Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]([NH:11][CH:12]1[C:34](=[O:35])[N:14]2[CH:15]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])[C:16]([CH3:20])([CH3:19])[S:17](=[O:18])[C@H:13]12)(=[O:10])[CH3:9].[Cl:36]N1C(=O)CCC1=O>O>[CH3:19][C:16](=[CH2:20])[CH:15]([N:14]1[C:34](=[O:35])[CH:12]([NH:11][C:8](=[O:10])[CH3:9])[CH:13]1[S:17]([Cl:36])=[O:18])[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:22]
Reactant: CC(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(C)(C)S(=O)[C@H]12
Reactant: O=C1CCC(=O)N1Cl
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(C)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(C)=O)C1S(=O)Cl

Procedure:
Toluene (500 ml.) was heated in equipment containing a Dean-Stark water trap to azeotropically remove any moisture which may be present. To the resulting dried toluene was added 1.0 gms. (2.4 mmol.) of p-nitrobenzyl 6-acetamido-2,2-dimethylpenam-3-carboxylate-1-oxide. The resulting mixture was refluxed again using a Dean-Stark water trap to remove any additional amounts of water which may be present. The mixture then was cooled, and 400 mg. (2.9 mmol) of N-chlorosuccinimide were added. The mixture then was refluxed for 1 hour. A sample of the reaction mixture was withdrawn, and the solvent was removed. The product which was obtain was consistent by nmr analysis with the structure of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:18][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:18][CH2:19][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:21])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](N)c1ccc(Br)cc1
Reactant: O=C(CCCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@H](NCCC(=O)c1ccccc1)c1ccc(Br)cc1
Reaction time: 8 h
Yield: 66 %

Procedure:
To a solution of (S)-1-(4-bromophenyl)ethanamine (100 g, 0.502 mol) and K2CO3 (138.8 g, 0.10 mol) in acetonitrile (1000 mL) was added a solution of 3-chloro-1-phenyl-propan-1-one (84.4 g, 0.502 mol) in acetonitrile (100 mL). The reaction mixture was stirred overnight. The solid was filtered, and the filtrate was concentrated to give crude (S)-3-(1-(4-bromo-phenyl)ethylamino)-1-phenylpropan-1-one (110 g, 66.2%), which was used in the next step without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([C:27]([C:29]1[CH:34]=[C:33](Cl)[N:32]=[CH:31][N:30]=1)=[O:28])[CH2:22][CH2:21]2.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([C:27]([C:29]1[N:30]=[CH:31][N:32]=[C:33]([N:1]3[CH2:2][CH2:3][CH:4]([N:7]4[C:15]5[C:10](=[N:11][CH:12]=[CH:13][CH:14]=5)[NH:9][C:8]4=[O:16])[CH2:5][CH2:6]3)[CH:34]=1)=[O:28])[CH2:22][CH2:21]2
Reactant: O=C(c1cc(Cl)ncn1)N1CCc2cc(Cl)ccc21
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1)N1CCc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 22 h

Procedure:
80 mg (0.27 mmol) 1-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one (dihydrochloride) were added to 100 mg (0.34 mmol) (5-chloro-2,3-dihydroindol-1-yl)-(6-chloropyrimidin-4-yl)-methanone and 100 μL (0.58 mmol) DIPEA in 10 mL DMF. The reaction mixture was stirred for 22 h at RT and then evaporated down i. vac. The residue was combined with 20 mL water and stirred for 30 min at RT. The precipitated product was suction filtered. The purification was carried out using a silica gel column. The product fractions were combined and the solvent was eliminated using the rotary evaporator. The residue was stirred with water, suction filtered and dried.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](=O)[NH:3][CH:2]=1.[Cl:8][C:9]1[C:14](I)=[CH:13]N=CN=1.Cl.[CH:17]([O:20][C:21](=[O:31])[C@H:22]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH2:23])([CH3:19])[CH3:18]>>[ClH:8].[CH:17]([O:20][C:21](=[O:31])[C@H:22]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[NH2:23])([CH3:19])[CH3:18].[CH:17]([O:20][C:21](=[O:31])[C@H:22]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[NH:23][C:4]1[C:5]([CH2:13][CH2:14][C:9]2[CH:26]=[CH:25][CH:24]=[CH:22][CH:21]=2)=[CH:6][N:1]=[CH:2][N:3]=1)([CH3:19])[CH3:18]
Reactant: O=c1ccnc[nH]1
Reactant: Clc1ncncc1I
Agent: CC(C)OC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Product: CC(C)OC(=O)[C@H](Cc1ccccc1)Nc1ncncc1CCc1ccccc1

