Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:17])=[N:8][C:9](Cl)=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[Cl:12])=[O:5])[CH3:2].CO.O.[CH2:21]([NH:23][NH2:24])[CH3:22]>C(N(CC)CC)C>[Cl:12][C:11]1[C:10]([N+:13]([O-:15])=[O:14])=[C:9]([NH:24][NH:23][CH2:21][CH3:22])[N:8]=[C:7]([CH3:17])[C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1Cl
Reactant: CCNN
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: CCNNc1nc(C)c(C(=O)OCC)c(Cl)c1[N+](=O)[O-]

Procedure:
27.9 g. of 4,6-Dichloro-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester (0.2 mol.) are dissolved in about 100 ml. of methanol and 20 ml. of water. 15 g. of triethylamine are added and at 25°-30° 4.5 g. ethyl hydrazine are dropped in with stirring. After the addition is complete, stirring is continued for 1 additional hour. On cooling, 4-chloro-6-(1-ethyl)hydrazino-2-methyl-5-nitropyridine-3-carboxylic acid, ethyl ester precipitates, yield 19.7 g. (65%) m.p. 117°-120°.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@H:13]2[O:25][CH2:26][CH3:27])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.O1CCOCC1>C(O)C>[ClH:1].[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]2[O:25][CH2:26][CH3:27])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCO[C@@H]1CNCC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 231.7 %

Procedure:
tert-Butyl cis(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-ethoxypiperidine-1-carboxylate obtained in Example (125a) (4.31 g, 10.8 mmol) was dissolved in ethanol (25 mL). A 4 N hydrochloric acid/dioxane solution (25 mL, 100 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure to obtain 4.22 g of the title compound as a pale pink amorphous solid (quant.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]1[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]([C:21]([O:23][CH3:24])=[O:22])#[C:16][C:17]([O:19][CH3:20])=[O:18]>>[CH3:20][O:19][C:17]([C:16]1[C:12]2([CH3:13])[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:9]([CH3:14])([C:15]=1[C:21]([O:23][CH3:24])=[O:22])[CH:10]=[CH:11]2)=[O:18]
Reactant: Cc1ccc(C)n1C(=O)OC(C)(C)C
Reactant: COC(=O)C#CC(=O)OC
Product: COC(=O)C1=C(C(=O)OC)C2(C)C=CC1(C)N2C(=O)OC(C)(C)C
Yield: 50 %

