Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.CN(C)C(=[O:10])C.[C:12]1(=[O:45])[N:16]([CH:17]2[C:38](=[O:39])[N:19]3[CH:20]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)=[O:27])[C:21]([CH3:25])([CH3:24])[S:22](=O)[C@H:18]23)[C:15](=[O:40])[C:14]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:13]12>C(OCC)(=O)C>[C:12]1(=[O:45])[N:16]([CH:17]2[C:38](=[O:39])[N:19]3[CH:20]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)=[O:27])[C@:21]([CH3:24])([OH:10])[CH2:25][S:22][C@H:18]23)[C:15](=[O:40])[C:14]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:13]12
Reactant: CC(=O)N(C)C
Reactant: COc1ccc(COC(=O)C2N3C(=O)C(N4C(=O)c5ccccc5C4=O)[C@H]3S(=O)C2(C)C)cc1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: COc1ccc(COC(=O)C2N3C(=O)C(N4C(=O)c5ccccc5C4=O)[C@H]3SC[C@@]2(C)O)cc1
Yield: 62 %

Procedure:
A mixture of 4 drops of conc, sulfuric acid in 60 ml. N,N-dimethylacetamide and 80 ml. of benzene was dried azeotropically for 30 minutes. p-Methoxybenzyl 6-phthalimido-2,2-dimethylpenam-3-carboxylate-1-oxide (5.0 g., 10 mmol) was then added. The reaction mixture was refluxed for 30 minutes, cooled and evaporated to near dryness. Ethyl acetate (150 ml.) was added to the product, and the resulting solution was evaporated in vacuo to dryness. A crystalline product formed during evaporation of the solvent. The product was then slurried with 50 ml. of ethyl acetate. Filtration gave 3.1 grams (62 percent) of p-methoxybenzyl 7-phthalimido-3α-methyl-3β-hydroxycepham-4-carboxylate as colorless crystals, mp 216°-217°: nmr (CDCl3) 76 (3, s, 3-CH3), 149 and 205 (2, ABq, J=14 Hz, 2-CH2), 230 (3, s, OCH3), 274 (1, s, 4-H), 300 (1, broad s, OH), 309 (2, s, ester CH2), 324 (1, d, J=4.5 Hz, azetidinone H), 335 (1, d, J=4.5 Hz, azetidinone H), 426 (4, q, p-CH3OC6H4ArH) and 469 Hz (4, m, phthalimido H); ir (mull) 3460 (OH), 1725 (ester C=O), 1739 and 1781 (phthalimido C=O) and 1802 cm-1 (azetidinone C=O, shoulder).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[C:9](=O)[CH2:8][CH2:7][CH2:6]2.Cl.[NH2:16][OH:17].C([O-])(=O)C.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])/[C:9](=[N:16]/[OH:17])/[CH2:8][CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1C)C(=O)CCC2
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1cc2c(cc1C)/C(=N/O)CCC2
Temperature: 60 °C
Yield: 92.4 %

Procedure:
To 6-methoxy-7-methyl-3,4-dihydronaphthalen-1(2H)-one (0.500 g, 2.63 mmol) in methanol (10 mL) were sequentially added hydroxylamine hydrochloride (0.292 g, 4.21 mmol) and sodium acetate (0.345 g, 4.21 mmol) at room temperature. The reaction mixture was heated at 60° C. for 2 h. The reaction mixture was concentrated under vacuum. The residue was dissolved in 25 mL ethyl acetate, transferred to a separating funnel and washed with water (2×10 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated to give (E)-6-methoxy-7-methyl-3,4-dihydronaphthalen-1(2H)-one oxime as viscous orange-colored liquid (0.498 g, 2.43 mmol, 92%). The product had an HPLC ret. time=3.10 min (condition B). LC/MS M+1=206.0.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[CH2:16][CH2:15][CH2:14][C:8]=3[C:9](=[O:13])[NH:10][C:11]=2[CH:12]=1)=[CH2:2].C1C=C(Cl)C=C(C(OO)=[O:25])C=1>C(Cl)(Cl)Cl>[O:25]1[CH2:2][CH:1]1[C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[CH2:16][CH2:15][CH2:14][C:8]=3[C:9](=[O:13])[NH:10][C:11]=2[CH:12]=1
Reactant: C=Cc1ccc2c3c(c(=O)[nH]c2c1)CCC3
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c2cc(C3CO3)ccc2c2c1CCC2
Reaction time: 15 h

