Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[C:21]2[C:16](=[CH:17][C:18]([C:22]([OH:24])=O)=[CH:19][CH:20]=2)[O:15][CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH2:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1>>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[C:21]2[C:16](=[CH:17][C:18]([C:22]([NH:29][C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)=[O:24])=[CH:19][CH:20]=2)[O:15][CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1CCOc2cc(C(=O)O)ccc21)OCc1ccccc1
Reactant: Nc1ccncc1
Solvent: O=S(Cl)Cl
Product: O=C(NC1CCOc2cc(C(=O)Nc3ccncc3)ccc21)OCc1ccccc1
Yield: 118.7 %

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 7 using 4-(benzyloxycarbonylamino)chromane-7-carboxylic acid (1.6 g), thionyl chloride (1.2 ml) and 4-aminopyridine (480 mg), the objective 4-(benzyloxycarbonylamino)-N-(4-pyridyl)chromane-7-carboxamide (2.34 g) was obtained as colorless crystals.
Reaction SMILES: B(Br)(Br)Br.C([O:8][C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[CH:12][CH:13]=1)CC.O>ClCCl>[OH:8][C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[CH:12][CH:13]=1
Reactant: CCCCCCc1ccc(-c2ccc(-c3ccc(OCCC)s3)cc2)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCCCCCc1ccc(-c2ccc(-c3ccc(O)s3)cc2)cc1
Reaction time: 8 h

Procedure:
A 1M solution of boron tribromide in dichloromethane (50 cm3) is added dropwise to a solution of 2-propyloxy-5-(4′-hexylbiphenyl-4-yl)thiophene [Zh. Org. Khim., (1979) Vol. 49, pp. 476] (1.0 g) and dichloromethane (50 cm3) at 0° C. under an atmosphere of nitrogen. The reaction solution is stirred overnight and water (100 cm3) added. The organic layer is separated off and the aqueous layer extracted with dichloromethane (2×100 cm3). The combined organic layers are washed with brine (2×100 cm3) and then dried (MgSO4), filtered and evaporated down. The residue is purified by column chromatography on silica gel using a 9:1 hexane/ethyl acetate mixture as eluent and recrystallisation from ethanol to yield 0.4 g of g 2-hydroxy-5-(4′-hexylbiphenyl-4-yl)thiophene.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11]([N+:20]([O-])=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.Cl[Sn]Cl>CO>[NH2:20][C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:17]([O:18][CH3:19])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OCc1ccccc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)O)c(N)cc1OCc1ccccc1

Procedure:
A solution of 4-benzyloxy-5-methoxy 2-nitrobenzoic acid (18.18 g, 60 mmol)(D. E. Thurston et al., Synthesis (1990), 81) and SnCl2.2H2O (137 g, 0.6 mol) (Showa Chemical Company, Japan) in MeOH (800 mL) was stirred at 70° C. for 5 h. The mixture was concentrated under vacuum to a thick syrup. Ethyl acetate (300 mL) was then added. The organic phase was washed with water until it turned to a clear solution, then washed with brine, and dried over MgSO4. After removal of solvent, the crude was recrystallized from ethyl acetate to obtain the title compound in the form of a yellow solid with a yield of 15.1 g (92%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:13])[C:10]=1[O:11][CH3:12])[C:5](O)=[O:6].C1(C)C=CC=CC=1.S(Cl)([Cl:23])=O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:13])[C:10]=1[O:11][CH3:12])[C:5]([Cl:23])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: COc1c(F)cc(C(=O)O)cc1F
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1c(F)cc(C(=O)Cl)cc1F
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To 3,5-difluoro-4-methoxybenzoic acid (310 mg), toluene (3 mL), N,N-dimethylformamide (1 droplet) and thionyl chloride (0.14 mL) were added to the solution, and then the mixture was stirred at 60° C. for 16 hours. The solvent was distilled off under reduced pressure and then azeotroped with toluene to obtain the title compound (347 mg) as a brown oily substance.
Reaction SMILES: Br[C:2]1[C:3]([F:22])=[C:4]([CH:19]=[CH:20][CH:21]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[N:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[N:25][CH:24]=1>>[F:22][C:3]1[C:2]([C:27]2[CH:28]=[N:23][CH:24]=[N:25][CH:26]=2)=[CH:21][CH:20]=[CH:19][C:4]=1[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6]
Reactant: OB(O)c1cncnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cccc(Br)c1F
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cccc(-c2cncnc2)c1F

