Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]12[CH2:10][CH2:9][C:6]([C:11]3[NH:19][C:18]4[C:17](=[O:20])[NH:16][C:15](=[O:21])[N:14]([CH2:22][CH2:23][CH3:24])[C:13]=4[N:12]=3)([CH2:7][CH2:8]1)[CH2:5][CH2:4]2.CCN(CC)CC>CS(C)=O.CCOC(C)=O>[O:21]=[C:15]1[N:14]([CH2:22][CH2:23][CH3:24])[C:13]2[N:12]=[C:11]([C:6]34[CH2:7][CH2:8][C:3]([CH:2]=[O:1])([CH2:10][CH2:9]3)[CH2:4][CH2:5]4)[NH:19][C:18]=2[C:17](=[O:20])[NH:16]1
Reactant: CCCn1c(=O)[nH]c(=O)c2[nH]c(C34CCC(CO)(CC3)CC4)nc21
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCn1c(=O)[nH]c(=O)c2[nH]c(C34CCC(C=O)(CC3)CC4)nc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 33.5 %

Procedure:
8-(4-Hydroxymethyl-bicyclo[2.2.2]oct-1-yl)-3-propyl-3,7-dihydro-purine-2,6-dione (2.70 g, 8.13 mmol) was dissolved in 40 mL of DMSO. Pyridine-SO3 (3.88 g, 3 eq) was added, followed by Et3N (7.4 mL, 7 eq) at rt. The resulting reaction mixture was stirred at rt for 18 h. It was then diluted with EtOAc and washed with 5% aq citric acid, H2O, brine, dried (Na2SO4) and concentrated under reduced pressure to afford 900 mg of the desired aldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[C:11]([CH:15]=1)[C:12](O)=[O:13].[CH:32]1([NH2:35])[CH2:34][CH2:33]1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)=[C:11]([CH:15]=1)[C:12]([NH:35][CH:32]1[CH2:34][CH2:33]1)=[O:13]
Reactant: COc1c(C)c(Cc2ccc(-c3ccncc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Reactant: NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1c(C)c(Cc2ccc(-c3ccncc3)c(C(=O)NC3CC3)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 65 %

Procedure:
5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(4-pyridyl)benzoic acid (100 mg, 0.2364 mmol) and cyclopropylamine (44 mg, 0.7719 mmol) were dissolved in methylene chloride (5 ml), then 4-dimethylaminopyridine (6 mg, 0.0491 mmol) and WSC-HCl (146 mg, 0.7616 mmol) were added thereto and the mixture was stirred for 6 hours at room temperature. The reaction solution was washed with water and dried and the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:5) to give N-[5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-(4-pyridyl)benzoyl]cyclopropylamine (71 mg, 0.1536 mmol, 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH:10]2[CH2:23][OH:24])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:11][CH:10]2[CH2:23][O:24][S:33]([CH3:32])(=[O:35])=[O:34])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CO)C1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(COS(C)(=O)=O)C1
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (6RS,7SR)-7-(3,4-dichlorophenyl)-6-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (735 mg) in THF (10 ml) were added triethylamine (0.41 mL) and methanesulfonyl chloride (0.21 mL) under ice-cooling, and the mixture was stirred for 1 hr. Triethylamine (0.14 ml) and methanesulfonyl chloride (0.076 ml) were added, and the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with 1 N hydrochloric acid, distilled water and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (863 mg).
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]2[N:11]([CH:12]=1)[CH2:10][CH2:9][C@@H:8]([CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][CH:24]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]5[CH:41]=[CH:40][C:39]([O:42][C:43]([F:46])([F:45])[F:44])=[CH:38][CH:37]=5)=[CH:30][CH:29]=4)[CH2:23][CH2:22]3)=[CH:17][CH:16]=1)[O:7]2)([O-:3])=[O:2].C=O.[C:49](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl>[CH3:49][N:27]([CH:24]1[CH2:23][CH2:22][N:21]([C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][C@H:8]3[O:7][C:6]4=[N:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][N:11]4[CH2:10][CH2:9]3)=[CH:20][CH:19]=2)[CH2:26][CH2:25]1)[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][C:39]([O:42][C:43]([F:46])([F:45])[F:44])=[CH:40][CH:41]=2)=[CH:30][CH:29]=1
Reactant: O=[N+]([O-])c1cn2c(n1)O[C@H](COc1ccc(N3CCC(Nc4ccc(OCc5ccc(OC(F)(F)F)cc5)cc4)CC3)cc1)CC2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CN(c1ccc(OCc2ccc(OC(F)(F)F)cc2)cc1)C1CCN(c2ccc(OC[C@@H]3CCn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
N-{1-[4-((S)-2-Nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-yl}-N-[4-(4-trifluoromethoxybenzyloxy)phenyl]amine (0.30 g) was suspended in 1,2-dichloroethane (2 ml). A 37% formaldehyde aqueous solution (0.362 ml) and sodium triacetoxyborohydride (149 mg) were added to the suspension and stirred at room temperature overnight. A 37% formaldehyde aqueous solution (0.362 ml) and sodium triacetoxyborohydride (149 mg) were further added thereto and stirred at room temperature for 1 day. A sodium hydrogen carbonate aqueous solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:1→methylene chloride:methanol=4:1) and crystallized from ether to afford the title compound as a pale yellow powder (130 mg).
Reaction SMILES: [CH3:1][O:2][P:3](=[O:14])([O:12][CH3:13])[O:4][CH:5]1[CH2:9][O:8]C(C)(C)[O:6]1.Cl>ClCCl.CO.COC>[CH3:1][O:2][P:3](=[O:14])([O:12][CH3:13])[O:4][CH:5]([OH:6])[CH2:9][OH:8]
Reactant: COP(=O)(OC)OC1COC(C)(C)O1
Agent: COC
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COP(=O)(OC)OC(O)CO
Temperature: 25 °C
Reaction time: 5 h
Yield: 69 %

