Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:17]#[N:18])[CH:5]=[C:6]([B:8]2[O:12]C(C)(C)C(C)(C)[O:9]2)[CH:7]=1.I([O-])(=O)(=O)=O.[Na+].C([O-])(=O)C.[NH4+].O>CC(C)=O>[C:17]([C:4]1[CH:5]=[C:6]([B:8]([OH:12])[OH:9])[CH:7]=[C:2]([F:1])[CH:3]=1)#[N:18]
Reactant: CC1(C)OB(c2cc(F)cc(C#N)c2)OC1(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: N#Cc1cc(F)cc(B(O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.00 g (4.05 mmol) of the compound from Example 21A is provided in 40 ml of acetone, 2.60 g (12.1 mmol) of sodium periodate, 0.70 g (9.11 mmol) of ammonium acetate and 40 ml of water are added and the mixture is stirred at room temperature overnight. The mixture is subsequently concentrated, a 2N aqueous sodium hydroxide solution is added to the residue and the precipitate that remains is filtered off with suction. Using a concentrated aqueous hydrogen chloride solution, the solution is adjusted to pH 3 and cooled to 0° C. The precipitate formed is collected by suction filtration, washed with water and dried under high vacuum. 384 mg (58% of theory) of the title compound are obtained.
Reaction SMILES: C(C(N1CCNCC1)C1C=CC([Cl:10])=CC=1)#N.C(=O)([O-])[O-].[K+].[K+].ClC(OCC)=O.[C:29]([CH:31]([N:39]1[CH2:44][CH2:43][N:42]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:41][CH2:40]1)[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)#[N:30]>C1C=CC=CC=1.O>[ClH:10].[C:29]([CH:31]([N:39]1[CH2:44][CH2:43][N:42]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:41][CH2:40]1)[C:32]1[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=1)#[N:30]
Reactant: N#CC(c1ccc(Cl)cc1)N1CCNCC1
Agent: CCOC(=O)Cl
Agent: CCOC(=O)N1CCN(C(C#N)c2ccc(Cl)cc2)CC1
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Solvent: O
Product: Cl
Reaction time: 2 h

Procedure:
To 11.7 g. of N-(α-cyano-4-chlorobenzyl)piperazine was added 70 ml. of benzene and then 6.9 g. of anhydrous potassium carbonate. To the resulting solution was added dropwise 5.4 g. of ethyl chloroformate dissolved in 30 ml. of benzene with cooling. After dropping, the mixture was stirred for 2 hours at 40° - 45°C. After cooling, water was poured into the mixture to dissolve inorganic substance. The benzene layer was separated, washed with water, dried over sodium sulfate, and the solvent distilled off. There was obtained 10.7 g. of N-(α-cyano-4-chlorobenzyl)-N'-ethoxycarbonylpiperazine as an oily substance. This product was dissolved in benzene and the resultant solution was saturated with dry hydrochloric gas to separate crystal which was collected by filtration. Recrystallization from acetone afforded N-(α-cyano-4-chlorobenzyl)-N'-ethoxycarbonylpiperazine hydrochloride having a melting point of 166°C.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:16])([CH3:15])[CH2:7][C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[CH3:17].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([CH3:17])=[C:2]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[O:19][CH3:18])[CH:11]=2)[C:6]([CH3:16])([CH3:15])[CH2:7][C:8]1=[O:14])[CH3:13]
Reactant: COc1ccccc1B(O)O
Reactant: CCN1C(=O)CC(C)(C)c2cc(C)c(Br)cc21
Product: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3ccccc3OC)cc21

