Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5](Cl)=[C:4]2[CH:9]=[N:10][C:11]([CH3:15])=[C:12]([O:13][CH3:14])[C:3]=12.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>>[CH3:15][C:11]1[N:10]=[CH:9][C:4]2=[C:5]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[N:6]=[N:7][C:2]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[C:3]2[C:12]=1[O:13][CH3:14]
Reactant: C1COCCN1
Reactant: COc1c(C)ncc2c(Cl)nnc(Cl)c12
Product: COc1c(C)ncc2c(N3CCOCC3)nnc(N3CCOCC3)c12

Procedure:
0.5 parts by weight of 1,4-dichloro-7-methyl-8-methoxypyrido (3,4-d) pyridazine and 3.6 parts by weight of morpholine are heated together at 80° C for 1.5 hours and, then, the excess morpholine is distilled off. To the residue is added water, whereupon an oily precipitate is obtained. This oil is triturated with a small amount of methanol to obtain crystals of 7-methyl-8-methoxy-1,4-dimorpholinopyrido (3,4-d)-pyridazine. Recrystallization from a mixture of methanol and water (1:3) yields crystals melting at 145°-146° C. Yield 0.5 parts by weight. Elementary analysis for C17H24O3N5
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:6][C@H:5]([CH2:7][O:8][C:9]2[C:10](C)=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14]C)=[O:13])[CH2:4][O:3]1.[OH-].[Li+]>CO.O>[CH3:1][C:2]1([CH3:20])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([OH:14])=[O:13])[CH2:4][O:3]1
Reactant: COC(=O)c1cccc(OC[C@@H]2COC(C)(C)O2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)OC[C@@H](COc2cccc(C(=O)O)c2)O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 105.7 %

Procedure:
Methyl 3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy)-2-methylbenzoate (4.2 g, 15 mmol) was dissolved in 20 mL of methanol and 1 mL of water. To the above solution was added lithium hydroxide (2.4 g, Seq.). After stirring the reaction mixture at room temperature for 4 h, the volatile was removed under vacuo and the residue was partitioned between EtOAc and H2O. The aqueous layer was separated, cooled with an ice bath, and then acidified with 10% aq. HCl. The acidic aqueous layer was extracted with EtOAc. The EtOAc layer was washed with NaCl (sat.), dried over Na2SO4, and concentrated to give 3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy)benzoic acid as a white solid (4 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH:22]=O)[C:8]([F:11])=[CH:9][CH:10]=1.Cl.[F:26][C:27]([F:31])([F:30])[CH2:28][NH2:29]>>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:14][C:13]=2[CH2:22][NH:29][CH2:28][C:27]([F:31])([F:30])[F:26])[C:8]([F:11])=[CH:9][CH:10]=1
Reactant: NCC(F)(F)F
Reactant: COC(=O)Cc1ccc(F)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Agent: Cl
Product: COC(=O)Cc1ccc(F)c(-c2ccc(C(F)(F)F)cc2CNCC(F)(F)F)c1

Procedure:
Prepared according to the procedure described in Example 4, Step 1, using the following starting materials: (6-fluoro-2′-formyl-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and 2,2,2-trifluoroethylamine hydrochloride.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([CH:8]([CH3:10])[CH3:9])[N:4]=1.[OH:11][CH:12]1[CH2:16][CH2:15][NH:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[OH:11][CH:12]1[CH2:16][CH2:15][N:14]([CH2:2][C:3]2[O:7][N:6]=[C:5]([CH:8]([CH3:10])[CH3:9])[N:4]=2)[CH2:13]1
Reactant: CC(C)c1noc(CCl)n1
Reactant: OC1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)c1noc(CN2CCC(O)C2)n1
Temperature: 65 °C
Yield: 81.4 %

