Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[C:12]([CH3:13])=[N:11][C:10]([CH3:14])=[N:9]2)[N:5]=[C:4]([S:15][CH3:16])[N:3]=1.[CH2:17]([Sn](CCCC)(CCCC)C=C)[CH2:18]CC>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>[CH3:14][C:10]1[N:11]=[C:12]([CH3:13])[N:8]([C:6]2[CH:7]=[C:2]([CH:17]=[CH2:18])[N:3]=[C:4]([S:15][CH3:16])[N:5]=2)[N:9]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CSc1nc(Cl)cc(-n2nc(C)nc2C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cc(-n2nc(C)nc2C)nc(SC)n1
Temperature: 110 °C

Procedure:
To a solution of 4-chloro-6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-(methylthio)pyrimidine (1-2) (1.01 g, 3.96 mmol, 1.0 eq.) in degassed toluene (20 mL) under nitrogen was added tetrakis(triphenylphosphine)palladium(0) (228 mg, 0.198 mmol, 0.050 eq.) followed by tributyl(vinyl)tin (1.16 mL, 3.96 mmol, 1.0 eq.) and the reaction heated to 110° C. for 2 hours. Toluene was removed by roto-evaporation and the resulting residue was purified by silica gel column chromatography (0-100% ethyl acetate in hexanes) to afford 4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-(methylthio)-6-vinylpyrimidine (1-3) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.48 (s, 1H), 6.72 (dd, 1H, J=17.3, 10.3 Hz), 6.57 (dd, 1H, J=17.3, 1.4 Hz), 5.73 (dd, 1H, J=10.3, 1.4 Hz), 2.91 (s, 3H), 2.61 (s, 3H), 2.42 (s, 3H). LRMS m/z (M+H) 248 found, 248 required.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:7][CH:6]1[CH2:8][N:9]1[C:17]2[N:16]=[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:28])[CH3:27])=[CH:21][CH:20]=3)[NH:14][C:13]=2[C:12](=[O:29])[N:11]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[F:37])[C:10]1=[O:38])=O.[BH4-].[Li+]>O1CCCC1>[F:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][N:11]1[C:12](=[O:29])[C:13]2[NH:14][C:15]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26](=[O:28])[CH3:27])=[CH:23][CH:24]=3)=[N:16][C:17]=2[N:9]([CH2:8][CH:6]2[CH2:7][CH:5]2[CH2:3][OH:2])[C:10]1=[O:38]
Reactant: COC(=O)C1CC1Cn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NC(C)=O)cc3)nc21
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2CO)cc1

Procedure:
This compound was prepared by the reduction of 2-[8-(4-acetylamino-benzyl)-1-(2-fluorobenzyl)-2,6-dioxo-1,2,6,7-tetrahydro-purin-3-ylmethyl]-cyclopropanecarboxylic acid methyl ester with lithium borohydride in tetrahydrofuran. MS, m/z(M+)=491.1966.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2([CH2:15][NH2:16])[CH2:14][CH2:13][CH:12]=[CH:11][O:10][CH2:9]2)[CH2:4][CH2:3]1.CC(O)=O.[CH3:21][N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]([CH:32]=O)[C:23]1=[O:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.[OH-].[Na+]>[CH3:21][N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]([CH2:32][NH:16][CH2:15][C:8]2([N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)[CH2:14][CH2:13][CH:12]=[CH:11][O:10][CH2:9]2)[C:23]1=[O:34]
Reactant: Cn1c(=O)c(C=O)cc2ccccc21
Reactant: CN1CCN(C2(CN)CCC=COC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN1CCN(C2(CNCc3cc4ccccc4n(C)c3=O)CCC=COC2)CC1
Yield: 69.3 %

