Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([N:15]([CH2:25][CH3:26])CC3C=CC(OC)=CC=3)[C:12]3=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:11]3[N:10]=2)=[CH:6][C:5]([C:32]#[N:33])=[CH:4][C:3]=1[N:34]1[CH2:39][CH2:38][C@@H:37]([NH:40][C:41](=[O:44])[O:42][CH3:43])[C@H:36]([OH:45])[CH2:35]1.C([O:53][P:54]([O:64][CH:65]([CH3:69])[C:66](O)=[O:67])([O:56]CC1C=CC=CC=1)=[O:55])C1C=CC=CC=1.C1CCC(N=C=NC2CCCCC2)CC1.ClC1C(NC2N=C(N(CC)CC3C=CC(OC)=CC=3)C3=NC=C(C#N)N3N=2)=CC(C#N)=CC=1N1CC[C@@H](NC(OC)=O)[C@H](C(OP(OCC2C=CC=CC=2)(OCC2C=CC=CC=2)=O)(C)C([O-])=O)C1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[P:54]([O:64][CH:65]([CH3:69])[C:66]([O:45][CH:36]1[CH:37]([NH:40][C:41]([O:42][CH3:43])=[O:44])[CH2:38][CH2:39][N:34]([C:3]2[CH:4]=[C:5]([C:32]#[N:33])[CH:6]=[C:7]([NH:8][C:9]3[N:14]=[C:13]([NH:15][CH2:25][CH3:26])[C:12]4=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:11]4[N:10]=3)[C:2]=2[Cl:1])[CH2:35]1)=[O:67])([OH:56])([OH:55])=[O:53]
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC(=O)OC)[C@H](O)C3)c2Cl)nn2c(C#N)cnc12
Reactant: CC(OP(=O)(OCc1ccccc1)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC(=O)OC)[C@H](C(C)(OP(=O)(OCc4ccccc4)OCc4ccccc4)C(=O)[O-])C3)c2Cl)nn2c(C#N)cnc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCNc1nc(Nc2cc(C#N)cc(N3CCC(NC(=O)OC)C(OC(=O)C(C)OP(=O)(O)O)C3)c2Cl)nn2c(C#N)cnc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl ((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate (0.040 g, 0.063 mmol), 2-((bis(benzyloxy)phosphoryl)oxy)propanoic acid (0.067 g, 0.19 mmol) in DCM (2 mL) was added DCC (0.039 g, 0.190 mmol) followed DMAP (0.77 mg, 0.006 mmol) and stirred at room temperature for 30 min. After completion of starting material (by LC-MS), reaction mixture was diluted with DCM (50 mL), filtered through celite and filtrate was washed with water and brine solution (5 mL). Combined organic extracts were dried over anhydrous Na2SO4, concentrated and purified by flash chromatography on silica gel using an ISCO system (eluted with 1:1 Hexanes and EtOAc) to give diastereomeric mixture of (3R,4R) 1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4 ((methoxycarbonyl)amino)piperidin-3-yl-2-((bis(benzyloxy)phosphoryl)oxy)propanoate (0.060 g,) as gummy liquid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[C:11]([C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1)#[N:12].C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[OH:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([C:11]#[N:12])[CH:18]=2)=[CH:3][CH:4]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Product: N#Cc1cccc(-c2ccc(CCO)cc2)c1
Temperature: 100 °C
Yield: 87.1 %

