Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([OH:23])=O)[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[CH3:56][N:57]([CH3:73])[CH:58]1[CH2:62][CH2:61][N:60]([CH2:63][C:64]2[CH:69]=[CH:68][C:67]([CH2:70][NH:71][CH3:72])=[CH:66][CH:65]=2)[CH2:59]1>C(Cl)Cl>[CH3:73][N:57]([CH3:56])[CH:58]1[CH2:62][CH2:61][N:60]([CH2:63][C:64]2[CH:69]=[CH:68][C:67]([CH2:70][N:71]([CH3:72])[C:21]([C:18]3[CH:17]=[C:16]([CH2:15][N:13]([S:10]([C:6]4[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[CH3:24])(=[O:11])=[O:12])[CH3:14])[O:20][CH:19]=3)=[O:23])=[CH:66][CH:65]=2)[CH2:59]1
Reactant: CNCc1ccc(CN2CCC(N(C)C)C2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)Cc3ccc(CN4CCC(N(C)C)C4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 5-{[(4-methoxy-2,6-dimethyl-benzenesulfonyl)-methyl-amino]-methyl}-furan-3-carboxylic acid (35 mg, 0.10 mmol), EDCI (27 mg, 0.14 mmol), HOBt (20 mg, 0.15 mmol), DIPEA (0.03 mL, 0.20 mmol), dimethyl-[1-(4-methylaminomethyl-benzyl)-pyrrolidin-3-yl]-amine hydrochloride (30 mg, 0.09 mmol) and DCM (10 mL).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7](Br)[CH:6]=[CH:5][C:3]=1[NH2:4].[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:10]1([C:2]2[CH:8]=[C:7]([C:2]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:3]=3)[CH:6]=[CH:5][C:3]=2[NH2:4])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OB(O)c1ccccc1
Reactant: Nc1ccc(Br)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1ccc(-c2ccccc2)cc1-c1ccccc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 163.1 %

Procedure:
2,4-dibromoaniline (10 mmol), benzeneboronic acid (24 mmol), tetrakis(triphenylphosphine)palladium(0) (1 mmol) and potassium carbonate (12 g) are put in a two-neck round-bottom flask and dissolved in toluene (30 mL) and H2O (10 mL). Subsequently, the resulting solution is stirred in a bath under a temperature of about 100° C. for 24 hours. After completion of the reaction, toluene is removed. The reaction mixture is extracted with dichloromethane and water, and then being distilled under reduced pressure. The resulting residence is filtered by silica gel column and distilled under reduced pressure again. Next, by re-crystallizing and filtering with dichloromethane and petroleum ether, 2,4-diphenylaniline (2.0 g) is yielded.
Reaction SMILES: [C:1]12[C:18](=[O:19])[O:17][C:15](=[O:16])[C:13]3[C:14]1=[C:5]([C:6]1[C:11]([CH:12]=3)=[CH:10][CH:9]=[CH:8][N:7]=1)[CH:4]=[CH:3][CH:2]=2.[N+:20]([O-])([O-:22])=[O:21].[Na+].O>S(=O)(=O)(O)O>[N+:20]([C:3]1[CH:2]=[C:1]2[C:18](=[O:19])[O:17][C:15](=[O:16])[C:13]3=[CH:12][C:11]4[C:6]([C:5]([CH:4]=1)=[C:14]23)=[N:7][CH:8]=[CH:9][CH:10]=4)([O-:22])=[O:21]
Reactant: O=C1OC(=O)c2cc3cccnc3c3cccc1c23
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C1OC(=O)c2cc3cccnc3c3cc([N+](=O)[O-])cc1c23
Temperature: 65 °C
Yield: 182.5 %

