Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)(=[O:20])=[O:19])[C:15](I)=[CH:16][C:9]=23)[CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:36]=2)O1.C(=O)(O)[O-].[Na+].O>CN(C)C=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>[F:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)(=[O:20])=[O:19])[C:15]([C:35]4[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:36]=4)=[CH:16][C:9]=23)[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=S(=O)(c1ccccc1)n1c(I)cc2c(-c3cccc(F)n3)ccnc21
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: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(-c4cccc(F)n4)ccnc3n2S(=O)(=O)c2ccccc2)CC1

Procedure:
A mixture of Example 309C (4 g, 7.09 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (2.63 g, 8.51 mmol), Pd(Ph3P)4 (0.410 g, 0.355 mmol), and an aqueous solution (15 mL) of sodium bicarbonate (1.788 g, 21.28 mmol) in dimethylformamide (50 mL) was stirred at 80° C. overnight. The reaction mixture was cooled, treated with water, and extracted with ethyl acetate (three times). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was triturated with a mixture of ethyl acetate and petroleum ether (1:1). The solids were filtered and vacuum oven-dried to give the title compound. MS (ESI+) m/z 535 (M+H)+.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][O:10][C:11]2[CH:12]=[N:13][N:14]([C:18]3[CH:19]=[CH:20][C:21]4[C:30]5[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25][C:24]=5[N:23]([CH3:38])[C:22]=4[N:39]=3)[C:15](=[O:17])[CH:16]=2)=[N:7][CH:8]=1>CO.CCOCC>[ClH:1].[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][O:10][C:11]2[CH:12]=[N:13][N:14]([C:18]3[CH:19]=[CH:20][C:21]4[C:30]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25][C:24]=5[N:23]([CH3:38])[C:22]=4[N:39]=3)[C:15](=[O:17])[CH:16]=2)=[N:7][CH:8]=1
Reactant: Cn1c2c(c3ccc(-n4ncc(OCc5ccc(F)cn5)cc4=O)nc31)CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Cn1c2c(c3ccc(-n4ncc(OCc5ccc(F)cn5)cc4=O)nc31)CCNCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 73 %

Procedure:
1.25 M HCl in MeOH (4.0 mL) was added to tert-butyl 2-(4-((5-fluoropyridin-2-yl)methoxy)-6-oxopyridazin-1(6H)-yl)-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate (55 mg, 0.11 mmol), and the resulting solution was stirred under N2 at ambient temperature for 18 h. Additional 1.25 M HCl in MeOH (2.0 mL) was added, and the resulting solution was stirred at ambient temperature for 24 h. The resulting solution was diluted with Et2O (30 mL), and the resulting solids were collected by filtration to provide the title compound (35 mg, 73%) as an off-white powder: mp 226-230° C. dec; 1H NMR (500 MHz, DMSO-d6) δ 9.12 (s, 2H), 8.64 (d, J=3.0 Hz, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.98 (d, J=2.5 Hz, 1H), 7.85 (ddd, J=11.5, 8.5, 2.5 Hz, 1H), 7.72-7.69 (m, 1H), 7.15 (d, J=8.5 Hz, 1H), 6.51 (d, J=3.0 Hz, 1H), 5.30 (s, 2H), 3.71 (s, 3H), 3.45-3.39 (m, 2H), 3.38-3.31 (m, 2H), 3.30-3.28 (m, 2H), 3.15-3.14 (m, 2H); ESI MS m/z 421 [M+H]+; HPLC (Method A) 98.8% (AUC), tR=11.6 min.
Reaction SMILES: Br[C:2]1[C:3]([NH:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([O:17][CH3:18])[CH2:13][CH2:12]2)=[N:4][C:5]([NH2:9])=[N:6][C:7]=1[CH3:8].[C:19]([O:23][CH2:24][CH3:25])(=[O:22])[CH:20]=[CH2:21]>C(N(CC)CC)C.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[NH2:9][C:5]1[N:4]=[C:3]([NH:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([O:17][CH3:18])[CH2:13][CH2:12]2)[C:2](/[CH:21]=[CH:20]/[C:19]([O:23][CH2:24][CH3:25])=[O:22])=[C:7]([CH3:8])[N:6]=1
Reactant: CO[C@H]1CC[C@H](Nc2nc(N)nc(C)c2Br)CC1
Reactant: C=CC(=O)OCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1c(C)nc(N)nc1N[C@H]1CC[C@H](OC)CC1
Temperature: 130 °C

