Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:62])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6C(=O)C(NC(OC)=O)(C6C=CC=CC=6)C)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:63]([O:67]C(N1CCCC1C(O)=O)=O)(C)(C)[CH3:64].[CH3:78][O:79][C:80]([NH:82][CH:83]([C:87]1[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=1)[C:84]([OH:86])=O)=[O:81].COC(NC(C1C=CC=CC=1)(C)C(O)=O)=O>>[CH3:1][O:2][C:3](=[O:62])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:32]=[CH:33][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH:45]([O:67][CH2:63][CH3:64])[CH2:44][N:43]6[C:84](=[O:86])[CH:83]([NH:82][C:80]([O:79][CH3:78])=[O:81])[C:87]6[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=6)=[N:40][CH:41]=5)=[CH:35][CH:36]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:7])[CH3:8]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(C)(NC(=O)OC)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Agent: COC(=O)NC(C)(C(=O)O)c1ccccc1
Product: CCOC1CC(c2ncc(-c3ccc(-c4ccc5cc(-c6cnc(C7CCCN7C(=O)C(NC(=O)OC)C(C)C)[nH]6)ccc5c4)cc3)[nH]2)N(C(=O)C(NC(=O)OC)c2ccccc2)C1

Procedure:
[1-(2-{5-[6-(4-{2-[4-Ethoxy-1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester was prepared following the procedure for [1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-propionyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester, substituting 4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester for Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester and Methoxycarbonylamino-phenyl-acetic acid for 2-Methoxycarbonylamino-2-phenyl-propionic acid. LCMS-ESI+: calc'd for C49H54N8O7: 866.41 (M+); Found: 867.35 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:13]=[C:12]([C@H:14]([NH:19][CH2:20][C@H:21]2[C@@H:25]([F:26])[CH2:24][N:23]([C:27]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:28])[CH2:22]2)[C:15]([CH3:18])([CH3:17])[CH3:16])[N:11]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40](F)[CH:39]=2)[N:10]=1.C(N(CC)CC)C.C(Cl)(Cl)=[O:53].C1(C)C=CC=CC=1.C(N1C([C@H:75]([N:80]([CH2:84][C@H:85]2[C@@H:89](F)CN(C(OCC3C=CC=CC=3)=O)C2)[C:81](Cl)=[O:82])[C:76](C)(C)[CH3:77])=NC(C2C=C(F)C=CC=2F)=N1)C1C=CC=CC=1.CC1OC(C)CNC1>ClCCl>[CH2:37]([N:11]1[C:12]([C@H:14]([N:19]([CH2:20][C@H:21]2[C@@H:25]([F:26])[CH2:24][N:23]([C:27]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:28])[CH2:22]2)[C:81]([N:80]2[CH2:84][C@@H:85]([CH3:89])[O:53][C@@H:76]([CH3:77])[CH2:75]2)=[O:82])[C:15]([CH3:18])([CH3:16])[CH3:17])=[N:13][C:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])=[N:10]1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CC(C)(C)[C@H](c1nc(-c2cc(F)ccc2F)nn1Cc1ccccc1)N(C[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F)C(=O)Cl
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)[C@@H](NC[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F)c1nc(-c2cc(F)ccc2F)nn1Cc1cccc(F)c1
Agent: CC1CNCC(C)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(C(=O)N(C[C@@H]2CN(C(=O)OCc3ccccc3)C[C@@H]2F)[C@@H](c2nc(-c3cc(F)ccc3F)nn2Cc2ccccc2)C(C)(C)C)C[C@H](C)O1
Temperature: 40 °C
Yield: 66.7 %

Procedure:
To a solution of (3R,4R)-benzyl 3-(((R)-1-(3-(2,5-difluorophenyl)-1-(3-fluorobenzyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropylamino)methyl)-4-fluoropyrrolidine-1-carboxylate (110 mg, 0.186 mmol) in dichloromethane (1.9 mL, 0.1 M solution) was added triethylamine (78 μL, 0.558 mmol) followed by addition of 20% phosgene in toluene (66 mg, 0.223 mmol) at room temperature. After the resulting solution was stirred at room temperature for 15 min (LC/MS (uplc): MH+654.3, 1.37 min for (3S,4R)-benzyl 3-((((R)-1-(1-benzyl-3-(2,5-difluorophenyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl)(chlorocarbonyl)amino)methyl)-4-fluoropyrrolidine-1-carboxylate), 2,6-dimethylmorpholine (64 mg, 0.558 mmol) was added and heat at 40° C. for overnight (in a seal tube). The reaction mixture was quenched with H2O and extracted with EtOAc. The organic layer was washed with NaHCO3 solution and brine, dried over anhydrous sodium sulfate, filtered and concentrated. After the volatile organic materials were removed in vacuo, the crude product was purified on preparative reverse phase HPLC. The combined fractions of the product were neutralized with saturated NaHCO3 solution, which was then extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield the desired (3R,4R)-benzyl 3-(((2S,6R)—N—((R)-1-(1-benzyl-3-(2,5-difluorophenyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl)-2,6-dimethylmorpholine-4-carboxamido)methyl)-4-fluoropyrrolidine-1-carboxylate (91 mg, 66.7%, over 2 steps). LC/MS (uplc): MH+733.5, 1.41 min.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6](=O)[C:7](=[CH:18]N(C)C)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.[CH2:25]([NH:32][NH2:33])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C>[ClH:1].[CH2:25]([N:32]1[C:6]2[C:5]3[CH:23]=[CH:24][C:2]([Cl:1])=[CH:3][C:4]=3[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])=[N:9][CH2:8][C:7]=2[CH:18]=[N:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NNCc1ccccc1
Reactant: CN(C)C=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2C1=O
Solvent: CCO
Product: Cl
Product: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCc1cnn(Cc3ccccc3)c1-2
Reaction time: 0.33 h

Procedure:
The mixture of 0.72 g of 8-chloro-1-(2-chlorophenyl)-4-dimethylaminomethylidene-3,4-dihydro-2-benzazepin-5-one, 0.64 g of benzylhydrazine and 35 ml of ethanol is refluxed for 45 minutes and evaporated under reduced pressure. The residue is taken up in 20 ml methylene chloride, the solution washed with aqueous sodium bicarbonate and stirred with 6 ml of N hydrochloric acid for 20 minutes. The aqueous solution is made basic with sodium carbonate, the mixture stirred, the organic layer separated, dried and evaporated. The residue is taken up in the minimum amount of ethanol, the solution acidified with ethereal hydrogen chloride and the precipitate formed filtered off, to yield the 1-benzyl-8-chloro-6-(2-chlorophenyl)-1H,4H-pyrazolo[4,3-d](2)benzazepine hydrochloride melting at 218°-221°.
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([O-:11])(O)=[O:9].[CH3:12][S:13]([NH:16][C:17]1[N:21]([C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[C:24]([F:33])[C:23]=2[Cl:34])[N:20]=[CH:19][CH:18]=1)(=[O:15])=[O:14].O>C(O)(=O)C>[CH3:12][S:13]([NH:16][C:17]1[N:21]([C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:30])[F:31])=[C:24]([F:33])[C:23]=2[Cl:34])[N:20]=[CH:19][C:18]=1[N+:8]([O-:11])=[O:9])(=[O:14])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: CS(=O)(=O)Nc1ccnn1-c1c(Cl)cc(C(F)(F)F)c(F)c1Cl
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1c([N+](=O)[O-])cnn1-c1c(Cl)cc(C(F)(F)F)c(F)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
1.07 ml (0.011 mol) of acetic anhydride and 0.45 ml (0.0106 mol) of 98 percent strength nitric acid are added successively to a solution of 3.8 g (0.01 mol) of 5-methanesulphonamido-1-(2,6-dichloro-3-fluoro-4-trifluoromethylphenyl)-pyrazole in 20 ml of glacial acetic acid at approximately 15° C. The mixture is stirred at room temperature for approximately 16 hours, and the reaction solution is then poured into 100 ml of water. The precipiate thus formed is filtered off with suction, washed until neutral and dried in vacuo. 