Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:19][CH:18]=1.[F:31][C:32]1([F:47])[CH2:37][CH2:36][N:35]([C:38]2([C:44]([NH2:46])=[O:45])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:34][CH2:33]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl>C(Cl)Cl.CCN(CC)CC>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][C:12]([C:14]([N:41]2[CH2:40][CH2:39][C:38]([C:44]([NH2:46])=[O:45])([N:35]3[CH2:34][CH2:33][C:32]([F:31])([F:47])[CH2:37][CH2:36]3)[CH2:43][CH2:42]2)=[O:16])=[CH:11][C:10]=1[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:28])=[O:29])=[CH:19][CH:18]=1
Reactant: CS(=O)(=O)CCCOc1ccc(-c2cc(C(=O)O)sc2-c2ccc(F)cc2Cl)cc1
Reactant: NC(=O)C1(N2CCC(F)(F)CC2)CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)CCCOc1ccc(-c2cc(C(=O)N3CCC(C(N)=O)(N4CCC(F)(F)CC4)CC3)sc2-c2ccc(F)cc2Cl)cc1
Reaction time: 3 h
Yield: 119.1 %

Procedure:
0.3 g of the compound obtained in stage 22A), 0.3 g of 4,4-difluoro-1,4′-bipiperidine-4′-carboxamide (described in Preparation 5, page 23, of Application WO 2008/068423), 0.45 ml of Et3N and 0.25 g of TBTU are added in order to 10 ml of CH2Cl2. After 3 hours at AT, the mixture is concentrated to dryness and the residue is taken up in AcOEt, washed with water, dried and concentrated to dryness. After purifying by chromatography on silica (elution gradient: CH2Cl2 up to CH2Cl2/MeOH 98/2), the compound obtained is dissolved in CH2Cl2, ethereal hydrochloric acid is added down to a pH of 1 and then the mixture is concentrated to dryness. 0.28 g of the expected compound is obtained.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C:3]2([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:7][CH2:6]2)[CH2:2]1.Cl[C:15]1[N:16]=[N:17][C:18]([C:21]2[O:25][N:24]=[C:23]([CH3:26])[N:22]=2)=[CH:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:26][C:23]1[N:22]=[C:21]([C:18]2[N:17]=[N:16][C:15]([N:1]3[CH2:5][CH2:4][C:3]4([C:9]5[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=5[O:7][CH2:6]4)[CH2:2]3)=[CH:20][CH:19]=2)[O:25][N:24]=1
Reactant: c1ccc2c(c1)OCC21CCNC1
Reactant: Cc1noc(-c2ccc(Cl)nn2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1noc(-c2ccc(N3CCC4(COc5ccccc54)C3)nn2)n1
Yield: 47.2 %

Procedure:
A solution (5 ml) of spiro[1-benzofuran-3,3′-pyrrolidine] (50 mg) obtained in Example 50-(5) and 3-chloro-6-(3-methyl-1,2,4-oxadiazol-5-yl)pyridazine (56 mg) obtained in Example 43-(2) and potassium carbonate (79 mg) in N,N-dimethylformamide was stirred at 95° C. for 3 days. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated. The residue was recrystallized from ethyl acetate to give the object product (45.1 mg, 47%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][O:5][C:4](=[O:7])[N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.[ClH:17].[CH:18]1([C:21]2[C:22]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[N:23][CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=2)[CH2:20][CH2:19]1>>[ClH:17].[CH:18]1([C:21]2[C:22]([N:31]3[CH2:36][CH2:35][N:34]([C:12]([C:11]4[CH:10]=[CH:9][C:8]([N:3]5[C@H:2]([CH3:1])[CH2:6][O:5][C:4]5=[O:7])=[CH:16][CH:15]=4)=[O:14])[CH2:33][CH2:32]3)=[N:23][CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:26]=2)[CH2:19][CH2:20]1
Reactant: C[C@@H]1COC(=O)N1c1ccc(C(=O)O)cc1
Reactant: FC(F)(F)c1cnc(N2CCNCC2)c(C2CC2)c1
Agent: Cl
Product: C[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C(F)(F)F)cc3C3CC3)CC2)cc1
Yield: 111.9 %

