Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Cl:6][C:7]([PH:15]([C:17]1(Cl)[CH:22]=[CH:21][CH:20]=[CH:19][CH2:18]1)=[O:16])([Cl:14])[C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9]>C(OCC)C.C(Cl)CCC>[Cl:14][C:7]([P:15]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16])([Cl:6])[C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9]
Reactant: CC(C)OC(=O)C(Cl)(Cl)[PH](=O)C1(Cl)C=CC=CC1
Reactant: CCNCC
Solvent: CCOCC
Solvent: CCCCCl
Product: CCN(CC)P(=O)(c1ccccc1)C(Cl)(Cl)C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 11.7 g of diethylamine in 100 ml of diethylether is added dropwise to a solution of 27.1 g of 1-methylethyl 2,2-dichloro-[(1-chloro)phenylphosphinyl]-acetate in 200 ml of ether at 0°. After stirring at room temperature for 1 hour, the solution is washed with water and with 10% sodium bicarbonate solution, then dried over MgSO4 and stripped to give a dark oil. The reaction product is dissolved in n-butyl chloride, washed with water, contacted with activated carbon, dried over MgSO4 and stripped to give substantially pure 1-methylethyl 2,2-dichloro-[(diethylamino)phenylphosphinyl]acetate.
Reaction SMILES: [CH:1]1([C:4]([CH:22]2[CH2:24][CH2:23]2)([OH:21])[CH2:5][N:6](CC2C=CC=CC=2)CC2C=CC=CC=2)[CH2:3][CH2:2]1.[H][H]>CO.[OH-].[OH-].[Pd+2].C>[NH2:6][CH2:5][C:4]([CH:22]1[CH2:24][CH2:23]1)([CH:1]1[CH2:3][CH2:2]1)[OH:21]
Reactant: OC(CN(Cc1ccccc1)Cc1ccccc1)(C1CC1)C1CC1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: NCC(O)(C1CC1)C1CC1
Yield: 81.4 %

Procedure:
To a solution of 0.28 g 1,1-dicyclopropyl-2-dibenzylamino-ethanol (0.00087 mol) in 10 ml methanol was added 0.060 g Pd(OH)2/charcoal (Fluka 7663; 20%) and the mixture was hydrogenated under 8 bar hydrogen pressure at 60° C. for 2 hours. The catalyst was removed by filtration and the mother liquor was concentrated and the residue was purified by chromatography on silicagel with MeCl2/MeOH/NH3 90:10:1 to yield 0.10 g (81% yield) of the title compound as colorless oil. 1H-NMR (CDCl3 300 MHz, δ ppm) 0.28-0.45 (m, 8H); 0.71-0.78 (m, 2H); 2.77 (s, 2H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[O:9][CH2:8][CH2:7][C:6]=2[CH:14]=1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:24]=2[CH:25]=[N:26][NH:27]3)[C:19]([Cl:32])=[CH:18][N:17]=1>>[Cl:32][C:19]1[C:20]([NH:22][C:23]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:24]=2[CH:25]=[N:26][NH:27]3)=[N:21][C:16]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:11]([CH3:12])[C:10](=[O:13])[O:9][CH2:8][CH2:7][C:6]=3[CH:14]=2)=[N:17][CH:18]=1
Reactant: CN1C(=O)OCCc2cc(N)ccc21
Reactant: Clc1ncc(Cl)c(Nc2cccc3[nH]ncc23)n1
Product: CN1C(=O)OCCc2cc(Nc3ncc(Cl)c(Nc4cccc5[nH]ncc45)n3)ccc21

