Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][C:4]=1[CH:5]=[O:6].B(Br)(Br)Br.C(=O)=O.CC(C)=O.C(=O)(O)[O-].[Na+]>O.ClCCl>[OH:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:13])([F:14])[F:15])=[CH:7][C:4]=1[CH:5]=[O:6]
Reactant: COc1ccc(OC(F)(F)F)cc1C=O
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: O
Product: O=Cc1cc(OC(F)(F)F)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
Under a nitrogen atmosphere, in a round-bottom flask were placed 300 mg (1.4 mmol) of 2-methoxy-5-trifluoromethoxybenzaldehyde and 30 ml of dichloromethane. To the system, cooled in a dry ice acetone bath, were added 0.26 ml (2.7 mmol) of boron tribromide (BBr3) over a period of ca. 1 minute. The reaction mixture was stirred for 1 hour, the dry ice/acetone bath was replaced with an ice bath and the mixture was stirred for 1 hour. To the system were added slowly 10 ml of saturated aqueous sodium bicarbonate followed by 10 ml of water, and the mixture was warmed to room temperature. The mixture was extracted with two portions of dichloromethane, and the extracts were dried (Na2SO4) and concentrated. The resulting oil (280 mg) was dissolved in CH2 Cl2, and the solution was extracted with two portions of 1M aqueous NaOH. The combined aqueous extracts were acidified with 2M aqueous HCl and extracted with three portions of dichloromethane. These dichloromethane extracts were dried (Na2SO4) and concentrated to obtain 200 mg of the title compound. 1H NMR (CDCl3) Δ 6.96 (d, 1H, J=9), 7.36 (m, 2H), 9.84 (s, 1H), 10.9 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.N1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:16]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.1 %

Procedure:
4-Bromobenzene-1-sulfonyl chloride (2.56 g, 10 mmol) in anhydrous CH2Cl2 (10 mL) was added to a mixture of 1-methylpiperazine (2.0 g, 20 mmol), pyridine (2.37 g, 30 mmol) and anhydrous CH2Cl2 (10 mL) at 0° C. The mixture was stirred at room temperature for 16 h, concentrated, recrystallised, and dried over P2O5 to yield the sub-title compound (2.27 g, 71%).
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[O:15][N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[F:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[N:29]1[CH:33]=[CH:32][N:31]=[C:30]1[CH3:34])[C:23](O)=[O:24]>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[O:15][N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[N:12]=3)[CH2:7][CH2:6]2)[C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:28]([N:29]3[CH:33]=[CH:32][N:31]=[C:30]3[CH3:34])=[C:20]([F:19])[CH:21]=2)[CH2:2][CH2:3]1
Reactant: Cc1nccn1-c1ccc(C(=O)O)cc1F
Reactant: CC(C)c1noc(N2CCC(NC3CC3)CC2)n1
Product: Cc1nccn1-c1ccc(C(=O)N(C2CC2)C2CCN(c3nc(C(C)C)no3)CC2)cc1F

Procedure:
The title compound is prepared from cyclopropyl-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-amine and 3-fluoro-4-(2-methyl-imidazol-1-yl)-benzoic acid following a procedure analogous to that described in Example 90. LC (method 19): tR=3.98 min; Mass spectrum (ESI+): m/z=453 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]1[C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([CH2:27][CH:28]=O)[N:22]=[CH:21]2.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.CC(O)=O>[O:33]1[CH2:34][CH2:35][N:30]([CH2:28][CH2:27][N:23]2[C:24]3[C:20](=[CH:19][C:18]([N:3]4[CH:4]=[CH:5][C:6]([C:8]5[CH:9]=[CH:10][C:11]([C:14]([F:15])([F:17])[F:16])=[CH:12][CH:13]=5)=[CH:7][C:2]4=[O:1])=[CH:26][CH:25]=3)[CH:21]=[N:22]2)[CH2:31][CH2:32]1
Reactant: O=CCn1ncc2cc(-n3ccc(-c4ccc(C(F)(F)F)cc4)cc3=O)ccc21
Reactant: C1COCCN1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=c1cc(-c2ccc(C(F)(F)F)cc2)ccn1-c1ccc2c(cnn2CCN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 33.5 %

