Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[S:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=2[C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([N+:31]([O-])=O)[CH:25]=2)=[O:16])=[CH:4][C:3]=1[N+:34]([O-])=O.CO.[S-2].[Na+].[Na+]>O>[NH2:34][C:3]1[CH:4]=[C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[S:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=2[C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([NH2:31])[CH:25]=2)=[O:16])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: Cc1ccc(S(=O)c2ccc(C)cc2-c2ccc(N)c([N+](=O)[O-])c2)c(-c2ccc(N)c([N+](=O)[O-])c2)c1
Agent: [Na+]
Agent: [S-2]
Solvent: CO
Solvent: O
Product: Cc1ccc(S(=O)c2ccc(C)cc2-c2ccc(N)c(N)c2)c(-c2ccc(N)c(N)c2)c1
Temperature: 25 °C
Yield: 91 %

Procedure:
To a suspension of 21.2 g. (0.076 moles) of (4-amino-3-nitrophenyl)-4-methylphenyl sulfoxide in 80 ml. of methanol a solution of 22 g. (0.17 moles) of sodium sulfide of 60% purity in 25 ml. of water is added in one hour, under boiling. The reaction mixture is refluxed for 3 hours, and the progress of the reaction is monitored by thin layer chromatography. Thereafter 1 g. of celite is added to the reaction mixture, which is then filtered while hot. The filtrate is diluted with 50 ml. of water, and is slowly cooled to room temperature. The precipitate is filtered off, and the substance remaining on the filter is washed base-free with water. The product is then dried at 50° to 60° C. to yield 17 g. of the title compound, melting at 131° to 132° C. Yield: 91% of theoretical,
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[N:12][C:13]=1[CH3:14])[N:10]=[C:9]([CH3:15])[CH:8]=[C:7]2O)[CH3:2].P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:7]1[CH:8]=[C:9]([CH3:15])[N:10]=[C:11]2[C:6]=1[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:13]([CH3:14])=[N:12]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOc1cc2c(O)cc(C)nc2nc1C
Product: CCOc1cc2c(Cl)cc(C)nc2nc1C
Temperature: 95 °C

Procedure:
6-Ethoxy-2,7-dimethyl-1,8-naphthyridin-4-ol (2.77 g) was added to phosphorus oxychloride (25 ml) at ambient temperature. The mixture was then heated at 95° C. for 1 hour. The mixture was worked up as described in example B1 to give 5-chloro-3-ethoxy-2,7-dimethyl-1,8-naphthyridine, m.p. 144°-7° C.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl-].[CH3:8][O:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[F:30][C:31]([F:41])([F:40])[C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1.O>C1COCC1>[CH3:8][O:9][CH:10]=[CH:36][C:35]1[CH:38]=[CH:39][C:32]([C:31]([F:41])([F:40])[F:30])=[CH:33][CH:34]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC=Cc1ccc(C(F)(F)F)cc1
Reaction time: 1 h
Yield: 60.4 %

