Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]12[C:23](=[O:24])[CH2:22][CH2:21][CH:3]1[CH:4]1[C:9]([CH2:10][CH2:11]2)=[C:8]([CH2:12][CH2:13][C:14]2([CH3:19])[O:18][CH2:17][CH2:16][O:15]2)[C:7](=[O:20])[CH2:6][O:5]1.C(=O)(O)[O-:26].[Na+]>ClCCl>[CH3:1][C:2]12[C:23](=[O:24])[CH2:22][CH2:21][CH:3]1[CH:4]1[CH:9]3[CH:10]([O:26][C:8]3([CH2:12][CH2:13][C:14]3([CH3:19])[O:15][CH2:16][CH2:17][O:18]3)[C:7](=[O:20])[CH2:6][O:5]1)[CH2:11]2
Reactant: CC1(CCC2=C3CCC4(C)C(=O)CCC4C3OCC2=O)OCCO1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(CCC23OC4CC5(C)C(=O)CCC5C(OCC2=O)C43)OCCO1
Temperature: -30 °C
Reaction time: 16 h

Procedure:
A solution of 70% meta-perobenzoic acid (939 mg, 3.8 mmol) in dichloromethane (20 mL) was added dropwise to a suspension of 3a-methyl-6-[2-(2-methyl-[1,3]dioxolan-2-yl)-ethyl]-1,2,4,5,9a,9b-hexahydro-3aH-9-oxa-cyclopenta[a]naphthalene-3,7-dione (800 mg, 2.53 mmol) and sodium bicarbonate (213 mg, 3.8 mmol) in dichloromethane (51 mL) at −30° C. The resulting mixture was stirred at −30° C. for 16 h. The reaction was then quenched with saturated solution of sodium thiosulfate. The resulting mixture was treated with saturated sodium carbonate solution and then extracted with dichloromethane (2×50 mL). The combined organic layer was dried with magnesium sulfate. The resulting solution was filtered and concentrated to yield the title compound as a white foam.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19]C4C=CC=C(O)C=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1.ClC1N=C(NC2C=CC3OCCOC=3C=2)C(F)=CN=1.[CH2:46]([C:48]1[CH:54]=[CH:53][C:51](N)=[CH:50][CH:49]=1)[CH3:47]>>[CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][NH:15][C:14]([C:51]4[CH:53]=[CH:54][C:48]([CH2:46][CH3:47])=[CH:49][CH:50]=4)([NH2:19])[N:13]=3)=[CH:4][C:3]=2[O:2]1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Reactant: CCc1ccc(N)cc1
Agent: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: CCc1ccc(C2(N)N=C(Nc3ccc4c(c3)OCCO4)C(F)=CN2)cc1

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 4-ethylaniline were reacted to yield N4-(3,4-ethylenedioxyphenyl)-2-(4-ethylphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.87 (bs, 1H), 7.42 (d, 2H, J=8.7 Hz), 7.26 (d, 1H, J=3.0 Hz), 7.13–7.08 (m, 3H), 6.95 (dd, 1H, J=2.4 and 8.7 Hz), 6.82 (d, 1H, J=9.0 Hz), 6.60 (bs, 1H), 4.23 (s, 4H), 2.59 (q, 2H, J=7.5 Hz), 1.20 (t, 3H, J=7.5 Hz); 19F NMR (CDCl3): −47549; LCMS: ret. time: 25.31 min.; purity: 99%; MS (m/e): 367 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:34])=[C:5]([C:25]([O:32][CH3:33])=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:17][CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[C:11]([CH:16]=1)[C:12]([O:14]C)=[O:13].Cl>[OH-].[Na+].O1CCOCC1.O>[CH3:1][O:2][C:3]1[C:4]([CH3:34])=[C:5]([C:25]([O:32][CH3:33])=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:17][CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[C:11]([CH:16]=1)[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1OCc1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1c(C)c(Cc2ccc(OCc3cccnc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 93.8 %

