Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[C:22]([CH3:23])=[CH:21][C:11]([C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[O:13])=[C:10]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:9]=1.[CH3:32][N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1>COCCOC.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>[CH3:23][C:22]1[C:8]([C:36]2[CH:35]=[N:34][N:33]([CH3:32])[CH:37]=2)=[CH:9][C:10]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:11]([CH:21]=1)[C:12]([NH:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:13]
Reactant: Cc1cc(C(=O)Nc2cccnc2)c(OCc2ccccc2)cc1Br
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1cc(C(=O)Nc2cccnc2)c(OCc2ccccc2)cc1-c1cnn(C)c1
Temperature: 120 °C

Procedure:
Sodium carbonate (0.30 ml, 0.30 mmol) was added to 4-bromo-5-methyl-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzamide (may be prepared as described in Example 9; 59 mg, 0.15 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (37.1 mg, 0.18 mmol) and palladium tetrakis (10.30 mg, 8.91 μmol) in 1,2-dimethoxyethane (3 ml). The mixture was heated in a microwave at 120° C. for 1 hour, the solvent was removed in vacuo and the solid purified by MDAP to yield the title compound as a white solid. 30 mg.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([SH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(C1ON=C(NC(NC2C=CC=C(O[C:41]3[C:50]4[C:45](=[CH:46][C:47]([O:53][CH2:54][CH3:55])=[C:48]([O:51][CH3:52])[CH:49]=4)[N:44]=[CH:43][N:42]=3)C=2)=O)C=1)(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+]>C(O)(C)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:41]3[C:50]4[C:45](=[CH:46][C:47]([O:53][CH2:54][CH3:55])=[C:48]([O:51][CH3:52])[CH:49]=4)[N:44]=[CH:43][N:42]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(S)c2)no1
Reactant: CCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)O
Product: CCOc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OC
Temperature: 70 °C
Yield: 48 %

Procedure:
A mixture of 1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea described in Example 44A (0.146 g 0.5 mmol), 4-chloro-7-ethoxy-6-methoxyquinazoline from Example 6B Step 1 (0.12 g, 0.5 mmol), and Cs2CO3 (0.161 mg, 0.5 mmol) in isopropanol (10 mL) was heated at 70° C. for 7 hours. It was quenched with water and extracted with CH2Cl2. Extracts were dried over MgSO4 and concentrated under reduced pressure. It was purified by silica gel chromatography with EtOAc/hexane as eluant to afford 1-(5-tert-butylisoxazol-3-yl)-3-[3-(7-ethoxy-6-methoxyquinazolin-4-ylthio)phenyl]urea as solid (0.118 g, 48%). 1H NMR (300 MHz, CDCl3) δ 9.3 (br, 1H), 8.74 (s, 1H), 8.05 (s, 1H), 7.86 (s, 1H), 7.62 (d, 1H), 7.37 (m, 3H), 7.25 (1H), 5.91 (s, 1H), 4.29 (q, 2H), 4.06 (s, 3H), 1.58 (t, 3H), 1.32 (s, 9H); LC-MS (ESI) m/z 494 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:9]([Cl:10])=[CH:8][C:7]([NH2:11])=[CH:6][C:3]=1[C:4]#[N:5].Br[CH2:13][CH2:14][O:15][CH2:16][CH2:17]Br.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-]>CN(C)C=O>[NH2:1][C:2]1[C:9]([Cl:10])=[CH:8][C:7]([N:11]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(N)cc(Cl)c1N
Reactant: BrCCOCCBr
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cc(N2CCOCC2)cc(Cl)c1N
Temperature: 180 °C
Yield: 91 %

