Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2C=CC(O)=[C:10]([C:11]3C4C(=CC=CC=4)C=CC=3O)[C:4]2=[CH:3][CH:2]=1.CC(C)([O-])C.CC(C)([O-])C.CC(C)([O-:36])C.[La+3].[N+:39](C)([O-:41])=[O:40]>O1CCCC1>[CH:4]1([CH:10]([OH:36])[CH2:11][N+:39]([O-:41])=[O:40])[CH2:5][CH2:6][CH2:1][CH2:2][CH2:3]1
Reactant: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Reactant: CC(C)(C)[O-]
Reactant: C[N+](=O)[O-]
Agent: [La+3]
Solvent: C1CCOC1
Product: O=[N+]([O-])CC(O)C1CCCCC1
Reaction time: 2 h
Yield: 91 %

Procedure:
Under a nitrogen atmosphere, 159 mg (0.56 mmol) of (S)-2,2'-dihydroxy-1,1'-binaphthyl were added to 7.56 cm3 of a THF solution of lanthanum tri-t-butoxide (4.9×10-2 mol.dm-3 as a monomer) at room temperature, followed by stirring for 2 hours. In the presence of 10 mol % (based on La) of the resultant solution, 2 mol equivalents (based on La) of LiCl and 10 mol equivalents (based on La) water, cyclohexylaldehyde reacted with nitromethane (10 equivalents) in tetrahydrofuran at -42° C. for 18 hours to give 1-cyclohexyl-2-nitroethanol represented by the formula ##STR8## With an optical purity of 90% ee. in a yield of 91%.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH2:17][C:16](=[O:18])[NH:15][C:14]3[CH:19]=[C:20]([Cl:26])[C:21]([N:23]([CH3:25])[CH3:24])=[CH:22][C:13]=3[N:12]=2)[CH:8]=[CH:9][CH:10]=1)=O.C(C([O:33][CH2:34][C:35]([NH2:37])=[S:36])=O)(C)(C)C>CCO.CCOC(C)=O>[Cl:26][C:20]1[C:21]([N:23]([CH3:24])[CH3:25])=[CH:22][C:13]2[N:12]=[C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([C:3]4[N:37]=[C:35]([CH2:34][OH:33])[S:36][CH:2]=4)[CH:6]=3)[CH2:17][C:16](=[O:18])[NH:15][C:14]=2[CH:19]=1
Reactant: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(C(=O)CBr)c1)=N2
Reactant: CC(C)(C)C(=O)OCC(N)=S
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3csc(CO)n3)c1)=N2
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 416.6 %

Procedure:
A mixture of 4-(3-bromoacetyl-phenyl)-8-chloro-7-dimethylamino-1,3-dihydro-benzo[b][1,4]diazepin-2-one (0.22 g) and 2-(tert.-butylcarbonyl-oxy)thioacetamide (0.11 g) in EtOH (3 mL) was heated at 80° C. for 0.5 h. The solution was diluted with AcOEt, washed with sat. NaHCO3 solution and with brine, dried and evaporated. The residue was stirred in a mixture of MeOH (8 mL) and 1.5N KOH (8 mL) at 20° C. for 20 min. H2O (30 ml) was added and the precipitated product collected by filtration to give the title compound (0.9 g) as yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:15][CH:14]([CH2:16][CH2:17][CH2:18][CH:19]=O)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[CH2:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[CH3:23].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:15][CH:14]([CH2:16][CH2:17][CH2:18][CH2:19][N:34]3[CH2:33][CH2:32][N:31]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[O:24][CH2:22][CH3:23])[CH2:36][CH2:35]3)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCOc1ccccc1N1CCNCC1
Reactant: COc1ccc(C2=NOC(CCCC=O)C2)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1ccccc1N1CCN(CCCCC2CC(c3ccc(OC)c(OC)c3)=NO2)CC1
Yield: 60.2 %

Procedure:
4-[3-(3,4-Dimethoxyphenyl)-4,5-dihydroisoxazol-5-yl]butanal (25.1 mg, 0.090 mmol), 1-(2-ethoxyphenyl)piperazine hydrochloride (20.0 mg, 0.082 mmol), molecular sieve (5 beads), NaBH(OAc)3 (52.4 mg, 0.247 mmol) and diisopropylethylamine (26.9 L, 0.082 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 23.1 mg (66.7%) of the target compound was obtained.
Reaction SMILES: CCN(CC)CC.[OH:8][CH2:9][C:10]1([CH2:23][OH:24])[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.[CH3:25][P:26](Cl)(Cl)=[O:27]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:25][P:26]1(=[O:27])[O:24][CH2:23][C:10]2([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:12][CH2:11]2)[CH2:9][O:8]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(CO)CC1
Reactant: CP(=O)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)COP(C)(=O)OC2
Temperature: 0 °C

