Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([N:15]3[CH:24]([CH3:25])[CH2:23][C:22]4[C:17](=[CH:18][C:19]([CH:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:20][CH:21]=4)[CH2:16]3)[N:12]=[C:11]([NH2:32])[N:10]=2)[CH2:5][CH2:4]1.[N:33]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([N:15]3[CH:24]([CH3:25])[CH2:23][C:22]4[C:17](=[CH:18][C:19]([CH:26]5[CH2:27][CH2:28][N:29]([C:38]([N:33]6[CH2:37][CH2:36][CH2:35][CH2:34]6)=[O:39])[CH2:30][CH2:31]5)=[CH:20][CH:21]=4)[CH2:16]3)[N:12]=[C:11]([NH2:32])[N:10]=2)[CH2:5][CH2:4]1
Reactant: O=C(Cl)N1CCCC1
Reactant: CC1Cc2ccc(C3CCNCC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: Cl
Product: CC1Cc2ccc(C3CCN(C(=O)N4CCCC4)CC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 138 starting from 4-(4-methylpiperazin-1-yl)-6-(3-methyl-7-piperidin-4-yl-3,4-dihydroisoquinolin-2(1H)-yl)pyrimidin-2-amine HCl salt and 1-pyrrolidinecarbonyl chloride. LCMS (M+H)+: m/z=519.2.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Br>>[CH3:16][C:13]1([CH3:17])[N:12]([CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[C:19]([F:18])([F:28])[F:29])[N:11]([CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)[C:14]1=[O:15]
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: FC(F)(F)c1ccccc1CBr
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1ccccc1C(F)(F)F

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2-(trifluoromethyl)benzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: Br[CH:2]([CH3:26])[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)[S:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[CH2:34][NH:33][CH2:32]2.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:25][O:24][C:18]1[CH:17]=[C:16]([CH:7]([S:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:26][N:33]2[CH2:34][C:35]3[C:31](=[CH:30][C:29]([O:28][CH3:27])=[C:37]([O:38][CH3:39])[CH:36]=3)[CH2:32]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1cc2c(cc1OC)CNC2
Reactant: COc1ccc(C(CCCCC(C)Br)Sc2ccc(C)cc2)cc1OC
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(CCCCCCN2Cc3cc(OC)c(OC)cc3C2)Sc2ccc(C)cc2)cc1OC
Yield: 61.1 %

Procedure:
A mixture of 1.79 g of 4-[6-bromo-1-[(4-methylphenyl)thio]heptyl]-1,2-dimethoxybenzene, 3.29 g of 5,6-dimethoxyisoindoline, 25 mL of acetonitrile, and 1.74 mL of N,N-diisopropylethylamine is heated under reflux for 2 days. The reaction is concentrated in vacuo and the black residue partitioned between chloroform and aqueous ammonia. The organic layer is dried (sodium sulfate) and the solvent removed at reduced pressure. Chromatography on silica gel with gradient elution progressing from hexane to chloroform to methyl alcohol, twice, gives 1.34 g of the desired product as a brown gum.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]([CH3:14])([CH3:13])[C:10](Cl)=[O:11]>C1C=CC=CC=1>[C:2]1([NH:1][C:10](=[O:11])[C:9]([CH3:14])([CH3:13])[CH3:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccccc1
Solvent: c1ccccc1
Product: CC(C)(C)C(=O)Nc1ccccc1
Yield: 60 %

Procedure:
The preparation of Example 1 was repeated with the changes that the starting reactants were aniline (24.18 g, 0.260 mole) and trimethylacetoyl chloride (15.06 g, 0.125 mole), the reaction was carried out in benzene and produced 13.24 g of crystals of the desired product (60% yield), mp 132°-132.5° C. Proton nuclear magnetic resonance (89.55 MHz) showed absorptions at 7.568-7.078 ppm (m, 5H; aryl H); 1.310 ppm (s, 9H; tert-butyl H).
Reaction SMILES: [C:1]([C:5]1[NH:9][N:8]=[C:7]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:17]([O-])(=O)=O.[Na+].[OH-].[Na+]>Cl.O>[C:1]([C:5]1[NH:9][N:8]=[C:7]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[Cl:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: [O-][Cl+2]([O-])[O-]
Reactant: CC(C)(C)C(=O)Nc1cc(C(C)(C)C)[nH]n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)C(=O)Nc1n[nH]c(C(C)(C)C)c1Cl
Yield: 165.2 %

