Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:3]=1/[CH:4]=[N:5]/[S@:6]([C:8]([CH3:11])([CH3:10])[CH3:9])=[O:7].[In].[CH2:18](Br)[CH:19]=[CH2:20].C([O-])(O)=O.[Na+]>[Na+].[Br-]>[Br:1][C:2]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:3]=1[C@H:4]([NH:5][S@:6]([C:8]([CH3:11])([CH3:10])[CH3:9])=[O:7])[CH2:20][CH:19]=[CH2:18]
Reactant: CC(C)(C)[S@](=O)/N=C/c1cc(F)ccc1Br
Reactant: C=CCBr
Agent: O=C([O-])O
Agent: [Br-]
Agent: [In]
Product: C=CC[C@@H](N[S@@](=O)C(C)(C)C)c1cc(F)ccc1Br
Reaction time: 36 h

Procedure:
To a stirred suspension of (S,E)-N-(2-bromo-5-fluorobenzylidene)-2-methylpropane-2-sulfinamide (I-44) (153 mg, 0.50 mmol) and indium powder (230 mg, 2.0 mmol) in saturated NaBr (10 mL, aq) was added allyl bromide (169 μL, 2.0 mmol). After stirring 36 hours the reaction mixture was charged with saturated aqueous NaHCO3 and stirred 30 minutes. The mixture was extracted with EtOAc and combined extracts were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography with EtOAc/Hex (5-35%) as eluent to yield the (S)-N-((R)-1-(2-bromo-5-fluorophenyl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (I-45A) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.52 (dd, J=5.3, 8.8 Hz, 1 H), 7.14 (dd, J=3.1, 9.8 Hz, 1 H), 6.88 (ddd, J=3.1, 7.7, 8.7 Hz, 1 H), 5.77 (dddd, J=6.1, 8.2, 10.9, 16.6 Hz, 1 H), 5.28-5.16 (m, 2 H), 4.98-4.89 (m, 1 H), 3.74 (s, 1 H), 2.76-2.63 (m, 1 H), 2.39 (dt, J=8.3, 14.2 Hz, 1 H), 1.24 (s, 9 H). 19F NMR (376 MHz, CDCl3) δ −113.87. MS m/z 348.0, 350.0 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]=2[CH3:24])=[CH:4][CH:3]=1.[C:25]([O:29][CH3:30])(=[O:28])[CH:26]=[CH2:27].N(C)(C1CCCCC1)C1CCCCC1>O1CCOCC1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:30][O:29][C:25](=[O:28])/[CH:26]=[CH:27]/[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]=2[CH3:24])=[CH:4][CH:3]=1
Reactant: C=CC(=O)OC
Reactant: Cc1[nH]c2ccccc2c1CCN1CCCC1c1ccc(Br)cc1
Agent: [Pd]
Agent: CN(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)/C=C/c1ccc(C2CCCN2CCc2c(C)[nH]c3ccccc23)cc1
Yield: 63.2 %

Procedure:
A solution of 3-{2-[2-(4-bromo-phenyl)-pyrrolidin-1-yl]-ethyl}-2-methyl-1H-indole (630 mg, 1.63 mmol), methyl acrylate (286 mg, 3.26 mmol), Pd2(dba)3 (14.9 mg, 0.0162 mmol), P(t-Bu)3HBF4 (18.9 mg, 0.0652 mmol) and Cy2NMe (414 μL, 1.95 mmol) in dioxane (10 mL) was heated at 100° C. by microwave for 60 minutes. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to provide a crude product, which was purified on silica gel column chromatography to give (E)-3-(4-{1-[2-(2-Methyl-1H-indol-3-yl)-ethyl]-pyrrolidin-2-yl}-phenyl)-acrylic acid methyl ester (400 mg, 63%). LCMS (m/z): 388.97 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.[C:14]1([SH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([BH3-])#N.[Na+]>P(Cl)(Cl)(Cl)=O>[CH3:1][N:2]([CH3:13])[CH2:3][CH:4]=[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[S:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CN(C)C=CC(=O)c1ccccc1
Reactant: Sc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)CC=C(Sc1ccccc1)c1ccccc1

