Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[N:16]=[C:15]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([OH:24])=[C:19]([CH2:25][CH3:26])[CH:18]=4)[O:14][N:13]=3)[CH:9]=[C:8]([O:27][CH3:28])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:29]([C@@H:31]1[O:33][CH2:32]1)Cl>C(O)(C)C.[OH-].[Na+].CC(=O)OCC>[CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[N:16]=[C:15]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH2:29][C@@H:31]5[CH2:32][O:33]5)=[C:19]([CH2:25][CH3:26])[CH:18]=4)[O:14][N:13]=3)[CH:9]=[C:8]([O:27][CH3:28])[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: ClC[C@H]1CO1
Reactant: CCc1cc(-c2nc(-c3cc(OC)nc(C4CCCC4)c3)no2)cc(C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCc1cc(-c2nc(-c3cc(OC)nc(C4CCCC4)c3)no2)cc(C)c1OC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 72 h
Yield: 55.8 %

Procedure:
A mixture of 4-[3-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1,2,4]oxadiazol-5-yl]-2-ethyl-6-methyl-phenol (150 mg, 395 μmol) and (R)-epichlorohydrine (366 mg, 3.95 mmol) in isopropanol (4 mL) and 3 N aq. NaOH (1 mL) is stirred at rt for 72 h. The mixture is diluted with EA (50 mL), washed with 1 M aq. NaOH solution (20 mL) followed by brine (20 mL), dried over MgSO4, filtered and concentrated. The crude product is purified on prep. TLC plates using heptane:EA 1:1 to give 2-cyclopentyl-4-[5-((S)-3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-6-methoxy-pyridine (96 mg) as a pale yellow oil; LC-MS**: tR=1.02 min, [M+H]+=436.18.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][CH3:10])[N:5]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:13][CH:12]=2)[C:4](=[O:23])[CH:3]=1.[C:24](Cl)(=[O:27])[CH:25]=[CH2:26].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CN(C)C(=O)C>[CH2:8]([C:6]1[N:5]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]([F:22])([F:20])[F:21])=[CH:15][CH:16]=2)[C:4](=[O:23])[C:3]2[CH2:26][CH2:25][C:24](=[O:27])[NH:1][C:2]=2[N:7]=1)[CH2:9][CH3:10]
Reactant: CCCc1nc(N)cc(=O)n1-c1ccc(OCC(F)(F)F)cc1
Reactant: C=CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCCc1nc2c(c(=O)n1-c1ccc(OCC(F)(F)F)cc1)CCC(=O)N2
Reaction time: 0.5 h

Procedure:
To a solution of 6-amino-2-propyl-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrimidin-4(3H)-one (270 mg) in N,N-dimethylacetamide (15 mL) was added acryloyl chloride (0.20 mL) at 0° C., and the mixture was stirred for 30 min, and then at room temperature overnight. To the reaction mixture was added potassium carbonate (570 mg) at room temperature, and the mixture was stirred for 1 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution under ice-cooling, and the mixture was extracted with a mixed solvent of ethyl acetate and THF. The extract was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (59.6 mg) as a solid.
Reaction SMILES: [C:1]([CH2:4][C:5]1([C:12]([OH:14])=[O:13])[CH2:9][CH2:8][C:7]([CH3:11])([CH3:10])[CH2:6]1)([OH:3])=O>C(OC(=O)C)(=O)C>[CH3:11][C:7]1([CH3:10])[CH2:8][CH2:9][C:5]2([C:12](=[O:13])[O:14][C:1](=[O:3])[CH2:4]2)[CH2:6]1
Reactant: CC1(C)CCC(CC(=O)O)(C(=O)O)C1
Solvent: CC(=O)OC(C)=O
Product: CC1(C)CCC2(CC(=O)OC2=O)C1
Temperature: 25 °C

