Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH2:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:14]=1>CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH:12][S:19]([C:15]3[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=3)(=[O:21])=[O:20])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: Nc1cc(F)cc2cccnc12
Agent: CN(C)c1ccncc1
Product: O=S(=O)(Nc1cc(F)cc2cccnc12)c1cccnc1
Yield: 31.9 %

Procedure:
In a similar fashion using route 14 general procedure 27, 6-fluoroquinolin-8-amine (Intermediate 48) (100 mg, 0.62 mmol), pyridine 3-sulfonyl chloride (Intermediate 17) (130 mg, 0.74 mmol) and DMAP (cat.) gave the title compound (60 mg, 32%) after purification by column chromatography with n-hexane/DCM (1:0-0:1) gradient elution followed by recrystallisation from DCM/n-pentane.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1([OH:21])[C:18]2[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=2)[NH:12][C:11]1=[O:20])[CH3:2].[CH3:22][N:23](C=O)C>[C-]#N.[Zn+2].[C-]#N>[C:22]([C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:20])[C:10]2([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[O:3][CH2:1][CH3:2])[OH:21])#[N:23]
Reactant: CN(C)C=O
Reactant: CCOc1ccccc1C1(O)C(=O)Nc2ccc(I)cc21
Agent: [C-]#N
Agent: [Zn+2]
Product: CCOc1ccccc1C1(O)C(=O)Nc2ccc(C#N)cc21
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
37.2 g (94 mMol) of the product 1a and 11.1 g (94 mMol) of zinc cyanide in 300 ml of DMF were heated to 95° C. Then 1.6 g (1.38 mMol) of tetrakis-(triphenylphosphine)palladium(0) were added in portions every 10 minutes. After 45 minutes, the reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, dried and concentrated in vacuo. The residue obtained in this way crystallizes from a little ethyl acetate. 24 g of the product were obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.O[CH:16]([C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1)[CH2:17][CH:18]=[CH2:19].C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1(C)C=CC=CC=1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:16]([C:20]2[CH:21]=[CH:22][C:23]([C:24]#[N:25])=[CH:26][CH:27]=2)[CH2:17][CH:18]=[CH2:19])=[CH:10][CH:9]=1
Reactant: C=CCC(O)c1ccc(C#N)cc1
Reactant: Oc1ccc(OC2CCCCO2)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: C=CCC(Oc1ccc(OC2CCCCO2)cc1)c1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 68.7 %

Procedure:
4-(Tetrahydro-2H-pyran-2-yloxy)phenol (19.0 g, 0.1 mol) and 4-(1-hydroxy-3-butenyl)benzonitrile (17.8 g, 0.1 mol) was mixed in toluene, and cooled to 0° C. (under nitrogen). TBP (22.9 g, 0.11 mol) was added, followed by ADDP. The mixture was stirred at rt overnight, filtered, and evaporated. Purification by chromatography on silica gave 24 g (68.7%) of the desired compound.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]([O:25][CH3:26])=[C:8]([O:23][CH3:24])[CH:9]=2)[N:4]=1.[CH:27]([NH2:31])([CH2:29][CH3:30])[CH3:28]>>[CH:27]([NH:31][CH2:2][C:3]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]([O:25][CH3:26])=[C:8]([O:23][CH3:24])[CH:9]=2)[N:4]=1)([CH2:29][CH3:30])[CH3:28]
Reactant: COc1ccc(-c2nc(CCl)nc3cc(OC)c(OC)cc23)cc1OC
Reactant: CCC(C)N
Product: CCC(C)NCc1nc(-c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc2n1

Procedure:
According to the same manner as that described in Example 56, 2-chloromethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinazoline was reacted with sec-butylamine to give 2-(sec-butylaminomethyl)-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinazoline. This compound was recrystallized from ethyl acetate - hexane. Colorless prisms, mp. 118°-120° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([CH3:11])[S:8][C:7]=2[CH:12]=1.B(Br)(Br)Br>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([CH3:11])[S:8][C:7]=2[CH:12]=1
Reactant: COc1ccc2cc(C)sc2c1
Agent: BrB(Br)Br
Product: Cc1cc2ccc(O)cc2s1
Yield: 93.2 %