3.5 g (80% of theory) of 5-methanesulphonamido-4-nitro-1-(2,6-dichloro-3-fluoro-4-trifluoromethylphenyl)-pyrazole of melting point 107°-115° C. are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25]([CH2:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:27])=[O:26]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:32]4[CH:31]=[CH:30][C:29]([CH2:28][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:34][CH:33]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(CS(C)(=O)=O)cc4)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and [4-[(methylsulfonyl)methyl]phenyl]boronic acid following a procedure analogous to that described in Example 28. LC (method 10): tR=1.60 min; Mass spectrum (ESI+): m/z=473 [M+H]+.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[OH:28][C:29]([CH3:34])([CH3:33])[C:30](O)=[O:31]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:30](=[O:31])[C:29]([OH:28])([CH3:34])[CH3:33])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: CC(C)(O)C(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: CC(C)(O)C(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (101 mg, 97%), MS (ISP) m/z=517.4 [(M+H)+], mp 201° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 2-hydroxy-2-methyl-propionic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]([C:15]([O:17]C)=[O:16])=[C:13]([CH2:19]Br)[NH:12][C:11]3[CH2:21][O:22][CH2:23][C:24](=[O:25])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:10]3[C:24](=[O:25])[CH2:23][O:22][CH2:21][C:11]=3[NH:12][C:13]3[CH2:19][O:16][C:15](=[O:17])[C:14]2=3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)C1=C(CBr)NC2=C(C(=O)COC2)C1c1ccc(F)c(Br)c1
Solvent: ClCCl
Product: O=C1COCC2=C1C(c1ccc(F)c(Br)c1)C1=C(COC1=O)N2
Temperature: 25 °C
Yield: 30.9 %

Procedure:
The product from Example 25B (0.30 g, 0.63 mmol) was heated neat under a nitrogen atmosphere to 130° C. for 15 minutes and cooled to ambient temperature. The residue was treated with methylene chloride and the resulting solid was collected by filtration, washed with methylene chloride and dried to provide the title compound (0.074 g) as a white solid.
Reaction SMILES: Br[C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:12][O:13][C:14](=[O:31])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=1>>[CH3:12][O:13][C:14](=[O:31])[CH2:15][C:16]1[CH:21]=[C:20]([C:2]2[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: COc1cccc(C=O)c1Br
Product: COC(=O)Cc1cccc(-c2c(C=O)cccc2OC)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: 2-bromo-3-methoxy-benzaldehyde and [3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid methyl ester.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[Cl:11][C:12]1[C:13]2[N:14]([CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[N:20]=2)[CH:15]=[CH:16][CH:17]=1.[OH-].[NH4+]>O>[Cl:11][C:12]1[C:13]2[N:14]([C:18]([CH:3]=[O:4])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[N:20]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: Fc1ccc(-c2cn3cccc(Cl)c3n2)cc1
Reactant: CN(C)C=O
Agent: [NH4+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1c(-c2ccc(F)cc2)nc2c(Cl)cccn12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
N,N-Dimethylformamide (10 mL) was cooled to 0° C. and treated with phosphorous oxychloride (1.0 mL, 11 mmol). After the addition was complete, the mixture was warmed to room temperature and stirred for 10 minutes. To this was added 8-chloro-2-(4-fluorophenyl)imidazo[1,2-α]pyridine (1.15 g, 4.7 mmol) and the resulting solution was stirred overnight. Water was added to the reaction. The mixture was neutralized to pH 7 with ammonium hydroxide. The aqueous phase was extracted with dichloromethane (3×50 mL). The combined organics were washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was recrystallized from acetonitrile to give 8-chloro-2-(4-fluorophenyl)imidazo[1,2-α]pyridine-3-carbaldehyde (1.1 g, 85%) as a white solid. 1H NMR (CDCl3): δ 10.05 (s, 1H), 9.60 (d, 1H), 7.86 (q, 2H), 7.65 (d, 1H), 7.23 (t, 2H), 7.08 (t, 1H); 19F NMR (CDCl3) δ −110.8; MS m/z 275 (M+1).