Procedure:
To a round bottomed flask equipped with a stir bar and reflux condenser, were added 1-(carboxymethyl)-3,3-dimethylcyclopentanecarboxylic acid (1.1 g, 5.5 mmol) and acetic anhydride (20 mL). The reaction mixture was refluxed for 3 h, cooled to RT, and concentrated to dryness to afford the title compound as a colorless solid. 1H NMR (300 MHz, DMSO-d6) δ 2.89 (s, 2H), 2.43-2.24 (m, 1H), 2.20-2.15 (m, 2H), 1.87-1.49 (m, 6H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][NH:20][CH:21]3[C:30]4[C:25](=[C:26]([O:31][Si](C(C)(C)C)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:27]=[CH:28][CH:29]=4)[CH2:24][CH2:23][CH2:22]3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][NH:20][CH:21]3[C:30]4[C:25](=[C:26]([OH:31])[CH:27]=[CH:28][CH:29]=4)[CH2:24][CH2:23][CH2:22]3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCCC2NCCc1nc(-c2ccccc2)c(-c2ccccc2)o1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Oc1cccc2c1CCCC2NCCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.9 %

Procedure:
A solution of 5-(t-butyldiphenylsilyloxy)-1-oxo-1,2,3,4-tetrahydronaphthalene (0.52 g), 2-(4,5-diphenyloxazol-2-yl)ethylamine (0.33 g) and p-toluenesulfonic acid (catalytic amount) in toluene (30 ml) was refluxed for 15 hours with Dean-stark equipment. The solution was evaporated in vacuo and MeOH (10 ml) was added to the residue. To the MeOH solution, NaBH4 (0.21 g) was added at 0° C. After being stirred for 30 minutes at room temperature, the solution was evaporated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine. The dried solvent was evaporated in vacuo, and the residue was purified by chromatography on silica gel to give 1-[2-(4,5-diphenyloxazol-2-yl)ethylamino]-1,2,3,4-tetrahydro-5-(t-butyldiphenylsilyloxy)naphthalene (0.25 g) and 1-[2-(4,5-diphenyloxazol-2-yl)ethylamino]-1,2,3,4-tetrahydro-5-hydroxynaphthalene (0.11 g). To a solution of 1-[2-(4,5-diphenyloxazol-2-yl)ethylamino]-1,2,3,4-tetrahydro-5-(t-butyldiphenylsilyloxy)naphthalene (0.25 g) in THF (2 ml) was added 1M-THF solution (2 ml) of tetra-n-butyl ammonium fluoride (TBAF). After being stirred for 1 hour at room temperature, the reaction mixture was partitioned between ethyl acetate and sat. NaHCO3. The organic layer was washed with brine. The dried solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel to give 1-[2-(4,5-diphenyloxazol-2-yl)ethylamino]-1,2,3,4-tetrahydro-5-hydroxynaphthalene (0.06 g).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](/[CH:13]=[CH:14]/[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:12]>CC(O)=O.CO.C(Cl)Cl.[Pd]>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([CH2:13][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:12]
Reactant: O=C(/C=C/c1cccnc1)c1ccc2ccccc2c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: O=C(CCc1cccnc1)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.8 %

Procedure:
A mixture of (2-naphthyl) [(E)-2-(3-pyridyl)-1-ethenyl]ketone (5.02 g) and palladium black (0.15 g) in AcOH—MeOH—CH2Cl2 (4 ml/50 ml/20 ml) was stirred under hydrogen atmosphere at room temperature for 3 hours. The catalyst was filtered off and the filtrate was concentrated in vacuo. The residue dissolved in ethyl acetate, washed with saturated aqueous NaHCO3 solution and brine, and dried. After removal of the solvent, the residue was recrystallized from hexane-ethyl acetate to give the titled compound (3.48 g) as colorless prisms.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12].[OH2:15].[OH2:16].[Sn](Cl)(Cl)(Cl)Cl>C(OCC)(=O)C>[NH2:8][C:5]1[CH:6]=[CH:7][C:2](/[CH:1]=[CH:1]/[C:2]2[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=2[S:11]([NH2:14])(=[O:16])=[O:15])=[C:3]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:4]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1S(N)(=O)=O
Reactant: O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: Nc1ccc(/C=C/c2ccc(N)cc2S(N)(=O)=O)c(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.2 %

