Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[C:6]([O:10][C:11](=[O:21])[NH:12][CH:13]1[CH2:18][CH2:17][CH:16]([CH:19]=[O:20])[CH2:15][CH2:14]1)([CH3:9])([CH3:8])[CH3:7]>C1COCC1>[C:6]([O:10][C:11](=[O:21])[NH:12][C@H:13]1[CH2:14][CH2:15][C@H:16]([CH:19]([C:11]2[O:10][C:1]3[CH:3]=[CH:8][CH:6]=[CH:7][C:2]=3[N:12]=2)[OH:20])[CH2:17][CH2:18]1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)NC1CCC(C=O)CC1
Reactant: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(O)c2nc3ccccc3o2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-methoxy-benzoxazole (1490 mg, 10 mmol, obtained by methylation of 4-hydroxybenzoxazole (J. Med. Chem. (1987), 30, 62) in THF (60 ml) was added dropwise a solution of i-PrMgCl (5 ml, 2M solution in THF). The red mixture was stirred at 0° C. for 1 h before dropwise addition of (4-formyl-cyclohexyl)-carbamic acid tert-butyl ester (1360 mg, 6 mmol) dissolved in THF (10 ml). The reaction was stirred at 0° C. for 30 min and at RT for 1 h. The reaction mixture was quenched with aq. ammonium chloride solution and extracted EtOAc. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by chromatograpy on SiO2 (hex/EtOAc 2:1, 1:1) affording 1300 mg (59%) of product as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[CH3:16][NH:17][O:18][CH3:19].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CCOC(C)=O.O>[Cl:1][C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([N:17]([O:18][CH3:19])[CH3:16])=[O:5]
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1Cl
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)c1ccc(C(F)(F)F)nc1Cl
Reaction time: 0.08 h
Yield: 93.1 %

Procedure:
To a suspension of 2-chloro-6-trifluoromethyl-nicotinic acid (200 mg, 0.88 mmol) and N,O-dimethylhydroxylamine hydrochloride (95 mg, 0.97 mmol) in CH2Cl2 (3 mL) was added N-methylmorpholine (0.106 ml, 0.97 mmol). The mixture was stirred for 5 minutes, to which was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (185 mg, 0.97 mmol). The mixture was stirred for 3 hours at room temperature, and then diluted with EtOAc and water. The organic layer was washed with 1N HCl, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The product was vacuum dried to yield the 2-chloro-N-methoxy-N-methyl-6-trifluoromethyl-nicotinamide (220 mg, 92%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C[N:8](C)[CH:9]=[O:10].[O:12]=[C:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:14][CH2:15][CH2:16][CH2:17]C(O)=O>O1CCCC1>[O:12]=[C:13]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:14][CH2:15][CH2:16][CH2:17][C:9]([NH2:8])=[O:10]
Reactant: O=C(O)CCCCC(=O)c1ccccc1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: NC(=O)CCCCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
Oxalyl chloride (0.508 ml) and N,N-dimethylformamide (catalytic amount) were added to a solution of 6-oxo-6-phenylhexanoic acid (1.00 g) in tetrahydrofuran (15 ml) at room temperature, which was stirred at room temperature for 1 hour and concentrated. The residue was dissolved in ethyl acetate (25 ml) and added dropwise to a stirred mixture of 25% aqueous ammonia (20 ml) and ethyl acetate (25 ml) at 0° C. After stirring at room temperature for 2 hours water (200 ml) was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to obtain 6-oxo-6-phenylhexanamide (885 mg, yield 89%) as colorless crystals. m.p. 113-114° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([OH:15])=[O:14].O/[N:17]=[C:18](/[C:20]1[CH:34]=[CH:33][C:23]([CH2:24][N:25]2[CH2:28][CH:27]([C:29]([O:31][CH3:32])=[O:30])[CH2:26]2)=[CH:22][CH:21]=1)\[NH2:19].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15]/[N:17]=[C:18](/[C:20]1[CH:34]=[CH:33][C:23]([CH2:24][N:25]2[CH2:28][CH:27]([C:29]([O:31][CH3:32])=[O:30])[CH2:26]2)=[CH:22][CH:21]=1)\[NH2:19])=[O:14]
Reactant: Nc1c(C(=O)O)cnn1-c1ccccc1
Reactant: COC(=O)C1CN(Cc2ccc(/C(N)=N/O)cc2)C1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COC(=O)C1CN(Cc2ccc(/C(N)=N/OC(=O)c3cnn(-c4ccccc4)c3N)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
A mixture of 5-amino-1-phenyl-1H-pyrazole-4-carboxylic acid (90 mg, 0.441 mmol), (Z)-methyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate (116 mg, 0.441 mmol), EDC (84 mg, 0.441 mmol) and HOBT (67.5 mg, 0.441 mmol) in DMF (1 mL) was stirred at RT for 1 hr. At this time, Et3N (0.061 mL, 0.441 mmol) was added and stirring was continued at RT for 3 days. The mixture was then heated to 50° C. for 10 minutes. The reaction mixture was partitioned between EtOAc (30 mL) and saturated sodium bicarbonate solution (30 mL). The organic layer was washed with saturated sodium bicarbonate solution (30 mL), water (30 mL) and brine (30 mL). After drying (MgSO4) and filtration, the organic layer was concentrated to afford (Z)-methyl 1-(4-(N′-(5-amino-1-phenyl-1H-pyrazole-4-carbonyloxy)carbamimidoyl)benzyl)azetidine-3-carboxylate (103 mg, 0.230 mmol) as a white solid. HPLC retention time=1.05 minutes (PHENOMENEX® Luna 4.6×30 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.1% TFA over a 2 minute gradient. MS:(M+H)=449.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[CH:6]=[CH:7][CH:8]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28](O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([O:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COc1cccc(CCc2ccccc2O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cccc(CCc2ccccc2OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 46.1 %

