Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][C@@H:12]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]2[N:23]([CH3:24])[N:22]=[CH:21][C:20]=2[NH:25][C:26]([C:28]2[N:29]=[C:30]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([CH:47]=[CH2:48])[C:42]=3[F:49])[S:31][C:32]=2[NH:33]C(=O)OC(C)(C)C)=[O:27])[CH2:14][CH2:13]1)=O)C1C=CC=CC=1.[H][H].B(Br)(Br)Br.C(Cl)Cl>CO>[NH2:33][C:32]1[S:31][C:30]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][CH3:48])[C:42]=2[F:49])=[N:29][C:28]=1[C:26]([NH:25][C:20]1[CH:21]=[N:22][N:23]([CH3:24])[C:19]=1[N:15]1[CH2:16][CH2:17][CH2:18][C@@H:12]([NH2:11])[CH2:13][CH2:14]1)=[O:27]
Reactant: C=Cc1cccc(-c2nc(C(=O)Nc3cnn(C)c3N3CCC[C@@H](NC(=O)OCc4ccccc4)CC3)c(NC(=O)OC(C)(C)C)s2)c1F
Reactant: [H][H]
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CCc1cccc(-c2nc(C(=O)Nc3cnn(C)c3N3CCC[C@@H](N)CC3)c(N)s2)c1F
Reaction time: 2 h

Procedure:
tert-butyl N-[4-[[5-[(4R)-4-(benzyloxycarbonylamino)azepan-1-yl]-1-methyl-pyrazol-4-yl]carbamoyl]-2-(2-fluoro-3-vinyl-phenyl)thiazol-5-yl]carbamate (51 mg, 0.086 mmol) was dissolved in methanol (50 mL) and hydrogenated on H-Cube at 60° C. and 50 bar hydrogen pressure to reduce the double bond. The solution was concentrated and the residue was dissolved in DCM (5 mL). 1.0M solution of boron tribromide in methylene chloride (0.35 ml, 0.35 mmol) was added and the mixture was stirred for 2 h. The solvent was distilled off and the residue was purified via reverse phase HPLC to afford 383. MS (ESI) m/z: 458.3 [M+H+].
Reaction SMILES: [CH:1]1(B(O)O)[CH2:3][CH2:2]1.[C:7]([N:10]1[CH2:15][CH2:14][C:13]2[N:16]([C@@H:27]3[C:35]4[C:30](=[C:31](Br)[CH:32]=[C:33]([F:36])[CH:34]=4)[CH2:29][C@H:28]3[OH:38])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=3)[C:22]#[N:23])[C:12]=2[CH2:11]1)(=[O:9])[CH3:8].C([O-])([O-])=O.[K+].[K+]>CC#N.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:7]([N:10]1[CH2:15][CH2:14][C:13]2[N:16]([C@@H:27]3[C:35]4[C:30](=[C:31]([CH:1]5[CH2:3][CH2:2]5)[CH:32]=[C:33]([F:36])[CH:34]=4)[CH2:29][C@H:28]3[OH:38])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=3)[C:22]#[N:23])[C:12]=2[CH2:11]1)(=[O:9])[CH3:8]
Reactant: CC(=O)N1CCc2c(c(-c3cccc(C#N)c3)nn2[C@@H]2c3cc(F)cc(Br)c3C[C@H]2O)C1
Reactant: OB(O)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(=O)N1CCc2c(c(-c3cccc(C#N)c3)nn2[C@@H]2c3cc(F)cc(C4CC4)c3C[C@H]2O)C1
Temperature: 110 °C
Reaction time: 2 h
Yield: 19.7 %

