Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5][NH2:6].C(N(CC)CC)C.[C:14]1([CH:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21](Cl)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[Br:2][CH2:3][CH2:4][CH2:5][NH:6][C:21](=[O:22])[CH:20]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCCCBr
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCBr)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred mixture of 3-bromopropylamine hydrobromide (2.91 g, 13.3 mmol) in 10 mL of CH2Cl2 was added 2.8 mL of triethylamine (20.0 mmol). The reaction mixture was stirred at room temperature for 10 minutes, followed by addition of diphenyl acetyl chloride (2.56 g, 11.1 mmol) and triethylamine (2.8 mL, 20 mmol) in CH2Cl2 (10 mL). The reaction mixture was stirred for 40 minutes at room temperature and then diluted with 200 mL of CH2Cl2. The solution was washed with aqueous 0.5 N HCl (100 mL×3), water (50 mL), NaHCO3 (sat, 100 mL) and NaCl (sat), dried over MgSO4. Removal of solvent gave the crude product as a light yellow solid that was used in the next step without further purification (3.33 g, 91%): 1H NMR (400 MHz, CDCl3) δ 7.56–7.45 (m, 10H), 5.88–5.69 (br, 1H), 4.92 (s, 1H), 3.47–3.39 (m, 2H), 3.35 (t, 2H, J=6.4 Hz), 2.16–1.98 (m, 2H).
Reaction SMILES: [CH3:1][CH:2]([CH:10]=[CH:11][CH:12]=[C:13]([CH3:20])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])[CH:3](OCC)[O:4]CC.O1CCCC1.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O>[CH3:1][CH:2]([CH:10]=[CH:11][CH:12]=[C:13]([CH3:20])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])[CH:3]=[O:4]
Reactant: CCOC(OCC)C(C)C=CC=C(C)CCC=C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)=CCCC(C)=CC=CC(C)C=O
Temperature: 22.5 °C
Reaction time: 24 h
Yield: 99.8 %

Procedure:
To a 250 mL four-neck reaction flask protected from atmospheric moisture by nitrogen gas throughout the course of the reaction a solution of 14.0 g 2,6,10-trimethyl-1,1-diethoxy-3,5,9-undecatriene (2D, 0.05 mol), 100 mL tetrahydrofuran and 1.2 g of PTSA was added. After stirred until homogeneous, 22 g of water was added, and further 24 h of stirring at 20-25° C. was needed until the reaction completed according to GC. Then a solution of 2 g of NaHCO3 in 20 mL water was added for neutralization. Removal of THF by vacuum distillation, 100 mL of cyclohexane was added and then stratification. The organic layer was washed with 30 mL of water, dried over anhydrous magnesium sulfate and subsequently filtered. Removal of the volatile organic solvents by evaporation at reduced pressure afforded 10.3 g of crude 2,6,10-trimethyl-3,5,9-undecatriene-1-aldehyde of formula (12).
Reaction SMILES: S(C1C=CC(C)=CC=1)([O-])(=O)=O.[C:12]([C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:24]=1[OH:25])[CH2:19][CH2:20]O)([CH3:15])([CH3:14])[CH3:13].[N:30]1([C:36]2[CH:41]=[CH:40][C:39]([CH2:42][C:43]([O:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:44])=[CH:38][CH:37]=2)[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:26]([C:23]1[CH:22]=[C:18]([CH:17]=[C:16]([C:12]([CH3:13])([CH3:15])[CH3:14])[C:24]=1[OH:25])[CH2:19][CH2:20][N:33]1[CH2:32][CH2:31][N:30]([C:36]2[CH:37]=[CH:38][C:39]([CH2:42][C:43]([O:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:44])=[CH:40][CH:41]=2)[CH2:35][CH2:34]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CCCCOC(=O)Cc1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)c1cc(CCO)cc(C(C)(C)C)c1O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCOC(=O)Cc1ccc(N2CCN(CCc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)CC2)cc1

