Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[O:20])[C@@H:3]([NH:5][C:6]1[N:11]=[C:10](Cl)[N:9]=[C:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:7]=1)[CH3:4].[F:21][C:22]1[CH:43]=[CH:42][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][CH:28]=2)=[CH:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2](=[O:20])[C@@H:3]([NH:5][C:6]1[N:11]=[C:10]([C:30]2[CH:29]=[CH:28][C:27]([O:26][C:25]3[CH:24]=[CH:23][C:22]([F:21])=[CH:43][CH:42]=3)=[CH:32][CH:31]=2)[N:9]=[C:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:7]=1)[CH3:4]
Reactant: C[C@H](Nc1cc(C(=O)OC(C)(C)C)nc(Cl)n1)C(N)=O
Reactant: CC1(C)OB(c2ccc(Oc3ccc(F)cc3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: C[C@H](Nc1cc(C(=O)OC(C)(C)C)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1)C(N)=O
Temperature: 80 °C
Yield: 56.9 %

Procedure:
To a mixture of (S)-tert-butyl 6-((1-amino-1-oxopropan-2-yl)amino)-2-chloropyrimidine-4-carboxylate (0.628 g, 2.09 mmol) in dioxane (10 mL) was added 2-(4-(4-fluorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.791 g, 2.52 mmol), 2M aqueous Na2CO3 (2.1 mL, 4.2 mmol) and PdCl2(dppf) (0.087 g, 0.11 mmol). The reaction vessel was flushed with argon, sealed and heated at 80° C. overnight. After cooling, the reaction mixture was evaporated in vacuo and the residue chromatographed over silica gel with 50-90% EtOAc in hexanes. The product fractions were evaporated in vacuo to give a residue which was triturated with 5 mL 1:1 EtOAc/hexanes. The solid was filtered off, rinsed twice with 2 mL 1:1 EtOAc/hexanes, and dried under vacuum to give (S)-tert-butyl 6-((1-amino-1-oxopropan-2-yl)-amino)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxylate as a cream-colored powder (0.537 g, 1.19 mmol, 57% yield). 1H NMR (400 MHz, DMSO-d6): 8.36 (2H, d, J=9.0 Hz), 7.97 (1H, d, J=6.6 Hz), 7.54 (1H, s), 7.31-7.24 (2H, m), 7.19-7.13 (2H, m), 7.09-6.99 (4H, m), 4.59-4.50 (1H, m), 1.55 (9H, s), 1.36 (3H, d, J=7.0 Hz). LC/MS: m/z=453.3 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:73])([O:58][C:59]1[CH:64]=[CH:63][C:62]([O:65][CH2:66][CH2:67][CH2:68][C:69]([F:72])([F:71])[F:70])=[CH:61][CH:60]=1)[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH:15]([C:46]2[CH:51]=[CH:50][C:49]([N+:52]([O-])=O)=[CH:48][C:47]=2[N+:55]([O-])=O)[CH2:16][O:17][C:18](=[O:45])/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:44])([F:43])[O:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][C:39]([F:42])([F:41])[F:40])=[CH:31][CH:30]=3)=[CH:23][CH:22]=2)=[O:12])=[CH:5][CH:4]=1>CN(C)C=O.O.[Zn]>[F:1][C:2]([F:73])([O:58][C:59]1[CH:64]=[CH:63][C:62]([O:65][CH2:66][CH2:67][CH2:68][C:69]([F:71])([F:72])[F:70])=[CH:61][CH:60]=1)[C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH:15]([C:46]2[CH:51]=[CH:50][C:49]([NH2:52])=[CH:48][C:47]=2[NH2:55])[CH2:16][O:17][C:18](=[O:45])/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:43])([F:44])[O:28][C:29]3[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH2:37][CH2:38][C:39]([F:42])([F:41])[F:40])=[CH:33][CH:34]=3)=[CH:23][CH:22]=2)=[O:12])=[CH:7][CH:8]=1
Reactant: O=C(/C=C/c1ccc(C(F)(F)Oc2ccc(OCCCC(F)(F)F)cc2)cc1)OCC(COC(=O)/C=C/c1ccc(C(F)(F)Oc2ccc(OCCCC(F)(F)F)cc2)cc1)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(C(COC(=O)/C=C/c2ccc(C(F)(F)Oc3ccc(OCCCC(F)(F)F)cc3)cc2)COC(=O)/C=C/c2ccc(C(F)(F)Oc3ccc(OCCCC(F)(F)F)cc3)cc2)c(N)c1
Yield: 89.2 %

