Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=CC(NC(C2(C(O)=O)CC2)=O)=CC=1.CN1CCOCC1.Cl[C:25]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[O:26].[CH2:32]([N:34]([CH2:55][CH3:56])[CH2:35][C:36]#[C:37][C:38]1[S:46][C:45]2[C:40](=[N:41][CH:42]=[CH:43][C:44]=2[O:47][C:48]2[CH:53]=[CH:52][C:51]([NH2:54])=[CH:50][CH:49]=2)[CH:39]=1)[CH3:33]>C1COCC1>[CH2:55]([N:34]([CH2:32][CH3:33])[CH2:35][C:36]#[C:37][C:38]1[S:46][C:45]2[C:40](=[N:41][CH:42]=[CH:43][C:44]=2[O:47][C:48]2[CH:49]=[CH:50][C:51]([NH:54][C:25](=[O:26])[O:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:52][CH:53]=2)[CH:39]=1)[CH3:56]
Reactant: CCN(CC)CC#Cc1cc2nccc(Oc3ccc(N)cc3)c2s1
Reactant: CC(C)COC(=O)Cl
Agent: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCN(CC)CC#Cc1cc2nccc(Oc3ccc(NC(=O)OCC(C)C)cc3)c2s1
Temperature: -78 °C

Procedure:
A 25 mL, single-neck, round-bottomed flask was charged with 1-((4-fluorophenyl)carbamoyl)cyclopropanecarboxylic acid (42 mg, 0.1694 mmol) and THF (2 mL) under nitrogen and cooled to −78° C. on a dry ice bath. N-methylmorpholine (0.037 mL, 0.34 mmol), and isobutyl chloroformate (0.019 ml, 0.15 mmol) were added. After 15 minutes 4-(2-(3-(diethylamino)prop-1-ynyl)thieno[3,2-b]pyridin -7-yloxy)benzenamine (40 mg, 0.11 mmol) in THF (1 mL) was added, and the reaction was allowed to warm to room temperature overnight. The reaction mixture was concentrated and the residue was purified on a Biotage 15M column (95:5 EtOAc/MeOH). The product was a white waxy solid (0.8 mg, 2%). 1H NMR (CDCl3, 400 MHz) δ 8.47 (d, J=5.5 Hz, 1H), 7.57 (s, 1H), 7.49 (m, 2H), 7.14 (m, 2H), 6.68 (br s, 1H), 6.54 (d, J=5.5 Hz, 1H), 3.98 (d, J=6.6 Hz, 2H), 3.72 (s, 2H), 2.65 (q, J=7, 14 Hz, 4H), 2.00 (m, 1H), 1.14 (t, J=7.0 Hz, 6H), 0.99 (d, J=7.0 Hz, 6H). LRMS (ESI pos) m/e 452 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[Cl:30])[C:3]1[S:7][C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:22]=[CH:21][C:17]4[O:18][CH2:19][O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])=[N:5][CH:4]=1.[Si:31]([O:38][C@@H:39]([CH2:43]Cl)[CH2:40][CH:41]=O)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].[BH4-].[Na+]>CO.O>[O:18]1[C:17]2[CH:21]=[CH:22][C:14]([C:11]3([C:9]([NH:8][C:6]4[S:7][C:3]([C@@H:2]([N:1]5[CH2:41][CH2:40][C@@H:39]([O:38][Si:31]([C:34]([CH3:36])([CH3:35])[CH3:37])([CH3:32])[CH3:33])[CH2:43]5)[C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=5[Cl:30])=[CH:4][N:5]=4)=[O:10])[CH2:12][CH2:13]3)=[CH:15][C:16]=2[O:20][CH2:19]1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CCl)CC=O
Reactant: N[C@H](c1cnc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)s1)c1ccc(F)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CCN([C@H](c2cnc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)s2)c2ccc(F)cc2Cl)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 59 %

