Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS[C:3](SC)=[C:4]1[C:13](=[O:14])[C:12]([CH2:18][CH2:19][CH3:20])([CH2:15][CH2:16][CH3:17])[C:11]2[C:6](=[CH:7][C:8]([F:21])=[CH:9][CH:10]=2)[C:5]1=[O:22].CSC(SC)=C1C(=O)C(CCCC)(CCCC)C2C(=CC=CC=2)C1=O.[NH2:50][C:51]1[CH:56]=[CH:55][C:54]([NH:57][C:58](=[O:64])[O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[CH:53][C:52]=1[S:65]([NH2:68])(=[O:67])=[O:66].NC1C=CC(OCC2C=CC=CC=2)=CC=1S(N)(=O)=O>>[F:21][C:8]1[CH:7]=[C:6]2[C:11]([C:12]([CH2:15][CH2:16][CH3:17])([CH2:18][CH2:19][CH3:20])[C:13](=[O:14])[C:4]([C:3]3[NH:50][C:51]4[CH:56]=[CH:55][C:54]([NH:57][C:58](=[O:64])[O:59][C:60]([CH3:62])([CH3:63])[CH3:61])=[CH:53][C:52]=4[S:65](=[O:66])(=[O:67])[N:68]=3)=[C:5]2[OH:22])=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)c(S(N)(=O)=O)c1
Reactant: CCCC1(CCC)C(=O)C(=C(SC)SC)C(=O)c2cc(F)ccc21
Agent: CCCCC1(CCCC)C(=O)C(=C(SC)SC)C(=O)c2ccccc21
Agent: Nc1ccc(OCc2ccccc2)cc1S(N)(=O)=O
Product: CCCC1(CCC)C(=O)C(C2=NS(=O)(=O)c3cc(NC(=O)OC(C)(C)C)ccc3N2)=C(O)c2cc(F)ccc21

Procedure:
The title compound was prepared according to the procedure of Example 5D, substituting the compound of Example 14H for the compound of Example 5C, and the compound of Example 17A for the compound of Example 2D. 1H NMR (300 MHz, DMSO-d6): δ 0.62 (m, 8 H) 0.91 (m, 2 H) 1.47 (d, J=17.28 Hz, 9 H) 1.93 (m, 2 H) 2.10 (m, 2 H) 7.63 (m, 5 H) 8.03 (s, 1 H) 9.77 (s, 1 H) 14.21 (s, 1 H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4](N)[CH:5]=[CH:6][C:7]=1[CH3:8].[BrH:10].N([O-])=O.[Na+]>O.[Cu](Br)Br>[Br:10][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([I:1])[CH:3]=1
Reactant: Br
Reactant: Cc1ccc(N)cc1I
Agent: Br[Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(Br)cc1I
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 71 %

Procedure:
A mixture of 3-iodo-4-methyl-phenylamine (5.0 g, 21 mmol) and 48% hydrobromic acid (30 ml) was heated at 90° C. for 30 minutes. After cooling in an ice bath, a solution of sodium nitrite (1.7 g, 25.2 mmol) in water (5 ml) was added and stirred for 15 minute. This mixture was added to a mixture of copper bromide (I) (3.6 g, 25.2 mmol), 48% hydrobromic acid (20 ml) and ice (50 g) cooled in an ice bath. After stirring for 20 minutes, the mixture was heated at 90° C. for 1 hour. After stirring at room temperature for 16 hours, the mixture was treated with water (350 ml) and extracted with dichloromethane (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution (100 ml), washed with saturated aqueous sodium chloride solution (100 ml), dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexane to give 5-bromo-2-methyl-1-iodo-benzene (4.4 g, 71% yield). 1H NMR (acetone-d6) δ 2.40 (s, 3H, CH3), 7.30 (d, 1H, J=8.2 Hz, Ar), 7.50 (dd, 1H, J=8.2 Hz, J=2.0 Hz, Ar), 8.00 (d, 1H, J=2.0 Hz, Ar).
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:26])[C:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@:18]([F:24])([C@@H:19]([OH:23])[CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:25])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][CH:5]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:27]([O:23][C@H:19]1[CH2:20][C@@:21]2([CH3:22])[C@@H:7]([CH2:6][CH:5]=[C:4]2[C:3](=[O:26])[CH2:2][Cl:1])[C@H:8]2[C@@:18]1([F:24])[C@:16]1([CH3:17])[C:11]([CH2:10][CH2:9]2)=[CH:12][C:13](=[O:25])[CH:14]=[CH:15]1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3CC=C(C(=O)CCl)[C@@]3(C)C[C@H](O)[C@@]12F
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)O[C@H]1C[C@]2(C)C(C(=O)CCl)=CC[C@H]2[C@@H]2CCC3=CC(=O)C=C[C@]3(C)[C@@]12F
Temperature: 25 °C

