Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[CH:22]=[C:21]([F:23])[C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]([CH2:39][CH2:40][OH:41])[CH2:36][CH2:37][OH:38]>>[OH:41][CH2:40][CH2:39][N:35]([CH2:36][CH2:37][OH:38])[CH2:34][CH2:33][CH2:32][CH2:31][NH:30][C:8](=[O:29])[NH:9][C:10]1[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]2[CH:22]=[C:21]([F:23])[C:20]([CH3:24])=[CH:19][C:18]=2[F:25])[C:11]=1[C:26]([NH2:27])=[O:28]
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)cc1F
Reactant: NCCCCN(CCO)CCO
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCCN(CCO)CCO)c2C(N)=O)cc1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 2-[(4-amino-butyl)-(2-hydroxy-ethyl)-amino]-ethanol by the procedure analogous to Example 6. HPLC ret. time: 3.1 minutes. 1H NMR (400 MHz, CD3OD) δ 7.20 (dd, 1H, J=6.0, 9.2 Hz), 7.04 (dd, 1H, J=6.8, 9.6 Hz), 5.45 (s, 2H), 3.63 (t, 4H, J=5.6 Hz), 3.28 (m), 2.74 (m, 4H), 2.68 (m, 2H), 2.25 (d, 3H, J=2.0 Hz), 1.56 (m, 4H) ppm; MS (APCl, m/z): 502 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH3:33])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1.NC1C(C#N)=C(N2CCC(C3N(C[CH2:66][OH:67])C=C(C4C=CC(F)=C(C(F)(F)F)C=4)N=3)CC2)N=CN=1>>[NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH2:33][CH2:66][OH:67])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1
Reactant: N#Cc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCO)CC1
Product: NC(=O)c1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCO)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamide using 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-hydroxy-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile instead of 4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile. LC-MS: (M+1=494, obsd.=494).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[C:6]([Br:11])[CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([NH2:14])=[O:13].[O:15]=[C:16](Cl)OC(Cl)(Cl)Cl.O>O1CCOCC1>[Br:11][C:6]1[C:5]2[NH:4][C:3]3[C:12](=[O:13])[NH:14][C:16](=[O:15])[NH:1][C:2]=3[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: NC(=O)c1[nH]c2c(Br)cccc2c1N
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: O
Product: O=c1[nH]c(=O)c2[nH]c3c(Br)cccc3c2[nH]1
Temperature: 25 °C
Yield: 100.4 %

Procedure:
8.0 g (32 mmol) 3-amino-7-bromo-1H-indole-2-carboxylic acid amide was suspended in 50 ml dioxan, and refluxed after the addition of 3.8 ml (32 mmol) diphosgene for 3 h. Having cooled down to room temperature, 20 ml water was carefully added and the precipitate was then sucked off. 9.0 g (32%) 6-bromo-1H-pyrimido[5,4-b]indole-2,4(3H,5H)-dione was obtained. ESI-MS [m/z]: 278, 280 [M−H]−
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[CH2:16]([Sn:20](Cl)([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19].[F:30][C:31]1[N:32]=[CH:33][N:34]2[CH:38]=[CH:37][S:36][C:35]=12.O>C1COCC1>[F:30][C:31]1[N:32]=[CH:33][N:34]2[CH:38]=[C:37]([Sn:20]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][CH2:17][CH2:18][CH3:19])[S:36][C:35]=12
Reactant: Fc1ncn2ccsc12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(F)c2s1
Reaction time: 0.17 h

