Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[Cl:19])[C:12](=[O:20])[C:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:10]2)=[CH:4][CH:3]=1.[Cl-].[CH3:27][Zn+].O>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:19][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:18]=1[N:9]([CH2:8][C:5]1[CH:6]=[N:7][C:2]([CH3:27])=[CH:3][CH:4]=1)[N:10]=[C:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:12]2=[O:20]
Reactant: CCOC(=O)c1nn(Cc2ccc(Br)nc2)c2c(Cl)cccc2c1=O
Reactant: C[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1nn(Cc2ccc(C)nc2)c2c(Cl)cccc2c1=O
Reaction time: 0.25 h

Procedure:
Ethyl 1-[(6-bromopyridin-3-yl)methyl]-8-chloro-4-oxo-1,4-dihydrocinnoline-3-carboxylate [(Example 69, Step 1), 0.11 g, 0.25 mmol] was dissolved in tetrahydrofuran (1.5 mL), sparged under nitrogen and treated with methylzinc chloride (0.18 mL, 2.0 M tetrahydrofuran solution, 0.35 mmol, 1.4 equiv) and 1,1′bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (10 mg, 0.013 mmol, 0.05 equiv). After stirring for 15 minutes, tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.050 mmol, 0.2 equiv) were added and the mixture was stirred at ambient temperature for an additional 2 hours. The mixture was poured into water, extracted twice with ethyl acetate and the combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 0:100; hexanes:ethyl acetate), providing the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].CN(C=O)C.N1C=CN=C1.[C:20]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])([CH3:22])[CH3:21]>O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[O:9][Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1c(F)cccc1Br
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1c(F)cccc1Br
Temperature: 60 °C
Yield: 82.6 %

Procedure:
A 500-mL three-neck, round bottomed flask, equipped with a stir bar, temperature probe and nitrogen inlet, was charged with 2-bromo-6-fluorophenol (25 g, 130.9 mmol, 1.00 eq), DMF (252 mL, 0.52 M), imidazole (12.3 g, 181 mmol, 1.38 eq) and tertbutyldimethylsilyl chloride (19.7 g, 131 mmol, 1.00 eq). The mixture was heated at 60° Celsius for 3 hours. The reaction was cooled to room temperature and diluted with water. The aqueous phase was extracted with ethyl acetate and the resultant organic solution washed with water and brine and dried over sodium sulfate. The organic phase was concentrated to dryness and purified using FCC to provide (2-bromo-6-fluorophenoxy)(tert-butyl)dimethylsilane as a colorless oil (33 g, 82%).
Reaction SMILES: C[O-].[Na+].C([O:6][CH2:7][CH3:8])=O.N#N.[CH2:11]([C:21]1[CH:30]=C2[C:24]([CH2:25][CH2:26][CH2:27][C:28]2=[O:31])=[CH:23][CH:22]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C1(C)C=CC=CC=1>[OH:31][CH:28]=[C:27]1[CH2:26][CH2:25][C:24]2[C:8](=[CH:30][C:21]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:22][CH:23]=2)[C:7]1=[O:6]
Reactant: CCOC=O
Reactant: CCCCCCCCCCc1ccc2c(c1)C(=O)CCC2
Agent: C[O-]
Agent: N#N
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCc1ccc2c(c1)C(=O)C(=CO)CC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of sodium methoxide (5.4 g, 40.5 mmoles), ethyl formate 7.4 g, 100 mmoles) and 100 mL dry toluene was cooled in an ice bath under inert atmosphere (N2 or Argon). A solution of 7-n-decyl-1-tetralone (11.5 g, 40 mmoles) in 100 mL dry toluene was added with rapid stirring. The ice bath was removed and the reaction was stirred at RT for 4 hours. The reaction was treated with 100 mL water and 100 l mL 6N HCl. The organic layer was separated and washed twice with 50 mL saturated NaCl, dried over anhydrous Na2SO4, filtered and evaporated to remove all the toluene. The oily residue was used for the next reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:36])[CH3:37])[CH:28]=4)[CH2:23][CH2:22]3)=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCCC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(F)cc4)CCCCC3)CC2)c1

