Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)([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:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([S:23][C:24]1[N:28]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[C:42]3[NH:46][N:45]=[N:44][N:43]=3)=[CH:32][CH:31]=2)[C:27]2=[C:47]([C:51]([OH:53])=[O:52])[S:48][C:49]([CH3:50])=[C:26]2[N:25]=1)[CH3:22].C(N(CC)CC)C>ClCCl>[CH2:21]([S:23][C:24]1[N:28]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[C:42]3[N:43]([C:1]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[N:44]=[N:45][N:46]=3)=[CH:32][CH:31]=2)[C:27]2=[C:47]([C:51]([OH:53])=[O:52])[S:48][C:49]([CH3:50])=[C:26]2[N:25]=1)[CH3:22]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCSc1nc2c(C)sc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCSc1nc2c(C)sc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trityl chloride (0.6 g) was added to a solution of 2-ethylthio-4-methyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl ]methyl]thieno[3,4-d]imidazole-6-carboxylic acid (0.92 g) and triethylamine (0.3 ml) in dichloromethane (20 ml). The mixture was stirred for 30 minutes at room temperature. The reaction mixture was washed with water, dried, and then the solvent was evaporated ...in vacuo. The residue was purified by silica gel column chromatography to give crystals. Recrystallization from ethyl acetate - hexane afforded colorless needles (1.36 g, 98%), m.p. 138°-140° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.C1C=CC=CC=1.[C:45]([C:47]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:50]=[CH:49][CH:48]=1)#[CH:46]>C1C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:47]1([C:45]#[C:46][C:2]2[CH:3]=[C:4]3[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]3=[CH:11][CH:12]=2)[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:50]=[CH:49][CH:48]=1
Reactant: C#Cc1cccc2ccccc12
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C1OC(=O)c2cc(C#Cc3cccc4ccccc34)ccc21
Reaction time: 1 h
Yield: 36.2 %

Procedure:
To a solution of 4-bromophthalic anhydride (4.54 g, 20.0 mmol), triphenylphosphine (520 mg, 2.0 mmol), cuprous iodide (190 mg, 1.0 mmol), bis(triphenylphosphine)palladium dichloride (280 mg, 0.4 mmol) in 2:1 triethylamine/benzene (75 mL) was added 1-ethynylnaphthalene (4.94 g, 32.5 mmol) in benzene (25 mL) by cannula transfer and the mixture was heated at reflux for 2 h. The cooled solution was filtered and the precipitate was added to water (150 mL), filtered and washed with water (3×5 mL). The crude yellow solid was recrystallized from toluene, filtered and washed with hexanes (3×5 mL). The product was then added to 0.15 M NaHCO3(aq), stirred vigorously for 1 h and filtered. The yellow solid was dried at reduced pressure to constant weight to yield 4-(1-naphthylethynyl)phthalic anhydride (2.16 g, 36.2%). mp 220-222° C.; 1H NMR (CDCl3, 300 MHz) δ7.48-7.68 (m, 3H), 7.82 (d, J=7.2 Hz, 1H), δ7.92 (t, J=8.1 Hz, 2H), δ7.99 (d, J=7.8 Hz, 1H), δ8.07 (d, J=8.0 Hz, 1H), δ8.20 (s, 1H), δ8.35 (d, J8.1 Hz, 1H); 13 C NMR (CDCl3, 300 MHz) δ92.0, 94.6, 119.3, 125.5, 125.8, 125.9, 127.0, 127.6, 128.4, 128.8, 129.7, 130.6, 131.7, 131.9, 132.2, 133.3, 133.4, 138.7, 162.3, 162.3. Anal. Calcd for C20H10O3: C, 80.53;H, 3.38. Found: C, 80.37;H, 3.36.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][C:4]=2[N:3]=[C:2]1[SH:14])[CH:11]=[CH:10][CH:9]=[CH:8]3.[ClH:15].[Cl:16][CH2:17][C:18]1[NH:19][CH:20]=[CH:21][N:22]=1>CN(C)C=O.C1(C)C=CC=CC=1>[ClH:16].[ClH:15].[NH:22]1[CH2:21][CH2:20][N:19]=[C:18]1[CH2:17][S:14][C:2]1[NH:3][C:4]2[CH:13]=[C:12]3[C:7](=[CH:6][C:5]=2[N:1]=1)[CH:8]=[CH:9][CH:10]=[CH:11]3
Reactant: ClCc1ncc[nH]1
Reactant: Sc1nc2cc3ccccc3cc2[nH]1
Agent: Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: c1ccc2cc3[nH]c(SCC4=NCCN4)nc3cc2c1
Temperature: 25 °C
Yield: 58.1 %

