Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[O:2]=[C:3]1[NH:9][C:8]2[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][CH:12]=[CH:13][C:7]=2[O:6][CH2:5][C@@H:4]1[NH:20]C(=O)OC(C)(C)C.C(OC(C)C)(C)C>O1CCOCC1>[ClH:1].[NH2:20][C@@H:4]1[C:3](=[O:2])[NH:9][C:8]2[C:10]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:11][CH:12]=[CH:13][C:7]=2[O:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)N[C@H]1COc2cccc(-c3ccccc3)c2NC1=O
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: C1COCCO1
Product: N[C@H]1COc2cccc(-c3ccccc3)c2NC1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2 mL of dioxane and 1.8 mL of a solution of hydrochloric acid in dioxane (4M) are added to a 25 mL round-bottomed flask containing 85 mg of 43 (0.24 mmol). The mixture is stirred for 4 h at RT under argon. The dioxane is concentrated, and taken up in 10 mL of isopropyl ether. The solid formed is disintegrated with isopropyl ether. 60 mg of amine 44 (cream-coloured solid) are obtained after filtration in the hydrochloride form.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]=[N+]=[N-]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH2:19]
Reactant: COC(=O)CCCCCCCCCCCCCCCN=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCCCCCCCCCCCCCCN

Procedure:
16-azidohexadecanoic acid methyl ester is catalytically hydrogenated with palladium/activated charcoal in methanol at 3 bar for three hours to give the corresponding amine (Zinic et al., Positionally Isomeric Organic Gelators: Structure-Gelation Study, Racemic versus Enantiomeric Gelators, and Solvation Effects, Chem. Eur. J. 2010; 16:3066-82).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([C:12]([S:14]C)=S)[CH2:11][CH2:10][CH2:9][S:8]1.[CH2:16]([NH2:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[CH2:16]([NH:28][C:12]([C:7]1([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:11][CH2:10][CH2:9][S:8]1)=[S:14])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CSC(=S)C1(c2ccccn2)CCCS1
Reactant: CCCCCCCCCCCCN
Product: CCCCCCCCCCCCNC(=S)C1(c2ccccn2)CCCS1
Temperature: 0 °C
Yield: 66.3 %

Procedure:
A solution of methyl 2-(pyrid-2-yl)tetrahydrothiophene-2-carbodithioate (10 g) in n-dodecylamine (15 g) is heated for 50 minutes at 110° C. The reaction mixture is chromatographed on silica gel (200 g) contained in a column of diameter 3.7 cm. Elution is carried out with a cyclohexane-ethyl acetate mixture (90:10 by volume; 1800 cc), one 300 cc fraction and three 500 cc fractions being collected. Fractions 2 to 4 are combined and concentrated to dryness (20 mm Hg; 2.7 kPa) at 40° C.; the residue (14.2 g) is dissolved in ethanol (75 cc). The solution, to which decolourising charcoal (0.3 g) is added, is filtered hot and then kept, after cooling, for 30 minutes at a temperature of about 0° C. The crystals which have appeared are filtered off, washed twice with ethanol (40 cc in total) and dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20° C. The resulting product (11.5 g) is dissolved in boiling ethanol (75 cc) and the solution, to which decolourising charcoal (0.3 g) is added, is filtered hot and then kept, after cooling, for 30 minutes at a temperature of about 0° C. The crystals which have appeared are filtered off, washed twice with ethanol (50 cc in total) and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 35° C. N-n-Dodecyl-2-(pyrid-2-yl)tetrahydrothiophene-2-carbothioamide (10.2 g), melting at 60° C., is thus obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].CC(N(C)C)=O.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[CH:26]=O.OS([O-])=O.[Na+]>O>[CH3:14][O:13][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][C:9]=1[O:11][CH3:12])[N:1]=[C:26]([C:25]1[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:23]([O:22][CH3:21])[CH:24]=1)[N:6]=[C:4]2[OH:5]
Reactant: COc1cc(N)c(C(N)=O)cc1OC
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc2nc(-c3cc(OC)c(OC)c(OC)c3)nc(O)c2cc1OC
Temperature: 139 °C
Reaction time: 8 h

