Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[C:3]=1[C:4]([N:6]1[C:14]2[C:9](=[C:10]([F:15])[CH:11]=[CH:12][CH:13]=2)[C:8]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[C:18]([OH:25])[CH:17]=2)=[N:7]1)=[O:5].[CH3:34][C:35](OC(C)=O)=[O:36].[Mg+2].[I-].[I-]>C(OCC)C>[C:35]([O:25][C:18]1[CH:17]=[C:16]([C:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][C:10]=3[F:15])[N:6]([C:4](=[O:5])[C:3]3[C:26]([C:30]([F:32])([F:31])[F:33])=[CH:27][CH:28]=[CH:29][C:2]=3[Cl:1])[N:7]=2)[CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21])(=[O:36])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1ccc(-c2nn(C(=O)c3c(Cl)cccc3C(F)(F)F)c3cccc(F)c23)cc1O
Agent: [I-]
Agent: [Mg+2]
Solvent: CCOCC
Product: CC(=O)Oc1cc(-c2nn(C(=O)c3c(Cl)cccc3C(F)(F)F)c3cccc(F)c23)ccc1C(=O)O
Temperature: 40 °C

Procedure:
A suspension of compound 26A (48 mg, 0.1 mmol), Ac2O (0.8 mL) and MgI2 (28 mg, 0.1 mmol) in anhydrous ethyl ether (3 mL) was refluxed at 40° C. for 0.5 h. The reaction was cooled to rt, quenched with H2O, extracted with ether, and concentrated. The crude product was dissolved in THF (10 mL)/H2O (10 mL) and refluxed at 80° C. for 1 h. The mixture was cooled to rt, diluted with H2O, and extracted with EtOAc. The combined organic extracts were concentrated and purified by flash chromatography PE/EA (5/1) to give the title compound as a white solid. LCMS (ESI): calc'd for C22H12ClF4N2O4 [M+H]+: 521. found: 521, 1H NMR (400 MHz, MeOD) δ 8.47 (1H, d, J=8.0 Hz), 8.11 (1H, d, J=8.0 Hz), 7.90-7.76 (5H, m), 7.53 (1H, t, J=1.6 Hz), 3.34 (1H, q, J=8.0 Hz), 2.31 (3H, s).
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.[C:9]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([CH3:23])[CH2:21]Br)=[C:15]([Cl:24])[CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>C(#N)C.C(Cl)Cl>[C:9]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([CH3:21])[CH2:23][N:4]2[CH2:5][C@H:6]([CH3:8])[O:7][C@H:2]([CH3:1])[CH2:3]2)=[C:15]([Cl:24])[CH:14]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(CBr)Cc1ccc(C(C)(C)C)cc1Cl
Reactant: C[C@@H]1CNC[C@H](C)O1
Solvent: CC#N
Solvent: ClCCl
Product: CC(Cc1ccc(C(C)(C)C)cc1Cl)CN1C[C@@H](C)O[C@@H](C)C1
Yield: 65 %

Procedure:
A solution of 23 g of 2,6-cis-dimethylmorpholine and 30.4 g of 3-(p-tert-butyl-o-chlorophenyl)-2-methylpropyl bromide in 150 ml of acetonitrile is refluxed for 4 hours. The crude product is dissolved in methylene chloride, the solution is washed with water, aqueous sodium bicarbonate solution and again with water, and dried over Na2SO4, the solvent is evaporated and the residue is distilled. There is obtained 22 g of N-[3-(p-tert-butyl-o-chlorophenyl)-2-methylpropyl]-2,6-cis-dimethylmorpholine (active ingredient no. 2); b.p. (0.05 mm) 133°-135° C.
Reaction SMILES: [CH2:1]([Li])CCC.[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[CH:17]([CH3:27])[CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH:13][C:12]([CH3:29])([CH3:28])[C:11]1[CH2:30][CH2:31][CH2:32][C:33](=O)[C:10]2=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[CH:17]([CH3:27])[CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH:13][C:12]([CH3:28])([CH3:29])[C:11]1[CH2:30][CH2:31][CH2:32][C:33](=[CH2:1])[C:10]2=1
Reactant: CC(CCCc1ccccc1)c1cc2c(cc1O)C1=C(CCCC1=O)C(C)(C)N2
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOCC
Product: C=C1CCCC2=C1c1cc(O)c(C(C)CCCc3ccccc3)cc1NC2(C)C
Reaction time: 8 h

