Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[C:2]([CH2:6][CH2:7][C:8]([NH2:10])=[NH:9])([O:4]C)=[O:3].Cl>>[ClH:1].[C:8]([CH2:7][CH2:6][C:2]([OH:4])=[O:3])(=[NH:9])[NH2:10]
Reactant: COC(=O)CCC(=N)N
Agent: Cl
Product: N=C(N)CCC(=O)O
Yield: 99 %

Procedure:
A solution of 7.8 g. (0.047 mole) of β-carbomethoxypropionamidine hydrochloride in 217 ml. of 12N hydrochloric acid is heated at steam bath temperatures for one hour. The solution is cooled, evaporated in vacuo to dryness, and the residual product triturated several times with ethylene dichloride and filtered, 7.1 g. (99% yield), m.p. 138° -140° C. (McElvain, et al., J. Am. Chem. Soc., 71, 40 (1949) reports a melting point for crude product of 131° -137° C.).
Reaction SMILES: [Cl:1][C:2]1[O:6][C:5]([C:7]([NH:9][C@@H:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])[CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)=[O:8])=[CH:4][C:3]=1[C:34]1[N:38]([CH3:39])[N:37]=[CH:36][C:35]=1[Cl:40].NN>O1CCCC1.CO>[NH2:12][CH2:11][C@@H:10]([NH:9][C:7]([C:5]1[O:6][C:2]([Cl:1])=[C:3]([C:34]2[N:38]([CH3:39])[N:37]=[CH:36][C:35]=2[Cl:40])[CH:4]=1)=[O:8])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:33])([F:32])[F:31]
Reactant: Cn1ncc(Cl)c1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)oc1Cl
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Product: Cn1ncc(Cl)c1-c1cc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)oc1Cl
Yield: 65 %

Procedure:
To a solution of 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-furancarboxamide (116 mg, 0.20 mmol) in tetrahydrofuran (1 ml) and methanol (1 ml) at 25° C. was added hydrazine (0.04 ml, 1.37 mmol) dropwise. After 12 h the solution was concentrated, dry loaded onto silica and purified by column chromatography (2% MeOH in DCM (1% NH4OH)). The free base was transferred to the HCl salt by addition of excess 2M HCl in Ether (2 ml) to the residue in DCM (2 ml) affording the HCl salt of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide (68 mg, 0.13 mmol, 65% yield) as a yellow solid: LCMS (ES) m/z=461, 463 (M, M+2)+, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.80 (d, J=9.09 Hz, 1H) 8.03 (br. s., 3H) 7.66-7.73 (m, 2H) 7.58-7.61 (m, 1H) 7.52-7.59 (m, 2H) 7.40-7.48 (m, 1H) 4.5-4.57 (m, 1H) 3.77 (s, 3H) 2.98-3.09 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:11]([CH3:19])([CH3:18])[O:12][SiH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1([C:11]([CH3:18])([CH3:19])[O:12][SiH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:10][CH2:9][N:8]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C(C)(C)O[SiH2]C(C)(C)C)CCNC1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C1(C(C)(C)O[SiH2]C(C)(C)C)CCN(CC(=O)OC(C)(C)C)C1
Reaction time: 1 h
Yield: 93.8 %

Procedure:
To a stirred mixture of 3-(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidine-3-carboxylic acid ethyl ester (444 mg, 1.54 mmol), triethylamine (214 μl, 1.54 mmol) and cesium carbonate (251 mg, 0.77 mmol) in acetonitrile (5 ml) was added tert-butyl bromoacetate (351 μl, 2.38 mmol) slowly. The mixture was stirred for 1 hour, filtered and concentrated. The residue was diluted with ethyl acetate, washed with water and dried over MgSO4. Solvent was removed under reduced pressure to give a crude product that was purified by column chromatography on silica gel. Elution with a solution of ethyl acetate in hexanes (1:4) provided 580 mg (94%) of the title compound.
Reaction SMILES: Cl.[Br:2][C:3]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:6]2[N:7]([CH3:13])[C:8]([CH2:10][CH2:11]Cl)=[N:9][C:5]=2[CH:4]=1.[C:20]1([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[Br:2][C:3]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:6]2[N:7]([CH3:13])[C:8]([CH2:10][CH2:11][N:29]3[CH2:30][CH2:31][CH:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:27][CH2:28]3)=[N:9][C:5]=2[CH:4]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: Cn1c(CCCl)nc2cc(Br)c3ccccc3c21
Agent: Cl
Product: Cn1c(CCN2CCC(c3ccccc3)CC2)nc2cc(Br)c3ccccc3c21

