Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=NC=1.[CH3:7][C:8]1[N:12]2[CH2:13][CH2:14][NH:15][C:16](=[O:17])[C:11]2=[C:10]([CH3:18])[C:9]=1[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][C:33]([OH:35])=O)=[CH:28][CH:27]=2)[N:20]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:57][O:58][CH2:59][CH2:60][NH2:61]>C1COCC1.O>[CH3:7][C:8]1[N:12]2[CH2:13][CH2:14][NH:15][C:16](=[O:17])[C:11]2=[C:10]([CH3:18])[C:9]=1[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([CH2:32][C:33]([NH:61][CH2:60][CH2:59][O:58][CH3:57])=[O:35])=[CH:30][CH:31]=2)[N:20]=1
Reactant: COCCN
Reactant: Cc1c(-c2ccnc(Nc3ccc(CC(=O)O)cc3)n2)c(C)n2c1C(=O)NCC2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: c1cncnc1
Solvent: O
Solvent: C1CCOC1
Product: COCCNC(=O)Cc1ccc(Nc2nccc(-c3c(C)c4n(c3C)CCNC4=O)n2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of the pyrimidine acid Example I-70 {4-[4-(6,8-dimethyl-1-oxo-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-7-yl)-pyrimidin-2-ylamino]-phenyl}-acetic acid (0.05 g), EDCI (1.2 eq., 0.028 g) and HOBt (1.2 eq., 0.02 g) in THF (3 mL) was stirred at room temperature under nitrogen for 1 hour. 2-Methoxyethylamine (1.2 eq., 0.013 mL) was then added and the resulting reaction stirred at room temperature for 16 hours. Water (5 mL) was added and the solvent removed under vacuum to leave an aqueous suspension which was extracted with dichloromethane (2×2 mL). The combined organics were stripped to yield the crude product as a yellow oil (0.0656 g). Purification of the crude material (prep. HPLC) produced the title compound as a white solid (0.0269 g, 47%, with a purity of 98.37% by LCMS.
Reaction SMILES: C(OC(=O)C)(=O)C.[O:8]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:9]1=[O:10].C(O)(=O)C.C(O)(=O)C.[I:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.S(=O)(=O)(O)O.[F:39][P-:40]([F:45])([F:44])([F:43])([F:42])[F:41].[K+]>ClCCl>[F:39][P-:40]([F:45])([F:44])([F:43])([F:42])[F:41].[C:28]1([I+:27][C:16]2[CH:17]=[C:18]3[C:13]([CH:12]=[CH:11][C:9](=[O:10])[O:8]3)=[CH:14][CH:15]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=c1ccc2ccccc2o1
Reactant: Ic1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=c1ccc2ccc([I+]c3ccccc3)cc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10 %

Procedure:
To 80 ml of acetic anhydride was suspended 7.3 g (0.05 mol) of coumarin and 16.1 g (0.05 mol) of iodobenzene diacetate, and 10 g (0.1 mol) of concentrated sulfuric acid was added dropwise thereto at 0 to 7° C. for 1 hour, followed by gradually warming to room temperature and reacting with stirring for 8 hours. After completion of the reaction, the reaction solution was poured in 200 ml of ice water, and 150 ml of dichloromethane was added thereto to dissolve insoluble substance. Then 18.4 g (0.1 mol) of potassium hexafluorophosphate was added to the obtained solution, followed by stirring at room temperature for 2 hours. The dichloromethane layer obtained by fractionation was washed with 100 ml of water twice. The obtained dichloromethane layer was semi concentrated under reduced pressure and the precipitated crystal was filtered off, followed by drying under vacuum at 50° C. for 2 hours to obtain 2.4 g of objective substance as pale yellow crystal (yield: 10%).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][CH2:15][C:16]2[CH:17]=[C:18]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH:19]=[C:20]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH:21]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.Cl.C(OCC)(=O)C>C(O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][CH2:14][CH2:15][C:16]2[CH:17]=[C:18]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH:19]=[C:20]([CH:22]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[OH:30])[CH:21]=2)(=[O:12])=[O:11])=[CH:8][CH:9]=1
Reactant: O=C(O)CCc1cc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc(C(=O)c2ccc(F)cc2)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)CCc1cc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc(C(O)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.7 %

