Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:8]=[C:9]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=2)[NH2:10])[CH:6]=1.[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([C:37]2[CH:42]=[CH:41][C:40]([CH2:43][C:44](O)=[O:45])=[C:39]([F:47])[CH:38]=2)[CH:24]=[N:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[CH3:19].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.O>N1C=CC=CC=1>[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([C:37]2[CH:42]=[CH:41][C:40]([CH2:43][C:44]([NH:10][C:9]3[CH:11]=[C:12]([C:14]([F:17])([F:15])[F:16])[CH:13]=[C:7]([N:5]4[CH:6]=[C:2]([CH3:1])[CH:3]=[N:4]4)[CH:8]=3)=[O:45])=[C:39]([F:47])[CH:38]=2)[CH:24]=[N:25][C:26]=1[O:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)[CH3:19]
Reactant: CCOc1cc(-c2ccc(CC(=O)O)c(F)c2)cnc1OCc1ccc(OC)cc1
Reactant: Cc1cnn(-c2cc(N)cc(C(F)(F)F)c2)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: O
Solvent: c1ccncc1
Product: CCOc1cc(-c2ccc(CC(=O)Nc3cc(-n4cc(C)cn4)cc(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Temperature: 16 °C
Reaction time: 1 h
Yield: 39.7 %

Procedure:
To a solution of 3-(4-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)aniline (160 mg, 0.663 mmol) and 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (274 mg, 0.663 mmol) in pyridine (8 mL) was added T3P® (2111 mg, 3.32 mmol) in portions. Then the mixture was stirred at 16° C. for 1 h. LCMS analysis showed the starting material disappeared. 10 mL of water was added dropwise into the reaction solution and then the mixture was filtered. The filter cake was washed with water (20 mL) and dried in vacuo to afford pure product 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(4-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)acetamide (200 mg, 0.263 mmol, 39.7% yield). 1H NMR (400 MHz, CD3OD): δ 8.24 (s, 1H), 8.06 (s, 1H), 7.96 (d, J=2.0 Hz, 1H), 7.87 (s, 1H), 7.74 (s, 1H), 7.57 (s, 1H), 7.48-7.42 (m, 3H), 7.40 (d, J=9.0 Hz, 3H), 6.91 (d, J=8.8 Hz, 2H), 5.37 (s, 2H), 4.18-4.13 (m, 2H), 3.86 (s, 2H), 3.79 (s, 3H), 2.16 (s, 3H), 1.43 (t, J=7.0 Hz, 3H). ES-LCMS: m/z 635.1 (M+H).
Reaction SMILES: [Cl: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.[CH2:18]([N:20]([CH2:34][CH3:35])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[NH:27][C:28]([CH:32]=O)=[C:29]([CH3:31])[CH:30]=1)=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:34]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[NH:27][C:28]([CH:32]=[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]([Cl:1])[CH:3]=3)[NH:12][C:11]2=[O:17])=[C:29]([CH3:31])[CH:30]=1)=[O:25])[CH3:35]
Reactant: CCN(CC)CCNC(=O)c1cc(C)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2cccc(Cl)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1cc(C)c(C=C2C(=O)Nc3cccc(-c4cccc(Cl)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 54.5 %

Procedure:
To a solution of 4-(3-Chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The reaction solution was evaporated, and purified on a silica gel column eluting with MeOH—CH2Cl2 5:95 to provide pure product 5-[4-(3-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (65 mg, 54%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[N:32]1([C:38]2[CH:43]=[N:42][CH:41]=[CH:40][N:39]=2)[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:31])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([N:35]4[CH2:36][CH2:37][N:32]([C:38]5[CH:43]=[N:42][CH:41]=[CH:40][N:39]=5)[CH2:33][CH2:34]4)=[O:24])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2
Reactant: c1cnc(N2CCNCC2)cn1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCN(c2cnccn2)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2-(1-piperazinyl)pyrazine as in General Procedure 10 to give the title compound. LCMS: m/z=593.98 (M+H+); retention time=0.79 minutes.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[O:7])=[C:4]([CH3:18])[CH:3]=1.[CH:19]([O-])=[O:20].[Na+].[C]=O>CN(C)C=O.O>[CH:19]([C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[O:7])=[C:4]([CH3:18])[CH:3]=1)=[O:20]
Reactant: Cc1cc(Br)ccc1C(=O)NCc1ccccn1
Reactant: O=C[O-]
Agent: [C]=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C=O)ccc1C(=O)NCc1ccccn1
Temperature: 25 °C
Yield: 30 %