Procedure:
A 1.0 N lithiumbis(trimethylsilyl)amide/THF solution (3.2 ml) and 0.75 ml of tri-n-butylstannyl chloride were added in that order to a solution of 7-fluoroimidazo[5,1-b]thiazole in dry THF in an argon atmosphere at −78° C. The mixture was stirred at the same temperature for 10 min. Water was added thereto, followed by extraction with ethyl acetate and washing with saturated brine. The extract was dried over anhydrous magnesium sulfate and then filtered. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=7:1) to give 820 mg of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]([C@H:5]1[CH2:7][C@@H:6]1[C:8]1[CH:13]=[C:12]([N:14]2[C:18]([CH3:19])=[N:17][C:16]([CH3:20])=[N:15]2)[N:11]=[C:10]([CH3:21])[N:9]=1)=O.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C(=O)(O)[O-].[Na+]>C(O)C.C(OCC)(=O)C>[CH3:20][C:16]1[N:17]=[C:18]([CH3:19])[N:14]([C:12]2[N:11]=[C:10]([CH3:21])[N:9]=[C:8]([C@H:6]3[CH2:7][C@@H:5]3[C:3]3[N:22]=[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]4[CH:2]=3)[CH:13]=2)[N:15]=1
Reactant: Nc1ccccn1
Reactant: Cc1nc([C@H]2C[C@@H]2C(=O)CCl)cc(-n2nc(C)nc2C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1nc([C@H]2C[C@@H]2c2cn3ccccc3n2)cc(-n2nc(C)nc2C)n1
Temperature: 80 °C

Procedure:
To a solution of 1-5 (30 mg, 0.10 mmol) and 2-aminopyridine (10 mg, 0.11 mmol) in ethanol (1 mL) was added sodium bicarbonate (16 mg, 0.20 mmol) in a single portion and the reaction was heated at 80° C. After 2 h the mixture cooled to room temperature, diluted with ethyl acetate (5 mL) and washed with saturated aqueous sodium bicarbonate (2×5 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography (50-100% EtOAc/hexanes) to give Example 1 as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.03 (dt, J=6.7, 1.2 Hz, 1H), 7.57 (s, 1H), 7.52 (br d, J=9.1 Hz, 1H), 7.45 (s, 1H), 7.13 (ddd, J=9.0, 6.8, 1.2 Hz, 1H), 6.74 (td, J=6.8, 1.1 Hz, 1H), 2.88 (s, 3H), 2.81-2.76 (m, 1H), 2.68-2.62 (m, 1H), 2.65 (s, 3H), 2.39 (s, 3H), 1.93-1.83 (m, 2H); MS: m/z=346.5 (M+H).
Reaction SMILES: C(O[BH-](O[C:11](=O)[CH3:12])OC(=O)C)(=O)C.[Na+].[NH2:15][CH:16]([CH2:24][NH:25][C:26]1[C:31]([CH2:32][CH3:33])=[C:30]([N:34]2[CH2:39][CH2:38][CH:37]([C:40]3[CH:49]=[CH:48][C:47]4[CH2:46][CH2:45][CH2:44][NH:43][C:42]=4[N:41]=3)[CH2:36][CH2:35]2)[N:29]=[CH:28][N:27]=1)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>O1CCCC1>[CH2:31]([CH:32]([CH2:11][CH3:12])[CH2:33][NH:15][CH:16]([CH2:24][NH:25][C:26]1[C:31]([CH2:32][CH3:33])=[C:30]([N:34]2[CH2:35][CH2:36][CH:37]([C:40]3[CH:49]=[CH:48][C:47]4[CH2:46][CH2:45][CH2:44][NH:43][C:42]=4[N:41]=3)[CH2:38][CH2:39]2)[N:29]=[CH:28][N:27]=1)[C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH3:30]
Reactant: CCc1c(NCC(N)C(=O)OC(C)(C)C)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1c(NCC(NCC(CC)CC)C(=O)OC(C)(C)C)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Reaction time: 0.17 h