Procedure:
2,5-Diamino-3-chloro-benzonitrile (387 mg), bis-(2-bromoethyl)ether (0.35 mL) and N,N-diisopropyl-ethylamine (1.25 mL) were mixed in N,N-dimethylformamide (4 mL) and heated to 180° C. for 30 minutes in a sealed microwave process vial. Saturated aqueous bicarbonate (20 mL) was added and the crude mixture was extracted with ethyl acetate (20 mL). The organic phase was washed with water (20 mL) and brine (20 mL), dried over sodium sulfate and concentrated in vacuo to furnish 0.50 g (91%) of the title compound as a brown solid. LC-MS (m/z) 238 (MH+); tR=2.31, (UV, ELSD) 85%, 95%. 1H NMR (500 MHz, DMSO-d6): 2.97 (m, 4H), 3.69 (m, 4H), 5.59 (s; 2H), 7.04 (d, 1H), 7.29 (d, 1H).
Reaction SMILES: O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[OH:16][C@H:17]1[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:19]([C:29]([OH:31])=O)[CH2:18]1.[NH2:32][C:33]1[CH:34]=[N:35][C:36]2[C:41]([CH:42]=1)=[CH:40][CH:39]=[CH:38][CH:37]=2.C(N(C(C)C)CC)(C)C>ClCCl>[N:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:42]=[C:33]([NH:32][C:29](=[O:31])[C@@H:19]2[CH2:18][C@@H:17]([OH:16])[CH2:21][N:20]2[C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH:34]=1
Reactant: Nc1cnc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)Nc1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 45 h
Yield: 109.1 %

Procedure:
Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (5.72 g) was added to a solution of trans-4-hydroxy-N-tert-butoxycarbonyl-L-proline (3.47 g), 3-aminoquinoline (2.17 g), and diisopropylethylamine (5 mL) in dichloromethane (100 mL) at 0° C. After stirring at room temperature for 45 hr, the solvent was removed in vacuo. Ethyl acetate (500 mL) and 2 N sodium carbonate (500 mL) were added to the residue. The separated organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform:methanol=50:1 to 30:1, 20:1, and 10:1, v/v) to afford the title compound (5.85 g) as a colorless sticky oil: 1H NMR (400 MHz, CD3OD) δ 1.3-1.5 (m, 9H), 2.1-2.2 (m, 1H), 2.3-2.4 (m, 1H), 3.5-3.7 (m, 2H), 4.4-4.6 (m, 2), 7.61 (m, 1H), 7.69 (m, 1H), 7.88 (m, 1H), 7.97 (m, 1H), 8.71-8.76 (m, 1H), and 8.93-8.94 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:14][C:15]3[C:20]([F:21])=[CH:19][CH:18]=[C:17]([F:22])[C:16]=3[Cl:23])[C:9](=O)[C:10](=O)[NH:11][C:5]2=[N:4][CH:3]=1.S(C)C>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:14][C:15]3[C:20]([F:21])=[CH:19][CH:18]=[C:17]([F:22])[C:16]=3[Cl:23])[CH2:9][CH2:10][NH:11][C:5]2=[N:4][CH:3]=1
Reactant: O=c1[nH]c2ncc(Br)nc2n(Cc2c(F)ccc(F)c2Cl)c1=O
Solvent: CSC
Solvent: C1CCOC1
Product: Fc1ccc(F)c(CN2CCNc3ncc(Br)nc32)c1Cl
Yield: 20 %

Procedure:
To a solution of 7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,4-dihydropyrazino[2,3-b]pyrazine-2,3-dione (2.5 mmol, 1.0 g) in THF (5 mL) was added BH3.Me2S (7.5 mmol, 3.75 mL, 2.0 M in THF). The resulting solution was refluxed for 2 hrs under N2. Excessive BH3 was quenched by addition of MeOH at rt then heating the reaction mixture for 10 min. After volatile components were removed on rotavap, the residue was subjected to a silica gel column chromatography by using 4:1 ratio of CH2Cl2/MeOH (pre-saturated with ammonia gas) as eluents, furnishing 7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]pyrazine in 20% yield (0.19 g).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:14]1[O:16][C@H:15]1[CH2:17]Cl>>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH2:17][C@@H:15]3[CH2:14][O:16]3)=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Oc1ccc(C2CCCCC2)cc1
Reactant: ClC[C@H]1CO1
Product: c1cc(C2CCCCC2)ccc1OC[C@@H]1CO1

