Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=[CH:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[CH3:41][O:42][C:43]1[CH:52]=[CH:51][CH:50]=[C:49]2[C:44]=1[CH2:45][CH2:46][N:47]([CH2:53][C:54]1[CH:59]=[CH:58][C:57]([C@@H:60]([NH2:62])[CH3:61])=[CH:56][CH:55]=1)[CH2:48]2>CN(C=O)C>[CH3:41][O:42][C:43]1[CH:52]=[CH:51][CH:50]=[C:49]2[C:44]=1[CH2:45][CH2:46][N:47]([CH2:53][C:54]1[CH:55]=[CH:56][C:57]([C@@H:60]([NH:62][C:6]([C:5]3[S:1][CH:2]=[N:3][CH:4]=3)=[O:8])[CH3:61])=[CH:58][CH:59]=1)[CH2:48]2
Reactant: O=C(O)c1cncs1
Reactant: COc1cccc2c1CCN(Cc1ccc([C@H](C)N)cc1)C2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2c1CCN(Cc1ccc([C@H](C)NC(=O)c3cncs3)cc1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
37 mg (0.29 mmol) Thiazole-5-carboxylic acid, 83 μl (0.48 mmol) DIPEA and 154 mg (0.481 mmol) TBTU in 0.5 mL DMF are stirred for 10 min at r.t. Then 80 mg (0.24 mmol) (S)-1-[4-(5-methoxy-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-phenyl]-ethylamine hydrochloride (example XXXIII.2) in 1.0 mL DMF and 102 μl (0.601 mmol) DIPEA are added and the resulting mixture is stirred at r.t. for 2 h. After that time, the reaction is quenched by the addition of 200 μL water and purified by HPLC.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[O:12][CH:11]([C:13]2[O:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[C:10]2=[C:19]3[N:32]([CH3:33])[C:31](=[O:34])[N:30]([CH3:35])[C:29](=[O:36])[C:20]3=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[N:9]2[CH2:8]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:43]1[CH:47]=[CH:46][N:45]=[CH:44]1>C(#N)C.O>[N:43]1([CH2:6][C@@H:7]2[O:12][C@@H:11]([C:13]3[O:14][C:15]([Cl:18])=[CH:16][CH:17]=3)[C:10]3=[C:19]4[N:32]([CH3:33])[C:31](=[O:34])[N:30]([CH3:35])[C:29](=[O:36])[C:20]4=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)[N:9]3[CH2:8]2)[CH:47]=[CH:46][N:45]=[CH:44]1
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)n3c(c2n(C)c1=O)C(c1ccc(Cl)o1)O[C@@H](COS(C)(=O)=O)C3
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: Cn1c(=O)c2c(-c3cccc(F)c3)n3c(c2n(C)c1=O)[C@H](c1ccc(Cl)o1)O[C@@H](Cn1ccnc1)C3
Temperature: 80 °C
Reaction time: 3.5 h

Procedure:
A mixture of ((8R)-10-(5-chlorofuran-2-yl)-5-(3-fluorophenyl)-1,3-dimethyl-2,4-dioxo-2,3,4,7,8,10-hexahydro-1H-pyrimido[4′,5′:3,4]pyrrolo[2,1-c][1,4]oxazin-8-yl)methyl methanesulfonate (117 mg, 0.217 mmol), cesium carbonate (142 mg, 0.435 mmol) and imidazole (22.51 mg, 0.331 mmol) in acetonitrile (6 mL) was heated at 80° C. for 16 hours, then at 85° C. for 3.5 hours. Further portions of imidazole (22.51 mg, 0.331 mmol) and cesium carbonate (142 mg, 0.435 mmol) were added and the mixture heated for a further 2 hours. The mixture was cooled to room temperature, diluted with water (30 ml) and extracted with DCM (2×30 ml). The combined organic extracts were washed with brine (30 ml) passed through a hydrophobic frit and evaporated under vacuum. Purification by chromatography on silica, eluting with 0-100% EtOAc/hexane then with 0-10% MeOH/DCM, afforded the title compound as a mixture of diastereomers.
Reaction SMILES: [O:1]=[C:2]1[N:8]([O:9][CH2:10][CH:11]=[CH2:12])[CH:7]2[CH2:13][N:3]1[N:4]([CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])[C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=12>C(Cl)Cl.FC(F)(F)C(O)=O>[O:1]=[C:2]1[N:8]([O:9][CH2:10][CH:11]=[CH2:12])[CH:7]2[CH2:13][N:3]1[N:4]([CH2:18][C:19]([OH:21])=[O:20])[C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=12
Reactant: C=CCON1C(=O)N2CC1c1ccccc1N2CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCON1C(=O)N2CC1c1ccccc1N2CC(=O)O
Reaction time: 0.25 h
Yield: 41 %