Procedure:
L-Phenylalanine isopropyl ester hydrochloride was prepared by Method LLL. 4(3H)-Pyrimidinone (Aldrich) was sequentially converted via Methods N and O to 4-chloro-5-iodopyrimidine. L-Phenylalanine isopropyl ester hydrochloride and 4-chloro-5-iodopyrimidine were coupled via Method P and the coupled product sequentially converted via Methods OOO and X to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:17][CH2:16]3)[CH:8]=2)[N:3]=1.[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O>[NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([N:35]=[CH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:17][CH2:16]3)[CH:8]=2)[N:3]=1
Reactant: N#Cc1c(N)nc2ccc(N3CCN(Cc4ccccc4)CC3)cc2c1Cl
Reactant: NCc1ccccc1
Solvent: O
Product: N#Cc1c(N)nc2ccc(N3CCN(Cc4ccccc4)CC3)cc2c1N=Cc1ccccc1

Procedure:
14 g of 2-amino-3-cyano-4-chloro-6-(4-benzylpiperazin-1-yl)quinoline and 28 mL of benzylamine are stirred at 125° C. for 4 hours. The reaction mixture is poured onto 100 mL of water. The precipitated material is filtered off, washed with 2×50 mL of water. After drying 8 g of the title compound is obtained, m.p.: 202° C.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([OH:25])=O)[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:26][CH2:27][C:28]([CH3:31])([OH:30])[CH3:29]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([NH:26][CH2:27][C:28]([OH:30])([CH3:31])[CH3:29])=[O:25])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Reactant: CC(C)(O)CN
Product: CC(C)(O)CNC(=O)Cc1csc(-c2cnn(C(C)(C)C)c2-c2ccc(F)cc2)n1

Procedure:
Using 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid and 1-amino-2-methyl-propan-2-ol and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([CH3:11])([C:8]([OH:10])=O)[CH2:4][CH2:3]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(=O)(O)[O-].[Na+].[NH:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[C:32]1[C:40]1[C:48]2[C:43](=[CH:44][CH:45]=[C:46]([NH2:49])[CH:47]=2)[N:42]([CH:50]2[CH2:55][CH2:54][CH2:53][CH2:52][O:51]2)[N:41]=1>CN(C=O)C>[NH:33]1[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[N:31]=[C:32]1[C:40]1[C:48]2[C:43](=[CH:44][CH:45]=[C:46]([NH:49][C:8]([C:5]3([CH3:11])[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)=[O:10])[CH:47]=2)[N:42]([CH:50]2[CH2:55][CH2:54][CH2:53][CH2:52][O:51]2)[N:41]=1
Reactant: CN1CCC(C)(C(=O)O)CC1
Reactant: Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CN1CCC(C)(C(=O)Nc2ccc3c(c2)c(-c2nc4ccccc4[nH]2)nn3C2CCCCO2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 39 %

