Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Cl)(Cl)Cl.[NH2:5][C:6]1[CH:11]=[CH:10][N:9]([C@H:12]2[C@@H:16]([OH:17])[C@H:15]([O:18]CC3C=CC=CC=3)[C@:14]([CH2:29][O:30]CC3C=CC=CC=3)([CH:26]([F:28])[F:27])[O:13]2)[C:8](=[O:38])[N:7]=1.N1C=CC=CC=1.CO>ClCCl>[NH2:5][C:6]1[CH:11]=[CH:10][N:9]([C@H:12]2[C@@H:16]([OH:17])[C@H:15]([OH:18])[C@@:14]([CH:26]([F:28])[F:27])([CH2:29][OH:30])[O:13]2)[C:8](=[O:38])[N:7]=1
Reactant: Nc1ccn([C@@H]2O[C@@](COCc3ccccc3)(C(F)F)[C@@H](OCc3ccccc3)[C@@H]2O)c(=O)n1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: CO
Solvent: c1ccncc1
Product: Nc1ccn([C@@H]2O[C@@](CO)(C(F)F)[C@@H](O)[C@@H]2O)c(=O)n1
Temperature: -78 °C
Reaction time: 3 h
Yield: 47.9 %

Procedure:
BCl3 (3.7 mL, 3.7 mmol) was added to a solution of compound 37 (0.175 g, 0.37 mmol) in dichloromethane (10 mL) cooled to −78° C. The reaction was stirred at −78° C. for 3 h, then warmed to 25° C. and stirred for a further 12 h. The reaction mixture was cooled to 0° C. and then pyridine was added into the mixture, followed by methanol. The reaction mixture was evaporated to dryness under reduced pressure. Purification by prep-HPLC afforded the product 38 (0.052 g, 41%) as a white solid. LC-MS (M+H)+=294.1
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[S:16][C:15]([C:18]([NH:20][C@@H:21]4[CH:26]5[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]5)[CH2:22]4)=[O:19])=[CH:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[C:29]([Cl:34])(=[O:33])[CH:30]([CH3:32])[CH3:31]>>[ClH:34].[N:23]12[CH2:24][CH2:25][CH:26]([CH2:27][CH2:28]1)[C@@H:21]([NH:20][C:18]([C:15]1[S:16][C:17]3[C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([NH:2][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:4]=4)=[CH:10][CH:11]=[CH:12][C:13]=3[CH:14]=1)=[O:19])[CH2:22]2
Reactant: Nc1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1
Reactant: CC(C)C(=O)Cl
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1

Procedure:
50 mg (0.12 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide hydrochloride (Example 21) and 25.7 mg (0.24 mmol) of isobutyryl chloride are reacted together by general method F. 35.1 mg (64.9% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:24])[N:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=2)[CH3:12])[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH2:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([NH2:31])=[O:30].O.[C:36]([OH:40])(=[O:39])[CH:37]=O>>[C:29]([C:28]1[CH:27]=[C:26]([NH:25][CH:37]([C:18]2[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][N:11]([CH3:12])[C:10]([NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=3)=[O:24])=[CH:16][CH:17]=2)[C:36]([OH:40])=[O:39])[CH:34]=[CH:33][CH:32]=1)(=[O:30])[NH2:31]
Reactant: O=CC(=O)O
Reactant: NC(=O)c1cccc(N)c1
Reactant: CN(CCc1ccc(B(O)O)cc1)C(=O)Nc1cccc(C#N)c1
Solvent: O
Product: CN(CCc1ccc(C(Nc2cccc(C(N)=O)c2)C(=O)O)cc1)C(=O)Nc1cccc(C#N)c1
Yield: 64 %

Procedure:
Using a procedure analogous to that used to prepare 2D, 23D (170 mg, 0.52 mmol) was reacted with 3-aminobenzamide and glyoxylic acid monohydrate to afford 58A (157 mg, 64%) as an oil. MS (ESI) m/z 472.3 (M+H)+.
Reaction SMILES: BrC1C=C[C:5]([NH:9][CH:10]2[CH2:19][CH2:18][C:13]3([O:17][CH2:16][CH2:15][O:14]3)[CH2:12][CH2:11]2)=[C:6]([OH:8])C=1.Br[CH2:21][CH2:22][Br:23].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:23][CH:22]1[CH:10]([CH:11]2[CH:12]=[CH:12][CH2:11][CH2:10][CH2:19]2)[CH2:19][CH2:18][C:13]2([O:14][CH2:15][CH2:16][O:17]2)[CH2:21]1.[O:8]1[CH:6]=[CH:5][N:9]=[CH:10][CH2:19]1
Reactant: Oc1cc(Br)ccc1NC1CCC2(CC1)OCCO2
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: BrC1CC2(CCC1C1C=CCCC1)OCCO2
Product: C1=COCC=N1
Temperature: 180 °C
Yield: 58 %

