Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([OH:51])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.CS(O[CH2:57][C:58]1([CH2:61][C:62]([O:64][CH3:65])=[O:63])[CH2:60][CH2:59]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOCC>[CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([O:51][CH2:57][C:58]3([CH2:61][C:62]([O:64][CH3:65])=[O:63])[CH2:60][CH2:59]3)[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:17][CH:18]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1
Reactant: COCCCc1cc(O)cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Reactant: COC(=O)CC1(COS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCC2(CC(=O)OC)CC2)c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl (3R,4S)-3-({cyclopropyl[3-hydroxy-5-(3-methoxy-propyl)benzyl]amino}carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-phenyl}piperidine-1-carboxylate (1 eq.) from Example 1/Step 2 in DMF (0.1 M) was added methyl (1-{[(methylsulfonyl)oxy]methyl}cyclopropyl)acetate (appendage 3) (2 eq.) and cesium carbonate (2 eq.). The reaction was heated to 80° C. and stirred for 18 h. After cooling to rt, the reaction was diluted with ether. The organic extract was washed with water, brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 20% EtOAc in toluene) to afford the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:24]([O-])=O)=[C:4]([CH:20]=[C:21]([F:23])[CH:22]=1)[NH:5][C:6]1[S:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[C:7]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[H][H]>[C].[Pd].C(OCC)(=O)C>[NH2:24][C:3]1[C:2]([F:1])=[CH:22][C:21]([F:23])=[CH:20][C:4]=1[NH:5][C:6]1[S:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[C:7]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: [H][H]
Reactant: CCOC(=O)c1c(Nc2cc(F)cc(F)c2[N+](=O)[O-])sc2ccccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Nc2cc(F)cc(F)c2N)sc2ccccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 19 and using ethyl 2-(3,5-difluoro-2-nitroanilino)benzo[b]thiophene-3-carboxylate, ethyl acetate, 10% palladium-carbon and hydrogen (60 atm kg/cm2), ethyl 2-(2-amino-3,5-difluoroanilino)benzo[b]thiophene-3-carboxylate is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][C:7]1[CH:15]=[CH:14][C:13]([C:16](=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][C:8]=1[C:9](Cl)=[O:10])=[O:5])[CH3:2].[CH:25]1[C:30]([C:31]([O:33][OH:34])=[O:32])=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([O:3][C:4]([O:6][C:7]1[CH:15]=[CH:14][C:13]([C:16](=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][C:8]=1[C:9]([O:34][O:33][C:31](=[O:32])[C:30]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:10])=[O:5])[CH3:2]
Reactant: CCCCCCCC(=O)c1ccc(OC(=O)OCC)c(C(=O)Cl)c1
Reactant: O=C(OO)c1ccccc1
Product: CCCCCCCC(=O)c1ccc(OC(=O)OCC)c(C(=O)OOC(=O)c2ccccc2)c1
Yield: 26 %

Procedure:
In a manner similar to that of Example 1-4, starting with 5.79 g (16.3 mmol) of 2-ethoxycarbonyloxy-5-octanoylbenzoyl chloride and 3.38 g (24.5 mmol) of perbenzoic acid (prepared as described in Example 1-3), 2 g of (2-ethoxycarbonyloxy-5-octanoyl)benzoyl peroxide are obtained in the form of a colourless oil in a yield of 26%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][CH2:11][CH2:10][CH2:9]2)=[O:5])[CH3:2].[CH3:16][O:17]C(Cl)Cl>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([CH:16]=[O:17])[CH:15]=1)[O:12][CH2:11][CH2:10][CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)CCCO2
Reactant: COC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1cc(C=O)c2c(c1)CCCO2

