Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:5]=1.O.[NH2:24][NH2:25]>CO>[Cl:10][C:9]1[C:4]([C:3]([NH:24][NH2:25])=[O:2])=[N:5][C:6]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)c1nc(Oc2cccc(C(F)(F)F)c2)ccc1Cl
Reactant: NN
Solvent: CO
Solvent: O
Product: NNC(=O)c1nc(Oc2cccc(C(F)(F)F)c2)ccc1Cl

Procedure:
3-chloro-6- [3-(trifluoromethyl)phenoxy]-2-picolinic acid methyl ester (0.72 g, 0.00217 mol) was dissolved in methanol (10 ml), and then mixed with hydrazine monohydrate (1.087 g, 0.00217×10 mol). The resultant mixture was refluxed for about 3 hours. The obtained reaction solution was concentrated, and the obtained residues were distributed in ethyl acetate-saturated sodium bicarbonate water. The organic phase separated from the solution was washed with water and then dried with anhydrous sodium sulfate. After distilling off the solvent, the obtained distillation residues were purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16](=[O:19])[CH2:17][CH3:18])[CH2:11][CH2:10][C:9]2=[O:20].CN(C)C1C=CC=CC=1>C(Cl)Cl.C(Cl)(Cl)Cl>[C:1]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16](=[O:19])[CH2:17][CH3:18])[CH2:11][CH2:10][C:9]2=[O:20])(=[O:3])[CH3:2]
Reactant: CCC(=O)N1CCC(=O)c2cc(N)ccc21
Reactant: CC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: CCC(=O)N1CCC(=O)c2cc(NC(C)=O)ccc21
Reaction time: 0.33 h
Yield: 90.1 %

Procedure:
A solution of acetyl chloride (0.604 g) in methylene chloride (5 ml) was added dropwise to a solution of 6-amino-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (1.526 g) and N,N-dimethylaniline (1.016 g) in methylene chloride (15 ml) with ice cooling over a period of 10 minutes and stirred for further 20 minutes. The mixture was diluted with chloroform, washed successively with 10% hydrochloric acid, water, and brine, dried over magnesium sulfate, and evaporated in vacuo. The residual solid was recrystallized from methanol to give 6-acetamido-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (1.64 g).
Reaction SMILES: [CH:1]1([C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[N+:13]([O-])=O)[N:6]([CH2:16][C:17]3[CH:21]=[CH:20][N:19]([CH2:22][CH3:23])[N:18]=3)[N:5]=2)[CH2:3][CH2:2]1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH:1]1([C:4]2[C:12]3[C:11]([NH2:13])=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]([CH2:16][C:17]3[CH:21]=[CH:20][N:19]([CH2:22][CH3:23])[N:18]=3)[N:5]=2)[CH2:2][CH2:3]1
Reactant: CCn1ccc(Cn2nc(C3CC3)c3c([N+](=O)[O-])cccc32)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCn1ccc(Cn2nc(C3CC3)c3c(N)cccc32)n1
Temperature: 60 °C
Yield: 103.8 %

Procedure:
To a suspension of 3-cyclopropyl-1-((1-ethyl-1H-pyrazol-3-yl)methyl)-4-nitro-1H-indazole (7.55 g, 24.3 mmol) in EtOH/H2O (70 mL/15 mL) was added iron powder (27.1 g, 485 mmol) and NH4Cl (1.30 g, 24.3 mmol). The reaction mixture was heated to reflux for 3 hours. The mixture was cooled to 60° C. and filtered through a pad of Celite washing with a 20:1 EtOH/Et3N (300 mL) and 1:1 MeOH/DCM (300 mL). The filtrate was concentrated under reduced pressure. The residue was dissolved in EtOAc (300 mL), washed with saturated NaHCO3 solution, dried (Na2SO4) and concentrated under reduced pressure to give the product (7.1 g).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[Br:15]Br>C(Cl)(Cl)(Cl)Cl.[W]>[Br:15][CH2:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)COc1ccc(C)cc1
Reactant: BrBr
Agent: [W]
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)COc1ccc(CBr)cc1

