Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OO.[OH:3][CH:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[N:7]([OH:12])[C:6]([CH3:14])([CH3:13])[CH2:5]1.[CH3:15]S(C)=O>CCCCCCC.C(OCC)(=O)C>[CH3:15][O:12][N:7]1[C:8]([CH3:10])([CH3:11])[CH2:9][CH:4]([OH:3])[CH2:5][C:6]1([CH3:14])[CH3:13]
Reactant: CS(C)=O
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Agent: OO
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CON1C(C)(C)CC(O)CC1(C)C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
A solution of 9.1 g (80 mmol) of 30% aqueous hydrogen peroxide is added dropwise, under nitrogen, over a 30-minute period to a mixture of 10.0 g (58.1 mmol) of 4-hydroxy-1-oxyl-2,2,6,6-tetramethylpiperidine, 17.8 g (64.0 mmol) of ferrous sulfate heptahydrate, and 100 ml of dimethyl sulfoxide which is initially at 23° C. The reaction temperature reaches 65° C. during the addition. After the peroxide is all added, the reaction mixture is stirred for 30 minutes. During this time, the temperature falls to 35° C. The reaction mixture is partitioned between methylene chloride (150 ml) and water (100 ml). The organic layer is dried over anhydrous magnesium sulfate and concentrated at reduced pressure to obtain a yellow liquid. Purification by flash chromatography on silica gel (10:1 heptane/ethyl acetate, then 4:1 heptane/ethyl acetate) affords 6.5 g (60% yield) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:40])(=[N:27][C:28](=[O:39])[NH:29][C:30]2[CH:35]=[CH:34][C:33]([N:36]([CH3:38])[CH3:37])=[CH:32][CH:31]=2)=[O:26])=[CH:21][CH:20]=1>>[CH3:37][N:36]([CH3:38])[C:33]1[CH:32]=[CH:31][C:30]([NH:29][C:28]([N:27]=[S:25]([C:22]2[CH:23]=[CH:24][C:19]([NH:18][C:2]3[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)=[CH:4][N:3]=3)=[CH:20][CH:21]=2)([CH3:40])=[O:26])=[O:39])=[CH:35][CH:34]=1
Reactant: CN(C)c1ccc(NC(=O)N=S(C)(=O)c2ccc(N)cc2)cc1
Reactant: C[C@H](CO)Nc1nc(Cl)ncc1-c1cccs1
Product: C[C@H](CO)Nc1nc(Nc2ccc(S(C)(=O)=NC(=O)Nc3ccc(N(C)C)cc3)cc2)ncc1-c1cccs1
Yield: 21 %

Procedure:
In the reaction of (R)-2-(2-chloro-5-(2-thienyl)pyrimidine-4-ylamino)propan-1-ol (146.4 mg, 0.54 mmol) with (RS)—S-(4-aminophenyl)-N-(4-dimethylamino-phenylcarbamoyl)-S-methylsulphoximide (164 mg, 0.49 mmol) according to procedure 5c, the desired product is obtained in 21% yield (59 mg) after chromatographic purification (silica gel, dichloromethane/ethanol (0%-20% ethanol)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[CH2:6][CH2:7][C:8]1[S:9][C:10]2[N:11]=[C:12]([NH2:23])[N:13]=[C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:15]=2[N:16]=1.[CH3:27][O:28][C:29]1[CH:39]=[CH:38][C:32]([O:33][CH2:34][C:35](O)=[O:36])=[CH:31][CH:30]=1>>[NH2:23][C:12]1[N:13]=[C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:35](=[O:36])[CH2:34][O:33][C:32]3[CH:38]=[CH:39][C:29]([O:28][CH3:27])=[CH:30][CH:31]=3)[CH2:19][CH2:18]2)[C:15]2[N:16]=[C:8]([CH2:7][CH2:6][C:5]3[CH:24]=[CH:25][CH:26]=[C:3]([O:2][CH3:1])[CH:4]=3)[S:9][C:10]=2[N:11]=1
Reactant: COc1ccc(OCC(=O)O)cc1
Reactant: COc1cccc(CCc2nc3c(N4CCNCC4)nc(N)nc3s2)c1
Product: COc1ccc(OCC(=O)N2CCN(c3nc(N)nc4sc(CCc5cccc(OC)c5)nc34)CC2)cc1
Yield: 66 %

