Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)CCCN=C=NCC.[NH2:12][C:13]1[C:14](=[O:26])[N:15]([CH3:25])[C:16](=[O:24])[N:17]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:18]=1[NH2:19].[CH3:27][O:28][C:29]1[C:38]([O:39][CH3:40])=[CH:37][CH:36]=[C:35]2[C:30]=1[C:31]([CH2:41][C:42](O)=O)=[CH:32][N:33]=[CH:34]2.ON1C2C=CC=CC=2N=N1>ClCCl.O>[CH2:20]([N:17]1[C:18]2[N:19]=[C:42]([CH2:41][C:31]3[C:30]4[C:35](=[CH:36][CH:37]=[C:38]([O:39][CH3:40])[C:29]=4[O:28][CH3:27])[CH:34]=[N:33][CH:32]=3)[NH:12][C:13]=2[C:14](=[O:26])[N:15]([CH3:25])[C:16]1=[O:24])[CH:21]([CH3:22])[CH3:23]
Reactant: CC(C)Cn1c(N)c(N)c(=O)n(C)c1=O
Reactant: COc1ccc2cncc(CC(=O)O)c2c1OC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: COc1ccc2cncc(Cc3nc4c([nH]3)c(=O)n(C)c(=O)n4CC(C)C)c2c1OC
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (20.6 ml, 0.11 mol) is added to a mixture of 5,6-diamino-1-isobutyl-3-methyl-1H-pyrimidine-2,4-dione (20 g, 0.094 mol), (5,6-dimethoxy-isoquinolin-4-yl)-acetic acid (26.7 g, 0.094 mol), and 1-hydroxybenzotriazole (19.2 g, 0.142 mol) in 1:1 dichloromethane-water (400 ml). The reaction is stirred at ambient temperature for 4.5 hours and the resultant solid collected by filtration. Slurrying in water (500 ml), filtration and washing with water (250 ml) followed by drying, further tritruation with methanol and drying gives an intermediate together with slightly less pure material from concentration of the methanol triturate. The intermediate (16.08 g) is dissolved in water (100 ml) and methanol (100 ml) followed by the addition of 4M aqueous sodium hydroxide (56 ml) and the resultant solution is heated at 70° C. over night. After cooling to ambient temperature, the methanol is evaporated and the residue acidified to pH 1 with concentrated hydrochloric acid. The resultant hydrochloride salt is collected by filtration and dried. The product is then be converted to the free base by treatment with aqueous sodium hydroxide to pH 11 and washing with water to afford 3-isobutyl-8-(5,6-dimethoxy-isoquinolin-4-ylmethyl)-1-methyl-3,7-dihydro-purine-2,6-dione [MH]+ 424.6.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1[C:17]([O:19][CH3:20])=[O:18]>C1(C)C=CC=CC=1.CO>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1[C:17]([O:19][CH3:20])=[O:18])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: COC(=O)c1sccc1N
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1sccc1Nc1ccccc1[N+](=O)[O-]

Procedure:
The title compound was prepared using the process of Example 1(a) but with 2-fluoro-nitrobenzene and methyl 3-aminothiophene-2-carboxylate (U.K. Pat. No. 837,086) as starting materials, m.p. 184° C., (toluene/MeOH, 2:1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8].[F:23][C:24]([F:34])([F:33])[C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>>[F:23][C:24]([F:33])([F:34])[C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]2[C:7]([NH:9][C:10]2([C:13]3[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=3)[CH2:12][CH2:11]2)=[O:8])=[CH:27][CH:26]=1
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCCCN3)CC2)cc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCCCN3Cc3ccc(C(F)(F)F)cc3)CC2)cc1

Procedure:
The title compound (D119) (74 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from (R)-methyl 4-(1-(piperidine-2-carboxamido)cyclopropyl)benzoate (D87) (50 mg) and 4-(trifluoromethyl)benzylbromide (0.039 ml). (Na2CO3: 2.5 eq; reaction time: 6 hrs; 60° C.)
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.[C:21]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=O)#[N:22]>>[C:21]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=[N:1][C:2]1[C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1)#[N:22]
Reactant: Nc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12
Reactant: N#Cc1cccc(C=O)c1
Product: N#Cc1cccc(C=Nc2cc(C(F)(F)F)cc3ncn(-c4ccccc4)c23)c1