Procedure:
A solution of ethyl 4-methylphenoxyacetate, which may be prepared as set forth by S. G. Powell and R. Adams in J. Am. Chem. Soc., 42, pages 646-658 (1920), (18.21 g, 0.094 mole) in 100 ml of dry CCl4 was stirred and refluxed under a 350 watt tungsten lamp. A solution of 15 g (0.094 mole) of bromine in 100 ml of CCl4 was added by means of an addition funnel over a period of 30 minutes. The colorless reaction mixture was evaporated in vacuo and the resulting oil distilled bulb-to-bulb taking a middle cut at 120°-140° at 0.17 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][CH2:20][O:21][NH2:22])=[C:9]2[CH3:23])=[O:7])=[CH:4][CH:3]=1.[O:26]=[CH:27][CH:28]([CH2:30]O)[OH:29]>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][CH2:20][O:21][N:22]=[CH:30][CH:28]([CH2:27][OH:26])[OH:29])=[C:9]2[CH3:23])=[O:7])=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)c(CCON)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: O=CC(O)CO
Product: COc1ccc2c(c1)c(CCON=CC(O)CO)c(C)n2C(=O)c1ccc(Cl)cc1

Procedure:
The title compound is prepared by reaction of O-2-[1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]ethylhydroxylamine with glyceraldehyde by the method of Example 1.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=O.[CH:17]1([C:20](=[O:25])[CH2:21][C:22](=O)[CH3:23])[CH2:19][CH2:18]1>C(O)(=O)C.S(=O)(=O)(O)O>[CH:17]1([C:20]([C:21]2[C:10]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[C:3]3[C:4]4[CH2:9][CH2:8][CH2:7][C:5]=4[S:6][C:2]3=[N:1][C:22]=2[CH3:23])=[O:25])[CH2:19][CH2:18]1
Reactant: Nc1sc2c(c1C(=O)c1cccs1)CCC2
Reactant: CC(=O)CC(=O)C1CC1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1nc2sc3c(c2c(-c2cccs2)c1C(=O)C1CC1)CCC3
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 18.4 %

Procedure:
To a stirred solution of 60 mg (0.24 mmol) (2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-thiophen-2-yl-methanone) (the preparation of which is described in example 2) in 2 ml acetic acid was added 40 mg (0.32 mmol) of 1-cyclopropyl-butane-1,3-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30% CH3CN/H20) afforded 15 mg (19%) cyclopropyl-(2-methyl-4-thiophen-2-yl-6,7-dihydro-5H-cyclopenta[4.5]thieno[2,3-b]pyridin-3-yl)-methanone as a light brown oil. ES-MS m/e (%): 340 (M+H+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:19][CH3:20])=[C:6]([CH:8]2[C:10]3([C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[O:12][CH:11]3[CH3:18])[O:9]2)[CH:7]=1>ClCCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:19][CH3:20])=[C:6]([CH:8]2[C:10](=[O:9])[CH:11]([CH3:18])[O:12][C:13]([CH3:17])([CH3:16])[C:14]2=[O:15])[CH:7]=1
Reactant: CCc1ccc(Br)cc1C1OC12C(=O)C(C)(C)OC2C
Solvent: ClCCCl
Product: CCc1ccc(Br)cc1C1C(=O)C(C)OC(C)(C)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 35.3 %

Procedure:
To ice-cold concentrated sulphuric acid (50 ml) is added a solution of crude 2-(5-bromo-2-ethylphenyl)-4,6,6-trimethyl-1,5-dioxaspiro[2.4]heptan-7-one (40 g) in 1,2-dichloroethane (50 ml) over 20 minutes. After further stirring at 0° C. for 1 hour the reaction mixture is carefully poured into ice (500 g), and the two phases separated. The aqueous phase is further extracted with dichloromethane (2×100 ml), then all organic fractions are combined, washed with water, and concentrated under reduced pressure. The crude product is re-dissolved in ethyl acetate (500 ml), extracted into 0.5M aqueous potassium carbonate, and washed with additional ethyl acetate (×2). The aqueous phase is then carefully acidified with concentrated hydrochloric acid, and the product extracted with ethyl acetate (3×150 ml). Organic fractions are combined, washed with brine then dried over magnesium sulfate, filtered, and the filtrate concentrated in vacuo. The crude product is further purified by flash column chromatography to afford 4-(5-bromo-2-ethylphenyl)-2,2,6-trimethylpyran-3,5-dione (14.10 g) as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]1[NH:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=1.[Br:22]Br.O>C(O)(=O)C>[Br:22][C:15]1[NH:14][C:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:10])([F:9])[F:11])=[CH:5][C:4]=2[Cl:12])=[N:17][C:16]=1[C:18]([F:21])([F:19])[F:20]
Reactant: BrBr
Reactant: FC(F)(F)c1cc(Cl)c(-c2nc(C(F)(F)F)c[nH]2)c(Cl)c1
Solvent: CC(=O)O
Solvent: O
Product: FC(F)(F)c1cc(Cl)c(-c2nc(C(F)(F)F)c(Br)[nH]2)c(Cl)c1
Yield: 70.1 %

