Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[OH-].[Na+].Cl.[C:10]([NH2:13])(=[NH:12])[CH3:11].C(Cl)Cl>O>[CH2:5]([O:4][C:2]([NH:13][C:10](=[NH:12])[CH3:11])=[O:3])[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: CC(=N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)NC(C)=N
Yield: 72 %

Procedure:
123 parts of ethyl chloroformate and 170.4 parts of 50% strength sodium hydroxide solution are added via two inlets to a mixture of 94.6 parts of acetamidine hydrochloride in 750 parts of methylene chloride and 250 parts of water, at from 10° to 15° C., in the course of 30 minutes, while stirring. After the mixture has been stirred at 25° C. for 15 minutes, the phases are separated. The aqueous phase is extracted with twice 100 parts of methylene chloride, and the solvent is removed from the organic extract to give 93.4 parts (72% of theory) of N-ethoxycarbonylacetamidine of melting point 111°-114° C.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:11]([C:12](SC)=[NH:13])[N:10]=[C:9]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])[S:8]1)=[N+:2]=[N-:3].[C:30]([NH:33]N)(=O)[CH3:31].O.[N:36]1C=CC=CC=1>>[N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:11]([C:12]2[NH:13][N:33]=[C:30]([CH3:31])[N:36]=2)[N:10]=[C:9]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])[S:8]1)=[N+:2]=[N-:3]
Reactant: CSC(=N)N1N=C(c2cc(F)ccc2F)SC1(CCCN=[N+]=[N-])c1ccccc1
Reactant: c1ccncc1
Reactant: CC(=O)NN
Solvent: O
Product: Cc1n[nH]c(N2N=C(c3cc(F)ccc3F)SC2(CCCN=[N+]=[N-])c2ccccc2)n1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of methyl 2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbimidothioate (0.034 g, 0.079 mmol) in 1 mL pyridine was added acetohydrazide (0.017 g, 0.240 mmol). The mixture was warmed to 80° C. and stirred for 16 hours, then treated with acetohydrazide (0.050 g) and stirred at reflux for 40 hours. The cooled mixture was treated with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic phases were washed with water (10 mL) and brine (10 mL), then dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (10-20% ethyl acetate/hexanes) to afford the desired product as a pale yellow solid, 0.010 g, 29%.
Reaction SMILES: [O:1]1[CH:6]([C:7]([OH:9])=[O:8])[CH:2]1[C:3]([OH:5])=O.[CH2:10]([K])[CH3:11].C(Cl)(=O)C(Cl)=O.[CH2:19]([NH2:25])[C:20]1[O:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([NH:25][C:3](=[O:5])[CH:2]1[O:1][CH:6]1[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:20]1[O:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)C1OC1C(=O)O
Reactant: NCc1ccco1
Reactant: CC[K]
Agent: O=C(Cl)C(=O)Cl
Product: CCOC(=O)C1OC1C(=O)NCc1ccco1
Yield: 47.7 %

