Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH:5]([C:7](=[CH2:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:6])(=O)C>P([O-])([O-])([O-])=O>[OH:4][C@@H:5]([C:7](=[CH2:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:6]
Reactant: C=C(C(=O)OCC)C(C)OC(C)=O
Agent: O=P([O-])([O-])[O-]
Product: C=C(C(=O)OCC)[C@@H](C)O
Temperature: 37 °C
Reaction time: 72 h
Yield: 41.3 %

Procedure:
A mixture of ethyl 2-(1-acetoxyethyl)acrylate (35.65 g) and "Lipase P" (8.88 g) in pH 7.0 phosphate buffer (0.1M) (2.8 l) was stirred at 37° C. for 72 hours. The whole mixture was extracted with ethyl acetate, and the combined extracts were dried. After removal at the solvent from the solution in vacuo, the crude product was purified by column-chromatography on silica gel (eluent : a mixture of hexane and ethyl acetate, 2:1) to give ethyl 2-[(1R)-1-hydroxyethyl]acrylate (11.40 g).
Reaction SMILES: C[O:2][C:3](=[O:59])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([C:43]5[CH:48]=[CH:47][CH:46]=[C:45]([Cl:49])[CH:44]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[C:50]([C:52]1[N:53]=[C:54]([CH3:58])[O:55][C:56]=1[CH3:57])=[O:51])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=2[CH3:19])=[CH:8][CH:7]=1.CO.[Li+].[OH-]>C1COCC1>[Cl:49][C:45]1[CH:44]=[C:43]([C:40]2[CH:41]=[CH:42][C:37]([C@H:35]3[CH2:34][O:33][C:29]4=[CH:30][C:31]5[CH2:32][C@@H:23]([C:21]([NH:20][C@@H:4]([CH2:5][C:6]6[CH:7]=[CH:8][C:9]([C:12]7[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=7[CH3:19])=[CH:10][CH:11]=6)[C:3]([OH:59])=[O:2])=[O:22])[N:24]([C:50]([C:52]6[N:53]=[C:54]([CH3:58])[O:55][C:56]=6[CH3:57])=[O:51])[CH2:25][C:26]=5[CH:27]=[C:28]4[O:36]3)=[CH:38][CH:39]=2)[CH:48]=[CH:47][CH:46]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)c1nc(C)oc1C)O[C@@H](c1ccc(-c2cccc(Cl)c2)cc1)CO3
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(C(=O)N2Cc3cc4c(cc3C[C@H]2C(=O)N[C@@H](Cc2ccc(-c3ccnc(C)c3C)cc2)C(=O)O)OC[C@H](c2ccc(-c3cccc(Cl)c3)cc2)O4)c(C)o1
Reaction time: 0.5 h

Procedure:
(S)-2-{[(3S,8S)-3-(3′-Chloro-biphenyl-4-yl)-7-(2,5-dimethyl-oxazole-4-carbonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester (0.0139 g) was dissolved in THF (0.3 mL) and MeOH (0.3 mL) and 0.3 mL of 2.0 N LiOH was added at 0° C. and stirred at that temperature for 30 min. pH was adjusted to 6-7, extracted with EtOAc, dried (Na2SO4), evaporated the solvents and dried under vacco to get the title compound. LCMS (m/z): 798.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=S)=[N:8][CH:9]=[CH:10][CH:11]=1.[NH3:29]>>[F:1][C:2]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[NH:29])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: COc1ccc(COc2cccnc2NC(=S)Nc2ccc(Cl)cc2)c(F)c1
Reactant: N
Product: COc1ccc(COc2cccnc2NC(=N)Nc2ccc(Cl)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of yellow mercuric oxide (0.54 g, 0.0025 mol), N-[3-(2-fluoro-4-methoxybenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)thiourea (0.8 g, 0.0021 mol) and methanolic ammonia solution (40 ml) was stirred for 2 days at room temperature. The solvent was removed in vacuo and the black residue was boiled with chloroform and filtered hot. Evaporation of the solvent followed by trituration with ether and recrystallisation from acetonitrile gave the desired product. Yield 0.37 g, (45%), m.p. 158°-161 ° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([I:12])[CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=O.S(Cl)([Cl:16])=O>CN(C=O)C>[Cl:16][C:5]1[C:4]2[C:9](=[C:10]([I:12])[CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=[CH:7][N:6]=1
Reactant: O=c1[nH]cnc2c(I)cc(Cl)cc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Clc1cc(I)c2ncnc(Cl)c2c1
Temperature: 25 °C