Procedure:
This was prepared analogously to the above product from 7-amino-1-phenyl-5-trifluoromethylbenzimidazole (1.0 g, 3.61 mmol) and 3-cyanobenzaldehyde (0.47 g, 3.61 mmol) yielding 0.90 g (64%) m/z, 391.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[C:14]2[C:6]([N:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)=[CH:5][C:4]2[CH:15]=[C:16]3[C:21]([C:3]1=2)=[CH:20][CH:19]([C:22]1[CH:34]=[CH:33][C:32]2[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25]([CH3:36])([CH3:35])[C:24]=2[CH:23]=1)[CH:18]=[CH:17]3.CN(C=O)C.[Br:43]N1C(=O)CCC1=O>O>[Br:43][C:15]1[C:4]2[CH:5]=[C:6]3[C:14]([C:2]([CH3:37])([CH3:1])[C:3]=2[C:21]2[C:16]=1[CH:17]=[CH:18][CH:19]([C:22]1[CH:34]=[CH:33][C:32]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[C:25]([CH3:36])([CH3:35])[C:24]=4[CH:23]=1)[CH:20]=2)=[C:13]1[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]1)=[N:7]3
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)C2=C(C=C3C=CC(c4ccc5c(c4)C(C)(C)c4ccccc4-5)C=C32)C=C2N=c3ccccc3=C21
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)C2=C(C=C3N=c4ccccc4=C31)C(Br)=C1C=CC(c3ccc4c(c3)C(C)(C)c3ccccc3-4)C=C12
Temperature: 100 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
The resulting 12,12-dimethyl-10-(9,9-dimethyl-9H-fluorene-2-yl)-10,12-dihydroindeno[2,1-b]carbazole (7.0 g) and DMF (140 ml) were added to a reaction vessel. The mixture was heated up to 100° C., dissolved, and cooled. N-bromo-succinimide (2.6 g) was added under ice-cooled conditions, and the mixture was stirred for 1 hour at a room temperature. Water (500 ml) was added, and the mixture was subjected to filtration to obtain a pale red powder of 7-bromo-12,12-dimethyl-10-(9,9-dimethyl-9H-fluorene-2-yl)-10,12-dihydroindeno[2,1-b]carbazole (5.7 g; yield 70.3%).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[Cl:20][C:21]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:23]2[C:24]([O:26][C:27](=O)[C:22]=12)=[O:25]>ClCCl>[F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[C:24](=[O:25])[C:23]5=[C:29]([Cl:32])[CH:30]=[CH:31][C:21]([Cl:20])=[C:22]5[C:27]4=[O:26])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C1OC(=O)c2c(Cl)ccc(Cl)c21
Reactant: NCCN1CCC(c2noc3cc(F)ccc23)CC1
Solvent: ClCCl
Product: O=C1c2c(Cl)ccc(Cl)c2C(=O)N1CCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C

Procedure:
A mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (2.44 gm, 9.24 mmoles) and 3,6-dichlorophthalic anhydride (2.01 gm; 9.27 mmoles) in dichloromethane (DCM, 50 ml) was stirred at room temperature for hr. White precipitates formed and the TLC of the reaction mixture showed that there was no starting amine remaining. The solvent was stripped down and the white solids which were poorly soluble in DCM were loaded onto a flash chromatography column, (SiO2 ; 30 gm) and the column was eluted with a solution of 1% CH3OH in DCM. The desired product thus obtained weighed 2.29 gm (54%). Recrystallization from hot ethanol yielded 2.15 gm of white crystals, m.p.=163°-164° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=CC3NC4CCN(CCN(CC)CC)C(=O)C=4C=3C)[C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[F:31].[C:32](Cl)(=[O:34])[CH3:33]>O1CCCC1>[F:31][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[NH:1][C:32](=[O:34])[CH3:33])[NH:8][C:7](=[O:11])[CH2:6]2
Reactant: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4cc(N)c(F)cc43)c(C)c2C1=O
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Product: CC(=O)Nc1cc2c(cc1F)CC(=O)N2
Temperature: 0 °C
Yield: 100.1 %

Procedure:
A stirred solution of 6-amino-5-fluoro-1,3-dihydro-indol-2-one (1.0 g, 6 mmol) obtained from Example 7 in 30 ml of tetrahydrofuran was added with tirethylamine (1.3 ml, 9 mmol). The solution was cooled down to 0° C. in an ice-water bath and added with acetyl chloride (1.3 ml, 9 mmol) dropwise. Upon the completion of the addition, the resulting mixture was heated to reflux for 1.5 hours and cooled until precipitate was formed. The solid was filtered, washed with water (50 ml×3) and dried in vacuo to give N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-acetamide (1.25 g, 99%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:18][C:19]1([CH3:35])[C:23]([CH3:25])([CH3:24])[O:22][B:21]([C:26]2[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=2)[C:29](Cl)=[O:30])[O:20]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:24][C:23]1([CH3:25])[C:19]([CH3:18])([CH3:35])[O:20][B:21]([C:26]2[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=2)[C:29]([NH:1][C:2]2[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:7])=[CH:4][CH:3]=2)=[O:30])[O:22]1
Reactant: CC1(C)OB(c2cccc(C(=O)Cl)c2)OC1(C)C
Reactant: Nc1ccc(C(=O)OCc2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OB(c2cccc(C(=O)Nc3ccc(C(=O)OCc4ccccc4)cc3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 13 h
Yield: 41.7 %

Procedure:
A mixture of benzyl 4-aminobenzoate (4.39 g, 19.3 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl chloride (4.30 g, 16.1 mmol) and N,N-diisopropylethylamine (7.49 g, 57.9 mmol) in methylene chloride (50 mL) was stirred at ambient temperature for 13 h. After this time, the reaction was concentrated under reduced pressure and purified by chromatography (silica, heptane to 1:3 ethyl acetate/heptane) to afford benzyl 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)benzoate (3.07 g, 78% pure by mass, 27% yield) as a light yellow sticky foam that was used without further purification.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@H:3]1[NH2:11].C(N(CC)CC)C.[C:19](Cl)(=[O:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[OH:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@H:3]1[NH:11][C:19](=[O:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCc1ccccc1)N[C@H]1c2ccccc2C[C@H]1O

Procedure:
To a cold (0° C.) solution of methylene chloride (30 ml) containing 2(R)-hydroxy-1(S)-aminoindane (750 mg, 5.0 mmol) and triethylamine (606 mg, 6.0 mmol) was added a solution of hydrocinnamoyl chloride (843 mg, 5.0 mmol) in 5 ml of methylene chloride. After 2 hr the reaction was poured into a separatory funnel containing 50 ml of methylene chloride and washed with 10% citric acid solution (2×30 ml). The organic layer was dried, filtered and concentrated to afford a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[CH3:11])([O-:3])=[O:2].S(=O)(=O)(O)O.O.[Br:18]([O-])(=O)=O.[K+]>C(O)(=O)C>[Br:18][C:6]1[C:5]([CH3:11])=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][C:7]=1[CH3:10]
Reactant: Cc1ccc([N+](=O)[O-])c(C)c1
Reactant: [O-][Br+2]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc([N+](=O)[O-])c(C)c1Br
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-nitro-m-xylene (0.96 g, 6.4 mmol) in acetic acid (8 mL) and sulfuric acid (4 g) and Water (4 mL) was added potassium bromate (1.18 g, 7 mmol) portion-wise over 20 minutes. The mixture was allowed to stir 72 hours at room temperature. The desired product was recovered together with starting material after partition between water, and ethyl acetate (2×) washing with water, saturated sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate, decanted and upon concentration under reduced pressure yielded the desired 2-bromo-1,3-dimethyl-4-nitrobenzene and starting material as an oily solid. The crude mixture was carried on to step two without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.C(=O)([O-])O.[Na+].[CH3:17][NH:18][CH3:19]>CC(C)=O>[Cl:11][C:6]1[C:7]([N+:8]([O-:10])=[O:9])=[C:2]([N:18]([CH3:19])[CH3:17])[N:3]=[CH:4][N:5]=1
Reactant: CNC
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CN(C)c1ncnc(Cl)c1[N+](=O)[O-]
Temperature: 45 °C
Yield: 92.9 %

Procedure:
To a mixture of 7.76 g of 4, 6-dichloro-5-nitropyrimidine, 3.70 g of sodium hydrogencarbonate and 80 ml of acetone was gradually dropwise added 50% aqueous dimethylamine (3.79 g) with ice cooling and stirring, and the mixture was stirred at room temperature for 30 minutes. Every 30 minutes, 50% aqueous dimethylamine (0.7 g) was added three times to the mixture, and the solvent was evaporated in vacuo. The residue was mixed with 70 ml of ethyl acetate, heated at 45° C. and the insoluble material was filtered off. The filtrate was dried over anhydrous sodium sulfate and the solvent evaporated. The residue was mixed with n-hexane and triturated. The precipitated crystals were filtered off to give 7.53 g of 4-chloro-6-dimethylamino-5-nitropyrimidine.
Reaction SMILES: CC1C=CC(S(O[C:12]2[CH:21]=[CH:20][C:19]3[C:18](=[O:22])[CH2:17][CH2:16][CH2:15][C:14]=3[CH:13]=2)(=O)=O)=CC=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([SH:30])=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C>O1CCOCC1.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].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[F:23][C:24]1[CH:29]=[CH:28][C:27]([S:30][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18](=[O:22])[CH2:17][CH2:16][CH2:15]3)=[CH:26][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc3c(c2)CCCC3=O)cc1
Reactant: Fc1ccc(S)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=C1CCCc2cc(Sc3ccc(F)cc3)ccc21
Yield: 77.8 %

Procedure:
To a solution of 5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl 4-methylbenzene-1-sulfonate (5.0 g, 17.0 mmol) in dioxane (75 mL) was added 4-fluorothiophenol (2.6 g, 20.4 mmol), Pd2(dba)3 (392 mg, 0.43 mmol), Xantphos (492 mg, 0.85 mmol) and DIEA (4.4 g, 34.0 mmol). The mixture was heated to reflux overnight under nitrogen. The mixture was filtered and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc=20:1 to 5:1) to give 3.6 g (77%) of the title compound as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 2.08-2.13 (m, 2H), 2.61 (t, J=6.4 Hz, 2H), 2.85 (t, J=6.0 Hz, 2H), 6.94 (br s, 1H), 6.98 (dd, J=8.4 Hz, 1.6 Hz, 1H), 7.10-7.14 (m, 2H), 7.49-7.53 (m, 2H), 7.88 (d, J=8.4 Hz, 1H). [M+H] Calc'd for C16H13FOS, 273. Found, 273.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.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>[C:17]([O:16][C:14]([NH:13][C@H:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:21])[CH:27]=2)=[CH:3][CH:4]=1)[C:10]([OH:12])=[O:11])=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Br)cc1)C(=O)O
Reactant: OB(O)c1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)O
Temperature: 25 °C

Procedure:
(R)-3-(4-Bromo-phenyl)-2-tert-butoxycarbonylamino-propionic acid (4.0 g, 11.6 mmol), 3-chlorophenylboronic acid (2.36 g, 15.11 mmol), Pd(PPh3)4 (0.067 g, 0.058 mmol) and 2M Na2CO3 aqueous solution (8.0 mL) are refluxed in 1,2-dimethoxyethane (70 mL) for 2.5 h under N2 atmosphere. After cooling to room temperature, the reaction mixture is diluted with EtOAc and washed with 1M HCl and brine. The organic layer is dried over Na2SO4 and concentrated. The residue is purified by flash column chromatography (silica gel, DCM/10% MeOH in DCM=100:0 to 0:100). to give (R)-2-tert-butoxycarbonylamino-3-(3′-chloro-biphenyl-4-yl)-propionic acid (containing impurities). HPLC retention time=1.56 minutes (condition A): MS (m+1)=376.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)(=O)=O)=CC=1.[CH:27]1([CH2:33][NH2:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C(O)(=O)/C=C/C(O)=O>CS(C)=O.C(O)(C)C>[CH:27]1([CH2:33][NH:34][CH2:11][CH:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: NCC1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)CC(=O)N4)cc1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CC(C)O
Solvent: CS(C)=O
Product: O=C1Cc2c(ccc3c2OC(CNCC2CCCCC2)CO3)N1
Temperature: 80 °C

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (0.80 g, 2.13 mmole), and cyclohexylmethylamine (1.33 g, 11.7 mmole) were combined in 15 ml of dry DMSO and heated to 80° C. for 6 hours under a nitrogen atmosphere. The reaction was allowed to cool and was partitioned between 100 ml of ethyl acetate and 150 ml of deionized water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to yield a black oil. This oil was column chromatographed on silica gel using 0.75% methanol/CH2Cl2 to remove impurities. A concentration of 2% methanol/CH2Cl2 eluted the desired product, which was as an oil (0.38 g, 56%) upon concentration in vacuum. This oil was crystallized from isopropanol with the addition of a solution of fumaric acid (0.15 g, 1.3 mmole) in hot isopropanol to give 0.39 g of the (S) enantiomer of the title compound as an off-white solid monofumarate, half hydrate, m.p. 187°-188° C.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[C:29](Cl)(=[O:33])[O:30][CH2:31][CH3:32]>C(Cl)Cl>[CH2:31]([O:30][C:29]([NH:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]2)[CH2:9]1)=[O:6])=[O:33])[CH3:32]
Reactant: CCOC(=O)Cl
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.7 %

