Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[C:14]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:31]3[N:32]=[N:33][NH:34][N:35]=3)[CH:11]=2)[N:6]=1)[CH:2]([CH3:4])[CH3:3].Cl[CH2:37][C:38]([NH2:40])=[O:39].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:40][C:38](=[O:39])[CH2:37][N:33]1[N:34]=[N:35][C:31]([C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[N:6]=[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:14]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[C:13]3[C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)=[N:32]1
Reactant: NC(=O)CCl
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(-c4nn[nH]n4)cc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(-c4nnn(CC(N)=O)n4)cc23)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 68.7 %

Procedure:
A mixture of tert-butyl [2-isobutyl-4-(4-methylphenyl)-6-(2H-tetrazol-5-yl)quinolin-3-yl]methylcarbamate (0.16 g, 0.33 mmol), 2-chloroacetamide (0.047 g, 0.50 mmol), potassium carbonate (0.070 g, 0.50 mmol) and N,N-dimethylformamide (5 ml) was stirred at 80° C. for 3 hrs. The reaction mixture was partitioned between ethyl acetate-tetrahydrofuran and water and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined and washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give tert-butyl [6-[2-(2-amino-2-oxoethyl)-2H-tetrazol-5-yl]-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methylcarbamate (0.12 g, yield 69%) as a pale-yellow powder.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][C:15]#[C:16][C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24](Cl)(=[O:26])[CH3:25].O>>[C:1]1([C:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]#[C:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=3)[CH2:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc(C#CCCN2CC=C(c3ccccc3)CC2)cc1
Reactant: CC(=O)Cl
Solvent: O
Product: CC(=O)Nc1ccc(C#CCCN2CC=C(c3ccccc3)CC2)cc1

Procedure:
The title compound is prepared from 4-[4-(3,6-dihydro-4-phenyl-1(2H)-pyridinyl-1-butynyl]benzenamine (Example 21) and acetyl chloride, containing 0.1 mol of water; mp 172°-173.4° C.
Reaction SMILES: [C:1]1([C:7]23O[C:10]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)([CH:11]4[C:16]2=[CH:15][CH:14]=[CH:13][CH2:12]4)[CH:9]([C:24]#[N:25])[CH:8]3[C:26]#[N:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O1CCCC1>[C:18]1([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:8]([C:26]#[N:27])[C:9]=2[C:24]#[N:25])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: N#CC1C(C#N)C2(c3ccccc3)OC1(c1ccccc1)C1=CC=CCC12
Solvent: C1CCOC1
Product: N#Cc1c(C#N)c(-c2ccccc2)c2ccccc2c1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
In a dry 2 L 3-necked round bottom flask equipped with a magnetic stirring bar, dropping funnel, gas inlet tube attached to an argon gas cylinder, was placed tetrahydro-1,4-diphenyl-1,4-epoxy-napthalene-2,3-dicarbonitrile (20 g) and dry tetrahydrofuran (450 ml) while purging the flask with argon gas. The mixture was stirred for 20 minutes. The flask was cooled to −78° C. (acetone/dry ice) and Lithium bis(trimethylsilyl)- amide (150 ml, 1.0 M THF) was added dropwise over 2 hours. The mixture was allowed to stir at this temperature, and saturated ammonium chloride (300 ml) was added. The mixture was allowed to warm to room temperature, and the white solid was filtered off. The organic layer of the filtrate was separated. The aqueous layer was washed with ether (100 ml). The combined organic layers were dried (magnesium sulfate). After the magnesium sulfate was filtered off, the solvent was evaporated with a rotary evaporator, the residue triturated with ether, and the solid filtered, dried under vacuum and weighed (17 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[N:11]/O)/[CH2:6][CH2:5]2.C(OCC)(=O)C>C(O)(=O)C.[Zn]>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH2:11])[CH2:6][CH2:5]2
Reactant: O/N=C1\CCc2cc(Br)ccc21
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: NC1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 59.2 %

Procedure:
Zinc dust (28.0 g, 428 mmol) was added to a suspension of (E)-5-bromo-2,3-dihydro-1H-inden-1-one oxime (19.4 g, 86 mmol) in acetic acid (30 mL). The suspension was stirred at rt for 48 h. The reaction was filtered over Kiezelguhr gel. The residue was rinsed with ethyl acetate (2×100 mL). The combined filtrates were concentrated under reduced pressure to obtain a yellow oil. The yellow oil was partitioned between ethyl acetate (200 mL) and 2 N aq. HCl (200 mL). The acidic layer was separated before being basified using aq. 4 N NaOH and a white suspension was formed. Ethyl acetate (200 mL) was added and the milky mixture was filtered over Kiezelguhr gel. The organic phase was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound as a clear light yellow oil (10.8 g, 59%). MS (ESI): m/z [M−NH2]+ 198.0
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH:29]=O)[CH:7]=2)[CH2:3][CH2:2]1.[CH3:32][NH:33][C@@H:34]1[CH2:38][CH2:37][NH:36][CH2:35]1>>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH2:29][N:36]3[CH2:37][CH2:38][C@@H:34]([NH:33][CH3:32])[CH2:35]3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Reactant: CN[C@@H]1CCNC1
Product: CN[C@@H]1CCN(Cc2cn(CC3CC3)c(=O)c3ccc(-c4cc(C(=O)NC5CC5)cc(F)c4C)cc23)C1

Procedure:
The title compound was prepared as a solid by the method of Example 75 step ii) using the product of Example 75 step i) and (R)—N-methylpyrrolidin-3-amine.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=1[OH:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[CH2:15](Cl)[CH2:16][OH:17].S(=O)(=O)(O)O>O.[I-].[K+]>[C:1]([C:5]1[CH:11]=[C:10]([O:12][CH2:15][CH2:16][OH:17])[CH:9]=[CH:8][C:6]=1[OH:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OCCCl
Reactant: CC(C)(C)c1cc(O)ccc1O
Agent: O=S(=O)(O)O
Agent: [I-]
Agent: [K+]
Solvent: O
Product: CC(C)(C)c1cc(OCCO)ccc1O
Temperature: 80 °C
Yield: 47.6 %

Procedure:
332 g (2 mol) of t-butylhydroquinone and 1 g of potassium iodide were dissolved in 2 l of water under nitrogen atmosphere, and were heated to 80° C. Thereafter, to the solution thus obtained, were dropwise added 232 g (2.8 mol) of 48% sodium hydroxide aqueous solution and 200 g (2.5 mol) of ethylene chlorohydrine at the same time for 3 hours while constantly maintaining alkaline. After finishing this dropwise addition, the resultant reaction mixture was heated for 8 hours at the reflux temperature. After cooling the reaction mixture thus obtained, the reaction mixture was neutralized with sulfuric acid and was extracted with toluene. After removing solvent, the remaining material was distilled under reduced pressure and the distillate was recrystallized from toluene to obtain 200 g of 2-t-butyl-4-(2'-hydroxyethoxy)phenol. The reaction formula (alkylation) is illustrated in the following. ##STR4##
Reaction SMILES: C([O:4][CH2:5][C@@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:33])[C:14]=2[NH:18][C:19](=[O:32])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[C:23]([F:31])[CH:22]=2)[C:9]1=[O:34])[CH3:7])(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>O>[F:31][C:23]1[CH:22]=[C:21]([CH2:20][C:19]([NH:18][C:14]2[C:13]([CH3:33])=[CH:12][CH:11]=[C:10]3[C:15]=2[CH:16]=[CH:17][N:8]([C@@H:6]([CH3:7])[CH2:5][OH:4])[C:9]3=[O:34])=[O:32])[CH:26]=[CH:25][C:24]=1[C:27]([F:30])([F:28])[F:29]
Reactant: CC(=O)OC[C@H](C)n1ccc2c(NC(=O)Cc3ccc(C(F)(F)F)c(F)c3)c(C)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1ccc2c(=O)n([C@@H](C)CO)ccc2c1NC(=O)Cc1ccc(C(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A round bottom flask was charged with (S)-2-(5-(2-(3-fluoro-4-(trifluoromethyl)phenyl)-acetamido)-6-methyl-1-oxoisoquinolin-2(1H)-yl)propyl acetate (200.00 mg, 0.41803 mmol), potassium carbonate (173 mg, 0.00125 mol), methanol (15 mL, 0.37 mol) and few drops of water. The reaction was stirred at room temperature for 1 h. The reaction mixture was filtered and the solvent was removed under reduced pressure. The residue was extracted with IPA:chloroforn, 1:3, washed with water and the solvent was removed under reduced pressure. The residue was purified by reverse phase prep HPLC to give the desired compound as light orange solid.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:7][CH2:6][CH2:5][N:4]2C(OC(C)(C)C)=O)[CH2:2]1.[C:15]([OH:21])([C:17]([F:20])([F:19])[F:18])=[O:16]>C(Cl)Cl>[F:18][C:17]([F:20])([F:19])[C:15]([OH:21])=[O:16].[CH2:2]1[C:3]2([CH2:7][CH2:6][CH2:5][NH:4]2)[CH2:1]1
Reactant: CC(C)(C)OC(=O)N1CCCC12CC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C1CNC2(C1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 4-azaspiro[2.4]heptane-4-carboxylate (Compound 11-1) (0.75 g, 3.80 mmol) and TFA (3 mL) were added in DCM (10 mL) and the mixture was stirred at room temperature for 1 hour and concentrated to give Compound 11-2 (800 mg, 99.6%) as a yellow oil.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].CCN(CC)CC.[CH3:13][O:14][C:15](=[O:53])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([Cl:34])[CH:32]=3)[N:27]([CH:35]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:26]=2[CH2:48][CH2:49][OH:50])=[CH:18][C:17]=1[O:51][CH3:52]>ClCCl>[CH3:13][O:14][C:15](=[O:53])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([Cl:34])[CH:32]=3)[N:27]([CH:35]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:26]=2[CH2:48][CH2:49][O:50][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:18][C:17]=1[O:51][CH3:52]
Reactant: COC(=O)c1ccc(OCCc2c(CCO)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1OC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OCCc2c(CCOS(C)(=O)=O)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
MeSO2Cl (0.03 mL, 0.39 mmol) and Et3N (0.07 mL, 0.48 mmol) were added to a solution of the alcohol from step 5 (0.11 g, 0.19 mmol) in dichloromethane (8 mL) at 0° C. Reaction was stirred at 0° C. for one hour and then warmed to room temperature and stirred an additional hour. Reaction solution was concentrated by rotary evaporation. Obtained 0.123 g of 4-{2-[1-Benzhydryl-5-chloro-2-(2-methanesulfonyloxy-ethyl)-1H-indol-3-yl]-ethoxy}-2-methoxy-benzoic acid methyl ester in quantitative yield.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[CH3:22][C:23]1[O:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)=[CH:26][N:27]=1>>[CH3:22][C:23]1[O:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:2]3[N:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]4[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=4)[N:3]=3)=[CH:30][CH:29]=2)=[CH:26][N:27]=1
Reactant: Cc1ncc(-c2ccc(N)cc2)o1
Reactant: CC(C)(O)c1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Product: Cc1ncc(-c2ccc(Nc3nc(-c4ccc(C(F)(F)F)cc4)cc(C(C)(C)O)n3)cc2)o1
Yield: 21.3 %

