Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1C=CC=CC=1C(=O)C.C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5[CH:46]=[C:45]([C:47](N)=[O:48])[CH2:44][CH:43]=[CH:42]5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1.[CH:55]([O-])=O.[Na+].C([O-])=O>P([O-])([O-])([O-])=O>[Cl:1][CH2:2][C:47]([C:45]1[CH:44]=[CH:43][CH:42]=[CH:55][CH:46]=1)=[O:48]
Reactant: O=C[O-]
Reactant: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Reactant: CC(=O)c1ccccc1Cl
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: O=C(CCl)c1ccccc1
Reaction time: 72 h

Procedure:
A reaction mixture, comprising ortho-chloroacetophenone (2-chloroacetophenone; 250 mM), as well as NADH (0.04 equivalent, based on the ketone), and sodium formate (5.5 equivalents, based on the ketone) at enzyme amounts of 60 U/mmol of an (S)-ADH from R. erythropolis (expr. in E. coli) and 60 U/mmol of a formate dehydrogenase from Candida boidinii (double mutants: C23S, C262A; expr. in E. coli), is stirred at a reaction temperature of 30° C. over a period of 72 hours in 50 ml of a phosphate buffer (100 mM; pH 7.0). Samples are taken during this period of time and the particular conversion is determined via HPLC. After 72 hours, complete conversion of the ketone to the desired alcohol was found. The organic components are then extracted with 2×50 ml methyl tert-butyl ether, the aqueous phase is discarded and the organic phase is dried. The filtrate which results after filtration is freed from the readily volatile constituents in vacuo and the resulting residue is investigated in respect of the formation rate by analysis via HPLC and 1H nuclear magnetic resonance spectroscopy. A formation rate of >99% was determined (FIG. 3).
Reaction SMILES: [NH2:1][C:2]1[C:11]([I:12])=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][N:3]=1.[OH-].[K+].C1COCC1.Cl>CO.O>[NH2:1][C:2]1[C:11]([I:12])=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: COC(=O)c1cnc(N)c(I)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ncc(C(=O)O)cc1I
Temperature: 25 °C
Reaction time: 22 h
Yield: 64.5 %

Procedure:
A solution of methyl 6-amino-5-iodonicotinate (723 mg, 2.6 mmol) and potassium hydroxide (729 mg, 13.0 mmol) in 40 mL methanol/H2O (3:1 ratio) was heated at 50° C. After 4 hours 10 mL THF was added and the reaction continued until 22 hours. The reaction was cooled to room temperature and concentrated HCl added until the solution was pH 4. The solution was concentrated to a volume of 15 mL and the resulting precipitate filtered, rinsed with H2O and 40% EtOAc/hexane to give the title compound as a white solid (443 mg, 65%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[SH:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:13](O)(=O)[CH2:14][CH:15]([CH3:17])[CH3:16].O>ClCCl>[CH3:16][CH:15]([CH3:17])[CH2:14][C:13]1[S:12][C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: Nc1cnc2ccccc2c1S
Reactant: CC(C)CC(=O)O
Solvent: O
Solvent: ClCCl
Product: CC(C)Cc1nc2cnc3ccccc3c2s1
Temperature: 140 °C

Procedure:
3-Aminoquinoline-4-thiol (4.6 g) was added to polyphosphoric acid (80 g). Isovaleric acid (3.5 mL) was added and the reaction mixture was heated at 140° C. for 2 hours. The reaction mixture was poured into a mixture of ice and water (300 mL). The mixture was filtered through a layer of Celite® filter aid to remove some insoluble material. The filtrate was made alkaline with 50% sodium hydroxide while cooling with ice and then extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and then concentrated under vacuum to provide an oil. The oil was dissolved in dichloromethane and then placed on a layer of silica gel and eluted with 1:1 ethyl acetate:hexanes. The eluant was concentrated under vacuum to provide 2-(2-methylpropyl)thiazolo[4,5-c]quinoline.
Reaction SMILES: [CH3:1][CH:2]([C:4](=[CH:10][CH:11]=[C:12]([CH3:19])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])[C:5](OCC)=[O:6])[CH3:3].[H-].C([Al+]CC(C)C)C(C)C.CCCCCC.O>C1(C)C=CC=CC=1>[CH3:3][CH:2]([C:4](=[CH:10][CH:11]=[C:12]([CH3:19])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:17])[CH3:18])[CH2:5][OH:6])[CH3:1]
Reactant: CCOC(=O)C(=CC=C(C)CCC=C(C)C)C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)=CCCC(C)=CC=C(CO)C(C)C
Temperature: -72 °C
Reaction time: 0.17 h
Yield: 84.4 %