Procedure:
To around bottom flask was added 6-chloro-8-iodo-3H-quinazolin-4-one (1000 mg, 3.3 mmol); and thionyl chloride (50 mL). DMF (0.1 mL) was then added, and the reaction was stirred at reflux for 2 h. The reaction was cooled to room temperature, then concentrated via rotovap. The product was then azeotroped 2× with DCM, then dried under vacuum yielding 4,6-dichloro-8-iodo-quinazoline, carried immediately to the next step. 1H NMR (400 MHz, DMSO) δ 9.24-9.20 (s, 1H), 8.77-8.73 (d, J=2.2 Hz, 1H), 8.36-8.31 (d, J=2.2 Hz, 1H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[C:16]2[NH2:22])([O-:12])=[O:11].N1C=CC=CC=1>O>[N+:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[C:16]2[NH:22][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([O-:12])=[O:11]
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1n[nH]c2ccc([N+](=O)[O-])cc12
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1n[nH]c2ccc([N+](=O)[O-])cc12)c1ccccc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
N-(5-Nitro-1H-indazol-3-yl)benzamide may be obtained in the following manner: 0.39 cm3 of benzoyl chloride is added dropwise to a solution of 0.6 g of 5-nitro-1H-indazole-3-amine and 5 cm3 of pyridine, cooled to 0° C. The medium is returned to a temperature in the region of 20° C. and stirred for 18 hours. After addition of 20 cm3 of distilled water, the medium is extracted with 20 cm3 and 10 cm3 of ethyl acetate. The organic phases are combined, dried over magnesium sulphate, filtered and concentrated by evaporation under reduced pressure. The residue thus obtained is purified by chromatography on a column of silica with a dichloromethane/methanol mixture (99/1 by volume) as eluent. 0.9 g of N-(5-nitro-1H-indazol-3-yl)benzamide is thus obtained in the form of an orange-coloured solid melting at 231° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([CH:13]=O)=[CH:8]2.C(O)(=O)[CH2:16][C:17]([OH:19])=[O:18].N1CCCCC1.Cl>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([CH:13]=[CH:16][C:17]([OH:19])=[O:18])=[CH:8]2
Reactant: COc1cccc2cc(C=O)ccc12
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COc1cccc2cc(C=CC(=O)O)ccc12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
5-Methoxynaphthalene-2-aldehyde (0.1 mole), malonic acid (0.2 moles), and dry pyridine (175 ml) are placed in a 1 1 round-bottom flask. The malonic acid is dissolved by shaking on a steam bath and piperidine (0.5 ml) is added. The reaction is allowed to take place on the steam bath for 4 hours. After standing at room temperature overnight, the mixture is refluxed for 1 hour and cooled. The reaction mixture is poured into 250 ml of ice water and acidified with concentrated hydrochloric acid (80 ml) with stirring. The product is collected by filtration, washed with water (4 × 150 ml) and air dried to give β-(5-methoxynaphth-2-yl)propenoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][C:14]=1[CH:22]=O.N1CCCCC1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:22][C:14]1[NH:15][C:16]2[C:21]([C:13]=1[CH3:12])=[CH:20][CH:19]=[CH:18][CH:17]=2
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: Cc1c(C=O)[nH]c2ccccc12
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C=C2C(=O)Nc3ccc(Cl)cc32)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 5-chloro-2-oxindole (167 mg), 3-methylindole-2-carbaldehyde (190 mg) (prepared according to Synthetic Communications, 1986, 16, 1799) and piperidine (10 mg) in ethanol was held in a sealed tube at 95° C. for 4 hours. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in a vacuum oven to give 5-chloro-3-(3-methyl-1H-indol-2-ylmethylene)-1,3-dihydroindol-2-one.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:22]C)[N:12]2[CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl>CO.O1CCOCC1>[NH2:24][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:22])[N:12]2[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCCCO3)c2n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CC3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 139.2 %

