Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[C:7]3[C:13]([C:14]#[N:15])=[CH:12][N:11](S(C4C=CC(C)=CC=4)(=O)=O)[C:8]3=[N:9][CH:10]=[C:5]2[CH:4]=[N:3]1.C1C(=O)N([Br:33])C(=O)C1.CN(C=O)C>O>[Br:33][C:12]1[NH:11][C:8]2=[N:9][CH:10]=[C:5]3[CH:4]=[N:3][N:2]([CH3:1])[C:6]3=[C:7]2[C:13]=1[C:14]#[N:15]
Reactant: Cc1ccc(S(=O)(=O)n2cc(C#N)c3c2ncc2cnn(C)c23)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncc2cnc3[nH]c(Br)c(C#N)c3c21
Temperature: 150 °C
Reaction time: 2 h
Yield: 43.5 %

Procedure:
A 10 mL microwave reaction vial was charged with 1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine-8-carbonitrile (0.011 g, 0.30 mmol, prepared using General Procedure AK from Preparation #1, Step D with NBS, General Procedure AE), NBS (0.012 g, 0.66 mmol) and DMF (2 mL). The suspension was heated in a microwave at about 150° C. for about 30 min (250 psi maximum pressure, 2 min ramp, 300 max watts). Additional NBS (134 mg, 0.754 mmol) was added and mixture was stirred at rt for about 2 h. To the reaction mixture was added water (4 mL) and the solid was collected by filtration and washed with water (5 mL). The solid was dried in a vacuum oven at about 70° C. for about 40 min to give 7-bromo-1-methyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine-8-carbonitrile (0.036 g, 43%): LC/MS (Table 2, Method c) Rt=1.25 min; MS m/z: 276 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][OH:5].[CH3:6][CH:7]([CH3:23])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:12]=1)=[O:9]>>[OH:5][CH2:4][CH2:3][CH2:2][N:20]1[CH2:21][CH2:22][CH:17]([C:13]2[CH:12]=[C:11]([NH:10][C:8](=[O:9])[CH:7]([CH3:6])[CH3:23])[CH:16]=[CH:15][CH:14]=2)[CH2:18][CH2:19]1
Reactant: OCCCCl
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCO)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 3-chloro-1-propanol and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 305.3 (M+H)+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][NH:7][C:8]#[N:9].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:16][C:17]1([CH3:20])[CH2:19][O:18]1.O>COCCOC>[CH3:16][C:17]1([CH3:20])[O:18][C:8](=[NH:9])[N:7]([CH2:6][C@H:2]2[CH2:3][CH2:4][CH2:5][O:1]2)[CH2:19]1
Reactant: CC1(C)CO1
Reactant: N#CNC[C@H]1CCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: CC1(C)CN(C[C@H]2CCCO2)C(=N)O1

Procedure:
A mixture of Example 32A (0.6 g, 4.9 mmol), cesium carbonate (1.6 g, 4.9 mmol) and 2,2-dimethyloxirane (0.35 g, 4.9 mmol, Alfa-aesar) in 1,2-dimethoxyethane (20 mL) was heated to 80° C. overnight. The mixture was poured into water, and extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried over Na2SO4, filtered, concentrated under reduced pressure to afford the title compound. LCMS (APCI+) m/z 198 (M+H)+.
Reaction SMILES: [CH2:1]([S:8][C:9]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:10][CH:11]=[C:12](N(C)C)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([OH:29])C>>[CH2:1]([S:8][C:9]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:10][CH:11]=[C:12]([OH:29])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=CC=C(C(=O)OCC)N(C)C)SCc1ccccc1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C(O)=CC=C(SCc1ccccc1)C(=O)OCC
Temperature: 20 °C
Reaction time: 0.03 h

