Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH:11]([C:13]1[CH:14]=[CH:15][C:16]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:17]([CH:27]=1)[C:18]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[O:19])=O.[C:36]([O:39][CH2:40][CH3:41])(=[O:38])[CH3:37].CCCCCC>O1CCCC1>[C:30]1([CH2:29][O:28][C:16]2[CH:15]=[CH:14][C:13](/[CH:11]=[CH:37]\[C:36]([O:39][CH2:40][CH3:41])=[O:38])=[CH:27][C:17]=2[C:18]([NH:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[O:19])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(C)=O
Reactant: O=Cc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)/C=C\c1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
0.5N KHMDS (1.81 ml, 0.90 mmol) was added to a solution of triethyl phosphonoacetate (0.20 g, 0.90 mmol) in tetrahydrofuran (5 ml) at −78° C. The solution was stirred at −78° C. for 15 minutes, then a suspension of 5-formyl-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzamide (may be prepared as described in Example 66; 200 mg, 0.60 mmol) in tetrahydrofuran (10 ml) was added dropwise over 3 minutes. The mixture was stirred at −78° C. for 15 minutes. It was then allowed to warm to room temperature and stirred for a further hour. The reaction was quenched with saturated NH4Cl (10 ml) and extracted with ethyl acetate (2×10 ml). The combined organic layers were dried (MgSO4) and the solvent removed in vacuo to give a brown solid. Trituration with 2:1 ethyl acetate/hexane yielded the title compound as a brown solid. 160 mg.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.[N+](C1C=CC(S(O[CH2:27][C@H:28]2[CH2:30][C:29]2([F:32])[F:31])(=O)=O)=CC=1)([O-])=O>>[Cl:1][C:2]1[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][CH:5]=[C:6]([O:8][CH2:27][C@H:28]2[CH2:30][C:29]2([F:32])[F:31])[CH:7]=1
Reactant: CCOC(=O)c1ncc(O)cc1Cl
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@H]2CC2(F)F)cc1
Product: CCOC(=O)c1ncc(OC[C@H]2CC2(F)F)cc1Cl

Procedure:
Using ethyl 3-chloro-5-hydroxypyridine-2-carboxylate and ((1R)-2,2-difluorocyclopropyl)methyl 4-nitrobenzenesulfonate, and in the same manner as in Example 5, the title compound was obtained.
Reaction SMILES: C1(COC2C=CC(C(O)=O)=NC=2)CC1.COC(C1C=CC(O)=CN=1)=O.O(CC(F)F)S(C(F)(F)F)(=O)=O.C[O:39][C:40]([C:42]1[CH:47]=[CH:46][C:45]([O:48][CH2:49][CH:50]([F:52])[F:51])=[CH:44][N:43]=1)=[O:41]>>[F:52][CH:50]([F:51])[CH2:49][O:48][C:45]1[CH:46]=[CH:47][C:42]([C:40]([OH:41])=[O:39])=[N:43][CH:44]=1
Reactant: COC(=O)c1ccc(OCC(F)F)cn1
Agent: COC(=O)c1ccc(O)cn1
Agent: O=C(O)c1ccc(OCC2CC2)cn1
Agent: O=S(=O)(OCC(F)F)C(F)(F)F
Product: O=C(O)c1ccc(OCC(F)F)cn1

Procedure:
The 5-(2,2-difluoro-ethoxy)-pyridine-2-carboxylic acid was prepared in a reaction sequence analogous to that in example 60 for the preparation of the 5-cyclopropylmethoxy-pyridine-2-carboxylic acid: Alkylation of the 5-hydroxy-pyridine-2-carboxylic acid methyl ester with 2,2-difluoroethyl triflate and hydrolysis of the 5-(2,2-difluoro-ethoxy)-pyridine-2-carboxylic acid methyl ester yielded the 5-(2,2-difluoro-ethoxy)-pyridine-2-carboxylic acid as an off-white solid. Mass (calculated) C8H7F2NO3 [203.143]; (found) [M+H]+=204.
Reaction SMILES: C([NH:8][CH2:9][CH2:10][CH2:11][C@@H:12]([C:14]([OH:16])=[O:15])[NH2:13])(OC(C)(C)C)=O.CCN=C=NCCCN(C)C.[ClH:28].[C:29]([NH:39][CH2:40][C:41]1[CH:49]=[CH:48][C:44]([C:45]([OH:47])=O)=[CH:43][CH:42]=1)([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>CN(C=O)C.CN(C1C=CN=CC=1)C>[ClH:28].[C:29]([NH:39][CH2:40][C:41]1[CH:42]=[CH:43][C:44]([C:45]([NH:13][C@H:12]([C:14]([OH:16])=[O:15])[CH2:11][CH2:10][CH2:9][NH2:8])=[O:47])=[CH:48][CH:49]=1)([O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:30]
Reactant: O=C(NCc1ccc(C(=O)O)cc1)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCC[C@H](N)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: NCCC[C@H](NC(=O)c1ccc(CNC(=O)OCc2ccccc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 38 %