Procedure:
A solution of 1.41 g (6.7 mmol) of 7-vinyl-1,2,3,5-tetrahydrocyclopenta[c]-quinolin-4-one in 200 ml of chloroform is mixed at room temperature with mCPBA. After 15 hours at room temperature, the batch is washed with saturated Na2SO3 (2×100 ml), dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography on silica gel with hexane-ethyl acetate yields 0.59 g of product.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.Cl.Cl[CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:32][CH2:33][N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[C:4]([C:26]([F:29])([F:27])[F:28])[CH:3]=1
Reactant: ClCCN1CCOCC1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(ccn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Agent: Cl
Product: O=C1S/C(=C\c2ccc3c(ccn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1CCN1CCOCC1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indol-5-yl}methylidene)-3-(2-morpholin-4-ylethyl)-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 243) and 4-(2-chloroethyl)morpholine hydrochloride following General Procedure H.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[F:15][C:16]([F:30])([F:29])[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].CO>C(OCC)(=O)C>[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:26]3[CH2:25][CH2:24][N:23]([C:20]4[CH:19]=[CH:18][C:17]([C:16]([F:29])([F:30])[F:15])=[CH:22][CH:21]=4)[CH2:28][CH2:27]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCN(c2ccc(C(F)(F)F)cc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 1-(4-trifluoromethylphenyl)piperazine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 89% overall yield. FDMS m/e=419 (M+ of free base). α[D]589 =-7.78 (c=0.72, methanol).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:24][C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:29]3[CH:28]=[N:27][C:26]([NH2:25])=[CH:31][CH:30]=3)[N:7]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(Br)n2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3ccc(N)nc3)n2)n1

Procedure:
The title compound was prepared from 6′-bromo-6-methyl-4-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl (example E.26) (0.150 g, 0.38 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.092 g, 0.42 mmol) according to the general procedure VI. Obtained as a white solid (0.080 g, 51%). MS (ISP) 407.3 [(M+H)+]; mp 208-211° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)=[CH:10][C:11]2[N:12]([C:14]([CH2:17][C:18]3[C:19]([O:28]C)=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=3)=[N:15][N:16]=2)[N:13]=1.C([O-])(O)=O.[Na+]>Br>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:30]2[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=2)=[CH:10][C:11]2[N:12]([C:14]([CH2:17][C:18]3[C:19]([OH:28])=[N:20][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:22][CH:23]=3)=[N:15][N:16]=2)[N:13]=1
Reactant: COc1nc(C(F)(F)F)ccc1Cc1nnc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: Oc1nc(C(F)(F)F)ccc1Cc1nnc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Temperature: 25 °C
Yield: 61.2 %

Procedure:
A suspension of 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-((2-methoxy-6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazine (Example 26) (100 mg, 0.19 mmol) in aqueous (48%) hydrobromic acid (2 mL) was refluxed for 1 h. After cooling to room temperature, the reaction mixture was adjusted to pH 7-8 by careful addition of saturated aqueous NaHCO3. The resulting suspension was filtered, and the collected solid was washed with water (10 mL×2), diethyl ether (5 mL), dried in a 50° C. vacuum oven overnight to afford 60 mg (62%) of the title compound as an off-white solid. HPLC/MS (method A): retention time=3.53 min, (M+H)+=516.0.
Reaction SMILES: [CH3:1][C:2]1[CH:7](/[CH:8]=[CH:9]/[C:10]([CH3:12])=[O:11])[C:6]([CH3:14])([CH3:13])[CH2:5][CH2:4][CH:3]=1.[SH:15][CH2:16][CH2:17][CH2:18][Si:19]([O:24][CH3:25])([O:22][CH3:23])[O:20][CH3:21].C1CCN2C(=NCCC2)CC1.Cl>>[CH3:21][O:20][Si:19]([O:22][CH3:23])([O:24][CH3:25])[CH2:18][CH2:17][CH2:16][S:15][CH:8]([CH:7]1[C:6]([CH3:14])([CH3:13])[CH2:5][CH2:4][CH:3]=[C:2]1[CH3:1])[CH2:9][C:10](=[O:11])[CH3:12]
Reactant: CC(=O)/C=C/C1C(C)=CCCC1(C)C
Reactant: CO[Si](CCCS)(OC)OC
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Product: CO[Si](CCCSC(CC(C)=O)C1C(C)=CCCC1(C)C)(OC)OC
Reaction time: 2.25 h
Yield: 71.3 %

