Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[S:14][C:13]([NH:15][CH:16]([CH3:18])[CH3:17])=[N:12][CH:11]=2)[CH:5]=[N:6][C:7]=1[O:8]C.Cl.[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[C:7](=[O:8])[NH:6][CH:5]=[C:4]([C:10]2[S:14][C:13]([NH:15][CH:16]([CH3:17])[CH3:18])=[N:12][CH:11]=2)[CH:3]=1
Reactant: COc1ncc(-c2cnc(NC(C)C)s2)cc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)Nc1ncc(-c2c[nH]c(=O)c(Br)c2)s1
Temperature: 90 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
A solution of 5-(5-bromo-6-methoxypyridin-3-yl)-N-isopropylthiazol-2-amine (390 mg, 1.18 mmol) in THF (1 mL) was added HCl (4 N, 10 mL) and heated at 90° C. overnight. The mixture was cooled to rt, neutralized with aq NaOH (5 N) and stirred for 1 h. The solid was filtered, rinsed with water and dried to give 3-bromo-5-(2-(isopropylamino)thiazol-5-yl)pyridin-2(1H)-one (359.4 mg, 96%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:14][C:15]2[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][N:18]=[C:17]([NH:25][C:26]3[CH:40]=[CH:39][C:29]([CH2:30][P:31](=[O:38])([O:35][CH2:36][CH3:37])[O:32][CH2:33][CH3:34])=[CH:28][CH:27]=3)[N:16]=2)=[C:7]2[C:11]=1[CH2:10][N:9]([CH3:12])[C:8]2=[O:13])#[N:2].BrC1C=CC(NC2C(C(F)(F)F)=CN=C(NC3C=CC(CP(=O)([O-])[O-])=CC=3OC)N=2)=C2C=1CN(C)[C:47]2=[O:52]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:14][C:15]2[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][N:18]=[C:17]([NH:25][C:26]3[CH:40]=[CH:39][C:29]([CH2:30][P:31](=[O:38])([O:35][CH2:36][CH3:37])[O:32][CH2:33][CH3:34])=[CH:28][C:27]=3[O:52][CH3:47])[N:16]=2)=[C:7]2[C:11]=1[CH2:10][N:9]([CH3:12])[C:8]2=[O:13])#[N:2]
Reactant: COc1cc(CP(=O)([O-])[O-])ccc1Nc1ncc(C(F)(F)F)c(Nc2ccc(Br)c3c2C(=O)N(C)C3)n1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(C#N)c4c3C(=O)N(C)C4)n2)cc1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(C#N)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to the procedure for Diethyl [4-({4-[(7-cyano-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzyl]phosphonate (Example 161) using [4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)-3-methoxybenzyl]phosphonate. MS (ES+): m/z 605.19 (100) [MH+]; HPLC: tR=1.09 min (UPLC, purity).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=O)[CH:2]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[NH2:44][CH2:45][CH:46]([OH:58])[CH2:47][N:48]1[CH2:57][CH2:56][C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH2:49]1>C(Cl)Cl>[CH2:49]1[C:50]2[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:56][CH2:57][N:48]1[CH2:47][CH:46]([OH:58])[CH2:45][NH:44][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][CH:15]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:8]=1
Reactant: O=C(O)c1cccc(-c2cccnc2)c1
Reactant: NCC(O)CN1CCc2ccccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1cccc(-c2cccnc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.9 %

Procedure:
To a solution of 3-(pyridin-3-yl)benzoic acid (150 mg, 0.75 mmol) in DCM (6 mL) was added EDCI (215 mg, 1.10 mmol), HOBt (148 mg, 1.10 mmol), Et3N (228 mg, 2.25 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (185 mg, 0.90 mmol). The mixture was stirred at room temperature for 16 h. The reaction solution was then washed with water and extracted with DCM. The organic layer was concentrated, dried and the residue purified by prep-HPLC to give the desired title product (110 mg, Yield 34%). 1H NMR (400 MHz, MeOD) δ 8.80 (d, J=2.0 Hz, 1H), 8.52 (dd, J1=4.8 Hz, J2=3.6 Hz, 1H), 8.10 (s, 1H), 8.09 (dd, J1=8.8 Hz, J2=1.6 Hz, 1H), 7.83 (d, J=7.6 Hz, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.51-7.46 (m, 2H), 7.06-6.95 (m, 4H), 4.15-4.10 (m, 1H), 3.69 (s, 2H), 3.60-3.47 (m, 2H), 2.85-2.79 (m, 4H), 2.69-2.59 (m, 2H). LCMS (m/z): 388.2 (M+1).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:4].[CH3:18][NH2:19]>CO>[CH3:18][NH:19][C:3]([C:5]1[N:6]=[CH:7][C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:4]
Reactant: COC(=O)c1cc2c(cn1)[nH]c1ccccc12
Reactant: CN
Solvent: CO
Product: CNC(=O)c1cc2c(cn1)[nH]c1ccccc12
Yield: 43 %

