Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(#N)C.C(O[C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10])(C)(C)C.[CH3:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)C([Cl:21])=O.Cl>C(N(CC)CC)C>[ClH:21].[CH3:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9]([N:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]1)=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CN(C(=O)Cl)c1ccccc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(C(=O)N1CCNCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
An acetonitrile (7 ml) solution containing N-(tert-butoxycarbonyl)piperazine (700 mg), N-methyl-N-phenylcarbamoyl chloride (700 mg) and triethylamine (1.05 mL) was stirred at room temperature for 15 hours to undergo reaction, and the resulting compound was acid-treated with hydrochloric acid to obtain 1-(N-methyl-N-phenylaminocarbonyl)piperazine hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]3([CH2:20][NH2:21])[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[N:12]=2)=[CH:4][CH:3]=1.[F:22][C:23]([F:39])([F:38])[C:24]1[O:28][N:27]=[C:26]([C:29]2[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=2)[C:32](O)=[O:33])[N:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]3([CH2:20][NH:21][C:32](=[O:33])[C:31]4[CH:35]=[CH:36][CH:37]=[C:29]([C:26]5[N:25]=[C:24]([C:23]([F:39])([F:38])[F:22])[O:28][N:27]=5)[CH:30]=4)[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: CN1CCC(CN)(c2csc(-c3ccc(Cl)cc3)n2)CC1
Product: CN1CCC(CNC(=O)c2cccc(-c3noc(C(F)(F)F)n3)c2)(c2csc(-c3ccc(Cl)cc3)n2)CC1
Yield: 23 %

Procedure:
This compound was synthesized from (4-(2-(4-chlorophenyl)thiazol-4-yl)-1-methylpiperidin-4-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (50 mg, yield 23%). 1H NMR (400 MHz, DMSO-d6) δ 8.54-8.51 (m, 1H), 8.39 (m, 1H), 8.18-8.16 (d, J=7.6 Hz, 1H), 8.04-8.02 (d, J=7.6 Hz, 1H), 7.91-7.89 (d, J=8.2 Hz, 2H), 7.69-7.65 (t, J=7.8 Hz, 1H), 7.52-7.49 (m, 3H), 3.49-3.48 (m, 2H), 2.66-2.63 (m, 2H), 2.31-2.28 (m, 2H), 2.12-2.04 (m, 5H), 1.90-1.84 (m, 2H). MS (ESI) m/z: Calculated for C26H23ClF3N6O2S: 561.12. found: 562.0 (M+H)+.
Reaction SMILES: CO[CH2:3][CH2:4][O:5][C:6]1[N:10]=[C:9]([CH:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:14][N:13]([C:28]([O:30]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:12]2)[O:8][N:7]=1.Cl.[OH:41][CH:42]1[CH2:45][NH:44][CH2:43]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:4]([O:5][C:6]1[N:10]=[C:9]([CH:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=3)[CH2:14][N:13]([C:28]([N:44]3[CH2:45][CH:42]([OH:41])[CH2:43]3)=[O:30])[CH2:12]2)[O:8][N:7]=1)[CH3:3]
Reactant: OC1CNC1
Reactant: COCCOc1noc(C2CC(c3ccc(CC(F)(F)F)cc3)CN(C(=O)Oc3ccc([N+](=O)[O-])cc3)C2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1noc(C2CC(c3ccc(CC(F)(F)F)cc3)CN(C(=O)N3CC(O)C3)C2)n1
Temperature: 150 °C
Yield: 17.8 %

Procedure:
110 mg (0.211 mmol) of the compound from Example 67A, 69.3 mg (0.633 mmol) of 3-hydroxyazetidine hydrochloride and 72.9 mg (0.527 mmol) of potassium carbonate were added to 3.5 ml of DMF and heated in a single-mode microwave (Emrys Optimizer) at 150° C. for 20 min. For workup, the reaction solution was combined and filtered, and the residue was purified by means of preparative HPLC. Enantiomer separation of 47.7 mg of the racemate according to Method 8D gave 14.7 mg of the title compound from Example 96 (enantiomer 1) and 17.1 mg of the title compound from Example 97 (enantiomer 2).
Reaction SMILES: S([O-])(OC(C)(C)S(OC1C=CC(O)=CC=1)(=O)=O)(=O)=O.[C:20]([OH:43])(=O)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=[CH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].C1(N=C=NC2CCCCC2)CCCCC1.[NH2:59][C@@H:60]([C:63]([OH:65])=[O:64])[CH2:61][OH:62].C(N(CC)CC)C>C(#N)C.O>[C:20]([NH:59][C@@H:60]([C:63]([OH:65])=[O:64])[CH2:61][OH:62])(=[O:43])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=[CH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCCCC=CC=CC=CC=CC=CC=CC(=O)O
Reactant: N[C@H](CO)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(OS(=O)(=O)[O-])S(=O)(=O)Oc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CCCCCCCCCC=CC=CC=CC=CC=CC=CC(=O)N[C@H](CO)C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 40.9 %

