Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]([CH3:5])=O)=[CH2:2].[Si:6]([O:13][NH2:14])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]>C(Cl)Cl>[Si:6]([O:13][N:14]=[C:3]([CH3:5])[CH:1]=[CH2:2])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: C=CC(C)=O
Reactant: CC(C)(C)[Si](C)(C)ON
Solvent: ClCCl
Product: C=CC(C)=NO[Si](C)(C)C(C)(C)C
Temperature: 5 °C
Reaction time: 18 h

Procedure:
The procedure followed was that described by Behforouz et al., J. Org. Chem. 58:7089-7091 (1993). In a 50 mL round bottom flask, dry 4 Å molecular sieves (Fisher, 3.4 g) were added to dry CH2Cl2 (distilled from CaH2, 10 mL) and cooled to 5° C. with an ice bath. Methyl vinyl ketone (Aldrich, new bottle, used without purification, 0.725 mL, 0.618 g, 3.84 mmol) was added. A solution of O-(tert-butyldimethylsilyl)hydroxylamine (Aldrich, used without purification, 1.0 g, 6.80 mmol) in dry CH2Cl2 (distilled from CaH2, 3 mL) was added dropwise over a period of 5 min. The ice bath was removed and the mixture was stirred at rt under N2 for 18 h. The sieves were removed by filtration and the CH2Cl2 was evaporated to dryness (roto-vap). Column chromatography with silica gel and CHCl3 as eluent afforded 1-(tert-butyldimethylsilyloxy)-2-methyl-1-aza-1,3-butadiene as a light oil (1.2 g, 81%, interpretation of the 1H NMR showed a 1:1 anti/syn mixture): 1H NMR (CDCl3) δ (anti) 0.17 (s, 6H), 0.94 (s, 9H), 1.97 (s, 3H), 5.35-5.75 (m, 2H), 6.41-6.53 (m, 1H); (syn) 0.17 (s, 6H), 0.94 (s, 9H), 1.99 (s, 3H), 5.35-5.75 (m, 2H), 7.15-7.25 (m, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:8])[CH2:5][CH2:6][OH:7].[Cl:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]([N:16]2[C:20](=[O:21])[C:19]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][NH:17]2)[CH:11]=1.Cl>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[ClH:9].[CH3:3][N:4]([CH3:8])[CH2:5][CH2:6][O:7][C:10]1[N:15]=[CH:14][N:13]=[C:12]([N:16]2[C:20](=[O:21])[C:19]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][NH:17]2)[CH:11]=1
Reactant: CN(C)CCO
Reactant: O=c1c(-c2cccnc2)c[nH]n1-c1cc(Cl)ncn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CCOc1cc(-n2[nH]cc(-c3cccnc3)c2=O)ncn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
99 mg (0.4 mmol, 60% in mineral oil) of sodium hydride are added to a solution of 35 μl (31 mg, 0.4 mmol) of N,N-dimethylethanolamine and 2 ml of anhydrous THF, and the mixture is stirred for 10 min 100 mg (0.4 mmol) of the compound from Example 23, suspended in 3 ml of anhydrous THF, and 6 mg (0.02 mmol) of tetra-n-butylammonium iodide are added, and the mixture is stirred at RT for 16 h. 1 N hydrochloric acid and water are then added, the mixture is concentrated on a rotary evaporator and the residue is stirred in methanol. The precipitated solid is filtered off, and the filtrate is concentrated under reduced pressure. The filter residue is stirred in diethyl ether, the precipitate is filtered off and the filter residue is purified further by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid). The resulting formate salt of the target compound is converted into the hydrochloride by addition of 2 ml 1 M hydrochloric acid and reconcentration.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:21]N(C=O)C.[OH-].[K+].IC>C1COCC1>[CH2:2]([N:9]1[CH2:14][CH2:13][C:12](=[O:15])[C:11]([CH3:21])([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCC1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C1(C)CN(Cc2ccccc2)CCC1=O
Reaction time: 0.12 h

