Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:42][CH3:43])=[C:10]([CH2:19][NH:20][C:21](=[O:41])[CH2:22][C:23]([NH:25][CH2:26][C:27]3[CH:28]=[C:29]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([CH:39]=O)[CH:34]=4)[CH:30]=[CH:31][CH:32]=3)=[O:24])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH:44]1[CH2:48][CH2:47][C@H:46]([NH:49]C(=O)OC(C)(C)C)[CH2:45]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O.C(O)(C(F)(F)F)=O>CS(C)=O.ClCCl>[NH2:49][C@H:46]1[CH2:47][CH2:48][N:44]([CH2:39][C:35]2[CH:34]=[C:33]([C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([CH2:26][NH:25][C:23](=[O:24])[CH2:22][C:21]([NH:20][CH2:19][C:10]4[C:11]([NH:12][CH:13]5[CH2:18][CH2:17][O:16][CH2:15][CH2:14]5)=[C:6]5[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]5=[N:8][C:9]=4[CH2:42][CH3:43])=[O:41])[CH:28]=3)[CH:38]=[CH:37][CH:36]=2)[CH2:45]1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1cccc(-c2cccc(C=O)c2)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1cccc(-c2cccc(CN3CC[C@H](N)C3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.2 %

Procedure:
To N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-3-biphenylyl)methyl]propanediamide (50 mg, 0.086 mmol) was added 1,1-dimethylethyl (3S)-3-pyrrolidinylcarbamate (32 mg, 0.172 mmol) followed by NaB(OAc)3H (36.4 mg, 0.172 mmol) and AcOH (4.91 μL, 0.086 mmol) in dimethyl sulfoxide (DMSO) (0.5 mL). The mixture was stirred overnight at room temperature. The reaction was quenched with saturated NaHCO3 and extracted with EtOAc (3×1 mL). Combined organic layers were washed with saturated NaCl, dried (Na2SO4) and concentrated. The crude products were redissolved in MeOH/DMSO (1/1) and purified using a Gilson HPLC (acidic condition). The product fractions were combined and the solvent evaporated using a GeneVac EZ-2 evaporator. To the resulting residue was added TFA (0.198 mL, 2.57 mmol) in dichloromethane (0.2 mL) and the mixture was placed in the Glas-Col evaporator overnight. The resulting residue was redissolved in MeOH/DMSO and purified using a Gilson HPLC (acidic condition). Product fractions were combined and the solvent evaporated using a GeneVac EZ-2 evaporator, and basified by amine cartridge to afford the title compound 6.3 mg (11%). LC-MS m/z 653 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[NH:16][C:15](/[CH:17]=[CH:18]/[C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]4)=[C:21]([O:31][CH3:32])[CH:20]=3)=[N:14][N:13]=2)[CH2:9][CH2:10]O)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:35])=O>>[Cl:35][CH2:10][CH2:9][CH:8]([C:12]1[NH:16][C:15](/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]3)=[C:21]([O:31][CH3:32])[CH:20]=2)=[N:14][N:13]=1)[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc(/C=C/c2nnc(C(CCO)c3ccc(F)cc3)[nH]2)ccc1-n1cnc(C)c1
Product: COc1cc(/C=C/c2nnc(C(CCCl)c3ccc(F)cc3)[nH]2)ccc1-n1cnc(C)c1
Temperature: 25 °C

Procedure:
A solution of 3-(4-fluorophenyl)-3-{5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-4H-[1,2,4]triazol-3-yl}propan-1-ol (83 mg) in phosphorus oxychloride (1 mL) was stirred at 120° C. for one hour. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 86 mg of the title compound. The property value of the compound as follows.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][C@@H:5]([C:8]([O:10][C@H]2C(C)(C)COC2=O)=[O:9])[CH2:4][CH:3]=1.O.[OH-].[Li+].Cl>C1COCC1.O.CO>[CH3:1][C:2]1[CH2:7][CH2:6][C@@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH:3]=1
Reactant: CC1=CC[C@H](C(=O)O[C@@H]2C(=O)OCC2(C)C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC1=CC[C@H](C(=O)O)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 102.2 %

Procedure:
(R)—((S)-4,4-dimethyl-2-oxotetrahydrofuran-3-yl) 4-methylcyclohex-3-enecarboxylate 502 (1.30 g, 5.15 mmol) in THF (10 mL), water (1 mL) and methanol (1 mL) was treated with lithium hydroxide monohydrate (2.16 g, 51.5 mmol) and warmed to 50° C. with stirring. After 1 hour, the reaction mixture treated with 1M HCl. The mixture was extracted with hexanes:THF (10:1), dried over sodium sulfate, filtered and concentrated to 0.738 g (quantitative yield) of (R)-4-methylcyclohex-3-enecarboxylic acid 503 as a white powder.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-])=[CH:9][C:8]=2[N:18]=1.[NH4+:32].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(Cl)(Cl)Cl>ClCCCl>[NH2:32][C:9]1[C:8]2[N:18]=[C:5]([CH2:4][CH2:3][O:2][CH3:1])[N:6]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: [NH4+]
Reactant: COCCc1nc2c[n+]([O-])c3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
A solution of tert-butyl 2-{2-[2-(2-methoxyethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate (10.6 g, 24.6 mmol) in 100 mL of 1,2-dichloroethane was heated to 60° C. and treated with 10 mL of concentrated NH4OH solution. To the rapidly stirred solution was added solid p-toluenesulfonyl chloride (7.05 g, 37.0 mmol) over a 10 min period. The reaction mixture was treated with an additional 1 mL concentrated NH4OH solution and then sealed in a pressure vessel and heating was continued for 2 h. The reaction mixture was then cooled and treated with 100 mL of CHCl3. The reaction mixture was then washed with H2O, 1% Na2CO3 solution (2×) and brine. The organic portion was dried over Na2SO4 and concentrated to give 10.6 g of tert-butyl 2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate as a brown foam.
Reaction SMILES: O=[C:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14](=[O:26])[NH:15][C@H:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH2:17]2)[CH2:3]1.[NH2:27][C:28]1[CH:37]=[C:36]2[C:31]([CH2:32][C@@H:33]([C:45](=[O:57])[NH:46][C@H:47]3[C:56]4[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=4)[CH2:50][CH2:49][CH2:48]3)[N:34]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:35]2)=[CH:30][CH:29]=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].Cl>ClCCCl.CCOC(C)=O>[C:10]([O:9][C:7]([N:5]1[C@H:4]([C:14](=[O:26])[NH:15][C@H:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH2:17]2)[CH2:3][C@H:2]([NH:27][C:28]2[CH:37]=[C:36]3[C:31]([CH2:32][C@@H:33]([C:45](=[O:57])[NH:46][C@H:47]4[C:56]5[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=5)[CH2:50][CH2:49][CH2:48]4)[N:34]([C:38]([O:40][C:41]([CH3:42])([CH3:43])[CH3:44])=[O:39])[CH2:35]3)=[CH:30][CH:29]=2)[CH2:6]1)=[O:8])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Reactant: CC(C)(C)OC(=O)N1Cc2cc(N)ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1Cc2cc(N[C@H]3C[C@@H](C(=O)N[C@@H]4CCCc5ccccc54)N(C(=O)OC(C)(C)C)C3)ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.8 %

Procedure:
To a solution of (S)-tert-butyl 4-oxo-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidine-1-carboxylate (73 mg, 0.20 mmol) in DCE (2.0 mL) was added (S)-tert-butyl 7-amino-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (86 mg, 0.20 mmol) and AcOH (12 μL, 0.20 mmol). Na(OAc)3BH (78 mg, 0.37 mmol) was then added, and the resulting reaction mixture was stirred at room temperature for 4 h. Additional AcOH (12 μL, 0.20 mmol) and Na(OAc)3BH (78 mg, 0.37 mmol) were added, and stirring was continued overnight at room temperature. The reaction mixture was poured into a separatory funnel containing 1N HCl and EtOAc. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (151 mg, 97%) as a colorless oil. MS (ESI+) m/z 764.5 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21]([C:23]5[N:24]=[C:25]([Si](C)(C)C)[S:26][CH:27]=5)=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.[F:39][C:40]([F:52])([F:51])[C:41]1[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43][CH:42]=1.C(N(C(C)C)CC)(C)C>Cl.O1CCOCC1.ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21]([C:23]5[N:24]=[CH:25][S:26][CH:27]=5)=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:47]([C:44]2[CH:43]=[CH:42][C:41]([C:40]([F:39])([F:51])[F:52])=[CH:46][CH:45]=2)(=[O:49])=[O:48])[CH2:16][CH2:15]4)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(C(=O)c2csc([Si](C)(C)C)n2)C1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cscn1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(C(F)(F)F)cc1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