Procedure:
Following a procedure similar to that described in Example 36(a), 456 mg of 2-[2-(3-methoxyphenyl)ethyl]phenol (prepared as described in Preparation 20), 600 mg of 1-t-butoxycarbonyl-4-hydroxypiperidine and 865 mg of triphenylphosphine were reacted with 575 mg of diethyl azodicarboxylate in 30 ml of methylene chloride. The reaction mixture was worked up as described in Example 6(a), and the crude product thus obtained was purified by column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 379 mg (yield 46%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([CH2:25][NH2:26])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>O1CCCC1>[C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:30])[CH3:31])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[CH:16][C:15]([CH2:25][NH:26][S:34]([CH3:33])(=[O:36])=[O:35])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(CN)ccc2c1=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(CNS(C)(=O)=O)ccc2c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.3 %

Procedure:
To a solution of crude tert-butyl[6-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.16 g) (Example 285) in tetrahydrofuran (2 mL) was added methanesulfonyl chloride (0.028 mL, 0.36 mmol) and triethylamine (0.050 mL, 0.36 mmol), and the mixture was stirred at room temperature for 4 h. The reaction mixture was washed with water (4 mL) and concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1 (v/v)) to give tert-butyl(2-isobutyl-6-{[(methylsulfonyl)amino]methyl}-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.13 g, 84%) as a pale yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:68]=[CH:67][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([C:62]([F:65])([F:64])[F:63])[C:57]=2[F:66])=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:68]=[CH:67][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([C:62]([F:65])([F:63])[F:64])[C:57]=2[F:66])[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)c1ccc(CNCCc2cccc(C(F)(F)F)c2F)cc1
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(CN(CCc2cccc(C(F)(F)F)c2F)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 75.2 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 3 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 106 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[2-(2-fluoro-3-trifluoromethyl-phenyl)-ethyl]-amine in 2 ml DMF were added. After stirring for 4 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:6) to give 112 mg light yellow solid (73%). MS (ISP) 497.4 (M+H)+.
Reaction SMILES: Br[C:2]1[S:18][C:5]2=[N:6][C:7]([CH3:17])=[CH:8][C:9]([NH:10][S:11]([CH:14]3[CH2:16][CH2:15]3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1.C([O-])([O-])=O.[K+].[K+].[NH:33]1[CH:37]=[C:36](B(O)O)[CH:35]=[N:34]1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][C:7]1[N:6]=[C:5]2[S:18][C:2]([C:36]3[CH:37]=[N:33][NH:34][CH:35]=3)=[C:3]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)[C:4]2=[C:9]([NH:10][S:11]([CH:14]2[CH2:16][CH2:15]2)(=[O:13])=[O:12])[CH:8]=1
Reactant: OB(O)c1cn[nH]c1
Reactant: COc1cccc(-c2c(Br)sc3nc(C)cc(NS(=O)(=O)C4CC4)c23)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(-c2c(-c3cn[nH]c3)sc3nc(C)cc(NS(=O)(=O)C4CC4)c23)c1
Temperature: 130 °C

