Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC[CH:10]1[CH2:15][O:14][CH:13]([N:16]2[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:12][S:11]1)C1C=CC=CC=1.B(Cl)(Cl)Cl.[CH3:29][OH:30].C(Cl)Cl>C(Cl)Cl>[OH:30][CH2:29][SH:11]1[CH2:10][CH2:15][O:14][CH:13]([N:16]2[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:12]1
Reactant: Cc1cn(C2CSC(COCc3ccccc3)CO2)c(=O)[nH]c1=O
Reactant: CO
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: Cc1cn(C2C[SH](CO)CCO2)c(=O)[nH]c1=O
Temperature: -78 °C
Reaction time: 4 h

Procedure:
1-(5-Benzyloxymethyl-1,4-oxathian-2-yl)thymine (0.14 g) was dissolved in methylene chloride (10 ml), and the solution cooled to -78° C. To the solution, 1M boron trichloride (4.1 ml) was added dropwise, and the mixture stirred at the same temperature for 4 hours. After adding a mixed solution of methanol-methylene chloride (1/1, 8 ml), the temperature of the reaction mixture was raised to room temperature. Upon concentrating the reaction mixture under reduced pressure, the resultant dark brown oil was purified on a silica gel column (eluent: chloroform/methanol=20/1) to obtain the desired product (0.07 g) as pale yellow solid.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[N:12]=[C:11]([CH3:13])[CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7](=[O:51])[N:8]2[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[N:28]=[N:29][N:30](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:31]=2)=[CH:17][CH:16]=1>ClCCl.CO>[ClH:1].[CH3:2][C:3]1[N:12]=[C:11]([CH3:13])[CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7](=[O:51])[N:8]2[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[NH:28][N:29]=[N:30][N:31]=2)=[CH:17][CH:16]=1
Reactant: Cc1cc2c(ccc(=O)n2Cc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(C)n1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: Cc1cc2c(ccc(=O)n2Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(C)n1
Reaction time: 0.5 h

Procedure:
Concentrated hydrochloric acid (0.3 ml) was added to a solution of 5,7-dimethyl-1-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,6-naphthyridin-2(1H)-one (280 mg) (A) in dichloromethane/methanol (4 ml) (3:1 v/v) and the mixture was stirred for 30 minutes. Volatile material was removed by evaporation and the residue was stirred with ether. The insoluble solid was collected by filtration and recrystallised from ethanol/methanol (1:1 v/v) to give 5,7-dimethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,6-naphthyridin-2(1H)-one hydrochloride (105 mg), as a solid, m.p. 278°-280° C. (decomposition); NMR (d6 -DMSO): 2.68(s,3H), 2.96(s,3H), 5.51(s,2H), 6.94(d,1H), 7.05(d,2H), 7.17(d,2H), 7.45-7.71(m,5H), 8.31(d,1H); mass spectrum (positive fast atom bombardment (+ve FAB), DMSO/methanol/nitrobenzyl alcohol(NBA)): 409(M+H)+ ; microanalysis, found: C, 64.1; H, 4.6; N, 18.7%; C24H20N6O.HCl.0.2H2O requires: C,64.1; H,4.8; N,18.7%.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[NH:10][CH:11]([CH3:23])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([OH:22])[CH:20]=2)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](=O)([O-])[O-].[Cs+].[Cs+].IC.[Cl-].[NH4+]>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:24])[NH:10][CH:11]([CH3:23])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:25])[CH:20]=2)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC(Cn1ncc2ccc(O)cc21)NC(=O)OCc1ccccc1
Agent: [Cl-]
Agent: [Cs+]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc2cnn(CC(C)NC(=O)OCc3ccccc3)c2c1
Reaction time: 3 h
Yield: 58.2 %

