Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:18]([CH3:22])=[C:19]([CH3:21])[N:20]=2)[CH:9]=[C:10]([C:12](OC(C)C)=[O:13])[CH:11]=1.[CH2:28]([CH2:30][NH2:31])[OH:29]>C1COCC1>[CH3:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:2]([CH3:1])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:18]([CH3:22])=[C:19]([CH3:21])[N:20]=2)[CH:9]=[C:10]([C:12]([NH:31][CH2:30][CH2:28][OH:29])=[O:13])[CH:11]=1
Reactant: Cc1cccc(C)c1CNc1cc(C(=O)OC(C)C)cn2c(C)c(C)nc12
Reactant: NCCO
Solvent: C1CCOC1
Product: Cc1cccc(C)c1CNc1cc(C(=O)NCCO)cn2c(C)c(C)nc12
Temperature: 100 °C

Procedure:
A reactor was charged with isopropyl 8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxylate (11.30 kg, 1 equiv., 27.02 mol) and THF (45 L), ethanolamine (18.97 kg, 11 equiv., 309.2 mol) was added at about 20° C. The suspension was heated to about 100° C. Some solvent was distilled off and then THF (35L) was added and the distillation was continued. The procedure of adding THF and distilling it off was repeated until complete conversion. To the suspension ethanol (140L) was added and the suspension was heated to reflux. To obtain a clear solution additional ethanol (13L) was added. The hot solution was filtered and then cooled. The white solid was filtered off, washed with ethanol and dried to yield the product as a white powder. (8271 g).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH2:3][CH2:4][CH:5]1[CH2:9][CH2:8][NH:7][C:6]1=[O:10].[H-].[Na+].Cl[CH2:16][C:17]([N:19]([C:22]1[C:23]([Cl:33])=[N:24][N:25]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH:26]=1)[CH2:20][CH3:21])=[O:18]>>[Cl:33][C:23]1[C:22]([N:19]([CH2:20][CH3:21])[C:17](=[O:18])[CH2:16][N:7]2[CH2:8][CH2:9][CH:5]([CH2:4][CH2:3][C:2]([F:1])([F:11])[F:12])[C:6]2=[O:10])=[CH:26][N:25]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[N:24]=1
Reactant: O=C1NCCC1CCC(F)(F)F
Reactant: CCN(C(=O)CCl)c1cn(-c2cccnc2)nc1Cl
Agent: [H-]
Agent: [Na+]
Product: CCN(C(=O)CN1CCC(CCC(F)(F)F)C1=O)c1cn(-c2cccnc2)nc1Cl

Procedure:
To 3-(3,3,3-trifluoropropyl)pyrrolidin-2-one in an appropriate reaction vessel may be added NaH (from about 1.0 eq to about 2.0 equivalent) in a solvent, such as THF (at a concentration between about 0.01 M to about 1 M) followed by 2-chloro-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylacetamide (from about 0.5 eq to about 1.5 eq). The reaction may be stirred at a temperature from about 0° C. to about 25° C. until determined to be complete. After completion of the reaction, the product may be obtained using standard organic chemistry techniques for workup and purification.
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:7]1([CH2:13][CH2:14][CH2:15][Cl:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.S(=O)(=O)(O)O>>[CH:1]1([C:10]2[CH:11]=[CH:12][C:7]([CH2:13][CH2:14][CH2:15][Cl:16])=[CH:8][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1=CCCCC1
Reactant: ClCCCc1ccccc1
Agent: O=S(=O)(O)O
Product: ClCCCc1ccc(C2CCCCC2)cc1
Reaction time: 14 h
Yield: 57 %