Procedure:
The ester obtained in Example 24 is dissolved in 2.5 cm3 of CH2Cl2 and 7.5 cm3 of trifluoroacetic acid. After 15 min, the solvent is evaporated by entraining it with toluene, and then the compound is crystallized from ether. 519 mg of the expected acid (41%) are obtained.
Reaction SMILES: [C:1]1(=O)[O:5][CH2:4][CH2:3][CH2:2]1.[NH2:7][CH2:8][CH2:9][CH2:10][OH:11]>>[OH:11][CH2:10][CH2:9][CH2:8][N:7]1[CH2:1][CH2:2][CH2:3][C:4]1=[O:5]
Reactant: NCCCO
Reactant: O=C1CCCO1
Product: O=C1CCCN1CCCO
Yield: 17.5 %

Procedure:
A solution of γ-butyrolactone (8.6g, 0.1 mol) and 3-amino-1-propanol (9 g, 0.12 mol) was heated at reflux for 18 hours. The crude product mixture was distilled under reduced pressure to give 1-(3-hydroxypropyl)-2-pyrrolidinone (2.5 g. 17%).
Reaction SMILES: C(Cl)(=O)C.[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][N:11]([C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:17])[CH2:10]2)#[N:6].NC1C=C2C(=CC=1)CN(C(N[C:42]1[CH:47]=[CH:46][C:45]([C:48](=[O:53])NCCC)=[CH:44][CH:43]=1)=O)C2>>[C:48]([N:26]1[CH2:25][CH2:24][CH:23]([CH2:22][CH2:21][CH2:20][CH2:19][NH:18][C:16]([N:11]2[CH2:10][C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:5]#[N:6])[CH:8]=3)[CH2:12]2)=[O:17])[CH2:28][CH2:27]1)(=[O:53])[C:45]1[CH:46]=[CH:47][CH:42]=[CH:43][CH:44]=1
Reactant: N#Cc1ccc2c(c1)CN(C(=O)NCCCCC1CCNCC1)C2
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Solvent: CC(=O)Cl
Product: N#Cc1ccc2c(c1)CN(C(=O)NCCCCC1CCN(C(=O)c3ccccc3)CC1)C2

Procedure:
The title compound was prepared as described in Example 278, substituting benzoyl chloride for acetyl chloride and 5-cyano-N-(4-(piperidin-4-yl)butyl)isoindoline-2-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.83 (s, 1H), 7.75 (dd, J=7.9, 1.5 Hz, 1H), 7.53 (d, J=7.9 Hz, 1H), 7.41-7.44 (m, 3H), 7.31-7.38 (m, 2H), 6.36 (t, J=5.5 Hz, 1H), 4.60-4.64 (m, 4H), 4.30-4.53 (m, 1H), 3.42-3.71 (m, 1H), 3.02-3.10 (m, 2H), 2.64-3.00 (m, 2H), 1.56-1.84 (m, 2H), 1.37-1.54 (m, 3H), 1.24-1.31 (m, 4H), 0.93-1.16 (m, 2H); MS (ESI(+)) m/e 431 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:18])[CH:9]2[CH:13]3[O:14][CH2:15][CH:16]([OH:17])[CH:12]3[O:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1.Cl.[CH3:20][N:21]1[CH:25]=[C:24]([NH2:26])[CH:23]=[N:22]1.C(N(C(C)C)C(C)C)C>CCCCO>[CH3:18][N:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:26][C:24]2[CH:23]=[N:22][N:21]([CH3:20])[CH:25]=2)[N:7]=1)[CH:9]1[CH:13]2[O:14][CH2:15][CH:16]([OH:17])[CH:12]2[O:11][CH2:10]1
Reactant: CN(c1ccnc(Cl)n1)C1COC2C(O)COC21
Reactant: Cn1cc(N)cn1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ccnc(Nc2cnn(C)c2)n1)C1COC2C(O)COC21
Temperature: 150 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
To a suspension of 6-((2-chloropyrimidin-4-yl)(methyl)amino)hexahydrofuro[3,2-b]furan-3-ol (358.0 mg, 1.32 mmol) and 1-methyl-1H-pyrazol-4-amine hydrochloride (178.6 mg, 1.34 mmol) in n-BuOH (5 mL) was added N-ethyldiisopropylamine (434.6 mg, 3.36 mmol). The reaction mixture was stirred at 150° C. in a sealed tube overnight and then concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/10) to give the title compound as a beige solid (300 mg, 68.4%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])[CH:5]=[CH:4][N:3]=1.Br[CH2:18][C:19](=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21]>COCCOC>[CH2:14]([O:13][P:9]([CH2:8][C:6]1[CH:5]=[CH:4][N:3]2[CH:18]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:1]=[C:2]2[CH:7]=1)([O:10][CH2:11][CH3:12])=[O:16])[CH3:15]
Reactant: CCOP(=O)(Cc1ccnc(N)c1)OCC
Reactant: CCOC(=O)C(=O)CBr
Solvent: COCCOC
Product: CCOC(=O)c1cn2ccc(CP(=O)(OCC)OCC)cc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.4 %

