Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:12][C@H:13]([CH2:17]O)[CH:14]([CH3:16])[CH3:15]>ClC1C=CC=CC=1>[CH:14]([C@H:13]1[CH2:17][O:11][C:9]([CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:12]1)([CH3:16])[CH3:15]
Reactant: CC(C)[C@H](N)CO
Reactant: O=C(O)CCc1ccccc1
Solvent: Clc1ccccc1
Product: CC(C)[C@H]1COC(CCc2ccccc2)=N1
Yield: 86 %

Procedure:
Under an argon atmosphere, a mixture of 3-phenylpropionic acid (3.0 mmol), (L)-valinol (3.6 mmol), Zn4(OCOCF3)6O (0.15 mmol) and chlorobenzene (5 mL) was heated under reflux for 12 hours. From the resulting solution, the solvent was removed using an evaporator, and the residues were purified by silica gel column chromatography (hexane/ethyl acetate=10/1 (V/V)) to give (S)-4-isopropyl-2-(2-phenylethyl)-1,3-oxazoline in 86% yield.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[CH3:12][Si:13](Cl)([CH3:15])[CH3:14]>>[CH3:12][Si:13]([CH3:15])([CH3:14])[N:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C1CCNCC1
Reactant: C[Si](C)(C)Cl
Product: CCOC(=O)C1CCN([Si](C)(C)C)CC1

Procedure:
In an alternative method, ethyl piperidin-4-ylcarboxylate was reacted with trimethylsilyl chloride, yielding ethyl N-trimethylsilylpiperidin-4-ylcarboxylate (B). Intermediate (B) was then reacted with a two to three molar excess of the Grignard reagent of an appropriately substituted halide, as described above, affording a 4-[bis(substituted)hydroxymethyl]piperidine (C), for example 4-[bis(4-trifluoromethylphenyl)hydroxymethyl]piperidine. Intermediate (C) was reacted with an appropriately substituted phenylalkyl halide, as described above, yielding the corresponding intermediate N-(substituted alkyl)-4-[bis(substituted)hydroxymethyl]piperidine (I). The N-oxide of (I) and the targeted salts and betaines were prepared as describes above.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2[N:6]([C:8]([CH3:11])=[N:9][N:10]=2)[N:7]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:12]([CH2:26][C:25]2[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)[C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])[C:5]2[N:6]([C:8]([CH3:11])=[N:9][N:10]=2)[N:7]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Cc1nnc2c(NC(=O)OC(C)(C)C)cc(Cl)nn12
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2cc(Cl)nn3c(C)nnc23)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 112.5 using tert-butyl (6-chloro-3-methyl-[1,2,4]triazolo[4,3-b]pyridazin-8-yl)carbamate (Step 112.4) and 4-methoxybenzylchloride at 80° C. for 1 hr. The crude product was purified by silica gel column chromatography (hexane/EtOAc 10-25%). tR: 5.35 min (HPLC 1); tR: 1.19 min (LC-MS 2); ESI-MS: 404 [M+H]+ (LC-MS 2); Rf=0.74 (hexane/EtOAc 1:1) Step 126.2: tert-butyl (6-(4-(4-chlorophenyl)-1-cyclopropyl-3-methyl-6-oxopyrrolo[3,4-c]pyrazol-5
Reaction SMILES: [CH3:1][S:2][C:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[NH:4].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:25]([C:26](O)=[O:27])=[C:24]([CH3:29])[O:23][N:22]=2)=[CH:17][CH:16]=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[C:25]([C:26]([N:5]([C:3]([S:2][CH3:1])=[NH:4])[C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])=[O:27])=[C:24]([CH3:29])[O:23][N:22]=2)=[CH:19][CH:20]=1
Reactant: CSC(=N)NC(=O)OC(C)(C)C
Reactant: COc1ccc(-c2noc(C)c2C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(-c2noc(C)c2C(=O)N(C(=N)SC)C(=O)OC(C)(C)C)cc1
Reaction time: 3 h
Yield: 59.2 %

