Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([C:8]([NH:10][C:11]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:12])=[O:9])=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:20]=[CH:19][C:7]([C:8]([NH:10][C:11]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:12])[CH3:13])=[O:9])=[CH:6][CH:5]=1
Reactant: CC(C)(C)CC(C)(C)NC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)CC(C)(C)NC(=O)c1ccc(N)cc1
Yield: 76.1 %

Procedure:
4-Nitro-N-(tert-octyl)benzamide (30 g, 0.108 mol) dissolved in 200 ml of ethyl acetate is hydrogenated for 1 hour 15 minutes at a temperature of 70-75° C. in a 500 ml hydrogenator in the presence of 4.8 g of 10% palladium-on-charcoal comprising 50% water as catalyst (hydrogen pressure: 8-10 bar). After filtering, concentrating the solvent and drying under vacuum, 20.4 g (Yield: 76%) of 4-amino-N-(tert-octyl)benzamide are obtained in the form of a pale yellow powder which is used as is in the following stage.
Reaction SMILES: C(P(=O)(OCC)OCC)#N.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[C:23]([CH3:25])[C:22]([O:26][CH2:27][O:28][CH3:29])=[C:21]([CH3:30])[C:20]=2[CH3:31])=[CH:14][C:13]=1[N:32]([CH3:40])[C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36].[O:41]=[C:42]1[NH:46][C:45](=[O:47])[CH:44]([CH2:48][C:49]2[CH:59]=[CH:58][C:52]([O:53][CH2:54][C:55](O)=[O:56])=[CH:51][CH:50]=2)[S:43]1.C(N(CC)CC)C>O1CCCC1>[O:41]=[C:42]1[NH:46][C:45](=[O:47])[CH:44]([CH2:48][C:49]2[CH:50]=[CH:51][C:52]([O:53][CH2:54][C:55]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[C:23]([CH3:25])[C:22]([O:26][CH2:27][O:28][CH3:29])=[C:21]([CH3:30])[C:20]=4[CH3:31])=[CH:14][C:13]=3[N:32]([CH3:40])[C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:56])=[CH:58][CH:59]=2)[S:43]1
Reactant: COCOc1c(C)cc(Oc2ccc(N)c(N(C)C(=O)OC(C)(C)C)c2)c(C)c1C
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCOc1c(C)cc(Oc2ccc(NC(=O)COc3ccc(CC4SC(=O)NC4=O)cc3)c(N(C)C(=O)OC(C)(C)C)c2)c(C)c1C
Temperature: 25 °C
Reaction time: 17 h
Yield: 75.9 %

Procedure:
7.34 g of diethyl cyanophosphonate were added to a mixture of 18.7 g of t-butyl N-[2-amino-5-(4-methoxymethoxy-2,3,5-trimethylphenoxy)phenyl]-N-methylcarbamate, 12.6 g of 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid, 4.55 g of triethylamine and 300 ml of anhydrous tetrahydrofuran. The resulting mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated by evaporation. Water was then added to the concentrate. After extraction with ethyl acetate, the extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography through a silica gel column (eluting solvent: n-hexane/ethyl acetate=1/1), whereby 23.1 g of the desired compound were obtained.
Reaction SMILES: [N:1]([CH:4]([C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([C:16]([F:19])([F:18])[F:17])[CH:7]=1)[CH3:5])=[N+]=[N-].[H][H]>[Pd].CO>[F:13][C:12]([F:14])([F:15])[C:10]1[CH:11]=[C:6]([CH:4]([NH2:1])[CH3:5])[CH:7]=[C:8]([C:16]([F:17])([F:18])[F:19])[CH:9]=1
Reactant: CC(N=[N+]=[N-])c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(N)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 91 %

