Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][O:12][CH3:13])[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7]2.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[S:24](Cl)(=[O:26])=[O:25]>N1C=CC=CC=1>[CH3:13][O:12][CH2:11][N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][S:24]([C:20]2[S:19][CH:23]=[CH:22][CH:21]=2)(=[O:26])=[O:25])[CH:7]=[C:8]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)c1cc2cccc(N)c2n1COC
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2n1COC
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
To a mixture of ethyl 7-amino-1-(methoxymethyl)-1H-indole-2-carboxylate (0.70 g) and pyridine (8 ml) was added thiophene-2-sulfonyl chloride (0.57 g) at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (1.03 g, yield 93%) as a yellow oil from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:23][C:24]2[CH:32]=[C:31]3[C:27]([CH:28]=[N:29][NH:30]3)=[CH:26][CH:25]=2)[C:5]2[C:10]([CH2:11]C)=[CH:9][N:8]([S:13]([C:16]3[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C:6]=2[N:7]=1.[NH2:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH2:45][CH2:44][N:43]([C:46](=[O:48])[CH3:47])[CH2:42][CH2:41]2)=[CH:36][CH:35]=1.C[Si](Cl)(C)C>C(O)CCC>[NH:30]1[C:31]2[C:27](=[CH:26][CH:25]=[C:24]([NH:23][C:4]3[C:5]4[C:10]([CH3:11])=[CH:9][N:8]([S:13]([C:16]5[CH:17]=[CH:18][C:19]([CH3:20])=[CH:21][CH:22]=5)(=[O:15])=[O:14])[C:6]=4[N:7]=[C:2]([NH:33][C:34]4[CH:35]=[CH:36][C:37]([N:40]5[CH2:41][CH2:42][N:43]([C:46](=[O:48])[CH3:47])[CH2:44][CH2:45]5)=[CH:38][CH:39]=4)[N:3]=3)[CH:32]=2)[CH:28]=[N:29]1
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: CCc1cn(S(=O)(=O)c2ccc(C)cc2)c2nc(Cl)nc(Nc3ccc4cn[nH]c4c3)c12
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(=O)N1CCN(c2ccc(Nc3nc(Nc4ccc5cn[nH]c5c4)c4c(C)cn(S(=O)(=O)c5ccc(C)cc5)c4n3)cc2)CC1
Temperature: 115 °C
Yield: 18.5 %

Procedure:
To a mixture of 2-Chloro-N-(1H-indazol-6-yl)-5-ethyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.08 g, 0.17 mmol) and 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (0.075 g, 0.34 mmol) in n-butyl alcohol (2 mL) was added TMSCl (0.011 mL, 0.086 mmol). After heating at 115° C. for 48 h, the mixture was purified by preparative HPLC to give 1-(4-(4-(4-(1H-indazol-6-ylamino)-5-methyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone (0.02 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]2[N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:5]=[CH:6][CH:7]=1.[CH3:19][Br:20]>C(C(C)=O)C>[CH3:19][N+:14]1([C@H:9]2[C@@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=3)[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:18][CH2:17][CH2:16][CH2:15]1.[Br-:20]
Reactant: Oc1cccc([C@H]2CCCC[C@H]2N2CCCC2)c1
Reactant: CBr
Solvent: CCC(C)=O
Product: C[N+]1([C@@H]2CCCC[C@@H]2c2cccc(O)c2)CCCC1
Product: [Br-]
Reaction time: 72 h

Procedure:
A solution of cis-2-(3-hydroxyphenyl)-1-pyrrolidinocyclohexane (0.6g) in ethylmethyl ketone was cooled in an ice/water bath and methyl bromide (1.5 ml) was added. The flask was tightly stoppered and set aside at room temperature for 72 hours. The solid (0.7g) was collected and recrystallised from ethyl acetate/ethanol to give cis-2-(3-hydroxyphenyl)-1-pyrrolidinocyclohexane methobromide (0.4g) m.p. 189° to 192° C.
