Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:12]2[N:13]([CH2:25][OH:26])[CH2:14][CH2:15][CH2:16][CH:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:12]2[N:13]([CH2:25][O:26][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:14][CH2:15][CH2:16][CH:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)C1CCCN(CO)c2c1cc(OCc1ccccc1)c1ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CCCN(COS(C)(=O)=O)c2c1cc(OCc1ccccc1)c1ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
A solution of 83 (0.138 g, 0.319 mmol, 1 equiv) in CH2Cl2 (3 mL) was cooled to 0° C. prior to sequential addition of Et3N (0.222 mL, 1.59 mmol, 5 equiv) and CH3SO2Cl (0.049 mL, 0.637 mmol, 2 equiv). The cooling bath was removed after 5 min and the mixture was stirred at 25° C. for 1 h. The reaction was quenched with the addition of saturated aqueous NaHCO3 (0.5 mL) and the layers were separated. The aqueous portion was extracted with EtOAc (2×5 mL) and the combined organic portions were dried (MgSO4), filtered, and concentrated. Radial chromatography (SiO2, 2 mm plate, 30% EtOAc-hexane) furnished 84 (0.143 g, 0.163 g theoretical, 89%) as a white solid: mp 134-135° C.; 1H NMR 400 MHz, CDCl3) major rotamer δ 8.40 (d, 8.2 Hz, 1H), 8.13 (d, J=8.6 Hz, 1H), 7.60-7.35 (m, 7H), 6.63 (s, 1H), 5.26 (d, J=11.7 Hz, 1H), 5.17 (d, J=11.6 Hz, 1H), 4.49-4.44 (m, 2H), 4.38-4.30 (m, 2H), 2.69-2.64 (m, 4H), 2.26-2.05 (m, 2H), 1.73-1.70 (m, 2H), 1.32 (s, 9H); 13C NMR (100 MHz, CDCl3) major rotamer δ 153.8, 153.6, 140.5, 136.7, 133.0, 128.8 (2C), 128.6, 128.1 (2C), 127.7, 127.6, 127.1, 125.2, 123.3, 122.8, 107.1, 80.8, 71.4, 70.2, 47.7, 37.1, 36.1, 28.3 (3C), 26.5, 24.4; IR (film) νmax 3056, 2974, 2933, 2862, 1692, 1615, 1590 cm−1; FABHRMS (NBA-NaI) m/z 534.1914 (M+Na+, C28H33NO6S requires 534.1926).
Reaction SMILES: C1([Li])C=CC=CC=1.[CH:8]([S:11]([N:14]1[C:18]2[CH:19]=[C:20](I)[CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[NH2:24])(=[O:13])=[O:12])([CH3:10])[CH3:9].C([Li])(C)(C)C.CN(C)[CH:32]=[O:33]>O1CCCC1>[CH:8]([S:11]([N:14]1[C:18]2[CH:19]=[C:20]([CH:32]=[O:33])[CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[NH2:24])(=[O:13])=[O:12])([CH3:10])[CH3:9]
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(I)cc21
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)n1c(N)nc2ccc(C=O)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 76 %

Procedure:
Add phenyllithium (750 mL, 1.8 M in cyclohexane/ether, 70/30) over 1 hour to a solution of 1-isopropylsulfonyl-2-amino-6-iodobenzimidazole (150 g, 0.41 mol) in tetra-hydrofuran (5.6 L) at −76° C. Stir for 15 minutes and then add tert-butyllithium (750 ml, 1.7 M in pentane). After 1 hour add dimethylformamide (250 mL) slowly over one hour and then warm to 0° C. Quench by pouring the reaction mixture into a mixture of cold saturated aqueous ammonium chloride (500 g, 5 L) and concentrated hydrochloric acid (300 mL). Separate the layers, wash the organic phase with water and then concentrate under reduced pressure. Slurry the residue in methanol (500 mL), filter the yellow precipitate, and dry to provide 85 g (76%) of the title compound.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C@H:26]4[CH2:28][O:27]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:29])[NH:6]2.[O:30]1[C:34]2([CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[O:33][CH2:32][CH2:31]1>CN(C=O)C>[O:30]1[C:34]2([CH2:39][CH2:38][N:37]([CH2:28][C@@H:26]([OH:27])[CH2:25][O:24][C:18]3[CH:17]=[C:16]4[C:21]([C:12]([O:11][C:10]5[C:2]([F:1])=[C:3]6[C:7](=[CH:8][CH:9]=5)[NH:6][C:5]([CH3:29])=[CH:4]6)=[N:13][CH:14]=[N:15]4)=[CH:20][C:19]=3[O:22][CH3:23])[CH2:36][CH2:35]2)[O:33][CH2:32][CH2:31]1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@H]1CO1
Reactant: C1CC2(CCN1)OCCO2
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@H](O)CN1CCC2(CC1)OCCO2
Temperature: 70 °C
Reaction time: 3 h
Yield: 69.7 %

