Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[CH3:23][C:24]1[C:28]([S:29](Cl)(=[O:31])=[O:30])=[C:27]([CH3:33])[O:26][N:25]=1>C1COCC1>[CH3:23][C:24]1[C:28]([S:29]([NH:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)(=[O:31])=[O:30])=[C:27]([CH3:33])[O:26][N:25]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Solvent: C1CCOC1
Product: Cc1noc(C)c1S(=O)(=O)NCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3,5-dimethyl-4-isoxazolesulfonyl chloride: ESMS m/e: 463.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C@:7]23[CH2:14][C@H:13]([N:15]=[N+]=[N-])[CH2:12][N:11]2[C:10](=[O:18])[N:9]([C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)[C:8]3=[O:27])=[CH:4][CH:3]=1>C(O)(=O)C.[Zn]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@:7]23[CH2:14][C@H:13]([NH2:15])[CH2:12][N:11]2[C:10](=[O:18])[N:9]([C:19]2[CH:20]=[C:21]([Cl:26])[CH:22]=[C:23]([Cl:25])[CH:24]=2)[C:8]3=[O:27])=[CH:28][CH:29]=1
Reactant: [N-]=[N+]=N[C@@H]1CN2C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)[C@@]2(Cc2ccc(Br)cc2)C1
Agent: [Zn]
Solvent: CC(=O)O
Product: N[C@@H]1CN2C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)[C@@]2(Cc2ccc(Br)cc2)C1
Reaction time: 1 h
Yield: 53.4 %

Procedure:
To a solution of (5R,7S)-5-(4-bromobenzyl)-3-(3,5-dichlorophenyl)-7-azido-1,3-diazabicyclo[3.3.0]octane-2,4-dione (0.83 g) in acetic acid (20 mL) was added zinc powder (0.90 g). After 1 hour at room temperature, the mixture was concentrated. The residue was suspended in satd. NaHCO3 and EtOAc. The mixture was filtered and the organic layer was collected, washed with brine, dried (Na2SO4), filtered and concentrated. Purification of the residue by chromatography (silica gel: CH2Cl2: Chromatotron) afforded the titled compound (0.42 g). MS (m/z) 468 (MH+). mp 64.4° C.
Reaction SMILES: [OH-].[K+].[C:3](=[S:5])=S.[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[C:8]=1[OH:14]>CCO.O>[NH2:6][C:7]1[C:8]2[O:14][C:3](=[S:5])[NH:13][C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: S=C=S
Reactant: Nc1cccc(N)c1O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cccc2[nH]c(=S)oc12
Yield: 49.7 %

Procedure:
A solution of KOH (0.875 g, 15.6 mmol) in EtOH (14.3 mL) and water (2.6 mL) was treated with carbon disulfide (0.828 g, 10.9 mmol), followed by of 2,6-diaminophenol (1.50 g, 12.1 mmol). The mixture was heated at reflux temperature for 3 h, concentrated, neutralized with 1M HCl to pH 7, and extracted with EtOAc. The extracts were combined, dried over Na2SO4 and concentrated in vacuo to afford the title compound (0.90 g, 45%), characterized by NMR and mass spectral analyses.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[C:11]([CH3:12])=[C:10]([CH3:13])[S:9][C:8]=2[F:14])=[CH:5][NH:4][N:3]=1.[C:15](=[O:20])=[N:16][C:17](Cl)=[O:18].Cl>N1C=CC=CC=1>[OH:20][C:15]1[N:16]=[C:17]([OH:18])[N:3]2[N:4]=[CH:5][C:6]([C:7]3[C:11]([CH3:12])=[C:10]([CH3:13])[S:9][C:8]=3[F:14])=[C:2]2[N:1]=1
Reactant: O=C=NC(=O)Cl
Reactant: Cc1sc(F)c(-c2c[nH]nc2N)c1C
Agent: Cl
Solvent: c1ccncc1
Product: Cc1sc(F)c(-c2cnn3c(O)nc(O)nc23)c1C
Temperature: 0 °C
Reaction time: 4 h

