Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Si:8]([O:25][CH2:26][CH2:27][C:28]1([F:41])[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N>ClCCl>[Si:8]([O:25][CH2:26][CH2:27][C:28]1([F:41])[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]1)([C:21]([CH3:24])([CH3:22])[CH3:23])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[Si](OCCC1(F)CCNCC1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
2.80 ml (37.06 mmol) of trifluoroacetic acid are added slowly to a solution of 3 g (6.17 mmol) of tert-butyl 4-(2-{[tert-butyldiphenylsilyl]oxy}ethyl)-4-fluoro-1-piperidinecarboxylate, obtained in step 12.3, in 20 ml of dichloromethane. Stirring is continued at room temperature for 5 hours. The reaction mixture is poured into a mixture of ice-water and 28% aqueous ammonia. The phases are separated by settling, the aqueous phase is extracted twice with dichloromethane and the combined organic phases are washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl.[Cl:8][C:9]1[N:14]([CH3:15])[C:13](=[O:16])[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[C:11]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)[N:10]=1.[C:33]1([C@@H:39]([NH2:43])[CH2:40][CH2:41][NH2:42])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(O)C>[ClH:8].[NH2:43][C@H:39]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:40][CH2:41][NH:42][C:9]1[N:14]([CH3:15])[C:13](=[O:16])[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[C:11]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)[N:10]=1
Reactant: Cn1c(Cl)nc(-c2ccncc2)c(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: NCC[C@H](N)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cn1c(NCC[C@H](N)c2ccccc2)nc(-c2ccncc2)c(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Aqueous sat. sodium carbonate (2 ml) was added to a solution of 2-chloro-3-methyl-6-(4-pyridyl)-5-(3-trifluoromethylphenyl)-4(3H)-pyrimidinone hydrochloride (730 mg, 2 mmol) and (S)-1-phenyl-1,3-propanediamine (360 mg, 2.4 mmol) in ethanol (10 ml). The mixture was stirred for 4 h at room temperature. It was evaporated and the remainder partitioned between dichloromethane and water. The organic solution was dried and evaporated followed by column chromatography on silica gel (dichloromethane:methanol conc. ammonium hydroxide=93 7:0.7). MS (m/z): 480 (M+H)+; C26H24F3N5O requir. 479.5 (free base).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH:9][C:10]1[CH:19]=[CH:18][C:17]([O:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]>>[CH3:30][C:27]1[CH:28]=[CH:29][C:24]([S:21]([O:20][C:17]2[CH:18]=[CH:19][C:10]([O:9][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[C:11]([CH:16]=2)[C:12]([O:14][CH3:15])=[O:13])(=[O:23])=[O:22])=[CH:25][CH:26]=1
Reactant: COC(=O)c1cc(OS(=O)(=O)c2ccc(C)cc2)ccc1O
Reactant: BrCc1ccccc1
Product: COC(=O)c1cc(OS(=O)(=O)c2ccc(C)cc2)ccc1OCc1ccccc1

Procedure:
(Bromomethyl)benzene (3.81 g, 22.26 mmol) was added to methyl 2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}benzoate (may be prepared as described in Description 36; 2.87 g, 8.90 mmol) and the resulting mixture was refluxed overnight. After cooling, the resulting precipitate was filtered and the filtrate was evaporated. The crude product was purified by silica gel chromatography, eluting with a 4:1 mixture of hexane:ethyl acetate to yield the title compound as a colourless oil. 2.7 g.