Procedure:
The compound of the title is prepared by condensing 5-bromo-2-(2-chloroethyl)-1-methyl-1H-naphth[1,2-d]imidazole hydrochloride with 4-phenylpiperidine according to the method described in the foregoing example. M.p. 182°-84° C.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[S]>O1CCOCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]=1
Reactant: c1ccc2c(c1)CCNC2
Agent: [S]
Solvent: C1COCCO1
Product: C1=NCCc2ccccc21
Yield: 96.5 %

Procedure:
6.0 g of 1,2,3,4-tetrahydroisoquinoline and 3.0 g of sulphur powder in 40 ml of dioxane are refluxed for 20 hours. The reaction mixture is evaporated, to the residue 60 ml of ether are added, the precipitated sulphur is filtered off and the filtrate is evaporated. 5.7 g of 3,4-dihydroisoquinoline are obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][C:16]1[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=1)[CH:11]=[CH:10][CH:9]=2)=[O:5])C.[Li+].[OH-]>CO.O>[C:18]1([CH3:22])[CH:19]=[CH:20][CH:21]=[C:16]([O:15][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:13]=2[CH:14]=[C:6]([C:4]([OH:5])=[O:3])[NH:7]3)[CH:17]=1
Reactant: CCOC(=O)c1cc2c(Oc3cccc(C)c3)cccc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cccc(Oc2cccc3[nH]c(C(=O)O)cc23)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
136 (520 mg, 1.761 mmol) is dissolved in 10 ml of methanol and treated with a solution of LiOH (84.3 mg, 3.52 mmol) in 5 ml of water. The mixture is stirred at room temperature for 18 hours. After evaporation, the crude product is acidified at 0° C. with 2M HCl and extracted with ethyl acetate. The organic layers are dried over sodium sulphate and evaporated.
Reaction SMILES: C([C:4]1[CH:5]=[CH:6][C:7]([N+:23]([O-])=O)=[C:8]([CH:22]=1)[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:11]=1)(=O)C.[CH2:26]([O:28]CC)[CH3:27]>C(O)C.ClCCl.[Pd]>[C:26]([C:5]1[CH:4]=[CH:22][C:8]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[CH:11]=2)=[C:7]([CH:6]=1)[NH2:23])(=[O:28])[CH3:27]
Reactant: CC(=O)c1ccc([N+](=O)[O-])c(Nc2cccc(-c3cccnc3)c2)c1
Reactant: CCOCC
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: CC(=O)c1ccc(Nc2cccc(-c3cccnc3)c2)c(N)c1
Yield: 80 %

Procedure:
30a from Example 12 (2 g, 6 mmol) is suspended in a mixture of ethanol (50 ml) and dichloromethane (10 ml) and is hydrogenated at ambient pressure using palladium (5% on activated carbon) as the catalyst. Filtration of the resulting solution through celite followed by evaporation of solvent leaves an oil. Trituration with a mixture of diethyl ether and petroleum ether (1:1) affords 1.46 g pure 31a (80%). Mp 175-176° C.
Reaction SMILES: [C:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[O:6][C:5]=1[NH:15][C@H:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:17][CH3:18])(=O)[CH3:2].[CH:25]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26]1>C(#N)C>[C:19]1([C@@H:16]([NH:15][C:5]([C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:14])[N:30]([CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[C:1]=2[CH3:2])=[O:6])[CH2:17][CH3:18])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC[C@H](Nc1oc(=O)c2ccccc2c1C(C)=O)c1ccccc1
Reactant: NC1CCCC1
Solvent: CC#N
Product: CC[C@H](NC(=O)c1c(C)n(C2CCCC2)c(=O)c2ccccc12)c1ccccc1
Temperature: 170 °C

Procedure:
A mixture of 4-acetyl-3-((S)-1-phenyl-propylamino)-isochromen-1-one (60 mg) and cyclopentylamine (0.06 mL) in acetonitrile (0.2 mL) was heated under microwave irradiation at 170° C. for 15 min. The reaction mixture was partitioned between 2M HCl (3 mL) and ethyl acetate (3 mL). The organic phase was absorbed on SiO2 and flash chromatographed (20 g SiO2 column, gradient heptane-ethyl acetate, the product came out with 40% ethyl acetate) to give 18 mg of the title compound as a colourless solid. LC-MS (m/z) 389.5 (MH+); tR=1.52.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[Br:17]Br>C1COCC1>[Br:17][C:11]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[N:9][CH:10]=1
Reactant: BrBr
Reactant: c1ccc(-n2ccnn2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Brc1cnnn1-c1ccccc1
Reaction time: 0.08 h

