Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=O)[CH2:12][C:11]3([CH3:20])[CH3:19])[CH:5]=[CH:6][CH:7]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[S:22])[CH2:12][C:11]3([CH3:20])[CH3:19])[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(=O)Nc2ccc(-c3cccc(Cl)c3)cc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: CC1(C)CC(=S)Nc2ccc(-c3cccc(Cl)c3)cc21

Procedure:
Prepared by heating under reflux overnight a mixture of 6-(3-chlorophenyl)-4,4-dimethyl-3,4-dihydroquinoline-2(1H)-one and an equal weight of phosphorus pentasulfide in pyridine was stirred. Removal of the pyridine in vacuo followed by treating the residue with 6N hydrochloric acid and recrystallization of the residue in ethanol gave the product as a yellow solid: mp. 197-1980 C. 1H-NMR (DMSO-d6) 8 12.34 (s, 1H), 7.75 (m, 1H), 7.64 (m, 2H), 7.57 (dd, 1H J=9.3 and 2.1 Hz), 7.48 (t, 1H, J=7.7 Hz), 7.41 (m, 1H),7.20 (d, 1H, J=8.3 Hz), 3.34 (s, 2H), 1.26 (s, 6H); MS (APCI (−)) m/z 300 [M−H]− Anal. Calc. For C17H16CINS: C, 67.65, H, 5.34, N, 4.64. Found: C, 67.77, H, 5.57, N 4.54.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([C:25]3[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=3)[C:18]3[C:13](=[CH:14][C:15]([O:39][CH3:40])=[C:16]([O:37][CH3:38])[CH:17]=3)[C:12]2=[O:41])=[CH:7][CH:6]=1)(=O)C.[H-].[Na+].CI.Cl>O1CCCC1.C(Cl)(Cl)Cl>[CH3:38][O:37][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:39][CH3:40])[C:12](=[O:41])[N:11]([C:8]1[CH:9]=[CH:10][C:5]([NH:4][CH3:1])=[CH:6][CH:7]=1)[C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]2[C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=1
Reactant: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2cc(OC)c(OC)cc2c(=O)n1-c1ccc(NC(C)=O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CNc1ccc(-n2c(C(=O)OC)c(-c3cc(OC)c(OC)c(OC)c3)c3cc(OC)c(OC)cc3c2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
To a solution of the compound obtained in Example 94 (260 mg) in tetrahydrofuran (3 ml) is added 60% sodium hydride (28 mg) under ice-cooling, and the mixture is stirred at room temperature for 30 minutes. To the reaction mixture is added dropwise methyl iodide (58 μl), and the mixture is stirred for five hours. To the reaction mixture are added dilute hydrochloric acid and chloroform. The chloroform layer is separated, washed, dried, and concentrated under reduced pressure. To the residue is added a mixture of methanol and 2M hydrochloric acid (1:1) (10 ml), and the mixture is heated under reflux for 16 hours. The reaction mixture is cooled to room temperature, and concentrated under reduced pressure to remove the methanol. To the resulting aqueous layer is added aqueous sodium hydrogen carbonate solution to adjust the pH value to pH 8. The mixture is extracted with chloroform. The extract is washed with water, dried, and concentrated under reduced pressure. The residue is crystallized from diethyl ether to give 6,7-dimethoxy-3-methoxycarbonyl-2-[4-(methylamino)phenyl]-4-(3,4,5-trimethoxyphenyl)-1(2H)-isoquinolinone (170 mg) as listed in Table 7.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:8][CH:9]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([OH:21])([CH3:20])[CH3:19])=[N:16][CH:17]=2)[N:11]=1.C1C(=O)N([Br:29])C(=O)C1.O>C(Cl)Cl>[Br:29][C:9]1[O:8][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:11][C:10]=1[C:12]1[CH:13]=[CH:14][C:15]([C:18]([OH:21])([CH3:19])[CH3:20])=[N:16][CH:17]=1
Reactant: CC(C)(O)c1ccc(-c2coc(-c3ccccn3)n2)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: O
Product: CC(C)(O)c1ccc(-c2nc(-c3ccccn3)oc2Br)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[5-(2-pyridin-2-yl-1,3-oxazol-4-yl)pyridin-2-yl]propan-2-ol from Step D (75 mg, 0.267 mmol) in DCM (1 mL) was added NBS (62 mg, 0.347 mmol). The reaction mixture was stirred at rt for 16 h. Water was added and the mixture extracted with DCM. The organics were dried (MgSO4), and concentrated to afford 2-[5-(5-bromo-2-pyridin-2-yl-1,3-oxazol-4-yl)pyridin-2-yl]propan-2-ol, which was used without further purification LCMS: m/z 360.0 (M+H)+.
Reaction SMILES: CCC([O-])(C)C.[K+].[Cl:8][C:9]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:10]=1[C:11]([O:13]C)=O.[C:23](#[N:25])[CH3:24]>C1(C)C=CC=CC=1.Cl.O.CCOC(C)=O>[Cl:8][C:9]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:10]=1[C:11](=[O:13])[CH2:24][C:23]#[N:25]
Reactant: COC(=O)c1cc(C(F)(F)F)ccc1Cl
Reactant: CC#N
Agent: CCC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: N#CCC(=O)c1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 83.4 %