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 57 using 3-bromo-2-fluoro-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 60.1) and pyrimidin-5-ylboronic acid to afford the title compound as a white powder. UPLC-MS (Condition 2) tR=1.04 min, m/z=378.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.39 (d, J=8.99 Hz, 2H) 7.51 (t, J=7.62 Hz, 1H) 7.74-7.91 (m, 4H) 9.09 (s, 2H) 9.27 (d, J=1.17 Hz, 1H) 10.72 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C:8]2[N:12]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:11]=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Li]CCCC.CN([CH:31]=[O:32])C>>[Br:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C:8]2[N:12]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:18])([CH3:20])[CH3:19])[C:11]([CH:31]=[O:32])=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(Br)cccc1-c1cncn1COCC[Si](C)(C)C
Reactant: CN(C)C=O
Agent: [Li]CCCC
Product: COc1c(Br)cccc1-c1cnc(C=O)n1COCC[Si](C)(C)C
Yield: 46.3 %

Procedure:
Reaction 5-(3-bromo-2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (485 mg, 1.26 mmol), 2.5 M n-BuLi (828 uL, 2.07 mmol), and DMF (494 uL, 6.38 mmol) for 2 h at −40° C. followed by column chromatography on silica gel (EtOAc/hexane 9:1) gave the title compound (240 mg, 47%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 0.00 (s, 9H), 0.94 (t, 2H, J=9.0 Hz), 3.61 (t, 2H, J=7.5 Hz), 3.93 (s, 3H), 5.83 (s, 2H), 6.86 (d, 1H, J=9.0 Hz), 7.38 (dd, 1H, J=9.0, 3.0 Hz), 7.94 (s, 1H), 8.38 (d, 1H, J=3.0 Hz), 9.89 (s, 1H). ES-MS m/z 413 (M+H).
Reaction SMILES: Cl.[NH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].O1[CH2:22][CH2:21]CC1>>[CH2:3]([N:2]([CH2:8][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:2]1)[CH2:21][CH3:22])[CH3:4]
Reactant: C1CCOC1
Reactant: O=C1CCCCCN1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Product: CCN(CC)CC1CCCCCN1