Procedure:
A mixture of crude 2,5-dimethyl-pyrrole-1-carboxylic acid tert-butyl ester (prepared according to a literature (Haiser, H.-P.; et al. J. Org. Chem. 1984 49(22) 4203-4209); 500 mg) and dimethyl acetylenedicarboxylate (0.5 mL, ca 4 eq) was stirred at 120° C. under argon for 2 h. Purification by silica gel flash chromatography on SiO2 eluting with EtOAc/heptane (gradient from 1:20 to 1:2 ratio) gave compound 780A (166 mg, 50% yield) as a colorless liquid. HPLC: 90% at 3.67 min (retention time) (YMC S5 ODS-A column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[C:8]([O:38][CH3:39])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:37])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:30]([C@H:32]3[CH2:36][CH2:35][NH:34][CH2:33]3)=[O:31])[CH2:26][CH2:25]2)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:45]=O>CO.O.[Pd]>[C:1]([C:5]1[CH:6]=[C:7]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[C:8]([O:38][CH3:39])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:37])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:30]([C@H:32]3[CH2:36][CH2:35][N:34]([CH3:45])[CH2:33]3)=[O:31])[CH2:26][CH2:25]2)=[O:13])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=O
Reactant: COc1c(NC(=O)c2cc3cccc(CN4CCN(C(=O)[C@H]5CCNC5)CC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: [Pd]
Solvent: CO
Solvent: O
Product: COc1c(NC(=O)c2cc3cccc(CN4CCN(C(=O)[C@H]5CCN(C)C5)CC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
100 mg of (S)-1-methyl-7-[4-(pyrrolidine-3-carbonyl)-piperazin-1-ylmethyl]-1H-indole-2-carboxylic acid (5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-amide are dissolved in 10 ml of methanol, combined with 14 μl of a 37% solution of formaldehyde in water and 20 mg of palladium on charcoal (10%) and hydrogenated for 4 hours at 4 bar. The catalyst is filtered off, the solvents are eliminated in vacuo and the residue is chromatographed on aluminium oxide (dichloromethane/methanol 95:5 to 80:20).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([OH:11])=O)[CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH2:17][CH2:16]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([N:18]2[C:19]3[C:15](=[CH:14][C:13]([F:12])=[CH:21][CH:20]=3)[CH2:16][CH2:17]2)=[O:11])[CH:3]=1
Reactant: Fc1ccc2c(c1)CCN2
Reactant: Cc1cc(Cl)cc(C(=O)O)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Cl)cc(C(=O)N2CCc3cc(F)ccc32)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.10 g (0.58 mmol) 4-chloro-6-methyl-pyridine-2-carboxylic acid and 80 mg (0.58 mmol) 5-fluoro-2,3-dihydro-1H-indole in 0.17 mL (1.2 mmol) TEA and 2.0 mL DMF were combined with 0.19 g (0.58 mmol) TBTU and stirred overnight at RT. The reaction mixture was diluted with water, the precipitated solid was suction filtered and dried.
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]([N:7]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3S[C:25]4[CH:27]=[CH:28][C:29]([Br:31])=[CH:30][C:24]=4[CH:23]=3)=[O:21])=[CH:15][N:14]=2)[CH2:8]1)=[O:6])[CH3:3].C(OC([N:37]1CC[C@H:39](NC2C=CC(N)=CN=2)[CH2:38]1)=O)C.BrC1C=C2C(=CC=1)N(CC)C(C(O)=O)=C2>>[ClH:1].[CH2:2]([O:4][C:5]([N:7]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[N:37]([CH2:38][CH3:39])[C:25]4[C:24]([CH:23]=3)=[CH:30][C:29]([Br:31])=[CH:28][CH:27]=4)=[O:21])=[CH:15][N:14]=2)[CH2:8]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)N1CC[C@H](Nc2ccc(N)cn2)C1
Reactant: CCOC(=O)N1CC[C@H](Nc2ccc(NC(=O)c3cc4cc(Br)ccc4s3)cn2)C1
Agent: CCn1c(C(=O)O)cc2cc(Br)ccc21
Agent: Cl
Product: CCOC(=O)N1CC[C@H](Nc2ccc(NC(=O)c3cc4cc(Br)ccc4n3CC)cn2)C1

Procedure:
With a method similar to that used for the preparation of (S)-3-{5-[(5-bromo-benzo[b]thiophene-2-carbonyl)-amino]-pyridin-2-ylamino}-pyrrolidine-1-carboxylic acid ethyl ester hydrochloride, (S)-3-{5-[(5-bromo-1-ethyl-1,4-indole-2-carbonyl)-amino]-pyridin-2-ylamino}-pyrrolidine-1-carboxylic acid ethyl ester hydrochloride was prepared from (S)-3-(5-amino-pyridin-2-ylamino)-pyrrolidine-1-carboxylic acid ethyl ester and 5-bromo-1-ethyl-indole-2-carboxylic acid. LCMS for C23H26BrN5O3 calcd. (m/e) 499, observed 500 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=[O:18])[C:8]3[C:13]4[CH2:14][CH2:15][CH2:16][CH2:17][C:12]=4[S:11][C:9]=3[O:10][C:4]=2[CH:3]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1C=CC=CC=1>[F:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=[O:18])[C:8]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[S:11][C:9]=3[O:10][C:4]=2[CH:3]=1
Reactant: O=C1Nc2ccc(F)cc2Oc2sc3c(c21)CCCC3
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Product: O=C1Nc2ccc(F)cc2Oc2sc3ccccc3c21

