Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:35]1[CH:39]=[CH:38][CH:37]=[C:36]1[C:40](Cl)=[O:41]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[C:40]([C:36]3[S:35][CH:39]=[CH:38][CH:37]=3)=[O:41])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1cccs1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N(Cc3ccc4ccc(C#N)cc4c3)C(=O)c3cccs3)cc2)CC1

Procedure:
Starting compound: 7-[[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile, thienoyl chloride.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].Cl.C(O[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])C>C(O)C>[CH2:1]([NH:4][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])[CH:2]=[CH2:3]
Reactant: C=CCN
Reactant: CCOc1ccncc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Product: C=CCNc1ccncc1[N+](=O)[O-]

Procedure:
Allyl amine (40 mL) was added to a solution of 4-ethoxy-3-nitropyridine hydrochloride [CAS No. 94602-04-7] (18.0 g) in ethanol (400 mL), and this was heated under reflux for eight hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. The fraction eluted by ethyl acetate-hexane (1:1) gave the title compound (13.6 g).
Reaction SMILES: Cl.[Br:2][C:3]1[S:4][C:5]([CH2:8][NH2:9])=[CH:6][N:7]=1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17](Cl)(=[O:19])=[O:18].C(N(CC)C(C)C)(C)C>ClCCl>[Br:2][C:3]1[S:4][C:5]([CH2:8][NH:9][S:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[Cl:10])(=[O:19])=[O:18])=[CH:6][N:7]=1
Reactant: NCc1cnc(Br)s1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(NCc1cnc(Br)s1)c1ccccc1Cl

Procedure:
In analogy to example 1, step 1, 2-bromo-5-aminomethyl-thiazole hydrochloride was reacted with 2-chlorobenzenesulfonylchloride and N,N-diisopropyl ethyl amine in dichloromethane to give N-(2-bromo-thiazol-5-ylmethyl)-2-chloro-benzenesulfonamide as an off-white solid. MS: 367.0 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:40]=[CH:39][C:5]([CH2:6][N:7]([CH2:35][CH:36]([CH3:38])[CH3:37])[S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C@@H:18]3[CH2:23][CH2:22][NH:21][CH2:20][C@H:19]3[O:24][Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:50][S:51](Cl)(=[O:53])=[O:52].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:35][CH:36]([CH3:38])[CH3:37])[S:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][C@@H:18]3[CH2:23][CH2:22][N:21]([S:51]([CH3:50])(=[O:53])=[O:52])[CH2:20][C@H:19]3[O:24][Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:30])[CH3:31])[CH:26]([CH3:28])[CH3:27])=[CH:15][CH:16]=2)(=[O:9])=[O:10])=[CH:39][CH:40]=1
Reactant: CC(C)CN(Cc1ccc(Cl)cc1)S(=O)(=O)c1ccc(O[C@@H]2CCNC[C@H]2O[Si](C(C)C)(C(C)C)C(C)C)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)CN(Cc1ccc(Cl)cc1)S(=O)(=O)c1ccc(O[C@@H]2CCN(S(C)(=O)=O)C[C@H]2O[Si](C(C)C)(C(C)C)C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of N-(4-chloro-benzyl)-N-isobutyl-4-((+/−)trans-3-triisopropylsilanyloxy-piperidin-4-yloxy)-benzenesulfonamide (185 mg, 304 μmol) in DCM (5 mL) was added DIPEA (106 μL, 609 μmol) followed by methanesulfonyl chloride (1 mL of a 231 μL, 3 mmol solution in 10 mL of DCM) and the reaction stirred at room temperature for 1 hour. Saturated aqueous NaHCO3 was then added, extracted with DCM, filtered through a phase separator and concentrated to give N-(4-Chloro-benzyl)-N-isobutyl-4-((+/−)trans-1-methanesulfonyl-3-triisopropylsilanyloxy-piperidin-4-yloxy)-benzenesulfonamide (271 mg, 100%). LCMS (m/z, Method A) ES+ 709 [M+23]+.
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH3:24])[CH3:23])[C:17]=1[N:25]=[C:26]=[O:27])[CH3:15]>>[CH2:11]([O:10][C:8](=[O:9])[CH:7]([C:26]([NH:25][C:17]1[C:16]([CH:14]([CH3:13])[CH3:15])=[CH:21][CH:20]=[CH:19][C:18]=1[CH:22]([CH3:24])[CH3:23])=[O:27])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:12]
Reactant: CCOC(=O)Cc1ccccc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CCOC(=O)C(C(=O)Nc1c(C(C)C)cccc1C(C)C)c1ccccc1

