Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2]([CH:4]=[N:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([C:13]([N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][N:18]3[CH:26]=[CH:27][CH:28]=[C:17]3[CH2:16]2)=[O:14])=[CH:9][CH:8]=1)C.C(O)(=O)C.[NH2:34]N>ClCCl>[CH:28]1[CH:27]=[CH:26][N:18]2[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:15]([C:13]([C:10]3[CH:11]=[CH:12][C:7]([C:6]4[NH:34][N:2]=[CH:4][N:5]=4)=[CH:8][CH:9]=3)=[O:14])[CH2:16][C:17]=12
Reactant: CN(C)C=NC(=O)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: NN
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(c1ccc(-c2ncn[nH]2)cc1)N1Cc2cccn2Cc2ccccc21
Yield: 42.4 %

Procedure:
A mixture of N-(dimethylaminomethylene)-4-(5H,11H-pyrrolo[2,1-c][1,4]-benzodiazepine-10-carbonyl)-benzamide (1.0 g) from Example 46, glacial acetic acid (15 ml), and anhydrous hydrazine (0.16 g) was refluxed for 15 hours and the volatiles removed in vacuo. Saturated aqueous sodium bicarbonate solution was added and the resultant solid was recovered by filtration. The solid was refluxed for 4 hours and the volatiles removed in vacuo to give a solid. The solid was dissolved in dichloromethane and filtered through a short column of hydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a steam bath with the gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (0.39 g), m.p. 225-227° C.; MS, m/z: 355 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(OCC)(=O)C>C(O)C.[Pt]>[NH2:15][C:13]1[CH:12]=[CH:11][C:3]([C:4]([O:6][C:7]([CH3:9])([CH3:10])[CH3:8])=[O:5])=[C:2]([Cl:1])[CH:14]=1
Reactant: CC(C)(C)OC(=O)c1ccc([N+](=O)[O-])cc1Cl
Agent: [Pt]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(N)cc1Cl
Temperature: 25 °C
Yield: 96.3 %

Procedure:
To a solution of tert-butyl 2-chloro-4-nitro-benzoate (2.05 g, 7.98 mmol) in ethanol 12 mL) and ethyl acetate (108 mL) was added platinum on activated charcoal (5%, 295 mg), and the mixture was stirred under at room temperature under a hydrogen atmosphere (1 bar). After filtration through a pad of diatomaceous earth, the filtrate was evaporated to afford tert-butyl 4-amino-2-chlorobenzoate (1.75 g, 96%). Orange solid, MS (EI)=227.2 (M+).
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.C(N(S(F)(F)[F:16])CC)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[F:16][CH2:1][S:2][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CS(=O)c1ccccc1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: FCSc1ccccc1
Reaction time: 48 h
Yield: 85.8 %

Procedure:
To a stirred solution of (methylsulfinyl)benzene (23.0 g, 164 mmol) in chloroform (80 mL) under argon at room temperature was added diethylaminosulfur trifluoride (43.0 mL, 328 mmol) dropwise and the reaction mixture was stirred for 2 days at this temperature then at 60° C. overnight. The mixture was added dropwise to a stirred solution of saturated aqueous sodium hydrogen carbonate at 0° C. then extracted 3 times with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated to give (fluoromethyl)(phenyl)sulfane (20.0 g, 86%) as a yellow oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[C:4]1[CH:24]=[CH:23][C:7]([C:8]([C:10]2[C:18]([Cl:19])=[C:17]([Cl:20])[C:16]([Cl:21])=[C:15]([Cl:22])[C:11]=2[C:12]([OH:14])=[O:13])=O)=[CH:6][CH:5]=1)[CH3:2].[CH2:27]([N:29]([CH2:41][CH3:42])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]([CH2:39][CH3:40])[CH2:37][CH3:38])[CH:31]=1)[CH3:28].C(OC(=O)C)(=O)C>CO>[CH2:39]([N:36]([CH2:37][CH3:38])[C:32]1[CH:31]=[C:30]([N:29]([CH2:41][CH3:42])[CH2:27][CH3:28])[CH:35]=[CH:34][C:33]=1[C:8]1([C:7]2[CH:23]=[CH:24][C:4]([N:3]([CH2:25][CH3:26])[CH2:1][CH3:2])=[CH:5][CH:6]=2)[C:10]2[C:11](=[C:15]([Cl:22])[C:16]([Cl:21])=[C:17]([Cl:20])[C:18]=2[Cl:19])[C:12](=[O:13])[O:14]1)[CH3:40]
Reactant: CCN(CC)c1cccc(N(CC)CC)c1
Reactant: CCN(CC)c1ccc(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)cc1
Solvent: CC(=O)OC(C)=O
Solvent: CO
Product: CCN(CC)c1ccc(C2(c3ccc(N(CC)CC)cc3N(CC)CC)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)cc1
Temperature: 90 °C
Yield: 61.6 %

