Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:38])[C:4]([CH3:37])([CH3:36])[CH2:5][NH:6][C:7]([C:9]1[C:10]([OH:35])=[C:11]2[C:16](=[C:17]([C:19]#[N:20])[N:18]=1)[N:15]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:14](=[O:28])[C:13]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:12]2)=[O:8].[OH-].[Na+].Cl>CO>[CH2:21]([N:15]1[C:16]2[C:11](=[C:10]([OH:35])[C:9]([C:7]([NH:6][CH2:5][C:4]([CH3:37])([CH3:36])[C:3]([OH:38])=[O:2])=[O:8])=[N:18][C:17]=2[C:19]#[N:20])[CH:12]=[C:13]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:14]1=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(CNC(=O)c1nc(C#N)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.4 %

Procedure:
A mixture of 3-[(1-benzyl-8-cyano-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carbonyl)-amino]-2,2-dimethyl-propionic acid methyl ester (50 mg, 0.098 mmol), 2M NaOH (3 mL) and MeOH (3 mL) was stirred at r.t. for 1 h. 1M HCl was added to acidify the mixture, and the resulting suspension was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The crude product was chromatographed (0-30% EtOAc/hexanes+2% AcOH) to give 26 mg of the title compound. MS: (+) m/z 497.15 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:16][N:17]1[C:21]2=[N:22][CH:23]=[C:24]([CH:26]=[CH2:27])[CH:25]=[C:20]2[CH:19]=[CH:18]1.[OH-].[K+]>CN1C(=O)CCC1>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:27][CH2:26][C:24]3[CH:25]=[C:20]4[CH:19]=[CH:18][N:17]([CH3:16])[C:21]4=[N:22][CH:23]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: C=Cc1cnc2c(ccn2C)c1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2cnc3c(ccn3C)c2)CCN(C)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, 1-methyl-5-vinyl-1H-pyrrolo[2,3-b]pyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:50]=[CH:49][C:6]([CH2:7][N:8]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([OH:36])=O)=[CH:32][C:31]=5[F:39])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[NH2:51][CH2:52][C:53]1[CH:58]=[CH:57][N:56]=[CH:55][CH:54]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([NH:51][CH2:52][C:53]6[CH:58]=[CH:57][N:56]=[CH:55][CH:54]=6)=[O:36])=[CH:32][C:31]=5[F:39])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:49][CH:50]=1
Reactant: NCc1ccncc1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3F)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)NCc4ccncc4)cc3F)cn2)cc1
Yield: 147.9 %

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-fluoro-benzoic acid (80.0 mg, 0.118 mmol) obtained in Step A in Example 1-D-21 and 4-(aminomethyl)pyridine (24.0 μl, 0.236 mmol) instead of 1-pyridine-3-yl-piperazine, amidation was carried out in the same manner as Step B in Example 1-D-21, to obtain a crude product of 4-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-3-fluoro-N-pyridin-4-ylmethyl-benzamide as a yellow solid (134 mg), and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-271) as a yellow powder (49.4 mg, 79%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:3]=1[CH2:21][C:22]([O:24][CH3:25])=[O:23].[Li+].[CH3:27][Si]([N-][Si](C)(C)C)(C)C.C1COCC1.C=O>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:3]=1[C:21](=[CH2:27])[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCC3
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C=C(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCC3
Yield: 36 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3yl]acetate (0.386 g; 1.1 mmol), LHMDS 1N in THF (1.21 mL; 1.21 mmol), para-formaldehyde (0.050 g; 1.65 mmol) in DMF (4 mL) for 4 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-100%) in heptane furnished 0.154 g (36%) of the title compound as a light yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:13])([CH3:12])[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([OH:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:21]([NH:29]C1CCNCC1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCOCC1.C(N(CC)CC)C>[OH:14][C:10]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([N:3]2[CH2:4][CH2:9][CH:10]([C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:21]([NH2:29])=[O:28])[CH2:11][CH2:2]2)[C:11]1([CH3:13])[CH3:12]
Reactant: CC1(C)C(Cl)=Nc2ccccc2C1(O)c1ccccc1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC1(C)C(N2CCC(c3ccccc3C(N)=O)CC2)=Nc2ccccc2C1(O)c1ccccc1
Temperature: 80 °C