Procedure:
16.5 parts by weight of cyclohexene are added dropwise at +10° C. to a mixture of 31 parts by weight of 3-phenylpropyl chloride and 20 parts by weight of 96% strength sulfuric acid. Stirring is continued for 14 hours at room temperature. The crude product is dissolved in CHCl3 /ice water and the organic solution is thoroughly washed with ice water, dried over Na2CO3 and distilled. 27 parts by weight of 3-(4-cyclohexylphenyl)-propyl chloride are obtained; boiling point 126°-130° C./0.2 mm Hg, yield 57% (based on 3-phenylpropyl chloride).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19](O)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][CH2:32][C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)=[CH:27][CH:26]=1)([CH3:24])[CH3:23]>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:31]([CH2:32][C:33]1[CH:34]=[CH:35][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:41][CH:42]=1)[C:28]1[CH:27]=[CH:26][C:25]([CH:22]([CH3:24])[CH3:23])=[CH:30][CH:29]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(CNc2ccc(C(C)C)cc2)cc1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Product: COC(=O)c1ccc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)cc2)cc1
Yield: 57.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (2.3 g) and methyl 4-{[(4-isopropylphenyl)amino]methyl}benzoate (2.3 g) as starting materials, methyl 4-{[N-(5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl)-N-(4-isopropylphenyl)amino]methyl}benzoate (2.56 g) was obtained.
Reaction SMILES: Br.[CH3:2][N:3]1[C@@H:19]2[CH2:20][C:8]3[CH:9]=[CH:10][C:11]([O:23][CH3:24])=[C:12]4[O:13][C@H:14]5[C:15]([O:21]C)=[CH:16][CH:17]=[C:18]2[C@:6]5([C:7]=34)[CH2:5][CH2:4]1.C(=O)=O>C(O)(=O)C.C(Cl)(Cl)Cl>[CH3:2][N:3]1[C@@H:19]2[CH2:20][C:8]3[CH:9]=[CH:10][C:11]([O:23][CH3:24])=[C:12]4[O:13][C@H:14]5[C:15]([CH:16]=[CH:17][C@@H:18]2[C@:6]5([C:7]=34)[CH2:5][CH2:4]1)=[O:21]
Reactant: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Agent: Br
Agent: O=C=O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COc1ccc2c3c1O[C@H]1C(=O)C=C[C@H]4[C@@H](C2)N(C)CC[C@]314

Procedure:
Anhydrous hydrogen bromide in glacial acetic acid (6 ml of 45% w/v solution) was added dropwise with stirring to a cooled (-15° C.) solution of thebaine (2 g) in chloroform (6 ml) over a period of 9 minutes. When the addition was complete the Drikold bath was removed and the temperature allowed to rise.
Reaction SMILES: Cl.[OH:2][C@H:3]1[CH2:7][NH:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4]1.[CH2:12]([N:14](CC)CC)[CH3:13].BrCC#N>CO>[C:12]([CH2:13][N:6]1[CH2:7][C@H:3]([OH:2])[CH2:4][C@H:5]1[C:8]([O:10][CH3:11])=[O:9])#[N:14]
Reactant: CCN(CC)CC
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Agent: Cl
Agent: N#CCBr
Solvent: CO
Product: COC(=O)[C@@H]1C[C@@H](O)CN1CC#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
To a solution of (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride (1 g, 5.51 mmol; Chem Impex) and triethylamine (1.919 mL, 13.77 mmol) in methanol (2 mL) was added 2-bromoacetonitrile (0.391 mL, 5.78 mmol) dropwise. The reaction was stirred at room temperature for 1 hour and then concentrated in vacuo. The residue was partitioned between water (10 mL) and dichloromethane (10 mL), and the organic layer was separated and concentrated. The resulting crude oil was purified by flash chromatography using an Agilent Technologies SuperFlash SF15-12 g cartridge eluting with a gradient of 10-100% ethyl acetate/hexanes over 15 minutes to isolate (2S,4R)-methyl 1-(cyanomethyl)-4-hydroxypyrrolidine-2-carboxylate (375 mg, 2.036 mmol, 37.0% yield) as an oil that solidified on standing. 1H NMR (300 MHz, CDCl3) δ ppm 4.50 (m, 1H), 3.92 (d, J=17.6 Hz, 1H), 3.76 (s, 3H), 3.73 (d, J=17.6 Hz, 1H), 3.71 (t, J=10.3 Hz, 1H), 3.47 (dd, J=10.0, 5.6 Hz, 1H), 2.72 (dd, J=10.0, 4.1 Hz, 1H), 2.23 (dddd, J=13.5, 10.0, 8.2, 5.5 Hz, 2H), 1.67 (d, J=4.6 Hz, 1H); MS (ESI+) m/z 185 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]([C:13]3[C:14]([F:34])=[C:15]([NH:20][S:21]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)(=[O:23])=[O:22])[CH:16]=[CH:17][C:18]=3[F:19])=[O:12])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.CS(C)=O.[C-:39]#[N:40].[K+]>O>[C:39]([C:2]1[C:3]2[C:10]([C:11]([C:13]3[C:14]([F:34])=[C:15]([NH:20][S:21]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=4)(=[O:22])=[O:23])[CH:16]=[CH:17][C:18]=3[F:19])=[O:12])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1)#[N:40]
Reactant: [C-]#N
Reactant: O=C(c1c(F)ccc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)c1F)c1c[nH]c2ncnc(Cl)c12
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ncnc2[nH]cc(C(=O)c3c(F)ccc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4)c3F)c12
Temperature: 150 °C
Yield: 13.1 %

