Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].C(O)C.[F:6][C:7](=[C:31]([F:33])[F:32])[CH2:8][CH2:9][CH:10]([C:21]([O:23]CC1C=CC=CC=1)=[O:22])[C:11]([O:13]CC1C=CC=CC=1)=[O:12]>O>[F:6][C:7](=[C:31]([F:32])[F:33])[CH2:8][CH2:9][CH:10]([C:21]([OH:23])=[O:22])[C:11]([OH:13])=[O:12]
Reactant: O=C(OCc1ccccc1)C(CCC(F)=C(F)F)C(=O)OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C(CCC(F)=C(F)F)C(=O)O

Procedure:
5.56 g (99 mmol) KOH flakes were dissolved in 6.82 ml water and 13.65 ml ethanol and then treated with 11.12 g (28.34 mmol) of dibenzyl 2-(3,4,4-trifluoro-3-butenyl)-malonate. After heating under reflux for 4 hours, the reaction mixture was poured into 30 ml water and washed with ether. The aqueous phase was acidified with dilute hydrochloric acid and extracted 4 times with ether. The organic phase was dried over sodium sulphate, filtered and then concentrated in a rotary evaporator.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:33])[C@@H:22]([NH:25]C(OC(C)(C)C)=O)[CH2:23][CH3:24])=[CH:9]1)=O)(C)(C)C.ClCCl.Cl>C(OCC)C>[NH2:25][C@@H:22]([CH2:23][CH3:24])[C:21]([NH:20][CH2:19][CH2:18][CH2:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:8][CH:9]=1)=[O:33]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCCc1cn(C(=O)OC(C)(C)C)c2ccccc12
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC[C@H](N)C(=O)NCCCc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 20 mL cintillation vial was charged with 3-[3-(2-(S)-tert-butoxycarbonylamino-butyrylamino)-propyl]-indole-1-carboxylic acid tert-butyl ester (280 mg, 0.61 mmol), dichloromethane (3.6 mL), and 1M hydrogen chloride in diethyl ether (3.0 mL). The resulting mixture was stirred at room temperature for 4 h, then concentrated in-vacuo and the residue placed under high vacuum overnight to yield 2-(S)-amino-N-[3-(1H-indol-3-yl)-propyl]-butyramide. 1H NMR (300 MHz, CD3OD) δ 7.51 (d, J=7.8 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 6.95-7.09 (m, 3H), 3.11-3.39 (m, 3H), 2.77-2.82 (m, 2H), 1.78-2.01 (m, 4H), and 0.94 (t, J=7.4 Hz, 3H); MS (ES+) 260 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[CH:11]1[CH:16]=[CH:15][C:14]([CH2:17]Br)=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+].O>CC#N>[CH2:17]([O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[Cl:1])[C:14]1[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=Cc1ccc(OCc2ccccc2)c(Cl)c1
Yield: 95 %

Procedure:
To a solution of 3-chloro-4-hydroxy-benzaldehyde (5.0 g, 32 mmol) and BnBr (6.6 g, 38 mmol) in CH3CN (100 mL) was added K2CO3 (8.8 g, 64 mmol). The mixture was heated at reflux for 2 hours. The resulting mixture was poured into water (100 mL), and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and evaporated under vacuum to give crude product, which was purified by column (petroleum ether/EtOAc 15:1) to give 4-benzyloxy-3-chloro-benzaldehyde (7.5 g, 95%). 1H NMR (CDCl3, 400 MHz) δ 9.85 (s, 1H), 7.93 (d, J=2.0 Hz, 1 H), 7.73 (dd, J=2.0, 8.4 Hz, 1 H), 7.47-7.34 (m, 5 H), 7.08 (d, J=8.8 Hz, 1 H), 4.26 (s, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:9](=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:3]=1.[S:16](Cl)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:16]([C:19]2[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[C:4]([C:9](=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCC(=O)c1cc(Cl)ccc1N
Solvent: c1ccncc1
Product: CCCCCC(=O)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C)cc1

Procedure:
A mixture containing 15 g of 4-chloro-2-hexanoylaniline and 10.5 g of tosyl chloride is heated in 100 ml of pyridine at 100° C. overnight. The solvent is evaporated off, the residue is taken up with hydrochloric water and extracted with methylene chloride and the extract is dried and concentrated. The crude reaction product crystallizes from isopropyl ether to give 14.5 g.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:5]=1OCC(N)=O.C(=O)([O-])[O-].[K+].[K+].C[N:25]1CCCC1=O>>[CH3:1][O:2][CH2:3][C:4]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:5]=1[NH2:25]
Reactant: CN1CCCC1=O
Reactant: COCc1cc([N+](=O)[O-])ccc1OCC(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COCc1cc([N+](=O)[O-])ccc1N
Temperature: 100 °C

