Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:21]([F:22])=[C:20]([CH3:23])[C:19]([F:24])=[C:18]([NH2:25])[C:14]=3[C:15](=[O:17])[CH:16]=2)=[CH:7][C:6]=1[F:26])(=[O:3])[CH3:2].[H-].[Na+].I[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].[Cl-].[NH4+]>CN(C)C=O>[C:1]([N:4]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:21]([F:22])=[C:20]([CH3:23])[C:19]([F:24])=[C:18]([NH:25][CH2:7][CH2:6][CH2:5][CH2:10][CH3:9])[C:14]=3[C:15](=[O:17])[CH:16]=2)=[CH:7][C:6]=1[F:26])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])(=[O:3])[CH3:2]
Reactant: CCCCCI
Reactant: CC(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)c(C)c(F)c3o2)cc1F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCCCCNc1c(F)c(C)c(F)c2oc(-c3ccc(N(CCCCC)C(C)=O)c(F)c3)cc(=O)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.2 %

Procedure:
510 mg (1.41 mmol) of 2-(4-acetylamino-3-fluorophenyl)-5-amino-6,8-difluoro-7-methyl-4H-1-benzopyran-4-one obtained in Example 109 (1) was dissolved in 30 mL of dimethylformamide under argon atmosphere, 58 mg (1.5 mmol) of sodium hydride (60% oil dispersion) and 0.37 mL (2.8 mmol) of 1-iodopentane were added under ice-cooling and the mixture was stirred at room temperature for 4 hours. The reaction solution was cooled on ice, 117 mg (2.93 mmol) of sodium hydride (60% oil dispersion) and 0.37 mL (2.8 mmol) of 1-iodopentane were added and the mixture was stirred at room temperature for 50 minutes. An aqueous solution of ammonium chloride was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform) to give 153 mg of 2-[4-[N-acetyl-N-(1-pentyl)amino]-3-fluorophenyl]-6,8-difluoro-7-methyl-5-(1-pentylamino)-4H-1-benzopyran-4-one (yield: 22%).
Reaction SMILES: N[C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.BrC1C(C)=C(C2C=CC=C(C(F)(F)F)C=2)C([Cl:42])=NC=1>>[Cl:42][C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(N)nc2c1-c1cccc(C(F)(F)F)c1
Reactant: Cc1c(Br)cnc(Cl)c1-c1cccc(C(F)(F)F)c1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(Cl)nc2c1-c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared from 4-{5-[2-amino-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Ex. 1, 100 mg, 0.22 mmol) using a similar method to that used for Intermediate 14 (73 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([NH:28][C:29](=[O:38])[C@H:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH3:31])[C@@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2C(OC(C)(C)C)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]([C@H:16]2[CH2:20][CH2:19][CH2:18][NH:17]2)[NH:28][C:29](=[O:38])[C@H:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH3:31])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](C(=O)N[C@H](c1ccc(OCc2ccccc2)cc1)[C@@H]1CCCN1C(=O)OC(C)(C)C)c1ccccc1
Agent: Cl
Product: C[C@H](C(=O)N[C@H](c1ccc(OCc2ccccc2)cc1)[C@H]1CCCN1)c1ccccc1
Yield: 4.5 %

