Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:19]=[C:18]([O:20]CC2C=CC=CC=2)[CH:17]=[CH:16][C:10]=1[C:11](=[NH:15])[O:12][CH2:13][CH3:14])C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[OH:8][C:9]1[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:10]=1[C:11](=[NH:15])[O:12][CH2:13][CH3:14]
Reactant: CCOC(=N)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=N)c1ccc(O)cc1O
Yield: 75 %

Procedure:
2,4-Dibenzyloxybenzoic acid was reacted with oxalyl chloride in toluene and DMF at 0-25° C. to give an acid chloride. The acid chloride was reacted with aqueous ammonia in methylene chloride to yield 87% (over 2 steps) of 2,4-dibenzyloxybenzamide. 2,4-Dibenzyloxybenzamide was reacted with triethyloxonium hexafluorophosphate in methylene chloride to yield 69% of ethyl 2,4-dibenzyloxybenzimidate. The ethyl 2,4-dibenzyloxybenzimidate was hydrogenated over a palladium/carbon catalyst with 1 atmosphere of hydrogen gas in ethanol, to yield 75% of ethyl 2,4-dihydroxybenzimidate. The overall yield for the reaction sequence was 34% for six steps.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][C:8]1[CH:9]=[CH:10][C:11]2[N:15]=[C:14]([N:16]3[CH2:20][CH:19]4[CH2:21][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH:18]4[CH2:17]3)[N:13]([CH2:31][CH:32]=[C:33]([CH3:35])[CH3:34])[C:12]=2[CH:36]=1.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C)C=O>[C:37]([NH:7][C:8]1[CH:9]=[CH:10][C:11]2[N:15]=[C:14]([N:16]3[CH2:17][CH:18]4[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[CH2:21][CH:19]4[CH2:20]3)[N:13]([CH2:31][CH:32]=[C:33]([CH3:35])[CH3:34])[C:12]=2[CH:36]=1)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)=CCn1c(N2CC3CN(C(=O)OC(C)(C)C)CC3C2)nc2ccc(N)cc21
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)=CCn1c(N2CC3CN(C(=O)OC(C)(C)C)CC3C2)nc2ccc(NC(=O)c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22 %

Procedure:
14 mg (0.04 mmol) of cesium carbonate were added to a solution of 35 mg (0.09 mmol) of tert-butyl 5-[6-amino-1-(3-methylbut-2-enyl)-1H-benzimidazol-2-yl]hexahydropyrrolo[3,4-c]pyrrole-2-carboxylate in 5 ml of dimethylformamide, and the mixture was stirred at room temperature for 30 minutes. Subsequently, 10 μl (0.08 mmol) of benzoyl chloride were added and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure and purified by means of preparative HPLC (acetonitrile/water+0.5% trifluoroacetic acid, gradient: 20/80 to 100/0). 10 mg (22% of the desired compound were obtained.
Reaction SMILES: C([O:4][C:5]1[C:6]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Na+].Cl>O.C(O)C>[OH:4][C:5]1[C:6]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)COc1ncccc1OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)COc1ncccc1O
Temperature: 25 °C
Yield: 91.9 %

