Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:11])[CH2:7][C:8](=O)[CH3:9].C([O-])(=O)C.[NH4+:16]>C1(C)C=CC=CC=1>[NH2:16][C:8]([CH3:9])=[CH:7][C:6]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)=[O:11]
Reactant: CC(=O)CC(=O)c1ccco1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CC(N)=CC(=O)c1ccco1
Yield: 48.9 %

Procedure:
The intermediate 3-amino-1-(2-furanyl)-2-buten-1-one was prepared as follows: A mixture containing 165 g of 1-(2-furanyl)-1,3-butanedione, 700 ml of toluene and 200 g of ammonium acetate was azeotroped for six hours, cooled and concentrated to dryness in vacuo. The residue was dissolved in isopropyl alcohol, the solution treated with decolorizing charcoal and filtered, and the filtrate concentrated to remove the solvent. The remaining residue was recrystallized from ether-ethanol and dried at room temperature to yield 80.2 g of 3-amino-1-(2-furanyl)-2-buten-1-one, m.p. 128°-130° C. Another 33.4 g of the product, m.p. 128°-130° C. was collected by concentrating the mother liquor and extracting the product with ether.
Reaction SMILES: [CH3:1][CH:2]([CH3:27])[CH2:3][C:4]([C:6]1[C:7]([C:22](OCC)=[O:23])=[N:8][N:9]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[CH:10]=1)=O.[CH3:28][NH:29][NH2:30]>C(O)C.O>[CH3:28][N:29]1[C:22](=[O:23])[C:7]2=[N:8][N:9]([CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][CH:13]=3)[CH:10]=[C:6]2[C:4]([CH2:3][CH:2]([CH3:27])[CH3:1])=[N:30]1
Reactant: CNN
Reactant: CCOC(=O)c1nn(Cc2cccc3ccccc23)cc1C(=O)CC(C)C
Solvent: CCO
Solvent: O
Product: CC(C)Cc1nn(C)c(=O)c2nn(Cc3cccc4ccccc34)cc12

Procedure:
A mixture of ethyl 4-(3-methyl-1-oxobutyl)-1-(1-naphthalenylmethyl)-1H-pyrazole-3-carboxylate (0.15 g) and methylhydrazine (0.1 ml) in ethanol (2 ml) was heated at reflux for 18 hours. The reaction was diluted with water and then extracted into ethyl acetate. The organic phase was washed with brine, dried, filtered and evaporated. The residue was chromatographed, eluting with dichloromethane:ethanol (19:1), to give the title compound (0.08 g).
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11]([CH2:30]Br)[CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:32]#[N:33].[Na+].C(OCC)(=O)C>CS(C)=O>[C:1]([O:9][CH2:10][CH:11]([CH2:30][C:32]#[N:33])[CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: CCCCCCCCCCCCCCCCOCC(CBr)COC(=O)c1ccccc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCCCCCCCCCCCCCOCC(CC#N)COC(=O)c1ccccc1
Temperature: 90 °C
Yield: 100.6 %

Procedure:
A mixture of 13.845 g (27.9 mM) of 2-bromomethyl-3-n-hexadecyloxypropyl benzoate n3 and 1.439 g (27.9 mM) of sodium cyanide (95% purity) in 150 ml of dimethylsulfoxide is heated at 90° C. for 1 hour. Theproduct is isolated by ethyl acetate extraction. The ethyl acetate layer is washed with water (four times) and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated to obtain 12.42 g of the crude product of the titled compound n3'.
Reaction SMILES: C1(N2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:15]4[N:19]([C:20]5C=CC(C(O)=O)=CC=5)N=CC=4)[CH:13]=3)C(CC)=N2)CCCC1.C1N=CN([C:36](N2C=NC=C2)=[O:37])C=1.Cl.CN[O:46]C.O>C(Cl)Cl.C(OCC)(=O)C>[CH3:36][O:37][N:19]([CH3:20])[C:15](=[O:46])[C:12]1[CH:11]=[CH:10][CH:9]=[CH:14][CH:13]=1
Reactant: CNOC
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCc1nn(C2CCCC2)c2cc(-c3ccnn3-c3ccc(C(=O)O)cc3)ccc12
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1ccccc1
Yield: 133.2 %

