Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11](=[O:12])[NH:10][C:9](=[O:13])[CH:8]=[N:7]1.[C:14]([C:18]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[C:20]([CH2:30][CH2:31][CH3:32])[N:19]=1)([CH3:17])([CH3:16])[CH3:15]>>[C:14]([C:18]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][N:27]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:11](=[O:12])[NH:10][C:9](=[O:13])[CH:8]=[N:7]3)[CH2:26][CH2:25]2)[CH:21]=[C:20]([CH2:30][CH2:31][CH3:32])[N:19]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: O=c1cnn(CCCCCl)c(=O)[nH]1
Reactant: CCCc1cc(N2CCNCC2)nc(C(C)(C)C)n1
Product: CCCc1cc(N2CCN(CCCCn3ncc(=O)[nH]c3=O)CC2)nc(C(C)(C)C)n1

Procedure:
2-{4-[4-(2-tert-Butyl-6-propyl-pyrimidin-4-yl)-piperazin-1-yl]butyl}-2H-[1,2,4]triazine-3,5-dione was prepared from 2-(4-chloro-butyl)-2H-[1,2,4]triazine-3,5-dione and 2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine by analogy to the process described in example 1.
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2[N:8]=[CH:9][N:10]=[C:11]([Cl:12])[C:6]=2[S:5][CH:4]=1.[C:13]([O-:16])(=[O:15])[CH3:14].[Na+].[I-].[K+]>CN(C=O)C.C(OCC)(=O)C>[C:13]([O:16][CH2:2][C:3]1[C:7]2[N:8]=[CH:9][N:10]=[C:11]([Cl:12])[C:6]=2[S:5][CH:4]=1)(=[O:15])[CH3:14]
Reactant: Clc1ncnc2c(CBr)csc12
Reactant: CC(=O)[O-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)OCc1csc2c(Cl)ncnc12
Temperature: 35 °C
Reaction time: 4 h

Procedure:
7-(Bromomethyl)-4-chlorothieno[3,2-d]pyrimidine (9.17 g, 33.0 mmol) was dissolved in DMF (54 mL) and then sodium acetate (27 g, 330 mmol) and potassium iodide (10.96 g, 66.0 mmol) were added thereto. The reaction mixture was stirred at 35° C. for 4 hours, diluted with ethyl acetate and washed with sat. sodium thiosulfate solution 5 times. The reaction mixture was dried with MgSO4, filtered, concentrated and purified by silica gel chromatography to obtain to obtain the title compound as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:19][CH3:20])[CH2:16][CH2:17][OH:18])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29](Cl)=[S:30])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:19][CH3:20])[CH2:16][CH2:17][OH:18])=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)=[S:30])=[CH:24][CH:23]=1
Reactant: S=C(Cl)Oc1ccc(Cl)cc1
Reactant: CCN(CCO)CCCCOc1ccc2c(c1)CCN2
Product: CCN(CCO)CCCCOc1ccc2c(c1)CCN2C(=S)Oc1ccc(Cl)cc1

Procedure:
In analogy to example 7.8, 2-{[4-(2,3-Dihydro-1H-indol-5-yloxy)-butyl]-ethyl amino}-ethanol and chloro-thioformic acid (4-chloro-phenyl)ester were converted to yield 5-{4-[Ethyl-(2-hydroxy-ethyl)-amino]-butoxy}-2,3-dihydro-indole-1-carbothioic acid O-(4-chloro-phenyl)ester as yellow viscous oil, MS: 449 (MH+, 1Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](Cl)=[C:7]3[N:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:8]3=[N:9][C:10]=2[CH:11]=1.[OH:19][CH2:20][CH2:21][N:22]([CH2:27][CH2:28][OH:29])[CH2:23][CH2:24][CH2:25][NH2:26].C1(O)C=CC=CC=1>>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([NH:26][CH2:25][CH2:24][CH2:23][N:22]([CH2:27][CH2:28][OH:29])[CH2:21][CH2:20][OH:19])=[C:7]3[N:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:8]3=[N:9][C:10]=2[CH:11]=1
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2n1
Reactant: NCCCN(CCO)CCO
Solvent: Oc1ccccc1
Product: COc1ccc2nc3cc(Cl)ccc3c(NCCCN(CCO)CCO)c2n1
Product: Cl

