Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[Cl:28][C:29]1[CH:39]=[CH:38][C:32]([O:33][CH2:34][C:35](Cl)=[O:36])=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:39]=[CH:38][C:32]([O:33][CH2:34][C:35]([N:24]([CH2:23][C:14]2[CH:15]=[C:16]([C:19]([F:21])([F:22])[F:20])[CH:17]=[CH:18][C:13]=2[C:7]2[C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:27])=[O:2])[CH:6]=2)[CH2:25][CH3:26])=[O:36])=[CH:31][CH:30]=1
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)COc1ccc(Cl)cc1

Procedure:
[2′-({[2-(4-Chloro-phenoxy)-acetyl]-ethyl-amino}-methyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]acetic acid (Compound 1-93) was prepared by following the procedures outlined in Example 1 and using (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and 4-chlorophenoxyacetyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[C:13]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:17][C:16]([C:19](O)=[O:20])=[CH:15][CH:14]=1>>[CH3:12][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][C:2]([NH:1][C:19]([C:16]3[CH:17]=[CH:18][C:13]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:14][CH:15]=3)=[O:20])=[CH:3][CH:4]=2)[N:9]=1
Reactant: Cc1ccc2ccc(N)cc2n1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Product: Cc1ccc2ccc(NC(=O)c3ccc(-c4ccccc4)cc3)cc2n1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-amino-2-methylquinoline (D66) (80 mg, 0.51 mmol) and 4-biphenylcarboxylic acid (149 mg, 0.75 mmol) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.07 (m, 3H), 8.01 (m, 3H), 7.81 (d, 1H), 7.75 (d, 2H), 7.66 (d, 2H), 7.50 (t, 2H), 7.42 (t, 1H), 7.24 (d, 1H), 2.75 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:18])[CH:9]2[CH:13]3[O:14][CH2:15][CH:16]([OH:17])[CH:12]3[O:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1.Cl.[CH3:20][N:21]1[CH:25]=[C:24]([NH2:26])[CH:23]=[N:22]1.C(N(C(C)C)C(C)C)C>CCCCO>[CH3:18][N:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:26][C:24]2[CH:23]=[N:22][N:21]([CH3:20])[CH:25]=2)[N:7]=1)[CH:9]1[CH:13]2[O:14][CH2:15][CH:16]([OH:17])[CH:12]2[O:11][CH2:10]1
Reactant: Cn1cc(N)cn1
Reactant: CN(c1ccnc(Cl)n1)C1COC2C(O)COC21
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ccnc(Nc2cnn(C)c2)n1)C1COC2C(O)COC21
Temperature: 150 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
To a suspension of 6-((2-chloropyrimidin-4-yl)(methyl)amino)hexahydrofuro[3,2-b]furan-3-ol (358.0 mg, 1.32 mmol) and 1-methyl-1H-pyrazol-4-amine hydrochloride (178.6 mg, 1.34 mmol) in n-BuOH (5 mL) was added N-ethyldiisopropylamine (434.6 mg, 3.36 mmol). The reaction mixture was stirred at 150° C. in a sealed tube overnight and then concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/10) to give the title compound as a beige solid (300 mg, 68.4%).
Reaction SMILES: [ClH:1].[CH2:2]([N:9]([CH2:11][CH2:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][C:14]1=[O:22])C)C1C=CC=CC=1>CO.[Pd]>[ClH:1].[CH3:2][NH:9][CH2:11][CH2:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][C:14]1=[O:22]
Reactant: CN(CCn1c(=O)[nH]c2ccccc21)Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CNCCn1c(=O)[nH]c2ccccc21
Yield: 94.5 %

Procedure:
22.9 g (72 mmol) of 1-[2-(N-benzyl-N-methylamino)ethyl]-2-benzimidazolinone hydrochloride are dissolved in 250 ml of methanol, treated with 2.5 g of palladium-on-carbon (10%) and hydrogenated at room temperature for 90 minutes. The residue obtained after filtration and concentration is recrystallized from methanol/ether, whereby there are obtained 15.5 g (94%) of 1-[2-(methylamino)ethyl]-2-benzimidazolinone hydrochloride, m.p. 177°-180°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[C:13]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:14]=3[S:15][C:16]=2[NH2:17])=O)=[CH:6][CH:5]=1.[CH:24]1([C:27](=[O:32])[CH2:28][C:29](=O)[CH3:30])[CH2:26][CH2:25]1>C(O)(=O)C.S(=O)(=O)(O)O>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:12]3[C:13]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:14]=4[S:15][C:16]=3[N:17]=[C:29]([CH3:30])[C:28]=2[C:27]([CH:24]2[CH2:26][CH2:25]2)=[O:32])=[CH:6][CH:5]=1
Reactant: CC(=O)CC(=O)C1CC1
Reactant: COC(=O)c1ccc(C(=O)c2c(N)sc3c2CCCCC3)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-c2c(C(=O)C3CC3)c(C)nc3sc4c(c23)CCCCC4)cc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 43.7 %

