Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:15]([OH:17])=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:22][N:23]1[CH2:28][CH2:27][CH:26]([CH2:29][NH2:30])[CH2:25][CH2:24]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:15]([NH:30][CH2:29][CH:26]3[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]3)=[O:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2ccc(-c3cc(F)cc(C(=O)O)c3)nc12
Reactant: CN1CCC(CN)CC1
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: CN1CCC(CNC(=O)c2cc(F)cc(-c3ccc4ncnc(N)c4n3)c2)CC1

Procedure:
Following the same reaction and purification procedure as above, the acid 3 (60 mg, 0.21 mmol) was reacted with (1-methyl-4-piperidyl)methanamine (CAS 7149-42-0) (54 mg, 0.42 mmol), HATU (166 mg, 0.42 mmol) and DIPEA (0.18 mL, 1.1 mmol) in DMF (1 mL) at room temperature to provide 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-5-fluoro-N-((1-methylpiperidin-4-yl)methyl)benzamide 10. LC/MS (ESI+): m/z 395 (M+H). 1H NMR (400 MHz, DMSO) δ 8.53 (d, J=8.8 Hz, 1H), 8.48 (d, J=10.6 Hz, 1H), 8.46-8.38 (m, 1H), 8.32 (s, 1H), 8.22 (s, 1H), 8.14 (d, J=8.8 Hz, 1H), 7.99 (s, 1H), 7.33 (d, J=8.5 Hz, 1H), 2.90 (d, J=7.8 Hz, 2H), 2.84-2.63 (m, 4H), 2.19 (s, 1H), 2.03 (s, 3H), 1.82 (s, 2H), 1.66 (s, 2H).
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([NH:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[C:15]([CH2:23][C:24]([O:26]CC)=[O:25])(=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[O-]CC.[Na+].O>C(O)C>[CH2:11]([NH:10][C:8]([C:7]1[CH:6]=[CH:5][C:4]([N:1]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:23]([C:24]([OH:26])=[O:25])[N:3]=[N:2]2)=[CH:14][CH:13]=1)=[O:9])[CH3:12]
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])cc1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
4-Azido-N-ethylbenzamide (267 mg, 1.40 mmol) and ethyl benzoylacetate (0.316 ml, 1.75 mmol, 1.25 eq.) were dissolved in ethanol (8 ml), sodium ethoxide (122 mg, 1.75 mmol, 1.25 eq.) was added, and the mixture was stirred at room temperature for 30 min, and then at 60° C. for 13 hr. Water (20 ml) was added to the reaction mixture, ethanol was evaporated, and the residue was diluted with 2% aqueous sodium carbonate solution (20 ml) and washed with ethyl acetate-hexane (3:1, 40 ml). The organic layer was extracted with 2% aqueous sodium carbonate solution (20 ml). The aqueous layers were combined, acidified (pH<3) with 6N hydrochloric acid, and stood still at 0° C. The precipitate was collected by filtration, washed with water and dried to give the title compound as a pale-yellow powder (465 mg, 1.38 mmol, 98.8%).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)=[N+]=[N-].[H][H]>[Pd].C1COCC1>[NH2:1][CH2:4][C@@H:5]([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])[CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][O:9][CH2:8]1
Reactant: [H][H]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](CN=[N+]=[N-])C[C@H]1CCCOC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@H](CN)C[C@H]1CCCOC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
The tert-butyl (S)-1-azido-3-((R)-tetrahydro-2H-pyran-3-yl)propan-2-yl(methyl)carbamate (2.1 g, 7.04 mmol, 1.0 equiv) and Pd/C (10%, 200 mg) were added to a flask. THF (30 mL) was added and the flask fitted with a gas inlet connected to a balloon of hydrogen gas. The flask was evacuated and back-filled with H2 from the balloon. This was repeated twice and the reaction mixture stirred for 17 h at ambient temperature. Analysis by LC/MS showed complete conversion to the desired amine. The catalyst was removed by filtration through a pad of Celite and the mixture evaporated. This provided 1.82 g (94%) of tert-butyl (S)-1-amino-3-((R)-tetrahydro-2H-pyran-3-yl)propan-2-yl(methyl)carbamate.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][C:14](=O)[N:15]3[CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:3]([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][C:14](=[S:35])[N:15]3[CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(C)N1C(=O)CCc2ccc(-n3c(C)ccc3C)cc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)N1C(=S)CCc2ccc(-n3c(C)ccc3C)cc21
Temperature: 25 °C
Yield: 11.9 %

