Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[C:6]([NH2:8])[CH:7]=1.[F:17][C:18]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:19]=1[C:20]([NH:22][C:23]1[C:24]([C:28](O)=[O:29])=[N:25][NH:26][CH:27]=1)=[O:21].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[C:6]([NH:8][C:28]([C:24]2[C:23]([NH:22][C:20](=[O:21])[C:19]3[C:18]([F:17])=[CH:34][CH:33]=[CH:32][C:31]=3[F:35])=[CH:27][NH:26][N:25]=2)=[O:29])[CH:7]=1
Reactant: CN1CCC(Oc2ccc(F)cc2N)CC1
Reactant: O=C(O)c1n[nH]cc1NC(=O)c1c(F)cccc1F
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN1CCC(Oc2ccc(F)cc2NC(=O)c2n[nH]cc2NC(=O)c2c(F)cccc2F)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-fluoro-2-(1-methyl-piperidin-4-yloxy)-phenylamine) (0.049 g, 0.22 mmol) was combined with 4-(2,6-difluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid (0.053 g, 0.20 mmol), EDC (0.048 g, 0.25 mmol), HOBt (0.034 g, 0.25 mmol) and DMF (1 ml) and the resulting reaction mixture was stirred at ambient temperature for 18 hours. The reaction mixture was reduced in vacuo and purified by preparative LC/MS to give 4-(2,6-Difluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid[5-fluoro-2-(1-methyl-piperidin-4-yloxy)-phenyl]amide as a buff solid. (0.010 g, 11%) (LC/MS: Rt 2.19, [M+H]+ 474.27).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]2[O:10][CH2:11][O:12][C:8]=2[C:7]=1[C:15]1[C:16]2[NH:23][CH:22]=[C:21]([C:24](O)=[O:25])[C:17]=2[N:18]=[CH:19][N:20]=1.[C:27]([O:31][C:32](=[O:41])[NH:33][C@H:34]1[CH2:39][CH2:38][C@H:37]([NH2:40])[CH2:36][CH2:35]1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32](=[O:41])[NH:33][C@H:34]1[CH2:35][CH2:36][C@H:37]([NH:40][C:24]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[C:8]5[O:12][CH2:11][O:10][C:9]=5[CH:13]=[CH:14][C:6]=4[O:5][CH2:4][CH2:3][O:2][CH3:1])[C:16]=3[NH:23][CH:22]=2)=[O:25])[CH2:38][CH2:39]1)([CH3:30])([CH3:28])[CH3:29]
Reactant: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)O)c[nH]c13)OCO2
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Product: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c[nH]c13)OCO2

Procedure:
Starting from 4-[5-(2-methoxy-ethoxy)-benzo[1,3]dioxol-4-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A72) and commercially available trans-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester the title compound was obtained as colorless solid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[C:6]([O:12][CH3:13])[CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[OH:14].CCN(CC)CC.[C:22](Cl)(=O)[CH2:23][CH3:24].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:13][O:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH2:4][C@@H:3]([OH:14])[C@H:2]([NH:1][CH2:22][CH2:23][CH3:24])[CH2:11]2
Reactant: CCC(=O)Cl
Reactant: COc1cccc2c1C[C@@H](O)[C@H](N)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCN[C@@H]1Cc2cccc(OC)c2C[C@H]1O
Temperature: 90 °C
Reaction time: 0.33 h

Procedure:
Compound 13A (1.50 g) was suspended in THF (15 mL) and Et3N (1.80 mL) and propionyl chloride (0.60 mL) were added. The solution was stirred for 20 minutes. LAH (1M in THF, 10 mL) was added drop-wise under stirring at rt and the reaction mixture were heated to 90° C. for 1200 sec. in a sealed microwave process vial. The reaction was quenched with wet Na2SO4. The mixture was diluted with THF (50 mL), filtered over dry Na2SO4 and concentrated in vacuo. Yield: 1.21 g of compound 14A as an oil. LC/MS (method 350): RT 0.40 min, ELSD 100%, UV 100%. MH+: 235.9. 1H NMR (500 MHz, CDCl3) δ 0.89 (t, J=7.6 Hz, 3H), 1.43-1.52 (m, 2H), 2.37-2.51 (m, 3H), 2.61-2.68 (m, 1H), 2.74-2.80 (m, 1H), 3.14 (dd, J=4.93, J=16.0, 1H), 3.22-3.29 (dd, J=16.9, J=5.9, 1H), 3.56-3.63 (m, 1H), 3.73 (s, 1H), 6.60 (d, J=8.05, 1H), 6.62 (d, J=7.89, 1H), 7.03 (t, J=7.86, 1H). 13C NMR (500 MHz, CDCl3) δ: 157.7 136.4, 127.0, 123.8, 121.2, 107.7, 71.0, 59.8, 55.7, 49.5, 35.7, 32.1, 24.1, 12.2.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](S(C)(=O)=O)=[CH:6][CH:5]=1)=[O:3].BrBr>C(O)(=O)C.Cl.O>[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)c1ccc(S(C)(=O)=O)cc1
Agent: BrBr
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)c1ccccc1

