Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]=O)[CH2:7][CH2:6][C:5]2([CH3:15])[CH3:14].[CH2:16]([Mg]Br)[CH3:17].C(OCC)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:17][CH2:16]1)[CH2:7][CH2:6][C:5]2([CH3:15])[CH3:14]
Reactant: CC[Mg]Br
Reactant: CC1(C)CCN(C=O)c2ccc(Br)cc21
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(C)CCN(C2CC2)c2ccc(Br)cc21
Temperature: 50 °C
Yield: 64 %

Procedure:
A stirred, cooled (0° C.) solution of 6-bromo-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-1-carbaldehyde (Intermediate 50, 21.8, 6.7 mmol) in anhydrous tetrahydrofuran (20 mL) under argon was treated with titanium tetra-iso-prop oxide (2.15 mL, 7.39 mmol) followed by 3M solution of ethyl magnesium bromide in diethyl ether (5.6 mL, 16.8 mmol) and the reaction mixture was then heated at 50° C. overnight. It was then cooled in an ice-bath, quenched with saturated aqueous ammonium chloride solution and extracted with diethyl ether (×2). The combined organic phase was dried over anhydrous sodium sulfate, filtered over celite and evaporated in vacuo to residue which was subjected to flash column chromatography over silica gel (230-400 mesh) using 5% ethyl acetate in hexane as the eluent to afford the title compound as an oil (1.2 g, 64%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.CCN(CC)CC.[CH3:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19]>C(Cl)Cl>[CH3:16][C:17]([CH3:22])([CH3:21])[C:18]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=1)=[O:19]
Reactant: Cc1ccc(N)nc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)C(C)(C)C)nc1
Reaction time: 2 h
Yield: 98.4 %

Procedure:
To a stirred solution of 5-methylpyridin-2-amine (200 g, 1.85 mol) in anhydrous CH2Cl2 (1000 mL) was added dropwise a solution of Et3N (513 mL, 3.70 mol) and 2,2-dimethyl-propionyl chloride (274 mL, 2.22 mol) at 0° C. under N2. The ice bath was removed and stirring was continued at room temperature for 2 hours. The reaction was poured into ice (2000 g). The organic layer was separated and the remaining aqueous layer was extracted with CH2Cl2 (3×). The combined organics were dried over Na2SO4 and evaporated to afford 2,2-dimethyl-N-(5-methyl-pyridin-2-yl)-propionamide (350 g), which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J=8.4 Hz, 1 H), 8.06 (d, J=1.2 Hz, 1 H), 7.96 (s, 1 H), 7.49 (dd, J=1.6, 8.4 Hz, 1 H), 2.27 (s, 1 H), 1.30 (s, 9 H).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21]OS(C)(=O)=O)[CH:18]=2)[NH:13][C:12]=1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>O1CCOCC1>[CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][N:32]3[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]3)[CH:18]=2)[NH:13][C:12]=1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: Cc1[nH]c2ccc(CCOS(C)(=O)=O)cc2c1C(=O)OCc1ccccc1
Solvent: C1COCCO1
Product: Cc1[nH]c2ccc(CCN3CCN(C)CC3)cc2c1C(=O)OCc1ccccc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
To a solution of 5-(2-methanesulfonyloxy-ethyl)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (424 mg, 1.1 mmol, Example 56, Step D) in dioxane (10 mL) was added 1-methylpiperazine (0.6 mL, 5.5 mmol). The mixture was stirred at 70° C. overnight and then partitioned between methylene chloride and water. The organic phase was washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give a solid residue, which was recrystallized from ethyl acetate to give 191 mg (45%) of the desired product as a white solid: mp 167-168° C.; MS(APCI+): m/z 392.3 (MH+); Anal. Calcd for C24H29N3O2.0.5H2O: C, 71.97; H, 7.55; N, 10.49. Found: C, 72.35; H, 7.54; N, 10.12.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][CH:4]=1.Br[C:11]1[CH:20]=[CH:19][C:14]([CH2:15][N:16]([CH3:18])[CH3:17])=[CH:13][CH:12]=1>O1CCCC1.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>[Br:9][C:6]1[CH:7]=[CH:8][C:3]([C:13]2[C:14]([CH2:15][N:16]([CH3:18])[CH3:17])=[CH:19][CH:20]=[CH:11][CH:12]=2)=[CH:4][CH:5]=1
Reactant: Brc1ccc(Br)cc1
Reactant: CN(C)Cc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CN(C)Cc1ccccc1-c1ccc(Br)cc1
Reaction time: 5 h

