Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])[C:9](=[O:16])[CH2:8][O:7][C:6]=2[CH:17]=1.I.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](SC)=[NH:25]>C(O)C.C([O-])(O)=O.[Na+]>[CH3:15][N:13]([CH3:14])[CH2:12][CH2:11][N:10]1[C:9](=[O:16])[CH2:8][O:7][C:6]2[CH:17]=[C:2]([NH:1][C:24]([C:20]3[S:19][CH:23]=[CH:22][CH:21]=3)=[NH:25])[CH:3]=[CH:4][C:5]1=2
Reactant: CN(C)CCN1C(=O)COc2cc(N)ccc21
Reactant: CSC(=N)c1cccs1
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CN(C)CCN1C(=O)COc2cc(NC(=N)c3cccs3)ccc21
Reaction time: 18 h
Yield: 87.5 %

Procedure:
A solution of 7-amino-4-(2-(dimethylamino)ethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (0.125 g, 0.531 mmol) in dry ethanol (10 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (0.3 g, 1.062 mmol) at room temperature and stirred overnight (18 hours). At this time, additional methyl thiophene-2-carbimidothioate hydroiodide (0.3 g, 1.062 mmol) was added, and stirring was continued for another 24 hours. The reaction was diluted with saturated NaHCO3 solution (20 mL), and the product was extracted into CH2Cl2 (2×20 mL). The combined CH2Cl2 layers were washed with brine (15 mL) and dried (Na2SO4). The solvent was evaporated, and the crude material was purified by column chromatography (5:95 (2M NH3 in MeOH):CH2Cl2) to obtain the title compound 5 (0.16 g, 88%) as a solid. 1H NMR (DMSO-d6) δ 2.19 (s, 6H), 2.43 (t, 2H, J=6.9 Hz), 3.97 (t, 2H, J=6.9 Hz), 4.58 (s, 2H), 6.48-6.58 (m, 4H), 7.06-7.14 (m, 2H), 7.60 (d, 1H, J=5.1 Hz), 7.74 (d, 1H, J=3.3 Hz); ESI-MS (m/z, %): 345 (MH+, 100), 128 (85); ESI-HRMS calculated for C17H21N4O2S (MH+), calculated: 345.1379; observed: 345.1384; HPLC-purity: 93.15% by area.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][CH:24]([CH:27]=O)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[N+:29]([C:32]1[CH:40]=[C:39]2[C:35]([CH2:36][CH2:37][NH:38]2)=[CH:34][CH:33]=1)([O-:31])=[O:30].C(O)(=O)C>ClCCl.C(OCC)(=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][CH:24]([CH2:27][N:38]2[C:39]3[C:35](=[CH:34][CH:33]=[C:32]([N+:29]([O-:31])=[O:30])[CH:40]=3)[CH2:36][CH2:37]2)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)C1
Reactant: O=[N+]([O-])c1ccc2c(c1)NCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CN2CCc3ccc([N+](=O)[O-])cc32)C1
Reaction time: 2 h

Procedure:
91.5 mmol (19.4 g) of solid sodium triacetoxyborohydride are added slowly, at 20° C., to a solution of 60.8 mmol (12.1 g) of 1-(tert-butyloxycarbonyl)-3-formylpyrrolidine, 60.8 mmol (10 g) of 6-nitroindoline and 60.8 mmol (3.65 g) of acetic acid in 100 ml of dichloromethane. After 2 hours' stirring, the reaction mixture is diluted with ethyl acetate. The organic phase is washed with water until pH=8, and the aqueous phase is then extracted with dichloromethane. After removal of the solvent by evaporation, the expected product is obtained.
Reaction SMILES: [CH3:1][N:2]([CH2:22][C@H:23]([C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[CH2:24][CH:25]=C)[C:3](=[O:21])[C:4]1[CH:9]=[C:8]([N:10]2[C:14]([C:15]([F:18])([F:17])[F:16])=[N:13][N:12]=[N:11]2)[CH:7]=[CH:6][C:5]=1[O:19][CH3:20].C[N+]1([O-])CC[O:38]CC1.S([O-])([O-])(=O)=S.[Na+].[Na+].I([O-])(=O)(=O)=O.[Na+]>[Os](=O)(=O)(=O)=O.O.O1CCCC1.CC(C)=O.C(O)(C)(C)C.O>[CH3:1][N:2]([CH2:22][C@H:23]([C:27]1[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=1)[CH2:24][CH:25]=[O:38])[C:3](=[O:21])[C:4]1[CH:9]=[C:8]([N:10]2[C:14]([C:15]([F:16])([F:18])[F:17])=[N:13][N:12]=[N:11]2)[CH:7]=[CH:6][C:5]=1[O:19][CH3:20]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CC[C@H](CN(C)C(=O)c1cc(-n2nnnc2C(F)(F)F)ccc1OC)c1ccc(F)cc1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(-n2nnnc2C(F)(F)F)cc1C(=O)N(C)C[C@@H](CC=O)c1ccc(F)cc1
Reaction time: 3 h

