Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])=[N:11][N:12]3[C:17]([N:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[CH:16][C:15]([CH3:24])=[N:14][C:13]=23)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[C:41](Cl)(=[O:43])[CH3:42]>C(Cl)Cl>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:10]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])=[N:11][N:12]3[C:17]([N:18]4[CH2:19][CH2:20][N:21]([C:41](=[O:43])[CH3:42])[CH2:22][CH2:23]4)=[CH:16][C:15]([CH3:24])=[N:14][C:13]=23)=[CH:7][CH:8]=1
Reactant: CC(=O)Cl
Reactant: Cc1cc(N2CCNCC2)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCN(c2cc(C)nc3c(-c4ccc(Cl)cc4)c(-c4ccccc4Cl)nn23)CC1
Reaction time: 0.33 h

Procedure:
To a mixture of 3-(4-chlorophenyl)-2-(2-chlorophenyl)-5-methyl-7-piperazin-1-yl-pyrazolo[1,5-a]pyrimidine, hydrochloride salt (6A-3; 25 mg, 0.049 mmol), Argonaut™ PS-DIEA (63 mg, 0.24 mmol) and diisopropylethylamine (0.020 ml, 0.11 mmol) in methylene chloride (1 ml), was added acetyl chloride (0.005 ml, 0.074 mmol). After stirring 20 minutes, the reaction was filtered, concentrated and then purified on a Biotage™ Flash 12S column using 0–50% ethyl acetate in hexanes as eluant to afford, after trituration from hexanes/methylene chloride, 7A-1 (19 mg, 79%) as a solid: +ESI MS (M+1) 480.3; 1H NMR (400 MHz, CD3OD) δ 7.49–7.34 (m, 6H), 7.23 (d, J=8.7 Hz, 2H), 6.14 (s, 1H), 3.84–3.78 (m, 4H), 3.71–3.61 (m, 4H), 2.57 (s, 3H), 2.10 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:19])[NH:6][C:7]2[C:12]([C:13]=1O)=[CH:11][C:10]1[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=1[CH:8]=2)(=O)[CH3:2].[NH2:20][NH2:21]>Cl.CC(N(C)C)=O>[CH3:2][C:1]1[NH:20][N:21]=[C:13]2[C:12]3[CH:11]=[C:10]4[CH:15]=[CH:16][CH:17]=[CH:18][C:9]4=[CH:8][C:7]=3[NH:6][C:5](=[O:19])[C:4]=12
Reactant: CC(=O)c1c(O)c2cc3ccccc3cc2[nH]c1=O
Reactant: NN
Agent: Cl
Solvent: CC(=O)N(C)C
Product: Cc1[nH]nc2c1c(=O)[nH]c1cc3ccccc3cc12
Temperature: 140 °C

Procedure:
A mixture of 3-acetyl-4-hydroxybenzo[g]quinolin-2(1H)-one (1-4) (3.95 g, 15.6 mmol, 1.0 equiv), hydrazine (0.74 ml, 0.75 g, 23.4 mmol, 1.5 equiv), and catalytic conc. HCl (2 drops) in DMA (30 ml) were heated to 140° C. under nitrogen for 55 hours. The solution was cooled and the solid precipitate was filtered, washed with methanol (100 ml×3), and dried to yield 3-methyl-2,5-dihydro-4H-benzo[g]pyrazolo[4,3-c]quinolin-4-one (1-5) as a tan solid. 1H NMR (500 MHz, DMSO-d6)) δ 11.14 (s, 1H), 8.61 (s, 1H), 7.97 (d, 1H, J=8.0 Hz) 7.85 (d, 1H, J=8.5 Hz), 7.70 (s, 1H), 7.50 (m, 1H), 7.41 (m, 1H), 2.59 (s, 3H). LRMS m/z/z (M+H) 250.2 found, 250.1 required.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Cl:13][C:14]1[C:15](F)=[CH:16][C:17]([F:27])=[C:18]([CH:26]=1)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CS(C)=O>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][O:12][C:15]3[C:14]([Cl:13])=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[C:17]([F:27])[CH:16]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: OCC1CCC2(CC1)OCCO2
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2CCC3(CC2)OCCO3)cc1F
Temperature: 75 °C
Yield: 43.5 %

