Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11](=[O:24])[CH:12]=[C:13]([C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[CH:22][N:23]=2)[CH:20]=1)[CH3:14]>C(#N)C.C(OCC)(=O)C>[CH3:9][O:10][C:11](=[O:24])[CH:12]=[C:13]([C:15]1[CH:16]=[CH:17][C:18]2[N:19]([C:21]([I:1])=[CH:22][N:23]=2)[CH:20]=1)[CH3:14]
Reactant: COC(=O)C=C(C)c1ccc2nccn2c1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)C=C(C)c1ccc2ncc(I)n2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 48.2 %

Procedure:
N-iodosuccinimide (252 mg, 1.12 mmol) was added to a mixture of 3-imidazo[1,2-a]pyridin-6-yl-but-2-enoic acid methyl ester (220 mg, 1.02 mmol) in acetonitrile (10 mL) which had been cooled to 0° C. under nitrogen atmosphere. The mixture was stirred for 1 h, then diluted with ethyl acetate (30 mL) and washed with saturated sodium bicarbonate solution (2×10 mL), and brine (1×15 mL). The organic layers were combined, dried over MgSO4 and concentrated in vacuo. The residue was purified by chromatography (chromatotron, 4μ plate, 50% ethyl acetate in hexanes) to yield 3-(3-iodo-imidazo[1,2-a]pyridin-6-yl)-but-2-enoic acid methyl ester as a pale yellow solid (168.1 mg, 48%). 1H NMR (250 MHz, CDCl3): δ 8.27 (bs, 1H), 7.77 (s, 1H), 7.64 (d, 1H, J=9.4), 7.41 (dd, 1H, J=9.4, J=1.6), 6.27 (d, 1H, J=0.62), 3.84 (s, 3H), 2.68 (d, 3H, J=0.62). MS [EI+] 343 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[C:6]=2[N:7]=1.[CH2:23]([NH2:25])[CH3:24]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:25][CH2:23][CH3:24])[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[C:6]=2[N:7]=1
Reactant: CCN
Reactant: FC(F)(F)c1ccc(C2COCc3c(Cl)nc(Cl)nc32)cc1
Product: CCNc1nc(Cl)nc2c1COCC2c1ccc(C(F)(F)F)cc1

Procedure:
2,4-dichloro-8-(4-(trifluoromethyl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine (Preparation Z) was reacted as described in Preparation Xa with ethanamine to give 2-chloro-N-ethyl-8-(4-(trifluoromethyl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine (Preparation Za). LC-MS (M+H)+=358.1.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([O:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]=1[CH:27]([OH:33])[C:28](=[NH:32])[O:29]CC)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[O:34]1CCC[CH2:35]1>C1(C)C=CC=CC=1>[CH2:9]([O:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]=1[CH:27]1[O:33][C:35](=[O:34])[NH:29][C:28]1=[O:32])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C1CCOC1
Reactant: CCOC(=N)C(O)c1c(OCc2ccccc2)ccc2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C(c2c(OCc3ccccc3)ccc3ccccc23)O1

Procedure:
By the procedure of Example 27, except that 2.1 equivalents rather than 3.2 equivalents of triethylamine were employed, ethyl 1-(2-benzyloxy-1-naphthyl)-1-hydroxymethanecarboximidate hydrochloride (4.0 g., 0.011 mole) in 180 ml. of tetrahydrofuran was converted to toluene recrystallized 5-(2-benzyloxy-1-naphthyl)-oxazolidine-2,4-dione (1.61 g., m.p. 197°-199.5° C.).
Reaction SMILES: [N:1]1([C:7]([CH2:9][C@@H:10]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:11]([O:13]CC2C=CC=CC=2)=[O:12])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[N:1]1([C:7]([CH2:9][C@@H:10]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:11]([OH:13])=[O:12])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: CC(C)C[C@H](CC(=O)N1CCCCC1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@H](CC(=O)N1CCCCC1)C(=O)O
Yield: 94.5 %

