Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:7]([O:20][CH2:21][CH2:22][NH:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5]C)=[O:4].[OH-].[K+].O>O1CCOCC1>[OH:1][CH:2]([C:7]([O:20][CH2:21][CH2:22][NH:23][C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(O)C(OCCNC(=O)OCc1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(NCCOC(c1ccccc1)(c1ccccc1)C(O)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
22.2 g of methyl 2-hydroxy-3-(2-benzyloxycarbonylaminoethoxy)-3,3-diphenylpropionate (from Example 10) were dissolved in 300 ml of dioxane, mixed with 148 ml of 1M KOH and stirred at room temperature overnight. The reaction mixture was subsequently mixed with water and the aqueous phase was extracted with ether. The aqueous phase was acidified with hydrochloric acid and extracted with ether, the organic phase was dried over sodium sulfate and the solvent was distilled off. The residue (17.5 g) was directly used further.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([NH2:10])(=[O:9])=[O:8].N1C=CC=C(S(N[C:21](=[O:47])[O:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[C:35]4[CH:36]=[C:37]([Cl:44])[C:38]([C:40]([F:43])([F:42])[F:41])=[CH:39][C:34]=4[N:33]=[C:32]3[CH2:45][CH3:46])=[CH:27][CH:26]=2)(=O)=O)C=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([NH:10][C:21](=[O:47])[O:22][CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([N:31]2[C:35]3[CH:36]=[C:37]([Cl:44])[C:38]([C:40]([F:41])([F:43])[F:42])=[CH:39][C:34]=3[N:33]=[C:32]2[CH2:45][CH3:46])=[CH:29][CH:30]=1)(=[O:9])=[O:8]
Reactant: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCOC(=O)NS(=O)(=O)c2cccnc2)cc1
Reactant: NS(=O)(=O)c1ccccn1
Product: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCOC(=O)NS(=O)(=O)c2ccccn2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 243 from 2-pyridinesulfonamide (Naito, T.; et al., Chem. Pharm. Bull., 1955, 3, 38) and 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1 of Example 243).
Reaction SMILES: C([O:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[NH:24][C:23]4[CH:25]=[CH:26][C:27]([O:29][CH3:30])=[CH:28][C:22]=4[N:21]=3)[CH2:16][CH2:15]2)=[CH:9][CH:8]=1)(C)(C)C>C(O)(C(F)(F)F)=O>[CH3:30][O:29][C:27]1[CH:26]=[CH:25][C:23]2[NH:24][C:20]([N:17]3[CH2:18][CH2:19][CH:14]([NH:13][C:10]4[CH:11]=[CH:12][C:7]([C:6]([OH:31])=[O:5])=[CH:8][CH:9]=4)[CH2:15][CH2:16]3)=[N:21][C:22]=2[CH:28]=1
Reactant: COc1ccc2[nH]c(N3CCC(Nc4ccc(C(=O)OC(C)(C)C)cc4)CC3)nc2c1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2[nH]c(N3CCC(Nc4ccc(C(=O)O)cc4)CC3)nc2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of (12) (0.03 g, 0.071 mmol) in TFA (5 mL) was capped with a drying tube and stirred at 25° C. for 12 h. The reaction mixture was then concentrated to a light brown oily residue (0.033 g, 97.5%); 1H NMR (DMSO) δ 13.00 (br s, 1H), 7.68 (d, 2H, J=8.6), 7.30 (d, 1H, J=8.7), 6.92 (d, 1H, J=2.2), 6.85 (dd, 1H, J=8.0, 2.3), 3.99 (d, 2H, J=13.3), 3.78 (s, 3H), 3.70 (m, 1H), 3.46 (t, 2H, J=11.2), 2.09 (d, 2H, J=10.7), 1.56 (m, 2H); 13C NMR (DMSO) δ 167.4, 156.2, 151.3, 150.0, 131.2, 131.0, 124.0, 117.1, 111.9, 111.3, 110.3, 96.6, 55.7, 47.3, 45.4, 30.2; HRMS (FAB) m/z 367.1777 (M+H)+ (C20H22N4O3 requires 367.1765); Anal. (C20H22N4O3 ·1CF3COOH·3/4H2O) C, H, N.
Reaction SMILES: FC(S(O[C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[N:12]=[C:11]([NH:23][CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[N:10]=1)(=O)=O)(F)F.O.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>C(#N)C>[C:30]([O:29][C:27]([NH:26][CH2:25][CH2:24][NH:23][C:11]1[N:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[CH:14]=[C:9]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[N:10]=1)=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)NCCNc1nc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C#N)cc2)n1
Reactant: C1COCCN1
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCNc1nc(-c2ccc(C#N)cc2)cc(N2CCOCC2)n1
Temperature: 90 °C

