Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S-:1][C:2]#[N:3].[Na+].[CH2:5]([N:7]([CH2:11][CH3:12])[C:8](Cl)=[O:9])[CH3:6]>C(#N)C>[CH2:5]([N:7]([CH2:11][CH3:12])[C:8]([S:1][C:2]#[N:3])=[O:9])[CH3:6]
Reactant: N#C[S-]
Reactant: CCN(CC)C(=O)Cl
Agent: [Na+]
Solvent: CC#N
Product: CCN(CC)C(=O)SC#N
Temperature: 80 °C
Reaction time: 0.83 h

Procedure:
A suspension of sodium thiocyanate (3.30 g, 40.7 mmol) in dry acetonitrile (25 mL) at 80° C. was treated dropwise with a solution of N,N-diethyl carbamoyl chloride (5.0 g, 36.9 mmol) in dry acetonitrile (15 mL). The reaction mixture was stirred at 80° C. for 50 min, cooled to room temperature, then filtered through a fine glass frit. The resulting filtrate was used as a 0.9 M solution of N,N-diethyl carbamoyl thiocyanate in acetonitrile.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([O:13]C)=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1.[OH2:15].[OH-].[Li+:17]>C1COCC1.O>[O:15]=[C:2]1[NH:6][C:5]2=[C:7]([C:11]([O-:13])=[O:12])[CH:8]=[CH:9][CH:10]=[C:4]2[O:3]1.[Li+:17]
Reactant: COC(=O)c1cccc2oc(Cl)nc12
Reactant: O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C([O-])c1cccc2oc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 149.5 %

Procedure:
To a solution of methyl 2-chlorobenzoxazole-4-carboxylate (100 mg, 0.47 mmol) in THF (6 mL) was added a solution of lithium hydroxide monohydrate (29.7 mg, 0.71 mmol) in H2O (3 mL). The reaction mixture was stirred at room temperature for 18 h and then concentrated to dryness to afford lithium 2-oxo-2,3-dihydrobenzoxazole-4-carboxylate (130 mg, 100%) as a yellow solid that was directly used in the next step without purification. MS consistent
Reaction SMILES: [CH2:1](C1(CC)C2C=C(C=O)C=CC=2C2C1=CC(Br)=CC=2)C.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[SH:28].CS(C)=O>O>[S:28]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[CH:1]1
Reactant: Nc1ccccc1S
Reactant: CCC1(CC)c2cc(Br)ccc2-c2ccc(C=O)cc21
Solvent: CS(C)=O
Solvent: O
Product: c1ccc2scnc2c1
Temperature: 195 °C
Reaction time: 0.75 h
Yield: 80.3 %

Procedure:
A mixture of 9,9-diethyl-7-bromo-fluorene-2-carboxaldehyde (49.35 g., 0.15 mol.), 2-aminothiophenol (20 ml. 0.187 mol., 1,25 eq.), and DMSO (110 ml) was heated in an oil bath to a bath temperature of 195° C., held there for 45 minutes, and then poured into water. The separated solids were collected, reslurried in 1:4 acetic acid-water (1000 ml.) filtered, and washed with water and dilute sodium bicarbonate solution. These solids, 80.05 g., were then reslurried in hot ethanol, (600 ml), cooled and filtered to get the product benzothiazole, 45.69 g., m.p. 133.6-135° C. An additional 6.6 g., m.p. 134.6-135.5° C., was obtained by chromatography of the ethanol filtrate. Total recovery was 52.29 g. (80.3% yield). Mass Spec: m/z 433, 435, (M+). Anal. Calculated for C24H20BrNS: C, 66.37; H, 4.64; Br, 18.40; N, 3.23; S, 7.37%. Found: C, 66.46; H, 4.52; Br, 18.54; N, 3.14; S, 7.19%.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[B-](F)(F)(F)[F:13].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CC#N.CC(O)=O>[Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[C:10]([F:13])=[CH:9][NH:8][C:6]=2[N:7]=1
Reactant: F[B-](F)(F)F
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC(=O)O
Solvent: CC#N
Product: Fc1c[nH]c2nc(Cl)nc(Cl)c12
Temperature: 70 °C
Reaction time: 18 h
Yield: 22.9 %