Procedure:
A solution of benzyl (2R)-2-(piperidinocarbonylmethyl)-4-methylvalerate (0.625 g) in methanol (10 ml) was hydrogenated over 10% palladium on carbon (80 mg) at 3 atmospheric pressure of hydrogen for 1 hour. After removal of the catalyst by filtration, the filtrate was concentrated in vacuo to give (2R)-2-(piperidinocarbonylmethyl)-4-methylvaleric acid (0.43 g) as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C:10]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([O:18][CH3:19])=[CH:12][C:11]=1[O:20][CH3:21].[Li]CCCC.[B:27](OC)([O:30]C)[O:28]C.O>C1COCC1>[CH3:21][O:20][C:11]1[CH:12]=[C:13]([O:18][CH3:19])[CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH2:9][S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:27]([OH:30])[OH:28]
Reactant: COB(OC)OC
Reactant: COc1cc(OC)c(CSc2ccccc2Br)c(OC)c1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(OC)c(CSc2ccccc2B(O)O)c(OC)c1
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 46 %

Procedure:
To a solution of 4.22 g (2-bromophenyl)(2,4,6-trimethoxybenzyl)sulfane (11.56 mmol) in 150 ml dry THF at −78° C. was added slowly 5.6 ml 2.5M n-BuLi. The solution was stirred at −78° C. for 25 minutes. 1.6 ml B(OMe)3 was added at −78° C. The reaction was stirred 2 hours at RT. 100 ml water was added, stirred overnight. The mixture was extracted with ethyl acetate (2×100 ml). The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by gradient chromatography (hexane:ethyl acetate 60:40) yielded 1.762 g product (5.3 mmol, 46% yield).
Reaction SMILES: [OH:1]O.[ClH:3].[CH3:4][C:5]1([CH3:17])[N:10]([N+:11]2[N-:12][O:13][C:14](=[NH:16])[CH:15]=2)[CH2:9][CH2:8][S:7][CH2:6]1>>[ClH:3].[CH3:4][C:5]1([CH3:17])[N:10]([N+:11]2[N-:12][O:13][C:14](=[NH:16])[CH:15]=2)[CH2:9][CH2:8][S:7](=[O:1])[CH2:6]1
Reactant: OO
Reactant: CC1(C)CSCCN1[n+]1cc(=N)o[n-]1
Agent: Cl
Product: CC1(C)CS(=O)CCN1[n+]1cc(=N)o[n-]1

Procedure:
1.2 g of a 35% strength aqueous hydrogen peroxide solution are added to a solution of 3 g of 3-(3,3-dimethyl-perhydro-1,4-thiazin-4-yl)-sydnone imine hydrochloride (step g of Example 14) at room temperature with stirring, whereupon the temperature rises somewhat. The mixture is stirred for 2 hours and then concentrated in a water jet vacuum and the residue is recrystallized from ethyl acetate. Yield: 2.5 g; m.p.: 192° C. (dec.).
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[CH:22]=[CH:21][C:20](I)=[CH:19][N:18]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[CH3:24][C:25]1[C:29](C(B(O)O)=O)=[C:28]([CH3:35])[O:27][N:26]=1>C(=O)([O-])[O-].[Na+].[Na+].COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[CH:22]=[CH:21][C:20]([C:29]5[C:25]([CH3:24])=[N:26][O:27][C:28]=5[CH3:35])=[CH:19][N:18]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Ic1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1
Reactant: Cc1noc(C)c1C(=O)B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cc1noc(C)c1-c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1