Procedure:
A mixture of 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[(2R)-oxiran-2-ylmethoxy]quinazoline (200 mg, 0.506 mmol), (prepared as described for the starting material in Example 48), and 1,4-dioxa-8-azaspiro[4.5]decane (195 μl, 1.52 mmol) in DMF (3 ml) was stirred at 70° C. under argon for 3 hours. The volatiles were removed under vacuum and the residue was purified by column chromatography eluting with methylene chloride/methanol (95/5 followed by 90/10). The fractions containing the expected product were combined and evaporated to dryness. The residue was triturated with diethyl ether, filtered and dried under vacuum to give 7-{(2R)-3-[(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)]-2-hydroxypropoxy}-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline (190 mg, 70%).
Reaction SMILES: [Cl-].[CH2:2]([O:9][C:10]([NH:12][S:13](N1C=CC(=[N+](C)C)C=C1)(=[O:15])=[O:14])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.Cl.[F:35][C:36]1([F:40])[CH2:39][NH:38][CH2:37]1>C(Cl)Cl>[F:35][C:36]1([F:40])[CH2:39][N:38]([S:13]([NH:12][C:10](=[O:11])[O:9][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)(=[O:14])=[O:15])[CH2:37]1
Reactant: C[N+](C)=c1ccn(S(=O)(=O)NC(=O)OCc2ccccc2)cc1
Reactant: FC1(F)CNC1
Agent: Cl
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NS(=O)(=O)N1CC(F)(F)C1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.8 %

Procedure:
To a stirred solution of N-(1-(N-((benzyloxy)carbonyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylmethanaminium chloride (Preparation 21, 3.15 g, 8.49 mmol) in CH2Cl2 (15 mL) were added N,N,-diisopropylethylamine (2.19 g, 17.0 mmol) and 3,3-difluoroazetidine hydrochloride (1.10 g, 8.49 mmol). The mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and the residue diluted with EtOAc (40 mL) and washed with water (40 mL). The aqueous washings were acidified with 2M aqueous solution of HCl and extracted with EtOAC (2×40 mL), the combined organic layers were dried over MgSO4 and concentrated to give the title compound as an amber oil (800 mg, 31%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([N:12]1[N:16]=[C:15]2[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]2=[N:13]1)[CH2:9][C:10]#[CH:11]>>[F:21][C:19]1[CH:18]=[CH:17][C:15]2=[N:16][N:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[N:13]=[C:14]2[CH:20]=1
Reactant: C#CCCn1nc2ccc(F)cc2n1
Reactant: Brc1ccccn1
Product: Fc1ccc2nn(CCC#Cc3ccccn3)nc2c1
Yield: 20 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (20 mg, 0.13 mmol) and 2-(but-3-ynyl)-5-fluoro-2H-benzo[d][1,2,3]triazole (24 mg, 0.13 mmol). Reaction time: 1 day. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) and SCX column (DCM, DCM/MeOH 98:2 to DCM/MeOH/NH4OH 95:4:1) to yield 7.6 mg (26 μmol, 21%) of 5-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a yellow solid.
Reaction SMILES: ClC[C:3]([NH:5][CH2:6][C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](OC(C)(C)C)=O)=[O:4].C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH2:6]1[NH:5][C:3](=[O:4])[CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][C@@H:7]12
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CNC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CN2CCC[C@H]2CN1
Temperature: 60 °C