Procedure:
The product from Example 16 (0.87 g, 3.56 mmol) was dissolved in DME (25 mL) and placed in a 100 mL flask. Ethyl bromopyruvate (0.76 g, 3.92 mmol) was added to the flask, and the reaction was allowed to stir under a N2 atmosphere for 16 h. After solvent removal in vacuo, the residue was taken up in abs EtOH (25 mL) and refluxed for 5 h. The reaction was cooled to room temperature and solvent was removed in vacuo. The residue was dissolved in aqueous K2CO3 and the product extracted with EtOAc. Purification via a chromatotron (97/2/1 CH2Cl2 /EtOH/NH4OH) produced 0.38 g (32%) of title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]([CH3:28])[CH2:25][CH2:26][OH:27])=[CH:20][CH:19]=1.C(N(CC)CC)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]([CH2:25][CH2:26][OH:27])[CH3:28])=[CH:22][CH:23]=1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Reactant: CN(CCO)c1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(CCO)c1ccc(N/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc1
Yield: 63 %

Procedure:
(4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (0.17 g, 0.61 mmol) and 2-[(4-amino-phenyl)-methyl-amino]-ethanol (0.10 g, 0.61 mmol) were stirred in N,N-dimethylformamide (3 mL) and triethylamine (0.16 mL) at 60-70° C. The reaction mixture is quenched by the addition of water. The solid material is then collected, washed with diethyl ether, water, and methanol, and then dried under vacuum to give (4Z)-6-bromo-4-[({4-[(2-hydroxyethyl)(methyl)amino]phenyl}amino)methylene]isoquinoline-1,3(2H,4H)-dione (0.16 g, 64%) as a rust colored powder.
Reaction SMILES: CC([C:4]1[CH:9]=[CH:8][CH:7]=[C:6](C(C)C)[C:5]=1[CH2:13][C:14]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=[O:15])C.[CH:33](C1C=CC=C(C(C)C)C=1CC(O)=O)(C)C.C1(C(C)C(O)=O)C=CC=CC=1>>[O:15]=[C:14]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:28])(=[O:29])[NH2:27])[C:19]([CH:22]([CH3:23])[CH3:24])=[CH:20][CH:21]=1)[CH:13]([C:5]1[CH:4]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:33]
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)O
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Agent: CC(C(=O)O)c1ccccc1
Product: CC(C)c1ccc(C(=O)C(C)c2ccccc2)c(C(C)C)c1OS(N)(=O)=O

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetic acid was replaced with α-phenylpropionic acid, mp 142°-144° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=2)[NH:12][N:11]=1.[N+](C1C=CC([O:29][P:30]([CH3:33])([CH3:32])=O)=CC=1)([O-])=O.N12CCCN=C1CCCCC2>ClCCl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][P:30]([CH3:33])([CH3:32])=[O:29])[CH:17]=2)[NH:12][N:11]=1
Reactant: CP(C)(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: Oc1ccc2[nH]nc(-c3cc4ccccc4[nH]3)c2c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CP(C)(=O)Oc1ccc2[nH]nc(-c3cc4ccccc4[nH]3)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 43 %

