Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:7]=[C:8]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:9]=[CH:10][C:11]=1[NH2:12])(=[O:3])C.NC1C=CC(N2CCN(C(OC(C)(C)C)=O)CC2)=CC=1CN.C1N=CN(C(N2C=NC=C2)=O)C=1>C1COCC1>[O:3]=[C:1]1[NH:4][CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])[CH2:15][CH2:14]3)[CH:7]=2)[NH:12]1
Reactant: CC(=O)NCc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Agent: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(CN)c2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)CNC(=O)N3)CC1
Temperature: 80 °C
Yield: 33 %

Procedure:
Therefore an alternative approach was adopted in which benzaldehyde 11 was nitrated to the known benzaldehyde 12, which in turn was subjected to reductive amination by condensing it with ammonium hydroxide, using sodium borohydride as reducing agent to produce amine 13 in high yield. Acetylation amine 13 generated acetamide 14, which was reacted with tert-butyl piperazine-1-carboxylate under Buchwald-Hartwig conditions to afford intermediate 15 in good yield. Reduction of nitro group of 15 over Pd—C in a Parr apparatus produced intermediate 16 in 91% yield high yield. Exposure of intermediate 16 under basic conditions rendered the desired diamine 17 in good yield after column purifications. Reaction of 17 with CDI in THF, heating the mixture at 80° C. for 6 hours, gave access to the key intermediate 10 in an overall yield of 33% from 14. Exposure of intermediate 10 to trifluoroacetic acid in a mixture of methanol and dichloromethane finally furnished the desired key intermediate 18 (scheme 2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:17][CH2:18][O:19][CH3:20])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH2:21]([Li])[CH2:22][CH2:23]C.C(I)C=C.[Cl-].[NH4+]>O1CCCC1.O>[CH2:23]([C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[C:5]([C:8]([O:17][CH2:18][O:19][CH3:20])([C:9]([F:12])([F:11])[F:10])[C:13]([F:14])([F:15])[F:16])[CH:6]=1)[CH:22]=[CH2:21]
Reactant: COCOC(c1ccc(Cl)nc1)(C(F)(F)F)C(F)(F)F
Reactant: [Li]CCCC
Agent: C=CCI
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)cnc1Cl
Yield: 63.9 %

Procedure:
To a solution of 2-chloro-5-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)pyridine (50 mg, 0.155 mmol) in tetrahydrofuran (2 mL), butyllithium (71 μL, 1.70 mmol) was added under −78° C. and the resultant mixture was stirred for 0.5 hour. Allyl iodide (71 μL, 0.773 mmol) was added under −78° C. and the resultant mixture was stirred at room temperature for 1 hour. The reaction solution was added with a saturated aqueous solution of ammonium chloride and water under room temperature and extracted with ethyl acetate. The organic layer was washed with brine, dried using anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate), and the title compound (36 mg, yield 64%) was obtained as a yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6]Cl)[CH3:3].[Mg].Cl[CH:10]1[C:16]2[CH:17]=[C:18]([S:21][CH3:22])[CH:19]=[CH:20][C:15]=2[CH:14]=[CH:13][C:12]2[CH:23]=[CH:24][CH:25]=[CH:26][C:11]1=2>O1CCCC1>[CH3:1][N:2]([CH3:3])[CH2:4][CH2:5][CH2:6][CH:10]1[C:16]2[CH:17]=[C:18]([S:21][CH3:22])[CH:19]=[CH:20][C:15]=2[CH:14]=[CH:13][C:12]2[CH:23]=[CH:24][CH:25]=[CH:26][C:11]1=2
Reactant: CN(C)CCCCl
Reactant: CSc1ccc2c(c1)C(Cl)c1ccccc1C=C2
Agent: [Mg]
Solvent: C1CCOC1
Product: CSc1ccc2c(c1)C(CCCN(C)C)c1ccccc1C=C2

Procedure:
The Grignard reagent is prepared from dimethylaminopropyl chloride (0.2 mole) and magnesium (0.2 g. atom) in 75 ml. of dry tetrahydrofuran following the method described in U.S. Pat. No. 2,996,503. A 15 ml. portion of this solution is cooled in an ice-bath and stirred while a solution of 4.7 g. (0.0172 mole) of 5-chloro-3-methylmercapto-5H-dibenzo[a,d]cycloheptene in 25 ml. of tetrahydrofuran is added dropwise. The usual precautions, such as careful drying of the apparatus and maintaining a nitrogen atmosphere, are observed. After stirring the mixture for 2 hours at room temperature, the bulk of the solvent is distilled at 30°C. under reduced pressure and the residue dissolved in benzene. The solution is cooled in an ice-bath and the excess Grignard reagent hydrolyzed by the dropwise addition of water. The benzene layer is decanted and the gelatinous precipitate washed with four 25 ml. portions of boiling benzene. After washing with water, the combined benzene solutions are extracted with 50 ml. of 0.5 M. citric acid. The acid extract is rendered alkaline with sodium hydroxide and the oily base extracted into benzene. Evaporation of the washed benzene extract under reduced pressure leaves 5-(3-dimethylaminopropyl)-3-methylmercapto-5H-dibenzo[a,d]cycloheptene as the oily residue weighing, typically, 4.2 g. (75%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[C:12]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:16][O:17][C:18]=3[CH3:19])[N:13]=2)[CH:10]=1)=[O:4].COC(C1C=CN2C=C(C3C(C4C=CC=CC=4)=NOC=3C)N=C2C=1)=O>>[CH3:19][C:18]1[O:17][N:16]=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]=1[C:12]1[N:13]=[C:8]2[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][N:9]2[CH:11]=1
Reactant: COC(=O)c1ccc2nc(-c3c(-c4ccccc4)noc3C)cn2c1
Agent: COC(=O)c1ccn2cc(-c3c(-c4ccccc4)noc3C)nc2c1
Product: Cc1onc(-c2ccccc2)c1-c1cn2cc(C(=O)O)ccc2n1
Yield: 88.7 %

Procedure:
As described for Example 11a, 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (2.0 g, 6.0 mmol), instead of 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine-7-carboxylic acid methyl ester, was converted to the title compound (1.7 g, 90%) which was obtained as a yellow solid. MS: m/e=318.4 [M−H]−.
Reaction SMILES: C([NH:9][NH2:10])(=O)C1C=CC=CC=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:23]([O:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][C:33]=1[C:41]([F:44])([F:43])[F:42])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].O.NN>C1COCC1>[CH2:23]([O:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH:9][NH2:10])=[O:37])=[CH:34][C:33]=1[C:41]([F:44])([F:43])[F:42])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: NNC(=O)c1ccccc1
Reactant: CCCCCCCCOc1ccc(C(=O)O)cc1C(F)(F)F
Agent: NN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCOc1ccc(C(=O)NN)cc1C(F)(F)F
Temperature: 20.5 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
A 5 L 3 neck, round bottom flask was inerted and charged with CDI (153 g, 0.94 mol, 1.2 equiv), 4-(Octyloxy)-3-(trifluoromethyl)benzoic acid (D5A) (250 g based on theoretical output of previous step, 0.78 mol), THF (2.5 L) and stirred at 18 to 23° C. for 1 hour. A separate 12 L round bottom flask was inerted and charged with hydrazine monohydrate (235 g, 4.71 mol, 6 equiv) and THF (1.2 L). The contents of the first flask was charged to the second flask over 1 hour. During the addition, the temperature was maintained at T<25° C. Once the addition was complete, the mixture was stirred for 2 hours at 18 to 23° C., at which point TLC indicated the reaction was complete. The mixture was concentrated under vacuum at 35 to 40° C. until approximately 10 to 15% of the original volume was attained. Water (2 L) and brine (2 L) were charged to the mixture which was then extracted with dichloromethane (2×2.5 L). There was a small emulsion during each extraction. The organic phases were combined, washed with brine (500 mL), dried with magnesium sulfate, filtered over Celite, and concentrated to afford the title product (247 g, 94% yield, 96% AUC by HPLC) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5](C(Cl)(Cl)Cl)[O:4][N:3]=1.