Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Al](C)C.[F:5][C:6]([F:10])([F:9])[CH2:7][NH2:8].C[O:12][C:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[C:23]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[N:24][O:25][C:26]=2[CH3:27])=[N:16][CH:15]=1.O>O1CCOCC1>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([C:23]2[C:22]([CH2:21][O:20][C:17]3[CH:18]=[CH:19][C:14]([C:13]([NH:8][CH2:7][C:6]([F:10])([F:9])[F:5])=[O:12])=[CH:15][N:16]=3)=[C:26]([CH3:27])[O:25][N:24]=2)=[CH:33][CH:32]=1
Reactant: NCC(F)(F)F
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2C)nc1
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: O
Product: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)NCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 401 μL, 0.8 mmol) was added dropwise (exothermic) to a solution of 2,2,2-trifluoroethylamine (79 mg, 63 μL, 0.8 mmol) in dioxane (5 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (72 mg, 0.2 mmol) in dioxane (2.5 mL) was added. The resulting mixture was then heated at 85-95° C. for 1 h and then cooled to room temperature and then poured into water and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (66 mg, 77%) which was obtained as a white solid. MS: m/e=426.0 [M+H]+.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[N:14]=[C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=3)[NH:12][C:11]=2[C:10](=[O:27])[N:9]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])[C:8]1=[O:36].[NH2:38][NH2:39]>CO.O1CCCC1>[F:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][N:9]1[C:10](=[O:27])[C:11]2[NH:12][C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=3)=[N:14][C:15]=2[N:7]([CH2:6][CH2:5][CH2:4][C:3]([NH:38][NH2:39])=[O:2])[C:8]1=[O:36]
Reactant: NN
Reactant: COC(=O)CCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NC(C)=O)cc3)nc21
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CCCC(=O)NN)cc1

Procedure:
Prepared by the reaction of 4-[8-(4-acetylamino-benzyl)-1-(2-fluorobenzyl)-2,6-dioxo-1,2,6,7-tetrahydro-purin-3-yl]-butyric acid methyl ester with hydrazine (10 equivalents) in methanol/tetrahydrofuran according to the general procedure of Kramer et al. as described in J. Heterocyclic Chem. 1994, 31, 1439. MS, m/z(M+H)=508.2111.
Reaction SMILES: [CH2:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([O:19][C:20]([N:22]1[CH2:28][CH2:27][CH2:26][C@@H:23]1[CH:24]=O)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C.C([O-])(O)=O.[Na+]>[C:15]([O:19][C:20]([N:22]1[CH2:28][CH2:27][CH2:26][C@@H:23]1[CH2:24][NH:12][C:11]1[CH:10]=[CH:9][C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: Nc1ccc(Cc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1CNc1ccc(Cc2ccccc2)cc1
Temperature: 5 °C
Reaction time: 3 h
Yield: 84.3 %

Procedure:
To a solution of 4-benzyl aniline (200 mg, 1.1 mmol) in dichloroethane (1.5 mL) was added a solution of N-(t-butoxycarbonyl)-D-prolinal (239 mg, 1.2 mmol) in dichloroethane (1.5 mL) at 0-5° C. Sodium triacetoxyborohydride (393 mg, 1.85 mmol) was added to the above solution. Acetic acid (65 mg, 1.1 mmol) in dichloroethane (1 mL) was added dropwise, over a period of 5 min at 0-5° C. The reaction mixture was stirred at 0-10° C. for 3 h. The mixture was diluted with saturated aq NaHCO3 and extracted with dichloromethane. Organic layer was dried over anhy. MgSO4 and the solvent was removed in vacuo to obtain the crude mixture, which was purified by silica gel flash chromatography to obtain the title product (340 mg, 85%).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[N:8]([CH3:9])[C:7]([N+:10]([O-:12])=[O:11])=[N:6][CH:5]=1.CC(C)([O-])C.[K+]>C1C=CC=CC=1>[CH3:9][N:8]1[C:4]([CH:3]=[CH2:2])=[CH:5][N:6]=[C:7]1[N+:10]([O-:12])=[O:11]
Reactant: Cn1c(CCCl)cnc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: C=Cc1cnc([N+](=O)[O-])n1C
Reaction time: 2 h

