Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH2:17])[CH2:10][CH2:9]2)=[CH:6][C:5](=[O:18])[N:4]([CH3:19])[C:3]1=[O:20].[N+:21]([C:24]1[CH:29]=[CH:28][C:27](F)=[CH:26][CH:25]=1)([O-:23])=[O:22]>CS(C)=O>[CH3:1][N:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:27]3[CH:28]=[CH:29][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=3)[CH2:10][CH2:9]2)=[CH:6][C:5](=[O:18])[N:4]([CH3:19])[C:3]1=[O:20]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cn1c(N2CCN(CCCN)CC2)cc(=O)n(C)c1=O
Solvent: CS(C)=O
Product: Cn1c(N2CCN(CCCNc3ccc([N+](=O)[O-])cc3)CC2)cc(=O)n(C)c1=O
Temperature: 80 °C
Yield: 76.9 %

Procedure:
To 20 ml of dimethyl sulfoxide were added 2.50 g of the above obtained compound (compound 59) and 1.90 g of 4-nitrofluorobenzene, and the resulting mixture solution was heated at 80° C. for 3 hours. After cooling, the deposited crystals were collected by filteration, washed, and dried to obtain 2.75 g of 1,3-dimethyl-6-{4-[3-(4-nitroanilino)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione (compound 58').
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O:15][CH2:16][CH2:17][CH3:18])=[C:7]([C:19]([OH:21])=[O:20])[C:6]=1[C:22]([OH:24])=O)[CH2:2][CH3:3].S(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH2:1]([O:4][C:5]1[C:6]2[C:22](=[O:24])[O:20][C:19](=[O:21])[C:7]=2[C:8]([O:15][CH2:16][CH2:17][CH3:18])=[C:9]2[C:14]=1[CH:13]=[CH:12][CH:11]=[CH:10]2)[CH2:2][CH3:3]
Reactant: CCCOc1c(C(=O)O)c(C(=O)O)c(OCCC)c2ccccc12
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CCCOc1c2c(c(OCCC)c3ccccc13)C(=O)OC2=O
Temperature: 65 °C
Yield: 103.7 %

Procedure:
1,4-Bis(propyloxy)-2,3-naphthalenedicarboxylic acid (8.91 g, 26.8 mmol) was suspended in chloroform (80 ml) and thionyl chloride (20.5 ml, 281.4 mmol) was added dropwise whilst monitoring the temperature (no significant change). The reaction was heated at 65° C. for 2.5 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The yellow/brown solid was azeotroped with chloroform (×3) to afford the title compound as a beige solid (8.74 g, 27.8 mmol).
Reaction SMILES: C[O:2][C:3](=[O:36])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][C:13]2[N:14]=[C:15]([NH:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=3[C:29]([CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])=[O:20])[S:16][CH:17]=2)[CH:7]=[N:6][CH:5]=1>[Li+].[OH-]>[CH:31]1([C:29]([C:23]2[CH:24]=[C:25]([CH3:28])[CH:26]=[CH:27][C:22]=2[NH:21][C:19](=[O:20])[NH:18][C:15]2[S:16][CH:17]=[C:13]([CH2:12][CH2:11][O:10][C:8]3[CH:7]=[N:6][CH:5]=[C:4]([CH:9]=3)[C:3]([OH:36])=[O:2])[N:14]=2)=[O:30])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: COC(=O)c1cncc(OCCc2csc(NC(=O)Nc3ccc(C)cc3C(=O)C3CCCC3)n2)c1
Agent: [Li+]
Agent: [OH-]
Product: Cc1ccc(NC(=O)Nc2nc(CCOc3cncc(C(=O)O)c3)cs2)c(C(=O)C2CCCC2)c1
Yield: 93 %