Procedure:
This material was prepared from 6-methoxy-2-methylbenzo[b]thiophene 1b (2.92 g, 16.4 mmole) by treatment with BBr3 in a manner as previously described for example 1d to give 2.51 g (93%) of a white solid. 1H NMR (DMSO-d6) δ9.43 (1H, s), 7.47 (1H, d, J=8.5 Hz), 7.14 (1H, d, J=2.2 Hz), 6.92 (1H, s), 6.78 (1H, dd, J=2.2, 8.5 Hz), 2.46 (3H, s). Anal. Calcd. for C9H8OS: C, 65.82; H, 4.91; S, 19.53. Found: C, 65.96; H, 5.11; S, 19.69.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:27]([O-])=O)=[C:6]([NH:8][CH2:9][C:10]2([CH3:26])[CH2:25][CH2:24][CH2:23][C:12]3([O:16][C:15](=[O:17])[N:14]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:13]3)[CH2:11]2)[CH:7]=1.[CH:30](O)=O.C(OC)(OC)OC>CO.[Fe]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:27]=[CH:30][N:8]([CH2:9][C:10]3([CH3:26])[CH2:25][CH2:24][CH2:23][C:12]4([O:16][C:15](=[O:17])[N:14]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:13]4)[CH2:11]3)[C:6]=2[CH:7]=1
Reactant: O=CO
Reactant: CC(C)(C)CN1CC2(CCCC(C)(CNc3cc(Cl)ccc3[N+](=O)[O-])C2)OC1=O
Agent: [Fe]
Solvent: COC(OC)OC
Solvent: CO
Product: CC(C)(C)CN1CC2(CCCC(C)(Cn3cnc4ccc(Cl)cc43)C2)OC1=O
Temperature: 65 °C

Procedure:
A solution containing 7-(((5-chloro-2-nitrophenyl)amino)methyl)-7-methyl-3-neopentyl-1-oxa-3-azaspiro[4.5]decan-2-one (0.100 g, 0.236 mmol) in MeOH (5 mL) was treated with iron (325 mesh) (0.132 g, 2.36 mmol) followed by formic acid (0.090 mL, 2.359 mmol) and trimethyl orthoformate (0.261 mL, 2.359 mmol). The resulting mixture was heated at 65° C. for 18 h. LCMS indicated partial conversion to desired product. Additional iron (0.100 g, 1.79 mmol), formic acid (0.200 mL, 5.22 mmol), and trimethyl orthoformate (0.500 mL, 4.53 mmol) were added, and the reaction was stirred at 80° C. for 3 h. The reaction was cooled to rt and filtered through filter paper. The collected solids were washed with MeOH, and the combined MeOH washings and filtrate were concentrated. The crude product was purified by reverse-phase HPLC (Sunfire Prep C18 column (30×150 mm); 14 minute run; 40 mL/min flow rate with at-column dilution; Solvent A: MeCN/0.1% TFA, Solvent B: water/0.1 TFA, gradient: 10-90% solvent A) to afford the title compound (0.071 g, 52% yield) as the TFA salt. 1H NMR (400 MHz, CDCl3) δ 8.88 (br. s., 1H), 7.89 (d, J=8.78 Hz, 1H), 7.56 (d, J=1.51 Hz, 1H), 7.49 (dd, J=1.63, 8.66 Hz, 1H), 7.27 (s, 1H), 4.08 (s, 2H), 3.26-3.40 (m, 1H), 3.06 (d, J=14.05 Hz, 1H), 2.92 (d, J=14.05 Hz, 1H), 2.05 (br. s., 1H), 1.79-1.99 (m, 2H), 1.69 (d, J=14.05 Hz, 1H), 1.58 (br. s., 1H), 1.42 (d, J=13.80 Hz, 1H), 1.28-1.37 (m, 2H), 1.27 (s, 3H), 0.95 (s, 9H). MS (m/z) 404.2 (M+H+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH2:2]1.[N+:10]([O-:13])(O)=[O:11]>>[N+:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH:2]([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[O:3][C:4]=2[CH:9]=1)([O-:13])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: c1ccc2c(c1)OCO2
Product: O=[N+]([O-])c1ccc2c(c1)OC(c1ccccc1)O2
Temperature: 0 °C