Reaction SMILES: [F:1][C:2]([S:5][CH2:6][C:7]([NH:9][CH:10]1[C:28](=[O:29])[N:12]2[C:13]([C:25]([O-:27])=[O:26])=[C:14]([CH:17]([S:19][C:20]3[NH:24][N:23]=[N:22][N:21]=3)[CH3:18])[CH2:15][S:16][C@H:11]12)=[O:8])([F:4])[F:3].[Na+].[C:31]([O:34][CH2:35]Br)(=[O:33])[CH3:32]>CN(C=O)C.O>[F:1][C:2]([S:5][CH2:6][C:7]([NH:9][CH:10]1[C:28](=[O:29])[N:12]2[C:13]([C:25]([O:27][CH2:35][O:34][C:31](=[O:33])[CH3:32])=[O:26])=[C:14]([CH:17]([S:19][C:20]3[NH:21][N:22]=[N:23][N:24]=3)[CH3:18])[CH2:15][S:16][C@H:11]12)=[O:8])([F:4])[F:3]
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)[O-])N2C(=O)C(NC(=O)CSC(F)(F)F)[C@H]2SC1
Reactant: CC(=O)OCBr
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCOC(=O)C1=C(C(C)Sc2nnn[nH]2)CS[C@@H]2C(NC(=O)CSC(F)(F)F)C(=O)N12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a cold solution of sodium 7-trifluoromethylmercaptoacetamido-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate (738 mg, 1.5 mmol) in dry DMF (10 ml) is added a solution of bromomethyl acetate (253 mg, 1.65 mmol) in DMF (1 ml). The reaction is stirred for 30 minutes at 0°C and 90 minutes at room temperature. The reaction is diluted with water and the aqueous mixture is extracted with ethyl acetate. The extracts are washed with water, dried and evaporated to give acetoxymethyl 7-trifluoromethylmercaptoacetamido-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate. The product is dissolved in ethyl acetate and is precipitated by the addition of petroleum ether.
Reaction SMILES: [OH:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[N+:29]([C:32]1[CH:33]=[C:34](O)[CH:35]=[CH:36][CH:37]=1)([O-:31])=[O:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[CH3:20][CH:19]([CH3:21])[C:18]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C@@H:2]([O:1][C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([N+:29]([O-:31])=[O:30])[CH:37]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:6][CH2:7]2)[CH:12]=1)=[O:22]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](O)c3ccccc3)CC2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](Oc3cccc([N+](=O)[O-])c3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40.7 %

Procedure:
A mixture of N-(3-{1-[(3S)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 3-nitrophenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (2.80 mg, 40.8% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 7.76 (dm, 1H), 7.71 (t, 1H, J=1.8 Hz), 7.50-7.40 (m, 2H), 7.40-7.25 (m, 7H), 7.17 (apparent dd, 1H, J=2.4, 8.2), 6.97 (apparent d, 1H, J=7.7 Hz), 5.45 (apparent dd, 1H, J=5.0, 8.1 Hz), 3.45 (m, 2H), 2.89 (m, 2H), 2.53 (apparent sept, partially hidden, 2H, J=8.3 Hz), 2.30-2.10 (m, 6H), 1.92 (m, 2H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 502.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.[NH2:10][C@@H:11]([CH3:28])[CH2:12][N:13]1[CH:17]=[CH:16][C:15]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([Cl:26])[C:19]=2[CH3:27])=[N:14]1>>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:10][C@@H:11]([CH3:28])[CH2:12][N:13]2[CH:17]=[CH:16][C:15]([C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([Cl:26])[C:19]=3[CH3:27])=[N:14]2)=[O:9])[N:6]=1
Reactant: Nc1nc(C(=O)O)cs1
Reactant: Cc1c(-c2ccn(C[C@H](C)N)n2)ccc(C#N)c1Cl
