Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1N[CH2:27][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:16][C:17]3[CH:26]=[CH:25][C:20]4[O:21][CH2:22][CH2:23][O:24][C:19]=4[CH:18]=3)[C:10]=2[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+:32].[CH3:33]O>O.[Pd]>[O:21]1[CH2:22][CH2:23][O:24][C:19]2[CH:18]=[C:17]([NH:16][C:15]3[C:10]4[CH2:9][NH:32][CH2:33][CH2:27][C:11]=4[N:12]=[CH:13][N:14]=3)[CH:26]=[CH:25][C:20]1=2
Reactant: [NH4+]
Reactant: CO
Reactant: c1ccc(CC2Cc3c(ncnc3Nc3ccc4c(c3)OCCO4)CN2)cc1
Agent: [Pd]
Agent: O=C[O-]
Solvent: O
Product: c1nc2c(c(Nc3ccc4c(c3)OCCO4)n1)CNCC2
Temperature: 60 °C

Procedure:
A mixture of 6-benzyl-5,6,7,8-tetrahydro-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrido[3,4-d]pyrimidin-4-amine (0.742 g, 1.98 mmol), ammonium formate (1.25 g, 19.83 mmol) and palladium, 10% wt. on activated carbon (75 mg) in methanol (10 mL) is heated to 60° C. for 2 h. The mixture is cooled to r.t. and filtered over celite. The filtrate is concentrated under reduced pressure to give a white solid which is dissolved in water. The mixture is extracted twice with a 3:1 mixture of chloroform: isoproanol. The combined organic extracts are dried over sodium sulfate and concentrated to dryness to give the title compound.
Reaction SMILES: ClC(N(C)C)=C(C)C.[N:9]1([C:13]([C:15]2[N:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@H:32]4[CH2:36][CH2:35][O:34][CH2:33]4)[CH:30]=3)[C:25]([OH:27])=O)=[CH:17][CH:16]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1.Cl.[F:38][CH:39]([F:46])[N:40]1[CH:44]=[CH:43][C:42]([NH2:45])=[N:41]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[N:9]1([C:13]([C:15]2[N:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@H:32]4[CH2:36][CH2:35][O:34][CH2:33]4)[CH:30]=3)[C:25]([NH:45][C:42]3[CH:43]=[CH:44][N:40]([CH:39]([F:46])[F:38])[N:41]=3)=[O:27])=[CH:17][CH:16]=2)=[O:14])[CH2:10][CH2:11][CH2:12]1
Reactant: Nc1ccn(C(F)F)n1
Reactant: O=C(O)c1cc(Oc2ccc(C(=O)N3CCC3)nc2)cc(O[C@H]2CCOC2)c1
Agent: CC(C)=C(Cl)N(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccn(C(F)F)n1)c1cc(Oc2ccc(C(=O)N3CCC3)nc2)cc(O[C@H]2CCOC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.1 %