Procedure:
A solution of 39.6 g (0.2 mol) of the benzodioxolan obtained as just described in 150 ml of acetic acid ester was added dropwise at 25° to 35° C. to 150 ml of a 33% nitric acid. The solution was poured into ice water after 2 hours and then extracted several times with acetic ester. The combined acetic ester phases were then washed several times with a solution of potassium bicarbonate and then with water, followed by drying and evaporation by concentration. Crystallization from ethanol furnished 37 g of a product of the melting point between 84° and 85° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].[C:23]([O-])(=[O:25])[CH3:24].[Na+]>C(OC(=O)C)(=O)C>[C:23]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22])(=[O:25])[CH3:24]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21
Temperature: 25 °C
Yield: 70.1 %

Procedure:
A mixture of 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (1.00 g, 3.39 mmol), sodium acetate (0.556 g, 6.78 mmol) and acetic anhydride (20 mL) was heated at reflux for 0.5 h. The reaction mixture was allowed to cool to ambient temperature and was concentrated in vacuo. Trituration of the residue in water (20 mL), followed by recrystallization of the resultant solid from hexanes/diethyl ether, afforded 1′-acetyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.802 g, 70%) as a colorless solid: mp 236-238° C. (hexanes/diethyl ether); 1H NMR (300 MHz, CDCl3) δ8.32-8.25 (m, 1H), 7.42-7.33 (m, 1H), 7.25-7.15 (m, 2H), 6.52 (s, 1H), 6.25 (s, 1H), 4.97-4.90 (m, 1H), 4.68-4.60 (m, 1H), 4.25-4.04 (m, 4H), 2.68 (s, 3H); 13C NMR (75 MHz, CDCl3) δ178.5, 171.0, 155.2, 145.1, 139.6, 138.6, 130.8, 129.4, 126.2, 123.7, 121.0, 116.8, 111.7, 99.6, 80.9, 64.6, 64.0, 58.8, 26.7; MS (ES+) m/z 360.1 (M+23).
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:5]([OH:7])=[O:6])[CH3:4].[CH2:8](O)[CH3:9]>>[ClH:1].[CH2:8]([O:6][C:5](=[O:7])[C@H:3]([CH3:4])[NH2:2])[CH3:9]
Reactant: C[C@H](N)C(=O)O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)[C@H](C)N

Procedure:
Hydrogen chloride gas was bubbled into a suspension of L-alanine (1) (100 g, 1.12 mol) in dry ethanol (800 ml) and the solution was refluxed for 2 hours. After concentration in vacuo the compound was recrystallised from ethanol-diethyl ether giving the title ester (2) (168.2g, 98%) as a white solid. δH (200 MHz; D2O) 1.11 (3H, t, J=7.1, CH2 CH3), 1.37 (3H, d, J=7.4, CHCH3), 4.03 (1H, q, J=7.2, CHCH3), 4.09 (2H, q, J=7.2, CH2CH3), 4.16 (2H, s, NH2); δC (125 MHz; D2O) 13.98 (CH3), 15.90 (CH3), 49.65 (CH), 64.29 (CH2), 171.57 (CO).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[N:15]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]5[CH2:32][CH2:31][CH2:30][CH2:29]5)=[CH:21][CH:20]=4)[N:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[Cl:33][C:34]1[CH:35]=[C:36]([N:40]=[C:41]=[O:42])[CH:37]=[CH:38][CH:39]=1>ClCCl>[Cl:33][C:34]1[CH:35]=[C:36]([NH:40][C:41]([NH:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([C:9]3[N:14]4[N:15]=[C:16]([NH:18][C:19]5[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]6[CH2:29][CH2:30][CH2:31][CH2:32]6)=[CH:21][CH:20]=5)[N:17]=[C:13]4[CH:12]=[CH:11][CH:10]=3)[CH:4]=2)=[O:42])[CH:37]=[CH:38][CH:39]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: NCc1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Solvent: ClCCl
Product: O=C(NCc1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1)Nc1cccc(Cl)c1
Reaction time: 8 h

