Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:10][CH:9]=[N:8][CH:7]=1.C([Li])CCC.C([Sn](Cl)(CCCC)CCCC)CCC.C1(C)C(C([O:38][C@@H:39]2[C@@H:43]([CH2:44][O:45]C(C3C(C)=CC=CC=3)=O)[O:42][C@@H:41]([N:55]3[C:59]4=[N:60][CH:61]=[CH:62][C:63](I)=[C:58]4[CH:57]=[CH:56]3)[CH2:40]2)=O)=CC=CC=1>C(OCC)C.CN(C=O)C>[C@@H:41]1([N:55]2[C:59]3=[N:60][CH:61]=[CH:62][C:63]([C:9]4[S:10][C:6]([C:2]5[S:1][CH:5]=[CH:4][CH:3]=5)=[CH:7][N:8]=4)=[C:58]3[CH:57]=[CH:56]2)[O:42][C@H:43]([CH2:44][OH:45])[C@@H:39]([OH:38])[CH2:40]1
Reactant: Cc1ccccc1C(=O)OC[C@H]1O[C@@H](n2ccc3c(I)ccnc32)C[C@@H]1OC(=O)c1ccccc1C
Reactant: c1csc(-c2cncs2)c1
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: OC[C@H]1O[C@@H](n2ccc3c(-c4ncc(-c5cccs5)s4)ccnc32)C[C@@H]1O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-(2-thienyl)thiazole (0.4 mmol) in diethyl ether was cooled to −78° C., and n-butyllithium (0.4 mmol, 1.57 M solution in hexane) was added thereto, followed by stirring at −78° C. for 30 min. Furthermore, tributylstannyl chloride was added thereto, followed by stirring at room temperature for 30 min. The reaction solution was separated between ethyl acetate and water. The organic layer was washed with saturated brine and concentrated, and 1-[2-deoxy-3,5-di-O-(toluoyl)-β-D-ribofuranosyl]-4-iodo-pyrrolo[2,3-b]pyridine (120 mg, 0.2 mmol), chlorobistriphenylphosphine palladium (5% mol), and DMF (2 mL) were added thereto, followed by stirring at 100° C. for 1 hr. The reaction solution was separated between ethyl acetate and water, and the organic layer was washed with saturated brine and water, dried over anhydrous sodium sulfate, and concentrated. After purification with a silica gel column and addition of sodium methoxide (1.6 mL), the resulting mixture was stirred at room temperature for 30 min. dDvas nucleoside (34 mg) was purified with a silica gel column and by HPLC.
Reaction SMILES: [CH3:1][N:2]([CH3:30])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:8]=[C:9]([C:16]([CH3:29])([CH3:28])[C:17]([N:19]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18])[CH:10]=[CH:11][C:12]=1[N+:13]([O-])=O>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:13][C:12]1[CH:11]=[CH:10][C:9]([C:16]([CH3:29])([CH3:28])[C:17]([N:19]([CH2:20][CH:21]([CH3:22])[CH3:23])[CH2:24][CH:25]([CH3:26])[CH3:27])=[O:18])=[CH:8][C:7]=1[NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:30])[CH3:1]
Reactant: CC(C)CN(CC(C)C)C(=O)C(C)(C)c1ccc([N+](=O)[O-])c(NCCCN(C)C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)CN(CC(C)C)C(=O)C(C)(C)c1ccc(N)c(NCCCN(C)C)c1
Temperature: 20 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
2-(3-{[3-(dimethylamino)propyl]amino}-4-nitrophenyl)-N,N-diisobutyl-2-methylpropanamide (44 mg) in solution in a mixture of ethyl acetate/ethanol 2:1 (3 ml), and 10% palladium on carbon (5 mg) are introduced into an autoclave. After stirring for 4 hours under a hydrogen atmosphere (3 bar) at a temperature of approximately 20° C., the catalyst is eliminated by filtration on celite and the filtrate is concentrated under reduced pressure at 40° C. in order to produce the expected compound in the form of an oil (39 mg; 95% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH:11]1[CH2:17][CH:16]2[N:18]([CH3:19])[CH:13]([CH2:14][CH2:15]2)[CH2:12]1)=O.[ClH:20].[NH2:21][OH:22].C([O-])(=O)C.[NH4+]>C(O)C.O>[ClH:20].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[C:9](/[CH:11]1[CH2:17][CH:16]2[N:18]([CH3:19])[CH:13]([CH2:14][CH2:15]2)[CH2:12]1)=[N:21]\[OH:22]
Reactant: NO
Reactant: CN1C2CCC1CC(C(=O)c1ccc(F)cc1F)C2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CN1C2CCC1CC(/C(=N/O)c1ccc(F)cc1F)C2

