Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(Cl)(=O)C(Cl)=O.[F:33][C:34]([F:46])([F:45])[C:35]1[CH:44]=[CH:43][C:38]2[N:39]=[C:40]([NH2:42])[S:41][C:37]=2[CH:36]=1.C(N(C(C)C)CC)(C)C>ClCCl.CN(C)C=O.CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](=[O:19])[NH:42][C:40]3[S:41][C:37]4[CH:36]=[C:35]([C:34]([F:46])([F:33])[F:45])[CH:44]=[CH:43][C:38]=4[N:39]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: Nc1nc2ccc(C(F)(F)F)cc2s1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4nc5ccc(C(F)(F)F)cc5s4)cc3)c(Cl)cc21
Reaction time: 0.5 h
Yield: 32.7 %

Procedure:
4-(6-Chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation B; 100 mg, 0.265 mmol) was diluted with dichloromethane (5 mL) followed by the addition of oxalyl chloride in dichloromethane (2M) (146 μL, 0.292 mmol) and dimethylformamide (1 drop). After stirring for 30 minutes a small aliquot was diluted with methanol for 5 minutes. Thin layer chromatography of this aliquot showed complete conversion to methyl ester. 6-(Trifluoromethyl)benzo[d]thiazol-2-amine (63.7 mg, 0.292 mmol) and diisopropyl ethylamine (116 μL, 0.664 mmol) were added and the reaction was stirred at 35° C. for 1 hour. The reaction was loaded directly onto a Biotage 25 cartridge and eluted with 5% ethyl acetate/hexanes to 70% ethyl acetate/hexanes to yield ethyl 6-chloro-7-(4-(6-(trifluoromethyl)benzo[d]thiazol-2-ylcarbamoyl)phenoxy)chroman-4-carboxylate (50 mg, 0.0867 mmol, 32.7% yield).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]([N:13]3[CH2:17][CH:16]([NH:18][CH3:19])[CH:15]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=4)[CH2:14]3)=[O:12])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[F:28][C:29]1[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:36][C:37]([OH:39])=O>>[CH:1]1([CH2:4][N:5]2[CH2:6][CH2:7][CH:8]([C:11]([N:13]3[CH2:14][CH:15]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=4)[CH:16]([N:18]([CH3:19])[C:37](=[O:39])[CH2:36][C:30]4[CH:31]=[CH:32][CH:33]=[C:34]([F:35])[C:29]=4[F:28])[CH2:17]3)=[O:12])[CH2:9][CH2:10]2)[CH2:3][CH2:2]1
Reactant: CNC1CN(C(=O)C2CCN(CC3CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)Cc1cccc(F)c1F
Product: CN(C(=O)Cc1cccc(F)c1F)C1CN(C(=O)C2CCN(CC3CC3)CC2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 87 (step c), the title compound N-[(3RS,4SR)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(2,3-difluoro-phenyl)-N-methyl-acetamide was prepared from (1-cyclopropylmethyl-piperidin-4-yl)-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-methanone instead of N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using 2,3-difluorophenylacetic acid instead of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and was obtained as a colorless semi-solid. MS m/e: 564.4 [M]+.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].O>CN(C=O)C>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:5]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CCBr
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCn1ccc([N+](=O)[O-])n1
Reaction time: 0.5 h
Yield: 45.1 %

Procedure:
A solution of 3-nitropyrazole (22.6 g.) in dry DMF (25 ml.) was added dropwise over 30 minutes to a suspension of sodium hydride (5.28 g.) in dry DMF (50 ml.) at 0°. The mixture was stirred for 30 minutes, ethyl 3-bromopropionate (36.8 g.) was added over 10 minutes, the mixture was kept at -15° for 17 hours and then allowed to warm to 20°. Water (550 ml.) was added, the solution was extracted with EtOAc (4×100 ml.) and the combined extracts were dried (MgSO4) and evaporated in vacuo to an oil. Fractionation on a silica medium pressure liquid chromatography column eluted with EtOAc/petrol (b.p.60°-80°) 1:1 v/v gave ethyl 3-(3-nitropyrazol-1-yl)propionate (19.2 g.) as a low melting solid. The n.m.r. spectrum in CDCl3 included the following resonances: 7 6 (d, 1H); 6.85 (d, 1H); 4.5 (t, 2H); 4.1 (q, 2H); 2.95 (t, 2H); 1.2 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].O=S(Cl)[Cl:16]>ClC(Cl)C>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:16])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: O=S(Cl)Cl
Solvent: CC(Cl)Cl
Product: O=C(Cl)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 80 °C

