Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:6][NH:7][C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.C1OCCOCCOCCOCCOC1.[F:41][C:42]1[CH:43]=[C:44]([S:48](Cl)(=[O:50])=[O:49])[CH:45]=[CH:46][CH:47]=1>O1CCCC1.O>[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:6][N:7]([S:48]([C:44]2[CH:45]=[CH:46][CH:47]=[C:42]([F:41])[CH:43]=2)(=[O:50])=[O:49])[C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cn(S(=O)(=O)c2cccc(F)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 109.6 %

Procedure:
To a suspension of sodium hydride (60% in oil, 60 mg) in tetrahydrofuran (5 mL) was added a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (323 mg) in tetrahydrofuran (5 mL) at 0° C., 15-crown-5 (330 mg) and 3-fluorobenzenesulfonyl chloride (292 mg) were added at the same temperature. The mixture was stirred at room temperature for 30 min, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous is sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:1→3:1) to give the title compound as a colorless oil (yield 527 mg, quantitative).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=O)=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[NH:12][C:11]2=[O:17])=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C1Cc2c(cccc2-c2cccc(Br)c2)N1
Reactant: Cc1cc(C(=O)NCCN2CCCC2)c(C=O)[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)NCCN2CCCC2)c(C=C2C(=O)Nc3cccc(-c4cccc(Br)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 71.6 %

Procedure:
To a solution of 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (64.8 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2-[4-(3-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (93 mg, 72%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)=S.CI>C(O)CCCC>[CH:15]1([C:12]2[CH:13]=[CH:14][C:9]([N:8]=[C:6]3[NH:5][CH2:4][CH2:3][CH2:2][NH:1]3)=[CH:10][CH:11]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NCCCNC(=S)Nc1ccc(C2CCCCC2)cc1
Solvent: CCCCCO
Solvent: CI
Product: c1cc(C2CCCCC2)ccc1N=C1NCCCN1

Procedure:
A solution of 2.9 g of N-(3-aminopropyl)-N'-(4-cyclohexylphenyl)thiourea and 0.65 ml of methyliodide in 20 ml of amyl alcohol is slowly heated to the boiling point and then refluxed for 1 hour. After distilling off the solvent, the residue is taken up in methylene chloride and washed with dilute alkaline solution and water. The methylene chloride is distilled off and the crude 2-(4-cyclohexylphenyl)imino-hexahydropyrimidine is recrystallised from acetonitrile. The purified product has a melting point of 179°-181° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([CH3:18])[C:10](=[O:19])[NH:9]2)=[CH:4][CH:3]=1.[Cl:20][CH2:21][C:22](Cl)=[O:23].C(N(CC)CC)C>C(O)(=O)C>[Cl:20][CH2:21][C:22]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([CH3:18])[C:10](=[O:19])[NH:9]2)=[CH:6][CH:7]=1)=[O:23]
Reactant: O=C(Cl)CCl
Reactant: CC1C(=O)NC(c2ccc(N)cc2)c2ccccc21
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CC1C(=O)NC(c2ccc(NC(=O)CCl)cc2)c2ccccc21

Procedure:
9.75 g. (0.0386 moles) of 1-(4'-aminophenyl)-1,4-dihydro-4-methyl-3(2H)-isoquinolinone are reacted, in 80 ml. of glacial acetic acid, with 5.64 g. (0.05 moles) of chloroacetyl chloride, in the presence of 5.06 g. (0.05 moles) of triethylamine. The reaction conditions are the same as described in Example 1. The crude product is recrystallized from butanol to yield 4.9 g. of the title compound; m.p. 238°-239°C.
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH3:4][C:5]([CH3:12])=[CH:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10]>CCOCC>[CH3:4][C:5]([CH3:12])=[CH:6][CH2:7][CH2:8][C:9]([O:11][CH3:3])=[O:10]
Reactant: C=[N+]=[N-]
Reactant: CC(C)=CCCC(=O)O
Solvent: CCOCC
Product: COC(=O)CCC=C(C)C
Temperature: 0 °C