Procedure:
In a solution of 2.0 g of 4-bromo-2-methyl-N-(2-pyridylmethyl)benzoic acid amide in 20 ml of N,N-dimethylformamide in an autoclave, 0.67 g of sodium formate and 0.10 g of dichlorobis(triphenylphosphine) palladium (II) were added, and stirred under 1.05 MPa carbon monoxide atmosphere at 110° C. for 3 hours. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, and poured in 100 ml of water, and extracted with ethyl acetate (50 ml×2). The organic phases together were dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (9:1), and 0.50 g of the aimed product was obtained as pale yellow crystal.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([C:13]1[N:18]=[C:17]([O:19]C)[CH:16]=[C:15]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[C:35]5[C:30](=[N:31][CH:32]=[CH:33][CH:34]=5)[NH:29][C:28]4=[O:36])[CH2:23][CH2:22]3)[CH:14]=1)=[O:12])[CH2:6][CH2:5]2.Cl.N1C=CC=CC=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([C:13]1[NH:18][C:17](=[O:19])[CH:16]=[C:15]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[C:35]5[C:30](=[N:31][CH:32]=[CH:33][CH:34]=5)[NH:29][C:28]4=[O:36])[CH2:23][CH2:22]3)[CH:14]=1)=[O:12])[CH2:6][CH2:5]2
Reactant: COc1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)cc(C(=O)N2CCc3cc(F)ccc32)n1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)cc(=O)[nH]1)N1CCc2cc(F)ccc21
Reaction time: 0.03 h

Procedure:
A well stirred mixture of 40 mg (0.082 mmol) 1-[6′-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-2′-methoxy-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-yl]-1,3-dihydro-imidazo-[4,5-b]pyridin-2-one and 0.020 g (1.7 mmol) pyridine hydrochloride was kept in a melt for 2 min using a hot air blower. After the reaction had cooled the mixture was dissolved in DMF and purified by preparative HPLC. The product-containing fractions were combined and lyophilised.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1>>[OH:4][CH2:3][CH2:2][N:1]([CH2:14][C:13]1[CH:16]=[CH:17][C:10]([O:9][CH3:8])=[CH:11][CH:12]=1)[CH2:5][CH2:6][OH:7]
Reactant: OCCNCCO
Reactant: COc1ccc(CCl)cc1
Product: COc1ccc(CN(CCO)CCO)cc1

Procedure:
2-[(2-Hydroxy-ethyl)-(4-methoxy-benzyl)-amino]-ethanol was prepared according to the general method as outlined in Example 1 (Step 4). Starting from diethanolamine (10.5 g, 100 mmol), and 4-methoxy benzyl chloride (15.6 g, 100 mmol). Yield 21 g, (98%); yellow oil; MS: 226 (M+H)+.
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[C:13]([Cl:14])=[C:12]([O:15]C)[C:11]([O:17]C)=[CH:10][C:7]=1[CH:8]=[O:9].O>C(Cl)Cl>[Cl:5][C:6]1[C:13]([Cl:14])=[C:12]([OH:15])[C:11]([OH:17])=[CH:10][C:7]=1[CH:8]=[O:9]
Reactant: COc1cc(C=O)c(Cl)c(Cl)c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=Cc1cc(O)c(O)c(Cl)c1Cl
Reaction time: 1 h
Yield: 91.8 %