Procedure:
5-(2-{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}ethoxy) nicotinic acid (23 mg, 95%) was prepared from 5-(2-{2-[3-(2-cyclopentanecarbonyl-4-methylphenyl)-ureido]-thiazol-4-yl}ethoxy) nicotinic acid methyl ester (0.025 g, 0.05 mmol) and 2.5M LiOH (20 ul) following the general procedure J.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:15]=[C:16]([S:20]([CH3:28])(=[N:22]C(OCC)=O)=[O:21])[CH:17]=[CH:18][CH:19]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:29][CH2:30][CH3:31].[O-]CC.[Na+].C(=O)(O)[O-].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:15]=[C:16]([S:20]([CH3:28])(=[NH:22])=[O:21])[CH:17]=[CH:18][CH:19]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:29][CH2:30][CH3:31]
Reactant: CCNc1ncnc2cc(OCc3cccc(S(C)(=O)=NC(=O)OCC)c3)c(Br)cc12
Agent: CC[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCNc1ncnc2cc(OCc3cccc(S(C)(=N)=O)c3)c(Br)cc12
Temperature: 60 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
According to GWP 6, (RS)-S-[3-({[6-bromo-4-(ethylamino)quinazolin-7-yl]oxy}methyl)-phenyl]-N-(ethoxycarbonyl)-S-methylsulphoximide (38 mg, 0.075 mmol) is dissolved in ethanol (5 mL), admixed with sodium ethoxide (19 mg, 0.27 mmol) and stirred at 60° C. for 3 hours. The reaction solution is admixed with saturated sodium bicarbonate solution and extracted with ethyl acetate. After drying of the organic phase over sodium sulphate and removal of the solvent, the residue is subsequently stirred up with methanol and the crystals are filtered off with suction to obtain the desired product in 45% yield (33 mg).
Reaction SMILES: [O:1]([C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][CH2:14][OH:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](O)(=[O:22])[CH2:19][CH:20]=[CH2:21]>ClCCl.N1(C2C=CN=CC=2)CCCC1>[O:1]([C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][CH2:14][O:15][C:18](=[O:22])[CH2:19][CH:20]=[CH2:21])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCC(=O)O
Reactant: OCCOc1ccc(Oc2ccccc2)cc1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: C=CCC(=O)OCCOc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.5 %

Procedure:
0.05 g of 4-pyrrolidinopyridine and 17.25 g of 2-(4-phenoxyphenoxy)-ethanol are added at room temperature, with stirring, to a solution of 6.45 g of 3-butenoic acid in 100 ml of dichloromethane. At a temperature of 0° C., 17.0 g (82.5 mmol) of N,N-dicyclohexylcarbodiimide are then added in portions, and the reaction mixture is stirred at room temperature for 3 hours. The reaction mixture is filtered. The precipitate which has been separated off is discarded, and the filtrate is washed with water and dried over sodium sulfate. After concentration by evaporation, the oily residue is purified by column chromatography on silica gel with hexane/ethyl acetate (9:1), yielding 20.0 g of 3-butenoic acid 2-(4-phenoxyphenoxy)-ethyl ester of the formula ##STR12## in the form of a colourless oil having a refractive index of nD23 : 1.5538.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:35])=[C:6]([C:8]2([S:22]([C:25]3[CH:26]=[N:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=3)(=[O:24])=[O:23])[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]([F:21])([F:20])[F:19])(=[O:17])=[O:16])[CH2:10][CH2:9]2)[CH:7]=1.[Cu](C#N)[C:37]#[N:38].CN(C)C=O>N1C=CC=CC=1.C(OCC)(=O)C.O>[C:37]([C:2]1[CH:3]=[CH:4][C:5]([F:35])=[C:6]([C:8]2([S:22]([C:25]3[CH:26]=[N:27][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:29][CH:30]=3)(=[O:24])=[O:23])[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]([F:20])([F:19])[F:21])(=[O:17])=[O:16])[CH2:10][CH2:9]2)[CH:7]=1)#[N:38]
Reactant: O=S(=O)(NC1CCC(c2cc(Br)ccc2F)(S(=O)(=O)c2ccc(C(F)(F)F)nc2)CC1)C(F)(F)F
Reactant: N#C[Cu]C#N
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: N#Cc1ccc(F)c(C2(S(=O)(=O)c3ccc(C(F)(F)F)nc3)CCC(NS(=O)(=O)C(F)(F)F)CC2)c1
Temperature: 180 °C
Yield: 66 %

