Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][S:10][CH:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:31][C@H:32]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:33][CH2:34][OH:35]>C1COCC1>[OH:35][CH2:34][CH2:33][C@H:32]([NH:31][C:13]([CH:9]1[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:12][CH2:11][S:10]1)=[O:15])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)N1CCSC1C(=O)O
Reactant: N[C@@H](CCO)c1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCSC1C(=O)N[C@@H](CCO)c1ccccc1
Temperature: -25 °C

Procedure:
Commercial 3-(tert-butoxycarbonyl)-1,3-thiazolidine-2-carboxylic acid (III) (1 g, 4.29 mmol) was dissolved in dry THF (50 ml). A mechanical stirrer was placed in the flask and the solution stirred vigorously. The solution was cooled down to −25° C. and N-methyl morpholine (1.084 g, 10.72 mmol) was added in dry THF (5 ml). A solution of isobutyl-chloroformate (0.615 g, 4.5 mmol) in dry THF (10 ml) was then added dropwise over a period of 10 minutes with continued vigorous stirring, the reaction's exotherm being maintained at the optimal temperature of −25° C. by the use of a dry-acetone bath. After the complete addition of the chloroformate, the reaction mixture was stirred at −25° C. for 30 min after which time an amine (IV)/(IV*), e.g., (3S)-3-amino-3-phenyl-1-propanol (0.778 g, 5.14 mmol) was added drop-wise over a period of 10 min. The reaction mixture was allowed to gradually warm to room temperature and stirred overnight. The solvent was removed and the residue re-dissolved in ethyl acetate (150 ml). The organic layer was washed subsequently with a saturated solution of ammonium chloride (100 ml), saturated bicarbonate (100 ml) and brine (100 ml). Organics then dried with magnesium sulfate and concentrated in vacuo. The product (V), e.g., tert-butyl 2-({[(1S)-3-hydroxy-1-phenyl-propyl]amino}carbonyl)-1,3-thiazolidine-3-carboxylate, was finally obtained as a white foam (1.5 g, 95%). The antipodal intermediate, tert-butyl 2-({[(1S)-3-hydroxy-1-phenyl-propyl]amino}carbonyl)-1,3-thiazolidine-3-carboxylate, as well as the racemic inter-mediate, tert-butyl 2-({[3-hydroxy-1-phenylpropyl]amino}carbonyl)-1,3-thiazolidine-3-carboxylate were made according to the same protocol, starting from commercial (3R)-3-amino-3-phenylpropan-1-ol or 3-amino-3-phenylpropan-1-ol, respectively.
Reaction SMILES: BrC1C(F)=CC2OCC(F)C3SC(C(OCC)=O)=[N:11]C=3C=2C=1.C([C@]1(O)CCN(C)C1=O)#C.[F:33][CH:34]1[C:43]2[S:42][C:41]([C:44]([O:46]CC)=O)=[N:40][C:39]=2[C:38]2[CH:49]=[C:50]([C:54]#[C:55][C@:56]3([OH:63])[CH2:60][CH2:59][N:58]([CH3:61])[C:57]3=[O:62])[C:51]([F:53])=[CH:52][C:37]=2[O:36][CH2:35]1>>[F:33][CH:34]1[C:43]2[S:42][C:41]([C:44]([NH2:11])=[O:46])=[N:40][C:39]=2[C:38]2[CH:49]=[C:50]([C:54]#[C:55][C@:56]3([OH:63])[CH2:60][CH2:59][N:58]([CH3:61])[C:57]3=[O:62])[C:51]([F:53])=[CH:52][C:37]=2[O:36][CH2:35]1
Reactant: CCOC(=O)c1nc2c(s1)C(F)COc1cc(F)c(C#C[C@]3(O)CCN(C)C3=O)cc1-2
Reactant: CCOC(=O)c1nc2c(s1)C(F)COc1cc(F)c(Br)cc1-2
Agent: C#C[C@]1(O)CCN(C)C1=O
Product: CN1CC[C@@](O)(C#Cc2cc3c(cc2F)OCC(F)c2sc(C(N)=O)nc2-3)C1=O

