Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[C:9]=2[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:5]=[CH:6][CH:7]=1.[N:31]1[CH:36]=[CH:35][CH:34]=C[CH:32]=1.C(Cl)(Cl)=[O:38].C1(N)CC1.Cl>ClCCl>[CH:36]1([NH:31][C:32]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=4)[C:9]=3[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:5]=[CH:6][CH:7]=2)=[O:38])[CH2:34][CH2:35]1
Reactant: O=C(Cl)Cl
Reactant: CCOC(=O)c1c(-c2cccc(N)c2)c2ccccc2n1Cc1cccc(OC)c1
Reactant: c1ccncc1
Agent: Cl
Agent: NC1CC1
Solvent: ClCCl
Product: CCOC(=O)c1c(-c2cccc(NC(=O)NC3CC3)c2)c2ccccc2n1Cc1cccc(OC)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 52.6 %

Procedure:
To a 25 mL round-bottomed flask at rt was charged with ethyl 3-(3-aminophenyl)-1-[(3-methoxyphenyl)methyl]indole-2-carboxylate (Example 93, 222 mg, 0.55 mmol) and dichloromethane (1.5 mL). The resulting solution was cooled to 0° C., to which was added pyridine (0.09 mL, 1.1 mmol) and phosgene (20% in toluene, 0.35 mL, 0.66 mmol). The mixture was left stirred at 0° C. for 2 hours and rt for 2 hours before it was concentrated in vacuo. The residue was dissolved in dichloromethane (2 mL) and cyclopropylamine (0.11 mL, 1.65 mmol) was added. The mixture was left at rt for 15 minutes before it was mixed with hydrochloric acid (1 N) and extracted with dichloromethane (10 mL). The organic layer was washed with aqueous sodium bicarbonate, brine, and dried over anhydrous magnesium sulfate. The crude mixture was purified with silica gel flash chromatography using hexane/ethyl acetate (3/1) as the eluant to give ethyl 3-{3-[(cyclopropylamino)carbonylamino]phenyl}-1-[(3-methoxyphenyl)methyl]indole-2-carboxylate (140 mg, 53%): MS (electrospray, MH+) calcd for C29H30N3O4 484.2, found 484.1; 1H NMR (DMSO-d6) δ 8.36 (s, 1H), 7.52-7.64 (m, 3H), 7.15-7.38 (m, 5H) 6.95 (ddd, J=6.9 Hz, 1H), 6.79 (dd, J=8.1, 1.9 Hz, 1H), 6.65 (dd, 1H), 6.59 (d, J=7.6 Hz, 1H), 6.38 (d, J=2.6 Hz, 1H), 5.77 (s, 2H), 4.10 (q, J=7.1 Hz), 3.68 (s, 3H), 2.50-2.60 (m, 1H), 0.97 (t, J=7.1 Hz), 0.60-0.64 (m, 2H), 0.39-0.41 (m. 2H).
Reaction SMILES: NC[CH2:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][OH:8].[C:12]([O:16][C:17]([NH:19][C:20](=[N:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])SC)=[O:18])([CH3:15])([CH3:14])[CH3:13].C([N:33](CC)CC)C.C(OCC)(=O)C>CN(C=O)C.[Hg]Cl>[C:17]([N:19]([CH2:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][OH:8])[C:20]([NH2:33])=[N:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18]
Reactant: CCN(CC)CC
Reactant: NCCc1cccc(CO)c1
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: Cl[Hg]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N=C(N)N(Cc1cccc(CO)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.4 %