Procedure:
Potassium tert butoxide (13.46 g, 0.120 mol) was added to methoxymethyl triphenyl phosphonium chloride (38.30 g, 0.112 mol) in 150 ml dry THF at −30° C. under argon atmosphere and stirred for 1 h. 4-trifluoromethylbenzaldehyde (15.0 g, 0.086 mol) in 60 ml THF was added dropwise at the same temperature and stirring continued for 3 h at room temperature. The reaction mixture was treated with 100 ml water, 150 ml petroleum ether and filtered through celite. Organic layer was separated and the aq. layer was extracted with petroleum ether (2×100 ml). Combined organic layer was washed with brine and dried over sodium sulfate. Solvent evaporation under reduced pressure followed by purification over silica gel using petroleum ether as eluent afforded (10.5 g) of the sub-title compound as a colorless liquid. This was directly taken for next step without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=2)[CH2:24][CH2:23]1>C(Cl)Cl.CO>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])=[N:7][C:2]([NH:33][C:32]2[CH:31]=[CH:30][C:29]([CH2:28][N:25]3[CH2:24][CH2:23][N:22]([CH3:21])[CH2:27][CH2:26]3)=[CH:35][CH:34]=2)=[N:3][CH:4]=1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: CN(C)C(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)N(C)C)n3)cc2)CC1
Yield: 32 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2-((2,5-dichloropyrimidin-4-yl)amino)-N,N-dimethylbenzamide and 4-((4-methylpiperazin-1-yl)methyl)aniline in 32% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 9.07 (s, 1H), 8.35 (d, 1H J=8.2 Hz), 8.05 (s, 1H), 7.46 (s, 2H, J=8.2 Hz), 7.38 (t, 1H, J=7.8 Hz), 7.29 (d, 1H, J=7.5 Hz), 7.21 (d, 2H, J=8.2 Hz), 7.10 (t, 1H, J=7.5 Hz), 7.01 (s, 1H), 3.45 (s, 2H), 3.11 (s, 3H), 3.04 (s, 3H), 2.43 (bs, 8H), 2.27 (s, 3H); MS (ESI): 480.1 [M+H]+.
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]([NH:32][C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[C:21]([NH:23][C@@H:24]([C@H:29]([OH:31])C)[C:25]([O:27][CH3:28])=[O:26])=[O:22])=[O:15])=[O:8])(=[O:3])[CH3:2].[CH3:43]N1CCOCC1.OC[C@H](NC([C@@H]1CCCN1)=O)C(OC)=O>C(Cl)Cl.CN(C=O)C>[C:1]([O:4][C@@H:5]([CH3:43])[C@@H:6]([NH:32][C:33]([O:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:34])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[C:21]([NH:23][C@@H:24]([CH2:29][OH:31])[C:25]([O:27][CH3:28])=[O:26])=[O:22])=[O:15])=[O:8])(=[O:3])[CH3:2]
Reactant: COC(=O)[C@@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@@H](COC(C)=O)NC(=O)OCc1ccccc1)[C@@H](C)O
Reactant: CN1CCOCC1
Agent: COC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@H](NC(=O)OCc1ccccc1)[C@H](C)OC(C)=O
Reaction time: 0.5 h
Yield: 17.5 %

Procedure:
(2S)-1-((2R)-3-acetoxy-2-(benzyloxycarbonylamino)-butanoyl)-pyrrolidine-2-carboxylic acid (5) (1.3 g, 2.62 mmol) was dissolved in CH2Cl2 (15 mL), NMM (0.43 mL) and IBCF (0.51 mL) was added at −10° C. and stirred for 30 minutes under inert atmosphere. A mixture of(S)-methyl-3-hydroxy-2-((S)-pyrrolidine-2-carboxamido)-propionate (4) (992 mg, 3.93 mmol) and NMM (0.43 mL) in DMF (5 mL) were added drop wise to the reaction mixture and stirring was continued for another 3 h at RT. The reaction mixture was diluted with DCM (200 mL), washed with water (20 mL), citric acid solution (2×20 mL) and brine (2×50 mL). The separated organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The obtained crude material was purified by silica gel column chromatography eluting with 5% CH3OH/CH2Cl2 to afford compound 6 (270 mg, 17.5%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.Cl.[N:26]1[C:31]2[CH2:32][CH2:33][NH:34][CH2:35][C:30]=2[C:29](=[O:36])[NH:28][CH:27]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:23][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([N:34]3[CH2:33][CH2:32][C:31]4[N:26]=[CH:27][NH:28][C:29](=[O:36])[C:30]=4[CH2:35]3)[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: O=c1[nH]cnc2c1CNCC2
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CCc4nc[nH]c(=O)c4C3)n2n1
Temperature: 25 °C
Yield: 38.8 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 52 mg, 0.151 mmol), 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one hydrochloride (78 mg, 0.395 mmol), and N,N-diisopropylethylamine (60 mg, 0.467 mmol) in DMF (0.5 mL) was stirred at 100° C. for 3 h. After cooling to room temperature, the mixture was filtered and the crude material recrystallized from hot methanol, providing the titled compound as a white solid (26.9 mg, 39%). 1H NMR (DMSO-d6) δ: 8.13 (br. s., 1H), 8.00 (d, J=8.6 Hz, 2H), 7.60 (d, J=8.6 Hz, 2H), 7.45 (s, 1H), 6.18 (s, 1H), 5.18 (s, 1H), 4.49 (br. s., 2H), 4.10 (t, J=6.7 Hz, 2H), 2.87 (t, J=6.7 Hz, 2H), 2.40 (s, 3H), 1.45 (s, 6H); ESI-MS: m/z 460.2 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH:4]([CH2:6][CH2:7][C:8]([OH:10])=O)[CH2:3]1.[Cl:11][C:12]1[CH:13]=[C:14]([NH2:23])[C:15]([NH2:22])=[CH:16][C:17]=1[C:18]([F:21])([F:20])[F:19].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>CN(C)C=O>[NH2:23][C:14]1[CH:13]=[C:12]([Cl:11])[C:17]([C:18]([F:21])([F:19])[F:20])=[CH:16][C:15]=1[NH:22][C:8](=[O:10])[CH2:7][CH2:6][CH:4]1[CH2:3][C:2](=[O:1])[CH2:5]1
Reactant: Nc1cc(Cl)c(C(F)(F)F)cc1N
Reactant: O=C(O)CCC1CC(=O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[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: Nc1cc(Cl)c(C(F)(F)F)cc1NC(=O)CCC1CC(=O)C1
Temperature: 25 °C
Reaction time: 40 h
Yield: 30.9 %