Procedure:
To a solution of (S)-N-(5-(amino(2-chloro-4-fluorophenyl)methyl)thiazol-2-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (1.2 mmol) in MeOH (10 mL) was added (R)-3-(tert-butyldimethylsilyloxy)-4-chlorobutanal (341 mg, 1.4 mmol). The reaction mixture was stirred at room temperature for 5 min. Then NaBH4 (68 mg, 1.8 mmol) was added and stirring was continued at room temperature for 1 h. The reaction was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO4. After the removal of solvent, the residue was purified by column chromatography (10-20% EtOAc/Hexane) to afford 1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-((S)-((R)-3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)(2-chloro-4-fluorophenyl)methyl)thiazol-2-yl)cyclopropanecarboxamide (446 mg, 59% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.79 (dd, J=8.6, 6.3 Hz, 1H), 7.25 (d, J=6.4 Hz, 1H), 7.01-6.94 (m, 2H), 6.85 (td, J=8.3, 1.7 Hz, 2H), 6.78 (d, J=7.9 Hz, 1H), 5.99 (s, 2H), 4.99 (s, 1H), 4.35-4.30 (m, 1H), 2.77 (dd, J=9.9, 6.2 Hz, 1H), 2.51-2.48 (m, 2H), 2.36 (dd, J=9.9, 4.3 Hz, 1H), 2.06-2.01 (m, 1H), 1.71-1.65 (m, 3H), 1.18 (t, J=3.0 Hz, 2H), 0.85 (s, 9H), −0.01 (d, J=7.3 Hz, 6H); HPLC ret. time 3.59 min, 10-99% CH3CN, 5 min run; ESI-MS 630.6 m/z (MH+).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13].[CH3:16][C:17]1[N:22]=[C:21]([SH:23])[N:20]=[C:19]([OH:24])[CH:18]=1.C(N(CC)CC)C>C(O)C>[Cl:9][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:3]=1[CH2:2][S:23][C:21]1[N:20]=[C:19]([OH:24])[CH:18]=[C:17]([CH3:16])[N:22]=1
Reactant: CCN(CC)Cc1cccc(Cl)c1CBr
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCN(CC)Cc1cccc(Cl)c1CSc1nc(C)cc(O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.3 %

Procedure:
A mixture of {[2-(bromomethyl)-3-chlorophenyl]methyl}diethylamine (13.2 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (1.07 g, 7.5 mmol), and triethylamine (8 mL, 57.4 mmol) in absolute ethanol (50 mL) was stirred at room temperature overnight. The mixture was evaporated and then co-evaporated with EtOAc (20 mL). The solid residue was treated with water (100 mL), and the solution was extracted with dichloromethane (5×100 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo. The crude product was purified by flash chromatography (0-15% MeOH/CH2Cl2), affording 2-[({2-chloro-6-[(diethylamino)methyl]phenyl}methyl)sulfanyl]-6-methylpyrimidin-4-ol (932 mg, 39% yield); 1H NMR (400 MHz, DMSO-d6): δ 0.96 (t, 6H, J=6.8 Hz), 2.21 (s, 3H), 2.86 (m, 4H), 4.69 (s, 2H), 6.01 (s 1H), 7.35 (m, 1H), 7.42 (m, 1H); M+ 352.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9]1.[Li]CCCC.C(N(C(C)C)CC)(C)C>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1([OH:13])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Brc1cccnc1
Reactant: O=C1CCCC1
Agent: [Li]CCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: OC1(c2ccncc2Br)CCCC1
Yield: 33.8 %

