Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:14][CH2:13][S:12][CH:11]2[C:15](O)=[O:16])(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:27])=O.CN(C=O)C>C(Cl)Cl>[C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:14][CH2:13][S:12][CH:11]2[C:15]([Cl:27])=[O:16])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: O=C(O)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1
Temperature: -10 °C
Yield: 100 %

Procedure:
Intermediate VIII (Scheme 3), e.g., 3-(biphenyl-4-ylsulfonyl)-1,3-thiazolidine-2-carboxylic acid (1.747 g, 5 mmol) was dissolved in DCM (20 mL). The resulting solution was cooled down to −10° C. and oxalyl chloride (0.645 mL, 7.5 mmol) was added slowly. DMF (0.1 mL) was added carefully. The reaction mixture was allowed to warm to RT over 1 h and stirred an additional hour at RT. As the reaction was complete, the solvents were evaporated. Toluene was added and evaporated to remove residual oxalyl chloride. This process was repeated twice, affording intermediate XXX, e.g., 3-(biphenyl-4-ylsulfonyl)-1,3-thiazolidine-2-carbonyl chloride as a yellow solid (1.839 g, quantitative yield). α-Aminophenylacetic acid (831 mg, 5.5 mmol) was dissolved in water (20 mL). TEA (2.77 mL, 20 mmol) was added carefully. THF (25 mL) was added to reaction mixture. The reaction mixture was cooled to 0° C. Acid chloride previously prepared XXX, e.g. 3-(biphenyl-4-ylsulfonyl)-1,3-thiazolidine-2-carbonyl chloride dissolved in THF (25 mL) was added dropwise. The reaction mixture was stirred 15 min at 0° C. and overnight at RT. Solvents were concentrated and the resulting aqueous fraction was acidified with HCl 5N and extracted with 3 portions of EtOAc. Combined organic phases were dried over MgSO4, filtrated and evaporated. The crude product was recrystallized in acetone/Et2O mixture, affording carboxylic acid Ia, e.g., ({[3-(biphenyl-4-ylsulfonyl)-1,3-thiazolidin-2-yl]carbonyl}amino)(phenyl)acetic acid in 97% purity by HPLC (943 mg, 39% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:36])[CH2:15][N:16]3[C:20]4[CH:21]=[CH:22][C:23]([O:25][CH2:26][CH2:27][O:28]C5CCCCO5)=[CH:24][C:19]=4[O:18][C:17]3=[O:35])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:37][CH3:38].C(O)(C(F)(F)F)=O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:36])[CH2:15][N:16]3[C:20]4[CH:21]=[CH:22][C:23]([O:25][CH2:26][CH2:27][OH:28])=[CH:24][C:19]=4[O:18][C:17]3=[O:35])[CH2:12][CH2:13]2)=[CH:4][C:3]=1[O:37][CH3:38]
Reactant: COc1cc(N2CCN(C(=O)Cn3c(=O)oc4cc(OCCOC5CCCCO5)ccc43)CC2)ccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COc1cc(N2CCN(C(=O)Cn3c(=O)oc4cc(OCCO)ccc43)CC2)ccc1Cl

Procedure:
To a solution of 3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-6-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-3H-benzooxazol-2-one (55) (50 mg) in THF was added 1 mL of TFA and the resultant solution was stirred for 1 hour. The reaction mixture was purified by HPLC to provide 3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-6-(2-hydroxy-ethoxy)-3H-benzooxazol-2-one (56): LCMS observed for (M+H)+: 462.5.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([CH2:21][C:22](OC)([O:24]C)[CH3:23])[C:13]=1[F:28]>CC(N(C)C)=O.Cl>[C:22]([CH2:21][C:14]1[C:13]([F:28])=[C:12]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:17]=[CH:16][C:15]=1[N+:18]([O-:20])=[O:19])(=[O:24])[CH3:23]
Reactant: OCc1ccccc1
Reactant: COC(C)(Cc1c([N+](=O)[O-])ccc(F)c1F)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(=O)Cc1c([N+](=O)[O-])ccc(OCc2ccccc2)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.3 %