Procedure:
A solution of ethyl 2-(7-(2,5-dimethyl-1H-pyrrol-1-yl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)propanoate (1.6 g, 4.70 mmol) and Lawesson reagent (1.9 g, 4.70 mmol) in toluene (20 mL) was heated to reflux for 2 h. The reaction mixture was cooled to ambient temperature and the mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 0-5% EtOAc in petroleum ether) to give ethyl 2-(7-(2,5-dimethyl-1H-pyrrol-1-yl)-2-thioxo-3,4-dihydroquinolin-1(2H)-yl)propanoate (0.20 g, 12%). 1H NMR (CDCl3, 400 MHz): δ 7.27 (d, J=8.0 Hz, 1H), 6.94 (d, J=8.06 Hz, 1H), 6.82 (s, 1H), 6.58 (m, 1H), 5.91 (s, 2H), 4.13 (q, J=7.2 Hz, 2H), 3.24 (m, 2H), 2.85 (m, 2H), 2.03 (s, 6H), 1.71 (d, J=7.2 Hz, 3H), 1.13 (t, J=7.2 Hz, 3H).
Reaction SMILES: C(O[C@H]1C2C(=CC(Br)=CC=2)[C@@H](NC[C@@H](O)[C@@H](N)CC2C=C(F)C=C(F)C=2)C1)C=C.[CH3:30][N:31]([C@@H:39]([CH2:43][CH2:44][CH:45]=[CH2:46])[C:40]([OH:42])=O)[C:32](=[O:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].[CH2:47]([O:50][CH:51]1[C:59]2[C:54](=[CH:55][C:56]([O:60][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)=[CH:57][CH:58]=2)[CH:53]([NH:67][CH2:68][C@@H:69]([O:79][Si:80]([C:83]([CH3:86])([CH3:85])[CH3:84])([CH3:82])[CH3:81])[C@@H:70]([NH2:78])[CH2:71][C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)[CH2:52]1)[CH:48]=[CH2:49]>>[CH2:47]([O:50][CH:51]1[C:59]2[C:54](=[CH:55][C:56]([O:60][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)=[CH:57][CH:58]=2)[CH:53]([NH:67][CH2:68][C@@H:69]([O:79][Si:80]([C:83]([CH3:86])([CH3:85])[CH3:84])([CH3:81])[CH3:82])[C@@H:70]([NH:78][C:40](=[O:42])[C@@H:39]([N:31]([CH3:30])[C:32](=[O:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:43][CH2:44][CH:45]=[CH2:46])[CH2:71][C:72]2[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=2)[CH2:52]1)[CH:48]=[CH2:49]
Reactant: C=CCOC1CC(NC[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](N)Cc2ccccc2)c2cc(Oc3ccccc3)ccc21
Reactant: C=CCC[C@@H](C(=O)O)N(C)C(=O)CCCCC
Agent: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c2cc(Br)ccc21
Product: C=CCC[C@@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](CNC1CC(OCC=C)c2ccc(Oc3ccccc3)cc21)O[Si](C)(C)C(C)(C)C)N(C)C(=O)CCCCC
Yield: 39.6 %

