Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][CH2:7][C:6]=2[CH:14]=1.[C:15]([CH2:17][CH2:18][NH:19][C:20](=[O:36])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][C:28]1[C:33]([Cl:34])=[CH:32][N:31]=[C:30](Cl)[N:29]=1)#[N:16]>>[Cl:34][C:33]1[C:28]([NH:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[C:20]([NH:19][CH2:18][CH2:17][C:15]#[N:16])=[O:36])=[N:29][C:30]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][CH2:7][C:6]=3[CH:14]=2)=[N:31][CH:32]=1
Reactant: N#CCCNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CN1C(=O)CCCc2cc(N)ccc21
Product: CN1C(=O)CCCc2cc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NCCC#N)n3)ccc21

Procedure:
The title compound was prepared from 7-amino-1-methyl-1,3,4,5-tetrahydro-1-benzazepin-2-one and N-(2-cyano-ethyl)-2-(2,5-dichloro-pyrimidin-4-ylamino)-benzamide in an analogous manner to Example 179. Product was isolated as a tan solid (20 mg, 30%). LCMS (m/e) 490 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 11.36 (s, 1H), 9.53 (s, 1H), 9.14 (m, 1H), 8.72 (d, 1H, J=8.6 Hz), 8.25 (s, 1H), 7.79 (d, 1H, J=7.8 Hz), 7.59 (s, 1H), 7.30 (m, 2H), 7.53 (m, 1H), 7.20 m, 2H), 3.54 (q, 2H, J=6 Hz), 3.21 (s, 3H), 2.81 (t, 2H, J=6 Hz), 2.56 (m, 2H), 2.15 (m, 2H), 2.03 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[OH:11].[CH3:12][C:13]([Si:16](Cl)([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1>CN(C=O)C.O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[O:11][Si:16]([C:13]([CH3:15])([CH3:14])[CH3:12])([CH3:18])[CH3:17]
Reactant: OC1CCc2c(Br)cccc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1CCc2c(Br)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-2,3-dihydro-1H-inden-1-ol INT-28 (2.56 g, 12.0 mm) in DMF (5 mL) were added TBDMSCl (2.17 g, 14.4 mmol) and imidazole (2 g, 30.0 mmol) and the reaction mixture stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with EA. The organic layers were washed with water and brine, and dried over MgSO4. The crude product was purified by chromatography (EA/hexane) to afford (4-bromo-2,3-dihydro-1H-inden-1-yloxy)(tert-butyl)dimethylsilane INT-29 (3.3 g, 84%) as a clear oil. LCMS-ESI (m/z) calculated for C15H23BrOSi: 327.3; found 195.0 [M−OTBS]+, tR=3.07 min. 1H NMR (400 MHz, CDCl3) δ 7.20 (d, J=7.8 Hz, 1H), 7.06 (d, J=7.4 Hz, 1H), 6.92 (t, J=7.7 Hz, 1H), 5.13 (t, J=7.0 Hz, 1H), 2.85 (ddd, J=16.4, 9.1, 2.9 Hz, 1H), 2.57 (dt, J=16.5, 8.3 Hz, 1H), 2.36-2.17 (m, 1H), 1.76 (dtd, J=12.8, 8.8, 7.1 Hz, 1H), 0.83-0.72 (m, 9H), 0.05-−0.06 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[S:19]1[CH:23]=[CH:22][C:21]([C:24](Cl)=[O:25])=[CH:20]1>>[S:19]1[CH:23]=[CH:22][C:21]([C:24]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:25])=[CH:20]1
Reactant: O=C(Cl)c1ccsc1
Reactant: CCN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CCN1CCC(c2c[nH]c3ccc(NC(=O)c4ccsc4)nc23)CC1

Procedure:
Beginning with 0.015 gm (0.061 mMol) 5-amino-3-(1-ethylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.012 mL (0.080 mMol) 3-thiophenecarbonyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].[P:5]([OH:8])([OH:7])[OH:6].P(Cl)(Cl)Cl>O1CCOCC1>[CH3:2][C:1]([P:5]([OH:8])([OH:7])=[O:6])([P:5]([OH:8])([OH:7])=[O:6])[OH:4]
Reactant: OP(O)O
Reactant: CC(=O)O
Solvent: ClP(Cl)Cl
Solvent: C1COCCO1
Product: CC(O)(P(=O)(O)O)P(=O)(O)O
Temperature: 92.5 °C
Yield: 5.2 %

