Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20]CC)=[O:19])[CH2:14][CH2:13]1.C(N(CC)CC)C>C(Cl)Cl>[CH2:5]([O:4][C:2]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 5 °C
Reaction time: 18 h
Yield: 77 %

Procedure:
Benzyl chloroformate (8.5 g) was added dropwise to a stirred mixture of ethyl piperidine-4-carboxylate (7.85 g), triethylamine (6.95 ml) and methylene chloride (50 ml) which had been cooled to 5° C. The mixture was stirred at ambient temperature for 18 hours. The mixture was partitioned between ethyl acetate and 2N aqueous hydrochloric acid. The organic phase was washed with water and with brine, dried (MgSO4) and evaporated. The residue was dissolved in methanol (100 ml) and 2N aqueous sodium hydroxide (125 ml) was added. The mixture was stirred at ambient temperature for 1 hour. The mixture was concentrated by evaporation and the residue was partitioned between diethyl ether and water. The aqueous phase was acidified to pH 3 by the addition of concentrated hydrochloric acid and the mixture was extracted with ethyl acetate. The organic extract was washed with water, dried (HgSO4) and evaporated to give 1-benzyloxycarbonylpiperidine-4-carboxylic acid (10.1 g).
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[C:26](=[O:45])[CH2:27][C@@H:28]([O:43][CH3:44])[C@@H:29]([N:34]([CH3:42])[C:35](=[O:41])[C@H:36]([CH:38]([CH3:40])[CH3:39])[NH2:37])[C@@H:30]([CH3:33])[CH2:31][CH3:32])[C@@H:4]([CH3:20])[C:5]([NH:7][C@H:8]([C:16]([O:18][CH3:19])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[S:6].[CH:46]1[C:58]2[CH:57]([CH2:59][O:60][C:61]([N:63]([CH3:70])[C:64]([CH3:69])([C:66](O)=[O:67])[CH3:65])=[O:62])[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[C:50]=2[CH:49]=[CH:48][CH:47]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl>[CH:55]1[C:56]2[CH:57]([CH2:59][O:60][C:61]([N:63]([CH3:70])[C:64]([CH3:65])([C:66]([NH:37][C@H:36]([C:35]([N:34]([C@@H:29]([C@@H:30]([CH3:33])[CH2:31][CH3:32])[C@H:28]([O:43][CH3:44])[CH2:27][C:26]([N:22]3[CH2:23][CH2:24][CH2:25][C@H:21]3[C@H:3]([O:2][CH3:1])[C@@H:4]([CH3:20])[C:5]([NH:7][C@@H:8]([CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:16]([O:18][CH3:19])=[O:17])=[S:6])=[O:45])[CH3:42])=[O:41])[CH:38]([CH3:39])[CH3:40])=[O:67])[CH3:69])=[O:62])[C:58]3[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:51]=2[CH:52]=[CH:53][CH:54]=1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=S)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](N)C(C)C
Reactant: CN(C(=O)OCC1c2ccccc2-c2ccccc21)C(C)(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=S)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)N(C)C(=O)OCC1c2ccccc2-c2ccccc21)C(C)C

Procedure:
According to general procedure D, from #77 (399 mg, ≦0.52 mmol, 1 eq.), N-[(9H-fluoren-9-ylmethoxy)carbonyl]-N,2-dimethylalanine (213 mg, 0.628 mmol, 1.2 eq.), dichloromethane (5 mL, 0.1 M), HATU (239 mg, 0.628 mmol, 1.2 eq.) and diisopropylethylamine (282 μL, 1.62 mmol, 3.1 eq.) was synthesized the crude desired material, which was purified by silica gel chromatography (Gradient: 0% to 50% acetone in heptane), providing #78 (231 mg, 46% over two steps). LC-MS: m/z 970.7 [M+H+], 992.6 [M+Na+], retention time=1.11 minutes; HPLC (Protocol C): retention time=9.260 minutes; 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ [10.19 (d, J=7.4 Hz) and 10.47 (d, J=7.8 Hz), total 1H], 7.89 (d, J=7.4 Hz, 2H), 7.61-7.67 (m, 2H), 7.41 (br dd, J=7.4, 7.4 Hz, 2H), 7.14-7.36 (m, 8H), [5.20 (ddd, J=11, 7, 5 Hz) and 5.38 (ddd, J=11, 8, 4 Hz), total 1H], [4.41 (dd, J=8.6, 8.4 Hz) and 4.46 (dd, J=8.2, 8.2 Hz), total 1H], 3.65 and 3.68 (2 s, total 3H), 3.23 and 3.24 (2 s, total 3H), 3.13 (br s, 3H), 2.88 and 2.93 (2 br s, total 3H), 2.84 and 2.85 (2 s, total 3H), 1.31 and 1.32 (2 s, total 3H), [1.15 (d, J=6.6 Hz) and 1.18 (d, J=6.4 Hz), total 3H].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[C:9]2[S:16][CH2:17][C:18]2[C:23](F)=[CH:22]C=[C:20](F)[C:19]=2F)=[CH:4][CH:3]=1.[NH:27]1C(C([O-])=O)=CN=C1.[Li+].[OH-]>C1COCC1.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[C:9]2[S:16][CH2:17][C:18]2[CH:19]=[CH:20][N:27]=[CH:22][CH:23]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnc(SCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Reactant: O=C([O-])c1cnc[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cnc(SCc2ccncc2)n1-c1ccc(F)cc1

