Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([N:20]1[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21]1)(OC(C)(C)C)=O>C(O)C>[NH:20]1[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21]1.[CH3:12][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O-:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Product: O[C@H]1CCNC1
Yield: 101.1 %

Procedure:
Prepare using the method of Intermediate 49 with p-toluenesulfonic acid monohydrate (0.254 g, 1.34 mmol), N-Boc-(S)-(+)-3-pyrrolidinol (0.250 g, 1.34 mmol) and ethanol (2 mL) to give the title compound as a white solid (0.35 g): MS (m/e): 88 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]2)=[C:4]2[C:10]([NH:11][C:12]([C:14]3[CH:23]=[N:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.C(Cl)[Cl:46]>>[ClH:46].[NH2:30][C@@H:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12]([C:14]4[CH:23]=[N:22][C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[N:15]=4)=[O:13])[C:4]=23)[CH2:25]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cnc5ccccc5n4)c23)C1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cnc5ccccc5n4)c23)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
(R)-tert-Butyl 1-(5-bromo-3-(quinoxaline-2-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (0.040 g, 0.071 mmol) was placed in DCM (3 mL) at room temperature. TFA (1 mL) was then added. The reaction was stirred at room temperature for 1 hour and concentrated to dryness to give the crude product, which was purified by reverse phase HPLC (0-50% ACN in water, Gilson system). The purified product was then dissolved in DCM (with minimal MeOH to aid solubility) and added dropwise to a stirring solution of 1M HCl in ether. The resulting solid was filtered, dried and collected to give (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)quinoxaline-2-carboxamide hydrochloride (0.007 g, 18% yield). LCMS (APCI+) m/z 466, 468 (M)+ (Method 2).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([NH:14][CH:15]=[O:16])[CH:6](O)[C:7](=[CH2:12])[CH2:8][CH2:9][O:10][CH3:11])[CH3:2].S(Br)([Br:20])=O.O>ClCCCl>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([NH:14][CH:15]=[O:16])[CH:6]=[C:7]([CH2:12][Br:20])[CH2:8][CH2:9][O:10][CH3:11])[CH3:2]
Reactant: C=C(CCOC)C(O)C(NC=O)C(=O)OCC
Reactant: O=S(Br)Br
Solvent: O
Solvent: ClCCCl
Product: CCOC(=O)C(C=C(CBr)CCOC)NC=O
Reaction time: 0.75 h

Procedure:
19.0 g (77.5 mmol) of 2-formylamino-3-hydroxy-6-methoxy-4-methylene-hexanoic acid ethyl ester are dissolved in 190 ml of 1,2-dichloroethane, and 7.20 ml (93.0 mmol) of thionyl bromide are added dropwise at room temperature. After 45 minutes, 100 ml of water are added and the mixture is stirred vigorously for 10 minutes. The organic phase is separated off, washed in succession with water, 1N potassium hydrogen carbonate solution and again with water, dried over sodium sulfate, filtered and concentrated by evaporation. 4-bromomethyl-2-formylamino-6-methoxy-hex-3-enoic acid ethyl ester is obtained in the form of a reddish-brown oil.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:6][OH:7])[C:3](=[O:5])[CH3:4].[CH3:9][S:10](Cl)(=[O:12])=[O:11]>N1C=CC=CC=1.C(Cl)Cl>[CH3:9][S:10]([O:7][CH2:6][C:2]([CH3:8])([CH3:1])[C:3](=[O:5])[CH3:4])(=[O:12])=[O:11]
Reactant: CC(=O)C(C)(C)CO
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)C(C)(C)COS(C)(=O)=O
Reaction time: 12 h
Yield: 85.5 %

