Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10]([CH2:12][O:13][C:14]3[C:15]([F:24])=[C:16]([C:20]([F:23])=[CH:21][CH:22]=3)[C:17]([NH2:19])=[O:18])=[N:9][C:8]=2[CH:25]=1)[CH:2]=[CH2:3]>CO.[Pd]>[F:24][C:15]1[C:14]([O:13][CH2:12][C:10]2[S:11][C:7]3[CH:6]=[CH:5][C:4]([CH2:1][CH2:2][CH3:3])=[CH:25][C:8]=3[N:9]=2)=[CH:22][CH:21]=[C:20]([F:23])[C:16]=1[C:17]([NH2:19])=[O:18]
Reactant: C=CCc1ccc2sc(COc3ccc(F)c(C(N)=O)c3F)nc2c1
Agent: [Pd]
Solvent: CO
Product: CCCc1ccc2sc(COc3ccc(F)c(C(N)=O)c3F)nc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 14.3 %

Procedure:
To a solution of 3-(5-allyl-benzothiazol-2-ylmethoxy)-2,6-difluoro-benzamide (0.1 g, 0.27 mmol) in 5 ml of anhydrous methanol was added to 20 mg of dry Pd—C. The reaction mixture was stirred at 25° C. for 12 h under hydrogen atmosphere. The reaction mixture was filtered over the celite bed. The filtrate was evaporated to dryness under reduced pressure and the compound was crystallized with ethyl acetate/hexane to give the title compound as light yellow solid (0.014 g, 14%). 1H NMR (DMSO-d6, 400 MHz): δ 0.92 (t, 3H, J=7.2 Hz), 1.62-1.68 (m, 2H), 2.71, 2H, J=7.2 Hz), 5.67 (s, 2H), 7.12 (dt, 1H, J=8.8 Hz (o-coupling) J=1.6 Hz), 7.32 (d, 1H, J=8.4 (o-coupling), 7.38 (dt, 1H, J=9.2 Hz (o-coupling), J=5.2 Hz), 7.83 (s, 1H), 7.89 (broad s, 1H), 8.01 (d, 1H, J=8.4 Hz (o-coupling). 8.17 (broad s, 1H). MS ES+(363.08), HPLC (method 5) Rt=17.64 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:16][CH3:17])[C:11]=1[CH:12]=[C:13]([CH3:15])[CH3:14])[C:6]([OH:8])=[O:7]>C(OCC)C>[CH3:17][O:16][C:10]1[CH:9]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:11]=1[CH2:12][CH:13]([CH3:14])[CH3:15])[C:6]([OH:8])=[O:7]
Reactant: COc1cc(C(=O)O)cc(OC)c1C=C(C)C
Solvent: CCOCC
Product: COc1cc(C(=O)O)cc(OC)c1CC(C)C

Procedure:
3,5-Dimethoxy-4-isobutyl-benzoyl chloride. Starting from 3-hydroxy-5-methoxy-benzoic acid methyl ester and 3-chloro-2-methyl-propene, 3-(2-methyl-2-propenyloxy)-5-methoxy-benzoic acid methyl ester is obtained. B.p. 148°-50°C/0.4 mmHg. By operating as described under C), 3,5-dimethoxy-4-(2-methylpropenyl)-benzoic acid is prepared. M.p. 159°-61°C (from diethyl ether). This compound is hydrogenated as under D) to give 3,5-dimethoxy-4-isobutyl-benzoic acid. M.p. 160°-62°C (from diethyl ether/light petroleum). The corresponding chloride melts at 48°-50°C (from ligroin upon cooling).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20]([S:23]([N:26]5[CH2:31][CH2:30][CH:29]([C:32]([O:34]CC)=[O:33])[CH2:28][CH2:27]5)(=[O:25])=[O:24])=[CH:19][C:18]=4[O:37][CH3:38])=[N:11][C:10]=3[N:9]([CH3:39])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([C:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20]([S:23]([N:26]5[CH2:27][CH2:28][CH:29]([C:32]([OH:34])=[O:33])[CH2:30][CH2:31]5)(=[O:25])=[O:24])=[CH:19][C:18]=4[O:37][CH3:38])=[N:11][C:10]=3[N:9]([CH3:39])[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C1CCN(S(=O)(=O)c2ccc(-c3nc4c(c(C5CCCCC5)nn4C)c(=O)[nH]3)c(OC)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(S(=O)(=O)N2CCC(C(=O)O)CC2)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
To a 2 ml methanol/3 ml tetrahydrofuran mixed solution of 82 mg (0.15 mmol) of the compound obtained in Example 53, 1 ml (1 mmol) of a 1M aqueous solution of sodium hydroxide was added, and the mixture was stirred at room temperature for 1 hour. Then, the solvent was distilled off under reduced pressure, and the residue was diluted with water. The aqueous layer was washed with ether, then acidified with a 2M aqueous solution of hydrochloric acid, and extracted with dichloromethane. The organic layer was washed with water and a saturated aqueous solution of sodium chloride. After the washed layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 77 mg (99%) of the captioned compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[NH:21][C:20]4=[O:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:32][C:33]([N:35]([CH2:38][CH3:39])[CH2:36][CH3:37])=[O:34]>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[N:21]([CH2:6][C:11](=[O:12])[N:13]([CH2:18][CH3:17])[CH2:14][CH3:15])[C:20]4=[O:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:32][C:33]([N:35]([CH2:38][CH3:39])[CH2:36][CH3:37])=[O:34])=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Reactant: CCN(CC)C(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)Cn1cc(C(=O)N2CCC(n3c(=O)n(CC(=O)N(CC)CC)c4ccccc43)CC2)c2ccc(Cl)cc21