Procedure:
Methyl 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-(3-pyridylmethyloxy)benzoate (0.165 g, 0.353 mmol) was dissolved in a mixed solution of an aqueous 1N NaOH solution (3 ml) and 1,4-dioxane (3 ml) and the resulting solution was stirred at room temperature for 6 hours. The reaction solution was diluted with water, rendered acidic with concentrated hydrochloric acid and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by silica gel column chromatography (hexand:ethyl acetate=2:3) to obtain the titled compound (0.150 g, 0.331 mmol, 88%).
Reaction SMILES: Br[C:2]1[CH:15]=[N:14][C:5]2[NH:6][C:7](=[O:13])[C:8]([CH3:12])([CH3:11])[NH:9][CH2:10][C:4]=2[CH:3]=1.[CH3:16][N:17]([CH2:22][C:23]1[O:24][C:25]2[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=2[C:27]=1[CH3:28])[C:18](=[O:21])[CH:19]=[CH2:20].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:11][C:8]1([CH3:12])[C:7](=[O:13])[NH:6][C:5]2[N:14]=[CH:15][C:2](/[CH:20]=[CH:19]/[C:18]([N:17]([CH3:16])[CH2:22][C:23]3[O:24][C:25]4[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=4[C:27]=3[CH3:28])=[O:21])=[CH:3][C:4]=2[CH2:10][NH:9]1
Reactant: CC1(C)NCc2cc(Br)cnc2NC1=O
Reactant: C=CC(=O)N(C)Cc1oc2ccccc2c1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CNC(C)(C)C(=O)N3)oc2ccccc12
Reaction time: 0.17 h
Yield: 59.7 %

Procedure:
A suspension of 7-bromo-3,3-dimethyl-1,3,4,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-2-one (0.27 g, 1.0 mmol) and N-methyl-N-(3-methylbenzofuran-2-ylmethyl)acrylamide (0.31 g, 1.4 mmol) in propionitrile (5 mL) and DMF (1.3 mL) was de-oxygenated with Ar for 10 min. The mixture was treated with (i-Pr)2EtN (0.37 mL, 2.1 mmol) and was de-oxygenated with Ar for 10 min. Pd(OAc)2 (22 mg, 0.098 mmol) and P(o-tol)3 (61 mg, 0.20 mmol) were added simultaneously, and the mixture was de-oxygenated a third time for 5 min. The mixture was heated to reflux overnight, then allowed to cool. The resulting precipitate was isolated by filtration, washed with EtOAc, dissolved in CH2Cl2/MeOH (1:1) and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 97:3) gave the title compound (0.25 g, 60%) as a white solid: MS (ESI) m/e 419 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]([C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][C:23]=1[O:30][CH3:31])[C:7]([C:15]([N:17]1C=CN=C1)=[O:16])=[C:8]([CH3:14])[NH:9]2)[CH3:2].N>CN(C=O)C>[C:26]([C:25]1[CH:28]=[CH:29][C:22]([CH:6]2[C:5]3[C:10](=[CH:11][CH:12]=[N:13][C:4]=3[O:3][CH2:1][CH3:2])[NH:9][C:8]([CH3:14])=[C:7]2[C:15]([NH2:17])=[O:16])=[C:23]([O:30][CH3:31])[CH:24]=1)#[N:27]
Reactant: CCOc1nccc2c1C(c1ccc(C#N)cc1OC)C(C(=O)n1ccnc1)=C(C)N2
Agent: N
Solvent: CN(C)C=O
Product: CCOc1nccc2c1C(c1ccc(C#N)cc1OC)C(C(N)=O)=C(C)N2
Temperature: 100 °C