Procedure:
To a solution of 1-[3-(4-methylpiperazin-1-yl)-2,3,4,5-tetrahydrooxepin-3-yl]methanamine (250 mg, 1.109 mmole) in 1,2-dichloroethane (4 ml) was added AcOH (290 μL, 5.07 mmole) then 1-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (190 mg, 1.015 mmole). After 20 min sodium triacetoxyborohydride (323 mg, 1.522 mmole) was added. After 16 hr the mixture was diluted with 1M aqueous NaOH and extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated. Flash column chromatography (gradient, 0-10% MeOH/CH2Cl2) gave the title compound as a pale yellow oil (279 mg, 69%). 1H-NMR (CDCl3, 500 MHz) d 7.70 (s, 1 H), 7.56 (m, 2 H), 7.35 (d, J=8.30 Hz, 1 H), 7.25 (m, 1 H), 6.24 (d, J=6.6 Hz, 1 H), 4.59 (m, 1 H), 4.25 (dd AB, J=12.94 and 44.19 Hz, 2 H), 3.80 (m, 2 H), 3.74 (s, 3 H), 2.71-2.61 (m, 6 H), 2.44 (m, 4 H), 2.28 (s, 3 H), 2.21-2.06 (m, 4 H), 1.51 (m, 1 H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([C@@H:12]3[O:19][C@H:18]([CH2:20][OH:21])[C@@H:16]([OH:17])[C@H:13]3[O:14][CH3:15])[C:6]=2[N:7]=1.[CH3:23][O-:24].[Na+].CO>>[NH2:1][C:2]1[N:3]=[C:4]([O:24][CH3:23])[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([C@@H:12]3[O:19][C@H:18]([CH2:20][OH:21])[C@@H:16]([OH:17])[C@H:13]3[O:14][CH3:15])[C:6]=2[N:7]=1
Reactant: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cc(C)c2c(Cl)nc(N)nc21
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(N)nc2c1c(C)cn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1OC

Procedure:
A solution of the compound from Step A (50 mg, 0.15 mmol) in 0.5M NaOMe/MeOH (4 mL) was stirred at reflux temperature for 1.5 h. The mixture was cooled, mixed with silica gel and evaporated to dryness. The silica gel was loaded onto a silica gel column and eluted with a solvent system of CH2Cl2/MeOH: 30/1. The fractions containing the product were collected and evaporated to yield 2-amino-7-(2-O-methyl-β-D-ribofuranosyl)-4-methoxy-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (40 mg). This was mixed with 2 N aqueous NaOH (4 mL) and stirred at reflux temperature for 10 h. The mixture was cooled in ice bath, neutralized with 2 N aqueous HCl and evaporated. The solid residue was suspended in MeOH, mixed with silica gel and evaporated. The silica gel was loaded onto a silica gel column and eluted with a solvent system of CH2Cl2/MeOH: 5/1. Appropriate fractions were pooled and evaporated to give the title compound (40 mg) as a white solid.
Reaction SMILES: P([O-])([O-])([S-])=[S:2].[C:6]([CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])#[N:7]>C(OCC)(=O)C.Cl>[C:6]([CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])(=[S:2])[NH2:7]
Reactant: [O-]P([O-])(=S)[S-]
Reactant: COC(=O)c1cccc(OCC#N)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(OCC(N)=S)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 78 %

Procedure:
4 N Hydrogen chloride-ethyl acetate solution (50 ml) and dithiophosphate=O,O-diethyl (4.47 ml, 26.67 mmol) were added in that order to methyl 3-cyanomethoxybenzoate (5.00 g, 26.15 mmol), and the resulting solution was stirred at room temperature for 12 hours. Crystals precipitated in the reaction solution were collected by filtration and washed with diethyl ether to give methyl 3-thiocarbamoylmethoxybenzoate (4.60 g, 78%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[NH+:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:7]=1[CH3:8].[CH2:15](Br)[C:16]#[CH:17]>>[CH3:8][C:7]1[CH:6]=[C:5]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:4]=[N:3][C:2]=1[NH:1][CH2:17][C:16]#[CH:15]
Reactant: C#CCBr
Reactant: Cc1cc(-c2ccccc2)[nH+]nc1N
Product: C#CCNc1nnc(-c2ccccc2)cc1C