Procedure:
To a solution of 2-(5-(2-oxo-4-(4-(trifluoromethyl)phenyl)pyridin-1(2H)-yl)-1H-indazol-1-yl)acetaldehyde (84 mg, 0.21 mmol) in CH2Cl2 (4.0 mL), MeOH (1.0 mL) and AcOH (0.50 mL) was added morpholine (0.06 mL, 0.7 mmol) and picoline-borane complex (25 mg, 0.23 mmol). After stirring at ambient temperature under nitrogen atmosphere for 1.5 h, the solution was treated with 1 N HCl (10.0 mL) and stirred vigorously for 30 minutes. The mixture was made basic with saturated aqueous NaHCO3 (25 mL) and extracted with CH2Cl2 (3×25 mL). The organics were dried over Na2SO4, filtered and concentrated to dryness. Purification by flash chromatography (silica gel, CH2Cl2/MeOH, 97:3) gave the title compound (33 mg, 33%) as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 8.14 (d, J=0.7 Hz, 1H), 7.95 (d, J=8.1 Hz, 2H), 7.85-7.77 (m, 5H), 7.48 (dd, J=8.9, 1.9 Hz, 1H), 6.95 (d, J=1.8 Hz, 1H), 6.85 (dd, J=7.1, 2.0 Hz, 1H), 4.63 (t, J=6.5 Hz, 2H), 3.64-3.62 (m, 4H), 2.91 (t, J=6.5 Hz, 2H), 2.54-2.52 (m, 4H); ESI MS m/z 469 [M+H]+.
Reaction SMILES: C(OC(C[N:12]1[C:16](=[O:17])[C@@H:15]2[C@H:13]1[CH2:14]2)=O)C1C=CC=CC=1.[C:18](=[O:21])(O)[O-:19].[Na+:22]>O1CCCC1.[Pd]>[C@@H:13]12[CH2:14][C@@H:15]1[C:16](=[O:17])[N:12]2[C:18]([O-:19])=[O:21].[Na+:22]
Reactant: O=C([O-])O
Reactant: O=C(CN1C(=O)[C@H]2C[C@H]21)OCc1ccccc1
Agent: [Pd]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C([O-])N1C(=O)[C@H]2C[C@H]21
Reaction time: 1 h

Procedure:
A mixture of (1R,4S)-2-benzyloxycarbonylmethyl-2-azabicyclo[2,1,0]pentan-3-one (21 mg, 0.091 mmol), 10% Pd/C (10 mg) and sodium bicarbonate (7.6 mg, 0.91 mmol) in tetrahydrofuran (3 ml) water (1 ml) was hydrogenated at 40 psi on the Parr shaker for 1 hr. The mixture was then filtered and the solid residue was washed with deionized water. The combined filtrate and washings were extracted twice with ether (10 ml) and the aqueous phase was concentrated in high vacuum to a volume of 3.5 ml. This solution was applied to a 1/2" disc (total product content on disc 400 μg) which was incubated on a Staph. aureus MB 108 plate at 37° C. for 60 hrs. This results in a 50 mm zone of inhibition.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([OH:23])=O)[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[CH3:56][O:57][CH:58]1[CH2:63][CH2:62][N:61]([CH2:64][C:65]2[CH:73]=[CH:72][C:68]([CH2:69][NH:70][CH3:71])=[CH:67][CH:66]=2)[CH2:60][CH2:59]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([N:70]([CH2:69][C:68]3[CH:67]=[CH:66][C:65]([CH2:64][N:61]4[CH2:62][CH2:63][CH:58]([O:57][CH3:56])[CH2:59][CH2:60]4)=[CH:73][CH:72]=3)[CH3:71])=[O:23])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:7]([CH3:9])[CH:8]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: CNCc1ccc(CN2CCC(OC)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)Cc3ccc(CN4CCC(OC)CC4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 5-{[(4-methoxy-2,6-dimethyl-benzenesulfonyl)-methyl-amino]-methyl}-furan-3-carboxylic acid (35 mg, 0.10 mmol), EDCI (26 mg, 0.13 mmol), HOBt (20 mg, 0.15 mmol), DIPEA (0.04 mL, 0.20 mmol), [4-(4-methoxy-piperidin-1-ylmethyl)-benzyl]-methyl-amine hydrochloride (32 mg, 0.10 mmol) and DCM (10 mL).
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][C:6]1([CH2:23][CH2:24][CH3:25])[C:11]2[NH:12][C:13]3[C:18]([C:10]=2[CH2:9][CH2:8][O:7]1)=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([OH:21])[C:14]=3[CH3:22])C.[CH3:27][C:28](C)(C)[CH2:29]CO.FC1C=C(C=CC=1)CO.C(O)C1C=CC=CC=1.[OH-].[Na+]>CCO.C(O)CCC.C(O)(C)C.CO>[C:19]([C:17]1[CH:16]=[C:15]([O:21][CH2:27][CH2:28][CH3:29])[C:14]([CH3:22])=[C:13]2[C:18]=1[C:10]1[CH2:9][CH2:8][O:7][C@:6]([CH2:5][C:4]([OH:3])=[O:26])([CH2:23][CH2:24][CH3:25])[C:11]=1[NH:12]2)#[N:20]
Reactant: CC(C)(C)CCO
Reactant: CCCC1(CC(=O)OCC)OCCc2c1[nH]c1c(C)c(O)cc(C#N)c21
Agent: OCc1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: OCc1ccccc1
Solvent: CCCCO
Product: CCCOc1cc(C#N)c2c3c([nH]c2c1C)[C@](CCC)(CC(=O)O)OCC3

