Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[C:4]([Cl:10])[CH:3]=1.C([Li])(C)(C)C.[CH2:16]([C@@H:18]1[O:20][CH2:19]1)[Cl:17]>C(OCC)C>[Cl:17][CH2:16][C@H:18]([OH:20])[CH2:19][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[C:4]([Cl:10])[CH:3]=1
Reactant: ClC[C@H]1CO1
Reactant: CSc1ccc(Br)cc1Cl
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CSc1ccc(C[C@@H](O)CCl)cc1Cl
Temperature: -100 °C
Reaction time: 0.83 h
Yield: 35 %

Procedure:
The solution of 1.1 g (4.6 mmol) 4-bromo-2-chloro-1-methylsulfanyl-benzene (e.g. Joshi, R. S et. al.; J. Karnatak University (1959), 4, 38-42) in 40 mL diethyl ether was cooled down to −115° C. Then, 3.0 mL tert-butyllithium (4.5 mmol; 1.5M solution in n-pentane) was added dropwise and after stirring for 50 min. at −100° C. 0.54 mL (6.9 mmol) (R)-(−)-epichlorohydrin was added. After 45 min. the reaction was allowed to warm to 0° C. and after another 1.5 h was quenched with water and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed using MPLC and tert-butyl methyl ether: n-heptane (1:2 v/v) as eluant to give the compound as a colorless oil (35%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](Cl)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=1.C(N(CC)CC)C.Cl.C(N(CC)CC)C>C(#N)C.C1C=CC=CC=1>[F:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:11][CH:12]=1
Reactant: c1c[nH]cn1
Reactant: Fc1ccc(C(Cl)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CC#N
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Fc1ccc(C(c2ccccc2)(c2ccccc2)n2ccnc2)cc1
Temperature: 50 °C
Yield: 90.1 %

Procedure:
34 g (0.5 mol) imidazole are dissolved at room temperature, with stirring, in a solution of 148.25 g, (0.5 mol) of (p-fluorophenyl)-(diphenyl)-methyl chloride in 500 ml acetonitrile. Following this, 51 g (0.5 mol) triethylamine are added dropwise; triethylamine hydrochloride separates immediately upon heating. For completion of the reaction, the mixture is heated at 50°C for 3 hours. After cooling, the reaction mixture is stirred together with 1 liter of benzene and washed salt-free with water. The benzene solution is dried over anhydrous sodium sulfate, filtered and concentrated by evaporation; giving 148 g of crude 1-[(p-fluorophenyl)-(bisphenyl)-methyl]-imidazole of m.p. 146°C (= 91% of the theory). By recrystallization from 300 ml benzene and 50 ml ligroin, the m.p. rises to 148°C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:7]2O)[CH3:2].O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:7]1[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)[N:10]=[CH:9][C:8]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2ccc(OCC)cc2c1O
Product: CCOC(=O)c1cnc2ccc(OCC)cc2c1Cl

Procedure:
Prepared as in Example 1b from ethyl 6-ethoxy-4-hydroxyquinoline-3-carboxylate (Example 13c) and POCl3 as pale yellow solid (100%). 1H NMR (400 MHz, DMSO-d6) δ 1.34-1.42 (m, 6H), 4.21 (q, J=7.2 Hz, 2H), 4.40 (q, J=7.2 Hz, 2H), 7.52 (d, J=2.8 Hz, 1H), 7.56-7.59 (m, 1H), 8.02 (d, J=8.8 Hz, 1H), 8.94 (s, 1H). MS 280, 282 (MH+).
Reaction SMILES: II.I[CH2:4]I.[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH2:15])=[CH:10][CH:9]=1)#[N:7]>C1(C)C=CC=CC=1.[Cu]>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:14]2([C:11]3[CH:10]=[CH:9][C:8]([C:6]#[N:7])=[CH:13][CH:12]=3)[CH2:4][CH2:15]2)=[CH:21][CH:20]=1
Reactant: C=C(c1ccc(Cl)cc1)c1ccc(C#N)cc1
Reactant: ICI
Agent: [Cu]
Agent: II
Solvent: Cc1ccccc1
Product: N#Cc1ccc(C2(c3ccc(Cl)cc3)CC2)cc1

