Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]2[N:7]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[CH2:8][C@@H:9](OS(C3C=CC(C)=CC=3)(=O)=O)[C@H:5]2[O:4][CH2:3]1.[CH3:31][NH2:32]>C(O)C>[OH:1][C@@H:2]1[C@H:6]2[N:7]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[CH2:8][C@H:9]([NH:32][CH3:31])[C@H:5]2[O:4][CH2:3]1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CN(C(=O)OCc3ccccc3)[C@H]3[C@@H]2OC[C@@H]3O)cc1
Solvent: CCO
Product: CN[C@H]1CN(C(=O)OCc2ccccc2)[C@H]2[C@@H]1OC[C@@H]2O
Temperature: 25 °C
Yield: 35 %

Procedure:
A stirred solution of tosylate (34b) (200 mg, 0.46 mmol) and methylamine in ethanol (33% wt, 6 mL) was heated in a sealed pressure vessel at 150° C. for 72 hours. The mixture was then allowed to cool to ambient temperature then solvents removed in vacuo. The residue was dissolved in dichloromethane (20 mL), washed with water (15 mL) then dried (Na2SO4), filtered and reduced in vacuo. Flash chromatography over silica, eluting with dichloromethane:methanol mixtures 97:3 to 95:5 gave methylaminoalcohol (57) as a pale yellow solid (47 mg, 35%). TLC (Rf=0.22, DCM:MeOH 93:7), HPLC-MS 293.1 [M+H]+, 315.2 [M+Na]+, 607.3 [2M+Na]+; δH (500 MHz, CDCl3) mixture of rotamers major:minor 3:2; 2.42 (1.8H, s, NHCH3 major), 2.3 (1.2H, s, NHCH3 minor), 3.14-3.16 (1H, m, CHNHCH3), 3.35-4.48 (7H, m, OCH2CHOH, CHCHCHCH2NCbz), 5.06 and 5.22 (0.8H total, each d, J=12.22 Hz, Cbz minor), 5.12 (1.2H, s, Cbz major), 7.27-7.37 (5H, m, aromatic CH).
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH:15]([C:18]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([CH3:27])[CH3:26])[C:19]=1[NH2:20])([CH3:17])[CH3:16].[CH3:28][C:29]([CH3:31])=O.C(O)(=O)C>ClCCCl>[CH:29]([NH:20][C:19]1[C:18]([CH:15]([CH3:17])[CH3:16])=[CH:24][CH:23]=[CH:22][C:21]=1[CH:25]([CH3:27])[CH3:26])([CH3:31])[CH3:28]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)Nc1c(C(C)C)cccc1C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.1 %

Procedure:
NaBH(OAc)3 (3.2 g, 15 mmol) was added into a solution of 2,6-diisopropylaniline (0.940 mL, 4.98 mmol), acetone (1.8 mL, 25 mmol) and acetic acid (0.57 mL, 10 mmol) in 1,2-dichloroethane (30 mL) at room temperature. After stirring at room temperature for 16 h, the reaction was quenched by adding 1M NaOH aq. solution (20 mL). The organic layer was extracted with CH2Cl2 (30 mL), and the volatiles were evaporated under reduced pressure. Column chromatography (silica gel, 20:1 hexane/ethyl acetate) gave the product (0.733 g, 66.8%). 1H NMR (300 MHz, CDCl3) δ 7.24-6.95 (m, 3H), 3.47-3.12 (m, 3H), 2.86 (br. s, 1H), 1.27 (d, J=7.0 Hz, 12H), 1.19 (d, J=6.4 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 142.4, 142.1, 123.6, 123.3, 51.6, 28.0, 24.5, 23.7. HRMS-ESI (m/z): [M+H]+ calcd for C15H26N, 220.2065; found, 220.2064.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:14]=3)=[CH:11][N:10]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:40]=[CH:39][C:38]([N:41]=[C:42]=[O:43])=[CH:37][CH:36]=1.[Na]>CN(C)C=O>[C:20]([NH:19][C:15]1[CH:14]=[C:13]([C:12]2[C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:42]([NH:41][C:38]4[CH:37]=[CH:36][C:35]([C:34]([F:33])([F:44])[F:45])=[CH:40][CH:39]=4)=[O:43])[CH:7]=[CH:6][CH:5]=3)=[N:9][N:10]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[CH:11]=2)[CH:18]=[CH:17][N:16]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: COc1ccc(Cn2cc(-c3ccnc(NC(C)(C)C)c3)c(-c3cccc(N)c3)n2)cc1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(-c3ccnc(NC(C)(C)C)c3)c(-c3cccc(NC(=O)Nc4ccc(C(F)(F)F)cc4)c3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.9 %