Procedure:
Potassium tert-pentoxide 1.7 M in toluene (7.35 mL, 12.5 mmol) was added drop wise to a solution of methyl 2-chloro-5-(trifluoromethyl)benzoate (2.0 g, 8.38 mmol) and ACN (1.32 mL, 25.15 mmol) in anhydrous toluene (30 mL). The mixture was stirred at room temperature for 20 min, then diluted with HCl 1 N (20 mL), water (75 mL) and EtOAc (100 mL). The organic layer was separated, washed with water (50 mL×2) and brine (50 mL×2), dried over sodium sulfate and concentrated. Column chromatography on silica gel (0 to 20% EtOAc/hexane) provided the title compound (1.73 g, 83%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[CH:8]=[CH2:9].[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])=[CH:15][C:14]=1[OH:27])=[O:12]>CC(C)=O>[CH2:7]([O:27][C:14]1[CH:15]=[C:16]([O:19][S:20]([C:23]([F:26])([F:24])[F:25])(=[O:22])=[O:21])[CH:17]=[CH:18][C:13]=1[CH:11]=[O:12])[CH:8]=[CH2:9]
Reactant: C=CCBr
Reactant: O=Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(OS(=O)(=O)C(F)(F)F)ccc1C=O
Reaction time: 2 h
Yield: 73.5 %

