Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]1)#[N:2].C(O)(=[O:35])C.ClC1C=CC=C(C(OO)=O)C=1>O>[C:1]([C:3]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:4][CH2:5][N+:6]1([O-:35])[CH2:11][CH2:10][C:9]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]1)#[N:2]
Reactant: CC(=O)O
Reactant: N#CC(CCN1CCC(C(=O)O)(c2ccccc2)CC1)(c1ccccc1)c1ccccc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O
Product: N#CC(CC[N+]1([O-])CCC(C(=O)O)(c2ccccc2)CC1)(c1ccccc1)c1ccccc1

Procedure:
6.3 Grams of 1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxylic acid was dissolved, at room temperature, in 100 ml. of glacial acetic acid. To that mixture was added 3.1 grams of m-chloroperbenzoic acid (85% by weight) and the resultant mixture was stirred at room temperature for a period of 11/2 hours, thereafter diluted with 500 ml. of water, cooled and filtered. The residual solid was washed successively with water chloroform, ether and warm methanol. Upon drying for 6 hours at 65° C. was afforded 1-(3-cyano-3,3-diphenylpropyl)-4-phenyl-N-oxidopiperidine-4-carboxylic acid, melting at about 186°-189° C., with decomposition.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[NH:4][CH2:3]1>C(OCC)(=O)C.[Pd]>[NH2:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([CH3:14])([CH3:1])[CH2:3][NH:4]2)=[CH:9][CH:8]=1
Reactant: CC1(C)CNc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(C)CNc2cc(N)ccc21
Yield: 89.5 %

Procedure:
A solution of 3,3-dimethyl-6-nitroindoline (60 mg, 0.31 mmol) in 3 mL of ethyl acetate was hydrogenated under an atmosphere of hydrogen with Pd-C 10% (10 mg) at rt for 3 h. Filtration over celite afforded 45 mg (90%) of 6-amino-3,3-dimethylindoline. Data for 6-amino-3,3-dimethylindoline: 1H NMR (400 MHz, CDCl3)6.80 (d, J=7.8, 1H), 6.08 (dd, J=7.8, 2.1, 1H), 6.01 (d, J=2.1, 1H), 3.60 (bs, 1H), 3.50 (bs, 2H), 3.26 (s, 2H) 1.25 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].B(Cl)([C@@H]1[C@@H](C)[C@H]2C(C)(C)[C@@H](C2)C1)[C@@H]1[C@@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([OH:10])[CH3:9]
Reactant: CC(=O)c1ccccc1Cl
Agent: C[C@@H]1[C@@H](B(Cl)[C@H]2C[C@@H]3C[C@@H]([C@@H]2C)C3(C)C)C[C@@H]2C[C@H]1C2(C)C
Product: C[C@@H](O)c1ccccc1Cl
Yield: 73.3 %

Procedure:
Reaction was carried out using 2′-chloroacetophenone (11.90 g, 76.77 mmol) and (+)-B-chlorodiisopinocamphenylborane ((+)-DIP-C1) (25.00 g, 77.88 mmol) and according to J. Org. Chem., 1985, vol. 50, p. 5446; and 1988, vol. 53, p. 2916, to give the title compound (8.81 g, 72%). The optical purity was determined by HPLC analysis using an optically active column after conversion to the acetate (using acetic anhydride and triethylamine in dichloromethane).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]([O:27]CC)=O)=[O:22])[CH2:17][CH2:16]3)=[N:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:32][NH2:33]>O1CCCC1>[F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:16][CH2:17][N:18]([C:21]([O:23][CH2:24][C:25]([NH:33][CH3:32])=[O:27])=[O:22])[CH2:19][CH2:20]3)=[N:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)COC(=O)N1CCN(c2ccc(-c3cccc(C(F)(F)F)c3)cn2)CC1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)COC(=O)N1CCN(c2ccc(-c3cccc(C(F)(F)F)c3)cn2)CC1