Procedure:
Acetic acid (50 g), phosphorous acid (240 gm) and 1,4-dioxane (1000 mL) was taken in a four necked round bottom flask fitted with an addition funnel, mechanical stirrer, condenser and thermometer pocket and allowed to stir at 90-95° C. Phosphorus trichloride (400 gm) was then added to the reaction mixture and allowed to heat at 90-95° C. The reaction mixture was cooled and distilled water (500 ml) was added to it. The reaction mixture was further heated to 90-95° C. It was then cooled and acetonitrile (1000 mL) was added to it. The solution was further cooled to 0-5° C. and stirred for 4-5 hrs. The precipitated solid was filtered, washed with acetonitrile and dried in vacuum oven to give 9 gm of product.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:17][OH:18]>>[N:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][C:12](=[N:17][OH:18])[CH2:11][CH2:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: O=C1CCN(CCN2CCCCC2)CC1
Agent: Cl
Product: ON=C1CCN(CCN2CCCCC2)CC1

Procedure:
1-(2-(1-Piperidinyl)ethyl)-4-piperidone oxime is prepared from 1-(2-(1-piperidinyl)ethyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.ClCCl.[Br:15]Br>[Fe]>[Br:15][C:7]1[CH:8]=[CH:9][C:4]([O:3][C:2]([F:10])([F:11])[F:1])=[CH:5][CH:6]=1
Reactant: BrBr
Reactant: FC(F)(F)Oc1ccccc1
Agent: [Fe]
Solvent: ClCCl
Product: FC(F)(F)Oc1ccc(Br)cc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
Trifluoromethoxybenzene 6c (11.35 g, 70 mmol) was dissolved in 3.57 mL liquid bromine, followed by addition of iron (0.24 g). The reaction mixture was stirred for 16 hours at 100° C. 450 mL of dichloromethane were added and the organic extract was washed with 6 M hydrochloric acid (140 mL), 10% sodium hydrogen sulfite solution (140 mL) and saturated sodium chloride solution (140 mL), combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound 1-bromo-4-(trifluoromethoxy)benzene 6d (14.1 g, yellow solid), yield: 83.8%. 1H NMR (400 MHz, CDCl3): δ 7.54-7.50 (m, 2H), 7.11-7.09 (m, 2H).
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]([NH:11][C:12]([O:14][CH3:15])=[O:13])=[C:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[Li+].[OH-]>CO>[CH3:15][O:14][C:12]([NH:11][C:4](=[C:5]1[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1)[C:3]([OH:16])=[O:2])=[O:13]
Reactant: COC(=O)NC(C(=O)OC)=C1CCOCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)NC(C(=O)O)=C1CCOCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of methoxycarbonylamino-(tetrahydropyran-4-ylidene)-acetic acid methyl ester (141 mg, 0.62 mmol) in methanol (1.8 mL) was added an aqueous LiOH solution (1M, 1.8 mL, 1.8 mmol). The resulting solution was stirred at room temperature for 16 hours and then washed with ethyl acetate. The ethyl acetate washing was discarded and the aqueous layer was acidified with concentrated HCl. The acidified aqueous layer was extracted twice with ethyl acetate. The combined organics were washed with brine, dried (MgSO4), and concentrated to give methoxycarbonylamino-(tetrahydropyran-4-ylidene)-acetic acid. To a solution of methoxycarbonylamino-(tetrahydropyran-4-ylidene)-acetic acid (23 mg, 0.11 mmol) in dimethylformamide (0.6 mL) was added HATU (41 mg, 0.11 mmol). After stirring for 5 minutes, a solution of {2-methyl-1-[2-(5-{6-[4-(2-pyrrolidin-2-yl-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamic acid methyl ester trihydrochloride (50 mg, 0.068 mmol) in dimethylformamide (0.6 mL) was added to the reaction, followed immediately by diisopropylethylamine (85 μL, 0.49 mmol). The reaction was stirred for 1 hour at room temperature then diluted with ethyl acetate. The organic layer was washed successively with saturated aqueous NaHCO3 solution, water and brine, dried (MgSO4), concentrated and purified by preparative reverse phase HPLC (Gemini, 15 to 50% ACN/H2O+0.1% HCO2H) to yield 11-[2-(5-{6-[4-(2-{1-[2-methoxycarbonylamino-2-(tetrahydropyran-4-ylidene)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl)-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (28 mg, 50%). LCMS-ESI+: calculated for C46H52N8O7: 828.95; observed [M+1]+: 830.32. 1H-NMR: 400 MHz, (CD3OD) δ: 8.24-8.07 (m, 3H), 7.96-7.76 (m, 7H), 7.45-7.34 (m, 2H), 5.28-5.18 (m, 2H), 4.27-4.23 (m, 1H), 4.05-3.98 (m, 1H), 3.94-3.86 (m, 1H), 3.84-3.41 (m, 12H), 2.48-1.98 (m, 13H), 1.02-0.90 (m, 6H) ppm.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12]CC)=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Cl:37])[C:21]=1[NH:22][C:23]1[C:32]2[C:27](=[C:28]([OH:35])[C:29]([O:33][CH3:34])=[CH:30][CH:31]=2)[O:26][C:25](=[O:36])[CH:24]=1>>[Cl:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Cl:37])[C:21]=1[NH:22][C:23]1[C:32]2[C:27](=[C:28]([O:35][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:29]([O:33][CH3:34])=[CH:30][CH:31]=2)[O:26][C:25](=[O:36])[CH:24]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Reactant: CCOC(=O)CCCCCCCCBr
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCCCCC(=O)O

