Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)=[C:7]([NH:22][C:23]([NH:25][C:26]2[C:31]([CH:32]([CH3:34])[CH3:33])=[CH:30][CH:29]=[CH:28][C:27]=2[CH:35]([CH3:37])[CH3:36])=[O:24])[C:6]1=[O:38])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].I[CH2:48][CH2:49][CH3:50]>CN(C=O)C.O>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:48][CH2:49][CH3:50])[CH:16]=2)=[C:7]([NH:22][C:23]([NH:25][C:26]2[C:27]([CH:35]([CH3:37])[CH3:36])=[CH:28][CH:29]=[CH:30][C:31]=2[CH:32]([CH3:33])[CH3:34])=[O:24])[C:6]1=[O:38])[CH2:2][CH2:3][CH3:4]
Reactant: CCCI
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(O)c2)c2cccnc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(OCCC)c2)c2cccnc21
Reaction time: 5 h
Yield: 82.8 %

Procedure:
To a suspension of N-{1-butyl-4-(3-hydroxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl }-N'-(2,6-diisopropylphenyl)urea (300 mg, 0.58 mmol), potassium carbonate (96 mg, 0.7 mmol) and potassium iodide (19 mg) in DMF (5 ml) was added 1-iodopropane (99 mg, 0.58 mmol) at room temperature, and the mixture was stirred at 40°-50° C. for five hours. After allowed to stand for cooling, the mixture was poured into water, and the mixture was extracted with ethyl acetate. The extracted was washed with water, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The resultant was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (20% ethyl acetate in hexane), and crystallized from ether/hexane to give the title compound (253 mg, 0.48 mmol).
Reaction SMILES: [CH:1]([CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1)=O.C1C2(CCN(C(OC(C)(C)C)=O)CC2)[CH2:17][CH:16]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[NH:15]1>>[CH2:6]1[C:3]2([CH2:17][CH:16]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[NH:15][CH2:1]2)[CH2:4][N:5]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: CC(C)(C)OC(=O)N1CC(C=O)C1
Reactant: CCOC(=O)C1CC2(CCN(C(=O)OC(C)(C)C)CC2)CN1
Product: CCOC(=O)C1CC2(CN1)CN(C(=O)OC(C)(C)C)C2
Yield: 93 %

Procedure:
This compound was prepared from 1,1-dimethylethyl 3-formyl-1-azetidinecarboxylate (650 mg, 3.5 mmol) in 93% yield in an analogous fashion to Intermediate 131 in Example 19.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:10][CH2:9][CH2:8][C:7]=1[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=2)[NH:13][CH:12]=1)=[O:5])[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=2)[NH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(c2c[nH]c3ccc(C#N)cc23)CCC1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)[C@@H]1CCC[C@@H]1c1c[nH]c2ccc(C#N)cc12
Reaction time: 1 h
Yield: 89 %

Procedure:
2-(5-Cyano-1H-indol-3-yl)-cyclopent-1-enecarboxylic acid ethyl ester (1.20 g, 4.3 mMol) was stirred and heated slightly until dissolved in methanol (250 mL). 10% palladium on carbon (300 mg) was added and the reaction was shaken in a Parr apparatus under hydrogen (50 psi) for 1 h. The reaction was filtered through Celite and sand, and the solvent was evaporated in vacuo. The product was obtained as a white solid (1.08 g, 89%). 1H NMR (400 MHz, CDCl3) δ 8.31 (1H, bs), 8.00 (1H, s), 7.37 (2H, AB, δv=18 Hz, J=8.4 Hz), 7.09 (1H, d, J=1.5 Hz), 3.63 (2H, m), 3.48 (1H, m), 3.28 (1H, q, J=6.5 Hz), 2.00–2.22 (5H, m), 1.76 (1H, m), 0.63 (3H, t, J=6.8 Hz); MS m/e 305.2 (M+Na).
Reaction SMILES: C([NH:9][NH2:10])(=O)C1C=CC=CC=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:23]([O:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][C:33]=1[C:41]([F:44])([F:43])[F:42])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].O.NN>C1COCC1>[CH2:23]([O:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH:9][NH2:10])=[O:37])=[CH:34][C:33]=1[C:41]([F:44])([F:43])[F:42])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: NNC(=O)c1ccccc1
Reactant: CCCCCCCCOc1ccc(C(=O)O)cc1C(F)(F)F
Agent: NN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(C(=O)NN)cc1C(F)(F)F
Temperature: 20.5 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
A 5 L 3 neck, round bottom flask was inerted and charged with CDI (153 g, 0.94 mol, 1.2 equiv), 4-(Octyloxy)-3-(trifluoromethyl)benzoic acid (D5A) (250 g based on theoretical output of previous step, 0.78 mol), THF (2.5 L) and stirred at 18 to 23° C. for 1 hour. A separate 12 L round bottom flask was inerted and charged with hydrazine monohydrate (235 g, 4.71 mol, 6 equiv) and THF (1.2 L). The contents of the first flask was charged to the second flask over 1 hour. During the addition, the temperature was maintained at T<25° C. Once the addition was complete, the mixture was stirred for 2 hours at 18 to 23° C., at which point TLC indicated the reaction was complete. The mixture was concentrated under vacuum at 35 to 40° C. until approximately 10 to 15% of the original volume was attained. Water (2 L) and brine (2 L) were charged to the mixture which was then extracted with dichloromethane (2×2.5 L). There was a small emulsion during each extraction. The organic phases were combined, washed with brine (500 mL), dried with magnesium sulfate, filtered over Celite, and concentrated to afford the title product (247 g, 94% yield, 96% AUC by HPLC) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>ClCCl>[C:16]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1cccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cccnc1)OCc1ccccc1
Reaction time: 8 h
Yield: 39.3 %

