Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[C:11]([CH2:13][C:14]1([N:25]2[CH:29]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:27]=[N:26]2)[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]1)#[N:12].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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:11]([CH2:13][C:14]1([N:25]2[CH:29]=[C:28]([C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[NH:8][CH:9]=[CH:10][C:3]=34)[CH:27]=[N:26]2)[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]1)#[N:12]
Reactant: Brc1ccnc2[nH]ccc12
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
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: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(-c3ccnc4[nH]ccc34)cn2)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 25.7 %

Procedure:
A mixture of 4-bromo-1H-pyrrolo[2,3-b]pyridine (1.1 g, 5.7 mmol), tert-butyl 3-(cyanomethyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate (2.00 g, 5.15 mmol) (Example 40, Step 1), tetrakis(triphenylphosphine)palladium(0) (0.30 g, 0.26 mmol) and sodium carbonate (1.64 g, 15.4 mmol) in 1,4-dioxane (100 mL) and water (50 mL) under N2(g) was stirred at 100° C. overnight. The reaction mixture was extracted with ethyl acetate (3×20 mL), The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure until 5 mL of solvent was left. The resulting precipitate (0.90 g) was collected by filtration and washed with ether. The filtrate was further concentrated under reduced pressure to a volume of about 3 mL. The precipitate formed was filtered, and washed with ether to afford additional product (0.50 g). The filtrate was concentrated under reduced pressure again. The residue was purified by flash chromatography on a silica gel column with methanol in dichloromethane (0-5%) to afford additional desired product (0.55 g). Total amount of product was 1.95 g (yield: 92.3%). LCMS (M+H)+: m/z=379.1.
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH2:32]([O:39][CH2:40][C@H:41]1[CH2:43][C@@H:42]1[C:44]1[CH:45]=[C:46]([OH:50])[CH:47]=[N:48][CH:49]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[C:51]([O:55][C:56]([N:58]1[CH2:61][CH2:60][C@H:59]1[CH2:62]O)=[O:57])([CH3:54])([CH3:53])[CH3:52]>C1(C)C=CC=CC=1>[C:51]([O:55][C:56]([N:58]1[CH2:61][CH2:60][C@H:59]1[CH2:62][O:50][C:46]1[CH:47]=[N:48][CH:49]=[C:44]([C@H:42]2[CH2:43][C@@H:41]2[CH2:40][O:39][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:45]=1)=[O:57])([CH3:54])([CH3:52])[CH3:53]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1CO
Reactant: Oc1cncc([C@H]2C[C@@H]2COCc2ccccc2)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc([C@H]2C[C@@H]2COCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.5 %

