Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]([OH:15])=O)=[C:11]([CH3:16])[O:10][N:9]=1.[CH2:17]([O:24][C:25](=[O:35])[NH:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH:30]([NH2:34])[CH2:29]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:17]([O:24][C:25](=[O:35])[NH:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH:30]([NH:34][C:13]([C:12]2[C:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:9][O:10][C:11]=2[CH3:16])=[O:15])[CH2:29]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1onc(-c2cnccc2Cl)c1C(=O)O
Reactant: NC1CCCC(CNC(=O)OCc2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2cnccc2Cl)c1C(=O)NC1CCCC(CNC(=O)OCc2ccccc2)C1
Yield: 66.1 %

Procedure:
Combine 3-(4-chloro-pyridin-3-yl)-5-methyl-isoxazole-4-carboxylic acid (0.50 g, 0.0021 mol) with (3-amino-cyclohexylmethyl)-carbamic acid benzyl ester (0.63 g, 0.0021 mol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.40, 0.0021 mol), 1-hydroxy-7-azabenzo-triazole (0.29 g, 0.0021 mol), and N,N-diisopropylethyl amine (1.10 mL, 0.0063 mol), in N,N-dimethylformamide (10 mL) and stir overnight at ambient temperature. Concentrate in vacuo and take up in water and extract with ethyl acetate. Wash the combined extracts with water and dry over sodium sulfate. Concentrate and elute over silica gel using methanol/dichloromethane to give 0.67 g (66%) of the desired amide. MS(ES): (M+1)+ 483.2, 485.2 m/z.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[C:12]([Cl:15])(=[O:14])[CH3:13].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)CCl>[ClH:15].[C:12]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2)(=[O:14])[CH3:13]
Reactant: Oc1cccc2cccnc12
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)c1ccc(O)c2ncccc12
Product: Cl
Temperature: 70 °C
Reaction time: 2 h

Procedure:
8-hydroxyquinoline (500 gms/3.44 moles) was dissolved in ethylene chloride (5 lits) at 25-30° C. in an inert atmosphere. To this solution was added acetyl chloride (260 ml/4.12 moles) drop wise in 2 hours. The reaction mass was stirred for 15-20 minutes. Then, aluminum chloride (1.15 Kg/8.62 moles) was added in lots in 2 hours. The reaction mass was stirred at 25-30° C. for 15-20 minutes and heated to 70° C. for 13-14 hours. After completion of reaction, the reaction mass was cooled to 25-30° C. and slowly quenched in a mixture of crushed ice (10 Kg) and conc. HCl (500 ml). The resulting slurry was stirred for 15-20 minutes. The crude 5-acetyl-8-hydroxyquinoline hydrochloride was isolated by filtration, washed with 2 liters of acetone and dried under vacuum for 1 hour. Yield: 680 gms.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[N:5][OH:6])[NH2:4].C(Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[N:10][CH:9]=1.[C:15]1(C)C=CC=CC=1>C(OCC)(=O)C>[Cl:1][CH2:2][C:3]1[N:4]=[C:15]([C:9]2[CH:8]=[CH:13][CH:12]=[CH:11][N:10]=2)[O:6][N:5]=1
Reactant: NC(CCl)=NO
Reactant: ClCc1cccnc1
Reactant: Cc1ccccc1
Solvent: CCOC(C)=O
Product: ClCc1noc(-c2ccccn2)n1
Temperature: 110 °C

Procedure:
Step-1: To the stirred solution of 2-chloroacetamidoxime (1.0 g, 9.2 mmol, prepared as per the procedure given in PCT/US02/22897) in toluene (15 ml) was added nicotinyl chloride (1.37 g, 9.67 mmol) and heated at 110° C. for 4 hr. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with aqueous saturated sodium bicarbonate solution (2×25). Organic layer was evaporated under vacuum to yield the crude product. The crude product was purified using silica gel column chromatography (15% Acetone-Hexane) to give 2-(3-chloromethyl-[1,2,4]-oxadiazole-5-yl)-pyridine in 55% (0.550 g) yield. MS: m/z: 196.7 (M+1).
Reaction SMILES: C1(NC2CCCCC2)CCCCC1.[OH-].[Na+].[C:16]([CH:19](C)[CH2:20][CH2:21][C:22]([N:24]1[CH2:31][CH2:30][CH2:29][C@H:25]1[C:26]([OH:28])=[O:27])=[O:23])(O)=O>CO>[CH3:16][CH2:19][CH2:20][CH2:21][C:22]([N:24]1[CH2:31][CH2:30][CH2:29][C@H:25]1[C:26]([OH:28])=[O:27])=[O:23]
Reactant: CC(CCC(=O)N1CCC[C@H]1C(=O)O)C(=O)O
Agent: C1CCC(NC2CCCCC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCC(=O)N1CCC[C@H]1C(=O)O

