Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[N:11]=[CH:10][C:9]([C:12]3[O:16][C:15]([CH:17]=[O:18])=[CH:14][CH:13]=3)=[CH:8][C:6]=2[N:7]=1.[CH2:25]1COCC1.C[Mg]Br.C(OCC)C>O>[Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[N:11]=[CH:10][C:9]([C:12]3[O:16][C:15]([CH:17]([OH:18])[CH3:25])=[CH:14][CH:13]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1ccc(-c2cnc3c(N4CCOCC4)nc(Cl)nc3c2)o1
Reactant: C1CCOC1
Agent: C[Mg]Br
Solvent: CCOCC
Solvent: O
Product: CC(O)c1ccc(-c2cnc3c(N4CCOCC4)nc(Cl)nc3c2)o1
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
To a 50 mL round bottom flask, 5-(2-chloro-4-morpholino-pyrido[3,2-d]pyrimidin-7-yl)furan-2-carbaldehyde (0.4 g, 0.0012 mol) and THF (15 mL) were added and cooled to 0-5° C. To the flask was slowly added 3.0 M methyl magnesium bromide in diethyl ether (0.6 mL, 0.0036 mol). The resulting reaction mixture was stirred at room temperature for 2 h. To the reaction mass, water was added and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced to get the crude product. The crude product was purified by column chromatography using 1% MeOH in chloroform [0.17 g, 40%]. LC-MS (ESI): Calculated mass: 360.1; Observed mass: 361.1 (RT: 1.29 min).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=1[Cl:40]>>[C:1]([O:5][C@@H:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=3[Cl:40])[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccc(CBr)c(Cl)c1
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Product: Cc1nc2c(ccn2Cc2ccc(F)cc2Cl)c(-c2ccc3c(c2)CCCO3)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 40 °C

Procedure:
The title compound was prepared in a manner similar to that described in Example 1, Step H from (S)-methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 1-(bromomethyl)-2-chloro-4-fluorobenzene, but purified on a ChiralPak ADH column (250×30 mm i.d., 5 um; ChiralTechnologies, West Chester, Pa.) under supercritical conditions maintained at 40° C., 140 bar, with MeOH modified CO2 (25% Isopropanol, 75% CO2) delivered at a combined flow rate of 90 g/min on a PIC Preplab 200 SFC system (Avignon, France). Triggered collections were made using a Knauer selectable wavelength UV-Vis detector at 230 nm (Rt=5.52 minutes): 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.50-7.42 (m, 1 H), 7.25-7.16 (m, 2 H), 7.14-7.05 (m, 2 H), 6.97-6.88 (m, 2 H), 6.30 (dd, J=3.5, 11.7 Hz, 1 H), 5.71-5.63 (m, 1 H), 5.61-5.52 (m, 2 H), 4.32-4.26 (m, 2 H), 2.96-2.79 (m, 2 H), 2.76 (s, 3 H), 2.08 (dd, J=5.0, 9.5 Hz, 2 H), 1.03-0.90 (s, 9 H); LC/MS (m/z) ES+=537.30 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[C:4]([F:31])[CH:3]=1.Cl.[NH2:33][OH:34].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[CH:22][C:23]([S:26]([CH2:29][CH3:30])(=[O:27])=[O:28])=[CH:24][CH:25]=2)[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:33]\[OH:34])=[C:4]([F:31])[CH:3]=1
Reactant: NO
Reactant: CCS(=O)(=O)c1ccc(C(CC(=O)c2ccc(=O)n(C)c2)c2ccc(Cl)cc2F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCS(=O)(=O)c1ccc(C(C/C(=N\O)c2ccc(=O)n(C)c2)c2ccc(Cl)cc2F)cc1

Procedure:
In analogy to example 151, step 3, 5-(3-(4-chloro-2-fluorophenyl)-3-(4-(ethylsulfonyl)-phenyl)propanoyl)-1-methylpyridin-2(1H)-one was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as a colourless solid, MS (ESI+): m/z=477.0 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1O)=[C:10]([O:14][CH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[CH:9]=[C:8]([O:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)[CH:7]=2)#[N:2].P(Cl)(Cl)([Cl:33])=O>C(#N)C>[Cl:33][C:12]1[C:11]2[C:6](=[CH:7][C:8]([O:21][CH2:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:9][C:10]=2[O:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:5]=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: N#Cc1cnc2cc(OCCCN3CCOCC3)cc(OC3CCOCC3)c2c1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: N#Cc1cnc2cc(OCCCN3CCOCC3)cc(OC3CCOCC3)c2c1Cl
Reaction time: 4 h

