Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[N-]=C=O.[NH2:14][C:15]1[N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=2)[CH2:19][N:18]=[C:17]2[O:28][CH:29]=[CH:30][C:16]=12>>[NH2:14][C:15]1[N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:10])[CH:22]=2)[CH2:19][N:18]=[C:17]2[O:28][CH:29]=[CH:30][C:16]=12
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NC1=c2ccoc2=NCN1c1cccc(N)c1
Agent: [N-]=C=O
Product: NC1=c2ccoc2=NCN1c1cccc(NC(=O)Nc2ccc(Cl)cc2)c1

Procedure:
The compound was prepared following the procedure described Example 232(b), using 4-chlorophenyl isocyanate as the isocyanate of choice and 4-Amino-3-(3-aminophenyl)furo[2,3-d]pyrimidine (10) as the diamine of choice. MS(ES) m/e 380 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[S:6][CH:7]=1)#[CH:2].Br[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([NH:31][NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:30])=[CH:24][CH:23]=1.C#C>>[C:36]([O:35][C:33]([NH:32][NH:31][C:29]([CH2:28][C:25]1[CH:24]=[CH:23][C:22]([C:2]#[C:1][C:3]2[N:4]=[C:5]([CH:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)[S:6][CH:7]=2)=[CH:27][CH:26]=1)=[O:30])=[O:34])([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)NNC(=O)Cc1ccc(Br)cc1
Reactant: C#Cc1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: C#C
Product: CC(C)(C)OC(=O)NNC(=O)Cc1ccc(C#Cc2csc(C3CCN(C(=O)OC(C)(C)C)CC3)n2)cc1
Yield: 18 %

Procedure:
Using tert-butyl 4-(4-ethynyl-1,3-thiazol-2-yl)piperidine-1-carboxylate and tert-butyl 2-[(4-bromophenyl)acetyl]hydrazinecarboxylate as starting materials, Sonogashira-Castero-Stephens acetylene coupling was performed under reaction conditions similar to those of Production Example 1, step 4 to give tert-butyl 4-[4-({4-[2-(tert-butoxycarbonyl)hydrazino]carbonylmethylphenyl}ethynyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (yield 18%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]([CH2:11][N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH:14]([NH:22][C:23]([C:25]2[NH:29][C:28]3[S:30][C:31]([Cl:33])=[CH:32][C:27]=3[CH:26]=2)=[O:24])[C:13]1=[O:34])(O)=[O:9].CCN=C=NCCCN(C)C.CN(C=O)C>CN(C)C1C=CN=CC=1.C1COCC1.O>[Cl:33][C:31]1[S:30][C:28]2[NH:29][C:25]([C:23]([NH:22][CH:14]3[CH2:15][C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:12]([CH2:11][C:8]([N:5]4[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]4)=[O:9])[C:13]3=[O:34])=[O:24])=[CH:26][C:27]=2[CH:32]=1
Reactant: OC1CCNCC1
Reactant: O=C(O)CN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NC1Cc2ccccc2N(CC(=O)N2CCC(O)CC2)C1=O)c1cc2cc(Cl)sc2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.9 %