Procedure:
A solution of 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylimidazole (0.7 g, 0.002 mol) and bromine (0.32 g, 0.1 ml, 0.002 mol) in glacial acetic acid (5 ml) was stirred and heated at reflux for 2 hours. The cooled suspension was poured into cold water (50 ) and the solid was filtered and washed with water. The solid was dissolved in glacial acetic acid (5 ml) and bromine (0.32 g, 0.1 ml, 0.002 mol) was added. The mixture was stirred and heated at reflux for 2 hours, cooled and poured into cold water (50 ml). The solid was filtered and washed thoroughly with water to give 5-bromo-2-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylimidazole (0.6 g) as a white solid, m.p. 295° C. with decomposition.
Reaction SMILES: [CH2:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)[CH2:2][CH3:3].[Br:9][C:10]1[CH:11]=[CH:12][C:13]([O:18][CH3:19])=[C:14]([CH:17]=1)[CH:15]=O>>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([O:18][CH3:19])=[C:14]([CH2:15][C:6]2[S:5][C:4]([CH2:1][CH2:2][CH3:3])=[CH:8][CH:7]=2)[CH:17]=1
Reactant: CCCc1cccs1
Reactant: COc1ccc(Br)cc1C=O
Product: CCCc1ccc(Cc2cc(Br)ccc2OC)s1

Procedure:
2-n-Propylthiophene and 5-bromo-2-methoxybenzaldehyde were used and treated in a manner similar to Reference Example 7 to give the target compound. APCI-Mass m/Z 325/327 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[NH:8][CH:9]=[CH:10][C:6]=2[C:5]([C:11]([OH:13])=O)=[CH:4][N:3]=1.[CH2:14]([NH2:18])[CH:15]([CH3:17])[CH3:16]>>[CH2:14]([NH:18][C:11]([C:5]1[C:6]2[CH:10]=[CH:9][NH:8][C:7]=2[C:2]([Cl:1])=[N:3][CH:4]=1)=[O:13])[CH:15]([CH3:17])[CH3:16]
Reactant: O=C(O)c1cnc(Cl)c2[nH]ccc12
Reactant: CC(C)CN
Product: CC(C)CNC(=O)c1cnc(Cl)c2[nH]ccc12

Procedure:
Prepared in a similar manner to Example 19 (e) from 7-chloro-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid using isobutylamine (28 mg) instead of tetrahydro-pyran-4-ylmethylamine to give the title compound (38 mg).
Reaction SMILES: C(OC([N:8]1[CH:12]([C:13]([N:15]2[CH2:19][CH2:18][CH2:17][CH:16]2[C:20]#[N:21])=[O:14])[CH2:11][CH2:10][CH:9]1[CH2:22][O:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([NH2:34])=[CH:26][CH:25]=1)=O)(C)(C)C.N1C=CC=CC=1.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>C(Cl)Cl>[C:20]([C@@H:16]1[CH2:17][CH2:18][CH2:19][N:15]1[C:13]([C@H:12]1[NH:8][C@@H:9]([CH2:22][O:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([NH:34][S:42]([CH3:41])(=[O:44])=[O:43])=[CH:26][CH:25]=2)[CH2:10][CH2:11]1)=[O:14])#[N:21]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1C(COc2ccc(N)c3ccccc23)CCC1C(=O)N1CCCC1C#N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(OC[C@H]2CC[C@@H](C(=O)N3CCC[C@H]3C#N)N2)c2ccccc12

