Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[CH:11]=2)[CH:5]=1.[C:25]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])[CH3:26]>>[C:29]([O:28][C:25](=[O:27])[CH2:26][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[CH:11]=2)[CH:5]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)c1cccc(-c2ccnc(COC3CCCCO3)c2)c1
Product: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(COC3CCCCO3)c2)c1

Procedure:
Reaction of (RS)-3-[2-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-benzoic acid methyl ester with tert-butyl acetate according to general procedure K (method d; example K8) yielded the title compound as a light yellow oil.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]([C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([NH:25][CH:26]([CH3:28])[CH3:27])[CH:19]=3)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Li+].[N:32]#[C:33]Br.C(O)C>ClCCl>[CH:26]([N:25]1[C:20]2[CH:19]=[C:18]([C:9]3[NH:8][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:11][C:10]=3[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:23]=[CH:22][C:21]=2[N:24]=[C:33]1[NH2:32])([CH3:28])[CH3:27]
Reactant: N#CBr
Reactant: CC(C)Nc1cc(-c2[nH]c(-c3ccccc3)nc2-c2ccccc2)ccc1N
Agent: C[O-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CCO
Product: CC(C)n1c(N)nc2ccc(-c3[nH]c(-c4ccccc4)nc3-c3ccccc3)cc21
Yield: 38.1 %

Procedure:
Stir a mixture of 2,4-diphenyl-5-(3-(isopropyl)amino-4-aminophenyl)imidazole (0.075 g, 0.20 mmol), lithium methoxide (0.41 mmol, 15 mg) and cyanogen bromide (0.6 mmol, 0.2 ml of 3N in dichloromethane) in dichloromethane (5 ml) under nitrogen for 1 hour. Add ethanol (5 ml), and continue stirring for 5 hours. Pour reaction mixture over an SCX column, and elute sequentially with methanol followed by 2N ammonia in methanol. Combine the basic fractions and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with 9:1 dichloromethane:methanol to provide the title compound as a white solid (30 mg, 38%).
Reaction SMILES: [C:1]([C:9]1[C:10]([NH:16][C:17](=[O:20])[CH2:18]Cl)=[CH:11][N:12]([CH3:15])[C:13]=1[CH3:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:21].[K+]>C(O)C>[C:1]([C:9]1[C:10]([NH:16][C:17](=[O:20])[CH2:18][I:21])=[CH:11][N:12]([CH3:15])[C:13]=1[CH3:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)c2ccccc2)c(NC(=O)CCl)cn1C
Reactant: [I-]
Agent: [K+]
Solvent: CCO
Product: Cc1c(C(=O)c2ccccc2)c(NC(=O)CI)cn1C
Yield: 87 %

Procedure:
N-(4-benzoyl-1,5-dimethyl(1H)pyrrol-3-yl)2-chloroacetamide (0.741 mole) and potassium iodide (1.62 mole) were refluxed in ethanol (3400 ml) for 5 hours with stirring. The reaction mixture was then cooled, the inorganic salts were filtered and the solvent was evaporated under vacuum. The obtained residue was purified by washing first with water and then with cold ethanol. M.p. 135°-137° C. Yield 87%.
Reaction SMILES: I[C:2]1[CH:20]=[CH:19][C:5]2[O:6][CH2:7][C:8]([F:18])([F:17])[C:9]3[N:10]([N:11]=[C:12]([C:14]([NH2:16])=[O:15])[CH:13]=3)[C:4]=2[CH:3]=1.[C:21]([C@:23]1([OH:29])[CH2:27][CH2:26][NH:25][C:24]1=[O:28])#[CH:22]>>[F:17][C:8]1([F:18])[CH2:7][O:6][C:5]2[CH:19]=[CH:20][C:2]([C:22]#[C:21][C@:23]3([OH:29])[CH2:27][CH2:26][NH:25][C:24]3=[O:28])=[CH:3][C:4]=2[N:10]2[N:11]=[C:12]([C:14]([NH2:16])=[O:15])[CH:13]=[C:9]12
Reactant: C#C[C@]1(O)CCNC1=O
Reactant: NC(=O)c1cc2n(n1)-c1cc(I)ccc1OCC2(F)F
Product: NC(=O)c1cc2n(n1)-c1cc(C#C[C@]3(O)CCNC3=O)ccc1OCC2(F)F