Procedure:
The compound obtained in Example 23-2 (350 mg) was dissolved in DMF (7 ml). After the addition of WSCI hydrochloride (265.0 g), DMAP (169 mg), and the compound obtained in Example 41-1 (276.0 mg), the mixture was stirred for 24 hours at room temperature. After the reaction, the solvent was removed by distillation. The residue was dissolved in chloroform, washed with 1 mol/l aqueous solution of hydrochloric acid and saturated aqueous solution of sodium hydrogencarbonate, and dried over sodium hydrogensulfate. The solvent was removed by distillation and the residue was purified by silica gel column chromatography (20 g, chloroform/methanol=10/1). 130 mg of the obtained product was dissolved in methanol (2.6 ml) and 4 mol/l hydrochloric acid/dioxane solution (2.6 ml) was added. The mixture was stirred for 70 minutes at room temperature. After the reaction, the solvent was removed by distillation and the residue was dried under vacuum to obtain hydrochloride of the title compound (147 mg) as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([CH2:23][C:24]#[C:25][CH3:26])[C:21]3[C:20](=[O:27])[NH:19][C:18](=[O:28])[N:17]([CH2:29][CH2:30][O:31][CH2:32][CH3:33])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[CH2:23]([N:22]1[C:21]2[C:20](=[O:27])[NH:19][C:18](=[O:28])[N:17]([CH2:29][CH2:30][O:31][CH2:32][CH3:33])[C:16]=2[N:15]=[C:14]1[N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[C:24]#[C:25][CH3:26]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)[nH]c(=O)n2CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CC#CCn1c(N2CCNCC2)nc2c1c(=O)[nH]c(=O)n2CCOCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-[7-(2-Butynyl)-1-(2,2-dimethylpropionyloxymethyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (50 mg) and potassium carbonate (15 mg) were dissolved in N,N-dimethylformamide (1.2 ml), and 2-bromoethylethyl ether (12 μl) was added to the solution. The mixture was stirred at 60° C. for 2 hours, diluted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. After the organic layer was concentrated by distillation, the residue was purified by silica gel column chromatography to give 4-[7-(2-butynyl)-1-(2,2-dimethylpropionyloxymethyl)-3-(2-ethoxyethyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester from the elution fraction of hexane-ethyl acetate (2:1). The obtained 4-[7-(2-butynyl)-1-(2,2-dimethylpropionyloxymethyl)-3-(2-ethoxyethyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester was dissolved in a solvent mixture of tetrahydrofuran (1.0 ml) and methanol (0.5 ml), sodium hydride (5 mg) was added to the solution, and the mixture was stirred at room temperature for 1 hour. After the reaction mixture was neutralized with 2N hydrochloric acid and extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation to give 4-[7-(2-butynyl)-3-(2-ethoxyethyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester. A quarter of the obtained 4-[7-(2-butynyl)-3-(2-ethoxyethyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester was dissolved in trifluoroacetic acid (0.5 ml), and the solution was stirred at room temperature for 30 minutes. After the solvent was removed by distillation, a half of the residue was purified by HPLC with a reversed phase column using water-acetonitrile-trifluoroacetic acid system as elution solvent to give 3.2 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:37])([F:36])[C:20]([C:22]1[S:26][C:25]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])=[N:24][CH:23]=1)=[O:21]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][CH:35]=[C:27]([C:25]4[S:26][C:22]([C:20](=[O:21])[C:19]([F:37])([F:18])[F:36])=[CH:23][N:24]=4)[CH:28]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(CN)c1coc(-c2ccc(F)cc2)n1
Reactant: O=C(O)c1cccc(-c2ncc(C(=O)C(F)(F)F)s2)c1
Product: CC(C)(CNC(=O)c1cccc(-c2ncc(C(=O)C(F)(F)F)s2)c1)c1coc(-c2ccc(F)cc2)n1