Procedure:
600 mg of Copper powder are cauterized with 10 mg of iodine in 10 ml of toluene. 1.2 g of Diiodomethane and 500 mg of 1-(4-cyanophenyl)-1-(4-chlorophenyl)-ethylene are added and the mixture refluxed for 140 hours and then filtered and the filtrate concentrated. The oily residue is chromatographed on silica gel with toluene as eluant.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:26]2[CH:35]=[C:34]3[C:29]([CH2:30][CH2:31][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:33]3)=[CH:28][CH:27]=2)O1>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:26]1[CH:35]=[C:34]2[C:29]([CH2:30][CH2:31][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:33]2)=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc2c(c1)CN(C(=O)OC(C)(C)C)CC2
Yield: 47.2 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (1 g, 3.3 mmol) was reacted with tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.8 g, 5.0 mmol) to afford the desired product (720 mg, 48%) as a brown solid: ESI MS m/z 463 [C26H26N2O4S+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[S:13][C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:14])[NH:7][C:6]=2[CH:5]=1.Cl.[F:16][C:17]1[CH:18]=[CH:19][C:20]2[C:24]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:23][S:22][C:21]=2[CH:31]=1>>[F:16][C:17]1[CH:18]=[CH:19][C:20]2[C:24]([CH:25]3[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][C:4]4[S:13][C:12]5[CH2:11][CH2:10][CH2:9][C:8](=[O:14])[NH:7][C:6]=5[CH:5]=4)[CH2:29][CH2:30]3)=[CH:23][S:22][C:21]=2[CH:31]=1
Reactant: Fc1ccc2c(C3CCNCC3)csc2c1
Reactant: O=C1CCCc2sc(CCCl)cc2N1
Agent: Cl
Product: O=C1CCCc2sc(CCN3CCC(c4csc5cc(F)ccc45)CC3)cc2N1
Yield: 25.4 %

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 24 using 0.5 g of 2-(2-chloroethyl)-4,6,7,8-tetrahydro-5H-thieno[3,2-b]azepin-5-one and 0.5 g of 4-(6-fluorobenzo(b)thiophen-3-yl)piperidine hydrochloride to give 0.2 g of 2-(2-(4-(6-fluoro-benzo(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno[3,2-b]azepin-5-one, m.p. 191°-193° C.
Reaction SMILES: Cl.CN.[B-](F)(F)(F)F.CCOC([C:14](C#N)=[N:15]OC(N(C)C)=[N+](C)C)=O.CCN(C(C)C)C(C)C.[CH3:35][O:36][C:37]1[C:38]([CH3:62])=[C:39]([C:46]([C:48]2[CH:49]=[C:50]3[C:55](=[CH:56][CH:57]=2)[NH:54][CH:53]=[C:52]([C:58]([OH:60])=O)[C:51]3=[O:61])=[O:47])[N:40]2[C:45]=1[CH:44]=[CH:43][CH:42]=[CH:41]2.Cl>CN(C=O)C>[CH3:35][O:36][C:37]1[C:38]([CH3:62])=[C:39]([C:46]([C:48]2[CH:49]=[C:50]3[C:55](=[CH:56][CH:57]=2)[NH:54][CH:53]=[C:52]([C:58]([NH:15][CH3:14])=[O:60])[C:51]3=[O:61])=[O:47])[N:40]2[C:45]=1[CH:44]=[CH:43][CH:42]=[CH:41]2
Reactant: COc1c(C)c(C(=O)c2ccc3[nH]cc(C(=O)O)c(=O)c3c2)n2ccccc12
Reactant: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: CN
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c[nH]c2ccc(C(=O)c3c(C)c(OC)c4ccccn34)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.8 %