Procedure:
A 1 N ethereal solution of butyllithium (9 ml.) is added with stirring, under a nitrogen atmosphere to a suspension of 3.57 g. (10 mmoles) of methyltriphenylphosphonium bromide (prepared from methyl bromide and triphenylphosphine) in 50 ml. of ether. 5,6,7,8,9,10-Hexahydro-2-hydroxy-3-(1-methyl-4-phenylbutyl)-6,6-dimethyl-10-oxo-benzo[c]quinoline (600 mg., 1.5 mmoles) dissolved in 100 ml. of ether is added and the mixture is stirred for four hours then allowed to stand overnight at room temperature. Ether is distilled off as tetrahydrofuran is added until most of the ether is replaced. The mixture was then refluxed for six hours, cooled and worked-up as described in Part A of Example 42 to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[N:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[N:3]=1
Reactant: Cc1ccc2c(N3CCN(C(=O)OC(C)(C)C)CC3)cccc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2c(N3CCNCC3)cccc2n1
Yield: 96 %

Procedure:
1,1-dimethylethyl 4-(2-methyl-5-quinolinyl)-1-piperazinecarboxylate (D2) (1.1 g) in a 25% solution of trifluoroacetic acid in dichloromethane (10 mL) was stirred at r.t. under an inert atmosphere for 3 hours. The reaction mixture was concentrated under reduced pressure and desalted by means of a 20 g SCX cartridge affording the title compound in 96% yield (0.74 g).
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:23]=3)=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:25]([O:24][C:22]1[CH:23]=[C:18]([C:14]2[CH:13]=[C:12]3[C:17](=[N:16][CH:15]=2)[NH:8][CH2:9][CH2:10][CH2:11]3)[CH:19]=[N:20][CH:21]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(-c3cncc(OCc4ccccc4)c3)cnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(COc2cncc(-c3cnc4c(c3)CCCN4)c2)cc1
Yield: 87.9 %

Procedure:
A solution of 6-(5-benzyloxy-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (790 mg, 1.9 mmol) in 20% TFA in DCM (21 mL) is stirred at room temperature for 16 h. The solvent is removed under vacuum to afford 6-(5-benzyloxy-pyridin-3-yl)-1,2,3,4-tetrahydro-[1,8]naphthyridine (530 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9](OS(C)(=O)=O)[CH2:8][N:7]1[CH2:16][CH3:17])=[O:5])[CH3:2].[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C)C=O>[N:18]([C@@H:9]1[CH2:8][N:7]([CH2:16][CH3:17])[C@H:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:10]1)=[N+:19]=[N-:20]
Reactant: CCOC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1CC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1CC
Temperature: 90 °C
Reaction time: 4 h

Procedure:
A mixture of 3.5 g of (2S,4R)-2-ethoxycarbonyl-N-ethyl-4-methanesulfonyloxy pyrrolidine, 1.54 g of sodium azide and 10 ml of dimethylformamide was stirred at 90° C. for 4 hours. After cooling, the reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic extract was washed with water, dried and concentrated under reduced pressure to obtain crude product. This was then subjected to a silica gel column chromatography (elution liq. toluene-ethyl acetate) to obtain pure (2S,4S)-4-azido-2-ethoxycarbonylN-ethyl pyrrolidine as an oily product. Yield 2.05 g.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:17][O:18][CH:19]([CH3:22])[CH2:20][Cl:21])[C:13]([O:15]C)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].C1COCC1>C1COCC1.O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:17][O:18][CH:19]([CH3:22])[CH2:20][Cl:21])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](COC(C)CCl)NC(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(CCl)OC[C@@H](NC(=O)OCc1ccccc1)C(=O)O

Procedure:
To a solution of (R)-methyl 2-(benzyloxycarbonylamino)-3-(1-chloropropan-2-yloxy)propanoate (583 mg, 1.77 mmol) in THF—H2O (8 mL-4 mL) was added lithium hydroxide monohydrate (223 mg, 5.30 mmol). The mixture was stirred at room temperature for 25 minutes THF was removed in vacuo and the mixture extracted with EtOAc and dried over Na2SO4. Solvent was removed to give crude (R)-2-(benzyloxycarbonylamino)-3-(1-chloropropan-2-yloxy)propanoic acid as an oil. MS [M+H] found 316.2.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH3:11])=[CH:6][C:5]=1[OH:12])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH3:11])=[CH:6][C:5]=1[OH:12]
Reactant: CCc1ccc([N+](=O)[O-])c(O)c1
Agent: [Pd]
Solvent: CO
Product: CCc1ccc(N)c(O)c1
Yield: 85.4 %