Procedure:
To a solution of 3-aminopyridine (10 g, 0.106 mol) and triethyl amine (16.3 mL, 0.117 mol) in dichloromethane (100 mL) at 0° C., was added benzyl chloroformate (15.2 mL, 0.106 mol) slowly. The reaction mixture was stirred overnight and was washed with water, saturated NaHCO3, dried over MgSO4, and evaporated. The residue was purified on a silica gel column to give the product (9.51 g)
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]#[N:9])[CH:2]=1.[OH-].[Na+].Br[CH2:14][CH2:15]Cl>C1(C)C=CC=CC=1.O>[C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([C:8]#[N:9])[CH2:15][CH2:14]2)[CH:2]=1
Reactant: ClCCBr
Reactant: Cc1cccc(CC#N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cccc(C2(C#N)CC2)c1
Temperature: 60 °C

Procedure:
To a stirred solution of 2-(m-tolyl)acetonitrile (4.2 g, 32 mmol) in toluene (15 mL) was added sodium hydroxide (30 mL, 50% w/w in water, 375 mmol), 1-bromo-2-chloroethane (9.3 mL, 112 mmol) and (n-Bu)4Br (0.5 g, 1.55 mmol). The mixture was heated at 60° C. overnight. After cooling to room temperature, the reaction mixture was diluted with water (40 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure and purified by silica gel chromatography to obtain the title compound.
Reaction SMILES: F[C:2](F)(F)[C:3](OC(=O)C(F)(F)F)=[O:4].C(O)(=O)C.P(=O)(O)(O)O.[Br:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[C:27]([C:34]([O:36][CH3:37])=[O:35])[N:28]2[CH3:33]>C(#N)C>[C:3]([C:26]1[C:25]2[C:29](=[CH:30][CH:31]=[CH:32][C:24]=2[Br:23])[N:28]([CH3:33])[C:27]=1[C:34]([O:36][CH3:37])=[O:35])(=[O:4])[CH3:2]
Reactant: COC(=O)c1cc2c(Br)cccc2n1C
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: O=P(O)(O)O
Solvent: CC#N
Solvent: CC(=O)O
Product: COC(=O)c1c(C(C)=O)c2c(Br)cccc2n1C
Reaction time: 0.17 h

Procedure:
33 ml of trifluoroacetic anhydride are added to a solution of 13.2 ml of acetic acid, of 1.6 ml of phosphoric acid and of 170 ml of acetonitrile, stirring is carried out for 10 min at room temperature and a solution of 20.6 g (77 mmol) of methyl 4-bromo-1-methyl-1H-indole-2-carboxylate in 120 ml of acetonitrile is added. The mixture is stirred for 4 h at room temperature and is poured onto water and extracted with ether. The organic phase is dried over sodium sulphate, the solvent is evaporated under reduced pressure and the residue is taken up in a mixture of cyclohexane and of dichloromethane. The precipitate is collected by filtration, washed with ether and dried under reduced pressure. 18.8 g (61 mmol) of product are obtained. The mother liquors are concentrated and the residue is purified by chromatography on a column of silica gel. 3.2 g (10 mmol) of additional product are isolated.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:6][NH:7][C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.C1OCCOCCOCCOCCOC1.[CH3:41][C:42]1[C:43]([S:48](Cl)(=[O:50])=[O:49])=[N:44][CH:45]=[CH:46][CH:47]=1>O1CCCC1.O>[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:6][N:7]([S:48]([C:43]2[C:42]([CH3:41])=[CH:47][CH:46]=[CH:45][N:44]=2)(=[O:50])=[O:49])[C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1cccnc1S(=O)(=O)Cl
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccnc1S(=O)(=O)n1cc(CN(C)C(=O)OC(C)(C)C)c(F)c1-c1cccnc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 47.4 %