Procedure:
To a stirred solution of 30 mg of 1-[1-(6-chloro-1H-indole-3-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one in 1 ml of DMF were added 1.1 eq. of NaH (55% in oil). The reaction mixture was stirred for 30 min. before the addition of 1.2 eq. of 2-chloro-N,N-diethyl-acetamide. The crude reaction mixture was purified by preparative HPLC to afforded 6 mg of the title compound as a white powder.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23](O)=[O:24])=[CH:13][CH:12]=2)[C:8]2[C:26]([C:30]([O:32][CH3:33])=O)=[CH:27][CH:28]=[CH:29][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].S(Cl)(Cl)=O.[H-].[Li+].[Al+3].[H-].[H-].[H-].Cl>C(Cl)(Cl)Cl.O1CCCC1>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH2:23][OH:24])=[CH:15][CH:16]=2)[C:8]2[C:26]([CH2:30][O:32][CH3:33])=[CH:27][CH:28]=[CH:29][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CCCCc1nc2cccc(COC)c2n1Cc1ccc(-c2ccccc2CO)cc1

Procedure:
A mixture of methyl 2-butyl-1-[2'-carboxybiphenyl-4-yl]methylbenzimidazole-7-carboxylate (0.44 g) and thionyl chloride (0.15 ml) in chloroform (4 ml) was heated for 30 minutes under reflux with stirring. The reaction mixture was concentrated, and the resulting product was used for the subsequent reaction without purification. A stirred solution of the above product in tetrahydrofuran (6 ml) was added dropwise to a suspension of aluminium lithium hydride (40 mg) in tetrahydrofuran (6 ml) under ice-cooling. The reaction mixture was stirred for one minutes at the same temperature, and to the mixture were added 2N-HCl and, then water, followed by extraction with chloroform. The extract was washed with water and dried (MgSO4), and the solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel to give an oil. Crystallization of this product from isopropyl ether afforded colorless prisms (0.13 g, 31%), m.p.126°-127° C.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][N:8]=1.C([O-])([O-])=O.[Na+].[Na+].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C(O)C.O>[NH2:6][C:7]1[N:8]=[CH:9][C:10]([CH2:11][OH:12])=[CH:14][CH:15]=1
Reactant: Nc1ccc(C(=O)O)cn1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Al+3]
Solvent: CCO
Solvent: O
Product: Nc1ccc(CO)cn1
Temperature: 0 °C
Yield: 50.3 %