Procedure:
A solution of 2.51 g of boron tribromide in methylene chloride is added to dropwise to a solution of 0.47 g of 2,3-dichloro-4,5-dimethoxybenzaldehyde in methylene chloride at -50° to -60° C. and the mixture is stirred at -50° C. to room temperature for 1 hour. The reaction mixture is poured into water and the aqueous mixture is extracted with ethyl acetate. The extract is evaporated to remove solvent. Methanol and 10% hydrochloric acid are added to the residue and the mixture is stirred at room temperature for 1 hour. To the reaction mixture are added water, and the mixture is extracted with ethyl acetate. The extract is washed with water, dried and evaporated to remove solvent. The residue is washed with n-hexane and dried to give 0.38 g of 2,3-dichloro-4,5-dihydroxybenzaldehyde.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[C:6]([I:8])[N:7]=1)[CH3:2].[F:12][C:13]1[C:18]([F:19])=[CH:17][C:16]([F:20])=[CH:15][C:14]=1[CH2:21][CH2:22][CH:23]=O>>[CH2:1]([C:3]1[N:4]2[CH2:9][CH2:10][NH:11][CH:23]([CH2:22][CH2:21][C:14]3[CH:15]=[C:16]([F:20])[CH:17]=[C:18]([F:19])[C:13]=3[F:12])[C:5]2=[C:6]([I:8])[N:7]=1)[CH3:2]
Reactant: CCc1nc(I)cn1CCN
Reactant: O=CCCc1cc(F)cc(F)c1F
Product: CCc1nc(I)c2n1CCNC2CCc1cc(F)cc(F)c1F

Procedure:
According to the general procedure (GP10), microwave-assisted Pictet-Spengler reaction (60 W; 140° C.; 6.5 bars; 10 min.) between 2-(2-ethyl-4-iodo-imidazol-1-yl)-ethylamine (2.331 mmol) and 3-(2,3,5-trifluoro-phenyl)-propionaldehyde (0.600 g; 3.189 mmol) afforded 3-ethyl-1-iodo-8-[2-(2,3,5-trifluoro-phenyl)-ethyl]-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine. LC-MS: tR=0.69 min.; [M+H]+=436.23 g/mol.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][CH:14]([O:17][CH3:18])[CH2:13][CH2:12]3)[C:8]2=O)=[CH:4][CH:3]=1.[CH3:19][Si:20]([CH3:28])([CH3:27])[CH2:21][CH2:22][S:23]([NH2:26])(=[O:25])=[O:24].CCN(CC)CC>C(Cl)CCl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][CH:3]=1)[CH2:6][C:7]1([CH2:16][CH2:15][CH:14]([O:17][CH3:18])[CH2:13][CH2:12]1)[C:8]2=[N:26][S:23]([CH2:22][CH2:21][Si:20]([CH3:28])([CH3:27])[CH3:19])(=[O:25])=[O:24]
Reactant: COC1CCC2(CC1)Cc1ccc(Br)cc1C2=O
Reactant: C[Si](C)(C)CCS(N)(=O)=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC1CCC2(CC1)Cc1ccc(Br)cc1C2=NS(=O)(=O)CC[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91 %

Procedure:
To a mixture of 6′-bromo-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one (3) (0.9822 g, 3.18 mmol, 1.0 equiv) and 2-(trimethylsilyl)ethanesulfonamide) (SESNH2)(0.6338 g, 3.50 mmol, 1.1 equiv) in C1CH2CH2Cl (10 mL), cooled to 0° C., were successively added Et3N (0.9 mL, 6.46 mmol, 2.0 equiv) and TiCl4 (1.0 M in CH2Cl2, 3.4 mL, 3.4 mmol, 1.1 equiv). After 10 min, the ice bath was removed. The reaction mixture was stirred at room temperature for 3 h and then heated at 110° C. for 42 h. The reaction mixture was cooled to room temperature, quenched with water, and extracted with CH2Cl2. The combined organic phase was dried (Na2SO4) and evaporated. The residue was purified by chromatography on silica gel eluted with hexanes/ethyl acetate to afford 1.3685 g (91%) of N-(5′-bromo-4-methoxyspiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-(trimethylsilyl)ethanesulfonamide (8) as a solid. LC-MS tR=2.31 min in 3 min chromatography, m/z 472, 474 (MH+); 1H NMR (400 MHz, CDCl3) δ 8.78 (br s, 1H), 7.67 (dd, J=8.2, 1.8 Hz, 1H), 7.29 (d, J=8.2 Hz, 1H), 3.39 (s, 3H), 3.29-3.21 (m, 3H), 2.98 (s, 2H), 2.16-2.12 (m, 2H), 1.80-1.76 (m, 2H), 1.62-1.57 (m, 2H), 1.42-1.33 (m, 2H), 1.21-1.17 (m, 2H), 0.10 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 189.97, 151.30, 137.91, 133.35, 127.50, 121.43, 78.10, 55.80, 51.79, 51.39, 39.55, 33.97, 28.60, 9.98, −1.93.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]#[N:28]>CC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([N:14]([CH2:26][C:27]#[N:28])[S:15]([CH3:18])(=[O:16])=[O:17])=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CS(=O)(=O)Nc1ccc(-c2ccnc(Cl)n2)cc1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CS(=O)(=O)N(CC#N)c1ccc(-c2ccnc(Cl)n2)cc1
Yield: 89 %