Procedure:
To a suspension of sodium hydride (60% in oil, 20 mg) in tetrahydrofuran (2 mL) was added a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (161 mg), 15-crown-5 (110 mg), crude 3-methylpyridine-2-sulfonyl chloride (153 mg) in tetrahydrofuran (1.5 mL) at room temperature, and the mixture was stirred at room temperature for 72 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→11:9) to give the title compound as a colorless oil (yield 113 mg, 47%).
Reaction SMILES: [C:1]([O:7]CC)(=O)[CH2:2][C:3]([CH3:5])=O.N.C(OC(C1C(C2[N+:27]([O-:28])=[C:26]([CH3:29])[CH:25]=CC=2)C(C(OCC)=O)=C(C)NC=1C)=O)C>C(O)C>[CH3:29][C:26]1[CH:25]=[CH:5][CH:3]=[C:2]([CH:1]=[O:7])[N+:27]=1[O-:28]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1cccc(C)[n+]1[O-]
Agent: N
Solvent: CCO
Product: Cc1cccc(C=O)[n+]1[O-]

Procedure:
Analogously to the process described in Example 1 there is obtained from 24.1 g of 2-methylpyridine-6-carboxaldehyde-1-oxide, 40 ml of ethanol, 50.4 ml of ethyl acetoacetate and 20 ml of 25% aqueous ammonia, 2,6-dimethyl-4-(2-methyl-1-oxido-6-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester which, after recrystallisation from ethanol, melts at 224°-225° (with decomposition).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:13]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:14]([NH2:16])=[O:15])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10])#[N:2].[CH3:23][N:24]=[C:25]=[O:26]>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([CH:13]([CH2:17][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)[C:14]([NH:16][C:25]([NH:24][CH3:23])=[O:26])=[O:15])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:10])=[O:11])#[N:2]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(N)=O)cc1C#N
Reactant: CN=C=O
Solvent: Cc1ccccc1
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.7 %

Procedure:
A solution of 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (135 mg, 0.42 mmol) and methyl isocyanate (72 mg, 1.26 mmol) in toluene (1 mL) was heated under reflux for 15 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo to afford a yellow semi-solid. The semi-solid was treated with a solution of 2/1 hexanes/ethyl acetate (3 mL) and a white precipitate formed. The suspension was placed in the freezer for 1 h and then filtered to afford 1-[2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionyl]-3-methyl-urea (55 mg, 35%) as a white solid: mp 237-239° C.; FAB-HRMS m/e calcd for C18H23N3O4S (M+H)+378.1487, found 378.1483.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH:10]=2)=[CH:5][CH:4]=1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][CH:12]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2=CCC(=O)CC2)cc1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: COc1ccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1

Procedure:
The title compounds were prepared as white solids from the hydrogenation of 4-(4-methoxy-phenyl)-cyclohex-3-enone (as prepared in the previous step) followed by reductive amination of the corresponding ketone with N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedures described in Step C of Example 5 and Step C of Example 4.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([S:8](Cl)(=[O:10])=[O:9])[C:5]([CH3:12])=[N:4]1)[CH3:2].[OH-].[NH4+:14].O>O1CCCC1>[CH2:1]([N:3]1[CH:7]=[C:6]([S:8]([NH2:14])(=[O:10])=[O:9])[C:5]([CH3:12])=[N:4]1)[CH3:2]
Reactant: [NH4+]
Reactant: CCn1cc(S(=O)(=O)Cl)c(C)n1
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCn1cc(S(N)(=O)=O)c(C)n1
Reaction time: 1 h
Yield: 29.7 %

