Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].II.[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[O:22]>C1COCC1>[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([OH:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=CCCCCCCCCCCCBr
Reactant: CCCCCBr
Agent: II
Solvent: C1CCOC1
Product: CCCCCC(O)CCCCCCCCCCCBr
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-bromopentane (2.54 ml, 20.51 mmol) in THF (5 ml) was added dropwise to a stirred suspension of Mg metal (0.54 g, 22.23 mmol) and a catalytic amount of iodine in dry THF (15 ml) at 75° C., after which stirring was continued for another 30 minutes. The generated Grignard reagent was cooled to room temperature and added slowly to a stirred solution of 12-bromododecanal (4.5 g, 17.09 mmol) in THF (40 ml) at 0° C. The reaction was warmed to room temperature and stirring continued another 1.5 hours, then quenched with NH4Cl solution, and extracted with EtOAc (3×50 ml). The combined organic layers were washed with brine solution, dried on MgSO4 and concentrated. The crude compound was purified over silica gel column (8% EtOAc in hexane) to give 17-bromoheptadecan-6-ol as an off-white low melting solid (3.34 g, 58%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([CH2:10][CH3:11])[CH:3]=1.[H-].[Na+].[CH3:14]I>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH3:14])=[C:4]([CH2:10][CH3:11])[CH:3]=1
Reactant: CI
Reactant: CCc1cc(Br)ccc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cc(Br)ccc1COC
Reaction time: 16 h
Yield: 68.5 %

Procedure:
To a solution of (4-bromo-2-ethyl-phenyl)-methanol (0.700 g, 3.25 mmol) in DMF (30 mL) was added NaH (0.156 g, 60% dispersion in mineral oil, 3.90 mmol) followed by MeI (0.22 mL, 3.58 mmol). The mixture was stirred for 16 hours and then partitioned between H2O and EtOAc. The aqueous layer was extracted with EtOAc, and the organic layer was washed with brine, dried over Na2SO4, and concentrated to a yellow oil. Purification by flash column chromatography (0% to 4% EtOAc in hexanes) gave the product as a clear oil (0.51 g, 69%). 1H NMR (300 MHz, CDCl3): δ 1.15 (t, J=7.6 Hz, 3 H), 2.58 (q, J=7.5 Hz, 2 H), 3.32 (s, 3 H), 4.35 (s, 2 H), 7.12 (m, 1 H), 7.24 (m, 1 H), 7.27 (d, J=2.1 Hz, 1 H).
Reaction SMILES: [O-:1]Cl.[Na+].[N+:4]([C:7]1[CH:8]=[CH:9][C:10]2[O:15][C@:14]([CH3:21])([CH:16]([O:19][CH3:20])[O:17][CH3:18])[CH:13]=[CH:12][C:11]=2[CH:22]=1)([O-:6])=[O:5]>ClCCl>[N+:4]([C:7]1[CH:8]=[CH:9][C:10]2[O:15][C@:14]([CH3:21])([CH:16]([O:19][CH3:20])[O:17][CH3:18])[C@H:13]3[O:1][C@H:12]3[C:11]=2[CH:22]=1)([O-:6])=[O:5]
Reactant: COC(OC)[C@]1(C)C=Cc2cc([N+](=O)[O-])ccc2O1
Reactant: [O-]Cl
Agent: [Na+]
Solvent: ClCCl
Product: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@@H]2O[C@@H]21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.05 M Na2HPO4 aqueous solution (16.6 ml) was added to 0.55 M NaOCl aqueous solution (41.5 ml, 22.8 mmol) at 0° C. To the aqueous solution was slowly added the solution of (2S)-6-nitro-2-methyl-2-dimethoxymethyl-2H-1-benzopyran (1.5 g, 5.7 mmol) and (S,S)-Mn(III) salen, catalyst (155 mg, 0.28 mmol) for an enantioselective epoxidation developed by Jacobsen in dichloromethane (8.5 ml). The solution was stirred at the room temperature for 12 hours. After the reaction was completed, the reaction mixture was filtered to remove the catalyst and the filtrate was extracted with dichloromethane (200 ml). The dichloromethane layer was washed with saturated brine solution, dried over anhydrous magnesium sulfate and concentrated to remove the dichloromethane. The crude product was purified by chromatography (developing solvent—n-hexane:ethyl acetate=4:1) to give (2S,3S,4S)-6-nitro-2-methyl-2-dimethoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran, the compound of formula 2 (1.4 g, yield: 88%).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:31]=[C:30]([NH:32][C:33]([NH:35][C:36](=[O:44])[CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[S:34])[CH:29]=[CH:28][C:5]=1[O:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:26][CH3:27])=[C:14]([C:17]([NH:19][CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[O:18])[CH:15]=2)[N:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[CH2:52]([N:54]=[C:55]=[O:56])[CH3:53]>O1CCCC1>[CH2:52]([NH:54][C:55]([N:23]1[CH2:22][CH2:21][CH:20]([NH:19][C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][C:13]=2[O:26][CH3:27])[N:10]=[CH:9][CH:8]=[C:7]3[O:6][C:5]2[CH:28]=[CH:29][C:30]([NH:32][C:33]([NH:35][C:36](=[O:44])[CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[S:34])=[CH:31][C:4]=2[F:3])=[O:18])[CH2:25][CH2:24]1)=[O:56])[CH3:53]
Reactant: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2cc1C(=O)NC1CCNCC1
Reactant: CCN=C=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNC(=O)N1CCC(NC(=O)c2cc3c(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)ccnc3cc2OC)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 81 %

