Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:24]([N:26]([CH3:43])[C:27]1[C:28]([CH3:42])=[N:29][CH:30]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:32]=1)[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:31]5[CH:30]=[N:29][C:28]([CH3:42])=[C:27]([N:26]([CH2:24][CH3:25])[CH3:43])[CH:32]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CCN(C)c1cc(B2OC(C)(C)C(C)(C)O2)cnc1C
Product: CCN(C)c1cc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cnc1C

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and ethyl-methyl-[2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-amine (Stage 165.1.1) to give the title compound as a white foam. (HPLC: tR 2.26 min (Method A); M+H=442 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.95 (s, 1H), 8.32-8.29 (m, 1H), 8.13-8.09 (m, 2H), 7.99-7.94 (m, 1H), 7.61-7.58 (m, 1H), 7.35-7.32 (m, 1H), 3.89 (s, 3H), 3.58 (s, 3H), 2.97 (q, 2H), 2.71 (s, 31-1), 2.45 (s, 3H), 1.97 (s, 3H), 1.09 (t, 3H))
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=2)=[CH:5][CH:4]=1.[CH:18](=O)[CH2:19][CH2:20][CH2:21][CH3:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[CH2:18]([NH:15][C:11]1[CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:16])([F:17])[F:1])=[CH:8][CH:7]=2)[CH:14]=[CH:13][CH:12]=1)[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: Nc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: CCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCCNc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Yield: 43.9 %

Procedure:
To a solution of 4′-(trifluoromethyl)-1,1′-biphenyl-3-ylamine (0.3 g, 1.26 mmol) in anhydrous CH2Cl2 (10 mL) under nitrogen at room temperature was added valeraldehyde (0.134 mL, 1.26 mmol), sodium triacetoxyborohydride (0.374 g, 1.76 mmol) and acetic acid (72 μl, 1.26 mmol). The resultant mixture was stirred for 17 h at room temperature. The reaction mixture was quenched with sat. NaHCO3 aq. (15 mL), then extracted with CH2Cl2 (2×20 mL). The organic solution was dried (Na2SO4) and the solvent was removed in vacuo. Purification by SPE (20 g Silica column) eluted with 1:200 EtOAc:cyclohexane afforded the title compound as a colourless oil (0.17 g).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][NH:33][CH3:34].C1COCC1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[CH2:1]([NH:8][C:9]1[CH:17]=[C:16]([N:18]2[CH2:19][CH2:20][N:21]([C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:22][CH2:23]2)[CH:15]=[CH:14][C:10]=1[C:11]([N:33]([CH3:34])[CH3:32])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=C(O)c1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1NCc1ccccc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1NCc1ccccc1
Yield: 56.5 %

Procedure:
A solution of 2-(benzylamino)-4-(4-benzoylpiperazin-1-yl)benzoic acid (80 mg, 0.2 mmol), 2 M dimethylamine THF solution (0.38 ml, 0.78 mmol), tiethylamine (0.08 ml, 0.57 mmol) and diphenylphosphoryl azide (0.045 ml, 0.2 mmol) in 15 ml THF was stirred for 16 hours. The run was quenched with 1 ml water and all the solvents were evaporated under vacuum. 2-(benzylamino)-N,N-dimethyl-4-(4-benzoylpiperazin-1-yl)benzamide (50 mg, 60%) was obtained by flash column chromatograph (60% ethyl acetate in hexanes). 1H NMR (500 MHz, DMSO-d6) δ (ppm) 2.95 (d, 6H), 3.15-3.20 (s, br, 4H), 3.62 (s, br, 2H), 3.70 (s, br, 2H), 4.38 (d, 2H), 6.22 (d, J=2.2 Hz, 1H), 6.24 (dd, J=2.2, 8.3 Hz, 1H), 7.00 (dd, J=2.5, 8.4 Hz, 1H), 7.32-7.48 (m, 10H), 8.82 (s, 1H). 13C NMR (125 MHz, CDCl3): δ (ppm) 30.1, 30.8, 48.1, 48.9, 49.4, 99.5, 103.7, 111.1, 120.7, 126.6, 127.6, 127.7, 129.0, 129.1, 130.3, 130.5, 130.6, 136.0, 139.6, 149.5, 153.4, 170.8, 172.3.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2.[CH:13]1([C:16]2(O)[C:25]3[C:20](=[CH:21][C:22]([F:27])=[CH:23][C:24]=3[F:26])[O:19][CH2:18][CH2:17]2)[CH2:15][CH2:14]1.FC1C=C(F)C=C2C=1C(C1C3C(=C(CSC)C=CC=3)NC=1)(C)CCO2>>[CH:13]1([C:16]2([C:9]3[C:8]4[C:12](=[C:4]([CH2:3][S:2][CH3:1])[CH:5]=[CH:6][CH:7]=4)[NH:11][CH:10]=3)[C:25]3[C:20](=[CH:21][C:22]([F:27])=[CH:23][C:24]=3[F:26])[O:19][CH2:18][CH2:17]2)[CH2:14][CH2:15]1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: OC1(C2CC2)CCOc2cc(F)cc(F)c21
Agent: CSCc1cccc2c(C3(C)CCOc4cc(F)cc(F)c43)c[nH]c12
Product: CSCc1cccc2c(C3(C4CC4)CCOc4cc(F)cc(F)c43)c[nH]c12