Procedure:
In the same manner as in Example 77 and using 8-fluoro-1,2,3,4-tetrahydro-[1]benzothieno[2,3-b][1,5]benzoxazepin-12(11H)-one, dichlorodicyano-p-benzoquinone and benzene, 8-fluoro-[1]benzothieno[2,3-b][1,5]benzoxazepin-12(11H)-one is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[CH3:2].C(O)C>[Pd].O1CCCC1>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[CH3:2]
Reactant: CCOC(=O)CC1=C(c2cccc(OC)c2)CCCC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CC1CCCCC1c1cccc(OC)c1
Reaction time: 18 h
Yield: 89.4 %

Procedure:
Combine [2-(3-methoxy-phenyl)-cyclohex-1-enyl]-acetic acid ethyl ester (9.91 g, 36.0 mmol), 10% Pd on carbon (2.06 g, 14.4 mmol), and ethanol (90 mL) and tetrahydrofuran (5 mL), degas, and add 50 psi H2 at room temperature. After 18 hours, filter off the Pd catalyst over celite eluting with ethyl acetate. Concentrate and flash chromatograph with 0% to 20% ethyl acetate/hexanes to yield the titled compound (8.89 g, 89%) as a clear oil. TLC Rf=0.42 in 6:1 hexanes:ethyl acetate. 1H NMR (CDCl3):1H NMR (CDCl3): 7.21 (t, 1H, J=8.1 Hz), 6.78 (d, 2H, J=7.5 Hz), 6.72 (s, 1H), 3.98 (q, 2H, J=7.0 Hz), 3.80 (m, 3H), 2.89 (m, 1H), 2.51 (m, 1H), 2.31 (m, 1H), 1.97 (m, 1H), 1.88 (m, 1H), 1.72 (m, 4H), 1.44 (m, 3H), 1.16 (t, 3H, J=6.6 Hz).
Reaction SMILES: [CH2:1]([O:4][NH:5][CH:6]1[CH2:11][NH:10][C@@H:9]([C:12]([NH2:14])=[O:13])[C:8]([CH:15]2[CH2:17][CH2:16]2)=[CH:7]1)[CH:2]=[CH2:3].[CH2:18]([O:21]N1C(=O)N2C[C@H]1C(C)=C[C@H]2C(N)=O)C=C>>[CH2:1]([O:4][N:5]1[C:18](=[O:21])[N:10]2[CH2:11][C@H:6]1[CH:7]=[C:8]([CH:15]1[CH2:16][CH2:17]1)[C@H:9]2[C:12]([NH2:14])=[O:13])[CH:2]=[CH2:3]
Reactant: C=CCON1C(=O)N2C[C@H]1C(C)=C[C@H]2C(N)=O
Reactant: C=CCONC1C=C(C2CC2)[C@H](C(N)=O)NC1
Product: C=CCON1C(=O)N2C[C@H]1C=C(C1CC1)[C@H]2C(N)=O

Procedure:
The title compound was prepared from (R)-5-(allyloxyamino)-3-cyclopropyl-1,2,5,6-tetrahydropyridine-2-carboxamide (Intermediate 244, 0.316 g, 1.33 mmol) following the procedure described for Intermediate 16. The desired product was obtained as a colorless oil (0.261 g, 74%).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)(C(C)(C)C)(C)C.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH:20]=[O:21].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:16][C:17]1[CH:18]=[C:19]([CH:20]([OH:21])[CH:9]([C:10]2[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=2)[OH:8])[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccncc1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1ccncc1)C(O)c1ccc(Cl)c(Cl)c1
Temperature: -40 °C
Reaction time: 0.75 h
Yield: 79.3 %

