Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[CH2:3]([C:5]1[O:6][C:7]2[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=2[C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11])[CH3:4]>C(O)C>[CH2:3]([C:5]1[O:6][C:7]2[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=2[C:9]=1[CH:10]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[OH:11])[CH3:4]
Reactant: CCc1oc2ccccc2c1C(=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCc1oc2ccccc2c1C(O)c1ccccc1
Yield: 92.9 %

Procedure:
Sodium borohydride (7.26 g; 0.192 mol) was added portionwise to the mixture of (2-ethyl-benzofuran-3-yl)-phenyl-methanone (24 g; 0.096 mol) in ethanol (300 mL) while stirring and cooling in ice bath under an atmosphere of nitrogen. The mixture was stirred at room temperature for one hour and the solvent was then evaporated. The residue was extracted with ether and the ethereal extracts were washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated to give a yellow solid (22.5 g), m.p. 98-99° C. Mass spectrum (ESI, [M+] m/z 252. 1HNMR (400 MHz, DMSO-d6): δ 1.24 (t, 3H, J=7.69 Hz), 2.91 (q, 2H, J=7.69 Hz), 5.86 (d, 1H, J=3.7 Hz), 5.98 (d, 1H, J=3.7 Hz), 7.06 (dt, 1H, J=7.25, 0.9 Hz), 7.13-7.21 (m, 2H), 7.28-7.32 (m, 2H), 7.4-7.46 (m, 4H). Elemental Analysis for C17H16O2: Calculated: C, 80.93; H, 6.39. Found: C, 81.03; H, 6.31.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH3:10][C:11]1([CH3:28])[CH2:16][CH:15]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][C:13]([CH3:27])([CH3:26])[NH:12]1>C1(C)C(C)=CC=CC=1>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:12]2[C:13]([CH3:27])([CH3:26])[CH2:14][CH:15]([O:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:16][C:11]2([CH3:28])[CH3:10])[N:7]=1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: Cc1ccccc1C
Product: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1c1nc(Cl)nc(Cl)n1

Procedure:
46.1 g of cyanuric chloride and 136.0 g of 2,2,6,6-tetramethyl-4-benzoyloxypiperidine are reacted in 300 ml of xylene as described in Example 1 and worked up. After recrystallization from isopropanol, 2,4-dichloro-6-(2,2,6,6-tetramethyl-4-benzoyloxy-piperidin-1-yl)-1,3,5-triazine are obtained as colorless crystals having a melting point of 145°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:10]1([C:16]([C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=O)=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH3:1][CH:2]1[CH2:7][NH:6][C:5]2=[N:8][C:16]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:9]=[C:4]2[CH2:3]1
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Reactant: Cc1cnc(N)c(N)c1
Product: CC1CNc2nc(-c3ccccc3)c(-c3ccccc3)nc2C1

Procedure:
The title compound was prepared from 5-methyl-pyridine-2,3-diamine and benzil analogously to Intermediate E;
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.N1C=CC=CC=1.C1C(=O)N(OC(ON2C(=O)CCC2=O)=O)[C:15](=[O:16])C1.Cl.[F:32][C@@H:33]1[CH2:37][CH2:36][NH:35][CH2:34]1.C(N(C(C)C)CC)(C)C>C(#N)C>[F:32][C@@H:33]1[CH2:37][CH2:36][N:35]([C:15]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[O:16])[CH2:34]1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: F[C@@H]1CCNC1
Reactant: Nc1nccs1
Agent: Cl
Solvent: c1ccncc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nccs1)N1CC[C@@H](F)C1
Reaction time: 0.33 h

