Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:20]1[N:29]=[C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]3[O:38][CH2:39][O:40][C:34]=3[CH:33]=2)[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:41]#[N:42])[CH:26]=2)[N:21]=1>CC(O)C>[CH2:8]([O:7][C:5]([CH:4]1[CH2:3][CH2:2][N:1]([C:20]2[N:29]=[C:28]([NH:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]4[O:38][CH2:39][O:40][C:34]=4[CH:33]=3)[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:41]#[N:42])[CH:26]=3)[N:21]=2)[CH2:11][CH2:10]1)=[O:6])[CH3:9]
Reactant: CCOC(=O)C1CCNCC1
Reactant: N#Cc1ccc2nc(Cl)nc(NCc3ccc4c(c3)OCO4)c2c1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(c2nc(NCc3ccc4c(c3)OCO4)c3cc(C#N)ccc3n2)CC1
Temperature: 25 °C
Yield: 83 %

Procedure:
3.71 g of ethyl isonipecotate, 2.38 g of triethylamine and 10 ml of 2-propanol were added to 1 g of 2-chloro-4-(3,4-methylenedioxybenzyl) amino-6-cyanoquinazoline. The obtained mixture was refluxed for 1 hour and cooled to room temperature. The crystals thus precipitated were recovered by filtration and washed with water and ether successively to give 1.126 g of the title compound.
Reaction SMILES: [C:1]([C:9]1[C:17]([N+:18]([O-])=O)=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[O:21][CH2:22][CH2:23]CC)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1C([N+]([O-])=O)=CC(C(O)=O)=CC=1OCC)(=O)C1C=CC=CC=1>>[NH2:18][C:17]1[C:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([O:21][CH2:22][CH3:23])[CH:11]=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14]
Reactant: CCCCOc1cc(C(=O)O)cc([N+](=O)[O-])c1C(=O)c1ccccc1
Agent: CCOc1cc(C(=O)O)cc([N+](=O)[O-])c1C(=O)c1ccccc1
Product: CCOc1cc(C(=O)O)cc(N)c1C(=O)c1ccccc1

Procedure:
By replacing in Example 1, step C, 4-benzoyl-3-n-butoxy-5-nitrobenzoic acid with 4-benzoyl-3-ethoxy-5-nitrobenzoic acid, and following the procedure described, 5-amino-4-benzoyl-3-ethoxybenzoic acid is obtained with a melting point of 229.5°-230.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:25])[C:5]([C:20]([O:22]CC)=[O:21])=[C:6]([CH3:19])[N:7]2[CH:16]1[CH2:18][CH2:17]1.[OH-].[Na+]>CCO>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:25])[C:5]([C:20]([OH:22])=[O:21])=[C:6]([CH3:19])[N:7]2[CH:16]1[CH2:17][CH2:18]1
Reactant: CCOC(=O)c1c(C)n(C2CC2)c2c(OC)c(F)c(F)c(N)c2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)c(C)n(C3CC3)c12
Yield: 93.5 %

Procedure:
A solution of ethyl 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-2-methyl-4-oxoquinoline-3-carboxylate (187 mg, 0.531 mmol) and 1M aq. NaOH (1 mL) in EtOH (3 mL) was stirred at 50° C. for 1 h. After the reaction mixture was concentrated in vacuo, the residue was dissolved in water and 2M HCl was added to pH<3. The resulting precipitate was collected by filtration in vacuo, washed with water and dried to yield 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-2-methyl-4-oxoquinoline-3-carboxylic acid (161 mg, 93%) as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[O:14][C:11]([CH2:15][CH:16](C(OC)=O)[C:17]([O:19][CH3:20])=[O:18])([CH2:12][CH2:13]2)[CH2:10][CH2:9]3)=[CH:4][CH:3]=1.[Cl-].[Li+]>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]23[O:14][C:11]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])([CH2:10][CH2:9]2)[CH2:12][CH2:13]3)=[CH:6][CH:7]=1
Reactant: COC(=O)C(CC12CCC(c3ccc(Br)cc3)(CC1)O2)C(=O)OC
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)CCC12CCC(c3ccc(Br)cc3)(CC1)O2
Temperature: 180 °C
Reaction time: 0.33 h

