Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[N:28]1([C:2]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:3]=2[C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)=[O:5])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: C1COCCN1
Reactant: CC(=O)c1ccc(N2CCN(C(=O)c3cc([N+](=O)[O-])ccc3F)CC2)cc1
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc([N+](=O)[O-])ccc3N3CCOCC3)CC2)cc1

Procedure:
The title compound was prepared according to the procedure described for example 1 from 1-{4-[4-(2-Fluoro-5-nitro-benzoyl)-piperazin-1-yl]-phenyl}-ethanone and morpholine (85%, yellow solid, MS (m/e): 439.3 (M+H, 100%)
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[CH:13][C:12]([C:25](O)=[O:26])=[C:11]([OH:28])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N=C=N.[Cl:32][C:33]1[CH:34]=[C:35]([C:40]2[CH:45]=[CH:44][C:43]([CH2:46][C@@H:47]([NH2:54])[C:48]3[O:52][N:51]=[C:50]([CH3:53])[N:49]=3)=[CH:42][CH:41]=2)[CH:36]=[CH:37][C:38]=1[F:39]>C1COCC1.ClCCCl>[Cl:32][C:33]1[CH:34]=[C:35]([C:40]2[CH:45]=[CH:44][C:43]([CH2:46][C@@H:47]([NH:54][C:25]([C:12]3[CH:13]=[C:14]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:19][CH:20]=4)[C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:10][C:11]=3[OH:28])=[O:26])[C:48]3[O:52][N:51]=[C:50]([CH3:53])[N:49]=3)=[CH:42][CH:41]=2)[CH:36]=[CH:37][C:38]=1[F:39]
Reactant: Cc1noc([C@H](N)Cc2ccc(-c3ccc(F)c(Cl)c3)cc2)n1
Reactant: O=C(O)c1cc(-c2ccc(C(F)(F)F)cc2)c(OCc2ccccc2)cc1O
Agent: N=C=N
Solvent: C1CCOC1
Solvent: ClCCCl
Product: Cc1noc([C@@H](Cc2ccc(-c3ccc(F)c(Cl)c3)cc2)NC(=O)c2cc(-c3ccc(C(F)(F)F)cc3)c(OCc3ccccc3)cc2O)n1
Reaction time: 12 h
Yield: 20.6 %

Procedure:
To a solution of 6-Benzyloxy-4-hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid (52 mg, 0.13 mmol) in THF:DCE (1:1, 2 mL) was added PS-Carbodiimide resin (0.14 g, 1.3 mmol/g) and 2-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylamine (0.03 g, 0.09 mmol) and stirred for 12 h, resin was filtered and washed with EtOAc (5 mL), filtrate was concentrated and silicagel chromatography of the residue gave pure 6-Benzyloxy-4-hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid [2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide (0.013 g).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC(OC)=CC=2)=CSC=1C([O:39][CH3:40])=O.C(OCC)(OCC)OCC.[Cl:51]C1C=CC(N)=CC=1>C(O)(=O)C>[Cl:51][C:4]1[CH:5]=[CH:6][C:1]([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][C:20]([O:39][CH3:40])=[CH:21][CH:22]=4)[C:10]=3[N:9]=[CH:8]2)=[CH:2][CH:3]=1
Reactant: COC(=O)c1scc(-c2ccc(OC)cc2)c1N
Reactant: Nc1ccc(Cl)cc1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: COc1ccc(-c2csc3c(=O)n(-c4ccc(Cl)cc4)cnc23)cc1
Yield: 86.9 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(4-methoxyphenyl)thiophene-2-carboxylate (80 mg, 0.3 mmol), triethyl orthoformate (0.66 ml), 4-chloroaniline (71.2 mg, 0.56 mmol), and acetic acid (0.08 ml) were used to give 96.2 mg (0.26 mmol, 86.9% yield) of the title compound.
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[C:5]([O:10]C)=[N:6][CH:7]=[CH:8][CH:9]=1.B(Br)(Br)Br.O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CCCCCCC>[F:12][CH:2]([F:1])[O:3][C:4]1[C:5]([OH:10])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: COc1ncccc1OC(F)F
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCCCCCC
Product: Oc1ncccc1OC(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97 %