Procedure:
To a solution of the product from Step A (0.95 g, 3.19 mmol) in DMF (10 mL) was added cesium carbonate (1.26 g, 3.70 mmol) followed by iodomethane (0.23 mL, 3.70 mmol) at room temperature. After stirring for 3 h, saturated aqueous ammonium chloride (30 mL) was added and the mixture extracted with ethyl acetate (3×65 mL). The combined extracts were washed with brine (10 mL), dried (MgSO4) and evaporated to a residue which was purified by chromatography (silica, 20% ethyl acetate in hexane to 30% ethyl acetate in hexane) to give a syrup (0.63 g, 92%): MS (ES) m/z 340(M+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2].[CH3:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[C:31]([O:38][CH3:39])[CH:30]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[C:33]1[CH:34]=[C:29]([CH3:28])[CH:30]=[C:31]([O:38][CH3:39])[CH:32]=1)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2]
Reactant: COc1cc(C)ccc1B(O)O
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1-c1cc(C)cc(OC)c1

Procedure:
4-Trifluoromethanesulfonyloxy-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (208 mg, 0.5 mmol), 4-methyl-2-methoxylphenylboronic acid (92 mg, 0.55 mmol), tetrakis(triphenylphosphine)palladium(0) (29 mg) and potassium phosphate (159 mg, 0.75 mmol) were heated together in dioxane (5 mL) to 80° C. overnight. The reaction mixture was then diluted with ethyl acetate and washed with brine twice. The organic layer was dried over sodium sulfate and concentrated to yield a yellow oil which was purified by flash column eluted with 30% ethyl acetate in hexane, then recrystallization from ethyl ether to yield 4-(3-methoxy-5-methyl-phenyl)-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester as a white powder.
Reaction SMILES: Br[C:2]1[C:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C:6]=2[C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])=[C:4]([F:26])[CH:3]=1.ClN1C(=O)CC[C:29]1=O.C[Sn](C)(C)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C(C)=CC=CC=1>[CH3:11][C:9]1([CH3:12])[O:8][C:7]2[C:2]([CH3:29])=[CH:3][C:4]([F:26])=[C:5]([N:13]3[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]3=[O:25])[C:6]=2[O:10]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Br)c3c2OC(C)(C)O3)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Sn](C)(C)C
Solvent: Cc1ccccc1C
Product: Cc1cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c2c1OC(C)(C)O2
Temperature: 120 °C

Procedure:
Synthesis of this compound starts with 3-(7-bromo-2,2-dimethyl-5-fluoro-1,3-benzodioxol-4-yl)-1-methyl-6-trifluoromethyluracil (Compound 17) which may be synthesized using the methods of Example 1, Steps F through H, by substituting N-bromosuccinimide for N-chlorosuccinimide in Step F. In a tube are placed 2.2 g (0.005 mole) of 3-(7-bromo-2,2-dimethyl-5-fluoro- 1,3-benzodioxol-4-yl)- 1 -methyl-6-trifluoromethyluracil, 0.95 g (0.0053 mole) of tetramethyl tin, 0.05 g (0.00005 mole) of tetrakis(triphenylphosphine)palladium(0), and 3 mL of xylene. The tube is sealed and heated at 120 ° C for approximately 20 hours after which it is cooled, the seal is broken, and the contents are removed. The reaction mixture is passed through a column of silica gel, eluting with heptane/ethyl acetate ( 1:1 ). The product-containing fractions are combined, and the solvent is evaporated under reduced pressure, yielding 3-(2,2-dimethyl-5-fluoro-7-methyl- 1,3-benzodioxol-4-yl)- 1 -methyl-6-trifluoromethyluracil as the residue.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][CH:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]2)=[N:22][CH:23]=1.[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([Cl:54])[C:40]=1[OH:55]>>[NH2:30][CH:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:21]2[N:20]=[CH:19][C:18]([NH:17][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:43]5[CH:44]=[C:39]([Cl:38])[C:40]([OH:55])=[C:41]([Cl:54])[CH:42]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])=[CH:23][N:22]=2)[CH2:25]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NC1CCCN(c2ncc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Product: NC1CCCN(c2ncc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)cc34)cn2)C1
Yield: 5.6 %