Procedure:
A mixture of 20.2 g. (50 mmole) of the tosylate of 3,5-di-tert.-butyl-4-hydroxyphenethyl alcohol, 13.8 g. (50 mmole) n-butyl 4-(piperazin-1-yl)-phenylacetate, 6.9 g. (50 mmole) powdered anhydrous potassium carbonate and 200 ml. butan-2-one is maintained at reflux temperature for 24 hours, then suction filtered hot and the filtrate evaporated in a vacuum. The residue is taken up in diethyl ether, the ether phase is extracted twice with water, then dried with anhydrous sodium sulphate and evaporated. By means of ligroin, the product is brought to crystallisation and recrystallised from n-butanol. Yield 14.3 g. (59% of theory); m.p. 103°-105° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][S:33]([C:36]3[CH:40]=[CH:39][O:38][CH:37]=3)(=[O:35])=[O:34])[C:27]=2[F:41])[CH:5]=[CH:4][N:3]=1.[CH3:42][Zn]C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O1CCOCC1>[F:41][C:27]1[C:28]([NH:32][S:33]([C:36]2[CH:40]=[CH:39][O:38][CH:37]=2)(=[O:35])=[O:34])=[CH:29][CH:30]=[CH:31][C:26]=1[C:9]1[N:10]=[C:11]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[S:12][C:8]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:42])[N:7]=1
Reactant: C[Zn]C
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cccc(NS(=O)(=O)c4ccoc4)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1nccc(-c2sc(C3CCN(C(=O)OC(C)(C)C)CC3)nc2-c2cccc(NS(=O)(=O)c3ccoc3)c2F)n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
1,1-dimethylethyl 4-(5-(2-chloro-4-pyrimidinyl)-4-{2-fluoro-3-[(3-furanylsulfonyl)-amino]phenyl}-1,3-thiazol-2-yl)-1-piperidinecarboxylate (150 mg, 0.242 mmol) was dissolved into 1,4-dioxane (3 mL) and the solution was degassed for 10 min. PdCl2(dppf)-CH2Cl2 adduct (13.83 mg, 0.017 mmol) and dimethylzinc (0.242 mL, 0.484 mmol) were added to the reaction mixture. The reaction mixture was stirred at 80° C. for 1 h. The reaction was quenched with methanol (3 mL) and water (10 mL) and extracted with EtOAc (3×). The extract was dried over Na2SO4, filtered, and concentrated. The residue was purified using column chromatography (40% to 100% EtOAc/hexane) to give the title compound (118 mg). MS (ESI): 600.3 [M+1]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[F:10].[C:11]([Cu])#[N:12].CN1CCCC1=O>C(Cl)Cl>[F:10][C:3]1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[C:11]#[N:12]
Reactant: COc1ccc(F)c(Cl)c1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: COc1ccc(F)c(C#N)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 2-Chloro-1-fluoro-4-methoxy-benzene (10.4 grams, 65.0 mmole), CuCN (6.4 grams, 71.0 mmole) and N-methylpyrrolidinone (100 ml) was refluxed for 18 hours. An additional 2.3 g CuCN was added, and the mixture was refluxed for 40 hours. The mixture was poured into 300 ml ice water and stirred for 10 minutes. This was poured into 100 ml methylene chloride and the layers were separated. The mixture was washed with water, dried over MgSO4, filtered, and concentrated to a solid (2.8 g). MW 137.12; MS (m/e) 137(M+).
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH2:11][O:12][CH3:13].[CH:14]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)=[O:15].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O.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>[CH:14]([C:16]1[CH:21]=[C:20]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[O:10][CH2:11][O:12][CH3:13])[CH:19]=[CH:18][CH:17]=1)=[O:15]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: COCOc1cc(C#N)ccc1I
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: [Cs+]
Solvent: CN(C)C=O
Product: COCOc1cc(C#N)ccc1-c1cccc(C=O)c1
Temperature: 100 °C
Yield: 89.9 %

