Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([CH:9]([OH:21])[C:10]#[C:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[C:13]=2[F:20])[CH2:5][CH2:4]1)[CH3:2].[H][H]>[C].[Pd].C(OCC)(=O)C>[CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([CH:9]([OH:21])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[C:13]=2[F:20])[CH2:5][CH2:4]1)[CH3:2]
Reactant: [H][H]
Reactant: CC[C@H]1CC[C@H](C(O)C#Cc2ccc(F)c(F)c2F)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC[C@H]1CC[C@H](C(O)CCc2ccc(F)c(F)c2F)CC1

Procedure:
A 200-ml ethyl acetate mixture containing 1-(trans-4-ethylcyclohexyl)-3-(2,3,4-trifluorophenyl)-2-propyne-1-ol (38 g) and 5% palladium carbon (50% in water, 2 g) was stirred for 4 hours at room temperature at a hydrogen pressure of 4 atm. After palladium carbon was removed by filtration using Celite, the filtrate was concentrated to obtain 1-(trans-4-ethylcyclohexyl)-3-(2,3,4-trifluorophenyl)-1-propanol (38 g).
Reaction SMILES: Cl[C:2]1[CH2:6][C:5]([CH3:8])([CH3:7])[CH2:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12].[N-:16]=[N+]=[N-].[Na+].O.C(Cl)Cl>CS(C)=O>[CH3:7][C:5]1([CH3:8])[CH2:6][C:2]2[NH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][C:3]=2[CH2:4]1
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)/C=C/C1=C(Cl)CC(C)(C)C1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cc2c([nH]1)CC(C)(C)C2
Temperature: 75 °C
Reaction time: 8 h
Yield: 37.2 %

Procedure:
A 250-mL single neck round bottomed flask equipped with a magnetic stirrer and nitrogen inlet was charged with 107a (17 g, 74 mmol) in DMSO (100 mL). To the solution was added sodium azide (9.6 g, 150 mmol). The mixture was then heated to 75° C. and stirred for 8 h. After cooling to rt (room temperature), H2O (100 mL) and CH2Cl2 (200 mL) were added and the organic layer was separated. The aqueous layer was extracted with CH2Cl2 (50 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography using a 100% hexane—1:1 hexane/ethyl acetate gradient to afford a 37% yield (5.7 g) of 107b.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([C:7](=O)[C:8](OC)=[O:9])[C:3]([O:5][CH3:6])=[O:4].[F:14][C:15]1[CH:34]=[CH:33][CH:32]=[CH:31][C:16]=1[CH2:17][N:18]1[C:22]2=[N:23][CH:24]=[N:25][CH:26]=[C:21]2[C:20]([C:27](=[NH:30])[NH:28][NH2:29])=[N:19]1>C(O)C>[F:14][C:15]1[CH:34]=[CH:33][CH:32]=[CH:31][C:16]=1[CH2:17][N:18]1[C:22]2=[N:23][CH:24]=[N:25][CH:26]=[C:21]2[C:20]([C:27]2[N:28]=[N:29][C:7]([C:2]([CH3:13])([CH3:1])[C:3]([O:5][CH3:6])=[O:4])=[C:8]([OH:9])[N:30]=2)=[N:19]1
Reactant: N=C(NN)c1nn(Cc2ccccc2F)c2ncncc12
Reactant: COC(=O)C(=O)C(C)(C)C(=O)OC
Solvent: CCO
Product: COC(=O)C(C)(C)c1nnc(-c2nn(Cc3ccccc3F)c3ncncc23)nc1O
Yield: 21.5 %

