Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]([F:38])([F:37])[CH:11]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH3:36])=[CH:30][CH:29]=1)[CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=1>C(Cl)(Cl)(Cl)Cl>[F:9][C:10]([F:37])([F:38])[CH:11]([C:28]1[CH:29]=[CH:30][C:31]([O:34][CH2:35][CH3:36])=[CH:32][CH:33]=1)[CH2:12][O:13][CH:14]([Br:1])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=1
Reactant: CCOc1ccc(C(COCc2cccc(Oc3ccccc3)c2)C(F)(F)F)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOc1ccc(C(COC(Br)c2cccc(Oc3ccccc3)c2)C(F)(F)F)cc1
Temperature: 0 °C

Procedure:
A catalytic amount of α,α'-azo-iso-butyronitrile was added to a solution of N-bromosuccinimide (0.14 g) and (RS)-1,1,1-trifluoro-2-(4-ethoxyphenyl)-3-(3-phenoxybenzyloxy)propane (0.3 g) in carbon tetrachloride (14 cm3). The reaction mixture was heated at the reflux temperature for 90 minutes, then cooled to 0° C., filtered, and the filtrate concentrated by evaporation under reduced pressure to leave (2RS)-1,1,1-trifluoro-2-(4-ethoxyphenyl)-3-[(RS)-α-bromo-3-phenoxybenzyloxy]-propane as a pale yellow oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[NH2:21][CH:22]([CH2:25][OH:26])[CH2:23][OH:24]>>[OH:24][CH2:23][CH:22]([NH:21][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:10](/[CH:9]=[CH:8]/[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:11]=1)[CH2:25][OH:26]
Reactant: NC(CO)CO
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(Cl)cc1
Product: COc1ccc(C(=O)NC(CO)CO)cc1/C=C/c1ccc(Cl)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-chlorophenyl)vinyl]benzoic acid obtained in step B of Example 2-2-7 and 2-amino-1,3-propanediol in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]([OH:18])=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:35]=[CH:36][C:37]=1[C:38](=[N:40]O)[NH2:39])[CH2:23][N:24]1[CH2:27][CH:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25]1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C>CN(C)C=O.ClCCl>[Cl:19][C:20]1[CH:21]=[C:22]([CH:35]=[CH:36][C:37]=1[C:38]1[N:40]=[C:16]([C:10]2[O:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]=2[C:12]([F:13])([F:14])[F:15])[O:18][N:39]=1)[CH2:23][N:24]1[CH2:27][CH:26]([C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[CH2:25]1
Reactant: O=C(O)c1onc(-c2ccccc2)c1C(F)(F)F
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(C(N)=NO)c(Cl)c2)C1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.9 %

Procedure:
A mixture of 3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxylic acid (1-D, 0.027 g, 0.105 mmol), tert-butyl 1-(3-chloro-4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate (0.036 g, 0.105 mmol), BOP-Cl (0.035 g, 0.136 mmol), and triethylamine (0.044 mL, 0.315 mmol) in N,N-dimethylformamide (1 mL) was shaken on platform shaker at room temperature overnight. The reaction mixture was diluted with dichloromethane, washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was loaded on a fitted funnel containing a pad of CELITE® topped with a pad of silica gel, eluted with a 5% mixture of ethyl acetate in hexane, eluted with dichloromethane, and then eluted with a 20% mixture of ethyl acetate in hexane to give tert-butyl 1-(3-chloro-4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (0.013 g, 0.023 mmol, 22% yield) as a white solid. The compound had an HPLC ret. time=2.13 min.−Column. CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. MS M+1=561.2.
Reaction SMILES: CS(O[C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:7]=1[C:16]([CH3:19])([CH3:18])[CH3:17])(=O)=O.C(O)=O.C(=O)([O-])[O-].[Li+].[Li+].CO>[Pd].[C].O>[C:12]([C:9]1[CH:10]=[CH:11][CH:6]=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:8]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1ccc(OS(C)(=O)=O)c(C(C)(C)C)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: O=CO
Product: CC(C)(C)c1cccc(C(C)(C)C)c1
Yield: 95.5 %

