Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[N:11]2[CH2:14][CH:13]([NH:15][CH2:16][C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)[CH2:12]2)=[CH:6][CH:5]=1.Cl[C:33]([O:35][CH3:36])=[O:34].O>O1CCCC1>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH:10]([C:7]2[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=2)[N:11]2[CH2:12][CH:13]([N:15]([CH2:16][C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)[C:33](=[O:34])[O:35][CH3:36])[CH2:14]2)=[CH:26][CH:27]=1
Reactant: COC(=O)Cl
Reactant: Fc1cc(F)cc(CNC2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N(Cc1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
24.4 mg of a 75% dispersion of sodium hydride in mineral oil are added, at room temperature under an argon atmosphere, to a solution of 330 mg of {1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorobenzyl)amine in 25 cm3 of tetrahydrofuran. The mixture is stirred at room temperature for 1 hour before adding thereto 59 mm3 of methyl chloroformate, and then the stirring is maintained for 18 hours under the same conditions. The reaction mixture is supplemented with 0.3 cm3 of distilled water and the tetrahydrofuran is expelled in a rotary evaporator. The residue obtained is extracted with dichloromethane, the organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by flash chromatography on silica gel [eluent: dichloromethane/methanol (97.5/2.5 by volume)]. 328 mg of methyl {1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-(3,5-difluorobenzyl)carbamate are obtained in the form of a colorless oil [1H NMR spectrum (300 MHz, CDCl3, δ in ppm): 2.97 (mt: 2H); 3.39 (mt: 2H); 3.71 (s: 3H); 4.24 (broad s: 1H); 4.45 (unresolved complex: 1H); 4.57 (s: 2H); from 6.65 to 6.80 (mt: 3H); from 7.15 to 7.30 (mt: 8H)].
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[OH:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[C:13]#[N:14].O>C(OCC)(=O)C>[OH:10][C:11]1[CH:18]=[CH:17][C:16]([N+:1]([O-:4])=[O:2])=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: N#Cc1ccccc1O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cc([N+](=O)[O-])ccc1O
Temperature: 20 °C
Reaction time: 24 h

Procedure:
A solution of 70 ml. 40% nitric acid and 10 ml. concentrated sulphuric acid is added dropwise at 10° C. in the course of 1 hour to 24 g. (0.2 mole) 2-hydroxybenzonitrile in 20 ml. water. The reaction mixture is subsequently stirred for 24 hours at 20° C. and then shaken out with 100 ml. ethyl acetate. After evaporation of the organic solvent, the solid residue obtained is extracted twice with 500 ml. amounts of boiling n-hexane. Purification takes place by means of column chromatography on silica gel (silica gel 60; elution agent ethyl acetate). After evaporation of the solvent and crystallisation from ethyl acetate/toluene, there are obtained 2 g. of the desired product in the form of white crystals.
Reaction SMILES: [C:1](Cl)(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[Cl:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([NH2:17])=[N:13][NH:14]2)=[CH:10][CH:9]=1>N1C=CC=CC=1>[Cl:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([NH:17][C:1](=[O:5])[CH:2]=[CH:3][CH3:4])=[N:13][NH:14]2)=[CH:10][CH:9]=1
Reactant: Nc1n[nH]c2cc(Cl)ccc12
Reactant: C/C=C/C(=O)Cl
Solvent: c1ccncc1
Product: CC=CC(=O)Nc1n[nH]c2cc(Cl)ccc12
Temperature: 6 °C
Reaction time: 0.17 h

