Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:5][C:4]=1[NH:24][C:25]1[O:29][N:28]=[C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:26]=1)#[N:2].C([O-])([O-])=[O:37].[K+].[K+].OO>CS(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:5][C:4]=1[NH:24][C:25]1[O:29][N:28]=[C:27]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:26]=1)(=[O:37])[NH2:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1ccc(C#N)c(Nc2cc(-c3ccccc3)no2)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1ccc(C(N)=O)c(Nc2cc(-c3ccccc3)no2)c1
Reaction time: 0.17 h
Yield: 15.3 %

Procedure:
To a solution of tert-butyl (1S,2R)-2-(4-cyano-3-(3-phenylisoxazol-5-ylamino)phenylamino)cyclohexylcarbamate (38 mg, 0.080 mmol) in DMSO (1 mL), K2CO3 (100 mg, 0.724 mmol) and H2O2 (50% aq., 0.800 mL) were added. After being stirred at 100 C for 10 min, the mixture was purified by HPLC to give tert-butyl (1S,2R)-2-(4-carbamoyl-3-(3-phenylisoxazol-5-ylamino)phenylamino)cyclohexylcarbamate (6 mg).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](OS(C2C=CC(C)=CC=2)(=O)=O)=[C:6]([O:21][CH3:22])[CH:5]=1)(=[O:3])[CH3:2].[C:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=1)#[CH:24]>C(Cl)Cl>[CH3:34][O:33][C:27]1[CH:26]=[C:25]([C:23]#[C:24][C:7]2[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][C:6]=2[O:21][CH3:22])[CH:30]=[CH:29][C:28]=1[O:31][CH3:32]
Reactant: COc1cc(C(C)=O)ccc1OS(=O)(=O)c1ccc(C)cc1
Reactant: C#Cc1ccc(OC)c(OC)c1
Solvent: ClCCl
Product: COc1cc(C(C)=O)ccc1C#Cc1ccc(OC)c(OC)c1

Procedure:
This product was prepared from toluene-4-sulfonic acid 4-acetyl-2-methoxy-phenyl ester and 4-ethynyl-1,2-dimethoxy-benzene following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: DCM; yield (120 mg, 77%); 1H NMR δ (CDCl3): 7.55 (d, J=8.26 Hz, 1H), 7.53-7.48 (m, 2H), 7.18 (dd, J=8.25 Hz, J=2.30 Hz, 1H), 7.07 (m, 1H), 6.84 (d, J=8.24 Hz, 1H), 3.98 (s, 3H), 3.91 (s, 6H), 2.61 (s, 3H); LCMS m/z: 310.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1)[C:12]([O:14]C)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(OC)cc(OCc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(OCc2ccccc2)cc(C(=O)O)c1
Yield: 90 %

Procedure:
4.45 g (0.0174 mmol) of methyl 3-(benzyloxy)-5-methoxybenzoate (161) was suspended in 120 mL of 95% ethanol and 5 mL water. An amount of 2.00 g (0.05 mmol) of sodium hydroxide was added. The mixture was heated at reflux for 1 h. After the mixture was evaporated, the residue was quenched with 150 mL of water. The solution was neutralized with dil aq HCl and then the precipitate was collected and washed with water and acetone to give 162.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:12])[N:3]=1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O>CN(C)C=O>[C:17]1([C:15]2[N:1]=[C:2]3[C:7]4[N:8]=[CH:9][CH:10]=[CH:11][C:6]=4[NH:5][C:4](=[O:12])[N:3]3[CH:14]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1nc(=O)[nH]c2cccnc12
Reactant: O=C(CBr)c1ccccc1
Solvent: CN(C)C=O
Product: O=c1[nH]c2cccnc2c2nc(-c3ccccc3)cn12
Temperature: 150 °C

