Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:20])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=[O:13])[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[C:3]1([F:19])[F:18].C(O)C.C(O)(C)C.CCOCC>O1CCCC1.O1CCOCC1>[F:1][C:2]1([F:20])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]([OH:13])[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[C:3]1([F:18])[F:19]
Reactant: O=C1c2ccccc2C(F)(F)C(F)(F)c2ccccc21
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CC(C)O
Product: OC1c2ccccc2C(F)(F)C(F)(F)c2ccccc21

Procedure:
In carrying out the process of the present invention, Compound I hereinabove, 10,11-dihydro-10,10,11,11tetrafluoro-5H-dibenzo[a,d]cyclohepten-5-one, or a derivative thereof, is contacted with a reducing agent selected from alkali or alkaline earth metal borohydrides, dissolved in a solvent relatively inert under reaction conditions comprising either a loweralkanol such as ethyl alcohol or isopropyl alcohol or an ether, such as dioxane or tetrahydrofuran, at a temperature of from 0° C. to the reflux temperature of the solvent for a period of from 1-6 hours to produce a corresponding 10,11-dihydro-10,10,11,11tetrafluoro-5H-dibenzo[a,d]cyclohepten-5-ol which, in turn, is treated with a halide compound selected from hydrogen chloride or hydrogen bromide, a phosphorous halide such as phosphorous pentachloride, or thionyl chloride. In carrying out the steps of the reaction, the cyclohepten-5-ol compound is treated with stirring at a temperature between about 0°-50° C. with thionyl chloride in at least equimolar amounts to produce the corresponding 5-chloro-10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene. The chloro substituent of the dibenzocycloheptene compound is then replaced with a malonic ester substituent by contacting the 5-halo compound with a loweralkyl ester of malonic acid in the presence of a strong base such as sodium hydride at a temperature of from 0° C. to 100° C. Preferably the malonate ester is first mixed with sodium hydride in mineral oil and the solution of malonic ester is then treated with an appropriate amount of the 5-chloro-10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene to produce the desired 10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-malonate dialkyl ester. The malonate ester is then decarboxylated by heating with a solution of a strong base, advantageously an alcoholic solution of an alkali metal hydroxide, to produce a corresponding 10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-acetic acid.
Reaction SMILES: CCN(CC1C=CC=CC=1)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.Cl.[N:32]1([CH2:38][CH2:39][CH2:40][O:41][C:42]2[CH:59]=[CH:58][C:45]([C:46]([N:48]3[CH2:56][C:55]4[C:50](=[CH:51][CH:52]=[C:53]([NH2:57])[CH:54]=4)[CH2:49]3)=[O:47])=[CH:44][CH:43]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.Br[CH2:61][CH2:62][CH2:63][C:64]([Cl:66])=[O:65]>C(Cl)Cl>[ClH:66].[N:32]1([CH2:38][CH2:39][CH2:40][O:41][C:42]2[CH:43]=[CH:44][C:45]([C:46]([N:48]3[CH2:56][C:55]4[C:50](=[CH:51][CH:52]=[C:53]([N:57]5[CH2:61][CH2:62][CH2:63][C:64]5=[O:65])[CH:54]=4)[CH2:49]3)=[O:47])=[CH:58][CH:59]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: Nc1ccc2c(c1)CN(C(=O)c1ccc(OCCCN3CCCCC3)cc1)C2
Reactant: O=C(Cl)CCCBr
Agent: C=Cc1ccc(C=C)cc1
Agent: CCN(CC)Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: C=Cc1ccccc1
Product: O=C(c1ccc(OCCCN2CCCCC2)cc1)N1Cc2ccc(N3CCCC3=O)cc2C1
Reaction time: 2 h

