Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][C:4]([SH:7])=[CH:3][CH:2]=1.C[O-].[Na+].CN(C=O)C.C1(C)C=CC(S(O[CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36](=[O:43])[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:31]=2)[C:28]#[N:29])(=O)=O)=CC=1>CO.O>[C:1]1([CH3:8])[CH:6]=[CH:5][C:4]([S:7][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36](=[O:43])[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:31]=2)[C:28]#[N:29])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S)cc1
Reactant: Cc1ccc(S(=O)(=O)OC(C#N)c2cccc(C(=O)c3ccccc3)c2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: Cc1ccc(SC(C#N)c2cccc(C(=O)c3ccccc3)c2)cc1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
p-Toluenethiol (372 mg) was dissolved in 2 ml of anhydrous methanol, and 1.20 ml of a 2.5 M methanol solution of sodium methoxide was added at room temperature in an atmosphere or argon. The mixture was cooled to -15° C., and stirred. Then, 4 ml of an anhhdrous DMF solution containing 1.170 g of O-(p-toluenesulfonyl)-m-benzoylmandelonitrile was added over 10 minutes. With continued stirring, the mixture was gradually warmed, and in 30 minutes, the temperature rose to 0° C. At this time, 30 ml of water was added to the reaction mixture, and the mixture was extracted with 20 ml of methylene chloride three times. The extract was washed with 20 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; benzene) to afford 837 mg (yield 82%) of alpha-(p-tolylthio)(m-benzoylphenyl)acetonitrile as colorless crystals.
Reaction SMILES: [NH2:1][C:2]([C:5]1[CH:13]=[CH:12][C:8]([CH2:9][CH2:10][NH2:11])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[C:14]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)#[N:15]>ClCCl.C(N(CC)CC)C>[NH2:1][C:2]([C:5]1[CH:13]=[CH:12][C:8]([CH2:9][CH2:10][NH:11][S:22]([C:19]2[CH:18]=[CH:17][C:16]([C:14]#[N:15])=[CH:21][CH:20]=2)(=[O:24])=[O:23])=[CH:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(N)c1ccc(CCN)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(N)c1ccc(CCNS(=O)(=O)c2ccc(C#N)cc2)cc1

Procedure:
4-(1-Amino-1-methylethyl)phenethylamine (A18, 2.132 g) was treated with 4-cyanophenylsulphonyl chloride (2.63 g) in dichloromethane (35 ml) and triethylamine (1.8 ml) to give N-{2-[4-(1-amino-1-methylethyl)phenyl]ethyl}-4-cyanobenzenesulphonamide, as an oil.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:20][Si:21]([CH3:36])([CH3:35])[CH2:22][CH2:23][O:24][C:25](ON1C(=O)CCC1=O)=[O:26]>O1CCOCC1.O>[CH3:20][Si:21]([CH3:36])([CH3:35])[CH2:22][CH2:23][O:24][C:25]([NH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1)=[O:26]
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Reactant: CCOC(=O)[C@H]1CC[C@H](N)CC1
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H]1CC[C@H](NC(=O)OCC[Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Ethyl trans-4-aminocyclohexanecarboxylate (J. Med. Chem., 1971, 14, 600-614) (29.5 g, 143 mmol) was dissolved in 1,4-dioxane (290 ml) and water (290 ml), triethylamine (30.0 ml, 215 mmol) and 1-[2-(trimethylsilyl)ethoxycarbonyloxy]pyrrolidine-2,5-dione (40.8 g, 157 mmol) were added under ice cooling and the resulting mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated and then the residue was diluted with ethyl acetate and washed with 10% aqueous citric acid solution, saturated sodium bicarbonate solution, and brine in that order. The organic layer was dried over anhydrous sodium sulfate and the solvent was concentrated under reduced pressure to give 44.3 g (98%) of the title compound as colorless needle-like crystals.
Reaction SMILES: C[N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].C[N:18]1[CH2:23][CH2:22][C:21]2=[C:24]([CH:27]=O)[NH:25][CH:26]=[C:20]2[C:19]1=[O:29].N1CCCCC1>C(O)C>[CH3:16][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:27][C:24]1[NH:25][CH:26]=[C:20]2[C:21]=1[CH2:22][CH2:23][NH:18][C:19]2=[O:29])(=[O:4])=[O:5]
Reactant: CN1CCc2c(c[nH]c2C=O)C1=O
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Solvent: C1CCNCC1
Solvent: CCO
Product: CNS(=O)(=O)c1ccc2c(c1)C(=Cc1[nH]cc3c1CCNC3=O)C(=O)N2
Temperature: 80 °C