Procedure:
A mixture of 3 g (14.92 mmol) of 2-(4-bromophenyl)ethanol, 2.85 g (19.40 mmol) of 3-cyanophenylboronic acid, 5.15 g (37.30 mmol) of potassium carbonate, 4.81 g (14.92 mmol) of tetran-butylammonium bromide and 0.067 g (0.30 mmol) of palladium diacetate in 15 ml of water is heated at 100° C. under an argon atmosphere overnight. It is cooled to ambient temperature, diluted with water and extracted with ethyl acetate. The organic phase is dried over sodium sulphate and evaporated. It is subsequently purified by chromatography on silica gel, eluting with a 70/30 then 50/50 mixture of cyclohexane and ethyl acetate, to give 2.90 g of product in the form of an oil, which is used as it is in the following step.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([CH2:20][N:21]([CH3:37])[C:22]2[N:31]=[C:30]([NH2:32])[C:29]3[C:24](=[CH:25][C:26]([O:35][CH3:36])=[C:27]([O:33][CH3:34])[CH:28]=3)[N:23]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.O.[Pd]>[CH3:34][O:33][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:35][CH3:36])[N:23]=[C:22]([N:21]([CH2:20][C:11]1([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH3:37])[N:31]=[C:30]2[NH2:32]
Reactant: COc1cc2nc(N(C)CC3(c4ccccc4)CCN(Cc4ccccc4)CC3)nc(N)c2cc1OC
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COc1cc2nc(N(C)CC3(c4ccccc4)CCNCC3)nc(N)c2cc1OC
Yield: 75.1 %

Procedure:
To a solution of N2-(1-Benzyl-4-phenyl-piperidin-4-ylmethyl)-6,7-dimethoxy-N2-methyl-quinazoline-2,4-diamine 10, (1.3 g) and ammonium formate (2.2 g) in 24 ml methanol and 6 ml water was added 10% Pd-C (250 mg). After stirring under reflux for two hours, the reaction mixture was cooled and filtered through celite®. The filtrate was concentrated to a small volume, made basic with potassium carbonate, and extracted with dichloromethane. The extract was dried over potassium carbonate, filtered, and evaporated. The residue was chromatographed on silica gel to provide 800 mg of 6,7-dimethoxy-N2-(4-phenyl-piperidin-4-ylmethyl)-N2-methyl-quinazoline-2,4-diamine 11 as a white powder, MS: 407 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([CH:13](O)[CH3:14])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.O=S(Cl)[Cl:18]>CN(C=O)C>[Cl:18][CH:13]([C:10]1[N:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[O:12][N:11]=1)[CH3:14]
Reactant: O=S(Cl)Cl
Reactant: CC(O)c1noc(-c2cccc(Cl)c2)n1
Solvent: CN(C)C=O
Product: CC(Cl)c1noc(-c2cccc(Cl)c2)n1
Temperature: 70 °C
Yield: 93 %

Procedure:
5 drops of DMF was added to 1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethanol (12.3 g, 54.9 mmol) in SOCl2 (150 mL) and the reaction was heated at 70° C. for 5 h. The excess SOCl2 was evaporated and the residue was purified by column chromatography (Hep to Hep-EA 5:1) to give 12.4 g (93%) of the title compound. 1H NMR: 1.96 (d, 3H) 5.20 (q, 1H) 7.46 (t, 1H) 7.59 (m, 1H) 8.04 (m, 1H) 8.17 (t, 1H)
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][C:20](Cl)=[N:21][C:22]([N:23]4[CH2:29][CH:28]5[O:30][CH:25]([CH2:26][CH2:27]5)[CH2:24]4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1>C(O)CO.CS(C)=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][C:20]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=4)=[N:21][C:22]([N:23]4[CH2:29][CH:28]5[O:30][CH:25]([CH2:26][CH2:27]5)[CH2:24]4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nc(N2CC3CCC(C2)O3)c2cnn(C3CCN(Cc4ccccc4)CC3)c2n1
Reactant: Nc1ccc(O)cc1
Solvent: CS(C)=O
Solvent: OCCO
Product: Oc1ccc(Nc2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(Cc5ccccc5)CC4)c3n2)cc1
Yield: 28.4 %

Procedure:
50 mg (0.11 mmol) of 1-(1-benzylpiperidin-4-yl)-6-chloro-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidine was dissolved in 1 mL ethylene glycol. 0.24 mmol (26.2 mg) 4-aminophenol was added and the mixture was heated under microwave irradiation to 220 C (15 min). The mixture was diluted with 1 mL DMSO and purified by HPLC (TFA buffers) to give 16 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:21]1([CH3:27])[CH:26]=CC=C[CH:22]=1>C(OC(OC(C)(C)C)N(C)C)(C)(C)C.CCOCC>[CH3:1][O:2][C:3](=[O:20])[C@@H:4]([NH:12][C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:4][C:3]([O:20][C:21]([CH3:22])([CH3:26])[CH3:27])=[O:2])=[CH:8][CH:7]=1
Reactant: Cc1ccccc1
Reactant: COC(=O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: CN(C)C(OC(C)(C)C)OC(C)(C)C
Solvent: CCOCC
Product: COC(=O)[C@H](Cc1ccc(CC(=O)OC(C)(C)C)cc1)NC(=O)OC(C)(C)C

