Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:13](=[O:16])[CH:14]=[CH2:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[O:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[O:30][CH2:31][C:32]1[S:36][C:35]([CH:37]=[O:38])=[N:34][CH:33]=1.C(N(CC)CC)C>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:13](=[O:16])[CH2:14][CH2:15][C:37]([C:35]2[S:36][C:32]([CH2:31][O:30][CH:25]3[CH2:26][CH2:27][CH2:28][CH2:29][O:24]3)=[CH:33][N:34]=2)=[O:38])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Reactant: O=Cc1ncc(COC2CCCCO2)s1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2ncc(COC3CCCCO3)s2)cc1Cl
Temperature: 25 °C
Yield: 42.5 %

Procedure:
To a solution of 4-[3-chloro-4-(methylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (526 mg) in ethanol (6 mL) were added 5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3-thiazole-2-carbaldehyde (402 mg), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (43.7 mg) and triethylamine (88 μL), and the mixture was stirred with heating under reflux for 1 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (366 mg, yield 43%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (9:1, volume ratio).
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[CH:20]=[C:19]([CH2:21][N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[CH:18]=[CH:17][C:16]=3[CH3:28])=[CH:12][CH:13]=2)[N:8]([CH3:29])[S:7]1(=[O:31])=[O:30].CCN(C(C)C)C(C)C.[C:42](O)(=[O:46])[C@@H:43]([CH3:45])[OH:44].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1.CCOC(C)=O>[F:32][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[CH:20]=[C:19]([CH:18]=[CH:17][C:16]=3[CH3:28])[CH2:21][N:22]3[CH2:27][CH2:26][N:25]([C:42](=[O:46])[C@H:43]([OH:44])[CH3:45])[CH2:24][CH2:23]3)=[CH:12][CH:13]=2)[N:8]([CH3:29])[S:7]1(=[O:31])=[O:30]
Reactant: Cc1ccc(CN2CCNCC2)cc1-c1ccc2c(n1)N(C)S(=O)(=O)N2CC1CC1(F)F
Reactant: C[C@@H](O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1ccc(CN2CCN(C(=O)[C@@H](C)O)CC2)cc1-c1ccc2c(n1)N(C)S(=O)(=O)N2CC1CC1(F)F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-5-[2-methyl-5-(piperazin-1-ylmethyl)phenyl]-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridine 2,2-dioxide (43-2) (2.3 g, 5.0 mmol, 1.0 eq) was dissolved in NMP (25 mL) and DIPEA (2.6 mL, 14.9 mmol, 3.0 eq), D-lactic acid (536 mg, 6.0 mmol, 1.2 eq) and HATU (2.8 g, 7.4 mmol, 1.5 eq) were added. The reaction mixture stirred at ambient temperature for 5 minutes and was then diluted with EtOAc (200 mL), washed with sodium bicarbonate (4×30 mL) and brine (30 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified by flash chromatography (120 g SiO2, 0-40% IPA in DCM) to afford (2R)-1-[4-(3-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridin-5-yl}-4-methylbenzyl)piperazin-1-yl]-2-hydroxypropan-1-one (43-3) as a white solid. 1H NMR (400 MHz, CD3OD): δ 7.37 (d, J=8.4 Hz, 1 H); 7.35 (s, 1 H); 7.26 (s, 2 H); 7.08 (d, J=8.4 Hz, 1 H); 4.54 (q, J=6.8 Hz, 1 H); 3.98 (d, J=6.8 Hz, 2 H); 3.64 (m, 4 H); 3.57 (s, 2 H); 3.38 (s, 3 H); 2.49 (m, 4 H); 2.36 (s, 3 H); 2.21 (m, 1 H); 1.67 (m, 1 H); 1.43 (m, 1 H); 1.18 (d, J=6.8 Hz, 3 H). HRMS m/z (M+H) 536.2136 found, 536.2138 required.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:36])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]([O:22]CC)=[O:21])[N:19]=[C:15]3[CH:14]=[C:13]([CH3:25])[C:12]=2[C@H:26]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:27]([O:29][CH3:30])=[O:28])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[OH-].[Na+]>CO>[CH2:1]([O:4][C:5]1([CH3:36])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]([OH:22])=[O:21])[N:19]=[C:15]3[CH:14]=[C:13]([CH3:25])[C:12]=2[C@H:26]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:27]([O:29][CH3:30])=[O:28])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(C(=O)OCC)cn23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(C(=O)O)cn23)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