Procedure:
12 g of β-carbolin-3-carboxylic acid methyl ester is suspended in 130 ml of methanol; 130 ml of 40% aqueous methylamine is added thereto and the whole is boiled at reflux for 2 hours. After cooling, the mixture is suction-filtered. By extraction with 300 ml of hot methanol and crystallization from dimethylformamide/hexane, the β-carbolin-3-carboxylic acid N-methylamide of melting point 264°-266° C. is isolated from the filter residue in 43% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21](O)=[O:22])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[OH:24][CH2:25][C:26]([NH:29][S:30]([C:33]1[S:37][C:36]([NH2:38])=[N:35][C:34]=1[CH3:39])(=[O:32])=[O:31])([CH3:28])[CH3:27]>>[OH:24][CH2:25][C:26]([NH:29][S:30]([C:33]1[S:37][C:36]([NH:38][C:21]([C:20]2[CH:19]=[N:18][N:11]3[C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[N:9][C:10]=23)=[O:22])=[N:35][C:34]=1[CH3:39])(=[O:32])=[O:31])([CH3:28])[CH3:27]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Reactant: Cc1nc(N)sc1S(=O)(=O)NC(C)(C)CO
Product: Cc1nc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)cc4)nc23)sc1S(=O)(=O)NC(C)(C)CO

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.4) and 2-amino-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.3) according to general procedure II. Yellow solid. MS (ISP) 587.1 [(M+H)+]; mp 274° C.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([OH:23])[CH2:22][CH2:21][CH2:20][CH:19]3[CH:15]2[CH2:16][CH2:17][NH:18]3)=[CH:10][CH:9]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2([OH:23])[CH2:22][CH2:21][CH2:20][CH:19]3[CH:15]2[CH2:16][CH2:17][N:18]3[C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])=[CH:12][CH:13]=1
Reactant: O=C(Cl)C1CC1
Reactant: OC1(c2ccc(Cl)cc2)CCCC2NCCC21
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(C1CC1)N1CCC2C1CCCC2(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The starting material was produced as follows: 2.74 g of Cyclopropanecarboxylic acid chloride was added dropwise to a solution of 7.2 g of (3aRS, 4SR, 7aRS)-4-p-chlorophenylhexahydro-4-indolinol and 2.5 ml of pyridine in 30 ml of methylene chloride at 0° to 10°. The mixture was stirred at room temperature for 1 hour, and then was washed first with a 10% tartaric acid solution, then with a sodium bicarbonate solution, then with a saturated salt solution. The organic phase was dried over sodium sulphate and concentrated to afford (3aRS, 4SR, 7aRS)-4-p-chlorophenyl-1-cyclopropylcarbonylhexahydro-4-indolinol. (M.P. 167°-169°).
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:20]=[C:19]3[C:14]([C:15]([N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:16][C:17]([CH3:21])=[N:18]3)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[NH:73]1[CH2:77][CH2:76][CH2:75][CH2:74]1>C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:21][C:17]1[CH:16]=[C:15]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:14]2[C:19](=[CH:20][C:11]([O:10][CH2:9][C:6]3[CH:7]=[N:8][C:3]([N:73]4[CH2:77][CH2:76][CH2:75][CH2:74]4)=[CH:4][CH:5]=3)=[CH:12][CH:13]=2)[N:18]=1
Reactant: Cc1cc(N2CCCC2)c2ccc(OCc3ccc(Cl)nc3)cc2n1
Reactant: C1CCNC1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1cc(N2CCCC2)c2ccc(OCc3ccc(N4CCCC4)nc3)cc2n1
Temperature: 25 °C
Yield: 90.6 %