Procedure:
232 g (2 mol) of 3,3-dimethyl-4-hydroxy-2-butanone (for the preparation, see Beilstein H 1 E III 3239, IV 4030 and Bull. Soc. Chim. France 1964, 2849) were reacted in 700 ml of absolute pyridine at 0° to 5° C. with 229 g (2 mol) of methanesulphonyl chloride. After standing for 12 hours at 20° C., the reaction mixture was diluted with methylene chloride and extracted by shaking with ice-water. The organic phase was dried, freed from solvent in vacuo and fractionated through a column. At a boiling point of 106° to 120° C./0.12 mm Hg, 332 g (that is to say 86% of theory) of 2,2-dimethyl-3-oxo-butyl methanesulphonate were isolated. ##STR10##
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:6][N:7]([CH2:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=1[C:24]1[CH:29]=[C:28]([CH:30]([CH3:32])[CH3:31])[CH:27]=[CH:26][C:25]=1[O:33][CH3:34])[C:8]1[N:9]=[N:10][NH:11][N:12]=1.C(N(CC)CC)C.Br[CH2:52][CH2:53][CH2:54][C:55]([O:57][CH2:58][CH3:59])=[O:56].O>CN(C)C=O>[F:41][C:38]([F:39])([F:40])[C:36]1[CH:35]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:42])[F:43])[CH:37]=1)[CH2:6][N:7]([CH2:13][C:14]1[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=[CH:16][C:15]=1[C:24]1[CH:29]=[C:28]([CH:30]([CH3:31])[CH3:32])[CH:27]=[CH:26][C:25]=1[O:33][CH3:34])[C:8]1[N:9]=[N:10][N:11]([CH2:52][CH2:53][CH2:54][C:55]([O:57][CH2:58][CH3:59])=[O:56])[N:12]=1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nn[nH]n1
Reactant: CCOC(=O)CCCBr
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2-c2cc(C(C)C)ccc2OC)n1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
(3,5-Bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-(2H-tetrazol-5-yl)-amine (400 mg) is dissolved in N,N-dimethylformamide (3 ml) and thereto are added triethylamine (2 ml) and ethyl 4-bromobutyrate (278 μl) and the mixture is stirred at 50° C. for 3 hours. To reaction mixture is added water, and extracted with ethyl acetate, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give ethyl 4-{5-[(3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-tetrazol-2-yl}-butyrate (360 mg) MS (m/z): 732 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:4]=1[OH:10].CO[C:13]1(OC)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH3:1][O:2][C:3]1[C:4]2[O:10][C:13]3([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[O:6][C:5]=2[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc(O)c1O
Reactant: COC1(OC)CCCCCC1
Product: COc1cccc2c1OC1(CCCCCC1)O2