Procedure:
The procedure is as in Example 2, starting with diethyl 5-benzylthio-2-dimethylamino-2,4-hexadienedioate (10 g) and 1N aqueous hydrochloric acid solution (41.3 cc) in ethanol (41.3 cc). The mixture is heated to boiling for 2 minutes, and then cooled to a temperature in the region of 20° C. After purification by chromatography on a silica column with a mixture of cyclohexane and ethyl acetate (30:70 by volume) as eluent, diethyl 5-benzylthio-2-hydroxy-2,4-hexadienedioate (6.3 g) (m.p. <40° C.) is obtained [Rf=0.6; thin layer chromatography on silica gel; eluent: cyclohexane/ethyl acetate (30:70 by volume)].
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:30])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])[CH:16]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:30])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]([OH:25])=[O:24])[CH:16]=1
Reactant: CC(C)(C)OC(=O)COc1cccc(C(=O)c2cnn(-c3ccc(F)cc3)c2N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1c(C(=O)c2cccc(OCC(=O)O)c2)cnn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
A mixture of 5-amino-4-[3-(tert-butoxycarbonylmethyloxy)benzoyl]-1-(4-fluorophenyl)pyrazole (1.0 g, 3.3 mmol) and trifluoroacetic acid (15 mnl, 194 mmol ) in methylene chloride (15 ml) was stirred overnight at room temperature. The organics were removed in vacuo and the residue was dissolved in toluene. The solution was concentrated and the residue was triturated between ethyl acetate and hexane to give 5-amino-4-[3-(carboxymethyloxy)benzoyl]-1-(4-fluorophenyl)pyrazole (0.8 g) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])/[CH:4]=[CH:5]\[C:6]([OH:8])=[O:7].[OH:10][C:11]([CH3:19])([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:12][SH:13].N1C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:9])[CH2:4][CH:5]([C:6]([OH:8])=[O:7])[S:13][CH2:12][C:11]([OH:10])([CH3:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCC(C)(O)CS
Reactant: COC(=O)/C=C\C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCC(C)(O)CSC(CC(=O)OC)C(=O)O
Reaction time: 3 h

Procedure:
A mixture of 2.6 g of maleic acid monomethyl ester, 3.2 g of 2-hydroxy-2-methylheptane-1-thiol, 0.5 ml of pyridine and 120 ml of methylene chloride is stirred for 3 hours at 30°. After the usual working up, 6-hydroxy-3-hydroxycarbonyl-6-methyl-4-thiaundecanoic acid methyl ester is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15]Br.[Na+].[Br-]>O>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][O:8][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][CH:5]=1
Reactant: Oc1cccc(Cl)c1
Reactant: BrCCCCBr
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Clc1cccc(OCCCCBr)c1
Temperature: 80 °C
Yield: 79 %

Procedure:
A 1 L flask provided with a stirrer was charged with 128.6 g (1.0 mol) of m-chlorophenol (available from Tokyo Chemical Industry Co., Ltd.), 52.0 g (1.3 mols) of sodium hydroxide (available from Wako Pure Chemical Industries Ltd.), 259.1 g (1.2 mols) of 1,4-dibromobutane (available from Tokyo Chemical Industry Co., Ltd.) and 300 g of water. The content was maintained at 80° C. for 4 hours. Then the reaction liquid was cooled to room temperature, and deposited NaBr, produced by side reaction, was filtered off. The organic phase was separated and subjected to distillation under reduced pressure to give 216.9 g of the target m-(4-bromobutoxy)chlorobenzene (yield: 79%, purity: 96%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:15]=[C:16]([C:32](OCC)=[O:33])[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[C:19]=3[CH3:20])=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].[CH3:37][N:38]([CH3:42])[CH2:39][CH2:40][NH2:41]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:15]=[C:16]([C:32]([NH:41][CH2:40][CH2:39][N:38]([CH3:42])[CH3:37])=[O:33])[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=4)[C:19]=3[CH3:20])=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CN(C)CCN
Reactant: CCOC(=O)c1cc(-c2ccnn2-c2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cc(C(=O)NCCN(C)C)c(=O)n1-c1cccc(C(F)(F)F)c1
Yield: 67 %

