Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[CH2:4]([C:13]1(O)[CH2:18]CC[CH2:15][CH2:14]1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl>O>[CH3:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:13]1[CH:14]=[CH:15][C:1]([OH:3])=[CH:2][CH:18]=1
Reactant: CCCCCCCCCC1(O)CCCCC1
Reactant: C1CO1
Agent: Cl
Solvent: O
Product: CCCCCCCCCc1ccc(O)cc1
Reaction time: 1 h

Procedure:
The resulting 292.4 grams of NCH-1.5 was then mixed with 1.9 grams CaO in an autoclave and reacted with 220 grams of ethylene oxide (EO) fed into the autoclave over a six-hour period at a temperature of 150° C. and a pressure of 50 psi. Pressure and temperature were controlled by EO charge rate and rate of flow of cooling water. After all the oxide was charged, the reaction was held for one hour and the autoclave was placed under a 50 mm vacuum for thirty minutes and the vacuum was broken with nitrogen. The resulting 5 mole ethoxylate of nonylcyclohexyl alcohol (NCH-5 pk) was then cooled to 50° C. and the catalyst was neutralized with HCl to a pH balance between 6 and 7, inclusive.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=2[C:12]([O:14]C)=[O:13])[CH2:3]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([C:29]2[O:30][C:31]([CH3:36])=[C:32]([CH2:34]I)[N:33]=2)[CH:26]=[CH:27][CH:28]=1>>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([C:29]2[O:30][C:31]([CH3:36])=[C:32]([CH2:34][O:1][CH:2]3[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]4[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=4[C:12]([OH:14])=[O:13])[CH2:3]3)[N:33]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1c(C)cccc1COC1CCCC(O)C1
Reactant: COc1cccc(-c2nc(CI)c(C)o2)c1
Product: COc1cccc(-c2nc(COC3CCCC(OCc4cccc(C)c4C(=O)O)C3)c(C)o2)c1

Procedure:
Using methyl 2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate and 2-(3-methoxyphenyl)-4-iodomethyl-5-methyloxazole as starting materials in the procedure of Example XXXI, gave the product 53 of molecular weight 465.55 (C27H31NO6), MS(ESI): 466.37 (M+H+).
Reaction SMILES: [NH:1]([C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH3:12])=[C:5]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[N:4]=1)[NH2:2].[CH3:23][C:24](=O)[CH2:25][C:26](=O)[CH3:27]>>[CH3:23][C:24]1[CH:25]=[C:26]([CH3:27])[N:1]([C:3]2[N:11]=[C:10]3[C:6]([N:7]=[CH:8][N:9]3[CH3:12])=[C:5]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=3)[N:4]=2)[N:2]=1
Reactant: Cn1cnc2c(Nc3ccc([N+](=O)[O-])cc3)nc(NN)nc21
Reactant: CC(=O)CC(C)=O
Product: Cc1cc(C)n(-c2nc(Nc3ccc([N+](=O)[O-])cc3)c3ncn(C)c3n2)n1

Procedure:
Was prepared according to Example 9 from (2-hydrazino-9-methyl-9H-purin-6-yl)-(4-nitro-phenyl)-amine and 2,4-pentanedione.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH:8]([NH:9][C@@H:10]2[CH2:27][C@H:13]3[CH2:14][N:15](C(OCC4C=CC=CC=4)=O)[CH2:16][C@@:12]3([C:28]([N:30]3[CH2:39][CH2:38][C:37]4[N:36]=[CH:35][C:34]([C:40]([F:43])([F:42])[F:41])=[CH:33][C:32]=4[CH2:31]3)=[O:29])[CH2:11]2)[CH2:7][CH2:6][O:5][CH2:4]1>CO.[Pd]>[CH3:1][O:2][C@H:3]1[C@@H:8]([NH:9][C@@H:10]2[CH2:27][C@H:13]3[CH2:14][NH:15][CH2:16][C@@:12]3([C:28]([N:30]3[CH2:39][CH2:38][C:37]4[N:36]=[CH:35][C:34]([C:40]([F:43])([F:41])[F:42])=[CH:33][C:32]=4[CH2:31]3)=[O:29])[CH2:11]2)[CH2:7][CH2:6][O:5][CH2:4]1
Reactant: COC1COCCC1N[C@@H]1C[C@H]2CN(C(=O)OCc3ccccc3)C[C@@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Agent: [Pd]
Solvent: CO
Product: CO[C@@H]1COCC[C@@H]1N[C@@H]1C[C@H]2CNC[C@@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1

