Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: IC.[CH3:3][C:4]1[CH:5]=[C:6]([OH:13])[C:7](=[CH:11][CH:12]=1)[C:8]([OH:10])=[O:9].[C:14](=O)([O-])[O-].[Li+].[Li+]>CN(C)C=O>[OH:13][C:6]1[CH:5]=[C:4]([CH3:3])[CH:12]=[CH:11][C:7]=1[C:8]([O:10][CH3:14])=[O:9]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(C(=O)O)c(O)c1
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(C)cc1O
Temperature: 60 °C
Reaction time: 3.5 h

Procedure:
Iodomethane (22.6 mL, 362 mmol, 1.1 equiv) was added to a suspension of 4-methylsalicylic acid (50.0 g, 329 mmol, 1 equiv) and lithium carbonate (26.8 g, 362 mmol, 1.1 equiv) in dimethylformamide (450 mL) at 23° C. The reaction flask was heated in an oil bath at 60° C. After 3.5 h, the warm suspension was partitioned carefully between ice water (500 mL) and ethyl acetate (800 mL). The layers were separated. The aqueous layer was extracted with ethyl acetate (800 mL). The organic layers were combined. The combined solution was washed sequentially with water (2×500 mL) then saturated aqueous sodium chloride solution (500 mL) and the washed solution was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. A small sample of the product (˜50 mg) was purified by flash-column chromatography (2% ethyl acetate-hexanes) and was characterized by 1H NMR, 13C NMR, IR, and HRMS. The balance of the product, methyl 2-hydroxy-4-methylbenzoate, was used directly in the next reaction without purification. TLC: (2% ethyl acetate-hexanes) Rf=0.15 (CAM); 1H NMR (500 MHz, CDCl3) δ: 10.70 (s, 1H), 7.70 (d, 1H, J=8.4 Hz), 6.79 (s, 1H), 6.69 (d, 1H, J=7.7 Hz), 3.92 (s, 3H), 2.34 (s, 3H); 13C NMR (125 MHz, CDCl3) δ: 170.5, 161.5, 147.0, 129.6, 120.4, 117.7, 109.8, 52.0, 21.8; FTIR (neat), cm−1: 3186 (m), 2956 (m), 1672 (s), 1623 (m), 1579 (m), 1504 (m), 1441 (s), 1338 (s), 1298 (s), 1250 (s), 1215 (s), 1157 (s), 1096 (s), 906 (s), 780 (s); HRMS (ESI): Calcd for (C9H10O3+H)+ 167.0703, found 167.0698.
Reaction SMILES: [CH3:1][N:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:3]1[N:8]=[C:7]([NH2:9])[N:6]=[C:5]([C:10]2[N:14]=[C:13](C(Cl)(Cl)Cl)[O:12][N:11]=2)[N:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[F:32][C:33]([F:44])([F:43])[CH2:34][O:35][CH2:36][CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>CN(C=O)C>[CH3:1][N:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:3]1[N:8]=[C:7]([NH2:9])[N:6]=[C:5]([C:10]2[N:14]=[C:13]([N:40]3[CH2:39][CH2:38][CH:37]([CH2:36][O:35][CH2:34][C:33]([F:32])([F:43])[F:44])[CH2:42][CH2:41]3)[O:12][N:11]=2)[N:4]=1
Reactant: FC(F)(F)COCC1CCNCC1
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(C(Cl)(Cl)Cl)n2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(N3CCC(COCC(F)(F)F)CC3)n2)n1
Reaction time: 0.08 h
Yield: 18 %