Procedure:
Using analogous reaction condition and reagents as described in Example 20 for the preparation of I-20a above, 3-bromo pyridine solution (1.0 g, 6.36 mmol) was reacted with cyclopentanone solution (0.6 mL, 70 mmol) in dry THF (6 mL), n-BuLi solution (4.0 mL, 7.6 mmol) and diisopropylethyl amine (1.0 mL, 70 mmol) in dry THF (6 mL) to afford the crude product. The crude was purified by column chromatography on silica gel (20% ethyl acetate in hexane) afforded 520 mg of the product (34% yield).
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:21]([NH2:23])=[O:22])[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:7])(C)(C)C.FC(F)(F)C(O)=O.[C:31]([O:35][C:36]([NH:38][CH2:39][CH:40](C)[C:41](O)=O)=[O:37])([CH3:34])([CH3:33])[CH3:32]>>[CH2:14]([O:13][C:11]([CH2:10][C@H:9]([NH:8][C:6]([CH:40]([CH3:41])[CH2:39][NH:38][C:36](=[O:37])[O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:7])[C:21](=[O:22])[NH2:23])=[O:12])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(CNC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(N)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(CNC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)OCc1ccccc1)C(N)=O

Procedure:
Benzyl (S)-3-(1-t-butoxyformamido)succinamate was deprotected using trifluoroacetic acid and then coupled with DL-N-(t-butoxycarbonyl)-2-methyl-β-alanine to yield t-Butyl [(RS)-2-[[(S)-2-[(benzyloxy)carbonyl]-1-carbamoylethyl]-carbamoyl]propyl]carbamate, m.p. 135°-136° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([OH:22])[C:5]2[CH2:11][CH:10]([CH2:12][CH2:13][C:14]3[CH:15]=[C:16]([C:19]([OH:21])=O)[NH:17][CH:18]=3)[CH2:9][NH:8][C:6]=2[N:7]=1.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.Cl.[NH2:42][C@H:43]([C:50]([O:52][CH3:53])=[O:51])[CH2:44][CH2:45][C:46]([O:48][CH3:49])=[O:47]>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([OH:22])[C:5]2[CH2:11][CH:10]([CH2:12][CH2:13][C:14]3[CH:15]=[C:16]([C:19]([NH:42][C@H:43]([C:50]([O:52][CH3:53])=[O:51])[CH2:44][CH2:45][C:46]([O:48][CH3:49])=[O:47])=[O:21])[NH:17][CH:18]=3)[CH2:9][NH:8][C:6]=2[N:7]=1
Reactant: COC(=O)CC[C@H](N)C(=O)OC
Reactant: Nc1nc(O)c2c(n1)NCC(CCc1c[nH]c(C(=O)O)c1)C2
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)CC[C@H](NC(=O)c1cc(CCC2CNc3nc(N)nc(O)c3C2)c[nH]1)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
A solution of 4-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6yl)ethyl]pyrrole-2-carboxylic acid (152 mg, 0.5 mmol), 2-chloro-4,6-dimethoxy-1,3,5-triazine (98 mg, 0.55 mmol), and 4-methylmorpholine (0.066 mL, 0.6 mmol) in DMF (3 mL) was stirred at room temperature for 2 hours. Dimethyl L-glutamate hydrochloride (0.116 g, 0.55 mmol) and 4-methylmorpholine (0.066 mL, 0.6 mmol) were sequentially added and the mixture was stirred overnight at room temperature. The solvent was removed in vacuo, and the residue chromatographed using chloroform:methanol (9:1) to give dimethyl N-{4-[2-(amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]pyrrol-2-ylcarbonyl}-L-glutamate (152 mg, 66%) as a white solid, mp 151-153° C.: 1H N (CDCl3 /1 drop CD3OD) δ 10.20 (br s, 1H), 7.27 (s, 1H, J=7.9 Hz), 6.70 (s, 1H), 6.82 (s, 1H), 5.83 (br s, 2H), 5.38 (br s, 1H), 4.80 (m, 1H), 3.84 (s, 3H), 3.73 (s, 3H), 3.42 (br d, 1H, J=10.1 Hz), 3.05 (m, 1H), 2.76 (dd, 1H, J=15.0, 4.4 Hz), 2.65 (m, 2H), 2.56 (m, 2H), 2.36 (m, 1H), 2.14 (m, 2H), 1.91 (m, 1H), 1.68 (m, 2H).
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:30]1[CH:39]=[CH:38][C:37]([OH:40])=[C:36]2[C:31]=1[CH:32]=[CH:33][C:34](=[O:41])[NH:35]2)[CH2:10][NH:11]CCCC#CC1C=CC(NC(=O)C(F)(F)F)=CC=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:43][CH2:44][CH2:45][C:46]#[C:47][C:48]1[CH:53]=[CH:52][C:51]([NH:54][C:55]([NH:57][CH2:58][C:59]2[C:60]([NH:72][CH:73]3[CH2:78][CH2:77][O:76][CH2:75][CH2:74]3)=[C:61]3[CH:69]=[N:68][N:67]([CH2:70][CH3:71])[C:62]3=[N:63][C:64]=2[CH2:65][CH3:66])=[O:56])=[CH:50][CH:49]=1>>[Si:1]([O:8][C@H:9]([C:30]1[CH:39]=[CH:38][C:37]([OH:40])=[C:36]2[C:31]=1[CH:32]=[CH:33][C:34](=[O:41])[NH:35]2)[CH2:10][NH:11][CH2:43][CH2:44][CH2:45][C:46]#[C:47][C:48]1[CH:53]=[CH:52][C:51]([NH:54][C:55]([NH:57][CH2:58][C:59]2[C:60]([NH:72][CH:73]3[CH2:74][CH2:75][O:76][CH2:77][CH2:78]3)=[C:61]3[CH:69]=[N:68][N:67]([CH2:70][CH3:71])[C:62]3=[N:63][C:64]=2[CH2:65][CH3:66])=[O:56])=[CH:50][CH:49]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)Nc1ccc(C#CCCCBr)cc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CNCCCC#Cc1ccc(NC(=O)C(F)(F)F)cc1)c1ccc(O)c2[nH]c(=O)ccc12
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)Nc1ccc(C#CCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(O)c3[nH]c(=O)ccc23)cc1