Procedure:
To a solution of 2-chloro-3,4-dihydro-3,3-dimethyl-4-phenylquinolin-4-ol (1.0g., 0.0035 mole) in dry dioxan (15 ml.) and triethylamine (1 ml.) was added 4-benzamidopiperidine (0.67 g., 0.0035 mole). After heating at 80° C for 41/2 hours, the reaction mixture was cooled, a small amount of solid was filtered off and the filtrate evaporated down to a residue. Trituration with hexane yielded the title compound as the crude free base (m.p. 78° - 81° C). The hydrobromide (1.05g., m.p. 166° - 168° C) was obtained as the monohydrate on crystallisation from isopropyl alcohol. [Found: C, 62.75; H, 6.2; N, 7.3% C29H31N3O2H2O HBr requires: C, 63.0; H, 6.2; N, 7.6%].
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[SH:9].CS(O[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)(=O)=O.C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1
Reactant: Fc1ccc(S)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Sc2ccc(F)cc2F)CC1
Temperature: 80 °C
Yield: 100 %

Procedure:
A mixture of 2,4-difluorobenzenethiol (0.810 mL, 7.15 mmol), tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (1.816 g, 6.5 mmol), and K2CO3 (1.348 g, 9.75 mmol) in ACN (16.25 mL) was heated at 80° C. overnight. The reaction mixture was poured into water and extracted twice with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford tert-butyl 4-((2,4-difluorophenyl)thio)piperidine-1-carboxylate (2.141 g) as a yellow oil, which was carried forward without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([Br:7])[S:4][C:3]=1[C:8]([NH2:10])=[O:9].[CH3:11][C:12]([CH3:14])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[Br:7][C:5]1[S:4][C:3]2[C:8](=[O:9])[NH:10][C:12]([CH3:14])([CH3:11])[NH:1][C:2]=2[CH:6]=1
Reactant: CC(C)=O
Reactant: NC(=O)c1sc(Br)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)NC(=O)c2sc(Br)cc2N1
Temperature: 70 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A mixture of 3-amino-5-bromothiophene-2-carboxamide (0.118 g, 0.530 mmol), acetone (2.0 mL), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (1.0 mL) was stirred for 1 h at 70° C. The mixture was poured into sat. aqueous sodium hydrogen carbonate (100 mL). Extraction with ethyl acetate (70 mL), washing with brine, drying over magnesium sulfate, filtration and concentration at reduced pressure gave the title compound (0.125 g, 90%) as a brown solid:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:35])[C@H:10]([CH3:34])[CH2:11][C@H:12]([NH:26]C(OC(C)(C)C)=O)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:36]>C1COCC1.O1CCOCC1>[ClH:36].[CH2:1]([O:8][C:9](=[O:35])[C@H:10]([CH3:34])[CH2:11][C@H:12]([NH2:26])[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: C[C@H](C[C@H](N)Cc1ccc(-c2ccccc2)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methyl-pentanoic acid (prepared using the procedure described in WO 2008083967)(1.0 g, 2.61 mmol) and benzyl bromide (468 mg, 2.74 mmol) in DMF (15 mL) is added potassium carbonate (541 mg, 3.91 mmol) and the mixture is stirred at room temperature for 2 hours. Water is added and the mixture is extracted with ethyl acetate. The combined organic layers are washed with water and dried over magnesium sulfate. The solvent is removed under reduced pressure and the residual oil is purified by column chromatography using heptane/EtOAc (4:1) to furnish (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methyl-pentanoic acid benzyl ester. Next, to a solution of (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methyl-pentanoic acid benzyl ester in THF (5 mL) is added 4M HCl in dioxane (3 mL) and the solution is stirred at room temperature for 1 hour. The solvent is removed under reduced pressure to give the title compound. MS 374.4 (M+1).
Reaction SMILES: [CH:1]([C@@H:3]1[N:7]([CH3:8])[C:6](=[O:9])[CH2:5][C@@H:4]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:2].C1COCC1.[C:21]1([CH3:29])[CH:26]=[CH:25][CH:24]=[C:23]([Mg]Cl)[CH:22]=1.[NH4+].[Cl-]>O>[OH:2][C@H:1]([C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([CH3:29])[CH:22]=1)[C@@H:3]1[N:7]([CH3:8])[C:6](=[O:9])[CH2:5][C@@H:4]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1C=O
Reactant: Cc1cccc([Mg]Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc([C@@H](O)[C@H]2[C@@H](c3ccccc3)CC(=O)N2C)c1
Reaction time: 1 h
Yield: 69.4 %