Procedure:
In a nitrogen atmosphere under normal pressure, 2,4-di-tert-butylphenyl methanesulfonate (30 g, 0.11 mols), formic acid (9.7 g, 0.21 mols), lithium carbonate (7.8 g, 0.11 mols) and methanol (180 g) were mixed at 25° C., and with stirring, 10 mass % Pd/carbon (50 mass % water-containing product) (6 g) (as metal palladium; 1 mass % relative to 2,4-di-tert-butylphenyl methanesulfonate) as supported by a carbon carrier having a specific surface area of 780 m2/g (by BET method) was put into it. With stirring, the reaction liquid was reacted at the same temperature for 4 hours. Water (10 mL) was added to the reaction liquid and Pd-carbon was separated through filtration, then heptane (30 g) was added to the filtrate. The organic layer obtained after extraction was concentrated under reduced pressure to give crude 1,3-di-tert-butylbenzene (20 g, yield 100% by mass). The result is shown in Table II-2.
Reaction SMILES: [C@@H:1]1([NH:12][C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[N:19]([O-])=[O:20].[Na+]>O.C(O)(=O)C>[C@@H:1]1([NH:12][C:13]([N:15]([N:19]=[O:20])[CH2:16][CH2:17][CH3:18])=[O:14])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: CCCNC(=O)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCN(N=O)C(=O)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 81.1 %

Procedure:
1-(β-D-glucopyranosyl)-3-n-propylurea (1.50 g) was dissolved in a mixture of water (10 ml) and acetic acid (2 ml), and to the resulting solution was added 560 mg (1.5 mol. equivalents) of sodium nitrite at ambient temperature under stirring to effect the nitrosation. The reaction mixture was treated with Amberlite IR-120 (H+ form) for the removal of sodium ion and then concentrated to dryness below 35° C and under a reduced pressure. Crystallisation of the residue from n-propanol gave 1.35 g of the titled compound. Yield 80%. mp. 112° C (decomposition with foaming). [α]D21 -6° (c 1.0, H2O).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C:13]3[O:14][C:15]4[C:20]([C:21](=[O:29])[C:22]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][C:18]([F:30])=[CH:17][CH:16]=4)[N:9]=[C:10](I)[C:3]=12.C([N:38]1[C:46]2[C:41](=[CH:42][CH:43]=[C:44](B3OC(C)(C)C(C)(C)O3)[CH:45]=2)[C:40]([CH3:56])=[N:39]1)(OC(C)(C)C)=O.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CN(C=O)C.C(O)C.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C:13]3[O:14][C:15]4[C:20]([C:21](=[O:29])[C:22]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][C:18]([F:30])=[CH:17][CH:16]=4)[N:9]=[C:10]([C:44]3[CH:45]=[C:46]4[C:41]([C:40]([CH3:56])=[N:39][NH:38]4)=[CH:42][CH:43]=3)[C:3]=12
Reactant: Nc1ncnc2c1c(I)nn2Cc1oc2ccc(F)cc2c(=O)c1-c1ccccc1
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1n[nH]c2cc(-c3nn(Cc4oc5ccc(F)cc5c(=O)c4-c4ccccc4)c4ncnc(N)c34)ccc12
Temperature: 80 °C
Reaction time: 12 h
Yield: 4 %

