Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].B(F)(F)F.[CH2:9]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:10]1[O:12][CH2:11]1.C(=O)(O)[O-].[Na+]>C(OCC)C>[CH3:1][C:2]1([CH3:4])[O:12][CH:10]([CH2:9][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][O:3]1
Reactant: CC(C)=O
Reactant: CCCCCOCC1CO1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CCCCCOCC1COC(C)(C)O1
Temperature: 25 °C
Yield: 94 %

Procedure:
To a mixture of 406 g of acetone and 10 g of boron trifluoride, 163 g of n-pentyl glycidyl ether obtained in a similar manner to Example 3 was added dropwise over 2 hours while cooling to maintain the temperature at 20 to 30° C. After reaction for 1 hour, the reaction mixture was poured into a large amount of a diluted aqueous solution of sodium bicarbonate for neutralization. Diethyl ether was added and the resulting mixture was stirred. The reaction mixture was allowed to stand to cause separation. The diethyl ether layer thus separated was dehydrated by the addition of sodium sulfate. From the residue, the solid was removed by filtration and then, the solvent was distilled off from the filtrate at room temperature under reduced pressure (133 Pa). To 215 g of 2,2-dimethyl-4-pentyloxymethyl-1,3-dioxolane thus obtained, 1000 mL of ethanol and 1000 mL of 0.1 N sulfuric acid were added. While stirring, the resulting mixture was heated to 80° C. After reaction for 10 hours, the reaction mixture was cooled to room temperature. The solution thus obtained was treated twice with 1000 mL of diethyl ether to extract an oil layer. To the extracted oil layer was added an aqueous solution of sodium bicarbonate, and the remaining acid was thereby neutralized. After separation and removal of the resulting water layer, and diethyl ether was distilled off, 20 g of sodium acetate was added to the residue. The resulting mixture was heated to 180° C. and stirred for 5 hours. After neutralization with 16.8 g of sodium bicarbonate, purification was effected by distillation under reduced pressure (133 to 266 Pa, 114 to 115° C.), whereby 108.7 g of monopentyl glyceryl ether was obtained. As a result of GLC, it was found that the resulting compound had a purity not less than 99% and the content of organochlorine compounds was not greater than 100 ppm.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)[OH:5]>C(O)C.[Ni]>[NH2:12][C:9]1[CH:8]=[CH:7][C:6]([CH:4]([OH:5])[CH2:3][N:2]([CH3:1])[CH3:15])=[CH:11][CH:10]=1
Reactant: CN(C)CC(O)c1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Solvent: CCO
Product: CN(C)CC(O)c1ccc(N)cc1
Reaction time: 4 h
Yield: 151.3 %

Procedure:
A pressure flask was charged with a suspension 2-(dimethylamino)-1-(4-nitrophenyl)ethanol (160 mg, 0.770 mmol) in ethanol (10 mL) and Raney nickel (0.5 mL). The flask was placed on a Parr shaker, purged with H2 (30 psi), and stirred for 4 h. The crude product was filtered through celite, and concentrated to obtain the crude product (210 mg) as an off-white solid: 1H NMR (300 MHz, CDCl3) δ 7.11-7.09 (m, 2H), 6.71-6.69 (m, 2H), 4.61-4.70 (m, 1H), 2.61-2.58 (m, 1H), 2.40-2.32 (m, 1H), 2.31 (s, 3H).
Reaction SMILES: ClC1N=C(N2CCOCC2)C2SC(C=O)=CC=2N=1.CN(C1CNCC1)C.Cl[C:28]1[N:29]=[C:30]([N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)[C:31]2[S:36][C:35]([CH2:37][N:38]([CH3:45])[CH:39]3[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40]3)=[CH:34][C:32]=2[N:33]=1.CC1(C)C(C)(C)OB([C:60]2[CH:61]=[N:62][C:63]([NH2:66])=[N:64][CH:65]=2)O1>>[CH3:45][N:38]([CH2:37][C:35]1[S:36][C:31]2[C:30]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[N:29][C:28]([C:60]3[CH:61]=[N:62][C:63]([NH2:66])=[N:64][CH:65]=3)=[N:33][C:32]=2[CH:34]=1)[CH:39]1[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40]1
Reactant: CN1CCC(N(C)Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)C1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: CN(C)C1CCNC1
Agent: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: CN1CCC(N(C)Cc2cc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3s2)C1
Yield: 14 %