Procedure:
4-Dimethylaminopyridine (5 mg, 0.038 mmol) and 4-hydroxypiperidine (42 mg, 0.41 mmol) were added to a suspension of N-[1-(carboxymethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide (Example 2; 150 mg, 0.38 mmol) and EDCI (79 mg, 0.41 mmol) in THF (0.5 mL) under an inert atmosphere. DMF (0.5 mL) was added and the mixture stirred at ambient temperature for 18 h. After pouring into water (10 mL) the resultant solid was filtered off and washed with 1M HCl aq. and water. Chromatography on silica gel (eluent gradient of CH2Cl2 to MeOH:CH2Cl2 (1:9)) afforded the title compound (109 mg, 59%) as an off white solid.
Reaction SMILES: [NH2:1][C:2]1[C:18]([O:19][CH3:20])=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[C:39]3[CH2:38][N:37]([S:40]([CH3:43])(=[O:42])=[O:41])[CH2:36][C:35](=[O:44])[NH:34][C:33]=3[CH:32]=[CH:31][C:30]=2[O:45][CH3:46])[C:25]([Cl:47])=[CH:24][N:23]=1>>[Cl:47][C:25]1[C:26]([NH:28][C:29]2[C:39]3[CH2:38][N:37]([S:40]([CH3:43])(=[O:42])=[O:41])[CH2:36][C:35](=[O:44])[NH:34][C:33]=3[CH:32]=[CH:31][C:30]=2[O:45][CH3:46])=[N:27][C:22]([NH:1][C:2]2[C:18]([O:19][CH3:20])=[CH:17][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:23][CH:24]=1
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N(C)C)CC2
Reactant: COc1ccc2c(c1Nc1nc(Cl)ncc1Cl)CN(S(C)(=O)=O)CC(=O)N2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3c(OC)ccc4c3CN(S(C)(=O)=O)CC(=O)N4)n1)CCN(CC(=O)N(C)C)CC2

Procedure:
The title compound was prepared from 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethyl-acetamide and 6-(2,5-Dichloro-pyrimidin-4-ylamino)-4-methanesulfonyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one in an analogous manner to example 730 (0.022 g, 12%). Mp118-121° C.; LCMS (m/e) 673 (M); 1H-NMR (DMSO, 400 MHz) δ 10.25 (s, 1H), 8.57 (s, 1H), 8.05 (s, 1H), 7.95 (s, 1H), 7.43 (s, 1H), 7.30 (s, 1H), 7.19-7.11 (q, 2H, J=9.00 Hz), 6.70 (s, 1H), 5.75 (s, 1H), 4.42-4.40 (br, 2H), 4.40-4.25 (br, 2H), 3.74 (s, 3H), 3.70 (s, 3H), 3.70-3.63 (br, 2H), 3.24 (s, 2H), 3.06-3.05 (d, 3H, J=4.29 Hz), 2.89 (s, 2H), 2.83-2.81 (d, 3H, J=7.83 Hz), 2.78 (s, 2H), 2.73 (s, 2H), 2.73-2.60 (br, 2H), 2.40-2.30 (br, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:12])([CH3:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]Br.[N:22]([C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[OH:34])=O.N1CCCCC1>C1(C)C=CC=CC=1>[CH3:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][N:3]1[C:2]2([O:34][C:25]3[CH:26]=[CH:27][C:28]4[C:33]([C:24]=3[N:22]=[CH:1]2)=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:10]([CH3:12])([CH3:11])[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: Cc1ccccc1CBr
Reactant: O=Nc1c(O)ccc2ccccc12
Reactant: CC1=Nc2ccccc2C1(C)C
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: Cc1ccccc1CN1c2ccccc2C(C)(C)C12C=Nc1c(ccc3ccccc13)O2

Procedure:
In 100 ml of toluene were dissolved 4.8 g of 2,3,3-trimethylindolenine, 5.6 g of 2-methylbenzyl bromide, 4.7 g of α-nitroso-β-naphthol and 5.0 g of piperidine. Nitrogen gas was bubbled into the solution for 10 minutes and then the solution was refluxed in a nitrogen current for 2 hours. After the reaction, the reaction mixture was concentrated and then column chromatography separation was carried out by using silica gel as a supporting carrier and toluene as a developing solvent. The solvent was removed by distillation and the obtained solid was recrystallized from methanol to obtain a white crystal of 1-(2-methylbenzyl)-3,3-dimethylspiro[indoline-2,3'-[3H]-naphtho[2,1-b](1,4)-oxazine].
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].O>C1COCC1>[CH3:19][S:20]([N:1]1[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]1)(=[O:22])=[O:21]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(S(C)(=O)=O)CC1
Reaction time: 1 h
Yield: 92 %

