Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[CH:11]=[C:12]3[C:20]([C:21]([CH3:23])([CH3:22])[C:9]=2[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:7]=2)=[C:19]1[C:14]([CH:15]=[CH:16][CH:17]=[CH:18]1)=[N:13]3.[C:30]1(C2C=CC=CC=2)[CH:35]=[CH:34][C:33]([N:36](C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>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.C1(C)C=CC=CC=1.C(O)C>[C:6]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:7]=[CH:8][C:3]([N:36]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:33]2[CH:32]=[CH:31][C:30]([C:2]3[C:10]4[CH:11]=[C:12]5[C:20]([C:21]([CH3:23])([CH3:22])[C:9]=4[C:8]4[C:3]=3[CH:4]=[CH:5][CH:6]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:7]=4)=[C:19]3[C:14]([CH:15]=[CH:16][CH:17]=[CH:18]3)=[N:13]5)=[CH:35][CH:34]=2)=[CH:4][CH:5]=1
Reactant: CC1(C)C2=C(C=C3N=c4ccccc4=C31)C(Br)=C1C=CC(c3ccccc3)C=C12
Reactant: CC1(C)OB(c2ccc(N(c3ccccc3)c3ccc(-c4ccccc4)cc3)cc2)OC1(C)C
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: CCO
Solvent: Cc1ccccc1
Product: CC1(C)C2=C(C=C3N=c4ccccc4=C31)C(c1ccc(N(c3ccccc3)c3ccc(-c4ccccc4)cc3)cc1)=C1C=CC(c3ccccc3)C=C12
Temperature: 73 °C
Reaction time: 8 h
Yield: 116.2 %

Procedure:
7-Bromo-12,12-dimethyl-10-phenyl-10,12-dihydro-indeno[2,1-b]carbazole synthesized in Example 1 (3.0 g), (biphenyl-4-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-phenylamine (3.7 g), a toluene/ethanol (4/1, v/v) mixed solvent (50 ml), and a 2M potassium carbonate aqueous solution (10 ml) were added to a nitrogen-substituted reaction vessel and aerated with nitrogen gas for 30 min under ultrasonic irradiation. The mixture was heated after adding tetrakis(triphenylphosphine)palladium (0.4 g), and stirred at 73° C. for 8 hours. After the mixture was cooled to a room temperature, a precipitated crude product was collected by filtration. 1,2-Dichlorobenzene (140 ml) was added to the crude product, and the crude product was dissolved while being heated, and after removing insoluble matter by filtration, a filtrate was concentrated under reduced pressure. Purification by recrystallization using 1,2-dichlorobenzene (100 ml) was performed to obtain a white powder of 7-[4-{(biphenyl-4-yl)-phenylamino}-phenyl]-12,12-dimethyl-10-phenyl-10,12-dihydroindeno[2,1-b]carbazole (2.7 g; yield 57.8%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH2:13][CH2:14][CH3:15])=[C:11]2[C:6]([CH:7]=[C:8]([C:17]([OH:19])=O)[C:9](=[O:16])[O:10]2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.CCCP(=O)=O.C(OCC)(=O)C.[NH2:41][C:42]1[CH:47]=[CH:46][C:45]([S:48]([NH2:51])(=[O:50])=[O:49])=[CH:44][C:43]=1[CH3:52]>C(Cl)Cl>[NH2:51][S:48]([C:45]1[CH:46]=[CH:47][C:42]([NH:41][C:17]([C:8]2[C:9](=[O:16])[O:10][C:11]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:12]=3[CH2:13][CH2:14][CH3:15])=[O:19])=[C:43]([CH3:52])[CH:44]=1)(=[O:49])=[O:50]
Reactant: CCCc1c(OC)ccc2cc(C(=O)O)c(=O)oc12
Reactant: Cc1cc(S(N)(=O)=O)ccc1N
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCc1c(OC)ccc2cc(C(=O)Nc3ccc(S(N)(=O)=O)cc3C)c(=O)oc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of Intermediate 1 (0.10 g, 0.381 mmol) in CH2Cl2 (5.0 mL) was added diisopropyl ethyl amine (0.1 mL, 0.572 mmol) and a 50% solution of propylphosphonic anhydride in ethyl acetate (0.340 mL, 0.572 mmol). The mixture was stirred for 30 minutes at room temperature. 4-Amino-3-methylbenzenesulfonamide [CAS # 53297-70-4] (0.071 g, 0.381 mmol) was added to the reaction mixture at room temperature and stirred overnight. The reaction mixture was then poured onto ice water (25 mL) and CH2Cl2 (25 mL) added. The organic layer was separated and washed with brine (25 mL), dried with Na2SO4, filtered and concentrated to dryness. The residue was triturated with CH2Cl2/Hexanes and then the solid was purified with a MPLC to give the title compound as a white solid.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.S1C=CC=C1CC([NH:15][CH:16]1[C:34](=[O:35])[N:18]2[C:19]([C:31]([OH:33])=[O:32])=[C:20]([C:23]3[S:24][C:25]([N:28]([CH3:30])[CH3:29])=[N:26][N:27]=3)[CH2:21][S:22][C@H:17]12)=O.CN(C)C1C=CC=CC=1.C[Si](C)(Cl)Cl.C(=O)(O)[O-].[Na+]>ClCCl.O.CO.N1C=CC=CC=1>[NH2:15][CH:16]1[C:34](=[O:35])[N:18]2[C:19]([C:31]([OH:33])=[O:32])=[C:20]([C:23]3[S:24][C:25]([N:28]([CH3:30])[CH3:29])=[N:26][N:27]=3)[CH2:21][S:22][C@H:17]12
Reactant: CN(C)c1nnc(C2=C(C(=O)O)N3C(=O)C(NC(=O)Cc4cccs4)[C@H]3SC2)s1
Agent: C[Si](C)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: O
Solvent: c1ccncc1
Product: CN(C)c1nnc(C2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Temperature: -40 °C
Yield: 45.8 %