Procedure:
Compound 14 (335 mg) was suspended in tetrahydrofuran (5 mL), and triethylamine (212 μL) and ethyl isocyanate (71.2 μL) were added to the suspension, followed by stirring at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the formed solid was filtrated, to thereby yield titled compound 15 (271 mg, yield: 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.[CH3:17][CH2:18][O:19][C:20](/[CH:22]=[CH:23]/[CH2:24]P(OCC)(OCC)=O)=[O:21].[H-].[Na+]>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:24]/[CH:23]=[CH:22]/[C:20]([O:19][CH2:18][CH3:17])=[O:21])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)/C=C/C=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Yield: 28.1 %

Procedure:
By the method of Preparation 1, 4,4'-dichlorobenzophenone (5.00 g, 19.9 mmol) was hologated using triethyl 4-phosphonocrotonate (5.23 g, 20.9 mmol) and sodium hydride (0.528 g, 22 mmol) to give, after purification, 1.94 g (28% yield) of title product, mp 99-100° C.
Reaction SMILES: [NH2:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[C:15]([Br:17])=[CH:16][C:7]=3[CH2:6][CH2:5][C:4]=2[N:3]=1.[CH2:22]([O:24][C:25](=[O:44])[C@H:26]([CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[NH:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1)[CH3:23]>C(Cl)Cl>[NH2:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([S:18]([NH:35][C:32]4[CH:31]=[CH:30][C:29]([C:28]([NH:27][C@H:26]([C:25]([O:24][CH2:22][CH3:23])=[O:44])[CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:36])=[CH:34][CH:33]=4)(=[O:20])=[O:19])[C:15]([Br:17])=[CH:16][C:7]=3[CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: Nc1nc2c(c(=O)[nH]1)-c1cc(S(=O)(=O)Cl)c(Br)cc1CC2
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(N)cc1)C(=O)OCC
Solvent: ClCCl
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(NS(=O)(=O)c2cc3c(cc2Br)CCc2nc(N)[nH]c(=O)c2-3)cc1)C(=O)OCC
Temperature: 25 °C
Yield: 26.1 %