Procedure:
Potassium carbonate (1.6 g, 11.5 mmol) and allyl bromide (1 ml, 11.5 mmol) were added to a solution of trifluoro-methanesulfonic acid 4-formyl-3-hydroxy-phenyl ester (1.55 g, 5.7 mmol) in acetone (50 ml). The reaction mixture was stirred at 55C. for 2 h, filtered and evaporated in vacuo. The residue was chromatographed (silica gel, EA:Hex, 1:20) to give 1.3 g (73%) of trifluoro-methanesulfonic acid 3-allyloxy-4-formyl-phenyl ester.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]([O:31]C)=[O:30])[CH2:25][CH2:24]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.Cl>CO>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([CH2:22][N:23]2[CH2:24][CH2:25][CH:26]([C:29]([OH:31])=[O:30])[CH2:27][CH2:28]2)[CH:16]=[CH:15]3)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1CCN(Cc2ccc3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3n2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3nc(CN4CCC(C(=O)O)CC4)ccc3c2)CC1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 1-((6-(trans-4-tert-butylcyclohexyloxy)quinolin-2-yl)methyl)piperidine-4-carboxylate (150 mg, 0.34 mmol) in MeOH (5 mL) was added NaOH (68 mg, 1.7 mmol, 5.0 eq) and H2O (0.5 mL). The reaction mixture was stirred at 85° C. for 2 h. Then the reaction was cooled to 0° C., the pH of the solution was adjusted to 6 with 3 N HCl. The mixture was filtrated, and the yellow solid was the desired product 1-((6-(trans-4-tert-butylcyclohexyloxy)quinolin-2-yl)methyl)piperidine-4-carboxylic acid (90 mg, yield: 46%). ESI-MS (M+1)+: 425.3, HPLC: 100%. 1H NMR (400 MHz, DMSO-d6) δ: 8.32 (d, 1H), 7.93 (d, 1H), 7.70 (d, 1H), 7.48 (s, 1H), 7.41 (d, 1H), 4.53 (br, 1H), 4.44˜4.40 (m, 1H), 3.33 (br, 3H), 3.14 (br, 2H), 2.49 (br, 1H), 2.22˜2.20 (m, 2H), 2.04˜1.80 (m, 6H), 1.37˜1.32 (m, 2H), 1.25˜1.20 (m, 2H), 1.10˜1.08 (m, 1H), 0.87 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[C:13]=1[C:14](Cl)=[O:15]>N1C=CC=CC=1>[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[NH:1][C:14](=[O:15])[C:13]1[C:17]([O:21][CH3:22])=[CH:18][CH:19]=[CH:20][C:12]=1[Cl:11])(=[O:5])[NH2:6]
Reactant: COc1cccc(Cl)c1C(=O)Cl
Reactant: NC(=O)c1ccccc1N
Solvent: c1ccncc1
Product: COc1cccc(Cl)c1C(=O)Nc1ccccc1C(N)=O
Temperature: 0 °C
Reaction time: 72 h
Yield: 86 %

Procedure:
2-Amino-benzamide (6.9 g, 50.8 mmol) was dissolved in 50 mL of pyridine and cooled to 0° C. 2-Chloro-6-methoxy-benzoyl chloride was added dropwise to the solution. After complete addition, the reaction was left to stir at room temperature for three days, which resulted in formation of a brown, cloudy solution. The reaction mixture was then poured into 150 mL of ice water. The precipitate was filtered and washed twice with water, twice with THF and finally twice with CH2Cl2 to obtain N-(2-carbamoylphenyl)-2-chloro-6-methoxybenzamide (13.3 g, 43.7 mmol, 86%).
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:32]=[CH:31][C:14]3[N:15]([CH2:27][C:28](O)=[O:29])[C:16]([CH2:18][C:19]4[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=4)=[N:17][C:13]=3[CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:34]([O:36][C:37](=[O:40])[CH2:38][NH2:39])[CH3:35].C(N(CC)CC)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[C:1]1([S:7]([NH:10][C:11]2[CH:32]=[CH:31][C:14]3[N:15]([CH2:27][C:28]([NH:39][CH2:38][C:37]([O:36][CH2:34][CH3:35])=[O:40])=[O:29])[C:16]([CH2:18][C:19]4[CH:20]=[CH:21][C:22]([C:23]#[N:24])=[CH:25][CH:26]=4)=[N:17][C:13]=3[CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ccc(Cc2nc3cc(NS(=O)(=O)c4ccccc4)ccc3n2CC(=O)O)cc1
Reactant: CCOC(=O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)Cn1c(Cc2ccc(C#N)cc2)nc2cc(NS(=O)(=O)c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2.7 g (6.1 mmol) of 4-[(5-benzenesulphonylamino-1-carboxymethyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile, 0.85 g (6.1 mmol) of glycine-ethyl ester-hydrochloride and 1.5 g (15 mmol) of triethylamine are dissolved in 80 ml dimethylformamide and after the addition of 2.4 g (7.5 mmol) of O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluroniumtetrafluoroborate the mixture is stirred for 16 hours at ambient temperature. The solvent is evaporated off, the residue chromatographed on silica gel and eluted with methylene chloride/ethanol 99:1 and 98:2. The desired fractions are concentrated by evaporation, the residue is triturated with ether, suction filtered and dried.
Reaction SMILES: C[O:2][C:3](=[O:33])[C@H:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15]([C:17]2[C:18]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=3)=[N:19][CH:20]=[CH:21][CH:22]=2)=[O:16])=[C:9]([F:32])[CH:8]=1)[CH3:5].COC(=O)COC1C=CC(CNC(C2C(OC3C=CC4OCOC=4C=3)=NC=CC=2)=O)=C(F)C=1>>[F:32][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=1[CH2:13][NH:14][C:15]([C:17]1[C:18]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=2)=[N:19][CH:20]=[CH:21][CH:22]=1)=[O:16])[O:6][C@H:4]([CH3:5])[C:3]([OH:33])=[O:2]
Reactant: COC(=O)[C@@H](C)Oc1ccc(CNC(=O)c2cccnc2Oc2cccc(C#N)c2)c(F)c1
Agent: COC(=O)COc1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)c(F)c1
Product: C[C@@H](Oc1ccc(CNC(=O)c2cccnc2Oc2cccc(C#N)c2)c(F)c1)C(=O)O