Procedure:
In a manner similar to Example 134, phenylacetic acid, ethyl ester was condensed with 2,6-bis(1-methylethyl)phenyl isocyanate to give the title compound, mp 168°-170° C.
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([N+:30]([O-])=O)[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][N:22]3[CH2:25][CH2:24][CH2:23]3)[CH2:16][CH2:15]2)=[O:13])[CH:6]=1>O1CCCC1.CO.[C].[Pd]>[NH2:30][C:28]1[CH:27]=[CH:26][C:3]([O:4][C:5]2[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][N:22]4[CH2:25][CH2:24][CH2:23]4)[CH2:16][CH2:15]3)=[O:13])[CH:6]=2)=[C:2]([F:1])[CH:29]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1)N1CCN(CCN2CCC2)CC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(Oc2cc(NC(=O)N3CCN(CCN4CCC4)CC3)ncn2)c(F)c1
Reaction time: 16.5 h
Yield: 31.6 %

Procedure:
4-[2-(Azetidin-1-yl)ethyl]piperazine-1-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-yl]amide (110 mg) was dissolved in tetrahydrofuran (3 ml) and methanol (3 ml), and then 10% palladium carbon (53 mg) was added, followed by stirring under a hydrogen atmosphere for 16.5 hrs. The catalyst was filtered off and washed with methanol. The filtrate and washings were concentrated under reduced pressure to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, heptane: ethyl acetate:ethanol=95:5 to 90:10). Fractions containing the target compound were concentrated to provide a crude product of the titled compound (32.4 mg) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:5]=[N:4][C:3]=1[N:16]1[CH2:21][CH2:20][NH:19][C@H:18]([CH3:22])[CH2:17]1.[CH3:23][O:24][C:25]([C:27]1[CH:32]=[N:31][C:30](Cl)=[CH:29][N:28]=1)=[O:26].C(N(CC)CC)C>CN1C(=O)CCC1>[CH3:23][O:24][C:25]([C:27]1[N:28]=[CH:29][C:30]([N:19]2[CH2:20][CH2:21][N:16]([C:3]3[N:4]=[N:5][C:6]([CH2:9][C:10]4[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=4)=[C:7]([CH3:8])[C:2]=3[CH3:1])[CH2:17][C@H:18]2[CH3:22])=[N:31][CH:32]=1)=[O:26]
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: Cc1c(Cc2cccnc2)nnc(N2CCN[C@H](C)C2)c1C
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: COC(=O)c1cnc(N2CCN(c3nnc(Cc4cccnc4)c(C)c3C)C[C@H]2C)cn1
Yield: 5.9 %

