Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:25]=[CH:24][C:5]2[NH:6][C:7]([N:9]3[CH2:14][CH2:13][C:12]4([C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[C:16](=[O:23])[O:15]4)[CH2:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1.[O:26]1CCO[CH2:28][CH2:27]1>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:27]([C:2]1[CH:25]=[CH:24][C:5]2[NH:6][C:7]([N:9]3[CH2:14][CH2:13][C:12]4([C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[C:16](=[O:23])[O:15]4)[CH2:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1)(=[O:26])[CH3:28]
Reactant: C1COCCO1
Reactant: O=C1OC2(CCN(c3nc4cc(I)ccc4[nH]3)CC2)c2ccccc21
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=O)c1ccc2[nH]c(N3CCC4(CC3)OC(=O)c3ccccc34)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Add 1-ethoxyvinyltri-N-butyltin (0.49 g, 1.35 mmol) and bis (triphenyl-phosphine) palladium (II) chloride (0.05 g) to a solution of 1′-(5-iodo-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one (0.12 g, 0.27 mmol) in dioxane (5 mL). Reflux the reaction mixture for 12 hours. After cooling to ambient temperature, concentrate the reaction mixture in vacuo, and add to a solution of 10% HCl (2 mL) in THF (5 mL). After stirring for 30 minutes, dilute the solution with EtOAc (30 mL), and wash with saturated NaHCO3 (30 mL) and saturated aqueous NaCl (30 mL). Dry the organic portion over Na2SO4, filter and concentrate. Purify by preparative TLC (10% MeOH—CH2Cl2) to obtain 1′-(5-acetyl-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12](=[O:22])[O:13][C@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1B(O)O>CC([O-])=O.CC([O-])=O.[Pd+2]>[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@H:14]([O:13][C:12](=[O:22])[NH:11][C:8]1([C:5]3[CH:6]=[CH:7][C:2]([C:27]4[CH:26]=[CH:25][C:24]([F:23])=[CH:29][C:28]=4[F:30])=[CH:3][CH:4]=3)[CH2:10][CH2:9]1)[CH2:15]2
Reactant: OB(O)c1ccc(F)cc1F
Reactant: O=C(NC1(c2ccc(Br)cc2)CC1)O[C@@H]1CN2CCC1CC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: O=C(NC1(c2ccc(-c3ccc(F)cc3F)cc2)CC1)O[C@@H]1CN2CCC1CC2
Yield: 22.8 %

Procedure:
Using general procedure E, (S)-quinuclidin-3-yl 1-(4-bromophenyl)cyclopropylcarbamate (0.446 g, 1.22 mmol), 2,4-difluorophenyl boronic acid (0.386 g, 2.44 mmol) and Pd(OAc)2 (0.015 g, 0.067 mmol) gave the title compound as a tan solid (0.111 g, 23%). 1H NMR (CDCl3) δ 7.43 (dd, J=8.4, 1.6 Hz, 2H), 7.40-7.33 (m, 1H), 7.31 (d, J=7.7 Hz, 2H), 6.99-6.81 (m, 2H), 5.54 (d, J=48.0 Hz, 1H), 4.82-4.65 (m, 1H), 3.30-3.07 (m, 1H), 2.98-2.44 (m, 5H), 1.97 (d, J=32.7 Hz, 1H), 1.83 (d, J=10.3 Hz, 1H), 1.64 (s, 1H), 1.52 (s, 1H), 1.39 (s, 1H), 1.31 (d, J=6.8 Hz, 4H) ppm. 13C NMR major rotomer (CDCl3) δ 162.2 (dd, J=12.8, 249.1 Hz), 159.8 (dd, J=11.8, 251.0 Hz), 156.9, 156.0, 142.6, 133.1, 131.3 (m), 128.9, 125.6, 124.9, 111.5 (dd, J=3.9, 21.2 Hz) 104.4 (dd, J=25.2, 29.4 Hz), 72.1, 71.6, 55.7, 47.4, 46.5, 35.7, 35.3, 25.5, 24.6, 24.4, 19.5, 18.1 ppm. Purity: LCMS >99.3% (214 nm & 254 nm): retention time 0.90 min: (M+1) 399.0
Reaction SMILES: [CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[N:6]([CH2:14][C:15](O)=[O:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.C1(N=C=NC2CCCCC2)CCCCC1.[C:35]([NH2:39])([CH3:38])([CH3:37])[CH3:36]>ClCCl.CN(C)C1C=CN=CC=1>[C:35]([NH:39][C:15](=[O:16])[CH2:14][N:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=2[C:4]2[CH2:3][N:2]([CH3:1])[CH2:19][CH2:18][C:5]1=2)([CH3:38])([CH3:37])[CH3:36]
