Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[N:11]=[C:10]2[O:23][CH3:24])=[C:4]([F:25])[CH:3]=1.[CH2:26](Br)[C:27]#[CH:28].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[Cl:1][C:2]1[C:7]([O:8][CH2:28][C:27]#[CH:26])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:21])([F:22])[C:17]([F:20])([F:18])[F:19])[N:11]=[C:10]2[O:23][CH3:24])=[C:4]([F:25])[CH:3]=1
Reactant: C#CCBr
Reactant: COc1nc(C(F)(F)C(F)(F)F)cc(=O)n1-c1cc(O)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C#CCOc1cc(-n2c(OC)nc(C(F)(F)C(F)(F)F)cc2=O)c(F)cc1Cl

Procedure:
using 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-2-methoxy-4-pentafluoroethyl-6(1H)-pyrimidinone and propargyl bromide with sodium carbonate in acetone there is obtained 1-[4-chloro-2-fluoro-5-(2-propynyloxy) -phenyl]-2-methoxy-4-pentafluoroethyl-6(1H)-pyrimidinone, 1H-NMR (CDCl3, 400 MHz): 7.35 ppm (d,1H), 6.98 ppm (d,1H), 6.67 ppm (s,1H), 4.77 ppm (m,2H), 3.99 ppm (s,3H), 2.58 ppm (t,1H);
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].CN(C=O)C.[OH:10][C:11]1[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14].C(=O)([O-])[O-].[K+].[K+]>O>[I:21][C:19]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([O:10][CH:2]([CH3:4])[CH3:3])[CH:20]=1
Reactant: CC(C)Br
Reactant: COC(=O)c1ccc(I)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(I)cc1OC(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Bromopropane (6.49 mL) was added to a DMF (70 mL) suspension of methyl 2-hydroxy-4-iodobenzoate (12.8 g) and potassium carbonate (12.7 g), and the mixture was stirred at 60 C for 2 hours. The reaction mixture was allowed to cool to room temperature, and then, water was added thereto, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to obtain the title compound (14.0 g).
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8]N)=[CH:4][CH:3]=1.[C:11]([N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)([O:13][CH2:14][CH3:15])=[O:12]>CCO>[CH3:10][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:19]3[CH2:20][CH2:21][N:16]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:17][C:18]=3[C:4]=2[CH:3]=1
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)N1CCc2[nH]c3ccc(C)cc3c2C1
Reaction time: 8 h
Yield: 85.7 %

Procedure:
Following a literature procedure (Harbert et al., J. Med. Chem. 1980, 23, 635-643) p-tolylhydrazine hydrochloride (0.500 g, 3.15 mmol) and 1-carbethoxy-4-piperidone (0.18 mL, 1.17 mmol) were suspended in EtOH (0.880 mL) and heated to reflux for 2 hours. The reaction mixture was removed from heat and allowed to stand overnight at ambient temperature. The resulting mixture was filtered and washed with 50% aqueous EtOH to afford the desired product as a beige powder (259 mg, 86%).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH:9]([C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17])[C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])#[N:4].Br[CH2:23][CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1.O>CN(C=O)C>[C:3]([CH2:5][CH2:6][CH2:7][CH2:8][C:9]([CH2:23][CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17])#[N:4]
Reactant: C=CCOC(=O)C(CCCCC#N)C(=O)OCC=C
Reactant: COC(=O)c1ccc(CCBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)C(CCCCC#N)(CCc1ccc(C(=O)OC)cc1)C(=O)OCC=C
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
5.62 g (140 mmol; 60% pure) of sodium hydride are added in portions to a solution of 48.64 g (127.73 mmol) of diallyl 2-(4-cyanobutyl)malonate in 160 ml of dry DMF at 0° C. The reaction solution is then allowed to reach room temperature and is stirred for 90 min. The reaction solution is then cooled to 0° C. again and, after addition of 45.72 g (153.3 mmol) of methyl 4-(2-bromoethyl)benzoate in 80 ml of dry DMF, stirred at this temperature for 45 min. The mixture is then stirred at room temperature overnight. The reaction mixture is mixed with water and extracted with ethyl acetate. After phase separation, the aqueous phase is extracted three more times with 200 ml of ethyl acetate each time. After combining the combined organic phases, the mixture is washed with saturated sodium chloride solution and dried over sodium sulfate, and then the solvent is stripped off in vacuo. The resulting crude product is purified by silica gel chromatography (mobile phase: cyclohexane/ethyl acetate 10:1→100% ethyl acetate). 18.53 g (43.3 mmol, 34% of theory) of a colorless liquid are obtained.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:8]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH2:7][CH2:6][N:5]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:4]1.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.C1(S(OCC2C(C3SC=CC=3)CCN(C)C2)(=O)=O)C=CC=CC=1>C1(C)C=CC=CC=1>[C:19]1([S:25]([O:1][CH2:2][CH:3]2[CH:8]([C:9]3[S:10][CH:11]=[CH:12][CH:13]=3)[CH2:7][CH2:6][N:5]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:4]2)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCCCCN1CCC(c2cccs2)C(CO)C1
Agent: CN1CCC(c2cccs2)C(COS(=O)(=O)c2ccccc2)C1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCN1CCC(c2cccs2)C(COS(=O)(=O)c2ccccc2)C1

