Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH:10]([CH3:14])[CH2:9]2)[CH:7]=1.[CH:17]12[CH2:23][CH:20]([CH:21]=[CH:22]1)[CH2:19][CH:18]2[CH:24]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:17]12[CH2:23][CH:20]([CH:21]=[CH:22]1)[CH2:19][CH:18]2[CH2:24][N:11]1[CH2:12][CH2:13][N:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:15][CH3:16])[CH2:9][CH:10]1[CH3:14]
Reactant: O=CC1CC2C=CC1C2
Reactant: COc1ccc(Cl)cc1N1CCNC(C)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COc1ccc(Cl)cc1N1CCN(CC2CC3C=CC2C3)C(C)C1
Reaction time: 8 h

Procedure:
48 mg (0.2 mmol) of 1-(5-Chloro-2-methoxy-phenyl)-3-methyl-piperazine was dissolved in 1.5 mL anhydrous 1,2-dichloroethane. 5-Norbornene-2-carboxaldehyde (25 mg, 0.2 mmol) was added, followed by followed by 63 mg (0.3 mmol) sodium triacetoxyborohydride [NaBH(OAc)3]. The reaction was stirred overnight, then quenched with 1.0 mL DMSO:methanol (1:1). The reaction mixture was filtered and purified by reverse-phase HPLC (2-99CH3CN in 0.085% TFA (aq), 50 mL/min, 2.0 mL injected), and the product 1-bicyclo[2.2.1]hept-5-en-2-ylmethyl-4-(5-chloro-2-methoxy-phenyl)-2-methyl-piperazine isolated as the mono-TFA salt. Theoretical (M+H)+ m/z=347.9; Found 348.0.
Reaction SMILES: [C:1]1([CH:6]=[CH:7][C:8](=[O:24])[C:9](=[CH:14][NH:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=2[CH3:23])[C:10]([O:12]C)=[O:11])[CH2:5][CH2:4][CH2:3][CH:2]=1.ClC1C(=O)C(Cl)=C(Cl)C(=O)C=1Cl.C(O)(=O)C>CN(C)C=O.O1CCOCC1>[C:1]1([C:6]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=3[CH3:23])[CH:14]=[C:9]([C:8](=[O:24])[CH:7]=2)[C:10]([OH:12])=[O:11])[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: COC(=O)C(=CNc1ccc(O)cc1C)C(=O)C=CC1=CCCC1
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1cc(O)ccc1-n1cc(C(=O)O)c(=O)cc1C1=CCCC1
Temperature: 25 °C
Yield: 195.3 %

Procedure:
In 5 ml of N,N-dimethylformamide was dissolved 0.7 g of methyl 5-(cyclopenten-1-yl)-2-(4-hydroxy-2-methylphenylaminomethylene)-3-oxo-4-pentenoate, and they were reacted at 140° C. for 2 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue was purified by a column chromatography (Wako Silica Gel C-200; eluent: chloroform) to obtain an oily substance. This oily substance was dissolved in 10 ml of dioxane, and 0.5 g of 2,3,5,6-tetrachloro-p-benzoquinone was added thereto. They were reacted at 80° C. for 30 minutes. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration, and washed with 5 ml of dioxane. These crystals were dissolved in a mixture of 5 ml of methanol and 5 ml of a 1N aqueous sodium hydroxide solution, the resulting mixture was subjected to reaction at room temperature for 30 minutes. The reaction mixture was adjusted to a pH of 5.5 with acetic acid and the precipitated crystals were collected by filtration, washed with water, and dried to obtain 1.3 g of 6-(cyclopenten-1-yl)-1-(4-hydroxy-2-methylphenyl)-4-oxo-1,4-dihydronicotinic acid having a melting point of 211°-213° C.
Reaction SMILES: Cl[CH2:2][CH:3]=O.C([O-])(O)=O.[Na+].[Br:10][C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=1>CCO>[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:2]=[CH:3][N:17]=2)[CH:16]=1
Reactant: Nc1ccc(Br)cn1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Brc1ccc2nccn2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In step 13-1, chloracetaldehyde (55% in water, 0.27 mL, 4.5 mmol) and NaHCO3 (143 mg, 1.7 mmol) were added to a solution of 5-bromopyridin-2-amine (173 mg, 1 mmol) in EtOH (7 mL). The mixture was heated to reflux and continued overnight. The reaction mixture was cooled to room temperature and concentrated under vacuum. Dichloromethane was added to extract the residue. The organic layer was washed with water, brine, dried over Na2SO4, filtered, and evaporated to give the crude product. The crude was purified column chromatography (Silica gel, EtOAc/Hexane, gradient) to give 6-bromoimidazo[1,2-a]pyridine (13-1).
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[O:8][CH:7]=[N:6][C:5]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CN(C)C=O.S(Cl)([Cl:22])=O>C(Cl)(Cl)Cl>[Cl:22][CH2:2][CH2:3][C:4]1[O:8][CH:7]=[N:6][C:5]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: OCCc1ocnc1-c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: ClCCc1ocnc1-c1ccccc1