Procedure:
To a solution of 2-nitro-5-ethylphenol (1 g, 6.4 mmol) in methanol (250 mL) was added 10% Pd/C (100 mg). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 min. and a hydrogen atmosphere was maintained at balloon pressure overnight. The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5%MeOH/CH2CH2) gave the desired product (750 mg, 91 %). 1H NMR (CD3OD): d 6.41-6.17 (m, 3H).
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:17]4[S:18][C:19]([C:28]([O:30]CC)=[O:29])=[C:20]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[N:21]=4)=[C:14]([CH3:16])[N:15]=3)[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:17]4[S:18][C:19]([C:28]([OH:30])=[O:29])=[C:20]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:21]=4)=[C:14]([CH3:16])[N:15]=3)[CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)c1sc(-c2c(C)nc3ccc(C4CCCCC4)cn23)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc2ccc(C3CCCCC3)cn2c1-c1nc(-c2ccccc2)c(C(=O)O)s1
Temperature: 50 °C
Reaction time: 12 h
Yield: 83.1 %

Procedure:
A mixture of ethyl 2-(6-cyclohexyl-2-methylimidazo[1,2-a]pyridin-3-yl)-4-phenyl-1,3-thiazole-5-carboxylate (204 mg, 0.458 mmol) obtained above in THF (5 mL) and MeOH (5 mL), was added 2N aqueous sodium hydroxide (750 μL), and the mixture was stirred at 50° C. for 12 h. The mixture was allowed to cool to rt and then neutralized by the addition of 1N aqueous hydrochloric acid (1.5 mL). The resulting precipitate was collected by filtration and then washed with water and diethyl ether to give the title compound (159 mg, 83%) as a gray solid.
Reaction SMILES: FC1C(F)=C(OCCCCCCCC)C=CC=1[B:18]([OH:20])[OH:19].Br[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[C:30]([F:43])[C:29]=2[F:44])=[CH:24][CH:23]=1.C([Li])CCC.C(OB(OC(C)C)OC(C)C)(C)C>>[F:44][C:29]1[C:30]([F:43])=[C:31]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:32]=[CH:33][C:28]=1[C:25]1[CH:26]=[CH:27][C:22]([B:18]([OH:20])[OH:19])=[CH:23][CH:24]=1
Reactant: CCCCCCCCOc1ccc(-c2ccc(Br)cc2)c(F)c1F
Reactant: CCCCCCCCOc1ccc(B(O)O)c(F)c1F
Agent: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Product: CCCCCCCCOc1ccc(-c2ccc(B(O)O)cc2)c(F)c1F

Procedure:
This was prepared using a similar method to that described for compound 5. Quantities: 4'-bromo-2,3-difluoro-4-octoxybiphenyl (8) (3.18g, 8.0 mmol), n-butyllithium (3.2 ml, 2.5M/hexane, 8.0 mmol), tri-isopropylborate (3.01 g, 16.0 mmol).
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.[NH2:13][C:14]1[C:22]2[NH:21][C:20](=[O:23])[NH:19][C:18]=2[CH:17]=[CH:16][CH:15]=1>C(O)C>[CH2:9]([O:8][C:7]1[C:6](=[O:11])[C:5](=[O:12])[C:4]=1[NH:13][C:14]1[C:22]2[NH:21][C:20](=[O:23])[NH:19][C:18]=2[CH:17]=[CH:16][CH:15]=1)[CH3:10]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: Nc1cccc2[nH]c(=O)[nH]c12
Solvent: CCO
Product: CCOc1c(Nc2cccc3[nH]c(=O)[nH]c23)c(=O)c1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 38.4 %