Procedure:
A suspension of 21-chloro-9-fluoro-11β-hydroxypregna-1,4,16-triene-3,20-dione (2.1g) in a mixture of glacial acetic acid (30 ml) and acetic anhydride (30 ml) containing p-toluenesulfonic acid hydrate (2.1g) is stirred at room temperature. After 30 hours the solution is mixed with sodium acetate hydrate (5.0g) and evaporated in vacuo. The residue is dissolved in chloroform, washed with water, dried and evaporated to afford the title compound. One crystallization from acetone affords 1.85g of the title compound, melting point 222°-223° C. (dec).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([N:32]1[CH2:31][CH2:30][CH:29]([NH:28][C:26]([C:22]2[C:18]3=[N:19][CH:20]=[CH:21][C:16]([C:8]4[CH:9]=[C:10]([O:14][CH3:15])[C:11]([F:13])=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)=[C:17]3[NH:24][C:23]=2[CH3:25])=[O:27])[CH2:34][CH2:33]1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: COc1cc(-c2ccnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COc1cc(-c2ccnc3c(C(=O)NC4CCN(C(C)=O)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f21) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([N:3]([CH:11]1[CH2:16][CH2:15][CH:14]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([NH:26][C:27]([C:29]4[S:30][CH:31]=[CH:32][CH:33]=4)=[NH:28])[CH:24]=3)[NH:19][CH:18]=2)[CH2:13][CH2:12]1)C(=O)OC(C)(C)C)[CH3:2].Cl>>[CH2:1]([NH:3][CH:11]1[CH2:16][CH2:15][CH:14]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([NH:26][C:27]([C:29]4[S:30][CH:31]=[CH:32][CH:33]=4)=[NH:28])[CH:24]=3)[NH:19][CH:18]=2)[CH2:13][CH2:12]1)[CH3:2]
Reactant: CCN(C(=O)OC(C)(C)C)C1CCC(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)CC1
Agent: Cl
Product: CCNC1CCC(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)CC1
Yield: 112.7 %

Procedure:
Compound 120 (0.26 g, 0.557 mmol) was treated with 1 N aqueous HCl solution at room temperature and the resulting solution was refluxed for 2 h. The reaction was brought to room temperature, filtered and washed with water (5 mL). The solvent was evaporated and crude was recrystallised from ethanol/ether to obtain compound 121 (0.23 g, 94%) as a solid in 2:3 ratio of diastereomners. 1H NMR (DMSO-d6) δ 1.22-1.29 (m, 3H), 1.53-1.62 (m, 2H), 1.80-2.16 (m, 6H), 2.74-3.23 (m, 4H), 7.08 (d, 1H, J=8.4 Hz), 7.24-7.52 (m, 3H), 7.68-7.72 (m, 1H), 8.14-8.18 (m, 2H), 8.59 (s, 1H), 8.97-9.09 (m, 2H), 9.64 (s, 1H), 11.20, 11.27 (2s, 1H), 11.42 (s, 1H); ESI-MS m/z (%): 367 (MH+ for free base, 18), 322 (100), 184 (19), 119 (39); ESI-HRMS calculated for C21H27N4S (MH+, free base), calculated: 367.1959; observed: 367.1950.
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C(Cl)(=O)C(Cl)=O.[C:17]([N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([NH2:33])[CH:31]=2)[CH:26]=[N:25]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(N(CC)CC)C>CN(C=O)C.ClCCl>[C:17]([N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([NH:33][C:1](=[O:10])[C:2]3[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=3[OH:4])[CH:31]=2)[CH:26]=[N:25]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: CC(C)(C)OC(=O)n1ncc2ccc(N)cc21
Reactant: O=C(O)c1ccccc1O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1ncc2ccc(NC(=O)c3ccccc3O)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 17.7 %

