Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3][CH2:2]1.C([O:14][C:15]([C:17]1[CH2:18][N:19]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])[C:20]2[C:25]([CH:26]=1)=[CH:24][C:23]([F:27])=[C:22](Cl)[N:21]=2)=[O:16])C>N1C=CC=CC=1>[O:1]1[C:6]2([CH2:11][CH2:10][N:9]([C:22]3[N:21]=[C:20]4[C:25]([CH:26]=[C:17]([C:15]([OH:16])=[O:14])[CH2:18][N:19]4[C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=4[F:36])=[CH:24][C:23]=3[F:27])[CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1COC2(CCNCC2)OC1
Reactant: CCOC(=O)C1=Cc2cc(F)c(Cl)nc2N(c2ccc(F)cc2F)C1
Solvent: c1ccncc1
Product: O=C(O)C1=Cc2cc(F)c(N3CCC4(CC3)OCCCO4)nc2N(c2ccc(F)cc2F)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 96 %

Procedure:
In a reaction similar to that of Step 1, Example 387, into oven-dried glassware maintained under dry N2 were placed 0.622 g (3.96 mmol) of 1,5-dioxa-9-azaspiro[5.5]undecane, from Step 4 Example 196, 0.500 g (1.3 mmol) of 7-chloro-6-fluoro-1-(2,4-difluorophenyl)-1,8-naphthyridine-3-carboxylic acid ethyl ester, and 15 mL of dry pyridine. The reaction was stirred at room temperature for 5 hours, then the solvent was removed by evaporation. The residue was dissolved in 50 mL of methylene chloride, which was washed with 50 mL of 5% sodium bicarbonate and 50 mL of water, dried over anhydrous sodium sulfate, filtered and dried. The product was purified by recrystallization from ethanol/water, isolated by filtration and dried under vacuum to afford 0.576 g of the title compound, mp 177°-178° C., MS (DCl/NH3) M/Z 504 (M+H) (base). Analysis calculated for C25H24F3N3O5 : C, 59.64; H, 4.80; N, 8.35. Found: C, 61.13; H, 5.09; N, 8.36.
Reaction SMILES: C([NH:4][CH:5]([C:12]1[NH:16][C:15]2[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:14]=2[N:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=O)C.Cl>C(O)C>[Cl:21][C:19]1[CH:18]=[CH:17][C:15]2[NH:16][C:12]([CH:5]([NH2:4])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[N:13][C:14]=2[CH:20]=1
Reactant: CC(=O)NC(c1ccccc1)c1nc2cc(Cl)ccc2[nH]1
Agent: Cl
Solvent: CCO
Product: NC(c1ccccc1)c1nc2cc(Cl)ccc2[nH]1
Temperature: 50 °C

Procedure:
1.34 g (4.47 mmol) N-acetyl-1-(5-chloro-1H-benzimidazol-2-yl)-1-phenyl-methylamine in 9 ml of ethanol are combined with 18 ml of conc. hydrochloric acid and heated to 50° C. for 2 days. The reaction mixture is evaporated down i. vac. and twice taken up in ethanol and evaporated down again.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[CH:15]([C:20]([C:22]1[N:26]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[N:25]=[C:24]([C:35]([F:38])([F:37])[F:36])[CH:23]=1)=[O:21])C(OC)=O.S(O)(O)(=O)=O>CO>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[CH2:15][C:20]([C:22]1[N:26]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[N:25]=[C:24]([C:35]([F:38])([F:37])[F:36])[CH:23]=1)=[O:21]
Reactant: COC(=O)C(C(=O)c1cc(C(F)(F)F)nn1-c1ccc(OC)cc1)c1ccc(-n2ccccc2=O)cc1F
Agent: O=S(=O)(O)O
Solvent: CO
Product: COc1ccc(-n2nc(C(F)(F)F)cc2C(=O)Cc2ccc(-n3ccccc3=O)cc2F)cc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 51.9 %