Procedure:
4-hydroxyphenyldimethylsulfomethyl sulfate (trade name: SANCELER-DSP, manufactured by Sanshin Kagaku Kogyo Co., Ltd.) 2.66 g (0.01 mol) was heated and dissolved in 40 ml of acetonitrile. Docosahexaenoic acid 3.28 g (0.01 mol) was added to the solution obtained in a stream of nitrogen, and stirred at 0° C. To the mixture solution, dicyclohexyl carbodiimide 2.06 g (0.01 mol) was added little by little, and the solution was stirred for 2 hours at 0° C. and then for 2 hours at room temperature. The solution reacted was filtered to remove dicyclohexyl urea, and the filtrate was distilled in vacuo to obtain oily residue. D-serine 1.05 g (0.01 mol) and triethyl amine 1.4 ml (0.01 mol) were added to 10 ml of water. An acetonitrile solution of the above oily residue was added to the mixture with stirring, and stirred for 10 hours at room temperature. After reaction, the reaction mixture was concentrated under reduced pressure. The concentrate was adjusted to pH 2 or 3 with 6N-HCl, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium acetate, and freed of solvent in vacuo. The oily residue obtained was purified by column chromatography (column: 2.5×15 cm) on 50 g of silica gel and N-docosahexaenoyl-D-serine 1.7 g was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:30])[C:16]([NH:18][C@H:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([OH:29])=[CH:24][CH:25]=3)[CH2:20]2)=O)=[CH:11][C:10]=1[CH2:31][CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N(CCO)(CCO)CCO.O>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:30])[CH2:16][NH:18][C@H:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([OH:29])=[CH:24][CH:25]=3)[CH2:20]2)=[CH:11][C:10]=1[CH2:31][CH2:32][O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@H]1CCc2ccc(O)cc2C1)[C@H](O)c1ccc(OCc2ccccc2)c(CCOCc2ccccc2)c1
Solvent: OCCN(CCO)CCO
Solvent: O
Solvent: C1CCOC1
Product: Oc1ccc2c(c1)C[C@@H](NC[C@H](O)c1ccc(OCc3ccccc3)c(CCOCc3ccccc3)c1)CC2
Yield: 65.3 %

Procedure:
(-)-(2R)-2-[4-Benzyloxy-3-(2-benzyloxyethyl)phenyl]-2-hydroxy-N-((2S)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide (low polarity isomer) (1.08 g) was dissolved in 20 ml of tetrahydrofuran, 438 μl of borane-dimethylsulfide complex was added to the solution, and the mixture was heated under reflux for 3 hours. Then, a solution of 1.14 g of triethanolamine in 1 ml of tetrahydrofuran was added and the mixture was again heated under reflux for 6 hours. After cooling, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was evaporated under reduced pressure and the resulting residue was recrystallized from ethyl acetate to give 687 mg of (-)-(1R)-1-[4-benzyloxy-3-(2-benzyloxyethyl)phenyl]-2-((2S)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-ylamino)ethanol having a melting point of 147 to 150° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13](=[O:14])[CH2:12][CH:11]([OH:15])[C:10]2=[O:16])=[CH:4][CH:3]=1.N1C=CC=CC=1.[Br:23][CH2:24][C:25](Br)=[O:26]>ClCCl>[Br:23][CH2:24][C:25]([O:15][CH:11]1[CH2:12][C:13](=[O:14])[N:9]([CH2:8][C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:10]1=[O:16])=[O:26]
Reactant: O=C1CC(O)C(=O)N1Cc1ccc(Cl)nc1
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CBr)OC1CC(=O)N(Cc2ccc(Cl)nc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
1.34 g (5.56 mmol) of 1-[(6-chloropyridin-3-yl)methyl]-3-hydroxypyrrolidin-2,5-dione (XI-1a) and 674 μl (8.34 mmol) of pyridine are dissolved in 15 ml of dichloromethane, and 1.12 g (5.56 mmol) of bromoacetyl bromide are added at 0° C. The mixture is stirred at room temperature for 30 minutes, and ice-water is then added. The organic is washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (silica gel 60, Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture dichloromethane:methanol (97:3) gives 1.44 g (55% of theory) of 1-[(6-chloropyridin-3-yl)methyl]-2,5-dioxopyrrolidin-3-yl bromoacetate.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([NH:15][C:16]([C:18]3[NH:19][C:20]4[C:25]([CH:26]=3)=[C:24]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH:23]=[CH:22][CH:21]=4)=[O:17])[CH2:11][CH2:10]2)[CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.Cl.[F:33]C1CCCNC1.CCN(C(C)C)C(C)C.[I-].C(C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#N>C(#N)CC.CCOC(C)=O>[F:33][CH:5]1[CH2:4][CH2:3][CH2:2][N:1]([CH2:7][CH2:8][N:9]2[CH2:10][CH2:11][CH:12]([NH:15][C:16]([C:18]3[NH:19][C:20]4[C:25]([CH:26]=3)=[C:24]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH:23]=[CH:22][CH:21]=4)=[O:17])[CH2:13][CH2:14]2)[CH2:6]1
Reactant: FC1CCCNC1
Reactant: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(CCN4CC=CCC4)CC3)cc12
Agent: Cl
Agent: N#CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCCC(F)C4)CC3)cc12
Temperature: 90 °C