Procedure:
A solution of 3-(3-oxocyclobutyl)propanoic acid (157 mg, 0.696 mmol) and 4-chloro-5-(trifluoromethyl)benzene-1,2-diamine (146 mg, 0.696 mmol) in N,N-dimethylformamide (2.5 mL) was cooled at 0° C. The solution was treated with N,N-diisopropylethylamine (0.364 mL, 2.09 mmol) dropwise followed by N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (291 mg, 0.765 mmol) in one portion. The solution was allowed to stir and slowly warm to room temperature. After 40 h, the reaction mixture was concentrated partially under high vac. The remaining brown liquid was taken up in 25 mL EA and 15 mL 1/1 sat NaHCO3/H2O and extracted. The aqueous phase was washed with two 15 mL portions of ethyl acetate and the combined organic phase was washed with 30 mL portions of H2O and brine. The organic phase was dried over MgSO4, filtered and concentrated to yield a tannish brown viscous oil/glass. The crude material was purified by flash chromatography (40 g silica gel, 50-80% EA/hept) to yield the title compound (72 mg, 31%) as a slightly tan glass/stiff foam: MS (ESI+) for C14H14ClF3N2O2 m/z 335.2 (M+H)+; MS (ESI−) for C14H14ClF3N2O2 m/z 333.3 (M−H)−; HPLC purity 78.2% (ret. time, 3.56 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:27]([C:24]2[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=2)(=[O:29])=[O:28])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)Nc2cnc(Oc3cc4ccccc4cn3)c(Cl)c2)cc1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 2) and 4-methylbenzene-1-sulfonyl chloride.
Reaction SMILES: [C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([N:7]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]3[CH:12]=[C:11]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:10]=[CH:9][C:8]2=3)=[CH:3][CH:2]=1.[Mn]([O-])(=O)(=O)=[O:34].[K+]>ClCCl>[C:1]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:2]=[CH:3][C:4]([N:7]2[C:20](=[O:34])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]3[CH:12]=[C:11]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:10]=[CH:9][C:8]2=3)=[CH:5][CH:6]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: c1ccc(-c2ccc(N3Cc4ccccc4-c4cc(-c5ccccc5)ccc43)cc2)cc1
Agent: [K+]
Solvent: ClCCl
Product: O=c1c2ccccc2c2cc(-c3ccccc3)ccc2n1-c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
16 g (0.039 mol) of 5-biphenyl-4-yl-2-phenyl-5,6-dihydrophenanthridine are dissolved in 300 ml of dichloromethane. and 62.13 g (0.393 mol) of potassium permanganate are added in portions to this solution, and the mixture is stirred at room temperature for two days. After this time, the remaining potassium permanganate is filtered off, the solution is evaporated and purified by chromatography (eluent: heptane/dichloromethane, 5:1). The residue is recrystallised from n-heptane. The yield is 14 g (88%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([C:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=2)[CH:10]=1)[C:5]([O:7][CH3:8])=[O:6].[NH4+].[Cl-].O>C(O)C.[Fe]>[CH3:1][O:2][C:3](=[O:24])[CH:4]([C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([C:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=2)[CH:10]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])c(C2=CCCCC2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COC(=O)C(C(=O)OC)c1ccc(N)c(C2=CCCCC2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 71 %

