Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:9]([O:11]C(C)(C)C)=[O:10])[CH2:3][O:4]C(C)(C)C.C(OC([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([CH2:32][CH:33]([NH:37][C:38](=[O:79])[CH:39]([NH:48][C:49](=[O:78])[CH:50]([S:58]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH2:40][C:41]([O:43]C(C)(C)C)=[O:42])[C:34](O)=[O:35])=[CH:24]1)=O)(C)(C)C>>[C:9]([CH:2]([NH:1][C:34]([CH:33]([NH:37][C:38](=[O:79])[CH:39]([NH:48][C:49](=[O:78])[CH:50]([SH:58])[CH2:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)[CH2:40][C:41]([OH:43])=[O:42])[CH2:32][C:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[NH:23][CH:24]=1)=[O:35])[CH2:3][OH:4])([OH:11])=[O:10]
Reactant: CC(C)(C)OC(=O)CC(NC(=O)C(Cc1ccccc1)SC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NC(Cc1cn(C(=O)OC(C)(C)C)c2ccccc12)C(=O)O
Reactant: CC(C)(C)OC[C@H](N)C(=O)OC(C)(C)C
Product: O=C(O)CC(NC(=O)C(S)Cc1ccccc1)C(=O)NC(Cc1c[nH]c2ccccc12)C(=O)NC(CO)C(=O)O

Procedure:
The title compound was prepared by condensing H-Ser(But)OBut with the protected dipeptide of Example 88, followed by deprotection and purification by HPLC (40%): (Pos. FAB) ? (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[NH2:15][C@@H:16]1[CH2:20][CH2:19][C@@:18]([CH3:22])([OH:21])[C:17]1([CH3:24])[CH3:23].CCN(C(C)C)C(C)C>CC#N>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:15][C@@H:16]3[CH2:20][CH2:19][C@:18]([OH:21])([CH3:22])[C:17]3([CH3:24])[CH3:23])=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: CC1(C)[C@H](N)CC[C@@]1(C)O
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC1(C)[C@H](Nc2c(C(N)=O)cnn3cc(Br)cc23)CC[C@@]1(C)O
Temperature: 120 °C
Yield: 88.1 %

Procedure:
A solution of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Preparation 5, 38.3 mg, 0.140 mmol) and (1R,3R)-3-amino-1,2,2-trimethylcyclopentanol (from Step 2 of Intermediate 20, 20 mg, 0.140 mmol) in MeCN (1 mL) was added DIPEA (0.050 mL, 0.279 mmol). The reaction was sealed and heated to at 120° C. for 60 min. The reaction was cooled and concentrated then purified by flash chromatography on silica gel using 30-70% ethyl acetate/hexanes as the eluent to afford the title compound (47 mg, 86% yield). HPLC (Conditions L): retention time=7.21 min., (condition P): retention time=8.31 min.; LCMS: 382.97 (M+2); 1H NMR (CDCl3, 400 MHz) δ 10.51 (br d, J=9.4 Hz, 1H), 7.84 (s, 1H), 7.57 (d, J=1.7 Hz, 1H), 6.97 (d, J=1.8 Hz, 1H), 5.45 (br s, 2H), 4.69 (q, J=9.5 Hz, 1H), 2.38 (m, 1H), 1.99 (m, 1H), 1.79 (m, 1H), 1.56 (m, 1H), 1.27 (s, 3H), 1.01 (s, 3H), 0.98 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:13]([N+:14]([O-:16])=[O:15])=[C:12]([OH:17])[C:11]([O:18]C)=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([OH:9])=[O:8].N1C=CC=CC=1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>C(OCC)(=O)C>[Cl:1][C:2]1[C:3]2[C:13]([N+:14]([O-:16])=[O:15])=[C:12]([OH:17])[C:11]([OH:18])=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: COc1cc2sc(C(=O)O)c(Cl)c2c([N+](=O)[O-])c1O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(O)c1sc2cc(O)c(O)c([N+](=O)[O-])c2c1Cl
Temperature: 90 °C

