Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-].[CH2:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl>[C:11]1([CH:10]2[CH2:9][CH:3]2[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C=Cc1ccccc1
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: ClCCl
Product: CCOC(=O)C1CC1c1ccccc1
Reaction time: 0.5 h

Procedure:
The reaction described in Example 3 was substantially repeated except that the Cu,K-PFIEP[SO3H] catalyst was replaced by the Cu,K-PFIEP[SO3H]/PFIEP[CO2H] (0.58 g) catalyst described above. The reaction mixture was allowed to stir for 0.5 hour after the addition of the solution of ethyl diazoacetate, CH2Cl2 and styrene. Analysis by gas chromatography showed that the combined yield of cis- and trans-ethyl-2-phenylcyclopropanecarboxylates was 95%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([B:18]3[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]3)[C:13]=2[CH3:27])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1.C1N=CN([C:33](N2C=NC=C2)=[O:34])C=1>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[C:3]2[N:4]([C:33](=[O:34])[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([B:18]4[O:22][C:21]([CH3:23])([CH3:24])[C:20]([CH3:26])([CH3:25])[O:19]4)[C:13]=3[CH3:27])[C:9](=[O:10])[CH:8]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1c(NC(=O)Cc2ncccc2Cl)cccc1B1OC(C)(C)C(C)(C)O1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1c(=O)cc2c(Cl)cccn2c1=O
Temperature: 110 °C
Reaction time: 5 h
Yield: 64.8 %

Procedure:
A mixture of 2-(3-chloropyridin-2-yl)-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (0.192 g, 0.497 mmol) and CDI (0.322 g, 1.986 mmol) in toluene (2 mL) was heated at 110° C. After 5 h, the cooled mixture was diluted with EtOAc and washed sequentially with water and brine. The combined aqueous layers were extracted with EtOAc, and the combined organic phases were dried and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc-hexanes, to provide racemic 5-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione as a bright yellow solid (0.133 g, 65% yield). Mass spectrum m/z 413 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ 8.26 (dt, J=7.6, 0.9 Hz, 1H), 7.94 (dd, J=7.5, 1.3 Hz, 1H), 7.36 (t, J=7.6 Hz, 1H), 7.27-7.18 (m, 2H), 6.36 (t, J=7.3 Hz, 1H), 6.31 (s, 1H), 1.57 (s, 3H), 1.36 (s, 12H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[C:15]([CH2:16][CH3:17])=[CH:14][C@H:13](O)[CH2:12][N:11]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:26]([O:29][NH:30][S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N+:40]([O-:42])=[O:41])(=[O:33])=[O:32])[CH:27]=[CH2:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)C)=O)=N\C(OC(C)C)=O>C1(C)C=CC=CC=1>[CH2:26]([O:29][N:30]([C@H:13]1[CH2:12][N:11]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[C:15]([CH2:16][CH3:17])=[CH:14]1)[S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N+:40]([O-:42])=[O:41])(=[O:33])=[O:32])[CH:27]=[CH2:28]
Reactant: CCC1=C[C@H](O)CN(C(=O)OC(C)(C)C)[C@@H]1CO[Si](C)(C)C(C)(C)C
Reactant: C=CCONS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=CCON([C@@H]1C=C(CC)[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
To a stirred suspension of (2S,5S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-3-ethyl-5-hydroxy-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 208, 6.36 g, 17.12 mmol), N-(allyloxy)-2-nitrobenzenesulfonamide (Intermediate 9) (8.84 g, 34.23 mmol) and triphenylphosphine (13.47 g, 51.35 mmol) in toluene (25 mL) at 0° C. was added dropwise (E)-diisopropyl diazene-1,2-dicarboxylate (9.95 ml, 51.35 mmol). The reaction mixture was warmed to room temperature and stirred for 30 minutes. Silica gel chromatography (0-40% ethyl acetate/hexanes) afforded the title compound (7.00 g, 66.8%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@@H:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6]Br.[CH2:17]([N:19](CC)[CH2:20]C)C.CNC>C1COCC1>[CH3:1][O:2][C:3](=[O:16])[C@@H:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6][N:19]([CH3:20])[CH3:17]
Reactant: COC(=O)[C@H](CCBr)NC(=O)OC(C)(C)C
Reactant: CCN(CC)CC
Agent: CNC
Solvent: C1CCOC1
Product: COC(=O)[C@H](CCN(C)C)NC(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 97 %

Procedure:
To a solution of (S)-4-bromo-2-tert-butoxycarbonylamino-butyric acid methyl ester (27.5 g, 93 mmol) in THF (100 mL) in a pressure reaction vessel was added triethylamine (26 mL) and dimethylamine (93 mL of 2.0 M in THF). The reaction vessel was sealed and heated to 60° C. for 16 hours and then cooled to room temperature. The reaction mixture was concentrated under reduced pressure and then dissolved in dichloromethane (500 mL). The solution was washed with water (3×200 mL) and brine (200 mL), dried over MgSO4, filtered through Celite and concentrated under reduced pressure. The residue was dried under high vacuum to afford 23.4 g of yellow oil (97% yield).
