Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([NH2:11])=[N:6]2.Br[C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:32])[CH3:31])=[CH:25][CH:24]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC([O-])(C)C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([NH:11][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:32])[CH3:31])=[CH:25][CH:24]=1)=[N:6]2
Reactant: CC(=O)Nc1ccc(Br)cc1
Reactant: Cc1nc(-c2cccc(C(F)(F)F)c2)n2nc(N)ncc12
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(Nc2ncc3c(C)nc(-c4cccc(C(F)(F)F)c4)n3n2)cc1
Yield: 39.1 %

Procedure:
In a similar manner as described for Example 41, 5-methyl-7-[3-(trifluoromethyl)phenyl]imidazo[5,1-f][1,2,4]triazin-2-amine (Intermediate 45) (0.025 g, 0.09 mmol), N-(4-bromophenyl)acetamide (0.018 g, 0.09 mmol), Pd2(dba)3 (0.008 g, 0.01 mmol), 2-(Di-t-butylphosphino)biphenyl (0.008 g, 0.03 mmol), and NaOtBu (0.011 g, 0.11 mmol) in 1,4-dioxane (1 mL) gave N-[4-({5-methyl-7-[3-(trifluoromethyl)phenyl]imidazo[5,1-f][1,2,4]triazin-2-yl}amino)phenyl]acetamide (0.015 g) as a yellow solid. 1H NMR (DMSO-d6): δ9.92 (s, 1H), 9.82 (s, 1H), 9.26 (s, 1H), 8.87 (s, 1H), 8.59 (d, J=7.4 Hz, 1H), 7.86-7.70 (m, 2H), 7.68-7.63 (m, 2H), 7.60-7.53 (m,2H), 2.53 (s, 3H), 2.02 (s, 3H). MS m/z 427 (M+1).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[CH:12][C:11]=2[CH2:15][CH2:16][C:17](OC)=[O:18])=[CH:6][CH:5]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[F:22][C:2]([F:1])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[CH:12][C:11]=2[CH2:15][CH2:16][CH2:17][OH:18])=[CH:6][CH:5]=1
Reactant: COC(=O)CCc1cnoc1-c1ccc(OC(F)(F)F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCCCc1cnoc1-c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
To a solution of methyl 3-[5-(4-trifluoromethoxyphenyl)-4-isoxazolyl]propionate (1.63 g) in tetrahydrofuran (25 ml) was gently added diisobutylaluminum hydride (1.0 M hexane solution, 13.2 ml) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 3-[5-(4-trifluoromethoxyphenyl)-4-isoxazolyl]propan-1-ol (1.36 g, yield 92%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 50–51° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][CH:6]=1.N1(C[C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=2)C=CC=C1>>[CH3:1][C:2]1[N:3]([C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: Ic1ccc(Cn2cccc2)cc1
Reactant: Cc1ccc[nH]1
Product: Cc1cccn1-c1ccc(I)cc1