Procedure:
Using in analogous manner the procedure described in example 1e), 2-[2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yl]-propan-2-ol (95 mg, 0.3 mmol) was reacted with 4-(2-methyl-oxazol-5-yl)-phenylamine (52 mg, 0.3 mmol) to give the title compound as light yellow solid (29 mg, 21%). MS ISP (m/e): 455.2 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.20, 7.78, 7.75 and 7.63 (4 d, 4×2H), 7.31 (s, 2H), 7.16 (s, 1H), 3.93 (s, 1H), 2.53 (s, 3H), 1.61 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:9][CH2:10][CH2:11]O)=[N:4][CH:5]=[N:6][C:7]=1[Cl:8].[C:13]([O:16][C:17](=[O:19])[CH3:18])(=O)[CH3:14]>>[C:17]([O:16][CH2:13][CH2:14][N:9]1[C:3]2[N:4]=[CH:5][N:6]=[C:7]([Cl:8])[C:2]=2[N:1]=[C:10]1[CH3:11])(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1c(Cl)ncnc1NCCO
Product: CC(=O)OCCn1c(C)nc2c(Cl)ncnc21
Yield: 21 %

Procedure:
2-(5-Amino-6-chloro-4-pyrimidinylamino)ethanol (Chem. Pharm. Bull., 1961, 9, 27) (5.71 g, 30.3 mmol) and acetic anhydride (50 ml) were heated together under nitrogen at 120° C. for 20 hours. The excess reagent was removed under reduced pressure and the residue was neutralised with aqueous sodium bicarbionate and extracted with dichloromethane (4×70 ml). The extracts were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with ethyl acetate) to give 3-(2-acetoxyethyl)-2-methyl-7-chlorimidazo-[4,5-d]pyrimidine (1.597 g, 21%), as a white solid.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH3:10][C:11]1[C:15](B(O)O)=[CH:14][N:13]([C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:10][C:11]1[C:15]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=2)=[CH:14][N:13]([C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:12]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc(C#N)cn1
Temperature: 135 °C
Yield: 53 %

Procedure:
To a solution of 6-Chloro-nicotinonitrile (0.2 g, 1.49 mmol) and 3-methyl-1-trityl-1H-pyrazole-4-boronic acid* (0.5 g, 1.36 mmol) in ethylene glycol dimethyl ether (3 ml), was added sodium carbonate (0.36 g, 3.39 mmol) in water (1.5 ml). The reaction mixture was degassed with nitrogen before addition of tetrakis(triphenylphosphine)palladium (0) and then heated in a CEM microwave at 135° C. for 30 minutes (50 W power). Reaction partitioned between water and ethyl acetate, aqueous basified with 2N NaOH, organic extracts were combined, dried (MgSO4) and solvent removed. Crude product suspended in small volume of methanol, white precipitate filtered to afford the title compound (0.32 g, 53% yield). LC/MS: (PS-A2) Rt 4.52 [M+H]+ 427.26. *This starting material can be made by the method described in EP1382603A1
Reaction SMILES: O[C@@H]1CC[C@H]([N:8]2[C:16](=O)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13]C=3)C2=O)CC1.CC1C=C2C(C=NN2)=CC=1O.[CH3:30][C:31]1[C:39]([OH:40])=[CH:38][CH:37]=[C:36]2[C:32]=1[CH:33]=[N:34][NH:35]2>>[NH:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:40][C:39]2[C:31]([CH3:30])=[C:32]3[C:36](=[CH:37][CH:38]=2)[NH:35][N:34]=[CH:33]3)[CH:15]=[CH:16]1
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@@H](O)CC1
Reactant: Cc1c(O)ccc2[nH]ncc12
Agent: Cc1cc2[nH]ncc2cc1O
Product: Cc1c(OC2=CC=CNC=C2)ccc2[nH]ncc12

Procedure:
The following compound of Example 408 was synthesized by carrying out reaction according to the method described in Example 385, except for using the cis-2-(4-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione obtained in Example 323, (c) and the 4-methyl-1H-indazol-5-ol obtained in Example 402, as starting materials.
Reaction SMILES: CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CC([O-])(C)C.[Na+].[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][NH:39][C@@H:38]([CH:42]([CH3:44])[CH3:43])[CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].[CH2:45]([C:52]1[CH:57]=[CH:56][CH:55]=[C:54](Br)[CH:53]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(Cl)Cl.CO>[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][N:39]([C:54]2[CH:55]=[CH:56][CH:57]=[C:52]([CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH:53]=2)[C@@H:38]([CH:42]([CH3:44])[CH3:43])[CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: Brc1cccc(Cc2ccccc2)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1cccc(Cc2ccccc2)c1
Temperature: 100 °C
Yield: 22.6 %

