Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]([CH3:15])[C:8](=[O:14])[CH:9]3[CH2:13][CH:10]32)=[CH:5][CH:4]=1.Cl[CH:17]([O:19]C)Cl>[Ti](Cl)(Cl)(Cl)Cl.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]([CH3:15])[C:8](=[O:14])[CH:9]3[CH2:13][CH:10]32)=[CH:5][C:4]=1[CH:17]=[O:19]
Reactant: COC(Cl)Cl
Reactant: COc1ccc2c(c1)C1CC1C(=O)N2C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc2c(cc1C=O)N(C)C(=O)C1CC21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a flame dried round bottom flask equipped with a nitrogen cap was added 935 mg (4.6 mmol) 6-Methoxy-3-methyl-1,1a,3,7b-tetrahydro-3-aza-cyclopropa[a]naphthalen-2-one, and 40 ml of methylene chloride. The solution was cooled to 0° C. and 46.1 ml (46.1 mmol) of 1.0 M titanium tetrachloride was added. Dichloromethylmethylether (2.09 ml (23.05 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched in 100 ml ice/1N HCl. The aqueous phase was extracted with chloroform (3×30 ml). The combined organics were then washed with saturated bicarbonate solution and then brine followed by drying over sodium sulfate and evaporation in vacuo. The crude residue was taken up in ethyl acetate whereupon crystals formed. Four crops totaling 902 mg were obtained. Mass spectrum APCI m/e 232 (p+1).
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])[C:13]([O:15][CH3:16])=[O:14])=O)C1C=CC=CC=1.[H][H]>Cl.[Pd]>[NH2:11][C@@H:12]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])[C:13]([O:15][CH3:16])=[O:14]
Reactant: [H][H]
Reactant: COC(=O)[C@H](CNC(C)=O)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Product: COC(=O)[C@@H](N)CNC(C)=O

Procedure:
To a solution of methyl 2(S)-benzyloxycarbonylamino-3-acetylaminopropionate (2.2 g) in ethanolic HCl was added 10% Pd/C (0.3 g) under nitrogen atmosphere. Hydrogen was applied to the mixture at 60 psi for 16 h. The mixture was filtered and concentrated in vacuo. The residue was triturated with diethyl ether to obtain the product. NMR (300 MHz, CD3OD) δ 4.20 (1H, m), 3.88 (3H, s), 3.82 (1H, m), 3.60 (1H, m), 1.99 (3H, s).
Reaction SMILES: [OH:1][CH:2]([CH2:15][OH:16])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:7][CH:6]=1.[C:17](Cl)(=O)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>ClCCl.N1C=CC=CC=1>[CH2:17]([O:1][CH:2]([CH2:15][O:16][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:7][CH:6]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: OCC(O)C#Cc1ccc(-c2cccs2)s1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOCC(C#Cc1ccc(-c2cccs2)s1)OCCCCCCCCCCCCCCCCCC
Reaction time: 48 h

Procedure:
170 mg (0.68 mmole) of 5-(3,4-dihydroxy-1-butynyl)-2,2-bithiophene was dissolved in a mixture of 10 ml of dichloromethane and 0.2 ml of pyridine. 0.7 g of stearoyl chloride dissolved in 10 ml of dichloromethane was then dropped into the reaction mixture in ice bath. This reaction solution was stirred for 2 days. It was monitored by thin layer chromatography to determine if there were 3 products obtained, i.e. a mixture of 1 diester and 2 monoesters.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH2:26][CH3:27])[C:7]([O:11][C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:15]=[CH:16][CH:17]=2)=[N:8][C:9]=1Cl)(=[O:3])[NH2:2].[Br:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>O>[Br:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][C:9]2[N:8]=[C:7]([O:11][C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:15]=[CH:16][CH:17]=3)[C:6]([CH2:26][CH3:27])=[N:5][C:4]=2[C:1](=[O:3])[NH2:2])=[CH:31][CH:30]=1
Reactant: CCc1nc(C(N)=O)c(Cl)nc1Oc1cccc(NC(=O)OC(C)(C)C)c1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCc1nc(C(N)=O)c(Oc2ccc(Br)cc2)nc1Oc1cccc(NC(=O)OC(C)(C)C)c1
Yield: 88.9 %