Procedure:
A solution of the Grignard reagent prepared from 344 mg of magnesium and 2.27 g of 1,4-dibromobenzene in 15 ml of THF (tetrahydrofuran) is added dropwise to a suspension of 2 g of 4-bromo-N,N-dimethylbenzylamine and 158 mg of tetrakistriphenylphosphinepalladium in 10 ml of THF. The addition is carried out at room temperature and under an argon atmosphere. After completion of the addition, the mixture is heated to boiling for an additional 5 hours and then evaporated under reduced pressure. The residue is then treated with ether and saturated ammonium chloride solution and the aqueous phase is separated. This is extracted with ether. The organic extracts are washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated. The residue is purified by chromatography on silica gel while eluting with methylene chloride/methanol 9:1. 4'-Bromo-N,N-dimethylbiphenylmethanamine, m.p. 60°-62° C., is obtained.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C:9]3[C:12]4[CH:13]=[CH:14][C:15]([OH:20])=[CH:16][C:17]=4[CH2:18][CH2:19][C:8]=3[C:7]1=[CH:6][CH2:5][C@@H:4]2[OH:21])[CH3:2].C.[H][H]>C1C=CC=CC=1>[CH2:1]([C@:3]12[CH2:11][CH2:10][C:9]3[C:12]4[CH:13]=[CH:14][C:15]([OH:20])=[CH:16][C:17]=4[CH2:18][CH2:19][C:8]=3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:21])[CH3:2]
Reactant: [H][H]
Reactant: CC[C@]12CCC3=C(CCc4cc(O)ccc43)C1=CC[C@@H]2O
Solvent: c1ccccc1
Product: CC[C@]12CCC3=C(CCc4cc(O)ccc43)[C@@H]1CC[C@@H]2O

Procedure:
Shake 13β-ethylgona-1,3,5(10),8,14-pentaene-3,17β-diol (0.28 g.) in benzene (35 cc.) with 10% palladised charcoal (300 mg.) in an atmosphere of hydrogen until 25 cc. of hydrogen has been absorbed. Filter off the catalyst, evaporate the solvent and recrystallize the residue from methanol to obtain the title product, m.p. 234°-8°; ultraviolet absorption peak at 280 mμ (ε 41,200).
Reaction SMILES: Cl.[NH2:2][C:3]1([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[CH2:4]1.C(N(CC)CC)C.[C:26](Cl)(=[O:28])[CH3:27]>ClCCl>[C:26]([NH:2][C:3]1([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[CH2:4]1)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: COC(=O)C1(N)CCc2cc(OC)ccc2C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1(NC(C)=O)CCc2cc(OC)ccc2C1

Procedure:
Methyl 2-amino-6-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxylate hydrochloride (13.6 g., 50 mM) was suspended in dry dichloromethane (200 ml.). The suspension was stirred and cooled in ice, and dry triethylamine (16.8 ml., 120 mM) was added, followed by acetyl chloride (4.3 ml., 60 mM). The mixture was stirred at room temperature for 16 hr. The solvent was evaporated in vacuo and the residue was dissolved in a mixture of ethyl acetate (1 l.) and water (500 ml.). The mixture was separated and the organic phase was washed successively with water (500 ml.), 2N hydrochloric acid (2×500 ml.), water (500 ml.) and saturated brine (500 ml.). The organic phase was dried (Na2SO4) and the solvent evaporated in vacuo. The solid was crystallised from ethyl acetate/petroleum ether (b.p. 60°-80°) to give methyl 2-acetylamino-6-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxylate, m.p. 160°-1°.
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15](Cl)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.[OH-].[Na+]>C(O)C>[C:1]1([C:7]2[N:16]=[C:15]([N:22]3[CH2:23][CH2:24][CH:19]([OH:18])[CH2:20][CH2:21]3)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1nc(-c2ccccc2)nc2ccccc12
Reactant: OC1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OC1CCN(c2nc(-c3ccccc3)nc3ccccc23)CC1
Yield: 41.9 %