Procedure:
To a stirred solution of 20 mg (0.06 mmol) 4-(2-Amino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carbonyl)-benzoic acid methyl ester in 1 ml acetic acid was added 10 mg (0.06 mmol) of 1-cyclopropyl-butane-1,3-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30% CH3CN/H20) afforded 11 mg (44%) 4-(3-cyclopropanecarbonyl-2-methyl-6,7,8,9-tetrahydro-5H-10-thia-1-aza-benzo[a]azulen-4-yl)-benzoic acid methyl ester as a light yellow solid. ES-MS m/e (%): 420 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:6][N:5]([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25]([OH:27])=O)[CH2:10]2)=[O:8])[CH2:4]1.Cl.O[N:30]=[C:31]([NH2:34])[CH2:32][CH3:33]>>[CH2:32]([C:31]1[N:34]=[C:25]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:19][CH:20]=3)[CH2:14][N:9]([C:7]([N:5]3[CH2:4][CH:3]([O:2][CH3:1])[CH2:6]3)=[O:8])[CH2:10]2)[O:27][N:30]=1)[CH3:33]
Reactant: COC1CN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)C1
Reactant: CCC(N)=NO
Agent: Cl
Product: CCc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CC(OC)C3)C2)n1

Procedure:
250 mg (0.647 mmol) of 1-[(3-methoxyazetidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 103A) and 88.7 mg (0.712 mmol) of N′-hydroxypropanimidamide hydrochloride were reacted according to the General Method 1. Yield: 151 mg (52% of theory).
Reaction SMILES: [CH2:1]([NH:8][C:9](=O)[CH:10]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)[C:11]1([OH:18])[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:28]>>[ClH:25].[ClH:28].[CH2:1]([NH:8][CH2:9][CH:10]([C:11]1([OH:18])[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCC(O)(C(C(=O)NCc2ccccc2)c2ccc(Cl)c(Cl)c2)CC1
Agent: Cl
Product: CN1CCC(O)(C(CNCc2ccccc2)c2ccc(Cl)c(Cl)c2)CC1