Procedure:
To a solution of Example 57d (0.300 g, 0.584 mmoles) in DMF (3 ml), ethanol (1.5 ml) and water (1.5 ml), N-Boc-3-methyl-6-indazoleboronic acid pinacol ester 98 (0.314 g, 0.877 mmoles) and sodium carbonate (0.185 g, 1.754 mmoles) were added and the system is degassed for 30 min. Tetrakistriphenylphosphine Palladium (0.033 g, 0.029 mmoles) was added under nitrogen atmosphere and heated to 80° C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as brown solid (0.012 g, 4% yield). MP: 277-279° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 12.75(s,1H), 8.23(s,1H), 7.84(d, J=8.2 Hz, 1H), 7.74(dd, J=8.2,3.0 Hz, 1H),7.66(m,2H), 7.59(dd, J=9.2,4.2 Hz, 1H), 7.38-7.32(m, 6H), 6.54(s,2H), 2.51(s,3H). Mass: 518.17(M++1).
Reaction SMILES: [CH2:1]([Mg]Cl)[CH3:2].[O:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:15])=[CH:13][C:8]=2[CH:7]=[CH:6]1>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[O:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)([OH:15])[CH2:1][CH3:2])=[CH:13][C:8]=2[CH:7]=[CH:6]1
Reactant: O=C(c1ccccc1)c1ccc2occc2c1
Reactant: CC[Mg]Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CCC(O)(c1ccccc1)c1ccc2occc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethylmagnesium chloride (2M in tetrahydrofuran, 10.63 mL, 21.26 mmol) under nitrogen at room temperature was added zinc chloride (0.5M in tetrahydrofuran, 5.67 mL, 2.84 mmol) via syringe. The mixture was stirred at room temperature for 1 h. The reaction mixture was brought to 0° C. and benzofuran-5-yl(phenyl)methanone (3.15 g, 14.17 mmol) in tetrahydrofuran (10 mL) was added via syringe. The reaction mixture was stirred at 0° C. for 2.5 h. The reaction mixture was cooled to room temperature and quenched with saturated aqueous NH4Cl. EtOAc was added, and the aqueous layer was separated and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), and concentrated to give a crude oil. The crude product was purified by silica flash chromatography (0-100% DCM/hexanes) to give 1-(benzofuran-5-yl)-1-phenylpropan-1-ol as an off-white oil. 1H NMR (400 MHz, Chloroform-d) δ ppm 7.69 (1H, d, J=1.6 Hz), 7.60 (1H, d, J=2.2 Hz), 7.39-7.45 (3H, m), 7.28-7.34 (3H, m), 7.22 (1H, tt, J=7.2, 1.4 Hz), 6.73 (1H, dd, J=2.2, 1.0 Hz), 2.38 (2H, q, J=7.3 Hz), 2.09 (1H, s), 0.90 (3H, t, J=7.3 Hz).
Reaction SMILES: [F:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][NH:15][CH2:14][CH:13]([C:17]([O:19][CH3:20])=[O:18])[CH2:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].C(N(CC)CC)C.Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:30]>ClCCl>[F:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:16][N:15]([C:29]([O:31][C:32]3[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=3)=[O:30])[CH2:14][CH:13]([C:17]([O:19][CH3:20])=[O:18])[CH2:12]2)=[CH:9][CH:10]=1)([F:4])[CH3:3]
Reactant: COC(=O)C1CNCC(c2ccc(C(C)(F)F)cc2)C1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CC(c2ccc(C(C)(F)F)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 1.30 g (3.78 mmol, purity 82%) of the compound from Example 50A in dichloromethane (44 ml) was admixed with 1.84 ml (1.34 g, 13.2 mmol) of triethylamine and then admixed at 0° C. with 762 mg (3.78 mmol) of 4-nitrophenyl chloroformate. The mixture was warmed to RT and stirred for 2 days. The reaction solution was washed with saturated aqueous sodium hydrogencarbonate solution and water, and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. Yield: 1.93 g (92% of theory, purity 81%, 2:1 mixture of methyl and ethyl ester)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([Br:8])=[CH:4][N:3]=1.N1C=CC=CC=1.[CH3:15][C:16]([CH3:21])([CH3:20])[C:17](Cl)=[O:18]>C(Cl)Cl>[Br:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:17](=[O:18])[C:16]([CH3:21])([CH3:20])[CH3:15])=[N:3][CH:4]=1
Reactant: Nc1cnc(Br)cn1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1cnc(Br)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
A solution of 2-amino-5-bromopyrazine (10.00 g, 57.47 mmol) and pyridine (5.6 mL, 68.96 mmol) in methylene chloride (144 mL) was cooled to 0° C. and then was treated slowly with trimethylacetyl chloride (8.6 mL, 68.96 mmol). The resulting reaction mixture was stirred at 0° C. for 30 min and then was allowed to warm to 25° C. where it was stirred for 18 h. At this time, the reaction mixture still contained the starting material 2-amino-5-bromopyrazine. The reaction mixture was treated with an additional amount of trimethylacetyl chloride (4.3 mL, 34.48 mmol) and then stirred at 25° C. for 4 h. The reaction mixture was then concentrated in vacuo to remove methylene chloride. The resulting residue was diluted with ethyl acetate (700 mL). The organic layer was washed with a 1N aqueous hydrochloric acid solution (2×200 mL) and a saturated aqueous sodium chloride solution (1×200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 65M, Silica, 1/9 ethyl acetate/hexanes) afforded N-(5-bromo-pyrazin-2-yl)-2,2-dimethyl-propionamide (12.19 g, 82%) as a white solid: mp 122–124° C.; (ES)+-HRMS m/e calcd for C9H12BrN3O (M+H)+ 258.0237, found 258.0240.
Reaction SMILES: COCN[C:5]([C:7]1[N:8]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:10][CH:11]=1)=[O:6].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:12]1([C:9]2[S:10][CH:11]=[C:7]([CH:5]=[O:6])[N:8]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COCNC(=O)c1csc(-c2ccccc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1csc(-c2ccccc2)n1
Temperature: -20 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
At −78° C., to a solution of 2-phenyl-thiazole-4-carboxylic acid methoxymethylamide (1 equiv) in THF was added LiAlH4 (1 equiv, 1 N in THF) and stirring for 1 h at −20° C. The reaction mixture was placed on an ice bath and quenched by 20% H2SO4 solution, extracted with ethyl acetate and dried over MgSO4. The solvent was removed under reduced pressure and purified by column chromatography to yield 42b (45.8%). 1H NMR (300 MHz, CDCl3) δ 10.1 (s, 1H), 8.17 (s, 1H), 8.02-8.00 (m, 2H), 7.50-7.48 (m, 3H). MS (ESI) m/z 244.1 (M+Na+MeOH)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][CH2:20][CH2:21][O:22][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCCC#Cc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: CS(=O)(=O)OCCCC#Cc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
In analogy to example 15.1, 5-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-yn-1-ol and methane sulfonyl chloride were converted to yield Methanesulfonic acid 5-[3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl ester, MS: 450 (MH+, 1Br).
Reaction SMILES: [CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=3)=O)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].[CH3:34][N:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)N>>[CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]3[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[N:35]([CH3:34])[C:22]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc([N+](=O)[O-])c3)CC2)c1
Reactant: CN(N)c1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4cccc([N+](=O)[O-])c4)n(C)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-(3-{1-[5-(3-nitrophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)propanamide and 1-methyl-1-phenylhydrazine: ESMS m/e: 539.2 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C1(C2C=CC(C)=CC=2)C=CC=CC=1.[Br:28]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][CH:2]([Br:28])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: BrCc1ccc(-c2ccccc2)cc1
Agent: Cc1ccc(-c2ccccc2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrC(Br)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
4-(Bromomethyl)biphenyl: A mixture of 4-phenyltoluene (4.83 g, 28.7 mmol), N-bromosuccinimide (5.64 g, 31.7 mmol), benzoyl peroxide (catalytic), and anhydrous carbon tetrachloride (35 mL) was refluxed for 24 hours. The mixture was cooled to room temperature and filtered to give a mixture (7.32 g) of 4-(dibromomethyl)biphenyl, 4-(bromomethyl)biphenyl, and 4-phenyltoluene (14:82:4 molar ratio by 1H-NMR). The product was used without further purification in the next step. 1H-NMR of the title compound (300 MHz, CDCl3) δ 7.56-7.60 (m, 4H), 7.33-7.48 (m, 5H), 4.55 (s, 2H). Partial 1H-NMR of 4-(dibromomethyl)biphenyl (300 MHz, CDCl3) δ 6.71 (s, 1H).
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]=1[C:10]#[N:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[O:1]([C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]=1[CH2:10][NH2:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1c(Nc2ccccc2)cccc1Oc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: NCc1c(Nc2ccccc2)cccc1Oc1ccccc1
Temperature: 25 °C