Procedure:
3-Amino-4-(2-fluoro-5-methyl-4-methylthiophenyl)pyrazole (2.74 g) is dissolved in pyridine (20 ml) and the mixture is cooled to 0° C. To the mixture is added N-(chlorocarbonyl)isocyanate (1.03 ml), and the mixture is stirred at room temperature for 4 hours. The reaction mixture is acidified by adding thereto 10% hydrochloric acid under ice cooling. The resulting precipitate is separated by filtration, washed with water and dried to give the title compound (3.4 g).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:12]3[CH:19]=[C:18]([C:20]4[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH:25]=4)[NH:17][C:13]=3[N:14]=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[S:33]1[CH:37]=[CH:36][N:35]=[CH:34]1.C([O-])(=O)C.[K+]>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([NH:10][C:11]2[C:12]3[CH:19]=[C:18]([C:20]4[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH:25]=4)[NH:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:3][C:2]=1[C:37]1[S:33][CH:34]=[N:35][CH:36]=1
Reactant: COc1ccc(Nc2ncnc3[nH]c(C4=CCN(C(=O)OC(C)(C)C)CC4)cc23)cc1I
Reactant: c1cscn1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Nc2ncnc3[nH]c(C4=CCN(C(=O)OC(C)(C)C)CC4)cc23)cc1-c1cncs1
Temperature: 100 °C
Reaction time: 17 h

Procedure:
Nitrogen was bubbled through a solution of tert-butyl 4-[4-(3-iodo-4-methoxyphenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (109.5 mg, 0.2 mmol), thiazole (85.1 mg, 1.0 mmol), potassium acetate (39.3 mg, 0.4 mmol), and tetrakis(triphenylphosphine)-palladium (23.1 mg, 0.02 mmol) in DMF (0.8 mL) for 3 min. The mixture was then heated to 100° C. and stirred for 17 h. The solvents were removed in vaccuo and the residue was dissolved in DMF (−2 mL). The DMF solution was filtered and sent to mass-directed HPLC purification to give the title compound. 1H-NMR (CD3OD, 400 MHz): δ=1.50 (s, 9H), 2.55 (m, 2H), 3.66 (m, 2H), 3.98 (s, 3H), 4.13 (m, 2H), 6.28 (s, br, 1H), 6.60 (s, 1H), 7.17 (d, J=9.2 Hz, 1H), 7.68 (dd, J=2.4, 8.8 Hz, 1H), 8.06 (d, J=2.8 Hz, 1H), 8.20 (s, 1H), 8.31 (s, 1H), 8.98 (s, 1H). MS (ES+): m/z 504.99 (MH+). HPLC: tR=2.95 min (ZQ2000, polar—5 min). The following EXAMPLES 300-301 are compounds of Formula (I) wherein X=C—CN.
Reaction SMILES: [CH:1]1[C:6]([NH:7]N)=[CH:5][CH:4]=[C:3]([N:9]2[CH:13]=[N:12][N:11]=[CH:10]2)[CH:2]=1.[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.Cl>O1CCOCC1>[N:12]1[N:11]=[CH:10][N:9]([C:3]2[CH:2]=[C:1]3[C:6](=[CH:5][CH:4]=2)[NH:7][CH:19]=[C:18]3[CH2:17][CH2:16][CH2:15][OH:14])[CH:13]=1
Reactant: NNc1ccc(-n2cnnc2)cc1
Reactant: C1=COCCC1
Agent: Cl
Solvent: C1COCCO1
Product: OCCCc1c[nH]c2ccc(-n3cnnc3)cc12
Yield: 29.6 %

