Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[CH2:7]([N:9]([CH2:22][CH3:23])[C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][NH:20][CH3:21])[CH2:14][CH2:13]1)=[O:11])[CH3:8].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:6])[C:3]([N:20]([CH3:21])[CH2:19][CH2:18][N:15]1[CH2:16][CH2:17][N:12]([C:10](=[O:11])[N:9]([CH2:22][CH3:23])[CH2:7][CH3:8])[CH2:13][CH2:14]1)=[O:4]
Reactant: CN(C)C(=O)Cl
Reactant: CCN(CC)C(=O)N1CCN(CCNC)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCN(CC)C(=O)N1CCN(CCN(C)C(=O)N(C)C)CC1
Temperature: 100 °C

Procedure:
5.4 g (0.05 mole) of dimethyl carbamic acid chloride dissolved in 20 cc. of toluene are added dropwise with stirring at room temperature to a solution of 12.1 g (0.05 mole) of 1-diethylcarbamoyl-4-(2-methylamino ethyl)-piperazine and 5.1 g (0.05 mole) of triethylamine in 40 cc. of toluene. Thereafter, the reaction mixture is stirred for another hour at about 100° C. The reaction mixture is cooled and the precipitated triethylamine hydrochloride is filtered off with suction and the filtrate is evaporated. The residue is dissolved in 150 cc. of ether, the ethereal solution is washed twice with 150 cc. of 5 n NaOH each time and the resulting solution is dried over anhydrous Na2SO4. Upon evaporation of the ether, 15.3 g (97.6% of the theoretical) of the oily crude urea are obtained.
Reaction SMILES: Cl.O1CCOCC1.[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:34]C)[N:19]2[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]2[CH2:31][CH2:30][O:29][C:28]([CH3:33])([CH3:32])[CH2:27]2)=[C:15]([NH2:36])[N:14]=1)[CH2:9][CH2:10][CH3:11]>CO>[NH2:36][C:15]1[N:14]=[C:13]([NH:12][CH2:8][CH2:9][CH2:10][CH3:11])[N:21]=[C:20]2[C:16]=1[NH:17][C:18](=[O:34])[N:19]2[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][O:29][C:28]([CH3:33])([CH3:32])[CH2:27]1
Reactant: CCCCNc1nc(N)c2nc(OC)n(CCCCC3CCOC(C)(C)C3)c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCCCNc1nc(N)c2[nH]c(=O)n(CCCCC3CCOC(C)(C)C3)c2n1
Reaction time: 8 h
Yield: 81.4 %

Procedure:
4M HCl in 1,4-dioxane (3 ml, 12.00 mmol) was added in one portion to a stirred solution of N2-butyl-9-[4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)butyl]-8-(methyloxy)-9H-purine-2,6-diamine (130 mg, 0.321 mmol) in methanol (3 ml) at room temperature and the mixture stirred under nitrogen overnight. The mixture was then concentrated and the residue dissolved in MeOH:DCM (1:15 ml) and loaded onto a 2 g aminopropyl SPE cartridge. The cartridge was washed with MeOH:DCM (1:1, 3 column volumes) and the desired fractions were concentrated in vacuo to give the title compound as a yellow solid (102 mg).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([CH:8]([OH:25])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH2:13][CH2:12]2)=[O:7])=[CH:4][CH:3]=1.[C:28](Cl)([Cl:30])=[O:29]>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[ClH:30].[ClH:30].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[O:7][C:28](=[O:29])[O:25][C:8]=2[CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH2:15][CH2:16]2)=[CH:26][CH:27]=1
Reactant: O=C(Cl)Cl
Reactant: COc1ccccc1N1CCN(CCC(O)C(=O)c2ccc(F)cc2)CC1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccccc1N1CCN(CCc2oc(=O)oc2-c2ccc(F)cc2)CC1
Product: Cl
Temperature: 0 °C

Procedure:
A solution of 20 g of 1-p-fluorobenzoyl-1-hydroxy-3-(4-(2-methoxyphenyl)-1-piperazinyl)propane in 200 cc of anhydrous chloroform is added in 60 minutes to 33 ml of a 20% phosgene solution in toluene, stirred and cooled to 0° C.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][C:15]=1[N+:22]([O-:24])=[O:23]>>[N+:22]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:14]=1[N:10]1[CH2:11][CH2:12][CH:7]([CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:8][CH2:9]1)[CH:18]=[O:19])([O-:24])=[O:23]
Reactant: O=Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: C1CCN(CC2CCNCC2)C1
Product: O=Cc1ccc(N2CCC(CN3CCCC3)CC2)c([N+](=O)[O-])c1

