Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([C@H:11]([NH:16][C:17]([C:19]2[C:27]3[N:26]=[C:25](Br)[CH:24]=[N:23][C:22]=3[N:21]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:20]=2)=[O:18])[C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].[CH3:37][N:38]1[CH:42]=[C:41]([Sn](CCCC)(CCCC)CCCC)[N:40]=[CH:39]1>CN(C=O)C.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.[Cu]I>[C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([C@H:11]([NH:16][C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([C:41]4[N:40]=[CH:39][N:38]([CH3:37])[CH:42]=4)[N:26]=3)[N:21]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:20]=2)=[O:18])[C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: CC(C)(C)[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CCC(C#N)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(C)cn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cn1cnc(-c2cnc3c(n2)c(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C(C)(C)C)cn3COCC[Si](C)(C)C)c1
Temperature: 80 °C
Yield: 95 %

Procedure:
In a pressure tube 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-]pyrazine-7-carboxylic acid [(R)-1-(4-cyano-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-amide (125 mg, 0.22 mmol) and 1-methyl-4-tributylstannanyl-1H-imidazole (97 mg, 0.26 mmol) were dissolved in DMF (2 mL). Pd(PPh3)4 (12.5 mg, 0.01 mmol) and CuI (8 mg, 0.04 mmol) were added. The tube was sealed and heated at 80° C. for 1.5 h. The reaction mixture was cooled to room temperature, quenched with H2O and extracted with EtOAc. The organic extracts were washed with saturated aqueous LiCl and brine, dried over MgSO4, and concentrated. The residue was purified by SiO2 chromatography (0-10% MeOH/EtOAc) to afford 121 mg (95%) of 2-(1-methyl-1H-imidazol-4-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-cyano-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-amide as a light brown gum.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:7][S:8][C:4]=2[CH:3]=1.[Cu](C#N)[C:18]#[N:19]>CN1CCCC1=O.Cl>[C:18]([C:2]1[CH:16]=[CH:15][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:7][S:8][C:4]=2[CH:3]=1)#[N:19]
Reactant: Brc1ccc2c(-c3ccccc3)csc2c1
Reactant: N#C[Cu]C#N
Agent: Cl
Solvent: CN1CCCC1=O
Product: N#Cc1ccc2c(-c3ccccc3)csc2c1

Procedure:
Combine 6-bromo-3-phenylbenzothiophene (0.5 g, 1.73 mmol) and copper cyanide (0.56 g, 6.23 mmol) and reflux 3 h in 1-methyl-2-pyrrolidinone (1.73 mL). Add ferric chloride (2.11 g, 7.79 mmol) in concentrated HCl (1.73 mL) and stir 1.5 h. Cool the mixture and partition between diethyl ether and brine. Dry the organic layer over Na2SO4, filter and evaporate onto silica gel. Purify the residue by chromatography on silica gel eluting with hexane/EtOAc (1:0 to 3:2 gradient) to give the desired intermediate that is used without further purification (0.27 g, 67%). MS (GCMS) m/z: 235 Mt
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=C[C:11]([CH:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)O)([O:12]N=C(C)C)[C:6]2=[CH:5][NH:4]1)[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CCOCC>ClCCl>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[C:11]([OH:12])=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCN1NC=C2C1=NC=CC2(ON=C(C)C)C(O)c1ccccn1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCn1ncc2c(O)c(-c3ccccn3)cnc21
Reaction time: 1 h
Yield: 95.2 %