Procedure:
In a 100 ml 3 necked round bottom flask, 1-phenyl-1H-1,2,3-triazole (1.2 g) was taken in dry THF (25 ml) under nitrogen. n-Butyl lithium (3.36 ml) was added at −78° C. and stirred for 5 minutes, then bromine (3.76 ml) was added dropwise to the above reaction mixture. Reaction mixture was stirred at −78° C. for 1 hour. TLC was checked no starting material and the reaction mixture was quenched with saturated ammonium chloride (50 ml) and ethyl acetate was added. The organic layer was washed with sodium bisulphate, brine, dried and concentrated. The crude product was purified by column chromatography using pet ether & ethyl acetate as eluent to give 5-bromo-1-phenyl-1H-1,2,3-triazole as yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[NH:15][CH:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:33][C:34]([F:37])([F:36])[F:35]>>[Br:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:33][C:34]([F:37])([F:36])[F:35])[CH:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: Brc1ccc2c(c1)OCCc1sc(-c3ncc[nH]3)nc1-2
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: FC(F)(F)Cn1ccnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reaction time: 0.75 h

Procedure:
To a solution of 8-Bromo-2-(1H-imidazol-2-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.430 g, 1.23 mmol;) in N,N-Dimethylformamide (17.2 mL, 222 mmol) was added Cesium Carbonate (0.805 g, 2.47 mmol;). After 45 min. 2-iodo-1,1,1-trifluoro-ethane (0.241 mL, 2.47 mmol) was added to the reaction mixture. The reaction mixture was stirred at 50 C 4 h. The reaction was quenched with water then extracted with EtOAc 2×. The organic layers was combined, dried Na2SO4, concentrated and purified by chromatography (EtOAc/Hex) (eluted at 35%) to give 8-Bromo-2-[1-(2,2,2-trifluoro-ethyl)-1H-imidazol-2-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene. MS: (ESI+)=330.1.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:21]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:22])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.[OH-].[Li+]>C1COCC1.O>[C:33]([O:32][C:30]([NH:29][CH:20]([C:21]([N:23]1[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1)=[O:22])[CH2:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:37])=[O:2])=[CH:7][CH:8]=2)=[CH:18][CH:17]=1)=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: COC(=O)CCc1ccc(Oc2ccc(CC(NC(=O)OC(C)(C)C)C(=O)N3CCOCC3)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC(Cc1ccc(Oc2ccc(CCC(=O)O)cc2)cc1)C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
The amide 13 (2.2 g, 4.3 mmol) was dissolved in THF (25 mL) and diluted with water (25 mL). Lithium hydroxide (0.41 g, 17.0 mmol) was added and the reaction mixture was stirred at room temperature for about 2 h. The THF was evaporated and the resulting aqueous layer was acidified with 2.0 M HCl and extracted into EtOAc (2×50 mL). The organic layer was washed with water (1×50 mL) and brine (1×50 mL), dried and concentrated to yield the desired acid compound 14 (2.0 g, 93.5%). 1H NMR (400 MHz, DMSO-d6): 12.1 (br, 1H), 7.20 (d, J=8.4 Hz, 2H), 7.17 (d, J=8.8 Hz, 2H), 7.14 (d, J=8.4 Hz, 1H), 6.86 (d, J=8.4 Hz, 2H), 6.82 (d, J=8.8 Hz, 2H), 4.52 (m, 1H), 3.22-3.47 (m, 8H), 2.72-2.80 (m, 4H), 1.28 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:15]=[CH:14][C:11]([CH2:12][OH:13])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:21]1[N:30]([CH3:31])[C:29](=[O:32])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[CH3:33])[N:22]=1>CN(C=O)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:15]=[CH:14][C:11]([CH2:12][O:13][C:21]3[N:30]([CH3:31])[C:29](=[O:32])[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][C:27]=4[CH3:33])[N:22]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1cccc2nc(Cl)n(C)c(=O)c12
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc2nc(OCc3ccc(C(=O)c4ccc(Cl)cc4)cc3)n(C)c(=O)c12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 20.6 %