Procedure:
A solution of the compound prepared in Example 75 (45 mg) was treated with copper cyanide (4 equivalents), pyridine (1 drop) and dimethylformamide (3 ml) and heated at 180° C. overnight. The reaction was diluted with ethyl acetate and water and filtered. The organic layer of the filtrate was washed with water and brine and dried, filtered and evaporated in vacuo. Purification by column chromatography gave the nitrile (27 mg, 66%). M/Z=559 (MH+).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12](=O)[C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][NH:15]2)=[CH:10][CH:9]=1>>[Cl:3][C:12]1[C:11]2[C:16](=[CH:17][C:8]([O:7][CH3:6])=[CH:9][CH:10]=2)[N:15]=[CH:14][C:13]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1c[nH]c2cc(OC)ccc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2cc(OC)ccc2c1Cl
Temperature: 25 °C
Yield: 73 %

Procedure:
Phosphorus oxychloride (88 ml) was added to ethyl 7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (58 g, 235 mmol) and the mixture was heated at reflux for 45 minutes under anhydrous conditions. Upon cooling to ambient temperature, phosphorus oxychloride was evaporated and the solid residue was added in portions to a mixture of ammonia (150 ml) and ice (200 g). External cooling as well as further addition of ammonia to maintain the pH around 8 was needed during this hydrolysis step. The aqueous phase was extracted with dichloromethane and the organic phase was washed with water and brine, dried (MgSO4) and concentrated to about 300 ml. Pentane (400 ml) was added and the precipitate formed collected by filtration. Drying under vacuum gave 4-chloro-3-ethoxycarbonyl-7-methoxyquinoline (45.5 g, 73%).
Reaction SMILES: C[O:2][C:3](=[O:23])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:5]C(C1C(C)=CC=CC=1Cl)=O.O[C:25]1C=C(CC(O)=O)C=CC=1>>[CH3:25][C:21]1[CH:22]=[C:17]([CH:18]=[CH:19][CH:20]=1)[CH2:16][C@@H:4]([C:3]([OH:2])=[O:23])[NH2:5]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)c1c(C)cccc1Cl
Reactant: O=C(O)Cc1cccc(O)c1
Product: Cc1cccc(C[C@H](N)C(=O)O)c1

Procedure:
N-[1-(2-Chloro-6-methylphenyl)carbonyl]-4-[[2-(3-hydroxphenyl))-1-oxoethyl]amino]-3-methyl-L-phenylalanine was prepared using the general procedure described in example 120 from 4-amino-3-methyl-N-[[(2-chloro-6-methylphenyl)carbonyl]-L-phenylalanine methyl ester (79.5 mg) and 2-(3-hydroxyphenyl)acetic acid (30 mg 0.2 mmol) to give 23 mg of a colorless glass. HR MS (C26H25N2O5Cl): Obs. Mass 481.1527. Calcd. Mass 481.1530 (M+H).
Reaction SMILES: [CH2:1]([OH:6])/[CH:2]=[CH:3]\[CH2:4][CH3:5].CN(C)C.[CH3:11][S:12](Cl)(=[O:14])=[O:13]>CCOCC>[S:12]([O:6][CH2:1]/[CH:2]=[CH:3]\[CH2:4][CH3:5])([CH3:11])(=[O:14])=[O:13]
Reactant: CC/C=C\CO
Reactant: CS(=O)(=O)Cl
Agent: CN(C)C
Solvent: CCOCC
Product: CC/C=C\COS(C)(=O)=O
Yield: 83.3 %