Procedure:
Following a procedure analogous to Example 1741e, 2-amino-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one and (2,5-dichloro-pyrimidin-4-yl)-(1H-indazol-4-yl)-amine were converted to 2-[5-chloro-4-(1H-indazol-4-ylamino)-pyrimidin-2-ylamino]-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one. TFA salt: 1H NMR (300 MHz, CDCl3) δ 11.91 (s, 1H), 8.04 (d, 1H), 8.00 (s, 1H), 7.54 (d, 1H), 7.42 (m, 2H), 7.29 (d, 1H), 7.21 (s, 1H), 6.87 (d, 1H), 4.33 (t, 2H), 3.32 (s, 3H), 2.66 (t, 2H); MS (m/e) 436 (M+1).
Reaction SMILES: [Br:1][C:2]([Br:12])=[CH:3][C@@H:4]1[C@H:6]([C:7](Cl)=[O:8])[C:5]1([CH3:11])[CH3:10].[C:13]1([C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH:22]([OH:28])[CH2:23]3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1.C1(C)C=CC=CC=1>O>[Br:1][C:2]([Br:12])=[CH:3][C@@H:4]1[C@H:6]([C:7]([O:28][CH:22]2[CH2:21][C:20]3[C:24](=[CH:25][CH:26]=[CH:27][C:19]=3[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:23]2)=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: CC1(C)[C@H](C=C(Br)Br)[C@@H]1C(=O)Cl
Reactant: OC1Cc2cccc(-c3ccccc3)c2C1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)[C@H](C=C(Br)Br)[C@@H]1C(=O)OC1Cc2cccc(-c3ccccc3)c2C1

Procedure:
In a manner similar to Example 12A, the reaction of 0.51 g (0.0016 mole) of (+)-cis-3-(2,2-dibromoethenyl)-2,2-dimethylcyclopropanecarbonyl chloride (an additional four drops were added 1 hour after original addition) with 0.33 g (0.0016 mole) of (+)-4-phenyl-2-indanol (EE 50%), 0.16 g (0.002 mole) of pyridine and toluene produced an oil. The oil was subjected to vacuum column chromatography, whereby the oil was placed on silica gel packed in a sintered glass suction funnel, and the eluant was drawn through by water aspirator vacuum. Elution was accomplished with hexane, then 24:1 hexane/ethyl acetate to give (+)-4-phenyl-2-indanyl (+)-cis-3-(2,2-dibromoethenyl)-2,2-dimethylcyclopropanecarboxylate as an oil, EE 50% (alcohol moiety). The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [OH:1][C:2]1[C:10]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:18])[N:6]2[CH3:17].[C:19]1(C)C=CC=C[CH:20]=1.C(O)C.C(C=P(CCCC)(CCCC)CCCC)#N>ClCCl.[Cl-].[Na+].O>[CH2:19]([O:1][C:2]1[C:10]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:18])[N:6]2[CH3:17])[CH3:20]
Reactant: Cc1ccccc1
Reactant: CN1C(=O)Cc2c1ccc(-c1cccnc1)c2O
Agent: CCCCP(=CC#N)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: CCOc1c(-c2cccnc2)ccc2c1CC(=O)N2C
Temperature: 105 °C