Procedure:
The title compound was prepared from ethyl 9-bromononanoate and 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (Example 29) following the procedures outlined in Examples 25 & 42. 1H NMR (400 MHz, DMSO-d6): δ 9.50 (s, 1H), 8.81 (s, 2H), 7.93 (d, 1H), 7.19 (d, 1H), 4.63 (s, 1H), 3.97 (t, 2H), 3.91 (s, 3H), 2.17 (t, 2H), 1.66 (m, 2H), 1.52-1.38 (m, 4H), 1.34-1.22 (m, 6H); MS (ESI): 508.9.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=2[I:22])[C:11](=[O:23])[N:10]([CH3:24])[C@@H:9]1[C:25]([CH3:28])([CH3:27])[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[Sn](Cl)(Cl)Cl.[CH3:34][O:35]C(Cl)Cl>ClCCl>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]2[CH:19]=[C:18]([CH:34]=[O:35])[C:17]([O:20][CH3:21])=[CH:16][C:15]=2[I:22])[C:11](=[O:23])[N:10]([CH3:24])[C@@H:9]1[C:25]([CH3:28])([CH3:27])[CH3:26])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1ccc(C[C@H]2C(=O)N(C)[C@H](C(C)(C)C)N2C(=O)OC(C)(C)C)c(I)c1
Reactant: COC(Cl)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(I)c(C[C@H]2C(=O)N(C)[C@H](C(C)(C)C)N2C(=O)OC(C)(C)C)cc1C=O
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 11.4 %