Procedure:
A mixture of 2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid dimethylamide (48 mg, 0.2 mmol), 5-methyl-4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (35.6 mg, 0.2 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 80° C. for 4 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give the title compound.
Reaction SMILES: [C:1]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([O:41][CH3:42])[CH2:40][N:10]3[C:11](=[O:39])[C@@H:12]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][C@@H:20]4[CH2:25][C@@:21]4([C:26]([O:28]CC)=[O:27])[NH:22][C:23](=[O:24])[C@@H:9]3[CH2:8]2)=[CH:3][CH:2]=1.O.CO>O1CCCC1>[C:1]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:2]=[CH:3][C:4]([C@@:7]2([O:41][CH3:42])[CH2:40][N:10]3[C:11](=[O:39])[C@@H:12]([NH:31][C:32]([O:34][C:35]([CH3:37])([CH3:38])[CH3:36])=[O:33])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][C@@H:20]4[CH2:25][C@@:21]4([C:26]([OH:28])=[O:27])[NH:22][C:23](=[O:24])[C@@H:9]3[CH2:8]2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@](OC)(c3ccc(-c4ccccc4)cc3)C[C@H]1C(=O)N2
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@](OC)(c3ccc(-c4ccccc4)cc3)C[C@H]1C(=O)N2
Agent: CO[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@H]2C(=O)N[C@]3(C(=O)O)C[C@H]3/C=C\CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N2C1
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CO[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@H]2C(=O)N[C@]3(C(=O)O)C[C@H]3C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (2R,6S,13aS,14aR,16aS,Z)-ethyl 2-(biphenyl-4-yl)-6-(tert-butoxycarbonylamino)-2-methoxy-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate (56 mg, 0.085 mmol), LiOH monohydrate (40.7 mg, 1.70 mmol) in tetrahydrofuran (2 mL)/water (0.5 mL)/MeOH (1 mL) was stirred at rt for 18 h. It was then concentrated in vacuo, and washed with ether. The aqueous phase was adjusted to pH=4 using 1N HCl and extracted with EtOAc. The EtOAc extract was dried over MgSO4, filtered and concentrated in vacuo to give 52 mg (97%) of (2R,6S,13aS,14aR,16aS,Z)-2-(biphenyl-4-yl)-6-(tert-butoxycarbonylamino)-2-methoxy-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylic acid as an off-white solid.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([CH3:10])([CH3:9])[C:3]1=[O:11].C1C=CC=CC=1.[CH2:18](O)[CH:19]([CH3:21])[CH3:20].CC1C=CC(S(O)(=O)=O)=CC=1>O>[CH3:1][C:2]1[C:3](=[O:11])[C:4]([CH3:10])([CH3:9])[CH2:5][CH2:6][C:7]=1[O:8][CH2:18][CH:19]([CH3:21])[CH3:20]
Reactant: CC1C(=O)C=CC(C)(C)C1=O
Reactant: CC(C)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC1=C(OCC(C)C)CCC(C)(C)C1=O
Temperature: 25 °C

