Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:56])[C:10]([NH:13][C:14](=[O:55])[C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:25]4[CH:26]=[C:27]([C:30]5[CH:31]=[N:32][N:33]([C:35]([C:48]6[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=6)([C:42]6[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=6)[C:36]6[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=6)[CH:34]=5)[CH:28]=[CH:29][C:24]4=[N:23][CH:22]=3)=[CH:17][C:16]=2[F:54])([CH3:12])[CH3:11])=[CH:5][CH:4]=1)[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:56])[C:10]([NH:13][C:14](=[O:55])[C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:25]4[CH:26]=[C:27]([C:30]5[CH:31]=[N:32][N:33]([C:35]([C:36]6[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=6)([C:42]6[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=6)[C:48]6[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=6)[CH:34]=5)[CH:28]=[CH:29][C:24]4=[N:23][CH:22]=3)=[CH:17][C:16]=2[F:54])([CH3:12])[CH3:11])=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C(O)C(C)(C)NC(=O)c2ccc(-c3cnc4ccc(-c5cnn(C(c6ccccc6)(c6ccccc6)c6ccccc6)c5)cn34)cc2F)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CCc1ccc(C(=O)C(C)(C)NC(=O)c2ccc(-c3cnc4ccc(-c5cnn(C(c6ccccc6)(c6ccccc6)c6ccccc6)c5)cn34)cc2F)cc1
Yield: 92.3 %

Procedure:
100 mg N1-[2-(4-ethylphenyl)-2-hydroxy-1,1-dimethylethyl]-2-fluoro-4-[6-(1-trityl-1H-4-pyrazolyl)-imidazo[1,2-a]pyridin-3-yl] benzamide obtained in Example 503 and 288 mg Dess-Martin reagent were stirred for 15 hours in dichloromethane. After an aqueous sodium bicarbonate solution and an aqueous sodium thiosulfate solution were added thereto, and the reaction solution was extracted with ethyl acetate and purified by NH silica gel chromatography, to give 92 mg of the title compound as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:20])[C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][C:11]=2[O:18][CH3:19])[CH:5]=[CH:6][C:7]=1[Cl:8].C([O-])([O-])=[O:22].[K+].[K+].OO>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:20])[C:10]2[CH:17]=[CH:16][C:13]([C:14]([NH2:15])=[O:22])=[CH:12][C:11]=2[O:18][CH3:19])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(C#N)ccc1C(O)c1ccc(Cl)c(Cl)c1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc(C(N)=O)ccc1C(O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
To a solution of 4-((3,4-dichlorophenyl)(hydroxy)methyl)-3-methoxybenzonitrile (165 mg, 0.535 mmol) in DMSO (3 mL) was added K2CO3 (222 mg, 1.60 mmol) followed by 30% H2O2 (1210 mg, 10.7 mmol) and the reaction was stirred at room temperature. After 45 minutes the product was purified without workup by direct injection onto a reverse phase column (Biotage C18-silica 12 g) eluting with 100:0:0.1 H2O:MeCN:HCO2H, to 0:100:0.1. The title compound was collected as a white solid (142 mg, 81%).
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[N:26]([CH:29]([CH3:31])[CH3:30])=[C:27]=[O:28]>ClCCl.CCOC(C)=O>[CH:29]([NH:26][C:27]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2][CH2:3]1)=[O:28])([CH3:31])[CH3:30]
Reactant: CC(C)N=C=O
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)NC(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
To a solution of benzyl piperazine-1-carboxylate (1, 5.0 g, 23 mmol) and diisopropylethylamine (5.86 g, 45.4 mmol) in dichloromethane (50 mL) was added 2-isocyanatopropane (4.83 g, 56.8 mmol) and the mixture was stirred overnight at room temperature. The mixture was diluted with EtOAc (300 mL), washed with water (100 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography eluting with to 0-20% CH2Cl2/92:7:1 CHCl3/MeOH/concentrated NH4OH in CH2Cl2 to afford the title compound (3.94 g, 57%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.45-7.25 (m, 5H), 5.14 (s, 2H), 4.19 (d, J=6.7 Hz, 1H), 4.05-3.90 (m, 1H), 3.60-3.45 (m, 4H), 3.44-3.25 (m, 4H), 1.20-1.10 (m, 6H); Multimode MS m/z 306 [M+H]+.
Reaction SMILES: [CH2:1]([CH:3]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:13][C:5]=2[O:4]1)[CH3:2].[H-].[Na+].[CH2:20](I)[CH3:21].O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([CH:3]1[C:8](=[O:9])[N:7]([CH2:20][CH3:21])[C:6]2[CH:10]=[CH:11][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:13][C:5]=2[O:4]1)[CH3:2]
Reactant: CCC1Oc2cc(C(=O)OC)ccc2NC1=O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCC1Oc2cc(C(=O)OC)ccc2N(CC)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
To a solution of 2-ethyl-7-methoxycarbonyl-3-oxo-3,4-dihydro-2-H-1,4-benzoxazine [prepared in Preparation 9(1)] (6.0 g) in dimethylformamide (60 ml) were added 60% sodium hydride (in oil) (1.02 g) and ethyl iodide (4.37 g) and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution and extraction with ethyl acetate was conducted. The solvent was distilled off under reduced pressure and the resulting residue was subjected to purification by column chromatography using ethyl acetate/hexane [1:4 (v/v)] to give 2,4-diethyl-7-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (6.0 g).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1)=O.[S:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26].N1CCCCC1.C(O)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1.O>[F:17][C:16]([F:19])([F:18])[O:15][C:12]1[CH:13]=[CH:14][C:9]([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[CH:1]=[C:24]2[S:20][C:21](=[O:26])[NH:22][C:23]2=[O:25])=[CH:10][CH:11]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1cccc(-c2ccc(OC(F)(F)F)cc2)c1
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C(=Cc2cccc(-c3ccc(OC(F)(F)F)cc3)c2)S1

