Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[N:7]=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:15]=3[F:23])[CH2:10][CH2:9]2)[O:5][C:4]1=[O:24])[CH3:2].O.O.Cl[Sn]Cl>CO>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][CH:8]([C:6]3[O:5][C:4](=[O:24])[N:3]([CH2:1][CH3:2])[N:7]=3)[CH2:9][CH2:10]2)=[C:15]([F:23])[CH:16]=1
Reactant: CCn1nc(C2CCN(c3ccc([N+](=O)[O-])cc3F)CC2)oc1=O
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: CCn1nc(C2CCN(c3ccc(N)cc3F)CC2)oc1=O
Yield: 571.3 %

Procedure:
5-[1-(2-Fluoro-4-nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (5b, 1.23 g, 4 mmol) on reacting with C2H5Br (0.53 g, 4.8 mmol) in DMF in the presence of base K2CO3 (1.38 g, 10 mmol) at room temperature (27° C.) for 10 h, after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography to afford pure compound 3-ethyl-5-[1-(2-fluoro-4-nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (6e, 1.27 g, 95%). Nitro compound (6e, 1.34 g, 4 mmol) on reduction with SnCl2.2H2O (2.71 g, 12 mmol) in methanol and refluxed at 65° C. for 4 h, after completion of reaction methanol is evaporated under vacuum and to this saturated sodium bicarbonate solution, is added to quench the excess stannous chloride and filtered through celite bed and purified in silica column (60-120) to afforded pure compound 5-[1-(4-amino-2-fluorophenyl)-4-piperidyl]-3-ethyl-2,3-dihydro-1,3,4-oxadiazol-2-one (7 g, 1.05 g, 86%). To a stirred solution of 5-nitro2-furanoic acid in DMF add HOBT (Hydroxybenzo triazole) (0.14 g, 1 mmol), EDCI (1-Ethyl-3-(3-dimethylaminopropyl)carbodi imide)) (0.19 g, 1 mmol) and amine compound (7g, 0.3 g, 1 mmol) and stirred for 2 h at room temperature (27° C.), after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography using ethyl acetate-hexane (7:3) as eluant to afford pure compound N2-4-[4-(4-ethyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidino]-3-fluorophenyl-5-nitro-2-furamide (8 g, 391 mg, 88%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[S:13][C:14]2[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([F:22])[C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[Cl:21][C:20]1[C:14]2[S:13][C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:16][C:15]=2[C:17]([F:22])=[CH:18][CH:19]=1
Reactant: Brc1ccccn1
Reactant: C#CCCc1nc2c(F)ccc(Cl)c2s1
Product: Fc1ccc(Cl)c2sc(CCC#Cc3ccccn3)nc12
Yield: 11.2 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (66 mg, 0.42 mmol) and 2-but-3-ynyl-7-chloro-4-fluoro-benzo[d]thiazole (100 mg, 0.42 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 7:3) to yield 15 mg (47 μmol, 11%) of 7-chloro-4-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole as a brown oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13](O)[CH:14]=[CH:15][C:16]1[CH:17]=[N:18][C:19]([CH3:22])=[N:20][CH:21]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)CC.Cl.[C:31](OCC)([O:36]CC)([O:33][CH2:34][CH3:35])[CH3:32]>[Cl-].[Na+].O>[CH2:34]([O:33][C:31](=[O:36])[CH2:32][CH:15]([C:16]1[CH:17]=[N:18][C:19]([CH3:22])=[N:20][CH:21]=1)[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:24])[CH3:35]
Reactant: CCOC(C)(OCC)OCC
Reactant: Cc1ncc(C=CC(O)CCCCCNC(=O)OC(C)(C)C)cn1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCC(=O)O
Solvent: O
Product: CCOC(=O)CC(C=CCCCCCNC(=O)OC(C)(C)C)c1cnc(C)nc1
Temperature: 150 °C