Procedure:
A suspension of 98.5 mg (0.25 mmol) of 7-(6-chloro-pyridin-3-ylmethoxy)-2-methyl-4-pyrrolidin-1-yl-quinoline hydrochloride, product of example 56, 16 mg (0.03 mmol) of BINAP, 2.8 mg (0.01 mmol) of Pd(II) acetate, and 99 mg (1 mmol) of sodium tert-butylate in toluene (4.5 ml) was treated at RT with 36 mg (0.5 mmol) of pyrrolidine and then heated at reflux under an argon atmosphere for 4 h. The reaction mixture was cooled to RT, diluted with methylene chloride (10 ml), and then filtered. The filtrate was concentrated in vacuo, the residue triturated with ether, filtered off by suction and dried in a high vacuum to give 88 mg (84%) of the 2-methyl-4-pyrrolidin-1-yl-7-(6-pyrrolidin-1-yl-pyridin-3-ylmethoxy)-quinoline as a white solid. ISP mass spectrum, m/e: 389.3 (M+1 calculated for C24H28N4O: 389).
Reaction SMILES: [O:1]=[C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[CH2:3]1.[H-].[Na+].[Cl:13][C:14]1[CH:15]=[C:16]([NH:20][C:21](=O)[O:22]C2C=CC=CC=2)[CH:17]=[CH:18][CH:19]=1.Cl>CN(C)P(=O)(N(C)C)N(C)C>[Cl:13][C:14]1[CH:15]=[C:16]([NH:20][C:21]([CH:3]2[C:2](=[O:1])[S:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]2=3)=[O:22])[CH:17]=[CH:18][CH:19]=1
Reactant: O=C1Cc2ccccc2S1
Reactant: O=C(Nc1cccc(Cl)c1)Oc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(Nc1cccc(Cl)c1)C1C(=O)Sc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 18.2 g of 2,3-dihydro-2-oxo-benzo[b]thiophene in 60 ml of hexamethylphosphoric acid triamide is added dropwise to a suspension of 5.9 g of a 50% strength sodium hydride/mineral oil suspension in 180 ml of hexamethylphosphoric acid triamide, whilst cooling, the reaction temperature being kept below 15°. After stirring for one hour at room temperature, 30.4 g of phenyl N-(3-chlorophenyl)-carbamate are addd in portions, with external cooling. The mixture is stirred for a further 16 hours at room temperature and poured onto a mixture of 100 ml of 2 N hydrochloric acid and 1,000 g of ice, whereupon an oil separates out; this oil crystallises on leaving to stand for several hours. The crystals are collected and dissolved in 300 ml of diethyl ether. The solution is washed with water and the organic phase is separated off, dried over sodium sulphate and evaporated to dryness. The residue is recrystallised from ether and gives N-(3-chlorophenyl)-2-oxo-2,3-dihydro-3-benzo[b]thiophenecarboxamide with a melting point of 175°-177°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH3:13])[N:10]([CH:14]3[C:18](=[O:19])/[C:17](=[CH:20]/[CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)/[CH2:16][C:15]3=[O:27])[N:9]=2)=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH3:13])[N:10]([CH:14]3[C:18](=[O:19])[CH:17]([CH2:20][CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH2:16][C:15]3=[O:27])[N:9]=2)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: Cc1cc(-c2ccc(Cl)cc2)nn1C1C(=O)C/C(=C\C2CCOCC2)C1=O
Agent: [Pd]
Solvent: CO
Product: Cc1cc(-c2ccc(Cl)cc2)nn1C1C(=O)CC(CC2CCOCC2)C1=O
Yield: 51.7 %

Procedure:
To a solution of 2-[3-(4-chloro-phenyl)-5-methyl-pyrazol-1-yl]-4-[1-(tetrahydro-pyran-4-yl)-meth-(E)-ylidene]-cyclopentane-1,3-dione (9 mg, 0.02 mmol) in methanol (0.1 ml) was added 5% palladium on activated charcoal (1 mg) and the reaction stirred for 6 hours under 1.5 bar of hydrogen. The solution was then filtered through a pad of Celite, washed with methanol (10 ml) and concentrated in vacuo to give a white solid, which was purified by reverse phase preparative HPLC (eluting with acetonitrile/water) to give 2-[3-(4-chloro-phenyl)-5-methyl-pyrazol-1-yl ]-4-(tetrahydro-pyran-4-ylmethyl)-cyclopentane-1,3-dione (4 mg).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:36])[CH:15]([CH2:19][C:20]1[C:25]([CH3:26])=[CH:24][C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:22][C:21]=1[CH3:35])[CH2:16][CH:17]=C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([OH:41])(C)C.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.O=[Os](=O)(=O)=O>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:36])[C@H:15]([CH2:19][C:20]1[C:21]([CH3:35])=[CH:22][C:23]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:24][C:25]=1[CH3:26])[CH2:16][CH:17]=[O:41])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCC(Cc1c(C)cc(OCc2ccccc2)cc1C)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: CC(C)(C)O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccccc2)cc(C)c1C[C@H](CC=O)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Yield: 418.3 %