Procedure:
9 g (0.04 mole) of 5-t-butyl-3-pivaloylaminopyrazole prepared in Example 4 was dissolved in 50 ml of concentrated hydrochloric acid, and 1.8 g of sodium chlorate dissolved in 40 ml of water was gradually added dropwise thereto. After completion of the reaction, the reaction product was neutralized with sodium hydroxide, and the solid thus formed was collected by filtration and dissolved in methanol. To the resulting solution was added water, whereby crystals were precipitated. The crystals were washed with water and dried to obtain 7.2 g of 5-t-butyl-4-chloro-3-pivaloylaminopyrazole. This product was recrystallized from hydrous methanol and found to have a melting point of 156° to 158° C.
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:11]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)=[CH:10][C:7]=2[CH:8]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)(=[O:21])[CH3:20]>>[N:1]1([C:6]2[CH:13]=[CH:12][C:11]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)=[CH:10][C:7]=2/[CH:8]=[CH:20]/[C:19]([C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)=[O:21])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1cc(-c2cccs2)ccc1N1CCCC1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Product: O=C(O)c1ccc(C(=O)/C=C/c2cc(-c3cccs3)ccc2N2CCCC2)cc1

Procedure:
The title compound was prepared by condensing 2-pyrrolidin-1-yl-5-thiophen-2-yl-benzaldehyde (Ex-63A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Red solid, mp 208–209° C. 1H-NMR (DMSO-d6) δ 12.50 (bs, 1H), 8.22 (d, J=8.5 Hz, 2H), 8.09–7.99 (m, 4H), 7.73 (d, J=15.5 Hz, 1H), 7.52–7.41 (m, 3H), 7.10–7.07 (m, 1H), 6.93 (d, J=9.0 Hz, 1H), 3.28 (m, 4H), 1.87 (m, 4H).
Reaction SMILES: C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Cl:19][C:20]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([OH:24])=[O:23].[Br:30]N1C(=O)CCC1=O>ClC1C=CC=CC=1.C(OCC)(=O)C>[Br:30][CH2:29][C:28]1[C:20]([Cl:19])=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([OH:24])=[O:23]
Reactant: Cc1cccc(C(=O)O)c1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: Clc1ccccc1
Product: O=C(O)c1cccc(CBr)c1Cl
Temperature: 85 °C

Procedure:
Benzoyl peroxide (1.33 g) was added to a suspension of 2-chloro-3-methylbenzoic acid (25 g) and N-bromosuccinimide (28.7 g) in chlorobenzene (250 mL) and the resulting mixture was heated to 85° C. for 4 h. The mixture was diluted with ethyl acetate (100 mL) and washed with 10% aqueous brine (3×100 mL). The organic layer was dried over magnesium sulphate, filtered and evaporated. The beige solid was recrystallised from ethyl acetate (˜75 mL)/isohexane (˜250 mL) to give the subtitled compound as a white solid. Yield 25.3 g.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][C:17]2[CH:20]=[N:21][NH:22][C:16]=2[CH2:15]1)=[O:13].[I:23]N1C(=O)CCC1=O>CN(C=O)C>[Cl:1][C:2]1[C:7]([C:8]([F:9])([F:11])[F:10])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][C:17]2[C:20]([I:23])=[N:21][NH:22][C:16]=2[CH2:15]1)=[O:13]
Reactant: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCc2cn[nH]c2C1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCc2c(I)n[nH]c2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.2 %