Procedure:
A solution of 24-4 (1.00 g, 2.98 mmol) in triethyl orthoacetate (50 mL) was treated with propionic acid (2.5 mg, 0.034 mmol) and heated to 150 ° C. for 3 h. The reaction mixture was cooled to room temperature and treated with 1 N HCl and brine (75 mL each). The mixture was extracted with two portions of ethyl acetate. The combined organics were washed with brine and dried (Na2SO4). Purification via PCTLC (SiO2, 4 mm, 10% EtOH; 90% CH2Cl2) afforded 24-5 (650 mg).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:15]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=2)[CH2:6][CH2:5]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Oc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-piperazin-1-yl-phenol (1.78 g, 10 mmol) in DMF (20 mL) was added bromomethyl-benzene (1.71 g, 10 mmol) dropwise and then the reaction was stirred at room temperature for 16 h. The mixture was poured into water and pH was adjusted to 7 with sat. aqueous NaHCO3, and then extracted with ethyl acetate (100 ml×2). The combined organic layers were washed with water and dried over anhy. Na2SO4. After removing the solvent under vacuum, the title compound was obtained (1.1 g, 41%) and MS (ESI) m/z 269 (M+H). 1H NMR (400 MHz, CDCl3) δ 2.62 (t, J=4.8 Hz, 4H), 3.08 (t, J=4.8 Hz, 4H), 3.57 (s, 2H), 6.74 (d, J=8.8 Hz, 2H), 6.83 (d, J=8.8 Hz, 2H), 7.28-7.34 (m, 5H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[CH3:27])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:36]2[CH:41]=[CH:40][C:39]([S:42]([NH2:45])(=[O:44])=[O:43])=[CH:38][CH:37]=2)O1>>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([C:36]3[CH:41]=[CH:40][C:39]([S:42]([NH2:45])(=[O:44])=[O:43])=[CH:38][CH:37]=3)=[CH:7][CH:6]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:21]([CH3:27])[CH:22]=1
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Product: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(-c2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
The title compound was prepared in analogy to example 166, from (−)-5-[3-(4-bromo-phenyl)-3-(4-chloro-2-methyl-phenyl)-propionyl]-1-methyl-1H-pyridin-2-one and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (CAS RN 214360-51-7). The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:ethyl acetate (100:0 to 100:0). Light brown solid. MS (ESI+): m/z=521.1 ([M+H]+).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:25])[N:6]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:7]([CH3:18])=[CH:8][C:9]=1OS(C(F)(F)F)(=O)=O)(=[O:3])[CH3:2].[CH:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O)([CH3:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:4]1[C:5](=[O:25])[N:6]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:7]([CH3:18])=[CH:8][C:9]=1[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH:26]([CH3:28])[CH3:27])(=[O:3])[CH3:2]
Reactant: CC(C)c1ccccc1B(O)O
Reactant: CCOC(=O)Cn1c(C)cc(OS(=O)(=O)C(F)(F)F)c(C(C)=O)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)Cn1c(C)cc(-c2ccccc2C(C)C)c(C(C)=O)c1=O

Procedure:
A mixture of 3-acetyl-4-trifluoromethylsulfonyloxy-6-methyl-1-ethoxycarbonylmethyl-2-pyridinone from step 2 above (2.5 g, 7.2 mmol), 2-isopropylbenzeneboronic acid (1.8 g, 11 mmol), potassium carbonate (1.5 g, 11 mmol), and Pd(PPh3)4 (1.7 g, 1.4 mmol) was heated to reflux under inert atmosphere for 3 h. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography using a gradient elution of 25-75% EtOAc:hexanes to give the title compound (0.72 g; HPLC RT=21.79 min, method B).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(C(C)C)CC)(C)C>ClCCl>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:3](=[O:4])[CH2:2][Br:1])[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: O=C(Br)CBr
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CBr)CC1
Temperature: 0 °C
Yield: 41.2 %

Procedure:
Bromo acetyl bromide (4.86 ml, 21.47 mmol, 1 eq) was added dropwise to a stirred ice cold mixture of the Piperazine-1-carboxylic acid tert butyl ester (4.0 g, 21.47 mmol, 1 eq) and diisopropyl ethyl amine (12.05 g, 92.5 mmol, 4.3 eq) in dichloromethane (108 ml). The resulting mixture was washed with water (2×50 mL) and saturated sodium chloride solution (100 mL), and dried over MgSO4. After filtration, the solvent was evaporated and the residue was purified with chromatography with (ethyl acetate/n-hexane 1/1) to give the product (2.72 g, 41%) as a orange oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([OH:12])=[CH:8][C:9]=2[CH3:11])[C:4]([CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:3]1.[H-].[Na+].[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:12][S:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:30])=[O:29])=[CH:8][C:9]=2[CH3:11])[C:4]([CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:3]1
Reactant: Cc1cc(O)cc2c(C3CCN(C)CC3)cn(C)c12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(OS(=O)(=O)c2ccccc2)cc2c(C3CCN(C)CC3)cn(C)c12