Yield: 3 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine and 3-(5-(2,2,2-trifluoroacetyl)thiazol-2-yl)benzoic acid as described in example 8 step 6 (7 mg, yield 3%). 1H NMR (400 MHz, DMSO-d6) δ 8.56-8.53 (t, J=5.5 Hz, 1H), 8.35 (m, 1H), 8.28 (m, 2H), 8.10-8.08 (m, 1H), 8.02-8.00 (m, 2H), 7.94 (m, 1H), 7.61-7.57 (t, J=7.8 Hz, 1H), 7.35-7.31 (t, J=8.7 Hz, 2H), 3.51-3.50 (d, J=5.8 Hz, 2H), 1.29 (s, 6H). MS (ESI) m/z: Calculated for C26H19F4N3O3S: 517.11. found: 516.1 (M−H)−.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][C:6]([CH2:11][NH2:12])([CH2:7][CH2:8]1)[CH2:5][CH2:4]2.C[O-].[Na+].C(O)(=O)C.C([BH3-])#N.[Na+].[CH3:24][O:25][C:26]1[CH:49]=[CH:48][C:29]([CH2:30][N:31]2[C:39]3[CH:38]=[CH:37][CH:36]=[C:35]([C:40]([O:42][CH3:43])=[O:41])[C:34]=3[C:33]([CH2:44][CH2:45]C=O)=[CH:32]2)=[CH:28][CH:27]=1>CO>[CH3:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:30][N:31]2[C:39]3[CH:38]=[CH:37][CH:36]=[C:35]([C:40]([O:42][CH3:43])=[O:41])[C:34]=3[C:33]([CH2:44][CH2:45][NH:12][CH2:11][C:6]34[CH2:9][CH2:10][N:3]([CH2:8][CH2:7]3)[CH2:4][CH2:5]4)=[CH:32]2)=[CH:48][CH:49]=1
Reactant: COC(=O)c1cccc2c1c(CCC=O)cn2Cc1ccc(OC)cc1
Reactant: NCC12CCN(CC1)CC2
Agent: C[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cccc2c1c(CCNCC13CCN(CC1)CC3)cn2Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of quinuclidin-4-ylmethanamine dihydrochloride (433 mg, 2.0 mmol) in MeOH (20 mL) at room temperature was added sodium methoxide (25 wt % in MeOH, 0.9 mL, 4.1 mmol) dropwise. The reaction mixture was stirred at room temperature for 1 h and then glacial acetic acid (0.3 mL, 4.7 mmol) was added to neutralize the basicity of the mixture. Sodium cyanoborohydride (255 mg, 4.1 mmol) was added, followed by methyl 1-(4-methoxybenzyl)-3-(2-oxoethyl)-1H-indole-4-carboxylate (691 mg, 2.4 mmol) from Step C above in MeOH (25 mL). The mixture was stirred at room temperature until the reaction was complete by TLC (1-2 h). The reaction mixture was concentrated, absorbed onto silica gel, and purified by column chromatography (80:18:2 methylene chloride/methanol/concentrated ammonium hydroxide) to afford methyl 1-(4-methoxybenzyl)-3-(2-(quinuclidin-4-ylmethylamino)ethyl)-1H-indole-4-carboxylate as colourless oil (53%): 1H NMR (300 MHz, CD3OD) δ 7.62 (d, J=8.1 Hz, 1H), 7.58 (d, J=7.5 Hz, 1H), 7.29 (s, 1H), 7.20-7.07 (m, 3H), 6.84 (d, J=6.0 Hz, 2H), 5.31 (s, 2H), 3.93 (s, 3H), 3.74 (s, 3H), 3.13 (t, J=7.2 Hz, 2H), 2.95 (t, J=7.8 Hz, 6H), 2.84 (t, J=7.2 Hz, 2H), 2.44 (s, 2H), 1.46 (t, J=7.8 Hz, 6H); MS (ESI+) m/z 462 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:16][C:6]2=[CH:7][C:8]3[C:9]([CH3:15])=[CH:10][CH:11]=[N:12][C:13]=3[CH:14]=[C:5]2[CH:4]=[CH:3]1.ClC1C=CC=C(C(OO)=O)C=1.C[Si]([C:33]#[N:34])(C)C.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(#N)C.CO>[CH3:1][C:2]1([CH3:17])[O:16][C:6]2=[CH:7][C:8]3[C:9]([CH3:15])=[CH:10][C:11]([C:33]#[N:34])=[N:12][C:13]=3[CH:14]=[C:5]2[CH:4]=[CH:3]1
Reactant: Cc1ccnc2cc3c(cc12)OC(C)(C)C=C3
Reactant: C[Si](C)(C)C#N
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(C#N)nc2cc3c(cc12)OC(C)(C)C=C3
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To a solution of 2,2,9-trimethyl-2H-pyrano[2,3-g]quinoline (4.36 g, 19.3 mmol) in chloroform (43.6 mL), a solution of m-chloroperbenzoic acid (7.35 g, 42.6 mmol) in chloroform (17.4 mL)-methanol (4.36 mL) was added dropwise at room temperature and the resulting mixture was stirred at room temperature for 1 hour. Upon the completion of the reaction, the reaction solution was extracted with aqueous sodium thiosulfate solution and the resulting organic phase was washed with aqueous sodium hydrogencarbonate solution and then with aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. After distilling off the solvent, acetonitrile (19.3 mL), trimethylsilylcyanide (7.27 mL, 57.9 mmol) and triethylamine (5.38 mL, 38.6 mmol) were added to the residue at room temperature, and the resulting solution was stirred at 70° C. for 3.5 hours. Upon the completion of the reaction, aqueous sodium hydrogencarbonate solution was added to the reaction solution, and it was extracted with chloroform and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by column chromatography (hexane/ethyl acetate=2/1) and the aimed product was obtained (yield: 55%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N:17]=[C:18]=[O:19])[CH:12]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:18](=[O:19])[NH:17][C:13]1[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=1)[CH2:6][CH2:5]2
Reactant: Brc1ccc2c(c1)CCN2
Reactant: O=C=Nc1cccnc1
Product: O=C(Nc1cccnc1)N1CCc2cc(Br)ccc21
Yield: 72 %