Procedure:
To a solution of 18.9 g. of 5-(2-chloroethyl)-1-methyl-2-nitroimidazole (prepared according to the procedure of British Patent 1,222,486) in 2.8 liters of anhydrous benzene cooled to 5°-10° C., 16.8 g. of potassium tert-butoxide is added. Stirring is continued for 2 hours at 5°-10° C. After filtration and concentration to dryness under vacuum at a temperature lower than 50° C., the resulting yellow oily residue is washed 3 times with 50 ml. of ethyl ether (or light petroleum). The title product is obtained, which is dried under vacuum at 40° C.; yield 12 g. (77.7%). A sample crystallized from ethyl ether melts at 106°-108° C.
Reaction SMILES: [CH3:1][N:2]([S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]([F:29])([F:28])[F:27])(=[O:19])=[O:18])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([O:14]CC)=[O:13])=[CH:8]2.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.CO>[CH3:1][N:2]([S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]([F:29])([F:27])[F:28])(=[O:18])=[O:19])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8]2
Reactant: CCOC(=O)c1cc2cccc(N(C)S(=O)(=O)c3ccccc3C(F)(F)F)c2[nH]1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(c1cccc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 78.1 %

Procedure:
Ethyl 7-(methyl{[2-(trifluoromethyl)phenyl]sulfonyl}amino)-1H-indole-2-carboxylate (3.7 g) was dissolved in a mixed solvent of tetrahydrofuran (25 mL)-methanol (25 mL). Aqueous potassium hydroxide solution (prepared by dissolving potassium hydroxide (1.5 g) in water (20 mL)) was added to this solution, and the mixture was stirred at room temperature for 2 days. The reaction solution was acidified with aqueous citric acid solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained colorless crystals were washed with ethyl acetate-hexane to give the title compound (2.7 g, yield: 63%) as colorless crystals. MS: 399(MH+). melting point: 211-212° C.
Reaction SMILES: CO.[CH3:3][S:4][C:5]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH3:10])[C:6]([O:8]C)=[O:7].[OH-].[Na+]>O>[CH3:3][S:4][C:5]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH3:10])[C:6]([OH:8])=[O:7]
Reactant: COC(=O)C(C)(SC)c1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CSC(C)(C(=O)O)c1cccs1
Yield: 99 %

Procedure:
Methanol (6 ml) and 4 ml of water were added to 1.08 g of methyl α-methylthio-α-(2-thienyl)propionate, and 500 mg of sodium hydroxide was added. The mixture was heated under reflux for 1 hour. Water (20 ml) was added, and the mixture was extracted with 10 ml of diethyl ether. The aqueous layer was adjusted to pH 1 with conc. hydrochloric acid, and extracted three times with 20 ml of diethyl ether. The organic layer was washed with 10 ml of water, and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure afforded 1.00 g of α-methylthio-α-(2-thienyl)propionic acid as colorless crystals in a yield of 99%.
Reaction SMILES: [OH:1][CH:2]([CH2:22][N:23]([CH2:34][CH2:35][CH3:36])[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:21])[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12]2)=[CH:7][CH:6]=1.[C:37]1([CH:43]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:44](Cl)=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:47]1([CH:43]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:44]([O:1][CH:2]([CH2:22][N:23]([CH2:34][CH2:35][CH3:36])[C:24]([O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:25])[CH2:3][O:4][C:5]2[CH:14]=[C:13]3[C:8]([C:9](=[O:21])[CH:10]=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:12]3)=[CH:7][CH:6]=2)=[O:45])[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CCCN(CC(O)COc1ccc2c(=O)cc(-c3ccccc3)oc2c1)C(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCN(CC(COc1ccc2c(=O)cc(-c3ccccc3)oc2c1)OC(=O)C(c1ccccc1)c1ccccc1)C(=O)OCc1ccccc1
Yield: 76 %

