Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:13][CH:12]=[CH:11][CH:10]=2)(=O)[CH2:2][CH3:3].C(N(CC)CC)C>CCO>[CH2:2]([C:1]1[N:16]([CH2:17][CH2:18][O:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:5]=1)[CH3:3]
Reactant: CCC(=O)Nc1cnc2ccccc2c1NCCOCCNC(=O)OC(C)(C)C
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCc1nc2cnc3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Reaction time: 72 h
Yield: 96.1 %

Procedure:
A solution of tert-butyl 2-(2-{[3-(propionylamino)quinolin-4-yl]amino}ethoxy)ethylcarbamate (15.00 g, 37.3 mmol) in 200 mL of EtOH was treated with triethylamine (13.0 mL, 93.2 mmol). The reaction was heated to reflux with stirring. After 3 days, the reaction was concentrated, triturated with ether and filtered to yield 13.78 g of tert-butyl 2-[2-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as an off white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C:10](=[CH2:13])[C:9]2=[O:14])=[CH:4][CH:3]=1.COC1C=CC=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27]NCC1.N1CCCC1>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:23]3[CH2:18][CH2:19][CH2:27][CH2:28]3)[C:9]2=[O:14])=[CH:4][CH:3]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: C=C1CCN(c2ccc(Br)cc2)C1=O
Solvent: O
Solvent: C1CCNC1
Product: O=C1C(CN2CCCC2)CCN1c1ccc(Br)cc1
Yield: 106.6 %

Procedure:
There were mixed 1.31 g of 1-(4-bromophenyl)-3-methylene-2-pyrrolidinone, 2.00 g of 4-(2-methoxyphenyl)piperazine and 5 ml of pyrrolidine. The mixture was refluxed for 1 hour and then cooled. Thereto was added water. The mixture was subjected to extraction with ethyl acetate twice. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography using a mixed solvent of chloroform/methanol=40/1 to obtain 1.79 g of 1-(4-bromophenyl)-3-pyrrolidinomethyl-2-pyrrolidinone.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([N:10]3[CH2:15][CH2:14][N:13]([C:16]([CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=O)[CH2:12][CH2:11]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:30]1COCC1>>[CH3:30][N:21]1[CH2:22][CH2:23][CH:18]([CH2:16][N:13]2[CH2:14][CH2:15][N:10]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[CH:3]=[CH:2][NH:1]4)[CH2:11][CH2:12]2)[CH2:19][CH2:20]1
Reactant: O=C(C1CCNCC1)N1CCN(c2cccc3[nH]ccc23)CC1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CN1CCC(CN2CCN(c3cccc4[nH]ccc34)CC2)CC1
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, a sample of the carbamate (1.5 g, 3.63 mmol) from example 11 in THF (20 mL) was treated with the dropwise addition of 1.0M lithium aluminium hydride in THF (35 mL, 10 equivalents) at 0° C. and the solution refluxed for 16 hours. After cooling to ambient temperature, the excess hydride was destroyed by the addition of ammonium chloride solution and the mixture filtered. Ethyl acetate (50 mL) was added, the solution washed with water (50 mL), brine (25 mL) and dried over anhydrous sodium sulfate. Filtration and concentration gave the titled product, which was converted to its hydrochloride salt by the action of ethereal-HCl.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([CH:21]=[O:22])=[CH:19][N:18]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[C:4]([F:31])[CH:3]=1.S(=O)(=O)([OH:34])N.Cl([O-])=O.[Na+].OP([O-])(O)=O.[K+]>C1COCC1.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:34])=[O:22])=[CH:19][N:18]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[C:4]([F:31])[CH:3]=1
Reactant: Cn1nc(-c2cnc3c(n2)c(C=O)cn3COCC[Si](C)(C)C)c2c(F)cc(Cl)cc21
Reactant: NS(=O)(=O)O
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2c(F)cc(Cl)cc21
Yield: 103.1 %

