Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:3]=1/[CH:4]=[N:5]/[S@:6]([C:8]([CH3:11])([CH3:10])[CH3:9])=[O:7].[CH3:20][Mg]Br.C1COCC1>ClCCl>[F:1][C:2]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:12][C:3]=1[CH:4]([NH:5][S@:6]([C:8]([CH3:11])([CH3:9])[CH3:10])=[O:7])[CH3:20]
Reactant: C[Mg]Br
Reactant: CC(C)(C)[S@](=O)/N=C/c1cc(C(F)(F)F)ccc1F
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(N[S@@](=O)C(C)(C)C)c1cc(C(F)(F)F)ccc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
To a solution of (S,E)-N-(2-fluoro-5-(trifluoromethyl)benzylidene)-2-methylpropane-2-sulfinamide (single enantiomer) (150 mg, 0.51 mmol, Step-1) in dichloromethane (5 mL) is added dropwise a solution of methylmagnesium bromide in THF (0.99 M, 2.57 mL, 2.54 mmol) at −78° C. The resulting mixture is stirred at −78° C. for 2 hours and at room temperature for 1 hour. The reaction is quenched by saturated aqueous ammonium chloride solution (50 mL), and the aqueous phase is extracted with EtOAc (50 mL×2). The combined organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (3:1-1:1) to give 63 mg (40% yield) of the title compound as a white solid.
Reaction SMILES: P(Br)(Br)[Br:2].[F:5][C:6]([F:16])([F:15])[C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9]O>C1(C)C=CC=CC=1>[F:5][C:6]([F:16])([F:15])[C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][Br:2]
Reactant: BrP(Br)Br
Reactant: OCc1ccccc1C(F)(F)F
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccccc1CBr
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 30 ml of phosphorus tribromide in 60 ml of absolute toluene was added dropwise at 20°-30° C. to a solution of 14 g of o-trifluoromethylbenzyl alcohol in 80 ml of absolute toluene. Subsequently, the reaction mixture was stirred at room temperature for 2 hours, the toluene was distilled under reduced pressure, the residue was dissolved in methylene chloride, treated with water and the mixture was adjusted to pH 8.0 with potassium hydrogen carbonate. The aqueous phase was extracted three times with CH2Cl2 and the organic phases were washed twice with water and once with saturated NaCl solution, dried over Na2SO4 and evaporated under reduced pressure. o-Trifluoromethylbenzyl bromide was obtained as the residue.
Reaction SMILES: [Cl-].[CH2:2]([O:9][C:10]([NH:12][S:13](N1C=CC(=[N+](C)C)C=C1)(=[O:15])=[O:14])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.Cl.[F:35][C:36]1([F:40])[CH2:39][NH:38][CH2:37]1>C(Cl)Cl>[F:35][C:36]1([F:40])[CH2:39][N:38]([S:13]([NH:12][C:10](=[O:11])[O:9][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)(=[O:14])=[O:15])[CH2:37]1
Reactant: FC1(F)CNC1
Reactant: C[N+](C)=c1ccn(S(=O)(=O)NC(=O)OCc2ccccc2)cc1
Agent: Cl
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NS(=O)(=O)N1CC(F)(F)C1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.8 %

