Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[O:5][C:6]1[C:7]([CH2:13][CH3:14])=[N:8][NH:9][C:10]=1[CH2:11][CH3:12].Cl.Cl[CH2:21][CH2:22][NH2:23]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[O:5][C:6]1[C:10]([CH2:11][CH3:12])=[N:9][N:8]([CH2:21][CH2:22][NH2:23])[C:7]=1[CH2:13][CH3:14]
Reactant: CCc1n[nH]c(CC)c1Oc1cc(Cl)cc(Cl)c1
Reactant: NCCCl
Agent: Cl
Product: CCc1nn(CCN)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Temperature: 150 °C
Yield: 54.3 %

Procedure:
A mixture of the pyrazole (390 mg, 1.37 mmol) of Example 3 and chloroethylamine hydrochloride (238 mg, 2.05 mmol) was stirred and heated at 150° C. for 24 hours. After cooling, the mixture was partitioned between saturated aqueous sodium bicarbonate solution (100 ml) and dichloromethane (2×50 ml). The combined organic layers were washed with brine (30 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The resulting brown oil was purified by flash chromatography on silica gel eluting with dichloromethane:methanol (90:10, by volume) to afford the title compound (244 mg) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:13]2[CH2:15][CH2:14]2)=[C:9]([F:12])[CH2:10][OH:11])=[CH:4][CH:3]=1>[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH:13]2[CH2:14][CH2:15]2)=[C:9]([F:12])[CH:10]=[O:11])=[CH:6][CH:7]=1
Reactant: OCC(F)=C(c1ccc(Cl)cc1)C1CC1
Agent: [Mn+4]
Agent: [O-2]
Product: O=CC(F)=C(c1ccc(Cl)cc1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
Activated manganese(IV) oxide (101.25 g, 1.16 mol) is added to a solution of 3-(p-chlorophenyl)-3-cyclopropyl-2-fluoro-2-propen-1-ol, (E)- and (Z)- (26.4 g, 0.116 mol) in hexanes. The resultant reaction mixture is stirred at room temperature overnight, filtered through a pad of diatomaceous earth, and concentrated in vacuo to obtain a residue. Flash column chromatography of the residue using silica gel and an ethyl acetate/hexanes solution (1:9) gives the title product as an oil (15.8 g, 60%).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]3[C:15]=2[CH:16]=[CH:17][C:18]([C:26]([F:29])([F:28])[F:27])=[N:19]3)[CH2:11][CH2:10][N:9]1[CH2:30][C:31](O)=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]1[O:40][NH2:41].C1CCC(N=C=NC2CCCCC2)CC1.CCOC(C)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]3[C:15]=2[CH:16]=[CH:17][C:18]([C:26]([F:27])([F:29])[F:28])=[N:19]3)[CH2:11][CH2:10][N:9]1[CH2:30][C:31]([NH:41][O:40][CH:35]1[CH2:36][CH2:37][CH2:38][CH2:39][O:34]1)=[O:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N2CCN(CC(=O)O)[C@@H](Cc3ccccc3)C2)c2ccc(C(F)(F)F)nc12
Reactant: NOC1CCCCO1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(N2CCN(CC(=O)NOC3CCCCO3)[C@@H](Cc3ccccc3)C2)c2ccc(C(F)(F)F)nc12
Reaction time: 3 h
Yield: 74.3 %

Procedure:
A solution of (S)-2-(2-benzyl-4-(8-methoxy-2-(trifluoromethyl)quinolin-5-yl)piperazin-1-yl)acetic acid (184 mg, 0.40 mmol) in CH2Cl2 (4 mL) at 0-5° C. was treated with O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (49 mg, 0.42 mmol), catalytic DMAP, and finally DCC (87 mg, 0.42 mmol). The reaction mixture was stirred for 3 h after which time the mixture was treated with EtOAc (5 mL), filtered and evaporated. The residue was purified by silica gel flash chromatography with 100% EtOAc, as eluant to afford intermediate 2-((S)-2-benzyl-4-(8-methoxy-2-(trifluoromethyl)quinolin-5-yl)piperazin-1-yl)-N-(tetrahydro-2H-pyran-2-yloxy)acetamide as an oil (166 mg, 74%). LC/MS (Method A) 5.76 min, [M+1]+ 559.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:32]=[CH:31][C:30]5[C:25](=[CH:26][CH:27]=[C:28]([OH:33])[CH:29]=5)[C:24]4=[O:34])=[CH:19][C:18]=3[F:35])[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:37][CH:38]1[CH2:40][CH2:39]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN1C(=O)CCC1>O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:32]=[CH:31][C:30]5[C:25](=[CH:26][CH:27]=[C:28]([O:33][CH2:37][CH:38]6[CH2:40][CH2:39]6)[CH:29]=5)[C:24]4=[O:34])=[CH:19][C:18]=3[F:35])[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCN(c3ccc(-n4ccc5cc(O)ccc5c4=O)cc3F)C2)C1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CCN(c3ccc(-n4ccc5cc(OCC6CC6)ccc5c4=O)cc3F)C2)C1
Temperature: 60 °C