Procedure:
A mixture of 4-Amino-pyrido[2,3-e]pyrimidin-2-one (95 mg) and α-bromo-acetophenone (117 mg) in 4 mL of dimethylformamide (DMF) was heated at about 150° C. for 20 min. The reaction mixture was concentrated in vacuo and the residue was subjected to flash chromatography on silica gel with 10% methanol/methylene chloride as the eluent to afford 2-Phenylimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(6H)-one. (Compound 15), m.p. 329°-330° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>ClCCl>[N:33]1([C:8]([C@@H:5]2[CH2:4][CH2:3][C@H:2]([OH:1])[CH2:7][CH2:6]2)=[O:10])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1
Reactant: C1COCCN1
Reactant: O=C(O)[C@H]1CC[C@@H](O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: O=C([C@H]1CC[C@@H](O)CC1)N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of cis-4-hydroxycyclohexanecarboxylic acid (720 mg, 0.5 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (1.33 g, 6 mmol) and 1-hydroxy-7-azabenzotriazole (816 mg, 6 mmol) in dichloromethane (6 ml) was treated with morpholine 1.3 ml, 15 mmol). After stirring at room temperature for 18 hours, the crude reaction was applied to a SCX ion exchange cartridge (Varian bond-elute, 5 g) and washed with methanol and then a mixture of 0.880 ammonia:methanol (1:9). The combined basic fractions were concentrated in vacuo, and the resulting residue was purified by column chromatography eluting with a mixture of 0.880 ammonia:ethanol:dichloromethane (1:9:90) to afford the title compound (D55); MS (ES+) m/e 214 [M+H]+.
Reaction SMILES: Br[C:2](Br)=[CH:3][CH:4]1[CH2:7][CH:6]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:5]1.C([Li])CCC.[Si:18]([O:35][CH2:36][CH2:37][CH:38]([C:47](=[O:52])NCOC)[CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[NH4+]>O1CCCC1.O>[Si:18]([O:35][CH2:36][CH2:37][CH:38]([C:47](=[O:52])[C:2]#[C:3][CH:4]1[CH2:7][CH:6]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:5]1)[CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])([C:31]([CH3:32])([CH3:34])[CH3:33])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COCNC(=O)C(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CC(=O)OC(C)(C)C
Reactant: CC(C)CC1CC(C=C(Br)Br)C1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CC1CC(C#CC(=O)C(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC(=O)OC(C)(C)C)C1
Yield: 96.7 %

Procedure:
1-(2,2-Dibromovinyl)-3-isobutylcyclobutane (40 g) and tetrahydrofuran (280 mL) were mixed. To the mixture was added n-butyllithium (2.66 M in hexane) (104 mL) dropwise at −78° C. The mixture was stirred at ice temperature and a solution of tert-butyl 5-(tert-butyldiphenylsilanyloxy)-3-methoxymethylcarbamoylvalerate (54 g) in tetrahydrofuran (100 mL) was added dropwise to the mixture. After stirring at ice temperature for 1 hr, saturated aqueous ammonium chloride (180 mL) and water (100 mL) were added to the reaction mixture. The mixture was extracted with ethyl acetate (600 mL), washed with saturated aqueous ammonium chloride (180 mL and 400 mL) and dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo. After an addition of silica gel (90 g) and ethyl acetate/hexane=1/20 (600 mL) into the resultant residue, the mixture was stirred at RT for 1 hr. The silica gel was filtered off and the filtrate was concentrated in vacuo to give the title compound (60.09 g) as a crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH2:8][S:9][C:10]2[N:14]=[C:13]([NH2:15])[NH:12][N:11]=2)=[CH:4][CH:3]=1.CCO[CH:21](OCC)[CH2:22][CH:23](OCC)OCC>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][S:9][C:10]2[N:14]=[C:13]3[N:15]=[CH:21][CH:22]=[CH:23][N:12]3[N:11]=2)=[CH:16][CH:17]=1
Reactant: Nc1nc(SCCOc2ccc(Cl)cc2)n[nH]1
Reactant: CCOC(CC(OCC)OCC)OCC
Product: Clc1ccc(OCCSc2nc3ncccn3n2)cc1
Yield: 42 %