Procedure:
This compound was prepared from 2-(3-methoxyphenethyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-amine using 4-methoxyphenoxyacetic acid in a yield of 66%, according to the procedure for the synthesis of example 50.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](Cl)=[O:6].[CH3:12][NH:13][CH3:14]>>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([N:13]([CH3:14])[CH3:12])=[O:6]
Reactant: CNC
Reactant: Cc1ccc(C(=O)Cl)cc1I
Product: Cc1ccc(C(=O)N(C)C)cc1I

Procedure:
By the reaction in the same manner as in Example 27-i) using 3-iodo-4-methylbenzoyl chloride (2.00 g) and 50% aqueous dimethylamine solution (20 ml), the title compound (1.72 g) was obtained as a pale-yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH:10]3[CH:12]=[CH:13][CH2:14][CH2:15][CH:9]3[CH:8]([CH3:16])[O:7][C:6]=2[C:5]([CH3:17])=[C:4]([C:18]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)([CH3:22])[CH2:19][CH2:20][CH3:21])[C:3]=1[CH3:30].[BrH:31].[O:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40][C:41](O)=[O:42])[CH2:34][CH2:33]1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[BrH:31].[O:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40][C:41]([O:1][C:2]2[C:11]3[CH:10]4[CH:12]=[CH:13][CH2:14][CH2:15][CH:9]4[CH:8]([CH3:16])[O:7][C:6]=3[C:5]([CH3:17])=[C:4]([C:18]([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)([CH3:22])[CH2:19][CH2:20][CH3:21])[C:3]=2[CH3:30])=[O:42])[CH2:34][CH2:33]1
Reactant: O=C(O)CCCN1CCOCC1
Reactant: CCCC(C)(c1ccc(F)cc1)c1c(C)c(O)c2c(c1C)OC(C)C1CCC=CC21
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCC(C)(c1ccc(F)cc1)c1c(C)c(OC(=O)CCCN2CCOCC2)c2c(c1C)OC(C)C1CCC=CC21

Procedure:
3.54 g. (11.27 mmole) of 1-Hydroxy-3-(4-fluorophenyl-1-methylbutyl)-trimethyl-6a,7,8,10a-tetrahydrodibenzo[b,d] pyran, 2.86 g. (11.27 mmole) of γ-morpholinobutyric acid hydrobromide and 2.50 g. (12.12 mole) of dicyclohexylcarbodiimide are combined in 200 ml. of methylene chloride and stirred at room temperature for 24 hours. The reaction mixture is cooled and the by-product of dicyclohexylurea is removed by filtration. The volume of methylene chloride is removed by filtration. The volume of methylene chloride is reduced and 25 ml. of cyclohexane is added. The mixture is cooled and the small amount of solid which forms is removed by filtration. All solvents are removed on a rotary evaporator and the residue is dried in vacuo. The resulting material is dissolved in a mixture of benzene and ether and placed in cold storage to yield the crystalline product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.CC(O)=O.[CH:18]([NH2:21])([CH3:20])[CH3:19].[BH3-]C#N.[Na+]>CO>[CH:18]([NH:21][CH:10]1[CH2:11][CH2:12][N:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:8][CH2:9]1)([CH3:20])[CH3:19]
Reactant: O=C1CCN(c2ccncc2)CC1
Reactant: CC(C)N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)NC1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
1-(Pyridin-4-yl)piperidin-4-one (1.5 g, 8.52 mmol, 1.0 eq.) was dissolved in MeOH (40 ml); AcOH (0.6 ml) and isopropylamine (1.39 ml, 17.04 mmol, 2.0 eq.) were added and the mixture was stirred for 3 hours at RT. NaCNBH3 (856 mg, 12.78 mmol, 1.5 eq.) was then added in portions at 0° C. and stirring was carried out for a further 14 hours at RT. The reaction mixture was concentrated under reduced pressure and the residue was taken up in water (100 ml) and extracted with DCM (150 ml). The org. phase was washed with sat. NaHCO3 solution (100 ml), dried over sodium sulfate, concentrated and purified by column chromatography (Alox, 2% MeOH in DCM). Yield: 64% (1.2 g, 5.47 mmol)
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.C[CH:17]([CH:21]1[C:25]2=[C:26](Br)[C:27]3[C:28]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:29][C:30]([F:33])=[CH:31][C:32]=3[N:24]2[CH2:23][CH2:22]1)[C:18]([O-:20])=[O:19]>>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:26]2[C:27]3[C:28]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:29][C:30]([F:33])=[CH:31][C:32]=3[N:24]3[CH2:23][CH2:22][CH:21]([CH2:17][C:18]([OH:20])=[O:19])[C:25]=23)[CH:2]=1
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Reactant: CC(C(=O)[O-])C1CCn2c1c(Br)c1c(S(C)(=O)=O)cc(F)cc12
Product: CS(=O)(=O)c1cc(F)cc2c1c(-c1cccc(-c3ccccc3)c1)c1n2CCC1CC(=O)O