Procedure:
4-(tert-Butyldimethylsilyloxymethyl)-pyridine (T. F. Gallagher et al, Bioorganic and Medicinal Chemistry; 1997, 5, 49) (67 g, 0.3 mol) was dissolved in THF (250 ml) and cooled to −40° C. The solution was treated with a 2M solution of lithuim diusopropylamide in THF (200 ml, 0.4 mol) and stirred for 45 minutes maintaining a temperature of −40 to −20° C., before the dropwise addition of 3,4-dichlorobenzaldehyde (55.13 g, 0.32 mol) in THF (250 ml). The mixture was allowed to warm to room temperature then stirred for a further 18 hours. After re-cooling to 0° C. the reaction was quenched with saturated ammonium chloride solution (500 ml), and the resulting two phase mixture separated. The aqueous phase was extracted with ethyl acetate and the combined organics concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution, water and brine, dried (MgSO4) and concentrated under reduced pressure to an oil (129 g). The oil was dissolved in THF (300 ml) and a 1M solution of tetrabutylammonium fluoride (360 ml, 0.36 mol) added dropwise. The solution was stirred at room temperature for 45 minutes, then concentrated to an oil under reduced pressure. The oil was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution, water and brine, dried (MgSO4) and evaporated under reduced pressure. The oil was triturated with hexane and the resulting solid filtered and washed with hexane to afford the title compound (67.58 g 79%) as a tan solid; MS(AP+) m/e 284/286/288 [M+H]+.
Reaction SMILES: N.[CH:2]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:15](=[O:28])[CH2:16][C@H:17]([NH:21]C(=O)C(F)(F)F)[C:18]([OH:20])=[O:19]>CO>[NH2:21][C@@H:17]([CH2:16][C:15]([C:3]1[CH:4]=[CH:5][C:6]2[O:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[C:10]=2[CH:2]=1)=[O:28])[C:18]([OH:20])=[O:19]
Reactant: O=C(C[C@H](NC(=O)C(F)(F)F)C(=O)O)c1ccc2oc3ccccc3c2c1
Agent: N
Solvent: CO
Product: N[C@@H](CC(=O)c1ccc2oc3ccccc3c2c1)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.5 %

Procedure:
Methanol (40 mL) was saturated with gaseous ammonia at room temperature. To this solution was added (S)-4-dibenzofuran-2-yl-4-oxo-2-(2,2,2-trifluoroacetylamino)-butyric acid (0.5 g, 0.0013 mol) obtained above in Example 1. The reaction mixture was stirred at room temperature for 24 hours and then concentrated to dryness in vacuo. The residue was recrystallized from boiling methanol to yield the title product as a white solid (0.37 g, quant); mp 182-187° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH2:22][C:23]([CH3:25])=[CH2:24])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17](N)=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10].[OH-:26].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH2:22][C:23]([CH3:25])=[CH2:24])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([OH:26])=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10]
Reactant: C=C(C)COc1ccc(Br)cc1CN(CC)c1ccc(C(N)=O)nn1
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C=C(C)COc1ccc(Br)cc1CN(CC)c1ccc(C(=O)O)nn1
Reaction time: 16 h
Yield: 87 %

Procedure:
6-[N-(5-Bromo-2-(2-methylprop-2-en-1-yloxy)benzyl)-N-ethylamino]pyridazine-3-carboxamide (430 mg, 1.09 mmol) was dissolved in THF/methanol (30 ml, 1:1) and sodium hydroxide solution added (2.9 ml, 2M, 5.8 mmol). The mixture was heated at reflux for 72 hours, allowed to cool and evaporated. The residue was dissolved in water (25 ml) and acetic acid added to pH-4. The solution was stirred for 16 hours and then the resulting colourless precipitate collected by filtration, washed with water and dried under vacuum to give the title compound as a colourless powder (387 mg, 87%).
Reaction SMILES: [OH:1][C:2]1([CH2:12][CH:13]=O)[CH2:11][CH2:10][CH2:9][C:4]2([O:8][CH2:7][CH2:6][O:5]2)[CH2:3]1.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]([NH2:24])[CH3:23])=[CH:18][CH:17]=1>>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]([NH:24][CH2:13][CH2:12][C:2]2([OH:1])[CH2:11][CH2:10][CH2:9][C:4]3([O:5][CH2:6][CH2:7][O:8]3)[CH2:3]2)[CH3:23])=[CH:18][CH:17]=1
Reactant: O=CCC1(O)CCCC2(C1)OCCO2
Reactant: C[C@H](N)c1ccc(Br)cc1
Product: C[C@H](NCCC1(O)CCCC2(C1)OCCO2)c1ccc(Br)cc1
Yield: 68 %