Procedure:
Substantially the same procedure as in Reference Example 63 was repeated using 3-methoxycatechol (18 g) and dimethoxycycloheptane (24.35 g) to give Compound IIbm-a (28.0 g, 93.5%) as a colorless solid.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([O:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].O>CCCCCC.CC(O)C>[C:11]([O:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:8](=[O:10])[CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:23][CH:22]=1)(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C(O)Cc1ccccc1
Reactant: CC(C)(C)C(=O)OCCOc1ccccc1
Solvent: CCCCCC
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)C(=O)OCCOc1ccc(C(=O)Cc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Polyphosphoric acid (PPA) (250 g) was charged to a reaction vessel and warmed to 50° C. (bath temperature) with mechanical stirring. 2-Phenylacetic acid (30.6 g, 0.225 mol) was added to PPA followed by 2-phenoxyethyl pivalate (50 g, 0.225 mol). After 3 hours TLC and HPLC indicated full conversion and water (1000 ml) was added. The mixture was stirred at room temperature for 2 h. The precipitated product was filtered and washed with water (300 ml). After drying in vacuo the crude product (65 g) was re-crystallized with hexane/i-PrOH 1:1 yielding the title compound as slightly yellow solid (51.49 g, 0.151 mol, 67%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.02 (2H, d, J=9.2 Hz, ArH), 7.32-7.22 (5H, m, ArH), 7.07 (2H, d, J=8.8 Hz, ArH), 4.37 (2H, m, CH2CH2OPiv), 4.31 (2H, s, ArCH2CO), 4.3 (2H, m, ArOCH2CH2), 1.12 (9H, s, 3×Me). 13C-NMR (100 MHz, DMSO-d6) δ (ppm): 196.4, 177.7, 162.6, 135.8, 131.2, 129.9, 129.8, 128.7, 126.8, 114.8, 66.5, 62.7, 44.8, 38.6, 27.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([C@@H:9]1[C@@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:12][NH:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:22]([C:24]1[CH:25]=[CH:26][C:27]([N:30]2[CH2:35][CH2:34][CH:33]([C:36](O)=[O:37])[CH2:32][CH2:31]2)=[N:28][CH:29]=1)#[N:23].N1CCC(C(O)=O)CC1>>[C:1]([O:5][C:6](=[O:21])[N:7]([C@H:9]1[C@H:13]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[CH2:12][N:11]([C:36]([CH:33]2[CH2:32][CH2:31][N:30]([C:27]3[CH:26]=[CH:25][C:24]([C:22]#[N:23])=[CH:29][N:28]=3)[CH2:35][CH2:34]2)=[O:37])[CH2:10]1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CNC[C@@H]1c1ccc(Cl)cc1
Reactant: N#Cc1ccc(N2CCC(C(=O)O)CC2)nc1
Agent: O=C(O)C1CCNCC1
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 1 (step f), the title compound rac-[(3S,4R)-4-(4-chloro-phenyl)-1-(5′-cyano-3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester was prepared from rac-[(3R,4S)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester instead of rac-[(3R,4S)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester using 5′-cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid instead of 141-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and was obtained as an orange oil. MS m/e: 524.3 [M]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([N:14]([CH2:22][C:23]2[C:31]3[O:30][CH:29]=[CH:28][C:27]=3[CH:26]=[C:25](Br)[CH:24]=2)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:9]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:39]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([N:14]([CH2:22][C:23]2[C:31]3[O:30][CH:29]=[CH:28][C:27]=3[CH:26]=[C:25]([C:41]3[CH:42]=[CH:43][O:39][CH:40]=3)[CH:24]=2)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:9]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(Cc1cc(Br)cc2ccoc12)[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Reactant: OB(O)c1ccoc1
Product: CC(C)(C)OC(=O)N(Cc1cc(-c2ccoc2)cc2ccoc12)[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1

Procedure:
From cis-3-[(5-bromobenzofuran-7-ylmethyl)tert-butoxycarbonyl-amino]-2-phenyl-piperidine-1-carboxylic acid tert-butyl ester (473 mg) and 3-furanboronic acid (102 mg).
Reaction SMILES: C([CH:4]([CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[C:5]([CH3:9])(O)[C:6]#[CH:7])(C)=C.O1C[CH2:18][CH2:17][CH2:16]1.[OH2:20]>[Pd].FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH3:9][CH:5]([CH2:4][CH2:10][CH2:11][CH:12]([CH3:13])[CH3:14])[CH2:6][CH2:7][CH2:16][C:17](=[O:20])[CH3:18]
Reactant: C#CC(C)(O)C(CC=C(C)C)C(=C)C
Reactant: O
Reactant: C1CCOC1
Agent: [Ag+]
Agent: [Pd]
Agent: O=S(=O)([O-])C(F)(F)F
Product: CC(=O)CCCC(C)CCCC(C)C