Procedure:
Part A. To methyl 2-[2-fluoro-4-(2-oxo-1(2H)-pyridinyl)phenyl]-3-[1-(4-methoxyphenyl)-3-(trifluoro-methyl)-1H-pyrazol-5-yl]-3-oxopropanoate (Part H, Example 71) (24 mg, 0.045 mmol) was added methyl alcohol (2.3 mL) and concentrated aqueous dihydrogen sulfate (0.048 mL). The reaction was then warmed to reflux. After 48 h, monitoring by LC/MS (C18 reverse phase, eluted with 0.05% TFA in acetonitrile/water) showed 90% of starting material remaining. An additional 0.80 ml-portion of 4M aqueous dihydrogen sulfate was added, and the reaction was maintained under reflux conditions for 6 h. The reaction was cooled to 0° C., and the resulting white precipitate was filtered to afford 1-(3-fluoro-4-{2-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-yl]-2-oxoethyl}phenyl)-2 (1H)-pyridinone (11 mg, 52%) as a white solid. LC/MS (ESI+): 472.1 (M+H)+. 1H NMR (enol form) (CD3OD) δ 7.70 (s, 1H), 7.60 (m, 2H), 7.43 (t, 1H), 7.28 (m, 3H), 7.20 (m, 1H), 6.98 (m, 2H), 6.62 (d, 1H), 6.44 (t, 1H), 4.42 (s 0.5H), 4.39 (br s, 0.5H), 3.81 (s, 3H).
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[NH:32]1[CH:36]=[C:35]([CH:37]=O)[N:34]=[CH:33]1.CC(O)=O>ClCCCl>[CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH2:37][C:35]4[N:34]=[CH:33][NH:32][CH:36]=4)[CH2:28][CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:6])=[O:7])[CH2:2][CH2:3]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCNCC3)co2)C2CC2)c(C)c1
Reactant: O=Cc1c[nH]cn1
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCN(Cc4c[nH]cn4)CC3)co2)C2CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-cyclopropyl-4-methoxy-2,6-dimethyl-N-{[4-(piperazin-1-ylcarbonyl)-1,3-oxazol-2-yl]methyl}benzenesulfonamide (30 mg, 0.07 mmol) in DCE (2 mL) were added 1-H-imidazole-4-carboxaldehyde (8 mg, 0.08 mmol) and AcOH (3 μL, 0.07 mmol) and the reaction mixture was stirred for 1 h at ambient temperature. STAB (20 mg, 0.09 mmol) was added and the reaction was stirred for 16 h. The reaction mixture was quenched with H2O (2 mL) and extracted with DCM (3×2 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep method D to afford the title compound.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12].[C:16]1([C:22]2[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=2[C:24](Cl)=[O:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>ClCCl>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([NH:12][C:24]([C:23]2[C:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:25])[CH:13]=[CH:14][CH:15]=1
Reactant: COc1cccc(N)c1
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cccc(NC(=O)c2ccccc2-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 103.4 %

Procedure:
Pyridine (3.6 mL, 45 mmol) and 3-methoxyaniline (1.54 g, 12.5 mmol) were added to a solution of 2-phenylbenzoyl chloride (3.25 g, 15 mmol) in dichloromethane (30 mL) The reaction mixture was stirred at room temperature for 2.5 hours. 1M HCl solution (45 mL) was added, and the organic layer was washed with 1M NaOH solution (10 mL), aqueous sodium bicarbonate (30 mL), and brine (30 mL). The organic phase was concentrated to dryness to give the title compound as a tan solid (3.92 g). MH+304: 1H (D6-DMSO) δ 3.67 (3H, s), 6.60 (1H, dd, J=8, 2), 7.04 (1H, d, J=8), 7.14 (1H, t, J=8), 7.18 (1H, m), 7.23-7.57 (9H, m), 10.0 (1H, s, NH).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[NH:26][C:25]4[C:24](=[O:27])[N:23]([CH2:28][CH2:29][CH3:30])[C:22](=[O:31])[N:21]([CH2:32][CH2:33][CH3:34])[C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:7][NH:6]1)=[O:4].[F:35][C:36]([F:46])([F:45])[C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=1)[CH2:40]Br.O>C(Cl)Cl>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[NH:26][C:25]4[C:24](=[O:27])[N:23]([CH2:28][CH2:29][CH3:30])[C:22](=[O:31])[N:21]([CH2:32][CH2:33][CH3:34])[C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:7][N:6]1[CH2:40][C:39]1[CH:42]=[CH:43][CH:44]=[C:37]([C:36]([F:35])([F:45])[F:46])[CH:38]=1)=[O:4]
Reactant: CCCn1c(=O)c2[nH]c(-c3ccc(OCC4CNC(C(=O)OC)C4)cc3)nc2n(CCC)c1=O
Reactant: FC(F)(F)c1cccc(CBr)c1
Solvent: ClCCl
Solvent: O
Product: CCCn1c(=O)c2[nH]c(-c3ccc(OCC4CC(C(=O)OC)N(Cc5cccc(C(F)(F)F)c5)C4)cc3)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-phenoxymethyl]-pyrrolidine-2-carboxylic acid methyl ester (50 mg, 0.106 mmol) and TEA (32 mg, 0.319 mmol) in DCM (5 ml), 3-trifluoro methyl benzyl bromide (30 mg, 0.127 mmol) was added at 0° C. Reaction mixture was stirred at room temperature for 4 hr. Water was added into it and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under vacuum to offer 4-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-phenoxymethyl]-1-(3-trifluoromethyl-benzyl)-pyrrolidine-2-carboxylic acid methyl ester as an off white solid (25 mg, 37%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[C:1]1([O:7][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: OCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: OCCCCCCCOc1ccccc1
Temperature: 25 °C
Yield: 101.6 %