Procedure:
1-(4-Fluorophenyl)-2-((pyridin-4-ylmethyl)thio)-1H-imidazole-5-carboxylic acid (51) was prepared in a similar manner as that described for the synthesis of compound 11 using ethyl 1-(4-fluorophenyl)-2-(pyridine-4-ylmethyl)thio)-1H-imidazole-5-carboxylate (50) (390 mg, 1.09 mmol), 1N LiOH (5 mL) in THF (5 mL) and MeOH (5 mL).
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][C:9]2[CH:18]=[CH:17][C:12]([O:13][CH2:14][CH2:15][OH:16])=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[N:4]1.Br[C:20]1[S:21][CH:22]=[CH:23][N:24]=1>CN(C)C=O.CS(C)=O>[S:21]1[CH:22]=[CH:23][N:24]=[C:20]1[O:16][CH2:15][CH2:14][O:13][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][N:3]2[CH:7]=[CH:6][CH:5]=[N:4]2)=[CH:18][CH:17]=1
Reactant: Brc1nccs1
Reactant: OCCOc1ccc(Cn2cccn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: c1cnn(Cc2ccc(OCCOc3nccs3)cc2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 40.6 %

Procedure:
To a mixture of 10 ml of anhydrous N,N-dimethylformamide and 110 mg of sodium hydride (60% oil dispersion) was added dropwise an anhydrous dimethylsulfoxide (5 ml) solution of 500 mg of 2-[4-(1-pyrazolyl)methylphenoxy]ethanol (produced in Reference Production Example 1 described below) under stirring over 10 minutes. After stirring at 60° to 70° C. for 2 hours, the mixture was cooled to 5° to 10° C., to which an anhydrous N,N-dimethylformamide (5 ml) solution of 488 mg of 2-bromothiazole was added dropwise over 10 minutes. The mixture was then stirred at room temperature over-night and then at 60° to 70° C. for further 2 hours. The reaction mixture was poured into 50 ml of ice water, which was extracted with twice with 30 ml of toluene. The organic layers were combined, washed with water, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, which afforded 280 mg of 4-(1-pyrazolyl)methylphenyl 2-(2-thiazolyl-oxy)ethyl ether (compound 5). Yield, 41%.
Reaction SMILES: C([NH:3][C:4]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[C:7](CCC)=[C:6](O)[CH:5]=1)C.[C:18]([C:24](OC)=O)#[C:19][C:20]([O:22][CH3:23])=[O:21]>[OH-].C([N+](C)(C)C)C1C=CC=CC=1.CO>[CH3:23][O:22][C:20]([CH:19]1[CH2:18][CH2:24][C:5]2[C:4](=[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]3=[CH:7][CH:6]=2)[NH:3]1)=[O:21]
Reactant: COC(=O)C#CC(=O)OC
Reactant: CCCc1c(O)cc(NCC)c2c1CCCC2
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CO
Product: COC(=O)C1CCc2ccc3ccccc3c2N1

