Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[O:11]=[C:12]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13]1.Cl.CN(C)CCCN=C=NCC.Cl.[CH3:33][NH:34][O:35][CH3:36].C(N(CC)CC)C>C(Cl)Cl>[CH3:36][O:35][N:34]([CH3:33])[C:17]([CH:14]1[CH2:15][CH2:16][C:12](=[O:11])[CH2:13]1)=[O:19]
Reactant: CNOC
Reactant: O=C1CCC(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)C1CCC(=O)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a slurry of 1-hydroxybenzotriazole (7.91 g, 58.5 mmol), 3-oxo-1-cyclopentanecarboxylic acid (5.00 g, 39.0 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (11.22 g, 58.5 mmol) in 44 mL DCM under nitrogen was added N,O-dimethylhydroxylamine hydrochloride (5.71 g, 58.5 mmol) followed by triethylamine (8.16 mL, 58.5 mmol) in portions. The reaction mixture became warm and was cooled with an ice bath for the remainder of TEA addition, then stirred at ambient temp under nitrogen for 2 d. The reaction mixture was concentrated in vacuo, and taken up in EA (300 mL), washed with water, sat'd aq. Sodium bicarbonate, brine, and the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo, to give (rac)-N-methoxy-N-methyl-3-oxocyclopentanecarboxamide as a yellow oil which was used without further purification. 1H NMR (400 MHz, CDCl3-d) δ ppm 3.74 (s, 3 H), 3.41-3.61 (m, 1 H), 3.23 (s, 3 H), 2.52-2.64 (m, 1 H), 2.34-2.50 (m, 2 H), 2.08-2.31 (m, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:9]=2[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[Br:19]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClC(Cl)(Cl)Cl>[Br:19][CH2:18][C:16]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:17]=1
Reactant: COC(=O)c1ccc(C)cc1-c1ccc(F)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1-c1ccc(F)cc1

Procedure:
A solution of methyl 2-(4-fluorophenyl)-4-methylbenzoate (54.18 g; 0.22 mol), N-bromosuccinimide (39.6 g; 0.22 mol), 2,2′-azobis(2-methylproprionitrile) (0.25 g; 1.5 mmol) and benzoylperoxide (0.25 g; 1 mmol) in tetrachloromethane (550 ml) was heated at reflux for 6 hours. The solid was filtered and the filtrate evaporated to give methyl 4-bromomethyl-2-(4-fluorophenyl)benzoate as an oil (79.7 g; 79%) which was used in the next step without purification.
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](NCC)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4CCN(C(OCC)=O)C[CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[Cl:45][C:46]1[CH:52]=[CH:51][C:49]([NH2:50])=[CH:48][CH:47]=1.NC1C=CC=CC=1>>[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:50][C:49]4[CH:51]=[CH:52][C:46]([Cl:45])=[CH:47][CH:48]=4)=[O:27])=[CH:23][CH:24]=3)[N:16]=[C:15]3[N:31]([CH2:34][CH3:35])[N:32]=[CH:33][C:14]=13)[CH2:6]2
Reactant: Nc1ccc(Cl)cc1
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: CCn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4ccc(Cl)cc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 4-chloroaniline as the aniline component. (22%, MS=504.2 (M+H))
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([S:15][CH3:16])[C:11]([O:13][CH3:14])=[O:12])=[CH:5][C:4]=1[C:17](=[O:30])[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1.C1C=C(Cl)C=C(C(OO)=[O:39])C=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([S:15]([CH3:16])=[O:39])[C:11]([O:13][CH3:14])=[O:12])=[CH:5][C:4]=1[C:17](=[O:30])[NH:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=1
Reactant: COC(=O)C(Cc1ccc(OC)c(C(=O)NCc2ccc(C(F)(F)F)cc2)c1)SC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)C(Cc1ccc(OC)c(C(=O)NCc2ccc(C(F)(F)F)cc2)c1)S(C)=O
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
To a solution of 1.50 g of methyl 3-[4-methoxy-3-[N-(4-trifluoromethylbenzyl)]carbamoylphenyl]-2-(methylthio)propionate in 30 ml of methylene chloride were added 800 mg of mCPBA under cooling with ice, and the mixture was stirred for 30 minutes. The reaction mixture was washed with saturated aqueous solution of sodium bicarbonate and saturated brine in sequence and dried over anhydrous sodium sulfate. Solvent was distilled off under reduced pressure, and the residue obtained was purified by means of column chromatography (silica gel, methylene chloride:methanol=100:1 to 50:1) to obtain 1.22 g of methyl 3-[4-methoxy-3-[N-(4-trifluoromethylbenzyl)]carbamoylphenyl]-2-(methylsulfinyl)-propionate as colorless crystals. To a solution of 1.02 g of methyl 3-[4-methoxy-3-[N-(4-trifluoromethylbenzyl)]-carbamoylphenyl]-2-(methylsulfinyl)propionate obtained in 20 ml of methylene chloride were added 550 mg of mCPBA under cooling with ice, and the mixture was stirred for 7 hours at room temperature. The reaction mixture was washed with saturated aqueous solution of sodium bicarbonate and saturated brine in sequence and dried over anhydrous sodium sulfate. Solvent was distilled off under reduced pressure, and the crystals obtained were recrystallized from hexane-ethyl acetate to obtain 750 mg of methyl 3-[4-methoxy-3-[N-(4-trifluoromethylbenzyl)]carbamoylphenyl]-2-(methylsulfonyl)propionate as colorless crystals. Melting point 144-145° C.
Reaction SMILES: [CH:1]([C@:4]1([C:17]([N:19]2[CH2:24][CH:23]=[C:22]([C:25]3[CH:26]=[N:27][CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=3)[CH2:21][CH2:20]2)=[O:18])[CH2:8][CH2:7][C@@H:6]([NH:9]C(=O)OC(C)(C)C)[CH2:5]1)([CH3:3])[CH3:2]>Cl.O1CCOCC1>[CH:1]([C@:4]1([C:17]([N:19]2[CH2:20][CH:21]=[C:22]([C:25]3[CH:26]=[N:27][CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=3)[CH2:23][CH2:24]2)=[O:18])[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@]1(C(=O)N2CC=C(c3cncc(C(F)(F)F)c3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)[C@]1(C(=O)N2CC=C(c3cncc(C(F)(F)F)c3)CC2)CC[C@@H](N)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 147.4 %