Procedure:
A mixture of intermediate D10 (0.433 g, 1.319 mmol), 1,2-dibromoethane (0.341 ml, 3.958 mmol and potassium carbonate (0.912 g, 6.596 mmol) in DMF (10 ml) was heated at 180° C. for 15 min. under microwave irradiation. After cooling to r.t. the r.m. was filtered through diatomaceous earth. The filtrate was evaporated in vacuo. The crude residue was purified by column chromatography (silica gel; DCM as eluent). The desired fractions were collected and evaporated in vacuo to yield a colorless oil that crystallized to yield D12 (0.271 g, 58%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[S:13][C:12]([CH:14]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:16]1C=CC=CC=1.Cl.NO.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C>CN(C)C=O.O>[CH2:1]([O:8][C:9]1[S:13][C:12]([C:14]#[N:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccccc2)s1
Reactant: c1ccncc1
Agent: Cl
Agent: NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(OCc2ccccc2)s1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 17.9 %

Procedure:
The resulting 5-benzyloxy-thiophene-2-carbaldehyde (171 mg) was dissolved in N,N-dimethylformamide (4 mL), pyridine (82 μl, 1.02 mmol) and hydroxylamine hydrochloride (65 mg, 0.94 mmol) were added thereto, followed by stirring for 30 minutes at 60° C., then, cooled on an ice bath. 1,1′-Carbonyldiimidazole (635 mg, 3.92 mmol) was added, the solution was warmed again to 60° C. and stirred for 35 minutes, triethylamine (272 μl, 1.96 mmol) was added, and the solution was further stirred for 30 minutes. The reaction mixture was cooled to room temperature, water was added, and the solution was extracted with ethyl acetate. The organic layer was sequentially washed with an aqueous solution of oxalic acid, an aqueous solution of saturated sodium bicarbonate and brine, dried over anhydrous sodium sulfate, and then, concentrated in vacuo. The resulting residue was purified by silica gel chromatography (hexane-ethyl acetate), and the title compound (30 mg, 0.14 mmol, 14%) was obtained.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]2[C:10]([CH2:11][CH3:12])=[C:9]([C:13]([OH:15])=[O:14])[N:8]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]4[NH:33][N:32]=[N:31][N:30]=4)=[CH:19][CH:18]=3)[N:6]2[N:7]=1)[CH3:2].CN(C)C=O.[C:39]1([C:45](Cl)([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(N(CC)CC)C>[CH2:1]([C:3]1[N:4]=[C:5]2[C:10]([CH2:11][CH3:12])=[C:9]([C:13]([OH:15])=[O:14])[N:8]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]4[N:30]([C:45]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)([C:52]5[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=5)[C:46]5[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=5)[N:31]=[N:32][N:33]=4)=[CH:21][CH:22]=3)[N:6]2[N:7]=1)[CH3:2]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCc1nc2c(CC)c(C(=O)O)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)n2n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1nc2c(CC)c(C(=O)O)n(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
A mixture consisting of 8.83 g of 2,7-diethyl-5-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo[1,5-b][1,2,4]triazole-6-carboxylic acid, 60 ml of N,N-dimethylformamide, 2.82 ml of triethylamine and 5.66 g of triphenylmethyl chloride was stirred overnight at room temperature. After removing the solvent by distillation under a reduced pressure, the thus obtained residue was mixed with 250 ml of ethyl acetate and then washed with 150 ml of water. Thereafter, the ethyl acetate layer was stirred overnight at room temperature, and the solid material thus precipitated was collected by filtration to give 6.98 g of 2,7-diethyl-5-[[2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo[1,5-b][1,2,4]triazole-6-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]([C:13](OC)=[O:14])[CH2:5]2.[BH4-].[Na+]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]([CH2:13][OH:14])[CH2:5]2
Reactant: COC(=O)C1Cc2cc(Br)cnc2NC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1Nc2ncc(Br)cc2CC1CO
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a suspension of methyl 6-bromo-2-oxo-1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxylate (285 mg, 1 mmol) in THF (10 mL) under Argon at room temperature was added sodium borohydride (151 mg, 4 mmol). The reaction mixture was stirred at 60° C. for 4 h, then diluted in EtOAc and washed four times with a NH4Cl solution (pH=6.5). The white organic phase was filtered to give the title compound contained by impurities as a white solid (59 mg). The filtrate was dried over sodium sulphate, filtered and concentrated in vacuo to give a yellow solid (143 mg). The crude was purified by preparative TLC (eluent: dichloromethane/MeOH 93/7) to give the title compound (10 mg, 4%) as a white solid.
Reaction SMILES: [H][H].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>>[C:3]1(=[O:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: Oc1ccccc1
Reactant: [H][H]
Product: O=C1CCCCC1
Product: OC1CCCCC1