Procedure:
17.9 mg (19.55 μmol, 0.044 eq.) Pd2(dba)3 and 5.9 mg (19.38 μmol, 0.044 eq.) P(o-tolyl)3 were dissolved in 6 ml dry toluene. Then 58.9 mg (610 μmol, 1.39 eq.) NaOt-Bu was added, followed by a solution of 101 mg (442 μmol) 3-(S)-Isopropyl-piperazine-1-carboxylic acid tert-butyl ester (85) and 110 mg (445 μmol, 1.01 eq.) 1-Benzyl-3-bromo-benzene (87). The resulting mixture was heated at 100° C. for 19 h. After filtrating the reaction mixture through celite the solvent was evaporated. Column chromatography (hexanes/EtOAc (3+1)) yielded 39.6 mg (100 μmol, 22.71%) 4-(3′-Benzylphenyl)-3-(S)-iso-propyl-piperazine-1-carboxylic acid tert-butyl ester (88).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=O)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[C:12]1([CH3:26])[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)=[CH:14][CH:13]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][NH:25][C:22]2[CH:21]=[CH:20][C:19]([O:18][C:15]3[CH:16]=[CH:17][C:12]([CH3:26])=[CH:13][CH:14]=3)=[CH:24][CH:23]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Br)cc1C=O
Reactant: Cc1ccc(Oc2ccc(N)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ncc(Br)cc1CNc1ccc(Oc2ccc(C)cc2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of 5-bromo-2-methoxy-pyridine-3-carbaldehyde (0.87 g, 4.03 mmol) in dry MeOH (15 mL) was treated with 4-p-tolyloxy-phenylamine (0.88 g, 4.43 mmol) and reflux for 2.5 h. The solution was cooled to 0° C. and treated slowly with NaBH4 (0.38 g, 10.1 mmol). The reaction stirred at room temperature overnight. Additional NaBH4 (0.38 g, 10.1 mmol) was added and the reaction was continued stirring for additional 6 h. The solvent was removed and the residue was partitioned between CH2Cl2 (20 mL) and water (10 mL). The organic portion was brought to the usual work-up to give a crude material. The product was yielded after chromatography purification (silica gel, 25% EtOAc/hexanes). MS (EI) 399, 401 (M+H)+.
Reaction SMILES: Cl.C(OC(=O)[NH:8][C@H:9]([C:11]1[N:12]=[N:13][N:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:15]=1)[CH3:10])(C)(C)C>O1CCOCC1>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([N:14]2[CH:15]=[C:11]([C@@H:9]([NH2:8])[CH3:10])[N:12]=[N:13]2)=[CH:21][CH:20]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cn(-c2ccc(Cl)cc2)nn1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](N)c1cn(-c2ccc(Cl)cc2)nn1
Reaction time: 1 h
Yield: 115 %

Procedure:
A solution of hydrogen chloride (4.0 M in 1,4-dioxane, 3.3 mL, 13.2 mmol, 10 equiv) was added to a solution of (S)-tert-butyl(1-(1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)ethyl)carbamate (425 mg, 1.32 mmol) in 1,4-dioxane (5 mL) at room temperature. The solution was stirred for 1 hour, by which time a white precipitate had formed. The reaction was concentrated in vacuo to give the hydrochloride salt of (S)-1-(1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)ethanamine (338 mg, white solid) in 99% yield. The material was used without purification. 1H NMR (400 MHz, CD3OD) δ 8.68 (s, 1H), 7.90 (d, J=9.0 Hz, 2H), 7.63 (d, J=9.0 Hz, 2H), 4.77 (q, J=6.9 Hz, 1H), 1.78 (d, J=6.9 Hz, 3H). MS m/z 223.1 (M+H)+; Rt-0.50 min.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[O:12][CH2:13][C:14]1[N:15]=[CH:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:18]=1.C(Cl)Cl.O.NN>C(O)C>[NH2:3][O:12][CH2:13][C:14]1[N:15]=[CH:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:18]=1
Reactant: CC(C)(C)OC(=O)n1cnc(CON2C(=O)c3ccccc3C2=O)c1
Agent: NN
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1cnc(CON)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.6 %

