Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Br:20][C:21]1[CH:28]=[C:27]([F:29])[C:24]([CH:25]=O)=[C:23]([F:30])[CH:22]=1.O>ClCCl>[Br:20][C:21]1[CH:28]=[C:27]([F:29])[C:24]([CH2:25][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:23]([F:30])[CH:22]=1
Reactant: O=Cc1c(F)cc(Br)cc1F
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Fc1cc(Br)cc(F)c1CN1CCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.2 %

Procedure:
Pyrrolidine (25 mL, 0.30 mol) and sodium triacetoxyborohydride (64 g, 0.30 mol) were added in portions to a stirred solution of Intermediate 18a, 4-Bromo-2,6-difluorobenzaldehyde (53.5 g, 0.24 mol) in dichloromethane (500 mL) on ice bath. The reaction mixture was intensively stirred for 12 h at RT. Water (400 mL) was added followed by addition of 5M aq. NaNSO4 to attain pH ˜2. The organic layer was separated. The aqueous one was extracted with CH2Cl2 (2×200 mL). The organic layers were discarded. The aqueous fraction was alkalized with K2CO3 to pH ˜10, and extracted with CHCl3 (2×300 mL). The organic extract was washed with brine, dried over anhydrous Na2SO4 (100 g) and evaporated in vacuo to give the title compound (52.5 g, 79%, 0.19 mol). LC/MS data: 275.9 and 277.9 (M+H)+ (calculated for C11H12BrF2N, 276.13). 1H NMR data (DMSO-d6): 7.40-7.48 (m, 2H, Ar—H), 3.66 (s, 2H, Ar—CH2), 2.38-2.46 (m, 4H pyrrolidine (CH2)2N), 1.61-1.71 (m, 4H, CH2CH2CH2CH2).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:3]=1[C:4]#[N:5].ClCC(=O)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[NH2:5][C:4]1[C:3]2[C:6]([O:10][CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]3)=[CH:7][CH:8]=[CH:9][C:2]=2[N:1]=[C:25]2[CH2:24][O:23][C:21](=[O:22])[C:20]=12
Reactant: CCOC(=O)CC(=O)CCl
Reactant: N#Cc1c(N)cccc1OC1CCCCC1
Product: Nc1c2c(nc3cccc(OC4CCCCC4)c13)COC2=O

Procedure:
Prepared as in Example 2a from 2-amino-6-(cyclohexyloxy)benzonitrile (Example 36b) and ethyl 4-chloro-3-oxobutanoate as an orange solid (29%). 1H NMR (400 MHz, DMSO-d6) δ 1.30-1.72 (m, 8H), 2.04-2.08 (m, 2H), 4.70 (m, 1H), 5.26 (s, 2H), 7.09 (d, J=8.0 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.64 (m, 2H), 8.14 (brs, 1H). MS 299 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]([NH2:15])=[NH:14])[CH:7]=[CH:6]2.[Cl:16][C:17]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:18]=1[CH:19]=[C:20]([C:23]#[N:24])[C:21]#[N:22]>>[NH2:24][CH2:23][C:20]1[C:21]([NH2:22])=[N:14][C:13]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]=2)=[N:15][C:19]=1[C:18]1[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:17]=1[Cl:16]
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Reactant: COc1ccc2cc(C(=N)N)ccc2c1
Product: COc1ccc2cc(-c3nc(N)c(CN)c(-c4ccc(Cl)cc4Cl)n3)ccc2c1

Procedure:
The title compound, MS: m/e=425.0 (M+H+), was prepared from 6-methoxy-naphthalene-2-carboxamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.Br[C:16]1[S:17][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][N:20]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:10]([O:9][C:8]([NH:7][CH:4]1[CH2:3][CH2:2][N:1]([C:16]2[S:17][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][N:20]=2)[CH2:6][CH2:5]1)=[O:14])([CH3:11])([CH3:13])[CH3:12]
Reactant: COC(=O)c1cnc(Br)s1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(N2CCC(NC(=O)OC(C)(C)C)CC2)s1
Temperature: 130 °C