Procedure:
A mixture of 2.8 g. of 7,10-dichloro-2-methoxypyrido [3,2-b]quinoline, 1.8 g. of 3-[bis(2-hydroxyethyl)amino]propylamine and 6.5 g. of phenol was treated as in Example 5 to obtain the title compound, m.p. 243°-245° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:14]#N)[CH2:13][CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[OH-:16].[K+].[OH2:18].Cl>C(O)CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:14]([OH:18])=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O
Reactant: [OH-]
Reactant: N#CC1(c2ccc3c(c2)OCO3)CCC1
Agent: Cl
Agent: [K+]
Solvent: OCCO
Product: O=C(O)C1(c2ccc3c(c2)OCO3)CCC1
Temperature: 180 °C
Yield: 65 %

Procedure:
1-Benzo[1,3]dioxol-5-yl-cyclobutanecarbonitrile (1.2 g) was slurried in ethylene glycol (10 mL) in a pressure tube and a large excess of KOH (1 g) was added. The tube was sealed and heated at 180° C. for 24 hours, cooled, poured into 100 mL of water, acidified with 1N HCl, extracted with ether, and the ether extracts were concentrated in vacuo and chromatographed on silica gel with an ethyl acetate:hexane:acetic acid mixture to give the desired 1-benzo[1,3]dioxol-5-yl-cyclobutanecarboxylic acid (850 mg, 65%). Data for this acid: MS 220 (M); 1H NMR (300 MHz, CDCl3): δ 11.4-11.8 (br. s, 1H), 2.78-6.85 (m, 3H), 5.95 (s, 2H) 2.75-2.85 (m, 2H), 2.40-2.55 (m, 2H), 1.8-2.2 (m, 2H); 13C NMR (75 MHz, CDCl3): δ 182.9, 147.9, 146.7, 137.2, 119.8, 108.2, 107.5, 101.3, 52.2, 32.6, 16.7.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9](=O)[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[N:17]1[C:21]([CH2:22][N:23]2C(=O)C3=CC=CC=C3C2=O)=[N:20][N:19]=[C:18]1[CH2:34][N:35]([CH3:37])[CH3:36].O.NN>C(O)C>[Cl:16][C:14]1[CH:13]=[CH:12][C:11]2[N:17]3[C:18]([CH2:34][N:35]([CH3:36])[CH3:37])=[N:19][N:20]=[C:21]3[CH2:22][N:23]=[C:9]([C:3]3[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[C:10]=2[CH:15]=1
Reactant: CN(C)Cc1nnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc(Cl)cc1C(=O)c1c(F)cccc1F
Agent: NN
Solvent: CCO
Solvent: O
Product: CN(C)Cc1nnc2n1-c1ccc(Cl)cc1C(c1c(F)cccc1F)=NC2

Procedure:
In the manner given in Example 27, 2',6'-difluoro-5-chloro-2-[3-[(dimethylamino)methyl]-5-(phthalimidomethyl)- 4H-1,2,4-triazol-4-yl]benzophenone is heated in ethanol with hydrazine hydrate to give 8-chloro-1[(dimethylamino)-methyl]-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[NH:4][CH:5]=[C:6]([C:8]2[CH:13]=[C:12](C)C=C(C)N=2)[CH:7]=1.O=C1NC=C(C2C=C(C)C=C(C)N=2)C=[C:19]1[C:20]([NH2:22])=O>>[NH2:1][C:2]1[C:3](=[O:16])[NH:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:22]=[CH:20][CH:19]=2)[CH:7]=1
Reactant: Cc1cc(C)nc(-c2c[nH]c(=O)c(N)c2)c1
Reactant: Cc1cc(C)nc(-c2c[nH]c(=O)c(C(N)=O)c2)c1
Product: Nc1cc(-c2ccncc2)c[nH]c1=O