Procedure:
The title compound was prepared according to the experimentals described for Example 23 above from 3-{[2-(4-chlorophenoxy)ethyl]sulfanyl}-1H-1,2,4-triazol-5-amine and malonaldehyde bis(diethyl acetal) in 42% yield; EM (calc.): 306.0; MS (ESI) m/e: 307.0 (M+H)+. 1H NMR (DMSO-d6, 400 MHz) δ ppm: 9.33 (dd, 1H), 8.81 (dd, 1H), 7.31 (m, 3H), 7.02 (dt, 2H), 4.33 (t, 2H), 3.62 (t, 2H).
Reaction SMILES: [CH:1]1([SH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[SH:7].Cl[CH:10]([CH3:14])[C:11](=O)[CH3:12]>>[CH3:14][C:10]1[S:8][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]2[S:7][C:11]=1[CH3:12]
Reactant: CC(=O)C(C)Cl
Reactant: SC1CCCCC1S
Product: CC1=C(C)SC2CCCCC2S1
Yield: 78 %

Procedure:
The procedure of Example 1(a) was followed using 1,2-cyclohexanedithiol and 3-chloro-2-butanone to give 4a,5,6,7,8,8a-hexahydro-2,3-dimethyl-1,4-benzodithiin as a colorless oil, bp 100°-102°/0.2 mm. Yield 78%. NMR 1.07-2.2 (8m), 1.85 (6s), 2.9-3.2 (2m). IR 2924, 2850, 1615, 1440, 1335, 1275, 1180, 985.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:38])[CH:7]([NH:22][CH:23]([C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH2:20])[CH:16]=2)[C:11]1=[O:21])([CH3:4])[CH3:3].ClCCl.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>N1C=CC=CC=1>[CH3:1][C:2]([O:5][C:6](=[O:38])[C@H:7]([NH:22][C@H:23]([C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH:20][S:43]([CH3:42])(=[O:45])=[O:44])[CH:16]=2)[C:11]1=[O:21])([CH3:4])[CH3:3]
Reactant: CC(C)CC(NC(CCN1C(=O)c2ccc(N)cc2C1=O)C(=O)OC(C)(C)C)C(=O)NCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)C[C@H](N[C@H](CCN1C(=O)c2ccc(NS(C)(=O)=O)cc2C1=O)C(=O)OC(C)(C)C)C(=O)NCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
100 mg of 2-[1-(benzylamino)carbonyl-3-methyl-butylamino]-4-(5-amino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butanoic acid-1,1-dimethylethyl ester, prepared as in Example 73 where the protecting group Rp, 1,1-dimethylethyl, was not removed following the condensation reaction seen in Scheme 2, was added to 5 mL dichloromethane under nitrogen. The mixture was cooled to 0° C. and 0.1 mL of pyridine was added, followed by 0.014 mL methanesulfonyl chloride. The mixture was allowed to warm to room temperature and was stirred overnight. The solvent was removed by Evaporation and the residue was purified by reverse phase H.P.L.C. The solvent was removed by evaporation to give the title compound; 45 mg
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][SH:12])=[CH:2]1.[C:13]([O:19][CH3:20])(=[O:18])[CH2:14][C:15]([CH3:17])=O.C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH3:20][O:19][C:13](=[O:18])[CH2:14][C:15]1([CH3:17])[C:2]2[NH:1][C:9]3[C:4]([C:3]=2[CH2:10][CH2:11][S:12]1)=[CH:5][CH:6]=[CH:7][CH:8]=3
Reactant: COC(=O)CC(C)=O
Reactant: SCCc1c[nH]c2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)CC1(C)SCCc2c1[nH]c1ccccc21
Reaction time: 12 h

Procedure:
Indole-3-ethanethiol (1.5 g.) and methyl acetoacetate are mixed with 50 ml. of benzene and the solution heated for 30 min. (bath temperature 70°-80°C.). p-Toluenesulfonic acid (0.15 g.) is added and the reaction mixture is subjected to reflux and stirring for 12 hours. Water formed in the reaction mixture during this period is collected by a water separator. After cooling the benzene solution is washed with a 10% solution of sodium bicarbonate, water, saturated brine and dried over sodium sulfate. Evaporation of the benzene solution yields the ester, 1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole-1-acetic acid methyl ester as the semi-solid, γmaxCHCl3 1715 cm-1.
Reaction SMILES: [C:1]([O:9][CH:10]([C:14](=[O:16])[CH3:15])[C:11](=[O:13])[CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH:20](OCC)[N:21]([CH3:23])[CH3:22])C>>[C:1]([O:9][CH:10]([C:14](=[O:16])[CH3:15])[C:11](=[O:13])[CH:12]=[CH:20][N:21]([CH3:23])[CH3:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(OCC)N(C)C
Reactant: CC(=O)C(OC(=O)c1ccccc1)C(C)=O
Product: CC(=O)C(OC(=O)c1ccccc1)C(=O)C=CN(C)C