Procedure:
0.67 cm3 of distilled crotonyl chloride is added to 50 mg of 6-chloro-1H-indazole-3-amine dissolved in 5 cm3 of pyridine and cooled to about 6° C. The mixture is stirred for 10 minutes and the temperature is then allowed to rise to about 19° C. over 22 hours. The reaction medium is then concentrated to dryness under reduced pressure (2 kPa; 40° C.) and the residue is then taken up in 50 cm3 of tetrahydrofuran and 25 cm3 of ethyl acetate. The organic phase is washed with 2×50 cm3 of distilled water and then with 50 cm3 of saturated aqueous sodium chloride solution. The resulting solution is dried over magnesium sulphate, filtered through a sinter funnel and then evaporated under the conditions described previously. The residue obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 4.5 cm), eluting with a cyclohexane/ethyl acetate mixture (80/20 by volume) and collecting 20 cm3 fractions. The fractions containing the expected product are combined and then evaporated under the conditions already described. After drying (90 Pa; 45° C.), 100 mg of N-(6-chloro-1H-indazol-3-yl)-2-butenamide, E form, are obtained in the form of a white solid melting at 226° C.
Reaction SMILES: [CH3:1][S:2]([CH:5]=[CH2:6])(=[O:4])=[O:3].[Cl:7][C:8]1[CH:17]=[CH:16][C:15]2[CH2:14][NH:13][CH2:12][CH2:11][C:10]=2[N:9]=1>CCO>[Cl:7][C:8]1[CH:17]=[CH:16][C:15]2[CH2:14][N:13]([CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:12][CH2:11][C:10]=2[N:9]=1
Reactant: C=CS(C)(=O)=O
Reactant: Clc1ccc2c(n1)CCNC2
Solvent: CCO
Product: CS(=O)(=O)CCN1CCc2nc(Cl)ccc2C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
Methylsulfonylethene (commercially available from Sigma-Aldrich, St. Louis, Mo.) (142 mg, 1.33 mmol) was added dropwise to a solution of 2-chloro-5,6,7,8-tetrahydro-1,6-naphthyridine (150 mg, 0.89 mmol, commercially available from D-L Chiral Chemicals, ST-0143) in EtOH (10 mL). The reaction mixture was stirred at 60° C. for 2 hours, and then concentrated and purified by flash chromatography on silica gel eluting with 0% to 5% MeOH in DCM to give 2-chloro-6-(2-(methylsulfonyl)ethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine (220 mg, 90% yield). 1H NMR (400 MHz, CD3OD) δ ppm 2.91-3.11 (9H, m) 3.43 (2H, t, J=6.65 Hz) 3.73-3.77 (2H, m) 7.26 (1H, d, J=8.22 Hz) 7.56 (1H, d, J=8.02 Hz) ppm; LC/MS m/z: 275 (M+1).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([CH2:19][N:20]3[CH:24]=[C:23]([C@@:25]([OH:32])([CH2:30][CH3:31])[C:26]([F:29])([F:28])[F:27])[N:22]=[N:21]3)=[CH:7][CH:8]=2)[N:3]=1.[CH3:33][S-:34].[Na+]>CN(C=O)C>[F:27][C:26]([F:29])([F:28])[C@:25]([C:23]1[N:22]=[N:21][N:20]([CH2:19][C:6]2[CH:5]=[C:4]3[C:9]([C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[CH:11][C:2]([S:34][CH3:33])=[N:3]3)=[CH:8][CH:7]=2)[CH:24]=1)([OH:32])[CH2:30][CH3:31]
Reactant: C[S-]
Reactant: CC[C@](O)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(Cl)nc3c2)nn1)C(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@](O)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(SC)nc3c2)nn1)C(F)(F)F

Procedure:
A solution of (S)-2-(1-{[2-chloro-4-(4-fluorophenyl)quinolin-7-yl]methyl}-1H-1,2,3-triazol-4-yl)-1,1,1-trifluorobutan-2-ol (85 mg, 0.18 mmol) and sodium thiomethoxide (51 mg, 0.72 mmol) in DMF (3 mL) was stirred at rt for 2 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduce pressure. Purification on silica gel (eluting with ethyl acetate/hexanes, 1:9) gave the title compound. MS (+ESI): 477 (M+H)+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30](=[O:39])[NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[NH2:38])([CH3:28])([CH3:27])[CH3:26].[CH3:40][O:41][C:42]([C:44]1[CH:45]=[CH:46][C:47]([C:50](O)=[O:51])=[N:48][CH:49]=1)=[O:43].CN1CCOCC1>CN(C=O)C.O>[C:25]([O:29][C:30]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[NH:38][C:50]([C:47]1[CH:46]=[CH:45][C:44]([C:42]([O:41][CH3:40])=[O:43])=[CH:49][N:48]=1)=[O:51])=[O:39])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)c1ccc(C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)nc1
Yield: 79 %

