Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[O:23][CH:24]=[CH:25][C:26]=4[CH3:27])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:28](OCC)=[O:29].[O-]CC.[Na+].Cl>C(O)C>[OH:29][CH:28]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[O:23][CH:24]=[CH:25][C:26]=4[CH3:27])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: CCOC=O
Reactant: Cc1ccoc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1ccoc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Temperature: 78 °C
Yield: 72.1 %

Procedure:
3-Methyl-furan-2-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (1.200 g, 3.33 mmol) and ethyl formate (0.8 mL, 9.95 mmol) were dissolved in anhydrous ethanol (30 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (6.2 mL, 16.63 mmol). This reaction mixture was heated at 78° C. for 0.5 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a light yellow precipitate. The suspension was filtered and the solids were washed with 0° C. EtOH to afford the pure 3-Methyl-furan-2-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.931 g, 2.4 mmol, 72%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.Br[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(N(CC)CC)C.Cl.[CH3:27][N:28]1[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]1>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]2[N:9]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:31]3[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][C:30]=3[C:5]=2[CH:4]=1
Reactant: CCOC(=O)CCBr
Reactant: CN1CCC(=O)CC1
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CCn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Yield: 7.9 %

Procedure:
Preparation of the title compound was carried out according to General Method 1 by using 4-chlorophenylhydrazine hydrochloride (10 g, 55 mmol), ethyl 3-bromopropionate (7.2 mL, 55 mmol), triethylamine (23 mL, 165 mmol) and N-methyl-4-piperidone hydrochloride (8.3 g, 55 mmol) in ethanol (100 ml) to obtain 1.4 g of ethyl 3-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)propanoate after purification on neutral alumina chromatography eluting with dichloromethane-hexane gradient.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([N+:18]([O-])=O)=[CH:13][CH:14]=2)[CH:9]1[CH3:21])=[O:5])[CH3:2].O.O.[Sn](Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:18][C:12]1[CH:11]=[C:10]2[C:15]([CH2:16][CH2:17][N:8]([CH2:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:9]2[CH3:21])=[CH:14][CH:13]=1
Reactant: CCOC(=O)CCN1CCc2ccc([N+](=O)[O-])cc2C1C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCN1CCc2ccc(N)cc2C1C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
0.90 g of 2-[2-(ethoxycarbonyl)ethyl]-1-methyl-7-nitro-1,2,3,4-tetrahydroisoquinoline was dissolved in 10 ml of ethanol, and 2.78 g of tin chloride dihydrate was added to the solution. The solution was heated under reflux with stirring for 2 hours. The resulting solution was neutralized with aqueous solution of sodium bicarbonate, and extracted with ethyl acetate. After washing with water and saturated aqueous solution of sodium chloride, the solution was dried with anhydrous sodium sulfate. The desiccant was separated by filtration, and the solvent was distilled off to obtain 0.69 g of 7-amino-2-[2-(ethoxycarbonyl)ethyl]-1-methyl-1,2,3,4-tetrahydroisoquinoline, which was an oily product. This product with no further purification was dissolved in 10 ml of DMF, and to this solution were added 0.92 g of separately synthesized 1-(benzyloxycarbonyl)-4-(carboxymethoxy)piperidine and 0.75 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. The solution was stirred overnight at room temperature, and the resulting solution was extracted with ethyl acetate, washed with water, saturated aqueous solution of sodium bicarbonate, and saturated aqueous solution of sodium chloride, and dried with anhydrous sodium sulfate. After separating the desiccant by filtration, the filtrate was purified by silica gel column chromatography to obtain 1.00 g of 7-[1-(benzyloxycarbonyl)piperidine-4-yloxyacetylamino]-2-[2-(ethoxycarbonyl)ethyl]-1-methyl-1,2,3,4-tetrahydroisoquinoline, which was an oily product (yield: 71%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]2([CH3:28])[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH2:21][CH2:20][CH2:19]2)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:37][C:38]1[N:42]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[C:41]2[CH:51]=[CH:52][CH:53]=[CH:54][C:40]=2[N:39]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][N:17]([CH2:37][C:38]2[N:42]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:48])([CH3:49])[CH3:50])[C:41]3[CH:51]=[CH:52][CH:53]=[CH:54][C:40]=3[N:39]=2)[C:18]2([CH3:28])[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:15]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[Si](C)(C)CCOCn1c(CCl)nc2ccccc21
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(CNC2(C)CCCc3cccnc32)cc1)Cc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1ccc(CN(Cc2nc3ccccc3n2COCC[Si](C)(C)C)C2(C)CCCc3cccnc32)cc1)Cc1ccccn1
Yield: 47.2 %