Procedure:
To a solution of phosphoric acid 2,2-dimethyl-[1,3]-dioxolan-4-yl ester dimethyl ester (600 mg, 2.5 mmol) in 3.0 mL of dichloromethane and 0.5 mL of methanol was added 3.5 mL of 1 M solution of hydrogen chloride in dimethylether dropwise. The reaction mixture was stirred for 5 h at room temperature and concentrated. The residue was purified by silica gel chromatography eluting with CH2Cl2-Methanol (9:1) to yield 321 mg (69%) of phosphoric acid 1,2-dihydroxy-ethyl ester dimethyl ester as an oil. 1H NMR (400 MHz, DMSO-d6) δ 4.99 (d, J=5.2 Hz, 1H, OH), 4.66 (t, J=5.6 Hz, 1H, OH), 3.93–3.98 (m, 1H), 3.78–3.83 (m, 1H), 3.65 (d, J=11.2 Hz, 6H), and 3.27–3.37 (m, 3H). 31P NMR (162 MHz, d6-DMSO) δ 2.5.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1.[C:12]1([C:18]2[N:19]=[C:20]3[N:25]=[C:24]([NH2:26])[CH:23]=[CH:22][N:21]3[CH:27]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C.CCCP(=O)=O>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:9]([NH:26][C:24]2[CH:23]=[CH:22][N:21]3[CH:27]=[C:18]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:19]=[C:20]3[N:25]=2)=[O:11])=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: Nc1ccn2cc(-c3ccccc3)nc2n1
Reactant: Cc1ncc(Cl)c(C(=O)O)n1
Agent: CCCP(=O)=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ncc(Cl)c(C(=O)Nc2ccn3cc(-c4ccccc4)nc3n2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 30.3 %