Procedure:
Et3N (943 μL, 6.76 mmol) and tert-butyl 4,4-bis(hydroxymethyl)piperidine-1-carboxylate (790 mg, 3.22 mmol) were combined in CH2Cl2 (25 mL) and cooled to 0° C. A solution of methylphosphonic dichloride (428 mg, 3.22 mmol) in CH2Cl2 (20 mL) was added dropwise over 1 h. The reaction was then allowed to warm to room temperature over 1 h. It was subsequently diluted with saturated NaHCO3 and extracted with CH2Cl2 (2×). The combined organic layers were washed with brine, dried (MgSO4), and evaporated to give the desired product as a colorless solid that was used without purification. MS: cal'd 306 (MH+), exp 306 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si](C(C)C)(C(C)C)C(C)C)[CH:6]=[C:5]2[CH:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:21]2[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]2)=[CH:31][CH:30]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C2CCN(C)CC2)c2cc(Br)ccc21
Reactant: OB(O)c1ccc(Cl)cc1
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: Cc1ccccc1
Product: CN1CCC(c2c[nH]c3ccc(-c4ccc(Cl)cc4)cc23)CC1

Procedure:
The title compound was prepared by the procedure of Example 10, beginning with 5-bromo-3-(1-methylpiperidin-4-yl)-1-(triisopropylsilyl)-indole (0.500 g, 1.11 mmol), 4-chlorophenylboronic acid (0.183 g, 1.17 mmol), tetrakis(triphenylphosphine)palladium(0) (0.064 g, 0.056 mmol), and 2M aqueous sodium carbonate solution (2 mL) in toluene (15 mL) to give 0.200 g of 5-(4-chlorophenyl)-3-(1-nethylpiperidin-4-yl)-1-(triisopropylsilyl)-indole (40%) as a white solid, which was desilylated by dissolving in 1 mL of tetrahydrofuran and treating with tetrabutylammonium fluoride (1M in tetrahydrofuran, 4 mL) to give the title compound (0.112 g, 83%) as an amorphous solid. FDMS m/e=325 (M+). EA calculated for C20H21N2Cl.½ H2O: C, 71.95; H, 6.64; N, 8.39. Found: C, 72.09; H, 6.68; N, 8.48.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH2:27][CH2:28][CH3:29])[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[CH:9]=O)[CH3:2].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[CH2:1]([C:3]1[N:4]=[C:5]([CH2:27][CH2:28][CH3:29])[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[CH2:9][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)[CH3:2]
Reactant: C1COCCN1
Reactant: CCCc1nc(CC)c(C=O)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)c(CN2CCOCC2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 12 h
Yield: 35 %

Procedure:
To a solution of 4′-[(4-ethyl-5-formyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.5 g) and morpholine (0.17 mL) in acetic acid (10 mL) was added sodium triacetoxyborohydride (0.41 g), and the mixture was stirred for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow oil (0.21 g, 35%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[C:12]([CH:16]1[CH2:20][CH2:19][C:18](=O)[CH2:17]1)([CH3:15])([CH3:14])[CH3:13].N1CCCC1>CO>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][C:18]1([CH2:19][CH2:20][CH:16]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:17]1)[CH2:9][C:8]2=[O:10]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: CC(C)(C)C1CCC(=O)C1
Solvent: C1CCNC1
Solvent: CO
Product: CC(C)(C)C1CCC2(CC(=O)c3cc(Br)ccc3O2)C1
Yield: 88.5 %

