Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[B-](F)(F)F.[Cl:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]2=[O:26])=[CH:9][C:8]=1[N+]#N.[OH2:29]>>[Cl:6][C:7]1[C:8]([OH:29])=[CH:9][C:10]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]2=[O:26])=[C:11]([F:13])[CH:12]=1
Reactant: O
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc([N+]#N)c(Cl)cc2F)c1=O
Agent: F[B-](F)(F)F
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0 23 g of 2-chloro-5-[3,6-dihydro-2,6-dioxo -3-methyl-4-trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorobenzenediazonium tetrafluoroborate is added to a solution of 75 g of cupric nitrate trihydrate in 50 ml of water. 67 mg of cuprous oxide are added thereto and the reaction mixture is stirred at room temperature for 10 minutes. The mixture is subsequently filtered, the filtrate is extracted with 50 ml of ethyl acetate and the organic phase is washed and evaporated under reduced pressure. The resulting crude product is crystallized from diethyl ether/n-hexane. There is obtained 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-1-methyl-6 -trifluoromethyl-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[CH:9]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[CH2:20]2>>[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]2=[CH:9][C:8]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:7]=1
Reactant: COc1ccc(C=O)cc1C1CCCC1
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: COc1ccc(C=C2C(=O)Nc3ccc(Br)cc32)cc1C1CCCC1

Procedure:
3-Cyclopentyl-4-methoxybenzaldehyde was condensed with 5-bromo-2-oxindole to give 0.3 g of 5-bromo-3-(3-cyclopentyl-4-methoxybenzylidene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[CH:7]=[CH:8][C:9]([OH:22])=[C:10]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=[CH:13][C:12]=3[OH:21])[C:4]2=[CH:3][CH:2]=1.C([Li])CCC.CC(C)[O-].[La+3:32].CC(C)[O-].CC(C)[O-]>C1COCC1.CCCCCC>[La:32].[CH:17]1[CH:16]=[C:15]2[CH:14]=[CH:13][C:12]([OH:21])=[C:11]([C:10]3[C:4]4[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=4)[CH:7]=[CH:8][C:9]=3[OH:22])[C:20]2=[CH:19][CH:18]=1
Reactant: [La+3]
Agent: CC(C)[O-]
Agent: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: [La]
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 258 mg (0.90 mmol) of (R)-1,1'-bi-2-naphthol in 4.5 ml of THF Was added dropwise 0.56 ml (0.90 mmol) of a 1.6N n-butyllithium solution in hexane, at 0° C. in an argon atmosphere. After completion of the dropping, the temperature was raised to room temperature, 95 mg (0.30 mmol) of powdery lanthanum isopropoxide was added, and the mixture was stirred at room temperature for 15 hours. The insoluble matter was allowed to precipitate and the supernatant was submitted, as a lanthanum/(R)-1,1'-bi-2-naphthol complex solution (0.05 mol/l), to the reaction proper.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[C:17]([F:31])=[C:18]([NH:22][S:23]([C:26]3[S:27][CH:28]=[CH:29][N:30]=3)(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1.[CH3:32][S:33]([N:36]1[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]1)(=[O:35])=[O:34]>>[F:31][C:17]1[C:16]([C:9]2[N:10]=[C:11]([CH:13]([CH3:15])[CH3:14])[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][CH:39]3[CH2:40][CH2:41][N:36]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:37][CH2:38]3)[N:7]=2)=[CH:21][CH:20]=[CH:19][C:18]=1[NH:22][S:23]([C:26]1[S:27][CH:28]=[CH:29][N:30]=1)(=[O:25])=[O:24]
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3nccs3)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3nccs3)c2F)c(-c2ccnc(NC3CCN(S(C)(=O)=O)CC3)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-1,3-thiazole-2-sulfonamide (70 mg, 0.141 mmol) and 1-(methylsulfonyl)-4-piperidinamine (126 mg, 0.706 mmol) the title compound was obtained as an off-white solid (43 mg, 48% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.96 (d, J=1.6 Hz, 1H), 8.08 (d, J=4.3 Hz, 1H), 7.71-8.02 (m, 2H), 7.39-7.49 (m, 1H), 7.25 (d, J=7.7 Hz, 1H), 6.95-7.23 (m, 2H), 5.90-6.23 (m, 1H), 3.64-3.94 (m, 1H), 3.37-3.64 (m, 3H), 3.24 (br. s., 0H), 2.65-2.93 (m, 5H), 1.79-2.00 (m, 2H), 1.39-1.59 (m, 2H), 1.24-1.40 (m, 6H). MS (ESI): 638.1 [M+H]+.
Reaction SMILES: O.O.[Sn](Cl)Cl.[Cl:6][C:7]1[C:16]([N+:17]([O-])=O)=[C:15]2[C:10]([N:11]=[CH:12][C:13]([CH3:20])=[N:14]2)=[CH:9][CH:8]=1>CCOC(C)=O.C(O)C>[Cl:6][C:7]1[C:16]([NH2:17])=[C:15]2[C:10](=[CH:9][CH:8]=1)[N:11]=[CH:12][C:13]([CH3:20])=[N:14]2
Reactant: Cc1cnc2ccc(Cl)c([N+](=O)[O-])c2n1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cnc2ccc(Cl)c(N)c2n1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Tin(II)-chloride dihydrate (21.7 g, 96.12 mmol, 5.4 equiv) was added at room temperature to a solution of 7-chloro-2-methyl-8-nitro-quinoxaline (3.98 g, 17.80 mmol) in a mixture of EtOAc (56 ml) and ethanol (28 ml). After 40 minutes at 80° C., the reaction mixture was cooled to room temperature, diluted with ice water, filtered, and extracted with EtOAc. The combined organic layers were washed with concentrated aqueous NaHCO3 solution and brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford 6-chloro-3-methyl-quinoxalin-5-ylamine, which was used in the next transformation without purification. MS (ES+): 194.2 (M+H)+.
Reaction SMILES: F[C:2](F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13]N=[C:11]([NH:26][CH:27]2[CH2:32]CNC[CH2:28]2)[N:10]=1.C(=O)([O-])[O-].[K+].[K+].IC.[CH3:41][N:42]([CH3:45])[CH:43]=O>C(OCC)(=O)C>[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][CH:2]=[C:11]([NH:26][CH:27]2[CH2:28][CH2:43][N:42]([CH3:45])[CH2:41][CH2:32]2)[N:10]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: CN(C)C=O
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Product: COc1ccc(F)cc1C(=O)c1ccc(NC2CCN(C)CC2)nc1N
Temperature: 0 °C
Reaction time: 4 h
Yield: 24 %