Procedure:
Intermediate A and N,N-dimethylethane-1,2-diamine were reacted together using an analogous method to that described in Step 1 of Example 1 to afford 5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-N-[2-(dimethylamino)ethyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (154 mg, 67%); 1H NMR (500 MHz, DMSO) δ 1.72 (3H, s), 2.10 (6H, s), 2.32 (2H, t), 3.36-3.32 (2H, m), 6.72 (1H, d), 7.67-7.64 (2H, m), 7.71 (1H, d), 7.88-7.82 (2H, m), 7.96-7.90 (4H, m), 8.07 (1H, s), 9.37 (1H, t); APCI-MSm/z: 535[MH+H]
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:15].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[CH2:14]([N:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:11](=[O:13])[CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[CH3:15]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CCCCCCCNCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCN(CC)C(=O)Cc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
A mixture of p-nitrophenylacetic acid (7.14 g, 0.0394 mol), ethylheptylamine (5.64 g, 0.0394 mol) and 1-hydroxybenzotriazole (6.0 g, 0.044 mol) in 35 ml of dimethylformamide (DMF), under nitrogen, is cooled in an ice bath. The mixture is then treated with the 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (7.68 g, 0.04 mol) in portions over 15 min. The mixture is stirred in the cold for 1 hr and at room temperature overnight. The mixture is diluted with 400 ml of ethyl acetate and washed twice with saturated NaHCO3. (Each wash is back extracted with ethyl acetate.) The pooled organic extract is washed sequentially with water (50 ml), 1N KHSO4 solution (3×50 ml), water (50 ml) and finally brine (50 ml). It is dried (Na2SO4) and concentrated in vacuo to yield the title compound. This residue is treated with Et2O-pentane, a solid filtered off and the filtrate concentrated in vacuo. The residue is chromatographed over 1400 ml of silica gel with 25% EtOAc-SSB with 42 ml fractions being collected. Fractions at approximately 70-104 yield the title compound as an oil.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH:15]3[CH2:17][CH2:16]3)=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:18][C@@H:19]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:20]([NH2:22])=[O:21]>>[C:20]([C@@H:19]([NH:18][C:10]([C:7]1[CH:6]=[C:5]([O:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12])[CH2:23][CH:24]([CH3:26])[CH3:25])(=[O:21])[NH2:22]
Reactant: O=C(O)c1cc(OCC2CC2)c(C2CC2)cn1
Reactant: CC(C)C[C@H](N)C(N)=O
Product: CC(C)C[C@H](NC(=O)c1cc(OCC2CC2)c(C2CC2)cn1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 24d, using 5-Cyclopropyl-4-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42c) and (S)-2-Amino-4-methyl-pentanoic acid amide (CAN 687-51-4) as starting materials and isolated (10.5 mg, 20%) as colorless oil; MS (ESI, m/z): 346.6 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2[NH:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][N:24]([CH3:26])[CH3:25])[CH2:19][CH2:18]1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([O:43][CH3:44])[C:29]=1[OH:45].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:27].[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]3[NH:16][C@H:17]2[CH2:18][CH2:19][C@H:20]([CH2:23][N:24]([CH3:25])[CH3:26])[CH2:21][CH2:22]2)[CH:31]=[C:30]([O:43][CH3:44])[C:29]=1[OH:45]
Reactant: CN(C)C[C@H]1CC[C@H](Nc2c(S(C)(=O)=O)cnc3ccc(Cl)nc23)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: COc1cc(-c2ccc3ncc(S(C)(=O)=O)c(N[C@H]4CC[C@H](CN(C)C)CC4)c3n2)cc(Cl)c1O

