Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:28])[CH2:12][CH2:13][CH2:14][N:15]([CH3:27])[C:16]([C:18]1[N:23]=[CH:22][C:21]([C:24](O)=[O:25])=[CH:20][CH:19]=1)=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.O1CCCC1.CO>O1CCCC1>[OH:25][CH2:24][C:21]1[CH:20]=[CH:19][C:18]([C:16]([N:15]([CH3:27])[CH2:14][CH2:13][CH2:12][N:11]([CH3:28])[C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:17])=[N:23][CH:22]=1
Reactant: CN(CCCN(C)C(=O)c1ccc(C(=O)O)cn1)C(=O)OCc1ccccc1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: CN(CCCN(C)C(=O)c1ccc(CO)cn1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 36.8 %

Procedure:
The compound (350 mg, 0.908 mmol) obtained in Example 5b was dissolved in tetrahydrofuran (4 mL), a borane-tetrahydrofuran complex (1.0 M tetrahydrofuran solution; 3.18 mL, 3.18 mmol) was added under ice cooling, and then the mixture was stirred at room temperature for 45 minutes. Methanol (1 mL) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=100:0→20:1, v/v) to give the title compound (124 mg; yield, 37%) as a colorless oily substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:18]=[C:17]([C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:20])[C:16]([C:27]3[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=3)=[CH:15][C:11]=2[C:12]([OH:14])=O)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[N:42]1[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][N:43]=1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:18]=[C:17]([C:19]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)=[O:20])[C:16]([C:27]3[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=3)=[CH:15][C:11]=2[C:12]([NH:48][C:45]2[CH:46]=[CH:47][N:42]=[N:43][CH:44]=2)=[O:14])=[CH:4][CH:3]=1
Reactant: Nc1ccnnc1
Reactant: Cn1cc(-c2cc(C(=O)O)c(OCc3ccc(F)cc3)cc2C(=O)N2CCOCC2)cn1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2cc(C(=O)Nc3ccnnc3)c(OCc3ccc(F)cc3)cc2C(=O)N2CCOCC2)cn1
Reaction time: 2 h

Procedure:
To a solution of 2-{[(4-fluorophenyl)methyl]oxy}-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-morpholinylcarbonyl)benzoic acid (may be prepared as described in Description 29; 95 mg, 0.22 mmol) in N,N-dimethylformamide (3 ml) was added diisopropylethylamine (0.08 ml, 0.43 mmol), 4-pyridazinamine (24.67 mg, 0.26 mmol), 1-hydroxy-7-azabenzotriazole (35.3 mg, 0.26 mmol) and EDC (62.2 mg, 0.32 mmol). The mixture was stirred for 2 hours, the solvent removed in vacuo and the residue was purified by MDAP to yield the title compound as a white solid. 50 mg.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([OH:15])=O.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([N:25]2[CH2:30][CH2:29][CH:28]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH2:27][CH2:26]2)=[C:21]([CH:24]=1)[C:22]#[N:23]>>[C:22]([C:21]1[CH:24]=[C:17]([NH:16][C:13]([C:3]2[CH:4]=[N:5][N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)[C:2]=2[CH3:1])=[O:15])[CH:18]=[CH:19][C:20]=1[N:25]1[CH2:30][CH2:29][CH:28]([N:31]2[CH2:32][CH2:33][O:34][CH2:35][CH2:36]2)[CH2:27][CH2:26]1)#[N:23]
Reactant: Cc1c(C(=O)O)cnn1-c1ccccn1
Reactant: N#Cc1cc(N)ccc1N1CCC(N2CCOCC2)CC1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCOCC4)CC3)c(C#N)c2)cnn1-c1ccccn1
Yield: 49.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 5-methyl-1-(2-pyridyl)pyrazole-4-carboxylic acid (2.0 g) and 5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (1.88 g), the title compound (1.52 g) was obtained, melting point: 251° C.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[N:28]1([C:34]2[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:38](=[O:39])[C:37]5[CH:41]=[CH:42][C:34]([N:28]6[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]6)=[CH:35][CH:36]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: O=C(O)c1ccc(N2CCCCC2)cc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)c1ccc(N2CCCCC2)cc1