Procedure:
Sodium borohydride (0.077 g) was added portionwise to a suspension of 3-[2-[(4-chlorophenyl)sulphonylamino]ethyl]-5-(4-fluorobenzoyl)benzenepropanoic acid (0.50 g) in ethanol (12 ml), and the resulting solution was stirred at room temperature for 18 hours. 2N hydrochloric acid (5 ml) was added dropwise followed by ethyl acetate (50 ml), and the mixture was stirred for 1 hour. The organic layer was separated, washed with water and dried (MgSO4). The solvent was evaporated and the residue was chromatographed on silica gel. The column was eluted with hexane/ethyl acetate (5:1), followed by hexane/ethyl acetate/acetic acid (50:50:1), gradually increasing the polarity to give a ratio of 10:90:1. The product fractions were combined and evaporated to give the title compound as a gum (0.36 g), Rf 0.45 (SS 15). Found: C,58.58; H,4.71; N,2.65. C24H23ClFNO5S requires C,58.59; H,4.71; N,2.85%.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[C:2]=[O:3].[CH:12]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:22])[C:16]=2[CH:15]=[CH:14][N:13]=1.BrC1C=CC(CN=C=O)=CC=1>>[CH:12]1[C:21]2[C:16](=[C:17]([NH:22][C:2]([NH:1][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:3])[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1
Reactant: CCCCCCCCN=C=O
Reactant: Nc1cccc2cnccc12
Agent: O=C=NCc1ccc(Br)cc1
Product: CCCCCCCCNC(=O)Nc1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 60F using 1-isocyanatooctane and 5-isoquinolinamine instead of the product from Example 60E and 1-bromo-4-(isocyanatomethyl)benzene. NMR (DMSO-d6) δ 9.53 (s, 1H), 9.23 (s, 1H), 8.65 (d, 1H), 8.99 (d, 1H), 8.05 (d, 1H), 7.86 (t, 1H), 7.01 (m, 1H), 3.15 (m, 2H), 1.51 (m, 2H), 1.28 (m, 5H), 0.83 (m, 3H); MS (ESI) (M+H)+ 300.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[S:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]([CH3:22])[CH2:19][CH2:18][C:17]2=[O:23].[BH4-].[Na+]>CO>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[S:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]([CH3:22])[CH2:19][CH2:18][CH:17]2[OH:23]
Reactant: CN1CCC(=O)c2cccc(CSc3nc4ccccc4[nH]3)c21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CCC(O)c2cccc(CSc3nc4ccccc4[nH]3)c21
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 78.8 %

Procedure:
To a solution of 8-(2-benzimidazolyl)thiomethyl-1-methyl-4-oxo-1,2,3,4-tetrahydroquinoline (300 mg) in methanol (10 ml) was added gradually sodium borohydride (35 mg) at 0° C. The reaction mixture was stirred for 40 minutes at room temperature. After distilling off the solvent, the resulting residue was extracted with dichloromethane, washed with water, and dried. Then the solvent was distilled off and the resulting residue was recrystallized from ethyl acetate-n-hexane to give 8-(2-benzimidazolyl)thiomethyl-1-methyl-4-hydroxy-1,2,3,4-tetrahydroquinoline (238 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[N:9]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:10]2[C:15]([N:16]=1)=[C:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[N:13]=[C:12]([C:23]1[CH:24]=[N:25][C:26]([NH2:29])=[N:27][CH:28]=1)[N:11]=2>CN1CCCC1=O>[CH2:30]([N:9]1[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:16][C:15]2[C:10]1=[N:11][C:12]([C:23]1[CH:28]=[N:27][C:26]([NH2:29])=[N:25][CH:24]=1)=[N:13][C:14]=2[N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[CH:31]([CH3:33])[CH3:32]
Reactant: CC(C)Cn1c(Cl)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Reactant: C1CNCCN1
Solvent: CN1CCCC1=O
Product: CC(C)Cn1c(N2CCNCC2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Temperature: 130 °C
Reaction time: 4 h

