Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:30]=[CH:29][C:5]([CH2:6][O:7][C@H:8]([C@@H:12]2[CH2:14][C@@H:13]2[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[N:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][N:22]=3)[CH2:17][CH2:16]2)[CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1.[Li]CCCC.[CH3:36][S:37]SC>C1COCC1>[CH2:27]([C:24]1[CH:23]=[N:22][C:21]([N:18]2[CH2:19][CH2:20][CH:15]([C@H:13]3[CH2:14][C@H:12]3[C@@H:8]([O:7][CH2:6][C:5]3[CH:29]=[CH:30][C:2]([S:37][CH3:36])=[CH:3][CH:4]=3)[CH2:9][O:10][CH3:11])[CH2:16][CH2:17]2)=[N:26][CH:25]=1)[CH3:28]
Reactant: CSSC
Reactant: CCc1cnc(N2CCC([C@H]3C[C@H]3[C@H](COC)OCc3ccc(Br)cc3)CC2)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cnc(N2CCC([C@H]3C[C@H]3[C@H](COC)OCc3ccc(SC)cc3)CC2)nc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a cold (−78° C.), stirred solution of the product of step G (90 mg, 0.190 mmol) in THF (1.9 mL) was added n-BuLi (0.9 mL of 2.5 M solution in hexane, 0.228 mmol). After 10 min, dimethyldisulfide (23.2 mg, 0.247 mmol) was added and the mixture stirred for 45 min at −78° C. The reaction was quenched with a saturated aqueous solution of NH4Cl, and the aqueous layer was extracted with EtOAc (×3). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under vacuum to leave a residue which was purified by column chromatography on silica (elution with 5:1 hexane:ethyl acetate) to yield the title compound. MS (ESI) m/z 442 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]([CH3:12])([CH3:11])[C:8]([CH3:10])=[CH:9][C:4]=2[CH:3]=1.CC(C)([O-])C.[Na+].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([SH:29])[CH:26]=[CH:27][CH:28]=1>C(O)C.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>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([S:29][C:2]2[CH:14]=[CH:13][C:5]3[O:6][C:7]([CH3:12])([CH3:11])[C:8]([CH3:10])=[CH:9][C:4]=3[CH:3]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: COc1cccc(S)c1
Reactant: CC1=Cc2cc(Br)ccc2OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(Sc2ccc3c(c2)C=C(C)C(C)(C)O3)c1
Reaction time: 48 h
Yield: 89.8 %

Procedure:
6-Bromo-2,2,3-trimethyl-2H-benzo[b]pyran (6.5 g) (see Preparation 4) was dissolved in absolute ethanol (135 ml), then sodium tert-butoxide (7.5 g), 3-methoxybenzenethiol (3.6 g) and tetrakis(triphenylphosphine)palladium(0) (0.35 g) were added and the mixture was heated under reflux under a nitrogen atmosphere for 48 hours. Further tetrakis(triphenylphosphine)palladium(0) (0.3 g) was added and heating was continued for a further 48 hours. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane and washed with water. The organic layer was dried (anhydrous sodium sulphate), the solvent removed under reduced pressure and the crude product chromatographed on silica using 1:1 hexane:dichloromethane as the eluent to yield 6-(3-methoxyphenyl)thio-2,2,3-trimethyl-2H-benzo[b]pyran (7.2 g) as an oil.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])=[N:11][C:6]=2[CH:5]=[N:4][N:3]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>CN1C(=O)CCC1.O>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[NH:12][C:10]1[CH:9]=[CH:8][C:7]2[C:2]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[N:3][N:4]=[CH:5][C:6]=2[N:11]=1
Reactant: Fc1ccc(Nc2ccc3c(Cl)nncc3n2)c(F)c1
Reactant: C1COCCN1
Solvent: O
Solvent: CN1CCCC1=O
Product: Fc1ccc(Nc2ccc3c(N4CCOCC4)nncc3n2)c(F)c1
Reaction time: 0.08 h