Procedure:
1,1-Dimethylethyl (2S)-2-{[(chloroacetyl)amino]methyl}-1-pyrrolidinecarboxylate (D11; 1.24, 4.5 mmol), was dissolved in 20 ml of DCM and treated with TFA (5 ml) at room temperature. After 1 h complete conversion into the desired material was observed and the reaction mixture was loaded onto a SCX cartridge. The product obtained after elution with 2M NH3 in MeOH was then dissolved in acetonitrile (30 ml) and treated with sodium carbonate (1.43 g, 10.34 mmol). The reaction mixture was heated at 60° C. for 6 hours; the crude obtained after removal is purified by flash-chromatography eluting with dichloromethane/MeOH 95/5 affording 310 mg.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[F:15])=[CH:4][CH:3]=1.[Mg].[C:17]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:18][C:19]([CH3:21])=[O:20].[NH4+].[Cl-]>CCOCC>[CH2:24]([O:23][C:17](=[O:22])[CH2:18][C:19]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[F:15])=[CH:4][CH:3]=1)([OH:20])[CH3:21])[CH3:25]
Reactant: CCOC(=O)CC(C)=O
Reactant: Fc1ccc(-c2ccc(Br)cc2)c(F)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CCOC(=O)CC(C)(O)c1ccc(-c2ccc(F)cc2F)cc1
Reaction time: 2 h

Procedure:
A solution of 2',4'-difluoro-4-biphenylylmagnesium bromide, obtained from 2.69 g. of 4-bromo-2',4'-difluorobiphenyl and 0.24 g. of magnesium in 100 ml. of ether, is added dropwise at 20° to a stirred solution of 1.3 g. of ethyl acetoacetate in 40 ml. of ether. The mixture is stirred for 2 hours more and the resulting alcoholate is decomposed with ice and saturated NH4Cl solution. The ether phase is dried and evaporated to give 3-(2',4'-difluoro-4-biphenylyl)-3-hydroxybutyric acid ethyl ester, m.p. 96°-97°.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29]([NH2:32])(=[O:31])=[O:30]>C1C=CC=CC=1>[C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[S:29](=[O:31])(=[O:30])[NH2:32])=[O:15])=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(C#Cc2ccccc2)cc1
Reactant: Nc1ccccc1S(N)(=O)=O
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: NS(=O)(=O)c1ccccc1NC(=O)c1ccc(C#Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.7 %

Procedure:
A benzene (30 ml) solution containing 3.00 g (13.5 mmol) of 4-phenylethynylbenzoic acid and 2 ml of thionyl chloride was heated under reflux for 2 hours and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in methylene chloride (30 ml), this solution was added dropwise under ice-cooling to a pyridine (50 ml) solution containing 2.32 g (13.50 mmol) of 2-aminobenzenesulfonamide, the mixture was stirred at room temperature for 18 hours and then methylene chloride was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with a 1 N hydrochloric acid aqueous solution, water and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was recrystallized from ethyl acetate-hexane to obtain 4.00 g (yield: 78.7%) of the title compound.
Reaction SMILES: [NH2:1][C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])=[CH:3][C:4]([O:6]CC)=O.[H-].[Na+].[CH3:18][O:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=O)[O:30]CC)=[CH:24][CH:23]=1>CN(C)C=O>[CH3:18][O:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[C:4](=[O:6])[CH:3]=[C:2]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:15])[NH:1][C:29]2=[O:30])=[CH:24][CH:23]=1
Reactant: CCOC(=O)C=C(N)c1ccccc1Cl
Reactant: CCOC(=O)Nc1ccc(OCOC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1ccc(-n2c(=O)cc(-c3ccccc3Cl)[nH]c2=O)cc1
Temperature: 0 °C
Yield: 87.2 %

