Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH3:25])[C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:10]=2)=[CH:5][CH:4]=1)=O.[C:26]([O:33][CH3:34])(=[O:32])[CH2:27][C:28]([O:30][CH3:31])=[O:29].C(O)(=O)C.N1CCCCC1>C1(C)C=CC=CC=1>[CH3:25][N:16]([CH2:15][C:11]1[CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[C:27]([C:26]([O:33][CH3:34])=[O:32])[C:28]([O:30][CH3:31])=[O:29])=[CH:8][CH:7]=2)[CH:14]=[CH:13][CH:12]=1)[C:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:24]
Reactant: CN(Cc1cccc(-c2ccc(C=O)cc2)c1)C(=O)c1ccccc1
Reactant: COC(=O)CC(=O)OC
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)C(=Cc1ccc(-c2cccc(CN(C)C(=O)c3ccccc3)c2)cc1)C(=O)OC

Procedure:
1.54 g (4.25 mmol) of N-(4′-formylbiphenyl-3-ylmethyl)-N-methylbenzamide (prepared as in Example 1(e)), 20 ml of toluene, 0.56 g (4.25 mmol)) of dimethyl malonate and 123 mg (0.85 mmol) of piperidine acetate are introduced into a three-necked flask under a stream of nitrogen. The mixture is refluxed for 5 hours, while separating off the water formed using Dean-Stark apparatus. The reaction medium is cooled, extracted with ethyl acetate and washed with water. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulfate and evaporated. The crude product is purified by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (70/30). After evaporation of the solvents, 1.4 g (75%) of the expected product are collected.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[S:17][CH:18]=[C:19]([CH2:21]Cl)[N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:25]([NH:28][CH2:29][CH2:30][CH3:31])[CH2:26][CH3:27].CN(C)C=O>O1CCCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[S:17][CH:18]=[C:19]([CH2:21][N:28]([CH2:29][CH2:30][CH3:31])[CH2:25][CH2:26][CH3:27])[N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(-c3nc(CCl)cs3)ncn2-c2cccc(Cl)c2C1=O
Reactant: CCCNCCC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1csc(-c2ncn3c2CN(C)C(=O)c2c(Cl)cccc2-3)n1
Yield: 44.5 %

Procedure:
A suspension of 1.0 g (0.00263 mol) of 7-chloro-3-(4-chloromethyl-thiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one in 60 ml of tetrahydrofuran was treated with 7.2 ml (0.0527 mol) of dipropylamine and 5 ml of dimethylformamide. After stirring at reflux for 16 hrs. the suspension obtained was filtered and the solution was completely freed from the solvents. The residue was chromatographed over silica gel with ethyl acetate as the eluent and recrystallized from hot isopropyl ether. There was obtained 0.52 g (44%) of 7-chloro-3-(4-dipropylaminomethyl-thiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo(1,5-a][1,4]benzodiazepin-6-one as white crystals; m.p. 121-123°.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[O:23])=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:32])[CH:3]=1.[NH:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=[C:34]1[CH2:42][C:43](O)=[O:44]>>[NH:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=[C:34]1[CH2:42][C:43]([NH:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([C:22]([N:24]5[CH2:25][CH2:26][O:27][CH2:28][CH2:29]5)=[O:23])=[CH:20][CH:21]=4)[S:15][C:8]=23)=[C:4]([F:32])[CH:3]=1)=[O:44]
Reactant: O=C(O)Cc1nc2ccccc2[nH]1
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)N5CCOCC5)cc4)sc23)c(F)c1
Product: O=C(Cc1nc2ccccc2[nH]1)Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)N5CCOCC5)cc4)sc23)c(F)c1
Yield: 6 %

Procedure:
Prepared from (4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)phenyl)(morpholino)methanone (Example 129, Step A) and 2-(1H-benzo[d]imidazol-2-yl)acetic acid according to the procedure of Example 89. The crude was purified by preparative HPLC to afford the desired product (1.9 mg, 6%). LRMS (ESI pos) m/e 607.9 (M+1). 1H-NMR (400 MHz, CD3OD) δ 8.53 (d, 1H), 7.94 (m, 4H), 7.81 (m, 2H), 7.61 (m, 4H), 7.47 (m, 2H), 6.74 (d, 1H), 3.73 (m, 8H), 3.50 (m, 2H); 19F NMR (376 MHz, CD3OD) δ −129.6.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12])([O-])=O>C(O)(=O)C.[Zn]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=[N+]([O-])c1ccc(O)cc1C(F)(F)F
Agent: [Zn]
Solvent: CC(=O)O
Product: Nc1ccc(O)cc1C(F)(F)F
Yield: 59.8 %