Reaction SMILES: CC([O-])(C)C.[K+].[CH2:7]([O:9]C=O)[CH3:8].[CH3:12][CH:13]([CH3:19])[CH2:14][CH2:15][C:16](=[O:18])C>C1COCC1.CC(=O)OCC>[OH:18][CH:16]=[C:15]([CH2:14][CH:13]([CH3:19])[CH3:12])[C:7](=[O:9])[CH3:8]
Reactant: CCOC=O
Reactant: CC(=O)CCC(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)C(=CO)CC(C)C
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 65.6 %

Procedure:
To a solution of KOtBu (50 g, 446 mmol) in THF (400 mL) is added during 30 min ethylformate (92 g, 1.25 mol). Strong gas evolution occurs. The mixture is cooled during the addition with a water bath at 10° C. After complete addition, the mixture is stirred until the gas evolution ceases (15 min). The mixture is cooled with ice at 0° C. and a mixture of 5-methyl-2-hexanone (34.25 g, 300 mmol) and ethylformate (41 g, 0.55 mol) is added slowly during 30 min. The mixture is stirred for 15 h, diluted with EA (500 mL) and washed with 1 N aq. HCl (100 mL), 1 M aq. NaH2PO4 solution (100 mL) and brine (100 mL). The organic extract is dried (MgSO4), filtered and evaporated to give crude 4-hydroxy-3-isobutyl-but-3-en-2-one (28 g) which is used without further purification; LC-MS: tR=0.80 min, [M+1]=143.39.
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]2[O:21][CH:20]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:25][CH:24]=3)[CH2:19][CH2:18][C:17]=2[CH:37]=1)[C:10]#N)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[OH-:41].[Na+:42].Cl.[OH2:44]>>[CH2:1]([O:8][CH:9]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]2[O:21][CH:20]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:25][CH:24]=3)[CH2:19][CH2:18][C:17]=2[CH:37]=1)[C:10]([O-:44])=[O:41])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+:42]
Reactant: N#CC(Cc1ccc2c(c1)CCC(Cc1ccc(OCc3ccccc3)cc1)O2)OCc1ccccc1
Reactant: O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C([O-])C(Cc1ccc2c(c1)CCC(Cc1ccc(OCc3ccccc3)cc1)O2)OCc1ccccc1

Procedure:
A mixture of 2-benzyloxy-3-[2-(4-benzyloxybenzyl)-3,4-dihydro-2H-benzopyran-6-yl]propanenitrile (0.23 g, 0.47 mmol), ethanol (10 ml) and 6N sodium hydroxide (2 ml) was heated to reflux for 5 hours. Water (50 ml) was added and the solution was acidified with concentrated hydrochloric acid (2 ml), then extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated to an oil (0.19 g). The product was dissolved in methanol and treated with sodium methoxide (21 mg). The solvent was removed and the solid dried (7 mg, m.p. 165°-169° C.).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[F:27][C:28]1[CH:41]=[CH:40][C:31]2[S:32][C:33]([S:36]([Cl:39])(=[O:38])=[O:37])=[C:34]([CH3:35])[C:30]=2[CH:29]=1>CS(C)=O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][S:36]([C:33]3[S:32][C:31]4[CH:40]=[CH:41][C:28]([F:27])=[CH:29][C:30]=4[C:34]=3[CH3:35])(=[O:38])=[O:37])=[C:18]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:35][C:34]1[C:30]2[CH:29]=[CH:28][CH:41]=[CH:40][C:31]=2[S:32][C:33]=1[S:36]([Cl:39])(=[O:37])=[O:38]
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(F)cc12
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c(S(C)(=O)=O)c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1c(S(=O)(=O)Cl)sc2ccccc12
Product: Cc1c(S(=O)(=O)Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2S(C)(=O)=O)sc2ccc(F)cc12
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 321.2 %

Procedure:
To an ice cooled suspension of sodium hydride (60-65% in mineral oil, 0.030 g) in absolute DMSO (3 ml) was added 4-(4-amino-3-methanesulfonyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.106 g). The mixture was stirred at 0-5° C. for 30 minutes, and a solution 5-fluoro-3-methylbenzo[b]thiophene-2-sulphonyl chloride (0.237 g) in absolute DMSO (1 ml) was added dropwise. The reaction mixture was stirred at rt for 5 h, quenched with ice/water/1 N HCl, and extracted with ethyl acetate. The organic phases were washed, dried and concentrated, and the residue was chromatographed over silica gel using heptane/ethyl acetate as eluent to obtain the desired compound (0.0.025 g) methylbenzo[b]thiophene-2-sulphonyl chloride (0.237 g) to obtain the desired compound (0.025 g) as a yellowish foam. MS (ISN): 581.3 (M−H)−
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](OC(C)(C)C)=O)[CH2:8]1.ClC1[N:45]=[CH:44][C:43]([Cl:46])=[CH:42][C:25]=1[C:26]([NH:28][C:29]1([C:32]2[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=2)[CH2:31][CH2:30]1)=[O:27]>>[Cl:46][C:43]1[CH:44]=[N:45][C:13]([N:9]2[CH2:10][CH2:11][CH2:12][CH:7]([CH2:6][O:5][C:4]3[CH:20]=[CH:21][CH:22]=[C:2]([F:1])[CH:3]=3)[CH2:8]2)=[C:25]([CH:42]=1)[C:26]([NH:28][C:29]1([C:32]2[CH:33]=[CH:34][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:40][CH:41]=2)[CH2:31][CH2:30]1)=[O:27]
Reactant: CC(C)(C)OC(=O)N1CCCC(COc2cccc(F)c2)C1
Reactant: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3Cl)CC2)cc1
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CCCC(COc4cccc(F)c4)C3)CC2)cc1
Yield: 112 %

Procedure:
The title compound (D203) (97 mg) was prepared according to the experimental procedure described in Description 160 starting from tert-butyl 3-((3-fluorophenoxy)methyl)piperidine-1-carboxylate (D45) (100 mg, 0.323 mmol) and reacting in the second step with methyl 4-(1-(2,5-dichloronicotinamido)cyclopropyl)benzoate (D97) (59 mg, 0.161 mmol).
Reaction SMILES: [C:1]([OH:13])(=O)[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Br:47][C:48]1[N:53]2[CH:54]=[C:55]([NH2:57])[N:56]=[C:52]2[C:51]([N:58]2[CH2:63][CH2:62][O:61][CH2:60][CH2:59]2)=[N:50][CH:49]=1>C(Cl)Cl>[Br:47][C:48]1[N:53]2[CH:54]=[C:55]([NH:57][C:1]([C:2]3[CH:11]=[CH:10][C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=3)=[O:13])[N:56]=[C:52]2[C:51]([N:58]2[CH2:59][CH2:60][O:61][CH2:62][CH2:63]2)=[N:50][CH:49]=1
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: Nc1cn2c(Br)cnc(N3CCOCC3)c2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cn2c(Br)cnc(N3CCOCC3)c2n1)c1ccc2ccccc2n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of quinaldic acid (236 mg, 1.36 mmol) in DCM (10 mL) were added HATU (519 mg, 1.36 mmol) and DIEA (201 μL, 1.15 mmol) at 0° C. The reaction mixture was stirred for 0.5 h at 0° C. and treated with compound 21b (313 mg, 1.04 mmol). The resulting mixture was stirred at rt overnight. The solids formed were collected by filtration, and the organic phase was washed with saturated aqueous NH4Cl (20 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (9:1 DCM/EtOAc) to give compound 21c. Mass Spectrum (LCMS, ESI pos.) Calcd. for C20H17BrN6O2: 453.0 (M+H). Found 453.1.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][OH:26])[CH:19]=2)=[O:17])[NH:13][C:12]1=[O:27])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:29].[Na+]>CC(C)=O.O.[Ru](Cl)(Cl)Cl>[Si:1]([O:8][C@@H:9]([C@H:11]1[C:12](=[O:27])[NH:13][C@@H:14]1[CH2:15][C:16]([C:18]1[CH:19]=[C:20]([CH2:24][C:25]([OH:29])=[O:26])[CH:21]=[CH:22][CH:23]=1)=[O:17])[CH3:10])([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1CC(=O)c1cccc(CCO)c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1CC(=O)c1cccc(CC(=O)O)c1