Procedure:
A mixture of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (200 mg, 1.06 mmol) and SelectFluor (560 mg, 1.58 mmol) in CH3CN (5 mL) and HOAc (1 mL) was stirred at 70° C. for 18 h. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give 2,4-dichloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine (50 mg).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][N:9]([C:12](=O)[CH3:13])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:16][OH:17].C([O-])(=O)C.[Na+]>C(O)C.O>[C:1]1([N:7]2[CH:11]=[CH:10][N:9]([C:12](=[N:16][OH:17])[CH3:13])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: CC(=O)N1C=CN(c2ccccc2)N1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=NO)N1C=CN(c2ccccc2)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 28 g (0.15 mol) of 1-phenyl-3-acetyltriazole (Example 1a), 12 g (0.19 mol) of hydroxylamine hydrochloride and 16 g (0.2 mol) of sodium acetate in 225 ml of ethanol/water 2:1 was stirred overnight at room temperature (=25° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH:13]([OH:15])[CH3:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:16](OC=C)(=[O:18])[CH3:17]>C1(C)C=CC=CC=1>[C:16]([O:15][C@@H:13]([C:10]1[N:11]=[N:12][N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)[N:9]=1)[CH3:14])(=[O:18])[CH3:17]
Reactant: Cc1cccc(-n2nnc(C(C)O)n2)c1
Reactant: C=COC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)O[C@H](C)c1nnn(-c2cccc(C)c2)n1
Yield: 42.3 %

Procedure:
A mixture of 1-[2-(3-methylphenyl)-2H-tetrazol-5-yl]ethanol (93 g, 460 mmol) and Novozyme 435® (10 g) in dry toluene (4800 mL) was stirred slowly. Vinyl acetate (39.2 g, 460 mmol) was added and the mixture was stirred at room temperature for 5 hours. Novozyme 435® was filtrated and washed with toluene (100 mL). The filtrate was concentrated and purified on silica using petroleum ether/ethyl acetate (6:1) as eluent giving the title product (47.92 g, 42%).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][C:20]([CH2:23][N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[CH:19][CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)=[N:4]1)[CH3:2].C(N(C(C)C)CC)(C)C.FC1C([CH:53]([C:57]([O-])=[O:58])[N:54]([CH3:56])[CH3:55])=C(F)C(F)=C(F)C=1F>CN(C)C=O>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][C:20]([CH2:23][N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[CH:19][CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:57](=[O:58])[CH2:53][N:54]([CH3:56])[CH3:55])=[CH:32][CH:31]=2)=[N:4]1)[CH3:2]
Reactant: CN(C)C(C(=O)[O-])c1c(F)c(F)c(F)c(F)c1F
Reactant: CCn1cc(-c2ccnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)cc23)c(-c2ccc(N)cc2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1cc(-c2ccnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)cc23)c(-c2ccc(NC(=O)CN(C)C)cc2)n1
Reaction time: 18 h
Yield: 57 %

Procedure:
A solution of [4-(1-ethyl-4-{2-[4-(4-morpholinylmethyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)phenyl]amine (0.104 mmol) in N,N-dimethylformamide (1 mL) was treated with diisopropylethylamine (0.4 mmol) and then pentafluorophenyl-N,N-dimethylglycinate (0.104 mmol). The reaction was stirred 18 h and purified directly on the Gilson reverse phase HPLC which provided the title product as a yellow solid (57%). ESMS [M+H]+: 564.2
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:24]1[C:33]2[N:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH2:27][CH2:26][CH2:25]1)[CH2:12][CH2:13][CH2:14][NH:15][C:16](C1C=CC=CN=1)=[O:17].[C:34]([OH:37])(=O)[CH3:35]>>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[CH2:10][N:11]([CH:24]1[C:33]2[N:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH2:27][CH2:26][CH2:25]1)[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:17])[C:4]1[CH:9]=[CH:35][C:34]([OH:37])=[N:1][CH:5]=1
Reactant: CC(=O)O
Reactant: O=C(NCCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21)c1ccccn1
Product: O=C(NCCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21)c1ccc(O)nc1
Reaction time: 0.5 h