Procedure:
The compound of Formula (5.5.11) was prepared in a manner analogous to that described in Example 1, substituting (R)-2-[3-fluoro-4-({[2-(3-cyano-phenoxy)-pyridine-3-carbonyl]-amino}-methyl)-phenoxy]-propionic acid methyl ester for the corresponding [4-({[2-(benzo[1,3]dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenoxy]-acetic acid methyl ester material.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1.[CH3:32][NH:33][CH2:34][C:35]([OH:37])=[O:36]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH2:28][N:33]([CH3:32])[CH2:34][C:35]([OH:37])=[O:36])=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1
Reactant: O=Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1
Reactant: CNCC(=O)O
Product: CN(CC(=O)O)Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1

Procedure:
The title compound was prepared following the procedure described for Example 94, but starting from 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde, obtained as described in Example 113, Step 1, (100 mg; 0.24 mmol) and 2-(methylamino)acetic acid (43.2 mg; 0.48 mmol) to give Example 130 as a white solid. 1H NMR: (DMSO-d6, 400 MHz) δ 8.76-8.73 (2H, m), 7.97 (2H, d, J=8.0 Hz), 7.93-7.88 (1H, m), 7.76-7.69 (1H, m), 7.63-7.58 (2H, m), 7.61-7.47 (4H, m), 3.78 (2H, s), 3.26 (2H, s), 2.32 (3H, s). LC/MS (Method C): 484 (M+H)+. HPLC (Method E) Rt 2.36 min (Purity: 98.9%).
Reaction SMILES: [C:1]([C:9]1[C:14]([NH2:15])=[CH:13][CH:12]=[C:11]([Cl:16])[N:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.C([Cl:27])(=O)CC.O>O1CCOCC1>[Cl:27][C:7]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:1]([C:9]1[C:14]([NH2:15])=[CH:13][CH:12]=[C:11]([Cl:16])[N:10]=1)=[O:8]
Reactant: Nc1ccc(Cl)nc1C(=O)c1ccccc1
Reactant: CCC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccc(Cl)nc1C(=O)c1ccccc1Cl
Reaction time: 2 h

Procedure:
43 grams of 2-benzoyl-3-amino-6-chloropyridine were dissolved in 100 ml of dioxane, then 16 ml of pyridine and finally with stirring 18 ml of propionyl chloride were added. The mixture was stirred for 2 hours, then water was added until crystallization began. The material which precipitated was recrystallized from methanol/water. Yield 48 grams; M.P. 40° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH2:20]([O:22][C:23](Cl)=[O:24])[CH3:21]>ClCCl>[C:8]([C:4]1[CH:3]=[C:2]([NH:1][C:23](=[O:24])[O:22][CH2:20][CH3:21])[CH:7]=[CH:6][CH:5]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1cccc(N)c1
Reactant: CCOC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)Nc1cccc(C(C)=O)c1
Yield: 91.5 %