Procedure:
To a solution of dimethyl 2-((4-(4-bromophenyl)-7-oxabicyclo[2.2.1]heptan-1-yl)methyl)malonate (305 mg, 0.77 mmol) in DMSO (3.0 mL) and water (0.03 mL) was added lithium chloride (98 mg, 2.3 mmol) and the reaction was stirred in a microwave reactor at 180° C. for 20 min. The resulting yellow reaction mixture was diluted with water and extracted with EtOAc. The organic phase was dried over MgSO4, filtered and concentrated by rotary evaporation in vacuo to afford 289 mg of a crude clear yellow film. Purification of the crude material by column chromatography (24 g silica gel, 0-30% EtOAc:Hept, monitor 230 nm) afforded 194 mg colorless film that solidified upon standing and which was used without further purification. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.54-1.67 (m, 4H), 1.68-1.79 (m, 2H), 2.04-2.16 (m, 4H), 2.42-2.48 (m, 2H), 3.61 (s, 3H), 7.31 (d, J=8.6 Hz, 2H), 7.53 (d, J=8.6 Hz, 2H). ESI-MS m/z: 341.1 [M+H]+, retention time 1.59 min (condition E).
Reaction SMILES: FC1C=CC(C(F)(F)F)=CC=1NC([NH:15][C:16]1[CH:32]=[CH:31][C:19]([O:20][C:21]2[CH:22]=[CH:23][C:24]([N+:28]([O-])=O)=[C:25]([CH:27]=2)[NH2:26])=[CH:18][CH:17]=1)=O>C(O)C.[Pd]>[CH:32]1[C:16]([NH2:15])=[CH:17][CH:18]=[C:19]([O:20][C:21]2[CH:22]=[CH:23][C:24]([NH2:28])=[C:25]([NH2:26])[CH:27]=2)[CH:31]=1
Reactant: Nc1cc(Oc2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(Oc2ccc(N)c(N)c2)cc1
Reaction time: 72 h

Procedure:
Pd/C (5%, 3.0 g) was introduced to a solution of 5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-2-nitroaniline (Intermediate 5) (21.6 g, 48 mmol) in ethanol (200 ml) under Ar. The starting material was hydrogenated under a H2 atmosphere for 3 days while being stirred. The reaction mixture was then filtered through celite and evaporated to give intermediate 6 as a black film. This crude material was chromatographed through silica gel (hexane-AcOEt, 4:1–3:1–2:1–1:1–0:1) to give purified intermediate 6 (13.0 g, 64%): MS m/e 421 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]([N:8]=[C:9]=[O:10])=[N:5][N:4]=1.[CH2:11]([NH:15][CH2:16][CH:17]=[O:18])[CH2:12][CH:13]=[CH2:14]>C1C=CC=CC=1>[CH2:11]([N:15]([CH2:16][CH:17]=[O:18])[C:9]([NH:8][C:6]1[S:7][C:3]([O:2][CH3:1])=[N:4][N:5]=1)=[O:10])[CH2:12][CH:13]=[CH2:14]
Reactant: C=CCCNCC=O
Reactant: COc1nnc(N=C=O)s1
Solvent: c1ccccc1
Product: C=CCCN(CC=O)C(=O)Nc1nnc(OC)s1

Procedure:
A mixture of 5-methoxy-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the diethyl acetal of 2-but-3-enylaminoacetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield the desired product the diethyl acetal of 2-[1-but-3-enyl-3-(5-methoxy-1,3,4-thiadiazol-2-yl)ureido]acetaldehyde.
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.[CH3:32][C:33]1[C:41]2[C:36](=[CH:37][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:40]=2)[NH:35][CH:34]=1.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:38]3[CH:37]=[C:36]4[C:41]([C:33]([CH3:32])=[CH:34][NH:35]4)=[CH:40][CH:39]=3)[C:3]=12
Reactant: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(I)c2c(N)ncnc21
Reactant: Cc1c[nH]c2cc(B3OC(C)(C)C(C)(C)O3)ccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c[nH]c2cc(-c3nn(C(C)c4oc5ccccc5c(=O)c4-c4cccc(F)c4)c4ncnc(N)c34)ccc12
Temperature: 80 °C
Reaction time: 12 h
Yield: 9.9 %