Procedure:
3-benzoyloxy-2,4-pentanedione is reacted with N,N-dimethyl-formamide diethyl acetal to form 4-benzoyloxy-1-dimethylamino-1-hexene-3,5-dione, and,
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([C:9](F)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[C:6]([CH2:19][CH2:20][CH3:21])=[CH:5][C:3]=1[NH2:4].[CH3:22][O-:23].[Na+]>CO>[CH3:22][O:23][C:9]([C:7]1[C:6]([CH2:19][CH2:20][CH3:21])=[CH:5][C:3]([NH2:4])=[C:2]([CH3:1])[CH:8]=1)([C:14]([F:16])([F:15])[F:17])[C:10]([F:12])([F:11])[F:13]
Reactant: C[O-]
Reactant: CCCc1cc(N)c(C)cc1C(F)(C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CO
Product: CCCc1cc(N)c(C)cc1C(OC)(C(F)(F)F)C(F)(F)F
Temperature: 0 °C
Yield: 79 %

Procedure:
2-Methyl-5-n-propyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline (1.6 g, 5 mmol) was dissolved in a 28% solution (9.6 g) of sodium methoxide in methanol, and the mixture was heated under reflux for 3 hr. After allowing to cool, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to give the desired compound (1.31 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:14])[CH3:13])[CH:9]=[CH:10][CH:11]=1.[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:21]=1)=[O:18]>>[C:12]([C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[O:5][CH2:4][CH2:3][CH2:2][N:29]1[CH2:30][CH2:31][CH:26]([C:22]2[CH:21]=[C:20]([NH:19][C:17](=[O:18])[CH:16]([CH3:15])[CH3:32])[CH:25]=[CH:24][CH:23]=2)[CH2:27][CH2:28]1)(=[O:14])[CH3:13]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: CC(=O)c1cccc(OCCCCl)c1
Product: CC(=O)c1cccc(OCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-[3-(3-chloropropoxy)phenyl]ethanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 423.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][NH:12][C:13](=[O:23])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-])=O)[CH2:7][CH2:6]1)=[O:4].CC(O)=O.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]([C@H:5]1[CH2:6][CH2:7][C@H:8]([CH2:11][NH:12][C:13](=[O:23])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH2:20])[CH2:9][CH2:10]1)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)[C@H]1CC[C@H](CNC(=O)c2ccccc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)[C@H]1CC[C@H](CNC(=O)c2ccccc2N)CC1

Procedure:
A solution 0.01 M of trans-4-[(2-Nitro-benzoylamino)-methyl]-cyclohexanecarboxylic acid methyl ester (1.8 g) in MeOH (550 mL) with ˜1% of glacial AcOH (5.5 mL) was submitted to continuous flow rate hydrogenation by H-Cube (ThalesNano®) using a 10% Pd/C cartridge (small cartridge, full hydrogen mode, flowrate of 1 mL/min). Finally, the solvent was removed under reduced pressure to obtain the titled compound as acetate salt (1.9 g, quantitative yield).
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=O)=[CH:3][CH:2]=1.O.ON1C2C=CC=CC=2N=N1.[CH3:28][NH:29][C:30]1[S:31][C:32]([S:36]([NH2:39])(=[O:38])=[O:37])=[C:33]([CH3:35])[N:34]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[NH2:39][S:36]([C:32]1[S:31][C:30]([N:29]([CH3:28])[C:8](=[O:10])[CH2:7][C:4]2[CH:3]=[CH:2][C:1]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:6][CH:5]=2)=[N:34][C:33]=1[CH3:35])(=[O:37])=[O:38]
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Reactant: CNc1nc(C)c(S(N)(=O)=O)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(N(C)C(=O)Cc2ccc(-c3ccccc3)cc2)sc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
138.2 mg (0.65 mmol) of 4-biphenylacetic acid and 99.7 mg (0.65 mmol) of 1-hydroxy-1H-benzotriazole hydrate are initially charged at room temperature in 5 ml of dimethylformamide. 150 mg (0.72 mmol) of 2-methylamino-4-methyl-1,3-thiazole-5-sulphonamide and 138.7 mg (0.72 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride are added, and the mixture is stirred at room temperature for 72 h. The reaction mixture is then filtered off with suction and the residue is recrystallized from 2-propanol. This gives a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])[CH2:8][S:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([N:30]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(Cl)(=O)C(Cl)=O>C(N(CC)CC)C>[C:19]([C:16]1[CH:15]=[C:7]([CH:6]=[C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[C:17]=1[OH:18])[CH2:8][S:9][CH2:10][CH2:11][C:12]([O:14][N:30]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:13])([CH3:22])([CH3:21])[CH3:20]
Reactant: ON(Cc1ccccc1)Cc1ccccc1
Reactant: CC(C)(C)c1cc(CSCCC(=O)O)cc(C(C)(C)C)c1O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(CSCCC(=O)ON(Cc2ccccc2)Cc2ccccc2)cc(C(C)(C)C)c1O
Yield: 11.6 %

