Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(C)(C)C#N)=N[C:3](C)(C)C#N.[CH3:13][C:14]([C:16]([O:18][CH2:19][CH2:20][CH2:21][Si:22](OC)([O:25][CH3:26])[O:23][CH3:24])=[O:17])=[CH2:15]>C1(C)C=CC=CC=1>[C:16]([O:18][CH2:19][CH2:20][CH2:21][Si:22]([CH3:3])([O:25][CH3:26])[O:23][CH3:24])(=[O:17])[C:14]([CH3:13])=[CH2:15]
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Reactant: C=C(C)C(=O)OCCC[Si](OC)(OC)OC
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)OCCC[Si](C)(OC)OC

Procedure:
Next, the 51.99 mg of silk fibroin fiber having a vinyl group (hereinafter referred to as a vinyl introduction SF), 10 ml of anhydrous toluene, 132.19 mg of azobisisobutyronitrile as an initiator, and 1.0 g of methacryloxypropylmethyldimethoxysilane (Product No KBM-503 produced by Shin-Etsu Chemical Co.Ltd: hereinafter referred to as KBM) were contained in a polymer glass tube, and then were subjected to several sets of deairing/nitrogen gas filling. Then, the materials were sealed to react with each other at 60° C. for a predetermined period. The resultant is a silk fibroin fiber (hereinafter referred to as KBM-g-SF) in which a high molecular chain containing an alkoxysilyl group in its end is bonded to a polymer-based material through graft polymerization. Table 1 shows the introduction ratio (%) of alkoxysilyl group in this case at each given reaction time. Note that, the introduction ratio was found according to the following Formula (1), in which ag expresses the weight of the vinyl introduced SF and bg expresses the weight of the KBM-g-SF. Introduction ratio (%)=((b−a)/a)×100  (1)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](OS(C(F)(F)F)(=O)=O)=[C:6]([C:8]2[N:13]=[C:12]([N:14]3[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]3)[CH:11]=[CH:10][CH:9]=2)[CH:7]=1.[CH3:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][SH:45])=[CH:40][CH:39]=1.CCN(C(C)C)C(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.CCCCCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][S:45][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][C:6]=2[C:8]2[N:13]=[C:12]([N:14]3[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]3)[CH:11]=[CH:10][CH:9]=2)=[CH:40][CH:39]=1
Reactant: COc1ccc(CS)cc1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3cc(C)ccc3OS(=O)(=O)C(F)(F)F)n2)c1C(F)(F)F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnn(-c2cccc(-c3cc(C)ccc3SCc3ccc(OC)cc3)n2)c1C(F)(F)F
Temperature: 90 °C
Reaction time: 15 h

Procedure:
To a solution of title compound from Example 243 Step A (2.74 g, 5.23 mmol), 4-methoxy α-toluenethiol (0.88 mL, 6.28 mmol) in 1,4-dioxane (75 mL) were added DIEA (1.83 mL, 10.5 mmol), Xantphos (0.61 g, 1.05 mmol) and tris(dibenzylideneacetone)dipalladium (0) (0.48 g, 0.52 mmol), and the reaction mixture was heated at 90° C. After 15 h, the reaction mixture was allowed to cool to ambient temperature, then was diluted with hexane. The resulting yellow solid was removed by filtration, and the collected organic filtrate was concentrated in vacuo. Purification by flash chromatography on silica gel (5 to 20% ethyl acetate in hexanes) provided the title compound: LCMS m/z 528.6 [M+H]+; 1H NMR (500 MHz, CD2Cl2) δ 8.11 (s, 1H), 7.94 (t, J=7.9 Hz, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.36 (m, 2 H), 7.17 (d, J=8.0 Hz, 1H), 7.04 (d, J=8.5 Hz, 2H) 6.74 (d, J=8.7 Hz, 2H) 4.35 (q, J=7.1 Hz, 2H), 3.87 (s, 2H), 3.73 (s, 3H), 2.37 (s, 3H), 1.37 (t, J=7.1 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+].CCCCCCC>C(OCC)(=O)C>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][N:3]1[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]1=[O:1])[CH3:16]
Reactant: CCOC(=O)CBr
Reactant: COc1cccnc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1cccc(OC)c1=O
Yield: 92 %