Procedure:
N-(4-(2-chloropyrimidin-4-yl)phenyl)methanesulfonamide (750 mg 2.64 mmol) and potassium carbonate (730 mg, 2 eq.) were placed in a round bottomed flask and suspended in acetone (50 mL). The mixture was stirred for several minutes before adding bromoacetonitrile (368 μL, 2 eq.). The reaction mixture was stirred at room temperature for 48 h. The crude reaction mixture was concentrated in vacuo and the residue taken up in ethyl acetate (200 mL) and washed with water (2×100 mL), brine (100 mL) and then dried (sodium sulfate). The organic phase was concentrated in vacuo to give N-(4-(2-chloropyrimidin-4-yl)phenyl)-N-(cyanomethyl)methanesulfonamide (762 mg, 89% yield) as a fawn solid. 1H NMR (300 MHz, d6-DMSO) δ 8.86 (1H, d, J=5.0 Hz); 8.28 (2H, d, J=8.7 Hz); 8.18 (1H, d, J=5.5 Hz); 7.66 (2H, d, J=8.7 Hz); 4.97 (2H, s); 3.22 (3H, s). LC-ESI-MS (method B): rt 5.9 min.; m/z 323.2/325.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][N:6]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].C([N-]C(C)C)(C)C.[Li+].[CH:30](=[O:33])[CH2:31][CH3:32].O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([N:6]([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:30]([OH:33])[CH2:31][CH3:32])[CH3:2]
Reactant: CCC=O
Reactant: CCOC(=O)CN(Cc1ccccc1)Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C(O)CC)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 8 h

Procedure:
A solution of 20 g (70.6 mmol) dibenzylamino-acetic acid ethyl ester in 240 ml tetrahydrofuran was stirred at −78° C. with 38.8 ml (77.6 mmol) lithium diisopropylamide (2M in heptane) for 30 minutes. 5.83 ml (77.6 mmol) Propionaldehyde in 5 ml tetrahydrofurane were added and stirring was continued overnight. The mixture was allowed to warm to room temprature, water was added and most of the organic solvent was removed by distillation. Extraction with ethylacetate and chromatography on silicagel with ethylacetate/heptane 1/5 yielded as first eluting fraction 6.85 g (28%) racemic (2S,3R and 2R,3S)-2-dibenzylamino-3-hydroxy-pentanoic acid ethyl ester, MS m/e (%): 342.3 (M+H+, 100) and as second eluting fraction 6.15 g (26%) racemic (2R,3R and 2S,3S)-2-dibenzylamino-3-hydroxy-pentanoic acid ethyl ester, MS m/e (%): 342.2 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:6]([CH3:16])[N:5]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:20])[N:3]=1.[C:29](Cl)(=[O:31])[CH3:30]>>[C:29]([N:25]1[CH2:24][CH2:23][CH:22]([N:21]([CH3:28])[C:19](=[O:20])[CH2:18][O:17][C:4]2[N:3]=[C:2]([CH3:1])[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[C:6]([CH3:16])[N:5]=2)[CH2:27][CH2:26]1)(=[O:31])[CH3:30]
Reactant: Cc1nc(OCC(=O)N(C)C2CCNCC2)nc(C)c1NC(=O)OC(C)(C)C
Reactant: CC(=O)Cl
Product: CC(=O)N1CCC(N(C)C(=O)COc2nc(C)c(NC(=O)OC(C)(C)C)c(C)n2)CC1