Procedure:
A mixture of 2-(3-cyclohex-1-enyl-4-nitro-phenyl)-malonic acid dimethyl ester (as prepared in the previous step, 200 mg, 0.600 mmol), iron powder (168 mg, 3.00 mmol) and NH4Cl (321 mg, 6.00 mmol) in 6 mL of ethanol was stirred at 80° C. for 16 h. After cooling to RT, the mixture was treated with 30 mL of H2O and extracted with EtOAc (3×20 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (30% EtOAc-hexane) to give 129 mg (71%) of the title compound as a faint yellow oil: Mass spectrum (ESI, m/z): Calcd. for C17H21NO4, 304.2 (M+H). found 304.1.
Reaction SMILES: C(O)(=O)C.CC1(C)CO[CH:9]([CH:12]([C@@H:14]2[C@:31]3([CH3:32])[C@H:17]([C:18]4[C@H:28]([CH2:29][CH2:30]3)[C@:26]3([CH3:27])[C:21]([CH2:22][C@@H:23]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH2:24][C@@H:25]3[O:33][CH2:34][O:35][CH3:36])=[CH:20][CH:19]=4)[CH2:16][CH2:15]2)[CH3:13])[O:8]C1>O1CCCC1>[Si:38]([O:37][C@H:23]1[CH2:24][C@H:25]([O:33][CH2:34][O:35][CH3:36])[C@@:26]2([CH3:27])[C:21](=[CH:20][CH:19]=[C:18]3[C@@H:28]2[CH2:29][CH2:30][C@@:31]2([CH3:32])[C@H:17]3[CH2:16][CH2:15][C@@H:14]2[CH:12]([CH:9]=[O:8])[CH3:13])[CH2:22]1)([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:39])[CH3:40]
Reactant: COCO[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@]21C
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COCO[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC2=CC=C3[C@@H]4CC[C@H](C(C)C=O)[C@@]4(C)CC[C@@H]3[C@]21C

Procedure:
In 5 ml of tetrahydrofuran was dissolved 20-(5,5-dimethyl-1,3-dioxan-2-yl)-3β-(tert-butyldimethylsilyl)oxy-1α-(methoxymethyl)oxypregna-5,7-diene, followed by addition of 5 ml of 80% acetic acid. The mixture was refluxed in an atmosphere of argon gas for 12 hours. The reaction mixture was then worked up in the same manner as Example 156 to give 50 mg of 3β-(tert-butyldimethylsilyl)oxy-1α-(methoxymethyl)oxypregna-5,7-diene-20-carbaldehyde showing the following physical properties.
Reaction SMILES: C([O:4][CH:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13](Br)[C:8]=2[O:7][C:6]1([CH3:16])[CH3:15])(=O)C.C([Li])CCC.[B:22](OC)([O:25]C)[O:23]C>O1CCCC1>[OH:4][CH:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([B:22]([OH:25])[OH:23])[C:8]=2[O:7][C:6]1([CH3:16])[CH3:15]
Reactant: CC(=O)OC1c2cccc(Br)c2OC1(C)C
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)Oc2c(B(O)O)cccc2C1O
Temperature: -80 °C
Reaction time: 0.25 h

