Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH2:15][CH2:16][C:17]#[N:18])[CH:8]=1.O.[OH-].[Na+]>CCOCC.C1COCC1>[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])[CH:8]=1
Reactant: N#CCCCOc1cccnc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: NCCCCOc1cccnc1
Yield: 53 %

Procedure:
To 2.9 g (0.073 mol) of lithium aluminum hydride stirred at 25° in 100 ml of anhydrous ether at 25° was added dropwise 4.7 g (0.029 mol) of 4-(3-pyridinyloxy)butyronitrile in 30 ml of ether and 20 ml anhydrous THF over 15 minutes. The reaction mixture was then stirred at reflux for 3.5 hours, cooled in an ice bath during the addition of 3 ml of H2O, followed by 3 ml of 15% NaOH solution and finally 9 ml of H2O. The granular solid was filtered, washed with CHCl3 and the filtrate was concentrated in vacuo. The residue was dissolved in CHCl3, washed with H2O, dried (MgSO4) and concentrated in vacuo to an oil. Distillation gave 2.6 g., b.p. 103°-107°/0.5 mm (53% yield) of the desired amine which was analyzed as the dihydrochloride obtained from 2-propanol-ether, m.p. 127°-131° .
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:4][C:3]=1[N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24].[O:29]=[C:30]1[NH:34][C:33](=[O:35])[CH:32]([CH2:36][C:37]2[CH:47]=[CH:46][C:40]([O:41][CH2:42][C:43](O)=[O:44])=[CH:39][CH:38]=2)[S:31]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:29]=[C:30]1[NH:34][C:33](=[O:35])[CH:32]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:41][CH2:42][C:43]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:15]4[CH2:16][CH2:17][CH2:18][CH2:19]4)=[CH:4][C:3]=3[N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:44])=[CH:46][CH:47]=2)[S:31]1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2N2CCCC2)ccc1N
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2N2CCCC2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 97 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-{2-amino-5-[2-(pyrrolidin-1-yl)phenoxy]phenyl}-N-methyl-carbamate (0.77 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (0.90 g), diethyl cyanophosphonate (0.52 g), triethylamine (0.32 g) and anhydrous tetrahydrofuran (30 ml) and the reaction mixture was purified to give the desired product (1.26 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:26][C:25](=[O:27])[C:24]4[C:23]5[C:18](=[CH:19][CH:20]=[CH:21][N:22]=5)[CH:17]=[CH:16][C:15]=4[N:14]=3)=[CH:11][C:10]([C:28]([F:31])([F:30])[F:29])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:32](#[N:34])C.O.CN>[Cl-].[Na+].O>[CH3:32][NH:34][C:25]([C:24]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]([C:28]([F:30])([F:31])[F:29])[CH:11]=2)=[O:26])=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[CH:21][CH:20]=[CH:19]2)=[O:27]
Reactant: CC#N
Reactant: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2ccc3cccnc3c12
Agent: CN
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CNC(=O)c1c(NC(=O)c2cc(C(F)(F)F)nn2-c2ncccc2Cl)ccc2cccnc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 62 %