Procedure:
3-Amino-8-bromo-5,6-dihydrobenzo[f]quinazolin-1(2H)-one-9-sulfonyl chloride (2.00 g, 4.50 mmole) and N-(4-aminobenzoyl)-L-glutamic acid diethyl ester (7.26 g, 22.5 mmole) (Aldrich) were placed together in a test tube and melted at 175° C. The mixture was heated for 1 hour, 20 minutes, the cooled residue suspended in methylene chloride and filtered to remove undissolved solid. The filtrate was evaporated to dryness and the residue subjected to chromatography on a Waters Prep 500 instrument (silica column, elution with methanol/methylene chloride (1:24)). The combined fractions containing product were evaporated and the residue dried under high vacuum. The solid was suspended in boiling ethanol (900 ml), the suspension cooled to room temperature and filtered to give diethyl N-(4-(((3-amino-8-bromo-1,2,5,6-tetrahydro-1-oxobenzo[f]quinazolin-9-yl)sulfonyl)amino)benzoyl)-L-glutamate (0.794 g, 260). Mp>250° C. 1H NMR (DMSO-d6, 200 MHz) δ: 1.12 (t, J=7 Hz, 3H, ester-CH3), 1.14 (t, J=7 Hz, 3H, ester-CH3), 1.89-2.09 (m, 2H, glu-CH2), 2.37 (t, J=7 Hz, 2H, glu-CH2), 2.48-2.59 (m, 2H, ArCH2), 2.77-2.85 (m, 2H, ArCH2), 3.99 (q, J=7 Hz, 2H, esterCH2), 4.05 (q, J=7 Hz, 2H, esterCH2), 4.29-4.40 (m, 1H, glu-CH), 6.84 (br s, 2H, NH2), 7.14 (d, J=9 Hz, 2H, Ar), 7.54 (s, 1H, Ar), 7.69 (d, J=9 Hz, 2H, Ar), 8.48 (d, J=8 Hz, 1H, NH), 9.37 (s, 1H, Ar), 10.87 (br s, 1H, NH), 11.04 (br s, 1H, NH). Anal. Calculated for C28H30BrN5O8S:1/4H2O C, 49.38; H, 4.51; Br, 11.73; N, 10.20; S, 4.71. Found: C, 49.33; H, 4.40; Br, 11.79; N, 10.20; S, 4.74.
Reaction SMILES: [NH3:1].[CH2:2]([O:4][C:5]([C:7]1[C:8]2[S:16][CH:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[C:23]([C:25]4[N:26]=[N:27][N:28]([CH2:30][C:31]5[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=5)[CH:29]=4)[CH:22]=[CH:21][C:20]=3[CH3:38])[C:9]=2[C:10](Cl)=[N:11][CH:12]=1)=[O:6])[CH3:3]>CC(O)C>[CH2:2]([O:4][C:5]([C:7]1[C:8]2[S:16][CH:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[C:23]([C:25]4[N:26]=[N:27][N:28]([CH2:30][C:31]5[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=5)[CH:29]=4)[CH:22]=[CH:21][C:20]=3[CH3:38])[C:9]=2[C:10]([NH2:1])=[N:11][CH:12]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1cnc(Cl)c2c(COc3cc(-c4cn(Cc5ccc(Cl)cc5)nn4)ccc3C)csc12
Reactant: N
Solvent: CC(C)O
Product: CCOC(=O)c1cnc(N)c2c(COc3cc(-c4cn(Cc5ccc(Cl)cc5)nn4)ccc3C)csc12
Temperature: 140 °C

Procedure:
Ammonia gas was bubbled into a solution of 4-chloro-3-{5-[1-(4-chloro-benzyl)-1H-[1,2,3]triazol-4-yl]-2-methyl-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.33 g, 0.60 mmol) (from Example 35 supra) in 2-propanol (30 mL) for 20 minutes. The mixture was heated in a microwave reactor at 140° C. for 2 hours. The reaction mixture was concentrated. The residue washed with hot methanol, filtered and dried to give 4-amino-3-{5-[1-(4-chloro-benzyl)-1H-[1,2,3]triazol-4-yl]-2-methyl-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white powder. (Yield 0.23 g, 72%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([P:17]([C:25]2[CH:30]=[C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:28]([O:35][CH3:36])=[C:27]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:26]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[PH2:24])[CH:8]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[CH2:41]([Li])[CH2:42][CH2:43][CH3:44].S([O-])(=O)(=O)C>CCCCCC.C1COCC1>[C:13]([C:9]1[CH:8]=[C:7]([P:17]([C:25]2[CH:30]=[C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:28]([O:35][CH3:36])=[C:27]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:26]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[P:24]2[C:44]3[C:43](=[CH:2][CH:1]=[CH:5][CH:10]=3)[CH2:42][CH:41]2[CH:7]([CH3:8])[CH3:6])[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]=1[O:11][CH3:12])([CH3:16])([CH3:15])[CH3:14]
Reactant: [Li]CCCC
Reactant: COc1c(C(C)(C)C)cc(P(c2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)c2ccccc2P)cc1C(C)(C)C
Agent: CS(=O)(=O)[O-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1c(C(C)(C)C)cc(P(c2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)c2ccccc2P2c3ccccc3CC2C(C)C)cc1C(C)(C)C
Reaction time: 1 h
Yield: 54.2 %