Procedure:
A mixture of 2-(4-(diethylamino)benzoyl)-3,4,5,6-tetrachlorobenzoic acid (8.70 g.) N,N,N',N'-tetraethyl-m-phenylenediamine (4.85 g.) and acetic anhydride (5 ml.) was heated (to 90° C.). Addition of methanol (10 ml.) and slurrying the resulting product with methanol (20 ml.) afforded 3-(2,4-bis(diethylamino)phenyl)-3-(4-(diethylamino)phenyl)-4,5,6,7-tetrachlorophthalide (I: X=Y4 =(CH3CH2)2N, Y2 =H, Z4 =Z5 =Z6 =Z7 =Cl) (7.85 g., m.p. 196°-197° C.).
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[C:6]12([O:16][CH2:17][CH:18]3[O:20][CH2:19]3)CC3C[CH:12](CC(C3)C1)[CH2:13]2.C12([OH:31])CC3CC(CC(C3)C1)C2.C(C1OC1)Cl>>[CH2:6]([O:16][CH2:17][CH:18]1[O:20][CH2:19]1)[CH:13]1[O:31][CH2:12]1
Reactant: C1C2CC3CC1CC(OCC1CO1)(C2)C3
Reactant: OC12CC3CC(CC(C3)C1)C2
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCC1CO1
Product: C(OCC1CO1)C1CO1
Yield: 61 %

Procedure:
The process gives a yield of 61% which is not bad. In this process, however, tin tetra-chloride (which is a Lewis acid) is used as the catalyst. For the safety reason of the catalyst, the solvent usable is limited to low-polarity solvents such as halides. Hence, in production of 1-adamantylglycidyl ether, when the starting raw material is changed from 1-adamantanol to an adamantanepolyol having two or more hydroxyl groups (which has very low solubility in low-polar solvents), the reactivity thereof is not certain. Further, there is a fear that epichlorohydrin itself polymerizes in the presence of an acid such as Lewis acid and the polymerizate remains as an impurity. As a process for obtaining a glycidyl ether from an alcohol, there is generally considered a process which comprises reacting an alcohol with an alkali metal or the like to synthesize an alcoholate and contacting the alcoholate with epichlorohydrin or epibromohydrin. However, there is no case in which this process has been applied to any polycyclic hydroxy compound having two or more hydroxyl groups.
Reaction SMILES: [F:1]C1C=CC=CC=1CC(=O)C(OCC)=O.Br[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br.[Mg].[C:26]([O:33]CC)(=O)[C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[F:1][C:17]1[CH:18]=[C:19]([CH2:20][C:26](=[O:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:22]=[CH:23][CH:24]=1
Reactant: BrCc1cccc(Br)c1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCOC(=O)C(=O)Cc1ccccc1F
Agent: [Mg]
Product: CCOC(=O)C(=O)Cc1cccc(F)c1
Yield: 80 %

Procedure:
The title compound was prepared as described for B4 using 3-bromobenzyl bromide (1.250 g, 5.00 mmol), magnesium (0.134 g, 5.50 mmol) and diethyl oxalate (1.462 g, 10.00 mmol). The product was isolated in the form of colorless oil in 80% yield and use instantly in next step.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH3:30])[NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([C:25]#[N:26])[CH:22]=[C:21]([CH:27]=[CH2:28])[N:20]=2)[C:12]=1[F:29])=[O:8].C1(SC2C=CC=CC=2)C=CC=CC=1>[Pd].CO.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]([CH3:30])[NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([C:25]#[N:26])[CH:22]=[C:21]([CH2:27][CH3:28])[N:20]=2)[C:12]=1[F:29])=[O:8]
Reactant: C=Cc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(C)nc3Cl)c2F)n1
Agent: [Pd]
Agent: c1ccc(Sc2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(C)nc3Cl)c2F)n1
Yield: 80.6 %