Procedure:
Freshly prepared diazomethane in ether was added to an ice-cooled solution of 5-methyl-4-hexenoic acid (4.5 g, 35.16 mmol) in ether (10 mL) until the solution became slightly yellow in color. The solvent was then evaporated under vacuum to afford the title product as a colorless liquid in near quantitative yield (4.90 g). This product was used in the next reaction step without further purification. 1H NMR (CDCl3) δ 1.62 & 1.68 [2s, 6H, C(CH3)2], 2.30 [m, 4H, (CH2)2], 3.69 (s, 3H, COOCH3) and 5.07 (t, 1H, CH).
Reaction SMILES: CN(C)CCC[N:6]1[CH2:11][CH2:10][N:9]([N:12]2[NH:16][CH:15]=[C:14]([C:17]3[N:18]([CH3:25])[C:19]([N+:22]([O-:24])=[O:23])=[CH:20][N:21]=3)[S:13]2)[CH2:8][CH2:7]1.[S:27]1[CH:31]=[CH:30][N:29]=[C:28]1N1CCNCC1.CN(C)CCCN1CCNCC1>>[S:27]1[CH:31]=[CH:30][N:29]=[C:28]1[N:6]1[CH2:11][CH2:10][N:9]([N:12]2[NH:16][CH:15]=[C:14]([C:17]3[N:18]([CH3:25])[C:19]([N+:22]([O-:24])=[O:23])=[CH:20][N:21]=3)[S:13]2)[CH2:8][CH2:7]1
Reactant: c1csc(N2CCNCC2)n1
Reactant: CN(C)CCCN1CCN(N2NC=C(c3ncc([N+](=O)[O-])n3C)S2)CC1
Agent: CN(C)CCCN1CCNCC1
Product: Cn1c([N+](=O)[O-])cnc1C1=CNN(N2CCN(c3nccs3)CC2)S1

Procedure:
The preparation of the subject compound is carried out essentially as described for the 2-[4-(3-dimethylaminopropyl)-1-piperazinyl] derivative (Example 35), an equivalent of 1-(2-thiazolyl)piperazine replacing the 1-(3-dimethylaminopropyl)piperazine. After recrystallization from 2-methoxyethanol, the pure compound melts at 297°-300° C.
Reaction SMILES: [OH:1][CH2:2][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[C:11](Cl)(=[O:20])[C:12]1[C:13]([O:18][CH3:19])=[CH:14][CH:15]=[CH:16][CH:17]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]([O:1][CH2:2][P:3]([O:7][CH2:8][CH3:9])([O:4][CH2:5][CH3:6])=[O:10])=[O:20]
Reactant: COc1ccccc1C(=O)Cl
Reactant: CCOP(=O)(CO)OCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOP(=O)(COC(=O)c1ccccc1OC)OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of diethyl (hydroxymethyl)phosphonate (1.2 mmol), 2-anisoyl chloride (1 mmol) and pyridine (2 mmol) in 5 mL CH2Cl2 were stirred at rt for 4 h. Extraction and chromatography provided diethylphosphonomethyl 2-methoxybenzoate as an oil.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:27]=[CH:28][C:29]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[C:21]([NH:23][CH:24]1[CH2:26][CH2:25]1)=[O:22].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[Cl:17][C:18]1[CH:19]=[C:20]([CH:27]=[CH:28][C:29]=1[N:30]1[CH2:31][CH2:32][N:33]([CH2:2][C:3]2[CH:12]=[N:11][C:10]3[N:9]4[CH2:13][CH2:14][CH2:15][C@H:8]4[C:7](=[O:16])[NH:6][C:5]=3[CH:4]=2)[CH2:34][CH2:35]1)[C:21]([NH:23][CH:24]1[CH2:26][CH2:25]1)=[O:22]
Reactant: O=C(NC1CC1)c1ccc(N2CCNCC2)c(Cl)c1
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: O=C(NC1CC1)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)c(Cl)c1
Temperature: 105 °C
Yield: 54.8 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (100 mg, 0.456 mmol), 3-chloro-N-cyclopropyl-4-(piperazin-1-yl)benzamide (128 mg, 0.456 mmol), (cyanomethyl)trimethylphosphonium iodide (166 mg, 0.684 mmol) and N,N-diisopropylethylamine (0.398 ml, 2.281 mmol) were suspended in propiononitrile (Volume: 1.370 ml) and heated in a closed vial at 90-120° C. for 4 h. The reaction mixture became a dark brown solution. It was cooled to room temperature, concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC (basic, 25-95% ACN in water, basic). The fractions were concentrated in vacuo and the resulting solid was recrystallized from water-MeOH (2:1, 15 mL) and dried in vacuum to afford (S)-3-chloro-N-cyclopropyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (120.4 mg, 0.250 mmol, 54.9% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.50-0.60 (m, 2 H) 0.61-0.72 (m, 2 H) 1.84-2.01 (m, 3 H) 2.12-2.23 (m, 1 H) 2.51-2.57 (m, 4 H) 2.77-2.86 (m, 1 H) 3.02 (br. s., 4 H) 3.35-3.46 (m, 3 H) 3.54-3.64 (m, 1 H) 3.95-4.03 (m, 1 H) 6.98 (d, J=1.77 Hz, 1 H) 7.16 (d, J=8.34 Hz, 1 H) 7.63 (d, J=1.77 Hz, 1 H) 7.75 (dd, J=8.34, 2.02 Hz, 1 H) 7.85 (d, J=2.02 Hz, 1 H) 8.39 (d, J=4.04 Hz, 1 H) 10.45 (s, 1 H). [M+H] calc'd for C25H29ClN6O2, 481; found, 481.
Reaction SMILES: Br[CH2:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:11]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>CS(C)=O>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:23]=[CH:24][C:3]([CH2:2][N:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)=[CH:4][CH:5]=2)=[CH:11][C:12]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CBr)cc1
Reactant: CN1CCNCC1
Solvent: CS(C)=O
Product: CN1CCN(Cc2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cc2)CC1