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
(3S,4R)-3-((1R)-1-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-4-{2-[3-(2-hydroxyethyl)phenyl]-2-oxoethyl}azetidin-2-one (3.0 g) prepared by reference example 15 and ruthenium trichloride (79 mg) were dissolved in acetone (77 ml) and to the solution was added at room temperature a solution of sodium periodate (3.3 g) in water (40 ml). The solution was stirred for 30 minutes. Further, a solution of sodium periodate (0.66 g) in water (4 ml) was added thereto and the solution was stirred for 3 hours. After removal of insoluble materials by filtration with celite, acetone was removed under reduced pressure. To the aqueous layer (about 50 ml) was added a saturated aqueous sodium chloride solution (100 ml) and the mixture was extracted with ethyl acetate (3×50 ml). The organic layers were combined, dried over magnesium sulfate and filtered. The solvent was removed under reduced pressure to give (3-{[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidin-2-yl]acetyl}phenyl)acetic acid (2.72 g).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1([CH:15]=[C:16]2[NH:25][CH:24]3[CH2:26][CH:19]4[CH:20]([CH2:21][CH2:22][CH2:23]3)[CH:18]4[C:17]2=[O:27])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)(C)C>CCOCC.C1(C)C=CC=CC=1>[C:1]1([CH:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:16]2[NH:25][CH:24]3[CH2:26][CH:19]4[CH:20]([CH2:21][CH2:22][CH2:23]3)[CH:18]4[C:17]2=[O:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C(=Cc2ccccc2)NC2CCCC3C(C2)C13
Reactant: Br[Mg]c1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: O=C1C(C(c2ccccc2)c2ccccc2)NC2CCCC3C(C2)C13
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a 100 mL three-neck round-bottomed flask equipped with a condenser and nitrogen inlet was added 0.71 mL (4.21 mmol) of a 3M solution of phenyl magnesium bromide in ether. The solution was cooled to 0° C. and a solution of 818 mg (3.24 mmol) 9-phenylmethylene-10-azatricyclo[4.4.1.05,7 ]undecan-8-one in 16 mL toluene was added. The reaction was warmed to room temperature, stirred for 2 hours, and then quenched with aqueous ammonium chloride solution. The reaction was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel using hexane/ethyl acetate as eluent to afford an oil, 196 mg (18%). This material gave a solid from isopropanol, mp 178-181° C.
Reaction SMILES: CSC(=S)NN=CC1N=C(C2C=CC=CC=2)NC=1C.C[S:21][C:22](=S)[NH:23][N:24]=[CH:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[NH:29][C:30]=1[Cl:31]>>[Cl:31][C:30]1[N:29]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:27]2[C:26]=1[CH:25]=[N:24][NH:23][C:22]2=[S:21]
Reactant: CSC(=S)NN=Cc1nc(-c2ccccc2)[nH]c1Cl
Agent: CSC(=S)NN=Cc1nc(-c2ccccc2)[nH]c1C
Product: S=c1[nH]ncc2c(Cl)nc(-c3ccccc3)n12

Procedure:
The general procedure of Example 62 is repeated but replacing the 3-[(5-methyl-2-phenyl-4-imidazolyl)-methylene]dithiocarbazic acid methyl ester employed in that example with 3-[(5-chloro-2-phenyl-4-imidazolyl)methylene]dithiocarbazic acid methyl ester.