Procedure:
In a sealed tube a solution of 5-bromo-N4-(trans-4-methoxycyclohexyl)-6-methylpyrimidine-2,4-diamine (811 mg, 2.57 mmol) and ethyl acrylate (559 uL, 5.15 mmol) in triethylamine (25 mL) was bubbled with argon for ˜10 minutes. Tetrakis(triphenylphosphin)-palladium (0) (297 mg, 0.257 mmol) was added, the vial was sealed, and the reaction was heated to 130° C. overnight. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (450 mL), washed with water, 0.1 N hydrochloric acid, brine, dried (MgSO4), filtered and concentrated. The crude product was purified by flash chromatography eluting with chloroform/methanol (0-10%) to afford (E)-ethyl 3-(2-amino-4-(trans-4-methoxycyclohexylamino)-6-methylpyrimidin-5-yl)acrylate (674 mg, 78%).
Reaction SMILES: O[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[CH3:15][C:16]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=1O>CO>[CH:12]([C:9]1[CH:10]=[CH:11][C:6]([CH:2]2[C:19]3[CH:18]=[CH:17][C:16]([CH3:15])=[C:21]([CH3:22])[C:20]=3[O:5][C:3]2=[O:4])=[CH:7][CH:8]=1)([CH3:14])[CH3:13]
Reactant: Cc1cccc(O)c1C
Reactant: CC(C)c1ccc(C(O)C(=O)O)cc1
Solvent: CO
Product: Cc1ccc2c(c1C)OC(=O)C2c1ccc(C(C)C)cc1
Yield: 44 %

Procedure:
Using hydroxy(4-isopropylphenyl)acetic acid synthesized in Reference Example 1 and 2,3-dimethylphenol, the title compound was synthesized in the same manner as in Reference Example 2. Yield 44%. Melting point: 58-60° C. (methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4](Cl)=[O:5].[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[CH2:21][N:22]([CH:26]1[C:35]2[N:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH2:29][CH2:28][CH2:27]1)[CH2:23][CH2:24][NH2:25]>C1COCC1.ClCCl.CCN(CC)CC>[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[CH2:21][N:22]([CH:26]1[C:35]2[N:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH2:29][CH2:28][CH2:27]1)[CH2:23][CH2:24][NH:25][C:4](=[O:5])[C:3]1[C:2]([Cl:1])=[CH:10][N:9]=[CH:8][C:7]=1[Cl:11]
Reactant: O=C(Cl)c1c(Cl)cncc1Cl
Reactant: NCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21)c1c(Cl)cncc1Cl
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 35.6 %

