Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[S:6]1(=[O:29])=[O:28])(C)(C)C.Br[CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1>>[C:22]1([C:7]2[S:6](=[O:28])(=[O:29])[N:5]([CH2:31][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)[C:9](=[O:10])[C:8]=2[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: BrCc1cccnc1
Reactant: CC(C)(C)N1C(=O)C(NCCCCc2ccccc2)=C(c2ccccc2)S1(=O)=O
Product: O=C1C(NCCCCc2ccccc2)=C(c2ccccc2)S(=O)(=O)N1Cc1cccnc1

Procedure:
The title compound was prepared from 2-tert-butyl-5-phenyl-4-[(4-phenylbutyl)amino]isothiazol-3(2H)-one 1,1-dioxide (Example 1) and 3-(bromomethyl)pyridine in a similar manner as described for e.g. Example 2 and 3 1H NMR (500 MHz, CDCl3): δ 8.80-8.76 (m, 1H), 8.62-8.58 (m, 1H), 7.89-7.85 (m, 1H), 7.53-7.41 (m, 5H), 7.34-7.24 (m, 3H), 7.22-7.17 (m, 1H), 7.09-7.04 (m, 2H), 5.31-5.25 (m, 1H), 4.84 (s, 2H), 2.90-2.83 (m, 2H), 2.49-2.42 (m, 2H), 1.44-1.35 (m, 4H); 13C NMR (125 MHz, CDCl3): δ 159.1, 150.3, 149.8, 141.6, 136.7, 135.5, 131.7, 130.3, 130.0, 128.8, 128.5, 128.4, 126.1, 124.7, 123.7, 107.0, 44.1, 41.1, 35.3, 29.0, 28.2; Mass Spectrum: M−H+ 448.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].O=[C:13]([CH3:30])[CH2:14][O:15][C:16]1[CH:29]=[CH:28][C:19]([CH2:20][CH:21]2[S:25][C:24](=[O:26])[NH:23][C:22]2=[O:27])=[CH:18][CH:17]=1.O>C1C=CC=CC=1>[Cl:11][C:7]1[CH:6]=[C:5]([CH:3]([OH:4])[CH2:2][NH:1][CH:13]([CH3:30])[CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:20][CH:21]3[S:25][C:24](=[O:26])[NH:23][C:22]3=[O:27])=[CH:28][CH:29]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: CC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(COc1ccc(CC2SC(=O)NC2=O)cc1)NCC(O)c1cccc(Cl)c1
Reaction time: 8 h
Yield: 13.3 %

Procedure:
A solution of 2.5 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared as described in Preparation 8) and 3.58 g of 5-[4-(2-oxopropoxy)benzyl]thiazolidine -2,4-dione in 50 ml of benzene was heated under reflux for 1.5 hours, whilst the water being formed during the reaction was continuously removed. At the end of this time, the benzene used was removed by distillation under reduced pressure. The resulting residue was dissolved in 100 ml of absolute methanol, and then 3 g of sodium borohydride were added to the resulting solution. The reaction mixture was allowed to stand overnight at room temperature, after which it was concentrated by evaporation under reduced pressure, and the concentrate was mixed with water. The resulting aqueous mixture was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using ethyl acetate, followed by a 10:1 by volume mixture of ethyl acetate and ethanol, as the eluent. The product was recrystallized from ethyl acetate, to give 0.74 g of the title compound as crystals, melting at 100°-125° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)[N:5]=[C:4]([S:16][CH3:17])[N:3]=1.[H][H]>[Pt].CO>[CH3:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=2)[N:5]=[C:4]([S:16][CH3:17])[N:3]=1
Reactant: CSc1nc(C)n(-c2ccc([N+](=O)[O-])cc2)n1
Reactant: [H][H]
Agent: [Pt]
Solvent: CO
Product: CSc1nc(C)n(-c2ccc(N)cc2)n1
Yield: 68 %

