Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:26])=[C:4]([C:8]2[N:9]=[C:10]([CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[N:27]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1[S:33]([O-:35])=[O:34].[Na+]>>[NH2:19][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([CH:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[N:9][C:8]=2[C:4]2[C:3]([F:26])=[C:2]([NH:1][S:33]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][N:27]=3)(=[O:35])=[O:34])[CH:7]=[CH:6][CH:5]=2)[CH:18]=[CH:17][N:16]=1
Reactant: Nc1nccc(-c2sc(C3CCOCC3)nc2-c2cccc(N)c2F)n1
Reactant: O=S([O-])c1cnccn1
Agent: [Na+]
Product: Nc1nccc(-c2sc(C3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cnccn3)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 278 using 4-[4-(3-amino-2-fluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-5-yl]-2-pyrimidinamine (100 mg, 0.269 mmol) and sodium 2-pyrazinesulfinate (135 mg, 0.808 mmol), the title compound was obtained as a yellow solid (30 mg, 21% yield). MS (ESI): 514 [M−H]+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9]([NH2:20])=[N:8][C:6]=2[N:7]=1.[CH3:21][N:22]([CH:24](OC)OC)[CH3:23]>>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[C:10]1[C:9]([N:20]=[CH:21][N:22]([CH3:24])[CH3:23])=[N:8][C:6]2[N:7]=[C:2]([N:1]=[CH:21][N:22]([CH3:24])[CH3:23])[N:3]=[CH:4][C:5]=2[CH:11]=1
Reactant: COC(OC)N(C)C
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Product: CN(C)C=Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(N=CN(C)C)nc2n1

Procedure:
2,7-Diamino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidine from Example 1 was reacted with DMF dimethyl acetal for 23 hours as described in Example 78. Workup as described above followed by purification on flash silica gel chromatography eluting sequentially with 100:0, 9:1, 4:1, and 7:3 ethyl acetate:methanol gave an oil that was crystallized from ethyl acetate to afford N'-[6-(2,6-dichlorophenyl)-7-[(dimethylamino)-methyleneamino]-pyrido[2,3-d]pyrimidin-2-yl]-N,N-dimethylformamidine, mp 269°-272° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:19]([C:28]([O:30][CH3:31])=[O:29])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:42][CH2:43]/[CH:44]=[CH:45]\[CH2:46]Br>C1COCC1>[Br:42][CH2:43]/[CH:44]=[CH:45]\[CH2:46][C@@:19]1([C:28]([O:30][CH3:31])=[O:29])[CH2:18][CH2:17][C@H:16]([C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[CH:15][CH:14]=2)[N:20]1[C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22]
Reactant: COC(=O)[C@@H]1CC[C@H](c2ccc(OCc3ccccc3F)cc2)N1C(=O)OC(C)(C)C
Reactant: BrC/C=C\CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)[C@]1(C/C=C\CBr)CC[C@H](c2ccc(OCc3ccccc3F)cc2)N1C(=O)OC(C)(C)C
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 38.2 %