Procedure:
Step EX (1): (S)-2-(N-methylhexanamido)hex-5-enoic acid (500 mg, 2.1 mmol) and (2R,3S)-N1-(3-(allyloxy)-6-phenoxy-2,3-dihydro-1H-inden-1-yl)-2-(tert-butyldimethylsilyloxy)-4-phenylbutane-1,3-diamine (1.2 g, 2.1 mmol, from Preparation BC) were coupled using a procedure analogous to Step CA (1) to afford 650 mg (40% yield) of (2S)-N-((2S,3R)-4-(3-(allyloxy)-6-phenoxy-2,3-dihydro-1H-inden-1-ylamino)-3-(tert-butyldimethylsilyloxy)-1-phenylbutan-2-yl)-2-(N-methylhexanamido)hex-5-enamide. LC-MS (M+H)+=782.65; 1H NMR (300 MHz, CDCl3) δ ppm 0.0 (m, 6H) 0.6-0.9 (m, 12H) 1.1-1.4 (m, 6H) 1.4-1.6 (m, 3H) 1.7-2.3 (m, 6H) 2.3-2.4 (s, 3H) 2.5-2.9 (m, 4H) 3.5-3.8 (m, 1H) 4.0-4.4 (m, 4H) 4.7-4.8 (m, 1H) 4.8-5.4 (m, 4H) 5.6-6.1 (m, 2H) 6.9-7.4 (m, 13H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[CH2:7][CH:8]([CH2:12][C:13](=[O:35])[NH:14][O:15][C:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9](O)=[O:10])([CH3:4])([CH3:3])[CH3:2].[NH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][OH:43]>>[C:1]([O:5][C:6](=[O:36])[CH2:7][CH:8]([C:9](=[O:10])[NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][OH:43])[CH2:12][C:13](=[O:35])[NH:14][O:15][C:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(CC(=O)NOC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reactant: NCCCCCO
Product: CC(C)(C)OC(=O)CC(CC(=O)NOC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NCCCCCO

Procedure:
This compound was prepared by reacting the compound of Example 63 with 5-amino-pentan-1-ol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:13])[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.C([Li])(C)(C)C.CCCCC.[B:24](OC)([O:27]C)[O:25]C>O1CCCC1>[CH3:10][C:7]1([CH3:11])[C:6]2[CH:12]=[C:2]([B:24]([OH:27])[OH:25])[CH:3]=[C:4]([CH3:13])[C:5]=2[O:9][CH2:8]1
Reactant: Cc1cc(Br)cc2c1OCC2(C)C
Reactant: COB(OC)OC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: Cc1cc(B(O)O)cc2c1OCC2(C)C

Procedure:
Following General Procedure A and using 5-bromo-3,3,7-trimethyl-2,3-dihydro-benzofuran (1.2 g, 5 mmol), 12 mL of anhydrous tetrahydrofuran, 1.7M solution of t-butyllithium in n-pentane (6.17 mL, 10.5 mmol) and trimethyl borate (1.2 mL, 10.5 mmol) the title compound was obtained as a foam that was used as such for the next step without purification and characterization. 5-Bromo-3,3,7-trimethyl-2,3-dihydro-benzofuran can be prepared as described in U.S. Pat. No. 6,093,838, incorporated herein by reference.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH2:11][CH2:10]1>C1COCC1>[O:15]=[C:9]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: O=C1CCC(=O)O1
Reactant: NCc1ccccc1
Solvent: C1CCOC1
Product: O=C(O)CCC(=O)NCc1ccccc1
Yield: 52.7 %

Procedure:
A mixture of benzyl amine (10.7 g) and succinic anhydride (10 g) was stirred in THF (1 liter) for 2 days. The solid was filtered and dissolved in 1N NaOH (110 mL). the aqueous phase was washed with Et2O and then made acidic with conc HCl while cooling in an ice-water bath. The solid was collected, washed with water and dried under high vacuum. There was obtained 10.9 g (53%) of the title compound as a white powder m.p. 137.5°-138°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH3:20])[CH:18]=[N:19][C:4]=2[CH:3]=1.[C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][C:24]=1[O:32][CH3:33])#[N:22]>C(#N)C1C=CC=CC=1>[CH3:33][O:32][C:24]1[CH:25]=[C:26]([C:2]2[N:7]=[C:6]([O:8][C@@H:9]([C@@H:11]3[CH2:12][C:13](=[O:16])[NH:14][CH2:15]3)[CH3:10])[C:5]3[N:17]([CH3:20])[CH:18]=[N:19][C:4]=3[CH:3]=2)[CH:27]=[CH:28][C:23]=1[C:21]#[N:22]
Reactant: COc1cc(B(O)O)ccc1C#N
Reactant: C[C@@H](Oc1nc(Cl)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Solvent: N#Cc1ccccc1
Product: COc1cc(-c2cc3ncn(C)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)ccc1C#N