Procedure:
The crude product of 1-azido-[3,5-bis(trifluoromethyl)phenyl]ethane obtained in Example 2-5 was added with palladium-fibroin (18 mg) and methanol (6 mL), and after the atmosphere was replaced with hydrogen, the mixture was stirred at room temperature. After stirring over 1 hour, the reaction mixture was filtered through Celite, and concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol=50:1 to 5:1) to obtain 77.6 mg of α-[3,5-bis(trifluoromethyl)phenyl]ethylamine as colorless oil.
Reaction SMILES: [NH2:1][C@H:2]([C:17]([NH:19][CH2:20][CH3:21])=[O:18])[CH2:3][C:4]1[CH:16]=[CH:15][C:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:6][CH:5]=1.N1C=CC=CC=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>ClCCl>[C:28]([NH:1][C@H:2]([C:17]([NH:19][CH2:20][CH3:21])=[O:18])[CH2:3][C:4]1[CH:16]=[CH:15][C:7]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])=[CH:6][CH:5]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: CCNC(=O)[C@@H](N)Cc1ccc(C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCNC(=O)[C@H](Cc1ccc(C(=O)OC(C)(C)C)cc1)NC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tert-butyl 4-[(2S)-2-amino-3-(ethylamino)-3-oxopropyl]benzoate was dissolved in dichloromethane (3.5 mL). Pyridine (0.05 mL) and acetic anhydride (0.05 mL) were added. The reaction was allowed to stir overnight at room temperature under nitrogen. The reaction was transferred to a separatory funnel and washed with saturated sodium bicarbonate. The aqueous layer was extracted three additional times with dichloromethane. The combined organic layer was dried over sodium sulfate, filtered, and concentrated. The resulting material was purified by column chromatography. 1H NMR 600 MHz (CDCl3) δ 7.86 (d, 2H, J=8.4 Hz), 7.23 (d, 2H, J=8.4 Hz), 6.89 (s, 1H), 6.47 (s, 1H), 4.68 (m, 1H), 3.15 (m, 2H), 3.06 (m, 2H), 1.93 (s, 3H), 1.55 (s, 9H), 0.99 (m, 3H). MS: cal'd 335 (MH+), exp 335 (MH+).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:16]([O:18]CC)=O)[CH2:7][C:8]1[C:9]([O:14][CH3:15])=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:4].C(N(CC)C(C)C)(C)C>CO>[CH3:15][O:14][C:9]1[C:8]([CH2:7][CH:6]2[NH:5][C:3](=[O:4])[CH2:2][NH:1][C:16]2=[O:18])=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: CCOC(=O)[C@H](Cc1cccnc1OC)NC(=O)CN
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncccc1CC1NC(=O)CNC1=O
Temperature: 70 °C
Reaction time: 36 h
Yield: 86 %

Procedure:
To a 100-mL round-bottomed flask was added ethyl glycyl-3-(2-methoxy-3-pyridinyl)alaninate (1.018 g, 3.62 mmol) and N,N-diisopropylethylamine (0.63 mL, 3.62 mmol) in MeOH (20 mL). The reaction mixture was stirred at 70° C. for 36 h. The solvent was partially removed under a vacuum and the solid formed was filtered, washed with MeOH and dried to give 3-((2-methoxy-3-pyridinyl)methyl)-2,5-piperazinedione (0.732 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[CH:11]1[C:20]2[C:15](=[C:16]([CH:21]([CH3:25])[C:22](O)=[O:23])[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:22](=[O:23])[CH:21]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[CH:14]=[CH:13][N:12]=[CH:11]2)[CH3:25]
Reactant: CC(C(=O)O)c1cccc2cnccc12
Reactant: NCc1ccc(Cl)cc1Cl
Agent: O=C(O)Cc1cccc2cnccc12
Product: CC(C(=O)NCc1ccc(Cl)cc1Cl)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 2,4-dichlorobenzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 359 (M+H)+; MS (ESI−) m/z 357 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.54 (d, J 7.1, 3H), 4.20 (m, 2H), 4.53 (q, J 7.1, 1H), 7.22 (d, J 8.4, 1H), 7.33 (m, 2H), 7.56 (s, 1H), 7.78 (t, J 7.8, 1H). 7.90 (d, J 6.5, 1H), 8.17 (d, J 8.1, 1H), 8.25 (d, J 6.4, 1H), 8.62 (m, 2H), 9.51 (s, 1H).
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].Cl.Cl.[NH2:9][C:10]1[C:19]2[N:20]=[C:21]([CH2:28][O:29][CH2:30][CH3:31])[N:22]([CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])[C:18]=2[C:17]2[CH:16]=[CH:15][C:14]([O:32][CH2:33][CH2:34][CH2:35][N:36]3[CH2:40][CH2:39][CH2:38][C:37]3=[O:41])=[CH:13][C:12]=2[N:11]=1.C(N(CC)CC)C>ClCCl>[NH2:9][C:10]1[C:19]2[N:20]=[C:21]([CH2:28][O:29][CH2:30][CH3:31])[N:22]([CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[C:18]=2[C:17]2[CH:16]=[CH:15][C:14]([O:32][CH2:33][CH2:34][CH2:35][N:36]3[CH2:40][CH2:39][CH2:38][C:37]3=[O:41])=[CH:13][C:12]=2[N:11]=1
Reactant: CC(C)N=C=O
Reactant: CCOCc1nc2c(N)nc3cc(OCCCN4CCCC4=O)ccc3c2n1CCCCN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(N)nc3cc(OCCCN4CCCC4=O)ccc3c2n1CCCCNC(=O)NC(C)C
Reaction time: 1.5 h
Yield: 71.2 %