Procedure:
A mixture of 3-(aminoethyl)benzyl alcohol (2.3 grams, 0.015 mol, 1 molequivalent), N,N′-bis(tert-butoxycarbonyl)-S-methylisothiourea (4.8 grams, 0.016 mol, 1.1 molequivalent), mercury chloride (4.5 grams, 0.016 mol, 1.1 molequivalent), and triethylamine (7 ml, 0.048 mol, 3 molequivalent) in dry DMF (25 ml) was stirred at room temperature overnight under nitrogen atmosphere. Ethyl acetate (100 ml) was then added and the suspension was filtered over Celite. The filtrate was washed with water, saturated aqueous NH4Cl, and brine, dried over MgSO4 and the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography (using a gradient eluent of a 10:90 to 30:70 mixture of EtOAc:hexanes), to give 1.9 grams (32%) of the pure product.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[C:9]([F:18])[C:8]=2[Cl:19])[N:5]=[CH:4][CH:3]=1.[N+:20]([O-])([OH:22])=[O:21].NC(N)=O>O>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:15])[F:16])=[C:9]([F:18])[C:8]=2[Cl:19])[N:5]=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21]
Reactant: O=[N+]([O-])O
Reactant: Nc1ccnn1-c1c(Cl)cc(C(F)(F)F)c(F)c1Cl
Agent: NC(N)=O
Solvent: O
Product: Nc1c([N+](=O)[O-])cnn1-c1c(Cl)cc(C(F)(F)F)c(F)c1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 61 %

Procedure:
10 g (0.032 mol) of 5-amino-1-(2,6-dichloro-3-fluoro-4-trifluoromethylphenyl)-pyrazole are introduced in portions into a boiling solution of 2.3 ml (0.034 mol) of 67% strength nitric acid and 0.1 g of urea in 30 ml of water. The suspension is allowed to cool, and the precipitate is filtered off and dried in vacuo at room temperature. The dry precipitate is introduced into 40 ml of 98% strength sulphuric acid at -5° C. , and the mixture is stirred for 12 hours at 0°-5° C. Thereafter, the reaction mixture is introduced into 350 ml of water, boiled up for a short time and allowed to cool to room temperature and the precipitate is filtered off. The precipitate is washed neutral with water and dried in vacuo at 40°-50° C. 7.0 g (61% of theory) of 5-amino-1-(2,6-dichloro-3-fluoro-4-trifluoromethylphenyl)-4-nitropyrazole of melting point 156° C. are obtained.
Reaction SMILES: [NH:1]([C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[NH2:2].[OH2:12]>C(O)(=O)C>[S:4]1[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=[C:3]1[N:1]1[C:8](=[O:12])[CH2:6][C:5]([CH3:11])=[N:2]1
Reactant: NNc1nc2ccccc2s1
Reactant: O
Solvent: CC(=O)O
Product: CC1=NN(c2nc3ccccc3s2)C(=O)C1

Procedure:
2 g (12.1 mmol) of 2-hydrazino-1,3-benzothiazole and 1.58 g (12.1 mmol) of acetoacetic ester are stirred in 40 ml of glacial acetic acid for 2 hours at 90° C. The mixture is then diluted with water and the precipitated crystals are filtered off with suction, washed again with water and dried under reduced pressure.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:10]([O:22]C)(=O)[C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=O)=[CH:13][CH:12]=1.C([N-][CH:28]([CH3:30])[CH3:29])(C)C.[Li+]>CCOCC>[C:1]([CH2:2][C:15]([C:14]1[CH:13]=[CH:12][C:11]([C:10](=[O:22])[CH2:2][C:1](=[O:3])[C:29]2[CH:28]=[CH:30][CH:9]=[CH:4][CH:5]=2)=[CH:20][CH:19]=1)=[O:17])(=[O:3])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Agent: [Li+]
Solvent: CCOCC
Product: O=C(CC(=O)c1ccc(C(=O)CC(=O)c2ccccc2)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 25.6 %