Procedure:
According to Scheme 14: A mixture of cyclopropylboronic acid (28 mg, 0.33 mmol), 3-[5-acetyl-1-((1R,2R)-4-bromo-6-fluoro-2-hydroxy-indan-1-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (11d) (0.05 g, 0.10 mmol), K2CO3 (83 mg, 0.606 mmol) and tetrakis(triphenylphosphine)palladium(0) (17 mg, 0.005, 0.015 mmol) in CH3CN (2 ml) and water (0.75 ml) was stirred at 110° C. for 2 h under microwave irradiation. The mixture was purified by reverse phase HPLC (CH3CN/water gradient with 0.1% trifluoroacetic acid) to give 9 mg of 3-[5-acetyl-1-((1R,2R)-4-cyclopropyl-6-fluoro-2-hydroxy-indan-1-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (20a).
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([N:9]2[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10]2)[S:7][CH:8]=1)(=[O:3])[NH2:2].[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(N(CC)CC)C.CO>C(Cl)Cl.N1C=CC=CC=1>[C:1]([C:4]1[N:5]=[C:6]([N:9]2[CH2:13][CH2:12][C@H:11]([O:14][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:10]2)[S:7][CH:8]=1)(=[O:3])[NH2:2]
Reactant: CS(=O)(=O)Cl
Reactant: NC(=O)c1csc(N2CC[C@H](O)C2)n1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: CO
Product: CS(=O)(=O)O[C@H]1CCN(c2nc(C(N)=O)cs2)C1
Reaction time: 1 h
Yield: 59.3 %

Procedure:
To a solution of (3S)-1-(4-carbamoyl-1,3-thiazol-2-yl)-3-hydroxypyrrolidine (1.42 g, 6.66 mmol) (obtained as described in Reference Example 20(7)) suspended in a mixture of methylene chloride (40 ml) and pyridine (9 ml) were added methanesulfonyl chloride (2.58 ml, 33.3 mmol) and triethylamine (4.67 ml, 33.3 mmol) in an ice bath, and the mixture was stirred for 1 hour. After checking the completion of the reaction, methanol (1.2 ml) was added thereto in an ice bath and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using 5% methanol in ethyl acetate→10% methanol in ethyl acetate as the eluant to afford (3S)-1-(4-carbamoyl-1,3-thiazol-2-yl)-3-methanesulfonyloxypyrrolidine (1.15 g, yield 60%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:42])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]#[C:12][C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31]3)=[CH:26][CH:25]=2)[N:14]=1>CCO.CN(C=O)C.CN(C=O)C.CCO.[Pd]>[CH3:1][O:2][C:3](=[O:42])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][C:13]1[C:18]([C:19]([F:21])([F:22])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:40])([CH3:41])[CH3:39])=[O:36])[CH2:31]3)=[CH:26][CH:25]=2)[N:14]=1
Reactant: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)C3)cc2)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)C3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 23.8 %