Procedure:
The iodoanisole derivative 27 (460.20 mg, 0.94 mmol) was dissolved in anhydrous dichloromethane (10 mL) and cooled to 0° C. under argon. After stirring for 15 min a solution of SnCl4 (1M in dichloromethane, 10.4 mL, 10.4 mmol) was added drop wise. After completion of the addition of SnCl4, 1,1-dichloromethyl methyl ether (0.84 mL, 9.4 mmol) was added drop wise. The color of the solution turned from light yellow to greenish brown. The reaction mixture was stirred for 45 min at 0° C. and then quenched with a saturated solution of ammonium chloride (2.0 mL). The light brown suspension was stirred for 30 min at room temperature and extracted with dichloromethane. The organic phase was dried over anhydrous Na2SO4, filtered and evaporated to afford a yellow oil. Flash chromatographic purification of the crude product gave pure (2S,5S)-tert-Butyl-5-(2′-iodo-4′-methoxy-5′-formylbenzyl)-2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate (28) as oil (57 mg, 10%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][NH:41][CH2:40][C:39]1=[O:44]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:41]3[CH2:42][CH2:43][NH:38][C:39](=[O:44])[CH2:40]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1CNCCN1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCNC(=O)C1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 2-piperazinone (Alfa) to give the title compound. HR-MS (ES, m/z) calculated for C33H38Cl2N5O3 [(M+H)+] 622.2346, observed 622.2346.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6]([S:22][C:23]3[N:28]=[C:27]([C:29]([O:31]C)=[O:30])[CH:26]=[CH:25][CH:24]=3)=[C:7]([CH:19]3[CH2:21][CH2:20]3)[N:8]2[C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH3:18])[CH:16]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6]([S:22][C:23]3[N:28]=[C:27]([C:29]([OH:31])=[O:30])[CH:26]=[CH:25][CH:24]=3)=[C:7]([CH:19]3[CH2:20][CH2:21]3)[N:8]2[C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH3:18])[CH:16]=2)=[CH:4][CH:3]=1
Reactant: CCn1cc(-n2c(C3CC3)c(Sc3cccc(C(=O)OC)n3)c3ccc(Cl)c(F)c32)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCn1cc(-n2c(C3CC3)c(Sc3cccc(C(=O)O)n3)c3ccc(Cl)c(F)c32)cn1
Temperature: 60 °C
Yield: 103.7 %

Procedure:
To a stirred solution of compound 9 (2.81 g, 5.97 mmol) in THF:water (4:1) (40 mL) was added 1M aq. NaOH solution (6.03 mL, 6.03 mmol) and the mixture was heated at 60° C. for 1 h. After completion of the reaction, the solvent was removed to afford Compound 1-92 (2.83 g, 100%) as a light brown solid. LC-MS: 457 (M++1).
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1.[C:11]([O:15][C:16](=[O:29])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[C:26][CH2:27][OH:28])[CH:20]=1)([CH3:14])([CH3:13])[CH3:12].[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CO>[C:11]([O:15][C:16](=[O:29])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](/[CH:25]=[CH:26]\[CH2:27][OH:28])[CH:20]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)COc1cccc(C#CCO)c1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: c1ccc2ncccc2c1
Solvent: CO
Product: CC(C)(C)OC(=O)COc1cccc(/C=C\CO)c1
Reaction time: 1 h
Yield: 76 %

Procedure:
Quinoline (54 μL) and a Lindlar catalyst (54 mg) were added to a stirred solution of [3-(3-hydroxyprop-1-ynyl)phenoxy]acetic acid tert-butyl ester (547 mg, 2.09 mmol) in methanol (4.3 mL) under a nitrogen atmosphere. The mixture was stirred for 1 hour in a balloon filled with hydrogen, filtered, and the filtrate was taken to dryness. The residue was purified by flash chromatography, eluting with hexane/ethyl acetate, dissolved in diethyl ether, and washed with 2 N hydrochloric acid (10 mL) and 10% sodium bicarbonate, dried over sodium sulfate, and concentrated to give cis-[3-(3-hydroxypropenyl)phenoxy]acetic acid tert-butyl ester as a colorless oil (420 mg, 76%).
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[N:6]([CH3:10])[CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.C([Li])CCC.B(OC)(OC)[O:19]C.OO>O1CCCC1>[CH3:10][N:6]1[CH2:7][CH2:8][O:9][C:4]2[CH:3]=[C:2]([OH:19])[CH:12]=[CH:11][C:5]1=2
Reactant: COB(OC)OC
Reactant: CN1CCOc2cc(Br)ccc21
Agent: OO
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCOc2cc(O)ccc21
Temperature: -78 °C
Reaction time: 0.58 h
Yield: 89.2 %

