Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]1[CH2:22][CH2:23][CH2:24][C:16]1=[C:15]2[C:25](=[O:27])[CH3:26].[CH3:28][NH:29][CH3:30]>C1COCC1>[CH3:28][N:29]([CH3:30])[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]1[CH2:22][CH2:23][CH2:24][C:16]1=[C:15]2[C:25](=[O:27])[CH3:26]
Reactant: CNC
Reactant: CC(=O)c1c2c(cc3ccc(Cl)cc13)CCC2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)c1c2c(cc3ccc(N(C)C)cc13)CCC2
Temperature: 85 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
An oven-dried sealed tube (0.5-2 mL) was equipped with a stir bar and charged with the precatalyst (0.003 g, 0.004 mmol). The tube was closed with a septum, then evacuated and refilled with nitrogen three times through a needle. LHMDS (0.3 mL of a 1.0 M solution in THF, 0.32 mmol) and compound 6b (0.038 g, 0.16 mmol) in THF (0.3 mL) were added via syringe. Finally, dimethylamine (0.3 mL of a 2.0 M solution in THF, 0.24 mmol) in THF (0.3 mL) was added at rt via syringe. The resulting solution was heated at 85° C. in an oil bath and stirred for 3 h. The consumption of the starting material was monitored by TLC. Once the reaction was complete, the mixture was cooled rt, diluted with sat'd aq ammonium chloride solution (10 mL), and then extracted with AcOEt (3×12 mL). The combined organic layers were dried over Na2SO4, gravity filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (n-hexane/AcOEt 9.25:0.7) and the pure product was isolated as a yellow solid (70% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[I:11]N1C(=O)CCC1=O>ClC(Cl)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Brc1cnc2[nH]ccc2c1
Solvent: CC(Cl)Cl
Product: Brc1cnc2[nH]cc(I)c2c1
Temperature: 95 °C
Reaction time: 8 h
Yield: 320.9 %

Procedure:
A mixture of 5-Bromo-1H-pyrrolo[2,3-b]pyridine (50 g, 252.5 mmol) and N-iodosuccinimide (13.6 g, 60.6 mmol) in dichloroethane (200 ml) was stirred at 95° C. overnight. The reaction was allowed to cool to room temperature and saturated Na2H2SO4 (200 ml) was added. The mixture was then extracted with ethyl acetate (400 ml×2). The combined organic layers were dried with Na2SO4, concentrated. Silica gel chromatography of the crude using a gradient of ethyl acetate and hexane afforded 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine (62.8 g, 77% yield).
Reaction SMILES: [CH:1]([NH:4][C:5]([O:7][CH:8]1[CH2:13][CH2:12][N:11](C(OCC2C=CC=CC=2)=O)[CH2:10][CH2:9]1)=[O:6])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[CH:1]([NH:4][C:5](=[O:6])[O:7][CH:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)OC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)NC(=O)OC1CCNCC1

Procedure:
Benzyl 4-(isopropylcarbamoyloxy)piperidine-1-carboxylate (113 mg) is dissolved in ethanol (3 mL), treated with palladium on carbon (10%, 38 mg) and the mixture is hydrogenated at room temperature for 8 hours under 3 bar hydrogen pressure. Then the catalyst is filtered off and washed with ethanol. The combined mother liquours are concentrated to give the title compound, which is used directly in the next step.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:13])[N:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1.C[O-].[Na+].OC1C=CC(NC(=O)N(C)C)=CC=1.[Na].[Cl:31][C:32]1[N:37]=[C:36](Cl)[CH:35]=[CH:34][N:33]=1>CS(C)=O.CO>[Cl:31][C:32]1[N:37]=[C:36]([O:1][C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:13])[N:10]([CH3:11])[CH3:12])=[CH:6][CH:7]=2)[CH:35]=[CH:34][N:33]=1
Reactant: CN(C)C(=O)Nc1ccc(O)cc1
Reactant: Clc1ccnc(Cl)n1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CS(C)=O
Solvent: CO
Product: CN(C)C(=O)Nc1ccc(Oc2ccnc(Cl)n2)cc1

