Azzindani/Open_Reaction_Data huggingface dataset:
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: Clc1ncnc2[nH]ccc12
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](O)C1
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: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])=[O:2].CC1(C)C(C2C=C(C=CC=2[O:30][S:31]([C:34]([F:37])([F:36])[F:35])(=O)=[O:32])C(OC)=O)=CCC1>>[CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][S:31]([C:34]([F:37])([F:36])[F:35])(=[O:32])=[O:30])[C:6]([O:8][CH3:9])=[O:7])=[O:2]
Reactant: COC(=O)c1ccc(O)c(C=O)c1
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C2=CCCC2(C)C)c1
Product: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C=O)c1

Procedure:
Compound 66.41B was synthesized from methyl 3-formyl-4-hydroxybenzoate 66.41A (commercially available from Aldrich) using a method analogous to the method used to prepare compound 66.6I from 66.6H. MS ESI m/e: 313.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[C:12]([CH3:17])=[CH:13][NH:14][C:15](=O)[C:6]=3[C:5]=2[CH:4]=1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:15]1[C:6]2[C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][C:9]=3[NH:8][C:7]=2[C:12]([CH3:17])=[CH:13][N:14]=1
Reactant: COc1ccc2[nH]c3c(C)c[nH]c(=O)c3c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2[nH]c3c(C)cnc(Cl)c3c2c1

Procedure:
7 g of 1,2-dihydro-8-methoxy-4-methyl-1-oxo-5H-pyrido(4,3-b)indole is heated in 200 ml of phosphorus oxychloride at reflux for 3 days and the excess of oxychloride is evaporated off under reduced pressure. The residue is taken up in 100 ml of boiling water, the mixture is heated to boiling point for 3 minutes and filtered. The filtrate is alkalized cold with ammonia and the precipitate formed is separated, dried, then recrystallized from acetonitrile, giving 5.8 g of yellow micro-crystalls.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[CH3:12][N:13]([CH3:27])[CH:14]1[CH2:19][CH2:18][C:17]([C:20]2[CH:21]=[C:22]([NH2:26])[CH:23]=[CH:24][CH:25]=2)=[CH:16][CH2:15]1>>[ClH:1].[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:17]2[CH2:18][CH2:19][CH:14]([N:13]([CH3:27])[CH3:12])[CH2:15][CH:16]=2)[CH:21]=1)=[O:5]
Reactant: CN(C)C1CC=C(c2cccc(N)c2)CC1
Reactant: O=C(Cl)c1c(F)cccc1Cl
Product: CN(C)C1CC=C(c2cccc(NC(=O)c3c(F)cccc3Cl)c2)CC1
Product: Cl
Yield: 147.3 %

Procedure:
Using a method similar to example 1, using 2-chloro-6-fluorobenzoyl chloride (132 mg, 0.69 mmol) and 3-(4-dimethylamino-cyclohex-1-enyl)-phenylamine (preparation 2, 124 mg, 0.57 mmol) provides the title compound (free base 208 mg, 98%). Free base: MS (ES): m/z=373.2 (M+H)+; 1H NMR (CDCl3): δ 7.68 (m, 2H), 7.52 (d, 1H), 7.36 (m, 2H), 7.25 (m, 1H), 7.23 (t, 1H), 7.10 (m, 1H), 6.12 (m, 1H), 2.50 (m, 4H), 2.36 (s, 6H), 2.15 (m, 2H), 1.58 (m, 1H). Hydrochloride salt: Anal. cal'd for C21H22ClFN2O.HCl 0.6H2O: C, 60.03; H, 5.81; N, 6.67. Found: C, 59.75; H, 5.31; N, 6.55.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[CH3:22][C:23]1([CH2:27][NH:28][C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])[CH2:26][NH:25][CH2:24]1.C(N(CC)CC)C>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:25]4[CH2:26][C:23]([CH2:27][NH:28][C:29](=[O:34])[C:30]([F:32])([F:33])[F:31])([CH3:22])[CH2:24]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CC1(CNC(=O)C(F)(F)F)CNC1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC1(CNC(=O)C(F)(F)F)CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Yield: 99.5 %