Procedure:
A mixture of 5-chloro-2-methylpyrimidine-4-carboxylic acid (100 mg, 0.579 mmol), 2-phenylimidazo[1,2-a]pyrimidin-7-amine (146 mg, 0.695 mmol, 1.2 eq), diisopropylethylamine (304 ul, 1.74 mmol, 3 eq) and propylphosphonic anhydride in ethyl acetate 50% (854 ul, 1.45 mmol, 2.5 eq) in tetrahydrofuran (6 ml) is stirred for 1 day at 25° C. The mixture is diluted with ethyl acetate and washed 2 times with water, the organic layer is dried over magnesium sulfate and evapoarted. The crude material was purified by flash chromatography over a 20 g silicagel column using ethyl acetate 100% as eluent to afford 5-chloro-2-methyl-N-(2-phenylimidazo[1,2-a]pyrimidin-7-yl)pyrimidine-4-carboxamide (64 mg, 30.3%) as a yellow solid. MS: m/e=365.1 (M+H+), mp: >250° C.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][O:7][C:8]1[CH:12]=[CH:11][S:10][CH:9]=1.O=P(Cl)(Cl)Cl.P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[CH3:6][O:7][C:8]1[CH:12]=[CH:11][S:10][C:9]=1[S:2]([Cl:1])(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccsc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccsc1S(=O)(=O)Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
Chlorosulfonic acid (CISO3H, 2.31 g, 19.62 mmol) was slowly added to a solution of 3-methoxythiophene (2.29 g, 19.62 mmol) in CHCl3 (80 ml) at 0° C. The resulting mixture was stirred at 0° C. for 30 min. The solvent was evaporated under reduced pressure at room temperature, the residue was suspended in POCl3 (15 ml, 156.96 mmol), and PCl5 (8.2 g, 39.24 mmol) was added slowly. The reaction was stirred at 60° C. for 18 h, then cooled to room temperature and poured onto crushed ice (200 g). The aqueous mixture was extracted with CHCl3 (2×150 ml) and the combined organic layers was dried (MgSO4). The solid was removed by filtration and the filtrate was concentrated to give 3-methoxy-2-thiophenesulfonyl chloride as a brown oil (1.81 g, 43% yield).
Reaction SMILES: C(N1C2C(=O)N(CCC3C=CC=CC=3)C([Cl:23])=NC=2N=C1N1CCCC(NC(=O)OC(C)(C)C)C1)C#CC.Cl.[NH2:39][CH:40]1[CH2:45][CH2:44][CH2:43][N:42]([C:46]2[N:54]([CH2:55][C:56]#[C:57][CH3:58])[C:53]3[C:52](=[O:59])[N:51]([CH2:60][C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=4[C:67]#N)[C:50]([C:69]#[N:70])=[N:49][C:48]=3[N:47]=2)[CH2:41]1>>[ClH:23].[NH2:39][CH:40]1[CH2:45][CH2:44][CH2:43][N:42]([C:46]2[N:54]([CH2:55][C:56]#[C:57][CH3:58])[C:53]3[C:52](=[O:59])[N:51]([CH2:60][CH2:61][C:66]4[CH:65]=[CH:64][CH:63]=[CH:62][CH:67]=4)[C:50]([C:69]#[N:70])=[N:49][C:48]=3[N:47]=2)[CH2:41]1
Reactant: CC#CCn1c(N2CCCC(N)C2)nc2nc(C#N)n(Cc3ccccc3C#N)c(=O)c21
Reactant: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2nc(Cl)n(CCc3ccccc3)c(=O)c21
Agent: Cl
Product: CC#CCn1c(N2CCCC(N)C2)nc2nc(C#N)n(CCc3ccccc3)c(=O)c21

