Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Br-].[CH:12]1([Zn+])[CH2:16][CH2:15][CH2:14][CH2:13]1.O1CCOCC1>Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1.CO>[CH:12]1([C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: [Zn+]C1CCCC1
Reactant: Clc1ncnc2[nH]ccc12
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CO
Solvent: C1COCCO1
Product: c1nc(C2CCCC2)c2cc[nH]c2n1
Temperature: 110 °C
Yield: 16.4 %

Procedure:
4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 0.503 g, 3.28 mmol), cyclopentylzinc bromide (47, 29.5 mL, 0.500 M in tetrahydrofuran, 14.7 mmol), [1,3-bis(diphenylphosphino)propane]nickel(II) chloride (0.178 g, 0.328 mmol) and 9.3 mL of 1,4-dioxane were combined. The reaction mixture was heated at 110° C. overnight. Methanol was added and the reaction was concentrated under vacuum. Ethyl acetate and water were added to the residue, filtered through a bed of celite, and the celite washed with ethyl acetate. The filtrate layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with ethyl acetate and hexane. Appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (48, 0.101 g). MS (ESI) [M+H+]+=188.0.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][S:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:11][S:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: CSc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CSc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
1-Chloro-4-nitrobenzene (15 g, 95 mmol) and 4-(methylmercapto)phenol (13.3 g, 95 mmol) were dissolved in dimethylsulfoxide (100 ml). Potassium carbonate (15.8 g, 134 mmol) was added thereto, and the mixture was stirred for 12 h at 100° C. After completion of the reaction, excess water was added to give precipitated solid. The solid was filtered, and dried to give 1-(4-methylsulfanylphenoxy)-4-nitrobenzene.
Reaction SMILES: [Na].Br[C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][N:4]=1.C(=O)([O-])O.[Na+].[CH3:15][O:16][CH2:17][CH2:18][OH:19]>>[Br:9][C:6]1[CH:7]=[CH:8][C:3]([O:19][CH2:18][CH2:17][O:16][CH3:15])=[N:4][CH:5]=1
Reactant: COCCO
Reactant: Brc1ccc(Br)nc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Product: COCCOc1ccc(Br)cn1
Temperature: 90 °C
Reaction time: 2.5 h

