Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:18][C:19]#[N:20]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[C:18](/[C:17]2[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:15]([O:14][CH3:13])[CH:16]=2)\[C:19]#[N:20])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(/C(C#N)=C/c2ccc(Cl)c([N+](=O)[O-])c2)cc1OC
Yield: 35.9 %

Procedure:
4-Chloro-3-nitrobenzaldehyde (557 mg) and 3,4-dimethoxybenzyl cyanide (532 mg) were subjected to condensation in accordance with process B of (production process 2), to thereby produce the target product (372 mg, yield: 36%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=2[F:40])=[C:6]([C:8]2[N:9]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:10]([CH3:23])=[C:11]3[C:16]=2[CH:15]=[C:14]([C:17](OCC)=[O:18])[NH:13][C:12]3=[O:22])[CH:7]=1.[CH2:41]([NH2:44])[CH2:42][CH3:43]>CO>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=2[F:40])=[C:6]([C:8]2[N:9]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:29])[CH3:30])[C:10]([CH3:23])=[C:11]3[C:16]=2[CH:15]=[C:14]([C:17]([NH:44][CH2:41][CH2:42][CH3:43])=[O:18])[NH:13][C:12]3=[O:22])[CH:7]=1
Reactant: CCCN
Reactant: CCOC(=O)c1cc2c(-c3cc(N)ccc3Oc3ccc(F)cc3F)n(COCC[Si](C)(C)C)c(C)c2c(=O)[nH]1
Solvent: CO
Product: CCCNC(=O)c1cc2c(-c3cc(N)ccc3Oc3ccc(F)cc3F)n(COCC[Si](C)(C)C)c(C)c2c(=O)[nH]1
Yield: 97.5 %

Procedure:
A mixture of Example 4e (0.05 g, 0.088 mmol) and propan-1-amine (1 mL, 12.16 mmol) in methanol (0.5 mL) in a sealed tube was heated by microwave at 120° C. for 2 hours, cooled and concentrated to afford the title compound (0.05 g, 98%). The product was used without purification.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].Br[C:17]1[S:18][CH:19]=[C:20]([Br:22])[N:21]=1>>[Br:22][C:20]1[N:21]=[C:17]([O:15][CH:12]2[CH2:13][CH2:14][N:9]([C:6]3[CH:5]=[N:4][C:3]([CH2:1][CH3:2])=[CH:8][N:7]=3)[CH2:10][CH2:11]2)[S:18][CH:19]=1
Reactant: CCc1cnc(N2CCC(O)CC2)cn1
Reactant: Brc1csc(Br)n1
Product: CCc1cnc(N2CCC(Oc3nc(Br)cs3)CC2)cn1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-42 using 1-(5-ethylpyrazin-2-yl)piperidin-4-ol and 2,4-dibromothiazole (0.480 g, 54%); MS: 369.2 (M+1).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][OH:5].[H-].[Na+].Br[CH:9]([CH3:13])[C:10]([OH:12])=[O:11]>>[CH3:1][S:2][CH2:3][CH2:4][O:5][CH:9]([CH3:13])[C:10]([OH:12])=[O:11]
Reactant: CC(Br)C(=O)O
Reactant: CSCCO
Agent: [H-]
Agent: [Na+]
Product: CSCCOC(C)C(=O)O
Yield: 77.9 %

