Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]2[CH2:20][CH2:19][C@@:13]3([NH:17][C:16](=[O:18])[O:15][CH2:14]3)[CH2:12]2)=[CH:7][CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:40][O:41][C:42]1[CH:43]=[C:44](O)[CH:45]=[CH:46][CH:47]=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>C1COCC1>[CH3:40][O:41][C:42]1[CH:47]=[C:46]([CH:45]=[CH:44][CH:43]=1)[O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C@@H:11]2[CH2:20][CH2:19][C@@:13]3([NH:17][C:16](=[O:18])[O:15][CH2:14]3)[CH2:12]2)=[CH:9][CH:10]=1
Reactant: O=C1N[C@@]2(CC[C@@H](c3ccc(CCCO)cc3)C2)CO1
Reactant: COc1cccc(O)c1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cccc(OCCCc2ccc([C@@H]3CC[C@]4(COC(=O)N4)C3)cc2)c1
Yield: 70.8 %

Procedure:
To a solution of (5R,7R)-7-(4-(3-hydroxypropyl)phenyl)-3-oxa-1-azaspiro[4.4]nonan-2-one (5.2 g, 18.89 mmol) in THF (150 mL) was added PS-triphenylphosphine 3 mmol/g (7.43 g, 28.3 mmol) followed by 3-methoxyphenol (2.457 mL, 22.66 mmol). After about 10 minutes a solution of di-tert-butylazodicarboxylate (5.22 g, 22.66 mmol) in THF (10 mL) was added. After about 4 hours the reaction mixture was filtered, rinsing with DCM and EtOAc. The filtrate was concentrated in vacuo and purified by chromatography on silica gel (DCM/EtOAc) to provide (5R,7R)-7-(4-(3-(3-methoxyphenoxy)propyl)phenyl)-3-oxa-1-azaspiro[4.4]nonan-2-one (5.1 g, 13.37 mmol, 70.8% yield) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[O:11])[C:5]([CH:23]=O)=[C:4](Cl)[N:3]=1.C(O)(C)C.O.[NH2:31][NH2:32]>O>[NH2:1][C:2]1[N:3]=[C:4]2[NH:31][N:32]=[CH:23][C:5]2=[C:6]([NH:8][CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[O:11])[N:7]=1
Reactant: Nc1nc(Cl)c(C=O)c(NCC(=O)Nc2cccc(C(F)(F)F)c2)n1
Reactant: NN
Solvent: O
Solvent: CC(C)O
Product: Nc1nc(NCC(=O)Nc2cccc(C(F)(F)F)c2)c2cn[nH]c2n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 34.2 %