Procedure:
Examples 362–368 were synthesized following the above mentioned procedure for example 359 using the intermediate (5-cyano-7-hydroxy-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester and coupling it with the following alcohols: ethanol, methanol, isopropanol, n-butyl alcohol, 3,3-dimethyl-1-butanol, 3-fluorobenzyl alcohol, and benzyl alcohol. The resulting esters were hydrolyzed using 10% NaOH (aq) in EtOH.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[NH2:8].[OH-].[K+].[F:12][C:13]([F:17])=[C:14]([F:16])[F:15].C1(O)C=CC=CC=1>O.CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([O:9][C:14]([F:16])([F:15])[CH:13]([F:17])[F:12])[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: FC(F)=C(F)F
Reactant: Nc1ccc(O)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: Oc1ccccc1
Product: Nc1ccc(OC(F)(F)C(F)F)cc1F
Reaction time: 0.33 h
Yield: 80 %

Procedure:
0.70 Gram of 3-fluoro-4-aminophenol, 0.06 g of potassium hydroxide and 10 ml of dimethylformamide were added to a reactor and stirred for 20 minutes at an oil bath temperature of from 60° to 70° C. This solution was then violently stirred at the same temperature for 2 hours under the stream of a tetrafluoroethylene gas in excess of said phenol. The reaction solution was cooled and after adding water, extracted with two 150-ml portions of diethyl ether. The ether layers were combined, washed with water, dried and concentrated to obtain a crude product. This crude product was subjected to chromatography on silica gel to obtain 1.00 g of 2-fluoro-4-(1,1,2,2-tetrafluoroethoxy)aniline.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C@H:11]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:12]([OH:14])=O)=[N:6][CH:7]=1.Cl.[F:24][C:25]([F:32])=[C:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C@H:11]([NH:15][C:16](=[O:17])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:12]([N:29]2[CH2:30][CH2:31][C:26](=[C:25]([F:32])[F:24])[CH2:27][CH2:28]2)=[O:14])=[N:6][CH:7]=1
Reactant: FC(F)=C1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCc1cnc(N)cn1)C(=O)O
Agent: Cl
Product: CC(C)(C)OC(=O)N[C@@H](CCCc1cnc(N)cn1)C(=O)N1CCC(=C(F)F)CC1
Yield: 81.8 %

