Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[C:26]1([CH3:35])[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1.Cl>C(#N)C>[O:25]=[C:19]1[CH:18]([N:12]2[CH2:11][C:10]3[C:14](=[CH:15][CH:16]=[C:8]([CH2:7][NH:6][C:33]([NH:32][C:29]4[CH:30]=[CH:31][C:26]([CH3:35])=[CH:27][CH:28]=4)=[O:34])[CH:9]=3)[C:13]2=[O:17])[CH2:23][CH2:22][C:21](=[O:24])[NH:20]1
Reactant: Cc1ccc(N=C=O)cc1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CC#N
Product: Cc1ccc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 46.7 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonate (0.37 g, 1.00 mmol) and p-tolyl-isocyanate (0.13 g, 1.00 mmol) in acetonitrile (30 mL) at 0° C. was added TEA (0.20 g, 2.0 mmol) dropwise over 10 min. The mixture was stirred at ambient temperature for 1.5 h and then 10% aqueous HCl solution (30 mL) was added. The solid precipitate was filtered, washed with water (20 mL) and dried in vacuo providing 1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-p-tolyl-urea as a white solid (0.19 g, 46% yield); mp 267-269° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 4.30 (99.66%); 1H NMR (DMSO-d6) δ 1.91-2.08 (m, 1H, CHH), 2.21 (s, 3H, CH3), 2.28-2.47 (m, 1H, CHH), 2.53-2.68 (m, 1H, CHH), 2.80-3.02 (m, 1H, CHH), 4.31 (d, 1H, CHH), 4.36-4.52 (m, 3H, CH2 and CHH), 5.11 (dd, J=4.8, 13.1 Hz, 1H, CH), 6.69 (t, 1H, NH), 7.02 (d, 2H, Ar), 7.29 (d, J=8.1 Hz, 2H, Ar), 7.42 (d, 1H, Ar), 7.51 (s, 1H, Ar), 7.69 (d, 1H, Ar), 8.52 (s, 1H, NH), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.28, 22.49, 31.20, 42.76, 45.72, 47.12, 51.56, 117.84, 121.86, 122.91, 126.89, 129.01, 129.84, 130.27, 137.81, 142.38, 144.93, 155.28, 167.95, 170.99, 172.85; LCMS: MH=407; Anal. Calcd for C22H22N4O4: C, 65.01; H, 5.46; N, 13.78. Found: C, 64.75; H, 5.48; N, 13.66.
Reaction SMILES: Cl[C:2](OCC)=[O:3].[S:7]1[CH:11]=[CH:10][N:9]=[C:8]1[NH:12][S:13]([C:16]1[CH:34]=[CH:33][C:19]([C:20]([NH:22][NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)=[NH:21])=[CH:18][CH:17]=1)(=[O:15])=[O:14]>C1COCC1>[Cl:32][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[Cl:31])[CH2:24][N:23]1[C:2](=[O:3])[NH:21][C:20]([C:19]2[CH:18]=[CH:17][C:16]([S:13]([NH:12][C:8]3[S:7][CH:11]=[CH:10][N:9]=3)(=[O:15])=[O:14])=[CH:34][CH:33]=2)=[N:22]1
Reactant: CCOC(=O)Cl
Reactant: N=C(NNCc1ccc(Cl)c(Cl)c1)c1ccc(S(=O)(=O)Nc2nccs2)cc1
Solvent: C1CCOC1
Product: O=c1[nH]c(-c2ccc(S(=O)(=O)Nc3nccs3)cc2)nn1Cc1ccc(Cl)c(Cl)c1
Temperature: 95 °C
Reaction time: 2 h