Procedure:
The title compound is prepared from (7-hydroxy-1,4-dioxa-spiro[4.5]dec-7-yl)-acetaldehyde and (S)-1-(4-bromo-phenyl)-ethylamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 68% of theory; LC (method 1): tR=3.83 min; Mass spectrum (ESI+): m/z=384/386 (Br) [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16](O)[CH:15]=[CH:14][C:3]=1[C:4]([O:6]CC1C=CC=CC=1)=[O:5].FC1C=C([N+:26]([O-:28])=[O:27])C=CC=1C.[O-][Mn](=O)(=O)=O.[K+]>>[F:1][C:2]1[CH:17]=[C:16]([N+:26]([O-:28])=[O:27])[CH:15]=[CH:14][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1ccc([N+](=O)[O-])cc1F
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1F
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: O=C(O)c1ccc([N+](=O)[O-])cc1F

Procedure:
This was prepared as described above in Example 33 except that benzyl 2-fluoro-4-hydroxybenzoate (prepared from 2-fluoro-4-nitrotoluene by oxidation with KMnO4 to give 2-fluoro-4-nitrobenzoic acid, followed by catalytic reduction to give 4-amino-2-fluorobenzoic acid, followed by diazotization/hydrolysis to give 4-hydroxy-2-fluorobenzoic acid which was converted to benzyl 2-fluoro-4-hydroxybenzoate in a fashion analogous to that described in Example 23) was used as starting material in place of benzyl 2-chloro-4-hydroxybenzoate.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:39]=[CH:38][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]([OH:37])=O)=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:40][CH2:41][CH2:42][CH2:43][CH2:44][OH:45]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:39]=[CH:38][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]([NH:40][CH2:41][CH2:42][CH2:43][CH2:44][OH:45])=[O:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCC(=O)O)cc2)cc1
Reactant: NCCCCO
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCC(=O)NCCCCO)cc2)cc1

Procedure:
The product from Example 104A and 4-amino-1-butanol were processed as described in Example 147 to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ8.95 (s, 1 H), 7.74 (t, 1 H), 7.26 (m, 6 H), 7.19 (m, 3 H), 7.04 (t, 1 H), 6.96 (m, 2 H), 6.86 (m, 4 H), 4.03 (d, 4 H), 3.35 (m, 2 H), 3.03 (m, 2 H), 2.91 (s, 3 H), 2.78 (t, 2 H), 2.39 (s, 3 H), 2.34 (m, 2 H), 1.37 (m, 4 H); MS (ESI+) m/z 616 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[OH:10].CCCCCC.C([OH:31])(C)C.CO.C(Cl)(Cl)Cl>C(OCC)(=O)C>[Cl:21][C:6]1[CH:5]=[N+:4]([O-:31])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[OH:10]
Reactant: CC(C)O
Reactant: COc1ccc([C@@H](O)Cc2c(Cl)cncc2Cl)cc1OC
Solvent: CCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc([C@@H](O)Cc2c(Cl)c[n+]([O-])cc2Cl)cc1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 41 %