Procedure:
The title compound was prepared from 4-Fluoro-3-nitro-benzoic acid (1.00 g, 5.40 mmol) dissolved in dichloroethane (25 mL) to which was added SOCl2 (6.427 g, 54.02 mmol). This mixture was heated to 80° C. for 12 h at which point all the solvent was removed on under vacuum and the crude oil was taken forward without purification (1.10 g, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[CH:11]1N(C2C=CC=CC=2)CCN1C1C=CC=CC=1.Cl.[OH2:29]>C(O)C>[OH:1][C:2]1[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[CH:11]=[O:29]
Reactant: CN(C)c1ccc(C2N(c3ccccc3)CCN2c2ccccc2)c(O)c1
Reactant: O
Agent: Cl
Solvent: CCO
Product: CN(C)c1ccc(C=O)c(O)c1

Procedure:
The reaction product (XV) obtained in accordance with Example 16 is suspended in warm ethanol. A clear solution is formed, following the addition of 5 ml of 5% aqueous hydrochloric acid. 10 ml of water are added and the aqueous solution is extracted by repeated shaking with 10 ml batches of chloroform. After the chloroform has been distilled off in vacuo from the combined chloroform extracts, 2-hydroxy-4-dimethylaminobenzaldehyde (XVI) is obtained in the form of pale yellow needles, melting at 77° to 78° C.
Reaction SMILES: [OH-].[Na+].C(#N)C.[NH2:6][C:7]1[NH:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1.[CH3:16][N:17]([CH3:22])[S:18](Cl)(=[O:20])=[O:19]>O>[CH3:16][N:17]([CH3:22])[S:18]([C:12]1[C:10]2[NH:11][C:7]([NH2:6])=[N:8][C:9]=2[CH:15]=[CH:14][CH:13]=1)(=[O:20])=[O:19]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Nc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CN(C)S(=O)(=O)c1cccc2nc(N)[nH]c12
Temperature: 25 °C
Yield: 92.5 %

Procedure:
To a solution of sodium hydroxide (1.8 g) in water (9 mL) add acetonitrile (44 mL). To this solution, add 2-aminobenzimidazole (3.0 g, 22.5 mmol) and dimethylsulfamoyl chloride (2.4 mL, 22.5 mmol). Stir the reaction mixture at room temperature, overnight. Then, cool the mixture at 0° C. and the product crystallized from solution. Filter the product and dry it in vacuum to provide 5.0 g (90% yield) of the title compound as a white solid. MS (ES+): m/z=241.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([OH:14])=[O:13].[CH3:15][Si](Cl)(C)C>>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: C[Si](C)(C)Cl
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1Cl
Product: COC(=O)Cc1ccc([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 7 h
Yield: 74 %

Procedure:
To a solution of 2-(2-chloro-4-nitrophenyl)acetic acid (step 2, 4.5 g, 21 mmol) in dimethyl acetate/methanol (4/1) was added trimethylsilylchloride (0.3 ml) and stirred for 7 h at room temperature. The solvent was removed and the residue was purified by SiO2 column chromatography with developing hexane/ethyl acetate (10/1) to give 3.6 g (74%) of title compound as yellow oil.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]Br.[CH3:7][O:8][C:9]([CH:11]1[CH2:14][CH2:13][CH2:12]1)=[O:10]>>[CH3:7][O:8][C:9]([C:11]1([CH2:5][CH2:4][CH2:3][CH2:2][Br:1])[CH2:14][CH2:13][CH2:12]1)=[O:10]
Reactant: COC(=O)C1CCC1
Reactant: BrCCCCBr
Product: COC(=O)C1(CCCCBr)CCC1