Procedure:
3-benzenesulphonyloxymethyl-1-pentyl-4-(2-thienyl)-piperidine (14) was prepared from 3-hydroxymethyl-1-pentyl-4-(2-thienyl)piperidine (13 g), benzenesulphonyl chloride (13 ml) and triethylamine (12.5 ml) in dry toluene (100 ml) as described for (2). Yield: 20.4 g, mass spectrum (M+ 407) in accordance with proposed structure
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([O:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[Cl:24])[CH:10]=[CH:9][C:8]=1[C:25]#[N:26])[CH3:5].O.[NH3:29]>C1C=CC=CC=1>[C:25]([C:8]1[CH:9]=[CH:10][C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][C:15]=2[Cl:24])=[CH:12][C:7]=1[O:6][CH:4]([CH3:5])[C:3]([NH2:29])=[O:2])#[N:26]
Reactant: COC(=O)C(C)Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1C#N
Reactant: N
Solvent: c1ccccc1
Solvent: O
Product: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1C#N)C(N)=O
Temperature: 0 °C
Yield: 57.1 %

Procedure:
A 10 g of methyl-α-[2-cyano-5-(2-chloro-4-trifluoromethyl phenoxy)phenoxy]propionate was dissolved in 20 ml of benzene. The solution was cooled at 0° C. and 10 g of 28% ammonia water was added dropwise to react them at room temperature for 2 hours. After the reaction, the benzene phase was separated and was washed with water. The benzene was distilled off and the product was recrystallized from methanol to obtain 5.5 g of the object compound having a melting point of 134° to 137° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][CH:17]([NH:21]C(=O)OC(C)(C)C)[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][CH:17]([NH2:21])[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:29][CH:30]=1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CC(NC(=O)OC(C)(C)C)CC4)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cn2ncc3c4c(cnc32)CC(N)CC4)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.4 %