Procedure:
Benzyltrimethylammonium hydroxide (40% aqueous solution) (3 drops) was added to a stirred solution of 1-ethylamino-3-hydroxy-4-propyl-5,6,7,8-tetrahydronaphthalene (2.33 g) and dimethyl acetylene dicarboxylate (1.42 g) in methanol (10 ml). The mixture was heated at reflux for 8 hours, cooled, filtered and the methanol removed in vacuo. The resulting oil, a mixture of the cis and trans tetrahydronaphthylamino acrylic acid esters, was heated on a steam bath with polyphosphoric acid (10 g) for 2 hours. The mixture was cooled, poured into water and the solution adjusted to pH7 with sodium bicarbonate. The resulting mixture was extracted with ethyl acetate. The extracts were dried (magnesium sulphate) and evaporated in vacuo giving crude tetrahydrobenzo quinoline-2-carboxylic acid methyl ester as a sticky solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19]C)[N:3]=1.COC1C=CC=CC=1C1N=[C:37]([NH:39][CH2:40][C:41]2[O:42][C:43]([CH3:46])=[N:44][N:45]=2)C2C(=CC(C)=CC=2)N=1.C(O)(=O)C(O)=O.CC1OC(CN)=NN=1.C(N(CC)CC)C>CN(C=O)C>[CH3:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([N:39]([CH3:37])[CH2:40][C:41]3[O:42][C:43]([CH3:46])=[N:44][N:45]=3)=[N:3][C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])=[N:5]2)=[CH:10][CH:9]=1
Reactant: COc1ccccc1-c1nc(NCc2nnc(C)o2)c2ccc(C)cc2n1
Reactant: COc1ccccc1-c1nc(Cl)c2ccc(C)cc2n1
Agent: Cc1nnc(CN)o1
Agent: O=C(O)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N(C)Cc3nnc(C)o3)nc(-c3ccccc3O)nc2c1
Reaction time: 6 h
Yield: 56 %

Procedure:
[2-(2-Methoxy-phenyl)-7-methyl-quinazolin-4-yl]-(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-amine 4-Chloro-2-(2-methoxy-phenyl)-7-methyl-quinazoline (400 mg, 1.48 mmol) was dissolved in 10 ml dry DMF followed by the addition of C-(5-Methyl-[1,3,4]oxadiazol-2-yl)-methylamine oxalate (234 mg, 1.48 mmol) then triethylamine (413 μl, 2.96 mmol). After 6 hours the reaction was complete, partitioned between EtOAc and water. The organic phase was separated, dried over MgSO4, filtered and concentrated to an oil. Purified by flash chromatography 60% EtOAc/40% hexanes to afford the desired product a white solid. Recovered 290 mg 56% yield. LC/MS (10-99%) M/Z 348.4, retention time 2.17 minutes.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:12]=[C:11]([I:13])[CH:10]=[C:6]([C:7]([OH:9])=O)[CH:5]=1.O.ON1C2C=CC=CC=2N=N1.[CH:26]1([N:32]=[C:33]=NC2CCCCC2)CCC[CH2:28][CH2:27]1.CNCCC>C1COCC1>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:12]=[C:11]([I:13])[CH:10]=[C:6]([C:7]([N:32]([CH3:33])[CH2:26][CH2:27][CH3:28])=[O:9])[CH:5]=1
Reactant: COC(=O)c1cc(I)cc(C(=O)O)c1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCCNC
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: CCCN(C)C(=O)c1cc(I)cc(C(=O)OC)c1
Temperature: 0 °C

Procedure:
Dissolve 5-iodo-isophthalic acid monomethyl ester (9.34 g, 30.5 mmol), 1-hydroxybenzotriazole hydrate (4.86 g, 36 mmol) and a solution of 1,3-dicyclohexylcarbodiimide (1 M in dichloromethane; 36 mL) in THF (70 mL). Cool to 0° C. for 15 min. Add methylpropylamine (3.69 mL, 36 mmol) and stir at room temperature for 12 h. Filter the solution though a filtering agent and wash with ethyl acetate, concentrate and purify (silica gel chromatography, eluting with 20:80 ethyl acetate:hexanes) to give the title compound.
Reaction SMILES: C([N:8](C(OC(C)(C)C)=O)[C@H:9]1[CH2:13][C@@H:12]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([Cl:24])=[N:18][C:19]=3[Cl:23])[C@H:11]([OH:25])[C@@H:10]1[OH:26])(OC(C)(C)C)=O.[N:34]1N[N:36]=[C:37]([CH2:39][OH:40])[CH:38]=1>>[Cl:24][C:17]1[N:16]=[C:15]2[C:20]([N:21]=[CH:22][N:14]2[C@@H:12]2[CH2:13][C@H:9]([N:8]3[N:36]=[C:37]([CH2:39][OH:40])[CH:38]=[N:34]3)[C@@H:10]([OH:26])[C@H:11]2[OH:25])=[C:19]([Cl:23])[N:18]=1
Reactant: OCc1cn[nH]n1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Product: OCc1cnn([C@H]2C[C@@H](n3cnc4c(Cl)nc(Cl)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared analogously to (1S,2R,3S,5R)-3-(di-Boc-amino)-5-(2,6-dichloro-purin-9-yl)-cyclopentane-1,2-diol (Step AA4) by replacing di-t-butyliminodicarboxylate (Step AA3) with (2H-[1,2,3]triazol-4-yl)-methanol.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]2=[O:23])=[N:13][C:12]=1[CH3:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)S(O[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[Si](C)(C)C)(=O)=O.[F-].[Cs+].C(OCC)(=O)C>C(#N)C>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH:21]=[CH:20][C:19]([O:22][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:18][C:17]2=[O:23])=[N:13][C:12]=1[CH3:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)c1ccccc1OS(=O)(=O)C(F)(F)F
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1nc(-n2ccc(Oc3ccccc3)cc2=O)sc1C(=O)NCc1ccccc1
Temperature: 60 °C
Yield: 14 %