Procedure:
Piperazine (2.0 g, 23 mmol) and N-methylpyrrolidone (10 ml) were added to 5-(8-chloro-9-isobutyl-6-morpholin-4-yl-9H-purin-2-yl)pyrimidin-2-amine (1.0 g, 2.6 mmol) and the resulting mixture was stirred at 130° C. for 4 hours. The reaction mixture was cooled and partitioned with methylene chloride and water, the organic layer was dried over magnesium sulfate, and the solvent was concentrated under reduced pressure. This compound (10 ml in liquid) was stored with N-methylpyrrolidone remaining and used for next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=2)[N:11]=1)[C:5]([O:7]C)=O.[OH-].[Na+].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH2:57][CH2:58][C:59]1[C:60](=[O:67])[NH:61][C:62]([CH3:66])=[CH:63][C:64]=1[CH3:65]>C(O)C.O.CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=2)[N:11]=1)[C:5]([NH:57][CH2:58][C:59]1[C:60](=[O:67])[NH:61][C:62]([CH3:66])=[CH:63][C:64]=1[CH3:65])=[O:7]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: COC(=O)c1cc(Cl)nc(-c2ccc(CN(C)C)cc2)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc(-c3ccc(CN(C)C)cc3)c2)c(=O)[nH]1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 44.7 %

Procedure:
To a solution of methyl 2-chloro-6-(4-((dimethylamino)methyl)phenyl)isonicotinate (0.48 g, 1.578 mmol) in ethanol (5 mL), NaOH (0.094 g, 2.368 mmol), dissolved in water (1 mL), was added and reaction mass heated at 60° C. for 1 h. On completion, solvent was evaporated under reduced pressure. Residue was washed with ether and acidified with 1N HCl till pH 8 and then with citric acid till pH 5-6. Aqueous layer was extracted with 20% MeOH/DCM and combined organic layers were concentrated under reduced pressure to afford the acid (0.47 g, crude) which was used in next step without further purification. To a solution of this acid (0.47 g, 1.64 mmol) in DMSO (4 mL), PyBOP (1.26 g, 2.43 mmol) was added and reaction stirred at rt for 15 min. Then 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (0.49 g, 3.28 mmol) was added and reaction stirred overnight. On completion, water was added and aqueous layer extracted with 20% MeOH/DCM. Combined organic layers were concentrated and residue purified by silica gel column chromatography affording 2-chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(4-((dimethylamino)methyl)phenyl)isonicotinamide (0.3 g, 43.6%)
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1.[CH:11]1([CH2:14]Br)[CH2:13][CH2:12]1>>[Cl:1][C:2]1[N:7]([CH2:14][CH:11]2[CH2:13][CH2:12]2)[C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1
Reactant: Cn1c(=O)cc(Cl)[nH]c1=O
Reactant: BrCC1CC1
Product: Cn1c(=O)cc(Cl)n(CC2CC2)c1=O

Procedure:
The sub-title compound was prepared by the method of example 9, part a) using 6-chloro-3-methyl uracil and cyclopropylmethyl bromide.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=CC=1.[C:8]([OH:11])(=[O:10])[CH3:9]>[Br-].C([N+](CCC)(CCC)CCC)CC.C([O-])(=O)C.[Co+2].C([O-])(=O)C.C([O-])(=O)C.[Mn+2].C([O-])(=O)C.O>[C:8]([OH:11])(=[O:10])[C:9]1[CH:1]=[CH:2][CH:3]=[N:4][CH:5]=1
Reactant: CC(=O)O
Reactant: Cc1cccnc1
Agent: [Co+2]
Agent: [Mn+2]
Agent: CC(=O)[O-]
Solvent: O
Product: O=C(O)c1cccnc1