Procedure:
In a round bottom flask under nitrogen was placed 5-nNitro-2-[(E)-2-(4-nitro-2-(aminosulfonyl)phenyl)ethenyl]benzenesulfonamide (Example 51, 0.38 g, 0.887 mmol) and 40 mL of ethyl acetate added. To this mixture was added tin chloride dihydrate (1.00 g, 4.44 mmol) and a reflux condenser was attached. The solution was heated in an oil bath to 80 C. and stirred for 16 hours. After cooling to room temperature the solution was diluted with ethyl acetate (250 mL) and washed with saturated sodium bicarbonate. The whole mixture was filtered thru Celite and the aqueous layer discarded. The organics were then washed with brine, dried (MgSO4) and concentrated on a rotovap to dryness. The crude material was then recrystallized from 10% methanol/dichloromethane and dried under vacuum to afford 100 mg of the title compound as a dark yellow solid (31%): 1HNMR (DMSO-d6) δ7.58 (d, J=8.5 Hz, 2H), 7.49 (s, 2H), 7.31 (br s, 4H), 7.15 (d, J=2 Hz, 2H), 6.75 (dd, J=8.5 Hz, 2 Hz, 2H), 5.65 (br s, 4H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([NH2:12])=[O:11])=[N:2]1.Br[CH2:14][CH2:15][CH2:16][O:17][CH3:18].[H-].[Na+].O>CN(C=O)C>[CH3:18][O:17][CH2:16][CH2:15][CH2:14][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[C:3]([C:10]([NH2:12])=[O:11])=[N:2][NH:1]2
Reactant: NC(=O)c1n[nH]c2ccccc12
Reactant: COCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCCc1cccc2[nH]nc(C(N)=O)c12
Temperature: 60 °C

Procedure:
Following the procedure for converting Compound 1e to Compound 1f, the indazole amide Compound 1e (0.31 g, 17.8 mmol) was treated with 1-bromo-3-methoxypropane (0.3 g, 19.6 mmol) in the presence of 95% NaH (0.05 g, 19.6 mmol) in DMF (50 mL) at 0° C. for 20 min and then warmed to 60° C. for 2 h. The mixture was cooled down to rt. Water was added and the aqueous solution was extracted with EtOAc several times. The organic layers were combined and washed with brine, then dried (Na2SO4) and evaporated in vacuo to an oil. The oil was purified by flash column chromatography (96:4:0.4; DCM:MeOH:NH4OH) to afford a 3-methoxypropyl indazole amide analog of Compound 1f (0.32 g, 73%). 1H NMR (CDCl3) δ 7.69 (d, J=8.13 Hz, 1H), 7.4 (m, 2H), 7.17 (m, 1H), 6.57 (bd s, 1H), 5.39 (bd s, 1H), 4.47 (t, J=6.65 Hz, 2H), 3.96 (s, 2H), 3.30 (t, J=5.78 Hz, 2H), 3.28 (s, 3H), 2.16 (m, 2H). ES-MS m/z 248 (MH+).
Reaction SMILES: Cl[C:2]1[C:3]([C:19]#[N:20])=[N:4][CH:5]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH:7]=1.[CH3:21][C:22]1[CH:23]=[CH:24][C:25](B2OC(C)(C)C(C)(C)O2)=[C:26]([NH:28]C(=O)OC(C)(C)C)[CH:27]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C(O)CCC>[CH2:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]#[C:8][C:6]2[CH:5]=[N:4][C:3]3[C:2]([CH:7]=2)=[C:25]2[CH:24]=[CH:23][C:22]([CH3:21])=[CH:27][C:26]2=[N:28][C:19]=3[NH2:20])=[CH:11][CH:12]=1)[CH3:18]
Reactant: CCOc1ccc(C#Cc2cnc(C#N)c(Cl)c2)cc1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(NC(=O)OC(C)(C)C)c1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCCCO
Product: CCOc1ccc(C#Cc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a round bottom flask with refluxing condenser were added 3-chloro-5-((4-ethoxyphenyl)ethynyl)picolinonitrile (from the previous step) (1 eq.), tert-butyl 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (from Example 5/Step 2) (1.25 eq.), K3PO4 (2 eq.), tris(dibenzylideneacetone)dipalladium(0) (0.05 eq.), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.1 eq.). n-Butanol and water (5:2, 0.2 M) were added, and the content were degassed (vacuum followed by nitrogen flush) for three times. The reaction mixture was stirred vigorously under nitrogen at 100° C. overnight in an oil bath. The content were cooled down and were taken up in 200 mL of water followed by extraction with methylene chloride. Combined organic layers were dried (Na2SO4) and concentrated. Flash chromatography (silica gel, 0-50% EtOAc in CH2Cl2) afforded the product 2-((4-ethoxyphenyl)ethynyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.C(O)(=O)C.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Fc1ccc(CN2CCOCC2)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 72 %

