Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][N:4]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[C:3]1=[O:19].[O:20]=[C:21]1[N:30]([CH:31]2[CH2:36][CH2:35][N:34]([C:37](Cl)=[O:38])[CH2:33][CH2:32]2)[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22]1>>[CH:16]1([CH2:15][N:4]2[CH2:5][C@@H:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:7][CH2:8][C@H:2]([NH:1][C:37]([N:34]3[CH2:35][CH2:36][CH:31]([N:30]4[CH2:29][C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[NH:22][C:21]4=[O:20])[CH2:32][CH2:33]3)=[O:38])[C:3]2=[O:19])[CH2:18][CH2:17]1
Reactant: N[C@H]1CC[C@H](c2ccccc2)CN(CC2CC2)C1=O
Reactant: O=C(Cl)N1CCC(N2Cc3ccccc3NC2=O)CC1
Product: O=C(N[C@H]1CC[C@H](c2ccccc2)CN(CC2CC2)C1=O)N1CCC(N2Cc3ccccc3NC2=O)CC1

Procedure:
The title compound was prepared with (3S,6R)-3-amino-1-(cyclopropylmethyl)-6-phenylazepan-2-one and 4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1-carbonyl chloride using a similar procedure to Example 4. MS 516 (M+1).
Reaction SMILES: C(O[C@@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)C.[N-:30]=[N+:31]=[N-:32].[Na+]>CO.O>[N:30]([C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[N+:31]=[N-:32]
Reactant: CC(=O)O[C@@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: [N-]=[N+]=N[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 35.2 %

Procedure:
To a solution of 3.0 g of (3S,4S)-4-acetoxy-3-tritylamino-2-oxoazetidine in 50 ml of methanol is added a solution of 0.65 g of sodium azide in 5 ml of water under ice-cooling, followed by stirring for two hours at 40°-50° C. The solvent is distilled off under reduced pressure. To the residue is added ethyl acetate, and the organic layer is separated, which is washed with water and concentrated. The residue is purified on a silica-gel column (ethyl acetate:n-hexane=1:1) to give 1.01 g of (3S,4R)-4-azido-3-tritylamino-2-oxoazetidine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[C:12]([O:17][CH2:18][CH3:19])(=[O:16])/[CH:13]=[CH:14]/[CH3:15].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CCCC)CCCC)CCC>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:18]([O:17][C:12](=[O:16])[CH:13]=[C:14]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2)[CH3:15])[CH3:19]
Reactant: Brc1ccc2cnccc2c1
Reactant: C/C=C/C(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCCCN(CCCC)CCCC
Solvent: CN(C)C=O
Product: CCOC(=O)C=C(C)c1ccc2cnccc2c1
Temperature: 140 °C
Reaction time: 3.5 h

Procedure:
A stirred solution of 6-bromoisoquinoline (1.75 g) in dry dimethylformamide (15 mL), under argon, was treated with ethyl crotonate (1.7 mL) then with palladium (II) acetate (0.14 g), then with tri-(o-tolyl)phosphine (0.3 g) and then with tributylamine (8 mL). The suspension was stirred, under argon, at 140° C. for 3.5 hours, then stood at room temperature for 3 days and then evaporated. The residual dark oil was treated with ethyl acetate (50 mL) and the resulting solution was washed with water (30 mL) then twice with brine (25 mL), then dried over magnesium sulfate and then evaporated. The residue was subjected to flash chromatography on silica eluting initially with cyclohexane and then with a mixture of cyclohexane and ethyl acetate (9:1, v/v) to give the title compound as an amber coloured oil which solidified on cooling. MS (ES)=242 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:17][C:16](=O)[C:15]3[C:10](=[CH:11][C:12]([O:21][CH3:22])=[C:13]([O:19][CH3:20])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:25])=O>CN(C=O)C>[Cl:25][C:16]1[C:15]2[C:10](=[CH:11][C:12]([O:21][CH3:22])=[C:13]([O:19][CH3:20])[CH:14]=2)[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:17]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2nc(-c3ccc(Cl)cc3)[nH]c(=O)c2cc1OC
Solvent: CN(C)C=O
Product: COc1cc2nc(-c3ccc(Cl)cc3)nc(Cl)c2cc1OC
Reaction time: 0.17 h
Yield: 86 %