Procedure:
To a solution of 24.0 g (0.2 mol) of acetophenone and 19.4 g (0.1 mol) of dimethyl terephthalate in 150 ml of ether was dropwise added an ether solution of 0.4 mol of lithium diisopropylamide at -20° C. over 2 hours. After the dropwise addition, the mixture was stirred for 1 hour under cooling with ice, then poured into ice-water. After neutralization with an ammonium chloride aqueous solution, it was extracted with ether, and the extract was dried and concentrated. Recrystallization of the residue from methanol gave 9.5 g (28%) of the title compound. m.p. 175°-177° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]2[CH:10]([NH:13][C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([NH2:24])[CH:20]=4)[N:15]=3)[CH2:11][O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2].Cl[C:26](OC1C=CC([N+]([O-])=O)=CC=1)=[O:27].Cl.Cl.[CH:40]([N:43]1[CH2:48][CH2:47][CH:46]([NH2:49])[CH2:45][CH2:44]1)([CH3:42])[CH3:41]>>[CH2:1]([O:3][C:4]1[C:9]2[CH:10]([NH:13][C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([NH:24][C:26]([NH:49][CH:46]5[CH2:47][CH2:48][N:43]([CH:40]([CH3:42])[CH3:41])[CH2:44][CH2:45]5)=[O:27])[CH:20]=4)[N:15]=3)[CH2:11][O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(C)N1CCC(N)CC1
Reactant: CCOc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CO2
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CCOc1cccc2c1C(Nc1ccc3cc(NC(=O)NC4CCN(C(C)C)CC4)ccc3n1)CO2

Procedure:
The title compound was prepared from rac-N2-(4-ethoxy-2,3-dihydro-benzofuran-3-yl)-quinoline-2,6-diamine (Example 175) (200 mg, 0.62 mmol), 4-nitrophenyl chloroformate (125 mg, 0.62 mmol) and 1-isopropyl-piperidin-4-ylamine dihydrochloride (CAS no: 534596-29-7) (134 mg, 0.62 mmol) in accordance with the general method 4 described in example 170 step C and was obtained as an off-white solid (190 mg, 62%); MS: m/e=490.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:29])=[C:6]([C:8]([CH3:28])([CH3:27])[CH2:9][C:10]([OH:26])([C:22]([F:25])([F:24])[F:23])[CH2:11][C:12]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:13]=2[C:14]#[N:15])[CH:7]=1.[F:30][C:31]1[CH:32]=[CH:33][C:34]([OH:58])=[C:35]([C:37]([CH3:57])([CH3:56])[CH2:38][C:39]([OH:55])([C:51]([F:54])([F:53])[F:52])[CH2:40][C:41]2[CH:48]=[C:47]([CH3:49])[C:44]([C:45]#[N:46])=[C:43]([CH3:50])[CH:42]=2)[CH:36]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH3:31])=[C:6]([C:8]([CH3:27])([CH3:28])[CH2:9][C:10]([OH:26])([C:22]([F:25])([F:24])[F:23])[CH2:11][C:12]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:13]=2[C:14]#[N:15])[CH:7]=1.[F:30][C:31]1[CH:32]=[CH:33][C:34]([O:58][CH3:2])=[C:35]([C:37]([CH3:56])([CH3:57])[CH2:38][C:39]([OH:55])([C:51]([F:54])([F:53])[F:52])[CH2:40][C:41]2[CH:48]=[C:47]([CH3:49])[C:44]([C:45]#[N:46])=[C:43]([CH3:50])[CH:42]=2)[CH:36]=1
Reactant: Cc1cc(C)c(C#N)c(CC(O)(CC(C)(C)c2cc(F)ccc2O)C(F)(F)F)c1
Reactant: Cc1cc(CC(O)(CC(C)(C)c2cc(F)ccc2O)C(F)(F)F)cc(C)c1C#N
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1cc(C)c(C#N)c(C)c1)C(F)(F)F
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1cc(C)cc(C)c1C#N)C(F)(F)F