Procedure:
A solution of 3-bromo-4-fluorobenzaldehyde (50.0 g) in 1,2-dichloroethane (500 mL) is cooled to 0° C. Acetic acid (14.1 mL) and morpholine (23.6 mL) are added slowly, maintaining the temperarture below 4° C. Sodium triacetoxyborohydride (78.3 g) is added all at once, maintaining the temperature below 5° C. The mixture is allowed to warm to rt and stirred for 18 hrs. The reaction is quenched with 1 N NaOH (200 mL) and extracted with CH2Cl2 (500 mL). The organic layer is washed with 1 N NaOH (2×200 mL). The aqueous layers are combined and back-extracted with CH2Cl2 (100 mL). The organic layers are combined and extracted with 0.5 N HCl (5×250 mL). The acidic aqueous layers are combined, and 2 N NaOH is added until the solution is basic (pH=12). The aqueous layer is then extracted with CH2Cl2 (6×100 mL). The organic layers are combined, dried (MgSO4) and concentrated in vacuo to a clear, colorless oil. The crude product is distilled (126° C., 0.3 Torr) to afford 48.9 g (72%) of the title compound as a clear, colorless oil. Physical characteristics: Bp 126° C. (0.3 Torr); 1H NMR (300 MHz, DMSO-d6) δ 7.62, 7.35-7.29, 3.56, 3.45, 2.34; 13C NMR (75 MHz, DMSO-d6) 8 157.3, 136.1, 133.3, 129.8, 116.2, 107.7, 66.1, 60.9, 53.0; IR (liq.) 2855, 2807, 1495, 1455, 1348, 1257, 1244, 1118, 1009, 862 cm−1; MS (ESI+) m/z 274 (M+H)+. Anal. Calcd for C11H13BrFNO: C, 48.20; H, 4.78; N, 5.11; Br, 29.15. Found: C, 48.04; H, 4.79; N, 5.11; Br, 28.18.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:6](=[CH:8][S:9][CH:10]=2)[N:7]=1.[CH3:12][CH2:13][O-:14].[Na+].O>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]([O:14][CH2:13][CH3:12])[C:5]2[C:6](=[CH:8][S:9][CH:10]=2)[N:7]=1
Reactant: CC[O-]
Reactant: Clc1nc(Cl)c2cscc2n1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1nc(Cl)nc2cscc12
Reaction time: 2 h