Procedure:
20 g of the 2-(2-methoxymethyl-4-nitrophenoxy)acetamide made in step 1 are dissolved in 55 ml of N-methylpyrrolidone, mixed with 29 g of potassium carbonate and heated for 3 hours at 100° C. Subsequently the reaction mixture is cooled to room temperature and the solvent is removed in vacuum at 60 to 80° C. The remaining residue is crystallized by addition of 100 ml water. 8.8 g of a yellowish product are obtained with a melting point of 90 to 92° C.
Reaction SMILES: [N+](C1C=CC=CC=1[Se]C#N)([O-])=O.[BH4-].[Na+].Br[CH2:16][CH2:17][C@@H:18]1[O:24][C@:23](/[CH:29]=[CH:30]/[CH:31]2[CH2:33][CH2:32]2)([C:25]([F:28])([F:27])[F:26])[C:22]2[CH:34]=[C:35]([Cl:38])[CH:36]=[CH:37][C:21]=2[NH:20][C:19]1=[O:39]>C1COCC1.C(O)C>[Cl:38][C:35]1[CH:36]=[CH:37][C:21]2[NH:20][C:19](=[O:39])[C@H:18]([CH:17]=[CH2:16])[O:24][C@:23](/[CH:29]=[CH:30]/[CH:31]3[CH2:33][CH2:32]3)([C:25]([F:26])([F:27])[F:28])[C:22]=2[CH:34]=1
Reactant: O=C1Nc2ccc(Cl)cc2[C@@](/C=C/C2CC2)(C(F)(F)F)O[C@H]1CCBr
Agent: N#C[Se]c1ccccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: C=C[C@@H]1O[C@](/C=C/C2CC2)(C(F)(F)F)c2cc(Cl)ccc2NC1=O
Reaction time: 1.5 h
Yield: 58.5 %

Procedure:
To a room temperature solution of 238 mg (1.05 mmol) of 2-nitrophenylselenocyanate in 3.0 mL of THF was added 9 mL of ethanol and 66 mg of sodium borohydride. After stirring 1.5 h, a solution of 153 mg of rel-(3S,5S)-trans-3-(2-bromoethyl)-7-chloro-5-cyclopropylethenyl-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one in 1.5 mL of dry THF and 5 mL of ethanol was added, and the resulting mixture was stirred at ambient temperature for 32 h. The reaction mixture was partitioned between water and ether, and the organic layer was washed.with aqueous bicarbonate and brine, dried and evaporated. The crude product was purified by column chromatography over silica gel (elution with 10-25% ethyl acetate in hexanes) to give 73 mg of the title compound as a pure solid which can be recrystallized from ethanol-hexanes: mp 165.5-166.5°; HRMS: Calcd. for C17H16NO2F3Cl (M+H)+: 358.082166. Found: 358.081658.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22]3)=[N:19][CH:20]=1)=[CH:11][C:10](Br)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[Cl:36][C:37]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[C:39]([Cl:52])[C:38]=1[OH:53]>>[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22]3)=[N:19][CH:20]=1)=[CH:11][C:10]([C:41]1[CH:42]=[C:37]([Cl:36])[C:38]([OH:53])=[C:39]([Cl:52])[CH:40]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(N2CCC(N(C)C(=O)OC(C)(C)C)C2)nc1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(N2CCC(N(C)C(=O)OC(C)(C)C)C2)nc1
Yield: 100.7 %

Procedure:
Following general procedure M, tert-butyl (1-(5-((3-acetyl-6-bromoquinolin-4-yl)amino)pyridin-2-yl)pyrrolidin-3-yl)(methyl)carbamate (80 mg, 0.15 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (72 mg, 0.25 mmol) to afford the desired product (94 mg, 100%) as a brown solid. ESI MS m/z 622 [C32H33Cl2N5O4+H]+
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:12].C(=O)(O)[O-].[Na+].[C:18](Cl)(Cl)=[S:19]>ClCCl.O>[F:1][C:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N:12]=[C:18]=[S:19]
Reactant: Nc1cccc(C(F)(F)F)c1F
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Fc1c(N=C=S)cccc1C(F)(F)F
Reaction time: 2 h
Yield: 89.1 %