Procedure:
To a solution of Example 57c (0.400 g, 0.758 mmoles) in DMF (4 ml), ethanol (2 ml) and water (2 ml), 3-methyl-6-indoleboronic acid pinacol ester 106 (0.390 g, 1.517 mmoles) and sodium carbonate (0.241 g, 2.27 mmoles) were added and the system is degassed for 30 min. Tetrakistriphenylphosphine Palladium (0.043 g, 0.037 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 (0.040 g, 10% yield). MP: 269-272° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 10.91 (s, 1H), 8.06 (s, 1H), 8.05 (d, J=7.8 Hz, 1H), 7.85 (t, J=7.2 Hz, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.63 (d, J=7.1 Hz, 1H), 7.56 (s, 1H), 7.53 (t, J=7.8 Hz, 1H), 7.25 (d, J=8.1 Hz, 1H), 7.28 (br s, 1H), 7.21 (s, 1H), 7.06 (dt, J=9.0, 2.8 Hz, 1H), 6.98 (br s, 2H), 6.04 (q, J=7.0 Hz, 1H), 2.28 (s, 3H), 1.91 (d, J=7.0 Hz, 3H). Mass: 530.99 (M+).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:15])=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:7]=[CH:6][C:5](/[C:8](/[CH3:15])=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=2)=[CH:19][CH:18]=1
Reactant: CCOC(=O)/C=C(\C)c1ccc(I)cc1
Reactant: OB(O)c1ccc(F)cc1
Product: CCOC(=O)/C=C(\C)c1ccc(-c2ccc(F)cc2)cc1

Procedure:
The colourless solid (E)-ethyl 3-(4′-fluoro-biphenyl-4-yl)-but-2-enoate was prepared from (E)-ethyl 3-(4-iodophenyl)-but-2-enoate (example 91a) and 4-fluorobenzene boronic acid by a procedure analogous to that described in example 52a.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]1[CH:20]=[CH:19][C:11]([C:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[O:13])=[CH:10][C:9]=1[N+:21]([O-])=O)(=[O:3])[CH3:2]>CCOC(C)=O.[Pd]>[C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]1[CH:20]=[CH:19][C:11]([C:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[O:13])=[CH:10][C:9]=1[NH2:21])(=[O:3])[CH3:2]
Reactant: CCN(CC)C(=O)c1ccc(NCCNC(C)=O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)c1ccc(NCCNC(C)=O)c(N)c1
Reaction time: 8 h
Yield: 120.6 %

Procedure:
Following general procedure 2C: A mixture of 4-{[2-(acetylamino)ethyl]amino}-N,N-diethyl-3-nitrobenzamide (0.150 g, 0.465 mmol) and 10% Pd/C in EtOAc (15 mL) was hydrogenated overnight at 40 psi. Usual work-up provided the title compound (0.164 g, 100%) which was used without further purification. 1H-NMR (CDCl3): δ 6.83 (dd, J=8.0 Hz, J=2.0 Hz, 1H), 6.76 (d, J=2.0 Hz, 1H), 6.53 (d, J=8.4 Hz, 1H), 6.26 (br t, 1H), 3.53 (q, J=5.6 Hz, 2H), 3.43 (br s, 4H), 3.23 (t, J=5.6 Hz, 2H), 1.99 (s, 3H), 1.17 (t, J=6.4 Hz, 6H). MS (ESI) (M+H)+=293.
Reaction SMILES: [C:1]12([CH2:11][OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Na+].F[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=1[Br:24]>O1CCCC1>[C:1]12([CH2:11][O:12][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=3[Br:24])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: N#Cc1ccc(F)c(Br)c1
Reactant: OCC12CC3CC(CC(C3)C1)C2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ccc(OCC23CC4CC(CC(C4)C2)C3)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
To a mixture of adamantan-1-ylmethanol (12.47 g, 75.00 mmol) in anhydrous tetrahydrofuran (100 mL) was added sodium hydride (60% w/w in mineral oil, 3.30 g, 82.50 mmol) at 0° C. The resulting mixture was stirred at ambient temperature for 2 h, followed by the addition of 4-fluoro-3-bromobenzonitrile (15.00 g, 75.00 mmol). Stirring was continued at ambient temperature for 17 h, cooled to 0° C. and quenched with saturated ammonium chloride solution (20 mL). The volatiles were removed by evaporation in vacuo. The residue was washed with water and diethyl ether to give the title compound as a pale yellow solid (21.00 g, 80%): 1H NMR (300 MHz, CDCl3) δ 7.80-7.78 (m, 1H), 7.56-7.51 (m, 1H), 6.88-6.84 (m, 1H), 3.57 (s, 3H), 2.02 (br s, 3H), 1.73-1.55 (m, 12H).
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[CH:11]=[C:10]([C:12]2[N:16]3[N:17]=[C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:19]=[CH:20][C:15]3=[N:14][CH:13]=2)[CH:9]=[N:8]1>C(O)(C(F)(F)F)=O.O>[NH:8]1[CH:9]=[C:10]([C:12]2[N:16]3[N:17]=[C:18]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[CH:19]=[CH:20][C:15]3=[N:14][CH:13]=2)[CH:11]=[N:7]1
Reactant: C[Si](C)(C)CCOCn1cc(-c2cnc3ccc(N4CCOCC4)nn23)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: c1n[nH]cc1-c1cnc2ccc(N3CCOCC3)nn12
Yield: 32.8 %