Reaction SMILES: [Si:1]([Cl:5])(Cl)(Cl)[Cl:2].[CH2:6]([Mg]Br)[CH:7]=[CH2:8].[Mg].[CH2:12](Br)[CH:13]=[CH2:14]>CCOCC>[CH2:6]([Si:1]([CH2:14][CH:13]=[CH2:12])([Cl:5])[Cl:2])[CH:7]=[CH2:8]
Reactant: Cl[Si](Cl)(Cl)Cl
Reactant: C=CC[Mg]Br
Reactant: C=CCBr
Agent: [Mg]
Solvent: CCOCC
Product: C=CC[Si](Cl)(Cl)CC=C
Reaction time: 1.5 h
Yield: 15 %

Procedure:
To a one-liter 3-neck flask with reflux condenser and dropping funnel, 29 g (170 mmoles) of SiCl4 in 150 mL of anhydrous ether were added. Allyl magnesium bromide solution [from 10 g (400 mmoles) of magnesium and 41.5 g (34 mmoles) of allyl bromide in 250 mL of anhydrous ether], filtered through glass wool, was added dropwise, MgBrCl precipitating. After boiling for 1.5 hours under reflux and washing the residue, diallyldichlorosilane was obtained at 56° C. and 16 hPa as a colorless liquid in a 15% yield.
Reaction SMILES: C([O:8][C:9](=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1)C1C=CC=CC=1.Cl[C:24]1[CH:40]=[CH:39][C:27]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)=[O:29])=[CH:26][N:25]=1.C1(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=NC=2)=O)C=CC=CC=1>>[CH3:38][O:37][C:33]1[CH:32]=[C:31]([NH:30][C:28]([C:27]2[CH:39]=[CH:40][C:24]([N:19]3[CH2:18][CH2:17][N:16]([C:13]4[CH:12]=[CH:11][C:10]([C:9]([OH:8])=[O:22])=[CH:15][CH:14]=4)[CH2:21][CH2:20]3)=[N:25][CH:26]=2)=[O:29])[CH:36]=[CH:35][CH:34]=1
Reactant: COc1cccc(NC(=O)c2ccc(Cl)nc2)c1
Reactant: O=C(OCc1ccccc1)c1ccc(N2CCNCC2)cc1
Agent: O=C(O)c1ccc(N2CCN(c3ccc(C(=O)Nc4ccccc4)cn3)CC2)cc1
Product: COc1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)nc2)c1

Procedure:
4-{4-[5-(3-Methoxy-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid was prepared from 4-piperazin-1-yl-benzoic acid benzyl ester and 6-chloro-N-(3-methoxy-phenyl)-nicotinamide with a method similar to the one described in the synthesis of 4-[4-(5-phenylcarbamoyl-pyridin-2-yl)-piperazin-1-yl]-benzoic acid above. HRMS m/z calcd for C24H24N4O4 [M+H]+: 433.1871. Found: 433.1868.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:9]([CH:12]2[CH2:14][CH2:13]2)[CH:10]=O)=[N:4][CH:5]=[CH:6][C:7]=1[Cl:8].[C:15]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].N1CCCCC1.C(O)(=O)C>C(O)C>[CH2:20]([O:19][C:17](=[O:18])[C:16](=[CH:10][CH:9]([C:3]1[C:2]([CH3:1])=[C:7]([Cl:8])[CH:6]=[CH:5][N:4]=1)[CH:12]1[CH2:14][CH2:13]1)[C:15]([O:23][CH2:24][CH3:25])=[O:22])[CH3:21]
Reactant: Cc1c(Cl)ccnc1C(C=O)C1CC1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: C1CCNCC1
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(=CC(c1nccc(Cl)c1C)C1CC1)C(=O)OCC
Yield: 71.2 %

Procedure:
A mixture of (3-methyl-4-chloro-pyridin-2-yl)-cyclopropyl-acetaldehyde (4.83 g, 23.0 mmol), diethyl malonate (7.02 g, 43.8 mmol), piperidine (3.62 mL, 36.6 mmol), and acetic acid (4.19 mL, 73.2 mmol) in ethanol (100 mL) was heated to reflux overnight. The reaction mixture was concentrated to dryness. The residue was purified by flash silica column chromatography (hexane:ethyl acetate, 4:1) to afford the title compound as a yellow oil (5.76 g, 71%).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:4]=2[O:3]1.ClC1C=CC=C(C(OO)=[O:30])C=1>ClCCl>[CH3:1][C:2]1([CH3:21])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=2[O-:30])[C:5]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:4]=2[O:3]1
