Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[S:3]1[C:7]([NH2:8])=[N:6][CH:5]=[N:4]1.[C:9]([C:11]1[CH:12]=[C:13]([S:18](Cl)(=[O:20])=[O:19])[CH:14]=[CH:15][C:16]=1[F:17])#[N:10].Cl>O>[C:9]([C:11]1[CH:12]=[C:13]([S:18]([NH:8][C:7]2[S:3][N:4]=[CH:5][N:6]=2)(=[O:20])=[O:19])[CH:14]=[CH:15][C:16]=1[F:17])#[N:10]
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Reactant: Nc1ncns1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1F
Reaction time: 0.08 h

Procedure:
Sodium hydroxide (5.08 g, 0.127 mol) was dissolved in water (60 mL) and 1,4-1,4-dioxane (300 mL). 1,2,4-Thiadiazol-5-amine (10 g, 0.1 mol) was added and the reaction stirred for 5 minutes. 3-Cyano-4-fluorobenzene-1-sulfonyl chloride (8.25 g, 0.0376 mol) was added and the reaction was allowed to stir for 3 hours at 20° C. After this time, the reaction was poured into 150 mL of 1N HCl. This solution was extracted with ethyl acetate (3×50 mL). The combined organics were dried over sodium sulfate, filtered and concentrated to give the title compound as a brown solid. LCMS Rt=1.22 minutes MS m/z 283 [MH]+ 1H NMR (d6-DMSO) δ 8.54 (s, 1H), 8.39 (dd, 1H), 8.19 (m, 1H), 7.71 (m, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:27][CH2:26][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[N:14]=[C:15]([OH:16])[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:29][C:30]1[CH:39]=[CH:38][C:33]([C:34]([O:36]C)=[O:35])=[CH:32][CH:31]=1>>[CH2:1]([N:8]1[CH2:27][CH2:26][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[N:14]=[C:15]([O:16][CH2:29][C:30]3[CH:39]=[CH:38][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=3)[C:10]=2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: O=[N+]([O-])c1cccc(-c2nc(O)c3c(n2)CCN(Cc2ccccc2)C3)c1
Product: O=C(O)c1ccc(COc2nc(-c3cccc([N+](=O)[O-])c3)nc3c2CN(Cc2ccccc2)CC3)cc1

Procedure:
The title compound was prepared from 6-benzyl-2-(3-nitro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ol (which was obtained in Intermediate 9) and methyl 4-(bromomethyl)benzoate according to Method A and Method B; LC retention time 3.25 min; MS: m/z (ESI) 494 (M−H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C([O-])(=O)C.[NH4+].[N+:17]([CH3:20])([O-:19])=[O:18]>>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1/[CH:4]=[CH:20]/[N+:17]([O-:19])=[O:18]
Reactant: C[N+](=O)[O-]
Reactant: COc1ccc(C=O)c(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COc1ccc(/C=C/[N+](=O)[O-])c(F)c1

Procedure:
A solution of 2-fluoro-4-methoxybenzaldehyde (5.0 g, 33 mmol) and ammonium acetate (1.0 g, 13 mmol) in nitromethane (40 mL) was heated on a steam bath for 2.5 h. The reaction mixture was concentrated under reduced pressure, and the sticky residue was partitioned between dichloromethane and water. The organic layer was washed with half-saturated brine, dried (MgSO4), filtered, and concentrated. The residue was triturated in hexane and the solid was filtered and washed with hexane and dried to give 5.57 g of crude product 2-fluoro-4-methoxy-1-((E)-2-nitrovinyl)benzene as an orange solid, M.P. 80-82° C. 1H NMR (CDCl3): δ 8.02 (d, J=13.5 Hz, 1H), 7.66 (d, J=13.5 Hz, 1H), 7.43 (m, 1H), 6.68-6.80 (m, 2H), 3.87 (s, 3H). GC/MS: 197 [M]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([NH:12][CH2:13][CH2:14][C:15](O)=[O:16])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1>C1COCC1>[OH:16][CH2:15][CH2:14][CH2:13][NH:12][S:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:11])=[O:10]
Reactant: COc1cccc(S(=O)(=O)NCCC(=O)O)c1
Solvent: C1CCOC1
Product: COc1cccc(S(=O)(=O)NCCCO)c1
Temperature: 25 °C