Procedure:
A mixture of 3-cyclobutyl-7-[(5-iodo-2-pyridinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine (E207) (252 mg, 0.6 mmol), 3,5 dimethyl-4-isoxazoyl boronic acid (168 mg, 1.2 mmol) and tetrakis(triphenylphosphine)palladium(0) in 2M sodium carbonate solution (5 ml) and ethylene glycol dimethyl ether (10 ml) was stirred at reflux for 14 hours. The reaction mixture was diluted with ethyl acetate and washed with a saturated solution of sodium bicarbonate, water, brine and dried (sodium sulfate). The organic layer was filtered, concentrated in vacuo and the resulting residue was purified by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (0.5:4.5:95) to afford the title compound (E222); MS (ES+) m/e 390 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.F[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To a solution of 1-methylpiperazine (0.605 ml, 5.45 mmol) in DMF (6.25 ml) was added 4-fluoronitrobenzene (0.750 ml, 7.07 mmol) and potassium carbonate (1.13 g, 8.18 mmol) and the reaction mixture stirred at 90° C. overnight. The reaction was then cooled to room temperature, diluted with DCM and washed with water. The organic phase was dried over MgSO4 and the solvent removed in vacuo. The residue was purified by silica gel silica chromatography using a 0-10% MeOH in DCM gradient to afford 1-methyl-4-(4-nitrophenyl)piperazine (1.03 g, 4.66 mmol, 85%) as a yellow solid. 1H NMR (DMSO) δ 2.37 (3H, s), 2.58 (4H, t), 3.45 (4H, t), 6.82 (2H, d), 8.12 (2H, d). LCMS (1) Rt: 1.63 min; m/z (ES+) 222.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[NH2:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:21])[C:10]=2[C:9]([OH:22])=[CH:8][C:7]=1Cl.C1(O)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[NH2:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:21])[C:10]=2[C:9]([OH:22])=[CH:8][C:7]=1[O:3][CH2:2][CH2:1][OH:4]
Reactant: OCCO
Reactant: Nc1c(Cl)cc(O)c2c1C(=O)c1ccccc1C2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Oc1ccccc1
Solvent: CN1CCCC1=O
Product: Nc1c(OCCO)cc(O)c2c1C(=O)c1ccccc1C2=O

Procedure:
47 parts of ethylene glycol, 13.7 parts of 1-amino-4-hydroxy-2-chloroanthraquinone, 24 parts of N-methylpyrrolidone, 1.2 parts of phenol and 6 parts of potassium carbonate are heated for 6 hours at 120°-125°C under nitrogen. After working up, 10.5 parts of 1-amino-2-(2'-hydroxyethoxy)-4-hydroxyanthraquinone are obtained.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)[OH:14])(=O)=O)=CC=1.[N-:26]=[N+:27]=[N-:28].[Na+]>CS(C)=O>[N:26]([CH2:12][C@@H:13]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=1)[OH:14])=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](O)c2ccc(F)c(C(F)(F)F)c2)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NC[C@H](O)c1ccc(F)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 98.5 %

Procedure:
(R)-2-(4-Fluoro-3-(trifluoromethyl)phenyl)-2-hydroxyethyl 4-methylbenzenesulfonate (3.5 g, 9.25 mmol) was dissolved in 20 mL of DMSO. Sodium azide (1.2 g, 18.5 mmol) was added and the mixture was stirred at 80° C. for 3 h. The clear solution was cooled to room temperature and extracted with ethyl acetate and water. The organic layer was dried and concentrated to give (R)-2-azido-1-(4-fluoro-3-trifluoromethylphenyl)-ethanol as a pale brown oil (2.27 g) which was used as is in the next step.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][O:50][C:51]1[CH:56]=[CH:55][C:54]([C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([NH2:63])[CH:58]=2)=[CH:53][C:52]=1[CH3:64]>CN(C=O)C>[CH3:49][O:50][C:51]1[CH:56]=[CH:55][C:54]([C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([NH:63][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:58]=2)=[CH:53][C:52]=1[CH3:64]
Reactant: COc1ccc(-c2cccc(N)c2)cc1C
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cccc(NC(=O)c3cc4cccc(O)c4oc3=O)c2)cc1C
Temperature: 25 °C
Yield: 60.5 %