Procedure:
Concentrated sulfuric acid (0.95 ml, 17.2 mmol, 0.5 equiv) is added to a solution of 6-aminonicotinic acid (5.0 g, 34.4 mmol) in ethanol (50 ml). After heating to reflux for 16 hours, the reaction mixture is carefully poured into a concentrated aqueous Na2CO3 solution. The aqueous phase is extracted three times with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue is dissolved in anhydrous THF (25 ml). At −60° C., lithium aluminium hydride (2.68 g, 68.6 mmol, 3.0 equiv) is carefully added. The mixture is warmed to 0° C., and then refluxed for 1 hour. After cooling, water (1.5 ml) and 5 N aqueous NaOH solution (1.5 ml) are added. The precipitate is filtered off, and the filtrate is concentrated in vacuo. The residue is purified via flash chromatography (EtOAc I MeOH 95:5) to afford the title compound (2.15 g, 72%). 1H NMR (400 MHz, d6-DMSO): δ=7.82 (d, J=1.7 Hz, 1H), 7.32 (dd, J=8.3/2.5 Hz, 1H), 6.40 (dd, J=9.3/1.0 Hz, 1H), 5.77 (br s, 2H), 4.88 (t, J=5.5 Hz, 1H), 4.27 (d, J=5.5 Hz, 2H). MS (ES+): 125 (M+H)+.
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][N:8]=1)[NH2:2].O=[C:10]([CH3:25])[CH:11]([C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=O)[CH2:12][C:13]([O:15][CH3:16])=[O:14]>C(O)C>[CH3:16][O:15][C:13](=[O:14])[CH2:12][C:11]1[C:10]([CH3:25])=[N:2][N:1]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][N:8]=2)[C:17]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)CC(C(C)=O)C(=O)c1ccccc1
Reactant: NNc1cnccn1
Solvent: CCO
Product: COC(=O)Cc1c(C)nn(-c2cnccn2)c1-c1ccccc1
Temperature: 135 °C

Procedure:
0.378 g (3.330 mmol) of 3-hydrazinopyrazine in 12.5 ml of ethanol was added to 0.600 g (2.561 mmol) of methyl 4-oxo-3-(phenylcarbonyl)pentanoate, and the mixture was heated at 135° C. in a sealed vessel in a microwave oven for 1.5 h. The solvent was removed under reduced pressure, and the residue was taken up in dichloromethane and washed twice with in each case 25 ml of water. The combined organic phases were dried over sodium sulfate and the solvent was removed under reduced pressure. Chromatography of the residue gave 0.115 g (13.8% of theory) of a light-yellow wax.
Reaction SMILES: C([O:8][C:9](=[O:39])[C@@H:10]([NH:23][C:24](=[O:38])[C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]2)=[CH:27][CH:26]=1)[CH2:11][CH2:12][C:13]([O:15]CC1C=CC=CC=1)=[O:14])C1C=CC=CC=1.[NH2:40][CH2:41][C@@H:42]([C:44]1[CH:45]=[CH:46][C:47]([OH:55])=[C:48]([NH:50][S:51]([CH3:54])(=[O:53])=[O:52])[CH:49]=1)[OH:43]>>[OH:43][C@H:42]([C:44]1[CH:45]=[CH:46][C:47]([OH:55])=[C:48]([NH:50][S:51]([CH3:54])(=[O:53])=[O:52])[CH:49]=1)[CH2:41][NH:40][CH:34]1[CH2:33][CH2:32][N:31]([C:28]2[CH:29]=[CH:30][C:25]([C:24]([NH:23][C@@H:10]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:9]([OH:39])=[O:8])=[O:38])=[CH:26][CH:27]=2)[CH2:36][CH2:35]1
Reactant: O=C1CCN(c2ccc(C(=O)N[C@@H](CCC(=O)OCc3ccccc3)C(=O)OCc3ccccc3)cc2)CC1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from (2S)-2-[4-(4-oxo-piperidin-1-yl)-benzoylamino]-pentanedioic acid dibenzyl ester (which was obtained in Example 156) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 179 as a white solid; mp>230° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.40–1.60 (m, 2 H), 1.90–2.10 (m, 4 H), 2.31 (t, J=7.5 Hz, 2 H), 2.65–3.20 (m, 7 H), 3.00 (s, 3 H), 3.85–4.00 (m, 2 H), 4.25–4.35 (m, 1 H), 4.65–4.80 (m, 1 H), 6.88 (d, J=8.4 Hz, 1 H), 6.95 (d, J=8.7 Hz, 2 H), 7.08 (dd, J=8.4, 1.2 Hz, 1 H), 7.25 (d, J=1.8 Hz, 1 H), 7.74 (d, J=8.7 Hz, 2 H), 8.14 (d, J=7.2 Hz, 1 H); MS (ES) m/z: 579.1 (MH+); HRMS Calcd. for C26H35N4O9S (MH+): 579.1973. Found: 579.1955.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9](Br)[C:8]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:14][C:7]=2[C:6]=1[OH:21])=[O:4].C([Sn](CCCC)(CCCC)[C:27]#[C:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)CCC>>[CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]([C:27]#[C:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:8]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:14][C:7]=2[C:6]=1[OH:21])=[O:4]
Reactant: CCCC[Sn](C#Cc1ccccc1)(CCCC)CCCC
Reactant: COC(=O)c1nc(Br)c2nc(-c3ccccc3)oc2c1O
Product: COC(=O)c1nc(C#Cc2ccccc2)c2nc(-c3ccccc3)oc2c1O

