Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[NH:16][C@@H:15]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:14][S:13]1.[CH:21]1([CH2:25]Br)[CH2:24][CH2:23][CH2:22]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[N:16]([CH2:25][CH:21]2[CH2:24][CH2:23][CH2:22]2)[C@@H:15]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:14][S:13]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1N[C@@H](CC(C)C)CS1
Reactant: BrCC1CCC1
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SC[C@H](CC(C)C)N1CC1CCC1

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4S)-2-(2-methyl-4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with cyclobutylmethyl bromide according to Method D2a to afford (4S)-2-(2-methyl-4-nitrophenylimino)-4-isobutyl-3-(cyclobutylmethyl)-1,3-thiazolidine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([NH:17][NH2:18])=[O:16]>C(O)C>[Cl:1][C:2]1[C:3]([OH:10])=[C:4]([CH:5]=[N:18][NH:17][C:15](=[O:16])[C:14]2[CH:19]=[CH:20][CH:21]=[C:12]([CH3:11])[CH:13]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Cl)c1O
Reactant: Cc1cccc(C(=O)NN)c1
Solvent: CCO
Product: Cc1cccc(C(=O)NN=Cc2cccc(Cl)c2O)c1
Temperature: 60 °C
Yield: 24.9 %

Procedure:
A suspension of 3-chloro-2-hydroxy-benzaldehyde (0.100 g, 0.639 mmol) and 3-methyl-benzoic acid hydrazide (0.096 g, 0.639 mmol) in ethanol (2 mL) was heated to 60° C. for 18 hours. The reaction mixture was cooled to room temperature to precipitate the product. The solid was collected via suction filtration and rinsed with ethanol to furnish 3-methyl-benzoic acid [1-(3-chloro-2-hydroxy-phenyl)-methylidene]-hydrazide as a white solid (0.046 g, 25%): mp 166-169° C.; 1H NMR (400 MHz, CDCl3) δ 8.59 (d, J=12.0 Hz, 1H), 7.76 (d, J=10.0 Hz, 2H), 7.47 (dd, J=15.6, 6.2 Hz, 4H), 6.97 (t, J=7.8 Hz, 1H), 2.39 (d, J=12.0 Hz, 3H); ESIMS m/z 289 ([M+H]+), 287 ([M−H]−).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:14]([OH:16])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:18][O:19][C:20](=[O:27])[C@H:21]([CH2:23][CH:24]([CH3:26])[CH3:25])[NH2:22].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(N(CC)CC)C.CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:14]([NH:22][C@H:21]([C:20]([O:19][CH3:18])=[O:27])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:16])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)NC(=O)OCc1ccccc1
Temperature: 50 °C

Procedure:
Nα -Benzyloxycarbonyl-D-alanyl-L-leucine, methyl ester is prepared by the following procedure. A solution of 8.92 g. of Nα -benzyloxycarbonyl-D-alanine, 7.28 g. of leucine methyl ester hydrochloride and 5.4 g. of 1-hydroxybenztriazole in 120 ml. of dimethylformamide is cooled to -10° C. with stirring and is treated with 5.6 ml. of triethylamine. The mixture is stirred for ten minutes at -10° C. and is treated with 8.6 g. of dicyclohexylcarbodiimide. The reaction is then stirred at -10° C. for fifteen minutes, brought to 0° C. and stirred to 10° during two hours following which it is stirred overnight at 20° C. The mixture is warmed to 50° C. and stirred for 2 hours.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[F:9].C([N-]C(C)C)(C)C.[Li+].CN(C)[CH:20]=[O:21]>O1CCCC1>[Br:1][C:2]1[C:3]([F:9])=[CH:4][CH:5]=[C:6]([Cl:8])[C:7]=1[CH:20]=[O:21]
Reactant: Fc1ccc(Cl)cc1Br
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1c(Cl)ccc(F)c1Br
Reaction time: 1 h
Yield: 13.3 %