Procedure:
To a suspension of 0.625 g of powdered phosphorous pentachloride in 20 ml of dichloromethane is added 0.474 g of pyridine under stirring at -40° C. To the resulting mixture is added dropwise a solution of 0.422 g of 7-thienylacetamido-3-(5-dimethylamino-1,3,4-thiadiazol-2-yl)-3-cephem-4-carboxylic acid (obtained in Example 42) in 10 ml of dichloromethane, 0.242 g of dimethylaniline and then 0.3 ml of dimethyldichlorosilane under stirring at -40° C. After stirring for 30 minutes at 0° C., to the reaction mixture is added 5 ml of methanol under stirring at -40° C., and the mixture is poured into cold water. The aqueous layer is neutralized to pH 5.5 with an aqueous solution of sodium bicarbonate and washed three times with dichloromethane. The solution is charged on a column of Amberlite XAD-II and eluted with water. The fractions containing the desired product are collected and lyophilized to give 0.140 g of 7-amino-3-(5-dimethylamino-1,3,4-thiadiazol-2-yl)-3-cephem-4-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH2:34]([C:41]1[S:45][C:44]([CH2:46][NH2:47])=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CS(C)=O.[Cl-].[Na+].O>[NH2:1][C:2]1[N:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:47][CH2:46][C:44]1[S:45][C:41]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:42][CH:43]=1)=[O:6]
Reactant: Nc1ccc(C(=O)O)c(N)n1
Reactant: NCc1ccc(Cc2ccccc2)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(C(=O)NCc2ccc(Cc3ccccc3)s2)c(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
To a solution of 2,6-diaminonicotinic acid described in Preparation Example A-15 (173 mg, 1.13 mmol) in dimethylsulfoxide (15 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (433 mg, 2.26 mmol), 1-hydroxybenzotriazole (346 mg, 2.26 mmol) and C-(5-benzyl-thiophen-2-yl)-methylamine described in Preparation Example 42 (230 mg, 1.13 mmol), and the solution was stirred at room temperature fro 16 hours 30 minutes. The reaction solution was poured into brine, the solution was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate and then concentrated. The obtained residue was subjected to NH silica gel column chromatography, eluted with solvent (ethyl acetate) and the title compound (114 mg, 0.34 mmol, 30%) was obtained.
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[N:15][C:14]=3[C:24]([OH:26])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:27]([O:31][C:32](=[O:46])[CH:33]([O:42][C:43](=[O:45])[CH3:44])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([NH2:41])[CH:36]=1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32](=[O:46])[CH:33]([O:42][C:43](=[O:45])[CH3:44])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([NH:41][C:24]([C:14]2[N:15]=[C:16]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[NH:17][C:13]=2[CH2:12][CH2:11][C:1]23[CH2:8][CH:7]4[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]4)[CH2:10]2)[CH2:2]3)=[O:26])[CH:36]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: O=C(O)c1nc(C2CCCCC2)[nH]c1CCC12CC3CC(CC(C3)C1)C2
Reactant: CC(=O)OC(Cc1cccc(N)c1)C(=O)OC(C)(C)C
Product: CC(=O)OC(Cc1cccc(NC(=O)c2nc(C3CCCCC3)[nH]c2CCC23CC4CC(CC(C4)C2)C3)c1)C(=O)OC(C)(C)C