Procedure:
To a solution of 4-[5-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]benzoic acid (100.0 mg, 0.250 mmol) in 1.2 mL of methylene chloride under at atmosphere of argon at 0° C. was added N,N-carbonyldiimidazole (48.2 mg, 0.297 mmol) with stirring. After 30 minutes N,O-dimethylhydroxylamine hydrochloride (59.9 mg, 0.614 mmol) was added and the resultant suspension was warmed to room temperature, stirred for 24 hours and then 10 mL of water and 10 mL of ethyl acetate were added. The organic layer was separated, washed with 10 mL of 1N NaOH, 10 mL of water, 10 mL of brine, dried over sodium sulfate, and filtered. Approximately 2 g of silica gel were added and the mixture was evaporated to dryness under reduced pressure. The residue was purified by column chromatography over silica gel eluting with a linear gradient from 10% ethyl acetate in hexanes to 50% ethyl acetate in hexanes over 20 minutes to yield 4-[5-(1-cyclopent)4-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]-N-methoxy-N-methylbenzamide (55 mg, 50%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][NH:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:21]=[N:20][CH:19]=[C:18](Cl)[N:17]=1>O1CCOCC1>[NH3:8].[Cl:15][C:16]1[N:17]=[C:18]([N:11]2[CH2:10][C@@H:9]3[CH2:14][C@H:12]2[CH2:13][N:8]3[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:19]=[N:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: Clc1cncc(Cl)n1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1cncc(Cl)n1
Product: N
Temperature: 40 °C
Reaction time: 72 h

Procedure:
A mixture of tert-butyl-(1S,4S)-(+)-2,5-diazabicyclo-[2.2.1]-heptane-2-carboxylate (10.0 g, 50.4 mmol), 2,6-dichloropyrazine (15.0 g, 101 mmol) and dioxane (100 ml) was stirred at 40° C. for 3 days. The mixture was evaporated. Aqueous sodium hydroxide (100 ml, 1 M) was added, the mixture was evaporated to the half volume. The mixture was extracted with ethyl acetate (2×100 ml). Chromatography on silica gel with dichloromethane, methanol and conc. ammonia (89:10:1) gave the title compound as free base. Yield 11.6 g (73%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.[NH2:12][C:13]1[CH:14]=[C:15]([CH2:19][OH:20])[CH:16]=[CH:17][CH:18]=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][OH:20])[CH:14]=1)=[O:11]
Reactant: Nc1cccc(CO)c1
Reactant: O=C(O)Cc1ccccc1Br
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1Br)Nc1cccc(CO)c1
Reaction time: 2 h

Procedure:
To a stirring solution of 2-(2-bromophenyl)acetic acid in dichloromethane (0.2 M) was added (3-aminophenyl) methan-1-ol (1.2 eq), triethylamine (1.5 eq), and EDAC (1.5 eq). After 2 hrs, the solution was washed with water, 10% HCl, 10% sodium carbonate, and water, dried over magnesium sulfate, filtered and concentrated in vacuo to afford a colorless solid. EI-MS m/z 320/322 (M+H)+
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([CH3:18])[CH:12]=2)=[CH:5][CH:4]=1.[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([CH3:31])[CH3:30])[C:24]=1[N:32]=[C:33]=[O:34])([CH3:22])[CH3:21]>>[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([CH3:30])[CH3:31])[C:24]=1[NH:32][C:33](=[O:34])[N:10]([CH2:9][C:6]1[CH:5]=[CH:4][C:3]([N:2]([CH3:19])[CH3:1])=[CH:8][CH:7]=1)[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([CH3:18])[CH:12]=1)([CH3:21])[CH3:22]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: Cc1ccc(NCc2ccc(N(C)C)cc2)cc1C
Product: Cc1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1C
Yield: 30.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using [(4-dimethylaminophenyl)methyl](3,4-dimethylphenyl)amine (1.4 g) and 2,6-diisopropylphenyl isocyanate (1.5 g) as starting materials, N′-(2,6-diisopropylphenyl)-N-[(4-dimethylaminophenyl)methyl]-N-(3,4-dimethylphenyl)urea (0.77 g) was obtained.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]([C:15]2([C:18]3[CH:28]=[CH:27][C:21]4[O:22][C:23]([F:26])([F:25])[O:24][C:20]=4[CH:19]=3)[CH2:17][CH2:16]2)=[O:14])[N:3]=1.[C:29]([O:33][C:34]([NH:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[F:25][C:23]1([F:26])[O:22][C:21]2[CH:27]=[CH:28][C:18]([C:15]3([C:13]([NH:12][C:4]4[N:3]=[C:2]([C:41]5[CH:42]=[CH:43][C:38]([CH2:37][NH:36][C:34](=[O:35])[O:33][C:29]([CH3:30])([CH3:31])[CH3:32])=[CH:39][CH:40]=5)[C:11]5[C:6]([CH:5]=4)=[CH:7][CH:8]=[CH:9][CH:10]=5)=[O:14])[CH2:17][CH2:16]3)=[CH:19][C:20]=2[O:24]1
Reactant: O=C(Nc1cc2ccccc2c(Br)n1)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Reactant: CC(C)(C)OC(=O)NCc1ccc(B(O)O)cc1
Product: CC(C)(C)OC(=O)NCc1ccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc3ccccc23)cc1