Procedure:
Into a 500-mL 3-necked round-bottom flask, was placed 2-amino-4,5-dimethoxybenzamide (12 g, 61.16 mmol, 1.00 equiv), dimethylacetamide (200 mL), 3,4,5-trimethoxybenzaldehyde (12 g, 61.16 mmol, 1.00 equiv) and NaHSO3 (9.55 g, 91.83 mmol, 1.50 equiv). The resulting solution was stirred overnight at 139° C. The mixture was cooled to room temperature. The resulting solution was diluted with 800 mL of water. The solids were collected by filtration. The filter cake was washed with 1×100 ml of water, 100 ml of diethyl ether and 100 mL of methanol. This resulted in 12 g (53%) of 6,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)quinazolin-4-ol as a brown solid. MS (ESI) m/z 373 [M+h]+
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18](OC(OC(C)(C)C)=O)[CH2:17][CH2:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][CH:34]=[CH:33]2)#[N:2].Cl>C(O)C.O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][CH:34]=[CH:33]2)#[N:2]
Reactant: CC(C)(C)OC(=O)ON1CCC(COc2cc3nccc(Oc4ccc5[nH]ccc5c4)c3cc2C#N)CC1
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: N#Cc1cc2c(Oc3ccc4[nH]ccc4c3)ccnc2cc1OCC1CCNCC1
Reaction time: 17 h
Yield: 7.5 %

Procedure:
6-Cyano-4-(1H-indol-5-yloxy)-7-[(1-(t-butoxycarbonyloxy)piperidin-4-yl)methyloxy]quinoline (0.25 g, 0.5015 mmol) was dissolved in ethanol (2 ml) and tetrahydrofuran (2 ml), and then concentrated hydrochloric acid (0.2 ml) was added at room temperature and the mixture was stirred for 17 hours. The solvent was distilled off under reduced pressure, saturated bicarbonate water was added, and then extraction was performed with a tetrahydrofuran and ethyl acetate mixed solvent, the extract was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was adsorbed onto NH silica gel and purified by column chromatography (ethyl acetate-methanol system) with NH silica gel, and the obtained crystals were suspended in ethanol and diluted with diethyl ether and hexane. The crystals were filtered out, washed with diethyl ether and dried by aspiration to obtain the title compound (15 mg, 0.0376 mmol, 7.51%).
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][CH:10]=2>O.Cl>[CH3:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:16]1[C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:5]=[N:1]1
Reactant: O=N[O-]
Reactant: Cc1ccccc1Nc1c(N)cnc2ccccc12
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1ccccc1-n1nnc2cnc3ccccc3c21
Temperature: 25 °C
Yield: 26.4 %

Procedure:
A solution of sodium nitrite (0.82 g, 12 mmol) in water (10 ml) was added dropwise to a stirred suspension of 3-amino-4-(2-methylphenylamino)quinoline (2.0 g,8 mmol) in 2M HCl (80 ml) at 0.5°. The solid gradually dissolved to give a pale orange solution which deposited a solid after about 1 hour. After warming to room temperature the solid was collected, washed with water and recrystallised from aqueous ethanol with charcoaling, to give the title compound as a white solid (0.55 g, 26%), m.p. 140°-142° .
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]#[N:41])[CH:35]=2)[CH:12]2[CH2:17][CH2:16][N:15]([CH:18]([CH3:32])[CH2:19][CH2:20][NH:21][C:22](=[O:31])[C:23]3[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:30])[CH2:14][CH2:13]2)=[CH:7][CH:6]=1)(=O)C.Cl>CO>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]#[N:41])[CH:35]=2)[CH:12]2[CH2:13][CH2:14][N:15]([CH:18]([CH3:32])[CH2:19][CH2:20][NH:21][C:22](=[O:31])[C:23]3[C:24]([CH3:30])=[CH:25][CH:26]=[CH:27][C:28]=3[CH3:29])[CH2:16][CH2:17]2)=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(N(Cc2cccc(C#N)c2)C2CCN(C(C)CCNC(=O)c3c(C)cccc3C)CC2)cc1
Agent: Cl
Solvent: CO
Product: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 26 h
Yield: 64.2 %