Procedure:
5-Bromoindoline (D50) (0.5 g, 2.5 mmol) was treated with 3-pyridylisocyanate as in the method of Example 1. The product was filtered-off and recrystallised from methanol/water to afford the title compound (0.58 g, 72%) as a white crystalline solid m.p. 220° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][CH2:12][CH2:13]O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O.C(=O)([O-])O.[Na+].S(Cl)([Cl:23])=O>>[Cl:23][CH2:13][CH2:12][CH2:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2
Reactant: OCCCc1ccc2ncccc2c1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: ClCCCc1ccc2ncccc2c1
Temperature: 70 °C
Yield: 72 %

Procedure:
0.52 g (2.77 mmol) 3-quinolin-6-yl-propan-1-ol were dissolved in 5.5 ml thionylchloride and heated to 70° C. for 50 minutes. Water and aqueous sodium hydrogencarbonate were added and the mixture was extracted three times with DCM. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo to give 0.41 g (72%) of a brown oil. MS(ISP): 206.2 [MH]+
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1I>>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: Clc1ccccc1I
Product: Clc1ccccc1-n1ccc2ccccc21

Procedure:
Prepared by Procedure C and Scheme O using 1H-indole and 1-chloro-2-iodobenzene: ESMS m/e: 227.9 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH:11](C(OCC1C=CC=CC=1)=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13].C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:2]([F:1])[CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCc1ccccc1)c1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)Cc1ccc(N)cc1F
Temperature: 60 °C
Yield: 60.4 %