Procedure:
A mixture of 2-(4-chlorophenyl)-6,7-dimethoxyquinazolin-4(3H)-one (200 mg), thionyl chloride (10 mL) and DMF (0.3 mL) was refluxed for 2 h. Solvents were removed under vacuum. The mixture was poured into ice cold water and stirred for 10 min. The solution was basified with ammonia and stirred for 5 min. The solution was extracted with chloroform (3×100 mL) and the combined chloroform layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent to give the product as an yellow color solid (180 mg, 86%), mp 204-206° C. 1H NMR (400 MHz, DMSO-d6): δ 8.47 (2H, d, J=8.4 Hz), 7.66 (2H, d, J=8.4 Hz), 7.52 (1H, s), 7.44 (1H, s), 4.08 (3H, s), 4.05 (3H, s).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([F:21])=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=2)[C:10](=O)[CH2:9][CH:8]1[CH3:23])=[O:6])([CH3:3])[CH3:2].Cl.[NH2:25][OH:26].C([O-])(=O)C.[Na+].O>C(O)C>[CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([F:21])=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=2)[C:10](=[N:25][OH:26])[CH2:9][CH:8]1[CH3:23])=[O:6])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)OC(=O)N1c2cc(C(F)(F)F)c(F)cc2C(=O)CC1C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)OC(=O)N1c2cc(C(F)(F)F)c(F)cc2C(=NO)CC1C
Reaction time: 0.17 h
Yield: 96.1 %

Procedure:
A stirred solution of 6-fluoro-2-methyl-4-oxo-7-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester (940 mg, 2.8 mmol), hydroxylamine hydrochloride (215 mg, 3.1 mmol), and sodium acetate (254 mg, 3.1 mmol) in ethanol (20 mL) was heated at reflux for 3 h. Water (25 mL) was added, and the volatiles were removed in vacuo. Ethyl acetate (100 mL) was added, and the mixture was stirred vigorously for 10 min. The aqueous phase was separated and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound as a white foam (937 mg, ca. 100%): 1H NMR (CDCl3) δ 1.1 (d, 3H), 1.28 (d, 3H), 1.34 (d, 3H), 2.73 (dd, 1H), 3.09 (d, 1H), 5.0-5.1 (m, 2H), 7.68 (d, 1H), 7.88 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[C:4](=[O:8])[N:5]([CH3:7])[N:6]=1.[CH3:16][O-:17].[Na+]>C(COC)OC.CO.C(OCC)(=O)C>[CH3:16][O:17][C:2]1[N:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[C:4](=[O:8])[N:5]([CH3:7])[N:6]=1
Reactant: Cc1ccccc1-n1c(Cl)nn(C)c1=O
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1nn(C)c(=O)n1-c1ccccc1C
Yield: 95 %

Procedure:
8.25 g of the title compound of Step B was dissolved in 80 mL of 1:1 dimethoxyethane/methanol under N2. 14.0 mL of sodium methoxide (30% solution in methanol) was added and the solution was heated at reflux for 3 h. The mixture was allowed to cool, diluted with ethyl acetate, washed with water, and then washed with saturated aqueous NaCl. The combined organic extracts were dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (50-70% ethyl acetate/hexanes as eluent) and triturated with 50% diethyl ether/hexanes to afford 6.7 g of the title compound of Step C (95% pure). 1H NMR (CDCl3): δ 7.35-7.27 (m,3H), 7.18 (d,1H), 3.94 (s,3H), 3.46 (s,3H), 2.22 (s,3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2=[N:14][N:15]([C:17]3[N:25]=[CH:24][CH:23]=[CH:22][C:18]=3[C:19]([O-])=[O:20])[CH:16]=[C:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[NH2:27][CH:28]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH:29]([OH:33])[C:30]([NH2:32])=[O:31]>CN(C)C=O>[NH2:32][C:30](=[O:31])[CH:29]([OH:33])[CH:28]([NH:27][C:19](=[O:20])[C:18]1[CH:22]=[CH:23][CH:24]=[N:25][C:17]=1[N:15]1[CH:16]=[C:10]2[CH2:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:13][CH2:12][C:11]2=[N:14]1)[CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Reactant: O=C([O-])c1cccnc1-n1cc2c(n1)CCN(Cc1ccccc1)C2
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1cc2c(n1)CCN(Cc1ccccc1)C2
Yield: 129.9 %

