Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH2:16])=[N:13][C:12]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[N:52]1([CH2:57][C:58]2[CH:66]=[CH:65][C:61]([C:62](O)=[O:63])=[CH:60][CH:59]=2)[CH:56]=[CH:55][CH:54]=[N:53]1>CN(C)C=O>[N:52]1([CH2:57][C:58]2[CH:66]=[CH:65][C:61]([C:62]([NH:16][C:14]3[S:15][C:11]([C:9]([NH:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:10])=[C:12]([CH3:17])[N:13]=3)=[O:63])=[CH:60][CH:59]=2)[CH:56]=[CH:55][CH:54]=[N:53]1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: O=C(O)c1ccc(Cn2cccn2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1nc(NC(=O)c2ccc(Cn3cccn3)cc2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Yield: 136.8 %

Procedure:
To a solution of 2-amino-4-methylthiazole-5-carboxylic acid benzylamide (0.47 g, 1.88 mmol), and N-methylmorpholine (0.23 mL, 2.08 mmol) in N,N-dimethylformamide (20 mL) at 0° C. was added (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (0.42 g, 2.09 mmol) and 4-pyrazol-1-ylmethyl-benzoic acid (0.42 g, 2.09 mmol). The resultant solution was allowed to warm to ambient temperature over 18 h, and concentrated in vacuo. The crude product was purified by flash column chromatography eluting with methanol/dichloromethane (0/100 to 30/70) to afford the title compound (1.11 g); MS (ES+) m/z 432 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[N:19]=[CH:18][CH:17]=[CH:16][C:13]=3[C:14]#[N:15])=[CH:8][CH:9]=2)[CH:4]=[N:3]1.Cl>CO.[OH-].[OH-].[Pd+2]>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[C:13]([CH2:14][NH2:15])=[CH:16][CH:17]=[CH:18][N:19]=3)=[CH:8][CH:9]=2)[CH:4]=[N:3]1
Reactant: Cn1ncc2cc(Oc3ncccc3C#N)ccc21
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: Cn1ncc2cc(Oc3ncccc3CN)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
2-(1-Methyl-1H-indazol-5-yloxy)-nicotinonitrile (3n) (0.132 g, 0.528 mmol) was suspended in MeOH (6 mL). Pd(OH)2 (0.060 mg, 0.427 mmol) was added under a nitrogen atmosphere followed by concentrated aqueous HCl (0.6 mL). The system was purged with H2 gas and the reaction stirred at room temperature for 3 hours under an H2(g) atmosphere. The reaction mixture was filtered through a pad of celite, washed through with MeOH. The organics were concentrated under reduced pressure to afford the crude product, which was purified by flash column chromatography (MeOH/Et3N/EtOAc) to provide the desired product (4n) (0.047 g, 35% yield).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][N:10]=[C:9]3[C:15]2[CH:16]=[C:17]([CH:32]=[CH:33][CH:34]=2)[O:18][CH2:19][CH2:20][NH:21]C(OCC2C=CC=CC=2)=O)=[N:4][CH:3]=[N:2]1.C(O)=O>[Pd].CO>[NH:1]1[C:5]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][N:10]=[C:9]3[C:15]2[CH:16]=[C:17]([CH:32]=[CH:33][CH:34]=2)[O:18][CH2:19][CH2:20][NH2:21])=[N:4][CH:3]=[N:2]1
Reactant: O=C(NCCOc1cccc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: NCCOc1cccc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1
Yield: 15.7 %