Procedure:
2-(6-Chloro-4-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (255 mg, 0.55 mmol) was dissolved in THF (8.3 ml) and water (2.8 ml). Sulfamic acid (517 mg, 5.3 mmol) was added. The reaction flask was cooled in an ice/water bath and a solution of sodium chlorite (104 mg, 1.15 mmol) and potassium phosphate monobasic (1.45 g, 10.6 mmol) in water (8 ml) was slowly added. After 1 h the reaction mixture was poured into ethyl acetate and water. The layers were separated and the aqueous layer was extracted once more with ethyl acetate. The combined organic layers were washed with water and sodium chloride solution, and dried over sodium sulfate. Evaporation of the solvent gave 270 mg of 2-(6-chloro-4-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid as a light yellow solid. (M+H)+=476.
Reaction SMILES: CNN.[Cl:4][C:5]1[C:13]2[O:12][C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:10][C:9]=2[C:8]([Cl:26])=[CH:7][C:6]=1[CH2:27][O:28][N:29]1C(=O)C2=CC=CC=C2C1=O>CN(C)C=O>[NH2:29][O:28][CH2:27][C:6]1[CH:7]=[C:8]([Cl:26])[C:9]2[O:10][C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[O:12][C:13]=2[C:5]=1[Cl:4]
Reactant: O=C1c2ccccc2C(=O)N1OCc1cc(Cl)c2c(c1Cl)OC(c1ccccc1)(c1ccccc1)O2
Agent: CNN
Solvent: CN(C)C=O
Product: NOCc1cc(Cl)c2c(c1Cl)OC(c1ccccc1)(c1ccccc1)O2
Temperature: 0 °C
Reaction time: 4 h
Yield: 78.3 %

Procedure:
Methylhydrazine (47 mg) (1.02 mmol) are added at 0° C. to a solution of 530 mg (1.02 mmol) of N-[(4,7-dichloro-2,2-diphenyl-1,3-benzodioxol-5-yl)methoxy]phthalimide in 10 ml of absolute dimethylformamide. The mixture is stirred at 0° C. for 1 hour and at room temperature for 4 hours. The solvent is removed in a high vacuum at room temperature and the residue is chromatographed on 30 g of silica gel (0.063-0.2 mm). The product is eluted with dichloromethane/ethanol (19:1 v/v). There are obtained 310 mg of 5-[(aminooxy)methyl]-4,7-dichloro-2,2-diphenyl-1,3-benzodioxol as a colourless oil.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([Br:12])[C:3]=1N.OS(O)(=O)=O.N([O-])=O.[Na+]>C(O)C>[Br:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([Br:12])[CH:3]=1
Reactant: Nc1c(Br)cc([N+](=O)[O-])cc1Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1cc(Br)cc(Br)c1
Temperature: 60 °C
Yield: 89 %

Procedure:
To an ice-cold solution of 2,6-dibromo-4-nitro-aniline (100 g, 0.34 mol) in 1.50 L of ethanol was added dropwise conc. H2SO4 (116 ml, 2.15 mol) over 30-45 min with constant stirring. The reaction mixture was heated to 60° C. and sodium nitrite (72 g, 1.09 mol) was added to the reaction mixture portion wise. The resulting yellow colored reaction mixture was heated slowly to 90° C. and refluxed for 2 to 2.5 h. After cooling to room temperature, the mixture was poured into ice water. The reddish brown solid thus obtained was filtered, washed with water and dried to give the desired compound as a brown solid (85.0 g, 90%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:15]=[CH:14][C:6]2[C:7](=O)[NH:8][CH2:9][C:10](=O)[NH:11][C:5]=2[CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:15]=[CH:14][C:6]2[CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:5]=2[CH:4]=1
Reactant: O=C1CNC(=O)c2ccc(C(F)(F)F)cc2N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc2c(c1)NCCNC2
Temperature: 68 °C
Reaction time: 24 h
Yield: 69.6 %