Procedure:
Coupling of sodium 2-(5-benzyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)nicotinate (106 mg, 0.297 mmol) and 3-amino-2-hydroxy-4-phenylbutanamide (80 mg, 0.412 mmol) in N,N-dimethylformamide (10 mL) according to example 1.3 and work-up gave 197 mg of the title compound a amorphous solid; ESI-MS [M+H]+: 511.2.
Reaction SMILES: CC(C[Al]CC(C)C)C.C([O:12][C:13](=O)[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24])C.O>C1COCC1>[CH3:22][C:19]1[CH:20]=[CH:21][C:16]([CH:15]=[CH:14][CH2:13][OH:12])=[C:17]([N+:23]([O-:25])=[O:24])[CH:18]=1
Reactant: CCOC(=O)C=Cc1ccc(C)cc1[N+](=O)[O-]
Agent: CC(C)C[Al]CC(C)C
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C=CCO)c([N+](=O)[O-])c1
Temperature: -35 °C
Reaction time: 0.25 h

Procedure:
Dibal-H (0.0255 mol) was added at −35° C. to a mixture of 3-(4-methyl-2-nitro-phenyl)-acrylic acid ethyl ester (0.0085 mol) in THF (80 ml) under N2 flow. The mixture was stirred at −35° C. for 15 minutes. H2O (20 ml) was added drop wise at −35° C. under N2 flow. The mixture was half-evaporated. CH2Cl2 was added. The mixture was filtered over celite. Celite was washed with CH2Cl2. The filtrate was washed with H2O. The organic layer was separated, dried (over MgSO4), filtered and the solvent was evaporated. Yield: 2 g of 3-(4-Methyl-2-nitro-phenyl)-prop-2-en-1-ol (e-2) (100%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.[CH3:13][N:14](C)C=O>>[C:13]([C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1)#[N:14]
Reactant: CN(C)C=O
Reactant: CC1(C)COc2ccc(Br)cc21
Product: CC1(C)COc2ccc(C#N)cc21

Procedure:
5-Bromo-2,3-dihydro-3,3-dimethylbenzofuran (15 g, 0.066 mole) was heated under reflux with cuprous cyanide (7.2 g. 0.08 mole) in dimethyl formamide (15 ml) as in Example 2. Work up yielded, after recrystallisation from petroleum ether (bp 60°-80° C.) with charcoaling, 5.7 g of product, mp 72°-75° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15]S(C3C=CC(C)=CC=3)(=O)=O)=[C:11]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.ClC1C=C(N2C(=O)[C:47](OS(C3C=CC(C)=CC=3)(=O)=O)=[C:46]([C:61]3C=CC(S(C)(=O)=O)=CC=3)[CH:45]=N2)C=CC=1.N>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:45][CH:46]([CH3:61])[CH3:47])=[C:11]([C:26]3[CH:27]=[CH:28][C:29]([S:32]([CH3:35])(=[O:33])=[O:34])=[CH:30][CH:31]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3cccc(Cl)c3)c2=O)cc1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)cc3)c2=O)cc1
Agent: N
Solvent: O
Product: CC(C)COc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O

Procedure:
The title compound was prepared according to the method of Example 335, substituting 2-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-4-tosyloxy-3(2H)-pyridazinone (prepared as an intermediate in Example 375) in place of 2-(3-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-4-tosyloxy-3(2H)-pyridazinone (yield: 0.486 g, 100%). mp 121-128° C. 1H NMR (300 MHz, DMSO d6) δ 0.78 (d, J=7 Hz, 6H), 1.84 (m, 1H), 3.30 (s, 3H), 4.20 (d, J=6 Hz, 2H), 7.37 (m, 2H), 7.66 (m, 2H), 7.92 (m, 2H), 8.07 (m, 2H), 8.19 (s, 1H). MS (DCI/NH3) m/z 417 (M+H)+, 434 (M+NH4)+. Anal. calc. for C21H21FN2O4S.0.50 H2O: C, 59.28; H, 5.21; N, 6.58. Found: C, 59.49; H, 4.97; N, 6.34.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:31])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10](I)[C:3]=12.[OH:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CN(C=O)C.C(O)C.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:31])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[CH2:33][OH:32])[C:3]=12
Reactant: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(I)c2c(N)ncnc21
Reactant: OCc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(-c2ccccc2CO)c2c(N)ncnc21
Temperature: 80 °C
Reaction time: 12 h
Yield: 31.2 %