Procedure:
The title compound was synthesized from Compound 31 and acetyl chloride in the same manner as in Example 32.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[C@@H:4]([CH3:6])[NH2:5].[CH2:8]1[CH2:14][S:11](=[O:13])(=[O:12])[O:10][CH2:9]1>C(#N)C>[CH3:1][O:2][C:3](=[O:7])[C@H:4]([NH:5][CH2:9][CH2:8][CH2:14][S:11]([OH:13])(=[O:12])=[O:10])[CH3:6]
Reactant: COC(=O)[C@@H](C)N
Reactant: O=S1(=O)CCCO1
Solvent: CC#N
Product: COC(=O)[C@@H](C)NCCCS(=O)(=O)O
Temperature: 25 °C
Yield: 57.7 %

Procedure:
To a solution of D-Alanine methylester (1.33 g, 12.9 mmol) in acetonitrile (15 mL was added 1,3-propane sultone (1.42 g, 11.7 mmol). The solution was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid material was filtered and washed with acetonitrile (2×15 mL). The solid was dissolved in water (30 mL). Dowex Marathon C ion exchange resin (strongly acidic) was added to the solution. The suspension was stirred for 15 minutes before the resin was removed by filtration. The filtrate was evaporated under reduced pressure and dried in vacuo, affording the title compound (1.52 g, 42%). 1H NMR (D2O, 500 MHz) δ ppm 4.07 (m, 1H), 3.72 (s, 3H), 3.14 (m, 2H), 2.89 (t, 2H, J=7.3 Hz), 2.03 (m, 2H), 1.46 (dd, 3H, J=1.95 Hz, 7.3 Hz). 13C (DMSO, 125 MHz) δ ppm 170.74, 55.62, 53.82, 47.96, 44.76, 21.53, 14.03. [α]D=+1.4° (c=0.0088 in water), ES-MS 224 (M−1).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]([OH:13])[CH2:11][NH2:12].[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](=O)[CH3:30])=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CO>ClCCl>[CH2:14]([O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:28][CH:29]([NH:12][CH2:11][CH:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)[OH:13])[CH3:30])=[CH:26][CH:27]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(=O)Cc1ccc(OCc2ccccc2)cc1
Reactant: NCC(O)c1cc2ccccc2o1
Solvent: ClCCl
Solvent: CO
Product: CC(Cc1ccc(OCc2ccccc2)cc1)NCC(O)c1cc2ccccc2o1

Procedure:
This was prepared in an identical manner to the compound described in Example 2 using 2-(2-benzofuranyl)-2-hydroxyethanamine (3.51 g) and 1-(4-benzyloxyphenyl)propan-2-one (4.75 g). Chromatography of the residual oily solid on Kieselgel 60 (4% methanol in dichloromethane) gave the title compound, m.p. 111°-122°, as a 20:80 mixture of diastereoisomers.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[O:1]([C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(Oc2ccccc2)c1

Procedure:
The title compound was prepared from [4-(3-hydroxy-phenyl)-8-trifluoromethylquinolin-3-yl]-phenyl methanone and phenyl boronic acid, following the procedure of Example 519: MS (ESI) m/z 470.
Reaction SMILES: COC[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][N:27]=4)=[CH:21][CH:20]=3)=[N:16][CH:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5].C(N(C(C)C)CC)(C)C.Cl[C:43](OC)=[O:44]>C(Cl)Cl>[CH3:32][C:29]1[CH:30]=[CH:31][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([O:18][C:17]3[C:12]([CH:9]4[CH2:10][CH2:11][N:6]([C:4]([O:44][CH3:43])=[O:5])[CH2:7][CH2:8]4)=[N:13][CH:14]=[CH:15][N:16]=3)=[CH:20][CH:21]=2)=[N:27][CH:28]=1
Reactant: COC(=O)Cl
Reactant: COCC(=O)N1CCC(c2nccnc2Oc2ccc(Nc3ccc(C)cn3)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)N1CCC(c2nccnc2Oc2ccc(Nc3ccc(C)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 5-methyl-N-(4-(3-(piperidin-4-yl)pyrazin-2-yloxy)phenyl)pyridin-2-amine (0.278 g, 0.548 mmol) (See step 3, Example 282), and diisopropylethylamine (0.502 mL, 2.88 mmol) in DCM (5 mL) was added methyl chloroformate (0.051 mL, 0.658 mmol). The reaction mixture was stirred at RT for 2 h. The reaction mixture was purified by ISCO column (40% EtOAc/Hexanes) to give the title compound. MS (ESI, pos. ion) m/z: 420.2 (M+1). IC50 (uM) 0.000107.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[CH2:26]([O:28][C:29](=[O:50])[CH:30]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:27]>C1(C)C=CC=CC=1.C(OCC)C>[CH2:26]([O:28][C:29](=[O:50])[CH:30]=[C:20]1[CH2:19][CH2:18][CH:17]([CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:25])([F:1])[F:24])[CH:4]=3)[CH2:14][CH2:13]2)[CH2:22][CH2:21]1)[CH3:27]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCC(CCN2CCN(c3cccc(C(F)(F)F)c3)CC2)CC1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)C=C1CCC(CCN2CCN(c3cccc(C(F)(F)F)c3)CC2)CC1
Yield: 44.7 %