Procedure:
5-Azaphenanthrene-1,10-dicarboxylic anhydride (17.0 g, 68.2 mmol) was dissolved in concentrated sulfuric acid (70 mL) and sodium nitrate (2.90 g, 34.1 mmol) was added to the warm solution. This mixture was heated to 65° C. and three additional aliquots of sodium nitrate (2.90 g, 34.1 mmol) were added after 5, 22, and 30 h. Each aliquot caused about a 20° C. temperature rise, with the temperature stabilizing again at about 65° C. The solution was heated for an additional 14 h after the last addition. The clear orange solution was cooled to room temperature and poured into water (500 mL), washing the residue from the reaction flask with water (5×40 mL). The aqueous suspension was allowed to cool to room temperature. The suspended solid was collected on a frit, washed with water (2×50 mL), and dried. This cream colored solid was heated at reflux in acetic acid (100 mL) containing acetic anhydride (10 mL) for 2 h and cooled to room temperature. The solid was collected on a frit, washed with acetic acid (25 mL) and ether (2×25 mL), and dried to give 18.31 g (91%) of the nitro compound as a cream colored solid: mp 268°-269° C.; 1H NMR (DMSO-d6, 300 MHz) δ 8.05 (dd, 1H, J=8.0, 4.4 Hz), 8.97 (dd, 1H, J=8.0, 1.5 Hz), 9.11 (d, 1H, J=2.2 Hz), 9.33-9.40 (m, 2H), 10.16 (d, 1H, J=2.2 Hz); MS (CI, CH4) m/e (%) 295 (M+H+, 100), 265 (6), 250 (5).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14](Br)[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[O:18][CH2:19][CH2:20][OH:21])[CH:5]=[CH:4][N:3]=1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([OH:33])([C:31]#[CH:32])[CH3:30])=[N:27][CH:28]=1.C(N(CC)CC)C>CS(C)=O.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>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([C:32]#[C:31][C:29]([C:26]4[CH:25]=[CH:24][C:23]([Cl:22])=[CH:28][N:27]=4)([OH:33])[CH3:30])[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[O:18][CH2:19][CH2:20][OH:21])[CH:5]=[CH:4][N:3]=1
Reactant: C#CC(C)(O)c1ccc(Cl)cn1
Reactant: Nc1nccc(-n2c(OCCO)nc3ccc(Br)cc32)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(O)(C#Cc1ccc2nc(OCCO)n(-c3ccnc(N)n3)c2c1)c1ccc(Cl)cn1
Temperature: 25 °C
Yield: 0.8 %

Procedure:
A solution of 2-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]ethan-1-ol (200 mg, 0.57 mmol), 2-(5-chloropyridin-2-yl)but-3-yn-2-ol (518 mg, 2.85 mmol), bis(triphenylphosphine)palladium(II) dichloride (400 mg, 0.57 mmol) and triethylamine (0.5 mL) in DMSO (0.5 mL) was irradiated under nitrogen in a 10-mL sealed tube with microwave radiation for 2 h at 100° C. The reaction mixture was cooled to room temperature and the solid material was removed by filtration. The filtrate was concentrated under vacuum and the crude product (50 mg) was purified by preparative HPLC to give 2 mg (1%) of 4-[1-(2-aminopyrimidin-4-yl)-2-(2-hydroxyethoxy)-1H-1,3-benzodiazol-6-yl]-2-(5-chloropyridin-2-yl)but-3-yn-2-ol as a light yellow solid: 1H NMR (400 MHz, DMSO) delta 8.61 (s, 1H), 8.38 (d, J=5.6 Hz, 1H), 8.16 (s, 1H), 7.98-7.82 (m, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.26-7.24 (m, 1H), 7.06 (d, J=5.2 Hz, 3H), 6.44 (s, 1H), 5.06 (t, J=5.6 Hz, 1H), 4.61 (t, J=4.8 Hz, 2H), 3.83-3.80 (m, 2H), 1.82 (s, 3H); LC-MS: m/z=+451 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:23]O>>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][CH:10]=1)[C:5]([O:7][CH3:23])=[O:6]
Reactant: CO
Reactant: Cc1ccc(Sc2ccccc2)c(C(=O)O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(C)ccc1Sc1ccccc1

