Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:36][CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[ClH:22].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:42]3[CH2:43][CH2:44][N:39]([CH2:38][CH2:37][OH:36])[CH2:40][CH2:41]3)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: OCCN1CCNCC1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCO)CC1
Product: Cl

Procedure:
[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 11) and 1-(2-hydroxy-ethyl)-piperazine in an analogous manner as described in example 25. LR-MS: 623.4 [(M+H)+]
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]12[CH2:12][CH2:11][C:8]([C:13]([O:15][CH3:16])=[O:14])([CH2:9][CH2:10]1)[CH2:7][CH2:6]2)=O.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[F:28][C:29]([F:42])([F:41])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]1NN=[N:38][N:37]=1>C(Cl)Cl>[CH3:1][N:2]1[C:36]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[C:29]([F:28])([F:42])[F:41])=[N:37][N:38]=[C:3]1[C:5]12[CH2:12][CH2:11][C:8]([C:13]([O:15][CH3:16])=[O:14])([CH2:9][CH2:10]1)[CH2:7][CH2:6]2
Reactant: FC(F)(F)c1ccccc1-c1nnn[nH]1
Reactant: CNC(=O)C12CCC(C(=O)OC)(CC1)CC2
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)C12CCC(c3nnc(-c4ccccc4C(F)(F)F)n3C)(CC1)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Carboxylate 1-B (2.76 g, 12.3 mmol) was dissolved in methylene chloride (100 ml). Oxalyl chloride (2.0 M, 15.3 ml) was added to the resulting solution followed by DMF (0.19 ml, 2.45 mmol). The reaction mixture was then stirred at room temperature under a nitrogen atmosphere for 2 hours before it was concentrated and stripped from toluene 3 times. The residue was redissolved in toluene (100 ml), treated with 5-[2-(trifluoromethyl)phenyl]-1H-tetrazole (3.15 g, 14.7 mmol) and heated at 100° C. under nitrogen for 12 hours. The product, 1,2,4-triazole 1-C, which precipitated out of reaction mixture as the HCl salt, was dissolved in methylene chloride, washed twice with saturated aqueous sodium bicarbonate solution, dried (MgSO4) and stripped to yield 1-C as a white solid. MS (ESI+)=394.2 (M+1); 1H NMR (500 MHz, CDCl3): δ 2.00 (6H, m), 2.18 (6H, m), 3.48 (3H, s), 3.72 (3H, s), 7.51 (1H, m), 7.71 (2H, m), 7.85 (1H, m) ppm.
Reaction SMILES: [CH3:1][C:2](C)([O-:4])[CH3:3].[Na+].CC(O)C.F[C:12]1[N:20]=[C:19]2[C:15]([N:16]=[CH:17][N:18]2[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)=[C:14]([NH2:27])[N:13]=1>C(OCC)(=O)C>[CH3:1][CH:2]([O:4][C:12]1[N:20]=[C:19]2[C:15]([N:16]=[CH:17][N:18]2[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)=[C:14]([NH2:27])[N:13]=1)[CH3:3]
Reactant: CC(C)(C)[O-]
Reactant: Nc1nc(F)nc2c1ncn2C1CCCCO1
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CC(C)Oc1nc(N)c2ncn(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98.4 %