Reaction SMILES: [N:1]([CH2:4][CH:5]([OH:10])[CH:6]([OH:9])[CH2:7][OH:8])=[N+:2]=[N-:3].CO[C:13](OC)([CH3:15])[CH3:14].S(=O)(=O)(O)O.[OH-].[Na+]>CC(C)=O>[N:1]([CH2:4][CH:5]([CH:6]1[CH2:7][O:8][C:13]([CH3:15])([CH3:14])[O:9]1)[OH:10])=[N+:2]=[N-:3]
Reactant: COC(C)(C)OC
Reactant: [N-]=[N+]=NCC(O)C(O)CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC1(C)OCC(C(O)CN=[N+]=[N-])O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 14.71 g of 4-azido-1,2,3-butanetriol in 30 ml of acetone is combined with 13.95 g of 2,2-dimethoxypropane, as well as 0.1 ml of concentrated sulfuric acid. The mixture is stirred overnight at room temperature, neutralized with 2N sodium hydroxide solution, and concentrated to dryness under vacuum. The residue is distilled with a water-jet aspirator. 2-Azido-(2,2-dimethyl-1,3-dioxolan-4-yl)ethanol passes over as a colorless oil at 130°-132° C./13 mm. Yield: 11.79 g (63% of theory).
Reaction SMILES: [CH3:1][Si:2]([CH:5](O)[CH3:6])([CH3:4])[CH3:3].[OH:8][C:9]1[CH:18]=[CH:17][C:16]2[CH:15]3[CH2:19][C:20](=[O:21])[CH:12]([CH:13]4[C:25](=[O:26])[O:24][C:22](=[O:23])[CH:14]43)[C:11]=2[CH:10]=1.C1(NC2CCCCC2)CCCCC1.C(N)(C)C.C([OH:47])(C)C>CN(C1C=CN=CC=1)C.C(#N)C>[CH3:1][Si:2]([CH3:4])([CH3:3])[CH2:5][CH2:6][O:47][C:22]([CH:14]1[CH:13]([C:25]([OH:24])=[O:26])[CH:12]2[C:20](=[O:21])[CH2:19][CH:15]1[C:16]1[CH:17]=[CH:18][C:9]([OH:8])=[CH:10][C:11]=12)=[O:23]
Reactant: O=C1CC2c3ccc(O)cc3C1C1C(=O)OC(=O)C21
Reactant: CC(O)[Si](C)(C)C
Reactant: CC(C)O
Agent: C1CCC(NC2CCCCC2)CC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CC(C)N
Product: C[Si](C)(C)CCOC(=O)C1C2CC(=O)C(c3cc(O)ccc32)C1C(=O)O
Reaction time: 8 h
Yield: 42 %

Procedure:
DMAP (0.96 g, 7.9 mmol, 10 mol %) and trimethylsilyl-ethanol (12.43 mL, 0.087 mol, 1.1 eq) were added to a stirred suspension of the anhydride from step A (20.5 g, 0.079 mol) in 200 mL acetonitrile and heated to reflux for 7 hours. By HPLC there was some starting material present and the two regioisomers of the opened anhydride were present in a 1:1 ratio. The reaction mixture was cooled and dicyclohexylamine (15.71 mL, 0.079 mol) was added dropwise. A precipitate formed instantaneously but was left overnight. The resulting white salt (40.73 g, 93%) was filtered, suspended in water, acidified with 2 M HCl and extracted with ethyl acetate. An emulsion formed, but was removed by filtration before the layers could be separated, and the organic layer was dried and evaporated in vacuo to give a mixture of the regioisomeric acid-esters as a beige foam (25.59 g, 93%). A hazy solution of the solids (25.59 g, 0.068 mol) in 150 mL isopropanol was treated with isopropylamine (5.79 mL, 0.068 mol) and left stirring overnight. The precipitate was isolated by filtration yielding a white solid (12.44 g, 42% yield) as a 86/17 mixture of diastereomers. This solid was slurried in 48 mL isopropanol for 1.5 hours giving a second white solid (10.69 g) as a 93/7 mixture of diasteroemers. This salt was cracked as described above to give a white foam (6.76 g) which was then triturated in 33 mL 20% diethyl ether/toluene at −20° C. The resulting