Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]=[O:10])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[N:3]=1.[C:24]1([Mg]Br)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[OH:10])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[N:3]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nc(Cl)c1C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nc(Cl)c1C(O)c1ccccc1
Temperature: 25 °C

Procedure:
To the solution of 2,4-dichloro-6-(2-(isopropylsulfonyl)phenylamino)pyrimidine-5-carbaldehyde (112.3 mg, 0.3 mmol) in THF (1.0 mL) was added phenylmagnesiumbromide (3.0 M in diethyl ether, 1.0 mL, 3.0 mmol) at 0° C. under argon atmosphere. After addition, the reaction mixture was slowly warmed to room temperature and further stirred overnight. To the reaction mixture was then added 2.0 mL of saturated aqueous NH4Cl at 0° C., dissolved in EtOAc (50 mL) and washed with H2O (10 mL) and brine (10 mL). The organic phase was dried over Na2SO4, concentrated in vacuo, and purified by silica gel chromatography (eluent: EtOAc in Hexanes: 0 to 33%) to afford (2,4-dichloro-6-(2-(isopropylsulfonyl)phenylamino)pyrimidin-5-yl)(phenyl)methanol as a colorless oil. MS (ES+): 452.0 (MH+).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18]C)=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:20][C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[C:8]=2[C:26]2[O:30][CH:29]=[N:28][CH:27]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+]>CO.C1COCC1.O.CCOC(C)=O>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([OH:18])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:20][C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[C:8]=2[C:26]2[O:30][CH:29]=[N:28][CH:27]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cnco3)n(CC(=O)N(C)C)c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)C(=O)Cn1c(-c2cnco2)c(C2CCCCC2)c2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-cyclohexyl-1-[2-(dimethylamino)-2-oxoethyl]-2-(1,3-oxazol-5-yl)-1H-indole-6-carboxylate (from Step 5) in MeOH/THF/H2O (0.05 M, 1:1:1, v:v:v) was added KOH (5 eq.). The resulting solution was stirred at RT overnight. The reaction mixture was diluted with EtOAc, then washed with hydrochloric acid (1N), brine, and dried over Na2SO4. Evaporation gave an off-white foam, which was purified by RP-HPLC (column: Waters X-terra C18, 19×150 mm, 5 micron; flow 20 mL/min) to give the title compound as a white powder after lyophilization (53%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:44]=[CH:45][C:46]=1[CH2:47][CH3:48])[CH2:6][C@@H:7]([NH:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([N:32]2[CH2:38][CH2:37][C:36]3[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=3[NH:34][C:33]2=[O:43])[CH2:28][CH2:27]1)=[O:25])[C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[CH2:12][CH2:11]1)=[O:9])[CH3:2].O.[CH:50]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:53]=[CH:52][C:51]=1[S:60]([OH:63])(=[O:62])=[O:61]>C(O)(C)C>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:44]=[CH:45][C:46]=1[CH2:47][CH3:48])[CH2:6][C@@H:7]([NH:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([N:32]2[CH2:38][CH2:37][C:36]3[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=3[NH:34][C:33]2=[O:43])[CH2:28][CH2:27]1)=[O:25])[C:8]([N:10]1[CH2:11][CH2:12][N:13]([CH:16]2[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]2)[CH2:14][CH2:15]1)=[O:9])[CH3:2].[CH:50]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:53]=[CH:52][C:51]=1[S:60]([O-:63])(=[O:62])=[O:61]
Reactant: O=S(=O)(O)c1ccc2ccccc2c1
Agent: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCN(C)CC3)CC2)cc1CC
Solvent: CC(C)O
Solvent: O
Product: O=S(=O)([O-])c1ccc2ccccc2c1
Temperature: 5 °C