Procedure:
Sodium t-butoxide (1.30 g, 13.53 mmol) was added to 2-propanol (16.95 ml, 220 mmol) portionwise with stirring over 5 mins. 2-Fluoro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (2 g, 8.43 mmol) was added and the reaction mixture heated and stirred at 50° C. for 4 hours and then allowed to cool to room temperature. The reaction mixture was then diluted with ethyl acetate (75 ml), washed with water (3×25 ml) and the combined aqueous layers extracted again with ethyl acetate (2×25 ml). The combined organic layers were dried by passage through a hydrophobic frit, filtered and evaporated to give an off-white solid (2.30 g). This material was dissolved in dichloromethane and purified using an aminopropyl SPE cartridge (70 g) eluted with a 0-100% ethyl acetate in cyclohexane gradient. The appropriate fractions were combined and evaporated to give a white solid (1.6 g) which was further purified by column chromatography using a reverse phase (C18) Flashmaster II system loading in 1:1 MeOH/DMSO and eluting with 0-50% acetonitrile (+0.1% TFA) in water (+0.1% TFA) gradient over 40 mins. collecting fractions in vials containing ca. 2 mL of saturated aqueous sodium bicarbonate solution. The appropriate fractions were combined, and extracted with dichloromethane (3×100 mL). The combined organic extracts were dried by passage through a hydrophobic frit and evaporated to give the title compound as a white solid (888 mg).
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].Br[CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[C:14]([O:18][C:19]([NH:21][C@H:22]1[CH2:25][NH:24][C:23]1=[O:26])=[O:20])([CH3:17])([CH3:16])[CH3:15]>CN(C)C=O>[C:14]([O:18][C:19]([NH:21][C@H:22]1[CH2:25][N:24]([C:2]([NH:3][CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:1])[C:23]1=[O:26])=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: N#C[O-]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)OC(=O)N[C@H]1CNC1=O
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNC(=O)N1C[C@H](NC(=O)OC(C)(C)C)C1=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a suspension of potassium cyanate (933 mg, 11.5 mmol) in 10 ml of dimethylformamide was added t-butyl bromoacetate (1.8 ml, 11 mmol). The mixture was heated to 100° C. for 1 hour and cooled to room temperature. (S)-3-[[(t-Butyloxy)carbonyl]amino]-2-azetidinone (1.860 g, 10 mmol) was then added, and the mixture was heated to 65° C. After being stirred at 65° C. for 1 hour, the mixture was heated to 100° C. and stirred for an additional hour. Additional isocyanate was prepared (using 933 mg of potassium cyanate and 1.8 ml of t-butyl bromoacetate as described above) and added to the reaction mixture at room temperature. After being heated at 65° C. for 1 hour and 100° C. for 1 hour, the reaction mixture was stirred at room temperature overnight.
Reaction SMILES: CO[CH:3]([O:6][CH3:7])[O:4][CH3:5].[CH2:8]([O:15][C:16]([NH:18][CH:19]1[CH2:23][O:22][CH2:21]C1=O)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CC1C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:7][O:6][C:3]1([O:4][CH3:5])[CH:19]([NH:18][C:16]([O:15][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:17])[CH2:23][O:22][CH2:21]1
Reactant: COC(OC)OC
Reactant: O=C(NC1COCC1=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC1(OC)COCC1NC(=O)OCc1ccccc1
Reaction time: 3 h

Procedure:
Trimethylorthoformate (29 ml) was added dropwise to a refluxing solution of 4-benzyloxycarbonylamino-tetrahydrofuran-3-one (18 g, 78 mmol) and PTSA (500 mg) in MeOH (100 ml). After 3 hours, the reaction mixture was filtered and concentrated to afford, after column chromatography, the title compound as a yellow oil, 16.2 g, 76%.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[NH:4][C:3]1=[O:13].CC(C)([O-])C.[K+].[CH3:20][O:21][CH:22]([O:26][CH3:27])[CH2:23][CH2:24]Br>CO>[CH3:20][O:21][CH:22]([O:26][CH3:27])[CH2:23][CH2:24][N:4]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11](=[O:12])[N:2]([CH3:1])[C:3]1=[O:13]
Reactant: Cn1c(=O)[nH]c2c(c1=O)CCCC2
Reactant: COC(CCBr)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Product: COC(CCn1c2c(c(=O)n(C)c1=O)CCCC2)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
After suspending 3-methyl-5,6,7,8-tetrahydro-1H-quinazoline-2,4-dione (CAS 85458-77-1) (500 mg) in methanol (10 ml), potassium tert-butoxide (342 mg) was added and the mixture was stirred at room temperature for 30 minutes. After then adding 3-bromopropionaldehyde dimethylacetal (0.57 ml), the mixture was heated to reflux for 5 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and extraction was performed with ethyl acetate. The organic layer was washed with water and brine in that order and then dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (235 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([C@@:20]([O:37][SiH:38]([CH3:40])[CH3:39])([C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:21][CH2:22][C:23]4[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=4[C:25]([CH:27]=[O:28])=[O:26])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.[OH-:41].[K+]>CCO.O.[N+]([O-])([O-])=O.[Ag+]>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([C@@:20]([O:37][SiH:38]([CH3:40])[CH3:39])([C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:21][CH2:22][C:23]4[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=4[C:25]([C:27]([OH:41])=[O:28])=[O:26])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: C[SiH](C)O[C@](CCc1ccccc1C(=O)C=O)(c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1)C(C)(C)C
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: C[SiH](C)O[C@](CCc1ccccc1C(=O)C(=O)O)(c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.7 %