Procedure:
To a suspension of ethyl 1-benzyl-4-oxopiperidine-3-carboxylate hydrochloride (20 g, 67.2 mmol) in THF (130 mL)/DMF (130 mL) was added KOH (powder, 7.64 g, 136 mmol) at room temperature. The reaction mixture was stirred for 5-10 min, then added iodomethane (4.62 mL, 73.9 mmol) dropwise. The reaction mixture was further stirred for 3 h at room temperature and then quenched with water. The aqueous phase was extracted with diethyl ether twice. The organic phases were combined and washed with water, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (0-20% EtOAc/heptanes) to provide ethyl 1-benzyl-3-methyl-4-oxopiperidine-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.15-7.45 (m, 5H), 4.00-4.21 (m, 2H), 3.66 (d, J=13.39 Hz, 1H), 3.47 (d, J=13.39 Hz, 1H), 3.30 (dd, J=2.78, 11.62 Hz, 1H), 2.96-3.08 (m, 1H), 2.77 (ddd, J=6.69, 11.68, 14.46 Hz, 1H), 2.36-2.45 (m, 1H), 2.27-2.35 (m, 1H), 2.14 (d, J=11.37 Hz, 1H), 1.15 (t, J=7.07 Hz, 3H), 1.09 (s, 3H).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[F:13][C:14]1[CH:15]=[C:16]([N:21]2[CH2:25][CH2:24][CH2:23][CH:22]2[C:26]2[CH:27]=[C:28]([C:43]([OH:45])=O)[CH:29]=[C:30]3[C:35]=2[O:34][C:33]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[CH:32][C:31]3=[O:42])[CH:17]=[C:18]([F:20])[CH:19]=1.OC1C=CC=C[N+]=1[O-].[NH:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1>C(Cl)Cl>[F:20][C:18]1[CH:17]=[C:16]([N:21]2[CH2:25][CH2:24][CH2:23][CH:22]2[C:26]2[CH:27]=[C:28]([C:43]([N:54]3[CH2:59][CH2:58][O:57][CH2:56][CH2:55]3)=[O:45])[CH:29]=[C:30]3[C:35]=2[O:34][C:33]([N:36]2[CH2:37][CH2:38][O:39][CH2:40][CH2:41]2)=[CH:32][C:31]3=[O:42])[CH:15]=[C:14]([F:13])[CH:19]=1
Reactant: O=C(O)c1cc(C2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [O-][n+]1ccccc1O
Solvent: ClCCl
Product: O=C(c1cc(C2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1)N1CCOCC1
Reaction time: 4 h
Yield: 58.1 %

Procedure:
N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (71.4 mg, 0.37 mmol) was added portionwise to a stirred solution of 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (85 mg, 0.19 mmol), 2-hydroxypyridine 1-oxide (41.4 mg, 0.37 mmol) and morpholine (0.033 mL, 0.37 mmol) at room temperature under nitrogen and stirred for 4 h. The reaction mixture was diluted with DCM, washed with water, brine, dried over MgSO4 and concentrated. The reaction mixture was purified by preparative HPLC. The fractions were evaporated to dryness, and the residue was dissolved in DCM, dried over MgSO4 and concentrated. The remaining solid was triturated with diethyl ether, filtered, washed with diethyl ether and dried under vacuum at 50° C. to afford 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-6-(morpholine-4-carbonyl)-2-morpholino-4H-chromen-4-one (58.0 mg, 59.3%) as a pale beige solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH2:4][CH2:5][CH2:6]Br.[N-:9]=[N+:10]=[N-:11].[Na+].O>CS(C)=O>[N:9]([CH2:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:8])=[N+:10]=[N-:11]
Reactant: COC(=O)CCCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)CCCN=[N+]=[N-]
Temperature: 47.5 °C
Reaction time: 5 h

Procedure:
To a solution of methyl-4-bromobutyrate in DMSO (0.6 M) was added with stirring NaN3 (1.5 eq). The suspension was heated (45-50° C., oil bath) with stirring for 5 h. After cooling, H2O was added and the mixture extracted with Et2O. The organic extracts were washed with brine and dried over Na2SO4. The solvent was removed in vacuo and the crude oil used without further purification (99%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[C:15]1([CH2:21][CH2:22][C:23](Cl)=O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1(C)C=CC=CC=1.O1CCCC1>[C:15]1([CH2:21][CH2:22][CH2:23][N:11]2[CH2:12][CH2:13][CH2:14][C@H:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:10]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: COc1cccc([C@H]2CCCNC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1cccc([C@H]2CCCN(CCCc3ccccc3)C2)c1