Procedure:
The dicyclohexylamine salt (8.7 g.) is dissolved in 60 ml. of methanol and 60 ml. sodium hydroxide are added while stirring. To this 100 ml. of Dowex 50 resin is added to make the pH acid. This is applied to a 300 ml. column of Dowex 50 resin and eluted with water. Those fractions which are COOH-reagent positive are pooled and lyophilized to obtain 4.78 g. of 1-(4-carboxy-4-methylbutanoyl)-L-proline.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[C:13]([NH2:14])=[CH:12][NH:11][N:10]=1.[N:15]1[N:19]2[CH:20]=[CH:21][CH:22]=[N:23][C:18]2=[C:17]([C:24](O)=[O:25])[CH:16]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[C:13]([NH:14][C:24]([C:17]2[CH:16]=[N:15][N:19]3[CH:20]=[CH:21][CH:22]=[N:23][C:18]=23)=[O:25])=[CH:12][NH:11][N:10]=1
Reactant: Cc1ccc(C)c(-c2n[nH]cc2N)c1
Reactant: O=C(O)c1cnn2cccnc12
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cnc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C)c(-c2n[nH]cc2NC(=O)c2cnn3cccnc23)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 56.4 %

Procedure:
A mixture of 3-(2,5-dimethylphenyl)-1H-pyrazol-4-amine (0.300 g, 1.60 mmol, 1 eq), pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (289.2 mg, 1.773 mmol, 1.11 eq), 7-azabenzotriazol-1-yloxy-tris-(pyrrolidino)phosphonium hexafluorophosphate (1.087 g, 2.096 mmol, 1.31 eq), N,N-diisopropylethylamine (1.0 mL, 5.7 mmol, 3.6 eq), and 4-dimethylaminopyridine (42.3 mg, 0.346 mmol, 0.22 eq) in 8.0 mL N,N-dimethylformamide was stirred at 50° C. for 3 hours. The reaction mixture was partitioned between ethyl acetate and water, and the organic portion washed with brine, dried over magnesium sulfate, and concentrated. The crude product was purified by flash chromatography on silica gel (40 to 100% ethyl acetate in dichloromethane) to yield 299.8 mg (56%) of N-(3-(2,5-dimethylphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=333.3; 1H NMR (400 MHz, DMSO-d6) δ: 9.67 (s, 0.7H), 9.55 (s, 0.3H), 9.32 (d, 1H), 8.64 (s, 1H), 8.49 (d, 1H), 8.27 (s, 1H), 7.29 (d, 1H), 7.22 (m, 3H), 2.34 (s, 3H), 2.24 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[C:23]1[NH:27][C:26]2[CH:28]=[C:29]([C:31]([O:33][CH3:34])=[O:32])[S:30][C:25]=2[CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:38]1[CH2:43][CH2:42][CH2:41][CH:40]=[CH:39]1.C(OCC)(=O)C>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[C:23]1[NH:27][C:26]2[CH:28]=[C:29]([C:31]([O:33][CH3:34])=[O:32])[S:30][C:25]=2[C:24]=1[CH:43]1[CH2:42][CH2:41][CH2:40][CH:39]=[CH:38]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrC1C=CCCC1
Reactant: COC(=O)c1cc2[nH]c(-c3ccc(OCc4ccccc4)cc3OCc3ccccc3)cc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2[nH]c(-c3ccc(OCc4ccccc4)cc3OCc3ccccc3)c(C3C=CCCC3)c2s1
Reaction time: 0.33 h
Yield: 84.7 %