Procedure:
A solution of 3.50 g of (S)-4-carboxymethyl)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]benzenepropanoic acid methyl ester in 40 mL of dry toluene and 10 mL of dimethylformamide di-t-butyl acetal was heated to a bath temperature of 80° C. for 4 hours. After cooling, the is mixture was diluted with 100 mL of ether and was washed with water and saturated sodium chloride solution and was dried over magnesium sulfate. The residue obtained after filtration and evaporation was chromatographed over 150 g of silica gel, eluting with 20% ethyl acetate-hexane to give 2.663 g of (S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino)-4-[2-(1,1-dimethylethoxy)2-oxoethyl]benzenepropanoic acid methyl ester.
Reaction SMILES: [OH:1][CH:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][O:10][C:6]=2[CH2:5][CH2:4][CH:3]1[CH2:17][CH2:18][OH:19].[S:20](Cl)([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>N1C=CC=CC=1>[C:11]1([C:8]2[C:7]3[CH:2]([OH:1])[CH:3]([CH2:17][CH2:18][O:19][S:20]([C:23]4[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=4)(=[O:22])=[O:21])[CH2:4][CH2:5][C:6]=3[O:10][N:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCCC1CCc2onc(-c3ccccc3)c2C1O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC2CCc3onc(-c4ccccc4)c3C2O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
In 30 ml pyridine was dissolved 4-hydroxy-5-(2-hydroxyethyl)-3-phenyl-4,5,6,7-tetrahydro-1,2-benzisoxazole (2.1 g) and the mixture was cooled to 0° C. Tosyl chloride (1.54 g) was added and the solution was stirred at 0° C. for 30 minutes. The reaction mixture was poured into ice water, then extracted four times with ether. The mixture was dried (Na2SO4) and then concentrated at room temperature to yield 2.67 g of 3-phenyl-5-(2-tosyloxyethyl)-4-hydroxy-4,5,6,7-tetrahydro-1,2-benzisoxazole.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4]([C:5](F)=[O:6])[C:3]=1[C:14](F)=[O:15].C(O)(=[O:19])C>>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4]2[C:5](=[O:19])[O:6][C:14](=[O:15])[C:3]=12
Reactant: CC(=O)O
Reactant: O=C(F)c1c(F)c(F)c(F)c(F)c1C(=O)F
Product: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Yield: 73.5 %

Procedure:
Into a 300 ml glass reactor equipped with a reflux condenser and a stirrer, 100 g (0.413 mol) of the 3,4,5,6-tetrafluorophthaloyldifluoride separated by distillation from the mixture of Example 2, and 100 ml of acetic acid were charged, and the mixture was reacted at 130° C. for 1.5 hours with vigorous stirring. Then, the inorganic substance was removed by filtration, and the residue was separated by distillation to obtain 66.8 g of tetrafluorophthalic anhydride. The yield was 73.5%.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([SH:20])=[CH:16][CH:15]=1.[OH-].[K+]>CN(C=O)C.O.[Cu-]=O>[CH3:8][C:6]1[CH:7]=[C:2]([S:20][C:17]2[CH:18]=[CH:19][C:14]([CH3:13])=[CH:15][CH:16]=2)[CH:3]=[C:4]([CH3:12])[C:5]=1[C:9](=[O:11])[CH3:10]
Reactant: Cc1ccc(S)cc1
Reactant: CC(=O)c1c(C)cc(I)cc1C
Agent: O=[Cu-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1c(C)cc(Sc2ccc(C)cc2)cc1C
Yield: 78.2 %