Procedure:
Following general procedure II, 6-chloro-N-{trans-4-[(dimethylamino)methyl]-cyclohexyl}-3-(methylsulfonyl)-1,5-naphthyridin-4-amine (24 mg, 0.061 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (28 mg, 0.10 mmol) followed by formation of the dihydrochloride salt to afford the desired product (23 mg, 64%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 8.89 (s, 1H), 8.54 (d, J=9.1 Hz, 1H), 8.34 (d, J=9.0 Hz, 1H), 7.83 (d, J=2.0 Hz, 1H), 7.60 (d, J=2.0 Hz, 1H), 5.83-5.73 (m, 1H), 4.04 (s, 3H), 3.38 (s, 3H), 3.08 (d, J=6.6 Hz, 2H), 2.93 (s, 6H), 2.50-2.43 (m, 2H), 2.07-1.95 (m, 3H), 1.73-1.63 (m, 2H), 1.46-1.35 (m, 2H). ESI MS m/z 519 [M+H]+; HPLC>99% (AUC), tR=9.77 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH2:36]([O:38][C:39]1[CH:45]=[C:44]([N:46]2[CH2:51][CH2:50][CH:49]([N:52]3[CH2:57][CH2:56][N:55]([S:58]([CH3:61])(=[O:60])=[O:59])[CH2:54][CH2:53]3)[CH2:48][CH2:47]2)[CH:43]=[CH:42][C:40]=1[NH2:41])[CH3:37].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:41][C:40]3[CH:42]=[CH:43][C:44]([N:46]4[CH2:51][CH2:50][CH:49]([N:52]5[CH2:57][CH2:56][N:55]([S:58]([CH3:61])(=[O:60])=[O:59])[CH2:54][CH2:53]5)[CH2:48][CH2:47]4)=[CH:45][C:39]=3[O:38][CH2:36][CH3:37])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: CCOc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: CCOc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 175 °C
Yield: 53.7 %

Procedure:
A mixture of 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (0.10 g, 0.20 mmol), 2-(ethyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}aniline (Example 222, Step D) (0.078 g, 0.20 mmol) and para-toluenesulfonic acid (0.093 g, 0.49 mmol) in i-PrOH (5 mL) was heated in a microwave at 175° C. for 25 min. The reaction mixture was concentrated onto silica gel and purified by flash chromatography. Recrystallization from DCM and diethyl ether afforded N-(2,6-difluorophenyl)-5-(3-{2-[(2-(ethyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}phenyl)amino]-4-pyrimidinyl}imidazo[1,2-a]pyridin-2-yl)-2-(methyloxy)benzamide (0.090 g, 53%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.80 (s, 1H), 9.35 (br. s., 1H), 8.36 (s, 1H), 8.24 (d, J=5.3 Hz, 1H), 8.12 (d, J=1.7 Hz, 1H), 7.75-7.83 (m, 1H), 7.71 (d, J=9.0 Hz, 1H), 7.36-7.49 (m, 3H), 7.29 (d, J=8.7 Hz, 1H), 7.15-7.25 (m, 2H), 6.88-7.01 (m, 1H), 6.67 (d, J=2.3 Hz, 1H), 6.56 (d, J=5.1 Hz, 1H), 6.49 (dd, J=8.7, 2.4 Hz, 1H), 4.07 (q, J=6.9 Hz, 2H), 4.00 (s, 3H), 3.68-3.80 (m, 2H), 3.04-3.17 (m, 4H), 2.87 (s, 3H), 2.57-2.73 (m, 6H), 2.38-2.46 (m, 1H), 1.79-1.89 (m, 2H), 1.47-1.61 (m, 2H), 1.25 (t, J=6.9 Hz, 3H). MS (M−H, ES−) 836.
Reaction SMILES: Cl.[O:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]1[CH2:13][CH2:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1.[CH2:23](N)[CH2:24][NH2:25]>C(O)C>[NH:20]1[CH2:23][CH2:24][N:25]=[C:19]1[C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][N:4]2[C:3](=[O:2])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]2=[O:12])=[CH:22][CH:21]=1
Reactant: N#Cc1ccc(CCN2C(=O)c3ccccc3C2=O)cc1
Reactant: NCCN
Agent: Cl
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1CCc1ccc(C2=NCCN2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.7 %