Procedure:
To a solution of 4-(4-chlorobenzoyl)benzyl alcohol (1.0 g) in DMF (20 ml) was added 60% sodium hydride (210 mg) and the mixture was stirred at room temperature for 10 minutes. Then, 2-chloro-3,5-dimethyl-4(3H)-quinazolinone (850 mg) was added and the mixture was stirred at room temperature for 1 hour and at 80° C. for 10 minutes. This reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate: chloroform=4:1:1) to provide the title compound as colorless solid (350 mg).
Reaction SMILES: [C:1]([C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1)#[N:2].[C:29]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][C:33]=1[F:41])(=[O:31])[NH2:30].C([O-])(=O)C.[K+]>C(#N)C.O>[C:29]([C:32]1[CH:37]=[CH:36][C:35]([C:8]2[CH:9]=[CH:10][C:5]([CH2:4][C@H:3]([NH:12][C:13]([C:15]3([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[O:14])[C:1]#[N:2])=[CH:6][CH:7]=2)=[CH:34][C:33]=1[F:41])(=[O:31])[NH2:30]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@H](C#N)Cc2ccc(I)cc2)CCOCC1
Reactant: NC(=O)c1ccc(B(O)O)cc1F
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@H](C#N)Cc2ccc(-c3ccc(C(N)=O)c(F)c3)cc2)CCOCC1
Temperature: 85 °C
Yield: 53 %

Procedure:
(S)-tert-Butyl 4-(1-cyano-2-(4-iodophenyl)ethylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 15, step (i), 200 mg) and 4-carbamoyl-3-fluorophenylboronic acid (73 mg) in acetonitrile (8 mL) were treated with potassium acetate (79 mg) in water (4 mL). Nitrogen was bubbled through the mixture and then 1,1 bis(di-tert-butylphosphino)ferrocene palladium dichloride (5 mg) was added and the mixture was heated at 85° C. for 18 h under nitrogen. The reaction mixture was evaporated onto silica and purified by chromatography on silica eluting with ethyl acetate/isohexane (50:50 to 100:0) to afford the sub-titled compound (108 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH2:9][CH:10]2O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH:9]=[CH:10]2
Reactant: OC1CCc2c(-c3cccs3)cccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C1=Cc2cccc(-c3cccs3)c2C1
Yield: 96.3 %

Procedure:
A stirred solution of 2.4 g (0.011 mole) of 4-(2-thienyl)-1-indanol and 0.15 g of p-toluenesulfonic acid in 60 mL of toluene was heated under reflux,, and the theoretical amount of water by-product was collected in a Dean-Stark trap. The reaction mixture was cooled and washed with two portions of 100 mL each of a 5% aqueous solution of sodium bicarbonate, then with two portions of 50 mL each of water. The organic layer was dried over magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to give 2.1 g of 7-(2-thienyl)-1H-indene as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[Cl:11].[NH2:12][C@H:13]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:26][CH:27]=2)[CH2:18][CH2:17]1>>[Cl:11][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:2]=1[Cl:1])[NH:8][C:9]([NH:12][C@H:13]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:26][CH:27]=2)[CH2:18][CH2:17]1)=[O:10]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)Nc3ccc(Cl)c(Cl)c3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure P and Scheme AB using 1,2-dichloro-4-isocyanatobenzene and N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 567.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:5]([O:17][CH3:18])=[C:6]([CH:16]=1)[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>N1C=CC=CC=1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:5]([O:17][CH3:18])=[C:6]([CH:16]=1)[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:13][CH:14]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1c(COc2ccc(N)cc2)cc(Br)cc1C(C)(C)C
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1c(COc2ccc(NS(C)(=O)=O)cc2)cc(Br)cc1C(C)(C)C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
step 4—To a solution of 118 (0.20 g, 0.55 mmol) in pyridine (3 mL) cooled to 0° C. was added methanesulfonyl chloride (0.081 g, 0.71 mmol). Stirring was continued at 0° C. for 30 min then at RT for 3 h. The reaction mixture was diluted with EtOAc, washed sequentially with aqueous CuSO4 and 2N HCl, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with EtOAc/hexane to afford 0.20 g (84%) of N-[4-(5-bromo-3-tert-butyl-2-methoxybenzyloxy)phenyl]methanesulfonamide (120) as a white solid.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:6]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>C(O)C>[N:12]1([C:2]2[S:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:6]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: C1CNCCN1
Reactant: CCOC(=O)c1cnc(Br)s1
Solvent: CCO
Product: CCOC(=O)c1cnc(N2CCNCC2)s1
Yield: 92 %

