Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:4].[NH2:26][CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].CO>>[C:24]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:4])[N:6]=1)#[N:25]
Reactant: NCC(=O)O
Reactant: COC(=O)c1nc(C#N)c2c(Oc3ccc(F)cc3)cccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2cccc(Oc3ccc(F)cc3)c12
Temperature: 25 °C
Yield: 86.6 %

Procedure:
A mixture of 1-cyano-8-(4-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid methyl ester (112 mg, 0.33 mmol), glycine (496 mg, 6.6 mmol), and a 0.5 M solution of sodium methoxide in methanol (12.5 mL, 6.25 mmol) was refluxed for 39 h before it was cooled to room temperature and concentrated in vacuo. Water (75 mL) was added and the pH of the yellow suspension was adjusted to pH=10 with 1 N HCl. The suspension was washed with methylene chloride (2×50 mL). The remaining aqueous layer was acidified to pH=3 with 1 N HCl. The resulting white precipitate was collected by filtration, washed with water, and dried in vacuo to give the title compound as a white solid (109 mg): 1H NMR (DMSO-d6, 200 MHz): δ=12.85 (bs, 1H), 9.57 (br s, 1H), 8.09 (d, 1H), 7.83 (t, 1H), 7.27 (m, 5H), 4.05 (d, J=5.8 Hz, 2H); MS: (+) m/z 382.00 (M+1).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([SH:30])[CH:25]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:23][C:24]1[CH:25]=[C:26]([S:30][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)[C@@H](NS(=O)(=O)c1ccc(F)cc1)C(=O)OC(C)(C)C
Reactant: Cc1cccc(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(Sc2ccc(S(=O)(=O)N[C@@H](C(=O)OC(C)(C)C)C(C)C)cc2)c1
Temperature: 70 °C

Procedure:
To a solution of N-[(4-fluorophenyl)-sulfonyl]-D-valine, 1,1-dimethylethyl ester, from Example 1b (3.0 g, 9.06 mmol) in 35 mL DMF was added m-thiocresol (3.23 mL, 27.2 mmol) and powdered K2CO3 (3.76 g, 27.2 mmol). The mixture was heated to 70° C. for 20 hours. After cooling to room temperature, the solution is washed with H2O (4×100 mL), and sat'd NaCl (2×100 mL), and dried over Mg2SO4. After concentration in vacuo, the residue was purified by flash chromatography (10:90 EtOAc/hexane) to afford N-[[4-[(3-methylphenyl)thio]phenyl]sulfonyl]-D-valine, 1,1-dimethylethyl ester, as a white solid (3.95 g, quantitative yield): MS MH+ calc'd for C22H29NO4S2 : 436, found: 436. Anal. calc'd for C22H29NO4S2 : C, 60.66; H, 6.71; N, 3.22; Found: C, 60.57; H, 6.47; N, 3.14.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:9]=NC(C)=N[CH:13]=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1.C([BH3-])#N.[Na+].[CH3:35][O:36][C:37]1[CH:44]=CC(C=O)=C[CH:38]=1>>[CH3:35][O:36][C:37]1[CH:44]=[CH:13][C:8]([CH2:7][N:5]2[CH2:6][C@@H:2]([CH3:1])[C@H:3]([C:15]3[NH:16][C:17](=[O:30])[C:18]4[CH:23]=[N:22][N:21]([CH:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)[C:19]=4[N:20]=3)[CH2:4]2)=[CH:9][CH:38]=1
Reactant: Cc1ncc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1
Reactant: COc1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: COc1ccc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cc1