Procedure:
Ethyl chloroformate (0.05 mL) was added to a solution of 4-(thiazol-2-ylsulfamoyl)-N-(3,4-dichlorobenzylamino)-benzamidine (0.044 mmol) and TEA (0.20 mL) in THF (5 mL) at room temperature and the resulting solution was stirred for 2 h. After concentrating in vacuo 1 N NaOH (4 mL) was added and the solution was heated to 95° C. overnight. After the mixture was cooled to room temperature, the solution was acidified with 1 N HCl and freeze dried. The crude material was purification by reverse phase chromatography to yield 4-[1-(3,4-dichloro-benzyl)-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-yl]-N-thiazol-2-yl-benzenesulfonamide (0.002 mmol).
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[C:3]#[CH:4].[Cl:6][C:7]1[CH:12]=[C:11]2[NH:13][C:14](=[O:40])[C:15]3([CH:20]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=4)[CH2:19][C:18](=[O:28])[NH:17][CH:16]3[C:29]3[CH:34]=[C:33](I)[CH:32]=[CH:31][C:30]=3[O:36][CH2:37][CH2:38][OH:39])[C:10]2=[CH:9][CH:8]=1.C(N(CC)CC)C>CN(C)C=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:6][C:7]1[CH:12]=[C:11]2[NH:13][C:14](=[O:40])[C:15]3([CH:20]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=4)[CH2:19][C:18](=[O:28])[NH:17][CH:16]3[C:29]3[CH:34]=[C:33]([C:4]#[C:3][CH:2]([CH3:5])[CH3:1])[CH:32]=[CH:31][C:30]=3[O:36][CH2:37][CH2:38][OH:39])[C:10]2=[CH:9][CH:8]=1
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(I)ccc2OCCO)N1
Reactant: C#CC(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C#Cc1ccc(OCCO)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1

Procedure:
In a manner similar to the method described in example 209a, 3-methyl-1-butyne (0.22 g, 3.2 mmol) was used in place of 3,3-dimethyl-1-butyne to react with racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-iodo-2-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.2 g, 0.32 mmol) prepared in Example 190c, CuI (3 mg), triethylamine (0.97 g, 9.6 mmol), and dichlorobis(triphenylphosphine)palladium (11.2 mg, 0.016 mmol) in anhydrous N,N-dimethylformamide to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-(3-methyl-1-butynyl)-2-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a off white solid (Yield 50 mg, 28%)
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.[Br:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=1[CH3:32].O>C(Cl)(Cl)Cl>[Br:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=1[CH2:32][Br:8]
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Solvent: O
Product: COC(=O)c1ccc(Br)c(CBr)c1
Temperature: 70 °C
Reaction time: 48 h

Procedure:
NBS (46.6 g, 262 mmol) and AIBN (0.72 g, 4.4 mmol) were added in one portion into a solution of methyl 4-bromo-3-methylbenzoate (50.0 g, 218 mmol) in CHCl3 (1 L) under N2. The mixture was stirred at 70° C. for 2 days. The reaction mixture was cooled to RT and water (500 mL) was added. The organic layer was washed with a saturated solution of NaHCO3 (50 mL), water (350 mL) and brine (500 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was washed with pentane (2×500 mL) affording the title compound as a yellow solid. HPLC (Method A), Rt 4.9 min (Purity: 98.2%). 1H NMR (DMSO-d6, 300 MHz) δ 8.24 (d, J=1.9 Hz, 1H), 7.85 (m, 2H), 4.87 (s, 2H), 3.91 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH3:37][C:38]1([CH3:44])[O:43][CH2:42][CH2:41][NH:40][CH2:39]1.[Cl-].[NH4+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:40]1[CH2:41][CH2:42][O:43][C:38]([CH3:44])([CH3:37])[CH2:39]1)=[O:6]
Reactant: Cc1cccc(C(=O)O)c1Br
Reactant: CC1(C)CNCCO1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cccc(C(=O)N2CCOC(C)(C)C2)c1Br

Procedure:
A solution of 2-bromo-3-methylbenzoic acid (344 mg, 1.6 mmol) and HATU (913 mg, 2.400 mmol) in DMF (10 mL) was stirred for 10 min at RT. 2,2-Dimethylmorpholine hydrochloride (364 mg, 2.400 mmol) and 1,1′-dimethyl triethylamine (2.23 mL, 12.80 mmol) were added and the reaction mixture was allowed to stir for 4 h at RT Ammonium chloride solution and EtOAc was added. The organic phase was separated and washed twice with brine. The organic phase was dried over MgSO4 and the solvent was removed under reduced pressure. The remaining residue was purified by flash chromatography (40-100% EtOAc/hexanes). (2-Bromo-3-methylphenyl)(2,2-dimethylmorpholino)methanone was obtained as a yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([SH:7])=[N:5][N:4]=[N:3]1.Br[CH2:9][CH2:10][CH2:11][Cl:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][N:2]1[C:6]([S:7][CH2:9][CH2:10][CH2:11][Cl:12])=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1S
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1nnnc1SCCCCl
Yield: 111.4 %