Procedure:
A mixture of (2,4-difluorophenyl)(8-methyl-8-azabicyclo[3.2.1 ]octan-3-yl)methanone (20 g), hydroxylamine hydrochloride (10.6 g) and ammonium acetate (18.7 g) was heated in 67.5 ml of refluxing ethanol-water (3.2 mixture) for 19 hours. The mixture was concentrated to approximately half of its original volume, and the precipitated solid (21.3 g) was collected.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[N:3]=[CH:2]1.[H-].[Na+].I[CH2:15][CH3:16].Cl>C1COCC1.O>[CH2:15]([N:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[N:3]=[CH:2]1)[CH3:16]
Reactant: CCI
Reactant: c1cncc(-c2c[nH]cn2)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCn1cnc(-c2cccnc2)c1
Reaction time: 0.33 h
Yield: 78.5 %

Procedure:
To a solution of 34 (36 mg, 0.25 mmol) in THF (5 mL) under argon was added sodium hydride (12 mg, 0.29 mmol) in one portion and the resultant slurry was stirred for 20 min. Iodoethane (26 μL, 0.32 mmol) was added and the resultant solution was stirred for 10 min. The reaction was stopped by the careful addition of aqueous hydrochloric acid (1 N, 2 mL), diluted with 13 mL of water and washed with ethyl acetate (3×15 ml). Dichloromethane was added (25 mL) and the aqueous was adjusted to pH 9 with NaOH(aq) (10 N). The organic fraction was collected and the aqueous fraction was extracted with dichloromethane (20 mL), the combined organic fractions were dried (Na2SO4), filtered and the solvent was removed in vacuo. The crude material was chromatographed on silica gel (CH3OH/CHCl3, 2.5/97.5, Rf=0.27) to afford the title compound 59 (34 mg, 79% yield) as a clear oil: 1H NMR (CDCl3) δ 8.93 (m, 1H), 8.44 (m, 1H), 8.07 (m, 1H), 7.54 (br s, 1H), 7.28 (m, 2H), 4.02 (q, J=7.4 Hz, 2H), 1.49 (t, J=7.4 Hz, 3H); LRMS (ESI) m/z calcd for C10H11N3 [M+H]+ 174. found 174; HRMS (ESI) m/z calcd for C10H11N3 [M+H]+ 174.1031. found 174.1042; HPLC>97% (tR=13.28 min, 60 (A):40 (B): 0.02 (C); tR=3.67 min, 80 (A):20 (B): 0.1 (C).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].C[O:7][C:8](=O)[C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=1.Cl>O.O1CCCC1>[CH3:16][N:15]([CH3:17])[C:12]1[CH:13]=[CH:14][C:9]([C:8]([NH:2][OH:3])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(N(C)C)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)c1ccc(C(=O)NO)cc1
Reaction time: 8 h
Yield: 44.2 %