Procedure:
A solution of 2-aminothiazole (10.02 g, 100 mmol) and pyridine (8.3 mL, 103 mmol) in anhydrous acetonitrile (300 mL) was added to a thick suspension of N,N′-disuccinimidyl carbonate (26.13 g, 102 mmol) in acetonitrile (25 mL) with a small acetonitrile rinse. The mixture was stirred thoroughly for another 20 minutes, and then (R)-3-fluoropyrrolidine hydrochloride (13.06 g, 104 mmol) and diisopropylethylamine (70 mL, 402 mmol) were added and the reaction was stirred at room temperature overnight before being concentrated under vacuum. The residue was dissolved into ethyl acetate (100 mL), and then partitioned with hexanes (20 mL) and 3:1 water/brine (20 mL). The aqueous phase was separated and repeatedly back-extracted with 5:1 ethyl acetate/hexanes. The combined organic phases were washed with brine, and the aqueous phase was back-extracted with more 5:1 solution. The combined organic phases were then concentrated. The solids were dissolved into 6:1 dichloromethane/hexanes, mixed with 4:1 water/brine, and filtered through diatomaceous earth with a 6:1 dichloromethane/hexanes rinse. The filtrate was washed with more dilute brine, and the aqueous phase was separated and back-extracted with more 6:1 solution. This wash with dilute brine was repeated two more times. Then the organic phase was dried (sodium sulfate) and concentrated under vacuum to give the title compound.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[CH:5][N:6]2[CH:10]=[CH:9][S:8][C:7]=12)=O.C1(P(=[CH:30][C:31]([O:33]C)=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:35]O>>[O:33]=[C:31]([CH3:30])/[CH:35]=[CH:1]/[C:3]1[N:4]=[CH:5][N:6]2[CH:10]=[CH:9][S:8][C:7]=12
Reactant: CO
Reactant: O=Cc1ncn2ccsc12
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CC(=O)/C=C/c1ncn2ccsc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
7-Formyl-imidazo[5,1-b]thiazole was dissolved in 15 ml of methanol. Methyl (triphenylphosphoranylidene)acetate (500 mg) was added to the solution. The mixture was stirred at room temperature for 15 min. The reaction solution was concentrated under the reduced pressure. The concentrate was purified by chromatography on silica gel to give 208 mg of 7-((E)-3-Oxo-1-buten-1-yl)imidazo[5,1-b]thiazole.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[CH:8]=2)[N:3]=1.[C:19]([C:21]1[CH:34]=[CH:33][C:24]([O:25][CH2:26][CH2:27][N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:23][CH:22]=1)#[CH:20].C(N(CC)CC)C>CN(C=O)C.C(#N)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[N:3]=[C:2]([C:20]#[C:19][C:21]2[CH:22]=[CH:23][C:24]([O:25][CH2:26][CH2:27][N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:33][CH:34]=2)[CH:11]=[CH:10]3)=[CH:13][CH:14]=1
Reactant: Clc1ccc(-c2ccc3nc(Br)ccc3c2)cc1
Reactant: C#Cc1ccc(OCCN2CCCC2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Clc1ccc(-c2ccc3nc(C#Cc4ccc(OCCN5CCCC5)cc4)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
In a nitrogen atmosphere, 0.6 mg CuI, 9.3 mg Pd(PPh3)2Cl2 and 318 mg (1 mmol) 2-bromo-6-(4-chloro-phenyl)-quinoline are added successively to a solution of 142 mg (0.66 mmol) 1-[2-(4-ethynyl-phenoxy)-ethyl]-pyrrolidine and 2.6 mL (18.67 mmol) triethylamine in 5 mL absolute DMF and 10 mL acetonitrile. The reaction mixture is stirred for 14 h at RT and evaporated down. The purification is carried out by column chromatography on silica gel (DCM/MeOH/NH3 90:10:1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]2[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:13]=[C:14]([CH3:15])[C:3]=12.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:15][C:14]1[C:3]2[C:4](=[N:5][C:6]3[C:11]([C:2]=2[N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:13]=1
Reactant: C1COCCN1
Reactant: Cc1nn(-c2ccccn2)c2nc3ccccc3c(Cl)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccccn2)c2nc3ccccc3c(N3CCOCC3)c12
Temperature: 100 °C
Yield: 36.5 %