Procedure:
Reaction of N-tert-Butoxycarbonyl-N-(2-pyridinylmethyl)-N′-(8-methyl-5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (120 mg, 0.26 mmol), 2-chloromethyl-1-(2-trimethylsilylethoxymethyl)-1H-benzimidazole (234 mg, 0.79 mmol) and diisopropylethylamine (229 μL, 1.31 mmol) in DMF (2.6 mL) for 18 h at 90° C. followed by purification of the crude material by radial chromatography (2 mm plate, 20:2:1 CHCl3—MeOH—NH4OH) afforded 90 mg (48%) of N-tert-butoxycarbonyl-N-(2-pyridinylmethyl)-N′-(1-(2-trimethylsilylethoxymethyl)-1H-benzimidazol-2-ylmethyl)-N′-(8-methyl-5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine as a colourless oil.
Reaction SMILES: [CH:1]1([N:7]([CH2:21][CH2:22][C:23]2[CH:28]=CC=C[CH:24]=2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4]CC1.[CH:29](=O)CC(C)C.CC(C)CCN.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:29][CH:5]([CH3:4])[CH2:6][CH2:1][N:7]([CH2:21][CH2:22][CH:23]([CH3:24])[CH3:28])[C:8](=[O:20])[NH:9][C:10]1[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=1
Reactant: CC(C)CC=O
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Agent: CC(C)CCN
Agent: CCOC(=O)CSc1cnc(N)s1
Product: CC(C)CCN(CCC(C)C)C(=O)Nc1ncc(SCC(=O)O)s1

Procedure:
Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid using isovaleraldehyde, 3-methylbutylamine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:15]#[C:16][Si](C)(C)C)[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[CH2:9][CH2:8][C:7]2([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CO>[C:15]([C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([OH:1])[CH:3]=1)[C:10](=[O:12])[CH2:9][CH2:8][C:7]2([CH3:14])[CH3:13])#[CH:16]
Reactant: CC1(C)CCC(=O)c2c(O)cc(C#C[Si](C)(C)C)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cc(O)c2c(c1)C(C)(C)CCC2=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.7 %

Procedure:
A solution of 8-hydroxy-4,4-dimethyl-6-trimethylsilanylethynyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 66, 2.2 g, 7.4 mmol) in methanol (20 mL) was treated with potassium carbonate (2.04 g, 14.8 mmol) and the resulting reaction mixture was stirred at ambient temperature for 5 h. The solvent was evaporated in vacuo, the residue was diluted with water and extracted with diethyl ether. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title compound as an oil (1.58 g,˜100%).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[C:7]([N+:11]#[C-:12])([CH3:10])([CH3:9])[CH3:8].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O>Cl(O)(=O)(=O)=O>[C:7]([NH:11][C:12]1[N:3]2[NH:4][CH:5]=[N:6][C:2]2=[N:1][C:17]=1[C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=1[O:14][CH3:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: Nc1nc[nH]n1
Reactant: [C-]#[N+]C(C)(C)C
Reactant: COc1ccccc1C=O
Agent: [O-][Cl+3]([O-])([O-])O
Product: COc1ccccc1-c1nc2nc[nH]n2c1NC(C)(C)C