Procedure:
The product of example 1b above, 2-phenoxy-6-(phenylamino)benzonitrile, (0.4 g, 1.4 mmol) was dissolved in dry tetrahydrofuran (20 mL) and stirred under argon in a room temperature water bath. Lithium aluminum hydride (0.28 g, 7.0 mmol) was added in portions over 10 minutes. The reaction mixture was heated to 60° C. for 1 hour. The reaction mixture was cooled to room temperature and anhydrous sodium sulfate was added followed by quenching by the addition of a freshly prepared saturated solution of anhydrous sodium sulfate. The solvent was evaporated and the residue triturated with ethyl acetate, filtered and evaporated. Flash chromatography on silica gel eluted with 0–3% methanol in methylene chloride gave the title compound as a white amorphous solid. ES (+) MS m/e=274 (M−NH3)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:14]([OH:17])[C:15]#[CH:16])[CH:8]=[CH:9][C:10]=1[N:11]([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].I[C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1>[Cu](I)I.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:1]([C:5]1[CH:6]=[C:7]([CH:14]([OH:17])[C:15]#[C:16][C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)[CH:8]=[CH:9][C:10]=1[N:11]([CH3:12])[CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1ccc(I)cc1
Reactant: C#CC(O)c1ccc(N(C)C)c(C(C)(C)C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Product: CN(C)c1ccc(C(O)C#Cc2ccc(C(=O)O)cc2)cc1C(C)(C)C
Yield: 62.2 %