Procedure:
75 mg (0.35 mmoles) of sodium triacetoxyborohydride in 6 ml of tetrahydrofuran is left under stirring for 10 minutes at TA. Then a mixture of 100 mg (0.208 mmoles) of tert-butyl 2-amino-3-{5-ethyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-piperidin-1-yl]pyrimidin-4-ylamino}-propionate and 0.228 mmoles of 2-ethyl-butylaldehyde in solution in 3 ml of tetrahydrofuran is added. The reaction mixture is stirred at ambient temperature for 4 hours 30 minutes. Then it is extracted with ethyl acetate after washing with a saturated solution of sodium bicarbonate. The organic phase obtained is dried over magnesium sulphate before being concentrated to dryness under reduced pressure (2 kPa). The residue is then chromatographed on silica gel with the following eluent: ethyl acetate-dichloromethane/methanol (80/20) 50-50. A mass my of expected product is obtained.
Reaction SMILES: Cl[CH:2]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)[CH2:3][N:4]1[CH2:7][CH2:6][CH2:5]1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:26]([NH2:37])=[N:27][CH:28]=[N:29][C:30]=2[N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C>C(#N)C>[N:4]1([CH2:3][CH:2]([N:34]2[CH2:35][CH2:36][N:31]([C:30]3[N:29]=[CH:28][N:27]=[C:26]([NH2:37])[C:25]=3[C:22]3[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=3)[CH2:32][CH2:33]2)[C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5]1
Reactant: FC(F)(F)c1ccc(C(Cl)CN2CCC2)cc1
Reactant: Nc1ncnc(N2CCNCC2)c1-c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Nc1ncnc(N2CCN(C(CN3CCC3)c3ccc(C(F)(F)F)cc3)CC2)c1-c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
In a microwave vial containing 1-[2-chloro-2-(4-trifluoromethyl-phenyl)-ethyl]-azetidine (32.26 mg; 0.12 mmol; 1.00 eq.) from last step in acetonitrile (2.00 ml) was added 5-(4-fluoro-phenyl)-6-piperazin-1-yl-pyrimidin-4-ylamine (33.43 mg; 0.12 mmol; 1.00 eq.), followed by DIPEA (0.06 ml; 0.37 mmol; 3.00 eq.). The clear solution was stirred at 60° C. overnight and then 75° C. for 3 h before the mixture was concentrated and purified with waters pre-HPLC. LC-MS: (M+1=501, obsd.=501)
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(F)nc1
Reactant: CC(C)(C)OC(=O)NCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1cccc(Oc2ccc([N+](=O)[O-])cn2)c1
Temperature: 100 °C
Yield: 42.7 %

Procedure:
A mixture of (3-hydroxy-benzyl)-carbamic acid tert-butyl ester (250 mg, 1.12 mmol), 2-fluoro-5-nitro-pyridine (150 mg, 1.12 mmol) and K2CO3 (120 mg) in N,N-dimethylformamide (3 mL) was heated under microwave condition at 100° C. for 10 min. The reaction mixture was poured into water, and extracted with ethyl acetate (2×). The solvent was removed, and the resulting residue was chromatographed using hexane/ethyl acetate (7:1) to give the title compound (165 mg, 43%). MS (DCI/NH3) m/z 346 (M+1)+.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[NH+:8]([O-:13])[C:7]([CH3:15])([CH3:14])[CH2:6]1)(=[O:3])[CH3:2].C(OOC(C)(C)C)(C)(C)C.[C:26]1([CH:32]([CH3:34])[CH3:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:32]([O:13][N:8]1[C:9]([CH3:12])([CH3:11])[CH2:10][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:6][C:7]1([CH3:15])[CH3:14])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:34])[CH3:33]
Reactant: CC(=O)OC1CC(C)(C)[NH+]([O-])C(C)(C)C1
Reactant: CC(C)c1ccccc1
Agent: CC(C)(C)OOC(C)(C)C
Product: CC(=O)OC1CC(C)(C)N(OC(C)(C)c2ccccc2)C(C)(C)C1
Reaction time: 0.5 h