Procedure:
To a solution of ethyl 2-(1-methylethyl)-5,9-dimethyl-2,4,8-decatrienate (280 mg, 1.14 mmol) in toluene (5 ml) chilled at -72° C. under argon atmosphere was dropwise added 0.92M solution of diisobutylaluminum hydride in hexane (3.72 ml, 3.42 mmol). After stirring at -72° C. for 10 minutes, the reaction mixture was mixed with water (1.5 ml) for stopping the reaction. The reaction mixture was vigorously stirred at room temperature for 1 hour, and precipitates were filtered off. The filtrate was concentrated and the residue was chromatographed on a silica gel column to give 2-(1-methylethyl)-5,9-dimethyl-2,4,8-decatrien-1-ol (214 mg, 84%).
Reaction SMILES: [C:1]([N:8]([CH3:28])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:29][C:30]1[CH:35]=[CH:34][C:33](Br)=[CH:32][N:31]=1>Cl>[NH2:29][C:30]1[N:31]=[CH:32][C:33]([C:19]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:17]([CH:18]=2)[CH2:16][NH:15][CH:12]2[CH2:13][CH2:14][CH:9]([N:8]([CH3:28])[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:10][CH2:11]2)=[CH:34][CH:35]=1
Reactant: COc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: Nc1ccc(Br)cn1
Agent: Cl
Product: COc1ccc(-c2ccc(N)nc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 4 (900 mg, 2.29 mmol) is coupled to 2-amino-5-bromopyridine (475 mg, 2.74 mmol) using Method A. On completion, the cooled reaction mixture is diluted with 1 M HCl (10 mL) and extracted with TBME (3×10 mL). The aqueous phase is then basified to pH 9 by careful addition of solid NaHCO3 and extracted into EtOAc (50 mL) and DCM (3×50 mL). The combined organic phases are dried over Na2SO4 and reduced in vacuo to yield the crude title product.
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=1[NH:37][CH:38]=[C:39]([C:45](OCC)=[O:46])[C:40]([O:42][CH2:43][CH3:44])=[O:41]>CCCCCC>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[C:29]2[C:28]=1[NH:37][CH:38]=[C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:45]2=[O:46]
Reactant: CCOC(=O)C(=CNc1cc(C(F)(F)F)ccc1Cl)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2c(Cl)ccc(C(F)(F)F)c2c1=O
Yield: 65.3 %

Procedure:
6 mL of Dowtherm was added to a long-neck 25 mL flask, fitted with a reflux condenser. The Dowtherm was heated to 200° C. and degassed for 20 minutes. Diethyl 2-((2-chloro-5-(trifluoromethyl)phenylamino)methylene)malonate (1 g, 2.73 mmol) was then added and the solution was then heated to reflux for 2.5 h under N2. The reaction mixture was cooled after 2.5 h, then diluted with hexane (12 mL) to produce a fine, light brown precipitate. The reaction mixture was filtered, and the precipitate washed with hexane until the color was removed. The product was air dried to obtain ethyl 8-chloro-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxylate as a light brown solid (0.57 g, 65%). 1H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 8.39 (s, 1H), 8.06 (d, J=8.3 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 4.24 (q, J=7.1 Hz, 2H), 1.29 (t, J=7.1 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:7]2=[C:8]([CH:17]([CH3:19])[CH3:18])[C:9]([C:11]3[O:15][N:14]=[C:13]([CH3:16])[N:12]=3)=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.[CH2:20]([NH:22][C:23]1[CH:24]=[C:25]2[CH:31]=[CH:30][NH:29][C:26]2=[N:27][CH:28]=1)[CH3:21].C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:20]([N:22]([C:2]1[C:7]2=[C:8]([CH:17]([CH3:19])[CH3:18])[C:9]([C:11]3[O:15][N:14]=[C:13]([CH3:16])[N:12]=3)=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1)[C:23]1[CH:24]=[C:25]2[CH:31]=[CH:30][NH:29][C:26]2=[N:27][CH:28]=1)[CH3:21]
Reactant: CCNc1cnc2[nH]ccc2c1
Reactant: Cc1noc(-c2cn3ncnc(Cl)c3c2C(C)C)n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(c1cnc2[nH]ccc2c1)c1ncnn2cc(-c3nc(C)no3)c(C(C)C)c12