Procedure:
tert-Butyl 4-(3-(1-(2,2-difluorobenzo[d][,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzylcarbamate was made by the procedure shown above starting from N-(1-bromoisoquinolin-3-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide and 4-((tert-butoxycarbonylamino)methyl)phenylboronic acid. ESI-MS m/z calc. 573.2. found 574.3 (M+1)+. Retention time 2.26 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.40 (s, 1H), 7.97 (d, J=8.2 Hz, 1H), 7.86 (d, J=8.6 Hz, 1H), 7.74-7.70 (m, 1H), 7.61 (d, J=1.2 Hz, 1H), 7.54-7.38 (m, 8H), 4.22 (d, J=5.9 Hz, 2H), 1.57-1.55 (m, 2H), 1.41 (s, 9H), 1.22-1.20 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([I:17])=[CH:11][CH:10]=2)=[O:5])[CH3:2].[O-:18][CH2:19][CH3:20].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[O:18][CH2:19][CH3:20])=[CH:13][C:12]([I:17])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CC[O-]
Reactant: CCOC(=O)c1cnc2ccc(I)cc2c1Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnc2ccc(I)cc2c1OCC
Temperature: 100 °C
Reaction time: 4 h
Yield: 38.1 %

Procedure:
To the suspension of 4-chloro-6-iodo-quinoline-3-carboxylic acid ethyl ester (example 1c, 1.5 g, 4.1 mmol) in anhydrous ethanol (25 mL) was added sodium ethoxide (0.7 g, 10.3 mol). The mixture was heated to 100° C. under a pressure tube and stirred for 4 h. After cooling to room temperature, the ice water was added. The solid was collected by filtration, washed with water and dried to obtain 6-iodo-4-ethoxy-quinoline-3-carboxylic acid ethyl ester (0.58 g, 38%) as a yellow solid. LC-MS m/e 372 (MH+)
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=[O:2].[CH3:24][CH:25]([CH3:35])[CH2:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1>>[CH3:24][CH:25]([CH3:35])[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:31][O:2][C:1]([C:4]23[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]2)[CH2:6][CH2:5]3)=[O:3])=[CH:33][CH:34]=1
Reactant: CC(C)Cc1ccc(CBr)cc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: CC(C)Cc1ccc(COC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Yield: 68.6 %

Procedure:
In a similar manner to Example 8, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (30.0 mg) and 4-(2,2-dimethylethyl)benzyl bromide (23.2 mg) were used to obtain (2S,4S)-1-[[N-[4-[4-(2,2-dimethylethyl)benzyl]oxycarbonyl bicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (29.9 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[C:11](Br)=[CH:12][N:13]=[C:7]2[N:6]=1)=[O:4].CC1(C)C(C)(C)OB([C:23]2[CH:24]=[C:25]([C:29]3[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:26]=[CH:27][CH:28]=2)O1>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[C:11]([C:27]3[CH:26]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]#[N:36])[CH:24]=[CH:23][CH:28]=3)=[CH:12][N:13]=[C:7]2[N:6]=1)=[O:4]
Reactant: CC1(C)OB(c2cccc(-c3ccccc3C#N)c2)OC1(C)C
Reactant: COC(=O)c1ccn2c(Br)cnc2n1
Product: COC(=O)c1ccn2c(-c3cccc(-c4ccccc4C#N)c3)cnc2n1