Procedure:
Similar to as described in General Procedure G, racemic ethyl 9-bromo-4,8-difluoro-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxylate was reacted with (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one to give a diasteromeric mixture of ethyl 4,8-difluoro-9-(((R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxylate. Following aminolysis of the ethyl ester (similar to as described in General Procedure M) a diasteromeric mixture of the titled compounds was obtained after purification by prep HPLC.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2](C)=[CH2:3].[OH:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][C:10](C=C(C)C([O-])=O)([CH2:11]3)[CH2:9]1)[CH2:15]2.C1C2C(=CC3C(C=2COC(=O)C(C)=C)=CC=CC=3)C=CC=1.CC(C)C#N>O1CCCC1>[CH2:3]=[CH:2][C:1]([O:6][C:10]12[CH2:9][C:8]3([OH:7])[CH2:17][CH:12]([CH2:13][CH:14]([CH2:15]3)[CH2:16]1)[CH2:11]2)=[O:5]
Reactant: C=C(C)C(=O)O
Reactant: CC(=CC12CC3CC(CC(O)(C3)C1)C2)C(=O)[O-]
Agent: C=C(C)C(=O)OCc1c2ccccc2cc2ccccc12
Agent: CC(C)C#N
Solvent: C1CCOC1
Product: C=CC(=O)OC12CC3CC(CC(O)(C3)C1)C2
Temperature: 25 °C

Procedure:
To a mixture of methacrylic acid (0.775 g, 9 mmol), 3-hydroxy-1 adamantylmethacrylate (1.42 g, 6 mmol), 9-anthrylmethylmethacrylate (1.38 g, 5 mmol) in 20 mL of tetrahydrofuran (THF) was added 2,2′-azobis(2-methylpropionitrile (0.16 g, 1 mmol). The resulting solution was purged by nitrogen for 30 minutes before it was heats to 72° C. for 18 hours under nitrogen. The solution was then cooled to room temperature and added drop-wise into 400 mL of de-ionized water. The solid was filtered with a frit funnel, washed with water (2×200 ml) and dried in a vacuum oven at 50° C. for 24 hours to afford 3.1 gram of P1 as white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(=O)(O)[O-].[Na+].[NH:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[C:36]1[C:44]1[C:52]2[C:47](=[CH:48][CH:49]=[C:50]([NH2:53])[CH:51]=2)[N:46]([CH:54]2[CH2:59][CH2:58][CH2:57][CH2:56][O:55]2)[N:45]=1>CN(C=O)C>[NH:37]1[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[N:35]=[C:36]1[C:44]1[C:52]2[C:47](=[CH:48][CH:49]=[C:50]([NH:53][C:13]([CH:10]3[CH2:9][CH2:8][N:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)[CH2:12][CH2:11]3)=[O:15])[CH:51]=2)[N:46]([CH:54]2[CH2:59][CH2:58][CH2:57][CH2:56][O:55]2)[N:45]=1
Reactant: Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1
Reactant: O=C(O)C1CCN(c2ccncc2)CC1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1)C1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 39 %

