Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:12][NH:11][CH2:10][CH2:9][C:7]=2[N:8]=1.Br[C:14]1[CH:15]=[N:16][CH:17]=[C:18]([CH:32]=1)[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1)=[O:20]>>[CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:12][N:11]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([CH:32]=3)[C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:29])[F:30])[CH:23]=3)=[O:20])[CH2:10][CH2:9][C:7]=2[N:8]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1cncc(Br)c1
Reactant: CSc1ncc2c(n1)CCNC2
Product: CSc1ncc2c(n1)CCN(c1cncc(C(=O)Nc3cccc(C(F)(F)F)c3)c1)C2

Procedure:
In a manner similar to that described for Example 138, 2-(methylsulfanyl)-5,6,7,8-tetrahydropyrido[4,3-d]-pyrimidine and 5-bromo-N-(3-(trifluoromethyl)phenyl)nicotinamide were converted to the title compound.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[C:10]([OH:14])([CH3:13])([CH3:12])[CH3:11]>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: CC(C)(C)O
Reactant: O=C(Cl)CCCCCBr
Product: CC(C)(C)OC(=O)CCCCCBr
Reaction time: 8 h
Yield: 85.8 %

Procedure:
6-Bromohexanoyl chloride (2 g, 9.37 mmol) was added to t-butanol (6.98 g, 93.7 mmol) under an inert atmosphere. The reaction mixture was stirred overnight and then was concentrated in vacuo, dissolved in ethyl acetate (150 ml), washed with saturated aqueous sodium bicarbonate and 10% aqueous citric acid, and dried over magnesium sulfate to yield t-butyl 6-bromohexanoate (2.02 g, 80% yield).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[CH3:10][O-:11].[Na+]>C1COCC1.CO>[C:4]1([CH:1]=[CH:2][C:10]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(C=Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Reaction of Aldehydes with Wang Resin-bound Acetophenones: Each packet of Acetophenone-Wang resin was transferred to a 250 mL PP bottle, to which a solution of NaOMe (51.2 mmol, 20 eq, 0.25 M) in 50% THF-MeOH (205 mL) and an aldehyde (51.2 mmol, 20 eq, 0.25 M) were added sequentially. After shaking at room temperature for 3 days, the packet was washed several times with MeOH (3×80 mL) and alternatively with DMF (80 mL) and MeOH (80 mL) for 3 cycles, followed by washes of DCM (2×80 mL) and MeOH (3×80 mL). The packet was air-dried overnight to afford a resin-bound Chalcone, that varied in color from yellow to dark red depending on the aldehyde used.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][NH:9]2)=[CH:5][CH:4]=1.N1C=CC=CC=1.Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1>CC(O)C>[Cl:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][N:9]2[C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[CH:5][CH:4]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Clc1ccc2c(c1)NCC2
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)O
Product: COc1cc2ncnc(N3CCc4ccc(Cl)cc43)c2cc1OC

Procedure:
To 6-chloroindoline hydrochloride (1 00 mg, 0.526 mmol) and pyridine (0.957 mmol, 77 μL) in dry i-PrOH (8 mL) was added 4-chloro-6,7-dimethoxyquinazoline (107 mg, 0.478 mmol). The mixture was refluxed for 2 hours under an atmosphere of dry N2(g) and then the solvent was removed in vacuo. The residue was partitioned between CHCl3 and 1M NaOH, and the organic phase was washed with brine, dried over Na2SO4(g) and concentrated in vacuo. The residue (171 mg) was purified by flash chromatography on silica using 80%EtOAc/CH2 Cl2 to yield 4-(6-chloro-2,3-dihydro-indol-1-yl)-6,7-dimethoxy-quinazoline as its free base (148 mg) (M.P. 229°-230° C.; LC-MS: 342 (MH+); anal. RP18-HPLC RT: 4.38 min.).
Reaction SMILES: [Cl:1]Cl.[CH3:3][C:4]([CH3:45])([CH3:44])[C:5](=[O:43])[CH:6]([N:20]1[CH:23](SC)[CH:22]([CH:26]([O:28][C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[O:30])[CH3:27])[C:21]1=[O:42])[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:8]>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Cl:1][CH:23]1[N:20]([CH:6]([C:5](=[O:43])[C:4]([CH3:45])([CH3:44])[CH3:3])[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C:21](=[O:42])[CH:22]1[CH:26]([O:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1)=[O:30])[CH3:27]
Reactant: CSC1C(C(C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)C(C)(C)C
Reactant: ClCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(OC(=O)OCc1ccc([N+](=O)[O-])cc1)C1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)C(C)(C)C)C1Cl
Temperature: -60 °C
Reaction time: 2 h