Reaction SMILES: [CH2:1]([NH:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[NH:9][C:8]([CH3:15])([CH3:14])[CH2:7]1)[CH2:2][CH2:3][CH3:4].[C:16]1(O)[C:20](=[O:21])[C:18](=O)[C:17]=1[OH:22]>C(C(CCCC)CO)C>[CH2:1]([N:5]([C+:16]1[C:17]([O-:22])=[C:18]([N:5]([CH:6]2[CH2:7][C:8]([CH3:15])([CH3:14])[NH:9][C:10]([CH3:12])([CH3:13])[CH2:11]2)[CH2:1][CH2:2][CH2:3][CH3:4])[C+:20]1[O-:21])[CH:6]1[CH2:7][C:8]([CH3:14])([CH3:15])[NH:9][C:10]([CH3:13])([CH3:12])[CH2:11]1)[CH2:2][CH2:3][CH3:4]
Reactant: O=c1c(O)c(O)c1=O
Reactant: CCCCNC1CC(C)(C)NC(C)(C)C1
Solvent: CCCCC(CC)CO
Product: CCCCN(c1c([O-])[c+](N(CCCC)C2CC(C)(C)NC(C)(C)C2)[c+]1[O-])C1CC(C)(C)NC(C)(C)C1
Yield: 88.2 %

Procedure:
Under agitation, 392.9 g (1.85 moles) of 4-n-butylamino-2,2,6,6-tetramethylpiperidine, 10.0 g (0.0877 mole) of quadratic acid, and 150 cc of 2-ethylhexanol were heated to boiling under reflux in a 1-liter agitated flask with water trap; s temperature rose from 205° to 217° C., and 2.8 cc of water was removed from the cycle. The reaction solution was then distilled. The residue was boiled with petroleum ether. After cooling, vacuum-filtering, and drying, 38.9 g was obtained (88.2% yield), mp 151°-152° C. Extinction (g/l.cm) at 278 nm: 25; at 335 nm: 83.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.[C:11](=O)([O-])[O-].[K+].[K+].IC.Cl>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]([O:9][CH3:11])=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(O)c(F)cc1Br
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc(C)c(Br)cc1F
Temperature: 25 °C
Yield: 93.4 %

Procedure:
To a mixture of 4-bromo-2-fluoro-5-methylphenol (29.6 g, 144.2 mmol) and potassium carbonate (30.0 g, 218 mmol) in acetone (500 mL) was added iodomethane (69.0 g, 486 mmol). The resulting suspension was stirred at reflux for 4 hours. The reaction mixture was cooled to RT, poured into HCl (250 mL of 1 N solution) and extracted with ethyl acetate (3×250 mL). The combined organic layers were washed with sodium bicarbonate solution, dried over sodium sulfate and filtered. Evaporation of the solvent and purification on a silica column (5% ethyl acetate—hexanes) yielded 29.50 g (93%) of the title compound as a clear, colorless oil: 1H NMR (CDCl3): δ 2.33 (3H, s), 3.85 (3H, s), 6.82 (1H, d, J=8.79 Hz), 7.23 (1H, d, J=10.25 Hz); MS m/z,
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:22][C:23]2[N:28]=[CH:27][C:26]3[O:29][CH2:30][CH2:31][O:32][C:25]=3[CH:24]=2)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[C].[Pd]>[OH2:16].[O:32]1[C:25]2[CH:24]=[C:23]([CH2:22][N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[N:28]=[CH:27][C:26]=2[O:29][CH2:30][CH2:31]1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCNCC1
Product: O
Temperature: 60 °C
Reaction time: 7 h
Yield: 121.7 %

Procedure:
To a solution of 5.9 g of tert-butyl (1-benzylpiperidin-4-yl)(2,3-dihydro-(1,4)dioxino(2,3-c)pyridin-7-yl methyl)carbamate in 30 mL of methanol, 1.2 g of 5% palladium carbon was added, and the mixture was stirred for 7 hours at 60° C. under a hydrogen atmosphere. The mixture was subjected to celite filtration, and 40 mL of ethyl acetate and 30 mL of a 0.5 mol/L sodium hydroxide aqueous solution were added to the filtrate. The organic layer was washed with saturated sodium chloride solution, dried using sodium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was recrystallized from 5 mL of ethyl acetate-15 mL of heptane to give 3.0 g of tert-butyl ((2,3-dihydro-(1,4)dioxino(2,3-c)pyridin-7-yl)methyl)(piperidin-4-yl)carbamate monohydrate as a white powder.