Procedure:
To a solution of 1-(1,1-dimethylethyl) 2-methyl (2S,5R)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-1,2-pyrrolidinedicarboxylate (D34, 0.2 g, 0.47 mmol) in dry THF (2 mL) at −78° C. was added LiHMDS (0.51 mL of a 1M solution in THF, 0.51 mmol). The mixture was allowed to warm to −30° C. and stirred for 30 min at this temperature. The yellow slurry was cooled to −78° C. and (2Z)-1,4-dibromo-2-butene (0.30 mL, 2.81 mmol) was added. The reaction mixture was left under stirring for 40 min and then quenched with a saturated ammonium chloride solution. The aqueous layer was extracted with ethyl acetate, dried (Na2SO4) and evaporated. The crude material was purified by chromatography on silica gel using cyclohexane/ethyl acetate (9:1) affording the title compound (101 mg, 38%); Rt (HPLC) 7.42 min. MS: (ES/+) m/z: 462 and 464 [MH+-Boc]; C28H33BrFNO5 requires 562.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][N:7]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:8](=[O:20])[N:9]2[C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[C:4]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])[CH:3]=1.[CH3:37][N:38]1[CH:42]=[C:41]([S:43](Cl)(=[O:45])=[O:44])[N:40]=[CH:39]1.C(N(C(C)C)CC)(C)C>C1COCC1.CN(C)C1C=CN=CC=1>[Cl:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:4]1[CH:3]=[C:2]([NH:1][S:43]([C:41]2[N:40]=[CH:39][N:38]([CH3:37])[CH:42]=2)(=[O:45])=[O:44])[CH:11]=[C:10]2[C:5]=1[CH2:6][N:7]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)[C:8](=[O:20])[N:9]2[C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:19]
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(N)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(NS(=O)(=O)c4cn(C)cn4)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 7-amino-5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one (150 mg, 0.278 mmol) (COMPOUND CCC4, STEP A) in 4 mL of THF cooled to 0° C. was added 1-methyl-1H-imidazole-4-sulfonyl chloride (100 mg, 0.556 mmol). A few crystals of 4-(dimethylamino)pyridine and diisopropylethylamine (53.9 mg, 0.417 mmol) were added. The resulting reaction mixture was stirred at 0° C. for 20 min, then heated to 70° C. for ca. 7.5 h. The reaction mixture was cooled to rt and partitioned between ethyl acetate and 1M aqueous HCl (added brine to improve the layer separation). The organic layer was concentrated under reduced pressure and triturated sequentially with Et2O, methanol, and CH2Cl2 to yield the N-[5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]-1-methyl-1H-imidazole-4-sulfonamide. Mass spectrum (ESI) 682.0 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([NH:20][CH:21]1[CH2:27][CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=2[NH:23][C:22]1=[O:32])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>CN(C)C=O>[CH2:1]([O:8][C:9]([CH2:11][N:23]1[C:24]2[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=2[CH2:26][CH2:27][CH:21]([NH:20][CH:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:22]1=[O:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1Nc2ccccc2CCC1NC(CCc1ccccc1)C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)C(NC(CCc2ccccc2)C(=O)OCc2ccccc2)CCc2ccccc21)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-(1-benzyloxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-one (4.0 g) in dry dimethylformamide was added under a nitrogen atmosphere to a stirred suspension of sodium hydride [from the 60% mineral oil dispersion (0.42 g) washed with petroleum ether (3×80 ml)] in dry dimethylformamide (100 ml) at room temperature to which tetrabutylammonium bromide (3.1 g) had been added. Stirring was continued for an additional 30 minutes at room temperature, when a solution of benzyl bromoacetate (2.2 g) in dry dimethylformamide (10 ml) was added. After an additional 30 minutes at room temperature, the reaction mixture was heated to 50°, and maintained at that temperature for 18 hours. The reaction mixture was cooled to room temperature, and the solvent removed under high vacuum. Water (150 ml) was added and the solution extracted with ethyl acetate (2×300 ml). The combined ethyl acetate solutions were washed with water (100 ml), dried over magnesium sulfate, and the solvent removed under reduced pressure to give a brown oil which was chromatographed on silica gel (250 g). Elution with toluene/ethyl acetate (1:1; 600 ml) gave an oil, characterized as isomer A of the title compound; NMR (CDCl3) 5.12 (s, 4H), 4.50 (q, 2H). Elution with an additional 2 liters of the solvent mixture gave an oil characterized as isomer B of the title compound; NMR(CDCl3)δ 5.17(s, 2H), 5.03 (d, 2H), 4.60 (q, 2H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:10]([C:14]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([F:25])[CH:19]=3)=[O:17])=[O:15])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:32][S:33]([O-:35])=[O:34].[Na+]>CN(C)C=O>[CH3:32][S:33]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:10]([C:14]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([F:25])[CH:19]=3)=[O:17])=[O:15])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1)(=[O:35])=[O:34]
Reactant: CS(=O)[O-]
Reactant: Cc1ccc(C(=O)C(=O)c2cccc(-c3ccc(F)cc3)c2-c2ccccc2)cc1F
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)C(=O)c2cccc(-c3ccc(S(C)(=O)=O)cc3)c2-c2ccccc2)cc1F
Yield: 25.8 %