Procedure:
A solution of 4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (1.47 g, 5.00 mmol), morpholine (0.87 g, 10.0 mmol) and potassium carbonate (1.38 g, 10.0 mmol) in N,N-dimethylformamide (20 mL) was heated under reflux at 100° C. for 12 hours. The solution was cooled to room temperature, and concentrated under reduced pressure. The residue was poured into water and organic matter was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue thus obtained was purified by basic silica gel column chromatography (hexane:chloroform=3:1) to give the title compound (0.63 g, 36% yield).
Reaction SMILES: [NH2:1][C:2]1[N:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1)=[O:5].CC1C=CC(S(O)(=O)=O)=CC=1.[N:35]1[CH:40]=[CH:39][C:38]([CH:41]=O)=[N:37][CH:36]=1.[BH4-].[Na+]>CS(C)=O>[F:19][C:13]([F:18])([C:10]1[CH:11]=[CH:12][C:7]([NH:6][C:4](=[O:5])[C:3]2[CH:20]=[CH:21][CH:22]=[N:23][C:2]=2[NH:1][CH2:41][C:38]2[CH:39]=[CH:40][N:35]=[CH:36][N:37]=2)=[CH:8][CH:9]=1)[C:14]([F:15])([F:16])[F:17]
Reactant: Nc1ncccc1C(=O)Nc1ccc(C(F)(F)C(F)(F)F)cc1
Reactant: O=Cc1ccncn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(Nc1ccc(C(F)(F)C(F)(F)F)cc1)c1cccnc1NCc1ccncn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
2-Amino-N-(4-pentafluoroethyl-phenyl)-nicotinamide (180 mg), TsOH (40 mg) and a solution of pyrimidine-4-carboxaldehyde in DMSO (10 ml) were stirred at 60 C. for 6 h. Treated with NaBH4 (200 mg) and stirred for 2 h at RT. MS (ES+): 566.3 (M+H)+; Calc'd for C26H28F5N7O2—565.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C@@H:5]1[C:25](=[O:26])[N:7]2[C:8]([C:22]([O-:24])=[O:23])=[C:9]([CH2:12][N+:13]3[N:14]([CH2:19][CH2:20][OH:21])[C:15]([NH2:18])=[CH:16][CH:17]=3)[CH2:10][S:11][C@H:6]12.C[Si](C)(C)NC(=O)C.Cl.[NH2:36][C:37]1[S:41][N:40]=[C:39](/[C:42](=[N:46]/[O:47][CH2:48][CH:49]=[CH2:50])/[C:43](Cl)=[O:44])[N:38]=1.C(OC(C)C)(C)C>O1CCCC1>[NH2:36][C:37]1[S:41][N:40]=[C:39]([C:42](=[N:46][O:47][CH2:48][CH:49]=[CH2:50])[C:43]([NH:4][C@@H:5]2[C:25](=[O:26])[N:7]3[C:8]([C:22]([O-:24])=[O:23])=[C:9]([CH2:12][N+:13]4[N:14]([CH2:19][CH2:20][OH:21])[C:15]([NH2:18])=[CH:16][CH:17]=4)[CH2:10][S:11][C@H:6]23)=[O:44])[N:38]=1
Reactant: C=CCO/N=C(\C(=O)Cl)c1nsc(N)n1
Reactant: Nc1cc[n+](CC2=C(C(=O)[O-])N3C(=O)[C@@H](N)[C@H]3SC2)n1CCO
Agent: CC(=O)N[Si](C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Product: C=CCON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccc(N)n3CCO)CS[C@H]12)c1nsc(N)n1
Reaction time: 1 h
Yield: 43.7 %