Procedure:
2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carboxaldehyde 10 was reacted with N,N-dimethyl-3-aminopyrrolidine using standard reductive amination conditions. The resulting crude oil (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-(1-methyl-pyrrolidin-3-yl)-amine was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine according to General Procedure A. The resulting solid was purified by mass directed chromatography (14% yield) to give 338. NMR (CDCl3, 400 MHz), 1.83-1.90 (1H, m), 2.06-2.12 (1H, m), 2.30 (3H, s), 2.31 (3H, s), 2.57-2.62 (2H, m), 2.58-2.65 (1H, m), 2.72 (1H, t, J=9.2), 3.30-3.35 (1H, m), 3.80-3.88 (2H, m), 3.88-3.94 (4H, m), 4.03-4.09 (4H, m), 5.22 (2H, br s), 7.28 (1H, s), 9.30 (2H, s). MS: (ESI+): MH+=441
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][C:11]1[N:15]=[CH:14][N:13]([C:16]2[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=2)[N:12]=1>C(OC(O)C)C.O.CCOC(C)=O>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:20][C:19]2[CH:18]=[CH:17][C:16]([N:13]3[CH:14]=[N:15][C:11]([CH3:10])=[N:12]3)=[CH:22][CH:21]=2)[N:7]=1
Reactant: Cc1ncn(-c2ccc(N)cc2)n1
Reactant: COc1ccnc(Cl)n1
Agent: CCOC(C)O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccnc(Nc2ccc(-n3cnc(C)n3)cc2)n1
Temperature: 75 °C

Procedure:
To a solution 2-chloro-4-methoxypyrimidine (2 g, 13.8 mmol) in ethoxyethanol (50 mL) was added 4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline (1.7 g, 10.6 mmol). The reaction was warmed to 75° C. for 16 h, cooled, and diluted with water and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc (4×). The combined organics were dried (MgSO4), and concentrated to give a near colorless solid which was homogeneous by analytical HPLC analysis and was used without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C1([SiH2]C2C=CC=CC=2)C=CC=CC=1.CO.Cl>O1CCCC1>[C:4]1([C@H:1]([OH:3])[CH3:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Agent: Cl
Agent: c1ccc([SiH2]c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](O)c1ccccc1

Procedure:
After dissolving a mixed solution of 0.25 mmol of [Rh(COD)Cl]2, 0.0005 mmolof(4S,4'S)-2,2'-bis(o-diarylphosphinophenyl)-4,4, 5,5'-tetrahydro-4,4'-bi(1,3-oxazole) prepared in Example 1 and 1 mmol acetophenone in 1 ml of tetrahydrofuran, the solution was stirred for an hour at room temperatures. At 0 ° C., 1 mmol of acetophenone and 1.5 mmol of diphenylsilane were added to the mixture. After the reaction mixture was stirred for 7 hours at 0° C., 5 ml of methanol and 10 ml of 0.1 N HCl aqueous solution were added. After the organic layer was extracted with diethyl ether and dried (Na2SO4), solvent was removed by vacuum distillation. The remainder was purified by using a silica column chromatography to obtain an optically active secondary alcohol, (R)-1-phenyl ethyl alcohol.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[Cl:27])=[CH:14][CH:15]=1)=[O:5])C.[NH2:28][C:29]1[N:34]=[CH:33][C:32]([CH2:35][N:36]([CH3:43])[CH2:37][C:38]([N:40]([CH3:42])[CH3:41])=[O:39])=[CH:31][CH:30]=1>C(Cl)Cl.CO>[CH3:41][N:40]([CH3:42])[C:38]([CH2:37][N:36]([CH2:35][C:32]1[CH:31]=[CH:30][C:29]([NH:28][C:4]([C:6]2[C:7]3[N:8]=[CH:9][CH:10]=[N:11][C:12]=3[C:13]([C:16]3[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=3[Cl:27])=[CH:14][CH:15]=2)=[O:5])=[N:34][CH:33]=1)[CH3:43])=[O:39]
Reactant: CN(CC(=O)N(C)C)Cc1ccc(N)nc1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2Cl)c2nccnc12
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN(C)CC(=O)N(C)C)cn3)c3nccnc23)c1F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 8-(2-chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 144.1), 2-[(6-amino-pyridin-3-ylmethyl)-methyl-amino]-N,N-dimethyl-acetamide (Step 119.1), stirring the reaction mixture for 72 h at rt. The title compound: ESI-MS: 583.0 [M+H]+; tR=4.02 min (System 1); TLC: Rf=0.36 (DCM/MeOH, 9:1).
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[CH3:17][C:18]1[O:19][C:20]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[C:21]([C:23](O)=[O:24])[N:22]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:23]([C:21]3[N:22]=[C:18]([CH3:17])[O:19][C:20]=3[C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=3)=[O:24])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: CC(F)(F)c1ccc(Cn2ncc(N)n2)o1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(C(F)(F)F)c2)o1
Product: Cc1nc(C(=O)Nc2cnn(Cc3ccc(C(C)(F)F)o3)n2)c(-c2cccc(C(F)(F)F)c2)o1