Procedure:
Following the procedure of Example 1, monoethyl potassium epoxysuccinate (1.0 g) was successively treated with oxalyl chloride (0.75 g) and furfurylamine (0.98 g) to give 0.57 g of ethyl N-furfuryl-2,3-epoxysuccinamate (Compound No. 14) as colorless needles melting at 72°-73° C.
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][N:8]=[C:9]([C:13]1[O:14][CH:15]=[CH:16][CH:17]=1)[C:10]([OH:12])=[O:11].Cl[CH2:19][C:20]([NH2:22])=[O:21]>CS(C)=O>[NH2:22][C:20]([CH2:19][O:7][N:8]=[C:9]([C:13]1[O:14][CH:15]=[CH:16][CH:17]=1)[C:10]([OH:12])=[O:11])=[O:21]
Reactant: NC(=O)CCl
Reactant: O=C(O)C(=NO)c1ccco1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)CON=C(C(=O)O)c1ccco1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
To a solution of potassium t-butoxide (2.24 g) in dimethylsulphoxide (10 ml) was added a solution of 2-hydroxyimino-2-(fur-2-yl)acetic acid (syn isomer) (1.551 g) in dimethylsulphoxide (10 ml). The mixture was stirred for 30 minutes and a solution of chloroacetamide (0.935 g) in dimethylsulphoxide (10 ml) was added. The mixture was stirred for a further 2 hours, when a clear solution had formed. This solution was poured into ice-water (50 ml) and the mixture was extracted with ethyl acetate. The layers were separated and the aqueous layer was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extracts were washed with brine and dried, and the solvent was evaporated. The resulting yellow oil was triturated with dichloromethane to give the title compound (0.51 g, 24%), m.p. 143°-145°; λ max (EtOH) 275nm (ε 14,100).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:12](=[O:15])[CH:13]=[CH2:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Br:23][C:24]1[CH:25]=[CH:26][C:27]([CH:30]=[O:31])=[N:28][CH:29]=1.C(N(CC)CC)C>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C>[Br:23][C:24]1[CH:25]=[CH:26][C:27]([C:30](=[O:31])[CH2:14][CH2:13][C:12](=[O:15])[CH:11]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=2)[CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[N:28][CH:29]=1
Reactant: O=Cc1ccc(Br)cn1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(C)(=O)=O)cc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2ccc(Br)cn2)cc1
Temperature: 25 °C
Yield: 82.2 %

Procedure:
To a solution of 4-[4-(methylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (3.00 g) in ethanol (50 mL) were added 5-bromopyridine-2-carbaldehyde (2.10 g), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (280 mg) and triethylamine (560 μL), and the mixture was stirred with heating under reflux overnight. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (3.89 g, yield 82%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). MS: 510 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([S:10][C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:6][C:5]=1[OH:15])([O-])=O.C(OCC)(=O)C.C(O)(=O)C>[Fe].O>[NH2:1][C:4]1[CH:9]=[C:8]([S:10][C:11]([F:14])([F:12])[F:13])[CH:7]=[CH:6][C:5]=1[OH:15]
Reactant: O=[N+]([O-])c1cc(SC(F)(F)F)ccc1O
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1cc(SC(F)(F)F)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.7 %

Procedure:
A mixture of 5.49 g of 2-nitro-4-(trifluoromethylthio)phenol and 10 ml of ethyl acetate was added dropwise to a mixture, which was heated to 80° C., of 6.4 g of electrolytic iron, ml of acetic acid and 20 ml of water. The reaction mixture was stirred for 30 minutes. The mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water, a saturated aqueous solution of sodium hydrogencarbonate and a saturated sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 2.0 g of 2-amino-4-(trifluoromethylthio)phenol.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:16]2[CH:21]=[CH:20][C:19](B3OC(C)(C)C(C)(C)O3)=[CH:18][N:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:31][C:32]1[CH:37]=[CH:36][C:35](I)=[CH:34][N:33]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[Br:31][C:32]1[N:33]=[CH:34][C:35]([C:19]2[CH:18]=[N:17][C:16]([C:8]3[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=3)=[CH:21][CH:20]=2)=[CH:36][CH:37]=1
Reactant: CC1(C)OB(c2ccc(-c3nc4ccccc4n3-c3ccccc3)nc2)OC1(C)C
Reactant: Brc1ccc(I)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Brc1ccc(-c2ccc(-c3nc4ccccc4n3-c3ccccc3)nc2)cn1
Temperature: 80 °C
Yield: 61 %