Procedure:
1-(4-Bromobutyl)cyclobutane carboxylic acid methyl ester was prepared from 1,4-dibromobutane and cyclobutane carboxylic acid methyl ester using the general procedure described in example 168.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][C:10]2([O:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][O-:16].[Na+]>CO>[CH2:1]([N:8]1[CH2:14][CH2:13][C:10]([OH:12])([CH2:11][O:16][CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CN2CCC3(CO3)C2)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCC1(O)CCN(Cc2ccccc2)C1

Procedure:
26.8 g (0.14 mol) of 5-benzyl-1-oxa-5-azaspiro[2,4]heptane are heated overnight under reflux with 2.6 ml (14 mmol) of 30% strength sodium methoxide solution in 200 ml of absolute methanol. The product is concentrated and distilled.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([C:9](C)=O)[CH3:8].[C:12]1([CH3:19])[CH:17]=[CH:16][CH:15]=[C:14]([SH:18])[CH:13]=1.C(Br)C#C>O>[CH3:19][C:12]1[CH:13]=[C:14]([S:18][CH2:9][C:7]#[CH:8])[CH:15]=[CH:16][CH:17]=1
Reactant: CCC(C)=O
Reactant: Cc1cccc(S)c1
Agent: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C#CCSc1cccc(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
A condenser, an internal thermometer, a mechanical stirrer and a dropping funnel were attached to a 5-L three-neck flask. Into the flask, were introduced 673 g of potassium carbonate and 1500 mL of methyl ethyl ketone. Into the dropping funnel, were introduced 500 g of m-toluenethiol and 200 mL of methyl ethyl ketone. Both were dropped in 10 minutes. The resulting mixture was intactly stirred at room temperature for 1 hour. The internal temperature was raised to 28° C. The three-neck flask was dipped in a water bath. Into the dropping funnel, were introduced 333 mL of propargyl bromide and 300 mL of methyl ethyl ketone. The dropping was then started. The dropping was carried out for 20 minutes while maintaining the internal temperature at about 55 to 65° C. by controlling the dropping. The stirring was intactly carried out under the water bath for 50 minutes. The resulting suspension of the reaction system was then directly filtered through a Buchner funnel, and the vessel and solids were washed with 900 mL of ethyl acetate. The obtained filtrate was subsequently vacuum concentrated. Further, 1500 mL of ethyl acetate, 2 L of water and 100 mL of 1 N HCl were added to separate an organic layer from an aqueous layer. The aqueous layer was extracted with 500 mL of ethyl acetate twice. The extract was washed with 1000 mL of a saturated brine twice and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to provide 601.14 g of a crude substance (yield 92%, purity 88%). Only 300 g of the crude substance was distilled to obtain 239.68 g of 3-methyl-1-prop-2-ynylthiobenzene at 100 to 102° C./7 mmHg (recovery ratio 80%, purity>98%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:11])[C:6]([CH3:10])([CH3:9])[CH2:7][OH:8].[CH3:12]OS(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O.O.CCCCCC>[CH3:3][O:4][C:5](=[O:11])[C:6]([CH3:10])([CH3:9])[CH2:7][O:8][CH3:12]
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)C(C)(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COCC(C)(C)C(=O)OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 55 %