Procedure:
F-7. 3-Amino-5-(4,6-dimethyl-2-pyridinyl)-2(1H)-pyridinone using 1,2-dihydro-2-oxo-5-(4,6-dimethyl-2-pyridinyl)-nicotinamide.
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]1[CH:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([O:20][C:21](=[O:23])[CH3:22])[C@H:8](OC(=O)C)[O:7]1)(=[O:3])[CH3:2].[Br:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH:36]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][C:43]=3[CH3:45])[NH:38][CH2:37]2)=[CH:31][CH:30]=1.C(O)(=O)C>CO>[C:1]([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([O:20][C:21](=[O:23])[CH3:22])[C@H:8]([N:38]2[C:39]3[C:44](=[C:43]([CH3:45])[CH:42]=[CH:41][CH:40]=3)[CH:36]([CH2:35][C:32]3[CH:31]=[CH:30][C:29]([Br:28])=[CH:34][CH:33]=3)[CH2:37]2)[O:7]1)(=[O:3])[CH3:2]
Reactant: Cc1cccc2c1C(Cc1ccc(Br)cc1)CN2
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)C1OC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)OC[C@H]1O[C@@H](N2CC(Cc3ccc(Br)cc3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
Add [(2R,4S,5R,6S)-3,4,5,6-tetraacetoxytetrahydropyran-2-yl]methyl acetate (10.6 mmol) and 3-[(4-bromophenyl)methyl]-4-methyl-indoline (10.6 mmol) to a solution of acetic acid (69.8 mmol) in methanol (80 mL). Stir at room temperature overnight. Filter the reaction mixture through a glass frit and wash the filter cake with methanol (2×10 mL). Dry the filter cake under vacuum to yield the title compound (2.3g, 3.6 mmol): MS (m/z): 632 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH:5]=O.[CH3:14][C:15]([S@@:18]([NH2:20])=[O:19])([CH3:17])[CH3:16]>C(Cl)Cl.S([O-])([O-])(=O)=O.[Cu+2]>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])/[CH:5]=[N:20]/[S@:18]([C:15]([CH3:17])([CH3:16])[CH3:14])=[O:19]
Reactant: O=Cc1ccc(C(F)(F)F)c(F)c1
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)[S@](=O)/N=C/c1ccc(C(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 3-fluoro-4-(trifluoromethyl)benzaldehyde (5.7 g, 29.7 mmol) in DCM (60 mL) was added (S)-2-methylpropane-2-sulfinamide (7.19 g, 59.3 mmol) and copper (II) sulfate (18.94 g, 119 mmol). The suspension was stirred at rt under N2 for 20 h. The suspension was then filtered through Celite® brand filter agent, and the solids were washed with DCM (2×20 mL). The filtrates were concentrated and purified by ISCO (120 g, SiO2, 10-50% EtOAc/hexanes) to give (S,E)-N-(3-fluoro-4-(trifluoromethyl)benzylidene)-2-methylpropane-2-sulfinamide as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH2:18][OH:19])[S:4]([C:7]1[C:8]2[CH:9]=[CH:10][N:11]=[CH:12][C:13]=2[CH:14]=[CH:15][CH:16]=1)(=[O:6])=[O:5])[CH3:2].N1C=CC=CC=1.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>ClCCl>[CH2:1]([N:3]([CH2:17][CH2:18][O:19][S:32]([C:29]1[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=1)(=[O:34])=[O:33])[S:4]([C:7]1[C:8]2[CH:9]=[CH:10][N:11]=[CH:12][C:13]=2[CH:14]=[CH:15][CH:16]=1)(=[O:5])=[O:6])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN(CCO)S(=O)(=O)c1cccc2cnccc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCN(CCOS(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1cccc2cnccc12
Temperature: 80 °C
Yield: 44.3 %