Procedure:
The procedure described above in Example 24 was employed. Thus, when 4-chloro-5-isopropyl-6-(3-methyl-[1,2,4]oxadiazol-5-yl)-pyrrolo[2,1-f][1,2,4]triazine (86 mg, 0.31 mmol), ethyl-(1H-pyrrolo[2,3-b]pyridin-5-yl)-amine (50 mg, 0.31 mmol) and diisopropylethylamine (162 μL, 0.93 mmol) in DMF (2.0 mL) were used, the title compound was obtained. LCMS; m/z 403 (M+H)+. Monohydrochloride salt: 1H NMR (400 MHz, DMSO-d6) δ 9.70 (1H, s), 8.20 (1H, s.), 8.02 (1H, s), 7.52 (1H, s), 7.29 (1H, s), 6.38 (1H, br. s.), 4.10 (2H, q, J=6.8 Hz), 3.24(1H, m), 2.30 (3H, s), 1.19 (3H, t, J=6.8 Hz), 0.59 (6H, d, J=7.1 Hz). (1H, m), 2.30 (3H, s), 1.19 (3H, t, J=6.8 Hz), 0.59 (6H, d, J=7.1 Hz).
Reaction SMILES: [K].C[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][C:6](=[O:8])[NH:5][C:4]1=[O:9].[C:16]1([C:26](Cl)=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.[C:29](OCC)(=O)C>O1CCCC1>[CH3:29][N:7]1[CH:3]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:4](=[O:9])[N:5]([C:26]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[O:27])[C:6]1=[O:8]
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: CC1(c2ccccc2)NC(=O)NC1=O
Reactant: CCOC(C)=O
Agent: [K]
Solvent: C1CCOC1
Product: CN1C(=O)N(C(=O)c2cccc3ccccc23)C(=O)C1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Methyl-5-phenylimidazolidine-2,4-dione potassium salt (228 mg) was suspended in tetrahydrofuran (5 mL), 1-naphthoyl chloride (188 mg) was added, and the mixture was stirred at room temperature overnight. To the reaction solution was added ethyl acetate (20 mL), and the mixture was filtered with a membrane filter (0.25 μm). After the solvent was distilled off, 364 mg of the resulting organic layer was purified by silica gel chromatography (hexane:ethyl acetate=2:1). Further recrystallization from ethyl acetate/IPE afforded 134 mg of white crystals.
Reaction SMILES: Br[C:2]1[C:3]([CH3:19])=[C:4]([CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:5]2[C:10]=1[C:9]([NH2:11])=[N:8][CH:7]=[N:6]2.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[NH:31][C:32]([NH:34][C:35]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:36]=1)=[O:33].FC1C=CC(C(F)(F)F)=CC=1NC(NC1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1)=O>>[NH2:11][C:9]1[C:10]2=[C:2]([C:38]3[CH:37]=[CH:36][C:35]([NH:34][C:32]([NH:31][C:22]4[CH:23]=[C:24]([C:27]([F:28])([F:30])[F:29])[CH:25]=[CH:26][C:21]=4[Cl:20])=[O:33])=[CH:40][CH:39]=3)[C:3]([CH3:19])=[C:4]([CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:5]2[N:6]=[CH:7][N:8]=1
Reactant: CC1(C)OB(c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3Cl)cc2)OC1(C)C
Reactant: Cc1c(Br)c2c(N)ncnn2c1CN1CCOCC1
Agent: CC1(C)OB(c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)OC1(C)C
Product: Cc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3Cl)cc2)c2c(N)ncnn2c1CN1CCOCC1
Yield: 26 %