Procedure:
650 g of 3-methyl-6-(phenylthio)-benzoic acid in 7.5 litres of absolute methanol are slowly treated with 300 ml of concentrated sulphuric acid and the mixture is heated for 24 hours under reflux. The mixture is concentrated and the residue poured on to an ice-cold sodium bicarbonate solution. The mass is extracted with ether, washed with water, dried over sodium sulphate and concentrated. There is obtained methyl 3-methyl-6-(phenylthio)-benzoate as a red-brown oil which crystallises on standing.
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH2:4]([O:6][C:7]([C@@H:9]1[CH2:13][S:12][C@@H:11]([CH2:14][SH:15])[CH2:10]1)=[O:8])[CH3:5]>C(OCC)C>[CH2:4]([O:6][C:7]([C@@H:9]1[CH2:13][S:12][C@@H:11]([CH2:14][S:15][CH3:3])[CH2:10]1)=[O:8])[CH3:5]
Reactant: C=[N+]=[N-]
Reactant: CCOC(=O)[C@@H]1CS[C@@H](CS)C1
Solvent: CCOCC
Product: CCOC(=O)[C@@H]1CS[C@@H](CSC)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
Diethylether solution of diazomethane (10 molar equivalents) was added to trans-4-ethoxycarbonyl-2-mercaptomethyltetrahydrothiophene (compound No. 15-1, 549 mg) and the mixture was stirred for 4 hours at room temperature. The mixture was concentrated in vacuo and the oil residue was purified by a silica gel column chromatography to give 407 mg (69%) of the titled compound (compound No. 18-1).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([OH:15])=[O:14])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:16]=[CH:17][CH:18]=[CH:19][C:3]1=2.[N+](=[CH2:22])=[N-]>O1CCOCC1>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([O:15][CH3:22])=[O:14])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:16]=[CH:17][CH:18]=[CH:19][C:3]1=2
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1ccc2c(=O)c3ccccc3ccc2c1
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
5.0 G. of 5-oxo-5H-dibenzo[a,d]cycloheptene-2-carboxylic acid (as prepared above) is suspended in 50 ml. of dioxane, added to excess ethereal diazomethane, and stirred until dissolution is complete. The solution is then evaporated to dryness to yield methyl (5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)carboxylate (m.p. 115°-116° C).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[F:8].[F:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]([O:23][CH3:24])=[O:22])[CH:16]=[CH:17][CH:18]=1>C1(C)C=CC=CC=1.CC(C)([O-])C.[K+]>[C:10]([CH:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1)[CH:19]([C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([F:12])[CH:14]=1)[CH2:20][C:21]([O:23][CH3:24])=[O:22])#[N:11]
Reactant: COC(=O)C=Cc1cccc(F)c1
Reactant: N#CCc1ccc(F)c(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)CC(c1cccc(F)c1)C(C#N)c1ccc(F)c(F)c1
Temperature: 65 °C
Reaction time: 5 h
Yield: 96.5 %

Procedure:
Under protective gas (Ar), 3.828 g (25.0 mmol) of (3,4-difluorophenyl)acetonitrile and 0.281 mg of potassium tert-butoxide were added to 4.099 g (22.7 mmol) of methyl 3-(3-fluorophenyl)acrylate in 25.0 ml of toluene, and the mixture was stirred in a closed vessel at 65° C. for 5 h. The solvent was removed under reduced pressure, the residue was taken up in ethyl acetate and the mixture was washed twice with in each case 25 ml of water. The combined organic phases were dried over sodium sulphate and the solvent was removed under reduced pressure. Chromatography of the residue on silica gel (ethyl acetate/heptane=20:80) gave 7.3 g (87% of theory) of the diastereomeric methyl 4-cyano-4-(3,4-difluorophenyl)-3-(3-fluorophenyl)butanoate (erythro:threo=65:35 according to integration of the methyl singlets in the 1H-NMR in CDCl3 at 3.68 and 3.59 ppm).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].[NH:6]([C:10]1[S:11][C:12]([CH2:15]O)=[CH:13][N:14]=1)[C:7]([NH2:9])=[NH:8].[OH-].[Na+]>Cl>[NH:6]([C:10]1[S:11][C:12]([CH2:15][S:5][CH2:4][CH2:3][NH2:2])=[CH:13][N:14]=1)[C:7]([NH2:9])=[NH:8]
Reactant: N=C(N)Nc1ncc(CO)s1
Reactant: NCCS
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N=C(N)Nc1ncc(CSCCN)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 697.2 %