Procedure:
1-(Pyridin-4-yl)piperidine-4-carboxylic acid (14 mg, 0.068 mmol), HOBt (12 mg, 0.088 mmol), EDC (17 mg, 0.088 mmol) and sodium bicarbonate (5 mg, 0.059 mmol) were added to a solution of 3-(1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (20 mg, 0.059 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 24 h, and then the solvent was removed in vacuum. Purification by flash chromatography (6% CH3OH/CH2Cl2) afforded the title compound (12 mg).
Reaction SMILES: [CH3:1][C@@H:2]([CH2:7][OH:8])[C:3]([O:5][CH3:6])=[O:4].S(=O)(=O)(O)O.[CH2:14]=[C:15]([CH3:17])[CH3:16]>ClCCl>[C:15]([O:8][CH2:7][C@H:2]([CH3:1])[C:3]([O:5][CH3:6])=[O:4])([CH3:17])([CH3:16])[CH3:14]
Reactant: C=C(C)C
Reactant: COC(=O)[C@@H](C)CO
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COC(=O)[C@@H](C)COC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl (S)-(+)-2-methyl-3-hydroxypropionate (2.36 g; 20 mmole) was dissolved in dry dichloromethane (30 ml), conc. sulfuric acid (0.2 ml) was added thereto, and isobutene (23.5 g) was introduced into the resultant mixture kept at -60° to -70° C., followed by stirring at room temperature for 3 hours. The reaction mixture was sealed and stirred overnight, and unreacted isobutene was removed therefrom by distillation. The mixture was washed successively with water and a saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give methyl (S)-3-t-butoxy-2-methylpropionate.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:16]=[C:15]([C:17]([O:19]CC2C=CC=CC=2)=[O:18])[CH:14]=[C:13]([C:27]([O:29]CC2C=CC=CC=2)=[O:28])[C:12]=1[O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:10])C1C=CC=CC=1.[OH-].[Na+]>CO.O>[CH2:38]([O:37][C:12]1[C:11]([C:9]([OH:10])=[O:8])=[CH:16][C:15]([C:17]([OH:19])=[O:18])=[CH:14][C:13]=1[C:27]([OH:29])=[O:28])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: O=C(OCc1ccccc1)c1cc(C(=O)OCc2ccccc2)c(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(C(=O)O)c(OCc2ccccc2)c(C(=O)O)c1

Procedure:
2-Benzyloxy-benzene-1,3,5-tricarboxylic acid tribenzyl ester (14) (52 g, 88 mmol) was hydrolyzed with NaOH (20 g, 0.5 mol) in 4:1 methanol-water (1 L). The solvents were removed under reduced pressure after the completion of hydrolysis, and the residue was dissolved in saline and extracted with recycling methylene chloride to remove the benzyl alcohol. 2-benzyloxy benzene-1,3,5-tricarboxylic acid (15) deposited after acidification of the solution. It was collected by filtration and dried under vacuum, yield 25.6 g, 92%.
Reaction SMILES: [K].[SH:2][C:3]1[N:4]([CH3:14])[C:5](=[O:13])[C:6]2[C:11]([CH3:12])=[N:10][NH:9][C:7]=2[N:8]=1.[Cl:15][C:16]1[CH:31]=[CH:30][C:19]([C:20]([C:22]2[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=2)=[O:21])=[CH:18][CH:17]=1>CN(C=O)C.O>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([C:22]2[CH:29]=[CH:28][C:25]([CH2:26][S:2][C:3]3[N:4]([CH3:14])[C:5](=[O:13])[C:6]4[C:11]([CH3:12])=[N:10][NH:9][C:7]=4[N:8]=3)=[CH:24][CH:23]=2)=[O:21])=[CH:30][CH:31]=1
Reactant: Cc1n[nH]c2nc(S)n(C)c(=O)c12
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1n[nH]c2nc(SCc3ccc(C(=O)c4ccc(Cl)cc4)cc3)n(C)c(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
To a solution of 6-mercapto-3,5-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one potassium (800 mg) in DMF (12 ml) was added 4-(4-chlorobenzoyl)benzyl bromide (1.05 g) and the mixture was stirred at room temperature for 1 hour. This reaction mixture was poured in water and the resulting crystals were collected by filtration, rinsed with water and methanol, and recrystallized from methanol to provide the title compound as colorless solid (1.086 g). 1H-NMR (DMSO-d6) δ: 2.44(3H,s), 3.42(3H,s), 4.60(2H,s), 7.63(2H,d,J=8.6Hz), 7.71(4H,s), 7.75(2H,d,J=8.6Hz), 13.29(1H,brs).
Reaction SMILES: O[C:2]1[C:3]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.S1C=CC=C1P.C(Cl)(Cl)(Cl)Cl.ClC(Cl)C.[NH2:32][C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][CH:41]=1)[NH:38][CH:37]=[CH:36]2>>[NH:38]1[C:39]2[C:35](=[CH:34][C:33]([NH:32][C:2]3[C:3]4[S:10][C:9]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)=[CH:8][C:4]=4[N:5]=[CH:6][N:7]=3)=[CH:41][CH:40]=2)[CH:36]=[CH:37]1
Reactant: Oc1ncnc2cc(-c3ccccc3)sc12
Reactant: Nc1ccc2[nH]ccc2c1
Agent: Pc1cccs1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: c1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Temperature: 25 °C