Procedure:
Compound 31 was prepared in accordance with the general synthesis instructions from 1.0 ml (0.1 mmol) 3-amino-1,2,4-triazole solution (0.1 M, MC), 0.575 ml (0.115 mmol) tert-butylisonitrile solution (0.2 M, MC), 0.500 ml (0.15 mmol) 2-methoxybenzaldehyde solution (0.3 M, MC) and 10 μl perchloric acid (w=20%) in a substance library.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:4]([C:17]([NH:19][O:20][CH2:21][C@H:22]2[CH2:26][O:25]C(C)(C)[O:23]2)=[O:18])[CH:3]=1>C(O)(=O)C.O>[OH:23][CH:22]([CH2:26][OH:25])[CH2:21][O:20][NH:19][C:17]([C:4]1[CH:3]=[C:2]([Cl:1])[N:7]=[N:6][C:5]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=1[F:16])=[O:18]
Reactant: CC1(C)OC[C@H](CONC(=O)c2cc(Cl)nnc2Nc2ccc(I)cc2F)O1
Solvent: O
Solvent: CC(=O)O
Product: O=C(NOCC(O)CO)c1cc(Cl)nnc1Nc1ccc(I)cc1F

Procedure:
6-Chloro-N-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-3-[(2-fluoro-4-iodophenyl)amino]pyridazine-4-carboxamide (38 mg, 0.07 mmol) was heated at 90° C. in acetic acid/water (85%, 1.5 mL) for 2 hours. The mixture was concentrated and purified by flash chromatography to give the desired adduct. LC/MS [Method B: rt: 7.02 min; m/z: 483 (M+1)].
Reaction SMILES: [H-].[Na+].[C:3](#[N:7])[CH2:4][C:5]#[N:6].I[C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1>C(#N)C>[C:5]([CH:4]([C:3]#[N:7])[C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1)#[N:6]
Reactant: O=Cc1ccc(I)cc1
Reactant: N#CCC#N
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: N#CC(C#N)c1ccc(C=O)cc1
Reaction time: 66 h

Procedure:
To a 0.10 formula weight of sodium hydride suspended in 1 L acetonitrile in an atmosphere of dry argon is added 0.11 mole malononitrile dissolved in 0.10 L acetonitrile while adequate external cooling is applied to maintain the temperature of the reaction mixture in the range 0° C. to 10° C. To this mixture 0.05 formula weight of 4-iodobenzaldehyde is added followed by a solution of 0,005 formula weight of tetrakis(triphenylphosphene)palladium[0] in 0.50L argon-saturated acetonitrile. The resulting mixture is refluxed under argon with rapid stirring for 66 hours. The resulting mixture is concentrated in vacuo to a volume of 100 ml and the resulting mixture is treated with 500 ml ethyl ether. The salt which precipitated is removed by filtration and, while not with ether, suspended in 0.5 L water. The resulting suspension is acidified to pH=1.0 with concentrated hydrochloric acid to precipitate the 4-(dicyanomethyl)benzaldehyde.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]2[CH:10]=[N:11][CH:12]=[C:13]([CH:19]=2)[C:14]([O:16]CC)=[O:15])=[CH:3][CH:2]=1.O[Li].O>C1COCC1.O>[N:1]1[CH:2]=[CH:3][C:4](/[CH:7]=[CH:8]/[C:9]2[CH:10]=[N:11][CH:12]=[C:13]([CH:19]=2)[C:14]([OH:16])=[O:15])=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cncc(/C=C/c2ccncc2)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cncc(/C=C/c2ccncc2)c1

Procedure:
A mixture of Example 18A (1.60 g, 6.3 mmol) and LiOH.H2O (2.64 g) in THF/water (50 mL/50 mL) was stirred at room temperature for 2 hours. The THF was removed under vacuum and the aqueous layer was acidified with 1N HCl (aq.). The solid was collected by filtration and dried to provide the desired product. MS (DCI/NH3) m/e 227 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:16]([CH2:18][C:19]([OH:21])=[O:20])=[O:17])[CH3:15])=[CH:10][CH:9]=1.S(=O)(=O)(O)[OH:23].O.[Mn]([O-])(=O)(=O)=O.[K+]>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:16]([CH2:18][C:19]([OH:21])=[O:20])(=[O:23])=[O:17])[CH3:15])=[CH:10][CH:9]=1
Reactant: O=S(=O)(O)O
Reactant: CC(c1ccc(-c2ccccc2F)cc1)S(=O)CC(=O)O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(c1ccc(-c2ccccc2F)cc1)S(=O)(=O)CC(=O)O

