Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC1C=CC(C=O)=CC=1.[CH3:21][O:22][C:23]1([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40](N4C=CN=C4C)=[CH:39][CH:38]=3)[CH:30]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[CH3:21][O:22][C:23]1([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([N:10]4[CH:11]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[N:8]=[CH:9]4)=[CH:39][CH:38]=3)[CH:30]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: COC1(c2cccc(OCc3ccc(-n4ccnc4C)cc3)c2)CCOCC1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Agent: O=Cc1ccc(F)cc1
Product: COC1(c2cccc(OCc3ccc(-n4cnc(-c5ccccc5)c4)cc3)c2)CCOCC1

Procedure:
The title compound was prepared from 4-phenylimidazole and 4-fluorobenzaldehyde according to the general procedure described for 4-methoxy-4-[3-[4-(2-methylimidazol-1-yl)benzyloxy]phenyl]-3,4,5,6-tetrahydro-2H-pyran (Example 2).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:17]([NH:19][CH2:20][C:21]2[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])=[O:18])[C:6]2[CH:7]=[N:8][N:9]([CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[C:10]=2[CH:11]=1>CO.[Pd]>[CH:12]1([N:9]2[C:10]3[CH:11]=[C:3]([CH3:2])[CH:4]=[C:5]([C:17]([NH:19][CH2:20][C:21]4[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=4[CH3:27])=[O:18])[C:6]=3[CH:7]=[N:8]2)[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(CBr)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c2cnn(C3CCCC3)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-(bromomethyl)-1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydro pyridine-3-yl)methyl)-1H-indazole-4-carboxamide (0.05 g, 0.13 mmol) was dissolved in methanol (2 mL) and Pd—C (10%, 0.01 g) was added to it. The resulting reaction mixture was stirred at room temperature for 1 h. On completion, the reaction mixture was filtered and concentrated to obtain solid compound which was washed with ether and pentane affording pure target compound (0.045 g, 91.89%). LCMS: 379.30 (M+1)+; HPLC: 98.15% (@ 254 nm) (Rt;6.603); 1H NMR (CD3OD, 400 MHz) δ 8.28 (s, 1H), 7.63 (s, 1H), 7.48 (s, 1H), 6.70 (s, 1H), 5.12 (m, 1H), 4.61 (s, 2H), 2.56 (s, 3H), 2.55 (s, 3H), 2.42 (s, 3H), 2.19-2.14 (m, 2H), 2.12-2.04 (m, 2H), 2.00-1.92 (m, 2H), 1.82-1.75 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:16][CH2:15][CH2:14][N:12]2[CH:13]=1.C1C(=O)N([I:24])C(=O)C1.[O-]S([O-])(=S)=O.[Na+].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:16][CH2:15][CH2:14][N:12]2[C:13]=1[I:24]
Reactant: Fc1ccc(-c2cn3c(n2)CCC3)c(F)c1
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nc3n(c2I)CCC3)c(F)c1
Temperature: 22.5 °C
Reaction time: 2 h
Yield: 62.1 %

