Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][CH2:12][C@@:11]([CH3:19])([C:15]([O:17][CH3:18])=[O:16])[CH2:10]2)[C:5]([F:20])=[CH:4][N:3]=1.[Cl:21][C:22]1[CH:23]=[C:24]2[C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][N:28]([S:40]([C:43]3[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=3)(=[O:42])=[O:41])[C:25]2=[N:26][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O>[Cl:21][C:22]1[CH:23]=[C:24]2[C:30]([C:2]3[N:7]=[C:6]([NH:8][C@H:9]4[CH2:14][CH2:13][CH2:12][C@@:11]([CH3:19])([C:15]([O:17][CH3:18])=[O:16])[CH2:10]4)[C:5]([F:20])=[CH:4][N:3]=3)=[CH:29][N:28]([S:40]([C:43]3[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=3)(=[O:41])=[O:42])[C:25]2=[N:26][CH:27]=1
Reactant: COC(=O)[C@]1(C)CCC[C@H](Nc2nc(Cl)ncc2F)C1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(Cl)cnc32)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@]1(C)CCC[C@H](Nc2nc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(Cl)cc34)ncc2F)C1

Procedure:
In a 25 mL round-bottomed flask were combined (1R,3S)-methyl 3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1-methylcyclohexanecarboxylate, 52h, (0.061 g, 0.202 mmol), 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (0.096 g, 0.222 mmol), disodium carbonate (0.064 g, 0.607 mmol) in 5 mL of THF and 1 ml of water. The reaction mixture was degassed via a stream of nitrogen. To the reaction was added tetrakis triphenyl phosphine palladium (0) (0.021 g, 0.202 mmol) and the reaction was stirred at reflux overnight. The reaction was concentrated in vacuo and purified by silica gel chromatography (4:1 Hexanes:EtOAc), yielding 85 mg of desired product, 52i.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]2[S:13][C:14]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=4)=[O:23])=[CH:17][C:15]=3[CH:16]=2)=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][N:3]=1.[OH-].[K+]>CO.O>[NH2:1][C:2]1[C:11]([C:12]2[S:13][C:14]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=4)=[O:23])=[CH:17][C:15]=3[CH:16]=2)=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: COC(=O)c1cnc(N)c(-c2cc3cc(NC(=O)Nc4cccc(C)c4)ccc3s2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cccc(NC(=O)Nc2ccc3sc(-c4cc(C(=O)O)cnc4N)cc3c2)c1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
To the stirring mixture of methyl 6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]nicotinate (420 mg, 0.972 mmol, 1 eq) in MeOH—H2O (3:1, 20 mL) at room temperature was added potassium hydroxide pellets (272 mg, 5 eq) and the reaction mixture was stirred at 65° C. for total of two hours, at which time the reaction mixture became a clear yellow solution. The solution was concentrated under reduced pressure to remove most part of methanol. The mixture was then cooled in an ice-bath, concentrated hydrochloride was added dropwise, and the pH was adjusted to about 3. After the mixture was stirred for about another 30 minutes, it was filtered through a Buchner funnel, rinsed with water, and 6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]nicotinic acid was obtained as a yellow solid in quantitative yield.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:14]2[N:19]3[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:22]=[C:18]3[N:17]=[C:16]([NH:29][NH2:30])[CH:15]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[C:31]([C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH:35]=O)#[N:32]>C(O)C>[C:31]([C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH:35]=[N:30][NH:29][C:16]1[CH:15]=[C:14]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:19]2[N:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:22]=[C:18]2[N:17]=1)#[N:32]
Reactant: N#Cc1ccccc1C=O
Reactant: NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: N#Cc1ccccc1C=NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.6 %