Procedure:
660 μl of a solution containing 850 mg of chlorine in 10 ml of carbon tetrachloride is added to a solution of 244 mg (0.395 mmol) of p-nitrobenzyl 4,4-dimethyl-2-[4-methylthio-3-(1-(p-nitrobenzyloxycarbonyloxy)-ethyl)-2-oxoazetidinyl]-3-oxopentanoate in 16 ml of methylene chloride at -60° C. The pale yellow solution is stirred at -60° C. for 2 hours, and the solvent is removed in vacuo, to give 236 mg of a colourless, non-crystalline solid. IR spectrum in CH2Cl2 : 2930, 2850, 1795, 1765, 1725, 1620, 1530, 1355 cm-1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.[CH3:12][CH:13]([CH2:15][CH:16]([NH2:20])[CH2:17][CH2:18][CH3:19])[CH3:14]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:20][CH:16]([CH2:17][CH2:18][CH3:19])[CH2:15][CH:13]([CH3:14])[CH3:12])=[O:7]
Reactant: Cc1ccc(C(=O)O)cc1C
Reactant: CCCC(N)CC(C)C
Product: CCCC(CC(C)C)NC(=O)c1ccc(C)c(C)c1

Procedure:
Prepared in a similar manner to example 4 using 3,4-dimethylbenzoic acid and 2-methylheptan-4-amine (example 2a). 1H NMR (500 MHz, CDCl3): δ 0.94 (m, 9H); 1.40 (m, 5H); 1.53 (m, 1H); 1.68 (m, 1H); 2.29 (s, 3H); 2.30 (s, 3H); 4.24 (m, 1H); 5.69 (d, 1H); 7.17 (d, 1H); 7.46 (d, 1H); 7.54 (s, 1H). MS (262, M+H).
Reaction SMILES: [Si](C=[N+]=[N-])(C)(C)[CH3:2].[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][C:22]([OH:24])=[O:23])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>C1(C)C=CC=CC=1.CO>[CH3:2][O:23][C:22](=[O:24])[CH2:21][CH:18]1[CH2:19][CH2:20][N:15]([C:13]([O:12][C:8]([CH3:11])([CH3:9])[CH3:10])=[O:14])[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At 0° C., TMSCHN2 (2.0 M in ether, 15 mL) was added dropwise to a mixture of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (6272 mg, 25.78 mmoL) in Toluene (60 mL) and MeOH (60 mL). After stirring at room temperature for 1 h, the mixture was concentrated. The crude tert-butyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate was used as it is without further purification.
Reaction SMILES: CC[N:3](C1C=CC=CC=1)CC.[C:12]1([C:22]([OH:24])=O)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C1COCC1>[C:12]1([C:22]([NH2:3])=[O:24])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: CCN(CC)c1ccccc1
Reactant: O=C(O)c1cccc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: NC(=O)c1cccc2ccccc12
Temperature: 23 °C
Reaction time: 0.08 h
Yield: 240.5 %

Procedure:
Diethylaniline (0.27 μL, 1.7 μmol, 1.1 equiv) was added in one portion to a stirred solution of the amine (0.8 mg, 1.5 μmol, 1 equiv) in THF (0.2 mL) at 0° C. under an argon atmosphere and the solution was stirred for 5 min. 1-Naphthoic acid (0.34 mg, 2.0 μmol, 1.3 equiv), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.38 mg, 2.0 μmol, 1.3 equiv) and 1-hydroxybenzotriazole (0.25 mg, 1.8 μmol, 1.2 equiv) were then added separately, each in one portion, to the above solution at 0° C. The reaction mixture was warmed to 23° C. over 14 h 45 min, then was quenched with saturated aqueous ammonium chloride solution (3 mL). The mixture was diluted with ethyl acetate (10 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (10 mL) and the combined organic layer was dried over sodium sulfate. Concentration in vacuo left a white solid, which was purified by flash column chromatography (80% ethyl acetate-hexanes) to give the naphthalene-1-carboxylic acid amide derivative (0.7 mg, 68%) as a white solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=O.C[O-:12].[Na+].CO>[Pd]>[OH:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:2][CH2:1][OH:12])=[CH:9][CH:8]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: C[O-]
Agent: [Pd]
Agent: [Na+]
Solvent: CO
Product: OCCc1ccc(O)cc1
Temperature: 45 °C