Procedure:
The process is performed according to the procedure described in Example 1 (step 1.4.). Starting with 1.50 g (3.43 mmol) of 2-(ethyloxy)-2-oxoethyl 4-{5-[3-(trifluoromethyl)phenyl]-2-pyridyl}-1-piperazinecarboxylate, obtained in step 3.4, and 8.6 ml (17.15 mmol) of a solution of methylamine (2M) in tetrahydrofuran, and after chromatography on silica gel, eluting with a 97/3 mixture of dichloromethane and methanol, followed by washing with diisopropyl ether, 1.18 g of product are obtained in the form of a white solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:12][OH:13].[OH-].[Na+].C(O)(=O)C>CCO.O>[F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=[N:12][OH:13]
Reactant: NO
Reactant: O=Cc1cc(F)ccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: ON=Cc1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.1 %

Procedure:
2,5-Difluorobenzaldehyde (28.5 g, 0.20 mol) was dissolved in 30 ml EtOH. 80 ml water, 80 g crushed ice and hydroxylamine hydrochloride (15.3 g, 0.22 mol) were added. 250 ml (0.50 mol) 2N NaOH were added drop wise and the yellow solution was stirred for 3 hours at room temperature. The reaction mixture was neutralized to pH 6 with acetic acid. The formed suspension was diluted with water and filtered. The crystals were washed with water and dried 2 hours at 50° C. and <20 mbar to obtain the desired product as a white solid (26.1 g, 83%). MS (m/e): 156.0 (M−H+).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][NH:7][CH2:8][CH2:9][NH2:10].CS[C:13](=N)[NH:14][N+:15]([O-:17])=[O:16].C(O)C>C(OCC)(=O)C>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][N:7]1[CH2:8][CH2:9][NH:10][C:13]1=[N:14][N+:15]([O-:17])=[O:16]
Reactant: CSC(=N)N[N+](=O)[O-]
Reactant: NCCNCC1CCCO1
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=[N+]([O-])N=C1NCCN1CC1CCCO1

Procedure:
Afterward, a mixture of 1.00 g Of N-[(tetrahydro-2-furanyl) methyl]ethylenediamine, 0.77/g of S-methyl-N-nitroisothiourea, 0.1 g of N,N-dimethylaminopyridine (DMAP) and 10 ml of ethanol was refluxed. After the completion of reaction, ethyl acetate was added, and insolubles were then removed by filtration. The filtrate was concentrated under a reduced pressure, and the precipitated crystals were then removed by filtration. Next, the filtrate was concentrated under a reduced pressure, and the resultant residue was purified by silica gel column chromatography (1:2 acetone/ethyl acetate) to obtain 0.25 g of 1-[(tetrahydro-2-furanyl) methyl]-2(nitroimino)imidazolidine as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[CH:39]=[CH:38][CH:37]=[N:36]2)[N:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([N:35]5[CH:39]=[CH:38][CH:37]=[N:36]5)[N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: Brc1cccc(-n2cccn2)n1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-n5cccn5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-pyrazol-1-yl-pyridine.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][CH:8]([CH3:24])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:13]=1)=[O:10].[C:25]([C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:40])[CH2:36][CH2:37][CH2:38]Cl)=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26]>>[C:25]([C:29]1[CH:30]=[CH:31][C:32]([C:35](=[O:40])[CH2:36][CH2:37][CH2:38][N:21]2[CH2:22][CH2:23][CH:18]([C:14]3[CH:13]=[C:12]([NH:11][C:9](=[O:10])[CH:8]([CH3:24])[CH3:7])[CH:17]=[CH:16][CH:15]=3)[CH2:19][CH2:20]2)=[CH:33][CH:34]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: CC(C)(C)c1ccc(C(=O)CCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCC(=O)c3ccc(C(C)(C)C)cc3)CC2)c1