Procedure:
The title compound, white solid (99 mg, 77%), MS (ISP) m/z=518.5 [(M+H)+], mp 182.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 4-piperidin-1-yl-benzoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:12])=[N:7][CH2:6][CH2:5]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH3:12])[NH:7][CH2:6][CH2:5]2
Reactant: CC1=NCCc2cc(Br)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC1NCCc2cc(Br)ccc21

Procedure:
In close analogy to the procedure described above, 6-bromo-1-methyl-3,4-dihydro-isoquinoline is reacted with sodium triacetoxyborohydride to provide the title compound.
Reaction SMILES: [F:1][CH:2]([F:22])[S:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH3:21])OCC[O:17]3)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.S(Cl)([Cl:26])(=O)=O>ClCCCl>[Cl:26][CH2:21][C:16]([C:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH:8]=[CH:9][C:4]([S:3][CH:2]([F:22])[F:1])=[CH:5][CH:6]=2)=[CH:11][CH:12]=1)=[O:17]
Reactant: CC1(c2ccc(-c3ccc(SC(F)F)cc3)cc2)OCCO1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCCl
Product: O=C(CCl)c1ccc(-c2ccc(SC(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
A solution of 8.0 g (25 mmol) of 2-[4'-[(difluoromethyl)thio][1,1'-biphenyl]-4-yl]-2-methyl-1,3-dioxolane and 30 mL of anhydrous 1,2-dichloroethane was cooled to 5° C. and sulfuryl chloride (2.3 mL, 3.8 g, 28 mmol) was added via syringe. The solution was allowed to warm to ambient temperature and concentrated to dryness. Acetone (40 mL), 5 mL of water, and 2 mL of 37% HCl were added, and the mixture was heated at 55° C. for 18 h. The mixture was diluted with 20 mL of water with cooling and seeding to precipitate the product. After filtration, washing with cold 50% aqueous MeOH and drying, the crude solid (7.2 g, 92%) was slurried in 80 mL of hot isopropanol (i-PrOH) allowed to cool with good stirring for 30 min, and filtered to afford 5.6 g of 2-chloro-1-[4'-[(difluoro-methyl)thio][1,1'-biphenyl]-4-yl]ethanone, m.p. 102-104° C. A second crop of 0.9 g was obtained by partial concentration of the filtrate. An analytical standard was prepared by chromatography and/or recrystallization from CH2Cl2 /MeOH, m.p. 104 to 105° C. 1H-NMR(CDCl3): δ4.75 (s, 2H), 6.88 (t, 1H), 7.65 (ABq, 4H) 7.7 (d, A of ABq, 2H), 8.05 (d, B of ABq, 2H).
Reaction SMILES: [F:1][C:2]1[C:10]([I:11])=[C:9]([CH3:12])[CH:8]=[CH:7][C:3]=1[CH:4]=[N:5][OH:6].[Cl:13]N1C(=O)CCC1=O.O>CN(C=O)C>[F:1][C:2]1[C:10]([I:11])=[C:9]([CH3:12])[CH:8]=[CH:7][C:3]=1[C:4](=[N:5][OH:6])[Cl:13]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccc(C=NO)c(F)c1I
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C(Cl)=NO)c(F)c1I
Temperature: 55 °C

Procedure:
To a solution of 2-fluoro-3-iodo4-methylbenzaldehyde oxime (0.48 g, 1.7 mmol) in DMF (0.5 mL) was added N-chlorosuccinimide (83 mg, 0.62 mmol) and the mixture was heated at 55° C. for 5 min. The mixture was allowed to cool to <50° C., an additional N-chlorosuccinimide (166 mg, 1.24 mmol) was added, then it was heated at 55° C. for 10 min. The reaction mixture was allowed to cool to RT, treated with water (5 mL), and extracted with ethyl acetate (3×20 mL). The combined ethyl acetate layers were washed with brine, dried and concentrated to afford the intermediate, 2-fluoro-3-iodo-4-methylbenzoyl chloride oxime as a light yellow amorphous solid, which was used without further purification. MS (ESI, pos. ion) m/z: 314.3 (M+1). Cyclopropylamine (0.60 mL, 8.6 mmol) was added dropwise to an ice-cold solution of the above obtained 2-fluoro-3-iodo-4-methylbenzoyl chloride oxime in anhydrous THF (2 mL). The reaction mixture was stirred at ambient for 3 h. The volatiles were removed under reduced pressure and the residue purified on a 40 g ISCO column (eluted with 25-60% ethyl acetate in Hexanes) to provide the title compound as an amorphous off-white solid. MS (ESI, pos. ion) m/z: 335.0 (M+1).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][CH:3]=1.[Na].[C:11](O)(=[O:13])C>C[O-].[Na+].CO>[N:7]1[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=1[C:8](=[NH:9])[O:13][CH3:11]
Reactant: CC(=O)O
Reactant: N#Cc1cccc(Br)n1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=N)c1ccccn1
Reaction time: 0.25 h