Procedure:
A mixture of 1 g (3.5 mmoles) of 1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 1.32 g (5.7 mmoles) of 3-methyl-3-trifluoroacetamidomethylazetidine hydrochloride and 2.3 g of triethylamine is heated under reflux in 12 ml of pyridine for 3 hours. The mixture is evaporated, water is added, and the product filtered. 1.6 g (100%) of 1-cyclopropyl-6,8-difluoro-7-(3-trifluoroacetamidomethyl-3-methyl-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are obtained, melting at 232°-7° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH:4](Br)[CH2:5][CH2:6][CH2:7][CH2:8][Cl:9].[O-:12][C:13]#[N:14].[K+].[CH3:16][OH:17]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:11])[CH:4]([NH:14][C:13]([O:17][CH3:16])=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][Cl:9]
Reactant: N#C[O-]
Reactant: COC(=O)C(Br)CCCCCl
Reactant: CO
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)NC(CCCCCl)C(=O)OC
Yield: 50.4 %

Procedure:
12.78 grams of 2-bromo-6-chlorohexanoic acid methyl ester, 6.08 grams of potassium cyanate and 2.72 grams of methanol were heated under powerful stirring in 70 ml of DMF for 1 hour. The reaction mixture was worked up in the manner described in Example 1. There were obtained 6.29 grams (50.3%) of 6-chloro-2-methoxycarbonylaminohexanoic acid methyl ester with boiling point of 113° C./0.0026 mbar.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([S:15]([C:18]3[CH:19]=[CH:20][C:21]([NH2:24])=[N:22][CH:23]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)O1.Cl[C:27]1[N:32]=[CH:31][C:30]([C:33]([OH:42])([C:38]([F:41])([F:40])[F:39])[C:34]([F:37])([F:36])[F:35])=[CH:29][N:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>O>[NH2:24][C:21]1[N:22]=[CH:23][C:18]([S:15]([C:12]2[CH:11]=[CH:10][C:9]([C:27]3[N:28]=[CH:29][C:30]([C:33]([OH:42])([C:34]([F:35])([F:36])[F:37])[C:38]([F:40])([F:41])[F:39])=[CH:31][N:32]=3)=[CH:14][CH:13]=2)(=[O:16])=[O:17])=[CH:19][CH:20]=1
Reactant: OC(c1cnc(Cl)nc1)(C(F)(F)F)C(F)(F)F
Reactant: CC1(C)OB(c2ccc(S(=O)(=O)c3ccc(N)nc3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: Nc1ccc(S(=O)(=O)c2ccc(-c3ncc(C(O)(C(F)(F)F)C(F)(F)F)cn3)cc2)cn1
Temperature: 100 °C
Yield: 32.5 %

Procedure:
A glass microwave reaction vessel was charged with 5-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-2-pyridinamine (262 mg, 0.73 mmol), 2-(2-chloropyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (102 mg, 0.36 mmol, Example X, Intermediate D), (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (15 mg, 0.02 mmol, Strem Chemical Inc, Newburyport, Mass.), cesium carbonate (355 mg, 1.1 mmol, Sigma-Aldrich, St. Louis, Mo.), DME (2 mL), and water (0.2 mL). The reaction mixture was purged with nitrogen for several minutes, and then stirred and heated in an Emrys Optmizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 30 min. The organic layer was taken and the solvent was removed under vacuum. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a silica gel column (12 g), eluting with a gradient of DCM to 3% 2M NH3/MeOH in DCM, to provide 2-(2-(4-((6-amino-3-pyridinyl)sulfonyl)phenyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol (56 mg) as a tan solid.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[C:3](=[N:5][OH:6])[CH3:4].[Li+].[OH-].[CH2:11]1[O:13][CH2:12]1>O>[OH:13][CH2:12][CH2:11][O:6][N:5]=[C:3]([C:2]([CH3:8])([CH3:7])[CH3:1])[CH3:4]
Reactant: C1CO1
Reactant: CC(=NO)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC(=NOCCO)C(C)(C)C
Temperature: 25 °C
Reaction time: 10 h
Yield: 90 %