Procedure:
A microwavable vial was charged with 4-hydroxy-1-methyl-5-pyridin-3-yl-1,3-dihydro-indol-2-one (48.1 mg, 0.2 mmol), toluene (2 ml), and ethanol (23.3 μL, 0.4 mmol). Cyanomethylene-tri-n-butylphosphorane (CAS#157141-27-0, 169 mg, 0.700 mmol) was then added to the vial. The reaction vial was sealed and was heated by microwave irradiation at 105° C. for 1 hour. The reaction mixture was cooled to room temperature and diluted with dichloromethane and brine. The layers were separated and the aqueous layer was extracted an additional two times with dichloromethane. The organic layers were combined dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethyl acetate-heptane, 0 to 100%). Further purification was accomplished via reverse phase HPLC (10 to 40% acetonitrile/water w/0.1% NH4OH) to afford 4-ethoxy-1-methyl-5-pyridin-3-yl-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 269.1289 (M+H)+, 1H NMR (400 MHz, CD2Cl2) δ ppm 1.16 (t, J=6.95 Hz, 3H), 3.20 (s, 3H), 3.60 (s, 2H), 3.85 (q, J=6.91 Hz, 2H), 6.68 (d, J=8.08 Hz, 1H), 7.28 (d, J=8.08 Hz, 1H), 7.32 (dd, J=7.83, 4.80 Hz, 1H), 7.85 (dt, J=7.89, 1.99 Hz, 1H), 8.51 (dd. J4.80, 1.77 Hz, 1H), 8.71 (d, J=2.78 Hz, 1H).
Reaction SMILES: [C@@H]1(NC2C3C=CN([C@H]4C[C@H:23]([OH:25])[C@H:22](CO)C4)C=3N=CN=2)C2C(=CC=CC=2)CC1.N1C=CN=C1.[Si](Cl)(C(C)(C)C)(C)C.[Si:41]([O:48][CH2:49][C@@H:50]1[CH2:54][C@@H:53]([N:55]2[C:59]3[N:60]=[CH:61][N:62]=[C:63]([NH:64][C@@H:65]4[C:73]5[C:68](=[CH:69][CH:70]=[CH:71][CH:72]=5)[CH2:67][CH2:66]4)[C:58]=3[CH:57]=[CH:56]2)[CH2:52][C@@H:51]1[OH:74])([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42].C(OC(=O)C)(=O)C>CN(C)C1C=CN=CC=1.CN(C=O)C.N1C=CC=CC=1>[C:23]([O:74][C@H:51]1[CH2:52][C@H:53]([N:55]2[C:59]3[N:60]=[CH:61][N:62]=[C:63]([NH:64][C@@H:65]4[C:73]5[C:68](=[CH:69][CH:70]=[CH:71][CH:72]=5)[CH2:67][CH2:66]4)[C:58]=3[CH:57]=[CH:56]2)[CH2:54][C@H:50]1[CH2:49][O:48][Si:41]([C:44]([CH3:47])([CH3:45])[CH3:46])([CH3:42])[CH3:43])(=[O:25])[CH3:22]
Reactant: OC[C@@H]1C[C@@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@@H]1O
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@@H]1O
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)O[C@H]1C[C@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
(1S,2S,4R)-4-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}-2-(hydroxymethyl)cyclopentanol (3.00 g, 8.23 mmol), 1H-imidazole (1.68 g, 24.7 mmol) and 4-(dimethylamino)-pyridine (100 mg, 0.818 mmol) were dissolved in DMF (90.0 mL) under an atmosphere of argon and the solution was cooled to 0° C. tert-Butyldimethylsilyl chloride (1.24 g, 8.23 mmol) was added and the mixture was stirred at rt for 2 h. LC/MS indicated complete conversion. The reaction was quenched with saturated aqueous sodium chloride solution (30 mL), extracted with EtOAc (3×50 mL), dried with MgSO4, filtered, and concentrated in vacuo. The remaining DMF was removed under high vacuum. Crude (1S,2S,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentanol (3.94 g, 8.23 mmol) and 4-(dimethylamino)-pyridine (100. mg, 0.818 mol) were dissolved in pyridine (70.0 mL) and acetic anhydride (4.66 mL, 49.4 mmol) was added. The mixture was stirred at rt overnight. The solvent was evaporated and the remaining pyridine was removed under high vacuum. The residue was purified via silica gel chromatography eluting with a gradient of 10 to 66% EtOAc in hexanes to afford the title compound (3.66 g, 86%). LC/MS: Rt=2.51 min, ES+ 521 (AA standard).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[CH:12])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1.I[C:37]1[N:41]([S:42]([C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=2)(=[O:44])=[O:43])[N:40]=[CH:39][CH:38]=1.C(NC(C)C)(C)C>C(OCC)(=O)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][C:37]2[N:41]([S:42]([C:45]3[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=3)(=[O:43])=[O:44])[N:40]=[CH:39][CH:38]=2)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH2:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1
Reactant: Cc1ccc(S(=O)(=O)n2nccc2I)cc1
Reactant: C#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCOCC4)c(OC)cc23)c2c1OCO2
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: COc1cc2c(Nc3c(Cl)cc(C#Cc4ccnn4S(=O)(=O)c4ccc(C)cc4)c4c3OCO4)ncnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.3 %

