Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])[N:5]=[C:4]([C:15]#[N:16])[CH:3]=1.IN1[C:22](=O)[CH2:21][CH2:20][C:19]1=[O:24]>C(#N)C>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:14])=[CH:9][CH:10]=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:15]#[N:16])[C:3]=1[C:22]1[O:24][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1CCC(=O)N1I
Reactant: N#Cc1cc(N)n(-c2c(Cl)cccc2Cl)n1
Solvent: CC#N
Product: N#Cc1nn(-c2c(Cl)cccc2Cl)c(N)c1-c1ccco1
Reaction time: 1 h

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichlorophenyl)pyrazole (0.1318 g) in acetonitrile (5 ml) at room temperature was added N-iodosuccinimide (0.1469 g). Stirring was continued for 1 hour and the mixture was then evaporated to dryness. The residue was taken up in dioxane (5 ml). Furan-2-boronic acid (0.1232 g), tetrakis(triphenylphosphine)palladium(0) (0.0554 g) and a solution of potassium carbonate (0.4405 g) in water (2 ml) were added. The mixture was heated under reflux for 48 hours, then cooled and partitioned between ether and water. The separated aqueous layer was extracted with ether and the combined ether layers were washed with brine, dried and evaporated. The green oily residue was purified by column chromatography on silica gel (4 g) eluted with dichloromethane. Combination and evaporation of suitable fractions followed by recrystallisation from toluene gave the title compound as a light brown solid, m.p. 222.6° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=[C:19]([O:31][CH3:32])[CH:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.C(O)C>Cl>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=[C:19]([O:31][CH3:32])[CH:18]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3cccnc3)c(OC)c2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1nn(Cc2ccc(OCc3cccnc3)c(OC)c2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
A mixture of ethyl 3-[3-ethoxy-1-[3-methoxy-4-(3-pyridylmethoxy)benzyl]-1H-pyrazole-4-yl]propionate (527 mg), 1 N aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature for two hours, diluted with 1 N hydrochloric acid (2.5 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained colorless crystals were collected by filtration, and 3-[3-ethoxy-1-[3-methoxy-4-(3-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (381 mg, yield: 77%) was obtained. This was recrystallized from ethanol-hexane. Melting point: 124–125° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:21]=[C:22]([N:27]=[C:28]=[S:29])[CH:23]=[CH:24][C:25]=1[Cl:26]>>[N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[S:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:28]([NH:27][C:22]2[CH:23]=[CH:24][C:25]([Cl:26])=[C:20]([Cl:19])[CH:21]=2)=[S:29])=[CH:7][CH:6]=1
Reactant: Nc1ccc(Sc2ccc3ccccc3n2)cc1
Reactant: S=C=Nc1ccc(Cl)c(Cl)c1
Product: S=C(Nc1ccc(Sc2ccc3ccccc3n2)cc1)Nc1ccc(Cl)c(Cl)c1