Procedure:
HATU (21 g, 55 mmol) was added to a solution of 2-aminophenylcarbamic acid t-butyl ester (Reference Compound No. 1-1, 10 g, 50 mmol), 5-methoxycarbonylpyridine-2-carboxylic acid (10 g, 55 mmol), and N-methylmorpholine (11 mL, 100 mmol) in DMF (100 mL), and then the reaction mixture was stirred at room temperature for 20 hours. Water (300 mL) was added thereto, and then the whole was extracted with ethyl acetate (300 mL) three times. The organic layer was washed with brine (200 mL), and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the obtained solid was collected by filtration to give 15 g of the title reference compound as a pale brown solid. (Yield 79%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:21]([F:24])([F:23])[F:22])=[CH:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=2)=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-:25].[Na+].Cl.[NH2:28]O.Cl>C1(C)C=CC=CC=1.O.CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:21]([F:24])([F:23])[F:22])[O:25][N:28]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CSc1ccc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1
Reactant: [OH-]
Reactant: NO
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Product: CSc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Temperature: 0 °C
Yield: 81.8 %

Procedure:
0.55 g of toluene and 0.33 g of N-methyl-2-pyrrolidone were added to 0.11 g (0.28 mmol) of 3-(3,5-dichlorophenyl)-4,4,4-trifluoro-1-(4-(methylthio)phenyl)-2-buten-1-one, and the mixture was cooled to 0° C. After adding in dropwise to this mixture the solution which was prepared by adding 0.11 g of water to 0.045 g (1.12 mmol) of sodium hydroxide, and then adding the solution in which 0.022 g (0.31 mmol) of hydroxylamine hydrochloride was dissolved into 0.046 g of water in dropwise, the mixture was stirred for one night at room temperature. The reaction was traced by high-performance liquid chromatography. Since the raw materials did not disappear, the solution in which 0.018 g (0.25 mmol) of hydroxylamine hydrochloride was dissolved into 0.038 g of water was added and stirred for 1 hour at room temperature. The aqueous solution which was prepared from 0.18 g (1.69 mmol) of 35% hydrochloric acid and 0.53 g of water was added in dropwise to the reaction solution, and the mixture was stirred for 1 hour. 5 ml of toluene was added and separation operation was performed. The toluene phase was washed twice with 3 ml of water. The solvent was distilled off under reduced pressure to obtain 0.093 g of 5-(3,5-dichlorophenyl)-3-(4-(methylthio)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (yield 81.3%).
Reaction SMILES: [N@:1]1([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3][CH:2]1[C:4]([O:6][CH3:7])=[O:5].B(F)(F)F.[CH3:22][CH2:23][O:24]CC.C(O)C>ClCCl>[CH2:11]([O:10][C:8]([NH:1][C@H:2]([C:4]([O:6][CH3:7])=[O:5])[CH2:3][O:24][CH2:23][CH3:22])=[O:9])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)C1CN1C(=O)OCc1ccccc1
Reactant: CCOCC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCO
Product: CCOC[C@H](NC(=O)OCc1ccccc1)C(=O)OC
Temperature: 25 °C

Procedure:
To a stirred solution of (S)-1-benzyl 2-methyl aziridine-1,2-dicarboxylate (prepared according to the literature procedure: Org. Biomol. Chem., 2005, 3, 3357, 2.7 g, 11.4 mmol) in dichloromethane (30 mL), boron trifluoride etherate (0.01 mL, 0.11 mmol) was added at 0° C. followed by absolute ethanol (1.05 g, 22.9 mmol). The reaction mixture was stirred at room temperature for an hour, after which the solution was quenched with saturated bicarbonate solution (2 mL), extracted with dichloromethane (3×25 mL), organic layers were washed with water (25 mL), brine solution (25 mL) and dried over sodium sulfate. The removal of solvents afforded crude product, which was purified by silica gel column chromatography using a gradient of ethyl acetate in pet. ether. Yield: 2.0 g (63%). 1H NMR (400 MHz, DMSO-d6) δ: 1.08 (t, 3H), 3.38-3.46 (m, 2H), 3.57-3.63 (m, 2H), 3.70 (s, 3H), 4.26-4.31 (m, 1H), 5.04 (s, 2H), 7.30-7.39 (m, 5H), 7.73 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:11]3([C:16]([F:18])([F:17])[CH2:15][O:14][C:13]([NH2:19])=[N:12]3)[CH2:10][CH:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[Cl:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[C:31]([Cl:33])[CH:32]=1>>[Cl:26][C:27]1[CH:28]=[C:29]([C:2]2[CH:3]=[C:4]3[C@@:11]4([C:16]([F:18])([F:17])[CH2:15][O:14][C:13]([NH2:19])=[N:12]4)[CH2:10][CH:9]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[O:8][C:5]3=[CH:6][CH:7]=2)[CH:30]=[C:31]([Cl:33])[CH:32]=1
Reactant: NC1=N[C@@]2(CC(c3ccccc3)Oc3ccc(Br)cc32)C(F)(F)CO1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Product: NC1=N[C@@]2(CC(c3ccccc3)Oc3ccc(-c4cc(Cl)cc(Cl)c4)cc32)C(F)(F)CO1
Yield: 17 %