Procedure:
A mixture of 5-chloromethyl-3-isopropyl-[1,2,4]oxadiazole (1.6 g, 10 mmol) and (RS)-3-hydroxypyrrolidine (960 mg, 11 mmol) were combined neat, diluted with MeCN (10 mL), and K2CO3 (2.75 g, 20 mmol) was added. The mixture was heated at 65° C. for 1 h, and was filtered upon cooling. The solvent was removed and the residue was taken up in CH2Cl2 and rinsed with water. The organic extract was dried over MgSO4, the solvent was removed, and the residue was taken up in ether and filtered in order to remove a small amount of quaternary ammonium byproduct. Solvent removal from the filtrate gave (RS)-3-hydroxy-1-[(3-isopropyl-1,2,4-oxadiazol-5-yl)methyl]pyrrolidine as an amber oil (1.72 g, 82% yield): 1H NMR (DMSO-d6) δ 4.76 (d, 1H, J=4.5 Hz), 4.19 (m, 1H), 3.90 (s, 2H), 3.05 (m, 1H), 2.79 (m, 1H), 2.69 (m, 1H), 2.53 (m, 1H), 2.43 (m, 1H), 1.98 (m, 1H), 1.54 (m, 1H), 1.25 (d, 6H, J=6.8 Hz); MS m/z 212.1 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[N:32]1[S:36][N:35]=[C:34]2[C:37]([S:41](Cl)(=[O:43])=[O:42])=[CH:38][CH:39]=[CH:40][C:33]=12>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:41]([C:37]4[C:34]5=[N:35][S:36][N:32]=[C:33]5[CH:40]=[CH:39][CH:38]=4)(=[O:43])=[O:42])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: O=S(=O)(Cl)c1cccc2nsnc12
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4cccc5nsnc45)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and benzo[1,2,5]thiadiazole-4-sulfonyl chloride. Purity (ELSD, based on MW=619.7)=80%.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].Br[CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C1C=CC=CC=1>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: Cc1cccc(C)c1N
Reactant: CCOC(=O)C(C)Br
Solvent: c1ccccc1
Product: CCOC(=O)C(C)Nc1c(C)cccc1C
Yield: 40 %

Procedure:
Chem. Soc. (1961), 3,303-3,308 discloses that 2,6-dimethylaniline and ethyl α-bromopropionate can be reacted in benzene to give ethyl α-(2,6-dimethylanilino)propionate. Though the reaction time is 96 hours, the yield achievable is only 37 percent. As is shown, however, in Chemische Berichte, 22 (1889), 1,792-1,795, the yield is virtually quantitative if the two sterically hindering substituents in the 2,6-position are absent, ie. if aniline is used as the starting material. A comparison of the reaction of aniline and of ortho-methylaniline with ethyl 2-chloropropionate for 12 hours at 120°-125° C. in the presence of sodium acetate (C.R. Acad. Sc. Paris, 264 (Series C, 1967), 1,864-1,865) shows a yield of 40 percent based on aniline and 20 percent based on ortho-methylaniline, and thus shows the effect of even one ortho-substituent. The same reaction with the methyl group in the meta-position or para-position instead of the ortho-position gives yields of 33 and 57 percent. Accordingly, the yield increases the more remote the substituent is from the amino group.
Reaction SMILES: [C:1]([O:5][C:6](N1CCCC[C@H]1C(O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH2:17].O[N:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=N1.CCN=C=NCCCN(C)C.Cl.N>C(Cl)Cl.CN(C=O)C>[C:1]([O:5][C:6]([NH:19][C:23]([C@@H:24]1[CH2:25][CH2:26][CH2:27][CH2:22][NH:21]1)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(=O)[C@@H]1CCCCN1
Yield: 56.9 %

Procedure:
(2S)—N-(tert-Butyloxycarbonyl)pipecolinic acid (3.0 g, 13.0 mmol) was dissolved in CH2Cl2/DMF (9:1, 150 ml). To this solution at 0° C. was added 1-hydroxybenzotriazole hydrate (2.0 g, 14.8 mmol) and water soluble carbodiimide (2.74 g, 13.7 mmol). After 1 h at 0° C. ammonia (35%, 25 ml) was added. After 18 h at 0° C. to room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (500 ml). This solution was washed with 0.3M KHSO4, sat. NaHCO3, water and brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (eluant: 4% methanol, 96% chloroform) to give a white solid identified as the title compound (1.7 g, 7.4 mmol, 57%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(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>[C:17]([O:16][C:14]([NH:13][C@H:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:21])[CH:27]=2)=[CH:3][CH:4]=1)[C:10]([OH:12])=[O:11])=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Br)cc1)C(=O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)O
Temperature: 25 °C

Procedure:
(R)-3-(4-Bromo-phenyl)-2-tert-butoxycarbonylamino-propionic acid (4.0 g, 11.6 mmol), 3-chlorophenylboronic acid (2.36 g, 15.11 mmol), Pd(PPh3)4 (0.067 g, 0.058 mmol) and 2M Na2CO3 aqueous solution (8.0 mL) are refluxed in 1,2-dimethoxyethane (70 mL) for 2.5 h under N2 atmosphere. After cooling to room temperature, the reaction mixture is diluted with EtOAc and washed with 1M HCl and brine. The organic layer is dried over Na2SO4 and concentrated. The residue is purified by flash column chromatography (silica gel, DCM/10% MeOH in DCM=100:0 to 0:100). to give (R)-2-tert-butoxycarbonylamino-3-(3′-chloro-biphenyl-4-yl)-propionic acid (containing impurities). HPLC retention time=1.56 minutes (condition A): MS (m+1)=376.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N+:11]([C:5]1[CH:4]=[CH:3][C:2]([O:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])([O-:13])=[O:12]
Reactant: Oc1ccccc1
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 123.1 %