Procedure:
Ethyl phenylmethyl (2-fluoro-4-nitrophenyl)propanedioate (3.86 g, 10.6 mmol) dissolved in ethanol (50 ml), was treated with ammonium formate (6.7 g, 10.6 mmol) under argon. Palladium on carbon 10% paste (380 mg) was added and the reaction was stirred under reflux for 3 hours (60° C.). The reaction was cooled to room temperature and the catalyst removed by filtration through celite. Solvent was removed to give a brown oil. The crude material was purified by chromatography on silica gel eluting with 0-50% ethyl acetate in hexane (1:1) over 45 minutes. Fractions were evaporated to give the title compound as a yellow oil (1.26 g, 6.4 mmol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2O.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[N:8]=[CH:7][CH:6]=1
Reactant: Oc1ccnc2ccc(F)cc12
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1ccc2nccc(Cl)c2c1

Procedure:
A mixture of 52 g (0.319 mol) of 6-fluoro-4-hydroxyquinoline and 100 ml of phosphorus oxychloride was stirred and heated under reflux for 3 hr. The reaction mixture was concentrated in vacuo. A slurry of the residue in methylene chloride was poured into ice-water, and the mixture neutralized with 3N sodium hydroxide. The organic phase was separated, and the aqueous phase was extracted with 250 ml of methylene chloride twice. The organic phases were combined, washed with water, dired over sodium sulfate, and concentrated in vacuo. The residue was crystallized from hexane to give 27.95 g of product, mp 71°-74°.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.[Cl:45][C:46]1[CH:54]=[C:53]2[C:49]([CH:50]=[C:51]([C:55](O)=[O:56])[NH:52]2)=[CH:48][CH:47]=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C.O>[Cl:45][C:46]1[CH:54]=[C:53]2[C:49]([CH:50]=[C:51]([C:55]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([O:34][C:35]4[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=4)[C:28]=3[F:44])=[O:56])[NH:52]2)=[CH:48][CH:47]=1
Reactant: O=C(O)c1cc2ccc(Cl)cc2[nH]1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4ccc(Cl)cc4[nH]3)c2F)c1
Reaction time: 1 h
Yield: 42.2 %

Procedure:
HATU (91 mg, 0.24 mmol) was added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.050 g, 0.16 mmol), 6-chloro-1H-indole-2-carboxylic acid (0.050 g, 0.24 mmol) and DIPEA (0.042 ml, 0.24 mmol) in DMF (1.5 mL). After 1 h, the reaction mixture was diluted with ethyl acetate and water. The organic layer was separated, dried over sodium sulfate and concentrated. The residue was purified by column chromatography (hexane/EtOAc) to give the title compound (0.033 g, 42%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.76 (s, 1H), 9.09 (t, 1H), 7.81 (s, 1H), 7.64 (d, 1H), 7.45-7.54 (m, 3H), 7.36-7.44 (m, 2H), 7.19 (s, 1H), 7.04 (dd, 1H), 4.56 (d, 2H). MS: m/z 488 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:18]=[C:19]([O:24][CH3:25])[C:20]=1[N+:21]([O-])=O)[O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])C1C=CC=CC=1>[Pd].C(O)C>[NH:21]([C:25]1[O:24][C:19]2[CH:18]=[C:11]([O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:10]=[C:9]([O:8][CH3:1])[C:20]=2[N:21]=1)[C:20]1[CH:19]=[CH:18][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)COc1cc(OC)c([N+](=O)[O-])c(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)COc1cc(OC)c2nc(Nc3ccccc3)oc2c1
Yield: 158.7 %

Procedure:
A mixture of methyl 3-benzyloxy-5-methoxy4-nitrophenoxyacetate(1 g), ethanol(30 mL) and 10% palladium on carbon catalyst(0.2 g) was stirred stirred under an atmosphere of hydrogen for 18 h. The mixture was filtered and the filtrate treated with phenylisothiocyanate(0.35 mL) followed by yellow mercuric oxide(0.85 g). The mixture was stirred at reflux for 4 h, then filtered and the filtrate was evaporated to dryness. The residue was purified by flash chromatography eluting with increasingly polar mixtures of ethyl acetate and hexane to give the product (0.75 g),[m/e329MH+].
Reaction SMILES: [H-].[Na+].[CH2:3]([C:10]#[N:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH2:13][CH2:14][N:15]([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17]>>[CH:16]([N:15]([CH:19]([CH3:21])[CH3:20])[CH2:14][CH2:13][CH:3]([C:10]#[N:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:18])[CH3:17]
Reactant: N#CCc1ccccc1
Reactant: CC(C)N(CCCl)C(C)C
Agent: [H-]
Agent: [Na+]
Product: CC(C)N(CCC(C#N)c1ccccc1)C(C)C
Reaction time: 0.25 h