[CH2:11]1[O:20][C:14]2([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[O:13][CH2:12]1>C(O)C>[CH2:11]1[O:20][C:14]2([CH2:19][CH2:18][N:17]([C:5]3[O:4][N:3]=[C:2]([CH3:1])[N:6]=3)[CH2:16][CH2:15]2)[O:13][CH2:12]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: Cc1noc(C(Cl)(Cl)Cl)n1
Solvent: CCO
Product: Cc1noc(N2CCC3(CC2)OCCO3)n1
Yield: 19.5 %

Procedure:
3-Methyl-5-trichloromethyl-1,2,4-oxadiazole (Moussebois and Eloy, Helv. Chim. Acta 1964, 47, 838) (1 g, 5 mmol) and 4-piperidone ethylene ketal (1.5 g, 10 mmol) in ethanol (20 ml) were heated reflux overnight. The solvent was evaporated and the residue taken up in dichloromethane and filtered. The filtrate was washed with dilute HCl, dried over sodium sulphate and evaporated to leave a pale yellow oil (0.22 g). The acid washing was neutralised with solid sodium bicarbonate and extracted with dichloromethane. Evaporation gave further oil (0.17 g, total 0.39 g), MS (+EI) 225 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[C:22](Cl)=[O:23].C(N(CC)CC)C>C1COCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[C:22]([NH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6])=[O:23]
Reactant: COC(=O)c1ccc(C)c(N)c1
Reactant: COc1ccc(Br)c(C(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C)c(NC(=O)c2cc(OC)ccc2Br)c1
Yield: 73.7 %

Procedure:
Methyl 3-amino-4-methylbenzoate (3.18 g), 2-bromo-5-methoxybenzene-1-carbonyl chloride (4.8 g) and triethylamine (5.4 ml) in THF (45 ml) were stirred at room temperature for 2.5 hour and then concentrated. The residue was dissolved in ethyl acetate and washed with 1N HCl, water, brine, dried (magnesium sulfate) and concentrated. The residue was recrystallised from hot ethyl acetate, washed with ether, and air dried to yield methyl 3-[(2-bromo-5-methoxybenzoyl)amino]-4-methylbenzoate as a white solid (5.36 g); NMR Spectrum: (DMSOd6) 2.39 (s, 3H), 3.83 (s, 3H), 3.87 (s, 3H), 7.02 (m, 1H), 7.23 (d, 1H), 7.42 (d, 1H), 7.60 (d, 1H), 7.75 (m, 1H), 8.12 (s, 1H), 10.06 (s, 1H); Mass Spectrum: M+H+ 377.
Reaction SMILES: [C:1]1([CH2:7][S:8](Cl)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C@H:19]([NH2:21])[CH3:20])=[CH:15][CH:14]=1.O.Cl>N1C=CC=CC=1>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C@H:19]([NH:21][S:8]([CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:10])=[O:9])[CH3:20])=[CH:15][CH:14]=1
Reactant: C[C@@H](N)c1ccc(Br)cc1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: C[C@@H](NS(=O)(=O)Cc1ccccc1)c1ccc(Br)cc1
Temperature: 10 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
Phenylmethanesulfonyl chloride (10.5 g, 55 mmol) was added into a solution of (R)-1-(4-bromophenyl)ethanamine (10 g, 50 mmol) in pyridine (100 mL) drop wise at 0° C. The reaction mixture was stirred at 10° C. for 1 hour. The reaction was poured into water (500 mL), the pH value adjusted to 5 with 6 N aqueous HCl, extracted with EtOAc (100 mL×4). The organic layer was dried over Na2SO4, filtered, and concentrated to provide the title compound (13 g, 73% yield) as pale yellow solid which was used in the next step without further purification.