Procedure:
In a 125 mL single neck round bottom flask with reflux condenser, 4-hydroxy-(6-phenyl)-thieno[3,2-d]pyrimidine was combined with thiphenylphosphine polymers (900 mg, 2.7 mmole), carbon tetrachloride (1.1 mL, 11 mmole) and dichloroethane (15 mL). Boiling chips were added and the mixture was refluxed for 18 hours. The mixture was cooled to ambient temperature and filtered into a second single neck round bottom flask. The polymer was washed with 25 mL 10% dichloroethane/tert-butanol. The organic layers were combined and 5-amino-indole (212 mg, 1.6 mmole) was added and the resulting solution was refluxed for 18 hours. The reaction mixture was cooled to ambient temperature and concentrated to a green-brownish residue. The residue was partitioned between 1 N NaOH and 15% 2-propanol/chloroform. The aqueous layer is extracted 2 times with 15 mL 15% isopropanol/CHCl3. The organic layers were combined and dried over sodium sulfate and concentrated to a black residue. The residue was triturated with methanol to give 57 mg of product: MP: 255-258° C. (dec); anal. RP18-HPLC RT: 4.38 minutes; TS-MS: 343 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[C@H:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(OCC)(=O)C.Cl>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:19]3[CH:20]=[CH:21][C:22]([O:25][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:23][CH:24]=3)[C@H:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)OC[C@@H](c1ccccc1)[C@H]2c1ccc(O)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ccc2c(c1)OC[C@@H](c1ccccc1)[C@H]2c1ccc(OS(C)(=O)=O)cc1
Temperature: 25 °C