Procedure:
6-Bromo-2-cyano-pyridine (20 g) was dissolved in a solution of sodium methoxide in methanol prepared from methanol (300 ml) and metallic sodium (1.26 g). After the solution was left to stand for 15 minutes, acetic acid (3.3 g) was added thereto, followed by concentration under reduced pressure. The resulting residue was dissolved in ether (300 ml) and insoluble materials were filtered out. The filtrate was concentrated under reduced pressure to obtain methyl 2-picoline imidate derivative.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH:12]1[O:16][C:15]([N:17](C)[CH3:18])=[N:14][C:13]1=[O:20].CN>CCOCC>[CH3:18][NH:17][C:15]1[O:16][CH:12]([CH2:11][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)[NH:7][CH:6]=2)[C:13](=[O:20])[N:14]=1
Reactant: CN(C)C1=NC(=O)C(Cc2c[nH]c3ccc(Cl)cc23)O1
Agent: CN
Solvent: CCOCC
Product: CNC1=NC(=O)C(Cc2c[nH]c3ccc(Cl)cc23)O1
Temperature: -6 °C
Yield: 63 %

Procedure:
To [(5-chloroindol-3-yl)methyl]-2-dimethylamino-2-oxazolin-4-one (200 mg) was added methylamine (20 ml). The mixture was refluxed at −6° C. for 1 hour. Removal of methylamine gave a residue, to which was added ether. The titled compound (120 mg) was obtained as a crystal.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([O:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][NH:16][C:17](=[O:23])[CH2:18][S:19][CH2:20][CH2:21][OH:22])[CH:6]=1)[CH3:3].[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([O:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][NH:16][C:17](=[O:23])[CH2:18][S:19][CH2:20][CH2:21][O:22][C:24](=[O:26])[CH3:25])[CH:6]=1)[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)Cc1ccnc(OC/C=C\CNC(=O)CSCCO)c1
Product: CC(=O)OCCSCC(=O)NC/C=C\COc1cc(CN(C)C)ccn1
Yield: 58 %

Procedure:
Following a procedure similar to that described in Example 67(c), but using N-[4-(4-dimethylaminomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-hydroxyethylthio)acetamide [prepared as described in step (a) above] and acetic anhydride as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a 58% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12].C([Sn](CCCC)(CCCC)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)CCC>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:12][C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[C:6]([CH3:8])=[CH:7][C:2]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])c(C)cc1-c1ccccn1
Temperature: 120 °C