Procedure:
A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (573 mg, 2.68 mmol), 3-tert-butylcyclopentanone (750 g, 5.36 mol) and pyrrolidine (362 mg, 5.092 mol) in methanol was refluxed overnight. The reaction mixture was removed in vacuo. The residue was diluted with an equal volume of H2O and then added HCl until pH=1. The mixture was extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-3′-tert-butylspiro[chroman-2,1′-cyclopentan]-4-one (0.8 g, 89%). 1H NMR (CDCl3): 0.77 (s, 9H), 1.34 (m, 1H), 1.48 (m, 2H), 1.63 (m, 2H), 1.81 (m, 2H), 2.09 (m, 2H), 2.72 (m, 2H), 6.73 (t, 1H), 7.47 (d, 1H), 7.89 (s, 1H).
Reaction SMILES: [H-].[Na+].[OH:3][NH:4][C:5](=[NH:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CO[C:16](=O)[CH:17]([NH:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([N:38]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[NH:40][C:39]2=[O:48])[CH2:34][CH2:33]1)=[O:31])[CH2:18][C:19]1[CH:20]=[C:21]2[C:25](=[C:26]([CH3:28])[CH:27]=1)[NH:24][N:23]=[CH:22]2>O1CCCC1>[CH2:6]([C:5]1[N:13]=[C:16]([CH:17]([NH:29][C:30]([N:32]2[CH2:33][CH2:34][CH:35]([N:38]3[CH2:47][C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[NH:40][C:39]3=[O:48])[CH2:36][CH2:37]2)=[O:31])[CH2:18][C:19]2[CH:20]=[C:21]3[C:25](=[C:26]([CH3:28])[CH:27]=2)[NH:24][N:23]=[CH:22]3)[O:3][N:4]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: N=C(Cc1ccccc1)NO
Reactant: COC(=O)C(Cc1cc(C)c2[nH]ncc2c1)NC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2nc(Cc3ccccc3)no2)cc2cn[nH]c12
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (8 mg, 0.366 mmol) was added to a solution of N-hydroxy-2-phenyl-acetamidine (50 mg, 0.366 mmol) in tetrahydrofuran (15 mL). The solution was stirred at 60° C. for 15 min. A solution of (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid methyl ester (60 mg, 0.122 mmol) in tetrahydrofuran (5 mL) was added. The reaction mixture was stirred at 60° C. for 18 h. The reaction was then cooled to room temperature and the solvent removed under reduced pressure. The residue was dissolved with methylene chloride and partitioned with water and extracted with methylene chloride (3×50 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduce pressure. Purification was carried out by preparative HPLC. LC/MS: tR=1.79 min, 591 (MH)+.
Reaction SMILES: [CH:1]([C:4]1[NH:5][C:6]2[C:11]([C:12]=1[CH:13]=O)=[CH:10][C:9]([O:15][CH3:16])=[CH:8][CH:7]=2)([CH3:3])[CH3:2].[C:17]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)(=[O:19])[CH3:18].N1CCCCC1>CO>[CH:1]([C:4]1[NH:5][C:6]2[C:11]([C:12]=1/[CH:13]=[CH:18]/[C:17]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)=[O:19])=[CH:10][C:9]([O:15][CH3:16])=[CH:8][CH:7]=2)([CH3:3])[CH3:2]
Reactant: CC(=O)c1ccncc1
Reactant: COc1ccc2[nH]c(C(C)C)c(C=O)c2c1
Solvent: C1CCNCC1
Solvent: CO
Product: COc1ccc2[nH]c(C(C)C)c(/C=C/C(=O)c3ccncc3)c2c1
Temperature: 40 °C
Yield: 66.3 %