Procedure:
The title compound was prepared in a manner analogous to that described for Intermediate 37, using Intermediate 35 in place of Intermediate 26. ES/MS calcd. for C45H61N8O5Si+ 821.5. found m/z=821.6 (M+H)+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[C:34]2[C:33]([NH:35][C:36]3[C:37]([O:42][CH:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[N:38][CH:39]=[CH:40][CH:41]=3)=[N:32][CH:31]=[N:30][C:29]=2[S:28][C:27]=1[C:49]([OH:51])=O.CCN(C(C)C)C(C)C.[CH3:61][N:62]([CH3:67])[CH2:63][CH2:64][CH2:65][NH2:66]>CN(C=O)C>[CH3:61][N:62]([CH3:67])[CH2:63][CH2:64][CH2:65][NH:66][C:49]([C:27]1[S:28][C:29]2[N:30]=[CH:31][N:32]=[C:33]([NH:35][C:36]3[C:37]([O:42][CH:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[N:38][CH:39]=[CH:40][CH:41]=3)[C:34]=2[C:26]=1[CH3:25])=[O:51]
Reactant: CN(C)CCCN
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3OC3CCOCC3)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C(=O)NCCCN(C)C)sc2ncnc(Nc3cccnc3OC3CCOCC3)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 24.7 %