Procedure:
To a suspension of N-{2-bromo-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-yl}cyclopropanesulfonamide (Example 95) (58 mg, 0.128 mmol), K2CO3 (57 mg, 0.412 mmol) and 1H-pyrazol-4-ylboronic acid (30 mg, 0.268 mmol) in 1,4-dioxane (1 mL) and water (0.4 mL), was added tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol). The reaction mixture was heated at 130° C. in a microwave reactor for 1 h and was then directly loaded onto a silica column, eluting with a gradient of 0-75% of ethyl acetate in cyclohexane and further purified by MDAP (acidic then basic conditions) to give the desired product and a white solid thought to be a salt of the desired product. The solid material was subsequently dissolved in DCM (1 mL) and treated with acetic acid (ca. 0.5 mL). The solvent was then removed to give a residue which was combined with the initially obtained product and the mixture further purified on silica, eluting with a gradient of 0-75% ethyl acetate in cyclohexane, to give the title compound (18 mg). LCMS (A) m/z: 441 [M+1]+, Rt 1.08 min (acidic).
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].[CH2:7]([N:14]1[CH2:18][CH2:17][C:16](=O)[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH4+].[Cl-]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:7]([N:14]1[CH2:18][CH2:17][C:16](=[CH2:1])[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C1CCN(Cc2ccccc2)C1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=C1CCN(Cc2ccccc2)C1
Reaction time: 0.5 h

Procedure:
Potassium tert-butylate (2.1 g, 18.8 mmol, dissolved in 20 ml abs. THF) was added to a suspension of methyltriphenylphosphonium bromide (7.5 g, 21 mmol) in dry THF (20 ml) under argon at 0° C. within 30 min. The yellow reaction mixture was stirred for 30 min at 0° C. before 1-benzyl-pyrrolidin-3-one (2.46 g, 15 mmol) dissolved in abs. THF (20 ml) was added dropwise within 30 min at 0° C. The mixture obtained was left for 30 min at 0° C., brought to RT within 1 h and stirred for a further 15 h. For working up, the mixture was added to sat. NH4Cl solution (50 ml) and then extracted with EtOAc (3×20 ml). The desired product P was converted into the corresponding hydrochloride by extraction with 2 N HCl (20 ml). The organic phase was washed with water (3×20 ml) and the combined aqueous phases were basified with K2CO3. The desired product P was obtained in the form of a layer of oil and was separated off by reextraction with EtOAc (3×20 ml). After drying of the combined organic phases over Na2SO4 and removal of the solvent, the desired product P was present in a sufficiently pure form (2.17 g, 83%).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[N:25]1[CH:30]=[C:29](B(O)O)[CH:28]=[N:27][CH:26]=1>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:29]4[CH:30]=[N:25][CH:26]=[N:27][CH:28]=4)=[C:4]([CH:9]=3)[C:3]([OH:2])=[O:24])[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: OB(O)c1cncnc1
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1cncnc1
Yield: 15.2 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with and pyrimidine-5-boronic acid (available from Combi-Blocks Inc.; 50 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2-pyrimidin-5-yl-benzoic acid (13 mg, 16%). 1H NMR (300 MHz, DMSO-d6) δ 13.42 (br s, 1H), 9.21 (s, 1H), 8.86 (s, 2H), 8.58 (s, 1H), 8.50 (s, 1H), 8.29-8.37 (m, 2H), 8.10 (d, J=8.5 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.67 (d, J=7.9 Hz, 1H).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([OH:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:7]([CH3:55])[CH:6]=[CH:5][C:4]1=[O:56])[CH3:2].[H][H]>C(OCC)(=O)C.[Rh]>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([OH:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:7]([CH3:55])[CH2:6][CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: CCC1C=C(C)C(O)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C=CC1=O)C(C)CC2OC
Reactant: [H][H]
Agent: [Rh]
Solvent: CCOC(C)=O
Product: CCC1C=C(C)C(O)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)CCC1=O)C(C)CC2OC