Procedure:
To a five-gallon stainless steel reactor, a solution of 4-hydroxyacetophenone (2500 g, 18.4 moles) and a 25% solution of sodium methoxide in methanol (39.1 g, 0.26 moles) in methanol (10,000 g, 312.5 moles), and palladium on carbon catalyst (ESCAT 10, 125 g) were charged. The reactor is purged three times with nitrogen (100 psi). Hydrogen is then charged to a pressure of 300 psi and the reactor is heated to 45° C. The temperature is maintained at 45° C. for three hours at a constant hydrogen pressure of 500 psi. The reactor is cooled to 30° C. and then discharged (12,245 g). The analysis of the solution gave a conversion of 97.6% and a selectivity of 96.0% (note Table 2).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([S:15]([NH2:18])(=[O:17])=[O:16])[CH:11]=[CH:12][C:13]=1[OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:21]=[C:22]([NH:36][C:37](OC2C=CC=CC=2)=[O:38])[C:23](=[CH:34][CH:35]=1)[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>>[C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([S:15]([NH:18][C:37]([NH:36][C:22]2[CH:21]=[C:20]([Cl:19])[CH:35]=[CH:34][C:23]=2[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[O:38])(=[O:16])=[O:17])[CH:11]=[CH:12][C:13]=1[OH:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1cc(S(N)(=O)=O)ccc1O
Reactant: O=C(Nc1cc(Cl)ccc1C(=O)OCc1ccccc1)Oc1ccccc1
Product: CC(C)(C)OC(=O)c1cc(S(=O)(=O)NC(=O)Nc2cc(Cl)ccc2C(=O)OCc2ccccc2)ccc1O
Yield: 93.1 %

Procedure:
320 mg (1.17 mmol) of 3-t-butoxycarbonyl-4-hydroxybenzenesulfonamide and 447 mg (1.17 mmol) of benzyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated in the same way as in Preparation Example 17 to obtain 611 mg (yield 93%) of benzyl 2-{[(3-t-butoxycarbonyl-4-hydroxybenzenesulfonylamino)carbonyl]amino}-4-chlorobenzoate. Properties: colorless amorphous, PMR (δ ppm, CDC13): 1.62 (9H, s), 5.35 (2H, s), 7.01-7.05 (2H, m), 7.37-7.41 (5H, m), 7.96 (1H, d), 8.10 (1H, dd), 8.46-8.48 (2H, m), 10.99 (1H, s), 11.66 (1H, s).
Reaction SMILES: [S:1]1(=[O:7])(=[O:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.[CH:13]([C:15]1[CH:20]=[CH:19][C:18]([CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=1)=[O:14]>O1CCCC1.CCCCCC>[O:6]=[S:1]1(=[O:7])[CH2:5][CH2:4][CH2:3][CH:2]1[CH:13]([OH:14])[C:15]1[CH:16]=[CH:17][C:18]([CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:19][CH:20]=1
Reactant: CCOC(=O)C(C)c1ccc(C=O)cc1
Reactant: O=S1(=O)CCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C(C)c1ccc(C(O)C2CCCS2(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33.7 %

Procedure:
Tetrahydrothiophene-1,1-dioxide (1.5 g) was dissolved in tetrahydrofuran (10 ml), and to the solution was added dropwise a 1.6 M solution of n-butyllithium in hexane (6.0 ml) at −60° C. The reaction mixture was gradually warmed to 0° C., stirred at the same temperature for 30 minutes, then a solution of ethyl 2-(4-formylphenyl)propionate (1.5 g) in tetrahydrofuran (2.0 ml) was added dropwise at 0° C., and the mixture was stirred at room temperature for 2 days. The reaction mixture was quenched with 10% aqueous citric acid, and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to give the title compound (800 mg, 39%).
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[Cl-].[Al+3].[Cl-].[Cl-].[C:13]([O:16][CH2:17][CH3:18])(=O)C>C1(OC)C=CC=CC=1>[CH3:13][O:16][C:17]1[CH:18]=[CH:4][C:3]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8])=[CH:2][CH:1]=1
Reactant: O=C1CCCC(=O)O1
Reactant: CCOC(C)=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Product: COc1ccc(C(=O)CCCC(=O)O)cc1
Reaction time: 3 h
Yield: 59 %