Procedure:
Similar to as described in General Procedure G, 9-iodo-4,4-difluoro-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2-carboxamide was reacted with (R)-3-ethynyl-3-hydroxypyrrolidin-2-one to give a mixture of titled compound after purification by prep HPLC.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:7]=[C:6]([N+:29]([O-])=O)[CH:5]=1>[Pd].C1COCC1>[CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:7]=[C:6]([NH2:29])[CH:5]=1
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(C(=O)OC)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOc1cc(N)cc(C(=O)OC)c1
Reaction time: 1.5 h
Yield: 99 %

Procedure:
A mixture of 3.55 g of 3-nitro-5-(octadecyloxy)benzoic acid methyl ester and 0.75 g of 10% palladium on carbon in 100 ml of THF was shaken under aninitial hydrogen pressure of 52 psi until uptake ceased after 1.5 hours. The catalyst was removed by filtration and the filtrate was concentrated at reduced pressure to give 3.28 g of pure 3-amino-5-(octadecyloxy)benzoicacid methyl ester.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=O)[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:20]=2)=[CH:14][C:13]=1[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Cl.[NH2:39][OH:40].C(OCC)(=O)C>N1C=CC=CC=1>[CH2:28]([O:27][C:25]([C:21]1[CH:20]=[C:19]([C:18](=[N:39][OH:40])[C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[C:13]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:14]=2)[CH:24]=[CH:23][CH:22]=1)=[O:26])[CH3:29]
Reactant: CCCCCCCCCCOc1ccc(C(=O)c2cccc(C(=O)OCC)c2)cc1CCC(=O)OCC
Reactant: NO
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCCCCCCCCOc1ccc(C(=NO)c2cccc(C(=O)OCC)c2)cc1CCC(=O)OCC
Temperature: 70 °C
Yield: 91.8 %

Procedure:
A mixture of 1.1 g of 2-(decyloxy)-5-[3-(ethyloxycarbonyl)benzoyl]benzenepropanoic acid, ethyl ester and 220 mg of hydroxylamine hydrochloride in 25 ml of pyridine was heated at 70° C. for approximately 18 hours. The reaction was allowed to cool to ambient temperature, ethyl acetate was added, and the solution was washed several times with 1N hydrochloric acid and water. The organic layer was dried over sodium sulfate and concentrated in vacuo to provide 1.04 g of the desired title product as an oil. NMR.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH2:8][P:9](=[O:12])([OH:11])[OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:15][CH:16](O)[CH2:17][CH:18](O)[CH3:19]>>[CH3:15][CH:16]1[CH2:17][CH:18]([CH3:19])[O:11][P:9](=[O:10])([CH2:8][C:7]2[CH:13]=[CH:14][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[O:12]1
Reactant: O=[N+]([O-])c1ccc(CP(=O)(O)O)cc1
Reactant: CC(O)CC(C)O
Product: CC1CC(C)OP(=O)(Cc2ccc([N+](=O)[O-])cc2)O1