Procedure:
A mixture of 7-[2-hydroxy-3-[N-(benzyloxycarbonyl)-propylamino]propoxy]flavone in crude form (5.09 g, 11 mmol), diphenylacetyl chloride (10.20 g, 44 mmol), and triethylamine (19.0 ml, 136 mmol) in toluene (65 ml) was refluxed under nitrogen for 18 hr. Toluene was removed by evaporation and the oily residue was dissolved in chloroform, washed twice with saturated NaHCO3 and once with water, and then dried (K2CO3). The dried solution, upon evaporation, gave a brown oil which was purified by HPLC (Water Associates PrepLC/Systems 500) using 3% acetone/CH2Cl2 that contained a small amount of NH4OH. A tan syrup of the title compound was obtained; 5.57 g (76% yield).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:18]=[CH:17][C:13]3[O:14][CH2:15][O:16][C:12]=3[CH:11]=2)[C:5]([C:19]#[N:20])=[C:4]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:3]=1.[OH:29][CH2:30][CH2:31][NH2:32].O>C1COCC1>[OH:29][CH2:30][CH2:31][NH:32][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:18]=[CH:17][C:13]3[O:14][CH2:15][O:16][C:12]=3[CH:11]=2)[C:5]([C:19]#[N:20])=[C:4]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:3]=1
Reactant: N#Cc1c(Cl)nc(OCc2ccccc2)c(C#N)c1-c1ccc2c(c1)OCO2
Reactant: NCCO
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(NCCO)nc(OCc2ccccc2)c(C#N)c1-c1ccc2c(c1)OCO2

Procedure:
30 mg (0.08 mmol) of 2-chloro-4-(1,3-benzodioxol-5-yl)-6-benzyloxy-3,5-pyridinedicarbonitrile (example 4, step 1) and 14.1 mg (0.23 mmol) of 2-hydroxyethylamine are shaken together in 0.5 ml of THF for about 16 h. Water is added to the reaction solution and the product that crystallizes out is filtered off with suction and dried under reduced pressure. The crude product is purified by silica gel chromatography using the mobile phases dichloromethane and dichloromethane/methanol 50:1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[O:32]>C1(C)C=CC=CC=1>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:31]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:32]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C=Nc1ccccc1F
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccccc4F)cc3)c2cc1OC
Yield: 73 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (51 mg) was dissolved in toluene (5 ml) with heat, 2-fluorophenyl isocyanate (0.2 ml) was added, and the admixture was refluxed with heat for 15 minutes. The resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 54 mg of the title compound (yield: 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([O-:17])=[O:16])=[CH:10][C:9]=2[CH3:18])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+]>>[CH3:18][C:9]1[CH:10]=[C:11]([CH2:14][C:15]([OH:17])=[O:16])[N:12]([CH3:13])[C:8]=1[C:6]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:20][CH:19]=1)=[O:7]
Reactant: Cc1cc(CC(=O)[O-])n(C)c1C(=O)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(CC(=O)O)n(C)c1C(=O)c1ccc(Cl)cc1
Reaction time: 3 h
Yield: 86 %

Procedure:
About 31 grams of the lower alkyl ester form of 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate are saponified in 225 ml. of an aqueous reaction medium containing 0.12 M.NaOH. Saponification is carried out at about 90° C. for a period of from about 2 to 4 hours. At the end of this period, the aqueous saponification medium is cooled to a temperature of 0° to 5° C. The resulting insoluble first crop of acetate salt product is removed from the aqueous mother liquor. An 86-88% yield of Zomepirac [sodium 5-(p-chlorobenzoyl)-1,4 -dimethylpyrrole-2-acetate] is thereby realized based on the amount of ester initially employed.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[F:9].[OH:10][C:11]1[CH:15]=[C:14]([N:16]2[C:24]3[CH:23]=[CH:22][N:21]=[CH:20][C:19]=3[N:18]=[CH:17]2)[S:13][C:12]=1[C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][O:10][C:11]1[CH:15]=[C:14]([N:16]2[C:24]3[CH:23]=[CH:22][N:21]=[CH:20][C:19]=3[N:18]=[CH:17]2)[S:13][C:12]=1[C:25]([O:27][CH3:28])=[O:26]
Reactant: Fc1ccccc1CBr
Reactant: COC(=O)c1sc(-n2cnc3cnccc32)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-n2cnc3cnccc32)cc1OCc1ccccc1F