Procedure:
1-Methyl-5-mercapto-1,2,3,4-tetrazole (4.6 g) and 1-bromo-3-chloropropane (9.4 g) are dissolved in acetone (100 ml). Potassium carbonate (6.8 g) is added to the solution and the mixture is refluxed for 3 hours. Acetone is distilled off and water is added to the residue. The mixture is extracted with chloroform and the chloroform solution is washed with saturated aqueous sodium chloride and dried over magnesium sulfate. Chloroform is distilled off and the residue is purified by silica gel column chromatography (Wakogel C-200 made by Wako Jun Yaku Co., Ltd.). The column is eluted with benzene-ether (5:1, V/V) to obtain 1-methyl-5-(3-chloropropyl)thio-1,2,3,4-tetrazole (8.5 g) as colorless liquid. nD14 =1.5396
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1.[CH2:15]([O:17][C:18](=[O:23])[CH:19]=[C:20](Cl)[CH3:21])[CH3:16]>O1CCCC1>[CH2:15]([O:17][C:18](=[O:23])/[CH:19]=[C:20](/[O:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([Br:7])[CH:9]=1)\[CH3:21])[CH3:16]
Reactant: CCOC(=O)C=C(C)Cl
Reactant: Oc1cccc(Br)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1cccc(Br)c1
Temperature: 23 °C
Yield: 38.8 %

Procedure:
Potassium t-butoxide (10.5 g, 0.094 mol) was added to a stirred solution of 3-bromo-phenol (8.18 g, 0.047 mol) in tetrahydrofuran (30 mL) at 23° C. under nitrogen and the reaction mixture was heated to reflux for 0.75 h. The reaction mixture was cooled to 23° C. and a solution of 3-chloro-but-2-enoic acid ethyl ester (prepared as in Example 191, 7.00 g, 0.047 mol) in tetrahydrofuran (40 mL) was added to the reaction mixture. The reaction mixture was refluxed for an additional 3 h. After this time, the mixture was concentrated in vacuo and the residue was diluted with water and extracted with diethyl ether. The organic layer was then washed with 5% aqueous sodium hydroxide solution followed by a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to afford (E)-3-(3-bromo-phenoxy)-but-2-enoic acid ethyl ester (5.20 g, 39%) as a yellow oil.
Reaction SMILES: [C:1]([N:4]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[C:25]([F:26])=[CH:24][C:23]([F:27])=[C:22]([NH2:28])[C:18]=3[C:19](=[O:21])[CH:20]=2)=[CH:11][C:10]=1[F:29])[CH2:5][CH2:6][CH2:7]Cl)(=[O:3])[CH3:2].[I-:30].[Na+]>C(C(C)=O)C>[C:1]([N:4]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[C:25]([F:26])=[CH:24][C:23]([F:27])=[C:22]([NH2:28])[C:18]=3[C:19](=[O:21])[CH:20]=2)=[CH:11][C:10]=1[F:29])[CH2:5][CH2:6][CH2:7][I:30])(=[O:3])[CH3:2]
Reactant: CC(=O)N(CCCCl)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CC(=O)N(CCCI)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Temperature: 25 °C
Yield: 93.2 %