Procedure:
6.15 g (0.03 mole) of 2,4-dichloro-thieno[3,4-d]pyrimidine are suspended in 250 ml. of absolute alcohol at 0°C. Whilst agitating constantly a solution of 0.03 mole sodium ethylate in ethyl alcohol is added drop by drop. The speed of addition is regulated in such a manner that the temperature of the reaction medium is maintained at between 0° and 5°C. One obtains a clear solution in which a precipitate is gradually formed. When the addition is completed, the agitation is continued for a further 2 hours at ordinary temperature. The reaction mixture is then poured into 2 liters of iced water and the precipitate formed is filtered off, washed with water and then dried in vacuo. After recrystallization from toluene, 5.2 g of 2-chloro-4-ethoxythieno[3,4-d]pyrimidine are obtained (81% of theory). M.P. 136°-140°C.
Reaction SMILES: [NH2:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([F:11])[CH:3]=1.[C:12]([C:16]1[CH:25]=[CH:24][C:19]([CH2:20][N:21]=[C:22]=[S:23])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>C(OCC)(=O)C>[NH2:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH2:6][NH:7][C:22]([NH:21][CH2:20][C:19]2[CH:24]=[CH:25][C:16]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:17][CH:18]=2)=[S:23])=[C:4]([F:11])[CH:3]=1
Reactant: CC(C)(C)c1ccc(CN=C=S)cc1
Reactant: NCc1cc(F)c(N)cc1F
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(CNC(=S)NCc2cc(F)c(N)cc2F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 25.1 %

Procedure:
The compound (330 mg) obtained in Step 1 and 4-t-butylbenzylisothiocyanate (428 mg) were dissolved in ethyl acetate (40 ml) and the solution was stirred at room temperature for 6 hours. The mixture was concentrated under reduced pressure and the residue was purified by column-chromatography (ethyl acetate/hexane=1/3) to yield the compound 1-13 (190 mg, 25%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:31]#[N:32])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][C@H:25]3[CH2:29][CH2:28][CH2:27][O:26]3)[C:17]([O:19]C(C)(C)C)=[O:18])[C:10](=[O:30])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:31]#[N:32])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][C@H:25]3[CH2:29][CH2:28][CH2:27][O:26]3)[C:17]([OH:19])=[O:18])[C:10](=[O:30])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(C[C@H]2CCCO2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(C[C@H]2CCCO2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
625 mg (purity 76%, 1.0 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[(2R)-tetrahydrofuran-2-yl]propanoate (mixture of enantiomerically pure diastereomers 1 and 2) were hydrolysed with TFA according to General Method 6A. Yield: 585 mg (purity 73%, quant.)
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[CH:11][N:10]=2)[N:6]=[CH:5]1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].CO>C(Cl)Cl>[CH3:19][S:20]([O:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[CH:11][N:10]=2)[N:6]=[CH:5]1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccnc(-c2cn(CCO)cn2)c1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 0° C. solution of methyl 2-[1-(2-hydroxyethyl)-1H-imidazol-4-yl]pyridine-4-carboxylate (500 mg, 2 mmol) in DCM (10 mL) was added TEA (255 mg, 2.5 mmol) followed by drop-wise addition of a solution of methanesulfonyl chloride (255 mg, 2.22 mmol) in DCM (2 mL). The solution was stirred at 0° C. for 1 hr and then allowed to warm to r.t. where stirring was continued for 1 hr. MeOH (1 mL) was then added and stirring was continued for 30 min. The solution was diluted with DCM (50 mL), washed with water (50 mL), dried (MgSO4), filtered, and concentrated to give the title compound as an oily residue (649 mg).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4]([O:14][CH2:15][CH:16]([OH:20])[CH2:17][NH:18][CH3:19])=[CH:3][CH:2]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1)[CH:26]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(O)(=O)C>[CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4]([O:14][CH2:15][CH:16]([OH:20])[CH2:17][N:18]([CH2:26][C:25]2[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=[C:23]([O:22][CH3:21])[CH:24]=2)[CH3:19])=[CH:3][CH:2]=1
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: CNCC(O)COc1cccc2[nH]c3ccccc3c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(CN(C)CC(O)COc2cccc3[nH]c4ccccc4c23)cc(OC)c1
Yield: 13 %