Procedure:
4.3 g (20 mmol) of 4-acetyloxy-2,2,6,6-tetramethylpiperidine-N-oxide synthesized by the method described in Synthesis Example 1 was dissolved in 20 mL of cumene and 11.7 g (80 mmol) of t-butyl peroxide was added slowly. After a nitrogen bubbling for 30 minutes, it was transferred to a UV laboratory reaction apparatus (System1) made by Heraeus K. K. Light irradiation was performed using a TQ150 type lamp for 10 minutes to carry out a reaction. The reaction mixture was concentrated by a rotary evaporator, and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate=5/1, volume ratio) to obtain 5.5 g of 1-cumyloxy-2,2,6,6-tetramethyl-4-acetyloxypiperidine was obtained (82.3% of yield).
Reaction SMILES: [H-].[Na+].[SH:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].F[C:11]1[CH:12]=[C:13]([C:19]([CH3:34])([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:14]=[CH:15][C:16]=1[CH:17]=O.O>CS(C)=O>[CH2:8]([O:7][C:5]([C:4]1[S:3][C:11]2[CH:12]=[C:13]([C:19]([CH3:34])([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:27]([O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:28])[CH:14]=[CH:15][C:16]=2[CH:17]=1)=[O:6])[CH3:9]
Reactant: CC(C)(C)OC(=O)C(C)(C(=O)OC(C)(C)C)c1ccc(C=O)c(F)c1
Reactant: CCOC(=O)CS
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1cc2ccc(C(C)(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc2s1
Reaction time: 0.25 h
Yield: 22 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.19 g, 4.75 mmol) was suspended in DMSO (2.5 mL) and ethyl mercaptoacetate (0.28 mL, 2.54 mmol) was added portionwise using a water bath to moderate the exotherm. On complete addition, the water bath was removed and stirring continued for 15 minutes. A solution of di-tert-butyl (3-fluoro-4-formylphenyl)(methyl)malonate (0.81 g, 2.30 mmol) in DMSO (0.5 mL) was added in one portion. The orange solution was warmed with a heat gun to give a dark brown solution. H2O was added (150 mL) and the products were extracted into EtOAc (2×100 mL). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by MPLC gave 0.22 g of desired product (pale yellow solid, 22%). 1H NMR (CDCl3) δ 8.01 (s, 1H), 7.88 (d, J=1.8 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.48 (dd, J=8.4, 1.8 Hz, 1H), 4.39 (q, J=7.2 Hz, 2H), 1.84 (s, 3H), 1.47 (s, 18H), 1.40 (t, J=7.2 Hz, 3H).
Reaction SMILES: COC1C=CC2C3C=C4C=CC(OC)=CC4=C(O)C=3CC=2C=1.[CH3:23][O:24][C:25]1[CH:45]=[CH:44][C:28]2[C:29]3[C:38]([CH2:39][CH2:40][C:27]=2[CH:26]=1)=[C:37]([OH:41])[C:36]1[C:31](=[CH:32][CH:33]=[C:34]([O:42][CH3:43])[CH:35]=1)[CH:30]=3.[Cl:46]C1C(=O)C(Cl)=C(Cl)C(Cl)(Cl)C=1Cl.O>CN(C=O)C>[CH3:23][O:24][C:25]1[CH:45]=[CH:44][C:28]2[C:29]3[C:38]([CH2:39][CH2:40][C:27]=2[CH:26]=1)=[C:37]([OH:41])[C:36]1[C:31](=[CH:32][CH:33]=[C:34]([O:42][CH3:43])[CH:35]=1)[CH:30]=3.[Cl:46][C:30]1[C:31]2[C:36]([C:37]([OH:41])=[C:38]3[C:29]=1[C:28]1[CH:44]=[CH:45][C:25]([O:24][CH3:23])=[CH:26][C:27]=1[CH2:40][CH2:39]3)=[CH:35][C:34]([O:42][CH3:43])=[CH:33][CH:32]=2
Reactant: O=C1C(Cl)=C(Cl)C(Cl)(Cl)C(Cl)=C1Cl
Agent: COc1ccc2c(c1)CCc1c-2cc2ccc(OC)cc2c1O
Agent: COc1ccc2c(c1)Cc1c-2cc2ccc(OC)cc2c1O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCc1c-2c(Cl)c2ccc(OC)cc2c1O
Temperature: 40 °C
Reaction time: 4 h
Yield: 83.9 %

Procedure:
The compound 3,9-dimethoxy-7-hydroxy-5,6-dihydro-benz[a]anthracene (compounds 23) was prepared analogously to compound 16 in example 5. To a solution of 600 mg of 23 in 10 ml of DMF was added in portions 600 mg of 2,3,4,4,5,6-hexachlorocyclohexa-2,5-dien-1-one. The mixture was then stirred at 40° C. for 4 hr. Then the reaction was poured into water and the product extracted with ethyl acetate. The crude material was passed through a silicagel column (hept./eth.ac.) and finally triturated with heptane-diisopropyl ether to provide 280 mg of 24 as orange crystals; Mp 140-141° C., Rf 0.28 (hept./eth.ac. 7/3) starting material Rf 0.30.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][CH2:11][C:12]([O:14]CC)=[O:13])[CH2:4][C:3]1([CH3:18])[CH3:17].[OH-].[Na+].Cl>O.CO>[OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][CH2:11][C:12]([OH:14])=[O:13])[CH2:4][C:3]1([CH3:18])[CH3:17]
Reactant: CCOC(=O)COC1CC(C)(C)N(O)C(C)(C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)CC(OCC(=O)O)CC(C)(C)N1O
Reaction time: 1 h