Procedure:
To a 0° C. solution of (±)-(4R*,5R*)-5-formyl-1-methyl-4-phenylpyrrolidin-2-one (Intermediate Z, 74 mg, 0.4 mmol) in anhyd. THF (5 mL) was added a solution of m-tolyl magnesium chloride (1M in THF, 0.5 mL, 0.5 mmol, 1.25 equiv). The reaction mixture was stirred for 1 h, then treated with a saturated NH4Cl solution and water. The resulting mixture was extracted with EtOAc, dried (Na2SO4) and concentrated under reduced pressure. The residue was triturated (Et2O/hex) to give (±)-(4R*,5R*)-5-[(1R*)hydroxy(3-methylphenyl)methyl]-1-methyl-4-phenylpyrrolidin-2-one (82 mg, 77%): mp 163-165° C.; TLC (EtOAc) Rf 0.45.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:14]O>>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([O:9][CH3:14])=[O:8]
Reactant: CO
Reactant: O=C(O)[C@H]1CCCCN1
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H]1CCCCN1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To (R)-Piperidine-2-carboxylic acid (5.00 g, 38.73) in 150 ml of dry methanol at 0° C. was added thionyl chloride (5.2 ml, 71.28 mmol) under Ar. The mixture was stirred at 0° C. for 30 min, then at RT overnight, evaporated and crystallized with EtOH/hexane to afford 4.96 g (92%) of the title product. 1H NMR (CD3OD) 3.67 (s, 3H), 3.57 (m, 1H), 2.79 (m, 1H), 2.69 (m, 1H), 2.01 (m, 1H), 1.98 (m, 1H), 1.73 (m, 1H), 1.55-1.45 (m, 4H); 13C NMR 171.22, 62.50, 51.35, 45.35, 29.52, 28.41, 23.82; MS m/z+144.0 (M+H).
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:9]=[C:10]([S:18](Cl)(=[O:20])=[O:19])[C:11]2[N:12]=[CH:13][CH:14]=[N:15][C:16]=2[CH:17]=1>N1C=CC=CC=1.C(Cl)Cl>[Cl:7][C:8]1[CH:9]=[C:10]([S:18]([NH:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:19])=[O:20])[C:11]2[N:12]=[CH:13][CH:14]=[N:15][C:16]=2[CH:17]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc2nccnc12
Reactant: NC1CCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(NC1CCCC1)c1cc(Cl)cc2nccnc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of cyclopentyl amine (0.134 mg, 1.6 mmol) in pyridine (5 ml) was added a solution of 7-chloroquinoxaline-5-sulfonyl chloride (0.26 g, 0.748 mmol, crude) in DCM (5 mL) at 0° C. The reaction was stirred at room temperature for 15 minutes before being partitioned between brine and ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. Purification on silica gel (rf=0.38 in 1:1 hexanes/ethyl acetate) afforded 7-chloro-N-cyclopentylquinoxaline-5-sulfonamide as an off-white powder.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].N1C=CC=CC=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[S:19][CH2:20][C:21]#[N:22]>C1COCC1>[C:21]([CH2:20][S:19][C:13]1[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=1[NH:11][C:1](=[O:3])[CH3:2])#[N:22]
Reactant: CC(=O)Cl
Reactant: N#CCSc1cc(F)ccc1N
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(F)cc1SCC#N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Acetyl chloride (1.9 ml) in THF (10 ml) and subsequently pyridine (2.15 ml) in THF (10 ml) was added to a stirred solution of (2-amino-5-fluoro-phenylsulfanyl)acetonitrile (4.39 g) in THF (40 ml) at 0° C. The mixture was stirred at 0° C. for 1 h. Then the solvent was removed in vacuo and the residue was triturated with water (100 ml). The precipitate was filtered off and dried. Crude yield 4.45 g (82%); mp 97-100° C. The title compound could be further purified by recrystallization from 96% ethanol; mp 100.5-101.5° C.; 1H-NMR (DMSO-d6), δ (ppm): 9.68 (s, 1H, NH), 7.50-7.30 (m, 2H, Ar—H), 7.23-7.07 (m, 1H, Ar—H), 4.26 (s, 2H, CH2), 2.05 (s, 3H, CH3); IR (KBr) ν (cm−1): 3239 (NH), 2244 (C≡N), 1641 and 1579 (amide).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24].C1COCC1.CC(C)([O-])C.[K+]>O>[O:24]=[C:23]1[CH2:22][CH2:21][CH2:20][CH2:19][N:17]1[C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)ccc21
Reactant: O=C(Cl)CCCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2cc(N3CCCCC3=O)ccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 50.1 %