Procedure:
1-Chloro-N,N,2-trimethyl-1-propenylamine (0.088 mL, 0.66 mmol) was added to a solution of 3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[(3S)-tetrahydrofuran-3-yloxy]benzoic acid (171 mg, 0.44 mmol) in DCM (10 mL) and the reaction was stirred at RT for 30 minutes. After this time 1-(difluoromethyl)pyrazol-3-amine hydrochloride (75 mg, 0.44 mmol) and DIPEA (0.154 mL, 0.89 mmol) were added sequentially. The resulting solution was stirred at RT for 16 hours after which time the solvent was removed in vacuo and ethyl acetate (20 mL) and water (20 mL) were added. The aqueous phase was extracted with ethyl acetate (2×20 mL), washed with a saturated solution of sodium hydrogen carbonate (20 mL), and brine (20 mL). The combined organic extracts were dried (MgSO4), filtered and evaporated. The residue was purified by flash column chromatography on silica, eluting with 50-100% ethyl acetate in isohexane, to give the desired product as a white solid (132 mg). 1H NMR δ (CDCl3): 2.40-2.12 (m, 4H), 4.03-3.89 (m, 4H), 4.25 (t, 2H), 4.71 (t, 2H), 5.01-4.96 (m, 1H), 6.76 (t, 1H), 7.03 (t, 1H), 7.08 (d, 1H), 7.11 (s, 1H), 7.22 (s, 1H), 7.38 (dd, 1H), 7.75 (d, 1H), 8.13 (d, 1H), 8.33 (d, 1H), 8.50 (s, 1H); 19F NMR δ (CDCl3): −93.84; m/z 500 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[S:8][C:7]([N:9]=[C:10]=[O:11])=[N:6][N:5]=2)[CH2:3][CH2:2]1.C([O:15][CH2:16][CH3:17])(=O)C>>[CH2:4]([N:5]([CH2:17][CH:16]=[O:15])[C:10]([NH:9][C:7]1[S:8][C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:5][N:6]=1)=[O:11])[C:1]#[CH:2]
Reactant: CCOC(C)=O
Reactant: O=C=Nc1nnc(C2CC2)s1
Product: C#CCN(CC=O)C(=O)Nc1nnc(C2CC2)s1

Procedure:
A mixture of 5-cyclopropyl-1,3,4-thiadiazol-2-yl isocyanate dimer (7 grams), the dimethyl acetal of 2-propargylaminocetaldehyde (5 grams) and ethyl acetate (50 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 2 hours. After this time the mixture is stripped of solvent under reduced pressure to yield the desired product the dimethyl acetal of 2-[1-propargyl-3-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)ureido]acetaldehyde as an oil.
Reaction SMILES: [CH3:1][C:2]1([C:16]([O:18][CH3:19])=[O:17])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH2:13][CH2:14][CH3:15])[C:6]([OH:12])=[CH:7][CH:8]=2)[O:3]1.[Br:20][CH2:21][CH2:22][CH2:23]Br.C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>C(Cl)Cl>[CH3:1][C:2]1([C:16]([O:18][CH3:19])=[O:17])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH2:13][CH2:14][CH3:15])[C:6]([O:12][CH2:23][CH2:22][CH2:21][Br:20])=[CH:7][CH:8]=2)[O:3]1
Reactant: BrCCCBr
Reactant: CCCc1c(O)ccc2c1OC(C)(C(=O)OC)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCC(C)=O
Product: CCCc1c(OCCCBr)ccc2c1OC(C)(C(=O)OC)CC2
Reaction time: 48 h
Yield: 79.5 %

Procedure:
A 100 ml single neck round bottom flask was charged with 1.30 g (4.9 mmole) of the compound of Example 24, 11.51 g (57 mmole) of 1,3-dibromopropane, 1.05 g (7.6 mmole) of anhydrous potassium carbonate, and 15 ml of methyl ethyl ketone. The flask was fitted with a magnetic stirring bar and condenser topped with a calcium chloride drying tube and the solution refluxed with stirring for 48 hours. Methylene chloride, 50 ml was added to the flask and insoluble solids were removed by filtration. The volatile solvents were then removed by rotary evaporation and the excess dibromopropane removed at reduced pressure. The crude bromoester was purified by high pressure liquid chromatography (10% ethyl acetate-hexane) to give 1.5 g (79%) of the title compound as a colorless oil. Calc: C, 56.11; H, 6.54, Br, 20.74; Found; C, 56.62, H, 6.52; Br, 20.25.
Reaction SMILES: [CH2:1]([P:3]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH:9]=[CH:8][C:7]=1[N+:21]([O-:23])=[O:22])(=[O:5])[OH:4])[CH3:2].[CH3:24][C:25]([CH3:32])([CH3:31])[C:26]([O:28][CH2:29]Cl)=[O:27].C(N(CC)CC)C>CN(C=O)C>[CH2:1]([P:3]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH:9]=[CH:8][C:7]=1[N+:21]([O-:23])=[O:22])(=[O:4])[O:5][CH2:29][O:28][C:26](=[O:27])[C:25]([CH3:32])([CH3:31])[CH3:24])[CH3:2]
Reactant: CCP(=O)(O)c1cc(Oc2ccc(Cl)cc2Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)C(=O)OCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCP(=O)(OCOC(=O)C(C)(C)C)c1cc(Oc2ccc(Cl)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
Following the procedures of Example 1, P-ethyl-2-nitro-5-(2,4-dichlorophenoxy)phenylphosphinic acid (0.30 g, 0.80 mmol) and chloromethyl 2,2-dimethylpropanoate (0.24 g, 1.6 mmol) are reacted together in the presence of triethylamine (0.23 ml) and DMF (3 ml) to give 2,2-dimethylpropionyloxymethyl P-ethyl-2-nitro-5-(2,4-dichlorophenoxy)phenylphosphinate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:21])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:22]([NH:26][S:27]([C:30]1[S:31][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:33][CH:34]=1)(=[O:29])=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([NH:26][S:27]([C:30]1[S:31][C:32]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:9]=[C:10]([CH3:21])[CH:11]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=4)[N:13]=3)[CH:3]=2)=[CH:33][CH:34]=1)(=[O:28])=[O:29])([CH3:25])([CH3:23])[CH3:24]
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(-c2cccc(Br)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-c2cccc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1

