Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[O:5]=[C:6]1[CH:15]=[C:14]([CH2:16][C:17]([OH:19])=[O:18])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1.[CH3:20]COCC>CO>[O:5]=[C:6]1[CH:15]=[C:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1
Reactant: O=C(O)Cc1cc(=O)[nH]c2ccccc12
Reactant: CCOCC
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)Cc1cc(=O)[nH]c2ccccc12
Reaction time: 8 h
Yield: 80 %

Procedure:
95 g (0.8 mol) of thionyl chloride are added dropwise in the course of approximately 1 h to a stirred suspension of 60 g (0.295 mol) of 2-oxo-1,2-dihydro-4-quinolineacetic acid in 1 1 of methanol. The mixture is left overnight. The solvent is driven off and the residue obtained is dissolved in 300 ml of boiling methanol. After the mixture is cooled, 300 ml of ether are added. The solid is drained and then recrystallized in methanol. 51.5 g (80%) of methyl 2-oxo-1,2-dihydro-4-quinolineacetate, melting point 209°-210° C., are obtained
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:16])=[CH:4][C:5]([O:14][CH3:15])=[C:6]([NH:8][C@@H:9]([CH3:13])[C:10]([OH:12])=O)[CH:7]=1.[N:17]1([CH:23]2[CH2:26][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24]2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C>[Br:1][C:2]1[C:3]([Cl:16])=[CH:4][C:5]([O:14][CH3:15])=[C:6]([NH:8][C@@H:9]([CH3:13])[C:10]([N:20]2[CH2:21][CH2:22][N:17]([CH:23]3[CH2:24][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26]3)[CH2:18][CH2:19]2)=[O:12])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(N2CCNCC2)C1
Reactant: COc1cc(Cl)c(Br)cc1N[C@@H](C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(Cl)c(Br)cc1N[C@@H](C)C(=O)N1CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.8 %

Procedure:
To a solution of (S)-2-(5-bromo-4-chloro-2-methoxyphenylamino)propanoic acid (1.6 g, 5.21 mmol), tert-butyl 3-(piperazin-1-yl)azetidine-1-carboxylate (1.88 g, 7.82 mmol), EDCI.HCl (2.0 g, 10.42 mmol), HOBt (1.41 g, 10.42 mmol) in DMF (20 mL) at 0° C., Et3N (1.58 g, 15.63 mmol) was added. The resulting mixture was stirred at RT for 16 h and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (methanol/dichloroethane=1:50) to afford the desired product (2.1 g, 76% yield). ESI-MS m/z: 531.3[M+H]+.
Reaction SMILES: CON=[C:4]([CH2:10][C:11](=O)[CH3:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:17]=1[NH:24][NH2:25]>C(O)(=O)C.C(OCC)(=O)C>[CH3:12][C:11]1[CH:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:24]([C:17]2[C:16]([Cl:15])=[CH:21][C:20]([Cl:22])=[CH:19][C:18]=2[Cl:23])[N:25]=1
Reactant: CCOC(=O)C(CC(C)=O)=NOC
Reactant: NNc1c(Cl)cc(Cl)cc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C)nn1-c1c(Cl)cc(Cl)cc1Cl
Temperature: 105 °C
Reaction time: 20 h
Yield: 42 %