Procedure:
The title compound was prepared starting from 450 mg (2.54 mmol) of the compound from Example 8A and 574 mg (2.54 mmol) of the compound from Example 172A in analogy to the synthesis of the compound from Example 193. 80 mg (8% of theory) of the target compound were obtained.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[CH2:27]([N:34]1[CH2:39][CH2:38][N:37]([CH2:40][C:41]([N:43]([C:45]2[CH:51]=[CH:50][C:48]([NH2:49])=[CH:47][CH:46]=2)[CH3:44])=[O:42])[CH2:36][CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[OH-].[Na+]>CN(C=O)C.CO>[CH2:27]([N:34]1[CH2:35][CH2:36][N:37]([CH2:40][C:41]([N:43]([C:45]2[CH:46]=[CH:47][C:48]([NH:49]/[C:16](=[C:6]3\[C:5](=[O:26])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=4)/[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:50][CH:51]=2)[CH3:44])=[O:42])[CH2:38][CH2:39]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CN(C(=O)CN1CCN(Cc2ccccc2)CC1)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C(=O)CN1CCN(Cc2ccccc2)CC1)c1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-[N-(4-benzylpiperazinomethylcarbonyl)-N-methyl-amino)-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4](=[O:15])[N:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[N:6]=1.[CH3:16]C1NNC(=O)C=1.BrCCCC1C=CC=CC=1>>[CH3:1][C:2]1[CH2:3][C:4](=[O:15])[N:5]([CH2:7][CH2:8][CH2:9][C:10]2[CH:16]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]=1
Reactant: CCCCCCCCN1N=C(C)CC1=O
Reactant: Cc1cc(=O)[nH][nH]1
Agent: BrCCCc1ccccc1
Product: CC1=NN(CCCc2ccccc2)C(=O)C1
Yield: 69 %

Procedure:
By a procedure similar to that for 2,4-dihydro-5-methyl-2-octyl-3H-pyrazol-3-one, starting from 3-methyl-3-pyrazoline-5-one (19.63 g, 0.20 mol) and 1-bromo-3-phenylpropane (39.80 g, 0.20 mol), 2,4-dihydro-5-methyl-2-(3-phenylpropyl)-3H-pyrazol-3-one (29.40 g, 69%) was obtained as colorless needles, m.p. 130°-105° C.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4]([CH2:7][CH:8]=1)(=[O:6])=[O:5].[Br:9]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)Cl>CCOCC>[Br:9][CH2:1][C:2]1[CH2:3][S:4]([CH2:7][CH:8]=1)(=[O:6])=[O:5]
Reactant: CC1=CCS(=O)(=O)C1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: O=S1(=O)CC=C(CBr)C1
Temperature: 0 °C
Yield: 34.2 %

Procedure:
In a reaction vessel, 21.0 gms (0.1591 moles) 3-methyl sulfolene, 28.32 gms (0.1591 moles) N-bromo succinimide, 1.9 gms (0.0008 moles) benzoyl peroxide and 250 ml chlorform were combined. The resulting mixture was heated to reflux and then refluxed for 20 hours. The reaction mixture was cooled to 0° C. and then filtered to remove the succinimide. The filtrate was stripped until only a small amount of solvent remained. The remaining solids were removed by filtration, and the remainder of the solvent was stripped to give an orange oil. Ether was added to the oil. After a few minutes, the solids crystallized. Filtration and drying yielded 11.5 gms of the product. The NMR and IR spectra confirmed the structure.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH2:7][CH2:8]O)([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:32]1(=[O:42])[NH:36][C:35](=[O:37])[C:34]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:33]12.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH2:7][CH2:8][N:36]1[C:35](=[O:37])[C:34]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:33]2[C:32]1=[O:42])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(CCO)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Nitrophenethyl alcohol (15 g) was dissolved in tetrahydrofuran (225 ml). After adding triphenylphosphine (26 g) and phthalimide (13.9 g) thereto, the mixture was ice-cooled and diethylazodicarboxylate (15.5 ml) was added dropwise thereinto. After stirring at room temperature for one hour, the resulting crystals were collected by filtration, washed with diethyl ether and dried, to give N-(3-nitrophenethyl)phthalimide as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@@H:20]1[CH2:24][CH2:23][N:22]([CH:25]([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)[CH2:21]1)[C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17](O)=[O:18])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH:39]1[O:44][NH2:45].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C(OCC)(=O)C>[C:26]1([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:22]2[CH2:23][CH2:24][C@@H:20]([N:8]([C:9]3[CH:10]=[CH:11][C:12](/[CH:15]=[CH:16]/[C:17](=[O:18])[NH:45][O:44][CH:39]4[CH2:40][CH2:41][CH2:42][CH2:43][O:38]4)=[CH:13][N:14]=3)[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:21]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N(c1ccc(/C=C/C(=O)O)cn1)[C@@H]1CCN(C(c2ccccc2)c2ccccc2)C1
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(c1ccc(/C=C/C(=O)NOC2CCCCO2)cn1)[C@@H]1CCN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 58.8 %

