Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28]([OH:30])=O)[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH2:33][C:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1)([CH3:36])[CH3:35].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH3:35][C:34]([NH:33][C:28]([C:23]1[CH:24]=[N:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:31])([F:1])[F:32])=[CH:8][CH:7]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=2)=[O:30])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1)[CH3:36]
Reactant: CC(C)(N)c1ccccn1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(NC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.2 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with 2-amino-2-(2-pyridyl)-propane (47 mg, 0.35 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 50 ml of dichloromethane, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide a residue. This material was purified by preparative thin-layer-chromatography on silica eluting with 4% methanol in dichloromethane. The product containing band was collected and eluted with 5% methanol in ethyl acetate to afford 50 mg of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH:5]=1.Cl[C:18]1[NH:19][C:20]2[C:25]([C:26](=[O:28])[N:27]=1)=[C:24]([CH3:29])[C:23]([O:30][CH3:31])=[C:22]([O:32][CH3:33])[CH:21]=2>CCO>[CH3:31][O:30][C:23]1[C:24]([CH3:29])=[C:25]2[C:20](=[CH:21][C:22]=1[O:32][CH3:33])[NH:19][C:18]([N:2]([CH3:1])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH:5]=1)=[N:27][C:26]2=[O:28]
Reactant: CNCc1cccc(C2CCN(C)CC2)c1
Reactant: COc1cc2[nH]c(Cl)nc(=O)c2c(C)c1OC
Solvent: CCO
Product: COc1cc2[nH]c(N(C)Cc3cccc(C4CCN(C)CC4)c3)nc(=O)c2c(C)c1OC
Temperature: 120 °C

Procedure:
In a heavy-walled pressure tube, a mixture of methyl-[3-(1-methylpiperidin-4-yl)benzyl]amine (0.14 g, 0.64 mmol) and 2-chloro-6,7-dimethoxy-5-methyl-1H-quinazolin-4-one (0.155 g, 0.60 mmol) in 4 mL of EtOH, was heated to 120° C. for 5 hours. After solvent removal, the residue was purified by flash chromatography eluting with CH2Cl2:MeOH:NH4OH (94.5:5:0.5), and the above-titled Example H-3 crystallized from CH2Cl2/cyclohexane. mp 155.7–158° C.; IR (KBr) νmax 2933, 1651, 1590 cm−1; 1H NMR (DMSO-d6, 2.49) δ 1.59–1.71 (m, 4H), 1.93 (m, 2H), 2.16 (s, 3H), 2.42 (m, 1 H), 2.60 (s, 3H), 2.82 (m, 2 H), 3.01 (s, 3H), 3.62 (s, 3H), 3.84 (s, 3H), 4.78 (s, 2H), 6.63 (br s, 1H), 7.03 (d, 1H, J=7.44), 7.11–7.13 (m, 2 H), 7.25 (t, 1H, J=7.74), 10.81 (br s, D2O, 1H); 13C NMR (DMSO-d6, 39.50) δ 13.44, 32.94, 35.12, 41.08, 46.09, 51.64, 55.44, 55.65, 59.76, 124.61, 125.32, 125.65, 128.44, 137.54, 146.43; MS (ES+) m/z 437 (M+H); Anal. (C25H32N4O3.0.25H2O)C: calcd, 68.08; found, 68.02; H: calcd, 7.43; found, 7.19; N: calcd, 12.70; found, 12.69.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[CH:45]([NH2:47])[CH3:46]>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:10]=[CH:11][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:22])[NH:47][CH:45]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][N:39]=3)[CH3:46])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:37])[CH3:38])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:13][CH:14]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Reactant: CC(N)c1ccccn1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)NC(C)c4ccccn4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Yield: 93 %

Procedure:
According to the procedure in Example 385F, the title compound was prepared using 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid (prepared in Example 385E) and (RS)-1-pyridin-2-yl-ethylamine: yield 93%.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=O.[CH3:13][C:14]([S@:17]([NH2:19])=[O:18])([CH3:16])[CH3:15]>ClCCl.S([O-])([O-])(=O)=O.[Cu+2]>[C:14]([S@:17](/[N:19]=[CH:1]/[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=[O:18])([CH3:16])([CH3:15])[CH3:13]
Reactant: CC(C)(C)[S@](N)=O
Reactant: COC(=O)c1cccc(C=O)c1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: COC(=O)c1cccc(/C=N/[S@](=O)C(C)(C)C)c1
Reaction time: 8 h
Yield: 14.3 %

