[N:14]=[C:13]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)[N:12]=[C:11]([NH:19][CH:20]([CH3:22])[CH3:21])[C:10]=1[C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:30]
Reactant: c1cn[nH]c1
Reactant: CC(C)Nc1nc(S(C)(=O)=O)nc(Cl)c1-c1c(F)cccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Nc1nc(-n2cccn2)nc(Cl)c1-c1c(F)cccc1Cl
Reaction time: 1 h
Yield: 93.1 %

Procedure:
A solution of 180 mg (2.64 mmol) of pyrazole in 4 ml of anhydrous DMF was treated with 106 mg (2.64 mmol) of NaH (60% suspension in mineral oil), with ice-cooling. After the mixture had been stirred for one hour, 500 mg (1.32 mmol) of the product of step d were added and the mixture was stirred for approximately 14 hours at 20 to 25° C. The product was precipitated by adding water. Filtration, washing with water and drying gave 450 mg of the title compound as colorless crystals of m.p. 185–187° C.
Reaction SMILES: [CH3:1][N:2]([S:22]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)(=[O:24])=[O:23])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][C:14]([CH2:17][CH2:18][C:19]([OH:21])=O)=[CH:15][N:16]=1)=[CH:8]2.[N:30]1(O)C2C=CC=CC=2N=[N:31]1.Cl.CN(C)CCCN=C=NCC.O.NN>O.CN(C)C=O>[NH:30]([C:19](=[O:21])[CH2:18][CH2:17][C:14]1[S:13][C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][CH:5]=[CH:4][C:3]=3[N:2]([CH3:1])[S:22]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)(=[O:24])=[O:23])=[N:16][CH:15]=1)[NH2:31]
Reactant: On1nnc2ccccc21
Reactant: CN(c1cccc2cc(-c3ncc(CCC(=O)O)s3)[nH]c12)S(=O)(=O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NN
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1cccc2cc(-c3ncc(CCC(=O)NN)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
To a mixture of 3-(2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3-thiazol-5-yl)propanoic acid (0.50 g), 1H-1,2,3-benzotriazol-1-ol (0.18 g) and N,N-dimethylformamide (15 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.26 g) at room temperature. The mixture was stirred at room temperature for 1 hr and hydrazine monohydrate (0.28 g) was added. The reaction mixture was stirred at room temperature overnight, and water was added. The resulting crystals were filtrated, washed with water, and dried to give the title compound (0.29 g, yield 57%) as yellow crystals. melting point 224-226° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10](O)=[O:11].[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[C:8]([C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:11]
Reactant: C1CCNCC1
Reactant: COc1c(C)c(Cc2cccc(C(=O)O)c2-c2ccncc2)c(OC)c(OC)c1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1c(C)c(Cc2cccc(C(=O)N3CCCCC3)c2-c2ccncc2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.7 %