Procedure:
Cysteamine hydrochloride (10.6 g; 9.3 mmoles) and 2-guanidino-5-hydroxymethylthiazole (16.0 g; 9.3 mmoles) [prepared in Step B] were dissolved in 80 ml of concentrated hydrochloric acid and the solution stirred at ambient temperature for 1 hour and then heated at reflux temperature for 3 hours. The reaction mixture was cooled, made basic (pH 11) with 40% aqueous NaOH and filtered to give 15 g of product. Recrystallization from acetonitrile yielded the title compound, mp 150°-153°.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:6][CH:7]=O)[CH2:3][CH:4]=O.Cl.[NH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:9])[CH:6]=[CH:7][N:11]([CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:4]=[CH:3]1
Reactant: CC(C)(CC=O)CC=O
Reactant: COC(=O)CCCN
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCCN1C=CC(C)(C)C=C1
Temperature: 25 °C
Yield: 26.1 %

Procedure:
Under nitrogen, 5.89 g (0.046 mole) of 3,3-dimethylglutaraldehyde, 7.03 g (0.0457 mole) of methyl 4-aminobutanoate hydrochloride (the compound of Example 9a), and 9 g of 5A molecular sieves were combined in 425 ml of chloroform at room temperature. 7.0 ml (0.05 mole) of triethylamine were added to the reaction mixture before it was warmed to reflux. After 21 hours the reaction mixture was cooled to room temperature, filtered, and the filtrate evaporated in vacuo. The residue was suspended in about 300 ml of ethyl ether and filtered. The filtrate was evaporated in vacuo to yield 8.56 g of crude product. The crude product was distilled to yield 2.5 g of the title compound as a clear liquid, bp 95° C./0.2 mm Hg.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([NH:20][NH:21][C:22](=[O:26])[CH2:23][CH2:24][CH3:25])=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:22]([NH:21][NH:20][C:18]([C@H:13]1[CH2:12][CH2:11][C@H:10]2[CH2:17][N:14]1[C:15](=[O:16])[N:9]2[OH:8])=[O:19])(=[O:26])[CH2:23][CH2:24][CH3:25]
Reactant: CCCC(=O)NNC(=O)[C@H]1CC[C@H]2CN1C(=O)N2OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCC(=O)NNC(=O)[C@H]1CC[C@H]2CN1C(=O)N2O
Yield: 90.3 %

Procedure:
To a solution of (2R,5S)-6-(benzyloxy)-N-butanoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 235 (0.31 g, 0.86 mml) in methanol (20 mL) was added 5% Pd/C (0.30 g). The mixture was hydrogenated under 10 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give (2R,5S)-N′-butanoyl-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 236 (0.21 g, 90%) as a brown foam.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15](I)[CH3:16].O>CN(C=O)C>[CH2:15]([O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)[CH3:16]
Reactant: Oc1ccc(I)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(I)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-iodophenol (2 g) and potassium carbonate (1.88 g) in DMF (20 ml) was added dropwise ethyl iodide (1.83 ml) at room temperature, and the mixture was stirred at 50° C. overnight. The resulting mixture was poured into water (50 ml), and extracted with diethyl ether (25 ml×3). The combined organic layer was washed with 0.5N hydrochloric acid, saturated aqueous NaHCO3 solution and brine, and dried over MgSO4. The solvent was evaporated to give 2.06 g of 1-ethoxy-4-iodobenzene as a slightly brown solid. The product was used for the next reaction without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[CH3:12][NH:13][CH3:14]>CO.C(OCC)(=O)C>[CH3:12][N:13]([CH3:14])[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: CNC
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C)c1nccc(C(F)(F)F)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
2-Chloro-4-trifluoromethylpyrimidine (600 μL, 5.0 mmol) was dissolved with 2.0M dimethylamine in methanol (10 mL), and stirred for 2 hours in a sealed tube at 60° C. The reaction mixture was diluted with ethyl acetate (50 mL), and the whole was washed with water (50 mL) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 640 mg of the title Reference Compound as a colorless oil (Yield: 67%).
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[C:8]([N+:15]([O-:17])=[O:16])[CH:7]=1>>[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([Cl:3])=[O:11])=[C:8]([N+:15]([O-:17])=[O:16])[CH:7]=1
Reactant: O=C(O)c1ccc(F)cc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(F)cc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
5 mL of thionyl chloride was added to 0.5 g of 4-fluoro-2-nitrobenzoic acid and stirred overnight. The thionyl chloride was removed to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[C:4]([S:12][CH2:13][C:14]([O:16]C)=[O:15])=[CH:5][NH:6]2>O1CCCC1.[Li+].[OH-].C(OCC)C>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[C:4]([S:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:5][NH:6]2
Reactant: COC(=O)CSc1c[nH]c2cc(F)cc(F)c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O)CSc1c[nH]c2cc(F)cc(F)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
Methyl 2-((4,6-difluoro-1H-indol-3-yl)thio)acetate (253 mg, 0.98 mmol) from Step A was dissolved in a mixture of tetrahydrofuran (8 mL) and 2.0 M aqueous LiOH (2 mL), then stirred vigorously at ambient temperature for 30 minutes. Tetrahydrofuran was removed in vacuo, the aqueous layer neutralized with 1.2 N HCl and extracted with CH2Cl2. The organic layer was dried over magnesium sulfate and removed in vacuo to produce an oily residue. After diluting the residue with diethylether and removing the solvent in vacuo a solid formed which was the desired product (232 mg, 0.95 mmol, 98% yield). LCMS>99% at 254 nm, RT=1.17 min, m/z=244 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH2:15][CH2:14][NH:13][CH2:12][C:11]=2[C:10]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=2)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:27](O)(=O)CC(CC(O)=O)(C(O)=O)O>CCOC(C)=O.C(Cl)Cl>[CH2:1]([N:8]1[C:16]2[CH2:15][CH2:14][N:13]([CH3:27])[CH2:12][C:11]=2[C:10]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=2)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: Fc1ccc(-c2cn(Cc3ccccc3)c3c2CNCC3)cc1Cl
Agent: C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN1CCc2c(c(-c3ccc(F)c(Cl)c3)cn2Cc2ccccc2)C1