Procedure:
A solution of 5-fluor-2-nitrobenzoic acid (2.6 g, 14.1 mmol, Aldrich Chemical Co., Milwaukee, Wis.) and phenol (1.5 g, 15.5 mmol, Aldrich Chemical Co., Milwaukee, Wis.) in DMF (70 mL) was treated with K2CO3 (5.9 g, 42.4 mmol) and heated to 120° C. for 6 hours. The reaction was cooled to room temperature and the solvent removed under reduced pressure. The resulting residue was dissolved in water and extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaCl, dried (Na2SO4), filtered, and concentrated to afford 34A (4.5 g).
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([O:11][C:12](=[O:14])[CH3:13])=[CH:9][C:8]([C:15](=[O:17])[CH3:16])=[C:7]([OH:18])[CH:6]=1)(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)=O.[CH3:24]CCCCC.CN(C)[CH:32]=[O:33]>CC(C)=O>[C:12]([O:11][C:10]1[C:5]([O:4][C:1](=[O:3])[CH3:2])=[CH:6][C:7]2[O:18][CH:24]=[C:16]([CH:32]=[O:33])[C:15](=[O:17])[C:8]=2[CH:9]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)Oc1cc(O)c(C(C)=O)cc1OC(C)=O
Reactant: CN(C)C=O
Reactant: CCCCCC
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(C)=O
Product: CC(=O)Oc1cc2occ(C=O)c(=O)c2cc1OC(C)=O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of [4,5-bis(acetyloxy)-2-hydroxyphenyl]ethanone (2.74 g, 0.0109 mol) in dimethylformamide (10 ml) at -78° C. under nitrogen was added phosphorous oxychloride (3.85 ml, 0.0414 mol) over 15 minutes. The reaction was kept at -78° C. for 15 minutes, 0° C. for 30 minutes and 22° C. for 4 hours. The reaction was poured into ice water (120 ml). The resulting precipitate, A, was stirred for 30 minutes, filtered and washed with water (3×20 ml). The filtrate, A, was extracted with chloroform (2×150 ml) and the organic extracts were combined, washed with water (3×200 ml), dried, filtered, and concentrated in vacuo to give an oily residue, C. The precipitate, A, was dissolved in acetone (50 ml) and the organic solution was dried over sodium sulfate, filtered and concentrated to 20 ml. Crystals formed and hexane (5 ml) was added. The crystals, B, were filtered and dried to give 1.32 g of the title compound, melting point 133°-135° C. The mother liquors from B and the residue, C, were combined and concentrated to dryness. The residue was crystallized from dichloromethane:hexane to give an additional 531 mg of desired product.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=O.O.[NH2:18][NH2:19]>C(O)CO>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=[N:18][NH2:19]
Reactant: COc1ccc(C(=O)c2sccc2Br)cc1
Reactant: NN
Solvent: OCCO
Solvent: O
Product: COc1ccc(C(=NN)c2sccc2Br)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture prepared form 18 g of (3-bromothien-2-yl) (4-methoxyphenyl)methanone, 12 ml of hydrazine hydrate (99%) and 120 ml of ethylene glycol was stirred at 120° for 2 hours. Thereafter, the mixture was cooled and diluted with 1000 g of ice water and quickly extracted with ether (3×500 ml). The combined ether solution was washed four times with water to remove unreacted hydrazine and dried over anhydrous magnesium sulfate overnight.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[C:31]([Cl:38])=[CH:30][C:29]4=[O:39])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[C:31]([Cl:38])=[CH:30][C:29]4=[O:39])[CH2:22][CH2:21]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cc(Cl)c3ccccc32)CC1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=c1cc(Cl)c2ccccc2n1CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.2 %