Procedure:
In an analogous manner to Example 1, step 2 4-[2-(benzylamino)-1-(3,4-dichlorophenyl)ethyl]-1-methylppiperidin-4-ol dihydrochloride was prepared from N-benzyl-2-(3,4-dichlorophenyl)-2-(4-hydroxy-1-methylpiperidin-4-yl)acetamide. HRMS: calcd for C21H26Cl2N2O.2.00 HCl, 464.0956; found (ESI_FT), 393.14924.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:33]=[C:32]([OH:34])[CH:31]=[CH:30][C:10]=1[C:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:17][CH:18]=2)[O:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:42][C:43]([Si:46](Cl)([CH3:48])[CH3:47])([CH3:45])[CH3:44]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:33]=[C:32]([O:34][Si:46]([C:43]([CH3:45])([CH3:44])[CH3:42])([CH3:48])[CH3:47])[CH:31]=[CH:30][C:10]=1[C:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:17][CH:18]=2)[O:13][CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=c1c(-c2ccc(O)cc2OCc2ccccc2)coc2cc(OCc3ccccc3)ccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2coc3cc(OCc4ccccc4)ccc3c2=O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 2′,7-dibenzyloxy-4′-hydroxy-isoflavone (0.450 g, 1 mmol) in 10 mL of DCM was added triethylamine (0.25 mL, 2 mmol) and TBDMSCl (0.225 g, 1.5 mmol). The reaction mixture was stirred at room temperature for ca. 6 hrs. After disappearance of starting material (TLC) the reaction was quenched with 1N HCl (ca. 2 mL). The mixture was extracted with DCM:water (2×10 mL:10 mL). The organic layer was dried over sodium sulfate and evaporated to give 0.507 g (90%) of fluffy, white solid: mp 132-133° C.; TLC Rf0.89 in hexanes:EtOAc (1:1); 1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H, OCH═), 8.04-8.02 (d, 1H, J=8.8 Hz, Ar—H5), 7.50-7.13 (m, 10+3H, C6H5, Ar—H6, H6′, H8), 6.53-6.48 (m, 2H, Ar—H3′/Ar—H5′), 5.27 (s, 2H, Ph-CH2), 5.08 (s, 2H, PhCH2), 0.93 {s, 9H, Si(CH3)3}, 0.16 {s, 6H, Si(CH3)2}; 13C NMR (100 MHz, DMSO-d6) δ 175.1, 163.3, 158.1, 157.9, 157, 155, 137.9, 136.8, 132.7, 129.2, 128.9, 128.8, 128.6, 128.1, 127.7, 127.6, 122.7, 118.4, 115.9, 115.3, 112.1, 105.9, 102.4, 70.8, 70.1, 26.2, 18.6; analysis calcd. for C35H36O5Si.0.25H2O: C, 73.78; H, 6.42. found: C, 73.85; H, 6.38.
Reaction SMILES: C([Mg]Cl)CCC.C([Li])CCC.[Br:12][C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][N:14]=1.CN(C)[CH:22]=[O:23]>O1CCCC1.CCCCCC.C(O)(=O)C.C1(C)C=CC=CC=1>[Br:12][C:13]1[N:14]=[CH:15][C:16]([CH:22]=[O:23])=[CH:17][CH:18]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc(Br)nc1
Agent: CCCC[Mg]Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=Cc1ccc(Br)nc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 66.1 %

Procedure:
n-Butylmagnesium chloride (4.00 mmol) in 2.00M tetrahydrofuran solution (2.00 mL) was added to ice-cooled n-butyllithium (8.06 mmol) in 1.55M hexane (20 mL). The mixture was stirred at 0° C. for 15 minutes to give a suspension. The suspension was added to a mixture of toluene (15 mL) and tetrahydrofuran (10 mL) containing 2,5-dibromopyridine (2.37 g, 10.0 mmol) over a period of 10 minutes or more while keeping the temperature below −5° C. to give a dark orange solution. The solution was stirred at 0° C. for 1.25 hours and then at 20° C. for one hour. The solution was cooled to 0° C., and N,N-dimethylformamide (1.0 mL, 13 mmol) was added thereto. After the mixture was stirred at 0° C. for 30 minutes, 1M aqueous acetic acid solution (20 mL) was added. The organic phase was separated, and the aqueous phase was extracted twice with ethyl acetate (10 mL). The organic phases were combined, washed with saturated aqueous sodium chloride (15 mL), dried over magnesium sulfate and concentrated under reduced pressure to remove the solvent. The resultant residue was purified by flash column chromatography on silica gel in a developing solvent system of hexane-ethyl acetate (20:1, v/v) to give the title compound (1.229 g, 66% yield) as a colorless solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1C(O)=O)=O.Br[C:17](=[CH:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19].C([O-])([O-])=O.[Na+].[Na+]>C(OC(=O)C)(=O)C.O.C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:8]2[C:9]([CH2:13][CH2:14][CH2:15]2)=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:23]=1[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)C(Br)=Cc1ccncc1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)c1cccs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(-c2ccncc2)c(-c2cccs2)n2c1CCC2

Procedure:
N-(2-Thienylcarbonyl)proline (4.69 g, 21 mmol) is dissolved in acetic anhydride (15 ml) at 60° C. (15 min), ethyl 2-bromo-3-(4-pyridyl)propenoate (6.40 g, 25 mmol) is added to the clear solution and the mixture is heated at 90° C. for 16 h, whereupon a tlc sample (Al2O3-ethyl acetate/THF 9:1) no longer indicates starting material. The cooled reaction mixture is treated with ethyl acetate (120 ml) and intensively stirred with saturated Na2CO3 solution (80 ml) for 15 min and diluted with water (50 ml). The ethyl acetate phase is separated off, the water phase is extracted with a further 3 portions of ethyl acetate (150 ml), and these organic phases are combined, washed with saturated Na2CO3 soln (50 ml) and, after drying (K2CO3 sicc.), concentrated in vacuo. 8 g are obtained as a residue, which is dissolved in a little ethyl acetate and purified by cc (Al2O3-ethyl acetate/n-hexane 2:1).
Reaction SMILES: [F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[C:8]([F:12])[C:9](N)=[CH:10][C:4]=2[O:3]1.Cl.N([O-])=O.[Na+].[I-:19].[Na+].S(=O)(O)[O-].[Na+]>O.ClCCl>[F:1][C:2]1([F:13])[O:3][C:4]2[CH:10]=[C:9]([I:19])[C:8]([F:12])=[CH:7][C:5]=2[O:6]1
Reactant: Nc1cc2c(cc1F)OC(F)(F)O2
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: O=S([O-])O
Solvent: ClCCl
Solvent: O
Product: Fc1cc2c(cc1I)OC(F)(F)O2
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 47.3 %