Procedure:
To a solution of COMPOUND 112 (59 mg, 0.11 mmol) in MeOH (1 mL) was added 6N HCl (2 mL) and the solution was stirred at room temperature for 26 hours to afford COMPOUND 142 as a white solid (36 mg, 67%) following a basic work-up and purification. 1H NMR (CDCl3) δ 0.91-1.12 (m, 2H), 0.98 (d, 3H, J=6.0 Hz), 1.51 (m, 1H), 1.68-1.75 (m, 3H), 2.09 (t, 1H, J=10.8 Hz), 2.31 (s, 6H), 2.49 (t, 1H, J=10.8 Hz), 2.71-2.83 (m, 3H), 3.22-3.34 (m, 2H), 3.67 (s, 2H), 3.88 (m, 1H), 6.50 (m, 4H), 6.93 (m, 3H), 7.34-7.48 (m, 4H), 8.48 (br s, 1H). 13C NMR (CDCl3) δ 13.36, 19.14, 29.10, 30.33, 30.92, 39.85, 43.62, 48.98, 52.18, 58.75, 60.55, 112.21, 116.34, 118.09, 127.24, 128.35, 128.91, 130.24, 130.63, 131.00, 131.49, 134.03, 138.60, 138.93, 141.24, 142.75, 169.89. ES-MS m/z 510 (M+H). Anal. Calcd. for C32H39N5O.0.1CH2Cl2.0.2C6H14: C, 74.70; H, 7.91; N, 13.08. Found. C, 74.89; H, 7.77; N, 13.20.
Reaction SMILES: [OH:1][C:2]1([CH3:25])[C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[C:5]=2[C@H:4]([CH3:24])[CH2:3]1.[ClH:26].O1CCOCC1>C(Cl)Cl>[ClH:26].[ClH:26].[CH3:24][C@H:4]1[C:5]2[C:10]([N:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)=[N:9][CH:8]=[N:7][C:6]=2[C:2]([CH3:25])([OH:1])[CH2:3]1
Reactant: C[C@@H]1CC(C)(O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@H]1CC(C)(O)c2ncnc(N3CCNCC3)c21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of tert-butyl 4-((5R)-7-hydroxy-5,7-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (28 mg, 0.080 mmol) in DCM (6 mL) was added to a 4.0M HCl solution in dioxane (1.4 mL, 5.63 mmol). The mixture was stirred at room temperature for 4 hours. A 4.0M HCl solution in dioxane (1.4 mL, 5.63 mmol) from a different bottle was added. The resulting mixture was stirred for 18 hours. The solvents were removed in vacuo to give (5R)-5,7-dimethyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride. DIPEA (41.5 mg, 0.321 mmol) was added to a suspension of this (5R)-5,7-dimethyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (25.8 mg, 0.0803 mmol), 3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (32.9 mg, 0.0964 mmol), and O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (36.6 mg, 0.0964 mmol) in CH2Cl2 (6 mL) at room temperature. The resulting mixture was stirred for 1 hour. The solvent was removed in vacuo. The residue was purified by a silica cartridge (5.0 g) eluted by EtOAc to give tert-butyl 2-(4-chlorophenyl)-3-(4-((5R)-7-hydroxy-5,7-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (46 mg, 100%) as a gel. LCMS (APCI+) [M-Boc+H]+ 472.2; Rt: 3.51 min.
Reaction SMILES: [CH2:1]([NH:5][CH:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]=1)[C:7]#[N:8])[CH:2]([CH3:4])[CH3:3].S(OC)(O[CH3:26])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([N:5]([CH:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]=1)[C:7]#[N:8])[CH3:26])[CH:2]([CH3:4])[CH3:3]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)CNC(C#N)c1cccc(Oc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)CN(C)C(C#N)c1cccc(Oc2ccccc2)c1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A mixture of α-(N-isobutylamino)-3-phenoxybenzeneacetonitrile (28.0 g; 0.1 mole), dimethyl sulfate (12.6 g; 0.1 mole), anhydrous potassium carbonate (15.0 g) and anhydrous acetone (100 ml) was stirred at a temperature of 50° C. for a period of 16 hours. The mixture was filtered and the solvent was removed from the filtrate by distillation under reduced pressure. The residue was treated with anhydrous diethyl ether, the etherial solution was separated and the ether was evaporated to give α-(N-isobutyl-N-methylamino)-3-phenoxybenzeneacetonitrile as a yellow oil. Proton nuclear magnetic resonance spectrum (d6 -acetone; δ in ppm): 0.85 (6H, d of d); 1.83 (1H, m); 2.23 (3H, s); 5.19 (1H, s); 7.0-7.5 (9H, m).
Reaction SMILES: [CH2:1]([N:4]([CH2:27][CH2:28][CH3:29])[C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:26]=2[N:25]=[CH:24][CH:23]=[CH:22]3)[CH:16]=1)[C:10]([O:12]C)=[O:11])=[O:6])[CH2:2][CH3:3].[OH-].[Li+].O>CO>[CH2:27]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:26]=2[N:25]=[CH:24][CH:23]=[CH:22]3)[CH:16]=1)[C:10]([OH:12])=[O:11])=[O:6])[CH2:28][CH3:29]
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc(-c2cccc3cccnc23)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCN(CCC)C(=O)c1cc(C(=O)O)cc(-c2cccc3cccnc23)c1
Reaction time: 8 h
Yield: 76.7 %