Procedure:
A stirred mixture of diethylaminomethyl polystyrene (247 mg, 3.2 mmol/g) and N-[4-(3-piperidin-1-ylpropoxy)-benzoyl]-5-aminoisoindoline hydrochloride (E13) (150 mg) in DCM (5 ml) at rt was treated with 4-bromobutanoyl chloride (0.05 ml) for 30 mins. The mixture was filtered and evaporated. The residue was redissolved in DMF (5 ml) and treated with sodium hydride (18 mg of a 60% suspension in mineral oil) and stirred for 2 h. A further portion of sodium hydride (18 mg) was added and the mixture stirred for 1 h. The reaction was partitioned between EtOAc (10 ml) and saturated sodium hydrogen carbonate solution (10 ml). The organic layer was washed with water (2×10 ml), brine (10 ml), dried (MgSO4) and evaporated. After chromatography [silica gel, step gradient 0-10% MeOH (containing 10% 0.880 ammonia solution) in DCM)] fractions containing the required product were evaporated, then redissolved in DCM, treated with excess 4M HCl in dioxan and evaporated. Crystallisation from EtOH/diethyl ether afforded the title compound (E15) (77 mg). MS electrospray (+ion) 448 (MH+). 1H NMR δ (DMSO-d6): 10.15 (1H, s), 7.60 (4H, m), 7.34 (1H, m), 7.0 (2H, d, J=8.5 Hz), 4.80 (4H, m), 4.13. (2H, t, J=6 Hz), 3.80 (2H, m), 3.05-3.58 (6H, m), 2.91 (2H, m), 2.21 (2H, m), 2.06 (2H, m), 1.28-1.90 (6H, m).
Reaction SMILES: [CH:1]1([CH3:13])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([C:10](Cl)=[O:11])[CH2:2]1.[CH3:14][CH:15]([OH:18])[CH2:16][NH2:17]>>[OH:18][CH:15]([CH3:14])[CH2:16][NH:17][C:10]([CH:3]1[CH:4]([CH:7]([CH3:9])[CH3:8])[CH2:5][CH2:6][CH:1]([CH3:13])[CH2:2]1)=[O:11]
Reactant: CC(O)CN
Reactant: CC1CCC(C(C)C)C(C(=O)Cl)C1
Product: CC(O)CNC(=O)C1CC(C)CCC1C(C)C

Procedure:
p-Menth-3-oyl chloride (3.0 g.) was reacted with isopropanolamine (3.0 g.) according to the procedure of Example 3. The product, N-(2-hydroxy-n-propyl)-p-menthane-3-carboxamide, was obtained as a viscous oil, boiling point: 184°/0.1 mm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH3:11])=[CH:5][CH:4]=1.[CH:27](=O)[CH2:28][CH3:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([N:12]([CH2:13][CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:18][CH2:19]2)[CH2:27][CH2:28][CH3:29])[CH3:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(CC(C)NCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCN(CC1CCN(C(=O)OC(C)(C)C)CC1)C(C)Cc1ccc(OC)cc1
Temperature: 22 °C
Reaction time: 16 h
Yield: 95.8 %

Procedure:
A mixture of N-[2-(4-methoxyphenyl)-1-methylethyl]-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]amine (0.87 grams, 2.4 mmole), propionaldehyde (0.2 ml, 2.5 mmole) and sodium triacetoxyborohydride (0.763 grams, 3.6 mmole) in 1,2-dichloroethane (25 ml) was stirred at 22° C. for 16 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between 100 ml ethyl ether and 25 ml 10% aqueous sodium carbonate. The dried (anhydrous magnesium sulfate) and concentrated organic phase was subjected to flash chromatography over silica gel 230-400 mesh eluting with 10% ethyl acetate/hexane. Product fractions were concentrated under reduced pressure to give N-[2-(4-methoxyphenyl)-1-methylethyl]-N-propyl-(1-tert-butoxycarbonylpiperidin-4-ylmethyl)amine as a syrup (0.93 grams, 95%), M+H 405.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20](F)=[N:21][CH:22]=3)[C:9]=2[F:24])[CH:5]=[CH:6][CH:7]=1.[NH:25]1[CH2:28][CH2:27][CH2:26]1.N12CCCN=C1CCCCC2.Cl>O>[N:25]1([C:20]2[CH:19]=[CH:18][C:17]([CH2:16][C:10]3[C:9]([F:24])=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[C:13]([O:14][CH3:15])=[CH:12][CH:11]=3)=[CH:22][N:21]=2)[CH2:28][CH2:27][CH2:26]1
Reactant: COc1ccc(Cc2ccc(F)nc2)c(F)c1-c1cccc(Cl)c1
Reactant: C1CNC1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: COc1ccc(Cc2ccc(N3CCC3)nc2)c(F)c1-c1cccc(Cl)c1
Temperature: 160 °C
Yield: 93.9 %

