Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:17][NH2:18].C(=O)(O)[O-].[Na+]>C1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[CH3:17][N:18]=[C:6]1[C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[CH2:10][CH2:9][C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]1=2
Reactant: CN
Reactant: O=C1c2ccccc2CCc2ccccc21
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CN=C1c2ccccc2CCc2ccccc21
Temperature: 25 °C
Reaction time: 288 h
Yield: 90 %

Procedure:
A solution of 52.5 g of titanium tetrachloride in 300 ml of anhydrous benzene is added slowly, under nitrogen, to a stirred, cooled (ice-bath) mixture of 100 g of 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one, 103 g of methylamine and 1200 ml of anhydrous benzene. After stirring at room temperature for 12 days the mixture is cooled, treated with concentrated aqueous sodium bicarbonate solution and filtered through Celite. The layers of the filtrate are separated, and the benzene layer is dried with magnesium sulfate. Removal of the solvent and crystallization of the residue from 200 ml of hexane gives 95.6 g (88% yield) of N-methyl-10,11-dihydro5H-dibenzo[a,d]cyclohepten-5-imine, mp 89°-90°. An analytical sample (hexane) also had mp 89°-90°. Nmr spectrum (in CDCl3): multiplets at τ 2.3-3.2 (8H) and 6.8-7.2 (4H) and singlet at 6.7 (3H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([C:8]1[CH:25]=[CH:24][C:11]2[N:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][CH:19]=[CH:18]4)[CH:13]=[N:14][C:10]=2[CH:9]=1)#[N:7].[OH-].[Na+].CN(C)[CH:30]=[O:31]>>[C:6]([C:8]1[CH:25]=[CH:24][C:11]2[N:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][CH:19]=[C:18]4[CH:30]=[O:31])[CH:13]=[N:14][C:10]=2[CH:9]=1)#[N:7]
Reactant: CN(C)C=O
Reactant: N#Cc1ccc2c(c1)ncn2-c1ccc2[nH]ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ccc2c(c1)ncn2-c1ccc2[nH]cc(C=O)c2c1
Temperature: 40 °C
Yield: 90 %

Procedure:
Phosphorus oxychloride (0.54 mL, 5.81 mmol, 1.5 eq) was added to dimethylformamide (10 mL) at room temperature, and to this solution was added 5-cyano-1-(indol-5-yl)benzimidazole (1.00 g, 3.87 mmol). The resulting reaction solution was heated at 40° C. under nitrogen for 2 hours. An aqueous solution of 10% sodium hydroxide (10 mL) was then added, followed by enough solid sodium hydroxide to adjust the pH to above 13. This mixture was heated at reflux under nitrogen for 1 hour, cooled, and the precipitated solid was filtered to afford the title compound (1.00 g, 90%) as an off-white solid. Mp, greater than 200° C.; IR (KBr) 2225, 1675 cm-1 ; 1H NMR (DMSO-d6) δ10.00 (s, 1H), 8.82 (s, 1H), 8.49 (s, 1H), 8.38 (d, J=0.7 Hz, 1H), 8.26 (d, J=2.0 Hz, 1H), 7.78 (d, J=8.6 Hz, 1H), 7.73 (dd, J=8.5 and 1.4 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.54 (dd, J=8.6 and 2.2 Hz, 1H); LRMS (m/z, relative intensity) 287 (18), 286 (M+, 100), 258 (18), 230 (11). HRMS calculated for C17H10N4O: 286.0853. Found: 286.0870.
Reaction SMILES: OS(O)(=O)=O.[F:6][C:7]1[CH:8]=[C:9]([C@@H:14]([OH:22])[C@@H:15]([NH:17][C@H:18]([CH3:21])[CH2:19]O)[CH3:16])[CH:10]=[CH:11][C:12]=1[F:13].[ClH:23]>ClCCl.C(OCC)C>[ClH:23].[F:6][C:7]1[CH:8]=[C:9]([C@@H:14]2[O:22][CH2:19][C@@H:18]([CH3:21])[NH:17][C@H:15]2[CH3:16])[CH:10]=[CH:11][C:12]=1[F:13]
Reactant: C[C@H](CO)N[C@@H](C)[C@H](O)c1ccc(F)c(F)c1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@@H]1CO[C@@H](c2ccc(F)c(F)c2)[C@H](C)N1
Yield: 49.8 %