Procedure:
The process is performed in the same way as in Example 1.4, and starting with 2.32 g (7.5 mmol) of (S)-5-(5-amino-2-pyrazinyl)-2-[[(1,1-dimethylethoxy)carbonyl]amino]pentanoic acid and 1.9 g (11.25 mmol) of 4-(difluoromethylene)piperidine hydrochloride, to give 2.61 g of 1,1-dimethylethyl (S)-[4-(5-amino-2-pyrazinyl)-1-[[4-(difluoromethylene)piperid-1-yl)carbonyl]butyl]carbamate in the form of an amorphous powder.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([C:11]3[N:16]=[C:15]([N:17]4[CH2:23][CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]4)[CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[F:31][CH:32]([F:47])[N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1>>[N:17]1([C:15]2[N:16]=[C:11]([N:10]3[C:4]4[CH:3]=[C:2]([C:36]5[CH:35]=[N:34][N:33]([CH:32]([F:31])[F:47])[CH:37]=5)[N:7]=[CH:6][C:5]=4[CH:8]=[N:9]3)[CH:12]=[CH:13][CH:14]=2)[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cccc(-n3ncc4cnc(Cl)cc43)n2)CC1
Reactant: CC1(C)OB(c2cnn(C(F)F)c2)OC1(C)C
Product: FC(F)n1cc(-c2cc3c(cn2)cnn3-c2cccc(N3CCCNCC3)n2)cn1
Yield: 35 %

Procedure:
Following the procedures as described in Example 45 and starting with tert-butyl 4-(6-(6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate and 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, 173 was obtained as a white solid (80 mg, 35%) over three steps. 1H-NMR (500 MHz, CD3OD) δ (ppm) 9.06 (s, 1H), 8.73 (s, 1H), 8.50 (s, 1H), 8.34 (s, 1H), 8.15 (s, 1H), 7.50-7.67 (m, 2H), 7.23 (d, J=7.5 Hz, 1H), 6.58 (d, J=8.0 Hz, 1H), 3.87-3.90 (m, 4H), 3.13-3.15 (m, 2H), 2.91-2.94 (m, 2H), 2.03-2.08 (m, 2H); MS (ESI) m/z: 411 [M+H]+.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[N:28]([CH3:29])[CH:27]=[N:26][CH:25]=2)=[CH:12][C:11]=1[F:30])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:30][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[N:28]([CH3:29])[CH:27]=[N:26][CH:25]=2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCC[C@@H]3c3cncn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cncc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1F
Yield: 95.7 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-imidazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (46 mg, 0.0767 mmol) prepared in Example 49c, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL), dichloromethane (1.0 mL), to yield the title compound (33 mg, 96%) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[O:21][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[O:26])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2C)o1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3nc(C)oc3-c3ccccc3C)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 2-methyl-5-o-tolyl-oxazole-4-carboxylic acid.
Reaction SMILES: O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Mg+2].[CH3:14][C@@:15]12[C@@H:24]([CH2:25][CH2:26][C@@](O)(C=C)C)[C@@:23]([OH:33])([CH3:32])[CH2:22][CH2:21][C@H:20]1[C:19]([CH3:35])([CH3:34])[CH2:18][CH2:17][CH2:16]2>[Pt]>[CH3:32][C:23]12[CH2:22][CH2:21][CH:20]3[C:15]([CH3:14])([CH2:16][CH2:17][CH2:18][C:19]3([CH3:34])[CH3:35])[CH:24]1[CH2:25][CH2:26][O:33]2
Reactant: C=C[C@](C)(O)CC[C@@H]1[C@@]2(C)CCCC(C)(C)[C@@H]2CC[C@@]1(C)O
Agent: [Pt]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: O
Product: CC1(C)CCCC2(C)C1CCC1(C)OCCC12
Reaction time: 48 h