Procedure:
0.86 ml of 3,4-diethoxycyclobut-3-ene-1,2-dione (5.9 mmol, 1.5 eq) was added to a solution of 0.59 g of 4-amino-1,3-dihydrobenzoimidazol-2-one (4.0 mmol, 1 eq) in 21 ml of ethanol. The reaction medium was stirred at ambient temperature for 2 days (formation of a precipitate). Ethanol was added in order to promote the fall of the precipitate, which was filtered off, washed with diethyl ether and dried under vacuum at 45° C. The residue was chromatographed on silica gel, eluted with 90/10 dichloromethane/methanol. 0.42 g of product was obtained in the form of a white solid. Yield=38.6%.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH3:19])=[C:6]2[C:10](=[C:11]([N+:14]([O-])=O)[C:12]=1[CH3:13])[C:9]([CH3:18])([CH3:17])[CH2:8][CH2:7]2)([O-])=O.O>CO.[Pd]>[NH2:1][C:4]1[C:5]([CH3:19])=[C:6]2[C:10](=[C:11]([NH2:14])[C:12]=1[CH3:13])[C:9]([CH3:17])([CH3:18])[CH2:8][CH2:7]2
Reactant: Cc1c2c(c([N+](=O)[O-])c(C)c1[N+](=O)[O-])C(C)(C)CC2
Agent: [Pd]
Solvent: O
Solvent: CO
Product: Cc1c(N)c(C)c2c(c1N)C(C)(C)CC2
Temperature: 55 °C
Reaction time: 84 h
Yield: 92.1 %

Procedure:
175 g (0.662 mol) of the resulted 5,7-dinitro-1,1,4,6-tetramethylindan was dissolved in 500 g of methanol, 17.5 g (50% water content) of 5%-Pd/C was added, then, the mixture was stirred for 84 hours at 50 to 60° C. under a hydrogen atmosphere. After completion of the reaction, the mixture was filtrated and filtrate was concentrated under reduced pressure. The resulted residue was distilled under reduced pressure to obtain 5,7-diamino-1,1,4,6-tetramethyl-indan as a pale yellow crystal. The yielded amount was 124 g (yield: 92.1%), the melting point was 77 to 78.5° C., and the boiling point was 148 to 150° C. (339 Pa).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]2[N:22](COCC[Si](C)(C)C)[CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])=[C:14]([C:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH:37]=2)[CH:13]=1)[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2].C(O)C.[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46].CCOCC.CCCCCC>C(Cl)Cl>[F:48][C:47]([F:50])([F:49])[C:45]([OH:51])=[O:46].[C:9]([O:8][CH2:7][CH:6]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]2[NH:22][CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])=[C:14]([C:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH:37]=2)[CH:13]=1)[CH2:5][O:4][C:1](=[O:3])[CH3:2])(=[O:11])[CH3:10]
Reactant: CC(=O)OCC(COC(C)=O)c1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCCCC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(=O)OCC(COC(C)=O)c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCCCC2)c1
Yield: 57 %

Procedure:
A solution of acetic acid 3-acetoxy-2-(4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-propyl ester (as prepared in the previous step, 102 mg, 0.175 mmol) in DCM (2 mL) was treated with ethyl alcohol (EtOH) (60 μl) and TFA (0.6 mL) at RT for 2 h and concentrated in vacuo. The reaction mixture was dissolved in DCM (10 mL) and poured into satd aq NaHCO3. The organic layer was separated, dried (Na2SO4) and concentrated. The solid obtained was suspended in 1:1 ether/hexane, sonicated and concentrated in vacuo. The resulting residue was dried in vacuo to obtain the title compound (57 mg, 57%): 1H-NMR (CDCl3; 400 MHz): δ 12.90 (br s, 1H), 9.75 (s, 1H), 8.32 (d, 1H, J=8.4 Hz), 7.78 (s, 1H), 7.24 (dd, 1H, J=8.4, 2.0 Hz), 7.06 (d, 1H, J=2.0 Hz), 5.82 (br s, 1H), 4.38 (m, 4H), 3.35 (m, 1H), 2.23-2.35 (m, 4H), 2.10 (s, 6H), 1.75-1.92 (m, 4H): Mass spectrum, (ESI, m/z): Calcd. for C24H26N4O5, 451.2 (M+H). found 451.0.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:41][O:42][C:43]1[C:44]2[N:57]=[C:56]([NH2:58])[S:55][C:45]=2[C:46]([N:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)=[N:47][CH:48]=1>C1COCC1>[CH3:41][O:42][C:43]1[C:44]2[N:57]=[C:56]([NH:58][C:1](=[O:9])[C:2]3[CH:3]=[CH:4][N:5]=[CH:6][CH:7]=3)[S:55][C:45]=2[C:46]([N:49]2[CH2:50][CH2:51][O:52][CH2:53][CH2:54]2)=[N:47][CH:48]=1
Reactant: O=C(O)c1ccncc1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)c3ccncc3)nc12

