Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH2:23])=[C:10]([O:11][C@@H:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[C:5]=2[O:4][CH:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.O.CCOC(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>[Cl:22][C:15]1[C:16]([F:21])=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[C@H:12]([O:11][C:10]1[C:5]2[O:4][CH:3]=[C:2]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:6]=2[CH:7]=[N:8][C:9]=1[NH2:23])[CH3:13]
Reactant: C[C@@H](Oc1c(N)ncc2c(Br)coc12)c1c(Cl)ccc(F)c1Cl
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: C[C@@H](Oc1c(N)ncc2c(-c3ccccc3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 100 °C
Yield: 41.5 %

Procedure:
A mixture of 3-bromo-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)-ethoxy]-furo[3,2-c]pyridin-6-ylamine (25 mg, 0.0595 mmol), phenylboronic acid (8.7 mg, 0.071 mmol), Cs2CO3 (58 mg, 0.18 mmol), and Pd(PPh3)4 (6.9 mg, 0.006 mmol) in DME (1.5 mL) and H2O (0.5 mL) was degassed and refilled with nitrogen (3×). This mixture was then heated at 100° C. using microwave for 30 min. LC-MS showed completion of the reaction. The reaction mixture was diluted with EtOAc (30 mL), washed with brine (10 mL), and dried over anhydrous sodium sulfate. The residue was purified by silica gel chromatography (Hexane:EtOAc=70:30) to give a brown oil, which was further purified by mass-directed purification to afford the title compound as a brown oil (10.3 mg). 1H NMR (CDCl3, 400 MHz): δ=1.93 (d, J=6.8 Hz, 3H), 6.70 (q, J=6.8 Hz, 1H), 7.10 (dd, J=9.1, 7.8 Hz, 1H), 7.33 (dd, J=9.1, 4.8 Hz, 1H), 7.42-7.55 (m, 5H), 7.67 (s, 1H), 8.12 (s, 1H), 8.18 (s, 1H). MS (ES+): 417.01/418.99 [MH+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH3:17])([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[NH2:30][C:31]1[CH:32]=[C:33]([S:37]([NH2:40])(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1>ClC(Cl)C.CN(C=O)C.ClCCl>[CH3:17][C:11]1([C:14](=[O:16])[NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([S:37](=[O:39])(=[O:38])[NH2:40])[CH:32]=2)[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C)(C(=O)Nc2cccc(S(N)(=O)=O)c2)CC1
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 40 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid (60 mg, 0.25 mmol) in dichloroethane (2.0 mL) were added DMF (2 drops) and pyridine (78 mg, 0.99 mmol), followed by oxalyl chloride (31 mg, 0.25 mmol). The mixture was stirred for 40 minutes, and 3-amino-benzenesulfonamide was added. The mixture was heated at 50° C. for 3 hours, and the mixture was cooled, diluted with dichloromethane, washed twice each with sat. aq. NaHCO3 and 1.0 N aq. HCl, dried over MgSO4, and concentrated. Silica gel chromatography (2-5% MeOH:CH2Cl2) gave the title compound in 40% yield. MS (ES+) [M+H]+=398.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([O:13][CH3:14])[C:5]=1[CH3:15].[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH3:1][O:2][C:3](=[O:16])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([O:13][CH3:14])[C:5]=1[CH2:15][Br:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c([N+](=O)[O-])ccc(OC)c1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c([N+](=O)[O-])ccc(OC)c1CBr
Temperature: 85 °C
Reaction time: 21 h
Yield: 128.3 %