Procedure:
A suspension of 3.0 g of methyl 3-formylbenzoate, 2.25 g of (R)-2-methyl-2-propanesulfinamide, and 6.0 g of copper (II) sulfate in 50 ml of dichloromethane was stirred overnight. The reaction mixture was filtered over Celite and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 700 mg of methyl 3-[(E)-{[(R)-tert-butylsulfinyl]imino}methyl]benzoate.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C@H:13]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:12]3)O1.Br[C:27]1[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:35])[F:34])=[N:31][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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:34][C:33]([F:36])([F:35])[C:30]1[N:31]=[CH:32][C:27]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C@H:13]([NH:18][S:19]([CH:22]([CH3:23])[CH3:24])(=[O:20])=[O:21])[CH2:12]3)=[CH:28][CH:29]=1
Reactant: FC(F)(F)c1ccc(Br)cn1
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(-c3ccc(C(F)(F)F)nc3)cc2C1

Procedure:
To a solution of N-[(2S)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide (190 mg, 0.52 mmol) in dry 1,4 dioxane (5 ml), polymer supported Pd(PPh3)4 (10 mg, 0.5 mmol/g, 0.005 mmol) was added along with 5-bromo-2-(trifluoromethyl)pyridine (176 mg, 0.78 mmol) and 500 μl of a 2M Na2CO3 solution in water. The resulting mixture was heated at 90° degrees for 3 hours. Then after cooling the resin was removed by filtration and then the solvent was removed under reduced pressure. The residue was taken up with DCM, washed with water and loaded on a 25M+ silica cartridge eluating with a cyclohexane/AcOEt 75/25 mixture. 150 mg of title compound were recovered as whitish solid (75%). Due to the use of chiral Intermediate 7, the final compound is believed to be N-{(2S)-5-[6-(trifluoromethyl)-3-pyridinyl]-2,3-dihydro-1H-inden-2-yl}-2-propanesulfonamide.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([O:12][CH2:13][C:14]([O:16]CC)=[O:15])[CH:3]=1.[OH-].[K+]>CO.O>[C:14]([CH2:13][O:12][C:4]1[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:5]=1[C:6]([OH:8])=[O:7])([OH:16])=[O:15]
Reactant: CCOC(=O)COc1cc(Cl)ccc1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)COc1cc(Cl)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.8 %

Procedure:
To a solution of methyl 4-chloro-2-(2-ethoxy-2-oxoethoxy)benzoate (10 g, 36.67 mmol) in methanol (250 mL) and water (50 mL) was added potassium hydroxide (4 g, 71.43 mmol). After stirring for 1.5 h at 25° C., the resulting mixture was concentrated under vacuum, dissolved in water (50 mL), adjusted to pH 6 with HCl (3N) and filtered to give 2-(carboxymethoxy)-4-chlorobenzoic acid as a white solid (7 g, 80%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]([O:10][CH3:11])=[O:9].C([Sn](CCCC)(CCCC)[C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1)CCC>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>[N:18]1[CH:19]=[CH:20][N:21]=[CH:22][C:17]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: COC(=O)c1cnccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cnccc1-c1cnccn1
Temperature: 100 °C
Reaction time: 3 h
Yield: 66.4 %

Procedure:
To a solution of methyl 4-chloro-3-pyridinecarboxylate (1200 mg; may be prepared as described in Intermediate 18) and 2-(tributylstannanyl)pyrazine (3000 mg) in toluene (20 mL), tetrakis(triphenylphosphine)palladium(0) (808 mg) in toluene (20 mL) was added and the reaction mixture was stirred at 100° C. for 3 h. Then the solvent was evaporated in vacuo and the crude product was added to a silica gel column and eluted with cyclohexane/EtOAc/MeOH=7/2.5/0.5. The evaporation of the collected fractions gave 1 g of the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([CH2:23][C:24]#[C:25][CH3:26])[C:21]3[C:20](=[O:27])[NH:19][C:18](=[O:28])[NH:17][C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:35]([O:41][CH2:42]Cl)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:22]([CH2:23][C:24]#[C:25][CH3:26])[C:21]3[C:20](=[O:27])[NH:19][C:18](=[O:28])[N:17]([CH2:42][O:41][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])[C:16]=3[N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2[nH]c(=O)[nH]c(=O)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)[nH]c(=O)n2COC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[7-(2-Butynyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (1.1 g) and potassium carbonate (0.43 g) were dissolved in N,N-dimethylformamide (15 ml), and chloromethyl pivalate (0.60 ml) was added to the solution while cooling on ice. After the mixture was stirred at room temperature overnight, the reaction mixture was diluted with ethyl acetate and washed with water. Insoluble white solid was collected by filtration, and washed with a mixture of hexane-ethyl acetate (1:1) to give 0.57 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].CC(C)([O-])C.[K+].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([O:23][CH3:24])[CH:18]=1.O>CC(N(C)C)=O>[F:9][C:3]1[CH:4]=[C:5]([O:8][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([O:23][CH3:24])[CH:18]=2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: COc1cc(Cl)ccn1
Reactant: Nc1ccc(O)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(Oc2ccc(N)c(F)c2)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.4 %