Procedure:
To a solution of the above amine (63 mg, 0.14 mmol) in acetic acid (2 mL) was added hydrobromide saturated acetic acid (2 mL). The reaction mixture was stirred for 30 minutes. Then it was triturated with diethyl ether four times to afford the title compound as a white solid (80 mg), which was dried in vacuo. 1H NMR (D2O) δ 1.81-2.01 (m, 4H), 2.16-2.20(m, 1H), 2.37-2.41 (m, 1H), 2.50-2.59 (m, 1H), 2.87-2.92 (m, 1H), 3.00 (br s, 2H), 3.11-3.16 (m, 1H), 3.37-3.42 (m, 1H), 3.53 (q, 1H, J=6.0 Hz), 4.25 (ABq, 2H, J=43.8, 15.3 Hz), 4.57-4.79 (m, 1H), 6.36 (d, 1H, J=9.6 Hz), 7.46-7.48 (m, 2H), 7.53 (s, 1H), 7.57-7.63 (m, 3H), 7.85 (t, 1H, J=6.3 Hz), 8.34 (d, 1H, J=7.8 Hz), 8.65 (d, 1H, J=5.4 Hz). 13C NMR (D2O) δ 20.33, 20.45, 36.87, 47.77, 48.22, 59.04, 114.10, 119.38, 125.90, 126.99, 130.69, 137.16, 139.46, 139.85, 140.66, 148.01, 150.87, 151.39. ES-MS m/z 457 [M+H]+. Anal. Calcd. for C26H28N6O2.3.0HBr.3.4H2O.0.2C4H10O: C, 41.52; H, 5.17; N, 10.84; Br, 30.92. Found: C, 41.70; H, 4.90; N, 10.71; Br, 30.63.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=1)C.[NH3:17]>CO>[CH3:15][C:10]1[CH:9]=[C:8]([NH:7][CH2:6][CH2:5][C:4]([NH2:17])=[O:3])[CH:13]=[C:12]([CH3:14])[CH:11]=1
Reactant: N
Reactant: CCOC(=O)CCNc1cc(C)cc(C)c1
Solvent: CO
Product: Cc1cc(C)cc(NCCC(N)=O)c1
Temperature: 25 °C
Yield: 100 %

Procedure:
3-(3,5-dimethyl-phenylamino)-propionic acid ethyl ester (0.0026 mol) in a 7N solution of NH3 in CH3OH was stirred at 80° C. in a sealed vessel. The reaction was cooled down to room temperature and the solvent was evaporated until dryness, yielding 0.5 g of 3-(3,5-dimethyl-phenylamino)-propionamide (100%).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[OH:22][C:23]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][N:26]4[CH2:25][CH2:24][C:23]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)([OH:22])[CH2:28][CH2:27]4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCC(O)(c2ccccc2)CC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 4-hydroxy-4-phenylpiperidine in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=463.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([C:6]1[CH:14]=[C:10]([C:11](O)=[O:12])[C:9]([OH:15])=[CH:8][CH:7]=1)=[O:5].S(Cl)([Cl:18])=O>>[CH3:1][O:2][CH2:3][C:4]([C:6]1[CH:14]=[C:10]([C:11]([Cl:18])=[O:12])[C:9]([OH:15])=[CH:8][CH:7]=1)=[O:5]
Reactant: O=S(Cl)Cl
Reactant: COCC(=O)c1ccc(O)c(C(=O)O)c1
Product: COCC(=O)c1ccc(O)c(C(=O)Cl)c1
Temperature: 25 °C
Yield: 101.5 %