Procedure:
10.0 g 1H-Naphth[2,3-d]imidazole-2-thiol and 8.0 g of 2-chloromethylimidazole-hydrochloride were heated for 3 hours at 90° in 50 ml of dimethylformamide. The reaction mixture was cooled to room temperature and then diluted with 200 ml of toluene. The residue was suction filtered, washed well with toluene, and crystallized from 700 ml of methanol, with the addition of 300 ml of ether. 10.3 g of 2-[(2-Imidazoline-2-ylmethyl)thio]-1H-naphth[2,3-d]imidazoldihydrochloride having an m.p. of 227°-228° were obtained.
Reaction SMILES: C(O[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=O)C.[O:18]1CC[CH2:20][CH2:19]1.[BH4-].[Na+]>CO>[OH:18][CH:19]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)=[CH:9][CH:10]=1)[CH3:20]
Reactant: CC(=O)Oc1ccc(-c2ccc(O)cc2)cc1
Reactant: C1CCOC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1ccc(-c2ccc(O)cc2)cc1
Reaction time: 2 h
Yield: 92.9 %

Procedure:
A solution containing 4-acetoxy-4'-hydroxy-1,1'-biphenyl from part A (5.0 g, 23.6 mmol) in methanol (500 mL) and tetrahydrofuran (30 mL) is treated with sodium borohydride (0.9 g, 23.8 mmol) in portions over 30 minutes at room temperature. After 2 hours, the reaction mixture is concentrated under reduced pressure, diluted with water (400 mL), acidified with 2N HCl and extracted with ethyl acetate. The organic layer is washed with water and brine, dried over MgSO4 and concentrated to a solid residue. Crystallization of the solid from ethyl acetate gives 4.7 g (92.9%) of the title compound, m.p. 159°-160° C.; MS (El m/z): 214 (M)+ and 199 (b.p. M-CH3)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:10].Br.Br[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1>>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:10]
Reactant: BrCc1ccncc1
Reactant: O=C(c1ccc(O)cc1F)N1CCC[C@H]1CN1CCCC1
Agent: Br
Product: O=C(c1ccc(OCc2ccncc2)cc1F)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure B using (2-Fluoro-4-hydroxy-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 4-(bromomethyl)pyridine hydrobromide. MS (ES+) 384.2
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.[O:15]([C:22]1[CH:23]=[C:24]([CH2:28]O)[CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[O:15]([C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=1)[CH2:28][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:10][CH:9]2[C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:7]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)C1CC1c1ccc(O)cc1
Reactant: OCc1cccc(Oc2ccccc2)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COC(=O)C1CC1c1ccc(OCc2cccc(Oc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 79 %