Procedure:
Following the procedure of Example 53, Step 4 using the benzil from Step 3 (2.15 g 8.2 mmol) and sodium methylsulfinate (1.05 g, 10 mmol) in dimethylformamide (20 ml), there was obtained 1 g (50%) of the desired sulfone: mp 146-147° C., after recrystallization from ethyl acetate and hexane. Anal. Calc'd. for C16H13FO4S (MW 320.34): C, 59.99; H, 4.09; S, 10.01. Found: C, 59.68; H, 4.17; S, 10.13.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([NH:7][CH2:8][CH2:9][CH3:10])=[N:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[H-].[Na+].Cl[CH2:20][C:21]1[CH:40]=[CH:39][C:24]([CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1.O>CN(C)C=O>[CH3:1][C:2]1[O:6][C:5]([N:7]([CH2:20][C:21]2[CH:40]=[CH:39][C:24]([CH2:25][O:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[CH2:8][CH2:9][CH3:10])=[N:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCCNc1nc(-c2ccccc2)c(C)o1
Reactant: COC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN(Cc1ccc(COc2ccc(CCC(=O)OC)cc2)cc1)c1nc(-c2ccccc2)c(C)o1
Reaction time: 0.5 h
Yield: 32.1 %

Procedure:
To a solution of 5-methyl-4-phenyl-N-propyl-1,3-oxazole-2-amine (407 mg, 1.88 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 82 mg, 2.04 mmol) at room temperature and the mixture was stirred for 30 min. Methyl 3-[4-[[4-(chloromethyl)benzyl]oxy]phenyl]propanoate (500 mg, 1.57 mmol) was added to the reaction mixture and the mixture was stirred at room temperature for 4 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (251 mg, yield 32%) as a pale-yellow oil.
Reaction SMILES: [C:1]([O:7][C@H:8]1[C@H:20]([O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[C@H:19]([O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[C@H:18]([CH3:35])[O:17][C@@H:9]1[S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C1C=C(Cl)C=C(C(OO)=[O:44])C=1.CSC>C(Cl)Cl>[C:1]([O:7][C@H:8]1[C@H:20]([O:21][C:22](=[O:27])[C:23]([CH3:24])([CH3:25])[CH3:26])[C@H:19]([O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[C@H:18]([CH3:35])[O:17][C@@H:9]1[S:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:44])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C[C@@H]1O[C@H](Sc2ccccc2)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Solvent: CSC
Solvent: ClCCl
Product: C[C@@H]1O[C@H](S(=O)c2ccccc2)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Temperature: -15 °C
Yield: 66.1 %

Procedure:
To a solution of phenyl 6-deoxy-2,3,4-tri-O-pivaloyl-1-thio-β-L-galactopyranoside 4 (2.47 g, 5.22 mmol) in 65 mL of CH2Cl2 at -78° C. is added mCPBA (1.53 g, 8.84 mmol). The reaction mixture is allowed to warm to -15° C. and then quenched with methyl sulfide (5.3 mL, 4.48 g, 17.4 mmol) and allowed to warm to room temperature. The reaction mixture is then diluted with 50 mL CH2Cl2, extracted with H2O (100 mL), saturated NaHCO3 (100 mL), saturated NaCl (100 mL), dried over Na2SO4, filtered and concentrated to afford a white solid. The sulfoxide is purified using flash chromatography (15% EtOAc/petroleum ether) to afford 1.81 g (66%) of 1,6-dideoxy-2,3,4-tri-O-pivaloyl-1-(phenylsulfinyl)-β-L-galactopyranose 5 as a mixture of diastereomers: Rf 0.05 and 0.13 (15% EtOAc/petroleum ether).
Reaction SMILES: [I:1][C:2]1[S:3][C:4]([C:7]2[S:8][C:9]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[CH:10][CH:11]=2)=[CH:5][CH:6]=1.[Br:17]N1C(=O)CCC1=O>CO>[I:1][C:2]1[S:3][C:4]([C:7]2[S:8][C:9]([C:12]3[S:13][C:14]([Br:17])=[CH:15][CH:16]=3)=[CH:10][CH:11]=2)=[CH:5][CH:6]=1
Reactant: Ic1ccc(-c2ccc(-c3cccs3)s2)s1
Reactant: O=C1CCC(=O)N1Br
Solvent: CO
Product: Brc1ccc(-c2ccc(-c3ccc(I)s3)s2)s1
Reaction time: 12 h
Yield: 95 %