Procedure:
8.70 g (8.38 mmol) of 2-(2,4-dinitrophenyl)-3-{[(2E)-3-(4-{difluoro[4-(4,4,4-trifluoro-butoxy)phenoxy]methyl}phenyl)prop-2-enoyl]oxy}propyl (2E)-3-(4-{difluoro[4-(4,4,4-tri-fluorobutoxy)phenoxy]methyl}phenyl)prop-2-enoate are dissolved in a mixture of 54 mL of N,N-dimethylformamide and 6 mL water. 13.9 g (51.4 mmol) ferric chloride hexahydrate are added. 5.60 g (85.7 mmol) zinc powder is added portion wise within 60 minutes. The mixture is allowed to react for 2 hours. The reaction mixture is partitioned between ethyl acetate and water and filtrated. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtrated and concentrated under reduced pressure. Filtration of the residue on 400 g silica gel using toluene:ethyl acetate 1:3 as eluent and crystallization from ethyl acetate:hexane mixture yielded 7.32 g of 2-(2,4-diaminophenyl)-3-{[(2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenoxy]methyl}phenyl)prop-2-enoyl]oxy}propyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenoxy]methyl}phenyl)prop-2-enoate as yellow crystals.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14]Br>C1COCC1>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:14][CH:13]([O:16][CH3:17])[O:12][CH3:11])=[CH:6][CH:5]=1
Reactant: COC(CBr)OC
Reactant: Sc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(CSc1ccc(Br)cc1)OC

Procedure:
NaH (1.2 g, 20.5 mmol, 60% in mineral oil) was added to a dry THF (20 ml) solution of 4-bromobenzene thiol (3.0 g, 15.8 mmol) and reacted at room temperature for 10 minutes. Next, bromoacetaldehyde dimethyl acetal (2.8 mL, 23.7 mmol) was added to the mixture and reacted while being refluxed for two days.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:37][C:38]([O:40][CH3:41])=[O:39])[C:8]([O:35][CH3:36])=[C:9]([NH:11][C:12](=[O:34])[NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([O:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27](C(O)=O)[CH:26]=3)=[CH:16][CH:15]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.CNC.[CH3:64][N:65]([CH:67]=[O:68])[CH3:66]>O>[CH3:41][O:40][C:38](=[O:39])[NH:37][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=[C:9]([NH:11][C:12]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([O:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([C:67](=[O:68])[N:65]([CH3:66])[CH3:64])[CH:26]=3)=[CH:16][CH:15]=2)=[O:34])[C:8]=1[O:35][CH3:36]
Reactant: COC(=O)Nc1cc(C(C)(C)C)cc(NC(=O)Nc2ccc(Oc3ccnc(C(=O)O)c3)c3ccccc23)c1OC
Reactant: CN(C)C=O
Agent: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)Nc1cc(C(C)(C)C)cc(NC(=O)Nc2ccc(Oc3ccnc(C(=O)N(C)C)c3)c3ccccc23)c1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a cold solution (0° C.) of 4-{4-[3-(5-tert-butyl-2-methoxy-3-methoxycarbonylamino-phenyl)-ureido]-naphthalen-1-yloxy}-pyridine-2-carboxylic acid (Example 14) (56 mg, 0.1 mmol) in DMF (1 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (23 mg, 0.12 mmol) and triethyl amine (0.070 mL, 0.5 mmol). The solution was allowed to stir at 0° C. for 30 min, then dimethylamine (2M solution in THF, 0.25 mL, 0.5 mmol) was added in one portion. The resulting solution was allowed to stir at room temperature for 12 h. Water (4 mL) was added and the product was extracted with EtOAc, dried over magnesium sulfate and concentrated via rotary evaporation. The resulting crude solid was purified by column chromatography (CH2Cl2:MeOH, 95:5) to provide the title compound as a light tan solid (45 mg, 77% yield).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH2:15]([O:17][C:18](=[O:48])[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25]([O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43]Br)[C:24]=1[CH2:45][CH2:46][CH3:47])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:15]([O:17][C:18](=[O:48])[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25]([O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:11][C:6]2[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=2[CH2:8][CH2:9][CH3:10])[C:24]=1[CH2:45][CH2:46][CH3:47])[CH3:16]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1OCCOCCOCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCCOCCOCCOCCOc2c(C(C)=O)ccc(OCCCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Reaction time: 25 h
Yield: 71.2 %