Procedure:
To a solution of [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone trifluoroacetic acid salt (0.0575 mmol, Example 22) in N,N-dimethylformamide (1.5 mL) were added potassium carbonate (55.6 mg, 0.4024 mmol, Aldrich) and iodomethane (14.8 mg, 0.104 mmol, Aldrich 99.5%) in N,N-dimethylformamide (0.35 mL). The reaction was stirred at 0° C. for 4 hrs. The resulting mixture was diluted with ethyl acetate (30 mL), washed with water, brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified on reversed phase HPLC to give [2-Amino-6-(1-methyl-piperidin-4-ylamino)-pyridin-3-yl]-(5-fluoro-2-methoxy-phenyl)-methanone as a white solid (4.8 mg, 24% yield). HRMS, observed: 358.1810, Calcd for M+: 358.1805.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:29])([C:25]([F:28])([F:27])[F:26])[C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[Cl:32].[C:33](Cl)(=O)[O:34]C1C=CC([N+]([O-])=O)=CC=1.[NH2:46][CH2:47][C:48]([CH3:51])([OH:50])[CH3:49]>O1CCCC1>[Cl:32][C:3]1[CH:4]=[C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]([OH:29])([C:21]([F:22])([F:23])[F:24])[C:25]([F:28])([F:26])[F:27])=[CH:18][CH:19]=3)[CH2:9][CH2:8]2)[CH:30]=[CH:31][C:2]=1[NH:1][C:33]([NH:46][CH2:47][C:48]([OH:50])([CH3:51])[CH3:49])=[O:34]
Reactant: CC(C)(O)CN
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(CC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1Cl
Solvent: C1CCOC1
Product: CC(C)(O)CNC(=O)Nc1ccc(CC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.6 %