Procedure:
Example 40 was prepared from 1-(4-fluorophenyl)cyclohexanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.56 (s, 2H), 7.42–7.36 (m, 2H), 7.30–7.20 (m, 2H), 7.05–6.96 (m, 3H), 6.85–6.79 (m, 1H), 3.28 (q, 2H, J=6.3 Hz), 2.95–2.87 (m, 2H), 2.57–2.41 (m, 2H), 2.36–2.28 (m, 4H), 2.06 (s, 1H), 1.96–1.84 (m, 4H), 1.83–1.75 (m, 2H), 1.71–1.54 (m, 9H), 1.24 (d, 6H, J=7.1 Hz); ESMS m/e: 508.3 (M+H)+.
Reaction SMILES: [C:1]([N:5]=[C:6]=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:8][C@@H:9]1[CH2:13][CH2:12][C@@H:11]([C:14]([N:16]2[CH2:23][CH2:22][C@:21]3([CH3:27])[C:24]([CH3:26])([CH3:25])[C@H:17]2[CH2:18][C:19]2[C:31]([OH:32])=[CH:30][CH:29]=[CH:28][C:20]=23)=[O:15])[CH2:10]1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[C:1]([NH:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][C@@H:11]([C:14]([N:16]2[CH2:23][CH2:22][C@:21]3([CH3:27])[C:24]([CH3:25])([CH3:26])[C@H:17]2[CH2:18][C:19]2[C:31]([OH:32])=[CH:30][CH:29]=[CH:28][C:20]=23)=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)[C@H]2Cc3c(O)cccc3[C@]1(C)CCN2C(=O)[C@@H]1CC[C@@H](N)C1
Reactant: CC(C)(C)N=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)N[C@@H]1CC[C@@H](C(=O)N2CC[C@@]3(C)c4cccc(O)c4C[C@@H]2C3(C)C)C1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
tert-Butylisocyanate (30 mg) is added to a solution of [(1R,3R)-3-amino-cyclopentyl]-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone (100 mg) and ethyldiisopropylamine (120 μL) in N,N-dimethylformamide (2 mL). The resulting solution is stirred at 40° C. overnight. Then, the solution is concentrated under reduced pressure and the residue is purified by HPLC on reversed phase (MeCN/H2O/F3CCO2H) to give the title compound.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C@H:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH3:12])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>CCOCC>[OH:8][CH2:9][C@@H:10]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C@H:11]([C:13]1[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=1)[CH3:12]
Reactant: C[C@@H](c1ccc(C(F)(F)F)cc1)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(C(F)(F)F)cc1)[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To tert-butyl (2S,3S)-1-(tert-butyldimethylsilyloxy)-3-(4-(trifluoromethyl)phenyl)butan-2-ylcarbamate (2000 mg, 4.5 mmol) in 25 mL ether at 0° C. was added 1.0 M tetrabutylammonium fluoride in THF (8.9 mL, 8.9 mmol). After the addition, the ice-bath was taken away. The reaction progress was monitored by TLC. After 60 minutes, the solvent was evaporated and 100 mL diethyl ether was added. The organic layer was washed with water and brine solution, and then dried over sodium sulfate. The crude product was then chromatographed eluting with 30% EtOAc in hexane. After removing the solvent, the desired product was obtained as a white solid (1.25 g, 84%). 1H NMR (400 MHz, CD3OD) 8 ppm 1.26-1.31 (m, 9 H) 1.34 (d, J=7.04 Hz, 3H) 3.02-3.13 (m, 1H) 3.61-3.67 (m, 2H) 3.75 (dd, J=8.71, 4.60 Hz, 1H) 7.44 (d, J=8.02 Hz, 2H) 7.57 (d, J=8.22 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11](Cl)[CH:10]=[C:9]([Cl:14])[N:8]=2)=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][N:17]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:8]=[C:9]([Cl:14])[CH:10]=[C:11]([O:22][C:20]3[CH:19]=[CH:18][N:17]=[C:16]([Cl:15])[CH:21]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: Clc1cc(Cl)nc(-c2ccc(Cl)s2)n1
Reactant: Oc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Clc1cc(Oc2cc(Cl)nc(-c3ccc(Cl)s3)n2)ccn1