Procedure:
The titled compound was prepared from 2-methylpyrrole (J. Org. Chem. 1956, 21, 918.) in an analogous manner to that of 4-(pyrrol-1-ylmethyl)phenyl iodide (EP 488 602 A1).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C@@H:14]([N:17]=[N+:18]=[N-:19])[C@H:13]([OH:20])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:24].[Cl-].[NH4+]>O1CCCC1.CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C@@H:14]([N:17]=[N+:18]=[N-:19])[C@H:13]([O:20][CH3:24])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=N[C@@H]1CCN(C(=O)OCc2ccccc2)C[C@H]1O
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CO[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 0.150 g (0.54 mmole) of (rac)-(3R,4R)-4-azido-3-hydroxy-piperidine-1-carboxylic acid benzyl ester in 3.75 mL of tetrahydrofuran-dimethylformamide (4:1) at 0 degrees, was added 0.026 g of sodium hydride (60% mineral oil dispersion). After stirring for 10 minutes, 0.060 mL of iodomethane was added. The mixture was warmed to room temperature, stirred for 2 hours, then cooled in an ice-bath, and 1 mL of saturated aqueous ammonium chloride solution added. The resulting mixture was partitioned between 50 mL of ethyl acetate and 50 mL of saturated aqueous ammonium chloride solution. The organic layer was successively with water, then brine and dried over anhydrous magnesium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatoraphy, eluting with hexanes-ethyl acetate (85:15) to give 0.085 g of (rac)-(3R,4R)-4-azido-3-methoxy-piperidine-1-carboxylic acid benzyl ester as a colorless oil.
Reaction SMILES: C(OP([CH2:9]/[C:10](/[CH3:17])=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[Cl:18][C:19]1[C:28]2[C:27]([CH3:30])([CH3:29])[CH2:26][CH:25]=[C:24]([CH:31]([CH3:33])[CH3:32])[C:23]=2[CH:22]=[C:21](/[C:34](/[CH2:39][CH3:40])=[C:35](/[F:38])\[CH:36]=O)[C:20]=1[O:41][CH2:42][CH3:43]>>[Cl:18][C:19]1[C:28]2[C:27]([CH3:30])([CH3:29])[CH2:26][CH:25]=[C:24]([CH:31]([CH3:32])[CH3:33])[C:23]=2[CH:22]=[C:21](/[C:34](/[CH2:39][CH3:40])=[C:35](/[F:38])\[CH:36]=[CH:9]\[C:10](\[CH3:17])=[CH:11]\[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:20]=1[O:41][CH2:42][CH3:43]
Reactant: CCOc1c(/C(CC)=C(/F)C=O)cc2c(c1Cl)C(C)(C)CC=C2C(C)C
Reactant: CCOC(=O)/C=C(\C)CP(=O)(OCC)OCC
Product: CCOC(=O)/C=C(C)/C=C/C(F)=C(/CC)c1cc2c(c(Cl)c1OCC)C(C)(C)CC=C2C(C)C

Procedure:
Following General Procedure I-1, ethyl 4-(diethoxyphosphoryl)-3-methyl-but-2E-enoate (139 mg, 0.53 mmol) and (2E)-3-(4-chloro-3-ethoxy-8-isopropyl-5,5-dimethyl-5,6-dihydronaphthalen-2-yl)-2-fluoro-pent-2-enal (Compound A-156, 32 mg, 0.09 mmol) were reacted to give the title compound as a colorless oil after purification by column chromatography (silica gel, 1% to 2% ethyl acetate in hexane).
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:13])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[CH:25]1[CH:26]=[CH:27][N:28]2[CH2:34][C:33]3[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=3[NH:31][CH2:30][C:29]=12.C(N(CC)C(C)C)(C)C>ClCCl>[CH:25]1[CH:26]=[CH:27][N:28]2[CH2:34][C:33]3[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=3[N:31]([C:7]([C:6]3[CH:10]=[C:2]([Cl:1])[C:3]([I:13])=[CH:4][C:5]=3[O:11][CH3:12])=[O:9])[CH2:30][C:29]=12
Reactant: COc1cc(I)c(Cl)cc1C(=O)O
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(I)c(Cl)cc1C(=O)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 5-chloro-4-iodo-2-methoxy benzoic acid of Step C (0.900 g, 2.88 mmol) and N,N-dimethylformamide (6.7 mL, 86.4 mmol) in anhydrous dichloromethane (14.4 mL) was added dropwise oxalyl chloride (0.263 mL, 3.02 mmol). The mixture was heated to reflux for 1 hour, then cooled to room temperature and evaporated to dryness. Fresh anhydrous dichloromethane (25 mL) was added, the resulting solution was concentrated and the residue dried in vacuo. The crude acid chloride thus obtained and 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.584 g, 3.17 mmol) were combined in anhydrous dichloromethane (14.4 mL), followed by addition of N,N-diisopropylethyl amine (0.447 mL, 3.46 mmol). After stirring at room temperature for 18 hours, the reaction mixture was diluted with dichloromethane (15 mL) and washed sequentially with 1 N hydrochloric acid, 1 N sodium hydroxide, and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated to afford the crude title amide which was recrystallized from diethyl ether to provide 1.23 g of slightly orange crystals, m.p. 191-192° C.
Reaction SMILES: [C:1]([Si:5]([CH3:16])([CH3:15])[O:6][CH2:7][CH2:8][C:9]([CH3:14])([CH3:13])[CH2:10][CH2:11][OH:12])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].O>ClCCl>[C:1]([Si:5]([CH3:16])([CH3:15])[O:6][CH2:7][CH2:8][C:9]([CH3:14])([CH3:13])[CH2:10][CH2:11][O:12][S:25]([CH3:24])(=[O:27])=[O:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(CCO)CCO[Si](C)(C)C(C)(C)C
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(CCO[Si](C)(C)C(C)(C)C)CCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
Step A To the solution of 5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-pentan-1-ol (1.1 g, 5 mmol) prepared in Example 116a Step B. and triethylamine (1.39 mL, 10 mmol) in dichloromethane (50 mL) at 0° C. was added a dichlormethane solution (10 mL) of methanesulfonyl chloride (Aldrich) (0.46 mL, 6 mmol). The reaction mixture was stirred at 0° C. for 1 h. Water was added. Organic layer was separated, the aqueous layer was extracted with dichlormethane. The combined organic layers were washed with diluted aqueous HCl solution, saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated to give methanesulfonic acid 5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-pentyl ester as a yellow oil (1.48 g, 99%).
Reaction SMILES: [CH2:1](Br)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:10][C:11]1[C:28]([CH3:29])=[CH:27][C:14]([O:15][CH2:16][C:17]([N:19]([CH3:26])[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:18])=[C:13]([CH3:30])[C:12]=1[CH3:31].C(N(CC)CC)C.[Cl-].[NH4+]>C(#N)C>[NH2:10][C:11]1[C:28]([CH3:29])=[CH:27][C:14]([O:15][CH2:16][C:17]([N:19]([CH3:26])[CH:20]2[CH2:25][CH2:24][N:23]([CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH2:22][CH2:21]2)=[O:18])=[C:13]([CH3:30])[C:12]=1[CH3:31]
Reactant: BrCCc1ccccc1
Reactant: Cc1cc(OCC(=O)N(C)C2CCNCC2)c(C)c(C)c1N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(OCC(=O)N(C)C2CCN(CCc3ccccc3)CC2)c(C)c(C)c1N
Temperature: 60 °C
Reaction time: 5 h
Yield: 88.1 %