Procedure:
To a suspension of 190 (see example 150) (100 mg, 0.28 mmol), 3-fluoropiperidine hydrochloride (43 mg, 0.208 mmol) and DIEA (0.189 ml, 1.12 mmol) in 0.5 ml of propionitrile is added cyanomethyl-triphenyl phosphonium iodide (81 mg, 0.336 mmol). The mixture is heated at 90° C. for 14 hours. The resulting solution is then diluted with EtOAc (20 ml) and washed twice with saturated sodium bicarbonate, dried over sodium sulfate and evaporated. The crude product is further purified by preparative HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[O:17])[CH:11]=1.C(N(CC)CC)C>[Br-].C([N+]1C(C)=C(CCO)SC=1)C.C(O)C>[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16](=[O:17])[CH:4]([C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[Br:1])[OH:5])[CH:11]=1
Reactant: O=Cc1cccnc1
Reactant: O=Cc1ccccc1Br
Agent: CC[n+]1csc(CCO)c1C
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(c1cccnc1)C(O)c1ccccc1Br

Procedure:
146 g (0.8 mol) of 2-bromobenzaldehyde, 85.6 g (0.8 mol) of 3-pyridinealdehyde, 20 g (0.08 mol) of 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazoliumbromide and 40.4 g (0.4 mol) of triethylamine in 500 ml of ethanol were heated at 75° C. for 16 hours. Thereafter, the ethanol was distilled off and the residue was taken up in methylene chloride. The solution was washed twice with water and then extracted twice with 300 ml of 4N hydrochloric acid. The acidic aqueous phase was then rendered slightly alkaline with 4N sodium hydroxide solution and extracted three times with methylene chloride. After the solvent had been distilled off, the crude product was stirred with isopropanol, filtered off under suction and dried to give a product of melting point 105°-108° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:9]([C:15](Cl)=[O:16])=[C:8]([CH3:18])[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][C:5]=2[N:4]=1.Cl.[C:23]([O:27][C:28](=[O:32])[CH2:29][CH2:30][NH2:31])([CH3:26])([CH3:25])[CH3:24]>>[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:9]([C:15]([NH:31][CH2:30][CH2:29][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:32])=[O:16])=[C:8]([CH3:18])[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][C:5]=2[N:4]=1
Reactant: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)Cl)c2nc1OC
Reactant: CC(C)(C)OC(=O)CCN
Agent: Cl
Product: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)NCCC(=O)OC(C)(C)C)c2nc1OC
Reaction time: 2.5 h