Procedure:
Prepared by Procedure K (KI) and Scheme E (K2CO3) using 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide and 1-(4-tert-butylphenyl)-4-chloro-1-butanone: ESMS m/e: 449.2 (M+H)+.
Reaction SMILES: Cl.Cl.[OH:3][C@H:4]1[C@@H:9]([CH3:10])[CH2:8][CH2:7][N:6]([CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][NH:17][CH:16]([CH3:20])[C:15]2=[O:21])[CH2:5]1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH:26]=[CH:27][C:28](O)=[O:29].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:22][C:23]1[CH:24]=[C:25](/[CH:26]=[CH:27]/[C:28]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][CH2:11][N:6]3[CH2:7][CH2:8][C@H:9]([CH3:10])[C@H:4]([OH:3])[CH2:5]3)[C:15](=[O:21])[CH:16]2[CH3:20])=[O:29])[CH:31]=[CH:32][C:33]=1[Cl:34]
Reactant: CC1NCCN(CCCN2CC[C@H](C)[C@H](O)C2)C1=O
Reactant: O=C(O)C=Cc1ccc(Cl)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1C(=O)N(CCCN2CC[C@H](C)[C@H](O)C2)CCN1C(=O)/C=C/c1ccc(Cl)c(Cl)c1
Reaction time: 1 h

Procedure:
To a suspension of (3S,4S)-4-methyl-piperidin-3-ol hydrochloride (intermediate 26; 0.04 g, 0.3 mmol) in dichloromethane (1 ml) was added triethylamine (0.04 ml, 0.3 mmol) and acetic acid (0.03 ml, 0.5 mmol) followed by a solution of crude 2-methyl-3-oxo-4-(3-oxo-propyl)piperazine-1-carboxylic acid tert-butyl ester (intermediate 14c; 0.08 g, 0.3 mmol) in dichloromethane (1 ml). Sodium triacetoxyborohydride (0.07 g, 0.4 mmol) was then added and the mixture stirred for 2 h, after which time the mixture was washed with saturated aq. sodium hydrogencarbonate solution, dried (Na2SO4) and concentrated. The crude residue was then treated with HCl in dioxane (2 ml, 4N) and stirred for 30 minutes after which time the reaction was concentrated to afford crude 1-[3-((3S,4S)-3-hydroxy-4-methyl-piperidin-1-yl)-propyl]-3-methyl-piperazin-2-one dihydrochloride as a white powder (0.1 g). To a solution of crude 1-[3-((3S,4S)-3-hydroxy-4-methyl-piperidin-1-yl)-propyl]-3-methyl-piperazin-2-one dihydrochloride (0.03 g, 0.1 mmol) in N,N-dimethylformamide (0.8 ml) was added 3,4-dichlorocinnamic acid (0.02 g, 0.1 mmol), triethylamine (0.05 ml, 0.4 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (0.04 g, 0.1 mmol) and the reaction shaken for 1 h, after which time the reaction mixture was directly purified by preparative HPLC. This afforded the titled product as a colorless gum. MS (ISP)=468.1 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][OH:5].Cl[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]>O1CCOCC1>[CH2:13]([O:12][C:10]([NH:1][C@@H:2]([CH2:3][CH2:4][OH:5])[C:6]([OH:8])=[O:7])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@@H](CCO)C(=O)O
Solvent: C1COCCO1
Product: O=C(N[C@@H](CCO)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice-cooled solution of H-Hse-OH (3 g) in dioxane/2M NaOH (100 mL/25 mL) was added benzyl chloroformate (4 mL) dropwise over 15 min. The reaction mixture was allowed to warm to RT and was stirred overnight at RT. The solvent was evaporated off and the aq. residue was extracted with Et2O and acidified with a 2M HCl solution. The aq. phase was extracted with DCM. The DCM layers were combined, dried (Na2SO4) and evaporated off to give the desired product as a white powder (4.13 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.[CH3:10]C1C=CC(S(O)(=O)=O)=CC=1>CO>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)C1CCOCC1
Solvent: CO
Product: COC(=O)C1CCOCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of tetrahydro-2H-pyran-4-carboxylic acid (520 mg, 4.00 mmol, 1.00 equiv) in methanol (50 mL) was added PTSA (35.0 mg, 0.200 mmol). The resulting mixture was stirred overnight at 80° C. in an oil bath, then cooled to ambient temperature and concentrated in vacuo. The residue was diluted with 30 mL of water and extracted with 3×30 mL of DCM. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated in vacuo. This resulted in 500 mg (87%) of methyl tetrahydro-2H-pyran-4-carboxylate as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[N:21]1([CH2:27][CH2:28][OH:29])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([N:24]2[CH2:25][CH2:26][N:21]([CH2:27][CH2:28][OH:29])[CH2:22][CH2:23]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: OCCN1CCNCC1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1)N1CCN(CCO)CC1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 2-piperazin-1-ylethanol (26.0 mg, 0.2 mmol). The title compound was obtained as a solid (23.0 mg, 50% yield). 1H NMR (300 MHz, d6-DMSO) δ: 8.75 (2H, s), 7.80 (1H, s), 4.87 (4H, m), 4.23 (4H, m), 4.04 (2H, m), 3.22 (2H, m). MS m/z: 462.90, 464.90 [M+H]+.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5](Cl)(=[O:10])[CH2:6][CH:7]([CH3:9])[CH3:8].O.[C:13]1([CH3:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:8][CH:7]([CH3:9])[CH2:6][C:5]([C:16]1[CH:17]=[CH:18][C:13]([CH3:19])=[CH:14][CH:15]=1)=[O:10]
Reactant: Cc1ccccc1
Reactant: CC(C)CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: Cc1ccc(C(=O)CC(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97 %