Procedure:
Compounds of the invention where the variable Y is an ethynyl-methyl (CH≡C—CH2—) group can, generally speaking, be synthesized in accordance with Reaction Scheme 12. The starting compound in accordance with this scheme is a 6-chromanoic acid ethyl ester derivative of Formula 3 which can be obtained as described above in connection with Reaction Scheme 1. The 6-chromanoic acid ethyl ester of Formula 3 is thereafter treated with α,α-dichloromethyl methyl ether in a suitable aprotic solvent such as methylene chloride to provide the 8-formyl-6-chromanoic acid ethyl ester derivative of Formula 12. The formyl compound of Formula 12 is reduced with sodium borohydride in methanol to give the corresponding hydroxymethyl compound of Formula 13. The hydroxymethyl compound of Formula 13 is then reacted with N-bromosuccinimide in the presence of triphenylphosphine in an aprotic solvent such as methylene chloride to give the 8-(bromomethyl)-6-chromanoic ester derivative of Formula 14. The 8-(bromomethyl)-6-chromanoic ester derivative of Formula 14 is reacted with trimethylsilyl acetylene in triethyl amine and dimethylformamide (DMF) under argon atmosphere in the presence of dichlorobis(triphenylphosphine)palladium(II) (Pd(PPh3)2Cl2). The trimethylsilyl group and the ethyl group of the ester moiety of the resulting 8-(trimethylsilylmethyl) 6-chromanoic acid ethyl ester are then removed by treatment with base (such as lithium hydroxide shown in the reaction scheme) to provide the 8-(ethynylmethyl)-6-chromanoic acid of Formula 15.
Reaction SMILES: [OH-].[K+].[CH3:3][CH:4]([O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([C:40]([O:42]C)=[O:41])=[C:12]([CH2:27][N:28]3[CH2:33][CH2:32][CH:31]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[CH2:30][CH2:29]3)[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)=[N:14]2)=[CH:9][C:8]=1[S:44]([CH3:47])(=[O:46])=[O:45])[CH3:5]>CO.O>[CH3:5][CH:4]([O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([C:40]([OH:42])=[O:41])=[C:12]([CH2:27][N:28]3[CH2:29][CH2:30][CH:31]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[CH2:32][CH2:33]3)[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:18]=3)=[N:14]2)=[CH:9][C:8]=1[S:44]([CH3:47])(=[O:46])=[O:45])[CH3:3]
Reactant: COC(=O)c1c(CN2CCC(N3CCOCC3)CC2)c(-c2cccc(C(F)(F)F)c2)nc2cc(OC(C)C)c(S(C)(=O)=O)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)Oc1cc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(N4CCOCC4)CC3)c(C(=O)O)c2cc1S(C)(=O)=O
Temperature: 25 °C
Yield: 95.8 %