Procedure:
350 mg (0.82 mmol) of 4-[3-(3-aminophenyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]-N-tert-butyl-pyridin-2-amine were dissolved in 30 ml of dry dimethylformamide and 110 μl (0.82 mmol) of p-trifluoromethyl-phenyl isocyanate were added to the resulting solution. The mixture was stirred overnight at room temperature, then poured into an aqueous solution of sodium hydrogenocarbonate and extracted with dichloromethane. The organic phase was dried over sodium sulphate and evaporated in vacuo. The residue was chromatographed on a silica gel column (dichloromethane-acetone 9/1), affording 302 mg (60%) of the title compound.
Reaction SMILES: [OH-].[Na+].Cl[C:4]1[C:7]([F:9])([F:8])[C:6]([F:11])([F:10])[C:5]=1[Cl:12].[CH:13]([OH:16])([CH3:15])[CH3:14]>>[CH:13]([O:16][C:4]1[C:7]([F:9])([F:8])[C:6]([F:11])([F:10])[C:5]=1[Cl:12])([CH3:15])[CH3:14]
Reactant: FC1(F)C(Cl)=C(Cl)C1(F)F
Reactant: CC(C)O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)OC1=C(Cl)C(F)(F)C1(F)F
Reaction time: 2 h

Procedure:
200 g (5 mol) of powdered sodium hydroxide are metered into a solution of 786 g (3.94 mol) of 1,2-dichloro-3,3,4,4-tetrafluorocyclobutene and 328 g (5.47 mol) of technical grade isopropanol at -10° C. The mixture is stirred for a further 2 hours, the solid is filtered off with suction and the filtrate is distilled.
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11]1[N:16]=[C:15](Cl)[C:14]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[C:13]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[N:12]=1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].O.[NH2:32][NH2:33]>C(O)(C)C>[CH3:1][C:2]([NH:10][C:11]1[N:16]=[C:15]([NH:32][NH2:33])[C:14]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[C:13]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[N:12]=1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3]
Reactant: NN
Reactant: CC(C)(Nc1nc(Cl)c(-c2ccc(F)cc2)c(-c2ccncc2)n1)c1ccccc1
Solvent: CC(C)O
Solvent: O
Product: CC(C)(Nc1nc(NN)c(-c2ccc(F)cc2)c(-c2ccncc2)n1)c1ccccc1
Temperature: 70 °C

Procedure:
2-((1-methyl-1-phenylethyl)amino)-4-chloro-5-(4-fluorophenyl)-6-(4-pyridyl)pyrimidine (218 mg, 0.52 mmol) was combined with a solution of hydrazine hydrate (130 mg 2.60 mmol) and isopropylalcohol (ca. 10 mL). The mixture was heated at 70° C. for 4 h. The reaction was cooled to RT, the solvent was evaporated in vacuo and the residue was purified by flash chromatography (2% MeOH:CHCl3) to provide the product as an off-white solid; MS m/z (M+H)+ 415; C24H23FN6 requir. 414.5.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[NH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>C1COCC1>[Cl:5][CH2:4][CH2:3][CH2:2][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: C1CCNCC1
Reactant: ClCCCBr
Solvent: C1CCOC1
Product: ClCCCN1CCCCC1
Temperature: 25 °C