Procedure:
To a stirred solution of N-(1-(N-((benzyloxy)carbonyl)sulfamoyl)pyridin-4(1H)-ylidene)-N-methylmethanaminium chloride (Preparation 21, 3.15 g, 8.49 mmol) in CH2Cl2 (15 mL) were added N,N,-diisopropylethylamine (2.19 g, 17.0 mmol) and 3,3-difluoroazetidine hydrochloride (1.10 g, 8.49 mmol). The mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and the residue diluted with EtOAc (40 mL) and washed with water (40 mL). The aqueous washings were acidified with 2M aqueous solution of HCl and extracted with EtOAC (2×40 mL), the combined organic layers were dried over MgSO4 and concentrated to give the title compound as an amber oil (800 mg, 31%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:22]2[C:27](=[O:28])[NH:26][C:25](=[O:29])[C:24]([C:30]#[N:31])=[N:23]2)[CH:5]=[C:6]([Cl:21])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[N:11]([CH2:19][OH:20])[N:10]=1.C(N(CC)C(C)C)(C)C.[C:41](Cl)(=[O:43])[CH3:42]>C(Cl)Cl>[Cl:21][C:6]1[CH:5]=[C:4]([N:22]2[C:27](=[O:28])[NH:26][C:25](=[O:29])[C:24]([C:30]#[N:31])=[N:23]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[N:11]([CH2:19][O:20][C:41](=[O:43])[CH3:42])[N:10]=1
Reactant: CC(=O)Cl
Reactant: CC(C)c1cc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)nn(CO)c1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCn1nc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)cc(C(C)C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
A solution of 2-[3,5-dichloro-4-(1-hydroxymethyl-5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile (200 mg, 0.43 mmol), N,N-diisopropylethylamine (0.23 mL, 1.29 mmol) and 4-N,N-dimethylaminopyridine (25.8 mg, 0.21 mmol) in methylene chloride (3.0 mL) cooled to 0° C. was treated with acetyl chloride (33.5 μL, 0.47 mmol). The reaction mixture was warmed to 25° C. over 3.5 h. The reaction mixture was then warmed to 40° C. and stirred overnight. At this time, the reaction mixture was cooled to 25° C. and then partitioned between methylene chloride (100 mL) and water (100 mL). The organics were then washed with a 1N aqueous hydrochloric acid solution (3×100 mL), water (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL). The organics were dried over magnesium sulfate, filtered, rinsed and concentrated in vacuo. ISCO CombiFlash chromatography (40 g, 0.5-4.0% methanol/methylene chloride) afforded acetic acid 3-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-phenoxy]-5-isopropyl-6-oxo-6H-pyridazin-1-ylmethyl ester (45.9 mg, 21%) as a yellow solid. ES+-HRMS m/e calcd for C20H16N6O6Cl2 (M+H+) 507.0581, found 507.0582.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:25])=[O:24])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(N)c2c1C
Reactant: O=S(=O)(Cl)c1ccccc1
Product: CCOC(=O)c1oc2cccc(NS(=O)(=O)c3ccccc3)c2c1C
Yield: 83 %

Procedure:
4-Benzenesulfonylamino-3-methyl-benzofuran-2-carboxylic acid ethyl ester was prepared from 4-amino-3-methyl-benzofuran-2-carboxylic acid ethyl ester (Example 60, Step 1), and benzenesulfonyl chloride according to the procedure of Example 68, Step 1. Yield: 83%. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.3 (t, J=7.2 Hz, 3 H) 2.6 (s, 3 H) 4.4 (q, J=7.1 Hz, 2 H) 6.6 (d, J=7.8 Hz, 1 H) 7.3 (m, 1 H) 7.6 (t, J=7.8 Hz, 3 H) 7.7 (m, 3 H) 10.1 (s, 1 H).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].CN1CCOCC1.[O:39]1[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41][CH2:40]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:45][CH:42]1[CH2:43][CH2:44][O:39][CH2:40][CH2:41]1)=[O:4]
Reactant: NC1CCOCC1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(NC1CCOCC1)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 40 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 30 mg, 0.07 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (38.2 μL, 0.348 mmol), tetrahydro-2H-pyran-4-amine (12.66 mg, 0.125 mmol), and BOP (55.4 mg, 0.125 mmol). The reaction mixture was stirred overnight and was then purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 50-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow rate=20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)-N-(tetrahydro-2H-pyran-4-yl)acetamide (14.3 mg, 0.028 mmol, 40%): LCMS=515.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.06-8.25 (2 H, m), 7.49-7.78 (7 H, m), 5.04-5.18 (1 H, m), 3.81-4.01 (2 H, m), 3.38-3.58 (2 H, m), 1.73-1.93 (2 H, m), 1.48-1.73 (2 H, m); Analytical LCMS: column: Mac-mod Halo C18, 4.6×50 mm, 2.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 90:10 acetonitrile:water with 10 mM ammonium acetate; Temperature: 45° C.; Gradient: 0-100% B over 4 minutes, flow rate=4 mL/min, product retention=2.6 min.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:4]=1[N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1.C(=O)(O)[O-].[Na+].[CH3:24][N:25]([CH3:29])[C:26](Cl)=[O:27].O>C(Cl)(Cl)Cl>[Br:9][C:7]1[CH:6]=[CH:5][C:4]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)=[C:3]([NH:2][C:26]([N:25]([CH3:29])[CH3:24])=[O:27])[CH:8]=1
Reactant: Nc1cc(Br)ccc1N1CCc2ccccc21
Reactant: CN(C)C(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CN(C)C(=O)Nc1cc(Br)ccc1N1CCc2ccccc21
Reaction time: 0.17 h
Yield: 40.3 %