Procedure:
Following general procedure D, tert-butyl 1-(5-(6-bromo-3-(cyclopropanecarbonyl)quinoline-4-ylamino)pyrimidin-2-yl)piperidin-3-ylcarbamate (150 mg, 0.26 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (112 mg, 0.39 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (8.0 mg, 8% over 2 steps) as a yellow solid. 1H NMR (500 MHz, MeOD+TFA-d) δ 9.33 (br s, 1H), 8.44 (s, 2H), 8.27 (dd, J=8.9, 1.8 Hz, 1H), 8.29-8.19 (m, 1H), 8.04 (d, J=8.9 Hz, 1H), 7.44 (br s, 2H), 4.81-4.71 (m, 1H), 4.48-4.44 (m, 1H), 3.46-3.31 (m, 3H), 2.84-2.77 (m, 1H), 2.23-2.16 (m, 1H), 1.96-1.87 (m, 1H), 1.80-1.60 (m, 2H), 1.21-1.15 (m, 4H); ESI MS m/z 549 [C28H26Cl2N6O2+H]+; HPLC>99% (AUC), tR=11.00 min.
Reaction SMILES: ClC(Cl)(OC(=O)[O:6][C:7]([Cl:10])(Cl)Cl)Cl.[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]2[CH2:25][NH:24][CH2:23][CH:22]2[N:26]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[C:31]([F:39])[CH:30]=2)[CH3:27])[CH:17]=[CH:18][C:19]=1[Cl:20].N1C=CC=CC=1>C(Cl)Cl>[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]2[CH:22]([N:26]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:37])([F:38])[F:36])=[C:31]([F:39])[CH:30]=3)[CH3:27])[CH2:23][N:24]([C:7]([Cl:10])=[O:6])[CH2:25]2)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN(Cc1ccc(C(F)(F)F)c(F)c1)C1CNCC1c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(Cc1ccc(C(F)(F)F)c(F)c1)C1CN(C(=O)Cl)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 137.3 %

Procedure:
To a stirred solution of carbonic acid ditrichloromethyl ester (triphosgene) (37 mg, 0.125 mmol) in CH2Cl2 (10 ml) at −78° C., was added a solution of [(3RS,4SR)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-(3-fluoro-4-trifluoromethyl-benzyl)-methyl-amine (Intermediate VIII-1), (130 mg, 0.31 mmol) and pyridine (0.05 ml, 0.68 mmol) in CH2Cl2 (5 ml) over 30 minutes. The temperature was raised to RT, and stirring was continued for 2 hours. The organic phase was washed with H2O, dried over Na2SO4. Purification by flash chromatography (SiO2, EtOAc/Hx 1:2) yielded 83 mg (55%) of the title compound as a light yellow oil.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][P:11](=[O:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:21]>CO.[OH-].[OH-].[Pd+2]>[ClH:21].[C:14]1([P:11]2(=[O:20])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=P1(c2ccccc2)CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: O=P1(c2ccccc2)CCNCC1
Reaction time: 18 h

Procedure:
A mixture of 1-benzyl-4-phenyl-1,4-azaphosphinane 4-oxide (1.18 g, 4.14 mmol), 20% Pd(OH)2/C (290 mg, 0.41 mmol), and concentrated HCl (0.75 mL) in MeOH (75 mL) was hydrogenated at 45 psi for 18 h. The mixture was filtered through Celite and evaporated. The solid residue was slurried in EtOAc and filtered to give the title compound as an off-white solid. 1H NMR (DMSO-d6, 600 MHz) δ 9.87 (bs, 1H), 9.28 (bs, 1H), 7.86-7.79 (m, 2H), 7.66-7.61 (m, 1H), 7.60-7.56 (m, 2H), 3.52-3.34 (m, 4H), 2.75-2.65 (m, 2H), 2.24-2.13 (m, 2H). MS: cal'd 196 (MH+), exp 196 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]O)=[CH:6][C:5]([S:10]([NH2:13])(=[O:12])=[O:11])=[C:4]([F:14])[CH:3]=1.P(Br)(Br)[Br:16]>C(Cl)Cl>[Br:16][CH2:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([F:14])=[C:5]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:6]=1
Reactant: NS(=O)(=O)c1cc(CO)c(Cl)cc1F
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: NS(=O)(=O)c1cc(CBr)c(Cl)cc1F
Reaction time: 24 h
Yield: 88.1 %