Procedure:
Ethyl isonipecotate (31.44 g, 200 mmol) and triethylamine (50.2 ml, 360 mmol) were dissolved in THF (500 ml), and under ice cooling, to the solution was added dropwise methanesulfonyl chloride (23.2 ml, 300 mmol). The mixture was stirred at the same temperature for 1 hour. Under ice cooling, water (200 ml) was added, and the organic layer was distilled off under reduced pressure. The aqueous layer was extracted with ethyl acetate (200 ml, 100 ml×2). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (50 ml×2), 1N-hydrochloric acid (50 ml×3), saturated sodium chloride solution (50 ml), successively, dried over magnesium sulfate and concentrated under reduced pressure. To the concentrate was added diisopropyl ether (100 ml), and the resulting precipitates were collected by filtration. The precipitates were washed with diisopropyl ether (50 ml×3), and dried under reduced pressure to give the titled compound (43.20 g, 184 mmol, Yield 92%) as white crystals.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].Cl.[CH3:24][C:25]1([OH:30])[CH2:29][CH2:28][NH:27][CH2:26]1>>[Br:1][C:2]1[C:3]([N:27]2[CH2:28][CH2:29][C:25]([OH:30])([CH3:24])[CH2:26]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: CC1(O)CCNC1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Agent: Cl
Product: CC1(O)CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 12.1 using 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2) and 3-methylpyrrolidin-3-ol hydrochloride to afford a white solid. UPLC-MS (condition 1) tR=2.79 min, m/z=460.9/461.9 [M+H]+, m/z=458.0/460 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.34 (s, 3H) 1.76-1.93 (m, 2H) 3.63 (d, 1H) 3.68 (d, 1H) 3.70-3.76 (m, 1H) 3.88-3.97 (m, 1H) 4.82 (s, 1H) 7.35 (d, J=8.31 Hz, 2H) 7.85 (d, J=9.05 Hz, 2H) 8.33 (d, J=2.20 Hz, 1H) 8.67 (d, J=2.20 Hz, 1H) 10.22 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([S:13][CH3:14])[N:5]([CH3:12])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O1[CH2:29][CH2:28][CH2:27][CH2:26]1.ICCCC>CN(C)C=O.C(OCC)(=O)C>[CH2:26]([NH:1][C:2]1[N:3]=[C:4]([S:13][CH3:14])[N:5]([CH3:12])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:27][CH2:28][CH3:29]
Reactant: C1CCOC1
Reactant: CCOC(=O)c1c(N)nc(SC)n1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCI
Solvent: CN(C)C=O
Product: CCCCNc1nc(SC)n(C)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
To ethyl 4-amino-1-methyl-2-(methylthio)imidazole-5-carboxylate (3.014 g, 14.00 mmol), prepared by the method of Gompper et al., Tetrahedron Lett. 1885 (1966), in dimethylformamide (50 mL) at 0° C. was added a solution of 1.0M sodium bis(trimethylsilyl)amide in tetrahydrofuran (14.0 mL, 14.0 mmol). After 1 hour, 1-iodobutane (1.75 mL, 15.4 mmol) was added and the reaction was stirred at ambient temperature for 18 hours. The mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate and evaporated under reduced pressure. Chromatography of the residue on silica gel eluting with 5% ethyl acetate in hexane afforded 2.706 g (71%) of the desired product as an oil. TLC (10% ethyl acetate/90% hexane) Rf =0.24. 1H NMR (CDCl3, 300 MHz) d 0.94 (t, 3H), 1.34 (t, 3H), 1.35-1.65 (m, 4H), 2.62 (s, 3H), 3.38-3.49 (m, 2H), 3.66 (s, 3H), 4.28 (q, 2H), 5.58 (br s, 1H). MS (DCl/NH3) m/e 272 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1F)[CH:5]=[O:6].[CH3:12][S-:13].[Na+].O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[S:13][CH3:12])[CH:5]=[O:6]
Reactant: O=Cc1cc(F)c(F)c(F)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CSc1c(F)cc(C=O)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.5 %