Procedure:
A mixture of 1-bromo-3-chloropropane (65.6 g, 0.417 mol) and piperidine (62 ml, 0.625 mol) in anhydrous THF (200 ml) was heated to reflux for 24 h. The mixture was cooled to RT and filtered to remove solids. The organics were concentrated under in vacuo. The resultant residue was taken up in 2N HCl and washed twice with ethyl acetate. The aqueous layer was basicified with 2N NaOH to pH 14. The compound was extracted three times with ethyl acetate and the combined organics dried over anhydrous magnesium sulfate. The solution was then concentrated under reduced pressure to give the desired compound as a yellowish oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:14]([CH2:23][CH3:24])=[N:13][C:7]=3[C:8]([NH2:12])=[N:9][C:10]=2[CH:11]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:47]([O:51][CH2:52][CH3:53])(=[O:50])[CH:48]=[CH2:49]>CN(C)C=O.C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:12][C:8]1[C:7]2[N:13]=[C:14]([CH2:23][CH3:24])[N:15]([CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:6]=2[C:5]2[CH:4]=[CH:3][C:2](/[CH:49]=[CH:48]/[C:47]([O:51][CH2:52][CH3:53])=[O:50])=[CH:11][C:10]=2[N:9]=1
Reactant: C=CC(=O)OCC
Reactant: CCc1nc2c(N)nc3cc(Br)ccc3c2n1CC1CCOCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1ccc2c(c1)nc(N)c1nc(CC)n(CC3CCOCC3)c12
Temperature: 120 °C
Yield: 72.4 %

Procedure:
A thick walled glass vessel, equipped with a stir bar, was charged with a warmed solution of 7-bromo-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine (2.5 g, 6.42 mmol) in N,N-dimethylformamide (50 mL). To the solution was added in succession, a solution of palladium acetate (144 mg, 0.642 mmol) and tri-ortho-tolylphosphine (390 mg, 1.28 mmol) in N,N-dimethylformamide (5 mL), triethylamine (2.7 mL) and a solution of ethyl acrylate (0.77 g, 7.7 mmol) in N,N-dimethylformamide (2 mL). The reaction mixture was purged with nitrogen. The vessel was sealed and heated at 120° C. for 18 hours. The reaction was cooled to ambient temperature and then concentrated to dryness under reduced pressure. The resulting solid was dissolved in dichloromethane (150 mL) and washed with saturated aqueous potassium carbonate (100 mL). The fractions were separated and the organic fraction was concentrated to dryness under reduced pressure. The resulting off-white solid was purified by chromatography using a HORIZON HPFC system (silica cartridge, 0-15% CMA/chloroform). A final recrystallization from acetonitrile provided 1.9 g of ethyl (2E)-3-[4-amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]prop-2-enoate as an off-white crystalline solid, mp 209-210° C.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:40])[CH2:15][C:16]1[CH:17]=[C:18]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[CH:19]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].Br[CH2:52][C:53]([CH3:55])=[CH2:54]>C1COCC1>[CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:40])[CH:15]([C:16]1[CH:17]=[C:18]([C:30]2[CH:31]=[CH:32][C:33]([C:36]([F:38])([F:39])[F:37])=[CH:34][CH:35]=2)[CH:19]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=1)[CH2:54][C:53]([CH3:55])=[CH2:52])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)CBr
Reactant: O=C(Cc1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1)N1C(=O)OCC1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C(C)CC(C(=O)N1C(=O)OCC1Cc1ccccc1)c1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
To a colorless solution of 4-benzyl-3-[2-(5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-acetyl]-oxazolidin-2-one (6.0 g, 11.00 mmol) in dry THF (22 ML) at −78° C. was added sodium hexamethyl disilazide (NaHMDS) (1 M in THF solution, 12.11 mL, 12.11 mmol), drop-wise, maintaining the internal temperature below −75° C. The resulting red solution was stirred at −78° C. for 30 minutes. To this was added 3-bromo-2-methyl propene (4.44 mL, 44 mmol) maintaining the temperature below −75° C. When the addition was at near completion, the reaction mixture turned green. At this point the dry-ice bath was quickly removed and replaced with water-ice bath and the addition was completed. The reaction mixture was stirred at 0° C. for an additional 30 min and quenched with saturated aqueous NH4Cl solution. The system was diluted with EtOAC (100 mL) and the organic phase was washed with saturated aqueous NaHCO3 solution (3×50 mL) and dried (MgSO4). Solvent was removed in vacuo and the crude mixture was purified by ISCO silica gel column to yield 4-benzyl-3-[2-(5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pent-4-enoyl]-oxazolidin-2-one (6.3 g, 95%)
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH2:3][NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]2[N:12]=[N:13][N:14]=[C:7]2[C:6]=1[N+:15]([O-])=O.CO>C1(C)C=CC=CC=1>[CH3:1][CH:2]([CH3:18])[CH2:3][NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]2[N:12]=[N:13][N:14]=[C:7]2[C:6]=1[NH2:15]
Reactant: Cc1cc(NCC(C)C)c([N+](=O)[O-])c2nnnn12
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1cc(NCC(C)C)c(N)c2nnnn12
Reaction time: 2 h
Yield: 88.5 %