Procedure:
4-Nitro-3-trifluoromethylphenol (0.414 g; 2.0 mmol) was dissolved in 25 ml of glacial acetic acid and zinc dust (2.62 g; 40 mmol) was added in small portions during 10 minutes allowing the temperature to rise up to +40° C. The mixture was stirred for ten minutes and filtered. The dust was washed with 3×10 ml of glacial acetic acid and filtrate was evaporated to dryness to give 0.212 g of 4-amino-3-trifluoromethylphenol. 1H NMR (400 MHz, DMSO-d6): 4.86 (2H, s), 6.72 (1H, d, J=8.7 Hz), 6.74 (1H, d, J=2.6 Hz), 6.78 (1H, dd, J=8.7 Hz, J=2.7 Hz), 8.91 (1H, s)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[NH2:22][CH2:23][C:24]1([OH:30])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>ClCCl>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:22][CH2:23][C:24]1([OH:30])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[N:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2cccnc2c1Cl
Reactant: NCC1(O)CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2cccnc2c1NCC1(O)CCOCC1
Temperature: 25 °C
Yield: 93.7 %

Procedure:
A solution of 4-chloro-3-nitro[1,5]naphthyridine (16.6 g, 79.0 mmol) in dichloromethane (250 mL) and triethylamine (14.3 mL, 102.7 mmol) was cooled to 4° C. A solution of 4-aminomethyltetrahydropyran-4-ol (11.4 g, 86.9 mmol) in dichloromethane (70 mL) was added dropwise over a period of 30 minutes. The reaction mixture was allowed to stir at ambient temperature over the weekend and then it was concentrated under reduced pressure. The residue was stirred with water (300 mL). The resulting solid was isolated by filtration, rinsed with water, and dried in a vacuum oven at 50° C. for 4 hours to provide 22.53 g of 4-[(3-nitro[1,5]naphthyridin-4-ylamino)methyl]tetrahydropyran-4-ol.
Reaction SMILES: O.[OH-].[Li+].[O:4]=[C:5]([C:34]1[N:42]2[C:37]([CH:38]=[CH:39][CH:40]=[CH:41]2)=[CH:36][C:35]=1[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([O:27][CH2:28][CH2:29][O:30]C(=O)C)[CH:24]=[CH:23][N:22]=3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)=[O:7]>CO>[OH:30][CH2:29][CH2:28][O:27][C:25]1[CH:24]=[CH:23][N:22]=[C:21]([N:18]2[CH2:19][CH2:20][N:15]([C:12]3[CH:11]=[CH:10][C:9]([NH:8][C:6](=[O:7])[C:5](=[O:4])[C:34]4[N:42]5[C:37]([CH:38]=[CH:39][CH:40]=[CH:41]5)=[CH:36][C:35]=4[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[CH:14][CH:13]=3)[CH2:16][CH2:17]2)[CH:26]=1
Reactant: CC(=O)OCCOc1ccnc(N2CCN(c3ccc(NC(=O)C(=O)c4c(-c5ccccc5)cc5ccccn45)cc3)CC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(Nc1ccc(N2CCN(c3cc(OCCO)ccn3)CC2)cc1)C(=O)c1c(-c2ccccc2)cc2ccccn12
Reaction time: 3 h
Yield: 43.6 %