Procedure:
Addition of 2-methylthioethanol (10.0 g, 0.108 mol) to sodium hydride (9.54 g of a 60% dispersion in mineral oil, 0.238 mol, washed twice with hexane) followed by reaction with 2-bromopropionic acid (16.6 g, 0.108 mol) gave 13.81 g (78% yield) of the title compound as a clear oil; bp 80-90° C./0.2 torr (bulb to bulb distillation, air bath temperature). 1HNMR 400 MHz (CDCl3) δ ppm: 1.49 (3H, d, J=7.0 Hz, CH3), 2.18 (3H, s, SCH3), 2.76 (2H, t, J=6.6 Hz, CH2), 3.74 (2H, t, J=6.6 Hz, CH2), 4.07 (1H, d, J=7.0 Hz, OCH).
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([C:8]2[C:9](OS(C(F)(F)F)(=O)=O)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=3)[CH2:6][CH2:5][O:4][CH2:3]1.[NH:30]1[C:38]2[C:33](=[CH:34][C:35](B(O)O)=[CH:36][CH:37]=2)[CH:32]=[CH:31]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[NH:30]1[C:38]2[C:33](=[CH:34][C:35]([C:9]3[C:8]([N:7]4[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]4[CH3:1])=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=4)[N:10]=3)=[CH:36][CH:37]=2)[CH:32]=[CH:31]1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCOC[C@@H]3C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc4[nH]ccc4c3)c(N3CCOC[C@@H]3C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 47.6 %

Procedure:
To a solution of (S)-methyl 3-(3-methylmorpholino)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (250 mg, crude) in dioxane (5 mL) was added Pd(PPh3)4 (33 mg, 0.03 mmol), 1H-indol-5-ylboronic acid (230 mg, 1.43 mmol), K3PO4 (361 mg, 1.71 mmol) and water (5 drops). The resulting solution was stirred for 1 h at 90° C. under an inert atmosphere of nitrogen and then concentrated in vacuo to give a residue, which was purified by silica gel column chromatography eluting with 1%-10% ethyl acetate in petroleum ether to afford (S)-methyl 2-(1H-indol-5-yl)-3-(3-methylmorpholino)quinoxaline-6-carboxylate as a yellow solid (110 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:20]2[S:24][C:23]3[CH:25]=[CH:26][C:27]([O:29][CH2:30][CH2:31]Cl)=[CH:28][C:22]=3[CH:21]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]2=[O:19])=[N:6][CH:7]=1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.[I-].[Na+].C(=O)(O)[O-].[Na+]>CN(C=O)C>[Br:1][C:2]1[C:3]([C:20]2[S:24][C:23]3[CH:25]=[CH:26][C:27]([O:29][CH2:30][CH2:31][N:37]4[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]4)=[CH:28][C:22]=3[CH:21]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]2=[O:19])=[N:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2cc3cc(OCCCl)ccc3s2)n1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(CCOc2ccc3sc(-c4nc(NCCN5C(=O)NC(=O)C5(C)C)ncc4Br)cc3c2)CC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
1-(2-{5-Bromo-4-[5-(2-chloroethoxy)benzo[b]thiophen-2-yl]pyrimidin-2-ylamino}ethyl)-5,5-dimethylimidazolidine-2,4-dione (0.15 g, 0.27 mmol) was dissolved in DMF (2 mL) and treated with N-methylpiperazine (0.061 mL, 0.55 mmol) and catalytic amount of sodium iodide (0.025 g). The mixture was heated to 70° C. and stirred overnight. The reaction was cooled down to room temperature and poured into a saturated aqueous solution of sodium bicarbonate (15 mL). The resulting precipitate was collected by filtration, dissolved in DMF (2 mL) and purified by preparative HPLC. The clean fractions were treated with 2 M ammonia in methanol and the organic volatiles removed to give a suspension of a white solid in the aqueous layer, which was collected by filtration, washed well with water and dried overnight in a vacuum oven at 60° C. Yield=0.062 g. MS (M+H)+ 603/605.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[C:25]3[C:20](=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:22]=[CH:23][CH:24]=3)[NH:19][N:18]=2)=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH:32]1(Br)[CH2:36][CH2:35][CH2:34][CH2:33]1>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([C:17]2[C:25]3[C:20](=[C:21]([C:26]([F:29])([F:27])[F:28])[CH:22]=[CH:23][CH:24]=3)[N:19]([CH:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)[N:18]=2)=[O:16])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC1CCCC1
Reactant: O=C(c1ccc(OCc2ccccc2)cc1)c1n[nH]c2c(C(F)(F)F)cccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(OCc2ccccc2)cc1)c1nn(C2CCCC2)c2c(C(F)(F)F)cccc12
Temperature: 50 °C
Reaction time: 24 h
Yield: 73.3 %