Procedure:
To a mixture of 1,4-dioxaspiro[4.5]decan-8-ylmethanol (5.00 g, 29.0 mmol) and tert-butyl 5-chloro-2,4-difluorobenzoate (7.22 g, 29.00 mmol) in anhydrous dimethyl sulfoxide (30 mL) was added cesium carbonate (18.90 g, 58.00 mmol) and the reaction mixture was heated at 70-80° C. for 4 hours. After cooling to ambient temperature, ethyl acetate was added (200 mL) and the mixture was washed with water (4×15 mL), brine (2×15 mL); dried over anhydrous sodium sulfate, and filtered. After concentration of the filtrate in vacuo, the residue was purified by silica gel column chromatography using 0-30% ethyl acetate in hexanes as eluent to afford the title compound as a colorless oil (5.06 g, 44%): 1H NMR (300 MHz, CDCl3) 7.85 (d, J=7.7 Hz, 1H), 6.60 (d, J=12.2 Hz, 1H), 3.95-3.93 (m, 4H), 3.83 (d, J=6.3 Hz, 2H), 1.98-1.87 (m, 4H), 1.84-1.71 (m, 4H), 1.64-1.56 (m, 1H), 1.56 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:13]1([C:19]2[N:23]=[C:22]([CH2:24][C:25](O)=[O:26])[O:21][N:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1CCCCC1>C(O)C>[CH2:11]([O:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:24]([C:22]3[O:21][N:20]=[C:19]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:23]=3)[C:25](=[O:26])[O:1]2)=[CH:6][CH:7]=1)[CH3:12]
Reactant: O=C(O)Cc1nc(-c2ccccc2)no1
Reactant: CCOc1ccc(C=O)c(O)c1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOc1ccc2cc(-c3nc(-c4ccccc4)no3)c(=O)oc2c1

Procedure:
5 parts of 2-hydroxy-4-ethoxy benzaldehyde and 7 parts of the ethyl ester of 3-phenyl-1,2,4-oxadiazole-5-acetic acid are dissolved in 80 parts of ethanol, then 0.3 part of piperidine is added. The mixture is heated under reflux for one hour, then the precipitate obtained after cooling is filtered. 8 parts of 7-ethoxy-3-(3-phenyl 1,2,4-oxadiazol-5-yl) coumarin are obtained which melts at 229° C. after crystallization in dioxane.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]([F:26])([F:25])[C:14]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:15]=1[NH2:16]>>[F:12][C:13]([F:25])([F:26])[C:14]1[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][C:15]=1[NH:16][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=1[OH:11]
Reactant: Cc1ccc(O)c(C(=O)O)c1
Reactant: Nc1cc(C(F)(F)F)ccc1C(F)(F)F
Product: Cc1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)ccc2C(F)(F)F)c1
Yield: 1.5 %

Procedure:
Using 5-methylsalicylic acid and 2,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:18])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]2[N:11]([CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:13][CH:14]=1.[CH3:19][N:20]1[C:24]([CH3:25])=[C:23]([C:26](O)=[O:27])[C:22](=[O:29])[N:21]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([NH:18][C:26]([C:23]2[C:22](=[O:29])[N:21]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:20]([CH3:19])[C:24]=2[CH3:25])=[O:27])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]2[N:11]([CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:13][CH:14]=1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Reactant: Nc1ccc(Oc2ccnn3cccc23)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnn4cccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 50 °C
Yield: 29.2 %