Procedure:
To a stirred mixture, under nitrogen, of 28.9 g (0.10 mole) of 1-(2-amino-4-bromophenyl)indoline hydrochloride and 16.8 g (0.20 mole) of anhydrous powdered sodium bicarbonate in 500 ml of chloroform was added a solution of 21.5 g (0.20 mole) of dimethylcarbamyl chloride in 25 ml of chloroform, over a 10 minute period. The mixture was heated under reflux for 7 hours, and 8.4 g (0.10 mole) of sodium bicarbonate and 10.7 g (0.10 mole) of the dimethylcarbamyl chloride were added. After heating under reflux for 2 days, equivalent amounts (8.4 g of sodium bicarbonate and 10.7 g of dimethylcarbamyl chloride) were added. After three days under reflux, the mixture was cooled and 500 ml of water was added. The phases were stirred vigorously for 0.5 hours and separated. The organic phase was washed three times with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was dissolved in 200 ml of dichloromethane and adsorbed on a chromatography column containing 1 kg of silica gel packed in and eluted with dichloromethane. The fractions containing product were combined and concentrated to afford 14.5 g (40%) of product. Recrystallization from toluene (charcoal)/hexane gave the analytical sample, mp 119°-121° C.
Reaction SMILES: CS(C)=O.[CH2:5]([OH:8])[CH2:6][OH:7].CC([O-])(C)C.[K+].Cl[C:16]1[CH:25]=[C:24]2[C:19]([C:20](=[O:32])[C:21]([C:29]([OH:31])=[O:30])=[CH:22][N:23]2[CH:26]2[CH2:28][CH2:27]2)=[CH:18][C:17]=1[F:33]>O>[CH:26]1([N:23]2[C:24]3[C:19](=[CH:18][C:17]([F:33])=[C:16]([O:7][CH2:6][CH2:5][OH:8])[CH:25]=3)[C:20](=[O:32])[C:21]([C:29]([OH:31])=[O:30])=[CH:22]2)[CH2:27][CH2:28]1
Reactant: OCCO
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1cn(C2CC2)c2cc(OCCO)c(F)cc2c1=O
Temperature: 90 °C
Reaction time: 6 h

Procedure:
To a mixture of DMSO (5 ml) and ethyleneglycol (6 ml), KOtBu (1.6 g, 14.23 mmol) was added portionwise over 10 min, and then heated to 90° C. To the mixture, 7chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (1.0 g) was added portionwise over 20 min, the temperature was increased to 105° C. and the mixture was stirred for 6 h. Water (30 ml) was added to the reaction solution and the pH of the solution was adjusted to pH=5. The resulting solution was left in the refrigerator overnight. The precipitate obtained was filtered, washed with cold water, and dried affording a 2:1 mixture of Intermediate 26A and Intermediate 26B (1.0 g).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=1)([OH:14])[CH:10]=[C:11]([CH3:13])C.[CH3:22][S-].[Na+]>CN(C)C=O>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=1)([OH:14])[CH:10]=[CH:11][CH2:13][CH3:22]
Reactant: COc1ccccc1C(O)(C=C(C)C)c1ncccc1C
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC=CC(O)(c1ccccc1O)c1ncccc1C
Temperature: 120 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
7.13 g of 1-(2-methoxyphenyl)-3-methyl-1-(3-methyl-2-pyridyl)-2-buten-1-ol were dissolved in 100 ml of dimethylformamide at room temperature and 5.29 g of sodium methanethiolate were added. After stirring at 120° C. for 2 hours the mixture was allowed to cool to room temperature and then evaporated. Water and ethyl acetate were added, and the organic phase was separated, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:4) for the elution. There were obtained 4.53 g of 1-(2-hydroxyphenyl)-4-methyl-1-(3-methyl-2-pyridyl)-2-buten-1-ol in the form of an oil.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][NH:7][C:8]1[CH:30]=[CH:29][C:11]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:16][CH2:15]2)=[O:13])=[CH:10][CH:9]=1)([CH3:3])[CH3:2].[Cl:31][CH2:32][C:33](Cl)=[O:34]>C(Cl)Cl>[CH:1]([O:4][CH2:5][CH2:6][N:7]([C:8]1[CH:30]=[CH:29][C:11]([C:12]([N:14]2[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:18][CH2:19]2)=[O:13])=[CH:10][CH:9]=1)[C:33](=[O:34])[CH2:32][Cl:31])([CH3:3])[CH3:2]
Reactant: O=C(Cl)CCl
Reactant: CC(C)OCCNc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Solvent: ClCCl
Product: CC(C)OCCN(C(=O)CCl)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1