Procedure:
To a suspension of 3-Methoxy-2-methyl-6-nitro-benzoic acid methyl ester (4.1 g, 18.2 mmol) and N-bromosuccinimide (3.89 g, 21.8 mmol) in 50 mL of CCl4 is added 2,2′-azobisisobutyronitrile (299 mg, 1.82 mmol) at room temperature. The reaction mixture is stirred at 85° C. for 21 hours and then cooled to room temperature. The reaction mixture is cooled to room temperature and then quenched by crushed ice. The mixture is extracted with ethyl acetate and washed with aqueous NaHCO3 solution followed by brine, dried over Na2SO4, filtered and evaporated in vacuo to afford the 2-Bromomethyl-3-methoxy-6-nitro-benzoic acid methyl ester (7.1 g) as orange oil. 1H-NMR (400 MHz, δ, ppm) CDCl3: 4.0 (s, 3H), 4.05 (s, 3H), 4.52 (s, 2H), 7.02 (d, 1H), 8.2 (d, 1H).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[CH3:10])=[O:4].C([Li])CCC.[Br:16][C:17]1[CH:24]=[CH:23][C:20](C#N)=[CH:19][CH:18]=1>O1CCCC1>[Br:16][C:17]1[CH:24]=[CH:23][C:20]([C:1]2[NH:2][C:3](=[O:4])[C:5]3[CH:9]=[CH:8][S:7][C:6]=3[CH:10]=2)=[CH:19][CH:18]=1
Reactant: N#Cc1ccc(Br)cc1
Reactant: CNC(=O)c1ccsc1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=c1[nH]c(-c2ccc(Br)cc2)cc2sccc12
Temperature: -70 °C
Reaction time: 2 h
Yield: 19.1 %

Procedure:
To a solution of N-methyl-2-methylthiophene-3-carboxamide (13.0 g) in tetrahydrofuran (130 ml) was dropwise added 2.5 M butyl lithium (74 ml) at −70° C. The reaction solution was stirred at −70° C. for 2 hr, followed by the addition of 4-bromobenzonitrile (15.3 g) at once. After the dry ice/acetone bath was removed, the reaction mixture was back to room temperature. Three hours later, an aqueous solution of saturated ammonium chloride and ether were added thereto, and then the resulting mixture was further stirred for 1 hr. The resulting white precipitates were collected by filtration, and washed with water, ether and n-hexane in this order. The resulting product was dried to give the title compound (4.9 g, yield; 19%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:30])[C:5]2[N:6]([C:8]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)[N:19]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1>C(O)C.[Pd]>[CH:25]1([NH:24][C:20]2[N:19]=[C:18]([C:8]3[N:6]4[CH:7]=[CH:2][CH:3]=[C:4]([CH3:30])[C:5]4=[N:10][C:9]=3[C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[CH:23]=[CH:22][N:21]=2)[CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: Cc1cc(Br)cn2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nc12
Agent: [Pd]
Solvent: CCO
Product: Cc1cccn2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.5 %

Procedure:
N-{4-[6-Bromo-2-(4-fluorophenyl)-8-methylimidazo[1,2-a]pyridin-3-yl]-2-pyrimidinyl}-N-cyclopentylamine (120 mg, 0.26 mmol) was dissolved in ethanol. To this solution was added 10% palladium on charcoal and the reaction was stirred under hydrogen atmosphere (1 atm) at room temperature for 3 hours. The catalyst was removed by filtration and the resulting solution concentrated to a solid. This solid was purified by silica gel chromatography (1:1 ethyl acetate:hexane) to give 70 mg (70%) of N-cyclopentyl-4-[2-(4-fluorophenyl)-8-methylimidazo[1,2-a]pyridin-3-yl]-2-pyrimidinamine as a yellowish foam. 1H NMR (CDCl3) δ 9.45 (d, 1H), 8.12 (d, 1H), 7.67 (q, 2H), 7.15 (m, 3H), 6.86 (t, 1H), 6.39 (d, 1H), 5.26 (d, 1H), 4.41 (m, 1H), 2.71 (s, 3H), 2.0–2.1 (m, 2H), 1.4–1.9 (m, 6H); 19F NMR (CDCl3) δ −113.7;
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][C:5]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[O:3].[N+:22]([C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O)([O-:24])=[O:23].CO.[OH-].[Na+]>O>[F:21][C:18]([F:19])([F:20])[CH2:17][O:16][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])=[CH:9][C:4]=1[C:2](=[O:3])[CH:1]=[CH:28][C:27]1[CH:30]=[CH:31][CH:32]=[C:25]([N+:22]([O-:24])=[O:23])[CH:26]=1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(C=Cc1cccc([N+](=O)[O-])c1)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
The title compound was prepared from a mixture of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone (200 mg, 0.633 mmol), 3-nitrobenzaldehyde (96 mg, 0.633 mmol), methanol (5 ml) and saturated NaOH (50 ul). The mixture was diluted with water (5 ml). The resulting yellow precipitate was collected by filtration, wash with water and dried under vacuum to give yellow solid (129 mg, 45%). 1H NMR (CDCl3): 8.48 (s, 1H), 8.28-8.24 (m, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.74 (d, J=15.9 Hz, 1H), 7.61 (d, J=16.2 Hz, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.36 (d, J=3.0 Hz, 1H), 7.18 (dd, J=3.3, 9.0 Hz, 1H), 6.96 (d, J=9.0 Hz, 1H), 4.49-4.36 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@:12]([CH2:22][OH:23])([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:25])[CH3:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1.C(OCC)(=O)C.O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C@@:12]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:27][CH2:28][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=3)=[CH:19][CH:20]=2)([CH2:22][OH:23])[CH2:11][O:10][C:9]1([CH3:25])[CH3:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C(C)(C)OC[C@@]1(CO)CCc1ccc(O)cc1
Reactant: Fc1cccc(OCCBr)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1C(C)(C)OC[C@@]1(CO)CCc1ccc(OCCOc2cccc(F)c2)cc1
Temperature: 85 °C
Reaction time: 4 h