Procedure:
A mixture of 3-cyano-4-hydroxy-7-(3-morpholin-4-ylpropoxy)-5-(tetrahydro-2H-pyran-4-yloxy)quinoline (500 mg) and phosphoryl chloride (2.5 ml) in acetonitrile (1.5 ml) was refluxed and stirred for 4 hours. After cooling, the solution was evaporated to dryness. The flask containing the residue was filled with ice chips and excess concentrated aqueous ammonia (25 ml) was added. This mixture was allowed to warm up while stirring overnight. The product was filtered off and air-dried. The title compound was obtained as a white solid (480 mg, 92%); Mass spectrum: M+H+ 432.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[C:20]([CH3:22])([CH3:21])[O:19][C:18]([NH:23][C@H:24]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:25][CH2:26][O:27][Si](C(C)(C)C)(C)C)=[N:17][S:16]2(=[O:42])=[O:41])=[CH:11][CH:10]=1)C1C=CC=CC=1.C(N(CC)CC)C>CO.[Pd]>[OH:27][CH2:26][CH2:25][C@H:24]([NH:23][C:18]1[O:19][C:20]([CH3:22])([CH3:21])[CH:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[S:16](=[O:41])(=[O:42])[N:17]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC1(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c2ccccc2)=NS(=O)(=O)C1c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC1(C)OC(N[C@@H](CCO)c2ccccc2)=NS(=O)(=O)C1c1ccc(O)cc1
Reaction time: 1 h
Yield: 20.5 %

Procedure:
Under inert gas, 762 mg [5-(4-benzyloxyphenyl)-6,6-dimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-1,4,3-oxathiazin-2-yl]-[(S)-3-(tert-butyldimethylsilanyloxy)-1-phenylpropyl]amine were initially charged in 20 ml of methanol and, with addition of 133 mg of 10% Pd/C, stirred under a hydrogen atmosphere for 1 hour. The completeness of the conversion was checked by LCMS, the reaction was once again admixed with 133 mg of 10% Pd/C and additionally 0.52 ml of triethylamine, and the mixture was stirred under a hydrogen atmosphere for a further 60 minutes. According to LCMS, the detachment of the silyl protecting group remained incomplete. After filtration to remove the solid residues, the filtrate was freed of the solvent under reduced pressure. The crude product was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (104 mg) with a molecular weight of 404.5 g/mol (C20H24N2O5S); MS (ESI): m/e=405 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.Cl[CH2:12][CH2:13][N:14]([CH2:25][CH2:26]Cl)[S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16].[NH2-].[Na+]>C1C=CC=CC=1>[C:21]1([CH3:24])[CH:20]=[CH:19][C:18]([S:15]([N:14]2[CH2:25][CH2:26][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)([C:9]#[N:10])[CH2:12][CH2:13]2)(=[O:17])=[O:16])=[CH:23][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)N(CCCl)CCCl)cc1
Reactant: N#CCc1ccc(Cl)cc1
Agent: [NH2-]
Agent: [Na+]
Solvent: c1ccccc1
Product: Cc1ccc(S(=O)(=O)N2CCC(C#N)(c3ccc(Cl)cc3)CC2)cc1
Reaction time: 1 h

Procedure:
To a solution of 60.3 parts of 4-chlorophenylacetonitrile and 118 parts of N,N-bis(2-chloroethyl)-4-toluenesulfonamide in 720 parts of dried benzene under N2 there is added portionwise with stirring at 10°-13° C 32.6 parts of sodamide. The cooling bath is then removed and the mixture is stirred for 1 hour during which time the temperature rises to 70° C and then falls back to 43° C. Ice cold water is added to the mixture and a fine solid forms. This is separated by filtration and washed successively with water and benzene and dried and then triturated in boiling methanol. The undissolved solid is separated by filtration, washed with water and dried to give 1-(4-toluenesulfonyl)-4-(4-chlorophenyl)-4-piperidinecarbonitrile melting at about 202°-206° C.
Reaction SMILES: [CH:1]1[C:9]([NH2:10])=[CH:8][C:7]2[CH2:11][CH2:12][N:5]3[C:6]=2[C:2]=1[C:3]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:4]=13.[C:19](Cl)(=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>ClCCl>[CH:1]1[C:9]([NH:10][C:19](=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:8][C:7]2[CH2:11][CH2:12][N:5]3[C:6]=2[C:2]=1[C:3]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:4]=13
Reactant: Nc1cc2c3c(c1)c1c(n3CC2)CCCCCC1
Reactant: CCCCCCC(=O)Cl
Solvent: ClCCl
Product: CCCCCCC(=O)Nc1cc2c3c(c1)c1c(n3CC2)CCCCCC1
Yield: 19.4 %