Procedure:
Phenol (0.098 g, 1.04 mmol) and 7-bromo-1-heptanol (0.243 g, 1.246 mmol) were dissolved in acetone (25 mL) in a 50 mL round bottomed flask. Potassium carbonate (0.86 g, 6.23 mmol) was added to this solution and the flask was fitted with a condenser and refluxed using an oil bath at 70° C. for a period of 26 hours. The reaction flask was then cooled to room temperature. The contents of the flask was then filtered through a fluted filter paper and washed with acetone (10 mL). The combined filtrate was then evaporated to dryness under reduced pressure. The residue obtained was dissolved in ethyl acetate (25 mL). The ethyl acetate solution was then washed with 1N. NaOH (3×5 mL), water (2×5 mL) and brine (2×5 mL). The organic layer was dried over Na2SO4. Removal of solvent from the dried extract under reduced pressure afforded the product. The product was then purified by flash chromatography (Si gel, 12×2.5 cm) using ethyl acetate: hexane (1:1) to afford the pure 7-(phenyloxy)-1-heptanol (0.22 g, quantitative yield). The product alcohol from step A was analyzed yielding the following confirmatory data: 1H-NMR (CDCl3) δ 1.31-1.52 (m, 6H), 1.52-1.63 (m, 2H), 1.73-1.89 (m, 2H), 1.97 (bs, 1H), 3.61 (t, 2H, J=6.57 Hz), 3.93 (t, 2H, J=6.50 Hz), 6.80-6.97 (m, 3H) and 7.20-7.28 (m, 2H); 13C-NMR (CDCl3) δ 25.5, 25.8, 29.0, 29.1, 32.4, 62.5, 67.7, 114.3, 120.3, 129.2 and 158.8; IR (neat): 3348 cm−1; MS (ES+): 209 (M+1).
Reaction SMILES: [N+](=[CH2:3])=[N-].[N+:4]([C:7]1[CH:37]=[CH:36][C:10]([CH2:11][O:12][C:13]([C:15]2[N:20]3[C:21](=[O:34])[C@@H:22]([NH:23][C:24](=[O:33])[CH2:25][O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C@H:19]3[S:18][CH2:17][C:16]=2[OH:35])=[O:14])=[CH:9][CH:8]=1)([O-:6])=[O:5]>C(Cl)(Cl)Cl>[N+:4]([C:7]1[CH:8]=[CH:9][C:10]([CH2:11][O:12][C:13]([C:15]2[N:20]3[C:21](=[O:34])[C@@H:22]([NH:23][C:24](=[O:33])[CH2:25][O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C@H:19]3[S:18][CH2:17][C:16]=2[O:35][CH3:3])=[O:14])=[CH:36][CH:37]=1)([O-:6])=[O:5]
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Reactant: C=[N+]=[N-]
Solvent: ClC(Cl)Cl
Product: COC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3 ml of an ethereal diazomethane solution (0.5 molar, 1.5 equivalents) are added in the course of about 10 minutes to a solution, cooled to 0° C., of 485 mg of 7β-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester in 10 ml of dry chloroform. The pale yellow solution is stirred for 1 hour at 0° C., flushed with nitrogen in order to remove excess diazomethane and concentrated in vacuo. The residue is recrystallised from methylene chloride and gives 7β-phenoxyacetamido-3-methoxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester of melting point 140.5°-142° C.
Reaction SMILES: [CH:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:19]=[C:18]([O:20][CH:21]3[CH2:38][CH:37]4[CH:23]([C:24](=[O:44])[N:25]([CH3:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH:32]5[C:34]([C:40](O)=[O:41])([NH:35][C:36]4=[O:39])[CH2:33]5)[CH2:22]3)[C:17]3[C:12](=[CH:13][C:14]([O:45][CH3:46])=[CH:15][CH:16]=3)[N:11]=2)[N:9]=1)([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.[CH:58]1([S:61]([NH2:64])(=[O:63])=[O:62])[CH2:60][CH2:59]1.C1CCN2C(=NCCC2)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:19]=[C:18]([O:20][CH:21]3[CH2:38][CH:37]4[CH:23]([C:24](=[O:44])[N:25]([CH3:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH:32]5[C:34]([C:40]([NH:64][S:61]([CH:58]6[CH2:60][CH2:59]6)(=[O:63])=[O:62])=[O:41])([NH:35][C:36]4=[O:39])[CH2:33]5)[CH2:22]3)[C:17]3[C:16](=[CH:15][C:14]([O:45][CH3:46])=[CH:13][CH:12]=3)[N:11]=2)[N:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3csc(NC(C)C)n3)nc2c1
Reactant: NS(=O)(=O)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3csc(NC(C)C)n3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5 %