Procedure:
DIEA (0.014 mL, 0.077 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.015 g, 0.070 mmol) and HATU (0.029 g, 0.077 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4′-Methoxy-3′-methyl-biphenyl-3-ylamine (0.015 g, 0.070 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.017 g of product in 61% yield: LCMS (ESI) m/z 402 (MH+).
Reaction SMILES: [Li+].[OH-].[CH3:3][C:4](=[CH2:34])[C:5]#[C:6][C@@H:7]([N:13]1[CH2:18][CH2:17][C@@H:16]([CH2:19][C:20]([O:22]C)=[O:21])[CH2:15][C@H:14]1[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11].Cl>O.C1COCC1>[CH3:34][C:4](=[CH2:3])[C:5]#[C:6][C@@H:7]([N:13]1[CH2:18][CH2:17][C@@H:16]([CH2:19][C:20]([OH:22])=[O:21])[CH2:15][C@H:14]1[C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=1)[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: C=C(C)C#C[C@H](CCC(C)C)N1CC[C@@H](CC(=O)OC)C[C@H]1c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)C#C[C@H](CCC(C)C)N1CC[C@@H](CC(=O)O)C[C@H]1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.5 %

Procedure:
A solution of LiOH (67 mg, 2.8 mmol) in H2O (1 ml) was added to a stirred solution of methyl {(2S,4R)-1-[(1S)-4-methyl-1-(3-methylbutyl)pent-4-en-2-yn-1-yl]-2-[4-(trifluoromethyl)phenyl]piperidin-4-yl}acetate (Step 1, 250 mg, 0.56 mmol) in THF (2 ml) at RT. The mixture was stirred at RT for 18 hrs, then at 60° C. for 3 hrs. After cooling to RT 2N HCl was added and the THF was removed in vacuo. The residue was partitioned between CH2Cl2/H2O. The pH of the aqueous layer was adjusted to ˜pH7 with saturated aqueous NaHCO3. The aqueous layer was extracted with CH2Cl2 (×3). The combined extracts were dried (Na2SO4) filtered and evaporated. The residue was purified by chromatography (silica, 4% MeOH/CH2Cl2) to give the acid (228 mg) as a colourless foam. 1H NMR (500 MHz, CD3OD): δ 0.83 (6H, d, J 6.6), 1.12-1.20 (2H, m), 1.33-1.43 (3H, m), 1.58 (2H, q, J 7.8), 1.80 (1H, dd, J 2.8, 12.8), 1.85-1.91 (5H, s), 2.18-2.26 (2H, m), 2.48 (1H, t, J 11.1), 2.98-3.04 (1H, m), 3.16 (1H, t, J 7.6), 3.55 (1H, dd, J 2.5, 11.3), 5.21 (1H, s), 5.24 (1H, s), 7.53 (2H, d, J 7.6), 7.62 (2H, d, J 8.2); M/Z (ES+) 436 (MH+).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[S:12]1[CH:16]=[C:15]([CH2:17][CH:18]([C:20]([OH:22])=[O:21])[NH2:19])[N:14]=[CH:13]1.C1COCC1.[C:28]1([C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[N+]=[N-])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(O)C>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([OH:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[C:28]1([CH:34]([O:21][C:20](=[O:22])[CH:18]([CH2:17][C:15]2[N:14]=[CH:13][S:12][CH:16]=2)[NH2:19])[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NC(Cc1cscn1)C(=O)O
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCO
Product: NC(Cc1cscn1)C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
After 21.84 g (123.6 mmol) of the compound (48) was dissolved in ethanol (200 ml) and THF (100 ml) with heating to the solution was added diphenyldiazomethane (24 g, 123.6 mmol) under ice-cooling over 35 min. little by little. The cooling bath was removed and the mixture was stirred for 1 h at room temperature. To the reaction mixture was added acetic acid (0.1 ml) for quenching the excess reagent, and the mixture was concentrated in vacuo. The residue was crystallized from ether and ethanol to yield 31.63 g (97.7%) of the compound (49).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2=[N:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:9]([CH:10]=O)[N:4]2[N:3]=1.C(O)(=O)[CH2:19][C:20]([OH:22])=[O:21].N1CCCCC1>N1C=CC=CC=1>[CH3:1][C:2]1[S:6][C:5]2=[N:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:9]([CH:10]=[CH:19][C:20]([OH:22])=[O:21])[N:4]2[N:3]=1
Reactant: O=C(O)CC(=O)O
Reactant: Cc1nn2c(C=O)c(-c3ccccc3)nc2s1
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: Cc1nn2c(C=CC(=O)O)c(-c3ccccc3)nc2s1
