Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[NH:12][C:13](=[O:20])[C:14]([CH:17]([CH3:19])[CH3:18])([CH3:16])[N:15]=2)=[N:9][CH:10]=1)[CH3:4].Br[CH2:22]/[CH:23]=[CH:24]/[C:25]([O:27][CH2:28][CH3:29])=[O:26]>O1CCCC1>[CH2:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:12]([CH2:22]/[CH:23]=[CH:24]/[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:13](=[O:20])[C:14]([CH:17]([CH3:19])[CH3:18])([CH3:16])[N:15]=2)=[N:9][CH:10]=1)[CH3:4]
Reactant: CCc1ccc(C2=NC(C)(C(C)C)C(=O)N2)nc1
Reactant: CCOC(=O)/C=C/CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/CN1C(=O)C(C)(C(C)C)N=C1c1ccc(CC)cn1
Temperature: 25 °C
Reaction time: 19 h
Yield: 25.3 %

Procedure:
A stirred suspension of sodium hydride (1.6 g, 53 mmol, 80% oil dispersion) in dry tetrahydrofuran is treated with a solution of 2-(5-ethyl-2-pyridyl)-4-isopropyl-4-methyl-5-oxo-2-imidazoline (10.24 g, 41.80 mmol) in dry tetrahydrofuran dropwise via addition funnel. After addition is complete and effervescence subsides, ethyl 4-bromocrotonate (12.9 g, 50.1 mmol, 75% technical grade) is added to the reaction mixture at once. The resulting mixture is stirred at room temperature under nitrogen for 19 hours. After this period, the reaction mixture is partitioned between water and ether. The layers are separated, and the organic layer is dried over magnesium sulfate, decolorized with activated charcoal, vacuum filtered through diatomaceous earth, and concentrated in vacuo to obtain a dark brown oil. The oil is purified by flash chromatography (2:1 hexanes/ethyl acetate eluent) to give the title product as a pale orange oil (3.78 g, 25%).
Reaction SMILES: F[C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH2:8][S:9][C@@H:10]3[CH:21]([NH:22][C:23](=[O:30])[CH2:24][C:25]4[S:26][CH:27]=[CH:28][CH:29]=4)[C:20](=[O:31])[N:11]3[C:12]=2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=C[CH:3]=1.CC[O:36]CC>>[O:36]1[CH2:3][CH2:2][CH2:33][CH2:32][CH:5]1[CH2:6][C:7]1[CH2:8][S:9][C@@H:10]2[CH:21]([NH:22][C:23](=[O:30])[CH2:24][C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)[C:20](=[O:31])[N:11]2[C:12]=1[C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14]
Reactant: CCOCC
Reactant: CC(C)(C)OC(=O)C1=C(Cc2ccc(F)cc2)CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N12
Product: CC(C)(C)OC(=O)C1=C(CC2CCCCO2)CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N12

Procedure:
Trituration of the oil with ether gave the cephem (X) as a white solid (29 mg), m.p. 175°-185° decomp. M+ m/e 478 (parent peak) and the fragmentations expected for the cephem (X).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[C:4]([CH3:11])[CH:3]=1.Cl.[N:13]1([CH2:19][CH:20]([N:24]2[CH:28]=[C:27]([C:29]3[C:30]4[CH:37]=[CH:36][N:35](COCC[Si](C)(C)C)[C:31]=4[N:32]=[CH:33][N:34]=3)[CH:26]=[N:25]2)[CH2:21][C:22]#[N:23])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(CC)CC)C>C1COCC1>[N:32]1[C:31]2[NH:35][CH:36]=[CH:37][C:30]=2[C:29]([C:27]2[CH:26]=[N:25][N:24]([CH:20]([CH2:21][C:22]#[N:23])[CH2:19][N:13]3[CH2:18][CH2:17][N:16]([C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=4[CH3:11])=[O:10])[CH2:15][CH2:14]3)[CH:28]=2)=[N:34][CH:33]=1
Reactant: Cc1cc(F)ccc1N=C=O
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CN4CCNCC4)c3)ncnc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1NC(=O)N1CCN(CC(CC#N)n2cc(-c3ncnc4[nH]ccc34)cn2)CC1
Reaction time: 1 h