Procedure:
In a manner analogous to that described in Example 6, the oily 1-{4-[N-(2-isopropyloxyethyl)-N-chloroacetylamino]benzoyl}-4-[2-(4-chlorophenyl)ethyl]piperazine is prepared from 1.35 g of 1-[4-(2-isopropyloxyethyl)aminobenzoyl]-4-[2-(4-chlorophenyl)ethyl]piperazine by reaction with chloroacetyl chloride; IR (CH2Cl2): 1650 cm-1 (broad); NMR (CDCl3): 1.15 (t, 3H), 1.8 (m, 2H), 2.5 (m) and 2.6 (t) (together 6H), 2.8 (t, 2H), 3.4 (m, 6H), 3.85 (m, 6H), 7.15 (d, 2H), 7.3 (m, 4H), 7.5 ppm (d, 2H).
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[Br:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[N:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:17]=[CH:18][C:11]=12.CI>C1COCC1>[Br:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[N:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:17]([CH3:1])=[CH:18][C:11]=12
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)ccnc21
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cc2c(Br)ccnc2n1S(=O)(=O)c1ccccc1
Temperature: -45 °C
Reaction time: 0.5 h

Procedure:
1.8M Lithium diisopropylamide (270 ml) was added dropwise over 20 min to a solution of 4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (82 g) in dry THF (820 ml) and the reaction was stirred at −45° C. for 30 min. Methyl iodide (90 ml) was added drop wise to the solution and the mixture was stirred at −45° C. for 45 min, then allowed to warm to RT. The reaction was quenched with water. The organic layer was collected and the aqueous layer extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulphate and concentrated in vacuo. The residue was triturated with ethyl acetate:cyclohexane (3:1). The solid material was collected and washed with ethyl acetate:cyclohexane (3:1) and dried in vacuo at 35° C. This residue was dissolved in DCM, washed with water, dried over magnesium sulphate and the solvent removed in vacuo to give the title compound (37.6 g) as a cream solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[S:9][C:10]3[CH:16]=[C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)[CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:3][CH2:2]1.[Cl:30][C:31]1[CH:32]=[N:33][C:34](I)=[N:35][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:30][C:31]1[CH:32]=[N:33][C:34]([N:1]2[CH2:6][CH2:5][CH:4]([O:7][C:8]3[S:9][C:10]4[CH:16]=[C:15]([CH:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]5)[CH:14]=[CH:13][C:11]=4[N:12]=3)[CH2:3][CH2:2]2)=[N:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3nc(OC4CCNCC4)sc3c2)CC1
Reactant: Clc1cnc(I)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc3nc(OC4CCN(c5ncc(Cl)cn5)CC4)sc3c2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 31.1 %

Procedure:
To a solution of tert-butyl 4-(2-(piperidin-4-yloxy)benzo[d]thiazol-6-yl)piperidine-1-carboxylate (337 mg, 0.807 mmol) and 5-chloro-2-iodopyrimidine (213 mg, 0.888 mmol) in DMF (10 mL) was added potassium carbonate (335 mg, 2.421 mmol). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was cooled to rt, diluted with water (30 mL), and extracted with EtOAc (3×10 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was recrystallized from EtOAc to afford tert-butyl 4-(2-((1-(5-chloropyrimidin-2-yl)piperidin-4-yl)oxy)benzo[d]thiazol-6-yl)piperidine-1-carboxylate (133 mg, 0.251 mmol, 31% yield) as an off white solid. LCMS (m/z)=531 (M+H)+.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([Cl-]C([O-])=O)[CH:2]=1.C([O:21]C1C=CC(CO)=CC=1)C1C=CC=CC=1.CN1CCOCC1>ClCCl>[N+:7]([C:6]1[CH:5]=[CH:4][C:3]([OH:21])=[CH:2][CH:1]=1)([O-:9])=[O:8]
Reactant: OCc1ccc(OCc2ccccc2)cc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=[N+]([O-])c1ccc(O)cc1

Procedure:
4-Nitrophenylchloroformate (260 g, 1.30 mmol) as a solution in 500 ml dichloromethane (DCM) is added to Wang resin (p-benzyloxybenzyl alcohol resin ex Calbiochem-Nova-biochem, 350 g, 0.60 mmol) suspended in 1000 ml DCM and N-methylmorpholine (196 ml, 1.79 mmol) and stirred at room temperature for 18 hours. The resin is filtered and washed successively using methanol, DCM and ether to give WANG PARA-NITROPHENOL RESIN. [IR. 1761.5 cm−1; Loading 1.20 mmol/g].
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([O:11][CH3:12])[CH:3]=1.[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1>>[F:13][C:14]1[CH:19]=[C:18]([C:2]2[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: COc1cc(I)cc([N+](=O)[O-])c1
Product: COc1cc(-c2cccc(F)c2)cc([N+](=O)[O-])c1
Yield: 81.7 %