Procedure:
A solution of 4-amino-3-fluorophenol (0.20 g, 1.6 mmol) in 4 mL of anhydrous DMA was treated with potassium tert-butoxide (0.24 g, 1.9 mmol). The resultant dark-red solution was stirred at RT for 1 hour in a capped vial. 4-Chloro-2-methoxypyridine (0.26 g, 1.6 mmol) was added and the reaction mixture was heated overnight at 100° C. Water (50 mL) was added and the solution was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried (Na2SO4), concentrated in vacuo and purified by silica gel column chromatography to obtain 2-fluoro-4-(2-methoxypyridin-4-yloxy)benzenamine (0.20 g, 58% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.02 (d, J=6.0 Hz, 1H), 6.95 (dd, J=2.8, 12.0 Hz, 1H), 6.82 (dd, J=8.4, 8.8 Hz, 1H), 6.73 (dd, J=2.0, 8.4 Hz, 1H), 6.54 (dd, J=2.4, 6.0 Hz, 1H), 6.10 (d, J=2.4 Hz, 1H), 5.17 (s, 1H), 3.81 (s, 3H); MS (ESI) m/z: 235.0 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]3[C:21]([CH2:23][O:24][CH2:25][CH3:26])([CH3:22])[CH2:20][CH2:19][CH2:18][S:17][C:16]=3[CH:27]=2)=[CH:6][CH:5]=1.[OH-].[Na+]>C1COCC1.C(O)C>[CH2:25]([O:24][CH2:23][C:21]1([CH3:22])[CH2:20][CH2:19][CH2:18][S:17][C:16]2[CH:27]=[C:12](/[CH:11]=[CH:10]/[C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:28])=[O:2])=[CH:9][CH:8]=3)[CH:13]=[CH:14][C:15]1=2)[CH3:26]
Reactant: CCOCC1(C)CCCSc2cc(/C=C/c3ccc(C(=O)OC)cc3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOCC1(C)CCCSc2cc(/C=C/c3ccc(C(=O)O)cc3)ccc21
Reaction time: 18 h
Yield: 89 %