Procedure:
To a solution of 1-ethyl-3-methyl-1H-pyrazole-4-sulfonylchloride (0.154 g, 0.73 mmol, Matrix Scientific) in tetrahydrofuran (10 mL) was added dropwise an aqueous solution of 30% ammonium hydroxide (0.20 mL, 1.7 mmol). The reaction mixture was stirred for 1 hour, water (2 mL) was added, and the solvent was concentrated under reduced pressure to precipitate a solid. The solid was isolated by filtration, rinsed with water, and dried to afford 41 mg of the title compound. 1H NMR (CDCl3) δ 7.80 (s, 1H), 4.75 (br s, 1H), 4.11 (q, 2H), 2.44 (s, 3H), 1.49 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:24]12([CH2:34][NH2:35])[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:18])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:12]2)=[CH:7][C:3]=1[C:4]([NH:35][CH2:34][C:24]12[CH2:33][CH:28]3[CH2:27][CH:26]([CH2:32][CH:30]([CH2:29]3)[CH2:31]1)[CH2:25]2)=[O:6]
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(Cl)c(C(=O)O)c2)C1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)C1

Procedure:
Prepared as described in Example 5c) using (+/−)-2-chloro-5-[3-[[(1,1-dimethylethoxy)carbonyl]amino]-1-pyrrolidinyl]-benzoic acid (Example 7b, 0.070 g), N,N′-carbonyldiimidazole (0.033 g), 1-adamantanemethylamine (0.036 ml) and dimethylformamide (3 ml) to give the subtitle compound as a gum.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1>>[C:9]1([C:3]2[N:4]=[C:5]([NH2:8])[N:6]=[N:7][C:2]=2[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([C:16]([F:27])([F:26])[F:15])[CH:22]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: Nc1nnc(-c2cccc(C(F)(F)F)c2)c(-c2ccccc2)n1
Yield: 31.9 %

Procedure:
5-Phenyl-6-[3-(trifluoromethyl)phenyl]-1,2,4-triazin-3-amine (120 mg, 31%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.30 g, 1.19 mmol) and 3-trifluoromethylphenylboronic acid (0.25 g, 1.30 mmol) according to the general procedure of Example 1.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C[O-].[Na+].I[CH2:15][CH2:16][CH3:17]>C(O)C>[CH2:15]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([NH2:10])=[O:9])[CH2:16][CH3:17]
Reactant: NC(=O)c1ccccc1O
Reactant: CCCI
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCOc1ccccc1C(N)=O

Procedure:
A 130 gm. portion of salicylamide in 500 ml. of ethanol is reacted with 52.4 gm. of sodium methoxide and 164.9 gm. of 1-iodopropane by heating at reflux. The mixture is cooled, precipitated in 1500 ml. of water and the solid is recrystallized from hot ethanol giving o-propoxybenzamide.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[Br:11][C:12]1[CH:13]=[C:14]([N+]([O-])=O)[C:15]([C:18]#[N:19])=[N:16][CH:17]=1.O>CN(C=O)C>[Br:11][C:12]1[CH:13]=[C:14]([O:8][C:7]2[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=2)[C:15]([C:18]#[N:19])=[N:16][CH:17]=1
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Reactant: Cc1ncccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ncccc1Oc1cc(Br)cnc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.9 %

Procedure:
To a solution of 2-methylpyridin-3-ol (11.8 g, 108 mmol) in DMF at 0° C. was added sodium hydride (60% dispersion in oil, 4.32 g, 108 mmol) in small portions and the reaction was warmed to ambient temperature. To this mixture was added 5-bromo-3-nitropicolinonitrile (24.6 g, 108 mmol) and the reaction was stirred overnight at ambient temperature. The reaction was poured into water (1000 mL) and the aqueous layer extracted with EtOAc. The combined organic layers were washed with water and brine, dried over MgSO4 and concentrated in vacuo to yield 5-bromo-3-(2-methylpyridin-3-yloxy)picolinonitrile (15 g, 48%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[C:9]([CH2:11][N:12]([CH3:14])[CH3:13])[CH:8]=[C:7]([CH2:15][N:16]([CH3:18])[CH3:17])[C:6]=1[OH:19])[CH3:3].[OH-].[Li+:21]>>[CH3:3][N:2]([CH2:4][C:5]1[CH:10]=[C:9]([CH2:11][N:12]([CH3:13])[CH3:14])[CH:8]=[C:7]([CH2:15][N:16]([CH3:18])[CH3:17])[C:6]=1[O-:19])[CH3:1].[Li+:21]
Reactant: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Agent: [Li+]
Agent: [OH-]
Product: CN(C)Cc1cc(CN(C)C)c([O-])c(CN(C)C)c1
Yield: 100.1 %