Procedure:
N-tert-Butyl-5-{3-[6-(4-chloro-phenyl)-4-methyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide was prepared from 2-(3-bromo-phenyl)-4-(4-chloro-phenyl)-6-methyl-pyrimidine (example E.44) (0.36 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.41 g, 1.2 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.14 g), which was subsequently deprotected.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][O:22][CH3:23].[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[C:34](Cl)=[O:35].C(N(CC)CC)C>ClCCl>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][O:22][CH3:23])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:34]([C:25]3[CH:26]=[CH:27][C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:24]=3)=[O:35])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=C(Cl)c1ccc2ccccc2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)c1ccc2ccccc2n1

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine and quinoline-2-carbonyl chloride were combined in dichloromethane and triethylamine (3 equivalents) to provide N2-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}-2-quinolinecarboxamide as a white solid, m.p. 78.1-79.9° C. 1H NMR (300 MHz, DMSO-d6) δ9.02 (t, J=6.1 Hz, 1H), 8.55 (d, J=8.5 Hz, 1H), 8.23 (d, J=8.5 Hz, 1H), 8.10 (t, J=7.6 Hz, 1H), 8.02 (d, J=7.6 Hz, 1H), 7.90-7.84 (m, 1H), 7.75-7.70 (m, 1H), 7.58 (dd, J=8.3, 1.0 Hz, 1H), 7.35-7.30 (m, 1H), 7.18-7.13 (m, 2H), 6.48 (broad s, 2H), 4.58 (m, 2H), 3.79 (t, J=6.7 Hz, 2H), 3.44 (m, 2H), 3.22 (m, 5H), 1.91-1.78 (m, 4H); MS (EI) m/e 468.2276 (468.2274 calcd for C27H28N6O2).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:15][C:14]=3[OH:26])[N:10]=[C:9]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][OH:45])=[CH:29][C:28]=3[OH:46])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:47](Cl)(=[O:51])[C:48]([CH3:50])=[CH2:49].N1C=CC=CC=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:15][C:14]=3[OH:26])[N:10]=[C:9]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][O:45][C:47](=[O:51])[C:48]([CH3:50])=[CH2:49])=[CH:29][C:28]=3[OH:46])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCCOc1ccc(-c2nc(-c3ccccc3)nc(-c3ccc(OCCCCCCCCCCCO)cc3O)n2)c(O)c1
Reactant: C=C(C)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: C=C(C)C(=O)OCCCCCCCCCCCOc1ccc(-c2nc(-c3ccccc3)nc(-c3ccc(OCCCCCC)cc3O)n2)c(O)c1
Temperature: 55 °C
Yield: 91.4 %