Procedure:
The title compound was prepared in a manner similar to the procedure described for the preparation of Example 117 Step 4, using the product of step 1, Example 119 (5-bromo-6-methyl-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine in place of 5-bromo-6-methyl-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine and Intermediate AAL (1-[2-chloro-5-(trifluoromethyl)-phenyl]-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-urea) in place of Intermediate AAN (1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-urea) 44 mg (26%) of the desired product was isolated. 1H-NMR (DMSO-d6) δ 9.72 (s, 1H), 8.67-8.63 (m, 2H), 7.85 (s, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.60 (d, J=8.7 Hz, 2H), 7.39-7.30 (m, 3H), 3.80 (s, 2H), 3.53-3.50 (m, 4H), 2.42-2.39 (m, 4H), 2.09 (s, 3H); MS [M+H]+=560.2; LCMS RT=2.66.
Reaction SMILES: [C:1]([O:5][NH:6][C:7]([C@:9]1([CH3:38])[C@H:14]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=[C:29]([CH3:37])[CH:28]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:8])([CH3:4])([CH3:3])[CH3:2].CO.[C:41](O)(=O)[CH3:42].[C:45]([BH3-])#N.[Na+]>CC(C)=O>[C:1]([O:5][NH:6][C:7]([C@:9]1([CH3:38])[C@H:14]([NH:15][S:16]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=[C:29]([CH3:37])[CH:28]=3)=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH2:13][CH2:12][N:11]([CH:41]([CH3:42])[CH3:45])[CH2:10]1)=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(=O)O
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCNC[C@]3(C)C(=O)NOC(C)(C)C)cc2)c2ccccc2n1
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCN(C(C)C)C[C@]3(C)C(=O)NOC(C)(C)C)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
To 324 mg (0.599 mmol) of (3S,4R)-N-tert-butoxy-3-methyl-4-(4-((2-methylquinolin-4-yl)methoxy)phenylsulfonamido)piperidine-3-carboxamide (Example 47, Step 8) was added methanol (5 mL), acetic acid (300 μL), acetone (135 μL), and sodium cyanoborohydride (61 mg, 0.971 mmol) and the resulting reaction was stirred at room temperature overnight. The reaction mixture was then concentrated and the residue was taken up in saturated aqueous sodium carbonate and extracted with ethyl acetate (3×). the combined organic extracts were dried over Na2SO4 and purified using column chromatography on silica gel eluting with 1% methanol/CH2Cl2 to give (3S,4R)-N-tert-butoxy-1-isopropyl-3-methyl-4-(4-((2-methylquinolin-4-yl)methoxy)phenylsulfonamido)piperidine-3-carboxamide (205 mg, 0.352 mmol, 59%) as a colorless solid. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.91 (s, 3H) 1.05 (dd, J=6.57, 1.26 Hz, 5H) 1.23-1.26 (m, 8H) 1.55-1.64 (m, 4H) 1.95 (dd, J=13.64, 4.04 Hz, 1H) 2.09 (d, J=12.38 Hz, 1H) 2.27 (td, J=12.13, 3.03 Hz, 1H) 2.73-2.81 (m, 4H) 2.85 (d, J=4.29 Hz, 1H) 2.91-3.01 (m, 2H) 5.57 (d, J=1.01 Hz, 2H) 6.01 (d, J=7.33 Hz, 1H) 7.09 (ddd, J=9.41, 2.78, 2.46 Hz, 2H) 7.42 (s, 1H) 7.56 (ddd, J=8.34, 7.07, 1.26 Hz, 1H) 7.74 (ddd, J=8.46, 6.95, 1.26 Hz, 1H) 7.83-7.87 (m, 2H) 7.89-7.94 (m, 1H) 8.09 (d, J=7.83 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:11][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[C:15]([N:17]=[C:18]=[S:19])=[O:16]>CCOCC>[NH2:6][C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[NH:1][C:18](=[S:19])[NH:17][C:15](=[O:16])[C:14]1[CH:20]=[CH:21][CH:22]=[C:12]([CH3:11])[CH:13]=1)=[O:5]
Reactant: Cc1cccc(C(=O)N=C=S)c1
Reactant: NC(=O)c1ccccc1N
Solvent: CCOCC
Product: Cc1cccc(C(=O)NC(=S)Nc2ccccc2C(N)=O)c1
Reaction time: 48 h
Yield: 89.3 %