Procedure:
Following the procedure for the preparation of 6-{(3S,4S)-4-methyl-1-[(2-methylpyrimidin-5-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting sodium cyanoborohydride and 4-methoxybenzaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 8.01 (s, 1H), 7.29 (d, J=8.3 Hz, 2H), 6.87 (d, J=8.7 Hz, 2H), 4.82-4.08 (m, 1H), 4.13-4.08 (m, 2H), 3.84-3.75 (m, 4H), 3.61-3.51 (m, 3H), 3.35 (t, J=8.7 Hz, 1H), 2.97 (d, J=9.9 Hz, 1H), 2.82-2.80 (m, 1H), 2.53-2.49 (m, 1H), 2.42-2.30 (m, 3H), 1.95-1.82 (m, 3H), 1.18 (d, J=7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[S:28](Cl)(=[O:30])=[O:29]>>[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[S:28]([NH:19][C:4]1[CH:5]=[CH:6][C:7]([S:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)=[C:2]([Cl:1])[CH:3]=1)(=[O:30])=[O:29]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: Nc1ccc(Sc2ccc3ccccc3c2)c(Cl)c1
Product: O=S(=O)(Nc1ccc(Sc2ccc3ccccc3c2)c(Cl)c1)c1ccc(Cl)cc1Cl

Procedure:
2,4-Dichloro-N-[3-chloro-4-(napthalen-2-ylsulfanyl)-phenyl]-benzene sulfonamide was synthesized (67%) from 3-chloro-4-(napthalen-2-ylsulfanyl)phenylamine (92) and 2,4-dichlorobenzenesulfonyl chloride, obtained from Maybridge, in a similar manner as described in example 93.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[C:13]([NH:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[C:19]([O:26][CH3:27])[CH:18]=1)(=[O:15])[CH3:14]>>[CH3:12][N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][C:17]([NH:16][C:13](=[O:15])[CH3:14])=[CH:18][C:19]=2[O:26][CH3:27])[CH2:7]1
Reactant: COc1cc(NC(C)=O)ccc1C(=O)O
Reactant: CN1CCc2c(N)cccc2C1
Product: COc1cc(NC(C)=O)ccc1C(=O)Nc1cccc2c1CCN(C)C2

Procedure:
The title compound was prepared in an analogous manner to Example 1 from 5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and 4-acetylamino-2-methoxybenzoic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:11])[NH:6]2.[C:12]1([C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][O:14]1)=O.C[Si](C)(C)N[Si](C)(C)C.[Na].Cl>CN(C=O)C>[C:12]1(=[C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[CH3:1])[NH:6][C:5]2=[O:11])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][O:14]1
Reactant: O=C1OCc2ccccc21
Reactant: Cc1cccc2c1CC(=O)N2
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Na]
Solvent: CN(C)C=O
Product: Cc1cccc2c1C(=C1OCc3ccccc31)C(=O)N2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1.4 %

Procedure:
To a solution containing 4-methyloxindole (0.15 g, 1.02 mmol) and phthalide (0.178 g, 1.33 mmol) in 3.0 mL DMF was added 2.14 mL of sodium hexamethyldisilazane (1.0 M in tetrahydrofuran (THF)) over 1 min. The solution was stirred at room temperature for 30 min and then poured into 50 mL of 4% HCl to give a yellow solid. The aqueous mixture was extracted with EtOAc and the organic phase washed with saturated NaHCO3, H2O, dilute HCl, brine and the solution dried with Na2SO4. The solvent was removed in vacuo and the solid obtained was purified by chromatography (silica gel, CHCl3/EtOAc, 7:3). The solid obtained was recrystallized from EtOAc/hexanes to afford the title compounds (3.8 mg) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]3[CH:19]=[C:18](I)[N:17]=[CH:16]3)[N:9]=2)=[CH:4][C:3]=1[CH3:21].[C:22]([NH:26][S:27]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)(=[O:29])=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([NH:26][S:27]([C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([C:18]2[N:17]=[CH:16][N:15]([C:10]3[N:11]=[C:12]([CH3:14])[CH:13]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:21])[CH:4]=4)[N:9]=3)[CH:19]=2)[CH:35]=1)(=[O:29])=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-n2cnc(I)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-n2cnc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1