Procedure:
With 4-nitrobenzylphosphonic acid and 2,4-pentanediol, the same procedure as in Reference Example 11 was followed, to yield 4,6-dimethyl-2-(4-nitrobenzyl)-1,3,2-dioxaphosphorinane-2-oxide, which was then recrystallized from ethanol-hexane to yield colorless needles having a melting point of 152° to 153° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:5]=[CH:4][N:3]=1.[CH2:15]([OH:19])[CH2:16][C:17]#[CH:18].[H-].[Na+].O>CN(C)C=O>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:7]=[C:2]([O:19][CH2:15][CH2:16][C:17]#[CH:18])[N:3]=[CH:4][N:5]=1
Reactant: C#CCCO
Reactant: Fc1ccccc1-c1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCCOc1cc(-c2ccccc2F)ncn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 57.8 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 450 mg of 4-chloro-6-(2-fluorophenyl)pyrimidine and 227 mg of 3-butyn-1-ol, to which 130 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 12 hours. The reaction mixture was then poured into water and extracted three times with ethyl acetate. The organic layers were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 302 mg of 4-(2-fluorophenyl)-6-(3-butynyloxy)pyrimidine (the present compound (152)).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:13])[C:5]([O:7]C)=[O:6].[OH-].[Li+]>O1CCCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:13])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(C(C)Oc2ccccc2)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(Oc1ccccc1)c1ccc(C(=O)O)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.8 %

Procedure:
To a solution of methyl 3-fluoro-4-(1-phenoxyethyl)benzoate (400 mg, 1.5 mmol) in mixed solution of tetrahydrofuran/methanol/water=3:1:1 (4 mL) was added lithium hydroxide (200 mg, 8.4 mmol). The mixture was stirred at room temperature for 2 hours. The suspension was concentrated in vacuo and quenched with hydrochloride acid aqueous (1N, 5 mL). To the residue, water (50 mL) was added and extracted with dichloromethane (2*50 mL). The combined organic phase was separated, dried over sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to give 3-fluoro-4-(1-phenoxyethyl)benzoic acid as pale solid (300 mg, 82%).
Reaction SMILES: [O:1]1[CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:2]12.[Cl-].[Li+].CN1C(=O)N(C)CC1>CN1CCCC1=O>[C:2]1(=[O:1])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C1CCCCCC2OC2CCCC1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN1CCN(C)C1=O
Solvent: CN1CCCC1=O
Product: O=C1CCCCCCCCCCC1
Yield: 94 %

Procedure:
For example, German Patent No. 3,744,094 discloses an isomerization of an epoxycyclododecane in the presence of a catalyst consisting of lithium chloride in a reaction medium consisting of N-methylpyrrolidone or N,N′-dimethylethyleneurea to produce cyclododecanone with a yield of 94%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=2)[CH:3]=1.[K+].[C:16]([C:18]1[N:19]=[C:20]([C:31]([O-])=[O:32])[N:21]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:22]=1)#[N:17].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:31]([C:20]2[N:21]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:22]=[C:18]([C:16]#[N:17])[N:19]=2)=[O:32])=[C:4]([C:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=2)[CH:3]=1
Reactant: Nc1ccc(Br)cc1C1=CCCCC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(Br)cc1C1=CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
To a mixture of 4-bromo-2-cyclohex-1-enyl-phenylamine (as prepared in the previous step, 1.23 g, 4.88 mmol), potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 1, step (d), 1.49 g, 4.88 mmol) and bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP) (2.27 g, 4.88 mmol) in 25 mL of DMF was added N,N-diisopropylethylamine (DIEA) (2.55 mL, 14.6 mmol). After stirring at RT for 16 h, the mixture was treated with 100 mL of EtOAc and washed with H2O (2×30 mL), brine (30 mL) and dried (Na2SO4). The organic solvent was evaporated and the residue was purified by flash chromatography on silica gel (5-10% EtOAc/hexane) to give 2.21 g (90%) of the title compound as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 9.70 (s, 1H), 8.26 (d, 1H, J=8.6 Hz), 7.78 (s, 1H), 7.36 (dd, 1H, J=8.6, 2.3 Hz), 7.31 (d, 1H, J=2.3 Hz), 5.94 (s, 2H), 5.86 (m, 1H), 3.66 (t, 2H, J=8.3 Hz), 2.19-2.33 (m, 4H), 1.75-1.88 (m, 4H), 0.97 (t, 2H, J=8.3 Hz), 0.00 (s, 9H).
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=1)#[CH:10].O>C(N(CC)CC)C>[CH3:19][CH:17]([C:14]1[CH:13]=[CH:12][C:11]([C:9]#[C:10][C:2]2[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:16][CH:15]=1)[CH3:18]
Reactant: C#Cc1ccc(C(C)C)cc1
Reactant: Nc1ncccc1Br
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)c1ccc(C#Cc2cccnc2N)cc1
Yield: 46.6 %