Procedure:
Compound 39A was prepared from Compound 1A using a procedure similar to that described in Example 1B, except using 2-methoxy phenylboronic acid as the starting material. MS (electrospray): mass calculated for C21H25NO2, 323.19; m/z found 324.2 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([F:21])=[C:4]([F:20])[C:5]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)C(C)C)(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH2:73]([SH:80])[C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:73]([S:80][C:2]1[C:3]([F:21])=[C:4]([F:20])[C:5]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])[C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1
Reactant: COC(=O)c1cc(Br)c(F)c(F)c1Nc1ccccc1F
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(SCc2ccccc2)c(F)c(F)c1Nc1ccccc1F
Temperature: 100 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
To a solution of methyl 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate (22.33 g, 62.01 mmol) in anhydrous 1,4-dioxane (200 mL) was added N,N-diisopropylethylamine (16.03 g, 124.04 mmol). Then Pd2(dba)3 (2.84 g, 3.10 mmol) followed by Xantphos (3.59 g, 6.20 mmol) and BnSH (8.09 g, 65.11 mmol) was added under nitrogen atmosphere. The mixture was stirred overnight at 100° C. under N2 atmosphere and then allowed to warm to ambient temperature. The insoluble matter was filtered off and the filter cake was washed ethyl acetate. The filtrate was diluted with water (300 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with water (100 mL) and brine (100 mL) sequentially, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 50:1, v/v) to give the desired product (pale yellow solid, 22.09 g, 88.3% yield). 1H NMR (400 MHz, CDCl3): δ 9.04 (s, 1H), 7.68 (dd, 1H), 7.18 (m, 5H), 6.97 (m, 4H), 3.97 (s, 2H), 3.80 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[NH:14][C:15]([NH2:24])=[C:16]2[C:20]([N:21]=1)=[N:19][C:18]([O:22][CH3:23])=[N:17]2)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH:34]1[CH2:39][CH2:38][O:37][C:36]([CH3:41])([CH3:40])[CH2:35]1>CN(C=O)C>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH:34]2[CH2:39][CH2:38][O:37][C:36]([CH3:41])([CH3:40])[CH2:35]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CC1(C)CC(CCBr)CCO1
Reactant: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCC3CCOC(C)(C)C3)c2n1
Temperature: 60 °C
Yield: 13.5 %

Procedure:
A mixture of 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate (0.2 g, 0.569 mmol) and anhydrous potassium carbonate (0.315 g, 2.277 mmol) in DMF was heated at 60° C. for 1 hour. The mixture was cooled to room temperature and 4-(2-bromoethyl)-2,2-dimethyltetrahydro-2H-pyran (0.151 g, 0.683 mmol) was added and the mixture heated at 50° C. for 18 hours. The mixture was quenched with water (2 ml) and extracted with DCM (2×5 ml). The DCM was separated through a hydrophobic frit and evaporated by blowing down under a stream of nitrogen. Addition of DMSO:MeOH (1:1) gave a precipitate which was collected by filtration, washed with methanol and dried in vacuo to give the title compound (29 mg).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][O:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([NH2:23])[CH:16]=1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[F:34])[C:29]#[N:30].C([O-])(O)=O.[Na+]>>[CH3:12][O:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([NH:23][C:29](=[NH:30])[C:28]2[CH:31]=[CH:32][C:33]([F:34])=[C:26]([Cl:25])[CH:27]=2)[CH:16]=1
Reactant: N#Cc1ccc(F)c(Cl)c1
Reactant: COC(=O)c1ccc(OC)c(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)c1ccc(OC)c(NC(=N)c2ccc(F)c(Cl)c2)c1
Temperature: 160 °C
Reaction time: 8 h
Yield: 44.9 %

Procedure:
Anhydrous p-toluene sulfonic acid (10 g, 52.57 mmol) was melted at 120° C. and 3-amino-4-methoxy benzoic acid methyl ester (3.88 g, 21.44 mmol) obtained in step 1 of Preparation Example 1 and 3-chloro-4-fluorobenzonitrile (5.0 g, 32.14 mol) were added thereto and stirred at 160° C. for 8 hours. The resulting solution was cooled to room temperature and the reaction was stopped by adding NaHCO3 thereto. The resulting mixture was extracted with ethyl acetate, the extract was dried over MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (3.24 g, 9.62 mmol) in a yield of 45%.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][C@H:5]1[F:17])=[N+]=[N-].C([O-])=O.[NH4+]>CO.[Pd]>[NH2:1][C@@H:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:6][C@H:5]1[F:17]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N=[N+]=[N-])[C@H](F)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](F)C1
Temperature: 50 °C
Reaction time: 5 h
Yield: 79.5 %