Procedure:
A mixture of ethyl 2-(methoxyimino)-4-oxopentanoate (2.00 g, 10.7 mmol) and 2,4,6-trichlorophenylhydrazine hydrochloride (3.39 g, 16.0 mmol) in acetic acid (40 ml) and 2-methoxuethanol (20 ml) was stirred for 20 h at 105° C. The solvent was under vacuum and the residue was dissolved in ethyl acetate. The organic solution was washed with 0.2N HCl and water, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by silica gel chromatography eluting with 10% ethyl acetate/n-hexane to give the title compound (1.50 g, 42%).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=O)[NH:10][C:4]=2[CH:3]=1.B.C1COCC1.O>C1COCC1>[Br:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:4]=2[CH:3]=1
Reactant: O=C1CCCc2ccc(Br)cc2N1
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: Brc1ccc2c(c1)NCCCC2
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of 8-bromo-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (500 mg, 2.082 mmol) in THF (20 mL) at RT was added borane-THF complex (1M solution in THF) (5.206 mL, 5.21 mmol). The reaction mixture was refluxed for 3 hours, after which the reaction mixture was cooled in an ice bath before the addition of a further amount of borane-THF complex (1M solution in THF) (7.290 mL, 7.29 mmol). The reaction mixture was once again refluxed overnight. The reaction mixture was cooled in an ice bath before the dropwise addition of water. The aqueous layer was then extracted with diethyl ether (3×25 mL). The organic layers were combined, passed through a hydrophobic frit and concentrated. This residue was purified on silica column eluting with ethyl acetate in cyclohexane (0-15%) to afford the title compound (400 mg). LCMS (A): m/z (M+H)+ 226/228, C10H12BrN requires 225/227 (acidic).
Reaction SMILES: Cl.[CH:2]1[C:15]2[C:14](=[C:16]3[CH2:21][CH2:20][N:19]([C:22](=[O:25])[CH2:23][NH2:24])[CH2:18][CH2:17]3)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>ClCCl>[O:25]=[C:22]([N:19]1[CH2:20][CH2:21][C:16](=[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[S:7][C:6]3[C:15]2=[CH:2][CH:3]=[CH:4][CH:5]=3)[CH2:17][CH2:18]1)[CH2:23][NH:24][C:34](=[O:35])[O:36][CH2:37][CH3:38]
Reactant: NCC(=O)N1CCC(=C2c3ccccc3Sc3ccccc32)CC1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NCC(=O)N1CCC(=C2c3ccccc3Sc3ccccc32)CC1
Reaction time: 0.25 h