Procedure:
A mixture of bis(triphenylphosphine)palladium(0)dichloride (0.811 g), 3-bromopyridin-2-amine (2 g), 1-ethynyl-4-isopropylbenzene (1.667 g) and copper iodide(I) (0.22 g) in triethylamine (38.6 mL) was heated under reflux. Water was added to the reaction mixture, the mixture was filtered through celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1273 mg) as a pale-yellow solid.
Reaction SMILES: [CH3:1][C:2]1([C:6]([OH:8])=O)[CH2:5][O:4][CH2:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[I:33][C:34]1[CH:42]=[C:41]2[C:37]([CH:38]=[N:39][N:40]2[C:43]2[C:48]([NH2:49])=[CH:47][N:46]=[C:45]([NH2:50])[N:44]=2)=[CH:36][CH:35]=1.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[NH2:50][C:45]1[N:44]=[C:43]([N:40]2[C:41]3[C:37](=[CH:36][CH:35]=[C:34]([I:33])[CH:42]=3)[CH:38]=[N:39]2)[C:48]([NH:49][C:6]([C:2]2([CH3:1])[CH2:5][O:4][CH2:3]2)=[O:8])=[CH:47][N:46]=1
Reactant: Nc1ncc(N)c(-n2ncc3ccc(I)cc32)n1
Reactant: CC1(C(=O)O)COC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC1(C(=O)Nc2cnc(N)nc2-n2ncc3ccc(I)cc32)COC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 3-methyloxetane-3-carboxylic acid (8.7 mg, 0.075 mmol) and HATU (28.5 mg, 0.075 mmol) was added a solution of crude 4-(6-iodo-1H-indazol-1-yl)pyrimidine-2,5-diamine (11% purity, 120 mg, 0.037 mmol) in DMF (0.5 mL) followed by triethylamine (0.016 mL, 0.112 mmol). The mixture was stirred at RT for 10 min, then diluted with EtOAc (10 mL) and washed with water (2×3 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give the crude compound. Purification by flash chromatography (Isolute column, 100% DCM to 3% MeOH in DCM) gave the title compound; m/z=+451.30 (M+H)+, (purity=76%). This intermediate was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([F:15])[CH:6]=1)=[O:4].B(Br)(Br)Br>ClCCl>[F:15][C:7]1[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1
Reactant: COC(=O)c1cc(F)nc2ccccc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)c1cc(F)nc2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 26.8 %

Procedure:
A solution of 2-fluoroquinoline4-carboxylic acid methyl ester (0.08 g) in dichloromethane (4 ml) was cooled to −50° C. and boron tribromide (0.08 ml) was added. After the addition of boron tribromide the reaction was warmed to room temperature and stirred for 1.5 h. The mixture was re-cooled to −50° C., quenched with water (10 ml), diluted with dichloromethane:water (1:1, 60 ml), the organic phase separated and solvent removed at reduced pressure to give 2-fluoroquinoline-4-carboxylic acid (0.02 g) after trituration with dichloromethane/petroleum ether. 1H NMR δ: 7.70-7.76 (2H, m), 7.85-7.96 (2H, m), 8.65 (1H, d), 14.24 (1H, brs). m/z (API−): 190 (MH+).
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[C:5]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])[CH2:4][C@@H:3]1[CH3:25].[C:26]([O:30][CH3:31])(=[O:29])[CH:27]=[CH2:28].C(=O)([O-])[O-].[Cs+].[Cs+].C([O-])(O)=O.[Na+]>CC(O)(C)C.O>[C:11]([O:10][C:9]([NH:8][C@@H:7]1[CH:6]=[C:5]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])[CH2:4][C@H:3]([CH3:25])[C@H:2]1[O:1][CH2:28][CH2:27][C:26]([O:30][CH3:31])=[O:29])=[O:15])([CH3:12])([CH3:13])[CH3:14]
Reactant: C[C@H]1CC(c2ccncc2[N+](=O)[O-])=C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O
Reactant: C=CC(=O)OC
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)(C)O
Solvent: O
Product: COC(=O)CCO[C@@H]1[C@@H](C)CC(c2ccncc2[N+](=O)[O-])=C[C@H]1NC(=O)OC(C)(C)C
Temperature: 35 °C
Reaction time: 16 h
Yield: 48 %