Procedure:
A mixture of 2.5 parts of 5-methyl-3-(methylthio)-1-(4-nitrophenyl)-1H-1,2,4-triazole and 120 parts of methanol is hydrogenated at normal pressure and at room temperature with 2 parts of platinum-on-characoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and petroleumether. The product is filtered off and dried, yielding 1.5 parts (68%) 4-[5-methyl-3-(methylthio)-1H-1,2,4-triazol-1-yl]benzenamine; mp. 130°-136° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]=[N:10][C:9]([C:13]([OH:15])=O)=[CH:8]2.[NH:16]1[CH:20]=[CH:19][N:18]=[C:17]1[NH:21][C:22]([C:24]1[C:32]2[NH:31][C:30]([NH2:33])=[N:29][C:28]=2[CH:27]=[CH:26][CH:25]=1)=[O:23].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:18]1[CH:19]=[CH:20][N:16]=[C:17]1[NH:21][C:22]([C:24]1[C:32]2[N:31]=[C:30]([NH:33][C:13]([C:9]3[N:10]=[CH:11][C:12]4[C:7]([CH:8]=3)=[CH:6][CH:5]=[CH:4][C:3]=4[O:2][CH3:1])=[O:15])[NH:29][C:28]=2[CH:27]=[CH:26][CH:25]=1)=[O:23]
Reactant: COc1cccc2cc(C(=O)O)ncc12
Reactant: Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3nc4c(C(=O)Nc5ncc[nH]5)cccc4[nH]3)ncc12
Yield: 37.8 %

Procedure:
32.3 mg (38%) of the 8-methoxy-isoquinoline-3-carboxylic acid [4-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide was synthesized according to General Procedure A from 41 mg (0.2 mmol) of 8-methoxy-isoquinoline-3-carboxylic acid, 48 mg (0.2 mmol) of intermediate B (2-amino-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide), 100 mg (0.264 mmol) of HBTU, 0.167 mL (0.97 mmol) of DIEA and 1 mL of DMF stirring at 80° C. for 2 h. LCMS: 428 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C([N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][C:22]([S:28](Cl)(=[O:30])=[O:29])=[CH:23][CH:24]=2)[CH2:19]1)=O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:28]([C:22]2[CH:21]=[C:20]3[C:25]([CH2:26][CH2:27][NH:18][CH2:19]3)=[CH:24][CH:23]=2)(=[O:29])=[O:30])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(N1CCc2ccc(S(=O)(=O)Cl)cc2C1)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc3c(c2)CNCC3)CC1
Yield: 35 %

Procedure:
The subtitle compound was prepared by the method of Example 16(a) from 1-t-butyloxycarbonylpiperazine and 2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl chloride. The product was purified on silica gel, eluting with CH2Cl2/MeOH (93/7, v/v) to afford the subtitle compound (35%) as a colourless solid. Rf 0.56 (CH2Cl2/MeOH 9/1, v/v). MS m/z 382 (MH+).
Reaction SMILES: [CH2:1]([C@:4]12[CH2:12][CH2:11][C@@H:10]3[C:13]4[CH2:14][CH2:15][C:16](=[O:21])[CH2:17][C:18]=4[CH2:19][CH2:20][C@H:9]3[C@@H:8]1[CH2:7][CH2:6][C@@H:5]2[OH:22])[CH2:2][CH3:3].C([C@]12CC[C@@H]3C4CCC(=O)CC=4CC[C@H]3[C@@H]1CC[C@@H]2O)C>>[CH2:1]([C@:4]12[CH2:12][CH2:11][C@@H:10]3[C@@H:13]4[C:18]([CH2:19][CH2:20][C@H:9]3[C@@H:8]1[CH2:7][CH2:6][C@@H:5]2[OH:22])=[CH:17][C:16](=[O:21])[CH2:15][CH2:14]4)[CH2:2][CH3:3]
Reactant: CCC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CC[C@@H]2O)CC(=O)CC4
Agent: CC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CC[C@@H]2O)CC(=O)CC4
Product: CCC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O