Procedure:
4-Fluoro-1-isocyanato-2-methylbenzene (10 mg, 0.068 mmol) was added to a solution of 4-piperazin-1-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile hydrochloride (20 mg, 0.034 mmol; from Example 12, Step 2) and triethylamine (28 uL, 0.20 mmol) in THF (0.39 mL). The reaction was stirred for one hour, then solvent was removed in vacuo. The residue was stirred in a 1:1 mixture of DCM:TFA for 1 hour, concentrated, and stirred in a solution of methanol (1 mL) containing ethylenediamine (0.2 mL) for one hour. Purification via preparative HPLC-MS, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH afforded product as the free base (11 mg, 67%). 1H NMR (400 MHz, d6-dmso): δ 12.12 (br s, 1H), 8.82 (s, 1H), 8.69 (s, 1H), 8.38 (s, 1H), 8.01 (s, 1H), 7.61 (d, 1H), 7.11 (dd, 1H), 7.02 (dd, 1H), 6.98 (d, 1H), 6.92 (dt, 1H), 5.01 (tt, 1H), 3.42-3.29 (m, 4H), 3.26-3.19 (m, 2H), 2.86 (dd, 1H), 2.81 (dd, 1H), 2.54-2.46 (m, 2H), 2.43-2.34 (m, 2H), 2.11 (s, 3H); LCMS (M+H)+: 488.3.
Reaction SMILES: [NH:1]([C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[C@H:2]([C:10]([NH:12][C@H:13]([C:18]([O:20]C(C)(C)C)=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(O)(C(F)(F)F)=O>O>[NH:1]([C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])[C@H:2]([C:10]([NH:12][C@H:13]([C:18]([OH:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
100 mg Z-Phe-Leu-OtBu was added to 5 mL CF3COOH to which a drop of water had been added. The mixture was stirred for 2 h at ambient temperature, concentrated in vacuo and co-evaporated with 10 mL toluene (2×) to obtain Z-Phe-Leu-OH in quantitative yield. 1H-NMR (CDCl3, 300 MHz): δ 7.31-7.04 (m, 10H), 6.82 (d, 1H, J=6.6 Hz), 5.79 (d, 1H, J=7.3 Hz), 4.93 (s, 2H), 4.44 (m, 2H), 2.94 (m, 2H), 1.51 (m, 3H), 0.77 (m, 6H).
Reaction SMILES: Br[C:2]1[C:3]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)=[N:4][N:5]2[C:10]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)=[CH:9][CH:8]=[CH:7][C:6]=12.[F:22][C:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:12]1([NH:11][C:10]2[N:5]3[N:4]=[C:3]([C:17]4[O:18][CH:19]=[CH:20][CH:21]=4)[C:2]([C:27]4[CH:26]=[CH:25][N:24]=[C:23]([F:22])[CH:28]=4)=[C:6]3[CH:7]=[CH:8][CH:9]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Brc1c(-c2ccco2)nn2c(NC3CCCC3)cccc12
Reactant: OB(O)c1ccnc(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cc(-c2c(-c3ccco3)nn3c(NC4CCCC4)cccc23)ccn1
Temperature: 75 °C
Yield: 23 %

Procedure:
N-[3-Bromo-2-(2-furyl)pyrazolo[1,5-a]pyridin-7-yl]-N-cyclopentylamine (0.2 g, 0.6 mmol) was dissolved in N,N-dimethylformamide (8 mL). To this solution was added 2-fluoro-4-pyridinylboronic acid (0.09 g, 0.64 mmol), dichlorobis(triphenylphosphine)-palladium (II) (0.020 g, 0.03 mmol) and saturated aqueous sodium carbonate (580 μl). The resulting solution was heated in a 75° C. oil bath overnight. Water was added to the reaction mixture and the product was extracted with ethyl acetate. The organic phase was dried (magnesium sulfate), filtered and concentrated to a solid. The product was purified by silica gel chromatography (7:1 hexane:ethyl acetate) to give 50 mg (24%) of N-cyclopentyl-3-(2-fluoro-4-pyridinyl)-2-(2-furyl)pyrazolo[1,5-a]pyridin-7-amine as a solid. 1H NMR (CDCl3) δ 8.1 (d, 1H), 7.5 (s, 1H), 7.24 (1H), 7.03(s, 1H), 6.96 (d, 1H), 6.75 (d, 1H), 6.5 (m, 1H), 6.01 (m, 2H), 4.0 (m, 1H), 2.19–2.09 (m, 2H); 1.88–1.77 (m, 4H), 1.77–1.64 (m, 2H);MS m/363 (M+1).
Reaction SMILES: CC1(C)O[C:6](=[O:8])[C:5](=[CH:9][NH:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)C(=O)O1>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[NH:10]1[C:11]2[C:12](=[CH:13][N:14]=[CH:15][CH:16]=2)[C:6](=[O:8])[CH:5]=[CH:9]1
Reactant: CC1(C)OC(=O)C(=CNc2ccncc2)C(=O)O1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=c1cc[nH]c2ccncc12
Temperature: 25 °C