Procedure:
A mixture of 1-phenyl-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-1H-benzo[d]imidazole (3 mmol), 2-bromo-5-iodopyridine (1.98 g, 7 mmol) (Compound 10), Pd(PPh3)4 (0.346 g, 0.3 mmol) and potassium carbonate (0.828 g, 6 mmol) in dioxane/water (50 mL/10 mL) was degassed and heated at about 80° C. overnight. The mixture was poured into ethyl acetate (250 mL), washed with water, then brine, dried over Na2SO4, loaded on silica gel and purified by flash column (hexanes/dichloromethane 1:1 to dichloromethane to dichloromethane/ethyl acetate 9:1 to 4:1). The desired fraction was collected and concentrated, then filtered to give a light yellow solid (Compound 11) (0.78 g, in 61% yield).
Reaction SMILES: CO[C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=2)=[CH:6][C:5]=1[CH2:19]Br.[CH2:22]([O:24][CH2:25][CH2:26][NH2:27])[CH3:23].C(N(CC)CC)C>C(O)C>[CH2:22]([O:24][CH2:25][CH2:26][N:27]1[CH2:19][C:5]2[C:4](=[CH:9][CH:8]=[C:7]([O:10][C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=3)[CH:6]=2)[C:3]1=[O:21])[CH3:23]
Reactant: CCOCCN
Reactant: COC(=O)c1ccc(Oc2ccc(OC)cc2)cc1CBr
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOCCN1Cc2cc(Oc3ccc(O)cc3)ccc2C1=O
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a mixture of 2-Bromomethyl-4-(4-methoxy-phenoxy)-benzoic acid methyl ester (0.2 grams, 0.57 mmol) and 3 mL of ethanol was added ethoxyethylamine (0.073 mL, 0.062 grams, 0.70 mmol) and triethylamine (0.098 mL, 0.071 grams, 0.7 mmol). After shaking for 4 hours at 50° C., the mixture was cooled to room temperature and concentrated under a stream of nitrogen. The residue was treated with methanesulfonic acid (3 mL) and methionine (0.13 grams). The mixture was shaken for 24 hours at room temperature and was then heated to 50° C. for 6 hours. After cooling to room temperature, the mixture was poured into aqueous 5 M sodium hydroxide with cooling in an ice bath, and the pH was adjusted to 8 with aqueous sodium bicarbonate. The aqueous phase was extracted 3 times with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Purification by radial chromatography (2 mm silica gel plate) eluting with 3% methanol-methylene chloride afforded 30 miligrams of 2-(2-Ethoxy-ethyl)-5-(4-hydroxy-phenoxy)-2,3-dihydro-isoindol-1-one as a colorless syrup. MS: 314.3 [M+H]+
Reaction SMILES: [CH:1]1([C@@:6]([OH:15])([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[C:7]([OH:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.O[C@H:29]1[CH:34]2[CH2:35][CH2:36][N:31]([CH2:32][CH2:33]2)[CH2:30]1.O>CN(C=O)C>[N:31]12[CH2:36][CH2:35][CH:34]([CH2:33][CH2:32]1)[C@H:29]([O:8][C:7](=[O:9])[C@:6]([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)([OH:15])[C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[CH2:30]2
Reactant: O=C(O)[C@](O)(c1cccs1)C1CCCC1
Reactant: O[C@@H]1CN2CCC1CC2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O[C@@H]1CN2CCC1CC2)[C@](O)(c1cccs1)C1CCCC1
Temperature: 25 °C
Yield: 47.7 %

Procedure:
510 mg (0.00225 mol) of (2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetic acid (obtained by hydrolysis of Intermediate I-15a) were dissolved in 7 ml of DMF. This solution was stirred at room temperature and 638 mg (0.00393 mol) of 1,1′-carbonyldiimidazol were added in several portions. After 4.5 h the reaction mixture was cooled to 0° C. and 315 mg (0.00248 mol) of (3S)-3-hydroxy-1-azabicyclo[2.2.2]octane and 83 mg (0.0021 mol) of HNa (60% dispersion in mineral oil) were added thereto. After stirring 112 h at room temperature the reaction mixture was treated with water and extracted three times with diethyl ether. The organic layers were combined, washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (eluent CHCl3/MeOH 15:1) to obtain 360 mg (47.6%) of the title product as an oil, structure confirmed by 1H-RMN.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([CH:11]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:12][C:13](O)=[O:14])([O:9][CH3:10])=[O:8]>>[CH3:10][O:9][C:7](=[O:8])[CH:11]([O:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:12][C:13]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:14]
Reactant: C1COCCN1
Reactant: COC(=O)C(CC(=O)O)Oc1ccccc1
Product: COC(=O)C(CC(=O)N1CCOCC1)Oc1ccccc1
Yield: 86 %