Procedure:
In a disposable sealed tube was added 2-(2-Amino-6-chloro-5-formyl-pyrimidin-4-ylamino)-N-(3-trifluoromethyl-phenyl)-acetamide (96.0 mg, 0.25 mmol, 1.0 eq.), isopropanol (2.0 mL), and hydrazine monohydrate (0.02 mL, 0.35 mmol, 1.4 eq.). The reaction was sealed and heated to 80° C. After 2 hrs, the reaction was spiked with 0.01 mL of hydrazine monohydrate, resealed, and allowed to continue stirring at 80° C. overnight. The reaction was then cooled to RT and the resulting yellow precipitate was filtered and rinsed with cold EtOH to give crude 2-(6-amino-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)-N-(3-trifluoromethyl-phenyl)-acetamide. The crude precipitate was then sonicated in 1.0 mL H2O, filtered, rinsed with an additional 1 mL H2O, and lyophilized overnight to give pure 2-(6-amino-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)-N-(3-trifluoromethyl-phenyl)-acetamide as a pale yellow solid (30 mg, 34%). LC/MSD (HP Series 1100 MSD): Expected MW: 351, Observed M+H, 352.1, Retention time: 1.19 min. ANALYTICAL HPLC: >90%, Retention time: 3.58 min (8 minute run). 1H-NMR (d6-DMSO): 12.5 (br s, 1H), 10.42 (s, 1H), 8.15 (s, 1H), 7.80 (m, 2H), 7.59 (t, 1H), 7.41 (d, 1H), 6.01 (br s, 2H), 4.40 (rotamer d, 2H) ppm.
Reaction SMILES: [F:1][C:2]([F:25])([C:7]1[CH:12]=[CH:11][C:10](N2C=NC(C3C=CC(C)=CC=3)=N2)=[CH:9][CH:8]=1)[C:3]([F:6])([F:5])[F:4].[F:26][C:27](I)([F:32])[C:28]([F:31])([F:30])[F:29].[Br:34][C:35]1[CH:40]=[CH:39][C:38]([I:41])=[CH:37][CH:36]=1>[Cu].CS(C)=O>[Br:34][C:10]1[CH:11]=[CH:12][C:7]([C:2]([F:25])([F:1])[C:3]([F:6])([F:5])[F:4])=[CH:8][CH:9]=1.[I:41][C:38]1[CH:39]=[CH:40][C:35]([C:27]([F:32])([F:26])[C:28]([F:31])([F:30])[F:29])=[CH:36][CH:37]=1
Reactant: Cc1ccc(-c2ncn(-c3ccc(C(F)(F)C(F)(F)F)cc3)n2)cc1
Reactant: Brc1ccc(I)cc1
Reactant: FC(F)(F)C(F)(F)I
Agent: [Cu]
Solvent: CS(C)=O
Product: FC(F)(F)C(F)(F)c1ccc(Br)cc1
Product: FC(F)(F)C(F)(F)c1ccc(I)cc1

Procedure:
1-(4-Pentafluoroethyl-phenyl)-3-p-tolyl-1H-[1,2,4]triazole. Pentafluoroethyl iodide (521 mg, 2.12 mmol) was condensed into a vial containing 1-bromo-4-iodobenzene (300 mg, 1.06 mmol), copper(0) powder (135 mg, 2.12 mmol), and DMSO (5 mL). The vial was then sealed and subjected to microwave irradiation at 150° C. for 60 min. GC-MS proved consumption of the starting material yielding both 1-bromo-4-pentafluoroethylbenzene and 1-iodo-4-pentafluoroethylbenzene intermediates. The mixture (1.06 mmol) was transferred to a 250 mL round bottom flask and 3-p-tolyl-1H-[1,2,4]triazole (169 mg, 1.06 mmol), Cs2CO3 (1.38 g, 4.24 mmol), CuI (202 mg, 1.06 mmol), 8-hydroxyquinoline (2 mg, 0.011 mmol), and DMF/H2O (12 mL; 10:1 solution) were added. The solution was stirred at reflux at 160° C. for 6 h. Upon completion, the cooled contents were poured into H2O and precipitation was allowed for 1 h. The precipitate was collected by vacuum filtration and dried overnight in a 45° C. vacuum oven. The crude 1-(4-pentafluoroethylphenyl)-3-p-tolyl-1H-[1,2,4]triazole intermediate was used in step 2 without further purification.
Reaction SMILES: [NH2:1][CH:2]([C:4]1([CH:10]([C:16]([F:19])([F:18])[F:17])[CH:11]([CH3:15])[C:12]([OH:14])=[O:13])SCCCS1)[CH3:3].Cl.C(#N)C.CI.[OH2:26]>>[NH2:1][C@H:2]([C:4]([CH:10]([C:16]([F:19])([F:18])[F:17])[CH:11]([CH3:15])[C:12]([OH:14])=[O:13])=[O:26])[CH3:3]
Reactant: CC(C(=O)O)C(C(F)(F)F)C1(C(C)N)SCCCS1
Reactant: O
Agent: Cl
Solvent: CI
Solvent: CC#N
Product: CC(C(=O)O)C(C(=O)[C@H](C)N)C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The above named compound is prepared by treating 317 mg (1 mMole) of 3-[2-(1-aminoethyl)1,3-dithian-2-yl]-4,4,4-trifluoro-2-methylbutyric acid with 1.0 ml of 1 N HCl and 10 ml of acetonitrile followed by treatment with 2 ml of methyl iodide. The mixture is stirred at 25° C. for 48hours then diluted with water. The mixture is then thoroughly washed with ether and the aqueous phase is concentrated to afford 3-alanyl-4,4,4-trifluoro-2-methylbutyric acid.
Reaction SMILES: C([O:9][C@H:10]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][C@@H:11]1[O:41][C@H:42]1[C@@H:60]([O:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[C@H:59]([O:69][CH2:70][C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)[C@@H:58]([CH2:77][O:78][CH2:79][C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=2)[O:57][C@@H:43]1[O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][C:53]([O:55][CH3:56])=[O:54])(=O)C1C=CC=CC=1.[Na]>C1(C)C=CC=CC=1.CO>[CH2:17]([O:16][C@H:15]1[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][C@H:11]([O:41][C@H:42]2[C@@H:60]([O:61][CH2:62][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[C@H:59]([O:69][CH2:70][C:71]3[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=3)[C@@H:58]([CH2:77][O:78][CH2:79][C:80]3[CH:81]=[CH:82][CH:83]=[CH:84][CH:85]=3)[O:57][C@@H:43]2[O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][C:53]([O:55][CH3:56])=[O:54])[C@H:10]1[OH:9])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)CCCCCCCCO[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1O[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)CCCCCCCCO[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1O[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1O
Reaction time: 1 h
Yield: 89.9 %