Procedure:
Z-2-Penten-1-ol (5.0 g, 58.1 mmol), trimethylamine (6.45 g, 63.9 mmol), methanesulfonylchloride (7.0 g, 61.1 mmol) and ether (30 ml) were allowed to react at ambient temperature for 1 hour. After the completion of the reaction, the insoluble matter was removed and washed with water. The washed substance was dried over sodium sulfate. The solvent was distilled off to obtain 7.95 g of Z-1-mesyloxy-2-pentene as pale yellow oily material (83.4%). This material was added to a mixture of 3,8-dimethyl-5-hydroxycarbostyril (7.0 g, 37.0 mmol), potassium carbonate (10.2 g, 74.0 mmol) and dimethylformamide (210 ml), and allowed to react at 70° C. for 1 hour. The reaction mixture was condensed under reduced pressure, and the residue was poured into water to obtain 7.36 g of the title compound as a brown solid (77.3%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:19][CH2:18]1.[F:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]([O:45][CH3:46])[C:31]=1[OH:47]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[N:17]2[CH2:22][CH2:21][CH:20]([CH2:23][N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[CH2:19][CH2:18]2)=[CH:3][C:2]([C:34]2[CH:33]=[C:32]([O:45][CH3:46])[C:31]([OH:47])=[C:30]([F:29])[CH:35]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: O=C(c1cnc2ccc(Br)cc2c1N1CCC(CN2CCCC2)CC1)C1CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(F)c1O
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(N4CCC(CN5CCCC5)CC4)c3c2)cc(F)c1O
Yield: 51.8 %

Procedure:
Following general procedure D, {6-bromo-4-[4-(pyrrolidin-1-ylmethyl)piperidin-1-yl]quinolin-3-yl}(cyclopropyl)methanone (26 mg, 0.059 mmol) was reacted with 2-fluoro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (32 mg, 0.118 mmol) to afford the desired product (15.4 mg, 52%) as a gray solid: 1H NMR (500 MHz, CD3OD) δ 8.78 (s, 1H), 8.27 (s, 1H), 8.03 (s, 2H), 7.23-7.04 (m, 2H), 3.99 (s, 3H), 3.54 (d, J=12.8 Hz, 2H), 3.28-3.11 (m, 6H), 3.05 (d, J=6.6 Hz, 2H), 2.63-2.51 (m, 1H), 2.20-1.89 (m, 7H), 1.80-1.58 (m, 2H), 1.41-1.16 (m, 4H).
Reaction SMILES: COC1C=C2C(C(NCC3N4N=[C:21]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH:22]=[N:23][C:18]4=NN=3)=CC=N2)=NC=1.CN1C[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:40]3[CH:41]=[CH:42][C:43]4[N:44]([C:46]([CH2:49]NC(=O)OC(C)(C)C)=[N:47][N:48]=4)[N:45]=3)[CH:37]=2)C1=O.[ClH:59]>>[ClH:59].[C:36]1([C:40]2[CH:41]=[CH:42][C:43]3[N:44]([C:46]([CH2:49][C:26]4[CH:25]=[C:24]5[C:29](=[CH:28][CH:27]=4)[CH:18]=[N:23][CH:22]=[CH:21]5)=[N:47][N:48]=3)[N:45]=2)[CH:35]=[CH:34][CH:33]=[CH:38][CH:37]=1
Reactant: CN1Cc2cc(-c3ccc4nnc(CNC(=O)OC(C)(C)C)n4n3)ccc2C1=O
Reactant: COc1cnc2c(NCc3nnc4ncc(-c5ccccc5)nn34)ccnc2c1
Agent: Cl
Product: c1ccc(-c2ccc3nnc(Cc4ccc5cnccc5c4)n3n2)cc1
Reaction time: 0.25 h