Procedure:
200 mg of phenethyl bromide was added to a mixture solution of 350 mg of the Compound (1) obtained in the Example 1 and 172 mg of triethylamine in 5 ml of acetonitrile, and the mixture was stirred for 5 hours at 60° C. Then, 5 ml of saturated ammonium chloride solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried and concentrated under reduced pressure to give a residue. The obtained residue was purified by amine-coated silica gel (Fuji Silysia Chemical Ltd.; NH-DM1020) column chromatography (methylene chloride:methanol=20:1) to give 390 mg (83%) of the above-mentioned compound (28).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([C:13]([F:16])([F:15])[F:14])[C:5]=1[NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])=[CH:20][CH:19]=1)([O-:3])=[O:2].S(OC)(O[CH3:35])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([C:13]([F:16])([F:15])[F:14])[C:5]=1[N:17]([CH3:35])[C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:29])([F:30])[CH:26]([F:28])[F:27])=[CH:20][CH:19]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Nc2ccc(OC(F)(F)C(F)F)cc2)c(C(F)(F)F)c1
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CN(c1ccc(OC(F)(F)C(F)F)cc1)c1c([N+](=O)[O-])cc([N+](=O)[O-])cc1C(F)(F)F

Procedure:
Following the procedure of Example 18, N-(2,4-dinitro-6-trifluoromethylphenyl)-4-(1,1,2,2-tetrafluoroethoxy)benzenamine was reacted with dimethyl sulfate and sodium carbonate in acetone to provide N-(2,4-dinitro-6-trifluoromethylphenyl)-N-methyl-4-(1,1,2,2-tetrafluoroethoxy)benzenamine.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Br:10])[CH:3]=1.[C:11]([OH:15])(=[O:14])[CH:12]=[CH2:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C(C)=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].O>[Br:10][C:4]1[CH:3]=[C:2](/[CH:13]=[CH:12]/[C:11]([OH:15])=[O:14])[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=1
Reactant: C=CC(=O)O
Reactant: COc1cc(Br)cc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1C
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc(Br)cc(/C=C/C(=O)O)c1
Temperature: 100 °C
Reaction time: 11 h
Yield: 32 %