Procedure:
5-(2-Hydroxyethyl)-4-phenyloxazole (10.0 g) was dissolved in chloroform (100 ml) and N,N-dimethylformamide (4.4 ml) was added. Under ice-cooling and stirring, 12.6 ml of thionyl chloride was added dropwise and the mixture was refluxed for an hour. The solvent was distilled off, followed by addition of saturated aqueous sodium hydrogen carbonate and extraction with ethyl ether. The ethyl ether layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off to give an oil (11.0 g) of 5-(2-chloroethyl)-4-phenyloxazole. This product was dissolved in methyl ethyl ketone (150 ml), followed by addition of sodium iodide (13.0 g). The mixture was refluxed under stirring for 24 hours. The resulting precipitate was filtered off and the filtrate was concentrated, followed by addition of water and extraction with ethyl ether. The ethyl ether layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off to give an oil of 5-(2-iodoethyl)-4-phenyloxazole, yield 14.4 g (83.2%).
Reaction SMILES: [O:1]=[C:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=[CH:4][C:5]1[O:9][C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:7][CH:6]=1.[CH2:25](O)[CH3:26]>>[CH2:25]([O:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:8]1[O:9][C:5]([CH:4]=[CH:3][C:2](=[O:1])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:6][CH:7]=1)[CH3:26]
Reactant: CCCCCC(=O)C=Cc1ccc(CCCCCCCC(=O)O)o1
Reactant: CCO
Product: CCCCCC(=O)C=Cc1ccc(CCCCCCCC(=O)OCC)o1
Temperature: 0 °C
Yield: 79 %

Procedure:
A mixture of II (9.94 g, 0.0298 mole), ethanol (190 ml), and ethyl ether-borontrifluoride complex (0.97 g) was stirred and heated under reflux for 1.5 hours. After cooling, the reaction mixture was poured into ice-water (600 ml) and extracted with three 300-ml portions of ether. The combined ethereal extracts were washed with cold 10% sodium carbonate (100 ml) and then with two 200-ml portions of cold water. The ethereal solution was dried over magnesium sulfate and evaporated to dryness from a water bath (60°C), at last under 15 mm Hg. The residual yellow oil (9.84 g) was purified by distillation under nitrogen from a potassium acetatecoated flask giving 8.57 g (79%) of IV, b0.2 198°-201°C, nD25 1.5217.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])=[N:6][CH:7]=1.[I:18]I>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[NH2:16][C:11]1[CH:12]=[CH:13][C:14]([I:18])=[CH:15][C:10]=1[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:17]
Reactant: II
Reactant: Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: Nc1ccc(I)cc1C(=O)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 32.1 %

Procedure:
To an ice cold stirring suspension of N-(5-chloropyridin-2-yl)-2-aminobenzamide (1.01 g, 4.09 mmol) in ethanol (80 mL) was added a mixture of iodine (1.04 g, 4.10 mmol) and silver sulfate (1.29 g, 4.09 mmol). The mixture was stirred at room temperature for 3 d and filtered. The filtrate was concentrated, partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by chromatography over silica gel, eluting with a step gradient of 5-10% ethyl acetate in dichloromethane. The chromatography product was slurried in isopropanol and filtered to give 0.49 g (32%) of an orange solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:16])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[Br:17]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:16])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: Cc1ccc2c(=O)c3ccccc3oc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=c1c2ccccc2oc2cc(CBr)ccc12
Yield: 98.2 %