Procedure:
Using the mixed anhydride procedure described in Example 2,-morpholine was coupled to 3-carbomethoxy 3-phenoxypropionic acid to give the desired product in 86% yield, mp 83°-84° C. Anal. Calcd for C15H19NO5 : C, 61.42; H, 6.53; N, 4.78. Found: C, 61.47; H, 6.50; N, 4.61.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:43])=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[C:25]([CH2:27][CH2:28][CH3:29])[CH:24]=[CH:23][C:22]=4[S:30](=[O:37])(=[O:36])[NH:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:17][C:16]=3[F:38])[C:10]([CH2:39][CH2:40][CH2:41][CH3:42])=[N:9]2)[CH:7]=1.[C:44](Cl)(=[O:46])[CH3:45]>>[C:44]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:43])=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[C:25]([CH2:27][CH2:28][CH3:29])[CH:24]=[CH:23][C:22]=4[S:30](=[O:37])(=[O:36])[NH:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[CH:17][C:16]=3[F:38])[C:10]([CH2:39][CH2:40][CH2:41][CH3:42])=[N:9]2)[CH:7]=1)(=[O:46])[CH3:45]
Reactant: CCCCc1nn(-c2cc(N)ccc2Cl)c(=O)n1Cc1ccc(-c2cc(CCC)ccc2S(=O)(=O)NC(C)(C)C)cc1F
Reactant: CC(=O)Cl
Product: CCCCc1nn(-c2cc(NC(C)=O)ccc2Cl)c(=O)n1Cc1ccc(-c2cc(CCC)ccc2S(=O)(=O)NC(C)(C)C)cc1F
Yield: 88 %

Procedure:
The reaction of 2-(5-amino-2-chlorophenyl)-5-n-butyl-4-[[2'-(N-t-butylsulfamoyl)-3-fluoro-5'-n-propylbiphenyl-4-yl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step C) with acetyl chloride was carried out according to the procedure of Example 69, affording an 88% yield of the title compound as a cream-colored solid, mp 125°-128° C.; satisfactory purity by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 676 (M+Li)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11](C(OC)=O)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:7][N:6]=1)=[O:4].[OH-].[K+]>O>[C:3]([OH:4])(=[O:2])[CH3:5].[F:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][NH:11][C:8]2[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=2)=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(N(Cc2ccc(F)cc2)C(=O)OC)cn1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(=O)O
Product: O=C(O)c1ccc(NCc2ccc(F)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of 811 g of 5-(N-carbomethoxy-N-p-fluorobenzylamino)-pyridine-2-carboxylic acid methyl ester and 5,000 ml of 20% aqueous potassium hydroxide is refluxed for 5 hours while stirring under nitrogen. The solution is diluted with 12,000 ml of water, filtered and the filtrate acidified with 1,200 ml of 38% hydrochloric acid to pH=3.5 while cooling and stirring for an hour. The precipitate is collected, washed 4 times with a total of 2,000 ml of water and dried at 70° and 3 mm Hg. 1,351 g thereof are dissolved in 16,000 ml of boiling dioxane, the solution filtered, the filtrate concentrated to about 7,000 ml at 10 mm Hg and allowed to cool to room temperature while stirring. The crystals formed are collected and 1,046 g thereof dissolved in 5,000 ml of glacial acetic acid at 95%. The solution is allowed to stand overnight at room temperature, the precipitate collected and washed with 500 ml of glacial acetic acid, followed by 1,000 ml of diethyl ether, to yield the 5-(p-fluorobenzylamino)-pyridine-2-carboxylic acid acetate.
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1)=O.P(Cl)(Cl)([Cl:21])=O>>[ClH:21].[CH2:11]1[N:10]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[CH:1][C:17]3=[C:18]2[C:13](=[CH:14][CH:15]=[CH:16]3)[CH2:12]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=CNc1ccccc1N1CCc2ccccc21
Product: C1=Nc2ccccc2N2CCc3cccc1c32
Product: Cl
Reaction time: 18 h

