Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:19]2[CH2:22][CH2:21][CH2:20]2)=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]([CH:12]([F:14])[F:13])=[N:6][C:7]=1[C:8]([F:11])([F:10])[F:9].CO[CH:25]1[CH2:29][CH2:28][CH:27](OC)O1>C(O)(=O)C.O>[F:13][CH:12]([F:14])[C:5]1[C:4]([C:15]([O:17][CH3:18])=[O:16])=[C:3]([CH:19]2[CH2:22][CH2:21][CH2:20]2)[C:2]([N:1]2[CH:25]=[CH:29][CH:28]=[CH:27]2)=[C:7]([C:8]([F:10])([F:11])[F:9])[N:6]=1
Reactant: COC1CCC(OC)O1
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(N)c1C1CCC1
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(-n2cccc2)c1C1CCC1

Procedure:
A solution of 1.62 g (5 mmol) of methyl 5-amino-2-(difluoromethyl)-4-cyclobutyl-6-(trifluoromethyl)-3-pyridinecarboxylate (example A-2 of U.S. Pat. No. 5,114,465) and 0.8 g (6 mmol) of 2,5-dimethoxytetrahydrofuran in 10 ml of acetic acid as heated at 70° C. for 2.5 h. The reaction mixture was then diluted with 100 ml of water and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate (3×100ml), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (10% EtOAc in hexane) to give the product, mp 70-71° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][N:7]3[C:12](=O)[CH2:13][CH2:14][CH:6]3[C:5](=[O:16])[C:4]=2[CH:3]=1.[OH2:17].O.O.C([O-])(=O)C.[Na+].Cl.[NH2:26]O>C(O)C.O>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][N:7]3[C:12](=[N:26][OH:17])[CH2:13][CH2:14][CH:6]3[C:5](=[O:16])[C:4]=2[CH:3]=1
Reactant: O=C1c2cc(Br)ccc2CN2C(=O)CCC12
Reactant: NO
Reactant: O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C1c2cc(Br)ccc2CN2C(=NO)CCC12
Temperature: 25 °C