Procedure:
0.25 g (0.38 mmol) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylic acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide and 86.2 mg (0.38 mmol) naphthalene-2-sulphonic acid monohydrate are suspended in 5 ml isopropanol and refluxed. The solution is cooled to ambient temperature within 6 days in 5° C. stages and filtered. The isolated solid is washed with isopropanol and dried for 12 hours at 60° C.
Reaction SMILES: [F:1][CH2:2][C@H:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([Cl:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)[CH3:4].C1(C(C)CO)C=CC=CC=1>>[F:1][CH2:2][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([Cl:14])(=[O:12])=[O:13])=[CH:9][CH:10]=1)[CH3:4]
Reactant: C[C@H](CF)c1ccc(S(=O)(=O)Cl)cc1
Agent: CC(CO)c1ccccc1
Product: CC(CF)c1ccc(S(=O)(=O)Cl)cc1

Procedure:
Following the procedures analogous to that used for the preparation of 4-((S)-2-fluoro-1-methyl-ethyl)-benzenesulfonyl chloride, but starting with 2-phenyl-1-propanol in step a.3.1, the title compound was prepared.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.Cl.[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:22][NH2:23].C(N(CC)CC)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:23][CH2:22][C:21]1[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:19]([F:18])[CH:20]=1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Reactant: COc1ccc(CN)cc1F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc1F
Reaction time: 0.25 h
Yield: 69.6 %

Procedure:
To a suspension of (4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (0.11 g, 0.39 mmol) and 3-fluoro-4-methoxy-benzylamine hydrochloride (75 mg, 0.39 mmol) in tetrahydrofuran (5 mL) is added triethylamine (0.13 mL, 0.98 mmol). After 15 minutes of stirring, the solvent is evaporated under reduced pressure. The solid material is collected by Buchner filtration, washed successively with diethyl ether, water, and methanol, and then dried under house vacuum to give (4Z)-6-bromo-4-{[(3-fluoro-4-methoxybenzyl)amino]methylene}isoquinoline-1,3(2H,4H)-dione as an off-white solid (0.11 g, 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([C:10]([OH:12])=O)[S:7][C:6]=2[CH:13]=1.[CH3:14][O:15][C:16](=[O:32])[CH:17]([CH:27]1[CH2:31][CH2:30][CH2:29][NH:28]1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=1>>[CH3:14][O:15][C:16](=[O:32])[CH:17]([CH:27]1[CH2:31][CH2:30][CH2:29][N:28]1[C:10]([C:8]1[S:7][C:6]2[CH:13]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[CH:9]=1)=[O:12])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=1
Reactant: O=C(O)c1cc2ccc(Cl)cc2s1
Reactant: COC(=O)C(Cc1cccc(C#N)c1)C1CCCN1
Product: COC(=O)C(Cc1cccc(C#N)c1)C1CCCN1C(=O)c1cc2ccc(Cl)cc2s1
Yield: 78.1 %

Procedure:
6-Chlorobenzo[b]thiophene-2-carboxylic acid (0.24 g, 1.14 mmol) is coupled to 3-(3-cyanophenyl)-2-(pyrrolidin-2-yl)-propionic acid methyl ester (0.295 g, 1.14 mmol) as described in EXAMPLE 1B to give 3-(3-cyanophenyl)-2-[1-(6-chlorobenzo[b]thiophene-2-carbonyl)-pyrrolidin-2-yl]-propionic acid methyl ester (0.40 g, 0.89 mmol). This material is treated and purified as described in EXAMPLE 1C to obtain the title compound (0.27 g, 0.46 mmol). NMR (DMSO-d6, 300 MHz) 9.31-9.15(m, 4H), 8.13(s, 1H), 7.95-7.85(m, 2H), 7.62-7.40(m, 5H), 4.53, 4.38(two m, 1H), 3.95-3.55(m, 2H), 3.60-3.53(m, 1H), 3.52-3.49(two s, 3H), 3.14-2.95(m, 1H), 2.94-2.80(m, 1H), 2.18-1.55(m, 4H): MS m/z: [M+H]+=470. Elemental analysis calculated with 1.0 mole of H2O: C=51.87, H=4.52, N=6.98; found C=51.93, H=4.23, N=6.75.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH3:16])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.C(OC(OCC)C[NH:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:35]([NH:34][C:10](=[O:12])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:14][CH2:15][CH3:16])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCOC(CNCc1ccccc1)OCC
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)NCc1ccccc1