Procedure:
0.4 g 2-(5-Chloro-2-thienyl)-4,6-dichloropyrimidine, 0.2 g 2-Chloro-4-hydroxypyridine, and 0.3 g potassium carbonate are refluxed in 30 mL dry acetonitril for 16 hours. The mixture is poured into water, and the product is extracted with toluene and purified by flash chromatography (0.38 g, m.p. 154°-156° C.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([NH:9][CH2:10][CH2:11][CH2:12]OS(C)(=O)=O)=[O:8].[Br-:18].[Li+]>CC(C)=O>[Br:18][CH2:12][CH2:11][CH2:10][NH:9][C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:8]
Reactant: CS(=O)(=O)OCCCNC(=O)c1ccccn1
Reactant: [Br-]
Agent: [Li+]
Solvent: CC(C)=O
Product: O=C(NCCCBr)c1ccccn1
Temperature: 25 °C
Yield: 81.3 %

Procedure:
A mixture of methanesulfonic acid 3-[(pyridine-2-carbonyl)-amino]-propyl ester (Example 57a) (1.96 g) and lithium bromide (3.29 g) in acetone (19 mL) was heated to reflux for 2 h. The reaction mixture was cooled to room temperature, concentrated in vacuo and the residue partitioned between EtOAc/H2O (60 mL, 1:1). The phases were separated and the aqueous phase further extracted with EtOAc (2×25 mL). The combined organics were dried (MgSO4) and concentrated in vacuo to a brown oil which solidified on standing. Purification by silica gel chromatography eluting with 0-100% EtOAc/cyclohexane gives the sub-titled compound (1.5 g) as a white solid.
Reaction SMILES: B(F)(F)F.CSC.C[O:9][C:10]1[CH:11]=[C:12]([C:17]2[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:23]=3)=[CH:20][N:19]([CH2:34][C:35]#[N:36])[N:18]=2)[CH:13]=[C:14]([CH3:16])[CH:15]=1>ClCCl>[OH:9][C:10]1[CH:11]=[C:12]([C:17]2[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:23]=3)=[CH:20][N:19]([CH2:34][C:35]#[N:36])[N:18]=2)[CH:13]=[C:14]([CH3:16])[CH:15]=1
Reactant: COc1cc(C)cc(-c2nn(CC#N)cc2-c2ccnc(-c3ccccc3)c2)c1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CSC
Product: Cc1cc(O)cc(-c2nn(CC#N)cc2-c2ccnc(-c3ccccc3)c2)c1
Reaction time: 24 h

Procedure:
Borontrifluoride-dimethylsulfide (0.13 mL, 1.2 mmol) was dropwise added to a solution of the methoxy compound (45.6 mg, 0.12 mmol) prepared in Example 23 in dichloromethane (4 mL) at room temperature under nitrogen atmosphere, and stirred for 24 hours. The reaction mixture was concentrated by vacuum distillation. The residue was treated in ethyl acetate (100 mL) and brine (50 mL) and the organic layer was dried over anhydrous magnesium sulfate and distilled under vacuum. Purification through column chromatography (silica gel, ethyl acetate) afforded pure hydroxy products (31 mg, 70%).
Reaction SMILES: [H-].[Na+:2].C[O:4][C:5]([C:7]1[S:8][C:9]([C:29]#[C:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:10][C:11]=1[N:12]([CH:22]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]1)[C:13]([CH:15]1[CH2:20][CH2:19][CH:18]([CH3:21])[CH2:17][CH2:16]1)=[O:14])=[O:6].Cl[C:36]1[CH:37]=[CH:38][C:39]2[N:40]([CH:42]=[CH:43][N:44]=2)[N:41]=1.[OH-].[Na+]>C1COCC1>[CH3:33][C:31]([CH3:34])([CH3:32])[C:30]#[C:29][C:9]1[S:8][C:7]([C:5]([O-:4])=[O:6])=[C:11]([N:12]([CH:22]2[CH2:27][CH2:26][CH:25]([O:28][C:36]3[CH:37]=[CH:38][C:39]4[N:40]([CH:42]=[CH:43][N:44]=4)[N:41]=3)[CH2:24][CH2:23]2)[C:13]([CH:15]2[CH2:20][CH2:19][CH:18]([CH3:21])[CH2:17][CH2:16]2)=[O:14])[CH:10]=1.[Na+:2]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)C1CCC(C)CC1)C1CCC(O)CC1
Reactant: Clc1ccc2nccn2n1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1CCC(C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)[O-])C2CCC(Oc3ccc4nccn4n3)CC2)CC1
Temperature: 80 °C
Yield: 14 %