Procedure:
To a solution of benzyl alcohol (221 mg, 2.05 mmol) in DMA (1.5 ml) was added 60% sodium hydride (82 mg, 2.05 mmol). The mixture was stirred for 1 hour at ambient temperature. A solution of 1,2-difluoro-3-(2,2-dimethoxypropyl)-4-nitrobenzene (534 mg, 2.05 mmol) in DMA (1.5 ml) was added and the mixture was stirred for 3 hours at ambient temperature. The mixture was diluted with 1N hydrochloric acid (10 ml) and extracted with ethyl acetate. The organic layer was evaporated and the residue was dissolved in THF (2 ml) and 6N hydrochloric acid (0.3 ml) was added. The mixture was stirred for 1 hour at ambient temperature and the solvents were removed under vacuum. The residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated. The solid was triturated with ether, filtered, washed with ether and dried under vacuum to give 3-acetylmethyl-1-benzyloxy-2-fluoro-4-nitrobenzene (350 mg, 56%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH2:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O)[CH3:2].C(Cl)(=O)C(Cl)=O.[Sn].[Cl-].[CH2:24]([C:31]1[O:32][C:33]([CH3:37])=[C:34]([CH3:36])[CH:35]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([C:31]1[O:32][C:33]([CH3:37])=[C:34]([CH3:36])[C:35]=1[C:6]([C:5]1[CH:9]=[C:10]([CH2:14][CH3:15])[C:11]([O:12][CH3:13])=[C:3]([CH2:1][CH3:2])[CH:4]=1)=[O:8])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Cc1cc(Cc2ccccc2)oc1C
Reactant: CCc1cc(C(=O)O)cc(CC)c1OC
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Sn]
Product: CCc1cc(C(=O)c2c(Cc3ccccc3)oc(C)c2C)cc(CC)c1OC

Procedure:
The title compound was prepared according to the procedure in Example 5, step 2, using 3,5-diethyl-4-methoxybenzoic acid (10.66 g, 51.3 mmol), oxalyl chloride (4.90 mL, 56.3 mmol), N,N-DMF (2 drops), tin TV chloride (6.60 mL, 56.3 mmol) and 2-benzyl-4,5-dimethylfuran (11.4 g, 61.3 mmol) to give 22.0 g, of the title compound. 1H NMR δ1.13 (t, 6 H), 1.83 (s, 3 H), 2.19 (s, 3 H), 2.61 (q, 4 H), 3.74 (s, 3 H), 3.82 (s, 2 H), 7.05 (d, 2 H), 7.23-7.27 (m, 3 H), 7.42 (s, 2 H). mass spectrum (EI), m/z 376 (M+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH2:10][CH2:11][CH3:12])=[C:6]([CH:8]=1)[NH2:7].[C:13](OCC)(=[O:18])[CH2:14][C:15]([CH3:17])=O>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH2:10][CH2:11][CH3:12])=[C:6]2[C:8]=1[C:13](=[O:18])[CH:14]=[C:15]([CH3:17])[NH:7]2
Reactant: CCCOc1ccc(F)cc1N
Reactant: CCOC(=O)CC(C)=O
Solvent: c1ccccc1
Product: CCCOc1ccc(F)c2c(=O)cc(C)[nH]c12
Temperature: 25 °C
Yield: 43.2 %

Procedure:
Amberlyst 15 (1.0 g, a product of Sigma Aldrich Corp.) was added to a benzene solution (200 ml) of 5-fluoro-2-propoxyaniline (10 g, 59 mmol) and ethyl acetoacetate (7.7 g, 59 mmol). The mixture was stirred while heating under reflux for 6 hours and using a Dean-Stark trap. The reaction mixture was cooled to room temperature, the resin was removed by filtration, and the filtrate was concentrated under reduced pressure. Diphenyl ether (20 ml) was added to the residue. The mixture was heated using a mantle heater and stirred under reflux for 2 hours. After the reaction mixture was cooled to room temperature, insoluble matter obtained by the addition of n-hexane-ethyl acetate (2:1) was collected by filtration. The substance remaining on the filter was washed with n-hexane-ethyl acetate (2:1), and dried to thereby obtain 6.0 g of powdery pale yellow 5-fluoro-2-methyl-8-propoxy-1H-quinolin-4-one (yield: 43%).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1.[Cl:21][C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([NH2:29])[N:23]=1>>[Cl:21][C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([NH:29][CH2:3][C:4]2[N:8]3[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]3=[N:6][C:5]=2[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[N:23]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: Cc1ccc2nc(-c3ccc(F)cc3)c(CCl)n2c1
Agent: Cl
Product: Cc1ccc2nc(-c3ccc(F)cc3)c(CNc3nc(C)cc(Cl)n3)n2c1