Procedure:
To a stirred solution of 2-(2,4-difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (93.5 g, 425 mmol) in DMF (550 mL), NIS (105 g, 467 mmol) was added portionwise over about 1 h, maintaining the temperature at about 20-25° C. with an ice-water bath. After the final addition, the reaction suspension was stirred for about 2 h. After a total of about 3 h from the start of addition of the NIS, the reaction mixture was poured into ice water (4 L) and was stirred at about 15-20° C. for about 15 min before the addition of a 10% solution of Na2S2O3 (500 mL). The resulting solution was stirred for about 1 h. The tan colored solid was collected by vacuum filtration, washed with water (5×200 mL), and dried overnight at room temperature. The solid was stirred with ether (300 mL), filtered, and washed with additional portions of ether (3×30 mL). This ether trituration process was repeated before the solid was dried in a vacuum oven at about 50-60° C. to give the title compound as a powdery solid (91.4 g, 52%): LC/MS (Table 1, Method h) Rt=1.40 min; MS m/z: 347.0 (M+H)+.
Reaction SMILES: [CH:1]([O:3][CH2:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([NH:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14])=O)=[CH:7][CH:6]=1)=[O:2].S(Cl)(Cl)=O>>[CH3:15][C:12]1([CH3:16])[CH2:13][O:14][C:9]([C:8]2[CH:17]=[CH:18][C:5]([CH2:4][O:3][CH:1]=[O:2])=[CH:6][CH:7]=2)=[N:11]1
Reactant: CC(C)(CO)NC(=O)c1ccc(COC=O)cc1
Solvent: O=S(Cl)Cl
Product: CC1(C)COC(c2ccc(COC=O)cc2)=N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
4-(Formyloxymethyl)-N-(1,1-dimethyl-2-hydroxyethyl)benzamide (64 mg) was added with thionyl chloride (56 μl) and stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure, and then the residue was added with water (5 ml) and extracted twice with ethyl acetate (5 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer silica gel column chromatography (developing solvent: hexane:ethyl acetate=2:1) to obtain 37.4 mg of the title compound. Yield: 63%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:43])([CH2:37][N:38]1[CH:42]=[N:41][CH:40]=[N:39]1)[C@H:10]([N:12]1[C:16](=[O:17])[N:15]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27](CC4C=CC=CC=4)[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH:14]=[N:13]1)[CH3:11].[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:43])([CH2:37][N:38]1[CH:42]=[N:41][CH:40]=[N:39]1)[C@H:10]([N:12]1[C:16](=[O:17])[N:15]([C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[CH:22][CH:23]=2)[CH:14]=[N:13]1)[CH3:11]
Reactant: [H][H]
Reactant: C[C@@H](n1ncn(-c2ccc(N3CCN(Cc4ccccc4)CC3)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: [Pd]
Solvent: CCO
Product: C[C@@H](n1ncn(-c2ccc(N3CCNCC3)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 100.1 %

Procedure:
To a solution of 170 mg of compound 21 in 20 ml of ethanol was added 20 mg of 10% Pd-C and the mixture was stirred at room temperature in a hydrogen stream for 9 hours. The catalyst was filtered off and washed with 5 ml of ethanol. The filtrate and the washing were combined and concentrated under reduced pressure to give 144 mg of 2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-(1-piperazinyl)phenyl]-3(2H,4H)-1,2,4-triazolone (Compound 22) as a pale yellow oil.
Reaction SMILES: [C:1](OC=C)(=[O:3])[CH3:2].[CH:7]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH2:8].N#N.[OH-].[Na+]>CO.O>[CH:1]([OH:3])=[CH2:2].[CH:7]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH2:8]
Reactant: C=COC(C)=O
Agent: C=COCCCC
Agent: N#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C=CO

Procedure:
172.2 g (2.00 moles) of vinyl acetate, 15.1 g (0.15 mole) of n-butyl vinyl ether, 56.2 g of methanol and 0.28 g of 2,2'-azobis-2,4-dimethylvaleronitrile were mixed and polymerized in an atmosphere of N2 at 62° C. for 8 hours. Subsequently, 749.2 g of 5% water-containing methanol and 8.0 g (0.20 mole) of caustic soda were added to the reaction product for saponification at 45° C. for 2 hours. The reaction mixture was milled and filtered to obtain a polymer portion, followed by washing with 5% water-containing alcohol to eliminate impurities such as sodium acetate therefrom. The purified polymer was dried under reduced pressure and milled to obtain 82.5 g of a white powdery vinyl alcohol/n-butyl vinyl ether (93/7 by molar ratio) copolymer (hereinafter referred to as PVA/n-BVE).
Reaction SMILES: [C:1]1([C:7]2O[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:10][C:11](=[O:18])[C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.[CH3:29][NH2:30]>CO.O>[C:1]1([C:7]2[N:30]([CH3:29])[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:10][C:11](=[O:18])[C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN
Reactant: CCOC(=O)c1c(-c2ccccc2)oc(-c2ccccc2)cc1=O
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(-c2ccccc2)n(C)c(-c2ccccc2)cc1=O