Procedure:
To N-[3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-1016, 62 mg, 0.12 mmol), 1.00 mL of dimethyl sulfoxide is added, followed by potassium cyanide (39.0 mg, 0.60 mmol). The reaction is heated at 150° C. in an oil bath for 4 hours, then at 150° C. overnight. The reaction is poured into water and extracted with ethyl acetate. The organic layer is concentrated under vacuum and purified by silica gel column chromatography, eluting with a gradient of 10-60% ethyl acetate in hexanes. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (P-1023, 8 mg). MS (ESI) [M+H+]+=508.1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22]([OH:24])=O)=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:40]([NH2:44])[CH2:41][CH2:42][CH3:43].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:26])([F:27])[F:28])=[N:20][C:21]([C:22](=[O:24])[NH:44][CH2:40][CH2:41][CH2:42][CH3:43])=[C:15]2[CH2:14]1)=[O:12])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Reactant: CCCCN
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCNC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (180 mg, 0.33 mmol) was dissolved in 10 mL of dichloromethane, followed by addition of butylamine hydrochloride (193 mg, 2.64 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (167 mg, 0.66 mmol) and triethylamine (100 mg, 0.99 mmol). The reaction mixture was stirred at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-(1-butylcarbamoyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 43a (120 mg, yield 60%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[CH:9][C:4]=2[CH:3]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[N:36][C:37]([NH2:40])=[CH:38][CH:39]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[N:36][C:37]([NH:40][C:7]3[N:8]=[CH:9][C:4]4[CH:3]=[C:2]([Br:1])[C:14](=[O:15])[N:13]([CH:16]5[CH2:20][CH2:19][CH2:18][CH2:17]5)[C:5]=4[N:6]=3)=[CH:38][CH:39]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CS(=O)c1ncc2cc(Br)c(=O)n(C3CCCC3)c2n1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc4cc(Br)c(=O)n(C5CCCC5)c4n3)nc2)CC1
Temperature: 120 °C
Yield: 21 %

Procedure:
Under a dry argon atmosphere were combined 6-bromo-8-cyclopentyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.78 g, 2.19 mmol, prepared as in Example 107 of WO 98/33798 (incorporated herein by reference)) and 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.67 g, 2.4 mmol) without solvent. The flask was evacuated and heated to 120° C. for 1 hour. The mixture was purified by chromatography on silica gel, eluting with chloroform, to give a yellow foam, 0.288 g. Recrystalization from acetonitrile gave 4-[6-(6-bromo-8-cyclopentyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.266 g, 21%). MS (APCI); M++1: Calc'd, 570.17. Found, 570.0.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:10][CH:9]=[C:8]([C:11]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:17]([OH:19])=O)=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:24]([N:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][C:34]=2[C:40]([F:43])([F:42])[F:41])[CH2:28][CH2:27]1)[CH3:25]>>[NH2:1][C:2]1[C:3]2[S:10][CH:9]=[C:8]([C:11]([NH:13][C:14]3[CH:15]=[C:16]([C:17](=[O:19])[NH:39][C:36]4[CH:37]=[CH:38][C:33]([CH2:32][N:29]5[CH2:28][CH2:27][N:26]([CH2:24][CH3:25])[CH2:31][CH2:30]5)=[C:34]([C:40]([F:43])([F:42])[F:41])[CH:35]=4)[CH:20]=[CH:21][C:22]=3[CH3:23])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Reactant: Cc1ccc(C(=O)O)cc1NC(=O)c1csc2c(N)ncnc12
Product: CCN1CCN(Cc2ccc(NC(=O)c3ccc(C)c(NC(=O)c4csc5c(N)ncnc45)c3)cc2C(F)(F)F)CC1