Procedure:
In a manner analogous to that described in Example 19, the cross coupling reaction of (2RS,4R)-6-bromo-5′,5′-difluoro-2-phenyl-5′,6′-dihydrospiro[chroman-4,4′-[1,3]oxazin]-2′-amine (intermediate B6.3) with 3,5-dichlorophenylboronic acid yielded the title compound (17% yield) as a white solid. MS (ISP): m/z=475.0 [M+H]+.
Reaction SMILES: C([O:4][CH2:5][CH:6]=[C:7]([CH3:9])[CH3:8])(=O)C.[CH3:10][C:11]([CH3:15])=[CH:12][CH:13]=O.C(O)(=O)C1C=CC=CC=1>>[CH3:10][C:11](=[CH:12][CH2:13][CH2:9][C:7](=[CH:6][CH:5]=[O:4])[CH3:8])[CH3:15]
Reactant: CC(=O)OCC=C(C)C
Reactant: CC(C)=CC=O
Agent: O=C(O)c1ccccc1
Product: CC(C)=CCCC(C)=CC=O
Yield: 48 %

Procedure:
60 parts of prenyl acetate, 40 parts of 3,3-dimethylacrolein and 2 parts of benzoic acid are heated together for 5 hours 30 minutes at 140° C and the product is worked up. 11.1 parts of citral is obtained having a boiling point of 104° C at 12 mm in a yield of 48% at a conversion of 32% (based on 3,3-dimethylacrolein).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[C@H:10]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]1[CH2:26][S:23](=[O:25])(=[O:24])[O:22][CH2:21]1>O1CCOCC1>[CH2:12]([C@H:10]([NH:11][CH2:21][CH2:20][CH2:26][S:23]([OH:25])(=[O:24])=[O:22])[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S1(=O)CCCO1
Reactant: N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)[C@H](Cc1ccccc1)NCCCS(=O)(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
To a solution of L-Phenylalanine benzylester (1.8 g, 6.8 mmol) in 1,4-dioxane (10 mL) was added 1,3-propanesultone (708 mg, 6.5 mmol). The solution was stirred at reflux. After 1 hour, 20 mL of 1,4-dioxane was added to allow for good stiffing. The reaction was stirred at reflux for an additional 1 hour. It was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×25 mL). The product was suspended 80% Acetone/EtOH. The suspension was stirred at reflux for 30 seconds. The solid was filtered and dried in the vacuum oven (50° C.) affording the title compound (1.14 g, 46%). 1H NMR (DMSO, 500 MHz) δ ppm 7.27 (m, 6H), 7.12 (m, 4H), 5.05 (dd, 2H, J=12.3 Hz), 4.49 (m, 1H). 3.29 (m, 1H), 3.00 (m, 1H), 2.98 (m, 1H), 2.61 (t, 2H, J=6.5 Hz), 1.97 (m, 2H). 13C (DMSO, 125 MHz) δ ppm 168.88, 135.21, 134.90, 130.00, 129.31, 129.07, 128.01, 67.98, 60.50, 49.77, 46.72, 35.87, 22.43. [α]D=+4.8° (c=0.00073 in water), ES-MS 378 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.CN(C=O)C.[H-].[Na+].[F:15][C:16]1[C:48]([F:49])=[CH:47][C:19]2[NH:20][C:21]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]4[C:36]([C:37]5[CH:42]=[CH:41][N:40]=[C:39](S(C)(=O)=O)[N:38]=5)=[CH:35][CH:34]=[CH:33][N:32]=4)=[CH:26][CH:25]=3)=[N:22][C:18]=2[CH:17]=1>O.C(OCC)(=O)C>[F:15][C:16]1[C:48]([F:49])=[CH:47][C:19]2[NH:20][C:21]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]4[C:36]([C:37]5[CH:42]=[CH:41][N:40]=[C:39]([NH:7][C:3]6[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=6)[N:38]=5)=[CH:35][CH:34]=[CH:33][N:32]=4)=[CH:26][CH:25]=3)=[N:22][C:18]=2[CH:17]=1
Reactant: CS(=O)(=O)c1nccc(-c2cccnc2Oc2ccc(Nc3nc4cc(F)c(F)cc4[nH]3)cc2)n1
Reactant: Nc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Fc1cc2nc(Nc3ccc(Oc4ncccc4-c4ccnc(Nc5cccnc5)n4)cc3)[nH]c2cc1F
Temperature: 0 °C
Reaction time: 0.58 h