Procedure:
To a solution of 2-chloro-4-fluoro-5-sulfamoylbenzoic acid (3.2 g, 12.65 mmol) in THF (10 mL) was added 1M BH3 THF (38 mL, 38.0 mmol). After stirring 12 h, the reaction mixture was quenched with MeOH and concentrated in vacuo. The residue was purified by chromatography (silica, EtOAc-Hex) to afford 4-chloro-2-fluoro-5-(hydroxymethyl)benzenesulfonamide (1.9 g). To a suspension of 4-chloro-2-fluoro-5-(hydroxymethyl)benzenesulfonamide (1.78 g, 7.43 mmol) in DCM (10 mL) was added PBr3 (2.21 g, 8.17 mmol). The reaction was stirred for 24 h when it was determined to be complete by GCMS. The reaction was carefully quenched with H2O and then partitioned between THF and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford 5-(bromomethyl)-4-chloro-2-fluorobenzenesulfonamide (1.98 g) as an off-white solid. 1H-NMR (DMSO-d6, 400 MHz) δ 8.08 (d, J=7.8 Hz, 1H), 7.84 (s, 2H), 7.80 (d, J=9.9 Hz, 1H), 4.83 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH:19]=[CH2:20])[C:12]([C:21]2[N:22](C3CCCCO3)[N:23]=[CH:24][CH:25]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+]>Cl.CO>[C:35]([O:34][C:32]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH:19]=[CH2:20])[C:12]([C:21]2[NH:22][N:23]=[CH:24][CH:25]=2)=[CH:11][CH:10]=1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: C=Cc1c(-c2ccnn2C2CCCCO2)ccc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1C(=O)OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: C=Cc1c(-c2ccn[nH]2)ccc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 108.9 %

Procedure:
A mixture of methyl 6-[bis-(tert-butoxycarbonyl)amino]-3-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-2-vinylbenzoate (Intermediate 10, 2.6 g) and concentrated hydrochloric acid (3 drops) in methanol (80 mL) was stirred at room temperature for 30 minutes. The solution was treated with saturated aqueous sodium bicarbonate solution and the mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water and the organic layer was dried (MgSO4) and filtered. The filtrate was concentrated in vacuo to give methyl 6-[bis-(tert-butoxycarbonyl)amino]-3-(2H-pyrazol-3-yl)-2-vinylbenzoate (2.38 g) as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:7]([C:15]([OH:17])=[O:16])=[C:8]([N:10](C)[C:11](=O)C)[N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:7]([C:15]([OH:17])=[O:16])=[C:8]([NH:10][CH3:11])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(N(C)C(C)=O)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CCCCc1nc(NC)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
The title compound can be prepared from 2-butyl-4-(N-methylacetamido)-1-(2'-(tetrazol-5-yl)-biphen-4-yl)methylimidazole-5-carboxylic acid by reaction with 3 molar equivalents of diisobutyl-aluminum hydride in THF at room temperature followed by aqueous workup (extraction from 0.1% aqueous HOAc with EtOAc and isolation (SiO2, 35:65:1 CH2Cl2 /MeOH/ NH4OH). Alternatively' the title compound could be prepared from 4-methylamino-5-benzyloxycarbonyl-2-butyl-1-(2'-(N-triphenylmethyltetrazol-5-yl-biphen-4-yl)methylimidazole (mentioned in Example 18, Step 2) by reaction as outlined in Example 18, Step 3.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:26][CH2:25][CH2:24]4)[CH2:19][CH2:18]3)=[O:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:32]([O:34]CC)=[CH2:33])CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:23]1([N:20]2[CH2:21][CH2:22][N:17]([C:15](=[O:16])[CH2:14][N:11]3[CH2:12][CH2:13][N:8]([C:5]4[N:4]=[N:3][C:2]([C:32](=[O:34])[CH3:33])=[CH:7][CH:6]=4)[CH2:9][CH2:10]3)[CH2:18][CH2:19]2)[CH2:26][CH2:25][CH2:24]1
Reactant: O=C(CN1CCN(c2ccc(Cl)nn2)CC1)N1CCN(C2CCC2)CC1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(N2CCN(CC(=O)N3CCN(C4CCC4)CC3)CC2)nn1
Temperature: 120 °C