Procedure:
4-Isopropenyl-3,7-dimethyl-6-octen-1-yn-3-ol (0.960 g; 5.10-3 mole) is kept at a temperature in the region of 40° C. and protected from light, in the presence of silver trifluoromethanesulphonate (1.285 g; 5.10-3 mole) in a mixture (50 cc) of tetrahydrofuran and water (3:1 by volume). After the reaction mixture has reacted for 20 hours and has been treated under the conditions of Example 1, the raw product obtained is hydrogenated in the presence of palladium on charcoal (5% in hexane). After chromatography on a silica column under reduced pressure with elution with a mixture of ether and petroleum-ether (3:7 by volume), 6,10-dimethylundecan-2-one (0.792 g) is obtained, having the following characteristics:
Reaction SMILES: [Li]CCCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.[Br:12][C:13]1[CH:14]=[C:15]([CH:19]=[O:20])[CH:16]=[N:17][CH:18]=1.O>C1COCC1>[Br:12][C:13]1[CH:14]=[C:15]([CH:19]([C:8]2[N:7]([CH3:6])[CH:11]=[CH:10][N:9]=2)[OH:20])[CH:16]=[N:17][CH:18]=1
Reactant: Cn1ccnc1
Reactant: O=Cc1cncc(Br)c1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cn1ccnc1C(O)c1cncc(Br)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
At −78° C., under N2 protection, n-BuLi (0.16 mL, 1.6 M, 1.0 mmol) was added to a solution of 1-methyl-1H-imidazole (82 mg, 1.0 mmol) in THF (10 mL) and the reaction mixture was stirred at −78° C. for 0.5 hour; then, 5-bromo-pyridine-3-carbaldehyde (186 mg, 1.0 mmol) was added to the above solution and stirring continued at −78° C. for additional 2 hours. The reaction mixture was poured into water (5.0 mL) and extracted with EtOAc (2×50 mL). The organic layer was dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product (210 mg, 78.4%) as white solid. MS: 268.1 & 270.1 (M+H+).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:10][C:9]1=[O:19])[CH2:2][CH2:3][CH3:4].[H][H]>C(O)C.[Pd]>[CH2:1]([O:5][CH2:6][CH2:7][N:8]1[CH2:12][CH:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:10][C:9]1=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCn1cc(-c2ccccc2)[nH]c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCOCCN1CC(c2ccccc2)NC1=O