(S)-Ethyl 5-(4-(allyloxy)-4-methylpiperidin-1-yl)-6-(1-(tert-butoxy)-2-methoxy-2-oxoethyl)-7-methylimidazo[1,2-a]pyridine-2-carboxylate (450 mg, 0.923 mmol, 1 equiv) was dissolved in MeOH (9 mL). To this solution was added 1 N NaOH (1.02 mL, 1.015 mmol, 1.1 equiv). The reaction was stirred at 60° C. for 2 h. Upon cooling to ambient temperature, the reaction was concentrated in vacuo. The residue was then azeotroped with toluene to give a pale brown solid (S)-5-(4-(allyloxy)-4-methylpiperidin-1-yl)-6-(1-(tert-butoxy)-2-methoxy-2-oxoethyl)-7-methylimidazo[1,2-a]pyridine-2-carboxylic acid (400 mg, 92% yield) which was used as is for further reactions. LCMS (ESI, M+1): 474.35.
Reaction SMILES: FC1C=CC(NC(=O)NC2C=CC(C3C=C4C(CN([C@@H](C(C)C)C(O)=O)C4=O)=CC=3)=CC=2)=CC=1.[CH3:35][CH:36]([CH3:69])[C@H:37]([N:42]1[CH2:50][C:49]2[C:44](=[CH:45][C:46]([C:51]3[CH:56]=[CH:55][C:54]([NH:57][C:58]([NH:60][C:61]4[CH:62]=[C:63]([CH3:67])[CH:64]=[CH:65][CH:66]=4)=[O:59])=[CH:53][CH:52]=3)=[CH:47][CH:48]=2)[C:43]1=[O:68])[C:38]([O:40]C)=[O:39]>>[CH3:35][CH:36]([CH3:69])[C@H:37]([N:42]1[CH2:50][C:49]2[C:44](=[CH:45][C:46]([C:51]3[CH:52]=[CH:53][C:54]([NH:57][C:58]([NH:60][C:61]4[CH:62]=[C:63]([CH3:67])[CH:64]=[CH:65][CH:66]=4)=[O:59])=[CH:55][CH:56]=3)=[CH:47][CH:48]=2)[C:43]1=[O:68])[C:38]([OH:40])=[O:39]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4cccc(C)c4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)cc2C1=O
Product: Cc1cccc(NC(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)O)C(C)C)C4)cc2)c1
Yield: 85 %

Procedure:
The compound of example 22 was prepared analogous to compound of example 8 by hydrolysis of compound of example 21.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[N:26]1([S:32]([C:35]2[CH:36]=[C:37]([NH2:41])[CH:38]=[CH:39][CH:40]=2)(=[O:34])=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.N1N2C=CC=NC2=C(C(O)=O)C=1.C(Cl)(=O)C(Cl)=O.NC1C=CC=CC=1>C1COCC1.CN(C=O)C.CN(C)C1C=CN=CC=1>[N:26]1([S:32]([C:35]2[CH:36]=[C:37]([NH:41][C:12]([C:11]3[CH:10]=[N:9][N:8]4[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]5[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=5)=[N:6][C:7]=34)=[O:14])[CH:38]=[CH:39][CH:40]=2)(=[O:34])=[O:33])[CH2:27][CH2:28][O:29][CH2:30][CH2:31]1
Reactant: Nc1cccc(S(=O)(=O)N2CCOCC2)c1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)c1cnn2cccnc12
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: Nc1ccccc1
Product: O=C(Nc1cccc(S(=O)(=O)N2CCOCC2)c1)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-(morpholine-4-sulfonyl)-phenylamine [CAS 22184-97-0; commercially available] according to general procedure II as follows: to a stirred solution of a pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (1.0 mmol) in THF (4 ml) was added at room temperature DMF (2 drops), the solution was cooled to 0° C. and oxalylchloride (1.5 mmol) was added. The reaction mixture was stirred at room temperature for 3 h and evaporated to dryness. The