Procedure:
The title compounds were prepared as an inseparable mixture by methods analogous to those described in Example 5 as a result of performing a Grignard reaction with a 1:1.4 mixture of 2-bromomethyl-4,6-dimethylbenzonitrile and 4-bromomethyl-2,6-dimethylbenzonitrile (prepared by N-bromosuccinimide bromination of 2,4,6-trimetbylbenzonitrile). The mixture was treated with boron tribromide according to methods analogous to those described in Example 7 followed by chromatography on a prep plate (silica gel, hexanes-isopropyl alcohol (97:3, 2×developed)) to afford 2-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-4,6-dimethylbenzonitrile, m.p. 136° C.-138° C., and 4-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-2,6-dimethylbenzonitrile, m.p. 152° C.-154° C. Methylation of 2-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2trifluoromethylpentyl]-4,6-dimethylbenzonitrile and 4-[4-(5 fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-2,6-dimethylbenzonitrile by analogous methods described in Example 8 gave the title compounds 2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-4,6-dimethylbenzonitrile, m.p. 134° C.-136° C., and 4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-2,6-dimethylbenzonitrile, m.p. 113° C.-115° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.F[C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=1>O>[N:1]1([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: NC(=O)c1ccc(F)cc1
Reactant: C1CNCCN1
Solvent: O
Product: NC(=O)c1ccc(N2CCNCC2)cc1
Yield: 90 %

Procedure:
A mixture of piperazine (7.56 g) and 4-fluorobenzamide (2.44 g) in water (10 mL) is heated at reflux for 27 h. The mixture is then allowed to cool slightly and the solid is collected and washed with water and dichloromethane, followed by drying to give 3.24 g of 4-(piperazin-1-yl)benzamide; mp 238-243° C., ms m/z 205; IR (mineral oil) 1609, 1255, 1665, 1389, 3149 cm-1. 1H NMR (DMSOd6) δ2.59, 2.80, 3.14, 6.90, 7.02, 7.72, 7.73.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]3=[O:21])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH:9]2[CH2:10][CH2:11][N:12]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]3=[O:21])[CH2:13][CH2:14]2)[S:30]([C:27]2[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[CH:29][CH:28]=2)(=[O:32])=[O:31])=[CH:6][CH:7]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1CCCCC1N1CCC(Nc2ccc(Cl)cc2)CC1
Product: COc1ccc(S(=O)(=O)N(c2ccc(Cl)cc2)C2CCN(C3CCCCC3=O)CC2)cc1

Procedure:
The title compound, MS (ISP): m/e=555.3 (M+H+), was prepared as for example 99, steps (A) to (F). Step (B) was performed using 4-chloro-aniline, and yielded (+/−)-trans-2-[4-(4-chloro-phenylamino)-piperidin-1-yl]-cyclohexanol, which was oxidized to (+/−)-2-[4-(4-chloro-phenylamino)-piperidin-1-yl]-cyclohexanone in step (C). This was then reacted with 4-methoxy-benzensulfonyl chloride in step (D), yielding (+/−)-N-(4-chloro-phenyl)-4-methoxy-N-[1-(2-oxo-cyclohexyl)-piperidin-4-yl]-benzenesulfonamide. The final step (F) was performed with bromobenzene.
Reaction SMILES: C([O:9][C:10]1[C:15](=[O:16])[N:14]2[CH2:17][CH2:18][CH:19]=[CH:20][C:13]2=[N:12][C:11]=1[C:21]([O:23]C)=O)(=O)C1C=CC=CC=1.Cl.[CH3:26][O:27][NH:28][CH3:29].CCN(C(C)C)C(C)C.[F:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44][NH2:45])=[CH:42][CH:41]=1.C(N(CC)CC)C>CN(C=O)C>[F:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44][NH:45][C:21]([C:11]2[N:12]=[C:13]3[CH2:20][CH:19]([N:28]([O:27][CH3:26])[CH3:29])[CH2:18][CH2:17][N:14]3[C:15](=[O:16])[C:10]=2[OH:9])=[O:23])=[CH:42][CH:41]=1
Reactant: CNOC
Reactant: COC(=O)c1nc2n(c(=O)c1OC(=O)c1ccccc1)CCC=C2
Reactant: NCc1ccc(F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C1CCn2c(nc(C(=O)NCc3ccc(F)cc3)c(O)c2=O)C1
Temperature: 65 °C