Procedure:
By reaction and treatment in the same manner as in Example 87 and using (R)-4-(4-methyl-2-oxooxazolidin-3-yl)benzoic acid (221 mg) described in Preparation Example 37 and 1-(3-cyclopropyl-5-trifluoromethylpyridin-2-yl)piperazine hydrochloride (615 mg) described in Preparation Example 76, the title compound (571 mg) was obtained.
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH2:22])[NH:20][N:21]=2)[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1.[CH2:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:40]=[CH:39][C:34]([C:35](OC)=[O:36])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)[CH3:24].Cl>C1(C)C=CC=CC=1.CO>[CH3:14][O:13][C:11]1[CH:10]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH:22][C:35](=[O:36])[C:34]3[CH:33]=[CH:32][C:31]([N:28]4[CH2:27][CH2:26][N:25]([CH2:23][CH3:24])[CH2:30][CH2:29]4)=[CH:40][CH:39]=3)[NH:20][N:21]=2)[CH:8]=[C:7]([O:6][CH3:5])[CH:12]=1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Reactant: CCN1CCN(c2ccc(C(=O)OC)cc2)CC1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: CCN1CCN(c2ccc(C(=O)Nc3cc(CCc4cc(OC)cc(OC)c4)n[nH]3)cc2)CC1
Temperature: 60 °C
Reaction time: 24 h
Yield: 51.3 %

Procedure:
Trimethylaluminium (2M in toluene, 1.51 mL, 3.02 mmol) was added dropwise to 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (299 mg, 1.21 mmol) and methyl 4-(4-ethylpiperazin-1-yl)benzoate (300 mg, 1.21 mmol) in toluene (6.0 mL) at 25° C. The resulting suspension was stirred at 60° C. for 24 h under nitrogen. The reaction mixture was added to methanol (100 mL) and was treated with HCl (2N aqueous solution, until the pH was 7 or lower). The crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness to afford impure product. The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 5% 7M NH3/MeOH in DCM. Pure fractions were evaporated to dryness to afford the title compound (288 mg, 51%) as a cream solid.
Reaction SMILES: [Cl-].[OH:2][NH3+:3].C([O-])(=O)C.[Na+].[CH:9](=O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>O.C(O)C>[CH:9](=[N:3][OH:2])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCC=O
Reactant: [NH3+]O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCCCCC=NO
Yield: 270.8 %

Procedure:
To hydroxylammonium chloride (0.39 g; 5.57 mmol) and sodium acetate (0.54 g; 6.57 mmol) dissolved in 5 ml of water is added 1-(6-Benzoyl-9-ethyl-9.H.-carbazol-3-yl)-octan-1-one (2.14 g; 5.03 mol) in 15 ml of ethanol. After refluxing for 7 h, H2O is added to the reaction mixture, the resulting white solid is filtered off, washed with water and dissolved in tetrahydrofurane (THF). After drying this THF solution over anhydrous MgSO4, condensation under reduced pressure affords 2.16 g of a pale yellow solid (97%).
Reaction SMILES: N#N.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][C:31]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:34](O)=[O:35])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>C1COCC1>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][C:31]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)([C:34]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:35])[CH2:30][CH2:29]1)=[O:27])([CH3:23])([CH3:24])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccccc2)CC1
Reactant: C1CCNCC1
Agent: N#N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCCCC2)(c2ccccc2)CC1
Temperature: 25 °C
Yield: 24.4 %