Procedure:
By using a method similar to that described in Example 35, but starting from 3-dimethylaminoacrylophenone (80 g), phosphorus oxychloride (40 cc), thiophenol (50.3 cc) and sodium cyanoborohydride (16 g), and crystallising the (Z)-isomer, a yellow solid is isolated after evaporation of the mother liquors under reduced pressure (2.7 kPa) at 30° C. followed by crystallisation of the residue obtained from a mixture of acetone and ethyl ether (25/75 by volume); the solid is recrystallised from methyl ethyl ketone (230 cc). 1-Dimethylamino-3-phenyl-3-phenylthio-2-propene (E) hydrochloride (14.3 g) is thus obtained in the form of a white solid melting at 146°-147° C.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([OH:9])=[O:8].[C:10]1([CH3:19])[CH:15]=[CH:14][CH:13]=[C:12](B(O)O)[CH:11]=1>>[C:10]1([CH3:19])[CH:15]=[CH:14][CH:13]=[C:12]([C:2]2[S:3][CH:4]=[CH:5][C:6]=2[C:7]([OH:9])=[O:8])[CH:11]=1
Reactant: O=C(O)c1ccsc1Br
Reactant: Cc1cccc(B(O)O)c1
Product: Cc1cccc(-c2sccc2C(=O)O)c1

Procedure:
prepared by reaction of 2-bromo-thiophene-3-carboxylic acid with m-tolylboronic acid. LC-MS (basic): tR=0.51 min; [M−H]−=217.3.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH:25]([CH3:27])[CH3:26])=[N:7][C:8]2[C:13]([C:14]=1OS(C(F)(F)F)(=O)=O)=[CH:12][C:11]([Cl:23])=[CH:10][C:9]=2[Cl:24])=[O:4].[CH2:28]([O:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)[CH3:29]>>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH:25]([CH3:27])[CH3:26])=[N:7][C:8]2[C:13]([C:14]=1[C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([O:30][CH2:28][CH3:29])[CH:36]=1)=[CH:12][C:11]([Cl:23])=[CH:10][C:9]=2[Cl:24])=[O:4]
Reactant: CCOc1cccc(B(O)O)c1
Reactant: COC(=O)c1c(C(C)C)nc2c(Cl)cc(Cl)cc2c1OS(=O)(=O)C(F)(F)F
Product: CCOc1cccc(-c2c(C(=O)OC)c(C(C)C)nc3c(Cl)cc(Cl)cc23)c1

Procedure:
The title compound was prepared in analogy to example 72 step C from 6,8-dichloro-2-isopropyl-4-trifluoromethanesulfonyloxy-quinoline-3-carboxylic acid methyl ester (prepared as described in example 72 step B) and 3-ethoxyphenylboronic acid. White solid. MS (ESI): 418.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[NH2:11].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][C:23](=[O:25])[NH:22][C:21]([CH3:26])=[C:20]2[C:27](O)=[O:28])=[CH:15][C:14]=1[O:30][CH3:31].C(Cl)CCl.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.Cl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][C:23](=[O:25])[NH:22][C:21]([CH3:26])=[C:20]2[C:27]([NH:11][C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][C:2]=2[F:1])[NH:8][N:7]=[CH:6]3)=[O:28])=[CH:15][C:14]=1[O:30][CH3:31]
Reactant: COc1cc(C2CC(=O)NC(C)=C2C(=O)O)ccc1Cl
Reactant: Nc1cc2cn[nH]c2cc1F
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COc1cc(C2CC(=O)NC(C)=C2C(=O)Nc2cc3cn[nH]c3cc2F)ccc1Cl
Temperature: 30 °C
Reaction time: 18 h
Yield: 29.3 %