Procedure:
5-(2-Adamantan-1-yl-ethyl)-2-cyclohexyl-1H-imidazole-4-carboxylic acid (Example 252) (690 mg, 1.94 mmol) was reacted with the product of step b (540 mg, 1.94 mmol) according to the procedure of Example 20, step d to afford colourless foam after purification by flash chromatography (silica, hexane/ethyl acetate 2:1) (287 mg, 24%). 1H NMR (300 MHz, CDCl3) 9.04 (1H, br s), 8.63 (1H, br s), 7.60 (2H, m), 7.25 (1H, m), 6.97 (1H, d), 5.11 (1H, m), 3.17-3.03 (4H, m), 2.80 (1H, m), 2.10-1.27 (399H, m).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C@@H:9]([NH:25][C:26](=[O:39])/[CH:27]=[CH:28]/[C:29]1[CH:34]=[C:33]([C:35]#[N:36])[CH:32]=[CH:31][C:30]=1[O:37][CH3:38])[CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[NH2:7][CH2:8][C@@H:9]([NH:25][C:26](=[O:39])/[CH:27]=[CH:28]/[C:29]1[CH:34]=[C:33]([C:35]#[N:36])[CH:32]=[CH:31][C:30]=1[O:37][CH3:38])[CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH2:13][CH2:12]1
Reactant: COc1ccc(C#N)cc1/C=C/C(=O)N[C@H](CNC(=O)OC(C)(C)C)CN1CCC(Oc2ccc(F)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(C#N)cc1/C=C/C(=O)N[C@H](CN)CN1CCC(Oc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of {(R)-2-[(E)-3-(5-cyano-2-methoxy-phenyl)-acryloylamino]-3-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-propyl}-carbamic acid tert-butyl ester (0.39 g, 0.71 mmol) in DCM (2 ml) is treated with 4M hydrogen chloride in dioxane (1 ml). The reaction mixture is stirred at room temperature for 1.5 hours and then the solvent evaporated. The residue is co-evaporated with ethanol (×2) to afford (E)-N-{(R)-1-aminomethyl-2-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-ethyl}-3-(5-cyano-2-methoxy-phenyl)-acrylamide.HCl salt. [MH]+ 453.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[C:12]=2[N+:23]([O-])=O)=[O:10])=[N:6][CH:7]=1>C(OCC)(=O)C.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>[NH2:23][C:12]1[C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[C:15]([O:17][CH3:18])=[CH:16][C:11]=1[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)=[O:10]
Reactant: COc1cc(C(=O)Nc2ccc(Br)cn2)c([N+](=O)[O-])c(OC)c1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)Nc2ccc(Br)cn2)c(N)c(OC)c1OC
Yield: 77.7 %

Procedure:
To a solution of the compound of N-(5-bromo(2-pyridyl))(3,4,5-trimethoxy-2-nitrophenyl)carboxamide (790 mg, 1.92 mmol) in ethyl acetate (5 ml) was added tin chloride (II) hydrate (1.73 g, 7.67 mmol). The mixture was stirred under reflux condition for 2 hrs. After filtered by Celite, the filtrate was added 1N sodium hydroxide solution and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to give (2-amino-3,4,5-trimethoxyphenyl)-N-(5-bromo(2-pyridyl))carboxamide (570 mg, 77%). MS found for C15H16BrN3O4 M+=382, (M+2)+=384.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:25][CH3:26])=[C:9]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[N+:22]([O-])=O)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:25][CH3:26])=[C:9]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[NH2:22])=[O:13])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(C(C)(C)C)cc1NC(=O)Nc1ccc(C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C(C)(C)C)cc1NC(=O)Nc1ccc(C)cc1N
Reaction time: 18 h
Yield: 94 %