Procedure:
7.4 g of hydroxylamine hydrochloride was dissolved in 200 ml of water to which was added dropwise 106 ml of 1 N aqueous solution of sodium hydroxide while cooling. The resulting mixture was added with stirring to 300 ml of a tetrahydrofuran solution containing 9.0 g of 4-dimethylaminobenzoic acid methyl ester dissolved at room temperature. After stirring for 8 hours, 5 ml of 1 N aqueous solution of sodium hydroxide was added thereto and the mixture was further stirred for 3 days. After adjusting the pH of the resulting mixture between 4 and 5 by adding a diluted aqueous hydrochloric acid solution, the mixture was extracted with ethyl acetate and the extract was dried with sodium sulfate and concentrated. The resulting crystals were recrystallized from acetonitrile to obtain 4 g of the desired compound having a melting point of 162° to 163° C. The structure of the compound was confirmed using mass spectrum and NMR spectrum, etc.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH2:9])=[CH:4][N:3]=1.CC(C)([O-])C.[Na+].Br[C:17]1[C:25]2[NH:24][C:23]3[CH:26]4[CH2:32][CH2:31][N:29]([CH2:30][C:22]=3[C:21]=2[CH:20]=[CH:19][CH:18]=1)[CH2:28][CH2:27]4>C(P([Pd]P(C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C)(C)C.O1CCOCC1>[CH3:1][C:2]1[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:17]2[C:25]3[NH:24][C:23]4[CH:26]5[CH2:32][CH2:31][N:29]([CH2:30][C:22]=4[C:21]=3[CH:20]=[CH:19][CH:18]=2)[CH2:28][CH2:27]5)=[CH:6][CH:7]=1
Reactant: C=Cc1ccc(C)nc1
Reactant: Brc1cccc2c3c([nH]c12)C1CCN(CC1)C3
Agent: CC(C)(C)[PH]([Pd][PH](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc(/C=C/c2cccc3c4c([nH]c23)C2CCN(CC2)C4)cn1
Temperature: 105 °C

Procedure:
A mixture of bis(tri-t-butylphosphino)palladium (26.3 mg, 0.052 mmol; Aldrich), the product of Example 1C (123 mg, 0.52 mmol), sodium t-butoxide (124 mg, 1.29 mmol; Aldrich) and the product of Example 1B (150 mg, 0.52 mmol) was combined with 1,4-dioxane (3 mL). The mixture was purged with a stream of nitrogen for 2 minutes, then heated at 105° C. for 6 hours in a sealed tube. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was dissolved in dimethyl sulfoxide (5 mL), filtered through a glass microfiber frit and purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 40-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound: 1H NMR (400 MHz, methanol-d4) δ ppm 2.05-2.15 (m, 4 H), 2.54 (s, 3 H), 3.02-3.12 (m, 2 H), 3.14 (pent, J=3.6 Hz, 1 H), 3.20-3.29 (m, 2 H), 4.23 (s, 2 H), 7.02 (t, J=7.6 Hz, 1 H), 7.23 (d, J=16.5 Hz, 1 H), 7.24-7.27 (m, 1 H), 7.31 (d, J=8.2 Hz, 1 H), 7.39 (d, J=7.3 Hz, 1 H), 7.68 (d, J=16.5 Hz, 1 H), 8.01 (dd, J=8.2, 2.4 Hz, 1 H), 8.61 (d, J=2.4 Hz, 1 H); MS (APCI) m/z=330 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([NH2:12])=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1.[CH2:13]([N:21]=[C:22]=S)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:1][N:2]1[C:3]2[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=2[N:12]=[C:22]1[NH:21][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CNc1ccc([N+](=O)[O-])cc1N
Reactant: S=C=NCCc1ccccc1
Product: Cn1c(NCCc2ccccc2)nc2cc([N+](=O)[O-])ccc21
Yield: 66.4 %

Procedure:
N1-methyl-4-nitro-benzene-1,2-diamine (2.0 g, 12.0 mmol) and phenethyl isothiocyanate (2.15 g, 13.2 mmol) were coupled using the procedure of intermediate example one part B to give the title compound as a yellow solid (2.36 g, 66%). 1H NMR (300 MHz, d6-DMSO) δ 8.01 (d, J=2.1 Hz, 1H), 7.90 (dd, J=8.7 and 2.4 Hz, 1H), 7.21-7.35 (m, 7H), 3.58-3.65 (m, 2H), 3.56 (s, 3H), 2.93-2.98 (m, 2H) ppm.
Reaction SMILES: [C:1]([C:3]1[NH:4][CH:5]=[CH:6][CH:7]=1)#[N:2].[C:8]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:13]=CC=C[CH:9]=1.C(O)C#C.N(C(OCC)=O)=NC([O-])=O>O1CCCC1>[CH2:13]([N:4]1[CH:5]=[CH:6][CH:7]=[C:3]1[C:1]#[N:2])[C:8]#[CH:9]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: N#Cc1ccc[nH]1
Agent: C#CCO
Agent: CCOC(=O)N=NC(=O)[O-]
Solvent: C1CCOC1
Product: C#CCn1cccc1C#N
Temperature: 5 °C
Yield: 46.7 %

