Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][N:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22](=O)[CH3:23])[N:20]=2)[N:15]=[N:14]1.[C:25]([NH:33][NH2:34])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][N:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19](/[C:22](=[N:34]/[NH:33][C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=3)/[CH3:23])[N:20]=2)[N:15]=[N:14]1
Reactant: CC(=O)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Reactant: NNC(=O)c1cccnc1
Product: C/C(=N\NC(=O)c1cccnc1)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Yield: 64.2 %

Procedure:
The title compound (17.0 mg, 59%) was synthesized from 1-[3-(7-fluoro-quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone (20.0 mg, 0.06 mmol) and nicotinic acid hydrazide (17.0 mg, 0.12 mmol) using the same procedure as described in the synthesis of example 72. 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.64, 11.38 (bs, 1H), 9.52 (s, 1H), 9.05 (s, 1H), 8.93 (dd, 1H), 8.78 (d, 1H), 8.42 (d, 1H), 8.20 (d, 1H), 7.84 (d, 1H), 7.56 (m, 2H), 6.26 (s, 2H), 2.49 (s, 3H). LCMS (method A): [MH]+=442, tR=2.10 min.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:21])([CH2:16][C:17]([F:20])([F:19])[F:18])[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.O>[F:18][C:17]([F:19])([F:20])[CH2:16][C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:21])[CH2:13][OH:14]
Reactant: CC(CC(F)(F)F)(NC(=O)OCc1ccccc1)C(=O)O
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(CO)(CC(F)(F)F)NC(=O)OCc1ccccc1
Reaction time: 0.08 h
Yield: 55.3 %

Procedure:
A solution of 2-(benzyloxycarbonylamino)-4,4,4-trifluoro-2-methylbutanoic acid (1.6 g, 5.2 mmol) in THF (17 ml) was cooled to 0° C. and triethylamine (910 ul, 6.5 mmol) was added, then ethyl chloroformate (624 ul, 6.5 mmol) dropwise over 40 min. A solution of sodium borohydride (491 mg, 13 mmol) in H2O (2.6 ml) was added dropwise over 2 h. The reaction was quenched by the addition of 1 M HCl, stirred for 5 min, and then extracted with EtOAc. The organic layer was washed with sat. NaHCO3, sat. NaCl, dried on Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography (15% to 100% EtOAc in hexanes) to afford the title compound as a clear oil (838 mg). 1H NMR (CDCl3, 400 MHz) δ 1.36 (s, 3H), 2.33-2.45 (m, 1H), 2.93-3.03 (m, 1H), 3.62 (br s, 1H), 3.65-3.76 (m, 2H), 5.07-5.10 (m, 3H), 7.28-7.39 (m, 5H). LRMS (ESI/APCI): 292 [M+H]+.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[CH:16]=[C:15]1[CH2:24][CH2:25][NH:26][S:27]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=1)(=[O:29])=[O:28])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.[CH2:46]([O:48][C:49](=[O:60])[C:50]1[CH:55]=[CH:54][C:53]([CH2:56][CH2:57][CH:58]=O)=[CH:52][CH:51]=1)[CH3:47].FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:58][CH2:57][CH2:56][C:53]2[CH:54]=[CH:55][C:50]([C:49]([O:48][CH2:46][CH3:47])=[O:60])=[CH:51][CH:52]=2)=[C:15]1[CH2:24][CH2:25][NH:26][S:27]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=1)(=[O:28])=[O:29])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=S(=O)(Cc1ccc(Cl)c(Cl)c1)NCCc1cc2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1ccc(CCC=O)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc(CCCc2c(CCNS(=O)(=O)Cc3ccc(Cl)c(Cl)c3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Temperature: -10 °C
Reaction time: 4 h
Yield: 56.5 %