Procedure:
1.1 g sodium and 2.5 g 2,5-dibromo-pyridine are added to 50 ml 2-methoxy-ethanol. The reaction mixture is heated to 90° C. and stirred for a further 2.5 hrs, then poured onto 75 ml of a saturated sodiumhydrogen carbonate solution and extracted three times with methylenchloride. The organic phases are combined, dried over sodium sulphate and concentrated and the residue is destilled. 2.2 g 5-Bromo-2-(2-methoxy-ethoxy)-pyridine are obtained., bp. 135° C./0.1 mbar MS (EI): 231 (M).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH:9]=[CH2:10])[CH2:7][O:6][C:5](=[O:8])[CH2:4]1.N1C=CC=CC=1.CN(C1C=CC=CN=1)C.[C:26](Cl)(=[O:40])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>C(Cl)Cl>[C:26]([O:1][CH2:2][C:3]1([CH:9]=[CH2:10])[CH2:7][O:6][C:5](=[O:8])[CH2:4]1)(=[O:40])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: C=CC1(CO)COC(=O)C1
Reactant: CCCCCCCCCCCCCC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CC1(COC(=O)CCCCCCCCCCCCC)COC(=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
A solution of 8b (0.2 g, 1.4 mmol) in CH2Cl2 (20 mL) was treated with pyridine (0.45 mL, 5.6 mmol), dimethylaminopyridine (0.034 g, 0.28 mmol), and tetradecanoyl chloride (0.76 mL, 2.8 mmol). After stirring for 2 h at room temperature, the reaction mixture was concentrated, and residue was purified by flash column chromatography over silica gel with hexane:EtOAc (3:1) as eluant to give 8c (0.49 g, 99%) as an oil: IR (neat) 1788 and 1741 cm-1 (C=O); 1H NMR (CDCl3) δ 0.86 (distorted t, 3 H, CH3), 1.25 (m, 20 H, CH3 (CH2)10CH2CH2CO), 1.60 (m, 2 H, CH3 (CH2)10CH2CH2CO), 2.31 (t, J=7.4 Hz, 2 H, CH3 (CH2)10CH2CH2CO), 2.60 (s, 2 H, H-3), 4.12 (AB q, J=11.3 Hz, 2 H, CH2OCOC13H27), 4.20 (AB q, J=9.3 Hz, 2 H, H-5), 5.19 (d, J=17.6 Hz, 1 H, CH=CHH), 5.28 (d, J=10.9 Hz, 1 H, CH=CHH), 5.84 (dd, J=10.9, 17.6 Hz, CH=CH2), 13C NMR (CDCl3) δ 14.02, 22.58, 24.69, 28.99, 29.11, 29.24, 29.34, 29.48, 29.53, 29.56, 31.81, 33.93, 36.57, 45.76, 66.63, 73.60, 116.63, 136.81, 173.27, 175.03. Anal. Calcd for C21H36O4 : C, 71.55; H: 10.30. Found. C, 71.46; H, 10.30.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=3)=[CH:11][C:10]([C:21]([OH:23])=O)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(N2C(C3C=CC=C(OCCO)C=3)=CC(C([N:48]3[CH2:52][C:51](=[O:53])[NH:50][CH2:49]3)=O)=N2)C=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=3)=[CH:11][C:10]([C:21]([N:48]3[CH2:52][C:51](=[O:53])[NH:50][CH2:49]3)=[O:23])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(-c2ccc(F)c(Cl)c2)n(-c2cccc(Br)c2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cccc(OCCO)c3)n(-c3cccc(Cl)c3)n2)CN1
Product: O=C1CN(C(=O)c2cc(-c3ccc(F)c(Cl)c3)n(-c3cccc(Br)c3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 99A in analogy to the synthesis of the compound of Example 23. 186 mg (79% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[CH:11][CH:10]=1)#[N:2].Cl.[CH3:28][C:29]1[CH:33]=[C:32]([NH:34][CH:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[NH:31][N:30]=1.C(N(CC)C1C=CC=CC=1)C>C(OCC)(=O)C>[CH3:28][C:29]1[CH:33]=[C:32]2[N:34]([CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[C:17](=[O:18])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)=[C:22]([CH2:23][CH2:24][CH3:25])[N:31]2[N:30]=1
Reactant: Cc1cc(NC2CCOCC2)[nH]n1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Agent: Cl
Solvent: CCN(CC)c1ccccc1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCOCC2)c2cc(C)nn12
Temperature: 180 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (0.96 g), 3-methyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine hydrochloride (0.3 g) and N,N-diethylaniline (10 mL) was stirred at 180° C. for 2 hr. The obtained reaction mixture was diluted with ethyl acetate, washed 3 times with 1 N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.27 g, 42%).
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:14].C(N(CC)CC)C.[CH3:22][CH:23]([OH:26])[CH2:24][CH3:25]>>[CH:23]([O:26][CH2:2][C:3]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:14])([CH2:24][CH3:25])[CH3:22]
Reactant: O=C1CCCc2c1ccc(O)c2CCl
Reactant: CCC(C)O
Solvent: CCN(CC)CC
Product: CCC(C)OCc1c(O)ccc2c1CCCC2=O

Procedure:
According to step (a) in the method of example A, 5-Chloromethyl-6-hydroxy-3,4-dihydro-2H-naphthalen-1-one (0.211 g, 1.0 mmol) was combined with triethylamine (0.167 ml, 1.2 mmol) in (±)butan-2-ol (3 ml, Aldrich Chemical) to produce 159 mg of desired product as an orange oil. Low resolution mass spectrum (APCI) m/z 249 [M+H]+.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][O:7][C@@H:6]1Br)(=[O:3])[CH3:2].[CH2:20]([OH:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Hg]C#N>C(#N)C.[Hg]Br>[C:1]([O:4][C@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][O:7][C@@H:6]1[O:27][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:3])[CH3:2]
Reactant: OCc1ccccc1
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](Br)OC[C@H]1OC(C)=O
Agent: Br[Hg]
Agent: N#C[Hg]
Solvent: CC#N
Product: CC(=O)O[C@@H]1[C@@H](OCc2ccccc2)OC[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 96.1 %

Procedure:
A solution of compound 2 (21 g, 61.9 mmol) in acetonitrile (200 ml) and benzyl alcohol (9.6 ml, 92.3 mmol) was vigorously stirred with molecular sieves (4 Å, 25 g), mercury bromide (25 g, 69.4 mmol), mercury cyanide (18.2 g, 12.0 mmol) under argon for 18 hours. The organic layer was filtered through celite and diluted with dichloromethane (250 ml) which was washed with water, aq. NaHCO3 and aq. NaCl and dried (Na2 SO4). The solvent was filtered and then evaporated under reduced pressure. The syrupy residue was chromatographed on silica gel (filter technique) using 1.5:1 hexane-ethyl acetate to give 3 (21.8 g, 90.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[C:25]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35]Cl)(=[O:27])[CH3:26].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[C:25]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][N:15]1[C:14](=[O:17])[N:11]2[N:12]=[CH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:10]2=[N:16]1)(=[O:27])[CH3:26]
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Reactant: CC(=O)Oc1ccccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccccc1Cn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn2c1=O
Temperature: 60 °C
Yield: 99.8 %