Procedure:
51.57 g of 2-cyano-pyrrol[prepared by the process of Can. J. Chem. Vol. 59, p. 2763 (1981)], 146.9 g of triphenylphosphine, and 43.95 g of propargyl alcohol were mixed together and 420 ml of tetrahydrofuran were added. The mixture was cooled at ±5° C., and over half an hour at 0° to 5° C., 97.5 g of ethyl azodicarboxylate were introduced. The temperature was allowed to return to ambient, and stirring was maintained for 18 hours. The solvent was evaporated under reduced pressure, and the crystallized residue was taken up in ethyl ether and filtered. After concentrating the filtrate, an oil was obtained which was chromatographed over silica. Elution with a hexane-ethyl acetate (7-3) mixture yielded 34 g of 1-(2-propynyl)-1H-pyrrole-2-carbonitrile.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH3:28])[NH:14][C:13](=[O:15])[C:12]3([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[N:11]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[H-].[Na+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C([O-])(O)=O.[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH3:28])[N:14]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:13](=[O:15])[C:12]3([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[N:11]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1C[C@@](C)(c2cc(F)cc(F)c2)NC(=O)C12CCCCC2
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1C(=O)C2(CCCCC2)N(C(=O)OC(C)(C)C)C[C@@]1(C)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of tert-butyl (3R)-3-(3,5-difluorophenyl)-3-methyl-5-oxo-1,4-diazaspiro[5.5]undecane-1-carboxylate from Step H (60 mg, 0.152 mmol) in THF (0.5 mL) at 0° C. was added NaH (12 mg of a 60% dispersion in oil, 0.30 mmol). After 5 min, ethyl bromoacetate (437 mg, 2.62 mmol) was added and the mixture was allowed to warm to ambient temperature and stirring was continued for 1 h. Saturated aqueous NaHCO3 (2 mL) was added and the mixture was extracted with EtOAc (2×5 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-95:5 to 60:40, to give the title compound. MS: m/z=425 (M−C4H7).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[O:3]1.[CH:17]([O:20][CH2:21][CH2:22]O)([CH3:19])[CH3:18]>>[CH:17]([O:20][CH2:21][CH2:22][O:15][C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1)([CH3:19])[CH3:18]
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: CC(C)OCCO
Product: CC(C)OCCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Yield: 11.8 %

Procedure:
Using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (609 mg, 2.76 mmol) and ethylene glycol monoisopropyl ether (432 mg, 4.15 mmol), the desired title compound (100 mg, yield 31%) was obtained by the same method as in Example 2 (2a).
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][CH:34]=[CH:33][C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[S:15](=[O:17])(=[O:16])[N:14]([CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:13](=[O:24])[CH2:12]2)=[C:7]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=1.[C:37](Cl)(=[O:39])[CH3:38]>N1C=CC=CC=1.CCOC(C)=O>[CH2:26]([O:25][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[N:11]1[CH2:12][C:13](=[O:24])[N:14]([CH2:18][CH2:19][Si:20]([CH3:21])([CH3:22])[CH3:23])[S:15]1(=[O:16])=[O:17])[CH2:4][C:3]1[CH:33]=[CH:34][CH:35]=[CH:36][C:2]=1[NH:1][C:37](=[O:39])[CH3:38])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(Cc3ccccc3N)cc2OCc2ccccc2)S1(=O)=O
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccccc1Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-[4-(2-aminobenzyl)-2-benzyloxyphenyl]-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (Example 4, Step A) (250 mg, 0.478 mmol) in pyridine (1.5 mL) is added acetylchloride (41 mg, 0.525 mmol). The mixture is stirred at ambient temperature for 30 min., then diluted with EtOAc and washed with 0.5N HCl, saturated NaHCO3 and brine. It is then dried over Na2SO4/MgSO4, filtered and concentrated to afford N-(2-{3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-benzyl}-phenyl)-acetamide as a gum: MS (M+H)+=566.1.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH:31]([CH3:33])[CH3:32])[N:25]=3)=[C:18]3[CH2:19][NH:20][CH2:21][CH2:22][N:17]3[N:16]=2)=[CH:11][CH:10]=1.Cl[C:35]([O:37][CH3:38])=[O:36]>O1CCCC1>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH:31]([CH3:33])[CH3:32])[N:25]=3)=[C:18]3[CH2:19][N:20]([C:35]([O:37][CH3:38])=[O:36])[CH2:21][CH2:22][N:17]3[N:16]=2)=[CH:11][CH:10]=1
Reactant: CC(C)Nc1nccc(-c2c(-c3ccc(F)cc3)nn3c2CNCC3)n1
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)N1CCn2nc(-c3ccc(F)cc3)c(-c3ccnc(NC(C)C)n3)c2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Triethylamine (96 mg, 0.948 mmol) was added to a solution of 4-[2-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl]-N-(1-methylethyl)-2-pyrimidinamine (i.e. the product of Step E) (0.150 g, 0.426 mmol) and methyl chloroformate (41.1 μL, 0.178 mmol) in tetrahydrofuran (40 mL). The reaction mixture was stirred at 25° C. for 24 h. The resulting mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane (50 mL) and treated with silica gel (10.0 g). The silica gel suspension was concentrated under reduced pressure to leave a mixture of silica gel and crude product, which was purified by silica gel chromatography using a gradient of ethyl acetate/hexanes (0:1 to 1:4) as eluant to give 25 mg of the title product, a compound of the present invention, as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#N)=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.C(O)=[O:15].O>C(OCC)(=O)C.[Al].[Ni]>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:15])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1C(F)(F)F
Reactant: O=CO
Agent: [Ni]
Agent: [Al]
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ccc(Cl)cc1C(F)(F)F
Temperature: 100 °C
Yield: 87 %