Procedure:
50 mg (0.134 mmol) of 2-[4-(9H-thioxanthen-9-ylidene)-1-piperidinyl]-2-oxoethanamine hydrochloride was dissolved in dichloromethane. 41 mg (0.405 mmol) of triethylamine was added to the obtained solution. A solution of 17.5 mg (0.161 mmol) of ethyl chloroformate in 0.5 ml of dichloromethane was added to the resultant mixture. After stirring for 15 minutes, the product was purified by the thin-layer silica gel chromatography (hexane: ethyl acetate=85:100) to obtain the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](Cl)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1([C@H:24]([CH2:26][OH:27])[NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:25][C@H:24]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:26][OH:27])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H](CO)c1ccccc1
Reactant: O=C(Cl)c1cccc(OCc2ccccc2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@@H](CO)c1ccccc1)c1cccc(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 3-benzyloxybenzoic acid (22 g, 96 mmol) in toluene (200 ml) was added dropwise thionyl chloride (14.1 ml, 19 mmol). The reaction mixture was heated at 90° C. for 2 hours, cooled to ambient temperature and volatiles removed under reduced pressure to afford crude 3-benzyloxybenzoyl chloride (32 g, quant.). The crude 3-benzyloxybenzoyl chloride was dissolved in CH2Cl2 and added dropwise over 30 min., to a vigorously stirred solution of (R)-(-)-2-phenylglycinol (15.8 g, 115 mmol) and triethylamine (16 ml, 15 mmol) in CH2Cl2 (200 ml) cooled to 0° C. The reaction mixture was allowed to warm ambient temperature and stirred for overnight. Solvent was removed under reduced pressure and the residue partitioned between ethyl acetate (1 L) and water (1 L). The aqueous layer was separated, extracted with ethyl acetate (2×500ml) and the combined organic phase washed with 1N HCl (500 ml), aqueous 4% NaHCO3 solution (500 ml) and brine (500 ml), dried over MgSO4 and concentrated under reduced pressure to give 2-(3-benzyloxybenzamido)-2(R)-phenylethan-1-ol (29 g, 88%) as pale yellow solids.
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][S:7][C:8](=[NH:10])[NH2:9].[O-]CC.[Na+].CN([CH:18]=[C:19]1[C:23](=O)[CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]1)C>C(O)C>[CH3:6][S:7][C:8]1[N:9]=[CH:18][C:19]2[CH2:20][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22][C:23]=2[N:10]=1
Reactant: CN(C)C=C1CN(C(=O)OC(C)(C)C)CC1=O
Reactant: CSC(=N)N
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: CSc1ncc2c(n1)CN(C(=O)OC(C)(C)C)C2
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-methyl-2-thiopseudourea sulfate (3.5 g, 25 mmol) in ethanol at 0° C. was added a solution of sodium ethoxide (9.6 mL, 21%). After stirring for 10 min, a solution of tert-butyl 3-[(dimethylamino)methylene]-4-oxopyrrolidine-1-carboxylate (2.0 g, 8.32 mmol) in ethanol was added, and the mixture was heated at 80° C. for 1 h. Additional 2-methyl-2-thiopseudourea sulfate (3.5 g, 25 mmol) and sodium ethoxide (9.6 mL, 21%) was added and heated at 80° C. for 1 h. The ethanol was removed under reduced pressure, the residue was diluted with ethyl acetate (400 mL), washed with saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate, and concentrated. The residue was purified on a Biotage silica gel cartridge (gradient 10-35% ethyl acetate in hexanes) to yield tert-butyl 2-(methylthio)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate.
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[C:9]([C:13]1[CH:47]=[CH:46][C:16]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2/[CH:25]=[CH:26]/[CH:27]([CH2:40][CH2:41][CH2:42][CH2:43][C:44]#[N:45])[CH2:28][CH2:29][C:30]2[CH:39]=[CH:38][C:33]([C:34]([NH:36][NH2:37])=[O:35])=[CH:32][CH:31]=2)=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>O1CCOCC1>[C:9]([C:13]1[CH:14]=[CH:15][C:16]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2/[CH:25]=[CH:26]/[CH:27]([CH2:28][CH2:29][C:30]2[CH:39]=[CH:38][C:33]([C:34]3[O:35][C:2](=[O:3])[NH:37][N:36]=3)=[CH:32][CH:31]=2)[CH2:40][CH2:41][CH2:42][CH2:43][C:44]#[N:45])=[CH:46][CH:47]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1ccc(COc2ccccc2/C=C/C(CCCCC#N)CCc2ccc(C(=O)NN)cc2)cc1
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(COc2ccccc2/C=C/C(CCCCC#N)CCc2ccc(-c3n[nH]c(=O)o3)cc2)cc1
Yield: 23 %

Procedure:
A solution of 566.6 mg (2.86 mmol) of trichloromethyl chloroformate in 2.5 ml of dry dioxane is mixed with 1.0 g of 4-[3-((E)-2-{2-[(4-tert-butylbenzyl)oxy]phenyl}vinyl)-7-cyanoheptyl]-benzohydrazide from Example 97A (crude product) in 7.5 ml of dioxane and heated to reflux for 3 hours. The mixture is then directly taken up on silica gel, concentrated to dryness and purified by flash chromatography (mobile phase: dichloromethane/methanol 5:1). 236 mg (0.429 mmol, 23% yield based on two stages) of a solid are obtained.
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([CH:46]([CH3:48])[CH3:47])=[N:43][C:42]=2[C:49]2[CH:50]=[C:51]([CH:53]=[CH:54][CH:55]=2)[NH2:52])[CH:38]=[CH:37][N:36]=1.[F:56][C:57]1[CH:58]=[CH:59][C:60]([O:67][CH3:68])=[C:61]([S:63](Cl)(=[O:65])=[O:64])[CH:62]=1>>[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([CH:46]([CH3:48])[CH3:47])=[N:43][C:42]=2[C:49]2[CH:50]=[C:51]([NH:52][S:63]([C:61]3[CH:62]=[C:57]([F:56])[CH:58]=[CH:59][C:60]=3[O:67][CH3:68])(=[O:64])=[O:65])[CH:53]=[CH:54][CH:55]=2)[CH:38]=[CH:37][N:36]=1
Reactant: CC(C)c1nc(-c2cccc(N)c2)c(-c2ccnc(Cl)n2)s1
Reactant: COc1ccc(F)cc1S(=O)(=O)Cl
Agent: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Product: COc1ccc(F)cc1S(=O)(=O)Nc1cccc(-c2nc(C(C)C)sc2-c2ccnc(Cl)n2)c1
Yield: 79 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]aniline (309 mg, 0.934 mmol) and 5-fluoro-2-(methyloxy)benzenesulfonyl chloride (210 mg, 0.934 mmol) the title compound of Step A was obtained as a white solid. (381 mg, 79% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.34 (s, 1H), 8.42 (d, J=5.3 Hz, 1H), 7.39-7.54 (m, 2H), 7.23-7.37 (m, 1H), 7.09-7.23 (m, 4H), 6.87 (d, J=5.3 Hz, 1H), 3.79 (s, 3H), 3.29-3.38 (m, 1H), 1.33 (d, J=6.9 Hz, 6H).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:18]([N:20]([CH2:23][CH2:24][Cl:25])[CH2:21][CH3:22])[CH3:19]>>[ClH:25].[CH2:18]([N:20]([CH2:23][CH3:24])[CH:21]([C:14]1[C:13]([CH3:16])=[CH:12][CH:11]=[C:10]2[C:15]=1[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[N:8][NH:9]2)[CH3:22])[CH3:19]
Reactant: CCN(CC)CCCl
Reactant: Cc1ccc2[nH]nc(-c3ccccc3)c2c1
Agent: Cl
Product: CCN(CC)C(C)c1c(C)ccc2[nH]nc(-c3ccccc3)c12
Yield: 58.1 %