Procedure:
To a two phase solution of 2-fluoro-3-trifluoromethyl-phenylamine (2 g, 11.17 mmole) in dichloromethane (40 ml) and sodium bicarbonate (6.57 g, 78.19 mmole) in water (30 ml) at 0° C. was added dropwise a solution of thiophosgene (1.28 g, 11.17 mmole) in dichloromethane (10 ml). After 2 hrs, the organic layer was separated, washed sequentially with 1M NaHCO3, brine and water. The organic layer was dried over Na2SO4, filtered and concentrated to yield 2.2 g (91%) of product as a viscous liquid. MS (ESI+) m/z 221 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH2:23][CH2:24][CH3:25])[CH:17]=O.Cl>CO>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:17]=[C:7]2[C:6](=[O:9])[C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=3[O:8]2)[CH:19]=[CH:20][C:21]=1[O:22][CH2:23][CH2:24][CH3:25]
Reactant: O=C1COc2cc(O)ccc21
Reactant: CCCOc1ccc(C=O)cc1OC
Agent: Cl
Solvent: CO
Product: CCCOc1ccc(C=C2Oc3cc(O)ccc3C2=O)cc1OC
Temperature: 25 °C
Yield: 34 %

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 3-methoxy-4-propyloxybenzaldehyde 1.55 g were dissolved in methanol 70 ml, concentrated hydrochloric acid 50 ml was added, and the mixture was refluxed for two hours. After the solution was cooled to room temperature, the precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 0.74 g.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[C:13]([C:24]([O:26][CH3:27])=[O:25])[C:12]2=[O:28])=[CH:2]1.CN(C)[C:31](=[O:33])[CH3:32]>C(O)CCO.O.[Zn]>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)=[C:13]([C:24]([O:26][CH2:27][CH2:32][CH2:31][OH:33])=[O:25])[C:12]2=[O:28])=[CH:2]1
Reactant: CC(=O)N(C)C
Reactant: COC(=O)C1=C(Nc2ccc(F)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Agent: [Zn]
Solvent: O
Solvent: OCCCO
Product: O=C(OCCCO)C1=C(Nc2ccc(F)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 16 %

Procedure:
A solution of the compound of Example 51 and zinc cluster catalyst (Zn4(OCOCF3)6O) (0.0019 g, 0.0020 mmol) in 1,3-propanediol (0.5 mL) and N,N-dimethylacetamide (0.5 mL) was stirred at 120° C. for 2 h then at 100° C. for 12 h. Cooled to ambient temperature, the reaction mixture was diluted with water, and the precipitate was collected by filtration. Ethyl acetate was added to the filtrate, and the precipitate was collected by filtration. Those precipitates were combined then purified by preparative HPLC to afford the titled compound as solid (0.0067 g, y. 16%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:55]2[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][CH:56]=2)[O:10][CH:11]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:12]2[CH2:16][CH:15]([OH:17])[CH2:14][N:13]2[C:18](=[O:48])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:47])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[CH:5][CH:4]=1.[C:63]1(=[O:69])[O:68][C:66](=[O:67])[CH2:65][CH2:64]1>>[CH3:62][O:61][C:58]1[CH:57]=[CH:56][C:55]([CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[O:10][CH:11]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:12]2[N:13]([C:18](=[O:48])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:47])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:14][CH:15]([O:17][C:63](=[O:69])[CH2:64][CH2:65][C:66]([OH:68])=[O:67])[CH2:16]2)=[CH:60][CH:59]=1
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)NCCCCCC(=O)N1CC(O)CC1C(OC(c1ccc(OC)cc1)c1ccc(OC)cc1)c1ccccc1
Reactant: O=C1CCC(=O)O1
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)NCCCCCC(=O)N1CC(OC(=O)CCC(=O)O)CC1C(OC(c1ccc(OC)cc1)c1ccc(OC)cc1)c1ccccc1