Procedure:
Add 4-chloro-2-trifluoromethyl-benzonitrile to formic acid (96%) (15 mL) and water (3 mL). Add nickel-aluminum alloy (1260 mg). Heat at 100° C. overnight. Dilute with ethyl acetate and filter through Celite®. Extract the filtrate with 1 N sodium hydroxide and saturated aqueous sodium chloride, dry (sodium sulfate), filter, and concentrate to give 4-chloro-2-trifluoromethylbenzaldehyde (555 mg, 87%): 1H NMR (400 MHz, MeOH-d4) δ 10.29 (m, 1H), 8.10 (d, 1H, J=8.4 Hz), 7.91 (d, 1H, J=1.6 Hz), 7.85 (dd, 1H, J=8.4, 1.6 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=3[C:13]=2[CH3:22])(=[O:11])=[O:10])=[C:4]([C:23]([F:26])([F:25])[F:24])[CH:3]=1.[F:27][C:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[CH:30][N:29]=1>COCCOC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]3[S:16][C:15]4[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=4[C:13]=3[CH3:22])(=[O:11])=[O:10])=[C:4]([C:23]([F:26])([F:25])[F:24])[CH:3]=2)[CH:31]=[CH:30][N:29]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: Cc1c(S(=O)(=O)Nc2ccc(Br)cc2C(F)(F)F)sc2ccc(F)cc12
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: CCO
Solvent: COCCOC
Product: Cc1c(S(=O)(=O)Nc2ccc(-c3ccnc(F)c3)cc2C(F)(F)F)sc2ccc(F)cc12
Yield: 68.5 %