precipitate was dissolved in pyridine (6 ml) and, while stirring at room temperature, 4-dimethylaminopyridine (1 mmol) and an aniline derivative (1 mmol) was added. The reaction mixture was allowed to stir at room temperature for 16 h, evaporated to dryness and the crude product purified by flash chromatography on silica gel (20 g, dichloromethane/methanol) to yield the product as a light yellow solid, which was further purified by crystallization from methanol/hexane. MS (ISP) 580.1 [(M−H)−]; mp 221° C.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]3[C:24]4[C:23]([O:25][CH2:26][CH3:27])=[N:22][CH:21]=[N:20][C:19]=4[NH:18][CH:17]=3)=[C:11]([F:28])[N:10]=2)=[CH:4][CH:3]=1.C([Li])(C)(C)C.O>O1CCCC1>[CH2:26]([O:25][C:23]1[C:24]2[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([NH:8][C:5]4[CH:6]=[N:7][CH:2]=[CH:3][CH:4]=4)=[N:10][C:11]=3[F:28])=[CH:17][NH:18][C:19]=2[N:20]=[CH:21][N:22]=1)[CH3:27]
Reactant: CCOc1ncnc2[nH]cc(Cc3ccc(Nc4ccc(Br)nc4)nc3F)c12
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ncnc2[nH]cc(Cc3ccc(Nc4cccnc4)nc3F)c12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
To (6-bromo-pyridin-3-yl)-[5-(4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-amine (P-4020, 0.040 g, 0.090 mmol) in 5.0 mL of tetrahydrofuran under nitrogen at −78° C., tert-butyllithium (0.531 mL, 1.70 M in hexane, 0.903 mmol) is added. The reaction is stirred at −78° C. for 30 minutes, then poured into water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified with silica gel column chromatography, eluting with 20-100% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (P-4021, 25.7 mg). MS (ESI) [M+H+]+=364.9.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][C@@H:6]([CH3:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH2:4][C@@H:3]1[CH3:18]>CCO.[Pd]>[CH3:8][C@H:6]1[CH2:7][N:2]([CH3:1])[C@H:3]([CH3:18])[CH2:4][N:5]1[C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=1
Reactant: C[C@@H]1CN(C)[C@@H](C)CN1c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: C[C@@H]1CN(c2ccc(N)cc2)[C@@H](C)CN1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.7 %

Procedure:
To a 250-mL round bottom flasked is added 10% Pd/C (150 mg). The flask is sealed with a septum, and flushed with a slow stream of N2. racemic-trans-[1,2,5-Trimethyl-4-(4-nitrophenyl)piperazine] (1.28 g, 5.13 mmol) is dissolved in EtOH (30 mL) and transferred via syringe into the flask. The flask is again flushed with N2 and then fitted with a balloon of hydrogen. An outlet needle is inserted through the septum and the flask is flushed with hydrogen before the outlet needle is removed. The resulting slurry is stirred vigorously under the H2 atmosphere at rt. After 24 h the yellow color of the solution dissipates and the hydrogen balloon is removed. The flask is flushed with nitrogen, DCM (24 mL) is added to the reaction mixture, and the resulting slurry is stirred at rt for 24 h. The reaction is filtered through a filtration tube packed with a short column of Celite, the Celite is washed with DCM (2×25 mL), and the combined filtrate evaporated to dryness on a rotary evaporator to provide crude racemic 4-(trans-2,4,5-trimethyl-piperazin-1-yl)-phenylamine (1.11 g, 98% recovery, 97% purity as determined by LC/MS analysis @ UV 254 nm detection). The crude product is used in the next step without further purification. LCMS-ESI (m/z): calcd for C13H21N3, 219; [M+H]+ found, 220.