Procedure:
To a solution of the 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (800 mg, 2.24 mmol), prepared as described in Example 1, in 30 mL of DMF was added 2-(chloromethyl)phenyl acetate (497 mg, 2.69 mmol), followed by K2CO3 (619 mg, 4.48 mmol). The reaction was heated at 60° C. for overnight. After this time, the reaction was allowed to cool to RT and then was diluted with 250 mL of EtOAc. The resultant solution was washed with saturated aqueous NaCl (100 mL×3). The organic layer was dried over MgSO4, filtered, evaporated under reduced pressure to provide the title compound, 2-((7,8-bis(4-chlorophenyl)-3-oxo-[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl)methyl)phenyl acetate, (1.13 gm) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:9]2[C:4](=[C:5]([Cl:14])[C:6]([Cl:13])=[C:7]([O:11][CH3:12])[CH:8]=2)[C:3]1=[O:15].[N+:22]([O-])([O:24]CCCCC)=[O:23]>>[CH3:1][C:2]1([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[CH2:10][C:9]2[C:4](=[C:5]([Cl:14])[C:6]([Cl:13])=[C:7]([O:11][CH3:12])[CH:8]=2)[C:3]1=[O:15]
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(c1ccccc1)C2
Reactant: CCCCCO[N+](=O)[O-]
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(c1ccc([N+](=O)[O-])cc1)C2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Amyl nitrate (40 ml.) is added in 10 ml. increments at two hour intervals to 2-methyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone (9.36 g., 0.03 mole) in polyphosphoric acid (150 g.) at 50°-60° C. with stirring. The total heating period is 8 hours. The reaction mixture is treated with crushed ice-water to precipitate 4.82 g. of 2-methyl-2-(4-nitrophenyl)-5-methoxy-6,7-dichloro-1-indanone which melts at 179°-180° C. after crystallization from butyl chloride
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][CH2:11][CH2:12][Cl:13]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH2:10][CH2:11][CH2:12][Cl:13])[CH:3]=1
Reactant: Sc1cccc(Cl)c1
Reactant: ClCCCBr
Product: ClCCCSc1cccc(Cl)c1

Procedure:
Prepared by Procedure R and Scheme Z using 3-chlorobenzenethiol and 1-bromo-3-chloropropane.
Reaction SMILES: CCN(C(C)C)C(C)C.[Si:10]([N:17]1[CH2:21][CH2:20][CH2:19][C:18]1=[O:22])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].Cl[CH2:24][C:25]([N:27]([C:30]1[C:31]([Cl:41])=[N:32][N:33]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:34]=1)[CH2:28][CH3:29])=[O:26]>C1COCC1>[Si:10]([N:17]1[CH2:21][CH2:20][CH:19]([CH2:24][C:25]([N:27]([C:30]2[C:31]([Cl:41])=[N:32][N:33]([C:35]3[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=3)[CH:34]=2)[CH2:28][CH3:29])=[O:26])[C:18]1=[O:22])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CCN(C(=O)CCl)c1cn(-c2cccnc2)nc1Cl
Reactant: CC(C)(C)[Si](C)(C)N1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCN(C(=O)CC1CCN([Si](C)(C)C(C)(C)C)C1=O)c1cn(-c2cccnc2)nc1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 65.2 %