Procedure:
4-Hydroxyphenyl-N,N-dimethylurea (12.0 grams; 0.066 mole) was mixed with a solution of sodium methylate (prepared by mixing sodium metal (1.53 grams) in 55 milliliters (ml) of methanol) and the resulting sodium 4-hydroxyphenyl-N,N-dimethylurea solution added gradually over a period of about one hour to a solution of 2,4-dichloropyrimidine (9.94 grams; 0.066 mole) in 50 ml. of dimethylsulfoxide. During the addition, the reaction temperature rose from about 55°C. to a temperature from between about 60° to about 65°C. The resulting reaction mixture was maintained at temperatures from between about 60° to about 70°C. for a period of about 30 minutes. The reaction mixture, which was nearly neutral, was poured into about 300 ml. of cold water and the resulting product precipitate recovered by filtration and washed with additional portions of water. The product precipitate was dissolved in acetonitrile and the resulting solution filtered with activated charcoal and then cooled to crystallize the product. The product thus obtained was recrystallized again from methylene chloride and dried. As a result of these operations, the desired title product was obtained as a white solid having a melting point of 192°C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:28][O:29][CH:30]([F:32])[F:31])[C:8]([NH:10][CH:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([OH:25])=[O:24])=[C:15]([CH2:18]OC(=O)C)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1.[I-].[Na+].Cl>O.C(#N)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:28][O:29][CH:30]([F:32])[F:31])[C:8]([NH:10][CH:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([O-:25])=[O:24])=[C:15]([CH2:18][N+:38]4[CH:39]=[CH:40][C:35]([O:34][CH3:33])=[CH:36][CH:37]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC(F)F)c3csc(N)n3)[C@H]2SC1
Reactant: COc1ccncc1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1cc[n+](CC2=C(C(=O)[O-])N3C(=O)C(NC(=O)C(=NOC(F)F)c4csc(N)n4)[C@H]3SC2)cc1
Yield: 13 %

Procedure:
A mixture of 7-[2-(2-aminothiazol-4-yl)-2-difluoromethoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid (syn isomer) (3.0 g), 4-methoxypyridine (4.0 g), sodium iodide (8.0 g), acetonitrile (4.0 ml) and water (1.0 ml) was heated for 2.0 hours at 65° to 68° C., and then water (100 ml) was added thereto. The mixture was adjusted to pH 3.0 with 1N-hydrogen chloride and the resultant precipitates were filtered off. The aqueous layer was subjected to column chromatography on macroporus nonionic adsorption resin "Diaion HP-20" and the elution was carried out with 30% aqueous methanol. The fractions containing the object compound were collected, concentrated in vacuo and lyophilized to give 7-[2-(2-aminothiazol-4-yl)-2-difluoromethoxyiminoacetamido]-3-(4-methoxy-1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (0.43 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[CH:9][S:8][C:7]=2[CH:11]=1.C([Li])CCC.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.Cl>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([B:17]([OH:22])[OH:18])[S:8][C:7]=2[CH:11]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc2ccsc2c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2cc(B(O)O)sc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a solution of 6-methoxybenzo[b]thiophene (18.13 g, 0.111 mol) in 150 mL of anhydrous tetrahydrofuran (THF) at -60° C. was added n-butyllithium (76.2 mL, 0.122 mol, 1.6M solution in hexanes), dropwise via syringe. After stirring for 30 minutes, triisopropyl borate (28.2 mL, 0.122 mol) was introduced via syringe. The resulting mixture was allowed to gradually warm to 0° C. and then distributed between 1N hydrochloric acid and ethyl acetate (300 mL each). The layers were separated, and the organic layer was dried over sodium sulfate. Concentration in vacuo produced a white solid that was triturated from ethyl ether hexanes. Filtration provided 16.4 g (71%) of 6-methoxybenzo[b]thiophene-2-boronic acid as a white solid. mp 200° C. (dec). 1H NMR (DMSO-d6) d 7.83 (s, 1H), 7.78 (d, J=8.6 Hz, 1H), 7.51 (d, J=2.0 Hz, 1H), 6.97 (dd, J=8.6, 2.0 Hz, 1H), 3.82 (s, 3H). FD mass spec: 208.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[NH:13][C:12]([CH3:14])=[N:11][C:10]=1[N+:15]([O-])=O.[C:19]([CH:22]1[CH2:27][CH2:26][O:25][C:23]1=[O:24])(=O)[CH3:20]>C(O)C.C(O)(=O)C.[Fe]>[OH:25][CH2:26][CH2:27][C:22]1[C:19]([CH3:20])=[N:15][C:10]2[N:11]([C:12]([CH3:14])=[N:13][C:9]=2[C:2]2[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=2[CH3:18])[C:23]=1[OH:24]
Reactant: Cc1cc(C)c(-c2[nH]c(C)nc2[N+](=O)[O-])c(C)c1
Reactant: CC(=O)C1CCOC1=O
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc(C)c(-c2nc(C)n3c(O)c(CCO)c(C)nc23)c(C)c1
Yield: 34.1 %