Procedure:
To a stirred solution of α-ionone (1.92 g, 10.0 mmol) and 3-mercaptopropyl-trimethoxysilane (1.96 g, 10.0 mmol) at 12° C. was rapidly added DBU (0.14 ml, 152 mg, 1.0 mmol). The temperature rose to 19° C. and the solution turned orange. After 135 minutes at 20° C, the reaction mixture was poured onto a cold stirred 5% aqueous HCl solution and extracted twice with Et2O. The organic phases were washed (H2O, saturated aqueous NaHCO3 and brine), dried (Na2SO4), filtered and concentrated. The crude extract was dried for 1 hour at 65-70° C./0.01 Torr to give 2.77 g of the title thioether (71%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].C(COC)OC>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.O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:3][CH:4]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Clc1ccc(-c2ccccc2)nc1
Temperature: 25 °C
Yield: 72.7 %

Procedure:
2,5-Dichloropyridine (30 g, 203 mmol), phenylboronic acid (24.72 g, 203 mmol) and potassium carbonate (84 g, 608 mmol) were added to dimethoxyethane (500 mL) and water (100 mL). The reaction mixture was degassed with nitrogen for 20 min, and Pd(PPh3)4 (2.3 g, 2.0 mmol) was added and reaction mixture was allowed to reflux for 18 h. The reaction was cooled to room temperature, the aqueous layer removed and dimethoxyethane was concentrated to dryness by rotary evaporation under vacuum. The residue was dissolved in DCM and passed through a silica gel plug, eluting with DCM. The solvent was removed and the crude product was chromatographed on silica with 40/60 (v/v) DCM/hexane to 50/50 (v/v) DCM/hexane to yield 28 g (73%) of the product as a white solid (HPLC purity: 99.7%).
Reaction SMILES: [CH3:1][S:2][CH:3]([C:5]1[CH:6]=[N:7][C:8]([C:14]([F:17])([F:16])[F:15])=[C:9]([CH:13]=1)C(O)=O)[CH3:4]>[Cu].C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[CH3:1][S:2][CH:3]([C:5]1[CH:13]=[CH:9][C:8]([C:14]([F:17])([F:16])[F:15])=[N:7][CH:6]=1)[CH3:4]
Reactant: CSC(C)c1cnc(C(F)(F)F)c(C(=O)O)c1
Agent: [Cu]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CSC(C)c1ccc(C(F)(F)F)nc1
Temperature: 240 °C
Yield: 44.5 %

Procedure:
To a dry 50 mL round bottom flask equipped with magnetic stirrer, nitrogen inlet, thermometer, and reflux condenser was charged 0.35 g (0.00132 moles) of 5-(1-methylthioethyl)-2-trifluoromethylnicotinic acid, 0.17 g (0.00264 moles) of copper powder and 10 mL of DowTherm A. The reaction was heated at 240° C. for 1 hour, then cooled to room temperature. The reaction mixture was extracted with 3 aliquots of 50 mL of ethyl acetate, and washed with 50 mL of water and 50 mL of saturated aqueous sodium chloride solution. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum on a rotary evaporator. The crude product thus obtained was chromatographed on silica gel with a gradient of 100% hexane to 50% ethyl acetate, 50% hexane. The pure fractions were combined, and concentrated under vacuum on a rotary evaporator to afford 0.13 g of the title compound as a pale yellow oil. 1H NMR (CDCl3): δ 1.62 (d, 3H), 1.94 (s, 3H), 3.93 (q, 1H), 7.68 (d, 1H), 7.90 (d, 1H), and 8.66 (s, 1H).
Reaction SMILES: [NH2:1][OH:2].[C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])#[N:4]>CO>[OH:2][NH:1][C:3](=[NH:4])[C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9]
Reactant: N#Cc1cccc(C(=O)O)c1
Reactant: NO
Solvent: CO
Product: N=C(NO)c1cccc(C(=O)O)c1

Procedure:
An aqueous 50% hydroxylamine solution was added to a methanol solution of 3-cyanobenzoic acid, followed by heating under reflux for 11 hours. The reaction liquid was concentrated, diluted with water, adjusted with 1 M hydrochloric acid to have a pH of from 2 to 3, and the precipitate was collected by filtration to obtain 3-[(hydroxyamino)(imino)methyl]benzoic acid. ES+: 181.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[NH:7][N:6]=1)=[O:4].Cl[Sn]Cl.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:20][C:17]1[CH:16]=[CH:15][C:14]([C:10]2[CH:9]=[C:8]3[C:13]([C:5]([C:3]([NH:2][CH3:1])=[O:4])=[N:6][NH:7]3)=[CH:12][CH:11]=2)=[CH:19][CH:18]=1
Reactant: CNC(=O)c1n[nH]c2cc(-c3ccc([N+](=O)[O-])cc3)ccc12
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CNC(=O)c1n[nH]c2cc(-c3ccc(N)cc3)ccc12
Temperature: 80 °C
Reaction time: 3 h
Yield: 93.9 %