Procedure:
Dowtherm A (60 mL) was brought to reflux and (a) (6.3 g, 25.4 mmol) was added portionwise over 2 minutes. The mixture was heated for a further 5 minutes then allowed to cool to room temperature. The resulting solid was washed with a small amount of cold ethanol and dried in vacuo (2.6 g, 69%).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[NH:9][C:10](=[O:31])[C:11]1[CH:16]=[C:15]([N:17]([CH3:19])[CH3:18])[CH:14]=[C:13]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[N:12]=1)C1C=CC=CC=1.[H][H]>[Pd].CO>[CH3:18][N:17]([CH3:19])[C:15]1[CH:14]=[C:13]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=2)[N:12]=[C:11]([C:10]([NH:9][NH2:8])=[O:31])[CH:16]=1
Reactant: [H][H]
Reactant: CN(C)c1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NN(Cc2ccccc2)Cc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Product: CN(C)c1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NN)c1

Procedure:
4-dimethylamino-6-[3-(trifluoromethyl)phenoxy] picolinic acid, N',N'-dibenzyl hydrazide (0.80 g, 0.00154 mol) was mixed with methanol (about 10 ml), and further with 10% palladium/carbon (0.2 g, 0.00154×0.12 mol) in a hydrogen atmosphere (about 0.5 kg/cm2). The resultant mixture was stirred at a temperature of about 50 to 60° C. for about 3 hours. The obtained reaction solution was filtered and concentrated, thereby obtaining an aimed product.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O.[CH2:13]([C@H:15]1[CH2:20][C@H:19]2[C@H:21]3[C@H:30]([CH2:31][CH2:32][C@:17]2([CH3:18])[C@H:16]1[O:34][C:35](=[O:38])[CH2:36]Br)[C@@H:29]1[C:24](=[CH:25][C:26](=[O:33])[CH2:27][CH2:28]1)[CH2:23][CH2:22]3)[CH3:14]>CC(C)=O>[CH2:13]([C@H:15]1[CH2:20][C@H:19]2[C@H:21]3[C@H:30]([CH2:31][CH2:32][C@:17]2([CH3:18])[C@H:16]1[O:34][C:35](=[O:38])[CH2:36][O:8][C:1](=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@@H:29]1[C:24](=[CH:25][C:26](=[O:33])[CH2:27][CH2:28]1)[CH2:23][CH2:22]3)[CH3:14]
Reactant: O=C(O)c1ccccc1
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)COC(=O)c1ccccc1
Yield: 89.1 %

Procedure:
In 30 ml of acetone is dissolved 0.49 g of benzoic acid, and 2 ml of 2 N-NaOH and 5 ml of water are added, followed by addition of 0.88 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one. The mixture is refluxed for 3 hours. After cooling, the solvent is distilled off under reduced pressure and the residue is extracted with 100 ml of ethyl acetate. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the residue is chromatographed on a silica gel column. After passage of 350 ml of diisopropyl ether, the solvent is distilled off under reduced pressure. To the residue is added a small amount of diisopropyl ether, followed by filtration to give 0.86 g of the above-identified compound as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH-:20].[Na+]>OS(O)(=O)=O>[NH2:1][C:2]1[CH:9]=[C:8]([C:10]2[C:15]([C:16]([F:19])([F:17])[F:18])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]([NH2:5])=[O:20]
Reactant: N#Cc1ccc(-c2ncccc2C(F)(F)F)cc1N
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)c1ccc(-c2ncccc2C(F)(F)F)cc1N
Temperature: 25 °C