Procedure:
To a solution of 3,4,5-trifluorobenzaldehyde (30.0 g, 0.187 mol) in anhydrous THF (400 mL) cooled in a cold water bath was added sodium thiomethoxide (14.4 g, 0.20 mol) in portions over 30 minutes. The mixture was stirred at room temperature for 18 hours, then poured into water and extracted with dichloromethane (1×500 mL, 2×200 mL). The combined extracts were washed with water, dried using magnesium sulfate, and concentrated. Purification of the product by silica gel chromatography using 2% dichloromethane/5% ethyl acetate in hexanes gave the 3,5-difluoro-4-(methylthio)-benzaldehyde as a clear colorless liquid (22.0 g, 62%). 1H NMR (CDCl3/400 MHz) 9.86 (t, J=1.5, 1H), 7.34-7.39 (m, 2H), 2.55 (s, 3H). HRMS m/z 188.0099 (M+, calcd 188.0107).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:23][CH3:24])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][NH2:34]>>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([NH:23][CH3:24])(=[O:22])=[O:21])=[CH:16][CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:34]1
Reactant: CNS(=O)(=O)c1ccc(-n2ccc(=O)c(C(=O)/C=C/N(C)C)n2)cc1
Reactant: NNc1ccccc1F
Product: CNS(=O)(=O)c1ccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3F)n2)cc1

Procedure:
The product was obtained starting from 4-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-N-methyl-benzenesulfonamide (A-30) and 2-fluoro-phenylhydrazine according to the method described for example 91. MS: M=426.1 (M+H)+
Reaction SMILES: [CH3:1][CH:2]([CH2:13][CH2:14][C:15]1[C:20]([CH3:22])([CH3:21])[CH2:19][CH2:18][CH2:17][C:16]=1[CH3:23])[CH:3]=[C:4]([C:9]([O:11]C)=[O:10])[C:5]([O:7][CH3:8])=[O:6].[OH-].[Na+].C([O-])(O)=O.[Na+]>C1COCC1.O>[CH3:8][O:7][C:5]([C:4](=[CH:3][CH:2]([CH3:1])[CH2:13][CH2:14][C:15]1[C:20]([CH3:22])([CH3:21])[CH2:19][CH2:18][CH2:17][C:16]=1[CH3:23])[C:9]([OH:11])=[O:10])=[O:6]
Reactant: COC(=O)C(=CC(C)CCC1=C(C)CCCC1(C)C)C(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(=CC(C)CCC1=C(C)CCCC1(C)C)C(=O)O