Procedure:
To a solution of (S)-4-hydroxymethyl-4-[2-(4-hydroxy-phenyl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (100 mg, 0.28 mmol) in DMF (5 ml) is added CsCO3 (120.5 mg, 0.37 mmol, 1.3 eq) and 1-(2-bromo-ethoxy)-3-fluoro-benzene (80.7 mg, 0.37 mmol, 1.3 eq). The reaction mixture is stirred at 85° C. for 4 hours. Ethyl acetate and water are then added, the organic layer is separated and the aqueous phase is extracted with ethylacetate (3×50 ml). The combined organic extracts are washed with brine, dried over MgSO4, and evaporated to dryness. Purification by flash chromatography (AcOEt/Hx 9:1) affords (S)-4-(2-{4-[2-(3-fluoro-phenoxy)-ethoxy]-phenyl}-ethyl)-4-hydroxymethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester as colorless oil.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:14]=[CH:13][C:7]2[NH:8][C:9](=[O:12])[CH2:10][S:11][C:6]=2[CH:5]=1.C(C1C=CC2NC(=O)CSC=2C=1)(=[O:17])C.BrBr>C(Cl)Cl>[Br:1][CH2:2][C:3]([C:4]1[CH:14]=[CH:13][C:7]2[NH:8][C:9](=[O:12])[CH2:10][S:11][C:6]=2[CH:5]=1)=[O:17]
Reactant: CC(=O)c1ccc2c(c1)SCC(=O)N2
Reactant: O=C1CSc2cc(CCBr)ccc2N1
Agent: BrBr
Solvent: ClCCl
Product: O=C1CSc2cc(C(=O)CBr)ccc2N1

Procedure:
Using the procedure described in Example 5 but replacing 6-(2-bromoethyl)benzothiazolinone by 7-(2-bromoethyl) 2,3-dihydro 3-oxo 1,4-benzothiazine (obtained using 7-acetyl 2,3-dihydro 3-oxo 1,4-benzothiazine (described in Ann. Chem. Rome, 1955, 45, 172) treated with bromine in methylene chloride to give 7-bromoacetyl 2,3-dihydro 3-oxo 1,4-benzothiazine, then by triethysilane in acidic medium to give 7-(2-bromoethyl)2,3-dihydro 3-oxo 1,4-benzothiazine, the product of the title is obtained.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH:4]=[CH:5][C:6]1[C:7]([Cl:16])=[N:8][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:11]=1.[Li+].[OH-]>>[Cl:16][C:7]1[C:6]([CH:5]=[CH:4][C:3]([OH:17])=[O:2])=[CH:11][CH:10]=[C:9]([C:12]([F:13])([F:14])[F:15])[N:8]=1
Reactant: COC(=O)C=Cc1ccc(C(F)(F)F)nc1Cl
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)C=Cc1ccc(C(F)(F)F)nc1Cl
Yield: 99.8 %