Procedure:
A 10 mL, CEM microwave vessel was charged with 3 (0.1040 g, 0.427 mmol), 1-(5-phenylpyridin-2-yl)hydrazine (4, 0.119 g, 0.641 mmol), a stirbar and 1 mL concentrated HCl. The vessel was sealed, and fitted with an 18-gauge needle and an Argon inlet. The slurry was placed in a heating block at 115° C. for 15 minutes with stirring. A volatile substance evolved during this time. The vessel was briefly cooled, and the seal was replaced. The vessel was irradiated on a CEM Explorer using the following parameters: ramp time 20 s, hold time 10 min, hold temperature 150° C., powermax=on, 75 W max. The resultant turbid aqueous solution was filtered and concentrated in vacuo. The solids were suspended in 3 mL hot EtOH, and cooled. The precipitate was isolated by filtration and washed with EtOH (3×3 mL). The solids were taken up in 2 mL H2O, and filtered through a 0.1 μm PVDF Ultra-free-CL centrifugal filter (Millipore Corp, PN UFC40W00, 2000 g for 5 minutes). The aqueous filtrate was lyophilized to afford 6-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)isoquinoline hydrochloride. Anal. Calcd for C21H15N5.HCl.1.7 H2O: C, 62.36; H, 4.83; N, 17.31. Found: C, 62.39±0.08; H, 4.48±0.02; N, 17.28±0.03.
Reaction SMILES: CS(C1C=CC([C:11]2[CH:16]=[CH:15][C:14]([C:17](=[C:25]3[CH2:30][C:29]([CH3:32])([CH3:31])[CH2:28][C:27]([CH3:34])([CH3:33])[CH2:26]3)[C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)=CC=1)(=O)=O.BrC1C=CC(C(=C2CC(C)(C)CC(C)(C)C2)C2C=CC(O)=CC=2)=CC=1.[CH3:60][C:61]1[C:65](B(O)O)=[C:64]([CH3:69])[O:63][N:62]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C1COCC1>[CH3:60][C:61]1[C:65]([C:11]2[CH:16]=[CH:15][C:14]([C:17](=[C:25]3[CH2:26][C:27]([CH3:33])([CH3:34])[CH2:28][C:29]([CH3:31])([CH3:32])[CH2:30]3)[C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)=[C:64]([CH3:69])[O:63][N:62]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)CC(C)(C)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(Br)cc2)CC(C)(C)C1
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1noc(C)c1-c1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Yield: 83 %

Procedure:
The Suzuki protocol described for (163) was employed. A round bottom flash was charged with 4-[(4-bromophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (14) (0.200 g, 0.5 mmol), PdCl2(PPh3)2 (0.035 g, 0.05 mmol), (3,5-dimethyl-4-isoxazolyl)boronic acid (0.141 g, 1.0 mmol), aqueous 2 M Na2CO3 (1.0 mL, 0.106 g, 1.0 mmol) solution, and 4:1 THF:H2O mixture (5 mL) under a nitrogen atmosphere. The reaction mixture was refluxed for 3 h. Regular work-up and purification gave 0.172 g (83%) of the title compound (235) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.30 (s, 1H), 7.29 (d, J=8.0 Hz, 2H), 7.21 (d, J=8.4 Hz, 2H), 6.94 (d, J=8.4 Hz, 2H), 6.67 (d, J=8.4 Hz, 2H), 2.38 (s, 3H), 2.20 (s, 2H), 1.91 (br s, 4H), 1.25 (s, 2H), 0.892 (s, 6H), 0.88 (s, 6H). LCMS (APCI): m/z 416.10 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[S:12]([NH:15][CH3:16])(=[O:14])=[O:13])=[N+]=[N-].[ClH:17]>C(O)C.[Pd]>[ClH:17].[NH2:1][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[S:12]([NH:15][CH3:16])(=[O:13])=[O:14]
Reactant: CNS(=O)(=O)c1cc(F)ccc1CN=[N+]=[N-]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CNS(=O)(=O)c1cc(F)ccc1CN
Reaction time: 14 h
Yield: 100 %