Procedure:
A solution of 5-mesityl-2-methyl-4-nitro-1H-imidazole (2.1 g, 8.56 mmol), α-acetyl-γ-butyrolactone (1.21 g, 9.42 mmol), and iron powder (2.39 g, 42.8 mmol) in ethanol (40 mL) and acetic acid (10 mL) was stirred at 80° C. for one day. The mixture was filtered through Celite and evaporated. The resulting crystals were washed with ethyl acetate, to give the title compound (0.95 g) as white crystals.
Reaction SMILES: [C:1]([CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:4][CH:5]=[CH2:6])#[N:2].Br[CH2:14][C:15]([O:17][CH3:18])=[O:16]>C1COCC1>[C:1]([C:3]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)([CH2:4][CH:5]=[CH2:6])[CH2:14][C:15]([O:17][CH3:18])=[O:16])#[N:2]
Reactant: C=CCC(C#N)c1ccccc1
Reactant: COC(=O)CBr
Solvent: C1CCOC1
Product: C=CCC(C#N)(CC(=O)OC)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a cooled solution (−78° C.) of 4-cyano-4-phenyl-1-butene (6.23 g, 39.6 mmol) in anhydrous THF was added LIDS (1M in THF, 43.5 mL, 43.5 mmol) dropwise. The solution was stirred at −78° C. for 0.5 hour, then methyl bromoacetate (6.67 g, 43.6 mmol) was added dropwise. After stirring at room temperature for 24 hours, the reaction mixture was concentrated under vacuum. The residual material was purified using silica gel column chromatography eluting with 0-20% EtOAc in hexanes. The appropriate fractions were combined and concentrated to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 7.38 (m, 5H), 5.57 (m, 1H), 5.14 (m, 2H), 3.49 (s, 3H), 3.49 (m, 2H), 2.78 (m, 2H) ppm. ES MS M+1=230.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[CH3:17][C:18]1[C:23]([CH2:24]O)=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=[C:20]([C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=2)[N:19]=1.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:24][C:23]3[C:18]([CH3:17])=[N:19][C:20]([C:30]4[CH:31]=[CH:32][C:33]([O:36][C:37]([F:39])([F:38])[F:40])=[CH:34][CH:35]=4)=[CH:21][C:22]=3[C:26]([F:27])([F:29])[F:28])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: Cc1nc(-c2ccc(OC(F)(F)F)cc2)cc(C(F)(F)F)c1CO
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)Cn1ccc2ccc(OCc3c(C(F)(F)F)cc(-c4ccc(OC(F)(F)F)cc4)nc3C)cc21

Procedure:
In analogy to the procedure described in example 5 f], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 6 b]) was reacted with [2-methyl-6-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-pyridin-3-yl]-methanol in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to yield the title compound as colorless solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([C:9]([NH2:11])=[NH:10])=[CH:7][N:6]=[C:5]([O:12][CH3:13])[CH:4]=1.C(=O)(O)[O-].[K+].Br[CH2:20][C:21]([C:23]1[N:24]([CH:29]([CH3:31])[CH3:30])[N:25]=[C:26]([CH3:28])[N:27]=1)=O>C1COCC1.O>[Cl:2][C:3]1[C:8]([C:9]2[NH:11][CH:20]=[C:21]([C:23]3[N:24]([CH:29]([CH3:31])[CH3:30])[N:25]=[C:26]([CH3:28])[N:27]=3)[N:10]=2)=[CH:7][N:6]=[C:5]([O:12][CH3:13])[CH:4]=1
Reactant: Cc1nc(C(=O)CBr)n(C(C)C)n1
Reactant: COc1cc(Cl)c(C(=N)N)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Cl)c(-c2nc(-c3nc(C)nn3C(C)C)c[nH]2)cn1
Yield: 96.5 %