Procedure:
To a solution of 8-(trifluoromethyl)-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione (1.5 g, 6.1 mmol) in THF (11 mL) at room temperature was added lithium aluminum hydride in THF (28 mL, 28 mmol) over 10 minutes. Once the addition was completed, the reaction was heated to 68° C. After 24 hours, additional lithium aluminum hydride in THF was added (12.3 mmol) over five minutes. After 3 hours, the reaction mixture was cooled to 0° C., and then quenched with water, 15% NaOH, and an additional portion of water. After filtering off the gray precipitate and rinsing with ethyl acetate, the solvent was removed from the filtrate. The resulting solid was then redissolved in ethyl acetate and transferred to a separatory funnel and washed with water (3×), dried with magnesium sulfate, filtered and concentrated to give a yellow solid. Further purification (15% ammonia in 2M solution of ethanollethyl acetate) yielded 0.918 g of desired product (69%).
Reaction SMILES: [B-][N+](C)(C)C.[C:6]([C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[C:12]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)[CH:11]=1)([CH3:9])([CH3:8])[CH3:7]>O1CCCC1>[C:6]([C:10]1[CH:18]=[CH:17][C:13]([CH2:14][OH:15])=[C:12]([O:19][CH:20]2[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH2:25]2)[CH:11]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2C(=O)O)CC1
Agent: [B-][N+](C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2CO)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The alcohol may be prepared as follows: To a solution of borane-trimethylamine complex (1.35 mL of a 1 M solution in tetrahydrofuran) in tetrahydrofuran (3 mL) stirring at 0° C., a solution of 4-tert-butyl-2-(1-Boc-piperidine-4-yl-oxy)benzoic acid (0.51 g, 1.35 mmol) in tetrahydrofuran (7 mL) was added slowly via cannula. After the addition was complete the reaction mixture was stirred at room temperature for 4 h, then an additional amount of borane-trimethylamine complex was added (1.35 mL of a 1 M solution in tetrahydrofuran). The reaction mixture was stirred at room temperature for another 2 h. After quenching with ice, the mixture was partitioned between brine and dichloromethane. The organic layer was separated and the aqueous layer was extracted with dichloromethane (3×). The combined organic layers were dried with magnesium sulfate, filtered, and concentrated in vacuo to a residue (0.42 g, 86%) which was identified as the title compound and used directly in the next step without further purification.
Reaction SMILES: [CH:1]1([CH:4]([O:6][C:7](=[O:34])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]([CH:30]4[CH2:33][CH2:32][CH2:31]4)[C:17]4[C:22]([C:23]=3[C:24]#[N:25])=[CH:21][CH:20]=[C:19]([O:26][CH2:27][CH2:28]Cl)[CH:18]=4)=[CH:11][CH:10]=2)[CH3:5])[CH2:3][CH2:2]1.CN(C=O)C.CC#N.[I-].[Na+].[CH3:45][S:46]([O-:48])=[O:47].[Na+]>Cl.CN(C=O)C>[CH:1]1([CH:4]([O:6][C:7](=[O:34])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]([CH:30]4[CH2:33][CH2:32][CH2:31]4)[C:17]4[C:22]([C:23]=3[C:24]#[N:25])=[CH:21][CH:20]=[C:19]([O:26][CH2:27][CH2:28][S:46]([CH3:45])(=[O:48])=[O:47])[CH:18]=4)=[CH:11][CH:10]=2)[CH3:5])[CH2:3][CH2:2]1
Reactant: CS(=O)[O-]
Reactant: CC(OC(=O)Nc1ccc(-c2c(C#N)c3ccc(OCCCl)cc3n2C2CCC2)cc1)C1CC1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(OC(=O)Nc1ccc(-c2c(C#N)c3ccc(OCCS(C)(=O)=O)cc3n2C2CCC2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.3 %

