Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([CH:15]([CH3:17])[CH3:16])[C:12]([OH:14])=[O:13].C(N(CC)CC)C.[C:25]([CH:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:30]=1)O)#[N:26]>CCOCC>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([CH:15]([CH3:17])[CH3:16])[C:12]([O:14][CH:27]([C:25]#[N:26])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:30]=1)=[O:13]
Reactant: N#CC(O)c1cccc(Oc2ccccc2)n1
Reactant: CC(C)C(C(=O)O)c1ccc2ccccc2c1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)C(C(=O)OC(C#N)c1cccc(Oc2ccccc2)n1)c1ccc2ccccc2c1
Reaction time: 18 h

Procedure:
To the acid chloride of 2-(2-naphthyl)-3-methylbutanoic acid (2.5 mmol) in ether is added 1.3 ml of triethylamine followed by the cyano(6-phenoxy-2-pyridyl)methanol in 5 ml of ether, from part A above, over about 2 minutes. The reaction mixture is stirred for about 18 hours and then quenched with saturated aqueous sodium bicarbonate. The organic phase is washed with aqueous sodium bicarbonate, water and brine, dried over calcium sulfate and solvent evaporated. The crude product is chromatographed on a circular chromatograph eluting with 20% ether/hexane to give cyano(6-phenoxy-2-pyridyl)methyl 2-(2-naphthyl)-3-methylbutanoate, MS m/e 436 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C@@H:12]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:13][CH2:14][CH:15]=[CH2:16].C([C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[C:32]([CH3:40])[CH:31]=1)=C>CC1C=C(C)C=C(C)C=1N1CCN(C2C(C)=CC(C)=CC=2C)C1=[Ru-4](Cl)(Cl)=CC1C=C(S(N(C)C)(=O)=O)C=CC=1OCCC.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C@H:12]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:13][CH2:14]/[CH:15]=[CH:16]/[C:30]1[CH:35]=[C:34]([C:36]([F:37])([F:39])[F:38])[CH:33]=[C:32]([CH3:40])[CH:31]=1
Reactant: C=CCC[C@H](NC(=O)OCc1ccccc1)c1cc(C(F)(F)F)ccc1Br
Reactant: C=Cc1cc(C)cc(C(F)(F)F)c1
Agent: CCCOc1ccc(S(=O)(=O)N(C)C)cc1C=[Ru-4](Cl)(Cl)=C1N(c2c(C)cc(C)cc2C)CCN1c1c(C)cc(C)cc1C
Solvent: ClCCl
Product: Cc1cc(/C=C/CC[C@@H](NC(=O)OCc2ccccc2)c2cc(C(F)(F)F)ccc2Br)cc(C(F)(F)F)c1
Temperature: 60 °C
Yield: 73.7 %

Procedure:
To a 100 mL RBF equipped with a reflux condenser was added benzyl {(1S)-1-[2-bromo-5-(trifluoromethyl)phenyl]pent-4-en-1-yl}carbamate (0.5 g, 1.13 mmol), 1-ethenyl-3-methyl-5-(trifluoromethyl)benzene (421 mg, 2.26 mmol) and dichloromethane (10 mL). The system was flushed with nitrogen and 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene[2-(1-propoxy)-5-(N,N-dimethylaminosulfonyl)phenyl]methyleneruthenium(II)dichloride (41 mg, 0.57 mmol) (Zhan catalyst-1B) was added before heating at 60° C. for 20 min. The reaction was cooled to room temperature and was directly purified by column chromatography to yield benzyl {(1R,4E)-1-[2-bromo-5-(trifluoromethyl)phenyl]-5-[3-methyl-5-(trifluoromethyl)phenyl]pent-4-en-1-yl}carbamate (500 mg, 0.833 mmol). 1H NMR (500 MHz, CDCl3) δ7.72 (m, 1H), 7.58 (s, 1H), 7.39 (b, 5H), 6.4 (d, J=8.2 Hz, 1H), 6.25 (m, 1H), 5.35 (m, 1H), 5.20 (m, 1H), 5.10 (s, 2H), 2.40 (s, 3H), 2.19 (m, 1H), 2.05 (m, 1H), 1.95 (m, 1H), 1.78 (m, 1H).