Procedure:
To a solution of 6-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine (63 mg, 0.191 mmol) in DMF (1 mL) was added N-iodosuccinimide (47 mg, 0.210 mmol). The reaction was allowed to stir for 2 h at rt then poured into ice water (10 mL). The product was extracted with EtOAc three times. The organic layers were combined, dried over anhydrous MgSO4, filtered and concentrated. Chromatography on silica gel (0-50% ethyl acetatehexanes) provided the desired product (48 mg, 55%). MS (ESI) mass calcd. C14H10ClF31N3O, 454.95. m/z found, 455.9 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.27 (br s, 1H), 7.81-7.74 (m, 1H), 7.52-7.43 (m, 2H), 5.13 (d, J=16.7 Hz, 0.6H), 4.82 (d, J=16.7 Hz, 0.6H), 4.47 (d, J=16.0 Hz, 0.4H), 4.37 (d, J=16.0 Hz, 0.4H), 4.27-4.19 (m, 0.4H), 3.95-3.85 (m, 0.4H), 3.45-3.50 (m, 1.2H), 2.62-2.66 (m, 0.8H), 2.51 (m, 0.6H), 2.46-2.37 (m, 0.6H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][C:3]=1[C:4]#[N:5].C(OC([N:19]1[C:27]2[N:22]([C:23](=[O:29])[N:24]=[C:25](Cl)[CH:26]=2)[CH2:21][C@@H:20]1[CH3:30])=O)(C)(C)C>>[F:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:25]2[CH:26]=[C:27]3[NH:19][C@@H:20]([CH3:30])[CH2:21][N:22]3[C:23](=[O:29])[N:24]=2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(CO)ccc1F
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C(=O)OC(C)(C)C
Product: C[C@H]1Cn2c(cc(OCc3ccc(F)c(C#N)c3)nc2=O)N1

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from 2-fluoro-5-(hydroxymethyl)benzonitrile and (S)-tert-butyl-7-chloro-2-methyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [C:1]([O:4][CH2:5][CH3:6])(=[O:3])[CH3:2].[CH3:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>>[OH:3][CH:1]1[CH2:2][CH2:12][C:11]2[C:5](=[CH:6][C:8]([CH3:7])=[CH:9][CH:10]=2)[O:4]1
Reactant: CCCCCC
Reactant: CCOC(C)=O
Product: Cc1ccc2c(c1)OC(O)CC2
Temperature: 5 °C

Procedure:
The resulting oil was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=19/1), and a fraction containing a desired compound was concentrated to obtain 4.64 g (24.1 mmol) of 2-ethoxy-7-methylchroman as pale-yellow oil. To 4.59 g (23.9 mmol) of the resulting 2-ethoxy-7-methylchroman were added 75 ml of acetonitrile, 25 ml of water and 5.3 ml (60.0 mmol) of a 35% hydrochloric acid aqueous solution, and the reaction was conducted at 60° C. for 1 hour with stirring. After the completion of the reaction, the reaction solution was extracted by adding thereto 50 ml of water and 200 ml of diethyl ether to obtain an organic layer. Further, the aqueous layer was re-extracted by adding thereto 100 ml of diethyl ether, and the thus obtained ether layer was combined with the organic layer obtained earlier. The organic layer was washed twice with 100 ml of a saturated aqueous solution of sodium bicarbonate and then with 100 ml of a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. Magnesium sulfate was then removed by filtration, and the filtrate was vacuum-concentrated to obtain 3.90 g of oil. This oil was homogenized by adding thereto 0.5 ml of ethyl acetate and 10 ml of hexane at 60° C., and cooled to 5° C. for crystallization to precipitate crystals. Further, the mother liquor was vacuum-concentrated, and then purified by silica gel column chromatography (eluent: hexane/ethyl acetate=7/1), and a fraction containing a desired compound was concentrated. This concentrated solution was homogenized by adding thereto 15 ml of hexane, and cooled to 5° C. for crystallization to precipitate crystals. These crystals were collected by filtration, and vacuum-dried at room temperature for 7 hours to obtain 2.68 g (16.3 mmol) of 2-hydroxy-7-methylchroman.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.I[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOCCOC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][N:7]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: CC(C)(C)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOCCOC
Product: CC(C)(C)COc1ccc(Cl)nc1
Reaction time: 0.5 h