white solid was collected by filtration and washed with 10 mL cold solvent. This afforded 1 as a white solid (4.59 g, 300% overall yield from the anhydride) of 98.2% purity by HPLC. 1H NMR (acetonitrile-d3) 7.12 (d, J=8.0 Hz, 1H), 6.76 (d, J=2.5 Hz, 1H), 6.72 (dd, J=8.0, 2.5 Hz, 1H), 4.20-4.06 (m, 2H), 3.65 (d, J=3 Hz, 1H), 3.61 (br s, 1H), 3.22 (br d, J=11.0 Hz, 1H), 2.93 (br s, 1H), 2.85 (dd, J=18.3, 2.3 Hz, 1H), 2.04 (br d, 1H), 0.99-0.93 (m, 2H), 0.03 (s, 9H). MS for MNa+ 399.4. Elemental analysis for C19H24O6Si, Theoretical: C, 60.62; H, 6.43. Found: C, 60.61; H, 6.58.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.F[B-](F)(F)F.[O:18]=[N+:19]=[O:20].S1(CCCC1)(=O)=O>COCCOC>[N+:19]([C:6]1[CH:5]=[C:4]([O:3][C:2]([F:11])([F:12])[F:1])[CH:9]=[CH:8][C:7]=1[OH:10])([O-:20])=[O:18]
Reactant: O=[N+]=O
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: F[B-](F)(F)F
Solvent: COCCOC
Solvent: O=S1(=O)CCCC1
Product: O=[N+]([O-])c1cc(OC(F)(F)F)ccc1O
Temperature: -50 °C
Reaction time: 6 h

Procedure:
To a mixture of 4-(trifluoromethoxy)phenol (4 g, 0.0225 mol) in ethylene glycol dimethyl ether (90 mL) was added a 0.5 M solution of nitronium tetrafluoroborate in sulfolane (46 mL, 0.0229 mol) at −50° C. The mixture was stirred at −50° C. under an atmosphere of nitrogen for 6 hours. The mixture was filtered through silica gel pad, and the pad was washed with 25% ethyl acetate/n-heptane. The solvent was removed under reduced pressure, and the residue was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and brine. The solvent was removed under reduced pressure, and the residue was purified by flash column chromatography on silica using 0%-50% ethyl acetate/n-heptane as a mobile phase to give 2-nitro-4-(trifluoromethoxy)phenol (2.5 g, 0.011 mol). TLC (ethyl acetate/n-heptane=25:75) Rf 0.50 MS: MH−: 222
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([CH:10]([NH:13][C:14]([N:16]1[C:24]2[C:19](=[CH:20][C:21]([O:25][C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH2:32])[CH:27]=3)=[CH:22][CH:23]=2)[CH:18]=[CH:17]1)=[O:15])[CH2:11][CH3:12])[CH3:9].Cl[C:34]([O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:35]>O1CCCC1>[CH2:8]([CH:10]([NH:13][C:14]([N:16]1[C:24]2[C:19](=[CH:20][C:21]([O:25][C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:34](=[O:35])[O:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH:27]=3)=[CH:22][CH:23]=2)[CH:18]=[CH:17]1)=[O:15])[CH2:11][CH3:12])[CH3:9]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCC(CC)NC(=O)n1ccc2cc(Oc3ccnc(N)c3)ccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(CC)NC(=O)n1ccc2cc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)ccc21
Temperature: 0 °C
Yield: 91.5 %

Procedure:
Tetrahydrofuran (20 ml) and triethylamine (1.73 ml, 12.4 mmol) were added to N1-(1-ethylpropyl)-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide (1.45 g, 4.29 mmol); phenyl chloroformate (1.15 ml, 9.1 mmol) was added thereto at 0° C. while stirring; and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was partitioned between ethyl acetate and water; and the organic layer was concentrated and subjected to silica gel column chromatography to yield a mixture (1.8 g) of phenyl N-(4-(1-((1-ethylpropyl)amino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate and phenyl N-(4-(1-((1-ethylpropyl)amino)carbonyl-1H-5-indolyl)-oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamate. A portion of 0.6 g of the mixture was dissolved in N,N-dimethylformamide (5 ml); 4-(1-pyrrolidinyl)piperidine (0.7 g, 4.7 mmol) and stirred for 2 hours; the reaction mixture was partitioned between ethyl acetate and water; the organic layer was concentrated; and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate:methanol=10:1) to yield as white crystals (202 mg, 0.391 mmol).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:18]=[CH:17][C:8]([O:9][C:10]([CH3:16])([CH3:15])[C:11]([O:13]C)=[O:12])=[CH:7][CH:6]=1)=[O:4].[N:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C(N(CC)CC)C.C(OCC)C>C(#N)C>[BrH:1].[BrH:1].[N:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:26][CH2:27][N:28]([CH2:2][C:3]([C:5]3[CH:18]=[CH:17][C:8]([O:9][C:10]([CH3:16])([CH3:15])[C:11]([OH:13])=[O:12])=[CH:7][CH:6]=3)=[O:4])[CH2:29][CH2:30]2)=[CH:21][CH:20]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: COC(=O)C(C)(C)Oc1ccc(C(=O)CBr)cc1
Solvent: CCOCC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Br
Product: CC(C)(Oc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1)C(=O)O
Reaction time: 8 h

Procedure:
The product from step (i) above (2.00 g) in acetonitrile (10 ml) was added dropwise over 15 minutes to a stirred solution of 1-(4-pyridyl)piperazine (1.04 g) and triethylamine (0.89 ml) in acetonitrile (15 ml) and the mixture stirred overnight. The precipitated solid was removed by filtration and the filtrate evaporated. Purification of the residue by flash chromatography on silica, eluting with 0 to 5% v/v methanol/dichloromethane, gave a yellow gum. Trituration of this gum with diethyl ether gave methyl 2-[4-[2-[4-(4-pyridyl)piperazin-1-yl]acetyl]phenoxy]isobutryate, 170 mg, as a white solid: m.p. 88°-90° C.; NMR (d6 DMSO)δ8.15(2H,d), 7.96(2H,d), 6.82(4H,m), 3.92(2H,s), 3.70(3H,s), 3.33(4H,t), 2.63(4H,t), 1.60(6H,s); m/e 398 (M+H)+ ; calculated for C22H27N3O4.0.25H2O: C, 65.8; H, 6.8; N, 10.5. found: C, 65.8 H, 7.1; N, 10.4%.
Reaction SMILES: [Br:1]Br.[CH2:3]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[CH2:4][CH2:5][CH3:6]>C(Cl)(Cl)Cl>[Br:1][C:9]1[S:8][C:7]([CH2:3][CH2:4][CH2:5][CH3:6])=[CH:11][CH:10]=1
Reactant: BrBr
Reactant: CCCCc1cccs1
Solvent: ClC(Cl)Cl
Product: CCCCc1ccc(Br)s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Bromine, 5 ml (15.63 g or 0.0977 mol), was added to a solution of 15.2 g (0.108 mol) of 2-butylthiophene in 400 ml of chloroform. Following the addition, the mixture was stirred for 10 minutes at room temperature and was then washed with 10% aqueous sodium carbonate solution. The organic layer was separated, dried and evaporated and the remaining oil was distilled under high vacuum to yield a colorless oil. Nmr (CDCl3): 0.89 ppm (t, 3, J=7.5 Hz, CH3), 1.2-1.7 (m, 4, CH2CH2), 2.7 (t, 2, J=7.5 Hz, CH2), 6.47 (d, 1, J=4 Hz, C4-H), 6.78 (d, 1, J=4 Hz, C3-H).