Procedure:
A mixture of tert-butyl methylthiocarbonoimidoylcarbamate (Preparation AU, 0.98 g, 5.16 mmol), 3-(4-methoxyphenyl)-5-methyl-4-isoxazolecarboxylic acid (Preparation Y, 1.17 g, 5 mmol), EDCI (1.2 g, 6.26 mmol) and DIPEA (1 g, 7.75 mmol) in DCM (30 mL) was stirred for 3 hours. The solvent was concentrated by rotovap and residue was purified by column with EtOAc/DCM (5/95) as the eluant. The product was obtained as a white solid (1.2 g, 60%). 1H NMR (CD3OD): δ 1.52 (s, 9H), 1.89 (s, 3H), 2.76 (s, 3H), 3.86 (s, 3H), 7.00, 7.02 (d, 2H), 7.47, 7.49 (d, 2H). MH+=406.19
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:42])=[CH:4][C:5]([O:40][CH3:41])=[C:6]([CH:39]=1)[C:7]([NH:9][C@H:10]1[CH2:15][CH2:14][N:13]([CH:16]([CH3:36])[CH2:17][C:18]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH2:12][C@H:11]1[O:37][CH3:38])=[O:8].ClCCl.[C:46](Cl)(=[O:50])[CH2:47][CH2:48][CH3:49]>C(N(CC)CC)C>[Cl:42][C:3]1[C:2]([NH:1][C:46](=[O:50])[CH2:47][CH2:48][CH3:49])=[CH:39][C:6]([C:7]([NH:9][C@H:10]2[CH2:15][CH2:14][N:13]([CH:16]([CH3:36])[CH2:17][C:18]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:19]([N:21]([CH3:22])[CH3:23])=[O:20])[CH2:12][C@H:11]2[O:37][CH3:38])=[O:8])=[C:5]([O:40][CH3:41])[CH:4]=1
Reactant: COc1cc(Cl)c(N)cc1C(=O)N[C@H]1CCN(C(C)CC(C(=O)N(C)C)(c2ccccc2)c2ccccc2)C[C@H]1OC
Reactant: CCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)Nc1cc(C(=O)N[C@H]2CCN(C(C)CC(C(=O)N(C)C)(c3ccccc3)c3ccccc3)C[C@H]2OC)c(OC)cc1Cl
Reaction time: 0.25 h
Yield: 46.5 %

Procedure:
To a stirred solution of 6.52 parts of cis-4-[(5-amino-4-chloro-2-methoxybenzoyI)amino]-3-methoxy-N,N,γ-trimethyl-α,α-diphenyl-1piperidinebutanamide in 195 parts of dichloromethane were added 2.6 parts of butanoyl chloride. After stirring for 15 minutes, 2.94 parts of N,N-diethylethanamine were added. The whole was stirred overnight at room temperature. The reaction mixture was washed successively with a sodium carbonate solution and water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was stirred in 2,2'-oxybispropane. The product was filtered off and dried, yielding 3.39 parts (46.5%) of cis-4-[[4-chloro-2-methoxy-5-[(1-oxobutyl)amino]benzoyl]amino]-3-methoxy-N,N,γ-trimethyl-α,α-diphenyl-1-piperidinebutanamide; mp. 130.7° C. (compound 65).
Reaction SMILES: [CH:1]1([C:5]2[C:13]([C:14]3[NH:15][C:16]([CH2:19][O:20][CH3:21])=[CH:17][N:18]=3)=[CH:12][C:8]([C:9](O)=[O:10])=[C:7]([CH3:22])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[NH:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH:1]1([C:5]2[C:13]([C:14]3[NH:15][C:16]([CH2:19][O:20][CH3:21])=[CH:17][N:18]=3)=[CH:12][C:8]([C:9]([N:24]3[CH2:29][CH2:28][CH:27]([C:30]4[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=4)[CH2:26][CH2:25]3)=[O:10])=[C:7]([CH3:22])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Reactant: COCc1cnc(-c2cc(C(=O)O)c(C)cc2C2CCC2)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: COCc1cnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25.6 %