Procedure:
400 ml of water, 92 g (0.8 mol) of 3,3-dimethylbutan-2-one oxime and 3.4 g of LiOH were initially charged, and 70 g (1.6 mol) of ethylene oxide were introduced such that the gas was taken up completely. Thereafter, the mixture was stirred at room temperature (RT) for 8-12 hours for the continued reaction. The upper phase was removed, admixed with ethyl acetate and washed with water. The organic phase was concentrated under reduced pressure at 100-200 mbar. Residue: 114-120 g of colorless oil, which corresponds to a yield of 90% yield; b.p. 106° C./35 mbar.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[NH:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C@H:20]([N:27]([C:35](=[O:37])[CH3:36])[C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[CH2:19][C@@H:18]2[CH3:38])=[O:16])=[CH:11][CH:10]=1.[H-].[Na+].[CH2:42](I)[CH3:43]>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3](=[O:39])[N:4]([CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([N:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C@H:20]([N:27]([C:35](=[O:37])[CH3:36])[C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)[CH2:19][C@@H:18]2[CH3:38])=[O:16])=[CH:13][CH:14]=1)[CH2:42][CH3:43]
Reactant: CCI
Reactant: COC(=O)NCCCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCN(CCCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 7 h
Yield: 35.1 %

Procedure:
(2S,4R)-[3-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-propyl]-carbamic acid methyl ester (41 mg, 0.074 mmol) was dissolved in THF/DMF (10:1, 3 mL). To this solution was added Sodium Hydride (2 mg, 0.089 mmol), followed by ethyl iodide (14 mg, 0.089 mmol). The reaction was stirred at room temperature for 7 hours and was quenched by adding 1 mL of water. The mixture was concentrated under reduced pressure and dissolved in DCM (15 mL). The reaction mixture was washed with sat. aq. NaHCO3 (15 mL), water (15 mL) and brine (15 mL). The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (5/95 ethyl acetate/hexane—50/50 ethyl acetate/hexane gradient) to afford slightly yellow solid product (15 mg, 35%).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.Br[CH2:12][C:13](=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(O)C>COCCOC>[CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:9]=2)[CH:8]=1
Reactant: CN(C)c1ccc(N)nc1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Solvent: COCCOC
Product: CCOC(=O)c1cn2cc(N(C)C)ccc2n1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
To a suspension of 0.2 g of 5-dimethylaminopyridine-2-amine in 3 mL of DME are added 215 μL of ethyl bromopyruvate. The reaction mixture is stirred at 20° C. for 16 hours and then, after addition of 3 mL of ethanol, for 16 hours at reflux, and finally concentrated under reduced pressure. The residue is filtered on a cartridge of 15 g of silica, eluting with a mixture of dichloromethane and methanol (98/2). The fractions containing the expected product are combined and washed with saturated sodium bicarbonate solution. The organic phase is dried and concentrated to dryness under reduced pressure to give 76 mg of ethyl 6-dimethylaminoimidazo[1,2-a]pyridine-2-carboxylate in the form of a green oil, which is used without further purification in the rest of the synthesis.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][CH:8]([CH2:11]OS(C(F)(F)F)(=O)=O)[CH2:7][C:6]=2[CH:5]=[C:4]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:3]=1.Br[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[Cl:1][C:2]1[C:10]2[O:9][CH:8]([CH2:11][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:7][C:6]=2[CH:5]=[C:4]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:3]=1
Reactant: CCOC(=O)c1cc(Cl)c2c(c1)CC(COS(=O)(=O)C(F)(F)F)O2
Reactant: BrCCc1ccccc1
Product: CCOC(=O)c1cc(Cl)c2c(c1)CC(CCCc1ccccc1)O2
Yield: 58 %