Reaction SMILES: [CH:1](=[O:5])/[CH:2]=[CH:3]/[CH3:4].[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.[N+](C1C=C([N+]([O-])=O)C=CC=1C(O)=O)([O-])=O.C([C@@H]1N[C@H](C(C)(C)C)N(C)C1=O)C1C=CC=CC=1>C(Cl)Cl.C(O)(C)C>[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C@H:3]([CH3:4])[CH2:2][CH:1]=[O:5])=[CH:7]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: C/C=C/C=O
Agent: CN1C(=O)[C@H](Cc2ccccc2)N[C@@H]1C(C)(C)C
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CC(C)O
Solvent: ClCCl
Product: C[C@H](CC=O)c1c[nH]c2ccccc12
Reaction time: 3 h
Yield: 71.8 %

Procedure:
Prepared according to general procedure from crotonaldehyde (100 μL, 1.25 mmol), indole (146 mg, 1.25 mmol), 2,4-dinitrobenzoic acid (53 mg, 0.25 mmol) and (2S,5S)-5-benzyl-2-tert-butyl-3-methyl-imidazolidin-4-one (62 mg, 0.25 mmol) in CH2Cl2 (2.25 mL) and isopropanol (0.25 mL) at −60° C. for 19 h at which time an additional 30 μL (0.36 mmol) of crotonaldehyde was added. The reaction was allowed to continue stirring for an additional 3 h to provide, after silica gel chromatography (20:80 EtOAc/hexanes), the title compound as a colorless oil (168 mg, 72% yield, 91% ee). IR (film) 3408, 2962, 2875, 2833, 2729, 1716, 1617, 1451, 1420, 1337, 1223, 1099, 1010, 772, 741 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.77 (dd, J=2.1, 2.1 Hz, 1H, CHO), 8.15 (s, 1H, NH), 7.68 (dt, J=0.6, 7.8 Hz, 1H, ArH), 7.35 (dt, J=1.5, 7.8 Hz, 1H, ArH), 7.27-7.15 (m, 2H, ArH), 6.94 (d, J=2.4 Hz, 1H, NCH), 3.68 (dt, J=7.2, 21 Hz, 1H, ArCH), 2.91 (ddd, J=2.4, 6.9, 16.2 Hz, 1H, CH2CO); 2.73 (ddd, J=2.1, 7.2, 16.2 Hz, 1H, CH2CO); 1.47 (d, J=6.9 Hz, 3H, CHCH3); 13C NMR (75 MHz, CDCl3) δ 203.0, 136.5, 126.1, 122.1, 120.7, 120.1, 119.3, 118.9, 111.4, 50.9, 26.0, 21.6; HRMS (CI) exact mass calcd for (C12H13NO) requires m/z 187.0997, found m/z 153.0993. [α]D=−2.2 (c=CHCl3). The enantiomeric ratio was determined by HPLC analysis of the alcohol, obtained by NaBH4 reduction of the aldehyde, using a Chiracel OD-H and OD guard column (10:90 ethanol/hexanes, 1 mL/min); S isomer tr=20.2 min and R isomer tr=17.6 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:12][N:11]([CH3:13])[C:10](=[O:14])[CH2:9]2)=[CH:4][C:3]=1Br.[Cl:16][C:17]1[CH:18]=[C:19]([C@H:23]([NH:26][C:27](=[O:44])[C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][C:29]=2[F:43])[CH2:24][OH:25])[CH:20]=[CH:21][CH:22]=1>>[NH2:1][C:2]1[C:3]([C:31]2[CH:32]=[CH:33][C:28]([C:27]([NH:26][C@@H:23]([C:19]3[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[CH:18]=3)[CH2:24][OH:25])=[O:44])=[C:29]([F:43])[CH:30]=2)=[CH:4][C:5]([CH:8]2[CH2:9][C:10](=[O:14])[N:11]([CH3:13])[CH2:12]2)=[CH:6][N:7]=1