Procedure:
Combine (S)-N-methyl-N-(2-(4-fluorophenyl)pent-4-enyl)-2-methoxy-5-(5-trifluoromethyl-1H-tetrazol-1-yl)benzamide (10 mmol), acetone/t-butanol/water (2/1/1, 56 mL), and a solution of N-methylmorpholine N-oxide (2.6 mL, 50% in water, 12.7 mmol). Add a solution of osmium tetraoxide (2.6 mL, 4% in water, 0.44 mmol). After 3 hours, evaporate in vacuo to remove most of the acetone and partition the evaporated reaction mixture between dichloromethane and an aqueous 10% solution of sodium thiosulfate. Separate the layer, dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Combine the residue, tetrahydrofuran (70 mL), and water (17.5 mL). Add sodium meta-periodate (3.2 g). After 1.5 hours, filter the reaction mixture, rinse the solids with dichloromethane, and evaporate the filtrate give the title compound.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:23])[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O.[NH:24]1[CH:28]=[CH:27][C:26]([NH2:29])=[N:25]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[NH:24]1[CH:28]=[CH:27][C:26]([NH:29][CH2:18][C:17]2[CH:16]=[C:15]([CH:22]=[CH:21][CH:20]=2)[O:14][CH2:13][CH:12]([OH:23])[CH2:11][N:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)=[N:25]1
Reactant: O=Cc1cccc(OCC(O)CN2CCc3ccccc3C2)c1
Reactant: Nc1cc[nH]n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: OC(COc1cccc(CNc2cc[nH]n2)c1)CN1CCc2ccccc2C1
Temperature: 60 °C
Yield: 11 %

Procedure:
To a solution of 3-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropoxy)benzaldehyde (200 mg, 0.64 mmol) in DCM (15 mL) was added 1H-pyrazol-3-amine (80 mg, 0.96 mmol). The solution was heated at 60° C. for 0.5 h. NaBH(OAc)3 (204 mg, 0.96 mmol) was then added into the reaction mixture which was heated at 60° C. for another 1 h. The reaction mixture was quenched by adding 1 N HCl aqueous solution and diluted with DCM and washed with NaHCO3 aqueous solution. The separated organic layer was concentrated and the crude product was purified by preparative HPLC purification. (26 mg, yield 11%). MS (ESI+) e/z: 379.1 [M+1]. 1H NMR (MeOD, 400 MHz), δ ppm: 7.33-7.18 (m, 7H), 7.00-6.96 (m, 2H), 6.84-6.80 (m, 1H), 4.48-4.44 (m, 3H), 4.28 (s, 1H), 4.06-3.98 (m, 2H), 3.59-3.56 (m, 2H), 3.42-3.39 (m, 2H), 3.20-3.15 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[O:14])[CH2:9][CH:8]2[CH2:24][CH:25]=[O:26])=[CH:4][CH:3]=1.[CH3:29][Mg]Br.[NH4+].[Cl-]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[O:14])[CH2:9][CH:8]2[CH2:24][CH:25]([OH:26])[CH3:29])=[CH:27][CH:28]=1
Reactant: C[Mg]Br
Reactant: O=CCC1CN(C(=O)COc2ccc(Cl)cc2)CCN1Cc1ccc(F)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)CC1CN(C(=O)COc2ccc(Cl)cc2)CCN1Cc1ccc(F)cc1
Yield: 89.5 %