Procedure:
2,2,6-Trifluorobenzo[d][1,3]dioxol-5-amine (8.0 g, 42 mmol) was added to concentrated hydrochloric acid (conc. HCl; 200 mL), cooled to 5° C., vigorously stirred and treated dropwise with a solution of sodium nitrite (4.3 g, 63 mmol) in water (10 mL) over 10 min. Stirring was continued for 30 min at 5-10° C. and the mixture was poured cautiously into a solution of sodium iodide (19 g, 130 mmol) in water (200 mL), rapidly stirred with dichloromethane (100 mL). After 20 min the mixture was treated with 10% sodium bisulfite solution (NaHSO3; 20 mL) and stirred for 20 min more. The phases were separated and the aqueous phase was extracted with dichloromethane (75 mL). The combined organic phases were washed with saturated NaCl (30 mL), dried (Na2SO4) and evaporated. The residue was purified by chromatography on silica with hexane to give the title compound as a clear liquid (6 g, 51%): 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=5.0 Hz, 1H), 6.90 (d, J=6.6 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −49.63 (s), −95.24 (s); EIMS m/z 302.
Reaction SMILES: C[C:2]1[N:6]2[C:7]3[CH:8]=[CH:9][C:10]([Cl:23])=[CH:11][C:12]=3[C:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[F:22])=[N:14][CH2:15][C:5]2=C[N:3]=1.NCC1CN=C(C2C=CC=CC=2F)C2C=C(Cl)C=CC=2N1.C(O[C:49](=[O:51])[CH3:50])(=O)C>ClCCl>[C:49]([NH:3][CH:2]1[CH2:15][N:14]=[C:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=2[F:22])[C:12]2[CH:11]=[C:10]([Cl:23])[CH:9]=[CH:8][C:7]=2[N:6]1[CH3:5])(=[O:51])[CH3:50]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ncc2n1-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Agent: NCC1CN=C(c2ccccc2F)c2cc(Cl)ccc2N1
Solvent: ClCCl
Product: CC(=O)NC1CN=C(c2ccccc2F)c2cc(Cl)ccc2N1C

Procedure:
U.S Pat. No. 4,280,957 (hereinafter the '957 patent) describes a synthetic process for preparing midazolam, which is depicted in Scheme 2 below. This process includes reacting 2-aminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-bezodiazepine (II) with acetic anhydride in dichloromethane to produce 2-acetamido-methyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-bezodiazepine (III). The latter is heated with polyphosphoric acid at 150° C. to produce 8-chloro-6-(2-fluorophenyl)-3a,4-dihydro-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine of formula (IV), which is purified by column chromatography. Compound IV is then mixed with toluene and manganese dioxide and heated to reflux to afford midazolam base, which is crystallized from ether to yield a product with mp of 152-154° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:13][C:6]2=[N:7][CH:8]=[C:9]([CH:11]=O)[CH:10]=[C:5]2[CH:4]=[CH:3]1.[CH:15]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[BH3-]C#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[CH3:1][C:2]1([CH3:14])[O:13][C:6]2=[N:7][CH:8]=[C:9]([CH2:11][NH:21][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:10]=[C:5]2[CH:4]=[CH:3]1
Reactant: NC1CCCCC1
Reactant: CC1(C)C=Cc2cc(C=O)cnc2O1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)C=Cc2cc(CNC3CCCCC3)cnc2O1
Reaction time: 8 h