Procedure:
To a solution of 3-fluoro-4-(pyrrolo[1,2-b]pyridazin-4-yloxy)-phenylamine (50 mg, 0.206 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (32 mg, 0.137 mmol) dissolved in dimethylformamide (3 mL), HATU (78 mg, 0.206 mmol) and triethylamine (0.05 mL, 0.343 mmol) were sequentially added and heated at 50° C. for 7 hours. The resulting mixture was concentrated and the resulting residue was extracted with dichloromethane and water. After phase separation, the organic layer was washed with sodium chloride aqueous solution, dried with magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate:hexane=1:3) to give the target compound as a white solid (16 mg, 0.04 mmol, 25% yield).
Reaction SMILES: [Cl-].[F:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Zn+])=[CH:5][CH:4]=1.[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[N:21](Cl)[C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3C=[N:17][C:16]=2[CH:27]=1>>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[NH:21][C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[C:7]([C:6]3[CH:9]=[CH:10][C:3]([F:2])=[CH:4][CH:5]=3)=[N:17][C:16]=2[CH:27]=1
Reactant: Clc1ccc2c(c1)N=Cc1ccccc1N2Cl
Reactant: Fc1ccc(C[Zn+])cc1
Agent: [Cl-]
Product: Fc1ccc(C2=Nc3cc(Cl)ccc3Nc3ccccc32)cc1
Yield: 71.3 %

Procedure:
4-Fluorobenylzinc chloride (0.5 ml, 0.5 M in THF, 0.4 mmol) and 8,5-dichloro-5H-dibenzo[b,e][1,4]diazepine (160FE64) (26 mg, 0.1 mmol) were reacted according GP10 to give 23 mg of the title compound (160FE70). MS (ESI) 323 (MH+). Purity for MH+ (UV/MS) 98/100.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][CH2:21][CH3:22].[N:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][CH2:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:29]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:30])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN
Reactant: O=C(Cl)N1CCOCC1
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)N1CCOCC1
Yield: 47.1 %

Procedure:
Using the general method of Example 149, 1-(3-aminopropyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g. 3.36 mmol) was reacted with 4-morpholinecarbonyl chloride (830 mg, 5.55 mmol) to provide 650 mg of N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]morpholine-4-carboxamide as a white powder, m.p. 193.4-194.6° C. Analysis: Calculated for C22H30N6O2: %C, 64.37; %H, 7.37; %N, 20.47; Found: %C, 64.00; %H, 7.32; %N, 20.16.
Reaction SMILES: [C:1](OC1C2C=CC(C#CC3C=CC(C(OCC)=O)=CC=3)=CC=2C(C)(C)CC=1)(=[O:3])[CH3:2].[CH3:30][C:31]1([CH3:53])[C:40]2[CH:39]=[CH:38][C:37]([C:41]#[C:42][C:43]3[CH:51]=[CH:50][C:46]([C:47]([OH:49])=[O:48])=[CH:45][CH:44]=3)=[CH:36][C:35]=2[C:34](=[O:52])[CH2:33][CH2:32]1>>[C:1]([O:52][C:34]1[C:35]2[CH:36]=[C:37]([C:41]#[C:42][C:43]3[CH:44]=[CH:45][C:46]([C:47]([OH:49])=[O:48])=[CH:50][CH:51]=3)[CH:38]=[CH:39][C:40]=2[C:31]([CH3:53])([CH3:30])[CH2:32][CH:33]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC=C3OC(C)=O)cc1
Reactant: CC1(C)CCC(=O)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Product: CC(=O)OC1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(5-acetoxy-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 105), 100.0 mg (0.31 mmol) of 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]benzoic acid (Compound 8) was converted into the title compound (white solid) using 0.08 ml (0.94 mmol) of acetic anhydride and 30 mg (0.16 mmol) of p-toluenesulfonic acid.
Reaction SMILES: [CH:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:14])[CH:5]=1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.[I:22]N1C(=O)CCC1=O.P(O)([O-])([O-])=O.[Na+].[Na+]>ClCCl>[I:22][C:13]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][C:6]([CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(C(C)C)cc1C
Reactant: O=C1CCC(=O)N1I
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc(I)c(C(C)C)cc1C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 94 %