Procedure:
3.5 gms of 2,6-diphenyl-3-ethoxycarbonyl-4-pyrone was dissolved in 33 mls of methanol. 2 mls of glacial acetic acid was added. 13.3 mls of 40% aqueous methylamine was then added very slowly at room temperature. After 6 hours the reaction mixture was diluted with 200 mls of water and extracted with methylene chloride. Evaporation yielded 3.5 gms of ethyl 2,6-diphenyl-1-methyl-4-oxonicotinate which was recrystallized from methylene chloride/ether. mp=177°-9°.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[N:15]1[CH:20]=[CH:19][C:18]([CH2:21]O)=[CH:17][CH:16]=1>>[N:15]1[CH:20]=[CH:19][C:18]([CH2:21][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1ccncc1
Product: N#Cc1ccnc(-n2nccc2OCc2ccncc2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and pyridin-4-ylmethanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.29 (2H, d, J=9.2 Hz), 5.72 (1H, d, J=2.0 Hz), 7.38 (2H, d, J=6.4 Hz), 7.44 (1H, dd, J=1.6 Hz, J=5.2 Hz), 7.57 (1H, d, J=2.0 Hz), 8.09 (1H, s), 8.65 (2H, d, J=5.2 Hz), 8.72 (1H, d, J=5.2 Hz). [M+H] Calc'd for C15H11N5O, 278. Found, 278.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH:13]=O)[CH2:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][CH2:6]1)=[O:4].C([O-])(=O)C.[Na+].Cl.[CH2:21]([O:28][NH2:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CO>[CH3:1][O:2][C:3]([C:5]1([CH:13]=[N:29][O:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:6][CH2:7][C:8]([CH3:11])([CH3:12])[CH2:9][CH2:10]1)=[O:4]
Reactant: NOCc1ccccc1
Reactant: COC(=O)C1(C=O)CCC(C)(C)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1(C=NOCc2ccccc2)CCC(C)(C)CC1
Yield: 26 %

Procedure:
A mixture of crude 1-formyl-4,4-dimethyl-cyclohexanecarboxylic acid methyl ester from Preparation 27 (22.9 mmol theoretical), sodium acetate (3.76 g, 45.8 mmol) and O-benzylhydroxylamine hydrochloride (7.32 g, 45.8 mmol) were stirred in methanol (100 mL) for 18 h. The methanol was removed in vacuo, water (100 mL) was added and the aqueous phase was extracted with EtOAc (50 mL×5). The combined organic extracts were dried (MgSO4) and were evaporated in vacuo. The residue was purified by flash column chromatography using an eluting system of hexane/EtOAc (99:1) to yield the title compound (1.83 g, 26%). MH+304.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6](OCC)=[O:7])[N:3]2[CH:11]=[N:12][CH:13]=[C:2]12.[BH4-].[Na+].CC(C)=O>CO>[OH:7][CH2:6][C:4]1[N:3]2[CH:11]=[N:12][CH:13]=[C:2]2[S:1][CH:5]=1
Reactant: CCOC(=O)c1csc2cncn12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Product: OCc1csc2cncn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.80 g of the ethyl imidazo[5,1-b]-thiazole-3-carboxylate prepared in Preparation 11 in 16 ml of methanol was added 400 mg of sodium borohydride, and the mixture was stirred at room temperature for 30 minutes. To the reaction solution was added dropwise 3 ml of acetone. The mixture was stirred for 30 minutes, and then concentrated to dryness under reduced pressure. To the residue were added 20 ml of methylene chloride and 20 ml of a saturated saline solution, and the mixture was stirred for 10 minutes. The organic layer was separated, and the aqueous layer was extracted with methylene chloride (20 ml×2). The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to give 0.615 of the title compound as light brown crystals.
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:12](=[O:27])[N:13]2[CH:17]([C:18]([NH:20][C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[O:19])[CH2:16][CH:15]=[N:14]2)[CH2:8][C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.[O:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]1[O:41][NH2:42].C(Cl)CCl.N1C2C(=NC=CC=2)N(O)N=1>ClCCl>[CH:1]1([CH2:6][C@H:7]([CH2:8][C:9](=[O:11])[NH:42][O:41][CH:36]2[CH2:37][CH2:38][CH2:39][CH2:40][O:35]2)[C:12]([N:13]2[C@H:17]([C:18]([NH:20][C:21]3[N:22]=[CH:23][CH:24]=[CH:25][N:26]=3)=[O:19])[CH2:16][CH:15]=[N:14]2)=[O:27])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C[C@@H](CC1CCCC1)C(=O)N1N=CCC1C(=O)Nc1ncccn1
Reactant: NOC1CCCCO1
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)Nc1ncccn1)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.6 %