Procedure:
584 mg (3.103 mmol) of dimethyl 2,2-dimethyl-3-oxobutanedioate were initially charged in 12 ml of ethanol and heated to reflux. Subsequently, 590 mg (2.069 mmol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboximidohydrazide suspended in 12 ml of ethanol were added and the mixture was boiled under reflux overnight. After cooling, the mixture was filtered, the filtercake was washed with a little ethanol and the filtrate was concentrated. The residue was stirred with 10 ml of acetonitrile. 188 mg of the target compound were obtained (purity 93%; 20% of theory).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[C:26](Br)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12].C(N(CC)CC)C.[CH3:41][C:42]1([CH3:49])[C:46]([CH3:48])([CH3:47])[O:45][BH:44][O:43]1>C(#N)C.O1CCCC1.C(OCC)(=O)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].ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[C:26]([B:44]3[O:45][C:46]([CH3:48])([CH3:47])[C:42]([CH3:49])([CH3:41])[O:43]3)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: COC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1Br
Reactant: CC1(C)OBOC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1B1OC(C)(C)C(C)(C)O1
Temperature: 100 °C

Procedure:
To a solution of EXAMPLE 71C (500 mg), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane (46.8 mg) and triethylamine (0.399 mL) in acetonitrile (7 mL) and tetrahydrofuran (3.5 mL) was added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.416 mL). The mixture was heated at 100° C. in a Biotage Initiator microwave reactor for 30 minutes, cooled, diluted with ethyl acetate, and washed with brine. The organic layer was concentrated. The residue was purified by flash chromatography, eluting with 0-17% ethyl acetate in dichloromethane to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]([OH:13])[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][CH:3]=1.O[C:15]1[CH:27]=[CH:26][C:18]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:17]([CH3:28])[CH:16]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.P(CCCC)(CCCC)CCCC>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([CH:8]([O:13][C:15]2[CH:27]=[CH:26][C:18]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:17]([CH3:28])[CH:16]=2)[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)COc1ccc(O)cc1C
Reactant: CCCCC(O)c1cccc(Br)n1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCCCC(Oc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(Br)n1
Temperature: 25 °C
Yield: 64.6 %

