Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:17]2[C:25]3[C:20](=[C:21]([CH2:26][S:27][CH3:28])[CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)[C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.ClC1C=CC(C(C2C=CC(Cl)=CC=2)C2C3C(=C(CS(C)=[O:48])C=CC=3)NC=2)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:17]2[C:25]3[C:20](=[C:21]([CH2:26][S:27]([CH3:28])=[O:48])[CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)[C:9]2[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)Cc1cccc2c(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)c[nH]c12
Reactant: CSCc1cccc2c(C(c3ccc(Cl)cc3)c3ccc(C#N)cc3)c[nH]c12
Product: CS(=O)Cc1cccc2c(C(c3ccc(Cl)cc3)c3ccc(C#N)cc3)c[nH]c12

Procedure:
The title compound was prepared starting from 60 mg (0.15 mmol) of the compound from Example 281 in analogy to the synthesis of the compound from Example 296. 62 mg (99% of theory) of the target compound were obtained as mixture of diastereomers.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][CH2:17][C:18]3[CH:19]=[C:20]([C:24](O)=[O:25])[O:21][C:22]=3[CH3:23])=[CH:12][CH:11]=2)=[N:8][CH:9]=1.[C:27]1([CH3:37])[C:28]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>O1CCCC1.CN(C1C=CN=CC=1)C>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][CH2:17][C:18]3[CH:19]=[C:20]([C:24]([NH:36][S:33]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[CH3:37])(=[O:34])=[O:35])=[O:25])[O:21][C:22]=3[CH3:23])=[CH:12][CH:11]=2)=[N:8][CH:9]=1
Reactant: Cc1ccccc1S(N)(=O)=O
Reactant: COc1ccc(-c2ccc(NCc3cc(C(=O)O)oc3C)cc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(NCc3cc(C(=O)NS(=O)(=O)c4ccccc4C)oc3C)cc2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 2.8 %