Procedure:
To 5.77 g of N-ethyl-N-(2-hydroxyethyl)-5-isoquinolinesulfonamide were added 100 ml of pyridine and 4.0 g of p-toluenesulfonyl chloride. The mixture thus obtained was heated at 80° C. for 48 hours, and then the pyridine was removed under reduced pressure to obtain a residue. To the residue was added 100 ml of dichloromethane, and the resultant mixture was washed thrice with a hydrochloric acid solution having a pH of 5 and dried with anhydrous magnesium sulfate. Then, the dichloromethane was removed under reduced pressure to obtain a residue. The residue was subjected to purification by silica gel column chromatography (Wacogel C-200, solvent: a 5% methanol solution in chloroform) to obtain 3.96 g of N-ethyl-N-(2-p-toluenesulfonyloxyethyl)-5-isoquinolinesulfonamide.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[C:5]2[N:6]=[CH:7][CH:8]=[C:9]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)[N:4]2[N:3]=1.[Cl:17]N1C2C=CC=CC=2N=N1>>[Cl:17][C:16]1[C:2]([CH3:1])=[N:3][N:4]2[C:9]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)=[CH:8][CH:7]=[N:6][C:5]=12
Reactant: Cc1cc2nccc(-c3cccnc3)n2n1
Reactant: Cln1nnc2ccccc21
Product: Cc1nn2c(-c3cccnc3)ccnc2c1Cl

Procedure:
As for Example 34, 2-methyl-7-(3-pyridyl)pyrazolo[1,5-a]pyrimidine is reacted with N-chlorobenzotriazole to give the product of the example.
Reaction SMILES: [C:1]([O:10][CH2:11][CH3:12])([O:7][CH2:8]C)([O:4][CH2:5]C)[CH2:2][CH3:3].[CH2:13]([C:15](CO)(CO)CC)O.COCCOCCOC.CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:2]([C:1]12[O:4][CH2:5][C:12]([CH2:13][CH3:15])([CH2:8][O:7]1)[CH2:11][O:10]2)[CH3:3]
Reactant: CCOC(CC)(OCC)OCC
Reactant: CCC(CO)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COCCOCCOC
Solvent: CCO
Product: CCC12COC(CC)(OC1)OC2

Procedure:
Into a flask as specified in Example 1 were charged 529 g of triethyl orthopropionate, 402 g of trimethylol propane, 330 g of diethylene glycol dimethyl ether, and 0.9 g of PTSA. The mixture was heated for 0.5 hour at 140° C., with 402 g of ethanol being distilled off. The temperature was lowered to 100° C., and the remaining diethylene glycol dimethyl ether was distilled off under reduced pressure. The residue was subjected to vacuum distillation. The fraction having a boiling temperature of 54° C. at a pressure of 0.5 mbar yielded 370 g of clear, low-viscous liquid having a boiling point of 223° C. at atmospheric pressure and with the following structure
Reaction SMILES: [C:1]([O:5]CC)(=O)[CH2:2][CH3:3].C[O-].[Na+].[CH:11](OCC)=O.[CH2:16]([S:18][C:19](=[NH:21])[NH2:20])[CH3:17].Cl>CN(C=O)C.CO>[CH2:16]([S:18][C:19]1[N:20]=[C:1]([OH:5])[C:2]([CH3:3])=[CH:11][N:21]=1)[CH3:17]
Reactant: CCSC(=N)N
Reactant: CCOC=O
Reactant: CCOC(=O)CC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCSc1ncc(C)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.5 %

Procedure:
To a solution of ethyl propionate (1.2 mL, 10 mmol) in DMF (1 mL) was added sodium methoxide (740 mg, 13 mmol), and to this was added ethyl formate (560 μL, 6.7 mmol) very slowly over 1 h period. The reaction mixture was stirred for 30 min then 2-ethyl-2-thiopseudourea (1.3 g, 6.7 mmol) in methanol (2.5 mL) was added at once. The mixture was heated and maintained at reflux for 2 h, cooled to room temperature and acidified to pH 6 with concentrated HCl. The resulting slurry was kept in ice bath for 30 minutes. The solid was collected and was rinsed with methanol. The solid was dried under vacuum to give 154 mg of the title compound. Mass spectrum 171.1 (CI, M+1).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]1=O.O=P(Cl)(Cl)[Cl:14]>O>[Cl:14][C:2]1[CH:3]=[N:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: O=c1cnc2ccccc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: Clc1cnc2ccccc2n1