Procedure:
To concentrated H2SO4 (100 ml) was added a solution of (1R, 2S)-1-(3,4-difluorophenyl)-2-[[(1R)-2-hydroxy-1-methylethyl]amino]propanol (17.1 g, 0.07 mole) in dichloromethane (100 ml). The reaction was worked up as in Example 1 to yield the crude reaction product as the free base. The crude product was dissolved in diethyl ether and treated with ethereal hydrogen chloride. The hydrochloride salt was recrystallized from ethanol-diethyl ether mixtures to give 9.2 g (49.8% of theory) of (2S, 3S, 5R)-2-(3,4-difluorophenyl)-3,5-dimethylmorpholine hydrochloride as a white solid. m.p. 318° C. [α]20D =+24.6° (c=0.710, 95% ethanol).
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[CH3:10][C:11]1([CH3:37])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21](O)=[O:22])[CH:19]=2)[NH:14][CH:13]([C:24]2[CH:29]=[C:28]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:27]=[CH:26][C:25]=2[CH3:36])[CH2:12]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH3:10][C:11]1([CH3:37])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]([NH:9][S:6]([CH:3]3[CH2:5][CH2:4]3)(=[O:8])=[O:7])=[O:22])[CH:19]=2)[NH:14][CH:13]([C:24]2[CH:29]=[C:28]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:27]=[CH:26][C:25]=2[CH3:36])[CH2:12]1
Reactant: NS(=O)(=O)C1CC1
Reactant: Cc1ccc(N2CCOCC2)cc1C1CC(C)(C)c2cc(C(=O)O)ccc2N1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(N2CCOCC2)cc1C1CC(C)(C)c2cc(C(=O)NS(=O)(=O)C3CC3)ccc2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.3 %

Procedure:
To a suspension of 60% sodium hydride (560 mg, 14 mmol) in N,N-dimethylformamide (5 mL) was added cyclopropanesulfonic acid amide (1.33 g, 14 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A24. A solution of 4,4-dimethyl-2-(2-methyl-5-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (800 mg, 2 mmol) and 1,1′-carbonyldiimidazole (690 mg, 4 mmol) in N,N-dimethylformamide (3 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B24. Solution B24 was added to Solution A24 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [4,4-dimethyl-2-(2-methyl-5-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (90 mg, 9%) as a white solid: MS (ESI) M+1=484.1.
Reaction SMILES: [NH2:1][PH:2](=[O:4])[OH:3].BrCC(O[CH2:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=O>CC(=O)CC>[NH2:1][PH:2](=[O:3])[O:4][CH2:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)CCOC(=O)CBr
Reactant: N[PH](=O)O
Solvent: CCC(C)=O
Product: CC(C)(C)CCO[PH](N)=O

Procedure:
A mixture of 4-(2-chloro-4-trifluoromethylphenoxy)-1,2-dinitrobenzene (2.15 g), α-amino-(n-propyl)methylphosphinic acid (1.63 g), K2CO3 (1.64 g) and DMSO (10 ml) is stirred at RT for one week and then poured into water and extracted with ether. The aqueous solution is acidified with dilute HCl and extracted with ether. The combined extracts are dried and evaporated to dryness to give the aminophosphinic acid (XVI; R is NO2, R1 is Me, R2 is H, R6 is Et, R5 is H, Y is Cl, Z is CF3). The aminophosphinic acid is reacted with neohexyl bromoacetate in 2-butanone under reflux to give neohexyl aminophosphinate (Compound 1, Table H).
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:25]([O:32][C:33]([C@H:35]1[CH2:39][CH2:38][CH2:37][NH:36]1)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:25]([O:32][C:33]([C@H:35]1[CH2:39][CH2:38][CH2:37][N:36]1[CH2:16][C:13]1[S:12][C:11]([NH:10][C:8]([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)=[O:9])=[N:15][CH:14]=1)=[O:34])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: O=C(OCc1ccccc1)[C@H]1CCCN1Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Yield: 78.6 %