Procedure:
2-N-methyl-2-N-phenyl-6-[5-(trichloromethyl)-1,2,4-oxadiazol-3-yl]-1,3,5-triazine-2,4-diamine (prepared in an analogous manner to Intermediate 60, 0.110 g, 0.285 mmol) was added to a mixture of potassium carbonate (0.071 g, 0.518 mmol) in DMF (2 mL) at room temperature and the mixture was stirred for 5 min. 4-[(2,2,2-trifluoroethoxy)methyl]piperidine hydrochloride (Intermediate 179, 0.060 g, 0.259 mmol) was added to the reaction mixture and stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, dissolved in water and extracted with EtOAc. The combined organic extracts was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by FCC (EtOAc:heptane 1:1) and preparative HPLC, Method A, to afford the title compound (22.1 mg, 18%).
Reaction SMILES: Br[C:2]1[C:15]2[C@:14]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:12]=3)[O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:27][CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30].[C:33]([Zn]C#N)#[N:34].CN(C=O)C>O.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>[NH2:20][C:17]1[O:18][CH2:19][C@@:14]2([N:16]=1)[C:15]1[C:2]([C:33]#[N:34])=[C:3]([O:27][CH2:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH:4]=[CH:5][C:6]=1[O:7][C:8]1[C:13]2=[CH:12][C:11]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)COc1ccc2c(c1Br)[C@]1(COC(N)=N1)c1cc(-c3cccnc3)ccc1O2
Reactant: N#C[Zn]C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)COc1ccc2c(c1C#N)[C@]1(COC(N)=N1)c1cc(-c3cccnc3)ccc1O2

Procedure:
A vial was charged with (S)—1′-bromo-2′-(neopentyloxy)-7′-(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (68.1 mg, 0.138 mmol), dicyanozinc (81 mg, 0.689 mmol), tetrakis(triphenylphosphine)palladium(0) (31.8 mg, 0.028 mmol), and DMF (689 μL). The vial was sealed and placed in a 120° C. oil bath for 12 hours. The mixture was diluted with water and extracted with DCM (3×). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was chromatographed on a 25-g SNAP column, eluting with a 90:10:1 mix of DCM/MeOH/NH4OH in DCM. This gave ca. 40 mg of a white powder that was impure by HPLC. The solid was combined with 104487-6-2 in DMSO/MeOH and purified by reverse-phase HPLC (10-90% CH3CN/H2O with 0.1% TFA). The fractions containing product were combined in saturated aq. sodium bicarbonate solution with the aid of methanol and extracted with DCM (3×). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated to give (S)-2-amino-2′-(neopentyloxy)-7′-(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthene]-1′-carbonitrile as an off-white powder after evaporation from DCM/hexane.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>O1CCCC1>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][C:2]([N:18]2[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]2)=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1)=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.9 %

Procedure:
To a solution of methyl 4-fluoro-3-nitrobenzoate (2.50 g, 12.6 mmol) in tetrahydrofuran (75 mL), tert-butyl piperazine-1-carboxylate (4.67 g, 25.2 mmol) and potassium carbonate (4.34 g, 25.2 mmol) were added sequentially under ice-cold conditions, and the mixture was stirred at room temperature for 1 hour. The reaction solution was added water under ice-cold conditions, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (ethyl acetate). The title compound (4.83 g (yield 100%)) was obtained as a yellow crystal.
Reaction SMILES: [CH:1]1([CH:5]=O)[CH2:4][CH2:3][CH2:2]1.[O:7]1[CH2:11][CH2:10][O:9][C:8]21[CH2:20][CH2:19][C@@H:18]1[C@@:13]34[C:27]5[C:22](=[CH:23][CH:24]=[C:25]([C:29]#[N:30])[C:26]=5[O:28][C@@H:12]23)[CH2:21][C@H:17]1[NH:16][CH2:15][CH2:14]4.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:1]1([CH2:5][N:16]2[CH2:15][CH2:14][C@@:13]34[C:27]5[C:22]6[CH2:21][C@@H:17]2[C@@H:18]3[CH2:19][CH2:20][C:8]2([C@@H:12]4[O:28][C:26]=5[C:25]([C:29]#[N:30])=[CH:24][CH:23]=6)[O:7][CH2:11][CH2:10][O:9]2)[CH2:2][CH2:3][CH2:4]1
Reactant: N#Cc1ccc2c3c1O[C@H]1C4(CC[C@H]5[C@@H](C2)NCC[C@@]351)OCCO4
Reactant: O=CC1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc2c3c1O[C@H]1C4(CC[C@H]5[C@@H](C2)N(CC2CCC2)CC[C@@]351)OCCO4
Reaction time: 1 h
Yield: 102.8 %