Procedure:
Lithium hydroxide monohydrate (0.048 g, 1.16 mmol) was added to a stirred solution of acetic acid 2-[2-(4-{4-[2-oxo-2-(2-phenyl-indolizin-3-yl)-acetylamino]-phenyl}-piperazin-1-yl)-pyridin-4-yloxy]-ethyl ester (0.35 g, 0.58 mmol) in methanol (15 mL) at r.t. under nitrogen and stirred for 3 h. The reaction mixture was evaporated to dryness, diluted with water and extracted with dichloromethane. The organic layer was washed with water and brine solution, dried over sodium sulfate and filtered. The filtrate was concentrated and purified by column chromatography over neutral alumina using 0-1% methanol in dichloromethane to afford N-(4-{4-[4-(2-hydroxy-ethoxy)-pyridin-2-yl]-piperazin-1-yl}-phenyl)-2-oxo-2-(2-phenyl-indolizin-3-yl)-acetamide (0.142 g, 44%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.C1COCC1.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.B.CSC>C(Cl)(Cl)Cl.CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@@H:7]([OH:11])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)ccc21
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: O[C@H]1CCc2cc(Br)ccc21
Temperature: 35 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
A round-bottomed flask was charged with 5-bromo-1-indanone (50.0 g, 0.24 mol), anhydrous THF (500 mL) and (R)-methyl-CBS-oxazaborolidine (10.0 g, 0.04 mol) and the solution was heated to 35° C. under N2. Borane-methylsulfide (10.0 M, 650 mL, 6.5 mol) was added dropwise over 1.5 hours. The mixture was stirred at 35° C. for 1 hour. Upon consumption of the starting material (TLC analysis), the reaction was cooled to 0° C. and was quenched with water (200 mL) at such a rate to maintain the reaction temperature below 5° C. The mixture was extracted with EtOAc (4×200 mL). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated to give a yellow solid. The solids were dissolved in hot CHCl3 (150 mL) and hexane (300 mL) and upon cooling to room temperature solids precipitated from the solution. After further cooling at 0° C., the solids were collected by vacuum filtration to afford (S)-5-bromo-indan-1-ol (22 g, 44%) as a light-yellow solid. This material was carried on to the next step without further purification.
Reaction SMILES: ClC1C=CC(S(N[C@@H]2CCCC[C@H]2CO)(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].BrCC1C=CC(C2OC=CN=2)=CC=1.[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([S:46]([N:49]([CH2:58][C:59]2[CH:64]=[CH:63][C:62]([C:65]3[O:66][CH:67]=[CH:68][N:69]=3)=[C:61](F)[C:60]=2F)[C@@H:50]2[CH2:55][CH2:54][CH2:53][CH2:52][C@H:51]2[CH2:56][OH:57])(=[O:48])=[O:47])=[CH:42][CH:41]=1>>[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([S:46]([N:49]([C@@H:50]2[CH2:55][CH2:54][CH2:53][CH2:52][C@H:51]2[CH2:56][OH:57])[CH2:58][C:59]2[CH:60]=[CH:61][C:62]([C:65]3[O:66][CH:67]=[CH:68][N:69]=3)=[CH:63][CH:64]=2)(=[O:48])=[O:47])=[CH:42][CH:41]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncco2)c(F)c1F)[C@@H]1CCCC[C@H]1CO
Agent: BrCc1ccc(-c2ncco2)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(N[C@@H]1CCCC[C@H]1CO)c1ccc(Cl)cc1
Product: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncco2)cc1)[C@@H]1CCCC[C@H]1CO
Yield: 13 %

Procedure:
The title compound was synthesized from 4-chloro-N-((1R,2R)-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (100 mg, 0.33 mmol), cesium carbonate (129 mg, 0.40 mmol), and 2-(4-(bromomethyl)phenyl)oxazole (94 mg, 0.40 mmol) according to the procedure described for 4-chloro-N-(2,3-difluoro-4-(oxazol-2-yl)benzyl)-N-((1R,2R)-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (Example 20) to give 4-chloro-N-((1R,2R)-2-(hydroxymethyl)cyclohexyl)-N-(4-(oxazol-2-yl)benzyl)benzenesulfonamide (21 mg, 13%). 1H NMR (400 MHz, CDCl3) δ ppm 7.98 (d, J=8.31 Hz, 2H), 7.70 (d, J=8.00 Hz, 3H), 7.43-7.51 (m, 4H), 7.23 (s, 1H), 4.73 (d, J=15.11 Hz, 1H), 4.09 (d, J=15.00 Hz, 1H), 3.66-3.81 (m, 2H), 3.07 (t, J=10.83 Hz, 1H), 2.62 (br. s., 1H), 1.62-1.73 (m, 1H), 1.37-1.62 (m, 4H), 1.06-1.28 (m, 2H), 0.81-1.06 (m, 2H). Analytical HPLC R.T.=22.99 min. MS [M+H]+=461. HRMS [M+H]+ calc'd 461.1302, found 461.1283. Chiral LC: R.T.=18.97 min., >98% ee.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14]([C:20]#[N:21])[CH2:15][CH2:16][O:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C=O)C>C1COCC1>[C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14]([CH2:20][NH2:21])[CH2:15][CH2:16][O:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CC1CCOc2cc(S(=O)(=O)c3ccccc3)ccc21
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: NCC1CCOc2cc(S(=O)(=O)c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.3 %