Procedure:
As shown in step 3(a)-iii of Scheme 3(a), 3-(difluoromethoxy)-2-methoxypyridine (270 mg, 1.54 mmol) was dissolved in 5 mL of DCM and BBr3 (540 μL; 1275 mg; 4.10 mmol) in heptane was added. The reaction mixture was stirred for 10 minutes at RT under an atmosphere of nitrogen, brought to reflux, and then stirred an additional 4 hours. The mixture was cooled and water was added to quench the reaction. The pH was adjusted to 7-8 with sodium bicarbonate, the organics partitioned, and the aqueous layer saturated with NaCl and extracted twice more with DCM. The combined organics were dried over Na2SO4, filtered, and the volatiles removed under reduced pressure. The product was purified by silica gel chromatography (DCM to 5% MeOH/DCM gradient) to yield 3-(difluoromethoxy)pyridin-2-ol as a white solid (Compound 2008, 986 mg, 97% yield): ESMS (M+H) 162.
Reaction SMILES: O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].[NH:12]([C:16]1[S:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N+:27]([O-])=O)[N:20]=1)[C:13]([NH2:15])=[NH:14]>CO.O>[NH:12]([C:16]1[S:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[NH2:27])[N:20]=1)[C:13]([NH2:15])=[NH:14]
Reactant: N=C(N)Nc1nc(-c2ccccc2[N+](=O)[O-])cs1
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: CO
Product: N=C(N)Nc1nc(-c2ccccc2N)cs1
Temperature: 60 °C
Yield: 82.8 %

Procedure:
A solution of 57 gm of sodium sulfide octahydrate in 400 ml of methanol and 120 ml of water was added dropwise over a period of 300 minutes to a hot (60° C.) solution of 16.9 gm of 2-guanidino-4-(2-nitro-phenyl)-thiazole in 120 ml of methanol. After an additional 2 hours of heating at 60° C., the solution was filtered with charcoal and evaporated to dryness. The residual solid was suspended in water, filtered off and dried, yielding 12.4 gm of the title compound, m.p. 198°-200° C.
Reaction SMILES: C([O:3][C:4](=O)[C@H:5]([CH2:14][C:15](OCC)=[O:16])[NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])C.[BH4-].[Na+]>C(O)C.[Cl-].[Na+].O>[C:10]([O:9][C:7]([NH:6][C@@H:5]([CH2:14][CH2:15][OH:16])[CH2:4][OH:3])=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CCOC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)OCC
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CO)CCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
A stirred solution of (S)-N-BOC diethyl Laspartate 3 (47.41 g, 0.16 mol) in absolute ethanol (770 ml) was cooled in ice, then sodium borohydride (60.8 g, 1.6 mol) was added in 10 g portions. The cooling bath was removed when the reaction subsided, and the reaction mixture was heated slowly to reflux for 1 h; after this time TLC (EtOAc-EtOH 3:1) analysis indicated complete consumption of the starting material. The reaction mixture was cooled to 25° C., and the lumps formed were broken-up to give a slurry that was poured into brine (450 ml). The mixture was filtered, the filtrate concentrated in vacuum to ca. 100 ml, and was extracted with ether (6×300 ml). The insoluble solid material was extracted by stirring in ether (4×1 L) for 2 h. The combined ether extracts were dried over MgSO4, filtered and concentrated to give 4 as a colourless oil (24 g, 73%), which crystallised on standing. Spectral data for this sample were consistent with those given in the literature2. 1H NMR (200 MHz, d6-DMSO) 6.45 (d, J=8.4 Hz, 1H), 4.57 (t,J=5.6 Hz, 1H), 4.35 (t,J=5.1 Hz, 1H), 3.40 (m, 4H), 3.23 (m, 1H), 1.62 (m, 1H), 1.40 (m, 1H), 1.36 (s, 9H); 13C NMR (50 MHz, d6-DMSO) 155.5, 77.4, 63.5, 58.0, 49.6, 34.4, 2.83.
Reaction SMILES: [OH:1][CH:2]([CH3:6])[C:3]([NH2:5])=[O:4].[C:7]([Si:11](Cl)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:10])([CH3:9])[CH3:8].N1C=CN=C1>CN(C)C1C=CN=CC=1.CN(C=O)C>[Si:11]([O:1][CH:2]([CH3:6])[C:3]([NH2:5])=[O:4])([C:7]([CH3:10])([CH3:9])[CH3:8])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(O)C(N)=O
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(N)=O
Temperature: 90 °C

