Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[C:30]1[NH:34][C:33](=[O:35])[O:32][N:31]=1)[O:5][CH2:6][C:7]1[S:11][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:9][C:8]=1[CH2:22][O:23]C(=O)C.[OH-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([O:5][CH2:6][C:7]2[S:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:14][CH:13]=3)=[N:9][C:8]=2[CH2:22][OH:23])[CH:27]=[CH:28][C:29]=1[C:30]1[NH:34][C:33](=[O:35])[O:32][N:31]=1
Reactant: CC(=O)OCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(-c2noc(=O)[nH]2)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=c1[nH]c(-c2ccc(OCc3sc(-c4ccc(C(F)(F)F)cc4)nc3CO)cc2F)no1
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 79.9 %

Procedure:
To a suspension of 150 mg of acetic acid 5-[3-fluoro-4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenoxymethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-4-ylmethyl ester in 5 mL of methanol at 0° C. was dropwise added 0.29 mL of a 1 molar aqueous solution of sodium hydroxide. After stirring for 15 minutes at 10° C., the reaction mixture was concentrated under reduced pressure. Ethyl acetate/a 1 molar aqueous solution of sodium hydrogenphosphate was added. The organic layer was separated and the aqueous layer extracted three times with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 110 mg of 3-{2-fluoro-4-[4-hydroxymethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-4H-[1,2,4]oxadiazol-5-one as a yellowish solid.
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].[C:17]1([C:23]2[CH2:27][CH2:26][CH2:25][C:24]=2[C:28](O)=[O:29])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CO>[C:12]([C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:4]([CH3:14])([CH3:15])[C@@H:3]([OH:16])[C@H:2]([NH:1][C:28]([C:24]3[CH2:25][CH2:26][CH2:27][C:23]=3[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:29])[C:7]=2[CH:8]=1)#[N:13]
Reactant: O=C(O)C1=C(c2ccccc2)CCC1
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Solvent: CO
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC(=O)C2=C(c3ccccc3)CCC2)[C@@H]1O

Procedure:
The title compound was prepared from (3S-trans)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (the title B compound of Example 1) and 2-phenyl-1-cyclopentenecarboxylic acid (the title C compound) by the same method as described for the compound of Example 2 to give a white powder, m.p. 156°-158° C. [α]D =+36.8° (c=0.72, MeOH).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:12]1[C:17]([S:18]([N:21]2[CH2:42][CH2:41][C:24]3([C:28](=[O:29])[N:27]([C:30]4[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=4)[CH2:26][CH2:25]3)[CH2:23][CH2:22]2)(=[O:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:3]([O:10][C:12]1[C:17]([S:18]([N:21]2[CH2:22][CH2:23][C:24]3([C:28](=[O:29])[N:27]([C:30]4[CH:31]=[CH:32][C:33]([O:36][C:37]([F:38])([F:39])[F:40])=[CH:34][CH:35]=4)[CH2:26][CH2:25]3)[CH2:41][CH2:42]2)(=[O:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1cccnc1Cl)CC2
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1cccnc1OCc1ccccc1)CC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a suspension of NaH (12 mg, 0.31 mmol) in DMF (2 mL) at 0° C. was added benzyl alcohol (25 uL, 0.25 mmol) and the mixture was stirred for 30 min at 0° C. A solution of 8-(2-chloro-pyridine-3-sulfonyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 188, 100 mg, 0.20 mmol) in DMF (500 uL) was added drop-wise and the reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo to give the crude residue which was purified by flash column chromatography (1:2 AcOEt/heptane) which afforded the desired product as a colourless solid (100 mg, 87%). MS (ESI): 562.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][C:6]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][C:7]=1[C:8]#[N:9].Cl[C:21]1[CH:31]=[C:25]2[N:26]([CH3:30])[CH2:27][CH2:28][CH2:29][N:24]2[C:23](=[O:32])[N:22]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][C:6]1[CH:13]=[CH:12][C:11]([CH2:14][O:15][C:21]2[CH:31]=[C:25]3[N:26]([CH3:30])[CH2:27][CH2:28][CH2:29][N:24]3[C:23](=[O:32])[N:22]=2)=[CH:10][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1cc(CO)ccc1Oc1ccc(F)c(Cl)c1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCc1ccc(Oc3ccc(F)c(Cl)c3)c(C#N)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from 2-(3-chloro-4-fluorophenoxy)-5-(hydroxymethyl)benzonitrile and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[C:50]([Cl:51])=[C:49]([Cl:52])[CH:48]=[CH:47][C:46]=1[F:53]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[C:46]([F:53])=[CH:47][CH:48]=[C:49]([Cl:52])[C:50]=3[Cl:51])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Fc1ccc(Cl)c(Cl)c1CBr
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3c(F)ccc(Cl)c3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)-3,4-dichloro-1-fluorobenzene and isolated as white solid. MS (m/e): 459.3 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:29]=[C:28]([N+:30]([O-])=O)[CH:27]=[CH:26][C:5]=1[O:6][C:7]1[CH:25]=[CH:24][C:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:9][CH:8]=1)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:29]=[C:28]([NH2:30])[CH:27]=[CH:26][C:5]=1[O:6][C:7]1[CH:25]=[CH:24][C:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:9][CH:8]=1
Reactant: CCCCCCCCCCCCOc1ccc(Oc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCCCCCOc1ccc(Oc2ccc(N)cc2N)cc1
Yield: 85 %