Procedure:
To a stirring solution of salicylic acid (1.06 g, 7.7 mmol) and DMF (1 drop) in dichloromethane (100 mL) at 0° C. was added oxalyl chloride (1.13 mL, mmol). After 1 h, the ice bath was removed and stirring was continued for 3.5 h. Solvent was removed under vacuum with minimum heat, and after evacuating further to remove residual oxalyl chloride, the residue was redissolved in dichloromethane (80 mL) and cooled to 0° C. To this solution was then added a solution of 1-Boc-6-aminoindazole (1.86 g, 8 mmol) in dichloromethane (10 mL). After stirring for 10 min, triethylamine (1.24 mL, 8 mmol) was added. After 1 h, the solution was transferred to a separatory funnel and washed with cold water (200 mL). The organic layer was then washed with cold satd aq NaHCO3 (200 mL), dried over MgSO4, filtered and concentrated under vacuum. The product was chromatographed over silica gel (0 to 60% EtOAc in hexane) and recrystallized from dichloromethane/hexanes to give 0.482 g (17%) of crystals.
Reaction SMILES: C[Li].[CH2:3]([O:5]CC)[CH3:4].[CH3:8][C:9]1([CH3:36])[CH2:18][CH2:17][C:16]([CH3:20])([CH3:19])[C:15]2[CH:14]=[C:13]([C:21]3([CH3:35])[C:25]4[CH:26]=[C:27](C=CC(O)=O)[CH:28]=[CH:29][C:24]=4[O:23][CH2:22]3)[CH:12]=[CH:11][C:10]1=2.Cl>C1COCC1>[CH3:35][C:21]1([C:13]2[CH:12]=[CH:11][C:10]3[C:9]([CH3:8])([CH3:36])[CH2:18][CH2:17][C:16]([CH3:19])([CH3:20])[C:15]=3[CH:14]=2)[C:25]2[CH:26]=[C:27]([C:3](=[O:5])[CH3:4])[CH:28]=[CH:29][C:24]=2[O:23][CH2:22]1
Reactant: CC1(C)CCC(C)(C)c2cc(C3(C)COc4ccc(C=CC(=O)O)cc43)ccc21
Reactant: CCOCC
Agent: Cl
Agent: [Li]C
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(c1)C(C)(c1ccc3c(c1)C(C)(C)CCC3(C)C)CO2
Temperature: -20 °C
Reaction time: 4 h