Procedure:
Conjugated malonate 3a (10 g, 29.5 mmol) in THF (130 ml) is vigorously stirred with NaOH (4.8 g, 118 mmol) in water (120 ml) at 25° C. for 5 h. After addition of conc. NaHCO3 the mixture is extracted with tert-butyl methyl ether. The organic phase, which contains aldehyde 5, is discarded. The water phase is acidified with conc. HCl to pH 2 and extracted with tert-butyl methyl ether. The organic phase is dried over MgSO4, filtered and evaporated under reduced pressure giving 7.5 g (82%) of crude 1b with Z-configuration, which isomerizes upon standing slowly to an E/Z 1:1 mixture. Analytical data of the Z-isomer: 1H-NMR (400 MHz, CDCl3): δ0.96 (s, 6 H), 1.1 (d, 3 H), 1.4-1.6 (6 H), 1.56 (s, 3 H), 1.85-2.0 (4 H), 3.8 (m, 1 H), 3.9 (s, 3 H), 7.2 (d, 1 H) ppm. 13C-NMR (400 MHz, CDCl3): 19.41 (t), 19.42 (q), 19.8 (q), 26.4 (t), 28.56 (q), 28.57 (q), 32.7 (t), 34.8 (s), 36.0 (d), 36.8 (t), 39.7 (t), 52.6 (t), 124.0 (s), 127.3 (s), 136.7 (s), 161.0 (d), 166.6 (s), 167.3 (s). Z-Configuration determined on freshly prepared 1b by non-decoupled 13C-NMR-(method described in J. Med. Chem. 50, 1322-1334, 2007). HSQC- and HMBC-analysis in DMSO-D6. MS (DIP, El): m/z (%) 308 (M+, 65), 290 (10), 275 (20), 259 (24), 243 (76), 215 (29), 190(27), 175 (32), 158(100), 140 (43), 123 (29), 121 (22).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].O=S(Cl)Cl.[CH:15]1[CH:20]=[CH:19][C:18]([CH2:21]Br)=[CH:17][CH:16]=1.[C:23]([O-])([O-])=O.[K+].[K+]>CO.CCOC(C)=O.[Na+].[I-]>[CH2:21]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:23])=[O:9])[C:18]1[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1ccccc1O
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccccc1OCc1ccccc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of salicylic acid (7 g, 0.05 mol) in methanol (100 mL) at −78° C., SOCl2 (8 mL, 0.11 mol, 2.2 equiv.) was added dropwise. The reaction mixture was stirred at 40° C. overnight, concentrated and extracted with EtOAc. The organic layer was washed with NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The product was then dissolved in DMF; BnBr (9 mL, 0.075 mol, 1.5 equiv.), K2CO3(27.5 g, 0.2 mol, 4 equiv.) and NaI (75 mg) were added. The reaction mixture was stirred at room temperature for 12 h, diluted with EtOAc, washed with water, 0.5N HCl, and brine, dried over Na2SO4, filtered, concentrated and chromatographed on silica gel eluting with hexanes/EtOAc (10:1), to give methyl 2-(benzyloxy)benzoate as an oil (6.8 g, 0.03 mol, 57%). To the methyl ester was added KOH (3.2 g, 0.06 mol, 2 equiv.) and THF/H2O (1:1) (20 mL). The reaction mixture was stirred at room temperature overnight and extracted with EtOAc. The aqueous layer was acidified to pH 2 with 2N HCl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to afford 2-(benzyloxy)benzoic acid as white crystals (m=4.5 g, 70%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH2:24][CH3:25])[CH:16]=1)[CH2:13][CH3:14])[CH2:7]2.[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1>C1COCC1>[CH2:24]([O:23][C:17]1[CH:16]=[C:15]([CH:12]([N:8]2[C:9](=[O:11])[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[NH:1][C:29]([CH:26]3[CH2:28][CH2:27]3)=[O:30])[CH2:7]2)[CH2:13][CH3:14])[CH:20]=[CH:19][C:18]=1[O:21][CH3:22])[CH3:25]
Reactant: O=C(Cl)C1CC1
Reactant: CCOc1cc(C(CC)N2Cc3cccc(N)c3C2=O)ccc1OC
Solvent: C1CCOC1
Product: CCOc1cc(C(CC)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Yield: 76 %