Procedure:
The compound is prepared using the method of Example II, with 16.20 g of 3-(3,5-di-tert-butyl-4-hydroxybenzylthio)propanoic acid, 10.66 g of N,N-dibenzylhydroxylamine, 5.06 g of triethylamine, and 6.35 g of oxalyl chloride. The residue is purified by preparative HPLC to give 3.0 g of a white solid: mp 84°-86° C.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:18][CH2:19][CH2:20][OH:21])[C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=2)[CH2:3][CH2:2]1.[C:22]([C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>>[CH:1]1([CH2:4][N:5]([CH2:18][CH2:19][CH2:20][O:21][C:29]2[CH:30]=[CH:31][C:26]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:27][CH:28]=2)[C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:16])([F:17])[F:15])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: N#Cc1ccc(N(CCCO)CC2CC2)cc1C(F)(F)F
Reactant: CC(C)(C)c1ccc(O)cc1
Product: CC(C)(C)c1ccc(OCCCN(CC2CC2)c2ccc(C#N)c(C(F)(F)F)c2)cc1

Procedure:
Synthesized as described in Example 1C from 4-[(cyclopropylmethyl)(3-hydroxypropyl)amino]-2-(trifluoromethyl)benzonitrile and 4-tert-butylphenol: MS (APCI) m/z 431 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([F:22])[CH:3]=1.[N+:23]([O-])([OH:25])=[O:24]>>[Cl:1][C:2]1[CH:3]=[C:4]([F:22])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]([CH3:20])[C:10]2=[O:21])=[C:6]([N+:23]([O-:25])=[O:24])[C:7]=1[OH:8]
Reactant: O=[N+]([O-])O
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c(O)c2[N+](=O)[O-])c1=O
Reaction time: 0.5 h

Procedure:
3-(4-Chloro-2-fluoro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (1.06 g) was added to ice-cold con. nitric acid (10 ml). After stirring for 30 min, crushed ice was added. The yellow crystals were collected by filtration to afford the title compound (1.2 g).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[OH:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][N:9]1[N:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[N:10]1
Reactant: c1ccc(-c2nn[nH]c2-c2ccccc2)cc1
Reactant: OCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: OCCCCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)n1