Procedure:
In an 8 mL vial equipped with a stir bar was placed 5-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-fluoro-pyridine (P-456,150 mg, 0.434 mmol), azetidine (88.0 uL, 1.30 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (306 uL, 2.17 mmol). The mixture was heated to 160° C. for 1 hour and then cooled to room temperature. The reaction mixture was treated with water (4 mL) and 1M HCl (6 mL). The aqueous portion was extracted with dichloromethane (2×30 mL), the organic portions were combined, washed with brine (15 mL), dried (MgSO4) and concentrated to produce 156 mg of P-569 as a white solid in 94% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])=[CH:4][CH:3]=1.[C:19]([CH2:23][CH2:24][C:25](Cl)=[O:26])([O:21][CH3:22])=[O:20]>N1C=CC=CC=1>[CH3:22][O:21][C:19](=[O:20])[CH2:23][CH2:24][C:25]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][NH:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])=[O:7])=[CH:17][CH:18]=1)=[O:26]
Reactant: COC(=O)CCC(=O)Cl
Reactant: CC(C)(C)OC(=O)NNC(=O)c1ccc(N)cc1
Solvent: c1ccncc1
Product: COC(=O)CCC(=O)Nc1ccc(C(=O)NNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 2-(4-aminobenzoyl)hydrazinecarboxylate (500 mg, 1.99 mmol) in anhydrous pyridine (10 mL) was added dropwise 3-carbomethoxypropionyl chloride (Fluka) (300 μL) at rt. After 60 min, aminomethyl resin (Polymers Laboratories PL-AMS, 1.96 mmol/g, 400 mg) was added and the resulting mixture was stirred overnight at rt. After filtration and rinsing the resin, water (80 mL) was added into the filtrate and a white solid precipitated out. Filtration and washing with water gave a white solid, which was dried under vacuo at 70° C. for 2 hrs. The title compound (461 mg) was obtained as a white solid (63%) in 96.0% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: FC(F)(F)[C:3]([NH:5][C:6]1[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:17]2[CH:22]=[CH:21][C:20](C(=O)C(F)(F)F)=[CH:19][CH:18]=2)[N:7]=1)=[O:4].C(O)=O.ClC1C=C(N2CC(C)C(NC=O)=N2)C=CC=1Cl.CCCCCC>ClCCl>[C:17]1([N:8]2[CH:9]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:10][C:6]([NH:5][CH:3]=[O:4])=[N:7]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(NC1=NN(c2ccc(C(=O)C(F)(F)F)cc2)C(c2ccccc2)C1)C(F)(F)F
Agent: CC1CN(c2ccc(Cl)c(Cl)c2)N=C1NC=O
Solvent: O=CO
Solvent: ClCCl
Solvent: CCCCCC
Product: O=CNC1=NN(c2ccccc2)C(c2ccccc2)C1
Reaction time: 0.5 h