Procedure:
The title compound (0.03 g) was prepared from 1-benzyl-3-(3-chloro-4-fluoro-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine (Example 2) and paraformaldehyde as in Example 35. The product was then dissolved in 1/1 EtOAc/CH2Cl2 and treated with 0.03 g (0.15 mmol) of citric acid to afford 0.05 g of the corresponding citrate salt. MS (ESI): exact mass calculated for C21H20ClFN2, 354.13. found, m/z 355.1 [M+H]+, 357.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.44-7.22 (m, 1H), 7.34 (t, J=7.7 Hz, 2H), 7.30-7.26 (m, 2H), 7.22 (t, J=9.1 Hz, 1H), 7.19-7.13 (m, 3H), 5.14 (s, 2H), 4.36 (s, 2H), 3.50 (t, J=5.8 Hz, 2H), 2.96 (s, 3H), 2.89 (t, J=5.8, 2H), 2.82-2.71 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[CH2:22][NH:21][CH2:20][CH2:19][C:11]=2[N:12]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[N:14]=1.C(N(CC)CC)C.[C:30](OC(=O)C)(=[O:32])[CH3:31]>ClCCl>[C:30]([N:21]1[CH2:20][CH2:19][C:11]2[N:12]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[N:14]=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[C:10]=2[CH2:22]1)(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: CS(=O)(=O)c1nc2c(c(-c3ccc(Cl)cc3Cl)n1)CNCC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2nc(S(C)(=O)=O)nc(-c3ccc(Cl)cc3Cl)c2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(2,4-dichlorophenyl)-2-(methylsulfonyl)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidine (100 mg, 0.279 mmol), triethylamine (78 μl, 0.558 mmol) in dichloromethane (2 ml) was added acetic anhydride (53 μl, 0.558 mmol) dropwise. The resulting mixture was stirred at room temperature overnight. The mixture was partitioned between ethyl acetate and water. Organic layer was separated and washed with brine, dried (MgSO4) and filtered. Concentration of filtrate afforded crude product 6-acetyl-4-(2,4-dichlorophenyl)-2-(methylsulfonyl)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidine in quantitative yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:16][CH:15]=2)[C@@H:10]([O:30][CH2:31][C:32]2[CH:41]=[C:40]3[C:35]([CH2:36][CH2:37][CH2:38][N:39]3[CH2:42][CH2:43][CH2:44][OH:45])=[CH:34][CH:33]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:46][S:47](Cl)(=[O:49])=[O:48]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]([F:27])([F:29])[F:28])=[CH:18][CH:19]=2)[C@@H:10]([O:30][CH2:31][C:32]2[CH:41]=[C:40]3[C:35]([CH2:36][CH2:37][CH2:38][N:39]3[CH2:42][CH2:43][CH2:44][O:45][S:47]([CH3:46])(=[O:49])=[O:48])=[CH:34][CH:33]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(OCCCOCC(F)(F)F)cc2)[C@@H](OCc2ccc3c(c2)N(CCCO)CCC3)C1
Product: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(OCCCOCC(F)(F)F)cc2)[C@@H](OCc2ccc3c(c2)N(CCCOS(C)(=O)=O)CCC3)C1