Procedure:
To a mixture of 1-bromo-2,5-dimethyl-4-nitrobenzene (185 mg, 1 mmol) and 2-(tributylstannyl)pyridine (202 mg, 1.1 mmol) in DMF (4 mL) was added tetrakis(triphenylphosphine) palladium (0) (58 mg, 0.05 mmol). The reaction tube was sealed, the mixture was purged with N2 for 3 min and then heated at 120° C. under N2 for overnight. The reaction was cooled to room temperature and poured into saturated aqueous ammonia chloride solution. The crude reaction mixture was extracted with ethyl acetate (3×15 mL). The organic extracts were combined, washed with brine and concentrated. The crude product was purified with silica chromatography (60% ethyl acetate in hexanes) to afford 2-(2,5-dimethyl-4-nitrophenyl)pyridine as a white solid. The obtained solid was dissolved in acetic acid/TFA (15 mL/200 uL). To this solution was added PtO2 (10% w/w). The reaction mixture was degassed and purged with H2 for several times and then vigorously stirred under 1 atm. H2 overnight. The mixture was filtered and the filtrate concentrated to afford 2,5-Dimethyl-4-(piperidin-2-yl)aniline as a yellow oil; ESMS m/z 205 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][NH:7][CH2:6][CH2:5][C:4]=2[N:3]=1.C=O.[C:14](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:14][N:3]1[C:8]2[C:9](=[CH:4][CH:5]=[CH:6][N:7]=2)[CH:10]=[CH:11][CH:2]1[Cl:1]
Reactant: Clc1ccc2c(n1)CCNC2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1c2ncccc2C=CC1Cl
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A solution of 250 mg of 2-chloro-5,6,7,8-tetrahydro-[1,6]naphthyridine (U.S. Pat. No. 6,169,093) in methylene chloride (6.1 mL) was treated with 0.148 mL of a 37% formalin solution, followed by 0.388 g of sodium triacetoxyborohydride. The reaction mixture was stirred at room temperature for 60 h and quenched by the addition of 2N sodium hydroxide (6 mL). After stirring for one h, the mixture was diluted with water and extracted with methylene chloride (2×). The organic layers were dried over sodium sulfate, filtered, and concentrated. Purification of the residue using silica gel chromatography provided N-methylchloronaphthyridine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:23][CH2:24][OH:25])[CH3:22])=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[CH:27]1([NH:30][C:31]([C:33]2[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=2)=[O:32])[CH2:29][CH2:28]1>>[CH:27]1([NH:30][C:31](=[O:32])[C:33]2[CH:40]=[CH:39][C:36]([C:37]3[NH:10][C:9]4[CH:8]=[CH:7][C:6]([NH:13][C:14](=[O:26])[C:15]5[CH:20]=[CH:19][C:18]([N:21]([CH2:23][CH2:24][OH:25])[CH3:22])=[CH:17][CH:16]=5)=[CH:5][C:4]=4[N:1]=3)=[CH:35][CH:34]=2)[CH2:28][CH2:29]1
Reactant: O=Cc1ccc(C(=O)NC2CC2)cc1
Reactant: CN(CCO)c1ccc(C(=O)Nc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)cc1
Product: CN(CCO)c1ccc(C(=O)Nc2ccc3[nH]c(-c4ccc(C(=O)NC5CC5)cc4)nc3c2)cc1

Procedure:
Compound 235 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)-4-(N-2-hydroxyethyl-N-methylamino)benzamide and 4-cyclopropylaminocarbonylbenzaldehyde. [M+H]+ calcd for C27H27N5O3: 470.22; found: 470.60.
Reaction SMILES: Br[C:2]1[C:14]([CH2:15][O:16]C2CCCCO2)=[CH:13][C:5]([O:6]C2CCCCO2)=[CH:4][C:3]=1[CH3:23].[Li]CCCC.[B:29](OC(C)C)(OC(C)C)[O:30]C(C)C.Cl>C1COCC1.O.CCOC(C)=O>[CH3:23][C:3]1[C:2]2[B:29]([OH:30])[O:16][CH2:15][C:14]=2[CH:13]=[C:5]([OH:6])[CH:4]=1
Reactant: Cc1cc(OC2CCCCO2)cc(COC2CCCCO2)c1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(O)cc2c1B(O)OC2
Temperature: -78 °C
Yield: 33.3 %