Procedure:
Potassium hydroxide (1.38 g, 24.63 mmol) was added to a solution of methyl 7-[(1-methylethyl)oxy]-6-(methylsulfonyl)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.6 g, 2.463 mmol) in methanol (60 mL) and water (20 mL). The reaction mixture was heated to reflux overnight, cooled to room temperature and diluted with water. The methanol was removed under reduced pressure. The residual mixture was acidified to pH 6 with 2N HCl and extracted with methylene chloride (three times). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to afford 7-[(1-methylethyl)oxy]-6-(methylsulfonyl)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (1.5 g, 96% yield). 1H NMR (400 MHz, DMSO-d6) δ8.82 (s, 1H), 8.03 (s, 1H), 7.91 (t, J=7.91 Hz, 2H), 7.79 (t, J=7.78 Hz, 1H), 7.70 (s, 1H), 5.08 (dt, J=5.93, 11.98 Hz, 1H), 4.11 (br. s., 2H), 3.56 (br. s., 4H), 3.38 (s, 3H), 2.99 (d, J=11.29 Hz, 2H), 2.53-2.59 (m, 1H), 2.42 (br. s., 4H), 2.34 (br. s., 1H), 1.78 (d, J=12.30 Hz, 2H), 1.43 (s, 3H), 1.41 (s, 3H), 1.22-1.39 (m, 3H); MS (m/z) 636.2 (M+H+).
Reaction SMILES: [NH2:1][CH:2]1[C:27](=[O:28])[N:4]2[C:5]([C:11]([O:13][CH:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])=[C:6]([CH2:9][Cl:10])[CH2:7][S:8][C@H:3]12.[NH2:29][C:30]1[S:31][CH:32]=[C:33](/[C:35](=[N:48]/[O:49][CH:50]([C:59]([O:61][CH:62]([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)=[O:60])[C:51]2[CH:56]=[CH:55][C:54]([OH:57])=[C:53]([OH:58])[CH:52]=2)/[C:36](ON2C3C=CC=CC=3N=N2)=[O:37])[N:34]=1>C1COCC1.C(OCC)(=O)C>[NH2:29][C:30]1[S:31][CH:32]=[C:33](/[C:35](=[N:48]/[O:49][CH:50]([C:59]([O:61][CH:62]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[C:69]2[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=2)=[O:60])[C:51]2[CH:56]=[CH:55][C:54]([OH:57])=[C:53]([OH:58])[CH:52]=2)/[C:36]([NH:1][CH:2]2[C:27](=[O:28])[N:4]3[C:5]([C:11]([O:13][CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[O:12])=[C:6]([CH2:9][Cl:10])[CH2:7][S:8][C@H:3]23)=[O:37])[N:34]=1
Reactant: Nc1nc(/C(=N/OC(C(=O)OC(c2ccccc2)c2ccccc2)c2ccc(O)c(O)c2)C(=O)On2nnc3ccccc32)cs1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1nc(/C(=N/OC(C(=O)OC(c2ccccc2)c2ccccc2)c2ccc(O)c(O)c2)C(=O)NC2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)CS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 5 h
Yield: 41.2 %

Procedure:
To a solution of diphenylmethyl 7-amino-3-chloromethyl-3-cephem-4-carboxylate (VIa) (685 mg, 1.65 mmol) in THF (8.3 ml) was added benzotriazol-1-yl 2-(2-aminothiazol-4-yl)-2-(Z)-(diphenylmethyloxycarbonyl-(3,4-dihydroxyphenyl) methyl]oxyiminoacetate (IIIa) (955 mg, 1.50 mmol) and the mixture was stirred for 5 hr at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water dried over MgSO4 and concentrated under reduced pressure. The crude product was chromatographed on a column of silica gel to afford 566 mg (41% yield) of the title compound.
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:26][CH3:27])[CH2:5][C:6]#[C:7][CH2:8][NH:9][C:10](=[O:25])[C:11](Cl)([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:3].C(=O)(O)[O-:29].[Na+]>O>[CH2:2]([N:4]([CH2:26][CH3:27])[CH2:5][C:6]#[C:7][CH2:8][NH:9][C:10](=[O:25])[C:11]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)([OH:29])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:3]
Reactant: O=C([O-])O
Reactant: CCN(CC)CC#CCNC(=O)C(Cl)(c1ccccc1)C1CCCCC1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCN(CC)CC#CCNC(=O)C(O)(c1ccccc1)C1CCCCC1

Procedure:
N-(4-Diethylamino-2-butynyl)-2-chloro-2-cyclohexyl-2-phenylacetamide hydrochloride (100 mg) was dissolved in water (1 ml) and the solution was refluxed for 20 minutes. After being cooled, the solution was made alkaline (pH 10) with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The extract was washed with sodium chloride aqueous solution, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of chloroform and methanol as an eluent to give N-(4-diethylamino-2-butynyl)-2-cyclohexyl-2-hydroxy-2-phenylacetamide (74 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].Cl.[NH2:11][OH:12].[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[N:11][OH:12])[NH2:6])[CH:7]=[CH:8][CH:9]=1
Reactant: N#Cc1cccc(Cl)c1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NC(=NO)c1cccc(Cl)c1
Temperature: 90 °C
Yield: 22.1 %