Procedure:
To a solution of 7β-amino-3-[3-amino-2-(2-hydroxyethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate trihydrochloride (2 g) and N-(trimethylsilyl)acetamide (5.85 g) in tetrahydrofuran (40 ml)was added (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-allyloxyiminoacetyl chloride hydrochloride (1.26 g) under ice-cooling. After being stirred for 1 hour at the same temperature, the reaction mixture was poured into diisopropyl ether (200 ml). The resulting precipitate was collected by filtration, dissolved in water (100 ml) and adjusted to pH 2.0 with 5% sodium bicarbonate solution. This solution was subjected to column chromatography on macroporous non-ionic adsorption resin "Diaion HP-20" (Trademark: prepared by Mitsubishi Chemical Industries). The desired compound was eluted with 10% isopropyl alcohol and lyophilized to give 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-allyloxyiminoacetamido]-3-[3-amino-2-(2-hydroxyethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate (syn isomer) (1.07 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[Br:16]Br>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([Br:16])=[CH:4][N:3]=1
Reactant: N#Cc1cccnc1N
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: N#Cc1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-aminopyridine-3-carbonitrile 1 (0.56 g, 4.6 mmol) was dissolved in 10 mL HOAC, to which one equivalent of Na2CO3 was added. Then, 1.1 equivalent of Br2 was added dropwise and reaction mixture was stirred at room temperature for 30 minutes. Orange precipitation was formed and filtered off to obtain the desired compound 2 in quantitative yield. The compound was carried on without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C@@H:15]1[CH2:17][O:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([CH3:28])=[CH:22]2.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>C1COCC1>[OH:16][C@@H:15]([CH2:17][N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)[CH2:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][C:23]([CH3:28])=[CH:22]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: C1CCNC1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OC[C@@H]1CO1
Solvent: C1CCOC1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OC[C@@H](O)CN1CCCC1
Temperature: 75 °C
Reaction time: 3 h
Yield: 36 %

Procedure:
A mixture of (2S)-6-methoxy-4-(2-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline (250 mg, 0.66 mmol), and pyrrolidine (1.5 ml) in THF (10 ml) was stirred at 75° C. for 3 hours under an atmosphere of nitrogen and then allowed to cool to ambient temperature. The mixture was filtered and the filtrate evaporated in vacuo. The residue was purified by silica gel chromatographyusing gradient elution with dichloromethane/methanolic ammonia (7M) (100/0 to 90/10) to give (2S)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (106 mg, 36%).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:17]=[CH:16][C:14]([NH2:15])=[C:13]([O:18][CH3:19])[CH:12]=3)=[CH:9][N:8]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[NH3:25]>O1CCOCC1>[NH2:15][C:14]1[CH:16]=[CH:17][C:11]([C:10]2[C:3]3[C:2]([NH2:25])=[N:7][CH:6]=[N:5][C:4]=3[N:8]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:9]=2)=[CH:12][C:13]=1[O:18][CH3:19]
Reactant: COc1cc(-c2cn(C3CCCC3)c3ncnc(Cl)c23)ccc1N
Reactant: N
Solvent: C1COCCO1
Product: COc1cc(-c2cn(C3CCCC3)c3ncnc(N)c23)ccc1N
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(4-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyaniline (0.45 g, 1.31 mmol), ammonia (115 ml, SG 0.88) and 1,4-dioxane (115 ml) was heated and stirred at 120° C. in a pressure vessel overnight. The mixture was allowed to cool to ambient temperature and the solvent was removed under reduced pressure to give a residue which was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was further extracted with ethyl acetate twice. The combined ethyl acetate extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated to give 5-(4-amino-3-methoxyphenyl)-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine as brown solids (0.32 g, 0.99 mmol): 1H NMR (DMSO-d6, 400 MHz) δ 8.09 (s, 1H), 7.24 (s, 1H), 6.88 (d, 1H), 6.79 (dd, 1H), 6.71 (d, 1H), 6.01 (broad, 2H), 5.06 (m, 1H), 4.79 (broad, 2H), 3.81 (s, 3H), 2.10 (m, 2H), 1.87-1.92 (m, 4H), 1.68 (m, 2H); MH+324.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[N:11][C:10]([CH3:13])=[N:9]2)=[C:4]([O:14][CH3:15])[CH:3]=1.[CH2:16]([OH:22])[CH2:17][CH2:18][CH2:19][C:20]#[CH:21].C(N(CC)CC)C>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:15][O:14][C:4]1[CH:3]=[C:2]([C:21]#[C:20][CH2:19][CH2:18][CH2:17][CH2:16][OH:22])[CH:7]=[CH:6][C:5]=1[N:8]1[CH:12]=[N:11][C:10]([CH3:13])=[N:9]1
Reactant: COc1cc(Br)ccc1-n1cnc(C)n1
Reactant: C#CCCCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc(C#CCCCCO)ccc1-n1cnc(C)n1
Temperature: 70 °C
Reaction time: 14 h