Procedure:
Prepared as described in general procedure (P) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (75 mg. 0.223 mmol), pyrrolidine-2(R)-carboxylic acid benzyl ester hydrochloride (73 mg, 0.31 mmol) and sodium triacetoxyborohydride (71 mg, 0.335 mmol) to afford 92 mg (78%) of the desired product after purification.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26]1([CH3:35])[C:27]([N:32]=[C:33]=[O:34])=[CH:28][CH:29]=[CH:30][CH:31]=1>ClCCl>[CH3:35][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:33](=[O:34])[O:18][C:15]1[CH:16]=[C:17]2[C:12]([CH2:11][CH2:10][CH2:9][N:8]2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:13][CH:14]=1
Reactant: Cc1ccccc1N=C=O
Reactant: Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1NC(=O)Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Temperature: 35 °C

Procedure:
A mixture of 1-benzyl-1,2,3,4-tetrahydroquinolin-7-ol (550 mg, 2.30 mM) and triethylamine (0.4 mL) in dry dichloromethane (DCM, 10 mL) was stirred for half an hour under nitrogen atmosphere at room temperature (35° C.). To the stirred reaction mixture, o-tolyl isocyanate (428 mg/ml, 3.45 mM) was added at once and then the reaction mixture was further stirred for 72 hours under N2 atmosphere at RT. The reaction mixture was concentrated under vacuum and then was added distilled water (15 mL) followed by the extraction with ether (3×15 mL). The ether layer was dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was finally chromatographed using chloroform-hexane (1:9) to give 8a as colorless oil. Yield: 700 mg, 81.78%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.CC(C)([O-])C.[K+].[Br:23][C:24]1[N:28]2[N:29]=[C:30]([Cl:34])[CH:31]=[C:32](Br)[C:27]2=[N:26][CH:25]=1>CN(C=O)C.C(OCC)(=O)C>[Br:23][C:24]1[N:28]2[N:29]=[C:30]([Cl:34])[CH:31]=[C:32]([N:8]([CH2:7][C:6]3[CH:15]=[CH:16][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:27]2=[N:26][CH:25]=1
Reactant: Clc1cc(Br)c2ncc(Br)n2n1
Reactant: COc1ccc(CNc2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3c(Br)cnc23)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.8 %

Procedure:
N-(4-Methoxybenzyl)aniline (215 mg, 1 mmol) was dissolved in dry DMF (4 mL), placed under a nitrogen atmosphere, and cooled to 0° C. in an ice bath. Potassium t-butoxide (1 mL, 1 mmol, 1M THF solution) was added and the mixture was allowed to stir for 10 min at 0° C. and room temperature for 30 min. The resulting mixture was cool to 0° C. Solid 3,8-dibromo-6-chloroimidazo[1,2-b]pyridazine (310 mg, 1 mmol) from Example XXIV, step 1a was added. The mixture was allowed to stir for 30 min at 0° C. and overnight at room temperature. The mixture was diluted with ethyl acetate (100 mL), washed sequentially with 10% LiCl, water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo and the resulting material was purified by silica gel chromatography (ethyl acetate/heptane, 25 min gradient: 5-50% ethyl acetate) to provide 0.27 g of 3-bromo-6-chloro-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyridazin-8-amine.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH2:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=2[N+:25]([O-])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO>[NH2:25][C:18]1[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:17]=1[CH2:16][CH2:15][NH:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1
Reactant: COc1ccc([N+](=O)[O-])c(CCNC2CCN(Cc3ccccc3)CC2)c1
Reactant: [H][H]
Solvent: CO
Product: COc1ccc(N)c(CCNC2CCN(Cc3ccccc3)CC2)c1