Procedure:
A solution of 4-chloro-N-({4-chloro-3-[(4-cyano-6-ethenyl-2-pyridinyl)oxy]-2-fluorophenyl}methyl)-2-methyl-1H-imidazole-5-carboxamide (53 mg, 0.119 mmol), diphenylsulfide (1.979 μl, 0.012 mmol) and palladium on carbon (12.64 mg, 0.012 mmol, 10%) in MeOH (8.0 ml) and ethyl acetate (8.00 ml) was reacted under H2 (40 psi) overnight. The reaction mixture was filtered through a pad of celite and concentrated to dryness. The residue was purified by flash chromatography on silica gel eluted with 0-5% 2M NH3 solution of MeOH in CH2Cl2 to give the title compound as a white solid (43 mg, 81%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.82 (1H, br. s.) 7.17-7.24 (2H, m) 7.09 (2H, d, J=5.4 Hz) 4.68 (2H, d, J=6.0 Hz) 2.61 (2H, q, J=7.5 Hz) 2.39 (3H, s) 1.07 (3H, t). LCMS: m/z 448 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][CH3:10])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:11][N:12]1[C:16]([CH3:17])=[C:15]([NH2:18])[CH:14]=[N:13]1.C(O)(C(F)(F)F)=O>COCCO>[Br:1][C:2]1[C:3]([NH:9][CH3:10])=[N:4][C:5]([NH:18][C:15]2[CH:14]=[N:13][N:12]([CH3:11])[C:16]=2[CH3:17])=[N:6][CH:7]=1
Reactant: CNc1nc(Cl)ncc1Br
Reactant: Cc1c(N)cnn1C
Solvent: O=C(O)C(F)(F)F
Solvent: COCCO
Product: CNc1nc(Nc2cnn(C)c2C)ncc1Br
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 17.1 %

Procedure:
To a mixture of 5-bromo-2-chloro-N-methylpyrimidin-4-amine (0.201 g, 0.903 mmol) and 1,5-dimethyl-1H-pyrazol-4-amine (0.12 g, 1.08 mmol) in 2-methoxyethanol (2 mL) was added TFA (0.070 mL, 0.9 mmol). The reaction was stirred in a sealed tube at 100° C. for 90 minutes. The resulting precipitate was collected by filtration. The isolated solid was further purified by reverse phase HPLC to give 5-bromo-N2-(1,5-dimethyl-1H-pyrazol-4-yl)-N4-methylpyrimidine-2,4-diamine (46 mg, 17%). LCMS (Method A): [MH+]=297.0 at 2.57 min. 1H-NMR (DMSO): δ 8.28 (s, 1H), 7.84 (s, 1H), 7.49 (s, 1H), 6.79 (d, J=3.4, 1H), 3.67 (s, 3H), 2.82 (d, J=3.6, 3H), 2.14 (s, 3H). Ki=0.017 uM.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.C1C(=O)N([Br:16])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([CH2:8][Br:16])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ncccc1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ncccc1Br
Temperature: 25 °C
Yield: 45.7 %

Procedure:
Heat a mixture of 3-bromo-2-methylpyridine (J. Med. Chem. 1987, 30, 871-880) (2.7 g, 15.8 mmol), NBS (3.10 g, 17.42 mmol), and benzoyl peroxide (190 mg, 0.78 mmol) in carbon tetrachloride (50 mL) overnight at 85° C. Cool to ambient temperature, filter, and concentrate in vacuo. Purify by chromatography on silica gel eluting with toluene to provide the title compound as a white solid (1.81 g, 45%).
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=2)=[CH:5][CH:4]=1)=[O:2].C([O-])([O-])=[O:23].[K+].[K+].OO.O>CS(C)=O>[CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]([NH2:19])=[O:23])=[CH:16][N:15]=2)=[CH:5][CH:4]=1)=[O:2]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(Oc2ccc(C=O)c3ccccc23)nc1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1ccc(Oc2ccc(C=O)c3ccccc23)nc1
Temperature: 0 °C