Procedure:
To a solution of 3-formyl-(4′-trifluoromethoxy-1,1′-biphenyl) (0.31 g, 1.16 mmol) and 2,4-thiazolidinedione (0.164 g, 1.4 mmol) in toluene (20 mL) were added piperidine (0.015 mL, 0.152 mmol) and benzoic acid (0.021 mg, 0.175 mmol), and the reaction was refluxed for 3 h with continuous removal of water. The solvent was then distilled off and the residue was crystallized from ether-pet ether to yield titled product as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-])=O)=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.C(O)(=O)C.C(O)C.[OH-].[NH4+]>[Zn].O>[NH2:12][C:11]1[C:2]([Cl:1])=[CH:3][CH:4]=[C:5]2[C:10]=1[CH:9]=[N:8][CH:7]=[CH:6]2
Reactant: O=[N+]([O-])c1c(Cl)ccc2ccncc12
Agent: [NH4+]
Agent: [OH-]
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: Nc1c(Cl)ccc2ccncc12

Procedure:
A mixture of 9.5 g. of 7-chloro-8-nitroisoquinoline, and 14.4 g. of zinc and 48 ml. of acetic acid in 450 ml. of ethanol and 70 ml. of water is heated on a steam bath for five minutes. The reaction mixture is cooled, made alkaline with aqueous ammonium hydroxide and extracted with ethyl acetate. The ethyl acetate is removed from the extract in vacuo to give, as the residue, 8-amino-7-chloroisoquinoline.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH3:10])[C:6]=2[CH:11]=1.[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH2:10][Br:12])[C:6]=2[CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1csc2ccc(Br)cc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1csc2ccc(Br)cc12
Temperature: 25 °C
Yield: 74 %