Procedure:
6.31 g (14.9 mmol) of 2-[4-[N-acetyl-N-(3-chloropropyl) amino]-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one obtained in Example 50 was dissolved in 240 mL of methyl ethyl ketone, 6.09 g (149 mmol) of sodium iodide was added and the mixture was heated at reflux for 4 hours. The reaction solution was cooled to room temperature and filtered. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform-chloroform:methanol=50:1) to give 7.17 g of 2-[4-[N-acetyl-N-(3-iodopropyl)amino]-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one (yield: 93%).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[CH:11]1([NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C([BH3-])#N.[Na+].Cl>C(#N)C.C(O)(=O)C>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH2:1][NH:17][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: NC1CCCCC1
Reactant: COc1cccc(C=O)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COc1cccc(CNC2CCCCC2)c1
Reaction time: 16 h
Yield: 83.2 %

Procedure:
A solution of m-anisaldeyde (500 mg, 3.67 mmol) and cyclohexylamine (420 μL, 3.67 mmol) in acetonitrile (30 mL) was stirred for 4 h and slowly treated with sodium cyanoborohydride (227 mg, 4.4 mmol). Glacial acetic acid was added until pH˜6 (pH paper), and the solution was stirred for 16 h. Conc. HCl (0.5 mL) was added and acetonitrile was evaporated under reduced pressure. The crude residue was quenched with water (100 mL) and extracted with ethyl acetate. The aqueous phase was basified with 10% aqueous NaOH until pH>7 and extracted with dichloromethane (3×50 mL). The organic phase was dried over magnesium sulfate, filtered, and evaporated under reduced pressure without heating to provide 670 mg of N-(3-methoxybenzyl)-cyclohexylamine (83% yield) as a light oil. 1H NMR (300 MHz, acetone-d6) δ 1.05-1.30 (m, 5H), 1.58 (m, 1H), 1.72 (m, 2H), 1.89 (m, 2H), 2.45 (m, 1H), 3.77 (s, 2H), 3.79 (s, 3H), 6.77 (dd, J=2.1 and 8.2 Hz, 1H), 6.92 (d, J=7.5 Hz, 1H), 6.96 (s, 1H), 7.21 (t, J=7.8 Hz, 1H) ppm.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[C:42](O)=[O:43])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:45]1([C:51]2[CH:52]=[C:53]([CH:56]=[CH:57][CH:58]=2)[CH2:54][NH2:55])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[C:42](=[O:43])[NH:55][CH2:54][C:53]1[CH:52]=[C:51]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:58]=[CH:57][CH:56]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](C(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Reactant: NCc1cccc(-c2ccccc2)c1
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](C(=O)NCc4cccc(-c5ccccc5)c4)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
According to general procedure D, 0.07 g of (2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1,2-dicarboxylic acid 1-benzyl ester and 3-phenylbenzylamine are reacted to afford the title compound as a colourless solid. Rf=0.15 (EtOAc-heptan 1:1:1); Rt=5.62.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[CH2:17]([SH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCO>[CH2:17]([S:24][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1cccnc1SCc1ccccc1
Yield: 95.9 %

Procedure:
In a similar fashion using route 38 general procedure 92, 2-chloro-3-nitro-pyridine(2 g, 12.7 mmol), Na2CO3 (1.75 g, 16.6 mmol), benzylmercaptan (1.87 g, 15.1 mmol) and EtOH (20 ml) at 90° C. for 4 h gave the title compound (3 g, 96%) which was used in the next step without further purification. The structure was confirmed by 1H NMR.
Reaction SMILES: O.[NH:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]([CH2:11][C@@H:12]([C:14](O)=[O:15])[NH2:13])=[CH:3]1.S(C)C.B>C1COCC1>[NH2:13][CH:12]([CH2:11][C:4]1[C:5]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[NH:2][CH:3]=1)[CH2:14][OH:15]
Reactant: N[C@@H](Cc1c[nH]c2ncccc12)C(=O)O
Agent: B
Solvent: O
Solvent: CSC
Solvent: C1CCOC1
Product: NC(CO)Cc1c[nH]c2ncccc12
Yield: 51.2 %