Procedure:
Under a nitrogen atmosphere, 1.0 g (1.72 mmol) of 2-(bis(3,5-di(tert-butyl)-4-methoxyphenyl)phosphino)phenylphosphine was added to 30 ml of THF, followed by cooling with an ice bath. Then, a 1.6M solution of 1.1 ml (1.72 mmol) of n-butyllithium in hexane was added dropwise thereto and, after dropping, the mixture was stirred for 1 hr, a solution of 448 mg (1.72 mmol) of MESYLATE in 10 ml of THF was added dropwise thereto, stirred for 1 hr and, after removing the ice bath, the mixture was stirred for 1 hr at room temperature. Following recooling with an ice bath, a 1.6M solution of 1.6 ml (2.58 mmol) of n-butyllithium in hexane was added dropwise thereto, after dropping, the ice bath was removed and the mixture was stirred overnight at room temperature. 1 ml of water was added to the reaction mixture to quench the reaction and the solvent was distilled off. 10 ml of water was added to the residue and extracted 3 times each with 20 ml of Et2O, and the combined organic layer was washed with 10 ml of water, the solvent was distilled off and the residue was purified by silica gel column chromatography to obtain 337 mg of the title compound. (Yield: 27%)
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([N:9]([CH:17]2[CH2:19][CH2:18]2)C(=O)OC(C)(C)C)[N:5]2[N:20]=[CH:21][C:22]([CH:23]=[O:24])=[C:4]2[N:3]=1.[N:25]1([C:31]2[N:38]=[CH:37][CH:36]=[CH:35][C:32]=2[C:33]#[N:34])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>C(O)(C)C>[CH:17]1([NH:9][C:6]2[N:5]3[N:20]=[CH:21][C:22]([CH:23]=[O:24])=[C:4]3[N:3]=[C:2]([N:28]3[CH2:29][CH2:30][N:25]([C:31]4[N:38]=[CH:37][CH:36]=[CH:35][C:32]=4[C:33]#[N:34])[CH2:26][CH2:27]3)[C:7]=2[CH3:8])[CH2:18][CH2:19]1
Reactant: Cc1c(Cl)nc2c(C=O)cnn2c1N(C(=O)OC(C)(C)C)C1CC1
Reactant: N#Cc1cccnc1N1CCNCC1
Solvent: CC(C)O
Product: Cc1c(N2CCN(c3ncccc3C#N)CC2)nc2c(C=O)cnn2c1NC1CC1
Temperature: 90 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
Tert-butyl 5-chloro-3-formyl-6-methylpyrazolo[1,5-a]pyrimidin-7-yl(cyclopropyl)carbamate (60 mg, 0.17 mmol) was mixed with 2-(piperazin-1-yl)nicotinonitrile (64 mg, 0.34 mmol) in i-propanol (1 mL). The reaction mixture was heated at 90° C. in the microwave for 1 hour. The reaction was cooled to room temperature and concentrated under vacuum. The residue was dissolved in (1:1) TFA/DCM (4 mL) and stirred at room temperature for 1 hour. The reaction was evaporated to dryness, quenched with 3N NaOH, filtered, washed with water, and dried under vacuum The product, 2-(4-(7-(cyclopropylamino)-3-formyl-6-methylpyrazolo[1,5-a]pyrimidin-5-yl)piperazin-1-yl)nicotinonitrile, was further purified by preparative TLC using 5% acetone/dichloromethane as the eluent (40 mg, 58% yield). LCMS (M+1=403)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[CH3:13][CH:14](O)[CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:14]([CH3:15])[CH3:13])[C:5]([O:7][CH3:8])=[O:6]
Reactant: CC(C)O
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC(C)C)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.4 %

Procedure:
A solution of 1.42 g (7.63 mmol) of methyl 3-chloro-4-hydroxybenzoate, 585 μL (7.63 mmol) of 2-propanol and 3.0 g (11.45 mmol) of triphenylphosphine in 20 mL of THF at 0° C. was treated with 2.25 mL (11.45 mmol) of diisopropyl azodicarboxylate. The mixture was stirred for 16 h at rt, then concentrated. Chromatography on a Biotage 40M cartridge using 19:1 v/v hexanes/EtOAc as the eluant afforded 1.77 g of the title compound: 1H NMR (500 MHz, CDCl3) δ 1.41 (d, J=6.2, 6H), 4.63-4.70 (m, 1H), 6.93 (d, J=8.7, 1H), 7.89 (dd, J=2.2, 8.6, 1H), 8.05 (d, J=2.0, 1H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.[NH3:17].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[NH:17])=[CH:4][CH:3]=1
Reactant: N
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: N=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: -30 °C