Procedure:
Following general procedure Z2, starting from 2-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-methyl-5-(3-trifluoromethyl-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([C:9]([O:11]CC)=[O:10])[C:3]=1[CH3:14].[OH-].[Na+]>>[C:9]([C:4]1[C:3]([CH3:14])=[C:2]([Cl:1])[C:7]([CH3:8])=[CH:6][N:5]=1)([OH:11])=[O:10]
Reactant: CCOC(=O)c1ncc(C)c(Cl)c1C
Agent: [Na+]
Agent: [OH-]
Product: Cc1cnc(C(=O)O)c(C)c1Cl
Yield: 85 %

Procedure:
4-Chloro-2-Ethoxycarbonyl-3,5-Lutidine (1 eq.) was suspended in 10% sodium hydroxide aqueous solution (4 eq.), the mixture was stirred and heated to 80ℑ C. After 4 hours a homogeneoussolution was obtained. The solution was washed with toluene and then acidified to pH 2.5. The white precipitate was extracted with dichloromethane (3×5 volumes). The combined organic extracts were dried over sodium sulfate, filtered and the solvent was evaporated under vacuum. The 2-carboxy-4-chloro-3,5-lutidine product was obtained as an off white solid in 85% yield.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]([C:15]2[C:16]([CH3:27])=[N:17][O:18][C:19]=2[C:20]2[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=2)[OH:14])[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([O:30][C:31]([CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)=[O:32])[CH3:29]>>[CH2:28]([O:30][C:31](=[O:32])[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:23]2[CH:24]=[CH:25][C:20]([C:19]3[O:18][N:17]=[C:16]([CH3:27])[C:15]=3[CH:13]([C:11]3[N:10]=[N:9][N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:12]=3)[OH:14])=[CH:21][CH:22]=2)=[CH:37][CH:36]=1)[CH3:29]
Reactant: CCOC(=O)CCc1ccc(B(O)O)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1cn(Cc2ccccc2)nn1
Product: CCOC(=O)CCc1ccc(-c2ccc(-c3onc(C)c3C(O)c3cn(Cc4ccccc4)nn3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using (1-benzyl-1H-[1,2,3]triazol-4-yl)-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-methanol and [4-(2-ethoxycarbonylethyl)phenyl]boronic acid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH2:10][C:9]([CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].Cl.N1CCCCC1.C(C1C=C2C(CCCC2=[O:43])=CC=1)(C)(C)C.C=O>C(O)C.Cl>[C:1]([C:5]1[CH:6]=[C:7]2[C:12]([CH2:11][CH2:10][CH:9]([CH2:15][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:8]2=[O:43])=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(c1)C=C(CN1CCCCC1)CC2
Reactant: CC(C)(C)c1ccc2c(c1)C(=O)CCC2
Agent: C=O
Agent: Cl
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)(C)c1ccc2c(c1)C(=O)C(CN1CCCCC1)CC2
Yield: 43 %