Procedure:
A solution of (S)-tert-butyl 2-((R)-(4-(benzyloxy)phenyl)((S)-2-phenylpropanamido)methyl)pyrrolidine-1-carboxylate (386 mg, 0.750 mmol) in HCl (2M in diethyl ether) (3.750 mL, 7.50 mmol) was stirred at room temperature for 4 h, then concentrated in vacuo. The residue was purified by HPLC (50% methanol/water with 0.1% TFA) to afford (S)-N-((R)-(4-(benzyloxy)phenyl)((R)-pyrrolidin-2-yl)methyl)-2-phenylpropanamide (14.7 mg, 0.034 mmol, 61.9% yield) as a slightly yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.23-7.43 (m, 11H), 6.94 (d, J=8.56 Hz, 2H), 6.81 (d, J=8.81 Hz, 2H), 6.64 (d, J=5.79 Hz, 1H), 4.99 (s, 1H), 4.79 (dd, J=8.18, 3.15 Hz, 1H), 3.67 (q, J=7.22 Hz, 1H), 3.31 (td, J=7.68, 3.27 Hz, 1H), 2.72 (td, J=6.67, 2.27 Hz, 1H), 1.72-1.84 (m, 2H), 1.60 (td, J=13.28, 6.17 Hz, 2H), 1.48-1.55 (m, 4H), 1.33-1.45 (m, 1H); LRMS (ESI) m/e 415.40 [(M+H)+, calcd for C27H31N2O2 415.24].
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][N:6]=[C:7]([CH3:9])[CH3:8])=[O:4]>C(O)C.C(O)(=O)C.O=[Pt]=O>[CH3:1][O:2][C:3]([NH:5][NH:6][CH:7]([CH3:9])[CH3:8])=[O:4]
Reactant: COC(=O)NN=C(C)C
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)NNC(C)C
Temperature: 25 °C
Reaction time: 22 h
Yield: 77.6 %

Procedure:
N′-Isopropylidene-hydrazine-carboxylic acid methyl ester (6.45 g) were dissolved in ethanol (50 mL) and acetic acid (50 mL). PtO2 (0.231 g) was added, and reaction was stirred at room temperature for 22 hours under an atmosphere of hydrogen. Mixture was evaporated under vacuum, giving N′-Isopropyl-hydrazine-carboxylic acid methyl ester (5.08 g, 77%) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[NH:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[Br:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([Br:30])[CH:29]=1)[CH2:25]Br>>[Br:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([Br:30])[CH:29]=1)[CH2:25][N:7]1[C:8]([C:9](=[O:18])[C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]1=[O:19]
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: BrCc1cc(Br)cc(Br)c1
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(Cc2cc(Br)cc(Br)c2)c(=O)[nH]c1=O
Yield: 74.4 %

Procedure:
5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 3,5-dibromobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (387 mg, yield: 74.4%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:9](=[CH:16]\[CH3:17])/[C@@H:10]([CH3:15])[CH2:11][N:12]([CH3:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1.COC1C=C(/C(=C/C)/[C@@H](C)CN(C)C)C=CC=1.O.C[Si](C)(C)[Cl:38]>CC(C)=O>[ClH:38].[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:9](=[CH:16]\[CH3:17])/[C@@H:10]([CH3:15])[CH2:11][N:12]([CH3:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1
Reactant: C[Si](C)(C)Cl
Agent: C/C=C(/c1cccc(OC)c1)[C@@H](C)CN(C)C
Agent: C/C=C(\c1cccc(OC)c1)[C@@H](C)CN(C)C
Solvent: CC(C)=O
Solvent: O
Product: Cl
Reaction time: 72 h