Procedure:
A mixture of 0.9500 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.677 g of 4-[4-acetyl-3-[2-[2-[2-(2-bromoethoxy)ethoxy]ethoxy]ethoxy]-2-propylphenoxy]butanoic acid ethyl ester and 1.0 g of anhydrous potassium carbonate in 40 ml of anhydrous acetone was stirred at reflux for 17 hours. An additional 1.0 g of potassium carbonate was added and reflux was continued for 25 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to an oil which was chromatographed on 200 g of silica gel. Elution with 30% ethyl acetate-toluene gave 2.3 g (71% yield) of 4-[4-acetyl-3-[2-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]ethoxy]-2-propylphenoxy]butanoic acid ethyl ester as an oil.
Reaction SMILES: [C:1]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-])=O)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)([CH3:4])([CH3:3])[CH3:2]>CO.[Ni]>[C:1]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1ccc2cc([N+](=O)[O-])ccc21
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)n1ccc2cc(N)ccc21
Temperature: 30 °C
Reaction time: 1 h
Yield: 44.3 %

Procedure:
To a solution of 1-tert-butyl-5-nitro-1H-indole (6.5 g, 0.030 mol) in MeOH (100 mL) was added Raney Nickel (0.65 g, 10%) under N2 protection. The mixture was stirred under hydrogen atmosphere (1 atm) at 30° C. for 1 h. The catalyst was filtered off and the filtrate was concentrated under vacuum to dryness. The residue was purified by column chromatography on silica gel (PE/EtOAc 1:2) to give 1-tert-butyl-1H-indol-5-amine (2.5 g, 45%). 1H-NMR (CDCl3, 400 MHz) δ 7.44 (d, J=8.8 Hz, 1H), 7.19 (dd, J=3.2 Hz, 1H), 6.96 (d, J=2.0 Hz, 1H), 6.66 (d, J=2.0, 8.8 Hz, 1H), 6.26 (d, J=3.2 Hz, 1H), 1.67 (s, 9H). MS (ESI) m/e (M+H+) 189.2.
Reaction SMILES: COCCOC[N:7]1[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=[O:15])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:9]([C:26]([O:28][CH3:29])=[O:27])=[C:8]1[CH3:30].Cl>CC(C)=O.O1CCCC1>[CH3:30][C:8]1[NH:7][C:12]([CH3:13])=[C:11]([C:14]([OH:16])=[O:15])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:9]=1[C:26]([O:28][CH3:29])=[O:27]
Reactant: COCCOCN1C(C)=C(C(=O)O)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OC)=C1C
Agent: Cl
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1