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 139 from 3-(chloromethyl)-2-(4-fluorophenyl)-6-methylimidazo[1,2-a]pyridine hydrochloride and 4-chloro-6-methylpyrimidin-2-amine. H-NMR (400 MHz, CDCl3) 8.021 (s, 1H), 7.73 (m, 2H), 7.51 (d, J=9.164 Hz, 1H), 7.10 (m, 2H), 6.50 (s, 1H), 5.28 (broad, 1H, D, NH), 4.98 (d, J=5.032 Ha, 2H, D, CH2), 2.29 (s, 3H, D, CH3), 2.26 (s, 3H) ppm; m/e+ 382.0, 384.1 for C20H17ClFN5 (M+H)+
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[N:5]1[C:12]([Cl:13])=[N:11][C:9](Cl)=[N:8][C:6]=1[Cl:7].Cl>C(OCC)C.C1(C)C=CC=CC=1>[Cl:7][C:6]1[N:5]=[C:12]([Cl:13])[N:11]=[C:9]([CH2:1][CH3:2])[N:8]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CC[Mg]Br
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCc1nc(Cl)nc(Cl)n1
Reaction time: 1 h
Yield: 63 %

Procedure:
1.5 equivalent of ethylmagnesium bromide dissolved in diethyl ether (prepared by reacting magnesium with ethyl bromide) are added dropwise to a suspension of one equivalent of cyanuric chloride in toluene, while keeping the temperature of the reaction mixture between 10° and 15° C. After the addition, this mixture is kept at room temperature for one hour. An aqueous solution containing 1.5 equivalent of hydrochloric acid is then added. The two phases are separated, the organic phase is dried over sodium sulfate, then the solvent is removed under reduced pressure. 2,4-dichloro-6-ethyl-1,3,5-triazine is purified by distillation under reduced pressure. Yield: 63%. B.P.: 83° C./17 mbars.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[Li+].CC([N-]C(C)C)C.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[CH2:8]([O:7][C:1](=[O:6])[CH2:2][C:3](=[O:4])[CH2:5][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:9]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)CC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CCc1ccccc1
Reaction time: 0.5 h

Procedure:
Ethyl acetoacetate (2.32 g, 20 mmol) is added to a pre-cold solution of LDA (2.0 M, 20 mL, 40 mmol) in THF (100 mL) at 0° C. After addition, the mixture is stirred for 30 min, then benzyl bromide (3.42 g, 20 mmol) is added dropwise. After stirred at 0° C. for 30 min, the reaction is quenched by 5 N HCl, extracted with ethyl ether. The combined organic layers are washed with water and brine until it is neutral.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH:10]2[CH2:27][CH:26]3[CH:12]([C:13](=[O:33])[N:14]([CH3:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH:20][CH:21]4[C:23]([C:29](O)=[O:30])([NH:24][C:25]3=[O:28])[CH2:22]4)[CH2:11]2)[CH:6]=[C:5]([O:34][CH3:35])[N:4]=1.[CH:36]1([S:39]([NH2:42])(=[O:41])=[O:40])[CH2:38][CH2:37]1.CCN=C=NCCCN(C)C.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH:10]2[CH2:27][CH:26]3[CH:12]([C:13](=[O:33])[N:14]([CH3:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH:20][CH:21]4[C:23]([C:29]([NH:42][S:39]([CH:36]5[CH2:38][CH2:37]5)(=[O:41])=[O:40])=[O:30])([NH:24][C:25]3=[O:28])[CH2:22]4)[CH2:11]2)[CH:6]=[C:5]([O:34][CH3:35])[N:4]=1
Reactant: COc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)nc(OC)n1
Reactant: NS(=O)(=O)C1CC1
Agent: CCN=C=NCCCN(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COc1cc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4C=CCCCCN(C)C(=O)C3C2)nc(OC)n1
Yield: 52.1 %