Procedure:
1.0 g (39 mmol) of the compound of Example 6 is added to a solution of 0.2 g sodium hydroxide in 20 mL of 1:1 water/methanol. The mixture is stirred for one hour, carefully acidified with 1% aqueous hydrogen chloride and then extracted with ethyl acetate. The organic extract is dried over anhydrous magnesium sulfate and then contentrated to afford the title compound as an orange solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[CH:7][NH2:8])=[CH:4][C:3]=1[CH3:11].CO.S([CH2:24][N+:25]#[C-:26])(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>COCCOC>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[N:25]([CH3:26])[CH:24]=[N:8][CH:7]=2)=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C=CN)ccc1Br
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CO
Product: Cc1cc(-c2cncn2C)ccc1Br
Yield: 59.9 %

Procedure:
(4-Bromo-3-methylbenzylidene)methylamine (D91, 2.15 g, 10.1 mmol) was dissolved in dry DME (30 ml) and methanol (70 ml) containing tosylmethylisocyanide (3.0 g; 15.4 mmol) and this solution was treated with potassium carbonate (2.8 g, 20.3 mmol). The whole was heated at reflux for 48 hours, cooled and evaporated in vacuo. The residue was partitioned between brine and chloroform (3 times), and the organics combined and dried over Na2SO4. The organics were filtered and evaporated in vacuo then the residue purified by flash silica gel chromatography (with chloroform as eluant) to yield the title compound as an orange gum (1.52 g, 60%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:21]C(OC(C)(C)C)=O)[CH2:15][C:16]2[N:17]=[CH:18][NH:19][CH:20]=2)=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].FC(F)(F)C(O)=O.C(Cl)Cl>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH2:21])[CH2:15][C:16]2[N:17]=[CH:18][NH:19][CH:20]=2)=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)C(Cc2c[nH]cn2)NC(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CCN(C(=O)C(N)Cc2c[nH]cn2)CC1
Reaction time: 1 h

Procedure:
To a solution of N-t-butoxycarbonylhistidine (2 g, 7.05 mmol) in THF (30 mL) was added 1-ethoxycarbonylpiperazine (1.36 mL, 1.3 eq.), EDCI (1.65 g, 1.2 eq. ), HOBt (1.2 g, 1.1 eq.) and the reaction mixture was stirred overnight. The reaction mixture was evaporated in vacuo to afford a crude product, which was dissolved in ethyl acetate, washed with saturated NaHCO3, 1M NaHSO4 and brine. The organic layer was evaporated. Flash column chromatography with 2%–6% MeOH in CH2Cl2 afforded 4-ethoxycarbonyl-1-(1-(t-butoxycarbonyl)amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine (820 mg). 4-Ethoxycarbonyl-1-(1-(t-butoxycarbonyl)amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine (200 mg, 0.5 mmol) was treated with trifluoroacetic acid/methylene chloride (1:1, 2.0 mL) with stirring at ambient temperture for 1 hour. Evaporation gave 4-ethoxycarbonyl-1-(1-amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine, which was treated with methylene chloride and triethylamine (0.5 mL), and the solvents evaporated to again afford 4-ethoxycarbonyl-1-(1-amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine. To a solution of 2-carboxy-4-methoxyquinoline (124 mg, 0.61 mmol) in THF (4 mL) was added a mixture of 4-ethoxycarbonyl-1-(1-amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine, THF (2 mL), and triethylamine (0.1 mL), followed by addition of EDCl (136 mg, 1.4 eq.), HOBt (98 mg, 1.4 eq.). The resulting mixture was stirred overnight. The crude product (245 mg, foam) was isolated from the reaction mixture by the same methods employed above. Flash column chromatography with 25%–6% MeOH in methylene chloride afforded 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-2-(imidazol-4-yl)ethyl]aminocarbonyl-4-methoxyquinoline; NMR (CDCl3) 1.25 (t, 3), 3.10–3.30 (m, 2), 3.20–3.65 (m, 9), 4.10 (m, 5), 5.40 (m, 1), 6.90 (s, 1), 7.55–7.60 (m, 3), 7.70 (t, 1), 8.02 (d, 1), 8.20 (d, 1), 9.0 (d, 1) ppm.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[CH3:9][O:10][C:11]1[C:16](B(O)O)=[CH:15][CH:14]=[CH:13][N:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[CH3:9][O:10][C:11]1[C:16]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=2)=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: Nc1cc(Br)ccn1
Reactant: COc1ncccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ncccc1-c1ccnc(N)c1
Temperature: 85 °C
Reaction time: 3 h
Yield: 93.9 %