Procedure:
A solution of methyl 2-(4-hydroxyphenyl)cyclopropanecarboxylate (0.158 g, 0.822 mmol), (3-phenoxyphenyl)methanol (0.150 g, 0.747 mmol) and tributylphosphine (0.301 g, 1.49 mmol) in toluene (15 mL) was stirred, 1,1′-(azodicarbonyl)dipiperidine (0.375 g, 1.49 mmol) was added, and the mixture was stirred at room temperature for 60 hr. Hexane (15 mL) was added to the reaction mixture, and the precipitated insoluble material was filtrated. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=0:100-30:70) to give the title compound (0.221 g, yield 72%) as colorless crystals.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C@H:12]([C@H:14]([C@@H:16]([C@@H:18]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][CH:23]=2)[OH:19])[OH:17])[OH:15])[OH:13])=[CH:6][CH:5]=1)([OH:3])=[O:2].C(O[C:35](=[O:37])[CH3:36])(=O)C.C(Cl)Cl>N1C=CC=CC=1>[C:1]([O:19][C@@H:18]([C@H:16]([C@@H:14]([C@@H:12]([CH2:11][O:10][C:7]1[CH:6]=[CH:5][C:4]([C:1]([OH:3])=[O:2])=[CH:9][CH:8]=1)[O:13][C:35](=[O:37])[CH3:36])[O:15][C:12](=[O:13])[CH3:11])[O:17][C:7](=[O:10])[CH3:6])[CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]([OH:30])=[O:29])=[CH:26][CH:27]=1)(=[O:2])[CH3:4]
Reactant: O=C(O)c1ccc(OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)COc2ccc(C(=O)O)cc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]([C@H](OC(C)=O)[C@@H](COc1ccc(C(=O)O)cc1)OC(C)=O)[C@@H](COc1ccc(C(=O)O)cc1)OC(C)=O
Temperature: 0 °C

Procedure:
2.10 g of 1,6-bis-O-(4-carboxy-phenyl)-D-mannitol were stirred at room temperature for 20 hours in 30 ml of pyridine with 5.1 ml of acetic anhydride. The reaction mixture was worked up extractively with ice-water and methylene chloride. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was recrystallized from methanol and methylene chloride. There was obtained 2,3,4,5-tetra-O-acetyl-1,6-bis-O-(4-carboxy-phenyl)-D-mannitol, MS: m/z 589 ([M-H]-).
Reaction SMILES: C[O-].[Na+].[NH2:4][C:5]1[C:10]([NH:11][C:12]([C:14]2([C:17]3[N:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:16][CH2:15]2)=O)=[CH:9][CH:8]=[C:7]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([C:29]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])[CH2:24]2)[N:6]=1>C(O)C(C)C.CO>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:14]2([C:12]3[NH:4][C:5]4=[N:6][C:7]([N:23]5[CH2:28][CH2:27][CH2:26][C@@H:25]([C:29]([N:31]6[CH2:35][CH2:34][CH2:33][CH2:32]6)=[O:30])[CH2:24]5)=[CH:8][CH:9]=[C:10]4[N:11]=3)[CH2:16][CH2:15]2)[N:18]=1
Reactant: Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ccc1NC(=O)C1(c2cccnn2)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)CO
Product: O=C([C@@H]1CCCN(c2ccc3nc(C4(c5cccnn5)CC4)[nH]c3n2)C1)N1CCCC1
Temperature: 110 °C
Yield: 38.1 %

Procedure:
Sodium methoxide (74.4 mg, 1.37 mmol) was added to a solution of (R)—N-(2-amino-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)-1-(pyridazin-3-yl)cyclopropanecarboxamide (100 mg, 0.22 mmol) in isobutanol (2 mL) and methanol (2 mL). The reaction mixture was heated to 110° C. for 16 h. The reaction mixture was concentrated under reduced pressure and the resulting crude was purified via preparative TLC to afford the title compound (35 mg). MS (ES+APCI) (M+H) 418.2; LCMS retention time: 3.439 min (Method W1).
Reaction SMILES: Cl[S:2]([N:5]=C=O)(=[O:4])=[O:3].[CH2:8]([N:15]1[CH2:20][CH2:19][C:18]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=2)([CH2:21][NH2:22])[CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1.C(O)=O>[CH2:8]([N:15]1[CH2:20][CH2:19][C:18]([CH2:21][NH:22][S:2]([NH2:5])(=[O:4])=[O:3])([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=2)[CH2:17][CH2:16]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Cc1cccc(NC2(CN)CCN(Cc3ccccc3)CC2)c1
Solvent: C1CCOC1
Solvent: O=CO
Product: Cc1cccc(NC2(CNS(N)(=O)=O)CCN(Cc3ccccc3)CC2)c1
Reaction time: 8 h