Procedure:
A mixture of 3-methyl-9H-xanthen-9-one (1.62 g, 7.71 mmol), N-bromosuccinic acid imide (1.37 g, 7.71 mmol), benzoyl peroxide (93 mg, 0.39 mmol) and carbon tetrachloride (15 ml) was heated under reflux for 15 hours. The insoluble matter was removed by filtration and the resulting filtrate was concentrated under a reduced pressure to give 3-bromomethyl-9H-xanthen-9-one (2.19 g, 7.57 mmol, 98%) as colorless crystals.
Reaction SMILES: C(O[CH2:5][C:6]1[CH:11]([C:12]([OH:14])=[O:13])[N:10]2[C:15](=[O:27])[CH:16]([NH:17][C:18](=[O:26])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@H:9]2[S:8][CH:7]=1)(=O)C.B(F)(F)F.[CH2:32]([O:34][C:35](=O)[CH3:36])C.P([O-])([O-])(O)=O.[K+].[K+]>C1(OC)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:32][O:34][C:35]1[CH:36]=[CH:12][C:11]([CH2:5][C:6]2[CH:11]([C:12]([OH:14])=[O:13])[N:10]3[C:15](=[O:27])[CH:16]([NH:17][C:18](=[O:26])[CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[C@H:9]3[S:8][CH:7]=2)=[CH:6][CH:5]=1
Reactant: CC(=O)OCC1=CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)O
Reactant: CCOC(C)=O
Agent: FB(F)F
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: COc1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(CC2=CS[C@@H]3C(NC(=O)Cc4ccccc4)C(=O)N3C2C(=O)O)cc1
Temperature: 0 °C

Procedure:
0.1 g of 3-acetoxymethyl-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid are dissolved in a solution of 0.056 g of anisole in 5 ml of chloroform, and the solution is cooled to 0°C and saturated with boron trifluoride gas for 15 minutes. The temperature of the reaction mixture is thereafter brought to room temperature over the course of 2 hours; 50 ml of acetic acid ethyl ester are added, and the mixture is again cooled to 0°C and slowly poured into 50 ml of a 10% strength aqueous dipotassium hydrogen phosphate solution. The pH value is adjusted to 7.5 and the mixture is thoroughly shaken. The aqueous phase is twice washed with 50 ml portions of acetic acid ethyl ester, the pH value is adjusted to 2 by means of 20% strength aqueous phosphoric acid, and three extractions with 50 ml portions of acetic acid ethyl ester are carried out. The oroganic extracts are repeatedly washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure. 3-(4-Methoxy-benzyl)-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid containing a small amount of the corresponding 2-methoxy-benzyl compound are thus obtained as the residue; in a thin layer chromatogram, this acid does not differ from the product of the process of example 1.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:15])[C:4]=2[C:3]=1[C:16]([O:18]CC)=[O:17].[OH-].[Na+].Cl>O>[F:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:15])[C:4]=2[C:3]=1[C:16]([OH:18])=[O:17]
Reactant: CCOC(=O)c1c(F)ccc2c1C(=O)c1ccccc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1c(F)ccc2c1C(=O)c1ccccc1-2

Procedure:
The ethyl 2-fluoro-fluoren-9-one-1-carboxylate is mixed with 500 ml of NaOH 6N and refluxed for 2 hours. After cooling, the mixture is diluted with twice its volume of water and acidified with concentrated HCl. The yellow precipitate that forms is filtered and washed with water. The melting point of the pure product isolated from column chromatography on silica gel (eluant: CHCl3 /CH3CO2C2H5 3/1) is: 209.210° C.
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([C:35]4[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=4)=[CH:10][C:11]=3[C:12]2([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:46]1[S:47][CH:48]=[CH:49][CH:50]=1)CCC>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.CCCCCC.C1COCC1>[CH2:25]([C:12]1([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:11]2[CH:10]=[C:9]([C:35]3[CH:36]=[CH:37][N:38]=[CH:39][CH:40]=3)[CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:14][C:2]([C:46]1[S:47][CH:48]=[CH:49][CH:50]=1)=[CH:3][CH:4]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: CCCCCCCCCCC1(CCCCCCCCCC)c2cc(Br)ccc2-c2ccc(-c3ccncc3)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCCCCC1(CCCCCCCCCC)c2cc(-c3ccncc3)ccc2-c2ccc(-c3cccs3)cc21
Temperature: 25 °C
Yield: 72.38 %

Procedure:
4-(7-bromo-9,9-didecyl-9H-2-fluorenyl)pyridine (2.32 g, 3.85 mmol) was weighed directly into a single-necked round bottom flask equipped with a magnetic stirrer and condenser which had been dried in an oven at 130° C. overnight. Toluene (20 ml, dried over CaCl2 and freshly distilled) and 2-(tributylstannyl)thiophene (1.47 ml 4.62 mmol) were added to the flask and the solution was degassed with nitrogen for 15 min. Tetrakis(triphenylphosphine)palladium (0) (0.34 g, 0.29 mmol) was added and the solution was heated at reflux for 16 hr under nitrogen. The reaction was cooled to room temperature and the toluene was removed under reduced pressure. The product was isolated by column chromatography using silica gel and 90:10 hexane/THF as the eluent to afford a yellow oil in 72.38% yield. If the oil was allowed to stand at room temperature it slowly solidified into a pale yellow waxy solid mp 58° C.-61° C. Mass Spec. m/z 605, (M+), 464, (M-C10 H21). Elemental Analysis: Calculated for C42H55NS: C, 83.25; H, 9.15; N, 2.31. Found: C, 83.34; H, 8.89; N, 2.31.
Reaction SMILES: [Cl:1][C:2]1[N:6]2[N:7]=[C:8]([CH3:27])[C:9]([CH2:18][C:19](=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:5]2=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[N:6]2[N:7]=[C:8]([CH3:27])[C:9]([CH2:18][CH:19]([OH:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)Cc1c(C)nn2c(Cl)ccc2c1-c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)CC(O)Cc1c(C)nn2c(Cl)ccc2c1-c1ccc(F)cc1
Reaction time: 1 h
Yield: 59.1 %