Procedure:
1 mol of sodium hydride was added to the solvent dimethylformamide, and 1 mol of hydroxypivalic acid methyl ester was added thereto while the temperature of the solution did not exceed 30° C. The solution was stirred at room temperature for 90 minutes. Then, 1.2 mol of p-toluenesulfonic acid methyl ester was added to the solution while the temperature of the solution did not exceed 30° C. Then, a water/hexane mixture having the same mass as that of the dimethylformamide was added to the solution, which was then stirred, after which water was removed therefrom. The resulting organic material was concentrated, and the residue was fractionated at 700 Pa and 93° C., thereby obtaining the intermediate 3-methoxy-2,2-dimethylpropionic acid methyl ester at a yield of 55%.
Reaction SMILES: [OH:1][C@:2]1([CH3:29])[C@@H:7]([CH3:8])[CH2:6][N:5]([C:9]2[C:14]([N+:15]([O-])=O)=[CH:13][N:12]=[C:11]3[O:18][CH2:19][CH2:20][C:10]=23)[CH2:4][C@H:3]1[NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25]>CO.[Pd]>[NH2:15][C:14]1[C:9]([N:5]2[CH2:6][C@H:7]([CH3:8])[C@:2]([OH:1])([CH3:29])[C@H:3]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:4]2)=[C:10]2[CH2:20][CH2:19][O:18][C:11]2=[N:12][CH:13]=1
Reactant: C[C@H]1CN(c2c([N+](=O)[O-])cnc3c2CCO3)C[C@@H](NC(=O)OC(C)(C)C)[C@]1(C)O
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CN(c2c(N)cnc3c2CCO3)C[C@@H](NC(=O)OC(C)(C)C)[C@]1(C)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of tert-butyl [(3R,4R,5S)-4-hydroxy-4,5-dimethyl-1-(5-nitro-2,3-dihydrofuro[2,3-b]pyridin-4-yl)piperidin-3-yl]carbamate (51 mg, 0.13 mmol) in MeOH (3.0 mL), 10 wt % Pd on carbon (19 mg) was added. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (balloon pressure) for 6 h. The mixture was filtered through a pad of diatomaceous earth (eluted with MeOH), and then concentrated under reduced pressure. The resulting crude product was used directly in the next step without further purification (44 mg, 92%). LCMS calc. for C19H31N4O4 (M+H)+: m/z=379.2. found 379.0.
Reaction SMILES: [O:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH2:6][NH:7][C:8](=[O:28])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[NH:18][C@@H:19]([C:24](OC)=[O:25])[CH2:20][CH2:21][S:22][CH3:23])[CH3:2].[Cl-].[Li+].[BH4-].[Na+]>O1CCCC1.C(O)C>[O:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH2:6][NH:7][C:8](=[O:28])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[NH:18][C@@H:19]([CH2:24][OH:25])[CH2:20][CH2:21][S:22][CH3:23])[CH3:2]
Reactant: COC(=O)[C@@H](CCSC)Nc1ccc([N+](=O)[O-])cc1C(=O)NCc1ccc(OC)c(OC)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2N[C@@H](CO)CCSC)cc1OC
Reaction time: 24 h
Yield: 74.1 %

Procedure:
To a solution of N-(3,4-dimethoxylbenzyl)-2-[(R)-1-methoxycarbonyl-3-(methylthio)propylamino]-5-nitrobenzamide (175 mg) in anhydrous tetrahydrofuran (3 mL) were added lithium chloride (31 mg), and then sodium borohydride (28 mg) in ethanol (3 mL) at ambient temperature. The mixture was stirred for one day. After evaporation of the solvent, the residue was partitioned between ethyl acetate and 10% citric acid aqueous solution. The separated organic layer was washed with water and brine and dried over magnesium sulfate. The residual solid was recrystallized from ethyl acetate-hexane to give N-(3,4-dimethoxylbenzyl)-2-[(R)-1-hydroxymethyl-3-(methylthio)propylamino]-5-nitrobenzamide (122 mg).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH3:11])=[C:5]([F:12])[C:4]=1[F:13].[O:14]1[C:18]2([CH2:23][CH2:22][CH:21]([CH:24]3[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]3)[CH2:20][CH2:19]2)[O:17][CH2:16][CH2:15]1.[Cl-].[NH4+]>C1COCC1.C1(C)C=CC=CC=1>[O:14]1[C:18]2([CH2:19][CH2:20][CH:21]([CH:24]3[CH2:29][CH2:28][C:27]([C:3]4[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH3:11])=[C:5]([F:12])[C:4]=4[F:13])([OH:30])[CH2:26][CH2:25]3)[CH2:22][CH2:23]2)[O:17][CH2:16][CH2:15]1
Reactant: CCOc1ccc(Br)c(F)c1F
Reactant: O=C1CCC(C2CCC3(CC2)OCCO3)CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOc1ccc(C2(O)CCC(C3CCC4(CC3)OCCO4)CC2)c(F)c1F
Temperature: 40 °C
Reaction time: 1 h
Yield: 120.3 %