Procedure:
2-(4-Aminophenylthio)quinoline 11.9 mmoles, 3.0 g) and 3,4-dichlorophenylisothiocyanate 11.9 mmoles, 2.42 g) were reacted according to procedure B to yield the title compound, 360 mg, 6.6%. Mass Spec (FD) 455. Calculated for C22H15Cl2N3S2 : C, 57.90 H. 3.31; N, 9.21. Found: C, 57.86; H, 3.53; N, 9.07. m.p. 125°-126°.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@@:5]3([CH3:38])[CH:9]([CH:10]4[CH2:11][C@H:12]([F:21])[C:13]5[C@@:18]([CH3:19])([C@:2]124)[CH:17]=[CH:16][C:15](=[O:20])[CH:14]=5)[CH2:8][C@@H:7]([CH3:22])[C@:6]3([O:26][C:27]([C:29]1[O:30][C:31]([O:34][C:35](=[O:37])[CH3:36])=[CH:32][CH:33]=1)=[O:28])[C:23]([OH:25])=[O:24].[CH2:39]1CCN2C(=NCCC2)CC1.S(OC)(OC)(=O)=O>C(OCC)(=O)C.Cl>[O:1]1[C@H:3]2[CH2:4][C@@:5]3([CH3:38])[CH:9]([CH:10]4[CH2:11][C@H:12]([F:21])[C:13]5[C@@:18]([CH3:19])([C@:2]124)[CH:17]=[CH:16][C:15](=[O:20])[CH:14]=5)[CH2:8][C@@H:7]([CH3:22])[C@:6]3([O:26][C:27]([C:29]1[O:30][C:31]([O:34][C:35](=[O:37])[CH3:36])=[CH:32][CH:33]=1)=[O:28])[C:23]([O:25][CH3:39])=[O:24]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC(=O)Oc1ccc(C(=O)O[C@]2(C(=O)O)[C@H](C)CC3C4C[C@H](F)C5=CC(=O)C=C[C@]5(C)[C@@]45O[C@H]5C[C@@]32C)o1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)[C@@]1(OC(=O)c2ccc(OC(C)=O)o2)[C@H](C)CC2C3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]34O[C@H]4C[C@@]21C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product of Step 1 (721 mg) is dissolved in ethyl acetate (25 mL). DBU (242 mg) is added, followed by dimethyl sulfate (201 mg) and the reaction is stirred at room temperature for 2 hours, then diluted with 0.2 M HCl. The organic phase is washed with water and brine, then dried over magnesium sulfate and evaporated. Purification by flash chromatography on silica gel eluting with hexanes-ethyl acetate (2:1) affords 5-acetoxyfuran-2-carboxylic acid (6S,9S,10S,11S,13S,16R,17R)-9,11-epoxy-6-fluoro-17-methoxycarbonyl-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl ester. Selected NMR signals (CDCl3) δ 0.96 (3H, d), 0.98 (3H, s), 1.40 (3H, s), 2.18 (3H, s), 2.76 (3H, s).
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:19]([NH:21][NH:22][C:23]2[C:28]([F:29])=[C:27]([NH:30][CH2:31][C:32]3[S:33][CH:34]=[CH:35][N:36]=3)[N:26]=[C:25]([CH3:37])[N:24]=2)=[O:20])[CH2:8][N:9]([O:12]C2CCCCO2)[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.CC(O)=O>O>[CH:1]1([CH2:6][C@@H:7]([C:19]([NH:21][NH:22][C:23]2[C:28]([F:29])=[C:27]([NH:30][CH2:31][C:32]3[S:33][CH:34]=[CH:35][N:36]=3)[N:26]=[C:25]([CH3:37])[N:24]=2)=[O:20])[CH2:8][N:9]([OH:12])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nc(NCc2nccs2)c(F)c(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)n1
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc(NCc2nccs2)c(F)c(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)n1
Yield: 51.1 %