Reactant: CC1(C)CC(c2ccccn2)c2cc([N+](=O)[O-])ccc2O1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1(C)CC(c2cccc[n+]2[O-])c2cc([N+](=O)[O-])ccc2O1
Yield: 30.9 %

Procedure:
245 mg of 3,4-dihydro-2,2-dimethyl-6-nitro-4-(2-pyridyl)-2H-1-benzopyran were dissolved in 5 ml of dichloromethane at room temperature and 149 mg of m-chloroperbenzoic acid were added. After stirring at room temperature for 3 days further m-chloroperbenzoic acid was added until starting material could no longer be detected by thin-layer chromatography. The mixture was washed in succession with sodium bisulphite solution, sodium bicarbonate solution and sodium chloride solution, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using 4% (v/v) ethanol/dichloromethane for the elution and the resulting foam was triturated with n-hexane to give 80 mg of 2-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1-benzopyran-4-yl)pyridine N-oxide of melting point 116-119° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]([S:10][C:11]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:12]=1[C:13](O)=[O:14])([CH3:9])[CH3:8].Cl.CN.[N:26]1C=CC=C[CH:27]=1>C(Cl)Cl.CN(C=O)C>[CH:7]([S:10][C:11]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:12]=1[C:13]([NH:26][CH3:27])=[O:14])([CH3:9])[CH3:8]
Reactant: c1ccncc1
Reactant: CC(C)Sc1ccc([N+](=O)[O-])cc1C(=O)O
Agent: CN
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=O)c1cc([N+](=O)[O-])ccc1SC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
Oxalyl chloride (1.75 mL, 19.6 mmol) was added dropwise to a suspension of 16A (2.41 g, 10 mmol) in DCM (20 mL) containing DMF (2 drops) at 0° C. The reaction mixture was warmed to rt and stirred overnight. The reaction mixture was concentrated in vacuo and coevaporated twice with toluene. The residue was dissolved in DCM (25 mL) and added portionwise to a solution of methylamine hydrochloride (2.03 g, 30.1 mmol) and pyridine (8.1 mL, 100 mmol) in DCM (25 mL) at 0° C. The reaction mixture was stirred overnight at rt. The reaction mixture was concentrated in vacuo and the residue was triturated with water to give 16B (2.08 g, 82%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH2:13][CH3:14])[C:9]([O:11][CH3:12])=[O:10])=[C:4]([CH2:15][N:16]([CH3:58])[C:17](=[O:57])[CH:18]([NH:30][C:31]2[CH:32]=[C:33]3[C:38](=[CH:39][CH:40]=2)[C:37]([N:41]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[N:36][CH:35]=[C:34]3[F:56])[C:19]2[CH:24]=[CH:23][C:22]([C@@H:25]([CH3:28])[CH2:26][OH:27])=[C:21]([CH3:29])[CH:20]=2)[CH:3]=1.[C:59](Cl)(Cl)=[O:60]>C(#N)C.ClCCl>[C:52]([O:51][C:49]([N:41]([C:42]([O:44][C:45]([CH3:48])([CH3:46])[CH3:47])=[O:43])[C:37]1[C:38]2[C:33](=[CH:32][C:31]([NH:30][C@H:18]3[C:17](=[O:57])[N:16]([CH3:58])[CH2:15][C:4]4[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=4[C@@H:8]([CH2:13][CH3:14])[C:9]([O:11][CH3:12])=[O:10])[NH:1][C:59](=[O:60])[O:27][CH2:26][C@H:25]([CH3:28])[C:22]4[CH:23]=[CH:24][C:19]3=[CH:20][C:21]=4[CH3:29])=[CH:40][CH:39]=2)[C:34]([F:56])=[CH:35][N:36]=1)=[O:50])([CH3:55])([CH3:54])[CH3:53]