Procedure:
Following the procedure of Example 1, Step 4, 4,5,7,8,9,10,11,12-octahydrocycloocta[b]pyrrolo[3,2,1-hi]indol-2-amine (0.15 g, 0.54 mmol), heptanoyl chloride (0.084 mL, 0.54 mmol) and poly-(4-vinylpyridine) (500 mg) in dichloromethane (12 mL) provided N-4,5,7,8,9,10,11,12-octahydrocycloocta[b]pyrrolo[3,2,1-hi]indol-2-ylheptanamide (37 mg). MS (ESI) m/z 353; HPLC purity 100% at 210-370 nm, 11.6 min.; 100% at 250 nm, 11.6 min.; Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN and MeOH) for 10 min, hold 4 min); HRMS: calcd for C23H32N2O+H+, 353.25874; found (ESI, [M+H]+), 353.2575.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([CH3:15])=[CH:6][C:7]([CH3:14])=[C:8]([CH2:10][C:11](O)=[O:12])[CH:9]=2)[CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:19])=O.CN(C)C=O>ClCCl>[CH:1]1([C:4]2[C:5]([CH3:15])=[CH:6][C:7]([CH3:14])=[C:8]([CH2:10][C:11]([Cl:19])=[O:12])[CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc(C)c(C2CC2)cc1CC(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(C)c(C2CC2)cc1CC(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.3 g of (5-cyclopropyl-2,4-dimethyl-phenyl)-acetic acid in 20 ml of dichloromethane are treated with 2.1 g of oxalyl chloride and a catalytic amount of dimethylformamide. The reaction mixture is stirred at room temperature for 2 hours. The solvent is removed in vacuo and the crude residue of (5-cyclopropyl-2,4-dimethyl-phenyl)-acetyl chloride (2.5 g) is used for the next step.
Reaction SMILES: [I:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9](O)[N:8]=2)=[CH:5][N:4]([CH:14]([CH3:16])[CH3:15])[N:3]=1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:9]1[N:8]=[C:7]([C:6]2[C:2]([I:1])=[N:3][N:4]([CH:14]([CH3:16])[CH3:15])[CH:5]=2)[CH:12]=[CH:11][N:10]=1
Reactant: CC(C)n1cc(-c2ccnc(O)n2)c(I)n1
Reactant: O=P(Cl)(Cl)Cl
Product: CC(C)n1cc(-c2ccnc(Cl)n2)c(I)n1

Procedure:
A solution of Intermediate 4-(3-iodo-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ol (438 mg, 1.33 mmol) in phosphorous oxychloride (10 ml) was heated at 110° C. for 16 h. The mixture was concentrated under vacuum, then aqueous sodium bicarbonate solution was carefully added and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to provide the title compound as a yellow solid. MS m/z 349.0 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:21]([CH3:23])[CH3:22])[C:6]2[O:10][C:9]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:20]=1)#[N:2].[O:24]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[O:28][CH2:27][CH:26]([CH2:35][NH2:36])[CH2:25]1>>[C:1]([C:3]1[CH:4]=[C:5]([CH:21]([CH3:22])[CH3:23])[C:6]2[O:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([NH:36][CH2:35][CH:26]4[CH2:25][O:24][C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=5[O:28][CH2:27]4)=[O:17])=[CH:18][CH:19]=3)=[N:8][C:7]=2[CH:20]=1)#[N:2]
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)O)cc3)oc12
Reactant: NCC1COc2ccccc2OC1
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4COc5ccccc5OC4)cc3)oc12