Procedure:
To a −78° C. solution of 2-Bromo-4-chloro-1-fluoro-benzene (2.90 g, 13.9 mmol) in 30 mL tetrahydrofuran under an atmosphere of nitrogen was added lithium diisopropylamide solution (1.8M in tetrahydrofuran/heptane/ethylbenzene, 10.0 mL, 18.0 mmol) at such a rate that the internal reaction temperature did not exceed −69° C. After 1 hour at −78° C., dimethylformamide (1.39 mL, 18.0 mmol) was added at such a rate that the internal temperature did not exceed −69° C. After 30 minutes at −78° C., the reaction was quenched with saturated aqueous ammonium hydroxide solution. The resulting mixture was extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (gradient elution with 0 to 5% ethylacetate/hexanes) to yield 2-Bromo-6-chloro-3-fluoro-benzaldehyde (440 mg, 1.85 mmol). MS (ESI) 236.9 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].N1C=CC=CC=1.[CH3:11][O:12][C:13]1[N:18]=[CH:17][C:16]([C:19]2[S:20][C:21]3[CH:27]=[C:26]([NH2:28])[CH:25]=[CH:24][C:22]=3[N:23]=2)=[CH:15][CH:14]=1>C(Cl)Cl>[CH3:11][O:12][C:13]1[N:18]=[CH:17][C:16]([C:19]2[S:20][C:21]3[CH:27]=[C:26]([NH:28][C:1](=[O:3])[CH3:2])[CH:25]=[CH:24][C:22]=3[N:23]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc(-c2nc3ccc(N)cc3s2)cn1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(-c2nc3ccc(NC(C)=O)cc3s2)cn1
Temperature: 25 °C
Yield: 39.3 %

Procedure:
Acetylchloride (3 μL, 0.037 mmol) and pyridine (3 μL, 0.037 mmol) was added to a sol. of 2-(6-methoxypyridin-3-yl)-1,3-benzothiazol-6-amine (9 mg, 0.034 mmol) in DCM (1 mL). The r.m. was stirred at r.t. o.n. Half of the solvent was distilled of in vacuo and a few drops of hexane were added. The precipitated solid was collected and dried in vacuo, to give the title compound (4 mg) as a white solid. 1H NMR δ 10.30 (s, 1H) 8.91 (d, 1H) 8.57 (d, 1H) 8.39 (dd, 1H) 8.03 (d, 1H) 7.63 (dd, 1H) 7.08 (d, 1H) 4.02 (s, 3H) 2.16 (s, 3H); MS m/z (M+H) 300, (M−H) 298.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.[CH3:11][S:12](C)(=[O:14])=[O:13]>>[CH3:11][S:12]([C:2]1[CH:7]=[C:6]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:4][N:3]=1)(=[O:14])=[O:13]
Reactant: CS(C)(=O)=O
Reactant: CC(=O)c1ccnc(Br)c1
Product: CC(=O)c1ccnc(S(C)(=O)=O)c1

Procedure:
Alternatively, (1-(2-bromo-pyridin-4-yl)-ethanone) could be converted to the corresponding methyl sulfone via the above procedure to afford 1-(2-methanesulfonyl-pyridin-4-yl)-ethanone. 1-(2-Methanesulfonyl-pyridin-4-yl)-ethanone can be converted to the title compound by methods described in example 86.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:6][CH2:7][C:8]1[S:9][C:10]2[N:11]=[C:12]([NH2:23])[N:13]=[C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:15]=2[N:16]=1.[CH3:29][O:30][C:31]1[CH:41]=[CH:40][C:34]([O:35][CH2:36][C:37](O)=[O:38])=[CH:33][CH:32]=1>>[NH2:23][C:12]1[N:13]=[C:14]([N:17]2[CH2:18][CH2:19][N:20]([C:37](=[O:38])[CH2:36][O:35][C:34]3[CH:40]=[CH:41][C:31]([O:30][CH3:29])=[CH:32][CH:33]=3)[CH2:21][CH2:22]2)[C:15]2[N:16]=[C:8]([CH2:7][CH2:6][C:5]3[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:3]([O:2][CH3:1])[CH:4]=3)[S:9][C:10]=2[N:11]=1
Reactant: COc1ccc(OCC(=O)O)cc1
Reactant: COc1ccc(CCc2nc3c(N4CCNCC4)nc(N)nc3s2)cc1OC
Product: COc1ccc(OCC(=O)N2CCN(c3nc(N)nc4sc(CCc5ccc(OC)c(OC)c5)nc34)CC2)cc1
Yield: 71 %