Procedure:
4-Iodo-3-methoxymethoxy-benzonitrile (600 mg, 2.08 mmol), 3-formylphenylboronic acid (450 mg, 3.0 mmol), Pd(PPh3)4 (200 mg, 0.17 mmol) and Cs2CO3 (1.2 g, 3.7 mmol) were mixed in N,N-dimethylformamide (15 mL), degassed and heated at 100° C. for 2 hours. After which, the mixture is allowed to cool to room temperature, an aqueous work up is performed, and the residue purified to afford the desired product (500 mg, 90%).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH2:6]([O:8][C:9](=[O:29])[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([F:20])=[CH:17][CH:18]=2)[C:13]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:12]1[CH3:28])[CH3:7]>>[CH2:6]([O:8][C:9](=[O:29])[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([F:20])=[CH:17][CH:18]=2)[C:13]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:26][CH:27]=2)=[C:12]1[CH3:28])[CH3:7]
Reactant: O=S(=O)(O)Cl
Reactant: CCOC(=O)Cn1c(C)c(Cc2ccccc2)c2cc(F)ccc21
Product: CCOC(=O)Cn1c(C)c(Cc2ccc(S(=O)(=O)Cl)cc2)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To chlorosulfonic acid (1.5 mL) at 0° C. under nitrogen was added portionwise over 10 minutes 2-(3-benzyl-5-fluoro-2-methyl-1H-indol-1-yl)acetic acid ethyl ester (900 mg, 2.76 mmol). After stirring at this temperature for 2 hours the solution was warmed to room temperature and stirred for a further 2 hours. The reaction mixture was then poured onto ice, and extracted with ethyl acetate. The separated organics were dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give 2-(3-(4-(chlorosulfonyl)benzyl)-5-fluoro-2-methyl-1H-indol-1-yl)acetic acid ethyl ester (˜1.1 g, 2.59 mmol, 94%) as a brown oil, which was used directly without further purification.
Reaction SMILES: [Se]=[O:2].[CH3:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]=[CH:6][CH:5]=1>O1CCOCC1>[CH3:15][O:14][C:10]1[CH:9]=[C:8]2[C:13]([C:4]([CH:3]=[O:2])=[CH:5][CH:6]=[N:7]2)=[CH:12][CH:11]=1
Reactant: O=[Se]
Reactant: COc1ccc2c(C)ccnc2c1
Solvent: C1COCCO1
Product: COc1ccc2c(C=O)ccnc2c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 52.8 %

Procedure:
A mixture of 1.9 g of selenium oxide dissolved in 35 ml of dioxane is added dropwise to a solution of 2.7 g of 4-methyl-7-methoxyquinoline in 35 ml of dioxane preheated to 65° C. At the end of the addition, the brown suspension is heated to a temperature in the region of 80° C. for 5 hours. The reaction medium is stirred for 16 hours at a temperature in the region of 20° C. The greenish suspension is suction-filtered and then washed with EtOAc. The filtrate is concentrated under reduced pressure. The suspension obtained is crystallized from isopropyl ether to give 1.54 g of 7-methoxyquinoline-4-carbaldehyde.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[C:5](#N)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O>[C:6]1([C:5]2[NH:3][CH2:2][CH2:1][N:4]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N#Cc1ccccc1
Reactant: NCCN
Solvent: O
Product: c1ccc(C2=NCCN2)cc1
Temperature: 200 °C
Yield: 87 %