Reaction SMILES: [O:1]1[CH2:18][CH:2]1[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:9][C:6]=1[C:7]#[N:8].[CH3:19][O:20][C:21]1[CH:30]=[CH:29][C:24]([O:25][CH2:26][CH2:27][NH2:28])=[CH:23][CH:22]=1>C(O)C>[OH:1][CH:2]([CH2:18][NH:28][CH2:27][CH2:26][O:25][C:24]1[CH:29]=[CH:30][C:21]([O:20][CH3:19])=[CH:22][CH:23]=1)[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: COCCOc1ccc(OCC2CO2)c(C#N)c1
Reactant: COc1ccc(OCCN)cc1
Solvent: CCO
Product: COCCOc1ccc(OCC(O)CNCCOc2ccc(OC)cc2)c(C#N)c1
Reaction time: 1 h

Procedure:
2.4 g of 2-(2,3-epoxypropoxy)-5-(2-methoxyethoxy)-benzonitrile and 8.35 g of 2-(4-methoxyphenoxy)ethylamine are dissolved in 30 ml of ethanol, the solvent is then evaporated and the resulting mixture stirred for 1 hour at 70°. The reaction melt is then dissolved in ether and allowed to crystallize under cooling. Purification is effected by recrystallization in benzene. The title compound is obtained (M.P. 95°-97°).
Reaction SMILES: [CH:1]1([C@H:6]([N:11]=[C:12]=[O:13])[C:7]([O:9][CH3:10])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:14]([C@@H:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[OH:24])[CH2:15][CH2:16][CH:17]=[CH2:18]>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C.CCOC(C)=O.Cl>[CH:1]1([C@H:6]([NH:11][C:12]([O:24][C@@H:20]2[CH2:21][CH2:22][CH2:23][C@H:19]2[CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18])=[O:13])[C:7]([O:9][CH3:10])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C=CCCC[C@@H]1CCC[C@H]1O
Reactant: COC(=O)[C@@H](N=C=O)C1CCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCCC[C@@H]1CCC[C@H]1OC(=O)N[C@H](C(=O)OC)C1CCCC1
Temperature: 85 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
A solution of methyl (2S)-cyclopentyl(isocyanato)acetate (1.57 g, 8.56 mmol) and (1R,2R)-2-pent-4-en-1-ylcyclopentanol (Intermediate A9) (1.20 g, 7.78 mmol) in PhMe (56 mL) was treated portionwise with DMAP (0.95 g, 7.78 mmol). The resulting mixture was stirred for 5 hours at 85° C., then cooled to 20° C., and diluted with EtOAc and HCl(aq.) (1N). The organic layer was separated, washed with brine, and dried over Na2SO4. Filtration and removal of the volatiles gave a residue that was purified by column chromatography (gradient elution, 4-40% Et2O/petroleum ether) to afford the title compound (1.97 g, 76%) as an oil. LCMS (ES+) m/z, 338 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]2([CH2:14][NH:13][CH2:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[CH3:17][C:18](OC(C)=O)=[O:19]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]2([CH2:12][N:13]([C:18](=[O:19])[CH3:17])[CH2:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CC2(CNC2)C1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(=O)N1CC2(C1)CN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of 2,6-diaza-spiro[3.3]heptane-2-carboxylic acid tert-butyl ester (130) (purchased from WUXI APPTEC®) ((500 mg, 2.73 mmol) in CH2Cl2 (10 mL) were added KOH (459 mg, 8.19 mmol) and Ac2O (279 mg, 2.73 mmol). The reaction mixture was stirred at RT for 1 h, then diluted with CH2Cl2 (20 mL), washed with H2O (20 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, and filtered, evaporated to give the product (131) (510 mg, 2.13 mmol, yield: 78%). ESI-MS (M+1): 241 calc. for C12H20N2O3 240.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[OH:7][CH:8]([C:11]1[N:12]=[C:13]([NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:18])[S:14][CH:15]=1)CO.CO>O>[C:20]1([NH:19][C:17](=[O:18])[NH:16][C:13]2[S:14][CH:15]=[C:11]([CH:8]=[O:7])[N:12]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Nc1ccccc1)Nc1nc(C(O)CO)cs1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CO
Product: O=Cc1csc(NC(=O)Nc2ccccc2)n1
Reaction time: 2 h

Procedure:
A solution of 0.76 g of sodium metaperiodate in 15 ml of water was added dropwise at room temperature to a mixture comprising 0.5 g of 4-(1,2-dihydroxyethyl)-2-(3-phenylureido)thiazole and 15 ml of methanol, and the mixture was stirred for 2 hours after completion of the dropwise addition. The solvent was then evaporated off under reduced pressure and the residue was washed with water, giving the desired compound as a white powder.