Procedure:
To 2 mL of a chloroform solution containing 149 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(4-chloro-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 2 mL of trifluoroacetic acid was added and stirred at room temperature for 3 hours. After the solvent was removed under reduced pressure and the residue was alkalized by aqueous saturated sodium hydrogen carbonate solution, it was extracted with ethyl acetate. The organic layer was washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; chloroform], to give 71 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-4-chloroquinolin-2(1H)-one as a pale yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[C:28]([F:38])=[CH:29][C:30]([F:37])=[C:31]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:32]=1>>[F:37][C:30]1[CH:29]=[C:28]([F:38])[C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[CH:32][C:31]=1[S:33]([NH2:36])(=[O:34])=[O:35]
Reactant: NS(=O)(=O)c1cc(Br)c(F)cc1F
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1cc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c(F)cc1F

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and commercially available 5-bromo-2,4-difluorobenzenesulphonamide (245 mg, 0.9 mmol) according to general procedure II. Obtained as a yellow solid (230 mg, 42%). MS (ISP) 614.3 [(M+H)+]; mp 281–284° C.
Reaction SMILES: Cl.[CH2:2]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH:5]2[CH2:4][NH:3]1.C([O-])([O-])=O.[K+].[K+].[Cl:16][CH2:17][CH2:18][CH2:19]Br>CC(C)=O>[Cl:16][CH2:17][CH2:18][CH2:19][N:3]1[CH2:4][CH:5]2[CH2:9][CH2:8][CH2:7][CH:6]2[CH2:2]1
Reactant: ClCCCBr
Reactant: C1CC2CNCC2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: ClCCCN1CC2CCCC2C1
Yield: 48.1 %

Procedure:
To a suspension of octahydrocyclopenta[c]pyrrole hydrochloride (5.00 g, 33.86 mmol) in acetone (150 mL) was added K2CO3 (35.68 g, 101.59 mmol) and 1-chloro-3-bromopropane (10.56 g, 67.72 mmol) in turn. The reaction mixture was heated to reflux for 12 h under N2. The solvent was removed, and the residue was treated with 200 mL of EtOAc. The mixture was washed with water followed by brine. The mixture was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was chromatographed with a silica gel column (eluting agent: 1:1 (v/v) PE/EtOAc) to afford the title compound (3.06 g, 56.63%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 188.7 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.24-1.28 (m, 1H), 1.38-1.40 (m, 2H), 2.06 (m, 1H), 2.46-2.50 (m, 2H), 2.56-2.57 (m, 3H), 2.63-2.68 (m, 2H), 2.70 (d, J=2.24 Hz, 2H), 2.71-2.73 (m, 2H), 3.60 (m, 2H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[CH2:4][NH:5][C@H:6]1[CH2:10][CH2:9][NH:8][CH2:7]1.Cl[C:17]1[N:22]=[CH:21][C:20]([Br:23])=[CH:19][N:18]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[Br:23][C:20]1[CH:19]=[N:18][C:17]([N:8]2[CH2:9][CH2:10][C@H:6]([NH:5][CH2:4][C:3]3[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:2]=3[Cl:1])[CH2:7]2)=[N:22][CH:21]=1
Reactant: Clc1ncc(Br)cn1
Reactant: Clc1ccc(CN[C@H]2CCNC2)c(Cl)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccc(CN[C@H]2CCN(c3ncc(Br)cn3)C2)c(Cl)c1
Yield: 87.4 %

Procedure:
Stir a mixture of (S)-(2,4-dichlorobenzyl)-pyrrolidin-3-ylamine (313 mg, 1.28 mmol), 2-chloro-5-bromopyrimidine (248 mg, 1.28 mmol) and diisopropylethylamine (335 μL, 1.91 mmol) in acetonitrile (2 mL) at 80° C. overnight. Concentrate and chromatograph on SCX-2 column to give the title compound (450 mg, 87%). Form the hydrochloride by essentially the procedure in Example 1 to give 1H NMR (400 MHz, MeOH-d4) δ 8.41 (2H, s), 7.62-7.67 (2H, m), 7.49 (1H, dd, J=8.31, 1.96 Hz), 4.46 (2H, d, J=5.62 Hz), 4.16 (1H, m), 3.99-4.05 (1H, m), 3.79-3.86 (2H, m), 3.65 (1H, m), 2.60 (1H, m), 2.28-2.37 (1H, m), MS (ES): m/z=402 [M+].
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:9]2[N:10]=[C:11]([O:21][CH3:22])[C:12]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[C:8]2[CH:7]=[CH:6][CH:5]=1.Br[CH2:24][CH:25]1[CH2:27][CH2:26]1.C(OCC)(=O)C>CN(C)C=O>[Br:3][C:4]1[N:9]2[N:10]=[C:11]([O:21][CH3:22])[C:12]([N:13]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[C:8]2[CH:7]=[CH:6][CH:5]=1
Reactant: BrCC1CC1
Reactant: COc1nn2c(Br)cccc2c1NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1nn2c(Br)cccc2c1N(CC1CC1)C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in oil; 24.6 mg) was added to a solution of tert-butyl N-(7-bromo-2-methoxypyrazolo[1,5-a]pyridin-3-yl)carbamate (140 mg) in N,N-dimethylformamide (10 mL) at room temperature and the reaction mixture was stirred for 30 minutes. (Bromomethyl)cyclopropane (0.06 mL) was added thereto at the same temperature, and the reaction mixture was stirred for 1 hour at 60° C. After completion of the reaction, the reaction mixture was gradually added to ice, extraction was performed with ethyl acetate, the organic extract was washed with water and brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure to afford a crude product of tert-butyl N-(7-bromo-2-methoxypyrazolo[1,5-a]pyridin-3-yl)-N-cyclopropylmethylcarbamate.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:10]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=2[O:8][C:7]([CH3:19])([CH3:18])[CH:6]=1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1C=CC=CC=1>[CH3:1][NH:2][C:3]([C:5]1[C:10]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=2[O:8][C:7]([CH3:19])([CH3:18])[CH:6]=1)=[S:29]
Reactant: CNC(=O)C1=CC(C)(C)Oc2ccc([N+](=O)[O-])cc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccccc1
Product: CNC(=S)C1=CC(C)(C)Oc2ccc([N+](=O)[O-])cc21
Yield: 165.1 %