Procedure:
The same autoclave as that used in Example 1 was charged with 25 parts by weight of 3-methylpyridine, 0.38 part by weight of cobalt acetate, 0.27 part by weight of manganese acetate, 1 part by weight of tetrapropylammonium bromide and 150 parts by weight of acetic acid having a 5 wt % water content, and the mixture was allowed to react in the same manner as in Example 1 to give 21.7 parts by weight of a crude nicotinic acid crystal. The conversion of the 3-methylpyridine was 93.7 mol %, the selectivity to the nicotinic acid was 99.0 mol %, and the yield of the nicotinic acid 92.8 mol %. The conversion and the yield in Example 2 were improved over those in Example 1 since the solvent was used in a larger amount in Example 2. The crude nicotinic acid had a bromine concentration of 608 ppm and showed a dissolved b value of 5.44.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6](=O)[C:5]([NH:10][C:11](=[O:16])[CH2:12][C:13](=[O:15])[CH3:14])=[CH:4][CH:3]=1.[O-]CC.[Na+].[Na].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>CO>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][N:10]1[C:11](=[O:16])[C:12]([C:13](=[O:15])[CH3:14])=[C:6]2[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=[C:5]12)[CH3:28]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)CC(=O)Nc1ccc(Cl)ccc1=O
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CCOC(=O)Cn1c2ccc(Cl)ccc-2c(C(C)=O)c1=O
Reaction time: 0.17 h

Procedure:
A mixture of 1-[(4-chloro-7-oxo-1,3,5-cycloheptatrien-1-yl)amino]-1,3-butanedione (5.8 g) and sodium ethoxide solution, prepared by dissolving 1.1 g of sodium in 200 ml of anhydrous, methanol-free ethanol, was heated at reflux for 5 hr. Thereafter, ethyl bromoacetate (10 ml) was added dropwise to the hot solution and refluxing was continued for an additional 10 min. The reaction mixture was evaporated to dryness. The residue was dissolved in chloroform and the solution filtered through a column of silica gel. Evaporation of the eluate gave 3.75 g of 3-acetyl-6-chloro-1,2-dihydro-2-oxocyclohepta[b]pyrrole-1-acetic acid ethyl ester, identical to the compound obtained from method A. Crystallization of the latter compound gave the product with mp 183.5° C.; nmr (CDCl3) δ1.27 (t, 3H), 2.7 (s, 3H), 4.2 (q, 2H), 4.85 (s, 2H), 6.85-9.3 (m, 4H); ir (white mineral oil) 1725, 1685 cm-1 ; uvλmax (MeOH) 293 nm (ε21,995), 256 (14,630), 231 (16,945); Anal Calcd for C15H14ClNO4 : C, 58.55% H, 4.59% N, 4.55%; Found: C, 58.53% H, 4.60% N, 4.54%.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1)[CH3:2]>C(O)C.[Pd]>[CH2:16]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=1)[CH3:17]
Reactant: CCN(CC)CCOc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCN(CC)CCOc1ccc(N)cc1
Yield: 91.4 %

Procedure:
A solution of 5 g (21 mmol) of 4-[2-(diethylamino)ethoxy]-nitrobenzene in 50 ml of ethanol was hydrogenated over 100 mg of 10% palladium-on-carbon at room temperature and under atmospheric pressure. After 4 hours the suspension was filtered through a filter aid and the filtrate was evaporated under reduced pressure to give 4 g (92%) of 4-[2-(diethylamino)ethoxy]-aniline as an oil.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([NH:12][S@:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([Br:11])[CH:5]=1.[N+:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28](Cl)(=[O:30])=[O:29])([O-:21])=[O:20]>C(Cl)Cl>[Br:11][C:6]1[CH:5]=[C:4]([C@H:3]([NH:12][S@:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])[CH2:2][NH:1][S:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N+:19]([O-:21])=[O:20])(=[O:29])=[O:30])[CH:9]=[C:8]([F:10])[CH:7]=1
Reactant: CC(C)(C)[S@](=O)N[C@H](CN)c1cc(F)cc(Br)c1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)[S@](=O)N[C@H](CNS(=O)(=O)c1ccccc1[N+](=O)[O-])c1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(S)—N—((S)-2-amino-1-(3-bromo-5-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (3.3 g, 9.78 mmol) was dissolved in DCM (32.6 mL) at 0° C., then TEA (1.405 mL, 10.08 mmol), and 2-nitrobenzene-1-sulfonyl chloride (2.169 g, 9.78 mmol) were added. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo and the crude product was purified to yield N—((S)-2-(3-bromo-5-fluorophenyl)-2-((S)-1,1-dimethylethylsulfinamido)ethyl)-2-nitrobenzenesulfonamide. LCMS (m/z): 522.1/524.1 (MH+), 0.94 min.
Reaction SMILES: [Na].Cl[C:3]1[N:8]=[C:7]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:6]=[C:5]([NH:15][S:16]([CH:19]=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=2)(=[O:18])=[O:17])[C:4]=1[O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][CH3:36].Cl>C(O)CO>[OH:28][CH2:29][CH2:30][O:35][C:3]1[N:8]=[C:7]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:6]=[C:5]([NH:15][S:16]([CH:19]=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=2)(=[O:18])=[O:17])[C:4]=1[O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][CH3:36]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1NS(=O)(=O)C=Cc1cccc(C)c1
Agent: Cl
Agent: [Na]
Solvent: OCCO
Product: COc1ccccc1Oc1c(NS(=O)(=O)C=Cc2cccc(C)c2)nc(-c2ncccn2)nc1OCCO
Yield: 145 %