Procedure:
HATU (0.105 g, 0.28 mmol) was added into a mixture of 5-methyl-4-(2-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-ylamino)thieno[2,3-d]pyrimidine-6-carboxylic acid (0.097 g, 0.25 mmol) and Hünig's base (44 μL, 0.25 mmol) in DMF (2.0 mL) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 hours. 3-Dimethylamino-1-propylamine (138 μL, 1.25 mmol) was added and the coolant removed. The reaction mixture was stirred at ambient temperature overnight. The solvent was concentrated in vacuo and the product purified by reverse phase preparative HPLC to yield off-white solid (0.029 g, 24%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH2:13][CH:14]([C:18]2([CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]2=[O:31])[C:15]([OH:17])=O)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.CN1CCOCC1.Cl.[CH2:56]([O:63][NH2:64])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>C(Cl)Cl>[CH2:56]([O:63][NH:64][C:15](=[O:17])[CH:14]([CH2:13][NH:12][S:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)(=[O:11])=[O:10])[C:18]1([CH2:32][CH:33]([CH3:34])[CH3:35])[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]1=[O:31])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: COc1ccc(S(=O)(=O)NCC(C(=O)O)C2(CC(C)C)CCN(CCc3ccccc3)C2=O)cc1
Reactant: NOCc1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)NCC(C(=O)NOCc2ccccc2)C2(CC(C)C)CCN(CCc3ccccc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 65 h
Yield: 108.4 %

Procedure:
A solution of α-[[[(4-methoxyphenyl)sulfonyl]amino]methyl]-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetic acid (290 mg, 0.577 mmol) in dry CH2Cl2 (5 mL) is treated with CDI (112 mg, 0.692 mmol). Afar 1 h, 4-methylmorpholine (0.095 mL, 0.866 mmol) and O-benzylhydroxyamine HCl (138 mg, 0.866 mmol) are added. The solution is stirred at room temperature under N2 for 65 h. The solvent had evaporated, and the residual gel is diluted with EtOAc (25 mL). The solution is washed with 1N HCl (10 mL), 1N NaOH (10 mL), and brine (10 mL). The organic layer is dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give 380 mg of an oil. The oil is purified by silica gel chromatography (30 g SG; 50% EtOAc/hexane) to provide 249 mg (71%) of the title compound as an oil:
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:10](=O)[CH2:9][CH:8]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[CH2:7][C:6]=2[N:5]=[CH:4][CH:3]=1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl.O>C(O)C>[ClH:24].[NH:22]([N:23]=[C:10]1[CH2:9][CH:8]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH2:7][C:6]2[N:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:11]1=2)[C:19]([NH2:21])=[NH:20]
Reactant: N=C(N)NN
Reactant: Cc1ccnc2c1C(=O)CC(c1ccncc1)C2
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1ccncc1)C2
Yield: 93.6 %