Procedure:
The procedure of Step 5 of Example 1 was repeated except for using 3-(4-aminothieno[3,2-d]pyrimidine-7-carboxamido)-4-methylbenzoic acid obtained in Step 4 of Example 8 and 4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzenamine to obtain the title compound (see Table 1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][Cl:19]>CN(C=O)C>[Cl:19][CH2:18][CH2:17][CH2:16][N:8]1[C:9]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:11][CH:10]=2)[CH2:5][CH2:6][C:7]1=[O:12]
Reactant: Cc1ccc2c(c1)CCC(=O)N2
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)CCC(=O)N2CCCCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
A reaction flask was charged with 6-methyl-3,4-dihydro-1H-quinolin-2-one (107LH05) (0.300 g, 1.26 mmol) in dry DMF (5 mL) under Argon. NaH (60% in oil, 0.055 g, 1.38 mmol) was added and the mixture was stirred at rt for 1 h. Then 1-bromo-3-chloropropane (0.198 g, 1.24 mmol) was added followed by stirring at rt for 20 h. The reaction mixture was quenched with water, and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash CC (SiO2; DCM) to give the crude title compound (107LH14) (0.257 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:28])[NH:8][C:9]2[C:13]([C:14]=1[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[O:22])[CH2:17][CH2:16]1)=[CH:12][S:11][CH:10]=2)=[O:5])[CH3:2].[CH3:29][O:30][C:31](=[O:40])[C:32]1[CH:37]=[CH:36][C:35]([CH2:38]Br)=[CH:34][CH:33]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:28])[N:8]([CH2:38][C:35]2[CH:34]=[CH:33][C:32]([C:31]([O:30][CH3:29])=[O:40])=[CH:37][CH:36]=2)[C:9]2[C:13]([C:14]=1[N:15]1[CH2:16][CH2:17][N:18]([C:21]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[O:22])[CH2:19][CH2:20]1)=[CH:12][S:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cscc2[nH]c1=O
Reactant: COC(=O)c1ccc(CBr)cc1
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cscc2n(Cc2ccc(C(=O)OC)cc2)c1=O
Yield: 51 %

Procedure:
The compound was prepared from 5-oxo-7-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-4,5-dihydro-2-thia-4-aza-indene-6-carboxylic acid ethyl ester (40) and methyl-4-bromomethylbenzoate by applying general procedure A. Yield 51%; 1H NMR (400 MHz, DMSO-d6) δ 1.25 (t, J=7.2 Hz, 3H), 3.30 (m, 4H), 3.82 (m, 7H), 4.27 (q, J=7.2 Hz, 2H), 5.28 (s, 2H), 7.12 (d, J=3.2 Hz, 1H), 7.16 (dd, J=5.2, 3.2 Hz, 1H), 7.37 (m, 2H), 7.47 (dd, J=1.2, 3.6 Hz, 1H), 7.79 (dd, J=1.2, 5.2 Hz, 1H), 7.91 (m, 2H), 8.13 (d, J=3.2 Hz, 1H) ppm; MS m/z=565 amu (M++1). Anal. (C28H27N3O6S2) C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]2[CH2:18][N:17]([C:19]([N:21]3[CH2:26][CH2:25][S:24][CH2:23][CH2:22]3)=[O:20])[CH2:16][CH:15]([C:27]([O:29]C)=[O:28])[CH2:14]2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].CC(C)([O-])C.[K+]>>[F:1][C:2]1[CH:3]=[C:4]([CH:13]2[CH2:18][N:17]([C:19]([N:21]3[CH2:26][CH2:25][S:24][CH2:23][CH2:22]3)=[O:20])[CH2:16][CH:15]([C:27]([OH:29])=[O:28])[CH2:14]2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:10])[F:11]
Reactant: COC(=O)C1CC(c2ccc(OC(F)(F)F)c(F)c2)CN(C(=O)N2CCSCC2)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: O=C(O)C1CC(c2ccc(OC(F)(F)F)c(F)c2)CN(C(=O)N2CCSCC2)C1