Procedure:
To the solution of 3-chloro-5-hydroxy-6-methoxy-4-nitro-benzo[b]thiophene-2-carboxylic acid (0.2 g), pyridine (6.3 ml) in ethyl acetate (5 ml) was gradually added aluminum trichloride (0.32 g). The reaction mixture was refluxed at 90° C. for two hours. To the warm reaction (60° C.) solution was added the mixture of concentrated hydrochloric acid and ice (1:1). The product was extracted into ethyl acetate, dried and evaporated. The residue was treated with diethyl ether and the resultant solid was filtered.
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:28])([CH3:27])[CH3:26])[CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1)O)[CH3:2].FC(F)(F)C(O)=O>>[CH2:1]([N:3]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:28])([CH3:27])[CH3:26])[CH2:4][CH2:5]/[CH:6]=[CH:7]/[C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])=[CH:11][CH:10]=1)[CH3:2]
Reactant: CCN(CCCCCC(C)(C)O)CCCC(O)c1ccc(NS(C)(=O)=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC/C=C/c1ccc(NS(C)(=O)=O)cc1)CCCCCC(C)(C)O

Procedure:
In the process as described in Example 2 the product from Example 15 is treated with trifluoroacetic acid to give the titled compound which is a compound of Formula I.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[C:4](=[O:15])[C:3]=1[CH:16]=O.Cl.[NH2:19][OH:20].C([O-])(=O)C.[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[C:4](=[O:15])[C:3]=1[CH:16]=[N:19][OH:20]
Reactant: O=Cc1c(Cl)ccn(-c2ccccc2Cl)c1=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=c1c(C=NO)c(Cl)ccn1-c1ccccc1Cl
Temperature: 75 °C
Yield: 92.1 %

Procedure:
A mixture of 4-chloro-1-(2-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-carbaldehyde obtained in Step B (995 mg), hydroxylamine hydrochloride (516 mg) and sodium acetate (609 mg) in methanol/water (4:1, 12.4 mL) was heated at 75° C. for 2 hr, cooled to room temperature, and poured into ice water. The resulting solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (968 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([N:16]([CH2:18][CH3:19])[CH3:17])=[O:15])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[N+:20]([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:20][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([N:16]([CH2:18][CH3:19])[CH3:17])=[O:15])[CH2:9]2)=[N:7][C:2]=1[NH2:1]
Reactant: CCN(C)C(=O)[C@@H]1CCCN(c2ccc([N+](=O)[O-])c(N)n2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCN(C)C(=O)[C@@H]1CCCN(c2ccc(N)c(N)n2)C1

Procedure:
To a solution of (R)-1-(6-amino-5-nitropyridin-2-yl)-N-ethyl-N-methylpiperidine-3-carboxamide (200 mg, 0.65 mmol) in ethanol (10 mL) was added palladium-on-carbon (0.2 g) in ethanol (10 mL) at room temperature. The mixture was subjected to a hydrogen atmosphere using a balloon filled with hydrogen gas. The mixture was filtered through Celite to afford the title compound. The filtrate was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:10][CH2:11][CH:12]2[CH2:16][CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13]2)N)=[CH:4][CH:3]=1.CO[CH:21](OC)[CH2:22][CH2:23][CH2:24][NH:25][CH3:26]>>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:8]([CH2:10][CH2:11][CH:12]1[CH2:16][CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13]1)[CH:21]=[C:22]2[CH2:23][CH2:24][NH:25][CH3:26]
Reactant: CNCCCC(OC)OC
Reactant: CC1(C)CCC(CCN(N)c2ccc(Cl)cc2)C1
Product: CNCCc1cn(CCC2CCC(C)(C)C2)c2ccc(Cl)cc12

Procedure:
The title compound is prepared by General Method 10 using 1-(4-chlorophenyl)-1-(2-(3,3-dimethylcyclopentyl)ethyl)hydrazine (Example 5) and 4,4-dimethoxy-N-methylbutan-1-amine.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:17][C:14]1[CH:13]=[CH:12][C:11]([CH:7]([CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]([OH:10])=[O:9])=[CH:16][CH:15]=1
Reactant: O=C(O)C(CC1CCCC1)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(C(CC2CCCC2)C(=O)O)cc1
Yield: 135.4 %