Procedure:
To a solution of methyl 5-(2,4-bisbenzyloxyphenyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate (1.36 g, 2.90 mmol) in N,N-dimethylformamide (15 ml) was added sodium hydride (60% in oil, 127 mg, 3.19 mmol) under ice-cooling and the mixture was stirred for 20 min. 3-Bromocyclohexene (0.34 ml, 2.95 mmol) was added and the mixture was stirred under ice-cooling for 50 min. Ethyl acetate (20 ml) was added to the reaction mixture, and the organic layer was washed successively with water (20 ml×3) and saturated brine (10 ml) and dried over sodium sulfate. After filtration and concentration, a mixed solvent (10 ml) of hexane:ethyl acetate (10:1) was added. The precipitated solid was collected by filtration. The solid was washed with a mixed solvent (5 ml×3) of hexane:ethyl acetate (10:1), and dried under reduced pressure to give methyl 5-(2,4-bisbenzyloxyphenyl)-6-(cyclohex-2-enyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate (1.35 g, yield 85%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([C:14]1[C:23]([CH3:24])=[N:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1)[CH2:11][C:12]#[CH:13]>>[F:9][CH2:8][C:4]1[N:3]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][C:14]2[C:23]([CH3:24])=[N:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: C#CCCc1nc2ccccc2nc1C
Reactant: FCc1cccc(Br)n1
Product: Cc1nc2ccccc2nc1CCC#Cc1cccc(CF)n1
Yield: 16.2 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (24 mg, 0.13 mmol) and 2-but-3-ynyl-3-methyl-quinoxaline (25 mg, 0.13 mmol). Reaction time: 14 hours. The crude residue was purified by preparative chromatography plate (Et2O/pentane 7:3) to yield 6.4 mg (21 μmol, 13%) of 2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-3-methylquinoxaline as a yellow solid.
Reaction SMILES: C1([C@H](C)C([O:10][CH2:11][C:12]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[F:34])([OH:26])[C:13]([S:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)([CH3:15])[CH3:14])=O)C=CC=CC=1.O.[OH-].[Li+].C(OCC)C>C1COCC1.O>[F:34][C:28]1[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:27]=1[C:12]([OH:26])([C:13]([S:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)([CH3:15])[CH3:14])[CH2:11][OH:10]
Reactant: COc1ccc(CSC(C)(C)C(O)(COC(=O)[C@@H](C)c2ccccc2)c2ccc(F)cc2F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(CSC(C)(C)C(O)(CO)c2ccc(F)cc2F)cc1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
In a mixed solvent of 100 ml of THF and 30 ml of water was dissolved 10.0 g (20.0 mmol) of 2-(2,4-difluorophenyl)-2-hydroxy-3-((4-methoxyphenyl)methylthio)-3-methylbutyl (S)-(+)-2-phenylpropionate ([α]25 +15.9° (c=1.09, MeOH)), and 1.68 g (40.0 mmol) of lithium hydroxide monohydrate was added thereto in divided portions with stirring under ice-cooling. The mixture was warmed to room temperature and stirred for 30 hours. To the reaction mixture was added diethyl ether, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution and dried. The solvent was removed by distillation under reduced pressure, and the residue was subjected to column chromatography using a mixed solvent of hexane and ethyl acetate (5:1) as an eluent. The solvent was removed by distillation under reduced pressure to obtain 7.3 g (99%) of (+)-2-(2,4-difluorophenyl)-3-((4-methoxyphenyl)methylthio)-3-methylbutane-1,2 -diol as a colorless oily substance.
Reaction SMILES: F[B-](F)(F)F.C(N([S+](F)F)CC)C.[Cl:14][C:15]1[N:20]=[CH:19][C:18]([C:21]2([C:28]#[N:29])[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]2)=[CH:17][CH:16]=1.[FH:30].[FH:31].F.C(N(CC)CC)C>C(Cl)Cl>[Cl:14][C:15]1[N:20]=[CH:19][C:18]([C:21]2([C:28]#[N:29])[CH2:26][CH2:25][C:24]([F:31])([F:30])[CH2:23][CH2:22]2)=[CH:17][CH:16]=1
Reactant: F
Reactant: N#CC1(c2ccc(Cl)nc2)CCC(=O)CC1
Agent: CCN(CC)[S+](F)F
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CC1(c2ccc(Cl)nc2)CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 54.1 %