Procedure:
N-(2-Methylpropyl)-5-methyl-8-nitrotetraazolo[1,5-α]pyridin-7-amine (9.60 g, 43.6 mmol) was dissolved in warm anhydrous toluene (900 mL) and methanol (100 mL) and then added to a 2 L stainless steel Parr vessel. The vessel was flushed several times with nitrogen, and 5% platinum on carbon (2.0 g) was added to the solution. The vessel was flushed multiple times with hydrogen, and then placed under hydrogen pressure (50 psi, 3.4×105 Pa). After two hours, no further hydrogen was consumed. The reaction mixture was filtered through a layer of filter agent (available from Aldrich, Milwaukee, Wis. under the trade name CELITE), and the filter cake was washed with hot toluene (1 L). The filtrate was concentrated under reduced pressure to yield 8.5 g N7-(2-methylpropyl)-5-methyltetraazolo[1,5-α]pyridine-7,8-diamine as a light orange solid, m.p. 159-162° C.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([OH:34])[CH:20]=3)[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.[CH3:35][C:36]([CH3:40])([CH3:39])[CH2:37]O.C(C=P(CCCC)(CCCC)CCCC)#N.O>C1(C)C=CC=CC=1>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([O:34][CH2:35][C:36]([CH3:40])([CH3:39])[CH3:37])[CH:20]=3)[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(O)c2)c1)C1CC1
Reactant: CC(C)(C)CO
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(OCC(C)(C)C)c2)c1)C1CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 52.1 %

Procedure:
Under a nitrogen atmosphere, to a solution of ethyl 3-cyclopropyl-3-(3-(((2′-fluoro-2-hydroxy-5′-methoxybiphenyl-4-yl)oxy)methyl)phenyl)propanoate (195 mg), 2,2-dimethyl-1-propanol (79 mg) in toluene (5.0 mL) was added cyanomethylenetributylphosphorane (0.25 mL), and the mixture was stirred at 100° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (117 mg) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[N+:10]([CH3:13])([O-:12])=[O:11].[OH-].[Na+].C(O)(=O)C>CCO>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH2:13][N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc(C(O)C[N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
A stirred solution of 4-methylbenzaldehyde (325 mg, 319 μL, 2.71 mmol) and nitromethane (531 μL, 9.89 mmol) in absolute EtOH (20 mL) at 0° C. was treated with 10% aq. NaOH (m/v) (1.14 mL, 2.84 mmol), stirred for 1 h and treated with 2% aq. acetic acid (m/v) (8.54 mL, 2.84 mmol). The reaction was stirred for 1 h at room temperature then partitioned between water (50 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (2×50 mL) and the combined organic extracts were washed with saturated NaHCO3 (50 mL) and brine (50 mL), dried (Na2SO4) and concentrated in vacuo to afford 1-(4-methylphenyl)-2-nitroethanol as a colorless oil. 1H NMR (CDCl3, 500 MHz) δ 7.28 (d, J=8.1 Hz, 2H), 7.21 (d, J=8.1 Hz, 2H), 5.42 (dt, J=9.6, 3.3 Hz, 1H), 4.60 (dd, J=13.3, 9.7 Hz, 1H), 4.49 (dd, J=13.3, 3.1 Hz, 1H), 2.79 (d, J=3.7, 1H), 2.36 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:28][CH2:27][C:12]2=[C:13]([N:20]3[CH2:23][CH:22]([C:24](O)=[O:25])[CH2:21]3)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[F:30][C:31]1([F:38])[CH2:37][CH2:36][CH2:35][NH2+:34][CH2:33][CH2:32]1>>[C:1]([O:5][C:6]([N:8]1[CH2:28][CH2:27][C:12]2=[C:13]([N:20]3[CH2:21][CH:22]([C:24]([N:34]4[CH2:35][CH2:36][CH2:37][C:31]([F:38])([F:30])[CH2:32][CH2:33]4)=[O:25])[CH2:23]3)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(N3CC(C(=O)O)C3)c2CC1
Reactant: FC1(F)CCC[NH2+]CC1
Agent: [Cl-]
Product: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(N3CC(C(=O)N4CCCC(F)(F)CC4)C3)c2CC1