Procedure:
N-{2-[3-(5-(1H-1,2,4-triazol-5-yl)(1H-indazol-3-yl))phenoxy]ethyl}(phenylmethoxy)carboxamide (0.056 g, 0.123 mmol) was treated with formic acid (2 mL), methanol (0.088 mL) and 10% palladium on carbon (0.060 g) under nitrogen for 3 h. The mixture was filtered though Celite and concentrated. The residue was taken up in aqueous 6 N hydrochloric acid and extracted with ether (3×). The aqueous layer was adjusted to pH 11 and extracted with dichloromethane. The organic fractions were dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by preparative HPLC (30–80% acetonitrile/water) and gave the title compound (0.0062 g, 16% yield) as the mono trifluoroacetic acid salt. 1H NMR (CD3OD) δ 8.77 (d, 1H), 8.54 (s, 1H), 8.12 (dd, 1H), 7.73 (m, 1H), 7.70 (m, 1H), 7.65 (m, 1H), 7.54 (t, 1H), 7.13 (m, 1H), 4.38 (t, 2H), 3.44 (t, 2H). ES-MS (m/z) 321 [M+1]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[C:30]4[C@H:37]([CH3:38])[CH2:36][CH2:35][C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:25][CH2:24]2)=[O:22])[CH2:9][N:10]([CH:18]([CH3:20])[CH3:19])C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.[ClH:39]>C(Cl)Cl>[ClH:1].[ClH:39].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:9][NH:10][CH:18]([CH3:20])[CH3:19])[C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[C:30]4[C@H:37]([CH3:38])[CH2:36][CH2:35][C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:25][CH2:24]2)=[O:22])=[CH:4][CH:3]=1
Reactant: CC(C)N(CC(C(=O)N1CCN(c2ncnc3c2[C@H](C)CC3)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)NCC(C(=O)N1CCN(c2ncnc3c2[C@H](C)CC3)CC1)c1ccc(Cl)cc1
Yield: 99 %

Procedure:
tert-Butyl 2-(4-chlorophenyl)-3-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate was treated with HCl (4M in dioxane, 2 mL) in DCM (10 mL) for 6 hours to provide 2-(4-chlorophenyl)-3-(isopropylamino)-1-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one dihydrochloride (24 mg, 99%). MS (APCI+) [M+H] +442.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:16]#[N:17])=[C:9]2Cl)=[O:5])[CH3:2].[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:16]#[N:17])=[C:9]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2ncc(C#N)c(Cl)c2c1
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: [Na+]
Product: CCOC(=O)c1ccc2ncc(C#N)c(-c3ccccc3)c2c1

Procedure:
Similar procedure as described in example 61g was used, starting from 4-chloro-3-cyano-quinoline-6-carboxylic acid ethyl ester (example 46c), phenylboronic acid, tetrakis(triphenylphosphine)palladium(0), and sodium carbonate solution to give 3-cyano-4-phenyl-quinoline-6-carboxylic acid ethyl ester. LC-MS m/e 303 (MH+).
Reaction SMILES: [OH-].[Na+].[CH:3]1([C:6]2[N:15]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([O:31]C)=[O:30])=[CH:19][CH:18]=3)[C:9]3=[N:10][CH:11]=[CH:12][C:13]([CH3:14])=[C:8]3[N:7]=2)[CH2:5][CH2:4]1>C(O)C>[CH:3]1([C:6]2[N:15]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([OH:31])=[O:30])=[CH:19][CH:18]=3)[C:9]3=[N:10][CH:11]=[CH:12][C:13]([CH3:14])=[C:8]3[N:7]=2)[CH2:5][CH2:4]1
Reactant: COC(=O)c1ccccc1-c1ccc(Cn2c(C3CC3)nc3c(C)ccnc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccnc2c1nc(C1CC1)n2Cc1ccc(-c2ccccc2C(=O)O)cc1
Yield: 81.4 %

Procedure:
Ethanol (40 ml) and a 10% aqueous solution (20 ml) of sodium hydroxide were added to 1.32 g (3.3 mmol) of 2-cyclopropyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-7-methyl-3H-imidazo[4,5-b]pyridine, followed by heating under reflux for 2 hours. After the reaction liquid was cooled, it was concentrated to about one-half the initial volume, and neutralized with 2N hydrochloric acid and acetic acid. The crystal thus precipitated was recovered by filtration and recrystallized from aqueous ethanol to give 1.03 g of the title compound (yield 81%). 1H-NMR (600 MHz, DMSO-d6); δ(ppm) 1.06 (4H, m), 2.27 (1H, tt, J=8.0, 5.0 Hz), 2.50 (3H, s), 5.63 (2H, s), 7.04 (1H, d, J=5.0 Hz), 7.27 (4H, m), 7.33 (1H, dd, J=8.0, 1.0 Hz), 7.43 (1H, ddd, J=8.0, 8.0, 1.0 Hz), 7.54 (1H, ddd, J=8.0, 8.0, 2.0 Hz), 7.70 (1H, dd, J=8.0, 2.0 Hz), 8.13 (1H, d, J=5.0 Hz), 12.70 (1H, br-s)
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([C:17]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])=[C:14]([CH3:25])[C:13]=2[CH:26]=1)C1C=CC=CC=1>C(O)C.O1CCCC1>[CH:19]1([C:17]([C:15]2[O:16][C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:26][C:13]=3[C:14]=2[CH3:25])=[O:18])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: Cc1c(C(=O)C2CCCCC2)oc2ccc(OCc3ccccc3)cc12
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(=O)C2CCCCC2)oc2ccc(O)cc12
Temperature: 60 °C
Reaction time: 3 h
Yield: 96.1 %