Procedure:
Sodium (315 mg) was dissolved in 7.7 ml of ethylene glycol and 700 mg of N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-(3-methylphenyl)ethenesulfonamide was added thereto with stirring. The reaction mixture was stirred at 90° C. for 30 minutes and poured into a mixture of 1N hydrochloric acid and ice. Crystals separated out therefrom were collected by filtration and the resulting crystals were purified by a silica gel column chromatography (chloroform-methanol=20:1). The resulting amorphous substance was crystallized in ether and collected filtration to give 533 mg of N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-(3-methylphenyl)ethenesulfonamide.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[CH:28]=[C:29]([S:33]([NH:36][CH:37]([CH3:39])[CH3:38])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[CH:37]([NH:36][S:33]([C:29]1[CH:28]=[C:27]([NH:26][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])[CH:32]=[CH:31][CH:30]=1)(=[O:35])=[O:34])([CH3:39])[CH3:38]
Reactant: CC(C)NS(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CC(C)NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-N-isopropyl-benzenesulfonamide [CAS 118837-66-4] according to general procedure II. Light yellow solid. MS (ISP) 552.0 [(M−H−]; mp 229° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:16]([CH2:18][C:19]([OH:21])=[O:20])=[O:17])[CH3:15])=[CH:10][CH:9]=1.[OH-].[K+].[CH:24](Cl)(Cl)Cl.CI>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH3:24][O:20][C:19](=[O:21])[CH2:18][S:16]([CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[CH:9][CH:10]=1)[CH3:15])=[O:17]
Reactant: ClC(Cl)Cl
Reactant: CC(c1ccc(-c2ccccc2F)cc1)S(=O)CC(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: COC(=O)CS(=O)C(C)c1ccc(-c2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
1.1 gm (3 millimols) of tetrabutylammonium iodide and 3.06 gm (10 millimols) of [1-(2'-fluoro-4-biphenylyl)-ethylsulfinyl]-acetic acid (m.p. 164°-165° C.) were added to a solution of 730 mgm (13 millimols) of potassium hydroxide in 20 ml of water, then 20 ml of chloroform and 2 ml of methyl iodide were added, and the mixture was stirred at room temperature for 10 hours. Afterwards, the organic phase was separated from the neutral aqueous phase, washed with dilute hydrochloric acid and then with water, dried and evaporated. The residue (3.6 gm) was purified by chromatography on 100 gm of silicagel (grain size: 0.05-0.2 mm) with cyclohexane ethyl acetate=1/4. After evaporation of the combined fractions with an Rf -value of 0.4 and recrystallization of the residue from isopropanol, 1.7 gm (53% of theory) of the title compound m.p. 75°-77° C. were obtained.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:20]([O:21]C(=O)C)[C@@H:19]([O:25]C(=O)C)[C@@H:18]([CH2:29][O:30]C(=O)C)[O:17][C@H:6]1[O:7][CH2:8][CH2:9][S:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])(=O)C.C[O-].[Na+].[Na]>CO>[O:7]([CH2:8][CH2:9][S:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[C@@H:6]1[O:17][C@H:18]([CH2:29][OH:30])[C@H:19]([OH:25])[C@H:20]([OH:21])[C@H:5]1[OH:4]
Reactant: COC(=O)CCSCCO[C@@H]1O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=O)CCSCCO[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reaction time: 4 h
Yield: 77.9 %