Procedure:
(Z)-(2R)-[3-(3-Methoxy-phenyl)-2-methyl-pent-3-enyl]-dimethyl-amine 201 g (0.86 mol) of a mixture of (Z)-(2R)-[3-(3-methoxy-phenyl)-2-methyl-pent-3-enyl]-dimethyl-amine, (E)-(2R)-[3-(3-methoxy-phenyl)-2-methyl-pent-3-enyl]-dimethyl-amine and by-products (see Example 1) are dissolved in 1 l of acetone and 15.5 g (0.86 mol) of water are added. 94.0 g (0.87 mol) of trimethylchlorosilane are then added dropwise and the mixture is stirred at 5° C.-8° C. for 72 h. The crystals which have precipitated out are filtered off with suction and rinsed with acetone. The product is then dried in a drying cabinet under 80-120 mbar at 40-50° C. The (Z)-(2R)-[3-(3-methoxy-phenyl)-2-methyl-pent-3-enyl]-dimethyl-amine hydrochloride crude product obtained is dissolved in 513 ml of water and the solution is adjusted to a pH of 11-12 with sodium hydroxide solution. 500 ml of ethyl acetate are added to the aqueous solution and the product is extracted. The ethyl ester phase which has been separated off is dried over sodium sulfate and concentrated on a rotary evaporator. The (Z)-(2R)-[3-(3-methoxy-phenyl)-2-methyl-pent-3-enyl]-dimethyl-amine obtained in this way is dissolved in 733 ml of acetone and 11.2 g (0.63 mol) of water are added. 67.8 g (0.63 mol) of trimethylchlorosilane are slowly added. The reaction mixture is stirred at 5-8° C. for 72 hours. The solid which has precipitated out is then filtered off with suction and rinsed with acetone. The product is dried in a drying cabinet under 80-120 mbar at 45-50° C. for 16 hours. The yield is 134.4 g (58%) with a purity of 100.0%. The ratio of Z to E isomer is 99.05:0.95.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:26])[N:6]2[C:11]1[CH:12]=[C:13]([N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:14]=[CH:15][CH:16]=1.[O:27]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.N1C=CC=CC=1>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Cu+2]>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]([C:37]1[CH:38]=[CH:39][C:34]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:35][CH:36]=1)[C:5](=[O:26])[N:6]2[C:11]1[CH:12]=[C:13]([N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[CH:14]=[CH:15][CH:16]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(-n2c(=O)[nH]c3c(N)ncnc32)c1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cccc(-n2c(=O)n(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)c1
Temperature: 37 °C

Procedure:
To a mixture of tert-butyl 3-(6-amino-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl)carbamate (24) (600 mg, 1.68 mmol) and 4 A MS (800 mg) in dry DMF (10 mL) were added 4-phenoxyphenylboronic acid (1.08 g, 5.06 mmol), Cu(OAc)2 (307 mg, 1.68 mmol) and pyridine (1 mL). The reaction mixture was heated to 37° C. overnight under O2 atmosphere, and filtered through a Celite pad. The filtrate was diluted with water (30 mL), extracted with EtOAc (10 mL×3). The combined organic layer was washed with water and brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (silica gel, 0 to 5% methanol in methylene chloride) to give tert-butyl 3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl(methyl)carbamate as a light yellow solid (31) (450 mg, 51%). LC-MS (ESI): m/z (M+1) 525.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[O:19]([CH2:26][CH:27]([OH:31])[CH2:28][CH2:29]Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:38]([OH:43])(=[O:42])[C:39]([OH:41])=[O:40]>C(O)CCC>[C:38]([OH:43])(=[O:42])[C:39]([OH:41])=[O:40].[O:19]([CH2:26][CH:27]([OH:31])[CH2:28][CH2:29][N:16]1[CH2:17][CH2:18][N:13]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=2)[CH2:14][CH2:15]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1cc(N2CCNCC2)cc(OC)c1OC
Reactant: OC(CCCl)COc1ccccc1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: COc1cc(N2CCN(CCC(O)COc3ccccc3)CC2)cc(OC)c1OC
Yield: 58 %

