Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@@H:16]([CH3:20])[C:17]([OH:19])=O)[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].C1C(=O)N(O)C(=O)C1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:44][N:45]1[CH2:49][C@@H:48]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[NH:47][C:46]1=[O:57]>>[CH3:44][N:45]1[CH2:49][C@@H:48]([C:50]([O:52][C:53]([CH3:55])([CH3:54])[CH3:56])=[O:51])[N:47]([C:17](=[O:19])[C@@H:16]([NH:15][C@H:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:20])[C:46]1=[O:57]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)O
Reactant: CN1C[C@@H](C(=O)OC(C)(C)C)NC1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1C(=O)N(C)C[C@H]1C(=O)OC(C)(C)C
Yield: 70.5 %

Procedure:
560 mg of (2S)-2-[N-((1S)-1-ethoxycarbonyl-3-phenylpropyl)amino]propionic acid, 230 mg of 1-hydroxysuccinimide, 413 mg of dicyclohexylcarbodiimide and 400 mg of tert.-butyl (4S)-1-methyl-2-oxo-imidazolidine-4-carboxylate are treated in the same manner as described in Example 1-(1), whereby 650 mg of tert.-butyl (4S)-1-methyl-3-{(2S)-2-[N-((1S)-1-ethoxycarbonyl-3-phenylpropyl)amino]propionyl}-2-oxo-imidazolidine-4-carboxylate are obtained as colorless viscous oil. Yield: 70.4%
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][S:17](=[O:20])[CH2:16][CH2:15]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([NH:12][CH3:13])[C:6]=2[N:7]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>O1CCOCC1>[CH3:13][NH:12][C:8]1[C:6]2[N:7]=[C:2]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:3]=[C:4]([N:14]3[CH2:19][CH2:18][S:17](=[O:20])[CH2:16][CH2:15]3)[C:5]=2[N:11]=[CH:10][N:9]=1
Reactant: CNc1ncnc2c(N3CCS(=O)CC3)nc(Cl)nc12
Reactant: C1CNCCN1
Solvent: C1COCCO1
Product: CNc1ncnc2c(N3CCS(=O)CC3)nc(N3CCNCC3)nc12

Procedure:
This compound was prepared analogous to Example 118 from 2-chloro-8-methylamino-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 278°-280° C.) and piperazine in dioxane at 80° C.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[C:9]([CH:27]=[CH:28][CH:29]=2)[CH2:10][N:11]2[C:15]3=[N:16][C:17]([NH:20][C:21]4[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=4)=[N:18][CH:19]=[C:14]3[CH:13]=[N:12]2)[CH2:3][CH2:2]1>CO.[Pd]>[CH3:26][N:24]1[CH:25]=[C:21]([NH:20][C:17]2[N:16]=[C:15]3[N:11]([CH2:10][C:9]4[CH:27]=[CH:28][CH:29]=[C:7]([CH:4]5[CH2:5][CH2:6][O:1][CH2:2][CH2:3]5)[CH:8]=4)[N:12]=[CH:13][C:14]3=[CH:19][N:18]=2)[CH:22]=[N:23]1
Reactant: Cn1cc(Nc2ncc3cnn(Cc4cccc(C5=CCOCC5)c4)c3n2)cn1
Agent: [Pd]
Solvent: CO
Product: Cn1cc(Nc2ncc3cnn(Cc4cccc(C5CCOCC5)c4)c3n2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
1-(3-(3,6-dihydro-2H-pyran-4-yl)benzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine was dissolved in methanol (8 mL) and palladium on carbon was added under an inert atmosphere. The reaction mixture was stirred overnight at rt under a hydrogen atmosphere. The mixture was filtered over Celite, then evaporated, and the residue was purified by preparative HPLC to afford the title compound (13 mg, 32 μmol, 38% over two steps). 1H NMR (d6-DMSO) δ 9.84 (s, 1H), 8.91 (s, 1H), 8.11-8.02 (m, 2H), 7.58 (s, 1H), 7.31-7.22 (m, 2H), 7.19-7.14 (m, 1H), 7.13-7.07 (m, 1H), 5.54 (s, 2H), 3.94-3.86 (m, 2H), 3.85 (s, 3H), 3.44-3.35 (m, 2H), 2.75-2.65 (m, 1H), 1.66-1.54 (m, 4H); LC-MS method B, (ES+) 390.2, RT=8.40 min.
Reaction SMILES: Br[CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[CH3:12][C:13]1[C:14]2[N:15]([N:19]=[C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH2:28])[CH:23]=3)[N:21]=2)[CH:16]=[CH:17][N:18]=1.C(N(CC)C(C)C)(C)C>C(O)C>[CH3:12][C:13]1[C:14]2[N:15]([N:19]=[C:20]([C:22]3[CH:27]=[CH:26][N:25]4[C:2]([CH3:11])=[C:3]([C:5]5[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:28]=[C:24]4[CH:23]=3)[N:21]=2)[CH:16]=[CH:17][N:18]=1
Reactant: Cc1nccn2nc(-c3ccnc(N)c3)nc12
Reactant: CC(Br)C(=O)c1ccccc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nccn2nc(-c3ccn4c(C)c(-c5ccccc5)nc4c3)nc12
Temperature: 80 °C
Yield: 18 %