Procedure:
7-Benzenesulfonyl-chroman-4-carbonitrile (300 mg, 1 mmol) was dissolved in 10 mL THF, and 237 ul (2.5 mmol) of BH3.DMF was added. The reaction mixture was stirred for one hour at room temperature, and then heated to 80° C. for twenty minutes. The reaction mixture was then cooled, quenched by addition of methanol, and diluted with water. The aqueous mixture was extrated with EtOAc. The organic phase was dried over MgSO4, and solvent was removed under reduced pressure to yield 95 mg (31%) of C-(7-benzenesulfonyl-chroman-4-yl)-methylamine. MS: 304 (M+H)+. This product was dissolved in 2N HCl/EtOH and recrystallized by addition of Et2O to afford 52 mg of the corresponding hydrochloride salt. Mp: 246.8-249.8° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:19]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:21]=1)[O:8][CH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](O)=[O:13])([CH3:4])([CH3:3])[CH3:2].[NH2:26][C:27]1[NH:31][N:30]=[N:29][N:28]=1.S(Cl)(Cl)=O>N1C=CC=CC=1.Cl>[C:1]([C:5]1[CH:6]=[C:7]([CH:19]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:21]=1)[O:8][CH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:26][C:27]1[NH:31][N:30]=[N:29][N:28]=1)=[O:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1nnn[nH]1
Reactant: CC(C)(C)c1cc(OCc2ccccc2C(=O)O)cc(C(C)(C)C)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CC(C)(C)c1cc(OCc2ccccc2C(=O)Nc2nnn[nH]2)cc(C(C)(C)C)c1
Yield: 31.9 %

Procedure:
A solution of 3.40 g (0.01 mole) of 2-(3,5-di-t-butylphenoxymethyl)benzoic acid and 1.03 g (0.01 mole) of 5-aminotetrazole in 30 ml of pyridine was treated with a dropwise addition of 2.36 g (0.02 mole) of thionyl chloride. The resulting solution was stirred for forty minutes before being diluted with 300 ml of 5% hydrochloric acid to give a gum which slowly crystallized. The solid was collected, rinsed with water and recrystallized from aqueous dimethylformamide to give 1.3 g of white solid 2-(3,5-di-t-butylphenoxymethyl)-N-(tetrazol-5-yl)benzamide, m.p. 251°-254° C.. Analysis: Calculated for C23H29N5O2 : %C, 67.8; %H, 7.2; %N, 17.2; Found: %C, 67.7; %H, 7.1; %N, 17.2.
Reaction SMILES: [F:1][CH:2]([F:38])[CH2:3][N:4]1[CH:12]=[C:11]2[C:6]([C:7]([CH:14]([O:16][CH2:17][C:18]3([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[CH2:23][CH2:22][N:21]([C:24](OC(C)(C)C)=O)[CH2:20][CH2:19]3)[CH3:15])=[CH:8][C:9]([CH3:13])=[CH:10]2)=[N:5]1.C([BH3-])#N.[Na+].C=O>FC(F)(F)C(O)=O.C(O)(=O)C>[F:38][CH:2]([F:1])[CH2:3][N:4]1[CH:12]=[C:11]2[C:6]([C:7]([CH:14]([O:16][CH2:17][C:18]3([C:31]4[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=4)[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]3)[CH3:15])=[CH:8][C:9]([CH3:13])=[CH:10]2)=[N:5]1
Reactant: Cc1cc(C(C)OCC2(c3ccc(F)cc3)CCN(C(=O)OC(C)(C)C)CC2)c2nn(CC(F)F)cc2c1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: Cc1cc(C(C)OCC2(c3ccc(F)cc3)CCN(C)CC2)c2nn(CC(F)F)cc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(±)-tert-Butyl 4-((1-(2-(2,2-difluoroethyl)-5-methyl-2H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (10 mg, 0.02 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 1 mL) and stirred at room temperature for 1 h. The reaction was concentrated, loaded onto a strong cation exchange cartridge in methanol, and flushed with several volumes of methanol which were discarded. The crude secondary amine was eluted in 2 M ammonia in methanol and concentrated. The resulting residue was dissolved in acetonitrile (1 mL), cooled to 0° C., and treated with sodium cyanoborohydride (5.9 mg, 0.01 mmol) and formalin (0.52 mL). After 5 min, the reaction was treated with a few drops of acetic acid. The ice bath was removed and stirring continued for 1 h. The reaction was concentrated and purified by column chromatography (10% methanolic ammonia/methylene chloride) to afford 4.5 mg (54%) as a clear oil. 1H-NMR (CDCl3, 500 MHz) δ 7.83 (s, 1H), 7.30-7.34 (m, 2H), 7.22 (m, 1H), 6.99-7.02 (m, 2H), 6.67 (m, 1H), 6.05-6.29 (m, 1H), 4.86 (q, J=6.4 Hz, 1H), 4.64-4.71 (m, 2H), 3.33-3.38 (m, 2H), 2.57 (m, 2H), 2.28 (s, 3H), 2.20 (s, 3H), 2.15-2.24 (m, 6H), 1.44 (d, J=6.4 Hz, 3H). Mass spec.: 446.63(MH)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([NH:9][CH2:10][CH2:11]O)[CH:6]=[CH:7][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:35]>N1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:35][CH2:11][CH2:10][NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCNc1cccc(C(F)(F)F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Product: FC(F)(F)c1cccc(NCCBr)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 258.8 %