Procedure:
To a stirred solution of 1-(6-bromo-2-pyridinyl)-1-pentanol (2.00 g, 8.19 mmol) and ethyl (4-hydroxy-2-methylphenoxy)acetate (1.89 g, 8.99 mmol) in dry THF (160 mL) at 0° C. (ice/water bath) under nitrogen was added ADDP (4.13 g, 16.37 mmol) portion-wise over 5 min followed by nBu3P (1.07 mL, 4.30 mmol) drop-wise over 1-2 min. The mixture was stirred with slow warming to rt over 21 h and then concentrated under vacuum, diluted with EtOAc (300 mL) and washed with water (200 mL). The aqueous layer was then re-extracted with EtOAc (300 mL) and the combined organic layer washed with brine (350 mL), dried (MgSO4), filtered and reduced to give a orange solid residue. Purification by SPE (silica, 20 g Cartridge) eluting with cyclohexane:EtOAc (gradient 1:0 to 1:1) afforded the title compound (2.31 g).
Reaction SMILES: CC([N:5]([C@H:9]([CH3:28])[C:10]([NH:12][C:13]1[CH:14]=[N:15][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=2[CH3:27])=[CH:17][CH:18]=1)=[O:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:27][C:21]1[C:22]([CH3:26])=[CH:23][CH:24]=[CH:25][C:20]=1[O:19][C:16]1[N:15]=[CH:14][C:13]([NH:12][C:10](=[O:11])[C@@H:9]([CH3:28])[NH2:5])=[CH:18][CH:17]=1
Reactant: Cc1cccc(Oc2ccc(NC(=O)[C@@H](C)N(C(=O)[O-])C(C)(C)C)cn2)c1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(Oc2ccc(NC(=O)[C@@H](C)N)cn2)c1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
1,1-dimethylethyl[(1R)-2-({6-[(2,3-dimethylphenyl)oxy]-3-pyridinyl}amino)-1-methyl-2-oxoethyl]carbamate (Intermediate 39, 29 mg) was dissoved in 3 mL of dry dichloromethane. To this solution at 0° C. under argon was added dropwise 30 equivalents of TFA (168 μl, 2.179 mmol). The reaction was stirred during 1 hour at 0° C. and 2 hours at room temperature. The reaction mixture was evaporated. The residue obtained was purified by SCX (3 CV of methanol were used first, then the residue was adsorbed on the cartridge, washed with 5 CV of methanol and desorbed with 2 CV of methanolic ammonia (1N)). Evaporation of the volatiles, afforded the title compound (21 mg).
Reaction SMILES: [CH:1]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.C(N(CC)CC)C.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[CH:1]1([C:7]([O:9][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: BrCc1ccccc1
Reactant: O=C(O)C1CC=CCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)C1CC=CCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(±)-3-Cyclohexene-1-carboxylic acid (50 g) was dissolved in N,N-dimethylformamide (550 ml), and triethylamine (170 ml) and benzyl bromide (61 ml) were added under ice cooling to stir the mixture at room temperature for 12 hours. Water was added, extraction was conducted with ethyl acetate, and the resultant organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1) to obtain the title compound (70.8 g) as a reddish brown oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH:34]1[CH2:39][CH2:38][C:37](=[O:40])[CH2:36][CH2:35]1.CCN(C(C)C)C(C)C>>[NH:2]=[C:1]([N:34]1[CH2:39][CH2:38][C:37](=[O:40])[CH2:36][CH2:35]1)[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Reactant: O=C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Product: N=C(c1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1)N1CCC(=O)CC1
Yield: 3 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 2.2 equivalent of both 4-piperidone as secondary amine and DIEA as base. The product was purified first by preparative HPLC and finally with a preparative TLC (eluent: petrolether/DCM/MeOH 2:3:1 containing 2% of a 7 M NH3 solution in MeOH).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[O:7][CH2:8][CH2:9][C:10]1[C:11](=[O:18])[NH:12][C:13](SC)=[N:14][CH:15]=1.[NH2:22][CH2:23][CH2:24][S:25][CH2:26][C:27]1[O:31][C:30]([CH2:32][N:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=1>>[CH3:35][N:33]([CH2:32][C:30]1[O:31][C:27]([CH2:26][S:25][CH2:24][CH2:23][NH:22][C:13]2[NH:12][C:11](=[O:18])[C:10]([CH2:9][CH2:8][O:7][C:6]3[CH:19]=[CH:20][CH:21]=[C:4]([CH2:3][O:2][CH3:1])[CH:5]=3)=[CH:15][N:14]=2)=[CH:28][CH:29]=1)[CH3:34]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: COCc1cccc(OCCc2cnc(SC)[nH]c2=O)c1
Product: COCc1cccc(OCCc2cnc(NCCSCc3ccc(CN(C)C)o3)[nH]c2=O)c1
Yield: 50.9 %

Procedure:
A mixture of 5-[2-[3-(methoxymethyl)phenoxy]ethyl]-2-(methylthio)-4(3H)-pyrimidinone (0.7 g ) and 5-[[(2-aminoethyl)thio]methyl]-N,N-dimethyl-2-furanmethanamine (0.54 g) was heated at 140° for 2 h. The residue was chromatographed (silica/methanol) to give the title compound (0.55 g) as a pale yellow oil.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[S:9][C:10]=1[Br:11])(=O)C.[OH-].[Na+].Cl>C(O)C.O1CCCC1>[Br:11][C:10]1[S:9][C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:19])[F:21])[CH:13]=2)=[N:7][C:6]=1[CH2:5][OH:4]
Reactant: CC(=O)OCc1nc(-c2cccc(C(F)(F)F)c2)sc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: OCc1nc(-c2cccc(C(F)(F)F)c2)sc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
To a mixed solution of the compound (2.0 g, 5.3 mmol) obtained in Example 64d in ethanol/tetrahydrofuran (v/v=1/1, 20 mL) was added 2N aqueous sodium hydroxide solution (5.3 mL, 11 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with 1N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=70/30) to give the title compound (1.6 g, 89%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:6]=2[CH:20]=1.[CH3:21][NH2:22].O>O1CCCC1.C1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:22][CH3:21])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:6]=2[CH:20]=1
Reactant: CN
Reactant: O=C1CN=C(c2ccccc2F)c2cc(Cl)ccc2N1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccccc1
Product: CNC1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1