Procedure:
The acid 18g (1.2 g, 2 mmol) was reacted with cyclopropane sulfonamide (73 mg, 0.6 mmol), EDAC (115 mg, 0.6 mmol) and DBU (215 mg, 1.4 mmol) in dry DCM (3 ml) according to the procedure described in Example 13 step f. Purification by column chromatography on silica gel eluted with diethyl ether-ethyl acetate gave the title compound, (185 mg, 70%), (M+H)+592.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: Clc1ccc(CBr)cc1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3ccc(Cl)cc3)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-4-chlorobenzene and isolated as white solid (5.1 mg, 31%). MS (m/e): 407.4 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]=[N:4][C:5]1[CH:6]=[CH:7][C:8]([C:15]([O:17][CH3:18])=[O:16])=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:10]=1.[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([NH:30][C:31](OC2C=CC=CC=2)=[O:32])[N:23]=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH3:29][O:28][C:26]1[CH:27]=[C:22]([O:21][CH3:20])[N:23]=[C:24]([NH:30][C:31]([NH:14][S:11]([C:9]2[CH:10]=[C:5]([N:4]=[CH:3][N:2]([CH3:19])[CH3:1])[CH:6]=[CH:7][C:8]=2[C:15]([O:17][CH3:18])=[O:16])(=[O:13])=[O:12])=[O:32])[N:25]=1
Reactant: COC(=O)c1ccc(N=CN(C)C)cc1S(N)(=O)=O
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1ccc(N=CN(C)C)cc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 0 °C

Procedure:
A suspension of 1.50 g of 5-(2-dimethylamino-1-azaethenyl)-2-methoxycarbonylbenzenesulfonamide, 1.61 g of 4,6-dimethoxy-2-phenoxycarbonylaminopyrimidine, 32 ml of acetonitrile and 0.83 ml of DBU is stirred initially at 0° C. and then at room temperature until the reaction has ended. The reaction mixture is then concentrated under reduced pressure. The residue is taken up in water and washed with diethyl ether. The aqueous phase is carefully acidified with conc. hydrochloric acid (pH 6) and the sulfonylurea precipitate is separated off, washed with diisopropyl ether and water and dried. This affords 1.89 g of the desired sulfonylurea, melting point 73-75° C.;
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23]C)[CH:19]=3)[C:14]=2[O:25][C:26]2[CH:40]=[CH:39][C:29]([O:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:28][CH:27]=2)[CH:5]=[C:6]([F:12])[C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[ClH:41].B(Br)(Br)Br>C(OC(=O)C)C.C(OCC)C>[ClH:41].[F:1][C:2]1[CH:3]=[C:4]([C:13]2[C:14]([O:25][C:26]3[CH:27]=[CH:28][C:29]([O:30][CH2:31][CH2:32][N:33]4[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]4)=[CH:39][CH:40]=3)=[C:15]3[C:20](=[CH:21][CH:22]=2)[CH:19]=[C:18]([OH:23])[CH:17]=[CH:16]3)[CH:5]=[C:6]([F:12])[C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3cc(F)c(S(C)(=O)=O)c(F)c3)ccc2c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1c(F)cc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1F
Temperature: 0 °C
Yield: 20 %

Procedure:
Dissolve the compound of Example 79 in ethylacetate (10 mL) and diethyl ether (5 mL). Add 2M HCl in diethyl ether (0.1 mL, 0.2 mmol). Concentrate the slurry and dry in vacuo. Dilute the residue in dichloromethane (5.0 mL) and blanket with nitrogen. Cool the solution to 0° C. with an external ice bath. Add BBr3 (0.1 mL, 1.1 mmol) and stir for 1 hour. Quench with water (1.0 mL) and dilute with dichloromethane (10 mL). Separate the layers, wash the organic layer with saturated aqueous NaHCO3(10 mL) and brine (10 mL). Dry with MgSO4, filter, and concentrate in vacuo. Chromatograph the residue on a column eluting the 6-(3,5-difluoro-4-methanesulfonyl-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-ol with a step gradient of methanol/dichloromethane (0 to 5%). Dissolve the free base in diethyl ether (5.0 mL) and ethyl acetate (6.0 mL). Add 2M HCl in diethyl ether (0.1 mL, 0.2 mmol). Collect the precipitate on filter paper and rinse with diethyl ether to give 31 mg of the title compound (20%): mass spectrum (ion spray): m/z: 554.3 (M+H−HCl).
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]2[CH:27]=[C:28]3[C:32](=[C:33]([CH3:35])[CH:34]=2)[NH:31][N:30]=[CH:29]3)[CH:20]=1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:35][C:33]1[CH:34]=[C:26]([O:25][C:21]2[N:22]=[CH:23][N:24]=[C:19]([N:14]3[CH2:13][CH2:12][C:5]4([O:4][C:3](=[O:17])[NH:2][C:7]5[N:8]=[CH:9][CH:10]=[CH:11][C:6]4=5)[CH2:16][CH2:15]3)[CH:20]=2)[CH:27]=[C:28]2[C:32]=1[NH:31][N:30]=[CH:29]2
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2cn[nH]c12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Oc2cc(N3CCC4(CC3)OC(=O)Nc3ncccc34)ncn2)cc2cn[nH]c12