Procedure:
A solution of N-(5-chloro-7-ethynyl-1,3-benzodioxol-4-yl)-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-amine (0.140 g, 0.28 mmol ), 5-iodo-1-[(4-methylphenyl)sulfonyl)-1H-pyrazole (0.147 g, 0.42 mmol) and diisopropylamine (0.078 ml, 0.56 mmol) in ethyl acetate (5 ml) was cooled to −20 C under a nitrogen atmosphere. To this mixture was added copper (I) iodide (0.016 g, 0.084 mmol) and bis(triphenylphospine)palladium (II) chloride (0.039 g, 0.056 mmol). The reaction mixture was allowed to warm to ambient temperature and then stirred overnight. The reaction mixture was filtered and then evaporated under reduced pressure. The residue was purified by flash chromatography on silica eluting with a mixture of 0-8% methanol in dichloromethane to give the product as a yellow solid (0.103 g, 51%). Mass Spectrum: M+H+ 717 and M+H− 715.
Reaction SMILES: COC1C=CC=CC=1C(Cl)=O.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][C:28]=1[F:34].[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43]([N:45]=[C:46]=[S:47])=[O:44]>C1(C)C=CC=CC=1.C(O)C>[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43]([N:45]=[C:46]=[S:47])=[O:44].[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH:31][C:46]([NH:45][C:43](=[O:44])[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[O:36][CH3:35])=[S:47])=[CH:29][C:28]=1[F:34]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: COc1ccccc1C(=O)Cl
Agent: COc1ccccc1C(=O)N=C=S
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4OC)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
2-Methoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2-methoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-methoxy-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (65 mg, yield 80%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([CH:16]4[CH2:18][CH:17]4[C:19]([OH:22])([CH3:21])[CH3:20])[N:13]([CH3:23])[C:12]=3[CH:24]=2)[C:4](=[O:25])[CH:3]=1.[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:33]O)=[N:31][CH:32]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>CCOC(C)=O.C1COCC1>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:33][O:1][C:2]2[CH:7]=[CH:6][N:5]([C:8]3[CH:9]=[CH:10][C:11]4[N:15]=[C:14]([CH:16]5[CH2:18][CH:17]5[C:19]([OH:22])([CH3:20])[CH3:21])[N:13]([CH3:23])[C:12]=4[CH:24]=3)[C:4](=[O:25])[CH:3]=2)=[N:31][CH:32]=1
Reactant: Cn1c(C2CC2C(C)(C)O)nc2ccc(-n3ccc(O)cc3=O)cc21
Reactant: OCc1ccc(Cl)cn1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1c(C2CC2C(C)(C)O)nc2ccc(-n3ccc(OCc4ccc(Cl)cn4)cc3=O)cc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 49.9 %

Procedure:
To a mixture of 4-hydroxy-1-(2-((1RS,2SR)-2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (100 mg), (5-chloropyridin-2-yl)methanol (85 mg), tributylphosphine (0.219 ml) and THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (223 mg), and the mixture was stirred at 60° C. for 2 h. The reaction mixture was diluted with EtOAc, quenched with water, and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO4, filtered through silica pad, and concentrated in vacuo. The residue was purified by column chromatography (hexane/EtOAc then EtOAc/MeOH), followed by recrystallization from IPA-IPE to give the title compound (68.4 mg) as an off-white solid.
Reaction SMILES: Br[CH:2]([CH3:8])[C:3]([O:5]CC)=[O:4].[OH:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C(#N)C.C(O)C.C(OCC)(=O)C>[CH:14]([C:13]1[CH:16]=[CH:17][C:10]([O:9][CH:2]([CH3:8])[C:3]([OH:5])=[O:4])=[CH:11][CH:12]=1)=[O:15]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(Oc1ccc(C=O)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.5 %

Procedure:
A solution of ethyl 2-bromopropanoate (6.38 ml, 49.1 mmol), 4-hydroxybenzaldehyde (5.00 g, 40.9 mmol) and potassium carbonate (6.79 g, 49.1 mmol) in acetonitrile (25 ml) was stirred at 60° C. for 16 hrs. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by alumina column chromatography (developing solvent; ethyl acetate) to give an oil. To a solution of the obtained oil (9.10 g, 40.9 mmol) in ethanol (200 ml) was added 1N aqueous sodium hydroxide solution (61.4 ml), and the mixture was stirred at room temperature for 16 hrs, and concentrated under reduced pressure. Ethyl acetate was added to the obtained residue. The mixture was washed with 1N hydrochloric acid and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained redsidue was powderized with isopropyl ether to give the title compound (5.68 g).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:28]1[CH:32]=[CH:31][CH:30]=[N:29]1>>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:30]3[NH:29][N:28]=[CH:32][CH:31]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: c1cn[nH]c1
Product: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 9 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage 11.1) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole to afford a white solid. UPLC-MS (Condition 3) tR=0.97 min, m/z=450.2 [M+H]+, m/z=448.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.78 (m, 1H) 1.78-1.88 (m, 1H) 2.94 (d, J=11.92 Hz, 1H) 3.19-3.34 (m, 2H) 3.38-3.50 (m, 1H) 4.20 (br. s, 1H) 4.81-4.93 (m, 1H) 6.33-6.45 (m, 1H) 7.83 (m, J=113.40, 8.20 Hz, 3H) 7.93 (d, J=8.66 Hz, 2H) 7.99-8.08 (m, 1H) 8.70-8.81 (m, 1H) 10.30 (s, 1H) 12.90-13.16 (m, 1H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([O:11]C)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[Al+3].[Cl-].[Cl-].[Cl-].[C:17](Cl)(=[O:19])[CH3:18]>ClCCCl>[C:17]([C:8]1[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][C:7]=1[OH:11])(=[O:19])[CH3:18]
Reactant: COc1cccc(NC(C)=O)c1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)Nc1ccc(C(C)=O)c(O)c1
Reaction time: 0.5 h