Procedure:
Glutaric anhydride (10.0 g) was dissolved in anisole (100 mL), aluminum chloride (25.7 g) was added, then stirred for three hours on ice. Ethyl acetate (300 mL) was added to the reaction solution, and the organic layer was washed with water (100 mL) and a saturated sodium chloride solution (100 mL). After drying on anhydrous sodium sulfate, filtration and vacuum condensation, the residue was washed with n-hexane to give the above-identified compound (11.5 g, yield 59%) as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:26])[CH:3]=1.[CH3:27][N:28]1[C:32](=[O:33])[CH:31]([CH3:34])[NH:30][C:29]1=[O:35]>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:30]5[CH:31]([CH3:34])[C:32](=[O:33])[N:28]([CH3:27])[C:29]5=[O:35])=[CH:3][C:4]=4[F:26])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: CC1NC(=O)N(C)C1=O
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2F)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)N(C)C(=O)C3C)cc2F)CC1
Yield: 27.5 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (167 mg) described in Preparation Example 121 and 3,5-dimethylimidazolidine-2,4-dione (51 mg) described in Preparation Example 217 and by the reaction and treatment in the same manner as in Example 536, the title compound (51 mg) was obtained.
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:17][C:18]1[CH:19]=[C:20]2[C:25](=[C:26]([Cl:28])[CH:27]=1)[CH2:24][CH:23](N1CCCC1)[CH2:22][CH2:21]2>C(Cl)(Cl)Cl.C(OCC)(=O)C>[Cl:17][C:18]1[CH:27]=[C:26]([Cl:28])[C:25]2[C:24]3[CH2:3][CH2:2][C:1](=[O:4])[NH:5][C:23]=3[CH2:22][CH2:21][C:20]=2[CH:19]=1
Reactant: Clc1cc(Cl)c2c(c1)CCC(N1CCCC1)C2
Reactant: C=CC(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: O=C1CCC2=C(CCc3cc(Cl)cc(Cl)c32)N1

Procedure:
16.2 g of acrylamide and 0.9 g of anhydrous p-toluenesulphonic acid were added to 30.6 g of 1-(6,8-dichloro3,4-dihydro-2(1H)-naphthyl)pyrrolidine. The mixture was heated under nitrogen to 100° for 2 hours and to 150° for 2 hours. After cooling, the reaction mixture was stirred at room temperature in 80 ml of a mixture of chloroform-ethyl acetate (1:1). There was obtained 8,10-dichloro-1,4,5,6-tetrahydrobenzo[f]quinolin-3(2H)-one which melts at 212°-214° after recrystallization from ethyl acetate.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[N:5]([CH2:8][C@@H:9]([NH:14][C:15]1[C:20]([F:21])=[CH:19][N:18]=[C:17]([Cl:22])[N:16]=1)[C:10]([CH3:13])([CH3:12])[CH3:11])=[N+:6]=[N-:7]>C1COCC1.C1(C)C=CC=CC=1>[Cl:22][C:17]1[N:16]=[C:15]([NH:14][C@@H:9]([C:10]([CH3:12])([CH3:11])[CH3:13])[CH2:8][N:5]2[CH:3]=[C:2]([CH2:1][OH:4])[N:7]=[N:6]2)[C:20]([F:21])=[CH:19][N:18]=1
Reactant: CC(C)(C)[C@@H](CN=[N+]=[N-])Nc1nc(Cl)ncc1F
Reactant: C#CCO
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)[C@@H](Cn1cc(CO)nn1)Nc1nc(Cl)ncc1F
Temperature: 120 °C

Procedure:
A mixture of prop-2-yn-1-ol (0.22 g, 3.85 mmol) and (S)—N-(1-azido-3,3-dimethylbutan-2-yl)-2-chloro-5-fluoropyrimidin-4-amine, 216a, (0.21 g, 0.77 mmol) in THF (4 mL) and toluene (4 mL) was heated in a pressure vial at 120° C. for 8 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product which contained two regioisomers was purified by silica gel chromatography (0-5% MeOH/CH2Cl2 gradient) to afford 100 mg of desired regioisomer, 217a, as well as 70 mg of the minor regioisomer (5-hydroxymethyl triazole).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH:22]1([CH2:25]Br)[CH2:24][CH2:23]1>CN(C=O)C>[CH:22]1([CH2:25][O:15][C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:14][CH:13]=2)[CH2:24][CH2:23]1
Reactant: BrCC1CC1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(OCC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 81.1 %