Procedure:
A similar procedure as described in Example 12, step 3 was used, starting from 1-iodo-3-methoxy-5-nitro-benzene (1.03 g, 3.69 mmol) and 3-fluoro-phenylboronic acid (800 mg, 5.72 mmol) to afford 3′-fluoro-5-methoxy-3-nitro-biphenyl (745 mg, 82%) as an amorphous white solid: EI(+)-HRMS m/e calculated for C13H10FNO3 (M)+ 247.0645, found 247.0645.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O.NN>[Ni].CCO>[N:1]1([CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(NCCN2CCOCC2)cc1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1ccc(NCCN2CCOCC2)cc1
Temperature: 65 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
A 50 mL round bottom flask was charged with (2-Morpholin-4-yl-ethyl)-(4-nitro-phenyl)-amine (0.315 g, 1.26 mmol) and EtOH (5 mL). Hydrazine Hydrate (0.278 mL, 8.82 mmol) was then added to the solution. Excess RaNi was then added in dropwise until gas evolution ceased. The suspension was then allowed to stir for an additional 1 h at 65° C. The suspension was cooled to room temperature and then was filtered over celite. The celite was washed with MeOH (˜20 mL) and the combined organic solutions were then concentrated in vacuo affording pure N-(2-Morpholin-4-yl-ethyl)-benzene-1,4-diamine as a light purple oil (0.220 g, 0.995 mmol, 79% yield).
Reaction SMILES: ClCCl.[CH3:4][C:5]([NH:15][CH:16]([CH3:20])[C:17](=O)[CH3:18])([C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([Cl:14])[CH:8]=1)[CH3:6].[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][C:29](Cl)=[O:30].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[CH3:6][C:5]([N:15]1[CH:16]([CH3:20])[C:17]([CH3:18])=[C:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[F:21])[C:29]1=[O:30])([C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([Cl:14])[CH:8]=1)[CH3:4]
Reactant: O=C(Cl)Cc1ccccc1F
Reactant: CC(=O)C(C)NC(C)(C)c1cc(F)cc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1=C(c2ccccc2F)C(=O)N(C(C)(C)c2cc(F)cc(Cl)c2)C1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.3 %

Procedure:
To 20 ml of dichloromethane were added 3.0 g of N-[1-methyl-1-(3-chloro-5-fluorophenyl)ethyl]-N-(1-methyl-2-oxopropyl)amine and 3.5 g of pyridine, and 3.0 g of (2-fluorophenyl)acetyl chloride was then added dropwise thereto at 5° to 10° C. After stirring at room temperature for 1 hour, a saturated aqueous sodium hydrogencarbonate solution was added, followed by extraction with dichloromethane. After dried over anhydrous sodium sulfate, the solution was concentrated by evaporation, and the resulting oil was dissolved in 20 ml of ethyl acetate. Next, 10 ml of a 28% methanol solution of sodium methylate was added thereto, and after stirring under reflux for 15 minutes, the temperature of the solution was returned to room temperature and water was then added, followed by extraction with ethyl acetate. Afterward, the solution was washed with 12% hydrochloric acid and a saturated aqueous solution of sodium hydrogencarbonate, and then dried over anhydrous sodium sulfate. Next, the solution was condensed by an evaporator, and then subjected to silica gel chromatography to obtain 2.2 g of 1-[1-methyl-1-(3-chloro-5-fluorophenyl)ethyl]-4,5-dimethyl-3-(2-fluorophenyl)-3-pyrroline-2-one.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[CH3:19][C:20]1[N:24]=[C:23]([C:25](O)=[O:26])[O:22][N:21]=1>CC#N.CO>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:25]([C:23]3[O:22][N:21]=[C:20]([CH3:19])[N:24]=3)=[O:26])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: Cc1noc(C(=O)O)n1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Solvent: CC#N
Solvent: CO
Product: Cc1noc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)n1
Yield: 5 %

Procedure:
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (219 mg, 0.84 mmol) was coupled with 3-methyl-1,2,4-oxadiazole-5-carboxylic acid using the method of Example 34(d). Crude product was suspended in MeCN and MeOH. Suspension was filtered to give 16 mg (5%) the title compound as a colourless solid. Filtrate was purified by CombiFlash (column: C-18 silica, eluent: 0-100% MeCN in water). Fractions containing the title compound were combined and suspended in MeCN. Suspension was filtered to give 9 mg (3%) the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.19 (d, 3H), 2.44 (s, 3H), 4.34 (d, 2H), 4.39-4.53 (m, 1H), 6.95 (d, 1H), 7.84 (d, 1H), 7.92 (dd, 1H), 7.98 (d, 1H), 8.06 (d, 1H), 9.42 (d, 1H).