Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:35][CH2:36][CH:37]([OH:41])[CH2:38][CH2:39][CH3:40].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:24](=[O:26])[O:41][CH:37]([CH2:36][CH3:35])[CH2:38][CH2:39][CH3:40])=[CH:18][CH:17]=1
Reactant: CCCC(O)CC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCC(CC)OC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1
Yield: 86.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 3-hexanol (27 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (62 mg, yield 73%).
Reaction SMILES: C(Cl)Cl.[N+:4]([O-:7])([OH:6])=[O:5].OS(O)(=O)=O.O[CH2:14][CH2:15][CH2:16][C:17]([O-:19])=[O:18].[K+]>O>[N+:4]([O:7][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])([O-:6])=[O:5]
Reactant: O=C([O-])CCCO
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=C(O)CCCO[N+](=O)[O-]
Reaction time: 0.25 h

Procedure:
CH2Cl2 (10 ml) was added to the HNO3/H2SO4 mixture, and the resulting solution was stirred for 15 minutes. Potassium 4-(hydroxy)butanoate (500 mg, 3.52 mmol) was then added in small portions to the methylenechloride solution kept at 0-5° C. The mixture was kept under stirring for 6 hours while the temperature was allowed to reach 25° C. gradually. Water (50 ml) was added to the reaction mixture and the resulting mixture was extracted with CH2Cl2 (3×25 ml). The combined organic phases were washed with water, dried over MgSO4 and concentrated to dryness under reduced pressure. 4-(Nitrooxy)butanoic acid was obtained as a yellow oil (300 mg, 57%) and used in the next step.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>CO>[F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[N:6]([S:23]([CH3:22])(=[O:25])=[O:24])[CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1COCCO1
Product: CS(=O)(=O)n1cc(F)c(=O)[nH]c1=O
Temperature: 80 °C
Reaction time: 10 h
Yield: 35.5 %

Procedure:
2.6 g. (0.02 mole) of 5-fluorouracil and 1.52 g (0.011 mole) of anhydrous potassium carbonate were suspended in 50 ml. of dioxane and then 2.53 g (0.022 mole) of methanesulfonyl chloride in 20 ml. of dioxane was dropwise added thereto. After stirring at 80°C. for 10 hours, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure and a resinous residue was obtained. The residue was dissolved in a small amount of methanol and allowed to stand at 0°C. overnight. There was obtained 1.48 g (45.4% yield) of 5-fluoro-1 -methanesulfonyluracil. Recrystallization of the product from methanol gave leaflets melting at 223°-224°C. The results of an elementary analysis thereof were well in agreement with the calculated value as follows:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:34])=[C:20]([NH:22][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:21]=2)[CH:5]=[CH:4][N:3]=1.[CH2:35]([O:37][CH2:38][CH2:39][NH2:40])[CH3:36]>>[CH2:35]([O:37][CH2:38][CH2:39][NH:40][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:14])[CH3:15])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:34])=[C:20]([NH:22][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:24])=[O:25])[CH:21]=2)[CH:5]=[CH:4][N:3]=1)[CH3:36]
Reactant: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Reactant: CCOCCN
Product: CCOCCNc1nccc(-c2sc(C(C)C)nc2-c2ccc(F)c(NS(=O)(=O)c3c(F)cccc3F)c2)n1
Yield: 36 %