Procedure:
A mixture of 27.03 g of m-aminoacetophenone, 27.14 g of diisopropylethylamine, 22.8 g of ethylchloroformate and 300 ml of dichloromethane was reacted as described in Example 1, giving 37.9 g of (3-acetylphenyl)carbamic acid, ethyl ester.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].[Br:13]Br.S(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH:1]([C:4]1[C:12]([Br:13])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc2ccccn2n1
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)c1nn2ccccc2c1Br

Procedure:
To a solution of 50 g of 2-isopropylpyrazolo[1,5-a]pyridine in 300 ml of chloroform were added about 20 ml of bromine until the solution became faintly yellow under stirring and cooling to 5°-15° C. After the addition was completed, the mixture was stirred at room temperature for 30 minutes, then poured into aqueous 10% sodium bisulfite solution and extracted with chloroform. The chloroform layer was washed with aqueous 10% sodium hydroxide and then water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give 75 g of crude 2-isopropyl-3-bromopyrazolo[1,5-a]pyridine, as colorless needles, mp 51°-52° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH2:12][C:13]2([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:5]([CH3:20])=[C:4]([CH3:21])[N:3]=1.[CH2:22]([NH:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C.C(OCC)C.CO>[CH2:30]([N:29]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH2:12][C:13]2([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:5]([CH3:20])=[C:4]([CH3:21])[N:3]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCC2(O)CCCCC2)c1C
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCOCC
Product: Cc1nc(N(Cc2ccccc2)Cc2ccccc2)c([N+](=O)[O-])c(NCC2(O)CCCCC2)c1C
Reaction time: 0.17 h
Yield: 78.8 %

Procedure:
A solution of 1-{[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]methyl}cyclohexanol (prepared as described in Part A, 27.1 mmol), dibenzylamine (15.6 mL, 81.3 mmol), and triethylamine (5.67 mL, 40.7 mmol) in toluene (100 mL) was heated at reflux for 7 d. The volatiles were removed under reduced pressure and the residue was partitioned between chloroform (300 mL) and water (100 mL). The aqueous layer was extracted with chloroform (2×75 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4, filtered, and concentrated to give a semi-solid. The semi-solid was triturated with 1:2 ethyl acetate/hexanes and filtered. The filtrate was concentrated to an orange oil that was purified on a Biotage (gradient elution, 0-30% ethyl acetate/hexanes) to yield an oil contained both product and dibenzylamine. The oil was dissolved in ethyl acetate (100 mL) and 1 M HCl in diethyl ether (50 mL) and methanol (100 mL) were added. The solution was stirred for 10 minutes and the solvent was removed in vacuo. The residue was triturated with 1:2 ethyl acetate/hexanes and filtered. The filtrate was concentrated, and the resulting oil was dissolved in chloroform (300 mL), washed with saturated aqueous sodium bicarbonate (50 mL), dried over MgSO4, filtered, and concentrated. The material was dissolved in ethyl acetate (400 mL) and washed with 10% aqueous citric acid (2×100 mL), saturated aqueous sodium bicarbonate (50 mL) and brine (50 mL), dried over MgSO4, filtered, and concentrated in vacuo to yield 1-({[2-(dibenzylamino)-5,6-dimethyl-3-nitropyridin-4-yl]amino}methyl)cyclohexanol (10.14 g, 79% yield over two steps).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]1=2.[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:15](Cl)=[O:16].C(N(CC)CC)C.Cl>ClCCl>[Cl:11][C:12]1[CH:13]=[C:14]([C:15]([N:4]2[CH2:5][CH2:6][O:1][C:2]3[CH:10]=[CH:9][N:8]=[CH:7][C:3]2=3)=[O:16])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: c1cc2c(cn1)NCCO2
Reactant: COc1ccc(C(=O)Cl)cc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)N2CCOc3ccncc32)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.9 %