Procedure:
Following the process described in example 3 (point B), starting from ethyl 7-chloro-2-trifluoromethanesulfonyloxymethyl-2,3-dihydrobenzofuran-5-carboxylate and 2-bromoethylbenzene, the title compound was prepared, which was purified by chromatography through a silica gel column, eluting with petroleum ether:ethyl acetate, 95:5 (58% yield).
Reaction SMILES: N1C=CN=C1.[OH:6][CH2:7][C@@H:8]1[NH:12][C:11](=[O:13])[CH2:10][CH2:9]1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C(Cl)Cl>[Si:14]([O:6][CH2:7][C@@H:8]1[NH:12][C:11](=[O:13])[CH2:10][CH2:9]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: O=C1CC[C@H](CO)N1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 15 h
Yield: 115.1 %

Procedure:
Imidazole (5.24 g, 77 mmols) was added to a CH2Cl2 (85 ml) solution of (5R)-5-(hydroxymethyl)-2-pyrrolidinone (4.03 g, 35 mmols). Then, during cooling with ice, a CH2Cl2 (15 ml) solution of tert-butyldimethylsilyl chloride (4.53 g, 30 mmols) was added, and the mixture was stirred for 15 hours at room temperature. The solvent was distilled off under reduced pressure, and then the residue was subjected to silica gel column chromatography (SiO2 300 g, MeOH—CHCl3 5:95 v/v) to obtain (5R)-5-[(tert-butyldimethylsilyloxy)methyl]pyrrolidin-2-one (7.92 g, 98.7%):
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>ClCCl>[N:14]1([S:2]([C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)(=[O:4])=[O:3])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCNC1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: O=C(O)c1ccc(S(=O)(=O)N2CCCC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 30.2 %

Procedure:
To a solution of 4-chlorosulfonylbenzoic acid (2 g, 9.07 mmol) in dichloromethane (10 mL) was added a solution of pyrrolidine (1.29 g, 1.51 mL, 18.1 mmol) in dichloromethane (10 mL) and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered and the white solid obtained was washed with water (50 ml) and diethyl ether (10 ml) and dried under vacuum to give 4-pyrrolidin-1-ylsulfonylbenzoic acid (700 mg, 30%). ESI-MS m/z calc. 255.0. Found 256.3 (M+1)+; Retention time: 1.18 minutes (3 min run); 1H NMR (400 MHz, DMSO) δ 13.49 (s, 1H), 8.15 (d, J=8.5 Hz, 2H), 7.92 (d, J=8.5 Hz, 2H), 3.17 (t, J=6.7 Hz, 4H), 1.65 (t, J=6.7 Hz, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]([OH:15])=[O:14])=[C:6]2[C:11]=1[S:10](=O)[CH2:9][CH2:8][NH:7]2.C(OCC)(=O)C>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]([OH:15])=[O:14])=[C:6]2[C:11]=1[S:10][CH2:9][CH2:8][NH:7]2
Reactant: O=C(O)c1ccc(Cl)c2c1NCCS2=O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)c1ccc(Cl)c2c1NCCS2
Yield: 19.3 %

Procedure:
A mixture of 8-chloro-3,4-dihydro-2H-1,4-benzothiazine-5-carboxylic acid-1-oxide (2.5 g) and stannous chloride dihydrate (4.51 g) in methanol (20 ml) was refluxed for 21 hours. To the reaction mixture was added ethyl acetate (200 ml), washed with water and dried over anhydrous sodium sulfate. After concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography eluting with dichloromethaneethanol (9:1) to give the title compound (450 mg, 19.6%). This compound was recrystallized from ethanol to give yellow needles, mp 220° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([C:17]([CH3:19])=O)[C:15]=2[OH:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:20][C:21]1[CH:30]=[C:29]([C:31]([NH:33][NH2:34])=[O:32])[CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24]>>[Br:20][C:21]1[CH:30]=[C:29]([C:31]([NH:33][N:34]=[C:17]([C:14]2[C:15]([OH:16])=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=3)[S:12][CH:13]=2)[CH3:19])=[O:32])[CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)c1ccc(C(=O)NN)cc1Br
Reactant: CC(=O)c1csc(-c2ccc(C(C)(C)C)cc2)c1O
Product: COC(=O)c1ccc(C(=O)NN=C(C)c2csc(-c3ccc(C(C)(C)C)cc3)c2O)cc1Br