Procedure:
Stir a mixture of 2-amino-4-(3-trifluoromethyl-pyridin-2-yl)-benzo-nitrile (0.50 mmol) in 70% H2SO4 (10 ml) at 110° C. for 1 hour. Cool to room temperature, neutralize with NaOH, extract with EtOAc, dry over Na2SO4, and concentrate under vacuum. Purify the residue by flash chromatography (3:2 hexanes/EtOAc) to give 2-amino-4-(3-trifluoromethyl-pyridin-2-yl)-benzamide.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[C:10]([O:13][C@@H:14]1[C@@H:27]([O:28][C:29](=[O:31])[CH3:30])[C@H:26]([O:32][C:33](=[O:35])[CH3:34])[CH2:25][S:24][C@H:15]1[O:16][C:17]1[CH:18]=[N:19][C:20](Br)=[CH:21][CH:22]=1)(=[O:12])[CH3:11]>>[C:10]([O:13][C@@H:14]1[C@@H:27]([O:28][C:29](=[O:31])[CH3:30])[C@H:26]([O:32][C:33](=[O:35])[CH3:34])[CH2:25][S:24][C@H:15]1[O:16][C:17]1[CH:18]=[N:19][C:20]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=2)=[CH:21][CH:22]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(Br)nc1
Reactant: COc1cncc(Br)c1
Product: COc1cncc(-c2ccc(O[C@@H]3SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)cn2)c1

Procedure:
By carrying out the operation analogously to example 137, starting from 3-bromo-5-methoxypyridine and 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, the desired product is obtained in the form of a white solid (yield=48%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:10][CH:9]1[C:24]([O:26][CH2:27][CH3:28])=[O:25])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[F:23][C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][NH:8][CH:9]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:10]2)=[CH:22][CH:21]=1
Reactant: [H][H]
Reactant: CCOC(=O)C1CN(CCOc2ccc(F)cc2)CCN1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CN(CCOc2ccc(F)cc2)CCN1
Yield: 100.4 %