Procedure:
A mixture containing 6 g (0.025 mole) of 2-phenyl-4-chloroquinazoline, 3.53 g (0.035 mole) of 4-hydroxypiperidine and 100 ml of 95% ethyl alcohol was refluxed for 3 hrs. One gram of sodium hydroxide (in one ml of water) was added and the mixture was refluxed for an additional 2 hr period. The mixture was filtered and the filtrate was added to 300 ml of water. The white crystalline precipitate was separated and recrystallized with methanol and water to give 3.2 g of the title compound, m.p. 165°-167° C.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C@@H]1([N:18]2[C:28]3[N:27]=[C:25]([NH2:26])[NH:24][C:22](=[O:23])[C:21]=3[N:20]=[CH:19]2)O[C@H](CO)[C@@H](O)[C@H]1O.[ClH:29].CO>CS(C)=O>[ClH:29].[NH2:26][C:25]1[NH:24][C:22](=[O:23])[C:21]2[N:20]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:19]=[N:18][C:28]=2[N:27]=1
Reactant: BrCc1ccccc1
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: Cl
Solvent: CS(C)=O
Solvent: CO
Product: Nc1nc2ncn(Cc3ccccc3)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Benzyl bromide (100 ml) was added dropwise to a suspension of guanosine (100 g) in dimethyl sulfoxide (500 ml) at room temperature, and the resulting reaction mixture was stirred at room temperature for 4 hours. Then, concentrated hydrochloric acid (250 ml) was added thereto. The reaction mixture was stirred at room temperature for 30 minutes, poured into methanol (3 L), and stirred overnight. Deposited crystals were collected by filtration, washed with methanol, and then dried by ventilation at 60° C. for 24 hours to give 82.5 g of the title compound.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][CH:12]([F:14])[F:13])[CH:8]=[C:7]([CH3:15])[N:6]=1)(=O)=O.[NH3:16]>C(Cl)(Cl)Cl.C(Cl)Cl>[NH2:16][C:5]1[N:10]=[C:9]([O:11][CH:12]([F:14])[F:13])[CH:8]=[C:7]([CH3:15])[N:6]=1
Reactant: Cc1cc(OC(F)F)nc(S(C)(=O)=O)n1
Reactant: N
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1cc(OC(F)F)nc(N)n1
Reaction time: 3 h
Yield: 85 %

Procedure:
4.0 g (0.017 mol) of 2-methylsulfonyl-4-difluoromethoxy-6-methylpyrimidine are suspended in 60 ml of chloroform. This suspension is saturated with gaseous ammonia, and then stirred for 3 hours at a temperature of between 20° and 25° C. The reaction mixture is subsequently diluted with 50 ml of methylene chloride; the organic phase is separated, washed with water and concentrated by evaporation. There are obtained, as crystalline residue, 2.5 g (85% of theory) of 2-amino-4-difluoromethoxy-6-methylpyrimidine, m.p. 137°-139° C.
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][CH:5]=1)=[C:2]=[O:3].[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][OH:22])[CH:16]=1>C1COCC1>[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][O:22][C:2]([NH:1][C:4]2[CH:5]=[CH:6][C:7]([C:8]([OH:10])=[O:9])=[CH:13][CH:14]=2)=[O:3])[CH:16]=1
Reactant: OCc1cccnc1
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(=O)O)cc1)OCc1cccnc1
Temperature: -78 °C
Yield: 96 %