Procedure:
2-({2-[(tert-butoxy)carbonylamino]ethyl}amino)-6-(4-cyanophenyl)pyrimidin-4-yl (trifluoromethyl)sulfonate (134 mg, 0.275 mmol) was dissolved in a 2 M solution of morpholine in acetonitrile and the resulting solution heated to 90° C. for 18h. The solution was cooled, water added and the suspension extracted thoroughly with ethyl acetate. Concentration of the combined organic layers gave a crude solid which was chromatographed (silica gel, 2% methanol/methylene chloride) to afford 234 mg of (tert-butoxy)-N-(2-{[4-(4-cyanophenyl)-6-morpholin-4-ylpyrimidin-2-yl]amino}ethyl)carboxamide as a off white solid. Removal of the tert-butoxy protecting group was accomplished in the following manner: the (tert-butoxy)-N-(2-{[4-(4-cyanophenyl)-6-morpholin-4-ylpyrimidin-2-yl]amino}ethyl)carboxamide produced as described above was dissolved in anhydrous hydrogen chloride in dioxane (2 mL of a 2M solution) and stirred at room temperature for 2 h. Concentration gave 134 mg of 4-{2-[(2-aminoethyl)amino]-6-imidazolyl-4-ylpyrimidin-4-yl}benzenecarbonitrile as its (2x) hydrochloride salt.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][CH:7]([CH2:9][CH2:10][OH:11])[CH3:8])[CH3:3].[H][H]>>[CH3:8][C@H:7]1[CH2:9][C:10](=[O:11])[C@H:4]([CH:2]([CH3:3])[CH3:1])[CH2:5][CH2:6]1
Reactant: CC(C)=CCCC(C)CCO
Reactant: [H][H]
Product: CC(C)[C@@H]1CC[C@@H](C)CC1=O

Procedure:
In another embodiment of the present invention, the present invention provides a process for producing menthol in good yields which comprises dehydrogenating citronellol in a reaction system containing a catalyst at a temperature of about 150° to about 260° C in an atmosphere of hydrogen under a pressure of 0 to about 5 kg/cm2.G to produce menthone, and then, in the same reaction system without separating the catalyst or adding additional catalyst, hydrogenating the menthone produced by decreasing the temperature to about 110° to about 130° C and increasing the hydrogen pressure to about 10 to about 50 kg/cm2.G to produce menthol.
Reaction SMILES: Br[CH:2](Br)[C:3]1[S:4][C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1.Cl.CC[OH:23]>[N+]([O-])([O-])=O.[Ag+]>[CH:2]([C:3]1[S:4][C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1)=[O:23]
Reactant: CCO
Reactant: CCOC(=O)c1nc(C(Br)Br)sc1-c1ccccc1
Agent: [Ag+]
Agent: Cl
Agent: O=[N+]([O-])[O-]
Product: CCOC(=O)c1nc(C=O)sc1-c1ccccc1

Procedure:
To a solution of an aqueous solution of the dibromo product (21b) obtained in Production Example 21 in EtOH was added an aqueous silver nitrate solution, followed by heating under reflux for 15 minutes. To the reaction liquid was added 1 M hydrochloric acid, the solid precipitated was removed by filtration, and the filtrate was then extracted with CHCl3. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:EtOAc) to obtain ethyl 2-formyl-5-phenyl-1,3-thiazole-4-carboxylate as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:9](I)=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].[CH2:12]([Sn](CCCC)(CCCC)CCCC)[CH:13]=[CH2:14].[Li+].[Cl-]>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:9]([CH2:14][CH:13]=[CH2:12])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: N#Cc1c(F)ccc(I)c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCc1ccc(F)c(C#N)c1Cl
Temperature: 100 °C