Procedure:
tert-Butyl ((1R,3S)-3-isopropyl-3-{[5-(trifluoromethyl)-3′,6′-dihydro-3,4′-bipyridin-1′(2′H)-yl]carbonyl}cyclopentyl)carbamate (24.0 mg, 0.0498 mmol) was dissolved in a 4 M solution of HCl in 1,4-dioxane (2.0 mL) to form a light yellow clear solution. After being stirred at room temperature for 1 h, the reaction mixture was concentrated in vacuo. The residue was treated with a 1 M solution of NaOH and the solution was extracted with methylene chloride three times. The extracts were dried, filtered and concentrated to provide 28 mg of product as a light yellow solid. LC-MS calculated for C20H26F3N3O: (M+H) 382; found 382.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:5]=[CH:6][C:7]=1I.C([Sn](CCCC)(CCCC)[C:22]1[N:23]=[CH:24][S:25][CH:26]=1)CCC>O1CCOCC1.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:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:5]=[CH:6][C:7]=1[C:22]1[N:23]=[CH:24][S:25][CH:26]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cscn2)c(F)c1
Reaction time: 34 h
Yield: 62 %

Procedure:
A solution of tert-butyl 3-fluoro-4-iodophenylcarbamate (500 mg, 1.48 mmol) and 4-(tributylstannyl)thiazole (0.578 mL, 1.80 mmol) in dioxane (6 mL) was degassed with Ar before being charged with Pd(Ph3P)4 (170 mg, 0.147 mmol). It was stirred at 100 C for 34 h, then concentrated in vacuo. The residue was loaded to a flash column, eluted with 0-25% EtOAc in hexane to give tert-butyl 3-fluoro-4-(thiazol-4-yl)phenylcarbamate (270 mg). MS 295.3 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16]I)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[CH3:22][O:23][C:24]1[N:29]=[CH:28][C:27]([CH2:30][C:31]2[C:32](=[O:38])[NH:33][C:34](=[S:37])[NH:35][CH:36]=2)=[CH:26][N:25]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][S:37][C:34]3[NH:35][CH:36]=[C:31]([CH2:30][C:27]4[CH:28]=[N:29][C:24]([O:23][CH3:22])=[N:25][CH:26]=4)[C:32](=[O:38])[N:33]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19]
Reactant: FC(F)(F)c1cc(Oc2ccc(CCI)cc2)ccc1Cl
Reactant: COc1ncc(Cc2c[nH]c(=S)[nH]c2=O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ncc(Cc2c[nH]c(SCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1
Temperature: 50 °C
Yield: 8.5 %