Procedure:
A mixture of tert-butyl {3-[(5-carbamoyl-6-chloro-3-ethylpyrazin-2-yl)oxy]phenyl}carbamate (500 mg), 4-bromophenol (440 mg), potassium carbonate (440 mg), and N-methylpyrrolidone (5 mL) was reacted at 100° C. for 4 hours. The reaction mixture was left to be cooled, and then water-saturated brine (1:1) was added thereto, followed by extraction with ethyl acetate. Then, the organic phase was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol=1:0-95:5, hexane:ethyl acetate=7:3-3:7) to obtain tert-butyl (3-{[6-(4-bromophenoxy)-5-carbamoyl-3-ethylpyrazin-2-yl]oxy}phenyl)carbamate (599 mg) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].[NH:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1>CCOCC>[Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([C:9]1[NH:8][CH:12]=[CH:11][CH:10]=1)=[O:4]
Reactant: c1cc[nH]c1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCOCC
Product: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Reaction time: 1 h
Yield: 84 %

Procedure:
To a mixture of anhydrous ether (130 mL) and trichloroacetyl chloride (95 mL; 0.85 mol) under a nitrogen purge was added pyrrole (50.03 g, 0.75 mol) dissolved in anhydrous ether (400 mL) via a dropping funnel over a 2-hour period. The now violet ether solution began to reflux slightly during addition. Refluxing was continued for an additional 1 hour before the reaction was quenched slowly with a solution of Na2CO3 (65 g) in water (200 mL). The layers were separated, and the red organic layer was washed four times with water and once with brine and finally dried over Na2SO4. The red ether solution was then treated twice with Norite (5 g) and filtered through Celite. The solvent was removed under vacuum to give the title compound (134.7 g, 0.63 mol, 85%). 1H-NMR (CDCl3): δ 9.65 (br s, 1H), 7.40 (m, 1H), 7.18 (m, 1H), 6.39 (dd, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C@H:17]2[C@H:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:20][N:19](CC3C=CC=CC=3)[CH2:18]2)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OC(Cl)C)=O>ClCCl>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C@H:17]2[C@H:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:20][NH:19][CH2:18]2)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1cn(C(=O)OC(C)(C)C)c2ccccc12
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CNC[C@H]1c1cn(C(=O)OC(C)(C)C)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of trans-tert-butyl-3-(1-benzyl-4-(ethoxycarbonyl)pyrrolidin-3-yl)-1H-indole-1-carboxylate (8.57 mmol) in dichloromethane (16 mL) was added 1-chloroethyl chloroformate (1.11 mL) slowly at 0° C. After addition, the mixture was warmed up to room temperature and stirred for 1 hr then concentrated under vacuum. Ethyl alcohol was added and the mixture was stirred at room temperature for 1 hr. The mixture was concentrated under vacuum to give the crude product as a white solid which was used for next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]([OH:18])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH: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.[NH2:53][C:54]1[S:55][C:56]([Br:59])=[CH:57][N:58]=1>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:18])[NH:53][C:54]1[S:55][C:56]([Br:59])=[CH:57][N:58]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncc(Br)s1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ncc(Br)s1)C1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (S)-Pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester (1.44 g, 5.78 mmol), HATU (2.2 g, 5.78 mmol), and DIEA (1.5 mL, 11.6 mmol)in DMF (30 mL) was stirred at room temperature for 1 h. The 2-Amino-5-bromo-thiazole hydrobromide salt (FW=259.95, 1.0 g, 3.85 mmol) was added. The reaction mixture was stirred at room temperature for 20 h. The mixture was filtered to afford the crude product. The mixture was filtered and separated by reverse phase HPLC (20-100% of buffer B; buffer A: water containing 0.1% TFA; buffer B: MeCN containing 0.1 TFA). The combined fraction was evaporated to dryness to furnish the desired product. MS: 504.1 (M+H+).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:8]=1[C:9]([OH:12])([CH3:11])[CH3:10].[CH2:18]([N:25]1[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[NH4+].[Cl-]>C1COCC1>[CH2:18]([N:25]1[CH2:30][CH2:29][C:28]([C:7]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:8]=2[C:9]([OH:12])([CH3:11])[CH3:10])([OH:31])[CH2:27][CH2:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(O)c1cc(F)ccc1Br
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(O)c1cc(F)ccc1C1(O)CCN(Cc2ccccc2)CC1
Temperature: -70 °C
Reaction time: 2 h

