Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([C:21]3[S:22][C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[N:25]=3)[N:19]=[C:18]([CH:30]([CH3:32])[CH3:31])[CH:17]=2)=[CH:12][CH:11]=1.O>CN(C=O)C>[Br:1][C:17]1[C:18]([CH:30]([CH3:32])[CH3:31])=[N:19][N:20]([C:21]2[S:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)[C:16]=1[C:13]1[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=1
Reactant: CC(C)c1cc(-c2ccc(F)cc2)n(-c2nc3ccccc3s2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1nn(-c2nc3ccccc3s2)c(-c2ccc(F)cc2)c1Br
Temperature: 25 °C

Procedure:
N-Bromosuccinimide (86.5 g, 486 mmol) was added in portions to the pyrazole (164 g, 486 mmol, Step A) in DMF (1 l) at 0° C. under an atmosphere of N2. This mixture was stirred and allowed to warm to room temperature overnight. The reaction mixture was poured into H2O (1 l) and the resulting precipitate was collected and washed with water. The product was dried overnight to give 184.1 g (91%), mp 146°-147° C. (hexanes).
Reaction SMILES: [C:1]([NH:13][C@H:14]([C:18]([OH:20])=O)[CH:15]([CH3:17])[CH3:16])(=[O:12])[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH:21]([N:24]([CH2:33][C@@H:34]([OH:44])[C@@H:35]([NH2:43])[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([CH3:23])[CH3:22].ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.CI>CN(C=O)C.C(OCC)(=O)C>[CH:21]([N:24]([CH2:33][C@@H:34]([OH:44])[C@@H:35]([NH:43][C:18](=[O:20])[C@H:14]([CH:15]([CH3:16])[CH3:17])[NH:13][C:1](=[O:12])[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:27])([CH3:23])[CH3:22]
Reactant: CC(C)N(C[C@@H](O)[C@@H](N)Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: CC(C)[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: CC(C)[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)CN(NC(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
To a mixture of 0.0643 g (0.24 mmol) of the acid from Step A, 0.0797 g (0.236 mmol) of the the amine from Step B, 0.032 g (0.24 mmol) of 1-hydroxybenzotriazole in 0.5 ml of anhydrous DMF was added 0.071 g (0.24 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide. After stirring overnight at room temperature the mixture was diluted to 30 ml with ethyl acetate and Washed successively with water, 5% aqueous sodium bicarbonate, 2% aqueous potassium bisulfate solution, and saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure and purification of the residue by column chromatography (silica gel, hexane/ethyl acetate 3:2) gave 0.091 g (65% yield) of the title compound, melting at 186°-189° C.: Rf (B)=0.19; Rf (C)=0.83; NMR (CDCl3) 1.0 (m, 12H, val and isopropyl CH3); 1.71 (s, 9H, t-butyl CH3); 2.3 (m, 1 H, val CH-β); 2.5-3.27 (m, 3H, butyl CH-3, CH2); 3.5 (m, 1 H, isopropyl CH); 4.31 (m, 2H, val CH-α, OH); 5.43 (broad s, 1 H, carbazate NH); 6.22 (broad d, 1H, butyl NH); 6.7-8.73 (m, 12H, aromatic, NH).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].[CH3:26][O:27][C:28]1[N:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][C:29]=1[C:30]([O:32][CH3:33])=[O:31].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:35]5[CH:36]=[N:37][C:28]([O:27][CH3:26])=[C:29]([C:30]([O:32][CH3:33])=[O:31])[CH:34]=5)[C:3]([CH3:25])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cnc1OC
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)cnc1OC
Yield: 83.3 %