Procedure:
To methyl 4-isopropyl-2-methylbenzoate (compound 198.1, 2.31 g, 12.0 mmol, 1.0 equiv) in a 100 mL round bottom flask was carefully added TFA (24 mL) and the mixture was cooled to 0° C. N-Iodosuccinimide (2.70 g, 12.0 mmol, 1.0 equi) was added portionwise over 2 minutes and the resulting mixture was added under nitrogen and stirred at 0° C. for 20 min then at room temperature for 15 hours. The mixture was carefully diluted. To a mixture of dichloromethane (50 mL) and added to saturated aqueous disodium phosphate to maintain a pH above 3 (total disodium phosphate about 500 mL). The mixture was shaken well, separated and the aqueous was extracted with additional DCM (5×25 mL). The combined organics was washed with a mix of saturated sodium sulfite (10 mL) plus water (40 mL) followed by brine (50 mL), dried (Na2SO4), filtered and removed in vacuo. The crude product was purified by silica column chromatography (hexanes to 3% ethyl acetate) to obtain the title compound as a light tan oil (3.59 g, 94%). 1H NMR (400 MHz, CDCl3): δ 8.35 (s, 1H), 7.08 (s, 1H), 3.87 (s, 3H), 3.17 (septet, J=6.8 Hz, 1H), 2.59 (s, 3H), 1.23 (d, J=6.8 Hz, 6H).
Reaction SMILES: [BH4-].[Na+].[CH3:3][CH:4]1[C:12](=[O:13])[C:11]2[C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[CH:8]=[CH:7][C:6]=2[CH2:5]1.O>CO>[OH:13][CH:12]1[C:11]2[C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[CH:8]=[CH:7][C:6]=2[CH2:5][CH:4]1[CH3:3]
Reactant: CC1Cc2ccc3ccccc3c2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1Cc2ccc3ccccc3c2C1O
Reaction time: 0.25 h
Yield: 78.2 %

Procedure:
Sodium borohydride (7.5 g) was added portion-wise at 0-20° C. to a solution of 18.1 g of 2,3-dihydro-2-methyl-benz[e]indene-1-one in 200 ml of methanol. The reaction was completed after 15 min of stirring, and the reaction mixture was poured into 400 ml of water. The organic layer was separated, and the water layer was extracted with diethyl ether. The combined organic layers were washed with water and brine, dried over magnesium sulfate, and evaporated to dryness. The crude product was recrystallized from cyclohexane to obtain 14.3 g (78%) of 2,3-dihydro-1-hydroxy-2-methyl-1H-benz[e]indene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9](=[O:11])[CH3:10].[C:12](OCC)(=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14].[H-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9](=[O:11])[CH2:10][C:12](=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1c(Cl)cccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=O)CC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C

Procedure:
To a solution of 2′,6′-dichloroacetophenone (12.5 g, 66 mmol) and diethyl oxalate (14.6 g, 100 mmol) in 450 mL of anhydrous toluene, cautiously add sodium hydride (60% dispersion in mineral oil, 2.8 g, 70 mmol). Cautiously heat the reaction mixture to reflux under N2 for 1 h, cool to ambient temperature and pour onto ice-cold 1M HCl. Separate the layers and extract the aqueous phase with EtOAc (2×200 mL). Wash the combined organic extracts with brine, dry over MgSO4 and evaporate to obtain the title compound which is used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23]([N:25]3[CH2:30][CH2:29][CH:28]([C:31]([O:33]CC)=[O:32])[CH2:27][CH2:26]3)=[O:24])=[C:16]2[N:15]=1.[Li+].[OH-]>C1COCC1.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23]([N:25]3[CH2:26][CH2:27][CH:28]([C:31]([OH:33])=[O:32])[CH2:29][CH2:30]3)=[O:24])=[C:16]2[N:15]=1
Reactant: CCOC(=O)C1CCN(C(=O)c2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)nc23)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1CCN(C(=O)c2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)nc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
(R)-ethyl 1-(5-(2-(2,5-di fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carbonyl)piperidine-4-carboxylate (49 mg, 0.10 mmol) was dissolved in 1:1 THF/MeOH (1.0 mL) and 1M LiOH (0.20 mL, 0.20 mmol) was added. The mixture was stirred at ambient temperature for 2 hours and the reaction mixture was concentrated. The residue was diluted in water and the mixture acidified with 2N HCl. The mixture was extracted with DCM and EtOAc. The combined organics were washed with brine, dried with MgSO4, filtered and concentrated. The residue was triturated with hexanes and the resulting white suspension was concentrated to afford the final product (43 mg, 92% yield) as a white solid. MS (apci) m/z=456.1 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:10]2[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:35]1([CH2:38][S:39](Cl)(=[O:41])=[O:40])[CH2:37][CH2:36]1>ClCCl>[CH2:13]([CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([CH2:2][NH:1][S:39]([CH2:38][CH:35]3[CH2:37][CH2:36]3)(=[O:41])=[O:40])[CH:12]=2)[CH2:7][CH2:8][CH:9]1[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(CN)cc2C1Cc1ccccc1
Reactant: O=S(=O)(Cl)CC1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCc2ccc(CNS(=O)(=O)CC3CC3)cc2C1Cc1ccccc1
Reaction time: 8 h
Yield: 75.7 %