Procedure:
N-(3-trifluoromethylphenyl)ethanolamine (4.17 g) and triphenyl phosphine (5.50 g) were dissolved in dry pyridine (35 ml) and stirred at 0° C. To this solution was added, portionwise, carbon tetrabromide (7.08 g). Stirring was continued for 1 hour and the reaction mixture was left to stand at room temperature overnight. A little more triphenyl phosphine (0.20 g) was added, and when virtually all starting alcohol had been consumed the pyridine was removed under reduced pressure to leave a brown residue (14.10 g). This was chromatographed on silica gel, eluting with ethyl acetate/hexane (1:9) as eluant to give the title compound as a light brown oil, yield 3.35 g.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]2[CH:13]([CH2:28][C:29]([CH3:40])([CH3:39])[CH2:30][O:31][Si](C(C)(C)C)(C)C)[CH2:14][C:15]([C:24]([O:26][CH3:27])=[O:25])=[C:16]3[NH:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=4[C:11]23[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+].C(OCC)C>C1COCC1.O>[CH2:1]([N:8]1[CH:12]2[CH:13]([CH2:28][C:29]([CH3:40])([CH3:39])[CH2:30][OH:31])[CH2:14][C:15]([C:24]([O:26][CH3:27])=[O:25])=[C:16]3[NH:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=4[C:11]23[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1=C2Nc3ccccc3C23CCN(Cc2ccccc2)C3C(CC(C)(C)CO[Si](C)(C)C(C)(C)C)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1=C2Nc3ccccc3C23CCN(Cc2ccccc2)C3C(CC(C)(C)CO)C1
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 97.3 %

Procedure:
To a solution of 873 mg (1.56 mmol) of methyl 3-benzyl-1,2,3,3a,4,5-hexahydro-4-[2,2-dimethyl-3-(t-butyldimethylsilyloxy)propyl]-7H-pyrrolo(2,3-d)carbazole-6-carboxylate in 30.5 mL of THF and 15 mL of water was added 5.24 g (20 eq) of p-toluenesulfonic acid. The reaction mixture was stirred for 90 min. at 20° C. and saturated aqueous K2CO3 solution was added until a pH=9-10 was obtained. Ethyl ether (100 mL) was added and the two layers were separated. The aqueous layer was extracted once with 100 mL of ethyl ether and twice with 100 mL of CH2Cl2. The combined organic layers were dried over MgSO4 and the solvents evaporated in vacuo (aspirator). The crude product was purified by column chromatography on silica gel (40 g). Elution with CH2Cl2 followed by ethyl ether gave 0.678 g (97.5%) of the title compound as a white foam. TLC: (Silica) Rf 0.50 (ethyl ether), detection with CAS (blue with developing yellow center), UV (long and short wave length).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:23])([CH3:22])[O:6][C@H:7]1[CH2:12][NH:11][CH2:10][C@@H:9]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:8]1)([CH3:4])[CH3:3].[F:24][C:25]1[CH:34]=[C:33]2[C:28]([CH:29]=[CH:30][C:31](=[O:38])[N:32]2[CH2:35][CH:36]=O)=[CH:27][CH:26]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH3:4][C:2]([Si:5]([CH3:23])([CH3:22])[O:6][C@H:7]1[CH2:12][N:11]([CH2:36][CH2:35][N:32]2[C:33]3[C:28](=[CH:27][CH:26]=[C:25]([F:24])[CH:34]=3)[CH:29]=[CH:30][C:31]2=[O:38])[CH2:10][C@@H:9]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:8]1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CNC[C@H](O[Si](C)(C)C(C)(C)C)C1
Reactant: O=CCn1c(=O)ccc2ccc(F)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(C)OC(=O)NC[C@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN(CCn2c(=O)ccc3ccc(F)cc32)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To cis-1,1-dimethylethyl [((3RS,5RS)-5-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-3-piperidinyl)methyl]carbamate (350 mg; 1.0 mmol) in MeOH (2 ml) and CHCl3 (8 ml) was added (7-fluoro-2-oxo-1(2H)-quinolinyl)acetaldehyde (for a preparation see Example 2(d) (200 mg; 1.0 mmol) and the reaction was allowed to stir at room temperature under N2 for 8 hours. Na(OAc)3BH (530 mg; 2.5 mmol) was added and the reaction was allowed to stir at room temperature under nitrogen for an additional 14 hours. The solvents were removed and the crude residue was purified by chromatography on silica gel using a 0-10% MeOH/DCM gradient to provide the desired compound (415 mg; 78%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.C(Cl)(=O)C([Cl:13])=O>C(Cl)Cl>[CH3:1][C:2]1[O:3][CH:4]=[C:5]([C:7]([Cl:13])=[O:9])[N:6]=1
Reactant: Cc1nc(C(=O)O)co1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1nc(C(=O)Cl)co1
Reaction time: 0.5 h