Procedure:
A mixture of 22.0 g (35.0 m moles) of 2-phenyl-4-(2-hydroxy-4-n-hexyloxy-phenyl)-6-[2-hydroxy-4-(11-hydroxy-undecyloxy)phenyl]-1,3,5-triazine, 4.4 g (42.0 m moles) of methacryloyl chloride (Fluka, 97%), 0.5 g (6.3 m moles) of pyridine in 100 mL of toluene (Merck, 99.5%) are heated at 80°-85° C. for 21 hours. After cooling to 55° C., there are added 8.9 g (87.5 m moles) of triethylamine (Fluka, 99.5%). The mixture is heated at 80° C. for further 7 hours then filtered hot. The filtrate is evaporated. The crude product (25.7 g ) is dissolved in 120 mL of CH2Cl2, filtered through a Kieselgel 60 pad (230-400 mesh; 6.5 cm diameter; h=5 cm) and eluted with 380 mL of CH2Cl2. Solvent removal and drying at 80° C./0.1 mmHg for 2 hours 30 min. give 22.3 g (91.4% yield ) of 2-phenyl-4-(2-hydroxy-4-hexyloxyphenyl)-6-[2-hydroxy-4-(11-methacryloyloxy-undecyloxy)-phenyl]-1,3,5-triazine, as an orange resin, Tg=-13° C. (DSC).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[C:7]([C:16]1[N:17]=[C:18]([NH2:21])[S:19][CH:20]=1)=[N:8][O:9][CH:10]([C:12](=[O:15])[NH:13][NH2:14])[CH3:11])([CH3:4])([CH3:3])[CH3:2].C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[C:35]([O:38][C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][C:47]=1[O:48][C:49](=[O:51])[CH3:50])[C:42]([Cl:44])=[O:43])(=[O:37])[CH3:36].CCOCC>C(Cl)Cl.CO>[ClH:44].[C:1]([O:5][C:6](=[O:22])[C:7]([C:16]1[N:17]=[C:18]([NH2:21])[S:19][CH:20]=1)=[N:8][O:9][CH:10]([C:12](=[O:15])[NH:13][NH:14][C:42](=[O:43])[C:41]1[CH:45]=[CH:46][C:47]([O:48][C:49](=[O:51])[CH3:50])=[C:39]([O:38][C:35](=[O:37])[CH3:36])[CH:40]=1)[CH3:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(ON=C(C(=O)OC(C)(C)C)c1csc(N)n1)C(=O)NN
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1OC(C)=O
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: CO
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)Oc1ccc(C(=O)NNC(=O)C(C)ON=C(C(=O)OC(C)(C)C)c2csc(N)n2)cc1OC(C)=O
Product: Cl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 89.6 %

Procedure:
In 10 ml of methylene chloride was suspended 0.659 g (2 mmole) of 2-(2-amino-1,3-thiazol-4-yl)-2-(1-carbazoylethoxyimino)acetic acid tert-butyl ester, and to the suspension was added 2.5 g (12.3 mmole) of N,O-bis(trimethylsilyl)acetamide to form a solution. To the ice-cooled solution was added 0.565 g (2.2 mmole) of 3,4-diacetoxybenzoic acid chloride and the mixture was stirred for 1.5 hours under ice-cooling. The resulting mixture was poured into 150 ml of ether and to the mixture was added a small amount of methanol while stirring. Resulting precipitates were collected by filtration, washed with ether and then dried to obtain 1.05 g of 2-(2-amino-1,3-thiazol-4-yl)-2-{1-[3-(3,4-diacetoxybenzoyl)carbazoyl]ethoxyimino}acetic acid tert-butyl ester.hydrochloride. (Yield: 98.0%)
Reaction SMILES: [F:1][C:2]1[C:7]2[O:8][C@@H:9]([CH2:12][OH:13])[CH2:10][O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:14]1(C)[C:15]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=1.[CH2:25](Cl)Cl>CN(C1C=CN=CC=1)C>[CH3:25][C:18]1[CH:19]=[CH:14][C:15]([S:20]([O:13][CH2:12][C@@H:9]2[O:8][C:7]3[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=3[O:11][CH2:10]2)(=[O:21])=[O:22])=[CH:16][CH:17]=1
Reactant: ClCCl
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: OC[C@H]1COc2cccc(F)c2O1
Agent: CN(C)c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2COc3cccc(F)c3O2)cc1
Reaction time: 1.5 h