Procedure:
tert-Butyl piperidin-4-ylcarbamate (4.5 g, 22 mmol), methyl 2-bromo-1,3-thiazole-5-carboxylate (5.0 g, 22 mmol), and diisopropylethylamine (3.8 ml, 22 mmol) were suspended in anhydrous DMF and heated to an external temperature of 130° C. for 1.5 hours. The DMF was removed and the solid was partitioned with EtOAc and water. The combined organic extracts were washed with brine, dried with MgSO4 and concentrated to a yellow solid (7.05 g, 94%).
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]3[N:10]=[C:11]([N+:13]([O-])=O)[CH:12]=[C:6]3[CH2:5]2)[CH2:3][CH2:2]1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[CH:1]1([N:4]2[CH2:9][CH2:8][N:7]3[N:10]=[C:11]([NH2:13])[CH:12]=[C:6]3[CH2:5]2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cc2n(n1)CCN(C1CC1)C2
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cc2n(n1)CCN(C1CC1)C2
Yield: 78.3 %

Procedure:
A mixture of 5-cyclopropyl-2-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine 135a (2.68 g, 12.9 mmol), Fe (3.6 g, 64.4 mmol) and NH4Cl (4.1 g, 77.4 mmol) in ethanol (30 mL) and water (5 mL) was heated at reflux for 2 h. After the completion of the reaction, the mixture was filtered off. And the solid was washed with ethanol (150 mL). The filtrate was evaporated in vacuo and the residue was extracted with methanol/methylene chloride (1/7). The combined extracts were dried over Na2SO4 and evaporated. The residue was purified on reverse phase Combi-flash to give 135b (1.8 g, 75%). MS: [M+H]+ 179.
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[N:3]=1.C(N(C(C)C)CC)(C)C.[C:22]([O:26][C:27]([C:29]1[C:37]2[CH2:36][CH2:35][N:34]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[CH:33]([CH2:47][NH2:48])[C:32]=2[S:31][C:30]=1[NH2:49])=[O:28])([CH3:25])([CH3:24])[CH3:23]>ClCCl>[C:22]([O:26][C:27]([C:29]1[C:37]2[CH2:36][CH2:35][N:34]([CH2:38][C:39]3[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=3)[CH:33]([CH2:47][NH:48][C:2]3[C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[S:4](=[O:12])(=[O:11])[N:3]=3)[C:32]=2[S:31][C:30]=1[NH2:49])=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: COc1ccc(CN2CCc3c(sc(N)c3C(=O)OC(C)(C)C)C2CN)cc1
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CN2CCc3c(sc(N)c3C(=O)OC(C)(C)C)C2CNC2=NS(=O)(=O)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 77.6 %