Procedure:
2-(2-Methoxycarbonylethylthio)ethyl 2,3,4,6-tetra-O-acetyl-β-D-galactopyranoside (19) (1.00 g; 2.32 mmol) was dissolved in 25 ml of dry methanol and added to a solution of sodium methoxide in methanol, prepared from sodium (~0.05 g) and 10 ml of methanol. Stirring was continued for 4 h after which the reaction mixture was neutralized with Duolite-H+ (methanol washed and dried). Filtration and evaporation of the solvent gave a quantitative yield of the title compound (28; 590 mg) which was pure according to TLC (SiO2, chloroform/methanol/water 65:35:10) and NMR (D2O, TMS as an external standard): δ 4.44 (d, 1H, J1,2 =7.62 Hz, H1), 4.08 (m, 1H, OCH2 --CH2), 3.72 (s, 3H, OCH3), 3.52 (dd, 1H, H2), 2.92-2.70 (m, 6H, CH2S, CH2CO) 13C-NMR (D2O, TMS as an external standard) δ 178.2 (CO), 105.8 (C-1), 78.1, 75.6, 73.6, 71.5 (C2-C5), 71.7 (C-6), 63.8 (O--CH2 of aglycon) 55.2 (OCH3), 37.1, 33.7, 29.3 (--CH2 of aglycon).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([O:13][CH3:14])=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:15][N:16]1CCCC1=O>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.[Zn]>[C:15]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([O:13][CH3:14])=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)#[N:16]
Reactant: COC(=O)C1(c2ccc(Cl)cc2)CC1
Reactant: CN1CCCC1=O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COC(=O)C1(c2ccc(C#N)cc2)CC1
Temperature: 150 °C
Yield: 75.7 %

Procedure:
A degassed mixture of methyl 1-(4-chlorophenyl)cyclopropanecarboxylate (4.748 g, 0.02254 mol), zinc cyanide (2.701 g, 0.02254 mol), bis(tri-t-butylphosphine)palladium (705 mg, 0.00135 mol) and zinc (265 mg, 0.00406 mol) powder in anhydrous N-methylpyrrolidinone (50.0 mL, 0.518 mol) was heated at 150° C. for 18 hours. The completion of the reaction is determined by LCMS and TLC. The reaction mixture was cooled to it, diluted with EtOAc, filtered through a pad of celite and the solid was washed with EtOAc. The filtrate was washed with 2 N NH4OH (100 mL) and brine successively, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by Combiflash with 2-15% EtOAc/hexanes to give the product as a colorless oil (3.434 g, 76% in yield). LC/MS: (M+H)=202.1.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[ClH:5].[C:6]([NH:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([OH:21])[CH:15]=1)=[O:13])([CH3:9])([CH3:8])[CH3:7]>C(#N)C>[ClH:5].[C:6]([NH:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][C:2]2[CH:4]=[CH:8][C:6]([CH3:9])=[CH:7][CH:1]=2)=[C:16]([O:21][C:17]2[CH:18]=[CH:19][C:14]([CH3:12])=[CH:15][CH:16]=2)[CH:15]=1)=[O:13])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)=O
Reactant: CC(C)(C)NCC(=O)c1ccc(O)c(O)c1
Agent: Cl
Solvent: CC#N
Product: Cc1ccc(Oc2ccc(C(=O)CNC(C)(C)C)cc2Oc2ccc(C)cc2)cc1
Yield: 64 %

Procedure:
The process of Example 1 was repeated substituting acetone for the acetonitrile as solvent. Starting with 26 g of 3,4-dihydroxyphenyl N-(tert-butyl)aminomethyl ketone hydrochloride there was obtained 33 g of 3,4-bis-(p-toluyloxy)phenyl N-(tert-butyl)aminomethyl ketone hydrochloride (64% yield) containing only a trace of tributylamine hydrochloride.