Procedure:
To a −78° C. solution of 7-bromo-4-methyl-3,4-dihydro-2H-1,4-benzoxazine (90%, 10.40 g, 41.0 mmol) in tetrahydrofuran (70 mL) under nitrogen was slowly added n-butyllithium solution (1.4 M in hexanes, 32 mL, 45 mmol) and the resulting suspension was stirred at −78° C. for 35 min. Trimethyl borate (6.0 mL, 54 mmol) was then added dropwise and the clear solution was stirred at −78° C. for 25 min and at ambient temperature for 16 h. The reaction was cooled to 0° C. and aqueous hydrogen peroxide (8.2 mL, 35%, 95 mmol) was slowly added. The resulting mixture was stirred at 0° C. for 10 min and at ambient temperature for 5 h. The insoluble material was removed by filtration and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was taken up into ethyl acetate (100 mL) and was acidified with hydrochloric acid (100 mL, 1 M). The layers were separated and the organic solution was extracted with water (2×50 mL). The combined aqueous solution was neutralized to pH ˜6-7 with 5 M sodium hydroxide and extracted with ethyl acetate (3×100 mL). This organic solution was washed with brine (200 mL) and dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with hexanes/ethyl acetate (2:1) to afford 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-ol (6.04 g, 89%) as a light brown solid: mp 84-87° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) δ6.59 (d, J=9.0 Hz, 1H), 6.40-6.28 (m, 2H), 5.42 (br s, 1H), 4.30 (dd, J=4.2, 4.2 Hz, 2H), 3.19-3.09 (m, 2H), 2.80 (s, 3H); 13C NMR (75 MHz, CDCl3) δ149.1, 145.6, 130.5, 114.7, 108.0, 104.1, 65.3, 49.8, 40.1; MS (ES+) m/z 166.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Na].[C:10]([CH2:12][N:13]=[CH:14]OC)#[N:11]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[N:11]=[CH:14][NH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: COC=NCC#N
Reactant: Oc1ccc(Br)cc1
Agent: [Na]
Solvent: CO
Product: Brc1ccc(Oc2c[nH]cn2)cc1

Procedure:
To a mixture of liquid 4-bromophenol (25 g, mp 64-68° C.) at 100-110° C. and its sodium salt [Prepared from 3.5 g (20 mmol) 4-bromo-phenol and sodium metal (0.46 g, 20 mmol) in anhydrous methanol. The resultant solution was concentrated and the residual solvent removed under vacuum overnight], neat methyl N-(cyanomethyl)methanimidate (2 mL, 20 mmol; Hosmane, R. S. et al, J. Org. Chem., p. 1212, 1984) was added dropwise over a period of 10 minutes under a slow stream of dry argon. The resultant mixture was stirred at 100° C. for 2 h, and the reaction product partitioned between methylene chloride (250 mL) and aqueous sodium hydroxide (1 M, 250 mL). The aqueous layer was separated and extracted with methylene chloride (3×50 mL). The organic extracts were combined, washed with brine (50 mL), dried over anhydrous potassium carbonate, filtered and concentrated. The residue was subjected to column chromatography on silica gel eluting with a mixture of 7:3 v/v chloroform and acetone. Collection and concentration of appropriate fractions provided the titled compound as white powder.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].S(Cl)([Cl:15])(=O)=O>CCCCCCC>[Cl:15][C:2]([CH3:4])([CH3:3])[C:1]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: CC(C)C(=O)c1ccccc1
Reactant: O=S(=O)(Cl)Cl
Solvent: CCCCCCC
Product: CC(C)(Cl)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Isobutyrophenone (30.0 g, 0.20 mole) was dissolved in heptane (10 ml) and sulfuryl chloride (35 g, 0.26 mole) was added at once. After a few minutes gas evolution occurred. After 3 h of stirring at room temperature the reaction mixture was concentrated. The concentrate was dissolved in heptane (250 ml) and washed with 150 ml of an aqueous 2 wt % sodium bicarbonate solution. After drying over magnesium sulfate the solvent was removed under reduced pressure. The yield of 2-chloro-2-methylpropiophenone was 36.4 g or 98%.
Reaction SMILES: CC([Si](C)(C)[O:6][C@@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C:12]([C:13]3[CH2:14][CH2:15][C@@H:16]4[C@:21]([C:23]=3[CH2:24][CH2:25]2)([CH3:22])[CH2:20][CH2:19][C@H:18]([O:28][CH:29]([O:31][CH2:32][CH3:33])[CH3:30])[C:17]4([CH3:35])[CH3:34])=[CH:11][CH2:10]1)[CH3:8])(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH2:32]([O:31][CH:29]([O:28][C@H:18]1[CH2:19][CH2:20][C@@:21]2([CH3:22])[C@@H:16]([CH2:15][CH2:14][C:13]3[C:12]4[C@:26]([CH3:27])([CH2:25][CH2:24][C:23]=32)[C@@H:9]([C@H:7]([OH:6])[CH3:8])[CH2:10][CH:11]=4)[C:17]1([CH3:35])[CH3:34])[CH3:30])[CH3:33]
Reactant: CCOC(C)O[C@H]1CC[C@]2(C)C3=C(CC[C@H]2C1(C)C)C1=CC[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@@]1(C)CC3
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(C)O[C@H]1CC[C@]2(C)C3=C(CC[C@H]2C1(C)C)C1=CC[C@H]([C@@H](C)O)[C@@]1(C)CC3
Reaction time: 24 h
Yield: 82.4 %