Procedure:
Preparation according to Preparation 22 using [(2S)-8-fluoro-2,3-dihydro-1,4-benzodioxin-2-yl]methanol (7.05 g, 38.0 mmol), toluenesulfonyl chloride (10.9 g, 57 mmol), TEA (8.0 ml, 57 mmol) and 4-DMAP (4.7 g, 38.0 mmol) in DCM (75 ml), stirred for 1.5 h. Flash column chromatography yielded 11.9 g of the title compound. MS m/z (rel. intensity, 70 eV) 184 (90), 153 (43), 139 (29), 128 (bp), 57 (25).
Reaction SMILES: C(OC([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=2)[CH:13]=[C:12]1[CH2:24][CH2:25][CH3:26])=O)C1C=CC=CC=1>CO.C(OCC)(=O)C.[Pd]>[CH2:24]([C:12]1[NH:11][C:19]2[C:14]([CH:13]=1)=[CH:15][CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=2)[CH2:25][CH3:26]
Reactant: CCCc1cc2ccc(C(=O)OC)cc2n1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCc1cc2ccc(C(=O)OC)cc2[nH]1
Reaction time: 0.33 h
Yield: 90.6 %

Procedure:
To a solution of methyl 1-benzyloxycarbonyl-2-propylindole-6-carboxylate (200 mg) in a mixture of methanol and ethyl acetate (1:1, 8 ml) was added 10% palladium on carbon (30 mg), and the mixture was stirred under hydrogen atmosphere or 20 minutes. The catalyst was removed by filtration through celite and washed with methanol. The filtrate was evaporated in vacuo to give methyl 2-propylindole-6-carboxylate (112 mg) as colorless crystals.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:27]=[C:28]([O:30][C@@H:31]([CH3:44])[CH2:32][O:33][Si:34]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36])[CH:29]=1)[C:12]([NH:14][C:15]1[CH:19]=[CH:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[N:16]=1)=[O:13])C1C=CC=CC=1>C1COCC1.C(O)C>[OH:8][C:9]1[CH:10]=[C:11]([CH:27]=[C:28]([O:30][C@@H:31]([CH3:44])[CH2:32][O:33][Si:34]([CH:41]([CH3:43])[CH3:42])([CH:35]([CH3:37])[CH3:36])[CH:38]([CH3:39])[CH3:40])[CH:29]=1)[C:12]([NH:14][C:15]1[CH:19]=[CH:18][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[N:16]=1)=[O:13]
Reactant: CC(C)[Si](OC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1)(C(C)C)C(C)C
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)[Si](OC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.1 %