Procedure:
To an anhydrous THF (50 mL) cooled at −70° C. stirred under nitrogen a 2.5 M solution of n-BuLi (4.22 mL, 10.54 mmol) was added. Then 2-bromo-5-fluoro-α,α-dimethyl-benzylalcohol (1.17 g, 5.02 mmol) [C.A.S.853271-16-6] was added dropwise. The resulting mixture was stirred at −70° C. for 2 h. Then a solution of 1-benzylpiperidin-4-one (1.33 g, 7.028 mmol) in anhydrous THF (10 ml) was added dropwise. Then, the resulting solution was stirred at r.t. overnight. The reaction mixture was poured into NH4Cl (aqueous sat. solution) at 5-10° C. The resulting aqueous solution was extracted with DCM. The organic layer was separated and concentrated in vacuo. The residue was purified by column chromatography (silica gel; heptane/EtOAc from 100/0 to 60/40 as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate D83 (0.4 g, 23%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19](=O)[CH3:20])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1.[CH3:22][C:23]([S@:26]([NH2:28])=[O:27])([CH3:25])[CH3:24]>>[CH3:22][C:23]([S@:26]([NH:28][CH:19]([C:4]1[CH:5]=[N:6][C:7]([O:8][C:9]2[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=2)=[C:2]([CH3:1])[CH:3]=1)[CH3:20])=[O:27])([CH3:25])[CH3:24]
Reactant: CC(=O)c1cnc(Oc2ccc(C(F)(F)F)nc2)c(C)c1
Reactant: CC(C)(C)[S@](N)=O
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)cnc1Oc1ccc(C(F)(F)F)nc1
Yield: 73 %

Procedure:
The title compound is prepared in 73% yield (1.67 g, colorless amorphous) from 1-(5-methyl-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)ethanone (1.69 g, 5.70 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (1.04 g, 8.56 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[C:7]([NH:11][CH2:12][C:13]1[C:14]([F:43])=[C:15]([F:42])[C:16]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([I:40])=[CH:36][C:35]=2[F:41])=[C:17]([CH:32]=1)[C:18]([NH:20][O:21][CH2:22][CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])=[O:19])(=[O:10])[CH:8]=C>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[C:28]([Si:25]([CH3:27])([CH3:26])[O:24][CH2:23][CH2:22][O:21][NH:20][C:18](=[O:19])[C:17]1[CH:32]=[C:13]([CH2:12][NH:11][C:7](=[O:10])[CH:8]=[O:2])[C:14]([F:43])=[C:15]([F:42])[C:16]=1[NH:33][C:34]1[CH:39]=[CH:38][C:37]([I:40])=[CH:36][C:35]=1[F:41])([CH3:31])([CH3:29])[CH3:30]
Reactant: C=CC(=O)NCc1cc(C(=O)NOCCO[Si](C)(C)C(C)(C)C)c(Nc2ccc(I)cc2F)c(F)c1F
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCONC(=O)c1cc(CNC(=O)C=O)c(F)c(F)c1Nc1ccc(I)cc1F
Reaction time: 3 h

Procedure:
Aqueous osmium tetroxide (4%, 0.1 mL) and sodium metaperiodate (12 mg, 0.056 mmol) were added to a solution of 5-(acryloylamino-methyl)-N-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide (7.3 mg, 0.011 mmol) obtained in Step B in tetrahydrofuran (4 mL) and water (1 mL). The mixture was stirred for 3 hours. After the disappearance of the starting material was confirmed by LC/MS, the reaction mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give N-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-[(2-oxo-acetylamino)-methyl]-benzamide. Subsequently, this was dissolved in methanol (2.0 mL). Sodium borohydride (3 mg, 0.079 mmol) was added to this solution at room temperature, and the mixture was stirred for 1 hour. After completion of the reaction, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The resultant crude product was purified by silica gel flash chromatography (Mega Bond Elut, Varian, 60% ethyl acetate/hexane as an eluent) to give N-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-[(2-hydroxy-acetylamino)-methyl]-benzamide (4.34 mg, 60% in 2 steps) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[CH2:7][O:6][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C@:17]([OH:38])([CH2:18][C@@H:19]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:20][C@@H:21]3[OH:29])[CH:16]=[CH:15]4)[CH2:12][CH2:11]2)[CH3:9])[O:4][CH2:3]1.[O:40]1[CH2:44]CO[CH:41]1C([C@@H]1[C@]2(C)[C@H]([C@H]3[C@H](CC2)[C@]2(C)[C@](O)(C[C@@H](O)C[C@@H]2O)C=C3)CC1)C>>[CH3:39][C:2]1([CH3:1])[CH2:7][O:6][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C@:17]([OH:38])([CH2:18][C@@H:19]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:20][C@@H:21]3[O:29][CH2:41][O:40][CH3:44])[CH:16]=[CH:15]4)[CH2:12][CH2:11]2)[CH3:9])[O:4][CH2:3]1
Reactant: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3C=C[C@@]4(O)C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C1OCCO1)[C@H]1CC[C@H]2[C@@H]3C=C[C@@]4(O)C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Product: COCO[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@]2(O)C=C[C@H]3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]12C
Yield: 74.2 %