Procedure:
Dry hydrogen chloride gas was bubbled through an ice cold solution of 4-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-benzonitrile (7.83 g, 28.3 mmol) in ethanol (400 mL) for 3 h, then the so obtained mixture was kept at 8° C. overnight. The reaction mixture was concentrated in vacuo, the residue was dissolved in dry ethanol (400 mL), ethylenediamine (2.0 mL, 29.7 mmol) was added and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo, the residue was partitioned between dichloromethane (400 mL) and concentrated ammonium hydroxide (400 mL), the phases were separated and the water phase was extracted with dichloromethane (2×200 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude product was recrystallized from 2-propanol to yield 5.58 g (62%) of the title compound as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:40])[C@H:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[O:28][C:29]4[CH:36]=[CH:35][C:34]([Br:37])=[C:33]([O:38][CH3:39])[C:30]=4[C:31]=3[CH3:32])=[O:26])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].[Li+].[OH-]>C1COCC1>[Br:37][C:34]1[CH:35]=[CH:36][C:29]2[O:28][C:27]([C:25]([NH:24][C:21]3[CH:20]=[CH:19][C:18]([C:15]4[CH:14]=[CH:13][C:12]([S:9]([NH:8][C@H:4]([CH:5]([CH3:6])[CH3:7])[C:3]([OH:40])=[O:2])(=[O:10])=[O:11])=[CH:17][CH:16]=4)=[CH:23][CH:22]=3)=[O:26])=[C:31]([CH3:32])[C:30]=2[C:33]=1[O:38][CH3:39]
Reactant: COC(=O)[C@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3oc4ccc(Br)c(OC)c4c3C)cc2)cc1)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1c(Br)ccc2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N[C@@H](C(=O)O)C(C)C)cc4)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 96 h
Yield: 56.3 %

Procedure:
To 89 mg of (R)-2-{4′-[(5-bromo-4-methoxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid methyl ester was added 1 mL of THF and 3 mL of LiOH solution (3.6 g LiOH/50 mL MeOH/50 mL H2O). The mixture was stirred at room temperature for 4 days. The solvents were removed under vacuum and the residue was dissolved in 5 mL of water. The solution was acidified and the resulting suspension was filtered. The solid product was dried under vacuum and triturated with 0.5 mL of chloroform to give 49 mg (56% yield) of (R)-2-{4′-[(5-bromo-4-methoxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.8 (dd, J=12.4, 6.8 Hz, 6 H) 2.0 (m, 1 H) 2.7 (s, 3 H) 3.6 (dd, J=9.3, 6.1 Hz, 1 H) 3.9 (s, 3 H) 7.7 (d, J=8.8 Hz, 1 H) 7.8 (d, J=8.8 Hz, 2 H) 7.9 (m, 4 H) 8.0 (d, J=8.8 Hz, 2 H) 8.1 (d, J=9.3 Hz, 1 H) 8.3 (s, 1 H) 10.6 (s, 1 H) 12.6 (s, 1 H).
Reaction SMILES: S([O-])([O-])(=O)=O.[Mg+2].[CH3:7][CH:8]([CH3:24])[CH2:9][NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][N:19]=2)[N:14]=[CH:13][C:12]=1[N+:21]([O-])=O.[H][H]>[Pt].C(OCC)(=O)C>[CH3:7][CH:8]([CH3:24])[CH2:9][NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][N:19]=2)[N:14]=[CH:13][C:12]=1[NH2:21]
Reactant: [H][H]
Reactant: CC(C)CNc1c([N+](=O)[O-])cnc2cccnc12
Agent: [Pt]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Product: CC(C)CNc1c(N)cnc2cccnc12

Procedure:
Magnesium sulfate (3 g) and a catalytic amount of 5% platinum on carbon were added to a solution of N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine (4.0 g, 16.2 mmol) in ethyl acetate (250 mL). The reaction mixture was reduced on a Parr apparatus at 50 psi (3.5 Kg/cm2) hydrogen for four hours. The reaction mixture was filtered to remove the catalyst and the filtrate was concentrated under vacuum to provide N4-(2-methylpropyl)[1,5]naphthyridin-3,4-diamine as a crude solid.
Reaction SMILES: [CH2:1]([N:10]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:11]1[C:19]2[C:14](=[CH:15][C:16]([Cl:21])=[CH:17][C:18]=2[Cl:20])[NH:13][C:12]=1[C:22]([O:24]CC)=[O:23])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].O.[OH-].[Li+].Cl>O1CCCC1.O>[CH2:1]([N:10]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:11]1[C:19]2[C:14](=[CH:15][C:16]([Cl:21])=[CH:17][C:18]=2[Cl:20])[NH:13][C:12]=1[C:22]([OH:24])=[O:23])[C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1N(CC(=O)c1ccccc1)Cc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(CN(Cc1ccccc1)c1c(C(=O)O)[nH]c2cc(Cl)cc(Cl)c12)c1ccccc1