Procedure:
A suspension of 88.31 g of 8-bromo-1,10a-dihydropyrrolo[1,2-b]isoquinoline-3,10[2H,5H]-dione in 95% ethanol (550 ml) was treated with a premixed solution of 85.73 g of sodium acetate trihydrate in water (300 ml) and 43.78 g of hydroxylamine hydrochloride in water (300 ml). The solution was refluxed for 2 hours. The reaction mixture was then cooled to room temperature at which time a precipitate began to separate from the mixture. The precipitate was isolated by vacuum filtration.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([S:11]([CH3:14])(=[O:13])=[O:12])=[N:8]2)=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.[CH3:24][Si:25]([CH3:32])([CH3:31])[CH2:26][CH2:27][O:28][CH2:29]Cl.CCOC(C)=O>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH2:29][O:28][CH2:27][CH2:26][Si:25]([CH3:32])([CH3:31])[CH3:24])[C:7]([S:11]([CH3:14])(=[O:13])=[O:12])=[N:8]2)=[CH:4][N:3]=1
Reactant: CS(=O)(=O)c1nc2nc(Cl)ncc2[nH]1
Reactant: C[Si](C)(C)CCOCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirring solution of 2-chloro-8-(methylsulfonyl)-7H-purine (570 mg, 2.45 mmol) and N,N-diisopropylethylamine (3.42 mL, 19.60 mmol) in anhydrous DMF (16.7 mL) was added 2-(trimethylsilyl)ethoxymethyl chloride (2.17 mL, 12.25 mmol). The reaction was stirred under N2 at RT for 20 h, then added to EtOAc (1.0 L) and washed with saturated NH4Cl (0.2 L). The aqueous layer was separated and back-extracted with EtOAc (0.2 L). The organic layers combined and evaporated under reduced pressure. Flash chromatography of the resulting residue utilizing a 24 g silica RediSep Rf® Gold column and employing a 0-40% EtOAc/hexane gradient afforded the title compound. LC-MS: calculated for C12H19ClN4O3SSi 362.06 observed m/e: 385.30 (M+23)′ (Rt 1.33/2.0 min)
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([CH3:11])=[N:4]1)[CH3:2].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:18]=[C:19]([CH:32]=[CH:33][CH:34]=1)[C:20]([C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26](=[O:31])[CH2:25]2)=[O:21]>C1COCC1>[O:31]=[C:26]1[CH2:25][C:24]2[C:28](=[CH:29][CH:30]=[C:22]([C:20]([C:19]3[CH:18]=[C:17]([NH:16][C:8]([C:7]4[N:3]([CH2:1][CH3:2])[N:4]=[C:5]([CH3:11])[CH:6]=4)=[O:10])[CH:34]=[CH:33][CH:32]=3)=[O:21])[CH:23]=2)[NH:27]1
Reactant: CCn1nc(C)cc1C(=O)O
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)CC(=O)N3)c1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)CC(=O)N3)c1
Temperature: 79 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
A dry 25 mL flask was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid (0.802 g, 4.67 mmol) and thionyl chloride (10 mL) and allowed to stir at 79° C. for 2 h. The thionyl chloride was then removed by distillation. The crude acid chloride was cooled to room temperature, and then dissolved in THF (5 mL). 5-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (0.905 g, 3.59 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for 2 h. The reaction mixture was then allowed to cool to room temperature. The room temperature reaction mixture was concentrated in vacuo, and the crude residue was dissolved in EtOH (5 mL). The ethanolic solution was treated with 1M NaOH(aq) (2 mL) and stirred for 30 min. The basic solution was acidified to a pH of 1 with 1M HCl(aq) yielding a tan precipitate. The tan solids were filtered to afford the pure 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-phenyl]-amide (1.05 g, 2.73 mmol, 76%).
Reaction SMILES: CS([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([C:15]2[C:16]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=2)=[O:14])=[CH:7][CH:6]=1)(=O)=O.[CH3:32][O:33][C:34](=[O:38])[C:35](Cl)=O>C1COCC1>[CH3:32][O:33][C:34]([C:35]1[N:22]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)[C:16]2[C:15]([C:13](=[O:14])[C:12]=1[CH2:11][C:8]1[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=1)=[CH:20][CH:19]=[C:18]([CH3:21])[N:17]=2)=[O:38]
Reactant: Cc1ccc(C(=O)CCc2ccc(S(C)(=O)=O)cc2)c(Nc2cccc([N+](=O)[O-])c2)n1
Reactant: COC(=O)C(=O)Cl
Solvent: C1CCOC1
Product: COC(=O)c1c(Cc2ccccc2)c(=O)c2ccc(C)nc2n1-c1cccc([N+](=O)[O-])c1
Temperature: 80 °C

Procedure:
3-(4-Methanesulfonyl-phenyl)-1-[6-methyl-2-(3-nitrophenylamino)-pyridin-3-yl]-propan-1-one (0.1 g) was dissolved in THF (5 mL). Chloro-oxo-acetic acid methyl ester (0.1 mL) was added, and the mixture heated by microwave at 80° C. for 1 h. The product was concentrated, the residue taken up in MeOH (5 mL), K2CO3 (0.1 g) added, and the mixture heated at 50° C. for 15 min. The product was cooled and concentrated, and purified by prep TLC (50% EtOAc/hexane) to provide 3-benzyl-7-methyl-1-(3-nitrophenyl)-4-oxo-1,4-dihydro[1,8]-naphthyridine-2-carboxylic acid methyl ester (Compound 104, ˜20 mg). M+H=508.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[CH:3][CH:2]=1.C(N(C(C)C)C(C)C)C.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O.[NH2:62][CH2:63][C:64]([N:66]1[CH2:70][CH2:69][CH2:68][C@H:67]1[C:71]#[N:72])=[O:65]>CN(C=O)C>[C:71]([C@@H:67]1[CH2:68][CH2:69][CH2:70][N:66]1[C:64](=[O:65])[CH2:63][NH:62][C:11]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[CH:2][CH:3]=1)=[O:13])#[N:72]
Reactant: N#C[C@@H]1CCCN1C(=O)CN
Reactant: O=C(O)c1ccnc2ccccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: N#C[C@@H]1CCCN1C(=O)CNC(=O)c1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Commercially available quinoline-4-carboxylic acid (0.078 g, 0.449 mmol) was dissolved in 7 ml of DMF, N-ethyl-N-isopropylpropan-2-amine (0.242 ml, 1.347 mmol), HOBT (0.069 g, 0.449 mmol) and TBTU (0.144 g, 0.449 mmol) were added. After 15 min a solution of (S)-1-(2-aminoacetyl)pyrrolidine-2-carbonitrile 2,2,2-trifluoroacetate (0.120 g, 0.449 mmol) (prepared as described under A.1 of the experimental part) in DMF was added. The mixture was stirred overnight at room temperature. The volatiles were evaporated, the residue was dissolved in ethyl acetate and extracted with 1 N citric acid, saturated sodium bicarbonate and brine. The solution was dried over sodium sulfate, filtrated and evaporated. It was purified using column chromatography (1-5 hexane-ethyl acetate).
Reaction SMILES: [C:1](Br)(=[O:3])[CH3:2].C[Si](C)(C)[O:7][C:8]1[CH:13]=[C:12]([O:14][Si](C)(C)C)[C:11]([Cl:19])=[CH:10][N:9]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:7][C:8]1[CH:13]=[C:12]([OH:14])[C:11]([Cl:19])=[CH:10][N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Br
Reactant: C[Si](C)(C)Oc1cc(O[Si](C)(C)C)c(Cl)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cc(O)c(Cl)cn1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 64 %