Procedure:
406 mg (0.99 mmol) of (E)-4-[2-(5-ethoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo[b]thiepin-8-yl)-vinyl]-benzoic acid methyl ester was dissolved in 4 ml of THF/ethanol=1/1 and treated with 1.32 ml of 3N NaOH(4 eq). The reaction flask was kept in the dark and stirring continued for 18 h at room temperature. The mixture was then poured onto crushed ice/diluted HCl, extracted twice with ethylacetate, the organic phase was washed with a small amount of water, dried over magnesium sulfate, filtrated and the solvent evaporated. Crystallization of the residue from hexane/ethylacetate (8/2) yielded 337 mg of the title compound as white crystals of m.p. 186-187° C.
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[C:11]([O:12][CH2:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[C:16]([F:22])[C:15]=2[F:23])=[CH:10][C:9]([N:24]2[C:32](=[O:33])[NH:31][C:30]3[C:25]2=[N:26][C:27]([CH3:36])=[N:28][C:29]=3[O:34][CH3:35])=[C:8]([Cl:37])[CH:7]=1)(O)=[O:2].[C:38](N1C=CN=C1)([N:40]1C=CN=C1)=O.CN.Cl>O1CCCC1>[Cl:37][C:8]1[C:9]([N:24]2[C:32](=[O:33])[NH:31][C:30]3[C:25]2=[N:26][C:27]([CH3:36])=[N:28][C:29]=3[O:34][CH3:35])=[CH:10][C:11]([O:12][CH2:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[C:16]([F:22])[C:15]=2[F:23])=[C:6]([CH:7]=1)[O:5][CH2:4][C:1]([NH:40][CH3:38])=[O:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(F)c(F)c1COc1cc(-n2c(=O)[nH]c3c(OC)nc(C)nc32)c(Cl)cc1OCC(=O)O
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Product: CNC(=O)COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(C)nc32)cc1OCc1c(OC)ccc(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
To a solution of 9-[4-carboxymethoxy-2-chloro-5-(2,3-difluoro-6-methoxy-benzyloxy)phenyl]-6-methoxy-2-methyl-7,9-dihydro-8H-purin-8-one (80 mg) in tetrahydrofuran (2 mL) was added 1,1′-carbonyldiimidazole (48 mg), and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added methylamine (40% methanol solution, 1 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 2 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate−ethyl acetate/methanol=6/1) to give the title compound (63 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@@H:4]([N:6]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:7][CH:8](OC)[O:9]C)[CH3:5].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>CC(=O)CC>[CH3:1][O:2][C:3](=[O:23])[C@@H:4]([N:6]([C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])[CH2:7][CH:8]=[O:9])[CH3:5]
Reactant: COC(=O)[C@H](C)N(CC(OC)OC)C(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCC(C)=O
Solvent: O
Product: COC(=O)[C@H](C)N(CC=O)C(=O)OCc1ccccc1
Yield: 108.8 %

Procedure:
A solution of (S)-2-[benzyloxycarbonyl-(2,2-dimethoxy-ethyl)-amino]-propionic acid methyl ester (26.0 g, 80.0 mmol) and pyridinium toluene-4-sulfonate (10.0 g, 40.0 mmol) in 2-butanone (260 mL) and water (8.6 mL, 0.48 mol) was heated under reflux for 16 h, then the solution was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated to afford the titled compound (24.3 g), which was directly used in the next step. Yellow oil, MS (ISP)=348.3 (M+Na)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][CH3:10])=[CH:4][CH:3]=1.O.[NH2:12][NH2:13]>>[NH:12]([C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][CH3:10])=[CH:4][CH:3]=1)[NH2:13]
Reactant: CNCc1ccc(Cl)nc1
Reactant: NN
Solvent: O
Product: CNCc1ccc(NN)nc1
Temperature: 150 °C
Reaction time: 12 h

Procedure:
1.0 g (6.4 mmol) 1-(6-chloropyridin-3-yl)-N-methylmethanamine [for preparation see EP 0 556 684-A1] are initially introduced into 1.5 ml (1.6 g, 31.9 mmol) hydrazine hydrate and the mixture is stirred at the boiling point at a bath temperature of 150° C. for 12 h. The cooled reaction solution is concentrated and the residue is dried in vacuo. 1.1 g of the title compound, which is employed without further purification, are obtained.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]1[CH2:14][C@H:13]([NH2:15])[CH2:12]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:23]1[C:28]([N+:29]([O-:31])=[O:30])=[CH:27][CH:26]=[CH:25][N:24]=1>CS(C)=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]1[CH2:12][C@H:13]([NH:15][C:23]2[C:28]([N+:29]([O-:31])=[O:30])=[CH:27][CH:26]=[CH:25][N:24]=2)[CH2:14]1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cccnc1N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
The crude amine from step 1, cesium carbonate (2.500 g, 1.535 mmol), 2-chloro-3-nitropyridine (394 mg, 2.488 mmol), and dry dimethylsulfoxide (5 mL) were added and the reaction mixture was stirred at 120° C. for 2 hours. The reaction was cooled and partitioned between water (100 mL), saturated sodium bicarbonate (20 mL) and ethyl acetate. The organic phase was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (dichloromethane to ethyl acetate gradient) gave the desired trans-N1-(benzo[d]thiazol-2-yl)-N3-(3-nitropyridin-2-yl)cyclobutane-1,3-diamine (580 mg, 1.699 mmol, 75% yield) as light-yellow solid.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH2:7]P(OC)(OC)=O)=[O:6].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:25][N:24]=[C:23]([CH3:26])[C:22]=2[CH:27]=O)=[CH:17][CH:16]=1>C1COCC1>[CH3:3][O:4][C:5](=[O:6])/[CH:7]=[CH:27]/[C:22]1[C:23]([CH3:26])=[N:24][O:25][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([Br:14])=[CH:16][CH:17]=1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1c(C)noc1-c1ccc(Br)cc1
Temperature: 25 °C

