Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)[CH3:2].[C:11]([Si:15]([CH3:23])([CH3:22])[O:16][CH2:17][CH2:18][C@@H:19]1[CH2:21][O:20]1)([CH3:14])([CH3:13])[CH3:12]>CC(=O)OCC>[C:11]([Si:15]([CH3:23])([CH3:22])[O:16][CH2:17][CH2:18][C@@H:19]([OH:20])[CH2:21][NH:8][C:7]1[CH:9]=[CH:10][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=1)([CH3:12])([CH3:14])[CH3:13]
Reactant: CCOc1ccc(N)cc1
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@H]1CO1
Solvent: CCOC(C)=O
Product: CCOc1ccc(NC[C@H](O)CCO[Si](C)(C)C(C)(C)C)cc1
Yield: 62 %

Procedure:
Starting from 4-ethoxyaniline (3.2 mL; commercial) and tert-butyl-dimethyl-((R)-2-oxiranyl-ethoxy)-silane (5.0 g; prepared according to WO 2007/144423) and following procedure A, the title compound was obtained after CC (EA/Hept 1:1) as a brown oil (5.22 g; 62% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:5].Cl[S:22]([OH:25])(=[O:24])=[O:23]>C(O)(C(F)(F)F)=O>[CH3:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([S:22]([OH:25])(=[O:24])=[O:23])=[CH:9][CH:8]=1)=[O:5]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1ccccc1C(=O)Nc1cccc2c1CCCC2
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1C(=O)Nc1ccc(S(=O)(=O)O)c2c1CCCC2
Temperature: 25 °C
Reaction time: 72 h
Yield: 68 %

Procedure:
To a 0° C. solution of amide (22) in TFA (1 mL per mmol amide), was added chlorosulfonic acid (2 eq) dropwise under nitrogen atmosphere. The temperature was allowed to warm to 25° C. and stirred for 72 hours. The reaction mixture was quenched by pouring into ice water. The desired product was collected via precipitation from either water/methanol, or ethyl acetate/methanol solution, resulting in a white solid (yield 68%). LC/MS (M+H)+ m/z 346, (M−H)− m/z 344. The crude material was used without further purification.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:4])=[O:3].[F:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20]>CN(C)C(=O)C.C(OCC)(=O)C>[F:16][C:17]1[CH:18]=[C:19]([NH:20][S:2]([C:5]2[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:4])=[O:3])[CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1cccc(F)c1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(S(=O)(=O)Nc2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To ethyl 3-(chlorosulfonyl)benzoate (1.0 g, 4.02 mmol) in N,N-dimethylacetamide (5 mL) was added 3-fluoroaniline (1.79 g, 16.08 mmol) dropwise over 30 seconds at room temperature. The mixture was stirred at room temperature for 4 hours, and then it was diluted with ethyl acetate (33 mL). The organic solution was washed with 1 N HCl (2×13 mL) and saturated NaCl (13 mL). The organic layer was concentrated, ethanol (8 mL) was added, and the mixture concentrated to give ethyl 3-{[(3-fluorophenyl)amino]sulfonyl}benzoate.
Reaction SMILES: Cl.[CH:2](=[C:9]1[C:14](=O)[C:13](=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][N:11]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:31][C:32]([F:37])([F:36])[CH2:33][NH:34][NH2:35]>CO>[C:3]1([CH:2]2[CH:9]3[CH2:10][N:11]([CH2:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:12][C:13](=[CH:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:14]3=[N:35][N:34]2[CH2:33][C:32]([F:37])([F:36])[F:31])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1C(=Cc2ccccc2)CN(CCc2ccccc2)CC1=Cc1ccccc1
Reactant: NNCC(F)(F)F
Agent: Cl
Solvent: CO
Product: FC(F)(F)CN1N=C2C(=Cc3ccccc3)CN(CCc3ccccc3)CC2C1c1ccccc1
Yield: 114.6 %