Procedure:
To a stirring solution of 2-methyl-oxazole-4-carboxylic acid (30 mg) in DCM (2.0 mL), oxalyl chloride (3.0 eq) was added at room temperature. The reaction mixture was stirred for 30 minutes. Solvents were evaporated and dried under vacuo to afford 2-methyl-oxazole-4-carbonyl chloride.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:16][CH3:17])[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].Cl.Cl.[CH3:22][N:23]([CH3:31])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=1.C(OC(O)C)C.C(=O)([O-])[O-].[Na+].[Na+]>O.N1C=CC=CC=1>[CH3:22][N:23]([CH3:31])[C:24]1[CH:25]=[C:26]([NH:30][C:2]2[C:11]3[C:6](=[C:7]([O:16][CH3:17])[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:18]#[N:19])[CH:27]=[CH:28][CH:29]=1
Reactant: CN(C)c1cccc(N)c1
Reactant: COc1cc2c(Cl)c(C#N)cnc2c(OC)c1OC
Agent: CCOC(C)O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: c1ccncc1
Product: COc1cc2c(Nc3cccc(N(C)C)c3)c(C#N)cnc2c(OC)c1OC
Yield: 66.3 %

Procedure:
A mixture of 0.279 g of 4-chloro-6,7,8-trimethoxy-quinoline-3-carbonitrile, 0.23 g of N,N-dimethyl-1,3-phenylenediamine dihydrochloride, 0.2 ml of pyridine, and 15 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 30 minutes. The mixture was cooled and added to 100 ml of water. To this mixture was added sodium carbonate to pH 9. The product was collected, washed with water, and dried to give 0.251 g of 4-(3-dimethylamino-phenylamino)-6,7,8-trimethoxy-quinoline-3-carbonitrile as a solid, mp 142-144° C.; mass spectrum (EI, m/e): M 378.1685.
Reaction SMILES: [NH2:1][CH:2]1[CH:7]2[CH:3]1[CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6]2.C(=O)(O)[O-].[Na+].[C:20](Cl)([O:22][CH2:23][CH:24]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21]>O.O1CCOCC1>[CH:35]1[C:36]2[CH:24]([CH2:23][O:22][C:20]([NH:1][CH:2]3[CH:7]4[CH:3]3[CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6]4)=[O:21])[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]=2[CH:32]=[CH:33][CH:34]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CC2C(N)C2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2C(C1)C2NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
tert-Butyl 6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate (1 g, 1.0 eq.) was added to a solution of sodium bicarbonate (0.84 g, 2.0 eq.) in water (5 ml) at 5° C. FMOC—Cl (1.56 g, 1.2 eq.) in 1,4-dioxane (10 ml) was added dropwise. The reaction mixture was stirred at room temperature for 3 h, transferred into iced water (50 mL), and extracted with EtOAc (2×100 mL). The combined organic layers was washed with brine (2×50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure (25° C., 20 mmHg) to afford 1.9 g of tert-butyl 6-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate (yield 90%).