Procedure:
The compound 2,6,6-trimethylcyclohexen-1,3-dione (43.6 g) was added to a mixture of benzene (250 ml), isobutanol (50 ml) and PTSA (500 mg) and heated under reflux for 3 hr in conjunction with a Dean and Stark water separator. The reaction was then cooled to room temperature, washed with aqueous sodium carbonate solution and brine and taken to dryness "in vacuo". Distillation of residue through a 6" vacuum jacketed vigreaux column yielded pure 2,6,6-trimethyl-3-isobutoxycyclohex-2-en-1 one (54.6 g) bp 104°-107°.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([C:11]([Cl:13])=[O:12])[C:5]2[O:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.[CH2:14]([N:16]([CH2:20][CH3:21])[CH2:17][CH2:18][NH2:19])[CH3:15]>C(Cl)Cl>[ClH:13].[Br:1][C:2]1[CH:10]=[C:9]([C:11]([NH:19][CH2:18][CH2:17][N:16]([CH2:20][CH3:21])[CH2:14][CH3:15])=[O:12])[C:5]2[O:6][CH:7]=[CH:8][C:4]=2[CH:3]=1
Reactant: O=C(Cl)c1cc(Br)cc2ccoc12
Reactant: CCN(CC)CCN
Solvent: ClCCl
Product: CCN(CC)CCNC(=O)c1cc(Br)cc2ccoc12
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.8 %

Procedure:
To an ice-cooled solution of 5-bromobenzo[b]furan-7-carboxylic acid chloride (1.5 g, 5.8 mmol) in 15 ml of CH2Cl2, there was added N,N-diethylethylenediamine (0.74 g, 6.4 mmol) in 10 ml of CH2Cl2. After stirring at ambient temperature overnight, the precipitate was collected on a filter to give the crude amide (1.14 g, 53.2%). This was recrystallized from ethanol (decolorization with charcoal) to give 0.54 g (24.8%) of the desired amide as a white solid, mp 202°-203.5° C. IR (KBr) 1675 (C=0) cm-1.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([NH:22][C:23]3[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=3)[CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[C:11]([CH3:32])[CH:10]=2)=[N:7][CH:8]=1)[CH3:2].[NH:33]1[CH2:38][CH2:37][CH2:36][C@@H:35]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:34]1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C>CN(C)C=O.O>[CH2:1]([C:3]1[CH:8]=[N:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([C:27]([N:33]4[CH2:38][CH2:37][CH2:36][C@@H:35]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:34]4)=[O:28])=[CH:30][CH:31]=3)[CH2:16][CH2:17][C:18]([F:20])([F:21])[F:19])=[C:11]([CH3:32])[CH:10]=2)=[N:5][CH:4]=1)[CH3:2]
Reactant: CCOC(=O)[C@@H]1CCCNC1
Reactant: CCc1cnc(-c2ccc(C(CCC(F)(F)F)Nc3ccc(C(=O)O)cc3)c(C)c2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)[C@@H]1CCCN(C(=O)c2ccc(NC(CCC(F)(F)F)c3ccc(-c4ncc(CC)cn4)cc3C)cc2)C1

Procedure:
A solution of 4-((1-(4-(5-ethylpyrimidin-2-yl)-2-methylphenyl)-4,4,4-trifluorobutyl)amino)benzoic acid, ethyl (3R)-piperidine-3-carboxylate (0.186 mL), 1-hydroxybenzotriazole monohydrate (0.185 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.231 g) and diisopropylethylamine (0.211 mL) in dimethylformamide (3 mL) was stirred at room temperature overnight. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.574 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1.[NH:32]1[CH2:35][CH:34]([OH:36])[CH2:33]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([CH2:28][N:32]4[CH2:35][CH:34]([OH:36])[CH2:33]4)=[CH:30][CH:31]=3)[N:20]=2)[N:10]=[N:9]1
Reactant: OC1CNC1
Reactant: O=Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1
Product: OC1CN(Cc2ccc(-c3noc(-c4nnn(-c5ccccc5F)c4-c4ccncc4)n3)cc2)C1