Procedure:
Prepared from the product of Example 4 and 4-fluoro-3-nitro-benzaldehyde.
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([Cl:14])[C:8]=2[CH2:7][CH2:6][C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]1=2.[CH3:19][S:20]([NH:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)(=[O:22])=[O:21]>>[Cl:14][C:13]1[C:8]2[CH2:7][CH2:6][C:5]3[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=3[C:3](=[CH:2][C:26]3[CH:25]=[C:24]([NH:23][S:20]([CH3:19])(=[O:22])=[O:21])[CH:29]=[CH:28][CH:27]=3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Reactant: Clc1cccc2c1CCc1ccccc1C2=CBr
Product: CS(=O)(=O)Nc1cccc(C=C2c3ccccc3CCc3c(Cl)cccc32)c1
Yield: 79.5 %

Procedure:
Following procedures essentially as described in Example 219, below, and using 5-bromomethylene-1-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (100 mg, 0.313 mmol) and 3-methanesulfonylamino-phenylboronic acid (74 mg, 0.344 mmol), affords 102 mg (79%) of the title compound (Example 205(a)) as a mixture of geometric isomers. MS (ES) 408 (M−H); HPLC reveals a 57:43 mixture of geometric isomers—54% at 3.061 min, 40% at 3.197 min—overall 94% purity. Separate geometric isomers on a 1000 micron silica gel chromatatron rotor, (10% to 13% ethyl acetate/hexanes) to afford 22 mg (17%) of the Z-isomer of the title compound (Example 205(b), (MS (ES) 410 (M+H). HPLC shows 98% purity. Continue to elute to give 11 mg (9%) of the E-isomer of the title compound (Example 205(c)) (MS (ES) 410 (M+H), 408 (M−H); HPLC shows 94% purity).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][C:9]([O-:11])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[Na+].[Br:13][C:14]1[C:15]([CH3:21])=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[Br:13][C:14]1[C:15]([CH3:21])=[C:16]([NH:17][C:9](=[O:11])[CH2:8][C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: O=C([O-])Cc1ncccc1Cl
Reactant: Cc1c(N)cccc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1c(Br)cccc1NC(=O)Cc1ncccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
A mixture of sodium 2-(3-chloropyridin-2-yl)acetate (7.39 g, 38 mmol), 3-bromo-2-methylaniline (4.7 mL, 38.4 mmol), DIEA (13.3 mL, 76 mmol) and HATU (14.6 g, 38.4 mmol) in DMF (127 mL) was stirred at room temperature. After 90 min the mixture was diluted with EtOAc and washed twice with 10% LiCl, then with brine. The combined aqueous layers were extracted with EtOAc, and the combined organic phases were dried and concentrated to a small volume. The solution was seeded with a crystal from an earlier batch and allowed to stand overnight to provide a precipitate which was collected by filtration and washed with 50% EtOAc-hexanes to provide a white solid. The filtrate was concentrated and recrystallized similarly three times to provide additional solid. The solids were combined to give N-(3-bromo-2-methylphenyl)-2-(3-chloropyridin-2-yl)acetamide as a white solid (11.43 g, 89% yield). Mass spectrum m/z 339, 341 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ 9.76 (br. s., 1H), 8.52 (d, J=3.5 Hz, 1H), 7.92 (d, J=7.9 Hz, 1H), 7.80 (dd, J=8.1, 1.1 Hz, 1H), 7.36 (d, J=7.9 Hz, 1H), 7.32-7.23 (m, 1H), 7.06 (t, J=8.0 Hz, 1H), 4.16 (s, 2H), 2.39 (s, 3H).
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:35]=[C:34]2[C:29]([CH2:30][CH2:31][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:33]2)=[CH:28][CH:27]=1>C(OCC)(=O)C>[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[CH:15]=[N:14][C:13]([NH:25][C:26]3[CH:35]=[C:34]4[C:29]([CH2:30][CH2:31][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:33]4)=[CH:28][CH:27]=3)=[N:12][C:11]=2[N:10]2[CH:22]=[CH:23][N:24]=[C:9]12
Reactant: CS(=O)c1ncc2c(=O)n(-c3ccccc3Cl)c3nccn3c2n1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2C1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Nc3ncc4c(=O)n(-c5ccccc5Cl)c5nccn5c4n3)cc2C1