Procedure:
A solution of 7-amino-2-[1-(3-ethoxy-4-methoxy-phenyl)-propyl]-2,3-dihydro-isoindol-1-one (1.0 g, 2.9 mmol) and cyclopropanecarbonyl chloride (0.32 mL, 3.5 mmol) in THF (10 mL) was heated to reflux for 40 min. The solvent was removed in vacuo. The residue was extracted with ethyl acetate (50 mL) and sodium hydrogen carbonate (sat, 50 mL). The organic layer washed with brine (50 mL) and dried over MgSO4. The solvent was removed in vacuo and the residue was purified with chromatography (Silica Gel) to cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as a white solid (900 mg, 76% yield): mp, 107-109° C.; 1H NMR (CDCl3) δ 0.84-0.92 (m, 2H, CH2), 0.99 (t, J=7 Hz, 3H, CH3), 1.02-1.13 (2H, CH2), 1.44 (t, J=7 Hz, 3H, CH3), 1.64-1.73 (m, 1H, CH), 2.00-2.16 (m, 2H, CH2), 3.86 (s, 3H, CH3), 4.00 (d, J=17 Hz, 1H, CHH), 4.09 (q, J=7 Hz, 2H, CH2), 4.27 (d, J=17 Hz, 1H, NCHH), 5.33 (dd, J=7, 9 Hz, 1H, NCH), 6.83-6.95 (m, 3H, Ar), 7.00 (d, J=8 Hz, 1H, Ar), 7.42 (t, J=8 Hz, 1H, Ar), 8.42 (d, J=8 Hz, 1H, Ar), 10.67 (s, 1H, NH); 13C NMR (CDCl3) δ 8.19, 11.18, 14.78, 16.18, 24.54, 45.64, 55.53, 55.97, 64.58, 111.46, 112.91, 116.68, 117.67, 119.51, 131.96, 132.94, 138.02, 141.37, 148.54, 149.04, 169.55, 172.70; Anal Calcd for C24H28N2O4: C, 70.57; H, 6.91; N, 6.86. Found: C, 70.54; H, 6.91; N, 6.86.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18](Cl)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][NH:22][CH3:23]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([N:22]([CH3:23])[CH3:21])[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc(Cl)n2)CC1
Reactant: CNC
Solvent: CO
Product: CN(C)c1ncnc(N2CCN(C(=O)OC(C)(C)C)CC2)n1

Procedure:
A solution of 2 mmol of 4-(4-Chloro-[1,3,5]triazin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester in 15 ml of 2M dimethylamine in methanol was stirred at room temperature for 1 hour. Concentration and purification by chromatography (SiO2; ethyl acetate/cyclohexane 1:1) yielded the title compound as a colorless solid. MS (m/e): 309.1 (MH+, 100%)
Reaction SMILES: [OH:1][CH:2]([C:5]1[N:6]=[C:7]([CH3:10])[S:8][CH:9]=1)[CH2:3][NH2:4].[OH:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](=O)[CH3:23])=[CH:17][CH:16]=1>>[OH:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[N:6]=[C:7]([CH3:10])[S:8][CH:9]=2)[CH3:23])=[CH:17][CH:16]=1
Reactant: Cc1nc(C(O)CN)cs1
Reactant: CC(=O)Cc1ccc(OCCO)cc1
Product: Cc1nc(C(O)CNC(C)Cc2ccc(OCCO)cc2)cs1