Procedure:
The title compound was prepared according to the procedure described in Example 1, Step A except using 2(S)-t-butoxycarbonylaminohexanoic acid (1.98 g, 8.57 mmol), EDC.HCl (1.96 g, 10.28 mmol), N-benzyl 2-aminoacetaldehyde diethyl acetal (1.91 g, 8.57 mmol), HOBT (1.15 g, 8.57 mmol) in DMF. The title compound was obtained as a yellow oil.
Reaction SMILES: [H-].[Na+].[C:3]1([C@@H:9]2[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:17]1[C:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=2[N:20]=[CH:19][N:18]=1.[NH4+].[Cl-]>C1COCC1>[C:3]1([C@@H:9]2[CH2:10][CH2:11][C@H:12]([O:15][C:17]3[C:26]4[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=4[N:20]=[CH:19][N:18]=3)[CH2:13][CH2:14]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O[C@H]1CC[C@@H](c2ccccc2)CC1
Reactant: Clc1ncnc2c1CCCC2
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: c1ccc([C@H]2CC[C@@H](Oc3ncnc4c3CCCC4)CC2)cc1
Temperature: 50 °C

Procedure:
0.5 g (16.7 mmol) of 80% NaH was added in portions to a solution of 1.85 g (105 mmol) of cis-4-phenylcyclohexanol in 30 ml of absolute THF. After this, the mixture was heated for 1 hour at 50° C., and 1.5 g (8.75 mmol) of 4-chloro-5,6,7,8-tetrahydroquinazoline, dissolved in 15 ml of absolute THF, were added dropwise. The reaction mixture was subsequently refluxed for 2 hours. After the mixture had cooled to room temperature, it was poured into saturated NH4Cl solution and this was extracted with ether, and the combined organic phase was dried over MgSO4. The solvent was evaporated in vacuo, and the residue (2.7 g) was purified by flash chromatography over silica gel, using n-hexane/ethyl acetate (2:1). Concentration gave 1.5 g (50.2% of theory), colorless crystals, m.p. 109° C. ##STR12##
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[N:8][C:9]([NH:13][C@H:14]3[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]3)=[N:10]2)=[CH:5][CH:4]=1.C([S-])C.[Na+]>CN(C=O)C>[OH:20][C@H:17]1[CH2:16][CH2:15][C@H:14]([NH:13][C:9]2[N:8]=[CH:7][C:6]3[C:11](=[CH:12][C:3]([OH:2])=[CH:4][CH:5]=3)[N:10]=2)[CH2:19][CH2:18]1
Reactant: COc1ccc2cnc(N[C@H]3CC[C@H](O)CC3)nc2c1
Agent: CC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Oc1ccc2cnc(N[C@H]3CC[C@H](O)CC3)nc2c1
Temperature: 110 °C

Procedure:
To a solution of trans-4-[(7-methoxyquinazolin-2-yl)amino]cyclohexanol (161 mg, 0.583 mmol) in DMF (10 mL) was added sodium ethanethiolate (248 mg, 2.95 mmol) and the mix heated to 110° C. for 16 hours. The reaction was cooled and the residue was purified directly via Biotage F/C eluting with 5-10% MeOH/DCM to afford the title compound as an off-white solid, 120 mg, 78%. 1H NMR (400 MHz, DMSO-D6) δ ppm 10.28 (1H, s) 8.79 (1H, s) 7.57 (1H, d, J=8.59 Hz) 6.96 (1H, d, J=8.08 Hz) 6.54-6.79 (2H, m) 4.54 (1H, d, J=3.54 Hz) 3.74 (1H, d, J=3.28 Hz) 3.38 (1H, s) 1.67-1.93 (4H, m) 1.20-1.39 (4H, m); MS (API+) for C14H17N3O2 m/z 260.2 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[C:7]([S:9][CH3:10])[N:6]=[C:5]([S:11][CH3:12])[CH:4]=1.[CH:13](O)=[O:14]>>[CH3:10][S:9][C:7]1[N:6]=[C:5]([S:11][CH3:12])[CH:4]=[C:3]([CH2:2][NH:1][CH:13]=[O:14])[N:8]=1
Reactant: CSc1cc(CN)nc(SC)n1
Reactant: O=CO
Product: CSc1cc(CNC=O)nc(SC)n1