Procedure:
540 mg (467 μmol) of compound 23 was dissolved in 5 ml of a methanol/dichloromethane 1/1 solvent mixture. Sodium (cat.) was then added to the mixture. After 1 hour at ambient temperature, the solution was neutralized with Amberlite resin IR 120 (H+). This was filtered and concentrated under vacuum. Chromatography of the crude product (elution: cyclohexane/ethyl acetate=2.75/1) yielded 442 mg (yield=90%) of product 24 in the form of a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:13])(O)[CH3:11])=[CH:4][CH:3]=1.[Br:14][CH2:15][C:16]1([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])OCC[O:17]1.CC1C=CC(S(O)(=O)=O)=CC=1.C(O)CCC>O.CC1C=CC=CC=1>[Br:14][CH2:15][C:16]1([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[O:13][CH:10]([CH2:9][CH2:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:11][O:17]1
Reactant: Clc1ccc(C2(CBr)OCCO2)c(Cl)c1
Reactant: CC(O)(O)CCc1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1ccc(CCC2COC(CBr)(c3ccc(Cl)cc3Cl)O2)cc1

Procedure:
A mixture of 11.2 parts of 1-[2-(4-chlorophenyl)ethyl]-ethanediol, 15.6 parts of 2-(bromomethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolane, 4 parts of 4-methylbenzenesulfonic acid, 40 parts of butanol and 225 parts of methylbenzene is stirred and refluxed for 5 days with water-separator. The reaction mixture is evaporated and the residue is dissolved in 2,2'-oxybispropane. The solution is stirred with silica gel. The latter is filtered off and the filtrate is evaporated, yielding 2-(bromomethyl)-4-[2-(4-chlorophenyl)ethyl]-2-(2,4-dichlorophenyl)-1,3-dioxolane as a residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[N:9]([CH:12]([CH2:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:13](=[O:16])[CH:14]=[CH2:15])[N:10]=[CH:11][C:4]=12.[OH:24][CH:25]([C:30]1[CH:31]=[CH:32][C:33]([CH:36]=[O:37])=[N:34][CH:35]=1)[C:26]([OH:29])([CH3:28])[CH3:27].C(N(CC)CC)C.O1CCCC1>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(O)C>[OH:24][CH:25]([C:30]1[CH:31]=[CH:32][C:33]([C:36](=[O:37])[CH2:15][CH2:14][C:13](=[O:16])[CH:12]([N:9]2[C:5]3=[N:6][CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]3[CH:11]=[N:10]2)[CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[N:34][CH:35]=1)[C:26]([OH:29])([CH3:27])[CH3:28]
Reactant: CC(C)(O)C(O)c1ccc(C=O)nc1
Reactant: C=CC(=O)C(CC1CCOCC1)n1ncc2c(OC)ccnc21
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccnc2c1cnn2C(CC1CCOCC1)C(=O)CCC(=O)c1ccc(C(O)C(C)(C)O)cn1
Temperature: 0 °C
Yield: 93 %