Procedure:
A mixture of 7-[2-fluoro-4-(6-hydroxy-1-oxo-1H-isoquinolin-2-yl)-phenyl]-2,7-diaza-spiro[4.4]nonane-2-carboxylic acid tert-butyl ester (250 mg), bromomethyl-cyclopropane (70 mg), cesium carbonate (170 mg) and NMP (5 mL) was heated for 4 hours at 60° C. The cooled reaction mixture was distributed between ethyl acetate and water. The organic phase was dried over magnesium sulfate and concentrated. The raw product was purified by preparative HPLC.
Reaction SMILES: COC(=O)[C@@H](C1C=CC=CC=1)O.[NH2:13][CH2:14][C:15]1([CH2:41][F:42])[CH2:19][CH2:18][N:17]([C:20]2[C:29]([O:30][CH3:31])=[C:28]3[C:23]([C:24](=[O:39])[C:25]([C:35]([O:37][CH3:38])=[O:36])=[CH:26][N:27]3[CH:32]3[CH2:34][CH2:33]3)=[CH:22][C:21]=2[F:40])[CH2:16]1>CO>[NH2:13][CH2:14][C@@:15]1([CH2:41][F:42])[CH2:19][CH2:18][N:17]([C:20]2[C:29]([O:30][CH3:31])=[C:28]3[C:23]([C:24](=[O:39])[C:25]([C:35]([O:37][CH3:38])=[O:36])=[CH:26][N:27]3[CH:32]3[CH2:34][CH2:33]3)=[CH:22][C:21]=2[F:40])[CH2:16]1
Reactant: COC(=O)c1cn(C2CC2)c2c(OC)c(N3CCC(CN)(CF)C3)c(F)cc2c1=O
Agent: COC(=O)[C@H](O)c1ccccc1
Solvent: CO
Product: COC(=O)c1cn(C2CC2)c2c(OC)c(N3CC[C@@](CN)(CF)C3)c(F)cc2c1=O
Reaction time: 72 h
Yield: 13.6 %

Procedure:
A solution of (R)-O-methylmandelic acid (2.2 g) in methanol (8 ml) was added to a solution of the compound (8.1 g) obtained in Example 2 in methanol (32 ml), and the mixture was left standing at room temperature for 3 days. The precipitated crystals were collected by filtration and recrystallized 4 times from methanol. The obtained crystals were suspended in water, and the suspension was made alkaline with potassium carbonate and extracted with chloroform. The extract was washed with water, dried and concentrated to give 1.1 g of the object compound, melting point 150°-152° C., optical purity not less than 95% ee (HPLC).
Reaction SMILES: [OH-].[K+].[SH2:3].[CH3:4][O:5][C:6](=[O:18])[C:7]([C:14]([O:16][CH3:17])=[O:15])=[C:8]([CH2:12]Cl)[CH:9]=[CH:10]Cl>C(O)C.O.CCOCC>[S:3]1[CH:10]=[CH:9][C:8]([CH:7]([C:14]([O:16][CH3:17])=[O:15])[C:6]([O:5][CH3:4])=[O:18])=[CH:12]1
Reactant: COC(=O)C(C(=O)OC)=C(C=CCl)CCl
Reactant: S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: COC(=O)C(C(=O)OC)c1ccsc1
Reaction time: 1 h
Yield: 74 %

