Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:11]/[N:12]=[C:13]2\[NH:14][C:15](=[O:27])[C:16]3[NH:17][CH:18]=[N:19][C:20]=3[N:21]\2[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=O)[CH:5]=[CH:6][CH:7]=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][C:9]1[N:14]2[C:15](=[O:27])[C:16]3[NH:17][CH:18]=[N:19][C:20]=3[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:13]2=[N:12][N:11]=1
Reactant: CCCCCn1/c(=N/NC(=O)Cc2cccc(Br)c2)[nH]c(=O)c2[nH]cnc21
Solvent: c1ccccc1
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(Cc3cccc(Br)c3)nnc12
Yield: 86 %

Procedure:
The mixture of 2-(3-bromophenyl)-N′-[(2E)-6-oxo-3-pentyl-1,3,6,7-tetrahydro-2H-purin-2-ylidene]acetohydrazide (1.8 g, 4.2 mmol) in benzene (100 mL) was refluxed overnight. The reaction mixture was concentrated to give the desired product 1.5 g. LCMS calculated for C18H20BrN6O (M+H): 415.1. found: 415.1.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:16]2[O:20][N:19]=[C:18]([CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])[N:17]=2)[CH2:11][C:12]([NH:14][OH:15])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+]>O1CCOCC1.O>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:16]2[O:20][N:19]=[C:18]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[N:17]=2)[CH2:11][C:12]([NH:14][OH:15])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CCc1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CCc1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 2 %

Procedure:
A solution of ethyl 3-(5-{(1R)-4-cyclohexyl-1-[2-(hydroxyamino)-2-oxoethyl]butyl}-1,2,4-oxadiazol-3-yl)propanoate (Example 54) (58 mg, 0.1 5 mmol) in 1,4-dioxan (2 ml) and water (1 ml) was treated with lithium hydroxide monohydrate (13 mg, 0.31 mmol) and stirred at room temperature for 2 hours. The reaction mixture was diluted with water and washed with diethylether (×2). The aqueous layer was acidified with hydrochloric acid (2M) (2 ml) and washed with ethyl acetate (×2). The combined organic layers were washed with brine, dried over anhydrous sodium sulphate, filtered and the solvent was removed under reduced pressure. The oil was purified by column chromatography on silica gel eluting with a gradient system of 100:0:0 (dichloromethane:methanol:acetic acid) gradually changing to 90:10:1 (dichloromethane:methanol:acetic acid) to afford the title compound as an orange gum (36 mg).
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])(=O)=O.[F:16][C:17]1[N:22]=[CH:21][C:20]([CH:23]([CH3:26])[CH2:24]O)=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Si:7]([O:6][CH2:24][CH:23]([C:20]1[CH:19]=[CH:18][C:17]([F:16])=[N:22][CH:21]=1)[CH3:26])([C:10]([CH3:11])([CH3:12])[CH3:13])([CH3:8])[CH3:9]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(CO)c1ccc(F)nc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(CO[Si](C)(C)C(C)(C)C)c1ccc(F)nc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 78.2 %

Procedure:
Tert-butyldimethylsilyl trifluoromethanesulfonate (2.160 mL, 9.41 mmol) was added to a solution of 2-(6-fluoropyridin-3-yl)propan-1-ol (1.39 g, 8.96 mmol) and N,N-diisopropylethylamine (3.35 mL, 19.26 mmol) in CH2Cl2 (45 mL) at 0° C., and the resulting mixture stirred at 0° C. for 2.5 h. The reaction mixture was subsequently concentrated onto silica gel and chromatographically purified (silica gel, 0 to 20% EtOAc/hexanes) to provide 5-(1-(tert-butyldimethylsilyloxy)propan-2-yl)-2-fluoropyridine (1.89 g, 7.01 mmol, 78% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J=2.2 Hz, 1H), 7.65 (td, J=8.1, 2.5Hz, 1H), 6.86 (dd, J=8.4, 2.9 Hz, 1H), 3.58-3.69 (m, 2H), 2.93 (sxt, J=6.7 Hz, 1H), 1.28 (d, J=7.0 Hz, 3H), 0.84 (s, 9H), −0.04 (s, 3H), −0.05 (s, 3H). 19F NMR (377 MHz, CDCl3) 6-72.06 (d, J=6.0 Hz, 1F). m/z (ESI, +ve) 270.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@:6]1([NH:11]C(OC(C)(C)C)=O)[CH2:8][C@H:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].[ClH:19].O1CCOCC1>>[ClH:19].[CH2:1]([O:3][C:4]([C@@:6]1([NH2:11])[CH2:8][C@H:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: Cl
Solvent: C1COCCO1
Product: C=C[C@@H]1C[C@]1(N)C(=O)OCC