Procedure:
The title compound was prepared following the procedure described for Example 94, but starting from 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde, obtained as described in Example 113, Step 1, (100 mg; 0.24 mmol) and 3-azetidinol (35.4 mg; 0.48 mmol) to give Example 135 as a white solid. 1H NMR: (DMSO-d6, 400 MHz) δ 8.75 (2H, dd, J=4.7, 1.5 Hz), 7.97-7.87 (3H, m), 7.76-7.69 (1H, m), 7.61 (2H, dd, J=4.7, 1.6 Hz), 7.57-7.47 (4H, m), 5.35 (1H, d, J=6.4 Hz), 4.27-4.19 (1H, m), 3.67 (2H, s), 3.55 (2H, dd, J=7.4, 5.8 Hz), 2.83 (2H, t, J=6.6 Hz). LC/MS (Method C): 470 (M+H)+. HPLC (Method E) Rt 2.13 min (Purity: 98.2%).
Reaction SMILES: [F:1][C:2]1[C:3]([C:15]#N)=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[CH3:14].[F:17][C:18]1[CH:23]=[CH:22][C:21]([Mg]Br)=[CH:20][CH:19]=1.Cl.[OH-:27].[Na+]>C1COCC1.C(Cl)Cl.O>[F:1][C:2]1[C:3]([C:15]([C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)=[O:27])=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[CH3:14]
Reactant: [OH-]
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: Cc1ccncc1-c1ccnc(C#N)c1F
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccncc1-c1ccnc(C(=O)c2ccc(F)cc2)c1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 65.3 %

Procedure:
To a solution of 3′-fluoro-4-methyl-3,4′-bipyridine-2′-carbonitrile (0.029 g, 0.136 mmol) in THF (Volume: 0.680 ml) cooled to 0° C. was added (4-fluorophenyl) magnesium bromide (0.170 ml, 0.340 mmol). The reaction mixture was allowed to stir at room temperature for 5 hr. Water and ice were carefully added, followed by acidification with 6 M HCl. After stirring for 20 min, CH2Cl2 was added and the pH was adjusted to 8.5 with aqueous 4 M NaOH. The layers were separated and the aqueous phase was extracted with CH2Cl2 (9×). The organics layers were combined, dried over Na2SO4, filtered, and concentrated to afford a residue. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (12 g column, 30 mL/min, 70-90% EtOAc in hexanes over 14 min, tr=8 min) gave the title compound (29 mg, 0.089 mmol, 65.3% yield). ESI MS (M+H)+=311.1.
Reaction SMILES: [Cl:1]C(OC(Cl)=O)C.C([N:21]1[CH2:24][CH:23]([O:25][CH2:26][CH:27]=[CH:28][CH3:29])[CH2:22]1)(C1C=CC=CC=1)C1C=CC=CC=1.CO>ClC(Cl)C>[ClH:1].[CH2:26]([O:25][CH:23]1[CH2:24][NH:21][CH2:22]1)[CH:27]=[CH:28][CH3:29]
Reactant: CC(Cl)OC(=O)Cl
Reactant: CC=CCOC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CC(Cl)Cl
Solvent: CO
Product: CC=CCOC1CNC1
Product: Cl
Temperature: 70 °C
Reaction time: 1 h

Procedure:
1-Chloroethylchloroformate (140 μL, 1.28 mmol) was added to a solution of 1-benzhydryl-3-(but-2-enyloxy)-azetidine (290 mg, 0.98 mmol) in dichloroethane (5 mL) at room temperature. The reaction mixture was then heated up to 70° C. and stirred for 1 hour. After cooling down to room temperature, methanol (5 mL) was added and the reaction mixture was stirred for an additional 1 hour at 70° C. After concentration to dryness, the crude mixture was triturated in pentane (2×15 mL) to give a yellow solid (161 mg, quantitative) which was used in the next step without further purification.
Reaction SMILES: C(NC1C=CC(S([N:14]=[N+:15]=[N-])(=O)=O)=CC=1)(=O)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:20][CH:19]=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24](=[N+:14]=[N-:15])[C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:23]=1
Reactant: COC(=O)Cc1ccc(Cl)cc1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COC(=O)C(=[N+]=[N-])c1ccc(Cl)cc1
Yield: 83.2 %