Procedure:
To a solution of the aldehyde from Step 2 (14 g, 24.6 mmol) in EtOH (118 mL) was added a solution of AgNO3 (10 g, 59 mmol) predissolved in H2O (23 mL) followed by a solution of KOH (118 mL, 118 mmol of 1M) dropwise. The mixture was stirred at room temperature overnight. The bulk of the EtOH was removed by evaporation, the aqueous was acidified with 1N HCl (118 mL) and extracted with EtOAc twice (100 mL). The organic extracts were dried over Na2SO4 and evaporated. The residue was purified by flash chromatography first with pure EtOAc then using 95:5 EtOAc: AcOH, to yield 5.0 g of the title compound. 1H NMR (CD3COCD3) d 0.15 (s, 6H), 0.95 (s, 9H), 2.0 (m, 2H), 2.95-3.18 (m, 2H), 4.95 (t, 1H), 7.35-7.65 (m, 8H), 7.75-7.97 (m, 5H), 8.0 (s, 1H), 8.32 (d, 1H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[N+:5]([C:8]1[CH:9]=[CH:10][C:11]2[O:16][CH2:15][CH2:14][NH:13][C:12]=2[CH:17]=1)([O-:7])=[O:6].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([N:13]1[C:12]2[CH:17]=[C:8]([N+:5]([O-:7])=[O:6])[CH:9]=[CH:10][C:11]=2[O:16][CH2:15][CH2:14]1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCO2
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)N1CCOc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Yield: 90 %

Procedure:
Under vigorous stirring at room temperature, acetyl chloride (1.02 g, 13 mmol) was added dropwise to a mixture of 6-nitro-3,4-dihydro-2H-benzo[1,4]oxazine (1.8 g, 10 mmol) and NaHCO3 (7.14 g, 85 mmol) in CH2Cl2 (50 mL). After addition, the reaction was stirred for 1 h at this temperature. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was treated with Et2O:hexane (1:2, 50 mL) under stirring for 30 min and then filtered to give 4-acetyl-6-nitro-3,4-dihydro-2H-benzo[1,4]oxazine as a pale yellow solid (2 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:35])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH3:33])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:34])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:35])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH3:33])[C:17]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:31][CH:32]=3)=[O:18])[C:10](=[O:34])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(C)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(C)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1C

Procedure:
105 mg (purity 91%, 0.19 mmol) of tert-butyl 4-({2-[4-(5-chloro-2-methylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate (racemate) were hydrolysed with TFA according to General Method 2. Yield: 47 mg (60% of theory)
Reaction SMILES: Cl.[CH2:2]([N:6]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C@H:7]([C:13]([OH:15])=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH:3]([CH3:5])[CH3:4].[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[S:33]([NH:36][C@H:37]([C:45]([OH:47])=[O:46])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)(=[O:35])=[O:34]>>[CH3:4][CH:3]([CH2:2][N:6]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C@H:7]([C:13]([OH:15])=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:45]([C@@H:37]([NH:36][S:33]([C:29]1[S:28][CH:32]=[CH:31][CH:30]=1)(=[O:35])=[O:34])[CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:46])[CH3:5].[CH3:5][CH:3]([CH2:2][N:6]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C@H:7]([C:13]([OH:15])=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:45]([C@@H:37]([NH:36][S:33]([C:29]1[S:28][CH:32]=[CH:31][CH:30]=1)(=[O:34])=[O:35])[CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:47])[CH3:4]
Reactant: O=C(O)[C@H](Cc1ccccc1)NS(=O)(=O)c1cccs1
Reactant: CC(C)CN([C@@H](CCCCN)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CC(C)CN([C@@H](CCCCNC(=O)[C@H](Cc1ccccc1)NS(=O)(=O)c1cccs1)C(=O)O)S(=O)(=O)c1ccc(N)cc1
Product: CC(C)CN([C@@H](CCCCNC(=O)[C@H](Cc1ccccc1)NS(=O)(=O)c1cccs1)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 156.9 %

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-L-lysine hydrochloride (400 mg, 1.03 mmol, example 5, step C) as described in general procedure Bc using Nα-(2-thiophenesulfonyl)-L-phenylalanine (311 mg, 1.2 mmol) which was prepared in step A of example 24. The final product was purified by preparative HPLC to yield 550 mg (80%) of Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-Nε-[N′α-(2-thiophenesulfonyl)-L-phenylalanyl]-L-lysine. The latter derivative was hydrogenolysed following the indications of general procedure E. Purification by HPLC gave the desired material (400 mg, 65%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:11][CH3:12])=[CH:5][C:6]=1[C:7]([O:9]C)=O.Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[NH2:32][CH2:33][CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39]>C(Cl)Cl>[CH2:11]([C:4]1[S:3][C:2]2[NH:1][C:14](=[O:16])[N:32]([CH2:33][CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:39])([CH3:41])[CH3:40])[C:7](=[O:9])[C:6]=2[CH:5]=1)[CH3:12]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCc1cc(C(=O)OC)c(N)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc2c(=O)n(CCNC(=O)OC(C)(C)C)c(=O)[nH]c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 191.3 %