Procedure:
This compound was prepared according to the procedure of Example 6. A mixture of 2.5 g (0.01 mole) of 1-(3,4,5-trimethoxyphenyl)piperazine, 2.0 g (0.01 mole) of 1-phenoxy-4-chloro-2-butanol and 2.5 g (0.01 mole) of anhydrous sodium carbonate in 100 ml of 1-butanol gave a red-brown gum as residue. The gum was converted to the oxalic acid salt and the salt was recrystallized from absolute ethanol to give 3.2 g (58%) of tan powder, m.p. 154°-156° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:9]1)C1C=CC=CC=1>[Pd].C(O)C>[C:18]1([CH3:21])[CH:17]=[CH:16][C:15]([O:14][CH:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[CH:20][CH:19]=1
Reactant: Cc1ccc(OC2CCCN(Cc3ccccc3)C2)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(OC2CCCNC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2.9 g of 1-benzyl-3-(p-tolyloxy) piperidine in 30 ml. of 95% ethanol is added to 0.42 g of 10% Pd-C, and hydrogenated at about 50° C. for 3 hours. Then the reaction mixture is cooled to ambient temperature, the 10% Pd-C is filtered off, and the ethanol is removed leaving a yellow oil of 3-(p-tolyloxy)piperidine.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH:16]2[CH2:18][CH2:17]2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[N:5]2[N:19]=[CH:20][C:21]([CH:22]=[O:23])=[C:4]2[N:3]=1.[F:24][C:25]1[CH:30]=[C:29](B(O)O)[CH:28]=[CH:27][N:26]=1.C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC.CCO>[CH:16]1([N:8]([C:6]2[N:5]3[N:19]=[CH:20][C:21]([CH:22]=[O:23])=[C:4]3[N:3]=[C:2]([C:29]3[CH:28]=[CH:27][N:26]=[C:25]([F:24])[CH:30]=3)[CH:7]=2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:18][CH2:17]1
Reactant: OB(O)c1ccnc(F)c1
Reactant: CC(C)(C)OC(=O)N(c1cc(Cl)nc2c(C=O)cnn12)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CC(C)(C)OC(=O)N(c1cc(-c2ccnc(F)c2)nc2c(C=O)cnn12)C1CC1
Temperature: 85 °C
Reaction time: 8 h
Yield: 27.2 %

Procedure:
To tert-butyl 5-chloro-3-formylpyrazolo[1,5-a]pyrimidin-7-yl(cyclopropyl)carbamate (1 g, 3 mmol) in 29 mL of a 2:1 mixture of 1,2-dimethoxyethane/EtOH was added 2-Fluoropyridine-4-boronic acid (500 mg, 3.55 mmol), tetrakis(triphenylphosphine)palladium(0) (173 mg, 0.15 mmol), and 2M aqueous solution of Na2CO3 (4.4 mL, 8.9 mmol). The mixture was stirred at 85° C. for 8 hours. The volatiles were removed by rotary evaporation and the residue was purified by silica gel chromatography (35% EtOAc/Hexanes) to provide 324 mg tert-butyl cyclopropyl(5-(2-fluoropyridin-4-yl)-3-formylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate (28% yield). LCMS (M+1=398)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([OH:16])=[C:5]([CH:8]=[C:9]([N+:13]([O-:15])=[O:14])[C:10]=1[O:11][CH3:12])[CH:6]=O.[CH:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](Cl)=[O:25])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:12][O:11][C:10]1[C:3]([O:2][CH3:1])=[C:4]2[C:5]([CH:6]=[C:23]([C:20]3[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=3)[C:24](=[O:25])[O:16]2)=[CH:8][C:9]=1[N+:13]([O-:15])=[O:14]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COc1c([N+](=O)[O-])cc(C=O)c(O)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1c([N+](=O)[O-])cc2cc(-c3ccccc3)c(=O)oc2c1OC

Procedure:
A mixture of 3,4-dimethoxy-2-hydroxy-5-nitrobenzaldehyde obtained from Preparation example (1a) (0.91 g), phenacetylchloride (1.1 ml) and potassium carbonate (2.0 g) was refluxed in dry acetone (40 ml) overnight. Acetone was evaporated, cold water added and filtered. Yield: 0.69 g.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)=[N:7][CH:6]=[CH:5][C:4]=2[C:3]=1[NH2:23].Cl[C:25]1[C:30]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][N:32]=2)=[CH:29][CH:28]=[CH:27][N:26]=1.CN(C1C=CC=CC=1C1C=CC=CC=1)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>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].C1COCC1>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=3)=[N:7][CH:6]=[CH:5][C:4]=2[C:3]=1[NH:23][C:25]1[C:30]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][N:32]=2)=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: Clc1ncccc1-c1ccncn1
Reactant: Cc1ccc2c(Nc3cccc(C(F)(F)F)c3)nccc2c1N
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Product: Cc1ccc2c(Nc3cccc(C(F)(F)F)c3)nccc2c1Nc1ncccc1-c1ccncn1
Temperature: 70 °C
Yield: 56.4 %