Procedure:
A solution of tert-butyl 3-(4-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)pyrrolidine-1-carboxylate (I138) (0.527 g, 0.906 mmol) in EtOH (10 mL) was added to a solution of 10% Pd/C (0.500 g) in DMF (6 mL). The reaction was stirred at room temperature for 24 hours under an atmosphere of hydrogen. The reaction was filtered through a pad of celite and washed through with EtOAc (80 mL). The solvent was removed in vacuo to afford a yellow oil. This was taken up in DMF/EtOH (1:1, 10 mL) and a slurry of 10% Pd/C (0.500 g, 1 eq) in DMF was added. The reaction was stirred under an atmosphere of H2 at room temperature for an additional 24 hours. The reaction was filtered through a pad of celite and washed through with EtOAc (80 mL). The solvent removed in vacuo to afford a yellow oil which was purified by column chromatography on silica gel (0-45% EtOAc in petroleum benzine 40-60° C.) to yield the title compound (I139) (0.126 g, 24%) as a brown oil; 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 7.58 (d, J=8.2 Hz, 2H), 7.39 (s, 1H), 7.30-7.17 (m, 6H), 3.91-3.72 (m, 2H), 3.75 (s, 2H), 3.68 (s, 3H), 3.66-3.52 (m, 1H), 3.47-3.21 (m, 3H), 3.17-3.04 (m, 4H), 2.23 (d, J=20.4 Hz, 1H), 1.97 (dd, J=21.1, 10.2 Hz, 1H), 1.48 (d, J=3.1 Hz, 9H). LCMS Method C: rt 6.91 min; m/z 585 [M+H], 607 [M+N]+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1.[CH3:16][NH2:17]>O>[Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:17][CH3:16])(=[O:14])=[O:13])=[CH:8][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(OCCCBr)cc1
Reactant: CN
Solvent: O
Product: CNS(=O)(=O)c1ccc(OCCCBr)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
3.4 g of 4-(3-bromopropoxy)benzenesulfonic acid chloride was suspended in water, and 6.2 ml a 20% aqueous methylamine solution was added to the suspension under ice cooling. The solution was stirred at room temperature for 2 hours and then extracted with chloroform (50 ml×2), and drying and concentration followed to obtain 2.9 g (yield: 87%) of 4-(3-bromopropoxy)-N-methylbenzenesulfonamide in an oily state.
Reaction SMILES: FC1C=C(C(Cl)=O)C=CC=1.[Cl:11][C:12]1[CH:18]=[C:17]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)[CH:16]=[CH:15][C:13]=1[NH2:14].[F:34][C:35]1[CH:36]=[C:37]([C:41]([N:43]=[C:44]=[S:45])=[O:42])[CH:38]=[CH:39][CH:40]=1>C1(C)C=CC=CC=1.C(O)C>[F:34][C:35]1[CH:36]=[C:37]([C:41]([N:43]=[C:44]=[S:45])=[O:42])[CH:38]=[CH:39][CH:40]=1.[Cl:11][C:12]1[CH:18]=[C:17]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)[CH:16]=[CH:15][C:13]=1[NH:14][C:44]([NH:43][C:41](=[O:42])[C:37]1[CH:38]=[CH:39][CH:40]=[C:35]([F:34])[CH:36]=1)=[S:45]
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Agent: O=C(Cl)c1cccc(F)c1
Agent: O=C(N=C=S)c1cccc(F)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(F)c4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
3-Fluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3-fluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-fluoro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (50 mg, yield 58%).
Reaction SMILES: N[C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[C:5]([O:11][CH3:12])=[N:4][CH:3]=1.N([O-])=O.[Na+].C(Cl)(Cl)Cl.N1C=CC=CC=1.[FH:27]>>[F:27][C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[C:5]([O:11][CH3:12])=[N:4][CH:3]=1
Reactant: F
Reactant: COc1ncc(N)nc1C(N)=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COc1ncc(F)nc1C(N)=O
Temperature: 10 °C
Reaction time: 1 h

Procedure:
In an atmosphere of nitrogen gas, 1.50 g of 6-amino-3-methoxy-2-pyrazinecarboxamide was dissolved in 12 mL of 70% hydrogen fluoride-pyridine solution at an ice-cooled temperature. Then, 0.71 g of sodium nitrite was added at −50° C., and the mixture thus obtained was stirred at 10° C. for one hour. After stirring the reaction mixture for an additional one hour, a mixture of 50 mL of ice water and 100 mL of chloroform was added, and the mixture thus obtained was separated into layers. The organic layer was washed with saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate and the solvent was removed under reduced pressure. Thus, 1.29 g of 6-fluoro-3-methoxy-2-pyrazinecarboxamide was obtained as a solid product.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[N+:7]([C:10]1[CH:18]=[CH:17][CH:16]=[C:12]([C:13](O)=[O:14])[C:11]=1[OH:19])([O-:9])=[O:8].[C]=O.[CH3:22][NH:23][CH3:24]>ClCCl.CN(C)C=O.O1CCCC1>[OH:19][C:11]1[C:10]([N+:7]([O-:9])=[O:8])=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([N:23]([CH3:24])[CH3:22])=[O:14]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1O
Reactant: CNC
Agent: O=C(Cl)C(=O)Cl
Agent: [C]=O
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cccc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 97 %