Procedure:
Analogously to Example 19, starting from 53.1 g (0.2 mol) of 2,4,6-tris(dimethylaminomethyl)phenol and 9.2 g (0.2 mol) of lithium hydroxide there are obtained 54.3 g of lithium 2,4,6-tris(dimethylaminomethyl)phenolate in the form of an orange solid of which the elemental analysis is as follows:
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37](Cl)(=[O:39])=[O:38]>>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:22][CH:23]=2)[S:37]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=2)(=[O:39])=[O:38])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-n3cccn3)cc2)c1
Agent: Cl
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-n3cccn3)cc2)S(=O)(=O)c2ccccn2)c1

Procedure:
The title compound of Step A was prepared from {3-[(4-pyrazol-1-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester, of Step A of Example 13a, and pyridine-2-sulfonyl chloride hydrochloride, of Preparation 47, following the method described in Example 3, Step B with a reaction time of 2 h. 1H NMR (400 MHz, CDCl3) δ8.66 (m, 1H), 7.95 (d, 1H), 7.85 (m, 2H), 7.68 (d, 1H), 7.49 (d, 2H), 7.45 (m, 1H), 7.16 (d, 2H), 7.08 (t, IH), 6.70 (m, 3H), 6.43 (m, 1H), 4.49 (s, 2H), 4.44 (s, 2H), 4.38 (s, 2H), 1.46 (s, 9H); MS 535 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([O:10][CH3:11])=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1.[I:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[N+:22]([O-:24])=[O:23])[NH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[I:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[N+:22]([O-:24])=[O:23])[N:15]([CH2:2][C:3]2[C:4]([O:10][CH3:11])=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=2)[N:14]=1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(I)c12
Reactant: COc1nc(C)ccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc(C)ccc1Cn1nc(I)c2c([N+](=O)[O-])cccc21
Yield: 101.9 %

Procedure:
A mixture of 3-(bromomethyl)-2-methoxy-6-methylpyridine (500 mg, 2.314 mmol) and 3-iodo-4-nitro-1H-indazole (668.8 mg, 2.314 mmol) (prepared as in Example 1, step E) was dissolved in dry N,N-dimethylformamide (11.6 mL) with stirring under an atmosphere of nitrogen. Potassium carbonate (479.7 mg, 3.471 mmol) was added and the mixture was stirred at ambient temperature for 16 hours. The mixture was diluted with water (50 mL) and extracted into ethyl acetate. The combined organic extracts were washed with brine and dried over sodium sulfate. The solution was filtered and concentrated under reduced pressure to give 3-iodo-1-((2-methoxy-6-methylpyridin-3-yl)methyl)-4-nitro-1H-indazole (1.0 g) which was used without purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:10][C@H:11]([CH2:19][C:20]1[N:21]=[N:22][N:23]([CH2:25][CH2:26]O)[CH:24]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:42]C(F)(C(F)(F)F)C(F)(F)C(F)(F)S(F)(=O)=O.F.F.F.C(N(CC)CC)C>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:10][C@H:11]([CH2:19][C:20]1[N:21]=[N:22][N:23]([CH2:25][CH2:26][F:42])[CH:24]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1cn(CCO)nn1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1cn(CCF)nn1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 144 h

Procedure:
Di-tert-butyl (4R)—N-(tert-butoxycarbonyl)-4-{[1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl]methyl}-L-glutamate (74 mg, 152.7 μmol) was dissolved in tetrahydrofuran (5 ml) and triethyl amine (319 μl, 2.3 mmol), Nonafluorobutanesulfonyl fluoride (185 mg, 611 μmol), and Triethylamine trihydrofluoride (98 mg, 611 mmol) were added subsequently. The mixture was stirred at room temperature for 6 days. The mixture was than concentrated in vacuo, and the residue was purified by silica gel chromatography to yield 30 mg (40%) of slightly impure product, which was used in the following step.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[C:13]([OH:15])=[O:14])([CH3:3])[CH3:2].[CH3:16]O>S(=O)(=O)(O)O>[CH:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[C:13]([O:15][CH3:16])=[O:14])([CH3:3])[CH3:2]
Reactant: CO
Reactant: CC(C)c1ccc2[nH]nc(C(=O)O)c2c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1n[nH]c2ccc(C(C)C)cc12

Procedure:
A mixture of 5-isopropyl-1H-indazole-3-carboxylic acid (1.44 g) and conc. sulphuric acid (2 drops) in methanol (20 ml) was stirred under reflux for 1 day. After removal of solvent by evaporation, the resulting residue was dissolved with ethyl acetate. The ethyl acetate extract was washed successively with aqueous sodium hydrogen carbonate solution, water, and brine, and was dried over magnesium sulfate, and concentrated under reduced pressure to give methyl 5-isopropyl-1H-indazole-3-carboxylate (1.39 g).