Procedure:
6-Methyl-N1-(3-(trifluoromethyl)phenyl)isoquinoline-1,5-diamine (0.100 g, 0.30 mmol), 4-(2-chloropyridin-3-yl) pyrimidine (0.057 g, 0.30 mmol), dicyclohexylphosphino)-N,N-dimethylaminobiphenyl (0.0094 g, 0.024 mmol), and Pd2(dba)3 (0.010 g, 0.012 mmol) were all placed in a sealed tube containing 5 mL of anhydrous THF. Lithium bis(trimethylsilyl)amide (1.0 M in THF, 0.90 mL, 0.90 mmol) was then added to the mixture and nitrogen was bubbled into the reaction mixture for 5 min. The tube was capped and the reaction heated to 70° C. overnight. The reaction was allowed to cool to room temperature and quenched with methanol. The volatiles were removed in vacuo. The residue was taken up in ethyl acetate and washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate and the purified by column chromatography on silica gel using a gradient of 20 to 60% EtOAc in hexanes to give 6-methyl-N5-(3-(pyrimidin-4-yl)pyridin-2-yl)-N1-(3-(trifluoromethyl)phenyl)isoquinoline-1,5-diamine as a yellow solid (80 mg, 56%). MS (M H)+ 473.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]([C@@H:5]1[CH2:10][C@@H:9]([NH:11][S:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:14])=[O:13])[C@H:8]([OH:23])[CH2:7][CH2:6]1)=[O:4].[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.CN1C=CN=C1>ClCCl>[CH3:35][C:25]1[CH:30]=[CH:29][C:28]([S:31]([O:23][C@@H:8]2[CH2:7][CH2:6][C@H:5]([C:3](=[O:4])[N:2]([CH3:1])[CH3:24])[CH2:10][C@H:9]2[NH:11][S:12](=[O:13])(=[O:14])[NH:15][C:16]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:22])(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN(C)C(=O)[C@H]1CC[C@@H](O)[C@H](NS(=O)(=O)NC(=O)OC(C)(C)C)C1
Agent: Cn1ccnc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CC[C@H](C(=O)N(C)C)C[C@H]2NS(=O)(=O)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 37.6 %

Procedure:
t-Butyl {[(1R,2R,5S)-5-(dimethylcarbamoyl)-2-hydroxycyclohexyl]sulfamoyl}carbamate (200 mg) was dissolved in dichloromethane (2.0 mL), and p-toluenesulfonyl chloride (136 mg) and N-methylimidazole (87.0 mL) were then added to the obtained solution. The obtained mixture was stirred at room temperature for approximately 20 hours. Thereafter, the reaction mixture was purified by silica gel column chromatography to obtain the title compound (107 mg, yield: 38%) in the form of powder.
Reaction SMILES: [C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[C:18]([OH:29])=[CH:19][C:20]4[O:25][CH2:24][C:23](=[O:26])[N:22]([CH3:27])[C:21]=4[CH:28]=3)[C:9]2=[O:30])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:37]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:31]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:17]4[C:18](=[CH:19][C:20]5[O:25][CH2:24][C:23](=[O:26])[N:22]([CH3:27])[C:21]=5[CH:28]=4)[O:29][CH2:37]3)[C:9]2=[O:30])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Reactant: CN1C(=O)COc2cc(O)c(C3C(=O)N(C(c4ccccc4)c4ccccc4)c4ccccc43)cc21
Product: CN1C(=O)COc2cc3c(cc21)C1(CO3)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 6-[1-(diphenylmethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-7-hydroxy-4-methyl-2H-1,4-benzoxazin-3(4H)-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(diphenylmethyl)-1-methyl-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indole]-2,2′(1′H,3H)-dione was obtained (32%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ7.47-7.23 (m, 11H), 7.19-7.10 (m, 1H), 7.07-6.98 (m, 1H), 6.88 (s, 1H), 6.72 (s, 1H), 6.64 (d, J=7.9 Hz, 1H), 6.20 (s, 1H), 4.93 (d, J=9.4 Hz, 1H), 4.82 (d, J=9.4 Hz, 1H), 4.57 (s, 2H), 3.01 (s, 3H); MS (ES+) m/z 489.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.O[C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:16]3[CH2:17][CH2:12][CH2:13][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](O)C1
Reactant: Clc1ncnc2[nH]ccc12
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](n2ccc3c(Cl)ncnc32)C1
Temperature: 25 °C
Yield: 9.6 %