Procedure:
This compound was prepared in analogy to Example 2 starting from 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acid(4-bromo-2-trifluoromethyl-phenyl)-amide (0.12 g) and 2-fluoropyridine-4-boronic acid (0.072 g) in 1,2-dimethoxyethane (1.5 ml), ethanol (0.32 ml) and 2 M aqueous sodium carbonate solution (1.0 ml) with tetrakis(triphenylphosphine)palladium (0.065 g) to obtain the title compound (0.085 g) as a colorless foam. MS (ISN): 483.4 (M−H)−
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:20]=[C:19]([N:21]4[CH2:26][CH2:25][N:24]([CH2:27][C:28]5[CH2:29][C:30]6([CH2:36][CH2:37][C:38]=5[C:39]5[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=5)[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]6)[CH2:23][CH2:22]4)[CH:18]=[CH:17][C:12]=3[C:13]([O:15][CH3:16])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[CH3:46][C:47]([CH3:49])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(OCC)(=O)C>[NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:20]=[C:19]([N:21]4[CH2:22][CH2:23][N:24]([CH2:27][C:28]5[CH2:29][C:30]6([CH2:36][CH2:37][C:38]=5[C:39]5[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=5)[CH2:31][CH2:32][N:33]([CH:47]([CH3:49])[CH3:46])[CH2:34][CH2:35]6)[CH2:25][CH2:26]4)[CH:18]=[CH:17][C:12]=3[C:13]([O:15][CH3:16])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: COC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC4(CCNCC4)C3)CC2)cc1Oc1cnc2[nH]ccc2c1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC4(CCN(C(C)C)CC4)C3)CC2)cc1Oc1cnc2[nH]ccc2c1
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 265H (320 mg) in dichloromethane (5 mL) was added acetone (143 mg) and sodium triacetoxyborohydride (157 mg). The mixture was stirred overnight. The mixture was diluted with ethyl acetate (200 mL) and washed with 2N aqueous NaOH, water and brine. After drying over Na2SO4, the mixture was filtered and the solvent was evaporated under vacuum to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]3[NH:13][CH:14]=[CH:15][C:5]=3[C:4]=2[CH:3]=1.[CH2:16]([C:18]([O-:20])=[O:19])[CH3:17].[C:21]([NH:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])(=[O:24])[CH:22]=[CH2:23]>ClCCl>[CH3:31][O:30][C:28]([CH2:27][CH2:26][NH:25][C:21]([CH:22]=[CH:23][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]3[NH:13][CH:14]=[CH:15][C:5]=3[C:4]=2[CH:3]=1)=[O:24])=[O:29].[CH2:16]([C:18]([O-:20])=[O:19])[CH3:17]
Reactant: O=c1[nH]c2ccc(Br)cc2c2cc[nH]c12
Reactant: C=CC(=O)NCCC(=O)OC
Agent: CCC(=O)[O-]
Solvent: ClCCl
Product: COC(=O)CCNC(=O)C=Cc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Yield: 11.5 %

Procedure:
This compound is prepared according to synthesis 68, from 70 mg (0.21 mmol) of 8-bromo-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate (synthesis 71) and 36 mg (0.23 mmol) of methyl 3-acryloylamino-propionate. After trituration in dichloromethane, 10 mg (12%) of 8-[2-(2-methoxycarbonyl-ethylcarbamoyl)-vinyl]-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a light brown solid.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH2:9][C@@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([N:18]2[CH2:22][C@@H:21]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH2:20][C@H:19]2[C:29]([NH:31][C:32]2[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=2)=[O:30])=[O:17])[CH2:12][CH2:11]1)=[O:7])([CH3:4])[CH3:3].[N-:42]=[C:43]=[O:44].[K+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.O>[C:2]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([C:16]([N:18]2[CH2:22][C@@H:21]([N:23]3[CH2:28][CH2:27][N:26]([C:43](=[O:44])[NH2:42])[CH2:25][CH2:24]3)[CH2:20][C@H:19]2[C:29]([NH:31][C:32]2[CH:33]=[CH:34][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:40][CH:41]=2)=[O:30])=[O:17])[CH2:12][CH2:11]1)=[O:7])([CH3:1])([CH3:3])[CH3:4]
Reactant: [N-]=C=O
Reactant: COC(=O)c1ccc(NC(=O)[C@@H]2C[C@H](N3CCNCC3)CN2C(=O)[C@H]2CC[C@@H](CNC(=O)OC(C)(C)C)CC2)cc1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc(NC(=O)[C@@H]2C[C@H](N3CCN(C(N)=O)CC3)CN2C(=O)C2CCC(CNC(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 33.5 %

Procedure:
To a solution of the compound prepared in Example 50 (150 mg) in acetic acid (2 mL) and water (2 mL) was added potassium isocyanate (105 mg) and the mixture stirred at room temperature for 4 days. The reaction mixture was then treated with saturated aqueous sodium bicarbonate (10 mL) and extracted into dichloromethane (3×10 mL). The combined organic phases were washed with brine, dried and concentrated. Purification by flash chromatography (silica gel, 5-10% methanol/dichloromethane) gave methyl 4-[(2S,4S)-1-{[4-({[(tert-butoxy)carbonyl]amino}methyl)cyclohexyl]carbonyl}-4-(4-carbamoylpiperazin-1-yl)pyrrolidine-2-amido]benzoate (54 mg) as a colourless oil.