Procedure:
Potassium hydroxide (0.14 g, 2.0 mmol) in ethanol (50 ml) was saturated with hydrogen sulphide at 0° C. To this was added methyl-2-methoxycarbonyl-5-chloro-3-chloromethylpenta-2,4-dienoate (0.62 g, 2.45 mmol) and addition of hydrogen sulphide was continued for 1 hour at room temperature. The reaction mixture was stirred for a further 4 hours. Potassium hydroxide (0.20 g, 2.8 mmol) was added and hydrogen sulphide passed for 0.5 hours. The reaction mixture was stirred at room temperature for 16 hours, diluted with water and ether extracted. The extracts were washed with saturated brine, dried and evaporated to give the title compound (0.39 g, 74%), b.p. 96°-98° C./0.3 mm. δ (CDCl3) 3.77 (6H, s, 2×CH3), 4.82 (1H, s, CH), 7.11-7.48 (3H, m, thienyl protons). νmax (film) 1740 cm-1C9H10O4S requires M,214. Found: M+, 214.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:29]([N:31]([CH2:38][CH2:39]O)[CH:32]([CH3:37])[C:33]([F:36])([F:35])[F:34])=[O:30])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]2[CH2:39][CH2:38][N:31]([CH:32]([CH3:37])[C:33]([F:35])([F:34])[F:36])[C:29](=[O:30])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(N(CCO)C(=O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1)C(F)(F)F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(N1CCn2c(CC3(c4ccc(Cl)cc4)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O)C(F)(F)F
Reaction time: 0.17 h
Yield: 92 %

Procedure:
To a stirred solution of 5-(benzyloxy)-2-((1-(4-chlorophenyl)cyclopentyl)methyl)-6-hydroxy-N-(2-hydroxyethyl)-N-(1,1,1-trifluoropropan-2-yl)pyrimidine-4-carboxamide (43) (102 mg, 176 μmol, Eq: 1.00) in dichloromethane (5 ml) was added triphenylphosphine (69.4 mg, 265 μmol, Eq: 1.5) at room temperature and the reaction mixture was stirred for 10 min. Then diisopropyl azodicarboxylate (53.5 mg, 51.5 μl, 265 μmol, Eq: 1.5) was added and the reaction mixture was stirred for 18 hrs at room temperature, concentrated, and chromatographed (silica gel, gradient, 0 to 5% methanol-dichloromethane) to obtain 9-(benzyloxy)-6-((1-(4-chlorophenyl)cyclopentyl)methyl)-2-(1,1,1-trifluoropropan-2-yl)-3,4-dihydro-1H-pyrazino[1,2-c]pyrimidine-1,8(2H)-dione (44) (white foam, 90.8 mg, 162 μmol, 91.9% yield).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:23])[C:5]([C:18]([O:20]CC)=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.C(O)(=O)C.S(=O)(=O)(O)O>O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:23])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c(N)c2c1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 105 °C
Reaction time: 0.67 h
Yield: 97.7 %

Procedure:
28.7 g of ethyl 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate (0.088 mol), 160 ml of acetic acid, and a mixture of 100 ml of water and 18 ml of concentrated sulfuric acid were stirred at 100-110° C. for 40 minutes. The reacting mixture was cooled and filtered. The precipitate was recrystallized from chloroform-ethanol to give 25.6 g 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (Sparcarboxylic acid, 0.086 mol), mp. 293-295C., in 98.0% yield.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[CH:10][C:9]([NH:12][S:13]([CH2:16][CH3:17])(=[O:15])=[O:14])=[CH:8][C:7]=2B2OC(C)(C)C(C)(C)O2)[CH2:3][CH2:2]1.Br[C:28]1[C:29]2[CH:38]=[CH:37][O:36][C:30]=2[C:31](=[O:35])[N:32]([CH3:34])[CH:33]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[CH:10][C:9]([NH:12][S:13]([CH2:16][CH3:17])(=[O:14])=[O:15])=[CH:8][C:7]=2[C:28]2[C:29]3[CH:38]=[CH:37][O:36][C:30]=3[C:31](=[O:35])[N:32]([CH3:34])[CH:33]=2)[CH2:2][CH2:3]1
Reactant: Cn1cc(Br)c2ccoc2c1=O
Reactant: CCS(=O)(=O)Nc1cnc(OCC2CC2)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)Nc1cnc(OCC2CC2)c(-c2cn(C)c(=O)c3occc23)c1
Temperature: 65 °C
Reaction time: 12 h
Yield: 47.3 %