Procedure:
In a 2,000 ml four-necked flask equipped with a reflux condenser and a thermometer were charged 515 g of benzonitrile and 10 g of titanium diisopropoxybis(acetonate). After addition of 4 g of water, the mixture was heated up to 185°-190° C. with stirring. Then, 300 g of ethylenediamine were added dropwise for 10 hours with stirring while maintaining the temperature at 185° C. or above. After completion of the addition of the diamine, the reaction mixture was heated up to 200° C. and maintained at that temperature for 6 hours. The resulting mixture was then subjected to vacuum distillation at 0.7 mmHg and at 160°-180° C. to obtain 635 g of 2-phenyl-2-imidazoline with a yield of 87%.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6](O)=[O:7])=[C:4]([F:12])[CH:3]=1.C(N1C=CN=C1)([N:15]1C=CN=C1)=O>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([NH2:15])=[O:7])=[C:4]([F:12])[CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cc(Br)cc(F)c1C(=O)O
Solvent: C1CCOC1
Product: Cc1cc(Br)cc(F)c1C(N)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-bromo-2-fluoro-6-methyl benzoic acid (200 g) was dissolved in 1 L of THF and treated portion wise with carbonyldiimidazole (180 g, 1.3 eq). The reaction mixture is stirred at ambient temperature for about 3 hours and then quenched by addition of aqueous ammonium hydroxide (400 ml). The resulting reaction mixture was stirred overnight at ambient temperature and then concentrated under reduced pressure to about 0.5 L volume. The resulting slurry was diluted by adding 1 L of water. The precipitated product was isolated by filtration, washed with water (3×300 ml), dried under vacuum at about 60° C. to obtain 174 g (87% isolated yield) of product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl[CH2:23][C:24]1[CH:25]=[C:26]([C:30]2[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=2)[CH:27]=[N:28][CH:29]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]2)[CH2:23][C:24]2[CH:25]=[C:26]([C:30]3[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=3)[CH:27]=[N:28][CH:29]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(-c2cncc(CCl)c2)cc(OC)c1OC
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Br)cc2)CC1
Product: COc1cc(-c2cncc(CN(c3ccc(Br)cc3)C3CCN(C(=O)OC(C)(C)C)CC3)c2)cc(OC)c1OC

Procedure:
4-(4-Bromophenyl)amino-1-(tert-butoxycarbonyl)piperidine (711 mg) and 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]([OH:11])(=[O:10])/[CH:5]=[CH:6]\[C:7]([OH:9])=[O:8].NC[C:14]([NH:16][C:17]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:25]([F:28])([F:27])[F:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15].[C:35](O)(=O)/C=C\C(O)=O>CO>[C:4]([OH:11])(=[O:10])/[CH:5]=[CH:6]\[C:7]([OH:9])=[O:8].[CH3:1][N:2]([CH3:35])[CH2:3][C:14]([NH:16][C:17]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:25]([F:28])([F:27])[F:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15]
Reactant: NCC(=O)NC(Cc1ccccc1)(c1ccccc1)C(F)(F)F
Reactant: CNC
Agent: O=C(O)/C=C\C(=O)O
Solvent: CO
Product: CN(C)CC(=O)NC(Cc1ccccc1)(c1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 64.5 %

Procedure:
To a stirred solution of dimethylamine (25 ml, 0.38 mol) in 150 ml of methanol at 0° C. under nitrogen, was added 2-chloro-N-[1,2-diphenyl-1-(trifluoromethyl)ethyl]acetamide (from Example 1) (7.0 g, 0.020 mol). The mixture was allowed to slowly warm to ambient temperature and stirred for 48 hours. The solvent was evaporated and the residue was dissolved in 150 ml of chloroform and 150 ml of water. The aqueous solution was basified to a pH of 10 with 50% NaOH. The phases were separated, the aqueous phase extracted with chloroform (2×75 ml) and the combined organic phases were washed with brine (75 ml), dried and evaporated to a dark oil, 7.2 g. This oil was purified by chromatograhy on a Prep 500 HPLC on silica gel, eluting with 10% ethylacetate/hexane. Pure fractions were combined and evaporated to 4.0 g of an oil. This oil was dissolved in 125 ml of methanol and treated with maleic acid (1.3 g, 0.012 mol) at reflux. The solution was concentrated to a volume of 75 ml. The crystalline salt which formed, was vacuum dried to give 3.61 g of 2-(dimethylamino)-N-[1,2-diphenyl-1-(trifluoromethyl)ethyl]acetamide maleate as a white solid, mp 213°-215° C.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32]>>[C:13]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: COc1ccccc1Br
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3)c2)cn1
Product: COc1ccccc1C(=O)c1cn(-c2cccc(-c3ccccc3)c2)cn1