Procedure:
The acid 110 (20 mg, 0.15 mmol), DMAP (28 mg, 0.225 mmol) and EDAC (58 mg, 0.3 mmol) was dissolved in DMF (1.5 mL). The reaction mixture was stirred overnight at R.T. whereafter cyclopropylsulphonamide (91 mg, 1.125 mmol) and DBU (114 μL, 0.75 mmol) was added. After stirring at RT overnight the reaction mixture was added to 5% citric acid and extracted three times with chloroform. The organic phase was dried over sodium sulphate and evaporated. The afforded residue was purified by preparative HPLC to give the title product (5.6 mg) (yield 24%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([Cl:16])[N:3]=1.Cl.[NH:18]1[CH2:23][CH2:22][CH:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:20][CH2:19]1.C(N(CC)CC)C>C(O)CCC>[ClH:16].[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:18]2[CH2:23][CH2:22][CH:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:20][CH2:19]2)[N:3]=1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: O=C(O)CC1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: COc1cc2nc(N3CCC(CC(=O)O)CC3)nc(N)c2cc1OC
Yield: 74.3 %

Procedure:
4-Amino-2-chloro-6,7-dimethoxyquinazoline (17.3 g), piperidine-4-acetic acid hydrochloride (12.0 g) and triethylamine (20 ml) in n-butanol (500 ml) were stirred under reflux for 20 hours. The mixture was then cooled to 0°-4° and the separated product collected. The solid was slurried with acetone (100 ml), filtered, slurried with chloroform (100 ml), filtered and washed with ether to give 4-amino-2-(4-carboxymethylpiperidino)-6,7-dimethoxyquinazoline hydrochloride (19.0 g). A sample was recrystallised from acetic acid and had an m.p. of 250°-252°.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][NH:23][CH2:24][CH2:25][C:26]#[N:27])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=[O:29].[K+].[K+].OO>CS(C)=O>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][NH:23][CH2:24][CH2:25][C:26]([NH2:27])=[O:29])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(CNCCC#N)ccc3c2)CC1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(CNCCC(N)=O)ccc3c2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)propanenitrile (233 mg, 0.64 mmol) in DMSO (2 mL) was added K2CO3 (265 mg, 2 mmol, 3.0 eq), the mixture was then cooled to 0° C., and followed by addition of aq. 30% H2O2 (0.3 mL). The reaction mixture was stirred at rt for 1 h, and quenched with water (10 mL). The solvent was removed by freeze n-dried. The crude product was purified by flash chromatography to give the title compound as a white solid (111 mg, 45%) (mobile phase: MeOH/H2O: 0%˜80%). ESI-MS (M+1)+: 383.3. HPLC: 97.84%. 1H NMR (400 MHz, CD3OD) δ: 7.86˜7.79 (m, 3H), 7.53˜7.50 (m, 1H), 7.33˜7.30 (m, 1H), 7.21˜7.16 (m, 1H), 4.42˜4.35 (m, 3H), 3.34˜3.27 (m, 2H), 2.71 (t, 2H), 2.32˜2.24 (m, 2H), 1.96˜1.87 (m, 2H), 1.51˜1.39 (m, 2H), 1.33˜1.20 (m, 2H), 1.17˜1.09 (m, 1H), 0.92 (s, 9H).
Reaction SMILES: [N+:1]([O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=O)([O-:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)[Cl:12].[Cl-]>C(Cl)Cl>[N+:1]([O:4][CH2:5][CH2:6][CH2:7][C:8]([Cl:12])=[O:10])([O-:3])=[O:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(O)CCCO[N+](=O)[O-]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(Cl)CCCO[N+](=O)[O-]
Temperature: 25 °C