Procedure:
A mixture of 5.26 g of N-methyl-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxamide prepared in accordance with Example 10-(3), 4.26 g of Lawesson's reagent, and 20 ml of benzene was heated at reflux for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromato- graphy (developing solution: methylene chloride) and then recrystallized from a mixture of ethyl acetate and n-hexane to obtain 4.84 g of N-methyl-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide.
Reaction SMILES: [C:1]([Br:4])(=O)[CH3:2].[CH3:5][NH:6][CH:7]([CH3:9])[CH3:8].[OH2:10]>CCOCC>[Br:4][CH2:1][C:2]([N:6]([CH3:5])[CH:7]([CH3:9])[CH3:8])=[O:10]
Reactant: CC(=O)Br
Reactant: CNC(C)C
Reactant: O
Solvent: CCOCC
Product: CC(C)N(C)C(=O)CBr

Procedure:
To a solution of 10 cm3 of acetyl bromide in 150 cm3 of ether, cooled to −20° C., one adds a solution of 26 cm3 of methylisopropylamine in 100 cm3 of ether. One leaves the mixture to return to 20° C. and agitates it for 30 minutes at 20° C. One dilutes with water, decants, extracts with ether, dries and separates by distillation. One obtains 13 g of expected product. B.p.=71/72° under 1 mmHg.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=2[CH3:17])[C:11]([OH:13])=O)[NH:4][N:3]=1.Cl.[F:19][C:20]1([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=2)[CH2:23][NH:22][CH2:21]1.CC1NC(C2C=C(C=CC=2C)C(O)=O)=C(C)N=1.Cl.N1CC(C2C=CC(C#N)=CC=2)C1>>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=2[CH3:17])[C:11]([N:22]2[CH2:21][C:20]([C:24]3[CH:25]=[CH:26][C:27]([C:28]#[N:29])=[CH:30][CH:31]=3)([F:19])[CH2:23]2)=[O:13])[NH:4][N:3]=1
Reactant: N#Cc1ccc(C2(F)CNC2)cc1
Reactant: Cc1ccc(C(=O)O)cc1-c1[nH]nc(C)c1C
Agent: Cc1nc(C)c(-c2cc(C(=O)O)ccc2C)[nH]1
Agent: Cl
Agent: N#Cc1ccc(C2CNC2)cc1
Product: Cc1ccc(C(=O)N2CC(F)(c3ccc(C#N)cc3)C2)cc1-c1[nH]nc(C)c1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5, except 3-(3,4-dimethyl-1H-pyrazol-5-yl)-4-methylbenzoic acid (compound 59.3) and 4-(3-fluoroazetidin-3-yl)benzonitrile (compound 43.4) were used in place of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7) and 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2), respectively. m/z (ES+) 389 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 12.45-12.26 (br, 1H), 7.95 (d, J=8.0 Hz, 2H), 7.79 (d, J=8.0 Hz, 2H), 7.65 (d, J=7.2 Hz, 1H), 7.52 (d, J=2.0 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 4.98-4.42 (m, 4H), 2.25 (s, 3H), 2.17 (s, 3H), 1.83 (s, 3H).