Reactant: CN1CC(c2cnc(N)c(Br)c2)CC1=O
Reactant: CC1(C)OB(c2ccc(C(=O)N[C@H](CO)c3cccc(Cl)c3)c(F)c2)OC1(C)C
Product: CN1CC(c2cnc(N)c(-c3ccc(C(=O)N[C@H](CO)c4cccc(Cl)c4)c(F)c3)c2)CC1=O

Procedure:
Following Step 6 in Scheme 50, using 4-(6-amino-5-bromopyridin-3-yl)-1-methylpyrrolidin-2-one and (S)—N-(1-(3-chlorophenyl)-2-hydroxyethyl)-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide, 4-(2-amino-5-(1-methyl-5-oxopyrrolidin-3-yl)pyridin-3-yl)-N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-2-fluorobenzamide was obtained as a diastereomeric mixture (33.3%). LCMS (m/z): 483.3 (MH+), 0.59 min; 1H NMR (400 MHz, CD3OD) δ ppm 8.79-8.61 (m, 1H) 7.97 (d, J=1.96 Hz, 1H) 7.93-7.82 (m, 2H) 7.48-7.39 (m, 3H) 7.39-7.25 (m, 3H) 5.25-5.14 (m, 1H) 3.95-3.76 (m, 3H) 3.69 (quin, J=8.22 Hz, 1H) 3.50 (dd, J=9.78, 7.43 Hz, 1H) 2.89 (s, 3H) 2.80 (dd, J=16.82, 9.00 Hz, 1H) 2.56 (dd, J=16.82, 8.22 Hz, 1H). The diastereomeric mixture was separated by chiral SFC (ChiralPak 5mic AD column, 4.6×100 (mm), IPA+0.1% DEA=40%, 5 mL/min). The polar diastereomer, 4-(2-amino-5-((R)-1-methyl-5-oxopyrrolidin-3-yl)pyridin-3-yl)-N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-2-fluorobenzamide, was obtained at Rt=1.41 min. LCMS (m/z): 483.3 (MH+), 0.586 min; 1H NMR (400 MHz, CD3OD) δ ppm 7.82 (d, J=1.56 Hz, 1H) 7.74 (t, J=7.83 Hz, 1H) 7.35 (d, J=2.35 Hz, 2H) 7.33-7.15 (m, 5H) 5.09 (t, J=5.87 Hz, 1H) 4.48 (s, 1H)) 3.83-3.63 (m, 3H) 3.50 (quint, J=8.22 Hz, 1H) 3.36 (dd, J=9.39, 7.43 Hz, 1H) 2.78 (s, 3H) 2.67 (dd, J=16.82, 9.00 Hz, 1H) 2.42 (dd, J=16.63, 8.41 Hz, 1H). The less polar diastereomer, 4-(2-amino-5-((S)-1-methyl-5-oxopyrrolidin-3-yl)pyridin-3-yl)-N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-2-fluorobenzamide, was obtained at Rt=2.16 min. LCMS (m/z): 483.3 (MH+), 0.585 min; 1H NMR (400 MHz, CD3OD) δ ppm 7.92 (d, J=2.35 Hz, 1H) 7.84 (t, J=8.02 Hz, 1H) 7.51-7.21 (m, 7H) 5.18 (t, J=5.87 Hz, 1H) 3.94-3.72 (m, 3H) 3.59 (quin, J=8.22 Hz, 1H) 3.50-3.42 (m, 1H) 2.88 (s, 3H) 2.82-2.70 (m, 1H) 2.51 (dd, J=16.82, 8.61 Hz, 1H).