Procedure:
In a similar manner as described for example B11, 172 mg of 1-(bromomethyl)-2-fluorobenzene, 200 mg of methyl 3-hydroxy-5-(1H-imidazo[4,5-c]pyridin-1-yl)thiophene-2-carboxylate, 121 mg of potassium carbonate in 5 ml anhydrous DMF yield the title compound.
Reaction SMILES: BrC1C=CC(S([O:11][C@@H:12]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:14]([C:24]([O:26][CH3:27])=[O:25])[CH2:13]2)(=O)=O)=CC=1.[Br:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[C:34]([O:41][CH2:42][CH3:43])[CH:33]=[C:32]2O.C([O-])([O-])=O.[Cs+].[Cs+]>CN1C(=O)CCC1.O>[Br:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[C:34]([O:41][CH2:42][CH3:43])[CH:33]=[C:32]2[O:11][C@H:12]1[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C@H:14]([C:24]([O:26][CH3:27])=[O:25])[CH2:13]1
Reactant: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(Br)cc2)CN1C(=O)OC(C)(C)C
Reactant: CCOc1cc(O)c2cc(Br)c(OC)cc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOc1cc(O[C@@H]2C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C2)c2cc(Br)c(OC)cc2n1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
A suspension of 1-t-butyl 2-methyl (2S,4S)-4-{[(4-bromophenyl)sulfonyl]oxy}pyrrolidine-1,2-dicarboxylate (25.0 g, 53.8 mmol), 6-bromo-2-ethoxy-7-methoxyquinolin-4-ol (16.1 g, 53.8 mmol) and Cs2CO3 (52.6 g, 162 mmol) in NMP (300 mL) was stirred at 75° C., under N2, for 2 hours. At 22° C., the reaction was diluted with water (500 mL) and extracted with EtOAc (3×500 mL). The combined EtOAc layers were washed with water (3×100 mL), brine (100 mL), dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel 60, eluting with 0 to 50% EtOAc in hexane, to give the title product. 1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H); 7.16 (s, 1H); 6.02 (s, 1H); 5.05 (m, 1H); 4.49 (m, 3H); 4.00 (s, 3H); 3.91 (m, 2H); 3.78 (s, 3H); 2.67 (m, 1H); 2.37 (m, 1H); 1.47 (s, 3H); 1.44 (s, 9H) ppm. LRMS (ESI) m/z 525.0 [(M+H)+; calcd for C23H30BrN2O7: 298.0].
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10](OCC)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)([Br:19])=O>>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Br:19])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Br)(Br)Br
Reactant: CCOc1cccc(Cc2ccccc2)n1
Product: Brc1cccc(Cc2ccccc2)n1
Temperature: 135 °C
Reaction time: 1 h

Procedure:
One hundred fifteen g. of 2-benzyl-6-ethoxypyridine and 200 g. of phosphorous oxybromide were heated together with stirring at 135°C. for 1 hour. The mixture gave off a gas during the first 15 minutes of the reaction but remained calm for the rest of the heating period. On cooling, the mixture became an intractable tar and the reaction flask was broken to obtain the crude product. It was partitioned between 2 liters of water, 270 ml. of 10N sodium hydroxide solution and 1 liter of chloroform. The organic extract was washed with 1 liter of water and dried over magnesium sulfate. Removal of the desiccant and solvent yielded a dark oil which was extracted with 750 ml. of petroleum ether (b.p. 60°-80°C.), and treated with decolorizing charcoal. Removal of the solids and solvent yielded the product as an amber oil. This material was used without further purification for the next step.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)=[CH:4][N:3]=1.[Br-].[CH:17]1([Zn+])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C1COCC1>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:17]1([C:2]2[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]3[N:11]=[C:12]([CH3:15])[S:13][CH:14]=3)=[CH:4][N:3]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Cc1nc(C#Cc2ccc(Cl)nc2)cs1
Reactant: [Zn+]C1CCCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1nc(C#Cc2ccc(C3CCCCC3)nc2)cs1
Temperature: 150 °C