Procedure:
4,5-Dimethyl-3-((R)-3-methyl-piperazin-1-yl)-6-pyridin-3-ylmethyl-pyridazine (350 mg, 1.18 mmol) and 5-chloro-pyrazine-2-carboxylic acid methyl ester (243.7 mg, 1.41 mmol) are added to a microwave vial followed by NMP (7 mL) and triethylamine (0.49 mL, 3.54 mmol). The vial is sealed and irradiated in the microwave at 145° C. for 30 min. The crude material is directly purified via flash chromatography on silica gel (0-20% methanol in CH2Cl2) to afford the title compound (30 mg, 6%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([Sn](C)(C)C)=[CH:3][CH:2]=1.N#N.Br[C:15]1[C:19]([Br:20])=[CH:18][S:17][CH:16]=1.CCOC(C)=O>C1(C)C=CC=CC=1.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:20][C:19]1[C:15]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)=[CH:16][S:17][CH:18]=1
Reactant: Brc1cscc1Br
Reactant: Cc1ccc([Sn](C)(C)C)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2cscc2Br)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
Through a solution of p-tolyltrimethyltin (3.17 g, 12.4 mmol) in dry toluene (8 mL) was bubbled N2 for 5 min to degas the solution. To this was added 3,4-dibromothiophene (2.31 g, 9.56 mmol) and a catalytic amount of Pd(PPh3)4 (552 mg, 5 mol %). The reaction mixture was brought to reflux (120° C.) and left overnight. The reaction was cooled to rt and the toluene was replaced by EtOAc. The insoluable salts were removed by filtration through a plug of celite. The product was purified by flash chromatography on a silica column eluting with hexane to afford 1.09 g (45%) of the titled compound as a clear, colorless oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:21]=[CH:20][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[O:10])=[C:7]([NH:22][C:23]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:24])[CH:6]=1)(=[O:3])[CH3:2].[N:31]1[CH:36]=[CH:35][C:34]([CH:37]=O)=[CH:33][CH:32]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([NH:4][C:5]1[CH:21]=[CH:20][C:8]([C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)=[O:10])=[C:7]([NH:22][C:23]([CH:25]2[CH2:30][CH2:29][N:28]([CH2:37][C:34]3[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=3)[CH2:27][CH2:26]2)=[O:24])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(NC(=O)c2ccc(NC(C)=O)cc2NC(=O)C2CCNCC2)cc1
Reactant: O=Cc1ccncc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccc(NC(=O)c2ccc(NC(C)=O)cc2NC(=O)C2CCN(Cc3ccncc3)CC2)cc1
Reaction time: 8 h
Yield: 76 %

Procedure:
To a stirred suspension of 4-acetylamino-N-(4-methoxyphenyl)-2-[(4-piperidinylcarbonyl)amino]benzamide (0.4 g, 0.97 mmol), 4-pyridinecarboxaldehyde (0.11 mL, 1.17 mmol) and acetic acid (0.085 mL, 1.46 mmol) in 1,2-dichloroethane (20 mL) was added sodium triacetoxyborohydride (0.31 g, 1.46 mmol). After stirring overnight, the white solid was filtered off and the filtrate was concentrated in vacuo. The residue was suspended in diethyl ether, sonicated, and filtered. The combined solids were then washed with water, filtered and dried in vacuo to give 0.37 g (76%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:5][C@H:4]([N:6]2[C:10]3=[N:11][CH:12]=[CH:13][N:14]=[C:9]3[C:8]([CH3:16])([CH3:15])[C:7]2=[O:17])[CH2:3]1.[NH:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[C:27](O)=[O:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl>[CH3:16][C:8]1([CH3:15])[C:9]2[C:10](=[N:11][CH:12]=[CH:13][N:14]=2)[N:6]([C@@H:4]2[CH2:5][C@H:2]([NH:1][C:27]([C:19]3[NH:18][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]=3)=[O:28])[CH2:3]2)[C:7]1=[O:17]
Reactant: O=C(O)c1nc2ccccc2[nH]1
Reactant: CC1(C)C(=O)N([C@H]2C[C@@H](N)C2)c2nccnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C(=O)N([C@H]2C[C@@H](NC(=O)c3nc4ccccc4[nH]3)C2)c2nccnc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 9.1 %