Procedure:
To a solution of {4-[6-(2-Chloro-ethoxy)-3-cyano-1-cyclobutyl-1H-indol-2-yl]-phenyl}-carbamic acid 1-cyclopropyl-ethyl ester (800 mg, 1.67 mmol) in 1:4 DMF/CH3CN (8 mL) is added sodium iodide (2.50 g, 16.7 mmol). The resulting mixture was refluxed overnight. An aqueous workup was performed in 0.5M HCl (200 mL) and extracted with EtOAc (2×100 mL). Organic layers were combined, dried over MgSO4 and concentrated. Solid product was triturated with ether and used without further purification. To 4 mL of a DMF solution containing the iodoethyl intermediate (0.56 mmol) was added the sodium methane sulfinate (113 mg, 1.11 mmol), and the reaction was stirred at room temperature overnight. An aqueous workup was performed in 0.5M HCl (200 mL) and extracted with EtOAc (2×100 mL). The organic layers were combined, dried over MgSO4 and concentrated. The mixture was purified over silica gel column (CH2Cl2) to provide 100 mg (35% yield) of {4-[3-Cyano-1-cyclobutyl-6-(2-methanesulfonyl-ethoxy)-1H-indol-2-yl]-phenyl}-carbamic acid 1-cyclopropylethyl ester, as an off-white powder.
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:8][Si:9](Cl)([CH3:11])[CH3:10].C(N(CC)CC)C>CCOCC>[CH3:8][Si:9]([CH3:11])([CH3:10])[S:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)CS
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)CS[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
To a solution of ethyl mercaptoacetate (9.0 mL, 83.2 mmol) in 15 mL of anhydrous ether under nitrogen atmosphere was added trimethylsilyl chloride (12.0 mL, 94.6 mmol) followed by triethyl amine (13.0 mL, 93.3 mmol) slowly. White precipitates were formed upon addition of triethyl amine. The suspension was allowed to stir at room temperature overnight. The white precipitate was removed by filtration. The filtrate was concentrated on a rotavap. The residue oil was distilled at 40° C. (0.5 mm Hg) to give 10.9 g (68%) of ethyl (trimethylsilylthio)acetate as a colorless oil.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[C:29]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:22]=[C:21]([NH2:30])[C:20]=2[N:19]=[CH:18]1>ClCCl.N1C=CC=CC=1.C(Cl)(Cl)Cl.CO>[NH2:30][C:21]1[C:20]2[N:19]=[CH:18][N:17]([CH2:16][CH2:15][CH2:14][CH2:13][NH:12][C:7](=[O:8])[C:6]3[CH:10]=[CH:11][C:3]([CH2:2][Cl:1])=[CH:4][CH:5]=3)[C:29]=2[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N:22]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Solvent: c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)c1ccc(CCl)cc1
Reaction time: 1 h

Procedure:
A solution of 4-(chloromethyl)benzoyl chloride (1.06 g, 5.6 mmol) in dichloromethane was added to a suspension of 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g, 3.9 mmol) in pyridine (250 mL). After 1 hour HPLC analysis indicated that the reaction was complete. The reaction mixture was concentrated under vacuum. The residue was combined with saturated aqueous sodium bicarbonate. A solid was isolated by filtration then dissolved in chloroform containing a small amount of methanol. The solution was washed with saturated aqueous sodium bicarbonate. The organic layer was concentrated under vacuum. The resulting residue was purified by column chromatography (silica gel eluting with 10% methanol in dichloromethane) to provide N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-4-(chloromethyl)benzamide as a solid, m.p. 240-300 (dec.). 1H NMR (500 MHz, DMSO-d6) δ8.49 (t, J=6.0 Hz, 1H), 8.21 (s, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.76 (d, J=8.0 Hz, 2H), 7.61 (d, J=8.0 Hz, 1H), 7.46 (d, J=8.0 Hz, 2H), 7.42 (t, J=8.0 Hz, 1H), 7.20 (t, J=8.0 Hz, 1H), 6.80 (broad s, 2H), 4.78 (s, 2H), 4.62 (t, J=7.0 Hz, 2H), 3.28 (q, J=6.0 Hz, 2H), 1.89 (quintet, J=7.0 Hz, 2H), 1.56 (quintet, J=7.0 Hz, 2H); MS (CI) m/e 408 (M+H).
Reaction SMILES: [CH:1]([B-](F)(F)F)=[CH2:2].[K+].Br[C:9]1[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:17])[F:16])=[N:13][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.[Pd](Cl)Cl.O1CCCC1>[F:16][C:15]([F:18])([F:17])[C:12]1[CH:11]=[CH:10][C:9]([CH:1]=[CH2:2])=[CH:14][N:13]=1
Reactant: FC(F)(F)c1ccc(Br)cn1
Reactant: C=C[B-](F)(F)F
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1ccc(C(F)(F)F)nc1
Temperature: 77.5 °C