Procedure:
To a solution N-[2-(1-benzhydryl-5-chloro-1H-indol-2-yl)ethyl]-1-(3,4-dichlorophenyl)-methanesulfonamide (3.0 g, 5.14 mmol), triethylsilane (1.79 g, 15.4 mmol), and 4-(3-oxopropyl)benzoic acid ethyl ester (1.26 g, 6.16 mmol) in dichloromethane (30 mL) at −20 to −25° C. was added trifloroacetic acid (2.93 g, 25.7 mmol) during a period of 1 min. The mixture was warmed to −10° C. and stirred for 4 h. Saturated aqueous NaHCO3 (20 mL) was added. The mixture was extracted with EtOAc (150 mL). The organic extract was dried over Na2SO4. The solvent is evaporated. The residue is purified by column chromatography, using a mixture of heptane and EtOAc (4:1) as elute to give a white solid (2.25 g, 56%). 1H NMR (CDCl3): δ6.9-7.6 (m, Ph, CHPh2), 7.97 (d, 1H, J=1.6 Hz), 7.41 (d, 1H, J=1.9 Hz), 6.50 (d, 1H, J=8.9 Hz), 4.35 (dd, 2H, J=7.1, 14.3 Hz), 4.13 (m, 1H), 3.92 (s, 2H), 2.95 (m, 2H), 2.71 (m, 6H), 1.96 (m, 2H), 1.38 (t, 3H, J=7.1 Hz).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18](=[O:34])[C:19]2[CH:24]=[CH:23][C:22]([C:25](C)(C)[O:26][SiH2]C(C)(C)C)=[CH:21][CH:20]=2)[C:12]=1[F:35])[CH2:9][CH3:10])(C)(C)C.N[C@@H](C1C(F)=[C:43]([C:48](C2C=CC(CO)=CC=2)=[O:49])C(Cl)=CC=1)CC>>[NH2:7][C@@H:8]([C:11]1[C:12]([F:35])=[C:13]([C:14]([Cl:17])=[CH:15][CH:16]=1)[C:18]([C:19]1[CH:20]=[CH:21][C:22]([CH2:25][O:26][C:48](=[O:49])[CH3:43])=[CH:23][CH:24]=1)=[O:34])[CH2:9][CH3:10]
Reactant: CC[C@@H](N)c1ccc(Cl)c(C(=O)c2ccc(CO)cc2)c1F
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(C(=O)c2ccc(C(C)(C)O[SiH2]C(C)(C)C)cc2)c1F
Product: CC[C@@H](N)c1ccc(Cl)c(C(=O)c2ccc(COC(C)=O)cc2)c1F

Procedure:
Step 2 ((R)-1-{3-[4-(tert-Butyl-dimethyl-silanyloxymethyl)-benzoyl]-4-chloro-2-fluoro-phenyl}-propyl)-carbamic acid tert-butyl ester was deprotected as Step 2 in the preparation of Example 2. A mixture of the doubly deprotected product [3-((R)-1-amino-propyl)-6-chloro-2-fluoro-phenyl]-(4-hydroxymethyl-phenyl)-methanone (=Example 50) and the trans-esterified product acetic acid 4-[3-((R)-1-amino-propyl)-6-chloro-2-fluoro-benzoyl]-benzyl ester (=Example 49) was obtained. Separation was achieved by column chromatography with 0-8% ammonia in methanol/dichloromethane.
Reaction SMILES: N([O-])=O.[Na+].[Br:5][C:6]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]([Br:16])[C:7]=1N>OS(O)(=O)=O.CCOC(C)=O>[Br:5][C:6]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]([Br:16])[CH:7]=1
Reactant: Nc1c(Br)cc([N+](=O)[O-])cc1Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(Br)cc(Br)c1
Yield: 40.9 %

Procedure:
NaNO2 (4.1 g, 59.1 mmol) was added portionwise to a solution of 2,6-dibromo-4-nitroaniline (5 g, 3.5 eq) in 20% H2SO4 and AcOEt (each 40 mL) at a rate to keep the internal temperature at 50-55° C. After heating for an additional 10 min, the mixture was cooled, diluted, and extracted with AcOEt. The combined organic layers were dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (cyclohexane/DCM//7/3 then 8/2) to yield expected compound as a white solid (1.94 g, 41% yield).
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH:2]=1.[Cl:7][SiH:8]([Cl:10])[Cl:9]>[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC>[Cl:7][Si:8]([Cl:10])([Cl:9])[C:2]([CH2:3][CH2:4][CH2:5][CH2:6][Si:8]([Cl:10])([Cl:9])[Cl:7])=[CH2:1]
Reactant: C1=CCCC=C1
Reactant: Cl[SiH](Cl)Cl
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Product: C=C(CCCC[Si](Cl)(Cl)Cl)[Si](Cl)(Cl)Cl
Temperature: 180 °C
Yield: 44.7 %