Procedure:
To a solution of cyclobutane carboxaldehyde (19.45 g, 231.2 mmol) in dichloromethane (500 mL) was added (4R,4aR,7aR,12bS)-1,2,3,4,4a,5,6,7a-octahydrospiro[4,12-methanobenzofuro[3,2-e]isoquinoline-7,2′-[1,3]dioxolane]-9-carbonitrile (25 g, 77.1 mmol). The reaction was stirred for 60 minutes at room temperature before sodium triacetoxyborohydride (32.7 g, 154.0 mmol) was added portionwise over 20 minutes. After one hour, the reaction was quenched with NaHCO3 solution and extracted with dichloromethane (×3). The dichloromethane phases were combined, washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica chromatography eluted with dichloromethane to 7% methanol in dichloromethane to give (4R,4aR,7aR,12bS)-3-(cyclobutylmethyl)-1,2,3,4,4a,5,6,7a-octahydrospiro[4,12-methanobenzofuro[3,2-e]isoquinoline-7,2′-[1,3]dioxolane]-9-carbonitrile (31.1 g, 98% pure LCMS, assume quant.); [M+H]+393.1.
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]([O:15][C:16]1[CH:24]=[CH:23][C:19]2[O:20][CH2:21][O:22][C:18]=2[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1)C.[CH3:26][C:27]1[O:31][C:30]([C:32]2([CH3:38])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[N:29][C:28]=1[CH2:39][CH2:40][O:41]S(C1C=CC(C)=CC=1)(=O)=O>>[O:20]1[C:19]2[CH:23]=[CH:24][C:16]([O:15][C:5]([CH3:14])([CH2:6][C:7]3[CH:12]=[CH:11][C:10]([O:41][CH2:40][CH2:39][C:28]4[N:29]=[C:30]([C:32]5([CH3:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]5)[O:31][C:27]=4[CH3:26])=[CH:9][CH:8]=3)[C:4]([OH:25])=[O:3])=[CH:17][C:18]=2[O:22][CH2:21]1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc2c(c1)OCO2
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3(C)CCCCC3)oc2C)cc1
Product: Cc1oc(C2(C)CCCCC2)nc1CCOc1ccc(CC(C)(Oc2ccc3c(c2)OCO3)C(=O)O)cc1

Procedure:
The title compound was prepared from 2-(benzo[1,3]dioxol-5-yloxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-[5-methyl-2-(1-methylcyclohexyl)oxazol-4-yl]-ethyl ester using the procedure of Example 78. 1H NMR (400 MHz, CDCl3) δ 7.17 (d, 2H, J=8.60 Hz), 6.79 (d, 2H, J=8.60 Hz), 6.65 (d, 1H, J=8.21 Hz), 6.47 (d, 1H, J=2.35 Hz), 6.37 (dd, 1H, J=8.21 Hz, J=2.35 Hz), 5.92 (d, 2H, J=0.78 Hz), 4.14 (t, 2H, J=6.25 Hz), 3.19 (d, 1H, J=14.08 Hz), 3.07 (d, 1H, J=14.08 Hz), 2.98 (t, 2H, J=6.25 Hz), 2.31 (s, 3H), 2.17-2.08 (m, 2H), 1.62-1.35 (m, 8H), 1.34 (s, 3H), 1.31 (s, 3H); MS (ES+) calcd for C30H35NO7: Found m/e 522.3 (M+1, 100%).
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]([CH3:12])[N:3]=1.Cl[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]2[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[S:26][C:27]=2[CH3:28])=[N:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:12][N:4]1[CH:5]=[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:2]([O:1][CH2:14][C:15]2[CH:20]=[N:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[S:26][C:27]=3[CH3:28])=[CH:17][CH:16]=2)=[N:3]1
Reactant: Cc1sc(-c2ccccc2)nc1COc1ccc(CCl)cn1
Reactant: COC(=O)Cc1cn(C)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cn(C)nc1OCc1ccc(OCc2nc(-c3ccccc3)sc2C)nc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 72 %

Procedure:
A mixture of methyl (3-hydroxy-1-methyl-1H-pyrazol-4-yl)acetate (255 mg), 5-chloromethyl-2-(5-methyl-2-phenyl-4-thiazolylmethoxy)pyridine (496 mg), potassium carbonate (415 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 5 hrs. The reaction mixture was poured into 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, and methyl [1-methyl-3-[6-(5-methyl-2-phenyl-4-thiazolylmethoxy)-3-pyridylmethoxy]-1H-pyrazol-4-yl]acetate (501 mg, yield 72%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][O:7][C:8]1[C:13]2[CH2:14][CH:15]([CH3:17])[O:16][C:12]=2[C:11]([C:18]([OH:20])=[O:19])=[CH:10][CH:9]=1>>[Cl:1][S:2]([C:9]1[CH:10]=[C:11]([C:18]([OH:20])=[O:19])[C:12]2[O:16][CH:15]([CH3:17])[CH2:14][C:13]=2[C:8]=1[O:7][CH3:6])(=[O:5])=[O:3]
Reactant: COc1ccc(C(=O)O)c2c1CC(C)O2
Reactant: O=S(=O)(O)Cl
Product: COc1c(S(=O)(=O)Cl)cc(C(=O)O)c2c1CC(C)O2
Temperature: 50 °C