Procedure:
A suspension of 4-chloro-6-methoxy-nicotinamidine hydrochloride (18.4 mmol) and potassium bicarbonate (7.37 g, 73.6 mmol) in THF (42 mL) and water (8.5 mL) was heated to reflux and treated with a solution of 2-bromo-1-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-ethanone (4.53 g, 18.4 mmol) in THF (14 mL) added dropwise. The reaction mixture was heated at reflux for 18 h before removal of volatile solvent in vacuo. The resultant suspension was filtered and the residue washed with water then dried to give the title compound as a brown solid (5.91 g, 97%). LCMS: RT=2.68 min, [M+H]+=333/335. 1H NMR 400 MHz (CDCl3) δ: 10.41 (1 H, s), 9.02 (1 H, s), 7.81 (1 H, s), 6.87 (1H, s), 5.91 (1 H, m), 4.00 (3 H, s), 2.41 (3 H, s), 1.55 (6 H, d, J=6.71 Hz).
Reaction SMILES: Cl.[F:2][C:3]([F:17])([F:16])[CH2:4][N:5]=[C:6]([NH2:15])[NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13]Cl)[N:12]=1.[SH:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22].[OH-].[Na+]>O>[F:2][C:3]([F:17])([F:16])[CH2:4][N:5]=[C:6]([NH2:15])[NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][S:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[N:12]=1
Reactant: COC(=O)CCS
Reactant: NC(=NCC(F)(F)F)Nc1nc(CCl)cs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)CCSCc1csc(NC(N)=NCC(F)(F)F)n1
Reaction time: 1 h

Procedure:
A mixture of 2-[2,2,2-trifluoroethyl]guanidino-4-chloromethylthiazole hydrochloride (4.6 g.) in EtoH (75 ml.) and methyl 3-mercaptopropionate (2.47 ml.) at 5° was treated dropwise with aqueous sodium hydroxide (1.8 g. in 15 ml. of water) over 10 minutes. The resulting solution was allowed to reach room temperature and was stirred for 1 hour. It was then poured into water and the precipitate filtered and crystallised from EtOH to give methyl 3-[2-(2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-ylmethylthio]propionate (1.93 g), m.p. 96°-98°.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11]([O:13]C)=[O:12])[S:8][C:7]=2[CH:15]=1.O.[OH-].[Li+].O>CO>[F:16][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[S:8][C:7]=2[CH:15]=1
Reactant: COC(=O)c1cc2ccc(C(F)(F)F)cc2s1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc2ccc(C(F)(F)F)cc2s1
Temperature: 75 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
A mixture of 400 mg of methyl 6-(trifluoromethyl)benzo[b]thiophene-2-carboxylate, 105 mg of lithium hydroxide monohydrate, 3 ml of water and 9 ml of methanol was stirred at 75° C. for 2 hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. To the residue was added water, and then washed with tert-butyl methyl ether 3 times. To the aqueous layer was added concentrated hydrochloric acid, and then extracted with chloroform 3 times. The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure to obtain 355 mg of 6-(trifluoromethyl)benzo[b]thiophene-2-carboxylic acid (the present compound 2).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[CH:8]=2)[N:3]=1.[NH2:22][C@H:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1>>[C@H:23]1([NH:22][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=4)[CH:8]=3)[N:3]=2)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1
Reactant: N[C@@H]1CCc2ccccc21
Reactant: COc1cccc(COc2ccc3nc(Cl)ccc3c2)c1
Product: COc1cccc(COc2ccc3nc(N[C@@H]4CCc5ccccc54)ccc3c2)c1
Temperature: 130 °C
Yield: 6.9 %

Procedure:
A stirred mixture of 2-chloro-6-(3-methoxy-benzyloxy)-quinoline (0.08 g, 0.4 mmol) and (R)-1-aminoindane (0.107 g, 1.00 mmol) was heated in a sealed tube for 20 h at 130° C. Purification by flash chromatography on silica gel (ethyl acetate in heptane, 0=>100%) yielded the title compound as a dark oil (11 mg, 10%), MS 397.5 [(M+H)+].
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12](=[O:25])[NH:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:15]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:28]I>CN(C)C=O>[CH3:28][N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12](=[O:25])[NH:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([C:21]([F:22])([F:23])[F:24])[CH:15]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CI
Reactant: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Oc1ccc2c(c1)CCCN2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCCc2cc(OC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)ccc21
Reaction time: 0.5 h