Procedure:
There was dissolved, in ethanol (2 mL), trifluoroacetic acid salt of (7-morpholin-4-yl-2-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-hydrazine (30.0 mg, 0.0557 mM), then 2-cyano-benzaldehyde (6.7 mg, 0.061 mM) was added to the solution and the mixture was stirred at room temperature for one hour. This reaction liquid was filtered and the resulting solid was purified by the NH-silica gel column chromatography (methanol/methylene chloride=1/20) to thus give the title compound (22.2 mg, yield: 94%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:24])[O:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18](OC)[CH:17]=2)[CH:14]=1)[C:9]([OH:11])=O.[CH3:25][O:26]C1C=CC(B(O)O)=CC=1.[NH2:36][C:37]1[S:38][CH:39]=[C:40]([CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[N:41]=1>>[CH2:46]([O:45][C:43](=[O:44])[CH2:42][C:40]1[N:41]=[C:37]([NH:36][C:9](=[O:11])[C:8]2[CH:7]=[C:6]([O:5][C@@H:4]([CH3:24])[CH2:3][O:2][CH3:1])[CH:14]=[C:13]([O:15][C:16]3[CH:17]=[CH:18][C:19]([O:26][CH3:25])=[CH:20][CH:21]=3)[CH:12]=2)[S:38][CH:39]=1)[CH3:47]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: COC[C@H](C)Oc1cc(Oc2cccc(OC)c2)cc(C(=O)O)c1
Product: CCOC(=O)Cc1csc(NC(=O)c2cc(Oc3ccc(OC)cc3)cc(O[C@@H](C)COC)c2)n1

Procedure:
{2-[3-(4-Methoxy-phenoxy)-5-((S)-2-methoxy-1-methyl-ethoxy)-benzoylamino]-thiazol-4-yl}-acetic acid ethyl ester was prepared from 3-{(1S)-2-methoxy-(methylethyl)oxy}-5-{[3-methoxy-phenyl]oxy}benzoic acid (prepared in analogy to the method described in general synthetic descriptions F, using 4-methoxyphenylboronic acid in step D)) and ethyl 2-aminothiazol-4-ylacetate following synthetic description A.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[Br-].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[Br:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:6]/[C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: BrCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: Fc1ccc(/C=C/CCCBr)cc1

Procedure:
4-Fluorobenzaldehyde (1.0 g) and 4-bromobutyl-triphenylphosphonium bromide (4.62 g) were treated in the same manner as in Preparation Example 83 to obtain the title compound.
Reaction SMILES: [OH:1][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].Cl.[C:18](OC(=O)CN)([CH3:21])([CH3:20])[CH3:19].C[N:28]1[CH2:33][CH2:32][O:31]CC1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[NH2:28][C@H:33]([C:32]([CH:4]([CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)[C:2](=[O:1])[OH:3])=[O:31])[C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: CC(C)(C)OC(=O)CN
Reactant: CN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)[C@H](N)C(=O)C(CCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)C(=O)O
Temperature: 25 °C
Reaction time: 168 h

Procedure:
To a solution of biotin (0.83 g, 3.4 mmol) in 60 mL of DMF was added glycine t-butyl ester hydrochloride (0.57 g, 3.4 mmol), N methylmorpholine (0.92 mL, 8.36 mmol), 1-hydroxybenzotriazole (0.61 g, 3.99 mmol) and 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.65 g, 3.4 mmol). The reaction mixture was stirred at room temperature for 7 days. The DMF was concentrated, ethyl acetate was added, and the organic layer was washed with water, 0.5 N HCl, saturated sodium. bicarbonate, and brine. The ethyl acetate layer was dried (MgSO4) and concentrated to yield tert-butylglycylbiotin as a white solid which was primarily one spot on TLC (0.611 g, 1.71 mmol, 50/o). Mass spec [M+H]+ at m/z 358.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1.[CH3:16]O>>[Cl:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1cccc(Cl)c1
Temperature: 80 °C