Procedure:
To a solution of 1,3-dibromo-5-methoxybenzene (9.18 mmol, 1 eq) in 2 ml of xylene under a nitrogen atmosphere, acrylic acid (0.63 ml, 9.18 mmol, 1 eq), Pd(OAc)2 (1 mole %, 20.66 mg), triphenylphosphine (4 mole %, 69.2 mg) and triethylamine (19.278 ml, 2.7, 2.1 eq) are added. The reaction mixture is stirred at 100° C. for 11 h. Thereafter, 20 ml of water and 2 g of sodium carbonate were added, and the mixture was stirred at 100° C. for some minutes. The aqueous phase was subsequently separated and acidified. The precipitate that formed was dried and purified by means of column chromatography (eluent hexane/ethyl acetate 1/1) to obtain the desired product in a yield of 32% (751 mg).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.C(N=C=NCCCN(C)C)C.[C:22]([C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[C:29]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH:28]=[C:27]2[C:40](O)=[O:41])#[N:23].C(N(CC)CC)C.[NH2:50][C:51]1[O:52][C:53]([C:56]2[O:57][CH:58]=[CH:59][CH:60]=2)=[N:54][N:55]=1>CN(C)C=O>[C:22]([C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[C:29]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH:28]=[C:27]2[C:40]([NH:50][C:51]1[O:52][C:53]([C:56]2[O:57][CH:58]=[CH:59][CH:60]=2)=[N:54][N:55]=1)=[O:41])#[N:23]
Reactant: N#Cc1ccc2nc(-c3ccccc3)cc(C(=O)O)c2c1
Reactant: Nc1nnc(-c2ccco2)o1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1ccc2nc(-c3ccccc3)cc(C(=O)Nc3nnc(-c4ccco4)o3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1.2 %

Procedure:
HOBt (0.0351 g, 0.260 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) (0.0460 g, 0.240 mmol) were added to a dimethylformamide (5.0 mL) solution of 6-cyano-2-phenyl-4-quinolinecarboxylic acid (0.0548 g, 0.200 mmol) described in Reference Example 22 and triethylamine (0.0223 g, 0.220 mmol), and the mixture was stirred at room temperature for 30 minutes. Commercially available 2-amino-5-(2-furyl)-1,3,4-oxadiazole (0.0332 g, 0.220 mmol) was added thereto, and the mixture was stirred at room temperature. The reaction solution was subjected to extraction with dichloromethane, washed with water and saturated saline, and dried over anhydrous sodium sulfate, and then, the solvent was distilled off. The obtained residue was fractionated by silica gel column chromatography, and the solvent was distilled off to obtain the title compound (0.001 g, 0.0024 mmol) as an amorphous substance.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:7]=[CH:8][C:9]=1[OH:10])([O-:3])=[O:2].[C:16]1([CH3:30])[CH:21]=CC(S(OCC(=C)C)(=O)=O)=C[CH:17]=1.C[O-].[Na+]>CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:7]=[CH:8][C:9]=1[O:10][CH2:21][C:16](=[CH2:17])[CH3:30])([O-:3])=[O:2]
Reactant: COC(=O)Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: C=C(C)COS(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C=C(C)COc1ccc(CC(=O)OC)cc1[N+](=O)[O-]

Procedure:
A mixture of 2.11g of methyl 3-nitro-4-hydroxyphenylacetate, 2.27g of methallyl p-toluenesulfonate was refluxed for one hour in 60ml of methanol containing natrium methoxide (natrium 0.25g). The reaction mixture was concentrated under reduced pressure and ethyl acetate and water were added to the residue. The ethyl acetate layer was isolated, and washed with water. After the extract was dried over magnesium sulfate, the solvent was distilled off and the residue was recrystallied from methanol to give the object compound having m.p. 30°- 31.5° C in a yield of 1.98g (74%).
Reaction SMILES: COCCOC.[CH2:7]([O:14][CH2:15][N:16]1[CH:20]=[C:19](B2OC(C)(C)C(C)(C)O2)[C:18]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:17]1[CH:35]=[O:36])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F:37][C:38]1[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=1[CH2:40]Br.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:7]([O:14][CH2:15][N:16]1[CH:20]=[C:19]([CH2:40][C:39]2[CH:42]=[CH:43][CH:44]=[CH:45][C:38]=2[F:37])[C:18]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:17]1[CH:35]=[O:36])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1c(B2OC(C)(C)C(C)(C)O2)cn(COCc2ccccc2)c1C=O
Reactant: Fc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1c(Cc2ccccc2F)cn(COCc2ccccc2)c1C=O
Temperature: 50 °C
Reaction time: 3 h
Yield: 90.7 %