Procedure:
A mixture of Example 1E (0.900 g, 2.501 mmol) and tert-butyl 7-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.994 g, 4.00 mmol) was heated in a capped vial at 90° C. for 1 hour. The reaction mixture were suspended and stirred in ethyl acetate. The solids were filtered and washed with ethyl acetate. The filter cake was stirred in saturated aqueous NaHCO3, filtered, washed with water, and oven-dried to provide the title compound. The filtrate was diluted with ethyl acetate and washed with saturated NaHCO3. The organic layer was dried over MgSO4, filtered, concentrated, and purified on an 80 g column using the ISCO Companion flash system eluting with CH2Cl2/ethyl acetate (6:4 to 5:5) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.44 (s, 9H), 2.77 (t, J=5.75 Hz, 2H), 3.58 (t, J=5.75 Hz, 2H), 4.54 (s, 2H), 7.07 (d, J=1.59 Hz, 1H), 7.21 (d, J=8.72 Hz, 1H), 7.53-7.66 (m, 5H), 7.69-7.74 (m, 1H), 7.76 (d, J=1.59 Hz, 1H), 9.12 (s, 1H), 10.71 (s, 1H). MS (ESI+) m/z 544.1 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([Li])CCC.[Cl-].[C:17]1([PH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CCCCCC.CCOCC>[C:24]1([P:23]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][N:2]([CH3:10])[CH3:1])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CN(C)Cc1ccccc1
Reactant: c1ccc(Pc2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Solvent: CCCCCC
Product: CN(C)Cc1ccccc1P(c1ccccc1)c1ccccc1
Reaction time: 30 h

Procedure:
A 15.0 ml portion of N,N-dimethylbenzenemethanamine and 300 ml of ether were mixed under a nitrogen atmosphere. A 58 ml portion of 2.6M butyl lithium in hexane was added and this mixture was stirred, under nitrogen for 30 hours. A mixture of 27.0 ml of diphenylphosphine chloride in 60 ml of ether was added dropwise and the mixture was stirred overnight. Water was added, the organic layer was separated and extracted twice with dilute hydrochloric acid. The combined acid extracts were basified with 10% sodium hydroxide, then extracted twice with ether. The ether extracts were combined, dried and evaporated, giving 15.9 of 2-(diphenylphosphino)-N,N-dimethylbenzenemethanamine as an oil.
Reaction SMILES: Cl[CH:2]([CH3:8])[C:3]([N:5]([CH3:7])[CH3:6])=[O:4].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[C:17]1[C:21]([CH3:22])=[CH:20][NH:19][N:18]=1.[CH3:23]C1C(C2C=CC=CC=2)=NNC=1>>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[C:17]1[C:21]([CH3:22])=[CH:20][N:19]([CH:2]([CH2:8][CH3:23])[C:3]([N:5]([CH3:7])[CH3:6])=[O:4])[N:18]=1
Reactant: Cc1c[nH]nc1-c1ccccc1
Reactant: CC(Cl)C(=O)N(C)C
Reactant: Cc1ccc(Cl)c(-c2n[nH]cc2C)c1
Product: CCC(C(=O)N(C)C)n1cc(C)c(-c2cc(C)ccc2Cl)n1

Procedure:
Using the procedure of Example 1, but substituting 2-bromo-N,N-dimethylbutyramide for 2-chloro-N,N-dimethylpropionamide and 3-(2-chloro-5-methylphenyl)-4-methylpyrazole for 4-methyl-3-phenylpyrazole there is obtained 3-(2-chloro-5-methylphenyl)-α-ethyl-N,N,4-trimethylpyrazole-1-acetamide isolated as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([NH:12][C:13](=[O:20])[CH2:14][C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)[CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].C1(C)C=CC=CC=1.CO>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6](=[O:8])[CH:14]([C:15]3[CH:19]=[CH:18][S:17][CH:16]=3)[C:13](=[O:20])[NH:12]2)=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)Cc1ccsc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: O=C1Nc2cc(Cl)ccc2C(=O)C1c1ccsc1
Reaction time: 2 h

