Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1.ClS([N:19]=[C:20]=[O:21])(=O)=O.O>C(#N)C>[F:14][C:2]([F:1])([F:13])[C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8](=[O:12])[N:9]2[C:20]([NH2:19])=[O:21])=[CH:5][CH:4]=1
Reactant: O=C1Cc2ccc(C(F)(F)F)cc2N1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CC#N
Solvent: O
Product: NC(=O)N1C(=O)Cc2ccc(C(F)(F)F)cc21
Reaction time: 0.75 h
Yield: 9.4 %

Procedure:
To a slurry of 6-trifluoromethyl-2-oxindole (8.0 g, 0.04 mole) in acetonitrile (80 ml) was added chlorosulfonyl isocyanate (6.65 g, 0.047 mole) and the mixture was stirred for 45 minutes. Water (100 ml) was then added and the aqueous mixture was stirred for one hour. The precipitate which formed was filtered off and recrystallized from acetonitrile to give 0.92 g of the title product. Extraction of the filtrate from the aqueous reaction mixture with ethyl acetate (300 ml) followed by drying the extract over MgSO4 and then evaporating it under reduced pressure gave additional product. Recrystallization from acetonitrile gave an additional 2.2 g of product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:9])=[C:6]([CH:8]=1)[NH2:7].N1C=CC=CC=1.[C:16](Cl)(=[O:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>ClC(Cl)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:9])=[C:6]([NH:7][C:16](=[O:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:8]=1
Reactant: CCCCCCCCC(=O)Cl
Reactant: Nc1cc(Cl)ccc1O
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: CCCCCCCCC(=O)Nc1cc(Cl)ccc1O
Reaction time: 2 h

Procedure:
5-Chloro-2-hydroxy aniline, 10.3 g (0.072 mole), is dissolved in 200 ml dichloroethane, containing 25 ml pyridine. The solution is stirred at 70° C. while nonanoyl chloride is added slowly. The solution is stirred for 2 hours. Excess pyridine is removed by washing the product with 4N hydrochloric acid. The product is then passed through a florisil column and crystallized at -20°. There is obtained N-(5-chloro-2-hydroxyphenyl) nonanamide (M.P. 93.5-94.0). Analysis shows 4.94% nitrogen and 12.53% chlorine as against calculated values of 49.4% and 12.49% respectively, for C15H22ClNO2.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](O)=[O:8])[C:4]([C:10]([F:13])([F:12])[F:11])=[N:3]1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[CH:27]=[C:28]([CH:45]=[CH:46][CH:47]=1)[O:29][C:30]1[CH:31]=[CH:32][C:33]2[N:34]([N:36]=[C:37]([NH:39][C:40]([CH:42]3[CH2:44][CH2:43]3)=[O:41])[N:38]=2)[CH:35]=1>CN(C)C=O.CN(C)C(=O)C>[CH:42]1([C:40]([NH:39][C:37]2[N:38]=[C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]4[CH:27]=[C:26]([NH:25][C:7]([C:5]5[C:4]([C:10]([F:13])([F:12])[F:11])=[N:3][N:2]([CH3:1])[CH:6]=5)=[O:8])[CH:47]=[CH:46][CH:45]=4)=[CH:35][N:34]3[N:36]=2)=[O:41])[CH2:43][CH2:44]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Reactant: Cn1cc(C(=O)O)c(C(F)(F)F)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)c(C(F)(F)F)n1
Yield: 69.7 %

Procedure:
In the same manner as in Example 18-4 and using 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (175 mg, 0.904 mmol), tetrahydrofuran (8 mL), oxalyl chloride (118 μL, 1.36 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (70.0 mg, 0.226 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (3 mL) as starting materials, the title compound (76.5 mg, 70%) was obtained as a white solid.
Reaction SMILES: C([Al](CC(C)C)CC(C)C)C(C)C.[NH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH:17]=[CH:18][NH:19]2.C(OC)(=O)[C:25]1[C:26](=[CH:28][CH:29]=[CH:30][CH:31]=1)[OH:27].Cl>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.C(Cl)Cl>[NH:19]1[C:20]2[C:16](=[C:15]([NH:14][C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[OH:27])[CH:23]=[CH:22][CH:21]=2)[CH:17]=[CH:18]1
Reactant: Nc1cccc2[nH]ccc12
Reactant: COC(=O)c1ccccc1O
Agent: CC(C)C[Al](CC(C)C)CC(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Oc1ccccc1Nc1cccc2[nH]ccc12
Temperature: 25 °C

Procedure:
92 ml of a 1.1 mole/liter solution of triisobutylaluminum in toluene were added with stirring under an inert atmosphere to a solution of 6.6 g of 4-amino indole in 250 ml of chloroform and then 9.6 ml of methyl salicylate were added. The mixture was refluxed for 20 hours and then cooled to ambient temperature. 300 ml of N hydrochloric acid and 300 ml of methylene chloride were added, followed by washing with water, drying over a desiccant, filtering, evaporating to dryness under reduced pressure at 50° C., triturating with ether, filtering and drying at 60° C. under reduced pressure to obtain 9.4 g of 2-[N-(1H-indol-4-yl)amino]phenol melting at ≃232° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C@H:11]([OH:18])[CH2:10]2)=[CH:4][CH:3]=1.[Cl:19][C:20]([Cl:30])=[CH:21][C@@H:22]1[C@H:24]([C:25](Cl)=[O:26])[C:23]1([CH3:29])[CH3:28].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:19][C:20]([Cl:30])=[CH:21][C@@H:22]1[C@H:24]([C:25]([O:18][C@H:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C@H:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:10]2)=[O:26])[C:23]1([CH3:28])[CH3:29]
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)Cl
Reactant: O[C@@H]1C[C@@H](Cc2ccc(F)cc2)c2ccccc21
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)O[C@@H]1C[C@@H](Cc2ccc(F)cc2)c2ccccc21
Yield: 81.9 %

Procedure:
In the manner of Example 4, the reaction of 1.00 g (0.004 mole) of trans-3-[(4-fluorophenyl)methyl]-1-indanol (96% trans, 4% cis) and 0.93 g (0.004 mole) of cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarbonyl chloride in the presence of 0.32 g (0.004 mole) of pyridine and 50 mL of toluene gave 1.42 g of trans-3-[(4-fluorophenyl)methyl]-1-indanyl cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate. The ir and nmr spectra were consistent with the proposed structure.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=2)[C:10]([C:22]([OH:24])=O)=[C:9]1[CH:25]([CH3:27])[CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.[F:32][C:33]1[CH:34]=[C:35]([CH2:39][NH2:40])[CH:36]=[N:37][CH:38]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=2)[C:10]([C:22](=[O:24])[NH:40][CH2:39][C:35]2[CH:36]=[N:37][CH:38]=[C:33]([F:32])[CH:34]=2)=[C:9]1[CH:25]([CH3:27])[CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc2c(C(=O)O)c(C(C)C)n(Cc3ccccc3)c2c1
Reactant: NCc1cncc(F)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(C(=O)NCc3cncc(F)c3)c(C(C)C)n(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Following General Procedure E, 1-benzyl-6-(ethoxylcarbonyl)-2-isopropyl-1H-indole-3-carboxylic acid (Compound 39, 93 mg, 0.254 mmol) in CH2Cl2 (6 ml) was added EDC (97 mg, 0.508 mmol) and DMAP (46 mg, 0.381mmol), followed by (5-fluoropyridin-3-yl)methanamine (81 mg, 0.63 mmol). The reaction was stirred at room temperature for 12 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→80% EtOAc-hexanes) to yield the title compound as a yellow solid.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.Cl[C:20]1[N:25]=[CH:24][N:23]=[C:22]([C:26]([C:28]2[CH:38]=[C:37]([CH3:39])[C:31]3[N:32]([CH3:36])[C:33](=[O:35])[O:34][C:30]=3[CH:29]=2)=[O:27])[CH:21]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:36][N:32]1[C:31]2[C:37]([CH3:39])=[CH:38][C:28]([C:26]([C:22]3[N:23]=[CH:24][N:25]=[C:20]([N:3]4[CH2:4][CH2:5][CH:6]([N:9]5[C:17]6[C:12](=[N:13][CH:14]=[CH:15][CH:16]=6)[NH:11][C:10]5=[O:18])[CH2:7][CH2:8]4)[CH:21]=3)=[O:27])=[CH:29][C:30]=2[O:34][C:33]1=[O:35]
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)cc2oc(=O)n(C)c12

Procedure:
72.8 mg (0.25 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one-dihydrochloride, 75 mg (0.25 mmol) 6-(6-chloropyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one and 0.22 mL (1.25 mmol) DIPEA were stirred in 2 mL DMF for 2 h at RT. The mixture was purified by preparative HPLC-MS. The fractions containing the product were combined, the organic solvent was eliminated i. vac. and the aqueous phase remaining was neutralised with a 4N aqueous NaOH solution. The precipitate was suction filtered, washed with water and dried in the CAD.
Reaction SMILES: [OH-].[Na+].BrBr.[O:5]1CCOCC1.[C:11]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[CH2:19][CH:18]([CH2:23][NH:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH2:17]2)(=[O:13])C.S([O-])([O-])(=O)=S.[Na+].[Na+].Cl>O>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([S:25]([NH:24][CH2:23][CH:18]2[CH2:17][C:16]3[C:20](=[CH:21][CH:22]=[C:14]([C:11]([OH:13])=[O:5])[CH:15]=3)[CH2:19]2)(=[O:26])=[O:27])=[CH:33][CH:32]=1
Reactant: CC(=O)c1ccc2c(c1)CC(CNS(=O)(=O)c1ccc(Cl)cc1)C2
Reactant: C1COCCO1
Agent: BrBr
Agent: Cl
Agent: O=S([O-])([O-])=S
Solvent: O
Product: O=C(O)c1ccc2c(c1)CC(CNS(=O)(=O)c1ccc(Cl)cc1)C2
Reaction time: 1 h
Yield: 86 %

Procedure:
Under ice-salt cooling, 4.90 g (122 mmol) of sodium hydroxide was dissolved in 50 ml of water, to which 1.6 ml (31.0 mmol) of bromine was added dropwise. This mixture was added to a solution of 100 ml of 90% dioxane containing 2.85 g (7.50 mmol) of 5-acetyl-2-[(4-chlorophenyl)sulfonylaminomethyl]indan under cooling in an ice-salt bath. Thereafter, stirring was conducted for 1 hour during which the temperature of the mixture was elevated to room temperature. The reaction solution was added with 10% sodium thiosulfate, and made acidic with 1N HCl, followed by extracting with ethyl acetate. The solvent was removed, and the residue was recrystallized from acetic acid to obtain 2.36 g of colorless crystals. Yield: 86%
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([O:16][CH3:17])(=[O:15])[CH2:11][C:12]([CH3:14])=[O:13]>C1C=CC=CC=1.N1CCCCC1.C(O)(=O)C>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:11]([C:12](=[O:13])[CH3:14])[C:10]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1
Reactant: COC(=O)CC(C)=O
Reactant: Cc1ccc(C=O)cc1
Solvent: C1CCNCC1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: COC(=O)C(=Cc1ccc(C)cc1)C(C)=O
Yield: 84.7 %

Procedure:
A solution of 4-methylbenzaldehyde (0.981 ml, 8.32 mmol), methyl acetoacetate (0.898 ml, 8.32 mmol), piperidine (0.041 ml, 0.416 mmol), and acetic acid (0.024 ml, 0.416 mmol) in benzene (12.5 ml) was refluxed with a Dean Stark apparatus for 1 day. The reaction was concentrated; the residue was dissolved in EtOAc, washed with water, sat. NaHCO3, Brine, dried with Na2SO4, filtered, and concentrated. Purification with column chromatography afforded a 2:3 mixture of E/Z isomers of methyl 2-(4-methylbenzylidene)-3-oxobutanoate (1539.1 mg, 7.05 mmol, 84.7% yield) as yellow oil: E=1H NMR (400 MHz, CHLOROFORM-d) d=7.67 (s, 1 H), 7.29 (d, J=8.2 Hz, 2 H), 7.18 (d, J=8.1 Hz, 2 H), 3.83 (s, 3 H), 2.37 (s, 3 H), 2.36 (s, 3 H) LCMS (m/z) ES+=219 (M+1). Z=1H NMR (400 MHz, CHLOROFORM-d) d=7.55 (s, 1 H), 7.33 (d, J=8.2 Hz, 2 H), 7.20 (d, J=8.1 Hz, 2 H), 3.86 (s, 3 H), 2.42 (s, 3 H), 2.38 (s, 3 H); LCMS (m/z) ES+=219 (M+1).
Reaction SMILES: CS[C:3]1[C:4]2[NH:5][C:6]([C:18]([F:21])([F:20])[F:19])=[N:7][C:8]=2[N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:10](=[O:12])[N:11]=1.[NH2:22][NH2:23]>O>[CH2:13]([N:9]1[C:8]2[N:7]=[C:6]([C:18]([F:21])([F:20])[F:19])[NH:5][C:4]=2/[C:3](=[N:22]\[NH2:23])/[NH:11][C:10]1=[O:12])[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: NN
Reactant: CCCCCn1c(=O)nc(SC)c2[nH]c(C(F)(F)F)nc21
Solvent: O
Product: CCCCCn1c(=O)[nH]/c(=N/N)c2[nH]c(C(F)(F)F)nc21
Temperature: 100 °C

Procedure:
A mixture of 6-(methylthio)-3-pentyl-8-(trifluoromethyl)-3,7-dihydro-2H-purin-2-one (0.15 g, 0.23 mmol) and hydrazine (0.80 mL, 25 mmol) in water (0.80 mL) was heated at 100° C. for 1 h. The solution was concentrated under reduced pressure and azeotropically treated with toluene twice. The resulting residue was used for next step without purification. LCMS calculated for C11H16F3N6O (M+H): 305.1. found: 305.1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[O:20][CH2:21][C:22]([F:25])([F:24])[F:23])([O-])=O>CO>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[O:20][CH2:21][C:22]([F:23])([F:24])[F:25]
Reactant: CCOC(=O)C1(c2ccc([N+](=O)[O-])c(OCC(F)(F)F)c2)CCCC1
Solvent: CO
Product: CCOC(=O)C1(c2ccc(N)c(OCC(F)(F)F)c2)CCCC1
Reaction time: 6 h
Yield: 81.8 %

Procedure:
To a stirred solution of ethyl 1-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopentane carboxylate (10 g), in dry MeOH (100 mL) Pd(OH)2 (2 g) was added and reduced under an atmosphere of H2 for 6 h at room temperature. The mixture was filtered through a pad of Celite™ washing with MeOH. The combined filtrates were concentrated under reduced pressure to yield ethyl 1-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate (7.5 g ) as a thick liquid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:21][CH2:22][CH2:23]OS(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:23][CH2:22][Cl:21])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2O)CC1
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2OCCCl)CC1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A solution of 4-(2-hydroxy-phenyl)-piperidine-1-carboxylic acid tert-butyl ester Compound 2a (0.67 g, 2.42 mmol), toluene-4-sulfonic acid 2-chloro-ethyl ester Compound 2b (1.13 g, 4.84 mmol), Cs2CO3 (1.60 g, 4.84 mmol) and DMF (20 mL) were heated and stirred at 50° C. overnight (18 hrs). The excess DMF was removed under reduced pressure and the white residue was mixed with AcOEt (100 mL), washed with water and dried over Na2SO4. The filtered dry solution was evaporated and the product was purified via flash chromatography (silica gel, 25% AcOEt/hexane) to provide 4-[2-(2-chloro-ethoxy)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester Compound 2c (0.78 g, 95%) as a colorless sticky oil. LC-MS (3.943 min.) m/z 362.1 (M+Na+).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1)=[O:3].[C:11]([Si](C)(C)C)#[CH:12].C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:11]([C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=1)#[CH:12]
Reactant: C#C[Si](C)(C)C
Reactant: CC(=O)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CO
Product: C#Cc1ccc(C(C)=O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71 %

Procedure:
2 g of 4-bromoacetophenone, 2.8 ml of ethynyltrimethylsilane, 140 mg of bis(triphenylphosphine)palladium dichloride, 3 ml of triethylamine and 14 mg of copper(I)iodide in 20 ml of N,N-dimethylformamide were stirred at 50° under argon for 2 hrs. After distillation of the solvent the residue was extracted once with 50 ml of ethyl acetate, once with 50 ml of 1N HCl and twice with 50 ml of water. The crude product was purified by silica gel chromatography in hexane/ethyl acetate 10:1 and distilled at 120°/0.1 Torr in a bulb-tube oven. 1.74 g (80%) were obtained as a colourless oil. This was dissolved in 17 ml of methanol, treated with 110 mg of potassium carbonate and stirred at room temperature for 1.5 hrs. After evaporation the product was extracted with 20 ml of ethyl acetate and 20 ml of water and then crystallized from 10 ml of hexane. 0.8 g (71%) of 1-(4-ethynyl-phenyl)-ethanone was obtained as white crystals. M.p. 71°.
Reaction SMILES: [C:1]1([C:9]([C:11]([C:13]2[CH:20]=[CH:19][C:16]([O:17]C)=[CH:15][CH:14]=2)=[O:12])=[O:10])[CH:8]=[CH:7][C:4]([O:5]C)=[CH:3][CH:2]=1>C(O)(=O)C.Br>[OH:5][C:4]1[CH:3]=[CH:2][C:1]([C:9]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([OH:17])=[CH:19][CH:20]=2)=[O:12])=[O:10])=[CH:8][CH:7]=1
Reactant: COc1ccc(C(=O)C(=O)c2ccc(OC)cc2)cc1
Agent: Br
Solvent: CC(=O)O
Product: O=C(C(=O)c1ccc(O)cc1)c1ccc(O)cc1
Reaction time: 8 h
Yield: 97 %

Procedure:
12 g of anisil was dissolved in 120 ml of acetic acid and 240 ml of 48% hydrobromic acid. The mixture was stirred vigorously and heated to reflux to for 4 hours. The temperature was then lowered to 90° C. and left overnight. The resulting solution was poured over ice and the precipitate was collected by filtration and washed with water. After drying, 10.43 g of product (yield: 75.0 mol %) with a purity of 76.8% was obtained. The purity was measured by gas chromatography.
Reaction SMILES: [C:1]([O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:18]([NH:20][CH2:21][C:22]([O:24]CC3C=CC=CC=3)=[O:23])=[O:19])[C:13](=[O:17])[O:14]2)=[CH:9][C:8]=1[Cl:32])(=[O:5])[CH2:2][CH2:3][CH3:4].C(O)(=O)C.[H][H].O1C2C(=CC=CC=2)C=CC1=O>O1CCOCC1.[Pd]>[C:1]([O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])[C:13](=[O:17])[O:14]2)=[CH:9][C:8]=1[Cl:32])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: [H][H]
Reactant: CCCC(=O)Oc1cc2oc(=O)c(C(=O)NCC(=O)OCc3ccccc3)cc2cc1Cl
Agent: [Pd]
Agent: O=c1ccc2ccccc2o1
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CCCC(=O)Oc1cc2oc(=O)c(C(=O)NCC(=O)O)cc2cc1Cl