Procedure:
A mixture of 2-chloro-6-fluoro-3-iodobenzonitrile (800 mg, 2.85 mmol), allyltributylstannane (1.245 mg, 3.761 mmol), LiCl (431 mg, 10.3 mmol) and Pd(PPh3)4 (100 mg) in 50 mL toluene was heated at 100° C. overnight. Cooled to rt. and diluted with 50 mL EtOAc and filtered. The filtrate was washed with water and brine, dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified via prep-TLC (ethyl acetate/Pet ether=1:5) to give 2-chloro-6-fluoro-3-(prop-2-en-1-yl)benzonitrile. 1H-NMR (400 MHz, CDCl3) δ ppm 7.37˜7.41 (m, 1H), 7.01˜7.06 (m, 1H), 5.78˜5.87 (m, 1H), 4.99˜5.12 (m, 2H), 3.44 (d, J=6.3 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:17][O:16][C@H:15]([C:18]([F:21])([F:20])[F:19])[C@H:14]1[CH2:13][S:12][C:11]([NH2:22])=[N:10]2.S(=O)(=O)(O)O.[N+:28]([O-])([OH:30])=[O:29].[OH-].[Na+]>C(O)(C(F)(F)F)=O>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:28]([O-:30])=[O:29])=[CH:4][C:3]=1[C@:9]12[CH2:17][O:16][C@H:15]([C:18]([F:19])([F:21])[F:20])[C@H:14]1[CH2:13][S:12][C:11]([NH2:22])=[N:10]2
Reactant: NC1=N[C@@]2(c3cccc(F)c3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: NC1=N[C@@]2(c3cc([N+](=O)[O-])cc(F)c3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(4aS,5S,7aS)-7a-(2,3-Difluorophenyl)-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine (1.42 g) was dissolved in TFA (6 mL), and the solution was cooled to 0° C. Sulfuric acid (conc., 1 mL) was added, followed by fuming nitric acid (0.30 mL) dropwise over 20 mins. After stirring at 0° C. for 1 h, the reaction mixture was poured onto ice (50 g) and basified to pH 12 with 2 N NaOH (aq.). After allowing the ice to melt, the mixture was extracted with EtOAc (3×75 mL), and the combined organic portions dried over MgSO4 and evaporated to afford the title compound (1.91 g, purity approx. 80%) which was used in the subsequent step without purification. 1H NMR (400 MHz, CDCl3) δ ppm 2.88 (dd, J=13.8, 3.9 Hz, 1 H), 3.11 (dd, J=13.6, 2.8 Hz, 1 H), 3.37 (dt, J=7.4, 3.5 Hz, 1 H), 3.93 (d, J=7.8 Hz, 1 H), 4.53-4.83 (m, 4 H), 8.09 (ddd, J=9.0, 6.3, 2.9 Hz, 1 H), 8.27 (dt, J=5.2, 2.6 Hz, 1 H)
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(=[S:3])[NH2:2].C([O-])(=O)C.[Na+].Br[CH:22]([CH:25]=O)[CH:23]=[O:24]>C1COCC1.C(O)(=O)C>[CH:23]([C:22]1[S:3][C:1]([N:4]2[CH2:8][CH2:7][CH2:6][C@H:5]2[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[N:2][CH:25]=1)=[O:24]
Reactant: O=CC(Br)C=O
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1c1ncc(C=O)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.7 %