Procedure:
A mixture of 5.0 g. of 3-amino-1,5-diphenyl-2-pyrazoline (prepared as described in Example 4) and 25.0 ml. of a mixture of formic acid and acetic anhydride (Example 15) is allowed to remain at room temperature for 30 minutes. Then hexane is added and the mixture is filtered. The solid obtained is dissolved in dichloromethane. The solution is columnized and recrystallized as described in Example 14 (B) to yield 3.55 g. of the product of the Example as off-white needles, m.p. 158°-160° C.
Reaction SMILES: [C:1]1([C:7]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](=[O:36])[CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[CH:21][CH:20]=1.[OH-].[K+]>>[CH3:35][O:34][C:31]1[CH:30]=[CH:29][C:28]([C:27]2[C:26](=[O:36])[C:25]([C:22]3[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=3)=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:33][CH:32]=1
Reactant: COc1ccc(CC(=O)Cc2ccc(OC)cc2)cc1
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(C2=C(c3ccccc3)C(c3ccccc3)=C(c3ccc(OC)cc3)C2=O)cc1
Yield: 91 %

Procedure:
Equivalent weights of benzil and the 1,3-bis(4-methoxyphenyl)propanone prepared in the first step are dissolved in, for example, alcohol and heated to incipient boiling. A condensation reaction is initiated by the addition of a small amount of an aqueous potassium hydroxide solution. The solution is heated at reflux to form a purple-black slurry which on purification results in an excellent yield (91%) of purple-colored crystalline 2,5-bis (4-methoxyphenyl)-3,4-diphenylcyclopentadienone, or α,α′-bis(4-methoxy)-tetracyclone, melting at approximately 186-188° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:11][CH:12]([C:15]1[CH:32]=[CH:31][C:18]([O:19][CH:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:21](O)=[O:22])=[CH:17][CH:16]=1)[CH2:13][CH3:14]>>[N:4]1[CH:3]=[C:2]([NH:1][C:21](=[O:22])[CH:20]([O:19][C:18]2[CH:31]=[CH:32][C:15]([CH:12]([CH3:11])[CH2:13][CH3:14])=[CH:16][CH:17]=2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=12
Reactant: CCCCCCCC(Oc1ccc(C(C)CC)cc1)C(=O)O
Reactant: Nc1cnc2ccccn12
Product: CCCCCCCC(Oc1ccc(C(C)CC)cc1)C(=O)Nc1cnc2ccccn12

Procedure:
3-Aminoimidazo[1,2-a]pyridine, synthesized by reduction of the corresponding nitro compound according to Example 31, was coupled with 2-(4-(1-methylpropyl)- phenoxynonanoic acid according to the procedure of Example 25 to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:27](=[O:28])[CH2:26][C:25](=[O:29])[NH:24][C:23]3[C:30]4[C:35]([CH:36]=[CH:37][C:22]2=3)=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:17][CH:16]=1.ClC1C=C(Cl)C=CC=1OCC(Cl)=O>>[Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:27](=[O:28])[CH2:26][C:25](=[O:29])[NH:24][C:23]3[C:30]4[C:35]([CH:36]=[CH:37][C:22]2=3)=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:17][CH:16]=1)=[O:8]
Reactant: O=C(O)COc1ccc(Cl)cc1Cl
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: O=C(Cl)COc1ccc(Cl)cc1Cl
Product: O=C(COc1ccc(Cl)cc1Cl)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 22.3 %

Procedure:
2,4-Dichlorophenoxyacetic acid (42 mg, 0.190 mmol) was made into acid chloride in a conventional manner. By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30 mg, 0.095 mmol) obtained in Example 1, (3), and 2,4-dichlorophenoxyacetic acid chloride mentioned above, the title compound (11 mg, yield 22%) was obtained in the same manner as that of Example 1.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[CH:19][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=3)[N:17]([CH2:28][CH:29]3[CH2:31][CH2:30]3)[CH:16]=2)=[O:14])=[N:9][CH:8]=1)C.C1(CN2C3C(=CC=C(F)C=3)C(C(NC3SC=C(SCC(O)=O)N=3)=O)=C2)CC1>>[CH:29]1([CH2:28][N:17]2[C:18]3[C:23](=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=3)[C:15]([C:13]([NH:12][C:10]3[S:11][C:7]([S:6][CH2:5][C:4]([OH:32])=[O:3])=[CH:8][N:9]=3)=[O:14])=[CH:16]2)[CH2:30][CH2:31]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)c2cn(CC3CC3)c3cc(C(F)(F)F)ccc23)s1
Agent: O=C(O)CSc1csc(NC(=O)c2cn(CC3CC3)c3cc(F)ccc23)n1
Product: O=C(O)CSc1cnc(NC(=O)c2cn(CC3CC3)c3cc(C(F)(F)F)ccc23)s1