Procedure:
The title compound was prepared from 4-cyclohexyl-phenol and R-epichlorohydrin employing the procedures as set forth in Step 1 of Example 1.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:25]=[CH:24][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:26][N:27]1[CH:31]=[CH:30][N:29]=[C:28]1[CH:32]=O.C(OC)(OC)OC.[BH4-].[Na+]>CO>[CH2:18]([N:17]([CH2:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:5]=[CH:4][C:3]([CH2:2][NH:1][CH2:32][C:28]3[N:27]([CH3:26])[CH:31]=[CH:30][N:29]=3)=[CH:25][CH:24]=2)=[CH:11][CH:12]=1)[CH2:21][CH2:22][CH3:23])[CH2:19][CH3:20]
Reactant: Cn1ccnc1C=O
Reactant: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CNCc3nccn3C)cc2)cc1
Reaction time: 22 h
Yield: 69.3 %

Procedure:
The compound (290.2 mg) obtained in Example 122-3 was dissolved in methanol (8.71 ml) and added with 1-methyl-2-imidazole carboxaldehyde (141.2 mg) and trimethyl orthoformate (272.2 mg), followed by stirring for 22 hours. The reaction solution was cooled with ice and then added with sodium borohydride (97.0 mg), followed by stirring at room temperature for 0.5 hour. The reaction solution was concentrated under reduced pressure and the residue was then added with water, followed by separation/extraction with chloroform. The organic layer was washed with saturate saline solution and dried with anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (256.8 mg) as a yellow oily substance.
Reaction SMILES: [OH-].[K+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][OH:10].[Cl:11][C:12]1[CH:13]=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[CH:16][C:17]=1F.O>C(#N)C>[Cl:11][C:12]1[CH:13]=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[CH:16][C:17]=1[O:10][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: OCc1ccccn1
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1ccc(OCc2ccccn2)c(Cl)c1
Reaction time: 0.42 h
Yield: 85 %

Procedure:
A mixture of 160 g of potassium hydroxide and 2-pyridylcarbinol in 8 L acetonitrile was stirred for 20-30 minutes. To this was added 400 g of 3-chloro-4-fluoronitrobenzene and the mixture was stirred at 40° C. for a minimum of 18 hours until the reaction was complete. Water was added and the precipitated yellow solids were filtered and washed with water. The product was dried (40-50° C., 10 mm Hg, 24 h) to the product in 85-95% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:9]([Cl:12])=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH2:13]([O:15][C:16](=[O:21])[CH2:17][C:18](=[NH:20])[NH2:19])[CH3:14]>C(O)C>[CH2:13]([O:15][C:16]([C:17]1[CH:7]([C:6]2[C:9]([Cl:12])=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:17]([C:16]([O:15][CH2:13][CH3:14])=[O:21])=[C:18]([NH2:19])[NH:20][C:18]=1[NH2:19])=[O:21])[CH3:14]
Reactant: CCOC(=O)CC(=N)N
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OCC)C1c1cc([N+](=O)[O-])ccc1Cl
Yield: 48 %

Procedure:
Upon boiling a solution of 9.3 g 3-nitro-6-chlorobenzaldehyde and 13.0 g amidinoacetic acid ethyl ester in 150 ml ethanol for 2 hours, 2,6-diamino-4-(3-nitro-6-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of m.p. 130° C (ethanol) is obtained.
Reaction SMILES: [F:1][CH:2]([F:35])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([N:19]2[CH2:27][C:26]3[C:21](=[C:22]([NH:28][C:29]([CH:31]4[CH2:33][CH2:32]4)=[O:30])[CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:34])[CH2:15][C:16]([OH:18])=O)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:48][OH:49].O>O1CCCC1>[F:1][CH:2]([F:35])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([N:19]2[C:20](=[O:34])[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][C:22]=3[NH:28][C:29]([CH:31]3[CH2:33][CH2:32]3)=[O:30])[CH2:27]2)[CH2:15][C:16](=[O:18])[NH:48][OH:49])[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12]
Reactant: NO
Reactant: O=C(O)CC(c1ccc(OC(F)F)c(OC(F)F)c1)N1Cc2cccc(NC(=O)C3CC3)c2C1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(CC(c1ccc(OC(F)F)c(OC(F)F)c1)N1Cc2cccc(NC(=O)C3CC3)c2C1=O)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.5 %