Procedure:
A solution of 4.30 gm (18.9 mMol) 5-bromo-3-methylbenzothiophene, 0.25 gm (1.03 mMol) benzoylperoxide, and 3.37 gm (18.9 mMol) N-bromosuccinimide in 50 mL carbon tetrachloride was heated at reflux for 3 hours. The reaction mixture was cooled to room temperature, filtered and the filtrate concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with hexane. Fractions containing the desired compound were combined and concentrated under reduced pressure to provide 4.28 gm (74%) of the desired compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=O)[CH2:5][C:6](=O)[CH3:7].[C:10]([CH2:12][C:13]([NH2:15])=[O:14])#[N:11].N1CCCCC1>CCO.O>[CH3:7][C:6]1[NH:15][C:13](=[O:14])[C:12]([C:10]#[N:11])=[C:4]([CH2:3][O:2][CH3:1])[CH:5]=1
Reactant: COCC(=O)CC(C)=O
Reactant: N#CCC(N)=O
Solvent: O
Solvent: C1CCNCC1
Solvent: CCO
Product: COCc1cc(C)[nH]c(=O)c1C#N
Temperature: 75 °C
Reaction time: 0.33 h
Yield: 59.9 %

Procedure:
1-(Methyloxy)-2,4-pentanedione (9.51 g, 73.12 mmol) and cyanoacetamide (6.17 g, 73.12 mmol) were dissolved in EtOH (76 mL) and heated until homogenous (ca. 75° C.). Piperidine (6.25 g, 73.12 mmol) was added and the reaction mixture heated at reflux for 20 mins, followed by cooling to room temperature. The contents were filtered to give a solid which was suspended in 140 mL water and stirred vigorously for 20 min. The heterogenous mixture was filtered to afford 6-methyl-4-[(methyloxy)methyl]-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (7.8 g, 65.6%). LCMS MH+=179.0 1H NMR (400 MHz, DMSO-d6) δ 12.47 (br s, 1H), 6.26 (s, 1H), 4.40 (s, 2H), 3.29 (s, 3H), 2.25 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:11]2[S:10](=[O:13])(=[O:12])[N:9]=[C:8]([C:14]3[C:15](=[O:30])[N:16]([NH:25][CH2:26][CH:27]4[CH2:29][CH2:28]4)[C:17]4[C:22]([C:23]=3[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=4)[NH:7][C:6]=2[S:5][CH:4]=1.C(N(CC)CC)C.[C:38]1([S:44](Cl)(=[O:46])=[O:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C)C=O>[CH:27]1([CH2:26][NH:25][N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]([OH:24])=[C:14]([C:8]3[NH:7][C:6]4[S:5][CH:4]=[C:3]([CH2:2][NH:1][S:44]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)(=[O:46])=[O:45])[C:11]=4[S:10](=[O:12])(=[O:13])[N:9]=3)[C:15]2=[O:30])[CH2:28][CH2:29]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=c1c(C2=NS(=O)(=O)c3c(CNS(=O)(=O)c4ccccc4)csc3N2)c(O)c2ccccc2n1NCC1CC1
Temperature: 23 °C
Reaction time: 0.75 h
Yield: 48.1 %