Procedure:
A solution of 3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid (100 mg, 0.38 mmol) in ethyl acetate (50 mL) was treated with 10% palladium on activated carbon. The reaction mixture was stirred under 60 psi of hydrogen gas at 25° C. for 16 h. The catalyst was removed by filtration through a pad of celite and was washed with ethyl acetate. The filtrate was concentrated in vacuo to afford 2-(4-amino-phenyl)-3-cyclopentyl-propionic acid (120 mg, 100%) as a white solid: mp 167-169° C.; EI-HRMS m/e calcd for C14H19NO2 (M+) 233.1415, found 233.1413.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH2:21])([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]([C:24]1[N:29]=[C:28]([NH:30][CH2:31][CH:32]2[CH2:39][CH2:38][C:35]3([CH2:37][CH2:36]3)[CH2:34][CH2:33]2)[C:27]([C:40](O)=[O:41])=[CH:26][N:25]=1)#[N:23].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([NH:21][C:40]([C:27]2[C:28]([NH:30][CH2:31][CH:32]3[CH2:39][CH2:38][C:35]4([CH2:37][CH2:36]4)[CH2:34][CH2:33]3)=[N:29][C:24]([C:22]#[N:23])=[N:25][CH:26]=2)=[O:41])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ncc(C(=O)O)c(NCC2CCC3(CC2)CC3)n1
Reactant: CC(C)(C)OC(=O)N1CCC(N)(Cc2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccccc2)(NC(=O)c2cnc(C#N)nc2NCC2CCC3(CC2)CC3)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of the 4-amino-4-benzylpiperidine-1-carboxylic acid tert-butyl ester (0.38 mmol, step 66.1) and 2-cyano-4-[(spiro[2.5]oct-6-ylmethyl)amino]pyrimidine-5-carboxylic acid (0.38 mmol) in DMF (1.3 mL) are added HOAt (0.51 mmol) and EDCI-HCl (0.51 mmol) at 0° C. After warming to room temperature and stirring for 15 h, the reaction mixture is diluted with AcOEt and washed with 1N aq. KHSO4, sat. aq. NaHCO3, and brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified by silica gel column chromatography to give 4-benzyl-4-({2-cyano-4-[(spiro[2.5]oct-6-ylmethyl)-amino]-pyrimidine-5-carbonyl}amino)piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH2:14]([Sn:18](Cl)([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17]>CCOCC>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Sn:18]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:14][CH2:15][CH2:16][CH3:17])[CH:7]=1
Reactant: Cc1ccnc(Br)c1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1cc(C)ccn1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution containing 2-bromo-4-methylpyridine (1.46 g, 8.49 mmol) in ether (15 mL) at −78° C. was treated with n-butyllithium (5.57 mL, 1.6 M in hexanes) dropwise, stirred at −78° C. for 1 hour, treated with tributyltin chloride (3.45 mL, 12.74 mmol), stirred at 0° C. for 4 hours, quenched with saturated ammonium chloride solution and partitioned between ether and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on neutral alumina eluting with 10% ethyl acetate in dichloromethane to give the title compound.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[N:13][CH:14]=2)=[CH:5][CH:4]=1.[CH3:23][O:24][CH2:25][CH2:26]Br>>[CH3:23][O:24][CH2:25][CH2:26][N:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:11]=[CH:10][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:21])[F:22])=[CH:8][CH:7]=3)=[CH:14][N:13]=2)[CH2:16][CH2:17]1
Reactant: FC(F)(F)c1ccc(-c2ccc(N3CCNCC3)nc2)cc1
Reactant: COCCBr
Product: COCCN1CCN(c2ccc(-c3ccc(C(F)(F)F)cc3)cn2)CC1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 55, starting from 4-(5-(4-trifluoromethylphenyl)pyridin-2-yl)piperazine and 2-methoxyethylbromide.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([CH2:14]O)[CH:10]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:20])=O>ClCCl>[Cl:20][CH2:14][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:16])[F:1])=[CH:4][CH:5]=2)[O:13][N:12]=1
Reactant: OCc1cc(-c2ccc(C(F)(F)F)cc2)on1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: FC(F)(F)c1ccc(-c2cc(CCl)no2)cc1
Temperature: 0 °C