Procedure:
To a solution of [4-(benzyloxy)phenyl](7-trifluoromethyl-1H-indazol-3-yl)methanone (0.372 g, 0.94 mmol) in 3 mL DMF was added in one portion sodium hydride (0.044 g, 1.1 mmol, 60% in oil). After the gas evolution ceased, cyclopentyl bromide (0.118 mL, 1.1 mmol) was added and the reaction was stirred at ambient to 50° C. for 24 hours. The cool reaction mixture was partitioned with EtOAc and 1 N HCl. The organic phase was washed with brine and dried (Na2SO4). The solvent was removed in vacuo. The resulting residue was purified by flash chromatography (silica gel, hexane-EtOAc, 9:1) to give 0.320 g of the title compound as a yellow solid.
Reaction SMILES: C(Cl)(=O)C.[NH:5]1[CH2:10][CH2:9][CH:8]([O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([N:18]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)=[O:17])[CH2:7][CH2:6]1.NC1C=C2C(=CC=1)CN(C(N[C:40]1[CH:45]=[CH:44][C:43]([C:46](=[O:51])NCCC)=[CH:42][CH:41]=1)=O)C2>>[C:46]([N:5]1[CH2:6][CH2:7][CH:8]([O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([N:18]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)=[O:17])[CH2:9][CH2:10]1)(=[O:51])[C:43]1[CH:44]=[CH:45][CH:40]=[CH:41][CH:42]=1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Reactant: O=C(NCCCOC1CCNCC1)N1Cc2ccccc2C1
Solvent: CC(=O)Cl
Product: O=C(NCCCOC1CCN(C(=O)c2ccccc2)CC1)N1Cc2ccccc2C1

Procedure:
The title compound was prepared as described in Example 278, substituting benzoyl chloride for acetyl chloride and N-(3-(piperidin-4-yloxy)propyl)isoindoline-2-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.21-7.50 (m, 9H) 6.27 (t, J=5.43 Hz, 1H) 4.57 (s, 4H) 3.40-3.58 (m, 6H) 3.07-3.21 (m, 2H) 1.74-1.93 (br m, 2H) 1.62-1.75 (m, 2H) 1.44 (br m, 2H); MS (ESI(+)) m/e 408 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[S:14][CH3:15].[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[C:19]([F:32])[C:18]=1[O:33][CH3:34].C(#N)C.O.C(OCC)(=O)C>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[C:18]([O:33][CH3:34])[C:19]=2[F:32])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[S:14][CH3:15]
Reactant: COc1c(Cl)ccc(B2OC(C)(C)C(C)(C)O2)c1F
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1SC
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)c(F)c(N)c1SC
Temperature: 115 °C

Procedure:
Methyl 4-amino-6-chloro-5-fluoro-3-(methylthio)picolinate (300 mg, 1.2 mmol), 2-(4-chloro-2-fluoro-3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (450 mg, 1.6 mmol) Cesium fluoride (370 mg, 2.4 mmol) and his (triphenylphosphine) palladium (II) chloride (84 mg, 0.12 mmol) were combined in 5 ml 1:1 acetonitrile-water and heated in a microwave reactor at 115° C. for 30 m. The mixture was shaken with 30 ml ethyl acetate and 10 ml water. The org. phase was washed with 10 ml sat. NaCl, dried (Na2SO3) and evaporated. The residue was chromatographed on silica with a 0-40% ethyl acetate-hexane gradient. The gummy material was stirred with hexane to produce the written compound as a white solid, 60 mg. Mp: 113-117° C. 1H NMR (400 MHz, CDCl3) δ 7.27-7.24 (m, 2H), 5.31 (s, 2H), 3.98 (d, J=1.1 Hz, 3H), 3.96 (s, 3H), 2.32 (s, 3H). 19F NMR (376 MHz, CDCl3) δ −127.97, −128.06, −140.43, −140.52. ESIMS m/z 375 ([M+H]+), 373 ([M−H]−).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=4)[CH2:16][N:15]([C:30](Cl)=[O:31])[CH2:14]3)[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[F:34][C:35]1([F:41])[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[F:34][C:35]1([F:41])[CH2:40][CH2:39][N:38]([C:30]([N:15]2[CH2:16][CH:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)[CH2:18][CH:13]([C:11]3[O:10][N:9]=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)[N:12]=3)[CH2:14]2)=[O:31])[CH2:37][CH2:36]1
Reactant: O=C(Cl)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3cccc(F)c3)no2)C1
Reactant: FC1(F)CCNCC1
Agent: Cl
Product: O=C(N1CCC(F)(F)CC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3cccc(F)c3)no2)C1