Procedure:
To a solution of (3R)-3-(cyclopentylmethyl)-4-oxo-4-{5-[(2-pyrimidinylamino)carbonyl]-4,5-dihydro-1H-pyrazol-1-yl}butanoic acid (183 mg, 0.49 mmol) in dichloromethane (DCM) (10 mL) was added N-methylmorpholine (0.14 mL, 1.27 mmol), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (69 mg, 0.59 mmol), EDC (112 mg, 0.59 mmol) and 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (67 mg, 0.49 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred for 2 hours. The reaction mixture was then washed with water (5 mL) and NaHCO3 solution (5 mL×3), and concentrated to provide the crude product as a mixture of diastereomers. This mixture was purified by Gilson HPLC (Sunfire Column 19×50 mm, flowrate 25 mL/min, 10 min, 5-70% MeCN:H2O) to afford (5S)-1-{(2R)-2-(cyclopentylmethyl)-4-oxo-4-[(tetrahydro-2H-pyran-2-yloxy)amino]butanoyl}-N-2-pyrimidinyl-4,5-dihydro-1H-pyrazole-5-carboxamide (80 mg, 34% yield). MS: 473 ([M+H]+).
Reaction SMILES: N1C=CN=CC=1C1C=CN=[C:9]([NH:13][CH2:14][C:15]2[CH:23]=[CH:22][C:18](C(O)=O)=[CH:17][CH:16]=2)N=1.[NH:24]([C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=1)[C:25]([NH2:27])=[NH:26].CN(/C=C/C(C1C=NC=CN=1)=O)C.CN(C)/C=C/C(C1C=NC=CC=1)=O>>[N:13]1[CH:9]=[CH:17][CH:16]=[C:15]([C:23]2[CH:22]=[CH:18][N:27]=[C:25]([NH:24][C:28]3[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=3)[N:26]=2)[CH:14]=1
Reactant: O=C(O)c1ccc(CNc2nccc(-c3cnccn3)n2)cc1
Reactant: N=C(N)Nc1ccc(C(=O)O)cc1
Agent: CN(C)/C=C/C(=O)c1cccnc1
Agent: CN(C)/C=C/C(=O)c1cnccn1
Product: O=C(O)c1ccc(Nc2nccc(-c3cccnc3)n2)cc1

Procedure:
Title compound was prepared according to the procedure described for the synthesis of compound 25a (scheme 6, step 3) replacing the guanindine 24 by 4-guanidinobenzoic acid (344) (Zlatoidsky P., Maliar T. Eur. J. Med. Chem Chim. Ther.; 1996, 31, 895-900) and (E)-3-(dimethylamino)-1-(pyrazin-2-yl)-prop-2-en-1-one (23a) by (E)-3-(dimethylamino)-1-(pyridin-3-yl)prop-2-en-1-one (345) (Zimmermann J., Buchdunger E., et al. Bioorg. Med. Chem. Lett., 1996, 6, 1221-1226). Yield of the product 28%. MS (m/z): 292.29 (calc) 293.1 (MH+) (found).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:11]1[CH:23]=[CH:22][C:14]([CH2:15][C:16]2[N:17]=[C:18]([NH2:21])[S:19][CH:20]=2)=[CH:13][CH:12]=1.BrCC(=O)CC1C=CC(Br)=CC=1.NC(N)=S>C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([C:11]2[CH:23]=[CH:22][C:14]([CH2:15][C:16]3[N:17]=[C:18]([NH2:21])[S:19][CH:20]=3)=[CH:13][CH:12]=2)=[CH:3][CH:2]=1
Reactant: Nc1nc(Cc2ccc(Br)cc2)cs1
Reactant: OB(O)c1ccncc1
Agent: NC(N)=S
Agent: O=C(CBr)Cc1ccc(Br)cc1
Solvent: CCO
Product: Nc1nc(Cc2ccc(-c3ccncc3)cc2)cs1

Procedure:
In a similar manner to Preparation 6, step 3, the Suzuki coupling reaction of pyridine-4-yl boronic acid and 4-(4-bromo-benzyl)-thiazol-2-ylamine, was prepared via reaction of 1-bromo-3-(4-bromo-phenyl)-propan-2-one and thiourea in ethyl alcohol according to the procedure described in Preparation 1, step 2, gave the title compound 7. LC/MS m/z 268.08 (M+H)+; HPLC Rt: 0.598 min.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[CH3:18][S:19]([NH:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)(=[O:21])=[O:20]>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:26]1[CH:25]=[CH:24][C:23]([NH:22][S:19]([CH3:18])(=[O:20])=[O:21])=[CH:28][CH:27]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: CS(=O)(=O)Nc1ccc(B(O)O)cc1
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(NS(C)(=O)=O)cc1
Yield: 99.9 %