Procedure:
{5-[4-(Trifluoromethyl)phenyl]isoxazol-3-yl}methan-1-ol (200 mg) was dissolved in dry dichloromethane (10 ml), and cooled to 0° C. The solution was stirred while adding a solution of thionyl chloride (2.74 ml) in dichloromethane (25 ml), then allowed to warm to room temperature and stirred overnight. Solvent was evaporated under reduced pressure, and the residue was purified by preparative thin layer chromatography, eluting with 30% ethyl acetate/hexane, to afford 3-(chloromethyl)-5-[4-(trifluoromethyl)phenyl]isoxazole, a compound of formula (25).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1([NH:18][C:19]2[C:20](=[O:38])[N:21]([C:26]3[C:27]([CH3:37])=[CH:28][C:29]([F:36])=[C:30]([CH:35]=3)[C:31]([O:33][CH3:34])=[O:32])[CH:22]=[C:23](Br)[N:24]=2)[CH2:17][CH2:16]1)C1C=CC=CC=1.C([O-])=O.[NH4+].CCN(C(C)C)C(C)C>C(O)C.[Pd]>[F:36][C:29]1[CH:28]=[C:27]([CH3:37])[C:26]([N:21]2[CH:22]=[CH:23][N:24]=[C:19]([NH:18][C:15]3([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[OH:8])[CH2:17][CH2:16]3)[C:20]2=[O:38])=[CH:35][C:30]=1[C:31]([O:33][CH3:34])=[O:32]
Reactant: COC(=O)c1cc(-n2cc(Br)nc(NC3(c4ccccc4OCc4ccccc4)CC3)c2=O)c(C)cc1F
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COC(=O)c1cc(-n2ccnc(NC3(c4ccccc4O)CC3)c2=O)c(C)cc1F
Temperature: 75 °C
Yield: 65 %

Procedure:
To methyl 5-[3-({1-[2-(benzyloxy)phenyl]cyclopropyl}amino)-5-bromo-2-oxopyrazin-1(2H)-yl]-2-fluoro-4-methylbenzoate (Example 318e, 2.310 g) in ethanol (30 mL) was added ammonium formate (3.53 g) and Pd/C (0.042 g). The reaction was heated at 75° C. for 3 h. Hunig's Base (3 mL) was added, and the reaction was heated at 90° C. for 4 h. Additional catalyst, ammonium formate and hunigs base were added, and the reaction was heated at 90° C. for 4 h. The reaction mixture was then filtered warm, through a fibre glass filter, washing through with 500 mL ethanol, followed by 500 mL DCM, followed by 500 mL 10% methanol/DCM. The DCM and MeOH/DCM filtrates were combined, evaporated, and the resulting residue partitioned between DCM and water. The organic layer was separated, dried (MgSO4), filtered, and evaporated to give the subtitle compound as a solid (1.063 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[S:18])OC2C=CC=CC=2)=[CH:7][C:6]([CH3:19])=[C:5]([CH2:20][CH2:21][CH3:22])[N:4]=1.[OH:23][C:24]1[CH:25]=[C:26]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1>>[CH3:1][O:2][C:3]1[C:8]([NH:9][C:10]([N:33]2[CH2:32][CH2:31][N:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([OH:23])[CH:25]=3)[CH2:35][CH2:34]2)=[S:18])=[CH:7][C:6]([CH3:19])=[C:5]([CH2:20][CH2:21][CH3:22])[N:4]=1
Reactant: CCCc1nc(OC)c(NC(=S)Oc2ccccc2)cc1C
Reactant: Oc1cccc(N2CCNCC2)c1
Product: CCCc1nc(OC)c(NC(=S)N2CCN(c3cccc(O)c3)CC2)cc1C
Yield: 48 %

Procedure:
Phenyl N-(2-methoxy-5-methyl-6-propylpyridin-3-yl)thiocarbamate and 1-(3-hydroxyphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.N1C=CC=CC=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)(=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([N:6]([CH3:7])[C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: CNc1ccc(Br)cc1[N+](=O)[O-]
Reactant: O=C(Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CN(C(=O)c1ccccc1)c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 97.7 %

Procedure:
6.8 g (29 mmol) of 4-bromo-N-methyl-2-nitroaniline were dissolved into 20 mL of pyridine. Furthermore, 5.0 g (35 mmol) of benzoyl chloride were added, and the whole was stirred under heating at 90° C. for 7 hours in an argon atmosphere. After the completion of the reaction, 200 mL of ethyl acetate were added, and the whole was washed with 10-mass % hydrochloric acid, 10-mass % K2CO3, and a saturated sodium chloride solution, and dried with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by means of silica gel column chromatography to obtain 9.5 g of 4′-bromo-N-methyl-2′-nitro-benzanilide as a greenish white solid (96% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:5]=[CH:4][C:3]=1[NH2:17].[CH3:18][O:19][C:20](=[O:25])[CH2:21][C:22](Cl)=[O:23]>>[CH3:18][O:19][C:20](=[O:25])[CH2:21][C:22]([NH:17][C:3]1[CH:4]=[CH:5][C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[CH:7][C:2]=1[F:1])=[O:23]
Reactant: COC(=O)CC(=O)Cl
Reactant: Nc1ccc(OCc2cccc(F)c2)cc1F
Product: COC(=O)CC(=O)Nc1ccc(OCc2cccc(F)c2)cc1F
Yield: 47 %