Procedure:
As in Example 1, 1,3-cyclohexadiene (0.98 g, 12.23 mmol), trichlorosilane (6.63 g, 48.95 mmol) and tetrabutylphosphonium chloride (0.35 g, 1.19 mmol) were added in a 25 mL stainless steel tube under nitrogen atmosphere. After sealing the cylinder with a cap, the reactor was maintained at 180° C. for 12 hours. The resulting mixture was distilled to yield 1.92 g (yield: 45%) of 2,6-bis(trichlorosilyl)-1-hexene.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.I[CH2:9][CH2:10][OH:11]>C1COCC1>[OH:11][CH2:10][CH2:9][N:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCNC1
Reactant: OCCI
Solvent: C1CCOC1
Product: OCCN1CCCNCC1

Procedure:
A 2.329 g portion of homopiperazine dissolved in 10 ml of THF was mixed with 830 mg of iodoethyl alcohol to carry out 24 hours of reaction at room temperature. The reaction mixture was concentrated under a reduced pressure, and the resulting residue was purified by Sephadex LH-20 (Pharmacia) (chloroform:methanol=1:1) and Diaion HP-20 (Mitsubishi Chemicals) to obtain 305 mg of 1-(2-hydroxyethyl)homo-piperazine. Next, Under cooling with ice, 150 mg of 1-(2-hydroxyethyl)homopiperazine and 159 mg of 2-chlorobenzoxazole were added to 3 ml of DMF, and the reaction was carried out for 17 hours at the same temperature and then for 24 hours at room temperature. The reaction mixture was concentrated under a reduced pressure, and the resulting residue was dissolved in 100 ml of ethyl acetate, washed with sodium hydrogencarbonate aqueous solution (pH 8) and water in that order, dehydrated with sodium sulfate and then concentrated under a reduced pressure. Thereafter, the resulting residue was purified by a silica gel column chromatography (chloroform:methanol=30:1) to obtain 72 mg of the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH2:19][C:18]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[O:17][N:16]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>[Pd].CO>[C:31]([O:30][C:28](=[O:29])[CH2:27][C:18]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[O:17][N:16]=[C:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=2)[CH2:19]1)([CH3:33])([CH3:34])[CH3:32]
Reactant: CC(C)(C)OC(=O)CC1(C(=O)OC(C)(C)C)CC(c2cccc(OCc3ccccc3)c2)=NO1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)CC1(C(=O)OC(C)(C)C)CC(c2cccc(O)c2)=NO1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 73.2 %

Procedure:
A mixture of tert-butyl 3-(3-(benzyloxy)phenyl)-5-(2-tert-butoxy-2-oxoethyl)-4,5-dihydro-1,2-oxazole-5-carboxylate (58.4 g), 10% Pd/C (containing about 55% water, 5.8 g), and methanol (500 mL) was stirred at room temperature for 45 minutes under a hydrogen atmosphere. The catalyst was filtered off, and then, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (34.5 g).
Reaction SMILES: C(O)(=O)C.[C:5]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])(=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:19][NH2:20]>CCO>[CH3:19][NH:20][C:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: CN
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C=C(NC)c1ccccc1
Reaction time: 15 h
Yield: 99.9 %

Procedure:
Acetic acid (44.7 mL, 780 mmol) was added to a solution of ethyl benzoylacetate (30 g, 156 mmol) and methyl amine (2M in THF, 390 mL, 780 mmol) in EtOH (150 mL). The reaction mixture was heated to reflux and stirred for 15 h. The reaction mixture was concentrated and partitioned between DCM and 1M HCl. The layers were separated, and the organic layer was dried over Na2SO4, filtered and concentrated to give the title compound (32 g, 99% yield) which was used with no further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35](O)=[O:36])=[CH:30][CH:29]=1.CCN=C=NCCCN(C)C>>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=4)[NH:10][N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:36])=[CH:30][CH:29]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Agent: CCN=C=NCCCN(C)C
Product: COc1ccc(CC(=O)Nc2cccc(-c3n[nH]c4ccc(C(N)=O)cc34)c2)cc1
Yield: 9.1 %