Procedure:
To the solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (10 g, 65.12 mmol, 1.0 eq) and (S)-tert-butyl 3-hydroxypiperidine-1-carboxylate (13.0 g, 65.12 mmol, 1.0 eq) and PPh3 (34.20 g, 130.24 mmol, 2.0 eq) in THF (400 mL), DEAD (22.68 g, 130.24 mmol, 2.0 eq) was added at 0° C. The resulted mixture was stirred and warmed to RT for 12 h. The reaction mixture was purified by column (10% EtOAc in petroleum ether) to afford (R)-tert-butyl 3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate (2.1 g, 10% in yield) as colorless oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[N:11][C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([CH:32]=3)[CH2:19][CH2:20][C:21]3[CH:29]=[C:25]([NH:26][C:27]=1[N:28]=2)[CH:24]=[CH:23][C:22]=3[CH2:30]O.[NH2:33][C@H:34]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[N:11][C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([CH:32]=3)[CH2:19][CH2:20][C:21]3[CH:29]=[C:25]([NH:26][C:27]=1[N:28]=2)[CH:24]=[CH:23][C:22]=3[CH2:30][NH:33][C@H:34]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35]1
Reactant: OCc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CC[C@H](NCc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)C1
Yield: 47 %

Procedure:
The desired compound was prepared according to the procedure of Example B191 step A, using [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]methanol trifluoroacetate and tert-butyl (3S)-3-aminopyrrolidine-1-carboxylate as the starting materials in 47% yield. LCMS for C28H34ClN6O2(M+H)+: m/z=521.3.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15](=[O:23])[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)=[O:5].C=O.[CH2:30](O)C>[OH-].[Na+].O>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]([CH:12]2[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][N:6]3[C:4](=[O:5])[C:3]4[C:2](=[CH:27][CH:26]=[CH:25][CH:24]=4)[NH:1][CH2:30]3)[CH2:14][CH2:13]2)=[O:23])=[CH:21][CH:20]=1
Reactant: CCO
Reactant: Nc1ccccc1C(=O)NCCN1CCC(C(=O)c2ccc(F)cc2)CC1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(c1ccc(F)cc1)C1CCN(CCN2CNc3ccccc3C2=O)CC1
Temperature: 25 °C
Yield: 50 %

Procedure:
A mixture of 6.5 parts of 2-amino-N-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]benzamide, 0.5 parts of paraformaldehyde, 3 drops of sodium hydroxide solution 50%, 80 parts of ethanol and 10 parts of water is stirred and refluxed overnight. The reaction mixture is allowed to cool to room temperature while stirring. The precipitated product if filtered off, washed with ethanol and crystallized from 200 parts of ethanol, yielding 3.3 parts (50%) of 3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,3-dihydro-4(1H)-quinazolinone; mp. 203.4° C.