Temperature: 5 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
90 g of 2-methyl-6-phenyl-imidazo[2,1-b]-1,3,4-thiadiazole-5-carbaldehyde, 60 g of malonic acid and 3 ml of piperidine in 95 ml of pyridine were boiled under reflux for 10 hours. The mixture was cooled to 5° C., stirred at this temperature for 2 hours and filtered. The residue was washed with water and dried. 92 g (84% of theory) of β-(2-methyl-6-phenyl-imidazo[2,1-b]-1,3,4-thiadiazol-5-yl)-propenoic acid of melting point 278°-280° C. (decomposition) were obtained.
Reaction SMILES: Cl[Mg][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:11]([C:13]1[N:14]=[C:15]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[S:16][CH:17]=1)=[O:12].[Cl-].[NH4+]>O1CCCC1>[OH:12][CH:11]([C:13]1[N:14]=[C:15]([CH:18]2[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23]2)[S:16][CH:17]=1)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Cl[Mg]CCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C=O)cs2)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C(O)CCc3ccccc3)cs2)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere and at −78° C., chloro(2-phenylethyl)magnesium (1M in diethyl ether, 3.77 ml) was added dropwise to a solution of tert-butyl 4-(4-formyl-1,3-thiazol-2-yl)piperidine-1-carboxylate (1.0 g) in tetrahydrofuran (10 ml). The reaction mixture was stirred at −78° C. for one hour, and more chloro(2-phenylethyl)magnesium (3M in diethyl ether, 0.20 ml) was then added dropwise. The reaction mixture was then stirred for 20 minutes. Saturated ammonium chloride solution was then added to the reaction mixture, and the aqueous phase was separated off. After extraction of the aqueous phase with ethyl acetate, the combined organic phases were dried over sodium sulphate and the solvent was removed under reduced pressure. This gave tert-butyl 4-[4-(1-hydroxy-3-phenylpropyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (790 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][NH2:14].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:14][CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[F:10])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: NCc1ccccc1F
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Fc1ccccc1CNc1nc(Cl)ncc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.5 %

Procedure:
To a magnetically stirred solution of 2,4-dichloro-5-fluoropyrimidine (0.105 g, 0.63 mmol) in anhydrous THF (5 mL) were added 2-fluorobenzylamine (0.085 g, 0.68 mmol) and triethylamine (0.127 g, 1.26 mmol), and the mixture was warmed to reflux and stirred for 5 h. The reaction mixture was cooled to room temperature and partitioned between CH2Cl2 (15 mL) and 1 N HCl (10 mL). The phases were separated and the aqueous phase was extracted with additional CH2Cl2 (15 mL). The combined organic extracts were washed with brine, dried over Na2SO4, and filtered. The solvent was removed under reduced pressure to yield (2-chloro-5-fluoropyrimidin-4-yl)-(2-fluorobenzyl)amine (0.157 g, 97%) as a yellow solid: mp 117-118° C.; 1H NMR (300 MHz, CDCl3) δ 7.95 (s, 1H), 7.45 (t, 1H), 7.35 (m, 1H), 7.15 (m, 2H), 5.60 (br s, 1H), 4.80 (d, 2H); ESIMS m/z 256 ([M+H]+). Alternatively, 2-chloro-5-fluoropyrimidin-4-yl)-(2-fluorobenzyl)amine was prepared using methods known in the literature, such as Boebel, T. et al. U.S. Patent Application Publication 2010/0022538.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[N:22][O:23]C(=O)C)[CH2:20][CH3:21])=[C:15](O)[C:14]=1[CH2:28][CH2:29][CH3:30]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]2[C:19]([CH2:20][CH3:21])=[N:22][O:23][C:15]=2[C:14]=1[CH2:28][CH2:29][CH3:30]
Reactant: CCCc1c(OCCCSc2ccc(CC(=O)OC)cc2Cl)ccc(C(CC)=NOC(C)=O)c1O
Solvent: c1ccncc1
Product: CCCc1c(OCCCSc2ccc(CC(=O)OC)cc2Cl)ccc2c(CC)noc12