Procedure:
1.02 g (5.0 mmol) of ethyl 2-bromothiazole-5-carboxylate and 4.31 g (50 mmol) of piperazine were dissolved in ethanol (20 ml) and the mixture was heated under reflux over a period of 4 h. The solution was then concentrated in vacuo, taken up in EA and washed successively with water and a satd aq. NaCl solution. Following drying of the organic phase over MgSO4, filtration and removal of solvent in vacuo there were obtained 1.12 g (4.6 mmol, 93%) of ethyl 2-piperazin-1-ylthiazole-5-carboxylate.
Reaction SMILES: [C:1]1([CH:7]([O:9][C:10](=[O:25])[NH:11][C:12]2[C:13]([CH3:24])=[N:14][O:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26]([O:28][C:29](=[O:46])[CH2:30][C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][CH:32]=1)[CH3:27]>>[CH2:26]([O:28][C:29](=[O:46])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:20]2[CH:21]=[CH:22][C:17]([C:16]3[O:15][N:14]=[C:13]([CH3:24])[C:12]=3[NH:11][C:10]([O:9][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH3:8])=[O:25])=[CH:18][CH:19]=2)=[CH:33][CH:32]=1)[CH3:27]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)c1ccccc1
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)OC(C)c3ccccc3)cc2)cc1

Procedure:
Following the procedure described in Example 36, Step 6, [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid 1-phenyl-ethyl ester and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester were reacted to provide {4′-[3-methyl-4-(1-phenyl-ethoxycarbonylamino)-isoxazol-5-yl]-biphenyl-4-yl}-acetic acid ethyl ester, which was hydrolyzed to the acid as described in Example 34, Step 2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4]Br.[CH3:7][C:8]1[NH:9][CH:10]=[CH:11][N:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:6])[CH2:4][N:9]1[CH:10]=[CH:11][N:12]=[C:8]1[CH3:7]
Reactant: Cc1ncc[nH]1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1ccnc1C
Temperature: 25 °C
Yield: 47 %

Procedure:
4 ml of bromo acetic acid methyl ester is dissolved in 30 ml DMF and 5.2 g of 2-methylimidazole and 11.2 g potassium carbonate are added. The reaction mixture is stirred at room temperature for several hours and then subjected to aqueous work up. After removal of the solvent the pure product is obtained by flash chromatography in 47 to 78% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([CH2:11][CH2:12][CH2:13][N:14]([CH3:25])[C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[N:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:9]=1[CH2:11][CH2:12][CH2:13][N:14]([CH3:25])[C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN(CCCC(=O)Nc1ccccc1N)C(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CN(CCCc1nc2ccccc2[nH]1)C(=O)OCc1ccccc1
Yield: 57.7 %

Procedure:
20.1 g (59 mmol) of benzyl [3-[(2-aminophenyl)carbamoyl]propyl]methylcarbamate are dissolved in 450 ml of toluene and treated with 7 g (37 mmol) of p-toluenesulphonic acid. The reaction mixture is thereafter heated to reflux for 2 hours, whereby the water formed is removed from the reaction mixture by means of a water separator. After evaporation and dissolution of the residue in ethyl acetate the solution is washed twice with saturated aqueous sodium bicarbonate solution and twice with saturated aqueous soiium chloride solution. The organic phase is dried over magnesium sulphate and evaporated. Chromatography of the crude product on silica gel with ethyl acetate as the elution agent yields 11 g (58%) of benzyl [3-(2-benzimidazolyl)propyl]methylcarbamate, m.p. 83°-86°.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][CH:6]=[C:5]([O:12][CH3:13])[C:4]=1OC.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(O)C.[C:27](=[O:30])([O-])[O-].[K+].[K+]>O>[CH3:1][S:2][C:3]1[CH:4]=[C:5]([O:12][CH3:13])[C:6]([O:30][CH3:27])=[CH:7][C:8]=1[NH2:9]
Reactant: COc1ccc([N+](=O)[O-])c(SC)c1OC
Reactant: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cc(N)c(SC)cc1OC

Procedure:
A reaction mixture was prepared containing 68.7 g. of 3-methylthio-4-nitroveratrole, 261 g. sodium dithionite (Na2S2O4), 1500 ml. of ethanol and 2250 ml. of water. The reaction mixture was heated at reflux temperature for about 1 hour and then cooled. The reaction mixture was then made basic with potassium carbonate and the resulting alkaline solution concentrated in vacuo to one-half its original volume. The aqueous solution was extracted twice with 2 l. portions of ether. The ether extracts were combined, dried, and the ether removed therefrom by evaporation in vacuo. The solid residue, comprising 2-methylthio-4,5-dimethoxy aniline formed in the above reaction, was recrystallized from a benzene-hexane solvent mixture to yield 33.6 g. of crystalline material melting at 69°-72° C.