Procedure:
A solution of 3.35 mL (30.0 mmol) 3-chlorobenzonitrile in ethanol (40 mL) was added to a solution of 2.47 g (35.5 mmol) hydroxylamine hydrochloride and 1.42 g (35.5 mmol) NaOH in water (20 mL) at r.t. and then heated at 90° C. for 24 h. After cooling, the reaction mixture was concentrated, the residue diluted with water, followed by filtration and drying to afford 1.13 g (93%) of the title compound. 1H NMR: 8.11 (s, 1H), 7.72 (s, 1H), 7.61 (m, 1H), 7.46 (m, 1H), 7.36 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[C:13]([C:19]([NH:21][CH3:22])=O)=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CNC(C1N(C)C2C(C=1)=CC=CC=2)=O>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[C:13]([CH2:19][NH:21][CH3:22])=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)c1cc2cc(OCc3ccccc3)ccc2n1C
Agent: CNC(=O)c1cc2ccccc2n1C
Product: CNCc1cc2cc(OCc3ccccc3)ccc2n1C
Yield: 69 %

Procedure:
According to the procedure of Preparation 1 (b), except substituting 5-benzyloxy-N,1-dimethylindole-2-carboxamide (37.4 g, 126.7 mmole) for the N,1-dimethylindole-2-carboxamide, the title compound (24.5 g, 69%) was prepared as a white solid: MS (ES) m/e 281 (M+H)+.
Reaction SMILES: ClC1C(CCCl)=C(C2C=CC=C(OC)C=2)N=C(N2CCOCC2)N=1.NC1C=C(S(N)(=O)=O)C=CC=1.C[O:37][C:38]1[CH:39]=[C:40]([C:44]2[C:45]3[CH2:58][CH2:57][N:56]([C:59]4[CH:64]=[CH:63][CH:62]=[C:61]([S:65]([NH2:68])(=[O:67])=[O:66])[CH:60]=4)[C:46]=3[N:47]=[C:48]([N:50]3[CH2:55][CH2:54][O:53][CH2:52][CH2:51]3)[N:49]=2)[CH:41]=[CH:42][CH:43]=1>>[OH:37][C:38]1[CH:39]=[C:40]([C:44]2[C:45]3[CH2:58][CH2:57][N:56]([C:59]4[CH:60]=[C:61]([S:65]([NH2:68])(=[O:67])=[O:66])[CH:62]=[CH:63][CH:64]=4)[C:46]=3[N:47]=[C:48]([N:50]3[CH2:55][CH2:54][O:53][CH2:52][CH2:51]3)[N:49]=2)[CH:41]=[CH:42][CH:43]=1
Reactant: COc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3c2cccc(S(N)(=O)=O)c2)c1
Agent: COc1cccc(-c2nc(N3CCOCC3)nc(Cl)c2CCCl)c1
Agent: Nc1cccc(S(N)(=O)=O)c1
Product: NS(=O)(=O)c1cccc(N2CCc3c(-c4cccc(O)c4)nc(N4CCOCC4)nc32)c1