Procedure:
5.2 g (40.0 mmol) of 6-chloropyridin-3-ol, 11.9 g (60.0 mmol) of 1-iodo-2,2-dimethylpropane, 19.6 g (60.0 mmol) of cesium carbonate and 120 ml of diethylene glycol dimethyl ether are divided into five portions of equal size and reacted portion-wise in a single-mode microwave oven (CEM Explorer) at 160° C. for 4 h. The five reaction mixtures obtained are then combined, the solid is filtered off and washed with diethylene glycol dimethyl ether and filtrate and wash solutions are combined. Most of the solvent is removed, and 300 ml of water are added to the concentrated (about 50 ml) solution. The mixture is stirred for 30 min, and the solid obtained is filtered off, washed once with water and dried under high vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[N:20]1([C:26]([C:28]2[NH:32][C:31]([CH:33]=O)=[CH:30][CH:29]=2)=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:33][C:31]4[NH:32][C:28]([C:26]([N:20]5[CH2:21][CH2:22][O:23][CH2:24][CH2:25]5)=[O:27])=[CH:29][CH:30]=4)[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Reactant: O=Cc1ccc(C(=O)N2CCOCC2)[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2ncnc(Nc3ccc(F)c(Cl)c3)c2C1=Cc1ccc(C(=O)N2CCOCC2)[nH]1
Temperature: 25 °C
Reaction time: 96 h
Yield: 58.9 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol), 5-(morpholine-4-carbonyl)-1H-pyrrole-2-carbaldehyde (62.5 mg, 0.3 mmol) and piperidine (3 drops) in ethanol (2 mL) was stirred at room temperature for 4 days. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 69 mg (59%) of the title compound. 1H NMR (360 MHz, DMSO-d6) δ 13.41 (br s, 1H, NH), 11.65 (br s, 1H, NH), 8.81 (br s, 1H, NH), 8.28 (s, 1H), 7.76 (s, 1H), 7.75 (m, 1H), 7.53 (m, 1H), 7.38 (t, J=9.05 Hz, 1H), 6.91 (d, J=3.6 Hz, 1H), 6.76 (d, J=3.6 Hz, 1H), 3.71 (m, 4H, 2×CH2), 3.65 (m, 4H, 2×CH2). MS 469 [M++1].
Reaction SMILES: [F:1][C:2]1([C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[N:20][OH:21])=[CH:15][CH:14]=2)[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.C1C(=O)N(Cl)C(=O)C1.[Cl:30][C:31]1[CH:36]=[C:35]([C:37](=[CH2:42])[C:38]([F:41])([F:40])[F:39])[CH:34]=[C:33]([Cl:43])[C:32]=1[Cl:44].C(=O)(O)[O-].[K+]>CCOC(C)=O.CN(C=O)C>[F:1][C:2]1([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH2:42][C:37]([C:35]4[CH:34]=[C:33]([Cl:43])[C:32]([Cl:44])=[C:31]([Cl:30])[CH:36]=4)([C:38]([F:41])([F:40])[F:39])[O:21][N:20]=3)=[CH:17][CH:18]=2)[CH2:3][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5]1
Reactant: C=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC(F)(c2ccc(C=NO)cc2)C1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
To a DMF (8 mL) solution of tert-butyl 3-fluoro-3-(4-((hydroxyimino)methyl)-phenyl)azetidine-1-carboxylate (Preparation 7, 486 mg, 1.65 mmol) was added NCS (232 mg, 1.65 mmol) in two portions over 10 minutes. The reaction was stirred at room temperature overnight. The reaction was diluted with EtOAc (8 mL) and 1,2,3-trichloro-5-(1,1,1-trifluoroprop-2-en-2-yl)benzene (546 mg, 1.98 mmol) was added, followed by potassium bicarbonate (248 mg, 2.48 mmol). The reaction was stirred at room temperature for 3 days. The reaction was concentrated under vacuum. The residue was partitioned between EtOAc (50 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were dried and condensed. The crude material was adsorbed on silica and chromatographed on a 40 g silica column eluting with a gradient of 0%-40% EtOAc/hexanes over 20 minutes. Fractions containing the desired material were combined and concentrated to yield 526 mg of a white solid. 1H NMR (CDCl3) δ 7.74 (d, 2H), 7.67 (s, 2H), 7.56 (d, 2H), 4.39-4.51 (m, 2H), 4.24 (m 2H), 4.12 (d, 1H), 3.72 (d, 1H), 1.5 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:17][C:12]3=[N:13][CH:14]=[CH:15][N:16]=[C:11]3[CH:10]=2)=[CH:5][C:4]=1[OH:18].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>CN(C)C=O>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][O:18][C:4]1[CH:5]=[C:6]([C:9]2[NH:17][C:12]3=[N:13][CH:14]=[CH:15][N:16]=[C:11]3[CH:10]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH3:31]
Reactant: CCOC(=O)CCl
Reactant: COc1ccc(-c2cc3nccnc3[nH]2)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(-c2cc3nccnc3[nH]2)ccc1OC
Temperature: 50 °C