Procedure:
The reaction of 1-(9H-carbazol-4-yloxy)-3-(methylamino)propan-2-ol (0.20 g, 0.74 mmol) with 3,5-dimethoxybenzaldehyde (0.185 g, 1.11 mmol) in the presence of 2-3 drops of glacial acetic acid and Na(OAc)3BH (0.157 g, 0.578 mmol) following the procedure similar to the one described in example 26, afforded the title compound as a brown colored paste (0.045 g, 13% yield) with 1H NMR (400 MHz, DMSO): δ 2.25(s, 3H), 3.40-3.60 (m, 2H), 3.51 (s, 2H), 3.65 (s, 6H), 4.10-4.13 (m, 1H), 4.15-4.25 (m, 2H), 5.00 (s, 1H), 6.31 (s, 1H), 6.49 (d, 2H, J=1.6 Hz), 6.67 (d, 1H, J=8.0 Hz), 7.05-7.12 (m, 2H), 7.25-7.35 (m, 2H), 7.43 (d, 1H, J=8 Hz), 8.17 (d, 1H, J=8.0 Hz), 11.23 (s, 1H). MS m/z: 421.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24](O)=[O:25])=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([F:36])([F:35])[F:34].C(Cl)(=O)C(Cl)=O.[CH3:43][N:44]([CH3:55])[CH2:45][CH2:46][CH2:47][NH:48][CH2:49][CH2:50][CH2:51][N:52]([CH3:54])[CH3:53].C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C=O>[CH3:54][N:52]([CH3:53])[CH2:51][CH2:50][CH2:49][N:48]([CH2:47][CH2:46][CH2:45][N:44]([CH3:43])[CH3:55])[C:24]([C:21]1[N:13]2[C:12]([CH2:11][N:10]([C:8]([C:6]3[CH:5]=[CH:4][C:3]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]([F:35])([F:36])[F:34])=[C:2]([CH3:1])[CH:7]=3)=[O:9])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14]2)=[CH:23][CH:22]=1)=[O:25]
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)O)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Reactant: CN(C)CCCNCCCN(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)N(CCCN(C)C)CCCN(C)C)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Reaction time: 2 h
Yield: 35.7 %

Procedure:
A suspension of 10-[(2-methyl-2′-trifluoromethyl-[1,1 l′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Example 1, Step F (0.50 g, 1.02 mmol) in dichloromethane (5 mL) containing a few drops of N,N-dimethylformamide was treated dropwise under nitrogen with oxalyl chloride (0.12 mL, 1.38 mmol). After gas evolution subsided, the reaction mixture was refluxed for an additional 15 minutes. The cooled solution was evaporated to dryness to give the crude acid chloride as a brown solid. The acid chloride was then dissolved in dichloromethane (5 mL) and slowly added to a solution of bis-(3-dimethylamino-propyl)-amine (0.90 mL, 4.04 mmol) and N,N-diisopropylethyl amine (1.1 mL, 6.31 mmol) in dichloromethane (5 mL). After stirring for 2 hours, the reaction was quenched with water. The organic layer was sequentially washed with 1 N hydrochloric acid, 1 N sodium hydroxide and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a brown oil. Purification was achieved by preparative HPLC on a Primesphere S C18 column (0.21×15 cm) using a solvent gradient from 60:40:0.1 to 80:20:0.1 acetonitrile-water-trifluoroacetic acid. After removal of the acetonitrile in vacuo, the aqueous solution was basified with 2.5 N sodium hydroxide then extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (0.24 g) as a white foam, m.p. 55–64 ° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][CH2:14][N:13]([C:17](OC(C)(C)C)=O)[CH2:12]1)[CH2:10][C:9]2=[O:28].C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][CH2:14][N:13]([CH3:17])[CH2:12]1)[CH2:10][C:9]2=[O:28]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C(=O)OC(C)(C)C)C1)O2
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C)C1)O2
Yield: 96.3 %

Procedure:
(±)-(E)-3-[1′-Methyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid methyl ester was synthesized starting from Intermediate 2 (800 mg, 2.37 mmol), according to the procedure for preparation of Example 13, Step A, using aqueous 37% formaldehyde solution (0.212 ml, 2.85 mmol), and NaBH(OAc)3 (754 mg, 3.55 mmol) giving (±)-(E)-3-[1′-methyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid methyl ester as yellow solid (720 mg).