Procedure:
[5-(Benzyloxy)-3-methyl-1-benzofuran-2-yl](cyclohexyl)methanone (7.3 g) synthesized in the above-mentioned (2) was dissolved in a ethanol (150 mL) and tetrahydrofuran (30 mL), and palladium carbon-ethylenediamine complex (1.0 g) was added at room temperature. The reaction mixture was stirred at 60° C. for 3 hr under hydrogen atmosphere (1 atm), allowed to cool to room temperature, and the catalyst was filtered. The filtrate was concentrated under reduced pressure to give a crude product (5.2 g, quantitative) of the title object compound as a colorless solid.
Reaction SMILES: S=[C:2]1[CH2:6][S:5][C:4](=[O:7])[NH:3]1.[CH2:8]([NH2:11])[C:9]#[CH:10]>C(O)C>[CH2:8]([NH:11][C:2]1[CH2:6][S:5][C:4](=[O:7])[N:3]=1)[C:9]#[CH:10]
Reactant: C#CCN
Reactant: O=C1NC(=S)CS1
Solvent: CCO
Product: C#CCNC1=NC(=O)SC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-thioxo-1,3-thiazolidin-2-one (12.8 g) in ethanol (200 mL) was added propargylamine (9.67 mL), and the mixture was stirred at room temperature overnight. The precipitate was collected by filtration, and washed with ethanol to give the title compound (11.9 g).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:6][CH:5]=1.O>C1C=CC=CC=1>[CH3:18][CH:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][OH:2])=[CH:5][CH:6]=1)[CH2:12][CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17]
Reactant: COC(=O)c1ccc(OC(C)CCCC(C)C)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(C)CCCC(C)Oc1ccc(CO)cc1

Procedure:
42 g of p-[(1,5-dimethylhexyl)oxy]benzoic acid methyl ester is dissolved in 250 ml of benzene and, with stirring, treated dropwise with 50 g of 70% bis(2-methoxy-ethoxy)sodium aluminum hydride. The reaction solution is further stirred at 25° C. for 5 hours and thereafter treated with water. The organic phase is separated off, dried under sodium sulfate, carefully filtered (using a filter aid) and evaporated under reduced pressure. There is obtained a residual of p-[(1,5-dimethylhexyl)oxy]benzyl alcohol; B.P. 180°-182° C./1.0 mmHg.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH2:17][C:18]4[CH:26]=[CH:25][CH:24]=[C:23]5[C:19]=4[CH:20]=[N:21][N:22]5C4CCCCO4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CO.O>[NH:22]1[C:23]2[C:19](=[C:18]([CH2:17][NH:16][C:12]3[N:11]=[C:10]([NH:9][C:6]4[CH:5]=[C:4]([CH:1]5[CH2:2][CH2:3]5)[NH:8][N:7]=4)[CH:15]=[CH:14][N:13]=3)[CH:26]=[CH:25][CH:24]=2)[CH:20]=[N:21]1
Reactant: c1cc(CNc2nccc(Nc3cc(C4CC4)[nH]n3)n2)c2cnn(C3CCCCO3)c2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: c1cc(CNc2nccc(Nc3cc(C4CC4)[nH]n3)n2)c2cn[nH]c2c1
Temperature: 80 °C

Procedure:
To a solution of 200 (215 mg, 0.5 mmol) in MeOH (5 mL) and water (1 mL) was added p-TsOH.H2O (95 mg, 0.5 mmol) and the mixture was heated in a sealed tube at 80° C. overnight. The solvent was evaporated in vacuo. The residue was purified by preparative HPLC to afford 110 mg (63%) of I-59 as white solid.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][C@:11]1([C:23]([O:25][CH3:26])=[O:24])[CH2:21][C@@H:20]([OH:22])[C@@H:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@@H:13]2[CH2:12]1.N1C=CC=CC=1>ClCCl>[C:1]([O:22][C@H:20]1[C@@H:14]2[O:15][C:16]([CH3:18])([CH3:19])[O:17][C@@H:13]2[CH2:12][C@@:11]([OH:10])([C:23]([O:25][CH3:26])=[O:24])[CH2:21]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)[C@@]1(O)C[C@@H](O)[C@@H]2OC(C)(C)O[C@@H]2C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@@]1(O)C[C@@H](OC(=O)c2ccccc2)[C@@H]2OC(C)(C)O[C@@H]2C1
Reaction time: 12 h
Yield: 86.1 %