Procedure:
To a stirred solution of 4-[N-(tert-butoxycarbonyl)amino]phenol (5.0 g, 23.89 mmol) in DMF (140 mL) was added cesium carbonate (19.5 g, 59.73 mmol). The reaction mixture was stirred at r.t. for 20 minutes, and then cyclopropylmethyl bromide (2.3 mL, 23.89 mmol) was added. The reaction mixture was stirred at r.t. for 2 days, cooled to r.t., filtered and partitioned between Et2O (2×25 mL) and water (100 mL). The layers were separated, and the aqueous fraction was further extracted with Et2O (3×50 mL). The combined organic fractions were washed with water (3×150 mL), dried (Na2SO4), filtered and concentrated in vacuo to give the title compound (5.1 g, 81%) as a light pink solid that was used without further purification. δH (DMSO-d6) 8.82 (1H, br. s), 7.09-7.06 (2H, m), 6.59-6.54 (2H, m), 3.50 (2H, d, J 6.9 Hz), 1.22 (9H, s), 0.97-0.90 (1H, m), 0.34-0.28 (2H, m), 0.08-0.03 (2H, m). LCMS (ES+) 207.0 ((M−tBu)+H)+, RT 3.20 minutes (Method 3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[C:12]([CH3:20])[CH:11]=1.[I-:21]>S([O-])([O-])(=O)=O.[Ag+2].CO>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([I:21])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[C:12]([CH3:20])[CH:11]=1
Reactant: COC(=O)c1ccc(-c2ccc(OC)cc2F)cc1C
Reactant: [I-]
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: COC(=O)c1ccc(-c2cc(I)c(OC)cc2F)cc1C

Procedure:
methyl 2′-fluoro-4′-methoxy-3-methylbiphenyl-4-carboxylate (100 mg, 0.365 mmol), methanol (3 mL), iodide (93 mg, 0.366 mmol) and silver sulfate (114 mg, 0.366 mmol) were stirred at room temperature for 1.5 hours. Reaction crude was quenched by Na2SO3 (sat., aq.). Volatiles were removed from the grayish brown mixture. The pot residue was worked up with H2O/EtOAc/Na2SO4/filtration/concentration to afford the title compound. LCMS (ESI) calc.=400.00; found=400.96 (M+1)+.
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.[C:7]([O:14][CH3:15])(=[O:13])[CH2:8][C:9]([O:11][CH3:12])=[O:10]>CC(C)=O>[CH3:12][O:11][C:9]([CH:8]([C:7]([O:14][CH3:15])=[O:13])[C@H:3]1[CH2:4][CH2:5][C:1](=[O:6])[CH2:2]1)=[O:10]
Reactant: COC(=O)CC(=O)OC
Reactant: O=C1C=CCC1
Solvent: CC(C)=O
Product: COC(=O)C(C(=O)OC)[C@H]1CCC(=O)C1
Temperature: 40 °C
Reaction time: 24 h
Yield: 99.4 %

Procedure:
Under an atmosphere of argon, 12.0 mg (0.02 mmol, S/C=50) of RuH[(R,R)-Tsdpen] (1,3,5-trimethylbenzene), 84 μL (1.0 mmol) of 2-cyclopentenone, 114 μL (1.0 mmol) of dimethyl malonate, and 1 mL of acetone were placed in a 20 mL Schlenk tube and stirred at 40° C. for 24 hours. This solution was purified by flash column chromatography (hexane/acetone=90/10, SiO2) to give 213 mg (99% yield) of the title compound. The optical purity was measured by HPLC (CHIRALPAK AS manufactured by Daicel Chemical Industries, Ltd., hexane:2-propanol=80:20, flow rate 1.0 mL/min, detection at 210 nm) and it was found to be 89% ee.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:4][N:5]2[C:10](Cl)=[CH:9][CH:8]=[N:7][C:6]=12.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C>[Br:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:4][N:5]2[C:10]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:9][CH:8]=[N:7][C:6]=12
Reactant: Clc1ccnc2c(Br)c(-c3ccccc3)nn12
Reactant: C1CCNC1
Solvent: CCO
Product: Brc1c(-c2ccccc2)nn2c(N3CCCC3)ccnc12
Yield: 77 %