Procedure:
N-BOC-(1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid ethyl ester (8.5 g, 33.3 mmol) was stirred under an N2 atmosphere with 200 mL of 4N HCl/dioxane (Aldrich) at rt for 3 h. The solvent was removed under reduced pressure keeping the temperature below 40 C. This gave 6.57 g (˜100%) of (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid ethyl ester hydrochloride as a light tan solid. 1H NMR (300 MHz, CD3OD) δ 1.31 (t, J=7.0 Hz, 3H), 1.69–1.82 (m, 2H), 2.38 (q, J=8.8 Hz, 1H), 4.29 (q, J=7.0 Hz, 2H), 5.22 (d, J=10.3 Hz, 1H), 5.40 (d, J=17.2 Hz, 1H), 5.69–5.81 (m, 1H). LC-MS (Method A, retention time: 0.58 min), MS m/z 156 (M++1).
Reaction SMILES: [C:1]([O-:4])(=O)[CH3:2].[K+].FC(F)(F)S([O-])(=O)=O.[CH2:14]([N+:21]12CC([CH2:26]1)[C:24]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)=[CH:23][CH2:22]2)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.[OH-].[Na+]>C1(C)C=CC=CC=1.CC(O)C>[CH2:14]([N:21]1[CH2:22][CH:23]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH:2]([CH2:1][OH:4])[CH2:26]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(=O)[O-]
Reactant: Fc1ccc(C2=CC[N+]3(Cc4ccccc4)CC2C3)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [K+]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(C)O
Product: OCC1CN(Cc2ccccc2)CC=C1c1ccc(F)cc1
Temperature: 25 °C

Procedure:
Potassium acetate (0.14 g) was added to a stirred solution of 1-benzyl-4-(4-fluorophenyl)-1-azoniabicyclo[3.1.1]hept-3-ene trifluoromethanesulphonate (0.5 g) in toluene (2.5 ml) and propan-2-ol (2.5 ml). The mixture was then boiled and stirred under reflux for 24 hours. The mixture was cooled to room temperature and toluene (10 ml) and water (5 ml) were added. The organic layer was separated, dried and evaporated to leave an oil. A solution of the oil in propan-2-ol (2 ml) and toluene (2 ml) was treated with 4M-NaOH (0.4 ml). The mixture was boiled under reflux for 2 hours then cooled to room temperature. Water (5 ml) and toluene 95 ml) were added. The organic layer was separated, washed with water (2×5 ml) and evaporated to give (+,−)-1-benzyl-3-hydroxymethyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine (ee 5.48%).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH:17]1([NH:20][C:21](=[O:38])[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[C:24](B3OC(C)(C)C(C)(C)O3)[CH:23]=2)[CH2:19][CH2:18]1>>[CH:17]1([NH:20][C:21](=[O:38])[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([C:2]3[CH:16]=[CH:15][C:5]4[C:6]([CH:9]5[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]5)=[N:7][O:8][C:4]=4[CH:3]=3)[CH:23]=2)[CH2:18][CH2:19]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Brc1ccc2c(C3CCNCC3)noc2c1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(C3CCNCC3)noc2c1