Procedure:
Benzoyl chloride (0.78 mL, 6.7 mmol) was added dropwise to 0° C. a solution of Example 13B (1.65 g, 6.7 mmol) and pyridine (0.82 mL, 10.1 mmol) in dichloromethane (40 mL). After stirring for 12 hours, the reaction mixture was washed with aqueous HCl (2N), saturated NaHCO3 solution, and brine, dried (MgSO4), filtered and concentrated. The concentrate was purified by flash chromatography using hexanes/ethyl acetate (3/2) to afford 2.02 g (86%) of the desired product as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[CH2:11]1[O:13][CH2:12]1.[H-].[Na+].O>O1CCOCC1>[NH:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[O:1][CH2:11][CH2:12][OH:13])[CH:7]=[CH:8]1
Reactant: Oc1cccc2cc[nH]c12
Reactant: C1CO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: OCCOc1cccc2cc[nH]c12
Temperature: 100 °C
Reaction time: 120 h
Yield: 33.9 %

Procedure:
A mixture of 7-hydroxyindole (1.00 g, 7.51 mmol) and ethylene oxide (0.33 g, 7.50 mmol) in dioxane (3 mL) was placed in a reaction tube. NaH (60% in oil; 0.100 g, 2.45 mmol) was added and the reaction mixture was stirred at 100° C. for 5 days. The reaction mixture was poured into water, extracted with EtOAc, dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel using toluene/EtOAc (1:1) as eluent to give 0.45 g (34%) of the title product. Pos-EI-MS shows M+ and 5 ions supporting the stated structure. HRMS m/z calcd for C10H11NO2 (M)+177.0790, found 177.0799.
Reaction SMILES: Br.[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.[C:14]1(=O)[O:19][C:17](=[O:18])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.C(N(CC)CC)C>C(Cl)(Cl)Cl>[OH:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][CH2:4][CH2:3][N:2]2[C:17](=[O:18])[C:16]3[C:15](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]2=[O:19])=[CH:12][CH:11]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCCCCc1ccc(O)cc1
Agent: Br
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCCCc1ccc(O)cc1
Temperature: 25 °C
Yield: 41.4 %

Procedure:
A mixture of 4-(4-aminobutyl)phenol hydrobromide 6 (8.2 g, 33.5mmol), phthalic anhydride 7 (5.0 g, 33.8 mmol), and triethylamine (4.6 mL, 33.5 mmol) in chloroform (50 mL) was stirred at reflux for 18 h, cooled to room temperature and concentrated by rotary evaporation. The residue was dissolved in acetic acid (50 mL) and stirred at 100° C. for 3 h. Solvent was evaporated and the resulting residue was purified by flash silica gel column chromatography eluting with CH2Cl2/EtOAc/hexanes (8:1:1, v/v) to give the desired product 8 as a white powder (4.1 g, 41% yield). 1H NMR (300 MHz, DMSO-d6) δ 1.57 (m, 4H), 2.46 (m, 2H), 3.58 (m, 2H), 6.64 (d, 2H), 6.95 (d, 2H), 7.82 (m, 4H), 9.12 (s, 1H). m/z (ESI): 296 [C18H17NO3+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[O:11]=[C:12]1[CH2:19][CH:18]2[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:15]([CH2:16][CH2:17]2)[CH2:14][NH:13]1>>[N+:8]([C:5]1[N:6]=[CH:7][C:2]([N:13]2[C:12](=[O:11])[CH2:19][CH:18]3[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:15]([CH2:16][CH2:17]3)[CH2:14]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)NC2
Product: CC(C)(C)OC(=O)N1C2CCC1CN(c1ccc([N+](=O)[O-])nc1)C(=O)C2
Yield: 78.4 %