Procedure:
By substituting an equivalent amount of 13β-n-propyl-17β-hydroxy gon-5 (10)-en-3-one for 13β-ethyl-17β-hydroxy-gon-5(10)-en-3-one in example 136, there is obtained 13β-n-propyl-17β-hydroxy-gon-4-en-3-one; infrared absorption peaks at 2.92, 6.01, 6.20 μ ; ultraviolet peak at 240 mμ (ε15,000).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][C@@H:12]([C:14](=[O:21])[CH2:15][C:16](OCC)=[O:17])[CH2:11][CH2:10][N:9]1[C:22]([O:24][CH3:25])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl.[NH2:29]O.Cl>CO.CO.O.O>[CH2:1]([C@H:8]1[CH2:13][C@@H:12]([C:14]2[O:21][NH:29][C:16](=[O:17])[CH:15]=2)[CH2:11][CH2:10][N:9]1[C:22]([O:24][CH3:25])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](Cc2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of cis-methyl 2-benzyl-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (2.15 g, 6.18 mmol) (from Example 1, Step 1) in MeOH (0.75 mL) was added to a solution of NaOH (0.26 g, 6.55 mmol) in MeOH/H2O (5 mL/0.3 mL) at −30° C. After 10 minutes was added a solution of hydroxylamine hydrochloride (0.86 g, 12.4 mmol) and NaOH (0.49 g, 12.4 mmol) in MeOH (6.1 mL) and H2O (6.1 mL). Stirring was continued at −30° C. for 30 minutes. The reaction mixture was then poured into concentrated HCl (7 mL) held at 80° C. The solution was stirred for 30 minutes. The organic solvent was evaporated and the aqueous phase extracted with ether (×3). The combined organic phases were dried over Na2SO4, and evaporated to yield a solid, 2.2 g. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×20 ID mm) using a gradient of 20-70% acetonitrile in H2O/MeCN/FA 95/5/0.2 buffer, over 18 minutes with a flow of 19 mL/minutes. The title compound was isolated (1.1 g, 57%). 1H NMR (600 MHz, cdcl3) δ 1.76-2.15 (m, 4H), 2.63 (m, 1H), 2.82 (m, 1H), 2.87-3.03 (m, 1H), 3.03-3.22 (m, 1H), 3.61 (s, 3H), 3.99 (m, 1H), 4.19-4.33 (m, 1H), 5.71 (s, 1H), 7.01-7.37 (m, 5H). MS m/z 317 (M+H)+.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7]1[N:12]=[C:11]([NH2:13])[C:10]([NH2:14])=[C:9]([NH2:15])[N:8]=1.C(=O)(O)[O-].[Na+].C(=O)=O.[OH:24][C:25]1[CH:26]=[C:27]([C:31]([C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([OH:41])[CH:36]=2)=O)=O)[CH:28]=[CH:29][CH:30]=1>O>[OH:24][C:25]1[CH:26]=[C:27]([C:31]2[N:14]=[C:10]3[C:11](=[N:13][C:33]=2[C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([OH:41])[CH:36]=2)[N:12]=[C:7]([NH2:6])[N:8]=[C:9]3[NH2:15])[CH:28]=[CH:29][CH:30]=1
Reactant: O=C(C(=O)c1cccc(O)c1)c1cccc(O)c1
Reactant: Nc1nc(N)c(N)c(N)n1
Agent: O=C([O-])O
Agent: O=C=O
Agent: O=S(=O)(O)O
Solvent: O
Product: Nc1nc(N)c2nc(-c3cccc(O)c3)c(-c3cccc(O)c3)nc2n1
Temperature: 80 °C

Procedure:
4.76 g (20.0 mmol) of 2,4,5,6-tetraaminopyrimidine sulfate was added in small portions to a solution of 3.36 g (40.0 mmol) sodium bicarbonate in 100 mL of water with vigorous stirring. A brisk evolution of CO2 gas was observed. The resulting suspension was heated to 80° C. and 4.84 g (20.0 mmol) of 3,3′-dihydroxybenzil was added to the mixture. The reaction mixture was refluxed for 3 hours, at which point a bright-yellow precipitate was formed in abundance.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH2:19][CH3:20])[C:7](=[O:18])[CH:8]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[C:3]=1[O:23][CH3:24].Cl[C:26]1[N:31]=[C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[S:39]([N:42]([CH3:44])[CH3:43])(=[O:41])=[O:40])[C:29]([Cl:45])=[CH:28][N:27]=1>>[Cl:45][C:29]1[C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[S:39](=[O:41])(=[O:40])[N:42]([CH3:43])[CH3:44])=[N:31][C:26]([NH:1][C:2]2[CH:22]=[CH:21][C:5]3[N:6]([CH2:19][CH3:20])[C:7](=[O:18])[CH:8]([NH:11][C:12](=[O:17])[C:13]([F:14])([F:15])[F:16])[CH2:9][CH2:10][C:4]=3[C:3]=2[O:23][CH3:24])=[N:27][CH:28]=1
Reactant: CCN1C(=O)C(NC(=O)C(F)(F)F)CCc2c1ccc(N)c2OC
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CCN1C(=O)C(NC(=O)C(F)(F)F)CCc2c1ccc(Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n1)c2OC
Yield: 33.7 %