Procedure:
Ten grams of 3,5-dibenzylidene-1-(2-phenylethyl)-4-piperidone monohydrochloride and 4.4 g of 70% aqueous 2,2,2-trifluoroethylhydrazine are reacted in 150 ml of methanol at reflux for 4 hours. The solvent is removed on a rotary evaporator leaving 13.1 g of brittle residue. The material is converted to 10.7 g of free base using potassium carbonate and ether extractions. The free base is dissolved in 50 ml of warm isopropyl ether and diluted with 20 ml of hexane. After the solution is cooled to room temperature, seeded and rubbed, the crystalline base gradually separates. After cooling overnight, the solid is filtered, washed with cold 5:2 isopropyl ether-hexane and dried to yield 3.6 g of product, melting point 113°-114° C, sintering at 105° C.
Reaction SMILES: [CH:1](N1CCCCC1)=[O:2].[CH2:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([Li])=[C:14]([F:19])[C:13]=1[F:20])[CH3:10]>C1COCC1.C1COCC1.CCCCCC>[CH2:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH:1]=[O:2])=[C:14]([F:19])[C:13]=1[F:20])[CH3:10]
Reactant: [Li]c1ccc(OCC)c(F)c1F
Reactant: O=CN1CCCCC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOc1ccc(C=O)c(F)c1F
Temperature: -20 °C

Procedure:
A solution of 0.1 mol of N-formylpiperidine in 10 ml of THF is added dropwise at -60° C. to the solution of 4-ethoxy-2,3-difluorophenyllithium in THF/hexane prepared according to 1b). The mixture is then warmed to -20° C. in the course of 1 hour. Customary working up (recrystallization from petroleum ether (boiling range 40°-60° C.) gives colourless crystals, m.p. 70° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]([C:21](=O)[CH3:22])=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)=[O:9])[CH2:4][CH2:3]1.Cl.[C:25]([NH2:33])(=[NH:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>C(O)CCC>[CH3:22][C:21]1[N:33]=[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:32]=[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:10]=1[C:8]([N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)=[O:9]
Reactant: N=C(N)c1ccccc1
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)N1CCN(C)CC1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1C(=O)N1CCN(C)CC1
Temperature: 25 °C

Procedure:
A mixture of 2-(4-methylpiperazin-1-ylcarbonyl)-1-(3-nitrophenyl)-1-buten-3-one (20 g), benzamidine hydrochloride (9.9 g) and triethylamine (11.4 ml) in n-butanol (200 ml) was refluxed for 2 hours. After evaporating the solvent, the residue was dissolved in a suspension of water (200 ml) and chloroform (200 ml). The separated organic layer was washed with saturated aqueous sodium chloride and dried over magnesium sulfate. To this solution was added activated manganese dioxide (120 g) and the mixture was refluxed for 1 hour with stirring vigorously. After cooling to a room temperature, manganese dioxide was filtered off. The filtrate was evaporated in vacuo, and the residue was subjected to column chromatography on alumina (200 g) eluting with chloroform. The fractions containing the object compound were combined and concentrated under reduced pressure. The crystals were recrystallized from diethyl ether to give 6-methyl-5-(4-methylpiperazin-1-ylcarbonyl)-4-(3-nitrophenyl)-2-phenylpyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[C:4]([F:11])[CH:3]=1.[CH3:12][O-:13].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:9]=[C:8]([O:13][CH3:12])[C:5]([C:6]#[N:7])=[C:4]([F:11])[CH:3]=1
Reactant: C[O-]
Reactant: N#Cc1c(F)cc(Br)cc1F
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Br)cc(F)c1C#N
Reaction time: 16 h
Yield: 53.6 %