Procedure:
The above prepared 5-methoxyacetylsalicylic acid (26.24 g, 0.1250 mol) was placed in a 500 ml round bottomed flask fitted with Argon purge and magnetic stir bar. Methylene chloride (125 ml) and several drops of dimethylformamide were then added. A 60 ml addition funnel was placed atop the flask and thionyl chloride (22.30 g, 0.1874 mol) was added dropwise over a period of 25 minutes. The addition funnel was replaced with a condenser and the reaction mixture was heated at reflux for a period of approximately 1 hour. Heating was stopped and the reaction mixture allowed to cool to room temperature. Excess thionyl chloride and methylene chloride were removed under-vacuum yielding 29.00 g of 5-methoxyacetylsalicyloyl chloride.
Reaction SMILES: [CH2:1]([S:8][C:9]1[S:19][C:12]2=[N:13][CH:14]=[C:15](I)[C:16](=[O:17])[N:11]2[N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[C:20]([Si:22]([CH3:25])([CH3:24])[CH3:23])#[CH:21]>C(N(CC)CC)C.O1CCCC1.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>[CH2:1]([S:8][C:9]1[S:19][C:12]2=[N:13][CH:14]=[C:15]([C:21]#[C:20][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:16](=[O:17])[N:11]2[N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCSc1nn2c(=O)c(I)cnc2s1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCSc1nn2c(=O)c(C#C[Si](C)(C)C)cnc2s1
Reaction time: 1 h
Yield: 80 %

Procedure:
In a mixture of 50 ml of triethylamine and 100 ml of tetrahydrofurane, 8.0 g of the thus obtained 2-heptylthio-6-iodo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was dissolved. To this solution, 0.68 g of bis(triphenylphosphine)palladium(II) chloride and 0.2 g of cuprous iodide were added as catalysts. To this mixture, a solution of 3.9 g of ethynyltrimethylsilane in 20 ml of triethylamine was added dropwise. The mixture was warmed to 60°~70° C. and stirred for 1 hour. Thereafter, further the same amounts as above of the catalysts and ethynyltrimethylsilane were added, and the mixture was stirred at 60°~70° C. for 3 hours. After cooling, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an ethyl acetate/toluene mixture as an eluent, and 5.9 g of 2-heptylthio-6-trimethylsilylethynyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. Yield 80%.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH:2]1[CH:10]1[C:22]2[NH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH2:13][CH2:12][NH:11]1.Cl[C:24]1[N:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[CH:26][N:25]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH:2]1[CH:10]1[C:22]2[NH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH2:13][CH2:12][N:11]1[C:24]1[N:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[CH:26][N:25]=1
Reactant: c1ccc2c(c1)CC(C1NCCc3c1[nH]c1ccccc31)O2
Reactant: Clc1ncc(-c2ccccn2)cn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(-c2cnc(N3CCc4c([nH]c5ccccc45)C3C3Cc4ccccc4O3)nc2)nc1

Procedure:
1-(2,3-dihydrobenzofuranyl)-2,3,4,9-tetrahydro-1H-β-carboline (prepared according to the process as disclosed in WO97/43287, Intermediate 10, page 25) (1.35 g, 4.66 mmol), 2-chloro-5-(2-pyridinyl)-pyrimidine (893 mg, 4.66 mmol) and N,N-diisopropylethylamine (1.4 mL) were stirred in DMF (10 mL, anhydrous) at 120° C. for 16 h. The resulting mixture was quenched with 10% NaCl and extracted with ethyl acetate. The extracted organic layer was washed with 10% NaCl, brine and then dried with MgSO4. The reaction mixture solvent was evaporated and the residue purified by column chromatography (silica gel, ethyl acetate:hexanes=4:6) to yield the product as a white solid.
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([CH3:19])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([O:20]C)=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4].B(Br)(Br)Br.C1C=CC=CC=1>C(Cl)Cl>[CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([CH3:19])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([OH:20])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC12CCC(=O)C(C)=C1c1ccc(OC)cc1C2
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: c1ccccc1
Product: CCCCC12CCC(=O)C(C)=C1c1ccc(O)cc1C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 9a-butyl-7-methoxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (76 mg, 0.267 mmol) in anhydrous CH2Cl2 (2 mL) was placed under a nitrogen atmosphere, cooled in an ice bath, and stirred while 1M BBr3 in CH2Cl2 (0.80 mL, 0.80 mmol) was added by syringe. The cooling bath was removed and the mixture was stirred at room temperature for 2 hours. The mixture was partitioned between EtOAc (20 mL) and water (20 mL) containing 2N HCl (2 mL). The organic phase was washed with brine (10 mL), dried over MgSO4, filtered, and evaporated under vacuum to an oil. This material was purified by preparative layer chromatography on a 0.1×20×20 cm silica gel GF plate using 5% MeOH in CH2Cl2 as the developing solvent. The product band was eluted with 10% MeOH in CH2Cl2 and the eluant evaporated under vacuum to give an oil which was lyophilized from benzene to afford 9a-butyl-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one as an amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:20]([NH:22][NH2:23])=[O:21])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.CCN(CC)CC.Cl[C:32](=[O:38])[C:33]([O:35][CH2:36][CH3:37])=[O:34]>C1COCC1>[NH2:1][C:2]1[C:3]([C:20]([NH:22][NH:23][C:32](=[O:38])[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:21])=[N:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:15])=[O:16])=[CH:12][CH:13]=2)=[CH:6][N:7]=1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(C(=O)NN)n2)cc1
Reactant: CCOC(=O)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)NNC(=O)c1nc(-c2ccc(S(=O)(=O)C(C)C)cc2)cnc1N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 58.5 %