Procedure:
100 mg (0.21 mmol) of the compound from Example 179A and 33 mg (0.2 mmol) of 4,4-difluoropiperidine hydrochloride were reacted according to the General Method 5. Yield: 37 mg (30% of theory)
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.CCN(CC)CC.ClC(OCC)=O.[N-:23]=[N+:24]=[N-:25].[Na+]>CC(C)=O>[Cl:1][C:2]1[S:6][C:5]([C:7]([N:23]=[N+:24]=[N-:25])=[O:9])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)c1ccc(Cl)s1
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: [N-]=[N+]=NC(=O)c1ccc(Cl)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 52.1 %

Procedure:
To a solution of 5-chloro-2-thiophene-carboxylic acid (5.00 g, 30.7 mmol) in 130 mL of acetone is added Et3N (4.29 mL, 30.7 mmol). The mixture is cooled to 0° C. and ethyl chloroformate (3.23 mL, 33.8 mmol) is added. The mixture is stirred at 0° C. for 1 h and sodium azide (3.40 g, 52.3 mmol) is added. The mixture is stirred at 0° C. for 2 h, then poured into 300 mL of ice water and the aqueous layer is extracted with CH2Cl2 (2×). The combined organics are washed with water (2×) and brine, then dried, filtered and concentrated. The crude residue is purified via flash column chromatography eluting with 10% EtOAc/hexanes to provide the title compound (3.00 g, 16.0 mmol) as a white solid. 1H NMR (CDCl3, 300 MHz) δ7.67 (d, 1H), 6.99 (d, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3]Cl.[Br:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9][OH:10].C(N(C(C)C)CC)(C)C.O>C1COCC1>[Br:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:8]([CH2:9][O:10][CH2:1][O:2][CH3:3])[CH:7]=1
Reactant: OCc1cccc(Br)c1
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: COCOCc1cccc(Br)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, chloromethyl methyl ether (6.09 mL) was added to a solution of 3-bromobenzylalcohol (5.00 g) and diisopropylethylamine (18.9 mL) in THF (45 mL) at 0° C., and the mixture was stirred at 60° C. for 1 hr. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude product (6.37 g) of the title compound. This compound was used for the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([N:13]2[CH2:17][CH:16]=[CH:15][CH2:14]2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[In].Cl>O.O1CCCC1>[N:13]1([S:10]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[NH2:1])(=[O:12])=[O:11])[CH2:14][CH:15]=[CH:16][CH2:17]1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)N2CC=CC2)c1
Agent: Cl
Agent: [In]
Solvent: C1CCOC1
Solvent: O
Product: Nc1cccc(S(=O)(=O)N2CC=CC2)c1
Reaction time: 24 h