Procedure:
To a round-bottom flask was added a solution of 4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoic acid (compound 246.4, 50.0 mg, 0.150 mmol, 1.00 equiv, 90%) in N,N-dimethylformamide (3 mL). 4-(Piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 41.0 mg, 0.170 mmol, 1.10 equiv), EDC.HCl (64.0 mg, 0.330 mmol, 2.00 equiv), and 4-dimethylaminopyridine (41.0 mg, 0.340 mmol, 2.00 equiv) were added to the reaction. The resulting solution was stirred for 3 h at 25° C., then quenched with water and extracted with 2×30 mL of ethyl acetate. The combined organic layers were concentrated in vacuo. The crude product (˜50 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (26.0% CH3CN up to 42.0% in 7 min, up to 100.0% in 2 min, down to 26.0% in 1 min); Detector, Waters 2489 254&220 nm. The fractions containing pure compound were combined and lyophilized to yield 18 mg (25%) of the title compound as a white solid. m/z (ES+) 469 (M+H)+. 1H NMR (300 MHz, CD3OD): δ 7.73-7.64 (m, 3H), 7.52-7.32 (m, 4H), ˜4.9 (1H partially obscured by water peak), 4.60 (s, 2H), 3.81-3.68 (m, 1H), 3.68-3.52 (m, 1H), 3.46 (s, 3H), 3.35-3.22 (m, 1H partially obscured by methanol solvent peak), 3.09-2.95 (m, 2H), 2.52 & 2.41 (2 singlets, amide rotamers, Ar—CH3, 3H), 2.16-1.97 (m, 6H), 1.94-1.58 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1.Cl.[CH3:33][NH2:34]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH2:28][NH:34][CH3:33])=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1
Reactant: O=Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1
Reactant: CN
Agent: Cl
Product: CNCc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1

Procedure:
The title compound was prepared following the procedure described for Example 94, but starting from 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde, obtained as described in Example 113, Step 1, (100 mg; 0.24 mmol) and methylamine hydrochloride (32.7 mg; 0.48 mmol) to give Example 129 as a white solid. 1H NMR: (DMSO-d6, 400 MHz) δ 8.76-8.73 (2H, m), 7.97-7.87 (3H, m), 7.76-7.69 (1H, m), 7.64-7.49 (6H, m), 3.76 (2H, s), 2.31 (3H, s). LC/MS (Method C): 428 (M+H)+. HPLC (Method E) Rt 2.14 min (Purity: 98.9%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]=O)=[CH:4][CH:3]=1.[C:11]([CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:13][CH2:14][CH3:15])=[O:12]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]=[CH:16][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CCc1ccc(Br)cc1
Solvent: ClCCl
Product: CCOC(=O)C=CCc1ccc(Br)cc1
Reaction time: 16 h

Procedure:
To a cold solution (-78° C.) of 15 g (62 mmol) of ethyl (4-bromophenyl)acetate (Compound A) in 150 ml of CH2Cl2 was added dropwise (over a span of 1 hour) 65 ml (65 mmol) of diisobutylaluminum hydride (DIBAL-H, 1M solution in hexane). After the DIBAL-H addition was complete, the reaction was stirred at -78° C. for an additional hour. The reaction was quenched by the dropwise addition of methanol (10 ml), followed by water (10 ml) and 10% HCl (40 ml). The mixture was then warmed to 0° C., stirred for 10 minutes and then washed with water (15 ml), 10% aqueous NaHCO3 (10 ml) and brine (10 ml). The organic phase was dried over MgSO4 and the solvent distilled off at ambient temperature to give crude (4-bromophenyl)acetaldehyde. To a cold solution (0° C.) of this crude aldehyde in 150 ml of CH2Cl2 was added a solution of 26 g (74.6 mmol) of (carbethoxymethylene)triphenylphosphorane in 50 ml of CH2Cl2. The mixture was stirred for 16 hours, concentrated in vacuo and purified by flash chromatography (silica, 10% EtOAc-hexane) to give ethyl 4-(4-bromophenyl)but-2-enoate as a mixture of E:Z isomers. This isomeric mixture was dissolved in 150 ml of EtOAc and hydrogenated over 1 g of 10% Pd/C for 6 hours. The catalyst was filtered off and the filtrate concentrated in vacuo to give the title compound as a white solid.
Reaction SMILES: COC1C=CC(C([NH:18][C:19]([C:21]2[N:26]=[CH:25][C:24]([NH:27][CH2:28][CH2:29][CH2:30][NH:31]C(=O)OC(C)(C)C)=[CH:23][C:22]=2[NH:39][C:40]2[CH:45]=[C:44]([CH3:46])[CH:43]=[C:42]([CH3:47])[N:41]=2)=[O:20])C2C=CC(OC)=CC=2)=CC=1.C([SiH](CC)CC)C.[C:55]([OH:61])([C:57]([F:60])([F:59])[F:58])=[O:56]>ClCCl>[OH:61][C:55]([C:57]([F:60])([F:59])[F:58])=[O:56].[NH2:31][CH2:30][CH2:29][CH2:28][NH:27][C:24]1[CH:23]=[C:22]([NH:39][C:40]2[CH:45]=[C:44]([CH3:46])[CH:43]=[C:42]([CH3:47])[N:41]=2)[C:21]([C:19]([NH2:18])=[O:20])=[N:26][CH:25]=1
Reactant: COc1ccc(C(NC(=O)c2ncc(NCCCNC(=O)OC(C)(C)C)cc2Nc2cc(C)cc(C)n2)c2ccc(OC)cc2)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)nc(Nc2cc(NCCCN)cnc2C(N)=O)c1
Reaction time: 2 h