Procedure:
To N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (0.26 g, 0.7 mmol) in 1,2-dimethoxyethane (7 mL) was added methyl 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (0.25 g, 0.86 mmol), tetrakis(triphenylphosphine)palladium (0) (42 mg, 0.04 mmol), and 2 M sodium carbonate (0.70 mL, 1.4 mmol). The reaction mixture was irradiated in the microwave at 120° C. for twenty minutes. The reaction mixture was diluted with ethyl acetate (5 mL) and washed with water (5 mL). The organics were dried over sodium sulfate and evaporated to dryness. The crude reaction mixture was purified by silica gel chromatography (eluting with 0-100% ethyl acetate in hexanes) to yield the product (0.29 g, 81%). ESI-MS m/z calc. 497.45. found 498.3 (M+1)+. Retention time 2.14 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:17]=[CH:18][C:19](=[O:27])[N:20]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH:21]=4)[S:15][C:8]=23)=[C:4]([F:30])[CH:3]=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[NH:39][C:40](=[O:45])[CH2:41][C:42](O)=[O:43].OC1C2N=NNC=2C=CC=1.C(Cl)CCl.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:26][N:24]([CH3:25])[CH2:23][CH2:22][N:20]1[C:19](=[O:27])[CH:18]=[CH:17][C:16]([C:14]2[S:15][C:8]3[C:9](=[N:10][CH:11]=[CH:12][C:7]=3[O:6][C:5]3[CH:28]=[CH:29][C:2]([NH:1][C:42](=[O:43])[CH2:41][C:40]([NH:39][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[O:32][CH3:31])=[O:45])=[CH:3][C:4]=3[F:30])[CH:13]=2)=[CH:21]1
Reactant: COc1ccccc1NC(=O)CC(=O)O
Reactant: CN(C)CCn1cc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)ccc1=O
Agent: O=C([O-])O
Agent: Oc1cccc2[nH]nnc12
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4ccc(=O)n(CCN(C)C)c4)sc23)c(F)c1
Yield: 52.3 %

Procedure:
To a solution of compound 422 (25 mg, 0.059 mmol) in DMF (0.5 mL) was added the acid 27 (25 mg, 0.12 mmol), hydroxybenzotriazole (11 mg, 0.071 mmol), then EDC (23 mg, 0.12 mmol). The reaction mixture was stirred at room temperature for 6 hours before the addition of saturated NaHCO3 (8 mL). The mixture was then extracted with dichloromethane; the extract was dried over anhydrous Na2SO4, filtered and concentrated. The residue was then purified by flash chromatography (eluent a gradient of 0 to 20% methanol in dichloromethane) to give title compound 417 as a white solid (19 mg, 53% yield). 1H NMR: (DMSO-d6) δ(ppm): 10.58 (s, 1H), 9.62 (s, 1H), 8.45 (d, J=5.6 Hz, 1H), 8.28 (d, J=2.8 Hz, 1H), 8.05 (d, J=8.4 Hz, 1H), 7.95 (dd, J=2.8, 9.6 Hz, 1H), 7.88-7.84 (m, 2H), 7.45 (t, J=8.8 Hz, 1H), 7.43-7.40 (m, 1H), 7.07-7.03 (m, 2H), 6.92-6.88 (m, 1H), 6.60 (d, J=5.6 Hz, 1H), 6.51 (d, J=9.6 Hz, 1H), 4.05 (t, J=6.0 Hz, 2H), 3.84 (s, 3H), 3.62 (s, 2H), 2.53 (t, J=6.4 Hz, 2H), 2.47 (s, 6H). MS (m/z): 308.5 ([M+2H]/2), 616.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](O)([CH3:10])[CH3:9])[C:5]([F:12])=[CH:4][CH:3]=1.CS(OS(C)(=O)=O)(=O)=O.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[N:7]=[C:6]([C:8]([CH3:10])=[CH2:9])[C:5]([F:12])=[CH:4][CH:3]=1
Reactant: CC(C)(O)c1nc(Br)ccc1F
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)c1nc(Br)ccc1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 84 %