Procedure:
A suspension of 4-{[4-(5-methoxy-pyridin-2-yl)-phenylamino]-methyl}-5-methyl-furan-2-carboxylic acid hydrochloride salt (166) (30 mg, 0.08 mmoles) in tetrahydrofuran (5 ml) was treated with toluene-2-sulphonamide (41 mg, 0.24 mmoles), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (34 mg, 0.176 mmoles) and 4-(N,N-dimethylamino)-pyridine (10 mg, 0.08 mmoles) and the mixture stirred at room temperature for 16 hours. Triethylamine (24.3 mg, 0.24 mmoles) was added and the mixture was stirred for a further 18 hours. The reaction mixture was concentrated and the residue was purified by HPLC to afford compound 167 as a yellow glass (1.1 mg)). LC/MS System A; Rt=2.72 mins, m/z (ES+)=492 (M+H for C26H25N3O5S) and m/z (ES−)=490 (M−H for C26H25N3O5S).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH3:9][O:10][C:11](=[O:38])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[Cl:37])[C:20](=[O:29])[C:21]#[C:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:13]=1>>[CH3:9][O:10][C:11](=[O:38])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]2[C:30]3[C:35](=[CH:34][C:33]([F:36])=[CH:32][C:31]=3[Cl:37])/[C:21](=[C:22](\[C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)/[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)/[C:20]2=[O:29])[CH:13]=1
Reactant: Clc1ccc(I)cc1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccc(F)cc2Cl)c1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccccc3)c3ccc(Cl)cc3)c3cc(F)cc(Cl)c32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1-chloro-4-iodo-benzene (commercially available) and 3-{[(2-chloro-4-fluoro-phenyl)-(3-phenyl-propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (300 Hz, CDCl3): δppm 3.90 (s, 3H), 5.38 (s, 2H), 6.01 (dd, 1H), 6.80 (dd, 1H), 7.27-7.40 (m, 9H), 7.45-7.50 (m, 3H), 7.92 (m, 2H).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([N:17]2[C:21](=[O:22])[NH:20][C:19]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[N:18]2)(=[O:16])=[O:15])=[C:10]([O:30][CH3:31])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:39][C:40]1[CH:41]=[C:42]([CH:47]=[CH:48][CH:49]=1)[C:43]([O:45][CH3:46])=[O:44]>CN(C)C=O.O>[C:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([N:17]2[C:21](=[O:22])[N:20]([CH2:39][C:40]3[CH:41]=[C:42]([C:43]([O:45][CH3:46])=[O:44])[CH:47]=[CH:48][CH:49]=3)[C:19]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)=[N:18]2)(=[O:16])=[O:15])=[C:10]([O:30][CH3:31])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(C(=O)NC(C)(C)C)ccc1S(=O)(=O)n1nc(-c2ccc(Cl)cc2)[nH]c1=O
Reactant: COC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Cn2c(-c3ccc(Cl)cc3)nn(S(=O)(=O)c3ccc(C(=O)NC(C)(C)C)cc3OC)c2=O)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
An amount of 50 mg (0.108 mmol) of N-tert-butyl-4-{[3-(4-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]sulphonyl}-3-methoxybenzenecarboxamide from Example 14 and 53 mg (0.161 mmol) of caesium carbonate was suspended in 1 ml of dimethylformamide and admixed with 32 mg (0.140 mmol) of methyl 3-bromomethylbenzoate. The mixture was stirred at 60° C. overnight. The suspension was diluted with water. It was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulphate and freed from the solvent on a rotary evaporator. The crude product was purified by preparative HPLC [Method 5]. This gave 40 mg (60% of theory) of the target compound.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[S:28])[NH:6]2.C(=O)([O-])[O-].[K+].[K+].[F:35][C:36]([F:40])([F:39])[CH2:37]I>CN(C)C=O>[F:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][N:13]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:19]2[C:11]([C:9]2[N:8]=[C:7]3[C:3]([NH:4][C:5]([S:28][CH2:37][C:36]([F:40])([F:39])[F:35])=[N:6]3)=[C:2]([NH2:1])[N:10]=2)=[N:12]1
Reactant: FC(F)(F)CI
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]c(=S)[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2nc(SCC(F)(F)F)[nH]c12
Temperature: 70 °C
Reaction time: 16 h
Yield: 27 %

Procedure:
150 mg (0.382 mmol) of the compound from example 28 were dissolved in 2 ml of dimethylformamide, and 58 mg (0.420 mmol) of potassium carbonate were added. The mixture was heated to 70° C. for 10 min and, after cooling, 38 μl (0.382 mmol) of trifluoroethyl iodide were added and the mixture was stirred at RT for 16 h. The mixture was concentrated, and the residue was adsorbed on silica gel and purified by means of chromatography on silica gel (eluent: dichloromethane/methanol=20:1). 49 mg of the title compound were obtained (25% of theory).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([C@H:12]3[CH2:17][CH2:16][C@H:15]([CH2:18][C:19]([O:21]CC)=[O:20])[CH2:14][CH2:13]3)=[CH:8][CH:7]=2)=[N:2]1.[OH-].[Li+].Cl>O1CCCC1.O>[NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[CH:8][C:9]([C@H:12]3[CH2:13][CH2:14][C@H:15]([CH2:18][C:19]([OH:21])=[O:20])[CH2:16][CH2:17]3)=[CH:10][CH:11]=2)=[N:2]1
Reactant: CCOC(=O)C[C@H]1CC[C@H](c2ccc(-c3cc[nH]n3)cc2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C[C@H]1CC[C@H](c2ccc(-c3cc[nH]n3)cc2)CC1