Procedure:
Quinoxalin-2-one (14.62 g, 100 mmol) was added to POCl3 (100 g, 0.65 mmol) and the mixture heated at reflux for 1.5 hours under N2. Upon cooling, the mixture was poured slowly, portionwise onto 700 ml of H2O. The black solution was extracted with CH2Cl2 (2×250 ml). The combined CH2Cl2 portions were washed with H2O, dried over Na2SO4, filtered, and evaporated to give a brown, solid 2-chloroquinoxaline. A portion of said product (4.00 g, 24.3 mmol) was combined with 5 ml of 1N HCl, and NaN3 (1.89 g, 29.1 mmol) in 220 ml of abs EtOH and heated at reflux for 7 hours. The mixture was allowed to cool overnight, which led to precipitation of yellow-brown needles of tetrazolo[1,5-a]quinoxaline (19).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[NH2:12][CH2:13][CH2:14][C@@H:15]([OH:19])[C:16]([OH:18])=[O:17].[OH-].[Na+].Cl>O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:12][CH2:13][CH2:14][C@@H:15]([OH:19])[C:16]([OH:18])=[O:17])=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: NCC[C@@H](O)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(C(=O)NCC[C@@H](O)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1.17 h

Procedure:
17.2 g of p-methoxybenzoyl chloride are added while stirring well to 6.0 g of (R)-4-amino-2-hydroxy-butyric acid and 150 ml of ion-free water. The mixture is then adjusted to pH 10.5 with 2 N sodium hydroxide and stirred at room temperature for 70 minutes. The clear solution is treated with ice and adjusted to pH 1.4 with 25% hydrochloric acid. The separated solid is filtered off and washed with water. The filtrate is adjusted to pH 5.5 with sodium hydroxide and concentrated in a water-jet vacuum. The clear colourless solution is adjusted to pH 1.4 with 25% hydrochloric acid and extracted firstly with ether and then with ethyl acetate. The aqueous phases are adjusted to pH 5.5, concentrated, acidified with 25% hydrochloric acid and extracted with ethyl acetate. The combined ethyl acetate extracts are evaporated and the residue is recrystallised from ethyl acetate. There is obtained (R)-4-(p-methoxybenzoylamino)-2-hydroxy-butyric acid of melting point 105°-106° C.; [α]D20 = -12.4°; [α]36520 =-60.5° (c=1.0 in water). A further amount of (R)-4-(p-methoxybenzoylamino)-2-hydroxy-butyric acid of melting point 103.5°-104.5° C. can be isolated from the mother liquors.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:48])[C:32]([C:46]#[N:47])=[CH:33][C@@H:34]3[CH2:38][CH2:37][CH2:36][N:35]3C(OC(C)(C)C)=O)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[ClH:49]>O1CCOCC1>[ClH:49].[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31]([C:32](=[CH:33][C@@H:34]3[CH2:38][CH2:37][CH2:36][NH:35]3)[C:46]#[N:47])=[O:48])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=C(C#N)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Agent: Cl
Solvent: C1COCCO1
Product: N#CC(=C[C@@H]1CCCN1)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 59 %