Procedure:
3-Chloro-benzo[d]isothiazole-1,1-dioxide (160 mg, 0.79 mmol) and diisopropylethylamine (150 μl, 0.86 mmol) were dissolved in dichloromethane (7 ml) at 0° C. 2-Amino-7-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (284 mg, 0.70 mmol) was added and the mixture was stirred for 15 minutes at 0° C., diluted with dichloromethane (10 ml) and washed with water (20 ml) and brine (20 ml). The organic phase was dried (MgSO4), filtered, and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography using a gradient of hexanes/ethyl acetate (1:1) to pure ethyl acetate as eluent, which afforded 309 mg (77%) of 2-amino-7-((1,1-dioxo-1H-benzo[d]isothiazol-3-ylamino)methyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an foam.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.ClCCl.CN(C=O)C.[CH3:19][S:20]([C:23]1[S:27][C:26]([C:28]([OH:30])=O)=[CH:25][CH:24]=1)(=[O:22])=[O:21].[CH3:31][C:32]([CH3:53])([CH3:52])[CH2:33][CH2:34][NH:35][C:36](=[O:51])[C@H:37]([CH3:50])[CH2:38][C@H:39]([OH:49])[C@@H:40]([NH2:48])[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CN(C=O)C.ClCCl>[CH2:41]([C@H:40]([NH:48][C:28]([C:26]1[S:27][C:23]([S:20]([CH3:19])(=[O:21])=[O:22])=[CH:24][CH:25]=1)=[O:30])[C@@H:39]([OH:49])[CH2:38][C@H:37]([C:36](=[O:51])[NH:35][CH2:34][CH2:33][C:32]([CH3:31])([CH3:52])[CH3:53])[CH3:50])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)s1
Reactant: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NCCC(C)(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1ccc(S(C)(=O)=O)s1)C(=O)NCCC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
N-Cyclohexylcarbodiimide-N′-methyl polystyrene (138 mg @ 1.70 mmol/g; ex. Novabiochem) was treated with dichloromethane (0.5 ml) followed by a solution of 1-hydroxybenzotriazole (32 mg, 0.24 mmol) in 4:1 dichloromethane/DMF (0.5 ml). 5-Methanesulfonyl thiophene-2-carboxylic acid (50 mg, 0.23 mmol) in DMF (0.5 ml) and (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-phenyl-hexanoic acid (3,3-dimethylbutyl)-amide (D2) (50 mg, 0.16 mmol) in dichloromethane (0.5 ml) were then added and the mixture was stirred gently overnight at room temperature. It was then diluted with dichloromethane (1 ml) and treated with methylisocyanate polystyrene (150 mg @ 1.80 mmol/g; ex. Novabiochem) and tris-(2-aminoethyl)-amine polystyrene (150 mg @ 3.20 mmol/g; ex. Novabiochem), and the mixture was stirred gently for a further 2 h. It was then filtered and the spent resins were washed with DMF (1 ml) and dichloromethane (1 ml). The combined filtrates were evaporated to dryness and the residue was triturated with diethyl ether to afford the title compound as a white solid (57 mg, 72%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[S:9][NH:10][C:11](=[O:12])[C:3]=12.C(N(C(C)C)CC)(C)C.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:29][C:30]([O:32][CH3:33])=[O:31]>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[S:9][N:10]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[C:11](=[O:12])[C:3]=12
Reactant: COC(=O)CBr
Reactant: Cc1cc(C)c2c(=O)[nH]sc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)Cn1sc2nc(C)cc(C)c2c1=O
Reaction time: 5 h
Yield: 51.5 %

Procedure:
To enhance the selectivity of N-alkylation over O-alkylation, pyridinothiazolone 4 (500 mg, 2.77 mmol) was suspended in CH2Cl2 (20 mL) containing of diisopropylethylamine (DIEA, 1.5 mL, 8.61 mmol) and Cs2CO3 (700 mg, 3.07 mmol). Methyl 2-bromoacetate (900 mg, 5.88 mmol) was then added at room temperature. The mixture was stirred for 5 h, concentrated under reduced pressure, and purified by chromatography on a silica gel column with elution of EtOAc/hexane (1:4) to give the title compound 7 (360 mg, 55% yield) accompanied by an O-alkylation side product (7%). Compound 7: C11H12N2O3S; white solid; mp 89-91° C.; IR vmax (neat) 2928, 1766, 1728, 1664, 1561, 1523, 1435, 1375, 1324, 1210 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.92 (1H, s), 4.54 (2H, s), 3.76 (3H, s), 2.70 (3H, s), 2.57 (3H, s); 13C NMR (100 MHz, CDCl3) δ 167.4, 164.3, 162.6, 162.3, 149.6, 122.4, 113.8, 52.8, 44.2, 24.9, 17.8; ESI-HRMS calcd for C11H13N2O3S: 253.0647. found: m/z 253.0657 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@@H:19]([NH2:23])[CH2:20][CH2:21][CH3:22])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl.N[C@@H](CCC)[C@@H:33](C1C=CC=C(OC)C=1)[OH:34]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:24]4[CH:25]=[CH:26][CH:27]=[C:28]([O:34][CH3:33])[CH:29]=4)[C@@H:19]([NH2:23])[CH2:20][CH2:21][CH3:22])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCC[C@H](N)[C@H](O)c1cccc(OC)c1
Reactant: CCC[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Agent: Cl
Product: CCC[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1cccc(OC)c1