Procedure:
The compound of Example 97A (32 mg, 0.07 mmol) was dissolved in CH2Cl2 (1 mL) and pyridine (0.5 mL) in a microwave reaction tube. Methanesulfonyl chloride (6.0 μL, 0.21 mmol) was added. It was reacted under microwave condition at 130° C. for 20 minutes. The mixture was filtered and purified by reverse phase HPLC to give the desired sulfonamide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16](Cl)[N:15]=[C:14]([N:19]3[CH2:22][CH2:21][CH2:20]3)[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:23]([NH2:25])[CH3:24]>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([NH:25][CH2:23][CH3:24])[N:15]=[C:14]([N:19]3[CH2:22][CH2:21][CH2:20]3)[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1ccc(S(=O)(=O)Nc2cc(Cl)nc(N3CCC3)n2)cc1
Reactant: CCN
Solvent: CCO
Product: CCNc1cc(NS(=O)(=O)c2ccc(N)cc2)nc(N2CCC2)n1
Temperature: 130 °C
Reaction time: 12 h
Yield: 42.3 %

Procedure:
0.2 g (0.00061 mol) of 4-amino-N-(2-azetidin-1-yl-6-chloro-pyrimidin-4-yl)-benzenesulfonamide was dissolved in 20 ml of ethanol, treated with 3.9 ml (0.061 mol) of ethylamine and stirred in an autoclave at 130° C. for 12 hours. The reaction mixture was free from solvent, the residue was suspended in 5 ml of ethanol and treated in an ultrasound bath for 15 minutes. The precipitate was filtered off, dissolved in 10 ml of 0.1N NaOH and filtered. The filtrate was adjusted to pH 6 with 0.1N HCl. The precipitate was filtered off under suction, washed with water and dried. There was obtained 0.090 g (44%) of 4-amino-N-(2-azetidin-1-yl-6-ethylamino-pyrimidin-4-yl)-benzenesulfonamide as beige crystals; m.p.: 260-262° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[CH3:3].CS[C:17]1[NH:22][C:21](=[S:23])[C:20]([CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[CH:19][N:18]=1>N1C=CC=CC=1>[CH3:3][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:17]2[NH:22][C:21](=[S:23])[C:20]([CH2:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=[CH:19][N:18]=2)[N:9]=1)[CH3:1]
Reactant: CN(C)Cc1nc(CSCCN)cs1
Reactant: CSc1ncc(Cc2cccnc2)c(=S)[nH]1
Solvent: c1ccncc1
Product: CN(C)Cc1nc(CSCCNc2ncc(Cc3cccnc3)c(=S)[nH]2)cs1

Procedure:
Following the procedure of Example 12, a mixture of 1.11 g. of 2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylamine and 1.24 g. of 2-methylthio-5-(3-pyridyl)methyl-4-pyrimidinethione in 15 ml. of pyridine was refluxed for 2 days. The desired reaction product was purified by gradient elution high pressure liquid chromatography over silica using an ethyl acetate/ethanol/ammonium hydroxide solvent system as the eluant. Fractions shown by tlc to contain 2-[2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl]amino-5-(3-pyridyl)methyl-4-pyrimidinethione free base were combined and the solvent removed by evaporation.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[C:10](=[O:11])[NH:9][C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[S:6]1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>CN(C)C=O>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][N:27]([CH2:2][CH2:3][CH2:4][CH:5]2[C:10](=[O:11])[NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6]2)[CH2:26][CH2:25]1
Reactant: O=C1Nc2ccccc2SC1CCCCl
Reactant: COc1ccccc1N1CCNCC1
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(CCCC2Sc3ccccc3NC2=O)CC1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 26.6 %

Procedure:
In 10 ml of dimethylformamide were dissolved 1.6 g of 2-(3-chloropropyl)-2H-1,4-benzothiazin-3(4H)-one and 2.55 g of 1-(2-methoxyphenyl)piperazine. The solution was stirred at 100° C. for 1.5 hour. The reaction mixture was poured into ice-water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over MgSO4, then concentrated under reduced pressure. The concentrate was subjected to a column chromatography on silica-gel (150 g). From the eluate with hexane-acetone (2:1, v/v) was obtained 0.7 g of 2-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-2H-1,4-benzothiazin-3(4H)-one as an oily substance. The 3/2 oxalate of this product was obtained as crystals, which were recrystallized from methanol and dichloromethane to give colorless prisms. The yield was 470 mg (13.3%), m.p. 202°-204° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C@H:12]1[NH:15][C:14](=[O:16])[C@H:13]1[NH:17]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:17][C@H:13]1[C@@H:12]([N:3]2[C:2](=[O:1])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]2=[O:11])[NH:15][C:14]1=[O:16]
Reactant: O=C1N[C@H](N2C(=O)c3ccccc3C2=O)[C@@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: N[C@@H]1C(=O)N[C@@H]1N1C(=O)c2ccccc2C1=O