Procedure:
Following General Procedure B, beginning with (R)-4-((R)-1-(6-chloro-3-methyl-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 2.06 (41 mg, 0.139 mmol) and 4-cyano-3-methoxyphenylboronic acid (31 mg, 0.18 mmol), 2-methoxy-4-(3-methyl-4-((R)-14(R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)benzonitrile 3B.14 was synthesized.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)[O:5][C:4](=[O:19])[C:3]=1[S:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH3:27]OC(=O)COC1C=CC(C(=O)C)=CC=1.C(N(CC)CC)C.C[Si](OS(C(F)(F)F)(=O)=O)(C)C.S1C=CC=C1C(C(OCC)=O)C(OCC)=O>ClCCl>[OH:1][C:2]1[C:7]([CH3:27])=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:17][CH:18]=2)[O:5][C:4](=[O:19])[C:3]=1[S:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)COc1ccc(C(C)=O)cc1
Reactant: O=C(O)COc1ccc(-c2cc(O)c(Sc3ccccc3)c(=O)o2)cc1
Agent: CCOC(=O)C(C(=O)OCC)c1cccs1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(-c2ccc(OCC(=O)O)cc2)oc(=O)c(Sc2ccccc2)c1O

Procedure:
The title compound (0.691 g, m.p. 194 - 197° C.) was prepared in a similar manner to that demonstrated in the preparation of [4-[4-hydroxy-2-oxo-3- (phenylthio) -2H-pyran-6-yl]phenoxy]-acetic acid using the following: Methyl-[4-(1-oxoethyl)phenoxy]-acetate (2.00 g, 8.81 mmol), triethylamine (3.68 mL, 26.4 mmol), trimethylsilyltriflate (2.38 mL, 12.3 mmol), dichoromethane (20.0 mL), diethyl 2-(thiophenyl)propane-1,3-dioate (1.34 g, 5.00 mmol.), 1H NMR (400 MHz, DMSO-d6) δ7.585 (d, 2 H, J=9 Hz), 7.325-7.286 (m, 2 H), 7.178 (d, 3 H, J=7.5 Hz), 7.063 (d, 2 H, J=9 Hz), 4.784 (s, 2 H), 2.042 (s, 3 H).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([CH:16]=[C:17]([O:19]CC2C=CC=CC=2)[CH:18]=1)[C:8]([NH:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1)=[O:9])[CH3:3].C1(SC)C=CC=CC=1>FC(F)(F)C(O)=O>[OH:19][C:17]1[CH:16]=[C:7]([CH:6]=[C:5]([O:4][CH:2]([CH3:3])[CH3:1])[CH:18]=1)[C:8]([NH:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1)=[O:9]
Reactant: CC(C)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2nccs2)c1
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1cc(O)cc(C(=O)Nc2nccs2)c1
Yield: 84.9 %

Procedure:
3-[(1-Methylethyl)oxy]-5-[(phenylmethyl)oxy]-N-1,3-thiazol-2-ylbenzamide (11.2 g) was dissolved in trifluoroacetic acid (60 mL) and treated with thioanisole (17.8 mL). The mixture was left to stir at ambient temperature for 18 hours before the trifluoroacetic acid was removed in vacuo. The residues were treated with isohexane (100 mL) and the solid filtered off, before being washed with further isohexane (2×20 mL). The solid was dissolved in ethyl acetate (200 mL) and washed with aqueous saturated sodium hydrogen carbonate solution (100 mL). The organics were washed with water (100 mL) and brine (100 mL), and dried (MgSO4) before evaporation in vacuo to afford a solid which was washed with isohexane (200 mL) and dried in vacuo to give the desired compound (7.18 g). 1H NMR δ (d6-DMSO): 1.27 (d, 6H), 4.55 (m, 1H), 6.49 (m, 1H), 7.02 (s, 1H), 7.14 (s, 1H), 7.25 (d, 1H), 7.54 (d, 1H), 9.73 (s, 1H), 12.44 (s, 1H). m/z 279 (M+H)+, 277 (M−H)−
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([I:11])[CH:3]=1.C(Cl)(=O)C([Cl:15])=O>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:15])=[O:7])=[C:4]([I:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1I
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(Cl)cc1I
Reaction time: 2 h