Procedure:
Part H. To tert-butyl-5-amino-1-indolinecarboxylate (1.90 g, 8.2 mmol) was added 5-bromovaleryl chloride (1.4 mL, 9.0 mmol) and 18 mL of THF. After stirring for 5 min at rt under N2, potassium tert-butoxide (9 mL, 9 mmol; 1.0 M in THF) was added in one portion, and the resulting brown solution was stirred under N2 for 30 min. A second portion of potassium tert-butoxide (9 mL) was added, and the resulting brown suspension was stirred for 15 min. An additional 0.10 mL-portion of 5-bromovaleryl chloride and a 4.5 mL-portion of potassium tert-butoxide were added, and the mixture was stirred for 30 min. The reaction was then poured into H2O (80 mL). The aqueous layer was washed with EtOAc (3×50 mL), and the combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated and the resulting residue was purified by radial chromatography (50% EtOAc in hexanes) to afford tert-butyl 5-(2-oxo-1-piperidinyl)-1-indolinecarboxylate as a pink solid (1.30 g, 50%). LRMS (AP+): 317.2 (M+H)+. 1H NMR (CDCl3) δ 7.40-7.80 (br m, 1H), 7.01 (s, 1H), 6.97 (d, 1H), 3.94 (t, 2H), 3.55 (br m, 2H), 3.09 (t, 2H), 2.49 (br m, 2H), 1.91 (br m, 4H), 1.52 (s, 9H).
Reaction SMILES: [CH2:1]([CH:3]([CH:10]([N+:12]([O-:14])=[O:13])[CH3:11])[CH2:4][CH:5]([OH:9])[C:6]([NH2:8])=[O:7])[CH3:2]>C(O)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[CH2:1]([CH:3]([CH:10]([N+:12]([O-:14])=[O:13])[CH3:11])[CH2:4][C:5](=[O:9])[C:6]([NH2:8])=[O:7])[CH3:2]
Reactant: CCC(CC(O)C(N)=O)C(C)[N+](=O)[O-]
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Product: CCC(CC(=O)C(N)=O)C(C)[N+](=O)[O-]
Temperature: 100 °C
Yield: 140.3 %