Procedure:
To a stirred solution of 3-(1H-pyrrolo[2,3-b]pyridin-3-yl)alanine monohydrate (10.0 g, 50.0 mmol) in THF (140 mL) at 0° C. was slowly added BF3.Et2O complex (7.0 mL, 60.0 mmol) followed by BH3.Me2S complex (10M in THF, 14.5 mL, 145.0 mmol). The reaction mixture was stirred at r.t. for 16 h and on completion the excess borane was quenched by the addition of MeOH (5 mL) at 0° C. The reaction mixture was concentrated, dissolved in EtOAc (120 mL) and washed with aqueous 20% NaOH solution (2×60 mL). The organic layer was then extracted into aqueous 2M HCl (2×150 mL). The combined acidic aqueous layers were then basified to pH 14 (addition of solid NaOH) and re-extracted with EtOAc (2×100 mL). The combined organic fractions were then dried over MgSO4, filtered and concentrated in vacuo to give the title compound as a white solid (4.9 g, 52%). δH (MeOD-d3) 12.13 (1H, br. s), 8.97 (1H, dd, J 4.7 and 1.5 Hz), 8.06 (1H, s), 7.82 (1H, m), 4.12 (1H, dd, J 10.3 and 4.9 Hz), 4.01 (1H, dd, J 10.3 and 6.5 Hz), 3.75 (1H, m), 3.59 (1H, dd, J 14.0 and 5.5 Hz), 3.37 (1H, dd, J 14.0 and 7.3 Hz). Exchangeable protons were not observed.
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[Cl-].[NH4+].[N:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[C:62]1[N:66]2[CH:67]=[C:68]([C:71]3[C:72]([C:95]4[CH:103]=[CH:102][C:98]([C:99]([OH:101])=O)=[CH:97][CH:96]=4)=[N:73][N:74]([C:76]([C:89]4[CH:94]=[CH:93][CH:92]=[CH:91][CH:90]=4)([C:83]4[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=4)[C:77]4[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=4)[CH:75]=3)[CH:69]=[CH:70][C:65]2=[N:64][CH:63]=1>O.C(OCC)(=O)C.CN(C)C=O>[N:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[C:62]1[N:66]2[CH:67]=[C:68]([C:71]3[C:72]([C:95]4[CH:96]=[CH:97][C:98]([C:99]([NH2:8])=[O:101])=[CH:102][CH:103]=4)=[N:73][N:74]([C:76]([C:83]4[CH:84]=[CH:85][CH:86]=[CH:87][CH:88]=4)([C:89]4[CH:90]=[CH:91][CH:92]=[CH:93][CH:94]=4)[C:77]4[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=4)[CH:75]=3)[CH:69]=[CH:70][C:65]2=[N:64][CH:63]=1
Reactant: O=C(O)c1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccccn4)n3c2)cc1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccccn4)n3c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 114.2 %

Procedure:
125 mg benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate, 1-hydroxy-1H-benzotriazole monohydrate, 83 mg diisopropylethylamine, and 18 mg ammonium chloride were added in this order to a mixture of 100 mg 4-{4-[3-(2-pyridyl)imidazo[1,2-a]pyridin-6-yl]-1-trityl-1H-3-pyrazolyl} benzoic acid obtained in Example 46 and 3 mL N,N-dimethylformamide, and the mixture was stirred at room temperature for 2 hour. Ethyl acetate and water were added to the reaction solution, the organic layer was separated, the solvent was evaporated, and the residue was purified by NH silica gel column chromatography (hexane/ethyl acetate) to give 114 mg of the title compound as a colorless amorphous.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[N:21][CH:22]=[CH:23][CH:24]=4)[N:19]([CH3:26])[N:18]=3)=[CH:15][N:16]=[C:11]2[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N)CN.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CN(C=O)C.ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[N:21][CH:22]=[CH:23][CH:24]=4)[N:19]([CH3:26])[N:18]=3)=[CH:15][N:16]=[C:11]2[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2cccnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: NCCN
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c2cccnc21
Temperature: 60 °C
Yield: 8.6 %