Procedure:
To a stirred solution of the acetophenone prepared in Step 2 (11.91 g, 60.5 mmol) in glacial acetic acid (133 ml) and hydrochloric acid (0.11 ml) at ambient temperature, was added a solution of bromine (8.22 g, 51.4 mmol) in glacial acetic acid (9.3 ml) over a period of three hours. The reaction mixture was diluted with water (500 ml) and extracted with chloroform. The combined chloroform extracts were dried (MgSO4) and concentrated in vacuo to give 15.66 g of crude 2-bromo-4′-methylsulfonyl)acetophenone: 1H NMR (CDCl3) δ3.10 (s, 3H), 4.45 (s, 2H), 8.08 (d, J=9 Hz, 2H), 8.17 (d, J=9 Hz, 2H). The sample was used without further purification.
Reaction SMILES: OS(O)(=O)=O.[CH3:6][C:7]1([CH3:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[CH2:9][CH2:8]1.[N+:19]([O-])([OH:21])=[O:20]>>[CH3:6][C:7]1([CH3:18])[C:16]2[C:11](=[CH:12][C:13]([N+:19]([O-:21])=[O:20])=[CH:14][CH:15]=2)[C:10](=[O:17])[CH2:9][CH2:8]1
Reactant: O=[N+]([O-])O
Reactant: CC1(C)CCC(=O)c2ccccc21
Agent: O=S(=O)(O)O
Product: CC1(C)CCC(=O)c2cc([N+](=O)[O-])ccc21
Reaction time: 0.33 h

Procedure:
To 1.7 mL (3.0 g, 30.6 mmol, 18M) H2SO4 at -5;C (ice-NaCl bath) was slowly added 783.0 mg (4.49 mmol) of 3,4-dihydro-4,4-dimethyl-naphthalen-1(2H)-one. A solution of HNO3 (426.7 mg 6.88 mmol, 0.43 mL, 16 , and 1.31 g (0.013 mol, 0.74 mL, 18 M) of H2SO4 were slowly added. After 20 min, ice was added and the resulting mixture was extracted with EtOAc. The combined extracts were concentrated under reduced pressure to give a yellow oil from which the title compound, a pale yellow solid, was isolated by column chromatography (10% EtOAC/hexanes).
Reaction SMILES: [Br:1][C:2]1[C:11]([CH3:12])=[CH:10][C:5]([O:6][CH2:7][CH2:8][NH2:9])=[CH:4][C:3]=1[CH3:13].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[Br:1][C:2]1[C:11]([CH3:12])=[CH:10][C:5]([O:6][CH2:7][CH2:8][NH:9][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:4][C:3]=1[CH3:13]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(OCCN)cc(C)c1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(OCCNS(C)(=O)=O)cc(C)c1Br
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cooled (0° C.) solution of 2-(4-bromo-3,5-dimethylphenoxy)ethanamine (100 mg) and triethylamine (63 μL) in dichloromethane (2 mL) is added methanesulfonyl chloride (32 μL). The mixture is stirred for 2 hours at 0° C. Then the mixture is partitioned between dichloromethane and water. The organic phase is separated, washed with brine and dried (MgSO4). The solvent is evaporated and the residue is purified by HPLC on reversed phase to give the title compound. Yield: 90 mg; LC (method 7): tR=1.01 min; Mass spectrum (ESI+): m/z=322 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4](=[O:8])[O:5][C:6]=1[CH3:7].[Br:9]N1C(=O)CCC1=O>CC(N=NC(C#N)(C)C)(C#N)C.C(Cl)(Cl)(Cl)Cl>[Br:9][CH2:1][C:2]1[O:3][C:4](=[O:8])[O:5][C:6]=1[CH3:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1oc(=O)oc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1oc(=O)oc1CBr
Yield: 106.5 %