Procedure:
To a solution of 4-bromo-2,6-difluoro-benzonitrile (15.0 g, 68.8 mmol) in tetrahydrofuran (150 ml) is added sodium methoxide (4.5 g, 82.6 mmol) at room temperature and the mixture is stirred for 16 h. The reaction mixture is concentrated under reduced pressure and the resulting solid is purified by column chromatography (silica gel, 5% ethyl acetate/hexane) to obtain 4-bromo-2-fluoro-6-methoxy-benzonitrile (8.5 g, 36.9 mmol, 53%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[CH:10]=[C:9]1[CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][C:19]1=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:32][C:33]1[S:37][C:36]([CH:38]=[CH:39][S:40](Cl)(=[O:42])=[O:41])=[CH:35][CH:34]=1>CC#N>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[CH:10]=[C:9]1[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([S:40]([CH:39]=[CH:38][C:36]2[S:37][C:33]([Cl:32])=[CH:34][CH:35]=2)(=[O:42])=[O:41])[CH2:20][C:19]1=[O:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)C=Cc1ccc(Cl)s1
Reactant: CC(C)(C)OC(=O)n1c(CN2CCNCC2=O)cc2cnccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(CN2CCN(S(=O)(=O)C=Cc3ccc(Cl)s3)CC2=O)cc2cnccc21
Reaction time: 8 h

Procedure:
To a solution of 2-(2-oxopiperazin-1-ylmethyl)pyrrolo[3,2-c]pyridin-1-carboxylic acid tert-butyl ester (0.71 g, 2.1 mmol), EXAMPLE 69, in CH3CN (7 mL) is added triethylamine (0.60 mL, 4.3 mmol) followed by 2-(5-chloro-thiophen-2-yl)-ethenesulfonyl chloride, EXAMPLE 3, (0.57 g, 2.1 mmol). The mixture is stirred overnight, then concentrated to dryness. The residue is diluted with CH2Cl2 and washed with saturated sodium bicarbonate and brine. The organic layer is dried over MgSO4, filtered and concentrated in vacuo to give the title compound (1.2 g, 2.1 mmol) as a light yellow solid. The crude material can be used in the subsequent step without further purification. 1H NMR (CDCl3, 300 MHz) δ8.80 (s, 1H), 8.42 (d, 1H), 7.88 (d, 1H), 7.55 (d, 1H), 7.14 (d, 1H), 6.98 (d, 1H), 6.41 (s, 1H), 6.36 (d, 1H), 5.00 (s, 2H), 3.98 (s, 2H), 3.61 (m, 4H), 1.71 (s, 9H). Ion spray MS, [M+H]+=537, 539, Cl pattern.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:3]=1[CH:4](O)[C:5]([OH:7])=[O:6].[C:14]1([CH:21]=[CH:20][C:18](O)=[CH:17][CH:16]=1)[OH:15].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[OH:15][C:14]1[CH:16]=[CH:17][C:18]2[O:7][C:5](=[O:6])[CH:4]([C:3]3[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:2]=3[CH3:1])[C:20]=2[CH:21]=1
Reactant: Cc1ccc(C)c(C(O)C(=O)O)c1
Reactant: Oc1ccc(O)cc1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: Cc1ccc(C)c(C2C(=O)Oc3ccc(O)cc32)c1

Procedure:
By the method described in GB 2068402A 2,5-dimethylmandelic acid (65 parts) was reacted with hydroquinone (33 parts) and 98% sulfuric acid (32 parts) and toluene (440 parts) to give 5-hydroxy-2-oxo-3-(2,5-dimethylphenyl)-2,3-dihydrobenzofuran (33 parts) which was isolated by crystallisation and chromatography. The 1Hnmr spectrum of the purified product was consistent with structure.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([CH3:12])[N:3]=1.[OH-].[NH4+:14]>>[NH2:14][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([CH3:12])[N:3]=1
Reactant: [NH4+]
Reactant: Cc1cc(C(F)(F)F)cc(Cl)n1
Agent: [OH-]
Product: Cc1cc(C(F)(F)F)cc(N)n1
Reaction time: 8 h