Procedure:
This compound was prepared from 2-(3,4-dimethoxyphenethyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-amine using 4-methoxyphenoxyacetic acid in a yield of 71%, according to the procedure for the synthesis of example 50.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[N:16][C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[N:14]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:13](=[O:30])[C:12]([CH3:31])=[C:11]3[NH:32][C:33](=[O:35])[CH3:34])=[CH:4][CH:3]=1.I[CH3:37]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[N:16][C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[N:14]([CH2:26][CH:27]([CH3:28])[CH3:29])[C:13](=[O:30])[C:12]([CH3:31])=[C:11]3[N:32]([CH3:37])[C:33](=[O:35])[CH3:34])=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1c(C)c(=O)n(CC(C)C)c2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Reactant: CI
Product: CC(=O)N(C)c1c(C)c(=O)n(CC(C)C)c2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12

Procedure:
Using the general procedure of EXAMPLE 12 the product of EXAMPLE 43 was reacted with iodomethane to afford the title compound. HPLC/MS: 542.2 (M+1), 544.2 (M+3); Rt=4.40 min.
Reaction SMILES: [CH3:1][C@:2]12[CH2:10][CH2:9][C:8]3[C:11]4[CH:12]=[CH:13][C:14]([O:19][CH3:20])=[CH:15][C:16]=4[CH2:17][CH2:18][C:7]=3[C:6]1=[CH:5][CH2:4][C:3]2=[O:21]>O1CCOCC1.[Ni]>[CH3:1][C@:2]12[CH2:10][CH2:9][C:8]3[C:11]4[CH:12]=[CH:13][C:14]([O:19][CH3:20])=[CH:15][C:16]=4[CH2:17][CH2:18][C:7]=3[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:21]
Reactant: COc1ccc2c(c1)CCC1=C2CC[C@]2(C)C(=O)CC=C12
Agent: [Ni]
Solvent: C1COCCO1
Product: COc1ccc2c(c1)CCC1=C2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 24 h
Yield: 68.5 %

Procedure:
Dissolve 13β-methyl-3-methoxygona-1,3,5(10),8,14-pentaen-17-one (1 g) in dioxan (33 cc). To the solution add Raney nickel catalyst (ca. 0.5 g) which has been prepared by the method of Pavlic and Adkins, J. Amer. Chem. Soc., 1946, 68, 1471 and allow to stand for 24 hours. Hydrogenate at room temperature and pressure until the theoretical amount of hydrogen (92 cc) for saturation of one ethylenic linkage has been absorbed. Towards the end of this period (5 hours) the rate of hydrogenation drops markedly. Evaporate the solvent after removal of catalyst to obtain a gum which readily crystallizes. Recrystallize once from ethanol to obtain the crude title product (0.69 g), m.p. 110°-120°; ultraviolet absorption peak at 278 mμ (ε14,700).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:20])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([F:19])[CH:13]=3)[O:11][C:6]=2[C:5]([F:21])=[C:4]([CH3:22])[C:3]=1[F:23].[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[C:24]([NH:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[O:11][C:6]3[C:5]([F:21])=[C:4]([CH3:22])[C:3]([F:23])=[C:2]([NH2:1])[C:7]=3[C:8](=[O:20])[CH:9]=2)=[CH:13][C:14]=1[F:19])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(F)c(N)c2c(=O)cc(-c3ccc(N)c(F)c3)oc2c1F
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)c(C)c(F)c3o2)cc1F
Temperature: 50 °C
Reaction time: 18 h
Yield: 99.8 %