Procedure:
As described for example 320a, 2-hydroxy-3-methoxy-pyridine was reacted with ethyl bromoacetate and potassium carbonate. Extractive workup followed by chromatography (SiO2, heptane:ethyl acetate=100:0 to 0: 100) afforded the title compound as a white solid (yield: 92%). MS: m/e=212.3[M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[C:17]([OH:19])[C:16]([O:20][CH3:21])=[CH:15][C:14]=2[CH:22]([CH2:26][CH3:27])[C:23](=O)[CH3:24])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:28][NH2:29].Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:13]3[CH:18]=[C:17]([OH:19])[C:16]([O:20][CH3:21])=[CH:15][C:14]=3[CH:22]([CH2:26][CH3:27])[C:23]([CH3:24])=[N:29][N:28]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCC(C(C)=O)c1cc(OC)c(O)cc1C(=O)c1ccc(OC)c(OC)c1
Reactant: NN
Agent: Cl
Solvent: CCO
Product: CCC1C(C)=NN=C(c2ccc(OC)c(OC)c2)c2cc(O)c(OC)cc21
Temperature: 25 °C

Procedure:
A solution of 14 g of 3-{2-[(3,4-dimethoxyphenyl)carbonyl]-4-hydroxy-5-methoxyphenyl}pentan-2-one and 4.7 mL of hydrazine in 280 mL of ethanol was heated at reflux for 0.5 hr. After allowing the solution to cool to room temperature, it was saturated with HCl gas. The mixture was then concentrated to a volume of about 5 mL, basified with concentrated ammonium hydroxide, and extracted with methylene chloride. The combined methylene chloride extracts were dried and concentrated, and the residue recrystallized from ethyl acetate/hexane. Yield: 1.5 g
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][C:8]1[N:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[CH:10][CH:9]=1>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][C:8]1[N:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[CH:10][CH:9]=1)(=[O:4])=[O:3]
Reactant: COC(=O)c1cccc(CO)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1cccc(COS(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methanesulphonyl chloride (0.28 ml) was added at 0° C. to a solution of methyl 6-hydroxymethylpicolinate (500 mg), TEA (0.5 ml) in DCM (5 ml). The mixture was stirred at rt for 1 hour, then diluted with DCM (50 ml) and washed with water (2×30 ml). Organic layer dried, solvent removed under vacuum to give expected product methyl 6-((methylsulfonyloxy)methyl)picolinate (770 mg). 1H NMR (CDCl3) δ: 8.11 (d, 1H), 7.93 (t, 1H), 7.70 (d, 1H), 5.44 (s, 2H), 4.01 (s, 3H), 3.16 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[CH:11]([F:13])[F:12]>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[CH:11]([F:12])[F:13]
Reactant: O=[N+]([O-])c1ccc(Cl)c(C(F)F)c1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1ccc(Cl)c(C(F)F)c1
Temperature: 115 °C
Yield: 76 %

Procedure:
To a suspension of iron powder (16 g) in acetic acid (95 ml) was added 1-chloro-2-difluoromethyl-4-nitro-benzene (5.1 g, 15 mmol) and the reaction mixture was heated to 115° C. for 15 minutes. The mixture was filtered and the residue was washed with acetic acide and CH2Cl2. Evaporation of the solvent gave the crude product. It was further purified by chromatography over silica gel to give 4-chloro-3-difluoromethyl-phenylamine (76%), MS: m/e=177.1 (M+).
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][C:7](=[O:21])[C:8](=O)[CH2:9][C:10](=O)[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:5]>CCO>[CH2:4]([O:6][C:7]([C:8]1[CH:9]=[C:10]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:3][N:2]=1)=[O:21])[CH3:5]
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)COc1ccccc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(COc2ccccc2)[nH]n1
Yield: 54.7 %