Procedure:
A mixture of 13.8 g of 3-acetoxy-2-(ethoxycarbonyl)methoxypyridine, 4.38 g of potassium carbonate and 60 ml of ethanol was stirred for over night at room temperature. The reaction solution was poured into a mixture of water, sodium chloride and hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 10.45 g of 3-hydroxy-2-(ethoxycarbonyl)methoxypyridine.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Br:8][C:9]1[C:17]2[C:16]([O:18][CH:19]3[CH2:24][CH2:23][CH2:22][N:21](NC(OC(C)(C)C)=O)[CH2:20]3)=[N:15][CH:14]=[N:13][C:12]=2[O:11][C:10]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl>[Br:8][C:9]1[C:17]2[C:16]([O:18][CH:19]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)=[N:15][CH:14]=[N:13][C:12]=2[O:11][C:10]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)NN1CCCC(Oc2ncnc3oc(-c4ccccc4)c(Br)c23)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Brc1c(-c2ccccc2)oc2ncnc(OC3CCCNC3)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Add a total of 3.4 ml of TFA in several portions at RT to a solution of 1.05 g (2.21 mmol) of tert-butyl rac-3-[(5-bromo-6-phenylfuro[2,3-d]pyrimidin-4-yl)oxy]-1-piperidinecarbamate in 2 ml of dichloromethane, and stir at RT for 2 h. Then dilute with dichloromethane, add satd. sodium hydrogencarbonate solution cautiously to the solution and then wash twice with satd. sodium hydrogencarbonate solution. Dry the organic phase over magnesium sulphate and concentrate under reduced pressure. Stir the oily residue with methanol, filter off the precipitated solid with suction and wash with methanol. Combine mother liquor and wash solution, concentrate under reduced pressure and stir again with a little methanol. Filter off the resulting crystals with suction, wash with methanol and combine with the first crystal fraction. A total of 550 mg (66.4% of theory) of the target compound are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:26][CH2:27][CH2:28][CH2:29][NH:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][CH2:36][CH2:37][CH2:38][NH2:39]>COCCOC.CN(C=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:39][CH2:38][CH2:37][CH2:36][NH:35][CH2:34][CH2:33][CH2:32][CH2:31][NH:30][CH2:29][CH2:28][CH2:27][NH2:26])=[O:8])=[CH:9][CH:10]=1
Reactant: NCCCNCCCCNCCCN
Reactant: O=C(O)c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: COCCOC
Product: NCCCNCCCCNCCCNC(=O)c1ccc(O)cc1
Reaction time: 48 h

Procedure:
According to the General Procedure using 4-hydroxybenzoic acid (80 mg, 0.58 mMol), dicyclohexylcarbodiimide (125 mg, 0.61 mMol), and spermine (430 mg, 2.13 mMol) in DME/DMF (4 ml, 3:1), activation during 3 h and coupling over 48 h. The product was eluted over silica gel with dichloromethane/methanol/0.880 ammonia solution (2:2:1). The desired amide was in fractions 8-12 and was homogeneous when monitored by tic on silica (CH2Cl2 /MeOH/NH4OH, 2:2:1), Rf =0.29, (23 mg, 12%), lyophilisation gave 7 mg of a colourless, viscous oil whose spectroscopic data include: pmr (90 MHz, 2H2O) 1.4-1.9 (m, 8H, 4×CH2 --CH2), 2.5-2.9 (m, 10H, 5×CH2 --N), 3.25 (t, J=7, 2H, CON2H--CH2 --CH2) 6.6-6.9 (m, 2H, 2×ArH 3,5), and 7.0-7.3 (m, 2H, 2×ArH2,6)ppm; M+1 323 (FAB matrix m-nitrobenzyl alcohol) C17H30N4O2 requires M+ 322).
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][C:37]([F:40])([F:39])[F:38])[CH:31]=1)[NH2:25]>C(O)(C)C.C(OCC)(=O)C>[CH3:21][C:22]1[CH:23]=[C:24]([NH:25][C:2]2[C:3]3[N:10]([CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:26]=[CH:27][C:28]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][C:37]([F:38])([F:39])[F:40])[CH:31]=1
Reactant: CC(C)(C)OC(=O)NCCn1ccc2ncnc(Cl)c21
Reactant: Cc1cc(N)ccc1Oc1cccc(OC(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: Cc1cc(Nc2ncnc3ccn(CCNC(=O)OC(C)(C)C)c23)ccc1Oc1cccc(OC(F)(F)F)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 103.5 %

Procedure:
tert-Butyl [2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate (297 mg) and 3-methyl-4-[3-(trifluoromethoxy)phenoxy]aniline (425 mg) were dissolved in isopropyl alcohol (2.97 mL), and the mixture was stirred at 80° C. for 16 hrs. After cooling to room temperature, the mixture was diluted with ethyl acetate (60 mL), and washed with aqueous sodium hydrogen carbonate (30 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→0:100) to give the title compound (563 mg) as a white powder.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][OH:4].[C:14]([O:29][C@H:30]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:31][C:32](O)=[O:33])(=[O:28])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(Cl)CCl.CI>C(Cl)Cl>[CH2:7]([O:6][CH2:5][C@H:2]([NH:1][C:32](=[O:33])[CH2:31][C@H:30]([O:29][C:14](=[O:28])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:3][OH:4])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCCCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)O
Reactant: N[C@H](CO)COCc1ccccc1
Solvent: CI
Solvent: ClCCl
Solvent: ClCCCl
Product: CCCCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)N[C@H](CO)COCc1ccccc1
Yield: 76.4 %