Procedure:
A 1.6M methyllithium solution in ethyl ether (3.4 ml, 5.4 mmol) is added to a solution of 3-Methyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2,3-dihydrobenzofuran-5-carboxylic acid (Example 2) (900 mg, 4.47 mmol) in THF (50 ml) at -20° C. The mixture is stirred for 4 h at -20° C. and is then poured onto ethyl acetate and a 1N hydrochloric acid solution. The organic phase is washed 2 times with water, dried over anhydrous magnesium sulphate and concentrated in vacuo at 40° C. in a rotary evaporator.
Reaction SMILES: CS(O)(=O)=O.CCOC(C)=O.C(OC([N:19]1[C@H:23]([C:24](=[O:29])[NH:25][CH2:26][CH:27]=[CH2:28])[C:22]([CH3:31])([CH3:30])[S:21][CH2:20]1)=O)(C)(C)C>O>[CH2:26]([NH:25][C:24]([C@@H:23]1[C:22]([CH3:31])([CH3:30])[S:21][CH2:20][NH:19]1)=[O:29])[CH:27]=[CH2:28]
Reactant: C=CCNC(=O)[C@H]1N(C(=O)OC(C)(C)C)CSC1(C)C
Agent: CS(=O)(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCNC(=O)[C@H]1NCSC1(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanesulfonic acid (155 mL; 2.39 mol) was added dropwise to the EtOAc solution of (4R)-4-allylcarbamoyl-5,5-dimethyl-thiazolidine-3-carboxylic acid tert-butyl ester in a 3-L flask. After stirring at room temperature overnight, the solution was cooled to 7° C. and H2O (400 mL) was poured in. The mixture was transferred to a 4-L separatory funnel [using H2O (30 mL) for rinsing] and the layers were separated. The organic fraction was extracted with H2O (190 mL). The combined H2O extracts were transferred to a 5-L flask and were cooled to 8° C. The pH was adjusted from 0.4 to 9.3 using 3 N NaOH (˜1.05 L). 2-Methyltetrahydrofuran (1.55 L) was poured in, followed by the addition of NaCl (150 g). The ice bath was removed and the mixture was allowed to warm to room temperature. The pH was readjusted to 9.0 using 3 N NaOH (˜1 mL). The mixture was transferred to a 4-L separatory funnel, using 2-methyltetrahydrofuran (50 mL) for rinsing, and the layers were separated. The aqueous phase was extracted with 2-methyltetrahydrofuran (950 mL). The organic extracts were vacuum-filtered through Celite directly into a 5-L distillation flask, using 2-methyltetrahydrofuran (200 mL) for rinsing. The solution was dried azeotropically and concentrated to a volume of 1.2 L by distillation of 2-methyltetrahydrofuran at one atmosphere. A measured aliquot was concentrated and weighed, which showed that 161 g of (4R)-5,5-Dimethyl-thiazolidine-4-carboxylic acid allylamide was present in solution [84% from (4R)-5,5-dimethyl-thiazolidine-3,4-dicarboxylic acid 3-tert-butyl ester]. This solution was then carried on directly into the next step. The concentrated aliquot from above yielded (4R)-5,5-Dimethyl-thiazolidine-4-carboxylic acid allylamide as a crystalline solid: mp=45–47° C., 1H NMR (300 MHz, CDCl3) δ 6.73 (br s, 1H), 5.87 (app ddt, J=10.2, 17.1, 5.7 Hz, 1H), 5.17–5.27 (m, 2H), 4.27 (AB q, JAB=9.7 Hz, Δν=22.5 Hz, 2H), 2.94 (app tt, J=1.5, 5.8 Hz, 2H), 3.51 (s, 1H), 1.74 (s, 3H), 1.38 (s, 3H); 13C NMR (75 MHz, DCl3) δ 169.7, 134.4, 116.9, 74.8, 57.2, 51.6, 41.9, 29.1, 27.3; MS (CI) m/z 201.1063 (201.1062 calcd for C9H17N2OS, M+H+); elemental analysis calcd for C9H16N2OS: C, 53.97; H, 8.05; N, 13.99; found: C, 53.93; H, 8.09; N, 14.07.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:16])[CH2:10]2)=[N:6][C:7]=1[NH2:8].[CH3:22][N:23]1[C:27]([C:28]2([C:31](=N)OCC)[CH2:30][CH2:29]2)=[N:26][CH:25]=[N:24]1.[S].C(O)(=O)C>C(O)C>[CH3:22][N:23]1[C:27]([C:28]2([C:31]3[NH:8][C:7]4=[N:6][C:5]([N:9]5[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([N:17]6[CH2:21][CH2:20][CH2:19][CH2:18]6)=[O:16])[CH2:10]5)=[CH:4][CH:3]=[C:2]4[N:1]=3)[CH2:30][CH2:29]2)=[N:26][CH:25]=[N:24]1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: CCOC(=N)C1(c2ncnn2C)CC1
Agent: [S]
Solvent: CCO
Solvent: CC(=O)O
Product: Cn1ncnc1C1(c2nc3ccc(N4CCC[C@@H](C(=O)N5CCCC5)C4)nc3[nH]2)CC1
Temperature: 80 °C
Yield: 18 %

Procedure:
(R)-(1-(5,6-Diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone, prepared during the previous step, was added to a suspension of ethyl 1-(1-methyl-1H-1,2,4-triazol-5-yl)cyclopropanecarbimidate (0.39 g, 2.0 mmol), sulfur (20 mg, 0.31 mmol) and acetic acid (0.96 mL, 15.5 mmol) in ethanol (10 mL) at room temperature. The reaction mixture was heated to 80° C. for 16 h. The mixture was concentrated under reduced pressure and the resulting crude was dissolved in ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting crude was purified via preparative TLC to afford the title compound (120 mg, 18%). MS (ES+APCI) (M+H) 421.2; LCMS retention time: 3.311 min (Method Y1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:15]([OH:17])=O)[CH2:12][C:11]([F:14])([F:13])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O[N:31]=[C:32]([C:34]1[CH:35]=[CH:36][C:37]([CH3:52])=[C:38]([NH:40][C:41]([C:43]2[N:47]3[CH:48]=[CH:49][CH:50]=[CH:51][C:46]3=[N:45][CH:44]=2)=[O:42])[CH:39]=1)[NH2:33]>CN1C(=O)CCC1.C(OCC)(=O)C.O>[F:14][C:11]1([F:13])[CH2:10][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])([C:15]2[O:17][N:31]=[C:32]([C:34]3[CH:35]=[CH:36][C:37]([CH3:52])=[C:38]([NH:40][C:41]([C:43]4[N:47]5[CH:48]=[CH:49][CH:50]=[CH:51][C:46]5=[N:45][CH:44]=4)=[O:42])[CH:39]=3)[N:33]=2)[CH2:12]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC(F)(F)C1
Reactant: Cc1ccc(C(N)=NO)cc1NC(=O)c1cnc2ccccn12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2noc(C3(NC(=O)OC(C)(C)C)CC(F)(F)C3)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 120 °C
Reaction time: 0.05 h