Procedure:
A resealable reaction vial, under nitrogen, was charged with pyridin-3-amine (0.04 g, 42.50 mmol) and DMF (0.80 ml, 0.1 M). This was cooled to 0° C. and 60% wt in oil sodium hydride added (0.01 g, 42.50 mmol). The reaction mixture was stirred at 0° C. under a nitrogen atmosphere for 35 min. 5,6-Difluoro-N-(4-(3-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine (0.04 g, 0.08 mmol) was added slowly to the mixture which was allowed to warm up to RT and stirred for 1 hr. The reaction mixture was heated to 60° C. and stirred for 1 hr. The reaction mixture was cooled to RT, then diluted with water and ethyl acetate. The layers were separated, the organic layer was dried over sodium sulfate and concentrated under reduced pressure to give oily residue, which was purified by silica prep plate (0.5% NH4OH/9.5% MeOH/Dichloromethane) followed by Gilson reverse phase chromatography (10% to 90% CH3CN/H2O/0.1% TFA) to afford 5,6-difluoro-N-(4-(3-(2-(pyridin-3-ylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine as a yellow solid. MS m/z=509.0 [M+H]+. Calc'd for C27H18F2N8O: 508.48.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[N:11]=[CH:10][C:9]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)=[CH:8][C:6]=2[N:7]=1.[F:24][C:25]1[C:30]([F:31])=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[CH:27][C:26]=1[NH:41][C:42](=[O:55])[NH:43][C:44]1[CH:54]=[CH:53][C:47]([C:48]([N:50]([CH3:52])[CH3:51])=[O:49])=[CH:46][CH:45]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>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.O.CCO>[F:24][C:25]1[C:30]([F:31])=[C:29]([C:2]2[N:3]=[C:4]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:5]3[N:11]=[CH:10][C:9]([C:12]4[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=4)=[CH:8][C:6]=3[N:7]=2)[CH:28]=[CH:27][C:26]=1[NH:41][C:42](=[O:55])[NH:43][C:44]1[CH:54]=[CH:53][C:47]([C:48]([N:50]([CH3:52])[CH3:51])=[O:49])=[CH:46][CH:45]=1
Reactant: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)c(F)c2F)cc1
Reactant: Cn1cc(-c2cnc3c(N4CCOCC4)nc(Cl)nc3c2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(-c3nc(N4CCOCC4)c4ncc(-c5cnn(C)c5)cc4n3)c(F)c2F)cc1
Temperature: 75 °C
Reaction time: 3 h
Yield: 10.9 %

Procedure:
To a 50 mL round bottom flask, 4-(2-chloro-7-(1-methyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-4-yl)morpholine (0.1 g, 0.0003 mol), 4-(3-(2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide (0.16 g, 0.00036 mol), cesium carbonate (0.244 g, 0.00075 mol), toluene (7 mL), EtOH (7 mL), and water (3 mL) were added. The reaction mixture was degassed with nitrogen for 5-10 min. To the same reaction flask, Pd(PPh3)2Cl2 (0.0105 g, 0.000015 mol) was added and again degassed with nitrogen for 5-10 min. The reaction mixture was stirred at 75° C. for 3 h. To the cooled reaction mixture, ice cold water was added to obtain the solid. The crude product was obtained by the filtration of the solid. The crude product was purified by column chromatography using 60-120 silica gel and 4% MeOH in chloroform to isolate the product. The isolated product was washed with MeOH and filtered. The compound was further purified by prep TLC using 7% MeOH in chloroform to yield the title compound [0.02 g, 11%]. 1H NMR (400 MHz, DMSO-d6): δ 9.38 (brs, 1H), 9.09 (d, J=2.0 Hz, 1H), 9.01 (brs, 1H), 8.53 (s, 1H), 8.32 (d, J=2.0 Hz, 1H), 8.24 (s, 1H), 8.14-7.97 (m, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H), 4.49 (brs, 4H), 3.92 (s, 3H), 3.81 (brs, 1H), 2.96 (s, 6H). LC-MS (ESI): Calculated mass: 613.2; Observed mass: 614.2 (RT: 0.63 min).
Reaction SMILES: [C:1]([NH:4][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][C:6]21[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]2)(=[O:3])[CH3:2].N1C=CC=CC=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>O>[CH3:26][S:27]([O:19][CH:16]1[CH2:17][CH2:18][C:6]2([CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]2[NH:4][C:1](=[O:3])[CH3:2])[CH2:14][CH2:15]1)(=[O:29])=[O:28]
Reactant: CC(=O)NC1c2ccccc2CC12CCC(O)CC2
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)NC1c2ccccc2CC12CCC(OS(C)(=O)=O)CC2
Temperature: 0 °C