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)/[CH:5]=[CH:6]/[CH:7]1[N:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])[C:10](=[O:21])[CH2:9][S:8]1.[H-].Cl>C(O)C>[OH:3][CH:4]([CH2:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)/[CH:5]=[CH:6]/[CH:7]1[N:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])[C:10](=[O:21])[CH2:9][S:8]1
Reactant: O=C(O)CCCCCCN1C(=O)CSC1/C=C/C(=O)CCc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [H-]
Solvent: CCO
Product: O=C(O)CCCCCCN1C(=O)CSC1/C=C/C(O)CCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium borohydride (1.25 molar equivalents) is added in small portions over 1/2 hour to a stirred solution of 7-[2-(3-oxo-5-phenyl-1-trans-pentenyl)-4-oxo-3-thiazolidinyl]heptanoic acid (1 molar equivalent) in ethanol maintained at 0° to 5° C. Upon completing the hydride addition, the reaction mixture is stirred at 0° to 5° for 1/2 hour, then at ambient temperature for 21/2 hours. The resulting reaction mixture is cooled to 0° to 5° C., diluted with ice water and cautiously acidified to Congo Red with 2 N hydrochloric acid providing a turbid aqueous mixture which is extracted several times with ether. The combined organic extract is dried over sodium sulfate and filtered. In vacuo evaporation of the filtrate at 40° to 50° C. leaves an oily residue which is purified by chromatography on silica gel providing the title compound as a viscous, pale yellow oil.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].C(N(CC)CC)C.[CH2:12]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH2:25][N:24]([C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:27])[CH2:23][CH:22]([C:34](Cl)=[O:35])[CH2:21]2)=[CH:16][CH:15]=1)[CH3:13].O>ClCCl>[CH2:12]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH2:25][N:24]([C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:27])[CH2:23][CH:22]([C:34]([NH:4][CH2:1][C:2]#[CH:3])=[O:35])[CH2:21]2)=[CH:16][CH:15]=1)[CH3:13]
Reactant: C#CCN
Reactant: CCc1ccc(C2CC(C(=O)Cl)CN(C(=O)N3CCOCC3)C2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCNC(=O)C1CC(c2ccc(CC)cc2)CN(C(=O)N2CCOCC2)C1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
18 μl (16 mg, 0.29 mmol) of propargylamine, 40 μl (29 mg, 0.29 mmol) of triethylamine and 1 mg (0.01 mmol) of N,N-dimethylaminopyridine were initially charged in 0.5 ml of dichloromethane, and 105 mg (0.29 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carbonyl chloride, dissolved in 1 ml of dichloromethane, were added. The reaction mixture was stirred at 0° C. for 30 minutes and at RT for 16 h. For work-up, water was added and the reaction mixture was extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (mobile phase dichloromethane/methanol 100:5). Yield: 108 mg (98% of theory.)
Reaction SMILES: [CH:1]1[C:10]2[C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][C:2]=1[NH2:18].[CH:19]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>ClC(Cl)C>[CH:1]1[C:10]2[C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][C:2]=1[NH:18][C:25]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:26]
Reactant: Nc1cc2c3c(c1)c1c(n3CCC2)CCCCC1
Reactant: O=C(Cl)C1CCCCC1
Solvent: CC(Cl)Cl
Product: O=C(Nc1cc2c3c(c1)c1c(n3CCC2)CCCCC1)C1CCCCC1
Yield: 53.7 %

Procedure:
Following the procedure of Example 1, Step 4, 5,6,9,10,11,12-hexahydro-4H,8H-cyclohepta[4,5]pyrrolo[3,2,1-ij]quinolin-2-amine (0.10 g, 0.42 mmol), cyclohexanecarbonyl chloride (0.056 mL, 0.42 mmol) and poly-(4-vinylpyridine) (600 mg) in dichloroethane (15 mL) provided 79 mg of N-5,6,9,10,11,12-hexahydro-4H,8H-cyclohepta[4,5]pyrrolo[3,2,1-ij]quinolin-2-ylcyclohexanecarboxamide. MS (ES) m/z 351.2; HPLC purity 100% at 210-370 nm, 11.3 min.; 99.5% at 252 nm, 11.3 min. (Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 ((Ammon. Form. Buff. pH=3.5/ACN and MeOH) for 10 min, hold 4 min); HRMS: calcd for C23H30N2O+H+, 351.24309; found (ESI, [M+H]+), 351.2443.