Procedure:
Following Example 290, the reaction of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (250 mg, 0.74 mmol) with 4-methoxyphenylacetic acid (0.15 g, 0.89 mmol) and EDCI (0.21 g, 1.11 mmol) furnished 27 mg (11% yield) of the title compound. 1H NMR (DMSOd6) δ 13.2 (br s, 1H), 10.3 (s, 1H), 8.6 (s, 1H), 8.2 (s, 1H), 8.1 (bs, 1H), 7.9 (d, 1H), 7.7 (m, 2H), 7.6 (d, 1H), 7.5 (t, 1H), 7.4–7.1 (m, 2H), 6.9 (d, 1H), 3.7 (s, 3H), 3.6 (s, 2H); ES-MS (m/z) 401 [M+H]+.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:9]1([C:2]2[O:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccc(Br)o1
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Product: O=Cc1ccc(-c2ccccc2)o1
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
A solution of 5-bromo-furan-2-carbaldehyde (1.08 g, 6.16 mmol, 1 eq), phenylboronic acid (0.90 g, 7.39 mmol, 1.1 eq), tetrabutylammonium bromide (1.99 g, 6.16 mmol, 1 eq), palladium acetate (30 mg, 0.0.12 mmol 0.02 eq), K2CO3 (2.13 g, 15.4 mmol, 2.5 eq) in water (10 mL) is stirred under nitrogen at room temperature overnight. Upon completion, the reaction mixture turns into a black mass floating in the solution. The reaction is diluted with 40 ML water and extracted with EtOAc (3×100 mL). The organic layers are combined and stirred with charcoal for 30 min, then dried over MgSO4 and filtered. The solvent is removed under reduced pressure to give an oil. The product is purified by silica gel chromatography using a Biotage Flash 40M column (10% EtOAc/heptane). Yield 70.1%. HRMS (FAB) calculated for C11H8O2+H 173.0603, found 173.0607.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:13]3[N:12]=[C:11]([NH:14][C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=4)[N:10]=[CH:9][C:8]=3[CH2:7][CH2:6][C:5]=2[N:24]=1.[H-].[Na+].I[CH3:28]>CN(C=O)C>[CH3:28][N:14]([C:11]1[N:10]=[CH:9][C:8]2[CH2:7][CH2:6][C:5]3[N:24]=[C:2]([CH3:1])[S:3][C:4]=3[C:13]=2[N:12]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1
Reactant: Cc1nc2c(s1)-c1nc(Nc3cccc([N+](=O)[O-])c3)ncc1CC2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc2c(s1)-c1nc(N(C)c3cccc([N+](=O)[O-])c3)ncc1CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.7 %