Procedure:
To a solution of 2,2-dimethyl-2H-pyrano[2,3-b]pyridine-6-carbaldehyde 18 (23 mg, 0.121 mmol) in MeOH (1 mL) was added cyclohexylamine (0.014 mL, 0.121 mmol), NaCNBH3 (15 mg, 0.242 mmol) and Zinc chloride (33 mg, 0.242 mmol) and stirred overnight. The solvent was removed by rotary evaporation and the residue dissolved in EtOAc and washed with 1M NaOH, water and brine, dried over MgSO4 and concentrated in vacuo. The product was used in the next step without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]2=[O:15])[CH2:3][CH2:2]1.Cl.[C:17]([C:19]1[CH:32]=[CH:31][C:22]([CH2:23][N:24]2[C:28]([CH2:29]Cl)=[CH:27][N:26]=[CH:25]2)=[CH:21][CH:20]=1)#[N:18].C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[N:1]1([CH2:29][C:28]2[N:24]([CH2:23][C:22]3[CH:31]=[CH:32][C:19]([C:17]#[N:18])=[CH:20][CH:21]=3)[CH:25]=[N:26][CH:27]=2)[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]2=[O:15])[CH2:3][CH2:2]1
Reactant: O=C1Nc2ccccc2C12CCNCC2
Reactant: N#Cc1ccc(Cn2cncc2CCl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Cn2cncc2CN2CCC3(CC2)C(=O)Nc2ccccc23)cc1
Reaction time: 15 h

Procedure:
A solution of spiro[3H-indole-3,4′-piperidin]-2(1H)-one, as described above in Step B, (110 mg, 0.54 mmol), 1-(4-cyanobenzyl)-5-chloromethylimidazole hydrochloride salt, as described in Example 1, Alternate Step A, (134 mg, 0.50 mmol), and triethylamine (0.21 mL, 1.5 mmol) in anhydrous acetonitrile (1.5 mL) was stirred at room temp. for 15 hours. The resulting mixture was diluted with ethyl acetate and the solution washed with sat'd aqueous sodium carbonate, dried (anhyd. sodium sulfate), filtered and concentrated under vacuum. The resulting residue was triturated with ethyl acetate to give a white solid which was collected to afford the title compound as a crystalline freebase, mp: 245-247° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].N1C=CC=CC=1.Cl[C:19](Cl)([O:21]C(=O)OC(Cl)(Cl)Cl)Cl>C(#N)C.C(Cl)Cl>[F:11][C:9]1[CH:8]=[CH:7][C:3]2[C:4](=[O:6])[O:5][C:19](=[O:21])[NH:1][C:2]=2[CH:10]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cc(F)ccc1C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CC#N
Product: O=c1[nH]c2cc(F)ccc2c(=O)o1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-amino-4-fluoro benzoic acid (L) (1.15 g, 7.40 mmol) in anhydrous acetonitrile (8 mL) at 55° C. were simultaneously added anhydrous pyridine (1.2 mL, 15 mmol) and a solution of triphosgene (0.73 g, 2.5 mmol) in anhydrous CH2Cl2 (5 mL) via syringe over a period of 15-20 minutes. After the addition was completed, the reaction mixture was stirred at 55° C. for another 2 hours. Much solid precipitated out. The solvent was distilled off. After cooling down to room temperature, water was added and the solid was filtered off, washed with water, followed by chilled CH2Cl2. The solid was dried under vacuum to give 7-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (M) as grayish solid. Yield: 1.02 g (76%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:41][CH2:42][C:43]([O:45]CC)=[O:44])[C:8]([C:10]1[CH:40]=[CH:39][C:13]2[N:14]([CH3:38])[C:15]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[NH:37])[NH:26][C:27]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:28])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].[OH-].[Na+]>ClCCl.CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:41][CH2:42][C:43]([OH:45])=[O:44])[C:8]([C:10]1[CH:40]=[CH:39][C:13]2[N:14]([CH3:38])[C:15]([CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:25](=[NH:37])[NH:26][C:27]([O:29][CH2:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[O:28])=[CH:23][CH:24]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)OCc3ccccc3)cc1)n2C)c1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: Cn1c(CNc2ccc(C(=N)NC(=O)OCc3ccccc3)cc2)nc2cc(C(=O)N(CCC(=O)O)c3ccccn3)ccc21
Yield: 62 %