Procedure:
To a stirred mixture of 7.2 g of 2-aminobenzamide and 200 ml of ether was added dropwise, a solution of 10 g of 3-methylbenzoyl isothiocyanate over 10 minutes. After 48 hours, the solid was collected, giving 14.8 g of the desired product as grey crystals, mp 194°-196° (dec.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH:14]2[CH2:17][NH:16][CH2:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:21]1[CH:26]=[CH:25][C:24]([C@@H:27]([NH:29][C:30](=[O:32])[CH3:31])[CH3:28])=[CH:23][CH:22]=1>>[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH:14]2[CH2:17][N:16]([C:21]3[CH:26]=[CH:25][C:24]([C@@H:27]([NH:29][C:30](=[O:32])[CH3:31])[CH3:28])=[CH:23][CH:22]=3)[CH2:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)N[C@@H](C)c1ccc(Br)cc1
Reactant: c1ccc(COc2ccc(OC3CNC3)cc2)cc1
Product: CC(=O)N[C@@H](C)c1ccc(N2CC(Oc3ccc(OCc4ccccc4)cc3)C2)cc1
Temperature: 30 °C
Reaction time: 48 h

Procedure:
Example 8.5 is prepared analogously to 8.1. 3-(4-Benzyloxy-phenoxy)-azetidine and (S)—N-[1-(4-bromo-phenyl)-ethyl]-acetamide (I.1) are used as starting materials. Reaction conditions are stirring for 2 days at 30° C.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:16])[CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.C[NH:18][C@H:19]([C:30]([OH:32])=[O:31])[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1.[CH3:33]S(C)=O>>[C:30]([C@@H:19]([NH:18][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:16])[CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]([CH3:33])[CH:22]=1)([OH:32])=[O:31]
Reactant: CN[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: CS(C)=O
Reactant: O=C(O)c1cc2cc(Cl)cc(Cl)c2nc1Cl
Product: Cn1cc(C[C@H](Nc2nc3c(Cl)cc(Cl)cc3cc2C(=O)O)C(=O)O)c2ccccc21

Procedure:
In close analogy to the procedure described in Example 1, 2,6,8-trichloroquinoline-3-carboxylic acid is reacted with N-methyl-L-tryptophan in DMSO to provide the title compound in good yield.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][C@@H:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[CH2:4]1)[CH3:2].[Cl:16][S:17](O)(=[O:19])=[O:18].O>ClCCCl>[CH2:1]([N:3]1[CH2:7][CH2:6][C@@H:5]([CH2:8][C:9]2[CH:10]=[C:11]([F:15])[CH:12]=[CH:13][C:14]=2[S:17]([Cl:16])(=[O:19])=[O:18])[CH2:4]1)[CH3:2]
Reactant: O=S(=O)(O)Cl
Reactant: CCN1CC[C@@H](Cc2cccc(F)c2)C1
Solvent: ClCCCl
Solvent: O
Product: CCN1CC[C@@H](Cc2cc(F)ccc2S(=O)(=O)Cl)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (R)-1-ethyl-3-(3-fluorobenzyl)pyrrolidine (Intermediate 97, 0.24 g) in DCE (1.2 mL) was added carefully to chlorosulfonic acid and the mixture was stirred at room temperature for 2 hours. The mixture was carefully poured into iced water and extracted with DCM, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give 2-((R)-1-ethyl-pyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonyl chloride (0.36 g) as an oil which was used without further charactersiation.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.[CH3:9][NH:10][CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C.CCOC(C)=O>[CH3:9][N:10]([CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)[C:6]([C:4]1[N:3]=[N:2][NH:1][CH:5]=1)=[O:8]
Reactant: O=C(O)c1c[nH]nn1
Reactant: CNCCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)c1c[nH]nn1
Reaction time: 4 h