Product: Cc1c(-c2ccn(C[C@H](C)NC(=O)c3csc(N)n3)n2)ccc(C#N)c1Cl
Yield: 16.65 %

Procedure:
(S)-2-amino-N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)-propan-2-yl)thiazole-4-carboxamide was prepared using the method of Example 34(d) starting from 2-Aminothiazole-4-carboxylic acid (0.504 g 3.49 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile (0.8 g, 2.91 mmol). The product was purified by Flash-chromatography. Yield 16.65%. 1H-NMR (400 MHz; CDCl3): δ 1.24 (d, 3H), 2.58 (s, 3H), 4.30 (dd, 1H), 4.40 (dd, 1H), 4.53 (m, 1H), 4.86 (s, 2H), 7.44 (d, 1H), 7.35 (s, 1H), 7.51 (d, 1H), 7.54 (dd, 1H), 7.57 (d, 1H), 7.63 (d, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][CH:26]=1)[O:7][C:8]1[C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=[CH:10][N:9]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO.[Cl-].[Na+].O>[OH:3][CH:1]([C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][CH:26]=1)[O:7][C:8]1[C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:2]
Reactant: CC(=O)c1cccc(Oc2ncccc2OCCCc2ccncc2)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(O)c1cccc(Oc2ncccc2OCCCc2ccncc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-(3-Acetylphenoxy)-3-[3-(pyridin-4-yl)propoxy]pyridine (0.20 g, 0.3 mmol) obtained in Example 60 is dissolved in methanol (10 ml), and thereto is added sodium borohydride (0.50 g, 13 mmol), and the mixture is stirred at room temperature for 10 minutes. To the reaction solution is added a saturated brine (50 ml), and the mixture is extracted with ethyl acetate (100 ml). The organic layer is washed with a saturated brine (50 ml×2); dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: chloroform/methanol) to give 2-[3-(1-hydroxyethyl)phenoxy]-3-[3-(pyridin-4-yl)propoxy]pyridine, which is further treated with fumaric acid to give the title compound (0.06 g), m.p. 93-97° C. (recrystallized from ethanol/diethyl ether).
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[N:5]=[N:6][CH:7]=[C:8]([O:10][Si](C)(C)C)[N:9]=1.Br[CH2:18][CH2:19][CH2:20][CH2:21][Cl:22].CO>ClC(Cl)C.II>[Cl:22][CH2:21][CH2:20][CH2:19][CH2:18][N:5]1[C:4](=[O:3])[NH:9][C:8](=[O:10])[CH:7]=[N:6]1
Reactant: C[Si](C)(C)Oc1cnnc(O[Si](C)(C)C)n1
Reactant: ClCCCCBr
Agent: II
Solvent: CC(Cl)Cl
Solvent: CO
Product: O=c1cnn(CCCCCl)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 25 h
Yield: 76.5 %

Procedure:
22.1 g of 3,5-Bis-trimethylsilanyloxy-[1,2,4]triazine (86 mmol) were dissolved in 150 mL of dichloroethane followed by addition of 14.7 g of 1-bromo-4-chloro-butane (86 mmol) and 0.218 g of iodine (0.858 mmol). The reaction mixture was stirred for 25 h at room temperature. Then, 300 mL of methanol were added and the mixture was stirred for an additional 10 minutes. The solvents were evaporated under reduced pressure and the residue was partitioned between dichloromethane and water. The aqueous phase was extracted several times with dichloromethane. The combined organic layers were washed with 10% aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the organic phase was evaporated under reduced pressure. The thus obtained crude product was purified via silica gel chromatography using dichloromethane-methanol 0-10% to yield 13.4 g of the desired product.