Procedure:
A mixture of 1-(4-bromo-2-methoxyphenyl)-3-methyl-1H-1,2,4-triazole (3.00 g), 5-hexyn-1-ol (2.45 mL), dichlorobis(triphenylphosphine)palladium(II) (786 mg), copper(I) iodide (213 mg) and triethylamine (110 mL) was stirred at 70° C. for 14 hr, allowed to cool to room temperature, and diluted with ethyl acetate, and the mixture was filtered through celite. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.80 g).
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:23](=[N:29][OH:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25].O>CCOCC>[C:1]1([C:7]2([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[O:30][N:29]=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(Cl)=NO
Reactant: C=C(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=NOC(c2ccccc2)(c2ccccc2)C1
Reaction time: 1 h

Procedure:
13.52 g (0.075 mol) of 1,1-diphenylethene and 5.06 g (0.05 mol) of triethylamine are dissolved in 200 ml of ether at 0° C., and 7.58 g (0.05 mol) of ethyl 2-chloro-2-hydroximinoacetate, dissolved in 100 ml of ether, are subsequently added dropwise in the course of approximately two hours. After stirring has been continued for one hour at room temperature, 100 ml of H2O are added, and the mixture is subsequently extracted using ether. After drying over a MgSO4, the ether is distilled off and the residue is purified over a silica gel column (eluent: n-heptane:ethyl acetate=8:2). In this way, 12.7 g (86% of theory) of product of melting point 78° to 81° C. are obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH2:17][NH2:18])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([O:27][C:28](=[O:40])[CH2:29][N:30]1[C:35](=[O:36])[C:34](Cl)=[N:33][C:32]([Cl:38])=[C:31]1[CH3:39])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:7]([CH2:9][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=1)[CH2:16][CH2:17][NH:18][C:34]1[C:35](=[O:36])[N:30]([CH2:29][C:28]([O:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:40])[C:31]([CH3:39])=[C:32]([Cl:38])[N:33]=1)[CH3:8])=[O:19])([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(Cc1cccc(CCN)c1)C(=O)OC(C)(C)C
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(Cl)nc(NCCc2cccc(CN(C)C(=O)OC(C)(C)C)c2)c(=O)n1CC(=O)OCc1ccccc1
Yield: 74.8 %

Procedure:
tert-Butyl-N-[3-(2-aminoethyl)benzyl]-N-methylcarbamate (preparation 15) (0.5 g, 1.89 mmol), benzyl-2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preparation 17) (0.6 g, 1.83 mmol) and triethylamine (0.5 ml, 3.66 mmol) in ethyl acetate (30 ml) were stirred at reflux for 24 hr. The resultant mixture was diluted with ethyl acetate (20 ml) and washed with water, sat aq brine, dried over MgSO4. Removal of the drying agent by filtration followed by evaporation of the solvent gave a red oil which was purified by chromatography (SiO2, gradient elution with 100% CH2Cl2; 99:1 CH2Cl2:MeOH; 98:2 CH2Cl2:MeOH) to give the desired product (0.76 g, 75%). 1H NMR (CDCl3) δ 1.45 (s, 9H), 2.20 (s, 3H), 2.80 (s, br, 3H), 2.90 (t, 2H), 3.70 (m, 2H), 4.20 (s, br, 2H), 4.80 (s, 2H), 5.20 (s, 2H), 6.10 (m, br, 1H), 7.10 (m, 3H), 7.25 (m, 1H), 7.35 (m, 5H). LRMS m/z=555.3 (M+1)+. Found C, 62.50, H, 6.34, N, 9.98%; C29H35N4O5Cl requires C, 62.75, H, 6.36, N, 10.09%.
Reaction SMILES: I[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[CH:6]=1.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13].C(NC(C)C)(C)C.O>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[O:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[CH:6]=[C:2]1[C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11]
Reactant: Ic1cc2ccccc2o1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1cc2ccccc2o1