Procedure:
The title compound was synthesized by using t-butyl [1-[7-(2-butynyl)-2-chloro-6-oxo-1-(2-phenylethyl)-6,7-dihydro-1H-purin-8-yl]piperidin-3-yl]carbamate according to the method described in Example 242 (f) and (g).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:36][CH:37]([F:39])[F:38])=[C:13]([C:15]2[C:19]([NH:20][C:21]([C:23]3[CH:24]=[N:25][N:26]4[CH:31]=[CH:30][CH:29]=[N:28][C:27]=34)=[O:22])=[CH:18][N:17]([CH2:32][C:33](O)=[O:34])[N:16]=2)[CH:14]=1.Cl.[CH3:41][N:42]([CH:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)[CH2:43][CH2:44][C:45]([O:47][CH3:48])=[O:46].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:36][CH:37]([F:39])[F:38])=[C:13]([C:15]2[C:19]([NH:20][C:21]([C:23]3[CH:24]=[N:25][N:26]4[CH:31]=[CH:30][CH:29]=[N:28][C:27]=34)=[O:22])=[CH:18][N:17]([CH2:32][C:33]([N:52]3[CH2:51][CH2:50][CH:49]([N:42]([CH3:41])[CH2:43][CH2:44][C:45]([O:47][CH3:48])=[O:46])[CH2:54][CH2:53]3)=[O:34])[N:16]=2)[CH:14]=1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Reactant: COC(=O)CCN(C)C1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCN(C)C1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid trifluoroacetate (100 mg, 0.17 mmol) in DMF (3 mL) was added methyl 3-[methyl(piperidin-4-yl)amino]propanoate hydrochloride (62 mg, 0.26 mmol), DIEA (67.2 mg, 0.52 mmol), HATU (79.2 mg, 0.21 mmol). The resulting solution was stirred at room temperature overnight and concentrated under vacuum. The residue was passed through a short pad of silica gel eluting with ethyl acetate/petroleum ether (10:1). The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (37.0% up to 43.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 37.0% in 2 min); Detector, UV 254/220 nm. This resulted in 45.2 mg (38%) of the formic acid salt of methyl 3-[[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidin-4-yl](methyl)amino]propanoate as an off-white solid. LCMS (Method 24) [M+H]+=645.2, RT=1.64 min. 1H NMR (300 MHz, DMSO-d6) δ: (ppm) 9.75 (s, 1H), 9.35 (dd, 1H, J=1.5, 6.9 Hz), 8.69-8.68 (m, 2H), 8.31 (s, 1H), 7.63 (dd, 1H, J=2.7, 8.7 Hz), 7.55 (d, 1H, J=2.7 Hz), 7.46 (d, 1H, J=8.7 Hz), 7.29 (dd, 1H, J=4.5, 7.2 Hz), 7.04 (t, 1H, J=73.2 Hz), 5.33-5.27 (m, 2H), 4.52-4.48 (m, 1H), 4.10-4.06 (m, 1H), 3.66 (s, 3H), 3.51-3.34 (m, 2H), 3.16-3.08 (m, 2H), 2.86-2.51 (m, 6H), 2.28-1.99 (m, 2H), 1.73-1.70 (m, 1H), 1.55-1.45 (m, 1H).
Reaction SMILES: C(N(CC)CC)C.FC(F)(F)C(O)=O.[CH2:15]([S:17]([NH2:20])(=[O:19])=[O:18])[CH3:16].[NH2:21][C@H:22]([C:24]([N:26]1[CH2:33][CH2:32][CH2:31][C@H:27]1[C:28]([OH:30])=[O:29])=[O:25])[CH3:23].O=[C:35]([CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:36]([O:38][CH2:39][CH3:40])=[O:37].C([BH3-])#N.[Na+]>C(O)C>[CH2:15]([S:17]([NH2:20])(=[O:19])=[O:18])[CH3:16].[CH2:39]([O:38][C:36]([CH:35]([NH:21][C@H:22]([C:24]([N:26]1[CH2:33][CH2:32][CH2:31][C@H:27]1[C:28]([OH:30])=[O:29])=[O:25])[CH3:23])[CH2:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:37])[CH3:40]
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Agent: CCS(N)(=O)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 0.5 h

Procedure:
Powdered activated 4 Å molecular sieve (13.5 g.) followed by triethylamine (11.13 ml.) were added to a stirred solution of L-alanyl-L-proline ethanesulphonamide trifluoroacetate (31.1 g.) in ethanol (450 ml.). Ethyl 2-oxo-4-phenylbutyrate (41.0 g.) was then added and the mixture was stirred at laboratory temperature for 30 minutes. A solution of sodium cyanoborohydride (7.7 g.) in ethanol (225 ml.) was then added during 15 hours and the mixture was stirred for a further 10 hours, filtered through a filter-aid and the filtrate was evaporated to dryness under reduced pressure. The residue was partitioned between saturated aqueous sodium carbonate solution (1000 ml.) and diethyl ether (1000 ml.) and the aqueous layer was separated, acidified to pH 3 with concentrated aqueous hydrochloric acid and extracted with methylene chloride. The extract was dried and evaporated to dryness under reduced pressure and the residue was purified by chromatography on a silica gel column using a 9:1 v/v mixture of methylene chloride and methanol as eluant. There were thus obtained the mixed isomers of N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline ethanesulphonamide in a ratio (as shown by high pressure liquid chromatography) of approximately 11:9 by weight. The isomers were separated by chromatography on a silica gel column using a 99:1 v/v mixture of ethyl acetate and acetic acid as eluant, and there were thus separately obtained N-[(1R)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-L-proline ethanesulphonamide, and N-[(1S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-L-proline ethane-sulphonamide, both of which were oils, the structures of which were confirmed by proton magnetic resonance and mass spectroscopy. The isomer initially present as 45% by weight of the mixture was considerably more active as an inhibitor of ACE than the other isomer.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[N:13](COCC[Si](C)(C)C)[CH:12]=2)=[O:10])[CH2:3]1.FC(F)(F)C(O)=O.C(N)CN>ClCCl>[OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[NH:13][CH:12]=2)=[O:10])[CH2:3]1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)NC2CCCC(O)C2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Solvent: ClCCl
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4CCCC(O)C4)c3n2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.7 %