Procedure:
A mixture of 1-chloro-4-{[4-(2-iodoethyl)phenyl]oxy}-2-(trifluoromethyl)benzene (400 mg, 0.938 mmol), 5-{[2-(methyloxy)-5-pyrimidinyl]methyl}-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (258 mg, 1.031 mmol) and K2CO3 (259 mg, 1.875 mmol) in DMF (3 mL) was heated with a microwave reactor at 50° C. for 15 min. Purification via reverse phase flash chromatography then afforded the title compound (44 mg, 0.080 mmol, 8.55% yield). LCMS: rt=3.76 min, [M+H+]=549
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[OH:28][CH:29]([CH2:33][CH3:34])[C:30](O)=[O:31]>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:30](=[O:31])[CH:29]([OH:28])[CH2:33][CH3:34])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: CCC(O)C(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: CCC(O)C(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (15 mg, 50.1%), MS (ISP) m/z=418.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (Intermediate A) (30 mg, 68.1 mmol) and 2-hydroxybutanoic acid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:24]1([C:26](=[CH:28][CH:29]=[CH:30][CH:31]=1)O)[OH:25].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C(C)=CC=CC=1>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]2([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[O:23][C:31]3[CH:30]=[CH:29][CH:28]=[CH:26][C:24]=3[O:25]2)=[CH:20][CH:19]=1
Reactant: Oc1ccccc1O
Reactant: COc1ccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: COc1ccc(C2(C3CCNCC3)Oc3ccccc3O2)cc1
Yield: 35.9 %

Procedure:
A solution of the above ketone (957 mg, 3.00 mmol), catechol (660 mg, 6.00 mmol) and p-TsOH.H2O (1.14 g, 6.00 mmol) in xylene (20 mL) was heated at reflux using a Dean-Stark apparatus to remove water for 24 hours. Standard work-up and purification gave 4-[2-(4-methoxy-phenyl)-benzo[1,3]dioxol-2-yl]-piperidine as a pale yellow oil (335 mg, 36%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]([OH:14])[CH2:12][N:11]([C:15]3[N:20]=[CH:19][N:18]([CH2:21][C:22]4[S:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=4)[C:17](=[O:31])[N:16]=3)[CH2:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13](=[O:14])[CH2:12][N:11]([C:15]3[N:20]=[CH:19][N:18]([CH2:21][C:22]4[S:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=4)[C:17](=[O:31])[N:16]=3)[CH2:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=c1nc(N2CC=C(c3ccc(F)cc3)C(O)C2)ncn1Cc1ccc(C(F)(F)F)s1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1CN(c2ncn(Cc3ccc(C(F)(F)F)s3)c(=O)n2)CC=C1c1ccc(F)cc1
Yield: 97.4 %