Procedure:
The title compound was prepared by acylation of 1.0 g (5.2 mmole) of the (R)(-)-3-(3-methoxyphenyl)-piperidine from Preparation 7, Part C, with 1.3 g (7.8 mmole) of 3-phenylpropionyl chloride in toluene, followed by reduction with 910 mg (24 mmole) of lithium aluminum hydride in tetrahydrofuran, using the procedure of Preparation 3. This afforded 1.9 g of an oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[NH2:24][C:25]1[N:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][C:26]=1[C:27]([NH:29][CH3:30])=[O:28]>>[NH2:24][C:25]1[N:34]=[CH:33][C:32]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]5[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)=[CH:31][C:26]=1[C:27]([NH:29][CH3:30])=[O:28]
Reactant: CNC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cnc1N
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: CNC(=O)c1cc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cnc1N

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 2-amino-N-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-nicotinamide (Stage 224.1.1) to give the title compound as an off-white solid. (HPLC: tR 2.01 min (Method A); M+H=443 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.92 (s, 1H), 8.54 (q, 1H), 8.14-8.11 (m, 2H), 8.10-8.06 (m, 2H), 7.96-7.92 (m, 1H), 7.47-7.44 (m, 1H), 7.27 (s, br, 2H), 3.89 (s, 3H), 3.57 (s, 3H), 2.78 (d, 3H), 1.95 (s, 3H))
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH:21]=[CH:20][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:38]([CH2:42][C:43](Cl)=[O:44])([CH3:41])([CH3:40])[CH3:39].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[C:22]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH:21]=[CH:20][C:3]=1[CH2:4][N:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)=[CH:8][CH:7]=1)[C:43](=[O:44])[CH2:42][C:38]([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Clc1cc(OC2CCCCO2)ccc1CNc1ccc(OCCN2CCCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC(=O)N(Cc1ccc(OC2CCCCO2)cc1Cl)c1ccc(OCCN2CCCC2)cc1
Reaction time: 1 h

Procedure:
To a solution of [2-chloro-4-(tetrahydro-pyran-2-yloxy)-benzyl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-amine (0.100 g, 0.232 mmol) and triethylamine (0.100 mL, 0.696 mmol) in 2 mL methylene chloride was added tert-butylacetyl chloride (0.081 mL, 0.58 mmol) dropwise. The reaction mixture was stirred for 1 hr. at room temperature. Saturated aqueous sodium bicarbonate was added and the layers were separated. The aqueous layer was extracted with an additional 2 mL of methylene chloride. The combined organic layers were concentrated to give the title compound of Step A. MS 529.2 (M+1)+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[C:9](OS(C(F)(F)F)(=O)=O)=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:18][C:19]([O:21][CH3:22])=[O:20].[Li+].[Cl-].[CH3:26][CH2:27]N(CC)CC.C([Sn](CCCC)(CCCC)C=C)CCC>O1CCOCC1.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>[CH3:1][O:2][C:3](=[O:23])[C:4]1[C:9]([CH:26]=[CH2:27])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:18][C:19]([O:21][CH3:22])=[O:20]
Reactant: CCN(CC)CC
Reactant: COC(=O)Cc1cccc(OS(=O)(=O)C(F)(F)F)c1C(=O)OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: C1COCCO1
Product: C=Cc1cccc(CC(=O)OC)c1C(=O)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.3 %