Procedure:
4,4′-difluorobenzophenone (25 g) was dissolved in anhydrous toluene (800 mL), and the solution was cooled at −30° C. Titanium tetrachloride (21.4 mL) was dropwise added to the solution under nitrogen, and ammonia gas was passed through the mixture for about 20 minutes. Then the mixture was warmed up to room temperature and stirred over night. Saturated potassium carbonate aqueous solution (400 mL) was added to the reaction mixture, and the mixture was stirred for an additional 1 hour. The organic layer was separated and washed with water and saturated saline once respectively. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated in vacuo to give crude product of 1,1-bis(4-fluorophenyl)methanimine (31.7 g). The crude product was dissolved in anhydrous toluene (80 mL), and trimethylsilylcyanide (171.86 mL) and zinc iodide (1.83 g) were added to the solution. Then the mixture was stirred at room temperature over night. The reaction mixture was washed with saturated sodium hydrogen carbonate aqueous solution and saturated saline in this order, and dried over anhydrous sodium sulfate. Then solvent was evaporated in vacuo to obtained crude product of 2-amino-2,2-bis(4-fluorophenyl)acetonitrile (30.84 g). The crude product was dissolved in anhydrous toluene (100 mL), and then 1M diisobutylaluminum hydride-toluene solution (500 mL) was dropwise added to the solution at −78° C. Then temperature of the mixture was raised by standing to room temperature, and the mixture was stirred over night. Sodium sulfate decahydrate was added to the reaction mixture, and the resultant mixture was stirred for one hour. Moreover, anhydrous magnesium sulfate was added to the reaction mixture, and the mixture was stirred for one hour. Then insolubles were removed by filtration. The filtrate was concentrated in vacuo, and then the obtained residue was purified by silica gel column chromatography (C-300; 100% ethyl acetate→100% methanol) to give the title compound (8.55 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([CH3:11])[C:5]=1[NH:12][C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14].[H-].[Na+].Br[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([CH3:11])[C:5]=1[N:12]([CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:13]([O:15][CH:16]([CH3:17])[CH3:18])=[O:14]
Reactant: CCOC(=O)CCCBr
Reactant: COC(=O)c1ccc(Br)c(C)c1NC(=O)OC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCN(C(=O)OC(C)C)c1c(C(=O)OC)ccc(Br)c1C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
Add a solution of 2-Isopropoxycarbonylamino-4-bromo-3-methyl-benzoic acid methyl ester (3.36 g, 10.18 mmol) in DMF (37 mL) to a suspension of sodium hydride 60% dispersion mineral oil (407 mg, 10.18 mmol) in DMF (37 mL) at 0° C. under an atmosphere of nitrogen and allow to reach room temperature over 1 h. Add ethyl 4-bromobutyrate (2.2 mL, 15.27 mmol) and stir at room temperature for 14 h. Dilute with ethyl acetate, wash with 1M HCl, water and brine. Dry the organic layer over anhydrous magnesium sulfate, filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to provide the titled compound (3.47 g, 77%): MS (ES+): 445 (M+H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][CH:10]([F:38])[C:11]([C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH:37]=[CH:36][CH:35]=[N:34]2)=[CH:29][CH:28]=1)([OH:26])[CH2:12][C:13]1[NH:14][CH:15]=[C:16]([CH2:18][C:19]2([C:22]([F:25])([F:24])[F:23])[CH2:21][CH2:20]2)[N:17]=1>C(#N)C>[Br:1][C:15]1[NH:14][C:13]([CH2:12][C:11]([C:27]2[CH:28]=[CH:29][C:30]([N:33]3[CH:37]=[CH:36][CH:35]=[N:34]3)=[CH:31][CH:32]=2)([OH:26])[CH:10]([F:9])[F:38])=[N:17][C:16]=1[CH2:18][C:19]1([C:22]([F:25])([F:24])[F:23])[CH2:20][CH2:21]1
Reactant: O=C1CCC(=O)N1Br
Reactant: OC(Cc1nc(CC2(C(F)(F)F)CC2)c[nH]1)(c1ccc(-n2cccn2)cc1)C(F)F
Solvent: CC#N
Product: OC(Cc1nc(CC2(C(F)(F)F)CC2)c(Br)[nH]1)(c1ccc(-n2cccn2)cc1)C(F)F
Reaction time: 1 h