Procedure:
26.0 g (70.3 mmol) (1-benzylpiperidin-4-yl)-[2-(5-methoxy-2-nitrophenyl)-ethyl]-amine were hydrogenated with 5.0 g (2.45 mmol) rhodium charcoal (5%, moistened with water) in 350 mL methanol in a 3 bar hydrogen atmosphere for 3 h at RT. The catalyst was removed by suction filtering and the solution concentrated by rotary evaporation. The residue was immediately reacted further without any further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[NH2:15])([CH3:4])([CH3:3])[CH3:2].C([O:21][C:22](=O)[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[CH:33]=2)[CH:27]=1)=[O:25])(C)(C)C>>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[NH:15][C:22](=[O:21])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[CH:33]=2)[CH:27]=1)=[O:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1N
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(F)ccc3NC(=O)OC(C)(C)C)c2)ccn1
Yield: 84.1 %

Procedure:
The compound was prepared from (2-amino-4-fluoro-phenyl)-carbamic acid tert-butyl ester (Example J2) (226 mg, 1.0 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (311 mg, 1.0 mmol) according to the general procedure M. Obtained as an off-white foam (390 mg, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24]([F:27])([F:26])[F:25])[N:5]2[CH2:22][CH2:21][N:20]([CH3:23])[C:7]3([CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]3)[C:6]=12.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:24]([F:26])([F:25])[F:27])[N:5]2[CH2:22][CH2:21][N:20]([CH3:23])[C:7]3([CH2:8][CH2:9][NH:10][CH2:11][CH2:12]3)[C:6]=12
Reactant: CN1CCn2c(C(F)(F)F)cc(Cl)c2C12CCN(C(=O)OC(C)(C)C)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCn2c(C(F)(F)F)cc(Cl)c2C12CCNCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a solution of tert-butyl 8-chloro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (750 mg, 1.84 mmol) in CH2Cl2 (2 mL) was added a prepared solution of 1:1 trifluoroacetic acid (2.0 mL, 26 mmol) in CH2Cl2 (2 mL). After stirring at room temperature for 2 hours, saturated aqueous sodium bicarbonate solution (75 mL) was slowly added. The mixture was extracted with EtOAc (2×75 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide 8-chloro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine] (555 mg, 98%) as a yellow-brown solid. ESI-MS m/z calc. 307.1, found 307.9 (M+1)+; Retention time: 1.12 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 9.72 (s, 1H), 9.38 (s, 1H), 6.49 (s, 1H), 3.98 (t, J=5.6 Hz, 2H), 3.36 (d, J=11.6 Hz, 2H), 3.26 (d, J=6.1 Hz, 4H), 2.78 (s, 2H), 2.40 (s, 3H), 2.11 (d, J=14.4 Hz, 2H), 1.69 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH:19]=[C:18]2[CH2:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][CH2:13][CH2:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH:19]=[C:18]3[CH2:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: COC(=O)CCn1cc(Cc2cccnc2)c2cc(CCN)ccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCn1cc(Cc2cccnc2)c2cc(CCNS(=O)(=O)c3ccc(F)cc3)ccc21
Reaction time: 0.5 h
Yield: 80.3 %