Procedure:
A solution of tert-butyl 3-[(3-(benzyloxy)-5-{(1S)-1-methyl-2-[(triisopropylsilyl)oxy]ethoxy}benzoyl)amino]-1H-pyrazole-1-carboxylate (90 mg, 0.144-mmol) in 1:1 mixture of THF/ethanol was evacuated and purged with nitrogen (×3). 10% Palladium on carbon was added and the reaction mixture was evacuated and purged with nitrogen and then evacuated and finally purged with hydrogen gas. The reaction mixture was left to stir at ambient temperature under an atmosphere of hydrogen for 6 hours. The Palladium catalyst was filtered through diatomaceous earth. The filtrate was evaporated to give a crude solid (70 mg)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[CH2:5][C:6]1[N:11]([CH2:12][O:13][CH2:14]CO)[C:10](=[O:17])[NH:9][C:8](=[O:18])[C:7]=1[CH2:19][CH3:20].O([C:32]([NH:34][O:35]C(OC1C=CC=CC=1)=O)=O)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=[N:71]/[C:72]([O:74]C(C)C)=O)=O)C>O1CCCC1.CCOCC>[OH:35][N:34]([CH2:32][CH2:14][O:13][CH2:12][N:11]1[C:6]([CH2:5][C:4]2[CH:3]=[C:2]([CH3:1])[CH:23]=[C:22]([CH3:24])[CH:21]=2)=[C:7]([CH2:19][CH3:20])[C:8](=[O:18])[NH:9][C:10]1=[O:17])[C:72]([NH2:71])=[O:74]
Reactant: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Reactant: O=C(NOC(=O)Oc1ccccc1)Oc1ccccc1
Reactant: CCc1c(Cc2cc(C)cc(C)c2)n(COCCO)c(=O)[nH]c1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCc1c(Cc2cc(C)cc(C)c2)n(COCCN(O)C(N)=O)c(=O)[nH]c1=O
Temperature: 10 °C
Reaction time: 24 h
Yield: 15.6 %

Procedure:
To a solution of 6-(3,5-dimethylbenzyl)-5-ethyl-1-(2-hydroxyethoxymethyl)uracil (0.2 g, 0.6 mmol), N,O-bis(phenoxycarbonyl)hydroxylamine (0.18 g, 0.66 mmol) and triphenylphosphine (0.19 g, 0.66 mmol) in tetrahydrofuran (6 ml) was added dropwise at 0° C. DIAD (diisopropylazodicarboxylate) (145 mg, 0.71 mmol). The reaction medium, concentrated, was subjected successively to two flash column chromatographies on silica gel, the first one using a mixture dichloromethane/methanol 49:1 as eluant and the second one, the mixture ethyl acetate/petroleum ether 2:3. It was thus obtained 6-(2,3-dimethyl-benzyl)-5-ethyl-1-(2-N,O-bis(phenoxycarbonyl)hydroxyaminoethoxymethyl) uracil (0.30 g, 85%), 0.15 g (0.25 mmol) which was dissolved in a ammonia saturated methanolic solution (10 ml) and stirred for 24 h at 10° C. The reaction medium, concentrated, subjected to a flash column chromatography on silica gel (dichloromethane/methanol 19:1) gave an oil which, taken again with ether, gave the 1-(2-N1-hydroxyureidoethoxymethyl)-6-(3,5-dimethylbenzyl)-5-ethyl-uracil (36.6 mg, 36%) in the form of a white solid.
Reaction SMILES: CC[O:3][CH2:4][CH3:5].O.[C:7]1([CH3:17])[CH:12]=[CH:11][C:10](S(O)(=O)=O)=[CH:9][CH:8]=1.[CH3:18]O>>[CH2:12]([C:11]1[CH:10]=[CH:9][CH:8]=[CH:18][C:5]=1[CH2:4][OH:3])[CH:7]=[CH2:17]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOCC
Reactant: CO
Solvent: O
Product: C=CCc1ccccc1CO
Temperature: 25 °C
Yield: 78 %

Procedure:
The crude THP ether B1-2 (18.54 g, 80 mmol) was dissolved in MeOH (160 mL) and p-toluenesulfonic acid monohydrate (PTSA, 1.52 g, 8 mmol) added. The resulting mixture was stirred at rt O/N, then concentrated under reduced pressure and the residue diluted with Et2O (100 mL). The organic layer was sequentially washed with 5% NaHCO3 (aq) solution (3×50 mL) and brine (1×50 mL), then dried over MgSO4. The solvent was evaporated under reduced pressure and the residue purified by flash chromatography (EtOAc/hexanes, 1:9), to obtain TB1 as a pale-yellow oil (9.2 g, 78%). TLC [EtOAc/hexanes (1:9), detection: UV, PMA; Rf=0.24]
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:11]([C:12]([NH:14][CH3:15])=[O:13])=[C:10]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:9][C:5]2=[N:6][C:7]=1[Cl:8].B([C:26]1[CH:27]=[CH:28][C:29]([F:35])=[C:30]([CH:34]=1)[C:31]([OH:33])=[O:32])(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>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>[Cl:8][C:7]1[N:6]=[C:5]2[O:9][C:10]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[C:11]([C:12](=[O:13])[NH:14][CH3:15])[C:4]2=[CH:3][C:2]=1[C:26]1[CH:27]=[CH:28][C:29]([F:35])=[C:30]([CH:34]=1)[C:31]([OH:33])=[O:32]
Reactant: O=C(O)c1cc(B(O)O)ccc1F
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(Cl)c(Br)cc12
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: [Cs+]
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(Cl)c(-c3ccc(F)c(C(=O)O)c3)cc12
Temperature: 65 °C
Reaction time: 16 h
Yield: 69.2 %