Procedure:
A catalytic amount of DMF (approximately 3 drops) was added to a stirred mixture of 4-chloro-2-iodobenzoic acid (24.47 g, 86.63 mmol) and oxalyl chloride (11.34 mL, 129.9 mmol) in DCM (100 mL) under a nitrogen atmosphere. The reaction mixture was stirred for 2 hours and then concentrated in vacuo to give 4-chloro-2-iodobenzoyl chloride as a yellow oil that solidified upon standing (26.07 g).
Reaction SMILES: [OH:1][C@:2]([C:32]1[CH:36]=[C:35]([CH3:37])[O:34][N:33]=1)([CH3:31])[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]2[O:14][CH2:13][CH2:12][N:11]3[C:15]([C:21](NC4CCOCC4)=[O:22])=[C:16]([C:18]([NH2:20])=[O:19])[N:17]=[C:10]3[C:9]=2[CH:30]=1.[CH3:38][C:39]([NH2:48])([CH3:47])[CH2:40][N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>>[OH:1][C@:2]([C:32]1[CH:36]=[C:35]([CH3:37])[O:34][N:33]=1)([CH3:31])[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]2[O:14][CH2:13][CH2:12][N:11]3[C:15]([C:21]([NH:48][C:39]([CH3:38])([CH3:47])[CH2:40][N:41]4[CH2:42][CH2:43][O:44][CH2:45][CH2:46]4)=[O:22])=[C:16]([C:18]([NH2:20])=[O:19])[N:17]=[C:10]3[C:9]=2[CH:30]=1
Reactant: CC(C)(N)CN1CCOCC1
Reactant: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(C(=O)NC4CCOCC4)n2CCO3)no1
Product: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(C(=O)NC(C)(C)CN4CCOCC4)n2CCO3)no1

Procedure:
Prepared as described for (R)-10-(3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-yn-1-yl)-N3-(tetrahydro-2H-pyran-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2,3-dicarboxamide replacing 4-aminotetrahydropyran with 2-methyl-1-morpholinopropan-2-amine. Off-white solid 20 mg, 12%).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N+:13]([O-])=O)=[CH:4][CH:3]=1.CC(O)=O>C(Cl)Cl.[Zn]>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH2:13])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccccc1Nc1ccc(Cl)cc1
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Nc1ccccc1Nc1ccc(Cl)cc1

Procedure:
To a solution of 2-(4-chloroanilino)-nitrobenzene (57.0 g) in CH2Cl2 (40 mL) was added AcOH (90 mL), then Zn powder (105 g) was added in small portions. After Zn powder was added, the color of the mixture became light green, filtered by suction, washed with CH2Cl2. The filtrate was concentrated to dryness. Water was added, filtered, and washed with water to give a brown solid. This solid was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[OH:12].[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C=O)C>[Cl:1][C:2]1[C:3]([O:12][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[CH3:8]
Reactant: Cc1c([N+](=O)[O-])ccc(O)c1Cl
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c([N+](=O)[O-])ccc(OCc2ccccc2)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.4 %

Procedure:
A solution of 2-chloro-3-methyl-4-nitrophenol (30.0g, 0.160 mol) in sieve-dried DMF (650 ml) was treated with sodium hydride (50%, 8.44g, 0.176 mol) and then benzyl bromide (30.1 g, 0.176 mol), while stirring at 0° C. The mixture was stirred at room temperature for 16 hours, then poured into 3 litres of water to precipitate an orange-coloured solid, which was recrystallised from ethanol to give 2-chloro-3-benzyloxy-6-nitrotoluene (31.3 g) m.p. 73°-74.5° C.
Reaction SMILES: [CH2:1]([C:4]1[N:5]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:6]2[C:11]([C:12]=1[CH2:13][C:14](O)=[O:15])=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]=[CH2:3].Cl.[NH2:25][C@@H:26]([CH2:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([Br:39])[CH:33]=1)[C:27]([O:29][CH3:30])=[O:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([C:4]1[N:5]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:6]2[C:11]([C:12]=1[CH2:13][C:14]([NH:25][C@@H:26]([CH2:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([Br:39])[CH:33]=1)[C:27]([O:29][CH3:30])=[O:28])=[O:15])=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]=[CH2:3]
Reactant: C=CCc1c(CC(=O)O)c2ccccc2n1C(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H](N)Cc1cc(F)cc(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCc1c(CC(=O)N[C@@H](Cc2cc(F)cc(Br)c2)C(=O)OC)c2ccccc2n1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.5 %