Procedure:
Hydrogen and phenol were then passed over the catalyst in a molar ratio of 4:1 at 150° C. and under a loading of 1.0 g of phenol/ml of catalyst×hour: After a run-in time of 150 hours, a cyclohexanone/cyclohexanol ratio of 4:1 was obtained at a conversion of 99.9% and a selectivity of 99.9%. After 600 hours, the experiment was discontinued (compare comment on Example 6).
Reaction SMILES: [CH3:1][CH:2]([CH2:18][CH:19]=C)[CH2:3][C@@H:4]1[CH2:8][N:7]([C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[C:6](=[O:17])[CH2:5]1.I([O-])(=O)(=O)=[O:22].[Na+]>CC(O)(C)C.C1COCC1.O.O=[Os](=O)(=O)=O>[OH:22][CH2:19][CH2:18][CH:2]([CH3:1])[CH2:3][C@@H:4]1[CH2:8][N:7]([C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[C:6](=[O:17])[CH2:5]1
Reactant: C=CCC(C)C[C@H]1CC(=O)N([C@@H](C)c2ccccc2)C1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Solvent: O
Product: CC(CCO)C[C@H]1CC(=O)N([C@@H](C)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
OsO4 (2 mL of a 4% wt solution in t-BuOH) was added to the alkene 88 (5.8 g, 0.021 mol) in THF/H2O (3:1, 100 mL). After 1 hour, sodium periodate (11.4 g, 0.053 mol) was added. After 2 hours, the suspension was filtered and the solids washed with dichloromethane. The filtrate was concentrated and the residue azeotroped with toluene. The residue was dissolved in ethanol and sodium borohydride (2.5 g) added. The suspension was stirred at room temperature overnight. 1N citric acid was added and the mixture diluted with ether. The resultant two layers were separated and the aqueous phase was extracted with ether and the combined organic dried (MgSO4) and concentrated. Flash chromatography (1:1 hexane/EtOAc) of the residue gave an oil. 4.2 g, 73%. MS, m/z (relative intensity): 276 [M+H, 100%].
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([CH3:8])=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:17]([C:19]1[CH:20]=[N:21][CH:22]=[C:23]([CH:26]=1)[C:24]#[N:25])#[CH:18]>C(#N)C.C(OCC)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:9][C:4]1[CH:3]=[C:2]([C:18]#[C:17][C:19]2[CH:20]=[N:21][CH:22]=[C:23]([CH:26]=2)[C:24]#[N:25])[CH:7]=[CH:6][C:5]=1[CH3:8]
Reactant: C#Cc1cncc(C#N)c1
Reactant: Cc1ccc(I)cc1C
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(C#Cc2cncc(C#N)c2)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
Combine 4-iodo-o-xylene (0.362 g, 1.561 mmol), bis(triphenylphosphine)palladium (II) dichloride (55 mg, 0.078 mmol), and copper (I) iodide (30 mg, 0.156 mmol) in triethylamine (0.653 mL, 4.683 mmol) and stir under nitrogen for 5 min at 80° C. Add a solution of 5-ethynylnicotinonitrile, (prepared essentially as described in PREPARATION 4), (200 mg, 1.561 mmol) in anhydrous acetonitrile (2.50 mL), and stir under nitrogen overnight. Cool to room temperature and dilute with diethyl ether. Wash with a saturated aqueous solution of sodium bicarbonate, dry (sodium sulfate), filter, and concentrate. Purify the residue by silica gel chromatography, eluting with 95:5 to 50:50 dichloromethane:ethyl acetate, to give the title compound as a yellow solid (225 mg, 62%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:13][CH:10]([CH:11]=[CH2:12])[CH:4]([CH:5]([OH:9])[CH2:6][C:7]#[N:8])[O:3]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[CH:32]([O:34][CH2:35][CH3:36])=[CH2:33].[Na].[H][H]>C(Cl)Cl>[CH3:1][C:2]1([CH3:14])[O:13][CH:10]([CH:11]=[CH2:12])[CH:4]([CH:5]([O:9][CH:32]([O:34][CH2:35][CH3:36])[CH3:33])[CH2:6][C:7]#[N:8])[O:3]1
Reactant: [H][H]
Reactant: C=COCC
Reactant: C=CC1OC(C)(C)OC1C(O)CC#N
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C=CC1OC(C)(C)OC1C(CC#N)OC(C)OCC
Reaction time: 2 h
Yield: 91 %