Procedure:
In analogy to example 1, the title compound is prepared from 2-fluoro-4-(3-fluoro-benzyloxy)-phenylamine and chlorocarbonyl-acetic acid methyl ester. Yield: 47%. Brownish solid. MS: m/e=336.1 (M++H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[OH:4].O=[C:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:31]=[CH:30][C:21]([CH2:22][CH:23]3[S:27][C:26](=[O:28])[NH:25][C:24]3=[O:29])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1>>[OH:4][C@H:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[CH2:2][NH:1][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[CH:31]=[CH:30][C:21]([CH2:22][CH:23]3[S:27][C:26](=[O:28])[NH:25][C:24]3=[O:29])=[CH:20][CH:19]=2)[CH2:16][CH2:17]1
Reactant: NC[C@H](O)c1cccnc1
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Product: O=C1NC(=O)C(Cc2ccc(N3CCC(NC[C@H](O)c4cccnc4)CC3)cc2)S1

Procedure:
The title compound was prepared from (1R)-2-amino-1-(3-pyridinyl)-1-ethanol (which was obtained in Example 135) and 5-[4-(4-oxo-1-piperidinyl)benzyl]-1,3-thiazolidine-2,4-dione (which was obtained in Example 38) in substantially the same manner, as described in Example 125. The product was obtained as a yellow solid; mp 87° C. (decomposed); 1H NMR (400 MHz, DMSO-d6) δ 1.38–1.43 (m, 2 H), 1.89–1.91 (m, 2 H), 2.62–2.71 (t, 2), 2.71–2.91 (m, 4 H), 3.23–3.27 (m, 1 H), 3.60–3.63 (m, 2 H), 4.58–4.61 (m, 1 H), 4.72–4.75 (m, 1 H), 6.38–6.85 (d, 2 H), 7.02–7.05 (d, 2 H), 7.34–7.37 (m, 1 H), 7.75–7.78 (m, 1 H), 8.45–8.46 (m, 1 H), 8.56–8.57 (m, 1 H); MS (ES) m/z: 427 (MH+).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[CH:5][C:6]2[S:10]N=N[C:7]=2[CH:11]=1.[C:14]1([N:20]=[C:21]=[S:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:21](=[N:20][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:22][C:7]=2[CH:11]=1
Reactant: S=C=Nc1ccccc1
Reactant: FC(F)(F)c1ccc2snnc2c1
Product: FC(F)(F)c1ccc2sc(=Nc3ccccc3)sc2c1

Procedure:
A solution of 5-(trifluoromethyl)-1,2,3-benzothiadiazole (5 g) in 50 ml of phenylisothiocyanate is heated at reflux under an inert atmosphere until the evolution of nitrogen ceases (approximately 3 hours). The excess phenyl isothiocyanate is removed by distillation. The residue is chromatographed on 1000 ml of silica gel eluting with pentane/dichloromethane (4:1). Fractions containing the desired product are combined and concentrated in vacuo. The resultant solid is recrystallized from hexane to yield 4 g of the title compound, melting point 122°-123° C.
Reaction SMILES: [NH:1]1C2(CCCCC2)[NH:4][CH2:3][C:2]1=[O:11].CC(C)CO[C:16](=[O:21])[CH2:17][CH:18]1[O:20][CH2:19]1>O.CC(C)=O>[CH2:17]1[C:16](=[O:21])[N:4]([CH2:3][C:2]([NH2:1])=[O:11])[CH2:19][CH:18]1[OH:20]
Reactant: CC(C)COC(=O)CC1CO1
Reactant: O=C1CNC2(CCCCC2)N1
Solvent: CC(C)=O
Solvent: O
Product: NC(=O)CN1CC(O)CC1=O
Temperature: 70 °C
Reaction time: 48 h