Procedure:
Using the above described procedure, the amide 102h (2.56 g, 3 mmol) was treated with succinic anhydride and after work-up the amide was isolated as a foam (2.8 g, 99%) and this was used in the next step without further purification.
Reaction SMILES: [CH2:1]([NH:13][C:14](=[O:36])[C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[C:18]([O:31][CH2:32][CH2:33]O)=[C:17]([Br:35])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(Br)(Br)(Br)[Br:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH2:1]([NH:13][C:14](=[O:36])[C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=2)[C:18]([O:31][CH2:32][CH2:33][Br:38])=[C:17]([Br:35])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCCCCCCCCCNC(=O)c1cc(Br)c(OCCO)c(-c2cccc(C(F)(F)F)c2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCCCCCCCCNC(=O)c1cc(Br)c(OCCBr)c(-c2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of N-dodecyl-3-bromo-5-(m-trifluoromethylphenyl)-4-(2-hydroxyethoxy)-benzamide (0.996 g, 1.74 mmol, 1 eq) in CH2Cl2 (9 mL) was added carbon tetrabromide (0.760 g, 2.29 mmol 1.3 eq) and triphenylphosphine (0.603 g, 2.29 mmol, 1.3 eq). The reaction was stirred at overnight at rt and concentrated in vacuo. The residue was purified by flash chromatography (15% EtOAc:hexane) to afford N-dodecyl-3-bromo-4-(2-bromo-ethoxy)-5-(m-trifluoromethylphenyl)-benzamide (0.951 g, 89%) as a colorless oil. . 1H NMR (CDCl3) δ 7.98 (d, 1H); 7.78-7.40 (m, 5H); 6.20 (bt, 1H); 4.52 (dd, 2H); 3.95 (dd, 2H); 3.42 (dd, 2H); 1.50 (m, 2H); 1.30 (m, 18H); 0.92 (t, 3H).
Reaction SMILES: C(N(CC)CC)C.[C:8]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:9].[CH2:16]([CH:18]([CH2:22][CH3:23])[C:19](Cl)=[O:20])[CH3:17]>C(#N)C>[C:8]([C:10](=[C:19]([OH:20])[CH:18]([CH2:22][CH3:23])[CH2:16][CH3:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:9]
Reactant: CCC(CC)C(=O)Cl
Reactant: CCOC(=O)CC#N
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C(C#N)=C(O)C(CC)CC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
With ice-cooling, 227 g (2.15 mol) of triethylamine were poured into a solution of 170 g (1.5 mol) of ethyl cyanoacetate in acetonitrile, and 101 g (0.75 mol) of 2-ethylbutyryl chloride were added dropwise at from 10 to 25° C. After 2 h of stirring at 25° C., the mixture was concentrated and the residue was dissolved in MTBE (methyl tert-butyl ether). By washing with 5% strength NaOH, the enolate was transferred into the aqueous phase, from which it was released by acidification to pH 3. The acidic aqueous solution was extracted and the extract was dried and concentrated. Customary purification gave 100 g (63% of theory) of the title compound as an oil (b.p. 78 to 80° C./1.5 mbar).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([OH:14])[C:8]([OH:13])=[C:9]([CH:12]=1)[C:10]#[N:11])=O.[C:15]1([NH:21][C:22]([NH2:24])=[S:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[ClH:25]>CN(C)C=O>[ClH:25].[NH:21]([C:22]1[S:23][CH:2]=[C:3]([C:5]2[CH:6]=[C:7]([OH:14])[C:8]([OH:13])=[C:9]([CH:12]=2)[C:10]#[N:11])[N:24]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N#Cc1cc(C(=O)CBr)cc(O)c1O
Reactant: NC(=S)Nc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Product: N#Cc1cc(-c2csc(Nc3ccccc3)n2)cc(O)c1O
Reaction time: 5 h

Procedure:
3.8 g of 5-(bromoacetyl)-2,3-dihydroxybenzonitrile dissolved in 25 ml of N,N-dimethylformamide are treated with N-phenylthiourea and stirred at 100° for 5 hours. Thereafter, the solvent is removed by evaporation. The residue is treated with 200 ml of 1N sodium carbonate solution and extracted three times with 100 ml of methylene chloride each time. The combined organic phases are washed with water, dried over sodium sulfate and evaporated. The residue is chromatographed on 30 g of silica gel with ethyl acetate. The thus-obtained crude product is treated with 40 ml of 1N hydrochloric acid, evaporated and crystallized from acetone. There is obtained 5-(2-anilino-4-thiazolyl)-2,3-dihydroxybenzonitrile hydrochloride of m.p. 245°-247°.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[Cl:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>CS(C)=O>[Br:1][C:2]1[C:3]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([Cl:12])=[CH:14][CH:15]=2)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cnc(Nc2ccc(Cl)cc2)c(Br)c1
Temperature: 90 °C
Yield: 68.5 %