Procedure:
Potassium vinyltrifluoroborate (362 mg, 2.7 mmol; Aldrich), 5-bromo-2-trifluoromethylpyridine (539 mg, 2.38 mmol; Aldrich) and triphenylphosphine (37.7 mg, 0.144 mmol) were added at room temperature to a solution of cesium carbonate (2.16 g, 6.63 mmol) in water (2 mL). Tetrahydrofuran (18 mL) was added, and the reaction flask was evacuated and purged with nitrogen (3 cycles). Palladium(II) chloride (9.2 mg, 0.052 mmol) was added, and the reaction flask was again evacuated and purged with nitrogen (3 cycles), then heated under nitrogen at 75-80° C. for 22 hours. The mixture was cooled to room temperature and the aqueous layer was separated and extracted with ethyl ether (2×5 mL). The combined organic phase was concentrated by distillation through a Vigreaux column at atmospheric pressure to a volume of approximately 2 mL, and the residue was purified by flash chromatography (40 g silica, eluted with hexanes-ethyl acetate, 100:0-90:10). The product-containing fractions were combined and concentrated by distillation through a Vigreaux column at atmospheric pressure to a volume of approximately 2 mL, then distilled bulb-to-bulb (air bath 80-90° C./10-20 torr) to provide the title compound: 1H NMR (300 MHz, methanol-d4) δ 5.56 (d, J=10.9 Hz, 1H), 6.08 (d, J=17.6 Hz, 1H), 6.86 (dd, J=17.8, 11.0 Hz, 1H), 7.77 (d, J=8.1 Hz, 1H), 8.11 (dd, J=8.3, 2.2 Hz, 1H), 8.74 ppm (d, J=1.7 Hz, 1H).
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([CH2:10]O)[CH:5]=1.C(Br)(Br)(Br)[Br:14].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:14][CH2:10][C:6]1[CH:5]=[C:4]([O:3][CH:2]([F:12])[F:1])[CH:9]=[CH:8][N:7]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cc(OC(F)F)ccn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)Oc1ccnc(CBr)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (4-(difluoromethoxy)pyridin-2-yl)methanol (250 mg; 1.42 mmol) in anh. DCM (12 ml) was treated at rt with CBr4 (473 mg; 1.42 mmol), and with PPh3 (374 mg; 1.42 mmol). The resulting mixture was further stirred at rt, under nitrogen, for 1 h. Concentration to dryness under reduced pressure, and subsequent purification by FC (DCM) afforded 2-(bromomethyl)-4-(difluoromethoxy)pyridine as a yellow oil which was directly used for the next reaction. LC-MS (conditions A): tR=0.56 min.; [M+H]+: 237.92 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH:5]=[C:6]([CH3:23])[C:7]=1[C:8]1[C:9](=[O:22])[N:10]([CH3:21])[C:11]2([CH2:18][CH2:17][N:16]([O:19][CH3:20])[CH2:15][CH2:14]2)[C:12]=1[OH:13].C(=O)([O-])O.[Na+].S(Cl)([Cl:39])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Cl:39][C:8]1([C:7]2[C:6]([CH3:23])=[CH:5][C:4]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)=[CH:3][C:2]=2[Cl:1])[C:12](=[O:13])[C:11]2([CH2:14][CH2:15][N:16]([O:19][CH3:20])[CH2:17][CH2:18]2)[N:10]([CH3:21])[C:9]1=[O:22]
Reactant: CON1CCC2(CC1)C(O)=C(c1c(C)cc(-c3ccc(Cl)cc3)cc1Cl)C(=O)N2C
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CON1CCC2(CC1)C(=O)C(Cl)(c1c(C)cc(-c3ccc(Cl)cc3)cc1Cl)C(=O)N2C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(3,4′-dichloro-5-methyl-biphenyl-4-yl)-4-hydroxy-8-methoxy-1-methyl-1,8-diaza-spiro[4.5]dec-3-en-2-one (100 mg, 0.224 mmol) and sodium hydrogen carbonate (47 mg, 0.560 mmol) in dichloromethane (5 ml) at −5° C. was added sulfuryl chloride (0.017 ml, 28.3 mg, 0.210 mmol) in dichloromethane (0.5 ml) dropwise. The reaction mixture was stirred at 0° C. for 30 minutes and at room temperature overnight, poured on saturated aqueous sodium carbonate, the layers were separated, the water phase extracted with ethyl acetate (3×20 ml), the combined organic phases washed with saturated aqueous sodium carbonate and brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate/cyclohexane 2:1). Yield: 65 mg of 3-chloro-3-(3,4′-dichloro-5-methyl-biphenyl-4-yl)-8-methoxy-1-methyl-1,8-diaza-spiro[4.5]decane-2,4-dione (title compound P1.9) as a gum.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:12]([OH:14])=O.CCN(C(C)C)C(C)C.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][N:34]([C:12]([C:3]2[S:4][C:5]3[N:6]=[CH:7][NH:8][C:9](=[O:11])[C:10]=3[C:2]=2[CH3:1])=[O:14])[CH2:33][CH2:32]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: Cc1c(C(=O)O)sc2nc[nH]c(=O)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)N2CCN(c3ccccc3F)CC2)sc2nc[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To a solution of 5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid, (2 g, 9.5 mmol) in DMF (20 mL) was added DIEA (5 mL, 28.5 mmol), 1-(2-fluorophenyl)piperazine (1.7 g, 9.5 mmol), and HATU (4.7 g, 12.3 mmol). The reaction mixture was stirred at RT overnight. The reaction mixture was diluted with EtOAc (60 mL) and the organic layer was washed successively with sat. NaHCO3 aq. (50 mL) and brine (50 mL). The organic layer was separated, dried over Na2SO4, and concentrated to give crude product as a gummy solid. Purification by flash column chromatography using EtOAc as the eluant afforded the 3.0 g of pure 6-(4-(2-fluorophenyl)piperazine-1-carbonyl)-5-methylthieno[2,3-d]pyrimidin-4(3H)-one, (yield: 86%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([F:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.O.[CH2:16](OCC)C>C(O)=O.C=O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([F:14])[CH2:13][CH2:12][N:11]([CH3:16])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Fc1cc(F)cc(C2(F)CCNC2)c1
Reactant: CCOCC
Agent: C=O
Solvent: O=CO
Solvent: O
Product: CN1CCC(F)(c2cc(F)cc(F)c2)C1
Temperature: 85 °C