Procedure:
To a solution of ethyl 4-[7-chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-3-oxo-butanoate (160 mg) in methanol (5 ml) was added sodium borohydride (23.4 mg) at 0° C. and the mixture was stirred at the same temperature for 1 hour. The mixture was partitioned between 1N hydrochloric acid and ethyl acetate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was purified by preparative thin-layer chromatography eluting with a mixture of ethyl acetate and hexane (1:3) and triturated with ethyl acetate to give ethyl 4-[7-chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-3-hydroxybutanoate (95 mg) as an yellow powder.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:25]=[CH:24][C:9]2[N:10]=[C:11]([NH:14][C@H:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[NH:26]1[CH2:31][CH2:30][S:29][CH2:28][CH2:27]1>C(#N)C>[C@H:15]1([NH:14][C:11]2[O:12][CH2:13][C:8]3[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:26]4[CH2:31][CH2:30][S:29][CH2:28][CH2:27]4)[CH:25]=[CH:24][C:9]=3[N:10]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1
Reactant: C1CSCCN1
Reactant: O=C(CCl)Nc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Solvent: CC#N
Product: O=C(CN1CCSCC1)Nc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Yield: 75.8 %

Procedure:
Prepared from 2-chloro-N-[2-((R)-indan-1-ylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (Example 3 step A) (100 mg, 0.281 mmol) and thiomorpholine (0.141 ml, 1.405 mmol) in acetonitrile (1 ml) according to the procedure described for Example 3 step B. Obtained the title compound as an off-white foam (90 mg, 76%), MS (ISP) m/e=423.2 [(M+H)+].
Reaction SMILES: N1C=CC=CC=1.Cl[C:8]([C:10]1[CH:11]=[CH:12][C:13]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])=[C:14]([CH:19]=1)[C:15]([O:17][CH3:18])=[O:16])=[O:9].[CH2:27]([O:34][C:35]1[C:43]2[N:39]([CH:40]=[C:41]([CH3:46])[C:42]=2[O:44][CH3:45])[CH:38]=[CH:37][CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl.C(O)C>[CH2:27]([O:34][C:35]1[C:43]2[N:39]([C:40]([C:8]([C:10]3[CH:11]=[CH:12][C:13]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])=[C:14]([CH:19]=3)[C:15]([O:17][CH3:18])=[O:16])=[O:9])=[C:41]([CH3:46])[C:42]=2[O:44][CH3:45])[CH:38]=[CH:37][CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)c1cc(C(=O)Cl)ccc1NC(=O)C(F)(F)F
Reactant: COc1c(C)cn2cccc(OCc3ccccc3)c12
Solvent: ClCCl
Solvent: CCO
Solvent: c1ccncc1
Product: COC(=O)c1cc(C(=O)c2c(C)c(OC)c3c(OCc4ccccc4)cccn23)ccc1NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.9 %

Procedure:
4.4 ml (54.3 mmol) of pyridine and then 15.0 g (48.4 mmol) of methyl 5-(chlorocarbonyl)-2-[(trifluoro-acetyl)amino]benzoate (described in Patent Application WO2003084956) are added, under argon, to the solution of 13.2 g (49.4 mmol) of 8-(benzyloxy)-1-methoxy-2-methylindolizine in 165 ml of dichloromethane. The reaction medium is stirred at ambient temperature for 3 hours. This is diluted with dichloromethane and this organic solution is washed with a saturated aqueous solution of sodium bicarbonate and then a saturated aqueous solution of sodium chloride, and dried over sodium sulphate. After concentration under reduced pressure, the solid obtained is taken up in ethanol, filtered and washed with ethanol, to give 16.2 g (61%) of an orange powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9]C(=O)C(F)(F)F)=[CH:4][C:3]=1[C:16]1[NH:20][C:19](=[O:21])[N:18]([C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([O:32][CH3:33])[CH:23]=2)[N:17]=1.Cl>CO>[ClH:1].[NH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([O:32][CH3:33])[CH:23]=3)[N:17]=2)[CH:4]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3cc(CNC(=O)C(F)(F)F)ccc3Cl)[nH]c2=O)cc1OC
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc(-n2nc(-c3cc(CN)ccc3Cl)[nH]c2=O)cc1OC
Yield: 205.2 %