Procedure:
2-Bromopropiophenone (0.034 ml, 0.221 mmol) was added to a solution of 4-(8-methyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)pyridin-2-amine (0.025 g, 0.111 mmol) in Ethanol (2.2 ml) and the mixture was heated at 80° C. for 40 hours. LC/MS analysis of the reaction mixture indicates reaction approximately 40% complete. The reaction mixture was transferred to a microwave reaction tube and N,N-diisopropylethylamine (0.059 ml, 0.332 mmol) was added. The reaction mixture was heated at 110° C. under standard microwave conditions for 2 hours. LC/MS analysis indicates reaction completion. The reaction mixture was concentrated in vacuo. The crude product was purified by flash chromatography (silica gel; 30-100% EtOAc/hexanes) to afford a tan solid (0.007 g, 0.020 mmol, 18.05% yield). 1H NMR (400 MHz, METHANOL-d4) δ 8.76 (d, J=4.5 Hz, 1H), 8.51 (s, 1H), 8.42 (d, J=6.5 Hz, 1H), 8.08 (d, J=4.5 Hz, 1H), 7.90 (dd, J=7.2, 1.6 Hz, 1H), 7.82-7.75 (m, 2H), 7.52 (t, J=7.5 Hz, 2H), 7.42 (s, 1H), 2.97 (s, 3H), 2.73 (s, 3H), LC/MS: (Method 2) Anal. Calcd. for [M+H]+C20H17N6: 341.15. Found: 341.07.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH:7](P(OC)(OC)=O)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2].[C:23]([C:27]1[O:31][CH:30]=[N:29][C:28]=1[CH:32]=O)([CH3:26])([CH3:25])[CH3:24].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:1]([O:5][C:6]([C:7]([NH:8][C:9](=[O:10])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[CH:32][C:28]1[N:29]=[CH:30][O:31][C:27]=1[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: COP(=O)(OC)C(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CC(C)(C)c1ocnc1C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(=Cc1ncoc1C(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 47.2 %

Procedure:
To a solution of N-(tert-Butoxycarbonyl)-α-dimethylphosphonoglycine-tert-butyl ester (11.8 g, 34.68 mmol) and 5-tert-butyloxazole-4-carboxaldehyde (6.9 g, 45.08 mmol) in DMF (50 mL) was added Cs2CO3 (12.4 g, 38.15 mmol) under an argon atmosphere at room temperature. The reaction mixture was stirred for 14 h at room temperature. After removal of solvent in vacuo, the residue was dissolved in AcOEt, successively washed with 10% citric acid, 5% NaHCO3 and saturated NaCl for three times, dried over Na2SO4, and concentrated in vacuo. The residual oil was purified by a silica gel column chromatography to yield 6.0 g (47%) of title compound as a white solid: mp 170-172° C.; 1H NMR (300 MHz, CDCl3) δ 7.74 (s, 1H), 6.55 (s, 1H), 1.54 (s, 9H), 1.49 (s, 9H), 1.38 (s, 9H); HRMS (EI): m/z 366.2159 (M+) (calcd for C19H30N2O5: 366.2154).
Reaction SMILES: C([CH:8]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[C:20]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])C1C=CC=CC=1>CCOC(C)=O.[Pt]>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:19][C:20]=1[O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(c1ccccc1)C(Cc1ccccc1)Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Agent: [Pt]
Solvent: CCOC(C)=O
Product: Nc1ccc(CC(C(=O)c2ccccc2)c2ccccc2)cc1OCc1ccccc1