Procedure:
Following Step 1 from General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (50 mg, 0.10 mmol) was reacted with 4-(methylsulfonamido)phenylboronic acid (52 mg, 0.24 mmol) to afford the desired product (40 mg, 62%) as a brown solid: ESI MS m/z 400 [C19H16N2O4S2+H]+.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[CH2:11][CH2:12][NH2:13].[CH3:18][S:19](Cl)(=[O:21])=[O:20].O>C(Cl)Cl>[CH3:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[CH2:11][CH2:12][NH:13][S:19]([CH3:18])(=[O:21])=[O:20]
Reactant: COc1ccccc1CCN
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: COc1ccccc1CCNS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
Pyridine (12.0 mL, 150 mmol) was added to a solution of 2-methoxyphenethylamine (15.1 g, 100 mmol) in CH2Cl2 (100 mL). The reaction was cooled to 0° C. and methanesulfonyl chloride (12.6 g, 110 mmol) was added. The reaction was stirred at 0° C. for 0.5 h and at room temperature for 2 h. Water was added and the aqueous layer was extracted with CH2Cl2 (2×). The organic solution was washed water (1×) and brine (1×), dried over MgSO4, filtered and concentrated to afford N-[2-(2-methoxy-phenyl)-ethyl]-methanesulfonamide (18.5 g).
Reaction SMILES: F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.[N:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:46]=[CH:45][C:41]([C:42]([OH:44])=O)=[CH:40][CH:39]=2)=[CH:34][CH:33]=1.[CH:47]1([NH:50][CH:51]2[CH2:56][CH2:55][N:54]([C:57]3[O:61][N:60]=[C:59]([C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)[N:58]=3)[CH2:53][CH2:52]2)[CH2:49][CH2:48]1>CN(C)C=O>[CH:47]1([N:50]([CH:51]2[CH2:52][CH2:53][N:54]([C:57]3[O:61][N:60]=[C:59]([C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)[N:58]=3)[CH2:55][CH2:56]2)[C:42](=[O:44])[C:41]2[CH:40]=[CH:39][C:38]([C:35]3[CH:34]=[CH:33][N:32]=[CH:37][CH:36]=3)=[CH:46][CH:45]=2)[CH2:49][CH2:48]1
Reactant: O=C(O)c1ccc(-c2ccncc2)cc1
Reactant: c1ccc(-c2noc(N3CCC(NC4CC4)CC3)n2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(-c2ccncc2)cc1)N(C1CC1)C1CCN(c2nc(-c3ccccc3)no2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (75 mg) and ethyldiisopropylamine (74 μL) are added to a solution of 4-pyridin-4-yl-benzoic acid (42 mg) in N,N-dimethylformamide (5 mL) at room temperature. The solution is stirred for 10 min prior to the addition of cyclopropyl-[1-(3-phenyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-amine (60 mg). The resulting mixture is stirred at 60° C. for 5 h, cooled to room temperature and concentrated in vacuo. The crude product is purified by HPLC (H2O/MeOH/TFA). LC (method 6): tR=1.44 min; Mass spectrum (ESI+): m/z=466 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:15])[C:5]2[S:10][CH2:9][CH2:8][C:7]([CH3:12])([CH3:11])[C:6]=2[C:13]=1[CH3:14].C([Li])CCC.CN(C)[CH:23]=[O:24].Cl>C(OCC)C>[CH3:11][C:7]1([CH3:12])[C:6]2[C:13]([CH3:14])=[C:2]([CH:23]=[O:24])[CH:3]=[C:4]([CH3:15])[C:5]=2[S:10][CH2:9][CH2:8]1
Reactant: Cc1cc(Br)c(C)c2c1SCCC2(C)C
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1cc(C=O)c(C)c2c1SCCC2(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-Bromo-3,4-dihydro-4,4,5,8-tetramethyl-2H-1-benzothiopyran (19.8 g, World Patent Application 95/04054) was dissolved in diethyl ether (350 mL) and treated with n-butyllithium (2.5N in hexanes, 42 mL). The mixture was stirred at room temperature for 1 h and then cooled in a dry-ice/acetone bath. Dimethylformamide (16 mL) was added over a period of several minutes and the reaction bath was allowed to warm to -40° C. Hydrochloric acid (1N aqueous, 100 mL) was added and the mixture was allowed to warm to 23° C. The organic phase was separated and washed with saturated aqueous sodium bicarbonate solution (100 mL). The organic phase was dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The residue was subjected to chromatography on silica gel using hexanes/ether (9:1) as eluent to afford the desired compound as a yellow semi-solid (7.7 g). 