Procedure:
To a solution of 4-ethyl-2-hydroxy-5-nitrohexanamide (0.036 g) in acetic acid (5 ml) was added chromium trioxide (0.25 g). The resulting mixture was heated at 100° C. for 40 minutes with stirring. After cooling, the mixture was evaporated to dryness. The resulting residue was diluted with water and then extracted with ethyl acetate. The extract was washed successively with water, an aqueous sodium bicarbonate and brine, and then dried over magnesium sulfate. The solvent was removed by distillation to give an oil. The oil was purified by a preparative thin layer chromatography [solvent: methanol-chloroform (5:95)] to give 4-ethyl-5-nitro-2-oxo-hexanamide (50 mg).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]2[O:12][CH2:11][CH2:10][NH:9][CH2:8]2)[N:6]=1.[CH3:13][NH:14][C:15]([CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](=O)[CH3:27])=[CH:21][CH:20]=1)=[O:16]>>[CH3:13][NH:14][C:15]([CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][CH:26]([N:9]2[CH2:10][CH2:11][O:12][CH:7]([C:5]3[N:6]=[C:2]([CH3:1])[S:3][CH:4]=3)[CH2:8]2)[CH3:27])=[CH:23][CH:24]=1)=[O:16]
Reactant: Cc1nc(C2CNCCO2)cs1
Reactant: CNC(=O)COc1ccc(CC(C)=O)cc1
Product: CNC(=O)COc1ccc(CC(C)N2CCOC(c3csc(C)n3)C2)cc1

Procedure:
Prepared by analogy to Example 13 by reaction of 2-(2-methyl-thiazol-4-yl)morpholine with 1-(4-methylaminocarbonylmethoxyphenyl)propan-2-one followed by purification on a silica gel column using ethyl acetate as eluant.
Reaction SMILES: C1C=C(O[C:8](OC2N=CC=CC=2)=[S:9])N=CC=1.CN(C1C=CC=CN=1)C.[NH2:26][C:27]1[CH:42]=[C:41]([F:43])[C:30]2[N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH:32]=[N:33][C:29]=2[C:28]=1[CH3:44]>C(Cl)Cl>[C:37]([O:36][C:34]([N:31]1[C:30]2[C:41]([F:43])=[CH:42][C:27]([N:26]=[C:8]=[S:9])=[C:28]([CH3:44])[C:29]=2[N:33]=[CH:32]1)=[O:35])([CH3:39])([CH3:40])[CH3:38]
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Reactant: Cc1c(N)cc(F)c2c1ncn2C(=O)OC(C)(C)C
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: Cc1c(N=C=S)cc(F)c2c1ncn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of di-2-pyridyl thionocarbonate (0.393 mg) and dimethylaminopyridine (0.01 g) in methylene chloride (100 mL) is added dropwise over 30 minutes a solution of 5-amino-1-tert-butoxycarbonyl-7-fluoro-4-methylbenzimidazole (0.409 g) in methylene chloride (70 mL). The mixture is stirred at room temperature for 3 hours then rotary evaporated. The residue is purified by flash chromatography on silica gel, eluting with 10% ethyl acetate/hexane to afford 1 -tert-butoxycarbonyl-7-fluoro-4-methyl-5-benzimidazolylisothiocyanate as a white solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[CH:28][C:27]=1[O:35][CH3:36].CCN(C(C)C)C(C)C.[CH3:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>CN(C=O)C>[NH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([N:50]2[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][CH2:49]2)=[O:32])=[CH:28][C:27]=1[O:35][CH3:36]
Reactant: CN1CCNCC1
Reactant: COc1cc(C(=O)O)ccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N2CCN(C)CC2)ccc1N
Reaction time: 18 h
Yield: 31.2 %