Procedure:
A solution of 2-benzyl-3-(3-benzyloxy-4-nitrophenyl)-1-phenylpropan-1-one (200 mg) in EtOAc (5 mL) is hydrogenated over 5% Pt/C (15 mg) at 1 atm for 18 h. The catalyst is filtered and the filtrate evaporated to give the title compound as a gum: (M+1)+=422.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([CH:21]=[O:22])=[CH:19][N:18]=[C:17]3[NH:23][CH:24]=[CH:25][C:16]=23)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34].O>CN(C)C=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([CH:21]=[O:22])=[CH:19][N:18]=[C:17]3[N:23]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:24]=[CH:25][C:16]=23)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cnc2[nH]ccc2c1NC1CCN(Cc2ccccc2)CC1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c(NC3CCN(Cc4ccccc4)CC3)c(C=O)cnc21
Reaction time: 0.5 h
Yield: 42 %

Procedure:
4-[(1-Benzylpiperidin-4-yl)amino]-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (672 mg, 2.01 mmol) in N,N-dimethylformamide (5 mL) was mixed with sodium hydride (55 wt % dispersion in mineral oil, 436 mg, 10.0 mmol) under cooling with ice, and the reaction mixture was stirred for 30 minutes. The reaction mixture was stirred with [2-(chloromethoxyl)ethyl]trimethylsilane (885 μL, 5.00 mmol) at room temperature for one day. After addition of water, the reaction mixture was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1 (v/v)) to give the title compound (392 mg, yield 42%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10](Cl)=[O:11].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:17]=[CH2:18]>C(Cl)Cl>[Cl:8][C:6]1[CH:5]=[C:4]2[C:3](=[C:2]([Cl:1])[CH:7]=1)[CH2:9][C:10](=[O:11])[CH2:18][CH2:17]2
Reactant: O=C(Cl)Cc1ccc(Cl)cc1Cl
Reactant: C=C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1CCc2cc(Cl)cc(Cl)c2C1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
149.4 g of 2,4-dichlorophenylacetyl chloride dissolved in 200 ml of methylene chloride were added dropwise within 60 minutes to 115 g of aluminum chloride in 700 ml of methylene chloride while stirring at 0° to 5°. Thereafter, ethylene was introduced at between 0° and 5° during 30 minutes, whereupon the mixture was stirred further at room temperature for 1 hour and thereafter treated at between 0° to 5° with 300 ml of ice-water. The methylene chloride phase was washed, respectively, with 2N hydrochloric acid, with water, with saturated sodium bicarbonate solution and again with water. The aqueous phases were extracted with methylene chloride. The methylene chloride phases were combined, dried and evaporated. The residue was triturated with 100 ml of low-boiling petroleum ether, a further 250 ml of low-boiling petroleum ether were later added thereto and the mixture was left to stand in a refrigerator for 72 hours. The solid was filtered off and filtered over 600 g of silica gel (particle size 0.2-0.5 mm) while eluting with chloroform. There was obtained 6,8-dichloro-3,4-dihydro-2(1H)-naphthalenone which exhibits a melting point of 90°-92° after recrystallization from low-boiling petroleum ether at 0° to 5°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[Br:23])[O:6][CH:7]([C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9].S(=O)(=O)(O)O>>[Br:23][C:22]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[O:6][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:20]=2[CH:21]=1
Reactant: CCOC(=O)C(=O)C(Oc1ccc(Br)c(OC)c1)C(=O)OCC
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1oc2cc(OC)c(Br)cc2c1C(=O)OCC
Temperature: 0 °C
Yield: 44.3 %