Procedure:
2.68 g (8.38 mmol) of Compound 1 obtained in Example 80 (3) was dissolved in 30 mL of pyridine, 0.88 mL (9.2 mmol) of acetic anhydride was added under ice-cooling and the mixture was stirred at 50° C. for 18 hours. The reaction solution was poured into ice water and the precipitated crystals were collected by filtration to give 3.03 g of 2-(4-acetylamino-3-fluorophenyl)-5-amino-6,8-difluoro-7-methyl-4H-1-benzopyran-4-one (yield: 100%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[C:21]([C:24]1[CH:29]=[C:28]([Cl:30])[C:27]([NH:31][C:32](=[O:44])[CH2:33][N:34]2[CH2:39][CH2:38][NH:37][CH:36]([C:40]([NH:42][CH3:43])=[O:41])[CH2:35]2)=[C:26]([Cl:45])[CH:25]=1)(=[O:23])[CH3:22].C(N(CC)CC)C>COCCO>[C:21]([C:24]1[CH:29]=[C:28]([Cl:30])[C:27]([NH:31][C:32](=[O:44])[CH2:33][N:34]2[CH2:39][CH2:38][N:37]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[C:7]3[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=3)[CH:36]([C:40]([NH:42][CH3:43])=[O:41])[CH2:35]2)=[C:26]([Cl:45])[CH:25]=1)(=[O:23])[CH3:22]
Reactant: Fc1ccc(N(CCCCCl)c2ccc(F)cc2)cc1
Reactant: CNC(=O)C1CN(CC(=O)Nc2c(Cl)cc(C(C)=O)cc2Cl)CCN1
Solvent: COCCO
Solvent: CCN(CC)CC
Product: CNC(=O)C1CN(CC(=O)Nc2c(Cl)cc(C(C)=O)cc2Cl)CCN1CCCCN(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 72 h
Yield: 19 %

Procedure:
A mixture of 2.07 parts of N-(4-chlorobutyl)-4-fluoro-N-(4-fluorophenyl)benzenamine, 2.5 parts of N-(4-acetyl-2,6-dichlorophenyl)-3-[(methylamino)carbonyl]-1-piperazineacetamide, 1.3 parts of N,N-diethylethanamine and 97 parts of 2-methoxyethanol was stirred for 3 days at 70° C. The reaction mixture was evaporated and the residue was taken up in water. The product was extracted twice with dichloromethane. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The desired fraction was collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding a first fraction of 0.74 parts (19.0%) of N-(4-acetyl-2,6-dichlorophenyl)-4-[4-[bis(4-fluorophenyl)amino]butyl]-3-[(methylamino)carbonyl]-1-piperazineacetamide; mp. 87.1° C. The second fraction was collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding a second fraction of 0.78 parts (20.1%) of N-(4-acetyl-2,6-dichlorophenyl)-4-[4-[bis(4-fluorophenyl)amino]butyl]-3[(methylamino)carbonyl]-1-piperazineacetamide; mp. 85.0° C. Total yield: 1.52 parts (39.1%) of N-(4-acetyl-2,6-dichlorophenyl)-4-[4-bis(4-fluorophenyl)amino]butyl]-3-[(methylamino)carbonyl]-1-piperazineacetamide (compound 97).
Reaction SMILES: C(Br)C1C=CC=CC=1.[CH3:9][C:10]1[CH:11]=[CH:12][C:13]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[N:14][C:15]=1[CH3:16].C(N(CC)CC)C.[H][H]>C(O)(C)C.[C].[Pd]>[CH3:9][C:10]1[CH:11]=[CH:12][C:13]([C:17]2[CH2:18][NH:19][CH2:20][CH2:21][CH:22]=2)=[N:14][C:15]=1[CH3:16]
Reactant: [H][H]
Reactant: Cc1ccc(-c2cccnc2)nc1C
Agent: [Pd]
Agent: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cc1ccc(C2=CCCNC2)nc1C
Temperature: 50 °C
Reaction time: 5 h
Yield: 19.6 %