Procedure:
From isonicotinic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 372 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([CH3:13])([CH3:12])[CH:10]=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:14][Mg+].[Br-]>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([CH3:13])([CH3:12])[CH:10]([OH:11])[CH3:14])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C[Mg+]
Reactant: CC(C)(C=O)c1ccc(Cl)c(Cl)c1
Agent: [Br-]
Solvent: CCOCC
Product: CC(O)C(C)(C)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
To a solution of 2-(3,4-dichlorophenyl)-2-methylpropanal (47.13 g, 0.217 mol) in Et2O (223 mL) at 0° C. was added a 3.0M solution of MeMgBr (217 mL, 0.651 mol) in Et2O. After stirring 2 h at 0° C., the reaction mixture was warmed to room temperature over 1 h. Then the reaction mixture was cooled to 0° C., quenched with H2O (100 mL) and 3N HCl (200 mL), extracted with EtOAc and washed with brine. The organic layer was dried over Na2SO4 and concentrated to afford the crude product, which was purified by column chromatography to yield 3-(3,4-dichlorophenyl)-3-methylbutan-2-ol (45.9 g, 90%). 1H NMR (400 MHz, CDCl3) δ 7.46 (d, 1H), 7.37 (d, 1H), 7.21 (dd, 1H), 3.83 (m, 1H), 1.31 (s, 3H), 1.29 (s, 3H), 1.05 (d, 3H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]=[C:6]2[N:5]=[C:4]([CH:15]([CH3:17])[CH3:16])[CH:3]=1.[SH-:18].[Na+]>O>[CH:15]([C:4]1[CH:3]=[C:2]([SH:18])[N:7]2[N:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]=[C:6]2[N:5]=1)([CH3:17])[CH3:16]
Reactant: [SH-]
Reactant: COC(=O)c1nc2nc(C(C)C)cc(Cl)n2n1
Agent: [Na+]
Solvent: O
Product: COC(=O)c1nc2nc(C(C)C)cc(S)n2n1
Reaction time: 3 h
Yield: 90.8 %

Procedure:
The product obtained in Step 2 (40 g) was added at 0° C. to a solution of sodium hydrosulfide (40 g) in one liter of water with stirring under a nitrogen stream. The mixture was stirred at 0° C. for one hour, then at room temperature for three hours, and the resulting yellow solution was washed with 200 ml of ethyl acetate. The aqueous layer was acidified with concentrated hydrochloric acid to pH 2.0, and the formed crystals were collected by filtration and washed with 100 ml of ethanol, affording 36 g of the objective compound as faint yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([NH:12][C:13](=[O:35])[O:14][CH2:15][C@@H:16]([N:21]([CH3:34])[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[Cl:33])=[O:23])[CH2:17][CH2:18][CH2:19][NH2:20])=[CH:5]2.CCN(C(C)C)C(C)C.[N:45]([CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])=[C:46]=[O:47]>C1COCC1>[Cl:33][C:27]1[C:28]([F:32])=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][NH:24][C:22](=[O:23])[N:21]([CH3:34])[C@H:16]([CH2:15][O:14][C:13](=[O:35])[NH:12][C:6]1[N:7]=[CH:8][C:9]2[C:4]([CH:5]=1)=[CH:3][C:2]([F:1])=[CH:11][CH:10]=2)[CH2:17][CH2:18][CH2:19][NH:20][C:46](=[O:47])[NH:45][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50]
Reactant: CCOC(=O)CN=C=O
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCCN)COC(=O)Nc1cc2cc(F)ccc2cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)NCCC[C@@H](COC(=O)Nc1cc2cc(F)ccc2cn1)N(C)C(=O)NCc1cccc(F)c1Cl
Yield: 79.5 %