Procedure:
To a mixture of tert-butyl 4-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}-1H-imidazole-1-carboxylate 121 (1.72 g, 5.00 mmol) in a solution of DCM (20 mL) and ethanol (4 mL) was added hydrazine hydrate (0.287 mL, 5.00 mmol) at room temperature. The mixture was stirred at room temperature overnight, filtered and concentrated to provide a residue which was washed with ether and methanol to give 122 (0.54 g, 51%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[CH2:19][C:20]([NH2:22])=[O:21].[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[CH:8]2[OH:12])=[CH:4][C:3]=1[CH2:19][C:20]([NH2:22])=[O:21]
Reactant: CC1(C2CCCC2)Cc2cc(CC(N)=O)c(Cl)c(Cl)c2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC1(C2CCCC2)Cc2cc(CC(N)=O)c(Cl)c(Cl)c2C1O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)acetamide (6.8 g., 0.02 mole) in ethanol (100 ml) is added sodium borohydride (760 mg. 0.02 mole). After one hour another portion of sodium borohydride (760 mg, 0.021 mole) is added and stirring continued for 3 hours. The reaction mixture is poured into ice water and extracted with ethyl acetate. The ethyl acetate extract is washed with water and dried over magnesium sulfate. The ethyl acetate is evaporated at reduced pressure to give (6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-hydroxy-2-methyl-1H-inden-5-yl)acetamide consisting of a mixture of two diastereomer, each of which is a racemate.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15](=[O:34])[NH:16][CH:17]1[CH2:22][CH2:21][N:20]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:19][CH2:18]1)([CH3:13])([CH3:12])[CH3:11].[CH2:35]([C:42](Cl)=[O:43])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl>[C:10]([O:14][C:15](=[O:34])[NH:16][CH:17]1[CH2:22][CH2:21][N:20]([S:23]([C:26]2[CH:27]=[CH:28][C:29]([CH2:32][NH:33][C:42](=[O:43])[CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:30][CH:31]=2)(=[O:25])=[O:24])[CH2:19][CH2:18]1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(CN)cc2)CC1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(CNC(=O)Cc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
Diisopropylethylamine (0.17 ml, 1.02 mmol) was added in one portion to a stirred solution of [1-(4-aminomethyl-benzenesulfonyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (0.25 g, 0.68 mmol) in DCM (10 ml) at room temperature. To this mixture was added benzyl carbonyl chloride (0.1 g, 0.68 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time the mixture was diluted with DCM (50 ml) and washed sequentially with HCl (1M solution, 20 ml), NaOH (1M solution, 20 ml) and brine (20 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated to give the title compound (0.32 g, 97% yield) as a white solid. δH (500 MHz, DMSO) 8.67 (t, J=5.99 Hz, 1 H) 7.66 (d, J=8.20 Hz, 2 H) 7.47 (d, J=8.35 Hz, 2 H) 7.19-7.36 (m, 5 H) 6.85 (d, J=7.25 Hz, 1 H) 4.38 (d, J=5.99 Hz, 2 H) 3.51 (s, 2 H) 3.46 (d, J=11.82 Hz, 2 H) 3.21 (br. s., 1 H) 2.33-2.43 (m, 3 H) 1.76 (d, J=10.56 Hz, 2 H) 1.30-1.45 (m, 12 H).