Procedure:
{2-[(1-Cyclopropylmethyl-6-trifluoromethyl-1H-indole-3-carbonyl)-amino]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester was hydrolysed according to the procedure given in the procedure for the synthesis of {2-[(1-cyclopropylmethyl-6-fluoro-1H-indole-3-carbonyl)-amino]-thiazol-4-ylsulfanyl}-acetic acid
Reaction SMILES: [C:1]([NH:5][C:6]1[N:15]([CH2:16][CH2:17][CH2:18][O:19][Si](C(C)(C)C)(C)C)[C:14](=[O:27])[C:13]2[C:8](=[C:9]([C:28]3[NH:32][C:31]4[C@@H:33]([CH3:37])[NH:34][C:35](=[O:36])[C:30]=4[CH:29]=3)[CH:10]=[CH:11][CH:12]=2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([NH:5][C:6]1[N:15]([CH2:16][CH2:17][CH2:18][OH:19])[C:14](=[O:27])[C:13]2[C:8](=[C:9]([C:28]3[NH:32][C:31]4[C@@H:33]([CH3:37])[NH:34][C:35](=[O:36])[C:30]=4[CH:29]=3)[CH:10]=[CH:11][CH:12]=2)[N:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H]1NC(=O)c2cc(-c3cccc4c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(NC(C)(C)C)nc34)[nH]c21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H]1NC(=O)c2cc(-c3cccc4c(=O)n(CCCO)c(NC(C)(C)C)nc34)[nH]c21
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a slurry of (R)-2-(tert-butylamino)-3-(3-((tert-butyldimethylsilyl)oxy)propyl)-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrolo-2-yl)quinazolin-4(3H)-one (500c; 0.047 g, 0.090 mmol) in 0.7 mL THF was added TBAF 1.0 M in THF (0.18 mL, 0.179 mmol). The reaction became a yellow solution. After 30 min, the reaction was adsorbed onto 0.7 g silica gel and purified by silica gel chromatography (12 g column) using 0-100% 90/10 DCM/MeOH in DCM. The product-containing fractions were concentrated to afford (R)-2-(tert-butylamino)-3-(3-hydroxypropyl)-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)quinazolin-4(3H)-one (0.033 g, 0.081 mmol, 90% yield) as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.91 (1H, br. s.), 7.88 (2H, d, J=7.8 Hz), 7.61 (1H, s), 7.17 (1H, t, J=7.7 Hz), 6.70 (1H, s), 6.61 (1H, s), 5.31 (1H, br. s.), 4.53 (1H, q, J=6.6 Hz), 4.09 (2H, t, J=6.3 Hz), 3.47 (2H, t, J=5.5 Hz), 1.83 (2H, quin, J=5.9 Hz), 1.49 (9H, s), 1.37 (3H, d, J=6.7 Hz). m/z (ESI, +ve ion) 410.1 (M+H)+.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]([CH3:12])[CH3:11])[NH2:3].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=O)[CH2:21][C:22]([CH:24]2[CH2:29][C:28]([CH3:31])([CH3:30])[O:27][C:26]([CH3:33])([CH3:32])[CH2:25]2)=O)=[CH:16][CH:15]=1.C(N(CC)CC)C>CO.CCOC(C)=O>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:2]([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:10]([CH3:12])[CH3:11])[N:3]=[C:22]([CH:24]3[CH2:25][C:26]([CH3:33])([CH3:32])[O:27][C:28]([CH3:31])([CH3:30])[CH2:29]3)[CH:21]=2)=[CH:18][CH:19]=1
Reactant: CC1(C)CC(C(=O)CC(=O)c2ccc(Cl)cc2)CC(C)(C)O1
Reactant: CN(C)c1ccccc1NN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C)c1ccccc1-n1nc(C2CC(C)(C)OC(C)(C)C2)cc1-c1ccc(Cl)cc1
Yield: 52.5 %