Procedure:
Hydrazine hydrate (0.197 mL, 4.06 mmol) was added to a stirring room temperature solution of 40 (1.0163 g, 4.06 mmol) in EtOH (4.1 mL, 1 M) under N2. The reaction was then heated to reflux until judged complete by HPLC. The reaction was concentrated and purified by silica gel chromatography (Combiflash column, 92:4:4 Hexanes: CH2Cl2:2N NH3 in EtOH): Only pure fractions were combined and concentrated to obtain 0.5474 g (54.7%) of 41. 1H (CDCl3, 400 MHz): δ 12.12 (1H, broad s), 7.28 (2H, t, J=7.8 Hz), 7.01-6.94 (3H, m), 6.91 (1H, s), 5.17 (2H, s), 4.36 (2H, q, J=7.0 Hz), 1.36 (3H, t, J=7.1 Hz) ppm. Partial 13C (CDCl3, 100 MHz): δ 158.11, 129.48, 121.26, 114.71, 107.83, 62.61, 61.31, 14.17 ppm. HPLC: 9.505 min.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(Cl)(Cl)Cl.[Cl:11][C:12]1[CH:27]=[CH:26][C:15]2[CH2:16][C:17]3[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=3[NH:19][C:20](=O)[C:14]=2[CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[Cl:11][C:12]1[CH:27]=[CH:26][C:15]2[CH2:16][C:17]3[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=3[NH:19][CH2:20][C:14]=2[CH:13]=1
Reactant: O=C1Nc2ccccc2Cc2ccc(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: Clc1ccc2c(c1)CNc1ccccc1C2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a suspension of 1.5 g lithium aluminium hydride in 100 ml tetrahydrofuran is added with ice cooling first 1.05 ml chloroform and thereafter portionwise 3.0 g of 8-chloro-5,6-dihydro-11H-dibenz[b,e]azepin-6-one. The mixture is stirred at room temperature for 15 hours. To the mixture is then added dropwise under ice cooling 9.0 ml of a saturated solution of potassium carbonate. The precipitate is filtered off and washed with ether. The filtrate is then evaporated and the residue recrystallised from methylene chloride/ether/petroleum ether to give the heading compound, m.p. 132°-135°.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][CH2:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15](=[NH+:19][O:20][CH3:21])[C:16]([OH:18])=O)[N:14]=1)=[O:8].[NH2:22][CH:23]1[C:38](=[O:39])[N:25]2[C:26]([C:35]([OH:37])=[O:36])=[C:27]([CH2:30][S:31][C:32](=[O:34])[CH3:33])[CH2:28][S:29][C@H:24]12>C(Cl)Cl.C(N(CC)CC)C>[C:32]([S:31][CH2:30][C:27]1[CH2:28][S:29][C@@H:24]2[CH:23]([NH:22][C:16](=[O:18])[C:15]([C:13]3[N:14]=[C:10]([NH:9][C:7](=[O:8])[CH2:6][Cl:5])[S:11][CH:12]=3)=[N:19][O:20][CH3:21])[C:38](=[O:39])[N:25]2[C:26]=1[C:35]([OH:37])=[O:36])(=[O:34])[CH3:33]
Reactant: CO[NH+]=C(C(=O)O)c1csc(NC(=O)CCl)n1
Reactant: CC(=O)SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSC(C)=O)CS[C@H]12)c1csc(NC(=O)CCl)n1
Reaction time: 0.25 h

Procedure:
3.8 ml of thionyl chloride and 26 ml of methylene chloride were added at 0° C. under nitrogen to a mixture of 15.3 g of the syn isomer of 2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminioacetic acid in 80 ml of methylene chloride and after standing at 0° C. for 15 minutes, 7 ml of triethylamine were added thereto. A mixture of 14.4 g of 7-amino-3-acetylthiomethyl-ceph-3-eme-4-carboxylic acid in 100 ml of methylene chloride and 14 ml of triethylamine were added to the mixture at 0° C. under nitrogen and the temperature was allowed to return to 20° C. The mixture was stirred for an hour and was then evaporated to dryness at 30°-35° C. under reduced pressure. The residue was taken up in 250 ml of water and the solution was raised through carbon black. 50 ml of 2 N hydrochloric acid were added thereto and the mixture was vacuum filtered. The product was washed with water and the raw product was suspended in 80 ml of ethanol. 7 ml of triethylamine were added thereto at 5° C. and 15 ml of 4 N sulfuric acid were added thereto all at once with stirring at 5° C. After standing for 15 minutes, the mixture was vacuum filtered and the product was empasted with ethanol, then with ether and was dried under reduced pressure to obtain the syn isomer of 3-acetylthiomethyl-7-[{2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetyl}amino]-ceph-3-eme-4-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([NH:24][CH2:25][C:26]2([C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:23])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.Cl[C:39]([O:41][CH2:42][CH2:43][O:44][CH3:45])=[O:40]>>[F:1][C:2]1[C:3]([C:22]([NH:24][CH2:25][C:26]2([C:32]3[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=3)[CH2:27][CH2:28][N:29]([C:39]([O:41][CH2:42][CH2:43][O:44][CH3:45])=[O:40])[CH2:30][CH2:31]2)=[O:23])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1
Reactant: COCCOC(=O)Cl
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccncc5)CCNCC4)c3F)s2)c1
Product: COCCOC(=O)N1CCC(CNC(=O)c2nccc(Sc3cnc(Nc4cc(C)ccn4)s3)c2F)(c2ccncc2)CC1