Procedure:
42.9 ml (0.50 mol, 3 eq) of oxalyl chloride were added dropwise to a suspension of 30 g (0.16 mol, 1 eq) of 3-nitrosalicylic acid in 1200 ml of dichloromethane. 30 drops of N,N-dimethylformamide were added (large amount of gas given off, adaptation of a system for trapping toxic carbon monoxide vapors). The reaction medium was stirred at ambient temperature for 24 hours. The reaction medium was cooled to 0-5° C. and then 246 ml (0.49 mol, 3 eq) of a 2 N solution of dimethylamine in tetrahydrofuran were added. The reaction medium was stirred at ambient temperature for 2 days. The reaction medium was concentrated to dryness and the residue was dissolved in 300 ml 1 N sodium hydroxide. The aqueous solution (red) was extracted 3 times with 300 ml of dichloromethane. The aqueous phase was cooled in a water-ice bath, and the pH was adjusted to 2 with approximately 50 ml of 6 N hydrochloric acid. The mixture (which had become yellow) was extracted 3 times with 300 ml of dichloromethane. The organic phases were combined, washed twice with 250 ml of water and then once with 250 ml of a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated. 33.5 g of 2-hydroxy-N,N-dimethyl-3-nitrobenzamide were obtained in the form of a yellow cotton solid. Yield=97%.
Reaction SMILES: C(OC([N:8]1[C:21]2[C:13](=[CH:14][C:15]3[CH2:16][O:17][CH2:18][C:19]=3[CH:20]=2)[C@@H:12]([N:22]([CH2:41][C:42]2[CH:47]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:45]=[C:44]([C:52]([F:55])([F:54])[F:53])[CH:43]=2)[C:23]2[N:24]=[N:25][N:26]([CH2:28][CH2:29][N:30]3[C:38](=[O:39])[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:31]3=[O:40])[N:27]=2)[CH2:11][CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl.O>[F:50][C:48]([F:49])([F:51])[C:46]1[CH:47]=[C:42]([CH:43]=[C:44]([C:52]([F:53])([F:54])[F:55])[CH:45]=1)[CH2:41][N:22]([C@@H:12]1[C:13]2=[CH:14][C:15]3[CH2:16][O:17][CH2:18][C:19]=3[CH:20]=[C:21]2[NH:8][CH2:9][CH2:10][CH2:11]1)[C:23]1[N:24]=[N:25][N:26]([CH2:28][CH2:29][N:30]2[C:31](=[O:40])[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:38]2=[O:39])[N:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(CCN3C(=O)c4ccccc4C3=O)n2)c2cc3c(cc21)COC3
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCNc3cc4c(cc32)COC4)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-9-((3,5-Bis-trifluoromethyl-benzyl)-{2-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-2H-tetrazol-5-yl}-amino)-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]indene-5-carboxylic acid tert-butyl ester (Example 106, Step 1) (0.39 mmol) in dichloromethane (5 mL), add trifluoroacetic acid (2 mL). After stirring at room temperature for 3 h, quench the reaction with concentrated sodium carbonate, dilute with dichloromethane (20 mL), and water (20 mL). Separate the organic phase and wash the aqueous with dichloromethane (2×10 mL). Dry the combined organics over sodium sulfate, filter, and remove solvent under vacuum. Chromatograph the product over silica gel eluting with ethyl acetate/hexane (10-50%) to provide the title intermediate as a colorless foam. MS (ES+): 730 (M+59).
Reaction SMILES: C[O-].[Na+].Br[CH2:5][C:6]1[O:10][C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[C:17]([F:20])([F:19])[F:18])=[N:8][CH:7]=1.[CH2:21]([SH:24])[CH2:22][CH3:23].O>CO>[CH2:21]([S:24][CH2:5][C:6]1[O:10][C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[C:17]([F:20])([F:19])[F:18])=[N:8][CH:7]=1)[CH2:22][CH3:23]
Reactant: CCCS
Reactant: FC(F)(F)c1ccncc1-c1ncc(CBr)o1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCSCc1cnc(-c2cnccc2C(F)(F)F)o1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sodium methoxide (130 μl, 30% in methanol) was added to a solution of 5-bromomethyl-2-(4-trifluoromethyl-3-pyridyl)-oxazole (160 mg) and n-propanethiol (60 μl), in methanol (7 ml), and the mixture was stirred at room temperature for 4 hours. Water (50 ml) was then added, and the mixture was extracted with ethyl acetate. The organic phase was washed with water, dried (MgSO4), filtered and concentrated. This gave the desired product in pure form as a pale yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:6][C:5]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[Na+]>CO.O>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:23])=[O:2])=[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=1
Reactant: COC(=O)c1ccc(Oc2ccccn2)cc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(Oc2ccccn2)cc1-c1ccccc1