Procedure:
To a suspension of (R)-quinuclidin-3-yl 2-amino-2-phenylacetate dihydrochloride (I25) (110 mg, 0.33 mmol) in DCM (5 ml), were added triethylamine (138 μl, 0.99 mmol) and ethyl carbonochloridate (38 μl, 0.40 mmol). The reaction was stirred at RT for 4 hours, and then solvent was evaporated. EtOAc was added, and the organic phase was washed with water and brine, dried over Na2SO4 and evaporated to obtain (R)-quinuclidin-3-yl 2-(ethoxycarbonylamino)-2-phenylacetate (60 mg; 55% yield). The product was used as such in the next step.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[C:3]=1[C:16]#[N:17].[CH2:18]([O:20][CH:21](OCC)OCC)[CH3:19]>C(O)C>[C:16]([C:3]1[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)=[N:5][NH:6][C:2]=1[N:1]=[CH:21][O:20][CH2:18][CH3:19])#[N:17]
Reactant: CCOC(OCC)OCC
Reactant: COc1cccc(Nc2n[nH]c(N)c2C#N)c1
Solvent: CCO
Product: CCOC=Nc1[nH]nc(Nc2cccc(OC)c2)c1C#N
Temperature: 120 °C

Procedure:
With stirring, a mixture of 4 g (17.45 mmol) of 5-amino-4-cyano-3-(3-methoxy-phenylamino)-pyrazole (Step 50.1) and 50 ml of orthoformic acid triethyl ester is heated at 120° C. for 1.5 hours, care being taken to ensure that the ethanol formed in the course of the reaction is distilled off from the reaction mixture. The reaction mixture is cooled to 30° C., approx. 100 ml of diethyl ether are added and the reaction mixture is cooled further to 0° C. and filtered. Washing with diethyl ether yields the title compound; m.p. 181-183° C.
Reaction SMILES: [BrH:1].Br.Br.N1CCCC1=O.[C:10]([C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].O>O1CCCC1>[Br:1][CH2:21][C:20]([C:17]1[CH:16]=[CH:15][C:14]([C:10]([CH3:13])([CH3:11])[CH3:12])=[CH:19][CH:18]=1)=[O:22]
Reactant: CC(=O)c1ccc(C(C)(C)C)cc1
Reactant: Br
Agent: O=C1CCCN1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(=O)CBr)cc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Pyrrolidone trihydrobromide (3.27 g, 10.0 mmol) was added to a solution of 1-(4-tert-butylphenyl)ethanone obtained (1.61 g, 9.13 mmol) in tetrahydrofuran (30 mL) and the mixture was heated to an external temperature of 60° C. and stirred for 30 min. After cooling, water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate and then the desiccant was filtered off, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane only→hexane:ethyl acetate=9:1) to afford the title compound as a colorless oil (472 mg).
Reaction SMILES: [CH3:1][C@H:2]1[C:10]2[C:9](O)=[N:8][CH:7]=[N:6][C:5]=2[CH2:4][CH2:3]1.O=P(Cl)(Cl)[Cl:14]>>[Cl:14][C:9]1[C:10]2[C@H:2]([CH3:1])[CH2:3][CH2:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: C[C@@H]1CCc2ncnc(O)c21
Product: C[C@@H]1CCc2ncnc(Cl)c21
Yield: 49 %

Procedure:
A mixture of (R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (5.8 g, 38.62 mmol) in POCl3 (20 mL) was refluxed for about 5 minutes. Excess POCl3 was removed under vacuum, and the residue was dissolved in DCM (50 mL). The mixture was then added to saturated NaHCO3 (200 mL). The aqueous phase was extracted with DCM (3×100 mL), and the combined organic phases were dried and concentrated. The residue was purified by silica gel chromatography, eluting with ethyl acetate to give (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (3.18 g, 49%). 1H NMR (CDCl3, 400 MHz) δ 8.81 (s, 1H), 3.47 (m, 1H), 3.20 (m, 1H), 3.05 (m, 1H), 2.41 (m, 1H), 1.86 (m, 3H), 1.47 (m, 3H).