Procedure:
To a solution of 3-(3,4-bis-difluoromethoxy-phenyl)-3-[7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-propionic acid (400 mg, 0.81 mmol) in tetrahydrofurane was added carbonyldiimidazole (200 mg, 1.21 mmol) at room temperature. The solution was stirred for 2 hours at room temperature. To the mixture was added hydroxylamine (120 mg, 1.6 mmol). The resulted mixture was stirred at room temperature for 2 hours. Water (5 ml) was added to the reaction mixture. THF was removed in vacuo and the resulted mixture was taken up in ethyl acetate (20 ml). The organic layer was washed with saturated sodium bicarbonate solution (3×10 ml), water (10 ml), brine (10 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The resulted oil was purified by HPLC (acetonitrile:water=45:55) to give cyclopropanecarboxylic acid {2-[1-(3,4-bis-difluoromethoxy-phenyl)-2-hydroxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as a white solid (230 mg, 46%): mp, 191–193° C.; 1HNMR (CDCl3): δ 0.88–0.93 (m, 2H, cyclopropyl ring CH2), 1.09–1.12 (m, 2H, cyclopropyl ring CH2), 1.64–1.67 (m, 1H, cyclopropyl ring CH), 2.84–2.92 (m, 1H, CHHCO), 3.38–3.48 (m, 1H, CHHCO), 4.18 (d, J=18 Hz, 1H, CHHN), 4.36 (d, J=18 Hz, 1H, CHHN), 5.47–5.49 (m, 1H, CHN), 6.52 (t, JH-F=75 Hz, 1H, OCF2H), 6.54 (t, JH-F=75 Hz, 1H, OCF2H), 6.99 (d, J=8 Hz, 1H, Ar), 7.25–7.31 (m, 3H, Ar), 7.45 (t, J=8 Hz, 1H, Ar), 8.43 (d, J=8 Hz, 1H, Ar), 9.20 (broad, 1H, NHOH), 10.35 (s, 1H, NHCO); 13C NMR (DMSO):30.82, 35.26, 38.47, 46.17, 47.50, 51.68, 112.50, 116.83, 117.01, 117.39, 117.66, 117.99, 120.56, 120.97, 121.73, 125.73, 133.41, 137.47, 138.38, 142.76, 146.83, 166.12, 168.68, 172.21, 179.98. Anal. Calcd. for C23H21F4N3O6: C, 54.02; H, 4.14; N, 8.22. Found: C, 53.89; H, 3.96; N, 8.22.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@@H:10]1[CH2:25][N:14]2[C:15]3[CH:16]=[C:17]([C:22]([OH:24])=O)[CH:18]=[CH:19][C:20]=3[CH:21]=[C:13]2[C:12](=[O:26])[NH:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=[N:42][C:37]2[CH:38]=[CH:39][CH:40]=[N:41][C:36]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.NC1C=NC=CC=1>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C@@H:10]1[CH2:25][N:14]2[C:15]3[CH:16]=[C:17]([C:22](=[O:24])[NH:42][C:37]4[CH:36]=[N:41][CH:40]=[CH:39][CH:38]=4)[CH:18]=[CH:19][C:20]=3[CH:21]=[C:13]2[C:12](=[O:26])[NH:11]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC[C@@H]1Cn2c(cc3ccc(C(=O)O)cc32)C(=O)N1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1cccnc1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC[C@@H]1Cn2c(cc3ccc(C(=O)Nc4cccnc4)cc32)C(=O)N1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 64 %