Procedure:
To an ice cold solution of 1.21 g. of 1'-acetamidospiro(cyclohexane-1,2'-indan)-4-ol (isomer B) [27 ] (prepared in Example 61B) in 12 ml. of pyridine, 1.2 ml. of methane sulfonyl chloride is added. After about 5 hours in the cold the mixture is poured into ice: water. The solid that precipitates is recrystallized from acetone: Skellysolve B to give 1.21 g. of 1'-acetamidospiro(cyclohexane-1,2'-indan-4-ol methanesulfonate (isomer B) [28], melting at 161° to 163° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[CH:5]=1)=[O:3].C(N(CC)CC)C.[Br:18][CH:19]([CH3:23])[C:20](Br)=[O:21]>CN(C)C=O.O>[C:2]([C:4]1[CH:5]=[C:6]([NH:10][C:20](=[O:21])[CH:19]([Br:18])[CH3:23])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:1]
Reactant: CC(Br)C(=O)Br
Reactant: CC(=O)c1cccc(N)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)c1cccc(NC(=O)C(C)Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
To a stirred solution of 3-amino acetophenone (1.0 g, 7.35 mmol) in dimethylformamide (DMF) (10.0 mL) was added triethylamine (Et3N) (1.11 g, 11.03 mmol) at 0° C. followed by the slow addition of 2-bromopropionyl bromide (1.75 g, 8.08 mmol). The reaction was stirred at room temperature (rt) under N2 atmosphere for 3 h, diluted with water (50.0 mL) and the precipitated pale brown solid was filtered and dried to give the title product in 80% yield. 1H NMR (CDCl3, 400 MHz): 8.47 (br s, NH), 8.09-8.08 (m, 1H), 7.92 (dd, J=8.0 Hz, J=1.2 Hz, 1H), 7.73 (dd, J=8.0 Hz, J=1.2 Hz, 1H), 7.46 (t, J=8.0 Hz, 1H), 4.60 (q, J=6.8 Hz, 1H), 2.62 (s, 3H), 1.96 (d, J=7.2 Hz, 3H). 13C NMR (CDCl3, 100 MHz): 198.0, 167.8, 137.8, 137.7, 129.5, 124.8, 124.6, 119.5, 44.8, 26.7, 22.7. ESI-MS calcd for C11H12BrNO2 (M+Na)+291.99. found 292.0.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([S:11][C:12]2[NH:16][C:15]([CH2:17][O:18]CC3C=CC(OC)=CC=3)=[N:14][C:13]=2[CH:28]([CH3:30])[CH3:29])[CH:7]=[C:8]([Cl:10])[CH:9]=1.Br[CH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.Cl>O.C(O)C.O1CCCC1>[Cl:10][C:8]1[CH:7]=[C:6]([S:11][C:12]2[N:16]([CH2:32][CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:15]([CH2:17][OH:18])=[N:14][C:13]=2[CH:28]([CH3:29])[CH3:30])[CH:5]=[C:4]([Cl:3])[CH:9]=1
Reactant: BrCCCc1ccccc1
Reactant: COc1ccc(COCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)[nH]2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1nc(CO)n(CCCc2ccccc2)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 40 %

Procedure:
To dry tetrahydrofuran was added 40 mg of 60% sodium hydride, and under ice-cooling, 200 mg of 5-(3,5-dichlorophenylthio)-4-isopropyl-2-(p-methoxybenzyloxymethyl)-1H-imidazole (101b)was added. After 20 minutes, 136 μl of 1-bromo-3-phenylpropane was added. After stirred at room temperature for 3 hours, the mixture was diluted with water and extracted with diethyl ether. The extract was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. To thus-obtained oil were added 10 ml of ethanol and 20 ml of 36% hydrochloric acid, and the mixture was stirred at 90° C. for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, an aqueous sodium hydrogen carbonate solution was added, and extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=1:1)to give 80 mg of Compound I-122 (yield 40%).