Procedure:
NaH (30 mg of a 60% oil dispersion, 0.75 mmol) was added to a solution of 5-(3,3-dimethyl-but-1-ynyl)-3-[(4-hydroxy-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (100 mg, 0.22 mmol) and 6-chloro-imidazo[1,2-b]pyridazine (167 mg, 1.08 mmol) in THF (4.0 mL) at room temperature. The reaction was heated at 80° C. overnight, cooled, aqueous NaOH (1.0 mL of a 1.0 N solution) was added and the reaction evaporated to dryness to give a brown solid. Purification by column chromatography on reverse phase C18 silica gel (100% water to 30% acetonitrile/water) provided the desired product as a solid (17 mg, 14%) after lyophilization. MS (m/z): 563.0 [M+H]; HPLC retention time: 5.55 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].Br[CH:15]([CH:33]([CH3:35])[CH3:34])[C:16]([O:18]CC1C=CC=C(OC2C=CC=CC=2)C=1)=[O:17]>>[CH3:13][O:12][C:8]1[CH:7]=[C:5]([NH:6][C@H:15]([C:16]([OH:18])=[O:17])[CH:33]([CH3:35])[CH3:34])[CH:4]=[C:3]([O:2][CH3:1])[C:9]=1[O:10][CH3:11]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: CC(C)C(Br)C(=O)OCc1cccc(Oc2ccccc2)c1
Product: COc1cc(N[C@H](C(=O)O)C(C)C)cc(OC)c1OC

Procedure:
By the above procedure, 3,4,5-trimethoxyaniline is reacted with m-phenoxybenzyl α-bromoisovalerate to yield the m-phenoxybenzyl ester of N-(3,4,5-trimethoxyphenyl)valine. MS m/e 465.2 (M+, 39.0), 182.9 (100).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH3:22])[CH:6]=[C:7]2[C:12]=1[O:11][CH:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2)=[O:2].[BH4-].[Na+]>C1COCC1.C(O)C>[OH:2][CH2:1][C:3]1[CH:4]=[C:5]([CH3:22])[CH:6]=[C:7]2[C:12]=1[O:11][CH:10]([C:13]([F:15])([F:16])[F:14])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2
Reactant: CCOC(=O)C1=Cc2cc(C)cc(C=O)c2OC1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C1=Cc2cc(C)cc(CO)c2OC1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
The ethyl 8-formyl-6-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate from Example 605a, Step 1 (0.32 g, 1.02 mmole) was dissolved in a mixture of THF (1.5 mL) and ethanol (1.5 mL) and the solution was chilled to 0° C. (ice bath). Sodium borohydride (0.04 g, 1.02 mmole) was added portionwise to the above solution and the mixture was allowed to stir for 1 hour. The reaction was quenched with 0.5N HCl (5 mL) and extracted with CH2Cl2 (2×10 mL). The combined extracts were washed with brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil (0.3 g, 93%): GCMS m/z 316.0 (M+). 1H NMR (CDCl3/400 MHz) 7.78 (s, 1H), 7.11 (s, 1H), 6.96 (s, 1H), 5.71 (q, 1H, J=7.0 Hz), 4.67 (m, 2H), 4.30 (m, 2H), 2.27 (s, 3H), 1.33 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[C:5]#[N:6].[Br:11]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.O>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[Cl:1]
Reactant: Cc1ccc(C#N)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)c(Cl)c1
Yield: 98.1 %