Procedure:
N-tert-Butyl-3-{1-[6-(4-chloro-3-methyl-phenyl)-4-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide was prepared from 4-(4-chloro-3-methyl-phenyl)-2-(4-iodo-imidazol-1-yl)-6-methyl-pyrimidine (example E.76) (0.41 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure VI. Obtained as a light grey solid (0.53 g) which was subsequently deprotected.
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]([C:12]2[CH:30]=[CH:29][C:15]([O:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[C:22]([CH2:27]O)[CH:21]=[CH:20]4)=[CH:14][CH:13]=2)=[CH:10][CH:9]=[N:8]1.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>>[N:8]1[NH:7][C:11]([C:12]2[CH:13]=[CH:14][C:15]([O:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[C:22]([CH2:27][N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[CH:21]=[CH:20]4)=[CH:29][CH:30]=2)=[CH:10][CH:9]=1
Reactant: C[Si](C)(C)CCOCn1nccc1-c1ccc(Oc2ccc3nc(CO)ccc3c2)cc1
Reactant: C1CCNC1
Product: c1cc(-c2ccc(Oc3ccc4nc(CN5CCCC5)ccc4c3)cc2)[nH]n1

Procedure:
The title product (243) is synthesized from intermediate E (75 mg, 0.17 mmol) and pyrrolidine according to procedure described for the synthesis of Example 250 from intermediate AU.
Reaction SMILES: [CH3:1][N:2]1[C:16]2[C:17]3[C:4]([CH2:5][C@@H:6]4[C:11]([C:12]=3[CH:13]=[CH:14][CH:15]=2)=[CH:10][C@@H:9]([CH2:18][N:19]=[N+]=[N-])[CH2:8][N:7]4[CH3:22])=[CH:3]1.[BH4-].[Na+].O>C(O)(C)C>[CH3:1][N:2]1[C:16]2[C:17]3[C:4]([CH2:5][C@@H:6]4[C:11]([C:12]=3[CH:13]=[CH:14][CH:15]=2)=[CH:10][C@@H:9]([CH2:18][NH2:19])[CH2:8][N:7]4[CH3:22])=[CH:3]1
Reactant: CN1C[C@H](CN=[N+]=[N-])C=C2c3cccc4c3c(cn4C)C[C@H]21
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CN1C[C@H](CN)C=C2c3cccc4c3c(cn4C)C[C@H]21
Reaction time: 24 h
Yield: 54.9 %

Procedure:
3.2 g 1,6-dimethyl-8β-azidomethyl-9, 10-didehydroergoline in 150 mls of isopropyl alcohol are treated with 6.4 g NaBH4 and heated to reflux under stirring and under nitrogen atmosphere for 24 hours. After this time further 2 g of NaBH4 are added and the heating is continued for 24 hours more. The reaction mixture is poured into water and extracted with chloroform. The chloroform extract is chromatographed onto SiO2 and the product is eluted with CH2Cl2 /MeOH/NH4OH (9/1/0.5). 1.6 g of 1,6-dimethyl-8β-aminomethyl-9, 10-didehydroergoline are thus obtained.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]=C=O)=[CH:13][CH:12]=2)=[N:9][CH:10]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Na+].[Na+]>Cl>[CH2:1]([C:5]1[CH:10]=[N:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)=[N:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cnc(-c2ccc(N=C=O)cc2)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCCc1cnc(-c2ccc(N)cc2)nc1
Temperature: 60 °C