Procedure:
2-hydroxy-propanamide (227 mg, 2.55 mmol), DMF (2 ml), tert-butylchlorodiphenyl-silane (1.0 ml, 1057 mg), imidazole (266 mg, 3.91 mmol) and 4-dimethylaminopyridine (93 mg, 0.764 mmol) dissolved in DMF (2 ml) were stirred under nitrogen atmosphere over the weekend. After the weedend the temperature was raised to 90° C. and was left to react for another 4 h. The mixture was then evaporated and extracted with DCM/water and the combined organic phases were evaporated. The product was purified by column chromatography. 1H-NMR (400 MHz; DMSO-d6): δ 1.04 (d, 9H), 1.12 (d, 3H), 4.00 (q, 1H), 7.04 (bs, 1H), 7.24 (bs, 1H), 7.40-7.51 (m, 6H), 7.58-7.66 (m, 4H).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].C(N(C(C)C)CC)(C)C.[Si:15](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[Si:15]([O:4][CH2:3][CH2:2][CH2:1][OH:5])([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCCCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](OCCCO)(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 78.4 %

Procedure:
A solution of 1,3-propanediol (4.22 g, 55 mmol) in anhydrous CH2Cl2 (10 mL) under argon was treated with diisopropylethyl amine (10 mL) and tert-butyldiphenylsilyl chloride (5.00 mL, 5.29 g, 19.23 mmol). Stirring was continued for 2 h. The sample was concentrated, and the residue was purified by column chromatography (silica, hexanes/ethyl acetate (10:1)] affording a colorless oil (4.74 g, 78%): 1H NMR δ 1.07 (s, 9H), 1.78-1.86 (m, 2H), 2.46-2.50 (m, 1H), 3.83-3.88 (m, 4H), 7.37-7.48 (m, 6H), 7.68-7.75 (m, 4H); 13C NMR δ 19.33, 27.08, 34.52, 62.11, 63.46, 128.01, 130.03, 133.50, 135.80; FAB-MS obsd 315.1779, calcd 315.1780 [(M+H)+, M=C19H26O2Si].
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C:4](=[O:7])[CH2:3]1.[CH3:8][C:9]([Si:12](Cl)([CH3:14])[CH3:13])([CH3:11])[CH3:10].N1C=CN=C1.O>CN(C=O)C>[Si:12]([O:1][C@H:2]1[CH2:6][NH:5][C:4](=[O:7])[CH2:3]1)([C:9]([CH3:11])([CH3:10])[CH3:8])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1C[C@@H](O)CN1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CNC(=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
To a suspension of (R)-4-hydroxypyrrolidin-2-one (purchased from Asta Tech or Aldrich) (5.030 g, 48.26 mmol) in DMF (24 mL) at 0° C. was added TBDMS-Cl (7.637 g, 50.67 mmol) followed by imidazole (4.978 g, 72.39 mmol). The resulting mixture was warmed to ambient temperature and stirred for 1 hour, then poured into 100 mL of water with stirring. The resulting suspension was filtered and the solids were washed with water and dried under reduced pressure to afford (R)-4-(tert-butyldimethylsilyloxy)pyrrolidin-2-one (10.14 g, 97.56% yield) that was used directly without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH2:34][CH2:35][CH3:36])[CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21]1>>[C:33]([NH:32][C:28]1[CH:27]=[C:26]([CH:23]2[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][CH2:17][NH:16][C:13]([C:8]3([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10][CH2:11][CH2:12]3)=[O:15])[CH2:21][CH2:22]2)[CH:31]=[CH:30][CH:29]=1)(=[O:37])[CH2:34][CH2:35][CH3:36]
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCC1
Reactant: CCCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CCCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(F)cc4)CCCC3)CC2)c1