Procedure:
A solution of 2-(4-((4-(4-amino-3-chlorobenzyl)piperidin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.416 mmol, 200 mg) and 4-nitrophenyl carbonochloridate (0.416 mmol, 84 mg) in tetrahydrofuran (5 mL) was stirred at room temperature for 30 minutes. 1-Amino-2-methylpropan-2-ol (0.832 mmol, 0.106 mL, 74.1 mg) was added and the reaction was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum and the residue purified by silica column chromatography (eluent: dichloromethane-5% methanol in dichloromethane) to afford the title compound (58.5 mg). MS (ESI) m/z 596.5 [M+H]+
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([C:12]#[N:13])=[CH:7][CH:8]=2)[N:3]1[CH2:14][CH:15]=C.I([O-])(=O)(=O)=[O:18].[Na+]>O1CCOCC1.O.O=[Os](=O)(=O)=O>[O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([C:12]#[N:13])=[CH:7][CH:8]=2)[N:3]1[CH2:14][CH:15]=[O:18]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCn1c(=O)ccc2ccc(C#N)cc21
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccc2ccc(=O)n(CC=O)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 107.2 %

Procedure:
A solution of 2-oxo-1-(2-propen-1-yl)-1,2-dihydro-7-quinolinecarbonitrile (600 mg, 2.9 mmol) in 1,4-dioxane (30 ml) and water (20 ml) was cooled to 0° C. and treated with OsO4 (4% in water, 3 ml) and sodium periodate (1.4 g, 6.67 mmol). The reaction was warmed to rt; 0.6 g and then 3.7 g more of sodium periodate were added. After 4 h in total, the solvent was evaporated and residue partitioned between water and 20% methanol-DCM. The phases were separated and the organic phase was dried and evaporated to afford the desired compound (660 mg, 107%).
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:9]C(Cl)(Cl)Cl>O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C#C)C=CC=CC=1>[Br:9][C:8]#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: ClC(Cl)(Cl)Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: BrC#Cc1ccccc1
Yield: 95 %

Procedure:
In a 10 mL round-bottom flask, 1.02 g of phenylacetylene (10 mmol), 2.1 g bromotrichloromethane (10.5 mmol) and 100 mg of tetra-n-butylammonium fluoride trihydrate (0.316 mmol) were stirred at 24° C. for 15 min. The temperature of the mixture rose to 33° C. in the course of the process. Analysis of the resulting mixture showed that it contained 1.72 g of 1-bromo-2-phenylacetylene (95% yield) and 0.05 g of the unconverted phenylacetylene.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](Cl)=[O:19])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[O:19])=[CH:13][CH:12]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(CCOc2ccc(NC(=O)Cl)cc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(CCOc2ccc(N=C=O)cc2)cc1
Yield: 94.8 %

Procedure:
A solution of 4-[2-(4-methylphenyl)ethoxy]phenylcarbamyl chloride (IV) (14.4 g, 0.05 mole) in toluene (80 ml) was heated at 60° C. for 1 hour and distilled under reduced pressure to obtain 12 g of 4-[2-(4-methylphenyl)ethoxy]phenyl isocyanate (III) as white crystals (yield, 94.9%). B.P., 170°-181° C./0.9 mmHg.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[N:16][O:17][C:18]=3[C:19]3[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=3)=[O:13])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cu][C:27]#[N:28]>CN1CCCC1=O>[C:1]1([CH:7]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[N:16][O:17][C:18]=3[C:19]3[CH:24]=[CH:23][C:22]([C:27]#[N:28])=[CH:21][CH:20]=3)=[O:13])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#C[Cu]
Reactant: O=C(c1cnoc1-c1ccc(I)cc1)N1CCC(c2ccccc2)C1
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(-c2oncc2C(=O)N2CCC(c3ccccc3)C2)cc1
Temperature: 150 °C
Reaction time: 2 h
Yield: 5.2 %