Procedure:
Prepared from 4-bromo-7-hydroxy-2-phenyl-oxazolo[4,5-c]pyridine-6-carboxylic acid methyl ester, example 3a, and tributyl(phenylethynyl)tin under conditions analogous to experimental example 3b. MS: (+) m/z 370.9 (M+1).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][CH2:16][CH:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C.Cl.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH2:44][CH2:45][NH:46][CH2:47][CH:48]=2)=[CH:39][CH:38]=1>C(#N)CC.O>[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH2:48][CH2:47][N:46]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][CH2:15][CH2:16][CH:8]5[C:7](=[O:17])[NH:6][C:5]=4[CH:4]=3)[CH2:45][CH:44]=2)=[CH:39][CH:38]=1
Reactant: O=C1Nc2cc(CO)cnc2N2CCCCC12
Reactant: Clc1ccc(C2=CCNCC2)cc1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCC#N
Product: O=C1Nc2cc(CN3CC=C(c4ccc(Cl)cc4)CC3)cnc2N2CCCCC12
Temperature: 90 °C
Reaction time: 2 h
Yield: 19 %

Procedure:
3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one (100 mg, 0.43 mmol) was suspended in propionitrile (1 mL) and (cyanomethyl)trimethylphosphonium iodide (103 mg, 0.41 mmol) was added followed by N-ethyl-N-isopropylpropan-2-amine (180 ul, 1.03 mmol). To the stirred mixture was then added 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (94.0 mg, 0.41 mmol). The reaction was heated to 90° C. with stirring 2 h. The reaction was then cooled to room temperature and diluted with water (3 mL) and filtered. The solids were collected and refluxed in ethanol (5 mL) for 1 h. The suspension was cooled back to room temperature and filtered. The precipitate was filtered off and dried in vacuum to afford the title compound (31.8 mg, 18%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.47 (s, 1H), 7.66 (d, J=2.0 Hz, 1H), 7.41-7.48 (m, 2H), 7.33-7.40 (m, 2H), 6.98 (d, J=2.0 Hz, 1H), 6.18 (s, 1H), 4.43-4.57 (m, 1H), 3.84 (d, J=11.4 Hz, 1H), 3.42 (s, 2H), 3.01 (d, J=2.8 Hz, 2H), 2.55-2.66 (m, 3H), 2.44 (br. s., 2H), 1.98-2.09 (m, 1H), 1.78-1.92 (m, 1H), 1.57-1.70 (m, 1H), 1.33-1.56 (m, 3H). [M+H] calc'd for C23H25ClN4O, 409. found, 409.
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][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[CH3:19][O:20][CH2:21][CH2:22][CH2:23][NH2:24]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:24][CH2:23][CH2:22][CH2:21][O:20][CH3:19])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: COCCCN
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Product: CCOC(=O)c1cnc2c(OC)cccc2c1NCCCOC

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.94 mmol) was treated with 3-methoxy-propylamine following general procedure B to afford 8-methoxy-4-(3-methoxy-propyl-amino)-quinoline-3-carboxylic acid ethyl ester (260 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid in quantitative yield using general procedure D and then transformed into the corresponding ethylamide (180 mg) following general procedure E. The above ethylamide (0.57 mmol) was subjected to reaction with methyl chloroformate according to general procedure F to furnish 3-ethyl-7-methoxy-1-(3-methoxy-propyl)-1H-pyrimido[5,4-c]quinoline-2,4-dione (35 mg). LCMS: m/z 344 [M+1]+.
Reaction SMILES: I[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[S:7][CH3:8].Br[C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].N#N>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C(O)C.C(COC)OC>[CH3:8][S:7][C:6]1[CH:5]=[CH:4][S:3][C:2]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CSc1ccsc1I
Reactant: OB(O)c1ccc(Br)cc1
Agent: [Pd]
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: CSc1ccsc1-c1ccccc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 82.7 %