Procedure:
6-Fluoro-1H-indazol-5-amine (102 mg, 0.676 mmol, 1.0 equiv) was combined with the product of Example 93, Step 4 (0.200 g, 0.676 mmol, 1.0 equiv), EDC (155 mg, 0.812 mmol, 1.2 equiv) and Et3N (113 μL, 0.812 mmol, 1.2 equiv) in DMF (2 mL) and stirred at 30° C. for 18 hours. The reaction mixture was diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HCl, once with satd. NaHCO3, and once with satd. NaCl. Solid precipitated out of the organic phase and was filtered and triturated with ether to provide 85.0 mg (29%) of the title compound as a white solid. MS (ES+) m/e 429 [M+H]+
Reaction SMILES: B(Br)(Br)Br.[C:5]([NH:8][C:9]1[NH:13][C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)=[N:11][C:10]=1[CH3:22])(=[O:7])[CH3:6]>C(Cl)Cl>[C:5]([NH:8][C:9]1[NH:13][C:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[N:11][C:10]=1[CH3:22])(=[O:7])[CH3:6]
Reactant: COc1ccc(-c2nc(C)c(NC(C)=O)[nH]2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(=O)Nc1[nH]c(-c2ccc(O)cc2)nc1C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 41.5 %

Procedure:
Methylene chloride, 125 ml was stirred and cooled to -78° C. in an acetone-dry ice bath. Boron tribromide (7.5 ml, 0.079 mole) was added, followed by 42 (6.15 g, 0.025 mole). After a 10 minutes period at -78° C., the bath was removed and the mixture was stirred at ambient temperature under a CaCl2 drying tube for 18 hours. The mixture was quenched in ice and water (500 ml) and the resulting mixture was neutralized with saturated NaHCO3 solution to pH 7. The aqueous layer was separated and evaporated to dryness in vacuo. The residue was triturated with boiling IPA and filtered hot. Evaporation of the filtrate to dryness under reduced pressure left an oil that was chromatographed on silica gel. The product was eluted with 80CHCl3 --20CH3OH saturated with concentrated NH4OH and then triturated with CH3CN to yield 2.4 g (41%) of 43; m.p. 277°-279° C.
Reaction SMILES: Cl.[NH2:2][OH:3].[Cl:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH:11]=O)[N:6]=1.C([O-])(=O)C.[Na+]>C(O)C>[Cl:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH:11]=[N:2][OH:3])[N:6]=1
Reactant: NO
Reactant: O=Cc1nccc(Cl)n1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=Cc1nccc(Cl)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Hydroxylamine hydrochloride (244 mg, 3.51 mmol), 4-chloropyrimidine-2-carboxaldehyde (500 mg, 3.51 mmol), and sodium acetate (288 mg, 3.51 mmol) were dissolved in dry ethanol (17.5 mL) and transferred to a flame-dried round bottom flask. The reaction was allowed to stir at room temperature for 20 minutes. It was then concentrated under reduced pressure, redissolved in ethyl acetate, and washed with water. The aqueous layer was extracted with ethyl acetate two times. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield the title compound.
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([C@@H:27]2[C@H:32]([NH:33][C:34](=O)[C:35]3[CH:49]=[CH:48][C:38]([C:39]([N:41]([CH:45]([CH3:47])[CH3:46])[CH:42]([CH3:44])[CH3:43])=[O:40])=[CH:37][CH:36]=3)[CH2:31][CH2:30][O:29][CH2:28]2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH3:17].CO.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[CH2:16]([O:18][C:19]1[CH:20]=[C:21]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[C:34]([C:35]1[CH:49]=[CH:48][C:38]([C:39]([N:41]([CH:45]([CH3:47])[CH3:46])[CH:42]([CH3:44])[CH3:43])=[O:40])=[CH:37][CH:36]=1)=[N:33][C@H:32]1[C@@H:27]2[CH2:28][O:29][CH2:30][CH2:31]1)[CH3:17]
Reactant: CCOc1cc([C@H]2COCC[C@H]2NC(=O)c2ccc(C(=O)N(C(C)C)C(C)C)cc2)ccc1OC
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N(C(C)C)C(C)C)cc1)=N[C@@H]1CCOC[C@H]21
Temperature: 0 °C