Procedure:
To a solution of Example 57c (0.300 g, 0.568 mmoles) in DMF (3 ml), ethanol (1.5 ml) and water (1.5 ml), 2-Hydroxymethylphenylboronic acid (0.173 g, 1.137 mmoles) and sodium carbonate (0.301 g, 2.844 mmoles) were added and the system is degassed for 30 min. Tetrakistriphenylphosphine Palladium (0.129 g, 0.112 mmoles) was added under nitrogen atmosphere and heated to 80° C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as off-white solid (0.090 g, 31% yield). MP: 185-189° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 8.09(s,1H), 8.04(dd, J=7.9,1.4 Hz, 1H), 7.84(m,1H), 7.66-7.35(m,10H), 7.17(dt, J=10.8,1.4 Hz, 1H), 7.04(m,1H), 6.01(q, J=6.7 Hz, 1H), 5.13(t, J=5.7 Hz, 1H), 4.54(m,2H), 1.87(d, J=7.1 Hz, 3H). Mass: 508.16(M++1).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10](C)[CH3:11])[C:5]=1[NH:13][C:14](=[O:30])[CH2:15][NH:16][CH:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)C.CO[C:33]1[CH:41]=[CH:40][C:39](OC)=[CH:38][C:34]=1[C:35](Cl)=[O:36].COC1C=CC=CC=1C(Cl)=O>>[CH2:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:2][CH3:1])[C:5]=1[NH:13][C:14](=[O:30])[CH2:15][N:16]([CH:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:35](=[O:36])[C:34]1[CH:33]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH3:11]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CNC(c1ccccc1)c1ccccc1
Reactant: COc1ccc(OC)c(C(=O)Cl)c1
Agent: COc1ccccc1C(=O)Cl
Product: CCc1cccc(CC)c1NC(=O)CN(C(=O)c1ccccc1)C(c1ccccc1)c1ccccc1

Procedure:
When in the procedure of Example 94 an appropriate amount of the product of Example 75 was substituted for the product of Example 4 and an appropriate amount of 2,5-dimethoxybenzoyl chloride was substituted for 2-methoxybenzoyl chloride and the general procedure of Example 94 was followed the title compound was obtained. Total yield, 0.35 g (51%).
Reaction SMILES: Br[C:2]1[C:3]([C:14]([F:17])([F:16])[F:15])=[N:4][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[C:6]=1[CH3:7].[Li]CCCC.CN([CH:26]=[O:27])C>C1COCC1>[CH3:7][C:6]1[N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[N:4]=[C:3]([C:14]([F:17])([F:16])[F:15])[C:2]=1[CH:26]=[O:27]
Reactant: CN(C)C=O
Reactant: Cc1c(Br)c(C(F)(F)F)nn1C1CCCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1c(C=O)c(C(F)(F)F)nn1C1CCCCO1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-pyrazole (1.17 g, 3.74 mmol) in THF (13 mL) was cooled to −78° C., then n-BuLi (1.6 M in hexane, 3.7 mL, 6.0 mmol) was added dropwise. The reaction was held at −78° C. for 10 minutes, then DMF (580 μL, 7.5 mmol) was added and the reaction was stirred at −78° C. for 1.5 h. The reaction was quenched at −78° C. by addition of sat'd NH4Cl and ether, the phases were separated and the aqueous phase was washed with ether. The combined organic phase was washed with water, then sat'd NaCl, dried over MgSO4 and reduced to dryness in vacuo to give the crude product, which was used without further purification (1.04 g). 1H NMR (400 MHz, CDCl3): δ 10.0 (s, 1H), 5.41 (m, 1H), 4.00 (m, 1H), 3.66 (m, 1H), 2.68 (s, 3H), 2.41 (m, 1H), 2.17 (m, 1H), 2.00 (m, 1H), 1.69 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[C:17]1[CH:18]=[N:19][C:20](S(C)=O)=[N:21][CH:22]=1)[CH:14]=[CH:13][O:12]2.[NH2:26][NH2:27]>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[C:17]1[CH:18]=[N:19][C:20]([NH:26][NH2:27])=[N:21][CH:22]=1)[CH:14]=[CH:13][O:12]2
Reactant: NN
Reactant: CS(=O)c1ncc(-c2c(-c3ccc(F)cc3F)nc3occn23)cn1
Solvent: CC#N
Product: NNc1ncc(-c2c(-c3ccc(F)cc3F)nc3occn23)cn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A round bottomed flask was charged with 6-(2,4-difluorophenyl)-5-(2-(methylsulfinyl)pyrimidin-5-yl)imidazo[2,1-b]oxazole (0.16 g, 0.44 mmol), ACN (20 mL) and hydrazine (0.10 mL, 3.2 mmol). The reaction mixture was stirred at about 80° C. for about 2 h. The reaction mixture was concentrated to dryness and then triturated with Et2O to give the title compound (0.13 g, 89%). LC/MS (Table 1, Method o) Rt=2.56 min; MS m/z 329.1.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12]C)[CH:8]=2)[N:3]=1.[C:14]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[C:19]([F:26])[CH:18]=1)([OH:16])=[O:15]>>[F:26][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1)[C:14]([OH:16])=[O:15]
Reactant: O=C(O)c1ccc(B(O)O)c(F)c1
Reactant: COc1ccc2nc(Cl)ncc2c1
Product: O=C(O)c1ccc(-c2ncc3cc(O)ccc3n2)c(F)c1
Yield: 38 %