Procedure:
To a solution of tert-butyl (2S)-2-[3-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-2-cyano-3-oxo-prop-1-enyl]pyrrolidine-1-carboxylate (84 mg, 0.13 mmol) in 1,4-dioxane (2 mL) and added 4N HCl in dioxane (0.16 mL). The solution was stirred for 16 hr at room temperature then concentrated. The residue was dissolved in methanol (˜1 mL) and added dropwise to ethyl ether (20 mL) while stirring. The resulting solid was collected by filtration to provide 42 mg (59%) of the title compound as an HCl salt. MS (pos. ion) m/z: 553 (M+1).
Reaction SMILES: [CH3:1][C@@:2]12[CH2:19][CH2:18][C@@H:17]3[C@:12]([CH3:22])([CH2:13][CH2:14][CH2:15][C:16]3([CH3:21])[CH3:20])[C@H:11]1[CH2:10][S:9][C:8]1[C:3]2=[C:4]([OH:24])[CH:5]=[C:6]([OH:23])[CH:7]=1.[CH3:25][Si](C=[N+]=[N-])(C)C>CO.C(Cl)Cl>[CH3:25][O:23][C:6]1[CH:7]=[C:8]2[C:3]([C@@:2]3([CH3:1])[C@H:11]([CH2:10][S:9]2)[C@:12]2([CH3:22])[C@H:17]([C:16]([CH3:20])([CH3:21])[CH2:15][CH2:14][CH2:13]2)[CH2:18][CH2:19]3)=[C:4]([OH:24])[CH:5]=1
Reactant: CC1(C)CCC[C@]2(C)[C@H]3CSc4cc(O)cc(O)c4[C@]3(C)CC[C@@H]12
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(O)c2c(c1)SC[C@@H]1[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]21C

Procedure:
(1R,10R,11S,16S)-1,11,15,15-Tetramethyl-8-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-3,5-diol (Compound No. 26) (346 mg, 1.0 mmol) was dissolved in MeOH (4 mL) and CH2Cl2 (12 mL). Trimethylsilyl diazomethane (0.80 mL, 2.0 M in ether, 1.6 mmol) was added portionwise over 29 h at room temperature, monitoring the reaction by 1H NMR. The mixture was then concentrated and purified by chromatography on silica gel (Hexanes/EtOAc, 4:1) followed by recrystallization from MeOH/water to give (1R,10R,11S,16S)-5-methoxy-1,11,15,15-tetramethyl-8-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-trien-3-ol (Compound No. 29) (142 mg, 39%) as a white solid. 1H NMR (CDCl3): δ 6.21 (d, 1H), 5.95 (d, 1H), 4.72 (s, 1H), 3.69 (s, 3H), 3.30 (m, 1H), 2.91 (m, 1H), 2.78 (m, 1H), 1.85-1.40 (m, 8H), 1.39 (s, 3H), 1.20-1.00 (m, 2H), 0.96 (s, 3H), 0.95 (m, 1H), 0.85 (s, 3H), 0.84 (s, 3H). MS m/z 359 (C22H32O2S−H+).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[C:9]1([S:15]([N:18]2[C:26]3[C:21](=[CH:22][C:23]([OH:27])=[CH:24][CH:25]=3)[CH:20]=[CH:19]2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C=O)C.O.C(OCC)C>[Br:8][C:22]1[C:23]([OH:27])=[CH:24][CH:25]=[C:26]2[C:21]=1[CH:20]=[CH:19][N:18]2[S:15]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:16])=[O:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(O)ccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=S(=O)(c1ccccc1)n1ccc2c(Br)c(O)ccc21
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
NBS (32.6 mg, 0.180 mmol) in DMF (1 mL) was added to a solution of 1-(phenylsulfonyl)-1H-indol-5-ol (Intermediate 8, 50.0 mg, 0.183 mmol) in DMF (1 mL) at room temperature. The mixture was stirred for 30 minutes and diluted with water and diethylether and transferred to a separation funnel. The organic phase was washed with water (3×), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography using 10% pentane in DCM as the eluent to give the title compound (50 mg) as a white solid. MS m/z 352/354 [M+H]+.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].CN(C)P(=O)(N(C)C)N(C)C.[OH:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Cl)=[CH:38][CH:37]=1>O>[OH:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:8]=[C:9]4[C:14](=[CH:15][CH:16]=3)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]4)[CH2:2][CH2:3]2)=[CH:38][CH:37]=1
Reactant: O=C1CCc2cc(N3CCNCC3)ccc2N1
Reactant: Oc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: O=C1CCc2cc(N3CCN(Cc4ccc(O)cc4)CC3)ccc2N1
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 19.5 %