Procedure:
To 100 ml of 1,2-dimethoxyethane solution containing 4.38 g (10.6 mmol) of ethyl 1-benzyloxymethyl-2-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrol-3-carboxylate obtained in Reference example 36-(c) were added 2.60 ml (21.4 mmol) of 2-fluorobenzyl bromide and 100 ml of 2M sodium carbonate aqueous solution, the mixture was degassed under reduced pressure and replaced with argon. Further, 2.47 g (2.14 mmol) of tetrakistriphenylphosphine palladium was added to the mixture, and the resulting mixture was stirred at 50° C. for 3 hours. After completion of the reaction, to the reaction mixture were added water and a saturated aqueous solution of sodium chloride, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=9:1→4:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 3.80 g of the title compound as a yellowish oil. (Yield: 91%)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:18]3[CH2:21][CH2:20][CH2:19]3)[N:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[C:12]=23)=[CH:4][CH:3]=1.BrC1C=CC(B2OC(C)(C)[C:31](C)(C)[O:30]2)=CC=1OC>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH:18]3[CH2:21][CH2:20][CH2:19]3)[N:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[C:12]=23)=[CH:6][C:7]=1[O:30][CH3:31]
Reactant: Nc1nccn2c(C3CCC3)nc(-c3ccc(Br)cc3)c12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1Br
Product: COc1cc(-c2nc(C3CCC3)n3ccnc(N)c23)ccc1Br

Procedure:
Prepared according to a procedure analogous to that described for 1-(4-bromophenyl)-3-cyclobutylimidazo[1,5-a]pyrazin-8-ylamine except using 2-(4-bromo-3-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane. MS (ES+): m/z 372.99, 374.96 [MH+].
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([O:17][CH2:18][C:19]([CH2:24]Cl)([CH3:23])[CH2:20][C:21]#[N:22])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(OCC)C>[CH2:1]([C:21]1[CH2:20][C:19]([CH2:18][O:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([CH3:24])[CH2:23][N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(CCl)(CC#N)COCc1ccccc1
Reactant: Cl[Mg]Cc1ccccc1
Solvent: CCOCC
Product: CC1(COCc2ccccc2)CN=C(Cc2ccccc2)C1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A benzylmagnesium chloride solution in ether (224 ml, 1 M, 0.224 mol) is heated to 30° C. and a solution of 4-benzyloxy-3-chloromethyl-3-methylbutyronitrile (75%, 40 g, 0.126 mol) in diethyl ether (140 ml) is slowly added dropwise (30 min.). The suspension formed is kept at reflux by warming after complete addition. After 2 h, the ether (310 ml) is distilled off (45 min.) and then replaced by toluene abs. (210 ml). The yellow toluene suspension is heated to 100° C. and then stirred at this temperature for 2 h. The batch, which is cooled to room temperature, is treated with dil. HCl (10% strength, 100 ml) and stirred until, in addition to the aqueous and the toluene phase, a third, oily phase separates. The oil phase and water phase are separated off, and the toluene phase is extracted 2 times in a separating funnel with dil. HCl (100 ml). The oil phase combined with the HCl phases is washed with toluene (50 ml) and then adjusted to pH 8-9 with NaOH (32%). After stirring for 30 min., the separated oily base fraction is taken up with diethyl ether, and the alkaline water phase is extracted a further 3 times with ether (450 ml). The collected ether extracts are dried over Na2SO4 sicc. and concentrated. A red-brown oily residue of 39.64 g (96% of theory, 78% according to gc) remains.
Reaction SMILES: [CH3:1][CH2:2][O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][CH:6]=1.[BH4-].[Na+]>CO>[CH2:14]([O:13][CH:4]([O:3][CH2:2][CH3:1])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][OH:12])=[CH:7][CH:6]=1)[CH3:15]
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(OCC)c1ccc(CO)cc1
Yield: 89.7 %