Procedure:
1,1′-(Azodicarbonyl)dipiperidine (207 mg, 0.82 mmol, 1.6 equiv.) was dissolved in 2.0 mL of toluene (dried with molecular sieve 3 Å) in a 10 mL round-bottom flask with a side neck. The flask was equipped with rubber septa and a magnetic stirrer. The atmosphere was exchanged with Ar (3 times), and the flask was cooled with an ice bath. Tributylphosphine (203 μL, 0.82 mmol, 1.6 equiv.) was added dropwise. The mixture was warmed to room temperature and stirred for 10 min. The resulting colorless solution was then added dropwise (via syringe) with ice cooling to a solution of 5-[(1S,2S)-2-(benzyloxymethyl)cyclopropyl]-3-pyridinol (131 mg, 0.51 mmol) and 1-(tert-butoxycarbonyl)-2(S)-azetidinylmethanol (154 mg, 0.82 mmol, 1.6 equiv.) in a 25 mL round-bottom flask (equipped with a magnetic stirrer and an Ar balloon). The resulting mixture was warmed to room temperature and stirred overnight. Air was bubbled through the mixture for 2 h. The solvent was evaporated, and the residue was purified by CC on SiO2 (15×1.0 cm, EtOAc) to give the crude product, which was further purified by preparative HPLC (Supelco Discovery C18, 250×21.2 mm, 5 μm particle size, UV detection at 270 nm, flow rate 12.5 mL/min, gradient from 20% to 100% CH3CN in water within 40 min, then 100% CH3CN for 20 min; tR 28.5-30.9 min) to give a colorless oil (170 mg, 79%). MS (EI) m/z 424 (M+, 0.5%).
Reaction SMILES: C1C2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH:23]([C:24](=[O:36])[NH:25][CH2:26][CH2:27][CH2:28]CC4C=CC=CC=4)[CH2:22][CH2:21][CH2:20][CH:19]3[CH2:37][CH:38](OC)OC)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9]C=3)C=2C=CC=1.[C:43]1([CH3:53])[CH:48]=[CH:47][C:46](S([O-])(=O)=O)=[CH:45][CH:44]=1.[NH+]1C=CC=CC=1.[C:60]1([CH3:66])[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>>[CH:47]1[C:48]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH:19]4[CH2:20][CH2:21][CH2:22][CH:23]3[C:24](=[O:36])[N:25]([CH2:26][CH2:27][CH2:28][CH2:66][C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)[CH:38]=[CH:37]4)=[O:17])[C:11]3[C:53](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:43]=2[CH:44]=[CH:45][CH:46]=1
Reactant: COC(CC1CCCC(C(=O)NCCCCc2ccccc2)N1C(=O)OCC1c2ccccc2-c2ccccc21)OC
Reactant: Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: O=C1C2CCCC(C=CN1CCCCc1ccccc1)N2C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
2-(2,2-Dimethoxy-ethyl)-6-(4-phenyl-butylcarbamoyl)-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (Compound 243, 1 g, 1.75 mmol) was dissolved in toluene (25 ml). Pyridinium p-toluene sulfonate (0.02 g, 0.08 mmol) was added and the reaction was stirred at 100° C. for 2 hours. After this time the reaction was cooled down, the toluene was evaporated and the residue was dissolved in EtOAc (75 mL), washed with saturated NaHCO3 solution (25 mL) and dried over Na2SO4. Flash chromatographic purification of the residue (1:2 EtOAc/hexanes) gave Compound 244 (0.770 g, 87%). Rf=0.5 (1:2 EtOAc/hexanes).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@H:17]([C:26]([OH:28])=[O:27])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1.[CH:29]([Cl:32])(Cl)Cl>CO>[C:26]([C@@H:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:29]([Cl:32])[CH:8]=2)[N:3]=1)[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][C:2]2[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=3)[N:3]=2)=[CH:23][CH:24]=1)([OH:28])=[O:27]
Reactant: ClC(Cl)Cl
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Solvent: CO
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccc(Oc2nc3ccc(Cl)cc3cc2C(=O)O)cc1)C(=O)O
Yield: 13 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with L-tyrosine to provide the title compound in 13% yield as yellow needles (flash chromatography on SiO2, eluent CHCl3, MeOH, AcOH—10, 1, 0.2).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH3:10])=[CH:5][C:6]=1[C:7]([OH:9])=O.S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=1[OH:25]>>[OH:25][C:17]1[CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=[CH:21][C:16]=1[NH:15][C:7]([C:6]1[CH:5]=[C:4]([CH3:10])[S:3][C:2]=1[Br:1])=[O:9]
Reactant: Cc1cc(C(=O)O)c(Br)s1
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Solvent: O=S(Cl)Cl
Product: Cc1cc(C(=O)Nc2ccc([N+](=O)[O-])cc2O)c(Br)s1

Procedure:
In the same manner as in Starting Material Synthesis Example 67 and using 2-bromo-5-methyl-3-thiophenecarboxylic acid, thionyl chloride and 2-amino-5-nitrophenol, N-(2-hydroxy-4-nitrophenyl)-2-bromo-5-methyl-3-thiophenecarboxamide is obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH:18]1([S:23]([CH2:26][C:27]2[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=2)[NH2:30])(=[O:25])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]1>C1COCC1.CC(O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:30][C:29]2[CH:31]=[CH:32][CH:33]=[C:27]([CH2:26][S:23]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)(=[O:25])=[O:24])[CH:28]=2)[N:7]=1
Reactant: Nc1cccc(CS(=O)(=O)C2CCCC2)c1
Reactant: Clc1ncnc(Cl)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=S(=O)(Cc1cccc(Nc2ncnc(Cl)n2)c1)C1CCCC1
Yield: 205.7 %