Procedure:
Following a procedure analogous to Example 113, N-(7-Amino-1-ethyl-6-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-2,2,2-trifluoro-acetamide (164 mgs) and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide (160 mgs) gave the title compound as an off-white solid (102 mgs). 1H-NMR (CDCl3, 400 MHz): 9.47 (s, 1H), 8.55 (d, J=8.3 Hz, 1H), 8.33 (d, J=8.9 Hz, 1H), 8.21 (s, 1H), 7.92 (d, J=8.1 Hz, 1H), 7.67-7.54 (m, 3H), 7.32-7.28 (m, 1H), 6.92 (d, J=8.8 Hz, 1H), 4.47-4.34 (m, 2H), 3.87 (s, 3H), 3.58-3.54 (m, 1H), 3.17-3.13 (m, 1H), 2.78 (s, 6H), 2.59-2.53 (m, 1H), 2.06-2.01 (m, 1H), 1.23-1.18 (m, 3H); LC/MS: found (M+H)+=656; MP:250-51° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:6]=[C:5]2[CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.[CH2:28]([Si:30]([C:35]#[CH:36])([CH2:33][CH3:34])[CH2:31][CH3:32])[CH3:29].C(N(CC)CC)C>C1(C)C=CC=CC=1.[Cu]I>[N:23]1([CH2:22][CH2:21][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([C:29]#[C:28][Si:30]([CH2:35][CH3:36])([CH2:33][CH3:34])[CH2:31][CH3:32])[CH:3]=3)[N:7]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:6]=2)[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: C#C[Si](CC)(CC)CC
Reactant: Cc1ccc(S(=O)(=O)n2cc(CCN3CCCC3)c3cc(Br)ccc32)cc1
Agent: [Cu]I
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC[Si](C#Cc1ccc2c(c1)c(CCN1CCCC1)cn2S(=O)(=O)c1ccc(C)cc1)(CC)CC
Yield: 39 %

Procedure:
To a solution of 5-bromo-3-(2-pyrrolidinylethyl)-1-(p-toluenesulfonyl)-indole (Example 5, 415 mg, 1 mmol) in toluene (20 mL), were added triethylsilylacetylene (0.72 mL, 4 mmol, dichlorbis(triphenylphosphine) palladium (II) (210 mg, 0.3 mmol), copper (I) iodide (57 mg, 0.3 mmol) and triethylamine (1 mL). The resulting mixture was stirred under argon at reflux overnight and then evaporated to dryness. Chromatography on silica gel (ethyl acetate followed by methanol) gave the title compound as a yellow oil (197 mg, 39%).
Reaction SMILES: [CH2:1]([C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]2([CH3:18])[CH3:17])=O)[CH3:2].[CH2:19]([Mg]Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Mg].C(Cl)C1C=CC=CC=1.[Cl-].[NH4+]>CCOCC>[CH2:1]([C:3]([C:5]1[CH2:6][CH:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]2([CH3:18])[CH3:17])=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:2]
Reactant: CCC(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: Cl[Mg]Cc1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: ClCc1ccccc1
Solvent: CCOCC
Product: CCC(=Cc1ccccc1)C1=CC=C2C(C1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6.1 g of (1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-naphthyl) ethyl ketone are dissolved in 25 ml of abs. ether and added dropwise at 0° to a benzylmagnesium chloride solution prepared from 0.6 g of magnesium and 4.3 g of benzyl chloride in 30 ml of abs. ether. After stirring at room temperature for 2 hours the reaction mixture is poured into a saturated ammonium chloride solution, extracted with ether, dried over sodium sulphate and evaporated. The thus-obtained oil is dissolved in 100 ml of toluene and, after the addition of 0.5 g of p-tlouenesulphonic acid, boiled at reflux overnight. After cooling the mixture is treated with 10% sodium bicarbonate solution, extracted with ether, dried and evaporated. The residue is purified by filtration over a short column (silica gel, elution agent hexane) and recrystallized from methylene chloride/methanol. There are obtained 3 g of 6-(α-ethylstyryl)-1,2,3,5-tetrahydro-1,1,4,4-tetramethylnaphthalene in colourless crystals, melting point 65°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][C:15]([CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)=[CH:14][N:13]=2)([O-])=O.C(O)(=O)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.[Fe]>[N:20]1([CH2:19][C:15]2[CH:16]=[C:17]3[N:18]=[C:10]([C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[NH2:1])[S:11][C:12]3=[N:13][CH:14]=2)[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: O=[N+]([O-])c1ccccc1-c1nc2cc(CN3CCCC3)cnc2s1
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Nc1ccccc1-c1nc2cc(CN3CCCC3)cnc2s1
Temperature: 25 °C
Yield: 98.7 %