Procedure:
In this example, the ability of Ascomycete sp. KSM-JL2842 for producing a dodecahydro-3a,6,6,9a-tetramethylnaphtho[2,1-b]furan intermediate was examined. At the outset, a platinum loopful of Ascomycete sp. KSM-JL2842 was inoculated into 2.1% YM broth (Becton Dickinson), shake-culture was conducted at 25° C. for 2 days, and the resultants were designated as starter strains. Subsequently, the starter strains were inoculated into a medium containing 2.1% YM broth, 0.1% magnesium sulfate heptahydrate, 1% Tween 80, and 2% sclareol to a concentration of 2%, and shake culture was conducted at 25° C. The culture solution was subjected to extraction and GC analysis via the method of Example 1, and the amounts of the dodecahydro-3a,6,6,9a-tetramethylnaphtho[2,1-b]furan intermediates to be produced were determined. The results are shown in Table 3. The units for the numerical values shown in Table 3 are “g/l.”
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1.CC(C1C=CC=C(Cl)C=1)=O.[NH2:27][C:28]1[N:29]=[CH:30][NH:31][C:32]=1[C:33]#[N:34]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:29]3[CH:30]=[N:31][C:32]([C:33]#[N:34])=[C:28]3[N:27]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1[nH]cnc1N
Reactant: O=C(CC(=O)C(F)(F)F)c1cccc(Cl)c1
Agent: CC(=O)c1cccc(Cl)c1
Product: N#Cc1ncn2c(C(F)(F)F)cc(-c3cccc(Cl)c3)nc12
Yield: 41.2 %

Procedure:
Reaction of 1-(3-chloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (251 mg, 1.0 mmol), prepared from commercially available 3-chloro-acetophenone according to general procedure A, and 4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (133 mg, 41%). MS (ISP) 323.1 [(M+H)+]; mp 221° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].[NH2:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@@H:14]1[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].CCN(C(C)C)C(C)C.O>CS(C)=O>[Br:1][C:2]1[C:3]([C:4]#[N:5])=[CH:6][C:7]([F:11])=[C:8]([NH:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH:9]=1
Reactant: N#Cc1cc(F)c(F)cc1Br
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cc(Br)c(C#N)cc1F
Yield: 93.4 %

Procedure:
A solution of 2-bromo-4,5-difluorobenzonitrile (218 mg, 1.00 mmol), tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (214 mg, 1.00 mmol) and DIEA (0.300 mL, 1.72 mmol) in DMSO (2 mL) was stirred at 100 C for 18 h. Water was added to induce precipitation. The precipitate was collected and dried on vacuum to give tert-butyl (1S,2R)-2-(5-bromo-4-cyano-2-fluorophenylamino)cyclohexylcarbamate as a solid (385 mg).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].Cl[C:10]1[N:15]=[C:14]([NH:16][C@H:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([OH:23])[CH2:18]2)[C:13]([F:24])=[CH:12][N:11]=1.[F:25][C:26]1[CH:27]=[C:28]2[C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][N:32]([S:44]([C:47]3[CH:53]=[CH:52][C:50]([CH3:51])=[CH:49][CH:48]=3)(=[O:46])=[O:45])[C:29]2=[N:30][CH:31]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O.[Cl-].[Na+].O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[F:24][C:13]1[C:14]([NH:16][C@H:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([OH:23])[CH2:18]2)=[N:15][C:10]([C:34]2[C:28]3[C:29](=[N:30][CH:31]=[C:26]([F:25])[CH:27]=3)[N:32]([S:44]([C:47]3[CH:53]=[CH:52][C:50]([CH3:51])=[CH:49][CH:48]=3)(=[O:45])=[O:46])[CH:33]=2)=[N:11][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(F)cnc32)cc1
Reactant: O[C@@H]1CCC[C@H](Nc2nc(Cl)ncc2F)C1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@H](O)C4)n3)c3cc(F)cnc32)cc1
Temperature: 70 °C