Procedure:
hydrolyzing said (+)-1-(2-methoxyethoxymethyl)-2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-carboxy-1,4-dihydropyridine with 1N hydrochloric acid in acetone or tetrahydrofuran to produce (-)-2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-carboxy-1,4-dihydropyridine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([N+:19]([O-])=O)=[C:8]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[CH:9]=1)=[O:4]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([NH2:19])=[C:8]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(Sc2ccccc2OC)c([N+](=O)[O-])s1
Solvent: C1CCOC1
Product: COC(=O)c1cc(Sc2ccccc2OC)c(N)s1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The procedure as in Example 20: step a was followed using 4-bromo-5-nitro-thiophene-2-carboxylic acid methyl ester ((Example 114, step c) 200 mg, 0.75 mmol) and 2-methoxy-benzenethiol (109 μL, 1.25 mmol, Aldrich Chemical Company) to isolate 4-(2-methoxy-phenylsulfanyl)-5-nitro-thiophene-2-carboxylic acid methyl ester. 4-(2-Methoxy-phenylsulfanyl)-5-nitro-thiophene-2-carboxylic acid methyl ester (200 mg, 0.61 mmol) was then treated with TiCl3 (20% aq. HCl solution, 5 mL, 6.1 mmol) in THF (6 mL). The reaction was stirred for 20 minutes at rt. The reaction mixture was concentrated in vacuo and then dissolved into EtOAc. The organic layer was washed several times with saturated NaHCO3. The combined organic layers were dried over sodium sulfate. Removal of the solvents in vacuo yielded 5-amino-4-(2-methoxy-phenylsulfanyl)-thiophene-2-carboxylic acid methyl ester. The procedure as in Example 20: step e was followed using 5-amino-4-(2-methoxy-phenylsulfanyl)-thiophene-2-carboxylic acid methyl ester (160 mg, 0.54 mmol), t-butylnitrite (96 μL, 0.81 mmol), and copper(II) bromide (112.6 mg, 0.65 mmol) resulting in 5-bromo-4-(2-methoxy-phenylsulfanyl)-thiophene-2-carboxylic acid methyl ester. The procedure as in Example 20: step b was followed using 5-bromo-4-(2-methoxy-phenylsulfanyl)-thiophene-2-carboxylic acid methyl ester (18 mg, 0.05 mmol) and m-CPBA (32 mg, 0.25 mmol) resulting in 5-bromo-4-(2-methoxy-benzenesulfonyl)-thiophene-2-carboxylic acid methyl ester. The procedure as in Example 20: step f was followed using 5-bromo-4-(2-methoxy-benzenesulfonyl)-thiophene-2-carboxylic acid methyl ester (45 mg, 11 mmol) and dimethyl aluminum amide (1M, 0.57 mL, 0.55 mmol) resulting in the title compound 5-bromo-4-(2-methoxy-benzenesulfonyl)-thiophene-2-carboxamidine (4 mg, 13%). 1H-NMR (CD3OD): δ: 8.30 (s, 1H), 8.12–8.14 (d of d, J=6.1, 1.8 Hz, 1H), 7.70–7.74 (m, 1H), 7.16–7.24 (m, 2H), 3.79 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][N:16]=2)[C:11]([OH:18])=[C:10]([C:19](OCC)=[O:20])[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:27]=1[S:33]([NH2:36])(=[O:35])=[O:34]>C1(C)C=CC=CC=1>[NH2:36][S:33]([C:27]1[CH:28]=[C:29]([Br:32])[CH:30]=[CH:31][C:26]=1[NH:25][C:19]([C:10]1[C:9](=[O:24])[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:17]2[C:12]([C:11]=1[OH:18])=[CH:13][CH:14]=[CH:15][N:16]=2)=[O:20])(=[O:35])=[O:34]
Reactant: CCOC(=O)c1c(O)c2cccnc2n(Cc2ccccc2)c1=O
Reactant: Nc1ccc(Br)cc1S(N)(=O)=O
Solvent: Cc1ccccc1
Product: NS(=O)(=O)c1cc(Br)ccc1NC(=O)c1c(O)c2cccnc2n(Cc2ccccc2)c1=O
Yield: 69.9 %

Procedure:
The product of Example 84B (0.065 g, 0.20 mmol) was reacted with the product of Example 84A (0.050 g, 0.20 mmol) in toluene (4 mL) at reflux for 3 hours. The reaction was cooled and the resulting precipitate was collected by filtration and dried to give to give the title compound as an off-white solid (0.074 g, 70%). MS (ESI+) m/z 528.9 (M+H)+, 530.9 (M+H)+, 551.1 (M+Na)+, 552.9 (M+Na)+; 1H NMR (300 MHz, DMSO-d6) δ 5.67 (s, 2H), 7.23 (m, 2H), 7.29 (m, 3H), 7.48 (dd, J=8.09, 4.78 Hz, 1H), 7.69 (s, 2H), 7.87 (dd, J=8.82, 2.21 Hz, 1H), 7.97 (m, 1H), 8.01 (d, J=2.21 Hz, 1H), 8.55 (dd, J=7.91, 1.65 Hz, 1H), 8.82 (dd, J=4.60, 1.65 Hz, 1H), 12.44 (s, 1H), 16.45 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:6]=[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)[N:4]=1)[CH3:2].C([O-])(=O)C.[Na+].[Br:29]Br>C(O)(=O)C>[Br:29][CH2:2][CH2:1][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:6]=[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)[N:4]=1
Reactant: BrBr
Reactant: CCc1nc(Nc2cccnc2)cc(-c2cccc(OC)c2)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cccc(-c2cc(Nc3cccnc3)nc(CCBr)n2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
[2-ethyl-6-(3-methoxyphenyl)pyrimidin-4-yl]-3-pyridylamine 14 (synthesized with a procedure similar to the one previously described) (1 eq) is dissolved in acetic acid, then sodium acetate (2 eq) is added. To this mixture, a solution of bromine (1 eq) in acetic acid is added dropwise. The reaction is stirred at room temperature for 3 h. The reaction mixture is concentrated under reduced pressure, water is added and the solution basified (pH ˜10-11) with sat. aq. Na2CO3 solution. The product 15 crashes out, is filtered off, dried, and used as is in the following step.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[N:16]=[C:15]([NH2:17])[N:14]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]5[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=5)=[C:21]([O:35][CH3:36])[CH:20]=4)[C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:37][PH:38](=[O:40])[CH3:39].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:17][C:15]1[N:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)=[C:21]([O:35][CH3:36])[CH:20]=2)[C:11]2=[N:12][CH:13]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([P:38](=[O:40])([CH3:39])[CH3:37])=[N:7][CH:6]=3)[CH:9]=[C:10]2[N:16]=1
Reactant: COc1ccc(COc2ccc(Cn3c(N)nc4cc(-c5ccc(Cl)nc5)cnc43)cc2OC)cc1
Reactant: C[PH](C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(COc2ccc(Cn3c(N)nc4cc(-c5ccc(P(C)(C)=O)nc5)cnc43)cc2OC)cc1
Temperature: 150 °C
Reaction time: 1 h
Yield: 146.1 %