Procedure:
A mixture of 4-(4-methoxy-1H-pyrazolo[3,4-b]pyridin-1-yl)-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (178 mg), 5-(1,2-dihydroxy-2-methylpropyl)pyridine-2-carbaldehyde (132 mg), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (18 mg), triethylamine (30 μL), tetrahydrofuran (5 mL) and ethanol (5 mL) was heated under reflux for 3 hr under argon stream. The reaction solution was poured into ice water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (268 mg, yield 93%) as a pale-yellow oil from the fraction eluted with ethyl acetate. MS: 511 (MH+).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C([Zn][C:33]#[N:34])#N.Cl[C:36]1[CH:37]=[C:38]([O:46][CH3:47])[C:39]([C:42]([O:44][CH3:45])=[O:43])=[N:40][CH:41]=1>CN(C=O)C.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]>[C:41]([C:36]1[CH:37]=[C:38]([O:46][CH3:47])[C:39]([C:42]([O:44][CH3:45])=[O:43])=[N:34][CH:33]=1)#[N:40]
Reactant: COC(=O)c1ncc(Cl)cc1OC
Reactant: N#C[Zn]C#N
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1ncc(C#N)cc1OC
Temperature: 120 °C
Yield: 86.7 %

Procedure:
In a 350-mL resealable vessel, Pd2dba3 (1.487 g, 1.623 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (1.444 g, 3.52 mmol), dicyanozinc (3.18 g, 27.1 mmol), and methyl 5-chloro-3-methoxypicolinate (step 1, 5.455 g, 27.1 mmol) were taken up in DMF (80 mL). The reaction mixture was purged with Argon and subsequently heated to 120° C. for 2 h. Upon cooling, the reaction mixture was concentrated under reduced pressure. The residue was filtered through Celite, and the filter cake was rinsed with 1% MeOH/DCM. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (33%-40% EtOAc/hexane) to afford the title compound as a white solid (4.51 g, 23.5 mmol, 87%)., MS m/z=193 [M+H]+. Calculated for C9H8N2O3: 192. 1H NMR in CDCl3 δ: 8.51 (d, 1H, J=1.6), 7.55 (d, 1H, J=1.6), 4.00 (s, 3H), 3.97 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([S:29](C)(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH3:33]>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([NH2:33])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)=CCCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O
Reactant: N
Product: CC(C)=CCCOc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 384 substituting 2-(3,4-difluorophenyl)-4-(4-methyl-3-pentenyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone. mp 70–73° C. 1H NMR (300 MHz, DMSO-d6) δ 1.5 (d, 6H), 2.27 (m, 2H) 4.43 (t, 2H), 4.5 (m, 1H), 7.5 (m, 2H), 7.6 (m, 1H), 7.8 (m, 2H), 7.92 (d, J=2 H, 2H), 8.2 (s, 1H). MS (DCI/NH3) m/z 462 (M+H)+, 479 (M+NH4)+. Anal. calc. for C22H21F2N3O4S: C, 57.26; H, 4.59; N, 9.11. Found, : C, 56.96; H, 4.70; N, 9.01.
Reaction SMILES: C(OC(=O)[N:7]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]([F:28])[CH:22]=1)[CH2:8][C:9](=[O:20])[NH:10][C:11]1[CH:16]=[C:15]([CH2:17]O)[CH:14]=[CH:13][C:12]=1[CH3:19])(C)(C)C.Cl.Cl.[N:32]1[CH:37]=[CH:36][CH:35]=[N:34][C:33]=1[N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>CS(C)=O>[F:28][C:23]1[CH:22]=[C:21]([NH:7][CH2:8][C:9]([NH:10][C:11]2[CH:16]=[C:15]([CH2:17][N:41]3[CH2:42][CH2:43][N:38]([C:33]4[N:32]=[CH:37][CH:36]=[CH:35][N:34]=4)[CH2:39][CH2:40]3)[CH:14]=[CH:13][C:12]=2[CH3:19])=[O:20])[CH:26]=[CH:25][C:24]=1[F:27]
Reactant: Cc1ccc(CO)cc1NC(=O)CN(C(=O)OC(C)(C)C)c1ccc(F)c(F)c1
Reactant: c1cnc(N2CCNCC2)nc1
Agent: Cl
Solvent: CS(C)=O
Product: Cc1ccc(CN2CCN(c3ncccn3)CC2)cc1NC(=O)CNc1ccc(F)c(F)c1