Procedure:
100 mg (0.27 mmol) of 2-iodo(5,2′:5′,2″-terthiophene) (1) obtained above in the first step of example 1 were diluted in 100 ml of methanol at 0° C. 2 equivalents of N-bromosuccinimide (NBS, 95 mg, 0.53 mmol) were then added. The mixture was left stirring, in the dark for 12 h. The solvent was then evaporated under reduced pressure. The crude product of the reaction was then purified by column chromatography using, as eluent, petroleum ether then a petroleum ether/dichloromethane (5/1: v/v) mixture. The expected product was isolated in the form of a yellow powder (115 mg; yield=95%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:24]=1[C:25]([NH2:27])=[O:26]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:24]=2[C:25]([NH2:27])=[O:26])[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Reactant: COc1ccc(N)c(C(N)=O)c1
Product: COc1ccc(Nc2nc(Cl)nc3c2ccn3S(=O)(=O)c2ccc(C)cc2)c(C(N)=O)c1

Procedure:
Using General Protocol II and starting with 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (1.64 g, 4.82 mmol) and 2-amino-5-(methyloxy)benzamide (1.0 g, 6.00 mmol), 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-5-(methyloxy)benzamide was isolated as a white solid (1.83 g, 81% Yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.36 (s, 3 H), 3.79 (s, 3 H), 6.61 (s, 1 H), 7.15 (dd, J=8.97, 2.93 Hz, 1 H), 7.31 (d, J=2.93 Hz, 1 H), 7.46 (d, J=8.05 Hz, 2 H), 7.67 (d, J=4.03 Hz, 2 H), 7.96 (ddd, J=8.60, 2.01, 1.83 Hz, 2 H), 8.08 (d, J=8.78 Hz, 1 H), 8.15 (s, 1 H), 11.48 (s, 1 H).
Reaction SMILES: [Si:1]([O:8][C@H:9]([C@@H:11]1[C@@H:14](SC)[N:13]([C:17](=[C:22]([CH3:24])[CH3:23])[C:18]([O:20][CH3:21])=[O:19])[C:12]1=[O:25])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:26]Cl>ClCCl.C(Cl)(Cl)(Cl)Cl>[Si:1]([O:8][C@H:9]([C@@H:11]1[C@@H:14]([Cl:26])[N:13]([C:17](=[C:22]([CH3:24])[CH3:23])[C:18]([O:20][CH3:21])=[O:19])[C:12]1=[O:25])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: ClCl
Reactant: COC(=O)C(=C(C)C)N1C(=O)[C@H]([C@H](C)O[Si](C)(C)C(C)(C)C)[C@H]1SC
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C(=C(C)C)N1C(=O)[C@H]([C@H](C)O[Si](C)(C)C(C)(C)C)[C@H]1Cl
Temperature: -10 °C
Yield: 36.1 %