Procedure:
A solution of 200 g of 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one in 2 liters of tetrahydrofuran and 250 ml of benzene was saturated with methylamine with cooling in an ice-bath. A solution of 190 g of titanium tetrachloride in 250 ml of benzene was added through a dropping funnel within 15 minutes. After completion of the addition, the mixture was stirred and refluxed for 3 hours. 600 ml of water were added slowly to the cooled mixture. The inorganic material was separated by filtration and was washed well with tetrahydrofuran. The water layer was separated and the organic phase dried over sodium sulphate and evaporated. The crystalline residue was collected to give 7-chloro-5-(2-fluorophenyl)-2-methylamino-3H-1,4-benzodiazepine of melting point 204°-206° C. An analytical sample was recrystallised from methylene chloride/ethanol and had a melting point of 204°-206° C.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]2[NH:11][C:12]([CH:15]=O)=[C:13]([CH3:14])[C:7]=2[C:6]1=[O:17].[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[CH2:23]2.N1CCCCC1>C(O)C>[CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]2[NH:11][C:12]([CH:15]=[C:23]3[C:22]4[C:26](=[CH:27][CH:28]=[C:20]([F:19])[CH:21]=4)[NH:25][C:24]3=[O:29])=[C:13]([CH3:14])[C:7]=2[C:6]1=[O:17]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN(C)C)CC2
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(C=C2C(=O)Nc3ccc(F)cc32)[nH]c2c1C(=O)N(CCN(C)C)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.8 %

Procedure:
A stirred solution of 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde (67 mg, 0.267 mmol), 5-fluoro-1,3-dihydro-indol-2-one (40 mg, 0.267 mmol) in 0.66 ml of ethanol was added dropwise with anhydrous piperidine (0.1 ml). The mixture was stirred at room temperature overnight. The resulting solid was filtered under reduced pressure, washed with ethanol (1 ml×3) and purified by silica gel column chromatography with triethylamine:methanol:dichloromethane (1:20:500) as eluents to give 5-(2-dimethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (60 mg, 54.8%) as a yellow solid.
Reaction SMILES: [C:1]([C:3]([O:5][CH2:6][CH3:7])=[O:4])#[N:2].[CH:8]([C:11]1OC(=O)[S:13][N:12]=1)([CH3:10])[CH3:9]>CC1C=CC(C)=CC=1>[CH:8]([C:11]1[N:2]=[C:1]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[S:13][N:12]=1)([CH3:10])[CH3:9]
Reactant: CCOC(=O)C#N
Reactant: CC(C)c1nsc(=O)o1
Solvent: Cc1ccc(C)cc1
Product: CCOC(=O)c1nc(C(C)C)ns1
Yield: 96.8 %

Procedure:
Ethyl cyanoformate (38.6 g, 0.39 mol) is added to a stirred solution of 5-isopropyl-[1,3,4]oxathiazolin-2-one (18.5 g, 0.13 mol) in p-xylene (180 ml). The mixture is refluxed for 6 hours and then the solvent is evaporated in vacuo to give crude ethyl 3-isopropyl-[1,2,4]thiadiazole-5-carboxylate (25.2 g, 97%) as a yellow oil, which is used without purification for the next step.
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=[O:17])=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Li+]>CO>[CH:18]1([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH2:16][OH:17])=[CH:14][N:15]=2)=[O:9])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Product: O=C(Nc1ncc(CO)s1)N(C1CCCCC1)C1CCCCC1
Yield: 96.8 %