1H NMR(CDCl3): δ 1.5 (6H), 2.0 (2H), 2.3 (3H), 2.8 (3H), 3.0 (2H), 7.4 (1H), 10.2 (1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[N:7]([C@H:9]([C:31]1[O:32][CH:33]=[CH:34][CH:35]=1)[C@H:10]([CH3:30])[CH2:11][O:12][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.CCOC(C)=O>CO>[C:1]([O:5][C:6](=[O:36])[N:7]([C@H:9]([C:31]1[O:32][CH:33]=[CH:34][CH:35]=1)[C@H:10]([CH3:30])[CH2:11][OH:12])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@@H](c1ccco1)N(C)C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@H](CO)[C@@H](c1ccco1)N(C)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a solution of 2.5.1b (20 g, 39.4 mmol) in MeOH (197 mL) was added tetrabutyl ammonium flouride (1.0 M in THF, 47.3 mL, 47.3 mmol, 1.2 equiv) at room temperature. After stirring for overnight, the reaction mixture was added water and EtOAc. The phase were separated and the aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/heptane) to give ((1S,2S)-1-Furan-2-yl-3-hydroxy-2-methyl-propyl)-methyl-carbamic acid tert-butyl ester (10.51 g, 99%). 1H NMR (400 MHz, CDCl3) 7.37 (s, 1H), 6.33 (s, 1H), 6.27 (br, s, 1H), 5.41 (br, s, 1H), 3.41 (br, s, 2H), 3.05 (s, 1H), 2.67 (s, 3H), 2.37 (m, 1H), 1.49 (s, 9H), 1.01 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C@H:20]([S:39][CH2:40][C:41]([CH3:48])([CH3:47])[CH2:42][C:43]([O:45]C)=[O:44])[CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([O:32]C4CCCCO4)([CH3:31])[CH3:30])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[OH-].[Na+].O>CO.C1COCC1.CCCCCC.C1COCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C@H:20]([S:39][CH2:40][C:41]([CH3:48])([CH3:47])[CH2:42][C:43]([OH:45])=[O:44])[CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([OH:32])([CH3:30])[CH3:31])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)CC(C)(C)CS[C@H](CCc1ccccc1C(C)(C)OC1CCCCO1)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(CS[C@H](CCc1ccccc1C(C)(C)O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1)CC(=O)O
Temperature: 60 °C
Reaction time: 48 h
Yield: 86.1 %

Procedure:
A solution of the product of Step 10 (10.1 g, 0.015 mol) and pyridinium p-toluenesulfonate (1.12 g, 0.045 mol) in a mixture of MeOH:THF 3:1 (80 mL) was warmed to 60° C. overnight. Most of the MeOH was evaporated and an aqueous solution of NH4Cl was added. The product was extracted with EtOAc, washed with brine and dried over Na2SO4. The residual oil was purified by flash chromatography on silica using 1:5 to 1:3 EtOAc:hexane. The product was then dissolved in a mixture of MeOH:THF, 3:1 (70 mL) and the solution was cooled down to 0° C. for the addition of a 1M solution of NaOH in water (35 mL, 0.036 mol). The reaction mixture was stirred 2 days at r.t. Most of the MeOH was evaporated and the solution was acidified with AcOH (acetic acid) to pH ≃5. An aqueous solution of NH4Cl was added and the acid was extracted with EtOAc. The organic phases were washed with brine and dried over Na2SO4. After evaporation of the solvent, the residual oil was purified by flash chromatography using 1:6 to 1:5 EtOAc:hexane (containing 2% AcOH) to give 7.6 g of the title product (87% yield).