Procedure:
To a solution of tert-butyl {3-[(6-{[bis(4-methoxyphenyl)methyl]carbamoyl}-5-[(4,6-dimethylpyridin-2-yl)amino]pyridin-3-yl)amino]propyl}carbamate (51 mg, 0.080 mmol) in dichloromethane (4 mL) was added triethylsilane (0.064 mL, 0.40 mmol) followed by TFA (0.8 mL) at ambient temperature. After 2 hours, the reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse phase HPLC (acetonitrile/water with 0.1% TFA, linear gradient) to afford 5-[(3-aminopropyl)amino]-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carboxamide TFA salt. MS ESI calc'd. for C16H23N6O [M+H]+ 315. found 315. 1H NMR (500 MHz, DMSO-d6) δ 11.74 (s, 1H), 8.22-8.04 (br s, 1H), 7.92-7.76 (m, 4H), 7.58 (s, 1H), 7.37 (s, 1H), 6.74-6.66 (br s, 2H), 3.22-3.16 (m, 2H), 2.94-2.84 (m, 2H), 2.40 (s, 3H), 2.25 (s, 3H), 1.90-1.82 (m, 2H).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=O.[NH2:15][C:16]([NH2:18])=[S:17].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[CH:4]=[CH:3][N:18]=[C:16]([SH:17])[N:15]=2)=[CH:8][CH:9]=1
Reactant: NC(N)=S
Reactant: CN(C)/C=C/C(=O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Sc1nccc(-c2ccc(Cl)cc2)n1
Temperature: 85 °C

Procedure:
To a solution of (2E)-3-(dimethylamino)-1-(4-chlorophenyl)prop-2-en-1-one (1.5 g, 7.2 mmol) in ethanol (25 ml) was added thiourea (0.60 g, 7.9 mmol) and potassium carbonate (K2CO3) (1.19 g. 8.63 mmol). The resulting suspension was heated to 85° C. for 12 hours then cooled to ambient temperature. The resulting solid was collected and thoroughly washed with water and hexanes to provide a beige solid: EI-MS (m/z) 222 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[OH:17][NH3+:18].O>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[N:18][OH:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: [NH3+]O
Reactant: O=C(Cn1cncn1)c1ccc(Cl)cc1Cl
Solvent: O
Solvent: CCO
Product: ON=C(Cn1cncn1)c1ccc(Cl)cc1Cl
Yield: 42.8 %

Procedure:
106.8 g (0.44 mol) of 1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-1-ethanone are dissolved in 780 ml of ethanol, 48 g of hydroxylammonium nydrochloride are added and the mixture is heated under reflux for five hours. Thereafter, 1000 ml of water are added and the reaction mixture is filtered. 51 g (45% of theory) of 1-(2,4-dichlorophenyl)-1-oximino-2-(1,2,4-triazol-1-yl)-ethane of melting point 165°-170° C. are obtained. ##STR15##
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O)=[O:4].[NH3:21].C=O>CO>[Cl:20][C:17]1[CH:18]=[CH:19][C:6]2[NH:5][C:3](=[O:4])[CH2:2][N:21]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7]=2[CH:16]=1
Reactant: N
Reactant: O=C(CCl)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: C=O
Solvent: CO
Product: O=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Temperature: 25 °C
Yield: 77.3 %