Procedure:
Prepared using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (50 mg, 0.15 mmol) and lithium borohydride (95 μL, 2M in THF) in MeOH (1 mL). Purification without work-up (silica gel, 10% EtOAc and 2% MeOH in CH2Cl2) afforded 49 mg (97%) of the desired compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:7]([O:9][C:10](=[O:11])[C:2]=12)=[O:8].[Cl-].[Al+3].[Cl-].[Cl-].[C:16]1([CH3:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:22][C:16]1[CH:21]=[CH:20][C:19]([C:7]([C:3]2[C:2]([C:10]([OH:9])=[O:11])=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:8])=[CH:18][CH:17]=1
Reactant: Cc1ccccc1
Reactant: O=C1OC(=O)c2ncccc21
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(C(=O)c2cccnc2C(=O)O)cc1

Procedure:
Employing 2,3-pyridinedicarboxylic anhydride (10.0 g), toluene (125 ml) and aluminum chloride (15.0 g), substantially the same reaction and process as in Reference Example 1 Process 1 and Step 1 were conducted to give 3-(4-methylbenzoyl)-2-pyridinecarboxylic acid as colorless crystals (7.8 g).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[N:10]=[C:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH2:27][CH:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1>C(Cl)(Cl)Cl>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH2:27][CH:28]1[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]1)[N:17]=[CH:16][N:15]=[C:14]2[NH:13][C:11]([NH:10][C@@H:8]1[CH2:9][C@H:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:12]
Reactant: COc1cc2c(N)ncnc2cc1OCC1CCN(C)CC1
Reactant: O=C=N[C@@H]1C[C@H]1c1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1cc2c(NC(=O)N[C@@H]3C[C@H]3c3ccccc3)ncnc2cc1OCC1CCN(C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
trans-2-Phenylcyclopropyl isocyanate (0.2 ml) was added to a stirred mixture of 4-amino-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (0.1 g) and chloroform (3 ml) and the resultant mixture was stirred at ambient temperature for 20 hours. The reaction mixture was diluted with chloroform (3 ml) and tris-(2-aminoethyl)amine polystyrene resin (0.5 g) was added. The mixture was stirred at ambient temperature for 1 hour. The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography, on silica using increasingly polar mixtures of methylene chloride and 2M methanolic ammonia as eluent. There was thus obtained the title compound (0.11 g); NMR Spectrum: (CDCl3) 1.24-1.38 (m, 2H), 1.41-1.57 (m, 2H), 1.87-2.05 (m, 5H), 2.21 (m, 1H), 2.3 (s, 3H), 2.91 (d, 2H), 3.05 (m, 1H), 3.97 (s, 3H), 4.04 (d, 2H), 7.1-7.26 (m, 6H partially obscured by CHCl3 peak), 7.34 (m, 1H), 8.66 (s, 1H), 8.72 (s, 1H), 10.31 (s, 1H); Mass Spectrum: M+H+ 462.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][NH:15][C:16](=[NH:35])[C:17]2[C:18]([CH3:34])=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH2:23][N:22]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:21][CH2:20]3)=O)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:14][N:15]=[C:16]([C:17]3[C:18]([CH3:34])=[C:19]4[C:24](=[CH:25][CH:26]=3)[CH2:23][N:22]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH2:21][CH2:20]4)[N:35]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: Cc1c(C(=N)NOC(=O)c2ccc(OC(C)C)c(Cl)c2)ccc2c1CCN(C(=O)OC(C)(C)C)C2
Solvent: C1COCCO1
Product: Cc1c(-c2noc(-c3ccc(OC(C)C)c(Cl)c3)n2)ccc2c1CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Yield: 55.2 %