Procedure:
To a solution of material from Example 78 (1.075 g, 4.67 mmol) in a mixture of THF (51.3 mL) and acetic acid (8.55 mL) is added sodium acetate (0.46 g, 5.60 mmol), followed by 2-bromomalonaldehyde (0.82 g, 5.13 mmol) and the reaction is stirred at room temp for 2 h. The solvent is removed in vacuo, the residue is partitioned between water and CH2Cl2 and the water layer is extracted with CH2Cl2 (1×20 mL). The organic layers are combined, partitioned with water and treated with solid sodium bicarbonate until the water layer has pH=8. The water layer is extracted with CH2Cl2 (2×25 mL), the organic layers are combined, washed with brine, dried over MgSO4, filtered and the solvent is removed in vacuo, The resulting residue is purified by BIOTAGE® Silica gel chromatography on a Thompson Single Step silica cartridge using an isocratic mixture of 40% ethyl acetate/60% CH2Cl2 to give 945 mg (68.1%) of the title compound as a yellow solid. LC/MS (Condition A): ret. T=3.23 min, (M+Na) 305.14. 1H NMR (400 MHz, chloroform-d) δ ppm 9.69 (1 H, s), 7.89 (1 H, s), 4.49 (1 H, br. s.), 3.36-3.87 (2 H, m), 2.32-2.51 (1 H, m), 2.03-2.29 (3 H, m), 1.46 (9 H, s).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([NH:12][C:13]([CH3:45])([CH3:44])[C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[CH2:41][NH2:42])=[CH:31][CH:30]=2)[C:18]1=[O:43])=[O:15])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:46][N:47]([CH3:51])[C:48](Cl)=[O:49]>>[CH2:2]([O:9][C:10]([NH:12][C:13]([CH3:45])([CH3:44])[C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[CH2:41][NH:42][C:48]([N:47]([CH3:51])[CH3:46])=[O:49])=[CH:33][CH:34]=2)[C:18]1=[O:43])=[O:15])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3CN)cc2)C1=O
Agent: Cl
Product: CN(C)C(=O)NCc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)C(C)(C)NC(=O)OCc3ccccc3)CCc3ccccc32)cc1

Procedure:
Prepared from 2-benzyloxycarbonylamino-2-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(aminomethyl)[1,1'-biphenyl]-4-yl]-methyl]-1H-benzazepin-3(R)-yl]propanamide, hydrochloride (Example 35, Step I) and dimethylcarbamyl chloride according to the procedure described in Example 37, Step A. 1H NMR (200 MHz, CD3OD): δ 1.39 (s, 6H), 1.82 (m, 1H), 2.18-2.58 (m, 3H), 2.81 (s, 6H), 4.20 (d, 5 Hz, 2H), 4.32 (m, 1H), 4.86 (d, 15 Hz, 1H), 5.01 (s, 2H), 5.31 (d, 15 Hz, 1H), 6.40 (t, 5 Hz, 1H), 7.06-7.40 (m, 17H). FAB-MS: calculated for C39H43N5O5 661; found 662 (M+H, 80%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22](Cl)(=[O:24])=[O:23])([O-:15])=[O:14]>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N+:13]([O-:15])=[O:14])(=[O:23])=[O:24])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: Cc1ccc(N)c2ncccc12
Product: Cc1ccc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])c2ncccc12
Yield: 54.5 %

Procedure:
In a similar fashion using route 14 general procedure 27, 5-methylquinolin-8-amine (Intermediate 44) (690 mg, 4.38 mmol) and 2-nitrobenzenesulfonyl chloride (1.15 g, 5.24 mmol) gave the title compound (820 mg, 57%). The structure was confirmed by 1H NMR.
Reaction SMILES: [CH3:1][CH:2]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:3]([C:5]1[CH:6]=[C:7]([OH:12])[CH:8]=[C:9]([CH:11]=1)[OH:10])[CH3:4].[CH3:18][C:19]1([CH3:30])[S:23][CH:22]([C:24](OCC)=[O:25])[C:21](=O)[CH2:20]1>C(O)C>[CH3:18][C:19]1([CH3:30])[S:23][C:22]2[C:24](=[O:25])[O:10][C:9]3[CH:11]=[C:5]([CH:3]([CH:2]([CH3:1])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:4])[CH:6]=[C:7]([OH:12])[C:8]=3[C:21]=2[CH2:20]1
Reactant: CCOC(=O)C1SC(C)(C)CC1=O
Reactant: CCCCCC(C)C(C)c1cc(O)cc(O)c1
Solvent: CCO
Product: CCCCCC(C)C(C)c1cc(O)c2c3c(c(=O)oc2c1)SC(C)(C)C3
Reaction time: 72 h