Procedure:
Iron powder (55 mmol, 3.1 g) was added to a solution of 2-(2-nitrophenyl)-6-(pyrrolidin-1-ylmethyl)thiazolo[5,4-b]pyridine (11.1 mmol, 3.8 g) in CH2Cl2 (100 mL) followed by acetic acid (10 mL). The reaction mixture was heated at reflux for 3 hours then cooled to room temperature. Na2CO3 (14 g) was added in portions. The mixture was passed through a pad of celite and rinsed with CH2Cl2. The combined filtrates were washed with Na2CO3 (3×20 mL), dried (MgSO4) and concentrated under reduced pressure to give 2-(6-(pyrrolidin-1-ylmethyl)thiazolo[5,4-b]pyridin-2-yl)aniline (3.4 g, 98% yield) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:28])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[C:29]1([CH2:37]O)[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][OH:36])[CH:30]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:28][CH2:37][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][OH:36])[CH:30]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1
Reactant: OCc1cccc(CO)c1
Reactant: O=C1c2ccccc2C(O)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Product: O=C1c2ccccc2C(OCc2cccc(CO)c2)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Yield: 55.3 %

Procedure:
The named compound was synthesised from 3-(4-chlorophenyl)-3-hydroxy-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one (541 mg, 1.37 mmol, 1 equiv.) and 1,3-benzenedimethanol (946 mg, 6.85 mmol, 5 equiv.) using General Procedure A and obtained as a white solid (390 mg, 75%). 1H NMR (300 MHz, CDCl3): 8.01-7.90 (m, 3H, O2N—C—CH and C(O)═C═CH), 7.62-7.53 (m, 2H, Ar—H), 7.39-7.17 (m, 9H, Ar—H), 6.95-6.91 (m, 2H, Ar—H), 4.80 and 4.13 (d: AB, J=15.0 Hz, 2H, N—CH2), 4.64 (d, J=5.1 Hz, CH2—OH), 3.93 and 3.73 (d: AB, J=11.4 Hz, 2H, OCH2), 1.95 (t, J=5.4 Hz, 1H, OH). 13C NMR (75 MHz, CDCl3): 168.51, 145.42, 144.88, 141.59, 137.45, 135.37, 133.39, 131.79, 130.56, 130.34, 129.17, 128.81, 128.38, 126.61, 126.51, 125.82, 124.32, 123.69, 95.55, 65.42, 65.35, 42.91. m/z (ES): 515 [M+H]+. HPLC: Rt=3.58 min. Anal.: calc. for C29H23ClN2O5+0.15 CH2Cl2: C, 66.34; H, 4.46; N, 5.31. Found: C, 66.12; H, 4.44; N, 5.03.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([O:11]CC)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+]>CO.ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([OH:11])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1nc(Cl)c(CC)[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCc1[nH]c(C(=O)O)nc1Cl
Temperature: 70 °C
Reaction time: 0.67 h
Yield: 107.4 %

Procedure:
Ethyl 4-chloro-5-ethyl-1H-imidazole-2-carboxylate obtained in Example (1c) (0.52 g, 2.56 mmol) was dissolved in methanol (8 mL) and dichloromethane (2 mL), and the solution was slowly added dropwise to a 3 N aqueous lithium hydroxide solution (3.5 mL, 10.5 mmol) heated to 70° C. Following stirring at that temperature for 40 minutes, the reaction solution was concentrated under reduced pressure and 1 N hydrochloric acid was added dropwise until the pH was 7. Thereafter, purification by reverse phase silica gel column chromatography (elution solvent: distilled water) gave 0.48 g of the title compound as a white solid (100%).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([C:16]#[CH:17])=[CH:14][N:13]=[C:12]([C:18]4[S:22][C:21]([CH2:23][NH:24]C(=O)OC(C)(C)C)=[CH:20][CH:19]=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[ClH:32]>CCO>[ClH:32].[NH2:24][CH2:23][C:21]1[S:22][C:18]([C:12]2[N:11]=[C:10]([NH:9][C:6]3[CH:5]=[C:4]([CH:1]4[CH2:2][CH2:3]4)[NH:8][N:7]=3)[C:15]([C:16]#[CH:17])=[CH:14][N:13]=2)=[CH:19][CH:20]=1
Reactant: C#Cc1cnc(-c2ccc(CNC(=O)OC(C)(C)C)s2)nc1Nc1cc(C2CC2)[nH]n1
Agent: Cl
Solvent: CCO
Product: C#Cc1cnc(-c2ccc(CN)s2)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 20 °C
Reaction time: 12 h
Yield: 20.9 %