Procedure:
A mixture of 14.0 g of 1-(2-formamidophenyl)indoline and 50 ml of fresh phosphorus oxychloride are stirred and heated under N2. The mixture is refluxed 4.0 hours, then left at room temperature 18 hours. Excess POCl3 is then removed, leaving a solid which is triturated and boiled with absolute ethanol. The mixture is stirred 1 hour to homogenize the fine solid, then filtered, washed with ethanol, and dried to afford 1,2-dihydroindolo[1,7-ab][1,5]benzodiazepine hydrochloride, m.p. 228°-230° C. dec.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=2[F:25])[N:3]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2([NH2:36])[CH2:35][CH2:34]2)=[CH:29][CH:28]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]2([NH:36][C:2]3[N:7]=[C:6]([O:8][CH2:9][C:10]([F:11])([F:13])[F:12])[N:5]=[C:4]([NH:14][C:15]4[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=4[F:25])[N:3]=3)[CH2:34][CH2:35]2)=[CH:31][CH:32]=1
Reactant: NC1(c2ccc(Cl)cc2)CC1
Reactant: COC(=O)c1ccc(Nc2nc(Cl)nc(OCC(F)(F)F)n2)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)c(F)c1
Temperature: 80 °C
Yield: 95.7 %

Procedure:
To a solution of methyl 4-(4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-3-fluorobenzoate (0.93 g, 2.45 mmol) in THF (10 mL) was added 1-(4-chlorophenyl)cyclopropanamine (0.5 g, 2.45 mmol) and Hunig's Base (1.71 mL, 9.8 mmol). The resulting mixture was refluxed at 80° C. for 16 hs. The precipitate was filtrated through a plug washing with THF to give a crude product that was purified by Biotage eluting with 4/1 to 3/2 hexane/ethyl acetate to give 1.2 g of methyl 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoro ethoxy)-1,3,5-triazin-2-ylamino)-3-fluorobenzoate as product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)[N:19]=3)[C:10]3[C:11]([N:17]=2)=[N:12][C:13](Cl)=[CH:14][CH:15]=3)=[CH:4][CH:3]=1.[CH:30]([Sn](CCCC)(CCCC)CCCC)=[CH2:31]>C1(C)C(C)=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)[N:19]=3)[C:10]3[C:11]([N:17]=2)=[N:12][C:13]([CH:30]=[CH2:31])=[CH:14][CH:15]=3)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2nc3nc(Cl)ccc3n2-c2ccnc(NC3CCCC3)n2)cc1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1C
Product: C=Cc1ccc2c(n1)nc(-c1ccc(F)cc1)n2-c1ccnc(NC2CCCC2)n1
Temperature: 160 °C
Yield: 87.4 %

Procedure:
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-chloroimidazo[4,5-b]pyridine (50 mg 0.12 mmol), vinyltributylstannane (4.3 ml 0.15 mmol) and PdCl2(PPh3)2 (8.6 mg 0.01 mmol) are dissolved in xylene (1 ml) and heated to 160° C. for 1 h under argon. The reaction mixture is purified over SiO2 (acetone/hexanes 15/85) to yield the title compound as colorless crystals (42 mg 86%)
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5]C[CH2:3][CH2:2]1.[CH3:8][O:9][CH:10](OC)[O:11][CH3:12].C[O-].[Na+]>OS(O)(=O)=O.CO>[CH3:8][O:9][C:10]1([O:11][CH3:12])[CH2:5][CH2:6][CH2:1][CH2:2][CH2:3]1
Reactant: O=C1CCCCC1
Reactant: COC(OC)OC
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC1(OC)CCCCC1