Procedure:
To a solution of tert-butyl 3-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoquinolin-7-ylcarbamate (3.0 g, 8.8 mmol) in dichloromethane (30 mL) was added trifluoroacetic acid (10 mL). The reaction was stirred at room temperature for 3 hours. The solvent was then removed under reduced pressure to give an oily residue that was triturated in diethyl ether to give a solid. The solid was filtered, washed with diethyl ether and dried under reduced pressure to give the desired product 3-(4-methoxy-benzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoquinolin-7-ylamine (TFA salt) as a brown solid (2.1 g, 92%). 1H NMR (400 MHz, DMSO-d6) δ 8.08 (bs, 2H), 8.07 (s, 1H), 8.02 (s, 1H), 7.161 (d, 2H, J=8.4 Hz), 6.84 (d, 2H, J=8.8 Hz), 5.53 (s, 2H), 3.69 (s, 3H), 3.67-3.52 (m, 1H) 3.23 (dd, J=4.4, 16 Hz, 1H), 3.16-3.04 (m, 2H), 2.930 (dd, J=9.6, 15.6 Hz, 1H), 2.19-2.29 (m, 1H), 1.85-1.98 (m, 1H). LCMS [M+H]: 309.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].[NH:16]1[CH2:21][CH2:20][S:19][CH2:18][CH2:17]1>C(N(CC)CC)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12]([N:16]1[CH2:21][CH2:20][S:19][CH2:18][CH2:17]1)(=[O:14])=[O:13]
Reactant: C1CSCCN1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)N2CCSCC2)c1Cl
Yield: 93.6 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (2.0 g, 6.88mmol), thiomorpholine (710 mg, 6.88 mmol) and triethylamine(l.92mL, 13.76mmnol) were reacted to form the desired product (2.30 g, 94%). 1H NMR (MeOD-d4): δ 7.95 (d, 1H), 7.85(d, 1H), 3.68 (t, 4H), 2.69 (t, 4H).
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[C:8]([C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[CH:15]=O)([CH3:11])([CH3:10])[CH3:9].N1CCCCC1>C(O)C>[C:21]([C:18]1[CH:17]=[C:14]([CH:15]=[C:7]2[S:1][C:2](=[S:3])[NH:4][C:5]2=[O:6])[CH:13]=[C:12]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:19]=1[OH:20])([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C1CSC(=S)N1
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)(C)c1cc(C=C2SC(=S)NC2=O)cc(C(C)(C)C)c1O
Yield: 69.5 %

Procedure:
To a solution of 14.6 g (110 mmol) of rhodanine and 25.7 g (110 mmol) of 3,5-di-tert-butyl-4-hydroxybenzaldehyde in 150 ml of ethanol, 1.08 ml (11.0 mmol) of piperidine was added, and the mixture was heated under reflux for 5 hours. After cooling, the precipitated crystals were filtered and washed with cooled ethanol to give 26.71 g of the desired compound (69.7% yield, pale yellow crystals).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][CH:17]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([NH2:34])=[C:30]([N+:35]([O-])=O)[CH:29]=3)[C:18]([N:20]3[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][CH2:21]3)=[O:19])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:38](O)=O>[Pd]>[CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][CH:17]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]4[NH:34][CH:38]=[N:35][C:30]=4[CH:29]=3)[C:18]([N:20]3[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][CH2:21]3)=[O:19])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1CCN(C(=O)C(Cc2ccc(N)c([N+](=O)[O-])c2)NS(=O)(=O)c2ccc(C3CCCCC3)cc2)CC1
Reactant: O=CO
Agent: [Pd]
Product: CC1CCN(C(=O)C(Cc2ccc3[nH]cnc3c2)NS(=O)(=O)c2ccc(C3CCCCC3)cc2)CC1