Procedure:
Thionyl chloride (11 g, 100 mmol) was added dropwise to a mixture of 3-chlorophenylacetic acid (1.7 g, 10 mmol) in methanol (20 mL) at 0° C. The resulting mixture was refluxed at 80° C. for 12 hours. The volatiles were removed under vacuum and the residue was diluted with water and extracted with ethyl acetate. The combined organic solution was washed with water, dried over sodium sulfate and the concentrated to give 1.5 g of methyl 2-(3-chlorophenyl)acetate as a yellow oil, which was used without further purification.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[N:6]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:7](=[O:18])[C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[N:12][O:11][C:9]=2[N:10]=1)[CH2:3][CH3:4].[C:26]([O:30][C:31](=[O:37])[NH:32][CH2:33][CH2:34][CH:35]=O)([CH3:29])([CH3:28])[CH3:27].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].O>CO>[C:26]([O:30][C:31](=[O:37])[NH:32][CH2:33][CH2:34][CH2:35][NH:1][CH:2]([C:5]1[N:6]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:7](=[O:18])[C:8]2[C:13]([C:14]([F:16])([F:15])[F:17])=[N:12][O:11][C:9]=2[N:10]=1)[CH2:3][CH3:4])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)NCCC=O
Reactant: CCC(N)c1nc2onc(C(F)(F)F)c2c(=O)n1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCC(NCCCNC(=O)OC(C)(C)C)c1nc2onc(C(F)(F)F)c2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.8 %

Procedure:
To a solution of 10 (0.358 mmol) in MeOH (5.0 mL) was added (3-oxo-propyl)-carbamic acid tert-butyl ester (116 mg, 0.671 mmol), followed by NaBH(OAc)3 (142 mg, 0.671 mmol). The reaction mixture was stirred at room temperature for 3 h. Water was added to quench the reaction, the aqueous phase was extracted with EtOAc three times. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by SiO2 chromatography (EtOAc:heaxanes/1:2) to give 11 (120 mg, 53%). 1H NMR (CDCl3): δ 7.35–7.18 (m, 5H), 5.67 (d, J=15.9 Hz, 1H), 5.18 (d, J=15.9 Hz, 1H), 7.47–7.34 (m, 5H), 5.73–5.66 (m, 2H), 5.48–5.46 (m, 1H), 4.92–4.91 (m, 1H), 2.02–1.80 (m, 2H), 1.46 (s, 9H), 0.92 (t, J=7.14 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23])([O-:14])=[O:13]>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:22]([NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N+:12]([O-:14])=[O:13])=[O:23]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: O=C=Nc1ccccc1[N+](=O)[O-]
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)Nc1ccccc1[N+](=O)[O-]
Yield: 42.7 %

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-nitro phenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-nitro phenyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound(0.44 g, 44%). EI-MS m/z 319(M+H)+
Reaction SMILES: [CH:1]1[C:11](=[C:12]([C:15]#[N:16])[C:13]#[N:14])[CH:10]=[CH:9][C:3](=[C:4]([C:7]#[N:8])[C:5]#N)[CH:2]=1.[CH2:17]([N:21]([CH2:37][CH2:38][CH2:39][CH3:40])[C:22]1[CH:27]=[CH:26][C:25]([CH:28]=[CH:29][C:30]2[S:31]C=[CH:33][CH:34]=2)=[C:24]([O:35][CH3:36])[CH:23]=1)[CH2:18][CH2:19][CH3:20].O.C(OCC)(=O)C>CN(C)C=O>[C:7]([C:4]([C:5]1[S:31][C:30]([CH:29]=[CH:28][C:25]2[CH:26]=[CH:27][C:22]([N:21]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:17][CH2:18][CH2:19][CH3:20])=[CH:23][C:24]=2[O:35][CH3:36])=[CH:34][CH:33]=1)=[C:3]1[CH:2]=[CH:1][C:11](=[C:12]([C:15]#[N:16])[C:13]#[N:14])[CH:10]=[CH:9]1)#[N:8]
Reactant: N#CC(C#N)=c1ccc(=C(C#N)C#N)cc1
Reactant: CCCCN(CCCC)c1ccc(C=Cc2cccs2)c(OC)c1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C(C#N)=c3ccc(=C(C#N)C#N)cc3)s2)c(OC)c1
Temperature: 50 °C
Yield: 14.5 %