Procedure:
was synthesised in the same way as (91a) from (1R,2S)-2-amino-1-(3-methoxyphenyl)pentan-1-ol hydrochloride (93b, 50 mg, 0.20 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)C#N.C[CH2:11][N:12](CC)CC>[Pd].CCO>[NH2:1][C:2]1[CH:3]=[C:4]([NH:12][CH3:11])[CH:7]=[CH:8][N:9]=1
Reactant: N#Cc1ccnc(N)c1
Reactant: CCN(CC)CC
Agent: [Pd]
Solvent: CCO
Product: CNc1ccnc(N)c1
Reaction time: 12 h

Procedure:
To a mixture of 2-aminoisonicotinonitrile (0.043 mol) and Pd/C (10%, 6.00 g) was added Et3N (40.0 mL) and EtOH (160.0 mL) in a parr bottle and hydrogenated at 50 psi for 12 h. Crude mixture was filtered through Celite®, concentrated under vacuo and dried under high vacuum to yield compound.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]2[C@H:10]([NH:11]C(=O)OCC3C=CC=CC=3)[C:9](=[O:22])[NH:8]2)[CH:5]=[N:4][CH:3]=[N:2]1.C(O)=O>CO.[Pd]>[N:1]1([CH2:6][C@H:7]2[NH:8][C:9](=[O:22])[C@H:10]2[NH2:11])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=C(N[C@@H]1C(=O)N[C@@H]1Cn1cncn1)OCc1ccccc1
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: N[C@@H]1C(=O)N[C@@H]1Cn1cncn1
Reaction time: 1 h

Procedure:
To a solution of benzyl ((2R,3S)-2-((1H-1,2,4-triazol-1-yl)methyl)-4-oxoazetidin-3-yl)carbamate (38 mg, 0.126 mmol) in MeOH (5 mL) was added Pd black (6.7 mg, 0.063 mmol) followed by formic acid (339 μL, 8.83 mmol). After 1 h of stirring, the mixture was filtered over celite, washing with MeOH, and the filtrate was concentrated in vacuo. The solution was lyophilized and the crude material was used directly in the subsequent step. LCMS: Rt=0.14 min, m/z=168.1 (M+1) Method 2m_acidic.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].Cl.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[CH2:19][NH:18][CH2:17][CH2:16]2>C(=O)([O-])O.[Na+].O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:18]2[CH2:17][CH2:16][C:15]3[C:20](=[CH:21][C:22]([O:23][CH3:24])=[C:13]([O:12][CH3:11])[CH:14]=3)[CH2:19]2)[N:7]=1
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COc1cc2c(cc1OC)CN(c1nc(Cl)nc(Cl)n1)CC2

Procedure:
To a 0° C. stirred slurry of cyanuric chloride (8.03 g, 43.5 mM) in saturated sodium hydrogen carbonate solution (300 mL) was added 6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline hydrochloride (10 g, 43.5 mM) in water (50 mL) at a rate that maintained the internal temperature below 8° C. After 10 min the product was extracted with methylene chloride, filtered through a cotton plug and concentrated to a solid. Filtration of a concentrated methylene chloride solution of the crude product through a 2×2 inch silica gel pad eluting with 50% ethyl acetate/hexanes provided pure product, 12.3 g, (83%).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:3][CH:2]=1.[C:15](Cl)([Cl:17])=[O:16]>C1(C)C=CC=CC=1>[Cl:14][C:10]1[CH:9]=[C:8]([N:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[C:15]([Cl:17])=[O:16])[CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)Cl
Reactant: Clc1cccc(Nc2ccccc2)c1
Solvent: Cc1ccccc1
Product: O=C(Cl)N(c1ccccc1)c1cccc(Cl)c1
Yield: 58 %