Procedure:
(+,-) cis 7-methoxy-4-(4-hydroxy-phenyl)-3-phenyl-chroman (7.5 g, 22.6 mmol) was dissolved in pyridine (35 ml), and methanesulfonylchloride (3.85 ml, 49.6 mmol) was added dropwise in 5 min. The reaction mixture was refluxed for 30 min, cooled to room temperature, and ethyl acetate (100 ml) was added. The reaction mixture was acidified with 6N Hydrochloric acid (100 ml), and the separated aqueous phase extracted with ethyl acetate (25 ml). The combined organic extracts were washed with 1N hydrochloric acid (50 ml), water (2×50 ml), dried with magnesium sulphate and evaporated to give a slightly yellow solid, which was recrystallised from ethanol, and vacuum dried.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([O:13][CH3:14])=[C:4](Cl)[N:3]=1.[NH3:16]>CS(C)=O.O>[NH2:16][C:4]1[N:3]=[C:2]([Cl:1])[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]=1[O:13][CH3:14]
Reactant: N
Reactant: COc1c(Cl)nc(Cl)nc1-c1ccco1
Solvent: CS(C)=O
Solvent: O
Product: COc1c(N)nc(Cl)nc1-c1ccco1
Temperature: 60 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
2,6-Dichloro-5-methoxy-4-furan-2-yl pyrimidine (500 mg, 2.0 mmol) (see Example 5 for the preparation of 2,6-dicholor-5-methoxy-4-furan-2-yl pyrimidine) was dissolved in dry DMSO (10 mL) and heated to 60° C. This mixture was treated with a gentle stream of ammonia. After approximately 2 h, conversion was complete to about a 95:5 ratio of mono-amino isomers (having a molar weight of 225 g/mol). This mixture was cooled and diluted with water (50 mL), and the product extracted with ethyl acetate (2×50 mL). Then, the product was washed with ethyl acetate, twice with water (25 mL), and once with saturated sodium chloride (25 mL). The result was dried and concentrated. The product was purified by column chromatography using silica with a 5 to 20% ramp of ethyl acetate/hexane to give the title compound (400 mg, 89% yield). The various isomers were not separated.
Reaction SMILES: C[Si](C)(C)N1C(=O)C2=CC=CC=C2C1=O.C[Si](C)(C)[O:18][C:19]([CH:21]([N:25]1[CH:28]([S:29][N:30]2[C:34](=[O:35])[C:33]3=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]3[C:31]2=[O:40])[CH:27]([NH:41][C:42](=[O:51])[CH2:43][O:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:26]1=[O:52])[C:22]([CH3:24])=[CH2:23])=[O:20]>CC(N(C)C)=O>[C:19]([CH:21]([N:25]1[CH:28]([S:29][N:30]2[C:34](=[O:35])[C:33]3=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]3[C:31]2=[O:40])[CH:27]([NH:41][C:42](=[O:51])[CH2:43][O:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:26]1=[O:52])[C:22]([CH3:24])=[CH2:23])([OH:20])=[O:18]
Reactant: C=C(C)C(C(=O)O[Si](C)(C)C)N1C(=O)C(NC(=O)COc2ccccc2)C1SN1C(=O)c2ccccc2C1=O
Agent: C[Si](C)(C)N1C(=O)c2ccccc2C1=O
Solvent: CC(=O)N(C)C
Product: C=C(C)C(C(=O)O)N1C(=O)C(NC(=O)COc2ccccc2)C1SN1C(=O)c2ccccc2C1=O
Temperature: 100 °C

Procedure:
A mixture of 1.8 g (5 mmoles) of phenoxymethylpenicillin-S-sulphoxide and 6.6 g (30 mmoles) of N-trimethylsilylphthalimide in 35 ml of dimethylacetamide was heated at 100°C for 2 hours. The reaction mixture (containing 1-(1-trimethylsilyloxycarbonyl-2-methylprop-2-enyl)-3-phenoxyacetamido-4-phthalimidothioazetidin-2-one) was evaporated to dryness, treated with 30 ml of dichloromethane and filtered. The filtrate was concentrated and purified by chromatography on a silica gel column impregnated with 1% acetic acid, using a 4:1 (v/v) mixture of toluene and acetone with 0.5% acetic acid as an eluent. There was obtained 1-(1-carboxy-2-methylprop-2-enyl)-3-phenoxyacetamido-4-phthalimidothio-azetidin-2-one.
Reaction SMILES: [Br:1]Br.[F:3][C:4]([F:23])([F:22])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]=[CH:12]2)=[N:9][CH:10]=1.O.O.O.C([O-])(=O)C.[Na+]>C(O)(=O)C>[F:23][C:4]([F:3])([F:22])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([Br:1])[CH2:12]2)=[N:9][CH:10]=1
Reactant: O=c1cc(C(F)(F)F)ncn1-c1ccc(C(F)(F)F)cn1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1C=C(C(F)(F)F)N(Br)CN1c1ccc(C(F)(F)F)cn1
Reaction time: 16 h