Procedure:
In the same manner as Example 1-A-01, from 4-[4-chloro-5-(2-chloroethyl)-6-(3-methoxyphenyl)-pyrimidin-2-yl]-morpholine and 3-aminobenzene sulfonamide, 4-(3-methoxy-phenyl)-7-(3-aminosulfonylphenyl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine was obtained, and subsequently, further in the same manner as Example 1-A-09, the desired compound was obtained.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:15]=[CH:14][C:7]2[NH:8][C:9](=O)[CH2:10][CH2:11][CH2:12][C:6]=2[CH:5]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:15]=[CH:14][C:7]2[NH:8][C:9](=[S:27])[CH2:10][CH2:11][CH2:12][C:6]=2[CH:5]=1
Reactant: O=C1CCCc2cc(OC(F)(F)F)ccc2N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: FC(F)(F)Oc1ccc2c(c1)CCCC(=S)N2
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 7-(trifluoromethoxy)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (30 g, 122 mmol) in toluene (2000 ml) was added Lawesson's reagent (29.7 g, 73.5 mmol) and the mixture was stirred at 100° C. for 2 hrs. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by column chromatography on silica eluting with 5% ethyl acetate in petroleum ether to give the title compound.
Reaction SMILES: [CH:1]1([N:4]2[CH2:16][C@@H:7]3[C@H:8]([C:12]([O:14][CH3:15])=[O:13])[NH:9][CH2:10][CH2:11][N:6]3[C:5]2=[O:17])[CH2:3][CH2:2]1.[CH:18]1(CN)CC1>>[CH:3]1([CH2:1][N:4]2[CH2:16][C@@H:7]3[C@H:8]([C:12]([O:14][CH3:15])=[O:13])[NH:9][CH2:10][CH2:11][N:6]3[C:5]2=[O:17])[CH2:2][CH2:18]1
Reactant: NCC1CC1
Reactant: COC(=O)[C@@H]1NCCN2C(=O)N(C3CC3)C[C@H]12
Product: COC(=O)[C@@H]1NCCN2C(=O)N(CC3CC3)C[C@H]12

Procedure:
Compound 97-C was prepared in analogy to compound 82-C by using cyclopropylmethanamine instead of cyclopropylamine.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10](=[O:12])[CH3:11])=[CH:2]1.CC(C)[O-].[Na+].C(O)(=O)C>C(O)(C)C.[Rh]>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C@@H:10]([OH:12])[CH3:11])=[CH:2]1
Reactant: CC(=O)c1csc2ccccc12
Agent: [Rh]
Agent: CC(C)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: C[C@H](O)c1csc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
To a solution of 4.45 g of 1-(1-benzothiene-3-yl)ethanone in 95 mL of isopropanol was added the asymmetric rhodium catalyst solution prepared as described above. Under reduced pressure (about 6600 Pa), an isopropanol solution of sodium isopropoxide (0.1 M, 10.0 mL) was added thereto. Further, the pressure was reduced to about 3700 Pa, followed by stirring at room temperature for 2 hours. To the reaction mixture was added acetic acid (2 mL) to stop the reaction, followed by concentrating under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain (1S)-1-(1-benzothiene-3-yl)ethanol (4.48 g, 94% ee) as a pale yellow oily substance. (HPLC analysis condition: CHIRALCEL OD-H column manufactured by (DAICEL CHEMICAL INDUSTRIES. Ltd., eluting solvent hexane/isopropanol=90/10, flow rate 1.0 mLmin−1, retention time: 8.1 min (S-isomer), 12.6 min (R-isomer)) EI: 178
Reaction SMILES: O[CH2:2][CH2:3][NH:4][CH2:5][C@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[OH:7].[O:14]([C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[O:14]([C:21]1[CH:22]=[CH:23][C:24]([CH2:25][N:4]2[CH2:3][CH2:2][O:7][C@@H:6]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:5]2)=[CH:27][CH:28]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Reactant: OCCNC[C@@H](O)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: c1ccc(Oc2ccc(CN3CCO[C@@H](c4ccccc4)C3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8 %

Procedure:
200 mg of (S)-2-Phenyl-morpholine (see synthesis in Example 1) was dissolved in 2 mL of dichloroethane and 253 μL of 4-Phenoxy-benzaldehyde was added. The reaction was stirred at room temperature 30 minutes and then 467 mg of sodium triacetoxyborohydride was added. The reaction was stirred overnight at room temperature. The reaction solution was then washed with aqueous saturated sodium bicarbonate solution several times followed by a brine wash. The organics were dried over sodium sulfate, filtered and concentrated in vacuo. Purification by preparatory chromatography gave the title compound. 8% yield. EI m/z 346=MH+
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.Br[C:17]1[C:18]([NH2:24])=[N:19][CH:20]=[C:21]([Br:23])[N:22]=1.CCN(CC)CC>CS(C)=O>[NH2:24][C:18]1[C:17]([NH:1][CH2:2][C@H:3]2[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]2)=[N:22][C:21]([Br:23])=[CH:20][N:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CN)C1
Reactant: Nc1ncc(Br)nc1Br
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H](CNc2nc(Br)cnc2N)C1
Temperature: 130 °C
Reaction time: 8 h
Yield: 25.3 %