Procedure:
Benzyl bromide in an amount of 1.06 g was added to a solution of 1 g of 5,6-dimethyl-2,3′-bipyridine in 15 mL of isopropyl alcohol, and stirred for 5 hours at 50° C. to finish the reaction. To the reaction solution, 0.18 g of 10% palladium carbon and 0.59 g of triethylamine were added. This admixture was put in an autoclave, the autoclave's atmosphere was replaced twice with nitrogen gas under a nitrogen pressure of 196 kPa, and then hydrogen gas was blown into the autoclave over 3 hours at 80° C. under a hydrogen pressure of 196 kPa until the absorption of hydrogen gas in a volume of 400 mL was completed. After the replacement with nitrogen, the catalyst was filtered out and the resulting filtrate was concentrated under a reduced pressure of 1.33 kPa until the quantity thereof was reduced to 1.70 g. Further thereto, 50 mL of water and 10 g of a 25% aqueous solution of sodium hydroxide were added. The resulting solution was extracted with three 200 mL portions of ethyl acetate, and the organic layer was concentrated. The thus obtained solid was adsorbed to NH2-modified silica gel (produced by Biotage Japan, Ltd.), and eluted with ethylacetate. The fraction obtained was concentrated, and the crystals thus deposited were dried to give 0.20 g of the entitled compound as light yellow crystals. Yield rate: 20%, EI-MS: (m/z) 188 (M+), melting point: 102-104° C.
Reaction SMILES: [CH3:1][N:2]1[C:13](=[O:14])[CH2:12][CH:11]([CH3:15])[C@H:3]1[C:4]([O:6]C(C)(C)C)=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH3:1][N:2]1[C:13](=[O:14])[CH2:12][CH:11]([CH3:15])[C@H:3]1[C:4]([OH:6])=[O:5]
Reactant: CC1CC(=O)N(C)[C@@H]1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1CC(=O)N(C)[C@@H]1C(=O)O
Reaction time: 5 h
Yield: 133.6 %

Procedure:
1,1-Dimethylethyl 1,3-dimethyl-5-oxoprolinate (0.770 g, 3.62 mmol) was suspended in dichloromethane (5 ml) and treated with trifluoroacetic acid (0.4 ml, 5.4 mmol). The mixture was stirred for 5 hrs and then evaporated. Azeotroping the resulting residue with toluene then gave unreacted starting material (0.600 g). This was again taken up in dichloromethane (2 ml) and treated with trifluoroacetic acid (2 ml) once more. After stirring for 2 hrs the mixture was evaporated and the residue again azeotroped with toluene (10 ml) to give crude 1,3-dimethyl-5-oxoproline (0.760 g) which was used without any additional purification.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([O:14][CH3:15])=[CH:13][C:8]=3[N:7]=[N:6]2)[CH2:3][CH2:2]1.S(Cl)([Cl:19])(=O)=O>C(O)(=O)C.C(OCC)(=O)C>[Cl:19][C:13]1[C:8]2[N:7]=[N:6][N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[C:9]=2[CH:10]=[CH:11][C:12]=1[O:14][CH3:15]
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1ccc2c(c1)nnn2CC1CC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc2c(nnn2CC2CC2)c1Cl
Temperature: 0 °C
Reaction time: 14 h