Procedure:
To a suspension of 3,5-dichloro-isonicotinoyl chloride (0.34 mmol) in THF (3 mL) at 0° C. was added a solution of N1-(1H-benzoimidazol-2-ylmethyl)-N1-(5,6,7,8-tetrahydro-quinolin-8-yl)-ethane-1,2-diamine (0.100 g, 0.312 mmol) in dichloromethane (3 mL), THF (1 mL) and Et3N (0.087 mL). After stirring at 0° C. for 5 min., the mixture was warmed to room temperature and stirred for 2.5 h. The solvents were evaporated and the residue was taken into saturated aqueous NaHCO3 (30 mL). The mixture was extracted with chloroform (3×20 mL). The extracts were dried over Na2SO4 and concentrated. Purification of the crude material by column chromatography on silica gel (200:1:1 CH2Cl2—CH3OH—NH4OH) provided 55 mg (44%) of COMPOUND 152 as a pale yellow solid 1H NMR (CDCl3) δ 1.55-1.70 (m, 1H), 1.78-1.85 (m, 1H), 2.03 (m, 1H), 2.29 (m, 1H), 2.66-2.82 (m, 3H), 3.20 (d, J=13.5 Hz, 1H), 3.39 (m, 1H), 3.55 (m, 1H), 3.90 (dd, J=10.8 Hz, 5.7 Hz, 1H), 4.12 (d, J=16.7 Hz, 1H), 4.30 (d, J=16.7 Hz, 1H), 6.99 (dd, 1H, J=7.8 Hz, 4.8 Hz, 1H), 7.15-7.21 (m, 2H), 7.27 (m, 1H), 7.41 (d, J=7.8 Hz, 1H), 7.54 (d, J=4.2 Hz, 1H), 7.63 (d, J=4.2 Hz, 1H), 8.40 (m, 1H), 8.56 (s, 2 H); 13C NMR (CDCl3) δ 21.79, 23.08, 29.32, 38.68, 48.54, 49.25, 61.63, 119.35, 122.24, 122.69, 123.19, 129.64, 133.76, 135.76, 138.70, 143.50, 144.39, 146.46, 148.03, 154.85, 157.38, 162.22; ES-MS m/z 496 (M+H). Anal. Calcd. for C25H24N6Cl2O.0.9CH2Cl2: C, 54.40; H, 4.55; N, 14.70; Cl, 23.56. Found: C, 54.64; H, 4.53; N, 14.62 Cl, 23.41.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][CH:13]1[CH2:15][CH:14]1[C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]#[N:26])[CH:23]=2)[N:18]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[N:17]=1.CCN(CC)CC>C(Cl)Cl.O>[CH:12]([CH:13]1[CH2:15][CH:14]1[C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]#[N:26])[CH:23]=2)[N:18]([S:27]([C:30]2[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=2)(=[O:28])=[O:29])[N:17]=1)=[O:11]
Reactant: Cc1ccc(S(=O)(=O)n2nc(C3CC3CO)c3cc(C#N)ccc32)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(S(=O)(=O)n2nc(C3CC3C=O)c3cc(C#N)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 106.9 %

Procedure:
Anhydrous DMSO (0.20 mL, 2.8 mmol) was added dropwise to a solution of oxalyl chloride (0.21 mL, 2.4 mmol) in 20 mL anhydrous CH2Cl2 under N2 at −78° C. and stirred for 30 min. A solution of 3-(2-hydroxymethyl-cyclopropyl)-1-(toluene-4-sulfonyl)-1H-indazole-5-carbonitrile (634 mg, 1.63 mmol) in 20 mL anhydrous CH2Cl2 was then added and stirring continued for 40 min. at −78° C. Et3N (1.25 mL, 8.98 mmol) was added and stirring continued for 10 min at −78° C. The reaction was warmed to room temperature and 25 mL water was added. The layers were partitioned, and the aqueous layer was extracted with CH2Cl2. The organic layers were pooled, extracted with brine, and dried over MgSO4, and concentrated in vacuo to give 3-(2-formyl-cyclopropyl)-1-(toluene-4-sulfonyl)-1H-indazole-5-carbonitrile (637 mg, 100%). 1H NMR (500 MHz, CDCl3) 9.54 (1H, d, J=3.66 Hz), 8.20 (1H, d, J=8.85 Hz), 8.05 (1H, s), 7.83 (2H, d, J=8.24 Hz), 7.77 (1H, dd, J=8.85, 1.53 Hz), 7.29 (2H, d, J=8.24 Hz), 2.82 (1H, m), 2.62 (1H, m), 2.39 (3H, s), 1.82 (2H, m).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)=[O:11])[C:4]1[S:5][CH:6]=[CH:7][CH:8]=1.C(O)(=O)C.[Cl:29]N1C(=O)CCC1=O>ClCCl>[Cl:29][C:6]1[S:5][C:4]([C@H:3]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[O:11])[CH2:2][OH:1])=[CH:8][CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(Nc1ccc(-c2ccncc2)cc1)N[C@H](CO)c1cccs1
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(Nc1ccc(-c2ccncc2)cc1)N[C@H](CO)c1ccc(Cl)s1
Yield: 36.3 %