Procedure:
To a solution of 0.59 g (2.42 mmol) of trans-4-azido-1-Boc-3-fluoropiperidine 4 in 10 mL of MeOH was added 0.61 g (9.67 mmol) of ammonium formate and 0.25 g (0.24 mmol Pd) of 10% Pd on carbon. The reaction mixture was stirred under N2-atmosphere at 50° C. for 5 h. After cooling, the mixture was filtered over diatomaceous earth and evaporated under reduced pressure. The crude mixture was then subjected to flash silicagel chromatography (5% Et3N in EtOAc, short path column) to give 0.42 g (80%) of trans-4-amino-1-Boc-3-fluoropiperidine 5 as an oil. 1H NMR (CDCl3): δ 1.39 (9H, s); 1.60 (2H, s(br)); 1.76-1.86 (1H, m); 2.65-2.76 (2H, m); 2.78-2.90 (2H, m); 3.89-3.97 (1H, m); 4.01 (1H, dm, J=48.5 Hz); 4.15-4.30 (1H, m). 19F NMR (CDCl3): δ −191.0 to −190.3 (1F, m). 13C NMR (CDCl3): δ 28.4 (3×), 31.8, 41.9 (br), 46.2 (br), 53.5 (d, J=18.5 Hz), 80.3, 93.0 (d, J=177.7 Hz), 154.6. IR (ATR, cm−1): ν=1685, 1415, 1244, 1152, 1028. MS (ES+) m/z (%): 204 (M-CH3+H+), 163 (M−3CH3+2H+, 100).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([N:12]1[N:16]=[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]2=[N:13]1)[CH2:9][C:10]#[CH:11]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]#[C:10][CH2:9][CH2:8][N:12]1[N:13]=[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]2=[N:16]1
Reactant: Brc1ccccn1
Reactant: C#CCCn1nc2ccccc2n1
Product: C(#Cc1ccccn1)CCn1nc2ccccc2n1
Yield: 62.5 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (92 mg, 0.58 mmol) and 2-(but-3-ynyl)-2H-benzo[d][1,2,3]triazole (100 mg, 0.58 mmol). Reaction time: 0.3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 90 mg of 2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole.
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[CH2:24]([CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)[CH2:28][CH2:27]1)[CH3:25]>CN(C=O)C>[CH2:24]([CH:26]1[CH2:27][CH2:28][N:29]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([NH:37]/[C:4](=[C:11]3\[C:12](=[O:23])[NH:13][C:14]4[C:19]\3=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=4)/[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:38][CH:39]=2)[CH2:30][CH2:31]1)[CH3:25]
Reactant: CCC1CCN(Cc2ccc(N)cc2)CC1
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Solvent: CN(C)C=O
Product: CCC1CCN(Cc2ccc(N/C(=C3\C(=O)Nc4ccc([N+](=O)[O-])cc43)c3ccccc3)cc2)CC1

Procedure:
Prepared analogously to Example 89 from 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-(4-ethylpiperidinomethyl)-aniline in DMF.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]1[C:15]2[CH:16]=[CH:17][O:18][C:14]=2[CH:13](O)[CH2:12][CH2:11]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:15]2[CH:16]=[CH:17][O:18][C:14]=2[CH2:13][CH2:12][CH:11]=1
Reactant: OC1CCC(c2cc3ccccc3o2)c2ccoc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C1=C(c2cc3ccccc3o2)c2ccoc2CC1
Yield: 85.3 %

Procedure:
To a mixture of 19.3 g of 4,5,6,7-tetrahydro-4-(2-benzofuryl)-benzofuran-7-ol in 400 mL of toluene was added 100 mg of p-toluenesulfonic acid monohydrate, and the mixture was placed on a Rotovap, and the solvent was distilled in vacuo (60° C.) until a residue was obtained. The residue was chromatographed on silica (hexane/methylene chloride 1.5:1) to afford 15.3 g (86%) of 6,7-dihydro-4-(2-benzofuryl)-benzofuran, (Formula Ill: R3 =H; ##STR53## R5 =2-benzofuryl) as an orange oil.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.[F:16][C:17]1[CH:42]=[CH:41][C:20]([C:21]([NH:23][C@H:24]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([N:34]4[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]4)[CH:32]=3)[O:27][CH2:26][C@@H:25]2[OH:40])=[O:22])=[CH:19][CH:18]=1.[O:43]1[CH2:46][C:45](=O)[CH2:44]1.C(=O)(O)[O-].[Na+]>C(#N)C.ClCCl>[F:16][C:17]1[CH:42]=[CH:41][C:20]([C:21]([NH:23][C@H:24]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([N:34]4[CH2:39][CH2:38][N:37]([CH:45]5[CH2:46][O:43][CH2:44]5)[CH2:36][CH2:35]4)[CH:32]=3)[O:27][CH2:26][C@@H:25]2[OH:40])=[O:22])=[CH:19][CH:18]=1
Reactant: O=C1COC1
Reactant: O=C(N[C@H]1c2cc(N3CCNCC3)ccc2OC[C@@H]1O)c1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CC#N
Product: O=C(N[C@H]1c2cc(N3CCN(C4COC4)CC3)ccc2OC[C@@H]1O)c1ccc(F)cc1
Reaction time: 0.33 h
Yield: 57.2 %