Procedure:
3-(2-Chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid methyl ester (200 mg, 0.753 mmol) was reacted with 0.5N-LiOH (2 eq) to give 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (189 mg, 99%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[CH2:9]([O:16][NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[N:23])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl.[OH-].[Na+]>[CH2:9]([O:16][N:17]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[N:23])[C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)CCCCCl
Reactant: N#CCCCCNOCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: N#CCCCCN(OCc1ccccc1)C(=O)CCCCCl
Temperature: 0 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
A solution of 5-chlorovaleryl chloride (3.66 g, 23.6 mmol) in CH2Cl2 (50 mL) was slowly dripped into a mixture of amine 2 (n=4) (4.08 g, 20.0 mmol) in CH2Cl2 (100 mL) and 1N NaOH (200 mL) which had been cooled to 0° C. The mixture was stirred at 0° C. for 30 minutes and at room temperature overnight. The layers were separated and the aqueous layer was further extracted with CH2Cl2 (2×150 mL). The combined organic extracts were washed with saturated sodium chloride, and solvent was removed in vacuo. The crude oil was passed through a short silica gel column, eluting with EtOAc, to give 6.0 g (93%) of (3) as an oil; NMR δ 1.57-1.97 (m, 8 H), 2.35 (t, 2 H, J=6), 2.40 (t, 2 H, J= 6), 3.50 (t, 2 H, J=6), 3.67 (t, 2 H, J=6), 4.80 (s, 2 H), 7.37 (s, 5 H). Anal. (C17H23ClN2O2) C, H, N.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[N+:26]([C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]([CH2:39][CH:40]=O)[C:34](=[O:42])[CH:33]=[CH:32]2)([O-:28])=[O:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:40][CH2:39][N:35]4[C:36]5[C:31](=[CH:30][C:29]([N+:26]([O-:28])=[O:27])=[CH:38][CH:37]=5)[CH:32]=[CH:33][C:34]4=[O:42])[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: O=CCn1c(=O)ccc2cc([N+](=O)[O-])ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3cc([N+](=O)[O-])ccc32)CC1
Temperature: 25 °C
Yield: 54.8 %

Procedure:
To 2 mL of a chloroform solution containing 0.32 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 0.21 g of (6-nitro-2-oxoquinolin-1(2H)-yl)acetaldehyde and 20 μL of acetic acid were added, then, to the reaction mixture, 0.29 g of sodium triacetoxyborohydride was added and stirred at room temperature for 2 nights. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; ethyl acetate], to give 0.28 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(6-nitro-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a pale yellow foam.
Reaction SMILES: [CH3:1][C:2]1([OH:15])[C:7]([CH3:13])([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[CH2:6][CH2:5][CH:4]=[C:3]1[CH3:14].[Li][CH2:17]CCC.CI>C1COCC1>[CH3:17][O:15][C:2]1([CH3:1])[C:3]([CH3:14])=[CH:4][CH2:5][CH2:6][C:7]1([CH3:13])[CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11]
Reactant: CC(C)=CCC1(C)CCC=C(C)C1(C)O
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: COC1(C)C(C)=CCCC1(C)CC=C(C)C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
To a solution of 1,2,6-trimethyl-6-(3-methyl-but-2-enyl)-cyclohex-2-enol (5.00 g, 24.0 mmol) in THF (80 ml) was added n-BuLi (1.6M in hexane, 16.5 ml, 26.4 mmol) at 0° C. After the mixture was stirred for 30 min, methyl iodide (5.18 g, 36.5 mmol) was added. The mixture was stirred at room temperature over night and then poured on ice and extracted with MTBE. The organic phase was washed with H2O and brine, dried (MgSO4) and concentrated in vacuo. The residue was distilled (bp. 75° C./0.2 Torr) to yield 5.0 g (93%) of an colorless oil containing 2 isomers: 1H-NMR (400 MHz, CDCl3): 5.64 (bs, 1H, 2-H), 5.23-5.15 (m, 1H, CH2CH═C(CH3)2), 3.30, 3.28 (2s, 3H, O—CH3), 2.22-2.12 (m, 1H), 1.99-1.88 (m, 3H), 1.75-1.58 (m, 10H), 1.20,1.18 (2s, 3H), 0.93, 0.79 (2s, 3H) ppm. MS (EI): 222 (M+, 1), 190 (11), 175 (10), 147 (60), 121 (100), 112 (30), 105 (57), 91 (40), 79 (25), 69 (14), 41 (45). IR (ATR): 2966s, 2926s, 1449s, 1377s, 1083vs, 858m cm−1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[CH:10]=[N:9]2)[CH:5]=[C:4]([Cl:16])[C:3]=1[CH:17]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:18](Cl)=[O:19].Cl[CH2:29][CH2:30][Mg].[NH4+].[Cl-].O>C1COCC1>[Cl:16][C:4]1[CH:5]=[C:6]([N:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[CH:10]=[N:9]2)[CH:7]=[C:2]([Cl:1])[C:3]=1[CH:17]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:18](=[O:19])[CH2:29][CH3:30]
Reactant: O=C(Cl)C(c1ccc(Cl)cc1)c1c(Cl)cc(-n2ncc(=O)[nH]c2=O)cc1Cl
Reactant: [Mg]CCCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CCC(=O)C(c1ccc(Cl)cc1)c1c(Cl)cc(-n2ncc(=O)[nH]c2=O)cc1Cl
Temperature: -75 °C
Yield: 17.3 %