Procedure:
2-chloro-6-methyl-4-(trifluoromethyl)pyridine (5.0 g) and conc ammonium hydroxide (150 mL) were heated at 180° C. in a steel reaction vessel with mechanical stirring overnight. The contents were allowed to cool and partitioned between CH2Cl2 and water. The CH2 Cl2 layer was dried (MgSO4) and concentrated in vacuo leaving 2-amino-6-methyl-4-(trifluoromethyl)pyridine as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.CCN(C(C)C)C(C)C.[NH2:21][C@H:22]1[CH2:27][CH2:26][C@@H:25]([OH:28])[C:24]([CH3:30])([CH3:29])[CH2:23]1>C1COCC1>[OH:28][C@@H:25]1[CH2:26][CH2:27][C@H:22]([NH:21][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=2)[CH2:23][C:24]1([CH3:30])[CH3:29]
Reactant: CSc1ncc(C#N)c(Cl)n1
Reactant: CC1(C)C[C@@H](N)CC[C@H]1O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc(C#N)c(N[C@H]2CC[C@@H](O)C(C)(C)C2)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a mixture of 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile (1.0 equiv.) and DIEA (3.0 equiv) in THF (0.05 M) was added (1R,4S)-4-amino-2,2-dimethylcyclohexanol (stereochemistry determined as described herein) (1.2 equiv.). The mixture was stirred at 50° C. overnight. After reaction completion, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (20% ethyl acetate in petroleum ether) to afford the title compound (82% yield) as a white solid. MS (ESI) m/z 293.1 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[O:6][CH:7]=1.[Cl:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][CH2:2][C:3]2[N:4]=[C:5](/[CH:8]=[CH:9]/[C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)[O:6][CH:7]=2)=[CH:29][CH:30]=1
Reactant: Oc1ccc(CCCCCl)cc1
Reactant: FC(F)(F)c1ccc(/C=C/c2nc(CCl)co2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(/C=C/c2nc(COc3ccc(CCCCCl)cc3)co2)cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
A suspension of 4-chloromethyl-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole (13.4 g), 4-(4-chlorobutyl)phenol (8.63 g) and potassium carbonate (6.46 g) in DMF (200 ml) was stirred at 60° C. for 24 hr. The reaction mixture was combined with water to give crystals, which were collected by filtration and washed with methanol-water (2:1) to give crude 4-[[4-(4-chlorobutyl)phenoxy]methyl]-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole (19.5 g) as colorless powders. A suspension of this product (18.5 g) and sodium iodide (31.8 g) in acetonitrile (240 ml) was refluxed for 22 hr. The reaction mixture was concentrated, diluted with ethyl acetate, successively washed with water, hypo-water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was washed with hexane to give the titled compound (12.3 g) as colorless needle crystals.
Reaction SMILES: O1CCCC1.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=O)[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:9][CH:8]=1>CO>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:9][CH:8]=1
Reactant: O=C(CN1CCCC1)Nc1ccc(Br)cc1
Solvent: CO
Solvent: C1CCOC1
Product: Brc1ccc(NCCN2CCCC2)cc1
Reaction time: 8 h

Procedure:
A 1 M solution of BH3 in tetrahydrofuran (7.7 ml, 7.7 mmol) was added dropwise to N-(4-bromo-phenyl)-2-pyrrolidin-1-yl-acetamide (0.22 g, 0.77 mmol) and the solution was stirred overnight at reflux then subsequently hydrolysed by slow addition of excess of methanol and refluxing for a further 2 hours. The solvent was removed under reduced pressure and aqueous ammonium chloride was added. The aqueous was extracted twice with ethyl acetate and the organics were combined, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the desired product. Yield 0.18 g, 86%. LCMS method: 2, RT: 4.62 min; MI: 267-269 [M+1].
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[F:16])=[O:5].[OH2:18].[OH-].[Na+]>CO>[F:16][C:10]1[CH:11]=[CH:12][C:13]([F:15])=[CH:14][C:9]=1[CH:7]1[CH2:8][CH:6]1[C:4]([OH:18])=[O:5]
Reactant: O
Reactant: CON(C)C(=O)C1CC1c1cc(F)ccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CC1c1cc(F)ccc1F
Temperature: 25 °C

Procedure:
A mixture of 2-(2,5-difluoro-phenyl)-cyclopropanecarboxylic acid methoxy-methyl-amide (9.6 g), water (20 mL), and NaOH (3.2 g) in MeOH (40 mL) was refluxed for 3 h. The reaction mixture was cooled down to room temperature and concentrated in vacuo. The residue was acidified by 6 N HCl followed by extraction with CH2Cl2. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo to give the title compound (7.8 g).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH:22]=O)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[F:25][C:26]1([F:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(O)C>[F:25][C:26]1([F:32])[CH2:31][CH2:30][N:29]([CH2:22][C:16]2([C:13]3[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)=[CH:15][CH:14]=3)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH2:28][CH2:27]1
Reactant: O=CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: FC1(F)CCNCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: CCO
Product: FC1(F)CCN(CC2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)CC1
Yield: 7.5 %

