Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:38]2[CH:39]=[N:40][N:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=23)=[N:4][C:5]([NH:8][C:9]2[C:14]([O:15][CH3:16])=[CH:13][C:12]([N:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:34])[C@@H:24]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:25])[CH2:19][CH2:18]3)=[C:11]([N+:35]([O-])=O)[CH:10]=2)=[N:6][CH:7]=1.[NH4+].[Cl-].O>C(O)C.[Fe]>[NH2:35][C:11]1[CH:10]=[C:9]([NH:8][C:5]2[N:4]=[C:3]([C:38]3[CH:39]=[N:40][N:41]4[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=34)[C:2]([Cl:1])=[CH:7][N:6]=2)[C:14]([O:15][CH3:16])=[CH:13][C:12]=1[N:17]1[CH2:18][CH2:19][N:20]([C:23](=[O:34])[C@@H:24]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH3:25])[CH2:21][CH2:22]1
Reactant: COc1cc(N2CCN(C(=O)[C@H](C)NC(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(N2CCN(C(=O)[C@H](C)NC(=O)OC(C)(C)C)CC2)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Yield: 69.7 %

Procedure:
A mixture of (S)-tert-butyl N-[1-(4-{4-[(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]-5-methoxy-2-nitrophenyl}piperazin-1-yl)-1-oxopropan-2-yl]carbamate (Intermediate 60, 100 mg, 0.15 mmol), iron (51.4 mg, 0.92 mmol) and NH4Cl (5.74 mg, 0.11 mmol) was heated at reflux in ethanol (3 mL) and water (1 mL) for 1 h. Purification by ion exchange chromatography, using an SCX column and eluting with 7M methanolic ammonia provided material that was further purified by FCC, eluting with O-5% CH3OH in CH2Cl2 to give the title compound (65 mg, 68%) as a yellow solid; m/z: ES+ MH+ 622.58.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:10](=[O:11])[N:9]([CH2:12][O:13][CH3:14])[CH:8]=[C:7]([S:15][CH2:16][CH2:17][C:18](OC)=O)[CH:6]=1.CC(C)([O-])C.[K+].Cl[CH2:29][C:30]1C=CC(OC)=[CH:32][CH:31]=1>C1COCC1>[CH2:16]([S:15][C:7]1[CH:6]=[C:5]([O:4][CH2:3][O:2][CH3:1])[C:10](=[O:11])[N:9]([CH2:12][O:13][CH3:14])[CH:8]=1)[C:17]1[CH:18]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COCOc1cc(SCCC(=O)OC)cn(COC)c1=O
Reactant: COc1ccc(CCl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCOc1cc(SCc2ccccc2)cn(COC)c1=O
Reaction time: 16 h
Yield: 82.2 %

Procedure:
A solution of methyl 3-{[5-(methoxymethoxy)-1-(methoxymethyl)-6-oxo-1,6-dihydropyridin-3-yl]sulfanyl}propanoate (Intermediate 16; 300 mg, 0.95 mmol) in THF (5 ml) was cooled to −45° C. and potassium tert-butoxide (117 mg, 0.10 mmol) was added. After stirring at this temperature for 1 hour 1-(chloromethyl)-4-methoxybenzene (154 ml, 1134 mmol) was added and the reaction stirred for 16 hours. The reaction mixture was partitioned between dichloromethane and water. The aqueous layer was re-extracted and the combined organics dried and concentrated under reduced pressure. The resultant residue was purified by column chromatography (SiO2: 80-100% ethyl acetate/petrol) to yield 5-(benzylsulfanyl)-3-(methoxymethoxy)-1-(methoxymethyl)pyridin-2(1H)-one (251 mg, 83%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:8]=[C:9]([S:13]([NH:16][C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:25]=2[NH:24][CH:23]=[CH:22]3)(=[O:15])=[O:14])[CH:10]=[CH:11][CH:12]=1.[OH-].[Na+].Cl.CN(C)[CH:31]=[O:32]>O>[Cl:6][C:7]1[CH:8]=[C:9]([S:13]([NH:16][C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:25]=2[NH:24][CH:23]=[C:22]3[CH:31]=[O:32])(=[O:14])=[O:15])[CH:10]=[CH:11][CH:12]=1
Reactant: O=S(=O)(Nc1cccc2cc[nH]c12)c1cccc(Cl)c1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2c(NS(=O)(=O)c3cccc(Cl)c3)cccc12