Procedure:
A solution of 5-chloro-N-(2,4-difluorophenyl)pyrido[3,2-d]pyridazin-2-amine (80 mg, 0.27 mmol) and morpholine (238 mg, 2.73 mmol) in 0.4 mL of NMP was heated in a microwave at 150° C. for 30 min. It was diluted with 1 mL of water and stirred for 5 min. The precipitated solid was filtered, rinsed sequentially with 2×2 mL of water, 2×2 mL of ether and 2 mL of EtOAc, then dried in a vacuum oven at 45° C. for 18 h to give the title compound as a tan solid. MS (ESI, pos.ion) m/z: M+1=344.0
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[CH3:11][O:12][C:13]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[CH:18]2)=[O:14].[H-].[Na+].CN(C)C=O>O>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4][N:20]1[C:21]2[C:17](=[CH:16][C:15]([C:13]([O:12][CH3:11])=[O:14])=[CH:23][CH:22]=2)[CH:18]=[CH:19]1
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(ccn2Cc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 53.2 %

Procedure:
2,4-Dichlorobenzyl chloride (8.68 g) is added to a mixture of 5-methloxycarbonylindole (6.49 g) 60% (sodium hydride (2.24 g) and N,N-dimethylformamide, while cooled in an ice-water bath. This is stirred at room temperature for 20 minutes, and water is added thereto. Then. this is extracted with ethyl acetate. After washed with water, the organic layer is dried, concentrated, purified through silica gel column chromatography (eluent: hexane/ethyl acetate=6/1), and finally recrystallized from ethyl acetate/hexane to obtain 1-(2,4-dichlorobenzyl)-5-methoxycarbonylindole (49) (6.59 g).
Reaction SMILES: C(OC(=O)[N:7]([C:17]1[CH:22]=[CH:21][C:20]([C:23]([C:25]2[C:33]3[C:28](=[N:29][CH:30]=[C:31]([Cl:34])[CH:32]=3)[NH:27][CH:26]=2)=[O:24])=[CH:19][N:18]=1)[CH2:8][C:9]1[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Cl:34][C:31]1[CH:32]=[C:33]2[C:25]([C:23]([C:20]3[CH:19]=[N:18][C:17]([NH:7][CH2:8][C:9]4[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=4)=[CH:22][CH:21]=3)=[O:24])=[CH:26][NH:27][C:28]2=[N:29][CH:30]=1
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C(=O)c3c[nH]c4ncc(Cl)cc34)cn2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CNc2ccc(C(=O)c3c[nH]c4ncc(Cl)cc34)cn2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.9 %

Procedure:
To [5-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (587, 0.020 g, 0.040 mmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (0.30 mL, 0.0039 mol). The reaction was stirred at room temperature for 2 hours, then poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (P-0405, 5.5 mg, 34%). MS (ESI) [M+H+]+=394.3.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[O:19]1[C:23]2[CH:24]=[CH:25][C:26]([CH2:28][C:29](O)=[O:30])=[CH:27][C:22]=2[O:21][CH2:20]1>>[O:19]1[C:23]2[CH:24]=[CH:25][C:26]([CH2:28][C:29]([NH:1][N:2]3[N:11]=[C:10]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]3=[O:18])=[O:30])=[CH:27][C:22]=2[O:21][CH2:20]1
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: O=C(Cc1ccc2c(c1)OCO2)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(1,3-benzodioxol-5-yl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.31 (dd, J=7.9, 1.3 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.97-8.01 (m, 1H), 7.89-7.93 (m, 1H), 6.96 (d, J=1.7 Hz, 1H), 6.89 (d, J=7.9 Hz, 1H), 6.84 (dd, J=7.9, 1.7 Hz, 1H), 6.00 (s, 2H), 3.81-3.83 (m, 4H), 3.58 (s, 2H), 3.08-3.10 (m, 4H); MS (ESI+) M/Z 409 (M+H)+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([CH:14]=[O:15])=[C:9]([Cl:16])[CH:8]=1)(=O)=O.[Si]([O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)(C(C)(C)C)(C)C>>[Cl:16][C:9]1[CH:8]=[C:7]([C:30]2[CH:31]=[CH:32][C:27]([OH:26])=[CH:28][CH:29]=2)[CH:12]=[C:11]([Cl:13])[C:10]=1[CH:14]=[O:15]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(B(O)O)cc1
Reactant: O=Cc1c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc1Cl
Product: O=Cc1c(Cl)cc(-c2ccc(O)cc2)cc1Cl