Procedure:
A solution of N-(5-tert-butyl-2-methoxyphenyl)-N′-(2-nitro-4-methylphenyl)urea (prepared in a manner analogous to Method B1a; 4.0 g, 11.2 mmol) in EtOH (100 mL) was added to a slurry of 10% Pd/C (0.40 g) in EtOH (10 mL), and the resulting mixture was stirred under an atmosphere of H2 (balloon) at room temp. for 18 h. The mixture was filtered through a pad of Celite® and concentrated in vacuo to afford the desired product (3.42 g, 94%) as a powder: mp 165-166° C.; 1H-NMR (DMSO-d6) δ 1.30 (s, 9H), 2.26 (s, 3H), 3.50 (br s, 2H), 3.71 (s, 3H), 6.39 (br s, 1H), 6.62 (s, 1H), 6.73 (d, J=8.46 Hz, 1H), 6.99 (dd, J=2.21, 8.46 Hz, 1H), 7.05 (d, J=8.46 Hz, 1H), 7.29 (s, 1H), 8.22 (d, J=2.57 Hz, 1H); FAB-MS m/z 328 ((M+H)+). C3. General Method of Thiourea Formation by Reaction with a Thioisocyanate
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([C:12]([S:14]C)=S)[CH2:11][CH2:10][CH2:9][S:8]1.[CH3:16][NH:17][CH3:18]>>[CH3:16][N:17]([CH3:18])[C:12]([C:7]1([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:11][CH2:10][CH2:9][S:8]1)=[S:14]
Reactant: CNC
Reactant: CSC(=S)C1(c2ccccn2)CCCS1
Product: CN(C)C(=S)C1(c2ccccn2)CCCS1
Temperature: 20 °C

Procedure:
A solution of methyl 2-(pyrid-2-yl)tetrahydrothiophene-2-carbodithioate (20 g) in dimethylamine (100 cc) is heated gradually for 3 hours 40 minutes, in an autoclave, up to a temperature of about 125° C. After cooling to a temperature of about 20° C., the autoclave is emptied and rinsed with methylene chloride (200 cc), the latter being added to the reaction mixture. The solution is concentrated to dryness (20 mm Hg; 2.7 kPa) at 40° C. The resulting residue (20.7 g) is dissolved in boiling ethanol (50 cc) and the solution, to which decolourising charcoal (0.5 g) is added, is filtered hot and then kept, after cooling, for 1 hour at a temperature of about 0° C. The crystals which have appeared are filtered off, washed twice with ethanol (20 cc in total) and dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20° C. The resulting product (14.1 g) is dissolved in boiling ethanol (45 cc) and the solution, to which decolourising charcoal (0.5 g) is added, is filtered hot and then kept, after cooling, for 1 hour at a temperature of 0° C. The crystals which have appeared are filtered off, washed twice with ethanol (20 cc in total) and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 45° C. N,N-Dimethyl-2-(pyrid-2-yl)-tetrahydrothiophene-2-carbothioamide (11.8 g), melting at 100° C., is thus obtained.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=C[CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2O)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].[N:22]1C=CC=C2C(N)CCC=12>>[CH2:1]([C:3]1[C:4]([NH:11][CH:12]2[C:20]3[C:15](=[N:22][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Reactant: NC1CCc2ncccc21
Product: CCc1cnc(CC)c(NC2CCc3ncccc32)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 6,7-dihydro-5H-cyclopenta[b]pyridin-5-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 8.48, 7.73, 7.66, 7.14, 5.82, 4.54, 3.22–3.07, 2.79, 2.70–2.57, 1.94 1.36–1.27; HRMS (FAB) calcd for C16H20N4+H 269.1766, found 269.1763.
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]([CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])=[CH:8]2)=[CH:4][CH:3]=1.Cl[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[N:33][CH:34]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:12]1([C:10]2[C:9]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:8][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([O:1][CH2:28][C:29]4[CH:34]=[N:33][C:32]([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=5)=[CH:31][CH:30]=4)=[CH:26][CH:25]=3)[CH:11]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCc1ccc(-c2ccccc2)nc1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CCc1cn(Cc2ccc(OCc3ccc(-c4ccccc4)nc3)cc2)cc1-c1ccccc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 97.7 %