Procedure:
Example 1 was prepared by General Method A using 6-bromo-3-piperidin-4-yl-1,2-benzisoxazole and Intermediate 5.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C@@H:4]([CH2:7][O:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[NH:3]1.[H-].[Na+].[CH2:17](Br)[CH:18]=[CH2:19]>C1COCC1>[CH2:19]([N:3]1[C@H:4]([CH2:7][O:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:6][C:2]1=[O:1])[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: O=C1CC[C@@H](COc2cccnc2)N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCN1C(=O)CC[C@H]1COc1cccnc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-((2-oxo-5-(S)-pyrrolidinyl)methoxy)pyridine, from Example 22a (450 mg, 2.34 mmol), in 10 mL of anhydrous THF at 0° C. was added NaH (80% dispersion, 186 mg, 2.68 mmol) was added, and the reaction mixture was stirred for 20 minutes at this temperature. The reaction was then warmed to room temperature, and allyl bromide (425 mg, 3.51 mmol) was added via syringe. After starting material was consumed, water was added to quench the reaction. The desired compound was extracted from the aqueous phase with ethyl acetate and chloroform. The organic layer was dried over MgSO4, then taken to dryness. The residue was purified by silica gel flash chromatography (5% MeOH/CHCl3) to give 450 mg of the title compound. MS (DCI/NH3) m/e: 233 (M+H)+. 1H NMR (D2O, 300 MHz) δ: 8.37-8.26 (m, 2H), 7.38-7.29 (m, 2H), 5.83-5.69 (m, 1H), 5.26-5.13 (m, 2H), 4.35-4.24 (m, 1H), 4.16-3.96 (m, 3H), 3.77-3.67 (m, 1H), 2.68-2.54 (m, 1H), 2.50-2.38 (m, 1H), 2.36-2.20 (m, 1H), 2.09-1.96 (m, 1H),
Reaction SMILES: [Na].[Cl:2][C:3]1[C:11]([Cl:12])=[C:10]2[C:6]([CH2:7][CH:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:9]2=[O:13])=[CH:5][C:4]=1[OH:20].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(O)C>[Cl:2][C:3]1[C:11]([Cl:12])=[C:10]2[C:6]([CH2:7][CH:8]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:9]2=[O:13])=[CH:5][C:4]=1[O:20][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)CBr
Reactant: O=C1c2c(cc(O)c(Cl)c2Cl)CC1c1ccccc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(c1ccccc1)C2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70 %

Procedure:
Sodium (629 mg., 27.3 mmol) is added to 50 ml. of absolute ethanol under a nitrogen atmosphere. After the sodium dissolves, 6,7-dichloro-5-hydroxy-2-phenyl-1-indanone (7.35 g., 25.1 mmol), and 75 ml. of additional absolute ethanol are added followed by 3.1 ml. of ethyl bromoacetate (28.1 mmol). The mixture is stirred at room temperature for 1 to 2 hrs., refluxed for 5-16 hrs. and then poured into a dilute acid-ether mixture. The crude reaction product collected and crystallized from 1:1 ethanol-water with activated charcoal provides a 70% yield of ethyl (6,7-dichloro-1-oxo-2-phenyl-5-indanyloxy)acetate, m.p. 113.5°-115°.
Reaction SMILES: C([C:11]([NH:13][CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=1)=[O:12])(OCC1C=CC=CC=1)=O.[CH:24]1([CH2:27][N:28]2[C:36]3[N:35]=[C:34]([CH2:37][C:38]4[CH:43]=[CH:42][C:41]([NH:44][CH3:45])=[CH:40][CH:39]=4)[NH:33][C:32]=3[C:31](=[O:46])[N:30]([CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=3[F:54])[C:29]2=[O:55])[CH2:26]C1>CN(C)C1C=CN=CC=1>[CH2:19]([O:21][C:11](=[O:12])[NH:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:19](=[O:21])[N:44]([C:41]2[CH:42]=[CH:43][C:38]([CH2:37][C:34]3[NH:33][C:32]4[C:31](=[O:46])[N:30]([CH2:47][C:48]5[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=5[F:54])[C:29](=[O:55])[N:28]([CH:27]5[CH2:24][CH2:26]5)[C:36]=4[N:35]=3)=[CH:39][CH:40]=2)[CH3:45])=[CH:22][CH:23]=1)[C:18]1[CH:22]=[CH:23][CH:15]=[CH:16][CH:17]=1
Reactant: CNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Reactant: O=C(NCc1ccc(C(=O)O)cc1)C(=O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Product: CN(C(=O)c1ccc(CNC(=O)OCc2ccccc2)cc1)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3C2CC2)cc1