Procedure:
A mixture of 2-methoxycarbonylmethyl-6-trifluoromethanesulfonyloxy-benzoic acid methyl ester (2.705 g, 7.6 mmol), LiCl (2.355 g, 55.6 mmol), NEt3 (1.5 mL, 10.8 mmol), Pd[P(C6H5)3]4 (1.09 g, 0.94 mmol), and tributyl (vinyl)tin (2.85 mL, 9.75 mmol) in dioxane (50 mL) was heated at reflux. After 3 h, the reaction was allowed to cool to rt, filtered through a pad of silica gel and concentrated. The crude product was purified by flash chromatography on SiO2 (13% EtOAc/hexanes) to afford 2-methoxycarbonylmethyl-6-vinyl-benzoic acid methyl ester as a yellow solid (1.50 g, 84%): 1H NMR (CDCl3) δ 3.67 (s, 3H), 3.89 (s, 5H), 5.32 (d, J=10.9 Hz, 1H), 5.68 (d, J=17.4 Hz, 1H) 6.82 (dd, J=17.4, 10.9 Hz, 1H), 7.20(d, J=7.1 Hz, 1H), 7.36(m, 1H), 7.50 (d, J=7.8 Hz, 1H).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([CH:23]([C:28]4[C:29]([CH3:45])=[C:30]([NH:34][C:35](=[O:44])[O:36][CH2:37][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH:31]=[CH:32][CH:33]=4)[CH2:24][N+:25]([O-])=O)=[CH:19][NH:20]3)=[CH:16][CH:15]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl-].[NH4+]>CO.O1CCCC1.[Zn]>[NH2:25][CH2:24][CH:23]([C:28]1[C:29]([CH3:45])=[C:30]([NH:34][C:35](=[O:44])[O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:31]=[CH:32][CH:33]=1)[C:18]1[C:17]2[C:21](=[CH:22][C:14]([N:11]3[CH2:12][CH2:13][CH:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[CH2:10]3)=[CH:15][CH:16]=2)[NH:20][CH:19]=1
Reactant: Cc1c(NC(=O)OCc2ccccc2)cccc1C(C[N+](=O)[O-])c1c[nH]c2cc(N3CCC(O[Si](C)(C)C(C)(C)C)C3)ccc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(NC(=O)OCc2ccccc2)cccc1C(CN)c1c[nH]c2cc(N3CCC(O[Si](C)(C)C(C)(C)C)C3)ccc12
Reaction time: 8 h
Yield: 102.4 %

Procedure:
To a solution of benzyl 3-(1-(6-(3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)-1H-indol-3-yl)-2-nitroethyl)-2-methylphenylcarbamate (1.0324 g, 1.642 mmol) and ammonium chloride (1.317 g, 24.63 mmol) in methanol (32.8 mL) and tetrahydrofuran (32.8 mL) under nitrogen was added zinc (1.610 g, 24.63 mmol), and the reaction was stirred overnight. The solution was filtered through a pad of CELITE® and rinsed with MeOH and THF. The filtrate was concentrated in vacuo, dissolved in EtOAc (100 mL) and water (40 mL). After separation of the layers, the aqueous layer was extracted with EtOAc (2×100 mL). The organic layers were combined, dried over MgSO4, filtered and concentrated in vacuo to give the desired product (1.007 g, 1.682 mmol, 102% yield) as a dark solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH2:6])=[N:2]1.[OH-].[K+].Cl[CH2:10][C@H:11]1[CH2:15][O:14][C:13]([CH3:17])([CH3:16])[O:12]1.O>CS(C)=O>[CH3:16][C:13]1([CH3:17])[O:12][C@@H:11]([CH2:10][N:1]2[CH:5]=[CH:4][C:3]([NH2:6])=[N:2]2)[CH2:15][O:14]1
Reactant: Nc1cc[nH]n1
Reactant: CC1(C)OC[C@H](CCl)O1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)OC[C@H](Cn2ccc(N)n2)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1H-pyrazol-3-amine in DMSO (15 mL) was added potassium hydroxide (3.18 g) at room temperature. After stirring at room temperature for 30 minutes, to the reaction mixture was added a solution of (R)-(+)-4-chloromethyl-2,2-dimethyl-1,3-dioxolane (3.0 g) in DMSO (10 mL), followed by stirring at room temperature for 3 days. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The obtained crude product was purified by basic silica gel column chromatography (hexane:ethyl acetate=1:1-1:3) to obtain 1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-1H-pyrazol-3-amine (1.0 g) as a pale violet oily substance.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[C:15]1([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29].CO>C(OCC)(=O)C>[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:24]3[CH2:25][CH2:26][CH:21]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:22][CH2:23]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OCC2CO2)c2cc[nH]c2c1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2ccccc2)CC1