Procedure:
19 g 2-(1-Methylethyl)imidazolidinone ((5); R4 =H, R5 =isopropyl) (0.15 moles) are dissolved in 100 ml water and 150 ml acetone. 2-Methylpropyl-3,4-epoxybutanoate (0.15 moles) are added and the mixture is heated and stirred for 48 h at 70° C. The acetone is evaporated in vacuo and 100 ml DMF are added, followed by boiling for 21 h. The mixture is reduced to a small volume in vacuo, the residue is taken up with 40 ml water and washed with 2×40 ml methylene chloride. The aqueous phase is evaporated to dryness and redissolved in 15 ml methanol. This is left to stand for 3 h at 0° C., filtered and dried to give oxiracetam as a white crystalline powder, m.p. 167°-70° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:31]2[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]2)=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: CN1CCNCC1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: CN1CCN(C(=O)c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)c(Cl)c2)CC1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 1-methylpiperazine via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(4-methylpiperazine-1-carbonyl)benzamide. MS (Q1) 469 (M)+.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[Na+].[Na+]>O>[C:1]([N:14]1[CH2:15][CH2:16][CH:11]([OH:10])[CH2:12][CH2:13]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1CCNCC1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(c1ccccc1)N1CCC(O)CC1
Temperature: 5 °C
Yield: 89.8 %

Procedure:
In this reference example, 7.03 g of benzoyl chloride was added dropwise to a mixture of 5.05 g of 4-hydroxypiperidine, 6.36 g of sodium carbonate and 60 ml of water at 10° C. with stirring. After the addition, the mixture was maintained at 5° C. for 2 hours. The reaction mixture was filtered, and then filtrate was extracted with dichloromethane. The extract was concentrated, and ether was added to crystallize, whereby 9.20 g of 1-benzoyl-4-hydroxypiperidine was obtained (yield: 90.1%).
Reaction SMILES: CN.CO.[S:5]1[CH:9]=[C:8]([CH:10]=O)[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]1=2.CC(O)=O.[BH3-][C:21]#[N:22].[Na+]>>[CH3:21][NH:22][CH2:10][C:8]1[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[S:5][CH:9]=1
Reactant: O=Cc1csc2ccccc12
Reactant: [BH3-]C#N
Agent: CN
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNCc1csc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
To a stirred solution of 2 M methylamine in methanol (75 mmole, 150 mmole) was added benzo[b]thiophen-3-carboxaldehyde (5.3 g, 33 mmole) and HOAc (4.3 mL, 75 mmole). The reaction was stirred at RT for 1 h, then NaBH3CN (2.1 g, 33 mmole) was added portionwise over 5 minutes. The reaction was stirred for an additional 16 h then was concentrated under vacuum. The residue was taken up in Et2O (300 mL) and washed with 1.0 N NaOH (300 mL) then with brine, dried (Na2SO4), and concentrated. Purification by flash chromatography on silica gel (5% (5% NH4OH/MeOH)/CHCl3) gave the title compound (2.81 g, 48%) as a brownish oil: 1H NMR (400 MHz, CDCl3) 6-7.87 (2d, 2H), 7.40 (m, 2H), 7.32 (s,1H), 4.02 (s, 2H), 2.56 (s, 3H), 1.5 (br s,1H).
Reaction SMILES: Br[C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:4][N:5]([CH3:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:20]([SH:24])[CH2:21][CH2:22][CH3:23].N1C2C(=CC=CC=2)C=CC=1.Cl>N1C=CC=CC=1>[CH2:20]([S:24][C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:4][N:5]([CH3:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCS
Reactant: Cn1nc(-c2ccccc2)c(Br)c1-c1ccccc1
Agent: Cl
Solvent: c1ccc2ncccc2c1
Solvent: c1ccncc1
Product: CCCCSc1c(-c2ccccc2)nn(C)c1-c1ccccc1
Yield: 97.1 %

Procedure:
A mixture of 4-bromo-1-methyl-3,5-diphenylpyrazole (21 g, 0.0671 mole), copper(1)salt of butanethiol (12.58 g, 0.08 mole), pyridine (10 ml) and quinoline (100 ml) is stirred and heated at 175° C to 180° C for 8 hours. The reaction mixture is cooled, poured into dilute hydrochloric acid (500 ml) and extracted with benzene. The benzene layer is separated and stripped in vacuo to give a brown oil. The oil is slurried with petroleum ether (b.p. 40° C to 60° C), filtered and the filtrate stripped in vacuo to give a brown syrup 21 g (97%), >95% pure by glc.