Procedure:
67.5 g (0.41 mol)3-acetamidoanisol are suspended in 200 ml 1,2-dichloroethane and cooled in an ice bath. 217 g (1.64 mol) AlCl3 and after it 38.5 g (0.49 mol) acetylchloride were added successively. Stirring was continued 1/2 hour. After 5 hours the reaction was quenched with ice and ethylacetate and water were added. The organic layer was seperated, washed with water, dried over MgSO4 and concentrated in vacuo. The residue was recrystallized from dioxane and water.
Reaction SMILES: C(ONC([N:8]1[CH2:12][CH:11]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:10]([CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:21][CH2:20]2)[CH2:9]1)=O)C=C.[OH-].[K+].O.NN>C(O)CO.CCOCC>[C:25]1([CH:22]2[CH2:21][CH2:20][N:19]([CH2:18][CH:10]3[CH:11]([C:13]4[CH:17]=[CH:16][S:15][CH:14]=4)[CH2:12][NH:8][CH2:9]3)[CH2:24][CH2:23]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: C=CCONC(=O)N1CC(CN2CCC(c3ccccc3)CC2)C(c2ccsc2)C1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Solvent: CCOCC
Product: c1ccc(C2CCN(CC3CNCC3c3ccsc3)CC2)cc1
Temperature: 25 °C
Yield: 84.7 %

Procedure:
A solution of 0.19 g (0.47 mmol) of 1-allyloxycarbamoyl-3-(SR)-(4-phenylpiperidinylmethyl)-4-(RS)-(3-thienyl)pyrrolidine, 0.52 g (9.4 mmol) KOH and 0.23 mL (4.7 mmol) of hydrazine hydrate in 5 mL of ethylene glycol was heated at 140° C. for 12 h. The reaction mixture was cooled to rt and diluted with ether. The reaction mixture was washed 3 times with H2O, dried over Na2SO4, filtered and the filtrate was concentrated to give 0.13 g of the title compound. 1H NMR (CDCl3) δ7.22-7.37 (m, 7H), 7.04 (d, 1H, J=4.3 Hz), 3.32-3.39 (m, 2H), Mass Spectrum (CI) m/e=327 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][CH2:8][C:9]([NH:11][S:12]([C:15]1[C:16]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]3[C:32]([CH:33]=[O:34])=[C:31]([Cl:35])[N:30]=[C:29]3[CH2:36][CH2:37][CH2:38][CH3:39])=[CH:23][CH:22]=2)=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:14])=[O:13])=[O:10])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)C>[C:1]([O:5][C:6](=[O:40])[NH:7][CH2:8][C:9]([NH:11][S:12]([C:15]1[C:16]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]3[C:32]([CH2:33][OH:34])=[C:31]([Cl:35])[N:30]=[C:29]3[CH2:36][CH2:37][CH2:38][CH3:39])=[CH:23][CH:22]=2)=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:14])=[O:13])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)CNC(=O)OC(C)(C)C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)CNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
To an ethanol (10 mL) solution of intermediate (1c) (738 mg, 1.25 mmol) was added solid sodium borohydride (62 mg, 1.6 mmol). The mixture was stirred at room temperature for 1 hour. After cooling to 0° C., the reaction was quenched by dropwise addition of a 50/50 solution of acetic acid/water until no effervescence was observed. EtOAc (100 mL) was added and the organic was washed 3 times with saturated aqueous NaCl (100 mL) and dried over anhydrous Na2SO4. The solvent was removed to provide intermediate (1d) as a white solid (600 mg). Anal. HPLC: retention time=3.3 minutes. Gradient conditions: 25% solvent B/75% solvent A to 95° A solvent B/5° A solvent B over 6 minutes. MS m/z: [M+H]+ calcd for C28H35ClN4O6S, 591.20. found 591.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]([CH2:17][C:18]1[N:28]=[CH:27][C:26]([I:29])=[CH:25][C:19]=1[C:20](OCC)=[O:21])S(C1C=CC(C)=CC=1)(=O)=O)[CH3:2].[O-]CC.[Na+].O.Cl>C(O)C>[OH:21][C:20]1[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:30])=[N:6][CH:17]=[C:18]2[C:19]=1[CH:25]=[C:26]([I:29])[CH:27]=[N:28]2
Reactant: CCOC(=O)CN(Cc1ncc(I)cc1C(=O)OCC)S(=O)(=O)c1ccc(C)cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ncc2ncc(I)cc2c1O
Reaction time: 5 h