Procedure:
Starting from 1,1′-biphenyl-3-ylboronic acid and (+/−)-methyl[9-bromo-6-fluoro-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate (Example 126, Step 1), the title compound was synthesized following the procedures described in Step 2 of Example 126 and Step 10 of Example 7.
Reaction SMILES: O1CCCCC1O[C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:10][CH:9]=1.C(Cl)Cl.CC1C=CC(S(O)(=O)=[O:37])=CC=1>CO>[OH:37][C:9]1[CH:8]=[CH:13][CH:12]=[C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: FC(F)(F)c1ccc(C#Cc2ccc(OC3CCCCO3)cc2)cc1
Solvent: ClCCl
Solvent: CO
Product: Oc1cccc(C#Cc2ccc(C(F)(F)F)cc2)c1
Temperature: 30 °C
Reaction time: 1 h
Yield: 9057.1 %

Procedure:
Compound 4 (13.84 g, 40 mmol), CH2Cl2 (75 ml) and MeOH (125 ml) were placed in a 250 ml round-bottomed flask, then TsOH (0.4 g, 0.4 mmol) was added. The reaction mixture was stirred at 30° C. for 1 hour. When the reaction was finished (TLC showed no starting material remaining), the solvent was removed by rotary evaporation and the residue was dissolved in EtOAc and filtered through silica gel. The solvent was removed and the solid was recrystallized from solvents of ethyl acetate and hexane (1:5) to give a pale yellow crystal 9.5 g (90%), mp 131-132° C., δH (CDCl3, 300 MHz): 7.59 (s, 4H, Ar—H), 7.44 (d, J=8.7, 2H, Ar—H), 6.82 (d, J=8.7, 2H, Ar—H), 5.16 (s, 1H, OH).
Reaction SMILES: [CH3:1][Mg]Cl.[Br:4][C:5]1[CH:6]=[CH:7][C:8]([C:11](=[O:13])[CH3:12])=[N:9][CH:10]=1>O1CCCC1>[Br:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])([CH3:1])[CH3:12])=[N:9][CH:10]=1
Reactant: CC(=O)c1ccc(Br)cn1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Methylmagnesium chloride 3.0 M in THY (0.3 mL) was added dropwise to a mixture of 1-(5-bromopyridin-2-yl)ethanone (100 mg, 0.5 mmol) in tetrahydrofuran (10 mL) at 0° C. After stirring for 1 h at room temperature, the reaction was quenched with 1 N NH4Cl and was extracted with EtOAc. The combined organic layer was washed with brine and dried over MgSO4, concentrated to give crude 2-(5-bromopyridin-2-yl)propan-2-ol (0.1 g, 100%). LCMS calculated for C8H11BrNO (M+H)+: m/z=215.9, 217.9; found: 215.8, 217.8.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH:20]=[O:21])=[C:12]2[Cl:22])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.Cl>CO>[ClH:22].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH:20]=[O:21])=[C:12]2[NH:23][CH2:24][CH2:25][N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCN1CCCC1
Reactant: CC(C)(C)c1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1
Agent: Cl
Solvent: CO
Product: CC(C)(C)c1ccc(-n2c(NCCN3CCCC3)c(C=O)c3ccccc32)cc1
Yield: 20 %