Procedure:
A solution of ethyl 4-isocyanatobenzoate 280 (2.0 g, 10.46 mmol) and pyridin-3-ylmethanol in THF was stirred at room temperature for 18 h then concentrated. The crude material was taken up in 2N HCl, heated to reflux for 16 h then cooled to −78° C. and lyophilized to give a solid material which was triturated with acetone to give title compound 281 (3.098 g, 96% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[CH:29][C:30]([CH:33]2[CH2:35][CH2:34]2)=[N:31][CH:32]=1>>[CH:33]1([C:30]2[CH:29]=[CH:28][C:27]([C:2]#[C:1][C:3]3[CH:4]=[N:5][N:6]4[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]5[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=5)=[N:8][C:7]=34)=[CH:32][N:31]=2)[CH2:35][CH2:34]1
Reactant: Brc1ccc(C2CC2)nc1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(C#Cc4ccc(C5CC5)nc4)c3n2)cc1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 5-bromo-2-cyclopropyl-pyridine (Example B.11) (257 mg, 1.3 mmol) according to general procedure II. Obtained as an orange solid (110 mg, 23%). MS (ISP) 473.0 [(M+H)+]; mp 138-140° C.
Reaction SMILES: C([CH:9]([O:16][C:17]([NH:19][CH2:20][C:21]1([CH2:27][C:28]([O:30][CH2:31][CH2:32][C:33]#[N:34])=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)C1C=CC=CC=1.[CH:35]1[CH:40]=[C:39](Cl)[CH:38]=[C:37]([C:42]([O:44]O)=[O:43])[CH:36]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:42]([O:44][CH:9]([O:16][C:17]([NH:19][CH2:20][C:21]1([CH2:27][C:28]([O:30][CH2:31][CH2:32][C:33]#[N:34])=[O:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:43])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:35][CH:36]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: N#CCCOC(=O)CC1(CNC(=O)OC(C(=O)c2ccccc2)c2ccccc2)CCCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: N#CCCOC(=O)CC1(CNC(=O)OC(OC(=O)c2ccccc2)c2ccccc2)CCCCC1
Temperature: 25 °C
Yield: 75 %

Procedure:
A solution of 2-cyanoethyl 1-{[(α-benzoylbenzyloxy)carbonyl]aminomethyl}-1-cyclohexane acetate (9) (115 mg, 0.248 mmol) in 4 mL of CH2Cl2 was added to a mixture of mCPBA (77%, 111 mg, 0.497 mmol) and Na2CO3 (52.7 mg, 0.497 mmol) at room temperature. The resulting suspension was stirred at room temperature with TLC monitoring. After completion of the reaction (about 8 hours) the reaction mixture was diluted with CH2Cl2, washed with saturated NaHCO3 solution and brine and dried over Na2SO4. After concentration in vacuo the residue was purified on silica gel (40% ethyl acetate in hexane) to afford 89 mg (75%) of the title compound. 1H NMR (CDCl3): δ 8.08 (2H, dd, J=6.8, 1.6 Hz); 7.91 (1H, s); 7.63-7.54 (3H, m); 7.44-7.40 (5H, m); 5.42 (1H, t, J=6.4 Hz); 4.22 (2H, t, J=6.2 Hz); 3.25 (2H, dd, J=6.4, 4.6 Hz); 2.65 (2H, t, J=6.2 Hz); 2.35 (2H, s); 1.53-1.37 (10H, m). 13C NMR (CDCl3): δ 172.11; 164.73; 154.75; 136.29; 133.70; 130.18; 129.85; 129.63; 128.85; 128.68; 126.85; 117.11; 91.41; 58.94; 47.93; 10.06; 38.09; 34.15; 26.00; 21.55; 18.16.
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6](=[O:23])[N:7]3[CH2:22][CH2:21][CH2:20][CH:8]3[C:9](=[O:19])[N:10]3C(C4C=CC=CC=4)[O:12][C:3]=1[C:4]=23.B.[Na].[C:28](OCC)(=O)C.O>CO>[OH:12][C:3]1[C:4]2[NH:10][CH:9]([O:19][CH3:28])[CH:8]3[CH2:20][CH2:21][CH2:22][N:7]3[C:6](=[O:23])[C:5]=2[CH:24]=[CH:25][C:2]=1[CH3:1]
Reactant: CCOC(C)=O
Reactant: Cc1ccc2c3c1OC(c1ccccc1)N3C(=O)C1CCCN1C2=O
Agent: B
Agent: [Na]
Solvent: CO
Solvent: O
Product: COC1Nc2c(ccc(C)c2O)C(=O)N2CCCC12
Temperature: -20 °C
Reaction time: 3 h