Reactant: Cc1ccc2c(c1)c1c(n2CC(=O)O)CCN(C)C1
Reactant: CC(C)(C)N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CC(=O)NC(C)(C)C)CCN(C)C1
Reaction time: 14 h
Yield: 14.5 %

Procedure:
To a solution of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetic acid (200 mg, 0.77 mmol) in dichloromethane (20 ml) was added N,N′-dicyclohexylcarbodiimide (191 mg, 0.92 mmol) followed by the addition of 4-dimethylaminopyridine (113 mg, 0.93 mmol) and tert butylamine (67 mg, 0.93 mmol). The resulting mixture was stirred at 25 deg C. for 14 h. The solvent was removed in vacuo and purified by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 ml) to obtain 35 mg of N-tert-butyl-2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetamide as trifluoroacetic acid salt. 1H NMR (DMSO-D2O) TFA SALT 7.21-7.20 (d, 2H), 7.0-6.95 (d, 1H), 4.60-4.50 (d, 2H), 3.75-3.65 (m, 2H), 3.50-3.38 (m, 2H), 3.10-3.0 (m, 2H), 2.90 (s, 3H), 2.30 (s, 3H), 1.20 (s, 9H).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].B(F)(F)F.CCOCC.[C:21]1(C)[CH:26]=CC=C[CH:22]=1>CC(C)=O>[C:5]([C:4]1[CH:8]=[CH:9][C:10]2[O:11][C:21]([CH3:26])([CH3:22])[S:1][C:2]=2[CH:3]=1)([OH:7])=[O:6]
Reactant: Cc1ccccc1
Reactant: O=C(O)c1ccc(O)c(S)c1
Agent: FB(F)F
Solvent: CC(C)=O
Solvent: CCOCC
Product: CC1(C)Oc2ccc(C(=O)O)cc2S1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
16 g of 3-mercapto-4-hydroxybenzoic acid (III) was dissolved in a mixture of 300 ml of toluene and 50 ml of acetone. 50 ml of boron trifluoride etherate was added and the mixture was stirred at room temperature for 4 hours. Ice (50 g) was added and the mixture was stirred for a further 1 hour. The organic layer was separated, washed with brine, dried with magnesium sulfate and evaporated to leave a solid residue. The residue was recrystallized from aqueous methanol to yield 15 g of 5-carboxy-2,2-dimethyl-1,3-benzoxathiole (IV), m.p. 124°-125° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH:10]=[CH:9][S:8]1)=[O:5])[CH3:2].[I:22]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]=[C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=2)[CH:10]=[C:9]([I:22])[S:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N=c1sccn1-c1cccc(C(F)(F)F)c1
Reactant: O=C1CCC(=O)N1I
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N=c1sc(I)cn1-c1cccc(C(F)(F)F)c1
Yield: 14.3 %

Procedure:
A solution of 2-ethoxycarbonylimino-3-(3-trifluoromethylphenyl)thiazoline (0.5 g) and N-iodosuccinimide (0.4 g) in chloroform (30 ml) was refluxed for 20 hours. After cooling, the reaction mixture was washed with an aqueous sodium sulfite solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was subjected to column chromatography to give 0.1 g of 2-ethoxycarbonylimino-3-(3-tri-fluoromethylphenyl)-5-iodothiazoline (Compound No. 42).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[CH:15]2.C(N(CC)CC)C.[OH-].[Na+]>O1CCCC1.O>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([NH2:11])=[CH:20][CH:19]=3)[CH:15]=[CH:16]2)=[O:7])=[CH:4][CH:3]=1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ccc2c(ccn2C(=O)c2ccc(F)cc2)c1
Reaction time: 18 h
Yield: 83.5 %

Procedure:
The 4-fluorobenzoyl chloride (5.2 g, 33 mmol) in 30 ml of tetrahydrofuran was added dropwise to a solution of the 5-amino-1H-indole (3.96 g, 30.0 mmol) and triethylamine (4.04 g, 40 mmol) at room temperature. The reaction was stirred for 18 hours and then poured into water. The mixture was made basic with sodium hydroxide solution then extracted with methylene chloride. The extract was dried (sodium sulfate) and concentrated. The residue was recrystallized from ethyl acetate/hexanes to give 6.37 g of product. (84%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)=[C:10]2[C:14]([CH3:16])([CH3:15])[CH2:13][CH2:12][O:11]2)=[CH:4][CH:3]=1.OO.[OH2:24].C(O)(=[O:27])C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:9]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)=[C:10]2[C:14]([CH3:16])([CH3:15])[CH2:13][CH2:12][O:11]2)(=[O:27])=[O:24])=[CH:4][CH:3]=1
Reactant: CC1(C)CCOC1=C(Sc1ccc(Cl)cc1)n1ccnc1
Reactant: O
Reactant: CC(=O)O
Agent: OO
Product: CC1(C)CCOC1=C(n1ccnc1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 49 %

Procedure:
20 g (0.062 mole) of (4-chlorophenylthio)-(imidazol-1-yl)-(3,3-dimethyl-tetrahydrofuran-2-ylidene)-methane (Example I-1) and 28 g (0.25 mole) of 30% strength hydrogen peroxide in 200 ml of glacial acetic acid are stirred at 50° C. for 20 hours. The reaction mixture is then poured into 1.5 liter of water and extracted with methylene chloride. The organic phase is dried over sodium sulphate and concentrated. 10.7 g (49% of theory) of (4-chlorophenylsulphonyl)-(imidazol-1-yl)-(3,3-dimethyltetrahydrofuran-2-ylidene)-methane of melting point 192°-194° C. are obtained.
Reaction SMILES: [F:1][CH:2]([F:20])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9](CCCN(C)C)[N:8]=[C:7]2I.[CH:21]([Mg]Cl)(C)C.[CH2:26]([Sn:30]([CH2:35][CH2:36][CH2:37][CH3:38])(Cl)[CH2:31][CH2:32][CH3:33])[CH2:27][CH2:28][CH3:29]>C1COCC1>[F:20][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[Sn:30]([CH2:35][CH2:36][CH2:37][CH3:38])([CH2:31][CH2:32][CH2:33][CH3:21])[CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CC(C)[Mg]Cl
Reactant: CCCC[Sn](Cl)(CCC)CCCC
Reactant: CN(C)CCCn1nc(I)c2cc(OC(F)F)ccc21
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2ccc(OC(F)F)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(5-(difluoromethoxy)-3-iodo-1H-indazol-1-yl)-N,N-dimethylpropan-1-amine (1.2 g, 2.78 mmol) in dry THF (25 mL) was added isopropylmagnesium chloride (1.5 mL, 2M in THF, 3 mmol) drop-wise at −16° C. under nitrogen atmosphere. The reaction was stirred for 30 minutes, then dibutylchloro (propyl)stannane (3.3 mL, 3.6 mmol) was added dropwise at −16° C. under nitrogen, then the reaction mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was quenched with a solution of saturated NH4Cl (40 mL) and product extracted with EtOAc (3×30 mL), organics combined dried with sodium sulfate, filtered and concentrated. Crude oil used into the next step without further purification (1.1 g, crude).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])[CH:3]=1.I[CH:17]([CH3:19])[CH3:18]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH:17]([CH3:19])[CH3:18])[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])[CH:3]=1
Reactant: CC(C)I
Reactant: Cc1cc(C)nc(-n2c(C)ccc2C)c1
Product: Cc1cc(CC(C)C)nc(-n2c(C)ccc2C)c1

Procedure:
By analogy to Example 71, Step A, the anion of 4,6-dimethyl-2-(2,5-dimethylpyrrol-1-yl)pyridine was alkylated with 2-iodopropane to give 4-methyl-6-(2-methylpropyl)-2-(2,5-dimethylpyrrol-1-yl)pyridine.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].C([O-])(=O)C.[K+].[C-:17]#[N:18].[Na+]>C(O)C.O>[O:5]=[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:2][C:17]#[N:18]
Reactant: O=C(CCCl)c1ccccc1
Reactant: [C-]#N
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CCCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.3 %

Procedure:
To a solution of 3-chloro-1-phenylpropan-1-one (5.0 g, 29.7 mmol) in hot ethanol (7 mL) was added potassium acetate (2.91 g, 29.77 mmol). After cooling to room temperature, the precipitated salt was removed via filtration. To the filtrate in a septum-sealed flask under a nitrogen bubbler was slowly added sodium cyanide (2.91 g, 59.3 mmol) as a solution in water (10 mL). After stirring at room temperature for 24 hours, ethanol (30 mL) was added, and the mixture was cooled in an ice bath. The precipitate was filtered and rinsed with ethanol to provide the product (3.42 g, 73%) as fluffy white solid.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[N+:24]([C:27]1[C:36]2[CH2:35][CH2:34][CH2:33][CH2:32][C:31]=2[CH:30]=[CH:29][C:28]=1[O:37][CH2:38][CH2:39][CH2:40]Br)([O-:26])=[O:25]>O>[N+:24]([C:27]1[C:36]2[CH2:35][CH2:34][CH2:33][CH2:32][C:31]=2[CH:30]=[CH:29][C:28]=1[O:37][CH2:38][CH2:39][CH2:40][N:10]1[CH2:11][CH2:12][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1c(OCCCBr)ccc2c1CCCC2
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c(OCCCN2CCN(c3ccccc3)CC2)ccc2c1CCCC2
Temperature: 60 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
1-Phenylpiperazine (2.77 g, 17.1 mmol), potassium carbonate (7.1 g, 51.4 mmol) and N,N-dimethylformamide (30 ml) were added to 5,6,7,8-tetrahydro-1-nitro-2-(3-bromopropoxy)naphthalene (4.8 g, 15.3 mmol) and the mixture was stirred at 60° C. for 8 hours. The reaction mixture was added with water (80 ml) and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The residue was purified by silica gel chromatography (Wako Gell C-300: 200 g, eluent: hexane/ethyl acetate=7/1 to 3/1) to give 5,6,7,8-tetrahydro-1-nitro-2-[3-(4-phenyl-1-piperazinyl) propoxy]naphthalene (5.5 g).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[O:27]1[CH2:32][CH2:31][O:30][CH2:29][CH:28]1[CH2:33][C:34](O)=[O:35]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:34](=[O:35])[CH2:33][CH:28]5[CH2:29][O:30][CH2:31][CH2:32][O:27]5)[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: O=C(O)CC1COCCO1
Agent: Cl
Product: O=C(CC1COCCO1)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (85 mg, 75%), MS (ISP) m/z=457.5 [(M+H)+], mp 192° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and rac-(1,4-dioxan-2-yl)-acetic acid.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[N:3]=[CH:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:24][C:25]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:26]=1[S:33](Cl)(=[O:35])=[O:34]>O1CCCC1.C(OCC)(=O)C>[S:1]1[CH:5]=[C:4]([N:6]([S:33]([C:26]2[CH:27]=[C:28]([F:32])[C:29]([F:31])=[CH:30][C:25]=2[F:24])(=[O:35])=[O:34])[C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[N:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)Nc1cscn1
Reactant: O=S(=O)(Cl)c1cc(F)c(F)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(F)c(F)cc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