Procedure:
[5-(3-Aminomethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (40 mg, 0.093 mmol) was dissolved in dichloromethane (1 ml). 3-Chlorophenyl isocyanate (13 μl, 0.103 mmol) was added and the mixture stirred overnight. The solvent was removed under reduced pressure and the product was purified by preparatory HPLC to give the desired product. LCMS RT: 2.86 min, MI: 582, Method: 2. 1H NMR (DMSO, 300 MHz): 9.38 (s, 1H), 8.99 (s, 1H), 8.16 (s, 1H), 7.96 (s, 1H), 7.86 (d, 1H), 7.66-7.49 (m, 5H), 7.17 (d, 2H), 7.11 (d, 1H), 7.01 (t, 1H), 6.84 (d, 2H), 4.39 (d, 2H), 3.98 (t, 2H), 2.81 (t, 2H), 2.53 (s, 4H), 1.67 (s, 4H).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][OH:15])[O:12][C@@H:11]([N:16]2[C:20]3[N:21]=[CH:22][N:23]=[C:24]([NH:25][C:26](=[O:33])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:19]=3[CH:18]=[CH:17]2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[S:35]([NH2:38])(=[O:37])=[O:36]>>[S:35](=[O:37])(=[O:36])([O:15][CH2:14][C@@H:13]1[C@@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[CH2:10][C@H:11]([N:16]2[C:20]3[N:21]=[CH:22][N:23]=[C:24]([NH:25][C:26](=[O:33])[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:19]=3[CH:18]=[CH:17]2)[O:12]1)[NH2:38]
Reactant: NS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2ccc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1CO
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2ccc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1COS(N)(=O)=O
Yield: 48 %

Procedure:
Using essentially the same procedure as example 43 step f, N-{7-[(2R,4S,5R)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-(hydroxymethyl)tetrahydrofuran-2-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}benzamide (0.524 g, 1.12 mmol) was reacted with chlorosulfonamide and the product was purified by flash chromatography (20 to 50% EtOAc/hexanes) to afford the title compound as a white foam (0.292 g, 48%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[N:22]=[C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[O:24][C:25]=3[CH3:26])=[CH:15][CH:14]=2)=[C:6]([CH2:8][C:9]#[N:10])[CH:7]=1.[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:33]([O:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]3[N:22]=[C:23]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[O:24][C:25]=3[CH3:26])=[CH:17][CH:18]=2)=[C:6]([CH2:8][C:9]#[N:10])[CH:7]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: BrCc1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ccc(O)cc2CC#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ccc(OCc3ccccc3)cc2CC#N)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 55.7 %

Procedure:
A mixture of 2-[5-hydroxy-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetonitrile (0.40 g), benzyl bromide (0.48 g), anhydrous potassium carbonate (0.14 g) and N,N-dimethylformamide (5 mL) was stirred at 90° C. for 3 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (0.27 g, 55%) of 2-[5-benzyloxy-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetonitrile from a fraction eluted with ethyl acetate-hexane (1:4, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 130-131° C.
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:9][O-:10].C[O-].[Na+].[Cl-].[NH4+]>CO>[CH3:9][O:10][C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: C[O-]
Reactant: Clc1nccnc1Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: COc1nccnc1Cl
Reaction time: 7 h

Procedure:
Commercially available 2,3 dichloropyrazine was dissolved in a suitable amount of methanol to which was added a slight excess of an alkali methoxide, preferably 1.05 equiv. of sodium methoxide. The mixture was then stirred for a period of 1-24 hr, preferably 7 hr, after which time the solution was neutralized with solid ammonium chloride, the solvent removed in vacuo, the residue taken up in an organic solvent chosen from a group consisting of diethyl ether, ethyl acetate, and methylene chloride, preferably methylene chloride, and filtered to remove unwanted salts. The filtrate was reduced in vacuo to afford 2-methoxy-3-chloro-pyrazine as white crystals which were used without further purification.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[CH:7][CH:8]=[C:9]2[C:13]([C:14]([C:16]3[C:24]([Cl:25])=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][C:17]=3[Cl:26])=[O:15])=[CH:12][NH:11][C:10]=12)(=[O:3])[CH3:2].[NH2:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][OH:33].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O>[C:1]([NH:4][C:5]1[N:6]=[CH:7][CH:8]=[C:9]2[C:13]([C:14]([C:16]3[C:17]([Cl:26])=[CH:18][C:19]([C:20]([NH:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][OH:33])=[O:22])=[CH:23][C:24]=3[Cl:25])=[O:15])=[CH:12][NH:11][C:10]=12)(=[O:3])[CH3:2]
Reactant: NCCOCCO
Reactant: CC(=O)Nc1nccc2c(C(=O)c3c(Cl)cc(C(=O)O)cc3Cl)c[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1nccc2c(C(=O)c3c(Cl)cc(C(=O)NCCOCCO)cc3Cl)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.2 %