Procedure:
A mixture of cyclohexanone (52 ml, 0.5 mol), trimethylorthoformate (66 ml, 0.6 mol), methanol (51 ml, 1.26 mol) and concentrated H2SO4 (1 drop) was refluxed for 18 hours. A solution sodium methoxide in methanol was added until the mi was neutral, and the mixture was fractionally distilled. 1,1-Dimethoxycyclohexane was obtained from the fraction b.p. 162°-164° C. (50.6 g, 70%).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.[CH3:18][NH2:19]>C1COCC1>[CH3:18][NH:19][CH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCI)CC1
Reactant: CN
Solvent: C1CCOC1
Product: CNCCCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
A solution of 4-(3-iodoprop-1-yl)-1-tert-butoxycarbonyl-piperidine (728 mg, 2.06 mmol,) in 5.0 mL of THF was treated with 5.0 mL of methylamine (70% in water) and the resulting mixture was stirred at rt for 18 h. The mixture was partitioned between diethyl ether (50 mL) and water (50 mL) and the layers were separated. The organic layer was washed with 50 mL of sat'd NaCl, dried and concentrated to afford 457 mg (83%) of the title compound: 1H NMR (500 MHz, CDCl3): δ 1.05-1.68 (19H), 1.47 (s, 9H), 2.45 (s, 3H), 2.56-2.68 (4H), 4.00-4.15 (2H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1OS(C(F)(F)F)(=O)=O)[C:6]([O:8][CH3:9])=[O:7])#[N:2].[Br-].[CH:22]1([Zn+])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>O1CCCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C:6]([O:8][CH3:9])=[O:7])#[N:2]
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C#N)c1
Reactant: [Zn+]C1CCCCC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C2CCCCC2)c(C#N)c1
Temperature: 25 °C

Procedure:
To a solution of methyl 3-cyano-4-(trifluoromethylsulfonyloxy)benzoate (0.7 g, 2.26 mmol) in tetrahydrofuran (30 mL) was added 0.5 M cyclohexylzinc(II) bromide solution in tetrahydrofuran (13.6 mL, 6.8 mmol) and bis(tri-tert-butylphosphine)palladium (0.058 g, 0.113 mmol) at room temperature. The mixture was heated under reflux for 2 h. The mixture was allowed to cool to room temperature, quenched with saturated aqueous sodium bicarbonate solution and filtered through Celite®. The filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography to provide the title compound as an oil (0.24 g). 1H NMR (400 MHz, CDCl3) δ ppm 1.24-1.33 (m, 1H), 1.42-1.53 (m, 4H), 1.77-1.84 (m, 1H), 1.86-1.95 (m, 4H), 2.99-3.08 (m, 1H), 3.93 (s, 3H), 7.45 (d, J=8.34 Hz, 1H), 8.17 (dd, J=8.15, 1.71 Hz, 1H), 8.27 (d, J=1.52 Hz, 1H).
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([CH2:37][O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([C:46]#N)[CH:41]=1)[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[H-].C([Al+]CC(C)C)C(C)C.C[OH:59].[H-]>C1C=CC=CC=1.O>[CH2:1]([O:17][CH2:18][CH:19]([CH2:37][O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]=[O:59])[CH:41]=1)[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CO
Reactant: CCCCCCCCCCCCCCCCOCC(COCc1cccc(C#N)c1)OCCCCCCCCCCCCCCCC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCOCC(COCc1cccc(C=O)c1)OCCCCCCCCCCCCCCCC
Yield: 40 %

Procedure:
A solution of 1,2-di-O-(n-hexadecyl)-3-O-(3-cyanobenzyl)-glycerol (5.0 g., 7.6 mmoles) and diisobutylaluminum hydride (1.17 g., 8.2 mmoles) in benzene (25 ml.) was stirred for 16 hours at ambient temperature. The reaction mixture was treated with methanol (4.22 ml.) and water (2.5 ml.) and stirred to decompose unreacted hydride, and then filtered and extracted with benzene (3×25 ml.). The combined benzene extract was dried (Na2SO4), filtered and evaporated in vacuo to an oil, which was purified by silica gel chromatography (elution with benzene) [2.0 g., 40% yield, oil, ir (CHCl3) 1700 cm-1, n.m.r. (CDCl3) δ 10.1 (s, 1, --ArCHO)].