Procedure:
The reaction and workup procedures of Example 110 were repeated except that 400 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-3β-(tert-butyldimethylsilyl)oxypregn-6-ene-1α,5α-diol was used in lieu of 400 mg of 20-(1,3-dioxolan-2-yl)pregn-6-ene-1α,3β,5α-triol to give 320 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-3β-(tertbutyldimethylsilyl)oxy-1α-(methoxymethyl)oxypregn-6-en-5α-ol showing the following physical properties.
Reaction SMILES: [O:1]=[C:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[CH:8]=2)[NH:3]1.C1COCC1.C(N(CC)C(C)C)(C)C.[CH3:30][O:31][CH2:32][C@H:33]1[CH2:37][CH2:36][CH2:35][NH:34]1>C(Cl)(Cl)Cl>[CH3:30][O:31][CH2:32][C@H:33]1[CH2:37][CH2:36][CH2:35][N:34]1[S:12]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2](=[O:1])[C:10]2=[O:11])(=[O:14])=[O:13]
Reactant: O=C1Nc2ccc(S(=O)(=O)Cl)cc2C1=O
Reactant: COC[C@H]1CCCN1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COC[C@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2
Reaction time: 1 h
Yield: 63.6 %

Procedure:
To a stirred cold suspension of 2,3-dioxo-2,3-dihydro-1H-indol-5-sulfonyl chloride (5.00 g, 20.4 mmol) in a 1:1 mixture of THF: CHCl3 (140 mL) was added dropwise, via syringe pump, a solution of N,N-diisopropylethylamine (7.11 mL, 40.8 mmol, 2 eq) and (R)-2-(Methoxymethyl)pyrrolidine (3.27 mL, 26.5 mmol, 1.3 eq) in CHCl3 (60 mL) over a period of 1.5 hours with cooling in an ice bath. After stirring an additional 1 h, the reaction was concentrated. The crude product was purified on Biotage KP silica gel eluting with 95/5 CH2Cl2/CH3OH followed by a second chromatography on silica gel eluting with EtOAc to give 4.21 g (63.8% ) of the title compound. NMR (400 MHz, DMSO-d6): consistent.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[CH2:7][CH:8]1[C:15]2[CH:14]=[C:13]([C:16]([O:18]C)=[O:17])[NH:12][C:11]=2[CH2:10][CH2:9]1)(=[O:3])[CH3:2].[OH-].[Li+].CO>C1COCC1>[C:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[CH2:7][CH:8]1[C:15]2[CH:14]=[C:13]([C:16]([OH:18])=[O:17])[NH:12][C:11]=2[CH2:10][CH2:9]1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1cccc(C(C)=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)c1cccc(CC2CCc3[nH]c(C(=O)O)cc32)c1
Yield: 9 %

Procedure:
The title compound was synthesized from methyl 4-(3-acetylbenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.006 g, 0.020 mmol) and lithium hydroxide (0.010 g, 0.24 mmol in 0.5 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (1 mL) was used. The resulting product was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-50% EtOAc/heptane affording the title compound: 0.5 mg, 9% yield. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.56-2.61 (m, 7H), 2.79-2.91 (m, 2H), 6.29 (s, 1H), 7.39-7.44 (m, 1H), 7.44-7.46 (m, 1H), 7.78 (s, 1H), 7.82-7.86 (m, 1H); LCMS-MS (ESI−) 282.2 (M−H); HPLC (UV=100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:13][CH:12]([O:14][CH3:15])[CH2:11]2)=[O:9])=[CH:4][C:3]=1[O:16][CH3:17].C(O)(C(F)(F)F)=O.[CH3:25][N:26]1[CH:30]=[C:29]([C:31]2[C:36]3[N:37]=[C:38](S(C)(=O)=O)[N:39]=[CH:40][C:35]=3[CH:34]=[CH:33][N:32]=2)[CH:28]=[N:27]1>FC(F)(F)CO.CCOC(C)=O>[CH3:17][O:16][C:3]1[CH:4]=[C:5]([C:8]([N:10]2[CH2:13][CH:12]([O:14][CH3:15])[CH2:11]2)=[O:9])[CH:6]=[CH:7][C:2]=1[NH:1][C:38]1[N:39]=[CH:40][C:35]2[CH:34]=[CH:33][N:32]=[C:31]([C:29]3[CH:28]=[N:27][N:26]([CH3:25])[CH:30]=3)[C:36]=2[N:37]=1
Reactant: COc1cc(C(=O)N2CC(OC)C2)ccc1N
Reactant: Cn1cc(-c2nccc3cnc(S(C)(=O)=O)nc23)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: OCC(F)(F)F
Product: COc1cc(C(=O)N2CC(OC)C2)ccc1Nc1ncc2ccnc(-c3cnn(C)c3)c2n1
Reaction time: 18 h
Yield: 20.4 %