Procedure:
To a solution of 2-(6-bromo-3-fluoro-pyridin-2-yl)-propan-2-ol (22.3 g, 95 mmol) and methanesulfonic acid anhydride (49.8 g, 286 mmol) in dichloromethane was added dropwise triethylamine (53.1 ml, 381 mmol) at 0° C. The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was quenched with aq. sodium carbonate solution and diluted with dichloromethane. The aqueous phase was extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo (volatile). The crude brown oil was chromatographed over silica (cyclohexane:ethyl acetate 9:1) to give the title compound as a clear liquid. 17.35 g (84% yield). TLC (cyclohexane/ethyl acetate 9:1) Rf=0.58; 1H-NMR (360 MHz, CDCl3): 7.26-7.15 (m, 2H), 5.72 (s, 1H), 5.47 (s, 1H), 2.12 (s, 3H, CH3).
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][NH:6][C:5](=[O:9])[C:4]=1[C:10]1[NH:21][C:20]2[CH:19]=[C:18]3[C:14]([CH:15]=[N:16][NH:17]3)=[CH:13][C:12]=2[N:11]=1.Cl.[NH2:23][CH2:24][C@H:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Br:33])[CH:28]=1)[OH:26].CN1CCOCC1>C(#N)C>[Br:33][C:29]1[CH:28]=[C:27]([C@H:25]([OH:26])[CH2:24][NH:23][C:3]2[CH:8]=[CH:7][NH:6][C:5](=[O:9])[C:4]=2[C:10]2[NH:21][C:20]3[CH:19]=[C:18]4[C:14]([CH:15]=[N:16][NH:17]4)=[CH:13][C:12]=3[N:11]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: NC[C@@H](O)c1cccc(Br)c1
Reactant: O=c1[nH]ccc(Cl)c1-c1nc2cc3cn[nH]c3cc2[nH]1
Agent: Cl
Solvent: CC#N
Solvent: CN1CCOCC1
Product: O=c1[nH]ccc(NC[C@@H](O)c2cccc(Br)c2)c1-c1nc2cc3cn[nH]c3cc2[nH]1
Temperature: 80 °C
Yield: 62.8 %

Procedure:
The mixture of crude 4-chloro-3-(1,7-dihydro-1,2,5,7-tetraaza-s-indacen-6-yl)-1H-pyridin-2-one hydrochloric acid salt (80 mg, 0.25 mmol), (S)-2-amino-1-(3-bromo-phenyl)-ethanol hydrochloric acid salt (96 mg, 0.37 mmol), N-methyl morpholine (0.5 ml, excess), and acetonitrile (15 mL) was heated to 80° C. overnight and cooled to room temperature. After concentration in vacuo, the residue was purified by prep. HPLC to yield the titled compound (73 mg, 63%). 1H NMR (400 MHz, CD3OD) δ 8.08 (s, 1H), 7.46 (s, 1H), 7.44 (s, 1H), 7.21-7.40 (m, 5H), 6.14 (d, J=7.5 Hz, 1H), 4.97 (m, 1H), 3.60-3.68 (m, 2H). LCMS (t=1.46 min), [M+H]+ 465.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].[CH3:22][Si:23]([C:26]1[O:27][CH:28]=[CH:29][C:30]=1C=O)([CH3:25])[CH3:24].[O:33]1CCC[CH2:34]1>>[O:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:34]([C:29]1[CH:30]=[C:26]([Si:23]([CH3:22])([CH3:24])[CH3:25])[O:27][CH:28]=1)[OH:33])[Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: C[Si](C)(C)c1occc1C=O
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCCCCCCBr
Reactant: C1CCOC1
Agent: [Mg]
Product: CC(C)(C)[Si](C)(C)OCCCCCCCCCCCC(O)c1coc([Si](C)(C)C)c1
Reaction time: 1 h

Procedure:
To a stirred suspension of magnesium turnings (0.142 g, 5.9 mmol) in tetrahydrofuran (1 ml) at room temperature under nitrogen was added a solution of 1-bromo-11-t-butyldimethylsiloxyundecane (1.06 g, 2.9 mmol) in tetrahydrofuran (1.5 ml). This mixture was heated to reflux and stirred for 1 hour, then cooled to 0° and diluted with tetrahydrofuran (3 ml). Trimethylsilyl-3-furanaldehyde (0.491 g, 2.9 mmol) was added dropwise in 2 ml of tetrahydrofuran. The solution was stirred for 1 hour at 0°, 4.5 hours at room temperature, quenched with saturated ammonium chloride solution and poured into ethyl ether. The organic portion was washed twice with water, once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give a yellow liquid. The alcohol (Rf =0.33, 20% ethyl ether/hexane) was purified by flash chromatography (silica, 10-15% ethyl ether/petroleum ether) to give a pale oil.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([S:22][CH3:23])[CH:17]=2)[CH2:9]1)C1C=CC=CC=1.CN(C)P(N(C)C)(N(C)C)=O.Cl[C:36]([O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:37]>C1(C)C=CC=CC=1>[CH3:23][S:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[NH:15][CH2:14][CH:10]1[O:11][CH2:12][CH2:13][N:8]([C:36]([O:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:37])[CH2:9]1
Reactant: CSc1cccc(NCC2CN(Cc3ccccc3)CCO2)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: Cc1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CSc1cccc(NCC2CN(C(=O)Oc3ccccc3)CCO2)c1