Procedure:
A solution of 4'-(1,2,4-triazol-4-yl)phenylhydrazine (25 g, 143 mmol) in dioxan (250 ml) was treated with dihydropyran (24 g, 286 mmol) followed by 1M hydrochloric acid (150 ml) and heated at reflux for 18 hours. The reaction mixture was evaporated with toluene then reevaporated. Inorganic solids were removed by treating the residue with a mixture of methanol and acetonitrile. The mother liquors were purified by column chromatography on silica using dichloromethane:methanol (9:1→4:1) as the eluant. The compound was recrystallised from acetonitrile to afford the title compound as a white solid (10.24 g, 30%), mp 205°-207° C. δ (360 MHz, d6 -DMSO) 1.81 (2H, quintet, J=7Hz, CH2), 2.75 (2H, t, J=8Hz, CH2), 3.46 (2H, dt, J1 =6Hz, J2 =5Hz, CH2), 4.43 (1H, t, J=5Hz, OH), 7.26 (1H, d, J=2Hz, Ar-H), 7.29 (1H, dd, J1 =9Hz, J2 =2Hz, Ar-H), 7.47 (1H, d, J=9Hz, Ar-H), 7.77 (1H, d, J=2Hz, Ar-H), 9.01 (2H, s, Triazole-H), 11.05 (1H, br s, indole NH). MS, CI+, m/z for (M+H)+ =243.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][C@H:28]4[C@H:32]([OH:33])[CH2:31][NH:30][CH2:29]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:30]1[CH2:31][C@@H:32]([OH:33])[C@H:28]([NH:27][C:25]([C:21]2[C:17]3=[N:18][CH:19]=[CH:20][C:15]([C:8]4[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)=[C:16]3[NH:23][C:22]=2[CH3:24])=[O:26])[CH2:29]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@@H]4CNC[C@H]4O)c(C)[nH]c23)c1
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@@H]4CN(C(C)=O)C[C@H]4O)c(C)[nH]c23)c1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-N-[(3R*,4R*)-4-hydroxypyrrolidin-3-yl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f17) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Cl[CH:2]([CH3:17])[C:3]([C:5]1[C:6]([CH:14]([CH3:16])[CH3:15])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12)=[O:4].[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Na+].[I-]>CO>[CH2:18]([NH:25][CH:2]([CH3:17])[C:3]([C:5]1[C:6]([CH:14]([CH3:16])[CH3:15])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12)=[O:4])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(Cl)C(=O)c1c(C(C)C)nn2ccccc12
Reactant: NCc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CC(NCc1ccccc1)C(=O)c1c(C(C)C)nn2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2.51 g of 2-chloro-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one and 2.25 ml of benzylamine in 20 ml of MeOH was added 10 mg of NaI and the solution was refluxed for 4 hours, then stirred at RT overnight. Crude 2-(benzylamino)-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one was purified on an Al2O3 column to yield 2.51 g of pure compound. Compound 1071.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:16]3=[CH:17][C:18]4[O:22][CH2:21][O:20][C:19]=4[CH:23]=[C:15]3[O:14][CH2:13]1)[C:5](=[O:12])[N:6]2[CH3:11].BrC1C=CC=C2C=1C1(COC3C=C4C(=CC1=3)CCO4)C(=O)N2CC1OC(C(F)(F)F)=CC=1.[F:56][C:57]1[N:62]=[CH:61][C:60](B(O)O)=[CH:59][CH:58]=1.N1C=C(B(O)O)C=NC=1>>[F:56][C:57]1[N:62]=[CH:61][C:60]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]2([C:16]4=[CH:17][C:18]5[O:22][CH2:21][O:20][C:19]=5[CH:23]=[C:15]4[O:14][CH2:13]2)[C:5](=[O:12])[N:6]3[CH3:11])=[CH:59][CH:58]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Agent: O=C1N(Cc2ccc(C(F)(F)F)o2)c2cccc(Br)c2C12COc1cc3c(cc12)CCO3
Agent: OB(O)c1cncnc1
Product: CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(-c3ccc(F)nc3)cccc21

Procedure:
Following the procedure as described in EXAMPLE 4.14, and making non-critical variations using 4′-bromo-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromo-1′-{[5-(trifluoromethyl)-2-furyl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and (6-fluoropyridin-3-yl)boronic acid to replace pyrimidine-5-boronic acid, the title compound was obtained (100%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.75-7.65 (m, 1H), 7.42-7.30 (m, 1H), 7.19-7.05 (m, 1H), 7.00-6.90 (m, 1H), 6.90-6.80 (m, 1H), 6.78-6.64 (m, 1H), 6.24-6.12 (m, 2H), 5.92-5.79 (m, 2H), 4.74-4.63 (m, 1H), 4.40-4.29 (m, 1H), 3.34-3.26 (m, 3H); MS (ES+) m/z 391.4 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[CH:18]1([N:13]2[C:12]([C:34]3[CH:35]=[CH:36][C:31]([CH3:30])=[CH:32][CH:33]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20][CH2:21]1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Product: Cc1ccc(-c2c3c(nn2C2CCC2)CCNCC3)cc1
Yield: 95.2 %