Procedure:
A solution of (4-amino-3-methoxyphenyl)(3-methoxyazetidin-1-yl)methanone (Preparation 28, 56 mg, 0.237 mmol), TFA (46 μL, 0.601 mmol) and 8-(1-methyl-1H-pyrazol-4-yl)-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine (Preparation 35, 35 mg, 0.121 mmol) in 2,2,2-trifluoroethanol (0.6 mL) was heated to reflux for 5 hours and then to 80° C. for 18 hours. The reaction was diluted with EtOAc, quenched with aqueous saturated NaHCO3 and the aqueous layer extracted with EtOAc. The combined organic layers were washed with water, brine, dried, concentrated in vacuo and purified by silica gel column chromatography eluting with 0 to 100% EtOAc in cyclohexane followed by a second chromatography eluting with 0 to 10% MeOH in EtOAc to afford the title compound (11 mg, 20%). 1H 1HNMR (500 MHz, DMSO-d6): δ 9.43 (s, 1H), 9.17 (s, 1H), 8.64 (s, 1H), 8.40 (d, J=5.2 Hz, 1H), 8.28 (s, 1H), 8.05 (d, J=8.1 Hz, 1H), 7.62 (d, J=5.2 Hz, 1H), 7.42-7.28 (m, 2H), 4.56 (s, 1H), 4.33-4.20 (m, 3H), 3.89-3.87 (m, 7H), 3.25 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:28])=[C:6]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[O:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[C:9]2=[O:27])[CH:7]=1.[C:29]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:28][CH2:29][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH2:17][C:18]4[O:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=4)[C:9]3=[O:27])[C:6]=2[CH:7]=1
Reactant: O=C1C(c2cc(Br)ccc2O)c2ccccc2N1Cc1ccc(C(F)(F)F)o1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccccc2C12COc1ccc(Br)cc12

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 3-(5-bromo-2-hydroxyphenyl)-1-((5-(trifluoromethyl)furan-2-yl)methyl)indolin-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 5-bromo-1′-((5-(trifluoromethyl)furan-2-yl)methyl)-2H-spiro[benzofuran-3,3′-indolin]-2′-one was obtained (78%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.36-7.27 (m, 2H), 7.17-6.98 (m, 3H), 6.8 (d, J=8.6 Hz, 1H), 6.78-6.72 (m, 2H), 6.39 (d, J=3.4 Hz, 1H), 5.07-5.87 (m, 3H), 4.69 (d, J=9.1 Hz, 1H); MS (ES+) m/z 463.9 (M+1), 465.9 (M+1).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]([C:9]1[CH:37]=[CH:36][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([S:20][C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][C@H:31]4[CH2:35][CH2:34][O:33][CH2:32]4)=[O:29])=[CH:23][CH:22]=3)[CH2:16][CH2:15]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].ClC1C=C(C=CC=1)C(OO)=[O:45]>ClCCl.CO>[F:5][C:4]([F:7])([F:6])[C:3]([C:9]1[CH:37]=[CH:36][C:12]([CH2:13][N:14]2[CH2:15][CH2:16][CH:17]([S:20]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][C@H:31]4[CH2:35][CH2:34][O:33][CH2:32]4)=[O:29])=[CH:23][CH:22]=3)=[O:45])[CH2:18][CH2:19]2)=[CH:11][CH:10]=1)([OH:8])[C:2]([F:38])([F:1])[F:39]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(Nc1ccc(SC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1)N[C@H]1CCOC1
Solvent: ClCCl
Solvent: CO
Product: O=C(Nc1ccc(S(=O)C2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1)N[C@H]1CCOC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(S)-1-(4-(1-(4-(1,1,1,3,3,3-Hexafluoro-2-hydroxypropan-2-yl)benzyl)piperidin-4-ylthio)phenyl)-3-(tetrahydrofuran-3-yl)urea (0.246 mmol, 142 mg) was dissolved in dichloromethane (5 mL) and the solution cooled to 0° C. 3-Chlorobenzoperoxoic acid (0.246 mmol, 42.4 mg) was added and the reaction mixture stirred for 2 hours. The reaction mixture was diluted with methanol and dichloromethane. The reaction mixture was washed with water and the organic layer separated, dried, and concentrated under vacuum. The residue was purified by silica column chromatography (eluting with a dichloromethane/methanol/ammonia gradient) to afford the title compound. MS m/z 594.5 [M+H]+