Procedure:
To a solution of 4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-3-((formyl)methyl)piperazine (0.31 g, 0.77 mmol) in anhydrous THF (20 mL) was added methyl magnesium bromide (0.26 mL, 0.77 mmol, 3.0 M solution in ether). The resultant mixture was stirred overnight at ambient temperature. At that time the mixture was poured into 5% aqueous NH4Cl solution and extracted with two portions of ether. The combined organic extracts were washed with brine, then dried over MgSO4, filtered and concentrated in vacuo to afford a yellow oil. Purification by flash column chromatography on silica gel afforded 0.29 g of 4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-3-(2-hydroxypropyl)piperazine, as a clear, colorless oil, which was converted to its hydrochloride salt; NMR (CDCl3) 7.6 (m, 2), 7.2 (m, 4), 6.9 (m, 2), 4.7 (m, 2), 4.4-3.0 (m, 10), 2.4-1.4 (m, 2), 1.3-1.0 (m, 3) ppm.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:11]=[CH:10][C:9]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N:26]([CH3:35])[C:27]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:28])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH3:35][N:26]([C:22]1[CH:21]=[C:20]([C:9]2[CH:10]=[CH:11][C:12]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:13][C:8]=2[O:7][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:25]=[CH:24][CH:23]=1)[C:27]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:28]
Reactant: CCCCCI
Reactant: CCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCCCCC)c1

Procedure:
In a manner similar to that of Example (25a), by reaction of 500 μL (3.8 mmol, 3.8 eq) of 1-iodopentane and 400 mg (1.0 mmol, 1 eq) of methyl 3-[2-hydroxy-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoate in 10 ml of methyl ethyl ketone in the presence of 500 mg (3.61 mmol, 3.6 eq) of potassium carbonate at 80° C. for 12 hours, methyl 3-[3′-(1-methyl-3-pentylureido)-2-pentyloxybiphenyl-4-yl]propanoate is obtained in oil form and is used in the following reaction without further purification.
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[C:15](Cl)(=[O:19])[CH:16]([CH3:18])[CH3:17].C(N(CC)CC)C>O1CCCC1>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:14][C:15](=[O:19])[CH:16]([CH3:18])[CH3:17]
Reactant: NC1CCc2oc3ccccc3c2C1
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1ccc2oc3c(c2c1)CCCC3
Yield: 52.1 %

Procedure:
Following the procedure of Example 1, tetrahydro-dibenzofuran-2-ylamine (0.94 g, 5.0 mmol), isobutyryl chloride (0.56 mL, 5.2 mmol), and triethylamine (2.1 mL, 15 mmol) in tetrahydrofuran (30 mL) provided N-(6,7,8,9-tetrahydro-dibenzofuran-2-yl)-isobutyramide (0.67 g). Mp 206.5-208.0° C.;MS m/z 258 ([M+H]+); Anal. Calcd. for C15H17NO2: C, 74.68; H, 7.44; N, 5.44; Found: C, 74.43; H, 7.39; N, 5.50.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:24](=[O:25])[C:23]2[C@@H:22]3[C:26]([CH3:28])([CH3:27])[C@@:19]([CH3:29])([CH2:20][CH2:21]3)[C:18]=2[NH:17]1>[OH-].[Na+]>[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:24](=[O:25])[C:23]2[C@@H:22]3[C:26]([CH3:28])([CH3:27])[C@@:19]([CH3:29])([CH2:20][CH2:21]3)[C:18]=2[N:17]1[CH3:5]
Reactant: COS(=O)(=O)OC
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Agent: [Na+]
Agent: [OH-]
Product: Cn1c2c(c(=O)n1-c1ccc(F)cc1F)[C@H]1CC[C@]2(C)C1(C)C
Yield: 10.6 %