Procedure:
A mixture of 1-(4-iodo-2,6-dimethylphenyl)ethanone (1.5 g, 5.5 mmol, 1.0 equiv), 4-methylbenzenethiol (1.02 g, 8.2 mmol, 1.5 equiv), copper(I) oxide (39.2 mg, 0.3 mmol, 0.05 equiv), and potassium hydroxide (614.1 mg, 11.0 mmol, 2.0 equiv) in DMF (4.4 mL) and H2O (1.1 mL) was heated at reflux for 20 h. The mixture was quenched with H2O (10 mL) and extracted with ether (2×20 mL). The organic layer was collected, dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (3.0% EtOAc in hexanes as eluant) to provide 1-(2,6-dimethyl-4-(p-tolylthio)phenyl)ethanone (1.16 g, 4.3 mmol) as yellow oil in 79% yield: 1H NMR (CD3OD, 500 MHz) δ 7.29 (d, J=8.0 Hz, 2 H), 7.20 (d, J=8.0 Hz, 2 H), 6.88 (s, 2 H), 2.45 (s, 3 H), 2.35 (s, 3 H), 2.15 (s, 6 H); ESI-MS: m/z 271.8 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH:5]1[CH2:7][CH:6]1[C:8]1[CH:13]=[CH:12][C:11]([O:14]C)=[C:10]([F:16])[CH:9]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH:5]1[CH2:7][CH:6]1[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([F:16])[CH:9]=1
Reactant: COC(=O)CC1CC1c1ccc(OC)c(F)c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CC1CC1c1ccc(O)c(F)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 84.4 %

Procedure:
After [2-(3-fluoro-4-methoxy-phenyl)-cyclopropyl]-acetic acid methyl ester (0.067 g, 0.28 mmol) obtained in Step E was dissolved in anhydrous DCM (2 mL), BBr3 1M DCM solution (0.42 mL, 0.42 mmol) was added thereto at −78° C., and the mixture was stirred at room temperature for 3 hours. After the termination of the reaction, the reactant was added with MeOH, concentrated under reduced pressure, and then purified by column chromatography (eluent, EtOAc/Hex=1/2) to obtain the title compound (0.053 g, 84%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:42][O:43][C:44]1[C:45]2[N:58]=[C:57]([NH2:59])[S:56][C:46]=2[C:47]([N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[N:48][CH:49]=1>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:59][C:57]2[S:56][C:46]3[C:47]([N:50]4[CH2:55][CH2:54][O:53][CH2:52][CH2:51]4)=[N:48][CH:49]=[C:44]([O:43][CH3:42])[C:45]=3[N:58]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)c3ccc(F)cc3)nc12
Reaction time: 8 h
Yield: 57 %

Procedure:
To a stirred solution of 79 mg (0.56 mmol) 4-fluoro-benzoic acid in 4 ml THF were added 225 mg (0.59 mmol) HATU and 0.12 ml (1.13 mmol) N-methylmorpholine and stirring continued at 30° C. for 8 h. 75 mg (0.28 mmol) 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine was then added and stirring continued at 35° C. for 48 h. The reaction mixture was then partitioned between tetrahydrofuran and saturated brine. The organic phases was dried over sodium sulfate and concentrated in vacuo. Flash chromatography (ethyl acetate/heptane) followed by trituration in ether afforded 62 mg (56%) 4-fluoro-N-(7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-yl)-benzamide as a white crystalline solid. ES-MS m/e (%): 389 (M+H+, 100).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([CH:19]([OH:40])[CH2:20][NH:21][C:22]([CH3:39])([CH3:38])[CH2:23][CH2:24][N:25]2[CH:29]=[CH:28][N:27]([C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[CH2:26]2)=[CH:15][C:10]=1[C:11](OC)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Ca+2].[Cl-].[BH4-].[Na+]>O1CCCC1.C(O)C>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([CH:19]([OH:40])[CH2:20][NH:21][C:22]([CH3:39])([CH3:38])[CH2:23][CH2:24][N:25]2[CH:29]=[CH:28][N:27]([C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)[CH2:26]2)=[CH:15][C:10]=1[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(C(O)CNC(C)(C)CCN2C=CN(c3ccc(OC)cc3)C2)ccc1OCc1ccccc1
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(N2C=CN(CCC(C)(C)NCC(O)c3ccc(OCc4ccccc4)c(CO)c3)C2)cc1
Reaction time: 12 h