Procedure:
A mixture of 4-[(3-phenylpyrrolidin-1-yl)carbonyl]-5-(4-iodophenyl)isoxazole (125 mg, 0.28 mmol) and copper(I) cyanide (101 mg, 1.13 mmol) in N-methylpyrrolidinone (5 mL) was stirred 150° C. for 2 h. Some material lost on work-up. The residue was purified on reversed phase HPLC to yield the title compound (5 mg). HRMS (ESI, pos. ion) m/z calcd for C21H17N3O2: 343.1321, found 343.1313.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C@@H:13]([NH:33][C:34](=[O:40])OC(C)(C)C)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23]3[C:28]([CH:29]([OH:31])[CH3:30])=[CH:27][CH:26]=[CH:25][N:24]3[CH:32]=2)=[CH:17][CH:16]=1.Cl.O1CCOCC1.C(N(CC)C(C)C)(C)C.[Cl:57][C:58]1[CH:59]=[C:60]([CH:75]=[CH:76][C:77]=1[O:78][CH:79]([CH3:81])[CH3:80])C(OC1C(F)=C(F)C(F)=C(F)C=1F)=O>O>[Cl:57][C:58]1[CH:59]=[C:60]([CH:75]=[CH:76][C:77]=1[O:78][CH:79]([CH3:81])[CH3:80])[C:34]([NH:33][C@@H:13]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23]3[C:28]([CH:29]([OH:31])[CH3:30])=[CH:27][CH:26]=[CH:25][N:24]3[CH:32]=2)=[CH:17][CH:16]=1)[CH2:12][N:3]1[C:2](=[O:1])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=[O:11])=[O:40]
Reactant: CC(O)c1cccn2cc(-c3ccc(C[C@@H](CN4C(=O)c5ccccc5C4=O)NC(=O)OC(C)(C)C)cc3)nc12
Reactant: CC(C)Oc1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1Cl
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1ccc(C(=O)N[C@@H](Cc2ccc(-c3cn4cccc(C(C)O)c4n3)cc2)CN2C(=O)c3ccccc3C2=O)cc1Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 99.6 %

Procedure:
A mixture of 1,1-dimethylethyl [(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]carbamate (1.79 g, 3.31 mmol) and 4M HCl in 1,4-dioxane (20 mL, 80 mmol) was stirred at room temperature for 45 minutes. The reaction was concentrated to dryness, redissolved in DMF (30 mL), and to this solution was added N,N-diisopropylethylamine (2.14 g, 16.55 mmol) and pentafluorophenyl 3-chloro-4[(1-methylethyl)oxy]benzoate (1.36 g, 3.31 mmol). The mixture was stirred overnight at room temperature, diluted with water, and extracted into ethyl acetate. The extracts were washed with water, dried (Na2SO4), and concentrated in vacuo to give the title compound (2.10 g, 100%) as a tan solid. MS (ES+) m/e 637 [M+H]+.
Reaction SMILES: C1(O[C:8](=[O:25])[NH:9][CH:10]2[CH2:15][CH2:14][C:13]([N:22]([CH3:24])[CH3:23])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)C=CC=CC=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[CH:37]1[CH2:42][CH2:41][CH2:40][NH:39][CH2:38]1>O1CCOCC1>[CH3:24][N:22]([CH3:23])[C:13]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11][CH:10]([NH:9][C:8]([N:39]2[CH2:40][CH2:41][CH2:42][CH:37]([C:31]3[C:30]4[C:34](=[CH:35][CH:36]=[C:28]([O:27][CH3:26])[CH:29]=4)[NH:33][CH:32]=3)[CH2:38]2)=[O:25])[CH2:15][CH2:14]1
Reactant: CN(C)C1(c2ccccc2)CCC(NC(=O)Oc2ccccc2)CC1
Reactant: COc1ccc2[nH]cc(C3CCCNC3)c2c1
Solvent: C1COCCO1
Product: COc1ccc2[nH]cc(C3CCCN(C(=O)NC4CCC(c5ccccc5)(N(C)C)CC4)C3)c2c1

Procedure:
The polar diastereoisomer of (4-dimethylamino-4-phenylcyclohexyl)-carbamic acid phenyl ester (330 mg, 0.98 mmole) was added to a solution of 5-methoxy-3-piperidine-3-yl-1H-indole (225 mg, 0.98 mmole) in dioxane (10 ml). The reaction mixture was then boiled under reflux for 32 hours. The reaction mixture was worked up by distilling off dioxane and diluting with water (10 ml). The reaction mixture was adjusted to pH 11 with 5M NaOH and extracted with EE (3×15 ml). The organic phase was dried with Na2SO4 and concentrated by evaporation. The polar diastereoisomer of 3-(5-methoxy-1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexyl)-amide was purified by column chromatography with methanol. It was obtained in a yield of 220 mg (47%) as a colourless solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([OH:19])=[C:8]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]=2[O:4][C:3]=1C(O)=O.N1C2C(=CC=CC=2)C=CC=1.Cl>C(OCC)(=O)C.[Cu]>[CH3:1][C:2]1[C:6]2[C:7]([OH:19])=[C:8]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[C:10]([C:11]([CH3:12])([CH3:14])[CH3:13])[C:5]=2[O:4][CH:3]=1
Reactant: Cc1c(C(=O)O)oc2c(C(C)(C)C)cc(C(C)(C)C)c(O)c12
Agent: [Cu]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccc2ncccc2c1
Product: Cc1coc2c(C(C)(C)C)cc(C(C)(C)C)c(O)c12
Temperature: 210 °C