Procedure:
The title compound (117 mg) was prepared according to Example 263 using 192 mg of 2-cyclobutyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 276, Step A) and 83 mg of 4-methylphenylboronic acid. MS (ESI): exact mass calculated for C18H23N3, 281.19. found, m/z 282.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.41-7.32 (m, 2H), 7.23-7.13 (m, 2H), 4.71-4.65 (m, 2H), 4.00-3.41 (m, 2H), 3.32-3.05 (m, 3H), 2.95-2.79 (m, 2H), 2.67-2.58 (m, 2H), 2.43 (s, 3H), 2.28-2.23 (m, 2H), 1.84-1.71 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10](=[O:15])[N:9]([CH3:16])[C:8]=2[N:7]=[CH:6]1)[CH3:2].Cl[CH2:18][CH2:19][CH2:20][CH2:21][P:22]([O:27][CH2:28][CH3:29])(=[O:26])[O:23][CH2:24][CH3:25].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:18][CH2:19][CH2:20][CH2:21][P:22](=[O:26])([O:27][CH2:28][CH3:29])[O:23][CH2:24][CH3:25])[C:10](=[O:15])[N:9]([CH3:16])[C:8]=2[N:7]=[CH:6]1)[CH3:2]
Reactant: CCOP(=O)(CCCCCl)OCC
Reactant: CCOCn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOCn1cnc2c1c(=O)n(CCCCP(=O)(OCC)OCC)c(=O)n2C
Temperature: 70 °C

Procedure:
44.8 g (0.2 mol) of 7-ethoxymethyl-3-methylxanthine were suspended in 500 ml of DMF, treated with 55 g (0.24 mol) of diethyl 4-chlorobutane-phosphonate and 50 g (0.32 mol) of activated potassium carbonate and heated at 70° C. for 4 hours and filtered, the filtrate was concentrated under reduced pressure and the oily residue which remained was taken up in ethyl acetate. filtered again and crystallized from diisopropyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.O[N:28]=[C:29]([NH2:33])[CH:30]([CH3:32])[CH3:31].[H-].[Na+]>C1COCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]3[O:20][N:33]=[C:29]([CH:30]([CH3:32])[CH3:31])[N:28]=3)=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: CC(C)C(N)=NO
Reactant: COC(=O)c1ccc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)ccc1-c1nc(C(C)C)no1
Yield: 17 %

Procedure:
The title compound was prepared by following the procedure as described for Example-40 by using methyl 4-(3-(2,6-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (Intermediate-21, 0.100 g, 0.25 mmol), N′-hydroxyisobutyrimidamide (0.077 g, 0.529 mmol), sodium hydride (0.020 g, 0.50 mmol) and dry THF (5.0 mL) at RT to afford 0.019 g of desired product. 1H NMR (DMSO-d6): 1.31 (d, J=6.9 Hz, 6H), 3.12 (m, 1H), 3.95 (s, 3H), 7.65-7.78 (m, 4H), 7.56 (s, 1H), 8.09 (d, J=8.7 Hz, 1H), 12.83 (br s, 1H); MS (m/z): 447.96 [M+H]+.
Reaction SMILES: [CH2:1]1COCC1.[C:6]1([CH:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[C:6]1([CH:12]2[CH2:17][CH2:16][C:15](=[CH2:1])[CH2:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C1CCC(c2ccccc2)CC1
Reactant: C1CCOC1
Solvent: Cc1ccccc1
Product: C=C1CCC(c2ccccc2)CC1
Reaction time: 0.17 h
Yield: 78 %