Procedure:
A mixture of 3-chloro-4-methylbenzonitrile (7.5 g, 50 mmol, 1.0 equiv), N-bromosuccinimide (9.14 g, 52 mmol, 1.1 equiv), and azobisisobutyronitrile (AIBN, 0.82 g, 5 mmol, 0.1 equiv) in carbon tetrachloride was heated to reflux temperature for 25 h. Water (50 mL) was added, and the product was extracted with CH2Cl2. The organic layers were washed with water, dried with MgSO4, and evaporated to provide 11.3 g of the title compound. This material was used in the next step without purification.
Reaction SMILES: C(CCC1C=CC([C:12]2[C:13]([CH3:43])([CH3:42])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:41])([C@@:18]4([CH3:40])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([C:37]([OH:39])=[O:38])[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)=CC=1)(O)=O.B([C:47]1[CH:48]=[C:49](/[CH:53]=[CH:54]/[C:55]([OH:57])=[O:56])[CH:50]=[CH:51][CH:52]=1)(O)O.B(O)O>>[C:55]([CH2:54][CH2:53][C:49]1[CH:48]=[C:47]([C:12]2[C:13]([CH3:43])([CH3:42])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:41])([C@@:18]4([CH3:40])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([C:37]([OH:39])=[O:38])[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)[CH:52]=[CH:51][CH:50]=1)([OH:57])=[O:56]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(CCC(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=C(O)/C=C/c1cccc(B(O)O)c1
Agent: OBO
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6cccc(CCC(=O)O)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for compound (1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(2-carboxyethyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (example 4a) using (E)-3-(3-boronophenyl)acrylic acid as the reactant boronic acid. The product was isolated as a white solid (34.4 mg, 80%). LCMS: m/e 585.63 (M−H)−, 6.47 min (method 3). 1H NMR (400 MHz, <DMSOmix>) δ ppm 0.89 (d, 6H), 0.97 (s, 6H), 1.00 (s, 3H), 1.01-1.66 (m, 17H), 1.68 (s, 3H), 1.80-1.94 (m, 2H), 2.02-2.12 (m, 1H), 2.13-2.22 (m, 1H), 2.26-2.39 (m, 1H), 2.55-2.60 (m, 2H), 2.83 (t, J=7.62 Hz, 2H), 2.94-3.07 (m, 1H), 4.58 (br. s., 1H), 4.71 (s, 1H), 5.20 (d, J=4.10 Hz, 1H), 6.88-6.98 (m, 2H), 7.08 (d, J=6.44 Hz, 1H), 7.13-7.22 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:9]2=[O:12])=[CH:4][CH:3]=1.[Br:17]Br>CC(O)=O>[Br:17][C:8]1([C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=2)[C:9]1=[O:12]
Reactant: CC(C)(C)C1CCc2ccc(Br)cc2C1=O
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(C)(C)C1(Br)CCc2ccc(Br)cc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
step b—To a solution of 109 (3 g, 10.7 mmol) and HOAc (40 mL) stirred at RT under N2 was added dropwise via cannula a solution of bromine (1.88 g, 605 μL, 11.7 mmol) in HOAc (20.0 mL) over 20 min. The solution was stirred for 1 h at RT then warmed reaction to 50° C. and stirred 1 h. An aliquot of neat bromine (100 μL) was added and heating continued. The total heating time was 2.5 h. The reaction mixture was poured over ice, partitioned between EtOAc and H2O and aqueous phase was neutralized with satd. aq. NaHCO3. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated. The product was purified by SiO2 chromatography eluting with hexanes to afford 3.8 g (quantitative) of 110.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10]C(O)=O)=[N:2]1.Cl[S:15]([OH:18])(=[O:17])=[O:16]>O1CCOCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][S:15]([OH:18])(=[O:17])=[O:16])=[N:2]1
Reactant: O=C(O)Cc1noc2ccccc12
Reactant: O=S(=O)(O)Cl
Solvent: C1COCCO1
Product: O=S(=O)(O)Cc1noc2ccccc12
Temperature: 62.5 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
1,2-Benzisoxazole-3-acetic acid (200 g; 1.13 mol) was suspended in 1,4-dioxane (600 mL). The mixture was cooled in an ice-bath and chlorosulfonic acid (82.6 mL, 1.24 mol, 1.1 eq) was added maintaining the internal temperature below 20° C. The mixture was heated to 60-65° C. for 9½ h and cooled to room-temperature. CELITE™ (20 g) was added followed by xylenes (1000 mL) and the mixture was stirred for one hour at room temperature. It was filtered and concentrated. The suspension obtained was heated to 50-60° C. for three hours and then gradually cooled to 0-5° C. and filtered. The precipitate was filtered off under a nitrogen atmosphere and washed with 400 mL 1,4-dioxane/xylenes (v/v=1:9). It was dried at 60° C. for approximately 16 hours in a vacuum oven (≦1 mm Hg) to give 218.14 g crystalline anhydrous 1,2-benzisoxazole-3-methanesulfonic acid (90.6%) with a HPLC purity of 99.4%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C@@H:10]1[C@@H:15]([NH:16]C(=O)OC(C)(C)C)[CH2:14][C@@H:13]([N:24]2[CH2:31][C:30]3[C:26](=[N:27][N:28]([S:32]([CH:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)(=[O:34])=[O:33])[CH:29]=3)[CH2:25]2)[CH2:12][O:11]1.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>ClCCl>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C@@H:10]1[C@@H:15]([NH2:16])[CH2:14][C@@H:13]([N:24]2[CH2:31][C:30]3[C:26](=[N:27][N:28]([S:32]([CH:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)(=[O:34])=[O:33])[CH:29]=3)[CH2:25]2)[CH2:12][O:11]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N2Cc3cn(S(=O)(=O)C4CCCC4)nc3C2)CO[C@@H]1c1cc(F)c(F)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1C[C@@H](N2Cc3cn(S(=O)(=O)C4CCCC4)nc3C2)CO[C@@H]1c1cc(F)c(F)cc1F
Reaction time: 1.5 h