Procedure:
0.36 g (5.31 mmol) of methylamine hydrochloride, 1.3 g (3.99 mmol) of TOTU and 1.37 g (10.63 mmol) of DIEA are added to 1 g (2.66 mmol) of 6-[(1-methoxy-2-methylindolizin-3-yl)carbonyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid in 23 ml of anhydrous DMF. The reaction medium is stirred at ambient temperature under a nitrogen atmosphere for 8 h. 0.36 g (5.33 mmol) of methylamine hydrochloride is added to the reaction medium. After 18 h at ambient temperature, the reaction medium is hydrolysed with a 1N solution of HCl and then extracted with ethyl acetate. The organic phase is washed with a saturated solution of sodium chloride, dried over sodium sulphate, and then concentrated under reduced pressure. The residue obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol (90/10) mixture. 0.06 g of a yellow solid is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[NH:9][CH:8]=[CH:7][C:6]2=O.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:6]1[C:5]2[C:10](=[CH:11][C:12]([CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: COc1cc2c(=O)cc[nH]c2cc1C
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc2c(Cl)ccnc2cc1C
Temperature: 25 °C
Yield: 71 %

Procedure:
6-Methoxy-7-methyl-1H-quinolin-4-one (73.9 g) was added to phosphorus oxychloride (160 ml), and the mixture was heated under reflux for 2 hr. The reaction solution was cooled to room temperature, and the solvent was then removed by distillation under the reduced pressure. Chloroform and water were added to the reaction solution, and the aqueous layer was neutralized with an aqueous potassium hydroxide solution. The organic layer was washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, hexane was added to the residue, and the precipitated crystal was collected by filtration to give 4-chloro-6-methoxy-7-methyl-quinoline (12.7 g, yield 71%).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C@@H:18]([OH:21])[CH2:19][OH:20])=[C:12](Br)[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]1([S:7]([C:10]2[CH:15]=[C:14]3[C:13]([CH2:16][CH2:17][C@H:18]([CH2:19][OH:20])[O:21]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(CC[C@@H](O)CO)c(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(c1ccccc1)c1ccc2c(c1)O[C@@H](CO)CC2
Yield: 88.8 %