Procedure:
A 250 mL round bottom flask was equipped with a magnetic stirrer and charged with 1-(3-nitrobenzenesulfonyl)-2,5-dihydro-1H-pyrrole (Example 92, 9.32 mmol, followed by 3:1 water/tetrahydrofuran v/v (50 mL). Indium powder (37.3 mmol) was added, followed by concentrated HCl (55.9 mmol). The reaction gives a slight exotherm and the indium forms a solid metal chunk. After 24 hours, TLC (dichloromethane/silica) indicated the reaction was mostly complete. The indium was removed with a pair of tweesers to a separate waste stream and the reaction was neutralized with sodium bicarbonate. The aqueous mixture was extracted with ethyl acetate (150 mL), the organic layer dried (Na2SO4), filtered, and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (20 mL) and loaded onto a 600 mL sintered glass funnel charged with silica gel (400 g). The silica plug was eluted with 9:1 dichloromethane:ethyl acetate, collecting 100 mL fractions. Fractions containing the desired product were combined and the solvent was removed under diminished pressure to afford 3-(2,5-dihydropyrrole-1-sulfonyl)-aniline as a white, crystalline solid. 1.50 g, (72%). m.p.: 187-188° C. LC/MS: m/z 224.8 [C10H12N2O2S+H]+. 1H-NMR (CDCl3): δ 4.0 (b, 2H); 4.13 (s, 4H); 5.66 (s, 2H); 6.84-6.87 (d, 1H, J=7.9 Hz); 7.13-7.14 (s, 1H); 7.18-7.20 (d, 1H, J=7.7 Hz); 7.26-7.31 (t, 1H, J=7.8 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([NH2:12])=[O:11])=[CH:4][C:3]=1Br.[C:14]1(B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.[Cl-].[Na+].O.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>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([NH2:12])=[O:11])=[CH:4][C:3]=1[C:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=1
Reactant: CC1(C)OB(C2=CCCCC2)OC1(C)C
Reactant: NC(=O)CCc1ccc(N)c(Br)c1
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: [Cl-]
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)CCc1ccc(N)c(C2=CCCCC2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
To a mixture of 3-(4-amino-3-bromo-phenyl)-propionamide (as prepared in the previous step, 100 mg, 0.411 mmol), 2-cyclohex-1-enyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (94.1 mg, 0.452 mmol) and Pd(PPh3)4 (47.5 mg, 0.0411 mmol) in 3 mL of 1,4-dioxane was added 2.0 M aq Na2CO3 solution (1.64 mL, 3.29 mmol). After stirring at 80° C. for 16 h under Ar, the reaction was cooled to RT and treated with 15 mL of brine. The mixture was extracted with EtOAc (2×30 mL) and the combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (1-3% MeOH/DCM) giving 88.1 mg (88%) of the title compound as a colorless oil. Mass spectrum (ESI, m/z): Calcd. for C15H20N2O, 245.2 (M+H). found 245.1.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[N:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)(=O)=O)=CC=1.[NH2:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[C:36](=[O:40])[NH:35][CH2:34]2>S1(CCCC1)(=O)=O.O>[Cl:29][C:26]1[CH:27]=[N:28][C:23]([N:20]2[CH2:19][CH2:18][CH:17]([C@H:15]3[CH2:16][C@H:14]3[CH2:13][CH2:12][NH:30][C:31]3[CH:32]=[C:33]4[C:37](=[CH:38][CH:39]=3)[C:36](=[O:40])[NH:35][CH2:34]4)[CH2:22][CH2:21]2)=[N:24][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1
Reactant: Nc1ccc2c(c1)CNC2=O
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: O=C1NCc2cc(NCC[C@@H]3C[C@@H]3C3CCN(c4ncc(Cl)cn4)CC3)ccc21
Temperature: 120 °C
Reaction time: 2 h