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:10][C@H:11]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]2)=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[Br:1][C:2]1[C:3]([NH:10][C@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([S:27]([CH3:26])(=[O:29])=[O:28])[CH2:12]2)=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CSc1ncc(Br)c(N[C@H]2CCCNC2)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc(Br)c(N[C@H]2CCCN(S(C)(=O)=O)C2)n1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of (5-bromo-2-methylsulfanyl-pyrimidin-4-yl)-(S)-piperidin-3-yl-amine (2.9 g, 9.6 mmol) and diisopropylethylamine (3.7 g, 28 mmol) in dichloromethane (50 ml) was cooled to 5° C. and treated with a solution of methanesulfonyl chloride (1.21 g, 10.5 mmol) in dichloromethane (20 ml). This was stirred at room temperature for 14 hours, washed with water, dried (MgSO4) and evaporated to give (5-bromo-2-methylsulfanyl-pyrimidin-4-yl)-((S)-1-methanesulfonyl-piperidin-3-yl)-amine as a white solid. MS (ES+): 382 (2602-33).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:49])[C@@H:9]([CH3:48])[C:10]([NH:12][C@@H:13]([CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)[C:14]([N:16]1[CH2:20][C@@H:19]([NH:21][C:22]([O:24][CH2:25][CH:26]2[C:38]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:32]3[C:27]2=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:23])[CH2:18][C@H:17]1[C:39]([OH:41])=O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:83]([NH2:90])[C:84]1[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=1>CN(C=O)C>[CH:28]1[C:27]2[CH:26]([CH2:25][O:24][C:22](=[O:23])[NH:21][C@H:19]3[CH2:18][C@@H:17]([C:39](=[O:41])[NH:90][CH2:83][C:84]4[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=4)[N:16]([C:14](=[O:15])[C@@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:49])[CH3:48])[CH:42]4[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]4)[CH2:20]3)[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]=2[CH:31]=[CH:30][CH:29]=1
Reactant: NCc1ccccc1
Reactant: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)O)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)NCc1ccccc1)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To (2S,4S)-1-{(S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-2-cyclohexyl-acetyl}-4-(9H-fluoren-9-ylmethoxycarbonylamino)-pyrrolidine-2-carboxylic acid (Intermediate 27) in DMF at 0° C. was added DIPEA (116 μL, 0.66 mmol) and HATU (93 mg, 0.24 mmol). The mixture was stirred at 0° C. for 15 minutes and then benzylamine (26.1 mg, 0.24 mmol) in DMF (0.5 mL) was added dropwise, the cooling bath removed and the reaction stirred for 2 h. The mixture was diluted with water and extracted with EtOAc. The combined extracts were washed with saturated ammonium chloride solution, saturated sodium bicarbonate solution, water, and brine and dried over anhydrous magnesium sulfate. Concentration gave ((3S,5S)-5-benzylcarbamoyl-1-{(S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-2-cyclohexyl-acetyl}-pyrrolidin-3-yl)-carbamic acid 9H-fluoren-9-ylmethyl ester as a foam which was used without purification.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH2:10][CH2:9][C:8]3=[C:11]([C:16]([O:18]CC)=[O:17])[S:12][C:13]([S:14][CH3:15])=[C:7]3[C:5]=2[N:6]=1.C(O)C.O1CCCC1.[OH-].[Na+]>O>[CH3:1][C:2]1[S:3][C:4]2[CH2:10][CH2:9][C:8]3=[C:11]([C:16]([OH:18])=[O:17])[S:12][C:13]([S:14][CH3:15])=[C:7]3[C:5]=2[N:6]=1