Procedure:
To a solution of (R)-4-(4-benzenesulfonyl-2-bromo-phenyl)-butane-1,2-diol (1.71 g) in THF (15 mL) were added palladium acetate (30 mg), racemic 2[P(t-Bu)2]-1,1-binaphthyl (53.1 mg) and K3PO4 (1.42 g) under Argon atmosphere. The reaction was heated at reflux for 48 hours; then water was added and the mixture was extracted 3 times with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via flash chromatography (hexane/EtOAc, 6/4) to afford ((R)-7-benzenesulfonyl-chroman-2-yl)-methanol (1.20 g).
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25]Br)=[C:15]1[CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])([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.[SH:36][C:37]1[CH:46]=[CH:45][C:40]([C:41]([O:43][CH3:44])=[O:42])=[CH:39][CH:38]=1.O>CN(C=O)C>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:36][C:37]2[CH:38]=[CH:39][C:40]([C:41]([O:43][CH3:44])=[O:42])=[CH:45][CH:46]=2)=[C:15]1[CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])([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
Reactant: CC(C)(C)[Si](C)(C)OCc1c(CCBr)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(S)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SCCc2c(CO[Si](C)(C)C(C)(C)C)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
1-benzhydryl-3-(2-bromoethyl)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-chloro-1H-indole (1 eq) was mixed with Methyl 4-mercaptobenzoate (2 eq) and KC2CO3 (1.9 eq) in DMF (0.09M). The resulting mixture was stirred at rt under N2 overnight. Water was then added, followed by regular work-up (eg. EtOAc extration, brine wash, etc) and column purification (1:6 EtOAc/Hexane as eluent) to give methyl 4-({2-[1-benzhydryl-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-chloro-1H-indol-3-yl]ethyl}sulfanyl)benzoate (yellow oil) in 81% yield.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[N:13]3[CH2:14][CH2:15][CH2:16][N:12]3[C:11](=[O:17])[C:10]=2[C:18]([OH:20])=O)[CH:6]=[CH:5][N:4]=1.[Cl:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][NH2:25].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][NH:25][C:18]([C:10]1[C:11](=[O:17])[N:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:9]=1[C:7]1[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=1)=[O:20]
Reactant: CSc1nccc(-c2c(C(=O)O)c(=O)n3n2CCC3)n1
Reactant: NCc1ccccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CSc1nccc(-c2c(C(=O)NCc3ccccc3Cl)c(=O)n3n2CCC3)n1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
To a solution of 3-(2-methylsulfanyl-pyrimidin-4-yl)-1-oxo-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazole-2-carboxylic acid, 14, (0.23 g, 0.78 mmol) and 2-chlorobenzylamine (0.10 mL, 0.78 mmol) in DMF (3 mL) is added 1-hydroxybenzotriazole (0.21 g, 1.57 mmol) and then 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (0.18 g, 0.94 mmol). The reaction solution is stirred at room temperature for 6 days then poured into aqueous saturated NaHCO3. The aqueous phase is extracted with three times with EtOAc and the combined organic phases are washed with aqueous saturated NH4Cl, and H2O, dried (MgSO4), filtered and concentrated in vacuo to afford the desired product which is used without further purification: 1H NMR (300 MHz, CDCl3) δ 9.49 (bd s, NH), 8.69 (d, J=5.1 Hz, 1H), 8.16 (d, J=5.1 Hz, 1H), 7.44-7.37 (m, 2H), 7.25-7.19 (m, 2H), 4.70 (d, J=5.4 Hz, 2H), 4.41 (t, J=7.2 Hz, 2H), 4.14 (t, J=7.2 Hz, 2H), 2.78 (dd, J=7.5, 7.5, 7.5, 7.5 Hz, 2H), 2.06 (s, 3H); ESI+ MS: m/z (rel intensity) 415.9 (100, M++H).
Reaction SMILES: C[O-].[Na+].[NH2:4][C:5]1[N:10]=[C:9]([CH:11]2[CH2:13][CH2:12]2)[N:8]=[C:7]([C:14]([O:16][CH2:17]C)=[O:15])[C:6]=1[Cl:19].Cl.[Cl-].[NH4+]>CO>[NH2:4][C:5]1[N:10]=[C:9]([CH:11]2[CH2:13][CH2:12]2)[N:8]=[C:7]([C:14]([O:16][CH3:17])=[O:15])[C:6]=1[Cl:19]
Reactant: CCOC(=O)c1nc(C2CC2)nc(N)c1Cl
Agent: C[O-]
Agent: Cl
Agent: [Cl-]
Solvent: CO
Product: COC(=O)c1nc(C2CC2)nc(N)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
Sodium methoxide in methanol (25%, 3 drops) was added to ethyl 6-amino-5-chloro-2-cyclopropyl-4-pyrimidinecarboxylate (i.e. the product of Example 7) (0.53 g) in methanol (15 mL). The mixture was boiled for 1 h. The mixture was allowed to cool to room temperature, and was partitioned between hydrochloric acid (0.28 g, 1.16 mmol) in methanol (5 mL). The mixture was boiled for 90 minutes. The mixture was allowed to cool to room temperature, and ammonium chloride (0.3 g, 5.6 mmol) was added. After 10 minutes the solvent was removed under reduced pressure. The mixture was extracted with ethyl acetate (50 mL), and the extracts evaporated to give the product as a white solid (0.24 g, 92% yield). Product recrystallized from ethyl acetate melted at 148.5-149.5° C.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[OH:12][C:13]1([CH3:40])[C@@H:18]([CH3:19])[CH2:17][N:16]([C:20]2[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][N:23]=[C:22]3[CH2:29][CH2:30][CH2:31][C:21]=23)[CH2:15][C@H:14]1[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36]>C(Cl)Cl>[OH:12][C:13]1([CH3:40])[C@@H:18]([CH3:19])[CH2:17][N:16]([C:20]2[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][N+:23]([O-:9])=[C:22]3[CH2:29][CH2:30][CH2:31][C:21]=23)[CH2:15][C@H:14]1[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36]
Reactant: C[C@H]1CN(c2c([N+](=O)[O-])cnc3c2CCC3)C[C@@H](NC(=O)OC(C)(C)C)C1(C)O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C[C@H]1CN(c2c([N+](=O)[O-])c[n+]([O-])c3c2CCC3)C[C@@H](NC(=O)OC(C)(C)C)C1(C)O
Reaction time: 2 h