Procedure:
Prepared according to Scheme 6, B conditions starting from Intermediate 8 and 4-carboxy-2-fluorophenylboronic acid, where the crude product of step 2 was purified by prep-HPLC (0.1% TFA as additive) after which most of the CH3CN was removed under reduced pressure and the remaining solvent was removed by lyophilization to give the product (40 mg, yield 38%). 1H NMR (MeOD 400 MHz): δ 9.42 (s, 1H), 8.13 (t, J=7.6 Hz, 1H), 8.02-7.95 (m, 2H), 7.86 (d, J=11.2 Hz, 1H), 7.62 (dd, J=9.2, 2.4 Hz, 1H), 7.32 (d, J=2.4 Hz, 1H). MS (ESI): m/z 284.9 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.O[CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].C1(N=C=NC2CCCCC2)CCCCC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([O:16][CH2:19][CH2:20][NH:21][C:22]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:28])=[O:15])[CH:7]=[CH:6]2
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc2cc([C@H](C)C(=O)OCCNC(=O)OC(C)(C)C)ccc2c1
Yield: 82.4 %

Procedure:
A solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 7.60 g, 33.0 mmol), tert-butyl N-(2-hydroxyethyl)carbamate (5.30 g, 32.9 mmol), N,N-dimethylaminopyridine (DMAP, 0.35 g, 2.86 mmol) and 1,3-dicyclohexylcarbodiimide (6.80 g, 33.0 mmol) in CH2Cl2 (200 mL) was stirred at ambient temperature overnight. The byproduct, dicyclohexyl urea, was removed by filtration. The filtrate was concentrated, dissolved in EtOAc (50 mL) and then cooled in a dry-ice bath to precipitate the remaining dicyclohexyl urea and then filtered. The filtrate was concentrated, dissolved in CH2Cl2 (15 mL) and hexane (200 mL) and then stirred until the product precipitated. The solid was dried under vacuum to give the title compound (10.12 g, 82% yield). Mp 82-84° C. 1H NMR (300 MHz, CDCl3) δ 7.72-7.65 (m, 3H), 7.42-7.38 (m, 1H), 7.16-7.11 (m, 2H), 5.05 (br, 1H), 4.13 (t, J=5.3 Hz, 2H), 3.91 (s, 3H), 3.87 (q, J=7.1 Hz, 1H), 3.30 (br. q, 2H), 1.58 (d, J=7.1 Hz, 3H), 1.45 (s, 9H). 13C NMR (75 MHz, CDCl3) δ 174.4, 157.6, 155.6, 135.4, 133.6, 129.2, 128.8, 127.1, 126.0, 125.8, 119.0, 105.5, 79.3, 63.7, 55.2, 45.2, 39.5, 28.2, 18.3. Mass spectrum (API-TIS) m/z 374 (MH)+. Anal. calcd. for C21H27NO5: C, 67.54; H, 7.29; N, 3.75. Found: C, 67.43; H, 7.16; N, 3.66.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)=[CH:22][CH:21]=1
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Reactant: COc1ccc(S)cc1
Product: COc1ccc(SCCCCOc2ccc3c(c2)CCC(=O)N3)cc1