Procedure:
Following general N—C coupling procedure 1, 5-Bromo-2-nitropyridine (1 gm, 4.93 mmol) was combined with tert-butyl 4-oxo-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (1.18 gm, 4.93 mmol) which gave tert-butyl 3-(6-nitropyridin-3-yl)-4-oxo-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (1.4 gm) in 78% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:23])=[C:6]([C:8]2[NH:9][C:10]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH3:22])[N:16]=3)=[CH:11][C:12]=2[C:13]#[N:14])[CH:7]=1.O.S(=O)(=O)(O)[OH:26].N>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:23])=[C:6]([C:8]2[NH:9][C:10]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH3:22])[N:16]=3)=[CH:11][C:12]=2[C:13]([NH2:14])=[O:26])[CH:7]=1
Reactant: CNc1nccc(-c2cc(C#N)c(-c3cc(Cl)ccc3C)[nH]2)n1
Reactant: O=S(=O)(O)O
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CNc1nccc(-c2cc(C(N)=O)c(-c3cc(Cl)ccc3C)[nH]2)n1
Temperature: 70 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 2-(5-chloro-2-methyl-phenyl)-5-(2-methylamino-pyrimidin-4-yl)-1H-pyrrole-3-carbonitrile (1.15 g, 3.55 mmol) in TFA (15.0 mL) were sequentially added water (2.25 mL) and 98% sulfuric acid (4.5 mL) under efficient stirring. The mixture was allowed to stir for 8 h at 70° C. and then was diluted by drop wise addition of water (45 mL). The reaction mixture was made basic (pH 10-12) by adding 30% aqueous ammonia (15 mL) under stirring. The precipitated solid was collected by filtration, washed with water and finally dried in a vacuum oven at 50° C. affording the title compound as an off-white solid (1.07 g, 88%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[N:7]([CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19]([C:24]3[CH:29]=[CH:28][C:27]([N:30]([CH:32]=[O:33])[CH3:31])=[CH:26][CH:25]=3)[CH:20]=[CH:21][C:22]=2[F:23])[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Cl:35][C:36]1[C:37]2[CH:47]=[CH:46][CH:45]=[CH:44][C:38]=2[S:39][C:40]=1[C:41](Cl)=[O:42]>>[C:1]([O:5][C:6](=[O:34])[N:7]([CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([C:41]([C:40]2[S:39][C:38]3[CH:44]=[CH:45][CH:46]=[CH:47][C:37]=3[C:36]=2[Cl:35])=[O:42])[CH2:16][C:17]2[CH:18]=[C:19]([C:24]3[CH:29]=[CH:28][C:27]([N:30]([CH:32]=[O:33])[CH3:31])=[CH:26][CH:25]=3)[CH:20]=[CH:21][C:22]=2[F:23])[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C=O)c1ccc(-c2ccc(F)c(CNC3CCC(N(C)C(=O)OC(C)(C)C)CC3)c2)cc1
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Product: CN(C=O)c1ccc(-c2ccc(F)c(CN(C(=O)c3sc4ccccc4c3Cl)C3CCC(N(C)C(=O)OC(C)(C)C)CC3)c2)cc1

Procedure:
The title compound was prepared from amine (261) (270 mg, 0.58 mmol) and 3-chlorobenzo[b]thiophene-2-carbonyl chloride (150 mg, 0.63 mmol) following Method D.
Reaction SMILES: [CH2:1]([C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([N:14]=C=O)[C:4]=1[CH2:17]/[CH:18]=[C:19](\[CH3:26])/[CH2:20][CH2:21][C:22]([O:24]C)=[O:23])[CH3:2].O.O.[OH-].[Li+]>O1CCOCC1>[NH2:14][C:5]1[C:4]([CH2:17]/[CH:18]=[C:19](\[CH3:26])/[CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[C:3]([CH2:1][CH3:2])[C:11]([CH3:12])=[C:10]2[C:6]=1[C:7](=[O:13])[O:8][CH2:9]2
Reactant: CCc1c(C)c2c(c(N=C=O)c1C/C=C(\C)CCC(=O)OC)C(=O)OC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCc1c(C)c2c(c(N)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.0 g of methyl (E)-6-(1,3-dihydro-6-ethyl-4-isocyanato-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate is dissolved in 50 ml of 1,4-dioxane and treated with 16 ml of water and 2.0 g of lithium hydroxide monohydrate. The mixture is stirred at room temperature for 2 hours and then partitioned between aqueous 1N sodium hydrogen sulfate and ethyl acetate. The organic phase is washed twice with water, once with brine, and dried over magnesium sulfate. The solvent is evaporated under reduced pressure and the residue purified by chromatography on silica gel, to give (E)-6-(4-amino-1,3-dihydro-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid.
Reaction SMILES: [CH2:1]([N:8]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@@H:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[H][H]>[Pt].CO>[CH2:25]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:9]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C@@H:10]([C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]1)[OH:11])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O[C@H](c1ccccn1)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Reactant: [H][H]
Agent: [Pt]
Solvent: CO
Solvent: CC(=O)O
Product: O[C@@H](C(Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1)[C@@H]1CCCCN1
Yield: 94.3 %