Procedure:
Prepared from 2,3-dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonyl chloride (13) 250 mg (0.80 mmol) and β-alanine tert-butyl ester hydrochloride 153 mg (0.80 mmol). Reaction was continued for 2.5 hours, and the crude product was eluted through a flash column (3:2 hexanes:ethyl acetate), 230 mg (68%), mp 140-142° C., Rf 0.47 (1:1 hexanes:ethyl acetate); 1H NMR (CDCl3): δ 8.31 (s, 1H), 6.37 (br s, 1H), 4.08 (s, 3H), 3.97 (s, 3H), 3.74 (q, 2H, methylene protons, J=6.1 Hz), 2.57 (t, 2H, J=6.3 Hz, J=6.1 Hz), 2.55 (s, 3H), 1.42 (s, 9H); MS (APCI): m/z 421 (M+H). Anal. Calcd. for C19H24N4O7: C, 54.28; H, 5.75; N, 13.33. Found: C, 54.25; H, 5.69; N, 13.00.
Reaction SMILES: C[C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][CH:5]([C:12]([OH:14])=O)[CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8].[C:19]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:38][C:39]1[CH:51]=[CH:50][C:42]2OC3C=CC=CC=3[C:41]=2[CH:40]=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH:15]1[C:16]2[C:40]3[CH:41]=[CH:42][CH:50]=[CH:51][C:39]=3[O:38][C:17]=2[CH:18]=[CH:2][C:3]=1[O:4][CH:5]1[CH2:6][CH:7]([C:9]([O:11][CH3:19])=[O:10])[NH:8][C:12]1=[O:14]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1ccccc1OC(C[C@H](N)C(=O)O)C(=O)O
Reactant: Oc1ccc2oc3ccccc3c2c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Product: COC(=O)C1CC(Oc2ccc3oc4ccccc4c3c2)C(=O)N1
Temperature: 2 °C
Reaction time: 15.5 h
Yield: 41.6 %

Procedure:
A mixture of the compound prepared as described in Example 4 (0.800 g), triphenylphosphine (1.450 g), and 2-hydroxydibenzofuran(1.019 g) intetrahydrofuran (7.0 ml) was cooled to approximately 2° C., and treated with a solution of diethylazodicarboxylate (0.963 g) in tetrahydrofuran (2.0 ml) over a two minute period. After the addition was complete, the reaction was allowed to warm to room temperature. After about 15.5 hours, the solution was concentrated in vacuo. The residue was diluted with toluene (5 ml), the insoluble material removed by filtration, and the filtrate concentrated is vacuo. The oil was dissolved in ethyl acetate and purified by preparative centrifugal thin-layer chromatography (4 mm plate, flow rate=8 ml/min), eluting with ethyl acetate/hexane (1:1) until first band elutes then solvent switched to hexane:ethyl acetate (1:3). The fractions containing the title compound were combined, dried over magnesium sulfate, filtered and concentrated in vacuo to give methyl 3-(2-dibenzofuranoxy)-2-pyrrolidone-5-carboxylate (427 mg). This material contains triphenylphosphine oxide as an impurity.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[OH:25].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[O:25][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: Cc1cccc(C)c1O
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cccc(C)c1OCc1ccc(-c2cc(C(N)=O)on2)cc1
Temperature: 90 °C
Yield: 81.2 %

Procedure:
To a mixture of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 30 mg, 0.107 mmol) in CH3CN (2 mL) were added 2,6-dimethylphenol (22 mg, 0.18 mmol) and K2CO3 (30 mg, 0.22 mmol). The mixture was heated at 90° C. for 16 h and then evaporated to dryness. The residue was purified by chromatography (66-75% EtOAc/hexanes) to give 3-[4-(2,6-dimethyl-phenoxymethyl)-phenyl]-isoxazole-5-carboxylic acid amide (28 mg, 81%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.39 (br. s., 1H), 8.01 (br. s., 1H), 7.94 (d, J=8.4 Hz, 2H), 7.55-7.69 (m, 3H), 7.00-7.09 (m, 2H), 6.88-6.98 (m, 1H), 4.86 (s, 2H), 2.25 (s, 6H).
Reaction SMILES: [CH:1]1[C:6]([CH2:7][C:8]([NH2:10])=[O:9])=[CH:5][CH:4]=[C:3]([OH:11])[CH:2]=1.[OH-].[Na+].[CH2:14]([CH:16]1[O:18][CH2:17]1)Cl.Cl.[CH:20]([NH2:23])([CH3:22])[CH3:21]>O>[CH3:21][CH:20]([NH:23][CH2:14][C@H:16]([OH:18])[CH2:17][O:11][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]([NH2:10])=[O:9])=[CH:1][CH:2]=1)[CH3:22]
Reactant: CC(C)N
Reactant: NC(=O)Cc1ccc(O)cc1
Reactant: ClCC1CO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)NC[C@H](O)COc1ccc(CC(N)=O)cc1
Temperature: 5 °C
Reaction time: 24 h
Yield: 96.9 %