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:28])[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>CN(C)C=O>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH:15]([S:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: COC(=O)c1ccc(S)cc1
Reactant: Clc1ccccc1C(Cl)Cn1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SC(Cn2ccnc2)c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
6.4 g of methyl 4-mercaptobenzoate were dissolved in 45 ml of dry dimethylformamide, and 1.7 g of a 55% w/w suspension of sodium hydride in mineral oil was added to the resulting solution, whilst ice-cooling. The resulting mixture was then stirred at room temperature for 30 minutes, after which a solution of 9.2 g of 1-[2-chloro-2-(2-chlorophenyl)ethyl]imidazole in 45 ml of dry dimethylformamide was added to the resulting solution, and the reaction mixture was heated at 50° C. for 6.5 hours. At the end of this time, the resulting solution was treated and purified in a similar manner to that described in Example 1, to give 8.08 g of the title compound as an oil.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:22][S-:23].[Na+]>C(OCC)(=O)C>[CH3:22][S:23][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccc(N(C)c2nc(SC)nc3ccccc23)cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 7.1 %

Procedure:
A mixture of (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (150 mg, 0.5 mmol), sodium methanethiolate (105 mg, 1.5 mmol) in 5 mL of solvent (THF:MeOH:water=3:1:1) was stirred at 70° C. for 4 h. The reaction mixture was diluted with 30 mL of ethyl acetate and it was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by chromatography on silica gel with acetate and hexane (1:5) as eluent, yielding 11 mg of title compound (7%). 1H NMR (CDCl3): 7.65 (d, J=8.4 Hz, 1H), 7.51-7.45 (m, 1H), 7.14-7.10 (m, 2H), 6.93-6.89 (m, 4H), 3.84 (s, 3H), 3.58 (s, 3H), 2.67 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][C:11]=3[CH:12]=2)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1.O>CN(C=O)C>[C:34]([C:33]1[CH:36]=[CH:37][C:30]([O:29][CH2:28][CH2:27][CH2:26][O:1][C:2]2[CH:3]=[C:4]([C:8]3[O:9][C:10]4[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][C:11]=4[CH:12]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:31][CH:32]=1)#[N:35]
Reactant: N#Cc1ccc(OCCCBr)cc1
Reactant: N#Cc1ccc2oc(-c3cccc(O)c3)cc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCCCOc2cccc(-c3cc4cc(C#N)ccc4o3)c2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
A mixture of 2-(3-hydroxphenyl)-5-cyanobenzofuran (125) (1.176 g, 5 mmol) and K2CO3 (0.829 g, 6 mmol) in dry DMF (25 mL) was heated up to 60° C. 4-(3-Bromopropoxy)benzonitrile (129) was added in one portion and the reaction was kept at 80-100° C. overnight. The mixture was cooled down to room temperature and poured into iced water (100 mL) and stirred for 30 min. A precipitate formed was separated by filtration, washed with water (50 mL) and ethanol (50 mL). Drying under high vacuum and recrystallization from the mixture of DMF and ethanol afforded the desired product as white solid (1.65 g, 84%): mp 157-158° C. (DMF/EtOH). 1H NMR (DMSO-d6) δ8.24 (d, J=1.6 Hz, 1H), 7.86 (d, J=8.6 Hz, 1H), 7.78 (d, J=8.8 Hz, 2H), 7.77 (dd, J=8.6, 1.6 Hz, 1H), 7.61 (s, 1H), 7.55 (d, J=7.8 Hz, 1H), 7.52 (m, 1H), 7.45 (dd, J=7.8, 7.8 Hz, 1H), 7.16 (d, J=8.8 Hz, 2H), 7.07 (dd, J=7.8, 1.7 Hz, 1H), 4.35-4.15 (m, 4H), 2.30-2.15 (m, 2H). HPLC (method B) tR 9.63 min (100.0 area %). Anal. (C25H18N2O3) C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH3:8])[CH:7]=1.[N+:10]([O-])([O-:12])=[O:11].[K+]>S(=O)(=O)(O)O>[Br:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[CH:4][C:5]([F:9])=[C:6]([CH3:8])[CH:7]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1cc(Br)ccc1F