Procedure:
Diethyl 3-methoxy-4-bromophenoxyoxalacetate (D10) (7.8 g, 20 mmoles) was stirred with concentrated sulphuric acid (50 ml) for 30 mins. The mixture was then poured into ice water (500 ml) and extracted with diethyl ether (250 ml). The organics were washed with saturated aqueous sodium bicarbonate, dried (Na2SO4) and evaporated to dryness. Flash chromatography on TLC silica gel eluting with dichloromethane gave the title compound (D11) (3.29 g, 44%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C@@H:18]3[CH3:30])=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1>Cl.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][C@@H:18]3[CH3:30])=[CH:15][N:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(Nc2cc(Cl)nn(C)c2=O)nc1
Agent: Cl
Solvent: CCO
Product: C[C@H]1CNCCN1c1ccc(Nc2cc(Cl)nn(C)c2=O)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 108.2 %

Procedure:
A mixture of 117a (3.0 g, 6.9 mmol) and 4.0M HCl/ethanol (20 mL) was stirred at room temperature for 2 h. The mixture was then concentrated under reduced pressure to afford crude 117b as a yellow solid (2.5 g, 98%), which was used in the next step without further purification. MS-ESI: [M+H]+ 335.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.C(N(CC)CC)C.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22](Cl)=[O:23]>ClCCl>[C:8]([C:5]1[N:6]=[CH:7][C:2]([NH:1][C:22]([C:18]2[S:17][CH:21]=[CH:20][CH:19]=2)=[O:23])=[CH:3][CH:4]=1)#[N:9]
Reactant: N#Cc1ccc(N)cn1
Reactant: O=C(Cl)c1cccs1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(NC(=O)c2cccs2)cn1
Temperature: 0 °C
Yield: 11.2 %

Procedure:
To a suspension of 5-amino-2-cyanopyridine (2.00 g, 16.8 mmol) in dry dichloromethane (50 mL) was added triethylamine (2.54 g, 25.21 mmol) and the mixture was stirred at 0° C. To the reaction mixture 2-thiophene carbonyl chloride (3.70 g, 25.21 mmol) was added drop wise over a period of 15 minutes, and the reaction mixture was stirred at 0° C. for about 1 hour and then at room temperature overnight. The reaction mixture was diluted with dichloromethane (50 mL) and washed with saturated sodium bicarbonate solution (50 mL) and water (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography (silica gel, 20-50% ethyl acetate in petroleum ether as an eluent) to obtain N-(6-cyanopyridin-3-yl)thiophene-2-carboxamide (compound 25a) Yield: 0.430 g (7.74%) and N-(6-cyanopyridin-3-yl)-N-(thiophene-2-carbonyl)thiophene-2-carboxamide (compound 25b). Yield: 1.3 g (33.75%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.CO.S(=O)(=O)(O)O.[CH2:22](O)[CH3:23]>>[CH2:22]([O:11][C:10](=[O:12])[CH2:9][C:6]1[CH:7]=[N:8][C:3]([C:2]([F:13])([F:1])[F:14])=[CH:4][CH:5]=1)[CH3:23]
Reactant: CCO
Reactant: O=C(O)Cc1ccc(C(F)(F)F)nc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: CCOC(=O)Cc1ccc(C(F)(F)F)nc1