Procedure:
To a solution of the above carboxylic acid (94 mg, 0.262 mmol) in 2 mL of DMF (2 mL) was added HATU (104.5 mg, 0.275 mmol), HOAt (18.6 mg, 0.137 mmol) and N,N′-diisopropylethylamine (96 uL, 0.55 mmol). After 15 min, 3-amino-pyridine (26 mg, 0.275 mmol) in 1 mL of DMF was added. The reaction mixture was warmed at 80° C. for 8 h. The reaction was concentrated and extracted with EtOAc several times. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated. Purification by silica gel chromatography gave 73 mg of [(R)-1-oxo-7-(pyridin-3-ylcarbamoyl)-1,2,3,4-tetrahydro-pyrazino[1,2-a]indol-3-ylmethyl]-carbamic acid tert-butyl ester, yield 64%. The product was characterized by 1H NMR and mass spectroscopy. ESI-MS m/z 436.48 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:31][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[O:21][CH:22]([CH3:30])[C:23]([O:25]C(C)(C)C)=[O:24])[C:7]=2[C:6]=1[CH3:32])=[O:4].FC(F)(F)C(O)=O>ClCCl>[F:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:12]2[C:7]3[C:6]([CH3:32])=[C:5]([C:3]([O:2][CH3:1])=[O:4])[S:31][C:8]=3[N:9]=[CH:10][N:11]=2)=[C:15]([CH:16]=1)[O:21][CH:22]([CH3:30])[C:23]([OH:25])=[O:24]
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC(C)C(=O)OC(C)(C)C)c2c1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC(C)C(=O)O)c2c1C

Procedure:
Prepared analogously to example 8.1 using methyl-4-(2-(1-tert-butoxy-1-oxopropan-2-yloxy)-4-fluorophenylamino)-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylate (2.1 g) and 50% trifluoroacetic acid in dichloromethane (20 ml).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[N:5]=[C:4]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:3]12.[CH:21](=O)[CH3:22].CC(O[Na])=O.C([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[CH:21](=[C:15]1/[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:3]2[C:2](=[O:1])[C:11]3[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=3)[N:5]=[C:4]/12)/[CH3:22]
Reactant: O=C(O)c1ccc2c(=O)n3c(nc2c1)CCCCCC3
Reactant: CC=O
Agent: CC(=O)O[Na]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: C/C=C1\CCCCCn2c1nc1cc(C(=O)O)ccc1c2=O
Temperature: 25 °C

Procedure:
A solution of 13-oxo-7,8,9,10,11,13-hexahydro-6H-azocino[2,1-b]quinazoline-3-carboxylic acid (100 mg, 0.37 mmol), acetaldehyde (5 mL) and CH3COONa (1 g) in acetic acid (10 mL) was stirred at 110° C. for 24 hours. After it was cooled to room temperature, the mixture was adjusted to pH around 8 with Na2CO3 and extracted with a mixture of dichloromethane/methanol (10/1) (3×30 mL). The combined organic layers were washed with brine and dried over Na2SO4. After filtration and concentration, the crude product obtained was used for the next step without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:14]([O:24][CH:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)[C:15]2[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH:11]=[CH:12][CH:13]=1.[N-:32]=[N+:33]=[N-:34].[Na+].O>CS(C)=O>[N:32]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:14]([O:24][CH:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)[C:15]2[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH:11]=[CH:12][CH:13]=1)=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: CN1CCC(OC(c2cccc(OCCCCCCl)c2)c2nc3ccccc3s2)CC1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CN1CCC(OC(c2cccc(OCCCCCN=[N+]=[N-])c2)c2nc3ccccc3s2)CC1
Temperature: 70 °C