Procedure:
A solution of (R)-2-amino-3-benzyloxy-1-propanol (0.46 g, 2.33 mmol) and (R)-3-tetradecanoyloxytetradecanoic acid (1.29 g, 2.83 mmol) in CH2Cl2 (20 mL) was treated with EDC.MeI (0.78 g, 2.79 mmol) and stirred for 16 h at room temperature. The reaction mixture was filtered through a short pad of Celite® and concentrated. Flash chromatography on silica gel with 45% EtOAc-hexanes afforded 1.1 g (69%) of 3-benzyloxy-(R)-2-[(R)-3-tetradecanoyloxytetradecanoylamino]propanol as a colorless solid: mp 42–44.5° C.; 1H NMR δ 0.88 (t, 6 H, J=˜6.5 Hz), 1.0–1.7 (m, 42 H), 2.50 (t, 2 H, J=7.5 Hz), 2.46 (m, 2 H), 3.56 (br s, 1 H), 3.5–3.75 (m, 3 H), 3.78 (dd, 1 H, J=11, 4 Hz), 4.08 (m, 1 H), 4.51 (s, 2 H), 5.17 (m, 1 H), 6.36 (d, 1 H, J=7.8 Hz), 7.2–7.4 (m, 5 H).
Reaction SMILES: [CH:1](NC(C)C)(C)[CH3:2].C([Li])CCC.[CH3:13][CH:14]1[CH2:18][CH2:17][O:16][C:15]1=[O:19].[Cl-].[NH4+].Cl>O1CCCC1.C(Br)=C>[CH3:13][C:14]1([CH:1]=[CH2:2])[CH2:18][CH2:17][O:16][C:15]1=[O:19]
Reactant: CC1CCOC1=O
Reactant: CC(C)NC(C)C
Agent: C=CBr
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=CC1(C)CCOC1=O
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 42.3 %

Procedure:
A solution of N,N-diisopropylamine (1.68 mL, 0.012 mol) in anhydrous tetrahydrofuran (20 mL) was cooled to −30° C. under a nitrogen atmosphere. A 2.5 M solution of n-butyllithium (4.4 mL, 0.011 mol) in hexanes was added and the reaction was allowed to warm to −10° C. The solution was stirred for 10 minutes before adding 3-methyl-dihydro-furan-2-one (1.0 g, 0.01 mol) in tetrahydrofuran (10 mL). The reaction mixture was stirred at −5° C. for 15 minutes before adding di-μ-bromobis(tri-tert-butylphosphino) dipalladium (I) (93 mg, 0.12 mmol) and vinyl bromide (1 M in tetrahydrofuran, 13 mL, 0.13 mmol). The reaction was allowed to warm to room temperature and was stirred for 2 h. The reaction mixture was then cooled to −10° C. before adding saturated aqueous ammonium chloride solution (20 mL) then hydrochloric acid (2 M) to pH 1. The layers were separated and the aqueous layer was extracted with diethyl ether (20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and evaporated to give an orange gum. The gum was purified by silica gel chromatography eluting with iso-hexanes/diethyl ether 1:1 to yield the title product (0.533 g, 42%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 1.38 (s, 3H), 2.11-2.22 (m, 1H), 2.31-2.41 (m, 1H), 4.20-4.36 (m, 2H), 5.16-5.26 (m, 2H), 5.84-5.96 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.Cl.Cl.[NH2:43][C@@H:44]([CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C@@H:45]([OH:56])[CH2:46][N:47]1[CH2:51][CH2:50][CH2:49][C@H:48]1[C:52]([F:55])([F:54])[F:53].CN1CCOCC1>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([NH:43][C@@H:44]([CH2:57][C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1)[C@@H:45]([OH:56])[CH2:46][N:47]1[CH2:51][CH2:50][CH2:49][C@H:48]1[C:52]([F:55])([F:53])[F:54])=[O:15])[CH:10]([CH3:11])[CH3:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)[C@@H](O)CN1CCC[C@H]1C(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN1CCC[C@H]1C(F)(F)F
Reaction time: 0.08 h