Procedure:
To a mixture of 1.2 g of 6-(1-piperazinyl)-3,4-dihydrocarbostyril, 1.17 g of potassium carbonate and 20 ml of hexamethylphosphoric triamide was added 651 mg of 4-hydroxybenzyl chloride and the mixture was stirred at 90° C. for 2.5 hours. The reaction mixture was poured into a large amount of water and extracted with chloroform. After washing with water, the extract was dried over anhydrous sodium sulfate. Chloroform was distilled off and the residue was purified through silica gel column chromatography to give 0.3 g of 6-[4-(4-hydroxybenzyl)-1-piperazinyl]-3,4-dihydrocarbostyril.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([OH:9])[CH:6]=[C:5]([OH:10])[N:4]=1.S(OCC)(O[CH2:15][CH3:16])(=O)=O>[OH-].[Na+]>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH2:15][CH3:16])[CH:6]=[C:5]([OH:10])[N:4]=1
Reactant: CCOS(=O)(=O)OCC
Reactant: COc1nc(O)cc(O)n1
Agent: [Na+]
Agent: [OH-]
Product: CCOc1cc(O)nc(OC)n1

Procedure:
14.2 g (0.1 mol) of 2-methoxy-4,6-dihydroxy-pyrimidine are added while stirring to 50 cc of sodium hydroxide solution 2N and the mixture is stirred for half an hour with heating to 50°. 17.0 g (0.11 mol) of diethyl sulphate are subsequently added dropwise over the course of 20 minutes and with stirring; by adding sodium hydroxide solution 2N the pH value should, if possible, be kept at between 8 and 8.2. The mixture is then stirred at 50°, sodium hydroxide solution 2N is added from time to time until the pH remains constant (approximately 3 hours). The reaction mixture is subsequently cooled to 0°, the precipitate is suction filtered and washed with a small quantity of ethanol. After drying in a high vacuum at 80°, the substance has a M.P. of 192°-194°.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:24]=[CH:25][C:26]=2[O:27][CH3:28])[CH2:10][C:11]2[O:12][C:13]3[C:19]([CH2:20][CH2:21][OH:22])=[CH:18][C:17]([Cl:23])=[CH:16][C:14]=3[N:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O-:29]C#N.[Na+].FC(F)(F)C(O)=O.O>C(Cl)Cl>[C:11](=[O:12])([OH:29])[NH2:15].[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:24]=[CH:25][C:26]=2[O:27][CH3:28])[CH2:10][C:11]2[O:12][C:13]3[C:19]([CH2:20][CH2:21][OH:22])=[CH:18][C:17]([Cl:23])=[CH:16][C:14]=3[N:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#C[O-]
Agent: COc1ccc(Cc2nc3cc(Cl)cc(CCO)c3o2)cc1OC1CCCC1
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NC(=O)O
Reaction time: 8 h

Procedure:
A suspension of 2-(3-cyclopentyloxy-4-methoxybenzyl)-5-chloro-7-(2-hydroxyethyl)benzoxazole (0.6 g, 0.0015 mol) and sodium cyanate (0.2 g, 0.0030 mol) was stirred in 4 ml of CH2Cl2 and then trifluoroacetic acid (0.34 g, 0.0030 mol) was added. The mixture was stirred overnight as the initial solid dissolved and a new solid began to form. The next day CH2Cl2 (50 ml) and water (50 ml) were added. The water layer was separated and extracted with 2×50 ml of CH2Cl2. The combined CH2Cl2 layers were washed with 50 ml of water, dried and evaporated to give 0.6 g of white crystalline solid. This material was recrystallized from 6 ml of toluene to give 0.3 g of title compound as white crystals, mp 97-98° C.