Procedure:
A solution of 1-(2-butoxyethyl)-4-phenyl-4-imidazolin-2-one in ethanol with 10% palladium or carbon catalyst is reduced in an atmosphere of hydrogen. After the theoretical amount of hydrogen is absorbed, the catalyst is filtered and filtrate concentrated to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]([OH:8])[C:5]2[CH:9]=[CH:10][O:11][C:4]=2[CH2:3]1.[CH3:12][C:13]([C:15]1[C:20]([Cl:21])=[C:19](F)[CH:18]=[CH:17][C:16]=1[Cl:23])=[O:14]>>[ClH:21].[C:13]([C:15]1[C:20]([Cl:21])=[C:19]([O:8][CH:6]2[CH2:7][N:2]([CH3:1])[CH2:3][C:4]3[O:11][CH:10]=[CH:9][C:5]2=3)[CH:18]=[CH:17][C:16]=1[Cl:23])(=[O:14])[CH3:12]
Reactant: CC(=O)c1c(Cl)ccc(F)c1Cl
Reactant: CN1Cc2occc2C(O)C1
Product: CC(=O)c1c(Cl)ccc(OC2CN(C)Cc3occc32)c1Cl
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 6-methyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-4-ol (Reference Example 1) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2,6-dichloro-3-fluoroacetophenone instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]23[O:16][C:15](=[O:17])[CH:14]2[CH2:13][CH2:12][CH2:11][CH2:10]3)=[O:8])=[CH:5][CH:4]=1.[CH:20]([NH2:24])([CH2:22][CH3:23])C.[CH3:25]OC(C)(C)C>>[CH3:23][CH:22]([CH3:25])[CH2:20][NH:24][C:15]([CH:14]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1([OH:16])[C:7](=[O:8])[C:6]1[CH:18]=[CH:19][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:17]
Reactant: COc1ccc(C(=O)C23CCCCC2C(=O)O3)cc1
Reactant: COC(C)(C)C
Reactant: CCC(C)N
Product: COc1ccc(C(=O)C2(O)CCCCC2C(=O)NCC(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
20.8 g (0.08 mol) of 6-(4-methoxy-benzoyl)-7-oxa-bicyclo[4.2.0]octan-8-one (compound of example 10) are dissolved in 270 ml of tert-butyl methyl ether. 10.46 g (0.143 mol) of sec-butylamine are slowly added to this solution over one hour. The reaction mixture is stirred for 24 hours at room temperature. After this time, 1H-NMR analysis shows that the reaction mixture consists of 60% starting material and 40% of the product. Another 10.46 g (0.143 mol) of sec-butylamine are added and the reaction mixture is stirred for another four hours at room temperature. After that time the solvent is partially distilled off and substituted by the slow addition of 50 ml heptane. The precipitation formed is collected and the remaining liquid further diluted with hexane, resulting in the formation of an additional precipitation. The solids are collected and washed with hexane to give a white powder that according to 1H-NMR analysis consists of 64% product and 36% of the starting material. These compounds are separated by flash chromatography on silicagel (eluent: toluene/ethyl acetate 9:1), providing 2-hydroxy-2-(4-methoxy-benzoyl)-cyclohexanecarboxylic acid 2-methyl-propyl-amide as a colorless solid with a melting point of 143-147° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:4])=[O:3].[N+:11]([O-])([OH:13])=[O:12].C(=O)(O)[O-].[Na+]>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)(=[O:4])=[O:3]
Reactant: O=[N+]([O-])O
Reactant: CS(=O)(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Product: CS(=O)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phenyl methyl sulphone (4.0 g) was added, portionwise, to fuming nitric acid stirred at 0° C. The reaction mixture was allowed to warm to room temperature, stirred for 1 hour, and then poured carefully onto ice. The solution was carefully neutralised with sodium bicarbonate and the mixture filtered at the pump. The solid collected was washed with water and dried under reduced pressure over potassium hydroxide to give the title compound as a white solid (5.63 g) in a sufficient state of purity for the next reaction.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:8]1([CH3:21])[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[C:9]=1[S:16]([O:19][NH2:20])(=[O:18])=[O:17]>C(Cl)Cl>[NH2:20][N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]1=[NH2+:7].[CH3:15][C:10]1[CH:11]=[C:12]([CH3:14])[CH:13]=[C:8]([CH3:21])[C:9]=1[S:16]([O-:19])(=[O:18])=[O:17]
Reactant: Nc1ccccn1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Product: Nn1ccccc1=[NH2+]
Temperature: 25 °C

Procedure:
A mixture of pyridin-2-amine (6.6 g, 20.0 mmol) in DCM (15 mL) was stirred at room temperature, and O-(mesitylsulfonyl)hydroxylamine (1.0 g, 10.0 mmol) was added slowly. The reaction mixture was stirred at room temperature for 12 h, and the solvent was removed under vacuum. The crude product was used for next step without further purification. ESI MS: m/z 110 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Br:13][C:14]1[CH:15]=[CH:16][C:17](F)=[C:18]([CH:21]=1)[C:19]#[N:20].O>CN(C)C=O>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([O:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:18]([CH:21]=1)[C:19]#[N:20]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: OCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(Br)ccc1OCCCc1ccccc1
Reaction time: 1 h
Yield: 90.9 %

Procedure:
3-Phenylpropanol (2.17 g) was dissolved in N,N-dimethylformamide (32 ml), and sodium hydride (60%, 0.638 g) was added at room temperature. After stirring for 1 hr, 5-bromo-2-fluorobenzonitrile (1.60 g) was added, and the mixture was further stirred at 40-50° C. for 3 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the object product (2.30 g) as a colorless oil.
Reaction SMILES: Br[CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]([OH:5])=[O:4].[C:20](O)(=[O:36])CCCCCCCCCCCCCCC.[OH-].[K+].[OH:40][CH:41]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]CCCCCC)[C:42]([OH:44])=[O:43]>CO.[N+](=C)=[N-]>[CH3:20][O:36][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]([O:5][CH3:41])=[O:4].[OH:40][CH:41]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:42]([OH:44])=[O:43]
Reactant: CCCCCCCCCCCCCCC(Br)C(=O)O
Reactant: CCCCCCCCCCCCCCC(O)C(=O)O
Reactant: CCCCCCCCCCCCCCCC(=O)O
Agent: C=[N+]=[N-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCC(O)C(=O)O
Product: CCCCCCCCCCCCCCC(OC)C(=O)OC