Procedure:
In 8 ml of N,N-dimethylformamide, 375 mg (1.84 mmol) of 7,7,8,8-tetracyanoquinodimethane was dissolved. With stirring under ice cooling, 600 mg (1.75 mmol) of dibutyl[3-methoxy-4-[2-(thiophene-2-yl)vinyl]phenyl]amine was dissolved in 2 ml of N,N-dimethylformamide and added dropwise. The mixture was stirred for 1 hour and further stirred with heating at 50° C. overnight. After the reaction mixture was poured into 80 ml of water, extraction with ethyl acetate, washing with a saturated saline solution, drying over anhydrous sodium sulfate and concentration were performed. The residue was purified by silica gel column chromatography and washed with chloroform to give 132 mg of a yellowish white crystal having a mp of 211-214° C. (yield: 14.5%).
Reaction SMILES: [CH:1](=[CH:10][C:11]([OH:13])=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(Cl)([Cl:16])=O>>[CH:1](=[CH:10][C:11]([Cl:16])=[O:13])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)C=CC=Cc1ccccc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)C=CC=Cc1ccccc1
Temperature: 45 °C

Procedure:
Cinnamylidene acetyl chloride was prepared by stirring approximately 17.15 gms of cinnamylidene acetic acid with 30 ml thionyl chloride in 300 ml of petroleum ether for 12 hours at room temperature. The reaction mixture was then refluxed for 4 hours in an oil bath at a temperature of approximately 40 to 50° C. The excess thionyl chloride and the petroleum ether were removed under reduced pressure. 1HNMR: δ=6.2 ppm (d, 2H), δ=6.9 ppm (q, 2H), δ=7.5 ppm (m, 5H). UV (in dichloromethane): λmax =333 nm, λmin =256 nm.
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14]([C:33]([O:35]CC)=[O:34])=[N:15][N:16]([C:22]([CH3:32])([CH3:31])[CH2:23][C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)[C:17]=2[O:18][CH2:19][O:20][CH3:21])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[Na+]>O1CCCC1.CO.C(Cl)Cl>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:14]([C:33]([OH:35])=[O:34])=[N:15][N:16]([C:22]([CH3:31])([CH3:32])[CH2:23][C:24]3[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=3)[C:17]=2[O:18][CH2:19][O:20][CH3:21])=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc(-c2c(C(=O)OCC)nn(C(C)(C)Cc3ccc(C)cc3)c2OCOC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCc1ccc(-c2c(C(=O)O)nn(C(C)(C)Cc3ccc(C)cc3)c2OCOC)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Ethyl 4-(4-hexylphenyl)-5-(methoxymethoxy)-1-(2-methyl-1-(p-tolyl)propan-2-yl)-1H-pyrazole-3-carboxylate (138 mg) was dissolved in 2 mL of tetrahydrofuran and 0.7 mL of methanol, mixed with 0.27 mL (1.4 mmol) of 5 M aqueous sodium hydroxide and stirred at room temperature for 20 hours. After completion of the reaction, the reaction mixture was diluted with methylene chloride and washed with saturated aqueous ammonium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give the desired product (crude yield 142 mg).
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Br)=[CH:6][CH:5]=1.[CH:13]1([S:16]([NH2:19])(=[O:18])=[O:17])[CH2:15][CH2:14]1.[O:20]=[C:21]1[C@:29]2([CH2:31][C@@H:30]2[C:32]2[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][CH:33]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22]1>>[C:36]([C:35]1[CH:34]=[CH:33][C:32]([C@H:30]2[C@@:29]3([C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]([CH2:10][C:7]4[CH:6]=[CH:5][C:4]([C:3]([NH:19][S:16]([CH:13]5[CH2:15][CH2:14]5)(=[O:18])=[O:17])=[O:12])=[CH:9][CH:8]=4)[C:21]3=[O:20])[CH2:31]2)=[CH:39][CH:38]=1)#[N:37]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: NS(=O)(=O)C1CC1
Reactant: N#Cc1ccc([C@H]2C[C@]23C(=O)Nc2ccccc23)cc1
Product: N#Cc1ccc([C@@H]2C[C@@]23C(=O)N(Cc2ccc(C(=O)NS(=O)(=O)C4CC4)cc2)c2ccccc23)cc1