Procedure:
8.7 g of ethyl 3-amino-3-(2-chlorophenyl)-2-propenoate was added dropwise to a 40 ml dimethylformamide of 1.8 g of sodium hydride (purity: 55%) with stirring at 0° C. The solution was stirred at room temperature for 15 minutes, cooled to 0° C. and added dropwise with a 20 ml dimethylformamide solution of 7.2 g of ethyl 4-methoxymethoxyphenylcarbamate. After stirring the solution at 120° C. for 2 hours, the solvent was distilled away under reduced pressure. The residue was dissolved with 200 ml of water and washed with diethyl ether. The obtained aqueous layer was added into a mixed solution of 50 ml of concentrated hydrochloric acid and 150 g of ice. The precipitated crystals were filtered out and dried under reduced pressure to obtain 10.0 g of 3-(4-methoxymethoxyphenyl)-6-(2-chlorophenyl)-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: C([BH3-])#N.[F:4][C:5]1[CH:55]=[CH:54][C:8]([C:9]([N:11]([CH2:18][C:19]2[CH:24]=[C:23]([C:25]3[CH:52]=[CH:51][C:28]4[N:29]([C:32]([C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=5)([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[N:30]=[N:31][C:27]=4[CH:26]=3)[CH:22]=[CH:21][C:20]=2[F:53])[CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:10])=[CH:7][CH:6]=1.C(O[C:59]1(O[Si](C)(C)C)[CH2:61][CH2:60]1)C.C(O)(=O)C>CO>[CH:59]1([N:15]2[CH2:16][CH2:17][CH:12]([N:11]([CH2:18][C:19]3[CH:24]=[C:23]([C:25]4[CH:52]=[CH:51][C:28]5[N:29]([C:32]([C:39]6[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=6)([C:45]6[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=6)[C:33]6[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=6)[N:30]=[N:31][C:27]=5[CH:26]=4)[CH:22]=[CH:21][C:20]=3[F:53])[C:9](=[O:10])[C:8]3[CH:7]=[CH:6][C:5]([F:4])=[CH:55][CH:54]=3)[CH2:13][CH2:14]2)[CH2:61][CH2:60]1
Reactant: O=C(c1ccc(F)cc1)N(Cc1cc(-c2ccc3c(c2)nnn3C(c2ccccc2)(c2ccccc2)c2ccccc2)ccc1F)C1CCNCC1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CO
Product: O=C(c1ccc(F)cc1)N(Cc1cc(-c2ccc3c(c2)nnn3C(c2ccccc2)(c2ccccc2)c2ccccc2)ccc1F)C1CCN(C2CC2)CC1
Temperature: 45 °C
Reaction time: 2 h
Yield: 66.1 %