Procedure:
The title compound was prepared, as a mixture, from 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoic acid (INTERMEDIATE 2), and 1-(3,4-dihydro-2H-1,5-benzodioxepin-3-yl)methanamine as described in EXAMPLE 1. Mass spectrum (ESI) 468.0 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.31 (d, J=8.5 Hz, 2H), 7.96 (d, J=8.5 Hz, 2H), 7.93 (d, J=1.5 Hz, 1H), 7.51 (d, J=1 Hz, 1H), 6.90-7.02 (m, 4H), 4.29 (m, 4H), 3.75 (t, J=6 Hz, 2H), 3.47 (septet, J=7 Hz, 1H), 2.65 (m, 1H), 1.46 (d, J=6.5 Hz, 6H).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C[O-].[Na+].[CH2:13](Br)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[C:15]1([CH2:14][CH2:13][CH:2]([C:3]([CH3:5])=[O:4])[C:1]([O:7][CH2:8][CH3:9])=[O:6])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: BrCCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1)C(C)=O
Reaction time: 20 h
Yield: 91.3 %

Procedure:
Ethyl acetoacetate (53.8 g., 0.29 mole) was dissolved in 110 ml. of anhydrous ethanol. Sodium methoxide (17.3 g., 0.36 mole) was added portionwise to the stirred solution, allowing the temperature to rise to 40°-50°. The mixture was then heated to reflux (80°-82°) and phenethyl bromide (53.8 g., 0.32 mole) added dropwise over 1 hour. Reflux was continued for 20 hours. The reaction mixture was cooled to 30°-35° and filtered over diatomaceous earth with ethanol wash. The combined filtrate and wash were concentrated in vacuo to a pot temperature of 50°, cooled to 25°, diluted with 150 ml. of hexane and 40 ml. of water, acidified to pH 6.5-7.0 with 6N HCl. The hexane layer was separated and washed with 25 ml. of fresh water. The aqueous layer were combined and back-washed with 40 ml. of fresh hexane. The hexane layers were combined, washed with 60 ml. of water, dried over 15 g. MgSO4, filtered and evaporated to yield title product as an oil (62 g., 91%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]2[N:8]=[C:9]([N+:11]([O-])=O)[CH:10]=[C:4]2[CH2:3]1>C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]2[N:8]=[C:9]([NH2:11])[CH:10]=[C:4]2[CH2:3]1
Reactant: CN1CCn2nc([N+](=O)[O-])cc2C1
Solvent: CCO
Product: CN1CCn2nc(N)cc2C1
Reaction time: 2 h
Yield: 988.6 %

Procedure:
A 500-mL Parr reactor bottle was purged with nitrogen and charged with 10% palladium on carbon (50% wet, 800 mg dry weight) and a solution of 128a (4.00 g, 2.20 mmol) in ethanol (160 mL). The bottle was attached to Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 45 psi and shaken for 2 h. After this time, the hydrogen was evacuated, and nitrogen was charged into the bottle. CELITE® 521 (1.0 g) was added, and the mixture was filtered through a pad of CELITE® 521. The filter cake was washed with ethanol (2×75 mL), and the combined filtrates were concentrated to dryness under reduced pressure to afford a 99% yield of 128b (3.31 g) as an orange solid. 1H NMR (300 MHz, CDCl3) δ 5.34 (s, 1H), 3.98 (t, 2H, J=5.4 Hz), 3.52 (s, 3H), 2.84 (t, 2H, J=5.7 Hz), 2.45 (s, 3H); MS (ESI+) m/z 153.1 (M+H)
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:20])=CC=1>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[S:20]
Reactant: NC(=O)c1cccc(I)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: NC(=S)c1cccc(I)c1
Yield: 98.8 %