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (0.150 g, 0.286 mmol) and 2-ethoxyethylamine (0.5 mL, 4.77 mmol), the title compound was obtained (64 mg, 36% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.92 (s, 1H), 8.08 (d, J=5.1 Hz, 1H), 7.66-7.77 (m, 1H), 7.36-7.46 (m, 2H), 7.20-7.32 (m, 4H), 6.19 (s, 1H), 3.35-3.51 (m, 6H), 3.24-3.30 (m, 1H), 1.36 (d, J=6.9 Hz, 6H), 1.10 (q, J=6.7 Hz, 3H). MS (ESI): 578.2 [M+H]+.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH:12]=[C:11]([C:13]3[CH:36]=[CH:35][C:16]4[N:17]([C:20]5[CH:21]=[C:22]([NH:26][C:27]([NH:29][CH2:30][C:31]([F:34])([F:33])[F:32])=[O:28])[CH:23]=[CH:24][CH:25]=5)[CH:18]=[N:19][C:15]=4[CH:14]=3)[CH:10]=[N:9]2)[CH2:4][CH2:3]1.[CH:37]1([CH:40]=O)[CH2:39][CH2:38]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)C>[CH:37]1([CH2:40][N:2]2[CH2:3][CH2:4][CH:5]([N:8]3[CH:12]=[C:11]([C:13]4[CH:36]=[CH:35][C:16]5[N:17]([C:20]6[CH:21]=[C:22]([NH:26][C:27]([NH:29][CH2:30][C:31]([F:33])([F:32])[F:34])=[O:28])[CH:23]=[CH:24][CH:25]=6)[CH:18]=[N:19][C:15]=5[CH:14]=4)[CH:10]=[N:9]3)[CH2:6][CH2:7]2)[CH2:39][CH2:38]1
Reactant: O=CC1CC1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4cnn(C5CCNCC5)c4)ccc32)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CCO
Product: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4cnn(C5CCN(CC6CC6)CC5)c4)ccc32)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-{3-[5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea HCl salt (20.0 mg, 0.0414 mmol) in 1,2-dichloroethane (2 mL) and ethanol (0.5 mL) was added cyclopropanecarboxaldehyde (4.6 μL, 0.062 mmol) and triethylamine (17 μL, 0.12 mmol). The suspension was stirred at r.t. for 1 h then sodium triacetoxyborohydride (18 mg, 0.083 mmol) was added. The reaction solution was stirred at r.t. overnight. The reaction solution was concentrated under reduced pressure to dryness. The residue was dissolved in MeOH, and purified by RP-HPLC (pH=10) to afford the desired compound. LCMS (M+H)+: m/z=538.2.
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[NH:15][C:16](=[O:33])[NH:17][C:18]2[S:19][CH:20]=[C:21]([CH2:23][C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[O:25])[N:22]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:34]>>[Cl-:34].[CH:1]1([C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[NH:15][C:16](=[O:33])[NH:17][C:18]2[S:19][CH:20]=[C:21]([CH2:23][C:24]([N:26]3[CH2:31][CH2:30][NH+:29]([CH3:32])[CH2:28][CH2:27]3)=[O:25])[N:22]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cl
Reactant: Cc1ccc(NC(=O)Nc2nc(CC(=O)N3CCN(C)CC3)cs2)c(C(=O)C2CCCC2)c1
Product: Cc1ccc(NC(=O)Nc2nc(CC(=O)N3CC[NH+](C)CC3)cs2)c(C(=O)C2CCCC2)c1
Product: [Cl-]

Procedure:
4-(2-{2-[3-(2-Cyclopentanecarbonyl-4-methylphenyl)-ureido]-thiazol-4-yl}-acetyl)-1-methyl-piperazinium chloride (392 mg) is prepared from 4-(2-{2-[3-(2-cyclopentanecarbonyl-4-methylphenyl)-ureido]-thiazol-4-yl}-acetyl)-1-methyl-piperazine (386 mg, 1.0 mmol) by treatment with anhydrous hydrogen chloride (5 ml, 4.0 M solution in dioxane) followed by collection of the solid product.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:27])[CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([NH:19]C(=O)OC(C)(C)C)[CH2:15][CH2:14]2)=[CH:6][CH:5]=1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O.C(Cl)[Cl:36]>>[NH2:19][CH:16]1[CH2:15][CH2:14][N:13]([CH2:12][C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:1]([NH2:2])=[O:3])=[CH:5][CH:6]=2)=[O:27])[CH2:18][CH2:17]1.[ClH:36]
Reactant: CC(C)(C)OC(=O)NC1CCN(CC(=O)Nc2ccc(C(N)=O)cc2)CC1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: NC(=O)c1ccc(NC(=O)CN2CCC(N)CC2)cc1