Procedure:
1-(4-tert-Butylphenyl)-2-chloro-1H-indole-3-carboxaldehyde is reacted with 1-(2-aminoethyl)pyrrolidine as described in Step 2 of Example 29 to obtain oil. The oil is dissolved in small amount of methanol and treated with 1M ethereal hydrochloric acid. The solvents are removed and the residue is triturated with ether to yield 1-(4-tert-butylphenyl)-2-(2-pyrrolidin-1-yl-ethylamino)-1H-indole-3-carboxaldehyde hydrochloride (20% yield) as a light beige solid. ESI/MS 390 (M+H); RT 3.42 min. NMR 10.68 (1H, s); 7.95 (1H, d, J=9 Hz); 7.67 (2H, d, J=9 Hz); 7.47 (2H, d, J=9 Hz); 7.10 (2H, m); 6.63 (1H, d, J=9 Hz); 3.54 (2H, m); 3.40 (2H, m); 3.21 (2H, m); 2.83 (2H, m); 1.91 (4H, m); 1.35 (9H, s).
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[C:10]([F:17])[CH:9]=2)=[CH:5][CH:4]=1)#[N:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:49][C@@H:50]1[CH2:54][CH2:53][CH2:52][N:51]1[CH2:55][C@@H:56]1[CH2:60][CH2:59][CH2:58][NH:57]1>CN(C=O)C>[F:17][C:10]1[CH:9]=[C:8]([C:6]2[S:7][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH:16]=[CH:15][C:11]=1[C:12]([N:57]1[CH2:58][CH2:59][CH2:60][C@H:56]1[CH2:55][N:51]1[CH2:52][CH2:53][CH2:54][C@H:50]1[CH3:49])=[O:14]
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1
Reactant: N#Cc1ccc(-c2ccc(C(=O)O)c(F)c2)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(-c2ccc(C#N)s2)cc1F
Yield: 12.6 %

Procedure:
The title compound is prepared in a manner substantially analogous to General Procedure D in 6 mL DMF using 4-(5-cyano-thiophen-2-yl)-2-fluoro-benzoic acid (181 mg, 0.73 mmol), EDC-HCl (210 mg, 1.1 mmol), HOBt (149 mg, 1.1 mmol), DIEA (0.31 mL, 1.8 mmol) and 2-(R)-Methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine (101 mg, 0.60 mmol) to give the title compound (30 mg, 12% yield). MS (ES+) 398.3 (M+H)+
Reaction SMILES: CI.[O:3]=[C:4]([N:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:39])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([F:38])([F:37])[F:36])[CH2:24][CH2:23]1)[CH2:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][C:10]=1[OH:21])=[O:8].[C:40]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[O:3]=[C:4]([N:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:39])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([F:37])([F:38])[F:36])[CH2:24][CH2:23]1)[CH2:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:11][C:10]=1[O:21][CH3:40])=[O:8]
Reactant: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(-c2ccccc2)cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(-c2ccccc2)ccc1C(=O)NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 78.84 %

Procedure:
Methyl iodide (21 mg, 0.009 ml, 0.148 mmol) was added to a stirred solution of 3-hydroxy-biphenyl-4-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide (prepared by the method as described above) (51 mg, 0.1 mmol) and K2CO3 (20 mg, 0.144 mmol) in DMF (3 mL) and the resulting mixture was stirred at 80° C. for 2 hrs. The mixture was filtered, the filtrate was diluted with cold water and filtered the solid precipitated out, dried to afford 41 mg (78.84% yield) of 3-methoxy-biphenyl-4-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. 1H NMR: (DMSO-d6): δ 8.8-8.7 (bs, 1H), 8.04-7.98 (bs, 1H), 7.88-7.74 (dd, 4H), 7.72-7.64 (t, 1H), 7.58-7.46 (m, 3H), 7.46-7.34 (m, 3H), 4.32-4.18 (bs, 1H), 4.04 (s, 3H), 3.8-3.66 (bd, 2H), 3.66-3.54 (bt, 3H), 3.22-3.04 (bs, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15](OC(=O)CC)(=O)[CH2:16]C.CN1C=CN=C1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH2:15][CH3:16])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: CCC(=O)OC(=O)CC
Reactant: O=C(O)Cc1ccc(F)c([N+](=O)[O-])c1
Agent: Cn1ccnc1
Product: CCC(=O)Cc1ccc(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
Treat a solution of 2-(4-fluoro-3-nitrophenyl)acetic acid (1.5 g, 7.53 mmol) in propionic anhydride (5.40 mL, 45.2 mmol) with 1-methylimidazole (0.600 mL, 7.53 mmol) and stir at RT overnight. Quench the mixture with H2O, stir for 1 h, extract with EtOAc (2×), wash the combined organics with satd. Na2CO3, then brine, dry the organics over MgSO4, concentrate to dryness and purify via silica gel chromatography (EtOAc/Hex) to afford the title compound (830 mg, 52%). 1H NMR (400 MHz, DMSO-d6): δ 8.00 (dd, J=7.4, 2.2 Hz, 1H), 7.61 (ddd, J=8.6, 4.6, 2.2 Hz, 1H), 7.53 (dd, J=11.4, 8.6 Hz, 1H), 3.95 (s, 2H), 2.56 (q, J=7.3 Hz, 2H), 0.96 (t, J=7.3 Hz, 3H); MS (ESI) m/z: 212.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]([OH:6])([CH3:5])[C:3]#[CH:4].Cl[CH2:8][CH2:9][O:10][CH2:11][CH2:12][CH3:13]>>[CH2:11]([O:10][CH2:9][CH2:8][O:6][C:2]([CH3:5])([CH3:1])[C:3]#[CH:4])[CH2:12][CH3:13]
Reactant: CCCOCCCl
Reactant: C#CC(C)(C)O
Product: C#CC(C)(C)OCCOCCC
Yield: 22 %