Procedure:
DIPEA (0.629 mL, 4.41 mmol) was dissolved in THF (20 mL) and cooled to about −78° C. n-Butylithium (1.77 mL, 4.41 mmol) was then added, and the reaction mixture was warmed to about 0° C. for 10 minutes, then re-cooled to about −78° C. Then, 1-(tert-butyldimethylsilyl)pyrrolidin-2-one (0.800 g, 4.01 mmol) was added, and the reaction mixture was warmed to 23° C. and stirred for 1 hour. The reaction was then re -chilled to −78° C., and 2-chloro-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylacetamide (0.600 g, 2.01 mmol) was then added dropwise as a solution in THF (3 mL). The reaction mixture was stirred cold for 30 minutes, then was allowed to slowly warm to room temperature. After 1 hour, the reaction was quenched with a NH4Cl solution and extracted with diethyl ether. The organics were washed with brine, dried over Na2SO4, and concentrated. The resulting oil was purified by flash column chromatography using 0-40% acetone/hexanes as eluent provided the intermediate 2-(1-(tert -butyldimethylsilyl)-2-oxopyrrolidin-3-yl)-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylacetamide (0.604 g, 1.31 mmol). 1H NMR analysis indicated a mixture of molecules present favoring the desired product of about 5:1 over main byproduct. The mixture carried through to the deprotection step without further purification. 2-(1-(tert-Butyldimethylsilyl)-2-oxopyrrolidin-3-yl)-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylacetamide (0.604 g, 1.31 mmol) was dissolved in THF (13 mL) and added was tetrabutylammonium fluoride (TBAF, 1.96 mL, 1.96 mmol). The reaction mixture was stirred for 30 minutes. The reaction product was concentrated onto CELITE® and purified by flash column chromatography using 40-100% acetone/hexanes as eluent providing the title compound (0.204 g, 30% over 2 steps).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH3:46])[N:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:56])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH3:46])[N:41]=5)=[O:56])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cccc(C)n4)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cccc(C)n4)cc2)CCN3CC(C)C)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 46.8 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(6-methyl-2-pyridinyl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.46 g) was dissolved in methylene chloride (13.8 ml), m-chloroperbenzoic acid (87 mg) was added to the mixture at 0° C., and the mixture was stirred for 20 minutes at 0° C. The reaction mixture was added to an aqueous solution of saturated sodium thiosulfate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(6-methyl-2-pyridinyl)methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 214) (157 mg).
Reaction SMILES: Cl.[CH2:2]([NH:9][CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O[CH:24](OCC)[CH2:25][NH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])C.Cl>CO.O>[CH2:30]([O:29][C:27]([NH:26][CH2:25][CH:24]1[C:13]2[NH:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12]=2[CH2:11][CH2:10][N:9]1[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCOC(CNC(=O)OCc1ccccc1)OCC
Reactant: c1ccc(CNCCc2c[nH]c3ccccc23)cc1
Agent: Cl
Solvent: O
Solvent: CO
Product: O=C(NCC1c2[nH]c3ccccc3c2CCN1Cc1ccccc1)OCc1ccccc1
Yield: 62 %

Procedure:
To a solution of 50 g of N-benzyl-tryptamine hydrochloride (i.e., 3-(2-(benzylamino)-ethyl)indole hydrochloride) in 500 ml of methanol-water (4:1) are added 57.9 g of N-benzyloxycarbonyl-aminoacetaldehyde diethylacetal and 25 ml of 10% hydrochloric acid, and the mixture is refluxed for 16 hours. After the reaction, the reaction mixture is evaporated under reduced pressure to remove solvent, and the resultant crystals are collected by filtration. After being washed with water and ether, said crystals are added to a saturated sodium bicarbonate solution, and then extracted with ethyl acetate. The extract is washed with water, dried and then evaporated to remove solvent. The residue (oil, 60 g) is purified by silica gel chromatography (Solvent: chloroform-methanol (20:1)). 46 g of 1,2,3,4-tetrahydro-1-((N-benzyloxycarbonylamino)methyl)-2-benzyl-β-carboline are thereby obtained as a caramel. Yield: 62%
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1.[N:11]1([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23]O)=[CH:19][C:18]=2[O:25][CH3:26])[CH:15]=[CH:14][CH:13]=[N:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>C1COCC1>[N:11]1([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:1]3[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]3)=[CH:19][C:18]=2[O:25][CH3:26])[CH:15]=[CH:14][CH:13]=[N:12]1
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: COc1cc(CO)ccc1Cn1cccn1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnn(Cc2ccc(Cn3cccn3)c(OC)c2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a mixture of Ethyl 1H-pyrazole-4-carboxylate (117 mg, 0.833 mmol), crude (4-((1H-pyrazol-1-yl)methyl)-3-methoxyphenyl)methanol (256 mg, 71%, 0.833 mmol) and Triphenylphosphine (328 mg, 1.249 mmol) in THF (8 ml) DEAD 40% in Toluene (0.494 ml, 1.249 mmol) was added slowly at 0° C. The reaction mixture was stirred at 0° C. for 2 h and continued to stir for 12 h at rt. A saturated solution of NaHCO3 was added and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude Ethyl 1-(4-((1H-pyrazol-1-yl)methyl)-3-methoxybenzyl)-1H-pyrazole-4-carboxylate. MS [M+H]+=341.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[OH:11].O[CH:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Na]>C1(C)C=CC=CC=1.O>[CH3:25][N:22]1[CH2:23][CH2:24][CH:19]([O:11][CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH2:20][CH2:21]1
Reactant: OC(c1ccccc1)c1nc2ccccc2s1
Reactant: CN1CCC(O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na]
Solvent: O
Solvent: Cc1ccccc1
Product: CN1CCC(OC(c2ccccc2)c2nc3ccccc3s2)CC1
Temperature: 25 °C