Procedure:
To a stirred suspension of (diethylamino)difluorosulfonium tetrafluoroborate (16.5 g, 72.1 mmol) in DCM (150 mL) at room temperature under nitrogen atmosphere was added 1-(6-chloro-pyridin-3-yl)-4-oxo-cyclohexanecarbonitrile (4.2 g, 18 mmol) followed by triethylamine trihydrofluoride (8.68 g, 53.8 mmol). The reaction mixture was stirred for 6 hours at room temperature. The resulting mixture was then quenched by adding a saturated aqueous solution of sodium bicarbonate, stirred for 10 minutes, and the resulting mixture was extracted with DCM (3×25 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (1:10 to 1:5 AcOEt/hexanes) to afford 1-(6-chloro-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile (2.5 g, 54%). LC-MS (m/z) 257.0 (MH+). 1H NMR (400 MHz, CDCl3) δ ppm 8.56 (d, J=2.2 Hz, 1 H), 7.79 (dd, J=8.4, 2.6 Hz, 1 H), 7.42 (d, J=8.4 Hz, 1 H), 2.09-2.41 (m, 8 H).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].Br[C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:9][O:8][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2
Reactant: C#CCCCC(=O)OC
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CCCC#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method D above, methyl 5-hexynoate (109 mg, 0.87 mmol) (see below) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (179 mg, 0.62 mmol) (Starting Material 1 supra) using (Ph3P)2PdCl2 (30 mg) and CuI (15 mg) as catalyst in DMF (4 mL) and Et3N (4 mL) as solvent at 70° C. for 15 h to yield (Z)-6-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-5-hexynoic acid methyl ester. (Yield 78 mg, 35%).
Reaction SMILES: N1(C(C([NH:12][CH:13]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:14]([NH:16][CH:17]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)[C:18]([OH:20])=O)=[O:15])=O)=O)CCCCCC1.[OH:40][CH2:41][CH2:42][NH2:43].[CH3:44][N:45]([CH:47]=[O:48])[CH3:46]>>[CH2:29]([O:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][CH:17]([NH:16][C:14]([CH:13]([NH:12][C:47]([N:45]2[CH2:46][CH2:37][CH2:36][CH2:13][CH2:14][CH2:44]2)=[O:48])[CH2:36][CH:37]([CH3:39])[CH3:38])=[O:15])[C:18](=[O:20])[NH:43][CH2:42][CH2:41][OH:40])=[CH:27][CH:26]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)CC(NC(=O)C(=O)N1CCCCCC1)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: NCCO
Reactant: CN(C)C=O
Product: CC(C)CC(NC(=O)N1CCCCCC1)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)NCCO
Reaction time: 8 h

Procedure:
A suspension of the resin prepared in Example AS (2-{2[(Azepane-1-carbonyl-carbonyl)-amino]-4-methyl-pentanoylamino }-3-(4-benzyloxy-phenyl) propionic acid kaiser oxime resin ester) (0.5 g, load Å 0.3-0.5 mmol/g resin) in 4 mL of DMF was treated with 2-hydroxyethylamine (2.5 mmol). The resulting suspension was shaken overnight, and the resin was removed by filtration. The resin was washed with additional DMF, and the combined solvent was removed under vacuum. The residue was dissolved in CH2Cl2 or ethyl acetate and washed with aqueous 0.5N HCl solution. The organic phase was dried and concentrated. The residue was purified give the title compound by preparative HPLC using the following conditions:
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[S:10][N:9]=[C:8]([CH3:11])[C:7]=1[CH2:12]O>C(Cl)(Cl)Cl>[Cl:3][CH2:12][C:7]1[C:8]([CH3:11])=[N:9][S:10][C:6]=1[Cl:5]
Reactant: O=S(Cl)Cl
Reactant: Cc1nsc(Cl)c1CO
Solvent: ClC(Cl)Cl
Product: Cc1nsc(Cl)c1CCl
Reaction time: 3 h
Yield: 100.2 %