Procedure:
To a solution of 6-(4-formylnaphthalen-1-yloxy)nicotinonitrile (Preparation 1) (3.83 g, 14.0 mmol) in DMSO (90 mL) was added K2CO3 (0.97 g, 7.0 mmol). The mixture was cooled to 0° C., H2O2 (27.5% w/v, 4.6 mL, 37.0 mmol) added dropwise and the reaction allowed to warm to rt. The mixture was poured into water (300 mL) and the resulting precipitate was filtered, washed with water and air dried to give the title compound which was used without further purification: RT=3.13 min; m/z (ES+)=292.9 [M+H]+.
Reaction SMILES: [OH: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][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].[C:27]([NH:37][CH2:38][C:39](=[O:45])[CH2:40][CH2:41][C:42](O)=[O:43])([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28].N1(C2C=CN=CC=2)CCCC1.C(N=C=NC(C)C)(C)C>ClCCl>[C:27]([NH:37][CH2:38][C:39](=[O:45])[CH2:40][CH2:41][C:42]([O: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][C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])=[O:43])([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]
Reactant: O=C(O)CCC(=O)CNC(=O)OCc1ccccc1
Reactant: O=C(CCCCCCCCCCCCCCCO)OCc1ccccc1
Agent: CC(C)N=C=NC(C)C
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: O=C(CCC(=O)OCCCCCCCCCCCCCCCC(=O)OCc1ccccc1)CNC(=O)OCc1ccccc1
Reaction time: 72 h
Yield: 29.2 %

Procedure:
This compound was prepared from the product of 15a (1.2 g; 3.2 mmol), 5-(Cbz-amino)-4-oxopentanoic acid (0.84 g; 3.2 mmol), 4-pyrrolidinylpyridine (50 mg), and N,N′-diisopropylcarbodiimide (0.50 g; 4.0 mmol) in dichloromethane (35 mL) according to Procedure D. The reaction time was 3 days. The crude product was purified on a 85×55 mm silica gel 60 column eluted with ethyl acetate-hexane (1:1) (1000 mL) collecting 13×50 mL fractions. Fractions containing the product (3-6) were evaporated and 0.57 g (29%) product was obtained (white solid, mp 78-81° C.).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].CN1CCOCC1.[C:15](Cl)(=[O:24])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1.C(OCC)(=O)C>[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH:6][C:15](=[O:24])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: COC(=O)CN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)CNC(=O)C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Glycine methyl ester hydrochloride was suspended in tetrahydrofuran, the suspension was cooled to -5° C. to -10° C., and then half of the N-methylmorpholine was added. Cinnamoyl chloride was added immediately, followed by the other half of the N-methylmorpholine. The reaction mixture was stirred for 30 minutes at low temperature, then it was allowed to warm to room temperature and stirring was continued for 2 to 3 hours. After being diluted with ethyl acetate (about 750 ml) the solution was washed with water (three times), an aqueous solution of 0.5 N hydrochloric acid (three times) and finally with water. The organic phase was dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was triturated with petroleum ether is order to induce crystallization. The product was left to stand for about 14 hours at 4° C., then it was filtered off and dried in a vacuum. It was used in the next step without further purification. 31 g of product were obtained.
Reaction SMILES: C(O[B:5]1[O:9][C:8]([CH3:11])([CH3:10])[C:7]([CH3:13])([CH3:12])[O:6]1)(C)C.C([Li])CCC.[F:19][C:20]1[CH:21]=[C:22]([CH:27]2[CH2:30][O:29][CH2:28]2)[CH:23]=[C:24]([F:26])[CH:25]=1>>[F:26][C:24]1[CH:23]=[C:22]([CH:27]2[CH2:30][O:29][CH2:28]2)[CH:21]=[C:20]([F:19])[C:25]=1[B:5]1[O:6][C:7]([CH3:12])([CH3:13])[C:8]([CH3:10])([CH3:11])[O:9]1
Reactant: Fc1cc(F)cc(C2COC2)c1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Product: CC1(C)OB(c2c(F)cc(C3COC3)cc2F)OC1(C)C