Procedure:
A mixture of dimethyl sulfate (0.56 mL, 5.9 mmol) and (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 14; 1.82 g, 6.0 mmol) in 1 M NaOH (25 mL) was heated at 45 degrees for 4.5 h, then a further portion of dimethyl sulfate (0.56 mL, 5.9 mmol) was added and the reaction was heated at 45 degrees overnight. NaOH was added and the mixture was extracted twice with ethyl acetate. The combined organic layers were evaporated and purified by column chromatography, eluting with 10-50% ethyl acetate/dichloromethane followed by recrystallization from ethyl acetate/hexanes to give (4S,7R)-2-(2,4-difluoro-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (199 mg, 11%) as a white solid. ES(+)-MS (M+H) 319.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[O:27]=[S:28]1(=[O:43])[CH2:33][CH2:32][N:31]([C:34]2[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=2)[CH2:30][CH2:29]1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:38](=[O:39])[C:37]3[CH:41]=[CH:42][C:34]([N:31]4[CH2:30][CH2:29][S:28](=[O:43])(=[O:27])[CH2:33][CH2:32]4)=[CH:35][CH:36]=3)[CH2:24][CH2:25]2)=[CH:4]1
Reactant: O=C(O)c1ccc(N2CCS(=O)(=O)CC2)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)c1ccc(N2CCS(=O)(=O)CC2)cc1

Procedure:
The title compound, light yellow solid (116 mg, 82%), MS (ISP) m/z=564.4 [(M+H)+], mp 269° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 4-(1,1-dioxo-1λ6-thiomor-pholin-4-yl)-benzoic acid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]1([S:11][CH2:12][CH2:13][OH:14])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>N1C=CC=CC=1>[C:1]([O:14][CH2:13][CH2:12][S:11][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: OCCSc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OCCSc1ccccc1

Procedure:
Acetylchloride (7.9g), β-phenylthioethyl-alcohol (15.4g) and pyridine (9.5g) were treated according to Example 1. On fractionation, a fraction (17.5g), b.p. 76.0°-77.0° C./0.04mmHg, of β-phenylthioethyl acetate was obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:15][OH:16])[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([CH3:14])=[CH:9][CH:10]=2)[S:5][CH2:4]1.I([O-])(=O)(=O)=[O:18].[Na+]>CO.O>[OH:1][CH2:2][C:3]1([CH2:15][OH:16])[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([CH3:14])=[CH:9][CH:10]=2)[S:5](=[O:18])[CH2:4]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: Cc1ccc2c(c1)SCC(CO)(CO)C2=O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccc2c(c1)S(=O)CC(CO)(CO)C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3,3-bis(hydroxymethyl)-7-methylthiochroman-4-one (300 mg, 1.26 mmol) in MeOH (6 ml) was admixed with a solution of sodium metaperiodate (286 mg, 1.34 mmol) in water (3 ml) and stirred at RT overnight. The reaction mixture was diluted with water (20 ml) and extracted with EtOAc (3×30 ml), the combined organic phases were dried over sodium sulfate and the solvent was removed under reduced pressure. After column chromatography purification of the residue (silica gel, 4:1 cyclohexane/EtOAc, 1% by vol. of acetic acid), the desired product was obtained as a white solid (186 mg, 58% of theory).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:32])=[C:4]([N:8]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.[N-:33]=[N+:34]=[N-:35].[Na+].[Cl-].[NH4+]>CN(C=O)C>[Cl:1][C:2]1[C:3]([CH3:32])=[C:4]([N:8]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)(=[O:23])=[O:24])[CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:33]=[N:34][NH:35][N:21]=3)[CH:15]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(=O)NCc2cccc(C#N)c2)c2cccc(Cl)c2C)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N(CC(=O)NCc2cccc(-c3nn[nH]n3)c2)c2cccc(Cl)c2C)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 25.2 %