Procedure:
A solution of the resultant ester from Example 6B (1.0 equivalent) in aqueous methanol is treated with NaOH (2.0 equivalents) and stirred until the reaction is deemed complete by TLC analysis. The mixture is acidified, diluted with water, and extracted into ethyl acetate which is dried and evaporated. Chromatography on silica gel provides the title product.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1.[H-].[Na+].I[CH3:20].O>CN(C=O)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:20])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1
Reactant: CI
Reactant: CCOC(=O)Cc1ccc(OCOC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)c1ccc(OCOC)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ethyl 2-(4-(methoxymethoxy)phenyl)acetate (1.75 g, 7.80 mmol) in DMF (50 mL) was slowly added sodium hydride (330 mg, 8.25 mmol) and iodomethane (1.13 g, 7.96 mmol) at 0° C. The reaction mixture was stirred for 1 hour at 0° C. The mixture was added water (50 mL) and extracted with EtOAc. The organic layer was dried with MgSO4. The organic layer was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography eluting with n-Hexane/EtOAc=15/1.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[C:15]2[O:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:3][CH2:6][C:7]1[C:15]2[O:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: OCc1cccc2cc(-c3ccccc3)oc12
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: ClCc1cccc2cc(-c3ccccc3)oc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
Thionyl chloride (0.65 ml) is added to a mixture of 7-hydroxymethyl-2-phenylbenzofuran (1.0 g), pyridine (0.38 ml) and methylene chloride (8 ml) under ice-cooling, and the mixture is stirred at room temperature for 30 minutes. The mixture is concentrated under reduced pressure to remove solvent, and the residue is dissolved in ethyl acetate. The solution is washed with water, dried and concentrated under reduced pressure to remove solvent. The residue is recrystallized from n-hexane, whereby 7-chloromethyl-2-phenylbenzofuran (0.9 g) is obtained. Yield: 83%.
Reaction SMILES: [F:1][C:2]1([F:21])[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C@@H:4]([C:18]([O-])=[O:19])[CH2:3]1.[Li+].Cl.[NH2:24][C@H:25]([C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1)[CH3:26]>>[F:21][C:2]1([F:1])[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:17])[F:15])[CH:9]=2)[C@@H:4]([C:18]([NH:24][C@H:25]([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)[CH3:26])=[O:19])[CH2:3]1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C([O-])[C@H]1CC(F)(F)CN1Cc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Li+]
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CC(F)(F)CN2Cc2cccc(C(F)(F)F)c2)cc1
Yield: 48.6 %

Procedure:
The title compound (D164) (37 mg) was prepared according to the general procedure for amides preparation (Method A) starting from lithium (R)-4,4-difluoro-1-(3-(trifluoromethyl)benzyl)pyrrolidine-2-carboxylate (D115) (51 mg) and (S)-methyl 4-(1-aminoethyl)benzoate hydrochloride (35 mg). (Reaction time: 48 hrs; RT).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:23]=[CH:22][C:8]2[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][CH2:19][C:7]=2[CH:6]=1)=[CH:15][CH:14]=[C:13](Cl)[C:12]=4[F:21])=[O:4].[CH3:24][C:25]1[CH:26]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:28]=[C:29]([CH3:35])[C:30]=1[O:31][CH2:32][CH2:33][CH3:34]>>[CH3:1][O:2][C:3]([C:5]1[CH:23]=[CH:22][C:8]2[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][CH2:19][C:7]=2[CH:6]=1)=[CH:15][CH:14]=[C:13]([C:27]1[CH:28]=[C:29]([CH3:35])[C:30]([O:31][CH2:32][CH2:33][CH3:34])=[C:25]([CH3:24])[CH:26]=1)[C:12]=4[F:21])=[O:4]
Reactant: COC(=O)c1ccc2c(c1)CCc1c-2[nH]c2c(F)c(Cl)ccc12
Reactant: CCCOc1c(C)cc(B2OC(C)(C)C(C)(C)O2)cc1C
Product: CCCOc1c(C)cc(-c2ccc3c4c([nH]c3c2F)-c2ccc(C(=O)OC)cc2CC4)cc1C