Procedure:
Following the procedure given for example 81, 3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)-N-((4-(pyridin-4-yl)piperidin-4-yl)methyl)picolinamide (compound example 45) was reacted with 2-methoxyethyl chloroformate to give the title compound. LC/MS (M+H)+: 638. Ret. time: 1.31 min. (Condition I); analytical HPLC Ret. time: 5.30 min (Condition H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]3[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=3[N:22]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:36]([OH:38])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[NH:40][C:41](=[NH:43])[CH3:42].N1(O)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[CH3:31][O:30][CH2:29][CH2:28][CH2:27][CH2:26][N:25]1[C:24]2[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=2[N:22]=[C:21]1[C:19]([N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C@H:12]1[CH2:11][C@@H:10]([C:36]2[O:38][N:43]=[C:41]([CH3:42])[N:40]=2)[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13]1)=[O:20]
Reactant: CC(=N)NO
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](c3nc(C)no3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 114.1 %

Procedure:
(3R,5S)-1-(tert-Butoxycarbonyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylic acid (265 mg), N-hydroxy acetamidine (56 mg), 1H-benzotriazol-1-ol (95 mg) and N,N-diisopropylethylamine (259 μl)) were dissolved in DMF (10 ml), WSC.HCl (144 mg) was added and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in toluene (15 ml), and the mixture was refluxed under heating for 15 hr. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure to give tert-butyl (3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate (324 mg). The obtained tert-butyl (3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate was dissolved in 4M hydrogen chloride-ethyl acetate (5 ml), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated, and the residue was diluted with aqueous sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure. The residue was dissolved in methanol (3 ml), 4M Hydrogen chloride-ethyl acetate (1 ml) was added and the mixture was stirred for 5 min. The solvent was evaporated under reduced pressure to give the object product (74 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:5][N:6]1[C:15](=[S:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]([O:20]CC)=[O:19])[C:7]1=[S:23].[OH-].[Na+].O1CCCC1.Cl>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:5][N:6]1[C:15](=[S:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]([OH:20])=[O:19])[C:7]1=[S:23]
Reactant: CCOC(=O)Cn1c(=S)n(Cc2ccc(Cl)c(Cl)c2)c(=S)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)Cn1c(=S)n(Cc2ccc(Cl)c(Cl)c2)c(=S)c2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 45.2 %

Procedure:
A mixture of ethyl 2-[3-(3,4-dichlorobenzyl)-1,2,3,4-tetrahydro-2,4-dithioxoquinazolin-1-yl]acetate (85 mg), 1N aqueous sodium hydroxide (0.5 ml) and tetrahydrofuran (1 ml) was stirred at room temperature for 20 hours. The reaction mixture was poured into a mixture of ethyl acetate and 0.5N hydrochloric acid. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. The solvent was removed and the residue was crystallized from chloroform to give 2-[3-(3,4-dichlorobenzyl)-1,2,3,4-tetrahydro-2,4-dithioxoquinazolin-1-yl]acetic acid (36 mg).
Reaction SMILES: [CH3:1][C:2]1([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][Si](C(C)(C)C)(C)C)=[CH:26][CH:25]=3)=[O:21])[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OCC)(=O)C>[CH3:1][C:2]1([CH2:13][N:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=3)=[O:21])[CH2:18][CH2:19]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: CC1(CN2CCN(C(=O)OCc3ccc(O[Si](C)(C)C(C)(C)C)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(CN2CCN(C(=O)OCc3ccc(O)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Reaction time: 0.33 h
Yield: 30.3 %

Procedure:
To a mixture of 4-(tert-butyldimethylsilanyloxy)benzyl 4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylate (400 mg, 0.75 mmol) and THF(10 ml), a 1M solution of tetrabutylammonium fluoride in THF (0.8 ml, 0.8 mmol) was added followed by stirring for 20 minutes with cooling on ice-bath. To the reaction mixture, ethyl acetate was added, and the solution was washed with a saturated ammonium chloride solution, water and a saturated saline solution in this order, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. To the residue, diethyl ether was added, and the precipitates were filtered off to afford 4-hydroxybenzyl 4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylate (95 mg, yield 30%) as a light yellow powder.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:30]=[CH:29][C:19]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)=[O:21])=[CH:18][CH:17]=1.C>CCCCCC.O>[F:28][C:24]1[CH:23]=[C:22]([C:20]([C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[CH:30][CH:29]=2)=[O:21])[CH:27]=[CH:26][CH:25]=1
Reactant: Nc1ccc(C(=O)c2cccc(F)c2)cc1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Agent: C
Solvent: O=S(Cl)Cl
Solvent: CCCCCC
Solvent: O
Product: CC(O)(C(=O)Nc1ccc(C(=O)c2cccc(F)c2)cc1)C(F)(F)F
Reaction time: 1 h