Procedure:
By the procedure similar to that described in Example 1, 3-phenyl-5-methylindazole (4.17 g) and diethylaminoethyl chloride hydrochloride (5.16 g) were treated to obtain 4.0 g of 1-diethylaminoethyl-3-phenyl-5-methylindazole hydrochloride (m.p. 131°-133° C).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=2[NH:7][C:6]1=[O:15].ClCCl.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(N(CC)CC)C>[CH3:19][S:20]([O:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=2[NH:7][C:6]1=[O:15])(=[O:22])=[O:21]
Reactant: Cc1ccc2c(c1)[nH]c(=O)n2CCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)[nH]c(=O)n2CCCOS(C)(=O)=O
Reaction time: 1 h
Yield: 58 %

Procedure:
To a stirred solution of 18.5 parts of 1,3-dihydro-1-(3-hydroxypropyl)-5-methyl-2H-benzimidazol-2-one in 325 parts of dichloromethane are added 11.9 parts of N,N-diethylethanamine. Then there are added dropwise (slowly) 11.5 parts of methanesulfonyl chloride. Upon completion, stirring is continued for 1 hour at reflux temperature. After cooling, the reaction mixture is washed with water, dried, filtered and evaporated. The solid residue is crystallized from 4-methyl-2-pentanone, yielding 15 parts (58%) of 3-(2,3-dihydro-5-methyl-2-oxo-1H-benzimidazol-1-yl)propyl methanesulfonate; mp 125° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][O:29][C:23]=3[CH:22]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][O:29][C:23]=4[CH:22]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: Cc1sc2nc(Cl)nc(NCCc3ccc4c(c3)OCO4)c2c1C
Product: Cc1sc2nc(-n3cccn3)nc(NCCc3ccc4c(c3)OCO4)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-5,6-dimethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5,6-dimethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:10]=[C:9]([CH2:11][O:12][C:13](=[O:15])[CH3:14])[NH:8][N:7]=1)(=[O:3])[CH3:2].[H-].[Na+].F[C:19]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][C:20]=1[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22]>CN(C=O)C>[C:13]([O:12][CH2:11][C:9]1[CH:10]=[C:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[N:7]([C:19]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][C:20]=2[C:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:22])[N:8]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)OCc1cc(COC(C)=O)[nH]n1
Reactant: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1cc(COC(C)=O)n(-c2ccc([N+](=O)[O-])cc2C(=O)c2ccccc2)n1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of 4.2 g. (20 mmol) of 3,5-diacetoxymethylpyrazole in 15 ml. of DMF was added dropwise to a suspension of 960 mg. (20 mmol) of NaH (50% in mineral oil) in 25 ml. of DMF stirred at 0° and under argon. After the evolution of H2 had ceased, 4.9 g. (20 mmol) of 2-fluoro-5-nitrobenzophenone was added in one portion. After stirring at 0° for 4 hours, the mixture was poured into ice-water and extracted with EtOAc. The organic phase was washed with dil. brine, dried (MgSO4) and concentrated. The residue was chromatographed on silica gel using benzene/EtOAc (1:1) as eluent. Removal of the solvents gave crude end product as a gum which was not purified further. The nmr (CDCl3) had signals at: δ2.00 (3H, s, CH3), 2.07 (3H, s, CH3), 4.82 (2H, s, CH2), 5.10 (2 H, s, CH2) 6.33 (1H, s, C=CH), and 7.30-8.67 (8H, m, C6H5 +C6H3).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[C:18]([OH:19])=[C:17]([Br:20])[CH:16]=[CH:15][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11].CN(C=O)C.Cl[CH2:27][C:28]([NH2:30])=[O:29]>O>[Br:7][C:8]1[C:18]([O:19][CH2:27][C:28]([NH2:30])=[O:29])=[C:17]([Br:20])[CH:16]=[CH:15][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1ccc(Br)c(O)c1Br
Reactant: NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Br)c(OCC(N)=O)c1Br
Temperature: 120 °C