Procedure:
3-Bromoimidazo[1,2-a]pyrimidine-7-carboxylic acid methyl ester was coupled with 3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 3-(2′-cyanobiphenyl-3-yl)-imidazo[1,2-a]pyrimidine-7-carboxylic acid methyl ester as a pale yellow powder: δH (400 MHz, CDCl3) 4.07 (3H, s), 7.50-7.54 (1H, m), 7.58-7.76 (6H, m), 7.81-7.84 (2H, m), 8.18 (1H, s), 9.10 (1H, d, J 7); m/z (ES+) 355 (M++H).
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:8]([CH3:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[CH2:5][NH:4][C:3]1=[O:14].C=O.[OH-].[Na+].[CH2:19]([OH:21])C>C(Cl)(Cl)Cl>[CH3:1][C@H:2]1[C@@H:8]([CH3:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[CH2:5][N:4]([CH2:19][OH:21])[C:3]1=[O:14]
Reactant: CCO
Reactant: C[C@@H]1C(=O)NCc2ccccc2[C@@H]1C
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: C[C@@H]1C(=O)N(CO)Cc2ccccc2[C@@H]1C
Yield: 61 %

Procedure:
A solution of 5.7 g. (0.030 moles) of cis-4,5-dimethyl-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one, 9 ml. (0.09 moles) of 35% aqueous formaldehyde solution and 0.05 g. of sodium hydroxide in 50 ml. of 92% ethanol is heated for 5 hours at 80° C., while stirring. The reaction mixture is cooled and the solvents are evaporated off in vacuo. The oil obtained is taken up in chloroform, washed several times with water and then dried over anhydrous sodium sulfate. After evaporation of the solvent in vacuo, the residual syrup is purified by recrystallization from diisopropyl ether. 4 g. (61% of theory) of cis-4,5-dimethyl-2-hydroxymethyl-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one are obtained. M.P. 91°-92° C.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[N:10][CH:11]=1)=[O:5].[F:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[CH2:21][Mg]Br.FC1C=C(F)C=CC=1CBr.[Mg].Cl>C1COCC1.CCOCC>[F:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[CH2:21][C:4]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[N:10][CH:11]=1)=[O:5]
Reactant: CON(C)C(=O)c1ccc(-n2ccnc2)nc1
Reactant: Fc1ccc(C[Mg]Br)c(F)c1
Agent: Cl
Agent: Fc1ccc(CBr)c(F)c1
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(Cc1ccc(F)cc1F)c1ccc(-n2ccnc2)nc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
A solution of the product from part (i) (6.5 g, 28 mmol) in THF (100 ml) was stirred under a nitrogen atmosphere at -70° C. and was treated with a solution of 2,4-difluorobenzylmagnesium bromide [from 2,4-difluorobenzyl bromide (8.1 g, 39 mmol) and magnesium (1.0 g, 42 mmol) using the method of Preparation 20(i)] in ether (100 ml). The mixture was stirred at -70° C. for 0.5 hours and was allowed to warm to room temperature before the addition of dilute hydrochloric acid (2N, 100 ml). The layers were separated and the aqueous phase was extracted with dichloromethane (100 ml). The combined organic extracts were dried (MgSO4) and evaporated under reduced pressure to yield the title compound as a pale yellow solid which was characterised by
Reaction SMILES: C([O:5][CH2:6][CH2:7][CH2:8][CH3:9])CCC.C(Br)C=C.C([Mg]Br)(C)C.C(=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C.Cl>[C:20]1([CH:6]([OH:5])[CH2:7][CH:8]=[CH2:9])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCCCOCCCC
Reactant: O=Cc1ccccc1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: CC(C)[Mg]Br
Agent: Cl
Solvent: C=CCBr
Product: C=CCC(O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To 0.90 ml (3.0 mmol) of tetraisopropoxytitanium and 5 ml of n-butyl ether solution containing allyl bromide (3.0 mmol) was added dropwise at −78° C. 6.2 ml of 0.97M n-butyl ether solution containing isopropylmagnesium bromide (6.0 mmol). After stirring at −50° C. to −40° C. for 1 hour, the reaction liquid was given 0.21 ml (2.1 mmol) of benzaldehyde and heated to 0° C. over 30 minutes. With 10 ml of 3N hydrochloric acid added, the solution was heated to room temperature and separated into layers. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate. After drying with anhydrous magnesium sulfate, the solution was freed of solvent by vacuum distillation. The residues were purified by silica gel chromatography. Thus there was obtained 252 mg of 1-phenyl-3-buten-1-ol (81% yields based on benzaldehyde).
Reaction SMILES: Cl[C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[Na].[K].[Li].[C:14](OCC)(=O)CC(OCC)=O.C(OC)(=O)CC(OC)=O>>[CH3:14][C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1ncccc1Cl
Agent: [K]
Agent: [Li]
Agent: [Na]
Solvent: COC(=O)CC(=O)OC
Product: Cc1cccnc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 3 h