Procedure:
170 gm (0.556 mol) of a diastereoisomeric mixture of [1-(2'-fluoro-4-biphenylyl)-ethylsulfinyl]-acetic acid were dissolved in 1.7 liters of acetone, and a solution of 19.9 gm (0.195 mol) of concentrated sulfuric acid inf 70 ml of water was added. While stirring, 67.2 gm (0.425 mol) of potassium permanganate were added in small portions, and the temperature was maintained at 20°-25° C. The mixture was stirred for 1 hour, the manganese dioxide was suction-filtered off, the filter cake was washed with acetone, and the filtrate was evaporated in vacuo. The residue was diluted with 4 liters of glacial acetic acid, and the precipitated crystalline reaction product was suction-filtered off, washed, dried and recrystallized from toluene. Yield: 158.2 gm (88.5% of theory); m.p. 144°-146° C.
Reaction SMILES: [Br:1][C:2]1[N:3]2[C:8]3[N:9]4[CH2:37][CH2:36][C:12]([CH3:38])([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C@H:18]([CH3:35])[O:19][C:20]5[CH:21]=[CH:22][C:23]([F:34])=[CH:24][C:25]=5[C:26]5[CH:33]=[C:30]([C:31]=1[N:32]=[C:4]2[CH:5]=[C:6]([CH3:49])[C:7]=3[C@H:39]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[C:40]([O:42][CH3:43])=[O:41])[CH:29]=[CH:28][CH:27]=5)[CH2:11][CH2:10]4.[Cl:50]N1C(=O)CCC1=O.C(OCC)(=O)C>C(#N)C>[Br:1][C:2]1[N:3]2[C:8]3[N:9]4[CH2:10][CH2:11][C:12]([CH3:38])([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C@H:18]([CH3:35])[O:19][C:20]5[CH:21]=[CH:22][C:23]([F:34])=[CH:24][C:25]=5[C:26]5[CH:33]=[C:30]([C:31]=1[N:32]=[C:4]2[C:5]([Cl:50])=[C:6]([CH3:49])[C:7]=3[C@H:39]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[C:40]([O:42][CH3:43])=[O:41])[CH:29]=[CH:28][CH:27]=5)[CH2:36][CH2:37]4
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3c(Br)n2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(Cl)c2nc3c(Br)n2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Reaction time: 3 h
Yield: 57.4 %

Procedure:
Methyl(2S)-2-[(22S)-8-bromo-17-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]-2-(tert-butoxy)acetate (50 mg, 0.068 mmol, 1.0 equiv) was dissolved in acetonitrile (1357 μl). To this solution was added 1-chloropyrrolidine-2,5-dione (9.06 mg, 0.068 mmol, 1.0 equiv) and stirred for 3 hours. The mixture was diluted by 15 mL Ethyl Acetate, washed by NaHCO3 and brine. The organic layer was dried, concentrated, and purified on ISCO 12 g column (0-100% EtOAc [2% TEA]/Hexane) to give the product (30 mg, 0.039 mmol, 57.3% yield).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]1(S(O)(=O)=O)C=CC=CC=1.CO>>[CH3:18][N:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:11][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:9]1
Reactant: O=S(=O)(O)c1ccccc1
Reactant: c1ccc(-c2cc(-c3ccccc3)[nH]n2)cc1
Solvent: CO
Product: Cn1nc(-c2ccccc2)cc1-c1ccccc1
Yield: 900.5 %