Procedure:
2-Isopropyl-5-methoxyindole-3-carboxaldehyde (105 mg, 0.48 mmol) was dissolved in anhydrous methanol (5 mL) under an atmosphere of Argon (g). 4-Acetylpyridine (87.2 mg, 0.72 mmol) and piperidine (61.3 mg, 0.72 mmol) were added to the reaction mixture and the solution was refluxed for 24 hours. A precipitate slowly formed which was collected, washed with cold MeOH (30 mL) and dried overnight in an oil driven vacuum pump equipped to a vacuum desiccator heated to 40° C. to yield a bright yellow powder (102 mg, 66%): TLC Rf 0.38 in 4:1 ethyl acetate/hexanes. Melting point=252-253° C. 1H NMR (600 MHz, d6-DMSO) δ 11.78 (s, 1H), 8.82-8.81 (m, 2H), 8.15-8.13 (d, 1H, J=15.24 Hz), 7.94 (m, 2H), 7.45 (d, 1H, J=2.28 Hz), 7.41-7.38 (d, 1H, J=15.18 Hz), 7.36-7.34 (d, 1H, J=8.7 Hz), 6.88-6.87 (dd, 1H, J1=2.34 Hz, J2=8.64 Hz), 3.87 (s, 3H), 3.54-3.49 (m, 1H), 1.35-1.34 (d, 6H, J=6.96 Hz); 13C NMR (150 MHz, d6-DMSO) δ 188.6, 155.7, 155.4, 151.1, 145.6, 139.6, 131.8, 126.6, 121.9, 113.5, 113.0, 111.6, 105.0, 104.4, 56.1, 26.0, 22.8. Elemental analysis calculated for C20H20N2O2: C, 74.98; H, 6.29; N, 8.74. Found: C, 74.78; H, 6.42; N, 8.68.
Reaction SMILES: I[C:2]1[CH:21]=[CH:20][C:5]2S[CH2:7][C:8](=[O:19])[N:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[O:22]=[C:23]1[NH:28][CH2:27][CH:26]2[CH2:29][CH2:30][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:32][CH:25]2[O:24]1.C(=O)([O-])[O-:41].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>C(Cl)Cl.CO.[Cu]I.O1CCOCC1>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:9]2[C:8](=[O:19])[CH2:7][O:41][C:5]3[CH:20]=[CH:21][C:2]([N:28]4[CH2:27][CH:26]5[CH2:29][CH2:30][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:32][CH:25]5[O:24][C:23]4=[O:22])=[CH:3][C:4]2=3)=[CH:12][CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCC2CNC(=O)OC2C1
Reactant: COc1ccc(CN2C(=O)CSc3ccc(I)cc32)cc1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [K+]
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(CN2C(=O)COc3ccc(N4CC5CCN(C(=O)OC(C)(C)C)CC5OC4=O)cc32)cc1
Temperature: 100 °C
Reaction time: 48 h
Yield: 58.9 %

Procedure:
In a 7 mL sealed vial were introduced 6-iodo-4-(4-methoxybenzyl)-2H-benzo[b][1,4]thiazin-3(4H)-one (0.2 g, 0.486 mmol), rac-(4aR*,8aR*)-tert-butyl 2-oxohexahydro-2H-pyrido[4,3-e][1,3]oxazine-7(3H)-carboxylate (Preparation A, 0.15 g, 0.584 mmol, 1.2 eq.), potassium carbonate (0.134 g, 2 eq.), (R,R)-(−)-N,N′-dimethyl-1,2-cyclohexanediamine (0.01 g, 0.06 mmol, 0.1 eq.), CuI (0.11 g, 0.57 mmol, 1 eq.) and dioxane (2.3 mL). The suspension was stirred at 100° C. for 2 days. The mixture was cooled to rt, diluted with DCM/MeOH (9:1, 2 mL) and filtered. The yellow salt obtained was washed with DCM/MeOH (9:1, 2×10 mL). The combined filtrates were concentrated under reduced pressure. The residue was purified (DCM/MeOH 9:1) to afford the title compound as a greenish foam (0.15 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][CH2:16]1.C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[O:13][CH2:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([NH2:21])[CH2:17][CH2:16]1
Reactant: COc1ccc2nccc(OCC3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2nccc(OC[C@H]3CC[C@H](N)CC3)c2c1

Procedure:
A solution of tert-butyl [4-(6-methoxy-quinolin-4-yloxymethyl)-cyclohexyl]carbamate (438 mg, 1.13 mmol) and TFA (1.5 ml) in dichloromethane (4 ml) was stirred at room temperature for 2 hours. The reaction mixture was poured onto ice/ammonium hydroxide and extracted with dichloromethane. The organic extracts were dried over Na2SO4 and concentrated.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.[CH2:16]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:36])[C@@H:28]([NH2:35])[CH2:29][CH2:30][S:31]([CH3:34])(=[O:33])=[O:32])[CH2:23][CH2:22]1)=[O:20])[CH3:17].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH2:16]([O:18][C:19]([N:21]1[CH2:22][CH2:23][N:24]([C:27](=[O:36])[C@@H:28]([NH:35][C:13]([C:4]2[CH:3]=[C:2]([OH:1])[N:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:5]=2)=[O:15])[CH2:29][CH2:30][S:31]([CH3:34])(=[O:32])=[O:33])[CH2:25][CH2:26]1)=[O:20])[CH3:17]
Reactant: O=C(O)c1cc(O)n(-c2ccccc2)n1
Reactant: CCOC(=O)N1CCN(C(=O)[C@@H](N)CCS(C)(=O)=O)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCS(C)(=O)=O)NC(=O)c2cc(O)n(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 190 mg of 5-Hydroxy-1-phenyl-1H-pyrazole-3-carboxylic acid and 299 mg of 4-((S)-2-Amino-4-methanesulfonyl-butyryl)-piperazine-1-carboxylic acid ethyl ester in 3 ml of DMF, 142 mg of HOBT, 178 mg of EDC and 0.2 ml DIPEA was added and the reaction mixture was stirred for 16 h at RT. Then, the solvents were removed under reduced pressure and the crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 327 mg.
Reaction SMILES: Cl[C:2]1[CH:12]=[C:6]2[N:7]([CH3:11])[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=1.BrC[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1.[F:24][C:25]1[CH:26]=[C:27]([CH2:32][OH:33])[CH:28]=[CH:29][C:30]=1[F:31]>>[F:24][C:25]1[CH:26]=[C:27]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:32][O:33][C:2]1[CH:12]=[C:6]2[N:7]([CH2:11][C:20]3[CH:21]=[CH:16][CH:17]=[C:18]([O:22][CH3:23])[CH:19]=3)[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: COc1cccc(CBr)c1
Reactant: OCc1ccc(F)c(F)c1
Product: COc1cccc(CN2CCCn3c2cc(OCc2ccc(F)c(F)c2)nc3=O)c1