Procedure:
A solution of 4-acetamidobenzenesulfonyl azide (1.43 g, 5.96 mmol) and methyl 2-(4-chlorophenyl)acetate (1 g, 5.42 mmol) in acetonitrile (27 mL) was cooled to 0° C. DBU (0.907 g, 0.891 mL, 5.96 mmol) was then added dropwise to the reaction mixture. The mixture was allowed to stir over night, after which it was passed through a plug of silica and purified by column chromatography (EtOAc) to give methyl 2-(4-chlorophenyl)-2-diazoacetate (0.95 g, 83%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)=[O:4].[C:13]([O:17][C:18](=[O:21])[CH:19]=[CH2:20])([CH3:16])([CH3:15])[CH3:14].N12CCN(CC1)CC2>C(OCC)(=O)C.CCCCCC>[C:13]([O:17][C:18](=[O:21])[C:19](=[CH2:20])[CH:9]([OH:10])[C:8]1[CH:11]=[CH:12][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: C1CN2CCN1CC2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C=C(C(=O)OC(C)(C)C)C(O)c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 73 %

Procedure:
4-(methoxycarbonyl)benzaldehyde (3.3 g, 20 mM), t-butylacrylate (3.5 ml, 24 mM) and 1,4-diazabicyclo[2,2,2]octane (449 mg, 4 mM) were mixed and stirred in a vessel at room temperature for 5 days. The resulting mixture was extracted with ethyl ether. The organic layer was separated, washed with 2N hydrochloric acid, water and an aqueous sodium bicarbonate solution in order, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/19), to obtain 4.1 g of the title compound as a white solid (yield 73%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:38]([O:40][C:41]([CH:43]1[C@@H:48]2[C@H:44]1[CH2:45][NH:46][CH2:47]2)=[O:42])[CH3:39]>>[CH2:38]([O:40][C:41]([CH:43]1[C@@H:48]2[C@H:44]1[CH2:45][N:46]([C:32]([N:12]1[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=[C:11]1[C:8]1[CH:9]=[N:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][C:7]=1[O:35][CH2:36][CH3:37])=[O:33])[CH2:47]2)=[O:42])[CH3:39]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CCOC(=O)C1[C@H]2CNC[C@@H]12
Product: CCOC(=O)C1[C@H]2CN(C(=O)N3C(c4cnc(C(C)(C)C)cc4OCC)=N[C@@](C)(c4ccc(Cl)cc4)[C@@]3(C)c3ccc(Cl)cc3)C[C@@H]12

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with (1S,5R)-3-aza-bicyclo-[3.1.0]hexane-6-carboxylic acid ethyl ester (Tyger Scientific) to give the title compound. HR-MS (ES, m/z) calculated for C37H43Cl2N4O4 [(M+H)+] 677.2656, observed 677.2655.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[O:14])=[N:9][CH:8]=1)C.C(N1CCCCC1=O)(OC(C)(C)C)=O.C1(N)CCCCC1.[CH3:50][N:51]([CH3:56])[S:52](Cl)(=[O:54])=[O:53]>>[CH:22]1([N:15]([CH:16]2[CH2:21][CH2:20][N:19]([S:52](=[O:54])(=[O:53])[N:51]([CH3:56])[CH3:50])[CH2:18][CH2:17]2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:3])=[O:28])=[CH:8][N:9]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(C2CCCCC2)C2CCNCC2)s1
Reactant: CN(C)S(=O)(=O)Cl
Agent: CC(C)(C)OC(=O)N1CCCCC1=O
Solvent: NC1CCCCC1
Product: CN(C)S(=O)(=O)N1CCC(N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCCC2)CC1