Procedure:
3-(3-Methoxy-benzenesulfonylamino)-propionic acid (0.755 g, 2.91 mmol), was dissolved in THF (10 mL), cooled in an ice-H2O bath, and treated with borane THF complex (3.49 mL of a 1M solution, 3.49 mmol) with stirring. After warming to room temperature over 1 h, the reaction was cooled in an ice bath, and quenched by dropwise addition of H2O, then partitioned between H2O and CH2Cl2. The aqueous layer was washed with CH2Cl2 (3×20 mL), dried (MgSO4). Filtration and concentration in vacuo gave the title compound which was used without further purification.
Reaction SMILES: O[N:2]=[C:3]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH:4]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>CCO.[Pd]>[NH2:2][CH:3]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH:4]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: CC(C)(C)OC(=O)C1CN(c2ccccc2)C(=O)C1=NO
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)C1CN(c2ccccc2)C(=O)C1N
Yield: 60.1 %

Procedure:
A solution of oxime of Example N (3.08 g, 10.6 mmol) in EtOH (80 ml) was hydrogenated at 1000 psi at 70° C. on 10% palladium on carbon. Filtration and concentration of the filtrate gave an oil which was chromatographed on silica gel eluting with 2/97.75/0.25 EtOH/CH2Cl2 /NH4OH to afford the title compound (1.76 g, 60%) as a white solid. Anal calcd for C15H20N2O3 : C, 65.20; H, 7.30; N, 10.14. Found: C, 64.95; H, 7.39; N, 10.04. MS Calcd for C15H20N2O3 276, found 276. DSC=105.0°-121.1° at 57.2 J/g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[CH:5]2.C([Li])CCC.[I:17]I.S([O-])([O-])=O.[Na+].[Na+]>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([I:17])=[CH:5]2
Reactant: II
Reactant: Cn1ccc2cc(Cl)ccc21
Agent: O=S([O-])[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Product: Cn1c(I)cc2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
A mixture of 5-chloro-1-methylindole (10.0 g, 60.4 mmole) and n-butyl lithium (29 mL of 2.5 M sol'n in hexanes, 72.5 mmole) in diethyl ether is heated at reflux temperature for 3 hours, cooled to 0° C., treated with iodine (18.4 g, 72.5 mmole), stirred at 0° C. for 1 hour, warmed to room temperature, stirred for 1 hour, and treated with aqueous sodium sulfite. After phase separation, the organic phase is dried over MgSO4 and concentrated in vacuo to give the title product as a brown oil which solidified on standing, 16.5 g (93.7% yield). The title product is used as in Example 4.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[S:25]1[C:29]([C:30]([OH:32])=O)=[CH:28][C:27]2[CH:33]=[CH:34][CH:35]=[CH:36][C:26]1=2.[Si:37]([O:44][CH2:45][CH2:46][C:47]1[C:48]([F:65])=[C:49]([CH:62]=[CH:63][CH:64]=1)[CH2:50][N:51]1[CH2:61][CH2:60][C:54]2([O:59][CH2:58][CH2:57][NH:56][CH2:55]2)[CH2:53][CH2:52]1)([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38].C(N(CC)CC)C>CN(C=O)C>[S:25]1[C:29]([C:30]([N:56]2[CH2:55][C:54]3([CH2:53][CH2:52][N:51]([CH2:50][C:49]4[CH:62]=[CH:63][CH:64]=[C:47]([CH2:46][CH2:45][O:44][Si:37]([C:40]([CH3:42])([CH3:41])[CH3:43])([CH3:38])[CH3:39])[C:48]=4[F:65])[CH2:61][CH2:60]3)[O:59][CH2:58][CH2:57]2)=[O:32])=[CH:28][C:27]2[CH:33]=[CH:34][CH:35]=[CH:36][C:26]1=2
Reactant: O=C(O)c1cc2ccccc2s1
Reactant: CC(C)(C)[Si](C)(C)OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCc1cccc(CN2CCC3(CC2)CN(C(=O)c2cc4ccccc4s2)CCO3)c1F
Reaction time: 1 h