Procedure:
To a stirred solution of 2,4-dichloro-1,3,5-triazine (150 mg, ABCR GmbH & CO. KG) in THF/i-PrOH (1:1; 1.9 mL) DIPEA (0.35 mL) was added at −40° C. Then a suspension of 3-[(cyclopentylsulfonyl)methyl]aniline (240 mg) in THF/2-PrOH (1:1, 0.94 mL) was added at this temperature. Under stirring the temperature of the reaction mixture was slowly raised over 2 hours to 0° C. The reaction mixture was then concentrated in vacuo to give the crude title compound (726 mg) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]2[CH2:6][CH:7]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=3)[CH2:8][C:9]=2[C:10](=[O:14])[C:11]=1[O:12][CH3:13].[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>O.C(N(CC)CC)C>[CH3:13][O:12][C:11]1[C:10](=[O:14])[C:9]2[CH2:8][CH:7]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([N:34]4[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]4)=[O:26])=[CH:27][CH:28]=3)[CH2:6][C:5]=2[C:4](=[O:29])[C:3]=1[O:2][CH3:1]
Reactant: COC1=C(OC)C(=O)C2=C(CC(CCCCOc3ccc(C(=O)O)cc3)C2)C1=O
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Product: COC1=C(OC)C(=O)C2=C(CC(CCCCOc3ccc(C(=O)N4CCN(C)CC4)cc3)C2)C1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 49.3 %

Procedure:
A mixture of 4-[4-(5,6-dimethoxy-4,7-dioxoindan-2-yl)butoxy]benzoic acid (500 mg), 1-methylpiperazine (250 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (479 mg), 1-hydroxybenzotriazole monohydrate (383 mg), triethylamine (0.697 ml), andTHF (20 ml) was stirred at room temperature for 10 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was purified by alumina column chromatography (ethyl acetate) and then with recrystallization from ethyl acetate-diisopropylether to yield the entitled compound (297 mg) as crystals.
Reaction SMILES: [C:1]1(OB=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:16]([O:23][C:24]1[CH:41]=[CH:40][C:39]([N:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[CH:38][C:25]=1[C:26]([NH:28][C:29]1[CH:34]=[C:33](Cl)[CH:32]=[CH:31][C:30]=1[C:36]#[N:37])=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)(Cl)Cl.COCCOC.O>[CH2:16]([O:23][C:24]1[CH:41]=[CH:40][C:39]([N:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[CH:38][C:25]=1[C:26]([NH:28][C:29]1[CH:34]=[C:33]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:32]=[CH:31][C:30]=1[C:36]#[N:37])=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=BOc1ccccc1
Reactant: N#Cc1ccc(Cl)cc1NC(=O)c1cc(N2CCCCC2)ccc1OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Solvent: O
Product: N#Cc1ccc(-c2ccccc2)cc1NC(=O)c1cc(N2CCCCC2)ccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
Water (0.74 mL), phenylboranic acid (0.12 g), sodium carbonate (0.21 g), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride (3.0 mg) were added to an ethylene glycol dimethyl ether (3.0 mL) suspension of the obtained 2-(benzyloxy)-N-(5-chloro-2-cyanophenyl)-5-(piperidin-1-yl)benzamide, followed by heating to reflux under a nitrogen atmosphere for 1 hour. After cooling the reaction mixture to room temperature, phenylboranic acid (0.12 g), sodium carbonate (0.21 g), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride (3.0 mg) were added thereto, followed by heating to reflux under a nitrogen atmosphere for 40 minutes. The reaction mixture was cooled to room temperature, and then chloroform and a 10% aqueous solution of citric acid were added thereto. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 90-50% hexane/ethyl acetate] to obtain 0.32 g of 2-(benzyloxy)-N-(4-cyanobiphenyl-3-yl)-5-(piperidin-1-yl)benzamide as a yellow solid.
Reaction SMILES: C(Cl)(=O)C(C)(C)C.[CH3:8]/[C:9](=[CH:13]\[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:16][CH:15]=1)/[C:10]([OH:12])=[O:11].C(N(CC)CC)C.[C:34]1(O)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl.N1C=CC=CC=1>[C:34]1([O:11][C:10](=[O:12])/[C:9](/[CH3:8])=[CH:13]/[C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:16][CH:15]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Oc1ccccc1
Reactant: C/C(=C\c1ccc(Cc2cccnc2)cc1)C(=O)O
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: ClCCl
Product: C/C(=C\c1ccc(Cc2cccnc2)cc1)C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.7 %