Procedure:
Prepared according to example 38c starting from 300 mg (0.58 mmol) of 10-(3-Carboxy-azetidin-1-yl)-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohept[f]indene-7-carboxylic acid tert-butyl ester (as DIPEA salt) and 120 mg (0.70 mmol) of 4,4-Difluoro-perhydro-azepinium chloride.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH:3]([C:5]1[CH:6]=[CH:7][C:8]2[C:17]3[NH:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:11](=[O:18])[N:10](COC)[C:9]=2[CH:22]=1)[CH3:4].[ClH:24]>C(O)C>[ClH:24].[ClH:24].[CH3:23][N:2]([CH3:1])[CH:3]([C:5]1[CH:6]=[CH:7][C:8]2[C:17]3[NH:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:11](=[O:18])[NH:10][C:9]=2[CH:22]=1)[CH3:4]
Reactant: COCn1c(=O)c2c(c3ccc(C(C)N(C)C)cc31)NCCC2
Agent: Cl
Solvent: CCO
Product: CC(c1ccc2c3c(c(=O)[nH]c2c1)CCCN3)N(C)C
Temperature: 80 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
The compound (15 mg, 0.05 mmol) prepared in step 6 was dissolved in ethanol (4 ml) and added with conc. hydrochloric acid (0.5 ml). The mixture was stirred overnight at 80° C. and the precipitate was collected by filteration to obtain the title compound (14 mg, yield: 86%, yellow solid).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[N:5][C:6]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:7][CH:8]=1.N1C=CN=C1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>CN(C=O)C.C(OCC)(=O)C>[O:1]([CH2:2][C:3]1[CH:4]=[N:5][C:6]([NH:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:7][CH:8]=1)[Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: OCc1cnc(Nc2ccccc2)nc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cnc(Nc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
5-Hydroxymethyl-2-(phenylamino)pyrimidine (280 mg, 1.39 mmol) obtained in Step 3 was dissolved in DMF (10 mL), and imidazole (190 mg, 2.76 mmol) and tert-butyldimethylsilylchloride (420 mg, 2.79 mmol) were added to the solution, followed by stirring at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:10) to obtain 5-(tert-butyldimethylsiloxymethyl)-2-(phenylamino)pyrimidine (423 mg, 82%).
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH3:6][C:7]1([CH3:17])[C@@H:9]([CH2:10][C:11](=O)[CH3:12])[C@H:8]1[C:14]([OH:16])=[O:15].Cl.[CH:19]([O:22][NH2:23])([CH3:21])[CH3:20]>O>[CH3:6][C:7]1([CH3:17])[C@@H:9]([CH2:10][C:11](=[N:23][O:22][CH:19]([CH3:21])[CH3:20])[CH3:12])[C@H:8]1[C:14]([OH:16])=[O:15]
Reactant: CC(C)ON
Reactant: CC(=O)C[C@H]1[C@@H](C(=O)O)C1(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C[C@H]1[C@@H](C(=O)O)C1(C)C)=NOC(C)C
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of 1.85 g of sodium bicarbonate in 50 ml of water, were added 1.70 g of (1R,cis)-2,2-dimethyl-3-(2-oxopropyl)cyclopropanecarboxylic acid and 1.15 g of isopropoxyamine hydrochloride at room temperature. The reaction mixture was stirred at room temperature for 4.5 hours and filtered through celite. The filtrate was acidified with concentrated hydrochloric acid to a pH of 2, and extracted with methylene chloride. The organic extract was washed with a sodium chloride solution, dried over magnesium sulfate, stripped and concentrated under high vacuum to give the desired product as a slightly amber oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][C:14]=2[CH3:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]1([S:27]([N:30]2[C:38]3[C:33](=[CH:34][C:35]([F:39])=[CH:36][CH:37]=3)[C:32](Br)=[CH:31]2)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([S:19][C:32]3[C:33]4[C:38](=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=4)[N:30]([S:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)(=[O:29])=[O:28])[CH:31]=3)=[CH:15][C:14]=2[CH3:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(c1ccccc1)n1cc(Br)c2cc(F)ccc21
Reactant: Cc1cc(S)ccc1C1CCN(C(=O)OC(C)(C)C)C1
Product: Cc1cc(Sc2cn(S(=O)(=O)c3ccccc3)c3ccc(F)cc23)ccc1C1CCN(C(=O)OC(C)(C)C)C1