Reactant: CC[C@@H](C(=O)OC)c1ccc(N)cc1CN(C)C(=O)C(Nc1ccc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ncc(F)c2c1)c1ccc([C@@H](C)CO)c(C)c1
Reactant: O=C(Cl)Cl
Solvent: CC#N
Solvent: ClCCl
Product: CC[C@@H](C(=O)OC)c1ccc2cc1CN(C)C(=O)[C@H](Nc1ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ncc(F)c3c1)c1ccc(c(C)c1)[C@@H](C)COC(=O)N2
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 33 %

Procedure:
A solution of 13F (235 mg, 0.293 mmol) in acetonitrile (4 mL) and dichloromethane (2 mL) was cooled to 0° C. To this solution was added phosgene (20% in toluene, 0.159 mL, 0.322 mmol). The mixture was stirred at 0° C. for 5 min, and rt for 1 h. The mixture was bubbled with Ar for 10 min to remove excess phosgene. The resulting solution was added dropwise over 3 h via a syringe pump into a solution of TEA (0.408 mL, 2.93 mmol) in CH2Cl2 (100 mL) at rt. The solution was stirred at rt for 16 h. The reaction mixture was concentrated and purified by flash chromatography to give a mixture of diastereoisomers (198 mg, 82% yield). The diastereoisomers (169 mg, 0.204 mmol) were separated by a prep chiral HPLC to give 13G (80 mg, 47.3% yield). MS (ESI) m/z: 827.9 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][C:4]([CH3:11])([CH3:10])[C:5](OCC)=[O:6].[H-].[H-].[H-].[H-].[Li+].[Al+3].CO>CCOCC>[F:1][C:2]([F:13])([F:12])[CH2:3][C:4]([CH3:11])([CH3:10])[CH2:5][OH:6]
Reactant: CCOC(=O)C(C)(C)CC(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CO
Product: CC(C)(CO)CC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 4,4,4-trifluoro-2,2-dimethylbutanoate (1 g, 5.05 mmol) in ether (25 ml) under nitrogen was added LAH (1M solution in ether, 20.2 mmol) and allowed to stir at room temperature for one hour. Methanol was slowly added to R×n until bubbling stopped. The reaction was then suspended in ether and Water. The suspension was washed with Water, dried over sodium sulfate, filtered, and concentrated without heat to produce an oil 4,4,4-trifluoro-2,2-dimethylbutan-1-ol (75-1). 1H NMR (500 MHz, CDCl3) δ 3.4 (s, 2H), 2.20-2.01 (m, 2H), 1.05 (s, 6H). (M+H)+: observed=157.16, calculated=157.15
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH2:10][CH2:11][CH3:12])[N:5]([CH2:7][CH2:8][NH2:9])[CH:6]=1.[F:13][C:14]([F:26])([F:25])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH:23]=O)=[CH:17][CH:16]=1>>[I:1][C:2]1[N:3]=[C:4]([CH2:10][CH2:11][CH3:12])[N:5]2[CH2:7][CH2:8][NH:9][CH:23]([CH2:22][CH2:21][C:18]3[CH:19]=[CH:20][C:15]([C:14]([F:13])([F:25])[F:26])=[CH:16][CH:17]=3)[C:6]=12
Reactant: O=CCCc1ccc(C(F)(F)F)cc1
Reactant: CCCc1nc(I)cn1CCN