Procedure:
3-amino-6-(4-isopropylsulfonylphenyl)pyrazine-2-carbohydrazide (2 g, 5.963 mmol) and Et3N (1.810 g, 2.493 mL, 17.89 mmol) were dissolved in THF (128.0 mL) and treated dropwise with ethyl 2-chloro-2-oxo-acetate (814.2 mg, 666.3 μL, 5.963 mmol) at 0° C. The reaction mixture was warmed slowly to room temperature and stirred for 1.5 h. The reaction mixture was filtered and grey solid washed with THF. The filtrate was evaporated to dryness azeotroping with acetonitrile. Then residue was then triturated with acetonitrile to give the product as a yellow solid (1.52 g, 58%); 1H NMR (400 MHZ, DMSO) d 1.19 (m, 6H), 1.32 (m, 3H), 3.34 (m, 1H), 4.32 (m, 2H), 7.88 (m, 2H), 8.56 (m, 2H), 9.07 (s, 1H), 10.95 (s, 1H) and 11.05 (s, 1H) ppm; MS (ES+) 436.32
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])=[N:10][N:11]3[C:16](O)=[CH:15][CH:14]=[N:13][C:12]=23)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.O=P(Cl)(Cl)[Cl:36]>C1(C)C=CC=CC=1>[Cl:36][C:16]1[N:11]2[N:10]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[C:12]2[N:13]=[CH:14][CH:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccnc2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccc(-c2c(-c3ccccc3Cl)nn3c(Cl)ccnc23)cc1
Temperature: 100 °C

Procedure:
To a slurry of 3-(4-chlorophenyl)-2-(2-chlorophenyl)-pyrazolo[1,5-a]pyrimidin-7-ol (I-12A-1a; 2.00 g, 5.61 mmol) and diisopropylethylamine (4.0 ml, 22 mmol) in toluene (60 ml) at room temperature was added POCl3 (2.1 ml, 22 mmol), dropwise. The mixture was heated at 100° C. for 7 hours, concentrated, in vacuo, and the purified by silica gel chromatography using 10% hexanes in methylene chloride as eluant to afford I-13A-1a (1.72 g, 82%) as a solid: +APcI MS (M+1) 374.1; 1H NMR (400 MHz, CD2Cl2) δ 8.49 (d, J=4.6 Hz, 1H), 7.54–7.38 (m, 6H), 7.28 (d, J=8.7 Hz, 2H), 7.12 (d, J=4.2 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[C:26]([CH3:37])=[N:27][C:28]([O:31][CH:32]2[CH2:36][CH2:35][O:34][CH2:33]2)=[CH:29][CH:30]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9]([C:25]1[C:26]([CH3:37])=[N:27][C:28]([O:31][CH:32]2[CH2:36][CH2:35][O:34][CH2:33]2)=[CH:29][CH:30]=1)=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1nc(OC2CCOC2)ccc1Br
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Product: Cc1nc(OC2CCOC2)ccc1C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and rac-3-bromo-2-methyl-6-(tetrahydro-furan-3-yloxy)-pyridine (Intermediate 13) in analogy to Example 1a): MS (ISP): 481.2 (M+H)+ and 483.2 ((M-Boc)+H)+ (100%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:26]=[CH:25][C:8]([O:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)=[C:7]([O:27][CH3:28])[CH:6]=1)(=[O:3])[CH3:2].[H-].[Na+].[CH3:31][C:32]([CH3:36])=[CH:33][CH2:34]Br>CN(C)C=O>[C:1]([N:4]([C:5]1[CH:26]=[CH:25][C:8]([O:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][CH2:18]2)=[C:7]([O:27][CH3:28])[CH:6]=1)[CH2:34][CH:33]=[C:32]([CH3:36])[CH3:31])(=[O:3])[CH3:2]
Reactant: COc1cc(NC(C)=O)ccc1OCCCN1CCN(c2ccccc2)CC1
Reactant: CC(C)=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(N(CC=C(C)C)C(C)=O)ccc1OCCCN1CCN(c2ccccc2)CC1
Yield: 75.6 %