Procedure:
To a solution of the product of Example 353E (16.9 mg, 0.038 mmol) in N,N-dimethylformamide (0.4 mL) was added triethylamine (0.012 mL, 0.083 mmol) and benzene sulfonyl chloride (0.006 mL, 0.042 mmol). The reaction mixture was stirred at 23° C. for 0.75 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with a gradient of 10% acetonitrile/0.1% trifluoroacetic acid in water to 95% acetonitrile/0.1% trifluoracetic acid in water to give the title compound (10.7 mg, 48%). 1H NMR (300 MHz, DMSO-d6) δ 0.14 (d, J=4.04 Hz, 2 H) 0.41 (d, J=7.72 Hz, 2 H) 1.01 (m, J=7.54, 7.54 Hz, 1 H) 2.83 (d, J=6.99 Hz, 2 H) 4.07 (d, J=6.25 Hz, 2 H) 6.38 (bs, 1 H) 7.30 (s, 1 H) 7.41 (t, J=7.54 Hz, 1 H) 7.65 (m, 3 H) 7.86 (m, 3 H) 8.06 (d, J=8.82 Hz, 1 H) 8.15 (d, J=6.99 Hz, 1 H) 8.42 (t, J=6.25 Hz, 1 H) 14.43 (bs, 1 H).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:7]2[CH2:19][C:20]([O:22]CC)=[O:21].Cl>CO>[CH3:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:7]2[CH2:19][C:20]([OH:22])=[O:21]
Reactant: CCOC(=O)Cc1c(-c2ccccc2)[nH]c2ccc(C)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc2[nH]c(-c3ccccc3)c(CC(=O)O)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
Aqueous sodium hydroxide (4M, 75 mL) was added to ethyl 5-methyl-2-phenyl-1H-indole-3-acetate (Description 5, 1.61 g) in methanol (150 mL) and the mixture was stirred at room temperature for 2 h. The mixture was cooled to 0° C. , the pH was adjusted to 3.0 with hydrochloric acid (2M) and the mixture was extracted with ethyl acetate. The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was recrystallized from ether to give the title compound as a colourless solid (1.1 g, 76%). 1H NMR (360 MHz, CDCl3) δ2.47 (3H, s), 3.85 (3H, s), 7.05 (1H, dd, J 8.3, 1.4 Hz), 7.27 (1H, d, J 11.2 Hz), 7.36-7.49 (4H, m), 7.62 (1H, d, J 9.2 Hz), and 8.05 (1H, br s). m/z (ES+) 266 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([C:11]([NH2:13])=[O:12])[NH:5][N:4]=1)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH:20]1([CH2:23]Br)[CH2:22][CH2:21]1>CN(C=O)C>[CH:20]1([CH2:23][N:5]2[C:6]([C:11]([NH2:13])=[O:12])=[C:7]([N+:8]([O-:10])=[O:9])[C:3]([CH2:1][CH3:2])=[N:4]2)[CH2:22][CH2:21]1
Reactant: CCc1n[nH]c(C(N)=O)c1[N+](=O)[O-]
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCc1nn(CC2CC2)c(C(N)=O)c1[N+](=O)[O-]
Yield: 23 %

Procedure:
A suspension of 3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (40.0 g, 217 mmol, prepared using procedure in WO9849166) in dry DMF (300 ml) was treated with cesium carbonate (77.8 g, 239 mmol). To this, in a single portion, was added cyclopropylmethyl bromide (32.2 g, 239 mmol) and the resultant suspension stirred at 20° C. for 6 h. After concentrating in vacuo, the residue was partitioned between EtOAc (200 ml) and water (200 ml), and the insoluble material removed by filtration. The solid was partitioned between water (200 ml) and DCM (200 ml), and undissolved solid removed by filtration. Combined organics were washed with brine (100 ml), dried (MgSO4), filtered and concentrated in vacuo to a solid (˜40 g). The two regioisomers were separated by crystallisation of the crude mixture. The more lipophilic component (Rf=0.27, DCM:MeOH 98:2) crystallised from a mixture of DCM (50 ml) and diisopropylether (200 ml) to give 1-(cyclopropylmethyl)-3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (11.9 g, 50.0 mmol, 23%). Crystallisation of the mother liquors from MeCN gave the more polar component (Rf=0.19, DCM:MeOH 98:2) (10.0 g, 42.0 mmol) which was confirmed as 1-(cyclopropylmethyl)-5-ethyl-4-nitro-1H-pyrazole-3-carboxamide by nOe studies. The mother liquors contained further material as a mixture of regioisomers (20.0 g, 84.0 mmol). 1-(cyclopropylmethyl)-3-ethyl-4-nitro-1H-pyrazole-5-carboxamide:
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][N:7]([C:9]3[C:24]([CH3:25])=[C:14]4[C:15]5[C:20]([CH2:21][CH2:22][N:13]4[C:12](=[O:26])[CH2:11][N:10]=3)=[C:19](I)[CH:18]=[CH:17][CH:16]=5)[CH:8]=2)[CH2:3][CH2:2]1.[CH3:27][C:28]1[CH:32]=[C:31]([Sn](CCCC)(CCCC)CCCC)[O:30][N:29]=1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([C:4]2[N:5]=[CH:6][N:7]([C:9]3[C:24]([CH3:25])=[C:14]4[C:15]5[C:20]([CH2:21][CH2:22][N:13]4[C:12](=[O:26])[CH2:11][N:10]=3)=[C:19]([C:31]3[O:30][N:29]=[C:28]([CH3:27])[CH:32]=3)[CH:18]=[CH:17][CH:16]=5)[CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC1=C2c3cccc(I)c3CCN2C(=O)CN=C1n1cnc(C2CC2)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C)no1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC1=C2c3cccc(-c4cc(C)no4)c3CCN2C(=O)CN=C1n1cnc(C2CC2)c1
Temperature: 140 °C
Reaction time: 0.02 h
Yield: 56.9 %