Procedure:
iv)—A solution of (3β,5α,20R)-20-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3-[(1-ethoxyethyl)oxy]-4,4-dimethylpregna-8,14-diene (18b; 16.4 g) in a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (42 ml) was stirred at 50° C. for 6 h and then at room temperature for 24 h. The reaction mixture was poured into water and the product was extracted into ethyl acetate. The combined organic phases were washed with brine and concentrated under reduced pressure. Column chromatography afforded (3β,5α,20R)-3-[(1-ethoxyethyl)oxy]-4,4-dimethylpregna-8,14-dien-20-ol (compound 19b; 10.6 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:8](=[O:12])(=[O:11])([OH:10])O>ClC1C=CC=CC=1Cl>[NH2:1][C:2]1[C:7]([S:8]([OH:12])(=[O:11])=[O:10])=[CH:6][C:5]([S:8]([OH:10])(=[O:12])=[O:11])=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: Nc1ccccc1
Solvent: Clc1ccccc1Cl
Product: Nc1ccc(S(=O)(=O)O)cc1S(=O)(=O)O

Procedure:
186.2 g (2 mols) of aniline are initially introduced into 500 ml of 1,2-dichlorobenzene and 208.3 g (2.04 mols) of 96% strength sulphuric acid are added dropwise. The mixture is heated for 8 hours at the boil under a water separator, during which period distillate passes over at a rate of 700 ml per hour, cooled and filtered with suction. After it has been dried, the precipitate weighs 338.5 g and contains 86.1% of p-sulphanilic acid (84.2% of the theoretical yield) and 11.2% of aniline-2,4-disulphonic acid (7.5%, relative to aniline).
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]=[C:29]([CH2:34]O)[CH:30]=[CH:31][C:32]=1[F:33].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>CCOC(C)=O.C1COCC1>[Cl:26][C:27]1[CH:28]=[C:29]([CH:30]=[CH:31][C:32]=1[F:33])[CH2:34][O: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])([CH3:20])[CH3:21])[N:13]([CH3:23])[C:12]=3[CH:24]=2)[C:4](=[O:25])[CH:3]=1
Reactant: OCc1ccc(F)c(Cl)c1
Reactant: Cn1c(C2CC2C(C)(C)O)nc2ccc(-n3ccc(O)cc3=O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1c(C2CC2C(C)(C)O)nc2ccc(-n3ccc(OCc4ccc(F)c(Cl)c4)cc3=O)cc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 41.1 %

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), (3-chloro-4-fluorophenyl)methanol (95 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, washed with water and brine successively, dried over MgSO4, filtered through a plug of NH silica gel, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH), followed by NH silica gel column chromatography (hexane/EtOAc). Then the resulting solid was recrystallized from IPA-EtOAc to give the title compound (58.4 mg) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]([OH:22])=O)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH3:23][S:24]([C:27]1[CH:28]=[C:29]([NH2:33])[CH:30]=[CH:31][CH:32]=1)(=[O:26])=[O:25]>>[CH3:23][S:24]([C:27]1[CH:28]=[C:29]([NH:33][C:20]([C:19]2[CH:18]=[N:17][N:11]3[C:12]([CH:14]4[CH2:15][CH2:16]4)=[CH:13][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[N:9][C:10]=23)=[O:22])[CH:30]=[CH:31][CH:32]=1)(=[O:25])=[O:26]
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)c1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Product: CS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C4CC4)cc(-c4ccc(Cl)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.28) and 3-methanesulfonyl-phenylamine according to general procedure II. Pale-yellow solid. MS (ISP) 467.4 [(M+H)+]; mp 235-238° C.