Procedure:
(1-Ethyl-4-isopropylideneaminooxy-1H-pyrazolo[3,4-b]-pyridine-4-yl)(2-pyridyl)carbinol (8.3 g) was dissolved in 150 ml of dichloromethane and to this was added 6.5 g of pyridinium chlorochromate The reaction mixture was stirred 1 hour and then 300 ml of ether was added, after which the mixture was filtered through a pad of magnesium silicate. The pad was washed with a total of 2 liters of ether and then with 1 liter of 5% methanol/dichloromethane. Concentration of the combined filtrate under a reduced pressure gave 5.8 g of the 1-ethyl-4-hydroxy-5-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine, whose identity was confirmed by its mass spectrum.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=2)[N:4]=1.[CH2:32]([NH:34][CH2:35][CH2:36][CH3:37])[CH3:33]>>[CH2:32]([N:34]([CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=2)[N:4]=1)[CH2:35][CH2:36][CH3:37])[CH3:33]
Reactant: CCOC(=O)c1c(CBr)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: CCCNCC
Product: CCCN(CC)Cc1nc2cc(OC)c(OC)cc2c(-c2ccc(OC)c(OC)c2)c1C(=O)OCC

Procedure:
According to the same manner as that described in Example 29, ethyl 2-bromomethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate was reacted with N-ethyl-N-propylamine to give ethyl 2-(N-ethyl-N-propylaminomethyl)-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate. Colorless prisms, mp. 105°-106° C.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9]([OH:13])(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].[OH:14][C:15]1[CH:16]=[C:17]([C:21](=[O:23])[CH3:22])[CH:18]=[CH:19][CH:20]=1>C(O)(=O)C.C(Cl)Cl>[C:21]([C:17]1[CH:18]=[CH:19][C:20]([C:9]2([OH:13])[C:10](=[O:11])[C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:7]2=[O:8])=[C:15]([OH:14])[CH:16]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)c1cccc(O)c1
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)c1ccc(C2(O)C(=O)c3ccccc3C2=O)c(O)c1
Temperature: 110 °C
Yield: 79.4 %

Procedure:
To a solution of ninhydrin (1.00 g, 5.61 mmol) in acetic acid (20 ml) was added 1-(3-hydroxy-phenyl)-ethanone (0.76 g, 5.61 mmol), followed by heating for 3 hrs at 110° C. The reaction mixture was diluted with methylene chloride, extracted with 2N NaOH aqueous solution, and the concentrated organic layer was purified using column chromatography (ethylacetate:hexane=1:2) to afford the title compound (White, 1.32 g, 79%).
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].[Cl:18][C:19]1[C:24]2[NH:25][C:26]([CH3:28])=[N:27][C:23]=2[CH:22]=[C:21]([O:29][C:30]2[CH:35]=[C:34](Cl)[N:33]=[CH:32][N:31]=2)[CH:20]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:18][C:19]1[C:24]2[NH:25][C:26]([CH3:28])=[N:27][C:23]=2[CH:22]=[C:21]([O:29][C:30]2[N:31]=[CH:32][N:33]=[C:34]([N:14]3[CH2:13][CH2:12][C:5]4([O:4][C:3](=[O:17])[NH:2][C:7]5[N:8]=[CH:9][CH:10]=[CH:11][C:6]4=5)[CH2:16][CH2:15]3)[CH:35]=2)[CH:20]=1
Reactant: Cc1nc2cc(Oc3cc(Cl)ncn3)cc(Cl)c2[nH]1
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cc(Oc3cc(N4CCC5(CC4)OC(=O)Nc4ncccc45)ncn3)cc(Cl)c2[nH]1

Procedure:
90 mg (0.35 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 110 mg (0.37 mmol) 7-chloro-5-(6-chloropyrimidin-4-yloxy)-2-methyl-1H-benzo[d]imidazole and 0.14 mL (0.81 mmol) DIPEA in 2.0 mL DMF were stirred for 3 h at RT and 4 h at 40° C. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were combined and freeze-dried.
Reaction SMILES: Cl.[C:2]1([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[S:13][CH:14]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:21][C:22]1[N:26]([CH3:27])[N:25]=[CH:24][C:23]=1[CH2:28][C:29](O)=[O:30]>>[Cl:21][C:22]1[N:26]([CH3:27])[N:25]=[CH:24][C:23]=1[CH2:28][C:29]([N:18]1[CH2:19][CH2:20][CH:15]([C:12]2[S:13][CH:14]=[C:10]([CH2:9][CH2:8][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:11]=2)[CH2:16][CH2:17]1)=[O:30]
Reactant: Cn1ncc(CC(=O)O)c1Cl
Reactant: c1ccc(CCc2csc(C3CCNCC3)n2)cc1
Agent: Cl
Product: Cn1ncc(CC(=O)N2CCC(c3nc(CCc4ccccc4)cs3)CC2)c1Cl