Procedure:
A solution of the product from Step B (1.53 g, 2.55 mmol) in methanol (18 mL) was bubbled with Ar for 15 min, and 10% Palladium on carbon (0.3 g) was added. The mixture was hydrogenated at 25 psi in Parr shaker overnight. Filtration and evaporation to dryness gave the product as yellow foam. 1H-NMR (400 MHz, CDCl3): δ 1.37-2.04 (m, 7H), 2.21 (d, J=5.8 Hz, 1H), 2.47-2.63 (m, 1H), 2.66-2.86 (m, 1H), 2.86-3.54 (m, 12H), 3.60 (br. s., 1H), 3.66-4.21 (m, 4H), 4.61-5.05 (m, 2H), 7.70 (br. s., 1H), 8.71 (br. s., 1H); LC/MS: C23H31F3N4O3: m/z 469.2 (M+H).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1.[C:9]([NH:11][C:12]([NH2:14])=[NH:13])#[N:10]>C(O)CCC>[ClH:1].[CH3:8][C:6]1[O:5][N:4]=[C:3]([NH:2][C:9]([NH:11][C:12]([NH2:14])=[NH:13])=[NH:10])[CH:7]=1
Reactant: N#CNC(=N)N
Reactant: Cc1cc(N)no1
Agent: Cl
Solvent: CCCCO
Product: Cc1cc(NC(=N)NC(=N)N)no1
Yield: 41.6 %

Procedure:
In a 2 liter three-necked flask are added 370 g of 3-amino-5-methyl-isoxazole hydrochloride, 231 g of 1-cyanoguanidine and 500 ml of butanol. The temperature is gradually raised to the refluxing temperature of the solvent, at which level it is then maintained during 10 minutes. The reaction mixture is allowed to cool and, after incipient crystallization, is poured over 2 liters of butanol. After complete crystallization, the resulting material is filtered, the solid is washed with 300 ml of isopropanol. The solid is recrystallized from 1 liter 90% ethanol, to give 250 g of (5-methyl-isoxazol-3-yl)biguanide hydrochloride. M.p. (Kofler) = 210°-212° C. M.p. (cap.) = 195°-196° C. with introduction at 185° C. and heating at a rate of 2° C./minute.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].C(O)(=O)C.[CH:16]([NH2:18])=[NH:17].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:11][C:6]1[CH:7]=[C:8]([F:10])[CH:9]=[C:2]2[C:3]=1[C:4]([NH2:5])=[N:17][CH:16]=[N:18]2
Reactant: N=CN
Reactant: N#Cc1c(F)cc(F)cc1F
Solvent: CC(=O)O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncnc2cc(F)cc(F)c12
Temperature: 100 °C
Reaction time: 16 h

Procedure:
2,4,6-Trifluoro-benzonitrile (3.59 mmol, 500 mg) is dissolved in DMA (5 mL) and then formamidine acetate is added (3.59 mmol, 373.75 mg) followed by DIEA (10.78 mmol, 1.39 g). The reaction is stirred for 16 hr at 100° C. A solid forms, is collected by filtration and the solid is washed with CH2Cl2. This gives desired product 5,7-Difluoro-quinazolin-4-ylamine (227 mg, LC/MS m/z=182 [M+H]+) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N:11]2[C:20](=[O:21])[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[C:12]2=[O:13])=[C:4]([F:22])[CH:3]=1.C(OCC)(=O)C>C(O)(=O)C.[Fe]>[NH2:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([F:22])=[C:5]([N:11]2[C:20](=[O:21])[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[C:12]2=[O:13])[CH:6]=1
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc([N+](=O)[O-])c(Cl)cc1F
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Reaction time: 0.17 h

Procedure:
Iron powder (7.30 g, 130.7 mmol) is added portionwise to a mixture of N-(4-chloro-2-fluoro-5-nitrophenyl)-1-cyclohexene-1,2-dicarboximide (10.6 g, 32.7 mmol) in acetic acid (100 mL) at 65° C. After the addition is complete, the reaction mixture is stirred for 10 minutes, and filtered through diatomaceous earth. The filtrate is concentrated in vacuo to obtain a dark solid. A mixture of the solid in an ethyl acetate/saturated sodium hydrogen carbonate solution is filtered through diatomaceous earth, and the phases are separated. The organic phase is washed sequentially with saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title product as a yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:25])[C@@H:4]([N:12]1[CH2:16][C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][C:13]1=[O:24])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O>[CH:6]1([CH2:5][C@H:4]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][C:13]2=[O:24])[C:3]([OH:25])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2ccccc2)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@H](CC1CCCCC1)N1CC(Oc2ccccc2)=CC1=O
Temperature: 23 °C
Reaction time: 2 h
Yield: 8.6 %