Procedure:
A 2.09 ml quantity of acetyl bromide and 0.10 ml of stannic chloride were added to a solution of 5.00 g of 2,4-bis(trimethylsilyloxy)-5-chloropyridine in 250 ml of dried dichloromethane. The mixture was stirred at room temperature for 3.5 hours. The mixture was neutralized with triethylamine and the solvent was distilled off. The residue was subjected to silica gel column chromatography using 40% ethyl acetate-benzene as an eluent, giving 2.07 g of the title compound in a yield of 64%.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH2:6]([CH:10]1[CH:21]2[C:22](=O)[CH:17]([CH2:18][CH2:19][CH2:20]2)[C:16]2(O)[CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:7][CH2:8][CH3:9]>C(O)(=O)C>[CH2:6]([C:10]1[C:21]2[CH2:20][CH2:19][CH2:18][CH2:17][C:22]=2[N:5]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCC1C2CCCC(C2=O)C2(O)CCCCC12
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CCCCc1c2c(nc3c1CCCC3)CCCC2

Procedure:
A 500 mL, one-necked flask equipped with a magnetic stirring bar, a Claisen adapter, and a reflux condenser equipped with a nitrogen inlet attached to a bubble (Note 6) is charged with 17.0 g (0.22 mol) of ammonium acetate, 82 g (0.41 mol) of cupric acetate monohydrate and 200 mL of glacial acetic acid, then flushed with nitrogen. The mixture is stirred and heated at reflux under a static atmosphere of nitrogen for 15 min., then the resulting solution is cooled slightly as 53 g (0.20 mol) of 8-n-butyl-2-hydroxytricyclo[7.3.1.02,7 ]tridecan-13-one is added in several portions. The blue-green reaction mixture is stirred and heated at reflux under nitrogen for 3 hrs., then the reaction flask is cooled in an ice bath for 2-3 hours. Precipitated cuprous acetate is removed by vacuum filtration using a fitted glass funnel (medium or coarse porosity) and washed with 100 mL of acetic acid. The combined filtrates are diluted with 500 mL of water, cooled in ice and carefully neutralized by slow addition of aqueous sodium hydroxide (Note 7). The resulting cloudy mixture is transferred to a separatory funnel and extracted with ether (400 mL, then 2×200 mL). The combined ether extracts are washed with 140 mL of 3% aqueous sodium hydroxide and 70 mL of saturated aqueous sodium chloride, then dried using anhydrous magnesium sulfate with 1 g of decolorizing charcoal (Norit). The solids are removed by filtration and washed with at least 200 ml of ether. The combined filtrates are concentrated to minimum volume using a rotary evaporator and residual solvent is removed under vacuum (1 mm). The product is obtained as a beige crystalline solid, mp 35°-37° C., 47 g (97%) (Note 8).
Reaction SMILES: Cl.Cl[C:3]1[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[Cl:28])[N:4]=1.Cl.[NH2:30][C:31]1[C:36]([C:37](=[O:42])[C:38]([F:41])([F:40])[F:39])=[CH:35][CH:34]=[C:33]([NH:43][CH2:44][CH2:45][NH2:46])[N:32]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:30][C:31]1[C:36]([C:37](=[O:42])[C:38]([F:39])([F:41])[F:40])=[CH:35][CH:34]=[C:33]([NH:43][CH2:44][CH2:45][NH:46][C:3]2[N:8]3[N:9]=[C:10]([CH:12]4[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]4)[N:11]=[C:7]3[CH:6]=[C:5]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[Cl:28])[N:4]=2)[N:32]=1
Reactant: NCCNc1ccc(C(=O)C(F)(F)F)c(N)n1
Reactant: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4Cl)nc(Cl)n3n2)CC1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4Cl)nc(NCCNc4ccc(C(=O)C(F)(F)F)c(N)n4)n3n2)CC1
Temperature: 130 °C