Procedure:
4-[4-(2-Phenylethyl)-1,3-thiazol-2-yl]piperidine hydrochloride (II-1, 280 mg) is reacted analogously to Example I-63 with (5-chloro-1-methyl-1H-pyrazol-4-yl)acetic acid (174 mg). After chromatographic purification, this gives 2-(5-chloro-1-methyl-1H-pyrazol-4-yl)-1-{4-[4-(2-phenylethyl)-1,3-thiazol-2-yl]piperidin-1-yl}ethanone (89 mg).
Reaction SMILES: [CH3:1][C:2]([NH2:10])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:3].[CH3:11][C:12]1[C:13]([CH:19]=O)=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:11][C:12]1[C:13]([CH2:19][NH:10][C:2]([CH3:3])([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=2)[CH3:1])=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=1
Reactant: Cc1cnc(C=O)c(C)c1
Reactant: CC(C)(N)c1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(CNC(C)(C)c2ccccn2)c(C)c1
Yield: 36 %

Procedure:
Using General Procedure B: Reaction of 1-methyl-1-pyridin-2-yl-ethylamine, 3,5-dimethylpyridine-2-carbaldehyde and NaBH(OAc)3 in CH2Cl2 gave (3,5-dimethyl-pyridin-2-ylmethyl)-(1-methyl-1-pyridin-2-yl-ethyl)-amine as a light brown oil (94 mg, 36%).
Reaction SMILES: [C:1](=[O:26])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[N:15]3[C:20](=[O:22])[CH3:21])[C:11]2[C:6]1=[C:7]([OH:25])[CH:8]=[C:9]([CH:23]=[O:24])[CH:10]=2)[NH2:2].[C:27](=O)([O-])[O-].[K+].[K+]>CC(C)=O.CI>[C:1](=[O:26])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[N:15]3[C:20](=[O:22])[CH3:21])[C:11]2[C:6]1=[C:7]([O:25][CH3:27])[CH:8]=[C:9]([CH:23]=[O:24])[CH:10]=2)[NH2:2]
Reactant: CC(=O)N1C2CN3OC(O)(C(COC(N)=O)c4c(O)cc(C=O)cc43)C21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc(C=O)cc2c1C(COC(N)=O)C1(O)ON2CC2C1N2C(C)=O
Temperature: 45 °C
Reaction time: 8 h
Yield: 19.3 %