Procedure:
A mixture of N-[6-(cyclopropylmethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]ethanesulfonamide (145 mg, 0.38 mmol), 4-bromo-6-methyl-6H,7H-furo[2,3-c]pyridin-7-one (25 mg, 0.11 mmol), K3PO4 (58 mg, 0.28 mmol), Pd(dppf)Cl2 (8 mg, 10%) in dioxane/H2O (1 mL/100 uL) was bubbled with nitrogen for 5 min. The sealed vial was stirred at 65° C. for 12 h. The reaction mixture was filtered through a short plug of celite; the celite plug was washed with EtOAc (15 mL). The filtrate was washed with water and brine; the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford a tan residue. The resulting residue was purified by prep-HPLC to afford the title compound (21 mg, 48%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.23-0.32 (m, 2H) 0.41-0.52 (m, 2H) 1.08-1.19 (m, 1H) 1.20-1.29 (m, 3H) 3.05-3.16 (m, 2H) 3.58-3.63 (m, 3H) 3.64-3.66 (m, 1H) 4.08-4.17 (m, 2H) 6.72-6.82 (m, 1H) 7.58-7.65 (m, 1H) 7.67-7.73 (m, 1H) 7.95-8.06 (m, 1H) 8.10-8.18 (m, 1H) 9.41-9.86 (m, 1H). LCMS (M+H)+=404.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9](=O)[CH:10]=[N:11][NH:12][C:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1.C([O-])(=O)C.[NH4+:27]>C(O)(=O)C>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[N:12]=[N:11][CH:10]=[C:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[N:27]=2)=[CH:15][CH:16]=1
Reactant: [NH4+]
Reactant: O=C(NN=CC(=O)c1c(F)cccc1F)c1ccc(Br)cc1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: Fc1cccc(F)c1-c1cnnc(-c2ccc(Br)cc2)n1
Temperature: 25 °C

Procedure:
A mixture of 1.85 g of 4-bromobenzoic acid [2-(2,6-difluorophenyl)-2-oxoethylidene] hydrazide and 0.77 g of ammonium acetate is heated in 15 ml of glacial acetic acid at 10° C. for 14 h. After cooling to room temperature, the reaction mixture is poured into ice-water and extracted with ethyl acetate, and the organic phase is washed with saturated sodium hydrogen carbonate and saturated sodium chloride solution. After the organic phase has been dried over sodium sulfate, filtering and concentration in a rotary evaporator are carried out. The residue is purified by means of flash chromatography (5% ethyl acetate in toluene). In this way the title compound is obtained in the form of yellow crystals.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:21]([CH:26]=O)=[CH:22][CH:23]=[CH:24][CH:25]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:20]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][N:17]1[CH2:18][CH2:19][N:14]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:15][CH2:16]1
Reactant: c1ccc(Oc2ccccc2N2CCNCC2)cc1
Reactant: O=Cc1ccccc1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: c1ccc(Oc2ccccc2N2CCN(Cc3ccccc3-c3ccccc3)CC2)cc1

Procedure:
151 mg of the target compound (0.36 mmol, 64.9%) was obtained using 1-(2-phenoxyphenyl)piperazine (277 mg, 1.09 mmol), biphenyl-2-carbaldehyde (100 mg, 0.55 mmol) and NaBH(OAc)3 (355 mg, 1.65 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([Si](C)(C)[O:24][CH2:25][CH:26]([CH3:51])[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([N:36]1[CH2:50][C:39]2=[C:40]3[N:45]([N:46]=[C:38]2[CH2:37]1)[C:44]([CH3:47])=[C:43]([Cl:48])[C:42]([CH3:49])=[N:41]3)=[O:35])(C)(C)C>C1COCC1>[Cl:48][C:43]1[C:42]([CH3:49])=[N:41][C:40]2[N:45]([N:46]=[C:38]3[CH2:37][N:36]([C:34]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[O:27][CH:26]([CH3:51])[CH2:25][OH:24])=[O:35])[CH2:50][C:39]3=2)[C:44]=1[CH3:47]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OC(C)CO[Si](C)(C)C(C)(C)C)C3
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OC(C)CO)C3
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 47.5 %