Procedure:
In a three neck flask kept under argon and containing 90 ml of CH2Cl2, 4-nitrooxybutanoic acid (800 mg, 5.3 mmol) prepared as described above was charged. Then PCl5 was added in one portion (1.25 g, 6.0 mmol) and the resulting mixture was stirred at room temperature. The reaction was checked by IR spectroscopy. After ca. 2 hours stirrer was removed and the reaction mixture was distilled under vacuum. The crude chloride (900 mg, 5.4 mmol) was used in the further steps without purification.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])[CH2:3]1.[OH-].[Na+].[N:14]#[C:15]Cl>C(Cl)Cl.O>[C:15]([N:5]1[C:4]([CH3:11])([CH3:10])[CH2:3][CH:2]([OH:1])[CH2:7][C:6]1([CH3:9])[CH3:8])#[N:14]
Reactant: CC1(C)CC(O)CC(C)(C)N1
Reactant: N#CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC1(C)CC(O)CC(C)(C)N1C#N

Procedure:
62.8 g (0.4 mole) of 4-hydroxy-2,2,6,6-tetramethyl piperidine are dissolved in 250 ml of methylene chloride a solution of 16 g (0.4 mole) of sodium hydroxide in 250 ml of water is introduced and 20.5 ml of cyanogen chloride are added dropwise to the mixture at 0° to 5° C. The mixture is stirred until it reaches room temperature, after which the organic phase is separated off, dried with sodium sulphate, filtered and the methylene chloride distilled off, leaving 31 g (42.5% of the theoretical) of 1-cyano-4-hydroxy-2,2,6,6-tetramethyl piperidine. Bp 0.5 = 135° C; melting point 96°-98° C.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1.[O:29]1[C:34]2[CH:35]=[C:36](/[CH:39]=[CH:40]/[C:41](O)=[O:42])[CH:37]=[CH:38][C:33]=2[O:32][CH2:31][CH2:30]1>>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:24][CH2:25][N:26]([C:41](=[O:42])/[CH:40]=[CH:39]/[C:36]4[CH:37]=[CH:38][C:33]5[O:32][CH2:31][CH2:30][O:29][C:34]=5[CH:35]=4)[CH2:27][CH2:28]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1
Reactant: O=C(O)/C=C/c1ccc2c(c1)OCCO2
Reactant: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCNCC1
Agent: Cl
Product: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCN(C(=O)/C=C/c2ccc3c(c2)OCCO3)CC1

Procedure:
The title compound was prepared from the product of Example 1, step J, and trans-3-(2,3-dihydro-1,4-benzodioxin-7-yl)prop-2-enoic acid, by the method of Example 1, step K, giving a solid that was mostly the more polar cyclohexyl diastereomers by LCMS. Mass spectrum (LCMS, ESI pos.) calcd. for C32H38N4O4: 543 (M+H). Found: 543
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([O:14]CC2C=CC=C(C#N)C=2)[C@H:9]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=O)(C)(C)C.[BH4-].[Na+].[CH3:32]O>>[OH:14][CH:10]1[CH2:11][CH2:12][CH2:13][NH:8][C:9]1([CH3:32])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](OCc2cccc(C#N)c2)[C@H]1c1ccccc1
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: CC1(c2ccccc2)NCCCC1O
Reaction time: 0.5 h