Procedure:
13 g of methyl 2-benzyloxy-5-(1-hydroxy-2-{3-[3-(4-methoxy-phenyl)-imidazol-1-yl]-1,1-dimethyl-propylamino}-ethyl)-benzoate in 100 mL tetrahydrofuran are reacted with a solution of 6.5 g of calcium chloride in 65 mL ethanol and 4.5 g of sodium borohydride analogously to the method used for Example 1c. After a reaction time of 12 hours, 3 g of calcium chloride, dissolved in 30 mL ethanol, and 2 g of sodium borohydride are added and stirring is continued for a further 12 hours. Then the mixture is worked up as described, except that extraction is carried out using chloroform rather than ethyl acetate. During the evaporation of this organic phase a solid is precipitated out. The solid is suction filtered, stirred with ethyl acetate and recrystallised from acetonitrile. Yield: 79.5 g (77%); m.p.=108-111° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].N12CCCN=[C:34]1[CH2:33][CH2:32][CH2:31]CC2.BrCC1CC1.O>C(O)C>[CH:33]1([CH2:34][O:1][C:2]2[CH:3]=[C:4]([C:10]3[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:27])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[O:24][CH2:25][CH3:26])[N:14]=3)[CH:5]=[CH:6][C:7]=2[O:8][CH3:9])[CH2:31][CH2:32]1
Reactant: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC)c(O)c2)n1
Reactant: C1CCC2=NCCCN2CC1
Agent: BrCC1CC1
Solvent: CCO
Solvent: O
Product: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC)c(OCC3CC3)c2)n1

Procedure:
A 0.2 g quantity of the N-[2-(3-hydroxy-4-methoxy phenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide obtained in Example 2 and 0.3 ml of 1,8-diazabicyclo[5,4,0]undec-7-ene were dissolved in 4 ml of ethanol, and 0.14 g of (bromomethyl)cyclopropane was added thereto. The mixture was heated and refluxed overnight. The reaction mixture was allowed to cool, water was then added thereto, and extraction was performed with ethyl acetate. After washing with water twice, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to give 0.18 g of white powdery N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:10][C:11]([CH3:22])([CH3:21])[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].BrC1C(NCCNC(=O)OC(C)(C)C)=NC(Cl)=NC=1>>[Br:1][C:2]1[C:3]([NH:10][C:11]([CH3:22])([CH3:21])[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CC(C)(N)CNC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)NCCNc1nc(Cl)ncc1Br
Product: CC(C)(CNC(=O)OC(C)(C)C)Nc1nc(Cl)ncc1Br