Procedure:
This Example illustrates the preparation of 6-tert-butyl-3-piperidinomethyl-1,2-dihydronaphthalene (Compound number 4 of Table I). Piperidine hydrochloride (8.9 g, 0.073 mol), 7-tert-butyl-1,2,3,4-tetrahydronaphthalen-1-one (7.0 g, 0.035 mol) and paraformaldehyde (2.2 g, 0.073 mol) were refluxed together in ethanol (150 ml) along with concentrated hydrochloric acid (1 ml) as a catalyst for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue dissolved in water then extracted with diethyl ether. The resulting aqueous solution was neutralized with sodium bicarbonate and extracted with diethyl ether (2×200 ml); the ethereal extracts were dried over magnesium sulphate and concentrated under reduced pressure to give 7-tert-butyl-2-piperidinomethyl-1,2,3,4-tetrahydronaphthalen-1-one (4.5 g, 43% yield) as a buff coloured solid melting at 62°-3°. The 7-tert-butyl-2-piperidinomethyl-1,2,3,4-tetrahydronaphthalen-1-one (4.5 g, 0.015 mol) was dissolved in methanol (100 ml) and sodium borohydride (0.6 g, 0.016 mol) was added portionwise over 30 minutes at room temperature. It was stirred for 3 hours at room temperature then the methanol was evaporated under reduced pressure and the residue treated with water (100 ml) and extracted with ether (2×100 ml) which was washed with brine, dried over magnesium sulphate and evaporated under reduced pressure to give a viscous oil (4.0 g) which crystallised on standing. Separation by column chromatography on silica gel (Merck 60) using a gradient elution of petrol 60°-80° to ethyl acetate gave the alcohol as two isomers:
Reaction SMILES: [Cl-].[Li+].[N-:3]=[N+:4]=[N-:5].[Na+].[Cl:7][C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[NH:11][C:12]1[C:13]2[CH:20]=[C:19]([C:21]#[N:22])[NH:18][C:14]=2[N:15]=[CH:16][N:17]=1>COC(O)C>[Cl:7][C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[NH:11][C:12]1[C:13]2[CH:20]=[C:19]([C:21]3[NH:22][N:5]=[N:4][N:3]=3)[NH:18][C:14]=2[N:15]=[CH:16][N:17]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Agent: COC(C)O
Agent: [Cl-]
Agent: [Li+]
Product: Clc1cccc(Nc2ncnc3[nH]c(-c4nnn[nH]4)cc23)c1
Reaction time: 6.5 h

Procedure:
19 mg (0.45 mmol) of lithium chloride and 19.5 mg (0.30 mmol) of sodium azide are added to a solution of 80.9 mg (0.30 mmol) of 4-(3-chloroanilino)-6-cyano-7H-pyrrolo[2,3-d]pyrimidine in 1 ml of methoxyethanol and the mixture is heated to boiling for 6.5 h. The cooled reaction mixture is poured onto water/HCl (conc.) 10:1, the mixture is stirred for 30 min, and the solid is filtered off and washed with water. Dissolving the crystals in THF/isopropanol, partial evaporation to crystallization, filtering off and washing with diethyl ether affords 4-(3-chloroanilino)-6-(tetrazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidine; HPLC: tRet(Grad20)=9.5; TLC-Rf=0.45 (CH2Cl2/methanol=7:1); FAB-MS: (M+H)+=313.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([C:26](OC(C)(C)C)=O)[CH2:22][CH2:21]4)[C:14]=3[S:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].ClC1[N:39]=[CH:38][C:37]([CH2:40][CH3:41])=[CH:36][N:35]=1>>[CH2:40]([C:37]1[CH:36]=[N:35][C:26]([N:23]2[CH2:24][CH2:25][N:20]([C:19]3[C:14]4[S:13][CH:12]=[C:11]([C:8]5[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=5)[C:15]=4[N:16]=[CH:17][N:18]=3)[CH2:21][CH2:22]2)=[N:39][CH:38]=1)[CH3:41]
Reactant: CCc1cnc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3c(-c4ccc(S(C)(=O)=O)cc4)csc23)CC1
Product: CCc1cnc(N2CCN(c3ncnc4c(-c5ccc(S(C)(=O)=O)cc5)csc34)CC2)nc1