Procedure:
2-(2-allyl-1-(tert-butoxycarbonyl)-1H-indol-3-yl)acetic acid (850 mg, 2.7 mmol) and (S)-methyl 2-amino-3-(3-bromo-5-fluorophenyl)propanoate hydrochloride (720 mg, 2.61 mmol) were combined in DCM (13 mL) and treated with HATU (1.49 g, 3.9 mmol) and iPr2NEt (1.13 mL, 6.5 mmol). After stirring for 16 h at room temperature, the reaction was partitioned between DCM and H2O. The organics were separated and dried over sodium sulfate. After removal of solvent, the crude product was purified by silica gel chromatography to provide (S)-tert-butyl 2-allyl-3-(2-(3-(3-bromo-5-fluorophenyl)-1-methoxy-1-oxopropan-2-ylamino)-2-oxoethyl)-1H-indole-1-carboxylate (0.98 g, 63%). MS (m/z) 573 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=2)[C:3]=1[CH2:23][C:24]([O:26][CH3:27])=[O:25].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:38]1[CH2:42]OC[CH2:39]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH3:22])=[CH:19][CH:20]=2)[C:3]=1[CH:23]([CH2:39][CH2:38][CH3:42])[C:24]([O:26][CH3:27])=[O:25]
Reactant: C1CCOC1
Reactant: CCc1ccc(-c2c(CC(=O)OC)c(C)nc3sc4c(c23)CCCC4)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCI
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(CC)cc1)CCCC3
Yield: 76.6 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(4-ethylphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.231 g; 0.61 mmol), LHMDS 1N in THF (0.67 mL; 0.67 mmol), 1-iodopropane (0.089 mL; 0.913 mmol) in DMF (2.4 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-30%) in heptane furnished 0.197 g (77%) of the title compound as a yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:6](N)[CH:5]=1)(=[O:3])[CH3:2].B(F)(F)[F:20].F.N([O-])=O.[Na+]>O1CCCC1.O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:6]([F:20])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: FB(F)F
Reactant: COc1ccc(-c2ccc(C(C)=O)cc2N)cc1
Agent: F
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(C(C)=O)cc2F)cc1
Temperature: 70 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of intermediate B (8.8 g.) in a mixture of tetrahydrofuran (28 ml.), water (9.5 ml.) and hydrofluoroboric acid (38.5 ml. of 42% w/v acid) was slowly added a solution of sodium nitrite (2.7 g.) in water (4.5 ml.) whilst maintaining the temperature of the reaction mixture below 5°C. The mixture was then stirred for a further period of 20 minutes at 0° - 5°C. The resulting diazonium fluoroborate was collected by filtration, washed with hydrofluoroboric acid (20 ml. of 10% w/v acid) and then with methanol/ether (60 ml. of 10% methanol in ether), and finally dried in vacuo. This product was suspended in xylene (85 ml.) and the suspension heated to 70°C. at which point decomposition took place. When the reaction had subsided the mixture was refluxed for 45 minutes, after which the xylene was removed by distillation in vacuo. The residue was extracted with hot benzene. The resulting extract was cooled, washed with dilute aqueous sodium carbonate and then water, dried over anhydrous sodium carbonate, and evaporated. The residue was distilled in vacuo to give a product, b.p. 146° - 156°C./0.2 mm. which solidified on cooling. This product was recrystallized from ethanol to give 4-acetyl-2-fluoro-4'-methoxybiphenyl, m.p. 103° - 106°C. (novel intermediate C).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O)=[CH:16][CH:15]=[CH:14][C:13]=2[C:27]([F:30])([F:29])[F:28])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[CH:34][CH:33]=1>>[C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][NH:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[CH:36][CH:37]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:27]([F:30])([F:29])[F:28])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: Nc1ccc(CCCC(=O)O)cc1
Product: O=C(O)CCCc1ccc(NCc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from 3-[3-benzoyl-8-(trifluoromethyl)quinolin-4-yl]benzaldehyde and 4-(4-amino-phenyl)-butyric acid according to the procedure of Example 66. MS (ES) m/z 567.0.