Procedure:
0.853 g (6.20 mmol) of K2CO3, 0.154 g (0.90 mmol) of Kl and 1.000 g (3.10 mmol) of ethyl 2,4-dibromo-3-hydroxybenzoate were introduced into 15 ml of DMF. 0.346 g (3.70 mmol) of chloroacetamide was added at RT, and the mixture was heated for 6 hours at 120° C. The mixture was then poured into water and extracted with diisopropyl ether. The combined organic phases were washed with water, dried over Na2SO4 and concentrated completely. Drying in an oil-pump vacuum gave ethyl 2,4-dibromo-3-(aminocarbonylmethoxy)benzoate as a brown oil.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH3:19])=[O:17].[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[C:23]([CH3:28])[CH:22]=1>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:25][C:24]3[CH:26]=[CH:27][C:21]([F:20])=[CH:22][C:23]=3[CH3:28])=[C:3]([C:16]([O:18][CH3:19])=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)OC)cnc12
Reactant: Cc1cc(F)ccc1N
Product: CCOC(=O)c1cnn2c(Nc3ccc(F)cc3C)c(C(=O)OC)cnc12
Yield: 100.4 %

Procedure:
In the same manner as in Example 1, step 4 and using methyl 7-chloro-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine-6-carboxylate (2.80 g, 9.87 mmol) obtained in Example 21, step 2 and 4-fluoro-2-methylaniline (1.85 g, 14.8 mmol), the title compound (3.69 g, 100%) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[CH:22]=O)=[O:16])([CH3:13])([CH3:12])[CH3:11]>C(O)C>[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[C:22]1[NH:9][C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=2[N:8]=1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCCC1C=O
Reactant: Nc1ccc(Br)cc1N
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCC1c1nc2ccc(Br)cc2[nH]1
Temperature: 80 °C
Yield: 55.5 %

Procedure:
A mixture of 4-bromo-benzene-1,2-diamine (2.4 g) and 2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2.55 g) in ethanol (5 mL) was heated in microwave at 80° C. for 1 hour. Mixture was concentrated and purified by flash column chromatography (silica gel, 20 to 80% ethyl acetate/hexane) to give 2-(6-bromo-1H-benzoimidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (2.6 g, yield 55%). LCMS-ESI−: calc'd for C16H20BrN3O2: 366.25. Found: 365.8 (M+H+).
Reaction SMILES: [Na].[SH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.Br[C:10]1[CH:11]=[CH:12][C:13]2[N:14]([C:16]([N+:19]([O-:21])=[O:20])=[CH:17][N:18]=2)[CH:15]=1>CN1CCCC1=O>[N+:19]([C:16]1[N:14]2[CH:15]=[C:10]([S:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=3)[CH:11]=[CH:12][C:13]2=[N:18][CH:17]=1)([O-:21])=[O:20]
Reactant: Sc1ccccn1
Reactant: O=[N+]([O-])c1cnc2ccc(Br)cn12
Agent: [Na]
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cnc2ccc(Sc3ccccn3)cn12