Procedure:
200 mg (0.85 mmol, 1 eq) 2-chloro-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine, 50 mg (0.043 mmol, 0.05 eq) tetrakis(triphenylphosphine)palladium(0), and 2 mL of 0.5 M cyclohexylzinc bromide in THF (1 mmol, 1.1 eq) were combined. The reaction mixture was heated at 150° C. in the microwave for 5 min, quenched with pH 7 PBS, extracted with DCM. Silica gel chromatography (gradient 0% to 40% EtOAc/Hexanes) gave 2-cyclohexyl-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (L-001106449). The mono HCl salt was made by dissolving the free base into diethyl ether, adding 1 eq of HCl, and isolated by filtration. LC-MS calculated for C17H18N2S 282, observed m/e 283.3 (M+H)+. 1H-NMR (500 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.30 (d, 1H), 8.03 (s, 1H), 7.71 (d, 1H), 2.94 (m, 1H), 2.69 (s, 3H), 1.35-1.91 (m, 10H).
Reaction SMILES: [OH:1][C@:2]1([C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])[C@:18]2([CH3:19])[C@H:5]([C@H:6]3[C:15]([C@@H:16]([C:20]4[CH:25]=[CH:24][C:23]([C@@H:26]([OH:28])[CH3:27])=[CH:22][CH:21]=4)[CH2:17]2)=[C:14]2[C:9](=[CH:10][C:11](=[O:29])[CH2:12][CH2:13]2)[CH2:8][CH2:7]3)[CH2:4][CH2:3]1.[CH2:37]([O:40][C:41]([NH:43][C@@H:44]([CH3:48])[C:45](O)=[O:46])=[O:42])[CH:38]=[CH2:39]>>[OH:1][C@:2]1([C:30]([F:35])([F:36])[C:31]([F:32])([F:33])[F:34])[C@:18]2([CH3:19])[C@H:5]([C@H:6]3[C:15]([C@@H:16]([C:20]4[CH:21]=[CH:22][C:23]([C@@H:26]([O:28][C:45](=[O:46])[C@@H:44]([NH:43][C:41]([O:40][CH2:37][CH:38]=[CH2:39])=[O:42])[CH3:48])[CH3:27])=[CH:24][CH:25]=4)[CH2:17]2)=[C:14]2[C:9](=[CH:10][C:11](=[O:29])[CH2:12][CH2:13]2)[CH2:8][CH2:7]3)[CH2:4][CH2:3]1
Reactant: C=CCOC(=O)N[C@@H](C)C(=O)O
Reactant: C[C@H](O)c1ccc([C@H]2C[C@@]3(C)[C@@H](CC[C@@]3(O)C(F)(F)C(F)(F)F)[C@@H]3CCC4=CC(=O)CCC4=C32)cc1
Product: C=CCOC(=O)N[C@@H](C)C(=O)O[C@@H](C)c1ccc([C@H]2C[C@@]3(C)[C@@H](CC[C@@]3(O)C(F)(F)C(F)(F)F)[C@@H]3CCC4=CC(=O)CCC4=C32)cc1
Yield: 44 %

Procedure:
In analogy to Example 5, 150 mg (0.29 mmol) of (8S,11R,13S,14S,17S)-17-hydroxy-11-[4-((S)-1-hydroxyethyl)phenyl]-1 3-methyl-17-pentafluoroethyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one were converted using (S)-2-allyloxycarbonylaminopropanoic acid and, after workup and purification, 87 mg (44%) of the title compound were isolated as a colourless foam.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20](F)[CH:19]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:22]2[CH:23]=[C:18]([Br:17])[CH:19]=[CH:20][C:21]=2[N+:24]([O-:26])=[O:25])[CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCC1CCCNC1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCC1CCCN(c2cc(Br)ccc2[N+](=O)[O-])C1
Temperature: 25 °C

Procedure:
A solution of (2-Piperidin-3-yl-ethyl)-carbamic acid tert-butyl ester (0.087 mmol, 0.020 g) and 4-Bromo-2-fluoronitrobenzene (1.0 eq, 0.019 g), N,N-diisopropylethylamine (1.2 eq, 13.5 μL) in ACN (2 mL) was irradiated using microwave for 18 minutes at a temperature of 130° C. The solution was then cooled to room temperature and concentrated in vacuo to provide {2-[1-(5-Bromo-2-nitro-phenyl)-piperidin-3-yl]-ethyl}-carbamic acid tert-butyl ester. HPLC-MS RT=2.37 min, mass calculated for formula C18H26BrN3O4 427.11, observed LCMS m/z 428.22 and 430.11 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:24][C:25]([N:27]3[CH2:32][CH2:31]O[CH2:29][CH2:28]3)=[O:26])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=3)[C:3]=12.[F:33]C1C=C(C=CC=1)C(CC#N)=O.N1CCCC1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:24][C:25]([N:27]3[CH2:32][CH2:31][CH2:29][CH2:28]3)=[O:26])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:33])[CH:18]=3)[C:3]=12
Reactant: O=C(Cn1nc(-c2ccc(F)cc2)c2c(Cl)c(-c3ccccc3)nnc21)N1CCOCC1
Reactant: N#CCC(=O)c1cccc(F)c1
Solvent: C1CCNC1
Product: O=C(Cn1nc(-c2cccc(F)c2)c2c(Cl)c(-c3ccccc3)nnc21)N1CCCC1