A solution of (R)-tert-butyl 1-(4-fluorophenyl)-4a-(2-(trimethylsilyl)thiazole-4-carbonyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate (76 mg, 0.103 mmol) in 4 M HCl/dioxane (3 mL) was stirred at room temperature for 1 hour. The solvent was removed in vacuo (azeotroping twice with toluene (˜4 mL)) to give a dark orange oil. This was dissolved in dichloromethane (3 mL) and 4-(trifluoromethyl)benzene-1-sulfonyl chloride (30.3 mg, 0.124 mmol) was added followed by diisopropylethylamine (90 μl, 0.516 mmol). The reaction mixture was stirred at room temperature for 0.5 hour. The solvent was removed in vacuo to give a dark orange oil. The crude product was purified by column chromatography on silica gel (gradient: 0-40% ethyl acetate in isohexane) to afford (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone as a white solid (44 mg). LCMS (Method F, ES-API): RT 2.65 min, m+H=589.2; 1H NMR (400 MHz, CDCl3): δ 8.86 (1H, d, J=2.1 Hz), 8.23 (1H, d, J=2.1 Hz), 7.84-7.82 (2H, m), 7.74-7.72 (2H, m), 7.45-7.40 (2H, m), 7.28 (1H, s), 7.19-7.13 (2H, m), 6.51 (1H, d, J=2.1 Hz), 5.48 (1H, dd, J=12.5, 2.1 Hz), 4.15 (1H, d, J=16.6 Hz), 3.92-3.87 (1H, m), 2.93-2.85 (2H, m), 2.72 (1H, d, J=12.6 Hz), 2.56-2.49 (2H, m).
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:3]=1[CH2:4][O:5][Si:6]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[CH:7]([CH3:9])[CH3:8].C([Li])CCC.[B:26](OC)([O:29]C)[O:27]C.[Cl-].[NH4+]>O1CCCC1>[F:20][C:17]1[CH:18]=[CH:19][C:2]([B:26]([OH:29])[OH:27])=[C:3]([CH2:4][O:5][Si:6]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[CH:7]([CH3:9])[CH3:8])[CH:16]=1
Reactant: CC(C)[Si](OCc1cc(F)ccc1Br)(C(C)C)C(C)C
Reactant: COB(OC)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)[Si](OCc1cc(F)ccc1B(O)O)(C(C)C)C(C)C
Temperature: 23 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a solution of 6.00 g (16.6 mmol) [(2-bromo-5-fluorobenzyl)oxy](triisopropyl)silane which was prepared according to intermediate example 299c in 60 mL tetrahydrofuran were added 7.31 mL n-butyllithium (2.5M in hexane) at −78° C. After 20 minutes of stirring 5.58 mL trimethyl borate were added and stirring was continued for additional 60 minutes. The mixture was allowed to warm to 23° C., poured into a saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. After filtration and removal of the solvent the residue was purified by chromatography to give 3.16 g (58%) of the title compound.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:18]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29](OCC)=[O:30])=[C:23]([F:34])[C:22]=3[F:35])=[C:17]([C:36]([F:39])([F:38])[F:37])[S:16][N:15]=2)=[CH:10][CH:9]=1>>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:18]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][OH:30])=[C:23]([F:34])[C:22]=3[F:35])=[C:17]([C:36]([F:39])([F:38])[F:37])[S:16][N:15]=2)=[CH:10][CH:9]=1
Reactant: CCOC(=O)CCc1ccc(OCc2c(-c3ccc(Cl)cc3)nsc2C(F)(F)F)c(F)c1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCCCc1ccc(OCc2c(-c3ccc(Cl)cc3)nsc2C(F)(F)F)c(F)c1F

Procedure:
The title compound was prepared according to the procedure described in Example 111 by LAH reduction of ethyl 3-(4-((3-(4-chlorophenyl)-5-(trifluoromethyl)isothiazol-4-yl)methoxy)-2,3-difluorophenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J=8.5 Hz, 2H), 7.46 (d, J=8.4 Hz, 2H), 6.89 (dd, J=10.5, 4.2 Hz, 1H), 6.72 (dd, J=10.5, 4.2 Hz, 1H), 5.06 (s, 2H), 3.71 (t, J=9.2 Hz, 2H), 2.74 (t, J=9.0 Hz, 2H), 1.87 (m, 2H), 1.45 (br, s, 1H).