Procedure:
The title compound was prepared in similar fashion from S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-phenylpiperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 80% overall yield. FDMS m/e=351 (M+ of free base). α[D]589 =-15.49 (c=0.86, methanol).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:15][C:16]([NH:18][C:19]1[CH:28]=[CH:27][C:22]2[NH:23][C:24](=[O:26])[NH:25][C:21]=2[CH:20]=1)=[O:17]>C(OCC)C>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:15][C:16]([NH:18][C:19]2[CH:28]=[CH:27][C:22]3[NH:23][C:24](=[O:26])[NH:25][C:21]=3[CH:20]=2)=[O:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCl)Nc1ccc2[nH]c(=O)[nH]c2c1
Reactant: c1ccc(CC2CCNCC2)cc1
Solvent: CCOCC
Product: O=C(CN1CCC(Cc2ccccc2)CC1)Nc1ccc2[nH]c(=O)[nH]c2c1

Procedure:
The title compound is prepared from 4-benzyl-piperidine and 2-chloro-N-(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-acetamide according to the method described in Example 142b. Melting Point: 270° C. (diethylether
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[H-].[Na+].Br[CH2:14][C:15]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH3:26])[C:21]1[N:27]([CH3:40])[C:28](=[O:39])[C:29]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[Cl:38])=[CH:30][C:20]2=1)=[O:16].C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1>C1COCC1.CCO.CCOC(C)=O>[CH2:9]([O:8][C:1](=[O:7])[C:2](=[O:4])[CH2:14][C:15]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH3:26])[C:21]1[N:27]([CH3:40])[C:28](=[O:39])[C:29]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[Cl:38])=[CH:30][C:20]2=1)=[O:16])[CH3:10]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(C(=O)CBr)ccc3n(C)c21
Agent: [H-]
Agent: [Na+]
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
940 mg (6.4 mmol) of diethyl oxalate are dissolved in 5 ml of anhydrous THF. 273 mg (6.8 mmol) of 60% NaH are added and the mixture is stirred at ambient temperature for 10 minutes. A solution of 1.3 g (3.2 mmol) of compound 6-(bromoacetyl)-3-(2,4-dichlorophenyl)-1,9-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one from preparation 1.2 above and 18 mg (0.052 mmol) of dibenzo-18-crown-6 dissolved in 20 ml of anhydrous THF is added, as are a few drops of anhydrous EtOH. The mixture is heated at 70° C. under argon for 3 hours. The mixture is allowed to return to ambient temperature. EtOAc is added to the reaction medium and the organic phase is washed with a 1N HCl solution. The organic phase is evaporated to dryness and the product obtained is triturated in water and filtered. The product is taken up in EtOH and evaporated to dryness.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:27])=[C:4]([C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[N:22][C:23]([CH3:26])=[N:24][CH:25]=4)[CH:18]=3)[NH:13][CH:12]=2)=[O:10])[C:5]([F:8])=[CH:6][CH:7]=1.[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35](Cl)(=[O:37])=[O:36].N1C=CC=CC=1>O1CCCC1>[F:27][C:3]1[C:4]([C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[N:22][C:23]([CH3:26])=[N:24][CH:25]=4)[CH:18]=3)[NH:13][CH:12]=2)=[O:10])=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:35]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[F:28])(=[O:37])=[O:36]
Reactant: Cc1ncc(-c2cnc3[nH]cc(C(=O)c4c(F)ccc(N)c4F)c3c2)cn1
Reactant: O=S(=O)(Cl)c1ccccc1F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1ncc(-c2cnc3[nH]cc(C(=O)c4c(F)ccc(NS(=O)(=O)c5ccccc5F)c4F)c3c2)cn1
Temperature: 60 °C
Yield: 41.2 %