Procedure:
A solution of 105 mg of pivaloyl chloride in one ml of methylene chloride was added to a solution of 200 mg of the acrylic acid(prepared as described in Example 15) and 0.1257 ml of triethylamine in 5 ml of methylene chloride at room temperature, and the mixture was stirred at room temperature for one hour. To it were added 1.47 g of phenol and 1.323 ml of pyridine, the mixture was stirred overnight at room temperature, and concentrated under reduced pressure. The residue was dissolved in diethyl ether, washed with a saturated aqueous solution of sodium bicarbonate, and a saturated aqueous solution of sodium chloride, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (3:2) as eluent to give 158 mg of the title compound having the following physical characteristics:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH:24]([O-])([O-])OCC.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]2[N:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][CH:12]=3)[CH:24]=[N:5][C:4]=2[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Cl)c1NCc1ccc(Oc2ccccc2)cc1
Reactant: CCOC([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Clc1cccc2ncn(Cc3ccc(Oc4ccccc4)cc3)c12
Temperature: 25 °C
Yield: 77.3 %

Procedure:
A mixture of 3-chloro-2-(4-phenoxybenzylamino)aniline (0.300 g) and ethyl ortho-formate (0.178 g) was heated at 120° to 130° C. for 5 hours while stirring and then cooled to room temperature. Toluene (100 ml) and a 5% sodium hydroxide solution (50 ml) were added thereto, followed by stirring for 10 minutes. The toluene layer was separated and washed with water, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove toluene. The residue was purified by silica gel column chromatography to give 7-chloro-1-(4-phenoxybenzyl)benzimidazole (0.239 g) as a colorless liquid. nD28.5 1.6362.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C@@H:7]([NH2:10])[CH2:8][OH:9])=[CH:3][CH:2]=1.C(O[C:16]([N:18]1[CH2:22][CH2:21][C@@H:20](COS(C)(=O)=O)[CH2:19]1)=O)(C)(C)C>C1(C)C=CC=CC=1>[OH:9][CH2:8][CH:7]([NH:10][CH2:16][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](COS(C)(=O)=O)C1
Reactant: N[C@@H](CO)c1ccccc1
Solvent: Cc1ccccc1
Product: OCC(NCN1CCCC1)c1ccccc1
Yield: 126.8 %