Procedure:
K3PO4 (2.59 g, 12.21 mmol) in water (6 mL) and 2-Me-THF (20 mL) was purged with a flow of nitrogen for 30 min. Added (1R,3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexanol, 75a, (1.00 g, 4.07 mmol) and 5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine, 44a, (2.03 g, 4.88 mmol) and then purged with nitrogen for another 15 min. The reaction was then heated to 70° C. and then charged with Tris(dibenzylideneacetone)dipalladium (0.07 g, 0.08 mmol) and X-Phos (0.14 g, 0.28 mmol) under nitrogen. (Note Color changed from purple to hunter green). The reaction was heated to reflux for 1 h and 20 min. The reaction was cooled slowly to room temperature overnight. The mixture was treated with 100 mL of brine and 100 mL of ethyl acetate and separated the two layers. The aqueous phase was extracted again with EtOAc (50 mL). Combined organic layers and passed through a plug of fluoracil, dried over Na2SO4, decanted and removed the solvent by rotoevaporation to give crude product which was then purified by silica gel chromatography (25-50% EtOAc/Hexanes) to afford the desired product.
Reaction SMILES: [I:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9](I)=[CH:10][CH:11]=3)[CH2:6][CH2:5][C:4]=2[CH:3]=1.B(OC(C)C)(OC(C)C)[O:18]C(C)C.C([Li])CCC.Cl>C1COCC1.CCCCCC>[I:1][C:2]1[CH:3]=[C:4]2[C:13]([C:12]3[CH:11]=[CH:10][C:9]([OH:18])=[CH:8][C:7]=3[CH2:6][CH2:5]2)=[CH:14][CH:15]=1
Reactant: Ic1ccc2c(c1)CCc1cc(I)ccc1-2
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Oc1ccc2c(c1)CCc1cc(I)ccc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8.8 g (20.4 mmol) of 2,7-diiodo-9,10-dihydrophenanthrene are dissolved in 250 ml of THF, and, after addition of 7.0 ml (30.5 mmol) of triisopropyl borate, 16.5 ml of a 15 percent soln. of n-butyllithium in hexane are added at −70° C. After 1 h, the batch is hydrolysed using 2 N hydrochloric acid and warmed to room temperature. The solution is extracted twice with MTB ether, dried over sodium sulfate, the solvent is removed in vacuo, and the resultant crude product is suspended in 80 ml of toluene and 30 ml of 2 N sodium hydroxide solution with vigorous stirring. After addition of 8 ml of 30% hydrogen peroxide, the batch is stirred at 30-40° C. for 30 min with gentle cooling, 200 ml of water are added, and the mixture is acidified using 2 N hydrochloric acid. The aqueous phase is separated off and extracted three times with ethyl acetate. The combined org. phases are washed with dil. ammonium iron(II) sulfate soln. and dried over sodium sulfate. The solvent is removed in vacuo, and the residue is filtered through silica gel with dichloromethane, giving 7-iodo-9,10-dihydrophenanthren-2-ol as colourless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[C:22]4[C:31](I)=[CH:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:23]4=[N:24][C:25]=3[CH:26]3[CH2:28][CH2:27]3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:40][C:41]1[CH:42]=[C:43]([CH:61]=[C:62]([F:64])[CH:63]=1)[CH2:44][N:45]1[C:49]([CH3:50])=[C:48](B2OC(C)(C)C(C)(C)O2)[C:47]([CH3:60])=[N:46]1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[C:22]4[C:31]([C:48]5[C:47]([CH3:60])=[N:46][N:45]([CH2:44][C:43]6[CH:61]=[C:62]([F:64])[CH:63]=[C:41]([F:40])[CH:42]=6)[C:49]=5[CH3:50])=[CH:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:23]4=[N:24][C:25]=3[CH:26]3[CH2:28][CH2:27]3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nn(Cc2cc(F)cc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cc4c(I)cn(C(=O)OC(C)(C)C)c4nc3C3CC3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1nn(Cc2cc(F)cc(F)c2)c(C)c1-c1cn(C(=O)OC(C)(C)C)c2nc(C3CC3)c(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc12
Yield: 45.1 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 5-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)-6-cyclopropyl-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (intermediate 57) (120 mg, 0.186 mmol) was coupled with 1-(3,5-difluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 24) (97.24 mg, 0.27 mmol) in sodium carbonate (59.1 mg, 0.483 mmol), Pd(PPh3)2Cl2 (6.5 mg, 0.009 mmol), 1,2-dimethoxyethane/water (15/2 ml) to afford 62 mg (45% yield) of titled compound. MS: m/z=739.2 (M+1).