Procedure:
To a stirring solution of 1-((tert-butoxycarbonyl)amino)-3,3-difluorocyclobutanecarboxylic acid (164) (45 mg, 0.18 mmol) in anhydrous NMP (1.3 mL) was added 1,1′-carbonyldiimidazole (CDI) (29 mg, 0.18 mmol). The reaction was stirred for 3 minutes. N-(5-(N′-hydroxycarbamimidoyl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (9) (69 mg, 0.22 mmol) was added and the reaction was stirred for 25 minutes. Then, the reaction was heated at 120° C. for 15 minutes. The crude product was taken up in ethyl acetate and water. The organic was washed with 2× water/brine mixture and dried over magnesium sulfate. The solvent was concentrated and the crude product was purified using silica gel chromatography using 60% ethyl acetate/hexanes to afford tert-butyl (3,3-difluoro-1-(3-(3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)cyclobutyl)carbamate (165). MS m/z 525.2 (M+1)+
Reaction SMILES: O.[Cl:2][C:3]1[C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:12])=[CH:7][C:6]([N+:19]([O-])=O)=[C:5]([F:22])[CH:4]=1>C(O)(=O)C.[Fe]>[Cl:2][C:3]1[C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:12])=[CH:7][C:6]([NH2:19])=[C:5]([F:22])[CH:4]=1
Reactant: CCCCCOC(=O)COc1cc([N+](=O)[O-])c(F)cc1Cl
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: CCCCCOC(=O)COc1cc(N)c(F)cc1Cl
Temperature: 80 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
A mixture of iron powders (115 g), acetic acid (29 g) and water (551 g) was heated at 80° C., and a solution of the compound (III) (132 g) in acetic acid (200 g) was dropwise added thereto in 1 hour, followed by heating under reflux for 5 hours. The reaction mixture was filtered to remove insoluble materials, and the filtrate was extracted with ethyl acetate. The extract was concentrated under reduced pressure. The residue was distilled off under reduced pressure to give 4-chloro-2-fluoro-5-(pentyloxycarbonylmethyloxy)aniline (Compound (II)) (90 g). Yield, 75%. b.p., 145°-149° C./0.4 mmHg. m.p., 32°-34° C.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C@@H:20]([OH:31])[CH2:21][C@@H:22]([C:27]([OH:30])([CH3:29])[CH3:28])[C:23]([NH:25][CH3:26])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=O)(C)(C)C.[C:39]1([CH2:49][C@H:50]([CH2:54][C:55]([N:57]2[CH2:62][CH2:61][O:60][CH2:59][CH2:58]2)=[O:56])[C:51](O)=[O:52])[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]=[CH:41][CH:40]=1.P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>>[C:39]1([CH2:49][C@H:50]([CH2:54][C:55]([N:57]2[CH2:58][CH2:59][O:60][CH2:61][CH2:62]2)=[O:56])[C:51]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:32][CH:33]2[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]2)[C@@H:20]([OH:31])[CH2:21][C@@H:22]([C:27]([OH:30])([CH3:28])[CH3:29])[C:23]([NH:25][CH3:26])=[O:24])=[O:17])[CH2:10][C:11]2[N:12]=[CH:13][S:14][CH:15]=2)=[O:52])[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]=[CH:41][CH:40]=1
Reactant: CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C)C(C)(C)O
Reactant: O=C(O)[C@@H](CC(=O)N1CCOCC1)Cc1cccc2ccccc12
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Product: CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)[C@@H](CC(=O)N1CCOCC1)Cc1cccc2ccccc12)C(C)(C)O
Yield: 80.1 %