Procedure:
The resultant 1-[4-(2,4-dinitrophenoxy)phenoxy]dodecane (35.58 g, 0.080 mol) and ethanol (700 ml) and 10% Pd/C (1.78 g) were introduced into a 2-liter (l) reaction bottle. After hydrogen passed through the reaction under normal pressure for 4 hours, the reaction mixture was filtered and concentrated to obtain a crude product. The crude product was recrystallized with ethanol to obtain 1-[4-(2,4-diaminophenoxy)phenoxy]dodecane (26.15 g, 0.068 mol). Yield: 85%. Spectrum:IR (KBr) 3412, 3333, 2923, 2850, 1614, 1515, 1462, 1366, 1219, 1084 cm−1. 1H NMR (DMSO-d6, 300 MHz). δ6.8˜6.7 (m, 4H), 6.45 (d, J=8.3, 1H), 6.02 (d, J=2.2 Hz, 1H), 5.79 (dd, J=8.4, J=2.4 Hz, 1H), 4.61 (s, 2H), 4.47 (s, 2H), 3.81 (t, J=6.3 Hz, 2H), 1.75˜1.55 (m, 2H), 1.40˜1.10 (m, 18H), 0.82 (t, J=6.3 Hz, 3H). 13C NMR (DMSO-d6, 75 MHz)δ 153.5, 152.7, 146.1, 140.9, 133.4,121.4, 116.8, 115.3, 103.2, 101.5, 68.0, 31.5, 29.2, 29.0, 28.9, 25.7, 22.3, 14.1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:17](=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:7]([C:12](OCC)=[O:13])[N:8]2[CH3:11])=[CH:4][CH:3]=1.O.[NH2:25][NH2:26]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:26][NH:25][C:12](=[O:13])[C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1
Reactant: NN
Reactant: CCOC(=O)C(=O)c1c(C(=O)OCC)n(C)c2cc(Cl)ccc12
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1n[nH]c(=O)c2c1c1ccc(Cl)cc1n2C

Procedure:
A solution of 4.38 g (13.5 mmol) of ethyl 6-chloro-2-(ethoxycarbonyl)-1-methyl-α-oxo-1H-indole-3-acetate (disclosed in WO-A-00/44751), of 65 ml of glacial acetic acid and of 2.7 ml (55.7 mmol) of hydrazine monohydrate is brought to reflux for 3 h.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(Cl)Cl.[CH3:25][C:26]([CH3:40])([CH2:29][O:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)[CH2:27][OH:28]>C(OCC)C>[CH3:25][C:26]([CH3:40])([CH2:29][O:30][CH2:31][C:32]1[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=1)[CH:27]=[O:28]
Reactant: COc1ccc(COCC(C)(C)CO)cc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc(COCC(C)(C)C=O)cc1