Procedure:
In accordance with the procedure of the step 1 of Example 10, 30.3 g of 3-methyl-1-butyne-3-ol was allowed to react with 48.5 g of 2-chloroethylpropyl ether to obtain 13.5 g of 3-(2-n-propoxyethoxy)-3-methyl-1-butyne.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[NH:9][CH:8]=1)=[N+:2]=[N-:3].CC([O-])(C)C.[K+].[Cl:23][C:24]1[N:25]=[C:26]2[N:30]([C:31]=1[S:32](Cl)(=[O:34])=[O:33])[CH:29]=[CH:28][S:27]2>C1COCC1>[N:1]([CH2:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[N:9]([S:32]([C:31]2[N:30]3[C:26]([S:27][CH:28]=[CH:29]3)=[N:25][C:24]=2[Cl:23])(=[O:33])=[O:34])[CH:8]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCCc1c[nH]c2ccc(F)cc12
Reactant: O=S(=O)(Cl)c1c(Cl)nc2sccn12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: [N-]=[N+]=NCCCc1cn(S(=O)(=O)c2c(Cl)nc3sccn23)c2ccc(F)cc12
Reaction time: 0.5 h
Yield: 88 %

Procedure:
A stirred solution of 3-(3-azidopropyl)-5-fluoro-1H-indole (150 mg, 0.53 mmol) in THF is treated with KOt-Bu (0.55 ml, 0.55 mmol, 1M in THF solution) under nitrogen at room temperature, stirred for 30 min, treated with 6-chloroimidazo[2,1-b]thiazole-5-sulfonylchloride (141 mg, 0.55 mmol), stirred for 18 h at room temperature, quenched with 1N HCl and water and diluted with EtOAc. The two phases are separated and the aqueous phase is extracted with EtOAc. The extracts are combined with the organic phase and are dried over MgSO4 and concentrated in vacuo. The resultant residue is purified by flash chromatography (silica gel, EtOAc/hexane: 3/7) to give the title product as a yellow solid, 203 mg (88% yield), mp 84–86° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10](O)=[O:11].C1COCC1>O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][OH:11]
Reactant: O=C(O)C1Cc2ccccc2N1
Solvent: C1CCOC1
Solvent: O
Product: OCC1Cc2ccccc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
A slurry of racemic indoline-2-carboxylic acid (5.00 g) and anhydrous THF (60 mL) is cooled to 0° C. under an atmosphere of nitrogen. To this slurry is added 1.0 M borane-THF complex (100 mL) via syringe over 40 minutes. The resulting solution is allowed to warm to room temperature while stirring overnight. Water (ca. 400 mL) is slowly added to quench the reaction. The mixture is extracted with diethyl ether (400 mL). The combined organic layers are washed with saturated sodium bicarbonate solution followed by brine, dried (Na2SO4), filtered, and concentrated to afford 4.31 g (94%) of the title compound as a colorless foam. Physical characteristics: MS (ESI+) m/z 150 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:12][CH:13]1[C:17](=[O:18])[N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][CH:14]1[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][C@H:13]2[C:17](=[O:18])[N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][C@H:14]2[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)C1CN(c2ccccc2)C(=O)C1N
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CN(c2ccccc2)C(=O)[C@@H]1NC(=O)Nc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68 %