Procedure:
The title compound was prepared in analogy to Example 60 starting from 4-bromomethyl-benzoic acid methyl ester, cyclopropanesulfonamide (commercially available), (1R,2S) and (1S,2R)-4-(2′-oxospiro[cyclopropane-1,3′-indoline]-2-yl)benzonitrile prepared as in Scheme 1. LC/MS m/e calcd. for C28H23ClN3O4S: 497, observed (M+H)+: 498.2, 1H NMR (400 MHz, DMSO-d6) δppm 0.69-0.79 (m, 2 H) 0.83-0.92 (m, 2 H) 2.11-2.18 (m, 1 H) 2.44-2.49 (m, 1 H) 2.91-3.00 (m, 1 H) 3.12-3.20 (m, 1 H) 3.27-3.32 (m, 1 H) 5.04 (s, 2 H) 6.15 (d, 1 H) 6.68 (t, 1 H) 6.91 (d, 1 H) 7.02-7.09 (m, 2 H) 7.28-7.37 (m, 2 H) 7.50-7.59 (m, 2 H) 7.77-7.82 (m, 2H) 7.87-7.94 (m, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[CH:14]([NH:16][NH:17]C=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C:34](=O)(O)[O-].[Na+]>CO.ClCCl.C(OCC)(=O)C.ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:34][CH2:14][N:16]=[N:17]2)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(N)ccc1OC
Reactant: O=CNNC=O
Reactant: O=C([O-])O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc(N2CCN=N2)ccc1OC
Temperature: 160 °C
Reaction time: 1.5 h

Procedure:
Alternately, according to the method of J. Med. Chem., 21, 1100 (1978), combine methyl 2-methoxy-5-aminobenzoate (1.8 g, 10 mmol), diformyl hydrazine (0.97 g, 11 mmol), and phosphorous pentoxide (1.84 g, 13 mmol). Heat to 160° C. After 1.5 hours, cool the reaction mixture and add a saturated aqueous solution of sodium bicarbonate. Extract three times with dichloromethane. Dry the combined organic layers over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with 40% ethyl acetate/dichloromethane and then 5% methanol/dichloromethane to give methyl 2-methoxy-5-(4H-triazol-1-yl)benzoate: mp; 179-182° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][CH2:14][C:15]3=[O:18])=[CH:11][CH:10]=2)O1.I[C:21]1[CH:26]=[CH:25][N:24]=[C:23]2[NH:27][N:28]=[CH:29][C:22]=12.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.O>[NH:27]1[C:23]2=[N:24][CH:25]=[CH:26][C:21]([C:9]3[CH:17]=[C:16]4[C:12]([CH2:13][CH2:14][C:15]4=[O:18])=[CH:11][CH:10]=3)=[C:22]2[CH:29]=[N:28]1
Reactant: Ic1ccnc2[nH]ncc12
Reactant: CC1(C)OB(c2ccc3c(c2)C(=O)CC3)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1CCc2ccc(-c3ccnc4[nH]ncc34)cc21
Yield: 56 %

Procedure:
To a mixture of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one (3 g, 11.6 mmol) and 4-iodo-1H-pyrazolo[3,4-b]pyridine (3.13 g, 12.8 mmol) in DME (20 mL) was added aq. sodium carbonate (2M, 11.62 mL, 23.2 mmol) followed by tetrakistriphenylphosphine palladium (978 mg, 0.846 mmol). The mixture was microwaved for 90 min at 150° C. The reaction mixture was diluted with ethyl acetate and water and the layers separated. The organic layer was filtered off since it contained a yellow precipitate (desired prod ca. 85% pure) and then it was washed with water and then dried (MgSO4), filtered and concentrated and added to the precipitate above. The solids were recrystallised from boiling MeOH-TRF to provide the pure ketone (1.62 g, 56%) as a yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([NH:8][C:9](=[O:17])OC2C=CC=CC=2)[N:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:4]=1)[CH3:2].[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][C:35]=1[O:36][CH3:37])[N:32]=[CH:31][N:30]=[C:29]2[S:38][C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][CH:45]=1)[NH2:42]>CS(C)=O.C(OCC)(=O)C>[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][C:35]=1[O:36][CH3:37])[N:32]=[CH:31][N:30]=[C:29]2[S:38][C:39]1[CH:40]=[C:41]([NH:42][C:9]([NH:8][C:6]2[N:5]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:4]=[C:3]([CH2:1][CH3:2])[CH:7]=2)=[O:17])[CH:43]=[CH:44][CH:45]=1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: CCc1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCc1cc(NC(=O)Nc2cccc(Sc3ncnc4cc(OC)c(OC)cc34)c2)n(-c2ccccc2)n1
Temperature: 70 °C
Yield: 34.2 %