Procedure:
To a solution of 2-methoxy-5-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-phenol [0.5 g, Example 28] in dimethylformamide (10 mL) and cesium carbonate (0.67g) was added ethyl chloroacetate (0.025 g). The reaction mixture was heated at 50° C. overnight. After cooling, the dimethylformamide was removed in vacuo and the residue partitioned between ethyl acetate and water. The organic fraction was dried over sodium sulfate, evaporated and subjected to flash column chromatography on silica eluting with 2.5% methanol in dichloromethane. This product was further triturated with a mixture of ethyl acetate and pentane to give the title compound as a white solid, m.p. 183–184° C. MS: 328 (MH+).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:6]=1)=[O:4].C(OCC)(=O)C>O1CCCC1>[S:9]1[CH:10]=[CH:11][C:7]2[CH:6]=[C:5]([C@@H:3]([OH:4])[CH2:2][Br:1])[CH:13]=[CH:12][C:8]1=2
Reactant: O=C(CBr)c1ccc2sccc2c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O[C@@H](CBr)c1ccc2sccc2c1
Temperature: -25 °C
Reaction time: 4 h
Yield: 94.3 %

Procedure:
A solution of 7.5 g of (+)-diisopinocamphenylchloroborane dissolved in 15 ml of tetrahydrofuran was cooled to -25° C. Thereto was added 4 g of 5-bromoacetylbenzo[b]thiophene. The resulting mixture was stirred for 4 hours at -20° C. to -15° C. The reaction mixture was added to a mixture of 80 ml of ethyl acetate and 80 ml of ice water. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: hexane:ethyl acetate=10:1) to obtain 3.8 g of (R)-1-(benzo[b]thiophen-5-yl)-2-bromoethanol.
Reaction SMILES: [CH3:1][C:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:16])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8](C(OCC)=O)[CH2:7][CH2:6]1.[Cl-].[Na+]>Cl>[CH3:16][C:2]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([CH3:1])[CH2:3][CH2:4][N:5]1[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1
Reactant: CCOC(=O)N1CCN(CCC(C)(C)c2ccccc2)CC1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Product: CC(C)(CCN1CCNCC1)c1ccccc1
Yield: 95.2 %