Procedure:
The compound obtained in Example 10 was deprotected as in Step 5-3), and subjected to a reaction with 2-chloro-5-ethylpyrimidine under conditions similar to Example 1 to obtain the title compound.
Reaction SMILES: Br[CH:2]1[CH2:8][CH2:7][O:6][C:5]2[CH:9]=[C:10]([Br:13])[CH:11]=[CH:12][C:4]=2[C:3]1=O.[NH2:15][NH:16][C:17]([NH2:19])=[S:18]>>[Br:13][C:10]1[CH:11]=[CH:12][C:4]2[C:3]3[N:19]=[C:17]([NH:16][NH2:15])[S:18][C:2]=3[CH2:8][CH2:7][O:6][C:5]=2[CH:9]=1
Reactant: NNC(N)=S
Reactant: O=C1c2ccc(Br)cc2OCCC1Br
Product: NNc1nc2c(s1)CCOc1cc(Br)ccc1-2
Temperature: 25 °C
Yield: 70.2 %

Procedure:
A solution of 4,8-dibromo-3,4-dihydro-2H-benzo[b]oxepin-5-one (1.5 g, 4.7 mmol) and thiosemicarbazide (455 mg, 5 mmol) in IMS (15 mL) was stirred at 85° C. for 2 h, allowed to cool down to RT and filtered to give the title compound as a beige solid (1.03 g, 70%). LCMS (Method B): RT=3.06 min, [M+H]+=312 and 314. 1H NMR (DMSO-d6): 10.10 (2H, bs), 9.80 (1H, bs), 8.27 (1H, d, J=8.6 Hz), 7.34 (1H, dd, J=8.6, 2.1 Hz), 7.22 (1H, d, J=2.1 Hz), 4.31 (2H, t, J=5.0 Hz), 3.19 (2H, t, J=5.0 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Cl.C(N1N=C(C2C=CC(OC)=C(OC)C=2)[C@H]2[C@H](CCCC2)C1=O)C1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:26][C:25]3[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=3[C:23]([F:22])([F:32])[F:33])[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: FC(F)(F)c1ccccc1CCl
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Agent: COc1ccc(C2=NN(Cc3ccccc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(Cc3ccccc3C(F)(F)F)C(=O)[C@H]3CCCC[C@@H]23)cc1OC

Procedure:
Prepared from compound 1 and 2-trifluoromethylbenzylchloride as described for compound 78. Purified by chromatography (dichloromethane). Crystallized from petroleum ether (60°-95° C.). M.p. 87°-88° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.C(OC([NH:29][C@H:30]1[C@@H:34]([CH3:35])[CH2:33][NH:32][CH2:31]1)=O)(C)(C)C.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:29][C@H:30]1[C@@H:34]([CH3:35])[CH2:33][N:32]([C:11]2[C:12]([O:14][CH3:15])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:17])[CH2:31]1
Reactant: C[C@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COc1c(N2C[C@@H](N)[C@@H](C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 35.4 %

Procedure:
A mixture of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (200 mg), cis-3-t-butoxycarbonylamino-4-methylpyrrolidine (150 mg), DBU (110 mg) and anhydrous acetonitrile (3 ml) was refluxed for 5 hours. After cooling, the resulting precipitate was collected by filtration. This precipitate was added to the mixture of concentrated hydrochloric acid-methanol (1:1, 6 ml) and stirred for 1.5 hours at room temperature. The reaction mixture was neutralized by concentrated aqueous ammonia and allowed to stand in the refrigerator. The resulting crystals were collected by filtration and washed with cold water to give the title compound (90 mg) as colorless prisms, mp 185°-188° C. (decompd.).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[C:7](/[CH:10]=[C:11](\[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)/[C:12](O)=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].S(Cl)(Cl)=O.[OH-].[NH4+:35]>>[CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[C:7](/[CH:10]=[C:11](\[CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)/[C:12]([NH2:35])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [NH4+]
Reactant: CCCCc1ncc(/C=C(\Cc2ccccc2)C(=O)O)n1Cc1ccccc1Cl
Agent: [OH-]
Solvent: O=S(Cl)Cl
Product: CCCCc1ncc(/C=C(\Cc2ccccc2)C(N)=O)n1Cc1ccccc1Cl

Procedure:
(E)-3-[2-n-Butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzyl-2-propenoic acid, prepared in Example 2, is treated with thionyl chloride and then ammonium hydroxide, as described in Example 57, to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[Cl:22])[C:13]2[C:12](=[O:23])[N:11](C)[CH:10]=[CH:9][C:8]=2[NH:7][C:6]=1[CH3:25])=[O:4]>CO>[CH3:1][O:2][C:3]([C:5]1[CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[Cl:22])[C:13]2[C:12](=[O:23])[NH:11][CH:10]=[CH:9][C:8]=2[NH:7][C:6]=1[CH3:25])=[O:4]
Reactant: COC(=O)C1=C(C)Nc2ccn(C)c(=O)c2C1c1cccc(Cl)c1Cl
Solvent: CO
Product: COC(=O)C1=C(C)Nc2cc[nH]c(=O)c2C1c1cccc(Cl)c1Cl