Procedure:
1-(Cyclopropylmethyl)-5-methoxy-1H-benzotriazole (10 g, 49 mmol) was dissolved in acetic acid (100 mL), cooled to 0° C. and treated with sulfuryl dichloride (4.8 mL, 59 mmol, 1.2 equiv) over three minutes. The mixture was warmed to ambient temperature over three hours and stirred for an additional 14 hours. The mixture was diluted with ethyl acetate and washed with aqueous saturated sodium bicarbonate. The organic layer was dried with magnesium sulfate, filtered and partially concentrated in vacuo to ˜30 mL, which was then treated with water. The resulting precipitate was filtered, collected and dried in vacuo, providing the titled compound.
Reaction SMILES: [CH:1]([CH:5]1[CH2:16][CH2:15][C:8]2([O:12][CH:11]([CH2:13]Cl)[CH2:10][O:9]2)[CH2:7][CH2:6]1)([CH2:3][CH3:4])[CH3:2].[CH3:17][C@H:18]1[CH2:23][C@@H:22]([CH3:24])[CH2:21][NH:20][CH2:19]1>C(OCC)(=O)C>[CH:1]([CH:5]1[CH2:16][CH2:15][C:8]2([O:12][CH:11]([CH2:13][N:20]3[CH2:21][CH:22]([CH3:24])[CH2:23][CH:18]([CH3:17])[CH2:19]3)[CH2:10][O:9]2)[CH2:7][CH2:6]1)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)C1CCC2(CC1)OCC(CCl)O2
Reactant: C[C@@H]1CNC[C@H](C)C1
Solvent: CCOC(C)=O
Product: CCC(C)C1CCC2(CC1)OCC(CN1CC(C)CC(C)C1)O2
Yield: 75.1 %

Procedure:
24.7 g (0.1 mol) of 8-s-butyl-2-chloromethyl-1,4dioxaspiro [4,5] decane and 45.2 g (0.4 mol) of cis-3,5-dimethylpiperidine are stirred at 140° C. for 16 hours and cooled, 200 ml of ethyl acetate are added, the mixture is washed three times with 200 ml of water each time, dried over sodium sulphate and concentrated in vacuo and the residue is purified by chromatography (silica gel; mobile phase: ethyl acetate). 24.3 g (75% of theory) of 8-s-butyl-2-(3,5-dimethylpiperidin-1-ylmethyl) -1,4-dioxaspiro[4,5] decane are obtained as an oil of refractive index nd20 1.4762.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH3:20])[C@H:13]3[C:14]([F:18])([F:17])[CH2:15][CH2:16][C@H:12]3[O:11][C:10]([NH2:19])=[N:9]2)[CH:7]=1.[F:22][C:23]([C:26]1[N:27]=[CH:28][C:29]([C:32](O)=[O:33])=[N:30][CH:31]=1)([F:25])[CH3:24]>>[NH2:19][C:10]1[O:11][C@@H:12]2[CH2:16][CH2:15][C:14]([F:17])([F:18])[C@@H:13]2[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:32]([C:29]3[CH:28]=[N:27][C:26]([C:23]([F:25])([F:22])[CH3:24])=[CH:31][N:30]=3)=[O:33])[CH:3]=[CH:4][C:5]=2[F:21])([CH3:20])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)O[C@@H]2CCC(F)(F)[C@@H]21
Reactant: CC(F)(F)c1cnc(C(=O)O)cn1
Product: CC(F)(F)c1cnc(C(=O)Nc2ccc(F)c([C@@]3(C)N=C(N)O[C@@H]4CCC(F)(F)[C@@H]43)c2)cn1
Yield: 52 %