Procedure:
By a method similar to Example 56, using 1,7-dimethyl-3-(1-methylpiperdin-4-yl)-5-hydroxy-1H-indol (1.98 mmol, 0.511 g) in THF (5.0 mL), sodium hydride (2.37 mmol, 0.095 g, 60% dispersion in mineral oil), and benzenesulfonyl chloride (2.18 mmol, 0.384 g), afforded 0.501 g (64%): ms (ion spray): m/z=399 (M+1); 1H NMR (DMSOd6): 7.85-7.77 (m, 3H), 7.67-7.62 (m, 2H), 7.01 (s, 1H), 6.64 (d, J=2.56 Hz, 1H), 6.55 (d, J=1.83 Hz, 1H), 3.94 (s, 3H), 2.82-2.72 (bd, 2H), 2.60 (s, 3H), 2.39 (tt, J=3.72 Hz, 1H), 2.18 (s, 3H), 1.91 (m, 2H), 1.67-1.54 (m, 2H), 1.47 (m, 2H); Calculated for C22H26N2O3S: C, 66.31; H, 6.58; N, 7.03. Found: C, 66.18; H, 6.58; N, 7.08.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[Br:5][CH2:6][CH2:7][CH2:8][CH2:9]Br.[OH-].[Na+]>O>[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][O:4][CH2:1][C:2]#[CH:3]
Reactant: BrCCCCBr
Reactant: C#CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C#CCOCCCCBr
Reaction time: 8 h

Procedure:
A mixture of 2-propyn-1-ol (10 g), 1,4-dibromobutane (60 ml), 50% aqueous sodium hydroxide (60 ml) and TAB (2 g) was stirred vigorously overnight. Water (250 ml) was added and the mixture was extracted with ether (2×200 ml). The organic extracts were dried and concentrated to a yellow oil which was purified by FCC eluting with H→H/ER (19:1) to give the title compound as a colourless oil (19.7 g), t.l.c. (H-ER 19:1) Rf 0.37.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:13]([C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[CH:12][CH:11]=[C:10]([NH:20][CH2:21][CH2:22][NH:23]C(OC(C)(C)C)=O)[N:9]=1)(C)(C)C.[ClH:32]>O1CCOCC1>[ClH:32].[NH2:7][C:8]1[C:13]([C:14](=[O:19])[C:15]([F:16])([F:18])[F:17])=[CH:12][CH:11]=[C:10]([NH:20][CH2:21][CH2:22][NH2:23])[N:9]=1
Reactant: CC(C)(C)OC(=O)NCCNc1ccc(C(=O)C(F)(F)F)c(NC(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: C1COCCO1
Product: NCCNc1ccc(C(=O)C(F)(F)F)c(N)n1
Reaction time: 20 h

Procedure:
2.5 g (5.57 mmol) of tert-butyl-[6-({2-[(tert-butoxycarbonyl)amino]ethyl}amino)-3-(trifluoroacetyl)-pyridin-2-yl]carbamate (Example 12A) were dissolved in 15 ml of a 4 N solution of hydrogen chloride in dioxane and stirred for 20 h. The reaction mixture was concentrated to half of its original volume, and the same amount of diethyl ether was added. The reaction mixture was stirred for 20 min, and the product was filtered off and washed with diethyl ether. This gave 1.4 g (89% of theory) of the product as a solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][N:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[NH2:13]OS(O)(=O)=O>CN(C=O)C>[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][N:9]=[CH:10][CH:11]=2)[N:6]([NH2:13])[CH:5]=1
Reactant: Cc1c[nH]c2cnccc12
Reactant: NOS(=O)(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(N)c2cnccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 60.7 %

Procedure:
60% Sodium hydride (6.69 g, 167 mmol) is added to a stirred solution of 3-methyl-1H-pyrrolo[2,3-c]pyridine (1.47 g, 11.2 mmol) in DMF (33 mL) portion wise at 0° C. for 1 h. Hydroxylamine-O-sulfonic acid (6.3 g, 55.8 mmol) is added in portions at 0° C. and stirred for 2 h at 0° C. The reaction mixture is quenched at 0° C. with water, concentrated in vacuo to remove DMF. The residue is triturated in DCM. The solid is filtered off and the filtrate is concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 10% MeOH in DCM to afford 3-methyl-pyrrolo[2,3-c]pyridin-1-ylamine (1 g, 61%). MS: 148 (M+H); 1H NMR (300 MHz, CDCl3): δ 8.85 (s, 1H), 8.27 (d, 1H), 7.46 (d, 1H), 7.09 (s, 1H), 2.30 (s, 3H).
Reaction SMILES: [NH2:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.N1C=CC=CC=1.Cl>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[F:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][CH:2]([NH:1][S:21]([C:18]2[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=2)(=[O:23])=[O:22])[C:3]([O:5][CH3:6])=[O:4])=[CH:13][CH:12]=1
Reactant: COC(=O)C(N)Cc1ccc(F)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)C(Cc1ccc(F)cc1)NS(=O)(=O)c1ccc(C)cc1
Yield: 80.7 %