Procedure:
With external cooling, 7-[(diethylamino)methyl[-hexahydro-2H-azepin-2-one hydrochloride (10.0 g, 0.043 mol) is added in batches to a suspension of lithium aluminium hydride (1.9 g, 0.05 mol) in anhydrous tetrahydrofuran (500 ml) and the mixture is refluxed for 1 hour after the initially violent reaction has ended. The excess lithium aluminium hydride is decomposed by the dropwise addition of 20% sodium hydroxide solution. The tetrahydrofuran phase is separated off from the precipitate formed and concentrated in vacuo. The oily residue remaining is then distilled over caustic potash under water jet vacuum. A colorless oil (4.7 g) is obtained, boiling point 12 mm Hg 102°-105° C.
Reaction SMILES: COC(N[C@@H](C(C)C)C(N1CC(=O)C[C@H]1C(OCC1C=CC=CC=1)=O)=O)=O.[CH3:28][CH:29]([CH3:76])[C@H:30]([NH:71][C:72](=[O:75])[O:73][CH3:74])[C:31](=[O:70])[N:32]1[C@H:40]([C:41]2[NH:42][C:43]([C:46]3[CH:51]=[CH:50][C:49]([C:52]4[CH:53]=[C:54]5[C:67](=[CH:68][CH:69]=4)[C:58]4[NH:59][C:60]([C@@H:62]6[CH2:66][CH2:65][CH2:64][NH:63]6)=[N:61][C:57]=4[CH:56]=[CH:55]5)=[CH:48][CH:47]=3)=[CH:44][N:45]=2)[CH2:39][C:34]2([O:38][CH2:37][CH2:36][O:35]2)[CH2:33]1.Cl.[CH3:78][O:79][C@H:80]([CH3:90])[C@H:81]([NH:85][C:86]([O:88][CH3:89])=[O:87])[C:82](O)=[O:83].Cl.O=C1CN[C@H](C(OCC2C=CC=CC=2)=O)C1.COC(N[C@@H](C(C)C)C(O)=O)=O>>[CH3:89][O:88][C:86](=[O:87])[NH:85][C@@H:81]([C@H:80]([O:79][CH3:78])[CH3:90])[C:82]([N:63]1[CH2:64][CH2:65][CH2:66][C@H:62]1[C:60]1[NH:59][C:58]2[C:67]3[C:54]([CH:55]=[CH:56][C:57]=2[N:61]=1)=[CH:53][C:52]([C:49]1[CH:48]=[CH:47][C:46]([C:43]2[NH:42][C:41]([C@@H:40]4[CH2:39][C:34]5([O:35][CH2:36][CH2:37][O:38]5)[CH2:33][N:32]4[C:31](=[O:70])[C@@H:30]([NH:71][C:72]([O:73][CH3:74])=[O:75])[CH:29]([CH3:76])[CH3:28])=[N:45][CH:44]=2)=[CH:51][CH:50]=1)=[CH:69][CH:68]=3)=[O:83]
Reactant: COC(=O)N[C@H](C(=O)O)[C@@H](C)OC
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(-c4ccc5c(ccc6nc([C@@H]7CCCN7)[nH]c65)c4)cc3)[nH]1)OCCO2)C(C)C
Agent: COC(=O)N[C@H](C(=O)N1CC(=O)C[C@H]1C(=O)OCc1ccccc1)C(C)C
Agent: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: Cl
Product: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(-c4ccc5c(ccc6nc([C@@H]7CCCN7C(=O)[C@@H](NC(=O)OC)[C@@H](C)OC)[nH]c65)c4)cc3)[nH]1)OCCO2)C(C)C

Procedure:
The title compound was prepared according to the method employed to prepare (S)-benzyl 1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-oxopyrrolidine-2-carboxylate, except that methyl (S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(2-((S)-pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate 3× HCl salt and (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid were used instead of (S)-benzyl 4-oxopyrrolidine-2-carboxylate hydrochloride and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid. MS (ESI) m/z 838.73 [M+H]+. (45 mg, 54%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:9]=[C:8]([Cl:10])[C:7]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:6][C:4]=1[NH2:5].[F:15][CH:16]([F:20])[C:17](O)=O>O>[Cl:10][C:8]1[C:7]([S:11](=[O:13])(=[O:14])[NH2:12])=[CH:6][C:4]2[NH:5][C:17]([CH:16]([F:20])[F:15])=[N:2][C:3]=2[CH:9]=1
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1N
Reactant: O=C(O)C(F)F
Agent: Cl
Solvent: O
Product: NS(=O)(=O)c1cc2[nH]c(C(F)F)nc2cc1Cl

Procedure:
To 25 ml of 6 N hydrochloric acid containing 2.22 g of 2-amino-4-chloro-5-sulfamylaniline was added 1.50 g of difluoroacetic acid and the mixture refluxed for 12 hours. The resultant solid was collected by filtration and then added to concentrated ammonium hydroxide to yield the free base which was then suspended in water at 50° C. The solid was then collected by filtration, dissolved in methanol, the methanol brought to a boil, charcoal added, and the suspension filtered through two sheets of filter paper, and then through Celite. Concentration in vacuo provided a brown solid which upon recrystallization from acetonitrile yielded a pink solid, m.p. 233°-235°.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:26][CH2:25][CH2:24][CH:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22]3)=[N:19][CH:20]=1)=[N:11][C:10](Cl)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[Cl:36][C:37]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[C:39]([Cl:52])[C:38]=1[OH:53]>>[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:26][CH2:25][CH2:24][CH:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22]3)=[N:19][CH:20]=1)=[N:11][C:10]([C:41]1[CH:40]=[C:39]([Cl:52])[C:38]([OH:53])=[C:37]([Cl:36])[CH:42]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCCC(NC(=O)OC(C)(C)C)C2)nc1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCCC(NC(=O)OC(C)(C)C)C2)nc1
Yield: 36.1 %