Procedure:
60 mg (0.23 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 60 mg (0.23 mmol) 5-(6-chloropyrimidin-4-yloxy)-7-methyl-1H-indazole and 100 μL (0.58 mmol) DIPEA in 0.8 mL DMF were stirred at RT over the weekend. The reaction mixture was purified by chromatography. The fractions containing product were combined and evaporated down i.vac. to leave the aqueous residue. This was neutralised with an aqueous saturated NaHCO3 solution. The precipitate formed was suction filtered and dried.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH2:6]([O:8][C:9](=[O:18])[CH2:10][C:11](=[O:17])[C:12]([CH3:16])([CH3:15])[CH:13]=[CH2:14])[CH3:7]>C(Cl)(Cl)Cl>[CH2:6]([O:8][C:9](=[O:18])[CH:10]([Cl:4])[C:11](=[O:17])[C:12]([CH3:16])([CH3:15])[CH:13]=[CH2:14])[CH3:7]
Reactant: C=CC(C)(C)C(=O)CC(=O)OCC
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: C=CC(C)(C)C(=O)C(Cl)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
Sulfuryl chloride (0.84 ml, 10.4 mmol) was added to a cooled (0°) solution of 4,4-dimethyl-3-oxo-hex-5-enoic acid ethyl ester (1.83 g, 9.93 mmol) in chloroform (7 ml). The resulting mixture was allowed to warm to room temperature and stir for 30 min, after which it was heated under reflux for 2 h. After cooling to room temperature the reaction mixture was diluted with chloroform, then was washed with sodium bicarbonate, water then brine. The organic phase was dried and evaporated to afford, as a brown oil, 2-chloro-4,4-dimethyl-3-oxo-hex-5-enoic acid ethyl ester (2.01 g, 93%). (Hayashi et al., J. Org. Chem., 65:8402-8405 (2000).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].O[CH2:7][CH2:8][CH:9]1[CH:15]=[CH:14][N:13]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:39])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C:12]2[CH:40]=[CH:41][CH:42]=[CH:43][C:11]=2[S:10]1>C(N(CC)CC)C>[CH3:1][S:2]([CH2:7][CH2:8][CH:9]1[CH:15]=[CH:14][N:13]([S:16]([C:19]2[CH:20]=[CH:21][C:22]([NH:25][C:26](=[O:39])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:23][CH:24]=2)(=[O:18])=[O:17])[C:12]2[CH:40]=[CH:41][CH:42]=[CH:43][C:11]=2[S:10]1)(=[O:4])=[O:3]
Reactant: O=C(Nc1ccc(S(=O)(=O)N2C=CC(CCO)Sc3ccccc32)cc1)c1ccccc1-c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)CCC1C=CN(S(=O)(=O)c2ccc(NC(=O)c3ccccc3-c3ccccc3)cc2)c2ccccc2S1