Procedure:
A solution of 1 of (4-chloro-3-trifluoromethyl-phenyl)-carbamic acid -1,2,3,4-tetrahydro-quinolin-6-yl ester (0.74 g., 2 mmol) in dry dimethylformamide (5 ml) was added to a stirred suspension of sodium hydride (0.048 g., 2 mmol) in dry dimethylformamide (5 ml) at −10° C. during 5 min. The reaction mixture was stirred for 30 min. Then methyl iodide (0.224 ml, 3.6 mmol) was added to the stirring reaction mixture. Stirring was continued for additional 1.25 hours during which the temperature was allowed to rise to room temperature (34° C.). The reaction mixture was quenched with water (0.2 ml), concentrated under vaccum, diluted with water (5 ml), extracted with chloroform (2×5 ml) and dried over sodium sulphate. The combined fractions of chloroform were concentrated under vaccum. The residue was chromatographed on silica gel using dichloromethane-hexane (20:80) as eluant to give 2q; yield: 0.42 g. (54.6%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=2)[CH:8]=[C:7](I)[CH:6]=1)[CH3:2].[CH:20]([C:23]1[N:24]=[N:25][S:26][CH:27]=1)([CH3:22])[CH3:21].C([O-])(=O)C.[K+]>CN(C=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=2)[CH:8]=[C:7]([C:27]2[S:26][N:25]=[N:24][C:23]=2[CH:20]([CH3:22])[CH3:21])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(I)cc(-c2ccc(C)cn2)c1
Reactant: CC(C)c1csnn1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2ccc(C)cn2)cc(-c2snnc2C(C)C)c1
Temperature: 120 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
A mixture of 3-iodo-5-(5-methyl-pyridin-2-yl)-benzoic acid ethyl ester (367 mg, 1 mmol), 4-isopropyl-[1,2,3]thiadiazole (640 mg, 5 mmol), palladium II tetrakis(triphenylphosphine) (35 mg, 0.03 mmol) and potassium acetate (196 mg, 2 mmol) in 10 mL of DMF was warmed to 120° C. and stirred for 16 hours. The reaction mixture was cooled and transferred directly onto a silica column and purified by liquid chromatography (0% to 10% EtOAc/hexanes) to give 250 mg of 3-(4-isopropyl-[1,2,3]thiadiazol-5-yl)-5-(5-methyl-pyridin-2-yl)-benzoic acid ethyl ester, MS (M+H)=368.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[NH:20][N:19]=[CH:18][CH:17]=2)[N:12]=[C:11]([N:21]2[CH2:26][C@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:24][C@H:23]([C:33]([O:35]C)=[O:34])[CH2:22]2)[N:10]=1.[OH-].[Na+]>CO>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[NH:20][N:19]=[CH:18][CH:17]=2)[N:12]=[C:11]([N:21]2[CH2:26][C@H:25]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:24][C@H:23]([C:33]([OH:35])=[O:34])[CH2:22]2)[N:10]=1
Reactant: COC(=O)[C@H]1C[C@@H](c2ccccc2)CN(c2nc(C)cc(Nc3ccn[nH]3)n2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Cc1cc(Nc2ccn[nH]2)nc(N2C[C@@H](C(=O)O)C[C@@H](c3ccccc3)C2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.8 %

Procedure:
To the solution of methyl cis-1-[4-methyl-6-(1H-pyrazol-5-ylamino)pyrimidin-2-yl]-5-phenylpiperidine-3-carboxylate trifluoroacetate (34.9 mg) in MeOH (3 ml) was added 2 M aqueous solution of NaOH (1 ml). And the mixture was stirred at room temperature for 1 hour. The mixture was concentrated followed by addition of TFA for neutralization. The residue was purified with preparative RP-HPLC to give cis-1-[4-methyl-6-(1H-pyrazol-5-ylamino)pyrimidin-2-yl]-5-phenylpiperidine-3-carboxylic acid trifluoroacetate (34.9 mg) as a colorless solid.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:5]([C:15]([O:17][CH3:18])=[O:16])[CH2:4]1.[F:19][C:20]([F:28])(S(F)(=O)=O)C(O)=O>[Cu]I.C(#N)C>[F:19][CH:20]([F:28])[O:1][CH2:2][C@@H:3]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:9])[C@H:5]([C:15]([O:17][CH3:18])=[O:16])[CH2:4]1
Reactant: COC(=O)[C@@H]1C[C@H](CO)CN1C(=O)OC(C)(C)C
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Agent: [Cu]I
Solvent: CC#N
Product: COC(=O)[C@@H]1C[C@H](COC(F)F)CN1C(=O)OC(C)(C)C
Temperature: 45 °C
Yield: 60.7 %