Procedure:
To a cold (5° C.) solution of chlorosulfonyl isocyanate in THF, anhydrous formic acid is added (Journal of Organic Chemistry, vol 54, page 5825,(1989)). The resultant mixture is stirred until gas evolution ceased, and treated with a solution of 1-benzyl-4-(3-methylphenylamino)-4-aminomethylpiperidine in THF. The mixture is stirred at room temp. overnight to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[CH:5]=[N:6][OH:7].OC1C(OS(C2C=CC(C)=CC=2)(=O)=O)=C(I)C=CC=1.[C:33]([O:37][CH2:38][CH3:39])(=[O:36])[C:34]#[CH:35]>C(#N)C.C(OCC)(=O)C>[CH2:38]([O:37][C:33]([C:34]1[O:7][N:6]=[C:5]([C:4]2[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([F:1])[CH:3]=2)[CH:35]=1)=[O:36])[CH3:39]
Reactant: O=[N+]([O-])c1ccc(C=NO)cc1F
Reactant: C#CC(=O)OCC
Agent: Cc1ccc(S(=O)(=O)Oc2c(O)cccc2I)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(-c2ccc([N+](=O)[O-])c(F)c2)no1
Yield: 70.1 %

Procedure:
To a solution of 3-fluoro-4-nitro-benzaldehyde oxime (6 g; 32.6 mmol) in acetonitrile (120 mL) was added hydroxy tosyloxy iodobenzene (16.58 g; 42.3 mmol) and ethyl propiolate (6.38 g; 65.2 mmol) under stirring. The resulting reaction mixture was stirred at 80° C. for 2-3 h. After the completion of the reaction, it was evaporated to dryness. The solid thus obtained was dissolved in ethyl acetate and washed with brine and dried over anhydrous Na2SO4. The solvent was removed and the residue was purified by flash chromatography over silica gel with 20% ethyl acetate in light petroleum to give 6.4 g (74%) of the title compound. IR (KBr): 3134, 3060, 2975, 1717, 1610, 1593, 1522, 1458, 1446 cm−1; MS (m/z): 279 (M−−1); 1H NMR (DMSO-d6) δ: 1.31-136 (t, 3H, CH2CH3), 4.36-4.43 (q, 2H, CH2CH3), 8.04 (d, 1H, J=9.0, 6′-H), 8.09 (s, 1H, 4-H), 8.16 (d, 1H), 8.30 (t, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5](=[O:10])[CH:6]([CH3:9])[CH:7]=[CH2:8].O.C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C>C(COC)OC>[CH3:9][C:6](=[C:5]1[O:10][CH2:2][CH2:3][O:4]1)[CH:7]=[CH2:8]
Reactant: C=CC(C)C(=O)OCCCl
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: COCCOC
Solvent: O
Product: C=CC(C)=C1OCCO1
Temperature: 20 °C
Reaction time: 2 h
Yield: 65.8 %

Procedure:
90.6 g (about 113 ml) of 20% potassium hydride in oil (density about 0.8) were washed twice with n-hexane under argon, and then treated with 700 ml of dimethoxyethane. Subsequently, a solution of 56.5 g (0.34 mol) of 2-methyl-but-3-enoic acid 2-chloroethyl ester with a content of 97.5% according to GC in 175 ml of dimethoxyethane was added thereto while stirring at 20° C. within 11/2 hours, and the mixture was stirred at room temperature for 1 hour. 250 ml of water were cautiously added dropwise thereto at 0-5° C. The aqueous phase was then separated and extracted three times with three 300 ml portions, a total of 900 ml, of n-hexane. Washing of the combined organic phases with 250 ml of saturated sodium chloride solution, drying and concentration gave a yellow liquid (50.5 g; GC: 83.4%), which, after the addition of 40 mg of 2,6-di-tert.butyl-p-cresol, was fractionated on a Vigreux column (20cm). This gave, at a boiling temperature of 93-94° C./19 mbar, 28.22 g (66% yield) of 2-(1-methyl-allylidene)-[1,3]dioxolane as a colourless oil with a content of 100% according to GC.
Reaction SMILES: Br.[NH2:2][CH:3]1[CH2:7][CH2:6][O:5][C:4]1=[O:8].[C:9](=N)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl.O>[C:10]1([C:9](=[N:2][CH:3]2[CH2:7][CH2:6][O:5][C:4]2=[O:8])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: NC1CCOC1=O
Agent: Br
Solvent: ClCCl
Solvent: O
Product: O=C1OCCC1N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 3-aminodihydrofuran-2(3H)-one hydrobromide (5 g, 27.5 mmol) in DCM (50 mL) was added benzophenone imine (5 g, 27.5 mmol) and the reaction mixture was stirred at RT for 3 days. The reaction mixture was diluted with water and DCM, the organic layer was extracted, washed with aquous sodium bicarbonate, brine, dried over sodium sulfate and concentrated in vacuo to give 3-[(diphenylmethylene)amino]dihydrofuran-2(3H)-one as a thick colorless gel which crystallized to a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([N+:14]([O-])=O)=[CH:9][C:8]=2[Cl:17])=[O:4].[H][H]>[Pt].O1CCCC1>[CH3:1][N:2]([CH3:18])[C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([NH2:14])=[CH:9][C:8]=2[Cl:17])=[O:4]
Reactant: [H][H]
Reactant: CN(C)C(=O)c1cc2cc([N+](=O)[O-])cc(Cl)c2[nH]1
Agent: [Pt]
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc2cc(N)cc(Cl)c2[nH]1