Procedure:
4-Fluorobenzenesulphonyl chloride (0.346 g) was added portionwise to a stirred solution of methyl 5-(2-aminoethyl)-3-(3-pyridylmethyl)-1H-indole1-propanoate (0.50 g) and triethylamine (0.33 g) in dichloromethane (5 ml) at room temperature. The mixture was stirred for 30 minutes and then washed with water and dried (MgSO4). The solvent was evaporated and the residue was chromatographed on silica gel using dichloromethane/methanol (50:1) as eluant. The product fractions were combined and evaporated to give the title compound as a gum (0.59 g).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([NH2:12])=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[Cl:13][C:14]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:15]=1[C:16]([N:18]=[C:19]=[O:20])=[O:17]>C(#N)C>[Cl:13][C:14]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:15]=1[C:16]([NH:18][C:19]([NH:12][C:4]1[O:3][C:2]([CH3:1])=[N:6][C:5]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:20])=[O:17]
Reactant: CCOC(=O)c1nc(C)oc1N
Reactant: O=C=NC(=O)c1c(F)cccc1Cl
Solvent: CC#N
Product: CCOC(=O)c1nc(C)oc1NC(=O)NC(=O)c1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 0.6 g. 2-methyl-4-carbethoxy-5-aminooxazole dissolved in 25 ml. acetonitrile was added 0.8 2-chloro-6-fluorobenzoylisocyanate under nitrogen at about 25° C. The reaction mixture was stirred at 25° C. for 12 hours and the solid was collected. Yield 0.7 g.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([O:11][C:12](=[O:27])[NH:13][C:14]1[C:15]([CH3:26])=[N:16][O:17][C:18]=1[C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=1)[CH3:10].[CH2:28]([O:30][C:31](=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1)[CH3:29]>>[CH2:28]([O:30][C:31](=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:22]2[CH:23]=[CH:24][C:19]([C:18]3[O:17][N:16]=[C:15]([CH3:26])[C:14]=3[NH:13][C:12]([O:11][CH:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])[CH3:10])=[O:27])=[CH:20][CH:21]=2)=[CH:35][CH:34]=1)[CH3:29]
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)c1cccc(F)c1F
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)OC(C)c3cccc(F)c3F)cc2)cc1

Procedure:
Following the procedure described in Example 36, Step 6, [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid 1-(2,3-difluoro-phenyl)-ethyl ester and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester were reacted to provide (4′-{4-[1-(2,3-difluoro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-acetic acid ethyl ester, which was hydrolyzed to the acid as described in Example 34, Step 2.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][N:7]=1.Br[CH2:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(O)C>[CH2:14]([O:13][C:11]([C:10]1[N:1]=[C:2]2[N:7]=[CH:6][CH:5]=[N:4][N:3]2[CH:9]=1)=[O:12])[CH3:15]
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1nccnn1
Solvent: CCO
Product: CCOC(=O)c1cn2nccnc2n1
Temperature: 25 °C
Yield: 1.8 %

Procedure:
A solution of 3-amino-1,2,4-triazine (5.0 g, 52 mmol) and ethyl bromopyruvate (11 mL, 88 mmol) in ethanol (50 mL) was heated to reflux for 20 minutes. The reaction was cooled to room temperature, and then partitioned between 200 mL of EtOAc and 200 mL of water. The layers were separated, and the organic layer was dried over MgSO4. The solids were removed by filtration, and then the solvent was removed by rotary evaporation. The residue was purified by chromatography (90 g SiO2, 50 to 70% EtOAc in hexanes) to give the desired product (181 mg, 1.8%). MS (ESI): 192.4 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:34])[NH:11][C:12]1[CH:13]=[C:14]([N:18]2[C:23](=[O:24])[C:22]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[N:21][C:20]3[CH:30]=[CH:31][CH:32]=[N:33][C:19]2=3)[CH:15]=[CH:16][CH:17]=1.O[N:36]1[C:40](=[O:41])[CH2:39][CH2:38][C:37]1=[O:42].C(N=C=NCCCN(C)C)C>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:34])[NH:11][C:12]1[CH:13]=[C:14]([N:18]2[C:23](=[O:24])[C:22]([CH2:25][CH2:26][C:27]([O:29][N:36]3[C:40](=[O:41])[CH2:39][CH2:38][C:37]3=[O:42])=[O:28])=[N:21][C:20]3[CH:30]=[CH:31][CH:32]=[N:33][C:19]2=3)[CH:15]=[CH:16][CH:17]=1
Reactant: O=C1CCC(=O)N1O
Reactant: COc1ccccc1NC(=O)Nc1cccc(-n2c(=O)c(CCC(=O)O)nc3cccnc32)c1
Agent: CCN=C=NCCCN(C)C
Product: COc1ccccc1NC(=O)Nc1cccc(-n2c(=O)c(CCC(=O)ON3C(=O)CCC3=O)nc3cccnc32)c1
Reaction time: 24 h
Yield: 84.4 %