Procedure:
Solid supported cyanoborohydride (2.5 mmol/g, 46 mg) was added to a solution of 4-fluoro-N-[2-fluoro-5-(1-trityl-1H-benzotriazol-5-yl)-benzyl]-N-piperidin-4-yl-benzamide (20 mg, 0.029 mmol), (1-ethoxy-cyclopropoxy)-trimethylsilane (25 mg, 0.145 mmol) and acetic acid (1.74 mg, 0.029 mmol) in 1 mL of methanol. The mixture was stirred at 45° C. for 2 h and then at 75° C. overnight. The mixture was cooled and filtered and the filtrate concentrated in vacuo to provide the crude product. Chromatography provided 14 mg of product. LC/MS: Retention time, 3.20 min; (M+H)=730.
Reaction SMILES: Br.[F:2][C:3]([F:17])([F:16])[C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]([NH2:15])[S:13][CH:14]=2)[CH:7]=[CH:8][CH:9]=1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.Cl>N1C=CC=CC=1>[CH3:28][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:15][C:12]2[S:13][CH:14]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([C:3]([F:2])([F:16])[F:17])[CH:5]=3)[N:11]=2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc(-c2cccc(C(F)(F)F)c2)cs1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3cccc(C(F)(F)F)c3)cs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.5 g of 4-(3-trifluoromethyl-phenyl)-thiazol-2-ylamine hydrobromide with 0.42 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 30 ml of 1N hydrochloric acid and the mixture was extracted twice with 40 ml of ethyl acetate each time. The organic phases were combined, dried with magnesium sulphate and the solvent was removed on a rotary evaporator. The residue was dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.4 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. 0.23 g of 4-methyl-N-[4-(3-trifluoromethyl-phenyl)-thiazol-2-yl]-benzenesulfonamide separated as colorless crystals upon neutralization with concentrated hydrochloric acid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[C:10]([CH2:12][O:13][CH3:14])[N:9]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]3)=[C:18]([O:28][CH3:29])[CH:17]=2)[N:7]=1)=[CH2:5])C.O.Cl>O1CCOCC1>[CH3:29][O:28][C:18]1[CH:17]=[C:16]([NH:15][C:8]2[N:7]=[C:6]([C:4](=[O:3])[CH3:5])[CH:11]=[C:10]([CH2:12][O:13][CH3:14])[N:9]=2)[CH:21]=[CH:20][C:19]=1[N:22]1[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]1
Reactant: C=C(OCC)c1cc(COC)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: COCc1cc(C(C)=O)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-(1-ethoxyvinyl)-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-6-(methoxymethyl)pyrimidin-2-amine (172 mg, 0.43 mmol) in 1,4-dioxane (30 mL) were added water (2 mL) and hydrochloric acid (conc., 0.11 mL, 1.30 mmol). The mixture was stirred at 50° C. for 20 min. The solvents were evaporated. Sodium bicarbonate (aq, 50% saturated) was added and the mixture was extracted with DCM. The organic phase was separated on phase separator and the solvents were evaporated to give the title compound, 160 mg (100%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:37])=[C:23]([C:25]4[N:26]=[CH:27][C:28]5[C:33]([CH:34]=4)=[C:32]([Br:35])[CH:31]=[CH:30][C:29]=5[F:36])[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:38].CCOCC>C(Cl)Cl>[ClH:38].[ClH:38].[ClH:38].[Br:35][C:32]1[CH:31]=[CH:30][C:29]([F:36])=[C:28]2[C:33]=1[CH:34]=[C:25]([C:23]1[C:22]([NH2:37])=[N:21][CH:20]=[C:19]([C:17]3[CH:16]=[N:15][N:14]([CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:18]=3)[CH:24]=1)[N:26]=[CH:27]2
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4cc5c(Br)ccc(F)c5cn4)c3)cn2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1cc2c(Br)ccc(F)c2cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-{4-[6-amino-5-(5-bromo-8-fluoroisoquinolin-3-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (82 mg, 0.14 mmol) in DCM (3.0 mL) was added 1.0 M of HCl in Et2O (3.0 mL, 3.0 mmol), and the mixture was stirred at ambient temperature for 1 h. Almost immediately a pale yellow solid precipitated. The solvents were evaporated, and the residue was transferred into a vial and dried in vacuo overnight, yielding the title compound as yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.09-2.28 (m, 4H), 3.03-3.16 (m, 2H), 3.39 (dd, J=13.8, 1.9 Hz, 2H), 4.47-4.58 (m, 1H), 7.61 (dd, J=9.8, 8.4 Hz, 1H), 8.12 (s, 1H), 8.23-8.32 (m, 2H), 8.42 (s, 1H), 8.46 (s, 1H), 8.48 (d, J=2.0 Hz, 1H), 8.71 (d, J=2.0 Hz, 1H), 9.01 (br. s., 1H), 9.16 (br. s., 1H), 9.65 (s, 1H). MS (ES+): m/z=466.73/468.63 [MH+]. HPLC: tR=1.88 min (ZQ2, polar—5 min).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:25][C:26]3[N:27](C(C)(C)C)[N:28]=[C:29]([CH3:31])[CH:30]=3)=[N:9][N:10]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]2=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]>C(O)=O>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([N:10]2[N:9]=[C:8]([NH:25][C:26]3[NH:27][N:28]=[C:29]([CH3:31])[CH:30]=3)[C:7]3[C:12](=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[C:11]2=[O:14])=[CH:16][CH:17]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: Cc1cc(Nc2nn(-c3ccc(C(C)(C)C)cc3)c(=O)c3cc([N+](=O)[O-])ccc23)n(C(C)(C)C)n1
Solvent: O=CO
Product: Cc1cc(Nc2nn(-c3ccc(C(C)(C)C)cc3)c(=O)c3cc([N+](=O)[O-])ccc23)[nH]n1
Yield: 52.9 %

Procedure:
15 mg 7-Nitro-4-(2-tert-butyl-5-methyl-2H-pyrazol-3-ylamino)-2-(4-tert-butyl-phenyl)-2H-phthalazin-1-one (preparation see ZB-1) were deprotected by heating in formic acid as described for ZA-1. Evaporation of excess formic acid and chromatography of the residue on silica, eluting with DCM and then with DCM/MeOH 20:1 gave 7 mg of the title product. 1H-NMR: (400 MHz, D6-DMSO) 11.9 (1H, br s), 9.53 (1H, br s), 8.98 (1H, s), 8.80 (1H, d), 8.71 (1H, d), 7.65 (2H, d), 7.54 (2H, d), 6.25 (1H, s), 2.20 (3H, s), 1.35 (9H, s); MS (ESI+)=418.31 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:11])[CH2:9][NH2:10])=[CH:4][CH:3]=1.Cl[C:13]1[S:17][N:16]=[C:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[N:14]=1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([CH3:11])[CH2:9][NH:10][C:13]2[S:17][N:16]=[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)[N:14]=2)=[CH:6][CH:7]=1
Reactant: C[C@H](CN)c1ccc(F)cc1
Reactant: COc1cccc(Cc2nsc(Cl)n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1cccc(Cc2nsc(NC[C@@H](C)c3ccc(F)cc3)n2)c1
Temperature: 180 °C
Yield: 83.9 %