Procedure:
A scintillation vial was charged with the product from Example 37B (31.3 mg, 0.100 mmol), lithium hydroxide (21 mg, 0.50 mmol) and 10 mL of 4:1 tetrahydrofuran/water and placed in a shaker overnight at room temperature. The reaction was neutralized by the addition of 4 M HCl, and the resultant mixture was concentrated and purified by RP-HPLC to provide the title product. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.07-1.17 (m, 2H), 1.42-1.53 (m, 2H), 1.70-1.88 (m, 5H), 2.14 (d, J=6.75 Hz, 2H), 2.44-2.48 (m, 1H), 6.63 (d, J=2.15 Hz, 1H), 7.26 (d, J=7.97 Hz, 2H), 7.65 (d, J=2.15 Hz, 1H), 7.68 (d, J=7.97 Hz, 2H), 12.46 (br, s, 2H); MS (ESI) m/z 285.0 [M+H]+.
Reaction SMILES: [C:1]1([NH2:8])[C:2]([NH2:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.[S:9](=O)(=[O:12])([OH:11])[OH:10]>>[NH2:7][C:2]1[CH:3]=[C:4]([S:9]([OH:12])(=[O:11])=[O:10])[CH:5]=[CH:6][C:1]=1[NH2:8]
Reactant: O=S(=O)(O)O
Reactant: Nc1ccccc1N
Product: Nc1ccc(S(=O)(=O)O)cc1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Concentrated sulfuric acid (200 mL) was added to benzene-1,2-diamine (20 g, 184.95 mmol, 1.00 equiv) at −40° C., and the solution was stirred for 30 minutes at room temperature, then overnight at 140° C. in an oil bath. Upon cooling to room temperature, the reaction was quenched by 500 g of ice. The solids were collected by filtration, and the crude product was purified by re-crystallization from water affording 9.8 g (28%) of 3,4-diaminobenzenesulfonic acid as a white solid.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[CH2:27]([O:32][C:33]([O:35][CH:36](I)[CH3:37])=[O:34])[C:28]([CH3:31])([CH3:30])[CH3:29]>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH:36]([O:35][C:33]([O:32][CH2:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:34])[CH3:37])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Reactant: CC(I)OC(=O)OCC(C)(C)C
Agent: [Na+]
Product: CC(OC(=O)OCC(C)(C)C)OC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 46.8 %

Procedure:
In the same manner as in Example 81, 100 mg of the title compound was prepared from 160 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 170 mg of 1-(neopentyloxycarbonyloxy)ethyl iodide.
Reaction SMILES: ClC1C=CC(C2NC(C3C=CC([O:19]C)=CC=3OCC)=NC2CC2CCCC2)=CC=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]2[N:41]([C:42]([N:44]3[CH2:49][CH2:48][N:47](C)[CH2:46][CH2:45]3)=[O:43])[C:40]([C:51]3[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][C:52]=3[O:59][CH2:60][CH3:61])=[N:39][CH:38]2[CH2:62][CH:63]2[CH2:67][CH2:66][CH2:65][CH2:64]2)=[CH:33][CH:32]=1>>[Cl:30][C:31]1[CH:32]=[CH:33][C:34]([CH:37]2[N:41]([C:42]([N:44]3[CH2:45][CH2:46][NH:47][C:48](=[O:19])[CH2:49]3)=[O:43])[C:40]([C:51]3[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][C:52]=3[O:59][CH2:60][CH3:61])=[N:39][CH:38]2[CH2:62][CH:63]2[CH2:64][CH2:65][CH2:66][CH2:67]2)=[CH:35][CH:36]=1
Reactant: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C)CC1
Reactant: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1
Product: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1C(=O)N1CCNC(=O)C1

Procedure:
4-[5-(4-Chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one was prepared from 5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole (Example 9) in an analogous manner as described for the preparation of [5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone (Example 24). HR-MS (ES, m/z) observed 539.2423, calculated for C29H36N4O4Cl [(M+H)+]539.2420.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[N:3]=1.C(C1C=CN=C(N2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)C=1)C>>[CH2:8]([C:4]1[N:3]=[C:2]([N:1]2[CH2:19][CH2:20][N:21]([C:24]3[CH:25]=[CH:26][C:27]([NH2:30])=[CH:28][CH:29]=3)[CH2:22][CH2:23]2)[CH:7]=[CH:6][CH:5]=1)[CH3:9]
Reactant: CCc1ccnc(N2CCN(c3ccc(N)cc3)CC2)c1
Reactant: CCc1cccc(N)n1
Product: CCc1cccc(N2CCN(c3ccc(N)cc3)CC2)n1