Procedure:
A solution of Example 651 (1.00 g, 4.10 mmol), (trimethylsilyl)acetylene (0.80 mL, 5.68 mmol), dichlorobis(triphenylphosphine)palladium(II) (49 mg, 0.13 mmol), diisopropylamine (1.08 mL, 7.74 mmol) and copper iodide (3 mg, 0.258 mmol) in tetrahydrofuran (5 mL) was stirred at room temperature for about 16 h. The solution was poured into water and was extracted with dichloromethane. The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel using hexane/ethyl acetate (9:1) as eluent to provide Example 652. 1H NMR (300 MHz, CDCl3) δ 0.29 (m, 9H), 6.94 (s, 1H), 7.23 (m, 1H), 7.33 (m, 1H), 7.43 (m, 1H), 7.54 (d, J=7.8 Hz, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.CCN(C(C)C)C(C)C.[F:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][C:32]=1[N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[NH2:29]>O1CCCC1>[F:25][C:26]1[CH:27]=[C:28]([NH:29][C:11](=[O:12])[C:10]2[CH:14]=[CH:15][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:8][CH:9]=2)[CH:30]=[CH:31][C:32]=1[N:33]1[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: Nc1ccc(N2CCCCC2)c(F)c1
Reactant: O=C(Cl)c1ccc(-c2ccccn2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(N2CCCCC2)c(F)c1)c1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(Pyrid-2-yl)benzoyl chloride (1.37 mmol, prepared as described in Example 1B, and DIEA (1.2 mL, 6.9 mmol) in tetrahydrofuran (5 mL) were treated with the product from Example 10B (260 mg, 1.34 mmol). The mixture was stirred overnight at room temperature and concentrated under reduced pressure. The residue was taken up in ethyl acetate (50 mL), washed with H2O (3×15 mL) and brine (15 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was triturated with 3:2 hexanes:ethyl acetate to provide the title compound as a solid. 1H NMR (300 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.72 (d, J=4.7 Hz, 1H), 8.25 (d, J=8.2 Hz, 2H), 8.05–8.10 (m, 3H), 7.94 (td, J=7.8 Hz, 1.7 Hz, 1H), 7.70 (dd, J=14.9 Hz, 2.4 Hz, 1H), 7.40–7.50 (m, 2H), 7.04 (t, J=9.4 Hz, 1H), 2.92–2.96 (m, 4H), 1.62–1.69 (m, 4H), 1.52–1.56 (m, 2H); MS (ESI+) m/z 376 (M+H)+.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH3:5][N:6]([CH3:26])[CH2:7][C@H:8]([CH3:25])[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]=1)=[O:10].C1C[O:30]CC1>>[CH3:26][N:6]([CH3:5])[CH2:7][C@H:8]([CH3:25])[C@:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18](=[O:30])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:12]=1)([OH:10])[CH2:1][CH3:2]
Reactant: CC[Mg]Br
Reactant: C1CCOC1
Reactant: C[C@@H](CN(C)C)C(=O)c1cccc(OCc2ccccc2)c1
Product: CC[C@](O)(c1cccc(OC(=O)c2ccccc2)c1)[C@@H](C)CN(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
A solution of ethylmagnesiumbromide (1M in THF; 0.15 mol; 150 ml) was charged into a 500 ml 3 necked round-bottom flask with an over-head stirrer, a thermometer, inert gas supply and an addition funnel at 10° C. under nitrogen. To this solution (2S)-3-(dimethylamino)-1-(3-(benzyloxy)phenyl)-2-methyl-1-propanone (3) (33.0 g; 0.11 mol) dissolved in THF (150 ml) was added dropwise at 10-15° C. After the addition was finished the batch was stirred at room temperature for 16 h and quenched with ammonium hydrogensulfate solution (150 ml). The phases were separated and the aqueous phase was re-extracted with 3-pentanone (150 ml). The combined organic phases were dried over sodium sulfate and the solvent was removed completely on the rotary evaporator at 45-50° C. and <10 mbar. A yellowish oil was obtained in 89% yield (32.0 g). [α]=−10.5° C.