Procedure:
tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-2-methyl-propyl]carbamate is synthesized by treating 5-Bromo-2,4-dichloropyrimidine with tert-butyl N-(2-amino-2-methyl-propyl)carbamate using similar experimental conditions as described for the synthesis of tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]ethyl]carbamate. LCMS (ESI) (M+H) 379
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:18]([O:20][CH3:21])=[O:19])=[N:11][NH:12][C:13]=1[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N+:29]([O-:31])=[O:30].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[N:12][N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N+:29]([O-:31])=[O:30])[C:10]=1[C:18]([O:20][CH3:21])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: COC(=O)c1n[nH]c(C(=O)OC)c1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1nn(-c2ccccc2[N+](=O)[O-])c(C(=O)OC)c1OCc1ccccc1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
A solution of dimethyl 4-benzyloxy-1H-pyrazole-3,5-dicarboxylate (2.5 g, 8.63 mmol) and 2-fluoronitrobenzene (1.45 g, 10.3 mmol) in anhydrous DMF (15 mL) was treated with Cs2CO3 (3.6 g, 11 mmol) and stirred at 50° C. for 6 hours. The solvent was removed in vacuo, the residue was suspended EtOAc, and the insoluble salts were removed by filtration. The filtrate solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel using a gradient elution of 1:4 to 1:2 to 1:1 EtOAc:hexanes. Collection and concentration of the appropriate fractions yielded the product as an oil. 1H NMR (400 MHz, CDCl3) δ 8.21 (d, J=8.0 Hz, 1H), 7.75 (t, J=7.6 Hz, 1H), 7.68 (t, J=7.9 Hz, 1H), 7.48-7.53 (m, 3H), 7.36-7.42 (m, 3H), 5.24 (s, 2H), 3.96 (s, 3H), 3.69 (s, 3H); ES MS (M+1)=412.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13](N(OC)C)=[O:14])=[CH:11][N:10]=[C:9]2[S:19][CH2:20][C:21]2[C:26]([F:27])=[CH:25][CH:24]=[C:23]([F:28])[C:22]=2[F:29])=[CH:4][CH:3]=1.FC1C=CC(N2[C:41]([C:42](O)=[O:43])=CN=C2SC(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.FC1C(F)=CC=C(F)C=1CBr.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([O:43][CH2:42][CH3:41])=[O:14])=[CH:11][N:10]=[C:9]2[S:19][CH2:20][C:21]2[C:26]([F:27])=[CH:25][CH:24]=[C:23]([F:28])[C:22]=2[F:29])=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)c1cnc(SCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Reactant: O=C(O)c1cnc(SC(c2ccccc2)(c2ccccc2)c2ccccc2)n1-c1ccc(F)cc1
Agent: Fc1ccc(F)c(CBr)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cnc(SCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1

Procedure:
Ethyl 1-(4-fluorophenyl)-2-((2,3,6-trifluorobenzyl)thio)-1H-imidazole-5-carboxylate (10) was prepared in a similar manner as that described for the synthesis of compound 9 using ethyl 1-(4-fluorophenyl)-2-mercapto-1H-imidazole-5-carboxylate (6) (202 mg, 0.76 mmol), 2,3,6-trifluorobenzyl bromide (0.1 mL, 0.76 mmol), and potassium carbonate (125.9 mg, 0.91 mmol) in acetone (3 mL).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]([CH3:47])[CH2:13][CH2:14][CH2:15][NH:16][C:17]1[C:29]2[C:28]3[C:23](=[CH:24][C:25]([C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:27]=3)[NH:22][C:21]=2[N:20]=[C:19]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH:41]([OH:46])[C:42]([F:45])([F:44])[F:43])[CH:36]=2)[N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]([CH3:47])[CH2:13][CH2:14][CH2:15][NH:16][C:17]1[C:29]2[C:28]3[C:23](=[CH:24][C:25]([C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:27]=3)[NH:22][C:21]=2[N:20]=[C:19]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41](=[O:46])[C:42]([F:44])([F:45])[F:43])[CH:36]=2)[N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3cccc(C(O)C(F)(F)F)c3)nc(NCCCN(C)CCCNC(=O)OC(C)(C)C)c12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3cccc(C(=O)C(F)(F)F)c3)nc(NCCCN(C)CCCNC(=O)OC(C)(C)C)c12
Temperature: 20 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
A mixture of methyl 4-((3-((3-((tert-butoxycarbonyl)amino)propyl)(methyl)amino)propyl)amino)-2-(3-(2,2,2-trifluoro-1-hydroxyethyl)benzyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (0.200 g, 0.304 mmol) and Dess-Martin periodinane reagent (0.567 g, 1.336 mmol) in DCM (7.50 mL) were stirred at 20° C. for one hour. After evaporation to dryness, the residue was purified by flash chromatography to afford methyl 4-((3-((3-((tert-butoxycarbonyl)amino)propyl)(methyl)amino)propyl)amino)-2-(3-(2,2,2-trifluoroacetyl)benzyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (181 mg, 91% yield) as a yellow foam: 1H NMR in DMSO-d6 is consistent with the desired product but complicated due to presence of hydrate form: MS m/z 657.3 (M+H)+; HPLC 96.0% @ 220 nm and 95.3% @ 254 nm, RT 1.87 and 1.96 (ketone+hydrate) minutes.