Procedure:
From 2-amino-6-ethylpyridine, in the same manner as 4-[4-(4-ethyl-pyridin-2-yl)-piperazin-1-yl]-phenylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([OH:24])([CH3:23])[C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=1)(=[O:11])=[O:10].[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:7]=[C:6]([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:5]=[CH:4][C:3]=1[S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([OH:24])([CH3:23])[C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: CC(O)(c1ccc(S(=O)(=O)c2ccc(F)cc2Cl)cc1)C(F)(F)F
Reactant: C1CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(O)(c1ccc(S(=O)(=O)c2ccc(N3CCCC3)cc2Cl)cc1)C(F)(F)F
Reaction time: 12 h
Yield: 61.5 %

Procedure:
50 mg 2-[4-(2-Chloro-4-fluoro-benzenesulfonyl)-phenyl]-1,1,1-trifluoro-propan-2-ol (0.13 mmol, prepared as in the previous examples) was combined in a pressure tube with 50 mg pyrrolidine. The resulting mixture was then placed into a preheated 100° C. bath. After stirring for 12 h, the mixture was diluted with 10 mL CH2Cl2 and sat. NaHCO3, then extracted (3×10% MeOH/CH2Cl2). The organics were dried (MgSO4) and concentrated under reduced pressure. Purification by flash chromatography (SiO2, 25% EtOAc/Hexanes) gave 35 mg of the product as a white solid (0.08 mmol). 1H NMR (CDCl3, 400 MHz) δ 8.09 (d, J=8.4 Hz, 1H), 7.92 (d, J=7.6 Hz, 2H), 7.70 (d, J=7.8 Hz, 2H), 6.49 (m, 2H), 3.32 (s, 4H), 2.04 (s, 4H), 1.78 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[S:28])[NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])=[CH:22][CH:21]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: S=C=Nc1ccc(Cl)cc1
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NC(=S)Nc1ccc(Cl)cc1
Yield: 87.9 %

Procedure:
Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.243 g, 1.0 mmol) and 4-chlorophenyl isothiocyanate (0.174 g, 1.03 mmol). Trituration in hexanes/ethyl acetate (1:1) gave the product (0.362 g); m.p. 179-180° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14](=[O:19])[NH:15][CH:16]1[CH2:18][CH2:17]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:16]1([NH:15][C:14]([C@@H:9]2[CH2:10][C@@H:11]([OH:13])[CH2:12][NH:8]2)=[O:19])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)NC1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC1CC1)[C@@H]1C[C@@H](O)CN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 178 %