Procedure:
To a stirred suspension of 6-(6-chloropyridin-3-yl)-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-amine (0.17 g, 0.34 mmol) in 1,4-dioxane (12 mL) was added dimethylphosphine oxide (0.053 g, 0.69 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.079 g, 0.14 mmol), palladium(II) acetate (0.015 g, 0.069 mmol), and cesium carbonate (0.22 g, 0.69 mmol). The reaction mixture was heated to 150° C. in a microwave reactor. After 1 h, the reaction mixture was allowed to cool to room temperature. The mixture was diluted with water and extracted with chloroform (×2). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to provide 0.27 g of a yellow solid. Chromatographic purification (Combi-Flash, 12 g SiO2 column, 5-10% 2M ammonia in methanol/dichloromethane elute) afforded 0.078 g (42%) of the product as a tan solid: 1H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J=1.8 Hz, 1H), 8.32-8.21 (m, 2H), 7.99 (dd, J=7.9, 5.1 Hz, 1H), 7.82 (d, J=1.8 Hz, 1H), 7.32 (d, J=8.6 Hz, 2H), 7.11 (d, J=1.7 Hz, 1H), 7.05 (s, 2H), 6.98-6.87 (m, 3H), 6.72 (dd, J=8.2, 1.7 Hz, 1H), 5.24 (s, 2H), 4.93 (s, 2H), 3.74 (s, 3H), 3.72 (s, 3H), 1.69 (d, J=13.5 Hz, 6H) ppm; (M+1)=544.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13]([CH:15]2[CH2:17][CH:16]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:14])[CH:3]=1.[F:24][C@@H:25]1[CH2:29][CH2:28][NH:27][CH2:26]1>CN1C(=O)CCC1.CS(C)=O.CO>[F:24][C@@H:25]1[CH2:29][CH2:28][N:27]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13]([CH:15]3[CH2:17][CH:16]3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:14])[CH:3]=2)[CH2:26]1
Reactant: Cc1cc2nc(NC(=O)C3CC3c3ccccc3)cc(Cl)n2n1
Reactant: F[C@@H]1CCNC1
Solvent: CS(C)=O
Solvent: CO
Solvent: CN1CCCC1=O
Product: Cc1cc2nc(NC(=O)C3CC3c3ccccc3)cc(N3CC[C@@H](F)C3)n2n1
Temperature: 25 °C
Yield: 25.8 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-2-phenylcyclopropanecarboxamide (8C, 200 mg, 0.612 mmol) and (R)-3-fluoropyrrolidine (109 mg, 1.22 mmol) in NMP (1.85 mL) was stirred at 100° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC (35-40% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (60 mg, 26%). 1H NMR (DMSO-d6) δ: 10.77 (s, 1H), 7.24-7.35 (m, 2H), 7.11-7.25 (m, 3H), 6.93 (s, 2H), 5.95 (s, 1H), 5.30-5.61 (m, 1H), 3.74-4.41 (m, 4H), 2.01-2.47 (m, 6H), 1.48 (dt, J=9.0, 4.7 Hz, 1H), 1.29-1.42 (m, 1H). ESI-MS: m/z 380.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11](C(O)=O)=[CH:10][C:9]=2[S:16][C:17]([F:20])([F:19])[F:18])=[CH:4][CH:3]=1.O>C(CN)O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][CH:11]=[CH:10][C:9]=2[S:16][C:17]([F:19])([F:18])[F:20])=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(SC(F)(F)F)c(-c2ccc(Cl)cc2)[nH]1
Solvent: O
Solvent: NCCO
Product: FC(F)(F)Sc1cc[nH]c1-c1ccc(Cl)cc1
Temperature: 160 °C
Reaction time: 5 h
Yield: 25.6 %