Procedure:
300 mg of N2-(3-chloro-2-methylphenyl)-N-(3-cyanobenzyl)-N2-[(4-methylphenyl)sulfonyl]glycinamide was dissolved in 5.00 mL of DMF, and 125 mg of sodium azide and 103 mg of ammonium chloride were added thereto, followed by stirring at 100° C. for 6 hours. The reaction liquid was concentrated under reduced pressure, and to the obtained residue was added water, followed by extraction with chloroform. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by preparative thin layer chromatography (chloroform:methanol=80:20). The obtained product was recrystallized from ethanol/diisopropyl ether to obtain 82.6 mg of N2-(3-chloro-2-methylphenyl)-N2-[(4-methylphenyl)sulfonyl]-N-[3-(2H-tetrazol-5-yl)benzyl]glycinamide.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17](=O)[CH2:18][CH2:19][CH:20]([O:23][CH3:24])[O:21][CH3:22])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([O:30][C:31](=[O:34])[NH:32][NH2:33])([CH3:29])([CH3:28])[CH3:27]>C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17](=[N:33][NH:32][C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:34])[CH2:18][CH2:19][CH:20]([O:23][CH3:24])[O:21][CH3:22])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: COC(CCC(=O)C1CCCN(C(=O)OCc2ccccc2)C1)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: COC(CCC(=NNC(=O)OC(C)(C)C)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1)OC
Reaction time: 4 h
Yield: 94.2 %

Procedure:
The product from step 1 (16.32 g, 46.70 mmol) was dissolved in 100 mL of CH2Cl2 and treated with tert-butylcarbazate (6.48 g, 49.04 mmol) followed by para-toluensulfonic acid monohydrate (0.44 g, 2.33 mmol) and the mixture was stirred 4 h. The mixture was poured into a separatory funnel and extracted with 50 mL 2M aq. Na2CO3. The aqueous phase was extracted with 50 mL of CH2Cl2 and the combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified using an ISCO® instrument (Red-Sep 330, 30%-100% EtOAc hexanes) to give 20.40 g of a clear oil. 1H NMR (300 MHz, DMSO-d6) δ 9.48 (bs, 1H), 7.40-7.28 (m, 5H), 5.04 (s, 2H), 4.32 (m, 1H), 4.05 (bd, 1H), 3.96 (bd, 1H), 3.20 (m, 6H), 2.88-2.63 (m, 2H), 2.31-2.11 (m, 1H), 1.87 (m, 1H), 1.66, (m, 1H), 1.59 (m, 1H), 1.42 (s, 9H), 1.40-1.24 (m, 5H). ES-MS m/z 463.9 [M+Na]+, HPLC RT (min) 3.67
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.O.[C:10]1([CH3:19])[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[O:18])=[CH:12][CH:11]=1>CN(C=O)C>[CH3:1][N:2]1[CH2:3][C:4](=[O:5])[NH:6][C:7]1=[N:8][C:17]([NH:16][C:13]1[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=1)=[O:18]
Reactant: Cc1ccc(N=C=O)cc1
Reactant: CN1CC(=O)N=C1N
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(NC(=O)N=C2NC(=O)CN2C)cc1
Reaction time: 3.5 h

Procedure:
To a stirring suspension of creatinine (11.88 g, 0.105 mole) in 100 ml dry DMF, p-tolylisocyanate (13.31 g- 0.100 mole) is added dropwise over a period of about 15 minutes with cooling. After stirring for 3.5 hrs., the mixture is poured into about 500 ml iced-water to give white crystals of product which are filtered off and washed with water. Recrystallization of the product from acetone-methanol and then from THF-methanol affords the product, 1-(1-methyl-4-oxo-2-imidazolidinylidene)-3-p-tolyl urea. The crystalline particles are reduced to finer size by adding a solution of the thus-obtained product in minimal DMF to about 1.1 liters of vigorously stirring water, filtering off and drying the resultant fine crystals in vacuo for 24 hours; m.p. 198°-200° C. dec.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([NH:7][C:8]([CH3:16])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])=[O:6].CN(CCN(C)C)C.C([Li])(CC)C.CCCCCC.CN([CH:42]=[O:43])C>C1COCC1>[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:4]2[C:3]=1[CH:42]([OH:43])[N:7]([C:8]([CH3:16])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH3:9])[C:5]2=[O:6]
Reactant: CC(C)(NC(=O)c1cccc(F)c1)c1ccccc1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(c1ccccc1)N1C(=O)c2cccc(F)c2C1O
Yield: 93.4 %