Procedure:
To 4-[4-(4-fluorophenyl)-5-hydroxy-5,6-dihydropyridin-1(2H)-yl]-1-{[5-(trifluoromethyl)thiophen-2-yl]methyl}-1,3,5-triazin-2(1H)-one (20.0 mg, 0.0442 mmol) synthesized in Synthesis Example 190, dichloromethane (1.0 mL), sodium bicarbonate (11.1 mg, 0.132 mmol), and Dess-Martin periodinane (28.1 mg, 0.0663 mmol; manufactured by Tokyo Chemical Industry Co., Ltd.) were added and the resultant mixture was stirred at room temperature for 1 day. Then, to the reaction solution, dichloromethane (4.0 mL) and Dess-Martin periodinane (30.0 mg, 0.0707 mmol) were added and the resultant mixture was stirred at room temperature for 2 hours. After the completion of the reaction, the reaction solution was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (19.4 mg, yield: 98%).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:6][C:5]2[CH:7]=[C:8]3[O:12][C:11]([CH3:14])([CH3:13])[O:10][C:9]3=[CH:15][C:4]=2[O:3]1.C([Li])CCC.[CH3:22][C:23]1([CH3:55])[O:27][C:26]2[C:28]([C:37]([C:39]3[C:49]4[O:50][C:51]([CH3:54])([CH3:53])[O:52][C:48]=4[CH:47]=[C:41]4[O:42][C:43]([CH3:46])([CH3:45])[O:44][C:40]=34)=[O:38])=[C:29]3[O:33][C:32]([CH3:35])([CH3:34])[O:31][C:30]3=[CH:36][C:25]=2[O:24]1>C1COCC1>[CH3:13][C:11]1([CH3:14])[O:10][C:9]2[C:15]([C:37]([C:28]3[C:26]4[O:27][C:23]([CH3:55])([CH3:22])[O:24][C:25]=4[CH:36]=[C:30]4[O:31][C:32]([CH3:35])([CH3:34])[O:33][C:29]=34)([C:39]3[C:49]4[O:50][C:51]([CH3:53])([CH3:54])[O:52][C:48]=4[CH:47]=[C:41]4[O:42][C:43]([CH3:45])([CH3:46])[O:44][C:40]=34)[OH:38])=[C:4]3[O:3][C:2]([CH3:16])([CH3:1])[O:6][C:5]3=[CH:7][C:8]=2[O:12]1
Reactant: CC1(C)Oc2cc3c(cc2O1)OC(C)(C)O3
Reactant: CC1(C)Oc2cc3c(c(C(=O)c4c5c(cc6c4OC(C)(C)O6)OC(C)(C)O5)c2O1)OC(C)(C)O3
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)Oc2cc3c(c(C(O)(c4c5c(cc6c4OC(C)(C)O6)OC(C)(C)O5)c4c5c(cc6c4OC(C)(C)O6)OC(C)(C)O5)c2O1)OC(C)(C)O3
Reaction time: 0.5 h

Procedure:
2,2,6,6-Tetramethylbenzo[1,2-d:4,5-d']bis(1,3)dioxole (8.80 g, 40.00 mmol, Example 5) was dissolved in THF (100 mL) and cooled to -20° C. n-Butyllithium (25.0 mL, 40.0 mmol, 1.6M) was added and the temperature was adjusted to ambient temperature over a period of 30 minutes and then recooled to -20° C. Bis(2,2,6,6-tetramethylbenzo-[1,2-d:4,5-d']bis(1,3)dioxole-4-yl)ketone (18.80 g, 39.83 mmol, Example 57) was added and the temperature was once more adjusted to room temperature and the mixture was stirred for 18 hours. The mixture was then poured on water/AcOH (100 mL, 2% AcOH) and extracted with diethyl ether (2×100 mL). The organic phase was washed with water (2×100 ml) and dried (Na2SO4). The solvent was evaporated and the product was washed with petroleum ether (20 mL, 40°-60° C.). Yield 10.80 g (64.1%). Spectral data see example 44.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:5][NH:6][C:7]1[C:8]2[N:21]([CH3:22])[N:20]=[C:19]([CH2:23][CH2:24][CH3:25])[C:9]=2[N:10]=[C:11]([CH2:13][CH2:14][C:15]([O:17]C)=[O:16])[N:12]=1.[OH-].[Na+].Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:5][NH:6][C:7]1[C:8]2[N:21]([CH3:22])[N:20]=[C:19]([CH2:23][CH2:24][CH3:25])[C:9]=2[N:10]=[C:11]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[N:12]=1
Reactant: CCCc1nn(C)c2c(NCc3ccc(OC)c(Cl)c3)nc(CCC(=O)OC)nc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCc1nn(C)c2c(NCc3ccc(OC)c(Cl)c3)nc(CCC(=O)O)nc12
Reaction time: 8 h
Yield: 88.9 %

Procedure:
4.3 g of methyl 3-[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-propionate are dissolved in 30 ml of tetrahydrofuran (THF) and, after addition of 10 ml of 10% NaOH, stirred at 60° for 8 hours. After addition of 10% HCl, the deposited crystals are separated off and recrystallized from methanol. 3.7 g of 3-[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]propionic acid, m.p. 178°, are obtained.
Reaction SMILES: [SH2:1].C(NCC)C.[CH3:7][C:8]1([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][O:9]1>CO>[OH:9][C:8]([CH3:7])([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][SH:1]
Reactant: S
Reactant: CCCCCC1(C)CO1
Solvent: CCNCC
Solvent: CO
Product: CCCCCC(C)(O)CS
Reaction time: 12 h