Procedure:
Following general procedure II, tert-butyl (1-{5-[(3-acetyl-6-chloro-1,5-naphthyridin-4-yl)amino]pyridin-2-yl}piperidin-3-yl)carbamate (100 mg, 0.20 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (68 mg, 0.24 mmol) to afford crude product (45 mg) which was carried forward without any purification: ESI MS m/z 623 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10]C)[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[CH:4]=[O:5].ClCCl.[Cl-].[Cl-].[Cl-].[Al+3]>O>[Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1cc(Cl)c(C=O)cc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COc1cc(C=O)c(Cl)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloro-4,5-dimethoxy-benzaldehyde (135, 2.00 g, 0.00997 mol), dichloromethane (73.44 mL) and aluminum trichloride (2.50 g, 0.0187 mol) were combined under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and washed with 5% ethyl acetate in hexane to provide an off-white solid (136, 757 mg, 41%). MS (ESI) [M−H+]−=185.0, 187.0.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C@:12]3([CH2:17][CH2:16][N:15]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH:26]([CH3:28])[CH3:27])[CH:20]=4)[C@@H:14]([CH3:29])[CH2:13]3)[N:11]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=3)[C:10](=[O:37])[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:38][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC.C(O)(=O)C>C1COCC1>[CH:1]1([N:7]=[C:8]2[C@:12]3([CH2:17][CH2:16][N:15]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH:26]([CH3:27])[CH3:28])[CH:20]=4)[C@@H:14]([CH3:29])[CH2:13]3)[N:11]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=3)[C:10](=[O:37])[N:9]2[CH3:38])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)Oc1cccc(CN2CC[C@@]3(C[C@@H]2C)C(NC2CCCCC2)=NC(=O)N3c2cccc(F)c2)c1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CI
Product: CC(C)Oc1cccc(CN2CC[C@@]3(C[C@@H]2C)C(=NC2CCCCC2)N(C)C(=O)N3c2cccc(F)c2)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
(5R,7S)-4-(cyclohexylamino)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one (11-10, 0.5 g, 0.1 mmoles) was dissolved in THF (2 mL) in an oven-dried flask and the solution was cooled under nitrogen to −78° C. in a dry ice/acetone bath. To the cooled reaction was added a 1 M solution of Lithium bis(trimethylsilyl)amide in THF (0.3 mL, 0.3 mmoles) dropwise, and the solution was warmed to −20° C. for 10 min. The solution was cooled to −50° C. and iodomethane (0.014 g, 0.1 mmole) was added and the reaction stirred for 30 min at −50° C. The reaction was then allowed to warm to rt. A drop of acetic acid was added and the volume was reduced. The residue was partitioned between saturated aqueous sodium bicarbonate (5 mL) and methylene chloride (5 mL). The organic layer was dried over sodium sulfate, filtered and reduced to a residue which was chromatographed on silica gel eluting with a gradient elution of 100% methylene chloride going to 30% methylene chloride/methanol/10% NH4OH solution over 20 min. The desired fractions were combined and the solvents removed to give the product.
Reaction SMILES: [N+]([O-])(O)=O.[N+:5]([O:8][CH2:9][CH2:10][NH2:11])([O-:7])=[O:6].[CH2:12]([CH:19]1[S:23][C:22](=[O:24])[NH:21][CH:20]1[C:25](O)=[O:26])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[N+:5]([O:8][CH2:9][CH2:10][NH:11][C:25]([CH:20]1[CH:19]([CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[S:23][C:22](=[O:24])[NH:21]1)=[O:26])([O-:7])=[O:6]
Reactant: O=C1NC(C(=O)O)C(Cc2ccccc2)S1
Reactant: NCCO[N+](=O)[O-]
Solvent: O=[N+]([O-])O
Product: O=C1NC(C(=O)NCCO[N+](=O)[O-])C(Cc2ccccc2)S1
Yield: 64.2 %