Procedure:
A solution of ethyl 4-(3-methyl-3-phenylbutyl)piperazine-1-carboxylate (1.17 g) in conc. hydrochloric acid (15 ml) was heated in a sealed tube for 12 hours at 120° C. The solution was concentrated and to the resultant residue was added 10% sodium hydroxide to make basic. The mixture thus obtained was saturated with sodium chloride and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated to give 0.85 g of 1-(3-methyl-3-phenylbutyl)piperazine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:11]([CH2:30][CH:31]([CH3:33])[CH3:32])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16]([C:26]([O:28]C)=[O:27])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:11]([CH2:30][CH:31]([CH3:33])[CH3:32])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[CH:17][C:16]([C:26]([OH:28])=[O:27])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2nc(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccccc3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)Cc1nc2ccc(C(=O)O)cc2c(-c2ccccc2)c1CNC(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To a solution of methyl 3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-phenylquinoline-6-carboxylate (0.58 g, 1.3 mmol) in tetrahydrofuran (6 ml)-methanol (6 ml) was added 1N aqueous sodium hydroxide solution (3 ml), and the mixture was stirred at 50° C. for 2 hrs. The reaction mixture was partitioned between tetrahydrofuran (50 ml)-ethyl acetate (50 ml) and 0.1N hydrochloric acid (100 ml) and the aqueous layer was extracted twice with tetrahydrofuran (25 ml)-ethyl acetate (25 ml). The organic layers were combined, washed with saturated brine (50 ml), and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was crystallized from diisopropyl ether-ethyl acetate to give 3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-phenylquinoline-6-carboxylic acid (0.56 g, 99%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:7][CH:8]=[CH2:9])[CH2:4][CH:5]=O.S(O)(O)(=O)=O.[NH2:15][OH:16].C([O-])(=O)C.[Na+].O>C(O)C>[CH3:1][O:2][CH:3]([CH2:7][CH:8]=[CH2:9])[CH2:4][CH:5]=[N:15][OH:16]
Reactant: C=CCC(CC=O)OC
Reactant: NO
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C=CCC(CC=NO)OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 46.2 %

Procedure:
A mixture of 3-methoxy-5-hexenal (3.0 g, contaminated with dichloromethane and triethylamine), hydroxylamine sulfate (990 mg) and sodium acetate (624 mg) in ethanol (6.5 mL)-water (0.65 mL) was stirred at room temperature for 12 hours. The reaction solution was poured into ice water, followed by extraction with ethyl acetate. The extract was washed with a saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography to obtain the title compound (500 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].[CH:15](O)=[O:16]>>[CH3:1][C:2]1[CH:8]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:6]=[CH:5][C:3]=1[NH:4][CH:15]=[O:16]
Reactant: Cc1cc(-c2cnn(C)c2)ccc1N
Reactant: O=CO
Product: Cc1cc(-c2cnn(C)c2)ccc1NC=O

Procedure:
A solution of 2-methyl-4-(1-methyl-1H-pyrazol-4-yl)aniline (Preparation 98, 100 mg, 0.534 mmol) in formic acid (3 mL) was heated to reflux for 3 hours. The reaction mixture was concentrated in vacuo. The residue was partitioned between aqueous saturated NaHCO3 solution (30 mL) and EtOAc (30 mL). The aqueous layer was re-extracted with EtOAc (30 mL).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:14][CH:12]([CH2:13]2)[O:11][C:10](=[O:15])[NH:9]3)=[CH:4][CH:3]=1.[Li]CCCC.CON(C)[C:24](=[O:32])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1.CCCCCC>[C:26]1([CH2:25][C:24]([C:2]2[CH:7]=[CH:6][C:5]([C:8]34[CH2:14][CH:12]([CH2:13]3)[O:11][C:10](=[O:15])[NH:9]4)=[CH:4][CH:3]=2)=[O:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C1NC2(c3ccc(Br)cc3)CC(C2)O1
Reactant: CON(C)C(=O)Cc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1NC2(c3ccc(C(=O)Cc4ccccc4)cc3)CC(C2)O1

Procedure:
A solution of 5-(4-bromo-phenyl)-2-oxa-4-aza-bicyclo[3.1.1]heptan-3-one (prepared according to WO2009/148916, 4 g) in dry THF (60 mL) was cooled to −78° C. and treated with n-BuLi (6.56 mL of a 2.5M solution in hexane) and stirred for 30 minutes at this temperature before addition of further n-BuLi (13.1 mL of a 2.5M solution in hexane). Stirring was continued at this temperature for 30 minutes before a solution of N-methoxy-N-methyl-benzeneacetamide (prepared according to US6407119B1, 4.6 g) in THF (10 mL) was added. After 10 minutes the reaction was quenched with saturated aqueous ammonium chloride solution, extracted with EtOAc and the combined organic phases washed with brine, filtered and concentrated. The residue was triturated with hexane/EtOAc to give the title compound which was used in the next step without further purification.