Procedure:
To a solution of tert-butyl (5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-ethynylpyrimidin-2-yl)thiophen-2-yl)methylcarbamate (Compound 168) (100 mg, 0.23 mmol, 1.0 equiv.) in EtOH (3 mL) was added HCl(g)/EtOH (saturated, 3 mL). After stirred at 20° C. for 12 h, the reaction mixture was concentrated in vacuum. The crude product was crystallized with THF/isopropyl to afford 2-(5-(aminomethyl)thiophen-2-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-ethynylpyrimidin-4-amine hydrochloride (Compound 167) (41.4 mg, 20.9%, two steps). LC-MS (m/z)=337.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.80-0.84 (m, 2H), 1.00-1.05 (m, 2H), 2.01-2.04 (m, 1H), 4.28 (d, J=5.2 Hz, 2H), 4.92 (s, 1H), 6.52 (s, 1H), 7.38 (d, J=3.6 Hz, 1H), 7.87 (d, J=4.0 Hz, 1H), 8.53 (s, 1H), 8.65 (bs, 2H), 9.13 (s, 1H).
Reaction SMILES: I[CH2:2]CI.[Cl:5][C:6](=[CH2:23])[CH2:7][C:8]1([CH3:22])[CH2:12][CH2:11][CH:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:9]1=[O:21].ICI.[OH-].[Na+].Cl>C1COCC1>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH:10]2[C:9]3([O:21][CH2:2]3)[C:8]([CH:7]=[C:6]([Cl:5])[CH3:23])([CH3:22])[CH2:12][CH2:11]2)=[CH:15][CH:16]=1
Reactant: C=C(Cl)CC1(C)CCC(Cc2ccc(Cl)cc2)C1=O
Reactant: ICCI
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ICI
Solvent: C1CCOC1
Product: CC(Cl)=CC1(C)CCC(Cc2ccc(Cl)cc2)C12CO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under argon atmosphere, anhydrous THF (9 ml) was combined with Sm (1.01 g, 6.71 mmol), and then, at room temperature, 1,2-diiodoethane (1.05 g, 3.73 mmol) was added. The reaction solution was stirred for 1 hour at room temperature, and then cooled to −7 degrees C. to −2 degrees C., and 2-(2-chloro-2-propenyl)-5-(4-chlorobenzyl)-2-methylcyclopentanone (Compound (V), (Ra)Xana=CH3, (Rb)Xbnb=CH2CCl═CH2, Ym=4-Cl) dissolved in diiodomethane (0.90 g, 0.00168×2.0 mol) and THF (5 ml) was added, and stirred for 1.5 hours at the same temperature. To this, a 2N aqueous solution of NaOH (8 ml) was added, and stirring was conducted for 1 hour while cooling with ice. A 2N aqueous solution of hydrochloric acid (8 ml) was added, and then extraction with hexane (100 ml×2) was conducted. The organic layer was washed with water (50 ml) and saturated brine (30 ml), and then dried over anhydrous sodium sulfate and concentrated to obtain a crude intended substance (0.44 g), which was used in the next reaction as it was.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH3:11])[C:7]=2[CH:12]=1.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[N+](C)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-]>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:20])=[C:8]([CH3:11])[C:7]=2[CH:12]=1
Reactant: COc1ccc2occ(C)c2c1
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: O
Product: COc1ccc2oc(C(=O)c3ccccc3)c(C)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a mixture of 5-methoxy-3-methyl-1-benzofuran (2.00 g) synthesized in Example A104(2), benzoyl chloride (1.68 mL) and nitromethane (20 mL) was added aluminum chloride (3.28 g), and the mixture was stirred at room temperature for 2 hr. Water was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% ethyl acetate/hexane) and further by silica gel column chromatography (20% ethyl acetate/hexane) to give the title object compound (2.03 g, 62%) as a yellow oil.