Procedure:
A stirred solution, cooled to 0° C., of 4.81 g (22.13 mmol) of N-(tert-butoxycarbonyl)-L-valine and 3.29 g (24.35 mmol) of HOBT in 40 ml of anhydrous dichloromethane was treated with 5.29 g (25.65 mmol) of DCC and stirred for 5 min. A solution of 3.70 g (20.12 mmol) of the compound from Example 2 and 8.85 ml (80.48 mmol) of N-methylmorpholine in 30 l of dichloromethane was then added dropwise. The cooling bath was removed and the reaction solution was stirred at room temperature for 2 h. The end of the reaction was determined by thin layer chromatography. The resulting urea was removed by filtration, the filtrate was concentrated in vacuo, and the crude product was purified by chromatography on 400 g of silica gel (dichloromethane: methanol). 6.89 g (68% of theory) of the title compound were obtained as a colourless foam. Rf = MS (DCI, NH3): m/e=503 (M+H)+
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1([C:11]#[N:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[NH2:12][CH2:11][C:4]1([OH:3])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: C[Si](C)(C)OC1(C#N)CCCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCC1(O)CCCCCC1
Temperature: 12.5 °C
Reaction time: 3 h
Yield: 76.2 %

Procedure:
A solution of 1-[(trimethylsilyl)oxy]cycloheptanecarbonitrile (737.5 g) in tetrahydrofuran (738 ml) was charged to a vessel containing 1 molar lithium aluminium hydride solution in tetrahydrofuran (4980 ml) and tetrahydrofuran (369 ml) whilst maintaining the temperature at 55° C. to 60° C. Tetrahydrofuran (738 ml) was charged and the reaction stirred for 3 hours at 60° C. to 65° C. The reaction was cooled to 10 to 15° C. and charged with water (193 ml), premixed sodium hydroxide solution [water (389 ml), sodium hydroxide (69 g)], tetrahydrofuran (738 ml) and water (193 ml) maintaining the temperature at 15° C. to 25° C. The mixture was stirred for 70 minutes and filtered. The filter cake was washed with tetrahydrofuran (1476 ml) twice. The filtrates and washes were combined and charged to a reaction vessel and concentrated to ca. 1480 mL at 65° C. to 70° C. The mixture was cooled to 15° C. to 25° C. and transferred to a container with tetrahydrofuran (369 ml), to provide the title compound (381 g) as a colourless solution in tetrahydrofuran (1613 ml).
Reaction SMILES: F[C:2](F)(F)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([N:15](C)[CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[O:14])=[CH:8][CH:7]=1)=O.[CH2:26](I)C.CC(C)=O>O>[CH2:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13]([NH:15][CH2:16][C:17]2([CH3:26])[CH:18]=[CH:19][N:20]=[CH:21][CH2:22]2)=[O:14])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CN(Cc1ccncc1)C(=O)Nc1ccc(NC(=O)C(F)(F)F)cc1
Reactant: CCI
Solvent: O
Solvent: CC(C)=O
Product: CCNc1ccc(NC(=O)NCC2(C)C=CN=CC2)cc1
Reaction time: 8 h