Procedure:
Example 72 (Compound 79) was synthesised following a similar procedure outlined in Example 68 (Compound 75), using 3-fluorobenzoylacetonitrile instead of 4-fluorobenzoylacetonitrile in step 1 and pyrrolidine instead of morpholine in step 7. Compound 79 was obtained as a yellow solid (13.1 mg).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([O:12]CC3C=CC(OC)=CC=3)[C:7]=2[C:22]2[CH:23]=[C:24]([NH:33][CH2:34][CH2:35][NH:36]C(=O)OC(C)(C)C)[C:25]3[CH2:30][O:29][C:28](=[O:31])[NH:27][C:26]=3[N:32]=2)[CH2:3][CH2:2]1.[ClH:44]>O1CCOCC1>[ClH:44].[NH2:36][CH2:35][CH2:34][NH:33][C:24]1[C:25]2[CH2:30][O:29][C:28](=[O:31])[NH:27][C:26]=2[N:32]=[C:22]([C:7]2[C:8]([OH:12])=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[CH:23]=1
Reactant: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(NCCNC(=O)OC(C)(C)C)c3c(n2)NC(=O)OC3)cc1
Agent: Cl
Solvent: C1COCCO1
Product: NCCNc1cc(-c2c(O)cccc2OCC2CC2)nc2c1COC(=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
To a solution of tert-butyl 2-[(7-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl)amino]ethylcarbamate (0.032 g, 0.054 mmol) in 1,4-dioxane (1 mL) was added 4N HCl in 1,4-dioxane (1 mL). The mixture was stirred at room temperature overnight. The resulting precipitate was collected by filtration, washed with ethyl acetate to give 5-[(2-aminoethyl)amino]-7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one hydrochloride as a solid (0.013 g, yield; 59%).
Reaction SMILES: [CH3:1]/[C:2](/[CH:7]=[CH:8]/[C:9](/[F:25])=[C:10](\[CH3:24])/[CH:11]=[CH:12]/[C:13]1[C:18]([Cl:19])=[CH:17][C:16]([O:20][CH3:21])=[C:15]([CH3:22])[C:14]=1[Cl:23])=[CH:3]\[C:4]([OH:6])=O.C1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[CH2:38]([NH2:40])[CH3:39]>CN(C)C=O>[CH2:38]([NH:40][C:4](=[O:6])/[CH:3]=[C:2](\[CH3:1])/[CH:7]=[CH:8]/[C:9](/[F:25])=[C:10](\[CH3:24])/[CH:11]=[CH:12]/[C:13]1[C:18]([Cl:19])=[CH:17][C:16]([O:20][CH3:21])=[C:15]([CH3:22])[C:14]=1[Cl:23])[CH3:39]
Reactant: CCN
Reactant: COc1cc(Cl)c(/C=C/C(C)=C(F)/C=C/C(C)=C/C(=O)O)c(Cl)c1C
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CCNC(=O)/C=C(C)/C=C/C(F)=C(C)/C=C/c1c(Cl)cc(OC)c(C)c1Cl

Procedure:
In a manner similar to that described in Example 26, 385 mg. (1 mmole) of (2E,4E,6Z,8E)-3,7-dimethyl-6-fluoro-9-(2,6-dichloro-3-methyl-4-methoxyphenyl)-nonatetraenoic acid were suspended in 15 ml. of dry benzene and treated with oxalyl chloride and dimethylformamide, followed by dry ethylamine. Work-up as described in Example 26 afforded N-ethyl (2E,4E,6Z,8E)-3,7-diemthyl-6-fluoro-9-(2,6-dichloro-3-methyl-4-methoxyphenyl)-2,4,6,8-nonatetraenamide.