Procedure:
A solution of 2-(4-bromo-3-methyl-5-((tetrahydro-2H-pyran-2-yloxy)methyl)phenoxy)tetrahydro-2H-pyran (2.93 g, 7.61 mmol) in anhydrous THF (25 mL) was made before cooling the reaction mixture on a −78° C. bath. Reaction mixture was then treated, dropwise, with n-BuLi (13.08 mL, 20.92 mmol) and allowed to stir for 1.0 h before (i-PrO)3B (77 mL, 25 mmol) was added via syringe. After the addition of (i-PrO)3B, the reaction mixture was warmed to room temperature and allowed to stir for 3 h before addition of 12 mL of 1N HCl. The reaction mixture was allowed to stir 20 hr before addition of EtOAc and water (1:1, 50 mL). The layers were separated and the water phase was further extracted with equal volume of EtOAc before the organic layers were combined and dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure. The residue was purified by silica gel column using Combiflash to give 7-methylbenzo[c][1,2]oxaborole-1,5(3H)-diol (415 mg, 33%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 2.33 (s, 3H), 4.82 (s, 2H), 6.51 (ds, 1H), 6.53 (s, 1H), 8.57 (s, 1H), 9.59 (s, 1H).
Reaction SMILES: C(O[C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2)(=O)C.CCCCCCC.S(=O)(=O)(O)O.[Br:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1>C(O)C>[C:5]12([C:32]3[CH:33]=[C:28]([Br:27])[CH:29]=[CH:30][C:31]=3[OH:34])[CH2:12][CH:11]3[CH2:10][CH:9]([CH2:8][CH:7]([CH2:13]3)[CH2:6]1)[CH2:14]2
Reactant: Oc1ccc(Br)cc1
Reactant: CC(=O)OC12CC3CC(CC(C3)C1)C2
Agent: O=S(=O)(O)O
Solvent: CCCCCCC
Solvent: CCO
Product: Oc1ccc(Br)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 20 °C

Procedure:
In a 100 ml three-necked flask, and under a nitrogen environment, is placed 1 g of 1-acetoxyadamantane and 10 ml of n-heptane. After total dissolution, 0.25 g of concentrated sulfuric acid is added drop by drop while keeping the temperature at 20° C., then 0.886 g of 4bromophenol is poured in slowly. After leaving 24 hours in vigorous agitation, 20 ml of denatured ethanol are added while maintaining the temperature at 20° C. Next, the solvent is evaporated to dryness under reduced pressure and a whitish raw product is obtained. The product is redissolved in water at approximately 60° C., it is washed to pH 6 and dried in a vacuum oven for 24 hours at 25° C. One collected 1.24 g of expected raw product (Melting point: 140°-141° C.).
Reaction SMILES: C[Si](C)(C)Cl.[CH2:6]([O:8][P:9](C(OCC)OCC)([CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:10])[CH3:7].C(O)C>ClCCl>[CH2:6]([O:8][PH:9]([CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:10])[CH3:7]
Reactant: CCOC(OCC)P(=O)(CC1CCCCC1)OCC
Agent: C[Si](C)(C)Cl
Solvent: CCO
Solvent: ClCCl
Product: CCO[PH](=O)CC1CCCCC1
Reaction time: 72 h

Procedure:
107 g of trimethylchlorosilane are added to a solution of 151 g of diethoxymethyl(cyclohexylmethyl)-phosphinic acid ethyl ester in 430 ml of dichloromethane that contains 10% by volume ethanol and the mixture is left to stand for 3 days at room temperature, then concentrated to dryness by evaporation and distilled under reduced pressure, yielding cyclohexylmethylphosphinic acid ethyl ester having a boiling point of 50° (3×10-4 bar).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:16](=[O:26])[C:17]([CH2:19][C:20]5[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=5)=[CH:18][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:15])[CH:10]=3.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>CS(C)=O>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:16](=[O:26])[C:17]([CH2:19][C:20]5[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=5)=[CH:18][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:15][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:10]=3
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=c1c(Cc2cccnc2)cn2c3cc(Br)ccc3c3cc(O)cc1c32
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)COc1cc2c(=O)c(Cc3cccnc3)cn3c4cc(Br)ccc4c(c1)c23
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
9-bromo-2-hydroxy-5-(3-pyridylmethyl)-4H-pyrido[3,2,1-jk]carbazole-4-one (200 mg) produced in Example 102 was suspended in dimethyl sulfoxide (8 ml). After adding potassium carbonate (136 mg), the mixture was stirred at room temperature for 30 minutes, and t-butyl bromoacetate (0.09 ml) was added. After stirring at room temperature for 2 hours, the reaction mixture was poured into ice water (20 ml) and the crystals precipitated were recovered by filtration. The thus obtained crude crystals were washed with water, ethanol and ether in succession and recovered by filtration to obtain the title compound (144 mg, 56%).
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[CH:5]=[C:6]([C:9]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:10][C:11]=1[OH:12])[CH:7]=[O:8]>C(O)(=O)C.O>[Br:1][C:10]1[C:9]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[C:6]([CH:5]=[C:4]([OH:3])[C:11]=1[OH:12])[CH:7]=[O:8]
Reactant: BrBr
Reactant: COC(=O)Cc1cc(O)c(O)cc1C=O
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)Cc1c(C=O)cc(O)c(O)c1Br
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
Bromine (192 μl) was added to a suspension of 3,4-dihydroxy-6-(methoxycarbonylmethyl)benzaldehyde (0.79 g) in acetic acid (15 ml). The reaction mixture was stirred at ambient temperature for 5-6 hours, diluted with water (30 ml) and extracted into ethyl acetate (200 ml). The organic phase was washed with NaHCO3, water (100 ml) and brine, dried and evaporated under reduced pressure to give a brown solid. This was purified by chromatography using aqueous acetonitrile mixtures to give 3-bromo-4,5-dihydroxy-2-(methoxycarbonylmethyl)benzaldehyde (300 mg); NMR (DMSO-d6) 3.61(s,3H); 4.24(s,2H); 7.24(s,1H); 9.8(s,1H): CI M/S (M+H)+ 291.
Reaction SMILES: [I:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:11](=O)([O-])[O-].[Cs+].[Cs+].CI>CC(N(C)C)=O.CCOCC>[I:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(I)c1O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Product: COc1c(I)cccc1C=O
Reaction time: 4.75 h