Procedure:
(S)-2-(3,5-dichloropyridin-4-yl)-1-(3,4-dimethoxyphenyl)ethanol (4 g, 12 mmol) was dissolved in ethyl acetate, and m-CPB acid was added to the solution. The mixture was stirred at RT for 5 hours. The formed solid was collected by filtration, washed with ethyl acetate and dried under vacuum to give 1.72 g of (−) (41% yield). Chiral HPLC analysis Rt=22.16 min; eluent:hexane:isopropanol=6:4; [α]D20=+68.91 (c=0.253, Methanol/CHCl3 1:1); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.15 (s, 2H), 6.99 (m, 1H), 6.79-6.88 (m, 2H), 5.03 (dd, J=8.50, 5.32 Hz, 1H), 3.75-3.98 (m, 6H), 3.42 (dd, J=13.57, 8.56 Hz, 1H), 3.19 (dd, J=13.51, 5.32 Hz, 1H), 2.06-2.15 (m, 1H); MS/ESI+ [MH]+: 344.19
Reaction SMILES: [C:1]([C@H:4]1[C@H:9]2[CH2:10][C@H:6]([CH:7]=[CH:8]2)[C@H:5]1[NH:11][C:12]1[C:17]([Cl:18])=[CH:16][N:15]=[C:14]2[NH:19][C:20]([C:22]3[CH:23]=[C:24]([CH:40]=[CH:41][CH:42]=3)[C:25]([N:27]3[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]3)=[O:26])=[N:21][C:13]=12)(=[O:3])[NH2:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:18][C:17]1[C:12]([NH:11][C@@H:5]2[C@@H:6]3[CH2:10][C@@H:9]([CH:8]=[CH:7]3)[C@@H:4]2[C:1]([NH2:2])=[O:3])=[C:13]2[N:21]=[C:20]([C:22]3[CH:42]=[CH:41][CH:40]=[C:24]([C:25]([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:26])[CH:23]=3)[NH:19][C:14]2=[N:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(-c3nc4c(N[C@H]5[C@@H](C(N)=O)[C@@H]6C=C[C@H]5C6)c(Cl)cnc4[nH]3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4cccc(C(=O)N5CCNCC5)c4)nc23)[C@H]2C=C[C@@H]1C2
Temperature: 25 °C
Reaction time: 6 h
Yield: 56.5 %

Procedure:
tert-butyl 4-(3-(7-((1R,2R,3S,4S)-3-carbamoylbicyclo[2.2.1]hept-5-en-2-ylamino)-6-chloro-3H-imidazo[4,5-b]pyridine-2-yl)benzoyl)piperazine-1-carboxylate (18) (160 mg, 0.27 mmol) was dissolved in 2 mL of 20% TFA solution in DCM. The reaction mixture was stirred at room temperature for 6 h. After 6 h, DCM was evaporated and the residue was triturated with ether to obtain the desired product (75 mg, 56% yield) as a light brown hygroscopic solid.
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH2:20][CH2:21][CH3:22])[NH:10][C:9](=[O:23])[C:7]=2[N:8]=1.C[O-].[Na+].[C:27](O)(=[O:29])C>CO>[CH3:27][O:29][C:3]1[N:4]=[N:5][C:6]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH2:20][CH2:21][CH3:22])[NH:10][C:9](=[O:23])[C:7]=2[N:8]=1
Reactant: CC(=O)O
Reactant: CCCOc1ccccc1-c1nc2nnc(SC)nc2c(=O)[nH]1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCOc1ccccc1-c1nc2nnc(OC)nc2c(=O)[nH]1