Procedure:
Then, 1.43 g of the 6,8,9,10,10a,11-hexahydro-3-methyl-1-phenyl-1H-oxazolo[5,4,3-jk]pyrrolo[2,1-C] [1,4]benzodiazepin-6,11-dione was dissolved in 110 ml of methanol. To the solution, cooled to 0° to 5° C., was slowly added 820 mg of sodium boron hydride with stirring, and the whole mixture was stirred at 0° to 5° C. for 2.5 hours. 800 ml of ethyl acetate and 500 ml of water were added to the reaction mixture, the ethyl acetate layer was separated, and the aqueous layer was extracted with ethyl acetate. The both ethyl acetate layers were combined, dehydrated and concentrated under reduced pressure. The concentrate was dissolved in 375 ml of 2:1 mixture of methyl alcohol and 0.01 N hydrochloric acid and subjected to hydrolyzation at room temperature for 3 hours with stirring. The liquid reaction mixture was extracted with chloroform, the chloroform layer was washed with water and then it was concentrated under reduced pressure at a temperature not exceeding 40° C. The concentrate was dissolved in 50 ml of methanol and heated under reflux for 30 minutes. The reaction mixture was concentrated under reduced pressure at 40° C. or below. The concentrate was dissolved into 4 ml of hot methanol, cooled to -20° C. and allowed to stand at this temperature for 3 days. Thus, 0.35 g of 2,3,5,10,11,11a-hexahydro-9-hydroxy-11-methoxy-8-methyl-1H-pyrrolo[2,1-C] [1,4]benzodiazepin-5-one was obtained in a colorless crystalline form. Recrystallization of the resulting product from methanol gave a colorless needle-like crystal having a melting point of 152.5° to 155.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:8]=2[C:9]2[C:10]([CH2:23][O:24][CH3:25])=[C:11]([C:20](O)=[O:21])[N:12]=[CH:13][C:14]=2[NH:15]3)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:40](=[N:44]O)([NH2:43])[CH2:41][CH3:42]>CN(C)C=O>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:8]=2[C:9]2[C:10]([CH2:23][O:24][CH3:25])=[C:11]([C:20]4[O:21][N:44]=[C:40]([CH2:41][CH3:42])[N:43]=4)[N:12]=[CH:13][C:14]=2[NH:15]3)=[CH:4][CH:3]=1
Reactant: CCC(N)=NO
Reactant: COCc1c(C(=O)O)ncc2[nH]c3cccc(Oc4ccc(Cl)cc4)c3c12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CCc1noc(-c2ncc3[nH]c4cccc(Oc5ccc(Cl)cc5)c4c3c2COC)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5.74 g of 5-(4-chlorophenoxy)-4-methoxymethyl-beta-carboline-3-carboxylic acid are dissolved in 150 ml of absolute dimethylformamide, mixed with 2.91 g of carbonyldiimidazole and stirred for 3 hours at room temperature. To this solution is added 3.96 g of propionamidoxime, it is stirred for 8 hours, 1 g of propionamidoxime is added once more and also stirred for 8 hours. After evaporation on the oil pump vacuum, it is taken up in toluene and refluxed for 8 hours. After evaporation, it is chromatographed twice over silica gel, first with methylene chloride/ethanol=10:1 and then with hexane: acetone=1:1 as eluant. After recrystallization from ethyl acetate/hexane and drying over phosphorus pentoxide at 80° C. in a vacuum, 2.2 g of 5-(4-chlorophenoxy-3-(3-ethyl-1,2,4-oxadizaol-5-yl)-4-methoxymethyl-beta-carboline with a melting point of 170° C. is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([N:15]2[C:23]([C:24]([NH:26][CH3:27])=[O:25])=[C:22]3[C:17]([CH:18]=[C:19]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[C:20]([CH:28]4[CH2:30][CH2:29]4)=[CH:21]3)=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:36](OC1N=CC(N)=CC=1)[C:37]1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].BrCC>C(#N)C>[CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([N:15]2[C:23]([C:24]([NH:26][CH3:27])=[O:25])=[C:22]3[C:17]([CH:18]=[C:19]([N:31]([CH2:36][CH3:37])[S:32]([CH3:35])(=[O:33])=[O:34])[C:20]([CH:28]4[CH2:29][CH2:30]4)=[CH:21]3)=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c2cc(C3CC3)c(NS(C)(=O)=O)cc2nn1-c1ccc(OCc2ccccc2)nc1
Reactant: Nc1ccc(OCc2ccccc2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCBr
Product: CCN(c1cc2nn(-c3ccc(OCc4ccccc4)nc3)c(C(=O)NC)c2cc1C1CC1)S(C)(=O)=O
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 80 %