Procedure:
To a stirred solution of 4-[3-[3-(2-methoxyphenyl)ureido]phenyl]-3-oxo-2-(2-carboxyethyl)-3,4-dihydropyrido[2,3-b]pyrazine (2.30 g) and N-hydroxysuccinimide (1.15 g) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.20 g) and the resulting mixture was stirred for 24 hours. The reaction mixture was concentrated, diluted with ethyl acetate, washed with a saturated sodium bicarbonate solution, water and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was triturated with ether to give 4-[3-[3-(2-methoxyphenyl)ureido]phenyl]-3-oxo-2-[2-succinimidooxycarbonylethyl)-3,4-dihydropyrido[2,3-b]pyrazine (2.35 g) as a solid.
Reaction SMILES: Br[C:2]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].[Cl:21][C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][CH2:27][NH:28]2)=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:21][C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][CH2:27][N:28]2[C:2]2([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)[C:10]3[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=3)[NH:4][C:3]2=[O:12])=[CH:24][CH:23]=1
Reactant: Clc1ccc2c(c1)NCC2
Reactant: O=C1Nc2cc(Cl)ccc2C1(Br)Cc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)N1CCc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
The mixture of rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (100 mg, 0.27 mmol) (from example 1c supra), 6-Chloro-2,3-dihydro-1H-indole (62 mg, 0.45 mmol) and K2CO3 (110 mg, 0.80 mmol) in DMF (1 mL) was stirred at room temperature overnight. Then water (10 mL) was added and the desired product was precipitated out. The crude product was purified by prep-HPLC to give 55 mg rac-6,6′-Dichloro-3′-(3-chloro-benzyl)-2,3,1′,3′-tetrahydro-[1,3′]biindolyl-2′-one. MS: [M+H]+=443
Reaction SMILES: C[C:2]1C=C(C)C=C[C:3]=1[N:9]=[C:10]=S.[CH3:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[N:20]=[C:21]=[S:22]>>[CH3:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[N:20]=[C:21]1[N:9]([CH3:10])[CH:3]=[CH:2][S:22]1
Reactant: Cc1cccc(N=C=S)c1C
Reactant: Cc1ccc(N=C=S)c(C)c1
Product: Cc1cccc(N=c2sccn2C)c1C

Procedure:
If 2,4-dimethyl-phenyl isothiocyanate in the above example is replaced by the same amount of 2,3-dimethyl-phenyl isothiocyanate and the procedure followed is an indicated, a solution of 2-(2,3-dimethyl-phenylimino)-3-methyl-thiazoline is obtained in a similar concentration and yield.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([O:22][CH3:23])[C:18]=1[CH:19]([CH3:21])[CH3:20])[C:12](OC)=[O:13]>CCOCC>[CH3:23][O:22][C:17]1[CH:16]=[C:11]([CH:10]=[C:9]([O:8][CH3:7])[C:18]=1[CH:19]([CH3:21])[CH3:20])[CH2:12][OH:13]
Reactant: COC(=O)c1cc(OC)c(C(C)C)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COc1cc(CO)cc(OC)c1C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
To a suspension of LiAlH4 (95%) (5.00 g, 125 mmol) in dry ether (100 mL) at 0° C. was added a solution of methyl 3,5-dimethoxy-4-i-propylbenzoate (15.7 g, 90.1 mmol), in ether (300 mL) under N2. The suspension was stirred at 0° C. for one hour then for an additional hour at room temperature. The reaction was quenched by slow addition of a saturated Na2SO4 aqueous solution (10 mL) at 0° C. The mixture was stirred overnight. The solid was filtered off and the filtrate was evaporated to dryness to give the desired alcohol (13.8 g, 88% yield) as white crystals. 1HNMR (CDCl3. ppm): δ 1.34 (d, J=7.2 Hz, 6H), 3.65 (hept., J=7.2 Hz, 1H), 3.88 (s, 6H), 4.70 (s, 2H), 6.62 (s, 2H).