Procedure:
In a dry three-neck flask equipped with a mechanical stirrer and an addition funnel was placed 110 g of pyridinium dichromate and 200 ml of dry CH2Cl2. The mixture was stirred vigorously and then 42 g of 2,2-dimethyl-3-(4-methoxyphenylmethoxy)propanol, the product of Example 5a, was added in one portion. The resulting reaction mixture was stirred for 4 hours. The black brown mixture was poured into 400 ml ethyl ether and the mixture was filtered through a dry silica gel column to obtain a colorless solution. Removal of the solvent gave a residue which was distilled through a vigreux column to obtain the title compound, bp 83°-100°/0.25 mm Hg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]2([CH2:20][C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](/[CH:22]=[CH:23]/[C:24](O)=[O:25])[CH:17]=3)[O:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:41][O:42][CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][O:44]1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][C:10]2([CH2:20][C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](/[CH:22]=[CH:23]/[C:24]([NH:41][O:42][CH:43]4[CH2:48][CH2:47][CH2:46][CH2:45][O:44]4)=[O:25])[CH:17]=3)[O:12]2)[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NOC1CCCCO1
Reactant: CC(C)(C)OC(=O)N1CC2(CC(=O)c3cc(/C=C/C(=O)O)ccc3O2)C1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC2(CC(=O)c3cc(/C=C/C(=O)NOC4CCCCO4)ccc3O2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 72.7 %

Procedure:
TEA (0.25 ml, 1.8 mmol) was added to a suspension of (E)-3-[1′-tert-butoxycarbonyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid (430 mg, 1.20 mmol) in DCM (13 ml) and the reaction mixture was stirred at RT for 5 min. The resulting clear solution was cooled down to 0° C., EDC (344 mg, 1.80 mmol) and HOBt (243 mg, 1.80 mmol) were added and the mixture was stirred at 0° C. for 2 h. NH2OTHP (168 mg, 1.43 mmol) was added and the mixture was stirred at RT overnight. The reaction mixture was washed with 5% aqueous NaHCO3 solution and brine, the organic layer was dried over Na2SO4, filtered and evaporated. The crude residue was purified by column chromatography on silica gel (eluent: DCM/MeOH 98:2) to give (E)-3-[1′-tert-butoxycarbonyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (0.40 g) as a pale yellow solid.
Reaction SMILES: [C:1]([CH2:6][O:7][C:8]1[CH:21]=[CH:20][C:11]([CH2:12][CH:13]2[S:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:10][CH:9]=1)(OCC)=O.[CH3:22][NH:23][C:24](=[O:32])[C:25]1[C:26](=[CH:28][CH:29]=[CH:30][CH:31]=1)[NH2:27].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:22][N:23]1[C:24](=[O:32])[C:25]2[C:26](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:27]=[C:1]1[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][CH:13]2[S:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:20][CH:21]=1
Reactant: CNC(=O)c1ccccc1N
Reactant: CCOC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccccc2c1=O
Temperature: 175 °C