Procedure:
A mixture of 2,6-dichloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4,-triazin-2(3H)-yl)-benzeneacetyl chloride (0.05 mol) in THF (200 ml) was stirred at −75° C. A solution of chloroethyl magnesium (0.1 mol; 2 M/THF) in THF (50 ml) was added dropwise at −75° C. The reaction mixture was stirred for 90 minutes, then the temperature was raised to −20° C. A saturated aqueous NH4Cl solution was added dropwise. Water was added and the product was extracted with CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was filtered over silica gel (eluent: CH2Cl2/CH3OH 98/2). Two fractions were collected and the solvent was evaporated, yielding 3.8 g (±)-2-[3,5-dichloro-4-[1-(4-chlorophenyl)-2-oxobutyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione (interm. 69).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]([CH2:24][C:25]([O:27]CC)=[O:26])[C:5](=[O:23])[N:6]2[C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][C:13]=1[S:21][CH3:22].[OH-].[Na+]>CO.O>[Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]([CH2:24][C:25]([OH:27])=[O:26])[C:5](=[O:23])[N:6]2[C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:19])[CH3:20])=[CH:14][C:13]=1[S:21][CH3:22]
Reactant: CCOC(=O)Cn1c(=O)n(-c2ccc(C(C)C)cc2SC)c2nc(C)nc(Cl)c21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CSc1cc(C(C)C)ccc1-n1c(=O)n(CC(=O)O)c2c(Cl)nc(C)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.5 %