Procedure:
To a solution of thiophene-3-acetic acid (1.4 g, 10 mmol) in dichloromethane (40 ml) was added oxalyl chloride (1.74 ml, 20 mmol) and dimethylformamide (catalytic, 3 drops) and the reaction stirred for 1 h. The solvent was evaporated and the residue co-evaporated with toluene (3×20 ml). The resulting acid chloride was dissolved in 1,2-dichloroethane (40 ml), methyl 2-amino-4-chlorobenzoate (1.5 g, 8 mmol) added and the reaction refluxed for 2 h. The residue remaining on evaporation of the solvent was triturated with diethyl ether to afford methyl 4-chloro-2-(3-thienyl)acetamidobenzoate as a tan solid (1 g), m.p. 96°-97° C. To a solution of the foregoing amide (0.5 g, 1.6 mmol) in tetrahydrofuran (25 ml) was added a solution of potassium hexamethyldisilazide in toluene (0.5M, 4 mmol) and the reaction stirred for 2 h. Methanol (5 ml) was added and the solvent evaporated. The residue was partitioned between aqueous sodium hydroxide (1M, 20 ml) and diethyl ether (20 ml), and the aqueous layer acidified with hydrochloric acid (5M). The resultant precipitate was collected and recrystallised from dimethylformamide/water to afford the title compound as a white solid; m.p. 341°-344° C. (from DMF/H2O) (Found: C, 55.07; H, 2.86; Cl, 12.94; N, 5.16; S, 11.42; C13H8ClNO2S, 0.5 H2O requires C, 55.32; H, 3.03, Cl, 12.56; N, 4.96; S, 11.36%); δ(DMSO-d6) 7.22 (1H, dd, J=8.6 and 2 Hz, 6-H), 7.31 (1H, s, 8-H), 7.43 (1H, d, J=4.9 Hz, 5'-H), 7.49-7.51 (1H, m, 4'-H), 7.76 (1H, s, 2'-H), 7.98 (1H, d, J=8.6 Hz, 5-H), 11.55 (1H, s, NH); m/z 277 (M+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:29]1[CH2:31][C@@H:30]1[CH2:32][O:33][C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[N:37]=[CH:36][CH:35]=1>C(O)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([CH2:31][C@@H:30]([OH:29])[CH2:32][O:33][C:34]3[C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[N:37]=[CH:36][CH:35]=3)[CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCNCC1
Reactant: c1ccc2c(OC[C@H]3CO3)ccnc2c1
Solvent: CCO
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCN(C[C@@H](O)COc2ccnc3ccccc23)CC1
Temperature: 25 °C
Yield: 46.4 %

Procedure:
Piperidine-4-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (4) (70.3 mg; 0.186 mmol) is dissolved in ethanol (10 mL) at ambient temperature. (R)-4-Oxiranylmethoxy-quinoline (91) (37.4 mg; 0.186 mmol) is added, then the mixture is refluxed for 22 hours. After cooling to ambient temperature, the solution is concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (50%→100% acetone in hexanes, then 5%→20% ethanol in acetone) affording the desired product (50 mg) as a yellow solid. ESMS: MH+ 580.4.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]([NH2:10])=O.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].P(Cl)(Cl)(Cl)=O>O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]#[N:10]
Reactant: NC(=O)C=Cc1cccs1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: N#CC=Cc1cccs1
Reaction time: 1 h

Procedure:
β-(Thien-2-yl) acrylamide (5.2 g.) was mixed with sodium metabisulphite (12.9 g.) and heated with phosphoryl chloride (2.4 ml.) on a steam bath. After 1 hr., more phosphoryl chloride (10 ml.) was added and the mixture heated for a further 3.5 hrs. The mixture was cooled in an ice-bath and iced water cautiously added. The mixture was extracted into chloroform and the chloroform layer was washed with saturated sodium hydrogen carbonate solution, dried over sodium sulphate, and evaporated in vacuo to a brown oil. Distillation gave β-(thien-2 -yl) acrylonitrile, 1.50 g. (33%), b.p. 82- 86° /0.5 mm., λmax. (EtOH) 306 nm, (ε 18600).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C@H:4]([CH:6]([CH3:8])[CH3:7])[NH2:5].[CH3:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[Cl-].N1CC[O:21]CC1>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3](=[O:9])[C@H:4]([CH:6]([CH3:8])[CH3:7])[NH:5][C:10]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:21]
Reactant: C1COCCN1
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: CN1CCOCC1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)[C@@H](NC(=O)N1CCOCC1)C(C)C
Reaction time: 8 h