Procedure:
A mixture of 3-iodobenzamide (500 mg, 2.0 mmol) in toluene (5 mL) was treated with Lawesson's reagent (404 mg, 1 mmol) and the mixture heated at reflux for 16 hours. After cooling, silica gel chromatography afforded 260 mg (99% yield) of 3-iodothiobenzamide, as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]1[NH:6][CH2:5][C:4]2([CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2)[O:3]1.C(N(CC)CC)C.[F:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>ClCCl>[F:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([N:6]2[CH2:5][C:4]3([CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]3)[O:3][CH:2]2[CH3:1])(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CC1NCC2(CCN(C)CC2)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1OC2(CCN(C)CC2)CN1S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
2,8-Dimethyl-1-oxa-3,8-diaza-spiro[4.5]decane (1.42 g, 8.38 mmol) was dissolved in dry dichloromethane (5 ml) under argon atmosphere. Distilled triethylamine (1.75 ml, 12.57 mmol) was added and the resulted solution was cooled to 0° C. p-Fluorobenzenesulfonyl chloride (1.63 gr, 8.37 mmol) was added and the reaction flask was allowed to warm to room temperature with stirring, and a white solid started to precipitate. After 30 min of stirring, dichloromethane (90 ml) was added and the resulting solution was washed with water (2×10 ml). The organic phase was dried with anhydrous sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography (silica, CH2Cl2/EtOH/NH4OH 140/10/1) to give AF715 (1.23 g, 98.7% chemical purity) as an off-white powder. 1H NMR. (CDCl3, 500 MHz) δ 7.89-7.87 (m, 2H, CHCSO2), 7.27-7.22 (m, 2H, CHCF), 5.05 (q, J=5.23, 1H, CHCH3), 3.33 (d, J=10.26 Hz, 1H, CHHNS), 3.19 (d, J=10.26 Hz, 1H, CHHNS), 2.52-2.42 (m, 114), 2.34-2.25 (m, 2H), 2.23 (s, 3H, NCH3), 2.18-2.09 (m, 1H), 1.77-1.72 (m, 2H), 1.52 (d, J=5.23 Hz, 3H, CH3CH), 1.25-1.18 (m, 1H), 1.10-1.03 (m, 1H) ppm; 13C NMR (CDCl3, 500 MHz) δ 166.45 and 164.42 (C), 134.0 (C), 130.37 (CH), 130.29 (CH), 116.68 (CH), 116.50 (CH), 86.95 (CH), 66.30 (C), 55.48 (CH2), 52.57 (CH2), 52.11 (CH2), 46.04 (CH3), 35.64 (CH2), 32.84 (CH2), 22.95 (CH3) ppm.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[C:12]([F:29])=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)=O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[CH3:38][C:39]([CH3:44])([CH3:43])[C:40](=[S:42])[NH2:41]>CC(N(C)C)=O.O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:42][C:40]([C:39]([CH3:44])([CH3:43])[CH3:38])=[N:41][C:9]=2[C:11]2[C:12]([F:29])=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cc1ccnc(Cl)n1)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1F
Reactant: CC(C)(C)C(N)=S
Agent: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of N-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (2.0 g, 4.53 mmol) in 40 mL DMA, 1.0 eq. NBS (0.806 g, 4.53 mmol) was added and the solution was allowed to stir 15 min at rt. 2,2-dimethylpropanethioamide (0.531 g, 4.53 mmol) was then added at rt. The reaction was heated to 60° C. for 2 hours. The reaction was not complete by LC-MS. The reaction mixture was then heated to 80° C. for an additional hour. The reaction mixture was diluted with water and extracted×2 with EtOAc. The combined EtOAc washings were washed with water×3 to remove DMA, dried over MgSO4, filtered and concentrated onto silica gel. The crude material was chromatographed in 10-80% EtOAc in Hexanes to give the desired product, 1.6 g (64%). MS (ESI): 539.1 [M+H]+.
Reaction SMILES: [N:1]1([C:11]([C:13]2[CH:17]=[C:16]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[S:15][CH:14]=2)=[O:12])[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>C(Cl)Cl>[N:1]1([C:11]([C:13]2[CH:17]=[C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:31](=[O:33])[CH3:32])[CH2:22][CH2:23]3)[S:15][CH:14]=2)=[O:12])[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)Cl
Reactant: O=C(c1csc(C2CCNCC2)c1)N1CCC[C@@H]2CCCC[C@@H]21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(c2cc(C(=O)N3CCC[C@@H]4CCCC[C@@H]43)cs2)CC1
Reaction time: 1 h
Yield: 66.7 %