Procedure:
In Scheme 1, step a, chloro-nitropyridine 1 is added in portions to an alkali metal salt of a malonic acid diester in excess malonic diester, such as for example the sodium, potassium or lithium salt of the malonic acid diester in an excess of the malonic acid diester, such as for example diethyl malonate or dimethyl malonate, at a temperature of about 50° C. to about 70° C. The alkali metal salt of the malonic acid diester may be prepared, for example, by adding an alkali metal, such as for example sodium metal, to an excess of the malonic acid diester as is well known to one skilled in the art. After about three hours at about 50° C. to about 70° C., the mixture is allowed to stand at ambient temperature for about 12 to about 24 hours. If the reaction is incomplete, the mixture is heated to about 80° C. for about 2 hours to about 4 hours, then concentrated to remove excess malonic acid diester, and then treated with a concentrated mineral acid such as for example hydrochloric acid or sulfuric acid and water. The mixture is heated at about 100° C. to about 110° C. for about 5 hours to about 9 hours to effect decarboxylation. After standing about 12 to about 24 hours at ambient temperature the mixture is washed with a suitable solvent, such as for example ethyl ether and ethyl acetate, basified to about pH 8 to about pH 9 with an alkali metal hydroxide, such as for example sodium hydroxide or potassium hydroxide, and extracted with a suitable organic solvent, such as for example ethyl acetate. The organic extract is filtered and concentrated under reduced pressure to afford the desired methyl-nitropyridine 2. Preparation of 2 by this “step a” procedure is referred to as a “two step, one pot synthesis”.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:11]=[O:12])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[CH2:24](O)[CH2:25][CH2:26][OH:27]>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:11]2[O:27][CH2:26][CH2:25][CH2:24][O:12]2)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1
Reactant: OCCCO
Reactant: O=Cc1cc(Br)cc2ccoc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1cc(C2OCCCO2)c2occc2c1

Procedure:
A mixture of 5-bromo-benzofuran-7-carbaldehyde (400 mg), 4-methylphenylsulphonic acid (0.38 g) and 1,3-propanediol (10 ml) in toluene (15 ml) was heated at reflux for 19 h, with azeotropic removal of water by Dean-Stark Apparatus. The reaction mixture was cooled, diluted with water (80 ml) and extracted with toluene (30 ml). The organic phase was dried, filtered and the filtrate evaporated in vacuo to give a brown oil. Purification by FCC eluted with hexane:ethyl acetate (7:1→3:1) gave the title compound as a yellow solid (427 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:17](=[O:19])[NH:16][CH:15]=[CH:14][C:13]=3[NH:12][C:11]([C:20]([F:23])([F:22])[F:21])=[C:10]2[C:24]#[N:25])=[C:5]([O:26][CH3:27])[CH:4]=1)#[N:2].F[B-](F)(F)F.[CH2:33]([O+](CC)CC)[CH3:34].ClCCl>CO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[N:16][C:17]=3[O:19][CH2:33][CH3:34])[NH:12][C:11]([C:20]([F:23])([F:22])[F:21])=[C:10]2[C:24]#[N:25])=[C:5]([O:26][CH3:27])[CH:4]=1)#[N:2]
Reactant: CC[O+](CC)CC
Reactant: COc1cc(C#N)ccc1C1C(C#N)=C(C(F)(F)F)Nc2cc[nH]c(=O)c21
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CCOc1nccc2c1C(c1ccc(C#N)cc1OC)C(C#N)=C(C(F)(F)F)N2