Procedure:
To a solution of methyl 3-(benzoyloxy)-4-oxo-6,7-dihydro-4H-pyrido[1,2-a]pyrimidine-2-carboxylate in anhydrous DMF were added O,N-dimethylhydroxylamine hydrochloride (2.5 eq.) and DIPEA (2.2 eq.). The mixture was stirred and warmed to 65° C. for 6 h. The mixture was cooled to room temperature and the solvent was removed under high vacuum. The residue was dissolved in methanol and p-fluoro-benzylamine (2.2 eq.) and triethylamine (2 eq.) were added. The mixture was stirred at 65° C. for 16 h. After cooling to room temperature the mixture was partitioned between aq. ammonium chloride and dichloromethane. The aq. phase was again extracted with dichloromethane. The combined organic phases were then extracted with 0.1 M NaOH. The aq. phase was then acidified to pH 5 ca. with 1 M aq. HCl and extracted with dichloromethane. The organic phase was dried over sodium sulfate, filtered and concentrated to dryness. The crude product so obtained was used in the subsequent step without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([S:22]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[CH2:10][CH2:11]2)(=[O:23])=[O:24])=[CH:26][CH:27]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(CCc2ccc(OC)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CCN2CCC(C(=O)O)(S(=O)(=O)c3ccc(OC)cc3)CC2)cc1

Procedure:
4-(4-methoxy-benzenesulfonyl)-1-[2-(4-methoxyphenyl)-ethyl]-piperidine-4-carboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl)-1-[2-(4-methoxyphenyl)-ethyl]-piperidine- 4-carboxylic acid ethyl ester (5.0 g, 10.8 mmol) dissolved in THF:methanol 3:1 and 10N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 4.0 g (85%); off white powder; mp 205° C.; MS: 434.5 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH2:3][CH2:4][N:5]1[C:10]2[N:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])O[C:6]1=[O:16].[O:18]=[S:19]1(=[O:35])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[NH:22][C:21]([CH2:29]C(OCC)=O)=[N:20]1.[H-].[Na+].C(O)(=O)C>C1COCC1.Cl>[O:35]=[S:19]1(=[O:18])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[NH:22][C:21]([C:29]2[C:6](=[O:16])[N:5]([CH2:4][CH2:3][CH:2]([CH3:1])[CH3:17])[C:10]3[C:9]([C:8]=2[OH:15])=[CH:14][CH:13]=[CH:12][N:11]=3)=[N:20]1
Reactant: CCOC(=O)CC1=NS(=O)(=O)c2ccccc2N1
Reactant: CC(C)CCn1c(=O)oc(=O)c2cccnc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2cccnc21
Temperature: 20 °C
Yield: 8.2 %

Procedure:
To a solution of the product of Example 12A (0.216 g, 0.92 mmol) and the product of Example 1C (0.247 g, 0.922 mmol) in anhydrous THF (7.5 mL) under nitrogen at 20° C. was added sodium hydride (95%, 0.089 g, 3.7 mmol). The reaction was heated at reflux for 3 hours, cooled to 20° C., and added dropwise glacial acetic acid (2.4 mL). The resulting mixture was heated at reflux for 1 hour, cooled to 25° C., and diluted with aqueous hydrochloric acid (0.5 M, 35 mL). The resulting precipitate was collected by filtration, washed with water and dried. The crude product was purified by flash column chromatography on silica gel eluting with hexanes and ethyl acetate (3:1) to give the title compound as a white solid (0.031 g, 20%). MS (ESI−) m/z 411 (M−H)−. The sodium salt of the title compound was prepared according to the procedure of Example 1D. MS (ESI−) m/z 411 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ 0.95 (s, 3H), 0.98 (s, 3H), 1.47 (m, 2H), 1.64 (m, 1H), 4.30 (t, J=7.72 Hz, 2H), 7.13 (dd, J=7.72, 4.78 Hz, 1H), 7.26 (d, J=8.09 Hz, 1H), 7.30 (d, J=7.72 Hz, 1H), 7.55 (t, J=7.72 Hz, 1H), 7.66 (d, J=8.09 Hz, 1H), 8.37 (dd, J=7.72, 1.84 Hz, 1H), 8.53 (dd, J=4.78, 2.21 Hz, 1H), 15.94 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[Li+].[CH3:13][CH:14]([N-]C(C)C)[CH3:15].C(I)C=C>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:15][CH:14]=[CH2:13])[C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)[N-]C(C)C
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Agent: C=CCI
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCC(C#N)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 104.2 %