Product: CCCc1nc(I)c2n1CCNC2CCc1ccc(C(F)(F)F)cc1

Procedure:
According to the general procedure (GP10), microwave-assisted Pictet-Spengler reaction (60 W; 140° C.; 6.5 bars; 10 min.) between 2-(4-iodo-2-propyl-imidazol-1-yl)-ethylamine (9.260 mmol) and 3-(4-trifluoromethyl-phenyl)-propionaldehyde (2.730 g; 13.503 mmol) afforded 1-iodo-3-propyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine. LC-MS: tR=0.80 min.; [M+H]+=463.88 g/mol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH2:13]1.[CH3:31][O:32][C:33](=[O:39])[NH:34][CH2:35]OC=N.C(O)(=O)C>ClC(Cl)Cl>[C:19]1([CH:18]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:15]2[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][CH2:9][N:8]3[C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[N:1]=[C:35]3[NH:34][C:33](=[O:39])[O:32][CH3:31])[CH2:17][CH2:16]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)NCOC=N
Reactant: Nc1ccccc1NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COC(=O)Nc1nc2ccccc2n1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of 60 parts of N-(2-aminophenyl)-4-(diphenylmethyl)-1-piperazinepropanamine, 20 parts of methyl(iminomethoxymethyl)carbamate, 42 parts of acetic acid and 450 parts of trichloromethane is stirred and refluxed overnight. The reaction mixture is evaporated and the residue is stirred in water. The latter is decanted and the residue is taken up again in water. The whole is alkalized with a diluted ammonium hydroxide solution and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane, yielding methyl [1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1H-benzimidazol-2-yl]carbamate; mp. 137.8° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:17]#[N:18].C(N(CC)CC)C>C(N(CC)CC)C.C1COCC1>[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[N:22]1[CH2:27][CH2:26][N:25]([CH2:11][C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]3[CH:8]=2)[CH2:24][CH2:23]1)[C:17]#[N:18]
Reactant: N#Cc1ccc(N2CCNCC2)c(Cl)c1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1ccc(N2CCN(Cc3cn4cc(Cl)ccc4n3)CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
A mixture of 6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (Example 4, Step 1; 0.140 g), 3-chloro-4-(piperazin-1-yl)benzonitrile (0.155 g), triethylamine (0.078 g), and THF (2.5 mL) is heated at reflux for 5.5 h and then stirred overnight at room temperature. A few drops of triethylamine are then added and the mixture is stirred an additional 4 h at reflux. After cooling, the mixture is concentrated and the residue is partitioned between dichloromethane and aq. sodium bicarbonate. The organic layers are dried over sodium sulfate and concentrated. Chromatography of the residue on silica gel using methanol/dichloromethane (4/96) gives 0.238 g of the title compound. A portion of the material is recrystallized from ethyl acetate/ethyl ether/hexane; mp 137-138° C.; MS m/z 385, 387; IR (mineral oil) 1501, 2225, 1130, 1342, 1490 cm-1. 1H NMR (CDCl3) δ2.77, 3.21, 3.79, 7.03, 7.14, 7.47-7.54, 7.61, 8.14.