Procedure:
To a solution of (2-methyl-4,5-dihydro-thiazolo[4,5-h]quinazolin-8-yl)-(3-nitro-phenyl)-amine (100 mg, 0.3 mmol) in dry DMF (2 mL) was added NaH (7.8 mg, 0.3 mmol) under anhydrous conditions. Once H2 evolution had ceased, iodomethane (22 μL, 50 mg, 0.4 mmol) was added dropwise and the mixture was stirred at room temperature overnight. It was then concentrated under vacuum and H2O (20 mL) was added. The product was extracted with CH2Cl2 (3×30 mL). The combined extracts were dried, filtered, and concentrated under vacuum. Flash column chromatography (10% EtOAc:hexane) afforded the pure title product as a yellow solid (40 mg, 38%): mp 203-204° C. Anal. RP-HPLC: tR 17.1 min (10-70% MeCN, purity 85%). 1H-NMR (CDCl3): δ 8.30 (t, 1H, J 2.3, Ph-H), 8.11 (s, 1H, Py-H), 7.95 (ddd, 1H, J 8.2, 2.3, 1.0, Ph-H), 7.65 (ddd, 1H, J 8.2, 2.3, 1.0, Ph-H), 7.44 (t, 1H, J 8.2, Ph-H), 3.58 (s, 3H, N—CH3), 2.98 (m, 4H, CH2—CH2), 2.69 (s, 3H, CH3). 13C-NMR (CDCl3): δ 169.86, 160.70, 159.30, 157.05, 155.27, 148.71, 146.74, 131.42, 129.33, 120.81, 119.36, 116.63, 38.18, 25.68, 24.22, 20.17. MS (ESI+): m/z 354.09 (M+H)+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(OC(=O)C)(=O)C.[Cl:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18]2>>[Cl:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][C:19]([C:22]([OH:24])=[O:23])=[C:18]2[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cc2cccc(Cl)c2[nH]1
Solvent: CC(=O)OC(C)=O
Product: O=C(O)c1[nH]c2c(Cl)cccc2c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Seventy percent nitric acid (3.4 ml) was added to dropwise to acetic anhydride (35 ml) with stirring at room temperature. The mixture was then cooled in an ice bath and 7-chloroindole-2-carboxylic acid (EP 0 622 356 A1, 1.71 g, 8.74 mmol) was added carefully. After stirring for an additional 1.5 h, the suspension was filtered and the filter cake washed with hexane and air-dried. The yield of 7-chloro-3-nitroindole-2-carboxylic acid , yellow solids, was 283 mg (14%). 1H-NMR (DMSO-d6) δ: 13.66 (1H, br s), 8.04 (1H, dd, J=1.1, 8.1 Hz), 7.53 (1H, dd, J=1.1, 7.7 Hz), 7.42 (1H, dd, J=7.7, 8.1 Hz).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[C:3]=1[C:13]#[N:14].C(O[CH:18](OCC)[N:19]([CH3:21])[CH3:20])C>C1(C)C=CC=CC=1>[N:7]1([C:4]2[C:3]([C:13]#[N:14])=[C:2]([N:1]=[CH:18][N:19]([CH3:21])[CH3:20])[NH:6][N:5]=2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: N#Cc1c(N2CCOCC2)n[nH]c1N
Reactant: CCOC(OCC)N(C)C
Solvent: Cc1ccccc1
Product: CN(C)C=Nc1[nH]nc(N2CCOCC2)c1C#N
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, a suspension of 4.00 g (20.7 mmol) of 5-amino-3-(morpholin-4-yl)-1H-pyrazole-4-carbonitrile in 85 ml of toluene is boiled under reflux for 5 hours with 4.17 ml (97%; 23.6 mmol) of N,N-dimethylformamide diethyl acetal, during which the solid dissolves. Cooling to RT (→crystallization), filtration with suction an d washing with toluene and hexane yield N′-[3-(morpholin-4-yl)-4-cyano-1H-pyrazol-5-yl]-N,N-dimethyl-formamidine; m.p. 182-183° C.; TLC: Rf=0.20 (ethyl acetate).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[F:13][C:14]1([F:58])[CH2:19][CH2:18][CH:17]([C:20]2[C:29]3[CH:28]([OH:30])[CH2:27][C:26]([CH3:32])([CH3:31])[CH2:25][C:24]=3[N:23]=[C:22]([CH:33]3[CH2:38][CH2:37][N:36]([C:39]4[N:44]=[CH:43][C:42]([OH:45])=[CH:41][N:40]=4)[CH2:35][CH2:34]3)[C:21]=2[CH:46]([F:57])[C:47]2[CH:52]=[CH:51][C:50]([C:53]([F:56])([F:55])[F:54])=[CH:49][CH:48]=2)[CH2:16][CH2:15]1>>[Si:6]([O:5][CH2:4][CH2:3][CH2:2][O:45][C:42]1[CH:41]=[N:40][C:39]([N:36]2[CH2:35][CH2:34][CH:33]([C:22]3[C:21]([CH:46]([F:57])[C:47]4[CH:52]=[CH:51][C:50]([C:53]([F:54])([F:55])[F:56])=[CH:49][CH:48]=4)=[C:20]([CH:17]4[CH2:18][CH2:19][C:14]([F:13])([F:58])[CH2:15][CH2:16]4)[C:29]4[CH:28]([OH:30])[CH2:27][C:26]([CH3:32])([CH3:31])[CH2:25][C:24]=4[N:23]=3)[CH2:38][CH2:37]2)=[N:44][CH:43]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC1(C)Cc2nc(C3CCN(c4ncc(O)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Product: CC1(C)Cc2nc(C3CCN(c4ncc(OCCCO[Si](C)(C)C(C)(C)C)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1

Procedure:
Reactions similar to those of Example 13 were performed except for using (3-bromopropoxy) (tert-butyl)dimethylsilane instead of ethyl iodide, and from 61 mg (94 μmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-hydroxypyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Example 4, 71 mg (87 μmol) of 2-{1-[5-(3-{[tert-Butyl(dimethyl)silyl]oxy}propoxy)pyrimidin-2-yl]piperidin-4-yl}-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])[C:8]([C:10]1[CH:11]=[CH:12][C:13]2[S:17][C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)=[N:15][C:14]=2[CH:28]=1)=[O:9].[ClH:35].CO.C(=O)([O-])[O-].[NH4+:42].[NH4+]>C(O)(=O)C.C(Cl)Cl.C(O)C>[ClH:35].[ClH:35].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])[C:8]([C:10]1[CH:11]=[CH:12][C:13]2[S:17][C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:42])[NH2:27])=[CH:22][CH:21]=3)=[N:15][C:14]=2[CH:28]=1)=[O:9]
Reactant: [NH4+]
Reactant: COC(=O)CCN(C(=O)c1ccc2sc(CNc3ccc(C#N)cc3)nc2c1)c1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)CCN(C(=O)c1ccc2sc(CNc3ccc(C(=N)N)cc3)nc2c1)c1ccccn1
Yield: 68 %