Procedure:
Example 101 was prepared from 1-(4-fluorophenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.51 (s, 1H), 7.37–7.24 (m, 6H), 7.02–6.95 (m, 2H), 6.51 (br s, 1H), 3.28 (dd, 2H, J=5.6, 11.6 Hz), 2.93 (d, 2H, J=11.6 Hz), 2.53–2.48 (m, 3H), 2.37–2.30 (m, 4H), 1.98–1.92 (m, 4H), 1.82–1.59 (m, 12H), 1.02 (t, 3H, J=7.6 Hz); ESMS m/e: 494.3 (M+H)+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[C:5]=1[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].[CH:19](OCC)=[O:20].C(O)(=O)C>COCCOC>[CH:19]([CH:13]([CH2:12][C:5]1[C:4]([F:3])=[CH:9][C:8]([F:10])=[CH:7][C:6]=1[F:11])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:20]
Reactant: CCOC(=O)CCc1c(F)cc(F)cc1F
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CC(=O)O
Product: CCOC(=O)C(C=O)Cc1c(F)cc(F)cc1F
Reaction time: 8 h
Yield: 100 %

Procedure:
To a suspension of NaH (1.240 g, 31.0 mmol) in DME (15 mL) was added dropwise a solution of ethyl 3-(2,4,6-trifluorophenyl)propanoate (1.8 g, 7.75 mmol) and ethyl formate (3.12 mL, 38.8 mmol) in DME (15 mL) at room temperature. The reaction mixture was then stirred overnight. It was neutralized with acetic acid (1.8 mL), then extracted with EA. The organic layer was collected, washed with brine, dried over Na2SO4, filtered, and concentrated to afford the title compound (2.017 g, 100% yield). LCMS: rt=2.98 and 3.67 min, [M+H+]=261.0, as a mixture of ketone (RT=2.98 min) and enol (RT=3.67 min) isomer.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:18]=[C:17]([CH3:19])[C:16]([OH:20])=[C:15]([CH3:21])[CH:14]=3)[N:9]=2)=[CH:5][CH:4]=1)[CH3:2].[CH2:22]([CH:24]1[O:26][CH2:25]1)Cl>C(O)(C)C.[OH-].[Na+].C(OCC)C>[CH3:21][C:15]1[CH:14]=[C:13]([C:10]2[N:9]=[C:8]([C:6]3[S:7][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=3)[O:12][N:11]=2)[CH:18]=[C:17]([CH3:19])[C:16]=1[O:20][CH2:22][CH:24]1[CH2:25][O:26]1
Reactant: ClCC1CO1
Reactant: CCc1ccc(-c2nc(-c3cc(C)c(O)c(C)c3)no2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(C)O
Product: CCc1ccc(-c2nc(-c3cc(C)c(OCC4CO4)c(C)c3)no2)s1
Temperature: 40 °C
Reaction time: 15 h
Yield: 28.3 %

Procedure:
A mixture of 4-[5-(5-ethyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenol (367 mg, 1.22 mmol) and epichlorohydrine (565 mg, 6.10 mmol) in isopropanol (20 mL) and 3 N aq. NaOH (6 mL) is stirred at 40° C. for 15 h. The mixture is diluted with diethyl ether, washed with sat. aq. NaHCO3 and water, dried over MgSO4, filtered and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to give 3-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-5-(5-ethyl-thiophen-2-yl)-[1,2,4]oxadiazole (123 mg) as a pale yellow oil; LC-MS: tR=1.15 min, [M+1]+=357.11.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[C:9]([O:13][C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[CH2:21]O)=[O:15])([CH3:12])([CH3:11])[CH3:10].C1C(COC(/N=N\C(OCC2C=CC(Cl)=CC=2)=O)=O)=CC=C(Cl)C=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[C:9]([O:13][C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[CH2:21][O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: Oc1cncc(Br)c1
Agent: O=C(/N=N\C(=O)OCc1ccc(Cl)cc1)OCc1ccc(Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(Br)c1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-7, 5-bromopyridin-3-ol was reacted with (S)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester in presence of di-(4-chlorobenzyl)azodicarboxylate and triphenylphosphine to give the title compound as a colorless oil. MS: 357.0 and 359.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[CH:4][C:3]=1[S:10](Cl)(=[O:12])=[O:11].[OH-].[NH4+:15].O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[CH:4][C:3]=1[S:10]([NH2:15])(=[O:12])=[O:11]
Reactant: CCc1ccc(Cl)c(S(=O)(=O)Cl)c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1ccc(Cl)c(S(N)(=O)=O)c1
Reaction time: 0.25 h