Procedure:
4-{[7-(Acetylamino)-1H-pyrrolo[2,3-c]pyridin-3-yl]carbonyl}-3,5-dichlorobenzoic acid (0.1 g, 0.25 mmol) was taken in a reaction vial. To it 2-(2-aminoethoxyl)ethanol (0.029 g, 2.8 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.073 g, 3.8 mmol), 1-hydroxybenzotriazole (0.051 g, 3.8 mmol) and dimethylformamide (2 mL) were added. The whole reaction mixture was stirred at room temperature for overnight. Water (20 mL) was added to the reaction mixture, extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to get the crude mass which was purified by flash column chromatography to get 4-{[7-(acetylamino)-1H-pyrrolo[2,3-c]pyridin-3-yl]carbonyl}-3,5-dichloro-N-[2-(2-hydroxyethoxyl)ethyl]benzamide (0.035 g, 29%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[O:17][C:18](Br)=[CH:19][CH:20]=2)=[O:15])[CH:8]=1)[CH3:2].[CH2:23]([O:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[O:17][C:18]([C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([O:30][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:32]=3)=[CH:19][CH:20]=2)=[O:15])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Reactant: OB(O)c1cccc(OCc2ccccc2)c1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2ccc(-c3cccc(OCc4ccccc4)c3)o2)c1
Temperature: 85 °C

Procedure:
The furyl bromide (99) (100 mg, 0.28 mmol) was coupled to 3-benzyloxy-phenylboronic acid (69 mg, 0.30 mmol) acid using Method E, except that the reaction was heated at 85° C. The crude product was purified by column chromatography eluting with 20% EtOAc in heptane to give the title compound.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[F:25][C:26]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:27]=1[CH:28]=[CH:29][C:30](O)=[O:31].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:25][C:26]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:27]=1[CH:28]=[CH:29][C:30]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:31]
Reactant: O=C(O)C=Cc1ccc(F)cc1F
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1ccc(F)cc1F
Yield: 99.4 %

Procedure:
The same procedures as in Example 2 were carried out from methyl L-tryptophanate hydrochloride (3.0 g), triethylamine (2.0 mL), 2,4-difluorocinnamic acid (2.6 g), WSC.HCl (2.7 g), and methylene chloride (80 mL), to give the captioned compound (4.5 g, 99%) as an oily product.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[C:4]([OH:6])=O.CCN(CC)CC.Cl.[CH3:15][O:16][NH:17][CH3:18].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:15][O:16][N:17]([CH3:18])[C:4]([C@@H:2]1[CH2:3][O:1]1)=[O:6]
Reactant: CNOC
Reactant: O=C(O)[C@@H]1CO1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)[C@@H]1CO1
Temperature: 0 °C
Reaction time: 4 h
Yield: 0.1 %