Procedure:
Ethyl 1-benzyl-4-[2-(4-fluorophenoxy)ethyl)-2-piperazinecarboxylate (977 mg) synthesized in accordance with Example 241 described later was dissolved in ethanol (15 ml), and 210 mg of 10% Pd-C was added. After replacing the atmosphere with hydrogen, the mixture was stirred. After completion of the reaction, the solution was evaporated, to give 752 mg (100%) of the title compound as a crude product.
Reaction SMILES: [C:1](=[O:5])([O-:4])OC.[Mg+2].COC(=O)[O-].[CH3:12][C:13]([C:15]1[S:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:18][CH:19]=1)=[O:14]>CN(C)C=O>[CH2:21]([O:20][C:17]1[S:16][C:15]([C:13]([CH2:12][C:1]([OH:4])=[O:5])=[O:14])=[CH:19][CH:18]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(C)=O)s1
Reactant: COC(=O)[O-]
Agent: [Mg+2]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)CC(=O)O)s1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A mixture of magnesium methyl carbonate and dimethylformamide (300 g of a 2.0mM/g solution) is heated in a 120° C. oil bath with stirring under carbon dioxide flushing for 1/2 hour. To this mixture is added 33.8 g (0.100 mole) of 5-(tetradecyloxy)-2-thienyl methyl ketone, and the oil bath temperature is raised to 130° C. to 150° C. Dry nitrogen is flushed through the mixture for 5 hours. The mixture is allowed to cool at room temperature under carbon dioxide flushing after which it is poured slowly into 3 liters of concentrated HCl-ice (1:1) with vigorous stirring. When the evolution of gas is complete, the precipitate is collected and washed with cold water, then dried to give 5-tetradecyloxythen-2-oylacetic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([NH:12][NH2:13])=[O:11])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[S:23])=[CH:17][CH:16]=1>CCO>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([S:8][CH3:9])=[N:4][C:3]=1[C:10]([NH:12][NH:13][C:22]([NH:21][C:18]1[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=1)=[S:23])=[O:11]
Reactant: CSc1ncc(Cl)c(C(=O)NN)n1
Reactant: Fc1ccc(N=C=S)cc1
Solvent: CCO
Product: CSc1ncc(Cl)c(C(=O)NNC(=S)Nc2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
5-Chloro-2-(methylthio)pyrimidine-4-carbohydrazide (8.28 g, 38.0 mmol) and 4-fluoro-phenyl isothiocyanate (5.811 g, 38.0) were added to a 1 liter flask. A minimal amount of EtOH was added, just to ensure proper mixing. This suspension was stirred at room temperature overnight. The EtOH was removed under vacuum to give 13.5 g (95% yield) of product as a light yellow solid. MS (M+H)+ 372.
Reaction SMILES: C([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][CH:21]3[CH2:23][C:24]4([CH2:29][CH:20]3[CH2:19]2)[O:28][CH2:27][CH2:26][O:25]4)=[C:14]([F:30])[CH:13]=1)=[O:10])C1C=CC=CC=1.C([Li])CCC.[C:36](OC[C@@H]1OC1)(=[O:40])[CH2:37][CH2:38]C>O1CCCC1>[F:30][C:14]1[CH:13]=[C:12]([N:11]2[CH2:38][C@H:37]([CH2:36][OH:40])[O:8][C:9]2=[O:10])[CH:17]=[CH:16][C:15]=1[N:18]1[CH2:19][CH:20]2[CH2:29][C:24]3([CH2:23][CH:21]2[CH2:22]1)[O:25][CH2:26][CH2:27][O:28]3
Reactant: O=C(Nc1ccc(N2CC3CC4(CC3C2)OCCO4)c(F)c1)OCc1ccccc1
Reactant: CCCC(=O)OC[C@H]1CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1O[C@@H](CO)CN1c1ccc(N2CC3CC4(CC3C2)OCCO4)c(F)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
24.12 g (58.5 mmol) of 2-[4-[[(benzyloxy)carbonyl]amino]-2-fluorophenyl]-hexahydro-1H-spiro[cyclopenta[c]pyrrol-5,2′-[1,3]dioxolane] prepared in the step 6 was dissolved in 250 ml of tetrahydrofuran, the temperature was cooled to −78° C., and 44 ml (70.4 mmol) of 1.6 M n-butyllithium was slowly added over 30 minutes. After the reaction mixture was stirred for 1 hour, 9.11 ml (60.0 mmol) of (−)-(R)-glycidyl butyrate was added dropwise over 30 minutes, and the mixture was stirred for 12 hours while raising the temperature to room temperature. After the reaction was completed, the solvent was removed under reduced pressure, 250 ml of ethyl acetate was added, the mixture was washed with a saturated aqueous solution of ammonium chloride and distilled water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 21.4 g (97%) of the title compound, of which NMR data is as follows.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:9])[NH:5][CH:6]=[CH:7][CH:8]=1.CC(C)([O-])C.[K+].[F:16][CH:17]([F:29])[O:18][C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1F>CS(C)=O.ClCCl>[F:16][CH:17]([F:29])[O:18][C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]1=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)c(OC(F)F)c1
Reactant: COc1ccc[nH]c1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1cccn(-c2ccc([N+](=O)[O-])cc2OC(F)F)c1=O
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
302 mg (2.41 mmol) of 3-methoxypyridone are dissolved in 8.2 ml of anhydrous dimethyl sulfoxide and admixed with 325 mg (2.89 mmol) of potassium tert-butoxide. After 30 min, 500 mg (2.41 mmol) of 2-(difluoromethoxy)-1-fluoro-4-nitrobenzene are added and the mixture is heated to 80° C. for 20 h. The reaction solution is diluted with dichloromethane and washed with water and 1N hydrochloric acid. After the organic phase has been dried over sodium sulfate, it is filtered and concentrated to dryness under reduced pressure. The residue is dissolved in dimethyl sulfoxide and purified by preparative HPLC with a water/acetonitrile gradient. The product fractions are combined and concentrated to dryness under reduced pressure. This affords 207 mg (28% of theory) of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[N:6][CH:7]=1.[CH2:24]([NH2:26])[CH3:25]>>[CH2:24]([NH:26][C:20]([C:17]1[S:16][C:15](/[CH:14]=[CH:13]/[C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[N:9][O:10][C:11]=2[CH3:23])=[N:19][CH:18]=1)=[O:22])[CH3:25]
Reactant: Cc1onc(-c2ccc(F)cn2)c1/C=C/c1ncc(C(=O)O)s1
Reactant: CCN
Product: CCNC(=O)c1cnc(/C=C/c2c(-c3ccc(F)cn3)noc2C)s1
Yield: 78 %

Procedure:
As described for example 77c, 2-{(E)-2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-vinyl}-thiazole-5-carboxylic acid (83 mg, 0.25 mmol) was converted, using ethylamine (2M solution in THF) instead of 4-aminotetrahydropyran, to the title compound (70 mg, 78%) which was obtained as a yellow solid after purification by chromatography (silica, 0 to 100% ethyl acetate in heptane). MS: m/e=359.1 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[O:28][CH2:27][CH2:26][CH2:25]3)[CH2:18][CH2:17]1.Cl.N1C=CC=CC=1>N1C=CC=CC=1>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][N:19]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[O:28][CH2:27][CH2:26][CH2:25]3)[CH2:20][CH2:21]1
Reactant: COc1ccc2[nH]cc(CCCCN3CCN(c4ccc5c(c4)CCCO5)CC3)c2c1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1ccc2[nH]cc(CCCCN3CCN(c4ccc5c(c4)CCCO5)CC3)c2c1
Reaction time: 3 h