Procedure:
To a 10 ml flask, 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (150 mg, 1.102 mmol) and 3-chloro-4-methoxy-benzoyl chloride (249 mg, 1.212 mmol) were dissolved in dichloromethane. Triethylamine (0.77 ml, 5.510 mmol) was added thereto and then stirred at room temperature for 2 hours. The reaction mixture was neutralized with 1N hydrochloric acid solution and extracted with dichloromethane. And the combined organic layer was dried over anhydrous magnesium sulfate (MgSO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of ethyl acetate. The fractions containing the product were collected and evaporated to obtain ivory-colored solid (238 mg, 71%).
Reaction SMILES: IC.[C:3]([O:7][C:8]([N:10]1[CH2:15][CH:14]=[C:13]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([OH:27])=[O:26])[CH:23]=3)[NH:18][CH:17]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[C:28](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH:12]=[C:13]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([O:27][CH3:28])=[O:26])[CH:23]=3)[NH:18][CH:17]=2)[CH2:14][CH2:15]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccc(C(=O)O)cc23)CC1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc2[nH]cc(C3=CCN(C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
Iodomethane (1.22 mL, 19.63 mmol) was added in one portion to 3-[1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole-5-carboxylic acid (6.72 g, 19.63 mmol) and potassium carbonate (3.26 g, 23.55 mmol) in DMF (60 mL) at ambient temperature. The resulting mixture was stirred at ambient temperature for 3 hours then quenched in water (200 mL) and extracted with MTBE (2×100 mL). The extract was washed sequentially with water (3×100 mL) and saturated brine, dried over MgSO4 and concentrated by evaporation then purified by flash silica chromatography, elution gradient 20 to 35% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 3-[1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole-5-carboxylate (5.09 g, 73%) as a colourless solid.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][C:11]([CH3:16])([CH3:15])[CH2:10][C:9]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[N:28](OCCC(C)C)=[O:29]>C1COCC1>[CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][C:11]([CH3:15])([CH3:16])/[C:10](=[N:28]/[OH:29])/[C:9]1=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CCON=O
Reactant: CC1(C)CC(=O)N(Cc2ccccc2)C(=O)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)CC(=O)N(Cc2ccccc2)C(=O)/C1=N\O
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 30.2 %

Procedure:
To a solution of 1-benzyl-4,4-dimethylpiperidine-2,6-dione (1.00 g, 4.32 mmol) in THF (20 mL) at −78° C. was slowly added LiHMDS (1.0M in THF, 4.8 mL, 4.8 mmol). The resulting thick white slurry was stirred at −78° C. for 20 min then isopentyl nitrite (0.70 mL, 5.20 mmol) was added dropwise which caused a bright orange color to appear. The reaction mixture was stirred at −78° C. for 30 min then gradually warmed to room temperature over 1 h and quenched with saturated aqueous NH4Cl. The biphasic mixture was stirred vigorously for 5 min then diluted with H2O and extracted with EtOAc (2×). The combined organics were dried over MgSO4 and concentrated. The crude residue was purified by SiO2 chromatography (20% to 50% EtOAc/hexanes) to isolate first 340 mg (30%) of (Z)-1-benzyl-4,4-dimethylpiperidine-2,3,6-trione 3-oxime as a white solid followed by 280 mg (25%) of (E)-1-benzyl-4,4-dimethylpiperidine-2,3,6-trione 3-oxime as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[F:50][C:51]([F:57])([F:56])[C:52]1([NH2:55])[CH2:54][CH2:53]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([NH:55][C:52]4([C:51]([F:57])([F:56])[F:50])[CH2:54][CH2:53]4)=[O:24])=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Reactant: NC1(C(F)(F)F)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1(C(F)(F)F)CC1)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 23 %

Procedure:
To a DMF (0.4 mL) solution of (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation I, 50 mg, 0.15 mmol) and HATU (87 mg, 0.23 mmol) was charged 1-(trifluoromethyl)cyclopropanamine hydrochloride (37 mg, 0.23 mmol), followed by drop-wise addition of DIEA (0.080 mL, 0.46 mmol). After stirring first at ambient temperature for 15 minutes and then at 85° C. overnight, the reaction was cooled and directly purified by reverse-phase chromatography (5 to 60% acetonitrile/water) to yield the final product as off-white solid (15 mg, 23%). LCMS (apci) m/z=435.0 (M+H).