Procedure:
To a solution (40 mL) of methyl 2-amino-5-ethylthiophene-3-carboxylate (0.5 g) in methylene chloride were added triphosgene (0.32 g) and triethylamine (0.59 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added tert-butyl (2-aminoethyl)carbamate (1 g), and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (20 mL), sodium methoxide (0.73 g) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was neutralized with hydrochloric acid (10% methanol solution), insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (0.7 g, 77%).
Reaction SMILES: [F:1][C:2]1([F:32])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[N:25][C:26]([O:29]C)=[CH:27][CH:28]=5)[C:20]([CH3:31])=[CH:19][CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.C(N(CC)CC)C>O1CCOCC1.Cl>[F:32][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH3:31])=[C:21]([C:23]5[CH:28]=[CH:27][C:26](=[O:29])[NH:25][CH:24]=5)[N:22]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: COc1ccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc(=O)[nH]c1
Temperature: 90 °C
Yield: 40.4 %

Procedure:
1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-3-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (482 mg, 1.10 mmol) was dissolved in a mixture of 6 mL of 1,4-dioxane and 3 mL of 4M aqueous hydrochloric acid. This solution was heated at 90° C. for 1.5 hours. The crude reaction mixture was quenched with one equivalent of triethylamine and then evaporated to dryness. The crude product was then partitioned between dichloromethane and water. The organic layer was separated, dried over sodium sulfate, and then purified on 12 g of silica gel utilizing a gradient of 0-10% methanol in dichloromethane to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide as a white solid (189 mg, 40%). ESI-MS m/z calc. 425.1. found 426.3 (M+1)+. Retention time 1.53 minutes. 1H NMR (400 MHz, DMSO-d6) δ 11.78 (s, 1H), 8.91 (s, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.66-7.64 (m, 2H), 7.56-7.55 (m, 2H), 7.41 (d, J=8.3 Hz, 1H), 7.34 (dd, J=1.7, 8.3 Hz, 1H), 6.36 (d, J=9.5 Hz, 1H), 2.28 (s, 3H), 1.52-1.49 (m, 2H), 1.18-1.15 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH:19](O)[CH3:20])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:24])=O.C(=O)([O-])O.[Na+]>ClCCCl>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH:19]([Cl:24])[CH3:20])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(O)c1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(Cl)c1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1

Procedure:
A mixture of 4-tert-butyl-2-[5-(1-hydroxyethyl)-benzofuran-2-yl]thiazole (1.5 g) and thionyl chloride (0.44 ml) in 1,2 dichloroethane (35 ml) was stirred under reflux for 2 hours. After cooling, the resulting mixture was adjusted to pH 7 with aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give 4-tert-butyl-2-[5-(1-chloroethyl)-benzofuran-2-yl]thiazole (1.31 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]3[N:26]=[N:27][NH:28][N:29]=3)[CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][C:22]([C:25]5[N:26]=[N:27][NH:28][N:29]=5)=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2ccc(-c3nn[nH]n3)cc21
Product: CC1c2cc(-c3nn[nH]n3)ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-7-(2H-tetrazol-5-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[NH:14][CH:13]=[N:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:15]([Li])CCC.IC.O>C1COCC1>[Si:1]([O:8][CH2:9][C:10]1[N:14]=[CH:13][N:12]([CH3:15])[CH:11]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3].[Si:1]([O:8][CH2:9][C:10]1[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCc1cnc[nH]1
Reactant: [Li]CCCC
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: Cn1cnc(CO[Si](C)(C)C(C)(C)C)c1
Product: Cn1cncc1CO[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 43 %
Yield: 14 %