Procedure:
To a mixture of methyl 3-[(dipropylamino)carbonyl]-5-(8-quinolinyl)benzoate (XLIX step 1, 175.5 mg, 0.45 mmol) in methanol (2 mL) is added lithium hydroxide (32.3 mg, 1.4 mmol) and water (500 microliter). After stirring overnight, the reaction mixture is partitioned between ethyl acetate (10 mL) and water (10 mL). The aqueous phase is separated and acidified with hydrochloric acid (1N), and extracted with chloroform (3×40 mL). The organic phase is washed with saline, dried (sodium sulfate) and concentrated under reduced pressure to give 3-[(dipropylamino)carbonyl]-5-(8-quinolinyl)benzoic acid (IX–L, 130 mg), NMR (300 MHz, CD3OD) δ 6 8.84, 8.39, 8.35, 8.05, 7.96, 7.90, 7.87, 7.79, 7.68, 3.50, 3.37, 1.76–1.61, 0.99 and 0.84.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.C[O:10][C:11]([CH:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:14]1)=O.Cl>O1CCCC1.O>[C:1]([CH2:2][C:11]([CH:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:14]1)=[O:10])#[N:3]
Reactant: CC#N
Reactant: COC(=O)C1CCN(C(=O)OCc2ccccc2)C1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: N#CCC(=O)C1CCN(C(=O)OCc2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 61.9 %

Procedure:
To a solution of acetonitrile (708 μL, 13.5 mmol) in tetrahydrofuran (30 mL) was added n-butyl lithium (1.6 M solution in hexane, 7.75 mL, 12.4 mmol) at −78° C. The solution was stirred at −78° C. for 10 minutes and a solution of EXAMPLE 24A (3.0 g, 11.34 mmol) in 10 mL of tetrahydrofuran was added. The mixture was stirred at −78° C. for 1 hour and was warmed up to −20° C. over 3 hours. Water was added and the mixture acidified to pH 3 with 2N hydrochloric acid. The mixture was partitioned between ethyl acetate and brine and the organic phase concentrated. The residue was purified by flash chromatography on silica gel using 30-80% ethyl acetate in hexane to give the title compound (1.91 g, 61%). MS(DCI): m/z 273 (M+1)+.
Reaction SMILES: C([O-])(=O)C.[Pb+2:5].C([O-])(=O)C.[CH3:10][O:11][CH2:12][C:13]([OH:15])=[O:14]>>[CH3:10][O:11][CH2:12][C:13]([O-:15])=[O:14].[Pb+2:5].[CH3:10][O:11][CH2:12][C:13]([O-:15])=[O:14]
Reactant: COCC(=O)O
Agent: CC(=O)[O-]
Agent: [Pb+2]
Product: COCC(=O)[O-]
Temperature: 100 °C