Procedure:
To 2.89 gms. (0.01 mole) of 1-(p-trifluoroacetamidophenyl)-3-methyl-3-(4-pyridylmethyl)urea [prepared by reacting 1-(p-aminophenyl)-3-methyl-3-(4-pyridylmethyl)urea (Example 6., supra.) with trifluoroacetic anhydride (method of Hickenbottom, Reactions of Organic Compounds, Longmans, London, 1963)] there is added 6.24 gms. (0.04 mole) of ethyl iodide in 50 ml. of dry acetone. The acetone is then stripped and the residue added to 50 ml. of water. The aqueous mixture is warmed to reflux for about 30 minutes and then allowed to stand overnight. The mixture is then stripped of water to give 1-(p-ethylaminophenyl)-4-methyl-3-(4-pyridylmethyl)urea.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1.CO[CH:11](OC)[N:12](C)C.NOS(O)(=O)=O>CN(C)C=O.CO.N1C=CC=CC=1>[I:8][C:6]1[CH:5]=[CH:4][N:3]2[N:12]=[CH:11][N:1]=[C:2]2[CH:7]=1
Reactant: Nc1cc(I)ccn1
Reactant: COC(OC)N(C)C
Agent: NOS(=O)(=O)O
Solvent: CO
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Ic1ccn2ncnc2c1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
To a stirred solution of the product from Step B above (220 mg, 1.00 mmol) in N,N-dimethylformamide (0.5 mL) was added N,N-dimethylformamide dimethyl acetal (0.37 mL, 2.60 mmol). The reaction mixture was heated to 130° C. overnight. After cooling to room temperature, the volatiles were removed under reduced pressure to afford a red oil, which was dissolved in 2.0 mL of methanol and 0.162 mL of pyridine. The solution was cooled in an ice bath and hydroxylamine-O-sulfonic acid (147 mg, 1.30 mmol) was added in one portion. The reaction mixture was allowed to warm to room temperature and was stirred overnight. The volatiles were removed under reduced pressure, and the residue was partitioned between saturated aqueous brine solution and ethyl acetate. The aqueous layer was further extracted with ethyl acetate, and the combined organic layers were washed with saturated aqueous brine solution (100 mL), dried over magnesium sulfate and concentrated under reduced pressure to afford the title compound as an orange solid. MS 246.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[CH:5]=[CH:4][C:3]=1[C:16](=[O:20])[CH2:17][CH2:18][CH3:19].Cl.[CH3:22]NC.C=O.Cl>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])[CH:5]=[CH:4][C:3]=1[C:16](=[O:20])[C:17](=[CH2:22])[CH2:18][CH3:19]
Reactant: CNC
Reactant: CCCC(=O)c1ccc(OCCN(CC)CC)cc1Cl
Agent: C=O
Agent: Cl
Product: C=C(CC)C(=O)c1ccc(OCCN(CC)CC)cc1Cl

Procedure:
A mixture of 8.9 g. (0.03 mole) of 1-[2-chloro-4-(2-diethylaminoethoxy)phenyl]-1-butanone, 2.7 g. (0.033 mole) of dimethylamine hydrochloride, 1.8 g. (0.06 mole) of paraformaldehyde and 5 ml. of concentrated hydrochloric acid is heated on the steam bath for 2 hours. The mixture is digested on the steam bath with 700 ml. of water, filtered and the filtrate added to 350 ml. of 10% aqueous sodium bicarbonate. The solution is heated on the steam bath for 1 hr., cooled and extracted with ether. The ether extract is washed with water, dried over sodium sulfate, filtered and evaporated to dryness on the steam bath. The product is obtained upon distillation in vacuo (0.3 mm.) as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([N:11]2[CH2:15][CH2:14][CH2:13][S:12]2(=[O:17])=[O:16])[CH:3]=1.[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:29]2[CH2:30][CH2:31][N:26]([C:20]3[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:19]=3[CH3:18])[CH2:27][CH2:28]2)=[O:8])=[C:4]([N:11]2[CH2:15][CH2:14][CH2:13][S:12]2(=[O:17])=[O:16])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1N1CCCS1(=O)=O
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Yield: 101.3 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 90 and using 4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)benzoic acid (661 mg) described in Preparation Example 178 and 1-(2,4-dimethylphenyl)piperazine (431 mg), the title compound (1.03 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:7]=12.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CN(C)C=O>[CH2:26]([NH:33][C:11]([C:9]1[NH:8][C:7]2=[C:2]([Cl:1])[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=1)=[O:13])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1cc2ccnc(Cl)c2[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccccc1)c1cc2ccnc(Cl)c2[nH]1
Temperature: 50 °C
Reaction time: 1 h
Yield: 27.5 %