Procedure:
(3S-cis)-4-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)-3-[(triphenylmethyl)amino]-2-azetidinone(7 g) and 2.81 g of p-toluenesulfonic acid are stirred in 50 ml of chloroform for 1 hour at 0° C. and for 3 hours at room temperature. The title compound is collected.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.Cl[C:31]1[N:32]=[N:33][C:34]([CH3:37])=[CH:35][CH:36]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:17][CH2:18][N:19]([C:31]4[N:32]=[N:33][C:34]([CH3:37])=[CH:35][CH:36]=4)[CH2:20][CH2:21]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1
Reactant: Cc1ccc(Cl)nn1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1ccc(N2CCC(c3cc(F)c(Nc4ncc(Cl)c(Nc5cc(C)[nH]n5)n4)cc3C)CC2)nn1
Temperature: 150 °C
Reaction time: 15 h

Procedure:
A suspension of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (20 mg, 0.05 mmol), 3-chloro-6-methylpyridazine (13 mg, 0.1 mmol) and Cs2CO3 (33 mg, 0.1 mmol) in dioxane (1 mL) was stirred at 150° C. in a sealed vial. After 15 h, additional 3-chloro-6-methylpyridazine (26 mg) and Cs2CO3 (66 mg) were added. The reaction was continued for an additional 3 h. The crude reaction mixture was purified by RP-HPLC to give 5-Chloro-N2-(2-fluoro-5-methyl-4-(1-(6-methylpyridazin-3-yl)piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as a white solid;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].CO.S(Cl)([Cl:20])(=O)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[C:6]([Cl:20])[C:7]=1[OH:8]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)Cc1ccc(O)c(Br)c1
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)Cc1cc(Cl)c(O)c(Br)c1
Yield: 60 %

Procedure:
To a stirred solution of ethyl 2-(3-bromo-4-hydroxyphenyl)acetate (20 g, 0.076 molo) in 200 ml of DCM was added MeOH (3.4 ml, 0.84 mol) and the mixture was refluxed. Sulfuryl chloride (6.8 ml 0.846 mol) was slowly added under over a period of 10 min. The reaction mixture was refluxed for a further 5 h. Upon completion of reaction, the mixture was poured onto crushed ice and extracted with DCM (×2). The combined organic layer were washed with 10% NaHCO3 solution and water, dried over Na2SO4, filtered and evaporated under vacuum to give ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate in 60% yield. (13.6 g). 1H NMR (CDCl3): 7.37 (s,1H); 7.27 (s,1H); 5.68 (bs, 1H); 4.16 (q, 2H); 3.48 (s, 2H); 1.29 (t, 3H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([C:12]1[CH:13]=[C:14]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][N:15]2[CH:24]=1)(OCC)=[O:8].O.Cl>CCOCC>[OH:8][CH2:7][C:12]1[CH:13]=[C:14]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[NH:17][CH2:16][N:15]2[CH:24]=1
Reactant: CCOC(=O)c1cc2c3ccccc3ncn2c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: OCc1cc2n(c1)CNc1ccccc1-2
Temperature: 25 °C
Reaction time: 2 h
Yield: 122.4 %

Procedure:
LiAlH4 (0.50 g, 0.013 m) was slurried in ether (200 ml) and to this was added a solution of the product of Example II (1.0 g, 0.007 m) in ether (50 ml). The reaction mixture was stirred at room temperature for 2 hrs. Water (30 ml) was added and the mixture was acidified with 10% HCl. The resulting mixture was extracted with ether, the ether extracts combined, dried over Na2SO4, filtered, and the solvent removed in vacuo to yield 1.02 g of a white solid. Crystallization from EtOAc/hexane afforded the product as a white solid; m.p. 128°-130° C.
Reaction SMILES: ClCC([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH:9]=[CH:8]2)=O>N1C=CC=CC=1>[NH:11]1[C:12]2[C:7](=[CH:6][CH:5]=[CH:14][CH:13]=2)[CH:8]=[CH:9][C:10]1=[O:15]
Reactant: O=C(CCl)c1ccc2[nH]c(=O)ccc2c1
Solvent: c1ccncc1
Product: O=c1ccc2ccccc2[nH]1
Reaction time: 2 h