Procedure:
A mixture of methanol (275 ml.) and 2-chloroacetamido-5-chlorobenzophenone (154.2 g., 0.5 mol) was heated to reflux with a steady stream of ammonia bubbling in. At reflux 37% formaldehyde solution (237 ml) was fed in over ca. 40 minutes. The reaction mixture was then heated under reflux for 5 hours. The flow of ammonia was stopped and the slurry of crystals was cooled to room temperature, filtered, washed with methanol (2 × 125 ml), hot water (4 × 500 ml) and dried. There was obtained 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (104.6 g., 77.3%), melting at 211.5° to 214.5° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][NH:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH2:39][CH:38]([C:42](O)=[O:43])[CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2[C:42]([CH:38]2[CH2:39][CH2:40][CH2:41][N:36]([C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])[CH2:37]2)=[O:43])=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCCN1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)N2CCCCC2C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
Piperidine-2-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (74) (1.00 g; 2.64 mmol) is dissolved in methylene chloride (25 mL) at ambient temperature. 1-tert-Butoxycarbonyl-piperidine-3-carboxylic acid (0.73 g; 3.17 mmol), N,N-diisopropylethylamine (0.75 g; 5.81 mmol) and PyBOP (1.65 g; 3.17 mmol) are added sequentially. The reaction is stirred for 19 hours at room temperature, then concentrated under reduced pressure. The residue is purified via silica gel chromatography (30%→50% ethyl acetate in hexanes) affording the desired product (81) as a solid. ESMS: MH+ 590.6
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]2[C:18]([NH2:19])=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1([S:25](N2C=C[N+](C)=C2)(=[O:27])=[O:26])C=CN=C1.FC(F)(F)S([O-])(=O)=O>CC#N>[C:1]1([N:7]2[S:25](=[O:27])(=[O:26])[NH:19][C:18]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][N:16]=4)[CH:11]=[CH:10][C:9]=3[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1c(CNc2ccccc2)ccc2cccnc12
Reactant: C[n+]1ccn(S(=O)(=O)n2ccnc2)c1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CC#N
Product: O=S1(=O)Nc2c(ccc3cccnc23)CN1c1ccccc1
Temperature: 25 °C
Yield: 4 %