Procedure:
A mixture of 2.6 g I.7 (7-chloro-5-nitro-1H-indole-2-carboxylic acid dimethylamide), 0.3 g Pt/C 10%, 10 ml methanol and 90 ml tetrahydrofuran was stirred ambient temperature under a pressure of 50 psi hydrogen. The catalyst was filtered and the solvent was evaporated. The resulting crude material was used for the next step without purification.
Reaction SMILES: [CH3:1][C:2]([CH3:17])=[CH:3][C:4]([NH:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])=[O:5].[Cl-].[Cl-].[Cl-].[Al+3]>ClCCCl.ClCCl>[CH3:1][C:2]1([CH3:17])[C:16]2[C:7](=[C:8]([C:9]([O:11][CH3:12])=[O:10])[CH:13]=[CH:14][CH:15]=2)[NH:6][C:4](=[O:5])[CH2:3]1
Reactant: COC(=O)c1ccccc1NC(=O)C=C(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)c1cccc2c1NC(=O)CC2(C)C
Temperature: 25 °C

Procedure:
A solution of 15.18 g of methyl 2-(3-methyl-but-2-enoylamino)benzoate and 35.07 g of aluminium trichloride in 250 ml of 1,2-dichloroethane is stirred at reflux over 30 minutes. The reaction mixture is cooled to room temperature, diluted with dichloromethane, washed with 1N HCl (2×) and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a brown solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.21 (3:7 EtOAc-heptane); Rt=3.98.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]([OH:25])=O)=[CH:19][C:18]=1[CH3:26].O[N:28]=[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][CH3:38])[NH2:30].CCN(C(C)C)C(C)C>>[CH3:7][O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:25][N:30]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][CH3:38])[N:28]=2)=[CH:19][C:18]=1[CH3:26]
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2C)c(OC)c1
Reactant: COc1ccccc1C(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2ccc(-c3nc(-c4ccccc4OC)no3)cc2C)c(OC)c1

Procedure:
Oxalyl chloride (112 μL; 1.32 mmol; 3 eq.), Intermediate 28 (120 mg; 0.44 mmol; 1 eq.), Intermediate 1 (73 mg; 0.44 mmol, 1 eq.) and DIEA (228 μL; 1.32 mmol; 3 eq.) were reacted according to general procedure 2. Purification by precipitation from DCM/n-pentane afforded the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]([C:10]([NH2:12])=[O:11])=[C:8]([OH:9])[C:4]=2[CH:3]=1.[C:15]1([CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]([C:10]([NH:12][CH:22]=[C:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:11])=[C:8]([OH:9])[C:4]=2[CH:3]=1
Reactant: O=CC(c1ccccc1)c1ccccc1
Reactant: NC(=O)c1sc2ccc(F)cc2c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(NC=C(c1ccccc1)c1ccccc1)c1sc2ccc(F)cc2c1O
Yield: 82.1 %