Procedure:
Add sodium triacetoxyborohydride (20 g, 94.4 mmol) to a slurry of 4-fluoro-N-[(3R,4S)-3-hydroxy-6-piperazin-1-yl-chroman-4-yl]benzamide hydrochloride (32.0 g, 78.5 mmol) and 3-oxetanone (6.87 g, 98.1 mmol) in acetonitrile (300 mL). Stir the slurry for 20 min. and add more sodium triacetoxyborohydride (20 g, 94.4 mmol) in one portion. Stir the brown mixture at 28° C. for approximately 2 hr. Add additional sodium triacetoxyborohydride (10 g, 47.2 mmol) and stir the mixture for 30 min. Add 3-oxetanone (2 g, 28.6 mmol) and after 20 min add additional 3-oxetanone (1 g, 14.3 mmol). Stir for 30 min., pour the mixture into a saturated aqueous sodium bicarbonate solution (1 L) and add dichloromethane (1 L). Separate the organic layer and concentrate in vacuo to obtain a pale grey solid. Purify the solid by silica gel column chromatography eluting with 3 to 6% isopropanol/dichloromethane to obtain the title compound as a white solid (19.2 g, 73%). LC-ES/MS m/z 428 [M+H]+.
Reaction SMILES: IC.[Cl:3][C:4]1[C:9]([OH:10])=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:7]=[C:6]([CH:15]2[CH2:17][CH2:16]2)[C:5]=1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[F:25].[C:26](=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Cl:3][C:4]1[C:9]([O:10][CH3:26])=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:7]=[C:6]([CH:15]2[CH2:16][CH2:17]2)[C:5]=1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[F:25]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(C2CC2)c(-c2ccc(F)cc2F)c(Cl)c1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1cc(C2CC2)c(-c2ccc(F)cc2F)c(Cl)c1OC
Yield: 69.4 %

Procedure:
Iodomethane (1.04 g) was added at room temperature to a mixture of methyl 2-chloro-6-cyclopropyl-2′,4′-difluoro-3-hydroxybiphenyl-4-carboxylate (1.66 g), potassium carbonate (1.36 g), and DMF (30 mL), and the resultant mixture was stirred at 60° C. for 3 hours in a nitrogen atmosphere. Water was added to the reaction mixture at room temperature, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.20 g).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([CH2:15][CH:16]([C:19]2[C:20]([CH3:26])=[N:21][C:22]([CH3:25])=[CH:23][CH:24]=2)[CH2:17][NH2:18])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:18][CH2:17][CH:16]([C:19]1[C:20]([CH3:26])=[N:21][C:22]([CH3:25])=[CH:23][CH:24]=1)[CH2:15][CH:12]1[CH2:13][CH2:14]1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: Cc1ccc(C(CN)CC2CC2)c(C)n1
Product: Cc1ccc(C(CNC(=O)c2cccc(Cl)c2Cl)CC2CC2)c(C)n1