Procedure:
A solution of 17-ethyl-1,20-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-14,18-diene-2,3,10,16-tetraone in ethyl acetate is hydrogenated at 40 p.s.i. in a shaker apparatus using hydrogen and 5% rhodium on carbon catalyst until one molar equivalent of hydrogen is consumed. Filtration to remove catalyst and evaporation to remove solvent affords the product reduced at the Δ14,15 -position.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.O[CH2:10][CH:11]([CH2:13]O)O.C1C([N+]([O-])=O)=CC=C(O)C=1.[OH-].[Na+]>S(=O)(=O)(O)O>[N:1]1[C:2]2[C:7](=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)[CH:13]=[CH:11][CH:10]=1
Reactant: OCC(O)CO
Reactant: Nc1ccc(O)cc1
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])c1ccc(O)cc1
Agent: [Na+]
Product: Oc1ccc2ncccc2c1
Temperature: 70 °C
Yield: 42 %

Procedure:
A mixture of 4-aminophenol (44.7 g, 0.41 mol), ferrous sulfate (14 g, 0.05 mol), glycerol (120 mL, 1.65 mol), p-nitrophenol (33.3 g, 0.24 mol), and concentrated sulfuric acid (20 mL) was heated gently to 70° C. Then a second portion of concentrated sulfuric acid (25 mL) was added dropwise to the reaction mixture and the mixture was stirred at reflux for 8 hours. After cooling down to room temperature, the reaction mixture was basified to pH=5.5 with 15% aqueous sodium hydroxide solution in an ice bath. The resulting precipitate was filtered, dried and 25 g of quinolin-6-ol was obtained as a yellow solid (42% yield).
Reaction SMILES: [C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=O)[CH2:11][C@H:10]2[C:15]([NH:17][CH2:18][CH:19]([OH:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:16])=[O:8])=[CH:3][CH:2]=1.[CH3:33][N:34]([CH3:36])[NH2:35]>>[C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:2]=[CH:3][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:35][N:34]([CH3:36])[CH3:33])[CH2:11][C@H:10]2[C:15]([NH:17][CH2:18][CH:19]([OH:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:16])=[O:8])=[CH:5][CH:6]=1
Reactant: O=C1C[C@@H](C(=O)NCC(O)c2ccccc2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: CN(C)N
Product: CN(C)N=C1C[C@@H](C(=O)NCC(O)c2ccccc2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 56 %

Procedure:
Following the general method as outlined in Example 17, starting from (2S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-oxo-2-pyrrolidinecarboxamide and N,N-dimethylhydrazine, the resultant crude reaction mixture was purified by column chromatography using DCM/MeOH (30:1) to collect the desired product, e.g. (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(dimethylhydrazono)-N-[(2RS)-2-hydroxy-2-phenylethyl]-2-pyrrolidinecarboxamide as a mixture of two isomers as a light yellow oil in 56% yield (90.2% purity by HPLC).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1.[CH:16]1([C:19](=[S:21])[NH2:20])[CH2:18][CH2:17]1>>[CH3:1][O:2][C:3]([C:4]1[N:20]=[C:19]([CH:16]2[CH2:18][CH2:17]2)[S:21][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)=[O:15]
Reactant: NC(=S)C1CC1
Reactant: COC(=O)C(=O)C(Cl)c1ccc(C)cc1
Product: COC(=O)c1nc(C2CC2)sc1-c1ccc(C)cc1