Procedure:
Example 107. A mixture of 2-(4-cyclopropyl-1H-imidazol-1-yl)-9-iodo-1-methyl-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (8 mg, 17 μmol), 3-methyl-5-(tributylstannyl)isoxazole (10 mg, 26 μmol) and Pd(PPh3)4 (1.0 mg, 0.9 μmol) in dioxane (0.2 mL) is heated to 140° C. for 1.5 h under N2 in a microwave reactor. The mixture was then concentrated in vacuo the residue obtained was purified by SFC (column: 2-Ethylpyridine 5 μm, 250×30 mm, 60 A, Princeton; eluent: 8% MeOH/CO2 for 1 min, then from 8% MeOH/CO2 to 13% MeOH/CO2 in 6 min; then from 13% MeOH/CO2 to 50% MeOH/CO2 in 1 min; flow 100 mL/min; UV detection at 220 nm) to afford the title compound (4 mg) as a beige solid. UPLC-MS: MS 414.2 (M+H+); UPLC rt 0.88 min. 1H NMR (400 MHz, CHLOROFORM-d): δ ppm 0.74-0.88 (m, 4 H); 1.74-1.91 (m, 1 H); 2.18 (s, 3 H); 2.42 (s, 3 H); 2.81 (td, J=14.68, 5.27 Hz, 1 H); 3.17 (td, J=13.49, 3.64 Hz, 1 H); 3.45 (m., 1 H); 3.91-4.02 (m, 2 H); 4.70 (d, J=10.79 Hz, 1 H); 6.32 (s, 1 H); 6.95 (s, 1 H); 7.45 (t, J=7.65 Hz, 1 H); 7.56 (d, J=7.78 Hz, 1 H); 7.66-7.76 (m, 2 H).
Reaction SMILES: [O:1]([CH2:8][CH2:9]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:12].Cl>N1C=CC=CC=1>[Br:12][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrP(Br)Br
Reactant: OCCOc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: BrCCOc1ccccc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 118.1 %

Procedure:
To 3.25 ml (0.04 mmol) of pyridine were added 13.82 g (0.1 mol) of 2-phenoxy ethanol and 10.83 g (0.04 mol) of phosphorus tribromide, followed by reacting at 0° C. for 1 hour while stirring. The reaction solution was warmed up to 50° C. and then reacted for 1 hour while stirring. After completion of the reaction, excess 1N hydrochloric acid (0° C.) were added to the reaction solution and then subjected to an extraction procedure using chloroform. The resulting organic layer was washed with 1N hydrochloric acid, water and an aqueous solution of sodium hydrogen carbonate, then dried on magnesium sulfate and concentrated under a reduced pressure. An obtained crude product was purified by distillation to obtain 9.5 g of a desired 2-bromoethylphenyl ether (yield 47%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][N:5]([CH3:8])[C:4](=[O:9])[C:3]=1[NH:10][CH2:11][CH2:12][CH2:13]O.[Cl:15]CCl.S(Cl)(Cl)=O>>[Cl:1][C:2]1[CH:7]=[N:6][N:5]([CH3:8])[C:4](=[O:9])[C:3]=1[NH:10][CH2:11][CH2:12][CH2:13][Cl:15]
Reactant: Cn1ncc(Cl)c(NCCCO)c1=O
Reactant: ClCCl
Solvent: O=S(Cl)Cl
Product: Cn1ncc(Cl)c(NCCCCl)c1=O
Reaction time: 3 h
Yield: 73.2 %