Procedure:
HATU (1179 mg, 3.10 mmol) was added to a solution of 4-amino-3-methoxybenzoic acid (461 mg, 2.76 mmol), DIPEA (1.24 mL, 7.12 mmol) and 1-methylpiperazine (230 mg, 2.30 mmol) in DMF (12 mL) and the reaction mixture was stirred for 18 hours. The reaction was partitioned between EtOAc and water. The organic phase was washed with saturated aqueous NaHCO3 solution, water, dried over Na2SO4 and concentrated in vacuo. The residue was purified by elution through an SCX-2 column to afford the title compound as brown oil (179 mg, 31%).
Reaction SMILES: [CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[NH:12][C:11]([N+]([O-])=O)=[N:10][C:9]=2[N:8]([CH2:19][CH2:20][CH2:21][CH3:22])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].[BrH:23]>>[CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[NH:12][C:11]([Br:23])=[N:10][C:9]=2[N:8]([CH2:19][CH2:20][CH2:21][CH3:22])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c2[nH]c([N+](=O)[O-])nc2n(CCCC)c1=O
Reactant: Br
Product: CCCCn1c(=O)c2[nH]c(Br)nc2n(CCCC)c1=O

Procedure:
1,3-Di-n-butyl-8-bromo xanthine was prepared from 1,3-di-n-butyl-8-nitro xanthine (0.5 g, 0.0016 mol) and concentrated hydrobromic acid (8 ml) using the procedure as described in Example 15. The title product was obtained after recrystallisation from ethanol, yield 0.4 g (91%), m.pt. 178° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C:4]1[CH:9]=[CH:8][C:7](O)=[C:6]([NH:11][C:12](=[O:33])[C:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:20]([CH3:32])[CH:19]=2)([CH2:16][CH3:17])[CH2:14][CH3:15])[CH:5]=1.S(O)(C1C=CC(C)=CC=1)(=O)=O.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[O:33][C:12]([C:13]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[C:20]([CH3:32])[CH:19]=3)([CH2:16][CH3:17])[CH2:14][CH3:15])=[N:11][C:6]=2[CH:5]=1)=[O:34]
Reactant: CCC(CC)(C(=O)Nc1cc(C(=O)OC)ccc1O)c1ccc(OCc2ccccc2)c(C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(CC)(c1ccc(OCc2ccccc2)c(C)c1)c1nc2cc(C(=O)OC)ccc2o1
Yield: 90.9 %

Procedure:
3-[2-(4-Benzyloxy-3-methyl-phenyl)-2-ethyl-butyrylamino]-4-hydroxy-benzoic acid methyl ester (5.80 g, 12.6 mmol), TsOH—H2O (478 mg, 2.51 mmol) in toluene (100 mL) are reacted analogous to Example 1, step E to give the title product (5.08 g, 91%). MS (ES) m/e: 444.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[C:13]([Cl:14])=[CH:12][C:11]([O:15][CH2:16][CH3:17])=[CH:10][C:9]=1[Cl:18].C(O[C:22](=[NH:24])[CH3:23])C.[C:25]([OH:28])(=[O:27])[CH3:26]>C(#N)C>[C:25]([OH:28])(=[O:27])[CH3:26].[NH:24]=[CH:22][CH2:23][NH:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[C:13]([Cl:14])=[CH:12][C:11]([O:15][CH2:16][CH3:17])=[CH:10][C:9]=1[Cl:18]
Reactant: CCOc1cc(Cl)c(-c2c(C)n[nH]c2N)c(Cl)c1
Reactant: CCOC(C)=N
Solvent: CC#N
Solvent: CC(=O)O
Product: CCOc1cc(Cl)c(-c2c(C)n[nH]c2NCC=N)c(Cl)c1
Reaction time: 8 h

Procedure:
To a solution of 5-amino-4-(4-ethoxy-2,6-dichlorophenyl)-3-methylpyrazole (4.8 g) (prepared from 4-ethoxy-2,6-dichloro benzaldehyde according to Example 1 C-F) in acetonitrile (50 mL) add ethylacetimidate (free base, 2.3 mL) followed by acetic acid (0.96 mL). Collect the precipitate that formed upon stirring overnight by filtration. Wash the solid with dry ether and dry to afford 5.02 g of (iminoethyl)[4-(4-ethoxy-2,6-dichlorophenyl)-3-methylpyrazol−5-yl]amine acetate salt as a white powder.