Procedure:
Under a stream of nitrogen N,N′-carbonyldiimidazole (3.62 g, 22.3 mmol) followed by piperidine (3.74 g, 43.9 mmol) is added to a solution of 1-(tert-butoxycarbonyl)-4-phenyl-4-piperidinecarboxylic acid (3.40 g, 11.1 mmol) in dry THF (50 mL). The mixture is heated to reflux 18 h, then cooled to ambient temperature and concentrated by means of evaporation. The remanence is redissolved in ethyl acetate (150 mL) and successively washed with NaHCO3 (50 mL, aq, sat.), dilute HCl (50 mL) at pH 3, brine (50 mL), then dried (MgSO4) and evaporated to dryness. This intermediate is purified by silica gel chromatography eluting with ethyl acetate-heptane-triethylamine (40:50:10) to furnish 1.01 g (24%) of 4-phenyl-4-(piperidine-1-carbonyl)-piperidine-1-carboxylic acid tert-butyl ester as a white crystalline solid. This is dissolved in a mixture of MeOH (10 mL) and THF (10 mL), then 2M HCl in MeOH (5 mL) is added and the mixture is stirred at ambient temperature for 2 h. Water (20 mL) is added and pH is adjusted to pH 12 by addition of 2M NaOH. The organic phase is separated and the aqueous phase is extracted with ethyl acetate (30 mL). Combined organic fractions are dried (MgSO4) and concentrated in vacuo to furnish 0.47 g (63%) of (4-Phenyl-piperidine-4-yl)-piperidin-1-yl-methanone. LC/MS (m/z) 273.1 (M+H+); tR=1.65 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C@H:14]([OH:19])[C:15]([F:18])([F:17])[F:16])[C:11](=[O:20])[N:10]([CH2:21][C:22]([O:24]C)=[O:23])[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Li+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C@H:14]([OH:19])[C:15]([F:18])([F:16])[F:17])[C:11](=[O:20])[N:10]([CH2:21][C:22]([OH:24])=[O:23])[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
The enantiomerically pure ester from Example 6A (1.6 g, 4.21 mmol) was dissolved in 77 ml of methanol and admixed with 17 ml of a 1M solution of lithium hydroxide in water. The mixture was stirred at RT for 1 h and then concentrated on a rotary evaporator. The residue was diluted with 100 ml of water and acidified to a pH of 1-2 using 1N hydrochloric acid. The precipitated product was isolated by filtration, washed in succession with water and cyclohexane and sucked dry. After further drying in an HV, the title compound (1.1 g, 71% of theory) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1I.[CH:15]([Sn](CCCC)(CCCC)CCCC)=[CH2:16]>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[CH:15]=[CH2:16]
Reactant: COC(=O)c1nc(Cl)c(Cl)c(N)c1I
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: C=Cc1c(C(=O)OC)nc(Cl)c(Cl)c1N
Yield: 184.6 %

Procedure:
Methyl 4-amino-5,6-dichloro-3-iodopicolinate (0.5 g, 1.4 mmol), vinyltributylstannane (530 μl, 0.57 mmol, 1.8 mmol), and bis(triphenylphosphine)palladium(II) chloride (0.10 g, 0.1 mmol) were combined in nitrogen-deaerated 1,2-dichloroethane (10 mL). The reaction mixture was heated at reflux for 8 hours. The cooled reaction mixture was diluted with ethyl acetate (30 mL) and stirred with 15% KHF2 solution (10 mL) for 30 minutes. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by flash chromatography (SiO2, ethyl acetate/hexane) to afford the title compound as a tan solid (0.26 g, 73%): mp 96-97° C.; 1H NMR (400 MHz, CDCl3) δ 6.85 (dd, J=18.1, 11.5 Hz, 1H), 5.72 (dd, J=11.5, 1.3 Hz, 1H), 5.53 (dd, J=18.1, 1.3 Hz, 1H), 5.19 (s, 2H), 3.91 (s, 3H); EIMS m/z 246 ([M−H)−].
Reaction SMILES: [Br:1][C:2]1[C:22]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[C:21]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:20]=[CH:19][C:3]=1[C:4]([CH:6]([C:14]([CH:16]1[CH2:18][CH2:17]1)=[O:15])C(OC(C)(C)C)=O)=[O:5].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:16]1([C:14](=[O:15])[CH2:6][C:4]([C:3]2[CH:19]=[CH:20][C:21]([S:28]([CH3:31])(=[O:30])=[O:29])=[C:22]([O:23][CH2:24][CH2:25][O:26][CH3:27])[C:2]=2[Br:1])=[O:5])[CH2:18][CH2:17]1
Reactant: COCCOc1c(S(C)(=O)=O)ccc(C(=O)C(C(=O)OC(C)(C)C)C(=O)C2CC2)c1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COCCOc1c(S(C)(=O)=O)ccc(C(=O)CC(=O)C2CC2)c1Br
Yield: 91.1 %