Procedure:
4-Methyl-6-phenyl-3-(prop-2-ynylamino)-pyridazine is prepared by heating 7 g of 3-amino-4-methyl-6-phenyl-pyridazinium and 9 ml of propargyl bromide at 60° C. for 2 hours. After evaporation of the excess propargyl bromide, the residue is taken up in 300 ml of anhydrous benzene, and 1.77 g of sodium are added. The mixture is heated under reflux for 15 hours and the solution is then poured into excess solid carbon dioxide and left in contact therewith for several hours.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]([C:13]([O:15]CC2C=CC=CC=2)=[O:14])=[C:11]([Cl:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[OH-].[Na+]>O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]([C:13]([OH:15])=[O:14])=[C:11]([Cl:25])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)c1ccc(OCc2ccccc2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Product: O=C(O)c1ccc(OCc2ccccc2)cc1Cl
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 97.1 %

Procedure:
To benzyl 4-benzyloxy-2-chlorobenzoate (1.12 g) were added ethanol (8.8 ml), 1,4-dioxane (2.2 ml) and 1N aqueous sodium hydroxide solution (4.7 ml) and the mixture was stirred at 70° C. for 1.5 hr. The solvent was evaporated and water was added to the residue for dissolution, which was washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and the precipitate was collected by filtration to give 4-benzyloxy-2-chlorobenzoic acid (810 mg) as a pale-yellow powder.
Reaction SMILES: O.[CH2:2]([NH:9][CH:10]([C:16]1[CH:21]=[CH:20][C:19]2[O:22][CH2:23][O:24][C:18]=2[CH:17]=1)CC(OC)=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:25](=[O:28])([O-:27])O.[Na+].[C:30]1(C)C=CC=CC=1>>[CH2:2]([NH:9][C@@H:10]([CH2:16][C:21]1[CH:30]=[CH:17][C:18]2[O:24][CH2:23][O:22][C:19]=2[CH:20]=1)[C:25]([OH:27])=[O:28])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1ccccc1
Reactant: COC(=O)CC(NCc1ccccc1)c1ccc2c(c1)OCO2
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C(O)[C@H](Cc1ccc2c(c1)OCO2)NCc1ccccc1
Temperature: 30 °C
Reaction time: 24 h

Procedure:
To 37 mL of water were added 7.49 g (23.9 mmol) of methyl (±)-3-benzylamino-3-(3,4-methylenedioxyphenyl)propionate and 1.00 g (12.0 mmol) of sodium hydrogen carbonate, and the mixture was maintained at 30° C. To the resulting mixture was added 37.5 mg of lipase (CAL; available from Roche, CHIRAZYME L-2 (trade name)) originated from Candida antarctica at the same temperature, and the mixture was reacted at 30° C. while stirring. After 24 hours, at the time when the conversion rate of the starting materials reached 29.1%, 40 ml of toluene was added to the reaction mixture. After the resulting mixture was stirred for 15 minutes at room temperature, the mixture was filtered and dried to obtain 1.52 g (Isolated yield based on methyl (±)-3-benzylamino-3-(4-fluorophenyl)propionate=21.2%) of 3-(R) or (S)-benzylamino-3-(3,4-methylenedioxyphenyl)propionic acid as white crystal.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22]>>[Cl:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH:22][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)(=[O:8])=[O:9])[CH:11]=1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Reactant: Nc1ccccc1Cl
Product: O=C(Nc1ccccc1Cl)c1cccc(S(=O)(=O)N2CCCCC2)c1

Procedure:
The entitled compound was produced according to the method of Example 73 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and 2-chloroaniline as the starting materials.
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[CH2:15][CH:14]([NH:19]C(OC(C)(C)C)=O)[CH2:13]3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:27].O1CCOCC1>C(O)(=O)C>[ClH:27].[C:1]1([NH:7][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[CH2:15][CH:14]([NH2:19])[CH2:13]3)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(C(=O)Nc3ccccc3)cc2C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: NC1Cc2ccc(C(=O)Nc3ccccc3)cc2C1