Procedure:
To a solution of cis-(octahydro-quinolin-1-yl)-(5-piperidin-4-yl-thiophen-3-yl)-methanone (CC-033) (0.026 g, 0.08 mmol) in DCM (1 mL) was added triethylamine (0.27 mmol) and acetyl chloride (0.11 mmol). The reaction mixture was stirred for 1 hour, and then the solvent evaporated. The product was purified by HPLC, eluting with 10%-98% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were concentrated under vacuum to give the title compound as a colourless oil (0.02 g). LCMS m/z 375.15 [M+H]+RT=9.73 min (Analytical Method 2). 1H NMR (400 MHz, CHCl3-d): δ 7.3 (s, 1H), 6.9 (s, 1H), 4.7 (m, 2H), 3.90-3.7 (m, 2H), 3.2-3.10 (m, 3H), 2.9-2.6 (m, 2H), 2.2 (s, 3H), 2.1-1.1 (m, 16H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[C:19]([N:24]3[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26][CH2:25]3)=[N:20][CH:21]=[CH:22][N:23]=2)[CH2:13][CH2:12]1.[C:31]([O-])([O-])=O.[Cs+].[Cs+].IC>C(#N)C>[CH3:31][O:30][CH:27]1[CH2:28][CH2:29][N:24]([C:19]2[C:18]([O:17][CH:14]3[CH2:13][CH2:12][N:11]([C:2]4[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:1]=4)[CH2:16][CH2:15]3)=[N:23][CH:22]=[CH:21][N:20]=2)[CH2:25][CH2:26]1
Reactant: OC1CCN(c2nccnc2OC2CCN(c3ccc4ccccc4n3)CC2)CC1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: COC1CCN(c2nccnc2OC2CCN(c3ccc4ccccc4n3)CC2)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of 1-(3-((1-(quinolin-2-yl)piperidin-4-yl)oxy)pyrazin-2-yl)piperidin-4-ol (see EXAMPLE 1.1; 100 mg, 0.25 mmol) in dry acetonitrile (CH3CN) (10 mL) was added Cs2CO3 (162 mg, 0.5 mmol). The reaction mixture was cooled to 0° C. with an ice bath, and iodomethane (70 mg, 0.50 mmol) was added dropwise to the reaction mixture. 1 hour later, the reaction mixture was warmed to RT, and stirred overnight. Then the reaction mixture was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product. The crude product was purified via flash chromatography on silica gel (20% to 45% EtOAc in petroleum ether) to give 2-(4-((3-(4-methoxypiperidin-1-yl)pyrazin-2-yl)oxy)piperidin-1-yl)quinoline (81 mg, 0.19 mmol, 78% yield) as a white solid. ESI-MS (M+1): 420 calc. for C24H29N5O2 419.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].[N+:8]([C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([N+]([O-])=O)[C:12]=1[C:13]#[N:14])([O-:10])=[O:9]>>[OH:4][CH2:3][C:2]([CH3:7])([CH3:1])[CH2:5][O:6][C:15]1[CH:16]=[CH:17][CH:18]=[C:11]([N+:8]([O-:10])=[O:9])[C:12]=1[C:13]#[N:14]
Reactant: CC(C)(CO)CO
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: CC(C)(CO)COc1cccc([N+](=O)[O-])c1C#N
Yield: 73 %

Procedure:
Prepared as in Example 215c from 2,2-dimethylpropane-1,3-diol and 2,6-dinitrobenzonitrile in 73% yield. 1H NMR (400 MHz, DMSO-d6) δ 0.94 (s, 6H), 3.29-3.31 (m, 2H), 3.95 (s, 2H), 4.69 (t, J=5.6 Hz, 1H), 7.69-7.71 (m, 1H), 7.84-7.90 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8](C(C(OCC)=O)C(OCC)=O)[CH3:9])[CH:2]=1.[C:21](=[O:24])(O)[O-:22].[Na+]>Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]([CH3:9])[C:21]([OH:22])=[O:24])[CH:2]=1
Reactant: CCOC(=O)C(C(=O)OCC)C(C)Cc1cccnc1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Product: CC(Cc1cccnc1)C(=O)O
Yield: 46.4 %

Procedure:
Diethyl 2-(1-(pyridin-3-yl)propan-2-yl)malonate (2.00 g, 7.55 mmol) was refluxed in conc. HCl (30 ml) for 16 h. The reaction mixture was neutralized using solid sodium bicarbonate (pH˜7) and extracted with ethyl acetate. The combined ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 580 mg (46.4%) of 2-((pyridin-3-yl)methyl)propanoic acid as a brown semi solid.