Procedure:
A solution of 1.61 g. (0.012 mole) of the sodium salt of 2-mercapto pyridine and 2.42 g. (0.01 mole) of 6-bromo-3-nitroimidazo [1,2-a] pyridine in 10 ml. N-methylpyrolidinone is heated at 150° C. for 40 minutes under a nitrogen atmosphere. The cooled solution is poured onto 100 ml. of ice-water and the resultant suspension is extracted with ethyl acetate. The combined extracts are washed with saturated aqueous sodium chloride and dried over magnesium sulfate. Evaporation of the solvent to a small volume and dilution with N-hexane yields crystalline material. The solids are purified by chromatography on silica gel. Elution with methylene chloride yields pure 3-nitro 6-(2-pyridylthio) imidazo [1,2-a] pyridine.
Reaction SMILES: C[O-].[Na+].[C:4]([OH:8])(=[O:7])[CH2:5][SH:6].Cl[CH2:10][C:11]#[C:12][CH2:13][C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].O>CO>[C:4]([OH:8])(=[O:7])[CH2:5][S:6][CH2:10][C:11]#[C:12][CH2:13][C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCC#CCC#CCCl
Reactant: O=C(O)CS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCCC#CCC#CCSCC(=O)O
Reaction time: 0.5 h

Procedure:
3.85 ml of a 30% solution of sodium methoxide in methanol were added dropwise to a solution of 742 μl of thioglycolic acid in 8 ml of methanol, under an inert atmosphere. The mixture was maintained under stirring for 30 min and then a solution of 2 g of 1-chloro-2,5-dodecadiyne in 20 ml of methanol was added under an inert atmosphere. The mixture was maintained under stirring for 15 hours at room temperature and then the reaction medium was poured over 100 ml of acid water (98 ml of water+2 ml concentrated H2SO4) and then extracted 3 times with ethyl ether. The combined organic phases were washed 3 times with water and then with a saturated aqueous solution of NaCl before being dried (Na2SO4), filtered and concentrated under vacuum in a rotary evaporator. The oily residue obtained crystallized at cold temperature. 3-Thia-5,8-pentadecadiynoic acid was recrystallized from diisopropyl ether.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[OH-].[Na+].[C:7]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:20][C:21]2[C:26]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[C:25](Cl)[N:24]=[C:23]([C:37]3[N:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[N:22]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8].C(O)(=O)C(C(C(O)=O)O)O>O1CCCC1.O>[CH3:8][C:7]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:20][C:21]2[C:26]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[C:25]([O:3][CH2:2][CH2:1][OH:4])[N:24]=[C:23]([C:37]3[N:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[N:22]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1)([CH3:10])[CH3:9]
Reactant: OCCO
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2ncccn2)nc1OCCO
Temperature: 50 °C
Reaction time: 12 h
Yield: 85 %

Procedure:
Ethylene glycol (315.29 g, 107 eq) was mixed in tetrahydrofuran (175 ml, 7 vol) and sodium hydroxide (19.01 g, 10 eq) was added. The mixture was heated to 50° C. for 30 minutes or until the solution became clear. To the clear solution was added 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidin-4-yl]-benzenesulfonamide (25 g, 1 eq) at 50° C. and stirred at 65° C. for 12 hours. The tetrahydrofuran was distilled out under vacuum at 210-220 mbar pressure at 35° C. The resulting solution was cooled to 10° C., a solution of tartaric acid (35.65 g, 5 eq) in water (100 ml, 4 vol) was added and stirred for 1.5 hours at the same temperature. The resultant solid was filtered, washed with a mixture of isopropyl alcohol (100 ml, 4 vol), ethanol (50 ml, 2 vol) and water (200 ml, 8 vol), and dried under vacuum at 60° C. to obtain the product as an off-white solid.