Procedure:
In a manner analogous to example 1 e, the process is carried out by a reaction of 900 mg (3.8 mmol) of 1-(3-tert-butyl-4-dimethylaminophenyl)prop-2-yn-1-ol with 805 mg (3.2 mmol) of 4-iodobenzoic acid, 30 mg (0.16 mmol) of copper iodide and 56 mg (0.08 mmol) of bis(triphenylphosphine)palladium chloride. 700 mg of 4-[3-(3-tert-butyl-4-dimethylaminophenyl)-3-hydroxyprop-1-ynyl]benzoic acid are obtained in the form of a beige solid (Mp=139° C., yield=64%).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11](=[O:18])(=[O:17])[N:12]([CH2:15][CH3:16])[CH2:13][CH3:14].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.Cl>O>[CH2:13]([N:12]([CH2:15][CH3:16])[S:11]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[N:23]1[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]1)[C:6]([OH:8])=[O:7])(=[O:18])=[O:17])[CH3:14]
Reactant: CN1CCNCC1
Reactant: CCN(CC)S(=O)(=O)c1cc(C(=O)O)ccc1Cl
Agent: Cl
Solvent: O
Product: CCN(CC)S(=O)(=O)c1cc(C(=O)O)ccc1N1CCN(C)CC1
Temperature: 80 °C

Procedure:
29 Grams of 4-chloro-3-diethylsulfamoyl-benzoic acid were heated with 30 g of N-methylpiperazine for 4 hours at 140° C. Subsequently the reaction solution, which had cooled down to 80° C., was introduced into 0.4 l of water, and the solution was neutralized with 5N HCl. As soon as the precipitate, which was amorphous at first, became crystallized, it was suction-filtered and recrystallized from methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][CH3:18])=[CH:11][C:3]=1[C:4](OC(C)(C)C)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:1][C:2]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][CH3:18])=[CH:11][C:3]=1[CH2:4][OH:5]
Reactant: COCCc1ccc(Cl)c(C(=O)OC(C)(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCc1ccc(Cl)c(CO)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 2-chloro-5-(2-methoxyethyl)benzoate from the previous step (1 eq.) in anhydrous THF (0.26 M) was added, at 0° C., lithium aluminum hydride (1.0 M THF solution, 3 eq.). The resulting suspension was stirred at 0° C. for 1 h and then at RT for 1 h. After carefully quenching with EtOAc and H2O, sat. aq. sodium potassium tartrate was added. The resulting biphasic mixture was vigorously stirred at RT for 30 min and then extracted with ether. The combined organic extracts were washed with brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded a cloudy oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 90:10→70:30 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [S:1]1[CH:13]2[CH:4]([NH:5][C:6](=O)[C:7]3[CH2:8][NH:9][CH2:10][CH2:11][C:12]=32)[CH:3]=[CH:2]1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:6]1[C:7]2[CH2:8][NH:9][CH2:10][CH2:11][C:12]=2[C:13]2[S:1][CH:2]=[CH:3][C:4]=2[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1NC2C=CSC2C2=C1CNCC2
Product: Clc1nc2ccsc2c2c1CNCC2
Temperature: 82.5 °C
Reaction time: 24 h
Yield: 86 %

Procedure:
A mixture of 3a,6,7,8,9,9b-hexahydrothieno[3,2-c]-2,7-naphthyridin-5(4H)-one (2.69 g, 13.04 mmol) in phosphorus oxychloride (70 ml) was heated at 80-85° C. with stirring for 24 hours and allowed to cool to room temperature. The excess solvent was removed in vacuo and the residue was carefully quenched with ice water. The aqueous mixture was treated with solid NaOH until product precipitation ceased (pH ˜5) and the off-white, amorphous solid was collected, washed with water, and dried to give the title compound (2.51 g, 86%).