Procedure:
55 mg (0.11 mmol) of 5-chloro-7-(2-chloro-4-fluorophenyl)-2-[1-(propan-2-yl)piperidin-4-yl][1,2,4]triazolo[1,5-c]pyrimidine hydrochloride (Example 52A), 39.9 mg (0.14 mmol) of 1-{2-amino-6-[(2-aminoethyl)amino]pyridin-3-yl}-2,2,2-trifluoroethanone hydrochloride (Example 13A) and 0.12 ml (0.69 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 58 mg (81% of theory) of the product as a solid.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[F:20][C:21]([F:30])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[CH2:22][NH2:23].CCN(C(C)C)C(C)C>>[F:30][C:21]([F:20])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[CH2:22][NH:23][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: NCC(F)(F)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NCC(F)(F)c2ccccn2)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 2,2-difluoro-2-pyridin-2-yl-ethylamine (example 59d) and DIEA to give 2-(2,2-difluoro-2-pyridin-2-yl-ethylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. The product was dissolved in methanol (5 mL). 2 M HCl in ether (2 mL) was added. After adding ether, the solid was collected by filtration, washed with ether and dried to give 2-(2,2-difluoro-2-pyridin-2-yl-ethylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one hydrochloride. LC-MS m/e 397 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:25]=[CH:24][C:6]([CH2:7][NH:8][C:9](=[O:23])[CH:10]([C:13]2[C:18]([F:19])=[CH:17][C:16]([O:20][CH3:21])=[CH:15][C:14]=2[F:22])[O:11][CH3:12])=[C:5]([OH:26])[CH:4]=1)#[N:2].Cl[CH2:28][C:29]([NH:31][CH3:32])=[O:30].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([C:3]1[CH:25]=[CH:24][C:6]([CH2:7][NH:8][C:9](=[O:23])[CH:10]([C:13]2[C:14]([F:22])=[CH:15][C:16]([O:20][CH3:21])=[CH:17][C:18]=2[F:19])[O:11][CH3:12])=[C:5]([O:26][CH2:28][C:29](=[O:30])[NH:31][CH3:32])[CH:4]=1)#[N:2]
Reactant: COc1cc(F)c(C(OC)C(=O)NCc2ccc(C#N)cc2O)c(F)c1
Reactant: CNC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CNC(=O)COc1cc(C#N)ccc1CNC(=O)C(OC)c1c(F)cc(OC)cc1F