Reactant: CCOC(=O)c1sc(SC)c2c1CCc1sc(C)nc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CSc1sc(C(=O)O)c2c1-c1nc(C)sc1CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.4 %

Procedure:
Ethyl 4,5-dihydro-2-methyl-8-methylthiothieno[3,4-e]benzothiazole-6-carboxylate (0.76 g) was suspended in a mixed solvent of ethanol (10 ml) and tetrahydrofuran (25 ml); a 2 N aqueous solution of sodium hydroxide (2.3 ml) was added at room temperature. After the reaction mixture was stirred at room temperature for 1 hour, the solution obtained was diluted with water (30 ml) and washed with diethyl ether. The water layer was acidified with 1 N hydrochloric acid (5 ml) and extracted with a mixed solvent of ethyl acetate and tetrahydrofuran. The ethyl acetate-tetrahydrofuran layer was washed with water and dried (MgSO4), after which the solvent was distilled off to yield 4,5-dihydro-2-methyl-8-methylthiothieno[3,4-e]benzothiazole-6-carboxylic acid (0.35 g, 50%), which was then recrystallized from ethyl acetate-hexane. Brown prisms. Melting point 273-274° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:11])[CH:3]=1.[C:12]1(C)C=CC=C[CH:13]=1.C(=O)([O-])[O-].[K+].[K+].S(OCC)(O[CH2:29][CH3:30])(=O)=O>COC(C)(C)C>[CH2:12]([O:11][C:4]1[CH:3]=[C:2]([F:1])[CH:10]=[CH:9][C:5]=1[C:6]([O:8][CH2:29][CH3:30])=[O:7])[CH3:13]
Reactant: Cc1ccccc1
Reactant: O=C(O)c1ccc(F)cc1O
Reactant: CCOS(=O)(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Product: CCOC(=O)c1ccc(F)cc1OCC
Temperature: 25 °C

Procedure:
To a liquid mixture of 4-fluoro-2-hydroxybenzoic acid 5.00 g, toluene 32 mL and potassium carbonate 13.29 g, diethyl sulfate 12.6 mL was dropped, followed by an hour's stirring at room temperature and further addition of 25 mL of toluene. After 16 hours' heating under reflux, the reaction liquid was allowed to cool off, to which tert-butyl methyl ether was added and the whole liquid was poured in ice water. The organic layer was extracted, washed with saturated brine and dried over magnesium sulfate. Distilling the solvent off, 6.52 g of the title compound was obtained.
Reaction SMILES: [F:1][CH:2]([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:12]3[CH2:20][CH2:19][NH:18][CH2:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:6][CH:5]=1.Cl[C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=1.C(N(CC)C(C)C)(C)C>>[Cl:29][C:28]1[C:23]([N:18]2[CH2:19][CH2:20][C:12]3[C:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([O:3][CH:2]([F:1])[F:21])=[CH:5][CH:6]=4)=[N:16][CH:15]=[N:14][C:13]=3[CH2:17]2)=[N:24][CH:25]=[CH:26][CH:27]=1
Reactant: FC(F)Oc1ccc(Nc2ncnc3c2CCNC3)cc1
Reactant: Clc1cccnc1Cl
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)Oc1ccc(Nc2ncnc3c2CCN(c2ncccc2Cl)C3)cc1
Temperature: 170 °C

Procedure:
The title compound was prepared according to the procedure given for Example 9 using N-(4-(difluoromethoxy)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (0.091 g, 0.31 mmol), 2,3-dichloropyridine (0.092 g, 0.62 mmol) and N,N-diisopropylethylamine (0.081 mL, 0.47 mmol) and heating the reaction mixture for 10 h at 170° C. to obtain 0.038 g of a light yellow solid.