Procedure:
In a 25 mL round-bottomed flask, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-hydroxycyclohexyl)amide (106 mg, 0.19 mmol) was dissolved dichloromethane (3 mL). Trifluoroacetic acid (0.2 mL, 2.6 mmol) was added and the orange reaction mixture was stirred at room temperature for 15 h. Additional trifluoroacetic acid (0.7 mL) was added and the reaction stirred for an additional 5 h. The reaction mixture was then concentrated under reduced pressure. The resultant crude solid was dissolved in dichloromethane (3 mL) and ethylenediamine (0.20 mL, 2.96 mmol) was added. The light yellow reaction mixture was stirred at room temperature for 20 h. The reaction mixture was concentrated and the residue was precipitated with water. The suspension was stirred for 1 h and the crude solid collected by filtration. The crude solid was sequentially washed with water, dichloromethane, ethyl acetate, and hexanes to afford 74 mg (91%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-hydroxy-cyclohexyl)-amide as a white solid and a 2:1 mixture of cis and trans isomers (unassigned). MS: [M+Na] 447.
Reaction SMILES: ClCCO[CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29].[Cl:30]CCOCCOCCOCCN1C(=O)C2C(=CC=CC=2)C1=O>>[Cl:30][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29]
Reactant: O=C1c2ccccc2C(=O)N1CCOCCOCCOCCOCCOCCCl
Reactant: O=C1c2ccccc2C(=O)N1CCOCCOCCOCCCl
Product: O=C1c2ccccc2C(=O)N1CCOCCOCCOCCOCCCl
Yield: 92 %

Procedure:
2-{2-[2-(2-{2-[2-(2-Chloroethoxy)-ethoxy}-ethoxyl-ethoxy)-ethoxy]-ethyl}-isoindole-1,3-dione. The title compound was prepared according to the synthesis of 2-(2-{[2-(2-Chloro-ethoxy)-ethoxy]-ethoxy}-ethyl)-isoindole-1,3-dione in 92% yield: 1H NMR (CDCl3) δ 7.84 (dd, 2 H), 7.71 (dd, 2H), 3.90 (t, 2H), 3.74 (q, 4 H), 3.67-3.58 (m, 18H). Mass spectrum, m/e Calcd for C20H29ClNO7+: 430.16 (100.0%). Found: 429.85.
Reaction SMILES: [C:1](=[NH:23])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]=2)=[CH:8][CH:7]=1)[NH2:2].FC(F)(F)C([O-])=O.[CH:31]([CH:33]([CH2:38][C:39]1[CH:40]=[N:41][C:42]([O:45][CH3:46])=[N:43][CH:44]=1)[C:34](OC)=O)=[O:32].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[CH3:46][O:45][C:42]1[N:41]=[CH:40][C:39]([CH2:38][C:33]2[C:31](=[O:32])[N:23]=[C:1]([O:3][CH2:4][CH2:5][C:6]3[CH:7]=[CH:8][C:9]([O:12][C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]=4)=[CH:10][CH:11]=3)[NH:2][CH:34]=2)=[CH:44][N:43]=1
Reactant: N=C(N)OCCc1ccc(Oc2cccc(C(F)(F)F)n2)cc1
Reactant: COC(=O)C(C=O)Cc1cnc(OC)nc1
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ncc(Cc2c[nH]c(OCCc3ccc(Oc4cccc(C(F)(F)F)n4)cc3)nc2=O)cn1
Temperature: 130 °C
Yield: 6.14 %

Procedure:
To the solution of 4-((6-(trifluoromethyl)pyridin-2-yl)oxy)phenethyl carbamimidate, Trifluoroacetate (200 mg, 0.456 mmol) and methyl 2-formyl-3-[2-(methyloxy)-5-pyrimidinyl]propanoate (205 mg, 0.913 mmol) in NMP (3 mL) was added K2CO3 (252 mg, 1.825 mmol). The mixture was heated with a microwave reactor at 130° C. for 1 h. Purification via MDAP then afforded the title compound (14 mg, 6.14% yield). LCMS: rt=3.11 min, [M+H+]=500
Reaction SMILES: [CH2:1]([O:3][CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[N:7]=1)[CH3:2].C1C(=O)N([Br:21])C(=O)C1.[CH3:22][CH2:23][OH:24]>>[Br:21][CH:5]([C:6]1[CH:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[N:7]=1)[CH:4]([O:24][CH2:23][CH3:22])[O:3][CH2:1][CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC=Cc1ccnc(SC)n1
Reactant: CCO
Product: CCOC(OCC)C(Br)c1ccnc(SC)n1
Temperature: 0 °C