Procedure:
Prepared analogously to Example 9 from 2-[N-(4-cyanophenyl)-aminomethyl]benzothiazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide, methanolic hydrochloric acid, methanol and ammonium carbonate. Yield: 68% of theory, C25H24N6O3S (488.57) Rf value: 0.13 (silica gel; methylene chloride/ethanol=4:1+a few drops of acetic acid) EKA mass spectrum: (M+H)+ =489
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Cl[C:42]1[CH:47]=[CH:46][N:45]=[C:44]([C:48]([N:50]2[CH2:55][CH2:54][N:53]([CH2:56][CH2:57][OH:58])[CH2:52][CH2:51]2)=[O:49])[CH:43]=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:47]=[CH:46][N:45]=[C:44]([C:48]([N:50]6[CH2:51][CH2:52][N:53]([CH2:56][CH2:57][OH:58])[CH2:54][CH2:55]6)=[O:49])[CH:43]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: O=C(c1cc(Cl)ccn1)N1CCN(CCO)CC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccnc(C(=O)N4CCN(CCO)CC4)c3)cn2)cc1
Yield: 52.3 %

Procedure:
Using 4-chloropicolinic acid chloride and 4-(2-hydroxyethyl)piperazine instead of N-Boc-piperazine, amidation was carried out in the same manner as Step A in Example 1-D-199, to obtain (4-chloro-pyridin-2-yl)-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone. Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (282 mg, 0.52 mmol), and (4-chloro-pyridin-2-yl)-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone (175 mg, 0.65 mmol) instead of 4-chloropicolinic acid t-butylamide, amination was carried out in the same manner as Example 1-D-07, to obtain a crude product of [4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-pyridin-2-yl]-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone as a colorless solid (210 mg), and then the PMB groups were removed according to the above Deprotection method 2, to obtain the desired compound (D-202) as a colorless powder (114 mg, 80%).
Reaction SMILES: FC1C(O[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[C:14]3=[N:21][NH:22][C:23]2[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=2)=[O:10])=C(F)C(F)=C(F)C=1F.[CH3:37][O:38][C:39]1[CH:46]=[CH:45][CH:44]=[C:43]([O:47][CH3:48])[C:40]=1[CH2:41][NH2:42]>O>[CH3:48][O:47][C:43]1[CH:44]=[CH:45][CH:46]=[C:39]([O:38][CH3:37])[C:40]=1[CH2:41][NH:42][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C:14]2=[N:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](=[O:31])(=[O:32])[NH2:30])=[CH:25][CH:24]=1)=[O:10]
Reactant: COc1cccc(OC)c1CN
Reactant: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(C(=O)Oc4c(F)c(F)c(F)c(F)c4F)cc32)cc1
Solvent: O
Product: COc1cccc(OC)c1CNC(=O)c1ccc2c(c1)C(=NNc1ccc(S(N)(=O)=O)cc1)C(=O)N2

Procedure:
The title compound was prepared from 2-oxo-3[(4-sulfamoyl-phenyl)-hydrazono]-2,3-dihydro-1H-indole-5-carboxylic acid pentafluorophenyl ester and 2,6dimethoxybenzylamine according to Procedure K: mp>250° C.; 1H NMR (DMSO-d6): δ 3.76 (s, 6H), 4.43 (d, J=4.2 Hz, 2H), 6.65 (d, J=8.4 Hz, 2H), 6.91 (d, J=8.2 Hz, 1H), 7.23 (s, 2H), 7.25 (d, J=8.2 Hz, 1H), 7.56 (d, J=8.6 Hz, 2H), 7.79 (m, 3H), 8.07 (s, 1H), 8.13 (brs, 1H), 11.27 (s, 1H), 12.76 (s, 1H); APCI−MS m/z 532 (M+Na)+; Anal. Calcd for C24H23N5O6S.1/2 H2O: C, 55.59; H, 4.67; N, 13.51; S, 6.18. Found: C, 55.69; H, 4.64; N, 13.61; S, 6.09.