Procedure:
1.3 ml (13.9 mmol) of phosphorous oxychloride was added dropwise to 14.5 ml of dimethylformamide at 10° C. or less under stirring in nitrogen atmosphere. After stirring at about 5° C. for 30 minutes, 2.50 g (8.15 mmol) of 3-chloro-N-(1H-indole-7-yl)benzenesulfonamide synthesized in the same manner as in Example 1 was added thereto in three portions. After stirring at about 5° C. for further 30 minutes, 200 ml of cooled water was added thereto. The reaction mixture was adjusted to pH about 14 by adding a 1N aqueous sodium hydroxide and then to pH about 2 by adding 1N hydrochloric acid, and then extracted by adding ethyl acetate thereto. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography, to give 1.45 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:12])OCC)=[CH:4][CH:3]=1.[NH2:13][NH:14][CH:15]=O>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[CH:15][NH:14][N:13]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=N)c1ccc(Br)cc1
Reactant: NNC=O
Solvent: Cc1ccccc1C
Product: Brc1ccc(-c2nc[nH]n2)cc1

Procedure:
Into a 1000 mL 3-necked flask, was placed a solution of ethyl 4-bromobenzenecarboximidoate (54.0 g, 237 mmol) in xylene (500 mL) To the mixture was added NH2NHCHO (14.22 g, 237 mmol). The resulting solution was heated to reflux overnight. The reaction mixture was cooled in an ice bath and filtered. The solid was washed with 700 mL of petroleum ether and dried in an oven under reduced pressure to afford 3-(4-bromophenyl)-1H-1,2,4-triazole (crude) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2=[N:11][CH:12]=[CH:13][C:14](Cl)=[C:9]2[NH:8][C:7]=1[CH3:16])=[O:5])[CH3:2].[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=2B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=2[C:14]2[CH:13]=[CH:12][N:11]=[C:10]3[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:7]([CH3:16])[NH:8][C:9]=23)[CH2:18][CH2:19]1
Reactant: CCOC(=O)c1c(C)[nH]c2c(Cl)ccnc12
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)c(OCC2CC2)c1
Product: CCOC(=O)c1c(C)[nH]c2c(-c3ccc(OC)cc3OCC3CC3)ccnc12

Procedure:
Starting from ethyl-7-chloro-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylate (example A3) and 2-(2-cyclopropylmethoxy-4-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example B.c5) the title compound is obtained as off-white solid.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([O:9][CH2:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:8])=[CH:4][CH:3]=1.[C:17]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)#[CH:18]>CCN(CC)CC.[Cu]I>[CH:19]1([C:17]#[C:18][C:2]2[O:6][C:5]([C:7]([O:9][CH2:10][CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)=[O:8])=[CH:4][CH:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: C#CC1CCCCC1
Reactant: O=C(OCC1CCCCC1)c1ccc(Br)o1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: O=C(OCC1CCCCC1)c1ccc(C#CC2CCCCC2)o1
Reaction time: 8 h