Procedure:
To a stirred solution of (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(diphenylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylic acid (142 mg) in DMF (3 mL) was added O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (67 mg), HOBT (77 mg), and EDCI hydrochloride (109 mg), and the resulting mixture was stirred at ambient temperature for 7 hours. The reaction mixture was diluted with ethyl acetate and washed successively with water, saturated NaHCO3 solution, and brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform:methanol=5:1) to give tert-butyl [(3R)-1-(diphenylmethyl)-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridyl)carbamate (100 mg) as a pale yellow oil.
Reaction SMILES: [NH2:1][C@:2]1([C:14]([OH:16])=[O:15])[CH2:6][CH2:5][C@H:4]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=2)[CH2:3]1.S(Cl)(Cl)=O.[CH3:21]O>>[CH3:21][O:15][C:14]([C@@:2]1([NH2:1])[CH2:6][CH2:5][C@H:4]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=2)[CH2:3]1)=[O:16]
Reactant: N[C@]1(C(=O)O)CC[C@H](c2ccc(Br)cc2)C1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@]1(N)CC[C@H](c2ccc(Br)cc2)C1
Temperature: 25 °C

Procedure:
The (1R,3S)-1-amino-3-(4-bromo-phenyl)-cyclopentanecarboxylic acid (79 g, 0.28 mol) suspended in MeOH (1.8 L) was cooled in an ice/water bath and thionyl chloride (178 mL, 2.44 mol) was added dropwise. Following the addition the reaction was heated to reflux. After 2 days the reaction mixture was cooled to room temperature, filtered, and rinsed with MeOH (2×200 mL). The filtrate was concentrated in vacuo to provide a white solid. The white solid was triturated with EtOAc (1 L), collected by filtration, rinsed with EtOAc (2×500 mL), and dried under vacuum to give the (1R,3S)-1-amino-3-(4-bromo-phenyl)-cyclopentanecarboxylic acid methyl ester; hydrochloride as a white solid (79 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].[CH2:21]([NH:23][CH2:24][CH:25]1[CH:29]([CH3:30])[CH2:28][NH:27][CH2:26]1)[CH3:22].C1CCN2C(=NCCC2)CC1>C(#N)C>[Cl:1][C:2]1[C:3]([N:27]2[CH2:28][CH:29]([CH3:30])[CH:25]([CH2:24][NH:23][CH2:21][CH3:22])[CH2:26]2)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18]
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: CCNCC1CNCC1C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCNCC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2Cl)CC1C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
A mixture of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.5 g), anhydrous acetonitrile (5 ml), 3-ethylaminomethyl-4-methylpyrrolidine (0.36 g) and DBU (0.25 g) was refluxed for 2 hours and allowed to stand overnight at room temperature. The resulting precipitate was collected by filtration, washed with acetonitrile and ether successively and recrystallized from chloroform-methanol-concentrated aqueous ammonia to give the title compound (0.56 g) as pale yellow powder, mp 254°-257° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[CH2:9]([N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O)(=O)C>ClC(Cl)C>[NH2:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:1][CH:19]1[CH2:18][CH2:17][N:16]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:21][CH2:20]1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Nc1ccncc1N
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Nc1ccncc1NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 144 h
Yield: 98.2 %