Reaction SMILES: C[O:2][C:3](=[O:44])[CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH:17]([F:19])[F:18])=[CH:13][CH:14]=2)[C:9]([C:20]2[N:21]=[C:22]3[C:28]([C:29](=[O:35])[NH:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][N:26]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:23]3=[N:24][CH:25]=2)=[N:8]1.CO.[OH-].[Li+].Cl>C1COCC1.O>[C:31]([NH:30][C:29]([C:28]1[C:22]2[C:23](=[N:24][CH:25]=[C:20]([C:9]3[C:10]4[C:15](=[CH:14][CH:13]=[C:12]([O:16][CH:17]([F:18])[F:19])[CH:11]=4)[N:7]([CH2:6][CH2:5][CH2:4][C:3]([OH:44])=[O:2])[N:8]=3)[N:21]=2)[N:26]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[CH:27]=1)=[O:35])([CH3:32])([CH3:33])[CH3:34]
Reactant: COC(=O)CCCn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2cc(OC(F)F)ccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCCC(=O)O)c4ccc(OC(F)F)cc34)nc12
Temperature: 75 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
In a round-bottomed flask, 4-{3-[7-tert-butylcarbamoyl-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-5-difluoromethoxy-indazol-1-yl}-butyric acid methyl ester (98 mg, 0.155 mmol) was suspended in THF (1.1 ml), methanol (1.1 ml) and water (1.1 ml). Then, aqueous 1.0 M lithium hydroxide (0.80 ml, 0.80 mmol) was added. The light yellow suspension was stirred at 75° C. for 8 h then cooled to room temperature and stirred overnight. The reaction was diluted with water and acidified with 1 M HCl until pH=˜2 then extracted with dichloromethane (3×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was triturated with diethyl ether to afford 81 mg (85%) of 4-{3-[7-tert-butylcarbamoyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-5-difluoromethoxy-indazol-1-yl}-butyric acid as a brown powder.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Si]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][C:32]([O:34][CH2:35][CH:36]=[CH2:37])=[O:33])[C:26]=2[CH3:38])=[CH:21][CH:20]=1)(C(C)(C)C)(C)C.[CH3:39]I.O>O1CCCC1>[OH:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]([CH3:39])[C:32]([O:34][CH2:35][CH:36]=[CH2:37])=[O:33])[C:26]=2[CH3:38])=[CH:23][CH:24]=1
Reactant: CI
Reactant: C=CCOC(=O)Cc1cccc(-c2ccc(O[Si](C)(C)C(C)(C)C)cc2)c1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC(=O)C(C)c1cccc(-c2ccc(O)cc2)c1C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
A bis(trimethylsilyl)amide lithium-11.0M tetrahydrofuran solution (2.47 ml, 2.47 mmol) was added dropwise to a solution of allyl (4′-{[tert-butyl(dimethyl)silyl]oxy}-2-methyl-1,1′-biphenyl-3-yl)acetate (675 mg, 1.70 mmol) obtained in Example (98-2) in tetrahydrofuran (6 ml) at −78° C. After the mixture was stirred for 30 minutes, methyl iodide (512 μl, 8.22 mmol) was added thereto and the mixture was stirred at −78° C. for 1 hour. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was dissolved in tetrahydrofuran (5 ml). A tetra-n-butylammonium fluoride-1.0M tetrahydrofuran solution (2.04 ml, 2.04 mmol was added to the solution and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel preparative thin layer chromatography (developing solvent: n-hexane/ethyl acetate=3/1) to give allyl 2-(4′-hydroxy-2-methyl-1,1′-biphenyl-3-yl)propanoate (457 mg, yield: 91%).
Reaction SMILES: [Na].Cl[C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][S:6][N:7]=1.[CH3:14][OH:15]>>[CH3:14][O:15][C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][S:6][N:7]=1
Reactant: CO
Reactant: Clc1nsnc1-c1cccnc1
Agent: [Na]
Product: COc1nsnc1-c1cccnc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of sodium (460 mg, 20 mmol) in methanol (10 ml) was added 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (750 mg, 3.8 mmol). The mixture was stirred at 50° C. for 1 h and evaporated. The residue was dissolved in water and extracted with methylene chloride. The combined organic phases were dried and evaporated to give the title compound, which crystallized with petroleum ether in a 630 mg (86%) yield.
Reaction SMILES: O.[NH2:2]N.C[N:5]([CH2:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)C>C(O)C>[C:11]1([C:9]2[CH2:8][CH2:7][NH:5][N:2]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NN
Reactant: CN(C)CCC(=O)c1ccccc1
Solvent: O
Solvent: CCO
Product: c1ccc(C2=NNCC2)cc1
Temperature: 0 °C
Yield: 89.8 %

Procedure:
Hydrazine monohydrate (6.2 g) was dissolved in ethanol (12 ml). Thereto was dropwise added a solution of 3-(N,N-dimethylamino)propiophenone (5.4 g) dissolved in ethanol (10 ml) in a nitrogen atmosphere at room temperature. The resulting mixture was refluxed for 3 hours with heating. The reaction mixture was poured into ice water. Extraction with chloroform was conducted, followed by drying and concentration, to obtain 4 g of a title compound.