Procedure:
The dimethylphosphinic acid 3-(1H-indol-2-yl)-1H-indazol-5-yl ester compound is prepared according to procedure F using 230 mg of 3-(1H-indol-2-yl)-1H-indazol-5-ol (intermediate B) in solution with 245 mg of dimethylphosphinic acid 4-nitrophenyl ester in 5 ml of dichloromethane (stabilized with amylene) to which 170 μl of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in solution in 2 ml of dichloromethane are added. After stirring for 24 h at ambient temperature, the solvent is evaporated off and the crude is purified by preparative LC/MS. The crystals obtained after concentration of the fractions are washed with ethyl acetate and then with isopropyl ether. 129 mg of expected product are collected. Yield=43%.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:9][C@@H:8]([S:10][C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][NH:6]1)=[N+]=[N-].Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:34]([O:33][C:31]([N:6]1[CH2:7][C@H:8]([S:10][C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][C@H:5]1[CH2:4][NH2:1])=[O:32])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: [N-]=[N+]=NC[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NC[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccccc1

Procedure:
(2S,4R)-2-azidomethyl-4-tritylsulfanyl-pyrrolidine and benzyl chloroformate/N-ethyldiisopropylamine in CH2Cl2 (see cabamate synthesis, Method A)—followed by Staudinger reduction gave (2S,4R)-2-aminomethyl-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid benzyl ester as white foam, MS: 509 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=2)=[CH:5][C:4]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C([Li])CCC.[CH2:27]1[O:29][CH2:28]1.O>C(COC)OC>[CH3:14][C:12]1([CH3:15])[CH2:11][O:10][C:9]([C:6]2[C:5]([CH:28]([OH:29])[CH3:27])=[C:4]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[N:13]1
Reactant: C1CO1
Reactant: CCCCCOc1cc(C2=NC(C)(C)CO2)ccc1OC
Agent: [Li]CCCC
Solvent: COCCOC
Solvent: O
Product: CCCCCOc1c(OC)ccc(C2=NC(C)(C)CO2)c1C(C)O
Temperature: -60 °C
Yield: 38.2 %

Procedure:
2-(4-Methoxy-3-pentyloxyphenyl)-4,4-dimethyl-4,5-dihydrooxazole (373 mg, 1.28 mmol, 1 eq) was dissolved in dimethoxyethane (7 ml). The solution was cooled to -60° C., and n-butyllithium (1.6M hexane solution)(1.76 ml, 2.82 mmol, 2.2 eq) was added dropwise. The mixture was stirred at said temperature for 1.5 hours. Ethylene oxide was added dropwise, and the mixture was stirred for 1.0 hour. The mixture was heated to room temperature, and further stirred for 2 hours. Water (50 ml) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (50 ml). The organic layers were combined, washed with saturated brine (100 ml) and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=3/1-2/1) to give [6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-3-methoxy-2-pentyloxyphenyl]ethanol (164 mg, 38.2%) as an oil.
Reaction SMILES: [NH2:1][C@:2]([CH3:28])([CH2:26][CH3:27])[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[C:18]3[C:19]([CH3:25])([CH3:24])[O:20][C:21]([CH3:23])=[N:22][C:17]=3[CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:11]=1)=[O:4].Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl>C(OCC)(=O)C.O>[CH2:26]([C@@:2]1([CH3:28])[NH:1][C:30](=[O:32])[N:5]([C:6]2[CH:7]=[N:8][C:9]([O:12][C:13]3[C:18]4[C:19]([CH3:25])([CH3:24])[O:20][C:21]([CH3:23])=[N:22][C:17]=4[CH:16]=[CH:15][CH:14]=3)=[CH:10][CH:11]=2)[C:3]1=[O:4])[CH3:27]
Reactant: CC[C@@](C)(N)C(=O)Nc1ccc(Oc2cccc3c2C(C)(C)OC(C)=N3)nc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CC[C@@]1(C)NC(=O)N(c2ccc(Oc3cccc4c3C(C)(C)OC(C)=N4)nc2)C1=O
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 187.7 %