Procedure:
2-(3H-[1,2,3]Triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.378 g) was added to a stirred solution of benzo[b]thiophene-2-carboxylic acid (0.186 g), 9-(3-(2-(tert-butyldimethylsilyloxy)ethyl)-2-fluorobenzyl)-1-oxa-4,9-diazaspiro[5.5]undecane (example 78, step d) (0.40 g), and triethylamine (0.383 g) in DMF (4 mL). After 1 h, the reaction mixture was partitioned between water and ethyl acetate. The ethyl acetate layer was washed twice with water and once with brine, dried over magnesium sulphate, filtered and evaporated in vacuo. Purification by silica gel chromatography eluting with 7:1:0.5, isohexane:ethyl acetate:triethylamine gave the subtitled compound as a gum. Yield 0.38 g.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][OH:11])[CH2:6][CH2:5]1.Cl[C:13]1[C:18]([CH3:19])=[N:17][CH:16]=[CH:15][N:14]=1>>[CH3:19][C:18]1[C:13]([NH:1][CH2:2][CH2:3][N:4]2[CH2:5][CH2:6][CH:7]([CH2:10][OH:11])[CH2:8][CH2:9]2)=[N:14][CH:15]=[CH:16][N:17]=1
Reactant: Cc1nccnc1Cl
Reactant: NCCN1CCC(CO)CC1
Product: Cc1nccnc1NCCN1CCC(CO)CC1
Temperature: 120 °C
Reaction time: 20 h
Yield: 28 %

Procedure:
A mixture of 1-(2-amino-ethyl)-4-piperidinemethanol (5.2 g), 2-chloro-3-methyl-pyrazine (5.0 g) and CaO (4.5 g) was stirred for 20 hours at 120° C. The reaction mixture was cooled and purified by column chromatography over silica gel (eluent: CH2Cl2/(CH3OH/NH3) 92/8). The pure fractions were collected and the solvent was evaporated, yielding 2.3 g (29%) 1-[2-[(3-methyl-2-pyrazinyl)amino]-ethyl]4-piperidinemethanol (intermediate 1).
Reaction SMILES: [C:1]1([N:7]=[C:8]([S:15][CH2:16][CH:17]2[CH2:19][CH2:18]2)[C:9]#[C:10][Si](C)(C)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[F:26][C:27]1[CH:32]=[CH:31][C:30]([SH:33])=[CH:29][CH:28]=1>CO>[F:26][C:27]1[CH:32]=[CH:31][C:30]([S:33][CH:10]=[CH:9][C:8](=[N:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[S:15][CH2:16][CH:17]2[CH2:19][CH2:18]2)=[CH:29][CH:28]=1
Reactant: Fc1ccc(S)cc1
Reactant: C[Si](C)(C)C#CC(=Nc1ccccc1)SCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Fc1ccc(SC=CC(=Nc2ccccc2)SCC2CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyclopropylmethyl N-phenyl-3-(trimethylsilyl)thiopropynimidate (0.91 g) was dissolved in methanol (15 mL), a small amount of potassium carbonate was dissolved thereto at room temperature, and the mixture was stirred for 1 hour. 4-fluorothiophenol (0.35 mL) was added thereto and further stirred for 5.5 hours. The reaction mixture was concentrated under reduced pressure, then the residue was subjected to silica gel column chromatography (hexane/ethyl acetate=20/1), medium pressure HPLC(hexane/ethyl acetate=99.2/0.8-98.5/1.5) to obtain cyclopropylmethyl 3-(4-fluorophenylthio)-N-(phenyl)thioacrylimidate (0.84 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.Cl.[CH:12]1([C:15]2[C:16]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[N:17][CH:18]=[C:19]([CH:21]3[CH2:23][CH2:22]3)[CH:20]=2)[CH2:14][CH2:13]1>>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:27]2[CH2:28][CH2:29][N:24]([C:16]3[C:15]([CH:12]4[CH2:13][CH2:14]4)=[CH:20][C:19]([CH:21]4[CH2:23][CH2:22]4)=[CH:18][N:17]=3)[CH2:25][CH2:26]2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: c1nc(N2CCNCC2)c(C2CC2)cc1C1CC1
Agent: Cl
Product: O=C(c1ccc(Br)nc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 96.9 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 1 and using 6-bromonicotinic acid (2 g) and 1-(3,5-dicyclopropylpyridin-2-yl)piperazine hydrochloride (3.2 g) described in Preparation Example 50, the title compound (4.1 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[F:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:25][C:24]2[CH:26]=[CH:27][CH:28]=[C:22]([F:21])[CH:23]=2)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Nc1cccc(F)c1
Reactant: Clc1nc(Cl)c2c(n1)CCS2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cccc(Nc2nc(Cl)nc3c2SCC3)c1
Temperature: 120 °C
Reaction time: 7 h