Procedure:
From 2,3-dichlorobenzoic acid and 3-cyclopropyl-2-(2,6-dimethyl-pyridin-3-yl)-propylamine. LCMS (MH+): m/z=377.1, tR (minutes, Method G)=1.68
Reaction SMILES: I[CH3:2].C[O:4][C:5]1[CH:10]=[C:9]([CH:11]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:14]2[CH3:27])[CH3:12])[CH:8]=[CH:7][N:6]=1>>[CH3:27][C:14]1[N:13]([CH:11]([C:9]2[CH:8]=[CH:7][N:6]([CH3:2])[C:5](=[O:4])[CH:10]=2)[CH3:12])[C:21]2[C:16]([C:15]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:18]=[CH:19][CH:20]=2
Reactant: CI
Reactant: CCOC(=O)c1c(C)n(C(C)c2ccnc(OC)c2)c2ccccc12
Product: CCOC(=O)c1c(C)n(C(C)c2ccn(C)c(=O)c2)c2ccccc12
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
Iodomethane (57.94 mg, 0.408 mmol) was added to (±)-ethyl 1-(1-(2-methoxypyridin-4-yl)ethyl)-2-methyl-1H-indole-3-carboxylate (Example 39; 50 mg, 0.136 mmol). The mixture was stirred in the microwave at 150° C. for 15 minutes. The mixture was evaporated to afford the title compound which was used without further purification (50 mg, yield: 100%) as a starting alkyl carboxylate in Step 3 of Example 36 in the synthesis of certain compounds of the invention.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[CH3:5][C:6]1[C:7]([N+:16]([O-:18])=[O:17])=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:9]=[CH:10][CH:11]=1.O>ClCCl>[CH3:5][C:6]1[C:7]([N+:16]([O-:18])=[O:17])=[C:8]([S:12]([NH:4][CH:1]([CH3:3])[CH3:2])(=[O:13])=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)N
Reactant: Cc1cccc(S(=O)(=O)Cl)c1[N+](=O)[O-]
Solvent: O
Solvent: ClCCl
Product: Cc1cccc(S(=O)(=O)NC(C)C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
To a solution of isopropylamine (13 mL, 155 mmol) in 60 mL of dichloromethane at 0° C. was added a solution of 5.3 g of 3-methyl-2-nitrobenzenesulfonyl chloride (prepared according to Courtin, A. Helv. Chim. Acta, 1976, 59, 379-387) in 60 mL of dichloromethane dropwise. The reaction mixture was stirred 2 hours at room temperature. Water was added and the layers were separated. The organic layer was dried (sodium sulfate) and the volatiles were removed with a rotary evaporator. The residue was purified by medium pressure liquid chromatography (MPLC), using 20-40% ethyl acetate in hexanes as eluant, to afford 4.3 g of the title compound as a yellow solid.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].C1(O)C=CC=CC=1.[OH:14][C@@H:15]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=1)[CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].CC1C=CC(S(O[CH2:44][CH:45]2[CH2:50][CH2:49][CH2:48][S:47][CH2:46]2)(=O)=O)=CC=1>CN(C=O)C>[OH:14][C@@H:15]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:44][CH:45]2[CH2:50][CH2:49][CH2:48][S:47][CH2:46]2)[CH:27]=1)[CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCSC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Oc1ccccc1
Product: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(OCC2CCCSC2)c1
Temperature: 100 °C

Procedure:
K2CO3 (0.72 g, 5.24 mmol) and phenol (7, Intermediate I) (0.3 g, 1.05 mmol) were added to a solution of (tetrahydro-2H-thiopyran-3-yl)methyl 4-methylbenzenesulfonate (0.29 g, 1.10 mmol) in DMF (10 mL). The reaction mixture was heated at 100° C. under reflux overnight and then cooled. The reaction mixture was extracted with EtOAc, organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (EtOAc:hexane 10-40% gradient) gave tert-butyl ((3R)-3-hydroxy-3-(3-((tetrahydro-2H-thiopyran-3-yl)methoxy)phenyl)propyl)carbamate as a light green solid. Yield (0.21 g, 52%); 1H NMR (400 MHz, CDCl3): δ 7.24 (t, J=8.0 Hz, 1H), 6.91 (d, J=8.0 Hz, 2H), 6.78 (d, 1H), 4.87 (bs, 1H), 4.71 (bs, 1H), 3.84-3.80 (m, 2H), 3.49 (bs, 1H), 3.21-3.13 (m, 2H), 2.82-2.77 (m, 1H), 2.62-2.47 (m, 3H), 2.18 (bs, 1H), 2.08-2.04 (m, 1H), 1.91-1.74 (m, 4H), 1.45 (s, 9H), 1.30-1.20 (m, 3H); MS: m/z 382.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:39]=[CH:38][CH:37]=[CH:36][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:35])[CH2:12][NH:13][C:14]([C:16]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27]CC3C=CC=CC=3)[NH:18][N:17]=2)=[O:15])[CH2:7][CH2:6]1>CO.[Pd]>[Cl:1][C:2]1[CH:39]=[CH:38][CH:37]=[CH:36][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:35])[CH2:12][NH:13][C:14]([C:16]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[OH:27])[NH:18][N:17]=2)=[O:15])[CH2:7][CH2:6]1
Reactant: O=C(NCC(=O)N1CCC(Oc2ccccc2Cl)CC1)c1cc(-c2ccccc2OCc2ccccc2)[nH]n1
Agent: [Pd]
Solvent: CO
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2Cl)CC1)c1cc(-c2ccccc2O)[nH]n1
Reaction time: 1.5 h
Yield: 81.6 %