Procedure:
In analogy to example 16.4, (RS)-N-(4-cyano-2-hydroxy-benzyl)-2-(2,6-difluoro-4-methoxy-phenyl)-2-methoxy-acetamide was alkylated with 2-chloro-N-methylacetamide/cesium carbonate in DMF to give (RS)-N-(4-cyano-2-methylcarbamoylmethoxy-benzyl)-2-(2,6-difluoro-4-methoxy-phenyl)-2-methoxy-acetamide as a colorless foam. MS 434.2 ([M+H]+)
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].Br[CH2:22][C:23]1[O:24][CH:25]=[CH:26][C:27]=1[C:28]([O:30][CH3:31])=[O:29]>>[CH3:31][O:30][C:28]([C:27]1[CH:26]=[CH:25][O:24][C:23]=1[CH2:22][N:8]1[C:9]([S:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19])=[O:29]
Reactant: COC(=O)c1ccoc1CBr
Reactant: Cc1cc(C)cc(Sc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: COC(=O)c1ccoc1Cn1c(Sc2cc(C)cc(C)c2)c(C(C)C)c(=O)[nH]c1=O
Yield: 33.7 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 2-bromomethyl-3-methoxycarbonylfurane were reacted by the same way with the example 1 to obtain the titled compound (139 mg, yield: 33.7%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18](=[O:23])[CH2:19][C:20](=O)[CH3:21])[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:24][C:25]([NH2:27])=[O:26].FC(F)F.[Yb].[F:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1>C(#N)C.O>[F:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]2[C:19]([C:18]([NH:17][C:14]3[CH:15]=[C:16]4[C:11](=[CH:12][CH:13]=3)[NH:10][N:9]=[C:8]4[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[O:23])=[C:20]([CH3:21])[NH:27][C:25](=[O:26])[NH:24]2)=[CH:36][CH:35]=1
Reactant: NC(N)=O
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(=O)CC(=O)Nc1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Agent: FC(F)F
Agent: [Yb]
Solvent: CC#N
Solvent: O
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)C(c2ccc(F)cc2)NC(=O)N1
Temperature: 100 °C
Yield: 34 %

Procedure:
The product from Step (e) (0.3 g, 0.96 mmol), urea (87 mg, 1.44 mmol) and Ytterbium trifluoromethane (60 mg, 0.096 mmol) were combined In acetonitrile (2 ml) and 4-fluorobenzaldehyde (0.1 ml, 0.96 mmol) was added. The reaction mixture was sealed and heated to 100° C. for 3 hours. The reaction was diluted with water (1 ml) and the solid product was collected by filtration. The solid was washed three times with 1:1 Et2O/CH3CN. The crude was purified by silica gel chromatography eluting with 10% MeOH in CH2Cl2 to afford the title compound, (0.15 g, 34%); MS (ES+) m/e 460 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([CH2:17]Cl)[C:9]2[C:4](=[CH:5][C:6]([Cl:21])=[C:7]([O:19][CH3:20])[CH:8]=2)[N:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(OCC)(=O)C>O>[Cl:1][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([CH2:17][N:26]2[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:21])=[C:7]([O:19][CH3:20])[CH:8]=2)[N:3]=1
Reactant: CCOC(=O)c1c(Cl)nc2cc(Cl)c(OC)cc2c1CCl
Reactant: CN1CCNCC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Cl)nc2cc(Cl)c(OC)cc2c1CN1CCN(C)CC1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 81.2 %

Procedure:
A mixture of ethyl 2,7-dichloro-4-(chloromethyl)-6-methoxy-3-quinolinecarboxylate (6.9 g, 20 mmol) and N-methylpiperazine (9 ml, 80 mmol) is heated to 60° C. for 30 min. The reaction mass is diluted with water and extraction is carried out with ethyl acetate. After decanting, the organic phase is washed with water, followed by drying over magnesium sulphate, filtering and evaporating under reduced pressure. The residue is taken up in water, agitated for 15 minutes, filtered, washed with water and dried under vacuum. The residue is purified by column chromatography (SiO2, MeOH/CH2Cl2:5/95 to 8/92). 6.7 g of product, a beige solid, is obtained.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[C:6]([Si:10]([CH3:13])([CH3:12])Cl)([CH3:9])([CH3:8])[CH3:7].C1(C)C(C)=CC=CC=1>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.CC1C=CC(C)=CC=1>[CH2:1]([O:5][Si:10]([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:13])[CH3:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: Cc1ccc(C)cc1
Solvent: Cc1ccccc1C
Product: CCCCO[Si](C)(C)C(C)(C)C