Procedure:
Degas a solution of 2-iodo-3-methylsulfanyl-thiophene (18 g, 70.3 mmol), 4-bromobenzeneboronic acid (14.1 g, 70.3 mmol), potassium carbonate (21.4 g, 155 mmol), tetrakis(triphenylphosphine)-palladium (0) (8.1 g, 7.02 mmol) in a mixture of anhydrous dimethoxyethane (300 ml) and absolute ethanol (150 ml) with Ar or N2 for 15 min and stir for 12 hours at 80° C. Cool the reaction mixture to room temperature, add water (100 ml) and extract the crude product with dichloromethane (3×150 ml). Purify the title compound by column chromatography using hexane as eluent solvent yielding the title compound 12 g (60%) as a white solid.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[NH:27][CH:26]=[CH:25]3)=[CH:18][C:17]=1[CH:31]=O.[NH2:33][CH2:34][CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.C(=O)(O)[O-].[Na+]>ClCCCl.ClCCl.C(O)(=O)C>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[NH:27][CH:26]=[CH:25]3)=[CH:18][C:17]=1[CH2:31][NH:33][CH2:34][CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: O=Cc1cc(-c2ccc3[nH]ccc3c2)ccc1F
Reactant: NCCN1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Product: Fc1ccc(-c2ccc3[nH]ccc3c2)cc1CNCCN1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.8 %

Procedure:
Sodium triacetoxyborohydride (530 g, 2.51 mmol) and then enough acetic acid to bring the pH to 5 were added to a solution of 5-(4-fluoro-3-formylphenyl)-1H-indole (200 mg, 0.84 mmol) and 1-(2-aminoethyl)pyrrolidine (191 mg, 1.67 mmol) in 15 mL of 1,2-dichloroethane. The mixture was stirred at ambient temperature overnight, and then it was diluted with dichloromethane, and neutralized with the careful addition of saturated sodium bicarbonate solution. The layers were separated and the aqueous phase extracted into dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated to leave the crude product. Chromatography (elution with methanol/dichloromethane) provided 90 mg of the title compound. LC/MS: Retention time, 0.34 min.
Reaction SMILES: C([O:3][C:4](=[O:34])[C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:14][CH2:15][CH2:16][N:17]2[C:25]3[C:24]([CH3:26])=[C:23]([CH3:27])[N:22]4[N:28]=[N:29][N:30]=[C:21]4[C:20]=3[N:19]=[C:18]2[CH2:31][CH2:32][CH3:33])(=[O:13])=[O:12])=[CH:7][CH:6]=1)C.[OH-].[Na+]>C(O)C>[CH3:27][C:23]1[N:22]2[N:28]=[N:29][N:30]=[C:21]2[C:20]2[N:19]=[C:18]([CH2:31][CH2:32][CH3:33])[N:17]([CH2:16][CH2:15][CH2:14][S:11]([C:8]3[CH:9]=[CH:10][C:5]([C:4]([OH:34])=[O:3])=[CH:6][CH:7]=3)(=[O:12])=[O:13])[C:25]=2[C:24]=1[CH3:26]
Reactant: CCCc1nc2c(c(C)c(C)n3nnnc23)n1CCCS(=O)(=O)c1ccc(C(=O)OCC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1nc2c(c(C)c(C)n3nnnc23)n1CCCS(=O)(=O)c1ccc(C(=O)O)cc1
Reaction time: 2 h
Yield: 95.9 %

Procedure:
4-[3-(5,6-Dimethyl-8-propyl-7H-imidazo[4,5-c]tetrazolo[1,5-a]pyridin-7-yl)propane-1-sulfonyl]benzoic acid ethyl ester (2.50 g, 5.16 mmol), prepared as described in Parts A-E of Example 92 using the modification of Example 99, was treated with aqueous sodium hydroxide (10 mL of 1 N) in ethanol (26 mL), and the reaction stirred for two hours and became homogeneous. The solvents were removed under reduced pressure, and the residual white solid was dissolved in water (50 mL). The solution was washed with ethyl acetate (3×10 mL) and then adjusted to pH 4 with the addition of concentrated hydrochloric acid. A white solid precipitated, which was isolated by filtration, washed with water, and dried for three hours in a vacuum oven at 60° C. to provide 2.26 g of 4-[3-(5,6-dimethyl-8-propyl-7H-imidazo[4,5-c]tetrazolo[1,5-a]pyridin-7-yl)propane-1-sulfonyl]benzoic acid as a white solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(Cl)Cl.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>N1C=CC=CC=1>[CH2:12]([C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][CH:2]1[O:1][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:13][CH:14]([CH3:15])[CH3:16]
Reactant: CCOC(=O)C1(CCC(C)C)CCCC1O
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1(CCC(C)C)CCCC1OC(=O)c1ccccc1
Reaction time: 12 h