Procedure:
The intermediate of stage 1 (0.54 g; 1.43 mmol) is stirred for 1 h at r.t. with 20 mL of TFA/DCM 1:4. The solvent is removed and to the residue is added methanolic HCl. Volatiles are evaporated, the residue is suspended in ether, filtered off with suction and dried to give 4-(2-(4-aminopiperidin-1-yl)acetamido)benzamide as a HCl salt (II.1).
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[N:11]=[C:10]([O:16][CH:17]([CH2:21][C:22]2[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:29])[C:18]([OH:20])=[O:19])[N:9]=1.[CH2:30](Br)[CH3:31].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:15][O:14][C:12]1[CH:13]=[C:8]([O:7][CH3:6])[N:9]=[C:10]([O:16][CH:17]([CH2:21][C:22]2[C:23]([Cl:29])=[CH:24][CH:25]=[CH:26][C:27]=2[Cl:28])[C:18]([O:20][CH2:30][CH3:31])=[O:19])[N:11]=1
Reactant: CCBr
Reactant: COc1cc(OC)nc(OC(Cc2c(Cl)cccc2Cl)C(=O)O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1c(Cl)cccc1Cl)Oc1nc(OC)cc(OC)n1

Procedure:
50 ml of a N,N-dimethylformamide solution of 1.65 g of 2 (4,6-dimethoxypyrimidin-2-yl)oxy-3-(2,6-dichlorophenyl)propionic acid, 0.5 g of ethyl bromide 0.6 g of potassium carbonate was stirred at 80° C. for 2 hours under heating. The reaction solution was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed and dried. Then, the solvent was distilled off to obtain colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:12]([C:20]3[C:21]([O:26][CH3:27])=[N:22][CH:23]=[CH:24][CH:25]=3)[C:11]=2[OH:28])=[CH:4][CH:3]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>N1C=CC=CC=1.CCOC(C)=O>[C:16]([C:14]1[CH:13]=[C:12]([C:20]2[C:21]([O:26][CH3:27])=[N:22][CH:23]=[CH:24][CH:25]=2)[C:11]([OH:28])=[C:10]([CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:3][CH:4]=2)[CH:15]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ncccc1-c1cc(C(C)(C)C)cc(CCc2ccc(N)cc2)c1O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ncccc1-c1cc(C(C)(C)C)cc(CCc2ccc(NS(C)(=O)=O)cc2)c1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 61 %

Procedure:
step 5—To a solution of 54 (156 mg, 0.415 mmol) in pyridine (5 mL) at 0° C. was added methanesulfonyl chloride (0.050 mL, 0.643 mmol). The reaction was gradually warmed to RT and stirred for 1.5 h then diluted with EtOAc. The organic layer was washed sequentially with saturated aqueous CuSO4, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (10 to 50% EtOAc) to afford 115 mg (61%) of N-(4-{2-[5-tert-butyl-2-hydroxy-3-(2-methoxy-pyridin-3-yl)-phenyl]-ethyl}-phenyl)-methanesulfonamide (56) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([NH2:14])[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([S:23](Cl)(=[O:25])=[O:24])[CH:18]=1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:16][C:2]([F:1])([F:15])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([NH:14][S:23]([C:19]3[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=3)(=[O:25])=[O:24])[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: Nc1cc(OC(F)(F)F)cc2cccnc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(OC(F)(F)F)cc2cccnc12)c1cccnc1
Yield: 84.6 %

Procedure:
In a similar fashion using route 14 general procedure 27, 6-(trifluoromethoxy)quinolin-8-ylamine (Intermediate 46) (110 mg, 0.48 mmol), pyridine-3-sulfonyl chloride (Intermediate 17) (102 mg, 0.57 mmol), pyridine (0.08 ml, 0.96 mmol), DMAP (cat.) and DCM (5 ml) gave the title compound (150 mg, 85%) after purification by column chromatography with n-hexane/DCM (50:50) as the eluent.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11]1)=[O:7])(C)(C)C.[CH2:19]([N:22]=[C:23]=[O:24])[CH2:20][CH3:21].[NH2:25][C:26]1[C:34]([Cl:35])=[CH:33][C:29](C(O)=O)=[C:28]([O:36][CH3:37])[CH:27]=1>>[NH2:25][C:26]1[C:34]([Cl:35])=[CH:33][C:29]([C:6]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:23]([NH:22][CH2:19][CH2:20][CH3:21])=[O:24])[CH2:11]2)=[O:7])=[C:28]([O:36][CH3:37])[CH:27]=1
Reactant: CCCN=C=O
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCCN)C1
Product: CCCNC(=O)NCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)C1