Procedure:
To a stirred solution of (S)-3-cyclohexyl-2-(2-oxo-4-phenoxy-2,5-dihydro-pyrrol-1-yl)-propionic acid methyl ester (0.205 g, 0.006 mol) in tetrahydrofuran-water (3:1, 5 mL) was added lithium hydroxide (504 mg, 0.012 mol). The reaction mixture was stirred at 23° C. for 2 h. After this time, the mixture was concentrated and the reaction mixture was diluted with water. The reaction mixture was acidified with 2N hydrochloric acid, during which time precipitation occurred. The precipitate was removed by filtration, washed with cold water and dried in vacuo to obtain (S)-3-cyclohexyl-2-(2-oxo-4-phenoxy-2,5-dihydro-pyrrol-1-yl)-propionic acid (170 mg, 86%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].C(#N)C.[Cl:10][CH2:11][C:12](Cl)=[O:13]>CO>[Cl:10][CH2:11][C:12]([NH:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5])=[O:13]
Reactant: NCC(O)CO
Reactant: O=C(Cl)CCl
Solvent: CO
Solvent: CC#N
Product: O=C(CCl)NCC(O)CO
Temperature: -10 °C
Reaction time: 15 h
Yield: 64.9 %

Procedure:
3-Amino-1,2-propanediol (16.8 g, 184 mmol) was dissolved in MeOH (90 mL) at RT and the solution was diluted with ACN (acetonitrile) (550 mL) TEA (30.5 mL, 219 mmol) was added and the reaction mixture was cooled to −10° C. Chloroacetyl chloride (22.2 g, 15.6 mL, 197 mmol) was added dropwise at −10° C. for 2 h under nitrogen atmosphere and further maintained at −10° C. for 1 h and the reaction mixture was allowed to RT and stirred overnight (15 h). The solvents were removed under vacuo. The residue was purified by flash column chromatography (normal phase, gradient 1 percent to 20 percent MeOH in EtOAc) to afford the title compound (20 g) as a colorless oil m/z 168.
Reaction SMILES: Br[C:2]1[C:3]([CH3:30])=[C:4]([C:11]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18](=[O:23])[N:17]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:16]3=[O:29])=[O:12])[N:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2.[C:31]([O:35][C:36](=[O:54])[CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42](B2OC(C)(C)C(C)(C)O2)=[CH:41][CH:40]=1)([CH3:34])([CH3:33])[CH3:32].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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].COCCOC>[CH3:28][O:27][C:25](=[O:26])[CH2:24][N:17]1[C:16](=[O:29])[C:15]2[C:20](=[CH:21][CH:22]=[C:13]([C:11]([C:4]3[N:5]4[C:10]([CH:9]=[CH:8][CH:7]=[CH:6]4)=[C:2]([C:42]4[CH:41]=[CH:40][C:39]([O:38][CH2:37][C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:54])=[CH:44][CH:43]=4)[C:3]=3[CH3:30])=[O:12])[CH:14]=2)[NH:19][C:18]1=[O:23]
Reactant: CC(C)(C)OC(=O)COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: COC(=O)Cn1c(=O)[nH]c2ccc(C(=O)c3c(C)c(Br)c4ccccn34)cc2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Product: COC(=O)Cn1c(=O)[nH]c2ccc(C(=O)c3c(C)c(-c4ccc(OCC(=O)OC(C)(C)C)cc4)c4ccccn34)cc2c1=O
Yield: 42.5 %