Procedure:
A mixture of 2.77 g (7.8 mmol) of 4-{2-[4-(3-trifluoromethyl-phenyl)piperazin-1-yl]ethyl}cyclohexanone (example 1, path 11, step b) and 3.13 g (9.0 mmol) of (triphenyl-λ5-phosphanylidene)acetic acid ethyl ester in 40 mL of toluene is refluxed overnight. After concentration of toluene, the residue is taken off in diethyl ether and the solid is filtered. The filtrate is concentrated and purified over 150 g of silica gel (eluant dichloromethane/heptane 98/2) to give 1.48 g (45%) of (4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexylidene)acetic acid ethyl ester as an oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1[C:9]([S:15]([CH3:18])(=[O:17])=[O:16])=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH2:11].[Br-:19].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[Br:19][C:14]1[CH:13]=[CH:12][C:10]([NH2:11])=[C:9]([S:15]([CH3:18])(=[O:17])=[O:16])[C:8]=1[CH3:7]
Reactant: [Br-]
Reactant: Cc1cccc(N)c1S(C)(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1c(Br)ccc(N)c1S(C)(=O)=O
Yield: 82.7 %

Procedure:
400 g (2.9 mol) of potassium carbonate were added to a solution of 134 g (0.73 mol) of 3-methyl-2-methylsulfonylaniline in 1200 ml of acetonitrile. At room temperature, 320 g (0.65 mol) of tetrabutylammonium tribromide were then added a little at a time, with vigorous stirring. The resulting precipitate was separated off, methyl tert-butyl ether was added to the filtrate and the filtrate was extracted with dilute hydrochloric acid and then with water. The organic phase was concentrated to dryness under reduced pressure. The resulting residue was once more taken up in methyl tert-butyl ether and washed two more times with hydrochloric acid and water. The organic phase was dried and concentrated under reduced pressure, giving 142 g (74%) of 4-bromo-3-methyl-2-methylsulfonylaniline as a brown solid of melting point 103–106° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([OH:16])=[O:15])[CH:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[C:23](Cl)([O:25][CH2:26][CH:27]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24].Cl>O.O1CCOCC1>[C:23]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([OH:16])=[O:15])[CH:9]=2)=[CH:6][CH:7]=1)([O:25][CH2:26][CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]2[C:39]1=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:24]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: Nc1ccc(-c2cccc(C(=O)O)c2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(Nc1ccc(-c2cccc(C(=O)O)c2)cc1)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Cool a mixture of 4′-aminobiphenyl-3-carboxylic acid (Preparation C, Step 4) (7.46 g, (35 mmol) and Na2CO3 (9.3 g, 87.7 mmol) in H2O /dioxane (2:1, 300 mL) to ˜5° C. Add Fmoc-Cl (9.05 g, 35 mmol), and stir the mixture at ice bath temperature for 4 hours. Allow reaction mixture to warm to room temperature and stir for 24 hours. Pour into ice water, and acidify with aqueous HCl. Collect the precipitate, wash with water, and dry in vacuo. Recrystallize from EtOAc to give the title compound, m.p. 270.5-272° C. HPLC; FAB MS m/z 436 [M+H]+.