Procedure:
A mixture of (2S,4R)-2-cyclopropylcarbamoyl-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (1.8 g, 6.6 mmol) and TFA (6 mL) in DCM (14 mL) was stirred at rt for 3 hours. The reaction was concentrated and dried to give 2 g of (2S,4R)4-hydroxy-pyrrolidine-2-carboxylic acid cyclopropylamide as a TFA salt.
Reaction SMILES: Cl[CH2:2][CH:3]=[CH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2.[CH2:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl-].[Na+].C(=O)([O-])O.[Na+]>CN(C)C=O.C(N(CC)CC)C>[CH2:16]([N:23]1[CH2:28][CH2:27][N:26]([CH2:2][CH:3]=[CH:4][C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]3)[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C1CCc2cc(C=CCCl)ccc2N1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CCc2cc(C=CCN3CCN(Cc4ccccc4)CC3)ccc2N1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
2.3 Grams of 6-(3-chloro-1-propenyl)-3,4-dihydrocarbostyril, 2.0 g of 4-benzylpiperazine and 2.0 ml of triethylamine were mixed in 50 ml of dimethylformamide and the mixture was stirred at 50° C. for 3 hours. The reaction mixture was poured into a mixture of 50 ml of a saturated sodium chloride aqueous solution with 50 ml of 5% of sodium hydrogencarbonate aqueous solution, and the organic layer was extracted with chloroform. The chloroform layer was washed with water and dried, then chloroform was removed by distillation to obtain a residue. The residue was recrystallized from ethanol-water to obtain 2.1 g of 6-[3-(4-benzylpiperazinyl)-1-propenyl]-3,4-dihydrocarbostyril, having the melting point of 151°-153° C. in colorless needle-like crystals. Then 2.1 g of 6-[3-(4-benzylpiperazinyl)-1-propenyl]-3,4-dihydrocarboxtyril, 0.2 g of platinum black and 2 ml of concentrated hydrochloric acid were mixed with 100 ml of ethanol and the mixture was subjected to catalytic reduction under 3 kg/cm2 of hydrogen gas at a room temperature for 5 hours. The reaction mixture was filtered and the mother liquor was concentrated to obtain a residue. The residue was recrystallized from methanol to obtain 1.8 g of 6-(3-piperzinopropyl)-3,4-dihydrocarbostyril dihydrochloride in colorless needle-like crystals. Melting point: 275° -278° C. (decomposed).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:10]=[C:9]([O:11][CH3:12])[C:7](=[S:8])[CH2:6][CH:5]=1)=[O:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][CH2:22][Cl:23].C1CCCCC1>CC(C)=O>[Cl:23][CH2:22][CH2:21][CH2:20][S:8][C:7]1[CH:6]=[CH:5][C:4]([C:2](=[O:3])[CH3:1])=[CH:10][C:9]=1[O:11][CH3:12]
Reactant: ClCCCBr
Reactant: COC1=CC(C(C)=O)=CCC1=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: C1CCCCC1
Product: COc1cc(C(C)=O)ccc1SCCCCl
Temperature: 25 °C

Procedure:
A mixture of 1-(4-thio-3-methoxyphenyl)ethanone (10.0 g, 54.9 mmol), potassium carbonate (9.0 g, 65.1 mmol), and acetone (100 ml) was stirred at reflux under nitrogen for 30 minutes. The reaction was cooled to ambient temperature and a solution of 1-bromo-3chloropropane (6.5 ml, 9.5 g, 60.4 mmol) dissolved in acetone (25 ml) was dripped into the reaction. After complete addition, the reaction was heated to reflux and stirred under nitrogen for 17 hours. After the reaction was carried to substantial completion, the reaction mixture was filtered and the resulting filter cake was washed with acetone. The filtrate was concentrated to provide an amber oil. A small sample was solidified by trituration with hot cyclohexane to provide 1-[4-[(3chloropropyl)thio]-3-methoxyphenyl]ethanone as a yellow solid, 11.7 g, m.p.=53°-55° C.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3C(=O)CCC3=O)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.N[C@@H:26]([CH2:36][CH2:37][CH2:38][CH3:39])[C@H:27]([OH:35])[C:28]([O:30]C(C)(C)C)=[O:29].C(=O)([O-])[O-].[Na+].[Na+]>O.O1CCOCC1>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:26]([CH2:36][CH2:37][CH2:38][CH3:39])[C@H:27]([OH:35])[C:28]([OH:30])=[O:29])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=C1CCC(=O)N1C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CCCC[C@H](N)[C@H](O)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@H](O)C(=O)O
Yield: 64.1 %