Procedure:
In a sealed tube, dissolve 3-chloro-6-{4-[2-(4-cyclobutylpiperazin-1-yl)-2-oxoethyl]-piperazin-1-yl}pyridazine (150 mg, 0.396 mmol), tributyl-(1-ethoxyvinyl)tin (157 mg 0.435 mmol), and Pd(PPh3)4 (23 mg, 0.020 mmol) in toluene (5 mL). Degas the mixture with N2 and seal the tube. Heat the solution at 120° C. overnight. Cool and filter through Celite. Wash the Celite bed with EtOAc (25 mL). Evaporate the solvent and dissolve the residue in 1N HCl and heat at 50° C. for 2 h. Cool and extract with CH2Cl2 (2×25 mL). Discard the extracts. Basify the aqueous phase with 10 N NaOH and extract with CH2Cl2 (2×25 mL). Combine the organic extracts and wash once with saturated aqueous KF solution (50 mL). Dry the organic extract and evaporate to yield the title compound. 1H NMR (CDCl3) δ 7.89 (d, 1H), 6.90 (d, 1H), 3.85 (t, 4H), 3.64-3.59 (m, 4H), 3.26 (s, 2H), 2.77 (s, 3H), 2.75-2.66 (m, 5H), 2.33-2.30 (m, 4H), 1.91-1.68 (m, 4H), 1.43-1.40 (m, 2H); LC-MS (M+1)387.11.
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH2:13][C:14]([NH2:16])=[NH:15])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([O:21][C:22](=[O:37])/[C:23](/O)=[C:24](\[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)/[C:25](O)=[O:26])([CH3:20])([CH3:19])[CH3:18].C[O-].[Na+].C(OCC)(=O)C>CO.CCCCCC>[C:17]([O:21][C:22]([C:23]1[C:24]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:25]([OH:26])[N:16]=[C:14]([CH2:13][C:8]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)[N:15]=1)=[O:37])([CH3:20])([CH3:18])[CH3:19]
Reactant: N=C(N)Cc1ncccc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)/C(O)=C(\OCc1ccccc1)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)c1nc(Cc2ncccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.4 %

Procedure:
To a stirred solution of 2-(3-phenyl-pyridin-2-yl)-acetamidine (162) (300 mg, 1.10 mmol) and (E)-2-benzyloxy-3-hydroxy-but-2-enedioic acid 4-tert-butyl ester (4) (511 mg, 1.66 mmol) in methanol (5 mL) was added sodium methoxide (1.3 mL, 3.32 mmol) at 0° C., then the reaction mixture was allowed to warm to room temperature, stirred for 16 h. Silica thin layer chromatography was performed (50% ethyl acetate in hexane, Rf=0.3). After completion of the reaction, it was quenched with water, methanol was evaporated and water (30 mL) was added. The mixture was extracted with ethyl acetate (3×30 mL) and the separated organic part was dried and concentrated to get a crude product, which was purified by a CombiFlash column (eluted at 90% ethyl acetate in hexane) to get 5-benzyloxy-6-hydroxy-2-(3-phenyl-pyridin-2-ylmethyl)-pyrimidine-4-carboxylic acid tert-butyl ester (163) (250 mg, 48.1%) as a yellow sticky product.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([CH:30]4[CH2:33][O:32][CH2:31]4)[CH2:26][C@H:25]3[CH3:34])=[CH:20][N:19]=2)[C:3]1=[O:35].[C:36]([C:40]1[CH:41]=[C:42]2[C:47](=[C:48]([F:50])[CH:49]=1)[C:46](=[O:51])[N:45]([C:52]1[N:59]=[CH:58][CH:57]=[C:56](Cl)[C:53]=1[CH:54]=[O:55])[N:44]=[CH:43]2)([CH3:39])([CH3:38])[CH3:37].CC([O-])=O.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:36]([C:40]1[CH:41]=[C:42]2[C:47](=[C:48]([F:50])[CH:49]=1)[C:46](=[O:51])[N:45]([C:52]1[N:59]=[CH:58][CH:57]=[C:56]([C:6]3[CH:5]=[C:4]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]5[CH2:29][CH2:28][N:27]([CH:30]6[CH2:33][O:32][CH2:31]6)[CH2:26][C@H:25]5[CH3:34])=[CH:20][N:19]=4)[C:3](=[O:35])[N:2]([CH3:1])[CH:7]=3)[C:53]=1[CH:54]=[O:55])[N:44]=[CH:43]2)([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3nccc(Cl)c3C=O)ncc2c1
Reactant: C[C@@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: C[C@@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3C=O)cn(C)c2=O)nc1
Temperature: 100 °C
Yield: 31.6 %