Procedure:
2-(6-benzyloxy-3-pyridyl)-5-cyclopropyl-6-(methanesulfonamido)-N-methyl-indazole-3-carboxamide (109) ESI-MS m/z calculated for [M+H]+: 492.1 was prepared according to procedure outlined in Method A using 6-benzyloxypyridin-3-amine instead of 4-bromoaniline. To a solution of compound (109) (120 mg, 0.24 mmol) in acetonitrile (10 mL) was added potassium carbonate (100 mg, 0.72 mmol) followed by bromoethane (0.09 mL, 1.2 mmol). The mixture was heated to 80° C. and stirred for 1.5 h. The mixture was cooled to RT and the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate (10 mL), washed with water (2 mL), brine (2 mL), dried (MgSO4) and concentrated in vacuo to afford 2-(6-benzyloxy-3-pyridyl)-5-cyclopropyl-6-[ethyl(methylsulfonyl)amino]-N-methyl-indazole-3-carboxamide (i) (100 mg, 80%). This material was used without purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.[F:13][C:14]1[CH:15]=[C:16]([NH2:22])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]>>[F:13][C:14]1[CH:15]=[C:16]([NH:22][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:12])[N:3]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: Cc1nc(Cl)c2ccccc2n1
Reactant: COc1ccc(N)cc1F
Product: COc1ccc(Nc2nc(C)nc3ccccc23)cc1F

Procedure:
The title compound was prepared from 4-chloro-2-methyl-quinazoline (150 mg, 0.84 mmol), 3-fluoro-4-methoxy-phenylamine (1 18.5 mg, 0.84 mmol) by a procedure similar to Example 78. 1H NMR (CDCl3): 7.89-7.75 (m, 4H), 7.53-7.48 (m, 1H)), 7.38-7.34 (m, 2H), 7.0 (t, J=8.7 Hz, 1H), 3.92 (s, 3H), 2.71 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:10][O:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:21]=[N:22][CH:23]=2)[C:19]=1Cl)=[O:13].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH3:10][O:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:21]=[N:22][CH:23]=2)[C:19]=1[NH:4][C:3]1[CH:5]=[CH:6][C:7]([I:9])=[CH:8][C:2]=1[F:1])=[O:13]
Reactant: Nc1ccc(I)cc1F
Reactant: COC(=O)c1ccc2cncn2c1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2cncn2c1Nc1ccc(I)cc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
To a stirred suspension 2-fluoro-4-iodo aniline (53.95 g, 0.256 mol) and 5-chloro-imidazo[1,5-a]pyridine-6-carboxylic acid methyl ester (62.0 g, 0.253 mol) in THF (500 mL) under nitrogen at −78° C., a solution of lithium bis(trimethylsilyl) amide (544 mL, 1M solution, 0.544 mol) was added dropwise over 1 hr, maintaining the temperature below −65° C., giving a red/brown solution. After stirring for 30 minutes at −78° C. the reaction mixture was allowed to warm to −30° C. and then quenched with addition water (100 mL). The solvent was removed in vacuo, before diluting with water (500 ml) and the mixture was extracted with 2-methyltetrahydrofuran (2×500 mL). The combined organic extracts were washed with water, then brine, dried (MgSO4), filtered and concentrated in vacuo. The resultant residue was triturated tert-butyl methyl ether (600 mL) to yield product as yellow/brown solid (87.2 g 83%). LCMS (Method B): RT=3.54 min, [M+H]+=412.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH2:14][CH:15]=O)=[CH:11][C:10]([CH2:17][CH2:18][CH3:19])=[N:9]2)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[BH3-]C#N.[Na+]>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:15][CH2:14][CH2:13][C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[N:9]=[C:10]([CH2:17][CH2:18][CH3:19])[CH:11]=2)[CH2:29][CH2:28]1
Reactant: CCCc1cc(CCC=O)n(-c2ccc(C)cc2)n1
Reactant: Fc1ccccc1N1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCCc1cc(CCCN2CCN(c3ccccc3F)CC2)n(-c2ccc(C)cc2)n1

Procedure:
93 mg (59.7%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-(4-methylphenyl)-3-propyl-1H-pyrazol-5-yl)propanal (95 mg, 0.371 mmol), 1-(2-fluorophenyl)piperazine (76 mL, 0.482 mmol), and NaCNBH3 (70 mg, 1.112 mmol).