Procedure:
To a solution of 2-chloro-5-ethylbenzenesulfonyl chloride (0.41 g, 1.7 mmol, the product of Step A) in tetrahydrofuran (30 mL) was added 30% ammonium hydroxide (0.41 mL, 3.5 mmol) dropwise. The reaction mixture was stirred for 15 minutes, during which time a suspension formed. To this mixture water (10 mL) was added, and the tetrahydrofuran was evaporated under reduced pressure to precipitate a solid. The solid was dissolved in diethyl ether, dried over magnesium sulfate, and concentrated under reduced pressure. Diethyl ether and hexane were added to precipitate a solid. The solid was isolated by filtration to afford 190 mg of the title compound. 1H NMR (CDCl3) δ 7.95 (s, 1H), 7.43 (d, 1H), 7.35 (d, 1H), 5.08 (br s, 2H), 2.71 (q, 2H), 1.25 (t, 3H).
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11](=O)[CH:12]=[N:13][OH:14])=[N:5]1)([CH3:3])[CH3:2].[NH2:16][CH:17]([C:20]#[N:21])[C:18]#[N:19].C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CC(O)C.CCOC(C)=O.O>[NH2:21][C:20]1[C:17]([C:18]#[N:19])=[N:16][C:11]([C:6]2[CH:7]=[CH:8][C:9](=[O:10])[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=2)=[CH:12][N+:13]=1[O-:14]
Reactant: CC(C)n1nc(C(=O)C=NO)ccc1=O
Reactant: N#CC(N)C#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)O
Product: CC(C)n1nc(-c2c[n+]([O-])c(N)c(C#N)n2)ccc1=O
Temperature: 50 °C
Reaction time: 3 h
Yield: 26.4 %

Procedure:
A mixture of (1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl) (oxo)acetaldehyde oxime (11.16 g), aminomalononitrile (13.6 g) and p-toluenesulfonic acid (10.2 g) in 2-propanol (200 ml) was stirred at 50° C. for 3 hours. Water, aq. NaHCO3 and EtOAc were added to the reaction mixture to give a pale yellow precipitate. The precipitate was collected by filtration to obtain 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-pyrazinecarbonitrile 4-oxide (3.84 g) as white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([C:17]([N:19]4[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]4)=O)([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([CH2:17][N:19]4[CH2:20][CH2:21][CH:22]([OH:25])[CH2:23][CH2:24]4)([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1
Reactant: O=C(N1CCC(O)CC1)C12CC(c3ccccc31)c1ccc(Cl)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OC1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
To a cooled suspension (0° C.) of 1-(2-chloro-9,10-dihydro-9,10-methanoanthracen-9-ylcarbonyl)piperidin-4-ol (described in example 1k) (6.95 g, 19.6 mmol) in diethyl ether (200 mL) under nitrogen was added lithium aluminum hydride (1.49 g, 39.2 mmol, 8 eq of hydride) in portions. The suspension was stirred at 0° C. for 30 min and warmed to room temperature. After 18 h at room temperature, the excess reagent was carefully quenched with the following in sequence: water (1.5 mL), 2.5N NaOH (1.5 mL) and additional water (4.5 mL). The suspension was stirred vigorously until the aluminum salts became a granular white solid. The suspension was diluted with ethyl acetate (100 mL), dried with a small amount of anhydrous magnesium sulfate and filtered. The filter cake was rinsed thoroughly with ethyl acetate. The solvent was removed to yield 6.16 g (92%) of the title compound as a white solid. No additional purification was required. TLC analysis (Rf 0.15, 50% ethyl acetate in hexane). 1H NMR (CDCl3, 300 MHz) 7.20 (m, 4H), 6.95 (m, 3H), 4.60 (s, 1H), 4.24 (s, 1H), 3.70 (m 1H), 3.34 (s, 2H), 2.88 (m, 2H), 2.58 (s, 2H), 2.37 (m, 2H), 1.85 (m, 2H), 1.57 (m, 2H) MS (CI, CH4) m/z 340 (M+1,98), 342 (33), 322 (100), 368 (M+29,22), 114 (26)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[O:20][CH3:21])[C:6](=[O:22])[C:5]2([C:24]1[CH:29]=[C:28]([CH2:30][O:31]COC)[CH:27]=[CH:26][C:25]=1[Cl:35])[OH:23].CO.Cl>ClCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[O:20][CH3:21])[C:6](=[O:22])[C:5]2([C:24]1[CH:29]=[C:28]([CH2:30][OH:31])[CH:27]=[CH:26][C:25]=1[Cl:35])[OH:23]
Reactant: COCOCc1ccc(Cl)c(C2(O)C(=O)N(Cc3ccc(OC)cc3OC)c3ccc(Cl)cc32)c1
Agent: Cl
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(CN2C(=O)C(O)(c3cc(CO)ccc3Cl)c3cc(Cl)ccc32)c(OC)c1