Procedure:
In a similar manner to Step 2 of Example 16, 3-fluoro-N-(1-methyl-1-phenylethyl)benzamide (2.00 g, 7.77 mmol) was dissolved in THF (80 mL), and the solution was treated with TMEDA (3.8 mL, 24.9 mmol), sec-butyllithium-hexane solution (1.01 mol/L, 24.6 mL, 24.9 mmol) and DMF (1.30 mL, 17.1 mmol). The mixture was purified by slurry using diisopropylether to obtain 4-fluoro-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (2.07 g, yield 93%).
Reaction SMILES: [CH2:1]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[CH2:25][CH2:26][OH:27])[CH2:2][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][CH2:17][CH3:18].Br[CH2:29][CH2:30][CH2:31][CH2:32][Cl:33].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:33][CH2:32][CH2:31][CH2:30][CH2:29][O:27][CH2:26][CH2:25][CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][N:19]1[CH2:1][CH2:2][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][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCN1CCCCC1CCO
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCN1CCCCC1CCOCCCCCl

Procedure:
2-(1-Octadecyl-2-piperidyl)ethan-1-ol and 1-bromo-4-chlorobutane are reacted in acetone in the presence of potassium carbonate at reflux temperature to obtain 2-[2-(4-chlorobutoxy)ethyl]-1-octadecylpiperidine.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][C:12]([F:14])=[CH:13][C:8]=2[O:7][N:6]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38]>CN(C)C=O>[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].[F:14][C:12]1[CH:11]=[CH:10][C:9]2[C:5]([CH2:4][CH2:3][CH2:2][N:25]3[CH2:24][CH2:23][N:22]([C:19]4[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=4)[CH2:27][CH2:26]3)=[N:6][O:7][C:8]=2[CH:13]=1
Reactant: Fc1ccc2c(CCCCl)noc2c1
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: Fc1ccc(N2CCN(CCCc3noc4cc(F)ccc34)CC2)cc1

Procedure:
A mixture of 5.0 g of 3-(3-chloropropyl)-6-fluoro-1,2-benzisoxazole, 4.0 g of 1-(4-fluorophenyl)piperazine, 10 g of potassium carbonate and a few crystals potassium iodide in 70 ml of dimethylformamide was stirred at 80° C. for 4.5 hr. The mixture was cooled, filtered and concentrated to an oil, which was stirred with water and extracted with ethyl acetate-ether. The organic extracts were washed with water (2×), saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The mixture was filtered and concentrated. The residue was purified by column chromatography (silica gel, tetrahydrofuran) to give an oil. The oil was converted to 4.5 g (45%) of product by treatment with oxalic acid. Two recrystallizations from ethyl acetate/methanol gave the analytical sample, mo 186°-187° C. (dec).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH2:24][C@@H:25]5[CH2:27][O:26]5)=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[OH:26][C@@H:25]([CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)[CH2:24][O:23][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([O:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][CH:2]=[CH:3]4)=[N:12][CH:13]=[N:14]2)=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: C1COCCN1
Reactant: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@@H]1CO1
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@@H](O)CN1CCOCC1
Yield: 65 %

Procedure:
Using an analogous procedure to that described in Example 297, (2S)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline (100 mg, 0.28 mmol), (prepared as described for the starting material in Example 297), was reacted with morpholine (73.2 mg, 0.84 mmol) to give (2S)-7-(2-hydroxy-3-morpholinopropoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline (82 mg, 63%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:22][CH2:21][C:14]2([C:19](=[O:20])[NH:18][CH2:17][CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:10])=[O:9].I[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:22][CH2:21][C:14]2([C:19](=[O:20])[N:18]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)[CH2:17][CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:9])=[O:10]
Reactant: O=C1NCCCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2
Reactant: FC(F)(F)c1ccc(I)cc1
Product: O=C1N(c2ccc(C(F)(F)F)cc2)CCCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2

Procedure:
This material was prepared in analogy to example 148 step F) from 9-(2-chloro-benzenesulfonyl)-2,9-diaza-spiro[5.5]undecan-1-one and 1-iodo-4-trifluoromethyl-benzene. White solid. MS (ESI): 487.1 MH+).