Procedure:
mCPBA (260 mg, 1.5 mmol) was added to a mixture of tert-butyl [(3R,5S)-4-hydroxy-4,5-dimethyl-1-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate (312 mg, 0.768 mmol) in DCM (3.2 mL). After 2 h, LCMS showed only 30% conversion of starting material. mCPBA was added several more times (to a total amount of about 10 eq.) until LCMS showed complete consumption of starting material (after approximately 7 h). A saturated solution of NaHCO3 was then added to the mixture and the resulting mixture was extracted with DCM. The combined organic extracts were dried and then concentrated to dryness under reduced pressure. The crude sub-title compound was used in the next step without further purification. LCMS calc. for C20H31N4O6 (M+H)+ m/z=423.2. found 423.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[CH:27][CH:26]=2)[C:8]2[C:13]([C:14]=1[Cl:15])=[CH:12][C:11](B1OC(C)(C)C(C)(C)O1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].Br[C:36]1[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][N:37]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[CH:29][CH:30]=2)[C:8]2[C:13]([C:14]=1[Cl:15])=[CH:12][C:11]([C:36]1[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][N:37]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)c2cc(B3OC(C)(C)C(C)(C)O3)ccc2n1-c1ccc(OC(C)C)cc1
Reactant: FC(F)(F)c1ccc(Br)nc1
Product: CCOC(=O)c1c(Cl)c2cc(-c3ccc(C(F)(F)F)cn3)ccc2n1-c1ccc(OC(C)C)cc1

Procedure:
The sub-title compound was prepared in accordance with Example 8(b), from 3-chloro-1-(4-isopropoxyphenyl)-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-indole-2-carboxylic acid ethyl ester (see step (c)) and 2-bromo-5-(trifluoromethyl)pyridine.
Reaction SMILES: N([C:3]([CH:5]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=3)(=[O:25])=[O:24])=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])N.Cl.C(O)(=[O:40])C>>[C:7]1([CH2:6][CH:5]([N:13]2[C:21]3[C:16](=[CH:17][C:18]([NH:22][S:23]([C:26]4[CH:31]=[CH:30][C:29]([O:32][C:33]([F:34])([F:35])[F:36])=[CH:28][CH:27]=4)(=[O:24])=[O:25])=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)[C:3]([OH:40])=[O:4])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(=O)O
Reactant: NNC(=O)C(Cc1ccccc1)n1ccc2cc(NS(=O)(=O)c3ccc(OC(F)(F)F)cc3)ccc21
Agent: Cl
Product: O=C(O)C(Cc1ccccc1)n1ccc2cc(NS(=O)(=O)c3ccc(OC(F)(F)F)cc3)ccc21
Temperature: 80 °C

Procedure:
To N-[1-(1-hydrazinocarbonyl-2-phenyl-ethyl)-1H-indol-5-yl]-4-trifluoro methoxy-benzenesulfonamide (0.07 g, 0.13 mmol) in acetic acid at ambient temperature under a laboratory atmosphere was added conc. HCl (1 ml) then the reaction vessel was capped. The dark red mixture was heated at 80° C. for 15 hours (the vessel was periodically uncapped then recapped to release pressure build up with in the vessel). The reaction was cooled to ambient temperature and concentrated in vacuo to a dark red powder. The crude product was subjected to gradient RP-HPLC (H2O: CH3CN) and the title compound was isolated as a red powder (0.06 g, 91% yield): MS (ESI) m/z 505, MS (ESI) m/z 503.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]Br)([O-:11])=[O:10]>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]([CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[C:12]([N+:9]([O-:11])=[O:10])[CH:13]=2)[CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[C:12]([N+:9]([O-:11])=[O:10])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Product: O=[N+]([O-])c1cccc(CN(Cc2cccc([N+](=O)[O-])c2)c2ccc(F)cc2)c1
Yield: 87 %

Procedure:
4-Fluoroaniline and 3-nitrobenzyl bromide were processed using the method described in Example 1A to provide 1.46 g (87%) of the title compound. 1H NMR (400 MHz, DMSO-D6) δ 4.88 (s, 4 H) 6.69-6.75 (m, 2 H) 6.97 (t, J=8.89 Hz, 2 H) 7.64 (t, J=7.81 Hz, 2 H) 7.70-7.74 (m, 2 H) 8.08-8.13 (m, 4 H).
Reaction SMILES: Br[C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[F:11][C:12]1[CH:13]=[CH:14][C:15]([OH:21])=[C:16](B(O)O)[CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(Cl)(Cl)Cl.C(O)(C)C.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].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>[S:8]1[CH:9]=[CH:10][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:14]3[CH:13]=[C:12]([F:11])[CH:17]=[CH:16][C:15]=3[OH:21])[C:7]1=2
Reactant: OB(O)c1cc(F)ccc1O
Reactant: Brc1cccc2ccsc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: Oc1ccc(F)cc1-c1cccc2ccsc12
Temperature: 100 °C
Yield: 80.2 %