Procedure:
A stirring solution of 5.7 grams (0.020 mole) of 3-acetoxy-7-bromo-2,3-dihydro-2,2-dimethylbenzofuran in 150 mL of tetrahydrofuran is cooled to -80° C., and 18.2 mL of n-butyllithium in hexanes (2.5 Molar-0.046 mole) is added dropwise during a 15 minute period, while maintaining the reaction mixture temperature at about -80° C. Upon completion of the addition, the reaction mixture is stirred at -80° C. for 15 minutes. After this time, 6.9 mL (0.061 mole) of trimethyl borate is added during a 1 minute period. The reaction mixture is then allowed to warm slowly to ambient temperature during a 3 hour period, where it is stirred for an additional 1 hour. After this time, the reaction mixture is concentrated under reduced pressure to a volume of about 50 mL. The concentrate is then poured into 500 mL of ice-water. The mixture is then made acidic with about 26 mL of aqueous 2N hydrochloric acid. The mixture is filtered, yielding 2,3-dihydro-3-hydroxy-2,2-dimethylbenzofuran-7-ylboronic acid.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:23](O)=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.Cl.[CH3:45][O:46][C@@H:47]([C@@H:56]([NH:61][CH3:62])[C@@H:57]([CH3:60])[CH2:58][CH3:59])[CH2:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50]>CC1CCCO1>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:23]([N:61]([CH3:62])[C@@H:56]([C@@H:57]([CH3:60])[CH2:58][CH3:59])[C@H:47]([O:46][CH3:45])[CH2:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[O:24])[CH:20]([CH3:21])[CH3:22])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC[C@H](C)[C@H](NC)[C@@H](CC(=O)OC(C)(C)C)OC
Reactant: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: CC1CCCO1
Solvent: CN1CCOCC1
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reaction time: 3 h
Yield: 113.1 %

Procedure:
To a mixture of N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-valine (18.53 g, 54.60 mmol, 1.3 eq.) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (9.58 g, 54.6 mmol, 1.3 eq.) in 2-methyltetrahydrofuran (118.00 mL, 0.34 M) was added N-methylmorpholine (6.52 mL, 59.1 mmol, 1.5 eq.) followed by #4 (11.80 g, 39.9 mmol, 1 eq.). After 3 hours, the reaction was quenched with water (50 mL) and stirred for 15 minutes. The aqueous layer was separated and back-extracted with 2-methyltetrahydrofuran (50 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to give a colorless oil, which was purified by silica gel chromatography (Gradient: 5% to 40% ethyl acetate in heptane) to give #5 (26.2 g, 91%) as a colorless foam. LC-MS (Protocol I) m/z 581.3 [M+H+]1604.3 [M+Na+], retention time=4.993 minutes; 1H NMR (400 MHz, DMSO-d6), possibly a mixture of rotamers, characteristic major signals: δ 7.88 (d, J=7.4 Hz, 2H), 7.71 (d, J=7.4 Hz, 2H), 7.62 (d, J=8.6 Hz, 1H), 7.41 (dd, J=7.4, 7.4 Hz, 2H), 7.27-7.34 (m, 2H), 4.13-4.32 (m, 4H), 3.70-3.82 (br m, 1H), 3.24 (s, 3H), 2.92 (br s, 3H), 2.54 (dd, J=15.7, 2.4 Hz, 1H), 2.17 (dd, J=15.4, 9.4 Hz, 1H), 1.95-2.07 (m, 1H), 1.70-1.83 (br m, 1H), 1.40 (s, 9H), 0.83-0.94 (m, 9H), 0.69 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH:18]3[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([O:25]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:19]3=[O:45])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:25][N:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH:18]([S:15]([C:12]2[CH:11]=[CH:10][C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[CH:14][CH:13]=2)(=[O:17])=[O:16])[C:19]1=[O:45]
Reactant: COc1ccc(-c2ccc(S(=O)(=O)C3CCCCN(OC(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2ccc(S(=O)(=O)C3CCCCN(O)C3=O)cc2)cc1
Reaction time: 0.5 h

Procedure:
3-(4′-Methoxy-biphenyl-4-sulfonyl)-1-trityloxy-azepan-2-one prepared from step G (5.1 mg, 0.00826 mmol) in 0.75 ml of anhydrous CH2Cl2 was added 0.75 ml of TFA and the resulting solution was stirred for 30 min. After TLC indicated the completion of the reaction (<30 min), the reaction mixture was concentrated under reduced pressure to gave a crude material, which was then purified by a column chromatography (0˜5% MeOH in CH2Cl2). MS: 376.0 (M+H)+, 398.1 (M+Na)+.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([NH2:14])[C:12]#[CH:13]>>[CH2:11]([NH:14][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])[C:12]#[CH:13]
Reactant: C#CCN
Reactant: O=S(=O)(Cl)c1ccccc1
Product: C#CCNS(=O)(=O)c1ccccc1