Procedure:
A solution of (R)-(-)-phenylglycinol (2.20 g, 16.1 mmol) and (3R)--N-tert-butyloxycarbonyl-3-methylsulphonyloxymethylpyrrolidine (1.0 g, 3.58 mmol), in toluene (20 ml), was heated at 150° C. for 6 h in sealed pressure tube (Aldrich). The solvent was then removed under vacuum and the residue taken up into ethyl acetate (200 ml) and washed with water (×4). The organic was dried (MgSO4) and evaporated and the crude product chromatographed on silica gel eluting with CH2Cl2 /MeOH (97:3) to give the title-α-(hydroxymethyl)benzylaminomethylpyrrolidine (1.0 g, 87%), δ (360 MHz, CDCl3) 1.45 (9H, s, OC(Me)3), 1.52-2.60 (5H, m, CH2 and CH), 2.90-3.76 (7H, m, 3 of CH2 and CH), 7.25-7.39 (5H, m, Ar--H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[N:11]([CH3:28])[C:10]=1[C:29](O)=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][NH:33]C(C1N(C)C(C(S(C2C=CC=CC=2)(=O)=O)N)=CC(=O)C=1OCC1C=CC=CC=1)=O>>[CH3:32][NH:33][C:29]([C:10]1[N:11]([CH3:28])[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:13][C:14](=[O:15])[C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:30]
Reactant: Cc1ccc(S(=O)(=O)NCc2cc(=O)c(OCc3ccccc3)c(C(=O)O)n2C)cc1
Reactant: CNC(=O)c1c(OCc2ccccc2)c(=O)cc(C(N)S(=O)(=O)c2ccccc2)n1C
Product: CNC(=O)c1c(OCc2ccccc2)c(=O)cc(CNS(=O)(=O)c2ccc(C)cc2)n1C
Yield: 54.34 %

Procedure:
3-Benzyloxy-1-methyl-4-oxo-6-[(toluene-4-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid methylamide (15-06) (280.0 mg, 54.34%) was synthesized as an off white solid from 3-benzyloxy-1-methyl-4-oxo-6-[(toluene-4-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid (13-06) (500.0 mg, 1.13 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-benzyoxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid methylamide (15-01).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=1
Reactant: O=C(CCCCl)Nc1ccccc1Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O
Product: ClCCCc1nc2ccccc2n1-c1ccccc1
Yield: 31.6 %

Procedure:
A solution of 4-chloro-N-(2-anilinophenyl)butyramide (0.5 g) and p-toluenesulfonic acid monohydrate (33 mg) in toluene (15 ml) was refluxed for 1.5 hours. Toluene was removed under reduced pressure to afford a residue, which was dissolved in dichloromethane (20 ml), washed with a saturated aqueous solution of sodium bicarbonate and water in turn and dried over magnesium sulfate. Removal of the solvent under reduced pressure afforded an oily residue, which was subjected to column chromatography on silica gel (5 g) eluting with a mixture of dichloromethane and ethyl acetate (10:1) to give crystals of 2-(3-chloropropyl)-1-phenyl-1H-benzimidazole (148 mg).
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[CH2:15][C:14]([F:17])([F:16])[CH2:13][CH2:12][C@H:11]1[C:18]1[C:22]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)=[CH:21][N:20]([CH2:33][C:34]([F:37])([F:36])[F:35])[N:19]=1)C1C=CC=CC=1.C(O)(=O)C>[OH-].[OH-].[Pd+2].C(OCC)(=O)C>[F:17][C:14]1([F:16])[CH2:15][C@@H:10]([CH2:9][OH:8])[C@H:11]([C:18]2[C:22]([C:23]3[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:30])=[O:31])=[CH:27][CH:28]=3)=[CH:21][N:20]([CH2:33][C:34]([F:37])([F:36])[F:35])[N:19]=2)[CH2:12][CH2:13]1
Reactant: CS(=O)(=O)c1ccc(-c2cn(CC(F)(F)F)nc2[C@@H]2CCC(F)(F)C[C@H]2COCc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(-c2cn(CC(F)(F)F)nc2[C@@H]2CCC(F)(F)C[C@H]2CO)cc1