Reaction SMILES: F[B-](F)(F)F.[CH3:6][N+:7]1[C:11](SC(C)CC)=[N:10][N:9]([CH:17]([CH3:20])[CH2:18][CH3:19])[N:8]=1.[OH-:21].[Na+]>O>[CH3:6][N+:7]1[C:11]([O-:21])=[N:10][N:9]([CH:17]([CH3:20])[CH2:18][CH3:19])[N:8]=1
Reactant: CCC(C)Sc1nn(C(C)CC)n[n+]1C
Reactant: [OH-]
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: O
Product: CCC(C)n1nc([O-])[n+](C)n1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
Thus, 1-methyl-3-(1-methylpropyl)-5-(1-methylpropylthio)tetrazolium tetrafluoroborate (137 mg, 0.43 mmol) was introduced into a recovery flask; an aqueous sodium hydroxide solution (prepared by the dissolution of sodium hydroxide (24 mg, 0.60 mmol) in water (10 mL)) was added to the recovery flask; and stirring was carried out for 30 minutes. Extraction with methylene chloride, drying over anhydrous sodium sulfate, and distillation of the solvent yielded 1-methyl-3-(1-methylpropyl)tetrazolium-5-olate (yield=65 mg, 100%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[N+:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])([O-:29])=[O:28].C1CCN2C(=NCCC2)CC1>>[N+:27]([CH:30]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:12](=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([O-:29])=[O:28]
Reactant: O=C(O)CCCCCc1ccccc1
Reactant: CCCCCC[N+](=O)[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCCC(C(=O)CCCCCc1ccccc1)[N+](=O)[O-]

Procedure:
6-Phenylhexanoic acid (0.150 g, 0.78 mmol) and CDI (0.253 g, 1.56 mmol) were added together and then reacted with nitrohexane (0.153 g, 1.17 mmol) and DBU (0.297 g, 1.95 mmol) according to the general procedure. Purification by column chromatography gave 0.090 g (38%) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.28 (m, 2H), 7.17 (m, 3H), 5.11 (dd, J=4.8, 10.4 Hz, 1H), 2.61 (m, 4H), 1.63 (m, 6H), 1.33 (m, 8H) 0.90 (t, J=6.8 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 199.5, 142.5, 128.6, 128.5, 126.0, 94.6, 39.5, 35.9, 31.3, 31.2, 29.9, 28.7, 25.7, 23.3, 22.4, 14.1 ppm; IR νmax (cm−1) 3027, 2930, 2858, 1731, 1559, 1454, 1363, 1030, 748, 699; HRMS (FAB) calcd for C18H27NO3 (MNa+) 328.1883, found 328.1881.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.[F:16][C:17]1[C:22]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[C:21]([F:29])[CH:20]=[CH:19][C:18]=1B(O)O>>[F:29][C:21]1[C:22]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[C:17]([F:16])[CH:18]=[CH:19][C:20]=1[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Reactant: OB(O)c1ccc(F)c(-c2cccnc2)c1F
Product: Fc1ccc(-c2ccnc3nc(C(F)(F)F)ccc23)c(F)c1-c1cccnc1
Yield: 31.7 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (50 mg, 0.22 mmol) was coupled to 2,4-difluoro-3-(pyridin-3-yl)benzeneboronic acid (66 mg, 0.28 mmol) as described in Example 7 part g), affording 5-(2,4-difluoro-3-pyridin-3-ylphenyl)-2-trifluoromethyl[1,8]naphthyridine (27 mg, 34%). δH (360 MHz, CDCl3) 7.28 (1H, m), 7.42-7.49 (2H, m), 7.63 (1H, d, J 4.6), 7.84-7.88 (2H, m), 8.35 (1H, dd, J 2.3 and 8.6), 8.69 (1H, dd, J 1.8 and 4.9), 8.80 (1H, s), 9.33 (1H, d, J 4.2). m/z (ES+) 388 [MH]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1Br.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([O:9][CH3:10])[C:3]=1[O:2][CH3:1]
Reactant: Fc1ccccc1Br
Reactant: COc1cccc(B(O)O)c1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cccc(-c2ccccc2F)c1OC
Temperature: 25 °C
Yield: 84.8 %

Procedure:
In the atmosphere of argon, 18.2 g of 2,3-dimethoxyphenylboronic acid, 17.5 g of 2-fluorobromobenzene, 2.31 g of tetrakistriphenylphosphine palladium (0), 300 mL of 1,2-dimethoxyethane and 150 mL of an aqueous 2M sodium carbonate solution were placed in a flask. The resulting mixture was stirred with heating under reflux for 8 hours. After cooling to room temperature, an aqueous phase was removed, and an organic phase was washed with saturated saline. The organic phase was dried with magnesium sulfate and then concentrated. Residues were purified by silica gel column chromatography, whereby 19.7 g of (yield 85%) of 2′-fluoro-2,3-dimethoxybiphenyl was obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.[CH2:15]([NH:17][CH2:18][C:19]12[CH2:26][CH2:25][CH2:24][N:23]1[CH2:22][CH2:21][CH2:20]2)[CH3:16].[I-].[Na+].[OH-].[Na+]>N1C=CC=CC=1>[N:23]12[CH2:24][CH2:25][CH2:26][C:19]1([CH2:18][N:17]([C:2]1[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1)[CH2:15][CH3:16])[CH2:20][CH2:21][CH2:22]2
Reactant: CCNCC12CCCN1CCC2
Reactant: O=[N+]([O-])c1ccc(Cl)c2ccccc12
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CCN(CC12CCCN1CCC2)c1ccc([N+](=O)[O-])c2ccccc12
Yield: 30.6 %

Procedure:
1-Chloro-4-nitronaphthalene (2.00 g, 9.63 mmol), 5-ethylaminomethyl-1-azabicyclo[3.3.0]octane (3.24 g, 19.3 mmol) and sodium iodide (580 mg) were added into anhydrous pyridine (20.0 ml) to react the mixture in a sealed tube for 20 hours at 190° C. After addition of aqueous sodium hydroxide solution subsequent to concentration in vacuo, the reaction mixture was extracted by ethyl acetate, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by column chromatography to afford the desired compound (1.00 g, 30.6%), as a yellow liquid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][O:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:5][CH2:4]1.[H-].[Na+].CS(O[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])(=O)=O.C(OCC)(=O)C>C1C=CC=CC=1>[CH2:37]([O:1][CH2:2][CH:3]1[CH2:4][O:5][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:7][CH2:8]1)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22]
Reactant: CCCCCCCCCCCCCCCCOS(C)(=O)=O
Reactant: OCC1COC(c2ccccc2)OC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCOCC1COC(c2ccccc2)OC1
Temperature: 50 °C
Yield: 96.8 %

Procedure:
A suspension of 7.769 g (40 mM) of 5-hydroxymethyl-2-phenyl-1,3-dioxane n1 and 2.08 g (52 mM) of 60% sodium hydride in oil in 150 ml of anhydrous benzene is heated at 50° C. for 1 hour then a solution of 17.28 g (54 mM) of n-hexadecyl methanesulfonate in 50 ml of anhydrous benzene is added. The reaction mixture is heated under refluxing for 7 hours. The product is isolated by ethyl acetate extraction. The ethyl acetate layer is washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated. Crystallization of the residue from n-pentane-methanol affords 16.203 g (97% yield) of the titled compound n2.
Reaction SMILES: Br[CH2:2]/[CH:3]=[C:4](\[CH3:9])/[C:5]([O:7][CH3:8])=[O:6].[CH3:10][NH:11][CH3:12]>O1CCCC1>[CH3:10][N:11]([CH3:12])[CH2:2]/[CH:3]=[C:4](\[CH3:9])/[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)/C(C)=C/CBr
Reactant: CNC
Solvent: C1CCOC1
Product: COC(=O)/C(C)=C/CN(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To methyl(2E)-4-bromo-2-methylbut-2-enoate (643 mg, 3.33 mmol) in tetrahydrofuran (6.66 mL) was added dimethylamine (5.00 mL, 9.99 mmol, 2M in THF). The reaction was stirred at 25° C. overnight, then concentrated in vacuo and purified by silica chromatography using 1-8% DCM/MeOH (visualized with potassium permanganate stain). The product was collected and concentrated to afford the desired product as a colorless oil. LRMS (ESI) calc'd for C8H16NO2 [M+H]+: 158, found 158.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH2:10])=[O:9])[CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1>>[C:8]([C:4]1[CH:3]=[C:2]([O:18][C:14]2[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=2)[NH2:11])[CH:7]=[CH:6][N:5]=1)(=[O:9])[NH2:10]