Procedure:
The product from step C (284 mg, 0.71 mmol) was heated to 60° C. in a mixture of TFA (5 mL) and water (1 mL) for 1 h. Upon cooling the reaction mixture was concentrated and partitioned between ethyl acetate and saturated sodium carbonate solution. The solid that formed at the solvent interface was removed by filtration and dried under vacuum to provide the pure title compound (63 mg, 33%) as a white solid: 1H NMR (500 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.40 (s, 1H), 8.17 (s, 1H), 7.89 (d, J=9.9 Hz, 1H), 7.84 (s, 1H), 7.15 (d, J=9.9 Hz, 1H), 3.79 (t, J=3.9 Hz, 4H), 3.52 (t, J=4.3 Hz, 4H); 13C NMR (125 MHz, DMSO-d6) δ 155.2, 136.1, 135.8, 128.4, 125.8, 125.1, 121.8, 109.2, 108.6, 65.6, 46.0; HPLC tR=13.6 min (Luna), >99%; ES-MS: (M+H)=271 m/z.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:18]=[C:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]3[C:25]3[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=3)[O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.O1CCCC1.[Pd]>[C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]3[C:25]3[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=3)[O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)COc1cccc(C2CCCCC2=Cc2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)COc1cccc(C2CCCCC2Cc2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 4 h
Yield: 69.7 %

Procedure:
To a solution of ethyl [3-[2-[(4,5-diphenyloxazol-2-yl)methylene]cyclohexan-1-yl]phenoxy]acetate (300 mg) in a mixture of ethanol (10 ml) and tetrahydrofuran (10 ml) was added 10% palladium on carbon (50 mg). After being stirred for 4 hours under hydrogen atmosphere, the reaction mixture was filtered. The solvent was evaporated in vacuo to give ethyl [3-[2-[(4,5-diphenyloxazol-2-yl)methyl]cyclohexan-1-yl]phenoxy]acetate (210 mg).
Reaction SMILES: [ClH:1].[NH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)[C:3]([NH2:5])=[NH:4].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[N+:40]([C:43]1[CH:52]=[CH:51][C:46]2[N:47]=[C:48]([NH2:50])[S:49][C:45]=2[CH:44]=1)([O-:42])=[O:41]>CN(C)C=O>[ClH:1].[NH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:50][C:48]2[S:49][C:45]3[CH:44]=[C:43]([N+:40]([O-:42])=[O:41])[CH:52]=[CH:51][C:46]=3[N:47]=2)=[O:12])=[CH:13][CH:14]=1)[C:3]([NH2:5])=[NH:4]
Reactant: Nc1nc2ccc([N+](=O)[O-])cc2s1
Reactant: N=C(N)Nc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: N=C(N)Nc1ccc(C(=O)Nc2nc3ccc([N+](=O)[O-])cc3s2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred, cold (-5° C.) solution of 1.07 g. of 4-guanidinobenzoic acid hydrochloride and 740 mg. of 1-hydroxybenzotriazole in 8 ml. of dimethylformamide was added 1.12 g. of dicyclohexylcarbodiimide in one portion. After two hours at 0° C., 950 mg. of 6-nitro-2-aminobenzothiazole was added and the reaction mixture was stirred at room temperature for two hours. The mixture was filtered and the filtrate applied to 35 g. of ionexchange resin GC 50 (H+ form). The column was washed with 200 ml. of water and sufficient methane until the washliquid became colorless. Following a second water/methanol wash the product was eluted from the column using a 0.05 M hydrochloric acid in methanol solution. The fractions containing the product are combined, concentrated to dryness and recrystallized from methanol, 60 mg., m.p. 311-329° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.Cl.Cl[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[N:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[N:18]=2)[N:3]=1
Reactant: CC(C)c1cccc(CCl)n1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(Br)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1cccc(Cn2nc(Br)c3c([N+](=O)[O-])cccc32)n1
Temperature: 35 °C
Reaction time: 0.33 h
Yield: 91.9 %