Procedure:
A mixture of cyclohexylmethyl 5-bromofuran-2-carboxylate (0.63 g, 2.19 mmol) and ethynylcyclohexane (0.32 g, 2.96 mmol) in Et3N (10 mL) was degassed by bubbling Ar. CuI (0.023 g, 0.119 mmol) and PdCl2(Ph3P)2 (0.0412 g, 0.0587 mmol) were added and the reaction mixture was degassed by alternating vac/Ar three 3 times. The reaction mixture was stirred at +70° C. under Ar overnight and concentrated under reduced pressure. The residue was partitioned between hexanes and aqueous NH4Cl (25%) and aqueous layer was extracted twice with hexanes. Combined organic layers were washed with brine, treated with activated charcoal and dried over anhydrous MgSO4. Concentration under reduced pressure gave cyclohexylmethyl 5-(cyclohexylethynyl)furan-2-carboxylate as an orange solid which was used directly in the next step without additional purification. Yield (0.75 g, quant.); 1H NMR (400 MHz, CDCl3) δ 7.10 (d, J=3.9 Hz, 1H), 6.50 (d, J=3.9 Hz, 1H), 4.10 (d, J=6.4 Hz, 2H), 1.56-2.66 (m, 1H), 1.63-1.84 (m, 9H), 1.42-1.60 (m, 4H), 1.10-1.40 (m, 6H), 0.96-1.10 (m, 2H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH:13]=[CH:14][C:15](Cl)=[O:16].[CH3:23][C:24]1[CH:32]=[C:28]([C:29]([OH:31])=[O:30])[C:27]([NH2:33])=[CH:26][CH:25]=1>C(Cl)(Cl)Cl>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH:13]=[CH:14][C:15]([NH:33][C:27]1[C:28](=[CH:32][C:24]([CH3:23])=[CH:25][CH:26]=1)[C:29]([OH:31])=[O:30])=[O:16]
Reactant: Cc1ccc(N)c(C(=O)O)c1
Reactant: COc1ccc(C=CC(=O)Cl)cc1OC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(C=CC(=O)Nc2ccc(C)cc2C(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
In a mixture of 3 g of 5-methylanthranilic acid in 30 ml of chloroform is dissolved 3 ml of triethylamine, to this mixture is added a solution of 4.2 g of 3,4-dimethoxycinnamoylchloride in chloroform under cooling. The mixture is stirred at room temperature for 2 hours and then heated under reflux for 2 hours. The reaction mixture is concentrated under a reduced pressure, to the residue is added water and hydrochloric acid is added to make the mixture the weakly acidic. The precipitated crystals are collected by filtration recrystallized from ethanol to obtain 4.8 g of N-(3,4-dimethoxycinnamoyl)-5-methylanthranilic acid as pale yellow needles.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[CH:12]=[N:13][N:14]3[C:19]([N:20]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[CH:18][C:17]([CH:37]=C)=[N:16][C:15]=23)[CH:2]=1.[O:39]1CCOCC1.N1C(C)=CC=CC=1C.[O-]S([O-])(=S)=O.[Na+].[Na+]>O=[Os](=O)(=O)=O.O>[CH3:36][Si:33]([CH3:34])([CH3:35])[CH2:32][CH2:31][O:30][CH2:29][N:20]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:27])[CH3:28])[C:19]1[N:14]2[N:13]=[CH:12][C:11]([C:3]3[CH:2]=[N:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[C:15]2[N:16]=[C:17]([CH:37]=[O:39])[CH:18]=1
Reactant: C=Cc1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2ncc(-c3cnc4ccccc4c3)c2n1
Reactant: C1COCCO1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: Cc1cccc(C)n1
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C=O)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 6000 %