Procedure:
4-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide (85 mg) was dissolved in DMSO (1 mL) and stirred for 1 h with methylpiperazine. The reaction mixture was concentrated, and the crude residue was purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide. MS (Q1) 421.3 (M)+.
Reaction SMILES: [CH3:1][Si:2]([CH3:12])([CH3:11])[C:3]#[C:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].[CH2:13](O)[CH3:14].N1C=CC=CC=1>O1CCCC1>[CH3:12][Si:2]([CH3:1])([CH3:11])[C:3]#[C:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:13][CH3:14])=[O:9]
Reactant: C[Si](C)(C)C#CCCCC(=O)O
Reactant: CCO
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)CCCC#C[Si](C)(C)C
Reaction time: 1 h

Procedure:
To a solution of 5.3 gm of 1,1-carbonyldiimidazole in 80 ml of dry tetrahydrofuran under argon, was added a solution of 5.03 gm of 6-trimethylsilyl-5-hexynoic acid in 15 ml of dry tetrahydrofuran. The mixture was stirred for 1 hour. Absolute ethanol (80 ml) and pyridine (1 ml) were then added, and the resulting mixture was stirred at room temperature for 48 hours. The solvent was evaporated and the residual oil was extracted with ether and 1.5% hydrochloric acid. The ethereal layer, which was washed with water and then dried, was evaporated to an oil. This material was purified by distillation, b.p. 70°-75° C. (0.6 mm Hg); IR: 2170, 1735 cm-1.
Reaction SMILES: C([N:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:6]([OH:14])=[N:5]1)(=O)C.[C:15](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CN(C=O)C>[CH3:15][O:14][C:6]1[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:8][NH:4][N:5]=1
Reactant: CCOC(=O)c1cn(C(C)=O)nc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: CCOC(=O)c1c[nH]nc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of ethyl 1-acetyl-3-hydroxy-1H-pyrazole-4-carboxylate (2.1 g, 10.6 mmol) and potassium carbonate (1.5 g, 10.6 mmol) in 45 mL of DMF is stirred at RT for 30 minutes. Dimethyl sulfate (1.0 mL, 10.6 mmol) in 25 mL of DMF is then added dropwise over 10 min, and the resulting reaction mixture is heated to 70° C. for 4 h. The solvent is evaporated in vacuo, and the residue is dissolved in water and extracted with CH2Cl2 (2×30 mL). The combined organic extracts are dried (Na2SO4), filtered, and evaporated in vacuo to give a yellow/brown oil. Purification by silica gel column chromatography (gradient from 50% EtOAc/hexane to 80% EtOAc/hexane) affords the title compound as a clear, viscous oil which slowly solidifies on standing.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH2:12][C:13](Cl)=[N:14][OH:15])[CH:9]=[CH:10][CH:11]=2)[CH2:3][CH2:2]1.[C:17]([C:19]1[C:20]([NH2:26])=[N:21][C:22]([NH2:25])=[CH:23][CH:24]=1)#[CH:18].C(N(CC)CC)C>O1CCCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=2)[CH2:12][C:13]2[CH:18]=[C:17]([C:19]3[C:20]([NH2:26])=[N:21][C:22]([NH2:25])=[CH:23][CH:24]=3)[O:15][N:14]=2)[CH2:3][CH2:2]1
Reactant: ON=C(Cl)Cc1cccc(OCC2CC2)c1
Reactant: C#Cc1ccc(N)nc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3cccc(OCC4CC4)c3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.2 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (3-cyclopropylmethoxy-phenyl)-acetohydroximoyl chloride (150 mg, 0.626 mmol) described in Manufacturing Example 66-1-4 and 3-ethynyl-pyridin-2,6-diamine (53.2 mg, 0.399 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (218 μL, 1.57 mmol). This mixture was stirred for 4 hours at room temperature. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:1˜ethyl acetate) to obtain the title compound (117 mg, 56%).
Reaction SMILES: I[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1.[CH3:15][Mg]Br>CCOCC.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:15][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1
Reactant: C[Mg]Br
Reactant: Fc1ccc(Cc2ccsc2I)cc1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Solvent: CCOCC
Product: Cc1sccc1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 48 %