Procedure:
0.48 g (2.2 mmoles) of 5-chloro-4-[N-(3-hydroxypropyl)-amino]-2-methyl-3(2H)-pyridazinone is dissolved in ml of dichloromethane, and 2.1 ml (28.8 mmoles) of thionyl chloride are dropped to the solution. Then it is boiled for 3 hours under stirring and reflux cooling. The solvent is evaporated and the crude product thus obtained is triturated with ether. Thus 0.38 g (73%) of the desired compound is obtained. M.p.: 91°-92° C.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][C:4]([NH:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[CH:17])[CH:14]=2)[NH:9][N:8]=1)=[O:5].[N:19]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=1)=[N+:20]=[N-:21].O.O[C@H]([C@@H]1C([O-])=C(O)C(=O)O1)CO.[Na+]>C(O)(C)(C)C.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:1][N:2]([CH3:18])[CH2:3][C:4]([NH:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[N:21]=[N:20][N:19]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=4)[CH:17]=3)[CH:14]=2)[NH:9][N:8]=1)=[O:5]
Reactant: Cc1cccc(CN=[N+]=[N-])c1
Reactant: C#Cc1ccc2[nH]nc(NC(=O)CN(C)C)c2c1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1cccc(Cn2cc(-c3ccc4[nH]nc(NC(=O)CN(C)C)c4c3)nn2)c1
Temperature: 60 °C

Procedure:
To a suspension of Example 282E (0.16 g, 0.660 mmol) in tert-butanol (1.2 mL) was added 1-(azidomethyl)-3-methylbenzene (0.098 g, 0.667 mmol), then water (1.2 mL). A solution of sodium (R)-2-((S)-1,2-dihydroxyethyl)-4-hydroxy-5-oxo-2,5-dihydrofuran-3-olate (0.057 mL, 0.066 mmol, 1.6 M in water) and an aqueous solution of copper (II) sulfate pentahydrate (0.019 mL, 6.6 μmol, 0.34M) was added. The reaction mixture was heated at about 60° C. for about 2 hours. The solvent was removed under reduced pressure and the residue was purified by reverse phase HPLC using acetonitrile/water (0.05 M ammonium acetate) gradient elution method to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.77 (s, 1H), 10.05 (s, 1H), 8.56 (s, 1H), 8.24 (s, 1H), 7.82 (d, 1H, J=8.6), 7.50 (d, 1H, J=8.8), 7.28 (t, 1H, J=7.6), 7.16 (m, 4H), 5.59 (s, 2H), 3.18 (s, 2H), 2.34 (s, 6H), 2.30 (s, 3H). MS (ESI+) m/z 390.3 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:41])[CH2:7][N:8]1[CH2:17][CH2:16][C:15]2[C:14]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28](=[O:40])[NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)[CH:23]=[CH:22]4)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:39][C:36]([F:37])([F:38])[C:32]1[CH:31]=[C:30]([NH:29][C:28]([N:24]2[C:25]3[C:21](=[CH:20][C:19]([O:18][C:14]4[C:15]5[CH2:16][CH2:17][N:8]([CH2:7][C:6]([OH:41])=[O:5])[CH2:9][C:10]=5[N:11]=[CH:12][N:13]=4)=[CH:27][CH:26]=3)[CH:22]=[CH:23]2)=[O:40])[CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)CN1CCc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN1CCc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)C1