Procedure:
A solution of 7-phenylaminomethyl-quinolin-8-ylamine (Intermediate 206) (350 mg, 1.4 mmol) and 1-(1H-imidazole-1-sulfonyl)-3-methyl-1H-imidazol-3-ium; trifluoromethanesulfonate (762 mg, 2.1 mmol) in MeCN (10 ml) was stirred at 0° C. then allowed to warm to room temperature overnight. The reaction mixture was concentrated in vacuo and the crude residue was purified by preparative HPLC (basic conditions) to give the title compound (18 mg, 4%).
Reaction SMILES: [C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C1C=CC([C:20]#[C:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[S:28][CH:27]([CH3:32])[CH2:26][C:25]3([CH3:34])[CH3:33])=CC=1)C.[OH-].[K+]>>[CH3:32][CH:27]1[CH2:26][C:25]([CH3:34])([CH3:33])[C:24]2[C:29](=[CH:30][CH:31]=[C:22]([C:21]3[CH:4]=[CH:3][C:2]([C:1]([OH:9])=[O:8])=[C:7]([C:6]#[CH:5])[CH:20]=3)[CH:23]=2)[S:28]1
Reactant: O=C([O-])c1ccccc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC(C)S3)cc1
Agent: [K+]
Agent: [OH-]
Product: C#Cc1cc(-c2ccc3c(c2)C(C)(C)CC(C)S3)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 37 mg (0.102 mmol) of ethyl 4(2,4,4-trimethyl-6-thiochromanyl)-ethynyl]benzoate (Compound 56) and 11 ml of ethanolic potassium hydroxide solution was stirred at room temperature for 16 hours. The solvent was removed in vacuo and the residue was taken up with water and then acidified with IN HCl. The mixture was extracted with three portions of ether. The organic extracts were combined and then washed with water and saturated NaCl solution and dried (MgSO4). The solvent was removed in-vacuo to give the title compound as an orange solid PMR (CDCl3): 1.17 (3H, s), 1.26 (3H, d, J=6.3 Hz), 1.34 (3H, s), 1.58 (1H, t, J=13.1 Hz), 1.92 (1H, dd, J=13.1 Hz, 2.4 Hz), 3.33-3.48 (1H, m), 7.20 (1H, d, J=8.1 Hz), 7.21 (1H, s), 7.45 (1H, d, J=8.1 Hz), 7.62 (2H, d, 8.4 Hz), 7.95 (2H, d, J=8.4 Hz).
Reaction SMILES: B.[CH2:2]([O:18][CH2:19][C:20]1[O:25][CH2:24][CH2:23][CH2:22][CH:21]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[OH-:26].[Na+].OO>O1CCCC1.O>[CH2:2]([O:18][CH2:19][C@H:20]1[C@H:21]([OH:26])[CH2:22][CH2:23][CH2:24][O:25]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCCCCCOCC1=CCCCO1
Reactant: [OH-]
Agent: B
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCCCCCOC[C@@H]1OCCC[C@H]1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
11 ml of a 1M tetrahydrofuran solution of borane was added dropwise, whilst ice-cooling, to a solution of 5.53 g of 6-hexadecyloxymethyl-3,4-dihydro-2H-pyran (prepared as described in Preparation 1) dissolved in 12 ml of tetrahydrofuran. The reaction mixture was stirred at room temperature for 3 hours, after which 4 ml of a 3N aqueous solution of sodium hydroxide were added to it, and then 4 ml of 30% hydrogen peroxide were added dropwise into it at 30°-40° C. The reaction mixture was then stirred at room temperature for 1 hour, after which it was poured in water. The mixture was then washed with a saturated aqueous solution of sodium chloride, and then the organic layer was separated, dried and condensed by evaporation under reduced pressure. The oily residue was subjected to column chromatography through 100 g of silica gel. The fraction eluted with mixtures of ethyl acetate and hexane ranging from 1:5 to 1:2 by volume gave 5.18 g of the title compound as crystals. Recrystallization from hexane gave needles, melting at 41.5°-43° C.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[C:6]([F:19])[CH:5]=1.[OH-].[Na+]>O1CCOCC1.CCOC(C)=O>[C:15]([O:14][C:12]([NH:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:20])=[O:2])=[CH:5][C:6]=1[F:19])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)c1ccc(CNC(=O)OC(C)(C)C)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1F
Reaction time: 18 h
Yield: 100.4 %

Procedure:
To a solution of 4-(tert-butoxycarbonylamino-methyl)-3-fluorobenzoic acid methyl ester from Example E3.5 (640 mg, 2.25 mmol) in dioxan (40 ml) was added 1N NaOH (4.5 ml, 4.5 mmol). The mixture was stirred for 18 h, diluted with EtOAc, washed with 1N KHSO4, water and brine and concentrated in vacuo to give a white solid identified as the title compound (608 mg, 100%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[C:6]2[CH2:11][CH2:10][O:9][C:8](=[O:12])[C:7]=12.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[N:19]1([C:2]2[N:3]=[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:5]=[C:6]3[CH2:11][CH2:10][O:9][C:8](=[O:12])[C:7]=23)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: O=C1OCCc2cc(-c3ccccc3)nc(Cl)c21
Reactant: C1COCCN1
Product: O=C1OCCc2cc(-c3ccccc3)nc(N3CCOCC3)c21

Procedure:
128 mg (98%) of 8-morpholine-4-yl-6-phneyl-3,4-dihydro-pyrano[3,4-c]pyridine-1-on was obtained in white solid using the method same as in Example 35 except that 110 mg of 8-chloro-6-phenyl-3,4-dihydro-pyrano[3,4-c]pyridine-1-on was added with morpholine instead of 4-fluoro-aniline.