Procedure:
Alternatively a solution of 12.5 mmol of trifluoromethanesulfonic anhydride dissolved in 10 ml dichloromethane is added over a period of 20 min to a cooled (ice-water bath) solution of 2.5 mmol of N-[(3R,4R)-3-(3-Ethoxy-4-methoxy-phenyl)-tetrahydro-pyran-4-yl]-N′,N′-diisopropyl-terephthalamide and 7.5 mmol of 4-dimethylamino-pyridine in 30 ml of dichloromethane. The solution is stirred over night and then added to a cooled (ice-water bath) mixture of 10 ml of methanol, 10 ml of triethyl amine and 20 ml of dichloromethane and the mixture is stirred for 1 h. After concentration under reduced pressure the solid residue is purified by column chromatography on SiO2 (di-isopropylether/methanol/triethyl amine 18/1/1 vol/vol/vol), the main product fraction is separated and concentrated yielding the title compound as grayish solid foam. M.p. 98-102° C. (unsharp, enamel-like shrinking starting at about 88° C.)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([OH:13])=O)=[CH:9][N:10]=2)[CH:7]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:35][O:36][C:37]1[CH:38]=[C:39]([CH:41]=[C:42]([O:46][CH3:47])[C:43]=1[O:44][CH3:45])[NH2:40].CCN(C(C)C)C(C)C>C(#N)C.CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([NH:40][C:39]3[CH:41]=[C:42]([O:46][CH3:47])[C:43]([O:44][CH3:45])=[C:37]([O:36][CH3:35])[CH:38]=3)=[O:13])=[CH:9][N:10]=2)[CH:7]=1
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: O=C(O)c1cnc2ccc(Br)cn12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc(NC(=O)c2cnc3ccc(Br)cn23)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.2 %

Procedure:
A stirring solution of 6-bromoimidazo[1,2-a]pyridine-3-carboxylic acid (0.91 g, 3.7 mmol), EDCI (1.08 g, 5.6 mmol), HOBt (0.76 g, 5.6 mmol) and 3,4,5-trimethoxyaniline (0.76 g, 4.1 mmol) in acetonitrile/DMF (8/3 mL) under argon was added i-Pr2NEt (2.00 g, 2.6 ml), 15.4 mmol) drop wise for 5 min at room temperature. The resulting off-brown homogeneous reaction mixture was continued to stir at room temperature for 18 h. Subsequently, the heterogeneous reaction mixture was diluted with water and the solid was collected by filtration. The solid was suction dried on funnel to obtain 6-bromo-N-(3,4,5-trimethoxyphenyl)imidazo[1,2-a]pyridine-3-carboxamide (1.1 g) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.17 (s, 1H), 9.64 (s, 1H), 8.56 (d, J=1.1 Hz, 1H), 7.75 (d, J=9.7 Hz, 1H), 7.64 (dd, J=9.5, 1.9 Hz, 1H), 7.15 (s, 2H), 3.78 (s, 6H), 3.63 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N:7]2[C:19]3[C:18]4[CH:17]=[C:16](B5OC(C)(C)C(C)(C)O5)[CH:15]=[CH:14][C:13]=4[N:12]=[CH:11][C:10]=3[N:9]([CH3:29])[C:8]2=[O:30])[C:4]([CH3:31])=[N:3]1.Br[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1>>[CH3:1][N:2]1[CH:6]=[C:5]([N:7]2[C:19]3[C:18]4[CH:17]=[C:16]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=5)[CH:15]=[CH:14][C:13]=4[N:12]=[CH:11][C:10]=3[N:9]([CH3:29])[C:8]2=[O:30])[C:4]([CH3:31])=[N:3]1
Reactant: Brc1ccccn1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(B4OC(C)(C)C(C)(C)O4)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccccn4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described in Example 112 using 1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Stage 114.1.1, 34.5 mg, 0.082 mmol) and 2-bromopyridine (Aldrich, Buchs, Switzerland, 0.011 ml, 0.114 mmol) to give the title compound as a white solid. (HPLC: tR 2.25 min (Method A); M+H=371 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.98 (s, 1H), 8.67-8.61 (m, 1H), 8.30-8.24 (m, 1H), 8.17-8.06 (m, 3H), 7.94-7.86 (m, 1H), 7.67-7.61 (m, 1H), 7.39-7.32 (m, 1H), 3.95 (s, 3H), 3.57 (s, 3H), 1.95 (s, 3H))
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25](F)=[O:26])[CH:11]3[C:28]([CH3:30])=[CH2:29])[C:5]2=[CH:4][CH:3]=1.[NH2:32][CH2:33][CH2:34][OH:35].CN1CCOCC1>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25]([NH:32][CH2:33][CH2:34][OH:35])=[O:26])[CH:11]3[C:28]([CH3:30])=[CH2:29])[C:5]2=[CH:4][CH:3]=1
Reactant: C=C(C)C1N(CC(=O)F)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: NCCO
Agent: CN(C)c1ccncc1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: C=C(C)C1N(CC(=O)NCCO)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 36.8 %