Procedure:
218 g of chlorosulphonic acid were introduced into a 500 ml round-bottomed flask and 65 g of finely ground 4-methoxy-2-methyl-2,3-dihydrobenzofuran-7-carboxylic acid were added in small amounts. The temperature rose to 38° C. The contents were then heated to 50° C. After cooling, the solution obtained was poured, in small amounts, onto ice, with stirring.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([CH3:30])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[CH:28][CH:27]=[N:26]3)=[CH:21][CH:20]=1)[C:10](=[O:17])[NH:11]2.Cl[CH:33]([F:35])[F:34]>>[CH3:1][O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([CH3:30])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[CH:28][CH:27]=[N:26]3)=[CH:21][CH:20]=1)[C:10]([O:17][CH:33]([F:35])[F:34])=[N:11]2
Reactant: FC(F)Cl
Reactant: COC(=O)COc1ccc(Cl)c2[nH]c(=O)c(Cc3ccc(-n4cccn4)cc3)c(C)c12
Product: COC(=O)COc1ccc(Cl)c2nc(OC(F)F)c(Cc3ccc(-n4cccn4)cc3)c(C)c12

Procedure:
The title compound was prepared by the method of Preparation 10c using [8-chloro-4-methyl-2-oxo-3-(4-pyrazol-1-ylbenzyl)-1,2-dihydroquinolin-5-yloxy]acetic acid methyl ester and chlorodifluoromethane.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:12][NH:13][C:14]([C:16]2[C:32]([OH:33])=[C:19]3[C:20](=[O:31])[N:21]([CH3:30])[CH2:22][C@H:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:18]3[N:17]=2)=[O:15])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:12][NH:13][C:14]([C:16]2[C:32]([OH:33])=[C:19]3[C:20](=[O:31])[N:21]([CH3:30])[CH2:22][C@H:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:18]3[N:17]=2)=[O:15])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(F)ccc1CNC(=O)c1nn2c(c1O)C(=O)N(C)C[C@@H]2c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1C[C@H](c2ccccc2)n2nc(C(=O)NCc3ccc(F)cc3C(=O)O)c(O)c2C1=O
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-fluoro-2-[({[(7S)-3-hydroxy-5-methyl-4-oxo-7-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]carbonyl}amino)methyl]benzoate (48 mg, 0.106 mmol) in MeOH (1 mL) was added aqueous 1N NaOH (233 μL, 0.233 mmol). The reaction was stirred at 45° C. overnight. Purification by reverse phase chromatography on a C-18 column using a gradient elution of 95-5% H2O (0.1% TFA)/CH3CN (0.1% TFA) and collection and concentration of the appropriate fractions afforded the title product. ES MS (M+1)=439.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:20]([OH:22])=[O:21])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1C=CC(S(O[CH2:34][CH2:35][F:36])(=O)=O)=CC=1>>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:34][CH2:35][F:36])[CH:12]=1)[C:20]([OH:22])=[O:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Product: CC(C)(C)OC(=O)N[C@H](Cc1cn(CCF)c2ccccc12)C(=O)O
Yield: 66.8 %

Procedure:
The procedure of Referential Example 1(a) was repeated, except that N-tert-butoxycarbonyl-D-tryptophan (700 mg) and 2-fluoroethyl 4-methylbenzenesulfonate (753 mg) were used, whereby the title compound (538 mg) was yielded.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:12]=[C:11]([C:13](N(OC)C)=[O:14])[NH:10][N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[CH3:19][Mg+].[Br-]>C1COCC1>[CH3:7][C:4]1[N:3]([C:8]2[CH:12]=[C:11]([C:13](=[O:14])[CH3:19])[NH:10][N:9]=2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: C[Mg+]
Reactant: CON(C)C(=O)c1cc(-n2c(C)ccc2C)n[nH]1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)c1cc(-n2c(C)ccc2C)n[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.6 %