Procedure:
The title compound was prepared by reacting 3,5-dichloro-4-formyl-phenyl trifluoromethanesulfonate (0.73 g, 2.26 mmol) with 4-tert-butyldimethylsilyloxyphenyl boronic acid (0.80 g, 3.2 mmol) according to method C to yield 0.30 g (50%) of a yellow solid: mp:178-180° C.; 1H NMR (DMSO-d6): δ 6.88 (2H, d, J=8.84 Hz), 7.72 (2H, d, J=8.71 Hz), 7.84 (2H, s), 9.95 (1H, s), 10.38 (1H, s); MS (EI) m/z 266.0/268.0/270.0 (M+).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([O:13][CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:10]=[C:9]([C:20]3[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]=[C:34]=[O:35])[CH:28]=1>>[N:1]1([C:7]2[N:12]=[C:11]([O:13][CH:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:10]=[C:9]([C:20]3[CH:26]=[CH:25][C:23]([NH:24][C:34]([NH:33][C:29]4[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=4)=[O:35])=[CH:22][CH:21]=3)[N:8]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C=Nc1cccnc1
Reactant: Nc1ccc(-c2nc(OC3CCOCC3)nc(N3CCOCC3)n2)cc1
Product: O=C(Nc1ccc(-c2nc(OC3CCOCC3)nc(N3CCOCC3)n2)cc1)Nc1cccnc1

Procedure:
1-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea was prepared by reacting the 4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]aniline and the corresponding 3-pyridylisocyanate. Product was purified by Gilson, HPLC. MS (ESI) m/z 477.53.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][N:11]=[CH:12][CH3:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[O-:14][C:15]#[N:16].[K+].Cl[O-].[Na+]>C(O)(=O)C.O>[CH3:13][C:12]1[NH:16][C:15](=[O:14])[N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:11]=1
Reactant: CC=NNc1cccc([N+](=O)[O-])c1
Reactant: N#C[O-]
Agent: [K+]
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: CC(=O)O
Product: Cc1nn(-c2cccc([N+](=O)[O-])c2)c(=O)[nH]1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
To a stirred, warm (40° C.) solution of 66.2 g (0.37 mole) of acetaldehyde 3-nitrophenylhydrazone (compound 40, FIG. 5) in one liter of acetic acid was added a solution of 30.0 g (0.37 mole) of potassium cyanate in 75 ml of water. The reaction mixture was cooled to 20° C. and stirred for 30 minutes. An aqueous 5% sodium hypochlorite solution (600 ml) was added to the mixture during a 30 minute period while maintaining a temperature of 20° C. A precipitate formed during the addition. After this addition was complete, the mixture was diluted with one liter of water and was filtered; the filtrate was saved for further use. The filter cake was triturated with a solution of ethyl acetate:n-heptane (1:1) and was filtered. The solid thus collected was dried under reduced pressure to yield 52.4 g of 4,5-dihydro-3-methyl-1-(3-nitrophenyl)-1,2,4-triazol-5(1H)-one.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:11])[NH:9][N:10]=[C:4]2[C:3]=1[I:12].C(N(CC)C(C)C)(C)C.[CH3:22][O:23][CH2:24]Cl>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:11])[N:9]([CH2:22][O:23][CH3:24])[N:10]=[C:4]2[C:3]=1[I:12]
Reactant: COCCl
Reactant: O=c1[nH]nc2c(I)c(Br)ccn12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCn1nc2c(I)c(Br)ccn2c1=O
Temperature: 20 °C
Reaction time: 3 h
Yield: 97.3 %