Procedure:
Prepared analogously to Example 104 from 1-methyl-2-[N-[4-(N-benzyloxycarbonylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and sodium hydroxide solution. Yield: 62% of theory, C33H31N7O5 (605.7) Rf value: 0.26 (silica gel; dichloromethane/methanol=9:1) ##EQU133##
Reaction SMILES: [Li+].[OH-].[CH3:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[C:11]=2[CH3:20])[C:7]2[CH:21]=[C:22]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH:23]=[C:24]([C:25]([O:27]C)=[O:26])[C:6]=2[N:5]=1>C1COCC1>[CH3:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[C:11]=2[CH3:20])[C:7]2[CH:21]=[C:22]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[CH:23]=[C:24]([C:25]([OH:27])=[O:26])[C:6]=2[N:5]=1
Reactant: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C)n2Cc1cccc(C(F)(F)F)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(Cn2c(C)nc3c(C(=O)O)cc(N4CCOCC4)cc32)cccc1C(F)(F)F
Temperature: 50 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
An aqueous solution of 2 N LiOH (1.2 mL) was added to a solution of methyl 2-methyl-1-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-1H-benzimidazole-4-carboxylate, prepared as described in Example 30 (180 mg, 0.4 mmol) in THF (10 mL) and stirred at 50° C. for 1 h. When TLC showed no starting material remaining, the mixture was cooled to rt and THF was removed under reduced pressure. The pH of the mixture was acidified to pH 3. The suspension was filtered and the filtrate was collected, and washed with water (10 mL) to give the product as a white solid (152 mg, yield 88%). 1H NMR (300 MHz, DMSO-d6): δ ppm 2.46 (s, 3H), 2.54 (s, 3H), 3.10 (t, 4H, J=4.8 Hz), 3.73 (t, 4H, J=4.8 Hz), 5.63 (s, 2H), 6.37 (d, 1H, J=7.8 Hz), 7.26 (t, 1H, J=7.8 Hz), 7.35 (d, 1H, J=2.4 Hz), 7.44 (d, 1H, J=2.4 Hz), 7.62 (d, 1H, J=7.8 Hz); LC-MS: m/e=434 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:21]=1Cl)[C:7]([C:9]1[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-])=O)[CH:10]=1)=[O:8])([O-])=O.[H][H].[OH-].[Na+]>[Pd].O1CCOCC1>[NH2:1][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:16])[CH:10]=1)=[O:8]
Reactant: [H][H]
Reactant: O=C(c1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1cccc(C(=O)c2cccc(N)c2)c1

Procedure:
To a closed glass vessel equipped with a thermometer and a stirrer, there are added 102 g (0.3 moles) of 3,3'-dinitro-4,4'-dichloro benzophenone, 5 g of 5% palladium/active carbon catalyst (available from Nihon Engelhardt Co.) and 300 ml of dioxane. While the mixture is being stirred at 70°-80° C., hydrogen is introduced in the vessel so that 41.5 l (1.85 moles) of hydrogen is absorbed into the mixture over 8 hours. After addition of 80 g (0.8 moles) of 40% aqueous sodium hydroxide, hydrogen is again introduced to the vessel with the mixture being stirred at 70°-80° C., so that it is absorbed 13.8 l (0.62 moles) over 3 hours. The reaction solution is filtered at 70°-80° C. to remove the catalyst. On cooling the solution, there is obtained 3,3'-diamino benzophenone, as yellow needle-like crystals. The crystals are filtered, washed with 30 ml of 50% aqueous solution of dioxane and dried. Yield 59.2 g (93%). M.P. 149°-151° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]([N:13]1[CH2:20][CH:19]2[CH:15]([CH2:16][NH:17][CH2:18]2)[CH2:14]1)=[O:12].Cl[C:22]1[N:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][N:23]=1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]([N:13]1[CH2:20][CH:19]2[CH:15]([CH2:16][N:17]([C:22]3[N:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][N:23]=3)[CH2:18]2)[CH2:14]1)=[O:12]
Reactant: COc1ccnc(Cl)n1
Reactant: COc1ccc(C(=O)N2CC3CNCC3C2)c(OC)c1
Product: COc1ccc(C(=O)N2CC3CN(c4nccc(OC)n4)CC3C2)c(OC)c1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 38 and 2-chloro-4-methoxypyrimidine. MS (ESI): mass calculated for C20H24N4O4, 384.43; m/z found 385.2 [M+H]+.