Procedure:
A mixture of 5-(p-chlorophenyl)-4-[(trifluoromethyl)thio]pyrrole-2-carboxylic acid (0.5 g, 0.00155 mol) in ethanolamine (1.5 mL) is stirred at 160° C. for five hours, cooled to room temperature overnight with stirring, poured into water and. extracted with ether. The combined organic extracts are washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a yellow syrup. Flash chromatography of the syrup using silica gel and a 1:4 ethyl acetate/hexanes solution gives the title product as an off-white solid (0.11 g, mp 59°-64° C.) which is identified by 1HNMR and 19FNMR spectral analyses.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=O.Cl.[CH:13]1([C:16](=[NH:18])[NH2:17])[CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[NH:18][C:16]([CH:13]3[CH2:15][CH2:14]3)=[N:17][CH:2]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: N=C(N)C1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ccc(-c2cnc(C3CC3)[nH]2)cc1
Temperature: 23 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To a solution of 89.0 g (320 mmol) 2-bromo-1-(4-bromophenyl)ethanone in 2.0 L N,N-dimethylformamide were added cyclopropanecarboximidamide hydrochloride, 132.8 g potassium carbonate and the mixture was stirred at 23° C. overnight. After removal of the solvent, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. After filtration and removal of the solvent the residue was purified by crystallisation to give 42.1 g (50%) of the title compound.
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[NH2:2].[Cl:14][C:15]1[CH:20]=[C:19]([N:21]=[C:22]=[O:23])[CH:18]=[C:17]([Cl:24])[N:16]=1>>[Cl:14][C:15]1[CH:20]=[C:19]([NH:21][C:22]([NH:2][NH:1][C:3]2[CH:12]=[C:11]([CH3:13])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=2)=[O:23])[CH:18]=[C:17]([Cl:24])[N:16]=1
Reactant: Cc1cc(NN)nc2ccccc12
Reactant: O=C=Nc1cc(Cl)nc(Cl)c1
Product: Cc1cc(NNC(=O)Nc2cc(Cl)nc(Cl)c2)nc2ccccc12

Procedure:
A solution of 2-hydrazinyl-4-methylquinoline (100 mg, 0.58 mmol) and 110 mg (1.0 eq) of 2,6-dichloro-4-isocyanatopyridine was reacted as outlined in Scheme 1 above to give the desired title compound. Spectroscopic data: 1H NMR (300 MHz, DMSO-d6) δ ppm 2.57 (s, 3 H) 6.80 (s, 1 H) 7.30 (t, J=7.47 Hz, 1 H) 7.50-7.64 (m, 2 H) 7.87 (d, J=8.20 Hz, 1 H) 8.78 (s, 1 H) 8.91 (br. s., 1 H).
Reaction SMILES: C([O:5][C:6]([C:8]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([OH:22])[N:11]=[C:10]([CH2:23][C:24]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:28][CH2:27][CH2:26][CH2:25]2)[N:9]=1)=[O:7])(C)(C)C.C(OC1C(C(O)=O)=NC(CC2C=CC=CC=2C2C=CC=CC=2)=NC=1O)C1C=CC=CC=1>>[CH2:15]([O:14][C:13]1[C:8]([C:6]([OH:7])=[O:5])=[N:9][C:10]([CH2:23][C:24]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:26][CH2:27][CH2:28]2)=[N:11][C:12]=1[OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1
Agent: O=C(O)c1nc(Cc2ccccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Product: O=C(O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1
Yield: 68.3 %

Procedure:
5-Benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (28-01) (2.7 g, 68.33%) was synthesized from 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid tert-butyl ester (27-01) (4.5 g, 9.77 mmol) as a yellow solid following the procedure as described for 5-benzyloxy-2-biphenyl-2-ylmethyl-6-hydroxypyrimidine-4-carboxylic acid (7-01).