Procedure:
1,4-Dimethylpiperidine-4-carboxylic acid (3 mg, 0.019 mmol), HOBt (4 mg, 0.029 mmol), EDC (5.5 mg, 0.028 mmol) and sodium bicarbonate (1.6 mg, 0.019 mmol) were added to a solution of 3-(1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (6.4 mg, 0.019 mmol) in DMF (6 mL). The reaction mixture was stirred at room temperature for 24 h, and then the solvent was removed in vacuo. Purification by flash chromatography (6% CH3OH/CH2Cl2) afforded the title compound (3.5 mg) as a solid. 1H NMR (400 MHz, CD3OD): δ 8.54 (s, 1H), 7.77 (m, 1H), 7.71 (m, 2H), 7.38 (m, 2H), 7.29 (m, 2H), 5.94 (d, 1H, J=8.0 Hz) 4.00 (m, 1H), 3.85 (m, 1H), 3.46 (m, 2H), 2.89 (s, 3H), 2.69 (m, 2H), 2.56 (m, 1H), 2.15 (m, 3H), 1.86 (m, 3H), 1.72 (m, 3H), 1.46 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[NH:16][C:15]4[N:23]=[CH:24][CH:25]=[CH:26][C:14]=4[N:13]3[C:27]=2[C:28]2[CH:33]=[CH:32][C:31]([C:34]3([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[CH2:37][CH2:36][CH2:35]3)=[CH:30][CH:29]=2)=[CH:6][CH:5]=1)([O-])=O.[BH4-].[Na+]>C1COCC1.CO.Cl[Ni]Cl>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[NH:16][C:15]4[N:23]=[CH:24][CH:25]=[CH:26][C:14]=4[N:13]3[C:27]=2[C:28]2[CH:33]=[CH:32][C:31]([C:34]3([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:43])([CH3:42])[CH3:44])[CH2:35][CH2:36][CH2:37]3)=[CH:30][CH:29]=2)=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc([N+](=O)[O-])cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(N)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
To a solution of tert-butyl (1-{4-[2-(4-nitrophenyl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl]phenyl}cyclobutyl)carbamate (317 mg, 0.49 mmol) in THF (10 mL) and MeOH (5 mL) cooled to 0° C. was added NiCl2 (245 mg, 1.03 mmol) and NaBH4 (84 mg, 2.04 mmol). The reaction was slowly allowed to warm to room temperature and stirred 30 min. The reaction was diluted with sat.NaHCO3aq and extracted with ethyl acetate (3×20 mL). The organic layers were combined, washed with brine. The organic phase was dried over sodium sulfate, filtered and concentrated gave the title compound as a yellow solid (214 mg, 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]([NH:13][CH3:14])=[O:12].C1C(=O)N([Br:22])C(=O)C1.C(OOCC1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:22][CH:10]([C:3]1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[Cl:1])[C:11]([NH:13][CH3:14])=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: CNC(=O)Cc1ccc(OC)cc1Cl
Agent: c1ccc(COOCc2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CNC(=O)C(Br)c1ccc(OC)cc1Cl
Temperature: 80 °C
Yield: 61.4 %

Procedure:
A mixture of 2-(2-chloro-4-methoxy-phenyl)-N-methyl-acetamide (70a) (0.22 g, 1.03 mmol), NBS (183 mg, 1.03 mmol), and 70% benzyl peroxide (36 mg, 0.103 mmol) in 6 mL of CCl4 was refluxed at 80° C. for three hours, cooled to room temperature, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography eluting with 1:1 EtOAc and hexanes to provide 185 mg white solid as the intermediate 70b. 1H NMR (300 MHz, CDCl3) δ 7.42 (d, 1H, J=8.85 Hz), 6.90 (d, 1H, J=2.63 Hz), 6.83–6.76 (m, 1H), 5.83 (s, 1H), 3.78 (s, 3H), 2.90 (d, 3H, J=4.90 Hz). LCMS (ESI+) [M+H]/z Calc'd 294, found 294.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH3:25])[CH2:20][CH2:19]2)(=[O:17])=[O:16])=[CH:11][C:5]=1[C:6]([O:8]CC)=[O:7])[CH3:2].[OH-].[Na+]>C1(C)C=CC=CC=1.O>[CH2:1]([O:3][C:4]1[N:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH3:25])[CH2:20][CH2:19]2)(=[O:16])=[O:17])=[CH:11][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOC(=O)c1cc(S(=O)(=O)N2CCN(CC)CC2)cnc1OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.4 %