Procedure:
A mixture of (+/−)-tert-butyl (1R,5S,6R)-6-hydroxy-5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-enylcarbamate (1.0 equiv.), methyl acrylate (30.0 equiv.) and CESIUM CARBONATE (1.2 equiv.) in t-BuOH (0.38 M) was stirred at 35° C. for 16 hrs. The reaction was cooled to room temperature, followed by the addition of NaHCO3(aq.) and water. The mixture was extracted with EtOAc and the combined organics were dried over MgSO4, filtered, and concentrated. The sample was purified by ISCO chromatography to yield (+/−)-methyl 3-((1R,2R,6S)-2-(tert-butoxycarbonylamino)-6-methyl-4-(3-nitropyridin-4-yl)cyclohex-3-enyloxy)propanoate in 48% yield. LC/MS (m/z)=436.1 (MH+), Rt=0.91 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].Br[CH2:14][C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: COC(=O)CBr
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cn1ccc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 5-nitroindole (3.24 g, 20 mmol), methyl bromoacetate (3.36 g, 22 mmol), cesium carbonate (32.58 g, 100 mmol) in 150 mL of DMF was stirred at room temperature for 3 h. The reaction mixture was poured into water and the solid was collected and dried to give methyl (5-nitro-1H-indol-1-yl)acetate as a pale yellow solid: MS (ESI) m/z 235.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][O:2]1.[Mn]([O-])(=O)(=O)=[O:12].[K+]>ClCCl.[O-2].[O-2].[Mn+4]>[C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][O:2]1
Reactant: c1ccc2c(c1)CCOC2
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [Mn+4]
Agent: [K+]
Agent: [O-2]
Solvent: ClCCl
Product: O=C1OCCc2ccccc21
Reaction time: 18 h
Yield: 80 %

Procedure:
To a solution of isochroman (5.0 g; 37.3 mmol) in dichloromethane (465 ml) stirred at room temperature was added, over 15 minutes, a homogeneous mixture of potassium permanganate and manganese dioxide (74.60 g) in a 1:3 ratio. The suspension obtained was left for 18 hours at room temperature. The suspension was filtered through a Büchner filter. The solvent was evaporated off under reduced pressure to give 4.42 g of crude product (80%), which was used for the following reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.[C:31]([C:33]1[CH:34]=[C:35]([OH:40])[CH:36]=[CH:37][C:38]=1[F:39])#[N:32]>>[Cl:1][C:2]1[C:3]([O:40][C:35]2[CH:36]=[CH:37][C:38]([F:39])=[C:33]([C:31]#[N:32])[CH:34]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([NH:11][C:12]2[N:13]=[CH:14][CH:15]=[CH:16][N:17]=2)(=[O:9])=[O:10])[CH:7]=1
Reactant: COc1ccc(CN(c2ncccn2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Reactant: N#Cc1cc(O)ccc1F
Product: N#Cc1cc(Oc2cc(F)c(S(=O)(=O)Nc3ncccn3)cc2Cl)ccc1F