Procedure:
To a solution of 1-[(1R)-2-hydroxy-1-(2-thienyl)ethyl]-3-[4-(4-pyridinyl)phenyl]urea (700 mg) and acetic acid (734 mg) in dichloromethane (10 mL) were added N-chlorosuccinimide (303 mg) and the mixture was refluxed for 3 hours. The mixture was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with chloroform/methanol (9:1) and crystallized from ethanol to afford 1-[(1R)-1-(5-chloro-2-thienyl)-2-hydroxyethyl]-3-[4-(4-pyridinyl)phenyl]urea (280 mg) as a crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=O)=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[F:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][C:29]=1[C:35]([F:38])([F:37])[F:36].C[Al](C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:32][C:31]3[CH:33]=[CH:34][C:28]([F:27])=[C:29]([C:35]([F:38])([F:36])[F:37])[CH:30]=3)=[O:21])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1OC
Agent: C[Al](C)C
Product: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1C(=O)Nc1ccc(F)c(C(F)(F)F)c1
Yield: 22 %

Procedure:
The title compound was prepared according to the procedure described in Example-31, by using methyl 4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (step-2 of Intermediate-15, 0.100 g, 0.26 mmol), 4-floro-3-trifloromethyl aniline (0.070 g, 1.5 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL) to afford 0.030 g of desired product. 1H NMR (DMSO-d6): δ 3.94 (s, 3H), 7.50-7.60 (m, 3H), 7.67-7.72 (m, 2H), 7.77-7.82 (m, 2H), 8.01 (m, 1H), 8.26 (m, 1H), 10.38 (br s, 1H), 12.80 (br s, 1H); MS (m/z): 525.17 [M+H]+.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][C:7]1[C:8](=[O:14])[NH:9][C:10](=[O:13])[NH:11][CH:12]=1>CS(C)=O>[N:1]([CH2:6][C:7]1[C:8](=[O:14])[NH:9][C:10](=[O:13])[NH:11][CH:12]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: O=c1[nH]cc(CCl)c(=O)[nH]1
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NCc1c[nH]c(=O)[nH]c1=O
Reaction time: 2 h
Yield: 98.5 %

Procedure:
Sodium azide (0.6 g, 9.34 mmol) was added to a solution of 5-(chloromethyl)-2,4(1H,3H)-pyrimidinedione (0.3 g, 1.67 mmol) in DMSO (5 ml) under nitrogen at room temperature. The reaction was stirred for 2 h then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give the 5-(azidomethyl)-2,4(1H,3H)-pyrimidinedione (0.275 g, 98%) as a yellow solid.
Reaction SMILES: [C:1]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C1C(=O)N([Br:22])C(=O)C1.C([O-])(=O)C.[NH4+]>CCOCC>[CH2:8]([O:7][C:1](=[O:6])[CH:2]([Br:22])[C:3](=[O:4])[CH3:5])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)CC(=O)OCc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(=O)C(Br)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirring dispersion of benzyl acetoacetate (20 ml, 116 mmol) and NBS (21.64 g, 122 mmol) in Et2O (1000 ml) was added ammonium acetate (0.893 g, 11.58 mmol). The reaction was stirred at RT for 4 hours and then filtered, washed with water (400 ml), brine, dried over MgSO4 and concentrated in vacuo to give the title compound as a yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.37-7.42 (5H, m, 5×ArH), 5.27 (2H, s, ArCH2OR), 4.82 (1H, s, CHBr), 2.42 (3H, s, RCOCH3).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][CH2:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18]COC)=[C:14]([F:22])[CH:13]=1.FC1C(F)=C(CCC)C=CC=1I.OB(O)C1C=CC(OCOC)=C(F)C=1.Cl>[Pd].O.CO>[F:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][CH2:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([F:22])[CH:13]=1
Reactant: CCCc1ccc(-c2ccc(OCOC)c(F)c2)c(F)c1F
Agent: [Pd]
Agent: CCCc1ccc(I)c(F)c1F
Agent: COCOc1ccc(B(O)O)cc1F
Solvent: O
Solvent: CO
Product: CCCc1ccc(-c2ccc(O)c(F)c2)c(F)c1F
Yield: 99.1 %