Procedure:
1.37 g (4.07 mmol) of N-[(9-fluorenyl)-methoxycarbonyl]-succinimide were added to a solution of 0.93 g (4.3 mmol) of tert-butyl 3(S)-amino-2(S)-hydroxyheptanoate in 40 ml of water/dioxan (1:1). The stirred mixture was adjusted to pH 9-10 with saturated sodium carbonate solution. After 17 hours the dioxan was removed by evaporation under a vacuum. The residual aqueous phase was washed with ethyl acetate, acidified with 2M hydrochloric acid and partitioned in ethyl acetate (three 100 ml aliquots). The three ethyl acetate aliquots were combined and washed with saturated sodium chloride solution, dried over anhydrous magnesium sulphate, filtered and the solvent was removed by evaporation to give crude tert-butyl 3(S)-[(9-fluorenyl)methoxyformamido]-2(S)-hydroxyheptanoate in the form of a pale yellow oil. This oil was chromatographed on silica gel using 20% ethyl acetate in hexane followed by 40% ethyl acetate in hexane for the elution. The chromatographed material was then stirred with 10 ml of trifluoroacetic acid/dichloromethane (1:1). After 30 minutes the solvent was removed by evaporation and the residual oil was triturated with 15 ml of diethyl ether/petroleum ether (1:2). There was obtained 1 g of 3(S)-[(9-fluorenyl)methoxyformamido]-2(S)-hydroxyheptanoic acid as a white solid MS m/e 384.1 [M+H].
Reaction SMILES: [C:1]1(=[O:6])[O:5][CH2:4][CH2:3][CH2:2]1.[C:7]1(=O)O[CH2:9][CH2:8]1>>[CH2:9]([CH:2]1[CH2:3][CH2:4][O:5][C:1]1=[O:6])[CH:8]=[CH2:7]
Reactant: O=C1CCCO1
Reactant: O=C1CCO1
Product: C=CCC1CCOC1=O

Procedure:
10.72 g of 3-(2-propenyl)dihydro-2(3H)-furanone of interest were prepared in the same manner as in Preparation Example 2Z-5 except that 8.61 g (100.0 mmol) of γ-butyrolactone were used instead of β-propiolactone described in Preparation Example 2Z-5.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.OC1C2N=N[NH:17][C:16]=2C=CC=1.C(N(C(C)C)CC)(C)C.CN>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:17][CH3:16])=[O:7])=[CH:4][CH:3]=1
Reactant: Oc1cccc2[nH]nnc12
Reactant: O=C(O)c1ccc(Br)cc1
Agent: CN
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-bromobenzoic acid (300 mg, 1.49 mmol), hydroxybenzotriazole (1.1 eq), 1(3-dimethylaminoprpyl)-3-ethylcarbodiimide HCl (1.1 eq) and diisopropylethylamine (2 eq) in DMF (2 mL) was stirred at rt for 20 min. Methylamine (1 eq) was added and the reaction stirred at rt for 16 h then quenched with saturated aqueous sodium hydrogencarbonate solution and extracted into ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo to give 4-bromo-N-methylbenzamide. 1H NMR (d6-DMSO) δ 10.07 (s, 1H), 9.03 (s, 1H), 8.56 (s, 1H), 8.38 (s, 1H), 8.32-8.36 (m, 2H), 8.05-8.09 (m, 2H), 7.94 (s, 1H), 7.67 (s, 1H), 3.87 (s, 3H), 2.83 (d, 3H); LC-MS method B, (ES+) 349.0, RT=6.68 min.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:7].[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:21]=1)=[O:18]>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:29]2[CH2:30][CH2:31][CH:26]([C:22]3[CH:21]=[C:20]([NH:19][C:17](=[O:18])[CH:16]([CH3:15])[CH3:32])[CH:25]=[CH:24][CH:23]=3)[CH2:27][CH2:28]2)=[CH:9][CH:10]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCCl)c1ccc(Cl)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme E using 5-chloro-1-(4-chlorophenyl)-1-pentanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 441.1 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30].[CH3:40][N:41]([CH3:48])[CH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16]([N:45]3[CH2:46][CH2:47][CH:42]([N:41]([CH3:48])[CH3:40])[CH2:43][CH2:44]3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30]
Reactant: CN(C)C1CCNCC1
Reactant: Cc1ccccc1-c1nc(S(C)(=O)=O)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Product: Cc1ccccc1-c1nc(N2CCC(N(C)C)CC2)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Yield: 86.4 %

Procedure:
In a similar manner to Example 1, 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine (Compound of Example 19; 85.9 mg) was reacted with 4-(dimethylamino)piperidine (23.1 mg) to obtain 6-[3,5-bis(trifluoromethyl)benzyl]-2-[4-(dimethylamino)piperidine-1-yl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxopyrimido[4,5-b][1,5]diazocine (80.5 mg, 86%).