Procedure:
Ethyl 2-ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)nicotinoate (10.2 g, 0.0275 mol) was dissolved in toluene (50 mL) and a solution of sodium hydroxide (1.1 g, 0.0275 mol) in water (20 mL) added to it. This two phase mixture was then stirred vigorously at ambient temperature overnight. The aqueous phase was separated off and adjusted to pH=5.6 by addition of c. hydrochloric acid. The precipitated product was slurried with ice cooling for 15minutes, filtered, water washed and dried under vacuo at 50° C. to afford the title compound (4.1 g, 43%) as an off-white solid. Mpt 206-207° C. d (CDCl3): 1.25 (3H, t), 1.39 (3H,t), 2.82 (2H, q), 3.03 (4H, m), 3.25 (4H, m), 4.50 (2H, q), 8.25 (1H, d), 8.56 (1H, d). m/z (Found:344 [M+H]+, 100%. C14H22N3O5S requires 344.38).
Reaction SMILES: [ClH:1].[N:2]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([NH2:13])=[NH:12])[CH2:6][CH2:5][CH2:4][CH2:3]1.CC[O-].[Na+].[CH2:21]([O:28][C:29]1[CH:30]=[C:31]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[C:32]([NH:34]N)=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl.CCOCC>C(O)C>[ClH:1].[CH2:21]([O:28][C:29]1[CH:30]=[C:31]([C:32]2[NH:34][N:13]=[C:11]([C:10]3[CH:14]=[CH:15][CH:16]=[C:8]([CH2:7][N:2]4[CH2:6][CH2:5][CH2:4][CH2:3]4)[CH:9]=3)[N:12]=2)[CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: N=C(N)c1cccc(CN2CCCC2)c1
Reactant: COc1ccc(C(=O)NN)cc1OCc1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: COc1ccc(-c2nc(-c3cccc(CN4CCCC4)c3)n[nH]2)cc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
To a stirred ethanolic suspension of 3-pyrrolidin-1-ylmethyl-benzamidine hydrochloride salt (1:2) (414 mg, 1.5 mmol, 1.5 eq.) in ethanol (15 ml) was added 1.2N NaOEt in ethanol (3.4 ml, 4 eq.) over 3 min. and stirring was then continued for 30 min. at r.t. 3-Benzyloxy-4-methoxy-benzoic acid hydrazide (272 mg, 1 mmol) in ethanol was added at 20° C. and the resulting mixture was heated to reflux for 50 hrs. Upon cooling, the product mixture was filtered, the solvent was evaporated and the residue chromatographed over 20 g SiO2 (Merck 230-400 mesh) with CH2Cl2-MeOH (2M NH3) 96:4 affording a solid. This material was dissolved in ethanol at r.t. and an excess 2N HCl/ether solution (1.0 ml, 2 mmol) was added. After 30 min. the solvent was evaporated and the residue dried under high vacuum at 30° C. overnight affording the title compound (326 mg, 89% yield) as a yellow solid. MS: m/e=441.6 (M+H+)
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]([OH:11])=O)=[CH:3][CH:2]=1.[CH3:18][O:19][C:20](=[O:41])[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=1[NH:28]C(C1C2C(=CC=CC=2)C=CC=1)=O.C([O-])(O)=O.[Na+]>O=S(Cl)Cl.CC(C)=O>[CH3:18][O:19][C:20](=[O:41])[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=1[NH:28][C:9](=[O:11])/[CH:8]=[CH:7]/[C:4]1[CH:3]=[CH:2][C:1]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: O=C(O)C=Cc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)c1ccc(O)cc1NC(=O)c1cccc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(O)cc1NC(=O)/C=C/c1ccc(-c2ccccc2)cc1
Reaction time: 18 h
Yield: 79.2 %