Procedure:
To a suspension of 140 mg (0.28 mmol) of the above 2-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-3-oxa-1,5-diaza-phenanthren-4-one in 5.60 mL of a mixture acetonitrile: H2O 4:1 (v/v) is added 74 μL (0.85 mmol) of methylamine (solution 40% in water). The reaction mixture is stirred for 6 hours at ambient temperature. Brine is then added to the mixture and the product is extracted with ethyl acetate (3 times). The regrouped organic phases are dried on Na2SO4, filtrated and evaporated. The purification of the residue by flash chromatography (SiO2, heptane and ethyl acetate as eluants) affords 84 mg (62%) of a white solid; LC/MS:475/477 (M+H)+, m.p.: 219-220° C.
Reaction SMILES: [C:1](Cl)(=O)C.C([NH:8][C:9]1[CH:10]=[CH:11][C:12]([Br:18])=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15])(=O)C>CO>[CH3:1][O:16][C:14](=[O:15])[C:13]1[CH:17]=[C:9]([NH2:8])[CH:10]=[CH:11][C:12]=1[Br:18]
Reactant: CC(=O)Cl
Reactant: CC(=O)Nc1ccc(Br)c(C(=O)O)c1
Solvent: CO
Product: COC(=O)c1cc(N)ccc1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Acetyl chloride (29.2 ml, 32.2 g, 410.7 mmol) was added dropwise to methanol (210 ml) at 0-10° C. under nitrogen atmosphere and the solution was stirred for 30 min at 0° C. After addition of 5-acetamido-2-bromobenzoic acid (21.2 g, 82.1 mmol) in methanol at 0° C. the solution was stirred for 3 h at 55° C. After evaporation of methanol ethyl acetate (160 ml) was added and stirring was continued for 1 h at room temperature. The precipitation was filtered off and it was dissolved in water. pH was adjusted to 8 with NaHCO3. The mixture was extracted with ethyl acetate, washed with water, dried over Na2SO4 and concentrated under vacuum.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:6]([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])[O-:5])[CH3:2].[C:13](#[N:16])[CH:14]=[CH2:15].[H-].[Na+].C(O)(=O)C>C(O)C>[C:13]([CH2:14][CH2:15][P:4]([CH:6]([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])(=[O:5])[O:3][CH2:1][CH3:2])#[N:16]
Reactant: C=CC#N
Reactant: CCOC(OCC)P([O-])OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(OCC)P(=O)(CCC#N)OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The starting material can be prepared as follows: A solution of 20 g of ethyl(diethoxymethyl)phosphonite (Aust. J. Chem. 33, 292 (1980)) and 5 g of acrylonitrile in 25 ml of ethanol is added to a stirred mixture of 1 g of sodium hydride (50% dispersion in oil) in 25 ml of ethanol at 0° C. under an atmosphere of nitrogen. The reaction mixture is allowed to warm to room temperature and stirred for 4 hours. 1 ml of glacial acetic acid is added and the mixture is concentrated under reduced pressure. The resulting crude product is dissolved in 50 ml of ethyl acetate, washed twice with 26 ml of water, and the organic extract is dried over magnesium sulphate, and then concentrated under reduced pressure. The crude product is distilled under reduced pressure to give ethyl 2-cyanoethyl(diethoxymethyl)phosphinate, b.p. 114° C./0.01 mbar, 31P=+40.8 ppm (CDCl3).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][C:3]=1[F:10].[NH:11]1[CH2:14][CH:13]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH3:22])[CH2:17][CH2:16]2)[CH2:12]1.C(C1C=CC=CC=1)C1C=CC=CC=1.C1CCN2C(=NCCC2)CC1>O.CN1C(=O)CCC1>[CH2:21]([N:18]1[CH2:19][CH2:20][N:15]([CH:13]2[CH2:12][N:11]([C:2]3[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][C:3]=3[F:10])[CH2:14]2)[CH2:16][CH2:17]1)[CH3:22]
Reactant: OCc1ccc(F)c(Cl)n1
Reactant: CCN1CCN(C2CNC2)CC1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CCN1CCN(C2CN(c3nc(CO)ccc3F)C2)CC1
Temperature: 25 °C
Yield: 110.1 %

Procedure:
To a mixed solution of a commercially available product of (6-chloro-5-fluoropyridin-2-yl)methanol (200 mg, 1.24 mmol) and NMP (2.00 mL) were added a mixture (627 mg) of 1-(azetidin-3-yl)-4-ethylpiperazine and benzylbenzene described in Production Example 1-3-2 and DBU (565 mg, 3.71 mmol) at room temperature. The resultant mixture was irradiated with a microwave at 180° C. for 8 hours. The reaction mixture was cooled to room temperature, then water was added thereto, and the resultant solution was extracted with dichloromethane. An organic layer was dried over anhydrous magnesium sulfate and then filtrated. The solvent was evaporated under a reduced pressure, and the resultant residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:4 and subsequently ethyl acetate) to give a crude product (402 mg) of the title compound.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[N:9]=[N:10][CH:11]=[C:12]([C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=4)[C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.[Br:20]N1C(C)(C)C(=O)N(Br)C1=O>>[Br:20][C:15]1[CH:14]=[C:13]([C:12]2[C:7]3[N:6]=[CH:5][N:4]([CH:1]4[CH2:3][CH2:2]4)[C:8]=3[N:9]=[N:10][CH:11]=2)[CH:18]=[CH:17][C:16]=1[F:19]
Reactant: Fc1ccc(-c2cnnc3c2ncn3C2CC2)cc1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Product: Fc1ccc(-c2cnnc3c2ncn3C2CC2)cc1Br
Yield: 25 %