Procedure:
To 3-(quinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)-5-vinylpyrazolo[1,5-a]pyrimidin-7-amine (0.7 g, 1.3 mmol) in 1,4-dioxide (10 mL) was added 2.5 wt % OsO4 in 1,4-dioxane (1.0 g, 0.02 mmol), 2,6-lutidine (0.6 mL, 5.2 mmol) and H2O (2 mL), and the resulting mixture was stirred at room temperature for 20 minutes. NaIO4 (0.8 g, 3.81 mmol) was then added and the reaction mixture was stirred at room temperature for 16 hours. LC/MS analysis at that time showed the diol intermediate still present. Therefore, more NaIO4 (0.3 g, 1.3 mmol) was added, and the reaction mixture was stirred for 12 hours for full conversion to the product. Saturated Na2S2O3 solution (10 mL) was added and the mixture was stirred for 10 minutes. Organics were then extracted with CH2Cl2 (4×40 mL), dried (Na2SO4) and concentrated in vacuo to give 7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidine-5-carbaldehyde as a yellow solid (0.6 g, 1.2 mmol, 92%). LCMS: 2.67 mins, m/z=550.0 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18](=[O:20])[N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C1CCNCC1
Reactant: O=C(O)Cn1c(-c2cccc(Br)c2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cn1c(-c2cccc(Br)c2)nc2cccnc21)N1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.6 %

Procedure:
Under nitrogen bubbling, a mixture of 2-(3-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.98 g, 0.015 mole) and 1,1'-carbonyldiimidazole (2.59 g, 0.016 mole) in 120 ml of tetrahydrofuran was stirred at room temperature for 4 hrs. The piperidine (2.55 g, 0.03 mole) was added and the reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was filtered and the filtrate was evaporated to dryness, then placed under high vacuum for 3 hrs. The solid was treated with water, collected by filtration, washed with water, and dried at 50° C. under high vacuum over the weekend to give 3.93 g (66%) of title compound, mp 157°-58° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)[C:9]2=[O:28])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34]Cl>C1COCC1.O>[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34][O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:17][CH:16]=3)[C:9]2=[O:28])=[CH:4][CH:3]=1
Reactant: O=C1N(c2ccc(O)cc2)CCCCN1c1ccc(Oc2ccccc2)cc1
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc(N2CCCCN(c3ccc(Oc4ccccc4)cc3)C2=O)cc1
Reaction time: 0.5 h

Procedure:
A solution of 1-(4-hydroxyphenyl)-3-(4-phenoxyphenyl)-[1,3]-diazepan-2-one (26 mg) was dissolved in THF (2 mL), and sodium hydride (80% in oil, 3 mg) was added. After 30 minutes, 2-dimethylaminoethyl chloride (hydrochloride, 11 mg) was added. After 16 hours, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried and concentrated. The residue was purified by preparative HPLC. The product with the molecular weight of 445.57 (C27H31 N3O3); MS (ESI): 446 ([M+H]+), was obtained in this way.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:27](O)=[O:28])[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:31]=[C:32]([NH2:37])[CH2:33][CH2:34][O:35][CH3:36]>>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([O:22][C:23]([F:25])([F:24])[F:26])=[CH:20][CH:21]=3)[CH2:13][CH:12]([C:27]3[O:28][N:37]=[C:32]([CH2:33][CH2:34][O:35][CH3:36])[N:31]=3)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1
Reactant: COCCC(N)=NO
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Product: COCCc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCC(O)CC3)C2)n1

Procedure:
200 mg (about 0.432 mmol) of the compound from Example 63A and 102 mg (0.865 mmol) of N′-hydroxy-3-methoxypropanimidamide were reacted according to the General Method 2. Yield: 92 mg (36% of theory)
Reaction SMILES: C([N:3]=[C:4]([NH:21][CH:22]([CH3:24])[CH3:23])[NH:5][CH2:6][CH2:7][CH2:8][NH:9][CH2:10][CH:11]1[CH2:16][CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[O:12]1)#N.[ClH:25]>>[ClH:25].[ClH:25].[O:12]1[C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=2[CH2:15][CH2:16][CH:11]1[CH2:10][NH:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]([NH:21][CH:22]([CH3:24])[CH3:23])=[NH:3]
Reactant: CC(C)NC(=NC#N)NCCCNCC1CCc2ccccc2O1
Agent: Cl
Product: CC(C)NC(=N)NCCCNCC1CCc2ccccc2O1
Reaction time: 2 h
Yield: 44.4 %