Procedure:
To a solution of terephthalaldehyde mono(diethyl acetal) (1.9 ml, 9.6 mmol) in methanol (35 ml) was added sodium borohydride (1.1 g, 28.8 mmol) while cooling. After 5 minutes at room temperature the reaction was quenched with water (50 ml) and the mixture was extracted with ethyl acetate (2×50 ml). The combined extracts were washed with water and brine, dried over sodium sulfate and concentrated in vacuo, leaving title product as a colorless oil (1.81 g, 90%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([OH:13])[CH:10]([CH2:14]O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH2:1]([N:8]1[CH2:12][CH:11]([OH:13])[CH:10]([CH2:14][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CN(Cc2ccccc2)CC1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)CC1CN(Cc2ccccc2)CC1O
Yield: 93.9 %

Procedure:
1-Benzyl-3-hydroxymethyl-4-hydroxypyrrolidine (66.2 g) and triethylamine (38.8 g) are added to dry dichloromethane (700 ml) and the mixture is cooled till a temperature of from -5° to -10° C. At this temperature, methanesulfonyl chloride (36.6 g) is added dropwise to the mixture with stirring. After the addition, the mixture is stirred for 30 minutes, and then washed with an aqueous sodium hydrogen carbonate and subsequently with water. Thereafter, the dichloromethane layer is separated, dried and concentrated to give 1-benzyl-4-hydroxy-3-methanesulfonylmethylpyrrolidine (80.8 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:24][CH3:25])[C:5]([O:22][CH3:23])=[C:6]([CH:8]([NH:10][C:11]2[CH:16]=[C:15](F)[CH:14]=[CH:13][C:12]=2[S:18]([CH3:21])(=[O:20])=[O:19])[CH3:9])[CH:7]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:24][CH3:25])[C:5]([O:22][CH3:23])=[C:6]([CH:8]([NH:10][C:11]2[CH:16]=[C:15]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH:14]=[CH:13][C:12]=2[S:18]([CH3:21])(=[O:20])=[O:19])[CH3:9])[CH:7]=1
Reactant: C1CNCCN1
Reactant: COc1cc(Cl)cc(C(C)Nc2cc(F)ccc2S(C)(=O)=O)c1OC
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Cl)cc(C(C)Nc2cc(N3CCNCC3)ccc2S(C)(=O)=O)c1OC
Yield: 2.8 %

Procedure:
A solution of [1-(5-chloro-2,3-dimethoxy-phenyl)-ethyl]-(5-fluoro-2-methanesulfonyl-phenyl)-amine (0.52 g, 1.34 mmol), piperazine (0.23 g, 2.68 mmol) and N,N-diisopropylethylamine (0.47 mL, 2.68 mmol) in acetonitrile was stirred at 80° C. for 24 h. The reaction mixture was cooled down and concentrated under reduced pressure. The residue was taken up in dichloromethane, washed with water, dried and concentrated in vacuo to yield the crude residue which was purified by preparative TLC (0.5% NH4OH/9.5% methanol/dichloromethane) to afford [1-(5-chloro-2,3-dimethoxy-phenyl)-ethyl]-(2-methanesulfonyl-5-piperazin-1-yl-phenyl)-amine (17 mg, 3%). 1H NMR (400 MHz, CD3OD): δ 7.42 (d, 1H), 6.87 (m, 2H), 6.25 (dd, 1H), 5.90 (s, 1H), 4.87 (m, 1H), 3.85 (s, 1H), 3.81 (s, 1H), 3.05-3.2 (m, 4H), 3.78 (m, 4H), 1.49 (d, 3H). MS (ESI) m/z: Calculated: 453.98; Observed: 454.4 (M+H+); 476.4 (M+Na+); 930.8 (2M+Na+). Mol. Wt.: 453.98 (C21H28ClN3O4S).