Procedure:
Using N-phenyl-2-(tert-butoxycarbonylamino)-5-indan carboxamide (27 mg, 0.077 mmol), 4N hydrochloric acid-dioxane (2.0 ml) and acetic acid (6.0 ml), a similar procedure to Example 24 was carried out to obtain N-phenyl-2-amino-5-indan carboxamide hydrochloride. Then using ethanol (1 ml), triethylamine (0.50 ml, 3.6 mmol), 4-chloro-5-methylthieno[2,3-d]pyrimidine (18 mg, 1.0 mmol), a similar procedure to b) in Example 19 was carried out. The product obtained was purified by silica gel chromatography (haxane:ethyl acetate=4:1 to 1:1) to obtain the title compound (8 mg, 0.020 mmol) having the following physical properties:
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:10]([C:11](=[O:14])[CH2:12][Br:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Br-:13].[C:1]1([C:7]2[CH:16]=[CH:15][C:10]([C:11](=[O:14])[CH2:12][N+:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccncc1
Reactant: O=C(CBr)c1ccc(-c2ccccc2)cc1
Product: O=C(C[n+]1ccccc1)c1ccc(-c2ccccc2)cc1
Product: [Br-]
Yield: 95 %

Procedure:
The title compound was prepared similarly to Example 1 from 4-phenylphenacyl bromide and pyridine in a yield of 95%.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O>CO>[O:6]=[C:4]1[C:3]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:2]=2[CH:1]=[CH:1][C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]1=2
Reactant: Cc1cc(C(=O)O)ccc1C(=O)O
Solvent: CO
Product: O=C(O)c1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
5-Oxo-5H-dibenzo[a,d]cycloheptene-2-carboxylic acid is prepared by esterifying 2-methylterephthalic acid with methanol, in the presence of acid catalyst, to afford the corresponding dimethyl ester which, in turn, is reacted with N-bromosuccinimide to afford 2-bromomethylterephthalic acid dimethyl ester. This diester is reacted with triphenylphosphine to afford 2,5-bis(carbomthoxy)benzyltriphenyl-phosphonium bromide which is treated with benzaldehyde and diazabicylononene, to afford, after alkaline hydroylsis, cis and trans stilbene 2,5-dicarboxylic acid. Hydrogenation of this latter compound with hydrogen over a 5% palladium on carbon catalyst affords 2-(2-phenethyl)terephthalic acid. Treatment with polyphosphoric acid yields 5-oxo-5H-dibenzo[a,d]-cycloheptane-2-carboxylic acid which can be recrystallized from aqueous dimethylformamide. 5-Oxo-5H-dibenzo[a,d]cycloheptene-2-carboxylic acid is prepared by successively treating 5-oxo-5H-dibenzo[a,d]cycloheptane-2-carboxylic acid with diazomethane, N-bromosuccinimide, and dimethylformamide/diazabicyclononene, followed by base hydrolysis and acidification.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[N:12]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=3)[N:11]=[N:10][N:9]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33].O>C(Cl)Cl>[C:32]([N:4]1[CH2:3][CH2:2][N:1]([CH2:7][C:8]2[N:12]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]([F:24])([F:22])[F:23])[CH:14]=3)[N:11]=[N:10][N:9]=2)[CH2:6][CH2:5]1)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: N#Cc1ccc(-n2nnnc2CN2CCNCC2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)N1CCN(Cc2nnnn2-c2ccc(C#N)c(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-[5-(1-piperazinylmethyl)-1H-tetrazol-1-yl]-2-(trifluoromethyl)benzonitrile (Example 101, 67 mg, 0.199 mmol) in DCM (2 mL) was added triethylamine (55 μL, 0.395 mmol) and then acetyl chloride (21 μL, 0.295 mmol). The reaction mixture was stirred at room temperature for 30 minutes under argon atmosphere. Water (2 mL) was added, and the mixture poured onto a hydrophobic cartridge. The heavier organic phase was concentrated under vacuum to leave white crystals. Purification by MDAP left a white solid, 4-{5-[(4-acetyl-1-piperazinyl)methyl]-1H-tetrazol-1-yl}-2-(trifluoromethyl)benzonitrile (48 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][NH:12][C:11](=[O:23])[C:10]=2[C:24]#[N:25])=[CH:5][CH:4]=1.Br[CH2:27][CH2:28][CH3:29]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][N:12]([CH2:27][CH2:28][CH3:29])[C:11](=[O:23])[C:10]=2[C:24]#[N:25])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2n[nH]c(=O)c(C#N)c2-c2ccc(OC)cc2)cc1
Reactant: CCCBr
Product: CCCn1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)c(C#N)c1=O
Yield: 72.6 %