Procedure:
3,4-Dichlorophenylacetonitrile (5 g, 26.87 mmol, 1 eq) in THF (50 mL) was cooled to −78° C. under Ar. LDA (2 M in THF, 16.1 mL, 32.2 mmol, 1.2 eq) was added and the reaction was warmed to 0° C. over 1 h. The reaction was re-cooled to −78° C. and allyl iodide (2.67 mL, 26.87 mmol, 1 eq) was added then the reaction was stirred at −78° C. for a further 2 h. The reaction was diluted with EtOAc (150 mL) and washed with aqueous HCl (1 M, 100 mL), saturated aqueous Na2S2O3 (100 mL) and saturated aqueous NaCl (100 mL). The organic extracts were dried over Na2SO4, filtered and concentrated by rotary evaporation to afford 2-(3,4-dichlorophenyl)-pent-4-ene-nitrile (6.3 g, ˜28 mmol) as a yellow oil.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([O:12][CH2:13][C:14]([CH3:16])=[CH2:15])[CH2:9]2)C=CC=CC=1.[Cl:23]CCCl.ClC(OC(Cl)C)=O>CO>[ClH:23].[CH3:16][C:14](=[CH2:15])[CH2:13][O:12][CH:10]1[CH2:11][NH:8][CH2:9]1
Reactant: ClCCCl
Reactant: C=C(C)COC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CC(Cl)OC(=O)Cl
Solvent: CO
Product: C=C(C)COC1CNC1
Product: Cl
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
A 16 mL flask was charged with 1-(diphenylmethyl)-3-[(2-methylprop-2-en-1-yl)oxy]azetidine (276 mg, 0.94 mmol; which may be prepared as described in Step 1) and 1,2-dichloroethane (4.1 mL). 1-Chloroethyl chloroformate (135 μL, 1.24 mmol) was added and the reaction mixture was stirred at 70° C. for 1.5 h. After cooling to room temperature, methanol (4.1 mL) was added and the reaction mixture was stirred at 70° C. for 1.5 h. The reaction mixture was concentrated to dryness and the residue was triturated in pentane to give the final product (192 mg, quantitative) as a brown oil.
Reaction SMILES: ClC(OCC(C)C)=O.[C:9]([O:13][C:14]([NH:16][C@H:17]([CH2:22][C:23]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=1[F:31])[CH2:18][C:19]([OH:21])=O)=[O:15])([CH3:12])([CH3:11])[CH3:10].CN1CCOCC1.[CH3:39][C@H:40]1[NH:46][CH2:45][CH2:44][C@@H:43]([CH3:47])[NH:42][C:41]1=[O:48]>ClCCl.CO.ClCCl>[C:9]([O:13][C:14]([NH:16][C@H:17]([CH2:22][C:23]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=1[F:31])[CH2:18][C:19]([N:46]1[CH2:45][CH2:44][C@@H:43]([CH3:47])[NH:42][C:41](=[O:48])[C@H:40]1[CH3:39])=[O:21])=[O:15])([CH3:10])([CH3:11])[CH3:12]
Reactant: C[C@@H]1CCN[C@H](C)C(=O)N1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Agent: CC(C)COC(=O)Cl
Solvent: CO
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@@H]1CCN(C(=O)C[C@@H](Cc2cc(F)c(F)cc2F)NC(=O)OC(C)(C)C)[C@H](C)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Isobutyl chloroformate (0.085 mL, 0.63 mmol) was added to a solution of (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (Intermediate 3, 210 mg, 0.63 mmol) and N-methylmorpholine (0.080 mL, 0.7 mmol) in 10 mL of dichloromethane at −20 to −30° C. and the resultant mixture was stirred for 1 h. A solution of (3R,7R)-3,7-dimethyl-1,4-diazepan-2-one in dichloromethane (5 mL) was added to the above solution. The reaction mixture was allowed to warm up to room temperature and stirring was continued overnight. The solution was subjected directly to flash chromatography on a Biotage® system (silica gel, 5% methanol/dichloromethane) to yield the title compound as a white solid. MS 358 (M−Boc+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.[CH3:19][O:20][C:21]1[CH:26]=[C:25]([CH2:27][C:28]#[N:29])[CH:24]=[C:23]([O:30][CH3:31])[CH:22]=1>CC(O)C.CO>[CH3:31][O:30][C:23]1[CH:24]=[C:25](/[C:27](=[CH:15]/[C:14]2[CH:17]=[CH:18][C:11]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])=[CH:12][CH:13]=2)/[C:28]#[N:29])[CH:26]=[C:21]([O:20][CH3:19])[CH:22]=1
Reactant: O=Cc1ccc(OCCCCCCCCO)cc1
Reactant: COc1cc(CC#N)cc(OC)c1
Solvent: CO
Solvent: CC(C)O
Product: COc1cc(OC)cc(/C(C#N)=C/c2ccc(OCCCCCCCCO)cc2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 43.2 %