Procedure:
A mixture of 3-biphenyl-4-yl-acrylic acid (0.449 g, 2.004 mmol) in SOCl2 (5 ml) was refluxed for 2 h. After cooling, the solvent was removed. The residue was dissolved in acetone and added into a stirred solution of 4-hydroxy-2-(naphthoylamino)-benzoic acid methyl ester (0.335 g, 2.004 mmol) in acetone (10 ml) with NaHCO3 (0.202 g, 2.405 mmol). After 18 h, the reaction mixture was concentrated. The residue was triturated with water, filtered and the solids rinsed with ether and dried to give 2-{[(2E)-3-(1,1′-biphenyl-4-yl)prop-2-enoyl]amino}-4-hydroxybenzoic acid methyl ester (0.593 g, 1.588 mmol, 79%) as an off-white solid, mp 292-296° C. 1H NMR (DMSO-d6) δ 3.88 (s, 3H), 6.57 (dd, 1H), 6.95 (d, 1H), 7.37-7.54 (m, 3H), 7.67 (d, 1H), 7.70-7.80 (m, 4H), 7.80-7.90 (m, 3H), 8.20 (dd, 1H), 10.55 (s, 1H), 11.20 (s, 1H); mass spectrum [ES(−)], m/z 372 (M−H)−.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][C:24]2=[O:29])=[CH:19][CH:18]=1>>[OH:1][C@H:2]([CH2:3][NH:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][C:24]2=[O:29])=[CH:21][CH:22]=1)[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15]
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CO1
Reactant: Nc1ccc(N2CCOCC2=O)cc1
Product: O=C1c2ccccc2C(=O)N1C[C@H](O)CNc1ccc(N2CCOCC2=O)cc1

Procedure:
In this case, 2-[(2S)-2-oxiranylmethyl]-1H-isoindole-1,3(2H)dione (II) is reacted with 4-(4-aminophenyl)-3-morpholinone (III) to give 2-((2R)-2-hydroxy-3-{[4-(3-oxo-4-morpholinyl)-phenyl]amino}propyl)-1H-isoindole-1,3(2H)dione (V). Subsequently, (V) is converted with a phosgene equivalent into 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}-methyl)-1H-isoindole-1,3(2H)dione (VI). Elimination of the phthalimide protective group affords 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholine-3-one (VII) which is finally reacted with 5-chlorothiophene-2-carbonyl chloride (IV) to give 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide (I).
Reaction SMILES: [CH:1]([O:4][C:5]1[NH:9][N:8]=[C:7]([NH2:10])[CH:6]=1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[Cl:20][C:21]1[N:26]=[C:25](Cl)[C:24]([Br:28])=[CH:23][N:22]=1>C1COCC1>[Br:28][C:24]1[C:23]([NH:10][C:7]2[CH:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[NH:9][N:8]=2)=[N:22][C:21]([Cl:20])=[N:26][CH:25]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CC(C)Oc1cc(N)n[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)Oc1cc(Nc2nc(Cl)ncc2Br)n[nH]1
Reaction time: 16 h

Procedure:
To a solution of 5-isopropoxy-1H-pyrazol-3-amine (11.6 g, 82.1 mmol) in THF (85 ml) was added DIPEA (16 ml) and 2,4-dichloro-5-bromopyrimidine (17 g, 74.6 mmol) and the resulting solution was aged at 40° C. for 16 hours. The mixture was partitioned between EtOAc and H2O, the organic layer was washed with brine and dried. The solvents were removed under reduced pressure and column chromatography gave the title compound as a solid. m/z: 332.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:27][CH2:26][CH:25]([N:28]([CH3:32])[C:29](=[O:31])[CH3:30])[CH2:24]2)=[CH:19][CH:18]=1)=O.OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O.C(Cl)Cl>[CH3:14][O:13][C:7]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:15]([C:17]1[CH:18]=[CH:19][C:20]([N:23]3[CH2:27][CH2:26][CH:25]([N:28]([CH3:32])[C:29](=[O:31])[CH3:30])[CH2:24]3)=[CH:21][CH:22]=1)=[N:1]2
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: CC(=O)N(C)C1CCN(c2ccc(C=O)cc2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCC(N(C)C(C)=O)C4)cc3)nc2c1
Temperature: 150 °C
Yield: 87.2 %