Procedure:
Combine 7-bromo-benzo[b]thiophene (6.53 g, 30.64 mmol), 5-fluoro-2-hydroxy phenyl boronic acid (4.87 g, 31.26 mmol), Pd(dppf)Cl2 (1.25 g, 1.53 mmol), 2-(di-tert-butylphosphino)biphenyl (0.28 g, 0.92 mmol), sodium carbonate (2 M, 30.64 mL, 61.92 mmol) in dioxane (60 mL, alternative THF) in a flask. Heat the mixture at 100° C. for 2 h. Dilute the mixture with chloroform/IPA (3/1). Wash the solution with aqueous saturated sodium chloride. Dry over sodium sulfate. Concentrate the solution in vacuo. Purify the residue by column chromatography (hexane to 10% ethyl acetate in hexane) to give the title compound (6.0 g, 80%) as a yellow solid. MS (ES) m/z 243 [M−1]+.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[CH:10][C:9]([CH2:17][CH2:18][CH:19]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:41][C:38]1[CH:37]=[CH:36][C:35]([CH:28]([C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)[N:29]2[CH2:30][CH2:31][N:32]([CH2:19][CH2:18][CH2:17][C:9]3[CH:10]=[C:11]([C:12]4[S:13][CH:14]=[CH:15][CH:16]=4)[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH2:33][CH2:34]2)=[CH:40][CH:39]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: O=CCCc1cc(-c2cccs2)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(C(c2ccc(F)cc2)N2CCN(CCCc3cc(-c4cccs4)n(-c4ccccc4)n3)CC2)cc1

Procedure:
65 mg (78%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)-propanal (40 mg, 0.142 mmol), 1-(bis(4-fluorophenyl)methyl)piperazine (41 mg, 0.142 mmol), DIPEA (0.040 mL, 0.213 mmol) and NaBH(OAc)3 (90 mg, 0.573 mmol).
Reaction SMILES: [CH2:1]([NH:4][C:5]([NH:7][C:8]1[C:23]([F:24])=[CH:22][C:11]2[O:12][C:13]([F:21])([F:20])[C:14](=[O:19])[N:15]([CH2:16][C:17]#[CH:18])[C:10]=2[CH:9]=1)=[S:6])[CH2:2][CH3:3]>ClCCl>[CH2:1]([N:4]1[C:13](=[O:12])[C:14](=[O:19])[N:7]([C:8]2[C:23]([F:24])=[CH:22][C:11]3[O:12][C:13]([F:21])([F:20])[C:14](=[O:19])[N:15]([CH2:16][C:17]#[CH:18])[C:10]=3[CH:9]=2)[C:5]1=[S:6])[CH2:2][CH3:3]
Reactant: C#CCN1C(=O)C(F)(F)Oc2cc(F)c(NC(=S)NCCC)cc21
Solvent: ClCCl
Product: C#CCN1C(=O)C(F)(F)Oc2cc(F)c(N3C(=O)C(=O)N(CCC)C3=S)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
Ethyl oxalyl chloride (0.487 ml, 4.36 mmol) was added to a stirred solution of 1-propyl-3-(2,2,7-trifluoro-3-oxo-4-(prop-2-ynyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)thiourea (1197 mg, 3.35 mmol) in dichloromethane (20 ml) at room temperature under nitrogen. The resulting mixture was stirred overnight at room temperature, and then evaporated in vacuo. Toluene was added to the yellow residue, and the resulting suspension was refluxed for 3 hours, resulting in a clear solution. The reaction mixture was cooled to room temperature, and the resulting precipitate was isolated and washed with heptane to yield 792 mg of crude product. This was then recrystallised from toluene. Some remaining impurity was removed by dissolving the solid in ethyl aceate, washing with aqueous sodium bicarbonate solution, drying over sodium sulfate, and evaporating in vacuo to yield 667 mg of the title compound (purity>95%).