Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[CH:13]=[N:14][C:15]([N:18]4[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]4)=[N:16][CH:17]=3)[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[CH:13]=[N:14][C:15]([N:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[N:16][CH:17]=3)[CH2:9][O:10][CH2:11]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C3(c4ccc(F)cc4)COC3)cn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(C2(c3cnc(N4CCNCC4)nc3)COC2)cc1
Yield: 100 %

Procedure:
A solution of tert-butyl 4-(5-(3-(4-fluorophenyl)oxetan-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate (22 mg, 0.05 mmol) in DCM (1 mL) was treated with TFA (0.5 mL) at 60° C. for 3 h and then concentrated under reduced pressure. The residue (30 mg, crude, yellow solid, 100% yield) was directly used into the next step without further purification. MS (ES+) C17H19FN4O requires: 314. found 315 [M+H]+; purity: 87% (UV254).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:24])([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[C:16](=O)[C:15]3[C:14]([C:26]([O:28]CC)=O)=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1.O.[NH2:32][NH2:33]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:9][C:10]3[C:15]4[C:16](=[N:32][NH:33][C:26](=[O:28])[C:14]=4[CH:13]=[CH:12][CH:11]=3)[C:17]2([CH3:24])[C:18]2[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cccc2c1C(=O)C(C)(c1nccn1C)C(c1ccc(F)cc1)N2
Reactant: NN
Solvent: O
Product: Cn1ccnc1C1(C)c2n[nH]c(=O)c3cccc(c23)NC1c1ccc(F)cc1
Temperature: 67 °C
Reaction time: 10 h
Yield: 14 %

Procedure:
Ethyl 2-(4-fluorophenyl)-3-methyl-3-(1-methyl-1H-imidazo 1-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (70 mg, 0.18 mmol) was added to hydrazine monohydrate (5 mL) and the mixture was stirred at 67° C. for 10 hr. The resulting mixture was concentrated and purified by prep-HPLC to obtain the title compound as a white solid (9 mg, yield 14%). LC-MS (ESI) m/z: 376 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.79 (s, 3H), 2.57 (s, 3H), 4.50 (s, 1H), 6.68-6.69 (d, J=0.9 Hz, 1H), 6.78-6.82 (m, 2H), 6.84-6.85 (d, J=0.9 Hz, 1H), 7.05-7.09 (m, 2H), 7.16-7.18 (dd, J1=8.0 Hz, J2=0.8 Hz, 1H), 7.34 (s, 1H), 7.43-7.45 (dd, J1=8.0 Hz, J2=0.8 Hz, 1H), 7.57-7.61 (t, J=7.6 Hz, 1H), 12.30 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=3)[O:10][N:9]=2)=[CH:4][CH:3]=1.Cl.C(O)(=O)C>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([C:13]3[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=3)[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(-c2cc(-c3ccc(Cl)cc3)no2)cc1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(-c2cc(-c3ccc(Cl)cc3)no2)cc1
Yield: 96.3 %

Procedure:
A mixture of methyl 4-[3-(4-chlorophenyl)-5-isoxazolyl]benzoate (1.50 g), conc. hydrochloric acid (30 ml) and acetic acid (100 ml) was heated under reflux for 5 hrs. After cooling, the reaction mixture was poured into water and the crystals were washed with water to give 4-[3-(4-chlorophenyl)-5-isoxazolyl]benzoic acid (1.38 g, yield 97%). Recrystallization from N,N-dimethylformamide-water gave colorless prism crystals. melting point: >300° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](I)[C:3]=1[C:4]#[N:5].C([Li])CCC.[Br:16][C:17]1[CH:18]=[C:19]2[C:26](=[CH:27][CH:28]=1)[O:25][CH2:24][C:21]1([CH2:23][CH2:22]1)[C:20]2=[N:29]S(C(C)(C)C)=O.[NH4+].[Cl-]>C1COCC1>[Br:16][C:17]1[CH:18]=[C:19]2[C:20]3([C:6]4[C:3](=[C:2]([F:1])[CH:9]=[CH:8][CH:7]=4)[C:4]([NH2:5])=[N:29]3)[C:21]3([CH2:22][CH2:23]3)[CH2:24][O:25][C:26]2=[CH:27][CH:28]=1
Reactant: N#Cc1c(F)cccc1I
Reactant: CC(C)(C)S(=O)N=C1c2cc(Br)ccc2OCC12CC2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: NC1=NC2(c3cc(Br)ccc3OCC23CC3)c2cccc(F)c21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 29.8 %

Procedure:
To a solution of 2-fluoro-6-iodobenzonitrile (1560 mg, 6.32 mmol) in THF (16 mL) at −78° C. was added n-butyllithium (2.64M solution in n-hexane, 2.39 ml, 6.32 mmol) dropwise. The mixture was stirred for 0.5 hour at −78° C. and to the solution was added a solution of N-(6-bromo-4H-spiro[chromene-3,1′-cyclopropan]-4-ylidene)-2-methylpropane-2-sulfinamide (1500 mg, 4.21 mmol) in THF (5 mL). The mixture was stirred for 1 hour at −78° C. and overnight at room temperature. To the mixture was added saturated aqueous NH4Cl. The mixture was extracted with EtOAc and the organic layer was concentrated in vacuo. The residue was purified by silica gel chromatography (hexane/AcOEt=100:0-0:100, then CHCl3:MeOH=85:15) to give 6′-bromo-4″-fluorodispiro[cyclopropane-1,3′-chromene-4′,1″-isoindol]-3″-amine (469 mg).
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:10]=[N:9][N:8]([CH2:11][C:12]2[N:13]=[C:14]([CH2:17][OH:18])[S:15][CH:16]=2)[N:7]=1)([O-:5])=[O:4].[CH3:19]I>C(Cl)Cl>[CH3:19][O:18][CH2:17][C:14]1[S:15][CH:16]=[C:12]([CH2:11][N:8]2[N:7]=[C:6]([N+:3]([O-:5])=[O:4])[CH:10]=[N:9]2)[N:13]=1
Reactant: CI
Reactant: O=[N+]([O-])c1cnn(Cc2csc(CO)n2)n1
Agent: N#N
Solvent: ClCCl
Product: COCc1nc(Cn2ncc([N+](=O)[O-])n2)cs1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (4-((4-nitro-2H-1,2,3-triazol-2-yl)methyl)thiazol-2-yl)methanol (419 mg, 1.74 mmol) in CH2Cl2 (15.0 mL) was added to a suspension of Ag2O (604 mg, 2.61 mmol) and MeI (0.33 mL, 5.21 mmol). The resulting mixture (protected form light) was stirred overnight at 40° C. The reaction mixture was filtered and the solvent was removed under reduced pressure. Purification of the residue by FC (1:1 hept-EA) gave the title compound as a yellow oil. TLC: rf (1:1 hept-EA)=0.36. LC-MS-conditions 07: tR=0.68 min, [M+H]+=256.27.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12]([N:14]=[C:15]=[S:16])[CH3:13].O>C(#N)C>[CH2:12]([NH:14][C:15](=[S:16])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH3:13]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CCN=C=S
Solvent: O
Solvent: CC#N
Product: CCNC(=S)Nc1ccc(C(=O)OC)cc1
Temperature: 80 °C

Procedure:
To a solution of methyl 4-aminobenzoate (2-2) (30.2 mg, 0.20 mmol) in anhydrous acetonitrile (0.4 mL) is added ethyl isothiocyanate (2-1) (17.52 μL, 0.20 mmol) and the reaction mixture is heated at 80° C. overnight. After cooling to room temperature, the mixture is poured into water (50 mL) and extracted with ethyl acetate (EtOAc) (3×50 mL). The combined organic layers are washed with brine and dried using MgSO4. The drying agents are removed by filtration and the solvent is removed under vacuum. The resulting residue is then purified by flash column chromatography (silica gel, EtOAc/hexane, 0%-40%) to provide methyl 4-(3-ethylthioureido)benzoate (2-3).
Reaction SMILES: Br[CH2:2][C:3]1[S:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7]([Cl:18])=[N:6][C:5]=2[CH:4]=1.[CH3:19][N:20]([CH2:25][CH:26]1[CH2:30][CH2:29][CH2:28][NH:27]1)[S:21]([CH3:24])(=[O:23])=[O:22].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:18][C:7]1[N:8]=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:10]2[S:11][C:3]([CH2:2][N:27]3[CH2:28][CH2:29][CH2:30][CH:26]3[CH2:25][N:20]([CH3:19])[S:21]([CH3:24])(=[O:23])=[O:22])=[CH:4][C:5]=2[N:6]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Reactant: CN(CC1CCCN1)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CC1CCCN1Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)S(C)(=O)=O
Temperature: 80 °C
Yield: 87.9 %

Procedure:
To a mixture of 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (0.50 g) and N-methyl-N-pyrrolidin-2-ylmethyl-methanesulfonamide (390 mg) in acetonitrile (10 mL) was added potassium carbonate (490 mg). The reaction mixture was heated at 80° C. for 16 h and then allowed to cool to room temperature. The reaction mixture was then partitioned between dichloromethane (20 mL) and saturated aqueous sodium bicarbonate solution (20 mL). The combined organics were washed with brine (30 mL), dried (MgSO4), reduced in vacuo and purified by column chromatography to give N-[1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-pyrrolidin-2-ylmethyl]-N-methyl-methanesulfonamide as a pale yellow solid (580 mg).
Reaction SMILES: [SH:1][CH2:2][CH:3]([CH3:14])[C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5].Cl.C(=O)(O)[O-].[Na+].Cl[C:22]1[C:27]2=[N:28][O:29][N:30]=[C:26]2[C:25]([N+:31]([O-:33])=[O:32])=[CH:24][CH:23]=1>C(C(C)=O)C.O>[CH3:14][CH:3]([CH2:2][S:1][C:22]1[C:27]2[C:26](=[N:30][O:29][N:28]=2)[C:25]([N+:31]([O-:33])=[O:32])=[CH:24][CH:23]=1)[C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5]
Reactant: CC(CS)C(=O)N1CCC[C@H]1C(=O)O
Reactant: O=[N+]([O-])c1ccc(Cl)c2nonc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCC(C)=O
Product: CC(CSc1ccc([N+](=O)[O-])c2nonc12)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 0.03 h

Procedure:
3 Mg of 1-(3-mercapto-2-methyl-1-oxopropyl)-L-proline was placed in a vial and dilute hydrochloric acid (0.1N, 2 ml) added to dissolve same. 3 Ml of 0.1M sodium bicarbonate solution was next added and the mixture was mixed in a vortex mixer. Thereafter, 3 ml of 1% (w/v) 4-chloro-7-nitrobenzofurazan in methyl ethyl ketone was added to the mixture, the vial was then closed and mixing was continued. The vial was held under running hot tap water, while shaking the vial, for about 2 minutes. The vial was then allowed to stand for 3 minutes, the organic (upper) layer was removed and was found to contain the title compound. The title compound was found to be fluorescent.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[S:9][CH:10]=1)[CH3:2].C1CCN2C(=NCCC2)CC1.[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Cl)=[CH:35][CH:34]=1>ClCCl>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[N:7]=[C:8]([N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:37][C:36]2[CH:39]=[CH:40][C:33]([O:32][CH3:31])=[CH:34][CH:35]=2)[S:9][CH:10]=1)[CH3:2]
Reactant: COc1ccc(CCl)cc1
Reactant: CCOC(=O)Cc1csc(NC(=O)OC(C)(C)C)n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CCOC(=O)Cc1csc(N(Cc2ccc(OC)cc2)C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.4 %

Procedure:
To a solution of (2-tert-Butoxycarbonylamino-thiazol-4-yl)-acetic acid ethyl ester (7.5 g, 26.11 mmol) in 100 mL of dry dichloromethane was added DBU (11.96 g, 78.56 mmol) followed by para-methoxybenzyl chloride (6.15 g, 39.28 mmol) and the reaction mixture was stirred for 18 hrs at room temperature. The reaction was quenched with water and the layers were separated. The organic layer was washed with brine and dried over anhydrous sodium sulphate and the solvent was removed in vacuo. The residue was purified by column chromatography (silica gel 60-120 mesh and 2-10% ethyl acetate in hexanes as eluent) to get the pure compound (8.0 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[S:17]([O-:20])(=[O:19])=[O:18].[Na+:21]>[Cl-].[Na+]>[O:4]1[CH2:5][CH2:6][N:1]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[S:17]([O-:20])(=[O:19])=[O:18])[CH2:2][CH2:3]1.[Na+:21]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)[O-])c1
Reactant: C1COCCN1
Agent: [Cl-]
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(N2CCOCC2)c(S(=O)(=O)[O-])c1
Temperature: 110 °C
Yield: 90 %

Procedure:
To 80 ml of morpholine, 82.5 g (0.3 mol) of sodium 2-chloro-5-nitrobenzenesulfonate was added with stirring. The reaction mixture was heated at about 110° C. on an oil bath with stirring for 30 minutes. After cooling, 100 ml of a saturated aqueous sodium chloride solution was added to the mixture. The crystals thus-precipitated were collected by filtration and washed with acetone to obtain 88 g (yield: 90%) of sodium 2-morpholino-5-nitrobenzenesulfonate. Melting Point: 208°-210° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[C:4]([CH3:10])[N:3]=1.[OH-].[K+].[Cl:13][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[C:18](Cl)[C:17]([N+:24]([O-:26])=[O:25])=[CH:16][C:15]=1[C:27]([F:30])([F:29])[F:28].Cl>O.CN(C)C=O>[Cl:8][C:7]1[C:2]([NH:1][C:18]2[C:17]([N+:24]([O-:26])=[O:25])=[CH:16][C:15]([C:27]([F:28])([F:29])[F:30])=[C:14]([Cl:13])[C:19]=2[N+:20]([O-:22])=[O:21])=[N:3][C:4]([CH3:10])=[C:5]([Cl:9])[CH:6]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Reactant: Cc1nc(N)c(Cl)cc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(Nc2c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c2[N+](=O)[O-])c(Cl)cc1Cl
Reaction time: 3 h

Procedure:
In 30 ml. of dimethylformamide, 1.8 g. of 2-amino-3,5-dichloro-6-methylpyridine was dissolved in 0.67 g. of powdery potassium hydroxide was gradually added with stirring. After the addition, a solution of 3.07 g. of 2,4-dichloro-3,5-dinitrobenzotrifluoride in 10 ml. of dimethylformamide was added dropwise at room temperature and the reaction was continued for about 3 hours. The reaction mixture was acidified with conc. HCl and was poured into water. The precipitate was filtered and recrystallized from methanol to obtain 2.96 g. of the object compound having a melting point of 128° to 130° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17](=O)[C:16]3[C:11](=[CH:12][C:13]([OH:20])=[C:14]([Cl:19])[CH:15]=3)[O:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.O.[NH2:22][NH2:23]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([C:16]3[CH:15]=[C:14]([Cl:19])[C:13]([OH:20])=[CH:12][C:11]=3[OH:10])=[N:22][NH:23][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: O=c1c(-c2cccc(Br)c2)coc2cc(O)c(Cl)cc12
Solvent: O
Solvent: CCO
Product: Oc1cc(O)c(-c2n[nH]cc2-c2cccc(Br)c2)cc1Cl
Yield: 80.8 %

Procedure:
This compounds was synthesised in the same manner as described above. 3-(3-Bromo-phenyl)-6-chloro-7-hydroxy-chromen-4-one (0.25 g, 0.71 mmol), hydrazine hydrate (5 ml), ethanol (10 ml). The quenched solution was extracted into ethyl acetate, washed (water), dried (MgSO4), and the solvent removed under vacuum to give a yellow oil which was purified by column chromatography to give 4-[4-(3-Bromo-phenyl)-1H-pyrazol-3-yl]-6-chloro-benzene-1,3-diol as a white solid (0.21 g, 80.8%); Rf 0.8 ethyl acetate/hexane (70/30).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:10])[CH2:8][CH3:9].[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[O:21][CH2:22][CH2:23][CH2:24][CH2:25]Cl>CS(C)=O.O>[CH2:7]([NH:10][CH2:25][CH2:24][CH2:23][CH2:22][O:21][C:12]1[CH:13]=[CH:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]=1)[CH2:8][CH3:9]
Reactant: ClCCCCOc1ccc2ccccc2c1
Reactant: CCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCCNCCCCOc1ccc2ccccc2c1
Temperature: 140 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and n-propyl amine (0.26 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 4-(2-naphthyloxy)-1-chlorobutane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 140° C. for 7 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to oily compound which was later crystallized by benzene hexane to get N-(n-propyl)-(4-(naphthalen-2-yloxy)butyl)amine, solid, m.p. 118° C., (yield 0.51 gm, 93.2%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:30])=[C:4]([C:8]2[C:20]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[CH:18]=4)[NH:13][C:12]=3[C:11]([C:27]([NH2:29])=[O:28])=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1.N1C=CC=CC=1>ClCCl>[CH3:30][C:3]1[C:2]([NH:1][C:36](=[O:37])[C:35]2[CH:39]=[CH:40][C:32]([CH3:31])=[CH:33][CH:34]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[C:8]1[C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[CH:18]=3)[NH:13][C:12]=2[C:11]([C:27]([NH2:29])=[O:28])=[N:10][CH:9]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Cc1c(N)cccc1-c1cnc(C(N)=O)c2[nH]c3ccc(N4CCOCC4)cc3c12
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)Nc2cccc(-c3cnc(C(N)=O)c4[nH]c5ccc(N6CCOCC6)cc5c34)c2C)cc1
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 52.1 %

Procedure:
To a solution of 4-(3-amino-2-methylphenyl)-6-morpholino-9H-pyrido[3,4-b]indole-1-carboxamide (0.0287 g, 0.071 mmol) and 4-methylbenzoyl chloride (0.013 g, 0.086 mmol) in dichloromethane (0.953 mL) under nitrogen was added pyridine (0.012 mL, 0.143 mmol). The vial was sealed and stirred at 40° C. After 15 min, the reaction was cooled to room temperature and concentrated in vacuo. It was diluted with MeOH (1 mL) and purified by reverse phase HPLC. The appropriate fractions were combined, basified with NaHCO3 (solid), and concentrated in vacuo. It was extracted with CH2Cl2 (3×). The organic layers were combined, dried over Na2SO4, and concentrated in vacuo to give the desired product (0.0192 g, 0.037 mmol, 51.7% yield) as a light yellow solid. LC/MS (M+H)=520.25; 1H NMR (400 MHz, DMSO-d6) δ ppm 11.56 (s, 1H), 10.00 (s, 1H), 8.31 (d, J=2.2 Hz, 1H), 8.15 (s, 1H), 7.92 (s, 1H), 7.90 (s, 1H), 7.75 (d, J=2.0 Hz, 1H), 7.70 (d, J=8.80 Hz, 1H), 7.55 (d, J=7.0 Hz, 1H), 7.45 (t, J=7.7 Hz, 1H), 7.35 (s, 1H), 7.33 (s, 1H), 7.25-7.32 (m, 1H), 6.53 (d, J=2.2 Hz, 1H), 3.68 (m, 4H), 2.80-2.91 (m, 4H), 2.38 (s, 3H), 1.94 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([O:12][C:13]2[CH:18]=[C:17](Cl)[N:16]=[CH:15][N:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][N:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CC[C@H](Oc2cc(Cl)ncn2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H]1CC[C@H](Oc2ccncn2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To an argon purged solution of cis/trans-4-(6-chloro-pyrimidin-4-yloxy)-cyclohexanecarboxylic acid ethyl ester (1:1) (1.05 g, 3.69 mmol) and triethylamine (0.52 ml, 3.69 mmol) in ethyl acetate (37 ml) was added palladium on charcoal 10% (0.078 g). The reaction mixture was purged with hydrogen gas and stirred under an atmosphere of hydrogen gas for 16 h at room temperature. The catalyst and the ammonium salts were removed by filtration over Decalite. The filtrate was concentrated in vacuo to give the title compound (0.92 g) as light yellow oil in quantitative yield.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:8]([O:11][CH2:12][C:13]#[CH:14])(=[O:10])[CH3:9].[I-].CO>CCN(CC)CC.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:3][C:2]([CH3:5])([CH3:4])[C:1](=[O:6])[C:14]#[C:13][CH2:12][O:11][C:8](=[O:10])[CH3:9]
Reactant: CC(C)(C)C(=O)Cl
Reactant: C#CCOC(C)=O
Agent: Cl[Pd]Cl
Agent: [I-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(=O)OCC#CC(=O)C(C)(C)C

Procedure:
Pivaloyl chloride (612 μl), propargyl acetate (644 μl), cupper iodide (12 mg) and bis-(triphenylphosphine) palladium(II)-dichloride (9.1 mg) in NEt3 (10 ml) were stirred at RT for 24 h. MeOH was added and the mixture was evaporated off. The residue was taken up in Et2O and the resulting suspension filtered off. The solution was washed with a 1M HCl solution, water, dried (Na2SO4) and evaporated off. Column chromatography (EA/Hept 1/3) afforded 343 mg of the desired compound.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][OH:5].[Cl:6][C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:23](Cl)=[N:22][C:21]([Cl:25])=[CH:20][N:19]=1)(=[O:16])=[O:15]>>[Cl:6][C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:23]([O:5][CH2:4][CH2:3][S:2][CH3:1])=[N:22][C:21]([Cl:25])=[CH:20][N:19]=1)(=[O:16])=[O:15]
Reactant: CSCCO
Reactant: O=S(=O)(Nc1ncc(Cl)nc1Cl)c1cccc(Cl)c1Cl
Product: CSCCOc1nc(Cl)cnc1NS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 31 using 2-methylsulphanylethanol (0.05 g) and 2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (0.1 g). Yield 0.06 g.
Reaction SMILES: CC1C=C(N[C:10]2[N:15]=[C:14]([N:16]3[CH:20]=[C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:18]([CH3:26])=[N:17]3)[CH:13]=[CH:12][N:11]=2)C=C(C)C=1.C(=O)([O-])[O-].[K+].[K+].ClC1C=CN=[C:36]([S:40]C)N=1>C(#N)C.C(OCC)(=O)C>[CH3:26][C:18]1[C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:20][N:16]([C:14]2[CH:13]=[CH:12][N:11]=[C:10]([S:40][CH3:36])[N:15]=2)[N:17]=1
Reactant: CCOC(=O)c1cn(-c2ccnc(Nc3cc(C)cc(C)c3)n2)nc1C
Reactant: CSc1nccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1cn(-c2ccnc(SC)n2)nc1C
Temperature: 80 °C
Yield: 707.8 %

Procedure:
To a solution of ethyl 3-methyl-1H-pyrazole-4-carboxylate 2 (5.0 g, 32 4 mmol) in anhydrous acetonitrile (60 mL) were added potassium carbonate (8.96 g, 64.9 mmol) and 4-chloro-2-(methylthio)pyrimidine 11 (5.47 g, 34.1 mmol) at room temperature (rt). The resulting suspension was heated at 80° C. for 8 hours with monitoring a reaction with LC-MS or thin layer chromatography (TLC). It was diluted with ethyl acetate and washed with brine. The collected organic layer was dried over anhydrous sodium sulfate and then concentrated in vacou. The resulting residue was recrystallized with methanol to give 7.88 g (83%) of ethyl 3-methyl-1-(2-(methylthio)pyrimidin-4-yl)-1H-pyrazole-4-carboxylate 12; MS (ESI) m/z 279 [M+H]+. The resulting pyrazole-4-carboxylate 12 (7.44 g, 26 7 mmol) was dissolved in 30 mL of DCM and then cooled to 0° C. To this was added 3-chloroperbenzoic acid (mCPBA, 13.2 g, 58.8 mmol) at the same temperature. The reaction was warmed to room temperature, stirred for 2 hours and then quenched by addition of saturated NaHCO3 solution. The collected organic layer was dried over anhydrous sodium sulfate and then concentrated in vacou. The resulting residue was recrystallized with iso-propylether to give 7.88 g (83%) of ethyl 3-methyl-1-(2-(methylsulfonyl)pyrimidin-4-yl)-1H-pyrazole-4-carboxylate 13 as a colorless solid (6.92 g, 83%); m/z 311 [M+H]+. The obtained sulfoxide 13 (3.0 g, 9.7 mmol) was mixed with acetic acid (0.42 mL, 9.7 mmol) and 3,5-dimethylaniline (1.4 mL, 9.7 mmol) in 10 mL of n-butanol. After being heated at reflux for 2 hours, the mixture was concentrated in vacou. The resulting residue was extracted with DCM, washed with a saturated NaHCO3 solution. The collected organic layer was dried over anhydrous sodium sulfate, concentrated in vacou and then recrystallized with ethyl acetate to afford 0.86 g (26%) of Compound No. 2 as a pale yellow solid; m/z 352 [M+H]+.