Procedure:
tert-Butyl 7-(aminomethyl)-1-benzyl-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (0.600 g, 1.637 mmol) was suspended in dichloromethane (5 mL) and triethylamine (0.228 mL, 1.637 mmol) and cooled to 0° C. Cyclopropylmethanesulfonyl chloride (0.253 g, 1.637 mmol) was added. The solid immediately dissolved. The mixture was stirred overnight and then diluted with dichloromethane and washed with brine (3×50 mL). The organic extract was collected dried on MgSO4 and evaporated under reduced pressure. The residue was purified by flash-chromatography on silica gel (100% dichloromethane 5 minutes then gradient to 1% MeOH in dichloromethane). Product was isolated as white powder (601.9 mg, 1.24 mmol, 76%).
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([OH:16])=O)[CH:13]=[C:8]2[C:7]([CH2:17][OH:18])=[CH:6]1.Cl.[CH3:25][O:26][NH2:27]>>[F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([NH:27][O:26][CH3:25])=[O:16])[CH:13]=[C:8]2[C:7]([CH2:17][OH:18])=[CH:6]1
Reactant: O=C(O)c1cc2c(CO)cn(Cc3ccc(F)cc3F)c2cn1
Reactant: CON
Agent: Cl
Product: CONC(=O)c1cc2c(CO)cn(Cc3ccc(F)cc3F)c2cn1

Procedure:
The title compound was prepared by coupling of 1-(2,4-difluoro-benzyl)-3-hydroxymethyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid and O-methyl hydroxylamine hydrochloride in a manner similar to step (c) of example 1. 1H NMR (CD3OD) δ; 8.76 (s, 1H), 8.41 (s, 1H), 7.58 (s, 1H), 7.23–7.29 (m, 1H), 6.88–7.00 (m, 2H), 5.54 (s, 2H), 4.80 (s, 2H), 3.82 (s, 3H). LCMS (APCI, M+H+): 348.0. HRMS calcd for C17H16F2N3O3 (M+H) 348.1160. found 348.1148. HPLC: 100% purity.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([C:15]([N:17]([CH:31]([CH3:33])[CH3:32])[C@@H:18]3[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]3)=[O:16])[C:12]([CH3:14])=[CH:13][C:8]=2[O:7][C:6]([CH3:35])([CH3:34])[C:5]1=[O:36].[H-].[Na+].CN(C)C=O.[C:44](Cl)(=[O:47])[CH2:45][CH3:46]>O>[CH:31]([N:17]([C:15]([C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[O:7][C:6]([CH3:34])([CH3:35])[C:5](=[O:36])[N:4]([CH2:3][CH2:2][O:1][C:44](=[O:47])[CH2:45][CH3:46])[C:9]=2[CH:10]=1)=[O:16])[C@@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:19]1)([CH3:32])[CH3:33]
Reactant: Cc1cc2c(cc1C(=O)N(C(C)C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1)N(CCO)C(=O)C(C)(C)O2
Reactant: CCC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(=O)OCCN1C(=O)C(C)(C)Oc2cc(C)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To tert-butyl (3R)-3-[{[4-(2-hydroxyethyl)-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (150 mg) were added sodium hydride (16 mg) and N,N-dimethylformamide (9 ml) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Then, to the mixture was added propionic chloride (0.03 ml), and the mixture was further stirred at room temperature for 2 hours. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate solution. The obtained ethyl acetate solution was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2) to give the title compound (110 mg) as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[C:16]([NH2:20])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([NH:20][CH2:11][C:10]1[CH:13]=[CH:14][CH:15]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:9]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: CC(C)(C)N
Product: CC(C)(C)NCc1cccc(-c2ccnc(Cl)n2)c1
Yield: 97 %