Procedure:
Prepared analogous to Example 1 from 6-(4-bromo-butoxy)-3,4-dihydro-carbostyril (m.p. 142°-147° C.) and 4-methoxy-thiophenol.
Reaction SMILES: [CH:1]1([CH:4]([NH:7][C:8]2[C:13]([N+:14]([O-])=O)=[C:12]([C:17]3[CH:22]=[C:21](F)[C:20]([O:24][CH3:25])=[CH:19][C:18]=3[CH3:26])[CH:11]=[CH:10][N:9]=2)[CH2:5][CH3:6])[CH2:3][CH2:2]1.[Cl:27][Sn]Cl>>[Cl:27][C:21]1[C:20]([O:24][CH3:25])=[CH:19][C:18]([CH3:26])=[C:17]([C:12]2[CH:11]=[CH:10][N:9]=[C:8]([NH:7][CH:4]([CH:1]3[CH2:3][CH2:2]3)[CH2:5][CH3:6])[C:13]=2[NH2:14])[CH:22]=1
Reactant: CCC(Nc1nccc(-c2cc(F)c(OC)cc2C)c1[N+](=O)[O-])C1CC1
Reactant: Cl[Sn]Cl
Product: CCC(Nc1nccc(-c2cc(Cl)c(OC)cc2C)c1N)C1CC1
Yield: 102 %

Procedure:
(1-Cyclopropyl-propyl)-[4-(5-fluoro-4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl]-amine (0.13 g, 0.34 mmol) and SnCl2 (0.19 g, 1.0 mmol) were treated substantially as described in Part D of Example 74a to yield 0.12 g (96%) of 4-(5-chloro-4-methoxy-2-methyl-phenyl)-N2-(1-cyclopropyl-propyl)-pyridine-2,3-diamine.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:24][S:25][CH2:26][C@H:27]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:3](=[O:23])[NH:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17].C(O)(C(F)(F)F)=O.C(Cl)Cl>>[NH2:1][C@@H:2]([CH2:24][S:25][CH2:26][C@H:27]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:3](=[O:23])[NH:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: CCCCCCCCCCCCOC[C@H](CSC[C@H](N)C(=O)NCCOCCOCCOCCC(=O)OC(C)(C)C)OCCCCCCCCCCCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCCCCCOC[C@H](CSC[C@H](N)C(=O)NCCOCCOCCOCCC(=O)O)OCCCCCCCCCCCC

Procedure:
A solution of (15R,19R)-tert-butyl 15-amino-19-(dodecyloxy)-14-oxo-4,7,10,21-tetraoxa-17-thia-13-azatritriacontan-1-oate in 1:1 TFA/DCM (0.1 M) was stirred at 25° C. for 1 hour. The reaction mixture was concentrated en vaccuo. The crude mixture was purified by reverse phase high performance liquid chromatography (HPLC) with C4 column eluting with a gradient of 40-100% MeCN/10 mM NH4OAc (95:5) in 10 mM NH4OAc (pH 9) to give the title product as a white solid after lyophilizing. 1H NMR (DMSO-d6): δ 8.04 (t, 1H), 7.36 (s, 1H), 5.04 (d, 2H), 3.58 (t, 2H), 3.19-3.50 (m, 20H), 2.77 (dd, 2H), 2.59 (dd, 2H), 2.40 (t, 2H), 1.43-1.48 (m, 4H), 1.21-1.28 (m, 36H), 0.85 (t, 6H). LRMS [M+H]=735.6.