Procedure:
This compound was prepared by a method similar to that described in example 79 except that N-carbobenzyloxycarbonyl-4-aminomethylbenzoic acid was used in place of N-acetyl-6-amino-2-pyridine carboxylic acid, 0.62 equivalents of 3-cyclopropylmethyl-8-[4-(methylamino)-benzyl]-1-(2-fluorobenzyl)-3,7-dihydropurine-2,6-dione, and 0.68 equivalents of 4-dimethylaminopyridine added as the final reagent. The product was purified by chromatography using silica gel eluted with 95:5 chloroform/methanol followed by crystallization from acetonitrile. MS, observe m/z(M+H)=701.3 and m/z(M−H)=699.4.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:20]=[C:19]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:30]5[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=5[F:37])[CH:28]=4)[N:23](C(OC(C)(C)C)=O)[CH:22]=3)[CH:18]=[N:17][CH:16]=2)[CH2:10]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:37][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]([F:36])[C:30]=1[C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[C:21]2[C:19]1[N:20]=[C:15]([N:11]2[CH2:12][CH2:13][CH2:14][CH:9]([NH2:8])[CH2:10]2)[CH:16]=[N:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)NC1CCCN(c2cncc(-c3cn(C(=O)OC(C)(C)C)c4ccc(-c5c(F)cccc5F)cc34)n2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCCN(c2cncc(-c3c[nH]c4ccc(-c5c(F)cccc5F)cc34)n2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A glass microwave reaction vessel was charged with tert-butyl 5-(2,6-difluorophenyl)-3-iodo-1H-indole-1-carboxylate (350 mg, 0.769 mmol), tert-butyl 1-(6-(tributylstannyl)pyrazin-2-yl)piperidin-3-ylcarbamate (436 mg, 0.769 mmol), Pd(PPh3)4 (89 mg, 0.077 mmol), and CuI (15 mg, 0.077 mmol) in DMF (6 mL). The reaction mixture was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 100° C. for 30 min. The mixture was diluted with DCM and water. The organic layer was separated, washed with water and brine, dried over Na2SO4, filtered and concentrated to give the crude product, tert-butyl 3-(6-(3-(tert-butoxycarbonylamino)piperidin-1-yl)pyrazin-2-yl)-5-(2,6-difluorophenyl)-1H-indole-1-carboxylate. MS (ESI, pos. ion) m/z: 606 (M+1). To a solution of tert-butyl 3-(6-(3-(tert-butoxycarbonylamino)piperidin-1-yl)pyrazin-2-yl)-5-(2,6-difluorophenyl)-1H-indole-1-carboxylate (466 mg, 0.769 mmol) in DCM (6 mL) was added TFA (4 mL) and the reaction was stirred at RT for 3 h, then solvent was removed. The residue was diluted with DCM and washed with saturated NaHCO3 aqueous solution twice. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified with RP-HPLC to give 1-(6-(5-(2,6-difluorophenyl)-1H-indol-3-yl)pyrazin-2-yl)piperidin-3-amine as a light brown solid. MS (ESI, pos. ion) m/z: 406 (M+1).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:30])=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([NH:21][NH:22]C(OC(C)(C)C)=O)=[O:20])=[CH:15][CH:14]=3)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1>Cl>[CH:1]1([NH:4][C:5]([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([NH:21][NH2:22])=[O:20])=[CH:15][CH:14]=3)[C:10]([CH3:30])=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NNC(=O)OC(C)(C)C)cc1
Agent: Cl
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NN)cc1

Procedure:
A solution of tert-butyl 2-({5′-[(cyclopropylamino)carbonyl]-2′-methyl-1,1′-biphenyl-4-yl}carbonyl)hydrazinecarboxylate (Intermediate 41) (2.37 g) in hydrogen chloride (4.0M solution in dioxane, 20 ml) was stirred at room temperature under nitrogen for 6 hours. The solvent was evaporated under vacuum, the residue was dissolved in water, basified with sodium hydroxide solution (2N) and extracted with ethyl acetate. The organic phase was dried (magnesium sulphate) and the solvent removed under vacuum to give the N-cyclopropyl-4′-(hydrazinocarbonyl)-6-methyl-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[CH:8][C:9]([CH3:12])=[N:10][CH:11]=2)[N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].BrCCC[CH2:23][N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34]>CN(C=O)C>[CH3:12][C:9]1[N:10]=[CH:11][C:6]([C:4]2[N:3]=[CH:2][N:1]([CH2:23][N:24]3[C:28](=[O:29])[C:27]4[C:26](=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:25]3=[O:34])[CH:5]=2)=[CH:7][CH:8]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: Cc1ccc(-c2c[nH]cn2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cn(CN3C(=O)c4ccccc4C3=O)cn2)cn1
Temperature: 80 °C
Reaction time: 24 h
Yield: 37 %