Procedure:
A mixture of 4-methyl-7-(4-pyridyl)-5,6,7,8-tetrahydroquinolin-5-one (0.1 g), aminoguanidine hydrochloride (0.049 g), concentrated hydrochloric acid (0.15 ml), water (0.15 ml) and ethanol (10 ml) was refluxed for 6 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with ethyl acetate. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol-water to give 5-guanidinoimino-4-methyl-7-(4-pyridyl)-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 76) (0.13 g) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:25][OH:26].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:25]\[OH:26])=[CH:4][CH:3]=1
Reactant: CC(C)CC(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)CC(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 151, step 3, 5-[3-(4-bromo-phenyl)-5-methyl-hexanoyl]-1-methyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless solid, MS (ESI+): m/z=391.1 [M+H]+.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:12]=[C:11]2[C:7]([NH:8][CH:9]=[N:10]2)=[C:6]([Cl:13])[N:5]=1.Cl[CH2:15][O:16][CH2:17][O:18][CH2:19][P:20]([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])=[O:21]>CN(C=O)C>[NH2:3][C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[CH2:15][O:16][CH2:17][O:18][CH2:19][P:20]([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])=[O:21])=[C:6]([Cl:13])[N:5]=1
Reactant: CCOP(=O)(COCOCCl)OCC
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOP(=O)(COCOCn1cnc2c(Cl)nc(N)nc21)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 60% sodium hydride in mineral oil (1.4 g, 34.5 mmol) in DMF (100 mL) was added 2-amino-6-chloropurine (5.78 g, 34.2 mmol) and the mixture was stirred for 1 hr at 25° C. To the resulting yellow solution was added dropwise a solution of above chloromethoxy(diethylphosphonomethoxy)methane in DMF (20 mL) under nitrogen. After stirring 15 hr at 25° C., volatiles were removed in vacuo. The residual oil was suspended in ethyl acetate (100 mL), washed with water (30 mL), brine and dried (MgSO4). The solvent was removed under reduced pressure, and the residual oil was chromatographed on silica gel using CH2Cl2 /3% MeOH as eluent to give the title compound as a colorless oil: yield 3.0 g (23%).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][C@H:9]([CH3:11])[CH2:8][CH2:7][C@H:6]1[C:12]([OH:14])=O)(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:18])=O>ClCCl.CN(C)C=O>[C:1]([O:4][CH:5]1[CH2:10][CH:9]([CH3:11])[CH2:8][CH2:7][CH:6]1[C:12]([Cl:18])=[O:14])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1C[C@H](C)CC[C@H]1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)OC1CC(C)CCC1C(=O)Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (1R, 2S, 4R)-2-Acetoxy-4-methyl-cyclohexanecarboxylic acid (109 mg, 0.54 mmol) in dichloromethane (2.7 ml) was added oxalyl chloride (545 ul, 1.09 mmol) followed by 1 drop of dimethylformamide. The reaction mixture was stirred for 4 h at room temperature. The solvents were then removed to obtain 119 mg (99%) of (1R*, 2S*, 4R*)-2-Acetoxy-4-methyl-cyclohexanecarboxylic acid chloride. NMR 1H (CDCl3, 400 MHz): 5.45 ppm (s, 1H); 2.46-2.42 ppm (m, 1H); 2.02 ppm (s, 3H); 2.02-1.96 ppm (m, 1H); 1.91-1.76 ppm (m, 3H); 1.70-1.61 ppm (m, 1H); 1.16-1.08 ppm (m, 1H); 0.99-0.88 ppm (m, 1H); 0.87 ppm (d, 3H).
Reaction SMILES: [F:1][C@H:2]1[C@H:7]2[NH:8][C:9](=[S:11])[O:10][C@H:6]2[CH2:5][C@H:4]([CH2:12][OH:13])[C@H:3]1[OH:14].[CH3:15]I.[OH-].[Na+]>CCO>[F:1][C@H:2]1[C@H:7]2[N:8]=[C:9]([S:11][CH3:15])[O:10][C@H:6]2[CH2:5][C@H:4]([CH2:12][OH:13])[C@H:3]1[OH:14]
Reactant: CI
Reactant: OC[C@H]1C[C@@H]2OC(=S)N[C@@H]2[C@H](F)[C@@H]1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSC1=N[C@@H]2[C@H](F)[C@H](O)[C@@H](CO)C[C@@H]2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.8 %

Procedure:
To a solution of (3aS,4S,5R,6R,7aS)-4-fluoro-5-hydroxy-6-(hydroxymethyl)hexahydrobenzo[d]oxazole-2(3H)-thione (490 mg, 2.22 mmol) in EtOH (8 mL) was added MeI (630 mg, 4.43 mmol) and 5 N NaOH (0.58 mL, 2.9 mmol). The mixture was stirred at room temperature for 2 h. The solvents were evaporated to give the crude product. This was purified by SiO2 column, eluted with 10%-20% MeOH in DCM to give (3aS,4S,5R,6R,7aS)-4-fluoro-6-(hydroxymethyl)-2-(methylthio)-3a,4,5,6,7,7a-hexahydrobenzo[d]oxazol-5-ol (370 mg, 71%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 4.78 (ddd, J=52.1 Hz, 3.8 Hz, 1.6 Hz, 1H), 4.64-4.68 (m, 1H), 4.03 (ddd, J=25.8 Hz, 7.6 Hz, 3.9 Hz, 1H), 3.91 (dd, J=10.9 Hz, 3.7 Hz, 1H), 3.61-3.71 (m, 2H), 2.48 (s, 3H), 2.17-2.30 (m, 2H), 1.95-2.02 (m, 1H), 1.65-1.72 (m, 1H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:18]=1[C:31]([F:34])([F:33])[F:32])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>CN(C)C=O>[CH2:24]([O:23][C:19]1[CH:20]=[CH:21][C:22]([Br:1])=[C:17]([O:16][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:18]=1[C:31]([F:33])([F:32])[F:34])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: FC(F)(F)c1c(OCc2ccccc2)cccc1OCc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1c(OCc2ccccc2)ccc(Br)c1OCc1ccccc1
Yield: 97.8 %