Procedure:
To a solution of 3,4-dichlorophenylisocyanate in CH2Cl2 (3 ml) was added a solution of aminopyrrolidinone of Example S (350 mg, 1.41 mmol) in CH2Cl2 (3 ml) and the resulting solution was stirred for 18 h at room temperature. Concentration in vacuo gave a solid which was triturated with CH2Cl2 and filtered to give the title compound (420 mg, 68%) as a solid. MS M+1 calcd for C20H19N3O4Cl2 437, found 437. DSC=249.1°-251.7° C. at 112.7 J/g.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][C:8]([NH:10][C@H:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH2:12][SH:13])=[O:9])[C:3]([OH:5])=[O:4].C(N(CC)CC)C.[F:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31]Cl.Cl>CO>[F:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31][S:13][CH2:12][C@@H:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[NH:10][C:8](=[O:9])[CH2:7][CH2:6][C@@H:2]([C:3]([OH:5])=[O:4])[NH2:1]
Reactant: Fc1ccccc1CCl
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: N[C@@H](CCC(=O)N[C@@H](CSCc1ccccc1F)C(=O)NCC(=O)O)C(=O)O
Temperature: 50 °C

Procedure:
A mixture of 3.07 g of glutathione, 2.8 cc of triethylamine and 100 cc of methanol is brought to a boil. Then a solution of 1.45 g of o-fluorobenzyl chloride in 20 cc of methanol is added. After this addition, the resulting mixture is heated for 3 hours at 50°C, then allowed to cool and, by addition of dilute hydrochloric acid, 3.35 g of a white product are precipitated which can then be crystallized in water. Thus a product having a melting point of around 200°C (with decomposition) is obtained.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]1[CH2:11][O:10][CH2:9][CH2:8]1.[OH2:12]>C1COCC1.C1C=CC=CC=1>[OH:10][CH2:11][C@H:7]1[C@@H:8]([CH2:9][OH:12])[CH2:9][CH:8]=[CH:7][CH2:11]1
Reactant: C1CCOC1
Reactant: O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: c1ccccc1
Product: OC[C@@H]1CC=CC[C@@H]1CO
Temperature: 0 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
(25.8 g) in THF (150 ml) is added with cooling to a stirred suspension of LiAlH4 (9 g) in THF (200 ml) under N2 at a rate such as to maintain the temperature at 0° C. After stirring for 18 hours at room temperature the mixture is gently refluxed for one hour and cooled in ice. The excess lithium aluminium hydride is decomposed by the careful addition of 1:1 THF-H2O mixture (100 ml). After dilution with chloroform (150 ml) the resulting mixture is filtered and the solid is washed with chloroform (3×25 ml). Concentration of the filtrate under reduced pressure yields an oily residue which is dissolved in benzene, dried over (MgSO4) and reconcentrated in vacuo to give the title compound as an oil (22 g, ca. 90%), νmax (film) 3350 cm-1.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH:26]1[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=[CH:27]1>>[N:26]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=[C:4]([N:13]3[CH2:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]3)[CH:3]=2)[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: C1=CNC=CN=C1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3CCCNCC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 1,4-diazepine. MS obsd. (ESI+) [(M+H)+] 437, 1H NMR (400 MHz, CD3OD) δ ppm 7.99 (d, J=7.2 Hz, 1 H), 7.86 (d, J=7.2 Hz, 1 H), 7.81 (d, J=8.8 Hz, 1 H), 7.72-7.68 (m, 2 H), 7.58-7.51 (m, 2 H), 6.31 (s, 1 H), 5.32 (s, 2 H), 4.54 (s, 2 H), 4.06-4.04 (m, 2 H), 3.90-3.87 (m, 2 H), 3.72 (s, 2 H), 3.63-3.61 (m, 2 H), 3.46-3.42 (m, 2 H), 2.45 (s, 3 H), 2.32 (s, 2 H).