Procedure:
Isopropyl isocyanate (0.187 mL, 1.90 mmol) was added dropwise to a stirred solution of 1-(3-{[4-amino-1-(4-aminobutyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propyl)pyrrolidin-2-one dihydrochloride (prepared as described in Example 398, 1.0 g, 1.90 mmol) and triethylamine (0.530 mL, 3.80 mmol) in dichloromethane (20 mL) at room temperature. After 1.5 hours, the solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica gel, gradient elution with 2-12% CMA in chloroform) followed by recrystallization from acetonitrile to yield 0.730 g of N-(4-{4-amino-2-(ethoxymethyl)-7-[3-(2-oxopyrrolidin-1-yl)propoxy]-1H-imidazo[4,5-c]quinolin-1-yl}butyl)-N′-isopropylurea as an opaque solid, mp 98-101° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[N:5]=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[O:24][CH3:25])[N:3]=1.C[Si]([N:30]=[N+:31]=[N-:32])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:25][O:24][C:17]1[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:16]=1[NH:15][C:4]1[N:3]=[C:2]([NH2:1])[N:6]([C:7]2[CH:8]=[CH:9][C:10]([C:11]3[NH:32][N:31]=[N:30][N:12]=3)=[CH:13][CH:14]=2)[N:5]=1
Reactant: COc1ccc(Nc2nc(N)n(-c3ccc(C#N)cc3)n2)c(OC)c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: COc1ccc(Nc2nc(N)n(-c3ccc(-c4nnn[nH]4)cc3)n2)c(OC)c1
Temperature: 110 °C
Yield: 22.8 %

Procedure:
4-[5-Amino-3-(2,4-dimethoxy-phenylamino)-[1,2,4]triazol-1-yl]-benzonitrile (52 mg, 0.15 mmol) and trimethylsilyl azide (20 mg, 0.165 mol) were suspended in 1 mL toluene with a catalytic amount of di-butyltin oxide and heated to 110° C. for 18 hours. The toluene was evaporated and the residue purified by preparative HPLC affording 13 mg product as the TFA salt.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.Br[C:24]1[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=1>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([C:24]3[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=3)[C:12]=2[CH3:21])[CH:5]=1
Reactant: Cn1cc(Br)cn1
Reactant: COC(=O)c1ccnc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Product: COC(=O)c1ccnc(Sc2c(C)n(-c3cnn(C)c3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 1, using the following starting materials: 2-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-isonicotinic acid methyl ester and 4-bromo-1-methyl-1H-pyrazole.
Reaction SMILES: [C:1](Cl)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C([N:19]1[CH2:24][CH2:23][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([N:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]1)C1C=CC=CC=1.C(=O)([O-])O.[Na+]>CO.C(Cl)(Cl)Cl>[CH2:4]([O:3][C:1]([N:19]1[CH2:24][CH2:23][C:22]([N:25]([CH3:27])[CH3:26])([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:21][CH2:20]1)=[O:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CN(C)C1(c2ccccc2)CCN(Cc2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CN(C)C1(c2ccccc2)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21 %