Procedure:
4,5-(Dimethylmethylenedioxy)-3-hydroxy-6-heptenenitrile (3.54 g) was dissolved in 50 ml of methylene chloride under a nitrogen atmosphere, and a catalytic amount of pyridinium p-toluenesulfonate was added under ice cooling, followed by adding dropwise 2.57 ml of ethyl vinyl ether. After stirring for 2 hours, the reaction mixture was poured into a saturated sodium hydrogen aqueous solution, and extracted with diethyl ether. The organic layer was washed with a saturated sodium chloride aqueous solution. The obtained organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to provide 4.41 g of 4,5-(dimethylmethylenedioxy)-3-(1-ethoxyethoxy)-6-heptenenitrile having the following properties (yield 91%).
Reaction SMILES: [I:1][C:2]1[NH:6][C:5]([C@@H:7]([NH:17]C(=O)OCC2C=CC=CC=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:15][CH3:16])=[O:14])=[N:4][CH:3]=1.Br>C(Cl)Cl.CC(O)=O.CO>[NH2:17][C@H:7]([C:5]1[NH:6][C:2]([I:1])=[CH:3][N:4]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:15][CH3:16])=[O:14]
Reactant: CNC(=O)CCCCC[C@H](NC(=O)OCc1ccccc1)c1ncc(I)[nH]1
Agent: Br
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: CNC(=O)CCCCC[C@H](N)c1ncc(I)[nH]1
Reaction time: 1 h

Procedure:
A solution of D6 in DCM (0.2 M) was treated with an excess of HBr solution in AcOH at 0° C. and the reaction mixture was stirred at this temperature for 1 h. Then solvents were removed under reduced pressure and excess reagents were removed by repeated addition of toluene and evaporation of the solvent. The residue obtained was dissolved in MeOH, passed through a SCX resin cartridge and the cartridge washed with MeOH. Then, the cartridge was treated with a 7N solution of NH3 in MeOH and the organic solution was concentrated under reduced pressure to give the title compound as a white powder. MS (ES+) C11H19IN4O: 351 (M+H)+.
Reaction SMILES: C([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[O:23][S:24]([C:27]([F:30])([F:29])[F:28])(=[O:26])=[O:25])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.O>[OH:5][CH:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[O:23][S:24]([C:27]([F:30])([F:28])[F:29])(=[O:25])=[O:26])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccccc2c1OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOC(=O)C(O)c1c(C)cc2ccccc2c1OS(=O)(=O)C(F)(F)F

Procedure:
A solution of ethyl 2-tert-butoxy-2-(3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate (6.0 grams, ˜13 mmol, semi pure) in DCM (60 mL) was treated with TFA (6.0 mL) at 23° C. The reaction was diluted with H2O (60 mL) and the organic phase collected. The aqueous layer was extracted with DCM (2×30 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue (5.5 grams) was used in the next reaction without further purification. 1H NMR (400 MHz, CDCl3): 8.08-8.06 (m, 1H), 7.81-7.78 (m, 1H), 7.69 (s, 1H), 7.62-7.55 (m, 2H), 5.81 (app. s, 1H), 4.35-4.21 (m, 2H), 3.26 (app. s, broad, 1H), 2.50 (s, 3H), 1.21 (t, J=7.0 Hz, 3H).
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5](I)=[CH:4][N:3]=1.[CH:10]1([OH:17])[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1.[C:18]1([C:24]#[CH:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[F:8][C:7]1[C:2]([O:16][CH:13]2[CH2:14][CH2:15][CH:10]([OH:17])[CH2:11][CH2:12]2)=[N:3][CH:4]=[C:5]([C:25]#[C:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=1
Reactant: Fc1cc(I)cnc1F
Reactant: OC1CCC(O)CC1
Reactant: C#Cc1ccccc1
Product: OC1CCC(Oc2ncc(C#Cc3ccccc3)cc2F)CC1