Procedure:
3-(4-Mercapto-2-methyl-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester was reacted with 1-benzenesulfonyl-3-bromo-5-fluoro-1H-indole using the procedure of step 1 of Example 3 to provide 3-[4-(1-Benzenesulfonyl-5-fluoro-1H-indol-3-ylsulfanyl)-2-methyl-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][C:8](=[O:16])[C:9]([CH3:15])([CH3:14])[CH:10]([Br:13])[CH2:11][Br:12])=[CH:4][CH:3]=1.[Br:19]Br>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]([Br:19])[C:8](=[O:16])[C:9]([CH3:14])([CH3:15])[CH:10]([Br:13])[CH2:11][Br:12])=[CH:4][CH:3]=1
Reactant: CC(C)(C(=O)COc1ccc(Cl)cc1)C(Br)CBr
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CC(C)(C(=O)C(Br)Oc1ccc(Cl)cc1)C(Br)CBr
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
107 g (0.269 mole) of 1-(4-chlorophenoxy)-4,5-dibromo-3,3-dimethyl-2-pentanone are dissolved in 400 ml of chloroform. 43 g (0.269 mole) of bromine are added dropwise at room temperature such that the solution is always decolorized. The mixture is then subsequently stirred at room temperature for 30 minutes, washed with water, dried over sodium sulphate and concentrated. 128 g (99% of theory) of 1-(4-chlorophenoxy)-3,3-dimethyl-1,4,5-tribromo-2-pentanone of refractive index nD20 1.5472 are obtained. ##STR107##
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])=[CH:10][C:9]=1[NH2:22])(C)(C)C.CC1(C)O[C:29]([C:31]2[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=2)[C:34]#[N:35])=[CH:28][C:27](=[O:39])O1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:29]([C:31]3[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=3)[C:34]#[N:35])[CH2:28][C:27](=[O:39])[NH:22][C:9]=2[CH:10]=1
Reactant: COc1ccccc1-c1ccc(NC(=O)OC(C)(C)C)c(N)c1
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccccc1-c1ccc2c(c1)NC(=O)CC(c1cccc(C#N)c1)=N2

Procedure:
Prepared from (3-amino-2′-methoxy-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G10) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light green powder (30 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:7]=1.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1B(O)O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:22]3[S:21][CH:25]=[CH:24][CH:23]=3)=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:7]=1
Reactant: OB(O)c1cccs1
Reactant: COc1ccc(Br)cc1NS(=O)(=O)c1ccc(I)cc1
Product: COc1ccc(Br)cc1NS(=O)(=O)c1ccc(-c2cccs2)cc1

Procedure:
The title compound was prepared from the product of Step 1 and 2-thienylboronic acid using a similar method to that described for Examples 237-243 (E237-E243). MS (ES−) 422/424 [M−H]−.