Procedure:
A flask was charged with 3-bromo-4-nitro-1H-indazole (64 g, 0.264 mol), 2-(chloromethyl)-6-isopropylpyridine hydrochloride (55 g, 0.264 mol), powdered potassium carbonate (91 g, 0.661 mol), and 500 mL of DMF. This mixture was warmed to 35° C. for 72 hours, then poured into 2 liters of cold water, upon which a tan solid precipitated. After stirring for 20 minutes, the solids were collected by filtration and dried under vacuum to give 91 g (92%) of 3-bromo-1-((6-isopropylpyridin-2-yl)methyl)-4-nitro-1H-indazole.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:10])[CH3:9])[CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[S:13][CH:14]=[C:15]([C:17]([OH:19])=[O:18])[N:16]=1.FC1C=C(C(O)C)C=C(F)C=1.FC1C=C(C(O)C)C=C(F)C=1B1OC(C)(C)C(C)(C)O1.FC1C=C([C@@H](O)C)C=C(F)C=1>>[F:1][C:2]1[CH:7]=[C:6]([C@@H:8]([OH:10])[CH3:9])[CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[S:13][CH:14]=[C:15]([C:17]([OH:19])=[O:18])[N:16]=1
Reactant: CC(O)c1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1
Agent: CC(O)c1cc(F)c(B2OC(C)(C)C(C)(C)O2)c(F)c1
Agent: CC(O)c1cc(F)cc(F)c1
Agent: C[C@H](O)c1cc(F)cc(F)c1
Product: C[C@H](O)c1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1

Procedure:
Following the procedure of Intermediate 109, replacing 1-(3,5-difluorophenyl)ethanol in step 1 (Intermediate 106) with (S)-1-(3,5-difluorophenyl)ethanol (commercial source).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH:15]2[CH2:17][CH2:16]2)=[C:6]([CH:8]2[C:12](=[O:13])[CH2:11][CH2:10][C:9]2=[O:14])[CH:7]=1.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1B(O)O.[F-].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].COCCOC>[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[C:2]1[CH:3]=[CH:4][C:5]([CH:15]2[CH2:17][CH2:16]2)=[C:6]([CH:8]2[C:12](=[O:13])[CH2:11][CH2:10][C:9]2=[O:14])[CH:7]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: O=C1CCC(=O)C1c1cc(Br)ccc1C1CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cs+]
Solvent: COCCOC
Product: O=C1CCC(=O)C1c1cc(-c2ccc(Cl)cc2Cl)ccc1C1CC1
Temperature: 160 °C