Procedure:
Following the procedure of Example 15, Step A, 20.4 g (100 mmole) of 3-chlorodiphenylamine [i.e., N-(3-chlorophenyl)aniline] and phosgene in toluene gave 15.4 g (58%) of N-(3-chlorophenyl)-N-phenylcarbamoyl chloride.
Reaction SMILES: [CH3:1][CH:2]([CH3:38])[C@@H:3]([NH:11][C:12]([C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:21]=2)[N:16](COCC[Si](C)(C)C)[CH:15]=1)=[O:13])[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH3:1][CH:2]([CH3:38])[C@@H:3]([NH:11][C:12]([C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:21]=2)[NH:16][CH:15]=1)=[O:13])[C:4]([N:6]1[CH2:7][CH2:8][CH2:9][CH2:10]1)=[O:5]
Reactant: CC(C)[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Oc3ccccc3)nc12)C(=O)N1CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@@H](NC(=O)c1c[nH]c2ncc(Oc3ccccc3)nc12)C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
To a solution of 2-phenoxy-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-methyl-1-(pyrrolidine-1-carbonyl)-propyl]-amide from Step 3 in dichloromethane (0.5 mL) was added trifluoroacetic acid (0.7 mL). The reaction mixture was stirred at room temperature overnight then concentrated. The residue was stirred with THF (1 mL), water (0.5 mL), and Et3N (0.5 mL) for 2 h then concentrated. The residue was partitioned between ethyl acetate and water and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over MgSO4 and concentrated. The residue was purified by SiO2 column chromatography (5% MeOH/CH2Cl2) to provide 0.049 g (46%, 2 steps) of 2-phenoxy-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-methyl-1-(pyrrolidine-1-carbonyl)-propyl]-amide as a white foam. MS: 408 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[C:14](Cl)(Cl)=[O:15]>C1(C)C=CC=CC=1>[N:1]([C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1)=[C:14]=[O:15]
Reactant: O=C(Cl)Cl
Reactant: Cc1cc(=O)oc2cc(N)ccc12
Solvent: Cc1ccccc1
Product: Cc1cc(=O)oc2cc(N=C=O)ccc12

Procedure:
A round bottom flask was charged with 7-amino-4-methyl-coumarin (50 mg, 0.285 mmol) under argon and treated with a 20% phosgene in toluene solution (2 ml) under. The reaction mixture was heated at reflux for 15 hrs under argon during which time a white solid precipitated out of solution. After cooling, the excess phosgene was removed by bubbling argon gas through from the solution for 10 minutes. The reaction mixture was then evaporated to afford the product as white solid, which was used directly in the next step. Yield: 50 mg (87%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[OH:8].C(N(CC)CC)C.[P:17](Cl)(Cl)([O:19][CH3:20])=[O:18]>CCOCC>[CH3:20][O:19][P:17]1(=[O:18])[O:8][C:7]2[CH:6]=[CH:5][C:4]([CH3:9])=[CH:3][C:2]=2[O:1]1
Reactant: Cc1ccc(O)c(O)c1
Reactant: COP(=O)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COP1(=O)Oc2ccc(C)cc2O1
Yield: 88319 %

Procedure:
3,4-Dihydroxytoluene (1.686 g, 13.58 mM) was dissolved in 40 ml of ether and, using 2.748 g of triethylamine and 2.022 g of methyl dichlorophosphate, the reaction mixture was treated in the same manner as in Reference Example 5. There was obtained 2,400 g (88.4% yield) of 2-methoxy-5-methyl-2-oxo-1,3,2-benzodioxaphosphole as a viscous oil.
Reaction SMILES: [NH2:1][C:2]1[C:3](Br)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:9]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[CH:10]=[CH2:11].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[C:3](/[CH:11]=[CH:10]/[C:9]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccnc1Br
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)/C=C/c1ncccc1N

Procedure:
950 mg (4.94 mmol) of the bromide from Example 5A, 1900 mg (14.83 mmol) of tert-butyl acrylate, 330 mg (1.50 mmol) of palladium(II) acetate, 450 mg (1.50 mmol) of tri-ortho-tolylphospine are dissolved in 15 ml of acetonitrile, and 1000 mg (9.88 mmol) of triethylamine are added. The mixture is stirred under reflux for 16 h. The reaction mixture is concentrated, mixed with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulphate, filtered, concentrated and purified by column chromatography on silica gel with cyclohexane/ethyl acetate (7:3). 95 mg (6% of theory) of product are obtained.
Reaction SMILES: [OH:1][CH:2](C=C)[CH2:3][O:4][C:5]1[CH:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[O:7][N:6]=1.F[C:17]([F:30])([F:29])S(O[Si](C(C)(C)C)(C)C)(=O)=O.CC1C=CC=C(C)N=1.Cl>C1COCC1>[F:30][CH:17]([F:29])[CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[O:7][N:6]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: C=CC(O)COc1cc(C(=O)OC)on1
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: COC(=O)c1cc(OCC(O)C(F)F)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.3 %