Procedure:
3-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(4-pyridyl)benzoic acid (21 mg, 0.0496 mmol) and piperidine (8.4 mg, 0.0988 mmol) were dissolved in methylene chloride (3 ml), then WSC-HCl (29 mg, 0.1512 mmol) was added thereto and the mixture was stirred at room temperature for 16 hours. The reaction solution was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer chromatography (methylene chloride:methanol=95:5) to give the title compound (8.2 mg, 0.0167 mmol, 34%).
Reaction SMILES: CC1C=CC(S(O[C@H:12]2[CH2:15][C@@H:14]([NH:16][C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13]2)(=O)=O)=CC=1.[O:27]1[C:35]2[C:30](=[N:31][CH:32]=[CH:33][CH:34]=2)[NH:29][C:28]1=[O:36].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.ClCCl>[O:36]=[C:28]1[N:29]([C@H:12]2[CH2:13][C@H:14]([NH:16][C:17](=[O:18])[O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:15]2)[C:30]2=[N:31][CH:32]=[CH:33][CH:34]=[C:35]2[O:27]1
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2C[C@@H](NC(=O)OCc3ccccc3)C2)cc1
Reactant: O=c1[nH]c2ncccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(N[C@H]1C[C@H](n2c(=O)oc3cccnc32)C1)OCc1ccccc1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
To a solution of cis-3-(((benzyloxy)carbonyl)amino)cyclobutyl 4-methylbenzenesulfonate (0.25 g, 0.666 mmol) in dry dimethylformamide (1.332 ml) was added oxazolo[4,5-b]pyridin-2(3H)-one (0.091 g, 0.666 mmol) and potassium carbonate (0.230 g, 1.665 mmol). The resulting mixture was heated at 50° C. for 14 hours, 100° C. for 3 hours, then 110° C. for an additional 20 hours. The mixture was diluted with dichloromethane and washed with water and brine then dried with magnesium sulfate and evaporated to dryness under reduced pressure. The crude was advanced directly to next step.
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]([CH3:22])[CH2:20][C:19](=[O:23])[NH:18][N:17]=3)=[CH:12][C:11]=2O)=[O:8])=[CH:5][CH:4]=1)#[N:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)(=O)C>O>[CH3:22][CH:21]1[CH2:20][C:19](=[O:23])[NH:18][N:17]=[C:16]1[C:13]1[CH:14]=[CH:15][C:10]2[N:9]=[C:7]([C:6]3[CH:25]=[CH:26][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[O:8][C:11]=2[CH:12]=1
Reactant: CC1CC(=O)NN=C1c1ccc(NC(=O)c2ccc(C#N)cc2)c(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Solvent: O
Product: CC1CC(=O)NN=C1c1ccc2nc(-c3ccc(C#N)cc3)oc2c1

Procedure:
250 mg (718 μmol) 4-cyano-N-[2-hydroxy-4-(4-methyl-6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-phenyl]-benzamide and 126 mg (718 μmol) para-toluenesulphonic acid monohydrate are refluxed with 10 ml glacial acetic acid for 3 h. Then the solv. is eliminated by rotary evaporation i.V., water is added to the residue and the product is filtered off.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([O:11]COCCOC)=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[N:8]=[C:7]([CH:22]=O)[N:6]=1)([CH3:4])[CH3:3].NCCC(O)=O.[S:30]1[CH2:34][C:33](=[O:35])[NH:32][C:31]1=[O:36]>>[CH3:3][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:18]([CH3:19])([CH3:21])[CH3:20])[N:8]=[C:7]([CH:22]=[C:34]2[S:30][C:31](=[O:36])[NH:32][C:33]2=[O:35])[N:6]=1)([CH3:1])[CH3:4]
Reactant: COCCOCOc1c(C(C)(C)C)nc(C=O)nc1C(C)(C)C
Reactant: O=C1CSC(=O)N1
Agent: NCCC(=O)O
Product: CC(C)(C)c1nc(C=C2SC(=O)NC2=O)nc(C(C)(C)C)c1O
Yield: 23.9 %

Procedure:
4,6-Bis-(1,1-dimethylethyl)-5-[(2-methoxyethoxy)methoxy]-2-pyrimidine carboxaldehyde (0.5 g, 1.5 mmoles) is treated with β-alanine (0.27 g, 3.1 mmoles) and 2,4-thiazolidinedione (0.22 g, 1.8 mmoles) according to the procedure of Example 6 to give 0.12 g (25%) of 5-[[4,6-bis-(1,1-dimethylethyl]-5-hydroxy-2-pyrimidinyl]methylene]-2,4-thiazolidinedione. MP=229°-232° C. dec.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH:2]=1.[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)=[O:24])=[C:21]([CH3:32])[NH:20][C:19]=1[CH:33]=O.N1CCCCC1>C(O)C>[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]2)=[O:24])=[C:21]([CH3:32])[NH:20][C:19]=1[CH:33]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[NH:11][C:10]1=[O:16]
Reactant: O=C1Cc2c(cccc2-c2cccnc2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cccnc4)c32)c(C)c1C(=O)N1CCN(C)CC1
Temperature: 70 °C