Reaction SMILES: [CH3:1][CH:2]1[S:6][C:5]([NH:7][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[CH3:9])=[N:4][C:3]1=[O:20].Br[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1.[Li]N([Si](C)(C)C)[Si](C)(C)C>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].C1(C)C=CC=CC=1>[CH3:1][C:2]1([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[S:6][C:5]([NH:7][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:18])([F:17])[F:19])[CH3:9])=[N:4][C:3]1=[O:20]
Reactant: CC1SC(N[C@@H](C)c2ccccc2C(F)(F)F)=NC1=O
Reactant: N#Cc1ccc(Br)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: Cc1ccccc1
Product: C[C@H](NC1=NC(=O)C(C)(c2ccc(C#N)cc2)S1)c1ccccc1C(F)(F)F
Temperature: 95 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-methyl-2-((S)-1-(2-(trifluoromethyl)phenyl)ethylamino)thiazol-4(5H)-one (0.2000 g, 0.662 mmol), 4-bromobenzonitrile (0.301 g, 1.65 mmol), Pd2(dba)3 (0.0303 g, 0.0331 mmol), (S)-2-(diphenylphosphino)-1-(2-(diphenylphosphino)-naphthalen-1-yl)naphthalene (0.0618 g, 0.0992 mmol), and LiN(TMS)2 (0.277 g, 1.65 mmol) was added toluene (8 mL) in a glove box. The mixture was gradually heated to 95° C. and stirred overnight. The reaction was quenched with NH4Cl (5 mL), and the reaction mixture was extracted three times with ethylacetate (30 mL). The organic phase was dried over Na2SO4, filtered and concentrated under vacuum. The crude was purified by chromatography on silica gel using 22% ethylacetate/hexane to remove the impurities and then 36% ethylacetate/hexane to obtain the product as a light yellow solid. MS (ESI, pos. ion) m/z: 404 (M+1), 402 (M-1). 1H NMR (CDCl3, 400 MHz): δ1.71-1.78 (m, 3H), 1.98-2.09 (m, 3H), 5.05 (q, J=8 Hz, 1H), 7.39-7.68 (m, 7H), 7.84 (d, J=8 Hz, 1H), 10.97 (s, 1H). % de (by 1H NMR): 48%.