Procedure:
A solution of the intermediate obtained in Step A above (93 mg, 0.16 mmol) in dichloromethane (6 mL) was treated with trifluoroacetic acid (3 mL) at room temperature. After 1.5 h, the reaction was concentrated to give the title compound.
Reaction SMILES: Cl.C([Si](C)(C)[O:7][CH2:8][C@@H:9]([N:11]1[C:15]2[N:16]=[CH:17][N:18]=[CH:19][C:14]=2[C:13]([C:20]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:41])[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=3)[CH:25]=[N:26][CH:27]=2)=[O:21])=[CH:12]1)[CH3:10])(C)(C)C>O1CCOCC1.C1COCC1>[OH:7][CH2:8][C@@H:9]([N:11]1[C:15]2[N:16]=[CH:17][N:18]=[CH:19][C:14]=2[C:13]([C:20]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:41])[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:39])([F:40])[F:38])[CH:32]=3)[CH:25]=[N:26][CH:27]=2)=[O:21])=[CH:12]1)[CH3:10]
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(NC(=O)Cc3cccc(C(F)(F)F)c3)c2)c2cncnc21
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: C[C@@H](CO)n1cc(C(=O)c2cncc(NC(=O)Cc3cccc(C(F)(F)F)c3)c2)c2cncnc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
10% Hydrochloric acid in 1,4-dioxane (0.2 mL) was added to N-(5-{7-[(S)-2-(tert-Butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl}-pyridin-3-yl)-2-(3-trifluoromethyl-phenyl)-acetamide (Preparation 105, 59 mg, 0.098 mmol) in THF (2 mL) and the mixture was stirred at room temperature for 18 hours. The mixture was evaporated in vacuo and triturated with ether-pentane to afford the title compound as an off white solid in 86% yield, 41 mg.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1B(O)O.Br[C:18]1[S:19][CH:20]=[CH:21][CH:22]=1>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:8]1([CH3:7])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:18]1[S:19][CH:20]=[CH:21][CH:22]=1
Reactant: Brc1cccs1
Reactant: Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1cccs1
Temperature: 25 °C
Yield: 344.3 %

Procedure:
Sodium carbonate (5 ml., 2M aqueous solution) followed by 2-methylphenylboronic acid (0.294 g, 2.4 mmol) were added to a solution of 2-bromothiophene (0.542 g, 2 mmol) and tetrakis(triphenylphosphine)palladium(0) (100 mg) in toluene (5 ml) and ethanol (5 ml) under nitrogen. The mixture was refluxed for 2 hours, cooled to room temperature and extracted with ethyl acetate (2×50 ml). The combined organic layers was dried over MgSO4 and evaporated. The residue was flash chromatographed on silica gel using hexane as eluent to afford 1.2 g of 2-(2-tolyl)thiophene as a colorless gum.