Procedure:
A mixture of 3-methyl-4-hydroxy-5,7-di-tert-butylbenzofuran-2-carboxylic acid (0.350 g, 1.14 mmol), quinoline (1.0 mL), and copper powder (0.072 g 1.14 mmol) was heated to 210° C. until gas evolution had ceased. The mixture was cooled, diluted with ethyl acetate (30 mL) and poured into 2N HCl. The biphasic mixture was filtered through a celite pad and the layers separated. The aqueous layer was extracted with ethyl acetate (50 mL) and the combined organic layers dried (Na2SO4) and concentrated. Flash chromatography afforded 3-methyl-4-hydroxy-5,7-di-tert-butylbenzofuran, compound 10b. 1H NMR d 1.46 (9H, s), 1.49 (9H, s), 2.46 (3H, s), 5.12 (1H, s), 7.11 (1H, s), 7.29 (1H, s).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:7][CH:6]=1)C=C.CN(C)[C:20]1[CH:25]=CC=C[CH:21]=1>>[CH2:25]([C:10]1[CH:9]=[C:8]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)[CH:7]=[CH:6][C:5]=1[OH:4])[CH:20]=[CH2:21]
Reactant: CN(C)c1ccccc1
Reactant: C=CCOc1ccc(C2=NNC(=O)CC2)cc1
Product: C=CCc1cc(C2=NNC(=O)CC2)ccc1O
Yield: 87 %

Procedure:
A mixture of 6(4-allyloxyphenyl)-4,5-dihydro-3(2H)-pyridazinone (81.8g, 0.36mole; and N,N-dimethylaniline (200 ml) was heated under reflux in an atmosphere of nitrogen for 6 hours, then allowed to cool overnight. The collected product was well washed with ether to give 6-(3-allyl-4-hydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone (71.5g, 87%, m.p. 240°-244° C). Recrystallisation from 2-methoxyethanol gave the pure material of m.p. 242°-244° C. (Found: C, 67.54; H, 6.20; N, 12.04; M+, 230. C13H14N2O2 requires: C, 67.81; H, 6.13; N, 12.17%, M, 230).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([F:42])=[C:14]([CH:20]([NH:33][C:34]2[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][CH:35]=2)[C:21]2[NH:25][C:24](=[O:26])[N:23]([C:27]3[N:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[N:22]=2)[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1)(C(C)(C)C)(C)C>C(O)(=O)C.O>[F:42][C:13]1[C:12]([O:11][CH2:10][CH2:9][OH:8])=[CH:17][C:16]([O:18][CH3:19])=[CH:15][C:14]=1[CH:20]([NH:33][C:34]1[CH:35]=[CH:36][C:37]([C:38]#[N:39])=[CH:40][CH:41]=1)[C:21]1[NH:25][C:24](=[O:26])[N:23]([C:27]2[N:28]=[CH:29][CH:30]=[CH:31][N:32]=2)[N:22]=1
Reactant: COc1cc(OCCO[Si](C)(C)C(C)(C)C)c(F)c(C(Nc2ccc(C#N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(OCCO)c(F)c(C(Nc2ccc(C#N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
After dissolving 3.4 g of 4-[({3-[2-(t-butyldimethylsilanyloxy)ethoxy]-2-fluoro-5-methoxyphenyl}-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)methyl)amino]benzonitrile in 100 ml of acetic acid, 5 ml of water was added and the mixture was stirred overnight at 50° C. The reaction mixture was concentrated, and the residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (2.25 g) as a light yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]#[C:13][Si](C)(C)C)[C:5]([O:7]C)=[O:6].C.CO.[OH-].[Na+]>CCO.CCN(CC)CC.[Cu]I>[O:1]1[C:2]2[CH:3]=[C:4]([C:5]([OH:7])=[O:6])[CH:9]=[CH:10][C:11]=2[CH:12]=[CH:13]1
Reactant: COC(=O)c1ccc(C#C[Si](C)(C)C)c(O)c1
Agent: [Cu]I
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CCO
Product: O=C(O)c1ccc2ccoc2c1
Temperature: 75 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
Methyl 3-hydroxy-4-[(trimethylsilyl)ethynyl]benzoate (3.0 g, 12.1 mmol) is dissolved in 1:1 EtOH/Et3N (30 mL), is treated with CuI (114 mg, 0.6 mmol), and the reaction is warmed to 75° C. for 3 h. The mixture is treated with DARCO and MeOH (15 mL) and heated to reflux for 1 h. The reaction is filtered through a fine fritted-glass funnel, the filtrate is treated with 3N NaOH (24.2 ml, 72.5 mmol), and the mixture is stirred overnight at RT. The mixture is concentrated to dryness, the residue is dissolved in H2O (20 mL), and the pH of the mixture is adjusted to 2 with 12N HCl. The resulting yellow precipitate is collected, washed with water, and is dried to give 1.83 g (93%) of benzofuran-6-carboxylic acid as a tan solid. HRMS (FAB) calcd for C9H6O3+H: 163.0395, found 163.0389 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])[CH2:4][NH:5][CH3:6].C1C=CC=CC=1.[CH3:15][O:16][CH:17]([C:19]1[S:23][C:22]([N:24]=[C:25]=[O:26])=[N:21][N:20]=1)[CH3:18].CCCCCC>C(OCC)C>[CH3:15][O:16][CH:17]([C:19]1[S:23][C:22]([NH:24][C:25](=[O:26])[N:5]([CH3:6])[CH2:4][CH:3]([O:7][CH3:8])[O:2][CH3:1])=[N:21][N:20]=1)[CH3:18]
Reactant: COC(C)c1nnc(N=C=O)s1
Reactant: CNCC(OC)OC
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: CCCCCC
Product: COC(CN(C)C(=O)Nc1nnc(C(C)OC)s1)OC
Yield: 94.2 %