Procedure:
4.00 g 2,4-dichloro-6,7-dihydro-thieno[3,2-d]pyrimidine are placed in 15 ml dimethylformamide, then first 4.50 ml diisopropylethylamine, then 2.50 ml 3-fluoro-aniline are added. The reaction mixture is stirred for 7 hours at 120° C., and after cooling evaporated down. The residue is extracted with dichloromethane and water, the organic phase is washed with saturated sodium chloride solution, dried and evaporated to dryness. The residue is purified by chromatography (NP_MPLC, Biotage cartridge (4*15 cm)). 2.60 g of the product are obtained as a powder.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4]([NH2:8])[CH2:5][CH2:6][CH3:7].C(N(CC)CC)C.[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25](Cl)=[O:26])=[CH:24][C:19]=2[O:18][CH2:17]1>ClCCl>[CH3:1][CH2:2][CH2:3][CH:4]([NH:8][C:25]([C:23]1[CH:22]=[CH:21][C:20]2[O:16][CH2:17][O:18][C:19]=2[CH:24]=1)=[O:26])[CH2:5][CH2:6][CH3:7]
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Reactant: CCCC(N)CCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(CCC)NC(=O)c1ccc2c(c1)OCO2
Reaction time: 1 h
Yield: 48.5 %

Procedure:
To a solution of heptan-4-amine (8.06 mL, 54 mmol) in triethylamine (15.3 mL, 108 mmol) and dichloromethane (135 mL), was added, dropwise at 0° C., a solution of benzo[1,3]dioxole-5-carbonyl chloride (10 g, 54 mmol) dissolved in dichloromethane (135 mL). The reaction mixture was stirred for 1 h. Solvent was removed under reduced pressure and the residue was dissolved in EtOAc. The organic layer was washed successively with 1 N aq. HCl, 1 N aq. NaOH, water, brine, dried (MgSO4) and concentrated. The residue was recrystallized in EtOAc and Hexanes to afford 6.9 g of N-(heptan-4-yl)benzo[d][1,3]dioxole-5-carboxamide (48.3%) as a white solid. 1H NMR (500 MHz, CDCl3): δ 0.92 (t, 6H), 1.38 (m, 6H), 1.53 (m, 2H), 4.11 (m, 1H), 5.63 (m, 1H), 6.01 (s, 2H), 7.98 (d, 1H), 7.27 (s, d, 2H). MS (M+H, 264).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[CH3:20][N:21]([CH3:38])[CH2:22][CH2:23][CH2:24][N:25]([CH3:37])[C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][C:27]=1[C:33]([F:36])([F:35])[F:34]>>[CH3:38][N:21]([CH3:20])[CH2:22][CH2:23][CH2:24][N:25]([CH3:37])[C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:17](=[O:19])[CH2:16][C:13]2[CH:12]=[CH:11][C:10]([N:3]3[C:4]4=[N:5][CH:6]=[CH:7][CH:8]=[C:9]4[N:1]=[CH:2]3)=[CH:15][CH:14]=2)=[CH:28][C:27]=1[C:33]([F:34])([F:36])[F:35]
Reactant: CN(C)CCCN(C)c1ccc(N)cc1C(F)(F)F
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Product: CN(C)CCCN(C)c1ccc(NC(=O)Cc2ccc(-n3cnc4cccnc43)cc2)cc1C(F)(F)F