Procedure:
Solution of 10.0 g (32.2 mmol) of 2,3,3′-trifluoro-4′-methoxymethoxy-4-propylbiphenyl [prepared by cross coupling reaction of 2,3-difluoro-4-propyliodobenzene with dihydroxy(3-fluoro-4-methoxymethoxyphenyl)borane in the presence of a Pd catalyst], 50 ml of methanol, and 10 ml of a concentrated hydrochloric acid was heated to reflux for 3 hours. Water in an amount of 50 ml was added to the reaction liquid and subjected to extraction with 100 ml of diethyl ether. After the organic layer thus obtained was washed with a diluted aqueous sodium bicarbonate solution twice and water thrice, it was dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure to obtain 8.5 g of a crude 2,3,3′-trifluoro-4′-hydroxy-4-propylbiphenyl. (Yield: 99.8%)
Reaction SMILES: [N:1]([CH2:4][S:5]([CH3:8])(=[O:7])=[O:6])=[C:2]=[O:3].[N+:9](=[C:11]1[N:15]=[CH:14][N:13]=[C:12]1[C:16]([NH2:18])=[O:17])=[N-:10]>CS(C)=O>[CH3:8][S:5]([CH2:4][N:1]1[C:2](=[O:3])[N:15]2[CH:14]=[N:13][C:12]([C:16]([NH2:18])=[O:17])=[C:11]2[N:9]=[N:10]1)(=[O:7])=[O:6]
Reactant: CS(=O)(=O)CN=C=O
Reactant: [N-]=[N+]=C1N=CN=C1C(N)=O
Solvent: CS(C)=O
Product: CS(=O)(=O)Cn1nnc2c(C(N)=O)ncn2c1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 67.9 %

Procedure:
Isocyanato-methanesulfonyl-methane (250 mg, 1.85 mmol) was added drop wise to a suspension of 5-diazoimidazole-4-carboxamide (210 mg, 1.53 mmol) in dry DMSO (2 mL) at room temperature under nitrogen. The resulting mixture was stirred at room temperature for 72 hours. The reaction was quenched by the pouring onto crushed ice. The resultant precipitate was collected by filtration and washed with Et2O (3 reaction volumes) and dried to give the title compound as a white solid (283 mg, 68%). 1H NMR (400 MHz, d6-DMSO) δ ppm: 8.94 (1H, s), 7.90 (1H, s), 7.75 (1H, s), 5.82 (2H, s), 3.15 (3H, s).
Reaction SMILES: [CH3:1][NH:2][C:3]([C@@:5]12[CH2:10][C@@H:9]1[C@@H:8]([N:11]1[CH:19]=[N:18][C:17]3[C:12]1=[N:13][C:14]([Cl:36])=[N:15][C:16]=3[NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[C:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]#[CH:35])[CH:23]=1)[C@H:7]([OH:37])[C@@H:6]2[OH:38])=[O:4].CNC([C@@]12C[C@@H]1[C@@H](N1C=NC3C1=NC(Cl)=NC=3NCC1C=CC=C(C#CCCCC3[N:72]=[N:73][N:74]([C:76]4[CH:81]=[CH:80][C:79]([F:82])=[C:78]([N+:83]([O-:85])=[O:84])[CH:77]=4)C=3)C=1)[C@H](O)[C@@H]2O)=O>>[CH3:1][NH:2][C:3]([C@@:5]12[CH2:10][C@@H:9]1[C@@H:8]([N:11]1[CH:19]=[N:18][C:17]3[C:12]1=[N:13][C:14]([Cl:36])=[N:15][C:16]=3[NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[C:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]3[N:72]=[N:73][N:74]([C:76]4[CH:81]=[CH:80][C:79]([F:82])=[C:78]([N+:83]([O-:85])=[O:84])[CH:77]=4)[CH:35]=3)[CH:23]=1)[C@H:7]([OH:37])[C@@H:6]2[OH:38])=[O:4]
Reactant: CNC(=O)[C@@]12C[C@@H]1[C@@H](n1cnc3c(NCc4cccc(C#CCCCc5cn(-c6ccc(F)c([N+](=O)[O-])c6)nn5)c4)nc(Cl)nc31)[C@H](O)[C@@H]2O
Reactant: C#CCCCCC#Cc1cccc(CNc2nc(Cl)nc3c2ncn3[C@H]2[C@H](O)[C@H](O)[C@]3(C(=O)NC)C[C@H]23)c1
Product: CNC(=O)[C@@]12C[C@@H]1[C@@H](n1cnc3c(NCc4cccc(C#CCCCCc5cn(-c6ccc(F)c([N+](=O)[O-])c6)nn5)c4)nc(Cl)nc31)[C@H](O)[C@@H]2O
Yield: 94 %