Procedure:
To a stirred solution of N-methyl-6-(4-nitrophenyl)-1H-indazole-3-carboxamide (154 mg, 0.52 mmol) in ethanol (10 Ml), was added SnCl2 (588 mg, 2.6 mmol) and the mixture was stirred at 80° C. for 3 h. The mixture was cooled to rt and saturated sodium bicarbonate aqueous solution was added. The organic layer was extracted three times and the combined organaic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was triturated in ethyl acetate and hexane to give 6-(4-aminophenyl)-N-methyl-1H-indazole-3-carboxamide (130 mg).
Reaction SMILES: [CH:1]([C:4]1[C:9]([C:10](OCC)=[O:11])=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:7]([CH:22]=[CH:23][CH2:24][CH2:25][CH3:26])=[C:6]([CH:27]([CH3:29])[CH3:28])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[C:7]([CH:22]=[CH:23][CH2:24][CH2:25][CH3:26])=[C:6]([CH:27]([CH3:28])[CH3:29])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCC=Cc1c(C(C)C)nc(C(C)C)c(C(=O)OCC)c1-c1ccc(Cl)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(Cl)cc1

Procedure:
The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 125, Step F. 1H NMR (300 MHz, CDCl3) (reported as a 6:1 mixture of olefin isomers): δ 0.73-0.83 (m, 3 H), 1.10-1.40 (14 H), 1.91 (m, 2 H), 3.93 (m, 2 H), 4.39 (d, J=5.0 Hz, 2 H), 5.25-5.45 (m, 1 H), 5.98 (m, 1 H), 7.11 (m, 2 H), 7.35 (m, 2 H). Rf=0.36 (10% ethyl acetate/n-hexane).
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:41][C:42]([N:44]([CH3:51])[CH2:45][C@@H:46]1[CH2:50][CH2:49][CH2:48][O:47]1)=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:41][CH2:42][N:44]([CH3:51])[CH2:45][C@@H:46]2[CH2:50][CH2:49][CH2:48][O:47]2)=[CH:34][CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CN(C[C@@H]1CCCO1)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN(C)C[C@@H]2CCCO2)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 27.7 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (16 mg) and 2-chloro-N-methyl-N—[(S)-tetrahydrofuran-2-ylmethyl]acetamide (10 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (4.8 mg) was obtained.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([NH:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[CH3:14])=[O:4].S(Cl)([Cl:20])(=O)=O.O>C(Cl)(Cl)Cl>[Cl:20][C:9]1[C:10]([O:12][CH3:13])=[CH:11][C:6]([NH:5][C:3](=[O:4])[C:2]([F:15])([F:16])[F:1])=[C:7]([CH3:14])[CH:8]=1
Reactant: COc1ccc(C)c(NC(=O)C(F)(F)F)c1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc(NC(=O)C(F)(F)F)c(C)cc1Cl
Reaction time: 8 h