Procedure:
A mixture of (2-hydrazino-phenyl)-dimethyl-amine hydrochloride (105 mg, 0.56 mmol), 1-(4-chloro-phenyl)-3-(2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl)-propane-1,3-dione (162 mg, 0.50 mmol), and triethylamine (0.08 mL, 0.56 mmol), in 1.4 mL of methanol was stirred at RT for 8 hrs. The mixture was diluted with 20 mL of EtOAc and washed with saturated NaHCO3 (40 mL) and brine (40 mL). The organic layer was dried over Na2SO4, concentrated, and the residue purified by flash chromatography on silica gel to give 115 mg (47%) of the title compound as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:9][CH:8]=1)=O.[CH3:17][C:18]1[NH:19][CH:20]=[CH:21][N:22]=1>>[C:14]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[C:20]3[N:19]([C:18]([CH3:17])=[N:22][CH:21]=3)[CH2:2][CH2:3][CH:4]=2)=[CH:8][CH:9]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)Nc1ccc(C(=O)CCCCl)cc1
Reactant: Cc1ncc[nH]1
Product: CC(=O)Nc1ccc(C2=CCCn3c2cnc3C)cc1

Procedure:
Combine 20 g (83.4 mmol) of N-[4-(4-chloro-1-oxobutan-1-yl)phenyl]acetamide with 50 g (0.61 mol) of 2-methylimidazole and heat to 175° C. for 18 hr. Crystallization from ethyl acetate provides the title compound.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:8][CH2:9][N:10]([C:13]2[C:18]([F:19])=[CH:17][C:16]([N+:20]([O-:22])=[O:21])=[CH:15][C:14]=2[F:23])[CH2:11][CH:12]=1)(=O)=O.[F:26][C:27]1[CH:28]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:30]=[CH:31][C:32]=1[F:33].[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[F:19][C:18]1[CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=[C:14]([F:23])[C:13]=1[N:10]1[CH2:11][CH:12]=[C:7]([C:30]2[CH:29]=[CH:28][C:27]([F:26])=[C:32]([F:33])[CH:31]=2)[CH2:8][CH2:9]1
Reactant: CC1(C)OB(c2ccc(F)c(F)c2)OC1(C)C
Reactant: O=[N+]([O-])c1cc(F)c(N2CC=C(OS(=O)(=O)C(F)(F)F)CC2)c(F)c1
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: [Cl-]
Solvent: COCCOC
Product: O=[N+]([O-])c1cc(F)c(N2CC=C(c3ccc(F)c(F)c3)CC2)c(F)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 62.6 %