Procedure:
The title compound was prepared by a procedure similar to that described for E2 starting from 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one, 1-(bromomethyl)-3-methoxybenzene and (3,4-difluorophenyl)methanol.
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH2:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.CO.[Pd]>[NH2:8][CH2:1][CH:2]1[CH2:7][CH2:6][N:11]([C:9]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:4][CH2:3]1
Reactant: NC(=O)NCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: NCC1CCN(C(=O)NCc2ccccc2)CC1

Procedure:
) 4 g of benzylurea 14a were dissolved in a mixture of ethyl acetate/CH3OH 3:1 with heating and, after addition of 0.2 g of 10% Pd on activated carbon, hydrogenated under standard conditions at 35 to 40° C. After the reaction was complete, the mixture was filtered through Celite and evaporated. 2.8 g; ESI-MS [M+H+]=248.15
Reaction SMILES: [CH2:1]([CH2:8][C:9](=O)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(N[C@H](C(O)=O)CC(C)C)(=O)=O)=CC=1.C(N[C@H](C(O)=O)CC(C)C)(=O)C>C1C=CC=CC=1.C(O)C>[CH2:12]([NH:19][C@H:9]([CH3:10])[CH2:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(=O)CCc1ccccc1
Reactant: NCc1ccccc1
Agent: CC(=O)N[C@@H](CC(C)C)C(=O)O
Agent: Cc1ccc(S(=O)(=O)N[C@@H](CC(C)C)C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Solvent: c1ccccc1
Product: C[C@H](CCc1ccccc1)NCc1ccccc1
Temperature: 25 °C