Reaction SMILES: [CH:1]([Si:4](Cl)([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[OH:21])[CH:16]=[O:17].N1C=CN=C1.C(O)(C(F)(F)F)=O.[Cl-].[NH4+]>CN(C=O)C.C(#N)C.CCOC(C)=O.CCCCCC>[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:21][Si:4]([CH:8]([CH3:10])[CH3:9])([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2])[CH:16]=[O:17]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: O=Cc1ccc(O)c(F)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[Si](Oc1ccc(C=O)cc1F)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 111.6 %

Procedure:
Add triisopropylsilyl chloride (74.32 g, 0.3855 mol), followed by DMF (25 mL), to a solution of 3-fluoro-4-hydroxybenzaldehyde (45.01 g, 0.3213 mol) and imidazole (43.74 g, 0.6425 mole) in DMF (313 mL) at 25-29° C. in a steady stream over 2 min. Stir for 1 hr at room temperature till the reaction complete as determined by HPLC (Column: 4.6 mm×25 cm Zorbax RX-C8; eluent: 50/50 0.1% TFA:acetonitrile; flow rate 2 mL/min; detector: 230 nm; temperature: 22° C.; injection: 10 μL). Pour the reaction mixture into saturated aqueous ammonium chloride solution (1 L) and extract with ether (3×1 L). Combine the ether layers, wash with brine (2×750 mL) and dried over sodium sulfate. Filter and concentrate to give a yellow oil (106.3 g). Purify the crude oil on 1 kg Merck silica gel grade 60 with 20:1 heptane/ethyl acetate (90.14 g, 94.6%).
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[S:19][C:18]=2[CH:30]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:1]([C:21]2[C:17]3[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:30][C:18]=3[S:19][C:20]=2[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[O:10])=[CH:3][CH:4]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2c(-c3ccc(OC)cc3)sc3cc(OC)ccc23)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of p-anisoyl chloride (1.54 g, 9.00 mmol) stirring at ambient temperature in anhydrous methylene chloride (100 ml) was added 6-methoxy-2-(4-methoxyphenyl)benzo [b]thiophene (1.62 g, 6.00 mmol). The resulting mixture was cooled to 0° C. and aluminum chloride (1.20 g, 9.00 mmol) was added in small portions over a five minute period. After 1 hour, the reaction mixture was poured into ice water (150 mL) and extracted with methylene chloride. The combined organic extracts were washed with 1N sodium hydroxide, water, brine, dried (magnesium sulfate), filtered, and concentrated. The resulting material was purified by flash chromatography (silica gel, 30% ethyl acetate in hexanes) giving 2.25 g (93%) of a the desired product as a light yellow solid. The product was further purified by recrystallization from acetone/methanol to give 2.11 g (87%): 1H NMR (300 MHz, DMSO-d6) δ 7.64-7.69 (m,3H), 7.29-7.32 (m, 3H). 6.86-7.00 (m, 5H), 3.83 (s, 3H) 3.76 (s, 3H); 13C NMR (75.5 MHz, DMSO-d6) δ 192.0, 163.6, 159.5, 157.4, 141.0, 139.4, 133.2, 131.8, 130.0, 129.6, 125.2, 123.3, 115.0, 114.4, 114.1, 105.1, 55.5, 55.1; IR (CHCl3) 3020, 3015, 2970, 2940, 2840, 1600, 1475, 1253, 1218, 1167; MS (FD) 404 (M+); Anal. Calcd for C24 H20O4S: C, 71.27; H, 4.98; S, 7.93; O, 15.82. Found: C, 71.50; H, 5.00; S, 7.98; O, 15.77.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[C:12]([CH3:17])=[CH:13][NH:14][C:15](=O)[C:6]=3[C:5]=2[CH:4]=1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:15]1[C:6]2[C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][C:9]=3[NH:8][C:7]=2[C:12]([CH3:17])=[CH:13][N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2[nH]c3c(C)c[nH]c(=O)c3c2c1
Product: COc1ccc2[nH]c3c(C)cnc(Cl)c3c2c1

Procedure:
7 g of 1,2-dihydro-8-methoxy-4-methyl-1-oxo-5H-pyrido(4,3-b)indole is heated in 200 ml of phosphorus oxychloride at reflux for 3 days and the excess of oxychloride is evaporated off under reduced pressure. The residue is taken up in 100 ml of boiling water, the mixture is heated to boiling point for 3 minutes and filtered. The filtrate is alkalized cold with ammonia and the precipitate formed is separated, dried, then recrystallized from acetonitrile, giving 5.8 g of yellow micro-crystalls.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([Cl:10])[CH:3]=1.[C-:11]#[N:12].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:11]#[N:12])=[C:4]([Cl:10])[CH:3]=1
Reactant: [C-]#N
Reactant: Clc1cc(Br)ccc1CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: N#CCc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 122.9 %

Procedure:
To a magnetically stirring solution of 4-bromo-1-bromomethyl-2-chloro-benzene (3.59 g, 12.67 mmol) from step 2 above and tetrabutylammonium bromide (0.41 g, 1.27 mmol) in CH2Cl2/H2O 1:1 (60.0 mL), was added a solution of KCN (2.48 g, 38.01 mmol) in H2O (30 mL). The resulting orange mixture was stirred at room temperature for 3 hours. The layers of the resulting reaction mixture were separated and the organic layer was washed with NaHCO3 sat solution (3×50 mL), then dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (30% EtOAc in Hexanes) to yield the intermediate as a clear oil (3.59 g, 100%). 1H NMR (400 MHz, CDCl3): δ 3.79 (s, 2H), 7.37–7.60 (m, 3H).
Reaction SMILES: [C:1]([C@@:5]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:9][C:10]([OH:12])=[O:11])[C:6]([OH:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17](Cl)(=O)CCCCC.BrCC(OC)=O.[Li+].CC([N-]C(C)C)C.IC>C1COCC1.C1COCC1.CCCCCC.C(C1C=CC=CC=1)C>[C:1]([C@@:5]([CH2:13][CH2:14][CH2:15][CH3:16])([CH:9]([CH3:17])[C:10]([OH:12])=[O:11])[C:6]([OH:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[C@](CC(=O)O)(C(=O)O)C(C)(C)C
Reactant: CCCCCC(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: COC(=O)CBr
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[C@@](C(=O)O)(C(C)C(=O)O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To mono t-butyl 2-(R)-(n-butyl)succinic acid (2.0 g, 8.70 mmol; prepared in three steps from hexanoylchloride using the procedure of Example 16, Step A for the synthesis of monomethyl-2-R-butylsuccinic acid, with substitution of t-butyl bromoacetate for methyl bromoacetate) in anhydrous THF (40 mL) at −78° C. was added LDA (2.2 eq., 19.1 mmol, 9.56 ml of a 2.0 M solution in THF/hexane/ethyl-benzene) and the reaction stirred for 1 h. Iodomethane (11.3 mmol, 1.6 g) was then added and the reaction allowed to warm to room temperature over 2 h. The solution was quenched with methanol (ca. 5 mL), evaporated to dryness, and the residue dissolved in ethylacetate (50 mL). This solution was extracted with saturated sodium bicarbonate (3×30 mL), the combined aqueous layers acidified to pH 3 with 1 N HCl, and these were extracted with ethylacetate (3×50 mL). The combined organic layers were dried (Na2SO4), concentrated, and purified by silica gel chromatography (Merck 60; 95:5 DCM/methanol) to afford mono t-butyl 2-(R)-(n-butyl)-3-(RS)-methylsuccinic acid as a light orange oil (1.25 g). The ratio of R/S diastereomers was >6:1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9].[F:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[NH:29][CH3:30]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:19]=[CH:20][C:21]([CH2:24][N:29]([C:28]3[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=3[F:26])[CH3:30])=[CH:22][CH:23]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1Cl
Reactant: CNc1ccccc1F
Product: CN(Cc1ccc(-c2nccnc2NS(=O)(=O)c2ccccc2Cl)cc1)c1ccccc1F
Yield: 79 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from 2-chloro-N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}benzene sulfonamide (Intermediate 8), and 2-fluoro-N-methyl-aniline, the title compound was isolated as a yellow solid in 79% yield (99% purity by HPLC).