Procedure:
Pass hydrogen sulfide, with ice cooling, into 150 ml. methanol until the weight increase amounts to 3.2 g., add thereto a solution of 370 mg. diethylamine in 11 ml. methanol and subsequently 4.8 g. 2-methyl-2-pentyl-oxirane in 18 ml. methanol, again pass hydrogen sulfide into the solution for 15 minutes, leave standing for 12 hours at room temperature, distill off the solvent, dissolve the residue in 50 ml. petroleum ether (b.p.=50°-70°), wash with water, dry over sodium sulfate and distill off the solvent to obtain as the residue, 2-hydroxy-2-methyl-heptanethiol as a colorless liquid;
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[C:4]([CH3:10])[N:3]=1.[OH-].[NH4+:12].CO>O>[NH2:12][C:6]1[C:7]([F:8])=[C:2]([Cl:1])[N:3]=[C:4]([CH3:10])[N:5]=1
Reactant: [NH4+]
Reactant: Cc1nc(Cl)c(F)c(Cl)n1
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nc(N)c(F)c(Cl)n1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
Part C: A mixture of 4,6-dichloro-5-fluoro-2-methylpyrimidine (1.55 g, 8.56 mmol), ammonium hydroxide (35%, 10.0 mL, 257 mmol), and MeOH (1.00 mL) was heated, in a sealed tube, at 70° C. for 2 h. The reaction mixture was cooled to RT, and a precipitate was formed. The reaction mixture was diluted with water (ca. 10 mL) and was stirred 30 min. The solids were collected by suction filtration, washed with water and air-dried to give 4-amino-6-chloro-5-fluoro-2-methylpyrimidine (845 mg, 61%) as a tan solid. LCMS (m/z): 162,164 (M+H)+
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Br[CH2:16][CH2:17][C:18]#[N:19].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:16][CH2:17][C:18]#[N:19])[CH:10]=2)[O:3]1
Reactant: N#CCCBr
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2cnn(CCC#N)c2)OC1(C)C

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (50 mg, 0.2 mmol), 3-bromopropionitrile (23 uL, 0.28 mmol, Aldrich, Cat. No. 109231) and cesium carbonate (250 mg, 0.77 mmol) in acetonitrile (1 mL) was stirred at 90° C. overnight. After cooling, it was diluted with ethyl acetate, washed with water twice and brine once, dried over Na2SO4. After filtration the filtrate was concentrated to yield 55 mg of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[CH:22](OCC)=[O:23]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH:8][CH:22]=[O:23])=[CH:4][CH:3]=1
Reactant: NCCc1ccc(Br)cc1
Reactant: CCOC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=CNCCc1ccc(Br)cc1
Yield: 100 %

Procedure:
4-Bromo-phenethylamine (4.45 g, 22.25 mmol) was dissolved in ethyl formate (100 mL). 5 mg of TsOH was added. The clear colorless solution was heated in an oil bath to reflux for 16 h. The reaction solution was cooled to r.t, passed through a short silica gel plug, rinsed with ethyl acetate. The filtrate was evaporated to yield 5.1 g (100%) of the title compound as a liquid which became a solid on standing. MS: 230 (M+H+).
Reaction SMILES: C([O:4][CH2:5][CH:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][N:13]=2)[CH2:7]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([N:8]2[CH2:7][CH:6]([CH2:5][OH:4])[O:10][C:9]2=[O:11])=[N:13][CH:14]=1
Reactant: CC(=O)OCC1CN(c2ccc(Br)cn2)C(=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C1OC(CO)CN1c1ccc(Br)cn1
Yield: 69.8 %