Procedure:
60 Grams of 6-(α-chloroacetyl)carbostyril was suspended in 0.5 kg of pyridine and stirred at 80°-90° C. for 2 hours, then the suspension was stirred under ice-cooling for 1 hour. The crystals thus precipitated were collected by filtration and recrystallized from methanol to obtain 70 g of 6-(α-pyridiniumacetyl)carbostyril chloride 1/2-hydrate in the form of colorless needle-like crystals. Melting point: over 300° C.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][CH2:5][C:6](=O)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[N:9]=1.[BH4-].[Na+].CC(C)=O>CO>[Br:14][C:10]1[N:9]=[C:8]([CH2:7][CH:6]2[O:16][C:3](=[O:2])[CH2:4][CH2:5]2)[CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)CCC(=O)Cc1cccc(Br)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Product: O=C1CCC(Cc2cccc(Br)n2)O1
Temperature: 1.5 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A solution of 490 mg of 5-(6-bromo-2-pyridyl)-4-oxo-pentanoic acid methyl ester in 20 ml of methanol is mixed under ice cooling with 72 mg of sodium borohydride and stirred for 1 hour at 0-3° C. Then, 2 ml of acetone is added, stirred for 1 more hour and the reaction mixture is evaporated to dryness. The residue is distributed between water and ethyl acetate, the organic phase is dried on sodium sulfate and concentrated by evaporation. 421 mg of 5-[(6-bromo-2-pyridyl)-methyl]-tetrahydrofuran-2-one is obtained as yellow oil.
Reaction SMILES: [C:1]1([C:7]2O[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:10][C:11](=[O:18])[C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.C(O)(=O)C.[CH2:31]([NH2:33])[CH3:32]>O>[CH2:31]([N:33]1[C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][C:11](=[O:18])[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:32]
Reactant: CCN
Reactant: CCOC(=O)c1c(-c2ccccc2)oc(-c2ccccc2)cc1=O
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)c1c(-c2ccccc2)n(CC)c(-c2ccccc2)cc1=O
Reaction time: 24 h

Procedure:
3.5 gms of 2,6-diphenyl-3-ethoxycarbonyl-pyr-4-one, 33 mls of methanol, 5 mls of water and 2 mls of glacial acetic acid were mixed. 7.6 mls of 70% aqueous ethylamine was then added slowly and the resulting mixture was allowed to stand at room temperature for 24 hours. The mixture was then diluted with 100 mls of water. The pH was adjusted to 2. Extraction with methylene chloride and evaporation of the solvent provided 3.0 gms of crude ethyl 1-ethyl-2,6-diphenyl-4-oxonicotinate as a brown oil. This material was dissolved in 20 mls of methanol. This solution was then added to 40 mls of 5% aqueous NaOH and heated on a steambath for 5 hours. The reaction mixture was cooled and acidified. Extraction with methylene chloride (3×50 mls) yielded an oily solid after evaporation. Crystallization from methylene chloride/ether yielded 1.6 gms of 1-ethyl-2,6-diphenyl-4-oxonicotinic acid. mp=210°-3° (dec).
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([Br:10])[NH:4][N:3]=1.[H-].[Na+].Br[CH2:14][CH:15]([OH:17])[CH3:16]>CN(C=O)C>[Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([Br:10])[N:4]([CH2:14][CH:15]([OH:17])[CH3:16])[N:3]=1
Reactant: CC(O)CBr
Reactant: O=[N+]([O-])c1c(Br)n[nH]c1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(O)Cn1nc(Br)c([N+](=O)[O-])c1Br
Temperature: 80 °C

Procedure:
A mixture of 3,5-dibromo-4-nitropyrazole (2) (40.0 g; 147 mmol) in DMF (200 ml) was added over 15 minutes to a suspension of NaH (6.5 g, 162 mmol; 60% dispersion in oil, prewashed with hexane) in DMF (320 ml) with stirring and under an inert atmosphere. After stirring for 35 minutes, a solution of 1-bromo-2-propanol (26.8 ml; 221 mmol) in DMF (80 ml) was added dropwise. The reaction mixture was heated at 80° C. for 2 hours and the DMF was then evaporated off under reduced pressure. A mixture of DCM/water (480 ml, 2/1) was added. The organic phase was extracted with DCM (2×160 ml). The combined organic phases were washed with water (3×400 ml). The organic phase was dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The 1-(3,5-dibromo-4-nitropyrazol-1-yl)-propan-2-ol was obtained as a white solid (23.3 g; 48%).