Procedure:
N-Bromosuccinimide (95 mg, 0.53 mmol) was added to a solution of 1,1-difluoro-2-[4-(1H-pyrazol-1-yl)phenyl]-3-(4-{[1-(trifluoromethyl)cyclopropyl]methyl}-1H-imidazol-2-yl)propan-2-ol (200 mg, 0.53 mmol) in acetonitrile (5 mL) at ambient temperature. After stirring for 1 hr, the reaction mixture was concentrated in vacuo. Chromatography over silica eluting with 0-100% ethyl acetate/hexane afforded 3-(5-bromo-4-{[1-(trifluoromethyl)cyclopropyl]methyl}-1H-imidazol-2-yl)-1,1-difluoro-2-[4-(1H-pyrazol-1-yl)phenyl]propan-2-ol as an orange solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](OC)=[O:9])[CH:5]=[CH:4][N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[OH:9][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: COC(=O)c1ccnc(C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: Cc1cc(CO)ccn1
Temperature: 5 °C
Reaction time: 2 h
Yield: 32.5 %

Procedure:
A solution of methyl 2-methyl-pyridine-4-carboxylate (800 mg, 6 mmol) in ether (5 ml) was added to lithium aluminium hydride (340 mg, 9 mmol) in ether (10 ml) cooled to 5° C. and the mixture stirred for 2 hours. Water was added, the mixture was filtered through diatomaceous earth and the pad was washed through with ethyl acetate. The filtrate was extracted with ethyl acetate and the combined extracts were washed with brine, dried (MgSO4) and the solvent removed by evaporation to give 4-hydroxymethyl-2-methylpyridine (240 mg, 38%) as a yellow oil. 1H NMR Spectrum: (CDCl3)2.48(s, 3H); 5.44(s, 2H); 7.00(d, 1H); 7.10(s, 1H); 8.40(d, 1H) MS-ESI: 124 [MH]+
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]3[CH2:22][CH2:21][CH2:20]3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH:23](=O)[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CCO>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]3[CH2:22][CH2:21][CH2:20]3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:23]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Nc1ncc(Br)c(N2CCN(CC3CCC3)CC2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2nc3c(N4CCN(CC5CCC5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 85 °C

Procedure:
To a mixture of 5-bromo-4-(4-(cyclobutylmethyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.036 g, 0.097 mmol) and EtOH (1 mL) was added p-anisaldehyde (0.015 g, 0.11 mmol) in EtOH (1.2 mL) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.29 mL, 0.29 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and purified by column chromatography on a Biotage SP1 system eluting with methanol (2-10%) in dichloromethane. The title compound was isolated as a pale yellow solid after trituration with diethyl ether (0.016 g, 37%); 1H-NMR (500 Mz, DMSO-d6): δ 1.63-1.73 (m, 2H), 1.77-1.93 (m, 2H), 2.00-2.10 (m, 2H), 2.42 (d, J=7.0 Hz, 2H, NCH2), 2.52-2.60 (m, 4H, piperazine N(CH2)2), 3.62 (m, 4H, piperazine N(CH2)2), 3.84 (s, 3H, OMe), 7.10 (d, J=9.0 Hz, 2H, ArH, C6H4—OMe), 8.13 (d, J=8.5 Hz, 2H, ArH, C6H4—OMe), 8.20 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.34 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 3.29 min—456/458 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 456.1395, calculated for C22H27BrN5O (M+H)+: 456.1399.
Reaction SMILES: [C:1]([CH:3]1[NH:6][C:5](=[O:7])[C@H:4]1[NH:8][C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)#[N:2].C(N(CC)CC)C.[Si:35](Cl)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]>C(Cl)Cl>[Si:35]([N:6]1[CH:3]([C:1]#[N:2])[C@H:4]([NH:8][C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:5]1=[O:7])([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]
Reactant: N#CC1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)N1C(=O)[C@@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1C#N
Yield: 44 %

Procedure:
To a mixture of 1.10 g of (3S,4RS)-4-cyano-3-tritylamino-2-azetidinone, 0.50 g of triethylamine and 20 ml of methylene chloride is added 0.56 g of tert-butyldimethylsilyl chloride under ice-cooling and stirring. The mixture is stirred at room temperature (approx. 25° C.) for 30 minutes and the reaction mixture is concentrated under reduced pressure. The residue is chromatographed on a a silicagel column [eluant: ethyl acetate-n-hexane (1:3)] to give 0.64 g of (3S,4RS)-1-tert-butyldimethylsilyl-4-cyano-3-tritylamino-2-azetidinone.