Procedure:
Treat a solution of (R)-4-Benzyl-3-[2-(4-benzyloxy-2,6-dimethyl-benzyl)-pent-4-enoyl]-oxazolidin-2-one (7.5 g, 16 mmol) in THF (120 mL) and water (40 mL) with 2.5% OsO4 in tBuOH (16 g, 1.6 mmol). Add Sodium periodate (10 g, 47 mmol) to the solution and stir the reaction for 3 hr at room temperature. Quench the reaction with water and extract with EtOAc. Wash the organic with 1N sodium thiosulfate and brine. Separate the organic, dry over MgSO4, filter, and remove the solvent. Purify the crude by silica gel column chromatography using Hexanes:EtOAc to elute the pure product. Remove the solvent to afford 3.25 g (43%) of desired product. MS (m/e): 486 (M+1).
Reaction SMILES: [Cl:1]C1C=C(C=CC=1O)C(O)=O.[CH2:12]([O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[C:22](Cl)[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][C:21]=1[Cl:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1Cl
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Product: Nc1ccc(OCc2ccccc2)c(Cl)c1

Procedure:
The 4-benzyloxy-3-chloroaniline was prepared from 3-chloro-4hydroxybenzoic acid using the same procedure described for the preparation of 4-benzyloxy-2-chloroaniline (Scheme 3). 1H NMR (300 MHz, CDCl3) δ:7.35 (m, 5 H), 6.77 (d, J=8.9 Hz, 1 H), 6.72 (d, J=2.1 Hz, 1 H), 6.49 (dd, J=8.9, 2.1 Hz, 1 H), 5.2 (s, 2 H), 3.55 (br s, 2 H).
Reaction SMILES: [C:1]1(=[O:8])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1.[CH2:9]([N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])[CH2:12][CH2:13][CH2:14][NH2:15])[CH3:10]>CO>[CH2:9]([N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])[CH2:12][CH2:13][CH2:14][NH:15][C:6]1[C:1](=[O:8])[CH:2]=[C:3]([NH:15][CH2:14][CH2:13][CH2:12][N:11]([CH2:9][CH3:10])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[C:4](=[O:7])[CH:5]=1)[CH3:10]
Reactant: O=C1C=CC(=O)C=C1
Reactant: CCN(CCCN)Cc1ccccc1OC
Solvent: CO
Product: CCN(CCCNC1=CC(=O)C(NCCCN(CC)Cc2ccccc2OC)=CC1=O)Cc1ccccc1OC
Reaction time: 6 h
Yield: 45.6 %