Procedure:
A mixture of 7-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Reference Example 1) (0.10 g, 0.51 mmol) and 1,1′-carbonyldiimidazole (0.09 g, 0.53 mmol) in N,N-dimethylformamide (3.4 mL) was stirred at 50° C. for 1 h. To the stirring solution was added benzylamine (0.11 mL, 1.02 mmol) and the reaction mixture was stirred at 65° C. until the reaction was complete by TLC analysis. The crude reaction mixture was poured into rapidly stirring water, and extracted with ethyl acetate (3×). The combined organic extracts were washed with water (3×) and saturated NH4Cl, and dried over Na2SO4. The organic extract was filtered and concentrated to provide N-benzyl-7-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (0.04 g, 0.14 mmol, 27%) as an off-white solid: mp 217-220° C.; 1H NMR (300 MHz, CDCl3) δ4.70 (2H, d, J=5.7 Hz), 6.45-6.61 (1H, m), 6.85 (1H, s), 7.31-7.39 (5H, m), 7.47 (1H, d, J=5.7 Hz), 8.06 (1H, d, J=5.7 Hz), 9.55 (1H, br s); APCI MS m/z 286 [C15H12ClN3O+H]+; HPLC (Method A) >99% (AUC), tR=16.3 min.
Reaction SMILES: [C:1]([O:9][C@@H:10]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:11](=[O:18])[CH2:12][CH:13]([CH3:17])[C:14](O)=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH:27]1[CH2:41][CH2:40][CH2:39][C@H:28]1[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.CCOCC>[C:1]([O:9][C@@H:10]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:11](=[O:18])[CH2:12][C@@H:13]([CH3:17])[C:14]([N:27]1[CH2:41][CH2:40][CH2:39][C@H:28]1[C:29]([O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:30])=[O:15])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CC(CC(=O)[C@H](Cc1ccccc1)OC(=O)c1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](CC(=O)[C@H](Cc1ccccc1)OC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (5S)-5-benzoyloxy-2-methyl-4-oxo-6-phenylhexanoic acid (740 mg., 2.17 mmole), L-proline, phenylmethyl ester, hydrochloride (525 mg., 2.17 mmole), 1-hydroxybenzotriazole hydrate (300 mg., 2.21 mmole), and diisopropylethylamine (0.45 ml., 2.6 mmole) in anhydrous tetrahydrofuran (8 ml.) at 0° under argon is added dropwise a solution of dicyclohexylcarbodiimide (457 mg., 2.21 mmole) in tetrahydrofuran (1.5 ml.). The resulting mixture is stirred at 0° for one hour and then warmed to room temperature. After stirring for 16 hours, the mixture is diluted with ether and washed with water, 1N hydrochloric acid (twice), 1N sodium bicarbonate, and brine. After drying (MgSO4), the solvent is removed at reduced pressure to give the desired product as a mixture of diastereomers. Flash chromatography [Whatman silica gel LPS-1; solvent, hexane:dichloromethane:ethyl acetate (6:2:2)] gives 460 mg. of 1-[(5S,2R)-5-(benzoyloxy)-2-methyl-1,4-dioxo-6-phenylhexyl]-L-proline, phenylmethyl ester; Rf =0.45 [silica gel, dichloromethane:ethyl acetate:hexane (4:3:3)].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[BH4-].[Na+].[CH3:15]O>C1COCC1>[CH3:15][C:9]1([OH:12])[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=2)[CH2:7][CH2:8]1
Reactant: CO
Reactant: COc1ccc2c(c1)C(=O)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(C)(O)CC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Step AA (1): To a solution of 6-methoxy-2,3-dihydro-1H-inden-1-one (24 g) in methanol (150 mL) and THF (50 mL) at 0° C. was added sodium borohydride (5.6 g), and the resulting suspension was stirred at 0° C. for 1 h and rt for 30 min. Solvents were evaporated, and water was added. The aqueous solution was extracted with EtOAc (×4), and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated in vacuo to give methyl 6-methoxy-2,3-dihydro-1H-inden-1-ol as a colorless oil (24.3 g), which was carried forward without purification. 1H NMR (400 MHz, CDCl3): 7.12 (1H, d), 6.95 (1H, d), 6.81 (1H, dd), 5.19 (1H, br. S), 3.79 (3H, s), 2.95 (1H, m), 2.74 (1H, m), 2.50 (1H, m), 1.94 (1H, m).