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][CH2:11][C:12]2[S:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[O:22]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23]1>>[O:22]1[CH2:26][CH2:25][CH:24]([NH:27][C:18]([C:14]2[S:13][C:12]([CH2:11][CH2:10][C:9]3[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=3[CH3:21])=[N:16][C:15]=2[CH3:17])=[O:20])[CH2:23]1
Reactant: NC1CCOC1
Reactant: CCCCc1noc(C)c1CCc1nc(C)c(C(=O)O)s1
Product: CCCCc1noc(C)c1CCc1nc(C)c(C(=O)NC2CCOC2)s1
Yield: 40 %

Procedure:
As described for example 48e, 2-[2-(3-butyl-5-methyl-isoxazol-4-yl)-ethyl]-4-methyl-thiazole-5-carboxylic acid (75 mg, 0.23 mmol) was converted, using rac-tetrahydrofuran-3-amine instead of isopropylamine, to the title compound (35 mg, 40%) which was obtained as a light brown oil. MS: m/e=378.3 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([S:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[C:8]#[N:9].[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[CH2:36][NH:35][CH2:34][CH2:33]2>>[CH3:19][O:18][C:12]1[CH:11]=[C:10]([C:7]([S:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:35]2[CH2:34][CH2:33][C:32]3[C:37](=[CH:38][C:39]([O:40][CH3:41])=[C:30]([O:29][CH3:28])[CH:31]=3)[CH2:36]2)[C:8]#[N:9])[CH:15]=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: COc1ccc(C(C#N)(CCCCCCl)Sc2ccc(C)cc2)cc1OC
Reactant: COc1cc2c(cc1OC)CNCC2
Product: COc1ccc(C(C#N)(CCCCCN2CCc3cc(OC)c(OC)cc3C2)Sc2ccc(C)cc2)cc1OC
Yield: 56.9 %

Procedure:
The procedure of Example 3 is repeated using 4.65 g of α-(5-chloropentyl)-3,4-dimethoxy-α-[(4-methylphenyl)thio]benzeneacetonitrile and 4.25 g of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline. This affords 3.67 g of the desired product as a light brown gum. MS(Hi res): m/z Calcd for C33H40N2O4S 0.5H2O 560.2209 Found 561.2287(M+H). Calcd for C33H40N2O4S 0.5H2O: C=69.77, H=7.17, N=4.58, S=5.33 Found C=69.56, H=7.25, N=4.92, S=5.63
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][C@H:6]([N:9]2C(=O)C3=CC=CC=C3C2=O)[C:5](=[O:20])[N:4]2[C@H:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23][N:3]12.O.NN>C(O)C>[NH2:9][C@@H:6]1[C:5](=[O:20])[N:4]2[C@H:21]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:22][CH2:23][N:3]2[C:2](=[O:1])[CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCN2C(=O)CC[C@H](N3C(=O)c4ccccc4C3=O)C(=O)N12
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)[C@@H]1CCN2C(=O)CC[C@H](N)C(=O)N12
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
2.48 g of tert.butyl 2,3,6,7,8,9-hexahydro-5,9-dioxo-8(S)-phthalimido-1H,5H-pyrazolo[1,2-a][1,2]diazepine-1(S)-carboxylate [prepared as described in Example 3(D)] were stirred at room temperature for 0.5 hours in 80 ml of ethanol with 0.3 g of hydrazine hydrate and the mixture was then evaporated. 