Procedure:
5.0 g (20.0 mmol) of 4-[(8-hydroxyoctyl)oxy]benzaldehyde, 3.5 g (19.8 mmol) of 3,5-(dimethoxyphenyl)acetonitrile are dissolved in 50 mL of propan-2-ol. The solution is heated to 60° C. and 2.0 mL (2.0 mmol) of a one molar solution of tetrabuthylamoniumhydroxyde in methanol are added drop wise. After 2 h at 60° C., the reaction mixture is cooled to 0° C. The precipitate is filtered off, washed with cold propan-2-ol and recristalized in propan-2-ol. 3.5 g of (2Z)-2-(3,5-dimethoxyphenyl)-3-{4-[(8-hydroxyoctyl)oxy]phenyl}prop-2-enenitrile are obtained as a white solid (42% yield). This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=1)=O.[CH3:20][N:21]([CH3:26])[C:22](=[S:25])[NH:23][NH2:24].C(OCC)(=O)C>C(O)C>[BrH:1].[C:16]([C:7]1[CH:6]=[C:5]([C:3]2[CH2:2][S:25][C:22]([N:21]([CH3:26])[CH3:20])=[N:23][N:24]=2)[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]=1[OH:15])([CH3:19])([CH3:18])[CH3:17]
Reactant: CN(C)C(=S)NN
Reactant: CC(C)(C)c1cc(C(=O)CBr)cc(C(C)(C)C)c1O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Br
Product: CN(C)C1=NN=C(c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)CS1
Temperature: 70 °C

Procedure:
196.4 g (0.6 mol) of 2-bromo-1-(3,5-di-tert.butyl-4-hydroxyphenyl)-ethanone from step (a) and 59.6 g (0.5 mol) of 4,4-dimethylthiosemicarbazide were suspended in 1500 ml of ethanol and slowly heated to 70° C. while stirring, a clear solution being produced. The solution was stirred at this temperature for 10 minutes and then cooled, and the solvent was removed under reduced pressure. Washing the residue, produced as an oil, by stirring with 500 ml of ethyl acetate produced a batch of crystals, which was again briefly heated to boiling in 500 ml of ethyl ester. The crystalline product was filtered off, washed with 150 ml of ethyl acetate and dried in a vacuum cabinet.