Procedure:
Methyl {6-[(1-bromo-2-methylindolizin-3-yl)carbonyl]-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl}acetate [described in Step 1.5.] (0.85 g; 1.81 mmol), tert-butyl[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenoxy]acetate [CAS 769968-17-4; D. Fan et al, Journal of Organic Chemistry, 2007, 72(14), 5350-5357] (0.91 g; 2.71 mmol), 5.4 mL of a molar solution of potassium phosphate, 17 mL of 1,2-dimethoxyethane and the catalyst PdCl2(dppf) (198 mg; 0.27 mmol) are successively introduced into a reactor, under argon. The mixture is heated at reflux for 2 hours under argon. The reaction medium is filtered through Celite. The filtrate is diluted with ethyl acetate and the solution is washed with a saturated solution of potassium hydrogen carbonate and with a saturated solution of sodium chloride, and then dried over sodium sulphate and concentrated to dryness. The residue obtained is purified by flash chromatography on silica (DCM/EtOH: 100/0 to 80/10). 0.46 g (42%) of a yellow-red powder is obtained.
Reaction SMILES: [F:1][C:2]1[C:24]([OH:25])=[CH:23][CH:22]=[C:21]([F:26])[C:3]=1[NH:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH:13]=1)[C:9]#[N:10].C([O-])([O-])=O.[K+].[K+].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].O>CN(C=O)C>[C:9]([C:8]1[CH:7]=[C:6]([CH2:5][NH:4][C:3]2[C:2]([F:1])=[C:24]([CH:23]=[CH:22][C:21]=2[F:26])[O:25][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH:11]=1)#[N:10]
Reactant: CCOC(=O)CBr
Reactant: N#Cc1cc(CNc2c(F)ccc(O)c2F)cc(-c2cccc(F)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(F)c(NCc2cc(C#N)cc(-c3cccc(F)c3)c2)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
To a solution of 3-[(2,6-Difluoro-3-hydroxy-anilino)methyl]-5-(3-fluorophenyl)benzonitrile (280 mg, 0.8 mmol, 1 eq) in DMF (10 mL) was added K2CO3 (550 mg, 4 mmol, 5 eq). The solution was stirred at room temperature for 30 min, then ethyl bromoacetate (200 mg, 1.2 mmol, 1.5 eq) was added dropwise. The reaction was stirred overnight, then water was added and the aqueous phase extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc, 15:1) to give the title compound as colorless oil (300 mg, 86%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:17][CH3:18])[C:11]2([C:14]([OH:16])=O)[CH2:13][CH2:12]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.CCOC(OC(OCC)=O)=O.[CH3:30][O:31][C:32]1[CH:37]=[C:36]([CH2:38][NH2:39])[CH:35]=[C:34]([C:40]2[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][CH:41]=2)[N:33]=1>C1COCC1>[Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:17][CH3:18])[C:11]2([C:14]([NH:39][CH2:38][C:36]3[CH:35]=[C:34]([C:40]4[CH:41]=[CH:42][C:43]([C:46]([F:47])([F:48])[F:49])=[CH:44][CH:45]=4)[N:33]=[C:32]([O:31][CH3:30])[CH:37]=3)=[O:16])[CH2:12][CH2:13]2)(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: CCN(C1(C(=O)O)CC1)S(=O)(=O)c1ccc(Cl)s1
Reactant: COc1cc(CN)cc(-c2ccc(C(F)(F)F)cc2)n1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: CCN(C1(C(=O)NCc2cc(OC)nc(-c3ccc(C(F)(F)F)cc3)c2)CC1)S(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Yield: 19.8 %