Procedure:
Method 3 was followed using 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.3 equiv.), butyllithium (1.1 equiv.) and 3-(3,5-difluorophenyl)oxetane (1.0 equiv.) to give 2-(2,6-difluoro-4-(oxetan-3-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. 1H NMR (400 MHz, <cdcl3>) δ ppm 6.90 (d, J=8.22 Hz, 2H), 5.07 (dd, J=6.06, 8.41 Hz, 2H), 4.70 (t, J=6.26 Hz, 2H), 4.13-4.23 (m, 1H), 1.39 (s, 12H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:15]([O-])=O)=[C:5]([CH:12]=[CH:13][CH:14]=1)[NH:6][CH2:7][CH2:8][CH2:9][O:10][CH3:11].CO>[Zn].C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][CH:12]=[C:5]([NH:6][CH2:7][CH2:8][CH2:9][O:10][CH3:11])[C:4]=1[NH2:15]
Reactant: COCCCNc1cccc(OC)c1[N+](=O)[O-]
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: COCCCNc1cccc(OC)c1N
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Into a 100 mL round bottomed flask was added 3-methoxy-N-(3-methoxypropyl)-2-nitroaniline (36A) (560 mg, 2.33 mmol) and methanol (46 mL). Zinc metal (2.11 g, 32.4 mmol) and acetic acid (2.0 mL) was added and the mixture was stirred at room temperature for 5 hr. The mixture was filtered through a fritted Buchner funnel and the solvent was removed under vacuum. Ethyl acetate (100 mL) was added and the precipitate was filtered through a Buchner funnel with a pad of Celite. The filtrate was concentrated under vacuum to leave 3-methoxy-N1-(3-methoxypropyl)benzene-1,2-diamine (37B) as a yellow oil which was used without further purification. ESI-MS:mlz 211.4 (M-F1-1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.[CH3:13][C:14]1[CH:15]=[C:16]([CH3:31])[N:17]=[C:18]([NH:20][S:21]([C:24]2[CH:25]=[CH:26][C:27]([NH2:30])=[CH:28][CH:29]=2)(=[O:23])=[O:22])[N:19]=1.C(N(CC)CC)C.C(N=C=NC(C)C)(C)C>C(Cl)(Cl)Cl>[CH3:31][C:16]1[CH:15]=[C:14]([CH3:13])[N:19]=[C:18]([NH:20][S:21]([C:24]2[CH:25]=[CH:26][C:27]([NH:30][C:10](=[O:12])[CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])=[CH:28][CH:29]=2)(=[O:23])=[O:22])[N:17]=1
Reactant: COc1ccccc1CC(=O)O
Reactant: Cc1cc(C)nc(NS(=O)(=O)c2ccc(N)cc2)n1
Agent: CC(C)N=C=NC(C)C
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccccc1CC(=O)Nc1ccc(S(=O)(=O)Nc2nc(C)cc(C)n2)cc1
Yield: 40 %

Procedure:
2-Methoxyphenylacetic acid (33 mg, 0.20 mmol) and sulfamethazine (55 mg, 0.20 mmol) were dissolved in 4 ml of chloroform. Triethylamine (70 μl, 0.55 mmol) and diisopropylcarbodiimide (50 μl, 0.20 mmol) were added to the reaction mixture. Solution was stirred and refluxed overnight. The reaction mixture was then evaporated to dryness, washed with water and purified on silica using gradient elution (chloroform to 2% methanol in chloroform) to obtain white crystals with the yield of 40%. 1H NMR (CDCl3, 500 MHz): 8.04 (2H, m), 7.54 (2H, m), 7.30 (2H, m), 6.98 (2H, m), 6.60 (1H, s), 3.95 (3H, s), 3.72 (2H, s), 2.33 (6H, s); MS (ESI+): m/z 449 (M+Na)+, 427 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:12]([S:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:22][N:23](C)[C:24](=O)OC(C)(C)C)[C:9]=2[F:32])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:33]([O:36]CC)(=[O:35])[CH3:34].Cl.[C:40]([O:43]CC)(=[O:42])[CH3:41]>CC(O)C.CO>[C:40]([OH:43])(=[O:42])/[CH:41]=[CH:34]/[C:33]([OH:36])=[O:35].[Cl:1][C:2]1[C:7]([C:8]2[N:12]([S:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)(=[O:14])=[O:15])[CH:11]=[C:10]([CH2:22][NH:23][CH3:24])[C:9]=2[F:32])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCOC(C)=O
Reactant: CN(Cc1cn(S(=O)(=O)c2cccnc2)c(-c2cccnc2Cl)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: CNCc1cn(S(=O)(=O)c2cccnc2)c(-c2cccnc2Cl)c1F
Product: O=C(O)/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl {[5-(2-chloropyridin-3-yl)-4-fluoro-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (465 mg) in ethyl acetate (3 mL), 2-propanol (2 mL) and methanol (3 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (6 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=1:1→1:9) to give a free base of the title compound as a pale-yellow oil (yield 297 mg). A solution of the obtained free base in ethyl acetate (5 mL) was added dropwise to a solution of fumaric acid (88 mg) in ethanol (5 mL) and the mixture was concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound as a white solid (yield 267 mg, 59%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15]NC([C@@H]1CCCNC1)=O>>[CH3:15][N:8]([C@H:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: CNC(=O)[C@@H]1CCCNC1
Product: CN(C(=O)OC(C)(C)C)[C@H]1CCCNC1