Procedure:
To a solution of (S)-2-(4-fluorophenyl)propan-1-amine (96 mg, 0.62 mmol, 1.5 equiv) and 5-chloro-3-(3-methoxybenzyl)-1,2,4-thiadiazole (100 mg, 0.42 mmol, 1.0 equiv) in NMP (0.8 mL) in a microwavable vial was added K2CO3 (230 mg, 1.68 mmol, 4.0 equiv). The mixture was heated by microwave for 15 minutes at 180° C. and then allowed to cool to room temperature. Purification by silica gel across a gradient of 10-30% EtOAc/Hexanes provided the title compound (126 mg, 84%). m/z=358.0 [M+H]+.
Reaction SMILES: C([N:5]1[C:20](=[O:21])[C:9]2[CH:10]=[N:11][C:12]3[C:13]([O:18][CH3:19])=[CH:14][CH:15]=[CH:16][C:17]=3[C:8]=2[N:7]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:6]1=[O:27])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:22]1([N:7]2[C:8]3[C:17]4[CH:16]=[CH:15][CH:14]=[C:13]([O:18][CH3:19])[C:12]=4[N:11]=[CH:10][C:9]=3[C:20](=[O:21])[NH:5][C:6]2=[O:27])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: COc1cccc2c1ncc1c(=O)n(C(C)(C)C)c(=O)n(C3CCCC3)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc2c1ncc1c(=O)[nH]c(=O)n(C3CCCC3)c12
Yield: 51.4 %

Procedure:
1-Cyclopentyl-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (8 mg) was prepared from 3-tert-butyl-1-cyclopentyl-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (18 mg, 0.05 mmol) with treatment of trifluoroacetic acid (20 L) in DCM (1 mL). LCMS: m/z 312 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:14]([O-])=O)=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1>C(O)C>[NH2:14][C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cc1cccc(-c2ccccc2)c1[N+](=O)[O-]
Solvent: CCO
Product: Cc1cccc(-c2ccccc2)c1N

Procedure:
3-Methyl-2-nitrobiphenyl (1 g) was heated at 90°-95° C. for 28 hours with hydrated sodium sulphide (4.5 g) and ethanol (25 ml) to give 2-amino-3-methyl-biphenyl (m.p. 66°-67° C.) which was recrystallised from hexane and converted into its hydrochloride salt.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][C:12]([C:18]3[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=3)([C:14]([F:17])([F:16])[F:15])[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1I.C([Mg]Cl)(C)C.[CH:32]([N:45]1[CH2:48][C:47](=[O:49])[CH2:46]1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[CH:32]([N:45]1[CH2:48][C:47]([C:7]2[CH:6]=[CH:5][C:4]([C:9]3[CH2:13][C:12]([C:18]4[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=4)([C:14]([F:17])([F:16])[F:15])[O:11][N:10]=3)=[CH:3][C:2]=2[Br:1])([OH:49])[CH2:46]1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: FC(F)(F)C1(c2cc(Cl)c(Cl)c(Cl)c2)CC(c2ccc(I)c(Br)c2)=NO1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: OC1(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2Br)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: -40 °C
Reaction time: 1.5 h

Procedure:
In an oven-dried flask containing 3-(3-bromo-4-iodophenyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (1000 mg, 1.67 mmol) in THF (25 mL) at −40° C. was slowly added isopropyl magnesium chloride (1.7 mL of 2.0M solution). The reaction was stirred at approximately −40° C. for 1.5 hours under nitrogen. 1-benzhydrylazetidin-3-one (520 mg in 4 mL THF) was slowly added. The reaction was stirred at −40° C. for an additional 30 minutes and allowed to warm to room temperature. Stirring was continued for 2 hours at room temperature. The reaction was quenched with saturated NH4Cl and extracted with EtOAc (2×75 mL). The combined organic phase was dried (Na2SO4) and concentrated under vacuum. The crude material was chromatographed (40 g Redi-Sep column) eluting from 100% heptane to 60:40 EtOAc:heptane, collecting the intermediate (615 mg, 52%) as a glass. 1HNMR (CDCl3) δ ppm: 7.87 (1H), 7.66-7.63 (3H), 7.45 (4H), 7.36-7.21 (7H), 4.39 (1H), 4.07 (1H), 3.73-3.58 (5H), 3.06 (1H); m/z (CI) 711 [M+H]+.