Procedure:
A suspension of 5-[4-[(carboethoxy)methoxy]benzyl]thiazolidine-2,4-dione obtained by following a procedure described in any of Examples 16-22 (100 g, 0.32 M), N-methyl anthranilamide (58.7 g, 0.39 M) and p-toluenesulfonic acid (˜200 mg) was taken in a round bottom flask fitted with a mechanical stirrer, oil bath and Dean-Stark condenser. The reaction mixture was heated to reflux (Internal temperature 150-155° C., oil bath temperature 170-180° C.) for a period of 45-55 h while monitoring the reaction by TLC. After completion of the reaction, the reaction mass was cooled to 80° C. and methanol (700 ml) was added slowly through a dropping funnel. The reaction mass was allowed to attain room temperature while stirring and the solid thus obtained was filtered and washed with methanol (150 ml) and dried at 100-120° C. for 1 h to afford 5-[4-[[3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]methoxy]benzyl]thiazolidine-2,4-dione as a white solid (68 g, Y=53%, P=98%).
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1)#[CH:2].[CH2:12]([C@H:17]1[CH2:22][CH2:21][C@H:20](O)[CH2:19][CH2:18]1)[CH2:13][CH2:14][CH2:15][CH3:16].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:12]([C@H:17]1[CH2:18][CH2:19][C@H:20]([O:10][C:9]([C@H:6]2[CH2:7][CH2:8][C@H:3]([C:1]#[CH:2])[CH2:4][CH2:5]2)=[O:11])[CH2:21][CH2:22]1)[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C#C[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CCCCC[C@H]1CC[C@H](O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C#C[C@H]1CC[C@H](C(=O)O[C@H]2CC[C@H](CCCCC)CC2)CC1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A mixture of 122 mg of trans-4-ethynylcyclohexanecarboxylic acid, 145 mg of trans-4-pentylcyclohexanol, 206 mg of dicyclohexylcarbodiimide and 12.2 mg of 4-(dimethylamino)pyridine in 10 ml of methylene chloride was stirred at room temperature for 21 hours. The separated white precipitate was filtered off, the filtrate was poured into 50 ml of water and extracted three times with 50 ml of methylene chloride each time. The organic phases were washed once with 50 ml of water, twice with 30 ml of 5% aqueous acetic acid each time and twice with 30 ml of water each time, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the residue on silica gel with 5% ethyl acetate/petroleum ether gave 159 mg (65%) of trans-4-ethynylcyclohexanecarboxylic acid trans-4-pentylcyclohexyl ester as a colourless crystallizing oil. Additional crystallization from isopropanol at -20° C. yielded and analytically pure ester; m.p. (C-I) 54.2° C., cl.p. (N-I) 40.5° C.
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(=O)C.[Pt]=O>[C:1]1([NH:7][C:8]([CH:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Nc1ccccc1)c1ccncc1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: O=C(Nc1ccccc1)C1CCNCC1
Yield: 22 %

Procedure:
4-(N-phenylcarbamoyl)pyridine [75.0 g, prepared as in Chem. Abs., 2013h (1958)] was hydrogenated in acetic acid (800 ml) using a platinum oxide catalyst at 50 p.s.i./30°. The catalyst was then removed by filtration, the solution evaporated, the residue basified to about pH 12 with sodium hydroxide, extracted with chloroform, and the organic extract discarded. The aqueous phase was evaporated to dryness, the residue boiled with chloroform, filtered and evaporated to leave 4-(N-phenylcarbamoyl)piperidine (17.0 g), m.p. 121°-127°. The hydrochloride salt, m.p. 231°-233°, was prepared in isopropanol from the free base and hydrogen chloride, and was recrystallised from isopropanol/ethyl acetate.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]2[C:15]([C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])([OH:16])[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-:26].[K+].[K+].OO>CS(C)=O>[CH2:1]([N:8]1[CH2:9][CH:10]2[C:15]([C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]([NH2:21])=[O:26])([OH:16])[CH:13]([CH2:12][CH2:11]2)[CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cccc(C2(O)C3CCC2CN(Cc2ccccc2)C3)c1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1cccc(C2(O)C3CCC2CN(Cc2ccccc2)C3)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 570.8 %

Procedure:
3-(3-Benzyl-8-hydroxy-3-aza-bicyclo[3.2.1]oct-8-yl)-benzonitrile (1.86 g, 5.84 mmol) in DMSO (30 mL) with potassium carbonate (0.121 g, 0.88 mmol) was charged with 30% aqueous hydrogen peroxide (2.98 mL, 29.2 mmol) and allowed to stir at room temperature for 2 h (or until judged complete by TLC). The reaction was cooled in an ice bath then quenched with water (50 mL) causing the product precipitate as white solids. The mixture was acidified to pH 1 with 1N HCl (25 mL) to dissolve the product and the aqueous layer was washed with ether (2×30 mL). The ether extracts were back extracted with water (1×30 mL). The combined acidic aqueous layers were neutralized to pH 8 with saturated aqueous NaHCO3 solution. The product was extracted with EtOAc (3×50 mL), washed with 50% saturated aqueous NaCl solution (3×50 mL) then dried by azeotroping with THF (3×100 mL) yielding a white solid (1.69 g, 86%). 1H NMR (400 MHz, CD3OD) δ 7.96 (t, J=1.5 Hz, 1H), 7.95 (d, J=7.9 Hz, 1H), 7.64 (d, J=7.4 Hz, 1H), 7.41–7.15 (m, 6H), 3.56 (br s, 2H), 2.88 (m, 2H), 2.61 (m, 2H), 2.46 (br, s, 2H), 1.76 (m, 2H), 1.35 (m, 2H); APCI MS m/z 337.2 (M+1)+; mp 210–214° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])[C:5](O)=[O:6].C(Cl)(=O)C([Cl:18])=O>CN(C=O)C.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])[C:5]([Cl:18])=[O:6]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(C(=O)Cl)cc1Cl
Yield: 96.7 %