Procedure:
A mixture of 2.6 g of (±)-N"-cyano-N-[3-[[(3,4-dihydro-2H-1-benzopyran-2-yl)-methyl]amino]propyl]-N'-(1-methylethyl)guanidine in 20 ml of hydrochloric acid 6N was stirred for 2 hours at reflux temperature. The reaction mixture was evaporated and the residue was dissolved in 10 ml of methanol. This solution was filtered and the filtrate was evaporated. The oily residue was dissolved in 10 ml of ethanol. The mixture was filtered and the filtrate was evaporated, yielding 1.32 g (44.4%) of (±)-N-[3-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]amino]propyl]-N'-(1-methylethyl)-guanidine dihydrochloride; mp. 97.5° C. (comp. 150).
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[CH2:21]([N:28]1[CH2:32][CH2:31][CH2:30][C:29]1=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])(O)=O.[Na+]>C1COCC1.C(O)(=O)C>[CH2:21]([N:28]1[CH2:32][CH2:31][CH:30]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C1CCCN1Cc1ccccc1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: c1ccc(CN2CCC(N3CCCCC3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
12.7 g (60.0 mmol) NaBH(OAc)3 and 2.3 mL acetic acid are added to a solution of 4.94 mL (50.0 mmol) piperidine and 8.03 mL (50.0 mmol) N-benzylpyrrolidinone in 200 mL THF. The reaction is stirred overnight at RT. The reaction solution is combined with 200 mL saturated NaHCO3 solution and extracted twice with 200 mL EtOAc. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac. The purification is carried out by column chromatography on silica gel (EtOAc/MeOH/NH3 8:2:0.2).
Reaction SMILES: [CH:1]1([C:4]2[NH:5][CH:6]=[CH:7][N:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:16][N:17]([CH3:22])[S:18](Cl)(=[O:20])=[O:19]>ClCCl>[CH:1]1([C:4]2[N:5]([S:18]([N:17]([CH3:22])[CH3:16])(=[O:20])=[O:19])[CH:6]=[CH:7][N:8]=2)[CH2:3][CH2:2]1
Reactant: c1c[nH]c(C2CC2)n1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)S(=O)(=O)n1ccnc1C1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67 %

Procedure:
Into a 500-mL round-bottom flask, was placed a solution of 2-cyclopropyl-1H-imidazole (compound 238.1, 12 g, 110.9 mmol) in dichloromethane (60 mL). Triethylamine (31.4 mL, 225.3 mmol), N,N-dimethylsulfamoyl chloride (13.2 mL, 121.87 mmol, 1.10 equiv) were added to the reaction. The reaction mixture was stirred for 4 h at room temperature, then quenched with 20 mL of water. The aqueous phase was extracted with 3×100 mL of dichloromethane. The combined organic layers were washed with 2×20 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:4) as eluent to furnish 16 g (67%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][OH:10].N1C=CN=C1.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C>[C:16]([Si:20]([O:10][CH2:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1])([CH3:23])[CH3:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cccc(F)c1F
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(F)c1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.2 %

Procedure:
To a solution of (2,3-difluoro-phenyl)-methanol (5.0 g, 35 mmol), imidazole (4.9 g, 72 mmol) and DMF (40 mL) was added tert-butyldimethylchlorosilane (5.4 g, 36 mmol). After stirring at ambient temperature for 24 hours, the mixture was partitioned between 400 mL of ether and 100 mL of water. The organic layer was washed twice with water, dried over MgSO4, filtered and concentrated in vacuo, affording 6.8 g of tert-butyl-(2,3-difluoro-benzyloxy)-dimethyl-silane as a colorless oil. 1H NMR (400 MHz, CDCl3) δ7.22 (m, 1H), 7.04 (m, 2H), 4.79 (s, 2H), 0.91 (s, 9H), 0.12 (s, 6H) ppm.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([C:14](O)=[O:15])[C@@H:9]1[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][Li]>C(OCC)C>[C:14]([C@H:10]1[CH2:11][CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C@H:9]1[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:15])[CH3:26]
Reactant: COc1ccc(C[C@H]2[C@@H](C(=O)O)CCCN2Cc2ccccc2)cc1
Reactant: [Li]C
Solvent: CCOCC
Product: COc1ccc(C[C@H]2[C@@H](C(C)=O)CCCN2Cc2ccccc2)cc1