Procedure:
This compound was prepared by method C using compound 12a and 2-bromoanisole. HRMS (ESI+): m/z=355.1459 [M+H]
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[CH:6]([OH:10])[C:7]([OH:9])=[O:8])([O-:3])=[O:2].S(Cl)(Cl)=O.[CH3:19]O>>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[CH:6]([OH:10])[C:7]([O:9][CH3:19])=[O:8])([O-:3])=[O:2]
Reactant: CO
Reactant: O=C(O)C(O)c1ccccc1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Product: COC(=O)C(O)c1ccccc1[N+](=O)[O-]

Procedure:
o-Nitromandelic acid (5 g.) and thionyl chloride (50 ml.) were mixed, heated under reflux on a steam bath for 1 hour and cooled, then the excess of thionyl chloride was removed on a rotary evaporator at room temperature. The crude o-nitromandeloyl chloride thus obtained was carefully mixed with methanol (70 ml.), and after the initial vigorous reaction had subsided, the mixture was heated under reflux on a steam bath for 1 hour, cooled, and the solvent evaporated under reduced pressure. The oil thus obtained was chromatographed on silica, and elution with diethyl ether/petroleum ether (b.p. 60°-80° C.), 6:4 by volume yielded methyl o-nitromandelate. The methyl o-nitromandelate thus obtained was reduced by the general process described under (a) above to give the required starting material;
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[OH:14].[H-].[Na+].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.O>CN(C)C=O>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[O:14][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COc1c(C)c(C)c(OC)c(O)c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(C)c(C)c(OC)c(Oc2ccc([N+](=O)[O-])cc2)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.6 %

Procedure:
5.8 g of 2,5-dimethoxy-3,4,6-trimethylphenol [prepared as described in step (a) above] in 10 ml of dimethylformamide were added to a suspension of 1.4 g of sodium hydride (as a 55% w/w dispersion in mineral oil) in 50 ml of dimethylformamide, whilst ice-cooling, and the mixture was stirred at room temperature for 2 hours. At the end of this time, a solution of 4.6 g of p-fluoronitrobenzene in 10 ml of dimethylformamide was added to the mixture, whilst ice-cooling. The mixture was then stirred at room temperature for 1 hour, and then at 80° C. for 7 hours. At the end of this time, the mixture was poured into water, and the resulting crude oil was extracted with benzene. The benzene extract was washed with water and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting oil was purified by column chromatography through silica gel, using a 4:1 by volume mixture of benzene and hexane, followed by benzene alone, as the eluent, to give 3.9 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([NH2:10])=O)=[N:6][CH:7]=1>O=P(Cl)(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]#[N:10])=[N:6][CH:7]=1
Reactant: NC(=O)c1cnc(Cl)cn1
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cnc(Cl)cn1
Yield: 64.1 %

Procedure:
Dissolve 5-chloropyrazine-2-carboxamide (Example 389, Part A) (0.0878 g, 0.557 mmol) in POCl3 (5.6 mL) and heat at reflux for 35 minutes. Concentrate the reaction mixture. Take up the dark oil in saturated aqueous NaHCO3 (15 mL) and extract with dichloromethane (2× 25 mL). Wash the organic layer with brine (1× 15 mL), dry over Na2SO4, filter and concentrate. Purify by flash chromatography, eluting with 10% ethyl acetate in hexanes to give the title compound (0.0498 g, 64.0%): GC/MS, MS ES+ 139 (M)+, time 10.6 min % of total 100%; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR 8.2 min, 100% purity.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][CH2:10][S:11]([CH2:13][C:14]([OH:16])=O)=[O:12])=[O:7].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[N:42]1([CH2:48][C:49]2[CH:50]=[C:51]([CH:57]=[CH:58][CH:59]=2)[O:52][CH2:53][CH2:54][CH2:55][NH2:56])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>ClCCl>[N:42]1([CH2:48][C:49]2[CH:50]=[C:51]([CH:57]=[CH:58][CH:59]=2)[O:52][CH2:53][CH2:54][CH2:55][NH:56][C:14](=[O:16])[CH2:13][S:11]([CH2:10][CH2:9][NH:8][C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:7])=[O:12])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: O=C(O)CS(=O)CCNC(=O)c1ccco1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(CS(=O)CCNC(=O)c1ccco1)NCCCOc1cccc(CN2CCCCC2)c1
Reaction time: 0.5 h
Yield: 51.7 %