Procedure:
4.23 g (20.6 mmol) (6-trifluoromethylpyridin-3-yl)acetic acid [obtainable from [6-trifluoromethyl)pyridin-3-yl]methanol analogously to the reaction sequence of Examples 37A, 38A and 41] are initially introduced into 200 ml ethanol under argon, 0.2 ml concentrated sulfuric acid are added and the mixture is heated under reflux for 5 h. After cooling, the reaction solution is concentrated, the residue is taken up in ethyl acetate and the mixture is washed with saturated sodium bicarbonate solution. The aqueous phase is re-extracted several times with ethyl acetate and the combined organic phases are dried over sodium sulfate, filtered and concentrated. The residue is purified by means of flash chromatography on silica gel (mobile phase: gradient cyclohexane→cyclohexane/ethyl acetate 1:1).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[N:4]=[N:5][NH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([C:20]1[CH:24]=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:22]([C:30]2[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][N:31]=2)[N:21]=1)=[O:19]>C(#N)C>[Cl:36][C:35]1[C:30]([N:22]2[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:24][C:20]([C:18](=[O:19])[CH2:17][N:5]3[N:6]=[N:7][C:3]([C:2]([F:9])([F:8])[F:1])=[N:4]3)=[N:21]2)=[N:31][CH:32]=[CH:33][CH:34]=1
Reactant: FC(F)(F)c1nn[nH]n1
Reactant: CCOC(=O)c1cc(C(=O)CBr)nn1-c1ncccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(C(=O)Cn2nnc(C(F)(F)F)n2)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.24 g (2.04 mmol) of 5-(trifluoromethyl)-2H-tetrazole and 348 mg (2.52 mmol) of potassium carbonate were initially charged in 15 ml of acetonitrile and stirred at RT for 15 min. 693 mg (1.57 mmol) of ethyl 3-(bromoacetyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylate, dissolved in 5 ml of acetonitrile, were added, and the reaction mixture was stirred at 70° C. for 5 min. Half of the solvent was distilled off, the residue was diluted with 80 ml of water and the mixture was extracted twice with dichloromethane. The combined organic phases are washed with sodium chloride solution, dried over sodium sulphate and concentrated. The desired product was isolated by chromatographic purification.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[Na+].[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][S:17]([O-:20])(=O)=[O:18])=[CH:11][CH:10]=1>C1(C)C=CC=CC=1.O>[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][S:17]([Cl:2])(=[O:20])=[O:18])=[CH:11][CH:10]=1
Reactant: O=S(=O)([O-])CCc1ccc(F)cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=S(=O)(Cl)CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.9 %

Procedure:
Phosphorus pentachloride (5.6 g, 27 mmol) was added portionwise over 10 minutes to a stirred suspension of 2-(4-fluorophenyl)ethanesulfonic acid sodium salt (9 mmol, contaminated with sodium bromide, total weight 2.87 g) in dry toluene (15 ml) at room temperature. The reaction mixture was heated under reflux for 90 minutes and was then stirred at room temperature overnight. The reaction mixture was diluted with water (20 ml) and the organic phase was separated. The aqueous phase was extracted with dichloromethane (20 ml) and the organic extracts were combined, dried over magnesium sulfate and concentrated under vacuum to give the title compound as an oil, (0.7 g) Rf 0.92 (dichloromethane).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([O:23]C)=[O:22])=[CH:15][CH:14]=1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>C1COCC1.Cl>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][CH:18]=1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCc1ccc(N(C(=O)OC(C)(C)C)S(C)(=O)=O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(c1ccc(CCC(=O)O)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 84.7 %

Procedure:
Methyl 3-(4-(N-(tert-butoxycarbonyl)methylsulfonamido)phenyl)propanoate (300 mg, 0.86 mmol) was dissolved in THF (3 ml), then LiOH 1N (2 ml) was added, and the mixture was stirred at RT for 6 hours. The reaction was diluted with HCl 1N, and the product was extracted with EtOAc. The organic phase was dried over Na2SO4 and evaporated under vacuum. The crude product was triturated in Petroleum Ether and filtered to give 250 mg of the desired product.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[H-].[Na+].[CH2:11](Br)[CH:12]=[CH:13][CH3:14]>CN(C=O)C>[CH2:11]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[I:1])[CH:12]=[CH:13][CH3:14]
Reactant: CC=CCBr
Reactant: Oc1ccccc1I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC=CCOc1ccccc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
An ice-cold solution of 2-iodophenol (10.0 g, 45.4 mmol) in DMF (100 mL) was added dropwise to a solution of NaH (2.16 g, 90.8 mmol) in DMF at 0° C. Crotylbromide (7.97 g, 59.0 mmol) was then added. The mixture was warmed to room temperature and stirred overnight. The reaction was quenched with water (50 mL) and the mixture was extracted with CH2Cl2 (3×). The combined organics were washed with brine and dried over Na2SO4 to give the title compound (12.2 g, 99%) as a yellow oil: 1H NMR (500 MHz, DMSO-d6) δ 7.76 (dd, J=7.8, 1.5 Hz, 1H), 7.27-7.22 (m, 1H), 6.80 (dd, J=8.4, 1.2 Hz, 1H), 6.70-6.65 (m, 1H), 5.95-5.80 (m, 1H), 5.75-5.65 (m, 1H), 4.55-4.45 (m, 2H), 1.76-1.70 (m, 3H); ESI MS m/z 275 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:6]([C:7]#[N:8])=[C:5](Br)[S:4][C:3]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11].C(=O)([O-])[O-].[Cs+].[Cs+].[OH:21][CH2:22][CH:23]1[O:28][CH2:27][CH2:26][NH:25][CH2:24]1.O1CCCC1>O>[Br:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([N:25]2[CH2:26][CH2:27][O:28][CH:23]([CH2:22][OH:21])[CH2:24]2)[S:4][C:3]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1sc(Br)c(C#N)c1Br
Reactant: OCC1CNCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1sc(N2CCOC(CO)C2)c(C#N)c1Br
Temperature: 90 °C
Reaction time: 4 h
Yield: 41 %