Procedure:
2-Butoxy-8-methoxy-9-(tetrahydro-2H-pyran-2-ylmethyl)-9H-purin-6-amine (6 mg, 85% pure) was dissolved in methanol (1 mL), treated with 4N hydrogen chloride in 1,4-dioxane (0.5 mL) and stirred for 5 hours at room temperature. The mixture was stripped to dryness to give the title compound (77.8:10.8 by LCMS) as a colourless gum (8 mg).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16]Cl)=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:7]=2[CH:25]=1.[CH2:28]([NH2:31])[C:29]#[CH:30].[I-].[K+]>CN(C)C=O>[F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16][NH:31][CH2:28][C:29]#[CH:30])=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:7]=2[CH:25]=1
Reactant: C#CCN
Reactant: FC(F)(F)c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CCl)n1-2
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCNCc1nnc2n1-c1ccc(C(F)(F)F)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Preparation 19, 8 -(trifluoromethyl)-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in dimethylformamide is reacted at room temperature with propargylamine in the presence of potassium iodide to give 8-(trifluoromethyl)-1-[[(2-propynyl)amino]methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 23 8 -Chloro-1-[[(2-propynyl)amino]methyl]-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][Si](C)(C)C)=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+]>CO>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2([N:4]([CH2:20][CH2:21][CH3:22])[CH2:1][CH2:2][CH3:3])[CH2:6][CH2:7]2)=[CH:9][CH:10]=1)#[CH:15]
Reactant: CCCN(CCC)C1(c2ccc(C#C[Si](C)(C)C)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(C2(N(CCC)CCC)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure E; dipropyl-[1-(4-trimethylsilanylethynyl-phenyl)-cyclopropyl]-amine (Intermediate 122, 45.0 mg, 0.14 mmols) in methanol (5 mL) was treated with potassium carbonate (50.0 mg, 0.37 mmol) and stirred overnight at ambient temperature. The crude alkyne (34 mg, 100%) was used directly in the next reaction.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([CH:14]=O)=[CH:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22](P(=O)(OCC)OCC)[P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26].CN(C)C=O.[H-].[Na+]>O>[CH2:1]([O:8][C:9]1[C:13](/[CH:14]=[CH:22]/[P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])=[CH:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cn(-c2ccccc2)nc1OCc1ccccc1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccccc1)OCC
Temperature: 25 °C
Reaction time: 15 h
Yield: 72.9 %

Procedure:
To a mixture of 3-benzyloxy-1-phenyl-1H-pyrazole-4-carbaldehyde (1.00 g), tetraethyl methylenediphosphonate (1.15 g) and N,N-dimethylformamide (30 mL) was added sodium hydride (60% in oil, 0.17 g) at 0° C. The mixture was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (3:1, v/v) to give diethyl (E)-2-(3-benzyloxy-1-phenyl-1H-pyrazol-4-yl)ethenylphosphonate as colorless crystals (1.08 g, yield 73%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 89-90° C.
Reaction SMILES: C(O)(=O)C(O)=O.C[O:8][CH:9](OC)[CH2:10][CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=2)[C:12]1=[O:22]>>[Cl:21][C:15]1[CH:14]=[C:13]2[C:18]([CH2:19][CH2:20][CH:11]([CH2:10][CH:9]=[O:8])[C:12]2=[O:22])=[CH:17][CH:16]=1
Reactant: COC(CC1CCc2ccc(Cl)cc2C1=O)OC
Agent: O=C(O)C(=O)O
Product: O=CCC1CCc2ccc(Cl)cc2C1=O
Yield: 95.5 %

Procedure:
For the acetal cleavage, 15 ml of a 10% aqueous oxalic acid solution were applied to 100 g of silica gel and 4.8 g of 7-chloro-1,2,3,4-tetrahydro-1-oxo-2-naphthaleneacetaldehyde dimethyl acetal were chromatographed on this mixture with methylene chloride as the eluent. There were obtained 3.8 g (95%) of 7-chloro-1,2,3,4-tetrahydro-1-oxo-2-naphthalene-acetaldehyde.
Reaction SMILES: BrBr.[Cl:3][C:4]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=1[NH2:6].[S-:12][C:13]#[N:14].[Na+]>C(O)(=O)C>[NH2:14][C:13]1[S:12][C:7]2[CH:8]=[C:9]([Cl:11])[CH:10]=[C:4]([Cl:3])[C:5]=2[N:6]=1
Reactant: N#C[S-]
Reactant: Nc1ccc(Cl)cc1Cl
Agent: BrBr
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1nc2c(Cl)cc(Cl)cc2s1
Reaction time: 16 h