Procedure:
A mixture of 3-(3,5-difluorophenyl)-3-fluoropyrrolidine (0.17 g, 0.85 mmol) in formic acid (2.45 mL) and aqueous formaldehyde (40%, 2.2 mL) was heated at 85° C. for 1 h. Water (100 mL) and diethyl ether was added, the phases were separated and the aqueous phase was basified by the addition of aqueous sodium hydroxide (5M, 20 mL). The aqueous phase was extracted with ethyl acetate (2×50 mL), the combined organic phase was dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel (ethyl acetate/methanol, 1:0 to 1:1) gave the title compound (0.12 g). The amine was converted to the oxalic acid salt and recrystallized from methanol/diethyl ether/diisopropyl ether: M.p. 128-129° C.; MS m/z (relative intensity, 70 eV) 215 (M+, bp), 194 (29), 193 (36), 151 (33), 57 (92).
Reaction SMILES: [CH2:1]([C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[C:16]([C:21]([O-:23])=[O:22])[CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Na+].Cl[CH2:26][CH:27]([OH:30])[CH2:28][OH:29].[I-].[K+].O>COCCOCCOC>[CH2:1]([C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[C:16]([C:21]([O:23][CH2:26][CH:27]([OH:30])[CH2:28][OH:29])=[O:22])[CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCCc1cc2ccc(C(=O)[O-])cc2[nH]1
Reactant: OCC(O)CCl
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: COCCOCCOC
Product: CCCCCCCCCCCc1cc2ccc(C(=O)OCC(O)CO)cc2[nH]1
Yield: 26 %

Procedure:
A mixture of sodium 2-(n-undecyl)indole-6-carboxylate (5.0 g) and 3-chloro-1,2-propanediol (1.64 g) in diglyme (50 ml) was refluxed for 30 minutes. Potassium iodide (2.5 g) was added and the mixture refluxed for 48 hours. The mixture was cooled, water (50 ml) was added and the resulting emulsion was extracted with dichloromethane (2×100 ml). The combined extracts were dried over anhydrous magnesium sulphate, filtered, and the solvent evaporated to dryness. The solid residue was recrystallised from cyclohexane, filtered off and dried to give (RS)-2,3-dihydroxyprop-1-yl 2-(n-undecyl)indole-6-carboxylate (1.5 g) in the form of a white solid, m.p. 110°-112° C.