Procedure:
A mixture of 0:307 g of the compound of Example 19, 15 ml of methanol and 1 ml of 10N hydrochloric acid is heated at 50° C. for 2 hours. The solvent is evaporated under reduced pressure and the residue obtained is taken up in dichloromethane and water. The organic phase is washed twice with water and then dried over anhydrous sodium sulphate. The solvents are evaporated under reduced pressure. The expected product is isolated after solidifying in cyclohexane, filtering and drying at 30° C. under reduced pressure for 6 hours; M.p.=107° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[C:12](Cl)(=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.C(N(CC)CC)C>C1COCC1>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[C:12]([NH: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)=[O:21]
Reactant: Nc1ccc2c(c1)CCC2=O
Reactant: COc1cccc(C(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cccc(C(=O)Nc2ccc3c(c2)CCC3=O)c1
Yield: 52 %

Procedure:
Reaction of 5-amino-indan-1-one (73 mg, 0.50 mmol) in THF (6 mL) with m-anisoyl chloride (90 μL, 0.65 mmol) in presence of triethylamine (90 μL, 0.65 mmol) according to method A gave 3-methoxy-N-(1-oxo-indan-5-yl)-benzamide (73 mg, 0.26 mmol, 52% yield) as a yellow powder after purification by chromatography on silica gel (eluent EtOAc/DCM 0/10 to 1/9).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH:4]([C:14]([O:16]C)=O)[CH2:3]1.C(C1NC=CN=1)(C1NC=CN=1)=O.Cl.[F:31][C:32]([F:36])([F:35])[CH2:33][NH2:34].N12CCCN=C1CCCCC2>O1CCCC1>[O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][CH:4]([C:14]([NH:34][CH2:33][C:32]([F:36])([F:35])[F:31])=[O:16])[CH2:3]1
Reactant: NCC(F)(F)F
Reactant: COC(=O)C1CC(=O)N(Cc2ccccc2)C1
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: O=C(NCC(F)(F)F)C1CC(=O)N(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.3 %

Procedure:
A mixture of 21.9 g (0.10 mole) methyl 5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylate in 150 ml tetrahydrofuran, was cooled to 0° C. in an ice bath under nitrogen and 24.3 g (0.15 mole) carbonyl diimidazole was added. The reaction was stirred at 0° C. for 30 minutes, then at room temperature for 30 minutes. A solution of 13.6 g (0.10 mole) of 2,2,2-trifluoroethylamine hydrochloride, 15.2 g (0.10 mole) 1,8-diazabicyclo[5.4.0]undec-7-ene and 100 ml tetrahydrofuran was added. The reaction was stirred at room temperature overnight. The solvent was removed at reduced pressure. The residue was taken up in dichloromethane and washed 3×150 ml saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate and the solvent removed under reduced pressure. The product was purified by column chromatography on silica with ethyl acetate to give 8.50 g of 5-oxo-1-(phenylmethyl)-N-(2,2,2-trifluoroethyl)-3-pyrrolidinecarboxamide, mp 110°-112° C.