Procedure:
390 mg (1.05 mmol) of 4-(4-cyano-2-methoxyphenyl)-5-oxo-2-(trifluoromethyl)-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carbonitrile and 398 mg of triethyloxonium tetrafluoroborate (2.1 mmol) are mixed under a dry argon atmosphere. After addition of dichloromethane (32 ml), the suspension is stirred until a solution is obtained (about 2 h), and then mixed with methanol and concentrated. The residue is purified by preparative HPLC to result in 250 mg (59% of theory) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([N:4]([CH2:22][CH2:23][CH3:24])[C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([C:17]2[NH:18][CH:19]=[CH:20][N:21]=2)[CH:16]=1)[C:10]([O:12]C)=[O:11])=[O:6])[CH2:2][CH3:3].[OH-].[Li+]>O1CCCC1.CO.O>[CH2:22]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([C:17]2[NH:21][CH:20]=[CH:19][N:18]=2)[CH:16]=1)[C:10]([OH:12])=[O:11])=[O:6])[CH2:23][CH3:24]
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc(-c2ncc[nH]2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCN(CCC)C(=O)c1cc(C(=O)O)cc(-c2ncc[nH]2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of the ester from step 1 (260 mg, 0.79 mmol) in 2:1:1 tetrahydrofuran/methanol/water (8 mL) is added lithium hydroxide (140 mg, 3.3 mmol). The reaction mixture is stirred at room temperature for 2 h, and concentrated under reduced pressure. The residue is partitioned between water (10 mL) and diethyl ether (10 mL). The aqueous layer is acidified to pH 4-5 with 1 N hydrochloric acid and extracted with 3:1 chloroform/2-propanol (3×30 mL). The combined organic layers are dried (sodium sulfate), filtered, and concentrated under reduced pressure to provide the title compound. 1H NMR (300 MHz, CD3OD) δ 8.64 (s, 1H), 8.10 (s, 1H), 8.01 (s, 1H), 7.28 (s, 2H), 3.52 (m, 2H), 3.26 (m, 2H), 1.75 (m, 2H), 1.59 (m, 2H), 1.02 (t, J=7 Hz, 3H), 0.75 (t, J=7 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4](C)[CH:3]=1.[H][H].[CH2:18](O)C>O.[Pt]=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][C:7]=1[CH3:18]
Reactant: CCOC(=O)/C=C/c1ccc(F)cc1C
Reactant: [H][H]
Reactant: CCO
Agent: O=[Pt]
Solvent: O
Product: CCOC(=O)CCc1ccc(F)c(C)c1

Procedure:
A mixture of (E)-ethyl 3-(4-fluoro-2-methylphenyl)acrylate (32.9 g, 0.16 mol) and platinum oxide hydrate (0.5 g, EM Scientific) in 95% ethanol (125 ml) was placed on a Parr apparatus. After the appropriate amount of hydrogen was taken up, the catalyst was filtered and the filtrate was concentrated in vacuo to give 33.7 g of ethyl 3-(4-fluoro-3-methylphenyl)propionate. A 1.0 g sample was purified by chromatography on silica gel with hexanes:dichloromethane as eluent to give 0.92 g of ethyl 3-(4-fluoro-3-methylphenyl) propionate as a colourless oil: NMR (CDCl3); δ6.78-7.26 (m, 3H, Ar), 4.13 (q, 2H, CH2), 2.90 (t, 2H, CH2), 2.54 (t, 2H, CH2), 2.31 (s, 3H, CH3), 1.24 (t, 3H CH3).
Reaction SMILES: [C:1](=O)(OC(Cl)(Cl)Cl)[O:2]C(Cl)(Cl)Cl.Cl.[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:27])[CH2:22][C:23]([F:26])([F:25])[F:24])[CH2:17][CH2:16]1.[CH3:28][O:29][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[C:38]=1[CH:37]([NH:39][C:40]1[CH:49]=[CH:48][C:47]3[C:42](=[CH:43][CH:44]=[C:45]([NH2:50])[CH:46]=3)[N:41]=1)[CH2:36][CH2:35]2>>[CH3:28][O:29][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[C:38]=1[CH:37]([NH:39][C:40]1[CH:49]=[CH:48][C:47]3[C:42](=[CH:43][CH:44]=[C:45]([NH:50][C:1]([NH:14][CH:15]4[CH2:16][CH2:17][N:18]([C:21](=[O:27])[CH2:22][C:23]([F:24])([F:25])[F:26])[CH2:19][CH2:20]4)=[O:2])[CH:46]=3)[N:41]=1)[CH2:36][CH2:35]2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CC2
Reactant: NC1CCN(C(=O)CC(F)(F)F)CC1
Agent: Cl
Product: COc1cccc2c1C(Nc1ccc3cc(NC(=O)NC4CCN(C(=O)CC(F)(F)F)CC4)ccc3n1)CC2

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, 1-(4-amino-piperidin-1-yl)-3,3,3-trifluoro-propan-1-one hydrochloride and rac-N2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine (Example 172); MS: m/e=542.8 (M+H+).