Procedure:
According to General Method 4A, 1.95 g (4.329 mmol) of the compound from Example 94A were reacted with 4.86 g (43.3 mmol) of potassium tert-butoxide. Yield: 1.66 g (83% of theory).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([OH:15])=[CH:13][C:12]([CH2:16][CH3:17])=[C:11]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([C:27]#[N:28])([CH3:26])[CH3:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[CH2:1]([O:8][C:9]1[C:14]([O:15][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:13][C:12]([CH2:16][CH3:17])=[C:11]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([C:27]#[N:28])([CH3:25])[CH3:26])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCBr
Reactant: CCc1cc(O)c(OCc2ccccc2)cc1OCCCCCC(C)(C)C#N
Product: CCCCCOc1cc(CC)c(OCCCCCC(C)(C)C#N)cc1OCc1ccccc1
Yield: 100 %

Procedure:
1-Benzyloxy-3-(6-cyano-6-methylheptyloxy)-4-ethyl -6-pentyloxy benzene was prepared in 100% yield as a white solid from 1-Benzyloxy-3-(6-cyano-6-methylheptyloxy)-4-ethyl-6-hydroxy benzene and 1-bromopentane.
Reaction SMILES: [H-].[Na+].[NH2:3][C@@H:4]([CH:7]([CH3:9])[CH3:8])[CH2:5][OH:6].Cl[CH2:11][C:12](OCC)=[O:13].[Cl-].[NH4+]>C1(C)C=CC=CC=1>[CH:7]([C@@H:4]1[NH:3][C:12](=[O:13])[CH2:11][O:6][CH2:5]1)([CH3:9])[CH3:8]
Reactant: CCOC(=O)CCl
Reactant: CC(C)[C@H](N)CO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: CC(C)[C@H]1COCC(=O)N1
Temperature: 25 °C
Yield: 65.2 %

Procedure:
To an ice cold, stirred suspension of sodium hydride (60% in oil, 1.3 g, 34.0 mmol) in toluene (45 mL) was added dropwise a solution of (S)-2-amino-3-methylbutan-1-ol (1.5 g, 15.0 mmol) in toluene (30 mL). After the addition was complete, the reaction mixture was warmed to room temperature and a solution of ethyl chloroacetate (2.0 g, 16.0 mmol) in toluene (8 mL) was added in a dropwise manner. The resulting mixture was then stirred at reflux for 20 h, cooled to room temperature, and solid ammonium chloride (1.8 g, 34.0 mmol) added to the reaction. The mixture was stirred for 20 min and then concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 95:5 CH2Cl2/CH3OH) to give (S)-5-isopropylmorpholin-3-one (1.4 g, 67%) as a light yellow solid. 1H NMR and MS consistent.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)N(S(C2C=CC=CC=2)(=O)=O)C=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[CH3:34][S:35]SC.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CO.O>[CH2:1]([N:8]1[C:18]2[C:19](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:11]=[C:9]1[S:35][CH3:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCc1ccccc1)c1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Reactant: CSSC
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CSc1cc2ccccc2n1Cc1ccccc1
Temperature: -20 °C
Yield: 100.5 %