Procedure:
A solution of methyl 4-(3-(2-chloro-5-((2,2,2-trifluoroacetamido)methyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (step-5 of Intermediate-26, 0.500 g) in methanol (20 mL) was added conc. HCl (5 mL) dropwise. The reaction mass was refluxed for 24 h. The reaction mass was concentrated to afford 0.450 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.78 (s, 3H), 3.85 (s, 3H), 4.10 (d, J=5.4 Hz, 2H), 7.63 (d, J=9.0 Hz, 1H), 7.74-7.84 (m, 4H), 7.94 (s, 1H), 8.57 (s, 2H), 12.81 (s, 2H); MS (m/z): 388.96 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:11](=[O:36])[NH:12][C@@H:13]2[C:21]3[C:16](=[CH:17][C:18]([C:22]4[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([F:29])[C:23]=4[C:30]4[N:34]=[C:33]([CH3:35])[O:32][N:31]=4)=[CH:19][CH:20]=3)[CH2:15][CH2:14]2)[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:28][C:26]1[CH:25]=[C:24]([F:29])[C:23]([C:30]2[N:34]=[C:33]([CH3:35])[O:32][N:31]=2)=[C:22]([C:18]2[CH:17]=[C:16]3[C:21](=[CH:20][CH:19]=2)[C@@H:13]([NH:12][C:11]([C:8]2([NH2:7])[CH2:9][CH2:10]2)=[O:36])[CH2:14][CH2:15]3)[CH:27]=1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)CC[C@@H]3NC(=O)C2(NC(=O)OC(C)(C)C)CC2)no1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)CC[C@@H]3NC(=O)C2(N)CC2)no1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-11 [C], (1-{(S)-5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-indan-1-ylcarbamoyl}-cyclopropyl)-carbamic acid tert-butyl ester (example 23) was treated with trifluoro-acetic acid (90%) in CH2Cl2 to yield the title compound light yellow amorphous solid. MS: 427.1 (MH+, 1Cl).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Br:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([OH:31])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:54][NH:55][CH2:56][CH2:57][CH2:58]O>C(Cl)Cl>[Br:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:58][CH2:57][CH2:56][NH:55][CH3:54])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1
Reactant: CNCCCO
Reactant: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CNCCCOc1cc2ncnc(Nc3ccc(Br)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.5 %

Procedure:
Diethyl azodicarboxylate (522 mg, 3 mmol) was added dropwise to a suspension of 4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (364 mg, 1 mmol), (prepared as described for the starting material in Example 48), triphenylphosphine (786 mg, 3 mmol) and 3-methylamino-1-propanol (178 mg, 2 mmol), (J.Am.Chem.Soc., 1954, 76, 2789), in methylene chloride (4 ml) under nitrogen. The mixture was stirred for 1 hour at ambient temperature, neutral alumina (˜20 g) was added to the reaction mixture and the solvent was removed by evaporation. The powder was poured onto a column of neutral alumina and was eluted with a mixture of methylene chloride/methanol (95/5 followed by 90/10 and 80/20). The purified product was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(3-methylaminopropoxy)quinazoline (220 mg, 50%).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:7]2[S:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([OH:24])=[CH:12][C:13]([CH:15]([CH:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:16])=[CH:14][C:4]=2[O:3]1.CI.[O-][CH2:29]C.[Na+]>>[CH3:25][C:2]1([CH3:1])[C:7]2[S:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([O:24][CH3:29])=[CH:12][C:13]([CH:15]([CH:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:16])=[CH:14][C:4]=2[O:3]1
Reactant: CC[O-]
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CCS1
Agent: [Na+]
Solvent: CI
Product: CCCCCC(C)C(C)c1cc(OC)c2c(c1)OC(C)(C)C1=C2CCS1

Procedure:
By reacting 1,2-dihydro-4,4-dimethyl-9-hydroxy-7-(3-methyl-2-octyl)-4H-thieno[2,3-c][1]benzopyran with methyl iodide in the presence of sodium ethoxide, there is obtained 1,2-dihydro-4,4-dimethyl-9-methoxy-7-(3-methyl-2-octyl)-4H-thieno[2,3-c][1]benzopyran.