Procedure:
A mixture of ethyl 2-(((2-ethoxy-2-oxoethyl)((4-methylphenyl)sulfonyl)amino)methyl)-5-iodonicotinate (Preparation 11, 8.20 g) and sodium ethoxide (2.6 g) in anhydrous ethanol (60 mL) is stirred for 5 h. The mixture is then poured into water and neutralized with 3 N aqueous hydrochloric acid. The resulting precipitate is filtered and dried.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([C:11]1[S:19][C:18]2[C:13](=[N:14][CH:15]=[CH:16][C:17]=2[O:20][C:21]2[CH:22]=[CH:23][C:24]3[C:28]([C:29]([OH:31])=O)=[C:27]([CH3:32])[S:26][C:25]=3[CH:33]=2)[CH:12]=1)=[O:10].[NH2:34][CH2:35][CH2:36][CH2:37][OH:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>>[OH:38][CH2:37][CH2:36][CH2:35][NH:34][C:29]([C:28]1[C:24]2[CH:23]=[CH:22][C:21]([O:20][C:17]3[CH:16]=[CH:15][N:14]=[C:13]4[CH:12]=[C:11]([C:9]([N:5]5[CH2:6][CH2:7][CH2:8][C@H:4]5[CH2:3][O:2][CH3:1])=[O:10])[S:19][C:18]=34)=[CH:33][C:25]=2[S:26][C:27]=1[CH3:32])=[O:31]
Reactant: NCCCO
Reactant: COC[C@@H]1CCCN1C(=O)c1cc2nccc(Oc3ccc4c(C(=O)O)c(C)sc4c3)c2s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@@H]1CCCN1C(=O)c1cc2nccc(Oc3ccc4c(C(=O)NCCCO)c(C)sc4c3)c2s1
Yield: 87.7 %

Procedure:
This material was prepared by the reaction of 6-[(2-{[(2S)-2-(methoxymethyl)-pyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridin-7-yl)oxy]-2-methylbenzo[b]thiophene-3-carboxylic acid 121b (45 mg, 0.093 mmole) with 3-amino-1-propanol (21 μL, 0.28 mmole), HBTU (53 mg, 0.14 mmole), and diisopropylethylamine (36 μL, 0.21 mmole) in a manner as previously described for example 117 to give a yellow solid (44 mg, 88%). 1NMR (DMSO-d6, 300 MHz) δ 8.58 (1H, d, J=5.27 Hz), 8.36 (1H, t, J=5.46 Hz), 8.03 (1H, s), 7.96 (1H, d, J=2.26 Hz), 7.82 (1H, d, J=8.85 Hz), 7.33 (1H, dd, J=1.70, 8.67 Hz), 6.75 (1H, d, J=5.27 Hz), 4.51 (1H, t, J=5.18 Hz), 4.30 (1H, m), 3.85 (2H, m), 3.37 (2H, m), 3.27 (3H, s), 2.60 (3H, s), 2.09–1.83 (4H, m), 1.71 (2H, m).