Procedure:
The title compound was prepared according to the method described for Library Protocol 2 using 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-2-yl)benzenesulfonamide (WO2012004743) and 3-cyano-4-fluorophenol.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:25])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[NH:6][C:5]1=[O:24])[CH:2]=[CH2:3].[H-].[Na+].Br.Br[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1>CN(C=O)C>[CH2:1]([C@@:4]1([CH3:25])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[C:5]1=[O:24])[CH:2]=[CH2:3]
Reactant: BrCc1ccccn1
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)NC1=O
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(Cc2ccccn2)C1=O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one (2.246 g, 6 mmol; Example 71D) in DMF (25 mL) was added sodium hydride, 60% dispersion in mineral oil (0.504 g, 12.60 mmol) and the mixture was stirred at 0° C. for 5 minutes. To this was added 2-(bromomethyl)pyridine hydrobromide (1.593 g, 6.30 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 10 min and quenched with saturated NH4Cl solution, extracted with EtOAc, washed with sat. aq. NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (eluent: 0 to 100% EtOAc in hexanes) to give the title compound. Mass Spectrum (ESI) m/z=465 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]([C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[C:15]3[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:14]=3[CH:13]=[C:12]([C:21]([OH:23])=O)[CH:11]=2)=[CH:7][C:6]=1[F:26])=[O:4].C([SiH2][O:33][C:34](C)(C)[C:35]1[CH:36]=[CH:37][C:38]([NH2:41])=[N:39][CH:40]=1)(C)(C)C.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:33][CH2:34][C:35]1[CH:36]=[CH:37][C:38]([NH:41][C:21]([C:12]2[CH:11]=[C:10]([O:9][C:8]3[CH:24]=[CH:25][C:5]([C:3](=[O:4])[N:2]([CH3:27])[CH3:1])=[C:6]([F:26])[CH:7]=3)[C:15]3[CH2:16][C:17]([CH3:19])([CH3:20])[O:18][C:14]=3[CH:13]=2)=[O:23])=[N:39][CH:40]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc(N)nc1
Reactant: CN(C)C(=O)c1ccc(Oc2cc(C(=O)O)cc3c2CC(C)(C)O3)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1ccc(Oc2cc(C(=O)Nc3ccc(CO)cn3)cc3c2CC(C)(C)O3)cc1F
Temperature: 50 °C
Reaction time: 8 h
Yield: 24.5 %

Procedure:
To a solution of 4-(4-dimethylcarbamoyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (143a) (381 mg, 1.02 mmol), 5-(tert-butyl-dimethyl-silanyloxymethyl)-pyridin-2-ylamine (22a) (365 mg, 1.53 mmol) and triethylamine (0.284 mL, 2.04 mmol) in 5 mL of DMF was added HATU (776 mg, 2.04 mmol). The mixture was stirred at 50° C. overnight, quenched with water, extracted with 3×EtOAc. The combined organic layer was washed with 2×H2O, dried with Na2SO4, concentrated and the resulting oil was purified by Biotage column chromatography with 50-100% EtOAc in hexanes to give a yellow solid (120 mg, 25% yield). 1H NMR (400 MHz, CDCl3) δ 8.76 (br. s., 1 H) 8.29 (d, J=8.59 Hz, 1 H) 8.21 (d, J=1.77 Hz, 1 H) 7.74 (dd, J=8.59, 2.27 Hz, 1 H) 7.35 (t, J=8.08 Hz, 1 H) 7.27 (s, 1 H) 7.11 (d, J=5.81 Hz, 1 H) 6.78 (dd, J=8.46, 2.40 Hz, 1 H) 6.68 (dd, J=10.61, 2.27 Hz, 1 H) 4.66 (s, 2 H) 3.11 (s, 3 H) 2.96 (s, 3 H) 2.88 (s, 2 H) 1.48 (s, 6 H); LCMS for C26H26FN3O5 m/z 480.20 (M+H).