Procedure:
To a solution of p-benzoquinone (0.1 g; 0.92 mmol) in 70 ml of MeOH was added when cold N1-ethyl-N1-(2-methoxy-benzyl)-propan-1,3-diamine (0.45 g; 2.0 mmol). The reaction mixture was agitated at e.t. and out of the light for 6 h, the was evaporated in a vacuum to give a crude material which was purified by flash chromatography. Eluting with CH2Cl2/MeOH/NH4OH 9.75:0.25:0.025 obtained 0.23 g of the compound XII as a pure red solid on TLC (eluant: CHCl3/MeOH/NH4OH 9.5:0.5:0.05). Yield 45%; 1H NMR (free base; CDCl3) δ: 1.11 (t, 6H), 1.72-1.85 (m, 4H), 2.56 (q, 8H), 3.18 (q, 4H), 3.62 (s, 4H), 3.82 (s, 6H), 5.26 (s, 2H), 6.83-6.95 (m, 4H), 7.19-7.43 (m, 4H+2H exchangeable with D2O); EI-MS: m/z=548 (M+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:16](=[O:28])[C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[CH:26][N:25]=[CH:24]3)=[CH:19][CH:18]=2)[N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][C:7]=12)#[N:2].[BH4-].[Na+]>CO.C(Cl)(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:16]([OH:28])[C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH:27]=[CH:26][N:25]=[CH:24]3)=[CH:21][CH:22]=2)[N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][C:7]=12)#[N:2]
Reactant: N#Cc1cc(C(=O)c2ccc(-n3ccnc3)cc2)n2c1ccc1ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: N#Cc1cc(C(O)c2ccc(-n3ccnc3)cc2)n2c1ccc1ccccc12
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a solution of 3-cyano-1-(4-imidazol-1-yl-benzoyl)-pyrrolo[1,2-a]quinoline (40 mg, 0.11 mmol) in 1:1 methanol/chloroform (10 mL) was added sodium borohydride portion-wise over 1 h and the reaction mixture was stirred overnight. It was worked up as described in Example 22 and the crude was purified by chromatography (5% methanol/chloroform) to yield the title compound (38.4 mg, 95%). 1H NMR (CDCl3/MeOH-d4): 8.80 (d, J=8.7 Hz, 1H), 7.93 (s, 1H), 7.80 (dd, J=7.8, 1.5 Hz, 1H), 7.53 (m, 8H), 7.38 (t, J=1.2 Hz, 1H), 7.12 (s, 1H), 6.57 (s, broad, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10](=O)[CH3:11])=[C:5]([CH3:13])[CH:4]=1.[Cl-].[NH2:15][OH:16]>CO>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6](/[C:10](=[N:15]/[OH:16])/[CH3:11])=[C:5]([CH3:13])[CH:4]=1
Reactant: COc1cc(C)c(C(C)=O)cc1C
Reactant: NO
Agent: [Cl-]
Solvent: CO
Product: COc1cc(C)c(/C(C)=N/O)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
To a solution of 0.5 g (2.6 mmol) of 1-(4-methoxy-2,5-dimethylphenyl)ethanone obtained in Step 2 and 0.36 g (5.1 mmol) of hydroxylamine chloride in 15 mL of methanol was added 1.0 g of a molecular sieve for dehydration. The reaction mixture was stirred at room temperature for 3 hours and filtered through celite and the filtrate was concentrated in a vacuum. The concentrate was stirred in water (20 mL) and the aqueous layer was extracted twice with 20 mL of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, followed by vacuum concentration. The residue was purified through silica gel chromatography to produce (E)-1-(4-methoxy-2,5-dimethylphenyl)ethanone oxime as a white solid (0.45 g, yield: 83%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:22][C:21](=[O:23])[C:20]4[C:15](=[C:16]([CH3:27])[CH:17]=[C:18]5[CH:26]=[N:25][NH:24][C:19]5=4)[N:14]=3)=[CH:11][C:10]([CH:28]([F:30])[F:29])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:31]([NH2:34])([CH3:33])[CH3:32]>C(#N)C.O>[CH:31]([NH:34][C:21]([C:20]1[C:15]([NH:14][C:13]([C:12]2[N:8]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[N:9]=[C:10]([CH:28]([F:29])[F:30])[CH:11]=2)=[O:22])=[C:16]([CH3:27])[CH:17]=[C:18]2[C:19]=1[NH:24][N:25]=[CH:26]2)=[O:23])([CH3:33])[CH3:32]
Reactant: CC(C)N
Reactant: Cc1cc2cn[nH]c2c2c(=O)oc(-c3cc(C(F)F)nn3-c3ncccc3Cl)nc12
Solvent: O
Solvent: CC#N
Product: Cc1cc2cn[nH]c2c(C(=O)NC(C)C)c1NC(=O)c1cc(C(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a suspension of 600 mg of the above 7-[2-(3-chloro-pyridin-2-yl)-5-difluoromethyl-2H-pyrazol-3-yl]-5-methyl-1H-8-oxa-1,2,6-triaza-cyclopenta[a]naphthalen-9-one in 10 mL of acetonitrile/water (4:1, v/v), is added 1.2 mL (14.0 mmol) of isopropylamine. The reaction mixture is stirred for 6 hours at ambient temperature and then concentrated in vacuo. The residue is taken-up with brine and ethyl acetate. The phases are separated and the aqueous layer is washed with ethyl acetate. The combined organic layers are washed with brine, dried over MgSO4 and concentrated in vacuo. Trituration of the residue in ethyl acetate affords 106 mg (15% over two steps) of the product as a pale yellowish solid; LC/MS:488/490 (M+H)+; m.p.: 250-253° C.
Reaction SMILES: [CH:1]([CH:4]1[C:8](=[O:9])[O:7][CH:6]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:26](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[N:5]1[C:46](=[O:51])[CH2:47][CH2:48][CH2:49][CH3:50])([CH3:3])[CH3:2].C(OC(C)C)(C)C>C1COCC1.[Pd]>[CH3:50][CH2:49][CH2:48][CH2:47][C:46]([N:5]([C@H:4]([C:8]([OH:9])=[O:7])[CH:1]([CH3:3])[CH3:2])[CH2:6][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]2[NH:23][N:24]=[N:25][N:26]=2)=[CH:14][CH:15]=1)=[O:51]
Reactant: CCCCC(=O)N1C(c2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)OC(=O)C1C(C)C
Agent: [Pd]
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](C(=O)O)C(C)C
Yield: 50.5 %