Procedure:
A mixture of 4-pyridin-3-yl-1,3-dihydroindol-2-one (42 mg, 0.2 mmol), 3,5-dimethyl-4-(4-methylpiperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (50 mg, 0.2 mmol) and piperidine (0.1 mL) in ethanol was heated in a sealed tube at 70° C. for 5 hours. The reaction was concentrated and the residue was crystallized from ethyl acetate/hexane to give the title compound.
Reaction SMILES: N1C(Cl)=NC(Cl)=N[C:2]=1Cl.[Na].[NH2:11][C:12]1[CH:17]=[C:16](N)[CH:15]=[CH:14][C:13]=1[S:19]([OH:22])(=[O:21])=[O:20]>>[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:2])=[CH:14][C:13]=1[S:19]([OH:22])(=[O:21])=[O:20]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Nc1ccc(S(=O)(=O)O)c(N)c1
Agent: [Na]
Product: Cc1ccc(N)c(S(=O)(=O)O)c1

Procedure:
31.4 Parts of 8-amino-naphthol-3,6-disulphonic acid are condensed with cyanuric chloride at 0° C. and pH 1 to 2. To the suspension of the primary condensation product is added an aqueous solution of 21 parts of the sodium salt of 2,4-diaminobenzenesulphonic acid and condensation is effected at a pH of 4 to 5. When the condensation is complete, the secondary condensation product is coupled at pH 6 to 6.5 with the diazo compound obtained from 18.7 parts of 2-amino-5-methylbenzenesulphonic acid. The red dye solution is then added to a suspension of 2-(2'-sulphophenylamino)-4,6-difluoro-1,3,5-triazine prepared by condensing 17.3 parts of 2-aminobenzenesulphonic acid with 13.5 parts of 2,4,6-trifluoro-1,3,5-triazine at 0° C. The hydrogen fluoride liberated during the condensation is neutralised continously by adding sodium carbonate solution. When the condensation is complete, the reaction product is isolated in the form of a red powder by evaporating the water under reduced pressure. The dye colours cellulose fibres in fast, bluish red shades.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])[CH:12]=[CH2:13].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(OCC)(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[C:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:12](=[CH2:13])[C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:3][CH:4]=1)#[N:10]
Reactant: N#CCc1ccc(Br)cc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=C(C(=O)OC(C)(C)C)c1ccc(CC#N)cc1

Procedure:
A mixture of 5 g of p-bromophenylacetonitrile, 4.6 ml of t-butyl acrylate, 57 mg of palladium diacetate, 310 mg of tri-o-tolylphosphine and 12 ml of triethylamine is refluxed for 5 hours. The reaction mixture is diluted with ethyl acetate and washed with 10% HCl and saturated sodium bicarbonate solution. After drying over magnesium sulfate the solvent is removed in vacuo to yield t-butyl p-(cyanomethyl)-phenylacrylate. This material is dissolved in ethanol and hydrogenated over 1.1 g of 10% palladium on carbon catalyst for 3 days at 3 atmospheres pressure of hydrogen. After filtration the solvent is removed in vacuo and the residue is chromatagraphed on silica gel with ether/hexane (1:1) as the eluent to afford p-(2-t-butoxycarbonyl-ethyl)-phenyl-acetonitrile; 2.8 g of this material is dissolved in 90 ml of tetrahydrofuran and 50 ml of methanol and to this is added 6.2 g of cobalt chloride in 90 ml of water followed by 2.1 g of sodium borohydride in small portions. After filtration and removal of solvent, the residue is chromatagraphed on silica gel with 7.5% ammonia saturated methanol in methylene chloride as the eluent to afford p-(2-t-butoxy-carbonyl-ethyl)-2-phenethylamine as an oil.