Procedure:
Using the method of Example 5, 6-aminomethyl-2,4-bis(methylthio)pyrimidine from Example 1, part E or Example 8 was reacted with formic acid to provide 2,4-bis(methylthio)-6-formylaminomethylpyrimidine as a light yellow solid. The structural assignment was confirmed by infrared and nuclear magnetic resonance spectral analyses.
Reaction SMILES: [CH:1]([CH:3]1[CH2:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1)=[CH2:2].C1C=C(Cl)C=C(C(OO)=[O:21])C=1>C(Cl)Cl>[O:21]1[CH2:2][CH:1]1[CH:3]1[CH2:12][CH2:11][C:6]2([O:7][CH2:8][CH2:9][O:10]2)[CH2:5][CH2:4]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CC1CCC2(CC1)OCCO2
Solvent: ClCCl
Product: C1COC2(CCC(C3CO3)CC2)O1
Temperature: 0 °C

Procedure:
To a solution of 8-vinyl-1,4-dioxaspiro[4.5]decane (370 mg, 2.20 mmol), prepared as described in Example 9 Step A, in DCM (20 mL) cooled to 0° C. was added mCPBA (532 mg, 2.37 mmol, 77%). The mixture was stirred warming to room temperature over 1 hour and then concentrated in vacuo without heating. The residue was purified by flash chromatography (silica gel, 0-50% ether/DCM) to afford the product.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:11]1([CH2:17][C:18]([OH:20])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].Cl>C(OC(=O)C)(=O)C.O.C(N(CC)CC)C>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:1]=[C:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:18]([OH:20])=[O:19])=[CH:3][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: O=C(O)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1ccc(C=C(C(=O)O)c2ccccc2)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Triethylamine was added to solution of p-anisaldehyde (10 g) and phenylacetic acid (10 g) in acetic anhydride (25 ml). Reaction mixture was stirred at 90° C. for 8 h. Reaction mixture was cooled and water (600 ml) solution of potassium carbonate (81 g) was added. After addition reaction mixture was heated at 60° C. for an hour. Before neutralising with concentrated hydrochloric acid the reaction mixture was cooled below 10° C. Precipitate was filtered and washed with water. 1H-NMR (400 MHz, d6-DMSO): 12.6 (bs, 1H), 7.67 (s, 1H), 7.4-7.3 (m, 3H), 7.2-7.1 (m, 2H), 7.0-6.9 (m, 2H), 6.8-6.7 (m, 2H), 3.70 (s, 3H). (M)+=254 (100%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C@H:6]([NH:20]C(OC(C)(C)C)=O)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH3:2].[ClH:29].O1CCOCC1>>[ClH:29].[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C@H:6]([NH2:20])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Reaction time: 1 h

Procedure:
To (R)-ethyl-4-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)butanoate (300 mg, 0.782 mmol) is added a solution of 4M HCl in 1,4-dioxane (3.92 mL, 15.65 mmol) at room temperature. After stirring for 1 hour, the reaction mixture is concentrated under reduced pressure to give (R)-3-amino-4-biphenyl-4-yl-butyric acid ethyl ester hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[S:8])[O:5][C:6]=1[CH3:7].C(N1C(=O)C2=CC=CC=[C:13]2[C:12]1=[S:21])C>>[CH3:1][C:2]1[N:3]=[C:4]([S:8][S:21][CH2:12][CH3:13])[O:5][C:6]=1[CH3:7]
Reactant: Cc1[nH]c(=S)oc1C
Reactant: CCN1C(=O)c2ccccc2C1=S
Product: CCSSc1nc(C)c(C)o1