Procedure:
A mixture of 1-(2,6-difluoro-4-nitrophenyl)-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate (1.18 g, 3.04 mmol), 2-(3,4-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.02 g, 4.25 mmol), lithium chloride (0.387 g, 9.12 mmol) and a 2.0 M aq. solution of sodium carbonate (4.56 mL, 9.12 mmol) in anhydrous DME (15 mL) was vigorously stirred while bubbling with N2 gas for 20 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.176 g, 0.152 mmol) was added, and the resulting mixture was degassed for 5 minutes more. The reaction flask was equipped with a condenser and placed in 100° C. oil bath. The dark mixture was stirred at 100° C. under a dry N2 atmosphere for 16 hours, and was then cooled to room temperature and partitioned between water (50 mL) and EtOAc (2×50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo, and the crude product was purified by column chromatography on silica gel using a solvent gradient of 0-40% EtOAc in hexanes to provide a yellow oil that solidified on standing. The solid was triturated with Et2O and hexanes, filtered and dried to provide the title compound (0.67 g, 63%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:16]#[N:17])[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[CH2:10][CH2:9]2)=[CH:4][C:3]=1Br.[CH3:19][C:20]1([CH3:35])[CH2:25][CH2:24][C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][CH2:21]1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.O.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]>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:16]#[N:17])[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:23]1[CH2:24][CH2:25][C:20]([CH3:35])([CH3:19])[CH2:21][CH:22]=1
Reactant: CC1(C)CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: N#CC1(c2ccc(N)c(Br)c2)CCS(=O)(=O)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)CC=C(c2cc(C3(C#N)CCS(=O)(=O)CC3)ccc2N)CC1
Temperature: 60 °C
Yield: 100 %

Procedure:
A solution of 4-(4-amino-3-bromo-phenyl)-1,1-dioxo-hexahydro-1λ6-thiopyran-4-carbonitrile (109 mg, 0.332 mmol, as prepared in the previous step) in DMF (4 mL) was treated with 2-(4,4-dimethyl-cyclohex-1-enyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (94.1 mg, 0.398 mmol) and aq Na2CO3 (1.32 mL, 2.66 mmol, 2.0 M). The mixture was degassed via sonication, placed under Ar, treated with Pd(dppf)Cl2 (24.3 mg, 0.034 mmol), and heated to 60° C. for 24 h. The cooled mixture was diluted with EtOAc and water. The aqueous layer was extracted with EtOAc (4×). The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification of the residue by silica gel chromatography on a 10-g Isolute SPE column (FlashMaster system) with 25% EtOAc-hexane afforded the title compound (119 mg, 100%) as a white solid. Mass spectrum (ESI, m/z): Calcd. for C20H26N2O2S, 359.2 (M+H). found 359.3.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([NH:8][NH2:9])=[O:7])([O-:3])=[O:2].[C:14](=S)=[S:15].O.Cl>N1C=CC=CC=1>[SH:15][C:14]1[O:7][C:6]([C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])=[N:8][N:9]=1
Reactant: S=C=S
Reactant: NNC(=O)c1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccccc1-c1nnc(S)o1

Procedure:
The reactions of Equation 36 above can be run according to similar procedures described in E. Hoggarth, J. Chem. Soc., 4811 (1952). Thus, in reaction 36a, 2-nitrobenzhydrazide XLVIII is reacted with carbon disulfide in pyridine solvent at 25° to 80° C. for about 4 to 16 hours, followed by addition of water and acidification with hydrochloric acid to form a 2-mercapto-5-(2-nitrophenyl)-1,3,4-oxadiazole of Formula (L). In reaction 36b, L is reacted with sodium hydroxide and methyl iodide in water at 0° to 30° C. for 0.2 to 1 hour to form Xk".
Reaction SMILES: [C:1]([C:4]1[N:8]2[CH:9]=[CH:10][N:11]=[CH:12][C:7]2=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>O>[OH:3][CH:1]([C:4]1[N:8]2[CH:9]=[CH:10][N:11]=[CH:12][C:7]2=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(=O)c1ccc2cnccn12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CC(O)c1ccc2cnccn12
Reaction time: 2 h
Yield: 69.1 %

Procedure:
2.0 g of 6-acetylpyrrolo[1,2-a]pyrazine prepared in Preparation Example 15 was added to 30 ml of water; and 0.5 g of sodium borohydride was added thereto. After reacting at 50° C. for 2 hours, the mixture was extracted with ethyl acetate (50 ml×3). The residue was chromatographed over silica gel to yield 1.4 g of 6-(1-hydroxyethyl)pyrrolo[1,2-a]pyrazine.