Procedure:
Using 2-(4-t-butylphenyl)-3-hydroxy-4-methylcarbonylthiophene (55 mg, 0.20 mmol) and methyl 2-bromo-4-hydrazinocarbonylbenzoate (60 mg, 0.22 mmol) as the starting materials, the desired product was obtained in the same manner as in Synthetic Example 65 as a yellow solid (92 mg, yield 87%).
Reaction SMILES: C(Cl)Cl.[CH3:4][C:5]([N+:11]([O-:13])=[O:12])([CH3:10])[CH2:6][CH2:7][CH2:8][OH:9].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>O>[CH3:21][S:22]([O:9][CH2:8][CH2:7][CH2:6][C:5]([CH3:10])([N+:11]([O-:13])=[O:12])[CH3:4])(=[O:24])=[O:23]
Reactant: CC(C)(CCCO)[N+](=O)[O-]
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(CCCOS(C)(=O)=O)[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.6 %

Procedure:
Anhydrous DCM (200 mL) was added via canula to a flask containing 4-methyl-4-nitropentanol (12.0 g, 81.8 mmol) under a nitrogen atmosphere. The solution was cooled in an ice bath for 15 minutes and triethylamine (17.1 mL, 1.5 equiv, 123 mmol) was added followed by the addition of methanesulfonyl chloride (8.23 mL, 1.3 equiv, 106 mmol) via syringe over one min. The mixture was stirred for 1 h at 0° C. Then water (100 mL) was added and the layers were separated. The organic layer was washed with 1 M HCl (100 mL), saturated NaHCO3 solution (100 mL) and brine (100 ml). The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give a liquid which crystallized upon addition of a mixture of 20% EA in hexanes (50 mL). The solid was filtered and dried under high vacuum to give a white solid (14.3 g, 78%). 1H NMR (CDCl3, 400 MHz): δ 1.61 (s, 6H), 1.73-1.77 (m, 2H), 2.02-206 (m, 2H), 3.02 (s, 3H), 4.23 (t, 2H). LRMS (ESI+) for C7H15NO5S (225.1); Found: 226 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][S:8][CH2:9][C:10]([CH2:12][S:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=O)=[O:5])[CH3:2].[C:21]([O:25][CH2:26][CH3:27])(=[O:24])[NH:22][NH2:23].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[CH2:26]([O:25][C:21]([NH:22][N:23]=[C:10]([CH2:12][S:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:9][S:8][CH2:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:24])[CH3:27]
Reactant: CCOC(=O)NN
Reactant: CCOC(=O)CCSCC(=O)CSCCC(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Product: CCOC(=O)CCSCC(CSCCC(=O)OCC)=NNC(=O)OCC
Temperature: 25 °C
Reaction time: 48 h
Yield: 91.3 %