Procedure:
[(2R)-2-(Cyclopentylmethyl)-3-(2-{5-fluoro-2-methyl-6-[(1,3-thiazol-2-ylmethyl)amino]-4-pyrimidinyl}hydrazino)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (67 mg, 0.13 mmol) in 4:1 AcOH:water (5 mL) was stirred at room temperature overnight. The solvents were removed in vacuo, and the resulting crude product was purified by RP-HPLC to provide [(2R)-2-(cyclopentylmethyl)-3-(2-{5-fluoro-2-methyl-6-[(1,3-thiazol-2-ylmethyl)amino]-4-pyrimidinyl}hydrazino)-3-oxopropyl]hydroxyformamide (30 mg, 51%). LCMS: (M+H)+: 452.1.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[O:21][CH2:20][C@H:19]([CH2:22]O)[C@@H:18]([CH2:24]O)[C@@H:17]2[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[CH3:33])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH2:48]([NH2:55])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:48]([N:55]1[CH2:24][C@H:18]2[C@H:17]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=3[CH3:33])[C@@H:16]([O:15][C@@H:13]([C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:34])[F:35])[CH:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:6]=3)[CH3:14])[O:21][CH2:20][C@@H:19]2[CH2:22]1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: NCc1ccccc1
Reactant: Cc1cc(F)ccc1[C@@H]1[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC[C@H](CO)[C@H]1CO
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(F)ccc1[C@@H]1[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC[C@@H]2CN(Cc3ccccc3)C[C@H]21
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
The intermediate from step I (2.44 g, 4.87 mmol) was combined with DMAP (0.15 g, 1.2 mmol) and dissolved in 38 mL DCM. The reaction vessel was cooled 0° C. followed by the sequential addition of triethylamine (2.72 mL, 19.5 mmol) and methanesulfonyl chloride (0.95 mL, 12.2 mmol). After 5 minutes, the reaction vessel was warmed to ambient temperature where it remained for 0.5 hr. The reaction was quenched by the addition of a saturated solution of NaHCO3. The aqueous mixture was extracted several times with DCM. The combined organic extracts were washed with 1 M HCl, brine, dried over Na2SO4, filtered through a fritted funnel and concentrated in vacuo. The crude bis-mesylate was dissolved in 50 mL n-butanol followed by the addition of benzylamine (3.19 mL, 29.2 mmol). The reaction vessel was heated to 100° C. for 3.5 hr. The volatiles were removed in vacuo and the crude residue was purified on silica gel and eluted with a combination of EtOAc/hexanes (35-95% EtOAc/hexanes linear gradient) which furnished the title compound. MS: (MH)+582.
Reaction SMILES: [CH3:1][C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4](OCC)=[O:5].[CH3:13][NH2:14]>CO>[CH3:1][C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([NH:14][CH3:13])=[O:5]
Reactant: CCOC(=O)c1cccnc1C
Reactant: CN
Solvent: CO
Product: CNC(=O)c1cccnc1C
Temperature: 50 °C
Yield: 95 %

Procedure:
To ethyl 2-methylnicotinate (24.2 g) was added a solution of 40% methylamine in methanol (150 ml), which was then heated in a sealed tube at 50° C. overnight. The reaction mixture was evaporated, to give the title compound as a pale yellow solid (20.781 g, yield; 95%).
Reaction SMILES: Cl.Cl.Cl[C:4]1[CH:9]=[CH:8][NH:7][C:6](=[O:10])[C:5]=1[C:11]1[NH:12][C:13]2[C:21]([N:22]=1)=[CH:20][C:19]1[C:18](=[O:23])[N:17]([CH2:24][CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:16][C:15]=1[CH:14]=2.Cl.[CH3:33][C@H:34]([NH2:41])[CH2:35][C:36]1[S:37][CH:38]=[CH:39][CH:40]=1.CCN(CC)CC>CCO>[CH3:33][C@H:34]([NH:41][C:4]1[CH:9]=[CH:8][NH:7][C:6](=[O:10])[C:5]=1[C:11]1[NH:12][C:13]2[C:21]([N:22]=1)=[CH:20][C:19]1[C:18](=[O:23])[N:17]([CH2:24][CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:16][C:15]=1[CH:14]=2)[CH2:35][C:36]1[S:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C1c2cc3nc(-c4c(Cl)cc[nH]c4=O)[nH]c3cc2CN1CCCN1CCCC1
Reactant: C[C@H](N)Cc1cccs1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: C[C@@H](Cc1cccs1)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)CN(CCCN1CCCC1)C3=O
Temperature: 100 °C
Yield: 47.4 %