Procedure:
Prepared according to the procedure of Example 11c) using (3,4-difluoro-phenyl)-[(5-hydroxymethyl-2-methyl-phenylcarbamoyl)-methyl]-carbamic acid tert-butyl ester and 1-(2-pyrimidyl)piperazine dihydrochloride to give the title compound as a 10 mM solution in dimethyl sulfoxide. An aliquot (30 mL) of this solution was diluted with dimethyl sulfoxide/water (220 mL of a 1:1 mixture) was analysed by HPLC on a 20 mm×3.9 mm Waters Symmetry C8 column, eluting with 30%-95% acetonitrile/ammonium acetate.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][NH2:6].[CH3:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:13]([O:16]CC)(=[O:15])C>>[CH3:1][S:2][CH2:3][CH2:4][CH2:5][NH:6][C:13](=[O:15])[O:16][C:9]1[CH:8]=[CH:7][CH:12]=[CH:11][CH:10]=1
Reactant: CCCCCC
Reactant: CSCCCN
Reactant: CCOC(C)=O
Product: CSCCCNC(=O)Oc1ccccc1
Yield: 93.08 %

Procedure:
3-Methylthiopropylamine (5.5 ml, 50 mmol) was used for reaction in the same manner as Production Example 310-1, and purification was performed by silica gel column chromatography (hexane/ethyl acetate system) to obtain the title compound (10.486 g, 46.54 mmol, 93.08%) as a yellow oil.
Reaction SMILES: [C:1]1([C:7]2[NH:11][C:10](=[O:12])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.[H-].[Na+].[CH3:20][C:21]1[C:25]([S:26](Cl)(=[O:28])=[O:27])=[C:24]([CH3:30])[O:23][N:22]=1>O>[CH3:20][C:21]1[C:25]([S:26]([N:11]2[C:10](=[O:12])[O:9][N:8]=[C:7]2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:28])=[O:27])=[C:24]([CH3:30])[O:23][N:22]=1
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Reactant: O=c1[nH]c(-c2ccccc2)no1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1noc(C)c1S(=O)(=O)n1c(-c2ccccc2)noc1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 9.3 %

Procedure:
At room temperature, a mixture of 2.0 g (15 mmol) of 3-phenyl-4H-[1,2,4]oxadiazol-5-one and 30 ml absolute tetrahydrofuran is admixed with stirring with 0.40 g (10 mmol) of a suspension of sodium hydride (60% strength) and then stirred at room temperature for 10 minutes. 1.9 g (10 mmol) of 3,5-dimethylisoxazol-4-sulphonyl chloride are subsequently added, and the mixture is stirred at room temperature for another 20 hours. For work-up, the reaction mixture is poured into 150 ml of water. The resulting mixture is extracted twice with 80 ml of ethyl acetate each time. The combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. The residue that remains is chromatographed over silica gel using methylene chloride as mobile phase. In this manner, 0.3 g (9% of theory) of 4-(3,5-dimethylisoxazole-4-sulphonyl)-3-phenyl-4H-[1,2,4]oxadiazol-5-one is obtained in the form of a colourless solid of melting point 90 to 95 C.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[C:10]([NH2:15])=[N:11][CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH:17]([C:22](=O)[CH2:23][CH3:24])[C:18]([O:20][CH3:21])=[O:19]>C(O)C>[CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:22]([CH2:23][CH3:24])[N:15]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1ncccc1OCC1CCCCC1
Reactant: CCC(=O)C(Cl)C(=O)OC
Solvent: CCO
Product: CCc1nc2c(OCC3CCCCC3)cccn2c1C(=O)OC