Procedure:
Methyl 2-amino-3-(4-fluorophenyl)propionate (2.01 g), p-toluenesulfonyl chloride (2.25 g) and 4-dimethylaminopyridine (309 mg) were dissolved in chloroform (30 ml), and pyridine (3.0 ml) was added to heat the mixture under reflux for 4.5 hours. P-Toluenesulfonyl chloride (2.20 g) was additionally added, and the mixture was heated under reflux for 3.5 hours. The reaction mixture was poured into ice and 1N hydrochloric acid (17 ml) to conduct liquid separation. The resultant organic layer was successively washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatagraphy on silica gel (hexane:ethyl acetate=9:1→2:1) to obtain the title compound (2.89 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23](=[S:25])[NH2:24])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].Br[CH2:27][C:28](=O)[C:29]([O:31][CH2:32][CH3:33])=[O:30]>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]3[S:25][CH:27]=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:24]=3)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CCc1ccc(C2CC(C(N)=S)CN(C(=O)N3CCOCC3)C2)cc1
Product: CCOC(=O)c1csc(C2CC(c3ccc(CC)cc3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
850 mg of the compound from Example 140A and 550 mg (2.82 mmol) of ethyl 3-bromo-oxopropanoate were reacted according to the General Method 3. Yield: 150 mg (12% of theory).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:20])C(=O)C1>CC#N.CCOC(C)=O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]#[N:12])[CH2:9][CH2:10]2)=[CH:6][C:7]=1[Br:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#CC1(c2ccc(N)cc2)CC1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#CC1(c2ccc(N)c(Br)c2)CC1
Reaction time: 8 h
Yield: 80.1 %

Procedure:
To a solution of 1-(4-amino-phenyl)-cyclopropanecarbonitrile (96 mg, 0.60 mmol) in MeCN (3 mL) at 0° C. was added NBS (108 mg, 0.60 mmol) and the reaction was allowed to stir overnight. The reaction was diluted with EtOAc (25 mL) and was then washed with saturated aqueous NaHCO3 (1×25 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo to give 114 mg (80%) of 1-(4-amino-3-bromo-phenyl)-cyclopropanecarbonitrile. The crude product was used without further purification.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[C:29]1([C:35]2[NH:36][C:37]3[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=3[N:39]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:11][N:8]1[C:7]([CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:17][CH2:18]2)=[N:6][C:5]2[C:9]1=[N:10][C:2]([N:36]1[C:37]3[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=3[N:39]=[C:35]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[N:3][C:4]=2[N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: c1ccc(-c2nc3ccccc3[nH]2)cc1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3c(-c4ccccc4)nc4ccccc43)nc21

Procedure:
Following General Procedure I for Buchwald coupling, 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol and 2-phenylbenzimidazole were reacted to give 207. LCMS m/z: 567.3 (MH+)
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:17].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](=[NH:31])OCC)=[CH:22][CH:21]=1>C(O)C>[ClH:17].[CH3:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:27](=[NH:31])[CH2:26][C:23]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1COc1cccnc1N
Reactant: CCOC(=N)Cc1ccc(OC)cc1
Agent: Cl
Solvent: CCO
Product: COc1ccc(CC(=N)Nc2ncccc2OCc2ccccc2C)cc1
Yield: 3 %