Reactant: NC(=O)c1cc(Cl)ccn1
Reactant: Nc1cccc(O)c1
Product: NC(=O)c1cc(Oc2cccc(N)c2)ccn1

Procedure:
Entry 44: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide was reacted with 3-aminophenol according to Method A1, Step 4 to form 3-(2-carbamoyl-4-pyridyloxy)aniline. According to Method C1a, 4-chloro-3-(trifluoromethylphenyl isocyanate was reacted with 3-(2-carbamoyl-4-pyridyloxy)aniline to afford the urea.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Cl:16][C:17]1[CH:22]=[C:21]([S:23]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[F:33])(=[O:25])=[O:24])[CH:20]=[CH:19][C:18]=1F>>[Cl:16][C:17]1[CH:22]=[C:21]([S:23]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[F:33])(=[O:24])=[O:25])[CH:20]=[CH:19][C:18]=1[O:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: O=S(=O)(Cc1ccccc1F)c1ccc(F)c(Cl)c1
Reactant: O=C(O)Cc1cc(O)cc(C(F)(F)F)c1
Product: O=C(O)Cc1cc(Oc2ccc(S(=O)(=O)Cc3ccccc3F)cc2Cl)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from example 25 step (iv) and the product from step (i).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][N:18]1[C:22]([Cl:23])=[CH:21][CH:20]=[N:19]1>CN(C=O)C>[Cl:23][C:22]1[N:18]([CH2:17][S:8][C:6]2[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=2)[N:19]=[CH:20][CH:21]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Clc1ccnn1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(SCn2nccc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 4 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (4.8 g, 33.9 mmol) was dissolved in anhydrous DMF (180 mL), then potassium carbonate (14.0 g, 102 mmol) and 1-(bromomethyl)-5-chloro-1H-pyrazole (8.5 mmol) in DMF (20 mL) were added. The mixture was stirred overnight at room temperature. The solid was removed by filtration and washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 3-10% DCM/MeOH to afford 2-{[(5-chloro-1H-pyrazol-1-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (88 mg, 1.0% yield for 6 steps); 1H NMR (400 MHz, DMSO-d6): δ 2.24 (s, 3H), 5.85 (s, 2H), 6.10 (bs, 1H), 6.30 (d, J=2.3 Hz, 1H), 7.93 (s, 1H); LRMS (ES+) m/z 257 (45%, M+1), 259 (15%, M+3).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH2:8][C:9]32[C:15](=[O:16])[NH:14][C:13](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.C(=O)(O)[O-:19].[Na+].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)(Cl)Cl>[O:19]1[CH:6]2[CH:7]1[CH2:8][C:9]1([C:15](=[O:16])[NH:14][C:13](=[O:17])[NH:12]1)[C:10]1[C:5]2=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=1
Reactant: O=C([O-])O
Reactant: O=C1NC(=O)C2(CC=Cc3ccc(F)cc32)N1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C1NC(=O)C2(CC3OC3c3ccc(F)cc32)N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 22 %

Procedure:
To a slurry of 2.6 g. (0.011 mole) of 7'-fluorospiro[imidazolidine-4,1'(2'H)-naphthalene]2,5-dione in 50 ml. of chloroform was added 125 ml. of a 5% sodium bicarbonate solution followed by 3.0 g. (0.014 mole) of m-chloroperbenzoic acid. The reaction mixture was allowed to stir at room temperature for 4 hours after which an additional 1.2 g. (0.0055 mole) of m-chloroperbenzoic acid were added. After stirring overnight at room temperature the mixture was poured into 100 ml. of a 5% sodium bicarbonate solution and the mixture extracted (2×100 ml.) with chloroform and then with ethyl acetate (2×100 ml.). The organic extracts were combined, washed with water and a brine solution and dried over magnesium sulfate. Removal of the solvent gave 600 mg. (22% yield) of the desired product.