A solution of tert-butyl thiazol-4-ylcarbamate (3.46 g, 17.3 mmol) in tetrahydrofuran (150 mL) at −78° C. was treated with lithium bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran, 20.8 mL, 20.8 mmol). The resulting mixture was stirred at −78° C. for 0.5 h, allowed to warm to ambient temperature and stirred for a further 0.5 h. The reaction mixture was cooled to −78° C. and treated with a solution of 2,4,5-trifluorobenzene-1-sulfonyl chloride (3.99 g, 17.3 mmol) in tetrahydrofuran (30 mL). The resulting mixture was stirred at −78° C. for 4 h, allowed to warm to ambient temperature and stirred for a further 16 h. The reaction mixture was diluted with ethyl acetate (300 mL) and washed with saturated aqueous ammonium chloride (2×150 mL) and brine (2×150 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with a gradient of ethyl acetate in hexanes to afford tert-butyl thiazol-4-yl((2,4,5-trifluorophenyl)sulfonyl)carbamate as a beige solid in 62% yield (4.23 g): 1H NMR (300 MHz, CDCl3) δ 8.79-8.75 (m, 1H), 8.06-7.96 (m, 1H), 7.53-7.48 (m, 1H), 7.15-7.04 (m, 1H), 1.34 (s, 9H); MS (ES+) m/z 394.7 (M+1).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([O:16][CH3:17])[C:6]=1[C:7]([OH:9])=[O:8])(O)=[O:2].C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[CH3:15][O:14][C:12]1[CH:13]=[C:5]2[C:6](=[C:10]([O:16][CH3:17])[CH:11]=1)[C:7](=[O:9])[O:8][C:1](=[O:2])[CH2:4]2
Reactant: COc1cc(CC(=O)O)c(C(=O)O)c(OC)c1
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc2c(c(OC)c1)C(=O)OC(=O)C2
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 83.1 %

Procedure:
2-Carboxymethyl-4,6-dimethoxybenzoic acid (60) (3.97 gm) was stirred in toluene (40.0 mL) at ambient temperature in a 100 mL flask with magnetic stirring. Acetic anhydride (1.72 mL) was added and the mixture heated to 110° C. Monitoring by HPLC revealed that the reaction was complete within 2.5 hours. Heat was then removed. Crystallization of 6,8-dimethoxyisochroman-1,3-dione (25) occurred as the solution cooled. The mixture was cooled to 2° C. After a short hold time, yellow crystalline solids were filtered, washed with fresh toluene and then dried on high vacuum. 6,8-Dimethoxyisochroman-1,3-dione (25) (3.05g) was isolated as a yellow crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:18]([CH3:19])[C:17]3[C:12](=[N:13][C:14]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28][N:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)[CH:22]=4)=[N:15][CH:16]=3)[N:11]([C:36]3[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=3)[C:39]#[N:40])[C:10]2=[O:44])=[CH:5][CH:4]=1.[OH-:45].[Na+].C(#N)C1C=CC=CC=1.OO>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:18]([CH3:19])[C:17]3[C:12](=[N:13][C:14]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28][N:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)[CH:22]=4)=[N:15][CH:16]=3)[N:11]([C:36]3[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=3)[C:39]([NH2:40])=[O:45])[C:10]2=[O:44])=[CH:7][CH:8]=1
Reactant: [OH-]
Reactant: COc1ccc(N2C(=O)N(c3cccc(C#N)c3)c3nc(Nc4cccc(CCN5CCN(C)CC5)c4)ncc3C2C)cc1
Agent: OO
Agent: [Na+]
Solvent: N#Cc1ccccc1
Solvent: CS(C)=O
Product: COc1ccc(N2C(=O)N(c3cccc(C(N)=O)c3)c3nc(Nc4cccc(CCN5CCN(C)CC5)c4)ncc3C2C)cc1

Procedure:
(±)-3-(3-(4-Methoxy-phenyl)-4-methyl-7-{3-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenylamino}-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl)-benzonitrile (0.25 g; 0.41 mmol) (from Example 7 supra) was dissolved in dimethyl sulfoxide (2.5 mL) and the resulting solution was cooled in an ice-water bath. Aqueous sodium hydroxide (1 M; 750 μL; 0.75 mmol) was added, resulting in the precipitation of the benzonitrile. Aqueous hydrogen peroxide (30%; 130 μL; 1.27 mmol) was then added. The cooling bath was removed. The solid went back into solution and a new solid precipitated out. After 3 hours the reaction mixture was diluted with water. The solid was collected, washed with water and air-dried under the house vacuum. Purification by flash chromatography (Biotage 12S; 90:10 to 60:40 chloroform-methanol gradient) and then crystallization from methanol-ethyl acetate gave (±)-3-(3-(4-methoxy-phenyl)-4-methyl-7-{3-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenylamino}-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl)-benzamide as a white solid. (Yield 35.7 mg; 14.3%). A second crop was collected by addition of ether to the mother liquor. (Yield 87.8 mg; 35.1%). Melting Point: 243–251° C. HR-MS(ES+) m/z Calculated for C34H38N8O3 ([M+H]+): 607.3140; Found: 607.3144.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH3:15])[CH2:10][CH2:9]2)[CH:5]=[C:4]([CH3:16])[N+:3]=1[O-:17].Cl[S:19]([OH:22])(=[O:21])=[O:20].C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[OH-:17].[NH2:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH3:15])[CH2:10][CH2:9]2)[CH:5]=[C:4]([CH3:16])[N+:3]=1[O:17][S:19]([OH:22])(=[O:21])=[O:20]
Reactant: CCN1CCN(c2cc(C)[n+]([O-])c(N)c2)CC1
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCN(c2cc(C)[n+](OS(=O)(=O)O)c(N)c2)CC1
Product: [OH-]
Reaction time: 8 h

Procedure:
A mixture of 1.00 grams of 2-amino-6-methyl-4-(4-ethyl-1-piperazinyl)pyridine-1-oxide, 1.15 grams of chlorosulfonic acid, and 2.50 grams of di-isopropylethylamine and 25 mls of chloroform is stirred overnight. The mixture is concentrated in vacuo. The residue is stirred with aqueous sodium bicarbonate, filtered, and washed with ether to give 2-amino-6-methyl-4-(4-ethyl-1-piperazinyl)-1-sulfooxypyridinium hydroxide, inner salt.
Reaction SMILES: OC[C@@H](NC(C1C=NC(N2CCCC2)=C(OCCC)N=1)=O)CC(C)C.[CH:26]1([CH2:31][O:32][C:33]2[N:38]=[C:37]([C:39](O)=[O:40])[CH:36]=[N:35][C:34]=2[N:42]2[CH2:47][CH2:46][C:45]([F:49])([F:48])[CH2:44][CH2:43]2)[CH2:30][CH2:29][CH2:28][CH2:27]1.[CH3:50][O:51][C:52](=[O:59])[C@H:53]([CH2:55][CH:56]([CH3:58])[CH3:57])[NH2:54]>>[CH3:50][O:51][C:52](=[O:59])[C@@H:53]([NH:54][C:39]([C:37]1[CH:36]=[N:35][C:34]([N:42]2[CH2:47][CH2:46][C:45]([F:48])([F:49])[CH2:44][CH2:43]2)=[C:33]([O:32][CH2:31][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[N:38]=1)=[O:40])[CH2:55][CH:56]([CH3:58])[CH3:57]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: O=C(O)c1cnc(N2CCC(F)(F)CC2)c(OCC2CCCC2)n1
Agent: CCCOc1nc(C(=O)N[C@H](CO)CC(C)C)cnc1N1CCCC1
Product: COC(=O)[C@H](CC(C)C)NC(=O)c1cnc(N2CCC(F)(F)CC2)c(OCC2CCCC2)n1

Procedure:
In analogy to the procedure described for the synthesis of 6-propoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide (example 10, step d) the title compounds was prepared from 6-cyclopentylmethoxy-5-(4,4-difluoro-piperidin-1-yl)-pyrazine-2-carboxylic acid and (S)-leucine methyl ester (commercially available). m/z (ES+): 469.1 (M+H).