Procedure:
As in Example 2, a melt of 10 g (0.0455 mol) of 3,5-diphenylpyrazole and 0.72 g (0.00455 mol) of benzenesulfonic acid was introduced and reacted over the course of 4.5 hours with 245 g (7.66 mol) of gaseous methanol (vaporized at 160° C.). 9.6 g (88.5%) of 1-methyl-3,5-diphenylpyrazole were obtained, boiling point 190° C./3 mbar, with a content of 98.2% (GC).
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.[C:8]([Si:12](Cl)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:11])([CH3:10])[CH3:9].[C:26](#N)[CH3:27]>>[Si:12]([NH:3][CH:6]([CH3:7])[C:13]1[CH:18]=[CH:17][C:26]([CH3:27])=[CH:15][CH:14]=1)([C:8]([CH3:11])([CH3:10])[CH3:9])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Reactant: CC#N
Product: Cc1ccc(C(C)N[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of racemic α,4-dimethyl-benemethanamine (4.00 g, 30.0 mmol) and triethylamine (6.1 mL, 43.8 mmol) in acetonitrile (100 mL) in a flame-dried flask under nitrogen was added dropwise t-butylchlorodiphenylsilane (7.7 mL, 29.6 mmol). The mixture was stirred at room temperature overnight and then filtered to remove the insoluble white precipitate (triethylamine hydrochloride). After removal of the solvent in vacuo, the crude product was taken up in ether and washed sequentially with H2O, saturated NaHCO3 solution and brine. The solution was dried (Na2SO4 /K2CO3) and concentrated to leave a clear oil which was distilled under high vacuum. The major fraction consisting of the title compound (6.7 g, 60%) distilled from 134° to 165° C. at 0.1 mm Hg.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:9]([O:10][CH3:11])=[C:8]([OH:12])[C:7]([CH3:13])=[C:6]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:4]=1[OH:5].[C:44]([Si:48](Cl)([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([CH3:47])([CH3:46])[CH3:45].N1C=CN=C1>ClCCl>[Si:48]([O:12][C:8]1[C:7]([CH3:13])=[C:6]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:4]([OH:5])=[C:3]([O:2][CH3:1])[C:9]=1[O:10][CH3:11])([C:44]([CH3:47])([CH3:46])[CH3:45])([C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: COc1c(O)c(C)c(CCCCCCCCCCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c(O)c1OC
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COc1c(O)c(CCCCCCCCCCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1OC
Temperature: 40 °C
Reaction time: 21 h

Procedure:
2,3-Dimethoxy-5-methyl-6-(10-trityloxydecyl)hydroquinone (80.4 g) was dissolved in dichloromethane (250 ml). tert-Butylchlorodiphenylsilane (26 ml) and imidazole (6.8 g) were added, and the mixture was stirred at 40° C. for 21 hours. The reaction mixture was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to column chromatography on silica gel and eluted with hexane/ethyl acetate (9:1) to obtain the desired compound (40 g).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[NH:10][C:11]([CH3:16])([CH2:13][CH:14]=O)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][O:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][O:25][CH3:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.CC(O)=O>[CH2:1]([O:8][C:9](=[O:17])[NH:10][C:11]([CH3:16])([CH2:13][CH2:14][N:22]([CH2:23][CH2:24][O:25][CH3:26])[CH2:21][CH2:20][O:19][CH3:18])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(CC=O)NC(=O)OCc1ccccc1
Reactant: COCCNCCOC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COCCN(CCOC)CCC(C)(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.1 %

Procedure:
To a 100-mL round-bottomed flask was added benzyl(2-methyl-4-oxobutan-2-yl)carbamate (1.04 g, 4.42 mmol) and bis(2-methoxyethyl)amine (0.776 mL, 5.30 mmol, Sigma-Aldrich) in 1,2-dichloroethane (20 mL) followed by AcOH (0.3 mL). The mixture was stirred at RT for 10 min, then sodium triacetoxyborohydride (1.124 g, 5.30 mmol, Sigma-Aldrich) was added portion wise. The reaction was stirred at RT for 1 h. Sat. NaHCO3 (20 mL) was added slowly and the mixture was extracted with EtOAc (40 mL×3). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified with silica gel chromatography (eluted with 10-90% EtOAc in Hex) to give benzyl(4-(bis(2-methoxyethyl)amino)-2-methylbutan-2-yl)carbamate (1.03 g, 2.92 mmol, 66% yield) as a colorless oil. MS (ESI, pos. ion) m/z: 353.1 (M+1); 1H NMR (400 MHz, CDCl3) δ ppm 7.27-7.40 (5H, m), 6.94 (1H, br. s.), 5.05 (2H, s), 3.45 (4H, t, J=5.8 Hz), 3.26 (6H, s), 2.64-2.73 (6H, m), 1.62 (2H, t, J=6.4 Hz), 1.36 (6H, s).
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:17][C:18](C)=[O:19].[C:21](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CCOC(C)=O>[CH:3]([N:4]1[CH2:5][CH2:6][NH:1][C:18](=[O:19])[CH2:17]1)([CH3:21])[CH3:2]
Reactant: CC(C)=O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CC(C)N1CCNC(=O)C1
Temperature: 70 °C
Yield: 78.8 %