Procedure:
3.26 g (27.44 mmoles) of thionyl chloride was added, at room temperature, to a solution of 1.50 g (9.15 mmoles) of (5-chloro-3-methyl-isothiazol-4-yl)-methanol dissolved in 10 ml of chloroform. The mixture was stirred for 3 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was subjected to vacuum distillation to remove the solvent contained therein, to obtain 1.67 g (yield: quantitative) of 4-chloromethyl-5-chloro-3-methylisothiazole.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([NH2:20])[N:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:22]OC(OC)OC.C([O-])(O)=O.[Na+]>C1(S(O)(=O)=O)C=CC=CC=1.C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH2:12][CH2:11][N:10]([C:13]2[N:14]=[C:15]3[NH:20][CH:22]=[N:19][C:16]3=[CH:17][CH:18]=2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(OC)OC
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(N)c(N)n2)C1
Agent: O=C([O-])O
Agent: O=S(=O)(O)c1ccccc1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1=CN(c2ccc3nc[nH]c3n2)CC1
Yield: 95.4 %

Procedure:
The solution of [1-(5,6-diamino-pyridin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (2 g, 6.82 mmole), trimethylorthoformate (3.83 g, 25.9 mmole), benzenesulfonic acid (43 mg, 0.27 mmole) and toluene (100 ml) was heated to reflux overnight. The reaction solution was basified with NaHCO3 and concentrated to afford crude [1-(3H-imidazo[4,5-b]pyridine-5-yl)-pyrrolin-3-yl]-carbamic acid tert-butyl ester (1.96 g, 94%) as a dark green solid. MS(ESI) m/z 304 [M+1].
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH2:15]([C:17]1[N:18]([CH2:31][CH2:32][CH2:33][C:34]#[CH:35])[C:19]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:22]=[C:21]([NH2:29])[C:20]=2[N:30]=1)[CH3:16]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].[Cu]I>[CH2:15]([C:17]1[N:18]([CH2:31][CH2:32][CH2:33][C:34]#[C:35][C:3]2[CH:2]=[CH:7][CH:6]=[CH:5][N:4]=2)[C:19]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:22]=[C:21]([NH2:29])[C:20]=2[N:30]=1)[CH3:16]
Reactant: C#CCCCn1c(CC)nc2c(N)nc3ccccc3c21
Reactant: Ic1cccnc1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCc1nc2c(N)nc3ccccc3c2n1CCCC#Cc1ccccn1
Reaction time: 1 h
Yield: 18.8 %

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (0.095 g, 0.03 eq.), 3-iodopyridine (0.626 g, 1.1 eq.), triethylamine (0.923 g, 3 eq.), and copper (I) iodide (0.035 g, 0.06 eq.) were added sequentially to a solution of 2-ethyl-1-(4-pentynyl) 1H-imidazo[4,5-c]quinolin-4-amine (0.85 g, 3.0 mmol, 1.0 eq.) in DMF. The reaction mixture was stirred for 1 hour and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel eluting with 4/96 methanol/dichloromethane). The product was recrystallized from a mixture of ethanol and 1,2-dichloroethane. The resulting solid was dissolved in 1:1 mixture of ethanol and 1,2-dichloroethane, treated with activated charcoal, combined with a few drops of 10% sodium hydroxide, heated and then filtered while still hot. The filtrate was concentrated under reduced pressure to provide 0.2 g of 2-ethyl-1-[5-(pyridin-2-yl)-4-pentynyl]-1H-imidazo[4,5-c]quinolin-4-amine as light brown granules, mp 188.0-192.0° C. 1H NMR (300 MHz, CDCl3) δ 8.70 (d, J=0.9 Hz, 1H), 8.55 (dd, J=4.7, 1.3 Hz, 1H), 8.06 (dd, J=8.2, 0.9 Hz, 1H), 7.82 (dd, J=8.4, 0.7 Hz, 1H), 7.71 (ddd, J=7.9, 1.7, 1.7 Hz, 1H), 7.48 (ddd, J=8.3, 7.2, 1.2 Hz, 1H), 7.25 (m, 2H), 5.46 (br s, 2H), 4.66 (t, J=7.9 Hz, 2H), 3.00 (q, J=7.4 Hz, 2H), 2.64 (t, J=6.5 Hz, 2H), 2.26 (m, 2H), 1.49 (t, J=7.4 Hz, 3H); MS (APCI) m/z 356 (M+H)+; Anal. calcd for C22H21N5.0.65H2O: C, 71.97; H, 6.12; N, 19.07. Found: C, 72.03; H, 6.06; N, 19.16.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]([F:20])([F:19])[O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1.[F:21][C:22]([F:29])([F:28])[C:23](OCC)=[O:24].OS(O)(=O)=O>C1(C)C=CC=CC=1>[F:21][C:22]([F:29])([F:28])/[C:23](/[OH:24])=[CH:17]/[C:16]([C:13]1[CH:12]=[CH:11][C:10]([O:9][C:8]([F:19])([F:20])[F:7])=[CH:15][CH:14]=1)=[O:18]
Reactant: CC(=O)c1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(/C=C(\O)C(F)(F)F)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 40.4 %