Procedure:
Add N-bromosuccinimide (4.67 g, 26.23 mmol) to a solution of 1,3-bis-benzyloxy-2-trifluoromethyl-benzene (9.40 g, 26.2 mmol) in dimethylformamide (100 mL) and stir. After 18 hours add water and extract with diethyl ether. Combine organic layers, dry with sodium sulfate, filter and concentrate under reduced pressure to yield the title compound as an orange oil (11.20 g, 98%): 1H NMR (CD3CN) δ 4.97 (2, 2H), 5.18 (s, 2H), 6.99 (d, 1H), 7.33-7.55 (m, 10H), 7.79 (d, 1H).
Reaction SMILES: C([O:5][NH:6][C:7](=[O:32])[CH2:8][N:9]([S:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)(=[O:23])=[O:22])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)(C)(C)C.C(O)C>C(Cl)Cl>[OH:5][NH:6][C:7](=[O:32])[CH2:8][N:9]([S:21]([C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)(=[O:23])=[O:22])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1
Reactant: COc1ccc(S(=O)(=O)N(CC(=O)NOC(C)(C)C)Cc2ccc3ccccc3n2)cc1
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N(CC(=O)NO)Cc2ccc3ccccc3n2)cc1
Reaction time: 8 h

Procedure:
(a) N-(t-Butyloxy)-2-[[4-methoxybenzenesulfonyl](2-quinolinylmethyl)amino]acetamide (1.15 g, 2.42 mmol) is dissolved in methylene chloride (30.0 mL) and ethanol (0.20 mL) in a glass sealed tube. Hydrochloric acid gas (from a lecture bottle) is bubbled through the solution for 20 minutes, and then the tube is sealed and stands at room temperature overnight. The next day, additional hydrochloric acid gas is bubbled through the solution for 20 minutes, more ethanol (0.20 mL) is added, and then the tube is sealed and stands at room temperature for two days. After that time, the solvent is removed. The product is purified by silca gel chromatography (5% to 15% methanol/methylene chloride with ~1% ammonium hydroxide) to give N-hydroxy-2-[[4-methoxybenzenesulfonyl](2-quinolinylmethyl)amino]acetamide, m.p. 177°-178° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.[CH2:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:15].C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:14]([N:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:15]
Reactant: Oc1ccc(OCCCCBr)cc1
Reactant: CCNc1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CCCCOc1ccc(O)cc1)c1ccccc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 6.9 %

Procedure:
To a solution of compound 12a (250 mg, 1.02 mmol) and N-ethylaniline (0.24 mL, 2.04 mmol) in acetonitrile (5.0 mL), diisopropylethylamine (0.42 mL, 3.05 mmol) was added dropwise. After the addition was complete, the reaction was stirred at 60° C. for 12 hours. The reaction mixture was concentrated and purified by column chromatography to isolate the compound 12 as a colorless oil (20 mg, 0.07 mmol, 12% yield). MS (ESI, positive) m/z calcd. for C18H24NO2 [M+H]+: 286.18, found: 286.18. 1H NMR (400 MHz, Chloroform-d) δ 7.23 (t, J=8 Hz, 1H), 6.65-6.81 (m, 8H), 4.71 (bs, 1H), 3.95 (t, J=5.2 Hz, 2H), 3.33-3.52 (m, 4H), 1.27-1.33 (m, 4H), 1.17 (t, J=6.8 Hz, 3H).