Procedure:
A solution of the above N-benzyl-1-(phenylsulfonyl)indole -3-carboxamide [XXIV: R8 =CH2Ph] (4.2 g, 11 mmol) in dry THF (200 mL) was treated at -78° C. with a solution of 2.5M n-BuLi in hexanes (9.1 mL, 23 mmol), and the stirred mixture was allowed to warm to -20° C. for 15 minutes, before being recooled to -78° C., when it was treated with methyldisulfide (2.5 mL, 28 mmol). The mixture was allowed to warm to 20° C., then quenched with water (25 mL). Volatiles were removed under reduced pressure, and the residue was extracted with EtOAc. Workup of the organic layer gave a crude product. This was dissolved in MeOH (300 mL), mixed with a solution of K2CO3 (6.9 g, 50 mmol) in water (125 mL), and heated under gentle reflux under N2 for 2 hours to ensure complete hydrolysis of the phenylsulfonyl group (J. Org. Chem. 1985;50:5451-5457). MeOH was removed under reduced pressure, and the residue was diluted with water and extracted with CH2Cl2. Chromatography of the resulting oil on Al2O3 (eluting with CH2Cl2) gave N-benzyl-2-(methylthio)indole -3-carboxalnide [XXV: R8 =CH2Ph] (2.8 g, 88% yield) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:31])[C:6]=1[C:7]1[CH:17]=[C:16]([NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[CH:15]=[CH:14][C:8]=1[O:9][CH2:10][C:11](O)=[O:12].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:65][O:66][CH2:67][CH2:68][NH2:69]>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:31])[C:6]=1[C:7]1[CH:17]=[C:16]([NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=2)[CH:15]=[CH:14][C:8]=1[O:9][CH2:10][C:11]([NH:69][CH2:68][CH2:67][O:66][CH3:65])=[O:12]
Reactant: COCCN
Reactant: Cn1ncc(Cl)c1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1OCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCNC(=O)COc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1c(Cl)cnn1C
Yield: 85.8 %

Procedure:
To a solution of 2-(2-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-(3-(trifluoromethyl)benzamido)phenoxy)acetic acid (0.060 g, 0.13 mmol) and N,N-diisopropylethylamine (0.034 g, 0.26 mmol) in dichloromethane (1.3 mL) was added HBTU (0.075 g, 0.20 mmol) followed by 2-methoxyethylamine (0.015 g, 0.2 mmol). After 1.5 hours the reaction was diluted with ethyl acetate, washed with water, 1 M HCl (×3) and brine, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography (1:1-1:0 EtOAc/hexane) to give a white solid (57.0 mg, 84%). LCMS m/z (%)=511 (M+H, 35Cl, 100), 513 (M+H, 37Cl, 30). 1H NMR (400 MHz, CDCl3) δ 3.35 (s, 3H) 3.39-3.52 (m, 4H) 3.78 (s, 3H) 4.52 (s, 2H) 6.60 (br. s., 1H) 7.02 (d, J=9.09 Hz, 1H) 7.55 (s, 1H) 7.63-7.67 (m, 2H) 7.74 (dd, J=8.97, 2.91 Hz, 1H) 7.84 (d, J=6.82 Hz, 1H) 7.92 (s, 1H) 8.08 (d, J=6.57 Hz, 1H) 8.14 (s, 1H).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[N:22]([CH2:23][CH2:24][CH3:25])[N:21]=[C:20]([CH2:26][CH3:27])[C:19]=2[C:28]([O:30][CH3:31])=[O:29])=[CH:13][CH:12]=1)(=[O:4])=[O:3].[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.OP([O-])(O)=O.[K+]>N1C=CC=CC=1>[CH2:26]([C:20]1[C:19]([C:28]([O:30][CH3:31])=[O:29])=[C:18]([CH2:17][C:14]2[CH:13]=[CH:12][C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[S:2]([NH:1][C:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:39])(=[O:3])=[O:4])=[CH:16][CH:15]=2)[N:22]([CH2:23][CH2:24][CH3:25])[N:21]=1)[CH3:27]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCn1nc(CC)c(C(=O)OC)c1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: c1ccncc1
Product: CCCn1nc(CC)c(C(=O)OC)c1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
To a solution of the compound obtained in example 44 (0.5 g, 1.13 mmol) in pyridine (10.8 mL) was added benzoyl chloride (0.13 mL) and the reaction mixture was stirred at room temperature under an argon atmosphere for 12 h. Then, saturated aqueous KH2PO4 (33 mL) was added and it was extracted with EtOAc. The organic phase was unwashed with 1N HCl, dried and concentrated to a crude product. This was chromatographed on silica gel (hexane-EtOAc, 1:1) to afford the title compound as a foam (0.64 g, 100%).