Procedure:
A procedure similar to that described in Example 2 was repeated, except that 100 mg (0.17 mmoles) of (2S, 4S, 5S)-5-[N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl]amino-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-methylhexanamide [prepared as described in Example 9(a)], 71 mg (0.22 mmoles) of 2(R)-(1-naphthylmethyl)-3-(morpholinocarbonyl)propionic acid, 0.03 ml (0.20 mmoles) of diethyl cyanophosphate, and 0.08 ml (0.57 mmoles) of triethylamine were used, obtain 104 mg (yield 75%) of the title compound as an amorphous substance.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@:15]3([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)[C:14]3[CH:13]=[C:12](Cl)[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[CH2:23]([OH:28])[C:24]([CH3:27])([CH3:26])[CH3:25].[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[N:34][CH:35]=1>>[F:29][C:30]1[CH:31]=[C:32]([C:2]2[CH:3]=[C:4]3[C@:15]4([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]4)[C:14]4[CH:13]=[C:12]([O:28][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[N:11]=[CH:10][C:9]=4[O:8][C:5]3=[CH:6][CH:7]=2)[CH:33]=[N:34][CH:35]=1
Reactant: CC(C)(C)CO
Reactant: NC1=N[C@@]2(COC1)c1cc(Br)ccc1Oc1cnc(Cl)cc12
Reactant: OB(O)c1cncc(F)c1
Product: CC(C)(C)COc1cc2c(cn1)Oc1ccc(-c3cncc(F)c3)cc1[C@@]21COCC(N)=N1

Procedure:
The title compound was synthesized by steps analogous to those described in Method A4, but using Intermediate 10B, neopentyl alcohol, and 5-fluoropyridin-3-ylboronic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-])=O.Cl[Sn]Cl.O.C([O-])(O)=O.[Na+]>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH2:9]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cc(Cl)ccc1Br
Temperature: 25 °C
Yield: 99.6 %

Procedure:
A mixture of 1-bromo-4-chloro-2-nitro-benzene (10.0 g, 42.3 mmol) and SnCl2 (24.0 g, 127 mmol) in EtOAc (100 mL) was heated to reflux for 1 hour. After cooling to room temperature, water and NaHCO3 were added slowly at 0° C. until the reaction was basic. The mixture was filtered through celite and rinsed with EtOAc. The filtrate was washed with aqueous NaHCO3 solution and brine, dried (MgSO4), filtered and concentrated to give 6A (8.7 g, 100%) as black crystals. Rt=2.489 min.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:4]=2[N:5]=[C:6]([NH:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[N:7]=1.[CH:27]1([NH:30][C:31](=[O:49])[C:32]2[CH:37]=[C:36](B3OC(C)(C)C(C)(C)O3)[C:35]([CH3:47])=[C:34]([F:48])[CH:33]=2)[CH2:29][CH2:28]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[CH:27]1([NH:30][C:31](=[O:49])[C:32]2[CH:33]=[C:34]([F:48])[C:35]([CH3:47])=[C:36]([C:2]3[C:3]4[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]5[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=5[F:26])[C:4]=4[N:5]=[C:6]([NH:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[N:7]=3)[CH:37]=2)[CH2:28][CH2:29]1
Reactant: O=c1ccc2c(Cl)nc(NC(CO)CO)nc2n1-c1c(F)cccc1F
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1nc(NC(CO)CO)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 100 °C
Yield: 9.8 %

Procedure:
4-Chloro-8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]-amino}pyrido[2,3-d]pyrimidin-7(8H)-one (0.056 g, 0.17 mmol), N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.065 g, 0.17 mmol), K2CO3 (0.07 g, 0.51 mmol) and tetrakis triphenyl phosphine palladium (10 mg, 0.05 eq) are dissolved in dioxane/water (3:1, 10 mL) and heated to about 100° C. for about 3 h. The mixture is concentrated and purified via reverse phase HPLC to afford the title compound (9 mg, yellow powder, mp 214.2-217.5): LC-MS m/z 540 (M+H)+, 1.69 min (ret time). HPLC indicates 96% pure.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.CN[C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[CH2:25])=[CH:20][N:19]=1.[OH-].[K+].[CH3:28][N:29]1C(=O)CCC1>>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:25][CH2:24][C:21]3[C:20]([NH:29][CH3:28])=[N:19][CH:18]=[CH:23][CH:22]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: C=Cc1ccc(NC)nc1
Reactant: CN1CCCC1=O
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Product: CNc1ncccc1CCn1c2c(c3cc(C)ccc31)CN(C)CC2

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, N-methyl-5-vinylpyridin-2-amine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.