Procedure:
First Step: 6.1 g of well dried magnesium and 20 mL of THF were placed in a reactor under nitrogen atmosphere, and heated to 40° C. 59.7 g of 1-bromo-4-ethoxy-2,3-difluorobenzene (1) dissolved in 300 mL of THF was slowly added dropwise thereto at a temperature range of from 40 to 60° C., followed by stirring for 60 minutes. Thereafter, 50.0 g of 4-(1,4-dioxaspiro[4,5]dec-8-yl)cyclohexanone (2) dissolved in 150 mL of THF was slowly added dropwise thereto at a temperature range of from 50 to 60° C., followed by stirring for 60 minutes. After cooling the resulting reaction mixture to 30° C., the reaction mixture was mixed with 900 mL of a 3% ammonium chloride aqueous solution and 500 mL of toluene cooled to 0° C. in a vessel and separated into an organic layer and an aqueous layer by standing still, so as to attain extraction. The resulting organic layer was fractionated and washed with water, a saturated sodium bicarbonate aqueous solution, and water, followed by drying over anhydrous magnesium sulfate. Thereafter, the solvent was distilled off under reduced pressure to obtain 100.1 g of 4-(1,4-dioxaspiro[4,5]dec-8-yl)-1-(4-ethoxy-2,3-difluorophenyl)cyclohexanol (3). The resulting compound (3) was a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[CH3:10][NH2:11]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:11][CH3:10])=[CH:4][N:3]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: CN
Solvent: CC#N
Product: CNCc1ccc(Cl)nc1

Procedure:
A mixture of 15.05g of 2-chloro-5-(chloromethyl) pyridine and 50ml of acetonitrile was dropwise added to a mixture of 36g of 40% methylamine aqueous solution and 200ml of acetonitrile during an hour at room temperature and stirred for an hour and a half. The reaction mixture was concentrated. The resulting residue to which 100ml of water was added, was neutralized by sodium hydrogen carbonate, saturated with sodium chloride and extracted with dichloromethane (200ml×2). The organic layer was dried over anhydrous magnesium sulfate, concentrated and purified by a column chromatography [developing solvent: dichloromethane-methanol (4:1)] to afford 8.77g of 2-chloro-5(methylaminomethyl)pyridine as a yellowish brown liquid.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:6](=[O:7])[C:4]1=[O:5].Br[CH2:15][CH2:16][CH:17]1[CH2:19][CH2:18]1>CN(C)C=O>[CH:17]1([CH2:16][CH2:15][N:3]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:6](=[O:7])[C:4]2=[O:5])[CH2:19][CH2:18]1
Reactant: BrCCC1CC1
Reactant: O=C1Nc2ccccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1C(=O)N(CCC2CC2)c2ccccc21
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a suspension of sodium hydride (1.61 g, 41.9 mmol, 60% dispersion in mineral oil) in anhydrous N,N-dimethylformamide (25.0 mL) was added isatin (6.17 g, 41.9 mmol) at 0° C. The reaction mixture was stirred for 0.5 h followed by the addition of (2-bromoethyl)cyclopropane (Maercker, A., et al, Justus Liebigs Ann. Chem. (1972), 759:132-157) (9.25 g, 61.2 mmol). The resulting mixture was stirred at ambient temperature for 16 h and quenched with water (50.0 mL). The mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers was washed with water (3×50.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness to yield the title compound (6.50 g, 90%) as a viscous gum: 1H NMR (300 MHz, CDCl3) δ 7.57-7.51 (m, 2H), 7.05 (t, 1H), 6.88 (d, 1H), 3.79-3.74 (m, 2H), 1.59-1.52 (m, 2H), 0.70-0.61 (m, 1H), 0.44-0.38 (m, 2H), 0.05-0.02 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 183.7, 158.2, 151.2, 138.4, 125.4, 123.6, 117.5, 110.3, 40.3, 32.2, 8.6, 4.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([OH:21])=O)[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@H:23]2[CH2:28][CH2:27][C@@H:26]([O:29][CH3:30])[CH2:25][CH2:24]2)[CH:3]=1.[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][CH2:35][NH2:36]>>[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][CH2:35][NH:36][C:19]([C:16]1[S:15][C:11]2[N:12]=[CH:13][N:14]=[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[O:22][C@H:23]3[CH2:28][CH2:27][C@@H:26]([O:29][CH3:30])[CH2:25][CH2:24]3)[C:10]=2[C:17]=1[CH3:18])=[O:21]
Reactant: CO[C@H]1CC[C@@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(=O)O)c(C)c23)CC1
Reactant: CN(C)CCCN
Product: CO[C@H]1CC[C@@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(=O)NCCCN(C)C)c(C)c23)CC1