Procedure:
To a solution of 5-fluoro-3-hydroxybenzo[b]-thiophene-2-carboxamide (400 mg, 1.89 mmol) in hot toluene (35 ml) were added diphenylacetaldehyde (577 mg, 2.84 mmol) and p-toluenesulfonic acid monohydrate (25 mg). The reaction mixture was stirred at reflux temperature for 2 hours with azeotropic removal of water, cooled, and evaporated under diminished pressure. The solid obtained was recrystallized from diethyl ether-hexane to yield 604 mg (82%) of 5-fluoro-3-hydroxy-N-(2,2-diphenylethenyl)benzo[b]thiophene-2-carboxamide, m.p. 186°-189° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:11]3[O:19][C@H:20]4[CH2:25][CH2:24][CH2:23][C@H:21]4[NH:22][C:10]=3[CH:9]=[CH:8][C:7]=2[N:6]=1)([CH3:3])[CH3:2].C=O.[BH3-][C:29]#N.[Na+]>C(O)(=O)C>[CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:17])([F:16])[F:18])[C:12]2[C:11]3[O:19][C@H:20]4[CH2:25][CH2:24][CH2:23][C@H:21]4[N:22]([CH3:29])[C:10]=3[CH:9]=[CH:8][C:7]=2[N:6]=1)([CH3:3])[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(C)Oc1cc(C(F)(F)F)c2c3c(ccc2n1)N[C@@H]1CCC[C@@H]1O3
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)Oc1cc(C(F)(F)F)c2c3c(ccc2n1)N(C)[C@@H]1CCC[C@@H]1O3
Yield: 97.5 %

Procedure:
Compound 133 was prepared according to General Method 5 (EXAMPLE 2) from (7aR,10aS)-7,7a,8,9,10,10a-hexahydro-3-isopropoxy-1-(trifluoromethyl)-cyclopenta[5,6][1,4]oxazino[2,3-f]quinoline (5 mg, 0.014 mmol), 37% aqueous formaldehyde solution (0.01 mL, 0.14 mmol) and NaBH3CN (9 mg, 0.14 mmol) in 1 mL acetic acid to afford 5 mg of (7aR,10aS)-7,7a,8,9,10,10a-hexahydro-3-isopropoxy-7-methyl-1-(trifluoromethyl)-cyclopenta[5,6][1,4]oxazino[2,3-f]quinoline. This material (5 mg, 0.01 mmol) carried on according to General Method 4 (EXAMPLE 1) by treatment with 4 mL of 1:1 acetic acid:concentrated HCl (3 mM) heated at 90° C. for 4 h to afford 3.9 mg (90%) of Compound 133, a yellow solid, after column chromatography (3:1 hexanes:EtOAc to 1:1 hexanes:EtOAc, gradient elution). 1H NMR (500 MHz, CDCl3) δ 10.58 (bs, 1H), 7.10 (s, 1H), 7.00 (d, J=8.8, 1H), 6.87 (d, J=8.8, 1H), 4.15 (m, 1H), 3.53 (m, 1H), 2.98 (s, 3H), 2.02 (m, 4H), 1.64 (m, 2H), 0.88 (t, J=6.8, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:19]([NH:21][NH:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:31]1[C:35]([CH2:36][C:37](O)=[O:38])=[N:34][N:33]=[N:32]1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:19]([NH:21][N:22]([CH2:23][CH:24]([CH3:25])[CH3:26])[C:37](=[O:38])[CH2:36][C:35]1[NH:34][N:33]=[N:32][N:31]=1)=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CNNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Reactant: O=C(O)Cc1nnn[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)Cc1nnn[nH]1)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 119.8 %

Procedure:
A solution of 0.416 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide and 0.282 g of 2-(1H-tetrazol-5-yl)acetic acid in 4 ml of dimethylformamide was treated at room temperature under nitrogen with 0.461 g of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride. The mixture was stirred for 0.5 hours at room temperature and evaporated. The residue was dissolved in ethyl acetate and washed with 5% aqueous sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over anhydrous magnesium sulphate and evaporated to give 0.630 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-2′-isobutyl-4-methyl-2′-[2-(1H-tetrazol-5-yl)acetyl]valerohydrazide in the form of an off-white foam.