Procedure:
To a solution of N-benzyl-2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxamide (0.20 g, 0.58 mmol) and 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.19 g, 0.64 mmol) in anhydrous acetonitrile (10 mL) was added cesium fluoride (0.22 g, 1.46 mmol). The reaction mixture was heated at 60° C. for 16 hours, followed by the addition of ethyl acetate (30 mL). The mixture was washed with saturated ammonium chloride (10 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography eluted with ethyl acetate/hexane (1/1) and further purified by recrystallization in ether to afford the title compound as a colorless solid in 14% yield (0.032 g): mp 67-70° C. (ether); 1H NMR (300 MHz, CDCl3) δ 8.76 (d, J=8.1 Hz, 1H), 7.45-7.25 (m, 8H), 7.11-7.08 (m, 2H), 6.35 (dd, J=8.1, 2.7 Hz, 1H), 6.05 (t, J=5.6 Hz, 1H), 5.81 (d, J=2.6 Hz, 1H), 4.58 (d, J=5.6 Hz, 2H), 2.69 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 167.8, 162.1, 161.8, 153.3, 152.8, 152.1, 137.7, 132.2, 130.3, 128.8, 127.9, 127.7, 126.4, 122.5, 121.1, 103.4, 100.2, 44.1, 17.3; MS (ES+) m/z 418.2 (M+1).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:31][CH2:32][CH:33]2[CH2:35][CH2:34]2)=[C:9]([C:11]2[C:12]3[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][C@H:24]4[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]4)=[O:22])[C:13]=3[N:14]=[CH:15][N:16]=2)[CH:10]=1)(=[O:4])[CH3:3].C([O:39][C@@H:40]([CH3:44])[C:41](Cl)=[O:42])(=O)C>>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:31][CH2:32][CH:33]2[CH2:34][CH2:35]2)=[C:9]([C:11]2[C:12]3[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][C@H:24]4[CH2:29][CH2:28][C@H:27]([NH:30][C:41](=[O:42])[C@@H:40]([OH:39])[CH3:44])[CH2:26][CH2:25]4)=[O:22])[C:13]=3[N:14]=[CH:15][N:16]=2)[CH:10]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: CC(=O)c1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: CC(=O)c1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)[C@H](C)O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from 4-[5-acetyl-2-(cyclopropylmethoxy)phenyl]-N-(trans-4-aminocyclohexyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f56) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.ClC(OC)=O.[N:32]1([C:37]2[CH:38]=[C:39]([CH:41]=[CH:42][CH:43]=2)[NH2:40])[CH:36]=[N:35][CH:34]=[N:33]1>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:40][C:39]3[CH:41]=[CH:42][CH:43]=[C:37]([N:32]4[CH:36]=[N:35][CH:34]=[N:33]4)[CH:38]=3)=[O:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Reactant: Nc1cccc(-n2cncn2)c1
Agent: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2cccc(-n3cncn3)c2)ncn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A cooled (0° C.) solution of 6-(cyclopropylmethyl(propyl)amino)pyrimidine-4-carboxylic acid (Intermediate 21, 112 mg; 0.45 mmol) in DCM was treated with diisopropylethylamine (78.4 mL; 0.52 mmol) and methyl chloroformate (36.2 mL; 0.47 mmol). After stirring at 0° C. for 15 minutes, 3-(1H-1,2,4-triazol-1-yl)aniline (Maybridge, 108 mg; 0.67 mmol) was added and the mixture stirred for 72 hours. The solvent was evaporated and the compound purified by preparative HPLC to give the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH:9]=O)=[CH:7][CH:6]=[CH:5][N:4]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:17].[Na+]>>[NH2:17][CH2:9][C:8]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ncccc1C=O
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Product: COc1ncccc1CN
Reaction time: 48 h
Yield: 69.9 %