Procedure:
3-Chloro-4-[(1-methylethyl)oxy]benzoic acid (D3; 4 g, 18. mmol), dichloromethane (DCM) (30 ml), oxalyl chloride (1.88 ml, 21.4 mmol) and DMF (1.4 μl, 0.019 mmol) were stirred under a blanket of nitrogen for 18 h. The solvent was removed in vacuo to give a yellow oil which crystallised on standing. The solid was dissolved in DCM and the solvent was removed in vacuo to give the title compound as a yellow solid (4.2 g).
Reaction SMILES: [OH-].[Li+].[C:3]1([S:9]([CH2:12][C:13]2[C:18]([C:19]([O:21]CC)=[O:20])=[C:17]([O:24][CH3:25])[C:16]([CH2:26][CH2:27][CH3:28])=[CH:15][CH:14]=2)(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O)=O>O1CCOCC1>[C:3]1([S:9]([CH2:12][C:13]2[C:18]([C:19]([OH:21])=[O:20])=[C:17]([O:24][CH3:25])[C:16]([CH2:26][CH2:27][CH3:28])=[CH:15][CH:14]=2)(=[O:11])=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCCc1ccc(CS(=O)(=O)c2ccccc2)c(C(=O)OCC)c1OC
Agent: [Li+]
Agent: [OH-]
Solvent: O=CO
Solvent: C1COCCO1
Product: CCCc1ccc(CS(=O)(=O)c2ccccc2)c(C(=O)O)c1OC
Temperature: 160 °C
Yield: 76.3 %

Procedure:
Lithium hydroxide (1M aqueous solution, 0.45 ml) was added to a solution of ethyl 6-(benzenesulphonylmethyl)-2-methoxy-3-propylbenzoate (Intermediate 24, 0.034 g) in dioxane and the solution was stirred and heated in the microwave at 160° C. for 15 minutes. The cooled solution was acidified by addition of formic acid and then purified by preparative HPLC (C18) eluting with a mixture of methanol and water containing 0.1% formic acid to give 6-(benzenesulphonylmethyl)-2-methoxy-3-propylbenzoic acid (0.024 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][C@@H:17]([CH2:20][NH2:21])[CH2:16]1.[O:22]=[C:23]1[NH:28][C:27]2[N:29]=[C:30]([CH:33]=O)[CH:31]=[CH:32][C:26]=2[S:25][CH2:24]1.[BH4-].[Na+]>C(Cl)Cl.CCO>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][C@@H:17]([CH2:20][NH:21][CH2:33][C:30]2[CH:31]=[CH:32][C:26]3[S:25][CH2:24][C:23](=[O:22])[NH:28][C:27]=3[N:29]=2)[CH2:16]1
Reactant: COc1ccc2nccc(CCN3CC[C@@H](CN)C3)c2n1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc2nccc(CCN3CC[C@@H](CNCc4ccc5c(n4)NC(=O)CS5)C3)c2n1
Reaction time: 24 h
Yield: 69.9 %