Procedure:
A 500 mL round bottom flask was charged with lead (II) acetate (Alfa 10719, 50.4 g, 0.133 mol) and methoxyacetic acid (209.8 g, 2.3 mol). The contents of the reactor were heated to 100° C. with an external oil bath and the volatile materials were distilled at 100 to 50 torr, head temperature to 65° C. The distillate was identified as a mixture of acetic acid and methoxyacetic acid. The pressure was further reduced and the excess methoxyacetic acid was removed. The title product was isolated as a colorless viscous liquid and diluted in water to give 87.6 grams of product (31% lead). Thermo-gravimetric analysis in air to 800° C. gave 32.5% lead oxide, calculated 32.8%. IR (thin film) 3441, 2943, 2834, 1731, 1585, 1428, 1202, 1114.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:10]2[CH:11]=[C:12]([C:14]([OH:16])=O)[S:13][C:9]=2[CH:8]=[CH:7][CH:6]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:29][C:30]([NH:32][NH2:33])=[O:31]>O1CCCC1>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:10]2[CH:11]=[C:12]([C:14]([NH:33][NH:32][C:30](=[O:31])[CH3:29])=[O:16])[S:13][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: CC(=O)NN
Reactant: COCOc1cccc2sc(C(=O)O)cc12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COCOc1cccc2sc(C(=O)NNC(C)=O)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.1 %

Procedure:
4-(Methoxymethyloxy)benzothiophene-2-carboxylic acid (7 g) was dissolved in tetrahydrofuran (100 ml) and CDI (7.3 g) and acetohydrazine (2.4 g) was added. The mixture was stirred at room temperature for 3 hr. The precipitated crystals were collected by filtration to give the title compound (3.9 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(O)(CC)(C)C.C(O)CO.[CH:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1I)([CH3:19])[CH3:18].[CH:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[SH:36])([CH3:29])[CH3:28].CCCCCCCCCCCC>C(OCC)(=O)C>[CH:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[CH:27]([CH3:29])[CH3:28])([CH3:19])[CH3:18]
Reactant: CC(C)c1ccccc1S
Reactant: CC(C)c1ccccc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCC(C)(C)O
Solvent: OCCO
Product: CC(C)c1ccccc1Sc1ccccc1C(C)C
Temperature: 100 °C
Reaction time: 24 h
Yield: 90.6 %

Procedure:
Cu(I) iodide (38 mg, 0.2 mmol) and potassium carbonate (276 mg, 2.0 mmol) were charged into a screw-capped test tube with Teflon-lined septum. The tube was evacuated and backfilled with argon (3 cycles). tert-Amyl alcohol (2-methyl-2-butanol) (1.0 mL, bench grade solvent without degassing and pre-drying), ethylene glycol (111 μL, 2.0 mmol, bench grade solvent), 2-isopropyliodobenzene (246 mg, 1.0 mmol) and 2-isopropylbenzenethiol (90% purity, 202 μL, 1.2 mmol) were added by syringes at room temperature. The tube was heated to 100° C. and stirred for 24 hours. The reaction mixture was then allowed to reach room temperature. Ethyl acetate (approx. 5 mL) and dodecane (227 μL, GC standard) were added. The aliquot was analyzed GC. The reaction mixture was then filtered and concentrated. The crude product was purified by column chromatography on silica gel using hexane as eluent to afford colorless oil as the titled product (245 mg, 91% yield). Rf=0.5 (hexane). 1H NMR (CDCl3, 300 MHz) δ 7.30 (d, 2 H, J=7.2 Hz), 7.18-7.24 (m, 2 H), 7.03-7.05 (m, 4 H), 3.50 (hept, 2 H, J=6.9 Hz), 1.25 (s, 3 H), 1.23 (s, 3 H). 13C NMR (CDCl3, 75 MHz) δ 149.2, 134.2, 132.1, 127.6, 126.7, 125.9, 30.9, 23.8. IR (neat, cm−1) 3058, 2962, 2929, 2867. MS (EI) m/z (relative intensity) 270 (100), 211 (90). HRMS (EI), Cald. for C18H22S 270.1442. Found 270.1445.
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[CH2:13]([O:15][C:16](=[O:39])[CH2:17][S:18][C:19]1[N:24]=[C:23]([NH:25][CH2:26][CH2:27][NH2:28])[C:22]([C:29](=[O:38])[NH:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[CH:21][N:20]=1)[CH3:14].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:13]([O:15][C:16](=[O:39])[CH2:17][S:18][C:19]1[N:24]=[C:23]([NH:25][CH2:26][CH2:27][NH:28][C:8](=[O:9])[C:7]2[CH:11]=[CH:12][C:4]([N:1]=[N+:2]=[N-:3])=[CH:5][CH:6]=2)[C:22]([C:29](=[O:38])[NH:30][C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)=[CH:21][N:20]=1)[CH3:14]
Reactant: CCOC(=O)CSc1ncc(C(=O)Nc2ccc(F)cc2)c(NCCN)n1
Reactant: [N-]=[N+]=Nc1ccc(C(=O)Cl)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CSc1ncc(C(=O)Nc2ccc(F)cc2)c(NCCNC(=O)c2ccc(N=[N+]=[N-])cc2)n1
Reaction time: 8 h
Yield: 15.6 %