Procedure:
4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbaldehyde (260 mg, 0.82 mmol), 4,4-difluoropiperidine hydrochloride (323 mg, 2.05 mmol), absolute ethanol (11 mL), activated 4 Å molecular sieves, titanium (IV) isopropoxide (1.209 mL, 4.09 mmol) and STAB (1.475 g, 6.96 mmol) were reacted in accordance with the general procedure D. The isolated waxy solid was purified by reverse phase preparative HPLC on a Xterra column eluting with a gradient of MeCN:H2O:Et3N (from 29.9:70:0.1 to 94.9:5:0.1 in 13 min) to give the title compound (26 mg, 6%). 1H NMR (400 MHz, CDCl3) δ 7.21 (d, 2H), 6.88 (d, 2H), 4.02 (t, 2H), 3.77-3.73 (m, 2H), 3.53-3.47 (t, 2H), 2.64 (t, 2H), 2.54 (m, 4H), 2.39 (s, 2H), 2.30-2.24 (m, 6H), 2.13 (d, 2H), 2.02 (m, 2H), 1.90-1.71 (m, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:26][CH2:25][C:24]1[CH:27]=[CH:28][C:21]([O:20][CH3:19])=[CH:22][CH:23]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: COc1ccc(CN)cc1
Product: CCOC(=O)c1cnc2c(OC)cccc2c1NCc1ccc(OC)cc1

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.94 mmol) was treated with 4-methoxybenzylamine following general procedure B to afford 8-methoxy-4-(4-methoxy-benzylamino)-quinoline-3-carboxylic acid ethyl ester (290 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid using general procedure D and then transformed into the corresponding ethylamide (190 mg) following general procedure E. The above ethylamide (0.41 mmol) was subjected to reaction with methyl chloroformate according to general procedure F to furnish 3-ethyl-7-methoxy-1-(4-methoxy-benzyl)-1H-pyrimido[5,4-c]quinoline-2,4-dione (110 mg). LCMS: m/z 422 [M+1]+.
Reaction SMILES: [C:1]([C:4]1[N:12]2[C:7]([C:8]3([CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=32)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[ClH:29].O1CCOCC1>C(Cl)Cl>[ClH:29].[C:4]1([C:1](=[O:3])[CH3:2])[N:12]2[C:7]([C:8]3([CH2:17][CH2:18][NH:19][CH2:20][CH2:21]3)[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=32)=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccc2n1-c1ccccc1OC21CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)c1ccc2n1-c1ccccc1OC21CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of tert-butyl 1′-acetylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate (600 mg, 1.57 mmol) in CH2Cl2 (6 mL) was added HCl in Dioxane (3.9 mL of 4 M, 15.7 mmol) and the mixture was stirred at room temperature for 1 hour. The mixture was evaporated to dryness to give 1-spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1′-ylethanone hydrochloride (499 mg, 99%) which was used without further purification. ESI-MS m/z calc. 282.1. found 283.3 (M+1)+; Retention time: 0.86 minutes (3 min run).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+]>O>[CH3:8][C:6]1[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]2=[C:2]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:7]=1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1nc(N2CCCC2)c2nc(-c3ccccc3)cc-2[nH]1
Yield: 52.7 %