Procedure:
Portionwise add aluminum trichloride (3.35 g, 25 mmol) to a solution of isovaleryl chloride (2 mL, 16.4 mmol) in anhydrous toluene (50 mL) at 0° C. Warm to room temperature and stir 12 h. Cool to 0° C. and slowly add cold water (500 mL). Extract with EtOAc, wash the organic phase with brine, dry over Na2SO4 and concentrate in vacuo to obtain the desired intermediate (2.8 g, 97%) as an orange oil suitable for use without additional purification. MS (APCI+) m/z: 176 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[N:14]=[C:15]([O:25][C@H:26]4[CH2:35][O:34][C@H:33]5[C@@H:28]([O:29]C(C6C=CC=CC=6)[O:31][CH2:32]5)[CH2:27]4)[N:16](COCC[Si](C)(C)C)[C:11]3=[CH:10][C:9]=2[Cl:42])=[CH:4][CH:3]=1.C(O)=O.OS([O-])(=O)=O.[K+].[OH-].[Na+].[NH4+].[Cl-]>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[N:14]=[C:15]([O:25][C@H:26]4[CH2:35][O:34][C@H:33]([CH2:32][OH:31])[C@@H:28]([OH:29])[CH2:27]4)[NH:16][C:11]3=[CH:10][C:9]=2[Cl:42])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1c(O[C@H]2CO[C@@H]3COC(c4ccccc4)O[C@H]3C2)nc2nc(-c3ccc(Br)cc3)c(Cl)cc21
Agent: O=S(=O)([O-])O
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O=CO
Product: OC[C@H]1OC[C@H](Oc2nc3nc(-c4ccc(Br)cc4)c(Cl)cc3[nH]2)C[C@@H]1O
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
5-(4-bromophenyl)-6-chloro-2-(((4aR,7R,8aS)-2-phenylhexahydropyrano-[3,2-d][1,3]dioxin-7-yl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine (1.5 g, 2.229 mmol) was dissolved in formic acid (30 ml, 782 mmol) and aqueous saturated KHSO4 (2 mL). The reaction was heated to 50° C. overnight, then diluted with EtOAc, followed by the addition of 3M NaOH until a pH of ˜13 was reached. After stirring 10 min at rt, saturated NH4Cl was added until a pH of ˜7 was reached. The aqueous phase was separated, and extracted with EtOAc (×2). The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by column chromatography on a Biotage™ 50 g column by eluting with 1% to 12% MeOH in CHCl3. LC-MS: calculated for C18H17BrClN3O4 453.01 observed m/e: 453.94 (M+H)+ (Rt 1.13/2 min).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:34])[CH:32]=[CH2:33])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[N:18]1([S:21]([C:24]2[CH:25]=[CH:26][C:27]([NH:30][C:31](=[O:34])[CH:32]=[CH2:33])=[CH:28][CH:29]=2)(=[O:22])=[O:23])[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]1
Reactant: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
Trifluoroacetic acid (3 ml) was added in one portion to a solution of 4-(4-Acryloylamino-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (1.23 g, 3.11 mmol) in DCM (6 ml). The resulting mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. After which time, the mixture was concentrated under vacuum to give the title compound (0.9 g, 98% yield) as an orange foam which was used without further purification.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=3)=[CH:29][N:28]=2)=[CH:23][CH:22]=1)[CH2:17][CH2:18][CH2:19][CH3:20].[C:40](O)(=[O:46])[CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>CN(C)C1C=CN=CC=1.ClCCl>[C:40]([O:39][C:36]1[CH:35]=[CH:34][C:33]([C:30]2[CH:31]=[N:32][C:27]([C:24]3[CH:23]=[CH:22][C:21]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:26][CH:25]=3)=[N:28][CH:29]=2)=[CH:38][CH:37]=1)(=[O:46])[CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: CCCCCc1ccc(-c2ncc(-c3ccc(O)cc3)cn2)cc1
Reactant: CCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCC(=O)Oc1ccc(-c2cnc(-c3ccc(CCCCC)cc3)nc2)cc1
Reaction time: 8 h
Yield: 76.4 %