Procedure:
A stirred mixture of phenyl 3-ethyl-1-phenyl-1H-pyrazol-5-ylcarbamate (prepared as described in Example 352A Step 3) (0.15 g, 0.50 mmol) and 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (prepared as described in Example 115B) (0.16 g, 0.50 mmol) in DMSO (2 mL) was heated at 70° C. for 15 h. After cooling to rt, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (2×20 mL). The organic layer was separated, dried over magnesium sulfate, and concentrated under reduced pressure to afford an oil which was recrystallized from diethyl ether. Further purification via preparative silica gel thin-layer chromatography (eluting with a mixture of 8% methanol in dichloromethane containing 0.5% ammonia) afforded 1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-ethyl-1-phenyl-1H-pyrazol-5-yl)urea (90 mg, 35%) as a colorless solid. 1H NMR (400 MHz, DMSO-d6) δ9.38 (s, 1H), 8.67 (s, 1H), 8.61 (s, 1H), 7.77 (s, 1H), 7.17-7.53 (m, 10H), 6.30 (s, 1H), 3.98 (s, 6H), 2.56 (m, 2H), 1.19 (m, 3H); LC-MS (ESI) m/z 527 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C@H:23]2[CH2:25][C@@H:24]2[C:26]([NH:28][C@@H:29]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]([F:42])([F:41])[F:40])=[CH:33][N:32]=2)[CH3:30])=[O:27])=[CH:19][CH:18]=1.O>ClCCl>[F:42][C:39]([F:40])([F:41])[CH2:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([C@H:29]([NH:28][C:26]([C@H:24]2[CH2:25][C@@H:23]2[C:20]2[CH:19]=[CH:18][C:17]([O:16][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[CH:22][CH:21]=2)=[O:27])[CH3:30])=[N:32][CH:33]=1
Reactant: C[C@@H](NC(=O)[C@H]1C[C@@H]1c1ccc(O)cc1)c1ccc(OCC(F)(F)F)cn1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: C[C@@H](NC(=O)[C@H]1C[C@@H]1c1ccc(OCC(=O)OC(C)(C)C)cc1)c1ccc(OCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.3 %

Procedure:
A mixture of tert-butyl 2-bromoacetate (0.063 ml, 0.434 mmol), potassium carbonate (109 mg, 0.789 mmol) and (1S*,2S*)-2-(4-hydroxyphenyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide (150 mg, 0.394 mmol) in dichloromethane (4 ml) was refluxed with stirring for 3 hours. After cooling to room temperature, the mixture was poured into water, and the aqueous layer was extracted with ethyl acetate, dried over magnesium sulfate and concentrated in vacuo. The residue was recrystallized from tetrahydrofuran/hexane. To give 137 mg (70% yield) of title compound as a white crystal:
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][CH:3]=1.[O-:10][C:11]#[N:12].[Na+].[O-]C#N>O>[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:11]([NH2:12])=[O:10])=[CH:4][CH:3]=1
Reactant: N#C[O-]
Reactant: NCc1ccncc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NC(=O)NCc1ccncc1
Reaction time: 5 h

Procedure:
5.1 ml of 5N HCl was added to a solution of 2.53 ml of 4-picolylamine and 1.66 g of sodium cyanate in 50 ml of water. After 5 hours, a further 0.166 g of cyanate were added and the pH adjusted to 7.5. After 18 hours the reaction mixture was evaporated to dryness, the residue extracted with 100 ml of hot 2-propanol. The filtrate was concentrated, cooled and the solid collected to give the title compound (3.03 g) mp 194-6° C. A further 0.63 g could be isolated as second and third crops.