Procedure:
This was prepared by a Method analogous to that as described above for Preparation 87 using 7-cyclopropyl-4-(4-fluorophenyl)-7H-imidazo[4,5-c]pyridazine (Preparation 93, 450 mg, 1.77 mmol) and 1,3-dibromo-5,5-dimethylhydantoin (253.3 mg, 0.885 mmol) to afford the title compound as a white solid in 25% yield, 500 mg.
Reaction SMILES: CC1(C)C(O)C(=O)OC1.[O:10]=[CH:11][C@H:12]([C@@H:14]([C@H:16]([C@H:18]([CH2:20][OH:21])[OH:19])[OH:17])[OH:15])[OH:13].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>[Pt].[Pd]>[OH:10][CH:11]1[O:17][C@@H:16]2[C@@H:18]([C:20]([O:15][C@@H:14]2[C@H:12]1[OH:13])=[O:21])[OH:19]
Reactant: O=C[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)CO
Agent: [Pd]
Agent: [Pt]
Agent: CC1(C)COC(=O)C1O
Product: O=C1O[C@H]2[C@H](OC(O)[C@@H]2O)[C@@H]1O

Procedure:
The resolving agents of the instant invention are known compounds. D(-)- and L(+)-2-hydroxy-3,3-dimethyl-1,4-butyrolactones are also known under the names D(-) and L(+) pantolactone and are readily available articles of commerce. 1,2-Isopropylidene-(+)-α-D-glucofuranurono-3,6-lactone and the corresponding L(-) compound may be prepared according to the method of J. Chem. Soc. 339 (1941). The corresponding L(-) compound may also be prepared from L-glucose. According to an alternative method of preparation oxidation of D-glucose with air in the presence of either platinum (heyns and R. Heinemann Ann., 1947, 558, 187) or palladium (M. Busch, G. P., 702, 729/1941) gave D-glucuronic acid, Evaporation of an aqueous solution of D-glucuronic acid yields crystalline D-glucofuranurono-6,3-lactone (F. Smith, J. Chem. Soc., 1944, 584; A Baeyer, Ann., 1870, 155, 257). 2,3-Isopropylidene-D(+)-ribonic acid-1,4-lactone may be prepazed from D(+)-ribonic acid-1,4-lactone according to the method of Can. J. Chem. 1958 36 1720 and the corresponding L(-) ribonic acid lactone is readily prepared from L-arabinose by conversion to potassium L-arabonate as described in Biochem. J. 1965 94 75 and subsequent reaction with 2,2-dimethoxypropane. 3,4-Isopropylidene-L-arabino-1,5-lactone may be prepared from potassium L-arabonate via L-arabonic acid. The corresponding D compound may also be prepared by conventional methods, e.g. using the same method of preparation as for the L form and selective recrystallisation.
Reaction SMILES: C(N(CC)CC)C.[N:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1.[N+:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)([O-:22])=[O:21].ClCCl>CN(C=O)C>[N:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:15][CH2:16][N:17]([C:27](=[O:28])[C:26]3[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:31][CH:30]=3)[CH2:18][CH2:19]2)=[CH:10][CH:9]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: c1cc(N2CCNCC2)ccn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCN(c2ccncc2)CC1
Temperature: 4 °C
Reaction time: 1 h
Yield: 65.2 %