Procedure:
0.8 g of N,N'-dicyclohexylcarbodiimide is added within 5 minutes while stirring to a solution of 1.0 g of 4-(2-[4-pentylphenyl]-5-pyrimidinyl)phenol, 0.4 g of caproic acid and 0.05 g of 4-(dimethylamino)pyridine in 30 ml of dichloro-methane. The reaction mixture is stirred overnight, then filtered, the filtrate is washed with saturated sodium bicarbonate solution and with water and concentrated. Chromatography of the residue on silica gel with hexane/ethyl acetate (vol. 4:1) and two-fold recrystallization of the fractions which are pure according to thin-layer chromatography give 1.0 g of 4-(2-[4-pentylphenyl]-5-pyrimidinyl)phenyl hexanoate; m.p. (C-SC) 124° C., phase transition (SC -SA) 185° C., cl.p. (SA -I) 224° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([N-]C(C)C)(C)C.[Li+].[Br:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Br.O>C1COCC1.C1CCCCC1>[Br:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][CH:1]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1cncc(Cc2cccnc2)c1
Reactant: BrCc1ccccc1Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: Brc1ccccc1CC(c1cccnc1)c1cccnc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 3,3′-methylenedipyridine (5.0 g, 29.4 mmol) in THF (300 mL) at 0° C. was treated with lithium diisopropylamide (39 mL of a 1.5 M solution of the mono-THF complex in cyclohexane, 58.7 mmol) dropwise over 10 min. After stirring at 0° C. for 30 min, 2-bromobenzylbromide (7.3 g as a solution in 100 mL THF, 29.4 mmol) was added dropwise via cannula. The reaction mixture was stirred for 1 h at 0° C. before being poured into H2O (300 mL) and extracted with CH2Cl2 (3×300 mL). The organic extracts were pooled, washed with saturated aqueous NaCl (2×200 mL), dried (Na2SO4), and concentrated under reduced pressure to provide 3,3′-[2-(2-bromophenyl)ethane-1,1-diyl]dipyridine. ESI+MS: 339.0 [M+H]+.
Reaction SMILES: [OH:1][C@H:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4].[CH3:8][S:9](Cl)(=[O:11])=[O:10]>C1(C)C=CC=CC=1>[CH3:8][S:9]([O:1][C@H:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4])(=[O:11])=[O:10]
Reactant: COC(=O)[C@@H](C)O
Reactant: CS(=O)(=O)Cl
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H](C)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
A stirred solution of (R)-methyl 2-hydroxypropanoate (1.0 g, 9.61 mmol) in toluene (15 mL) was cooled to 0° C. Methanesulfonyl chloride (0.82 mL, 10.6 mmol) was added drop wise. After 2 h, the solution was warmed to room temperature and further stirred for 45 min. The resulting heavy white precipitate was removed by vacuum filtration and the clear solution was concentrated to provide 1.75 g (99%) of (R)-methyl 2-((methylsulfonyl)oxy)propanoate as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 5.14 (q, J=7.0 Hz, 1H), 3.81 (d, J=4.5 Hz, 3H), 3.16 (d, J=4.5 Hz, 3H), 1.62 (d, J=7.0 Hz, 3H). (S)-methyl 2-((methylsulfonyl)oxy)propanoate was prepared in an analogous fashion using (S)-methyl 2-hydroxypropanoate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[CH:22]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C1C(=O)N([Br:34])C(=O)C1>C1COCC1>[Br:34][C:22]1[C:21]2[C:25](=[C:17]([C:14]3[N:13]=[C:12]([C:4]4[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:10])[CH3:11])=[C:2]([Cl:1])[CH:3]=4)[O:16][N:15]=3)[CH:18]=[CH:19][CH:20]=2)[N:24]([CH3:26])[CH:23]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4ccn(C)c34)no2)cc1Cl
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(Br)cn(C)c34)no2)cc1Cl
Temperature: 20 °C
Reaction time: 16 h
Yield: 90.6 %