Procedure:
A 250-mL round-bottomed flask equipped with a magnetic stirrer was charged with 150c (7.44 g, 1.0 eq., 30.0 mmol) and THF (100 mL). Under N2 protection, a solution of MeMgBr (3.0 Min ether) (25 mL, 2.5 eq., 75.0 mmol) was added at 0° C. The mixture was stirred at room temperature for 5 h and quenched with saturated NH4Cl solution (30 mL). The mixture was concentrated under reduced pressure and the residue was extracted with ethyl acetate (3×50 mL). The combined organic layer was evaporated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 4:1 petroleum ether/ethyl acetate to afford 150d as a white solid (5.40 g, 89%). MS-ESI: [M+H]+ 204.0. 1H NMR (500 MHz, CDCl3) δ 6.74 (s, 1H), 5.92 (s, 2H), 2.61 (s, 3H), 2.15 (s, 6H).
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[S:10][C:9]([CH2:11][NH:12][C:13](=[O:15])[CH3:14])=[N:8][CH:7]=1)(=[O:5])[CH3:4].Br>C(O)(=O)C>[C:13]([NH:12][CH2:11][C:9]1[S:10][C:6]([C:3](=[O:5])[CH2:4][Br:1])=[CH:7][N:8]=1)(=[O:15])[CH3:14]
Reactant: BrBr
Reactant: CC(=O)NCc1ncc(C(C)=O)s1
Agent: Br
Solvent: CC(=O)O
Product: CC(=O)NCc1ncc(C(=O)CBr)s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 107.4 %

Procedure:
A solution of bromine (1.61 g) in acetic acid (4 ml) was added dropwise to a mixture of 5-acetyl-2-acetylaminomethylthiazole (2.00 g), 30 (W/W) % hydrobromic acid solution in acetic acid (5 ml) and acetic acid (40 ml) at ambient temperature. After stirring for 24 hours at ambient temperature, the resulting precipitate was collected by filtration and washed with acetic acid to give 2-(acetylaminomethyl)-5-bromoacetylthiazole (3.00 g).
Reaction SMILES: [C:1]([C:4]1[S:5][C:6]([Br:9])=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[C:10](OC)(=[O:15])[C:11]([O:13][CH3:14])=[O:12].C[O-].[Na+].Cl>CO>[CH3:14][O:13][C:11](=[O:12])[C:10](=[O:15])[CH2:2][C:1]([C:4]1[S:5][C:6]([Br:9])=[CH:7][CH:8]=1)=[O:3]
Reactant: CC(=O)c1ccc(Br)s1
Reactant: COC(=O)C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(=O)CC(=O)c1ccc(Br)s1
Temperature: 20 °C
Reaction time: 4 h
Yield: 88.1 %

Procedure:
To a solution of 2-acetyl-5-bromothiophene (25 g, 122 mmol) and dimethyl oxalate (23 g, 194 mmol) in dry methanol (800 mL) was added a solution of NaOMe in MeOH (25%, 51 mL, 224 mmol) at ambient temperature. The reaction mixture was stirred at 20° C. for 4 h and then acidified to pH 1 with 6 N aqueous HCl. The yellow solid was collected by filtration, washed with H2O, and dried under high vacuum to afford 4-(5-bromo-thiophen-2-yl)-2,4-dioxo-butyric acid methyl ester (31.3 g, 88%). 1H-NMR (DMSO-d6): δ 8.14 (s, 1H), 7.46 (d, 1H), 7.05 (s, 1H), 3.85 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[O:22])=[CH:4][C:3]=1[CH3:35].[CH2:36]([S:38]([NH2:41])(=[O:40])=[O:39])[CH3:37]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH:41][S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:24][CH2:25][CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:27][CH2:28]2)=[O:22])=[CH:4][C:3]=1[CH3:35]
Reactant: CCS(N)(=O)=O
Reactant: Cc1cc(Nc2c(C(=O)N3CCC(c4ccccc4)CC3)cnc3c(C(=O)O)cnn23)ccc1F
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccc(F)c(C)c3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 55.9 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(4-fluoro-3-methylphenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (60 mg, 0.13 mmol) obtained in step 2 and ethanesulfonamide (56 mg, 0.51 mmol), the title compound (0.041 g, 57%) was obtained.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)(=[O:13])=[O:12])=[O:9])=[N:4][CH:3]=1.[CH3:21][S:22](C)=O>CO>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:8](=[O:9])[NH:7][C:5]2[S:6][C:2]([S:22][CH3:21])=[CH:3][N:4]=2)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Nc1ncc(Br)s1)NS(=O)(=O)c1cccc(Cl)c1
Reactant: CS(C)=O
Solvent: CO
Product: CSc1cnc(NC(=O)NS(=O)(=O)c2cccc(Cl)c2)s1