Procedure:
4,5-Diphenyl-1,2,3-triazole was treated with 9-bromononan-1-ol and potassium carbonate in butanone to give after chromatography the title compound as a light brown oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].[F:10][C:11]1[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1>C(Cl)Cl>[F:10][C:11]1[CH:12]=[C:13]([S:17]([NH:6][C@@H:5]([CH2:7][OH:8])[C:4]([O:3][CH3:2])=[O:9])(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)[C@@H](N)CO
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@H](CO)NS(=O)(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
A suspension of L-serine-methyl ester hydrochloride (1.6 g, 10.3 mmol) in CH2Cl2 (70 mL) was added with TEA (1.1 mol eq, 1.6 mL) and the mixture was stirred at r.t. for 10 minutes. Then 3-fluorobenzensulfonyl chloride (1 mol eq, 2.0 g) and additional TEA (1.1 mol eq) were added and the solution hated at 60° C. overnight. The solvent was removed under reduced pressure, water was added to the residue (100 mL) and the aqueous phase extracted with EtOAc (3×40 mL). The recombined organic phases were dried over Na2SO4 and evaporated to reduced pressure. The residue was recrystallized from ethylic ether to afford 2F as a pale yellow solid (2.80 g, 95% yield). 1HNMR (DMSO, 200 MHz) δ 3.41 (s, 3H), 3.48 (m, 2H), 4.01 (m, 1H), 5.20 (t, 1H), 7.58 (m, 2H), 7.81 (m, 2H), 8.52 (d, 1H, J=8).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:5](=[O:16])[C:6]2[CH:11]=[C:10]([S:12](=[O:15])(=[O:14])[NH2:13])[S:9][C:7]=2[N:8]=1.[C:24]([O-:27])(=[O:26])[CH3:25].[Na+]>CN(C)C=O>[C:24]([O:27][CH2:2][C:3]1[N:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:5](=[O:16])[C:6]2[CH:11]=[C:10]([S:12](=[O:15])(=[O:14])[NH2:13])[S:9][C:7]=2[N:8]=1)(=[O:26])[CH3:25]
Reactant: NS(=O)(=O)c1cc2c(=O)n(-c3ccccc3Cl)c(CBr)nc2s1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1nc2sc(S(N)(=O)=O)cc2c(=O)n1-c1ccccc1Cl
Temperature: 80 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To 10.5 g of 3,4-dihydro-2-bromomethyl-3-(2-chlorophenyl)-4-oxo-6-sulfamoylthieno[2,3-d]pyrimidine were added 100 ml of dimethylformamide and 6.0 g of sodium acetate, and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was poured onto water, and the mixture was extracted with ethyl acetate, washed with water and concentrated to give 8.7 g of the residue. This residue was purified by silica gel column chromatography to give 5.3 g of an oily substance, which was crystallized from ethanol to afford 3.4 g of the title compound, m.p. 192.5°-194° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([C:18]3[C:26]([O:27][CH3:28])=[CH:25][C:24]([CH3:29])=[C:23]4[C:19]=3[CH:20]=[CH:21][N:22]4C(OC(C)(C)C)=O)([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:8][C:7]=2[CH:37]=1)#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+]>CCO>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([C:18]3[C:26]([O:27][CH3:28])=[CH:25][C:24]([CH3:29])=[C:23]4[C:19]=3[CH:20]=[CH:21][NH:22]4)([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:8][C:7]=2[CH:37]=1)#[N:2]
Reactant: CCOC(=O)C(C)(c1nc2cc(C#N)ccc2o1)c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Product: CCOC(=O)C(C)(c1nc2cc(C#N)ccc2o1)c1c(OC)cc(C)c2[nH]ccc12
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of (±)-tert-butyl 4-(2-(5-cyanobenzo[d]oxazol-2-yl)-1-ethoxy-1-oxopropan-2-yl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 144-C) (44 mg, 0.087 mmol) in EtOH (874 μL), was added cesium carbonate (142 mg, 0.437 mmol). The reaction mixture was heated up to 60° C. and stirred for 2 hrs. The reaction mixture was quenched with a saturated solution of sodium bicarbonate at 0° C. The layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organic layers were dried over magnesium sulfate and concentrated to give crude product that was purified via FCC (4 g column): Heptane/AcOEt: 100/0 to 50/50 to obtain the title compound. 1H NMR (600 MHz, DMSO-d6) δ ppm 11.05 (br. s., 1H) 8.36-8.60 (m, 1H) 7.72-8.02 (m, 2H) 7.13 (t, J=2.93 Hz, 1H) 6.81 (s, 1H) 5.12 (dd, J=3.21, 1.83 Hz, 1H) 4.02-4.28 (m, 2H) 3.62 (s, 3H) 2.43-2.48 (m, 3H) 2.03 (s, 3H) 1.08 (t, J=7.11 Hz, 3H). HRMS calcd. for C23H21N3O4 (M+H)+ 404.1610. found 404.1619.