Procedure:
11-Acetyl-4-formyl-6,9-dihydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (55 mg) was dissolved in a mixture of acetone (2 ml) and methyl iodide (2 ml). To the solution was added potassium carbonate (150 mg), and the mixture was stirred at 45° C. overnight under nitrogen atmosphere. The mixture was cooled to room temperature and filtered, and the filter cake was washed with a mixture of chloroform and acetone (1:1, v/v, 10 ml). The filtrate and the washings were combined and evaporated in vacuo. The residue was subjected to column chromatography on silica gel, and elution was carried out with a mixture of chloroform and acetone (4:1, v/v). The desired fractions were collected and evaporated to dryness. The residue was subjected to preparative thin layer chromatography, which was developed with a mixture of chloroform and methanol (1:1, v/v) to afford 11-acetyl-4-formyl-9-hydroxy-6-methoxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (11 mg).
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][C:7]1[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][C:8]=1[OH:9].[OH-].[Na+].Cl.CN([CH:21]=[O:22])C>O>[OH:9][C:8]1[C:7]([CH3:6])=[C:13]([OH:14])[CH:12]=[CH:11][C:10]=1[CH:21]=[O:22]
Reactant: CN(C)C=O
Reactant: Cc1c(O)cccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1c(O)ccc(C=O)c1O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To an ice-cooled solution of POCl3 (4.9 g, 32.2 mmol) in dry DMF (10.0 mL, 64.4 mmol) was slowly added a solution of 2-methylresorcinol (2.0 g, 16.1 mmol) in dry DMF (5.0 mL). After stirring at room temperature for 12 h, the mixture was cooled to 0° C. and then carefully treated with iced water (15 mL). 2 M sodium hydroxide was added to adjust pH to 10. The resulting mixture was heated to reflux for 10 min. Then, the mixture was acidified by 3 M HCl (pH=3). The resulting solid was collected by filtration, and the precipitate was washed with water (10 mL×3). The obtained orange solid (4.0 g, 46%) was dried in vacuo and used for the next reaction without further purification. 1H-NMR (DMSO-d6, 400 MHz): δ9.71 (1H, s), 7.43 (1H, d, J=8.5 Hz), 6.55 (1H, d, J=8.5 Hz), 1.97 (3H, s).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].I[CH3:17]>CN(C=O)C>[CH3:17][N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: CI
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c2ccccc2c2ccccc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 76.7 %

Procedure:
To a solution of carbazole (3.34 g, 20 mmol) in DMF (80 mL) at 0° C. was added NaH (0.72 g, 30 mmol). After heating at 80° C. for 1.5 h, iodomethane (3.4 g, 24 mmol) was added dropwise. The resulting mixture was kept at 80° C. overnight. After cooling down to 0° C., the reaction mixture was carefully quenched with water and extracted with ethyl acetate three times. The combined organic phase was washed with water and brine. Then the organic layer was dried over anhydrous sodium sulfate and the solvent was removed. The residue was purified by silica gel chromatography using petroleum ether and ethyl acetate as eluent (EA:PE=1:5) to afford methylated carbazole 1b (2.78 g) as yellow oil in 77% yield. 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J=8.0 Hz, 2H), 7.46 (t, J=8.0 Hz, 2H), 7.36 (d, J=8.0 Hz, 2H), 7.22 (t, J=8.0 Hz, 2H), 3.79 (s, 3H). 13C NMR (400 MHz, CDCl3) δ 140.9, 125.6, 122.7, 120.2, 118.8, 108.4, 28.9.
Reaction SMILES: [C@:1]12([CH3:28])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:10]([O:12][CH:13]([C:18]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=1[N+:25]([O-:27])=[O:26])[C:14](C)([CH3:16])[CH3:15])=[O:11]>CO>[C@:1]12([CH3:28])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:10]([O:12][CH:13]([C:18]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=1[N+:25]([O-:27])=[O:26])[CH:14]([CH3:15])[CH3:16])=[O:11]
Reactant: CC(C)(C)C(OC(=O)C1CC2CC[C@]1(C)C2(C)C)c1ccc(I)cc1[N+](=O)[O-]
Solvent: CO
Product: CC(C)C(OC(=O)C1CC2CC[C@]1(C)C2(C)C)c1ccc(I)cc1[N+](=O)[O-]
Reaction time: 48 h
Yield: 39 %