Procedure:
To a solution of 7-bromo-8-iodo-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (1.0 g, 2.94 mmol) in DMF (10 mL) and N,N-diisopropylethylamine (2.6 mL, 14.7 mmol) at 20° C. was added chloromethyl methyl ether (473 mg, 5.9 mmol). The resulting reaction mixture was stirred for an additional 3 h at 20° C. and then quenched by addition of H2O (25 mL). The quenched reaction mixture was extracted with Et2O/EtOAc (2:1, 3×50 mL). The combined organic extract was washed with saturated aqueous NaHCO3 solution (30 mL), then brine (30 mL), dried over MgSO4, filtered and concentrated in vacuo to obtain the title compound as a light yellow solid (1.1 g, 2.86 mmol). MS: [M+H]+=384.0. 1H NMR (400 MHz, CDCl3) δ 3.46 (s, 3H), 5.34 (s, 2H), 6.68 (d, J=7.15 Hz, 1H), 7.65 (d, J=7.15 Hz, 1H).
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:17][CH:18]=[C:19]([C:21]([O:23]C)=[O:22])[N:20]=2)=[CH:12][CH:11]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CO.[Li+].[OH-].Cl>C1COCC1>[C:1]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[O:17][CH:18]=[C:19]([C:21]([OH:23])=[O:22])[N:20]=2)=[CH:14][CH:15]=1)([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: COC(=O)c1coc(-c2ccc(CNC(=O)OC(C)(C)C)cc2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccc(-c2nc(C(=O)O)co2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
To a solution of methyl 2-[4-(N-Boc-aminomethyl)-phenyl]-oxazol-4-ylcarboxylate (1.66 g, 5 mmol) in THF (25 ml)/methanol (25 ml) was added 1M aqueous LiOH (25 ml, 25 mmol). After stirring at room temperature for 3 h, the solution was acidified with 2M aqueous HCl to pH 5-6, and partitioned between ethyl acetate (150 ml) and water (150 ml). The organic layer was washed with brine (150 ml), dried over sodium sulfate and concentrated in vacuo giving the title compound as a white solid (1.58 g, 4.96 mmol).
Reaction SMILES: C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([OH:28])[CH2:20][CH2:21][CH:22]2[O:27][CH2:26][CH2:25][CH2:24][O:23]2)=[CH:15][CH:14]=1>ClCCl>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:28])[CH2:20][CH2:21][CH:22]2[O:23][CH2:24][CH2:25][CH2:26][O:27]2)=[CH:15][CH:14]=1
Reactant: OC(CCC1OCCCO1)c1ccc(Br)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C(CCC1OCCCO1)c1ccc(Br)cc1
Reaction time: 2 h
Yield: 86.1 %

Procedure:
PCC (8.16 g, 59.8 mmol) was admixed with 9 g SiO2 and ground (mortar & pestle) and suspended in Dichloromethane (360 mL). To the suspension was added in one portion Example J1, 1-(4-bromophenyl)-3-(1,3-dioxan-2-yl)propan-1-ol (9 g, 29.9 mmol) dissolved in 5 mL of the same solvent. The reaction mixture was stirred for 2 hours an filtered through celite (rinse with (CH2Cl2). After being concentrated the residue was charged (CH2Cl2) to a 40 M Biotage silica gel cartridge. Gradient elution 15-70% B over 750 mL (A=Hexanes; B=ethyl acetate) gave Example J2, 1-(4-bromophenyl)-3-(1,3-dioxan-2-yl)propan-1-one 7.7 g (86%). 1H NMR (500 MHz, CDCl3) δ 7.84 (d, J=8.7 Hz, 2H), 7.59 (d, J=8.5 Hz, 2H), 4.65 (t, J=4.9 Hz, 1H), 4.09-4.06 (m, 2H), 3.74 (dt, J=11.0, 2.4 Hz, 2H), 3.06 (t, J=7.3 Hz, 2H), 2.07-2.01 (m, 3H), 1.35-1.31 (m, 1H). LCMS: RT=1.9 minutes (condition 1); C13H15BrO3 Calcd.: 299. found: 299 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:4]=1[CH2:5][NH:6]C(=O)OC(C)(C)C)#[N:2].[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22]>C(Cl)(Cl)Cl>[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22].[NH2:6][CH2:5][C:4]1[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:3]=1[C:1]#[N:2]
Reactant: CC(C)(C)OC(=O)NCc1ccc(F)cc1C#N
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(F)ccc1CN
Reaction time: 1 h
Yield: 100 %