Procedure:
A procedure similar to that described in Example 1 was repeated, but using 210 mg of N-(2-nitrooxyethyl)amine nitrate and 250 mg of 5-benzyl-2-oxothiazolidine-4-carboxylic acid, to obtain 220 mg of the title compound as pale yellow columnar crystals, melting at 123°-124° C. (after recrystallization from ethanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]([C:19](=O)[CH3:20])=[C:16]([CH3:18])[N:17]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(O)C.[OH-].[Na+].Cl.[NH2:28][NH:29][C:30]([NH2:32])=[O:31]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]([C:19](=[N:28][NH:29][C:30]([NH2:32])=[O:31])[CH3:20])=[C:16]([CH3:18])[N:17]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: NNC(N)=O
Reactant: COc1cc(-c2nc(C)c(C(C)=O)s2)cc(OC)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(-c2nc(C)c(C(C)=NNC(N)=O)s2)cc(OC)c1OC
Temperature: 25 °C
Yield: 69 %

Procedure:
2-(3,4,5-trimethoxyphenyl)-4-methyl-5-acetylthiazole (3.7 g corresponding to its 0.012 mol) was dissolved into 50 ml of ethanol, and 32 ml of an aqueous 2% solution of sodium hydroxide (0.013 mol) and 1.8 g (0.016 mol) of semicarbazide hydrochloride were added to the solution. The whole mixture was then heated for 5 hours under a reflux condenser. After cooling the reaction mixture to room temperature, the mixture was introduced into one liter of iced water. The precipitate which separated was collected by filtration, washed with water and was recrystallized from ethanol to obtain the object consisting of yellow needle-like crystals amounting to 3.0 g and melting at 240° to 242° C. The yield was 69%.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][N:14]=2)[CH2:4][O:3]1.O.[Cl-].[NH4+]>O1CCCC1>[CH3:1][C:2]1([CH3:22])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:12][C:13]2[N:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=2)[CH2:4][O:3]1
Reactant: CC1(C)Cc2c(cccc2Oc2ccc([N+](=O)[O-])cn2)CO1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)Cc2c(cccc2Oc2ccc(N)cn2)CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.7 %

Procedure:
To a solution of 2-(3,3-dimethylisochroman-5-yl)oxy-5-nitro-pyridine (Intermediate 171, 80 mg) in tetrahydrofuran (5 ml)/water (2.5 ml) iron (70 mg, 1.3 mmol) and then ammonium chloride (70 mg, 1.3 mmol) were added and the reaction mixture was stirred overnight at room temperature. The catalyst was filtered off and the residue was diluted with an aqueous saturated solution of NaHCO3 (5 ml) and extracted with ethyl acetate (3×10 ml). The organic layer was dried over sodium sulfate, filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane/ethyl acetate 8:2 to cyclohexane/ethyl acetate 4:6 as eluents affording the title compound (25 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[Cl:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:30]=1[C:24]1([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[CH2:23][CH:22]2[CH2:31][C:32]([O:34]CC)=[O:33]>>[Cl:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:30]=1[C:24]1([CH2:25][CH2:26][N:27]([C:9](=[O:11])[CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[C:12]([F:15])([F:14])[F:13])[CH2:28][CH2:29]1)[CH2:23][CH:22]2[CH2:31][C:32]([OH:34])=[O:33]
Reactant: CCOC(=O)CC1CC2(CCNCC2)c2c(Cl)cccc21
Reactant: O=C(O)Cc1ccc(F)cc1C(F)(F)F
Product: O=C(O)CC1CC2(CCN(C(=O)Cc3ccc(F)cc3C(F)(F)F)CC2)c2c(Cl)cccc21