Procedure:
p-Hydroxyphenylacetamide (30.02 g) was dissolved in 106.5 g of water containing sodium hydroxide (9.6 g) and the solution was cooled to 5° C. Epichlorohydrin (18.5 g, 98.9% e.e.) was dropped in the solution over a period of 10 minutes and the mixture was stirred for 24 hours at the same temperature. After confirmation of the progress of the reaction being 98% by HPLC, the reaction mixture was neutralized with 0.1 N hydrochloric acid at the same temperature and then dropped in isopropylamine (240 g) under cooling to 10° C. over a period of 1 hour and the reaction temperature was raised to room temperature and stirred for 3.5 hours. After the reaction, the reaction mixture was condensed in vacuo until crystals beginning to separate, cooled and filtrated by suction and dried in vacuo to give crude (S)-atenolol (51.26 g). The optical purity of it was 91.2% e.e. by measurement of Chiral column OD (Daisel Chemical Industries Ltd.).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:15])[CH2:12][CH2:13][CH3:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[CH2:16]([O:18][C:19]1[CH:20]=[CH:21][C:22]([NH2:26])=[N:23][C:24]=1[CH3:25])[CH3:17]>>[CH2:16]([O:18][C:19]1[CH:20]=[CH:21][C:22]([NH:26][CH:4]=[C:5]([C:11](=[O:15])[CH2:12][CH2:13][CH3:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[N:23][C:24]=1[CH3:25])[CH3:17]
Reactant: CCCC(=O)C(=COCC)C(=O)OCC
Reactant: CCOc1ccc(N)nc1C
Product: CCCC(=O)C(=CNc1ccc(OCC)c(C)n1)C(=O)OCC

Procedure:
Ethyl 2-(ethoxymethylene)-3-oxohexanoate (22.4 g) was added to a suspension of 5-ethoxy-6-methylpyridin-2-amine (14.9 g) in IMS (50 ml). After the initial exotherm had subsided IMS (100 ml) was added and the mixture boiled under reflux until a solution was obtained. This solution was cooled and filtered to give ethyl 2-(5-ethoxy-6-methylpyrid-2-ylaminomethylene)-3-oxohexanoate, m.p. 117°-120° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Cl:7][C:8]1[CH:9]=[C:10]([C@H:15]2[CH2:19][CH2:18][N:17]([C@H:20]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=4)[C:21]3=[O:35])[CH2:16]2)[CH:11]=[C:12]([Cl:14])[CH:13]=1>N1C=CC=CC=1.CS(C)=O>[Cl:14][C:12]1[CH:11]=[C:10]([C@H:15]2[CH2:19][CH2:18][N:17]([C@H:20]3[CH2:24][CH2:23][N:22]([C:25]4[CH:26]=[CH:27][C:28]([S:31]([NH:1][C:2]5[S:3][CH:4]=[CH:5][N:6]=5)(=[O:32])=[O:33])=[CH:29][CH:30]=4)[C:21]3=[O:35])[CH2:16]2)[CH:9]=[C:8]([Cl:7])[CH:13]=1
Reactant: O=C1[C@@H](N2CC[C@H](c3cc(Cl)cc(Cl)c3)C2)CCN1c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nccs1
Solvent: CS(C)=O
Solvent: c1ccncc1
Product: O=C1[C@@H](N2CC[C@H](c3cc(Cl)cc(Cl)c3)C2)CCN1c1ccc(S(=O)(=O)Nc2nccs2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Synthesized according to General Procedure 12, Method A: To a solution of 2-aminothiazole (15.9 mg, 0.16 mmol) in pyridine (0.4 mL) was added 4-[(3R,3′S)-3-(3,5-dichlorophenyl)-2′-oxo-1,3′-bipyrrolidin-1′-yl]benzene-1-sulfonyl chloride (25 mg, 0.05 mmol) and the reaction mixture was stirred at RT for 1 hour. The reaction mixture was diluted with DMSO, filtered and purified by reverse phase HPLC using 5%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) to afford the desired product.
Reaction SMILES: [BH4-:1].[Na+:2].[C:3]([OH:6])(=[O:5])[CH3:4]>C1C=CC=CC=1>[C:3]([O:6][BH-:1]([O:6][C:3](=[O:5])[CH3:4])[O:5][C:3](=[O:6])[CH3:4])(=[O:5])[CH3:4].[Na+:2]
Reactant: CC(=O)O
Reactant: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(=O)O[BH-](OC(C)=O)OC(C)=O