Procedure:
Prepared analogously to 1.4 from 0.1 g 4-[4-fluoro-2-(cis-4-methoxy-cyclohexyloxy)phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and 42 μl N,N-dimethyl-1,3-propanediamine.
Reaction SMILES: [OH-].[Li+].[CH3:3][O:4][C:5]1[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][C:6]=1[C:7]([O:9]C)=[O:8].Cl>O.O1CCCC1.CO>[CH3:3][O:4][C:5]1[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(C=O)ccc1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C=O)cc1C(=O)O
Reaction time: 8 h

Procedure:
Lithium hydroxide (1.04 g, 0.043 mol, 3 eq) in water (10 mL) was added to a stirred solution of methyl 2-methoxy-5-formylbenzoate (2.8 g, 0.014 mol, 1 eq) in a mixture of tetrahydrofuran (30 mL) and methanol (20 mL). The solution was stirred overnight, acidified to pH 1 with 10% HCl and the organic solvents removed in vacuo. The aqueous solution was extracted with ethyl acetate (100 mL) and the organic solution washed with brine (100 mL), then extracted with saturated aqueous sodium bicarbonate (3×100 mL). The basic solution was washed with ethyl acetate (100 mL), then acidified to pH 1 with 10% HCl and back extracted with dichloromethane (3×100 mL). The organic solution was dried over sodium sulfate and evaporated in vacuo to give a cream coloured powder (2.01 g, 77%). 1H NMR (CDCl3) δ9.99 (s, 1H, O═C—H), 4.14 (s, 3H, CH3).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1/[CH:19]=[CH:20]/[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1/[CH:19]=[CH:20]/[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][Cl:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: OCc1cccc(/C=C/c2ccc3ccccc3n2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: ClCc1cccc(/C=C/c2ccc3ccccc3n2)c1
Reaction time: 2 h

Procedure:
Solid N-chlorosuccinimide (0.76 g 5.72 mmol) is added in portions over 5 minutes to a stirred solution of 3-[2(E)-(quinolin-2-yl)ethenyl]benzyl alcohol (1.14 g, 4.58 mmol) and triphenylphosphine (1.50 g, 5.72 mmol) in dichloromethane (100 ml) at 0°-5° C. The mixture is stirred for a further 2 hours at 0°-5° C. then evaporated and the residue chromatographed on silica in ethyl acetate-hexane (1:3).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10](C(Cl)(Cl)Cl)[N:9]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH2:22])[N:17]=3)[C:8]=2[CH:23]=1.[O:24]1[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26][CH2:25]1>CN(C)C=O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([O:30][CH:27]3[CH2:28][CH2:29][O:24][CH2:25][CH2:26]3)[N:9]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH2:22])[N:17]=3)[C:8]=2[CH:23]=1
Reactant: OC1CCOCC1
Reactant: Nc1nccc(-n2c(C(Cl)(Cl)Cl)nc3ccc(Br)cc32)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1nccc(-n2c(OC3CCOCC3)nc3ccc(Br)cc32)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
Sodium hydride (200 mg, 5.00 mmol, 60% dispersion in mineral oil) was added in several portions into a solution of 4-[6-bromo-2-(trichloromethyl)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (500 mg, 1.23 mmol) and oxan-4-ol (1.00 g, 9.79 mmol) in N,N-dimethylformamide (10 mL) under an atmosphere of nitrogen. The reaction mixture was stirred overnight at room temperature and then filtered through a frit filter. The filtrate was purified on a C18 column (acetonitrile/water, 5:95-80:20) to give 170 mg (28%) of 4-[6-bromo-2-(oxan-4-yloxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine as a brown solid. LC-MS: m/z=+390 (M+H)+.