Procedure:
Add 2-(S)-dibenzylamino-3-phenyl-1-pyridin-2-yl-propan-1-(S)-ol (1.05 g, 2.57 mmol), 5% platinum on carbon sulfided (215 mg), glacial acetic acid (2 mL) and methanol (40 mL) and stir 18 h under 1 atmosphere of hydrogen gas. Add filter agent, filter and concentrate. Add ethyl acetate and wash with saturated aqueous sodium bicarbonate, dry (magnesium sulfate) and concentrate to give the title compound as a white foam (1.005 g, 94%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]#[N:11])[CH:8]=2)[CH:3]=[CH:2]1.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[CH2:14]>ClCCCl.C(Cl)Cl>[C:10]([C:7]1[CH:8]=[C:9]2[C:4]([C:3]([CH2:14][CH2:13][C:12]([O:16][CH2:17][CH3:18])=[O:15])=[CH:2][NH:1]2)=[CH:5][CH:6]=1)#[N:11]
Reactant: N#Cc1ccc2cc[nH]c2c1
Reactant: C=CC(=O)OCC
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOC(=O)CCc1c[nH]c2cc(C#N)ccc12
Temperature: 120 °C
Reaction time: 2 h

Procedure:
1H-indole-6-carbonitrile (D12) (3.2 g), ferric chloride (3.7 g) and ethyl acrylate (7.3 mL) in DCE (7 mL) was added to a sealed tube. The tube was sealed, and the reaction mixture was stirred at 120° C. for 2 hours. After cooling, the reaction mixture was diluted with DCM. The organic layer was washed with 0.5 M HCl, brine, dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was purified by column chromatography (20% EtOAc in hexane) to afford ethyl 3-(6-cyano-1H-indol-3-yl)propanoate (D106) (3.1 g) as a yellow solid. δH (CDCl3, 400 MHz): 1.24 (3H, t), 2.71 (2H, t), 3.11 (2H, t), 4.14 (2H, q), 7.24 (1H, dd), 7.36 (1H, dd), 7.67 (1H, d), 7.70 (1H, dd), 8.36 (1H, br s). MS (ES): C14H14N2O2 requires 242. found 243.1 (M+H+).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:18])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
38.3 g (277.4 mmol) of the benzene compound represented by the above formula (8) was added dropwise to a dichloromethane solution (400 ml) containing 38.8 g (291.2 mmol) of aluminum chloride and 40.9 g (291.2 mmol) of benzoyl chloride cooled to 0° C. After addition, the resulting mixture was stirred for 2 hours. After a reaction, the reaction product was washed with water, the solvent was removed, and the obtained product was purified by column chromatography to obtain a benzophenone derivative represented by the following formula (19) as 41.0 g (169.2 mmol, yield of 61%) of a white solid.
Reaction SMILES: C([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[C:28]([F:31])([F:30])[F:29])[CH2:17][C@H:16]2[CH3:32])(=[O:14])=[O:13])=[C:8]([F:33])[CH:7]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:33][C:8]1[CH:7]=[C:6]([OH:5])[CH:11]=[CH:10][C:9]=1[S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[C:28]([F:30])([F:29])[F:31])[CH2:17][C@H:16]1[CH3:32])(=[O:14])=[O:13]
Reactant: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(OC(C)(C)C)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(O)cc1F
Reaction time: 1 h

Procedure:
A solution of (2R)-1-[(4-tert-butoxy-2-fluorophenyl)sulfonyl]-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazine (375 mg, 0.76 mmol) in DCM (25 mL) was added TFA (5 mL). The reaction was allowed to stir for 1 hour, after which it was judged complete by LCMS. The reaction was concentrated in vacuo to remove excess TFA, and the crude oil was dissolved in DCM (20 mL) and washed with saturated NaHCO3(aq) (3×25 mL). The organic phase was dried over Na2SO4, and decanted, then concentrated in vacuo affording the desired phenol in >95% purity, which was used in subsequent synthetic steps without purification. HRMS: calcd for C18H17F5N2O3S+H+, 437.09528. found ([M+H]+), 437.09527.