Procedure:
8.11 g of crude p-(5-butyl-2-pyrimidinyl)phenyl isocyanate were introduced in small portions into 40 ml of 8 N hydrochloric acid heated to 60° C., whereby strong foaming took place. After completion of the addition the mixture was heated to slight boiling for 4 hours and then poured on to ice and an excess of solid sodium carbonate. The aqueous phase was extracted once with 300 ml of diethyl ether and twice with 100 ml of diethyl ether each time. The combined extracts were filtered. The filtrate was washed twice with water, dried over sodium sulphate and concentrated, whereby 5.16 g of yellowish, crystalline p-(5-butyl-2 pyrimidinyl)aniline were obtained; m.p. 154.5°--155.5° C.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.[OH:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[Cl:20])[NH2:16].C(O)(=O)C>O>[Cl:20][C:19]1[CH:18]=[CH:17][C:15]([N:16]2[C:1](=[O:11])[C:2]3[CH2:10][CH2:9][CH2:8][CH2:7][C:3]=3[C:4]2=[O:6])=[CH:14][C:13]=1[OH:12]
Reactant: Nc1ccc(Cl)c(O)c1
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: O
Solvent: CC(=O)O
Product: O=C1C2=C(CCCC2)C(=O)N1c1ccc(Cl)c(O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
A mixture of 15.2 g. of 3,4,5,6-tetrahydrophthalic anhydride, 14.4 g. of 3-hydroxy-4-chloroaniline and 50 ml. of glacial acetic acid was refluxed with stirring for 2 hours and then, the reaction mixture was cooled to a room temperature and water was added to precipitate a crystal and the crystal was separated by a filtration and recrystallized from isopropanol to obtain N-(4-chloro-3-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide (m.p.: 236.5°-238° C.; yellow crystal) (yield: 87.5%).
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[CH:15]=[C:16]([Br:20])[C:17]([OH:19])=[CH:18][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+].Cl>CO>[Br:20][C:16]1[C:17]([OH:19])=[CH:18][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH:10]([CH:12]([CH3:14])[CH3:13])[C:9]=2[CH:15]=1
Reactant: CC(C)C1CN(C(=O)C(F)(F)F)CCc2cc(O)c(Br)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)C1CNCCc2cc(O)c(Br)cc21
Reaction time: 3 h
Yield: 97.3 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-7-hydroxy-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.018 g, 0.047 mmol) in methanol (1 mL) was treated with 15% aqueous NaOH (1 mL), and stirred for 3 hours at 50 C. The product mixture was brought to pH 7-8 with 10% aqueous HCl, extracted three times with EtOAc (50 mL), dried with MgSO4, and concentrated to give 0.013 g of a white solid. 1H NMR (400 MHz, CD3OD) d 7.10 (s, 1 H), 6.60 (s, 1 H), 3.30 (m, 1 H), 3.2-3.0 (m, 2 H), 2.78 (m, 1H), 2.7-2.5 (m, 2H), 2.3-2.1 (m, 2 H), 1.05 (d, 3 H), 0.73 (d, 3 H). MS calculated for C13H18BrNO+H: 284, observed: 284.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:9]2)=[CH:4][C:3]=1[OH:18].[CH:19]#[C:20][CH:21](O)[CH2:22][CH2:23][CH3:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O>[C:20]([CH:21]([O:18][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([F:12])[C:2]=1[F:1])[O:9][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:7][CH2:6]2)[CH2:22][CH2:23][CH3:24])#[CH:19]
Reactant: CCCCCC1CCc2cc(O)c(F)c(F)c2O1
Reactant: C#CC(O)CCC
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C#CC(CCC)Oc1cc2c(c(F)c1F)OC(CCCCC)CC2
Reaction time: 18 h

Procedure:
10.0 g (39.0 mmol) of 7,8-difluoro-2-pentylchroman-6-ol are initially introduced in 140 ml of THF together with 4.0 g (41.0 mmol) of 1-hexyn-3-ol and 11.3 g (42.9 mmol) of triphenylphosphine, and 9.1 ml (46.8 mmol) of DIAD are added over the course of 20 min with ice-cooling. After 18 h at RT, water is added, and the mixture is extracted a number of times with MTBE. The combined organic phases are washed with water and saturated sodium chloride soln., and the solution is dried using sodium sulfate. The residue remaining after removal of the solvents is purified by column chromatography (SiO2, n-heptane:MTBE=2:1), giving 6-(1-ethynylbutoxy)-7,8-difluoro-2-pentylchroman as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:12]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16](=[O:24])[C:15]2=[C:25](Br)[CH:26]=[CH:27][N:14]2[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:12]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16](=[O:24])[C:15]2=[C:25]([CH3:37])[CH:26]=[CH:27][N:14]2[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)c1nn2ccc(Br)c2c(=O)n1-c1ccccc1
Reactant: CB1OB(C)OB(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccn2nc([C@H](CCOCc3ccccc3)NC(=O)OC(C)(C)C)n(-c3ccccc3)c(=O)c12
Temperature: 120 °C
Yield: 85.3 %