Procedure:
To a solution of 2,2,2-Trifluoro-N-(5-methoxy-2-methylphenyl)acetamide (8.16 g) in chloroform (35 mL) was added sulfuryl chloride (3.12 mL) under ice-cooling, and the mixture was stirred overnight. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. To the residue was added hexane, and the mixture was stirred at room temperature for 1 hour. The precipitate was collected by filtration, washed with hexane, and then dried under reduced pressure to obtain the title compound (7.02 g). 1H-NMR (CDCl3) δ ppm: 2.23 (3H, s), 3.90 (3H, s), 7.24 (1H, s), 7.59 (1H, s), 7.60-7.82 (1H, br).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C@H:5]1[CH2:9][CH:8]([OH:10])[CH2:7][N:6]1[S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH3:2].[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.O>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:21])[C@H:5]1[CH2:9][CH:8]([O:10][S:28]([C:25]2[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[CH2:7][N:6]1[S:11]([C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1)(=[O:12])=[O:13])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)[C@H]1CC(O)CN1S(=O)(=O)c1ccc(C)cc1
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)[C@H]1CC(OS(=O)(=O)c2ccc(C)cc2)CN1S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
To a cold solution of 11.85 g (38 mmoles) 1-(4-toluenesulfonyl)-4-hydroxy-D-proline ethyl ester in 37 mL pyridine at 0° C. was added 8.0 g (41 mmoles) of 4-toluenesulfonyl chloride portionwise in 15 minutes. The cold solution was stirred one hour at 0° C. and then 48 h at room temperature. Water (100 mL) was added dropwise in the solution cooled at 0° C. which was stirred 30 minutes at 0° C. The precipitate was filtered and washed with cold water and ether to give 15.55 g of titled compound. MP 122° C. [α]20 =+26.36° (c=2, chloroform)
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:22]([OH:24])=O)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:26]1[C:30]2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1.CN>C(Cl)Cl>[CH3:30][NH:26][C:22](=[O:24])[C@H:12]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: On1nnc2ccccc21
Reactant: COc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN
Solvent: ClCCl
Product: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
To a stirred solution of N-(Benzyloxycarbonyl)-O-methyl-L-tyrosine (155 g, 0.471M) in dry CH2Cl2 was added 1-hydroxybenzotriazole (63.6 g, 0.471M) followed by a solution of DCC (97.2 g, 0.471M) in CH2Cl2 (100 ml) added slowly at 0° C. After warming to room temperature over 1 hr, a solution of methylamine (30 g) in CH2Cl2 (250 ml) was added dropwise to the reaction mixture which was then stirred overnight at room temperature. The reaction was then filtered, washed with saturated aqueous sodium bicarbonate (×2), dried (MgSO4) and concentrated in vacuo to give a solid. Recrystallisation from ethyl acetate/hexane gave the desired amide (142 g); m.p. 167°-170°; (Found: C, 66.72; H, 6.58; N, 8.29. C19H22N2O4 requires C, 66.65; H, 6.48; N, 8.18%) νmax (CHCl3) 3440, 1710 and 1672 cm-1 ; δ(CDCl3) 2.70 (3H, d, J=5 Hz, NCH3); 2.98 (2H, m, CH2C6H4); 3.77 (3H, s, OCH3); 4.30 (1H, dd, J=7.6 and 3 Hz, α-CH); 5.06 (2H, m, OCH2C6H5); 5.43 (1H, m, OCONH); 5.84 (1H, m, CONH); 6.80 (2H, d, J=8.6 Hz, Tyr H-3 and H-5); 7.15 (2H, d, J=8.6 Hz, Tyr H-2 and H-6); 7.32 (5H, m, C6H5); m/e 343 (100%, [m+1]+).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1.O[Li].O.Cl>C1COCC1.O>[Br:13][C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH:4]([NH:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C:3]([OH:22])=[O:2])=[CH:12][CH:11]=1
Reactant: COC(=O)C(COc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC(COc1ccc(Br)cc1)C(=O)O
Reaction time: 6 h
Yield: 78 %

Procedure:
To a solution of the compound obtained in step d above (22d) (1.087 g, 2.91 mmol) in THF (40 mL) at 0° C. was added a solution of LiOH H2O (244 mg, 5.82 mmol) in water (10 mL). After being stirred for 6 h, 0.5 N HCl (5 mL) was added and the reaction was concentrated under vacuum. The residue was diluted with EtOAc and washed with brine. The combined organic layers were dried over Na2SO4 and concentrated; the residue was purified by silica gel column chromatography to give the title compound as a colourless oil (816 mg, 78% yield).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].[C:15]1([C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:22]2[CH2:23][CH2:24][N:25]([CH2:2][CH2:3][N:4]3[C:8](=[O:9])[C:7]4=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]4[C:5]3=[O:14])[CH2:26][CH2:27]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Product: O=C1c2ccccc2C(=O)N1CCN1CCC(=C(c2ccccc2)c2ccccc2)CC1
Yield: 88 %

Procedure:
The title compound was prepared in a yield of 88% in a similar manner to that described in Preparation 1' by reacting N-(2-bromoethyl)phthalimide and 4-diphenylmethylenepiperidine.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[NH:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[C:14](SC)=[N:13][C:12]=2[CH:24]=1>N1C=CC=CC=1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[NH:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[C:14]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:13][C:12]=2[CH:24]=1
Reactant: CSC1=Nc2cc(Cl)ccc2Nc2ccccc21
Reactant: C1CCNCC1
Solvent: c1ccncc1
Product: Clc1ccc2c(c1)N=C(N1CCCCC1)c1ccccc1N2
Temperature: 160 °C
Yield: 17.7 %

Procedure:
Piperidine (37 mg, 0.44 mmol) was added to crude 8-chloro-11-methylsulfanyl-5H-dibenzo[b,e][1,4]diazepine (166JO50) (90 mg, purity 50%, 0.218 mmol) in pyridine (2 mL) and the resulting mixture was heated in a capped tube at 160° C. for 10 h. The mixture was concentrated and flash chromatographed (SiO2, heptane:EtOAc 8:1-6:1) to give 12 mg of the title compound (166JO69A). MS (ESI) 312 (MH+). Purity for MH+ (UV/MS) 100/100.