Procedure:
A 100 mL round-bottom flask was charged with (2S,4S)-1-tert-butyl 2-methyl 4-(hydroxymethyl)pyrrolidine-1,2-dicarboxylate (3.33 g, 12.84 mmol), CuI (0.489 g, 2.56 mmol), and anhydrous acetonitrile (57.1 mL). The reaction was heated to 45° C. (ext. oil bath). 2,2-difluoro-2-(fluorosulfonyl)acetic acid (2.655 mL, 25.68 mmol) was added at 45° C. over 30 minutes via syringe pump. The reaction was heated for 30 minutes. Upon completion as monitored by TLC, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was diluted in EtOAc and washed with sodium bicarbonate (aq). The bicarbonate layer was back extracted with ethyl acetate twice. Combined organic layers were washed with brine, dried over sodium sulphate, filtered and concentrated. The resulting residue was further purified via silica gel chromatography (10 to 40% EtOAc/Hexanes) to afford (2S,4S)-1-tert-butyl 2-methyl 4-((difluoromethoxy)methyl)pyrrolidine-1,2-dicarboxylate (2.41 g, 61%). MS (ESI) m/z 210.21
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([F:13])([F:12])[O:9]C(F)(F)[C:7]=2[CH:16]=1.[C-:17]#[N:18].[Na+]>CS(C)=O>[F:13][C:10]1([F:12])[O:11][C:6]2[CH:5]=[CH:4][C:3]([CH2:2][C:17]#[N:18])=[CH:16][C:7]=2[O:9]1
Reactant: FC1(F)Oc2ccc(CCl)cc2C(F)(F)O1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1ccc2c(c1)OC(F)(F)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
A mixture of 6-chloromethyl-2,2,4,4-tetrafluoro-4H-benzo[1,3]dioxine (6.2 g) and NaCN (2.07 g, 42.3 mmol) in DMSO (50 mL) was stirred at room temperature for 2 h. The reaction mixture was poured into ice and extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4, and evaporated to give a crude product, which was purified by silica gel column (Petroleum Ether/EtOAc 10:1) to give (2,2-difluoro-benzo[1,3]dioxol-5-yl)-acetonitrile (4.5 g, 68% over 3 steps). 1H NMR (CDCl3, 300 MHz) δ 7.57-7.60 (m, 2H), 7.20 (d, J=8.7 Hz, 1H), 3.82 (s, 2H).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][C:10]([OH:12])=[O:11])[N:8]=1)=[O:2].[Cl:13]N1C(=O)CCC1=O>O1CCCC1>[Cl:13][C:6]1[S:5][C:4]([NH:3][CH:1]=[O:2])=[N:8][C:7]=1[CH2:9][C:10]([OH:12])=[O:11]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=CNc1nc(CC(=O)O)cs1
Solvent: C1CCOC1
Product: O=CNc1nc(CC(=O)O)c(Cl)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.3 %

Procedure:
To a solution of 2-formamido-4-carboxymethylthiazole (2.0 g) in tetrahydrofuran (20 ml) was added N-chlorosuccinimide (1.58 g) and stirred at room temperature overnight. The reaction mixture was added N-chlorosuccinimide (0.5 g) and stirred at the same temperature overnight. The reaction mixture was evaporated under reduced pressure and purified by column chromatography on silica gel (SiO2 =200 ml, chloroform:methanol:acetic acid=20:1:0.1) to give two fractions. The fraction 1 (upper spot by TLC) was purified by column chromatography on silica gel (SiO2 =200 ml, methanol:chloroform=2:8), then the elution was evaporated under reduced pressure. The residue was dissolved in a mixture of water and ethyl acetate, adjusted to pH 8.7 with saturated sodium hydrogencarbonate, and washed with ethyl acetate (×2). The aqueous layer was adjusted to pH 3.0 with 1N-hydrochloric acid, extracted with ethyl acetate (×2), dried over magnesium sulfate, and evaporated under reduced pressure to give white solid which was precipitated from ethyl acetate and N-hexane to give 5-chloro-2-formamido-4-carboxymethylthiazole (694 mg, 29.3%) as a white powder.