Procedure:
To a stirred solution of N-tert-butyl-2-(1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (306 mg, 638 μmol) in DMF (15 mL) was added ethylenediamine (1.92 g, 2.15 mL, 31.9 mmol) followed by TBAF (1.91 mL, 1.91 mmol) and the mixture heated at 60° C. under nitrogen for 15 h. The mixture was cooled, diluted with dichloromethane, washed with water and brine, then dried (MgSO4), filtered and concentrated to obtain an oil. This was triturated with water to remove tetrabutylammonium hydroxide, filtered, and the residue purified by chromatography (silica, 5-10% methanol in dichloromethane) to obtain N-tert-butyl-2-(1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (19.2 mg, 55.0 μmol, 9%) as a light yellow powder. MS (M+H)+=350; 1H NMR (DMSO-d6) δ: 9.12 (s, 1H), 8.84 (dd, J=8.2, 1.6 Hz, 1H), 8.70 (dd, J=4.5, 1.5 Hz, 1H), 8.42 (s, 1H), 7.93 (s, 1H), 7.39 (dd, J=8.0, 4.5 Hz, 1H), 4.22 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:6]([O:8][CH3:9])=[O:7])#[N:2].[NH2:15][OH:16]>CCO>[NH2:2][C:1](=[N:15][OH:16])[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(OC)c(C#N)c1
Reactant: NO
Solvent: CCO
Product: COC(=O)c1ccc(OC)c(C(N)=NO)c1
Yield: 98.7 %

Procedure:
A solution of methyl 3-cyano-4-methoxybenzoate (518 mg, 2.71 mmol), hydroxylamine (810 μL, 50% in water, 13.55 mmol) in EtOH (20 mL) was heated for 18 h at 60° C. after which time solvents were removed under vacuum, solid residue was triturated with water filtered and dried under vacuum overnight to give the title compound as an off-white solid (600 mg, quant). 1H NMR (DMSO-d6, 300 MHz) δ 9.48 (s, 1H), 7.97-7.95 (m, 2H), 7.20-7.17 (m, 1H), 5.70 (bs, 2H), 3.87 (s, 3H), 3.82 (s, 3H). LC/MS (Method B): 225.1 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]([NH:26]C(=O)OC(C)(C)C)([CH3:25])[CH2:10][CH2:11][N:12]1[C:16]([CH3:17])=[N:15][C:14]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[N:13]1>ClCCl>[CH3:25][C:9]([NH2:26])([CH3:8])[CH2:10][CH2:11][N:12]1[C:16]([CH3:17])=[N:15][C:14]([C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)=[N:13]1
Reactant: Cc1ccc(-c2nc(C)n(CCC(C)(C)NC(=O)OC(C)(C)C)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2nc(C)n(CCC(C)(C)N)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A total of 11 mL trifluoroacetic acid are added dropwise to a solution of 2.97 g (8.3 mmol) of tert.butyl [1,1-dimethyl-3-(5-methyl-3-p-tolyl-[1,2,4]triazol-1-yl)-propyl]-carbamate in 80 mL dichloromethane and the mixture is stirred overnight at ambient temperature. The solvent is distilled off and the residue is combined with diethyl ether and stirred. The precipitated solid is filtered off and washed. Yield: 2.11 g (68%, trifluoroacetate); mass spectroscopy [M+H]+=259.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([NH2:25])[CH3:24])=[CH:19][CH:18]=1.C(N(CC)CC)C>CN(C=O)C.O>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([NH:25][C:2]2[C:3]3[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH3:24])=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])c1cc2c(Cl)ncnc2s1
Reactant: COc1ccc(C(C)N)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(C)Nc2ncnc3sc([N+](=O)[O-])cc23)cc1

Procedure:
A mixture of 4-chloro-6-nitrothieno[2,3-d]pyrimidine (prepared as disclosed in Bull. Chim. Soc. Fr. 1975, 3-4, Pt. 2, 592) (500 mg, 2.3 mmol), 1-(4-methoxyphenyl)ethanamine HCl (513 mg, 2.8 mmol), and triethylamine (581 mg, 5.7 mmol) in DMF (7 mL) was allowed to react for 24 hours at 20° C. The reaction mixture was diluted with water and extracted thrice into Et2O. The organic portions were combined, washed with brine, and dried (Na2SO4). The mixture was filtered through silica gel, and the solvent was removed in vacuo. The residue was purified by flash chromatography (40 percent EtOAc in pentane), yielding 385 mg.