Procedure:
A 1M solution of tetrabutyl-ammonium fluoride in THF (1.26 mL; 1.26 mmol; 1.2 eq.) was added to a cold (0° C.) solution of {2-[2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethoxy]-phenyl}-(6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]inden-2-yl)-methanone (540 mg; 1.05 mmol; 1 eq.) in THF (5 mL) and the resulting mixture was stirred at room temperature for 2.5 hours. After dilution with EA, the solution was washed with sat. aq. NaHCO3, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (50% EA in cyclohexane to EA) afforded the title compound (200 mg, 48%) as a white foam. 1H NMR (DMSO-d6) δ 7.52-7.36 (m, 1H), 7.37-7.23 (m, 1H), 7.23-7.14 (d, J=8.4 Hz, 1H), 7.09-6.96 (m, 1H), 4.96-4.73 (m, 3H), 4.55-4.38 (m, 2H), 3.51-3.37 (m, 2H), 2.84 (s, 1.5H), 2.80 (s, 1.5H), 2.62 (s, 1.5H), 2.55 (s, 1.5H), 1.24-1.11 (dd, J=6.2, 2.3 Hz, 2H). HPLC (max plot) 99.1%, Rt 3.35 min. UPLC/MS: (MS+) 401.2 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH3:14][Mg]Br>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:13])([CH3:14])[C:9]([F:11])([F:12])[F:10])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Br)cc1)C(F)(F)F
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)(c1ccc(Br)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4′-Bromo-2,2,2-trifluoroacetophenone (1.80 mL, 11.9 mmol) was stirred in THF (60 mL) at 0° C. under an argon atmosphere. Methylmagnesium bromide (19.8 mL, 59.3 mmol) was added and the reaction mixture was stirred at 0° C. for 1 hour and then allowed to warm to ambient temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-25% EtOAc/hexanes). Desired fractions were identified, combined, and concentrated in vacuo to afford a racemic mixture of the title compounds. The racemic residue was resolved by Chiral SFC purification (Chiral Technology AZ-H 2.1×25 cm, 5 uM column, eluted with 5% methanol).
Reaction SMILES: [BH4-].[Na+].[N:3]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]=[O:25])=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.C1COCC1.Cl>O.C(O)C>[N:3]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: O=Cc1ccc(-c2ccc(-n3ccc4ccccc43)cc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: OCc1ccc(-c2ccc(-n3ccc4ccccc43)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium borohydride (783 mg, 20.6 mmol) was added portion-wise to a stirred solution of aldehyde (prepared in example 4) (3.06 g, 10.3 mmol) in a mixture of anhydrous THF and ethanol (1:1; 100 mL) at room temperature. The reaction mixture was stirred for 10 minutes at room temperature (TLC control), poured into water (50 mL) and acidified to pH 4 with 2N hydrochloric acid, and then extracted with diethyl ether (3×20 mL). The combined extract was washed with 0.5 N hydrochloric acid (2×10 mL), water and finally brine. The ethereal solution was dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification of the product by flash column chromatography, using 30% ethyl acetate/hexane as eluent, afforded the title compound has a white solid (2.80 g, 91%); 1H NMR (CDCl3, 300 MHz) δ 7.55-7.78 (7H, m, Ar—H), 7.52 (2H, d, J=8 Hz, Ar—H), 7.41 (1H, d, J=3.5 Hz, Ar—H), 7.22 (3H, m, Ar—H), 6.72 (1H, d, J=3.5 Hz, Ar—H), 4.79 (2H, d, J=5.5 Hz, CH2O).
Reaction SMILES: [C:1]([N:3]=[C:4](OC1C=CC=CC=1)[NH:5][C:6]1[CH:7]=[N:8][CH:9]=[N:10][CH:11]=1)#[N:2].[CH3:19][C@@H:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[C:1]([N:3]=[C:4]([NH:27][C@@H:20]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:19])[NH:5][C:6]1[CH:11]=[N:10][CH:9]=[N:8][CH:7]=1)#[N:2]
Reactant: C[C@@H](N)c1ccccc1
Reactant: N#CN=C(Nc1cncnc1)Oc1ccccc1
Solvent: CN(C)C=O
Product: C[C@@H](NC(=NC#N)Nc1cncnc1)c1ccccc1
Reaction time: 18 h