Procedure:
Sodium methane thiolate (0.42 g, 6.0 mmol) was added to a suspension of N-[(5-bromo-1,3-thiazol-2-yl)carbamoyl]-3-chlorobenzenesulfonamide (0.60 g, 1.5 mmol) in methanol (30 ml). The mixture was heated under refluxed for 60 hours and concentrated under reduced pressure. A part of the crude (80 mg) was dissolved in acetonitrile-water and acidified using acetic acid. The precipitate formed was redissolved in DMSO and purified by preparative RP-HPLC: 14 mg lyophilisate, MS: m/e 362.1 (MH−).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:17]#[CH:18])[C:5]([CH3:16])=[C:6]([NH:8]C(=O)OC(C)(C)C)[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:17]#[CH:18])[C:5]([CH3:16])=[C:6]([CH:7]=1)[NH2:8]
Reactant: C#Cc1cc(Cl)cc(NC(=O)OC(C)(C)C)c1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C#Cc1cc(Cl)cc(N)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.6 %

Procedure:
To a solution of 1,1-dimethylethyl (5-chloro-3-ethynyl-2-methylphenyl)carbamate (242 mg, 0.91 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (500 μl). The solution was stirred at ambient temperature for 1 hour. The solution was partitioned between saturated sodium bicarbonate and dichloromethane. The aqueous layer was extracted twice with dichloromethane. The combined organic portions were washed with brine, dried over sodium sulfate, filtered and concentrated in-vacuo to afford an orange oil which was purified by column chromatography (silica gel, 50% dichloromethane in hexane). The product was collected to afford 60 mg, 0.36 mmol (40%) of 5-chloro-3-ethynyl-2-methylaniline as a white solid. 1H NMR (400 MHz, CDCl3): 6.90 (d, 1H), 6.63 (d, 1H), 3.71 (br s, 2H), 3.24 (s, 1H), 2.23 (s, 3H); MS (EI) for C9H8ClN: 166 (MH+).
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[CH2:6][C:7]1([OH:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.CN(C)C=O>C1C=CC=CC=1>[C:7]12([CH2:6][C:5]3[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=3[O:14]1)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2
Reactant: OC1(Cc2ccccc2F)CCCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: c1ccc2c(c1)CC1(CCCCCC1)O2
Temperature: 0 °C
Yield: 44.2 %

Procedure:
To a stirred suspension of 23.32 g of sodium hydride (as a 50% dispersion in mineral oil) in 1.5 liters of benzene (dried over molecular sieves) was rapidly added a solution of 69.9 g of 1-(2-fluorobenzyl)-1-hydroxycycloheptane in 500 ml of benzene. After the addition the mixture was heated to reflux under nitrogen, and 100 ml of dimethylformamide (distilled over BaO) was added to the refluxing mixture. After 118 hours of reflux, the mixture was cooled in ice water and treated with 2.0 liters distilled water. After stirring for a few minutes the phases were separated and the aqueous phase was extracted with hexane (once with 2 liters and twice with one liter). The combined organic extracts were washed with water (1.0 liter) and saturated sodium chloride solution (1.0 liter) and thereafter dried over anhydrous sodium sulfate. Filtration and concentration in vacuo afforded 65.9 g of a crude oil which was given a preliminary purification by preparative HPLC using dichloromethane as solvent. This treatment afforded 28.09 g of product as well as 9.2 g of unreacted starting material. The product was further purified by preparatory HPLC, using hexane/dichloromethane (4:1) as a solvent. This treatment afforded 21.18 g of product as an oil which was 97.6% pure by GC. Vacuum distillation of this material afforded 6.17 g of pure distillate, b.p. 85°-87° C. @ 0.20 mm.