Procedure:
A solution of acid 18 (0.3 g, 0.97 mmol) in THF (15 mL) was added with DEPC (0.19 mL, 1.3 mol eq) and the mixture was stirred at room temperature several minutes. Then [2-methoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 27I (0.22 g, 1.1 mol eq) and a catalytic amount of TEA were added, then the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, water was added to the residue that is extracted with EtOAc (3×30 mL) and washed with brine (1×30 mL). The separated organic phase was dried over Na2SO4, evaporated to dryness and the residue was purified by flash chromatography (1/1 EtOAc/Petroleum ether) to afford a white solid (110 mg) after crystallization from ethyl ether. Yield=26%. 1HNMR (DMSO, 400 MHz) δ 1.21 (t, 5H, J=6.2), 1.41 (m, 2H), 3.54 (m, 2H), 3.94 (s, 3H), 4.18 (bs, 2H), 6.70 (s, 1H), 7.25 (d, 1H, J=2.1), 7.57 (d, 2H, J=2.3), 7.84 (d, 2H, J=8), 8.27 (m, 3H). [M+1] 574.66 (C24H23ClF3N3O4S2 requires 574.04).
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].[C:14](=[O:20])=[N:15][S:16]([Cl:19])(=[O:18])=[O:17]>CCOCC>[CH3:12][CH:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[NH:6][C:14]([NH:15][S:16]([Cl:19])(=[O:18])=[O:17])=[O:20])[CH3:13]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CCOCC
Product: CC(C)c1cccc(C(C)C)c1NC(=O)NS(=O)(=O)Cl
Temperature: -15 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
A solution of 2,6-diisopropylaniline (30.0 g, 0.169 moles) in 150 mL Et2O was added dropwise to a solution of N-chlorosulfonyl isocyanate (14.73 mL, 0.169 moles) in 100 mL Et2O at -15° C. (acetone/ice bath) under an atmosphere of N2. The resulting off-white suspension was stirred at -15° C. for 1 hour and the solid was collected by vacuum filtration. The solid was washed with hexanes and air dried to give 53.79 g (99%) of the title compound as a white solid, mp 130°-134° C.
Reaction SMILES: [CH2:1]([CH:3]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]2[C:5](=[C:6]([Cl:21])[C:7]([Cl:20])=[C:8]([O:18]C)[CH:9]=2)[C:4]1=[O:22])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-]>CCCCCCC>[CH2:1]([CH:3]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]2[C:5](=[C:6]([Cl:21])[C:7]([Cl:20])=[C:8]([OH:18])[CH:9]=2)[C:4]1=[O:22])[CH3:2]
Reactant: CCC1C(=O)c2c(cc(OC)c(Cl)c2Cl)C1c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCCC
Product: CCC1C(=O)c2c(cc(O)c(Cl)c2Cl)C1c1ccccc1

Procedure:
A stirred mixture of 2-ethyl-3-phenyl-5-methoxy-6,7-dichloro-1-indanone (13.9 g., 0.0415 mole) and aluminum chloride (13.6 g., 0.104 mole) in heptane (120 ml. is refluxed for five hours then cooled. The heptane is decanted, and the residue is treated with ice water (100 ml.) containing hydrochloric acid. The gum which separates is extracted into ether, washed with water, dried over magnesium sulfate, and the ether evaporated at reduced pressure affording 11.3 g. of 2-ethyl-3-phenyl-5-hydroxy-6,7-dichloro-1-indanone which melts at 220°-222° C. after recrystallization from methanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:12](S(C3C=CC(C)=CC=3)(=O)=O)[CH:11]=[CH:10][C:5]2=[N:6][C:7]=1[C:8]#[N:9].C1COCC1.[OH-].[Na+].Cl>CO>[Br:1][C:2]1[CH:3]=[C:4]2[NH:12][CH:11]=[CH:10][C:5]2=[N:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(C#N)c(Br)cc32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1nc2cc[nH]c2cc1Br
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 6-bromo-1-tosyl-1H-pyrrolo[3,2-b]pyridine 5-carbonitrile (2.46 g, 6.54 mmol), THF (6 mL) and MeOH (6 mL) was added 1N NaOH (3 mL). The reaction mixture was stirred for 30 minutes and then neutralized with 1N HCl and extracted with EtOAc (2×). The organic phase was dried over MgSO4 and concentrated in vacuo to give crude intermediate 6-bromo-1H-pyrrolo[3,2-b]pyridine 5-carbonitrile, which was subsequently dissolved in DMF (10 mL) and cooled to 0° C. Sodium hydride (60%, 314 mg, 7.85 mmol) was added, and the reaction mixture was stirred 30 minutes. Next, iodomethane (0.49 mL, 7.85 mmol) was added, and the reaction mixture was stirred for 30 minutes while warming to RT. The solution was subsequently diluted with EtOAc (100 mL), quenched and washed with brine. The aqueous layer was back-extracted with EtOAc (2×). The combined organic layers were dried over MgSO4, concentrated in vacuo, and purified by silica gel chromatography (2% MeOH/DCM) to give the title compound as a white solid (1.05 g, 68%). 1H NMR (500 MHz, CDCl3) δ ppm 7.90 (s, 1H), 7.43 (d, 1H, J=3.5 Hz), 6.76 (d, 1H, J=3.5 Hz), 3.85 (s, 3H); ESI-MS m/z [M+H]+ calc'd for C9H6BrN3, 236, 238; found 236, 238.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([NH:19][NH2:20])=[O:18])=[C:4]2[CH2:3]1.[Cl:21][CH2:22][C:23](OC(=O)CCl)=O>CN(C)C=O>[Cl:21][CH2:22][C:23]1[O:18][C:17]([C:16]2[N:15]=[CH:14][N:5]3[C:6]4[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=4[C:8](=[O:9])[N:2]([CH3:1])[CH2:3][C:4]=23)=[N:19][N:20]=1
Reactant: O=C(CCl)OC(=O)CCl
Reactant: CN1Cc2c(C(=O)NN)ncn2-c2ccccc2C1=O
Solvent: CN(C)C=O
Product: CN1Cc2c(-c3nnc(CCl)o3)ncn2-c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.3 %