Procedure:
In analogy to the procedure described in example 8(b), the (3R,4R)-3-[1-(3-hydroxy-propyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2,2,2-trifluoro-ethoxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester was reacted with methanesulfonyl chloride to yield the (3R,4R)-3-[1-(3-methanesulfonyloxy-propyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2,2,2-trifluoro-ethoxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester which was used without further purification or characterization.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:17]([CH2:18][CH:19]([F:21])[F:20])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:22]([CH3:24])[CH3:23])[S:14]2)[C@H:10]1[O:25]CC1C=CC=CC=1)C1C=CC=CC=1.B(Cl)(Cl)Cl.CO.[NH4+].[OH-]>ClCCl>[F:21][CH:19]([F:20])[CH2:18][C@H:17]1[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:22]([CH3:24])[CH3:23])[S:14]2)[C@@H:10]([OH:25])[C@@H:9]1[OH:8]
Reactant: CN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](CC(F)F)O[C@@H]2S1
Agent: ClB(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CN(C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CC(F)F)O[C@@H]2S1
Yield: 24.2 %

Procedure:
A solution of 109 (270 mg, 0.6 mmol) in dichloromethane (20 mL) was treated with BCl3 (6 mL, 6 mmol, 1M in dichloromethane) for 2 hours at −60° C., then the reaction was quenched with methanol (20 mL). Volatiles were distilled out under vacuum to give a residue, which was dissolved into methanol (5 mL) and neutralized by Con. NH4OH (2 ml, 26% aqueous solution). After concentration, the crude product was purified by a silica gel column, eluted with 10% methanol in dichloromethane to give the title compound as a white solid (41 mg, 25%); (ES, m/z) [M+H]+ 283.0; 1HNMR (300 MHz, D2O) δ 6.17 (d, J=6.3 Hz, 1H), 5.77-6.14 (m, 1H), 4.12 (t, J=6.0 Hz, 1H), 3.93 (t, J=5.1 Hz, 1H), 3.68-3.73 (m, 1H), 3.43-3.48 (m, 1H), 2.91 (s, 6H), 1.99-2.35 (m, 2H).
Reaction SMILES: [CH2:1]([N:4]([CH2:10][S:11]([C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:13])=[O:12])[C:5](=[O:9])[C@@H:6]1[O:8][CH2:7]1)[CH:2]=[CH2:3].[F-].[NH4+].C1COCC1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:1]([N:4]1[C@H:10]([S:11]([C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:13])=[O:12])[C@@H:6]([CH2:7][OH:8])[C:5]1=[O:9])[CH:2]=[CH2:3]
Reactant: C=CCN(CS(=O)(=O)C(C)(C)C)C(=O)[C@H]1CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCN1C(=O)[C@H](CO)[C@H]1S(=O)(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 197 mg (0.757 mmol) of N-allyl-N-tert.-butylsulphonylmethyl-(R)-glycidic acid amide in 1 ml of tetrahydrofuran is introduced at 0°, with the exclusion of moisture, into 8 ml of a tetra-n-butyl; ammonium fluoride/THF solution which has been prepared from 5.0 g of tetra-n-butylammonium fluoride trihydrate by dehydrating at 60° C./0.1 torr and making up to 20 ml with tetrahydrofuran. The reaction mixture is stirred for 2 hours at room temperature and then partitioned between methylene chloride and phosphate buffer solution (pH 8.0). The crude product obtained by drying over sodium sulphate and concentration by evaporation of the organic phase is chromatographed over preparative silica gel plates using hexane/ethyl acetate (1:3). the title compound is obtained in the form of colourless crystals.