Procedure:
prepared by reaction of 3-chloro-2-oxo-3-p-tolyl-propionic acid methyl ester with cyclopropanecarbothioic acid amide. LC-MS: tR=1.04 min; [M+H]+=274.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([N:17]3[CH:21]=NC=N3)[C:14]3=[C:22]([CH3:26])[N:23]=[C:24]([CH3:25])[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([O:37][CH3:38])[CH:36]=1)CN>>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([O:37][CH3:38])[CH:36]=1)[CH2:21][NH:17][C:15]1[C:14]2=[C:22]([CH3:26])[N:23]=[C:24]([CH3:25])[N:13]2[N:12]=[C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:16]=1
Reactant: COc1cc(CN)cc(OC)c1
Reactant: COc1ccc(-c2nc(-n3cncn3)c3c(C)nc(C)n3n2)cc1OC
Product: COc1cc(CNc2nc(-c3ccc(OC)c(OC)c3)nn3c(C)nc(C)c23)cc(OC)c1

Procedure:
Prepared analogously to Example 1 from Example 37A (80 mg, 0.23 mmol) and 3,5-dimethoxybenzylamine (396 mg, 2.32 mmol). Purification is carried out by flash chromatography (eluent dichloromethane/methanol 80:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][O:8][C:9]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[C:10]=2[NH2:11])=[CH:5][CH:4]=1>C(O)(=O)C.C(O)C.[Fe]>[NH2:11][C:10]1[C:9]([O:8][CH2:7][C:6]2[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:16]
Reactant: COc1ccc(COc2cccc([N+](=O)[O-])c2N)cc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc(COc2cccc(N)c2N)cc1
Yield: 84.2 %

Procedure:
To a solution of 2-(4-methoxybenzyloxy)-6-nitroaniline (3 g) in acetic acid (6 ml) and ethanol (24 ml) was added iron (3.06 g), and the mixture was refluxed for 3 hours. Insoluble material was filtered off, and the filtrate was concentrated in vacuo. To the residue was added saturated sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was pulverized with diethyl ether to give 2-amino-3-(4-methoxybenzyloxy)aniline (2.25 g).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:29])[CH2:15][NH:16][CH2:17][C:18]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1)[CH3:3].C(N(CC)CC)C.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(OCC)(=O)C>[CH3:3][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:11])[CH3:12])[C:5]=1[NH:13][C:14](=[O:29])[CH2:15][N:16]([CH2:17][C:18]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1)[C:37](=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH3:1]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CNCC1(c2ccccc2)CCCC1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CN(CC1(c2ccccc2)CCCC1)C(=O)c1ccccc1
Reaction time: 96 h

Procedure:
To a solution of 0.48 g of the product of Example 6 and excess triethylamine in ethyl acetate at room temperature was added 0.16 mL benzoyl chloride all at once. The reaction mixture was allowed to sit 4 days at room temperature. The solution was then diluted with ethyl acetate and washed with dilute HCl, NaHCO3, and NaCl solutions, dried over MgSO4, filtered, and concentrated to an oil which was crystallized from diethyl ether. The white solid was collected by filtration. 0.48 g (61%). NMR (CDCl3) δ 1.12 (12H, d), δ 1.6-2.15 (8H, m), δ 2.99 (2H, m), δ 3.27 (2H, bs), δ 3.80 (2H, bs), δ 6.20 (1H, bs) δ 7.04-7.42 (13H, m). IR (KBr) 3269, 2963, 2869, 1696, 1600, 1520, 1461, 1254, 1222, 703 cm-1.