Procedure:
2 g of 1-[3-(4- acetamido-2- methoxyphenoxy)-n-propyl]-4-phenyl-piperazine, 232 mg of 65% sodium hydride, 940 mg of 3-methyl-2- butenyl bromide and 60 ml of anhydrous dimethylformamide are treated in the same manner as described in Example 13. 1.78 g of 1-{3-[4-(N-acetyl-N-(3-methyl-2-butenyl)-amino)-2-methoxyphenoxy]-n-propyl}-4-phenyl-piperazine are thereby obtained as a pale yellow oil. Yield: 86.3%
Reaction SMILES: CO.[CH3:3][NH2:4].[C:5]([C:7]1[CH:8]=[C:9]([S:13](Cl)(=[O:15])=[O:14])[CH:10]=[CH:11][CH:12]=1)#[N:6]>>[NH2:6][CH2:5][C:7]1[CH:8]=[C:9]([S:13]([NH:4][CH3:3])(=[O:15])=[O:14])[CH:10]=[CH:11][CH:12]=1
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Reactant: CN
Solvent: CO
Product: CNS(=O)(=O)c1cccc(CN)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(Step 1) To a 40% methylamine methanol solution (5 ml) was added 3-cyanobenzenesulfonyl chloride (0.88 g) at 0° C., and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, saturated brine was added, and the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure. 10% Palladium carbon powder (0.46 g) was added to a solution (10 ml) of the residue in ethanol, and the mixture was stirred overnight under a hydrogen atmosphere (1 atm). The solution was filtered through celite. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate) to give 3-(aminomethyl)-N-methylbenzenesulfonamide (0.38 g) as a colorless oil.
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH2:11][CH3:12])(=[O:9])[C:4]([O:6]CC)=O.[C:13]([C:16]1[O:17][CH:18]=[CH:19][CH:20]=1)(=[O:15])[CH3:14].Cl>O1CCCC1>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:13](=[O:15])[CH2:14][C:4](=[O:6])[C:3]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CC(=O)c1ccco1
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)CC(=O)c1ccco1
Temperature: 70 °C
Reaction time: 1 h
Yield: 58.2 %

Procedure:
To a suspension of sodium hydride (5.4 g of 60% dispersion in mineral oil, 136 mmol, mineral oil was removed by washing twice with hexanes) in 100 mL of tetrahydrofuran at ambient temperature was added diethyl oxalate (12.3 mL, 91 mmol). To this mixture was added 2-acetylfuran (5.0 g, 45 mmol) as a solution in 25 mL of tetrahydrofuran. The resulting mixture was stirred at 70° C. for 1 h. The reaction was cooled to room temperature and then 10% HCl was added slowly until the solution was acidic. The tetrahydrofuran was removed in vacuo and the residue was taken up in ethyl acetate. The organics were washed with brine, dried (MgSO4) and concentrated to afford 5.5 g (58%) of the title compound which was used without purification.