Procedure:
(a.m) (±)-4-(2,3-Dichlorophenyl)-1,4,5,6-tetrahydro-2,6-dimethyl-5-oxo-1,6-naphthyridine-3-carboxylic acid methyl ester; mp 290°-291° C. (from methanol); process (b).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH3:18])[C:11]3[N:12]([C:14](I)=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.[C:19]([C:21]1[CH:22]=[CH:23][C:24]([NH2:27])=[N:25][CH:26]=1)#[CH:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH3:18])[C:11]3[N:12]([C:14]([C:20]#[C:19][C:21]4[CH:22]=[CH:23][C:24]([NH2:27])=[N:25][CH:26]=4)=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)cn2c(I)cnc12
Reactant: C#Cc1ccc(N)nc1
Product: Cc1cc(-c2ccc(Cl)cc2)cn2c(C#Cc3ccc(N)nc3)cnc12

Procedure:
The title compound was prepared from 6-(4-chloro-phenyl)-3-iodo-8-methyl-imidazo[1,2-a]pyridine (example C.21 step 2) (737 mg, 2 mmol) and 5-ethynyl-pyridin-2-ylamine (example D.1) (307 mg, 2.6 mmol) according to general procedure II. Obtained as an off-white solid (240 mg, 33%). MS (ISP) 359.0 [(M+H)+], 361.0 [(M+2+H)+]; mp 231-234° C.
Reaction SMILES: [Na].[C:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH2:13](Cl)[CH2:14][CH3:15]>C(O)C>[C:2]([C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[CH:10][CH:11]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: CCCCl
Agent: [Na]
Solvent: CCO
Product: CCCOc1ccc(C(C)(C)C)cc1

Procedure:
Into 70 ml. of ethanol (absolute), 0.92 g. of sodium metal was dissolved and 6.0 g. (0.04 M) of 4-tert-butylphenol was added and then, 3.5 g. (0.044 M) of n-propylchloride was added. The mixture was refluxed for 20 hours and ethanol was distilled off and water was added. The reaction product was extracted with benzene and benzene layer was washed with 3% NaOH aqueous solution and with water and dehydrated over sodium sulfate and then, benzene was distilled off and a residue was distilled under a reduced pressure to obtain 4-tert-butyl-1-n-propoxybenzene. The product was dissolved into 6 ml. of glacial acetic acid and then, 12 ml. of fuming nitric acid (d=1.5) was added at 0° to 5° C. to react them for 1 hour and then, the reaction was continued at the ambient temperature for 1 hour at 35° to 40° C. for 4 hours. The reaction mixture was poured into ice water and the product was extracted with chloroform and washed with water, with 3% Na2CO3 aqueous solution and with water and dehydrated over sodium sulfate and chloroform was distilled off and the residue was recrystallized from ethanol to obtain 4.5 g. (43%) of a pale yellow crystal. (melting point of 106° to 107° C.)
Reaction SMILES: CON(C)[C:4](=[O:24])[CH2:5][CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=[C:9]1[CH2:21][CH2:22][CH3:23].[CH2:26]([Mg]Br)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>C(OCC)C>[CH2:21]([C:9]1[N:8]([CH2:7][CH2:6][CH2:5][C:4](=[O:24])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=1)[CH2:22][CH3:23]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCC(=O)N(C)OC
Reactant: CCCCCC[Mg]Br
Solvent: CCOCC
Product: CCCCCCC(=O)CCCn1c(CCC)nc2cnc3ccccc3c21

Procedure:
The general method described in Part E of Example 37 was used to react N-methoxy-N-methyl-4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyramide (6.10 g, 17.9 mmol) with n-hexylmagnesium bromide (13.5 mL of a 2 M solution in diethyl ether, 27 mmol) to provide 1-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)decan-4-one (6.10 g) as a yellow oil that was used directly in the next step without further purification.