Reaction SMILES: [Mg].BrCCBr.Cl[CH2:7][Si:8]([CH3:16])([CH3:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[CH:18]=[CH2:19].[Cl-].[NH4+]>C(OCC)C.O.[Cu]Br>[CH3:15][Si:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:16])[CH2:7][CH2:19][CH2:18][C:17]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: C[Si](C)(CCl)c1ccccc1
Reactant: C=CC(=O)OCC
Agent: [Cu]Br
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Solvent: O
Solvent: BrCCBr
Product: CCOC(=O)CCC[Si](C)(C)c1ccccc1
Temperature: -10 °C
Yield: 47.9 %

Procedure:
To a stirred mixture of 7.9 g (0.329 mole) of magnesium metal and 0.5 mL of 1,2-dibromoethane in 150 mL of diethyl ether was added dropwise a solution of 50 g (0.271 mole) of (chloromethyl)dimethylphenylsilane in 100 mL of diethyl ether. The addition required 30 minutes. Upon completion of addition, the resultant solution was transferred using a cannula to a flask containing 15.5 g (0.108 mole) of copper(I) bromide which was under a nitrogen atmosphere and was cooled in a dry ice/acetone bath. To this flask was added dropwise a solution 10.8 g (0.108 mole) of ethyl acrylate in 50 mL of diethyl ether. The addition required 40 minutes. Upon completion of addition, the reaction mixture was allowed to warm to -10° C. It was then diluted with 400 mL of diethyl ether, and a solution of 14.2 g of ammonium chloride in 40 mL of water was added dropwise while maintaining the temperature at -10° C. to 0° C. Upon completion of addition, the reaction mixture was filtered, and the solvent was evaporated under reduced pressure, leaving a residue. This residue was passed through a column of silica gel, eluting with diethyl ether/petroleum ether (5:95). The product-containing fractions were combined, and the solvent was evaporated, yielding 12.95 g of ethyl 5-methyl-5-phenyl-5-silahexanoate as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9](=[N:15]O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C(O)(=O)C.O>C(O)C.[Zn]>[NH2:15][CH:9]([C:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)=[O:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(Br)cc1
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(N)C(=O)c1ccc(Br)cc1
Temperature: 1 °C
Reaction time: 0.08 h

Procedure:
Step C″: Dissolve ethyl 3-(4-bromophenyl)-2-(hydroxyimino)-3-oxopropanoate (12.8 kg dry mass (15.75 kg wet), 42.65 mol, 1 eq, prepared in step B above) in ethanol (110 L) in a 400-L vessel at an internal temperature of 20° C. Cool the solution to an internal temperature of 1° C. over 20 min and add zinc dust (6.429 kg, 98.01 mol, 2.3 eq) portion-wise over 30 min at an internal temperature of 2 to 3° C. Prepare a solution of acetic acid (19.5 L), water (2.5 L), and ethanol (11.5 L) in a feeder. Add about 1 to 2% of the solution to the zinc suspension at 0° C. After 5 min, no exotherm is observed. Add another 1 to 2% of the solution. A rise of temperature could be observed. Add the rest of the solution, slowly in the beginning but continuously over 95 min at an internal temperature of −2 to 2° C. Cool the suspension to an internal temperature of −5° C. and stir for 15 min. to provide the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[S:7][C:6]=2[CH:11]=1.[Cl:12][CH2:13][CH2:14][N:15]=[C:16]=[O:17].C(N(CC)CC)C>C(C(C)=O)C>[Cl:12][CH2:13][CH2:14][NH:15][C:16]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[S:7][C:6]=2[CH:11]=1)=[O:17]
Reactant: O=c1oc2ccc(O)cc2s1
Reactant: O=C=NCCCl
Solvent: CCC(C)=O
Solvent: CCN(CC)CC
Product: O=C(NCCCl)Oc1ccc2oc(=O)sc2c1
Reaction time: 0.33 h

Procedure:
5-hydroxy-1,3-benzoxathiol-2-one (14.0 grams) was mixed with 2-chloroethyl isocyanate (8.79 grams) in 170 milliliters of methyl ethyl ketone in the presence of 0.84 gram of triethylamine. The resulting mixture was heated at reflux temperature with stirring for 6 hours and 20 minutes. The solvent was then removed by evaporation in vacuo. The residue was recrystallized from carbon tetrachloride (containing a small amount of ethyl acetate). A subsequent recrystallization from toluene gave the purified product, 5-[(2-chloroethyl)carbamoyloxy]-1,3-benzoxathiol-2-one, as a white crystal line solid with a melting point of 105.5°-107.5° C. Elemental analysis calculated for C10H8ClNO4S (percent): carbon--43.88; hydrogen--2.95; nitrogen--5.12. Found: carbon--43.7; hydrogen--3.13; nitrogen--5.37.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH3:11].[CH3:12][O-:13].[Na+]>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][OH:13])[NH2:8]
Reactant: C[O-]
Reactant: Cc1ccc([N+](=O)[O-])cc1F
Agent: [Na+]
Solvent: CS(C)=O
Product: Nc1ccc(CCO)c(F)c1

Procedure:
2-Fluoro-4-nitrotoluene and p-formaldehyde were allowed to undergo the reaction in DMSO in the presence of sodium methoxide, and then the resulting compound was subjected to catalytic hydrogenation in the same manner as shown in Reference Example 3 to obtain 3-fluoro-4-(2-hydroxyethyl)aniline. F: 156.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:28])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH2:20][C:21]4[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=4)=[C:14]([C:16]([O:18]C)=O)[N:15]=[C:7]3[C:6]=2[CH:27]=1.C[O-].[Na+].C([NH2:34])=O>>[Br:1][C:2]1[C:3]([F:28])=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([CH2:20][C:21]4[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=4)=[C:14]([C:16]([NH2:34])=[O:18])[N:15]=[C:7]3[C:6]=2[CH:27]=1
Reactant: COC(=O)c1nc2n(c1Cc1ccnn1C)C1CC(C1)c1cc(F)c(Br)cc1-2
Reactant: NC=O
Agent: C[O-]
Agent: [Na+]
Product: Cn1nccc1Cc1c(C(N)=O)nc2n1C1CC(C1)c1cc(F)c(Br)cc1-2
Yield: 57 %

Procedure:
10-bromo-9-fluoro-3-((1-methyl-1H-pyrazol-5-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was prepared similarly to as described in General Procedure L. Methyl 10-bromo-9-fluoro-3((1-methyl-1H-pyrazol-5-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was reacted with sodium methoxide and formamide to afford 66 mg (57% yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]([CH2:21][N:22]=[C:23]=O)[CH2:16][CH2:17][O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]([CH2:21][NH:22][CH3:23])[CH2:16][CH2:17][O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C=NCC1CCOc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCC1CCOc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 7-(3-fluoro-benzenesulfonyl)-4-isocyanatomethyl-chroman (0.12 g, 0.35 mmol) in THF (15 ml) at 0° C. was added LiAlH4 (0.52 ml, 1.0 M in THF, 0.525 mmol). The mixture was stirred at 0° C. for 2 hours, then was quenched with one drop of H2O, 3 drops of 2N NaOH, and 3 drops of H2O again. The precipitate was filtered off. The solution was diluted with EtOAc, washed with water, dried with MgSO4, filtered and concentrated. The residue was purified with preparative TLC to give [7-(3-Fluoro-benzenesulfonyl)-chroman-4-ylmethyl]-methyl-amine free base, which was further treated with a few drops of 2N HCl in EtOH and dried under vacuum to give the corresponding HCl salt: 33.5 mg. MS: 336.2 (M+H)+, 377.2 (M+CH3CN+H)+, 671.3 (2M+H)+.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH:9]1[C:18]2[C:17]3=[N:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[N:16]3[CH:15]=[CH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1>C1COCC1>[Br:8][C:23]1[CH:24]=[CH:25][C:20]2[N:19]=[C:17]3[C:18]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=4[CH:14]=[CH:15][N:16]3[C:21]=2[CH:22]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc2c(c1)ccn1c3ccccc3nc21
Solvent: C1CCOC1
Product: Brc1ccc2nc3c4ccccc4ccn3c2c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
32.6 g (183 mmol) of NBS are added to a solution of 40 g (183 mmol) of benzimidazo[2,1-a]isoquinoline in 500 ml of THF, and the mixture is stirred at 60° C. for 4 h. The solution is subsequently stirred at room temperature overnight, the solid is filtered off with suction, washed with ethanol and dried. Yield: 51.3 g (181 mmol), 98%.