Procedure:
To a solution of 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indole (D58) (300 mg) in THF (10 mL) was added NBS (160 mg). The reaction mixture was stirred at 20° C. for 16 h. The reaction mixture was concentrated and the residue was purified by column chromatography (15% ethyl acetate in hexane) to afford 3-bromo-7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indole (D59) (330 mg). δH (DMSO-d6, 400 MHz): 1.36 (6H, d), 3.70 (3H, s), 4.88 (1H, m), 7.32 (1H, dd), 7.45 (1H, d), 7.56 (1H, dd), 7.68 (2H, m), 8.12 (1H, dd), 8.20 (1H, d). MS (ES): C20H17BrClN3O2 requires 445; found 446.0 (M+H+).
Reaction SMILES: CN1C(C)=[C:9]2[C:4]([N:5]([CH3:15])[C:6](=[O:14])[N:7]([CH3:13])[C:8]2=[O:12])=N1.Br[CH2:17][C:18]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26]2[CH:31]=[C:30]([F:32])[C:29]([O:33][CH2:34][CH:35]3[CH2:38][CH2:37][CH2:36]3)=[C:28]([F:39])[CH:27]=2)[N:25]=1)=[O:19].[H-].[Na+]>CN(C=O)C>[CH:35]1([CH2:34][O:33][C:29]2[C:30]([F:32])=[CH:31][C:26]([C:24]3[N:25]=[C:21]([NH:20][C:18](=[O:19])[CH2:17][N:25]4[C:9]5[C:8](=[O:12])[N:7]([CH3:13])[C:6](=[O:14])[N:5]([CH3:15])[C:4]=5[CH:23]=[C:24]4[CH3:26])[S:22][CH:23]=3)=[CH:27][C:28]=2[F:39])[CH2:38][CH2:37][CH2:36]1
Reactant: O=C(CBr)Nc1nc(-c2cc(F)c(OCC3CCC3)c(F)c2)cs1
Reactant: Cc1c2c(=O)n(C)c(=O)n(C)c2nn1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(c(=O)n(C)c(=O)n2C)n1CC(=O)Nc1nc(-c2cc(F)c(OCC3CCC3)c(F)c2)cs1

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 2 (50 mg, 0.258 mmol) with 2-bromo-N-{4-[4-Cyclobutylmethoxy-3,5-difluorophenyl]-1,3-thiazol-2-yl}acetamide (129 mg, 0.308 mmol) in the presence of NaH (16 mg, 0.375 mmol) in dry DMF (5.0 mL) to give 65 mg of the product as an off-white solid; 1H NMR (δ ppm, 300 MHz, DMSO-d6) 1.82-1.88 (m, 4H), 2.00-2.06 (m, 2H), 2.26 (s, 3H), 2.65-2.70 (m, 1H), 3.17 (s, 3H), 3.33 (s, 3H), 4.10 (d, J=6.6 Hz, 2H), 5.33 (s, 2H), 6.06 (s, 1H), 7.63 (d, J=8.7 Hz, 2H), 7.77 (s, 1H), 12.71 (br s, 1H); APCI-MS (m/z) 530.16 (M+H)+.