Procedure:
In a manner similar to the method described in example 34b, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-fluorocarbonylmethyl-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.2 g, 0.433 mmol) prepared in example 116d was reacted with 2-amino-ethanol (61 mg, 0.86 mmol), N-methylmorpholine (90 mg, 0.86 mmol) and 4-dimethylaminopyridine (5 mg) in tetrahydrofuran to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(2-hydroxy-ethyl)aminocarbonyl-methyl]-2′-isopropenyl-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off-white solid (Yield: 80 mg, 36.8%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[CH2:31][NH:32][CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36]>ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([N:32]([CH2:31][C:23]1[N:22]([CH2:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH3:14])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=1)[CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])=[O:6]
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Reactant: Cc1ccccc1Cn1c(CNCCC(C)C)nc2ccccc21
Solvent: ClCCl
Product: COc1ccc(C(=O)N(CCC(C)C)Cc2nc3ccccc3n2Cc2ccccc2C)c(OC)c1
Yield: 95 %

Procedure:
A solution of 5.4 mmole 2-(chloromethyl)-1-[(2-methylphenyl)methyl]benzimidazole in 20 mL of dry Acetonitrile is treated with 10 mL of isoamylamine for 16 hr at room temperature. The solvent is removed in vacuo and the residue is partitioned between 30 mL of ethyl acetate and 10 mL of 1 N NaOH. The ethyl acetate layer is dried over anhydrous Na2SO4 and solvent removed in vacuo to afford 1.6 g 92% ({1-[(2-methylphenyl)methyl]benzimidazol-2-yl}methyl) (3-methylbutyl)amine. 2,4-dimethoxybenzoylchloride 1.5 eq is treated with 1.0 eq of ({1-[(2-methylphenyl)methyl]benzimidazol-2-yl}methyl) (3-methylbutyl)amine in dichloromethane at room temperature for 1 hr. The reaction is quenched with 1 N NaOH and partitioned between dichloromethane and water. The organic layer is dried with Na2SO4 and the solvent removed in vacuo. The residue is chromatographed (SiO2) with ethyl acetate to afford 95% of (2,4-dimethoxyphenyl)-N-({1-[(2-methylphenyl)methyl]benzimidazol-2-yl}methyl)-N-(3-methylbutyl)carboxamide (Compound 1). Mass Spec M+ 486.
Reaction SMILES: S([O:6][CH3:7])(OC)(=O)=O.[CH3:8][C@@:9]12[C:25](=[O:26])[CH2:24][CH2:23][C@H:22]1[C@H:21]1[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([OH:27])=[CH:17][C:18]=3[CH2:19][CH2:20]1)[CH2:11][CH2:10]2.[OH-].[K+]>O1CCCC1>[CH3:8][O:6][CH3:7].[CH3:8][C@@:9]12[C:25](=[O:26])[CH2:24][CH2:23][C@H:22]1[C@H:21]1[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([OH:27])=[CH:17][C:18]=3[CH2:19][CH2:20]1)[CH2:11][CH2:10]2
Reactant: COS(=O)(=O)OC
Agent: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC
Reaction time: 1 h

Procedure:
Into a mixture of 0.39 ml of dimethyl sulfate and 5 ml of tetrahydrofuran, 1 g of estrone and 0.76 ml of 30% KOH aqueous solution dissolved in 5 ml of tetrahydrofuran were added over a period of one hour. The reaction temperature was maintained at 15° - 20°C. The resulting mixture was stirred for one hour. Then, after the addition of 10 ml of 1% KOH aqueous solution, Example 1 was repeated to obtain 1.049 g of the 100% purity methyl ether of estrone in a 99.8% yield.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[OH:10].C(N(CC)CC)C.[S:18](Cl)([CH3:21])(=[O:20])=[O:19].O>C(Cl)Cl>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[O:10][S:18]([CH3:21])(=[O:20])=[O:19]
Reactant: OC1Cc2ccccc2C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OC1Cc2ccccc2C1
Yield: 99.9 %