Procedure:
4-(2-Ethoxy-vinyl)-2-methylsulfanyl-pyrimidine (18-2, 0.236 g, 1.20 mmol) was dissolved in 5 mL EtOH and the resulting solution was cooled to 0° C. NBS (0.214 g, 1.20 mmol) was added in small portions. After 2 h the reaction was concentrated in vacuo. Purification by flash column chromatography (eluting with 98:2 DCM/MeOH) provided the titled compound. 1H NMR (CDCl3) δ 8.50 (d, 1H, J=5.0 Hz), 7.09 (d, 1H, J=5.1 Hz), 5.05 (d, 1H, J=6.8 Hz), 4.81 (d, 1H, J=6.9 Hz), 3.77 (m, 2H), 3.53 (m, 2H), 2.57 (s, 3H), 1.26 (t, 3H, J=7.0 Hz), 1.08 t, 3H, J=7.1 Hz).
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:21])[O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH:16]([CH2:18][CH2:19][CH3:20])[CH3:17])[CH:11]=[CH:10]2)([CH3:3])[CH3:2].CN(CCN(C)C)C.[Si:30](OS(C(F)(F)F)(=O)=O)([C:33](C)(C)C)([CH3:32])[CH3:31].[Li]CCCC.Cl[Si](C)(C)C>CCOCC.C1COCC1.CCCCC>[CH:1]([NH:4][C:5](=[O:21])[O:6][C:7]1[C:8]([Si:30]([CH3:33])([CH3:32])[CH3:31])=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH:16]([CH2:18][CH2:19][CH3:20])[CH3:17])[CH:11]=[CH:10]2)([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCCC(C)n1ccc2cc(OC(=O)NC(C)C)ccc21
Agent: CN(C)CCN(C)C
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCCC(C)n1ccc2c([Si](C)(C)C)c(OC(=O)NC(C)C)ccc21
Temperature: 0 °C

Procedure:
To a stirred solution of 1-(pentan-2-yl)-1H-indol-5-yl isopropylcarbamate (11) (5.752 g, 19.9 mmol, 1.0 equiv.) in Et2O (143 mL) and THF (48 mL) was added TMEDA (4.19 mL, 27.9 mmol, 1.4 equiv.), and the solution was cooled to 0° C. Then, a solution of TBSOTf (5.50 mL, 23.9 mmol, 1.2 equiv.) in n-pentane (16 mL) was added, and the reaction mixture was left to stir for 5 minutes at 0° C., at which point the ice bath was removed and the reaction was stirred for 45 additional minutes. TMEDA (8.97 mL, 59.8 mmol, 3.0 equiv.) was added and the mixture was cooled to −78° C., followed by the slow addition of n-BuLi (2.5 M in hexanes, 23.9 mL, 59.8 mmol, 3.0 equiv.) over 10 minutes. The reaction mixture was stirred at −78° C. for 3 h before chlorotrimethylsilane (TMSCl, 17.4 mL, 140 mmol, 7.0 equiv.) was added slowly over 15 minutes. The reaction mixture was stirred at −78° C. for an additional 1 h. The reaction mixture was quenched with 4 mL of MeOH, followed by 200 mL of 2 M hydrochloric acid, and allowed to warm to room temperature over 1 h with vigorous stirring. Diethylether (100 mL) was added, and the organic phase was separated. The organic phase was washed with 100 mL of water, 100 mL of brine, dried over MgSO4 and concentrated. The crude material was purified via column chromatography (hexane:EtOAc, (gradient of 19:1→15:1→9:1, v/v)) to give 4-(trimethylsilyl)-1-(pentan-2-yl)-1H-indol-5-yl isopropylcarbamate (22) as a very viscous colorless liquid (6.15 g, 86%). 1H NMR (500 MHz, CDCl3) δ7.34 (d, J=8.8 Hz, 1H), 7.21 (d, J=3.3 Hz, 1H), 6.91 (d, J=8.8 Hz, 1H), 6.66 (d, J=3.2 Hz, 1H), 4.75 (d, J=8.0 Hz, 1H), 4.46 (m, 1H), 3.94 (m, 1H), 1.87 (m, 1H), 1.76 (m, 1H), 1.47 (d, J=6.8 Hz, 3H), 1.30-1.15 (m, 8H), 0.88 (t, J=7.4 Hz, 3H), 0.41 (s, 9H).