Reaction SMILES: [F:1][B-](F)(F)F.N#[O+].[CH3:8][O:9][C:10](=[O:34])[C:11]1[CH:23]=[C:22]([C:24]2([C:29]3[O:30][CH:31]=[CH:32][CH:33]=3)SCCS2)[CH:21]=[C:13]([C:14]([N:16]([CH3:20])[CH2:17][CH2:18][CH3:19])=[O:15])[CH:12]=1.C1C=CN=CC=1.[FH:41]>ClCCl>[CH3:8][O:9][C:10](=[O:34])[C:11]1[CH:23]=[C:22]([C:24]([F:1])([F:41])[C:29]2[O:30][CH:31]=[CH:32][CH:33]=2)[CH:21]=[C:13]([C:14]([N:16]([CH3:20])[CH2:17][CH2:18][CH3:19])=[O:15])[CH:12]=1
Reactant: F[B-](F)(F)F
Reactant: F
Reactant: CCCN(C)C(=O)c1cc(C(=O)OC)cc(C2(c3ccco3)SCCS2)c1
Agent: N#[O+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCN(C)C(=O)c1cc(C(=O)OC)cc(C(F)(F)c2ccco2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
Under nitrogen and in a plastic vessel, dissolve nitrosonium tetrafluoroborate (84.8 μg, 0.72 mmol) and pyridinium poly(hydrogen fluoride) (70% hydrogen fluoride, 30% pyridine, 300 μL) in dichloromethane (2 mL) and cool to 0° C. Add dropwise 5-(2-furan-2-yl-[1,3]dithiolan-2-yl)-N-methyl-N-propyl-isophthalamic acid methyl ester in dichloromethane (1.5 mL) to the mixture, warm up to room temperature and stir for 2 h. Dilute the mixture with dichloromethane (20 mL) and filter the organic liquid though a pad of aluminum oxide and magnesium sulfate mixture. Concentrate the filtrate and purify (silica gel chromatography, 1:99 to 30:70 ethyl acetate:hexanes) to give the title compound (30%).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH:11]1[CH2:17][CH:16]2[N:18]([CH3:19])[CH:13]([CH2:14][CH2:15]2)[CH2:12]1)=O.O.[NH2:21][NH2:22]>C(O)C>[F:8][C:6]1[CH:7]=[C:2]2[C:3]([C:9]([CH:11]3[CH2:17][CH:16]4[N:18]([CH3:19])[CH:13]([CH2:14][CH2:15]4)[CH2:12]3)=[N:21][NH:22]2)=[CH:4][CH:5]=1
Reactant: CN1C2CCC1CC(C(=O)c1ccc(F)cc1F)C2
Reactant: NN
Solvent: O
Solvent: CCO
Product: CN1C2CCC1CC(c1n[nH]c3cc(F)ccc13)C2
Yield: 19.9 %

Procedure:
A mixture of (2,4-difluorophenyl)(8-methyl-8-azabicyclo-[3.2.1]octan-3-yl)methanone (25.5 g), hydrazine hydrate (21 g) and ethanol (250 ml) was heated at reflux for 16 hours. The reaction mixture was concentrated to an oil on the rotary evaporator. The residue was dissolved in DMF (350 ml) and potassium carbonate (25 g) was added to the mixture which was refluxed for 16 hours. The mixture was cooled, filtered and stripped down in vacuo. The residue was dissolved in hot ethanol to yield 4.96 g of a solid. Recrystallization from ethanol gave 3.88 g of crystals, m.p. 235°-236° C.