Procedure:
A mixture of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (600 mg), 5-chloromethyl-2-phenylpyridine (370 mg), potassium carbonate (450 mg) and N,N-dimethylformamide (10 ml) was stirred at 80° C. for 5 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to obtain a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). After a mixture of the resulting colorless oily substance, 1N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, 1N hydrochloric acid (5 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[4-phenyl-1-[4-(6-phenyl-3-pyridylmethoxy)benzyl]-3-pyrrolyl]propionic acid (820 mg, yield: 98%). This was recrystallized from acetone-hexane. Melting point: 185–186° C.
Reaction SMILES: [C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:16](=[O:23])[CH2:17][CH2:18][CH2:19][C:20]=53)=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[Cl-:25]>CN(C=O)C>[Cl:25][CH:17]1[C:16](=[O:23])[C:15]2[C:14]3[C:22]4=[C:10]([O:9][CH2:8][CH:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[N:21]4[C:20]=2[CH2:19][CH2:18]1)[CH:11]=[CH:12][CH:13]=3
Reactant: O=C1CCCc2c1c1cccc3c1n2C(c1ccccc1)CO3
Reactant: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C1c2c(n3c4c(cccc24)OCC3c2ccccc2)CCC1Cl
Temperature: 65 °C
Reaction time: 50 h
Yield: 71.3 %

Procedure:
A mixture of 1-phenyl-1,2,9,10-tetrahydro[1,4]oxazino[2,3,4-jk]carbazol-7(8H)-one (0.441 g, 1.45 mmol), anhydrous CuCl12 (0.430 mmol, 3.20 mmol), anhydrous LiCl (0.308 g, 7.27 mmol), and DMF (3 mL) is stirred at 65° C. for 50 h. After cooling, the mixture is stored in the refrigerator overnight and then partitioned between CH2C2 and brine. The organic layers are dried over sodium sulfate and taken to dryness. Chromatography on silica gel gel (60 mL) using ethyl acetate/CH2Cl2/hexane (5:45:50) gave 0.349 g (71%) of 8-chloro-1-phenyl-1,2,9,10-tetrahydro[1,4]oxazino[2,3,4-jk]carbazol-7(8H)-one (mixture of diastereomers).
Reaction SMILES: O=S(Cl)[Cl:3].[Cl:5][C:6]1[CH:11]=[C:10]([CH2:12]O)[CH:9]=[CH:8][N:7]=1>C(Cl)Cl>[Cl:5][C:6]1[CH:11]=[C:10]([CH2:12][Cl:3])[CH:9]=[CH:8][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccnc(Cl)c1
Solvent: ClCCl
Product: ClCc1ccnc(Cl)c1
Yield: 97.5 %

Procedure:
SOCl2 (4.2 g, 35.5 mol) was added dropwise to a suspension of the alcohol (5 g, 34.8 mmol) in CH2Cl2 (50 mL) at −5° C. with stirring. The mixture was stirred at room temperature overnight, then quenched with water (100 mL), and extracted with CH2Cl2 (3×100 mL). The organic layers were combined, washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The crude material was further purified by silica gel chromatography (EtOAc/Hexane=1/5) and afforded the title compound (5.5 g, near quantitative yield) as an oil.
Reaction SMILES: Br[C:2]1[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH2:18]([Sn](CCCC)(CCCC)C=C)[CH2:19]CC>O1CCOCC1.C(OCC)(=O)C.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.F[P-](F)(F)(F)(F)F.C([N+]1C=CN(C)C=1)CCC>[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:6]1[O:5][N:4]=[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:2]=1[CH:18]=[CH2:19]
Reactant: CCOC(=O)c1noc(-c2ccccn2)c1Br
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[n+]1ccn(C)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C=Cc1c(C(=O)OCC)noc1-c1ccccn1
Yield: 414.3 %