Procedure:
4,5-Dimethyl-1,3-dioxolene-2-one (11.4 g) was mixed with N-bromosuccinimide (19.6 g) and 2,2-azobis(2-methylpropionitrile) (0.5 g) in freshly distilled carbon tetrachloride (350 mL) and refluxed for 6 hours under an argon atmosphere. The reaction mixture was cooled in an ice bath after reflux and the precipitate formed was filtered off. The tiltrate was washed with water and brine, and dried over sodium sulfate. The solvent was evaporated to yield a yellow oil (20.54 g) which was distilled to obtain the pure monobromomethyl compound as a light yellow oil (11.86 g, 54%), bp 93° C. at 0.45 mm; 1H NMR (CDCl3) δ2.15 (s, 3H), 4.21 (S, 2H); IR (film) 1820, 1728, 1392, 1201, 1236, 768 cm-1.
Reaction SMILES: [F:1][C:2]([F:56])([F:55])[CH2:3][C@H:4]([NH:37]C(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)[C:5]([NH:7][C@@:8]([C:23]1[CH:28]=[C:27]([O:29][C:30]([F:35])([F:34])[CH:31]([F:33])[F:32])[CH:26]=[C:25]([F:36])[CH:24]=1)([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6].N1CCCCC1>C(Cl)Cl>[NH2:37][C@@H:4]([CH2:3][C:2]([F:55])([F:56])[F:1])[C:5]([NH:7][C@@:8]([C:23]1[CH:28]=[C:27]([O:29][C:30]([F:35])([F:34])[CH:31]([F:33])[F:32])[CH:26]=[C:25]([F:36])[CH:24]=1)([C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:6]
Reactant: O=C(N[C@@H](CC(F)(F)F)C(=O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: C1CCNCC1
Product: N[C@@H](CC(F)(F)F)C(=O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 106.3 %

Procedure:
To a solution of (9H-fluoren-9-yl)methyl (S)-4,4,4-trifluoro-1-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylamino)-1-oxobutan-2-ylcarbamate (10 mg, 0.01 mmol) in DCM (0.5 mL) was added piperidine (20 mg, 0.1 mmol). The reaction mixture was stirred at rt for 1.5 h and concentrated. The residue was purified by preparative HPLC (Axia column, 30×100 mm, 30-100% MeOH/H2O with 0.1% TFA over 12 min, flow rate 40 mL/min, monitoring at 220 nm) to yield (S)-2-amino-4,4,4-trifluoro-N—((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)butanamide (Example 323A) as a white solid (6 mg, 82% yield). LCMS: RT=3.1 min [M+H] 565.22 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm). 1H NMR (400 MHz, CDCl3) δ ppm 8.14 (1H, s), 7.17-7.22 (1H, m), 7.12 (2H, t, J=7.33 Hz), 7.03-7.08 (2H, m), 6.96-7.02 (2H, m), 6.88 (3H, s), 6.59 (2H, d, J=7.07 Hz), 5.85 (1H, t, J=2.53 Hz), 4.09 (1H, s), 3.91 (1H, d, J=13.14 Hz), 3.71 (1H, d, J=13.39 Hz), 2.66 (2H, m). (R)-2-amino-4,4,4-trifluoro-N—((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)butanamide (Example 323B) was prepared in the same method here and isolated as a white solid (6 mg, 82% yield). LCMS: RT=3.1 min [M+H] 565.22 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm). 1H NMR (400 MHz, CDCl3) δ ppm 7.80 (1H, s), 7.19 (1H, t, J=7.33 Hz), 7.08-7.15 (4H, m), 6.93-7.00 (2H, m), 6.84-6.92 (2H, m), 6.81 (1H, s), 6.58 (2H, d, J=7.07 Hz), 5.84 (1H, t, J=2.65 Hz), 4.26 (1H, d, J=5.56 Hz), 3.76-3.86 (2H, m), 2.53 (1H, d, J=10.61 Hz), 2.43-2.49 (1H, m). The stereochemistry of (S)-2-amino-4,4,4-trifluoro-N—((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)butanamide (Example 323A) and (R)-2-amino-4,4,4-trifluoro-N—((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)butanamide (Example 323B) was assigned arbitrarily.
Reaction SMILES: [C:1]12([OH:13])[CH2:10][C:5]3([OH:11])[CH2:6][CH:7]([CH2:9][C:3]([OH:12])([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N(CC)CC)C.[O:21]1C[CH2:24][CH2:23][CH2:22]1.C(Cl)(=O)C=C>O>[C:22]([O:13][C:1]12[CH2:10][C:5]3([OH:11])[CH2:6][CH:7]([CH2:9][C:3]([OH:12])([CH2:4]3)[CH2:2]1)[CH2:8]2)(=[O:21])[CH:23]=[CH2:24]
Reactant: C1CCOC1
Reactant: OC12CC3CC(O)(C1)CC(O)(C3)C2
Agent: C=CC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: C=CC(=O)OC12CC3CC(O)(CC(O)(C3)C1)C2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
10 mmol of 1,3,5-adamantanetriol, 10 mmol of triethylamine, and 40 ml of tetrahydrofuran were mixed, and 10 mmol of acrylic acid chloride was added dropwise to this mixture for about 30 minutes. After completion of the dropwise addition, the mixture was stirred at room temperature for 6 hours. After the reaction had been completed, to the reaction mixture was added water and the resultant mixture was purified by column chromatography to give 1-acryloyloxy-3,5-dihydroxyadamantane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C@@H:14]3[CH2:16][O:15]3)[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH3:17]>CO>[NH2:17][CH2:16][C@@H:14]([C:12]1[O:11][N:10]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH:13]=1)[OH:15]
Reactant: N
Reactant: Clc1ccc(-c2cc([C@@H]3CO3)on2)cc1Cl
Solvent: CO
Product: NC[C@H](O)c1cc(-c2ccc(Cl)c(Cl)c2)no1