Procedure:
A mixture of crude t-butyl 2-[2-bromo-3-(2-methoxyethoxy)-4-methylsulphonylbenzoyl]-3-cyclopropyl-3-oxopropanoate (10.2 g) and 4-toluenesulphonic acid (2 g) in dry toluene was stirred and heated at reflux for 2 hours. The cooled mixture was washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness to give 3-cyclopropyl-1-[2-bromo-3-(2-methoxyethoxy)-4-methylsulphonylphenyl]propan-1,3-dione (7.5 g) as a brown oil which was not purified further NMR(CDCl3) 0.9(4H,m), 1.5(1H,m), 3.1(3H,s), 3.3(3H,s), 3.6(2H,t), 4.2(2H,t), 5.7(1H,s), 7.15(1H,d), 7.8(1H,d).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][C:11](=O)[C:12]([CH3:20])([CH3:19])[CH2:13][N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)[CH3:9])=[CH:4][CH:3]=1.B.C1COCC1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][CH2:11][C:12]([CH3:19])([CH3:20])[CH2:13][N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(NC(=O)C(C)(C)Cn1ccnc1)c1ccc(Cl)cc1
Agent: B
Solvent: C1CCOC1
Product: CC(NCC(C)(C)Cn1ccnc1)c1ccc(Cl)cc1

Procedure:
In a similar manner to Example 52d, N-[1-(4-chlorophenyl)ethyl]-3-(imidazol-1-yl)-2,2-dimethylpropionamide (4.0 g) in THF (100 ml) was treated with BH3/THF (52.1 ml, 1M) to give an oil which was distilled at 165° C. (0.05 mmHg) and the lower boiling fraction redistilled to give N-[1-(4-chlorophenyl)ethyl]-3-(imidazol-1-yl)-2,2-dimethylpropylamine, b.p. 160° C. (0.03 mmHg).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].C(=O)([O-])[O-].[K+].[K+].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Br)=[CH:19][CH:18]=1.O>CN(C)C=O>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[CH:19][CH:18]=1
Reactant: COC(=O)CC(=O)OC
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(Br)cc1)C(=O)OC
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
A mixture of dimethyl malonate (42.6 g, 322.73 mmol, 4.00 equiv) and potassium carbonate (22.3 g, 161.59 mmol, 2.00 equiv) in N,N-dimethylformamide (200 mL) was stirred for 30 min at 50° C. A solution of 1-bromo-4-(bromomethyl)benzene (20 g, 80.65 mmol, 1.00 equiv) in N,N-dimethylformamide (80 mL) was then added dropwise with stirring to the reaction mixture. The resulting solution was stirred at 50° C. for 2 h. Water (100 mL) was added and the mixture was extracted with 1×400 mL of ethyl acetate. The organic layer was washed with 2×100 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 22 g (91%) of dimethyl 2-(4-bromobenzyl)malonate as a white solid. LC-MS: (ES, m/z): 301 [M+H]+, 126, 120.
Reaction SMILES: [CH3:1][C:2]12[CH2:17][CH:6]([N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:8]1=[O:9])[CH:5]=[CH:4][CH2:3]2.IC1C2CC(C)(C(=O)N2[C:27](OC(C)(C)C)=[O:28])CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CO>[C:13]([O:12][C:10]([NH:7][CH:6]1[CH2:17][C:2]([CH3:1])([C:8]([O:28][CH3:27])=[O:9])[CH2:3][CH:4]=[CH:5]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1C(=O)C2(C)CC=C(I)C1C2
Reactant: CC(C)(C)OC(=O)N1C(=O)C2(C)CC=CC1C2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Product: COC(=O)C1(C)CC=CC(NC(=O)OC(C)(C)C)C1
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 1-methyl-7-oxo-6-azabicyclo[3.2.1]oct-3-ene-6-carboxylate, 52e, (4.93 g, 20.78 mmol) in MeOH (100 mL) was added cesium carbonate (13.54 g, 41.56 mmol). The reaction was stirred overnight and then concentrated in vacuo. The cesium salts were precipitated with Et2O and filtered. The ether filtrate was evaporated to give 5.5 g of a yellow oil that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.CCOC(C)=O>CC(O)=O.[Zn]>[Cl:1][C:2]1[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][CH2:6][N:7]1[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: O=[N+]([O-])c1ccc(OCCN2CCCC2)c(Cl)c1
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1ccc(OCCN2CCCC2)c(Cl)c1