Procedure:
In a mixed solvent of 3 ml of methanol and 1 ml of water, 0.83 g of ethyl 2-[6-chloro-2-methyl-8-oxo-9-(4-isopropyl-2-methylthiophenyl)-8 9-dihydropurin-7-yl]acetate was dissolved, and subsequently, 80 mg of sodium hydroxide was added thereto. The reaction mixture was stirred for 30 minutes at room temperature. Water was poured into the reaction mixture. The reaction mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:chloroform—methanol=8:1) to yield 0.47 g of 2-[6-chloro-2-methyl-8-oxo-9-(4-isopropyl-2-methylthiophenyl)-8,9-dihydropurin-7-yl]acetic acid as an oil.
Reaction SMILES: [CH2:1]([C:4]1([S:7]([N:10]2[C:14]3=[CH:15][C:16]4[S:20][CH:19]=[N:18][C:17]=4[C:21]([F:22])=[C:13]3[N:12]([C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][C:24]=3[Cl:30])C2=O)(=[O:9])=[O:8])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].C[Si](C)(C)[O-].[K+].[NH4+].[Cl-]>C1COCC1>[CH2:1]([C:4]1([S:7]([NH:10][C:14]2[C:13]([NH:12][C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][C:24]=3[Cl:30])=[C:21]([F:22])[C:17]3[N:18]=[CH:19][S:20][C:16]=3[CH:15]=2)(=[O:9])=[O:8])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(S(=O)(=O)n2c(=O)n(-c3ccc(Br)cc3Cl)c3c(F)c4ncsc4cc32)CC1
Agent: C[Si](C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCC1(S(=O)(=O)Nc2cc3scnc3c(F)c2Nc2ccc(Br)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
To a solution of 7-((1-allylcyclopropyl)sulfonyl)-5-(4-bromo-2-chlorophenyl)-4-fluoro-5H-imidazo[4′,5′:4,5]benzo[1,2-d]thiazol-6(7H)-one (60 mg, 0.111 mmol) in THF (5 mL) was added potassium trimethylsilanolate (15 mg, 0.111 mmol). The mixture was stirred at room temperature for 1 h and treated with saturated NH4Cl (aq.). The aqueous layer was extracted with ethyl acetate (10 mL×2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to give a residue, which was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1-3:1, v/v) to give the product as a white solid (50 mg, 87.5% yield). 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 7.98 (s, 1H), 7.90 (d, 1H), 7.76 (d, 1H), 7.45 (m, 1H), 6.80 (s, 1H), 6.63 (s, 1H), 5.75-5.60 (m, 1H), 5.03 (m, 2H), 2.92-2.81 (m, 1H), 2.12-2.01 (m, 1H), 1.93-1.85 (m, 2H), 1.20-1.11 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]2[O:14][CH:15]=[CH:16][C:3]=12.[CH:17]1([C@H:23]([NH2:25])[CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[OH-].[K+]>CN1CCCC1=O>[CH:17]1([C@H:23]([NH:25][C:2]2[N:7]=[N:6][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:4]3[O:14][CH:15]=[CH:16][C:3]=23)[CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C[C@@H](N)C1CCCCC1
Reactant: Clc1nnc(-c2ccccc2)c2occc12
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: C[C@@H](Nc1nnc(-c2ccccc2)c2occc12)C1CCCCC1
Temperature: 140 °C
Reaction time: 6 h
Yield: 43.8 %

Procedure:
0.10 g of 4-chloro-7-phenyl-furano[2,3-d]pyridazine and 0.165 g of (R)-1-cyclohexylethylamine was dissolved in 1 ml of N-methylpyrrolidone, and the solution was stirred at 140° C. for 6 hours. After cooling the solution, an aqueous 5% KOH solution was added thereto, and the solution was extracted with chloroform. By purifying the extract by silica gel chromatography, 0.061 g of (R)-4-(1-cyclohexylethylamino)-7-phenyl-furano[2,3-d]pyridazine was obtained.
Reaction SMILES: [C:1]([O:9][CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]CO.C(OC(C)C)(C)C>>[C:1]([O:9][CH2:10][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][NH2:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1
Reactant: NCCCCCCCCO
Solvent: CC(C)OC(C)C
Product: NCCCCCCCCOC(=O)c1ccccc1
Yield: 90 %

Procedure:
In an argon atmosphere, a mixture of methyl benzoate (3.0 mmol), 8-aminooctan-1-ol (3.6 mmol), Zn4(OCOCF3)6O (1.25 mol % in terms of mole number) and diisopropyl ether (5.0 ml) was heated to reflux for 20 hours, and as a result, 8-aminooctyl benzoate was obtained at a yield of 90%. The yield of 8-benzoylaminooctyl benzoate was 7%.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].[C:6]1(=O)[O:11][C:9](=[O:10])[C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:7]12.C(N(CC)CC)C.C1(C)C=CC=CC=1>O>[CH2:6]([O:11][C:9]([NH:1][CH2:2][CH:3]([OH:5])[CH3:4])=[O:10])[C:7]1[CH:8]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(O)CN
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: CC(O)CNC(=O)OCc1ccccc1
Yield: 142.1 %

Procedure:
To a round bottom flask equipped with Dean-Stark trap was added (1) (2 g, 7.4 mmol), phthalic anhydride (1.1 g, 7.4 mmol), triethylamine (0.1 mL) and toluene (50 mL). The reaction mixture was heated to reflux and water produced was collected. After refluxing for 2 hours, the solvent was removed. The residue was acidified using 1 N HCl, filtered and washed with water, dried to give 2.2 g of (2). 1H NMR (DMSO-d6, 400 MHz): δ 7.8 (m, 4H), 7.3 (m, 5H), 7.1 (d, 2H), 6.8 (d, 2H), 5.05 (m, 1H), 3.3 (m, 2H).