Procedure:
Compound 24b (200 mg, 0.63 mmol) was dissolved in methanol (8 mL). Potassium carbonate (175 mg, 1.27 mmol) was added. Under the protection of argon, the mixture was allowed to react at room temperature for 5 hrs. The reaction was monitored by TLC (petroleum ether/ethyl acetate=5/1). After the reaction completed, the mixture was diluted with water, and extracted with ethyl acetate. The organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate. Column chromatography (petroleum ether/ethyl acetate=5/1) afforded 120 mg of white solid (compound 24c), yield 70%.
Reaction SMILES: C(OP(C[N:10]1C2C3C=CC=C(C(F)(F)F)C=3C([N+]([O-])=O)=CC=2NC(=O)C1=O)(=O)OCC)C.[CH2:33]([O:35][P:36]([CH2:41][N:42]1[C:51]2[CH:50]=[C:49]([N+:52]([O-:54])=[O:53])[C:48]3[C:55]([C:59](F)(F)F)=[CH:56][CH:57]=[CH:58][C:47]=3[C:46]=2[NH:45][C:44](=[O:63])[C:43]1=[O:64])(=[O:40])[O:37][CH2:38][CH3:39])[CH3:34]>>[CH2:33]([O:35][P:36]([CH2:41][N:42]1[C:51]2[CH:50]=[C:49]([N+:52]([O-:54])=[O:53])[C:48]3[C:55]([C:59]#[N:10])=[CH:56][CH:57]=[CH:58][C:47]=3[C:46]=2[NH:45][C:44](=[O:63])[C:43]1=[O:64])(=[O:40])[O:37][CH2:38][CH3:39])[CH3:34]
Reactant: CCOP(=O)(Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c3c(C(F)(F)F)cccc3c21)OCC
Reactant: CCOP(=O)(Cn1c(=O)c(=O)[nH]c2c3cccc(C(F)(F)F)c3c([N+](=O)[O-])cc21)OCC
Product: CCOP(=O)(Cn1c(=O)c(=O)[nH]c2c3cccc(C#N)c3c([N+](=O)[O-])cc21)OCC

Procedure:
(6-nitro-7-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f]quinoxalin-1-yl)-methanephosphonic acid diethyl ester and (6-nitro-7-trifluoromethyl-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f]quinoxalin-4-yl)-methanephosphonic acid diethyl ester
Reaction SMILES: [CH:1]1([C:7]2[N:11]3[C:12]4[C:17]([NH:18][C:19](=[O:20])[C:10]3=[CH:9][N:8]=2)=[CH:16][CH:15]=[C:14](/[CH:21]=[CH:22]/[C:23]([O:25][CH3:26])=[O:24])[CH:13]=4)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C(O)(=O)C.[Pd]>[CH:1]1([C:7]2[N:11]3[C:12]4[C:17]([NH:18][C:19](=[O:20])[C:10]3=[CH:9][N:8]=2)=[CH:16][CH:15]=[C:14]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:13]=4)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: COC(=O)/C=C/c1ccc2[nH]c(=O)c3cnc(C4CCCCC4)n3c2c1
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)CCc1ccc2[nH]c(=O)c3cnc(C4CCCCC4)n3c2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Methyl(E)-3-(1-cyclohexyl-4-oxo-4,5-dihydroimidazo-[1,5-a]quinoxalin-8-yl)acrylate as synthesized in Example 154, 2.0 g was dissolved in 100 mL of acetic acid, and to the solution 10% Pd/C 200 mg was added in nitrogen atmosphere. After substituting the atmosphere with hydrogen, the reaction liquid was stirred at 25° C. for 2 days. The reaction liquid was filtered through Celite and from the filtrate the solvent was distilled off to provide 1.48 g of the title compound.
Reaction SMILES: [CH2:1]1[C:6]2[S:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:5]=2[CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[Na+].[Na+].Cl[CH2:21][CH2:22][CH2:23][C:24]#[N:25]>C(#N)C.CC1C=CC=CC=1>[CH2:1]1[C:6]2[S:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:5]=2[CH2:4][CH2:3][N:2]1[CH2:21][CH2:22][CH2:23][C:24]#[N:25]
Reactant: N#CCCCCl
Reactant: c1ccc2c3c(sc2c1)CNCC3
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: N#CCCCN1CCc2c(sc3ccccc23)C1
Yield: 101.4 %

Procedure:
A mixture of 1,2,3,4-tetrahydro-[1]benzothieno[2,3-c]pyridine (0.02 mol), Na2CO3 (5 g), KI (0.1 g) and 4-chlorobutanenitrile (0.025 mol) in acetonitrile (50 ml) and methylbenzene (150 ml) was stirred and refluxed overnight, then cooled, filtered and the filtrate was evaporated. The residue (oil) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 98/2). The pure fractions were collected and the solvent was evaporated, yielding 5.2 g of 3,4-dihydrobenzothieno[2,3-c]-pyridine-2(1H)-butanenitrile (interm. 6).