Procedure:
A round bottom flask was charged with 0.44 g (3.23 mM) of 2-methoxy-3-pyridine carboxaldehyde (24), 1.24 g (16.15 mM) of ammonium acetate, and 0.61 g (19.69 mM) of sodium cyanoborohydride. The flask was then flushed with argon, and then 50 mL of dry MeOH was added by syringe. The reaction was stirred for 2 days, at which point the MeOH was evaporated off 25 mL of water was added, and the mixture was brought to pH 2 with conc. HCl. This was extracted twice with EtOAc to remove the alcohol side product. The mixture was brought to pH 10 using sodium hydroxide pellets, saturated with NaCl, and extracted twice with DCM and once with EtOAc. The combined organics were dried and evaporated to give 0.31 g (69%) of 3-aminomethyl-2-methoxypyridine (25).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([O:13][C:14]([F:17])([F:16])[F:15])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].[C:18](Cl)(=O)C(Cl)=O>CN(C)C=O.ClCCCl>[N+:1]([C:4]1[CH:12]=[C:11]([O:13][C:14]([F:15])([F:16])[F:17])[CH:10]=[CH:9][C:5]=1[C:6]([O:8][CH3:18])=[O:7])([O-:3])=[O:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(OC(F)(F)F)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(=O)c1ccc(OC(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 48 h

Procedure:
2-Nitro-4-trifluoromethoxybenzoic acid (4.7 g) was heated under reflux conditions for 2 hours with oxalyl chloride (1.95 ml) and 1,2-dichloroethane (25 ml) containing N,N-dimethylformamide (2 drops). The solvents were evaporated to dryness, the residue dissolved in drv dichloromethane and added to a solution of triethylamine (2.08 g) in dry methanol. After 2 days, the solvent was evaporated and the residue partitioned between dichloromethane and sodium bicarbonate solution. The organic phase was dried (magnesium sulphate), evaporated and the residue purified by chromatography, eluting with dichloromethane/hexane to give methyl 2-nitro-4-trifluoromethoxybenzoate (4.9 g) as a yellow liquid, NMR (CDCl3) 3.9(s,3H), 7.5(m,1H), 7.75(brs, 1H), 7.85(d,1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:23]=[CH:22][C:12]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[O:14])=[C:11]([Cl:24])[CH:10]=1.[CH3:25][N:26]([CH3:30])[C:27](Cl)=[O:28].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:13]([C:12]1[CH:22]=[CH:23][C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:27](=[O:28])[N:26]([CH3:30])[CH3:25])=[CH:10][C:11]=1[Cl:24])=[O:14]
Reactant: CN(C)C(=O)Cl
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2N)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2NC(=O)N(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-(2-aminophenylamino)-2-chloro-2′-methylbenzophenone (Compound 156, 1.2 g, 3.5 mmol), dimethylcarbamyl chloride (0.32 ml, 3.5 mmol) and potassium carbonate (1.0 g, 7 mmol) in N,N-dimethylformamide (20 ml) was stirred at room temperature for 16 hours. The reaction mixture was poured into water (100 ml) and was extracted with ethyl acetate (3×75 ml). The organic phase was dried (MgSO4), filtered and evaporated in vacuo to give the crude product. The crude product was purified by flash chromatography by using ethyl acetate/pentane mixtures from 1:9 to 1:1. Trituration with diethyl ether/pentane 1:1 afforded the pure title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH:34]=[O:35])[CH2:24][CH:23]2[OH:36])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].C(=O)([O-])[O-].C1(C)C=CC(S([CH2:50][N:51]=[C:52]=O)(=O)=O)=CC=1.O>CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[O:35][CH:52]=[N:51][CH:50]=3)[CH2:24][CH:23]2[OH:36])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11]
Reactant: O=Cc1ccccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(O)C1
Reactant: Cc1ccc(S(=O)(=O)CN=C=O)cc1
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: O
Product: O=C(NC1(C(=O)NC2CCN(c3ccccc3-c3cnco3)CC2O)CCCCC1)c1cc2ccccc2o1
Yield: 100.9 %