Procedure:
A solution of 100 mg (0.485 mmol) of 3-(cyclohexylmethoxy)pyridine-2-amine and 399 mg (2.42 mmol) of methyl 2-chloro-3-oxopentanoate in 4 ml of ethanol was heated at reflux overnight. The mixture was then cooled and concentrated and the residue obtained was purified by preparative HPLC (Method 6). This gave 26 mg (17% of theory) of methyl 8-(cyclohexylmethoxy)-2-ethylimidazo[1,2-a]pyridine-3-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:7])=[CH:5][N:6]=1.[C:8]([NH:17][C:18](OC1C=CC=CC=1)=[O:19])(OC1C=CC=CC=1)=[O:9]>O1CCOCC1>[CH3:7][C:4]1[S:3][C:2]2=[N:1][C:8](=[O:9])[NH:17][C:18](=[O:19])[N:6]2[CH:5]=1
Reactant: O=C(NC(=O)Oc1ccccc1)Oc1ccccc1
Reactant: Cc1cnc(N)s1
Solvent: C1COCCO1
Product: Cc1cn2c(=O)[nH]c(=O)nc2s1
Yield: 93.6 %

Procedure:
A mixture of 2-amino-5-methylthiazole (2.0 g), diphenyl imidodicarbonate (CAS 99911-94-1) (4.5 g) and 1,4-dioxane (40 ml) was heated to reflux for 8 hours. After standing to cool, the precipitate was collected by filtration to obtain the title compound (3.00 g).
Reaction SMILES: [CH:1]1([N:4]([CH2:32][C:33]2[CH:34]=[C:35]([CH:48]=[C:49]([CH2:51][CH2:52][CH2:53][O:54][CH3:55])[CH:50]=2)[O:36][CH2:37][C:38]2[CH:47]=[CH:46][C:41]([C:42]([O:44]C)=[O:43])=[CH:40][CH:39]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][NH:9][CH2:8]2)=[O:6])[CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([N:4]([CH2:32][C:33]2[CH:34]=[C:35]([CH:48]=[C:49]([CH2:51][CH2:52][CH2:53][O:54][CH3:55])[CH:50]=2)[O:36][CH2:37][C:38]2[CH:47]=[CH:46][C:41]([C:42]([OH:44])=[O:43])=[CH:40][CH:39]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:17][CH:18]=3)[CH2:11][CH2:10][NH:9][CH2:8]2)=[O:6])[CH2:3][CH2:2]1
Reactant: COCCCc1cc(CN(C(=O)[C@H]2CNCC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCc2ccc(C(=O)OC)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCCCc1cc(CN(C(=O)[C@H]2CNCC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCc2ccc(C(=O)O)cc2)c1
Reaction time: 18 h