Procedure:
A mixture of 2.1 g of 1-[4-(5-methoxyindol-3-yl)butyl]-4-(chroman-6-yl)piperazine [can be prepared according to Example 1], 1.8 g of pyridine hydrochloride and 50 ml of pyridine is boiled for 3 hours. It is cooled and evaporated, and the residue is worked up in the customary manner and gives 1-[4-(5-hydroxyindol-3-yl)-butyl]-4-(chroman-6-yl)piperazine, m.p. 220°-222°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:10]([O-:12])=[O:11])=[C:7]([NH2:9])[CH:8]=1.C(N(CC)CC)C.C(Cl)Cl.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:10]([O-:12])=[O:11])=[C:7]([N:9]([S:24]([CH3:23])(=[O:26])=[O:25])[S:24]([CH3:23])(=[O:26])=[O:25])[CH:8]=1
Reactant: COc1ccc([N+](=O)[O-])c(N)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc([N+](=O)[O-])c(N(S(C)(=O)=O)S(C)(=O)=O)c1
Reaction time: 18 h

Procedure:
To a solution of 5-Methoxy-2-nitro-phenylamine (5.0 g, 0.030 mol) and Triethylamine (10.0 mL, 0.0717 mol) in Methylene chloride (100 mL, 2 mol) at 0° C. was added dropwise Methanesulfonyl chloride (5.1 mL, 0.065 mol). The mixture was stirred for 18 hours. The mixture was poured into 1N Hydrochloric Acid (200 mL). The aqueous was extracted with dichloromethane (3×100 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated. The oil was purified by silica gel chromatography using 20%→100% Ethyl Acetate:Hexane solvent gradient. N-(5-Methoxy-2-nitro-phenyl)-N-(methylsulfonyl)methanesulfonamide isolated as a yellow solid (7.75 g, 80%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[NH:10][C:11]([C:13]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][NH:15][N:14]=1)=O>C(O)(=O)C>[CH3:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]2[NH:1][C:11]([C:13]3[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][NH:15][N:14]=3)=[N:10][C:3]=2[CH:4]=1
Reactant: Cc1cc(N)c(NC(=O)c2n[nH]cc2[N+](=O)[O-])cc1C
Solvent: CC(=O)O
Product: Cc1cc2nc(-c3n[nH]cc3[N+](=O)[O-])[nH]c2cc1C
Temperature: 25 °C
Yield: 107 %

Procedure:
A stirred solution of 4-nitro-1H-pyrazole-3-carboxylic acid (2-amino-4,5-dimethylphenyl)amide [5.7 g, Reference Example 36(a)] in acetic acid (100 mL) was heated at 120° C. for 1 hour, then cooled to ambient temperature and then evaporated. The oily residue was partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate and then evaporated to give 5,6-dimethyl-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole (5.70 g) as an orange solid. LC-MS (METHOD B): RT=2.30 minutes, 258.11 (M+H)+.
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.Cl.[CH:18]1([C:21]2[C:22]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[N:23][CH:24]=[C:25]([CH:27]3[CH2:29][CH2:28]3)[CH:26]=2)[CH2:20][CH2:19]1>>[CH:18]1([C:21]2[C:22]([N:30]3[CH2:31][CH2:32][N:33]([C:11]([C:10]4[CH:9]=[CH:8][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:16])=[CH:15][CH:14]=4)=[O:13])[CH2:34][CH2:35]3)=[N:23][CH:24]=[C:25]([CH:27]3[CH2:29][CH2:28]3)[CH:26]=2)[CH2:19][CH2:20]1
Reactant: c1nc(N2CCNCC2)c(C2CC2)cc1C1CC1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1
Agent: Cl
Product: O=C(c1ccc(N2CCCS2(=O)=O)cc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 69.3 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoic acid (241 mg) described in Preparation Example 16 and 1-(3,5-dicyclopropylpyridin-2-yl)piperazine hydrochloride (280 mg) described in Preparation Example 87 and by the reaction and treatment in the same manner as in Example 86, the title compound (323 mg) was obtained.