Procedure:
To a round bottomed flask was added 5-(cis-3-aminocyclobutyl)-7,7-dimethyl-5H-pyrrolo[2,3-b]pyrazin-6(7H)-one (0.1518 g, 0.497 mmol), 1H-benzimidazole-2-carboxylic acid (0.097 g, 0.597 mmol, ChemBridge Corporation), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.246 g, 0.647 mmol, GenScript) and triethylamine (0.277 ml, 1.989 mmol, Sigma-Aldrich Chemical Company, Inc.) in DCM (1.658 ml) to stir at room temperature for 5 h. Solvent was evaporated in vacuo. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage SNAP HP-silica gel column (50 g), eluting with a gradient of 10% to 100% EtOAc in hexane. LCMS showed product was not isolated at ≧95%. The crude product was taken up in DCM and loaded onto an AccuBond SCX cartridge. The cartridge was rinsed with DCM followed by MeOH to remove impurities. The column was then rinsed with 2.0 ammonia in MeOH. The fractions were evaporated in vacuo. The residue was taken up in MeOH at which time a precipitate was noted to form. The round bottomed flask was placed in the freezer overnight. The solid was filtered from the filtrate and washed with cold MeOH to give the title compound (17.1 mg, 0.045 mmol, 9.13% yield). LCMS showed product peak at 1.757 min (m+1=377.0).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)=[CH:4][C:3]=1[CH3:13].[H-].[Na+].I[CH3:17]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:17])[CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[CH3:13]
Reactant: Cc1cc(-c2ncc[nH]2)ccc1Br
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(-c2nccn2C)ccc1Br
Reaction time: 0.5 h

Procedure:
2-(4-Bromo-3-methylphenyl)imidazole (D88, 900 mg; 3.8 mmol) was dissolved in dry THF (30 ml) under argon and treated with sodium hydride (114 mg of an 80% dispersion in mineral oil; 3.8 mmol). After stirring for 30 minutes, iodomethane (237 μl; 3.8 mmol) was added and stirring continued for 18 hours. Evaporated in vacuo, the residue partitioned between water and CHCl3, the organic phase then dried over Na2SO4, filtered and evaporated in vacuo. The residue was purified by flash silica gel chromatography using CHCl3 as eluant to yield the title compound as a clear, colourless gum (600 mg; 63%).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1F)[NH:18][CH:17]=[N:16][C:15]2=[O:23].O>CN(C)C=O>[CH2:1]([O:8][C:21]1[CH:20]=[C:19]2[C:14]([C:15](=[O:23])[N:16]=[CH:17][NH:18]2)=[CH:13][C:12]=1[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1nc[nH]c2cc(F)c(F)cc12
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1nc[nH]c2cc(OCc3ccccc3)c(F)cc12
Temperature: 60 °C
Yield: 83.2 %

Procedure:
Benzyl alcohol (4.27 g, 39.5 mmol) was added dropwise to a stirred suspension of sodium hydride (1.6 g of a 60% dispersion in mineral oil, 40.0 mmol) in dimethylformamide (50 ml) at 0° C. The reaction was stirred at 0° C. for 1 hour before addition of 6,7-difluoroquinazolin-4(1H)-one (3.60 g, 19.8 mmol) whereupon the reaction was heated to 60° C. for 2 hours. The reaction was cooled to ambient temperature, poured into water (200 ml) and the resultant solid collected by suction filtration. Drying of the solid in vacuo yielded 7-(benzyloxy)-6-fluoroquinazolin-4(1H)-one (4.45 g, 83% yield) as a pale brown solid:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH:15]=[C:14]([CH3:25])[C:13]=1[O:26][CH3:27].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:35][C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37].O>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:35][C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37])=[C:4]([CH3:9])[C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH:15]=[C:14]([CH3:25])[C:13]=1[O:26][CH3:27]
Reactant: COc1c(C)cc(-c2cccc(F)c2)cc1CNc1c(F)ccc(O)c1C
Reactant: CC(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: O
Product: COc1c(C)cc(-c2cccc(F)c2)cc1CNc1c(F)ccc(OCC(=O)OC(C)C)c1C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
To a solution of 4-fluoro-3-[[5-(3-fluorophenyl)-2-methoxy-3-methyl-phenyl]methylamino]-2-methyl-phenol (94 mg, 0.25 mmol, 1.0 eq) in acetone (4 mL) at room temperature was added Cs2CO3 (124.4 mg, 0.38 mmol, 1.5 eq). The reaction mixture was stirred for 30 min, then isopropyl bromoacetate (55.3 mg, 1.2 mmol, 1.2 eq) was added and stirring continued for a further 2 h. Water was added and the aqueous layer extracted with EtOAc. The organic extract was washed with water and brinc, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (petroleum ether:EtOAc, 20:1) to give the title compound as a colorless oil (65 mg, 54%).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:5][N:4]2[C:18]([C:21]#[N:22])=[CH:19][CH:20]=[C:3]12.[OH-:23].[Li+].OO>O1CCCC1.O>[O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:17])[F:16])=[CH:10][CH:9]=2)=[CH:5][N:4]2[C:18]([C:21]([NH2:22])=[O:23])=[CH:19][CH:20]=[C:3]12
Reactant: N#Cc1ccc2c(=O)[nH]c(-c3ccc(C(F)(F)F)cc3)cn12
Reactant: [OH-]
Agent: OO
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)c1ccc2c(=O)[nH]c(-c3ccc(C(F)(F)F)cc3)cn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.5 %