Procedure:
To a solution of intermediate 51, 2-azidomethyl-5-fluoro-N-methyl-benzenesulfonamide, (560 mg, 2.3 mmol) in ethanol (10 mL) was added 6N HCl (1 mL) and 10% Pd—C (100 mg) and the mixture hydrogenated with 1 atm of H2 for 14 hrs. The catalyst was removed by filtration through Celite and the filtrate concentrated in vacuo to provide 630 mg (Yield >100%) of the title compound. 1H NMR (500 MHz, DMSO-D6) δ ppm: 4.36 (2 H, d, J=5.2 Hz) 7.63-7.70 (2 H, m) 7.77-7.83 (1 H, m) 8.11 (1 H, d, J=4.9 Hz) 8.41 (3 H, s); LC/MS m/z 219 (M+H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][C:11]1[CH:12]=[C:13]([C@@:18]2([O:28][C@H:27]([CH2:29][OH:30])[C@@H:25]([OH:26])[C@H:23]([OH:24])[C@H:21]2[OH:22])[O:19][CH3:20])[CH:14]=[CH:15][C:16]=1[F:17].C(O[C:35](=[O:37])[CH3:36])(=O)C.Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:18]([O:22][C@@H:21]1[C@@H:23]([O:24][C:21](=[O:22])[CH3:23])[C@H:25]([O:26][C:25](=[O:26])[CH3:27])[C@@H:27]([CH2:29][O:30][C:35](=[O:37])[CH3:36])[O:28][C@:18]1([C:13]1[CH:14]=[CH:15][C:16]([F:17])=[C:11]([CH2:10][C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)[CH:12]=1)[O:19][CH3:20])(=[O:19])[CH3:13]
Reactant: CO[C@@]1(c2ccc(F)c(Cc3cc4ccccc4s3)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CO[C@@]1(c2ccc(F)c(Cc3cc4ccccc4s3)c2)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To the above-obtained toluene solution of methyl 1-C-[3-(1-benzothien-2-ylmethyl)-4-fluorophenyl]-α-glucopyranoside were added pyridine (7.39 g) and 4-dimethylaminopyridine (19 mg). Thereto was added acetic anhydride (7.94 g) at 1.7 to 3.3° C., followed by stirring at room temperature for 12 hours. To the reaction mixture was added hydrochloric acid (2 M, 50 ml), followed by extraction. The organic layer was washed with a 5% aqueous sodium hydrogencarbonate solution (75 ml) and successively with an aqueous sodium chloride solution (25%, 50 ml), and subjected to vacuum distillation to distil off the solvent until the residue became 15 ml, to obtain, as a toluene solution, methyl 2,3,4,6-tetra-O-acetyl-1-C-[3-(1-benzothien-2-ylmethyl)-4-fluorophenyl]-α-glucopyranoside.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:10](=O)[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1)=[O:4].[NH:19]1[CH2:22][CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH3:1][O:2][C:3]([CH:5]1[CH:10]([N:19]2[CH2:22][CH2:21][CH2:20]2)[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1)=[O:4]
Reactant: C1CNC1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1N1CCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.9 %

Procedure:
To a solution of 4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (100 mg, 0.389 mmol) in DCE (11 mL) was added azetidine (33 mg, 0.578 mmol). The mixture was stirred at RT for 10 min, then sodium triacetoxyborohydride (132 mg, 0.623 mmol) was added and stirring was continued for 2 h. Water was added to the reaction mixture before being loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH then eluted with 2 M NH3 in MeOH to give the title compound as a colourless oil (102 mg, 88%).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([CH2:24][CH2:25][CH3:26])=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:17]=2)=[O:12])=[CH:4][C:3]=1[CH3:27].[CH2:28]([CH:30]1[O:32][CH2:31]1)Cl>CC(O)C.[OH-].[Na+].O>[CH3:27][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([CH2:24][CH2:25][CH3:26])=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:17]=2)=[O:12])[CH:6]=[C:7]([CH3:8])[C:2]=1[O:1][CH2:28][CH:30]1[CH2:31][O:32]1
Reactant: CCCc1sc(C(=O)CCc2cc(C)c(O)c(C)c2)cc1-c1ccccc1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCCc1sc(C(=O)CCc2cc(C)c(OCC3CO3)c(C)c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.5 %