Procedure:
To a solution of 4-benzyl-2-(3-methylthioanilino)methylmorpholine (1.7 g.) in toluene (50 ml.) is added hexamethylphosphoramide (1 ml.) and then phenyl chloroformate (1.5 ml.). The mixture is heated under reflux for 18 hours, the toluene is then removed under reduced pressure, the oily residue is dissolved in ether and the ethereal solution is washed successively with sodium hydroxide solution, water, hydrochloric acid and water before drying over anhydrous magnesium sulphate. Evaporation of the dried filtered ethereal solution gives yellow oil (2.4 g.) or 2-(3-methylthioanilino)methyl-4-phenoxycarbonylmorpholine, which is dissolved in dimethylsulphoxide (20 ml.) and this solution is added to a solution of sodium methylsulphinylmethide [prepared in the usual way from sodium hydride (2.4 g.) and dimethylsulphoxide (50 ml.) ]. Water (1.8 ml.) is then added when the temperature of the mixture rises to about 60°C. The solution is stirred for 1 hour and then poured into water containing ice and the mixture extracted with ether (3 × 100 ml.). The ethereal solution is washed with water, dried (MgSO4) and filtered and the filtrate is treated with an ethereal solution of oxalic acid to precipitate 2-(3-methylthioanilino)methylmorpholine oxalate, m.p. 114°-115°C. after recrystallisation from acetone.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.CN(C)C=O.[CH3:12][O:13][C:14]([C:16]1[S:17][C:18]([C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[N:26]([CH:30]([CH3:32])[CH3:31])[CH:25]=C3)=[CH:19][CH:20]=1)=[O:15]>ClCCl>[CH3:12][O:13][C:14]([C:16]1[S:17][C:18]([C:21]2[CH:29]=[C:28]3[C:27](=[CH:23][CH:22]=2)[N:26]([CH:30]([CH3:32])[CH3:31])[CH:25]=[C:2]3[CH:1]=[O:5])=[CH:19][CH:20]=1)=[O:15]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)c1ccc(-c2ccc3c(ccn3C(C)C)c2)s1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccc3c(c2)c(C=O)cn3C(C)C)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.7 %

Procedure:
To anhydrous dichloromethane (30 mL) was added oxalyl chloride (0.1 mL, 1.2 mmol). N,N-dimethylformamide (0.1 mL, 1.2 mmol) was added at 0° C., and stirred for 30 min at 0° C. To this reaction solution was added 5-(1-isopropyl-indol-5-yl)thiophene-2-carboxylic acid methyl ester (0.3 g, 1.0 mmol) obtained in Preparation 32, which was then stirred for 1 h at room temperature. The solvent was removed, tetrahydrofuran (30 mL) and 20% aqueous ammonium acetate solution (30 mL) were added to the residue, and the mixture was heated for 30 min while being stirred under reflux. The reaction solution was cooled, ethyl acetate was added, and the mixture was washed with aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting solid was filtered, washed with ethyl acetate and dried to give the title compound (0.32 g, 99% Yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH2:20][C:21]([OH:23])=O)=[CH:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)[C:25]([Cl:27])=O.[N+](=C)=[N-].Cl>>[CH2:1]([O:8][C:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH2:20][C:21](=[O:23])[CH2:25][Cl:27])=[CH:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cn(C(=O)OCc2ccccc2)c2ccccc12
Reactant: O=C(Cl)C(=O)Cl
Agent: C=[N+]=[N-]
Agent: Cl
Product: O=C(CCl)Cc1cn(C(=O)OCc2ccccc2)c2ccccc12
Yield: 87 %