Procedure:
3-(2-Chloro-pyrimidin-4-yl)-benzaldehyde (intermediate 1) and tert butylamine were coupled by procedure B. The yield was 97%. LC-MS showed the product had the expected M+H+ of 276. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) 8.6 (d, 1H) 8.1 (s, 1H) 7.9 (d, 1H) 7.6 (d, 1H) 7.5 (m, 2H) 1.2 (s, 9H).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:21][C:22]1[C:23](=[O:29])[N:24]([CH3:28])[CH:25]=[CH:26][CH:27]=1>CN(C=O)C.C(Cl)Cl>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:21][C:22]2[C:23](=[O:29])[N:24]([CH3:28])[CH:25]=[CH:26][CH:27]=2)[N:3]=1
Reactant: Cn1cccc(CBr)c1=O
Reactant: O=[N+]([O-])c1cccc2[nH]nc(I)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1cccc(Cn2nc(I)c3c([N+](=O)[O-])cccc32)c1=O
Reaction time: 8 h
Yield: 50.6 %

Procedure:
3-Iodo-4-nitro-1H-indazole (0.38 g, 1.3 mmol) was reacted with K2CO3 (0.36 g, 2.6 mmol) in DMF (4 mL) for 15 minutes. 3-(Bromomethyl)-1-methylpyridin-2(1H)-one (0.28 g, 1.4 mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was diluted with CH2Cl2 (30 mL), filtered and concentrated. The residue was partitioned between CHCl3 and saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and concentrated. The residue was suspended in EtOAc (8 mL), stirred for 20 minutes and then filtered to provide 3-((3-iodo-4-nitro-1H-indazol-1-yl)methyl)-1-methylpyridin-2(1H)-one (0.27 g, 50% yield) as a solid.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].CN(C)C=O.Cl[CH:16]([N:27]1[CH:31]=[N:30][CH:29]=[N:28]1)[CH:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)[CH3:18]>O>[C:1]1([S:7][CH:16]([N:27]2[CH:31]=[N:30][CH:29]=[N:28]2)[CH:17]([O:19][C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: Cc1ccc(OC(C)C(Cl)n2cncn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(OC(C)C(Sc2ccccc2)n2cncn2)cc1

Procedure:
13 q (0.12 mol of thiophenol were added slowly at 25° C. to a solution of 4.0 g of sodium hydride (80% strength by weight suspension in mineral oil) and 100 ml of N,N-dimethylformamide, followed, after stirring for 30 minutes, by 19.8 g (0.08 mol) of 1-chloro-1-(1,2,4-triazol-1-yl)-2-(4-methylphenoxy)-propane. After a reaction time of 24 hours at 25° C., 100 ml of water were added. Extraction with methyl tert-butyl ether was carried out, after which the organic phase was washed and was worked up in a conventional manner.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9](Cl)=[O:10])=[CH:3][CH:2]=1.[CH3:12][NH:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH2:7]([O:8][C:9]([N:13]([CH3:12])[CH:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:18][CH2:19]1)=[O:10])[C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CN(C(=O)OCc1ccccc1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 49 %

Procedure:
Cbz-Cl (0.393 ml, 2.8 mol, 1.2 eq.) was added to a mixture of tert-butyl 4-(methylamino)-piperidine-1-carboxylate (500 mg, 2.336 mmol, 1.0 eq.) and K2CO3 (616 mg, 4.67 mmol, 2.0 eq.) in DCM (6 ml), and the mixture was stirred for 14 hours at RT. The reaction mixture was diluted with DCM (100 ml), washed with water and sat. NaCl solution (in each case 40 ml), dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (silica gel, 15% ethyl acetate in hexane). Yield: 49% (400 mg, 1.149 mmol)