Procedure:
A solution of 2-amino-4,6-dimethoxybenzamide (0.797 g, 4.07 mmol) and N-(1-(4-formylphenyl)pyrrolidin-3-yl)-N-methylacetamide (1.0 g, 4.07 mmol) in DMA (75 mL) was treated with NaHSO3 (0.466 g, 4.5 mmol) and p-TsOH (0.078 g, 0.41 mmol). The mixture was heated at 150° C. for 15 hours, cooled to room temperature, diluted with CH2Cl2 (200 mL), and washed with saturated NaHCO3 (100 mL) and water (200 mL). The organic phase was dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 1:1 CH2Cl2/92:7:1 CHCl3/MeOH/concentrated NH4OH to 100% 92:7:1 CHCl3/MeOH/concentrated NH4OH, to afford the title compound (1.5 g, 88%) as a light brown solid. 1H NMR (300 MHz, DMSO-d6): δ 11.68 (s, 1H), 8.10 (d, J=8.8 Hz, 2H), 6.55-6.67 (m, 3H), 6.44 (d, J=2.2 Hz, 1H), 4.67-5.22 (m, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.43-3.60 (m, 2H), 3.22-3.26 (m, 2H), 2.76-2.89 (m, 3H), 1.91-2.27 (m, 5H). ESI MS m/z 423 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:15](=[O:16])[CH:14]=[C:13]2[C:4](=[N:5][C:6]3[C:11]([S:12]2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.C(N(CC)CC)C.[CH2:24]([SH:28])[CH2:25][CH2:26][CH3:27].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClC(Cl)C>[CH2:24]([S:28][C:14]1[C:15](=[O:16])[C:2]([CH3:1])=[CH:3][C:4]2[C:13]=1[S:12][C:11]1[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=1)[N:5]=2)[CH2:25][CH2:26][CH3:27]
Reactant: Cc1cc2nc3ccccc3sc-2cc1=O
Reactant: CCCCS
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CCCCSc1c2sc3ccccc3nc-2cc(C)c1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2-methyl-phenothiazin-3-one (0.23 g) in 12 ml dichloroethane was added triethylamine (0.8 ml) and n-butanethiol (0.7 ml). The mixture was stirred at room temperature for 72 hours. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (0.22 g) was added. The mixture was stirred at room temperature for 2 hours. The mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue was chromatographed on neutral alumina (Act III) eluting with 15% EtOAc/hexane to give the title compound (120 mg), m.p. 97° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9]2[C:10]([NH2:15])=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:4]([CH3:16])=[N:3]1.Br[CH2:18][C:19]([N:21]([CH:30]([CH3:32])[CH3:31])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)=[O:20].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C.C(Cl)Cl>[CH:30]([N:21]([C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)[C:19](=[O:20])[CH2:18][NH:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[NH:8][C:5]1[C:4]([CH3:16])=[N:3][N:2]([CH3:1])[C:6]=1[CH3:7])([CH3:31])[CH3:32]
Reactant: COc1ccc(N(C(=O)CBr)C(C)C)cc1
Reactant: Cc1nn(C)c(C)c1Nc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(N(C(=O)CNc2ccccc2Nc2c(C)nn(C)c2C)C(C)C)cc1
Temperature: 80 °C
Yield: 80.7 %

Procedure:
To a solution of N-(1,3,5-Trimethyl-1H-pyrazol-4-yl)-benzene-1,2-diamine (7.56 g, 35.0 mmol) and 2-bromo-N-isopropyl-N-(4-methoxy-phenyl)-acetamide (7.18 g, 38.5 mmol) in DMF (70 mL) was added potassium carbonate (14.5 g, 105 mmol) and potassium iodide (581 mg, 3.5 mmol). The solution was heated at 80° C. for 15 h and subsequently poured into DCM (100 mL). The mixture was extracted with H2O (×4), 1N HCl (×2) and brine, dried over MgSO4 and concentrated in vacuo. The resulting foam was purified by trituration with Et2O to yield the title compound (11.9 g):
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1.[CH3:17][O:18][NH2:19].Cl>C(O)C>[CH3:17][O:18][N:19]=[C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CON
Reactant: CCOC(=O)CC(=O)c1ccc(OC)cc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CC(=NOC)c1ccc(OC)cc1
Temperature: 80 °C

Procedure:
A mixture of ethyl 3-(4-methoxyphenyl)-3-oxopropanoate (500 mg) and MeONH2.HCl (207 mg) in ethanol (4 mL) was heated at 80° C. for 2 h. Ethanol was removed in vacuo, and saturated sodium bicarbonate was added to the residue. The aqueous solution was extrated with ethyl acetate (x4), and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated in vacuo to give the title compound as a colorless oil, which was used directly in the Step B. HPLC retention time: 2.02 min (method A). MS (ESI) (M+H)+ 252.14.