Procedure:
Prepared by analogy to Example 13 by reaction of 2-hydroxy-2-(2-methyl-thiazol-4-yl)ethanamine with 1-[4-(2-hydroxyethoxy)phenyl)propan-2-one followed by purification on a silica gel column using methylene chloride/methanol=9:1 as eluant.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH3:10])[S:5][C:6]=1[O:7][CH2:8][CH3:9].C([Li])CCC.[Li]C1SC=C[N:21]=1.[S:22](Cl)(Cl)(=[O:24])=[O:23]>CCOCC.CCCCCC>[CH2:8]([O:7][C:6]1[S:5][C:4]([CH3:10])=[N:3][C:2]=1[S:22]([NH2:21])(=[O:24])=[O:23])[CH3:9]
Reactant: CCOc1sc(C)nc1Br
Reactant: O=S(=O)(Cl)Cl
Reactant: [Li]c1nccs1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CCOc1sc(C)nc1S(N)(=O)=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 11.1 g of 4-bromo-5-ethoxy-2-methylthiazole [prepared by the method of D. S. Tarbell et al., J. Amer. Chem. Soc., 72, 3138 (1950) in 50 ml ether was cooled to -60°, and 35.9 ml of a 1.7M solution of n-butyl lithium in hexane was added dropwise while maintaining the temperature below -45°. The resulting heavy yellow-brown suspension was diluted with an additional 25 ml ether and stirred 20 minutes at a temperature of -50° to -30°. The ethereal suspension of the lithiothiazole was added via syringe to a solution of 8.0 ml sulfuryl chloride in 50 ml hexane, while maintaining the temperature between -30° and -20°. After the suspension was stirred 15 minutes at -30°, it was allowed to warm to -5° and stirred 3.5 hours. The reaction mixture was poured into 500 ml ice-water. The two-phase suspension was extracted twice with ether. The combined organic solution was washed with water and brine, then dried over magneisum sulfate, filtered, and the solvent evaporated. The resulting oily solid was dissolved in 150 ml of tetrahydrofuran; the solution was cooled to 0°, and 6.7 ml of ammonium hydroxide added dropwise. The brown suspension was allowed to warm to ambient and stirred 3 hours. The solvent was evaporated, and the residual black oil partitioned between methylene chloride and water. The organic solution was washed with water followed by brine, then stirred 0.5 hour with magnesium sulfate and charcoal. The mixture was filtered through Celite@ and the solvent was evaporated. Trituration of the resulting brown oily solid with 1-chlorobutane gave 4.2 g of the title compound as a tan solid, m.p. 118°-120°. IR: 3.05 and 3.15μ (SO2NH2).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13](Br)=[C:12]([F:17])[CH:11]=1)(=[O:9])=[O:8].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:23]2[CH:24]=[CH:25][C:20]([C:19]([F:30])([F:29])[F:18])=[CH:21][CH:22]=2)=[C:12]([F:17])[CH:11]=1)(=[O:9])=[O:8]
Reactant: O=S(=O)(NCCCCO)c1ccc(Br)c(F)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: O=S(=O)(NCCCCO)c1ccc(-c2ccc(C(F)(F)F)cc2)c(F)c1

Procedure:
Using a method analogous to that described in Example 40, 4-bromo-3-fluorophenyl-sulfonic acid-(4-hydroxybutyl)-amide and 4-trifluoromethylphenyl boronic acid were reacted to give the title compound as a white solid. δC (DMSO, 62.9 MHz): 26.4, 29.5, 43.2, 62.2, 115.4 (d, J 25.4), 123.2, 125.7, 129.4, 130.8 (d, J 22.2), 131.6, 137.6, 141.5 (d, J 6.8) and 159.3 (d, J 253.9).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[CH3:16])[CH:2]=[CH2:3].C(N(CC)CC)C.[C:24](Cl)(Cl)=[S:25]>C(Cl)(Cl)Cl.ClCCl>[CH2:1]([N:4]1[CH2:5][CH2:6][CH2:7][N:8]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[CH3:16])[C:24]1=[S:25])[CH:2]=[CH2:3]
Reactant: C=CCNCCCNc1cc(Cl)ccc1C
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: C=CCN1CCCN(c2cc(Cl)ccc2C)C1=S
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.4 %

Procedure:
To an ice-cold solution of the diamine of Step C (3.4 g) and triethylamine (4.0 mL) in dry chloroform (50 mL) was added dropwise under nitrogen thiophosgene (1.1 mL). After 30 minutes at ambient temperature, additional triethylamine (1.0 mL) and thiophosgene (0.28 mL) were added. After 15 minutes, no starting material remained. The reaction was quenched with water, the pH adjusted to 8 with triethylamine, and extracted with dichloromethane. The extracts were combined, dried over sodium sulfate and concentrated in vacuo to give a brown oil. The crude material was dissolved in dichloromethane and absorbed onto a column of Merck-60 flash silica gel. Elution with 10% ethyl acetate in hexane provided a yellow solid which was triturated with diethyl ether to give the title compound (1.69 g, 42.4%) as a white solid, m.p. 71-72° C.