Procedure:
(R or S)-1-(4-Iodo-2-nitrophenyl)-2,2-dimethyl-1-propyl (1S)-camphanate: (RS)-1-(4-Iodo-2-nitrophenyl)-2,2-dimethyl-1-propyl (1S)-camphanate (2.07 g) was dissolved in boiling methanol (100 mL) and left at room temperature for two days. Crystals formed were filtered to yield pure single diastereomer (R or S)-1-(4-iodo-2-nitrophenyl)-2-methyl-1-propyl (1S)-camphanate (0.409 g, 39%). The absolute configuration of the single diastereomer camphanate is not determined. 1H NMR (400 MHz, CDCl3): δ 8.23 (d, 1H, J=2.0 Hz, Ph-H), 7.89 (dd, 2H, J=2.0 and 8.4 Hz, Ph-H), 7.30 (d, 1H, J=8.4 Hz, Ph-H), 6.56 (s, 1H, Ph-CH), 2.42 (m, 1H), 2.07 (m, 1H), 1.94 (m, 1H), 1.73 (m, 1H), 1.11, 1.04 and 0.87 (3 s, 9H, CH3 3), 0.95 (s, 9H, (CH3)3C).
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[Br:15]Br>CC(O)=O>[Br:15][C:11]1[CH:10]=[C:9]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:7][C:6]=1[NH:5][C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Nc1ccc([N+](=O)[O-])cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(C)(C)Nc1ccc([N+](=O)[O-])cc1Br
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
To a solution of N-tert-butyl-4-nitroaniline (1 g, 5.1 mmol) in AcOH (5 mL) was added Br2 (0.86 g, 54 mmol) dropwise at 15° C. After addition, the mixture was stirred at 30° C. for 30 min and then filtered. The filter cake was basified to pH 8-9 with aqueous NaHCO3. The aqueous layer was extracted with EtOAc (10 mL×3). The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated under vacuum to give (2-bromo-4-nitro-phenyl)-tert-butyl-amine (0.6 g, 43%). 1H-NMR (CDCl3, 400 MHz) δ 8.37 (dd, J=2.4 Hz, 1H), 8.07 (dd, J=2.4, 9.2 Hz, 1H), 6.86 (d, J=9.2 Hz, 1H), 5.19 (brs, 1H), 1.48 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].[CH3:27]I>CN(C=O)C>[CH3:27][O:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CI
Reactant: COC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)C2)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)C2)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 2-hydroxy-4-(1-tert-butyloxycarbonyl-3-pyrrolidinyloxy)benzoate from Step 1 above (2.26 g, 6.70 mmol) in DMF (40 mL) under N2, was added NaH (400 mg, 10.1 mmol). The reaction mixture was cooled, and CH3I (0.83 mL, 13.4 mmol) was added via syringe. The reaction mixture was allowed to warm to ambient temperature, and stirred for an additional 2 hours. The solvent was removed under reduced pressure, and the residue was partitioned between ethyl acetate and aqueous NaHCO3. The ethyl acetate layer was dried (MgSO4), filtered, and evaporated under reduced pressure. The residue was purified using pressurized silica gel column chromatography, eluting with 20% ethyl acetate in hexanes. Methyl 2-methoxy-4-(1-tert-butyloxycarbonyl-3-pyrrolidinyloxy)-benzoate was obtained as a colorless oil which crystallized on standing overnight.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][N:18]=[CH:17][C:16]=2[CH2:20][CH2:21][C:22](O)=[O:23])=[CH:11][CH:10]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:22](=[O:23])[CH2:21][CH2:20][C:16]2[CH:17]=[N:18][O:19][C:15]=2[C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=2)[CH:3]=1
Reactant: Nc1cccnc1
Reactant: O=C(O)CCc1cnoc1-c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCc1cnoc1-c1ccc(Cl)cc1)Nc1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
A mixture of 3-aminopyridine (0.18 g), 3-[5-(4-chlorophenyl)-4-isoxazolyl]propionic acid (0.50 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.35 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.45 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-(3-pyridyl)-3-[5-(4-chlorophenyl)-4-isoxazolyl]propionamide (0.60 g, yield 96%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from acetone-hexane. melting point: 197–198° C.
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([CH:30]2[CH2:35][CH2:34][N:33]([C:2]3[C:3]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:4][C:5]4[C:10]([N:11]=3)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=4)[CH2:32][CH2:31]2)=[CH:28][CH:29]=1
Reactant: COc1ccc(C2CCNCC2)cc1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Cl)nc2c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC(c4ccc(OC)cc4)CC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
A solution of methyl 3-chloro-2-phenylquinoxaline-6-carboxylate (150 mg, 0.50 mmol, 1.00 equiv), 4-(4-methoxyphenyl)piperidine (191 mg, 1.00 mmol, 2.00 equiv), and DIEA (194.8 mg, 1.51 mmol, 5.00 equiv) in DMF (4 mL) was placed in an 8-mL sealed tube and stirred overnight at 100° C. in an oil bath. The reaction was then quenched by the addition of water, and the resulting mixture was concentrated under vacuum. Purification via silica gel column (ethyl acetate/petroleum ether (1:50)) yielded 179.6 mg (63%) of methyl 3-(4-(4-methoxyphenyl)piperidin-1-yl)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [N:1]1([C:6]2[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.N1C=CC=CC=1.Cl[C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21]>O1CCCC1>[N:1]1([C:6]2[CH:12]=[CH:11][C:9]([NH:10][C:20](=[O:21])[O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1ccc(-n2ccnc2)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(-n2ccnc2)cc1)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
To a solution of 4-(1H-imidazol-1-yl)aniline (1.00 g, 6.28 mmol) and pyridine (1.52 ml, 18.8 mmol) in tetrahydrofuran (20 ml) was added 2,2,2-trichloroethyl chloroformate (1.30 ml, 9.42 mmol) with ice-cooling, the mixture was stirred for 1 hour with ice-cooling, the reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain the desired product (1.83 g, 87.1%) as a solid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.F[C:16]1[C:17]([CH3:36])=[N:18][C:19]2[C:24]([N:25]=1)=[C:23]([C:26]1[NH:34][C:33]3[CH2:32][CH2:31][NH:30][C:29](=[O:35])[C:28]=3[CH:27]=1)[CH:22]=[CH:21][CH:20]=2>CS(C)=O>[CH3:36][C:17]1[C:16]([NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]2)=[N:25][C:24]2[C:19]([N:18]=1)=[CH:20][CH:21]=[CH:22][C:23]=2[C:26]1[NH:34][C:33]2[CH2:32][CH2:31][NH:30][C:29](=[O:35])[C:28]=2[CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Solvent: CS(C)=O
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 100 °C
Reaction time: 2 h
Yield: 1 %