Procedure:
To (3-amino-2,6-difluoro-phenyl)-[5-(2-methyl-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone (50, 0.220 g, 0.602 mmol) in 4.01 mL of tetrahydrofuran, 2-fluoro-benzenesulfonyl chloride (20, 0.352 g, 1.807 mmol) and pyridine (0.146 mL, 1.807 mmol) are added and the reaction is heated at 60° C. overnight. The reaction is partitioned between brine/water and ethyl acetate/tetrahydrofuran. The organic layer is separated and the solvent is removed under vacuum. The resulting residue is purified by silica gel column chromatography eluting with 0-10% methanol in dichloromethane, then triturated with ethyl acetate/heptane to provide the desired compound as a light tan solid (P-1520, 0.130 g, 0.248 mmol, 41.2% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH3:18])[C:11]([CH3:17])=[C:12]([CH:16]=2)[C:13]([OH:15])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(C(Cl)=O)=O.[NH2:25][C:26]1[C:27]([F:34])=[C:28]([OH:33])[CH:29]=[CH:30][C:31]=1[F:32].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.C1COCC1.CCOC(C)=O.O.CN(C=O)C>[F:34][C:27]1[C:28]([OH:33])=[CH:29][CH:30]=[C:31]([F:32])[C:26]=1[NH:25][C:13](=[O:15])[C:12]1[CH:16]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH:9]=[C:10]([CH3:18])[C:11]=1[CH3:17]
Reactant: Cc1cc(-c2cccc(F)c2)cc(C(=O)O)c1C
Reactant: Nc1c(F)ccc(O)c1F
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(-c2cccc(F)c2)cc(C(=O)Nc2c(F)ccc(O)c2F)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.7 %

Procedure:
To a solution of 5-(3-fluorophenyl)-2,3-dimethyl-benzoic acid (3.82 g, 15.6 mmol, 5.8 eq) in DCM (30 mL) was added (COCl)2 (5.96 g, 46.8 mmol, 17.0 eq) and DMF (0.5 mL). The mixture was stirred at room temperature under N2 for 2 h then the solvent removed in vacuo. The residue obtained was dissolved in THF (10 mL) and added to a mixture of 3-amino-2,4-difluoro-phenol (intermediate X(a)) (0.4 g, 2.75 mmol, 1.0 eq) and Na2CO3 (0.87 g, 8.26 mmol, 3.0 eq) in THF. The reaction was stirred at room temperature overnight then water and EtOAc were added. The organic extract was washed with water, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (DCM:MeOH, 0:1 to 1:50) to give the title compound as a solid (0.16 g, 15%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]2[C:8]=1[CH:9]=[C:10]([C:17]([O:19][CH3:20])=[O:18])[NH:11]2.[OH-].[Na+].CN([CH:26]=[O:27])C>>[CH:26]([C:9]1[C:8]2[C:12](=[C:13]([CH3:16])[CH:14]=[CH:15][C:7]=2[CH3:6])[NH:11][C:10]=1[C:17]([O:19][CH3:20])=[O:18])=[O:27]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc2c(C)ccc(C)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1[nH]c2c(C)ccc(C)c2c1C=O
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 26 %

Procedure:
A 500-ml 3-necked flask dried with heating was charged with 71 ml of anhydrous DMF. Then 21.5 ml (230 mmol) of phosphorus oxychloride was added dropwise at O° C. over a period of 40 minutes and stirring was continued until the solution turned red. A solution of 50 g (246 mmol) of methyl 4,7-dimethylindole-2-carboxylate in 200 ml of anhydrous DMF was added dropwise at 20°-30° C. over a period of at least 30 minutes, and the reaction mixture was stirred at 90° C. for 2 hours. The reaction mixture was poured upon 500 g of ice and made basic by gradually adding 225 ml of aqueous solution of 40 g of sodium hydroxide. The solution thus obtained was refluxed for 1 minute and immediately filtered. The crystals precipitated were washed with 100 ml of water four times and dried under reduced pressure. The crude product was purified by silica gel column chromatography to provide 29.5 g of light yellow crystals. Yield: 26%