Procedure:
There was suspended 3.0 g (0.0122 mol) of 2-[2-(2-furoylamino)ethylsulfinyl)acetic acid inl 100 ml of dichloromethane and added 1.87 g (0.0122 mol) of HOBt and 2.52 g (0.0122 mol) of DCC under cooling with ice, and the mixture was stirred for 30 minutes under cooling with ice. Thereto was added 3.04 g (0.0122 mol) of N-3-[3-(piperidinomethyl)phenoxy]propylamine, and the mixture was stirred for 18 hours at room temperature. The precipitate was filtrated off, and the filtrate was washed with 5 % aqueous solution of sodium hydroxide and with water and dried over Glauber's salt. Then the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=5:1) to give 3.0 g of the titled compound as crystals.
Reaction SMILES: [CH:1]([CH2:3][O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[CH:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])[CH2:6]1)=[O:2].[BH4-].[Na+].O>CO>[OH:2][CH2:1][CH2:3][O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[CH:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])[CH2:6]1
Reactant: C[C@]12CC[C@H](OCC=O)CC1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[C@]12CC[C@H](OCCO)CC1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 87 %

Procedure:
To a solution of 4.0 g of 3β-formylmethoxy-androstan-17-one in 50 ml of methanol 0.60 g of sodium borohydride were added slowly at -78° C. After 1/2 hr 20 ml of water were added, the methanol was distilled under reduced pressure, and the mixture was extracted with methylene chloride; the organic layer was washed with water, dried over sodium sulfate and evaporated to dryness under reduced pressure. The crude product was purified by flash-chromatography (SiO2) using n-hexane/ethyl acetate 80/20 as eluant to give 3.5 g of the title compound as a white solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([NH:46][C:47]([NH2:49])=[O:48])[CH:6]=[CH:7][C:8]=1[C:9]1[C:17]2[C:16]([NH:18][C@H:19]([C:21]3[N:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:25](=[O:33])[C:24]4=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]4[N:22]=3)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=2[N:11](COCC[Si](C)(C)C)[CH:10]=1.B(Br)(Br)Br.N>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([NH:46][C:47]([NH2:49])=[O:48])[CH:6]=[CH:7][C:8]=1[C:9]1[C:17]2[C:16]([NH:18][C@H:19]([C:21]3[N:26]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:25](=[O:33])[C:24]4=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]4[N:22]=3)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=2[NH:11][CH:10]=1
Reactant: COc1cc(NC(N)=O)ccc1-c1cn(COCC[Si](C)(C)C)c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Agent: BrB(Br)Br
Agent: N
Solvent: ClCCl
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5ccc(NC(N)=O)cc5O)c34)n(-c3ccccc3)c(=O)c12
Yield: 11.2 %

Procedure:
(S)-1-(3-Methoxy-4-(4-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)urea (34 mg, 0.05 mmol) was treated with boron tribromide (1M in dichloromethane, 1.5 mL, 1.5 mmol) in dichloromethane (1.0 mL) and then with a solution of ammonia (7N in methanol, 5.0 mL, 35.0 mmol) according to the method described in Example 41. The residue was purified using SP1® Purification System (0% to 10% dichloromethane-methanol) to obtain 3 mg (12% yield) of the title compound.