Procedure:
Prepared according to Example 131, using (R)-3-amino-1-boc-piperidine (180 μL, 0.759 mmol, CNH Technologies, Inc., Woburn, Mass.), 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 75 mg, 0.253 mmol), and DMSO (2.5 mL) and stirring at 100° C. for 2 h. Purification by column chromatography (silica gel: 0.5 to 10% MeOH/DCM) and reverse phase chromatography (Phenomenex Gemini column, 10 micron, C18, 100 Å, 150×30 mm, 0.1% TFA in ACN/H2O, gradient 5% to 95%) provided tert-butyl (3R)-3-((3-methyl-8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)-2-quinoxalinyl)amino)-1-piperidinecarboxylate (1.2 mg, 1.0%) as the free base after washing with saturated aq. NaHCO3, extracting with 10% MeOH/DCM, drying over Na2SO4, and concentrating under reduced pressure. 1H NMR (CDCl3) δ: 12.37-12.47 (m, 1H), 7.93-7.98 (m, 1H), 7.66-7.71 (m, 1H), 7.37-7.44 (m, 1H), 7.11-7.16 (m, 1H), 5.43-5.49 (m, 1H), 4.10-4.19 (m, 2H), 3.63-3.70 (m, 4H), 2.93-3.00 (m, 3H), 2.57-2.60 (m, 3H), 2.04-2.06 (m, 2H), 1.78-1.91 (m, 3H), 1.59-1.77 (m, 9H). m/z (ESI, +ve) 477.2 (M+H)+.