Procedure:
A solution of 3-(4-hydroxy-3,5-dimethyl-phenyl)-1-(4-phenyl-5-propyl-thiophen-2-yl)-propan-1-one (250 mg, 0.661 mmol) in 2-propanol (2 mL) and 3 N aq. NaOH (1 mL) is treated with epichlorohydrine (122 mg, 1.32 mmol) and the mixture is stirred at rt for 18 h, then diluted with water and extracted with EA. The solvent of the organic extract is evaporated to give crude 3-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-1-(4-phenyl-5-propyl-thiophen-2-yl)-propan-1-one (257 mg) as a yellow oil; LC-MS: tR=1.18 min, [M+1]+=435.20.
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O>>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: COc1ccccc1B(O)O
Reactant: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(Br)s1
Product: COc1ccccc1-c1ccc(S(=O)(=O)Nc2cccc(-c3nnn[nH]3)c2)s1
Yield: 27.6 %

Procedure:
The product was prepared according to General Procedure 3, described in Example 22, starting from 5-bromo-N-[3-(1H-tetrazol-5-yl)phenyl]thiophene-2-sulfonamide (Intermediate 17) (19 mg, 0.05 mmol) and 2-methoxyphenylboronic acid (9 mg, 0.06 mmol) giving 5.7 mg (28%) of the title compound. MS (ESI+) calcd for C18H15N5O3S2 413.061631, found 413.062971.
Reaction SMILES: FC(F)(F)C1C=C(C=C(C(F)(F)F)C=1)N.N[C:17]1[CH:18]=[C:19]([CH:31]=[CH:32][C:33]=1OC)[C:20]([NH:22]C1C=CC(F)=C(F)C=1)=[O:21]>>[C:20]([NH2:22])(=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[CH:17][CH:18]=1
Reactant: COc1ccc(C(=O)Nc2ccc(F)c(F)c2)cc1N
Agent: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: NC(=O)c1ccccc1
Yield: 11.5 %

Procedure:
The title compound was synthesized as in Example 1 using 3,5-bis(trifluoromethyl)aniline (1.3 mL, 8.2 mmol), CSI (0.85 mL, 9.8 mmol), and 3-amino-N-(3,4-difluorophenyl)-4-methoxy-benzamide (0.63 g, 2.3 mmol) to give 0.032 g of benzamide, 3-[[[[[[3,5-bis(trifluoromethyl)phenyl]amino]-carbonyl]amino]sulfonyl]amino]-N-(3,4-difluorophenyl)-4-methoxy-. Microanalysis: C23H16F8N4O5S.1.63 H2O; calculated: C=43.04; H=3.02; N=8.73. found: C=43.05; H=2.68; N=8.55. MS: M+−1=611 Da. Mp 175-178° C.
Reaction SMILES: Cl.C(C1C=CC(C(N)=N)=CC=1)CCCC.C(OC(=O)C(=COCC)C#N)C.CC[O-].[Na+].[OH-].[Na+].[C:34]([C:36]1[C:37](O)=[N:38][C:39]([C:42]2[CH:47]=[CH:46][C:45]([CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[CH:44][CH:43]=2)=[N:40][CH:41]=1)#[N:35].P(Cl)(Cl)([Cl:56])=O>C(O)C>[Cl:56][C:37]1[C:36]([C:34]#[N:35])=[CH:41][N:40]=[C:39]([C:42]2[CH:47]=[CH:46][C:45]([CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[CH:44][CH:43]=2)[N:38]=1
Reactant: CCCCCc1ccc(-c2ncc(C#N)c(O)n2)cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: CCCCCc1ccc(C(=N)N)cc1
Agent: CCOC=C(C#N)C(=O)OCC
Agent: CC[O-]
Solvent: CCO
Product: CCCCCc1ccc(-c2ncc(C#N)c(Cl)n2)cc1

Procedure:
The starting material can be obtained according to the procedure of A. R. Todd and F. Bergel, J. Chem. Soc. 1937, 365 by reaction of p-n-pentylbenzamidine hydrochloride with α-ethoxymethylene-α-cyanoacetic acid ethyl ester and sodium ethylate in ethanol and then with sodium hydroxide solution. The resulting 5-cyano-4-hydroxy-2-(4-n-pentylphenyl)-pyrimidine (melting point 199°-205° C) is treated with phosphorus oxychloride to give 4-chloro-5-cyano-2-(4-n-pentylphenyl)-pyrimidine having a melting point of 96.0°-96.3° C.