Procedure:
Dissolve 3-[(phenacyl)benzylamino]-2-carbethoxy-4,6-dichloroindole (0.5 g, 1.07 mmol) in tetrahydrofuran (10 mL) and water (10 mL). Add lithium hydroxide monohydrate (0.16 g, 3.74 mmol) and stir for 24 hours. Heat at reflux for 6 hours and pour into 1N hydrochloric acid (100 mL). Extract into ethyl acetate, dry (MgSO4) and evaporate the solvent in vacuo. Recrystallize (ethyl acetate/hexane) to give the title compound; mp 266°-7° C.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.Cl.[CH3:14]OC(OC)(C)C>>[Br:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH3:14])=[O:11])=[CH:7][CH:8]=1
Reactant: O=C(O)Cc1ccc(CBr)cc1
Reactant: COC(C)(C)OC
Agent: Cl
Product: COC(=O)Cc1ccc(CBr)cc1

Procedure:
5 g (22 mmol) of 2-(4-bromomethyl-phenyl)-acetic acid are stirred at room temperature overnight in 50 ml of 2,2-dimethoxypropane with addition of 2 ml of aqueous conc. hydrochloric acid. After concentration, methanol is added twice in each case, the mixture is concentrated again and the residue is then dried in vacuo.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]2=[O:28])[CH2:11]1)=[O:7])(C)(C)C.[NH2:29][C:30]1[C:38]([Cl:39])=[CH:37][C:33](C(O)=O)=[C:32]([O:40][CH3:41])[CH:31]=1>>[NH2:29][C:30]1[C:38]([Cl:39])=[CH:37][C:33]([C:6]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][N:18]3[C:26](=[O:27])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]3=[O:28])[CH2:11]2)=[O:7])=[C:32]([O:40][CH3:41])[CH:31]=1
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCCN2C(=O)c3ccccc3C2=O)C1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCN2C(=O)c3ccccc3C2=O)C1

Procedure:
2-(3-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)propyl)-2,3-dihydro-1 H-isoindole-1,3-dione (1 g) as starting compound was reacted and treated in the same manner as in Example 67 using 4-amino-5-chloro-2-methoxybenzoic acid (0.50 g) to give 4-amino-5-chloro-N-(1-(3-(2,3-dihydro-1,3-dioxo-1 H-isoindol-2-yl)propyl)-pyrrolidin-3-ylmethyl)-2-methoxybenzamide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O>[C:10]1([C:2]2[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CSc1ccc(Br)cc1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CSc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 94.9 %

Procedure:
A 100 mL of reactor equipped with magnetic stir bar was charged with 140 mg (0.15 mmol) of {[(t-Bu)2P(OH)]2PdCl}2 (from Experiment 7), 2.03 g (10.0 mmol) of 4-bromothioanisole, 1.83 g (15.0 mmol) of PhB(OH)2 and 4.16 g (30.0 mmol) of K2CO3 in 13 mL of DME and 7 mL of H2O. The reaction mixture was refluxed for 12 h until the starting material was completely consumed as judged by TLC. The reaction was cooled to room temperature, transferred to a separatory funnel, and diluted with 300 mL of hexane and 100 mL of H2O. The layers were separated, and organic layer was washed with H2O (2×100 mL), brine (100 mL), and dried over mgSO4, filtered, and solvents removed from the filtrate by rotary evaporation. The resulting residue was chromatographed on silicon gel using hexane as eluant. The eluate was concentrated by rotary evaporation followed by high vacuum to give 1.90 g (95% yield) of 4-phenylthioanisole. It was >95% pure by 1H NMR and GC/MS. 1H NMR (300 MHz, CDCl3): δ7.47-7.39 (m, 5H), 7.31 (m, 2H), 7.22 (m, 2H), 2.39 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3): δ140.5, 138.0, 137.6, 128.8, 127.4, 127.1, 126.9, 126.8 ppm.