Procedure:
A mixture of 3,4-diaminopyridine (1.1 g, 10.1 mmol), 1-benzyl-4-piperidone (3.2 g, 16.9 mmol) sodium triacetoxyborohydride (4.0 g, 18.9 mmol), and acetic acid (10.7 mL) in dichloroethane (10 mL) was stirred for about 6 days at room temperature. The reaction was concentrated to near dryness, and partitioned between chloroform (5×50 mL) and 1N sodium hydroxide (50 mL). The organic phase was dried over magnesium sufate and concentrated to give the title compound (2.8 g). MS 283 (M+1).
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].C(O[SiH](OCC)OCC)C.N[CH2:16][CH2:17][CH2:18][Si:19]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Rh].[Rh].[Rh].[Rh].C1(C)C=CC=CC=1>[CH2:1]([NH2:4])[CH:2]=[CH2:3].[NH2:4][CH:17]([CH3:16])[CH2:18][Si:19]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]
Reactant: CCO[Si](CCCN)(OCC)OCC
Agent: [Rh]
Agent: CCO[SiH](OCC)OCC
Agent: [C-]#[O+]
Solvent: C=CCN
Solvent: Cc1ccccc1
Product: CCO[Si](CC(C)N)(OCC)OCC
Temperature: 110 °C

Procedure:
A three-neck flask equipped with a reflux condenser, stirring rod and thermometer was charged with 14 grams of allylamine (0.25 mole), 41 grams of triethoxy silane (0.25 mole), 0.32 gram of 1,5-cycloctadiene (2.9×10-3 mole) and 30 ml. of toluene, and heated in an oil bath maintained at a temperature of 110° C. When the temperature of the mixture reached 85° C., 0.22 gram of tetrarhodium dodecacarbonyl (2.9×10-4 mole) was added to the mixture as a catalyst. About 60 minutes after the addition of the catalyst, the reaction temperature reached 110° C. At the end of the period the reaction mixture was subjected to gas chromatography analysis. It was found that gamma-aminopropyl triethoxy silane was obtained in a yield of 78% on an allylamine basis, while the yield of beta-aminopropyl triethoxy silane was 5.6% on an allylamine basis.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:34][CH2:35][C@H:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[OH:37]>C1COCC1>[OH:37][C@@H:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:35][NH:34][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:18]
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NC[C@@H](O)c1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CON=C1C[C@@H](C(=O)NC[C@@H](O)c2ccccc2)N(C(=O)OC(C)(C)C)C1
Temperature: -25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
To a solution of the central building block, e.g. (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid (Intermediate 7) (24.2 mmol, 6.24 g) in dry THF (125 ml) at −25° C. was added NMM (2.5 eq, 60.4 mmol, 6.64 ml) followed by isobutylchloroformate (1.05 eq, 25.4 mmol, 3.3 ml). The resulting mixture was stirred at −25° C. for 30 min and an amine or an amine salt, e.g. (S)-2-amino-1-phenylethanol (1.51 eq, 36.5 mmol, 5 g) was then added. The mixture was allowed to gradually warm to rt. After 16 h, the solvents were removed. The residue was dissolved in AcOEt, washed twice with NH4Cl saturated solution, then twice with 10% NaHCO3 solution. The organic layer was dried over Na2SO4, filtrated and concentrated to afford the desired product, e.g. tert-butyl (2S,4EZ)-2-({[(2S)-2-hydroxy-2-phenylethyl]amino}carbonyl)-4-(methoxyimino)-1-pyrrolidine-carboxylate (8.76 g, 96%) as a pale yellow oil in 88.5% purity by HPLC.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([C:9]2[C:10]3[S:21][CH:20]=[CH:19][C:11]=3[N:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=2)=[O:8])=[CH:4][CH:3]=1.[CH3:22][NH:23][CH3:24].O>CCO>[CH3:22][N:23]([CH3:24])[C:2]1[S:6][C:5]([C:7]([C:9]2[C:10]3[S:21][CH:20]=[CH:19][C:11]=3[N:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Br)s1)c1nc(C(F)(F)F)nc2ccsc12
Reactant: CNC
Solvent: CCO
Solvent: O
Product: CN(C)c1ccc(C(=O)c2nc(C(F)(F)F)nc3ccsc23)s1
Yield: 42 %

Procedure:
A suspension of 5-bromo-2-thienyl 2-trifluoromethylthieno[3,2-d]pyrimidin-4-ylmethanone (0.3 g, 0.76 mmol) in EtOH (20 mL) was treated with 40% aqueous dimethylamine (5 mL), refluxed for 1 h, cooled, treated with water (25 mL), concentrated in vacuo and the aqueous mixture extracted with EtOAc (2×25 mL), the combined extracts washed with brine (25 mL), dried (MgSO4) and concentrated in vacuo. The resulting red oil was purified by chromatography [SiO2; heptane-EtOAc (1:1)] to give the title compound (0.115 g, 42%) as a red solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[C:22]([C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1)#[N:23].[BH4-].[Na+]>O1CCCC1>[C:16]1([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][CH2:28][C:27]4[CH:30]=[CH:31][C:24]([C:22]#[N:23])=[CH:25][CH:26]=4)=[CH:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: Nc1ccc(C(=O)N2CCN(c3ccccc3)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ccc(CNc2ccc(C(=O)N3CCN(c4ccccc4)CC3)cc2)cc1
Temperature: 50 °C