Procedure:
At ambient temperatures, 5.4 grams (0.045 mole) of methylaminoacetaldehyde dimethylacetal was slowly added to a 50 milliliter benzene solution containing 8.4 grams (0.045 equivalents) of the 5-(1-methoxyethyl)-1,3,4-thiadiazol-2-yl isocyanate dimer (prepared above). The resulting solution was refluxed for 20 minutes; hexane was added resulting in the formation of an oil, the mixture was topped on a roto-vac at 70° C. to 13.2 grams of a hazy viscous oil which was dissolved in diethylether, and filtered. The diethylether solution was topped on a roto-vac at 70° C. to yield 12.9 grams of a red oil of 3-[5-(1-methoxyethyl)-1,3,4-thiadiazol-2-yl]-1-methyl-1-(2,2-dimethoxyethyl)urea.
Reaction SMILES: [CH3:1]COCC.C[Li].[O:8]=[C:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].[Cl-].[Ce+3].[Cl-].[Cl-]>O1CCCC1>[OH:8][C:9]1([CH3:1])[CH2:13][CH2:12][CH2:11][CH:10]1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19]
Reactant: CCOCC
Reactant: CC(C)(C)OC(=O)NC1CCCC1=O
Agent: [Ce+3]
Agent: [Cl-]
Agent: [Li]C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCCC1(C)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 82 %

Procedure:
A 1.6 M ether solution of methyllithium (13.59 mL, 21.75 mmol) was added to a stirred suspension of tert-butyl 2-oxocyclopentylcarbamate (1.97 g, 9.89 mmol, from Step 2) and cerium(III) chloride (5.36 g, 21.75 mmol) in tetrahydrofuran (50 mL) at −78° C. under nitrogen. After 2.5 h at −78° C., the mixture was quenched with saturated ammonium chloride, allowed to warm to room temperature, and filtered through a short bed of Celite to remove insoluble cerium salt. The filter cake was rinsed with ethyl acetate. The filtrated was extracted with ethyl acetate three times. The combined ethyl acetate phase was washed with saturated ammonium chloride and brine respectively, dried (MgSO4), filtered and concentrated. Silica gel chromatography, eluting with 0 to 50% ethyl acetate in hexanes, gave tert-butyl 2-hydroxy-2-methylcyclopentylcarbamate as yellow solid (1.47 g, 82% yield). 1H NMR analysis indicated the presence of approximately a 3:1 diastereomeric mixture.