Procedure:
To a mixture of 2-(5-bromo-2-cyclopropylphenyl)cyclopentane-1,3-dione (0.100 g, 0.34 mmol), 2,4-dichlorophenylboronic acid (0.090 g, 0.47 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]palladium(II)chloride (22 mg, 0.027 mmol) and cesium fluoride (0.152 g, 1.0 mmol) is added 1,2-dimethoxyethane (1 ml). After evacuating and flushing with nitrogen (×3) the mixture is heated at 160° C. for 15 minutes under microwave irradiation. After dilution with distilled water the crude product is extracted with ethyl acetate (×3), and the organic phase is washed with brine, dried over magnesium sulfate and concentrated in vacuo. The crude product is then purified by flash column chromatography on silica gel (isohexane/ethyl acetate eluant) and further triturated with hexanes to afford 2-(2′,4′-dichloro-4-cyclopropylbiphenyl-3-yl)-cyclopentane-1,3-dione as a white powder.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[CH:2].[Cl:9][C:10]1[CH:15]=[CH:14][C:13](/[C:16](/[C:33]2[CH:38]=[CH:37][C:36](I)=[CH:35][CH:34]=2)=[CH:17]/[CH2:18][O:19][C:20]2[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[C:22]([CH3:32])[CH:21]=2)=[CH:12][CH:11]=1>O1CCCC1.C(N(CC)CC)C.C1C=CC=CC=1.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.[Cu]I>[Cl:9][C:10]1[CH:11]=[CH:12][C:13](/[C:16](/[C:33]2[CH:34]=[CH:35][C:36]([C:2]#[C:1][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=3)=[CH:37][CH:38]=2)=[CH:17]/[CH2:18][O:19][C:20]2[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[C:22]([CH3:32])[CH:21]=2)=[CH:14][CH:15]=1
Reactant: C#Cc1ccccn1
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(Cl)cc2)c2ccc(I)cc2)cc1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(Cl)cc2)c2ccc(C#Cc3ccccn3)cc2)cc1C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2-Ethynylpyridine (250 mg, 2.42 mmol) was added under nitrogen atmosphere to a degassed solution of methyl (Z)-[4-[3-(4-chlorophenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]-acetate (500 mg, 0.91 mmol; example 7) in a mixture of tetrahydrofuran (8 mL) and triethylamine (8 mL) The solution was cooled, tetrakis(triphenylphosphine)palladium (96 mg, 0.083 mmol) and copper(I) iodide (27.6 mg, 0.145 mmol) were added. The reaction mixture was stirred at ambient temperature for 72 h, diluted with benzene (100 mL) and washed with water (2×50 mL). The organic solution was dried with anhydrous potassium carbonate and subsequently evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, benzene-chloroform/ether 2:1) yielding methyl (E)-[4-[3-(4-chlorophenyl)-3-[4-(pyridin-2-ylethynyl)phenyl]allyloxy]-2-methylphenoxy]acetate.
Reaction SMILES: C[C:2]1[CH:6]=[C:5](C)[N:4]([C:8](=N)[NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[N:3]=1.CS(O)(=O)=O.C(N)CC>>[NH2:3][CH2:2][CH2:6][CH2:5][NH:4][CH:8]=[N:9][S:10]([C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1)(=[O:12])=[O:11]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)n2nc(C)cc2C)cc1
Agent: CS(=O)(=O)O
Solvent: CCCN
Product: Cc1ccc(S(=O)(=O)N=CNCCCN)cc1

Procedure:
The compound of Example 10 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of n-propylamine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 255.34; found mol. wt. (M+H) 256.2; 511.0 (Dimer)
Reaction SMILES: [C:1]([NH:4][NH2:5])(=[O:3])[CH3:2].[C:6]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)(=O)[CH3:7]>C(O)C>[N:12]1[CH:13]=[CH:14][C:9]([C:6](=[N:5][NH:4][C:1](=[O:3])[CH3:2])[CH3:7])=[CH:10][CH:11]=1
Reactant: CC(=O)c1ccncc1
Reactant: CC(=O)NN
Solvent: CCO
Product: CC(=O)NN=C(C)c1ccncc1
Temperature: 25 °C
Yield: 68.3 %

Procedure:
A mixture of 2.22 gm (0.03 mole) of acetic acid hydrazide, 3.63 gm (0.03 mole) of 4-acetylpyridine and 100 ml of absolute ethanol is refluxed 2 hr. The hot solution is filtered. The filtrate is diluted with water to the cloud point. The mixture is cooled to room temperature and then chilled in the refrigerator. The product is collected, washed with water and dried to yield 3.63 gm (69%) of the title compound having a melting point of 178.1° C.