Procedure:
Methanesulfonyl chloride (0.02 ml, 0.278 mM) was added to Compound 19 as prepared in Example 26 (0.151 g, 0.278 mM) and triethylamine (0.07 ml, 0.55 mM) following the procedure described in Example 29 to give the solid product. m/z (MH+) 623.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][SH:4].[CH2:7]([OH:10])[C:8]#[CH:9].[OH-].[K+].CN(C)C=O>O>[OH:10][CH2:7][CH:8]=[CH:9][S:4][CH2:3][C:2]([F:6])([F:5])[F:1]
Reactant: FC(F)(F)CS
Reactant: C#CCO
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: OCC=CSCC(F)(F)F
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 2.32 g 2,2,2-trifluoroethanethiol, 1.12 prop-2-yne-1-ol, 300 mg potassium hydroxide and 40 ml dimethylformamide is stirred at ambient temperature for 20 hours. The mixture is poured into 150 ml of water and extracted with 100 ml ethyl acetate (3 times). The organic phase is washed with water, dried and concentrated. The crude product is purified by column chromatography to obtain 75 mg of pure 1-hydroxy-3-(2,2,2-trifluoroethylthio)-prop-2-ene.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[CH2:22][CH2:23][CH3:24].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH2:21]([N:11]1[CH2:12][CH2:13][C:9]([C:4]2[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=2)([OH:14])[CH2:10]1)[CH2:22][CH2:23][CH3:24]
Reactant: OC1(c2cc(F)cc(F)c2)CCNC1
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: CCCCN1CCC(O)(c2cc(F)cc(F)c2)C1
Temperature: 120 °C
Yield: 55.3 %

Procedure:
In a sealed tube a mixture of enantiomer E1 of 3-(3,5-difluorophenyl)pyrrolidin-3-ol (0.18 g, 0.92 mmol), acetonitrile (5 mL), potassium carbonate (0.25 g, 1.84 mmol) and n-butylbromide (0.1 mL, 1.01 mmol) was heated under microwave irradiation at 120° C. for 45 min. Aqueous sodium carbonate (10%, 5 mL) was added and the aqueous phase was extracted with ethyl acetate (2×50 mL), the combined organic phase was dried (Na2SO4) and evaporated. Purification on a Biotage Isolute SCX-3 SPE column (washed with methanol and eluted with methanol/triethylamine, 4:1) and by flash chromatography on silica gel (ethyl acetate/methanol, 7:1) gave the title compound (0.13 g). [α]D=+21.9° (methanol). The amine was converted to the oxalic acid salt and recrystallized from methanol/diisopropyl ether: M.p. 146-147° C.; MS m/z (relative intensity, 70 eV) 255 (M+, 5), 212 (bp), 98 (66), 57 (51), 182 (39), 127 (18).
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH2:5][C:6]1[O:12][C:9]([CH2:10]O)=[CH:8][CH:7]=1)[CH3:4].S(Cl)([Cl:15])=O.CS(O)(=O)=O>C(#N)C>[ClH:15].[CH3:2][N:3]([CH2:5][C:6]1[O:12][C:9]([CH2:10][Cl:1])=[CH:8][CH:7]=1)[CH3:4]
Reactant: O=S(Cl)Cl
Reactant: CN(C)Cc1ccc(CO)o1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CC#N
Product: CN(C)Cc1ccc(CCl)o1
Temperature: 10 °C

Procedure:
Combine 5-[(dimethylamino)methyl]-furfuryl alcohol hydrochloride (1.72 kg, 8.97 mol) and acetonitrile (4.3 L). Cool to about 10° C. Add thionyl chloride (1.02 kg, 8.54 mol) dropwise, while maintaining the temperature of the reaction at below about 40° C. After the addition of thionyl chloride is complete, add methanesulfonic acid (1.3 kg, 13.5 mol). Distill to remove about 1.8 L of distillate to give the title compound as a solution.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([C:12]([OH:14])=O)[CH3:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C([NH:22][C@H:23]([C:28]([NH2:30])=[O:29])[CH2:24][CH2:25][CH2:26][CH3:27])(OC(C)(C)C)=O>>[Cl:8][C:6]1[CH:5]=[C:4]([NH:9][CH:10]([C:12]([NH:30][C:28](=[O:29])[C@@H:23]([NH2:22])[CH2:24][CH2:25][CH2:26][CH3:27])=[O:14])[CH3:11])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(N)=O
Reactant: CC(Nc1cc(Cl)cc(Cl)c1)C(=O)O
Product: CCCC[C@H](N)C(=O)NC(=O)C(C)Nc1cc(Cl)cc(Cl)c1

Procedure:
Following General Procedure D and using N-(3,5-dichlorophenyl)-D,L-alanine (from Example B above) and L-norleucine amide (fronm Example F above), the title compound was prepared. The reaction was monitored by tlc (Rf=0.15 in 3% methanol/dichloro methane) and purification of this compound was by thin layer chromatography with 3% methanol/dichloromethane.