Procedure:
2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethyl 4-methylbenzenesulfonate from step 1 of Example 5 (100 mg, 0.23 mmol) was dissolved in sulfolane and 5-aminoisoindolin-1-one (68 mg, 0.46 mmol) from step 3 of this example added. The mixture was at stirred 110° C. for 3 and at 120° C. for 2 hours. The mixture was cooled to RT, diluted with 4:1 water:saturated sodium bicarbonate (40 ml), extracted with EtOAc (3×30 ml), the organic fractions combined, washed with brine, dried over Na2SO4, filtered, the volatiles removed in vacuum. The product was purified by chromatography on SiO2 eluting with 80% acetone:hexanes to give the titled compound. LRMS calc: 411.18; obs: 412.08 (M+1). Compounds reported in Table 7 are prepared by a general procedure analogous to that described in Example 44 above.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[N:13][CH:14]=2)=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.I[CH2:38][C:39]([NH2:41])=[O:40].C(OCC)(=O)C>CN(C)C=O.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12](=[N:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[N:13]([CH2:38][C:39]([NH2:41])=[O:40])[CH:14]=2)=[CH:26][CH:27]=1
Reactant: NC(=O)CI
Reactant: COc1ccc(COc2ccc(NS(=O)(=O)c3ccc(C)cc3)nc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc(COc2ccc(=NS(=O)(=O)c3ccc(C)cc3)n(CC(N)=O)c2)cc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 299.7 %

Procedure:
To a suspension of N-{5-[(4-methoxybenzyl)oxy]pyridin-2-yl}-4-methylbenzenesulfonamide (10.0 g, 26.0 mmol) in N,N-dimethylformamide (85 mL) were added N,N-diisopropylethylamine (6.8 mL, 39.0 mmol) and iodoacetamide (5.77 g, 31.0 mmol), and the mixture was stirred at 60° C. for 5 hr. After cooling to room temperature, ethyl acetate and water were added, and the mixture was extracted 3 times with a mixed solution of ethyl acetate and tetrahydrofuran. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was washed with ethyl acetate and collected by filtration to give the title compound (34.4 g, 75%) as a white solid.
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[NH2:8][C:9]1[CH:10]=[C:11]([CH:28]=[CH:29][C:30]=1[CH3:31])[O:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([N:19]=[C:20]([NH:22][C:23]([CH:25]3[CH2:27][CH2:26]3)=[O:24])[N:21]=2)[CH:18]=1>CN(C)C(=O)C>[CH:25]1([C:23]([NH:22][C:20]2[N:21]=[C:16]3[CH:15]=[CH:14][C:13]([O:12][C:11]4[CH:28]=[CH:29][C:30]([CH3:31])=[C:9]([NH:8][C:5]([CH:1]5[CH2:4][CH2:3][CH2:2]5)=[O:6])[CH:10]=4)=[CH:18][N:17]3[N:19]=2)=[O:24])[CH2:26][CH2:27]1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)cc1N
Reactant: O=C(Cl)C1CCC1
Solvent: CC(=O)N(C)C
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)cc1NC(=O)C1CCC1
Yield: 47.6 %

Procedure:
In the same manner as in Example 24 and using cyclobutanecarbonyl chloride (56.0 μL, 0.489 mmol), N,N-dimethylacetamide (5 mL) and N-[6-(3-amino-4-methylphenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (140 mg, 0.433 mmol) as starting materials, the title compound (83.5 mg, 45%) was obtained as a white solid.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:14]=[C:15]([NH:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=[CH:17][C:18]=1[CH3:19]>>[C:21]([NH:20][C:15]1[CH:16]=[CH:17][C:18]([CH3:19])=[C:13]([NH:12][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([CH2:2][Cl:1])=[CH:4][CH:5]=2)[CH:14]=1)(=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: Cc1ccc(NC(=O)c2ccccc2)cc1N
Product: Cc1ccc(NC(=O)c2ccccc2)cc1NC(=O)c1ccc(CCl)cc1
Yield: 99 %

Procedure:
Using an analogous procedure to that described in Example 37, 4-chloromethylbenzoyl chloride was reacted with N-(3-amino-4-methylphenyl)benzamide to give the title compound in 99% yield; NMR Spectrum: (DMSOd6) 2.19 (s, 3H), 4.84 (s, 2H), 7.22 (d, 1H), 7.54 (m, 6H), 7.84 (s, 1H), 7.96 (m, 4H), 9.92 (s, 1H), 10.22 (s, 1H); Mass Spectrum: M−H− 377.