Procedure:
To 100 ml. of ethanol was added 6.2 g. of 5-(3-methyl-2-octyl)resorcinol and 6.2 g. of ethyl 5,5-dimethyl-3-oxotetrahydrothiophene-2-carboxylate. The mixture was cooled in ice and hydrogen chloride was bubbled in for one-half hour. The mixture was stoppered and held at room temperature for 3 days. It was then concentrated and ether added, extracted with water and then washed with dilute aqueous sodium bicarbonate solution. The etheral solution was dried over magnesium sulfate and concentrated. The product was crystallized from acetonitrile to give 5.0 g., m.p. 155°-163°C.
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]([N:10]=[C:11]=[O:12])=[N:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[O:13]1[CH2:17][CH2:16][O:15][CH:14]1[CH2:18][NH:19][CH2:20][CH3:21]>C1C=CC=CC=1>[C:1]([C:5]1[S:6][C:7]([NH:10][C:11]([N:19]([CH2:18][CH:14]2[O:15][CH2:16][CH2:17][O:13]2)[CH2:20][CH3:21])=[O:12])=[N:8][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nnc(N=C=O)s1
Reactant: CCNCC1OCCO1
Solvent: c1ccccc1
Product: CCN(CC1OCCO1)C(=O)Nc1nnc(C(C)(C)C)s1
Reaction time: 1 h

Procedure:
2-t-Butyl-1,3,4-thiadiazol-5-yl isocyanate dimer (3grams) and a solution of N-(1,3-dioxolan-2-ylmethyl)-N-ethylamine (2 grams) in benzene (10 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The mixture is warmed on a steam bath with stirring for a period of about 1 hour. After this time the mixture is stripped of solvent under reduced pressure to yield a solid residue. The residue is recrystallized to yield the desired product N-(2-t-butyl-1,3,4-thiadiazol-5-yl) -N'-(1,3-dioxolan-2-ylmethyl)-N'-ethylurea.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([N:19]3[CH:23]=[CH:22]N=C3)=[O:18])=[C:4]2[CH2:3]1.C(=NO)([NH2:26])C>CN(C)C=O>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]3[O:18][N:26]=[C:23]([CH3:22])[N:19]=3)=[C:4]2[CH2:3]1
Reactant: CC(N)=NO
Reactant: CN1Cc2c(C(=O)n3ccnc3)ncn2-c2ccccc2C1=O
Solvent: CN(C)C=O
Product: Cc1noc(-c2ncn3c2CN(C)C(=O)c2ccccc2-3)n1
Reaction time: 5.5 h

Procedure:
9.30 g (30.2 mmol) of 1-[(5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepin-3-yl)carbonyl]imidazole are suspended in 60 ml of N,N-dimethylformamide and the suspension is treated with 3.0 g (40.5 mmol) of acetamidoxime. After stirring at 60° for 5.5 hours the mixture is evaporated to dryness, 70 ml of glacial acetic acid are added to the residue and the solution is heated to 120° for 2.5 hours. The solution is then evaporated and the residue is partitioned between methylene chloride and saturated sodium bicarbonate solution. The organic phase is separated, dried over magnesium sulphate and evaporated. By recrystallization of the residue from methylene chloride and ethyl acetate there is obtained 4,5-dihydro-5-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 257°-260°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)(=[O:21])=[O:20])=[CH:15][C:14]=2[O:29][CH2:30][C:31](OC)=[O:32])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][NH2:36]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)(=[O:20])=[O:21])=[CH:15][C:14]=2[O:29][CH2:30][C:31](=[O:32])[NH:36][CH3:35])[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CN
Reactant: COC(=O)COc1cc(S(=O)(=O)c2cccc(F)c2)ccc1C1CCN(C(=O)OC(C)(C)C)C1
Product: CNC(=O)COc1cc(S(=O)(=O)c2cccc(F)c2)ccc1C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 90 °C