Procedure:
Ethyl 2-hydroxy-1-iso-pentyl-cyclopentane carboxylate (6.84 g) was diluted using 60 ml of methylene chloride. At room temperature and with magnetic stirring, pyridine (3.66 ml) was slowly added, then benzoyl chloride (5.33 ml) was dropwise added. Upon the completion of the addition, the reaction was continued for 12 hours. Then solvent was removed, and the residue was extracted using ethyl acetate and water. Organic layer was washed, in turn, using 10% hydrochloric acid aqueous solution to pH of about 2, using saline solution to neutrality, using 10% aqueous solution of sodium carbonate for three times, and then using saline solution to neutrality. The organic layer was dried, and removing solvent gave 11.73 g of brown liquid. MS: m/e 332(M+), 287(M+—OCH2CH3), 259(M+—CO2CH2CH3), 227(M+—C6H5CO), 211 (M+—C6H5CO2), 182, 171, 140, 105(base), 7
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[CH3:10][S:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19](Cl)=[O:20])=[CH:14][CH:13]=1.[Cl-].[Al+3].[Cl-].[Cl-]>>[F:1][C:2]1[CH:7]=[C:6]([C:19](=[O:20])[CH2:18][C:15]2[CH:16]=[CH:17][C:12]([S:11][CH3:10])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[O:8][CH3:9]
Reactant: CSc1ccc(CC(=O)Cl)cc1
Reactant: COc1ccccc1F
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)Cc2ccc(SC)cc2)cc1F

Procedure:
1-(3-Fluoro-4-methoxyphenyl)-2-[4-(methylthio)phenyl]-ethan-1-one was prepared by Friedel Crafts acylation of 2-fluoroanisole with 4-(methylthio)phenylacetyl chloride in the presence of aluminum chloride: 1H NMR (CDCl3 /300 MHz) δ 7.80-7.70 (m, 2H), 7.24-7.15 (m, 4H), 6.98 (t, J=8.26 Hz), 4.17 (s, 2H), 3.95 (s, 3H), 2.46 (s, 3H). 19F NMR (CDCl3 /282.2 MHz): -134.804 (m).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:5](N)=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.C(O)C.S(=O)(=O)(O)O.N([O-])=O.[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:7]([Cl:9])[CH:8]=1
Reactant: Nc1c(Cl)cc(Cl)cc1[N+](=O)[O-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cc(Cl)cc(Cl)c1
Yield: 95 %

Procedure:
207 parts of 4,6-dichloro-2-nitro-aniline are introduced into 400 parts of ethanol and 900 parts of water, and 400 parts of concentrated sulfuric acid (98 percent strength by weight) are then added to the mixture. A solution of 105 parts of NaNO2 in 175 parts of water is run in at 80° C., as described in Example 1. The mixture is cooled and the product is filtered off. 182 parts (95% of theory) of 3,5-dichloro-nitro-benzene, of melting point 56°-59° C., are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5](O)=[O:6].S(Cl)([Cl:14])=O>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([Cl:14])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(C)cc(C(=O)O)c1
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(C(=O)Cl)c1

Procedure:
3,5-Dimethylbenzoic acid (25 g, 0.17 mol) and N,N-dimethylformamide (0.1 mL) were added to thionyl chloride (50 mL) at 0° C. The mixture was heated to reflux for 2 hours. The excess thionyl chloride was distilled off under reduced pressure and toluene (50 mL) was added to the residue. Toluene was distilled off under reduced pressure to obtain oily 3,5-dimethylbenzoyl chloride. A solution of propyleneimine (14 mL, 0.18 mol) in tetrahydrofuran (160 mL) was added to 1N aqueous sodium hydroxide (180 mL). To the solution was added dropwise 3,5-dimethylbenzoyl chloride at 0° C. After complete addition, the mixture was further stirred for 30 minutes. The reaction mixture was extracted with ethyl acetate. The extract was dried and the solvent was distilled off to obtain 31 g of the title compound (0.16 mol, yield 99%).