Procedure:
To a solution of (2R)-2-amino-2-methyl-N-[6-[(2,4,4-trimethyl-3,1-benzoxazin-5-yl)oxy]-3-pyridyl]butanamide (Intermediate 205, 143 mg, 0.37 mmol) and TEA (0.21 mL) in ethyl acetate (2.5 mL) at 0° C., triphosgene (44 mg, 0.15 mmol) dissolved in ethyl acetate (2.5 mL) was added drop wise in 10 min. The reaction mixture was stirred at 0° C. for 40 min. The reaction mixture was diluted with water (5 mL) and ethyl acetate (10 mL). Phases were separated and the aqueous was back-extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated and the residue was purified by flash chromatography on silica gel using ethyl acetate as eluent affording the title compound (115 mg) as white solid.
Reaction SMILES: [OH:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH3:12])[C:6]=2[CH:5]=[C:4]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH:3]=1.Cl[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][O:21][CH2:20]1>>[CH2:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]([O:1][C:2]2[C:10]3[N:9]=[C:8]([CH3:11])[N:7]([CH3:12])[C:6]=3[CH:5]=[C:4]([C:13]([N:15]([CH3:16])[CH3:17])=[O:14])[CH:3]=2)[CH2:20][O:21]1
Reactant: Cc1nc2c(O)cc(C(=O)N(C)C)cc2n1C
Reactant: ClC1COCc2ccccc21
Product: Cc1nc2c(OC3COCc4ccccc43)cc(C(=O)N(C)C)cc2n1C
Yield: 12 %

Procedure:
The title compound was prepared as a white solid in 12% yield (38 mg) from 4-hydroxy-N,N,1,2-tetramethyl-1H-benzimidazole-6-carboxamide (0.20 g, 0.85 mmol, WO 2004054984) and 4-chloro-3,4-dihydro-1H-isochromene (0.20 g, 1.2 mmol, STEP 1) by the same manner in STEP 1 of Example 1:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:5]([F:14])=[CH:4][C:3]=1[N:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18](=[O:23])[C:17]([C:24](N(OC)C)=[O:25])=[N:16]1.[CH3:30][Mg+].[Br-]>C1COCC1>[C:24]([C:17]1[C:18](=[O:23])[C:19]([O:21][CH3:22])=[CH:20][N:15]([C:3]2[CH:4]=[C:5]([F:14])[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[CH:7][C:2]=2[F:1])[N:16]=1)(=[O:25])[CH3:30]
Reactant: C[Mg+]
Reactant: COc1cn(-c2cc(F)c(N3CCOCC3)cc2F)nc(C(=O)N(C)OC)c1=O
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cn(-c2cc(F)c(N3CCOCC3)cc2F)nc(C(C)=O)c1=O
Temperature: -78 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
A solution of 1-(2,5-difluoro-4-morpholin-4-ylphenyl)-N,5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (0.51 g, 1.2 mmol) in THF (40 mL) was added dropwise to MeMgBr (1.0 M in THF, 5.0 mL, 5.0 mmol) at −78° C. under N2. The mixture was stirred at −78° C. for 2 h. The reaction was quenched with 1 M HCl aqueous solution (5.0 mL) at −78° C. The mixture warmed up to room temperature, diluted with AcOEt, and washed with brine. The organic layer was dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with AcOEt/MeOH (10/0 to 10/1) to give the title compound (340 mg, 75% yield) as a pale yellow solid: 1H NMR (300 MHz, DMSO-d6): δ ppm 2.49 (3H, s), 2.91-3.21 (4H, m), 3.54-3.89 (7H, m), 7.19 (1H, dd, J=12.7, 7.7 Hz), 7.74 (1H, dd, J=12.8, 7.2 Hz), 8.46 (1H, d, J=1.5 Hz). LC-MS (ESI) m/z 366 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[CH2:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C1C2C(COC([N:32]=[C:33]=[S:34])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:14])[CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:33](=[S:34])[NH2:32])[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)CC1CCNCC1
Solvent: ClC(Cl)Cl
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)CC1CCN(C(N)=S)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of piperidin-4-ylacetic acid tert-butyl ester (10.72 g, 50.0 mmol) in chloroform (100 ml) was added to a solution of 9-fluorenylmethoxycarbonyl isothiocyanate (14.07 g, 50.0 mmol) in chloroform (100 ml) and the mixture was stirred at room temperature for 1 hour. Then, piperidine (80 ml) was added and the mixture was stirred at room temperature for 30 minutes. After the reaction solution was concentrated, water was added, and it was extracted with ethyl acetate and washed with a saturated brine. The organic layer was dried over magnesium sulfate and the residue obtained by vacuum concentration was washed with isopropyl ether and the title compound was obtained (11.35 g, 98%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([CH3:8])=[CH:6][CH:7]=1.[Mg].[CH3:11][O:12][C:13]([C:15]12[CH:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:22][CH2:21][C:20](=[O:30])[CH:19]1[CH2:18][N:17]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:16]2)=[O:14].[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[CH3:11][O:12][C:13]([C:15]12[CH:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:22][CH2:21][C:20]([OH:30])([C:2]3[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([CH3:9])[CH:3]=3)[CH:19]1[CH2:18][N:17]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:16]2)=[O:14]
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(=O)CCC2c1ccccc1
Reactant: Cc1ccc(Br)cc1C
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(O)(c1ccc(C)c(C)c1)CCC2c1ccccc1
Temperature: -7 °C
Reaction time: 4 h