Procedure:
The title compound was prepared from 3-(3,4-dichlorophenyl)-5-[(2S)-oxiran-2-yl]isoxazole (which was obtained in Example 108), in methyl alcohol and ammonia in substantially the same manner as described in Example 105, and was obtained as a white solid (0.43 g, 80% yield), mp 105° C.; MS (ES) m/z: 273 (MH+); 1H NMR (400 MHz, CDCl3) δ 3.18 (m, 2H), 4.83 (m, 1H), 6.56 (s, 1H),7.54 (d, 1H), 7.62 (d, 1H), 7.90 (s, 1H).
Reaction SMILES: [O:1]1[C:6]2([CH2:11][CH2:10][CH:9]([N:12]3[C:17](=[O:18])[C:16]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]5[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=5)=[CH:22][CH:21]=4)=[C:15]([CH2:34][CH2:35][CH3:36])[N:14]4[N:37]=[CH:38][N:39]=[C:13]34)[CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3][CH2:2]1.C([BH3-])#N.[Na+].O1CCCC1>C(OCC)(=O)C>[OH:1][CH2:2][CH2:3][CH2:4][O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([N:12]2[C:17](=[O:18])[C:16]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([C:26]4[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=4)=[CH:24][CH:25]=3)=[C:15]([CH2:34][CH2:35][CH3:36])[N:14]3[N:37]=[CH:38][N:39]=[C:13]23)[CH2:8][CH2:7]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCCO3)c2ncnn12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCCCO)CC2)c2ncnn12
Temperature: 50 °C
Reaction time: 6 h