Procedure:
A solution of {4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,8-dihydro-6H-pyrido[3,4-d]pyrimidin-7-yl}-acetic acid tert-butyl ester (250 mg, 0.44 mmol), DCM (5 mL), and TFA (5 mL) is stirred at rt for 1 h. The solution is concentrated in vacuo and separated via semi-prep HPLC (C18; 10-100% I/H2O with 0.1% NH4OH) to give the title compound. MS (ESI) m/z 512.0 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 8.41 (s, 1 H), 8.33 (d, J=9.1 Hz, 1 H), 8.06 (s, 1 H), 7.93 (d, J=3.5 Hz, 1 H), 7.89 (s, 1 H), 7.57 (t, J=8.1 Hz, 1 H), 7.38-7.47 (m, 2 H), 7.12 (dd, J=9.0, 2.4 Hz, 1 H), 6.74 (d, J=3.5 Hz, 1 H), 4.08 (s, 2 H), 3.56 (s, 2 H), 3.26 (t, J=6.1 Hz, 2 H), 3.07 (t, J=5.7 Hz, 2 H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([N:7]2[CH2:12][CH2:11][NH:10][CH:9]([C:13]([F:16])([F:15])[F:14])[CH2:8]2)=[C:5]([N+:17]([O-])=O)[CH:4]=[N:3]1.[NH4+].[Cl-]>CO.O.[Zn]>[CH3:1][N:2]1[C:6]([N:7]2[CH2:12][CH2:11][NH:10][CH:9]([C:13]([F:16])([F:15])[F:14])[CH2:8]2)=[C:5]([NH2:17])[CH:4]=[N:3]1
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCNC(C(F)(F)F)C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: Cn1ncc(N)c1N1CCNC(C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
To a solution of (±)-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)-3-(trifluoromethyl)piperazine (420 mg, 1.5 mmol) in MeOH (20 mL) and H2O (5 mL) was added zinc (590 mg, 4 mmol) and NH4Cl (805 mg, 10 mmol). The reaction mixture was stirred at ambient temperature for 2 hours and filtered through Celite. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using PE/EtOAc (10/1˜1/10) as eluting solvents to afford (±)-1-methyl-5-(3-(trifluoromethyl)piperazin-1-yl)-1H-pyrazol-4-amine (340 mg, 90%) as red solid. 1H NMR (500 MHz, DMSO-d6) δ (ppm): 6.84 (s, 1H), 3.38-3.52 (m, 5H), 3.13-3.17 (m, 2H), 2.94-3.00 (m, 2H), 2.50-2.78 (s, 3H), 1.98 (m, 1H); MS (ESI) m/z: 250 (M+1+).
Reaction SMILES: [BH4-].[Li+].CO.[F:5][C:6]([F:26])([F:25])[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[C:18]([C:20](OCC)=[O:21])[CH:17]=[CH:16][N:15]=2)=[CH:10][CH:9]=1>O1CCCC1>[F:26][C:6]([F:5])([F:25])[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[C:18]([CH2:20][OH:21])[CH:17]=[CH:16][N:15]=2)=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1ccnc(-c2ccc(OC(F)(F)F)cc2)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1ccnc(-c2ccc(OC(F)(F)F)cc2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 51.8 %

Procedure:
After lithium borohydride (3.0 M solution in tetrahydrofuran) (0.05 mL) and methanol (0.006 mL) was added dropwise to an ice-cold solution of ethyl 2-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxylate (29 mg) in tetrahydrofuran (3.0 mL), the mixture was stirred for 1 hr, then returned to room temperature and stirred for 30 min. After the solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate. After washing with 2N hydrochloric acid, saturated sodium hydrogen carbonate solution and brine, the organic phase was separated out. The solvent was distilled off under reduced pressure to afford the title compound (13 mg) as the residue.