Procedure:
3-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)propylamine (1.1 g) as starting compound was reacted and treated in the same manner as in Example 34 using n-propyl isocyanate (0.40 ml) and 4-amino-5-chloro-2-methoxybenzoic acid (0.87 g) to give 4-amino-5-chloro-2-methoxy-N-(1-(3-(3-n-propylureido)propyl)pyrrolidin-3-ylmethyl)benzamide.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1[N:7]=[CH:8][S:9][C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:12].N1C=CC=CC=1>ClCCl>[C:1]([O:12][CH:11]([C:10]1[S:9][CH:8]=[N:7][C:6]=1[CH3:5])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:3])[CH3:2]
Reactant: Cc1ncsc1C(O)c1ccccc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC(c1ccccc1)c1scnc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetyl chloride (0.6 ml) was added to a solution of 1-(4-methyl-5-thiazolyl) -1-phenylmethanol (800 mg) and pyridine (0.5 ml) in dichloromethane (30 ml) at 0° C. under an atmosphere of dry nitrogen. The mixture was allowed to warm room temperature and was then stirred overnight. Evaporation and purification of the residue by flash chromatography gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[C:5]2[C:10]([O:32][CH3:33])=[N:11][N:12]([C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]=2[CH:3]=1.[CH3:34][NH:35][C:36](Cl)=[O:37].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:34][NH:35][C:36](=[O:37])[O:9][CH2:8][C:6]1[C:5]2[C:10]([O:32][CH3:33])=[N:11][N:12]([C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:4]=2[CH:3]=[C:2]([Cl:1])[N:7]=1
Reactant: CNC(=O)Cl
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(CO)c12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)OCc1nc(Cl)cc2c1c(OC)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 35 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
A solution of (6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)methanol (Intermediate 35B, 200 mg, 0.439 mmol) and methylaminoformyl chloride (45.1 mg, 0.483 mmol) in DCM (1462 μl) was treated with DIEA (153 μl, 0.877 mmol) and stirred @ 35° C. for 1 h Reaction was dilluted in with DCM and concentrated in vacuo on silica. Material was purified by normal phase column chromotography eluting with Hex/EtOAc (0-40%) affording (6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)methyl methylcarbamate (172 mg, 0.335 mmol, 76% yield) as a white solid. MS: [M+H]+ m/z 513.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:23]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[C:10]1[C:11]([CH3:22])=[CH:12][C:13]([C:16]([NH:18][CH2:19][CH2:20]O)=[O:17])=[N:14][CH:15]=1.C(Cl)[Cl:34]>S(Cl)(Cl)=O>[Cl:34][CH2:20][CH2:19][NH:18][C:16]([C:13]1[CH:12]=[C:11]([CH3:22])[C:10]([CH:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[S:23]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])=[CH:15][N:14]=1)=[O:17]
Reactant: ClCCl
Reactant: Cc1cc(C(=O)NCCO)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Solvent: O=S(Cl)Cl
Product: Cc1cc(C(=O)NCCCl)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-N-(2-hydroxyethyl)-4-methylpyridine-2-carboxamide (120 mg, 0.258 mmol) obtained in Example 17 in methylene chloride (5 ml), thionyl chloride (100 μl) was added, and the mixture was stirred for 4 hours at room temperature. Thionyl chloride (100 μl) was added to the reaction solution, and the mixture was stirred for 1.5 hours at room temperature. The reaction solution was concentrated under reduced pressure, subsequently saturated aqueous sodium hydrogencarbonate was added thereto, and the mixture was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting concentration residue was subjected to silica gel column chromatography, and the fraction obtained from an elution with 35% ethyl acetate/hexane was concentrated under reduced pressure, to obtain the title compound (102 mg, 0.211 mmol, 82%) as a white solid.
Reaction SMILES: [CH2:1]([Cl:6])/[CH:2]=[CH:3]/[CH2:4][Cl:5].[CH3:7][N:8]([CH3:10])[CH3:9]>C1(C)C=CC=CC=1>[Cl-:5].[Cl:6][CH2:1][CH:2]=[CH:3][CH2:4][N+:8]([CH3:10])([CH3:9])[CH3:7]
Reactant: CN(C)C
Reactant: ClC/C=C/CCl
Solvent: Cc1ccccc1
Product: C[N+](C)(C)CC=CCCl
Product: [Cl-]
Temperature: 110 °C
Yield: 82 %