Procedure:
Triethylamine (3.48 ml) was added to a stirred suspension of 1-(4-pyridyl)piperazine (4.08 g) in DMF (50 ml). The mixture was cooled to 4° C., and 4-nitrobenzoylchloride (4.64 g) added. The mixture was stirred for 1 hour at 4° C. and then for 16 hours at ambient temperature. Dichloromethane (250 ml) was then added and the mixture washed with water (3×30 ml), saturated brine (1×30 ml), then dried (MgSO4) and the solvents evaporated. The residual oil was purified by flash chromatography on silica gel using 5% v/v methanol/dichloromethane and then with 10% v/v methanol/dichloromethane as eluant to give 1-(4pyridyl)-4-(4-nitrobenzoyl)piperazine (5.09 g) as a yellow solid. m.p. 158-160° C.; microanalysis. found: C, 61.3; H, 5.3; N, 17.6%; C16H16N4O3 requires: C, 61.5; H, 5.2; N, 17.9%: NMR: 3.42(6H+H2O,m), 3.87(2H,bs), 6.93(2H,d), 7.84(2H,d), 8.30(2H,d), 8.41(2H,d): MS: m/z 313 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:46]=[C:45]([CH3:47])[CH:44]=[C:43]([Cl:48])[C:3]=1[O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([C:25]2[CH:30]=[CH:29][C:28]([C:31]3[C:32]([CH2:37][CH2:38][CH2:39][O:40][CH3:41])=[N:33][CH:34]=[CH:35][CH:36]=3)=[CH:27][C:26]=2[CH3:42])[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:10][CH:9]=1.ClC1C=C(C=CC=1)C(OO)=[O:54]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:20]([O:19][C:18](=[O:24])[NH:17][CH2:16][CH:15]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[C:32]([CH2:37][CH2:38][CH2:39][O:40][CH3:41])=[N+:33]([O-:54])[CH:34]=[CH:35][CH:36]=2)=[CH:27][C:26]=1[CH3:42])[CH2:14][C:11]1[CH:10]=[CH:9][C:8]([O:7][CH2:6][CH2:5][O:4][C:3]2[C:43]([Cl:48])=[CH:44][C:45]([CH3:47])=[CH:46][C:2]=2[Cl:1])=[CH:13][CH:12]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: COCCCc1ncccc1-c1ccc(C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)c(C)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COCCCc1c(-c2ccc(C(CNC(=O)OC(C)(C)C)Cc3ccc(OCCOc4c(Cl)cc(C)cc4Cl)cc3)c(C)c2)ccc[n+]1[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl (3-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-2-{4-[2-(3-methoxypropyl)pyridin-3-yl]-2-methylphenyl}propyl)carbamate (1 eq.) from EXAMPLE 16, step 1 in CH2Cl2 (0.03M) at room temperature was added m-chloroperoxybenzoic acid (1.1 eq.). The reaction mixture was stirred for 3 h at room temperature, poured in saturated aqueous NaHCO3 and extracted with EtOAc. The organic extract was washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated. Purification by column chromatography on silica gel, eluting with CH2Cl2/MeOH 5%, afforded the title compound as a foam
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[C:9]([O:11]COC)[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]1>CO>[OH:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]1
Reactant: COCOc1ccc(C2CCCC(=O)C2)c(OCOC)c1
Solvent: CO
Product: O=C1CCCC(c2ccc(O)cc2O)C1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
(±)-3-[2,4-Bis(methoxymethoxy)phenyl]cyclohexanone (35 mg) in methanol (4 ml) containing acidic ion exchange resin (300 mg) was stirred at 50° C. for 6 hr, and then at ambient temperature for 16 hr. The mixture was evaporated in vacuo and the residue was redissolved in acetone (4 ml) containing water (2 drops) and stirred at 50° C. for 8 hr, then at ambient temperature for 64 hr. The mixture was filtered through celite and purified by flash column chromatography (SiO2, petroleum ether/ethyl acetate 1:1 v/v) to furnish the title compound as a white solid containing an equilibrium mixture of cyclized and uncyclized forms (31 mg, 76%). δH (DMSO) 1.1-2.3 (8H, overlapping m), 3.0 (1H, m), 6.08 (0.5H, bs), 6.16 (1H, bd), 6.25 (0.5H, bs), 6.53 (0.5H, bs), 6.75 (0.5H, d), 6.89 (0.5H, b), 8.98 (0.5H, bs), 9.02 (0.5H, bs), 9.17 (0.5H, bs); m/z (ES−) 205 (M−H)−.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][NH:25][CH2:26][CH3:27])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][NH:25][CH2:26][CH3:27])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCNCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNCc1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 151.7 %