Procedure:
A mixture of 3-{(1R,2R)-2-[(benzyloxy)methyl]-4,4-difluorocyclohexyl}-4-[4-(methylsulfonyl)phenyl]-1-(2,2,2-trifluoroethyl)-1H-pyrazole (2.15 g, 3.97 mmol) and Pearlman's catalyst (1.0 g) were stirred together in ethyl acetate (50 mL) containing acetic acid (5 mL) under an atmosphere of hydrogen at rt for 20 h. The reaction mixture was then filtered through a Celite® pad and the filtrate was washed with saturated aqueous solutions of NaHCO3 and NaCl before drying over Na2SO4. Solvent removal in vacuo yielded {(1R,2R)-5,5-difluoro-2-[4-[4-(methylsulfonyl)phenyl]-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]cyclohexyl}methanol as a faint-yellow, thick syrup. 1H NMR (400 MHz, acetone d6) δ 8.06 (1H, s), 7.96 (2H, d, J= 8.4 Hz), 7.79 (2H, d, J= 8.4 Hz), 5.08 (2H, q, J=8.8 Hz), 3.70 (1H, m), 3.47 (1H, m), 3.36 (1H, m), 3.16 (3H, s), 3.09 (1H, m), 2.38 (1H, m), 2.25 (1H, m), 2.15-1.30 (5H, m).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([CH3:14])[N:3]=1.COCCOC.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[Cl:1][C:2]1[N:3]=[C:4]([CH3:14])[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:7]=1
Reactant: COC(=O)Cc1c(C)nc(Cl)nc1Cl
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Solvent: O
Product: COC(=O)Cc1c(C)nc(Cl)nc1-c1ccccc1
Yield: 66.1 %

Procedure:
To a suspension of methyl 2-(2,4-dichloro-6-methylpyrimidin-5-yl)acetate (4.42 g; 18.80 mmol) in a mixture of degassed DME (75 mL) and water (25 mL) was added phenyl boronic acid (5.73 g; 47 mmol), Tetrakis(triphenylphosphine) palladium(0) (2 g; 1.731 mmol) and diisopropyl ethylamine (12.96 mL; 75 mmol). The reaction was stirred under reflux for 3.5 h. The reaction mixture was partitioned between brine and ethyl acetate. The phases were separated and the water layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulphate and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (5-40%) in heptane to give 3.44 g (65%) of the title compound as a white solid. ESI/APCI(+): 277 (M+H).
Reaction SMILES: [OH-].[Na+].CO.[CH:5]1([C:8]2[CH:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:30][CH2:29][C:28]5[N:27]=[C:26]([CH2:31][CH2:32][CH3:33])[C:25]([C:34]([O:36]C)=[O:35])=[CH:24][C:23]=5[C:22]4=[O:38])[CH2:17][CH2:16]3)[C:11]([O:39][CH2:40][CH3:41])=[CH:10][C:9]=2[C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[CH2:7][CH2:6]1.Cl>C(OCC)(=O)C.C1COCC1>[CH:5]1([C:8]2[CH:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:30][CH2:29][C:28]5[N:27]=[C:26]([CH2:31][CH2:32][CH3:33])[C:25]([C:34]([OH:36])=[O:35])=[CH:24][C:23]=5[C:22]4=[O:38])[CH2:17][CH2:16]3)[C:11]([O:39][CH2:40][CH3:41])=[CH:10][C:9]=2[C:42]2[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=2)[CH2:6][CH2:7]1
Reactant: CCCc1nc2c(cc1C(=O)OC)C(=O)N(C1CCN(Cc3cc(C4CC4)c(-c4ccc(F)cc4)cc3OCC)CC1)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CCCc1nc2c(cc1C(=O)O)C(=O)N(C1CCN(Cc3cc(C4CC4)c(-c4ccc(F)cc4)cc3OCC)CC1)CC2
Temperature: 50 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
A 2 M aqueous sodium hydroxide solution (1.50 mL) was added at room temperature to a methanol (2 mL)-THF (2 mL) solution of methyl 6-(1-((2-cyclopropyl-5-ethoxy-4′-fluorobiphenyl-4-yl)methyl)piperidin-4-yl)-5-oxo-2-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate (670 mg), and the mixture was stirred at 50° C. for 1 hour. The reaction mixture was neutralized with hydrochloric acid at room temperature. Then, ethyl acetate was added thereto, and the mixture was concentrated. Then, the deposited solid was collected by filtration and washed with diethyl ether. The obtained solid was recrystallized (ethanol/hexane) to obtain the title compound (442 mg).