Procedure:
A mixture of 2-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(3-pyrrolidin-1-yl-propyl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-one dihydrochloride (17) (2.2 g, 4.9 mmol), (1S)-1-methyl-2-thien-2-ylethylamine hydrochloride (13b) (870 mg, 4.9 mmol) and Et3N (3.44 mL, 24.5 mmol) in EtOH (20 mL) was heated at 100° C. for 12 h. The mixture was concentrated, diluted with water (20 mL) and extracted with CHCl3 (5×20 mL) the combined organic layer was dried, concentrated to a residue that was purified on silica gel column using 10% NH4OH/methanol in CH2Cl2 to get pure 2-[4-((S)-1-methyl-2-thiophen-2-yl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-6-(3-pyrrolidin-1-yl-propyl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-one (18a) (1.2 g, 51%). 1H NMR (DMSO-d6) δ 1.33 (d, 3H, J=3.0 Hz), 1.55-1.85 (m, 6H), 2.3-2.45 9 m, 6H), 3.15-3.25 (m, 2H), 3.56 (t, 2H, J=6.0 Hz), 3.95-4.15 (m, 1H), 4.51 (s, 2H), 6.15 (d, 1H, J=9.0 Hz), 6.91-6.96 (m, 1H), 7.05 (t, 1H, J=3.0 Hz), 7.31-7.36 (m, 2H), 7.66 (s, 0.5H), 7.79 (d, 1H, J=3.0 Hz), 7.93 (s, 0.5H), 11.14 (d, 1H, J=9.0 Hz), 11.24 (bs, 1H). ESI-MS m/z 517.67 (M++1).
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[N:8]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[C:23]([O:24][CH3:25])=[CH:22][C:21]([CH3:26])=[CH:20][C:19]=3[O:27][CH3:28])[N:17]=2)[C:9]([CH3:12])=[CH:10][CH:11]=1.S(O[CH:37]([CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1)[CH3:38])(C(F)(F)F)(=O)=O.O>CCCCCC>[CH:39]1([CH2:37][CH2:38][C:15]2[S:14][C:13]([N:8]3[C:7]([CH3:6])=[CH:11][CH:10]=[C:9]3[CH3:12])=[N:17][C:16]=2[C:18]2[C:23]([O:24][CH3:25])=[CH:22][C:21]([CH3:26])=[CH:20][C:19]=2[O:27][CH3:28])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: CC(OS(=O)(=O)C(F)(F)F)C1CCCCC1
Reactant: COc1cc(C)cc(OC)c1-c1csc(-n2c(C)ccc2C)n1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Product: COc1cc(C)cc(OC)c1-c1nc(-n2c(C)ccc2C)sc1CCC1CCCCC1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 9.1 %

Procedure:
10 ml of 1.6M n-butyllithium in hexane are added, at −30° C., to 4.27 g of 2-(2,5-dimethylpyrrol-1-yl)-4-(2,6-dimethoxy-4-methylphenyl) thiazole and the mixture is left stirring for 30 minutes at −30° C. 4.2 g of cyclohexylethanol triflate are added at −45° C., the mixture is then warmed to 0° C., water is added, this mixture is extracted with Et2O and the extracts are dried and evaporated. The gum formed is chromatographed on silica, eluting with cyclohexane/EtOAc (1/1; v/v). 0.52 g of the expected compound is obtained in the form of a colourless gum.
Reaction SMILES: [C:1]([CH:6]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:3][CH2:4][CH3:5])=[O:2].[Br:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][C:28]=1[F:35]>C(Cl)Cl>[CH2:4]([O:3][C:1](=[O:2])[CH:6]=[CH:31][C:30]1[CH:33]=[CH:34][C:27]([Br:26])=[C:28]([F:35])[CH:29]=1)[CH3:5]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Br)c(F)c1
Solvent: ClCCl
Product: CCOC(=O)C=Cc1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 86.4 %

Procedure:
To a solution of (carbethoxymethylene)-triphenylphosphorane (4.2 g, 12 mmol) in CH2Cl2 at 10 degrees Celsius was added 4-bromo-3-fluoro-benzaldehyde (2.3 g, 11.4 mmol) dropwise over 30 minutes. This mixture was stirred for another 45 minutes at room temperature until the starting material had been consumed, and then the solvent was removed in vacuo. The crude product was purified by column chromatography (PET:EtOAc=1:1) to get desired product (2.69 g, 87%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[C:7]([CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[N:4]=1.[CH3:12][N:13]([CH3:29])[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:26]=[C:27]=[O:28])(=[O:25])=[O:24])(=[O:16])=[O:15]>C(Cl)Cl>[CH3:11][O:10][C:5]1[CH:6]=[C:7]([CH3:9])[N:8]=[C:3]([CH2:2][NH:1][C:27]([NH:26][S:23]([C:18]2[C:17]([S:14]([N:13]([CH3:29])[CH3:12])(=[O:16])=[O:15])=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:25])=[O:24])=[O:28])[N:4]=1
Reactant: CN(C)S(=O)(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: COc1cc(C)nc(CN)n1
Solvent: ClCCl
Product: COc1cc(C)nc(CNC(=O)NS(=O)(=O)c2ccccc2S(=O)(=O)N(C)C)n1
Reaction time: 18 h
Yield: 49.9 %