Procedure:
To a stirred solution of (4-amino-phenyl)-(4-phenyl-piperazin-1-yl)-methanone (0.5 g, 1.78 mmol) in tetrahydrofuran (10 mL) was added 4-cyanobenzaldehyde (0.4 g, 2.67 mmol) followed by sodium borohydride and the reaction was heated to 50° C. for 2 hours. On cooling, the reaction was quenched by the addition of water (10 mL) and the aqueous solution basified by the addition of ammonium chloride (˜pH 8). The aqueous mixture was extracted using dichloromethane (3×10 ml) and the organic extracts combined, dried over magnesium sulfate and concentrated in vacuo to afford the title compound as an off white solid (604 mg, 98% yield). HPLC retention time 7.17 min. Mass spectrum (ES+) m/z 397 (M+H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[CH:23])[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.I[C:25]1[CH:26]=[C:27]([C:31]2[O:35][N:34]=[C:33]([CH3:36])[N:32]=2)[CH:28]=[CH:29][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.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>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[C:23][C:29]4[CH:30]=[CH:25][CH:26]=[C:27]([C:31]5[O:35][N:34]=[C:33]([CH3:36])[N:32]=5)[CH:28]=4)[CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH2:20]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCC(=O)CC1
Reactant: Cc1noc(-c2cccc(I)c2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(C2(C#Cc3cccc(-c4nc(C)no4)c3)CCC(=O)CC2)cc1OC1CCCC1
Reaction time: 15 h
Yield: 78 %

Procedure:
A stirred mixture of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-one (0.200 g, 0.64 mmol) and 5-(3-iodophenyl)-3-methyl-[1,2,4]oxadiazole (0.201 g, 0.70 mmol) in dry triethylamine (4.6 mL) was treated under argon with a mixture of tetrakis(triphenylphosphine)palladium (0.032 g, 0.028 mmol), cuprous iodide (0.0067 g, 0.035 mmol), and triphenylphosphine (a small crystal) at 70° C. for 1 h and at 25° C. for 15 h. The reaction mixture was concentrated in vacuo and a solution of the residue was dissolved in methylene chloride, was treated with cold dilute hydrochloric acid and was dried over anhydrous sodium sulfate. The crude product was chromatographed (silica, 5 to 10% ethyl acetate in methylene chloride/hexanes 1:1) and the pure fractions were combined, concentrated in vacuo, crystallized from ethyl ether and dried at 60° C. in vacuo to afford the titled compound as an off-white powder (0.235 g, 78%), mp 88°-91° C. Anal. (C29H30N2O4) calcd: C 74.02, H 6.43, N 5.95, found: C 73.77, H 6.53, N 5.78.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:10])[CH:9]=1)[CH:5]=O.[C:11]1([CH:17](P(=O)(OCC)OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CS(C)=O.CC(C)([O-])C.[K+]>O>[C:11]1([C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:5][C:4]2[CH:3]=[C:2]([Br:1])[CH:9]=[C:8]([Br:10])[CH:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1cc(Br)cc(Br)c1
Reactant: CCOP(=O)(OCC)C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Brc1cc(Br)cc(C=C(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 9 h
Yield: 73.5 %

Procedure:
Under an atmosphere of argon, 3,5-dibromobenzaldehyde (12.1 g, 46 mmole) and diethyl diphenylmethylphosphonate (15 g, 49 mmole, 1.1 eq) were dissolved into dimethyl sulfoxide (DMSO) (60 ml). To the resultant solution, potassium t-butoxide (6.2 g, 55 mmole, 1.2 eq) was added in small portions and the obtained solution was stirred at the room temperature for 9 hours and left standing for one night. After water (60 ml) was added, the reaction mixture was subjected to extraction with ethyl acetate (250 ml). The obtained organic layer was washed with water (100 ml) and a saturated aqueous solution of sodium chloride (50 ml) and dried with magnesium sulfate. Then, the solvent was removed by distillation and a deep brown oil was obtained. The obtained oil was purified by the column chromatography (silica gel/hexane and hexane+3% dichloromethane, successively) and a white solid (14.0 g, 74%) was obtained.