Procedure:
A mixture of 2-amino-3-(2-methylbenzyloxy)pyridine (5.2 g, 24.2 mmol) and ethyl 4-methoxyphenylacetimidate hydrochloride (6.1 g, 26.7 mmol) in ethanol (80 ml) was heated under reflux for 2 hours, then the solvent evaporated. The residue was taken up in chloroform, filtered to remove an insoluble solid, and the filtrate purified by flash chromatography (chloroform/methanol) to obtain the product (0.29 g), m.p. 58°-67° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]3[N:15]=[C:16]([CH3:19])[C:17](I)=[C:13]3[N:12]=[C:11]([N:20]3[CH2:24][CH2:23][CH2:22][C@H:21]3[CH2:25][OH:26])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([C:17]2[C:16]([CH3:19])=[N:15][N:14]3[C:9]([C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=4)=[CH:10][C:11]([N:20]4[CH2:24][CH2:23][CH2:22][C@H:21]4[CH2:25][OH:26])=[N:12][C:13]=23)=[CH:30][CH:29]=1
Reactant: Cc1nn2c(-c3ccc(F)c(F)c3)cc(N3CCC[C@H]3CO)nc2c1I
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(-c2c(C)nn3c(-c4ccc(F)c(F)c4)cc(N4CCC[C@H]4CO)nc23)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
(S)-(1-(7-(3,4-Difluorophenyl)-3-iodo-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)methanol (74 mg), 4-methylphenylboronic acid (27 mg) and tetrakis(triphenylphosphine)palladium (10 mg) are added to toluene (7 mL), ethanol (3 mL) and 1 N NaHCO3 aqueous solution (1.5 mL) and stirred overnight under argon atmosphere at 85° C. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure, concentrated and purified by column chromatography to yield the target compound (41 mg).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[C:24]3[C:28](=[C:29]([C:31]([NH2:33])=[O:32])[CH:30]=2)[NH:27][CH:26]=[C:25]3[CH:34]2[CH2:39][CH2:38][N:37]([S:40]([CH2:43][CH3:44])(=[O:42])=[O:41])[CH2:36][CH2:35]2)[CH:13]=[C:14]([CH2:16][NH:17][CH2:18]C(C)C)[CH:15]=1)#[N:9].[CH3:45]NCC(C)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[C:24]3[C:28](=[C:29]([C:31]([NH2:33])=[O:32])[CH:30]=2)[NH:27][CH:26]=[C:25]3[CH:34]2[CH2:39][CH2:38][N:37]([S:40]([CH2:43][CH3:44])(=[O:42])=[O:41])[CH2:36][CH2:35]2)[CH:13]=[C:14]([CH2:16][N:17]([CH3:45])[CH3:18])[CH:15]=1)#[N:9]
Reactant: CNCC(C)C
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(C#N)cc(CNCC(C)C)c4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(C#N)cc(CN(C)C)c4)cc23)CC1
Yield: 61 %

Procedure:
The title compound was prepared according to the general procedure of 5-(3-cyano-5-{[(2-methylpropyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting trimethylamine (300 μL, 0.3 mmol) for methyl(2-methylpropyl)amine to afford 10.5 mg of the title compound (61%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[C:11]([O:13]C)[N:10]=[C:9]([C:15]([O-:17])=[O:16])[CH:8]=2)[CH:6]=1.Cl>C(O)(=O)C>[ClH:1].[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:8]=[C:9]([C:15]([OH:17])=[O:16])[NH:10][C:11](=[O:13])[CH:12]=2)[CH:6]=1
Reactant: COc1cc(-n2cnc(Cl)c2)cc(C(=O)[O-])n1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)c1cc(-n2cnc(Cl)c2)cc(=O)[nH]1
Temperature: 95 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(4-chloro-1H-imidazol-1-yl)-6-methoxypyridine-2-carboxylate (C34) (20.9 mg, 0.074 mmol) in acetic acid (0.5 mL) was added concentrated hydrochloric acid and the reaction was stirred at 95° C. for 18 hours. Removal of solvent in vacuo afforded the title compound as a white solid. Yield: 20.4 mg, 0.074 mmol, 100%. LCMS m/z 240.3 (M+1). 1H NMR (400 MHz, CD3OD) δ 7.19 (d, J=7.5 Hz, 1H), 7.94-7.98 (m, 2H), 9.01-9.05 (m, 1H).
Reaction SMILES: [C:1](=[S:3])=[S:2].Cl[C:5]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:6]=1[NH2:7].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:12][C:10]1[CH:11]=[CH:5][C:6]2[N:7]=[C:1]([SH:3])[S:2][C:8]=2[CH:9]=1
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: S=C=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Sc1nc2ccc(Cl)cc2s1
Temperature: 150 °C
Yield: 93 %

Procedure:
91 g of carbon disulfide are added dropwise to a stirred suspension of 162 g of 2,4-dichloroaniline and 414 g of potassium carbonate in 1,000 ml of dimethylformamide at about 25°-30° C. in the course of 40 minutes, under a nitrogen atmosphere. The mixture is then warmed to an internal temperature of 150° C. in the course of 2 hours, and this temperature is maintained for 16 hours. The batch is cooled and filtered and the filtrate is largely freed from dimethylformamide. 600 ml of water are added to the residue which remains, the mixture is acidified and the product which precipitates is filtered off and dried. 187.6 g (93.2% of theory) of 6-chloro-2-mercaptobenzothiazole of melting point 258° C. are obtained.