Procedure:
To a solution of piperazin-2-one (1, 0.5 g, 5 mmol) and acetone (0.58 g, 10 mmol) in 1,2-dichloroethane (20 mL) was added sodium triacetoxyborohydride (3.18 g, 15.0 mmol) and the mixture was heated at 70° C. for 2 h. The mixture was diluted with EtOAc/saturated Na2CO3 (100/50 mL), washed with brine (20 mL), dried (Na2SO4), filtered and concentrated to afford the crude title compound (0.56 g, 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([N:16]3[C:20]([CH2:21][CH3:22])=[C:19]([C:23](O)=[O:24])[C:18]([CH2:26][CH3:27])=[N:17]3)[CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.[N:28]1([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:32][CH2:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([N:16]3[C:20]([CH2:21][CH3:22])=[C:19]([C:23]([N:36]4[CH2:37][CH2:38][CH:33]([N:28]5[CH2:32][CH2:31][CH2:30][CH2:29]5)[CH2:34][CH2:35]4)=[O:24])[C:18]([CH2:26][CH3:27])=[N:17]3)[CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: CCc1nn(-c2cccc(/C=C/c3ccc(Cl)cc3)c2)c(CC)c1C(=O)O
Reactant: C1CCN(C2CCNCC2)C1
Product: CCc1nn(-c2cccc(/C=C/c3ccc(Cl)cc3)c2)c(CC)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 2, 1-{3-[(E)-2-(4-chloro-phenyl)-vinyl]-phenyl}-3,5-diethyl-1H-pyrazole-4-carboxylic acid (intermediate 1) and 4-pyrrolidin-1-yl-piperidine gave the title compound as colorless oil. MS: 517.3 (MH+, 1 Cl).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[CH:5][C:6]([CH2:13][C:14]([O:16]C(C)(C)C)=[O:15])=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:21][C:2]([F:1])([F:22])[C:3]1[CH:4]=[CH:5][C:6]([CH2:13][C:14]([OH:16])=[O:15])=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2
Reactant: CC(C)(C)OC(=O)Cc1ccc(C(F)(F)F)c2ncccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cc1ccc(C(F)(F)F)c2ncccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.1 %

Procedure:
To a solution of tert-butyl 2-(8-(trifluoromethyl)quinolin-5-yl)acetate (400 mg, 1.28 mmol) in DCM (5 mL) was added TFA (10 mL) dropwise. The reaction was stirred at room temperature overnight. After the reaction was complete, the solvent was removed and the residue was purified (silica gel chromatography) to give the final product 2-(8-(trifluoromethyl)quinolin-5-yl)acetic acid (180 mg, 54%). LC-MS (0.05% TFA): [M+1]+ 256.1. 1H-NMR (DMSO-d6, 400 MHz): δ 12.70 (s, 1H), 9.07 (m, 1H), 8.56 (m, 1H), 8.15 (d, 1H), 7.74 (m, 1H), 7.68 (m, 1H), 4.23 (s, 2H). 13C-NMR (DMSO-d6, 100 MHz): δ 171.9, 151.0, 144.0, 138.3, 133.5, 127.87, 127.83, 127.78, 125.3, 123.1, 122.2, 37.7.