Procedure:
To a toluene (50 ml) suspension of potassium t-butoxide (3.3 g, 29 mmol) and 1-(4-trifluoromethoxy-phenyl)-ethanone (3.9 ml, 24 mmol) under an argon atmosphere was added dropwise ethyl trifluoroacetate (3.4 ml, 29 mmol) at 10° C. The suspension was stirred at ambient temperature for 14 h. The pH value of the mixture was adjusted to 6 with 10% H2SO4, the solution was extracted two times with t-butyl methylether and the combined extracts were washed with brine/ice water 1/1. The organic layer was dried over sodium sulfate, concentrated under reduced pressure and the residue purified by column chromatography (silica gel, n-heptane/ethyl acetate) to yield 2.9 g (9.7 mmol, 40%) of the title compound as orange oil.
Reaction SMILES: [CH3:1][C:2]1[NH:12][C:5]2[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[C:3]=1[CH3:13].[H-].[Na+].[Cl:16][C:17]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:18]=1[C:19]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1)=[O:20].O>CN(C=O)C>[Cl:16][C:17]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:18]=1[C:19]([C:21]1[CH:22]=[CH:23][C:24]([CH2:25][N:12]2[C:5]3[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=3[C:3]([CH3:13])=[C:2]2[CH3:1])=[CH:27][CH:28]=1)=[O:20]
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(Cl)cc1Cl
Reactant: Cc1[nH]c2cnn(C)c(=O)c2c1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C)n(Cc2ccc(C(=O)c3ccc(Cl)cc3Cl)cc2)c2cnn(C)c(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
A solution of 2,3,5-trimethyl-1H-pyrrolo[2,3-d]-pyridazin-4(5H)-one (354 mg) in DMF (30 ml) was dripped into a suspension of 60% sodium hydride-oil (96 mg) in DMF (8 ml) on an ice-water bath. The mixture was stirred at room temperature for 1 hour, after which a solution of 4-(2,4-dichlorobenzoyl)benzyl bromide (757 mg) in DMF (15 ml) was added and the mixture was further stirred at room temperature for 1.5 hours. The reaction was stopped by adding water and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developer: n-hexane-ethyl acetate 1:1) to provide the title compound as light-yellow powder (612 mg, yield 70%).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]#[N:12].[CH3:22][O:23][C:24](=[O:35])[CH:25]=[CH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29](OC)[CH:28]=1>>[NH2:12][C:11]1[C:10]2[C:9]3[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=3[N:3]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:2]=2[N:1]=[C:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:25]=1[C:24]([O:23][CH3:22])=[O:35]
Reactant: COc1ccc(Cn2c(N)c(C#N)c3c2CCCC3)cc1
Reactant: COC(=O)C=Cc1cccc(OC)c1
Product: COC(=O)c1c(-c2ccccc2)nc2c(c1N)c1c(n2Cc2ccc(OC)cc2)CCCC1
Yield: 73 %

Procedure:
Using a procedure similar to Description 6, the title compound (D12) was prepared in 73% yield from 2-amino-3-cyano-1-(4-methoxyphenyl)methyl-4,5,6,7-tetrahydroindole (D5) and methyl-3-methoxycinnamate.