Procedure:
HCL-Valine methyl ester (25 g) was dissolved under argon in 600 mL of freshly distilled THF and 100 mL of dry DMF and 1.0 equivalents of N-methyl morpholine. The resulting solution was cooled to -15° and an additional 1.1 equivalent of N-methyl morpholine followed by 1.1 equivalents of morpholine chloride was added. The reaction was allowed to come slowly to room temperature and stir overnight. The reaction is then poured into 300 mL of 1N HCL and extracted with ethyl acetate (2×200 mL). The combined organic fractions were washed with 1N HCL (50 mL), brine (50 mL), dried over MgSO4, filtered and the solvents were removed under reduced pressure to give 33 g of N-morpholinecarbonyl-valine methyl ester as a white solid: NMR (100 MHz, CDCl3 δ 0.9 (dd, 6), 2.1 (septet, 1), 3.0 and 3.65 (morpoline triplets, 4 and 4), 4.98 (N-H).
Reaction SMILES: [C:1]12([C:11]3[C:12]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:13][C:14]([CH3:18])=[C:15](Br)[CH:16]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(=O)=O.CC(C)=O.[Li]CCCC.C([O:42][B:43](OC(C)C)[O:44]C(C)C)(C)C>C1COCC1.CCCCCC>[C:1]12([C:11]3[C:12]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:13][C:14]([CH3:18])=[C:15]([B:43]([OH:44])[OH:42])[CH:16]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1cc(OCc2ccccc2)c(C23CC4CC(CC(C4)C2)C3)cc1Br
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: CCCCCC
Product: Cc1cc(OCc2ccccc2)c(C23CC4CC(CC(C4)C2)C3)cc1B(O)O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 60.4 %

Procedure:
To a solution of 5-(1-adamantyl)-4-benzyloxy-2-methylphenyl bromide (2.66 g, 6.47 mmol) in THF (10 mL) at −78° C. (dry ice/acetone bath) under argon was added 1.6 M n-BuLi (11.64 mmol) in hexane (7.3 mL) in one portion. This mixture was stirred at −78° C. for 15 min. Tri(isopropyl)borate (4.5 mL, 19.40 mmol) was added, and the resulting solution was stirred at −78° C. for 20 min before being allowed to warm to room temperature with stirring overnight. The reaction mixture was quenched with 1 N HCl (40 mL) and then extracted with EtOAc (100 and 60 mL). The combined organic extracts were washed with brine and dried. Solvents were removed at reduced pressure, and the residue was washed with hexane to give 1.47 g (60%) of 5-(1-adamantyl)-4-benzyloxy-2-methylphenylboronic acid as a white solid, mp 243-247° C. IR 3226, 2903, 2848, 1328 cm−1; 1H NMR (CDCl3) δ 1.74 (bs, 6H, AdCH2), 2.05 (bs, 3H, AdCH), 2.20 (bs, 6H, AdCH2), 2.82 (s, 3H, CH3), 5.19 (s, 2H, C6H5CH2), 6.85 (s, 1H, 3-ArH), 7.31-7.54 (m, 5H, C6H5), 8.19 ppm (s, 1H, 6-ArH).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH3:13][O:14][C:15]1[C:29]([O:30][CH3:31])=[CH:28][C:18]2[CH2:19][C@H:20]([C:25]([OH:27])=O)[S:21][CH2:22][C:23](=[O:24])[C:17]=2[CH:16]=1.[NH2:32][C:33]1[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][CH:34]=1.ON1C2C=CC=CC=2N=N1>ClCCl.CN(C)C=O.O>[CH2:43]([O:42][P:38]([CH2:37][C:36]1[CH:35]=[CH:34][C:33]([NH:32][C:25]([C@H:20]2[CH2:19][C:18]3[CH:28]=[C:29]([O:30][CH3:31])[C:15]([O:14][CH3:13])=[CH:16][C:17]=3[C:23](=[O:24])[CH2:22][S:21]2)=[O:27])=[CH:47][CH:46]=1)([O:39][CH2:40][CH3:41])=[O:45])[CH3:44]
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Reactant: COc1cc2c(cc1OC)C(=O)CS[C@@H](C(=O)O)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOP(=O)(Cc1ccc(NC(=O)[C@H]2Cc3cc(OC)c(OC)cc3C(=O)CS2)cc1)OCC
Temperature: 0 °C
Reaction time: 15 h
Yield: 41.3 %