Procedure:
500 ml (10 eq.) Cbz chloride were added dropwise to 50 g (1 eq.) 1-benzyl-N,N-dimethyl-4-phenylpiperidin-4-amine over a period of 1 h and the reaction mixture obtained was stirred for 2 h at room temperature. The reaction course was monitored by thin-layer chromatography (10% MeOH/CHCl3). Once the conversion was complete, the reaction mixture was cooled to 0° C., made alkaline with saturated sodium hydrogen carbonate solution and extracted 3 times with 300 ml EtOAc. The combined organic phases were dried with Na2SO4. Following removal of the solvent under reduced pressure, the residue was purified by column chromatography (silica gel; 50% EtOAc/heptane). 12 g (21%) of product were obtained in the form of an oil.
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][C:17](C)=[CH:16][CH:15]=2)[O:6][C:7]=1[C:8]1C=CC=CC=1.[CH3:21]/C(/C(C)=O)=N\O.C1(C)C=CC=C(C=O)C=1>>[I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:15]=[C:16]([CH3:21])[CH:17]=[CH:18][CH:19]=2)[O:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Reactant: CC(=O)/C(C)=N/O
Agent: Cc1cccc(C=O)c1
Product: Cc1cccc(-c2nc(CI)c(C)o2)c1

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, diacetylmonoxime and m-tolualdehyde gave 4-iodomethyl-5-methyl-2-m-tolyloxazole.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)=[CH:4][CH:3]=1.C([Li])CCC.[CH2:20]([N:27]1[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[NH4+]>C1COCC1>[CH2:20]([N:27]1[CH2:32][CH2:31][C:30]([C:2]2[CH:14]=[CH:13][C:5]([O:6][CH:7]3[CH2:12][CH2:11][CH2:10][CH2:9][O:8]3)=[CH:4][CH:3]=2)([OH:33])[CH2:29][CH2:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Brc1ccc(OC2CCCCO2)cc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(c2ccc(OC3CCCCO3)cc2)CCN(Cc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 51.2 %

Procedure:
A solution of 2-(4-bromophenoxy)-tetrahydropyran (7.2 g, 28 mmol) in THF (70 ml) was cooled to −60° C., to which n-butyl lithium (1.53 M) hexane solution (20 ml, 30.8 mmol) was added dropwise, and the mixture was stirred for 30 minutes. Then, a solution of 1-benzyl-4-piperidone (5.3 g, 28 mmol) in THF (20 ml) was added dropwise to this mixture, which was stirred for 3 hours while being allowed to reach a temperature of 0° C. Saturated ammonium chloride aqueous solution was added to the reaction mixture, which was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=20/1) to afford 1-benzyl-4-[4-(tetrahydropyran-2-yloxy)phenyl]piperidin-4-ol (5.27 g, yield 51%) as an orange-colored oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:19]3[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=3)[C:22]#[N:23])[CH:17]=2)[N:12]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH:11]=1.C[CH2:38][O:39]CC>CO>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:19]3[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=3)[C:22](=[NH:23])[O:39][CH3:38])[CH:17]=2)[N:12]([S:27]([C:30]2[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=2)(=[O:28])=[O:29])[CH:11]=1
Reactant: CCOCC
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cccc(C#N)c3)cc12
Agent: Cl
Solvent: CO
Product: COC(=N)c1cccc(-c2cnc3c(c2)c(-c2ccccc2OC)cn3S(=O)(=O)c2ccc(C)cc2)c1

Procedure:
HCl gas was bubbled through a suspension of 3-[3-(2-Methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzonitrile (287.8 mg, 0.60 mmol) in 3.5 mL of anhydrous MeOH. The mixture was then stirred for 5 hours at room temperature before ether (20 mL) was added. The precipitate was then collected by filtration and dried to afford methyl 3-(3-(2-methoxyphenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzimidate without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O1CCCC1>[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:23][C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[O:16])=[CH:20][CH:19]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NCc2ccc(Cl)cc2)CC1
Reaction time: 16 h
Yield: 102 %