Procedure:
The ketone of (a) above (3.2 g) was suspended in methanol under nitrogen and the temperature brought to -40° C. Sodium borohydride (0.3 g) was added portionwise. The mixture was stirred for 30 min and then concentrated in vacuo, azeotroping with tetrahydrofuran. Borane tetrahydrofuran complex (64 ml, 1.0M in tetrahydrofuran) was added and the mixture was heated at reflux overnight. The mixture was cooled and quenched carefully with methanol, and the mixture was then concentrated in vacuo. The resulting residue was dissolved in ethanol (100 ml) and potassium carbonate (4.2 g) was added. The mixture was heated at reflux for 12 h. The mixture was cooled and evaporated and the residue was extracted with ethyl acetate and water. The organic extract was washed with brine, dried (MgSO4) and evaporated to afford 3-hydroxy-2-methyl-2-phenylpiperidine as a white solid. 1H NMR (360 MHz, CDCl3) δ7.79 (2H, d, ArH), 7.40 (2H, t, ArH), 7.15-7.19 (1H, m, ArH), 3.89 (1H, mc), 2.89-3.01 (2H, m), 1.67-1.91 (4H, m), 1.39 (3H, s, CH3).
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.[CH3:25][NH:26][CH:27]1[CH2:31][CH2:30][NH:29][CH2:28]1>>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([N:29]4[CH2:30][CH2:31][CH:27]([NH:26][CH3:25])[CH2:28]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: CNC1CCNC1
Product: CNC1CCN(c2ccc3c(C(=O)NCC4CCC(F)(F)CC4)c(Cl)ccc3n2)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, and methyl-pyrrolidin-3-yl-amine. 1H NMR (400 MHz, DMSO-d6): δ 8.73-8.76 (m, 1H), 7.70-7.73 (m, 1H), 7.48-7.54 (m, 2H), 6.94-6.96 (m, 1H), 3.53-3.56 (m, 3H), 3.22-3.29 (m, 4H), 2.31-2.34 (m, 5H), 2.01-2.13 (m, 3H), 1.73-1.86 (m, 6H), 1.23-1.32 (m, 2H). m/z: 458.2 [M+H]+
Reaction SMILES: [N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[NH:3][C:2]=1[C:10]1[C:18]2[N:17]3[CH:19]=[CH:20][CH:21]=[C:16]3[CH:15]([NH2:22])[C:14]=2[CH:13]=[CH:12][CH:11]=1.[Cl:23][C:24]1[CH:25]=[C:26]([C:33](O)=[O:34])[C:27]2[CH:32]=[CH:31][NH:30][C:28]=2[N:29]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[NH:3][C:2]=1[C:10]1[C:18]2[N:17]3[CH:19]=[CH:20][CH:21]=[C:16]3[CH:15]([NH:22][C:33]([C:26]3[C:27]4[CH:32]=[CH:31][NH:30][C:28]=4[N:29]=[C:24]([Cl:23])[CH:25]=3)=[O:34])[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: NC1c2cccc(-c3nc4ccncc4[nH]3)c2-n2cccc21
Reactant: O=C(O)c1cc(Cl)nc2[nH]ccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(NC1c2cccc(-c3nc4ccncc4[nH]3)c2-n2cccc21)c1cc(Cl)nc2[nH]ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 9.8 %

Procedure:
In a 100 ml round-bottomed flask, a mixture of 69 mg of 5-(3H-imidazo[4,5-c]pyridin-2-yl)-9H-pyrrolo[1,2-a]indol-9-ylamine obtained according to stage 4 of Example 3, 48 mg of 6-chloro-1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid obtained according to the preceding stage, 51 mg of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI) and 36 mg of 1-hydroxybenzotriazole (HOBt) in 5 ml of dimethylformamide is stirred for 3 hours under argon at ambient temperature. The reaction medium is evaporated to dryness under vacuum and the residue is chromatographed on silica gel (15-40 μm), elution being carried out with a gradient of methanol (4% to 6% v/v) in dichloromethane. The valuable fractions are combined and evaporated to dryness under vacuum, the residue is triturated from a solution of sodium bicarbonate and filtered, and the solid is washed with water. The precipitate is dissolved in methanol and the solvent is evaporated to dryness under vacuum. 11 mg of 6-chloro-1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid [5-(3H-imidazo[4,5-c]pyridin-2-yl)-9H-pyrrolo[1,2-a]indol-9-yl]amide are obtained in the form of a solid, the characteristics of which are the following: