Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][C@H:20]([C:33]1[NH:37][C:36]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:35]=2[N:34]=1)[CH2:21][CH2:22][C:23]([O:25]CC1C=CC=CC=1)=[O:24].C[Si](I)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][C@H:20]([C:33]1[NH:37][C:36]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:35]=2[N:34]=1)[CH2:21][CH2:22][C:23]([OH:25])=[O:24]
Reactant: O=C(CC[C@H](Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1)OCc1ccccc1
Agent: C[Si](C)(C)I
Product: O=C(O)CC[C@H](Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 15c from 6-chloro-4-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-benzyloxycarbonyl-propylamino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and trimethylsilyl iodide.
Reaction SMILES: Cl.[C:2]1([CH:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:9]2[CH2:12][CH:11]([OH:13])[CH2:10]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.S(=O)(=O)=O.O>O1CCCC1.CS(C)=O>[C:14]1([CH:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[N:9]2[CH2:12][C:11](=[O:13])[CH2:10]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: Cl
Agent: O=S(=O)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.3 %

Procedure:
To a stirred solution of 1-(diphenylmethyl)azetidin-3-ol hydrochloride salt, (20 g, 72.5 mmol) in tetrahydrofuran (69 ml) and DMSO (173 ml) was added triethylamine (50.5 ml, 362.6 mmol) at 0° C. Then sulphur trioxide:pyridine complex (69 g, 433 mmol) was added portionwise to the reaction mixture over 10 minutes. The resulting yellow solution was stirred at room temperature for 2 hours. Then the reaction mixture was poured in to cold water (173 ml) and extracted with (1:1) ethyl acetate:hexane (5×200 ml). The combined organic layer was washed with water (200 ml), saturated aqueous sodium chloride solution (200 ml), dried over anhydrous sodium sulphate and concentrated in vacuo. Crude product was purified over 100-200 silica gel using 5% v/v ethyl acetate in hexane to get 11.4 g (67%) of the title compound as a white solid.
Reaction SMILES: [CH:1]1([CH:4]=O)[CH2:3][CH2:2]1.[NH2:6][C:7]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([NH2:11])=[O:10]>O.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[Cl:16][C:15]1[CH:14]=[CH:13][CH:12]=[C:8]2[C:7]=1[NH:6][C:4]([CH:1]1[CH2:2][CH2:3]1)=[N:11][C:9]2=[O:10]
Reactant: NC(=O)c1cccc(Cl)c1N
Reactant: O=CC1CC1
Agent: Cl[Fe](Cl)Cl
Solvent: O
Product: O=c1nc(C2CC2)[nH]c2c(Cl)cccc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
EDCI hydrochloride (22.0 g) and 1-hydroxybenzotriazole (11.4 g) were added to a solution of 2-amino-3-chlorobenzoic acid (12.8 g) in DMF (100 mL), and subsequently ammonia water (22.0 ml) was added thereto. The reaction solution was stirred at room temperature for 3 hours. Water was added to the reaction solution, and the deposit was filtrated and dried under reduced pressure to obtain 2-amino-3-chlorobenzamide (9.7 g). Iron(III) chloride hexahydrate (6.3 g) and cyclopropanecarbaldehyde (1.3 ml) were added to a suspension of the obtained 2-amino-3-chlorobenzamide (2.0 g) in water (30 ml), and the mixture was stirred overnight at 100° C. After cooling, water was added to the reaction solution, and the deposit was filtrated and dried under reduced pressure to obtain 8-chloro-2-cyclopropylquinazolin-4(1H)-one (2.0 g). Compound (115) was obtained as a yellow solid (yield based on 6 steps: 18%) according to Example 114(2) using the obtained 8-chloro-2-cyclopropylquinazolin-4(1H)-one instead of compound (114a).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:20]=[C:19]([Cl:29])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[CH:11][CH:10]=1.[C:30](Cl)(=O)[CH3:31].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:20]=[C:19]([Cl:29])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]2[N:14]=[C:30]([CH3:31])[O:16][N:15]=2)=[CH:17][CH:18]=1
Reactant: N=C(NO)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1nc(-c2ccc(OCCCOc3c(Cl)cc(OCC=C(Cl)Cl)cc3Cl)cc2)no1
Reaction time: 4 h

Procedure:
100 mg of 4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-N-hydroxybenzamidine are placed in 2 ml of toluene. 20 mg of acetyl chloride and 2 ml of pyridine are added, and heating is carried out for 4 hours at 120° C. The reaction mixture is concentrated, and the residue is taken up in ethyl acetate and washed with dilute hydrochloric acid and water. Concentration of the organic phase and purification over silica gel yield the title compound (compound 1.10).
Reaction SMILES: [CH3:1][Mg]Br.[CH:4]1[N:5]=[CH:6][N:7]2[CH2:12][CH2:11][O:10][CH:9]([C:13]3[CH:24]=[CH:23][C:16]([C:17](N(OC)C)=[O:18])=[CH:15][CH:14]=3)[C:8]=12.[Cl-].[NH4+]>O1CCCC1>[CH:4]1[N:5]=[CH:6][N:7]2[CH2:12][CH2:11][O:10][CH:9]([C:13]3[CH:14]=[CH:15][C:16]([C:17](=[O:18])[CH3:1])=[CH:23][CH:24]=3)[C:8]=12
Reactant: CON(C)C(=O)c1ccc(C2OCCn3cncc32)cc1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C2OCCn3cncc32)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3 mmol of methylmagnesium bromide solution (3M in diethyl ether) are added to a solution of 0.97 mmol of 4-(5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-8-yl)-N-methoxy-N-methylbenzamide in 10 ml of absolute tetrahydrofuran under argon. The reaction solution is stirred at room temperature for 4 hours and then poured into saturated aqueous ammonium chloride solution and extracted with tert-butyl methyl ether. The combined organic phases are dried over magnesium sulphate and evaporated. The title compound is obtained as a beige solid from the residue by flash chromatography (SiO2 60F).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[CH2:21][CH:20]([CH2:22][CH:23]3[CH2:28][CH2:27][N:26]([CH2:29][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:25][CH2:24]3)[C:18](=[O:19])[C:13]2=[CH:14][C:15]=1[O:16][CH3:17]>C(OCC)(=O)C>[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[CH2:21][CH:20]([CH2:22][CH:23]3[CH2:24][CH2:25][N:26]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:27][CH2:28]3)[C:18](=[O:19])[C:13]2=[CH:14][C:15]=1[O:16][CH3:17].[C:1]([O-:7])(=[O:6])[CH2:2][C:3]([O-:5])=[O:4]
Reactant: O=C(O)CC(=O)O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CCOC(C)=O
Product: O=C([O-])CC(=O)[O-]
Temperature: 25 °C

Procedure:
Malonic acid (1.18 g, dissolved in 35 ml of 2-propanol and 5 ml of water) is added slowly to a solution of Donepezil (3.79 g) in ethyl acetate (70 ml) with stirring at room temperature. The solid precipitated is filtered and dried at 55° C. under vacuum to give the title compound. Melting point: 165.7° C.
Reaction SMILES: [F:1][CH:2]([F:23])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:13][CH:14]2[CH2:16][CH2:15]2)[C:6]([CH2:17][OH:18])=[C:5]([C:19]([F:22])([F:21])[F:20])[N:4]=1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(N(CC)CC)C>[C:24]([O:18][CH2:17][C:6]1[C:7]([CH2:13][CH:14]2[CH2:15][CH2:16]2)=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:3]([CH:2]([F:1])[F:23])=[N:4][C:5]=1[C:19]([F:22])([F:20])[F:21])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(CO)c1CC1CC1
Solvent: CCN(CC)CC
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(COC(=O)c2ccccc2)c1CC1CC1

Procedure:
Reaction of methyl 2-(difluoromethyl)-5-(hydroxymethyl)-4-(cyclopropylmethyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (U.S. Pat. No. 5,169,432 example A compound A4) with. Benzoyl chloride and triethylamine according to the procedure in example 99 of U.S. Pat. No. 5,169,432 gave the product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1)=O)[CH3:2].[N+:16]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)([O-:18])=[O:17].Cl.[N+]([C:30]1C=CC(N)=C[CH:31]=1)([O-])=O>C(O)CCC>[CH2:1]([O:3][C:4](=[O:15])[CH:5]=[C:6]([NH:23][C:22]1[CH:24]=[CH:25][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1)[CH2:2][CH2:30][CH3:31]
Reactant: CCOC(=O)CC(=O)c1cccc(F)c1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCCCO
Product: CCCCOC(=O)C=C(Nc1ccc([N+](=O)[O-])cc1)c1cccc(F)c1
Temperature: 118 °C
Yield: 20.8 %

Procedure:
3-(3-Fluorophenyl)-3-oxo-propionic acid ethyl ester, 106.3 grams (0.506 moles), 4-nitro-aniline, 63.0 grams (0.456 moles), and 4-nitro-aniline hydrochloride 4.0 grams (0.023 moles) were placed in a dry 2 L round-bottom flask. To the mixture was added 1.3 L of n-butanol, the flask was fitted with a Soxhlet extractor (cup volume of 0.3 L), condenser and nitrogen inlet. Dry, activated 4 Å sieves (200 grams) were placed in the extractor cup and the reaction mixture heated to reflux at 118° C. under nitrogen and maintained at that temperature for 90 hours. The reaction mixture was decanted while hot from a small amount of solids and chilled to −15° C. for 48 hours Crystalline solids were collected by vacuum filtration. The crystals were washed with 0.2 L of cold ethanol and two 0.2 L portions of hexanes and vacuum dried at 50° C. overnight to yield 35.8 grams (20.8% yield) of the title compound.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]2[NH:13][CH2:12][CH:11]([CH2:14][CH3:15])[O:10]2)[CH:6]=[CH:7][CH:8]=1.[CH:18]([N:21]=[C:22]=[O:23])([CH3:20])[CH3:19]>CC(C)=O>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]2[N:13]([C:22](=[O:23])[NH:21][CH:18]([CH3:20])[CH3:19])[CH2:12][CH:11]([CH2:14][CH3:15])[O:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCC1CNC(c2cccc(C(F)(F)F)c2)O1
Reactant: CC(C)N=C=O
Solvent: CC(C)=O
Product: CCC1CN(C(=O)NC(C)C)C(c2cccc(C(F)(F)F)c2)O1

Procedure:
Four and four-tenths grams of 2-(m-trifluoromethylphenyl)-5-ethyl-1,3-oxazolidine was dissolved in dry acetone and 1.8 ml of isopropyl isocyanate was added dropwise. The mixture was heated at reflux for two hours, cooled and stripped on the rotary evaporator. Yield was 5.9 g of a thick, sticky gum. The structure was confirmed by NMR and infrared spectroscopy.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH:11]=[N:10][CH:9]=[N:8]1.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1([CH2:27]Br)[O:25][CH:24]([CH3:26])[CH2:23][CH2:22][O:21]1.[I-].[Na+]>O.CS(C)=O>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1([CH2:27][N:7]2[CH:11]=[N:10][CH:9]=[N:8]2)[O:25][CH:24]([CH3:26])[CH2:23][CH2:22][O:21]1
Reactant: c1nc[nH]n1
Reactant: CC1CCOC(CBr)(c2ccc(Cl)cc2Cl)O1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC1CCOC(Cn2cncn2)(c2ccc(Cl)cc2Cl)O1
Temperature: 100 °C
Reaction time: 36 h

Procedure:
A mixture of 10.8 parts of potassium carbonate, 5.4 parts of 1H-1,2,4-triazole, 20.5 parts of 2-(2,4-dichlorophenyl)-2-(bromomethyl)-4-methyl-1,3-dioxane, 0.2 parts of sodium iodide and 100 parts of dimethylsulfoxide is stirred during 36 hours at 100° C., cooled and poured onto 600 parts of water. The reaction mixture is extracted three times with ethyl acetate and the combined organic layers are washed with 200 parts of water, dried, filtered and evaporated. The residual oil is purified by column-chromatography over silica gel using ethyl acetate as eluent. The pure fractions are collected and the eluent is evaporated, yielding 1-[2-(2,4-dichlorophenyl)-4-methyl-1,3-dioxan-2-ylmethyl]-1H-1,2,4-triazole; nD22 : 1.5505.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10](O)=[O:11])=O)(C)(C)C.[NH2:13][CH2:14][CH:15]1[CH2:17][CH2:16]1.[C:18]([OH:24])([C:20]([F:23])([F:22])[F:21])=[O:19]>>[F:21][C:20]([F:23])([F:22])[C:18]([OH:24])=[O:19].[NH2:8][CH2:9][C:10]([NH:13][CH2:14][CH:15]1[CH2:17][CH2:16]1)=[O:11]
Reactant: NCC1CC1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: NCC(=O)NCC1CC1

Procedure:
The title was compound prepared from tert-Butoxycarbonylamino-acetic acid, using aminomethylcyclopropane and TFA, following procedures analogous to that described in Example 1A.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[OH:11].[C:12](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[O:11][CH3:12]
Reactant: O=[N+]([O-])c1cccc(Br)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c(Br)cccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
2-Bromo-6-nitrophenol (5.0 g, 22.9 mmol) was dissolved in DMF (3 mL), potassium carbonate (4.75 g, 34.4 mmol) was added and the reaction was stirred for 30 minutes. Next iodomethane (2.15 mL, 34.4 mmol) was added and the reaction was stirred overnight. The crude reaction was filtered, diluted with ethyl acetate and washed with brine (twice) and water (twice). The organic layer was dried over sodium sulfate, filtered and concentrated to provide 1-bromo-2-methoxy-3-nitrobenzene (5.12 g, 96%). LC retention time 0.92 [J].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[CH3:18][N:19](C=O)C>[C-]#N.[C-]#N.[Zn+2].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:18]([C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1)#[N:19]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Br)cc1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)OC(=O)NCCc1ccc(C#N)cc1
Temperature: 150 °C
Yield: 31 %

Procedure:
Compound 113 (530 mg, 1.8 mmol) was dissolved in dry DMF (17 mL) under N2. Zn(CN)2 (416 mg, 3.6 mmol) and Pd(PPh3)4 (200 mg, 0.18 mmol) was added. The reaction mixture was stirred and heated at 150° C. in a microwave instrument (CEM Discover®) for 20 min and the reaction mixture was then concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc/hexanes (20˜80%) to yield 114 (540 mg, 31%) as a white solid. MS (APCI, negative): m/z 245 [M−H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]2)[CH:7]=1.[CH2:18]([OH:21])[C:19]#[CH:20].C(N(CC)CC)C>O1CCOCC1.CCOC(C)=O.[Cu]I>[CH3:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]2[CH:7]=[C:2]([C:20]#[C:19][CH2:18][OH:21])[CH:3]=[CH:4][C:5]=2[N+:15]([O-:17])=[O:16])[CH2:9][CH2:10]1
Reactant: C#CCO
Reactant: CC1CCN(c2cc(Br)ccc2[N+](=O)[O-])CC1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC1CCN(c2cc(C#CCO)ccc2[N+](=O)[O-])CC1
Temperature: 80 °C
Yield: 76.7 %

Procedure:
To a round bottom flask containing 1-(5-bromo-2-nitro-phenyl)-4-methyl-piperidine (as prepared above, 400 mg, 1.33 mmol) in 8 mL of dioxane was added propargyl alcohol (155 μL, 2.64 mmol), bis-dichloro(triphenylphosphinyl)palladium (II) (56.3 mg, 0.0798 mmol), copper (I) iodide (5.0 mg, 0.02 mmol) and triethylamine (741 μL, 5.32 mmol). The result was heated at 80° C. for 16 h. The reaction was then diluted with EtOAc (50 mL), washed with water (2×50 mL), dried (Na2SO4), and concentrated in vacuo. Purification of the crude material by preparative thin layer chromatography (75% EtOAc-hexanes) afforded 280 mg (77%) of the title compound as a reddish oil. 1H-NMR (CDCl3; 400 MHz): δ 7.73 (d, 1H, J=8.6 Hz), 7.17 (d, 1H, J=1.6 Hz), 6.98 (dd, 1H, J=8.6, 1.6 Hz), 3.23-3.26 (m, 2H), 4.53 (s, 2H), 1.73-1.42 (m, 5H), 2.86-2.79 (m, 2H), 1.00 (d, 3H, J=6.4 Hz).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[C@@H:34]([OH:35])[CH2:33][CH2:32][NH:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[C@@H:34]([OH:35])[CH2:33][CH2:32][N:31]([C:36](=[O:39])[CH2:37][CH3:38])[CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: CCC(=O)Cl
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@H]4CNCC[C@@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: CCC(=O)N1CC[C@H](O)[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-N-[(3S*,4S*)-4-hydroxypiperidin-3-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f39) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][CH:8]=1.Cl.Cl.[NH2:33][CH:34]1[CH2:37][NH:36][CH2:35]1.CN1CCCC1>C(O)C>[NH2:33][CH:34]1[CH2:37][N:36]([C:20]2[C:21]([Cl:23])=[C:22]3[C:17]([C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14][N:13]3[C:11]3[C:10]([F:30])=[CH:9][CH:8]=[C:7]([NH2:6])[N:12]=3)=[CH:18][C:19]=2[F:25])[CH2:35]1
Reactant: NC1CNC1
Reactant: Nc1ccc(F)c(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)n1
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: Nc1ccc(F)c(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Cl)c32)n1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
To 190 mg of N,N-dimethylformamide were added 57 mg of 1-(6-amino-3-fluoropyridine-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 37 mg of 3-aminoazetidine dihydrochloride, and 100 mg of N-methyl-pyrrolidine, and the mixture was stirred at 90° C. for 30 minutes. After adding 0.2 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 40 mg of the title compound as a colorless powder.
Reaction SMILES: [CH3:1][N:2]1[C:19]2[CH:18]=[C:17]3[O:20][CH2:21][CH2:22][O:23][C:16]3=[CH:15][C:14]=2[C:4]2([C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]2=[O:13])[C:3]1=[O:24].C(=O)([O-])[O-].[Cs+].[Cs+].Br.Br[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1>CN(C)C=O.O.C(OCC)(=O)C>[CH3:1][N:2]1[C:19]2[CH:18]=[C:17]3[O:20][CH2:21][CH2:22][O:23][C:16]3=[CH:15][C:14]=2[C:4]2([C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)[C:5]2=[O:13])[C:3]1=[O:24]
Reactant: CN1C(=O)C2(C(=O)Nc3ccccc32)c2cc3c(cc21)OCCO3
Reactant: BrCc1ccccn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)C2(C(=O)N(Cc3ccccn3)c3ccccc32)c2cc3c(cc21)OCCO3
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 23 %

Procedure:
To a stirred solution of 6-methyl-2,3-dihydrospiro[1,4-dioxino[2,3-f]indole-8,3′-indole]-2′,7(1′H,6H)-dione (0.07 g, 0.21 mmol) in N,N-dimethylformamide (5 mL) was added cesium carbonate (0.20 g, 0.61 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 min, 2-(bromomethyl)pyridine hydrobromide (0.08 g, 0.31 mmol) was added and the mixture was stirred at ambient temperature for 18 h. The mixture was diluted with water and ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography and eluted with ethyl acetate/hexanes (3/2) to afford 6-methyl-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[1,4-dioxino[2,3-f]indole-8,3′-indole]-2′,7(1H,6H)-dione (0.02 g, 26%): mp 87-89° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.64-8.63 (m, 1H), 7.71-7.62 (m, 2H), 7.26-7.17 (m, 2H), 6.96-6.47 (m, 3H), 6.47 (s, 1H), 6.46 (s, 1H), 5.33 (s, 2H), 4.24-4.06 (m, 4H), 3.22 (s, 3H); MS (ES+) m/z 414.0 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:11](=[O:13])[CH3:12])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.C1N2CN3CN(C2)CN1C3.C1(C)C=CC=CC=1.FC(F)(F)[C:33](O)=[O:34]>>[C:11]([C:3]1[C:2]([OH:1])=[C:10]([CH:33]=[O:34])[C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1)(=[O:13])[CH3:12]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(=O)c1cc2c(cc1O)OCO2
Agent: C1N2CN3CN1CN(C2)C3
Solvent: Cc1ccccc1
Product: CC(=O)c1cc2c(c(C=O)c1O)OCO2
Temperature: 40 °C
Reaction time: 12 h
Yield: 6 %

Procedure:
A solution of 1-(6-hydroxybenzo[d][1,3]dioxol-5-yl)ethanone (1.5 g, 8.3 mmol) in trifluoroacetic acid (15 mL) was added with hexamethylenetetramine (1.7 g, 13 mmol), and the mixture was stirred at 40° C. for 12 hours. The reaction mixture was added with toluene, and then the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was successively washed with water, saturated aqueous sodium hydrogencarbonate, and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, the solvent was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluted with chloroform/methanol (100:0→97:3)) to obtain 6-acetyl-5-hydroxybenzo[d][1,3]dioxole-4-carboxaldehyde (0.11 g, 6%).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([CH2:6][O:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)=[C:4]([F:16])[CH:3]=1.[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CC(C)(C(=O)CC(=O)C(C)(C)C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu]Cl.CN1C(=O)CCC1>[F:16][C:4]1[CH:3]=[C:2]([O:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][C:5]=1[CH2:6][O:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9]1
Reactant: Fc1cc(Br)ccc1COC1CCCCO1
Reactant: Oc1ccccc1
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: Fc1cc(Oc2ccccc2)ccc1COC1CCCCO1
Temperature: 120 °C
Yield: 67.8 %

Procedure:
Mix under argon atmosphere 2-(4-bromo-2-fluorobenzyloxy)-tetrahydropyran (2.9 g, 10 mmol), phenol (1.9 g, 20 mmol), 2,2,6,6-tetramethylheptane-3,5-dione (184.3 mg, 1.0 mmol), cesium carbonate (6.5 g, 20 mmol) and anhydrous NMP (20 mL). Degas the flask and fill with argon: Add copper(I) chloride (495 mg, 5 mmol) quickly. Degas the flask three times then fill with argon. Heat at 120° C. for 3 h. Cool to ambient temperature. Dilute with EtOAc and filter. Concentrate in vacuo and purify by chromatography on silica gel to obtain the desired intermediate (2.05 g, 68%). MS (ES+) m/z: 325 (M+Na)+.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:33])[C:21]([O:24][C:25]2[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[CH:26]=2)([CH3:23])[CH3:22])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:51])[C@@H:15]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si](C(C)(C)C)(C)C)[CH2:37]2)=[CH:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:33])[C:21]([O:24][C:25]2[CH:26]=[C:27]([CH3:32])[CH:28]=[C:29]([CH3:31])[CH:30]=2)([CH3:22])[CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:51])[C@@H:15]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([OH:43])[CH2:37]2)=[CH:10]1
Reactant: Cc1cc(C)cc(OC(C)(C)C(=O)O[C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)C=C3C=C[C@H](C)[C@H](CC[C@@H]4C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O4)[C@H]32)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cc(C)cc(OC(C)(C)C(=O)O[C@H]2C[C@H](O)C=C3C=C[C@H](C)[C@H](CC[C@@H]4C[C@@H](O)CC(=O)O4)[C@H]32)c1
Yield: 68.6 %

Procedure:
A procedure similar to that described in Example 2, above, was followed, but using 978 mg of (4R,6R)-6-([1S,2S,6S,8S,8aR]-2-{1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-[2-(3,5-dimethylphenoxy)-2-methylpropionyloxy]-2-methyl-1-naphthyl}ethyl)tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example 178, above] and 18.5 ml of a 1.0 molar solution of tetrabutylammonium fluoride in tetrahydrofuran, to give 464 mg of the title compound as white crystals, melting at between 129° and 131° C.