Procedure:
{2-[3-Cyclohexyl-3-piperidin-4-yl-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester was pre-pared in a similar manner to the synthesis of example 12 from N-Boc piperidone, cyclo-hexylamine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl, Boc deprotection, reaction with dimethylsulfamoyl chloride and hydrolysis of the ester moiety as described in general procedure (I) gave the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH:25]1([NH2:28])[CH2:27][CH2:26]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:28][CH:25]4[CH2:27][CH2:26]4)=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: NC1CC1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NC3CC3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and cyclopropylamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.51-0.66 (m, 2H) 0.66-0.82 (m, 2H) 2.43 (s, 3H) 2.87 (dt, J=7.39, 3.51 Hz, 1H) 7.65 (dd, J=8.08, 1.52 Hz, 1H) 7.73 (s, 1H) 7.77 (d, J=7.83 Hz, 1H) 8.16 (br. s., 1H) 8.38 (d, J=5.81 Hz, 2H) 8.68 (d, J=4.04 Hz, 1H) 8.83-8.93 (m, 1H) 12.92-13.43 (m, 1H). MS m/z [M+H]+ 360.1
Reaction SMILES: [C:1]1([C@@H:7]2[C:9]3([CH2:13][CH2:12][CH2:11][CH2:10]3)[C@H:8]2[C:14](O)=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19]1[C:24]([NH2:25])=[CH:23][CH:22]=[C:21]([O:26][CH3:27])[N:20]=1>>[CH3:17][O:18][C:19]1[C:24]([NH:25][C:14]([C@@H:8]2[C:9]3([CH2:13][CH2:12][CH2:11][CH2:10]3)[C@H:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:15])=[CH:23][CH:22]=[C:21]([O:26][CH3:27])[N:20]=1
Reactant: COc1ccc(N)c(OC)n1
Reactant: O=C(O)[C@H]1[C@H](c2ccccc2)C12CCCC2
Product: COc1ccc(NC(=O)[C@H]2[C@H](c3ccccc3)C23CCCC3)c(OC)n1
Yield: 53.1 %

Procedure:
trans-2-Phenylspiro[2.4]heptane-1-carboxylic acid (300 mg, 1.39 mmol) and 2,6-dimethoxy-pyridin-3-ylamine (214 mg, 1.39 mmol) were reacted as described under General Procedure D to furnish the title compound (260 mg, 52%) as a purple solid. 1H NMR (300 MHz, CDCl3) δ 8.54 (d, J=8.2 Hz, 1H), 7.61 (br s, 1H), 7.32-7.14 (m, 5H), 6.30 (d, J=8.2 Hz, 1H), 4.02 (s, 3H), 3.89 (s, 3H), 2.87 (d, J=5.7 Hz, 1H), 2.05 (d, J=5.7 Hz, 1H), 1.93-1.90 (m, 2H), 1.67-1.42 (m, 6H). mp 131-133° C. ESIMS m/z [M+H]+ 353.2.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[CH2:5]([C:8]1[N:9]([CH2:21][CH2:22][CH2:23][CH:24]=O)[C:10]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:20]=1)[CH2:6][CH3:7].[OH-].[Na+]>C(O)C.O>[CH3:3][O:2][N:4]=[CH:24][CH2:23][CH2:22][CH2:21][N:9]1[C:10]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:20]=[C:8]1[CH2:5][CH2:6][CH3:7]
Reactant: CON
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCC=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCc1nc2cnc3ccccc3c2n1CCCC=NOC
Temperature: 0 °C
Reaction time: 72 h
Yield: 105.3 %

Procedure:
Methoxylamine hydrochloride (3.37 g, 40.3 mmol) was added to a stirred solution of 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyraldehyde (10.0 g, 35.5 mmol) in ethanol (100 mL) cooled to 0° C., followed by addition of 50% sodium hydroxide solution (12.5 M, 3.2 mL, 40 mmol) in water (7 mL). The reaction mixture was allowed to warm to ambient temperature and stirred for 3 days. The reaction mixture was then concentrated under reduce pressure and diluted with dichloromethane (150 mL) and water (50 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (50 mL). The combined organics were dried over potassium carbonate, filtered and concentrated to afford 11.6 g of 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-butyraldehyde O-methyloxime as a reddish oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@@H:19]([NH2:23])[CH2:20][CH2:21][CH3:22])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C1COCC1.C(N(CC)CC)C.[C:42](Cl)(=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C@@H:19]([NH:23][C:42](=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:20][CH2:21][CH3:22])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCC[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC[C@H](NC(=O)C(C)(C)C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
To a stirred solution of (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-phenylpentan-2-amine (91a, 13 mg, 0.03 mmol) dissolved in dry THF (150 μmol) were added, at r.t., triethylamine (27.8 μl, 0.20 mmol) and pivaloyl chloride (12.3 ul, 0.1 mmo). The reaction was stirred over night. The solvent was removed under reduced pressure, and the product purified by preparative HPLC.