Procedure:
A mixture of 4′-{[4-(1,5-dioxaspiro[5.5]undec-9-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.56 g), sodium cyanoborohydride (0.2 g), boron trifluoride-diethyl ether complex (0.4 mL) and tetrahydrofuran (15 mL) was stirred at 50° C. for 6 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.28 g, 33%).
Reaction SMILES: [N:1]([C@@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])=[C:2]=[O:3].Cl.[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[C:28]([C:30]3[CH:39]=[C:38]4[C:33]([CH2:34][CH2:35][NH:36][CH2:37]4)=[CH:32][CH:31]=3)[N:27]=[C:26]([NH2:40])[N:25]=2)[CH2:20][CH2:19]1.C(N(CC)CC)C>C(#N)C>[NH2:40][C:26]1[N:27]=[C:28]([C:30]2[CH:39]=[C:38]3[C:33]([CH2:34][CH2:35][N:36]([C:2]([NH:1][C@@H:4]([CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:5]([O:7][CH3:8])=[O:6])=[O:3])[CH2:37]3)=[CH:32][CH:31]=2)[CH:29]=[C:24]([N:21]2[CH2:20][CH2:19][N:18]([CH3:17])[CH2:23][CH2:22]2)[N:25]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)N=C=O
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)N1CCc2ccc(-c3cc(N4CCN(C)CC4)nc(N)n3)cc2C1
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
Methyl (2S)-2-isocyanato-3-phenylpropanoate (12.5 mg, 0.0609 mmol) (Aldrich, Cat. #409731) was added to a mixture of 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt (25.0 mg, 0.0576 mmol) and triethylamine (32 uL, 0.23 mmol) in acetonitrile (1.0 mL). After 30 min., the mixture was concentrated, and purified by flash chromatography on a silica gel column with MeOH in dichloromethylene (0-5%) to afford the desired product (30 mg, 98%). Analytic LCMS (M+H)+: m/z=530.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[CH2:7][CH2:8][CH2:9][C@@H:10]([OH:12])[CH2:11][C:5]=2[CH:4]=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1C=CC=CC=1>[CH3:25][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O:12][C@@H:10]2[CH2:9][CH2:8][CH2:7][C:6]3[CH:13]=[CH:14][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH2:11]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc2c(c1)C[C@H](O)CCC2
Solvent: c1ccncc1
Product: COc1ccc2c(c1)C[C@H](OS(=O)(=O)c1ccc(C)cc1)CCC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.8 %

Procedure:
To a solution of (R)-3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ol (108.96 g) in pyridine (550 ml) was added portionwise p-toluenesulfonyl chloride (129.66 g) at 10° C.~13° C. The reaction mixture was stirred at ambient temperature for 1 day. The solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate (1600 ml) and water (1080 ml). The organic layer was washed successively with 1N hydrochloric acid solution (1080 ml), aqueous sodium hydrogen carbonate (1080 ml), and brine (500 ml), dried over magnesium sulfate, and evaporated in vacuo to give a colorless powder. The colorless powder was washed with n-hexane (twice) to give (R)-3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl 4-methylbenzenesulfonate (182.23 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH:9]=O)=[N:5][CH:6]=[CH:7][N:8]=1.Cl.[NH2:12][OH:13].C(N(CC)CC)C>C(O)C>[CH3:1][O:2][C:3]1[C:4]([CH:9]=[N:12][OH:13])=[N:5][CH:6]=[CH:7][N:8]=1
Reactant: COc1nccnc1C=O
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1nccnc1C=NO
Temperature: 60 °C
Yield: 32.2 %

Procedure:
A mixture of 3-methoxypyrazine-2-carboxaldehyde (Tetrahedron (1999), 56(2), 265-273) (2.1 g, 15 mmol), hydroxylamine hydrochloride (1.27 g, 18 mmol), ethanol (20 ml) and triethylamine (4.17 ml, 30 mmol) was heated at 60° C. for 90 minutes. The volatiles were removed by evaporation and residue was purified by column chromatography on silica gel eluting with hexane/EtOAc (100:0 increasing in polarity 0:100) to give the title compound (740 mg, 32%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([CH2:25][CH:26]4[CH2:31]CN(C(OC(C)(C)C)=O)CC4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.FC1C=C2C(C(C3C=NNC=3)=CN2S(C2C=CC=CC=2)(=O)=O)=CC=1.CS(OCC1C[N:71]([C:73]([O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:74])[CH2:70]1)(=O)=O>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([CH2:25][CH:26]4[CH2:31][N:71]([C:73]([O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:74])[CH2:70]4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(COS(C)(=O)=O)C1
Reactant: CC(C)(C)OC(=O)N1CCC(Cn2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)CC1
Agent: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2ccc(F)cc21
Product: CC(C)(C)OC(=O)N1CC(Cn2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)C1
Yield: 76 %