Procedure:
100 mg (approx. 0.24 mmol) of the compound from Example 23A are introduced into 3 ml of DMF. Then 2.94 mg (0.024 mmol) of 4-N,N-dimethylaminopyridine and 340 μl of ammonia (28% by weight solution in water, 2.41 mmol) are added, and the mixture is heated at 100° C. for 3 h. After cooling, the crude product is directly purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). 32 mg (37% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][CH2:6][C:7]1[CH:8]=[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[NH:10][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[H-].[Na+].CI.[CH3:29]COCC>CN(C=O)C.O>[CH3:29][N:10]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:7]([CH2:6][O:5][C:4]2[CH:22]=[CH:23][CH:24]=[C:2]([CH3:1])[CH:3]=2)[CH:8]=[C:9]1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)c1cc(COc2cccc(C)c2)c(C(=O)OCC)[nH]1
Reactant: CCOCC
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(COc2cccc(C)c2)c(C(=O)OCC)n1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Diethyl 4-(3-methylphenoxy)methylpyrrole-2,5-dicarboxylate (107 g, 0.41 mol) is dissolved in dry DMF (200 ml) and added dropwise over 10 minutes to an ice-cooled suspension of hexanes-washed sodium hydride (0.41 mol) in dry DMF (400 ml). The resulting mixture was then stirred for one hour, then recooled in an ice bath and treated dropwise over 15 minutes with methyl iodide (30 ml, 0.49 mol). Stirring is continued for an additional thirty minutes, then the mixture is slowly poured into a separatory funnel containing ether (500 ml) and water (one liter). The ether layer was washed with water and saturated brine, then dried over sodium sulfate and the solvent removed in vacuo to give diethyl 1-methyl-4-(3-methylphenoxy)methylpyrrole-2,5-dicarboxylate.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:20][CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:14](N(OC)C)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH:27]([Mg]Br)=[CH2:28].Cl>O1CCCC1>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:20][CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:14](=[O:15])[CH:27]=[CH2:28])=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:2][CH2:3]1
Reactant: C=C[Mg]Br
Reactant: CON(C)C(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: C=CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
To a solution of 2-[4-(cyclopropylsulfonyl)phenyl]-N-methoxy-N-methyl-3-(tetrahydro-2H-pyran-4-yl)propanamide (10.2 g) in tetrahydrofuran (100 mL) was added dropwise vinylmagnesium bromide (1.0M tetrahydrofuran solution, 73 mL) under ice-cooling. The reaction mixture was stirred overnight at room temperature, 1M hydrochloric acid (80 mL) was added and the mixture was further stirred for 30 min. The reaction mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (4.25 g, yield 46%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio). melting point 92-93° C. MS: 349 (MH+).
Reaction SMILES: O[C:2]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)=[C:3]1[C:20]([O:22]CC)=[O:21].C([SiH](CC)CC)C.B(F)(F)F.CCOCC.Cl>C(Cl)Cl>[CH3:32][O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)[CH:3]1[C:20]([OH:22])=[O:21]
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccccc1OC
Agent: CC[SiH](CC)CC
Agent: Cl
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccccc1C1c2ccccc2C(c2ccc3c(c2)OCO3)C1C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 101.9 %

Procedure:
To a solution of ethyl (1RS)-1-hydroxy-1-(2-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate (100 mg, 0.23 mmol) in CH2Cl2 (5 ml) was added triethylsilane (32 mg, 0.28 mmol), followed by boron trifluoride etherate (0.13 mi, 1.05 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 10 min, at which time was added slowly 3M HCl. The mixture was extracted with EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3, H2O and saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo to provide the title compound (91 mg, 96%) as a mixture of Δ1 and Δ2 double bond isomers.
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([N:12]2[C:17]([CH3:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[N:14][C:13]2=[O:23])[CH:6]=1)C>Cl>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([OH:24])=[O:3])=[CH:6][C:7]=1[N:12]1[C:17]([CH3:18])=[CH:16][C:15]([C:19]([F:20])([F:21])[F:22])=[N:14][C:13]1=[O:23]
Reactant: CCOC(=O)c1ccc(Cl)c(-n2c(C)cc(C(F)(F)F)nc2=O)c1
Agent: Cl
Product: Cc1cc(C(F)(F)F)nc(=O)n1-c1cc(C(=O)O)ccc1Cl
Temperature: 85 °C
Yield: 32.5 %