Procedure:
Using 5,6-bis(4-methoxyphenyl)-4-cyano-2H-pyridazin-3-one and 1-bromopropane as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 72.6%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Br:10])[C:3]=1[OH:11].[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=1[C:23]([F:26])([F:25])[F:24]>>[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([O:11][C:3]2[C:2]([NH:1][C:18](=[O:19])[C:17]3[CH:21]=[CH:22][C:14]([O:13][CH3:12])=[C:15]([C:23]([F:26])([F:24])[F:25])[CH:16]=3)=[CH:7][C:6]([O:8][CH3:9])=[CH:5][C:4]=2[Br:10])=[O:19])=[CH:16][C:15]=1[C:23]([F:26])([F:25])[F:24]
Reactant: COc1cc(N)c(O)c(Br)c1
Reactant: COc1ccc(C(=O)Cl)cc1C(F)(F)F
Product: COc1cc(Br)c(OC(=O)c2ccc(OC)c(C(F)(F)F)c2)c(NC(=O)c2ccc(OC)c(C(F)(F)F)c2)c1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 20, Step c, from 2-amino-6-bromo-4-methoxyphenol and 4-methoxy-3-trifluoromethyl benzoyl chloride. The product was obtained as an off-white solid, m.p. 205–208° C.; MS m/e 622 (M+H)+.
Reaction SMILES: [F:1][C@:2]12[C@@H:21]([OH:22])[CH2:20][C@@:19]3([CH3:23])[C@@H:12]([CH2:13][CH:14]=[C:15]3[C:16](=[O:18])[CH3:17])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:25])[CH2:4][CH2:5][C:6](=[O:24])[CH:7]=1.[OH2:26]>CS(C)=O.CO.Cl>[C:21]([C@@H:14]1[CH2:13][C@@H:12]2[C@:19]([CH3:23])([CH2:20][C@H:21]([OH:22])[C@@:2]3([F:1])[C@H:11]2[CH2:10][CH2:9][C:8]2[C@:3]3([CH3:25])[CH2:4][CH2:5][C:6](=[O:24])[CH:7]=2)[C@H:15]1[C:16](=[O:18])[CH3:17])(=[O:26])[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:3]=1
Reactant: O
Reactant: CC(=O)C1=CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Agent: Cl
Solvent: CO
Solvent: CS(C)=O
Product: CC(=O)[C@H]1[C@H](C(=O)c2ccccc2)C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1-Phenyl-1-tetrahydropyranyloxyacetonitrile (1.3 g.) is added to a suspension of 57% sodium hydride-paraffin (275 mg.) in dry dimethylsulfoxide (20 ml.) in a nitrogen atmosphere. The mixture is stirred at room temperature for 90 minutes to yield a homogeneous solution of the anion. To the anion is added a solution of 9-fluoro-11β-hydroxypregna-4,16-diene-3,20-dione (1.04 g.) in dry dimethylsulfoxide. After 30 minutes, the mixture is poured into water and extracted with ethyl acetate. The extracts are combined, washed with water, dried over magnesium sulfate and evaporated to afford 2.55g. of a gum. This is dissolved in methanol (25 ml.), conc. hydrochloric acid (2 drops) is added and the solution is maintained in a bath at 55°-60°C for 5.0 hours. The methanol is evaporated in vacuo, the residue is dissolved in ethyl acetate, washed with a diluted sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated to afford the crude product as a gum. This is absorbed on a dry column of silica gel (40 g.) and the column is eluted successively with chloroform, ethyl acetate-chloroform (1:9) and ethyl acetate. Crystallization of the material (1.1 g.) eluted with ethyl acetate-chloroform from acetone-hexane affords the analytical specimen (690 mg.), melting point 250° -252°C, dec.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:37])([F:36])[C:20]([C:22]1[S:26][CH:25]=[C:24]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])[CH:23]=1)=[O:21]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][CH:35]=[C:27]([C:24]4[CH:23]=[C:22]([C:20](=[O:21])[C:19]([F:18])([F:36])[F:37])[S:26][CH:25]=4)[CH:28]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(-c2csc(C(=O)C(F)(F)F)c2)c1
Reactant: CC(C)(CN)c1coc(-c2ccc(F)cc2)n1
Product: CC(C)(CNC(=O)c1cccc(-c2csc(C(=O)C(F)(F)F)c2)c1)c1coc(-c2ccc(F)cc2)n1
Yield: 17 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine and 3-(5-(2,2,2-trifluoroacetyl)thiophen-3-yl)benzoic acid as described in example 8 step 6 (30 mg, yield 17%). 1H NMR (400 MHz, DMSO-d6) δ 8.67 (d, J=1.2 Hz, 1H), 8.43 (m, 1H), 8.16-8.12 (m, 2H), 8.00-7.97 (dd, J=9.0 Hz, 5.3 Hz, 2H), 7.92-7.90 (m, 2H), 7.84-7.82 (m, 1H), 7.57-7.53 (t, J=7.8 Hz, 1H), 7.30-7.25 (t, J=9.0 Hz, 2H), 3.56 (d, J=6.4 Hz, 2H), 1.34 (s, 6H). MS (ESI) m/z: Calculated for C26H20F4N2O3S: 516.11. found: 515.5 (M−H)−.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([OH:12])=O.FC(F)(F)C(O)=O.[N:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]2)=[N:22][CH:21]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C([O-])(O)=O.[Na+]>CN(C=O)C.CCN(CC)CC>[N:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:27][CH2:28][CH:29]([NH:32][C:10]([C:2]3[NH:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=3)=[O:12])[CH2:30][CH2:31]2)=[N:22][CH:21]=1
Reactant: NC1CCN(c2ccncn2)CC1
Reactant: O=C(O)c1nc2ccccc2[nH]1
Agent: O=C([O-])O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1CCN(c2ccncn2)CC1)c1nc2ccccc2[nH]1
Reaction time: 3 h