Procedure:
Starting from 4,5-dimethyl-2-thiono-4-oxazoline and N-ethylthiophthalimide there is obtained (4,5-dimethyl-2-oxazolyl)ethyl-disulphide. nD20 =1.5467.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[N:12][C:13](S(C)=O)=[N:14][CH:15]=2)[N:10]2[CH:22]=[CH:23][N:24]=[C:9]12.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:28][CH:27]=1>C(OCC)(=O)C>[C:35]([O:34][C:33](=[O:39])[NH:32][C:29]1[CH:28]=[CH:27][C:26]([NH:25][C:13]2[N:12]=[C:11]3[C:16]([C:17](=[O:18])[N:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[C:9]4[N:10]3[CH:22]=[CH:23][N:24]=4)=[CH:15][N:14]=2)=[CH:31][CH:30]=1)([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Reactant: CS(=O)c1ncc2c(=O)n(-c3ccccc3Cl)c3nccn3c2n1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(Nc2ncc3c(=O)n(-c4ccccc4Cl)c4nccn4c3n2)cc1

Procedure:
A mixture of Example 1E (330.0 mg, 0.917 mmol) and tert-butyl 4-aminophenylcarbamate (306 mg, 1.468 mmol) was heated in a capped vial at 100° C. for 1 hour. The residue was dissolved in ethyl acetate and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4, filtered, concentrated, and purified on a 40 g column using the ISCO Companion flash system eluting with hexane/ethyl acetate (5:5 to 4:6) to provide the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[CH2:9][CH2:8]2)([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)[F:16].[B-](F)(F)(F)F.C1[N+]2(O)CC[N+](F)(CC2)C1>CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[CH:9]([F:16])[CH2:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(c1)CCC2=O
Reactant: F[B-](F)(F)F
Agent: O[N+]12CC[N+](F)(CC1)CC2
Solvent: CO
Product: CC(C)(C)c1ccc2c(c1)CC(F)C2=O

Procedure:
5-tert-butyl-indan-1-one (7.53 g, 40 mmol) was dissolved in methanol (400 ml). Accufluor (32.18 g) was added, and the reaction heated to reflux for 2 hours. After cooling and removing the solvent under vacuum, the residue was taken in methylene chloride and filtered. The filtrate was washed with water, dried with magnesium sulfate, and filtered, and the solvent removed under vacuum to give 5-tert-Butyl-2-fluoro-indan-1-one, which was used without further purification. 1H NMR (300 MHz, CDCl3) 7.73 (d, 1H), 7.48 (d, 1H), 7.45 (s, 1H), 5.18-5.35 (m, 1H), 3.54-3.65 (m, 1H), 3.12-3.29 (m, 1H), 1.36 (s, 9H). MS (CSI) m/e 224 (M+NH4)+
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](O)=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:25])=O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:25])=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1Cl
Temperature: 0 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
A suspension of 7-benzyloxy-3-nitroquinolin-4-ol (75.0 g, 253 mmol), which was made in a separate run, in 500 mL of N,N-dimethylformamide was placed under an atmosphere of nitrogen. The suspension was treated with phosphorous oxychloride (27.8 mL, 304 mmol) dropwise over 1.5 h. After 18 h, the reaction mixture was cooled to 0° C. and then poured into 1 L of ice water. The mixture was stirred until the ice had melted. A tan/yellow precipitate was collected by vacuum filtration. The solid was dissolved in dichloromethane (500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield 71.7 g of 7-benzyloxy-4-chloro-3-nitro-quinoline as an orange solid.
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[C:12]([C:13]2[O:17][N:16]=[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:11][CH:10]=[C:9]([NH2:26])[N:8]=1.[OH-].[Na+].[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34]Cl>CN(C)C=O>[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][C:15]2[CH:14]=[C:13]([C:12]3[C:7]([NH2:6])=[N:8][C:9]([NH2:26])=[CH:10][CH:11]=3)[O:17][N:16]=2)=[CH:20][CH:21]=1
Reactant: COc1cccc(CCl)c1
Reactant: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)c(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cccc(COc2ccc(Cc3cc(-c4ccc(N)nc4N)on3)cc2)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 77.7 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 4-(5-(2,6-diamino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (30 mg, 0.11 mmol) described in Manufacturing Example 18-1-1 was added a 5 N sodium hydroxide aqueous solution (21.2 μL, 0.11 mmol), which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was concentrated under a reduced pressure, which gave a white solid. To a mixture of this solid and N,N-dimethylformamide (1 mL) was added an N,N-dimethylformamide (1 mL) solution of 3-methoxybenzyl chloride (17.0 mg, 0.11 mmol), which was stirred for 12 hours at 60° C. This reaction mixture was cooled to room temperature, and then partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (34.4 mg, 81%).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:11]([OH:17])(=[O:16])[CH2:12][C:13]([CH3:15])=[O:14].C(O)(=O)C.N1CCCCC1>C1C=CC=CC=1.O>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[C:12]([C:13]([CH3:15])=[O:14])[C:11]([OH:17])=[O:16]
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: CC(=O)CC(=O)O
Solvent: CC(=O)O
Solvent: O
Solvent: c1ccccc1
Product: CC(=O)C(=Cc1cccc(Cl)c1Cl)C(=O)O