Procedure:
A solution of methyl 3-chloro-4-(3-(2-propyl-3-hydroxy-4-(1-acetoxyiminopropyl)phenoxy)propylthio)phenylacetate (Step D; 6.19 grams) in dry pyridine (65 mL) was refluxed for 3 hours. The solvent was removed in vacuo and the residue partitioned between isopropyl acetate and 0.1N HCl. The organic was washed once more with 0.1N HCl. The organic was dried over magnesium sulfate, filtered and evaporated to an oil. The crude product was placed on a slica gel column and eluted with hexane/CH2Cl2 (1:1) until the product appeared in the eluant. The mobile phase was changed to 100% CH2Cl2 and elution continued until all the title compound was recovered.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32].O>N1C=CC=CC=1>[OH:22][C:21]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:13](=[O:28])[C:12]=1[C:7]1[NH:6][C:5]2[CH:29]=[CH:30][C:2]([NH:1][C:31](=[O:33])[CH3:32])=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3cccnc3n(CCC(C)C)c1=O)N2
Temperature: 100 °C
Yield: 71.6 %

Procedure:
To the product of Example 205 (0.020 g, 0.047 mmol) in pyridine (0.5 mL) was added acetic anhydride (0.057 g, 0.0053 mL, 0.056 mmol). The reaction mixture was heated in a microwave reactor at 100° C. for 30 minutes. The reaction was poured into 30 mL of water. The solid was collected by filtration to give the title compound (15.8 mg, 72%). 1H NMR (300 MHz, DMSO-d6) δ 0.98 (d, J=6.62 Hz, 6 H) 1.57 (m, 2 H) 1.70 (m, 1 H) 2.10 (s, 3 H) 4.48 (m, 2 H) 7.48 (dd, J=8.09, 4.78 Hz, 1 H) 7.66 (d, J=8.82 Hz, 1 H) 7.78 (m, 1 H) 8.30 (d, J=1.84 Hz, 1 H) 8.55 (dd, J=7.72, 1.84 Hz, 1 H) 8.87 (dd, J=4.60, 1.65 Hz, 1 H) 10.39 (s, 1 H) 14.21 (br s, 1 H). MS (ESI−) m/z 468 (M−H)−.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[C:16]1[CH2:20][N:19](C(OC(C)(C)C)=O)[CH:18]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:17]=1>ClCCl>[F:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[C:16]1[CH2:20][NH:19][CH:18]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:17]=1.[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(F)ccc2F)=CC1c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(F)c(C2=CC(c3ccccc3)NC2)c1
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (20 mL) was added to a solution of tert-butyl 4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxylate (2-3,700 mg, 1.96 mmol, 1 equiv) in dichloromethane (50 mL) at 23° C., and the resulting mixture was stirred for 30 minutes, then concentrated to give 4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrole (24) as a TFA salt (brown oil). LRMS m/z (M+H) 258.1 found, 258.1 required.