Procedure:
A mixture of benzothiazol-2-ylphenylmethanol (0.36 g), 4-hydroxy-1-methylpiperidine (0.17 g) and para-toluenesulfonic acid (0.57 g) in toluene (22 mL) is heated overnight in a Dean-Stark apparatus. The mixture is cooled back to room temperature and poored into water, alcalinised with 1N sodium hydroxyde and extracted twice with ethyl acetate. Pooled organic extracts are washed with brine, dried over magnesium sulfate and concentrated. The residue is purified by column chromatography over silica gel (gradient dichloromethane/methanol from 98/2 to 90/10) to give 2-[(1-methylpiperidin-4-yloxy)phenylmethyl]benzothiazole melting at 115° C.
Reaction SMILES: N[C:2]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[C:8]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:3]=1[C:4](OC)=[O:5].C(O)(=O)C.[CH:32]([NH2:34])=[NH:33]>COCCO>[CH2:21]([O:20][C:8]1[CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:33][CH:32]=[N:34]2)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1c(N)cc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: N=CN
Solvent: CC(=O)O
Solvent: COCCO
Product: O=c1[nH]cnc2cc(OCc3ccccc3)cc(OCc3ccccc3)c12
Yield: 89.5 %

Procedure:
A mixture of methyl 2-amino-4,6-dibenzyloxybenzoate (7.7 g), formamidine acetate (7.2 g) and 2-methoxyethanol (100 ml) was stirred and heated to reflux until all of the starting material had reacted. The mixture was evaporated and the residue was triturated under water (60 ml). The resultant solid was isolated, washed with water and dried under vacuum to give 5,7-dibenzyloxy-3,4-dihydroquinazolin-4-one (6.8 g); NMR Spectrum: (DMSOd6) 5.24 (s, 4H), 6.75 (s, 1H), 6.8 (s, 1H), 7.3–7.7 (m, 10H), 7.95 (s, 1H), 11.75 (br s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH3:12])[C:6]=2[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:21][N:22]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[C:25]2[CH:37]=[CH:38][N:39]([S:40]([C:43]3[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=3)(=[O:42])=[O:41])[C:24]=2[C:23]1=[O:50]>>[CH3:12][N:7]1[C:6]2[C:13]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:2]([C:26]3[C:25]4[CH:37]=[CH:38][N:39]([S:40]([C:43]5[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=5)(=[O:42])=[O:41])[C:24]=4[C:23](=[O:50])[N:22]([CH3:21])[CH:27]=3)[CH:3]=[CH:4][C:5]=2[O:10][CH2:9][C:8]1=[O:11]
Reactant: CN1C(=O)COc2ccc(Br)c(Oc3ccccc3)c21
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(B4OC(C)(C)C(C)(C)O4)cn(C)c(=O)c32)cc1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ccc5c(c4Oc4ccccc4)N(C)C(=O)CO5)cn(C)c(=O)c32)cc1

Procedure:
This compound was synthesized according to the procedure of Example 10, Step 5, using 6-bromo-4-methyl-5-phenoxy-2H-1,4-benzoxazin-3(4H)-one and 6-methyl-1-[(4-methylphenyl)sulfonyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one as the starting materials. LCMS calculated for C30H26N3O6S (M+H)+: m/z=556.2. found: 556.0.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[C:12]([NH2:13])=[C:11]([C:14]#[N:15])[CH:10]=[N:9]2)=[CH:6][CH:7]=1.S(=O)(=O)(O)[OH:17]>>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[C:12]([NH2:13])=[C:11]([C:14](=[O:17])[NH2:15])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: N#Cc1cnn(-c2ccc(Cl)nn2)c1N
Reactant: O=S(=O)(O)O
Product: NC(=O)c1cnn(-c2ccc(Cl)nn2)c1N

Procedure:
A mixture of 3 g. of 3-chloro-6-(4-cyano-5-amino-1-pyrazolyl)-pyridazine (prepared according to Example 24) and 10.5 ml. of concentrated sulphuric acid is stirred at room temperature for one hour. Then the mixture is poured onto ice, the precipitate filtered, washed with water and triturated with 15 ml. of hot ethanol, filtered and dried. Yield: 3.05 g. (93.5%); m.p.: 314°-317° C.