Procedure:
A mixture of 2,3-dichlorobenzaldehyde (0.88 g), 3-nitrooxy-2,2-bis(nitrooxymethyl)propyl ester of acetoacetic acid (1.78 g), acetic acid (50 mg), and piperidine (50 mg) in benzene (10 ml) was refluxed for 1.75 hours, during which time water formed was removed azeotropically. The resulting mixture was cooled, washed successively with water, an aqueous sodium bicarbonate and water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3-nitrooxy-2,2,-bis(nitrooxymethyl)propyl ester of 2-(2,3-dichlorobenzylidene)acetoacetic acid. Ethyl 3-aminocrotonate was mixed with the product obtained above. The resulting mixture was stirred for 1.5 hours at 80° to 90° C., and then cooled. The mixture in ethyl acetate was washed with an aqueous sodium chloride. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was subjected to column chromatography and eluted with a mixture of ethyl acetate and toluene (1:12 by volume). The fractions containing the desired compound were collected and evaporated under reduced pressure to give yellowish powders. The powders were recrystallized from ethanol to give yellowish crystals of 3-nitrooxy-2,2-bis(nitrooxymethyl)propyl ester of 4-(2,3-dichlorophenyl)-5-ethoxycarbonyl-2,6-dimethyl-1,4-dihydropyridine-3-carboxylic acid (1.39 g), mp 135° to 137° C.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:20].[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[C:30](Cl)=[O:31].C(N(CC)CC)C>C(Cl)Cl>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3](=[O:20])[CH:2]([NH:1][C:30]([C:22]2[NH:21][C:29]3[C:24]([CH:23]=2)=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:31])[N:8]=1
Reactant: NC1N=C(c2ccccc2F)c2ccccc2NC1=O
Reactant: O=C(Cl)c1cc2ccccc2[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1N=C(c2ccccc2F)c2ccccc2NC1=O)c1cc2ccccc2[nH]1
Reaction time: 0.17 h

Procedure:
3-(RS)-Amino-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (1.5 gm, 5.57 mmol), indole-2-carbonyl chloride (1.05 gm, 5.85 mmol) and triethylamine (0.814 ml, 5.85 mmol) were combined in CH2Cl2 (15 ml) and stirred 10 min. The reaction was concentrated and chromatographed on silica gel (5% MeOH in CH2Cl2) to give the title compound as a white solid from CH2Cl2 : (m.p. 290°-291°).