Procedure:
Prepared from 4-cyclohexyl-N-[1-((4-amino-3-nitrophenyl)-methyl)-2-(4-methyl-piperidin-1-yl)-2-oxoethyl]-benzenesulphonamide and cyclising with formic acid in the presence of palladium/charcoal analogously to Example 1.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[C:12]2[CH2:17][C:16]([CH3:19])([CH3:18])[CH2:15][C:14]([CH3:21])([CH3:20])[CH2:13]2)=[CH:7][CH:6]=1.[OH-].[Na+].Cl>CCO.C1COCC1>[OH:28][C:25]1[CH:26]=[CH:27][C:22]([C:11](=[C:12]2[CH2:13][C:14]([CH3:21])([CH3:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH2:17]2)[C:8]2[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:29])=[O:2])=[CH:6][CH:7]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(CC(=O)O)cc2)CC(C)(C)C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of methyl{4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}acetate (153) (0.20 g, 0.51 mmol) in a mixture of EtOH (6 mL) and THF (6 mL) was added an aqueous solution of 1 N NaOH (7 mL). The mixture was stirred at 60° C. for 2 h. Upon cooling, the mixture was acidified to pH=2 with an aqueous solution of 1 N HCl. The mixture was extracted with EtOAc (2×50 mL). The combined organic extract washed with brine and dried over Na2SO4. Upon concentration and trituration with hot hexanes (containing 1% methanol), the title compound 154 was obtained as a white solid (0.185 g, 96%). mp 220-221° C. 1H NMR (400 MHz, DMSO-d6): δ 0.86 (s, 6H), 0.87 (s, 6H), 1.23 (s, 2H), 1.87 (s, 2H), 1.89 (s, 2H), 3.49 (s, 2H), 6.64 (d, J=8.4 Hz, 2H), 6.90 (d, J=8.5 Hz, 2H), 7.03 (d, J=8.1 Hz, 2H), 7.14 (d, J=8.1 Hz, 2H), 9.24 (s, 1H), 12.26 (s, 1H). LCMS (ESI): m/z 401 (M+Na)+, 377 (M−H)−. Anal. Calcd for C25H30O3. ⅙H2O: C, 78.71; H, 8.01; Found: C, 78.73; H, 7.98.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])[CH2:25][CH:24]2[O:39][CH2:40][C:41]2[CH:42]=[CH:43][C:44]3[O:49][CH2:48][CH2:47][N:46]([CH2:50][CH2:51][CH2:52][O:53][CH3:54])[C:45]=3[CH:55]=2)=[CH:19][CH:18]=1.[CH2:56]([O:58][C:59](=[O:68])[CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[C:63](O)[CH:62]=1)[CH3:57].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:56]([O:58][C:59]([CH2:60][C:61]1[CH:62]=[C:63]([CH:64]=[CH:65][CH:66]=1)[O:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:30])[CH2:25][CH:24]2[O:39][CH2:40][C:41]2[CH:42]=[CH:43][C:44]3[O:49][CH2:48][CH2:47][N:46]([CH2:50][CH2:51][CH2:52][O:53][CH3:54])[C:45]=3[CH:55]=2)=[CH:21][CH:22]=1)=[O:68])[CH3:57]
Reactant: CCOC(=O)Cc1cccc(O)c1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(CO)cc3)cc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)Cc1cccc(OCc2ccc(C3CCN(C(=O)OCc4ccccc4)CC3OCc3ccc4c(c3)N(CCCOC)CCO4)cc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.1122 g of diisopropyl azodicarboxylate is added dropwise to a solution of 0.246 g of benzyl 4-(4-hydroxymethylphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 270c), 0.1061 g of ethyl(3-hydroxyphenyl)acetate, 0.1396 g of triphenylphosphine and 5 ml of tetrahydrofuran. The solution is stirred at room temperature for 1 hour and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.28 (1:1 EtOAc-heptane); Rt=5.91.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][C@H:10]2[C@@:15]3([CH2:21][C:20](=[O:22])[NH:19][CH2:18][CH2:17][S:16]3(=[O:24])=[O:23])[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]Cl)[CH:26]=1>CS(C)=O.C(OCC)(=O)C>[C:3]1([CH2:9][C@H:10]2[C@@:15]3([CH2:21][C:20](=[O:22])[N:19]([CH2:31][C:27]4[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=4)[CH2:18][CH2:17][S:16]3(=[O:23])=[O:24])[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1C[C@]2(CCCC[C@H]2Cc2ccccc2)S(=O)(=O)CCN1
Reactant: ClCc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C1C[C@]2(CCCC[C@H]2Cc2ccccc2)S(=O)(=O)CCN1Cc1cccnc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 27.3 %

Procedure:
A stirred suspension of sodium hydride (5.5 g, 60% dispersion in mineral oil) in dimethyl sulfoxide (400 ml) was heated at 60° C. for 1 hour under nitrogen atmosphere. (1S,6S)-1-Phenylmethyl-11-oxo-7-thia-10-azaspiro[5.6]-dodecane 7,7-dioxide (40.0 g) and 3-pyridylmethyl chloride (25 g) were added to the nearly clear solution and the mixture was allowed to stand at room temperature for 15 minutes. The mixture was diluted with ethyl acetate (2 l) and washed with saturated aqueous sodium bicarbonate (2 l) and brine (2 l). The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was triturated with ethyl acetate and recrystallized from ethanol to give (1S,6S)-1-phenylmethyl-10-(3-pyridylmethyl)-11-oxo-7-thia-10-azaspiro[5.6]dodecane 7,7-dioxide (14.0 g).
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=[O:7])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].[OH-:22].[Na+]>O1CCOCC1>[OH:22][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=[O:7])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: [OH-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(O)c1ccccc1C(=O)c1ccc(O)c([N+](=O)[O-])c1