Procedure:
Compound 204 (94%) was synthesized from compound 201 following the same procedure as for compound 203. 1H NMR (CD3OD, 400 MHz) δ 8.65-8.58 (m, 1H), 8.45 (s, 1H), 8.23-8.19 (m, 1H), 8.03 (s, 1H), 7.65 (t, J=8.8 Hz, 1H), 7.41 (s, 1H), 7.33-7.25 (m, 2H), 5.07 (d, J=6.8 Hz, 1H), 4.80 (s, 1H), 4.72 (br s, 2H), 4.00 (d, J=6.8 Hz, 1H), 2.87 (s, 3H), 2.51 (t, J=6.8 Hz, 2H), 2.07-2.04 (m, 1H), 1.97-1.91 (m, 2H), 1.82 (t, J=5.2 Hz, 2H), 1.74-1.69 (m, 2H), 1.39-1.35 (m, 1H). HRMS calculated for C34H33ClFN10O5 (M+H)+: 715.2308. Found 715.2302.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].C1(CN)CCCCC1.[O:18]=[C:19]1[C:27]2([CH2:31][O:30][C:29]3[CH:32]=[C:33]4[C:37](=[CH:38][C:28]2=3)[CH2:36][CH2:35][O:34]4)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[CH2:39][C:40]1[CH:48]=[CH:47][C:43]([C:44](O)=[O:45])=[CH:42][CH:41]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][C:44](=[O:45])[C:43]1[CH:47]=[CH:48][C:40]([CH2:39][N:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]3([CH2:31][O:30][C:29]4[CH:32]=[C:33]5[C:37](=[CH:38][C:28]3=4)[CH2:36][CH2:35][O:34]5)[C:19]2=[O:18])=[CH:41][CH:42]=1
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Reactant: Cc1cccc(C)c1N
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: Cc1cccc(C)c1NC(=O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 2,6-dimethylaniline to replace cyclohexanemethylamine, and 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-(2,6-dimethylphenyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (28%) as a colorless solid: mp>250° C.; 1H NMR (300 MHz, CDCl3) δ7.95-7.89 (m, 2H), 7.51-7.45 (m, 2H), 7.37 (s, 1H), 7.24-7.02 (m, 6H), 6.82-6.75 (m, 1H), 6.49 (s, 1H), 6.44 (s, 1H), 5.04 (ABq, 2H), 4.86 (ABq, 2H), 4.60-4.50 (m, 2H), 3.12-2.91 (m, 2H), 2.27 (s, 6H); 13C NMR (75 MHz, CDCl3) δ178.0, 165.3, 161.9, 161.4, 141.8, 139.8, 135.5, 134.1, 133.6, 132.7, 128.8, 128.3, 127.9, 127.8, 127.6, 124.0, 123.7, 120.0, 118.8, 109.1, 93.3, 80.7, 72.4, 57.8, 43.8, 29.0, 18.5; MS (ES+) m/z 517.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14]([NH:17][C:18]4[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=4)=[N:15]3)=[C:10]([CH3:30])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:31]([NH2:35])(=[O:34])[CH:32]=[CH2:33].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:30][C:10]1[N:9]=[C:8]([C:4]2[CH:3]=[C:2](/[CH:33]=[CH:32]/[C:31]([NH2:35])=[O:34])[CH:7]=[CH:6][CH:5]=2)[N:16]2[C:11]=1[CH:12]=[N:13][C:14]([NH:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=1)=[N:15]2
Reactant: C=CC(N)=O
Reactant: COc1cc(Nc2ncc3c(C)nc(-c4cccc(Br)c4)n3n2)cc(OC)c1OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cc(Nc2ncc3c(C)nc(-c4cccc(/C=C/C(N)=O)c4)n3n2)cc(OC)c1OC
Temperature: 25 °C
Yield: 8.3 %