Procedure:
A stirred suspension of 4-chloro-3-(6-methyl-2-oxo-4-trifluoromethyl-2H-pyrimidin-1-yl)-benzoic acid ethyl ester (3.34 g, 9.26 mmol) in 12N aq. HCl solution (10 mL) was heated at 85° C. for 1 h. After cooling to room temperature the organics were extracted into DCM (3×100 mL). The combined organic layer was dried over MgSO4 and filtered. Concentration in vacuo gave a yellow solid which was purified via silica gel flash chromatography (eluting with a gradient of 5% to 10% MeOH in DCM, followed by 9% MeOH and 1% AcOH in DCM) to give 4-chloro-3-(6-methyl-2-oxo-4-trifluoromethyl-2H-pyrimidin-1-yl)-benzoic acid (1.0 g, 33%) as a cream solid. MS (M+H)+: 332.8, tR=2.364 min (method 1); 1H NMR (CDCl3) δ 8.17 (1H, dd, J=8.4, 2.4 Hz), 8.04 (1H, d, J=1.5 Hz), 7.72 (1H, d, J=8.4 Hz), 6.72 (1H, s), 2.17 (3H, s).
Reaction SMILES: Cl[CH2:2][C:3]#[C:4][CH2:5][NH:6][C:7](=[O:22])[C:8]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[I-].[Na+].[CH3:25][NH:26][CH3:27]>O1CCOCC1>[CH3:25][N:26]([CH3:27])[CH2:2][C:3]#[C:4][CH2:5][NH:6][C:7](=[O:22])[C:8]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(NCC#CCCl)C(O)(c1ccccc1)C1CCCCC1
Reactant: CNC
Agent: [I-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CN(C)CC#CCNC(=O)C(O)(c1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-(4-chloro-2-butynyl)-2-cyclohexyl-2-hydroxy-2-phenylacetamide (0.5 g), sodium iodide (0.1 g), and 50% aqueous dimethylamine (1.5 ml) in 1,4-dioxane (5 ml) was stirred at room temperature overnight. After removal of the solvent, saturated sodium bicarbonate aqueous solution and ethyl acetate were added to the residue. The organic layer was separated, washed with sodium chloride aqueous solution, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of chloroform =nd methanol (20:1) as an eluent to give N-(4-dimethylamino-2-butynyl)-2-cyclohexyl -2-hydroxy-2-phenylacetamide (0.49 g) as oil.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](Cl)(=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1>>[CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1)=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cc2cc3ccccc3s2)cc1
Reactant: COc1cccc(C(=O)Cl)c1
Product: COc1cccc(C(=O)c2c(Cc3ccccc3)sc3ccccc23)c1

Procedure:
Prepared from 2-benzyl-benzo[b]thiophene and m-anisoyl chloride according to the procedure in Example 8. White solid: MS (EI): [M+], 358.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[C:10]2[N:22]=[C:21]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=3)[NH:20][C:11]2=[N:12][C:13]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[OH-].[Na+].Cl>C1COCC1.C(O)C>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[C:10]2[N:22]=[C:21]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)[NH:20][C:11]2=[N:12][C:13]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(-c2nc3cc(-c4ccncc4F)c(-c4cccnc4)nc3[nH]2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2nc3cc(-c4ccncc4F)c(-c4cccnc4)nc3[nH]2)cc1
Temperature: 60 °C
Yield: 32.6 %

Procedure:
To a solution of methyl 4-[6-(3-fluoropyridin-4-yl)-5-pyridin-3-yl-3H-imidazo[4,5-b]pyridin-2-yl]benzoate (Example 10, 0.041 g, 0.097 mmol) in a mixture of THF/ethanol 1:1 (1.2 mL), 2N sodium hydroxide aqueous solution (0.1 mL) was added. The mixture was heated at 60° C. for 3 h and then neutralised with 2N hydrogen chloride aqueous solution. The solvent was evaporated and the crude mixture was purified by silica gel flash chromatography (78:10:10:2 dichloromethane/ethanol/ethyl acetate/acetic acid) to give the title compound (0.013 g, 31% of yield).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:12]=[C:13]=[S:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH2:15]([NH2:18])[CH2:16][NH2:17]>C(Cl)Cl>[CH3:1][C:2]1[C:3]([NH:12][C:13]([NH:17][CH2:16][CH2:15][NH2:18])=[S:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Cc1c(N=C=S)ccc2cccnc12
Reactant: NCCN
Solvent: ClCCl
Product: Cc1c(NC(=S)NCCN)ccc2cccnc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 8-methyl-7-quinolinylisothiocyanate (1.36 g) in CH2Cl2 (50 mL) is added dropwise to ethylene diamine (2.26 mL) in solution in CH2Cl2 (50 mL). The mixture is stirred for 30 minutes at room temperature then rotary evaporated. The residue is suspended in CH2Cl2 (50 mL) and ether (50 mL) and filtered. The precipitate is dried in vacuo to afford N-(8-methyl-7-quinolinyl)-N'-2-aminoethylthiourea as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([C:15]([N:17]2[CH2:22][CH2:21][C:20]3([CH2:31][C:30](=[O:32])[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([NH:33][C:34]5[N:38]=[CH:37][N:36](COCC[Si](C)(C)C)[N:35]=5)[CH:28]=4)[O:23]3)[CH2:19][CH2:18]2)=[O:16])[CH:4]=1.C(O)(C(F)(F)F)=O.C(N)CN>C(Cl)(Cl)Cl.[OH-].[Na+]>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([C:15]([N:17]2[CH2:18][CH2:19][C:20]3([CH2:31][C:30](=[O:32])[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([NH:33][C:34]5[NH:38][CH:37]=[N:36][N:35]=5)[CH:28]=4)[O:23]3)[CH2:21][CH2:22]2)=[O:16])[CH:4]=1
Reactant: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(Nc4ncn(COCC[Si](C)(C)C)n4)ccc2O3)nc2c(OC)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(Nc4nnc[nH]4)ccc2O3)nc2c(OC)cccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-6-[1-(2-trimethylsilanylethoxymethyl)-1H-[1,2,4]triazol-3-ylamino]spiro[chroman-2,4′-piperidin]-4-one (27.0 mg, 0.0419 mmol) was dissolved in CHCl3 (1 mL), and TFA (1 mL) and ethane-1,2-diamine (35.0 mg, 0.583 mmol) was added thereto. After stirring at room temperature for 16 h, the reaction mixture was diluted with CHCl3 and 1N NaOH aq. The aqueous layer was extracted with CHCl3 and combined organic layer was washed with brine, dried over MgSO4. The desiccant was removed through filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel thin-layer chromatography (CHCl3/MeOH=9/1) to obtain the intended compound as a yellow foam. 1H-NMR (400 MHz, CDCl3) δ7.95 (1H, d, J=2.8 Hz), 7.93 (1H, s), 7.76 (1H, dd, J=8.4, 1.2 Hz), 7.61 (1H, dd, J=8.8, 2.8 Hz), 7.46 (1H, dd, J=8.4, 8.4 Hz), 7.19 (1H, br s), 7.11 (1H, s), 7.08 (1H, d, J=8.4, 1.2 Hz), 6.93 (1H, d, J=8.8 Hz), 4.50-4.60 (1H, m), 4.08 (3H, s), 4.03 (3H, s), 3.90-4.10 (1H, m), 3.50-3.65 (1H, m), 3.25-3.40 (1H, m), 2.73 (1H, d, J=16.8 Hz), 2.68 (1H, d, J=16.8 Hz), 2.15-2.30 (1H, m), 1.95-2.10 (1H, m), 1.50-1.90 (2H, m). MS [M+H]+=515.
Reaction SMILES: Cl.[CH:2]12[NH:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][C:4](=[O:10])[CH2:3]2.[C:11]([O:15][C:16](=O)[O:17]C(C)(C)C)([CH3:14])([CH3:13])[CH3:12]>CCO>[C:11]([O:15][C:16]([N:9]1[CH:6]2[CH2:7][CH2:8][CH:2]1[CH2:3][C:4](=[O:10])[CH2:5]2)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: O=C1CC2CCC(C1)N2
Agent: Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Temperature: 60 °C
Yield: 99.1 %

Procedure:
To a solution of 8-aza-bicyclo[3.2.1]octan-3-one hydrochloride (4.5 g, 0.028 mol) in 100 mL of EtOH was added carbonic acid di-tert-butyl ester (12 g, 2 eq.) and 11 mL of TEA. The resulting mixture was heated at 60° C. for 3 h. The volatile fraction was removed and the residue was partitioned between EtOAc and water. The EtOAc layer was washed with saturated sodium chloride, dried over Na2SO4 and concentrated. Silica gel column purification with 20% EtOAc in hexane gave 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (6.25 g).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH2:27]([N:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1[N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)[CH3:28]>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:41]2[CH2:42][CH2:43][N:38]([C:30]3[N:29]([CH2:27][CH3:28])[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[N:31]=3)[CH2:39][CH2:40]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: CCn1c(N2CCNCC2)nc2ccccc21
Product: CCn1c(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)nc2ccccc21

Procedure:
Prepared analogously to Example 10 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 1-ethyl-2-(piperazin-1-yl)-1H-benzimidazole.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[C:13]([F:14])=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[C:22][Si](C)(C)C)=[CH:17][CH:16]=2)[N:11]=[C:10]([C:27]([O:29][CH3:30])=[O:28])[C:9]=1[Cl:31]>CO.O>[NH2:7][C:8]1[C:13]([F:14])=[C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]#[CH:22])=[CH:19][CH:20]=2)[N:11]=[C:10]([C:27]([O:29][CH3:30])=[O:28])[C:9]=1[Cl:31]
Reactant: COC(=O)c1nc(-c2ccc(C#C[Si](C)(C)C)cc2)c(F)c(N)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C#Cc1ccc(-c2nc(C(=O)OC)c(Cl)c(N)c2F)cc1
Temperature: 23 °C
Yield: 97.6 %

Procedure:
Potassium carbonate (100 mg, 0.74 mmol, 1.0 equiv) was added to a stirred mixture of methyl 4-amino-3-chloro-5-fluoro-6-(4-((trimethylsilyl)ethynyl)phenyl)picolinate (280 mg, 0.74 mmol, 0.10 equiv) in methanol (3.7 mL) at 23° C. The heterogeneous pale yellow mixture was stirred at 23° C. for 30 m. The reaction mixture was diluted with water (200 mL) and extracted with dichloromethane (5×50 mL). The organic layers were dried (magnesium sulfate), gravity filtered, and concentrated by rotary evaporation to afford the title compound as a tan powder (220 mg, 96%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[C:14]([O:21][CH2:22][CH2:23][N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[CH:15]=[CH:16][C:17]=2[N+:18]([O-])=O)=[N:2]1.[Sn].Cl>C(O)C>[CH2:27]([N:24]([CH2:25][CH3:26])[CH2:23][CH2:22][O:21][C:14]1[CH:15]=[CH:16][C:17]([NH2:18])=[C:12](/[CH:11]=[CH:10]/[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)[CH:13]=1)[CH3:28]
Reactant: CCN(CC)CCOc1ccc([N+](=O)[O-])c(/C=C/c2n[nH]c3ccccc23)c1
Agent: Cl
Agent: [Sn]
Solvent: CCO
Product: CCN(CC)CCOc1ccc(N)c(/C=C/c2n[nH]c3ccccc23)c1

Procedure:
Crude (E)-N-(2-{3-[2-(1H-indazol-3-yl)vinyl]-4-nitrophenyloxy}ethyl)diethylamine (2.0 g, 5.2 mmol) obtained in Step 1 was dissolved in ethanol (20 mL) and the solution was treated by tin (1.9 g, 16 mmol) and concentrated hydrochloric acid (1.0 mL) at room temperature in a similar manner to Example 2, to obtain (E)-{4-[2-(diethylamino)ethoxy]-2-[2-(1H-indazol-3-yl)vinyl]phenyl}amine. In a similar manner to Example 29, (E)-{4-[2-(diethylamino)ethoxy]-2-[2-(1H-indazol-3-yl)vinyl]phenyl}amine (0.49 g, 1.4 mmol) was dissolved in THF (15 mL) and the solution was added with triethylamine (0.58 ml, 4.2 mmol) and 3-methylthiophenecarbonyl chloride (0.23 g, 1.4 mmol), followed by stirring at room temperature for 1 hour. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure and the residue was triturated in ethyl acetate to obtain Compound 237 (0.42 g, 63%).