Procedure:
(R)-tert-butyl 3-(aminomethyl)piperidine-1-carboxylate (4.97 g, 22.40 mmol) was dissolved in DMSO (80 ml), and then 3,5-dibromopyrazine-2-amine (8.5 g, 33.60 mmol) and Et3N (6.3 ml) were added, followed by stirring at 130° C. overnight. After the completion of the reaction, the reaction mixture was extracted with H2O, EA, and brine, followed by drying (Na2SO4), filtration, and concentration under reduced pressure, and the residue was purified by column chromatography (EA:Hex=1:1), to give (R)-tert-butyl 3-(((3-amino-6-bromopyrazine-2-yl)amino)methyl)piperidine-1-carboxylate (2.19 g, two steps: 26%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].O[N:21]=[C:22]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][OH:31])=[CH:26][CH:25]=1)[NH2:23]>>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:12][N:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([CH2:30][OH:31])=[CH:26][CH:25]=3)[N:21]=2)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19]
Reactant: NC(=NO)c1ccc(CO)cc1
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Product: COCc1cc(-c2nc(-c3ccc(CO)cc3)no2)ccc1-c1ccccc1C

Procedure:
The title compound was obtained following procedure described for example 54 step 1 but starting from Intermediate 28 (248.00 mg; 0.90 mmol) and Intermediate 74 (150.00 mg; 0.90 mmol). Recrystallization from Et2O/pentane gave the title compound as a white powder. 1H NMR (DMSO-d6, 300 MHz) δ 8.32 (d, J=1.5 Hz, 1H), 8.16 (dd, J=7.9, 1.8 Hz, 1H), 8.10-8.07 (m, 2H), 7.55 (d, J=8.3 Hz, 2H), 7.41 (d, J=7.9 Hz, 1H), 7.36-7.26 (m, 3H), 7.15-7.13 (m, 1H), 5.38 (t, J=5.7 Hz, 1H), 4.61 (d, J=5.7 Hz, 1H), 4.22 (d, J=12.7 Hz, 1H), 4.15 (d, J=12.7 Hz, 1H), 3.25 (s, 3H), 2.03 (s, 3H). LC/MS (Method B): 387.2 (M+H)+. HPLC (Method A) Rt 5.51 min (Purity: 97.0%).
Reaction SMILES: [NH:1]([C:3]1[N:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:7]([C:13]1[CH:27]=[CH:26][C:16]([CH2:17][NH:18]C(=O)OC(C)(C)C)=[CH:15][CH:14]=1)=[N:8]2)[NH2:2].C1C=CC2N(O)N=NC=2C=1.[C:44](O)(=O)[C:45]1[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=1.CCN(C(C)C)C(C)C.C(Cl)CCl>CN(C=O)C.C(O)(=O)C>[C:28]1([C:6]2[C:7]([C:13]3[CH:27]=[CH:26][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=3)=[N:8][C:9]3[CH:10]=[CH:11][N:12]4[C:44]([C:45]5[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=5)=[N:2][N:1]=[C:3]4[C:4]=3[CH:5]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(O)c1ccncc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2nc3ccnc(NN)c3cc2-c2ccccc2)cc1
Agent: On1nnc2ccccc21
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: NCc1ccc(-c2nc3ccn4c(-c5ccncc5)nnc4c3cc2-c2ccccc2)cc1
Temperature: 80 °C