Procedure:
A solution of ethyl 4-bromo-5-(pyridin-2-yl)isoxazole-3-carboxylate (2-C) (170 mg, 0.572 mmol), tributyl(vinyl)tin (0.504 mL, 1.72 mmol), dichlorobis(triphenylphosphine)-palladium(II) (24.1 mg, 0.034 mmol), and 1-butyl-3-methylimidazolium hexafluorophosphate (0.012 mL, 0.057 mmol) in dioxane (3 mL) was heated to 170° C. via microwave for 120 minutes. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (10 mL), washed with brine (10 mL), and dried over anhydrous sodium sulfate. Concentration gave a crude product which was purified by silica gel chromatography with hexanes/ethyl acetate (4/1) to give ethyl 5-(pyridin-2-yl)-4-vinylisoxazole-3-carboxylate (60 mg, 2.37 mmol, 41% yield). The compound had an HPLC retention time=2.80 min.—Column: YMC S5 COMBISCREEN® 4.6×50 mm; Gradient time: 4 min; Flow rate=4 ml/min; Solvent A=10% MeOH—90% Water—0.2% H3PO4; Solvent B=90% MeOH—10% water—0.2% H3PO4; Start % B=0; Final % B=100. LC-MS: M+1=245.2. 1H NMR (400 MHz, MeOD) δ ppm 1.42 (t, 3H), 4.47 (q, J=7.19 Hz, 2H), 5.49 (dd, J=11.80, 1.25 Hz, 1H), 5.85 (dd, J=18.07, 1.51 Hz, 1H), 7.26 (dd, J=18.07, 11.80 Hz, 1H), 7.51 (ddd, J=7.03, 5.02, 1.76 Hz, 1H), 7.93-8.02 (m, 2H), and 8.72-8.75 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[C:10]([C:14]3[CH:19]=[CH:18][C:17]([NH:20]CC4C=CC=CC=4)=[CH:16][CH:15]=3)([CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[C:10]([C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)([CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CC2(c2ccc(NCc3ccccc3)cc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC2CC2(c2ccc(N)cc2)C1
Yield: 97.8 %

Procedure:
To a solution of 1-(4-benzylamino-phenyl)-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (3.0 g, 8.2 mmol) in methanol (20 mL) was added 10% Pd/C (600 mg, 20% by weight). Flask was evacuated and hydrogen was introduced. The reaction mixture was stirred under hydrogen and progress of the reaction was monitored by TLC. On completion, the reaction mixture was filtered through celite pad using methanol as solvent. The filtrate was evaporated to provide the title compound (2.2 g, 97%) as brown solid and subjected to further reaction without any purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:24]2[CH2:29][C:28]([CH3:31])([CH3:30])[CH2:27][C:26]([CH3:33])([CH3:32])[CH2:25]2)[C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([CH3:23])([CH3:22])[C:17]([O:19]CC)=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CCO>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:24]2[CH2:29][C:28]([CH3:31])([CH3:30])[CH2:27][C:26]([CH3:33])([CH3:32])[CH2:25]2)[C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([CH3:23])([CH3:22])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(OC(C)(C)C(=O)O)cc2)CC(C)(C)C1
Yield: 82.5 %

Procedure:
The hydrolysis conditions described for 191 were used. A solution of ethyl 2-({4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)-2-methylpropanoate (227) (0.15 g, 0.33 mmol) in THF/EtOH (1:1, 6 mL) was treated with 1 N NaOH (3 mL, excess) at 70° C. for 1 h. Reaction mixture was cooled and poured into 20% aqueous HCl (40 mL). Standard work-up followed by purification afforded 0.115 g (82%) of the title compound 228 as an off-white solid. 1H NMR (300 MHz, DMSO-d6): δ 13.0 (br s, 1H), 9.26 (s, 1H), 7.00 (d, J=8.7 Hz, 2H), 6.92 (d, J=8.4 Hz, 2H), 6.72 (d, J=8.7 Hz, 2H), 6.67 (d, J=8.4 Hz, 2H), 1.89 (d, J=4.5 Hz, 4H), 1.48 (s, 6H), 1.25 (br s, 2H), .88 (s, 12H). LCMS (ESI): m/z 421 (M−H)−. Anal. Calcd for C27H4O4.H2O, C, 73.77; H, 8.19; Found: C, 74.78, H, 8.14.