Procedure:
To a mixture of 1-t-butoxycarbonyl-4-carboxypiperidine (2.3 g, 10 mmol), 4-chlorobenzylamine (1.56 g, 11 mmol), and 1-hydroxy-7-azabenzotriazole (1.5 g, 11 mmol) in tetrahydrofuran (20 mL) at room temperature under argon, was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.1 g, 11 mmol), and the resulting mixture was stirred for 16 h. The solvent was evaporated under vacuum, and the residue was dissolved in ethyl acetate (50 mL). The resulting solution was washed sequentially with 0.01 M aqueous hydrochloric acid (50 mL), 1.0 M aqueous sodium hydroxide (25 mL), and brine (25 mL) before drying (anhydrous sodium sulfate) and evaporation under vacuum to obtain 4-(N-(4-chlorobenzyl)aminocarbonyl)-1-t-butoxycarbonylpiperidine (3.6 g, quantitative yield).
Reaction SMILES: [OH:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4](=[O:16])[C:3]=1[C:17]([NH:19][CH2:20][C:21]([O:23]CC)=[O:22])=[O:18].CI.[C:28](=O)([O-])[O-].[Na+].[Na+].Cl>CN(C)C=O>[OH:1][C:2]1[N:7]([CH3:28])[C:6](=[O:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4](=[O:16])[C:3]=1[C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18]
Reactant: CCOC(=O)CNC(=O)c1c(O)[nH]c(=O)n(Cc2ccccc2)c1=O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(O)c(C(=O)NCC(=O)O)c(=O)n(Cc2ccccc2)c1=O
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 28.2 %

Procedure:
A mixture of ethyl N-{[6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycinate (295 mg, 0.85 mmoles), methyl iodide (62 uL, 1.0 mmoles) and sodium carbonate (320 mg, 3.0 mmoles) in dimethylformamide (5.0 mL) was stirred under argon at 100° C. for 2.5 hours. The mixture was cooled, poured into 1 molar hydrochloric acid and extracted with ethyl acetate (×2). The ester was hydrolysed by stirring in a mixture of ethanol (5 mL) and 1 molar sodium hydroxide solution (4 mL) for 4 hours. The mixture was acidified and extracted with ethyl acetate. Purification by preparative HPLC (acetonitrile-water—0.1% TFA, 20-100%) and crystallization from ether-hexane gave the title compound (80 mg, 28%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.11 (br. s., 1 H), 10.09 (br. s., 1 H), 7.28-7.36 (m, 4 H), 7.19-7.29 (m, 1 H), 5.01 (s, 2 H), 4.14 (d, J=5.81 Hz, 2 H), 3.21 (s, 3 H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#N.[H-].C([Al+]CC(C)C)C(C)C.CC[O:26]CC.Cl>ClCCl.CCCCCC>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:26]
Reactant: N#Cc1cc(C(F)(F)F)ccc1Br
Reactant: CCOCC
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCCCCC
Solvent: ClCCl
Product: O=Cc1cc(C(F)(F)F)ccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromo-5-(trifluoromethyl)benzonitrile (10.0 g, 40 mmol) in dichloromethane (100 mL) was dropwise added a 1.0 M solution of diisobutylaluminum hydride in hexane (48 mL). The resulting solution was stirred under nitrogen at ambient temperature for 1 h and was then diluted by addition of ether (100 mL). After cooling in an ice bath, a 3 N solution of HCl was carefully added, and the mixture was vigorously stirred at ambient temperature for 15 min. The organic layer was washed with brine, dried (MgSO4) and evaporated. The resulting oil was purified by flash chromatography (5% EtOAc/hexane) affording 5 g of 2-bromo-5-trifluoromethylbenzaldehyde. 1H NMR (CDCl3) δ 10.39 (s, 1H), 8.18 (d, J=2 Hz, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.70 (dd, J=8.5 Hz, 2 Hz, 1H).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:9]2=[O:24])(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>C(#N)C>[O:15]=[C:11]1[C:12]2[C:8](=[CH:7][C:6]([N:5]([CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[S:2]([CH3:1])(=[O:3])=[O:4])=[CH:14][CH:13]=2)[C:9](=[O:24])[N:10]1[CH2:16][C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18]
Reactant: ClCCN1CCCCC1
Reactant: CC(C)(C)OC(=O)CN1C(=O)c2ccc(NS(C)(=O)=O)cc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN1C(=O)c2ccc(N(CCN3CCCCC3)S(C)(=O)=O)cc2C1=O
Temperature: 90 °C
Yield: 86 %