Procedure:
To a stirred solution of [((3S)-1-{2-[6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amine (0.22 g, 0.77 mmole) in dry CH2Cl2 (25 mL) and dry EtOH (10 mL) at RT was added 3-oxo-3,4-dihydro-2H-pyrido[1,4]thiazine-6-carboxaldehyde (0.15 g, 0.77 mmole). After 24 h, at RT was added NaBH4 (0.03 g, 0.85 mmole). After 24 h, silica gel (5 g) was added to the reaction solution and the suspension was concentrated under vacuum to a dry solid. Purification on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) afforded the title compound (0.25 g, 70%) as light yellow solid: 1H NMR (400 MHz, CD3OD) δ 8.78 (d, J=4.5 Hz, 1H), 18.29 (d, J=9.1 Hz, 1H), 7.85 (m, 2H), 7.36 (d, J=9.1 Hz, 1H), 7.15 (d, J=5.8 Hz, 1H), 4.38 (s, 2H), 4.19 (s, 3H), 3.91 (m, 2H), 3.82 (m, 4H), 3.67 (s, 2H), 3.31 (m, 2H), 3.18 (m, 1H), 2.55 (m, 2H), 2.10 (m, 2H). LC-MS (ES) m/e 465 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:11][C:5]([CH:6](O)[CH2:7][CH2:8][CH3:9])=[CH:4][CH:3]=1.[OH2:12]>>[CH2:7]([CH:6]1[C:2]([OH:11])([CH3:1])[CH:3]=[CH:4][C:5]1=[O:12])[CH2:8][CH3:9]
Reactant: CCCC(O)c1ccc(C)o1
Reactant: O
Product: CCCC1C(=O)C=CC1(C)O
Yield: 81 %

Procedure:
Into a four necked flask equipped with an agitator and a thermometer, 5-methyl-α-n-propyl-furfuryl alcohol (40 parts) and water (1200 parts) were charged, and the resultant mixture was stirred at a temperature of 95° to 100° C. in a nitrogen stream, during which the pH was maintained at 4.9 to 5.3. After confirming the complete consumption of the starting compound by gas chromatography, the reaction mixture was cooled and extracted with methyl isobutyl ketone. The extract was concentrated to give 2-n-propyl-3-hydroxy-3-methyl-4-cyclopentenone in a yield of 81 %.
Reaction SMILES: Cl[C:2]1([S:8](Cl)(=[O:10])=[O:9])[NH:6][C:5]([Cl:7])=[CH:4][S:3]1.[CH:12]1([NH2:15])[CH2:14][CH2:13]1>C1(C)C=CC=CC=1.C(O)C>[CH:12]1([N:15]([NH:15][CH:12]2[CH2:14][CH2:13]2)[S:8]([C:2]2[S:3][CH:4]=[C:5]([Cl:7])[N:6]=2)(=[O:10])=[O:9])[CH2:14][CH2:13]1
Reactant: O=S(=O)(Cl)C1(Cl)NC(Cl)=CS1
Reactant: NC1CC1
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=S(=O)(c1nc(Cl)cs1)N(NC1CC1)C1CC1

Procedure:
In analogy to Example 13, the N-cyclopropyl-2-N-cyclopropylamino-4-chlorothiazolesulphonamide was prepared by reacting 2,4-dichlorothiazole-sulphonyl chloride from Example 1 with cyclopropylamine. Following chromatography on silica gel using toluene/ethanol (5:1) as the eluent, 15.0 g of product were obtained (51% of the theoretical yield), m.p. 176°-177° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Br[CH2:7][C:8]1[CH:12]=[CH:11][S:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[S:10]1[CH:11]=[CH:12][C:8]([CH2:7][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:9]1
Reactant: c1c[nH]cn1
Reactant: BrCc1ccsc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: c1cn(Cc2ccsc2)cn1

Procedure:
In a 3 neck, round-bottomed flask reflux a mixture of 11.6 g (0.17 mol) imidazole, 30 g (0.17 mol) 3-bromomethylthiophene, 46 g (0.33 mol) K2CO3 and 400 ml dry acetone. After refluxing for 4 hours filter the reaction mixture and wash the inorganic solids with acetone. Remove the acetone under vacuum and partition the residue betwen H2O/EtOAc. Wash the EtOAc layer several times with H2O, dry (Na2SO4) and concentrate the washed material to obtain a pale yellow oil.