Procedure:
The procedure described above for the synthesis of 1-chloro-3-[2-(3-methylbenzo[b]thiophen-2-yl)propan-2-one was followed, reacting 1-(benzyloxycarbonyl)indol-3-yl acetic acid (22.49 g, 72.7 mmol) with oxalyl chloride (7.0 mL, 10 g, 80 mmol, then ethereal diazomethane, then dry HCl gas. Flash chromatography over silica gel (15-20% ethyl acetate in hexanes) gave pure product (21.64 g, 87% yield): 1H NMR (400 MHz, CDCl3) δ 3.97 (d, J=1.0 Hz, 2H) 4.15 (s, 2H) 5.45 (s, 2H) 7.27-7.30 (m, 1H) 7.33-7.51 (m, 7H) 7.63 (s, 1H) 8.19 (br. s, 1H); HRMS (ESI+) calcd for C19H17ClNO3 (MH+) 342.0892. found 342.0900.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][CH2:16][CH:17]([NH2:19])[CH3:18].[C:20]1([CH3:30])[CH:25]=[CH:24][C:23](S(O)(=O)=O)=[CH:22][CH:21]=1>>[C:2]1([C:1]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:15][CH2:16][CH:17]([N:19]=[C:30]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:18])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: CC(N)CN
Product: CC(CN=C(c1ccccc1)c1ccccc1)N=C(c1ccccc1)c1ccccc1
Temperature: 80 °C

Procedure:
255.1 g of benzophenone, 298 ml of 1,2-diaminopropane and 0.2 g of p-toluenesulphonic acid are mixed and heated for 30 minutes under reflux. Approximately 250 ml are then distilled off, the remainder is allowed to cool to approximately 80° C. and approximately 350 ml of 2-ethoxyethanol (ethylene glycol monoethyl ether) are added, followed, while stirring, by 70 ml of water and the whole is allowed to crystallise in an ice bath. N,N'-bis-(diphenylmethylene)-1,2-propylenediamine is obtained which can be purified by recrystallisation from ethanol (approximately 180 ml) and should be dried thoroughly before further reaction.
Reaction SMILES: [CH3:1][S-:2].[Na+].[CH:4]1([O:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=2[N+]([O-])=O)[C:13]([O:15][CH3:16])=[O:14])[CH2:8][CH2:7][CH2:6][CH2:5]1.[Cl-].[Na+]>CN1CCN(C)C1=O.O>[CH:4]1([O:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=2[S:2][CH3:1])[C:13]([O:15][CH3:16])=[O:14])[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(OC2CCCC2)c1
Reactant: C[S-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: COC(=O)c1ccc(SC)c(OC2CCCC2)c1
Reaction time: 4 h
Yield: 91.6 %