Procedure:
A round-bottom flask was charged with intermediate 106, tert-butyl 2-cyano-4-fluorobenzylcarbamate, (1.9 g, 7.591 mmol) then treated with trifluoroacetic acid (20 ml) at room temperature. After 1 h, the reaction mixture was concentrated to give a yellow oil which was dissolved in CHCl3 and re-concentrated to afford the title compound (2.01 g, 100% yield) as a pale yellow solid. LCMS (M+H) calcd for C8H8FN2: 151.07; found: 151.08.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([Cl:11])[N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>CN(C=O)C>[NH2:1][C:2]1[N:10]=[C:9]([Cl:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:23][C:22]1[CH:25]=[CH:26][C:19]([F:18])=[CH:20][CH:21]=1
Reactant: Nc1nc(Cl)nc2nc[nH]c12
Reactant: Fc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(Cl)nc2c1ncn2Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 1970.7 %

Procedure:
6-Amino-2-chloropurine (5.02 g) and potassium carbonate (5 g, 36 mmol) were suspended in DMF (200 ml) and thereto was added 4-fluorobenzyl chloride (5 ml, 42 mmol). The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo to dryness, and to the residue was added water. The mixture was extracted with chloroform and the organic layer was washed with water, dried on sodium sulfate and concentrated in vacuo to dryness. The residue was purified with silica gel chromatography (2% methanol/chloroform) to give the subject compound (162 g).
Reaction SMILES: [C:1]([C:4]1[C:14]([OH:15])=[CH:13][C:12]2[CH:11]3[CH2:16][CH:7]([CH2:8][N:9]([C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:10]3)[C:6]=2[CH:5]=1)(=O)[CH3:2].Cl.[NH2:24][OH:25].C([O-])(=O)C.[Na+]>CO.O>[F:20][C:18]([F:21])([F:19])[C:17]([N:9]1[CH2:10][CH:11]2[CH2:16][CH:7]([C:6]3[CH:5]=[C:4]([C:1](=[N:24][OH:25])[CH3:2])[C:14]([OH:15])=[CH:13][C:12]=32)[CH2:8]1)=[O:22]
Reactant: CC(=O)c1cc2c(cc1O)C1CC2CN(C(=O)C(F)(F)F)C1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=NO)c1cc2c(cc1O)C1CC2CN(C(=O)C(F)(F)F)C1
Yield: 89.1 %