Procedure:
The product from Example 9 (0.90 g) was added in a steady stream to a stirred solution of 2.3 g of 2-(N,N-dimethylsulfamoyl)benzenesulfonyl isocyanate in 20 ml dry methylene chloride at room temperature. The reaction solution was stirred for an additional 18 hours and the solvent was removed in vacuo. The resulting yellow foam was stirred with 1-chlorobutane for ca. one hour. The mixture was filtered and the collected solids dried to yield 1.3 g of N'-[(4-methoxy-6-methylpyrimidin-2-yl)methylaminocarbonyl]-N,N-dimethyl-1,2-benzenedisulfonamide, m.p. 153°-156° C., as a light yellow solid.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[Cl:21][C:22]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](O)=O>>[Cl:21][C:22]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]1[O:15][N:14]=[C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[CH:7]2)[N:16]=1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3cccc(Cl)c3Cl)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 241 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 2,3-dichlorobenzoic acid: MS (ES): m/z 438 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[C:16]([C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
Reactant: COc1ccc(B(O)O)cc1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2ccccc2C(=O)NCCc2c[nH]c3ccc(Cl)cc23)cc1
Yield: 94 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methoxybiphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176 mmol), 4-methoxyphenylboronic acid (0.028 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.067 g (94%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methoxybiphenyl-2-carboxamide as a white solid.
Reaction SMILES: O(C([N:10]1[CH2:15][CH2:14][CH:13]([C:16](=[O:24])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[CH2:12][CH2:11]1)=O)C1C=CC=CC=1.[OH-].[K+].[ClH:27]>O.C(O)C>[ClH:27].[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]([CH:13]1[CH2:14][CH2:15][NH:10][CH2:11][CH2:12]1)=[O:24]
Reactant: O=C(c1ccccc1F)C1CCN(C(=O)Oc2ccccc2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(c1ccccc1F)C1CCNCC1
Temperature: 25 °C
Yield: 40 %