Procedure:
To a solution of methyl 4-{[3-({cyclopropyl[((3R,4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidin-3-yl)carbonyl]amino}methyl)-5-(3-methoxypropyl)phenoxy]methyl}benzoate (1 eq.) from Example 18 in methanol (0.03) was added 1 N aqueous NaOH (2.2 eq.). The reaction was heated to reflux and stirred for 18 h. The volatiles were removed in vacuo and the resulting solid residue was triturated with ether. The resulting residue was then taken up in EtOAc and the insolubles were removed via filtration. To the filtrate was then slowly added ether to precipitate out the sodium salt of the title compound as a white solid.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[O:15]1[CH:17]2[CH2:18][CH2:19][CH2:20][CH:16]12.[OH-].[K+]>CCOCC.CCCCCC>[O:7]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:17]2[CH2:18][CH2:19][CH2:20][CH:16]2[OH:15])=[CH:10][CH:9]=1)[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: C1CC2OC2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCCCCC
Product: OC1CCCC1Oc1ccc(Oc2ccccc2)cc1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
A mixture of 52 g of 4-hydroxydiphenyl ether and 23.5 g of 1,2-epoxycyclopentane is heated to 150° C. To this melt are added in the course of 25 minutes 6.7 g of 90% potassium hydroxide powder and the mixture is stirred for one hour at 130° C. After cooling, the reaction mixture is taken up in ether/hexane (1:1) and the organic solution is washed 4 times with 10% potassium hydroxide solution and 3 times with saturated sodium chloride solution. The organic phase is dried over sodium sulphate and concentrated by rotary evaporation under reduced pressure. Distillation of the crude product yields 2-(4-phenoxyphenoxy)-cyclopentan-1-ol as a colourless oil with a boiling point of 181°-185° C./0.001 torr and a refractive index of nD20 =1.5812.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[Cl:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11]Cl>>[Cl:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1
Reactant: ClCc1ccccc1Cl
Reactant: O=C1CCNCC1
Product: O=C1CCN(Cc2ccccc2Cl)CC1

Procedure:
1-(2-Chlorobenzyl)-4-piperidone is prepared from 4-piperidone and 2-chlorobenzyl chloride essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:23][O:24][C:25]1[N:30]=[CH:29][C:28](B(O)O)=[CH:27][N:26]=1>>[F:18][C:17]1[C:12]2[N:13]([C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:28]4[CH:27]=[N:26][C:25]([O:24][CH3:23])=[N:30][CH:29]=4)[CH:3]=3)=[CH:10][N:11]=2)[CH:14]=[CH:15][C:16]=1[C:19]([OH:22])([CH3:21])[CH3:20]
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Reactant: COc1ncc(B(O)O)cn1
Product: COc1ncc(-c2cc(-c3cnc4c(F)c(C(C)(C)O)ccn34)ccc2F)cn1
Yield: 4 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 2-methoxypyrimidine-5-boronic acid were coupled in the same way as in Example 30 to give 2-{8-fluoro-3-[4-fluoro-3-(2-methoxypyrimidin-5-yl)phenyl]imidazo[1,2-α]pyridin-7-yl}propan-2-ol as an off-white solid (5 mg, 4%): m/z (ES+) 421 [MH+].
Reaction SMILES: [C:1]([N:3]=[C:4]([NH:9][CH3:10])[NH:5][CH2:6][CH2:7][SH:8])#[N:2].[H-].[Na+].Cl[CH2:14][C:15]1[O:19][C:18]([CH2:20][N:21]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:31])=[CH:17][CH:16]=1>CN(C)C=O>[C:1]([N:3]=[C:4]([NH:9][CH3:10])[NH:5][CH2:6][CH2:7][S:8][CH2:14][C:15]1[O:19][C:18]([CH2:20][N:21]2[C:22](=[O:31])[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29]2=[O:30])=[CH:17][CH:16]=1)#[N:2]
Reactant: CNC(=NC#N)NCCS
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(CCl)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=NC#N)NCCSCc1ccc(CN2C(=O)c3ccccc3C2=O)o1
Reaction time: 2 h
Yield: 55.8 %

Procedure:
To a stirred solution of N"-cyano-N-(2-mercaptoethyl)-N'-methylguanidine (1.0 g) and sodium hydride (0.152 g) in dry dimethylformamide (4 ml) at room temperature was added slowly a solution of 2-(5-chloromethyl-2-furanylmethyl)-1H-isoindole-1,3(2H)-dione (1.74 g) in dry dimethylformamide (8 ml). After stirring for 2 hr in the solution was evaporated to dryness and the oily residue suspended in an ethyl acetate (25 ml)-water (20 ml) mixture. The solid residue was filtered and crystallised from methanol to give the title compound (1.4 g) m.p. 179°-182°.