90 ml of 2N acetic acid were added, the mixture was stirred at room temperature for 1 hour and was then filtered. The filtrate was made basic with solid sodium carbonate and then extracted twice with dichloromethane. The combined dichloromethane extracts were dried over magnesium sulphate and evaporated to give 1.58 g (93%) of tert.butyl 8(S)-amino-2,3,6,7,8,9-hexahydro-5,9-dioxo-1H,5H-pyrazolo[1,2-a][1,2]diazepine-1(S)-carboxylate in the form of a gum.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]=[C:10]=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:12][C:13]1[N:18]=[N:17][C:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:36])([F:35])[F:34])=[O:26])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1>>[CH2:8]([NH:9][C:10]([NH:12][C:13]1[N:18]=[N:17][C:16]([N:19]2[CH2:20][CH2:21][N:22]([C:25](=[O:26])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:36])([F:35])[F:34])[CH2:23][CH2:24]2)=[CH:15][CH:14]=1)=[O:11])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: O=C=NCCc1ccccc1
Product: O=C(NCCc1ccccc1)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 5, making variations only as required to use 2-phenylethylisocyanate in place of (2-isocyanatocyclopropyl)benzene to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)-methanone, the title compound was obtained as a white solid (19% yield). 1H NMR (500 MHz, CDCl3) δ 7.92, 7.60, 7.64, 7.58, 7.37, 7.13-7.24, 7.09, 3.96-4.03, 3.82-3.89, 3.40-3.56, 3.22-3.34, 2.86.
Reaction SMILES: [Cu][C:2]#[N:3].[C:4]([O:7][C@H:8]1[C@@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@H:11]([N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][C:20](Cl)=[N:21][C:22]=3[Cl:26])[O:10][C@@H:9]1[CH2:28][O:29][C:30](=[O:32])[CH3:31])(=[O:6])[CH3:5]>O>[C:4]([O:7][C@H:8]1[C@@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@H:11]([N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][C:20]([C:2]#[N:3])=[N:21][C:22]=3[Cl:26])[O:10][C@@H:9]1[CH2:28][O:29][C:30](=[O:32])[CH3:31])(=[O:6])[CH3:5]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: N#C[Cu]
Solvent: O
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 100 °C

Procedure:
Copper (I) cyanide was added to a solution of (2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-(2,6-dichloro-9H-purin-9-yl)tetrahydro-3-furanyl acetate (J. Med. Chem., 248, 35, 1992) (22 g, 40 mmol) in N′N′-dimethylformamide (150 ml). The suspension was heated to 100° C. for 2 hours and was then allowed to cool to room temperature. The reaction mixture was poured into water (700 ml) with stirring. The solid was filtered off and stirred in dichloromethane (700 ml) for 30 minutes. The solid was filtered off again and then stirred in dichloromethane (700 ml) for another 30 minutes. The dichloromethane portions were combined and evaporated under reduced pressure to a volume of 500 ml. The dichloromethane was then dried over anhydrous sodium sulphate. The solvent was removed under reduced presure. The residue was redissolved in dichloromethane (300 ml). The solvent was removed under reduced pressure. The residue was then stirred in diethylether (300 ml) for 20 minutes. The solid was filtered off and dried to give the title compound (14.8 g).