Procedure:
A mixture of 3-bromo-2-chloro-5-nitropyridine (2.374 g, 10 mmol) and 4-chloroaniline (2.55 g, 20.00 mmol) in dimethylsulfoxide (20 mL) was heated at 90° C. for 2 hours. After cooling to ambient temperature, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified on silica gel eluting with 1:20 ethyl acetate/heptanes to give the crude product. This material was then triturated with 10% ethyl acetate in heptanes to give title compound (2.25 g, 6.85 mmol, 68.5% yield).
Reaction SMILES: N[C:2]1[S:3][C:4]([I:12])=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.C(ON=O)(C)(C)C>CN(C=O)C.[Cl-].[Na+].O>[CH2:10]([O:9][C:7]([C:5]1[N:6]=[CH:2][S:3][C:4]=1[I:12])=[O:8])[CH3:11]
Reactant: CCOC(=O)c1nc(N)sc1I
Agent: CC(C)(C)ON=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncsc1I
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
A solution of 10.68 g of 2-amino-4-ethoxycarbonyl-5-iodothiazole in 140 ml of DMF was cooled in ice under an argon atmosphere. t-Butylnitrite (6.15 ml) was added to the cooled solution, and the mixture was stirred at room temperature for 30 min. The reaction solution was poured into brine, and the mixture was extracted three times with ethyl acetate. The organic layers were combined, followed by washing three times with brine. The organic layer was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1 to 3:1) to give 5.08 g of 4-ethoxycarbonyl-5-iodothiazole.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:11][C:12]1[CH:13]=[C:14]([NH:15][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cccnc1Nc1cccc(Cl)c1

Procedure:
A mixture of 2-chloro-3-nitropyridine (2.27 g), 3-chloroaniline (1.5 ml) and potassium carbonate (2.2 g) in 1,4-dioxane (30 ml) was refluxed for 20 hours. The insoluble materials were removed by filtration and the filtrate was concentrated. Silica gel column chromatography (chloroform-methanol, 50:1) afforded 2-(3-chlorophenylamino)-3-nitropyridine (404 mg) as an orange solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:9]=[CH:10][C:5]2=[C:4]([N:17]2[CH2:23][CH:22]3[O:24][CH:19]([CH2:20][CH2:21]3)[CH2:18]2)[N:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O>[CH:19]12[O:24][CH:22]([CH2:21][CH2:20]1)[CH2:23][N:17]([C:4]1[N:3]=[C:2]([C:33]3[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=3)[N:7]=[C:6]3[N:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[N:9]=[CH:10][C:5]=13)[CH2:18]2
Reactant: Clc1nc(N2CC3CCC(C2)O3)c2cnn(-c3ccccc3)c2n1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(-c4ccccc4)c3n2)cc1

Procedure:
6-Chloro-4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine (2.5 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.0 mmol) are dissolved in a microwave vial in DME (18 mL). Na2CO3 (2.5 mL, 2M in water) is added along with a catalytic amount of tetrakis triphenylphosphine palladium. The mixture is heated in a sealed tube under microwave irradiation at 185 C for 40 min. The mixture is diluted with 50 mL EtOAc and washed with a saturated solution of NaHCO3 (2×50 mL). The aqueous layers are extracted with EtOAc (50 mL) and the combined organic layers are dried over MgSO4, filtered and concentrated in vacuo. Purification gives the title compound.
Reaction SMILES: [C:1]([C:5]1[NH:9][N:8]=[C:7]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:17]([O-])(=O)=O.[Na+].[OH-].[Na+]>Cl.O>[C:1]([C:5]1[NH:9][N:8]=[C:7]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[Cl:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C(=O)Nc1cc(C(C)(C)C)[nH]n1
Reactant: [O-][Cl+2]([O-])[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)C(=O)Nc1n[nH]c(C(C)(C)C)c1Cl
Yield: 165.2 %

Procedure:
9 g (0.04 mole) of 5-t-butyl-3-pivaloylaminopyrazole prepared in Example 4 was dissolved in 50 ml of concentrated hydrochloric acid, and 1.8 g of sodium chlorate dissolved in 40 ml of water was gradually added dropwise thereto. After completion of the reaction, the reaction product was neutralized with sodium hydroxide, and the solid thus formed was collected by filtration and dissolved in methanol. To the resulting solution was added water, whereby crystals were precipitated. The crystals were washed with water and dried to obtain 7.2 g of 5-t-butyl-4-chloro-3-pivaloylaminopyrazole. This product was recrystallized from hydrous methanol and found to have a melting point of 156° to 158° C.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH2:22][CH3:23])[N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:21]([O:20][C:16]1[N:15]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[CH:19]=[CH:18][CH:17]=1)[CH2:22][CH3:23]
Reactant: COC(=O)c1ccccc1S
Reactant: CCCOc1cccc(C#N)n1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCOc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 7.2 %

Procedure:
A mixture of methyl thiosalicylate (0.24 g, 1.4 mmol), 2-cyano-6-propoxypyridine (0.23 g, 1.4 mmol), triethylamine (0.30 ml, 2.1 mmol) and toluene (20 ml) was refluxed for 48 hrs as described in Example 1. The reaction mixture was concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography, eluted with hexane-ethyl acetate (5:1, v/v) and recrystallized from hexane-ethyl acetate to give the titled compound (0.03 g, 7%) as crystals.