Procedure:
A stirred mixture of 5,6-dihydro-3-methylthio-5-oxo-7-(2-propoxyphenyl)pyrimido[5,4-e][1,2,4]triazine (0.80 g) and sodium methoxide (prepared from sodium, 0.28 g and methanol) in methanol (50 ml) was heated under reflux for 1.5 hours. The cooled reaction mixture was neutralised by the addition of glacial acetic acid (0.7 ml) to afford a yellow precipitate (0.63 g) which was recrystallised from methanol to afford the title compound, 0.47 g, m.p. 221-°222° C.
Reaction SMILES: [C:1]([C:3]1[CH:7]=[CH:6][O:5][CH:4]=1)#[N:2].C[O-].[Na+].[C:11](O)(=[O:13])C>CO>[O:5]1[CH:6]=[CH:7][C:3]([C:1](=[NH:2])[O:13][CH3:11])=[CH:4]1
Reactant: CC(=O)O
Reactant: N#Cc1ccoc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1ccoc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-cyanofuran (3.76 g, 40.1 mmol) was dissolved in methanol (30 ml), and sodium methoxide (0.1 g, 1.9 mmol) was added. The mixture was stirred at room temperature for 18 hours. After the reaction was completed, acetic acid (0.14 g, 2.3 mmol) was added to neutralize the reaction solution, and the solution was concentrated under reduced pressure. Diethyl ether was added to the concentrated residue, and insolubles were removed by filtration. The filtrate was concentrated under reduced pressure to give the crude product of methyl 3-furancarboximidate as a pale yellow oil.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:9]([OH:11])=O)=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[NH2:12][C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([CH3:20])=[CH:15][C:14]=1[NH2:21]>[OH-].[NH4+]>[NH2:12][C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([CH3:20])=[CH:15][C:14]=1[NH:21][C:9]([C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:8][NH:7][N:6]=1)=[O:11]
Reactant: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Reactant: Cc1cc(N)c(N)cc1C
Agent: [NH4+]
Agent: [OH-]
Product: Cc1cc(N)c(NC(=O)c2n[nH]cc2[N+](=O)[O-])cc1C
Temperature: 70 °C

Procedure:
Method B Polyphosphoric acid (500 g) was added to a 1 L flask equipped with an overhead stirrer and heated to 70° C. under nitrogen. A blended mixture of 4-nitro-3-pyrazole carboxylic acid (50 g) and 1,2-diamino-4,5-dimethylbenzene (43.4 g) was added and the mixture was heated to 180° C. After 1 hour at this temperature the reaction mixture was cooled to 130° C. and poured into ice water (2.5 kg). This mixture was stirred with an overhead stirrer and then treated with aqueous ammonium hydroxide (350 mL, 30%) until the pH was 2.1. After stirring for a further 15 minutes the mixture was filtered and the filtered solid was washed three times with water (200 mL) then dried under vacuum to give 4-nitro-1H-pyrazole-3-carboxylic acid (2-amino-4,5-dimethylphenyl)amide as a brown solid. (b) 4-Nitro-1H-pyrazole-3-carboxylic acid (2-amino-4-ethyl-5-methylphenyl)amide
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[OH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:12][C:11]=1[C:26](=[O:28])[CH3:27]>C(O)(C)C>[CH3:6][N:4]([CH3:5])/[CH:3]=[CH:27]/[C:26]([C:11]1[CH:12]=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][CH:17]=2)[CH:14]=[CH:15][C:10]=1[OH:9])=[O:28]
Reactant: CC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)ccc1O
Reactant: COC(OC)N(C)C
Solvent: CC(C)O
Product: CN(C)/C=C/C(=O)c1cc(-c2ccc(C(F)(F)F)cc2)ccc1O
Temperature: 45 °C
Reaction time: 1 h

Procedure:
N,N-Dimethylformamide dimethyl acetal (0.76 mL, 5.701 mmol) was added to a solution of 1-[4-hydroxy-4′-(trifluoromethyl)biphenyl-3-yl]ethanone (Preparation 37, 795 mg, 2.84 mmol) in isopropyl alcohol (4.7 mL). The reaction mixture was heated for 18 hours at 45° C. under an atmosphere of nitrogen. After 1 hour, crystallization was observed therefore the stirring was stopped. After 18 hours at 45° C., a yellow precipitate had formed. The reaction mixture was allowed to cool, the yellow precipitate was collected by filtration and washed with cold isopropyl alcohol to afford the title compound as fine yellow needle crystals (669 mg, 70%).