Procedure:
A solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.149 g) in dichloromethane (3 ml) was added to a solution of (R)-(−)-1,2,4,5-tetrahydro-7,8-dimethoxy-5-oxo-3-benzothiepin-2-carboxylic acid (0.183 g) and diethyl 4-aminobenzylphosphonate (0.158 g) in N,N-dimethylformamide (DMF) (3 ml) at 0° C., followed by the addition of 1-hydroxybenzotriazole (HOBt) (0.109 g). This mixture was stirred at 0° C. for 1 hour and at room temperature for 15 hours, after which it was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), after which the solvent was distilled off; the residue was treated with ethanolisopropyl ether and the solid was removed by filtration. The filtrate was concentrated and the residual oil was subjected to silica gel column chromatography. From the fraction eluted with ethyl acetate-chloroform-methanol (15:15:1, v/v), (2R)-(−)-N-[4-(diethoxyphosphorylmethyl)phenyl]-1,2,4,5-tetrahydro-7,8-dimethoxy-5-oxo-3-benzothiepin-2-carboxamide (0.136 g, 41%) was obtained. Colorless amorphous solid. Melting point 96-98° C. Optical rotation [α]D (23° C.) −155.00 (c=0.50, CHCl3).
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[ClH:11].[Cl:12]Cl.N(OC(C)C)=O>O.C(O)C>[Cl:11][C:10]1[CH:2]=[C:3]([CH:7]=[C:8]([Cl:12])[CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: ClCl
Reactant: Cl
Reactant: Nc1ccccc1C(=O)O
Agent: CC(C)ON=O
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(Cl)cc(Cl)c1
Yield: 75 %

Procedure:
137 parts of 2-aminobenzoic acid are introduced into 800 parts of ethanol, 50 parts of hydrochloric acid (20% strength of weight) and 500 parts of water. 163 parts of chlorine gas are passed in over 2 hours at 80° C. 300 parts of hydrochloric acid (36 percent strength by weight) are added. 125 parts of isopropyl nitrite are introduced in the course of 7 hours at 80° C. The mixture is cooled, 800 parts of water are added and the product is filtered off. 143 parts of 3,5-dichlorobenzoic acid (75% of theory) of melting point 173°-178° C. are obtained.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)(N1C=CN=C1)=[O:2].[CH:13]1([C:19]2[C:27]3[C:22](=[CH:23][C:24](C(O)=O)=[CH:25][CH:26]=3)[N:21]([CH3:31])[C:20]=2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[O:38][CH2:39][C:40]([N:42]([CH3:54])[CH2:43][CH2:44][O:45][CH2:46][CH2:47][N:48]([CH3:53])[S:49](=[O:52])(=[O:51])[NH2:50])=[O:41])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(#N)C>[CH:13]1([C:19]2[C:27]3[C:22](=[CH:23][C:24]([C:1]([N:8]4[CH:12]=[CH:11][N:10]=[CH:9]4)=[O:2])=[CH:25][CH:26]=3)[N:21]([CH3:31])[C:20]=2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[O:38][CH2:39][C:40]([N:42]([CH3:54])[CH2:43][CH2:44][O:45][CH2:46][CH2:47][N:48]([CH3:53])[S:49](=[O:52])(=[O:51])[NH2:50])=[O:41])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: CN(CCOCCN(C)S(N)(=O)=O)C(=O)COc1ccccc1-c1c(C2CCCCC2)c2ccc(C(=O)O)cc2n1C
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: CN(CCOCCN(C)S(N)(=O)=O)C(=O)COc1ccccc1-c1c(C2CCCCC2)c2ccc(C(=O)n3ccnc3)cc2n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
Carbonyldiimidazole (405 mg, 2.50 mmol) was added to a stirred solution of intermediate 8 (300 mg, 0.50 mmol) in dry acetonitrile (CH3CN) (25 mL). The reaction mixture was stirred at room temperature for 1 h, upon which complete conversion was observed. The resulting solution was evaporated and the residue was purified by silica flash chromatography (gradient AcOEt/CH3CN 1:0 to 0:1) to yield 315 mg (97%) of 2-{2-[3-cyclohexyl-6-(1H-imidazol-1-ylcarbonyl)-1-methyl-1H-indol-2-yl]phenoxy}-N-methyl-N-(2-{2-[methyl(sulfamoyl)amino]ethoxy}ethyl)acetamide 9 as a white powder: m/z=651 (M+H)+.