Reaction SMILES: [F-].[K+].[Br:3][C:4]1[C:11]([OH:12])=[C:10]([O:13][CH:14]2CCCC2)[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7].F[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1.O>CS(C)=O>[Br:3][C:4]1[C:11]([O:12][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[C:10]([O:13][CH3:14])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: O=Cc1ccc(OC2CCCC2)c(O)c1Br
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(C=O)c(Br)c1Oc1ccc([N+](=O)[O-])cc1
Temperature: 140 °C
Reaction time: 6 h
Yield: 81 %

Procedure:
To a stirred suspension of potassium fluoride (125 mg, 2.104 mmol) in dry DMSO (2.5 ml) was added a solution of 2-bromo-4-cyclopentoxy-3-hydroxy-benzaldehyde (500 mg, 1.754 mmol) in DMSO (2.5 ml). A solution of 4-fluoronitrobenzene (500 mg, 2.631 mmol) in DMSO (2.5 ml) was added to the above suspension and the reaction mixture was stirred at 140° C. for 6 h. The reaction mixture was cooled to room temperature and the contents were poured into water (100 ml) and extracted with ethyl acetate (50 ml×3). The organic extracts were combined and washed with 1N sodium hydroxide (25 ml×2), water and brine and dried over anhydrous sodium sulfate. The dried organic layer was concentrated in vacuo to give 2-bromo-3-(p-nitrophenoxy)-4-methoxy benzaldehyde as a pale yellow solid (500 mg) mp: 115-117° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([CH3:24])([CH3:23])[C:10]([CH:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15]CC)=O)=[O:11]>OS(O)(=O)=O>[F:8][C:7]1[C:2]([F:1])=[C:3]2[C:4]([C:13]([OH:15])=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:10](=[O:11])[C:9]2([CH3:23])[CH3:24])=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C(C)(C)c1cccc(F)c1F
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1=C(O)c2ccc(F)c(F)c2C(C)(C)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To 10 mL concentrated H2SO4 stirred at room temperature, was added diethyl 2-(2-(2,3-difluorophenyl)-2-methylpropanoyl)malonate (1.53 g, 4.5 mmol). The mixture was stirred at room temperature for 2 hours, M+1=297. The mixture was then poured into 100 g crushed ice and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to give 1.2 g of the title compound as a pale yellow solid. MS (m/z)=297 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][C:11]1[S:12][C:13](=[CH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][C:26]=3[C:33]([F:36])([F:35])[F:34])=[C:20]([O:37][CH3:38])[CH:19]=2)[C:14](=[O:16])[N:15]=1)(C)(C)C.[ClH:40].C(OCC)C>C(OCC)(=O)C.CO>[ClH:40].[NH2:7][CH2:8][CH2:9][NH:10][C:11]1[S:12][C:13](=[CH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][C:26]=3[C:33]([F:35])([F:34])[F:36])=[C:20]([O:37][CH3:38])[CH:19]=2)[C:14](=[O:16])[N:15]=1
Reactant: COc1cc(C=C2SC(NCCNC(=O)OC(C)(C)C)=NC2=O)ccc1Oc1ccc(C#N)cc1C(F)(F)F
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COc1cc(C=C2SC(NCCN)=NC2=O)ccc1Oc1ccc(C#N)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 30 %

Procedure:
LC/MS (m/z) [M+1]+563.1 (calculated for C26H25F3N4O5S, 562.56). (2-{5-[4-(4-Cyano-2-trifluoromethyl-phenoxy)-3-methoxy-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-ethyl)-carbamic acid tert-butyl ester (0.09 g, 0.14 mmol) was dissolved in a 5/3 mixture of ethyl acetate/methanol (6 mL). To the reaction was then added aqueous 4.0N HCl (4 mL). The reaction mixture was stirred at room temperature for 2 days and the solvent evaporated in vacuo to yield a crude oil. Diethyl ether was added to the residue and the solvent evaporated in vacuo to give a solid which was recrystallized from MeOH and diethyl ether to yield compound as a solid (0.020 g, 30%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH3:28])[C:17](=[O:27])[CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:10]=2)=[CH:5][CH:4]=1)#[N:2].N>CO.[Ni]>[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH3:28])[C:17](=[O:27])[CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:25])[CH3:23])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: CN(Cc1cccc(-c2ccc(C#N)cc2)c1)C(=O)CNC(=O)OC(C)(C)C