Procedure:
The 2-iodo-3-(4-fluorophenylmethyl)thiophene prepared in step 1 was taken up in ether and methylmagnesium bromide (3.0M in ether, 2.42 mL, 7.26 mmol) and dichloro [1,3-bis(diphenylphosphino)propane]nickel(II) (164 mg, 0.302 mmol) were added and the reaction mixture was stirred for 17 hours at ambient temperature. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with ethyl acetate. The organic phase was washed with 1N aqueous H3PO4, saturated aqueous NaHCO3, saturated aqueous Na2S2O3, and brine, dried over MgSO4, filtered, and concentrated in vacuo. Chromatography on silica gel (10% ethyl acetate/hexane) gave 2-methyl-3-(4-fluorophenylmethyl)thiophene (602 mg, 48%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][NH:6][C:7]1[N:12]=[CH:11][C:10]([F:13])=[CH:9][N:8]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[Cl:30][C:31]1[C:32]([F:42])=[CH:33][C:34]([F:41])=[C:35]([S:37](Cl)(=[O:39])=[O:38])[CH:36]=1>O1CCCC1>[Cl:30][C:31]1[C:32]([F:42])=[CH:33][C:34]([F:41])=[C:35]([S:37]([N:6]([CH2:5][C:4]2[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:3]=2[O:2][CH3:1])[C:7]2[N:12]=[CH:11][C:10]([F:13])=[CH:9][N:8]=2)(=[O:39])=[O:38])[CH:36]=1
Reactant: COc1ccc(CNc2ncc(F)cn2)c(OC)c1
Reactant: O=S(=O)(Cl)c1cc(Cl)c(F)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncc(F)cn2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 26.5 %

Procedure:
N-(2,4-Dimethoxybenzyl)-5-fluoropyrimidin-2-amine (Preparation 18, 4.00 g, 15.2 mmol) was dissolved in tetrahydrofuran (40 mL) and cooled to −78° C. A 1.0 M solution of lithium hexamethyldisilazide in tetrahydrofuran (17 mL, 17 mmol) was added drop-wise to the solution and the solution was stirred for 30 minutes at −78° C. A solution of 5-chloro-2,4-difluorobenzenesulfonyl chloride (3.42 g, 13.8 mmol) in tetrahydrofuran was added drop-wise to the reaction mixture and it was stirred at −78° C. for 1 h then allowed to warm gradually to ambient temperature. The reaction mixture was stirred for 16 hours then quenched with saturated aqueous ammonium chloride (50 mL). The aqueous phase was extracted with ethyl acetate (×2). The combined organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was adsorbed onto diatomaceous earth and purified by silica gel column chromatography (hexanes to dichloromethane gradient elution) to afford the title compound as a white solid (1.73 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7]/[C:8](=[CH:25]\[C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:29])[F:30])=[CH:28][CH:27]=3)/[C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: COc1cc2c(cc1N1CCOCC1)CCC2=O
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1ccc(C(F)(F)F)cc1)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 13 (100 mg, 04048 mmol) in toluene 10 mL was added 4-(trifluoromethyl)benzaldehyde 84 (70.4 mg, 0.404 mmol). PTSA (153.9 mg, 0.809 mmol) was added to the reaction mass, then stirred at 120° C. for 6 h. The reaction mass was diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude 85 which was purified through flash chromatography by using 100-200 mesh silica gel. The compound 85 was eluted at 28% ethyl acetate in hexane to afford yellow coloured solid compound (E)-6-methoxy-5-morpholino-2-(4-(trifluoromethyl)benzylidene)-2,3-dihydro-1H-inden-1-one 85.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([C:9](=[O:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.[Br:14]Br.C(C1C=CC=CC=1)(=O)C>C(O)(=O)C>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[C:9](=[O:11])[CH2:10][Br:14]
Reactant: CC(=O)c1cccc(C(F)(F)F)c1
Reactant: BrBr
Solvent: CC(=O)c1ccccc1
Solvent: CC(=O)O
Product: O=C(CBr)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
m-(Trifluoromethyl)acetophenone (10 g, 0.054 mol) was dissolved in 100 ml acetic acid. Bromine (9.1 g, 0.057 mol) was separately dissolved in 20 ml acetic acid and added portionwise over 0.5 hours to the acetophenone solution. The mixture was stirred for 15 hours, poured onto 150 g ice and extracted with 300 ml ether. The organic layer was washed 1×300 ml H2O, 1×300 ml saturated NaCl, dried (MgSO4) and evaporated to yield title product as a pale yellow liquid.
Reaction SMILES: [C:1]([N:5]1[C:10]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[O:9][C:8]2[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=2[C:6]1=[O:20])(=[O:4])[CH2:2][CH3:3].C([Mg]Cl)CCC.C(O[C@H:31]1[NH:34][C:33](=[O:35])[C@@H:32]1[C@H:36]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[CH3:37])(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C(OCC)(=O)C>[Si:39]([O:38][C@@H:36]([C@@H:32]1[C@@H:31]([C@@H:2]([CH3:3])[C:1]([N:5]2[C:10]3([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[O:9][C:8]3[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=3[C:6]2=[O:20])=[O:4])[NH:34][C:33]1=[O:35])[CH3:37])([C:42]([CH3:43])([CH3:44])[CH3:45])([CH3:40])[CH3:41]
Reactant: CCC(=O)N1C(=O)c2ccccc2OC12CCCCC2
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: CCCC[Mg]Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)N1C(=O)c2ccccc2OC12CCCCC2
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 53 %