Procedure:
A stirred mixture of N'-cyano-N-(5-pyrimidyl)-O-phenylisourea (0.5 g, 0.00209 mol), (R)-α-methylbenzylamine (1.0 mL) and DMF (4 mL) was kept, under nitrogen, at ambient temperature for 18 hours and concentrated in vacuo. The residue was allowed to crystallize from EtOAc-tert-butyl methyl ether. The solid was triturated with Et2O and tert-butyl methyl ether and crystallized from EtOAc to give product: NMR (CDCl3) δ1.61 (d, 3H), 4.92 (m, 1H), 6.05 (broad s, 1H), 7.38 (m, 6H), 8.56 (s, 2H), 8.97 (s, 1H); IR (Nujol) 3262, 3109, 3054, 2174, 1600, 1570 cm-1 ; MS m/z (relative intensity) 266 (M+, 100), 251 (24.3), 161 (4.0), 146 (33.0), 120 (40.5), 105 (100).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[C:5]([NH:7][N:8]([C:12](=[O:31])/[CH:13]=[CH:14]/[C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:16]=1)[CH:9]([CH3:11])[CH3:10])=[O:6].C([O-])([O-])=O.[K+].[K+].Br[CH2:42][CH2:43][O:44][CH3:45]>CC(C)=O>[CH:9]([N:8]([C:12](=[O:31])/[CH:13]=[CH:14]/[C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH:16]=1)[NH:7][C:5](=[O:6])[C:4]1[CH:32]=[CH:33][CH:34]=[C:2]([O:1][CH2:42][CH2:43][O:44][CH3:45])[CH:3]=1)([CH3:11])[CH3:10]
Reactant: CC(C)N(NC(=O)c1cccc(O)c1)C(=O)/C=C/c1cn(C(=O)OC(C)(C)C)c2ccccc12
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCCOc1cccc(C(=O)NN(C(=O)/C=C/c2cn(C(=O)OC(C)(C)C)c3ccccc23)C(C)C)c1
Temperature: 60 °C

Procedure:
To solution containing (E)-tert-butyl 3-(3-(2-(3-hydroxybenzoyl)-1-isopropylhydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate (100.0 mg, 0.22 mmol) and K2CO3 (35.8 mg, 0.26 mmol) dissolved in acetone (5.0 ml), 1-bromo-2-methoxyethane (0.024 ml, 0.26 mmol) was added drop-wise. The reaction mixture was refluxed at 60° C. for 48 hr. After concentration under reduced pressure, the solution was separated through silica gel chromatography (CHCl3:methanol=60:1) so that ivory solid form of (E)-tert-butyl 3-(3-(1-isopropyl-2-(3-(2-methoxyethoxy)benzoyl)hydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate was obtained (62.4 mg, 55.5%).
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:9]([O:21][CH3:22])[CH:8]=1)=[O:5].N[C:34]1C=C(OC2C=CC=CC=2)C=CC=1C(NC1C=CC(OCCN2CCCC2)=C(OC)C=1)=O>>[CH3:22][O:21][C:9]1[CH:8]=[C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:26][C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:24][CH:23]=3)[N:1]=[CH:34]2)[CH:12]=[CH:11][C:10]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: COc1cc(NC(=O)c2ccc(Oc3ccccc3)cc2N)ccc1OCCN1CCCC1
Reactant: COc1cc(NC(=O)c2ccc(-c3ccccc3)cc2N)ccc1OCCN1CCCC1
Product: COc1cc(-n2cnc3cc(-c4ccccc4)ccc3c2=O)ccc1OCCN1CCCC1

Procedure:
Using 2-amino-N-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4-phenyl-benzamide [Example C5] in the manner of 2-amino-N-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4-phenoxy-benzamide in Example C2, gave the title compound as a cream solid;
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])[N:12]=1.[Br:21]Br.O.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[Br:21][SH:9]1[CH:10]=[C:11]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])[N:12]=[C:8]1[NH:7][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1
Reactant: BrBr
Reactant: N#Cc1cccc(-c2csc(Nc3cnccn3)n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1cccc(C2=C[SH](Br)C(Nc3cnccn3)=N2)c1

Procedure:
3-[2-(Pyrazin-2-ylamino)-thiazol-4-yl]-benzonitrile (1.5 g, 5.36 mmol) is suspended in hot glacial acetic acid (10 ml) and bromine (0.275 ml) is added dropwise at room temperature with stirring. The resultant suspension is stirred at room temperature for 10 minutes. Water (ca. 100 ml) is added to the mixture, which is basified to pH 9 with solid potassium carbonate. The resulting precipitate is filtered and washed with water to yield 3-[S-bromo-2-(pyrazin-2-ylamino)-thiazol-4-yl]-benzonitrile, m.p. 215° C. (dec.), m.s. 279 (ES+, M+—Br).