Procedure:
2-Indanol (5.14 g, 38.3 mmoles) in methylene chloride (20 ml) at 0° C. was added with triethylamine (6.13 ml 4.46 g, 44.1 mmoles) and a solution of mesyl chloride (3.26 ml, 4.83 g, 42.1 mmoles) in methylene chloride (4 ml). The temperature was raised to room value, then the mixture was poured into water and the organic phase separated, washed with water, anhydrified and dried to give 8.12 g of the title product (yield: 99%)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([OH:24])=O)[CH:17]=1)[CH2:10][C:9]2([CH3:26])[CH3:25])=[O:5])[CH3:2].[CH3:27][N:28](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.CN>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:24])[NH:28][CH3:27])[CH:17]=1)[CH2:10][C:9]2([CH3:26])[CH3:25])=[O:5])[CH3:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(C(=O)O)c1)N2
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(C(=O)NC)c1)N2
Yield: 101.7 %

Procedure:
The mixture solution of 2-(3-carboxy-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.2 g, 3.3 mmol), o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (1.52 g, 4.0 mmol), triethylamine (2.0 mL), methylamine (228.1 mg, 5.8 mmol) in dry dichloromethane (20.0 mL) was stirred at room temperature for 1 hour, LC/MS showed that reaction finished completely. The reaction mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 4,4-dimethyl-2-(3-methylcarbamoyl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.23 g, quant.) as a light yellow solid which was used for next step without further purification: MS (ESI) M+1=367.1.
Reaction SMILES: [C:1]1([C:7](=[O:11])[CH2:8][CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:22]([O:29][C:30]1[CH:35]=[C:34]([CH2:36]Br)[CH:33]=[CH:32][C:31]=1[N+:38]([O-:40])=[O:39])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH2:22]([O:29][C:30]1[CH:35]=[C:34]([CH:33]=[CH:32][C:31]=1[N+:38]([O-:40])=[O:39])[CH2:36][CH:8]([CH2:9][CH3:10])[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:11])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1OCc1ccccc1
Reactant: CCCC(=O)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1)C(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 1-phenylbutan-1-one (203 mg, 1.37 mmol) in THF (2.5 mL) at −78° C. is added dropwise LiHMDS (1.62 mL of 1.0 M solution in THF, 1.62 mmol) over a period of 15 min. The solution is stirred at −78° C. for 1 h then a solution of 2-benzyloxy-4-bromomethyl-1-nitrobenzene (Example 83, step C) (400 mg, 1.25 mmol) in THF (2.5 mL) is added dropwise. The mixture is allowed to warm to RT and stirred there for 1 h then is quenched with saturated ammonium chloride solution. The mixture is extracted with EtOAc and the organic phase is washed with brine then dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue is purified by flash chromatography using a gradient of 5-100% EtOAc/hexane as eluent to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.[CH2:16]1[O:25][C:24]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][C:18]=2[O:17]1>>[O:25]1[C:24]2[CH:23]=[CH:22][C:20]([NH:21][C:6]3[N:5]=[C:4]([NH:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[N:3]=[C:2]([Cl:1])[N:7]=3)=[CH:19][C:18]=2[O:17][CH2:16]1
Reactant: Clc1nc(Cl)nc(Nc2ccccc2)n1
Reactant: Nc1ccc2c(c1)OCO2
Product: Clc1nc(Nc2ccccc2)nc(Nc2ccc3c(c2)OCO3)n1
Yield: 42 %

Procedure:
The reaction of 4,6-dichloro-N-phenyl-[1,3,5]triazine-2-amine with 3,4-methylenedioxyaniline using the method described for the synthesis of CT-32028 provided CT-32042 (51 mg, 42% yield). 1H NMR (d6-DMSO) δ 10.05–10.29 (m, 2 H), 7.57–7.80 (m, 2 H), 7.21–7.42 (m, 3 H), 6.80–7.13 (m, 3 H), 6.03 (s, 2 H).