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 1 using 2-(4-fluoro-2-(trifluoromethyl)phenyl)acetic acid and ethyl 2-(7-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate. LC-MS Method 1 tR=1.88, min, m/z=486, 484
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:3]=1.[C:20]([O:24][C:25](=[O:32])[NH:26][C@@H:27]1[CH2:31][CH2:30][NH:29][CH2:28]1)([CH3:23])([CH3:22])[CH3:21].C(N(CC)CC)C>CN(C=O)C.O.C(Cl)Cl>[OH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:4]1[N:3]=[C:2]([N:29]2[CH2:30][CH2:31][C@@H:27]([NH:26][C:25](=[O:32])[O:24][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:28]2)[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1ccc2c(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)nc(-c3ccccc3O)nc2c1
Reaction time: 12 h
Yield: 84.8 %

Procedure:
To 2-(4-chloro-7-methyl-quinazolin-2-yl)-phenol (644 mg, 2.4 mmol) in 2.9 mL of DMF at room temperature was added sequentially (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (857 mg, 4.6 mmol) and triethylamine (662 μL, 4.8 mmol), and the reaction mixture was stirred for 12 h. The reaction mixture was diluted with water (10 mL) and CH2Cl2 (10 mL). The organic layer was separated and dried (Na2SO4), and the residue was purified by silica gel chromatography with 25-85% ethyl acetate/hexanes to give tert-butyl (R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (856 mg, 86%). LC/MS: m/z 421 (M+H)+ at 2.82 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:23])[C:4]([N:6]([CH2:15][CH:16](OCC)[O:17]CC)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:8]=1[CH3:14])=[O:5].O.FC(F)(F)C(O)=O.CCOC(C)=O>ClCCl>[CH3:1][NH:2][C:3](=[O:23])[C:4]([N:6]([CH2:15][CH:16]=[O:17])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:8]=1[CH3:14])=[O:5]
Reactant: CCOC(CN(C(=O)C(=O)NC)c1cccc(C)c1C)OCC
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)C(=O)N(CC=O)c1cccc(C)c1C
Reaction time: 16 h
Yield: 95.7 %

Procedure:
To a solution of the ester from Step D (719 mg, 2.23 mmol) in 10 mL of dichloromethane at room temperature was added water (1 mL) and trifluoroacetic acid (1 mL). After 16 hours, the reaction was poured into EtOAc, washed with sat, NaHCO3 soln. and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the aldehyde (0.53 g, 100% yield) as a yellow oil which was sufficiently pure for use in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([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:6][CH:7]=1.[CH3:23][O:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.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]>[CH3:23][O:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=1[C:2]1[CH:3]=[CH:4][C:5]([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:6][CH:7]=1
Reactant: COc1ccc(B(O)O)c(OC)c1
Reactant: O=C(Nc1ccc(Br)cn1)C1(c2ccc3c(c2)OCO3)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)nc2)c(OC)c1
Temperature: 80 °C

Procedure:
1-Benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid (5-bromo-pyridin-2-yl)-amide (36.1 mg, 0.10 mmol) was dissolved in 1 mL of N,N-dimethylformamide in a reaction tube. 2,4-Dimethoxybenzeneboronic acid (24 mg, 0.13 mmol), 0.1 mL of an aqueous 2 M potassium carbonate solution, and a catalytic amount of Pd(dppf)Cl2 (6.6 mg, 0.0090 mmol) were added and the reaction mixture was heated at 80° C. for three hours. The resulting material was cooled to room temperature, filtered, and purified by reverse-phase preparative liquid chromatography to yield the pure product as a trifluoroacetic acid salt. ESI-MS m/z calc. 418.2. found 419.0 (M+1)+. Retention time 3.18 minutes. 1H NMR (400 MHz, CD3CN) δ 1.25-1.29 (m, 2H), 1.63-1.67 (m, 2H), 3.83 (s, 3H), 3.86 (s, 3H), 6.04 (s, 2H), 6.64-6.68 (m, 2H), 6.92 (d, J=8.4 Hz, 1H), 7.03-7.06 (m, 2H), 7.30 (d, J=8.3 Hz, 1H), 7.96 (d, J=8.9 Hz, 1H), 8.14 (dd, J=8.9, 2.3 Hz, 1H), 8.38 (d, J=2.2 Hz, 1H), 8.65 (s, 1H).