Procedure:
About 125 parts of 1,4-dichlorobutene-2 and 60 parts of trimethylamine are mixed with 700 parts toluene. This mixture is allowed to react (reflux) at 110°C. for 18 hours. This mixture yields about 82% 4-chloro-2-butenyltrimethylammonium chloride.
Reaction SMILES: Cl.C([CH:4]1[C:8]([CH3:10])([CH3:9])[C:7]2[CH:11]=[C:12]([C:19](=[NH:21])O)[CH:13]=[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=2[O:5]1)C.[CH2:22]([NH2:26])[CH2:23][CH2:24][CH3:25].CO.C(Cl)(Cl)[Cl:30]>O1CCOCC1>[ClH:30].[CH2:22]([NH:26][C:19]([C:12]1[CH:11]=[C:7]([C:8]([CH3:4])([CH3:10])[CH3:9])[C:6]2[O:5][CH2:18][C:15]([CH3:16])([CH3:17])[C:14]=2[CH:13]=1)=[NH:21])[CH2:23][CH2:24][CH3:25]
Reactant: ClC(Cl)Cl
Reactant: CCC1Oc2c(C(C)(C)C)cc(C(=N)O)cc2C1(C)C
Reactant: CCCCN
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCCCNC(=N)c1cc(C(C)(C)C)c2c(c1)C(C)(C)CO2
Reaction time: 3 h
Yield: 55.7 %

Procedure:
To a solution of ethyl 7-tert-butyl-2,3-dihydro-3,3-dimethylbenzofuran-5-carboximidic acid hydrochloride (400 mg, 1.29 mmol) in dioxane (10 mL) is added excess butylamine (0.5 mL). A color change from red to yellow is observed during the addition, and a precipitate forms. The reaction is also monitored by TLC (10% MeOH/CHCl3). After 3 h, the white solid is collected by filtration and washed with MeOH to give the title compound as a white powder (243 mg, 55.7%), mp=236°-237° C.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:33]([N:38]([CH3:46])[C:39](=[O:45])[C@H:40]([CH:42]([CH3:44])[CH3:43])[NH2:41])[C@@H:34]([CH3:37])[CH2:35][CH3:36])[CH2:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C@H:12]([O:31][CH3:32])[C@@H:13]([CH3:30])[C:14](=[O:29])[NH:15][C@H:16]([C:24]1[S:25][CH:26]=[CH:27][N:28]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:6].[CH:47]1[C:59]2[CH:58]([CH2:60][O:61][C:62]([NH:64][CH2:65][C:66]([CH3:71])([CH3:70])[C:67](O)=[O:68])=[O:63])[C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[C:51]=2[CH:50]=[CH:49][CH:48]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C)C=O>[CH:56]1[C:57]2[CH:58]([CH2:60][O:61][C:62]([NH:64][CH2:65][C:66]([CH3:71])([CH3:70])[C:67]([NH:41][C@H:40]([C:39]([N:38]([C@@H:33]([C@@H:34]([CH3:37])[CH2:35][CH3:36])[C@H:3]([O:2][CH3:1])[CH2:4][C:5]([N:7]3[CH2:11][CH2:10][CH2:9][C@H:8]3[C@H:12]([O:31][CH3:32])[C@@H:13]([CH3:30])[C:14](=[O:29])[NH:15][C@H:16]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)[CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:6])[CH3:46])=[O:45])[CH:42]([CH3:44])[CH3:43])=[O:68])=[O:63])[C:59]3[C:51](=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:52]=2[CH:53]=[CH:54][CH:55]=1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](N)C(C)C
Reactant: CC(C)(CNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)CNC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reaction time: 18 h
Yield: 60.5 %