Procedure:
A solution of 40.5 g of 1-phenoxycarbonyl-4-(2-fluorobenzoyl)piperidine, 500 ml of ethanol and 500 ml of 30% of potassium hydroxide solution was stirred at a temperature slightly below reflux overnight. The reaction mixture was cooled to room temperature, diluted with 250 ml of water, and the ethanol partially removed under reduced pressure The aqueous suspension was extracted with ether (2×150 ml) and the ether fraction subsequently extracted with 1N hydrochloric acid (2×200 ml). The aqueous solution was basified with 25% sodium hydroxide solution, extracted with ether (2×150 ml) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give an oil. The oil was dissolved in a minimum amount of ethanol and a solution of ethereal hydrogen chloride was added dropwise until a precipitate formed. The solid was collected and dried to give 9.7 g (40%) of product. Recrystallization twice from ethanol-ether gave the analytical sample, mp 185°-187° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[N:25]1([CH2:31][C:32]2[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CCO>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:36]([C:35]3[CH:34]=[CH:33][C:32]([CH2:31][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:39][CH:38]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Brc1cnc2[nH]c(-c3ccc(CN4CCOCC4)cc3)nc2c1N1CCN(Cc2cccnc2)CC1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a mixture of 5-bromo-3-nitro-4-(4-pyridin-3-ylmethyl-piperazin-1-yl)-pyridin-2-ylamine (0.047 g, 0.12 mmol) and EtOH (3.5 ml) was added 4-morpholin-4-ylmethyl-benzaldehyde (0.032 g, 0.16 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.48 ml, 0.48 mmol). The reaction mixture was stirred at 80° C. for 20 h, then allowed to cool to room temperature and concentrated in vacuo. The residue was absorbed on silica gel, the free-running powder was placed on a 10 g isolute silica column, and elution of the column with a gradient of methanol (2 to 12%) in ethyl acetate/dichloromethane (v:v; 4:1) afforded a yellow solid which was triturated with diethyl ether. The precipitate was collected by filtration, and was successively washed with diethyl ether, water, and diethyl, then dried in vacuo (0.009 g, 14%). 1H-NMR (500 MHz, DMSO-d6) 2.38 (br t, 4H) and 3.59 (t, J=4.6 Hz, 4H) (morpholine N(CH2)2 and morpholine O(CH2)2), 2.62 (br s, 4H, piperazine N(CH2)2), 3.67 (br s, 4H, piperazine N(CH2)2), 3.53 (s, 2H) and 3.62 (s, 2H) (NCH2-pyridyl and C6H4CH2), 7.39 (dd, J=5.3, 7.1 Hz, pyridine 5-H), 7.47 (d, J=7.7 Hz, 2H) and 8.14 (d, J=8.0 Hz, 2H) (3,5-C6H4 and 2,6-C6H4), 7.78 (d, J=7.5 Hz, 1H, pyridine 4-H), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 8.50 (dd, J=1.6, 4.7 Hz, 1H, pyridine 6-H), 8.56 (d, J=1.6 Hz, 1H, pyridine 6-H), 13.48 (br s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [S:1]1[C:5]2[C:6]3[N:7]([CH:19]=[CH:20][N:21]=3)[CH2:8][C:9]3[N:10]([CH:11]=[N:12][C:13]=3[C:14]([O:16]CC)=[O:15])[C:4]=2[CH:3]=[CH:2]1.[OH-].[K+]>C(O)C.O>[S:1]1[C:5]2[C:6]3[N:7]([CH:19]=[CH:20][N:21]=3)[CH2:8][C:9]3[N:10]([CH:11]=[N:12][C:13]=3[C:14]([OH:16])=[O:15])[C:4]=2[CH:3]=[CH:2]1
Reactant: CCOC(=O)c1ncn2c1Cn1ccnc1-c1sccc1-2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ncn2c1Cn1ccnc1-c1sccc1-2

Procedure:
7. By hydrolyzing ethyl 8H-diimidazo[1,5-a:1',2'-d]thieno[2,3-f][1,4]diazepine-7-carboxylate with potassium hydroxide in ethanol/water in an analogous manner to that described in Example 5 there is obtained 8H-diimidazo[1,5-a:1',2'-d]thieno[2,3-f][1,4]diazepine-7-carboxylic acid of m.p. 225°-227° C.
Reaction SMILES: [Br: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]>>[Br: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: ClCCCBr
Reactant: Sc1cccc(Br)c1
Product: ClCCCSc1cccc(Br)c1

Procedure:
Prepared by Procedure R and Scheme Z using 3-bromobenzenethiol and 1-bromo-3-chloropropane.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1/[N:12]=[CH:13]/[N:14](C)C)#[N:2].N[C:18]1[CH:19]=[C:20]([C:24]#[CH:25])[CH:21]=[CH:22][CH:23]=1>CC(O)=O>[C:24]([C:20]1[CH:19]=[C:18]([NH:2][C:1]2[C:3]3[C:4](=[CH:5][CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=3)[N:12]=[CH:13][N:14]=2)[CH:23]=[CH:22][CH:21]=1)#[CH:25]
Reactant: CN(C)/C=N/c1ccc([N+](=O)[O-])cc1C#N
Reactant: C#Cc1cccc(N)c1
Solvent: CC(=O)O
Product: C#Cc1cccc(Nc2ncnc3ccc([N+](=O)[O-])cc23)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
A mixture of (E)-N′-(2-cyano-4-nitrophenyl)-N,N-dimethylformamidine (1.00 g, 4.58 mmol) and 3-aminophenylacetylene (0.64 g, 5.49 mmol) in HOAc (15 mL) was stirred at 100° C. for 3 h. The resulting mixture was cooled to room temperature. The precipitate was filtered out, washed with ether, and dried in vacuo to give 1.23 g (93%) of N-(3-ethynylphenyl)-6-nitroquinazolin-4-amine as a yellow solid.