Procedure:
A mixture of 1-oxo-3-(4-trifluoromethyl-phenyl)-1,2-dihydro-pyrrolo[1,2-a]pyrazine-6-carbonitrile, (Example 2), (0.03 g, 98.9 82 mol), suspended in tetrahydrofuran (1 mL) was treated with a solution of lithium hydroxide (7.11 mg, 0.29 mmol) in water (500 μL) and 30 wt % aqueous hydrogen peroxide (40.4 μL, 0.39 mmol). The reaction was stirred at room temperature overnight. At this time, the reaction was concentrated in vacuo. The resulting residue was triturated with water. The resulting solid was collected by filtration and then dried in vacuo to afford 1-oxo-3-(4-trifluoromethyl-phenyl)-1,2-dihydro-pyrrolo[1,2-a]pyrazine-6-carboxylic acid amide (20 mg, 61%) as light yellow solid. 1H NMR (methanol-d4) δ ppm 7.94 (d, J=1.5 Hz, 1H), 7.85-7.90 (m, 2H), 7.80-7.84 (m, 2H), 7.77 (s, 1H), 7.52 (d, J=0.8 Hz, 1H). LC-MS calcd. for C15H11F3N3O2 [(M+H)+] 322, obsd. 322.0.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#N.CC(C[AlH]CC(C)C)C.Cl.[OH-:28].[Na+]>C1COCC1.CCOCC>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][N:6]2[CH2:7][CH2:8][CH:3]([CH:1]=[O:28])[CH2:4][CH2:5]2)=[CH:12][CH:13]=1
Reactant: [OH-]
Reactant: N#CC1CCN(CCc2ccc(F)cc2)CC1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=CC1CCN(CCc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-cyano-1-[2-(4-fluorophenyl)ethyl]piperidine (1.00 g, 4.3 mmol) in THF (20 mL) under argon at 0° C. was added DIBAL-H (4.6 mL of a 1.0M solution in THF, 4.6 mmol) via syringe. After stirring overnight at room temperature, 10% aqueous HCl (25 mL) was added and the solution was stirred for 3 hours. The entire mixture was then poured into 10% aqueous NaOH (50 mL), then extractd 2× with ether. The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated to afford a pale yellow oil. The oil was chromatographed on silica gel, eluting with EtOAc. The appropriate fractions were combined and evaporated to afford an oil. This oil was distilled (b.p. 166° C., 0.05 mm Hg) to afford 1-[2-(4-fluorophenyl)ethyl]-4-piperidinecarboxaldehyde, obtained as a colorless oil. Anal. Calcd for C14H18FNO: C, 71.46; H, 7.71; N, 5.95. Found: C, 71.08, H, 7.81; N, 5.86.
Reaction SMILES: [Mg].Br[C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH3:11])[C:6]([O:12][CH3:13])=[CH:5][CH:4]=1.C[Mg]Br.[C:17](=[O:19])=[O:18].Cl>O1CCCC1.O>[CH3:11][O:10][C:7]1[C:8]([CH3:9])=[C:3]([CH:4]=[CH:5][C:6]=1[O:12][CH3:13])[C:17]([OH:19])=[O:18]
Reactant: O=C=O
Reactant: COc1ccc(Br)c(C)c1OC
Agent: C[Mg]Br
Agent: Cl
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O)c(C)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a mixture of magnesium turnings (0.059 g, 2.40 mmol) in tetrahydrofuran (1 ml) was added a solution of 6-bromo-2,3-dimethoxy toluene (0.660 g, 2.3 mmol) in tetrahydrofuran (1 ml). The reaction was initiated by addition of methylmagnesium bromide and the solution was stirred at room temperature overnight under nitrogen. To the mixture was then added an excess of dry ice. When the addition was complete, water was added (2 ml) followed by 1.5 M hydrochloric acid to pH 2. The water phase was extracted with ethyl acetate (2×5 ml) and the combined organic layers were dried over sodium sulfate, filtered and concentrated to give 3,4-dimethoxy-2-methylbenzoic acid (0.315 g, 70% yield). MS (EI) for C10H12O4: 195 (M−H).
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[O-].[Na+].Br[CH:15]([CH3:26])[C:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])=O>O1CCCC1>[C:3]1([C:2]2[NH:9][C:15]([CH3:26])=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N=C(N)c1ccccc1
Reactant: CC(Br)C(=O)c1ccc(Cl)cc1Cl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1[nH]c(-c2ccccc2)nc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C

Procedure:
A suspension of 47.3 g (0.302 mol) of benzamidine hydrochloride, 16.3 g (0.302 mol) of sodium methylate in 250 ml of tetrahydrofuran was heated under reflux for 1 hour, and cooled to 25° C. A solution of 85.2 g (0.302 mol) of the above-mentioned crude 2-bromo-2′,4′-dichloropropiophenone in 160 ml of tetrahydrofuran was added dropwise in such a manner that the reaction temperature did not exceed 30° C. After the addition was complete, 16.3 g (0.302 mol) of sodium methylate was added, and the resultant was heated under reflux for 1 hour. Subsequently, the reaction solution was cooled to room temperature, and insolubles were then filtered off. The filtrate was evaporated to dryness under reduced pressure, to recover a residual solid. This solid was successively washed with water and toluene and then dried, to give 50.4 g (55.0% crude yield) of crude crystals of the desired product. The crude crystals were recrystallized using a mixture of acetonitrile and DMF, to give colorless purified crystals.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][C:8](=O)[NH:9]2)=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]>O=S(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:13][C:3]3[CH:2]=[CH:11][CH:10]=[C:5]([CH3:6])[CH:4]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: O=c1ncc2cc([N+](=O)[O-])c(F)cc2[nH]1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: Cc1cccc(Nc2ncnc3cc(F)c([N+](=O)[O-])cc23)c1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 175.8 %

Procedure:
A suspension of 7-fluoro-6-nitroquinazolone (2.40 g, 11.48 mmol) in neat SOCl2 (25 mL) containing 2 drops of DMF was refluxed for 3 hours until it became clear. The excess SOCl2 was then removed in vacuo and dry benzene was added to the residue and then distilled under reduced pressure to remove all traces of SOCl2 giving crude 4-chloro-7-fluoro-6-nitroquinazoline, which was dissolved in dry CH2Cl2 (50 mL) and added to a stirred solution of m-toluidine in isopropanol (i-PrOH) (30 mL). The reaction mixture was stirred at 20° C. for 30 minutes and then hexane (200 mL) was added to precipitate the product as the HCl salt. The precipitate was filtered, washed with hexane, and then dissolved in MeOH/H2O (4:1, 150 mL) with gentle warming. Excess Et3N was then added to the solution followed by water (400 mL) to precipitate the product as the free base which was then filtered, washed with water and dried under reduced pressure to give 7-fluoro-4-[(3-methylphenyl)-amino]-6-nitroquinazoline (3.01 g, 88%) as a yellow powder, mp (CH2Cl2/hexane) 191-192° C.