Procedure:
To a solution of 5-(2-benzyloxy-phenyl)-1H-pyrazole-3-carboxylic acid {2-[4-(2-chloro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide (0.075 g, 0.00014 mole), in methanol (50 mL) was added 10% Pd/C (0.015 g) and the resulting mixture was stirred under an atmosphere of hydrogen for 1.5 hours. The mixture was then filtered through celite, the celite was washed with methanol and the organic layers were concentrated under reduced pressure. The resulting residue was recrystallized from a mixture of ethyl acetate and methanol to afford 0.052 g (83%) of 5-(2-hydroxy-phenyl)-1H-pyrazole-3-carboxylic acid {2-[4-(2-chloro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 455.16 (M+1)+, 90.34%, 1H NMR (DMSO-d6): δ 13.2 (s, 1H), 10.2 (s, 1H), 8.0 (s, 1H), 7.64 (m, 1H), 7.42 (m, 1H), 7.24 (m, 2H), 7.18 (m, 1H), 7.06 (s, 1H), 6.96 (m, 2H), 6.84 (t, 1H), 4.7 (m, 1H), 4.2 (d, 2H), 3.61 (m, 2H), 3.4 (m, 2H), 1.9 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:18][CH3:19])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:6]=1[N+:15]([O-])=O>CO>[CH3:19][O:18][CH:3]([O:2][CH3:1])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:6]=1[NH2:15]
Reactant: COC(=O)c1ccc(CC(OC)OC)c([N+](=O)[O-])c1
Solvent: CO
Product: COC(=O)c1ccc(CC(OC)OC)c(N)c1
Yield: 62.1 %

Procedure:
4-Carbomethoxy-2-nitrophenylacetaldehyde dimethylacetal (8.75 g, 41.43 mmole) was reduced under hydrogen (50 psi, 0.45 g of 10% Pd/carbon) in 170 mL of methanol for 2.5 h. The solution was filtered through celite and evaporated to an oil. Crystallization from ether and hexanes gave 6.16 g of 2-amino-4-carbomethoxy-phenylacetaldehyde dimethylacetal.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[CH2:2].Cl[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.F[K].C(P)(C)(C)C>C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.[Pd].O1CCOCC1>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccc(B(O)O)cc1
Reactant: Clc1ccccc1-c1cccnc1
Agent: [Pd]
Agent: CC(C)(C)P
Agent: F[K]
Solvent: C1COCCO1
Product: C=Cc1ccc(-c2ccccc2-c2cccnc2)cc1
Temperature: 80 °C
Yield: 50 %

Procedure:
This Example was carried out in the same manner as Example 10, except that 23.42 g (0.158 mol) of 4-vinyl-phenyl boronic acid, 20.0 g (0.1055 mol) of 3-(2-chloro-phenyl)pyridine, 500□ of 1,4-dioxane, 27.54 g (0.474 mol, 3.3 equivalent) of fluoro-potassium, 1.69 g (0.0084 mol, 5.3 mol %) of t-butylphosphine [P( t-Bu)3)], and 2.6 g (0.0028 mol, 1.8 mol %) of palladium tris(dibenzylidene acetone) [Pd2(dba)3] were used. Finally, after the resulting solution was heated to reflux at 80° C. for 24 hours, the 3-(4′-vinyl-biphenyl-2-yl)pyridine was isolated. The yield was 50%.