Procedure:
2.3 cm3 of 4-bromo-ortho-xylene and 0.42 g of magnesium turnings in a mixture of 20 cm3 of diethyl ether and 20 cm3 of tetrahydrofuran were heated at reflux for one hour. After cooling to a temperature in the region of -7° C., a solution of 3.11 g of methyl(3aRS,4SR,7aRS)-2-benzyl-7-oxo-4-phenyloctahydroisoindole-3a-carboxylate in 20 cm3 of diethyl ether was added over 25 minutes. The reaction mixture was stirred for four hours at a temperature in the region of 25° C. and then hydrolysed by 50 cm3 of a saturated aqueous ammonium chloride solution. The aqueous phase was separated by settling and extracted with 25 cm3 of ethyl acetate. The organic phases were combined, dried over magnesium sulphate and concentrated under reduced pressure. After purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (80/20 by volume) mixture, 1.995 g of methyl(3aRS,4SR,7RS,7aRS)-2-benzyl-7-hydroxy-7-(3,4-dimethylphenyl)-4-phenyl-octahydroisoindole-3a-carboxylate were obtained, the characteristic of which compound, used as it was in the following stage, was as follows:
Reaction SMILES: [CH3:1]I.[Br:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([I:11])[N:5]=1.O>CN(C=O)C>[Br:3][C:4]1[C:9]([O:10][CH3:1])=[CH:8][CH:7]=[C:6]([I:11])[N:5]=1
Reactant: CI
Reactant: Oc1ccc(I)nc1Br
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(I)nc1Br
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
Add K2CO2 (6.22 g, 45.1 mmol) and methyl iodide (24.6 g, 10.77 mL, 173.3 mmol) to 2-bromo-6-iodopyridin-3-ol, 2 (14.9 g, 49.5 mmol), dissolved in DMF (30 mL). Heat the reaction medium at 100° C. for 2 h, then leave it to cool to room temperature. Then stop the reaction with H2O and stir it for a further 30 min. The precipitate is then filtered, washed with H2O and dried in air to give 3 (15.7 g, 100%) in solid form, light brown: 1H NMR (CDCl3) δ 7.61 (d, 1H, J=8.4 Hz), 6.86 (d, 1H, J=8.4 Hz), 3.93 (s, 3H); m/z obs.=314 (M+1), 315.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][Cl:6])=[O:3].[OH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][OH:16])[N:10]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:6][CH2:5][O:4][C:2]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:2]([O:4][CH2:5][Cl:6])=[O:3])[N:10]=1)=[O:3]
Reactant: O=C(Cl)OCCl
Reactant: OCc1cccc(CO)n1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C(OCCl)OCc1cccc(COC(=O)OCCl)n1
Yield: 95 %

Procedure:
The reaction of the compound of the formula (II) with the compound of the formula (III) is carried out at a temperature between -30° C. and +10° C., preferably at about -5° C. This reaction will be described in detail hereinafter. At least 2 moles of chloromethyl chloroformate of the formula (III) [as calculated for 2,6-bis(hydroxymethyl)pyridine of the formula (II)] are dissolved in the desired solvent, preferably in chloroform, and a solution containing an organic base, preferably pyridine, in the same molar amount as the compound of the formula (III) in the same solvent is added at a temperature lower than 10° C., preferably at about -5° C., under stirring. The suspension obtained is stirred for about 20 minutes while care is taken to avoid any increase of the temperature. Then, 2,6-bis(hydroxymethyl)pyridine of the formula (II) is added to the above mixture at the same temperature at such a rate that the temperature reaches at most -5° C. The suspension is stirred for about 20 minutes to give a brown solution. After washing this solution with water and evaporation, a practically pure product with 95 to 97% of 2,6-bis(chloromethyloxy-carbonyloxymethyl)pyridine content is obtained. The product obtained after washing with water and making free of the solvent can be used without any purification or, if desired, may be further purified by chromatography on a silicagel column or on an other adsorbent, e.g. on a synthetic resin.