Procedure:
tert-butyl (3R)-6-cyclohexyl-3-{3-[(ethylamino)methyl]-1,2,4-oxadiazol-5-yl}hexanoate (preparation 74) (288 mg, 0.76 mmol) was treated with TFA (5 ml) and stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM and the solvents removed under reduced pressure. The residue was azeotroped from toluene (×3) and DCM (×3) to afford the title compound (373 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[C:31]5[O:30][CH2:29][CH2:28][C:27]=5[CH:26]=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.C(OC(=O)[NH:38][CH2:39][CH2:40][NH2:41])(C)(C)C.Cl>>[NH2:38][CH2:39][CH2:40][NH:41][C:12](=[O:14])[CH2:11][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([C:15]([N:17]2[CH2:18][CH2:19][CH:20]([C:23]3[C:31]4[O:30][CH2:29][CH2:28][C:27]=4[CH:26]=[CH:25][CH:24]=3)[CH2:21][CH2:22]2)=[O:16])=[CH:7]1
Reactant: O=C(O)Cn1cc(C(=O)N2CCC(c3cccc4c3OCC4)CC2)c2ccc(Cl)cc21
Reactant: CC(C)(C)OC(=O)NCCN
Agent: Cl
Product: NCCNC(=O)Cn1cc(C(=O)N2CCC(c3cccc4c3OCC4)CC2)c2ccc(Cl)cc21

Procedure:
Analogous to general procedure I, the coupling of {6-chloro-3-[4-(2,3-dihydro-benzofuran-7-yl)-piperidine-1-carbonyl]-indol-1-yl}-acetic acid (prepared herein) with (commercially available) (2-amino-ethyl)-carbamic acid tert-butyl ester gave, after treatment with HCl and neutralisation, the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.I[C:12]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]>>[N:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([NH:1][C:12]3[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][C:13]=3[C:14]([OH:16])=[O:15])[C:10]=2[NH:9][CH:8]=1
Reactant: Nc1cccc2nc[nH]c12
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1I
Product: O=C(O)c1cccc([N+](=O)[O-])c1Nc1cccc2nc[nH]c12
Yield: 25 %