Procedure:
The coupling of (4S,4aR,7aR)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-4,4a,5,6,7,7a-hexahydro-cyclopenta[e][1,3]oxazin-2-ylamine (intermediate XIIIa-1) and 5-(1,1-difluoro-ethyl)-pyrazine-2-carboxylic acid (CAS 1262803-63-315) following procedure Q yielded the title compound as a white solid (52% yield). MS: m/z=470.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[NH:13][C:14]1[N:15]=[C:16]([O:39][CH3:40])[C:17]2[C:22]([C:23]3[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]([NH2:30])[CH:24]=3)=[CH:21][N:20]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:18]=2[N:19]=1)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6].[C:41](O)(=O)[CH3:42]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[NH:13][C:14]1[N:15]=[C:16]([O:39][CH3:40])[C:17]2[C:22]([C:23]3[CH:28]=[CH:27][C:26]4[NH:29][C:41]([CH3:42])=[N:30][C:25]=4[CH:24]=3)=[CH:21][N:20]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:36])[CH3:38])[C:18]=2[N:19]=1)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6]
Reactant: CC(=O)O
Reactant: COc1nc(Nc2ccc(C(=O)N(C)C)cc2Cl)nc2c1c(-c1ccc(N)c(N)c1)cn2COCC[Si](C)(C)C
Product: COc1nc(Nc2ccc(C(=O)N(C)C)cc2Cl)nc2c1c(-c1ccc3[nH]c(C)nc3c1)cn2COCC[Si](C)(C)C
Temperature: 115 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
3-Chloro-4-(5-(3,4-diaminophenyl)-4-methoxy-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N,N-dimethylbenzamide (1 equiv) was dissolved in acetic acid (40 equiv) and stirred at 115° C. for 3 h. After the reaction was complete, the solvent was removed under high vacuum. The residue was purified by silica gel column chromatography (10% ethyl acetate in petroleum ether) to afford the title compound (73% yield). MS (ESI) m/z 606.2[M+1]+.
Reaction SMILES: [CH2:1]([C:9]1[CH:21]=[CH:20][C:19]2[C:18]3[C:13](=[CH:14][C:15]([C:22]4[S:23][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[N:25][N:26]=4)=[CH:16][CH:17]=3)[CH2:12][C:11]=2[CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-:33].C[N+](C)(C)CC1C=CC=CC=1>N1C=CC=CC=1>[CH2:1]([C:9]1[C:10](=[O:33])[C:11]2[C:19](=[CH:20][CH:21]=1)[C:18]1[C:13](=[CH:14][C:15]([C:22]3[S:23][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[N:25][N:26]=3)=[CH:16][CH:17]=1)[CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccc2c(c1)Cc1cc(-c3nnc(CCCCCC)s3)ccc1-2
Reactant: [OH-]
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCC1=CC=C2C(=Cc3cc(-c4nnc(CCCCCC)s4)ccc32)C1=O
Temperature: 0 °C
Yield: 53.3 %

Procedure:
To a solution of 0.20 g (0.45 mM) of 2-octyl-7-(5-hexyl-1,3,4-thiadiazole-2-yl)fluorene in 20 ml of pyridine, 0.27 ml of 40%-trimethylbenzylammonium hydroxide aqueous solutions as added at 3.5°-4.5° C. under stirring on ice water bath, followed by stirring for 0.5 hour at 3.5°-4.5° C. After the reaction, the reaction mixture was poured into ice water to precipitate a crystal. The crystal was recovered by filtration, washed with water and dissolved in toluene, followed by drying with anhydrous sodium sulfate and distilling-off of the solvent under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=20/1) and recrystallized from a mixture solvent of toluene-acetone to obtain 0.11 g of 2-octyl-7-(5-hexyl-1,3,4-thiadiazole-2-yl)fluorenone (Yield: 53.3%). ##STR89##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[NH:12][C:11](=[O:13])[C:10]([CH3:14])=[N:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[N:12]=[C:11]([O:13][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:10]([CH3:14])=[N:9]2)=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1cc(Cl)ccn1
Reactant: Cc1nn(-c2ccc(F)cc2)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(-c2ccc(F)cc2)nc1Oc1ccnc(C(F)(F)F)c1
Temperature: 100 °C

Procedure:
To a solution of 2-(4-fluorophenyl)-2,3-dihydro-5-methyl-4H-1,2,3-triazol-4-one (i.e. the product of Step C, 3.1 g, 16 mmol) in N,N-dimethylformamide (70 mL) was added anhydrous potassium carbonate (6.2 g, 45 mmol) under an atmosphere of nitrogen. 4-Chloro-2-trifluoromethyl-pyridine (2.9 g, 16 mmol) was added and the mixture was heated to 100° C. for 20 h. The reaction mixture was diluted with water, then extracted with diethyl ether. The organic layer was washed successively with water and saturated aqueous sodium chloride solution, dried (MgSO4), filtered, and concentrated under reduced pressure. The crude material was purified by chromatography on silica gel eluting with 0 to 20% ethyl acetate in hexanes to obtain the title compound (4.2 g) as a viscous light yellow oil that solidified upon standing to form an off-white solid.