Agent: [Ni]
Agent: N
Solvent: CO
Product: CN(Cc1cccc(-c2ccc(CN)cc2)c1)C(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
tert-Butyl (2-{[(4′-cyanobiphenyl-3-yl)methyl](methyl)amino}-2-oxoethyl)carbamate (1.3 g) was dissolved in MeOH (20 ml), and a 28% aqueous ammonia solution (2 ml) was added thereto. Then, Raney nickel (205 mg) was added thereto under an argon atmosphere, followed by stirring at room temperature overnight under a hydrogen atmosphere at 1 atm. The reaction mixture was filtered and washed with water, and then the filtrate was extracted with CHCl3. The organic layer was concentrated under reduced pressure, and then the obtained residue was purified by silica gel column chromatography (0 to 10% MeOH/CHCl3) to obtain tert-butyl {2-[{[4′-(aminomethyl)biphenyl-3-yl]methyl}(methyl)amino]-2-oxoethyl}carbamate (900 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2O.S([O-])([O-])=O.[NH4+:17].[NH4+].N>O>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH2:17]
Reactant: [NH4+]
Reactant: Cc1cnc2c(O)cccc2c1
Agent: N
Agent: O=S([O-])[O-]
Solvent: O
Product: Cc1cnc2c(N)cccc2c1
Yield: 91.3 %

Procedure:
3-methylquinolin-8-ol (Intermediate 30) (150 mg, 0.9 mmol) and ammonium sulphite (250 mg, 1.8 mmol) were added to aqueous ammonia (3 ml) and heated for 48 h. After cooling, water was added and the mixture was extracted with DCM. The organic phase was dried (Na2SO4) and concentrated in vacuo to give the title compound (130 mg, 86%).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:18]3[S:25][C:24]([S:26][CH3:27])=[CH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:13][CH2:12]1)=[O:10])(C)(C)C.[ClH:37]>C(Cl)Cl.O1CCOCC1>[ClH:35].[ClH:37].[NH2:7][CH:8]([CH2:28][C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1)[C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[C:18]3[S:25][C:24]([S:26][CH3:27])=[CH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:15][CH2:16]1)=[O:10]
Reactant: CSc1cc2ncnc(N3CCN(C(=O)C(Cc4ccc(Cl)cc4)NC(=O)OC(C)(C)C)CC3)c2s1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CSc1cc2ncnc(N3CCN(C(=O)C(N)Cc4ccc(Cl)cc4)CC3)c2s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of {1-(4-chlorobenzyl)-2-[4-(6-methylsulfanyl-thieno[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester in DCM (4 mL) was added HCl in Dioxane (4M, 1 mL). The mixture was stirred at room temperature for 4 hours. The solvent was removed to afford the product 2-Amino-3-(4-chlorophenyl)-1-[4-(6-methylsulfanyl-thieno[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-propan-1-one dihydrochloride quantitatively. MS (ESI+) [M+H]+ 448.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][CH2:8][C:9]1([NH2:22])[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1.[OH-].[Na+].[O-]S([O-])(=O)=O.[Mg+2]>C(OCC)C.O>[NH2:22][C:9]1([C:8]#[N:7])[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1
Reactant: NCC1(N)CCN(Cc2ccccc2)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: N#CC1(N)CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of lithium aluminium hydride (1 M in THF, 10.4 ml) in dry diethyl ether (15 ml), cooled to 0° C., under an argon atmosphere is added dropwise 4-amino methyl-1-benzyl-piperidine-4-ylamine (900 mg, 4.18 mmol) in dry diethyl ether (15 ml). The reaction mixture is heated at reflux for 24 h and then cooled to 0° C. Water (0.25 ml) is added followed by a 15% aqueous NaOH (0.25 ml) and then water (0.7 ml). After warming to room temperature MgSO4(150 mg) is added and stirred for 15 minutes. The solids are removed by suction filtration and the filtrate evaporated to give an oil. The solids are extracted with refluxing diethyl ether (80 ml) using a Soxhlet extractor for 14 hours. The diethyl ether is removed in vacuo and the two oils combined and purified by chromatography on silica eluting with 10-25% 2M ammonia in methanol solution in dichloromethane to give 4-Amino-1-benzyl-piperidine-4-carbonitrile; [M+H]+ 220