Procedure:
A mixture of methyl 3-[(2-hydroxybut-3-en-1-yl)oxy]isoxazole-5-carboxylate (2.71 g), t-butyldimethylsilyl trifluoromethanesulfonate (4.03 g), 2,6-dimethylpyridine (1.64 g) and THF (30 mL) was stirred at room temperature for 2 hr. To the reaction mixture was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, and then saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was mixed with tetraoxide osmium (7% immobilized catalyst, 2.31 g), sodium periodate (13.6 g), acetonitrile (30 mL), acetone (30 mL) and water (20 mL), and the obtained mixture was stirred at room temperature for 3 days. The precipitate was removed by filtration, and the filtrate was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was mixed with toluene (20 mL), diethylaminosulfur trifluoride (5.04 mL) was slowly added dropwise thereto at room temperature, and the obtained mixture was stirred at room temperature for 2 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was mixed with THF (20 mL), tetrabutylammonium fluoride (1.0M THF solution, 25.4 mL) was slowly added dropwise thereto at 0° C., and the obtained mixture was stirred at 0° C. for 30 min. To the reaction mixture was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a white powder (370 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[C:14]2[CH:15]=[C:16]([C:31]([OH:33])=O)[CH:17]=[C:18]3[C:23]=2[O:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:20][C:19]3=[O:30])[CH:5]=[C:6]([F:8])[CH:7]=1.CCN(C(C)C)C(C)C.[CH3:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[C:14]2[CH:15]=[C:16]([C:31]([N:47]3[CH2:48][CH2:49][N:44]([CH3:43])[CH2:45][CH2:46]3)=[O:33])[CH:17]=[C:18]3[C:23]=2[O:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:20][C:19]3=[O:30])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1cc([C@H]2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=O)c2cc([C@H]3CCCN3c3cc(F)cc(F)c3)c3oc(N4CCOCC4)cc(=O)c3c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
8-[(2R)-1-(3,5-difluorophenyl)pyrrolidin-2-yl]-2-morpholino-4-oxo-chromene-6-carboxylic acid (see Example 1.03b for preparation, 97 mg, 0.21 mmol), DIPEA (0.185 mL, 1.06 mmol) and 1-methylpiperazine (0.047 mL, 0.43 mmol) were mixed at room temperature in DCM (3 mL). N-propylphosphonic acid anhydride, cyclic trimer (50 wt % solution in EtAc) (0.633 mL, 1.08 mmol) was then added and the reaction mixture was stirred at 25° C. for 1 hour. The reaction mixture was purified by preparative HPLC to afford 8-[(2R)-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)]-6-(4-methylpiperazine-1-carbonyl)-2-morpholino-4H-chromen-4-one (67 mg, 59%) as a white foam.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].Br[CH2:11][CH:12]1[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH2:11][CH:12]1[CH2:14][CH2:13]1
Reactant: BrCC1CC1
Reactant: Cc1cccc(O)c1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cccc(OCC2CC2)c1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.3 %

Procedure:
A 250 mL flask with stirbar was charged with 2-bromo-3-methylphenol (2.86 g, 15.3 mmol), (bromomethyl)cyclopropane (1.80 mL, 18.6 mmol) and cesium carbonate (7.46 g, 22.9 mmol) in dimethylformamide (50 mL). The mixture was stirred for 16 hours at ambient temperature and then heated at 50° C. for 3 hours. The mixture was cooled to ambient temperature and partitioned between ethyl acetate (200 mL) and saturated aqueous sodium chloride (200 mL). The organics were washed twice with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to provide the title compound (3.7 g, 100%).