Procedure:
To a mixture of 7-(3-bromophenyl)-5-methyl-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (Example 9) (0.054 g, 0.12 mmol), acrylamide (0.025 g, 0.35 mmol), palladium (II) acetate (2.7 mg, 0.012 mmol) and tris(o-tolyl)phosphine (7.3 mg, 0.024 mmol) in acetonitrile (1 mL) was added triethylamine (0.050 mL, 0.35 mmol). The solution was heated to reflux for 30 minutes. After cooling to room temperature, the solution was filtered, and silica gel (1 g) was added, followed by evaporation of the volatiles under reduced pressure. The pre-adsorbed solids were loaded into a solid loading cartridge and subjected to a gradient elution using ethyl acetate:hexanes (50:50) to ethyl acetate:hexanes (100:0) to ethyl acetate:methanol (99:1) using a RediSep silica gel cartridge (4 g; ISCO). The appropriate fractions were combined and concentrated under reduced pressure to give (2E)-3-(3-{5-methyl-2-[(3,4,5-trimethoxyphenyl)amino]-imidazo[5,1-f][1,2,4]triazin-7-yl}phenyl)prop-2-enamide (0.0046 g) as a yellow solid. 1H NMR (CD3OD): δ9.05 (s, 1H), 8.49 (s, 1H), 8.37 (d, J=7.3 Hz, 1H), 7.67-7.51 (m, 4H), 7.05 (s, 2H), 6.68 (d, J=15.9 Hz, 1H) 3.74 (s, 3H), 3.72 (s, 6H), 2.60 (s, 3H). MS m/z 461 (M+1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[N:27][O:28][CH3:29])[C:7]([NH:9][C@@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:22]([OH:24])=[O:23])=[C:14]([CH2:17][O:18]C(=O)C)[CH2:15][S:16][C@H:11]12)=[O:8].[OH-].[Na+].P(=O)(O)(O)O.[Cl-].[Na+]>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[N:27][O:28][CH3:29])[C:7]([NH:9][C@@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:22]([OH:24])=[O:23])=[C:14]([CH2:17][OH:18])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1ccco1
Agent: O=P(O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12)c1ccco1
Reaction time: 20 h
Yield: 69.5 %

Procedure:
A reaction mixture consisting of (6R,7R)-7-[2-(fur-2-yl)-2-methoxyiminoacetamido]-3-acetoxymethylceph-3-em-4-carboxylic acid (syn isomer) (8.0 g), sodium hydroxide (2.6 g), demineralised water (120 ml), orthophosphoric acid (2.2 ml) and a slurry (18 ml) of Rhodosporidium toruloides CBS14 prepared as in (a) above was incubated at 25°C on an orbital shaker. After 20 hr. it was shown by t.l.c. (silica gel plates with 0.5M sodium chloride as solvent) that the reaction was complete. The reaction mixture was centrifuged, and the supernatant decanted and filtered through an asbestos pad. Methyl isobutyl ketone (14 ml) was added to the clear filtrate, the mixture was magnetically stirred and a 20% solution of orthophosphoric acid was added dropwise until the pH was 2.0. The mixture was then allowed to settle, the lower aqueous layer pipetted off and the solvent layer containing a copious white precipitate was vacuum filtered. The precipitate was washed with methyl isobutyl ketone (10 ml) and ice cold water (2 × 10 ml). The product was then sucked dry and dried in vacuo at room temperature to yield title compound (5.01 g). IR and NMR spectra of the product were consistent with it being title compound. The purity was estimated to be 92.2% by HPLC.