Procedure:
The title compound, yellow oil, MS: m/e=312.1 (M+H+), can be prepared in accordance with the general method of example 18 from 2,3-difluoro-5-iodopyridine, cyclohexane-1,4-diol and phenylacetylene.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].O=S(Cl)Cl.[CH3:19]O>>[F:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:19])=[O:8]
Reactant: Cc1c(C(=O)O)cc(F)cc1[N+](=O)[O-]
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(F)cc([N+](=O)[O-])c1C
Yield: 25 %

Procedure:
To a solution of conc. H2SO4 (700 mL) was added portion-wise 5-fluoro-2-methylbenzoic acid (80 g, 520 mmol) at −5˜0° C. Then a mixture of conc. HNO3 (60.4 g, 624 mmol) in conc. H2SO4 (60 mL) was added drop-wise at −5˜0° C. in a period of about 1.5 hrs. After the addition, the mixture was stirred at this temperature for 2 hrs. TLC (petroleum ether/EtOAc=1:1) showed the reaction was complete. The mixture was poured into crash ice with vigorous stirring and the precipitate was collected by filtration. The precipitate was dissolved in EtOAc, washed with brine, dried over anhydrous Na2SO4, concentrated to give crude 5-fluoro-2-methyl-3-nitrobenzoic acid (54 g). A solution of this crude 5-fluoro-2-methyl-3-nitrobenzoic acid (54 g) in dry methanol (500 mL) was cooled to 0° C., SOCl2 (64.52 g, 542.3 mmol) was added drop-wise. After the addition, the mixture was heated to reflux for 16 hrs. TLC (petroleum ether/EtOAc=1:1) showed the reaction was complete. Solvent was removed under reduced pressure to give crude product. The crude product was purified by silica gel chromatography (petroleum ether to petroleum ether/EtOAc=50:1) to give methyl 5-fluoro-2-methyl-3-nitrobenzoate (28 g, yield 25% for two steps) as a white solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 2.59 (s, 3H), 3.95 (s, 3H), 7.60-7.63 (dd, 1H), 7.74-7.77 (dd, 1H); LC-MS (ESI) m/z: 214 (M+1)+, 216 (M+3)+.
Reaction SMILES: [CH2:1]([OH:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:9][NH:10][CH2:11][C:12]#[CH:13].[CH2:14]=O.[OH-].[Na+]>>[CH3:9][N:10]([CH2:14][C:5]1[O:6][C:2]([CH2:1][OH:7])=[CH:3][CH:4]=1)[CH2:11][C:12]#[CH:13]
Reactant: OCc1ccco1
Reactant: C#CCNC
Reactant: C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C#CCN(C)Cc1ccc(CO)o1
Temperature: 0 °C

Procedure:
To furfuryl alcohol (2.49 g; 25.4 mmoles) which was cooled in an ice-water bath to 5° was added N-methylpropargylamine hydrochloride (4.0 g; 37.9 mmoles) and 40% formalin (3.13 ml; 41.7 mmoles), and the mixture stirred while allowed to reach ambient temperature. After 1 hour of stirring the solution was allowed to stand at ambient temperature for 41/2 days. The reaction mixture was poured into ice water, made strongly basic with 40% aqueous NaOH and extracted with five portions of methylene chloride. The combined organic phase was dried, filtered and evaporated under reduced pressure to give the product as an oil (quantitative yield). Vacuum distillation yielded the title compound, bp 102°-106°/0.3 mm Hg.
Reaction SMILES: [CH3:1][C:2]1[N:3]([NH2:11])[C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.Cl.Cl[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1>>[CH3:1][C:2]1[N:3]([NH:11][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1cc2ccccc2n1N
Reactant: Clc1ccncc1
Agent: Cl
Product: Cc1cc2ccccc2n1Nc1ccncc1