Procedure:
In an apparatus fitted with a Dean Stark trap, reflux a solution of 1.0 kg (6.75 mol) of benzylacetone, 725 g (6.75 mol) of benzylamine and 5.0 g of p-toluenesulfonic acid hydrate in 7 liters of benzene for 14 hours. Remove the solvent in vacuo, and dissolve the residue in 6.5 liters of methanol. With cooling and stirring, carefully add 125 g of NaBH4 and stir the mixture for 16 hours at room temperature. Remove the methanol in vacuo, and add 2 liters water and 4 liters benzene, and extract the product into the benzene. After drying (MgSO4), filter and distill (b.p. 145°-150° C./0.5 mm). Dissolve 1,028 g (4.288 mol) of the distillate and 1.23 kg (4.328 mol) of N-p-toluenesulfonyl-(L)-leucine in 7.2 liters of boiling ethanol and allow to cool to room temperature without agitation. Wash the precipitate with a small amount of ice-cold ethanol, recrystallize from 4.8 liters of ethanol, wash with ice-cold ethanol and filter off the solid product that is highly enriched with the salt of the undesired S enantiomer. Combine the mother liquor from the original precipitation and that from the recrystallization, remove the solvent and recover the free base by basifying with 500 ml of 20% aqueous NaOH and extracting with benzene. After drying (MgSO4), filtering and removing the benzene, dissolve the residue [487 g (2.04 mol)] and 346 g (2.06 mol) of N-acetyl-(L)-leucine in 2.0 liters of boiling ethanol and allow the solution to cool to room temperature. Filter and recrystallize once from 1.8 liter of ethanol followed by recrystallization from 4.0 liters of acetonitrile to obtain the desired R salt, m.p. 151°-152° C. Basify with 400 ml of aqueous 2.5N NaOH, extract with ether, dry (MgSO4), filter and remove the solvent in vacuo to obtain the product (2), [α]26D =+4.5° (c=5.0, ethanol).
Reaction SMILES: CCN=C=NCCCN(C)C.[CH3:12][N:13]([CH3:18])[CH2:14][C:15](O)=[O:16].[CH3:19][N:20]1[C:28]2[CH:27]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH2:37][NH:38][CH3:39])=[C:31]([C:40]([F:43])([F:42])[F:41])[CH:30]=3)[N:25]=[C:24]([C:44]#[N:45])[C:23]=2[N:22]=[N:21]1.Cl>C1COCC1.C(OCC)(=O)C.C(N(CC)CC)C>[C:44]([C:24]1[C:23]2[N:22]=[N:21][N:20]([CH3:19])[C:28]=2[CH:27]=[C:26]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH2:37][N:38]([CH3:39])[C:15](=[O:16])[CH2:14][N:13]([CH3:18])[CH3:12])=[C:31]([C:40]([F:41])([F:43])[F:42])[CH:30]=2)[N:25]=1)#[N:45]
Reactant: CN(C)CC(=O)O
Reactant: CNCCCc1ccc(-c2cc3c(nnn3C)c(C#N)n2)cc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(C)CC(=O)N(C)CCCc1ccc(-c2cc3c(nnn3C)c(C#N)n2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
EDCI (290 mg) was added to the mixture of 2-(dimethylamino)acetic acid (155 mg), methyl-6-(4-(3-(methylamino)propyl)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]-triazolo[4,5-c]pyridine-4-carbonitrile, triethylamine (0.5 ml) in THF (5 ml). The mixture was stirred at rt for 5 hours, then diluted with ethyl acetate (100 ml), washed with sodium bicarbonate (50 ml), brine (50 ml), dried over sodium sulphate, solvent removed, residue dissolved in MeOH/NMP (3:1, 6 ml), and purified by basic hplc to give free base which was then converted to HCl salt as usual (70 mg). 1H NMR (CD3OD) δ: 8.68 (s, 1H), 8.5 (s, 1H), 8.46 (d, 1H), 7.65 (d, 1H), 4.47 (s, 3H), 4.27 (s, 2H), 3.60 (t, 2H), 3.04 (s, 3H), 2.96 (s, 6H), 2.90 (t, 2H), 1.95 (m, 2H). MS m/z 460 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[CH3:12][C@H:13]1[CH2:18][NH:17][CH2:16][CH2:15][N:14]1[C:19](=[O:27])[C@:20]([OH:26])([CH3:25])[C:21]([F:24])([F:23])[F:22].C(N(CC)CC)C>C(Cl)Cl>[CH3:12][C@H:13]1[CH2:18][N:17]([C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:16][CH2:15][N:14]1[C:19](=[O:27])[C@:20]([OH:26])([CH3:25])[C:21]([F:24])([F:22])[F:23]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: C[C@H]1CNCCN1C(=O)[C@@](C)(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1CN(C(=O)c2ccc(C#N)cc2)CCN1C(=O)[C@@](C)(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
4-Cyanobenzoyl chloride (0.30 g) was added to a stirred solution of the (R)-[2-(S)-methyl-1-(3,3,3-trifluoro-2-hydroxy-2-methylpropionyl)piperazine] (Example 27; 0.40 g) and triethylamine (0.30 ml) in DCM (10 ml). The reaction mixture was allowed to stir at room temperature for 17 hours (overnight), and then partitioned between DCM (20 ml) and 2 M HCl (20 ml). The organic phase was separated, dried and concentrated to give a gum. The residue was purified by chromatography on an 8 g silica Biotage cartridge eluting 1:1 EtOAc/isohexane to give the title compound (0.445 g) as a white solid. NMR (DMSO-d6, 100° C.): 1.17 (d, 3H), 1.58 (s, 3H), 3.05-3.14 (m, 1H), 3.23-3.29 (m, 2H); 3.73 (brs, 1H), 3.88 (brs, 1H), 4.47 (d, 1H), 4.79 (brs, 1H), 6.79 (s, 1H), 7.58 (d, 2H), 7.88 (d, 2H); m/z 368.