Procedure:
To a stirred solution of 16-2 (0.08 g, 0.2 mMol), HOBT (0.03 g, 0.2 mMol), and isonicotinic acid (0.02 g, 0.2 mMol) in anhydrous DMF (1 mL) was added DIEA (0.08 mL, 0.5 mMol) followed by EDC (0.04 g, 0.2 mMol). The solution was heated in a microwave reactor at 80° C. for 12 min. The solution was then treated with 0.5 mL of acetic acid and was heated in a microwave reactor at 80° C. for 30 minutes. Upon cooling to room temperature, the volatiles were evaporated in vacuo and the solution was filtered through a syringe filter and purified on a C18 reverse phase HPLC to give 16-3 as a solid. Mass (M+1) calculated: 429.1822 observed: 429.1811
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][C@@H:5]([CH3:8])[CH2:4][N:3]1[C@H:9]([C:24]1[CH:32]=[CH:31][C:27]([C:28]([O-:30])=[O:29])=[CH:26][CH:25]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][Si](C(C)(C)C)(C)C)[CH:11]=1.[Li+].[CH2:34](N1[C@@H](C)CN([C@@H](C2C=C(O)C=CC=2)C2C=CC(Cl)=CC=2)[C@H](C)C1)[CH:35]=[CH2:36].Cl>O1CCCC1>[CH2:36]([N:6]1[C@@H:5]([CH3:8])[CH2:4][N:3]([C@H:9]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:31][CH:32]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=2)[C@H:2]([CH3:1])[CH2:7]1)[CH:35]=[CH2:34]
Reactant: C=CCN1C[C@@H](C)N([C@H](c2ccc(Cl)cc2)c2cccc(O)c2)C[C@@H]1C
Reactant: C[C@@H]1CN[C@@H](C)CN1[C@H](c1ccc(C(=O)[O-])cc1)c1cccc(O[Si](C)(C)C(C)(C)C)c1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCN1C[C@@H](C)N([C@H](c2ccc(C(=O)O)cc2)c2cccc(O)c2)C[C@@H]1C
Yield: 30 %

Procedure:
A solution of crude lithium 4-((αR*)-α-((2R*,5S*)-2,5-dimethyl-1-piperazinyl)-3-tert-butyldimethylsiloxybenzyl)benzoate (11.5 g, from 23 mmol of Example 2 by the procedure of Example 6, Method B) in tetrahydrofuran was treated with 6M aqueous hydrochloric acid at room temperature for 18 hours. After dilution with water, the mixture was extracted with diethyl ether and the aqueous layer was adjusted to pH 8 with aqueous sodium hydroxide and extracted with dichloromethane. The aqueous layer was titrated to pH 6 with concentrated hydrochloric acid and the precipitated solid was collected by filtration, washed with water and dried under vacuum (60° C.) to give 2.65 g (30%) of (±)-4-((αR*)-α-((2R*,5S*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzoic acid as an off-white powder. NMR (DMSO-d6) δ: 0.9 (d, J=6 Hz, 3H); 1.05 (d, J=6 Hz, 3H); 1.8 (dd, J1 =11 Hz, J2 =7 Hz, 1H); 2.1 (dd, J1 =11 Hz, J2 =7 Hz, 1H); 2.5 (m, 6H); 2.7 (d, J=11 Hz, 1H); 2.9 (dd, J1 =7 Hz, J2 =14 Hz); 3.1 (dd, J1 =14 Hz, J2 =5 Hz, 1H); 4.9-5.2 (m, 3H); 5.6-5.8 (m, 1H); 6.5 (dd, J1 =8 Hz, J2 =2 Hz, 1H); 6.8 (m, 2H); 7.1 (t, J=8 Hz, 1H); 7.3 (m, 1H); 7.4 (d, J=8 Hz, 2H); 7.9 (d, J=8 Hz, 2H). Calc. for C23H28N2O3 1.25 H2O: C, 68.55; H, 7.63; N, 6.95. Found: C, 68.61; H, 7.66; N, 7.02. Mass spectrum (Cl--CH4): m/z 381 (M+1, 44%), 153 (100%), 227 (17%).