Procedure:
1-(4-Acetyl-5-hydroxy-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone (190 mg, 0.605 mmol), hydroxylamine HCl (99 mg, 1.21 mmol) and sodium acetate (118 mg, 1.21 mmol) were combined in methanol (4 mL) and H2O (1 mL) and warmed to 65° C. for 18 hours. The mixture was cooled, diluted with H2O and extracted with ethyl acetate which was dried (Na2SO4), filtered and concentrated to provide a yellow oil (177 mg, 93%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:22])[CH2:8][CH2:7]1)=[O:5])[CH3:2]>O1CCCC1.[Ni].C(O)C>[NH2:19][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:22])[C:13]=1[NH:12][CH:9]1[CH2:8][CH2:7][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:10]1
Reactant: CCOC(=O)N1CCC(Nc2c(C)cccc2[N+](=O)[O-])CC1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)N1CCC(Nc2c(C)cccc2N)CC1
Temperature: 40 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
1-Ethoxycarbonyl-4-[(2-methyl-6-nitrophenyl)amino]piperidine (38 mg) was dissolved in tetrahydrofuran (0.4 ml), added with a suspension of Raney nickel in ethanol (0.2 ml) and stirred at 40° C. for 2 hours under hydrogen gas atmosphere. After insoluble matters were removed, the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer silica gel column chromatography (developing solvent: hexane:ethyl acetate=2:1) to obtain (28.6 mg) of the title compound. Yield: 83%.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:25][CH:24]([CH2:26][OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[Cl:28][C:29]1[C:34]([F:35])=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[Cl:28][C:29]1[N:30]=[CH:31][C:32]([C:2]2[C:3]([N:22]3[CH2:23][CH:24]([CH2:26][OH:27])[CH2:25]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:18])([F:20])[F:19])=[CH:14][CH:15]=3)=[O:8])[CH:21]=2)=[CH:33][C:34]=1[F:35]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC(CO)C2)c(Br)c1
Reactant: CC1(C)OB(c2cnc(Cl)c(F)c2)OC1(C)C
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC(CO)C2)c(-c2cnc(Cl)c(F)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 53 using 5-bromo-6-(3-(hydroxymethyl)azetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 135.1) and 2-chloro-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. HPLC (Condition 4) tR=5.57 min, UPLC-MS (Condition 3) tR=1.13 min, m/z=497.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.55-2.70 (m, 1H) 3.39-3.53 (m, 4H) 3.73 (t, J=1.00 Hz, 2H) 4.69 (t, J=1.00 Hz, 1H) 7.34 (d, J=8.21 Hz, 2H) 7.83 (m, J=9.40 Hz, 2H) 8.04 (d, J=1.95 Hz, 1H) 8.09 (m, J=9.40 Hz, 1H) 8.38 (d, J=1.95 Hz, 1H) 8.77 (d, J=2.35 Hz, 1H) 10.19 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]=1[C:7]#[N:8].S(=O)(=O)(O)[OH:14].N>>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]=1[C:7]([NH2:8])=[O:14]
Reactant: CC(C)(C)c1csc(N)c1C#N
Reactant: O=S(=O)(O)O
Agent: N
Product: CC(C)(C)c1csc(N)c1C(N)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 180 g (1 mole) of 2-amino-3-cyano-4-tert.-butyl-thiophene and 750 ml of 95-97% strength sulphuric acid was stirred at 100°-110° C. for one hour, whereupon a slightly exothermic reaction started, so that when a temperature of 100° C. was reached no further heating was required. The reaction mixture was left to cool and was stirred into 5 liters of ice-water and neutralized with about 3 liters of 25% strength aqueous ammonia solution. The solid product which precipitated was filtered off, washed with water and dried at 50° C. 194 g of 2-amino-3-aminocarbonyl-4-tert.-butyl-thiophene of melting point 145° C. were obtained in this manner.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([C:13]([F:16])([F:15])[F:14])[CH:7]=1)=[O:4].[N:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[CH2:2][NH:30][C:27]2[CH:26]=[CH:25][C:24]([O:23][C:20]3[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=3)=[CH:29][CH:28]=2)=[CH:7][C:8]=1[C:13]([F:16])([F:15])[F:14]
Reactant: O=C(CCl)Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1ccc(Oc2ccncc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CNc1ccc(Oc2ccncc2)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 100 °C
Yield: 4.7 %

Procedure:
A solution of 146.1 mg (0.54 mmol) of compound 9 in dimethylformamide (DMF) is given to a solution of 100 mg (0.54 mmol) of compound 2 and 0.1 ml (0.59 mmol) N-Ethyl-diisopropylamine in DMF. The reaction mixture is heated to 100° C. for 6 h, then evaporated and the residue is purified by preparative HPLC to yield 10.7 mg (5%) colourless solid.
Reaction SMILES: C([O-])=O.[NH4+].[N+:5]([C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[C:11]([C:17]([O:19][CH3:20])=[O:18])[NH:12]2)([O-])=O.C(#N)C>[Pd].CO>[NH2:5][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[C:11]([C:17]([O:19][CH3:20])=[O:18])[NH:12]2
Reactant: COC(=O)c1cc2c([N+](=O)[O-])cccc2[nH]1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CC#N
Product: COC(=O)c1cc2c(N)cccc2[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 24.1 %

Procedure:
Ammonium formate (63 g, 1.00 mol) was added cautiously to a suspension of the product of Example 2 (45.6 g, 0.207 mol) and 10% palladium on charcoal (5 g) in methanol (700 ml) under an argon blanket at 45° C. The mixture was stirred for 4 h, cooled to room temperature, and after 18 h filtered and evaporated in vacuo to give a dark brown semi-solid. This was taken up into acetonitrile (500 ml), filtered (to remove ammonium formate) and evaporated in vacuo to give a dark brown gum. Purification by column chromatography [silica; ethyl acetate-hexane (1:10 to 1:1)] gave the product (9.5 g) as a grey solid.