Procedure:
The title compound was prepared from 2-methyl-1H-indol-1-amine and 4-chloropyridine hydrochloride at 120° C. for 30 minutes in substantially the same manner as in Example 17, m.p. 75°-78° C.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH2:26][CH2:27][C:28]5[N:29]([C:31]([C:34]([F:37])([F:36])[F:35])=[N:32][N:33]=5)[N:30]=4)[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[CH2:6][CH2:5]1)(=O)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>>[CH3:38][S:39]([N:4]1[CH2:5][CH2:6][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([N:19]3[CH2:20][CH2:21][N:22]([C:25]4[CH2:26][CH2:27][C:28]5[N:29]([C:31]([C:34]([F:35])([F:36])[F:37])=[N:32][N:33]=5)[N:30]=4)[CH2:23][CH2:24]3)=[CH:17][CH:18]=2)[CH2:8][CH2:9]1)(=[O:41])=[O:40]
Reactant: CC(=O)N1CCN(CCOc2ccc(N3CCN(C4=Nn5c(nnc5C(F)(F)F)CC4)CC3)cc2)CC1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)N1CCN(CCOc2ccc(N3CCN(C4=Nn5c(nnc5C(F)(F)F)CC4)CC3)cc2)CC1
Yield: 75 %

Procedure:
Obtained in 75% yield by an analogous method to Example 26, starting from 6-[4-[4-[2-(piperazin-1-yl)ethoxy]phenyl]piperazin-1-yl]-3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in Example 32, preparation of starting materials) and methanesulfonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([OH:12])=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CN(C=O)C>C(Cl)Cl>[CH2:20]([O:12][C:8]1[CH:9]=[N:10][C:11]2[C:6]([CH:7]=1)=[N:5][CH:4]=[CH:3][C:2]=2[Cl:1])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Oc1cnc2c(Cl)ccnc2c1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Clc1ccnc2cc(OCc3ccccc3)cnc12
Temperature: 65 °C

Procedure:
A pyrex reaction tube was charged with 8-chloro-1,5-naphthyridin-3-ol (165 mg, 914 μmol), potassium carbonate (631 mg, 4568 μmol), 1-(chloromethyl)benzene (376 μl, 4568 μmol) and 3.7 mL DMF. The tube was sealed and the mixture was heated at 65° C. for 3 h. The reaction was diluted with DCM and washed with water. The organic portion was dried, filtered, and concentrated. The crude material was purified by silica gel chromatography, 0-25% EtOAc in DCM to provide product as a white solid. MS: [M+H]=271.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][N:10]3[C:15]=2[C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[N:13][C:12]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH:31]=2)C#N)=[N:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:32][OH:33].[OH-:34].[K+]>O1CCOCC1.O.C(Cl)(Cl)Cl>[C:1]1([C:7]2[CH:8]=[CH:9][N:10]3[C:15]=2[C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[N:13][C:12]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH:31]=2)[C:32]([OH:34])=[O:33])=[N:11]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)c1
Reactant: CO
Reactant: [OH-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(O)c1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)c1
Temperature: 95 °C
Yield: 49 %

Procedure:
To a stirred solution of 5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)nicotinonitrile (50.0 mg, 0.124 mmol) in dioxane (5 mL)/MeOH (2 mL) was added KOH (34.8 mg, 0.620 mmol) dissolved in water (2 mL) in a pressure tube. The contents were heated at 95° C. for 12 h. The reaction mixture was allowed to cool and concentrated under reduced pressure to give a white solid. The solid was dissolved in CHCl3 and washed with 1.5 N HCl (5 mL) and the organic layer was separated and dried over anhydrous Na2SO4, filtered and concentrated to give 5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)nicotinic acid (24.0 mg, 49.0%) as an off-white solid. LCMS Condition B-23: retention time 1.64, [M+1]=423.2. HPLC Condition B-1: retention time 5.80 min, purity 98.80%. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.94 (d, J=4.4 Hz, 2H), 6.83 (d, J=2.8 Hz, 1H), 7.21-7.52 (m, 8H), 7.89 (t, J=1.7 Hz, 1H), 7.96 (d, J=2.8 Hz, 1H), 8.38 (br s, 1H), 8.98 (s, 1H), 9.19 (s, 1H), 9.52 (s, 1H).