Procedure:
To a solution of 5-(1H-Imidazol-4-yl)-2-methyl-pyridine (1 eq) in DMF was added potassium carbonate (4 eq) at room temperature under dry conditions. After heating the reaction mixture in a 80° C. oil bath for 1 hour, N-(4-bromobutyl)phtalimide (3.9 eq) was added to the mixture. The solution was left stirring in a 80° C. oil bath for 24 hours. Upon cooling, the reaction was filtered and the solid was washed with ethyl acetate. The filterate was diluted with ethyl acetate and washed with NH4Cl(sat), H2O, NaCl(sat), dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography using an initial solvent gradient of 97% DCM, 3% MeOH and 0.1% TEA (1L) to afford the product (37%). MH+(361).
Reaction SMILES: [CH2:1]([C@@:8]12[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][C@H:17]1[CH2:16][CH2:15][C:14]1[CH:13]=[C:12]([C:23]([OH:25])=[O:24])[CH:11]=[CH:10][C:9]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH:28](=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl>O.CCOC(C)=O>[CH2:1]([C@@:8]12[CH2:21]/[C:20](=[CH:28]\[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)/[C:19](=[O:22])[CH2:18][C@H:17]1[CH2:16][CH2:15][C:14]1[CH:13]=[C:12]([C:23]([OH:25])=[O:24])[CH:11]=[CH:10][C:9]2=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC[C@@]2(Cc3ccccc3)c3ccc(C(=O)O)cc3CC[C@@H]2C1
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1C[C@H]2CCc3cc(C(=O)O)ccc3[C@]2(Cc2ccccc2)C/C1=C\c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
(4bS,8aR)-4b-benzyl-7-oxo-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-2-carboxylic acid (6.5 g, 19.44 mmol) was suspended in water (65 mL). 2.5 M NaOH (11.7 mL, 29.16 mmol) was added followed by benzaldehyde (2.16 mL, 21.38 mmol). Over time (at 50° C. for 4 hours or at 25° C. over night) the mixture became homogeneous. The reaction was considered complete when there was less than 2% of (4bS,8aR)-4b-benzyl-7-oxo-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-2-carboxylic acid (Preparation 5) remaining. The mixture was cooled to 25° C. if it was not already at 25° C. EtOAc (65 mL) was added to the mixture followed by aqueous 2 M HCl (29 mL). Crystallization normally occurred during the acid addition or shortly thereafter. The mixture was stirred for 60 minutes. Heptane (65 mL) was added and the mixture was stirred for an additional 60 minutes. Do not worry about separating out the aqueous phase; filter the entire mixture and wash the solid with water followed by heptane. A pale yellow solid (6.55 g, 80% yield) was obtained. 1H NMR (DMSO): δ 1.70 (m, 1H), 1.85 (m, 1H), 2.45 (m, 3H), 2.65 (d, 3H), 2.95 (m, 2H), 3.50 (d, 1H), 6.15 (d, 2H), 6.25 (d, 1H), 6.70 (t, 2H), 6.90 (t, 1H), 7.30 (d, 1H), 7.50 (m, 5H), 7.70 (d, 2H), 12.75 (s, 1H).
Reaction SMILES: [Li]CCCC.[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH:8]=[CH:7]1.[Cl:15][CH2:16][CH2:17][CH2:18]I.[NH4+].[Cl-]>C1COCC1.[Cu]I>[Cl:15][CH2:16][CH2:17][CH2:18][C:7]1[O:6][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH:8]=1
Reactant: c1ccc2occc2c1
Reactant: ClCCCI
Agent: [Cu]I
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: ClCCCc1cc2ccccc2o1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 25.9 %

Procedure:
n-BuLi in heptanes (1.5 ml, 2.4 mmol, 1.6M) was added drop wise to benzofuran (236 mg, 2.0 mmol) in THF (5 ml) at −20° C. under argon. The reaction mixture was stirred at −15° C. for 30 min, then 1-chloro-3-iodopropane (322 μl, 3.0 mmol) and copper (I) iodide (38 mg, 0.2 mmol) were added. The reaction was stirred at −15° C. for 1 h, then NH4Cl (sat. aq., 5 ml) was added. The product was extracted with diethyl ether (2×30 ml) and the organic layer was washed with brine (10 ml), dried (K2CO3), filtered and concentrated in vacuo. The product was purified by column chromatography (0-1% diethyl ether in heptanes) to give 2-(3-chloro-propyl)-benzofuran (101 mg, 26%). 1H NMR (CDCl3): δ2.23 (tt, 2H), 2.97 (dt, 2H), 3.62 (t, 2H), 6.45 (q, 1H), 7.21 (m, 2H), 7.42 (m, 1H), 7.50 (m, 1H).
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([NH:12][C:13]3[N:18]=[C:17]([CH:19]=O)[CH:16]=[CH:15][CH:14]=3)=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.C(Cl)Cl>[C:1]1([C:7]2[S:11][C:10]([NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[C:17]([CH2:19][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)[N:18]=3)=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CCNCC1
Reactant: O=Cc1cccc(Nc2ncc(-c3ccccc3)s2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: c1ccc(-c2cnc(Nc3cccc(CN4CCCCC4)n3)s2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-(5-Phenyl-thiazol-2-ylamino)-pyridine-2-carbaldehyde (6-5, 0.025 g, 0.088 mmol) was dissolved in 1 mL dichloroethane. Piperidine (0.014 mL, 0.14 mmol), acetic acid (0.010 mL) and NaBH(OAc)3 (0.030 g, 0.14 mmol) were added. The reaction was stirred at room temperature for 1 h. The reaction was then diluted with CH2Cl2, washed with water and extracted 1× with CH2Cl2. The combined organic phases were dried over Na2SO4, filtered, concentrated. Purification by reverse phase HPLC afforded the titled compound. 1H NMR (CDCl3): δ 9.94 (bs, 1H), 7.61 (m, 4H), 7.59 (d, 2H, J=8.0 Hz), 7.41 (t, 2H, J=7.5 Hz), 7.29 (d, 1H, J=7.3 Hz), 7.06 (d, 1H, J=7.4 Hz), 6.77 (d, 1H, J=8.1 Hz), 3.73 (s, 2H), 2.56 (bs, 4H), 1.64 (m, 4H), 1.26 (m, 2H). M+1: 351.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2O.[Br-:14].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[Br:14][C:5]1[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=[CH:7][CH:6]=1
Reactant: Cc1cc(Cl)cc2c(O)ccnc12
Reactant: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: Cc1cc(Cl)cc2c(Br)ccnc12
Temperature: 25 °C