Procedure:
0.1 moles of n-butanol, 0.15 moles of t-butyldimethylchlorosilane and 0.0005 moles of triethylbenzyl ammonium chloride were heated under reflux (77°-106° C.) in 50 ml of p-xylene. After termination of the reaction, excess silylating agent and xylene were distilled off at reduced pressure.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[Ru:21](Cl)([Cl:23])[Cl:22]>CO>[Ru:21]([Cl:23])[Cl:22].[C:14]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1.[C:14]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1.[C:14]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cl[Ru](Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: O
Product: Cl[Ru]Cl
Temperature: 75 °C

Procedure:
To a 100 cc glass flask is added 50 mls. of methanol, 5.0 gram of triphenylphosphine and 1.0 gram of ruthenium trichloride hydrate. The resulting mixture is stirred and heated by means of an oil bath under an atmosphere of nitrogen to a temperature of 75° C. and maintained at that temperature for 6 hours. Tris(triphenylphosphine) ruthenium dichloride is formed as a brown insoluble powder, which is recovered by filtration (3.9 gram). 1.0 Gram of this powder is dissolved in a mixture containing 150 mls. of methanol and 1.5 grams of sodium acetate trihydrate. The mixture is stirred and then heated under N2 by means of an oil bath to a temperature of 75° C. which is maintained for a period of 4 hours. This results in formation of a yellow precipitate, which is recovered by filtration and is identified as the desired hydridoacetato tris(triphenylphosphine) ruthenium (0.8 gram).
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[CH:24]=[CH:23]C(C#N)=[CH:19][C:18]=4[F:25])=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[C:28]([OH:31])(=[O:30])[CH3:29]>C(O)C.O>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[CH:24]=[CH:23][C:29]([C:28]([OH:31])=[O:30])=[CH:19][C:18]=4[F:25])=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CC(=O)O
Reactant: N#Cc1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)c(F)c1

Procedure:
4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-fluorobenzonitrile (E271) (150 mg, 0.45 mmol) was dissolved in a mixture of ethanol (1 ml) and water (1.5 ml), treated with sodium hydroxide (150 mg, 4.5 mmol) and heated at reflux for 2 hours. The reaction was then treated with acetic acid (0.39 ml, 6.75 mmol) and concentrated in vacuo. The resulting residue was purified by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (2:18:80) to afford the title compound. MS (ES+) m/e 356 [M+H]+.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[CH:10][CH:11]=1)=[O:5].[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)([O-:15])=[O:14].[OH:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:34]=1[N:33]=[CH:32][CH:31]=[CH:30]2>>[OH:24][C:25]1[C:26]([N:12]([CH2:20][C:19]2[CH:22]=[CH:23][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=2)[C:9]2[CH:8]=[CH:7][C:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])=[CH:11][CH:10]=2)=[CH:27][CH:28]=[C:29]2[C:34]=1[N:33]=[CH:32][CH:31]=[CH:30]2
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: Oc1cccc2cccnc12
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Product: CCOC(=O)c1ccc(N(Cc2ccc([N+](=O)[O-])cc2)c2ccc3cccnc3c2O)cc1

Procedure:
The title compound was prepared by both Method A and method B presented for the compound of Example 1 with the change that benzocaine (Sigma), 4-nitro-benzaldehyde (Sigma) and 8-hydroxy quinoline were used as starting materials. Product purified by column chromatography: C25H21N3O5; (MW: 443.2); yield; 50 mg (30.9%, Method A). HPLC (CH3CN/H2O 70:30 Phenomenex C-18 254 nm): Tr=8.82 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.[CH3:13][O-:14].[Na+].C=O>CS(C)=O.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:12])[CH:4]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)[CH2:13][OH:14]
Reactant: C[O-]
Reactant: COC(=O)Cc1ccc(Cl)cc1
Agent: C=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)C(CO)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52 %

Procedure:
To a stirred solution of (4-Chloro-phenyl)-acetic acid methyl ester (2 g, 10.8 mmol) in DMSO (22 mL) was added sodium methoxide (29.2 mg, 0.54 mmol) at 0° C. Paraformaldehyde (342 mg, 11.4 mmol) was then added and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with EtOAc (100 mL), washed with water (3×20 mL), brine (20 mL), dried (Na2SO4) and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (gradient of hexane:EtOAc 100:0 to 84:16) to afford the title compound as a colourless gum in 52% yield, 1.2 g.