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc(Br)c([N+](=O)[O-])cc1F
Temperature: 0 °C
Reaction time: 72 h
Yield: 104.5 %

Procedure:
5-Bromo-2-fluorotoluene (7.65 g) was added to concentrated sulfuric acid (40 ml), and potassium nitrate (4.2 g) was added portionwise to the mixture at -20° C. The temperature of the reaction mixture was given back to room temperature to conduct stirring for 3 days, and then poured into ice water to conduct extraction with ethyl acetate. After an organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off to obtain the title compound (9.9 g) as a pale yellow oil.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH:5]1([N:9]2[CH2:15][CH2:14][C:13]3[CH:16]=[C:17]([O:20][C:21]4[N:22]=[CH:23][C:24]([C:27]([OH:29])=O)=[N:25][CH:26]=4)[CH:18]=[CH:19][C:12]=3[CH2:11][CH2:10]2)[CH2:8][CH2:7][CH2:6]1>C1(C)C=CC=CC=1>[CH:5]1([N:9]2[CH2:15][CH2:14][C:13]3[CH:16]=[C:17]([O:20][C:21]4[N:22]=[CH:23][C:24]([C:27]([Cl:3])=[O:29])=[N:25][CH:26]=4)[CH:18]=[CH:19][C:12]=3[CH2:11][CH2:10]2)[CH2:8][CH2:7][CH2:6]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cnc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)cn1
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cnc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (5 ml) was added slowly to 5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-pyrazine-2-carboxylic acid (E123a) (485 mg). The resulting reaction mixture was stirred at room temperature for 1 hour and then heated at reflux for a further 1 hour. The reaction mixture was cooled, diluted with toluene and concentrated in vacuo to afford the title compound which was used without further characterisation.
Reaction SMILES: C([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[C:14]([O:20][CH3:21])[C:11]=2[C:12]=1[CH3:13])=[O:7])(C)(C)C.[C:22](O)([C:24]([F:27])([F:26])[F:25])=[O:23].ClCCl>>[CH3:21][O:20][C:14]1[C:11]2[C:12]([CH3:13])=[C:8]([C:6]([OH:5])=[O:7])[O:9][C:10]=2[CH:17]=[CH:16][C:15]=1[CH2:18][O:19][C:22](=[O:23])[C:24]([F:27])([F:26])[F:25]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1c(CO)ccc2oc(C(=O)OC(C)(C)C)c(C)c12
Solvent: ClCCl
Product: COc1c(COC(=O)C(F)(F)F)ccc2oc(C(=O)O)c(C)c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 190 mg of 4-methoxy-5-hydroxymethyl-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester was added 4 mL of TFA/dichloromethane (1:1) and the solution was stirred at room temperature for 3 h. When the reaction was done, the solvents were removed under vacuum and the residue was triturated with acetonitrile. Filtration of the suspension gave 184 mg of 4-methoxy-3-methyl-5-(2,2,2-trifluoro-acetoxymethyl)-benzofuran-2-carboxylic acid as a white solid.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[N:7][C:8]#[N:9])[S:5][CH3:6])[CH3:2].[CH:10]1(N)CC1.C(N)C>>[CH:1]1([NH:3][C:4](=[N:7][C:8]#[N:9])[S:5][CH3:6])[CH2:10][CH2:2]1
Reactant: NC1CC1
Reactant: CCNC(=NC#N)SC
Agent: CCN
Product: CSC(=NC#N)NC1CC1

Procedure:
1-Cyclopropyl-2-methyl-3-cyanoisothiourea was prepared following the same procedure as for 1-ethyl-2-methyl-3-cyanoisothiourea (see EXAMPLE 250) except cyclopropylamine was used in lieu of ethylamine. 1H NMR (CDCl3) δ 0.66-0.76 (m, 2H), 0.83-0.92 (m, 2H), 2.43 (s, 3H), 2.64 (br s, 1H), 6.78 (br s, 1H).