Procedure:
A mixture of 106a (260.0 mg, 0.56 mmol), 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-chloronicotinaldehyde 103b (200.0 mg, 0.56 mmol), PdCl2(dppf) (50.0 mg, 0.056 mmol), NaOAc (90.0 mg, 1.1 mmol), K3PO4 (300 mg, 1.1 mmol) in acetonitrile (30 mL) was heated at 100° C. for 3 h. The solvent was evaporated in vacuo. The residue was purified by flash column chromatography eluting with CH2Cl2/methanol (10:1) to afford 106b (120 mg, 34%) as a brown solid. LCMS: [M+H]+ 679.3
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@:11]3([C:15](=[O:16])[N:14]([CH2:17][CH2:18][CH3:19])[C:13](SCCC)=[N:12]3)[CH2:10][C@H:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[NH4+:30].[I-]>N.CCO>[NH2:30][C:13]1[N:14]([CH2:17][CH2:18][CH3:19])[C:15](=[O:16])[C@:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[O:8][C@@H:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:10]2)[N:12]=1
Reactant: [NH4+]
Reactant: CCCSC1=N[C@]2(C[C@H](c3ccccc3)Oc3ccc(Br)cc32)C(=O)N1CCC
Agent: N
Agent: [I-]
Solvent: CCO
Product: CCCN1C(=O)[C@@]2(C[C@H](c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Yield: 22.6 %

Procedure:
A solution of (2R,4S)-6-bromo-2-phenyl-1′-propyl-2′-(propylthio)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (75 mg, 0.16 mmol), and NH4I (46 mg, 0.32 mmol) in NH3/EtOH (4 mL, 1.5 N) was heated at 110° C. in a tube in a microwave reactor for 2-2.5 h. After cooling, the mixture was concentrated in vacuo to give a residue, which was purified by preparative TLC to afford (2R,4S)-2′-amino-6-bromo-2-phenyl-1′-propylspiro-[chroman-4,4′-imidazol]-5′(1′H)-one (15 mg, 23%). 1H-NMR (MeOD): 1.00 (m, 3H), 1.45 (m, 2H), 2.23 (m, 1H), 2.48 (m, 1H), 3.75 (m, 2H), 5.85 (m, 1H), 6.90 (m, 1H), 7.14 (m, 1H), 7.40 (m, 6H).
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]1[CH:29]=[CH:28][C:11]([CH2:12][CH:13]([C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=1)([CH3:6])([CH3:5])[CH3:4].Cl.O>C(OCC)C.[Cl-].[Zn+2].[Cl-]>[C:3]([O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][CH:13]([CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[OH:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:28][CH:29]=1)([CH3:4])([CH3:5])[CH3:6]
Reactant: CCOC(=O)C(Cc1ccc(OC(C)(C)C)cc1)C(=O)c1cccc(Cl)c1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C(Cc1ccc(OC(C)(C)C)cc1)C(O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of zinc chloride (5.79 g, 42.5 mmol) in diethyl ether (150 ml) was added sodium borohydride (3.22 g, 85.0 mmol), and the mixture was stirred at room temperature for 30 min. Insoluble material was filtered off, and to the filtrate was added a solution of ethyl 2-(4-tert-butoxybenzyl)-3-(3-chlorophenyl)-3-oxopropanoate (8.26 g, 21.2 mmol) in diethyl ether (100 ml) at 0° C. The mixture was stirred for 30 min. and 1N hydrochloric acid was added to stop the reaction. Water (200 ml) was further added and the mixture was extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1-2:1) to give the objective substance (7.12 g, 86%).