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.58 g, 10 mmol) in N,N-dimethylcetamide (15 mL) was added thionyl chloride (1.25 g, 10.5 mmol) and the mixture stirred at -20° to -10° C. for 1 hour. 4-Amino-3'-fluorobenzophenone (1.44 g, 6.7 mmol) was added in one portion and the reaction mixture stirred at room temperature overnight. The mixture was poured into water to yield an oil and a cloudy solution. The cloudy solution was decanted from the oil and filtered by suction through a pad of Celite. The Celite pad was washed with methylene chloride and the solution added to a solution of the gum in methylene chloride. The solution was dried (MgSO4), filtered and the solvent removed in vacuo. The resulting oil was chromatographed on silica gel (ethyl ether), the proper fractions combined and the solvent removed to yield an oil. The oil was dissolved in 50 mL of hexane containing enough methylene chloride to give a clear solution and the solution concentrated on a steambath until the solution became cloudy. The resulting pale yellow solid was collected by filtration and dried to yield 1.51 g (63%) of N-[4-(3-fluorophenylcarbonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylproanamide, mp 121.5°-3° C. 1H-NMR (250 MHz, d6-DMSO): 1.59 (s, 3H, CH3) 3.32 (s, 1H, OH) 7.46-7.60 (m, 4H, aromatic) 7.75 (d, 2H, J=9.1 Hz aromatic) 7.96 (d, 2H, J=8.2 Hz, aromatic) 10.33 (s, 1H, NH). MS (CI, CH4): 356 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][C:14]([S:18]([N:21]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[C:22]3[S:23][CH:24]=[CH:25][N:26]=3)(=[O:20])=[O:19])=[CH:15][CH:16]=2)[CH:11]=[CH:10][N:9]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:43][C:44]#[N:45]>CN(C=O)C>[C:44]([CH2:43][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][C:14]([S:18]([N:21]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=3)[C:22]3[S:23][CH:24]=[CH:25][N:26]=3)(=[O:20])=[O:19])=[CH:15][CH:16]=2)[CH:11]=[CH:10][N:9]=1)#[N:45]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccccc4O)nccc3c2)cc1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccccc4OCC#N)nccc3c2)cc1
Temperature: 60 °C

Procedure:
To a vial charged with 1-(2-hydroxyphenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (113 mg, 0.224 mmol) was added DMF (898 μl) and Cs2CO3 (219 mg, 0.673 mmol) and bromoacetonitrile (53.8 mg, 0.45 mmol) respectively. The mixture was heated to 60° C. overnight affording conversion to desired product fairly cleanly. m/z (ESI) 543.2 (M+H)+. The mixture was dried under reduced pressure and purified with a 25 g Interchim column (25 μm silica) ramping EtOAc in heptane (0-100%, 10% DCM throughout) affording product as a light brown solid. m/z (ESI) 543.2 (M+H)+
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH2:11][F:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][C:15]=1[C:29]1[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=1>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([CH2:11][F:12])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:16][C:15]=1[C:29]1[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: FCc1ccn2c(Br)cnc2n1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3C#N)c2)OC1(C)C
Product: N#Cc1ccccc1-c1cc(-c2cnc3nc(CF)ccn23)ccc1F
Yield: 67 %

Procedure:
3-Bromo-7-fluoromethylimidazo[1,2-α]pyrimidine (115 mg, 0.50 mmol) was coupled with 2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 2′-fluoro-5′-(7-fluoromethylimidazo[1,2-α]pyrimidin-3-yl)biphenyl-2-carbonitrile (116 mg, 67%) as a white powder: δH (400 MHz, CDCl3) 5.57 (2H, d, J 47), 7.20 (1H, dd, J 7 and 1), 7.42 (1H, dt, J 9 and 1), 7.55 (1H, dt, J 8 and 1), 7.60-7.66 (3H, m), 7.70-7.74 (1H, m), 7.85 (1H, dd, J 8 and 1), 7.90 (1H, s), 8.91 (1H, d, J 7); m/z (ES+) 347 (M++H).