Procedure:
3-Bromo-7-chloro-2-phenylpyrazolo[1,5-α]pyrimidine (100 mg, 0.32 mmol) was dissolved in ethanol. To this solution was added pyrrolidine (0.5 mL) and the reaction mixture heated at reflux for 10 minutes. The resulting mixture was concentrated in vacuo, then dissolved in dichloromethane and the organic phase was washed with water, dried over magnesium sulfate, filtered and concentrated. The resulting solid was crystallized from methanol to give 85 mg (77%) of 3-bromo-2-phenyl-7-pyrrolidin-1-ylpyrazolo[1,5-α]pyrimidine as a solid. 1H NMR (CDCl3):δ 8.17 (m, 3H), 7.50 (m, 3H), 5.80 (d, 1H), 4.09 m (broad s, 4H), 2.10 (broad s, 4H); MS m/z 343 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[CH:7][CH:8]=1.[Br:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=[O:15].[NH4+].[Cl-]>C1COCC1>[Br:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[OH:15]
Reactant: O=Cc1ccccc1Br
Reactant: COc1cccc([Mg]Br)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cccc(C(O)c2ccccc2Br)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 80.5 %

Procedure:
3-Methoxyphenyl magnesium bromide (1.0 M solution in THF; 5.4 mL, 5.4 mmol) was taken in a flask under N2 and cooled (0° C.). 2-Bromobenzaldehyde (1 g, 5.4 mmol) in anhydrous THF (10 mL) was added dropwise via syringe over 5 min. The reaction mixture was stirred at this temperature for 20 min. and slowly brought to room temperature. After stirring for another 30 min. satd. NH4Cl solution (20 mL) was added and the mixture was extracted with Et2O (3×25 mL). The combined Et2O extracts were washed with water, brine, dried (MgSO4) and evaporated under reduced pressure to give a yellow oil. The oil was purified by mplc using CH2Cl2 as eluent to give 1.275 g (81%) of the alcohol as a colorless oil. 1H NMR (CDCl3)d: 2.71 (s, 1H, OH), 3.78 (s, 3H, CH3), 6.15 (s, 1H, CH), 6.80-7.58 (m, 8H, Ar—H). 13C NMR (CDCl3)d: 55.80, 75.16, 113.29, 119.90, 123.39, 128.33, 129.11, 129.71, 130.08, 133.39.
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]2[C:5]([C:6](=[O:20])[C:7]3[CH:8]=[CH:9][C:10]([C:17](O)=[O:18])=[CH:11][C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:22]>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:15]=[C:14]2[C:5]([C:6](=[O:20])[C:7]3[CH:8]=[CH:9][C:10]([C:17]([Cl:22])=[O:18])=[CH:11][C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(O)c1ccc2c(c1)C(=O)c1cc(F)ccc1C2=O
Solvent: Cc1ccccc1C
Product: O=C(Cl)c1ccc2c(c1)C(=O)c1cc(F)ccc1C2=O
Yield: 87.4 %

Procedure:
7-Fluoro-9,10-dihydro-9,10-dioxo-2-anthroic acid (15 g), phosphorus pentachloride (12 g) and xylene (300 ml) were heated for 15 minutes at 100°-130° till a clear solution was obtained. This was concentrated to small volume and allowed to crystallise. The product was washed with light petroleum (bp 40°-60°) to give 7-fluoro-9,10-dihydro-9,10-dioxo-2-anthroyl chloride (14 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([OH:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21]Br.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]2[O:9][CH2:21][CH2:20][O:8][C:6]=2[CH:7]=1
Reactant: O=[N+]([O-])c1cc(F)cc(O)c1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(F)cc2c1OCCO2
Temperature: 80 °C
Yield: 93 %

Procedure:
A mixture of 5-fluoro-3-nitro-1,2-benzenediol (6.55 g, 37.9 mmol), anhydrous potassium carbonate (21 g, 151.6 mmol) and 1,2-dibromoethane (8.2 mL) in DMF (70 ml) was heated at 80° C. under argon for 5 h. The reaction was cooled to rt, water (200 ml) added and the aqueous phase extracted with ethyl acetate (3×200 ml). The organics were washed with brine, dried, filtered and evaporated to afford the desired compound (6.96 g, 93%).