Procedure:
A benzenesulfonyl chloride derivative of the general formula (2) is reacted with propargylamine to obtain an N-propargylbenzenesulfonamide derivative of the general formula (4). A compound of the general formula (4) is reacted with 2-trifluoromethylbenzoyl halide to synthesize a compound of the general formula (1).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[CH:3]=1.C1C(=O)N([Cl:28])C(=O)C1>CN(C=O)C>[Cl:28][C:3]1[N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH2:11])[C:10]=2[C:2]=1[I:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1ncnc2c1c(I)cn2-c1cccc([N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(I)c(Cl)n2-c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
To a suspension of 5-iodo-7-(3-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (17) (1.6 g, 4.2 mmol) in DMF (30 mL) was added NCS (840 mg, 6.3 mmol). The resulting mixture was stirred at r.t. overnight. Another portion of NCS (560 mg, 4.2 mmol) was introduced. After the stifling was continued for 8 hrs, the reaction was quenched with water (100 mL). The resulting white precipitates was collected by filtration to afford 6-chloro-5-iodo-7-(3-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (18) (1.7 g, 91% yield) as a yellow solid. LC-MS (ESI): m/z (M/M+2) 414.6/416.6.
Reaction SMILES: [CH:1]1([CH2:5][N:6]2[CH:14]=[C:13]3[C:8]([CH:9]=[C:10]([C:15]4[CH:16]=[C:17]([CH:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)[N:18]5[C:23]=4[C:22]([NH2:24])=[N:21][CH:20]=[N:19]5)[CH:11]=[CH:12]3)=[N:7]2)[CH2:4][CH2:3][CH2:2]1.ClC[C:33]([N:35]([CH3:37])[CH3:36])=[O:34]>>[NH2:24][C:22]1[C:23]2=[C:15]([C:10]3[CH:11]=[CH:12][C:13]4[C:8]([CH:9]=3)=[N:7][N:6]([CH2:5][CH:1]3[CH2:2][CH2:3][CH2:4]3)[CH:14]=4)[CH:16]=[C:17]([CH:25]3[CH2:30][CH2:29][N:28]([C:33]([N:35]([CH3:37])[CH3:36])=[O:34])[CH2:27][CH2:26]3)[N:18]2[N:19]=[CH:20][N:21]=1
Reactant: CN(C)C(=O)CCl
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(CC5CCC5)nc4c3)c12
Product: CN(C)C(=O)N1CCC(c2cc(-c3ccc4cn(CC5CCC5)nc4c3)c3c(N)ncnn23)CC1
Yield: 85 %

Procedure:
In a manner similar to the procedure described for Example 369 and using 5-[2-(cyclobutylmethyl)-2H-indazol-6-yl]-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine and substituting dimethylcarbamyl chloride for 2-chloro-N,N-dimethylacetamide as starting materials, 60 mg, (85%) of the desired product was isolated. LC-MS [M+H]+=473.3, RT=2.55 min.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH3:20])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][C:5]=1[CH:21]=O)[CH3:2].[NH2:23][C:24]1[C:25]([C:38]([NH2:40])=[O:39])=[N:26][N:27]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[C:28]=1[CH2:29][CH3:30]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[N:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH3:20])[CH2:15][CH2:14]2)(=[O:11])=[O:12])=[CH:6][C:5]=1[CH:21]1[NH:23][C:24]2=[C:28]([CH2:29][CH3:30])[N:27]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[N:26]=[C:25]2[C:38](=[O:39])[NH:40]1)[CH3:2]
Reactant: CCc1c(N)c(C(N)=O)nn1Cc1ccccn1
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1C=O
Solvent: Cc1ccccc1
Product: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1C1NC(=O)c2nn(Cc3ccccn3)c(CC)c2N1
Yield: 51.5 %

Procedure:
A solution of 1-(6-ethoxy-5-formyl-3-pyridylsulfonyl)-4-ethylpiperazine(1.1 g, 4.9 mmol, from step (a) above) and 4-amino-5-ethyl-1-(2-pyridylmethyl)-1H-pyrazole-3-carboxamide (1.2 g, 4.9 mmol) in toluene (10 mL) was heated to reflux for 4 hours and the solution was concentrated under vacuum. The resulting product was recrystallised from ethyl acetate to give a pale brown solid (1.4 g, 52%).