Procedure:
To 4-bromopyridin-2-amine (0.5 g, 2.8 mmol), 2-methoxypyridin-3-ylboronic acid (0.52 g, 3.4 mmol) in DMF (25 mL) was added 1N sodium carbonate (10 mL, 2.3 mmol), followed by 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.21 g, 0.26 mmol). The reaction mixture was stirred for 3 hours at 85° C. and then cooled to room temperature. The product was extracted with ethyl acetate (2×50 mL), dried with MgSO4, filtered, and concentrated in vacuo. The crude product was purified by chromotography (Biotage: 100 to 90/10% ethyl acetate-ethyl acetate/methanol) to yield 2-methoxy-3,4′-bipyridin-2′-amine (0.53 g, 2.63 mmol, 93% yield) as a brown powder. The product was taken directly to the next step.
Reaction SMILES: [CH3:1][O-:2].[Na+].[NH2:4][C:5]1[N:10]=[C:9](C(Cl)(Cl)Cl)[N:8]=[C:7]([C:15]([F:18])([F:17])[F:16])[N:6]=1.O.Cl>CO>[NH2:4][C:5]1[N:10]=[C:9]([O:2][CH3:1])[N:8]=[C:7]([C:15]([F:18])([F:17])[F:16])[N:6]=1
Reactant: Nc1nc(C(F)(F)F)nc(C(Cl)(Cl)Cl)n1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1nc(N)nc(C(F)(F)F)n1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
1.8 g of a 30% by weight solution of sodium methanolate in methanol (corresponding to 0.01 mol of sodium methanolate) were added at 22° C. to a solution of 28.8 g (0.1 mol) of 2-amino-4-trichloromethyl-6-trifluoromethyl-1,3,5-triazine in 100 ml of methanol. The pale yellow solution was then refluxed for 30 minutes. The progress of the reaction was followed by thin-layer chromatography on silica gel (mobile phase: diethyl ether/hexane 1:1). After the reaction was complete, 20 ml of water were added, followed by 2 normal hydrochloric acid until the pH was 6-7. After this most of the methanol was removed at 40° C. under reduced pressure, adding 150 ml of water a little at a time so that the product did not agglomerate. To complete precipitation of the product, the resulting mixture was then stirred at 5° C. for 1 hour, after which the product was separated off, washed with a little water and dried at 40° C. under reduced pressure.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)(=[O:14])=[O:13].[C:28](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1.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>[CH3:28][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)(=[O:14])=[O:13]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cc(C(F)(F)F)ccc2Br)CC1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccc(C(F)(F)F)cc1S(=O)(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C
Yield: 94 %

Procedure:
1,1-dimethylethyl 4-{[2-bromo-5-(trifluoromethyl)phenyl]sulfonyl}-1-piperazinecarboxylate (may be prepared as described in Description 22) (2.59 g, 5.47 mmol), potassium carbonate (1.513 g, 10.94 mmol) in 1,4-dioxane (80 ml) were stirred for 5 min then trimethylboroxin (1.523 ml, 10.94 mmol) and Pd(PPh3)4 (0.632 g, 0.547 mmol) were added and the reaction mixture heated at 100° C. for 1.5 h. Further trimethylboroxin (0.5 mL) was added and the mixture heated at 100° C. for 30 min before allowing to cool overnight. The mixture was concentrated under vacuum then EtOAc (150 ml) added, washed with 200 ml of water, dried on a phase separation cartridge and evaporated under vacuum. Crude material (3.1 g) purified via Biotage (40+M silica column) using a gradient EtOAc/i-hex from 10/90 to 30/70. Desired fractions were collected and concentrated under vacuum to give the title compound (2.1 g).