Procedure:
BDAM (3.00 grams) was suspended in 40 milliliters of toluene and 2 molar equivalents of THF were added at 0° C. After a homogeneous solution was formed, 1 molar equivalent (2 milliliters) of TEAL was added. After 10 minutes of stirring, 2.50 grams of 4-phenylcyclohexanone were added. After 3 hours of stirring the reaction mixture was hydrolyzed and worked up as described in Example 1. A total of 1.93 grams of 4-phenyl-1-methylenecyclohexane was isolated (78% yield).
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[C:5]([F:10])[C:4]=1[C@H:11]([NH2:13])[CH3:12].C([O:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:34]2[C:42]3[C:37](=[CH:38][C:39]([C:43](O)=[O:44])=[CH:40][CH:41]=3)[C:36]([CH3:46])=[C:35]2[CH3:47])=[CH:29][CH:28]=1)=[O:20])(C)(C)C>>[CH3:47][C:35]1[N:34]([CH2:33][C:30]2[CH:31]=[CH:32][C:27]([C:22]3[C:21]([C:19]([OH:20])=[O:18])=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:28][CH:29]=2)[C:42]2[C:37]([C:36]=1[CH3:46])=[CH:38][C:39]([C:43](=[O:44])[NH:13][C@@H:11]([C:4]1[C:5]([F:10])=[CH:6][CH:7]=[C:8]([F:9])[C:3]=1[F:2])[CH3:12])=[CH:40][CH:41]=2
Reactant: C[C@@H](N)c1c(F)ccc(F)c1F
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Agent: Cl
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@H](C)c3c(F)ccc(F)c3F)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (R)-1-(2,3,6-trifluorophenyl)ethanamine hydrochloride and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 557 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5](I)=[CH:4][N:3]=1.[CH3:10][O:11][C:12](=[O:21])[C:13]1[CH:18]=[C:17]([C:19]#[CH:20])[CH:16]=[N:15][CH:14]=1>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[CH3:10][O:11][C:12](=[O:21])[C:13]1[CH:18]=[C:17]([C:19]#[C:20][C:5]2[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][C:6]=2[NH2:8])[CH:16]=[N:15][CH:14]=1
Reactant: Nc1cc(Cl)ncc1I
Reactant: C#Cc1cncc(C(=O)OC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)c1cncc(C#Cc2cnc(Cl)cc2N)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A 250 mL round bottom flask flushed with N2 was charged with 2-chloro-5-iodo-pyridin-4-ylamine (1.00 g, 3.93 mmol), 5-ethynyl-nicotinic acid methyl ester (0.633 g, 3.93 mmol), copper(I) iodide (0.037 g, 0.196 mmol), bis(triphenylphosphine)palladium(II) chloride (0.138 g, 0.196 mmol) and triethyl amine (50 mL). The reaction mixture was stirred at 100° C. for 3 h. The reaction was cooled to room temperature, filtered and the precipitate washed thoroughly with ethyl acetate. The filtrate was washed with water twice. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford crude product 5-(4-amino-6-chloro-pyridin-3-ylethynyl)-nicotinic acid methyl ester as a brown solid which was taken onto next step without any purification. ESI-MS: m/z 288.0 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.Cl[C:12](OC(Cl)(Cl)Cl)=[O:13]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([F:9])[C:5]([N:6]=[C:12]=[O:13])=[C:4]([F:10])[CH:3]=1
Reactant: Nc1c(F)cc(Cl)cc1F
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C=Nc1c(F)cc(Cl)cc1F

Procedure:
40 g of 4-chloro-2,6-difluoroaniline were dissolved in 300 ml of absolute toluene. With stirring, 100 ml of trichloromethyl chloroformate were added dropwise at 20° C. The mixture was slowly heated to reflux. After three and half hours, the mixture was concentrated and the resulting isocyanate was used directly for the synthesis of intermediate 3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:38]([O:40][C:41]([C:43]1[N:44]([CH2:49][CH2:50][CH2:51]Br)[CH:45]=[N:46][C:47]=1[CH3:48])=[O:42])[CH3:39].N1C=CN=C1.[H-].[Na+]>CN(C=O)C.C1COCC1>[CH2:38]([O:40][C:41]([C:43]1[N:44]([CH2:49][CH2:50][CH2:51][O:29][C:26]2[CH:25]=[CH:24][C:23]([C:22]([N:15]3[C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[C@H:12]([N:8]([C:9](=[O:11])[CH3:10])[C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH2:13][C@@H:14]3[CH3:31])=[O:30])=[CH:28][CH:27]=2)[CH:45]=[N:46][C:47]=1[CH3:48])=[O:42])[CH3:39]
Reactant: CCOC(=O)c1c(C)ncn1CCCBr
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)ncn1CCCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Temperature: 80 °C