Procedure:
7-Butyryloxy-3-carboxymethylaminocarbonyl-6-chlorocoumarin was prepared as follows. 920 mg (2 mMol) 7-butyryloxy-3-benzyloxycarbonylmethylaminocarbonyl-6-chlorocoumarin were dissolved in 50 ml dioxane. 100 mg palladium on carbon (10%) and 100 μl acetic acid were added to the solution and the suspension stirred vigorously in a hydrogen atmosphere at ambient pressure. After the uptake of hydrogen seized the suspension was filtered. The product containing carbon was extracted five times with 25 ml boiling dioxane. The combined dioxane solutions were let to cool upon which the product precipitated as a white powder. Reduction of the solvent to 20 ml precipitates more product. The remaining dioxane solution is heated to boiling and heptane is added until the solution becomes cloudy. The weights of the dried powders were 245 mg, 389 mg and 58 mg, totaling 692 mg (1.88 mMol, 94%) of white product. 1H NMR (dDMSO): δ1.02 ppm (t, 3H, J=7.4 Hz, butyric methyl), δ1.73 ppm (m, 2H, J1≈J27.3 Hz, butyric methylene), δ2.70 ppm (t, 2H, J=7.2 Hz, butyric methylene), δ4.07 ppm (d, 2H, J=5.6 Hz, glycine methylene), δ7.67 ppm (s, 1H, coumarin), δ8.35 ppm (s, 1H, coumarin), δ8.90 ppm (s, 1H, coumarin), δ9.00 ppm (t, 1H, J=5.6 Hz, amide).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[C:10](=[O:27])[CH:11]=[CH:12][N:13]3[C:18]=2[CH:17]=[CH:16][CH:15]=[C:14]3[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[C:4]([F:28])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:34]([O:36]CC)=[CH2:35])CCC>C1(C)C=CC=CC=1.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>[C:34]([C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[C:10](=[O:27])[CH:11]=[CH:12][N:13]3[C:18]=2[CH:17]=[CH:16][CH:15]=[C:14]3[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[C:4]([F:28])[CH:3]=1)(=[O:36])[CH3:35]
Reactant: O=c1ccn2c(-c3ccc(F)cc3F)cccc2c1-c1c(F)cc(Br)cc1F
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(F)c(-c2c(=O)ccn3c(-c4ccc(F)cc4F)cccc23)c(F)c1
Temperature: 90 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1-(4-bromo-2,6-difluorophenyl)-6-(2,4-difluorophenyl)-2H-quinolizin-2-one (30 mg, 0.067 mmol) in toluene (1.4 mL) was added tributyl(1-ethoxyvinyl)stannane and tetrakis(triphenylphosphine)palladium (7.74 mg, 0.007 mmol) and heated to 90° C. for 1½ h. The reaction was cooled, filtered through celite, and diluted with THF. The mixture was added 2N HCl and stirred for 20 min to complete the reaction. The crude mixture was diluted with H2O and EtOAc. The organic layer was washed with H2O, brine, dried over MgSO4, and condensed. The crude residue was purified via silica gel chromatography (hexanes/ethyl acetate) to give the title compound (7.9 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[CH3:19].[H-].[Na+].I[CH2:23][CH:24]([CH3:26])[CH3:25]>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:23][CH:24]([CH3:26])[CH3:25])[N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[CH3:19]
Reactant: CC(C)CI
Reactant: COc1ccc(-c2n[nH]c3c(F)cccc23)c(C)c1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2nn(CC(C)C)c3c(F)cccc23)c(C)c1
Yield: 99.8 %

Procedure:
Prepared according to Method D step B from 7-fluoro-3-(4-methoxy-2-methylphenyl)-1H-indazole (0.300 g, 1.20 mmol), sodium hydride (60% in oil, 0.058 g, 1.50 mmol) and 1-iodo-2-methylpropane (0.23 mL, 2.00 mmol) to give the title compound (0.374 g) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][C:3]1=O>C1COCC1>[CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH2:3]1
Reactant: CN1C(=O)COc2ccccc21
Solvent: C1CCOC1
Product: CN1CCOc2ccccc21
Reaction time: 2 h
Yield: 100.3 %

Procedure:
To a stirred solution of 4-methyl-4H-benzo[1,4]oxazin-3-one (2.18 g, 13.37 mmol) in THF (5 mL) was added borane-tetrahydrofuran complex (4.02 g, 46.8 mmol) at room temperature. After stirring the solution for 2 h, the reaction mixture was refluxed for 4 h. After complete conversion, reaction mixture was quenched by adding MeOH (10 ml) and evaporated the solvents. The residue obtained was extracted with ethyl acetate (30×2 ml) and the organic layer was washed with water (20 mL), brine (20 mL) and evaporation of solvent gave 4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine 2.0 g.