Procedure:
Sodium thiomethoxide (8.05 g, 0.115 mol) is added portionwise to a stirred solution of methyl 3-cyclopentyloxy-4-nitrobenzoate (26.5 g, 0.1 mol) in N,N'-dimethylimidazolidinone (200 mL) at ambient temperature under an atmosphere of nitrogen and stirring continued for 4 hours. The mixture is then diluted with water (1200 mL) containing sodium chloride (200 g) and extracted with ethyl acetate (2×300 mL). The combined extract is washed with saturated brine (2×300 mL) and then evaporated under reduced pressure to give methyl 3-cyclopentyloxy-4-(methylthio)benzoate (24.4 g, 91.7%) as an orange brown solid which is used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24].C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:46][CH2:47][N:48]2[CH:52]=[CH:51][N:50]=[N:49]2)(=O)=O)=CC=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:46][CH2:47][N:48]4[CH:52]=[CH:51][N:50]=[N:49]4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24]
Reactant: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(O)c(OC)cc23)cc1Cl
Reactant: Cc1ccc(S(=O)(=O)OCCn2ccnn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(OCCn4ccnn4)c(OC)cc23)cc1Cl
Temperature: 120 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
A starting compound (N-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinolyl)oxy]phenyl}-N′-propylurea, 80 mg), potassium carbonate (138 mg), and 2-(1H-1,2,3-triazol-1-yl)ethyl 4-methyl-1-benzenesulfonate (59 mg) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at 120° C. for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC by development with chloroform-methanol to give 92 mg (yield 92%) of the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:3]=[CH:2]1.C(N(CC)CC)C.[C:18](Cl)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[C:18]([N:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:3]=[CH:2]1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCOC(=O)c1c[nH]cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of ethyl imidazole-4-carboxylate (1.4 g), triethylamine (1.2 g) and chloroform (20 ml) was stirred at room temperature while trityl chloride (3.06 g) was added, and the mixture was stirred at room temperature for 1 h. The resulting solution was washed with water, dried and evaporated to dryness under reduced pressure, and the residue was crystallised from a mixture of ethyl acetate and cyclohexane, to give ethyl 1-tritylimidazole-4-carboxylate, mp 163°-164°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[C:21]#[CH:22]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:22][C:21]#[CH:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C#CCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a vigorously stirred suspension of piperazine-1-carboxylic acid tert-butyl ester (4.2 g, 22.5 mmol) and K2CO3 (1.2 eq, 27 mmol, 3.7 g) was added propargyl bromide (80 wt % in toluene, 1.2 eq, 27 mmol) dropwise via syringe over 20 minutes. The mixture was stirred at room temperature overnight (about 20 hours), concentrated in vacuo and partitioned between water and EtOAc. The organic-phase was washed twice with water, dried over MgSO4, filtered and evaporated to afford a clear yellow oil that partially solidified upon prolonged standing and was used directly without further purification. 1H NMR (400 MHz, CDCl3) d 1.47 (s, 9H), 2.28 (t, 1H), 2.54 (m, 4H), 3.34 (d, 2H, J=2.4 Hz), 3.49 (m, 4H). MS: m/z 225 (M+1).
Reaction SMILES: [CH3:1][NH:2][CH3:3].C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C@H:17]1[CH2:34][C@@:32]2([CH3:33])[C@@H:28]([CH2:29][CH2:30][C@@H:31]2[OH:35])[C@@:27]2([CH:36]=[CH2:37])[C@H:18]1[C:19]1[CH:20]=[CH:21][C:22]([OH:38])=[CH:23][C:24]=1[CH2:25][CH2:26]2>>[CH3:1][N:2]([CH3:3])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C@H:17]1[CH2:34][C@@:32]2([CH3:33])[C@@H:28]([CH2:29][CH2:30][C@@H:31]2[OH:35])[C@@:27]2([CH:36]=[CH2:37])[C@H:18]1[C:19]1[CH:20]=[CH:21][C:22]([OH:38])=[CH:23][C:24]=1[CH2:25][CH2:26]2
Reactant: C=C[C@@]12CCc3cc(O)ccc3[C@H]1[C@@H](CCCCCCCl)C[C@@]1(C)[C@H]2CC[C@@H]1O
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C=C[C@@]12CCc3cc(O)ccc3[C@H]1[C@@H](CCCCCCN(C)C)C[C@@]1(C)[C@H]2CC[C@@H]1O

Procedure:
In the reaction with dimethylamine (2 M in tetrahydrofuran, 10 equivalents) with the addition of sodium carbonate analogously to instructions 17.2, 33 mg of mixture 30b yields 30 mg of amine 32b as a colorless foam (GC-MS: m/z theor.: 425, pract.: 425).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[CH2:11]([NH2:16])[C:12]([CH3:15])([CH3:14])[CH3:13]>>[CH3:13][C:12]([CH3:15])([CH3:14])[CH2:11][NH:16][C:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=1)=[O:10]
Reactant: CC(C)(C)CN
Reactant: O=C(O)c1cccc(Br)n1
Product: CC(C)(C)CNC(=O)c1cccc(Br)n1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using 6-bromo-pyridine-2-carboxylic acid and neopentylamine.