Procedure:
To #86 (100 mg, 0.152 mmol, 1 eq.) in dichloromethane (4 mL, 0.038 M) and N,N-dimethylformamide (0.5 mL) was added #93 (51.6 mg, 0.152 mmol, 1 eq.) followed by diisopropylethylamine (80.0 μL, 0.457 mmol, 3 eq.) and HATU (89.8 mg, 0.229 mmol, 1.5 eq.). The reaction was stirred for 18 hours and then concentrated in vacuo. The residue was taken up in ethyl acetate (6 mL) and was washed with 1 M aqueous hydrochloric acid solution (2×2 mL) and with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was taken up in dichloromethane (250 mL) and filtered; the filtrate was concentrated in vacuo onto silica and purified by silica gel chromatography (Gradient: 0% to 50% acetone in heptane) to provide #94 (90 mg, 60%) as a white solid. LC-MS: m/z 979.8 [M+H+], 1002.7 [M+Na+], retention time=1.15 minutes; 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic product signals: δ [8.64 (br d, J=8.6 Hz) and 8.86 (br d, J=8.6 Hz), total 1H], 7.86-7.91 (m, 2H), [7.77 (d, J=3.3 Hz) and 7.79 (d, J=3.3 Hz), total 1H], 7.67-7.73 (m, 2H), [7.63 (d, J=3.3 Hz) and 7.65 (d, J=3.3 Hz), total 1H], 6.87-6.95 (m, 1H), [5.39 (ddd, J=11, 8, 4 Hz) and 5.52 (ddd, J=11.5, 9, 4 Hz), total 1H], [4.44 (dd, J=8.4, 8.4 Hz) and 4.55 (dd, J=8.4, 8.4 Hz), total 1H], 3.16, 3.20, 3.21 and 3.25 (4 s, total 6H), 2.96 and 3.06 (2 br s, total 3H), 0.69-0.77 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([O:14][CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[O:5][C:4](=[O:20])[CH:3]=1.[B-](F)(F)(F)[F:22].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([O:14][CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[O:5][C:4](=[O:20])[C:3]=1[F:22]
Reactant: F[B-](F)(F)F
Reactant: COc1ccc2c(N)cc(=O)oc2c1OC1CCCC1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: COc1ccc2c(N)c(F)c(=O)oc2c1OC1CCCC1
Reaction time: 18 h

Procedure:
A mixture of 4-amino-8-(cyclopentyloxy)-7-methoxy-2H-chromen-2-one (100 mg, 0.36 mmol, Example 3, Step 1), Selectfluor (160 mg, 0.45 mmol), and acetonitrile (1.5 mL) were stirred vigorously for 18 h, concentrated, and then purified by silica gel chromatography (7:3→1:4; hexanes:ethyl acetate) to give 4-amino-8-(cyclopentyloxy)-3-fluoro-7-methoxy-2H-chromen-2-one: MS (ESI): 294.0.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:14])[C:4]([C:6]1[CH:10]=[C:9]([N+:11]([O-])=O)[NH:8][N:7]=1)=[O:5]>O1CCCC1.CO>[NH2:11][C:9]1[NH:8][N:7]=[C:6]([C:4]([N:3]([O:2][CH3:1])[CH3:14])=[O:5])[CH:10]=1
Reactant: CON(C)C(=O)c1cc([N+](=O)[O-])[nH]n1
Solvent: CO
Solvent: C1CCOC1
Product: CON(C)C(=O)c1cc(N)[nH]n1
Reaction time: 18 h
Yield: 95.5 %

Procedure:
6.40 g (32.00 mmol) of N-methoxy-N-methyl-5-nitro-1H-pyrazole-3-carboxamide are dissolved in 500 ml of tetrahydrofuran/methanol mixture (50:50). The solution is purged under argon and 220 mg of palladium on charcoal (10%) are added. The solution is then degassed with hydrogen and stirred under a hydrogen atmosphere for 18 h. After degassing with argon, the solution is filtered on Celite and the solvent is concentrated to yield 5.2 g of 5-amino-N-methoxy-N-methyl-1H-pyrazole-3-carboxamide in the form of a white solid.