Procedure:
Following the general method as outlined in Intermediate 20, starting from 6-fluoro-1-(phenylsulfonyl)-3-(1H-pyrazol-4-yl)-1H-indole (Intermediate 5; 1.22 g; 3.56 mmol) and tert-butyl 3-(((methylsulfonyl)oxy)methyl)azetidine-1-carboxylate (1.40 g; 5.28 mmol), 1.37 g (76%) of the title compound as a yellow solid.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:21][CH2:22][C:23](Cl)=[O:24]>ClCCl>[Cl:21][CH2:22][C:23]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)=[O:24]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CCl)CC1
Temperature: 3 °C
Reaction time: 1 h

Procedure:
2.00 g (10.74 mmol) tert-butyl 1-piperazinecarboxylate, 1.30 g (12.89 mmol, 1.2 eq.) triethylamine were dissolved into 25 ml dichloromethan under argon gas. After cooling to 3° C., 1.33 g (11.81 mmol, 1.1 eq.) chloroacetyl chloride was diluted with 5 ml dichloromethane and added dropwise slowly into reaction solution. After stirring at 3° C. for 1 hour, 20 ml purified water was added, organic layer was separated and aqueous layer was extracted once with 40 ml dichloromethane again. Organic layer was collected, dried with magnesium sulfate and concentrated with decompression. Purifying residues by chromatography using silicagel, 2.00 g (71%) target compound as yellow syrup was yielded.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=1)(=O)=O.[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1>>[CH2:17]([O:16][C:12]1[CH:11]=[C:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:24]2[CH:28]=[CH:27][N:26]=[CH:25]2)[CH:15]=[CH:14][CH:13]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CS(=O)(=O)OCCCCc1cccc(OCc2ccccc2)c1
Reactant: c1c[nH]cn1
Product: c1ccc(COc2cccc(CCCCn3ccnc3)c2)cc1
Yield: 61 %

Procedure:
In substantially the same manner as in Reference Example 88, 4-(3-benzyloxyphenyl)butyl methanesulfonate was allowed to react with imidazole to give 1-[4-(3-benzyloxyphenyl)butyl]imidazole. The yield was 61%. Oily substance.
Reaction SMILES: [CH2:1]([N:4]([CH2:12][C:13](=O)[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3].Cl.[NH2:22][OH:23].N1C=CC=CC=1>C(O)C>[CH2:1]([N:4]([CH2:12][C:13](=[N:22][OH:23])[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3]
Reactant: C=CCN(CC(=O)c1cccnc1)C(=O)OC(C)(C)C
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: C=CCN(CC(=NO)c1cccnc1)C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 91.8 %

Procedure:
tert-Butyl N-allyl-N-[2-oxo-2-(3-pyridyl)ethyl]carbamate (31.34 g 113.41 mmol) is dissolved in ethanol (110 mL) with stirring under nitrogen. Hydroxylamine hydrochloride (18.31 g, 260.85 mmol) and pyridine (12.84 mL, 158.78 mmol) are added. The resulting solution is heated at 80° C. under nitrogen for 2 hours and then is cooled to room temperature. The solvents are partially evaporated and the resulting residue is then partitioned between 2 M sodium hydroxide (150 ml) and dichloromethane (500 mL). The phases are separated and the aqueous phase is re-extracted with dichloromethane (2×250 mL). The organic extracts are combined and evaporated under reduced pressure. The crude product is purified by silica gel column chromatography using a gradient of 0-10% 0.14 M ammonia/methanol solution in dichloromethane to give the title compound (30.34 g, 91.82%) as a mixture of E/Z isomers. ES/MS (m/e) M+1=292.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:39])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([CH3:35])([CH3:34])[C:31](=[O:33])[CH3:32])=[CH:26][C:25]=3[O:36][CH2:37][CH3:38])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:42][S:43]([CH2:46][CH2:47][CH2:48][N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)(=[O:45])=[O:44]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:39])[C:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:52]3[CH2:53][CH2:54][N:49]([CH2:48][CH2:47][CH2:46][S:43]([CH3:42])(=[O:44])=[O:45])[CH2:50][CH2:51]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([CH3:35])([CH3:34])[C:31](=[O:33])[CH3:32])=[CH:26][C:25]=3[O:36][CH2:37][CH3:38])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(C(C)(C)C(C)=O)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCCN1CCNCC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C(C)=O)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[4-(1,1-dimethyl-2-oxo-propyl)-2-ethoxy-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title product as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 25% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C39H49N4O5SCl2 [(M+H)+] 775.2795, observed 775.2795.