Procedure:
2-Bromohexadecanoic acid (m.p. 51.5°-52.5° C) prepared from palmitic acid of high purity according to the method of Schwenk, E. and Papa, D; J. Am. Chem. Soc., 70 (1948) 3626, was treated with a solution of potassium hydroxide in 95 % methanol in an oil bath at 90° C at which 2-hydroxyhexadecanoic acid (m.p. 86.1°-86.3° C after recrystallization from ethanol and then from dichloromethane) was formed. Methyl 2-methoxyhexadecanoate (m.p. 28.6°-30.6° C) was obtained from 2-hydroxydecanoic acid by esterification and etherification with diazomethane using borone trifluoride as catalyst for the esterification whereafter it was reduced with lithium aluminum hydride to the formation of 2-methoxyhexadecanol-1 (m.p. 34.3°-34.9° C) which was purified by chromatography on silicic acid, 2-methoxyhexadecyl p-toluenesulphonate (m.p. 38°-39° C) was prepared by treating 2-methoxyhexadecanol with p-toluenesulphonylchloride in pyridine.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.CS(O[CH2:17][CH2:18][C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)(=O)=O>>[S:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[CH2:18][CH2:17][N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: CS(=O)(=O)OCCc1cccs1
Product: O=Cc1cccc2c1ccn2CCc1cccs1
Yield: 39.1 %

Procedure:
The same procedures used in Example 1 were repeated except for using 435 mg of indole-4-carbaldehyde and 680 mg of 2-(thien-2-yl)ethyl methanesulfonate instead of the benzyl bromide used in Example 1 to give 299 mg of 1-[2-(thien-2-yl)ethyl]indole-4-carbaldehyde as an orange-colored oily substance. The yield thereof was found to be 39%.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[Cl:16][C:17]1[CH:18]=[C:19]([CH2:28][NH2:29])[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][CH:25]([F:27])[F:26]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:29]([CH2:28][C:19]3[CH:20]=[CH:21][C:22]([O:23][CH2:24][CH:25]([F:26])[F:27])=[C:17]([Cl:16])[CH:18]=3)[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: NCc1ccc(OCC(F)F)c(Cl)c1
Agent: Cl
Product: O=C1c2ccnc(Cl)c2CN1Cc1ccc(OCC(F)F)c(Cl)c1
Yield: 84 %

Procedure:
The title compound is prepared in 84% yield (225 mg, colorless amorphous solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (200 mg, 0.72 mmol) and (3-chloro-4-(2,2-difluoroethoxy)phenyl)methanamine hydrochloride (195 mg, 0.75 mmol, Amine-33) in a similar manner to Intermediate-2.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:19](I)[CH3:20]>C(#N)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:19][CH3:20])=[CH:4][N:3]=1
Reactant: Oc1cnc(Cl)c2ccccc12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1cnc(Cl)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
To a solution of 1-chloroisoquinolin-4-ol (1.0 g, 5.5 mmol) in acetonitrile (10 mL) was added K2CO3 (2.3 g, 16.7 mmol) followed by ethyl iodide (0.87 ml, 11.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for overnight. The solvent was evaporated under reduced pressure and the residue was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get 1-chloro-4-ethoxyisoquinoline (0.7 g, 62%) as off-white solid. 1H NMR (400 MHz, CD3OD): δ ppm 8.26-8.24 (m, 2H), 7.79 (s, 1H), 7.76-7.26 (m, 2H), 4.29-4.24 (q, J=6.8 Hz, 2H), 1.58-1.54 (t, J=6.8 Hz, 3H); MS: MS m/z 207.7 (M++1).