Procedure:
To a solution of the crude acid 2 (˜72.0 g, ˜0.810 mol, 1.0 equiv.) in CH2Cl2 (1600 mL) was added NEt3 (120 mL, 0.859 mol, 1.06 equiv.), DMAP (92 mg, 0.00082 mol, 0.001 equiv.) and O,N-Dimethyl-hydroxylamine hydrochloride (95.74 g, 0.982 mol, 1.21 equiv.) at 0° C. The resultant mixture was stirred for 10 minutes at −5° C. and EDCI (198.5 g, 1.035 mol, 1.27 equiv.) was added. The reaction mixture was stirred for 4 hours at 0° C. and diluted with hexanes (800 mL). The mixture was filtered through a pad of silica gel (2 cm thick of silica gel in a 3 L filtration funnel) and washed with Et2O (10×300 mL). The solvent was removed under reduced pressure to afford the crude amide 3 (92.2 g, 0.709 mmol, 87.5% for two steps) as slight-yellow oil. This crude product was dissolved in 1,2-dichloroethane (200 mL) and dried over molecular sieves at −20° C. for 2 hours before used in the next step).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=O)[C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.[C:15]([C:19]1[CH:34]=[CH:33][C:22]([CH2:23][NH:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:15]([C:19]1[CH:34]=[CH:33][C:22]([CH2:23][N:24]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:12]([C:9]2[C:10]([F:11])=[C:2]([F:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:14])=[CH:21][CH:20]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)c1ccc(CNCCc2ccccc2)cc1
Reactant: O=C(O)c1c(F)c(F)cc2cc[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CN(CCc2ccccc2)C(=O)c2c(F)c(F)cc3cc[nH]c23)cc1
Temperature: 25 °C
Yield: 33 %

Procedure:
87 mg (0.44 mol) of 5,6-difluoro-1H-indol-7-carboxylic acid, 106 mg (0.40 mmol) of (4-tert-butyl-benzyl)-[2-phenyl-ethyl]-amine and 84 mg (0.44 mmol) of EDC.HCl were dissolved in 4 ml DCM. The reaction mixture was stirred at rt over night. The solvent was evaporated and the residue was purified by column chromatography (20 g silica gel; heptane/EtOAc 4:1) to yield 59 mg (33%) product as a colorless viscous oil. MS (ISP) 447.2 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[Si]([O:25][CH2:26][C@H:27]1[O:31][C@@H:30]([N:32]2[CH:39]=[C:38]([CH3:40])[C:36](=[O:37])[NH:35][C:33]2=[O:34])[C@H:29]([O:41][CH2:42][CH2:43][O:44][N:45]([CH2:48][CH3:49])[CH2:46][CH3:47])[C@@H:28]1[OH:50])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[CH2:48]([N:45]([CH2:46][CH3:47])[O:44][CH2:43][CH2:42][O:41][C@@H:29]1[C@H:28]([OH:50])[C@@H:27]([CH2:26][OH:25])[O:31][C@H:30]1[N:32]1[CH:39]=[C:38]([CH3:40])[C:36](=[O:37])[NH:35][C:33]1=[O:34])[CH3:49]
Reactant: CCN(CC)OCCO[C@@H]1[C@H](O)[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(CC)OCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.4 %

Procedure:
A mixture of triethlyamine trihydrogenfluoride (4.39 mL, 26.81 mmol) and triethylamine (1.87 mL, 13.41 mmol) in THF (53.6 mL) was added to 5′-O-tert-butyldiphenylsilyl-2′-O-[2-(N,N-diethylaminooxy)ethyl]-5-methyluridine (3.28 g, 5.36 mmol). The reaction mixture was stirred at room temperature for 18 h. Solvent was removed in vacuo. The residue was placed on a silica gel column and eluted with CH2Cl2/MeOH/NEt3, 89:10:1, to yield the title compound (1.49 g).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9](F)[C:10]([F:21])=[C:11]([N:15]4[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]4)[C:12]=3[F:14])[C:7](=[O:23])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1.[NH3:27]>C(O)C>[NH2:27][C:9]1[C:10]([F:21])=[C:11]([N:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)[C:12]([F:14])=[C:13]2[C:8]=1[C:7](=[O:23])[C:6]([C:24]([OH:26])=[O:25])=[CH:5][N:4]2[CH:1]1[CH2:3][CH2:2]1
Reactant: N
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCNCC3)c(F)c(F)c2c1=O
Solvent: CCO
Product: Nc1c(F)c(N2CCNCC2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1

Procedure:
In the same manner as described in Example 13, 1-cyclopropyl-5,6,8-trifluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was allowed to react with ammonia in ethanol in a sealed tube to give 5-amino-1-cyclopropyl-6,8-difluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 263°-264° C.