Procedure:
A suspension of Zn powder (620 mg, 9.48 mmol) and 1-(2-(2-chloro-4-nitrophenoxy)ethyl)pyrrolidine (320 mg, 1.19 mmol) in AcOH:H2O (3:1 mL) was heated at 55° C. for 2 h. After cooling the reaction to RT, any solid was removed by filtration and rinsed with AcOH and CH2Cl2. Once the combined filtrate was concentrated using a rotavap, the resulting residue was adjusted pH to 10 with NH4OH and extracted with CH2Cl2 (2×50 mL). The combined organic layers were washed with H2O (10 mL), then dried over MgSO4. After removal of the solvent under vacuum the pale brownish oil (0.26 g, 93%) was carried forward without further purification. MS (ESI) 241 (M+H)+.
Reaction SMILES: C([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[CH:26]=[C:25]([C:27]([OH:29])=[O:28])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)=[CH:9]1)(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[CH:26]=[C:25]([C:27]([OH:29])=[O:28])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)=[CH:9]1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc(C(=O)O)c3ccccc3n2)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc(-c2c[nH]c3ccccc23)nc2ccccc12
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a 10 mL pear-shaped flask was added 2-(N-Boc-3-indolyl)-4-quinolinecarboxylic acid or ester (1 mmol) and 3 mL of a 50% mixture of TFA and DCM. The reaction mixture was stirred for 30 min at 20° C. The solvent was removed under reduced pressure and the residual solid lyophilized to give 2-(3-indolyl)-4-quinolinecarboxylic acid or ester (95-100% yield).
Reaction SMILES: [C:1]1([C:11]([N:13]2[C:17](=[O:18])[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:15][C:14]2=[O:31])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[CH2:33][C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:35].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[C:1]1([C:11]([N:13]2[C:17](=[O:18])[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:15]([CH2:33][C:34](=[O:35])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:14]2=[O:31])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1C(=O)c1cccc2ccccc12
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)N(C(=O)c2cccc3ccccc23)C(=O)C1(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
3-Naphthylcarbonyl-5,5-diphenylimidazolidine-2,4-dione (100 mg) was dissolved in DMF (2 mL), 2-bromoacetophenone (52 mg) was added, and potassium carbonate (36 mg) was further added. The reaction solution was stirred at room temperature overnight. Ethyl acetate (100 mL) was added to the reaction solution, and the solution was washed with 1N hydrochloric acid, an aqueous saturated sodium bicarbonate solution and a saturated brine in turn. After the solution was dried over anhydrous magnesium sulfate, the solvent was distilled off. The resulting residue was recrystallized from IPE to obtain 69 mg of white crystals.
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[CH2:3][C@H:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].ClCCl.[C:23]([O:27][C:28]([NH:30][C@@H:31]([CH3:35])[C:32](Cl)=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24]>C(N(CC)CC)C>[C:23]([O:27][C:28]([NH:30][C@@H:31]([CH3:35])[C:32]([N:1]1[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[CH2:3][C@H:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Cl
Reactant: O=C(OCc1ccccc1)[C@@H]1CC2=C(CCCC2)N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1C2=C(CCCC2)C[C@H]1C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
Introduce 200 g of benzyl (2S)-2,3,4,5,6,7-hexahydro-1H-indole-2-carboxylate and 1.5 liters of dichloromethane into a reactor, then bring the temperature of the reaction mixture to 0° C. and add 107 ml of triethylamine and then 162 g of (2S)-2-[(tert-butoxycarbonyl)amino]propionyl chloride. Subsequently, bring the mixture to ambient temperature. After stirring for 1 hour at that temperature, wash the mixture with water and then with a dilute acetic acid solution. The benzyl (2S)-1-{(2S)-2-[(tert-butoxycarbonyl)amino]propionyl}-2,3,4,5,6,7-hexahydro-1H-indole-2-carboxylate solution so obtained is used as it is in the following Step.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][CH3:34])[CH2:3][N:4]1[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[C:28]([F:31])([F:30])[F:29])[N:15]=[CH:14]3)/[S:6][C:5]1=[O:32].[CH3:35][S:36](Cl)(=[O:38])=[O:37]>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:16]2[C:17]3[C:13](=[CH:12][C:11](/[CH:10]=[C:7]4/[C:8](=[O:9])[N:4]([CH2:3][C@@H:2]([NH:1][S:36]([CH3:35])(=[O:38])=[O:37])[CH2:33][CH3:34])[C:5](=[O:32])[S:6]/4)=[CH:19][CH:18]=3)[CH:14]=[N:15]2)=[C:22]([C:28]([F:30])([F:29])[F:31])[CH:23]=1
Reactant: CC[C@H](N)CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O
Reactant: CS(=O)(=O)Cl
Product: CC[C@@H](CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O)NS(C)(=O)=O