Procedure:
Prepared from (S)-3-(tert-butoxycarbonylamino)piperdine in the same scale and manner as the (3R) isomer described in Preparative Example 35. Yields were 96% and 93% for the first two steps. Product yield was treated as quantitative for last step and used as reagent in a further reaction (Example 94). LC/MS 1.30 min, [M+1]+ 215.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[CH2:15][CH2:14][NH:13][CH2:12][C:7]=3[N:8]2[CH3:11])=[CH:4][CH:3]=1.[BH-](OC(C)=O)(OC(C)=O)O[C:18](C)=O.[Na+]>CO.C(Cl)Cl.C=O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[CH2:15][CH2:14][N:13]([CH3:18])[CH2:12][C:7]=3[N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cn1c2c(c3ccc(Br)cc31)CCNC2
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN1CCc2c(n(C)c3cc(Br)ccc23)C1
Reaction time: 1 h
Yield: 88 %

Procedure:
7-Bromo-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (1.24 g, 4.68 mmol) was dissolved in a mixture of MeOH (20 mL) and CH2Cl2 (5 mL) and formaldehyde (0.56 mL, 37% aqueous solution) was added. After stirring for 1 h, NaBH(OAc)3 (1.98 g, 9.34 mmol) was added and the mixture stirred for a further 10 minutes. The mixture was diluted with methylene chloride (50 mL), washed with saturated Na2CO3 solution, concentrated and purified by flash column chromatography (40 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 90% methylene chloride over 30 min at 40 mL/min) to provide the title compound (1.15 g, 88%) as a white powder: 1H NMR (500 MHz, CDCl3) δ 7.40 (d, J=1.6 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.16 (dd, J=8.3, 1.7 Hz, 1H), 3.61 (s, 2H), 3.55 (s, 3H), 2.86-2.76 (m, 4H), 2.56 (s, 3H).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[F:18][C:19]([F:33])([F:32])[C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:23]Br>>[F:18][C:19]([F:32])([F:33])[C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:27]=1)[CH2:23][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 3,5-bis(trifluoromethyl)benzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [O:1]1[C@@H:6]2[C@H:2]1[C@H:3]([OH:19])[C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:5]2.[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21].C(Cl)[Cl:26]>C(O)(C)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[ClH:26].[C:20]([NH:24][C@@H:6]1[CH2:5][C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:3]([OH:19])[C@H:2]1[OH:1])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)N
Reactant: O[C@H]1[C@H]2O[C@H]2CC1(c1ccccc1)c1ccccc1
Reactant: ClCCl
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CC(C)O
Product: CC(C)(C)N[C@@H]1CC(c2ccccc2)(c2ccccc2)[C@@H](O)[C@H]1O
Product: Cl
Reaction time: 0.5 h

Procedure:
To a solution of (-)-rel-(1R,2R,3S)-2,3-epoxy-5,5-diphenylcyclopentan-1-ol (297 mg) in methylene chloride (3 ml) and isopropyl alcohol (1.2 ml) was added titanium(IV) isopropoxide (0.46 ml) with ice bath cooling. After being stirred for 30 minutes, t-butylamine (0.25 ml) was added thereto, and the mixture was stirred at room temperature overnight. The solution was evaporated in vacuo and the residue was dissolved in diethyl ether (3 ml). To the solution was added 3N hydrochloric acid (1.66 ml) in an ice bath, and the mixture was stirred for 3 hours. The resulting precipitates were collected by filtration, washed with diethyl ether (3 ml), and dried to give (-)-rel-(1R,2S,3R)-3-t-butylamino-5,5-diphenylcyclopentane-1,2-diol hydrochloride (0.36 g).