Procedure:
A mixture of 2-[[3-(5-chloropentyloxy)phenyl](1-methyl-piperidin-4-yloxy)-methyl]benzothiazole (200 mg) and sodium azide (85 mg) in dimethylsulfoxide (3 mL) is heated overnight at 70° C., then cooled back to room temperature. Water is added and the product is extracted with ethyl acetate. Pooled extracts are washed with water, then brine, dried over magnesium sulfate and concentrated under reduced pressure to give 2-[[3-(5-azidopentyloxy)phenyl](1-methyl-piperidin-4-yloxy)methyl]benzothiazole used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[Li]CCCC.CN([CH:27]=[O:28])C>C1COCC1>[CH:27]([C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1)=[O:28]
Reactant: CN(C)C=O
Reactant: O=C(Nc1ccc(Br)cc1)OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(NC(=O)OCc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Benzyl 4-bromophenylcarbamate (20 g, 65.3 mmol) was taken in anhydrous THF (440 mL) and cooled to −78° C. To this solution, n-BuLi (55 mL, 137.2 mmol) was added dropwise and stirred for 0.5 h at −78° C. To this mixture, DMF (7.6 mL) was added dropwise and the reaction was allowed to warm to room temperature over a period of 5 h. The reaction mixture was quenched with 1 N HCl and then concentrated to remove THF, followed by addition of water. The mixture was extracted with three portions of ethyl acetate. The combined organic phases were washed with H2O, brine, and dried (MgSO4) filtered and concentrated. Trituration with hexanes and then with 20% ethyl acetate in hexanes afforded the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)=[N:12][CH:13]=2)[CH:5]=[N:4][C:3]=1[Cl:27].Br[CH2:29][C:30](=O)[C:31]([O:33][CH2:34][CH3:35])=[O:32]>COCCOC>[C:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][N:14]([C:11]2[N:12]=[CH:13][C:8]([C:6]3[N:7]4[CH:29]=[C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:1]=[C:2]4[C:3]([Cl:27])=[N:4][CH:5]=3)=[CH:9][CH:10]=2)[CH2:15][CH2:16]1)=[O:21])([CH3:24])([CH3:26])[CH3:25]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(Cl)c(N)n3)cn2)CC1
Solvent: COCCOC
Product: CCOC(=O)c1cn2c(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3)cnc(Cl)c2n1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
A mixture of compound 87a (1.60 g, 4.09 mmol), and ethyl 3-bromo-2-oxopropanoate (1.72 mL, 12.3 mmol) in DME (25 mL) was stirred at 80° C. under Argon for 3 days. After cooling to rt, the mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (20-60% EtOAc/heptane) to give compound 87b as a light brown solid. 1H-NMR (CDCl3; 400 MHz) δ 8.43 (d, J=2.2 Hz, 1H), 8.38 (d, J=9.0 Hz, 1H), 7.74 (dd, J=8.8, 2.4 Hz, 1H), 7.66 (d, J=2.7 Hz, 1H), 6.81 (d, J=8.8 Hz, 1H), 4.44-4.52 (m, 2H), 3.68-3.75 (m, 4H), 3.60 (d, J=5.1 Hz, 4H), 1.51 (s, 9H), 1.43 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:16]([C:17](=[O:19])[CH:18]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:5]([N+:20]([O-])=O)[CH:4]=1.Cl[Sn]Cl>C(O)C.O>[NH2:20][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[C:9]1[O:10][C:11]2[C:16]([C:17](=[O:19])[CH:18]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: COc1ccc(-c2cc(=O)c3ccccc3o2)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2cc(=O)c3ccccc3o2)c(N)c1
Temperature: 25 °C
Yield: 58.6 %

Procedure:
2-(4-Methoxy-2-nitrophenyl)-4H-chromen-4-one (1.5 g, 5.04 mmol) was dissolved in ethanol (30 mL) and heated at reflux. SnCl2 (4.97 g 26.23 mmol) was added. The mixture was heated under reflux for 20 min. The reaction mixture was cooled to rt diluted with water, neutralized and extracted with ethyl acetate to give the crude compound. This was purified by column chromatography using 3% MeOH in CH2Cl2 to give 2-(2-amino-4-methoxyphenyl)-4H-chromen-4-one (790 mg, 58%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Mg].C([O:14][B:15](OC(C)C)[O:16]C(C)C)(C)C.S(=O)(=O)(O)O>C1COCC1.C(OCC)C>[CH3:1][C:2]1[CH:3]=[C:4]([B:15]([OH:16])[OH:14])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(Br)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(C)cc(B(O)O)c1

Procedure:
3,5-Dimethylbromobenzene (10 g, 54 mmol) and magnesium (2.5 g, 108 mmol) were dissolved in 100 mL of THF and stirred at reflux for five hours. After this time, triisopropylborate (10 g, 54 mmol) as a solution in diethylether (50 mL) was added to the solution, followed by stirring at room temperature overnight. The THF was removed in vacuo to leave a crude oil. This oil was taken up in 100 mL of diethylether and 100 mL of 10% sulfuric acid (aqueous) and stirred for two hours. The organic layer was separated and neutralized with saturated sodium bicarbonate solution, whereafter the solvent was removed in vacuo to yield a white solid. The solid was washed generously with pentane. Yield: 4.0 g (49%).