Procedure:
9.4 g (34.7 mmol) of 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid hydrazide were stirred at room temperature for 3 hours in 75 ml of N,N-dimethyl- formamide with 27.1 g (41.5 mmol) of chloroacetic anhydride. After evaporating the solvent the residue was stirred at room temperature overnight with 75 ml of a 10% solution of phosphorus pentoxide in methanesulphonic acid. The reaction mixture was treated with ice, made alkaline with conc. sodium hydroxide solution and extracted four times with methylene chloride. By drying the organic phase over magnesium sulfate, evaporation of the solvent and chromatography of the residue on silica gel while eluting with ethyl acetate there were obtained 6.9 g (61%) of 3-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one of m.p. 221°-222°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7](O)[CH:6]=[CH:5]2.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.S(=O)(O)[O-].[Na+]>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[CH:6]=[CH:5]2
Reactant: Nc1ccc(O)cc1
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: Oc1ccc(Nc2ccc3cc(Br)ccc3c2)cc1
Yield: 70 %

Procedure:
A mixture of 334 mg (1.50 mmol, Aldrich) of 6-bromo-2-naphthol, 218 mg (2.00 mmol, Aldrich) of 4-aminophenol, and 1.0 g of sodium bisulfite in 5 ml of H2O was heated to 150° in a closed Pyrex tube for 76 hours. The reaction was cooled, added to 25 ml of H2O and extracted with 25 ml of ethyl acetate. The organic extract was dried (MgSO4) and concentrated in vacuo to give a solid. The crude solid was purified by flash chromatography (10×5.0 cm, 1: EtOAc/petroleum ether) followed by recrystallization (EtOAc/petroleum ether) to afford 330 mg (70%) of title compound as small grey-white crystals, m.p. 179°-180°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([C:15]([CH3:17])=[O:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O>[Ni].C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([C:15]([CH3:17])=[O:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Agent: [Ni]
Solvent: CCO
Product: CC(=O)c1ccc(-c2ccc(N)cc2)o1
Reaction time: 1 h
Yield: 81.5 %

Procedure:
A mixture of 58 g (0.25 mole) of methyl 5-(p-nitrophenyl)-2-furyl ketone, 2 tsp. of Raney Ni and 750 ml of ethanol was shaken under hydrogen pressure for one hour with the theoretical amount of H2 being absorbed. An additional 2000 ml of ethanol was added to the reaction mixture. The mixture was heated to reflux and the catalyst was removed by filtration. The filtrate was treated with ethereal HCl and the resulting solid was filtered and air-dried to yield 41 g (8.15%) of methyl 5-(p-aminophenyl)-2-furyl ketone. An analytical sample was prepared by drying a sample at room temperature in the vacuum pistol, m.p. scinters above 160°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:15]=[C:16]([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[CH:17]=[C:18]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH:19]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:15]=[C:16]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH:17]=[C:18]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH:19]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCc1cc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc(Cc2ccc(F)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCc1cc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc(Cc2ccc(F)cc2)c1
Yield: 82.6 %

Procedure:
A mixture of ethyl 3-[2-[(4-chlorophenyl)sulphonylamino]ethyl]-5-[(4-fluorophenyl)methyl]benzenepropanoate (500 mg), 2N sodium hydroxide solution (1.5 ml) and methanol (5 ml) was heated under reflux for 1 hour and then evaporated. The residue was dissolved in a small volume of water, and the solution was made acidic with 2N hydrochloric acid. The resulting mixture was extracted several times with ether and the combined extracts were dried (MgSO4) and evaporated to give the title compound,(390 mg), m.p. 85°-87° C. Found: C,60.78A H,5.06; N,2.87. C24H33ClFNO4S requires C,60.56; H,4.87; N,2.94%.