Procedure:
The title compound is prepared as described in Example 1 but using (4-imidazo[4,5-b]pyridin-3-yl-phenyl)-acetic acid (Step 7.1) and 4-[(3-dimethylamino-propyl)-methyl-amino]-3-trifluoromethyl-phenylamine (Step 5.1). Title compound: ES-MS: 511.0 [M+H]+; single peak at tR=3.33 min (System 1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1.[CH3:18][N:19]([CH:21]=O)[CH3:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:17])[C:9]([C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=1)=[CH:18][N:19]([CH3:21])[CH3:20]
Reactant: CN(C)C=O
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccccc1Cl
Product: CN(C)C=C(C(=O)c1ccccc1Cl)c1ccc(Cl)cc1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
To 13.2 g of 1-(2-chlorophenyl)-2-(4-chlorophenyl)ethanone in 100 mL of DMF was added 23.8 g of N,N-dimethylormamide dimethyl acetal. The mixture was stirred at 75° C. for 16 hours. The solution was then concentrated and used without further purification in the next step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][NH:18]1)=[O:16])([CH3:4])([CH3:3])[CH3:2].[C:24](O)(=[O:37])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C@@H:17]1[CH2:22][CH2:21][CH2:20][CH2:19][N:18]1[C:24](=[O:37])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCCCCNC(=O)C1CCCCN1
Reactant: CCCCCCCCCCCCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCCC(=O)N1CCCC[C@H]1C(=O)NCCCCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
(S)-(6-{[1-(1-Tridecanoyl-piperidin-2-yl)-methanoyl]-amino}-hexyl)-carbamic acid tert-butyl ester was obtained by treating a solution of {6-[(1-piperidin-2-yl-methanoyl)-amino]hexyl}-carbamic acid tert-butyl ester in DCM (100 mL) with tridecanoic acid (2.36 g, 1.1 equiv.) in the presence of HATU (5.0 g, 1.3 equiv.) and DIEA (4.2 mL, 2.4 equiv.). After 2 hours of stirring at rt the reaction was judged to be complete by tlc monitoring. DCM was added (50 mL) and the reaction mixture was washed 3 times with citric acid (0.5 M). 3 times with an aqueous saturated solution of NaHCO3 and with brine. Drying over Na2SO4, evaporation in vacuo gave a residue which was purified via flash chromatography (SiO2) using EtOAc:chexanes (6:4) as eluant. (S)-(6-{[1-(1-Tridecanoyl-piperidin-2-yl)-methanoyl]-amino}-hexyl)-carbamic acid tert-butyl ester (4.6 g) was obtained as a yellow oil in a 87% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:14][C:15]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:16]=1[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[O:20])[CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]([CH2:14][C:15]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:16]=1[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:9][C:10]([F:11])([F:12])[F:13])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)C=Cc1ccc(OC)cc1CN(CC(F)(F)F)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1ccc(OC)cc1CN(CC(F)(F)F)C(=O)OC(C)(C)C
Reaction time: 6 h
Yield: 95.4 %

Procedure:
To 10% Pd/C (5 g, 4.7 mmol, prewetted with DMF) was added a solution of methyl 2-[N-(tert-butoxycarbonyl)-N-(2,2,2-trifluoroethyl)amino]methyl-4-methoxycinnamate (45.85 g, 113 mmol) in methanol (100 mL). The mixture was shaken under hydrogen (50 psi) in a Parr apparatus for 6 hr, then was filtered through a pad of celite® to remove the catalyst. The filtrate was concentrated to afford the title compound (43.71 g, 95%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.11 (d, J=8 Hz, 1H), 6.78 (dd, 1H), 6.65 (s, 1H), 4.63 and 4.60 (2s, 2H), 3.84 and 3.70 (2m, 2H), 3.77 (s, 3H), 3.66 (s, 3H), 2.86 (t, 2H), 2.53 (t, 2H), 1.50 and 1.44 (2s, 9H).
Reaction SMILES: [CH:1]1([C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13]Br)=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[C-:15]#[N:16].[Na+].O>CN(C)C=O>[CH:1]1([C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:15]#[N:16])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc(CBr)cc1)C1CCC1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1ccc(C(=O)C2CCC2)cc1