Procedure:
Ethyl 3,5-dibromo-4-cyanothiophene-2-carboxylate (0.360 g, 1.06 mmol), cesium carbonate (1.05 g, 3.21 mmol), 2-hydroxymethylmorpholine (137 mg, 1.17 mmol), and tetrahydrofuran (4.5 mL, 36 mmol) were combined in a 15 mL pressure vessel equipped with a stir bar. The vessel was sealed, and the r×n was heated @ 90° C. with stirring for 4 hours. The reaction was cooled to rt. The r×n was poured into water/saline. The reaction vessel was washed out with additional water, then ethyl acetate, and these were added to the quench which was then transferred to a separatory funnel. The aqueous layer was extracted 3× with EtOAc. The extracts were combined, washed with saline, dried over Na2SO4, filtered, added Celite, concentrated in vacuo, and dried on high vac 30 min. Purified dry load via silica gel chromatography (gradient elution: 0-60% EtOAc/hexanes) to give 163 mg solid (41% yield). 1H NMR (400 MHz, DMSO) δ 4.91 (t, J=5.7 Hz, 1H), 4.25 (q, J=7.1 Hz, 2H), 3.99-3.92 (m, 3H), 3.69-3.58 (m, 2H), 3.50 (dt, J=10.5, 5.2 Hz, 1H), 3.41 (dt, J=11.5, 5.8 Hz, 1H), 3.37-3.27 (m, 1H, under H2O peak), 3.15-3.08 (m, 1H), 1.26 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([F:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].B(Br)(Br)Br.[CH2:18](O)[CH:19]=C>C(Cl)Cl>[Br:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([F:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH2:11][CH:18]=[CH2:19])=[O:9]
Reactant: COC(=O)c1cc(CBr)ccc1F
Reactant: C=CCO
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C=CCOC(=O)c1cc(CBr)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-bromomethyl-2-fluorobenzoate (12.49 g, 50.6 mmol) in methylene chloride (150 mL) at 0° C. is added BBr3 (5.26 mL, 55.62 mmol) slowly, via syringe. The solution is then warmed to room temperature over 2.5 hours, and then is cooled back down to 0° C., and allyl alcohol (103 mL, 1.52 mol) is added dropwise. The solution is then stirred overnight, after which time it is diluted with CH2Cl2 (250 mL), then washed with sat'd aq. NaHCO3 (2×300 mL), brine (150 ml), and dried over MgSO4. Evaporation of solvent yields allyl 5-bromomethyl-2-fluorobenzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH2:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[S:13]1[CH:17]=[C:16]([C:18](O)=[O:19])[N:15]=[CH:14]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH:12][C:18]([C:16]3[N:15]=[CH:14][S:13][CH:17]=3)=[O:19])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1cccc2ccc(Cl)nc12
Reactant: O=C(O)c1cscn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc2ccc(Cl)nc12)c1cscn1
Yield: 67 %

Procedure:
A solution of 2-chloroquinolin-8-amine (222 mg), thiazole-4-carboxylic acid (129 mg, 1 eq), HATU (570 mg, 1.5 eq), and DIEA (246 uL, 2.0 eq) in DMF (3 mL) was stirred at room temperature overnight. The product was precipitated by the addition of water (20 mL), the product was collected by filtration and recrystallized from methanol to obtain the product as a grey solid (194 mg).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>>[N:10]1([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C1CCNCC1
Reactant: N#Cc1ccccc1F
Product: N#Cc1ccccc1N1CCCCC1

Procedure:
According to a similar manner to that in Reference Example 12, the title compound was synthesized from 2-fluorobenzonitrile and piperidine.