Procedure:
A solution of the 4-isopropyl-3-pentanoyl-2-[2′-(1-trityl-1H-tetrazol-5-yl)-biphenyl-4-yl]oxazolidin-5-one (1.0 g, 1.5 mmoles) in 20 ml of THF is hydrogenated under 5 bars, at 60° C., in the presence of Pd(5%)/C (100 mg). After completion of the reaction, the mixture is cooled and the catalyst is filtered off. After working up the reaction mixture as in Example 4, valsartan (0.33 g, molar yield: 53%) is isolated by crystallization from isopropyl ether.
Reaction SMILES: [C:1]([C:3]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[CH:24][N:23]=[C:22]4[CH3:26])=[CH:17][CH:16]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4]1)#[N:2].OO.C(=O)([O-])[O-:30].[K+].[K+].O>CS(C)=O>[CH3:26][C:22]1[N:21]([C:18]2[CH:19]=[CH:20][C:15]([CH2:14][O:13][C:9]3[CH:8]=[C:7]([C:3]4([C:1]([NH2:2])=[O:30])[CH2:6][CH2:5][CH2:4]4)[CH:12]=[CH:11][CH:10]=3)=[CH:16][CH:17]=2)[CH:25]=[CH:24][N:23]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1nccn1-c1ccc(COc2cccc(C3(C#N)CCC3)c2)cc1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1nccn1-c1ccc(COc2cccc(C3(C(N)=O)CCC3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 203.6 %

Procedure:
To a solution of 1-cyano-1-[3-[4-(2-methylimidazol-1-yl)benzyloxy]phenyl]-cyclobutane (2.90 g, 8.4 mmol) in DMSO (5 ml) cooled to 0° C. was added 30% H2O2 (2.0 ml) and potassium carbonate (0.4 g). The mixture was allowed to warm to room temperature and stirred overnight, and then stirred for 6 hrs at 60° C. Water (100 ml) was added and the mixture extracted with ethyl acetate (100 ml×3). The combined organic layers were extracted with 2N HCl (100 ml×2) and the aqueous layer washed with ethyl acetate (100 ml×3). The aqueous acidic layer was basified to pH=9 with 5N NaOH (150 ml) and extracted with ethyl acetate (100 ml×3). The combined organic extracts were washed with water (100 ml), brine (100 ml), dried (MgSO4) and concentrated in vacuo to afford crude product as white solid. Recrystallization from ethyl acetate gave 2.13 g (70%) of the titled compound as a white solid.
Reaction SMILES: [O:1]1[CH2:5][CH:4]([OH:6])[CH:3]2[O:7][CH2:8][CH:9]([OH:10])[CH:2]12.N1C=CC=CC=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>ClCCl>[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([O:6][CH:4]2[CH2:5][O:1][CH:2]3[CH:9]([OH:10])[CH2:8][O:7][CH:3]23)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: OC1COC2C(O)COC12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2COC3C(O)COC23)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.8 %

Procedure:
To a solution of hexahydrofuro[3,2-b]furan-3,6-diol (10.00 g, 68.4 mmol) in dichloromethane (60 mL) was added pyridine (1.08 g, 13.7 mmol) and then the mixture was cooled to 0° C., and 4-methylbenzenesulfonyl chloride (15.66 g, 82.1 mmol) was added. The mixture was stirred at 0° C. for 30 min, and then warmed to room temperature overnight. The resulting mixture was diluted with dichloromethane (250 mL), washed with 1M HCl (300 mL) followed by water (300 mL) and brine (300 mL). The separated organic phase was dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified with a silica gel column chromatography (EtOAc/PE (v/v)=2/1) to afford the desired product as colorless oil (10.24 g, 49.8%).