Procedure:
α-Bromo-p-tolyl cyclobutyl ketone (18.5 g) in dimethylformamide (50 ml) was added during 35 minutes to sodium cyanide (4 g) in dimethylformamide (100 ml) which was cooled below 10° and stirred. The solution was allowed to warm to 20° during 2 hours and poured into water (1 l). The mixture was extracted with ether (3× 200 ml) and the combined extracts were dried over magnesium sulphate, filtered and evaporated. The residue was extracted with light petroleum (b.p. 60°-80°) (7× 250 ml) and the extracts were evaporated to leave an oil which partly crystallised on standing.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[N+:17]([O-])([OH:19])=[O:18].[OH-].[Na+]>OS(O)(=O)=O>[NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[C:5]([N+:17]([O-:19])=[O:18])[CH:4]=2
Reactant: Nc1c2c(nc3ccccc13)CCCC2=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Nc1c2c(nc3ccc([N+](=O)[O-])cc13)CCCC2=O
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
To 100ml of cold H2SO4 was added 5.00 g of 9-amino-3,4-di-hydroacridin-1(2H)-one. The mechanically stirred solution was cooled to 20° C. and 2.1ml (1 eq) of concentrated HNO3 (70 wt % solution) was added dropwise. Stirring was continued for 15 minutes after the addition, whereupon the reaction was complete. The reaction mixture was poured into excess crushed ice and made basic with a slight excess of 50% NaOH solution. More ice was added during the neutralization to keep the solution cool. The resulting precipitate was filtered and chromatographed over silica gel (EtOAc). The fractions containing the product were evaporated to a solid which was triturated with pentane to yield 4.77 g (79%) of a solid after drying, melting point 254° C. (with decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22]([C:24]3[C:25]([CH3:31])=[N:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)[CH2:12][O:13][CH3:14])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:32]([F:35])([F:34])[F:33].ClC1C=C(C=CC=1)C(OO)=[O:41].N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22]([C:24]3[CH:25]([CH3:31])[N:26]([OH:41])[CH:27]=[CH:28][C:29]=3[CH3:30])=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)[CH2:12][O:13][CH3:14])(=[O:9])=[O:10])=[CH:4][C:3]=1[C:32]([F:35])([F:33])[F:34]
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1c(C)ccnc1C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCN(c1cc(Cl)cnc1C(=O)C1=C(C)C=CN(O)C1C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
To a solution of 4-Chloro-N-[5-chloro-2-(2,4-dimethyl-pyridine-3-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (100 mg, 0.182 mmol) in 3.5 mL of DCM was added meta-chloroperoxybenzoic acid (77%, 95 mg, 0.424 mmol). After thirty hours the crude mixture was added 1.0 ml of pyridine and the mixture was concentrated. The mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated. The crude was used at next step without any further purification. MS: (M+H)/z=564.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]([OH:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.[C:33](OC=C)(=[O:35])[CH3:34]>>[C:33]([O:11][C@@H:9]([C@H:8]([C:6]1[CH:5]=[CH:4][C:3]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[C:2]([F:1])[CH:7]=1)[CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH3:10])(=[O:35])[CH3:34]
Reactant: C=COC(C)=O
Reactant: CC(O)C(CCc1ccccc1)c1ccc(-c2ccccc2)c(F)c1
Solvent: CCN(CC)CC
Product: CC(=O)O[C@H](C)[C@@H](CCc1ccccc1)c1ccc(-c2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
10.4 g of (2RS,3SR)-3-(2-fluoro-4-biphenylyl)-5-phenylpentan-2-ol was dissolved in 100 ml of vinyl acetate, and 4.3 ml of triethylamine was added. Then, 518 mg of immobilized lipase (Toyothium LIP) was added, followed by stirring at room temperature for 5 days. The enzyme was filtered off and washed with ethyl acetate. The filtrate and the washing liquid were put together, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1→5/1) to obtain 5.47 g of (2R,3S)-2-acetoxy-3-(2-fluoro-4-biphenylyl)-5-phenylpentane and 4.79 g of the above identified compound, respectively, as colorless oily substances. The absolute configuration of the above identified compound was determined by Mosher method (J. Am. Chem. Soc., vol. 113, p. 4092 (1991)).