Procedure:
Under a nitrogen atmosphere, 273 mg (1.0 mmol) of 3-propionyl-spiro[2,3-dihydro-4H-1,3-benzoxazine-2,1′-cyclohexan]-4-one was charged in a 30-ml three-necked flask to dissolve it in 2 ml of tetrahydrofuran. To the resulting solution, 2.44 ml (2.2 mmol) of a tetrahydrofuran solution (0.9M) of n-butylmagnesium chloride was slowly added dropwise at room temperature. The resulting mixture was reacted for 25 minutes under the same conditions. After cooling to 5° C., 2 ml of a tetrahydrofuran solution of 287 mg (1.0 mmol) of (3R,4R)-4-acetoxy-3-[(R)-1-tert-butyldimethylsilyloxyethyl]azetidin-2-one was added at the same temperature. The resulting mixture was stirred for 15 minutes, added with 10 ml of ethyl acetate and then added dropwise with 2 ml of a 10% aqueous solution of citric acid. After separation, the organic layer was washed with 2 ml of a saturated aqueous solution of sodium bicarbonate and 2 ml of a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by column chromatography, whereby 263 mg (0.53 mmol) of a condensation product was obtained (yield: 53%, β:α=92:8).
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1([O:17]C(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH3:25][N:26]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45][C:44]([C:47]#[N:48])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1)[S:27]([CH2:30][C:31](O)=[O:32])(=[O:29])=[O:28].C(N(C(C)C)C(C)C)C.Cl.NO>CN(C)C=O>[OH:17][NH:8][C:31](=[O:32])[CH2:30][S:27]([N:26]([CH3:25])[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:42]=[CH:43][C:44]([C:47]#[N:48])=[CH:45][CH:46]=2)=[CH:37][CH:36]=1)(=[O:28])=[O:29]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CN(Cc1ccc(-c2ccc(C#N)cc2)cc1)S(=O)(=O)CC(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1ccc(-c2ccc(C#N)cc2)cc1)S(=O)(=O)CC(=O)NO
Reaction time: 16 h
Yield: 8.1 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU 263 mg, 0.72 mmol) was added to a solution of 2-({methyl[(4'-cyanobiphenyl-4-yl)methyl]amino}sulfonyl)acetic acid (185 mg, 0.48 mmol) and N-ethyl-N,N-diisopropylamine (0.08 ml, 0.48 mmol) in anhydrous dimethylformamide (3 ml) at ambient temperature under an atmosphere of nitrogen. After stirring for 20 minutes a solution of hydroxylamine hydrochloride (131 mg, 1.92 mmol) and N-ethyl-NN-diisopropylamine (0.33 ml, 1.92 mmol) in anhydrous dimethylformamide (1 ml) was added and the solution was stirred for a further 16 hours. The mixture was partitioned between aqueous phosphate buffer (at pH 7) and ethyl acetate. The organic layer was washed with water, dried (MgSO4) and the solvent evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (dichloromethane/methanol/aqueous ammonia 90:10:1 as eluent) to give the title compound as a colourless solid (14 mg).