Procedure:
Sodium hydride, 80% in mineral oil (2.82 g, 94 mmol), was washed with petroleum ether and dried under a N2-stream. Dry DMF (100 mL) was added. Benzyl cyanide (12.1 g, 103 mmol) was added to the stirred suspension over a period of 20 min. The temperature rose to approx. 45° C. The mixture was stirred for another 15 min. 2-Chloroethyl-diisopropylamine (15.4 g, 94 mmol) was added. All the amine was consumed within 30 min. Most of the DMF was evaporated under reduced pressure and the residue was dissolved in water/diethyl ether. The aqueous phase was extracted once with diethyl ether and the combined organic phases were extracted twice with 2 M HCl. The combined aqueous phases were made alkaline (11 M NaOH) and extracted twice with diethyl ether. The combined organic phases were then dried (Na2SO4) and the solvent was evaporated. The crude product was chromatographed on silica (petroleum ether-triethylamine, 40:1), affording the title compound, 16.8 g (67%), as a colourless liquid. 1H NMR (CDCl3) δ1.01 (m, 12H), 1.97 (m, 2H), 2.62 (m, 2H), 3.00 (m, 2H), 4.02 (dd, 1H), 7.17-7.40 (m, 5H).
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH2:18][C:19]1([CH3:24])[O:23][CH2:22][CH2:21][O:20]1)[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[C:5]1[CH3:17].C1C=C(Cl)C=C(C(OO)=[O:34])C=1>>[CH3:1][C:2]([CH3:25])([CH2:18][C:19]1([CH3:24])[O:23][CH2:22][CH2:21][O:20]1)[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N+:9]([O-:34])=[CH:8][C:7]=2[N:6]=[C:5]1[CH3:17]
Reactant: Cc1nc2cnc3ccccc3c2n1CC(C)(C)CC1(C)OCCO1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: Cc1nc2c[n+]([O-])c3ccccc3c2n1CC(C)(C)CC1(C)OCCO1

Procedure:
The general method described in Steps 9 and 10 of Example 1 was used to aminate 1-[2,2-dimethyl-3-(2-methyl-[1,3]dioxolan-2-yl)propyl]-2-methyl-1H-imidazo[4,5-c]quinoline (5.80 g, 17.1 mmol) by reaction with m-CPBA (7.5 g) to provide 1-[2,2-dimethyl-3-(2-methyl-[ 1,3]dioxolan-2-yl)propyl]-2-methyl-5-oxido-1H-imidazo[4,5-c]quinoline followed by reaction with p-toluenesulfonyl chloride (5.7 g, 30 mmol) and ammonium hydroxide solution (150 mL) to provide 1-[2,2-dimethyl-3-(2-methyl-[ 1,3]dioxolan-2-yl)propyl]-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine as a light brown solid after recrystallization from a mixture of acetonitrile, methanol, and water, mp 209-211° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)[CH2:12][CH2:13][CH2:14][CH2:15][S:16][CH3:17])=[C:8]([CH3:28])[C:7]=2[CH:29]=1.[CH3:30][NH:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl-].[NH4+]>CN(C)C=O.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:27]=[CH:26][C:22]([C:23]([N:31]([CH3:30])[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:24])=[CH:21][CH:20]=3)[CH2:12][CH2:13][CH2:14][CH2:15][S:16][CH3:17])=[C:8]([CH3:28])[C:7]=2[CH:29]=1
Reactant: CCOC(=O)CCNC
Reactant: COc1ccc2oc(C(CCCCSC)Nc3ccc(C(=O)O)cc3)c(C)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(CCCCSC)c2oc3ccc(OC)cc3c2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
To a mixture of 4-{[1-(5-methoxy-3-methyl-1-benzofuran-2-yl)-5-(methylsulfanyl)pentyl]amino}benzoic acid (460 mg) synthesized in Example A120(4), ethyl 3-(methylamino)propanoate (219 mg), 1-hydroxybenzotriazole monohydrate (256 mg), triethylamine (464 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (320 mg), and the mixture was stirred overnight at room temperature. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30-50% ethyl acetate/hexane) to give the title object compound (514 mg, 88%) as a pale-brown oil