Procedure:
To a solution of 3-iodo-2-hydroxy-benzaldehyde (4.0 g, 16.06 mmol) in DMA (32 mL) was added cesium carbonate (5.85 g, 18 mmol) followed by methyl iodide (1.12 mL, 18 mmol). The resulting mixture was stirred for 4.75 hours then diluted with ether, washed with water, dried over magnesium sulfate and concentrated. The residue was purified by silica chromatography (50 g silica; eluted with 0-20% ethyl acetate in hexanes) to give the title compound as an oil.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([OH:19])=O)=[N:8][C:9]=2[S:10]([CH2:13][CH:14]([CH3:16])[CH3:15])(=[O:12])=[O:11])[CH2:3][CH2:2]1.Cl.[F:21][C:22]([F:32])([F:31])[C@H:23]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[NH2:24]>>[F:32][C:22]([F:21])([F:31])[C@@H:23]([NH:24][C:17]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([S:10]([CH2:13][CH:14]([CH3:15])[CH3:16])(=[O:11])=[O:12])[N:8]=1)=[O:19])[C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)CS(=O)(=O)c1nc(C(=O)O)ccc1C1CC1
Reactant: N[C@@H](c1cccnc1)C(F)(F)F
Agent: Cl
Product: CC(C)CS(=O)(=O)c1nc(C(=O)N[C@@H](c2cccnc2)C(F)(F)F)ccc1C1CC1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(isobutylsulfonyl)picolinic acid (Example 351 b) and (S)-2,2,2-trifluoro-1-(pyridin-3-yl)ethanamine hydrochloride (CAN 336105-46-5) as starting materials. MS (EI): m/e=442.4 [M+H]+.
Reaction SMILES: C(O)(=O)/C=C/C(O)=O.[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[O:19][C:18]3=[CH:20][S:21][CH:22]=[C:17]3[C:16](N3CCN(C)CC3)=[N:15][C:14]=2[CH:30]=1.[Cl:31]C1C=CC2OC3=CSC=C3C(N3CCN(C)CC3)=NC=2C=1.P(Cl)(Cl)(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[O:19][C:18]3=[CH:20][S:21][CH:22]=[C:17]3[C:16]([Cl:31])=[N:15][C:14]=2[CH:30]=1
Reactant: CN1CCN(C2=Nc3cc(Cl)ccc3Oc3cscc32)CC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: Cc1ccccc1
Product: ClC1=Nc2cc(Cl)ccc2Oc2cscc21

Procedure:
A 4.0 g. portion of 7-chloro-thieno[3,4-b][1,5-benzoxazepin-10(9H)-one (Example 4) and 4.0 g. of phosphorus pentachloride in 100 ml. of dry toluene are refluxed for 41/2 hours concentrated and triturated with toluene, giving 7,10-dichlorothieno[3,4-b][1,5]benzoxazepine.