Procedure:
A sample of crude 9-Chloro-10-fluoro-5,11-dihydro-6H-benzo[a]carbazole-3-carboxylic acid methyl ester (prepared as in example 57, step 2) and 2-(3,5-Dimethyl-4-propoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane are coupled as in example 19, step 2 to afford the title material: ESMS m/z/z 458 (M+H+).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH2:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[NH:15][C:16](=[O:26])[C:17]2[CH:22]=[N:21][N:20]([CH2:23][CH2:24][CH3:25])[C:18]=2[N:19]=1)[CH3:6].[Br:27][CH2:28][C:29](Br)=[O:30]>ClCCl>[Br:27][CH2:28][C:29]([C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:5][CH3:6])=[C:9]([C:14]2[NH:15][C:16](=[O:26])[C:17]3[CH:22]=[N:21][N:20]([CH2:23][CH2:24][CH3:25])[C:18]=3[N:19]=2)[CH:10]=1)=[O:30]
Reactant: O=C(Br)CBr
Reactant: CCCn1ncc2c(=O)[nH]c(-c3ccccc3OCC)nc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCn1ncc2c(=O)[nH]c(-c3cc(C(=O)CBr)ccc3OCC)nc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 90.5 %

Procedure:
Aluminum trichloride (1.34 g, 0.010 mol) was added portionwise to a stirred solution of 6-(2-ethoxyphenyl)-1-n-propyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 13; 1.0 g, 0.0034 mol) and bromoacetyl bromide (1.35, 0.0067 mol) in dichloromethane (30 ml) at 0° C. The reaction solution was allowed to warm to room temperature, stirred for 14 hours, then for a further 2 hours under reflux. The cool reaction mixture was added dropwise to ice/water (50 g) and the resulting mixture stirred for 1 hour. The organic phase was separated and the aqueous phase extracted with dichloromethane (2×50 ml); the combined organic solutions were then washed with brine (10 ml) and dried (Na2SO4). Removal of the solvent by evaporation under vacuum gave an off-white solid which, when triturated with ether (20 ml) and dried, afforded the product as a white solid (1.29 g, 92%). A sample crystallised from ethyl acetate-hexane as colourless crystals, m.p. 164-166° C. Found: C, 51.88; H, 4.56; N, 13.13. C18H19BrN4O3 requires C, 51.56; H, 4.57; N, 13.36%.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]2[CH:9]([OH:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:7]=2[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:23]([Si:27]([CH3:30])([CH3:29])Cl)([CH3:26])([CH3:25])[CH3:24].O>O1CCCC1>[Si:27]([O:1][CH2:2][C:3]1[C:8]2[CH:9]([OH:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:7]=2[CH:6]=[CH:5][CH:4]=1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cccc2c1C(O)CCCCC2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cccc2c1C(O)CCCCC2
Reaction time: 8 h

Procedure:
To a solution of 4-(hydroxymethyl)-5,6,7,8,9,10-hexahydrobenzo[a]cycloocten-5-ol (11.51 g, 55.80 mmol), 4-N,N-dimethylaminopyridine (0.5 g) and triethylamine (9.33 ml, 67.0 mmol) in tetrahydrofuran (70 ml) was added tert-butyldimethylchlorosilane (9.25 g, 61.4 mmol) at room temperature and the mixture was stirred as it was overnight at room temperature. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=15/1-9/1) to give the objective substance.