Procedure:
Bromine (0.15 ml) was added in one portion to a suspension of 1-(5-trifluoromethyl-2-pyridyl)-4-trifluoromethylpyrimidin-6-one (compound No. 2 in Table I) (0.5 g) and sodium acetate trihydrate (1.1 g) in acetic acid (4.8 ml). After stirring for 16 hours, the solvent, was removed under reduced pressure, and the residue was poured into water and aqueous sodium bicarbonate solution. Rigourous extraction into diethylether followed by drying over magnesium sulphate and removal of the solvent under reduced pressure, gave 1-(5-trifluoromethyl-2-pyridyl)-3-bromo-4-trifluoromethylpyrimidin-6-one as a pale yellow solid (m.p. 142-143° C.). The compound showed (CDC13) 8.90 (1H,s), 8.80 (1H,s), 8.2 (1H,dg), 8.16 (1H,d).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[NH:9][C:8]([OH:10])=[C:7]([C:11]3[C:19](=O)[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[N:12]=3)[C:5]=2[CH:6]=1.[Cl-].[OH:22][NH3+:23].O>N1C=CC=CC=1>[CH:1]1[CH:2]=[CH:3][C:4]2[NH:9][C:8]([OH:10])=[C:7]([C:11]3[NH:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:19]=3[N:23]=[O:22])[C:5]=2[CH:6]=1
Reactant: O=C1C(c2c(O)[nH]c3ccccc23)=Nc2ccccc21
Reactant: [NH3+]O
Agent: [Cl-]
Solvent: O
Solvent: c1ccncc1
Product: O=Nc1c(-c2c(O)[nH]c3ccccc23)[nH]c2ccccc12
Temperature: 25 °C
Yield: 90.2 %

Procedure:
Indirubin (0.64 g, 2.4 mmol) was dissolved in anhydrous pyridine (25 mL), and hydroxylammonium chloride (1.67 g, 24 mmol) was added to the solution. The reaction liquid was heated and refluxed for 2.5 hours and then cooled to room temperature. The reaction liquid was poured into water (100 mL), and the precipitated crude crystals were collected by suction filtration. The resulting crude crystals were recrystallized from methanol/water to give red needle-shaped crystals of indirubin-3′-oxime (0.60 g, 89%).
Reaction SMILES: [NH2:1][C:2]([C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:7]=1[F:13])([CH3:5])[CH2:3][OH:4].C(N(CC)CC)C.Br[CH:22]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:23](Cl)=[O:24]>C(#N)C>[Br:12][C:10]1[CH:9]=[CH:8][C:7]([F:13])=[C:6]([C:2]([NH:1][C:23](=[O:24])[CH:22]=[CH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([CH3:5])[CH2:3][OH:4])[CH:11]=1
Reactant: CC(N)(CO)c1cc(Br)ccc1F
Reactant: O=C(Cl)C(Br)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(CO)(NC(=O)C=Cc1ccccc1)c1cc(Br)ccc1F
Temperature: 25 °C
Yield: 10.3 %

Procedure:
A solution of (RS)-2-amino-2-(5-bromo-2-fluoro-phenyl)-propan-1-ol (1.5 g, 6 mmol) and triethylamine (1.01 ml, 7.3 mmol) in acetonitrile (31 ml) was cooled to 0° C. A solution of (RS)-2-bromo-3-phenyl-propionyl chloride (CAS 42762-86-7) (1.637 g, 6.6 mmol) in acetonitrile was added dropwise. After complete addition the reaction mixture was left to warm to room temperature. After 1 hour the reaction mixture was evaporated under reduced pressure and directly purified by chromatography on silica gel using a gradient of heptane and ethyl acetate=100/0 to 50/50 as the eluent. Besides the N-[(RS)-1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-3-phenyl-acrylamide (0.233 g, 10% of theory), the (2RS)-bromo-N-[(RS)-1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-3-phenyl-propionamide (mixture of diastereoisomers 3:2) was obtained as a white solid (1.985 g, 71.5% of theory). Mass (calculated) C18H18Br2FNO2 [459.156]; (found) [M+H]+=457, [M+2-H]+=459, [M+4-H]+=461.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.[C:11]([C:14]1[C:15]([CH3:29])=[C:16](Br)[C:17](=[O:27])[N:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[N:19]=1)(=[O:13])[CH3:12]>O.CN(C)C=O>[C:11]([C:14]1[C:15]([CH3:29])=[C:16]([S:10][C:7]2[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=2)[C:17](=[O:27])[N:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[N:19]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)c1nn(-c2ccc(Cl)cc2)c(=O)c(Br)c1C
Reactant: Sc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1nn(-c2ccc(Cl)cc2)c(=O)c(Sc2ccc(Cl)cc2)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a solution of 97% sodium hydroxide (51 mg) in a mixture of water (3 ml) and N,N-dimethylformamide (10 ml) was added 4-chlorothiophenol (0.19 g), followed by stirring at room temperature for 30 minutes. Then, 6-acetyl-4-bromo-2-(4-chlorophenyl)-5-methyl-3(2H)-pyridazinone (0.30 g) was added, followed by stirring at room temperature for 1 hour. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. After washing with water and a brine, the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation, the resulting crude crystals were recrystallized from ethyl acetate/hexane to obtain 6-acetyl-2-(4-chlorophenyl)-4-(4-chlorophenylthio)-5-methyl-3(2H)-pyridazinone (260 mg) (Compound No. 1-29).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:14]=[C:13]([CH3:15])[NH:12][N:11]=1.C(N(CC)C(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:9][C:10]2[CH:14]=[C:13]([CH3:15])[NH:12][N:11]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Cc1cc(N)n[nH]1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2ccnc(Cl)n2)n[nH]1
Temperature: 50 °C
Reaction time: 18 h
Yield: 25.8 %