Procedure:
N-[(1S)-1-{[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methyl}propyl]methanesulfonamide was prepared from 3-[(2S)-2-aminobutyl]-(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione (Example 154) and methanesulfonyl chloride following General Procedure U.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CCCCCC>C(OCC)(=O)C>[C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77 %

Procedure:
To a solution of tert-butyl 4-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine-1-carboxylate (5.06 g, 14.6 mmol) in ethyl acetate (80 ml) was added a 4 N solution of hydrogen chloride in ethyl acetate (40 ml), and the mixture was stirred at room temperature for 5 hours. Hexane (200 ml) was added to the reaction mixture and a precipitated solid was collected by filtration. The obtained solid was added to an aqueous saturated sodium bicarbonate solution (300 ml), followed by stirring at room temperature for 2 hours. The obtained powder was collected by filtration to yield 2.77 g (77.0%) the desired product.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[S:6][CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][C@H:3]1[C:13]([OH:15])=[O:14].C(N(CC)CC)C.[Cl:24][C:25]1[CH:37]=[CH:36][C:28]([O:29][C:30]([CH3:35])([CH3:34])[C:31](Cl)=[O:32])=[CH:27][CH:26]=1>ClCCl>[Cl:24][C:25]1[CH:37]=[CH:36][C:28]([O:29][C:30]([CH3:34])([CH3:35])[C:31]([N:4]2[C@@H:3]([C:13]([OH:15])=[O:14])[C:2]([CH3:16])([CH3:1])[S:6][C@H:5]2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:32])=[CH:27][CH:26]=1
Reactant: CC1(C)SC(c2ccccc2)N[C@H]1C(=O)O
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(Oc1ccc(Cl)cc1)C(=O)N1[C@@H](C(=O)O)C(C)(C)S[C@H]1c1ccccc1
Temperature: 0 °C

Procedure:
1.17 g (5 mmoles) of 5,5-dimethyl-2-phenylthiazolidine-4(S)-carboxylic acid and 0.7 ml of triethylamine are dissolved in 20 ml of dichloromethane while stirring and the solution is cooled to 0° C. Then, 2-(4-chlorophenoxy)-isobutyryl chloride dissolved in 4 ml of dichloromethane is added under stirring. After stirring for 3 hours, the solution is washed with water, dried over anhydrous magnesium sulphate and evaporated. The obtained syrup is recrystallized from methanol by adding water to give the title compound in a yield of 1.39 g (64%), m.p.: 177°-181° C., [α]D21 =0° (c=0.94, dimethylsulphoxide).