Procedure:
To a solution of methyl 2-[(3S,4R)-3-[(1S)-1-(tert-butyldimethylsilyloxy)ethyl]-4-methylthio-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (60 mg) in dichloromethane (2 ml) was added a solution of chlorine (24 mg) in carbon tetrachloride (0.2 ml) at -50° C. The solution was allowed to warm to -10° C. during 30 minutes and cooled to -50° C. An additional solution of chlorine (12 mg) in carbon tetrachloride (0.1 ml) was added. The solution was allowed to warm to -5° C. and evaporated. The residue was chromatographed on silica gel (1.5 g, eluting with 8-10% ethyl acetate in hexane) to give 21.0 mg (36.1%) of methyl 2-[(3S,4R)-3-[(1S)-1-(tert-butyldimethylsilyloxy)ethyl]-4-chloro-2-oxoazetidin-1-yl]-3-methylbut-2-enoate. NMR (CDCl3)δ: 0.12 (s, 6H), 0.93 (s, 9H), 1.34 (d, J=6.5 Hz, 3H), 2.01 (s, 3H), 2.29 (s, 3H), 3.56 (dd, J=1.5, 5 Hz, 1H), 3.77 (s, 3H), 4.30 (dq, J=5, 6.5 Hz, 1H), 5.80 (d, J=1.5 Hz, 1H).
Reaction SMILES: [C:1]([O:5][NH:6][C:7]([C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([CH3:20])([CH3:19])[NH:16]2)=[CH:11][CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([O:5][NH:6][C:7]([C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][C:15]([CH3:20])([CH3:19])[NH:16]2)=[CH:11][CH:10]=1)=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)C=Cc2ccc(C(=O)NOC(C)(C)C)cc2N1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(C)CCc2ccc(C(=O)NOC(C)(C)C)cc2N1
Yield: 111.6 %

Procedure:
A solution of 7-tert-butyloxycarbamoyl-1,2-dihydro-2,2-dimethylquinoline (3.4 g, 0.012 mol) in 150 mL of ethyl acetate was hydrogenated under an atmosphere of hydrogen with Pd-C 10% (340 mg) at rt for 7 h. Filtration over celite afforded 3.7 g (100%) of pure 7-tert-butyloxycarbamoyl-1,2,3,4-tetrahydro-2,2-dimethylquinoline. The title compound was prepared by General Method 12 (EXAMPLE 147) from 7-tert-butyloxycarbamoyl-1,2,3,4-tetrahydro-2,2-dimethylquinoline (3.7 g, 0.012 mol) to afford 2.35 g (100%) of 7-amino-1,2,3,4-tetrahydro-2,2-dimethylquinoline as a light reddish oil. Data for 7-amino-1,2,3,4-tetrahydro-2,2-dimethylquinoline: 1H NMR (400 MHz, CDCl3) 6.77 (d, J=7.9, 1H), 6.00 (dd, J=7.9, 2.2, 1H), 5.81 (d, J=2.2, 1H), 3.47 (bs, 1H), 3.40 (bs, 2H), 2.66 (t, J=6.7, 2H), 1.65 (t, J=6.7, 2H), 1.18 (s, 6H).
Reaction SMILES: [F:1][CH:2]1[CH2:8][N:7]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-])=O)[CH2:6][CH2:5][CH:4]([NH:18]C(=O)OC(C)(C)C)[CH2:3]1.C(OC([NH:33][C:34]1[S:38][C:37]([C:39]2[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47](O)=[O:48])=O)(C)(C)C.CO.C(Cl)Cl.N>CO>[NH2:33][C:34]1[S:38][C:37]([C:39]2[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47]([NH:15][C:10]1[CH:11]=[N:12][N:13]([CH3:14])[C:9]=1[N:7]1[CH2:6][CH2:5][C@H:4]([NH2:18])[CH2:3][C@H:2]([F:1])[CH2:8]1)=[O:48]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCC(NC(=O)OC(C)(C)C)CC(F)C1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CC[C@H](N)C[C@H](F)C1

Procedure:
Following the procedure for Example 101, Intermediate 20, tert-butyl 6-fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ylcarbamate and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25 gave, after silica gel column chromatography (0-10% MeOH/DCM, 1% 7 N ammonia in MeOH), a white solid (93 mg, 7% over three steps). Compound 122 was obtained as a single enantiomer from SFC chiral separation of the racemic mixture. 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 7.88 (s, 1H), 7.38-7.28 (m, 2H), 7.08-6.98 (m, 3H), 6.18-6.07 (m, 2H), 4.83-4.66 (m, 1H), 4.30-4.21 (m, 1H), 4.16-4.09 (m, 1H), 3.74 (s, 3H), 3.40-3.16 (m, 3H), 3.11 (m, 1H), 2.98-2.89 (m, 1H), 1.95-1.76 (m, 2H). LCMS (ES+) m/z 466 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1([CH3:14])[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:1]([O:12][C:10]1[CH2:11][C:6]([CH3:14])([CH3:5])[CH2:7][C:8](=[O:13])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: CC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)OC1=CC(=O)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.4 %