Procedure:
Reaction of 4-aminobenzimidazole (prepared by literature methods Rabinowitz, J. L. J. Am. Chem. Soc., 1951, 73, 3030-3037; van der Want, G. M. Rec. Trav. Chim., 1948, 67, 45-51) and 2-iodo-3-nitrobenzoic acid as above gave 2-(3H-benzimidazol-4-ylamino)-3-nitrobenzoic acid (25%, crude). Purification was by treatment with ethereal CH2N2 followed by chromatograph gave methyl 2-(3H-benzimidazol-4-ylamino)-3-nitrobenzoate (18% yield); mp (EtOAc/Et2O) 146-148° C.; 1H NMR [(CD3)2SO] δ 3.69 (s, 3 H, OCH3), 6.54 (br s, 1 H, ArH), 7.00 (t, J=7.9 Hz, 1 H, ArH), 7.11-7.19 (m, 2 H, 2xArH), 8.12-8.20 (m, 3 H, 3xArH), 10.06 (br s, diphenylamine NH), 12.51 (br s, 1 H, imidazole NH). Also isolated was methyl 2-[(3-methyl-3H-imidazol-4-yl)amino]-3-nitrobenzoate (6%); mp (EtOAc) 219-221° C.; 1H NMR [(CD3)2SO] δ 3.40 (s, 3 H, OCH3), 4.09 (s, 3 H, NCH3), 6.71 (d, J=7.6 Hz, 1 H, ArH), 6.96-7.05 (m, 2 H, 2xArH), 7.43 (d, J=8.0 Hz, 1 H, ArH), 7.99 (dd, J=7.7, 1.6 Hz, 1 H, ArH), 8.11 (dd, J=8.3, 1.5 Hz, 1 H, ArH), 8.15 (s, 1 H, ArH), 9.70 (s, 1 H, NH).
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([CH2:9][NH:10][CH:11]=O)[N:5]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.O=P(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.O>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([CH2:9][N+:10]#[C-:11])[N:5]=2)[CH2:3][CH2:2]1
Reactant: O=CNCc1noc(C2CC2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [C-]#[N+]Cc1noc(C2CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 5-cyclopropyl-3-formylaminomethyl-1,2,4-oxadiazole (60 mmol) and triethylamine (176 mmol) in CH2Cl2 (100 ml) was charged dropwise with POCl3 (60 mmol) at 0° C. The mixture was then left for 30 min. with stirring at 0° C., whereafter a solution of Na2CO3 (60 mmol) in H2O (50 ml) was added. The mixture was heated to room temperature, whereafter the organic phase was separated, dried and evaporated in vacuo. The residue was treated with ether, decanted and the solution was evaporated to give the title compound as an oil. The oil was processed without any further purification. The compound was characterized by its IR stretching band at 2160 cm-1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][N:25]=[CH:26]2)=[CH:21][C:20]=1F>CN(C)C(=O)C>[C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([O:14][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][C:19]=2[Cl:18])[CH:26]=[N:25][CH:24]=[CH:23]3)[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1cc2ccncc2cc1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Oc2cc3ccncc3cc2Cl)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
450 mg (0.21 mmol) trans-(4-Hydroxy-cyclohexyl)-carbamic acid tert-butyl ester were dissolved in 25 ml N,N-dimethyl acetamide. Under an argon atmosphere, 101 mg (4.2 mmol) sodium hydride were added and the mixture was stirred at room temperature. After 30 minutes, 250 mg (0.14 mmol) 7-chloro-6-fluoro-isoquinoline (6) were added and the solution was heated to 80° C. After 4 h, the solvent was removed under reduced pressure. The residue was taken up in H2O and extracted three times with ethyl acetate. The combined organic layers were dried over MgSO4 and evaporated. The crude product was purified by preparative HPLC, which delivered 18 mg of the title compound. Rt=1.38 min (Method #1). Detected mass: 377.2/379.3 (M+H+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]([CH2:21][C:22]2[CH:42]=[CH:41][C:25]([CH2:26][O:27][C:28]3[CH:40]=[CH:39][C:31]4[CH:32]([CH2:35][C:36]([OH:38])=[O:37])[CH2:33][O:34][C:30]=4[CH:29]=3)=[CH:24][CH:23]=2)[C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[Cl-].[Ca+2:46].[Cl-]>CO.O>[C:1]1([CH2:7][CH2:8][N:9]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:26][O:27][C:28]3[CH:40]=[CH:39][C:31]4[CH:32]([CH2:35][C:36]([O-:38])=[O:37])[CH2:33][O:34][C:30]=4[CH:29]=3)=[CH:41][CH:42]=2)[C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Ca+2:46].[C:1]1([CH2:7][CH2:8][N:9]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:26][O:27][C:28]3[CH:40]=[CH:39][C:31]4[CH:32]([CH2:35][C:36]([O-:38])=[O:37])[CH2:33][O:34][C:30]=4[CH:29]=3)=[CH:41][CH:42]=2)[C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CC1COc2cc(OCc3ccc(CN(CCc4ccccc4)c4nc(-c5ccccc5)cs4)cc3)ccc21
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C([O-])CC1COc2cc(OCc3ccc(CN(CCc4ccccc4)c4nc(-c5ccccc5)cs4)cc3)ccc21
Yield: 81.2 %

Procedure:
To a solution of {6-[(4-{[(2-phenylethyl)(4-phenyl-1,3-thiazol-2-yl)amino]methyl}benzyl)oxy]-2,3-dihydro-1-benzofuran-3-yl}acetic acid (0.541 g, 0.938 mmol) in methanol (5 mL) was added 2 M aqueous sodium hydroxide solution (1 mL), and the mixture was concentrated under reduced pressure. Water (50 mL) and methanol (20 mL) were added to the obtained residue, and a solution of calcium chloride (0.111 g, 1.00 mmol) in water (5 mL) was added thereto. The mixture was concentrated under reduced pressure, and the precipitated solid was collected by filtration and washed with water to give the title compound (0.454 g, yield 81%) as a pale-yellow amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[CH2:16][CH:15]([C:17]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH:29]=[CH:28][N:27]=[CH:26]4)=[CH:21][CH:20]=3)=[O:18])[CH2:14]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[BH4-].[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[CH2:14][CH:15]([CH:17]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH:29]=[CH:28][N:27]=[CH:26]4)=[CH:21][CH:20]=3)[OH:18])[CH2:16]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN2CC(C(=O)c3ccc(-n4ccnc4)cc3)C2)cc1OC
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccc(CCN2CC(C(O)c3ccc(-n4ccnc4)cc3)C2)cc1OC

Procedure:
In a manner similar to Example 27, react [1-[2-(3,4-dimethoxyphenyl)ethyl]azetidin-3-yl][4-(1H-imidazol-yl)phenyl]methanone with sodium borohydride to obtain the title compound.