Procedure:
197 g (1.23 mol) of bromine were slowly added dropwise, while cooling with ice, to a solution of 200 g (1.23 mol) of 2,4-dichloroaniline and 200 g (2.46 mol) of sodium thiocyanate in 1.5 1 of glacial acetic acid. Stirring was carried out for 16 hours at about 20° C., after which the solid was separated off and washed with 10% strength sodium hydroxide solution and water.
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([O:30]C(=O)C(C)(C)C)[CH:24]=[CH:23][C:22]=3[CH2:21]2)=O)=[CH:4][CH:3]=1.Cl[CH2:40][C:41]([N:43]([CH3:45])[CH3:44])=O>>[CH3:44][N:43]([CH3:45])[CH2:41][CH2:40][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([OH:30])[CH:24]=[CH:23][C:22]=3[CH2:21]2)=[CH:37][CH:38]=1
Reactant: CN(C)C(=O)CCl
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCC(=O)c2ccc(O)cc2)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCCCc2ccc(OCCN(C)C)cc2)c1
Yield: 56.3 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)propylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and 2-chloro-N,N-dimethylacetamide (14 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (16 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6]([CH:25]=1)[C:7]([NH:9][CH:10]1[CH2:19][C:18]2[C:13](=[CH:14][C:15]([CH3:24])=[C:16]([S:20](=[O:23])(=[O:22])[NH2:21])[CH:17]=2)[O:12][CH2:11]1)=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH3:34][N:35]=[C:36]=[S:37].C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6]([CH:25]=1)[C:7]([NH:9][CH:10]1[CH2:19][C:18]2[C:13](=[CH:14][C:15]([CH3:24])=[C:16]([S:20]([NH:21][C:36]([NH:35][CH3:34])=[S:37])(=[O:22])=[O:23])[CH:17]=2)[O:12][CH2:11]1)=[O:8]
Reactant: COc1ccc(Cl)cc1C(=O)NC1COc2cc(C)c(S(N)(=O)=O)cc2C1
Reactant: CN=C=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CNC(=S)NS(=O)(=O)c1cc2c(cc1C)OCC(NC(=O)c1cc(Cl)ccc1OC)C2
Temperature: 80 °C
Reaction time: 0.42 h

Procedure:
1.64 g (4 mmol) of 3-(5-chloro-2-methoxybenzamido)-6-sulfamoyl-7-methylchroman were dissolved in 10 ml of dry DMSO, and 1.65 g (12 mmol) of finely powdered potassium carbonate and 0.35 g (4.8 mmol) of methyl isothiocyanate were added. After the mixture had been stirred at 80° C. for 25 minutes, it was cooled, introduced into ice-water, clarified with charcoal and acidified to pH 1. The precipitate was filtered off with suction, dried, purified over a silica gel column using ethyl acetate/toluene 2:1 and recrystallized from ethanol. Melting point: 207°-208° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@H:5]([CH2:7][OH:8])[CH2:4][C@H:3]1[CH2:9][O:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:17][S:18]([O:8][CH2:7][C@H:5]1[CH2:6][N:2]([CH3:1])[C@H:3]([CH2:9][O:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH2:4]1)(=[O:20])=[O:19]
Reactant: CN1C[C@H](CO)C[C@H]1COc1cccnc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1C[C@H](COS(C)(=O)=O)C[C@H]1COc1cccnc1

Procedure:
To a 386 mg (1.84 mmol) sample of 3-(trans-1-methyl-4-hydroxymethyl-2(S)-pyrrolidinylmethoxy)pyridine (from Example 48a above) dissolved in 12 mL of methylene chloride were added 262 μL (3.38 mmol) of methanesulfonyl chloride, 470 μL of triethylamine and a catalytic amount of DMAP, and the reaction mixture was stirred for 5 hours at room temperature. The reaction was quenched with water, the product extracted from the mixture, the solvent removed, and the product purified by column chromatography on silica gel, eluting with 20:1 chloroform:methanol to afford 320 mg of the title compound.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.Cl[CH2:32][C:33]1[N:34]=[N:35][N:36]([CH2:38][CH3:39])[CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:38]([N:36]1[CH:37]=[C:33]([CH2:32][N:7]2[C:6]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[S:10][C:5]=3[C:4](=[O:17])[N:3]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:2]2=[O:1])[N:34]=[N:35]1)[CH3:39]
Reactant: CCn1cc(CCl)nn1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1cc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)nn1