Procedure:
A mixture of 3-[4-(3-fluoro-benzenesulfonyl)-2-methoxycarbonylmethoxy-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (120 mg, prepared as described in Example 13) and methylamine (2M in THF, 1.2 mL) was heated at 90° C. in a sealed tube for 16 hours. The reaction mixture was cooled and concentrated under reduced pressure, and the crude residue was purified via flash chromatography (hexane/EtOAc, 3/7) to give 109 mg of 3-[4-(3-fluoro-benzenesulfonyl)-2-methylcarbamoylmethoxy-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester as a colorless oil.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:52][CH3:53])=[C:42]([O:45][CH:46]4[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]4)[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1.C(N(C(C)C)CC)(C)C.[CH3:64][C:65]1[C:69]([C:70](O)=[O:71])=[C:68]([CH3:73])[O:67][N:66]=1>C(Cl)Cl>[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:52][CH3:53])=[C:42]([O:45][CH:46]4[CH2:47][CH2:48][N:49]([C:70]([C:69]5[C:65]([CH3:64])=[N:66][O:67][C:68]=5[CH3:73])=[O:71])[CH2:50][CH2:51]4)[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: Cc1noc(C)c1C(=O)O
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(=O)c2c(C)noc2C)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 32.3 %

Procedure:
HATU (0.31 g) was added to a solution of N-(3-chloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride (300 mg), diisopropylethylamine (0.45 ml) and 3,5-dimethyl-4-isoxazolecarboxylic acid (0.141 g) in methylene chloride (9 ml). The resulting mixture was stirred at room temperature for 2.5 hrs. Methylene chloride (20 ml) was added and the organics washed with aqueous sodium hydroxide (2M, 30 ml) and water (30 ml). The crudes were then purified by flash column chromatography eluting with methanol/methylene chloride (2.5/97.5). Fractions containing the desired product were evaporated to a white foam which was triturated with diethyl ether (20 ml) to give N-(3-chloro-2-fluorophenyl)-6-({1-[(3,5-dimethylisoxazol-4-yl)carbonyl]piperidin-4-yl}oxy)-7-methoxyquinazolin-4-amine as a white solid (0.107 g). 1H NMR Spectrum: (DMSO d6 373K) 1.80 (m, 2H), 2.01 (m, 2H), 2.20 (s, 3H), 2.40 (s, 3H), 3.47 (m, 2H), 3.75 (m, 2H), 3.96 (s, 3H), 4.76 (m, 1H), 7.23 (m, 1H), 7.23 (s, 1H), 7.40 (m, 1H), 7.58 (m, 1H), 7.89 (s, 1H), 8.39 (s, 1H), 9.25 (br s, 1H); Mass Spectrum: (M+H)+ 526.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C(=O)N([Br:27])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:27][C:8]1[NH:9][C:10]2[C:15]([C:7]=1[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)=[CH:14][CH:13]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:11]=2
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c[nH]c2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.6 %

Procedure:
To a solution (0.14 M) of methyl 3-cyclohexyl-1H-indole-6-carboxylate (from Step 2) in CCl4 was added freshly crystallized NBS (1.1 eq.) portionwise over a period of 1 h at RT. The resulting mixture was stirred for 2 h at RT, then washed with water (3×) and a saturated aqueous solution of sodium thiosulfate (2×). After phase cut, the aqueous phases were back-washed with EtOAc and die combined organic phases dried over Na2SO4 and evaporated. The resulting brown solid was dissolved in hot DCM and filtered rapidly over a pad of silica-gel using DCM as the eluant to give the title compound (49.6%) as a solid, 1H NMR (300 MHz, DMSO-d6, 300 K) δ 1.32-1.48 (m, 3H), 1.65-1.99 (m, 7H), 2.69-2.89 (m, 1H), 3.89 (s, 3H), 7.59 (d, J 7.6, 1H), 7.75 (d, J 7.6, 1H), 7.92 (s, 1H), 12.02 (br s, 1H); MS (ES+) m/z 337 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C1(P(=[CH:29][CH:30]=[O:31])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:29][CH:30]=[O:31])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: O=CC=Cc1cccc(Cl)c1
Yield: 59.4 %

Procedure:
A solution of 3.00 g of 3-chlorobenzaldehyde and 6.49 g of (triphenylphosphoranylidene)acetaldehyde in 100 ml of acetonitrile was heated under reflux for 5 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 2.11 g (yield 59%) of 3-(3-chlorophenyl)-2-propenal as a solid.