Procedure:
To a stirred solution of tert-butyl 2-(5-(methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (prepared in an analogous manner as previously described in Example 34, Scheme 34, Steps 1, 2, 3) (400 mg, 1.129 mmol) in acetonitrile (10 ml), potassium carbonate (312 mg, 2.257 mmol), and 1-(2-chloroethyl)piperidine hydrochloride (249 mg, 1.354 mmol) were added. The reaction was heated at 90° C. under microwave irradiation for 2 hours. The solid inorganic salts were filtered off and the filtrate was evaporated to dryness. The resulting crude was crystallized from EtOH affording tert-butyl 2-(1,3-dioxo-5-(N-(2-(piperidin-1-yl)ethyl)methylsulfonamido)isoindolin-2-yl)acetate (450 mg, 0.967 mmol, 86% yield, MS/ESI+ 465.9 [MH]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][NH2:12].C(N(C(C)C)C(C)C)C.[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][NH:12][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)C(=O)Cl
Reactant: NNc1ccc([N+](=O)[O-])cc1Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)NNc1ccc([N+](=O)[O-])cc1Cl
Temperature: 0 °C
Yield: 89.9 %

Procedure:
To a stirred and chilled (0° C.) solution containing 25 g (0.133 mol) of 2-chloro-4-nitrophenylhydrazine and 18.06 g (0.14 mol) of ethyldiisopropylamine in 200 ml of tetrahydrofuran was added dropwise 16.75 g (0.139 mol) of pivaloyl chloride. The reaction mixture was briefly heated to reflux and then concentrated under reduced pressure. The residue was treated with water, filtered and dried to give 32.5 g (90% yield) of the desired product as a yellowish solid; m.p. 123° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([Cl:14])[N:13]=1)[C:5](N(OC)C)=[O:6].[CH3:15][Li]>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[CH3:15])[CH:11]=[C:12]([Cl:14])[N:13]=1
Reactant: CON(C)C(=O)c1cc(Cl)nc(Cl)c1
Reactant: [Li]C
Solvent: CCOCC
Product: CC(=O)c1cc(Cl)nc(Cl)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
2,6-Dichloro-N-methoxy-N-methylisonicotinamide (Intermediate 47, 780 mg, 3.3 mmol) in anhydrous diethylether (13 ml) was cooled to −78° C. Methyllithium (1.6 M solution in diethyl ether (5.2 ml, 8.3 mmol) was added dropwise. The mixture was stirred at −78° C. for 1 h and quenched with ammonium chloride solution, followed by warming to room temperature. The reaction mixture was diluted with water (20 ml) and extracted with diethyl ether (2×30 ml), dried over sodium sulphate and concentrated in vacuo to give the title compound (575 mg).
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].C(N(CC)CC)C.[CH2:12]([O:19][C:20](Cl)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[C:13]1([CH2:12][O:19][C:20]([NH:4][CH2:1][CH:2]=[CH2:3])=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C=CCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCNC(=O)OCc1ccccc1
Temperature: -5 °C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
Into a 250 mL single neck flask were placed allylamine (5 mL, 66.6 mmol) and triethylamine (11.1 mL, 80 mmol) in methylene chloride (80 mL). The mixture was cooled to −5° C. before being treated with benzylchloroformate (10 mL, 70 mmol) gradually. The reaction mixture was warmed up to RT while stirring overnight. The product was extracted with EtOAc and the organic layer was separated and washed twice with H2O, dried over anhydrous Na2SO4, filtered, and concentrated under reduced vacuum. The resulting oil was further purified via flash chromatography (Silica gel, isocratic) and eluting with a solvent of Hexanes/EtOAc 20% to provide the intermediate title compound, (phenylmethoxy)-N-prop-2-enylcarboxamide, (8.7 g, 68%) as oil. Electron spray M.S. 192 (M*+1).