Procedure:
A suspension of sodium borohydride (69.8 mg.) in benzene (15 ml.) is treated with acetic acid (92 mg.) and refluxed for 1 hour under nitrogen to afford a clear solution of sodium triacetoxyborohydride. To this solution is added a solution of 2S,3R,6R-6-(2-oxoethyl)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane (158 mg.) in benzene (5 ml.) and the mixture refluxed for 5 hours under nitrogen. The solvent is removed in vacuo, the residue diluted with water and extracted with methylene chloride. Removal of the solvent from the dried organic phase affords a residue which is plate chromatographed on silica gel, using ethyl acetate:chloroform (4:1) as the developing solvent. The major band is eluted with ethyl acetate to afford 2S,3R-6-(2-hydroxyethyl)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane (121 mg.):
Reaction SMILES: [CH3:1][C:2]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][NH:3]1.Cl[CH2:20][C:21]([N:23]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[F:40])[CH:24]1[CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25]1)=[O:22].[C:41](=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH2:1]([C:2]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]1[CH2:20][C:21]([N:23]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[F:40])[CH:24]1[CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25]1)=[O:22])[CH3:41]
Reactant: O=C([O-])[O-]
Reactant: O=C(CCl)N(Cc1ccccc1F)C1Cc2ccccc2C1
Reactant: Cc1ccccc1C1(C)NCCc2ccccc21
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCC1(c2ccccc2C)c2ccccc2CCN1CC(=O)N(Cc1ccccc1F)C1Cc2ccccc2C1

Procedure:
A mixture of 1-Methyl-1-o-tolyl-1,2,3,4-tetrahydro-isoquinoline (96 mg, 0.40 mmol), 2-chloro-N-(2-fluoro-benzyl)-N-indan-2-yl-acetamide (147 mg, 0.40 mmol), and potassium carbonate (111 mg, 0.80 mmol) in actonitrile (10 ml) is heated at reflux for 30 hours. The reaction mixture is cooled, treated with water, and extracted with ethyl acetate. The combined extracts are washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue is purified by preparative thin layer chromatography to give 2-(1-Ethyl-1-o-tolyl-3,4-dihydro-1H-isoquinolin-2-yl)-N-(2-fluoro-benzyl)-N-indan-2-yl-acetamide (Compound 4) as a pale yellow oil. LSMS 519.3 (MH+).
Reaction SMILES: Cl.[C:2]([CH2:10][N:11]1[CH2:16][CH2:15][N:14]([NH:17][CH2:18][C:19]#[N:20])[CH2:13][CH2:12]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:21]([O-])=[O:22].[Na+]>O>[C:2]([CH2:10][N:11]1[CH2:12][CH2:13][N:14]([N:17]([CH2:18][C:19]#[N:20])[N:21]=[O:22])[CH2:15][CH2:16]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=N[O-]
Reactant: N#CCNN1CCN(CC(=O)c2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N#CCN(N=O)N1CCN(CC(=O)c2ccccc2)CC1

Procedure:
A solution prepared by adding 10 ml of water and 19 ml of 1N hydrochloric acid to 1.6 g of 4-(benzoylmethyl)-1-(cyanomethylamino)piperazine was cooled to 4° to 5° C., and with stirring, 1.7 g of sodium nitrite was added. The mixture was reacted at 4° to 5° C. for 1.5 hours with stirring. The reaction mixture was extracted with chloroform. The extract was washed with water and dried, and chloroform was distilled off to give 4-(benzoylmethyl)-1-(N-nitrosocyanomethylamino)piperazine as a red oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[CH3:19].[H-].[Na+].I[CH:23]([CH3:25])[CH3:24]>>[Cl:1][C:2]1[C:10]2[C:6](=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=3[CH3:19])[N:8]([CH:23]([CH3:25])[CH3:24])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2n[nH]c3c(Cl)cccc23)c(C)c1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2c3cccc(Cl)c3nn2C(C)C)c(C)c1
Yield: 36 %

Procedure:
Prepared according to Example 101 from 7-chloro-3-(4-methoxy-2-methylphenyl)-1H-indazole (0.150 g, 0.52 mmol), sodium hydride (60% in oil, 0.025 g, 1.04 mmol) and 2-iodopropane (0.07 mL, 0.7 mmol) to give the title compound (0.059 g) as a white solid.