Procedure:
This compound was prepared according to the method described in Example 2 by employing 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (70 mg, 0.287 mmol), pyrrolidine (Aldrich Chemical Company) (0.12 mL, 1.44 mmol) and K2CO3 (0.397 g, 2.87 mmol) in H2O (2 mL). The crude material was purified by flash chromatography on silica gel with 20:1 CHCl3:MeOH as eluant to give 42.1 mg (53%) of the title compound as an off-white solid. An analytical sample was obtained by recrystallization from EtOH. 1H NMR (CDCl3; 500 MHz): δ 2.07 (t, 4, J=6.3), 2.58 (s, 3), 3.88-3.90 (m, 4), 6.71 (s, 1), 7.36-7.46 (m, 3), 7.63 (d, 2, J=7.7). MS m/z: 279.5 (M+1), 277.5 (M−1). HRMS: Calcd for M+H: 279.1610. Found: 279.1613.
Reaction SMILES: [NH2:1][C@H:2]1[C:5](=[O:6])[N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[O:16][CH3:17])[C@H:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]1[O:28][CH2:27][CH2:26][O:25]1.C(N(CC)CC)C.[O:36]([CH2:43][C:44](Cl)=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(OCC)(=O)C>[CH3:17][O:16][C:9]1[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:8]=1[CH2:7][N:4]1[C:5](=[O:6])[C@H:2]([NH:1][C:44](=[O:45])[CH2:43][O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@@H:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]1[O:28][CH2:27][CH2:26][O:25]1
Reactant: COc1ccc(CN2C(=O)[C@H](N)[C@@H]2c2ccccc2C2OCCO2)c(OC)c1
Reactant: O=C(Cl)COc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc(CN2C(=O)[C@H](NC(=O)COc3ccccc3)[C@@H]2c2ccccc2C2OCCO2)c(OC)c1
Reaction time: 0.75 h

Procedure:
The amino compound from Example 3 (4.22 g, 11 mmol) was dissolved in ethyl acetate (60 ml) and cooled in an ice-alcohol bath. Triethylamine (1.67 g, 16.5 mmol) was added, followed by the dropwise addition of phenoxyacetyl chloride (2.06 g, 12.1 mmol) over a period of 5 minutes. The reaction was stirred for 45 minutes with cooling and then filtered. The filtrate was washed with 5% NaHCO3 and brine. The dried filtrate was evaporated to give the title product; 2.0 g. The product was recrystallized from ethyl acetate-ether; 1.02 g, mp 137-138°. The solid which was filtered from the reaction solution was stirred with hot ethyl acetate (100 ml) and filtered. The filtrate was treated with ether (200 ml) and cooled to give additional product; 3.91 g, mp 138-139°.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][CH2:12][C:13]2[CH:36]=[CH:35][C:16]([C:17]([NH:19][C@H:20]([C:32]([OH:34])=[O:33])[CH2:21][CH2:22][CH2:23][NH:24][C:25](OC(C)(C)C)=O)=[O:18])=[CH:15][CH:14]=2)[CH:4]=[CH:3][CH:2]=1.Cl.O1[CH2:43][CH2:42]OCC1>CO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][CH2:12][C:13]2[CH:36]=[CH:35][C:16]([C:17]([NH:19][C@@H:20]([CH2:21][CH2:22][CH2:23][NH:24][CH2:25][C:43]3[CH:42]=[CH:4][CH:3]=[CH:2][N:1]=3)[C:32]([OH:34])=[O:33])=[O:18])=[CH:15][CH:14]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)c1ccc(CNc2cccc3cccnc23)cc1)C(=O)O
Agent: Cl
Solvent: CO
Product: O=C(N[C@@H](CCCNCc1ccccn1)C(=O)O)c1ccc(CNc2cccc3cccnc23)cc1
Reaction time: 15 h

Procedure:
The compound obtained in Example 16-3 (122.6 mg) was dissolved in methanol (1.2 ml) and 4 mol/l hydrochloric acid/dioxane solution (1.2 ml) was added. After the reaction for 1 hour, the reaction solution was concentrated and dried under reduced pressure. The resulting residue was dissolved in methanol (2 ml), and pyridine-2-aldehyde (18 μl) and triethylamine (27 μl) were added. After 15 hours, the reaction solution was concentrated and dried under reduced pressure. The residue was again dissolved in methanol (2 ml) and sodium borohydride (22 mg) was added. After the reaction for 1 hour, the reaction solution was concentrated. The residue was purified by silica gel column chromatography (4 g, chloroform/methanol/water=7/3/0.5) to obtain the title compound (114.0 mg) as an orange solid.