Procedure:
Acetyl chloride (1.1 ml, 15.65 mmol) was added to a stirred solution of 5,5-dimethyl-cyclohexane-1,3-dione (2.1 g, 14.23 mmol) and pyridine (1.14 ml), in chloroform (50 ml). The mixture was stirred at room temperature for about 1.5 hours, then washed with water, 0.1N HCl, saturated aqueous sodium hydrogen carbonate and water. The organic phase was dried over sodium sulfate and evaporated to dryness to give 2.5 g (96%) of the title compound as a colourless oil, which was used as such without any further purification.
Reaction SMILES: N(C(C)C)C(C)C.[Li]CCCC.[CH:13]1([C:18]([O:20][CH3:21])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.[CH2:22](I)[I:23]>C1COCC1>[I:23][CH2:22][C:13]1([C:18]([O:20][CH3:21])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)C1CCCC1
Reactant: ICI
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C1(CI)CCCC1
Temperature: -10 °C
Reaction time: 1 h
Yield: 51.9 %

Procedure:
To a stirred solution of HN(iPr)2 (1.31 mL, 9.36 mmol) in THF (5 mL) was added n-BuLi (1.58 M in hexane, 5.43 mL, 8.58 mmol) with keeping −10° C. under N2, and the mixture was stirred at −10° C. for 1 h. Then, to this mixture was added a solution of methyl cyclopentanecarboxylate (1.00 g, 7.80 mmol) in THF (3 mL) dropwise at 0° C., and the mixture was stirred at 0° C. for 2 h. Finally, to this mixture was added CH2I2 (0.628 mL, 7.80 mmol) at 0° C., and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with sat. NH4Cl aq. (50 mL), extracted with Et2O (75 mL) for two times, and the combined organic layer was washed with brine (75 mL). The organic layer was dried over Na2SO4, filtered and concentrated. Removal of the solvent gave a residue, which was chromatographed on a column of silica gel eluting with EtOAc/hexane (1:20→1:10) to give 1.085 g (52%) of title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([OH:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:14]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[Br:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([O:13][CH3:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(O)c(C)cc1Br
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1cc(OC)c(C)cc1Br

Procedure:
A mixture of 800 mg of material from step b. 10 ml of dry reagent grade acetone, 456 mg of K2CO3, and excess methyl iodide was stirred a refluxed for 3 days. Ether extraction provided the ester in a form suitable for further transformation.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:22]=[CH:21][C:11]([O:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:23](#[N:25])[CH3:24]>>[O:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][O:12][C:11]2[CH:21]=[CH:22][C:8]([C:5]3[CH:4]=[CH:3][C:2]([CH2:24][C:23]#[N:25])=[N:7][CH:6]=3)=[CH:9][CH:10]=2)[CH2:16][CH2:17]1
Reactant: CC#N
Reactant: Fc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Product: N#CCc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1

Procedure:
In another aspect, the invention relates to a process for preparing 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide dihydrochloride comprising the steps of: (1) reacting 4-(2-chloroethyl)morpholine with 4-bromophenol to yield 4-(2-(4-bromophenoxy)ethyl)morpholine; (2) coupling 4-(2-(4-bromophenoxy)ethyl)morpholine with 6-fluoropyridin-3-yl-3-boronic acid to yield 4-(2-(4-(6-fluoropyridin-3-yl)phenoxy)ethyl)morpholine; (3) reacting 4-(2-(4-(6-fluoropyridin-3-yl)phenoxy)ethyl)morpholine with acetonitrile to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetonitrile; (4) converting 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetonitrile to methyl 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetate; (5) reacting methyl 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetate with benzylamine to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide; and (6) contacting 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide with hydrochloric acid to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide dihydrochloride.