Procedure:
The mixture of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-(2-formylphenyl)piperidin-3-ol (3 g, 6 mmol) obtained in Step 1 of Example 61, photassium carbonate (2 g, 20 mmol) and p-toluenesulfonylmethyl isocyanate (TosMIC; 1.8 g, 9 mmol) was refluxed in 500 ml of methanol for about 2 hours. 150 ml of water was added to the concentrated reaction mixture, which was then extracted with dichloromethane. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was purified with column chromatography to give 3.2 g of the titled compound.
Reaction SMILES: COC(=O)N[C@@H](C(C)C)C(N1[C@H](C2NC(C3C=CC(C4C=CC5C(=CC=C(C6NC([C@@H]7CCCN7[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]7[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=7)=NC=6)C=5)C=4)=CC=3)=CN=2)CC2(OCCO2)C1)=O.Cl.Cl.Cl.[F:69][C:70]1([F:121])[C:82]2[CH:81]=[C:80]([C:83]3[NH:87][C:86]([C@@H:88]4[CH2:92][CH2:91][CH2:90][N:89]4[C:93](=[O:106])[C@@H:94]([NH:101][C:102](=[O:105])[O:103][CH3:104])[CH:95]4[CH2:100][CH2:99][O:98][CH2:97][CH2:96]4)=[N:85][CH:84]=3)[CH:79]=[CH:78][C:77]=2[C:76]2[C:71]1=[CH:72][C:73]([C:107]1[CH:108]=[CH:109][C:110]3[N:114]=[C:113]([C@@H:115]4[CH2:119][CH2:118][CH2:117][NH:116]4)[NH:112][C:111]=3[CH:120]=1)=[CH:74][CH:75]=2>>[CH3:60][O:59][C:57](=[O:58])[NH:56][C@H:49]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:48]([N:116]1[CH2:117][CH2:118][CH2:119][C@H:115]1[C:113]1[NH:112][C:111]2[CH:120]=[C:107]([C:73]3[CH:74]=[CH:75][C:76]4[C:77]5[C:82](=[CH:81][C:80]([C:83]6[NH:87][C:86]([C@@H:88]7[CH2:92][CH2:91][CH2:90][N:89]7[C:93](=[O:106])[C@@H:94]([NH:101][C:102]([O:103][CH3:104])=[O:105])[CH:95]7[CH2:100][CH2:99][O:98][CH2:97][CH2:96]7)=[N:85][CH:84]=6)=[CH:79][CH:78]=5)[C:70]([F:69])([F:121])[C:71]=4[CH:72]=3)[CH:108]=[CH:109][C:110]=2[N:114]=1)=[O:61]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(-c4ccc5cc(-c6cnc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)ccc5c4)cc3)[nH]1)OCCO2)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)C(F)(F)c2cc(-c4ccc5nc([C@@H]6CCCN6)[nH]c5c4)ccc2-3)[nH]1)C1CCOCC1
Agent: Cl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)C(F)(F)c2cc(-c4ccc5nc([C@@H]6CCCN6C(=O)[C@H](NC(=O)OC)c6ccccc6)[nH]c5c4)ccc2-3)[nH]1)C1CCOCC1

Procedure:
The title compound was prepared according to the method employed to prepare (S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester, except that methyl (S)-2-((S)-2-(5-(9,9-difluoro-7-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)-9H-fluoren-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate 3HCl salt was used instead of methyl (S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate 3HCl salt. MS (ESI) m/z 914.51 [M+H]+. (86.2 mg, 53%).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([NH2:10])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[CH2:26][NH:27][NH2:28]>C(O)C>[NH2:10][C:6]1[NH:28][N:27]([CH2:26][C:25]2[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=2[F:23])[C:4](=[O:3])[CH:5]=1
Reactant: NNCc1ccccc1F
Reactant: CCOC(=O)C=C(N)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Nc1cc(=O)n(Cc2ccccc2F)[nH]1
Reaction time: 2 h

Procedure:
30.2 g of β-amino-β-ethoxyacrylic acid ethyl ester together with 2 g of p-toluenesulphonic acid were dissolved in 300 ml of ethanol and 27.1 g of o-fluorobenzylhydrazine were added under nitrogen. After stirring for 2 hours, the mixture was left to stand overnight and the compound identified above, which had separated out as a precipitate, was filtered off and recrystallised from ethanol. Melting point: 146°, 11 g (27%).