Procedure:
A solution of 1,3-bis[(2-ethoxycarbonylethyl)thio]acetone (6.22 g, 19.3 mmol), ethyl carbazate (2.40 g, 23.1 mmol) and a catalytic amount of p-toluenesulfonic acid in anhydrous acetonitrile (50 mL) containing molecular sieve was stirred for 2 days at room temperature. The reaction was quenched with water/ethyl acetate and filtered. The filtrate was extracted with ethyl acetate. The organic extract was washed with aqueous sodium bicarbonate, dried over sodium sulfate, and concentrated. The residue was triturated with hexane, affording 7.2 g of 1,3-bis[(2-ethoxycarbonylethyl)thio]acetone ethoxycarbonylhydrazone. 1H NMR (CDCl3) δ 2.2-2.4 (m, 9), 2.6-2.8 (m, 8H), 3.42 (s, 2H), 3.54 (s, 2H), 4.1-4.3 (m, 6H), 8.82 (br s, 1H).
Reaction SMILES: [N:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:6][CH:5]=1)=[C:2]=[S:3].C(N(CC)CCOC1C=CC(N)=CC=1)C>>[CH2:15]([N:11]([CH2:12][CH3:13])[CH2:10][CH2:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([N:1]=[C:2]=[S:3])=[CH:17][CH:16]=1)[CH3:14]
Reactant: S=C=Nc1ccc(OCCN2CCCC2)cc1
Agent: CCN(CC)CCOc1ccc(N)cc1
Product: CCN(CC)CCOc1ccc(N=C=S)cc1

Procedure:
The title compound is prepared as described in Example 1 for 1-[2-(4-isothiocyanato-phenoxy)-ethyl]-pyrrolidine but using 4-(2-diethylamino-ethoxy)-phenylamine. Title compound: ES-MS: 251.1 [M+H]+; single peak at tR=6.99 min (System 1).
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])(C)(C)C.Br[C:20]1[CH:21]=[C:22]([S:26]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)(=[O:28])=[O:27])[CH:23]=[N:24][CH:25]=1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:18])=[C:10]([C:16]#[C:17][C:20]2[CH:25]=[N:24][CH:23]=[C:22]([S:26]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)(=[O:28])=[O:27])[CH:21]=2)[CH:11]=1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: O=S(=O)(c1cncc(Br)c1)N1CCOCC1
Product: O=C(O)COc1ccc(Cl)cc1C#Cc1cncc(S(=O)(=O)N2CCOCC2)c1

Procedure:
Following the general method as outlined in Example 35, starting from tert-butyl(4-chloro-2-ethynyl phenoxy)acetate (Intermediate 3) and 4-[(5-bromopyridin-3-yl)sulfonyl]morpholine (Apollo), the title compound was obtained as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[CH3:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:25]3[CH:26]=[CH:27][C:22]([CH3:21])=[CH:23][CH:24]=3)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Reactant: Cc1ccc(B(O)O)cc1
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3ccc(C)cc3)o2)c1

Procedure:
Methyl ester (16) (100 mg, 0.30 mmol) was coupled to 4-methyl-phenylboronic acid (44 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound. Yield: 45 mg, 44%; LC/MS tr 1.60 min; MS(ES+) m/z 350 (M+H)
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]3[N:17]=[C:18]([NH2:20])[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]3[N:17]=[C:18]([NH:20][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([N:28]5[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]5)[CH:23]=4)[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2cccc3nc(N)nn23)cc1
Reactant: CN1CCN(c2cccc(Br)c2)CC1
Product: CN1CCN(c2cccc(Nc3nc4cccc(-c5ccc(S(C)(=O)=O)cc5)n4n3)c2)CC1
Yield: 43.2 %

Procedure:
[5-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 5-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75 mg, 0.26 mmol) and 1-(3-bromo-phenyl)-4-methyl-piperazine (73 mg, 0.29 mmol) in a manner analogous to Example 77 to yield [5-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine (52 mg, 43%) as a yellow powder following purification on a 12 g Isco silica gel column using methanol in dichloromethane (0-10%) as eluent. MP=251° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.52 (s, 1H), 8.33 (d, J=8.6 Hz, 2H), 8.12 (d, J=8.6 Hz, 2H), 7.61-7.72 (m, 2H), 7.53 (s, 1H), 7.26 (d, J=7.5 Hz, 1H), 7.07 (t, J=15.0 Hz, 8.6 Hz, 1H), 6.86 (d, J=7.5 Hz, 1H), 6.45 (d, J=7.5 Hz, 1H), 3.33 (s, 3H), 3.04 (s, 4H), 2.44 (s, 4H), 2.22 (s, 3H). MS=463 (MH)+.