Procedure:
A mixture of 5-bromo-6-chloro-2-(4-fluorophenyl)-N-methylfuro[2,3-b]pyridine-3-carboxamide (3.0 g, 7.8 mmol), 5-borono-2-fluorobenzoic acid (1.58 g, 8.60 mmol), Pd(Ph3P)4 (0.90 g, 0.78 mmol) and cesium carbonate (3.82 g, 11.7 mmol) was evacuated and charged with N2 (3×) and then diluted with water (0.95 ml)/DMF (9.5 ml). The mixture was again evacuated and charged with N2 (3×) and heated to 65° C. under N2 atmosphere. The reaction was allowed to stir at 65° C. for 16 h. LCMS showed peak with the expected M+H. The mixture was diluted with EtOAc (30 mL) and washed with 1M HCl, and sat aq NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give solid which was triturated with DCM to give the expected product 5-(6-chloro-2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)-2-fluorobenzoic acid (2.4 g, 5.4 mmol, 69% yield) consistent by LCMS and NMR. LC-MS retention time: 2.64 min; m/z (MH+): 443. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 3u C18 2.0×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 2 min, and an analysis time of 4 min where solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. 1H NMR (400 MHz, DMSO-d6) δ 13.46 (br. s, 1H), 8.55 (d, J=4.8 Hz, 1H), 8.21 (s, 1H), 8.10-8.04 (m, 2H), 8.00 (dd, J=7.0, 2.5 Hz, 1H), 7.82 (ddd, J=8.5, 4.5, 2.5 Hz, 1H), 7.52-7.39 (m, 3H), 2.82 (d, J=4.8 Hz, 3H).
Reaction SMILES: C(N(CC)CC)C.[C:8]([NH:12][C:13](=[NH:16])[O:14][CH3:15])([O:10][CH3:11])=[O:9].[CH:17]1([NH:23][S:24](Cl)(=[O:26])=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C1COCC1.C(Cl)Cl>[C:8]([N:12]([S:24](=[O:26])(=[O:25])[NH:23][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:13](=[NH:16])[O:14][CH3:15])([O:10][CH3:11])=[O:9]
Reactant: O=S(=O)(Cl)NC1CCCCC1
Reactant: COC(=N)NC(=O)OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=N)N(C(=O)OC)S(=O)(=O)NC1CCCCC1
Temperature: -70 °C
Reaction time: 8 h

Procedure:
Triethylamine (112 g) is added to a stirred solution of N-carbomethoxy-O-methylisourea (132.1 g) in anhydrous THF (900 ml). The solution is cooled to -70° C. under an N2 atmosphere and solution of cyclohexylsulfamoyl chloride (198 g) in anhydrous THF (400 ml) is added dropwise to the reaction mixture. The reaction mixture is warmed to RT filtered through Celite®, washed with anhydrous THF and evaporated to yield an oil which is taken up in methylene chloride, washed with 0.5N HCl and allowed to stand overnight. The organic layer is washed with 0.5N HCl, dried, filtered, washed with methylene chloride, evaporated and dried under high vacuum affording the desired product as an oil which is used in the next step without further purification.