Procedure:
A mixture of 6-chloro-4-hydroxy-8-methylquinoline (1.9 g, 9.8 mmol) and triphenylphosphine dibromide (6.2 g, 14.7 mmol) in acetonitrile (50 mL) was refluxed for 2 hours. The mixture was allowed to cool to room temperature then concentrated. The residue was purified by silica gel chromatography eluting with 0-10% EtOAc/hexanes to afford the title compound as a white solid: 1H NMR (500 MHz, CDCl3): δ 8.67 (d, J=4.7 Hz, 1H); 8.06 (d, J=2.2 Hz, 1H); 7.71 (d, J=4.6 Hz, 1H); 7.58 (s, 1H); 2.79 (s, 3H); LC1: 1.88 min. (M+H) 256.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH3:30])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:15]S(C3C=CC(OC)=CC=3)(=O)=O)=[CH:10][C:9]=2[O:27][CH3:28])[CH:7]=1.[CH3:31][N:32]1[CH:36]=[C:35]([S:37](Cl)(=[O:39])=[O:38])[C:34]([C:41]([F:44])([F:43])[F:42])=[N:33]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH3:30])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:15][S:37]([C:35]3[C:34]([C:41]([F:44])([F:43])[F:42])=[N:33][N:32]([CH3:31])[CH:36]=3)(=[O:39])=[O:38])=[CH:10][C:9]=2[O:27][CH3:28])[CH:7]=1
Reactant: COc1ccc(S(=O)(=O)NCc2ccc(-c3cc(F)ccc3OC)c(OC)c2)cc1
Reactant: Cn1cc(S(=O)(=O)Cl)c(C(F)(F)F)n1
Product: COc1cc(CNS(=O)(=O)c2cn(C)nc2C(F)(F)F)ccc1-c1cc(F)ccc1OC

Procedure:
Prepared in a similar manner to N-(5′-fluoro-2,2′-dimethoxy-biphenyl-4ylmethyl)-4-methoxy-benzenesulfonamide (Example 6) using 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-sulfonyl chloride instead of 4-methoxybenzene sulfonyl chloride. Title compound: MS (ESI) m/z: 474.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][NH:11][C:12]([CH3:19])([CH3:18])[C:13]([O:15]CC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21](N)=[O:22]>O>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:12]([CH3:18])([CH3:19])[C:13](=[O:15])[NH:20][C:21]1=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)NCCOCc1ccccc1
Reactant: NC(N)=O
Solvent: O
Product: CC1(C)C(=O)NC(=O)N1CCOCc1ccccc1
Temperature: 180 °C

Procedure:
A mixture of ethyl 2-(2-benzyloxyethylamino)-2-methylpropionate (29 g) and urea (8.5 g) was heated at 180° C. for 1 h. After cooling to room temperature water (250 ml) was added and the resulting mixture was extracted with diethyl ether (500 ml). The organic phase was washed with brine (400 ml) and dried (Na2SO4). Evaporation of the solvents in vacuo afforded 9a as an oil: 28 g.