Procedure:
To 1H-1,2,3-triazole-4-carboxylic acid (150 mg, 1.327 mmol) and tert-butyl 4-(2-(methylamino)ethyl)piperidine-1-carboxylate (step 1) (322 mg, 1.327 mmol) in DMF (6 ml) was added DIPEA (0.695 ml, 3.98 mmol) and 50% T3P® in DMF (1.549 ml, 2.65 mmol). The resulting orange solution was stirred for 4 hrs. The mixture was diluted with EtOAc (200 ml) and washed with 1M HCl (2×50 ml). The organics were dried (MgSO4) and concentrated under reduced pressure. The crude residue in was dissolved in DCM and applied to a 12 g silica cartridge eluting with 0-100% EtOAc/iso-hexane. The product fractions were concentrated to give tert-butyl 4-(2-(N-methyl-1H-1,2,3-triazole-4-carboxamido)ethyl)piperidine-1-carboxylate as a gum.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C@@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][C:3]=1[F:20].[C:21]([Si](C)(C)C)#[CH:22].C(N(CC)CC)C>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.C1(C)C=CC=CC=1>[C:21]([C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C@@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][C:3]=1[F:20])#[CH:22]
Reactant: C#C[Si](C)(C)C
Reactant: C[C@@H](COc1ccc(Br)c(F)c1)NC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C#Cc1ccc(OC[C@H](C)NC(=O)OC(C)(C)C)cc1F
Temperature: 100 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
Under nitrogen, a mixture of tert-butyl [(1S)-2-(4-bromo-3-fluorophenoxy)-1-methylethyl]carbamate (23.3 g), ethynyl(trimethyl)silane (13.1 g), bis(triphenylphosphine)palladium(II) dichloride (4.70 g), cuprous iodide (1.27 g), triethylamine (14.0 mL), and toluene (20 mL) was stirred at 100° C. overnight. The precipitate was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in THF (200 mL), and tetrabutylammonium fluoride (1.0 M solution in THF, 201 mL) was added dropwise at room temperature. The mixture was stirred at room temperature for 2 hr. 1 M hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) and washed with hexane to give the title compound (12.2 g) as a light brown solid.
Reaction SMILES: CN(C=O)C.[F:6][C:7]([F:18])([F:17])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.[CH2:19](Br)[CH:20]=[CH2:21].C(=O)([O-])[O-].[Cs+].[Cs+]>CCOC(C)=O.O>[F:6][C:7]([F:17])([F:18])[CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:21][CH:20]=[CH2:19])=[CH:14][CH:15]=1
Reactant: C=CCBr
Reactant: Oc1ccc(OCC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCOc1ccc(OCC(F)(F)F)cc1
Temperature: 60 °C

Procedure:
To a DMF 30 ml solution of 4-(2,2,2-trifluoroethoxy)phenol (2.6 g, 13.6 mmol) and allyl bromide (3.53 ml, 40.8 mmol) was added cesium carbonate (4.85 g, 14.9 mmol). This suspension was heated to 60° C. for 18 hr, diluted with AcOEt and water. The organic layer was separated, and the aqueous layer was extracted twice with AcOEt. The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and chromatographed on silica gel eluting with 10% AcOEt/hexanes to give the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)(=[O:3])[CH3:2].[NH:14]1C2[C:17](=CC=CC=2)[CH2:16][C:15]1=[O:23].[Cl-].[Cl-].[Cl-].[Al+3].C(Cl)(=[O:30])C>>[C:1]([C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[NH:14][CH:15]=[CH:16][C:17]=3[C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[CH2:16]([C:15]([O-:23])=[O:30])[CH3:17]
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2
Reactant: O=C1Cc2ccccc2N1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Product: CCC(=O)[O-]

Procedure:
Synthesis of 5-acetyl-1,3-dihydro-indol-2-one is described by Peng Cho Tang (US2003/0069421 A1). This compound was prepared according to this procedure from 6.65 g (50 mmol) of 1,3-dihydro-indol-2-one, aluminium trichloride (150 mmol) and acetyl chloride (100 mmol) to give, after trituration in water and drying, 7.32 g (83%) of 5-acetyl-1,3-dihydro-indol-2-one in the form of a beige solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[CH3:11][CH2:12][O:13][C:14]([CH2:16][CH:17]1[C:22](=O)[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:15].[CH3:24]C(O)C>>[F:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:22]1[CH:17]([CH2:16][C:14]([O:13][CH:12]([CH3:24])[CH3:11])=[O:15])[CH2:18][CH2:19][CH2:20][C:21]2=1
Reactant: CC(C)O
Reactant: NNc1ccc(F)cc1
Reactant: CCOC(=O)CC1CCCCC1=O
Agent: Cl
Product: CC(C)OC(=O)CC1CCCc2c1[nH]c1ccc(F)cc21

Procedure:
A mixture of 1-(4-fluorophenyl)hydrazine hydrochloride (5 g), ethyl 2-cyclohexanoneacetate (5.6 g) and 2-propanol (100 ml) is refluxed under nitrogen for 9 hours. After cooling the mixture is filtered and the solution evaporated to dryness. The residue is purified through a silica gel column eluiting with methylene chloride/methanol (100/1) to give 4 g of isopropyl 6-fluoro-1,2,3,4-tetrahydrocarbazol-1-yl-acetate.