Procedure:
To a solution of 5-(tert-butyldimethylsilanyloxymethyl)-1H-imidazole (Amino, Y.; Eto, H.; Eguchi, C., Chem. Pharm. Bull., 1989, 37, 1481-1487) (3.158 g, 14.9 mmol) in anhydrous THF (25 ml), cooled to −78° C. under nitrogen, was added a 1.6 M solution of butyllithium in hexanes (10.2 ml, 16.4 mmol). The mixture was stirred under nitrogen at −78° C. for 30 min, then iodomethane (0.97 ml, 15.6 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 5 h. Water (150 ml) was then added and the mixture was extracted with diethyl ether (150 ml). The organic extract was washed with brine, dried (MgSO4) and evaporated in vacuo. The residue was purified by flash chromatography (alumina, 40% EtOAc/hexane) to yield 0.4732 g (14%) of 4-(tert-butyldimethylsilanyloxymethyl)-1-methyl-1H-imidazole and 1.463 g (43%) of 5-(tert-butyldimethylsilanyloxymethyl)-1-methyl-1H-imidazole.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH2:10])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Cl:11][C:12]1[C:21]2[C:16](=[C:17]([I:23])[C:18]([CH3:22])=[CH:19][CH:20]=2)[N:15]=[CH:14][N:13]=1.CC(O)C>CCOC(C)=O>[ClH:11].[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:12]3[C:21]4[C:16](=[C:17]([I:23])[C:18]([CH3:22])=[CH:19][CH:20]=4)[N:15]=[CH:14][N:13]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc2c(Cl)ncnc2c1I
Reactant: Nc1ccc2c(c1)CCC2
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: Cc1ccc2c(Nc3ccc4c(c3)CCC4)ncnc2c1I
Product: Cl
Temperature: 110 °C
Yield: 86.5 %

Procedure:
2,3-Dihydro-1H-inden-5-amine (109 mg, 821 μmol), 4-chloro-8-iodo-7-methylquinazoline (250 mg, 821 μmol) and IPA (5 mL) were added to microwave-vial. The reaction mixture was heated at 110° C. for 10 min. A precipitate formed upon cooling. The crude product was diluted with EtOAc (20 mL), filtered, washed twice with EtOAc (20 mL) and air-dried to give N-(2,3-dihydro-1H-inden-5-yl)-8-iodo-7-methylquinazolin-4-amine hydrochloride (311 mg, 87%) as an amorphous off-white solid. MS (M+H)+ 402.
Reaction SMILES: C(OC([N:8]1[CH2:44][CH2:43][C:11]2([O:15][C:14]([NH:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[CH:22][N:21]=[C:20]4[NH:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)=[C:30]([Cl:42])[CH:29]=3)=[N:13][CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:42][C:30]1[CH:29]=[C:28]([NH:27][C:20]2[C:19]3[C:24](=[CH:25][CH:26]=[C:17]([NH:16][C:14]4[O:15][C:11]5([CH2:43][CH2:44][NH:8][CH2:9][CH2:10]5)[CH2:12][N:13]=4)[CH:18]=3)[N:23]=[CH:22][N:21]=2)[CH:33]=[CH:32][C:31]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN=C(Nc1ccc3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c3c1)O2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1cc(Nc2ncnc3ccc(NC4=NCC5(CCNCC5)O4)cc23)ccc1OCc1ccccn1

Procedure:
N4-[3-Chloro-4-(pyridin-2-ylmethoxy)-phenyl]-N6-(1-oxa-3,8-diaza-spiro[4.5]dec-2-en-2-yl)-quinazoline-4,6-diamine is prepared from 2-{4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-quinazolin-6-ylamino}-1-oxa-3,8-diaza-spiro[4.5]dec-2-ene-8-carboxylic acid tert-butyl ester by standard BOC deprotection methods using TFA in methylene chloride. MS ESI (+) m/z 516, 518 (M+1, Cl pattern) detected; 1H NMR (400 mHz, CDCl3) δ 8.61 (s, 1H), 8.58 (d, 1H), 8.22 (bs, 1H), 7.97 (d, 1H), 7.70 (m, 2H), 7.67 (d, 1H), 7.64 (dd, 1H), 7.35 (d, 1H), 7.26 (m, 1H), 7.02 (d, 1H), 5.31 (s, 2H), 3.73 (s, 2H), 3.05 (m, 2H), 2.96 (m, 2H), 1.97 (m, 2H), 1.80 (m, 2H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][C:5]2[CH:7]=[C:8]([CH3:14])[CH:9]=[C:10]([N+:11]([O-])=O)[C:4]=2[O:3]1>C1COCC1.[Pd]>[CH3:1][C@@H:2]1[CH2:6][C:5]2[CH:7]=[C:8]([CH3:14])[CH:9]=[C:10]([NH2:11])[C:4]=2[O:3]1
Reactant: Cc1cc2c(c([N+](=O)[O-])c1)O[C@H](C)C2
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1cc(N)c2c(c1)C[C@@H](C)O2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The mixture of (R)-2,5-dimethyl-7-nitro-2,3-dihydrobenzofuran (3e) (0.84 g, 4.3 mmol) and Pd/C (100 mg, 15%) in THF (10 mL) was introduced H2 at ambient temperature. It was stirred at ambient temperature for 12 h. The mixture was filtered through Celite and concentrated to give the title compound (3f) as a solid. MS-ESI (m/z): 164 (M+1)+.