Procedure:
To a mixture of (S)-5-amino-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)pentyl 6-fluoroisoquinolin-3-ylcarbamate (0.40 g, 0.792 mmol), DIEA (0.276 mL, 1.58 mmol) and THF (2 mL), ethyl isocyanatoacetate (0.108 mL, 0.950 mmol) was added. The mixture was refluxed for 30 min, and concentrated. The remaining residue was purified on silica gel column (DCM/MeOH) to give (S)-ethyl 1-(2-chloro-3-fluorophenyl)-5-((6-fluoroisoquinolin-3-ylcarbamoyloxy)methyl)-4-methyl-3,10-dioxo-2,4,9,11-tetraazatridecan-13-oate (0.40 g, 80%). LRMS (M+H+) m/z 635.6.
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH3:25])[CH2:6][O:7][C:8]1[CH:24]=[CH:23][C:11]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=2[OH:22])=O)=[CH:10][CH:9]=1)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[OH:21][C:18]1[CH:19]=[CH:20][C:15]2[N:14]=[C:12]([C:11]3[CH:23]=[CH:24][C:8]([O:7][CH2:6][C@@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH3:25])=[CH:9][CH:10]=3)[O:22][C:16]=2[CH:17]=1
Reactant: CC(=O)N[C@@H](C)COc1ccc(C(=O)Nc2ccc(O)cc2O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(=O)N[C@@H](C)COc1ccc(-c2nc3ccc(O)cc3o2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
To a solution of 4-{[(2S)-2-(acetylamino)propyl]oxy}-N-(2,4-dihydroxyphenyl)benzamide (628 mg) and triphenylphosphine (716 mg) in THF (6.0 mL) was added dropwise a toluene solution (2.2 M, 1.24 mL) of diethyl azodicarboxylate, and the mixture was stirred under a nitrogen atmosphere at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/methanol) to give the title compound (326 mg).
Reaction SMILES: [N:1]1[C:10]2[N:9]3[CH:11]=[CH:12][CH:13]=[C:8]3[CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:21][C:22]1[CH:23]=[CH:24][C:25]([CH3:40])=[C:26]([CH:39]=1)[C:27]([NH:29][C:30]1[N:35]=[CH:34][C:33]([C:36](Cl)=[O:37])=[CH:32][CH:31]=1)=[O:28].O>ClCCl>[N:1]1[C:10]2[N:9]3[CH:11]=[CH:12][CH:13]=[C:8]3[CH2:7][N:6]([C:36]([C:33]3[CH:32]=[CH:31][C:30]([NH:29][C:27](=[O:28])[C:26]4[CH:39]=[C:22]([F:21])[CH:23]=[CH:24][C:25]=4[CH3:40])=[N:35][CH:34]=3)=[O:37])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1cnc2c(c1)NCc1cccn1-2
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3-c3ncccc32)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.4 %

Procedure:
To a chilled (0° C.) solution of 0.343 g of 5, 6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine and 1.1 ml of triethylamine in 5 ml of dichloromethane is added 1.17 g of 6-(5-fluoro-2-methylbenzoyl)aminopyridine-3-carbonyl chloride. The mixture is stirred at room temperature for 16 hours. To the mixture is added 50 ml of dichloromethane and 20 ml of water. The organic layer is separated and washed with 20 ml each of 1M NaHCO3 and brine. The organic layer is dried (Na2SO4) and passed through a thin pad of hydrous magnesium silicate and the pad washed with dichloromethane. The filtrate is concentrated and the residue chromatographed on silica gel prep-plates with ethyl acetate-hexane (1:1) as eluent. The product is crystallized from ethyl acetate to give 0.38 g of white crystals, m.p. 226°-234° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][CH:6]([C:12]([OH:14])=[O:13])[CH2:5]2.S(Cl)(Cl)=O.[CH3:19]O>>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([C:12]([O:14][CH3:19])=[O:13])=[CH:5]2
Reactant: CO
Reactant: O=C(O)C1Cc2cc(O)ccc2CN1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc2cc(O)ccc2cn1
Temperature: 25 °C
Yield: 67 %

Procedure:
To a solution of 6-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (1.0 g, 5.2 mmol) in MeOH (50 mL) was added thionyl chloride (0.56 mL, 7.8 mmol) slowly. The reaction was heated at reflux for 18 h and then cooled to rt. The solvent was evaporated. The residue was redissolved in DCM and saturated NaHCO3 solution was added. The mixture was extracted with DCM (2×) and the combined organic solutions were dried over Na2SO4 and concentrated to give methyl 6-hydroxyisoquinoline-3-carboxylate as a white solid (0.72 g, 67%). LCMS: (FA) ES+ 208.2.