Procedure:
A solution of 33.9 g. of cis-1-benzyl-2-(p-methoxybenzyl)-3-piperidinecarboxylic acid in 340 ml. of diethyl ether is stirred at room temperature while 200 ml. of 1M methyl lithium is added dropwise. After this addition is completed, the reaction mixture is stirred and refluxed for 4 hours and poured over ice. The ether layer is separated and washed with 100 ml. of saturated aqueous sodium bicarbonate solution, dried, and filtered. The filtrate is concentrated to yield cis-3-acetyl-1-benzyl-2-(p-methoxybenzyl)piperidine.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@@H:9]([C:21](=[O:37])[N:22]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:33][CH2:34][CH2:35][OH:36])[CH3:23])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)C)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[OH:36][CH2:35][CH2:34][CH2:33][O:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][CH2:24][N:22]([CH3:23])[C:21](=[O:37])[C@H:9]([NH:7][CH3:6])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1
Reactant: CN(CCc1ccccc1OCCCO)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)CCc1ccccc1OCCCO
Temperature: 0 °C
Reaction time: 1.75 h
Yield: 69.4 %

Procedure:
A solution of N-[(1R)-1-(N-{2-[2-(3-hydroxypropoxy)phenyl]ethyl}-N-methylcarbamoyl)-2-(2-naphthyl)ethyl]-N-methylcarbamic acid tert-butyl ester (383 mg, 0.74 mmol) in dichloromethane (4 ml) was cooled to 0° C. Trifluoroacetic acid (4 ml) was added. The reaction mixture was stirred for 105 min at 0° C. Dichloromethane (40 ml) was added. A saturated aqueous solution of sodium hydrogen carbonate (40 ml) was added dropwise. Solid sodium hydrogen carbonate was added, until pH 7 was obtained. The phases were separated. The aqueous phase was extracted with dichloromethane (3×60 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (30 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 216 mg of (2R)-N-(2-(2-(3-hydroxypropoxy)phenyl)ethyl)-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[C:13]([F:20])[CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24][CH2:23]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1>[F:20][C:13]1[CH:12]=[C:11]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:10])[CH:19]=[CH:18][C:14]=1[C:15](=[O:17])[NH:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24][CH2:23]1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(=O)O)c(F)c1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(=O)N[C@H]2CC[C@H](O)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To (S)-4-(1-(tert-butoxycarbonylamino)ethyl)-2-fluorobenzoic acid (40.8 mg, 0.144 mmol) was added NMP (0.5 ml), trans-4-aminocyclohexanol (41.5 mg, 0.360 mmol), Hunig's Base (0.101 ml, 0.576 mmol) and HATU (110 mg, 0.288 mmol) The reaction was stirred at room temperature for 6 hours, followed by LCMS. To the reaction was added 0.5 ml of NMP, filtered, purified by prep LC and lyophilized to give 33 mg of tert-butyl (S)-1-(3-fluoro-4-(trans-4-hydroxycyclohexylcarbamoyl)phenyl)ethylcarbamate as the TFA Salt. LCMS m/z 381.1 (M+H)+, Rt 0.70 min.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[C:19]([O:26][CH2:27][CH3:28])[CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)=[C:19]([O:26][CH2:27][CH3:28])[CH:18]=1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Reactant: CCOc1cc(Cl)ccc1B(O)O
Product: CCOc1cc(Cl)ccc1-c1c(-c2cc(C#N)ccn2)ncn1C

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 4-chloro-2-ethoxyphenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C18H15ClN4O, 340. Found, 339, 341.