Procedure:
To a solution of sodium hydride (60% in mineral oil, 0.471 g, 11.03 mmol) in THF (10 mL) at 0° C. was added trimethyl phosphonoacetate (1.1 mL, 7.58 mmol). Additional THF (15 mL) was added to facilitate stirring and the solution was warmed to room temperature over 15 minutes. After cooling to 0° C., 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde (1.834 g, 6.89 mmol) in THF (8 mL) was added and the reaction was stirred at room temperature for 10 minutes. The mixture was extracted with EtOAc and aqueous NH4Cl, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][NH:20][C:21]([CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22]>>[CH3:19][NH:20][C:21]([CH:23]1[CH2:28][CH2:27][N:26]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[N:3][C:2]([Cl:1])=[N:7][C:6]=3[CH:8]=2)[CH2:25][CH2:24]1)=[O:22]
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CNC(=O)C1CCNCC1
Product: CNC(=O)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
Reaction between 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 from Example 3 and piperidine-4-carboxylic acid methylamide, using General Procedure B-3 yielded 1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidine-4-carboxylic acid methylamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH3:33])[CH2:12][C:13](=[O:25])[N:14]1[CH2:19][CH2:18][N:17]([C:20]2[S:21][CH:22]=[CH:23][N:24]=2)[CH2:16][CH2:15]1.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[C:38]([O:46][C:47]([F:50])([F:49])[F:48])[CH:37]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:42]([C:39]1[CH:40]=[CH:41][C:36]([O:35][CH3:34])=[CH:37][C:38]=1[O:46][C:47]([F:48])([F:49])[F:50])(=[O:44])=[O:43])[C:6](=[O:11])[C:5]2([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH3:33])[CH2:12][C:13](=[O:25])[N:14]1[CH2:15][CH2:16][N:17]([C:20]2[S:21][CH:22]=[CH:23][N:24]=2)[CH2:18][CH2:19]1
Reactant: COc1ccccc1C1(CC(=O)N2CCN(c3nccs3)CC2)C(=O)Nc2ccc(Cl)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(CC(=O)N3CCN(c4nccs4)CC3)(c3ccccc3OC)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 89.3 %

Procedure:
With 300 mg of the compound obtained in Step 46-1 and 200 mg of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 409 mg of the title compound (yellow amorphous) was obtained by a similar method to Example 2.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Br:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][C:9]=1[Cl:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:2]([N:12]([CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:11]1[CH:13]=[CH:14][C:8]([Br:7])=[C:9]([Cl:15])[CH:10]=1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCBr
Reactant: Nc1ccc(Br)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCN(CCCCC)c1ccc(Br)c(Cl)c1
Yield: 106.4 %

Procedure:
1-Bromopentane (0.42 mL, 3.4 mmol) was added to a mixture of 4-bromo-3-chloroaniline (200 mg, 0.9 mmol) and potassium carbonate (199 mg, 1.4 mmol) in DMF (20 mL) and the reaction was heated to 13 0˜˜C overnight. The mixture was cooled, diluted with water (20 mL) and extracted with petroleum ether (3×25mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified via flash column chromatography using 9:1 petroleum ether:ethyl acetate as eluent to give N,N-Dipentyl-4-bromo-3-chloroaniline (1) (332 mg, 68%). 1HNMR (CDCI3) 67.02 (d, IH, ArH); 3.12 (t, 4H, 2×NCH2); 0.95 (t, 6H, 2×CH3). MS; 347 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5])[CH3:2].Cl[CH2:13][CH:14]1[O:19][CH2:18][CH2:17][CH2:16][O:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:15]1[CH2:16][CH2:17][CH2:18][O:19][CH:14]1[CH2:13][NH:5][C:4]1[C:6]([CH2:10][CH3:11])=[CH:7][CH:8]=[CH:9][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1cccc(CC)c1N
Reactant: ClCC1OCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cccc(CC)c1NCC1OCCCO1

Procedure:
2,6-Diethylaniline (75 grams), 2-chloromethyl-1,3-dioxane (14 grams), potassium carbonate (34 grams) and dimethylformamide (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 18 hours. After this time the mixture is filtered and distilled to yield the desired product N-(1,3-dioxan-2-ylmethyl)-2,6-diethylaniline.