Procedure:
(S)-tert-Butyl (3-(benzyloxy)-1-(5-bromo-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)propyl)carbamate (0.6 g, 1.08 mmol) was dissolved in 36 mL anhydrous dimethylformamide in a pressure reactor vessel. 2,4,6-Trimethylboroxine (1.36 mL, 9.76 mmol), potassium carbonate (3 g, 21.68 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.13 g, 0.11 mmol) were added under argon conditions. The reaction mixture was heated at 120° C. for 2 h and then cooled and filtered through a plug of Celite, washing several times with ethyl acetate. The combinated filtrates were washed with water, saturated ammonium chloride solution and brine, dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified using SP1® Purification System (0% to 20%, hexane-ethyl acetate) to give 0.45 g (85% yield) of the title compound as a white solid.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]C=1C(O)=O>C(Cl)Cl>[CH3:7][O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:1]=1[C:2]([Cl:4])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1c(C(=O)O)ccc2ccccc12
Solvent: ClCCl
Product: COc1c(C(=O)Cl)ccc2ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Oxalyl chloride (118 μL, 1.35 mmol) was added dropwise to a partial solution of 1-methoxy-2-naphthoic acid (3-A) (210 mg, 1.04 mmol) in methylene chloride (2.0 mL). The mixture bubbled for several min and then cleared. After stirring for 3 h at room temperature, the mixture was evaporated in vacuo to give 1-methoxy-2-naphthoyl chloride (3-B). Methylene chloride (5.0 mL) was added followed by methylamine hydrochloride (330 mg, 5.05 mmol) and N,N-diisopropylethylamine (441 μL, 2.53 mmol) and the resulting mixture stirred at room temperature 18 h. Methylene chloride was added and the mixture washed with water, 1N HCl, 10% NaHCO3, brine, dried (MgSO4) and concentrated in vacuo to provide 1-methoxy-N-methyl-2-naphthamide (3-C).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:12][CH:11]([OH:13])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Si:1]([O:8][CH:9]1[CH2:12][C:11](=[O:13])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1CC(O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CC(=O)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 3-(tert-butyldimethylsilyloxy)cyclobutanol (2.59 g, 13 mmol), sodium bicarbonate (3 ml, 38 mmol), and Des-Martin periodonane (7 g, 15 mmol) in DCM (40 ml) was stirred at RT in 4 h, the solid was filtered; the filtrated was purified by ISCO (5% EtOAc/Hexanes) to give the title compound as a colorless oil.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:32])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]2[C:17](OS(C(F)(F)F)(=O)=O)=[CH:18][C:19]([CH3:21])=[N:20][C:13]=2[N:12]([CH3:30])[C:11]1=[O:31])(=[O:3])[CH3:2].[CH3:33][NH:34][CH3:35]>O1CCCC1>[C:1]([O:4][C@H:5]([CH3:32])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]2[C:17]([N:34]([CH3:35])[CH3:33])=[CH:18][C:19]([CH3:21])=[N:20][C:13]=2[N:12]([CH3:30])[C:11]1=[O:31])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(OS(=O)(=O)C(F)(F)F)cc(C)nc2n(C)c1=O
Reactant: CNC
Solvent: C1CCOC1
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(N(C)C)cc(C)nc2n(C)c1=O
Temperature: 0 °C