Procedure:
A mixture of 2,4-dichloropyrimidine (2.97 g, 20 mmol), 3-amino-5-methyl-1H-pyrazole (2.14 g, 22 mmol), and N,N-diisopropylethylamine (2.82 g, 22 mmol) in dry THF (75 ml) was stirred at 50° C. for 18 hours. The solvent was removed by evaporation, and the residue partitioned between DCM (75 ml) and water (50 ml). The resulting precipitate was collected by filtration washed with water and then ether, and dried under vacuum at 50° C. to give the title compound (1.08 g, 26%) as a colourless crystalline solid.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[Cl:5][C:6]1[CH:11]=[C:10](I)[CH:9]=[CH:8][N:7]=1.O>C(O)C>[Cl:5][C:6]1[CH:11]=[C:10]([O:1][CH2:2][CH3:3])[CH:9]=[CH:8][N:7]=1
Reactant: Clc1cc(I)ccn1
Reactant: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1ccnc(Cl)c1

Procedure:
33 ml sodium ethoxide was added to 19.2 g 2-chloro-4-iodopyridine in 150 mL ethanol. The reaction was refluxed overnight. Then water was added and extracted with tert-butyl-methylether. The organic layer was evaporated and the residue cleanded by chromatography on silica gel (petrolether/EtOAC:9/1) to yield 5 g of the desired compound.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][CH:9]([C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[CH3:28])[CH2:10][CH2:11][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH3:13])(=O)=O.CN(C=O)C.[N-:34]=[N+:35]=[N-:36].[Na+]>C(OCC)(=O)C>[N:34]([CH2:6][CH2:7][O:8][CH:9]([C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[CH3:28])[CH2:10][CH2:11][N:12]([CH3:13])[C:14](=[O:15])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N+:35]=[N-:36]
Reactant: Cc1ccc(Cl)cc1C(CCN(C)C(=O)OC(C)(C)C)OCCOS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(Cl)cc1C(CCN(C)C(=O)OC(C)(C)C)OCCN=[N+]=[N-]
Temperature: 80 °C

Procedure:
2-(3-(tert-Butoxycarbonyl(methyl)amino)-1-(5-chloro-2-methylphenyl)propoxy)ethyl methanesulfonate (414 mg, 0.95 mmol) was dissolved into anhydrous DMF (15 mL), solid NaN3 (186 mg, 2.86 mmol) was added and the reaction mixture was heated to 80° C. overnight. The reaction mixture was cooled to room temperature and diluted with ethyl acetate, the organic phase was washed with water and brine, dried over Na2SO4 and concentrated in vacuo to the crude product (270 mg, 74%), which was used for next step without purification.