Procedure:
According to GP1 tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (1.88 g; compound B50) is reacted with 4-(chloromethyl)-1-ethyl-1H-1,2,3-triazole (827 mg; compound D21) in the presence of potassium carbonate (1.22 mg) in DMF (30 ml). Using WU2 the title compound is obtained after flash column chromatography [silica gel, eluent: cyclohexane/EtOAc, 1/1 (v/v)] as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:15][CH2:16][C@:17]2([CH3:23])[CH2:21][O:20]C(=O)[NH:18]2)[CH:5]=[C:6]([CH3:14])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].O[Li].O>C(O)C.O>[NH2:18][C@:17]([CH3:23])([CH2:16][CH2:15][C:4]1[CH:5]=[C:6]([CH3:14])[C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[C:2]([Br:1])[CH:3]=1)[CH2:21][OH:20]
Reactant: CCCCCOc1c(C)cc(CC[C@]2(C)COC(=O)N2)cc1Br
Agent: [Li]O
Solvent: CCO
Solvent: O
Product: CCCCCOc1c(C)cc(CC[C@@](C)(N)CO)cc1Br
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-4-[2-(3-Bromo-5-methyl-4-pentyloxy-phenyl)-ethyl]-4-methyl-oxazolidin-2-one (58 mg, 0.15 mmol) in ethanol (2 ml) is added a solution of LiOH-hydrate (180 mg, 4.28 mmol) in water (1.5 ml). The mixture is stirred at 90° C. for 2 h. After cooling to RT and extraction with AcOEt (2×20 ml), the organic phase is dried using MgSO4. Evaporation of solvent is followed by reverse phase preparative HPLC (20×250 mm, RP18: 10 μm) using acetonitrile/water/trifluoroacetic acid=900/100/1 as eluent to yield the title compound as white solid. MS (ESI+): m/z=358/360 (MH+).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[N:15][N:16]3[CH:21]=[CH:20][CH:19]=[N:18][C:17]=23)=[O:12])=[C:6]([O:22][CH3:23])[CH:5]=1.[OH-].[NH4+:26].N>C(#N)C.CS(C)=O>[C:3]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[N:15][N:16]3[CH:21]=[CH:20][CH:19]=[N:18][C:17]=23)=[O:12])=[C:6]([O:22][CH3:23])[CH:5]=1)(=[O:2])[NH2:26]
Reactant: COC(=O)c1ccc(NC(=O)c2cnn3cccnc23)c(OC)c1
Reactant: [NH4+]
Agent: N
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CC#N
Product: COc1cc(C(N)=O)ccc1NC(=O)c1cnn2cccnc12
Temperature: 50 °C
Yield: 35 %

Procedure:
A mixture of 3-methoxy-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-benzoic acid methyl ester (5 mg) and an aqueous solution of ammonium hydroxide (concentrated, 1 mL) and a mixture of 3-methoxy-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-benzoic acid methyl ester (5 mg) and a solution of ammonia (2 M in MeOH, 1 mL) were stirred at room temperature for 2 days. The two mixtures were then combined and dimethyl sulfoxide (1 mL) was added followed by acetonitrile (1 mL). A solution of ammonia (2 M in MeOH, 1 mL) and an aqueous solution of ammonium hydroxide (concentrated, 2 mL) were then added and the resulting mixture was heated to 50° C. for 24 hours. A second portion of 3-methoxy-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-benzoic acid methyl ester (35 mg) was added followed by dimethyl sulfoxide (5 mL), acetonitrile (5 mL), a solution of ammonia (2 M in MeOH, 5 mL) and an aqueous solution of ammonium hydroxide (concentrated, 5 mL) and the resulting mixture was heated to 85° C. for 3 days. The white precipitate which formed was collected by filtration, washed with water, methanol and diethyl ether to afford after drying 15 mg (35% yield) of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (4-carbamoyl-2-methoxy-phenyl)-amide as light yellow solid. MS=312 [M+H]+.
Reaction SMILES: [CH2:1]([CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][NH:20][S:21]([C:24]3[N:25]=[CH:26][N:27]([CH3:29])[CH:28]=3)(=[O:23])=[O:22])[CH:15]=2)[CH2:10][CH:9]1[NH:30]C(=O)OCC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].C(O)C>>[NH2:30][CH:9]1[CH:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][NH:20][S:21]([C:24]3[N:25]=[CH:26][N:27]([CH3:29])[CH:28]=3)(=[O:23])=[O:22])[CH:15]=2)[CH2:10]1
Reactant: CCOC(=O)NC1Cc2ccc(OCCNS(=O)(=O)c3cn(C)cn3)cc2C1Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cn1cnc(S(=O)(=O)NCCOc2ccc3c(c2)C(Cc2ccccc2)C(N)C3)c1

Procedure:
To ethyl 1-benzyl-6-(2-(1-methyl-1H-imidazole-4-sulfonamido)ethoxy)-2,3-dihydro-1H-inden-2-ylcarbamate (192 mg, 0.385 mmol) was added 2N potassium hydroxide in ethanol (10 mL, 20.00 mmol) and microwave at 100° C. for 1 h. Washed with 50% brine and extracted with dichloromethane. The combined org. layers were washed with brine, dried, filtered and evaporated to obtain the desired N-(2-(2-amino-3-benzyl-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide as an orange grease. m=142 mg (63%)