Procedure:
To a solution of 80 mg 1H-Benzoimidazole-2-carboxylic acid in 1 mL DMF and 0.2 mL NEt3, 200 mg 1-Pyrimidin-4-yl-piperidin-4-ylamine trifluoroacetate and 125 mg BOP-Cl were added and the mixture was stirred for 3 h. Finally, 3 mL saturated NaHCO3 solution were added and the mixture was filtered through a chem elut® cartridge by elution with ethyl acetate. After removal of the solvent under reduced pressure the crude product was subjected to the next reaction step without further purification. Yield: 160 mg.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:21])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:20])[C@H:17]([CH3:19])[NH2:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CN1CCOCC1.[C:29]([NH:36][C@H:37]([C:39](O)=[O:40])[CH3:38])([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].C(ON1C2C(=CC=CC=2)CC(=C=O)C1OCC)C>C(Cl)Cl.O>[CH2:2]([O:9][C:10](=[O:21])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:20])[C@H:17]([CH3:19])[NH:18][C:39](=[O:40])[C@H:37]([CH3:38])[NH:36][C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: CCOC1C(=C=O)Cc2ccccc2N1OCC
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
L-alanyl-L-proline benzyl ester hydrochloride (13.0 g, 41.6 mmol) was dissolved in methylene chloride (650 ml) under an argon atmosphere in a flask fitted with an over-head stirrer. N-methylmorpholine (4.8 ml, 43.6 mmol) was syringed into the solution and, after 5 minutes, Boc-L-alanine (7.9 g, 41.6 mmol) was added followed by 1-ethoxy-carbonyl-2-ethoxy-1,2-dihydroquinoline (11.8 g, 47.8 mmol). The resulting solution was stirred at room temperature overnight. The reaction mixture was poured into a separatory funnel containing water (300 ml) and the layers separated. The aqueous layer was extracted with chloroform (200 ml) and the combined organic extracts were washed with0.5 N hydrochloric acid (3×200 ml), water (2×200 ml), saturated sodium bicarbonate (2×200 ml) and brine (200 ml). The organic layer was then dried over magnesium sulfate, filtered and concentrated on a rotary evaporator. Addition of ether-hexane gave crude Boc-L-alanyl-L-alanyl-L-proline benzyl ester which could be recrystallized from ethyl acetate-hexane to give the pure product (15.1 g) mp 124-126° C.