Procedure:
A solution of 1,1-dimethylethyl 6-[{[({3-chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)oxy]amino}(imino)methyl]-5-methyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Preparation 18; 413 mg; 0.823 mmol) in 1,4-dioxane (15 ml) was stirred at 110° C. for ca. 18 h. The mixture was cooled to room temperature and the solvent removed. Purification by flash chromatography on silica gel, eluting with 5-25% ethyl acetate in cyclohexane followed by 13-63% ethyl acetate in cyclohexane, gave the title compound as a white foam (220 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([C:19]([O:21][CH3:22])=[O:20])[C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:8]=1)=[O:6].C(=O)([O-])[O-].[K+].[K+].[N:29]1[CH:34]=[CH:33][C:32]([C:35]([OH:48])([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:31][CH:30]=1>O.C(OCC)(=O)C.C1(C)C=CC=CC=1>[OH:48][C:35]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[CH:32]1[CH2:33][CH2:34][N:29]([CH2:2][CH2:3][CH2:4][C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([C:19]([O:21][CH3:22])=[O:20])[C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:8]=2)=[O:6])[CH2:30][CH2:31]1
Reactant: COC(=O)C(Cc1ccc(C(=O)CCCCl)cc1)C(=O)OC
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)C(Cc1ccc(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 120 h
Yield: 75.4 %

Procedure:
Mix together [4-(4-chloro-1-oxobutyl)phenyl]methyl-propanedioic acid, dimethyl ester (300 mg, 0.92 mmol), potassium carbonate (350 mg, 2.5 mmol), α-(4-pyridyl)benzhydrol (500 mg, 1.9 mmol), water (3 mL) and toluene (7 mL). Heat the mixture to reflux. After 5 days, cool to room temperature. Add ethyl acetate and water. Wash the organic phase with brine, dry over anhydrous magnesium sulfate and concentrate. Purify by flash chromatography (150 g of silica gel, 10% methanol/chloroform as eluent) to give the title compound (387 mg, 76%). Additionally, compounds derived from all permutations of substituents as set forth in the illustrative examples following Step F can be prepared by the synthetic procedure depicted in Step H.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH:8]=O)([CH3:3])[CH3:2].[CH2:15]([O:17][C:18]([CH:20]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:19])[CH3:16]>C1(C)C=CC=CC=1>[CH2:15]([O:17][C:18](=[O:19])/[CH:20]=[CH:8]/[C:7]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:6]=1)[CH3:16]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C=O)cc1OC(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/c1ccc(OC)c(OC(C)C)c1
Temperature: 25 °C

Procedure:
A mixture of 3-isopropoxy4-methoxy-benzaldehyde (3.9 g, 20 mmol) and (ethoxycarbonylmethylene)triphenylphosphorane (6.96 g. 20 mmol) in toluene (100 ml) is heated at reflux for 2 hours, cooled to ambient temperature and evaporated. The crude product is taken in to dichloromethane and eluted through a pad of, silica to afford (E)-3-(3-isopropoxy-4-methoxy-phenyl)-acrylic acid ethyl ester, TLC Rf 0.70 (1:1 hexane-ethyl acetate). This intermediate is dissolved in nitromethane (10 ml), 1,1,3,3-tetramethylguanidine (0.5 ml) is added and the reaction heated at 70° C. for 36 hours. The solvent is evaporated, the residue is taken into ethyl acetate and washed with 2N aqueous HCl, water and brine. After drying over sodium sulfate and evaporation, the crude product is purified by flash column chromatography (4:1 hexane-ethyl acetate elution) to afford 3-(3-isopropoxy-4-methoxy-phenyl)-4-nitro-butyric acid ethyl ester, 1H NMR (400 MHz, CDCl3) δ 1.20 (t J 7 3H), 1.38 (d J 7 6H), 2.75 (d J 6 2H), 3.90 (m 1H), 4.10 (m 2H), 4.48-4.78 (m 3H), 6.75-6.86 (m 3H). This intermediate is converted into [1-(3,5-diisopropoxy-phenyl)-6-isopropoxy-7-methoxy-isoquinolin-4-yl]-acetic acid using the general procedure for Intermediate 20. Characterised as the ethyl ester, [MH]+ 496.