Procedure:
2-(4-hydroxy-3-nitrobenzoyl)benzoic acid is prepared as follows: a mixture of 10.0 g of 2-(4-chloro-3-nitrobenzoyl)benzoic acid, 200 ml of aqueous sodium hydroxide (1.5 M) and 20 ml of dioxane is heated at reflux for 12 hours. After cooling, the mixture is added to 200 ml of 1:1 concentrated sulfuric acid-ice water with stirring. The resulting solid is filtered, washed with water to a pH of about 6 and dried to obtain 9.5 g of 2-(4-hydroxy-3-nitrobenzoyl)benzoic acid as a light yellow solid. MS: (EI 70 eV); M+,(%): 287 (36); 197 (31); 166 (100); 149 (75); 120 (34).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([Cl:18])[CH:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Br:19]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=2)=[CH:12][C:13]=1[Cl:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Oc2ccc(C#N)c(Cl)c2)cc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(Oc2ccc(CBr)c(Cl)c2)cc1Cl
Temperature: 25 °C
Yield: 17.7 %

Procedure:
To a stirred solution of 2-chloro-4-(3-chloro-4-methyl-phenoxy)-benzonitrile (14.41 g) in CCl4 (100 ml) under argon were added N-bromosuccinimide (9.5 g) and dibenzoylperoxide (1.38 g). The mixture was heated to reflux for 2.5 h. After cooling to room temperature, the mixture was filtered. The filter cake was washed with cyclohexane. The combined filtrate was concentrated to dryness to give the crude product (19.75 g) as a light orange solid. Part of the product was purified by repeated chromatography (SiO2, cyclohexane/ethyl acetate 1:0=>4:1) to give the title compound as an off-white solid (3.27 g).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[C:12]([CH3:32])[CH:11]=1>>[CH3:30][C:29]1[C:24]([N:21]2[CH2:20][CH2:19][N:18]([C:16]([C:13]3[CH:14]=[CH:15][C:10]([N:4]4[CH2:3][C@H:2]([CH3:1])[CH2:6][S:5]4(=[O:8])=[O:7])=[CH:11][C:12]=3[CH3:32])=[O:17])[CH2:23][CH2:22]2)=[N:25][CH:26]=[C:27]([CH3:31])[CH:28]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C)CC2)c(C)c1
Reactant: C[C@H]1CNS(=O)(=O)C1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C[C@H](C)CS4(=O)=O)cc3C)CC2)c(C)c1
Yield: 17.5 %

Procedure:
Using (S)-4-methylisothiazolidine 1,1-dioxide (110 mg) described in Preparation Example 4 and (4-bromo-2-methylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (210 mg) described in Preparation Example 118 and by the reaction and treatment in the same manner as in Example 4, the title compound (42 mg) was obtained.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH3:12])[CH:11]=1)[C:7]#[N:8].[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([CH:21]([CH3:23])[CH3:22])=[C:16]([Cl:24])[N:15]=1.C(OCC)(=O)C>CN(C=O)C>[Cl:13][C:14]1[N:19]=[C:18]([O:3][C:4]2[CH:5]=[C:6]([CH:9]=[C:10]([CH3:12])[CH:11]=2)[C:7]#[N:8])[C:17]([CH:21]([CH3:22])[CH3:23])=[C:16]([Cl:24])[N:15]=1
Reactant: Cc1cc(O)cc(C#N)c1
Reactant: CC(C)c1c(Cl)nc(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C#N)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 88 %