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide was dissolved in DMF at room temperature and K2CO3 was added. 3-(3-Bromo-propyl)-5-methyl-3H-imidazole-4-carboxylic acid ethyl ester (prepared from the dibromide and the corresponding imidazole with NaH in THF) was added and the reaction was allowed to heat to 80° C. overnight. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO4, filtered and concentrated down. The crude residue was purified by silica gel chromatography (2% MeOH/95% CH2Cl2 to 10% MeOH/90% CH2Cl2) to afford (2S,4R)-3-[3-(4-{4-[acetyl(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-propyl]-5-methyl-3H-imidazole-4-carboxylic acid ethyl ester. The ester (0.080 g, 0.12 mmol) was hydrolyzed to the acid by dissolving in tetrahydrofuran and ethanol and sodium hydroxide (1N) was added. The mixture was stirred at room temperature 16 hours. The mixture was cooled to room temperature, acidified to form a white precipitate. The solid was filtered to give (2S,4R)-3-[3-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-propyl]-5-methyl-3H-imidazole-4-carboxylic acid in 61% yield.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.C([Li])CCC.[CH3:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C(OCC)C>[S:4]1[CH:5]=[CH:6][C:2]([C:22]([OH:28])([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])=[C:3]1[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCCCCC(=O)CCCCC
Reactant: Brc1ccsc1-c1cccs1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCCCC(O)(CCCCC)c1ccsc1-c1cccs1
Reaction time: 0.25 h
Yield: 61.9 %

Procedure:
3-Bromo-2,2′-bithiophene (IIIa) (0.500 g, 2.04 mmol) in dry diethylether (20 mL) was added slowly to a solution of n-butyllithium (1.6 M in hexane, 1.25 mL, 2.04 mmol) in dry diethylether (20 mL) at −78° C. over 2 h under N2. The mixture was stirred for 15 minutes at the same temperature. Freshly distilled 6-undecanone (0.42 mL, 2.04 mmol) was added via a syringe to the mixture at −78° C., followed by stirring overnight at room temperature. The reaction was quenched with an aqueous NH4Cl-solution (2.5 M, 10 mL) and water (10 mL) at 0° C. The organic phase was separated and the aqueous phase was extracted with diethylether. The combined organic phases were washed with brine, dried over MgSO4 and evaporated under reduced pressure to give a crude oil. The oily residue was purified by column chromatography (eluent hexane/EtOAc 90:10) to afford the title compound (IIu) as a yellow oil (0.425 g, 62.0%). 1H-NMR (CDCl3): δ=7.35 (dd, J=1.3 Hz, J=5.3 Hz, 1H), 7.23 (d, J=5.4 Hz, 1H), 7.09 (dd, J=1.3 Hz, J=3.5 Hz, 1H), 7.01 (dd, J=5.3, J=3.5 Hz, 1H), 6.98 (d, J=5.4 Hz, 1H), 2.02 (s, 1H), 1.83-1.60 (m, 4H), 1.42-1.05 (m, 12H), 0.84 (t, J=6.7 Hz, 6H). 13C-NMR (CDCl3): δ=146.06, 136.07, 129.93, 129.19, 128.92, 127.78, 127.31, 125.41, 78.68, 43.60, 32.75, 24.00, 23.21, 14.70.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[SH:9].[CH3:10]I>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[S:9][CH3:10]
Reactant: Cc1cccc(C)c1S
Reactant: CI
Product: CSc1c(C)cccc1C

Procedure:
This compound was synthesized from 2,6-dimethylthiophenol and methyl iodide according to general method 4 described earlier.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:35])[N:6]2[CH2:16][CH2:17][CH2:18][N:19]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([OH:34])=[O:33])=[CH:27][CH:26]=1)[CH2:20][CH2:21][CH2:22][OH:23].[CH3:36]O>Cl[Si](C)(C)C>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:35])[N:6]2[CH2:16][CH2:17][CH2:18][N:19]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][C:32]([O:34][CH3:36])=[O:33])=[CH:29][CH:30]=1)[CH2:20][CH2:21][CH2:22][OH:23]
Reactant: CO
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(CCCO)Cc3ccc(CC(=O)O)cc3)c2n1
Agent: C[Si](C)(C)Cl
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(CCCO)Cc3ccc(CC(=O)OC)cc3)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the product from step (ii) (0.38 g) in MeOH, chlorotrimethylsilane (3 mL) was added and the mixture stirred at rt for 1 hr. The solvent was removed to give the subtitle compound as a cream solid (0.39 g); MS multimode (+) 501.