Procedure:
A pressure tube was charged with (R)-3-(5-acetoxyhexyl)-1,7-dimethyl-5-trifluoromethanesulfonyloxypyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (100 mg, 0.208 mmol) and tetrahydrofuran (1 ml). After cooling to 0° C., dimethylamine gas was introduced until approximately 1 ml had collected. The tube was sealed and heated at 55° C. for 18 hours. After cooling to room temperature, the tube was carefully vented and the dimethylamine was evaporated to provide crude (R)-3-(5-acetoxyhexyl)-1,7-dimethyl-5-(N,N-dimethylamino)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.
Reaction SMILES: O1CCOC1[C:6]1[CH:7]=[C:8]([C:15]([OH:17])=[O:16])[C:9]([C:12]([OH:14])=[O:13])=[N:10][CH:11]=1.[C:18]([O:21][C:22](=O)[CH3:23])(=[O:20])C>N1C=CC=CC=1>[O:21]1[CH2:22][CH2:23][O:20][CH:18]1[C:7]1[CH:6]=[CH:11][N:10]=[C:9]([C:12]([OH:14])=[O:13])[C:8]=1[C:15]([OH:17])=[O:16]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1cc(C2OCCO2)cnc1C(=O)O
Solvent: c1ccncc1
Product: O=C(O)c1nccc(C2OCCO2)c1C(=O)O
Yield: 92 %

Procedure:
A solution of 5-(1,3-dioxolan-2-yl)-2,3-pyridinedicarboxylic acid (2.86 g, 0.012 mol), acetic anhydride (11.3 mL, 0.12 mol) and pyridine is stirred at room temperature for 1 hour and 45 minutes, then at reflux temperature for 4 hours. The reaction mixture is concentrated in vacuo to give the title compound as an oil (2.64 g, 100%), identified by IR spectra analysis.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[NH2:34][C:35]1[C:40]([C:41]([C:43]2[N:44]([CH2:48][CH3:49])[N:45]=[CH:46][CH:47]=2)=O)=[CH:39][C:38]([Br:50])=[CH:37][N:36]=1>O1CCCC1>[Br:50][C:38]1[CH:39]=[C:40]([C:41]([C:43]2[N:44]([CH2:48][CH3:49])[N:45]=[CH:46][CH:47]=2)=[CH:2][O:3][CH3:4])[C:35]([NH2:34])=[N:36][CH:37]=1
Reactant: CCn1nccc1C(=O)c1cc(Br)cnc1N
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCn1nccc1C(=COC)c1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 75.3 %

Procedure:
To a solution of (methoxymethyl)triphenylphosphonium chloride (866 mg, 2.53 mmol) in tetrahydrofuran (20 ml) was added potassium bis(trimethylsilyl)amide (5.0 ml, 0.5M, 2.5 mmol). The red-orange reaction mixture was stirred at room temperature for 45 minutes. A solution of (2-amino-5-bromo-pyridin-3-yl)-(2-ethyl-2H-pyrazol-3-yl)-methanone (339 mg, 1.15 mmol) in tetrahydrofuran (10 ml) was added to the reaction mixture. The combined solution was stirred for 4 hours, and then quenched with saturated, aqueous ammonium chloride. The mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated in vacuo. The crude material was purified by flash chromatography (0 to 100% [10% methanol in ethyl acetate] in hexanes) to give 280 mg (75%) of 5-bromo-3-[1-(2-ethyl-2H-pyrazol-3-yl)-2-methoxy-vinyl]-pyridin-2-ylamine. MS: m/z 323.2+325.2 (M+H+).
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[N:6][C:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][C:12]=2[O:23][CH3:24])=[N:8][CH:9]=1)(=O)[CH3:2].Cl.[NH2:41][OH:42]>>[OH:42]/[N:41]=[C:1](/[C:4]1[C:5]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[N:6][C:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][C:12]=2[O:23][CH3:24])=[N:8][CH:9]=1)\[CH3:2]
Reactant: NO
Reactant: COc1cc(N2CCOCC2)ccc1Nc1ncc(C(C)=O)c(Nc2ccccc2NC(=O)OC(C)(C)C)n1
Agent: Cl
Product: COc1cc(N2CCOCC2)ccc1Nc1ncc(/C(C)=N/O)c(Nc2ccccc2NC(=O)OC(C)(C)C)n1

Procedure:
This intermediate was prepared in the same way as for Intermediate 3 in Example 298 in Example 299, using hydroxylamine hydrochloride instead of methoxylamine hydrochloride. MS: m/z 550.4 (ES+).