Procedure:
At 0° C., NaH (60%, 125 mg, 3.06 mmol, 1.0 eq.) was added to 3-hydroxy-5-methyl-benzonitrile (408 mg, 3.06 mmol) in 10 mL of DMF solution. The reaction mixture was stirred at 0° C. for 5 minutes. 2,4,6-Trichloro-5-isopropyl-pyrimidine (691 mg, 3.06 mmol) was then added. The reaction mixture was stirred at 0° C. for 30 minutes. Ethyl acetate was added to the reaction mixture, which was then washed with brine. The organic layer was concentrated and purified (silica gel, 0-50% EtOAc/hexane) to give a white solid (868 mg, 88%). LC-MS shows 322.1 (M+1). 1H NMR (300 MHz, CDCl3): δ 7.41 (s, 1H), 7.26 (s, 1H), 7.19 (s, 1H), 3.60 (m, 1H), 2.42 (s, 3H), 1.42 (d, 6H).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([CH2:11][NH:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[N:16][N:17]2[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([OH:10])[C:6]([F:9])([F:8])[F:7])[CH3:2].[CH2:28](N)CC.C1(N2C3C=CC=C(NCC4(C(F)(F)F)CO4)C=3C=N2)C=CC=CC=1>>[F:7][C:6]([F:9])([F:8])[C:5]([CH2:4][NH:3][CH2:1][CH2:2][CH3:28])([OH:10])[CH2:11][NH:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[N:16][N:17]2[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCCN
Reactant: CCNCC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F
Agent: FC(F)(F)C1(CNc2cccc3c2cnn3-c2ccccc2)CO1
Product: CCCNCC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F

Procedure:
Prepared similarly to Intermediate 15 from n-propylamine and 1-phenyl-N-{[2-(trifluoromethyl)-2-oxiranyl]methyl}-1H-indazol-4-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[C:29]([C:31]([NH:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([OH:41])[CH:36]=2)=[O:32])[CH:28]=[CH:27][C:3]=1[C:4]([NH:6][C@H:7]([C:24]([OH:26])=[O:25])[CH2:8][NH:9][C:10](=[O:23])[C:11]1[CH:16]=[C:15]([N+]([O-])=O)[CH:14]=[C:13]([N+]([O-])=O)[CH:12]=1)=[O:5].ClC1C=C(C(NCC2C=CC=C(O)C=2)=O)C=CC=1[C:45]([NH:47][C@H:48](C(O)=O)CNC(=O)C1C=CC=CC=1[N+]([O-])=O)=O.ClC1C=C(C(NCC2C=CC=C(O)C=2)=O)C=CC=1C(N[C@H](C(O)=O)CNC(=O)C1C=CC=C([N+]([O-])=O)C=1)=O.ClC1C=C(C(NCC2C=CC=C(O)C=2)=O)C=CC=1C(N[C@H](C(O)=O)CNC(=O)C1C=CC([N+]([O-])=O)=CC=1)=O>>[Cl:1][C:2]1[CH:30]=[C:29]([C:31]([NH:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([OH:41])[CH:36]=2)=[O:32])[CH:28]=[CH:27][C:3]=1[C:4]([NH:6][C@H:7]([C:24]([OH:26])=[O:25])[CH2:8][NH:9][C:10](=[O:23])[C:11]1[CH:16]=[CH:15][C:14]([N:47]([CH3:48])[CH3:45])=[CH:13][CH:12]=1)=[O:5]
Reactant: O=C(NCc1cccc(O)c1)c1ccc(C(=O)N[C@@H](CNC(=O)c2ccccc2[N+](=O)[O-])C(=O)O)c(Cl)c1
Reactant: O=C(NCc1cccc(O)c1)c1ccc(C(=O)N[C@@H](CNC(=O)c2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)C(=O)O)c(Cl)c1
Agent: O=C(NCc1cccc(O)c1)c1ccc(C(=O)N[C@@H](CNC(=O)c2ccc([N+](=O)[O-])cc2)C(=O)O)c(Cl)c1
Agent: O=C(NCc1cccc(O)c1)c1ccc(C(=O)N[C@@H](CNC(=O)c2cccc([N+](=O)[O-])c2)C(=O)O)c(Cl)c1
Product: CN(C)c1ccc(C(=O)NC[C@H](NC(=O)c2ccc(C(=O)NCc3cccc(O)c3)cc2Cl)C(=O)O)cc1

Procedure:
N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]-amino]carbonyl]benzoyl]-3-(3,5-dinitrobenzoyl)amino-L-alanine; N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(2-nitrobenzoyl)amino-L-alanine; N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(3-nitrobenzoyl)amino-L-alanine; N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(4-nitrobenzoyl)amino-L-alanine),