Procedure:
4-Azidobenzoyl chloride (67 mg, 0.37 mmol) was added to a solution of [4-(2-aminoethylamino)-5-(4-fluorophenylcarbamoyl)pyrimidin-2-ylsulfanyl]acetic acid ethyl ester (145 mg, 0.37 mmol) in DMF (2.0 mL). DIPEA (100 μL, 0.55 mmol, 1.5 eq) was then added to the reaction mixture and the acylation was allowed to proceed overnight at ambient temperature. The reaction mixture was concentrated by rotary evaporation and purified using flash chromatography (4 g silica gel, 10 mL/min flow rate) to yield the titled product (31 mg, 16%) as a clear glass. 1H NMR: (d6-DMSO) δ 10.23 (s, 1H), 8.67 (m, 1H), 8.55 (s, 1H), 7.81 (d, 2H), 7.62 (m, 2H), 7.13 (m, 3H), 4.07 (q, 2H), 3.97 (s, 2H), 3.60 (m, 2H), 3.42 (m, 2H), 1.14 (t, 3H); HPLC: Rt=4.36 min; MS (ESI): m/z 537.31 (M−H)−; IR (KBr): 2126 cm−1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[C:4]([F:21])[CH:3]=1.[NH:22]1[C:30]2[C:25](=[CH:26][C:27](B(O)O)=[CH:28][CH:29]=2)[CH:24]=[CH:23]1>>[F:21][C:4]1[CH:3]=[C:2]([C:27]2[CH:26]=[C:25]3[C:30](=[CH:29][CH:28]=2)[NH:22][CH:23]=[CH:24]3)[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:9]
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: O=C(c1ccc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Product: O=C(c1ccc(-c2ccc3[nH]ccc3c2)cc1F)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure SS starting from (4-bromo-2-fluoro-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 5-Indole boronic acid. MS (M+H) 392.2
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([Sn](CCCC)(CCCC)CCCC)[S:10][C:3]=12.ClC1C=CN=C2C=C(C3SC=CN=3)SC=12.Br[C:40]1[N:41]=[CH:42][N:43]([CH3:45])[CH:44]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:40]3[N:41]=[CH:42][N:43]([CH3:45])[CH:44]=3)[S:10][C:3]=12
Reactant: Cn1cnc(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2nccc(Cl)c2s1
Agent: Clc1ccnc2cc(-c3nccs3)sc12
Product: Cn1cnc(-c2cc3nccc(Cl)c3s2)c1
Yield: 29 %

Procedure:
Starting from the compound 98 (scheme 19), following the procedure described above for the synthesis of compound 10 (scheme 2, step 2, example 12) but replacing 2-bromothiazole with 4-bromo-1-methyl-1H-imidazole, title compound 224 was obtained in 29% yield. MS (m/z): 250.1 (100%), 252.1 (37%) (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[CH2:6][O:7][CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])([O-])=O.[Cl-].[NH4+].C(OCC)(=O)C>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[CH2:6][O:7][CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCCOCc1ccccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCOCc1ccccc1N
Temperature: 80 °C
Reaction time: 2 h
Yield: 43.3 %

Procedure:
To a solution of tert-butyl (2-((2-nitrobenzyl)oxy)ethyl)carbamate (C11, 154 mg) in ethanol (5 mL) and water (1 mL), iron powder (174 mg) and ammonium chloride (167 mg) were added at room temperature, and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was cooled to room temperature, and then ethyl acetate was added to the reaction mixture. The insoluble matter was removed by filtration through Cerite, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (eluent, 75% hexane/25% ethyl acetate) to obtain oily tert-butyl (2-((2-aminobenzyl)oxy)ethyl)carbamate (C12, 60 mg).