Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]([CH2:30][CH:31]([CH3:33])[CH3:32])[C@@H:13]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][C@H:15]([C:26]([O:28][CH3:29])=[O:27])[CH2:14]1)=[O:11].CS(O[CH2:39][CH2:40][CH2:41][CH2:42][O:43][CH3:44])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[CH3:44][O:43][CH2:42][CH2:41][CH2:40][CH2:39][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]([CH2:30][CH:31]([CH3:33])[CH3:32])[C@@H:13]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:16][C@H:15]([C:26]([O:28][CH3:29])=[O:27])[CH2:14]1)=[O:11]
Reactant: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2nc3ccccc3[nH]2)CN(C(=O)OC(C)(C)C)C1
Reactant: COCCCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)OC)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 70 °C
Reaction time: 12 h
Yield: 80.5 %

Procedure:
1-tert-Butyl 3-methyl (3R,5S)-5-[(1H-benzimidazol-2-ylcarbonyl)(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (30 g) and 4-methoxybutyl methanesulfonate (12.5 g) were dissolved in DMA (600 ml), cesium carbonate (32 g) was added, and the mixture was stirred at 70° C. for 12 hr. The reaction mixture was poured into ice water (1000 ml), and the mixture was extracted twice with ethyl acetate (1000 ml). The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:4-1:1) was concentrated under reduced pressure to give the object product (28.7 g).
Reaction SMILES: [OH:1][CH2:2][CH:3]([C:5]1[CH:14]=[CH:13][C:8]2[C:9](=[O:12])[O:10][CH2:11][C:7]=2[C:6]=1[CH3:15])[CH3:4].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+].O>C(Cl)Cl>[CH3:15][C:6]1[C:7]2[CH2:11][O:10][C:9](=[O:12])[C:8]=2[CH:13]=[CH:14][C:5]=1[CH:3]([CH3:4])[CH:2]=[O:1]
Reactant: Cc1c(C(C)CO)ccc2c1COC2=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1c(C(C)C=O)ccc2c1COC2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-(2-Hydroxy-1-methylethyl)-4-methyl-2-benzofuran-1(3H)-one (161 mg, 0.781 mmol, 1.0 eq) was dissolved in DCM (6 ml). To above solution was added Dess-MartinPeriodinane (397 mg, 0.937 mmol, 1.2 eq). The reaction was stirred at rt for 2 hr. To the reaction was added DCM (10 Ml), Na2S2O3 (6 mL) and H2O (6 mL). The mixture was stirred at r.t. for 30 minutes and formed two layers. The bottom layer was separated and washed with aqueous NaHCO3, brine and water, dried over Na2SO4, filtered, and concentrated to dryness. The crude product was used to next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[C:11]([OH:19])(=[O:18])[C:12]([CH2:14][C:15](O)=[O:16])=[CH2:13].Cl>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:8]2[C:15](=[O:16])[CH2:14][CH:12]([C:11]([OH:19])=[O:18])[CH2:13]2)=[CH:5][CH:4]=1
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: COc1ccc(CN)cc1
Agent: Cl
Product: COc1ccc(CN2CC(C(=O)O)CC2=O)cc1

Procedure:
4-Methoxybenzylamine was added to an aqueous solution of itaconic acid and heated under reflux for 12Hours. After completion of the reaction, this was cooled in an ice bath and mixed with 1 M hydrochloric acid, and the thus precipitated crystals were collected by filtration to obtain 1-(4-methoxybenzyl)-5-oxopyrrolidine-3-carboxylic acid as colorless crystals. EP: 250.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([CH2:9][CH3:10])=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:11][C:12]1[N:17]=[C:16]([SH:18])[N:15]=[C:14]([OH:19])[CH:13]=1.C(N(CC)CC)C.C(OCC)C>C(O)C>[CH2:9]([C:4]1[C:3]([CH2:2][S:18][C:16]2[N:15]=[C:14]([OH:19])[CH:13]=[C:12]([CH3:11])[N:17]=2)=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:10]
Reactant: Cc1cc(O)nc(S)n1
Reactant: CCc1ncccc1CBr
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CCOCC
Product: CCc1ncccc1CSc1nc(C)cc(O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.9 %

Procedure:
To a 0° C. mixture of 3-(bromomethyl)-2-ethylpyridine (21.9 mmol) and 6-methyl-2-sulfanylpyrimidin-4-ol (2.0 g, 14 mmol) in absolute ethanol (200 mL) was added triethylamine (11 mL, 79 mmol). The mixture was stirred at room temperature overnight. Diethyl ether (300 mL) was added to the clear solution. The precipitate was removed by filtration. The filtrate was recovered, evaporated, and co-evaporated with EtOAc (1×100 mL). The residue was treated with water (300 mL). The solid material was recovered by filtration, washed with water (3×50 mL), diethyl ether (2×50 mL), and hexanes (1×50 mL), and dried in vacuo, affording 2-{[(2-ethylpyridin-3-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (1.9 g, 52% yield), which was used without further purification.
Reaction SMILES: [N:1]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30][CH2:29][C@H:2]1[C:3]([NH:5][C@@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27]N)=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].N[CH2:40][C:41]([NH:43][C@H:44]([C:49]([NH:51][C@H:52]([C:57]([NH2:59])=[O:58])[CH2:53][CH2:54][S:55][CH3:56])=[O:50])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:42].Cl>>[N:1]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30][CH2:29][C@H:2]1[C:3]([NH:5][C@@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27][CH2:40][C:41]([NH:43][C@H:44]([C:49]([NH:51][C@H:52]([C:57]([NH2:59])=[O:58])[CH2:53][CH2:54][S:55][CH3:56])=[O:50])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:42])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CN)C(N)=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)NN
Agent: Cl
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Yield: 82 %

Procedure:
Condensation of BocPro-DPhe-PheNHNH2 (1.98 g.) and HGly-Leu-MetNH2 hydrochloride salt (Example 7, 1.3 g.) by the acyl azide method (Yajima et al., Chem. Pharm. Bull., vol. 19, p. 1900, 1971) gave BocPro-DPhe-Phe-Gly-Leu-MetNH2 in 82% yield. De-t-butoxycarbonylation of BocPro-DPhe-Phe-Gly-Leu-MetNH2 (1.8 g.) using hydrogen chloride in acetic acid gave HPro-DPhe-Phe-Gly-Leu-MetNH2, which was isolated as the amorphous white solid phosphate (1:1) salt monohydrate in 59% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH3:9].[Li]CCCC.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C>C1COCC1>[CH3:9][S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:15]([OH:20])[OH:16]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CSc1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ccccc1B(O)O
Reaction time: 0.42 h
Yield: 84.9 %

Procedure:
2-Bromothioanisole (29.0 g, 143 mmol) was dissolved in dry THF (400 mL) and cooled to −75° C. n-BuLi (62.0 mL, 2.5 M in hexane, 155 mmol) was added over 50 minutes. After stirring 25 minutes, triisopropyl borate (46 mL, 199 mmol) was added over 35 minutes. The cold bath was removed and the reaction was stirred at room temp for 16 hours. The resulting solution was cooled in an ice bathours, and 6 M HCl (100 mL) was added. This mixture was stirred at room temp 5 hours and concentrated to about half of the original volume. The concentrated solution was partitioned between Et2O and water. The organic layer was extracted with 2 M NaOH, which was subsequently reacidified with 6 M HCl and extracted several times back into Et2O. These Et2O washes were dried over Na2SO4, filtered, and evaporated to yield a beige solid (20.4 g, 85%). 1H NMR (CDCl3): δ 8.01 (dd, 1H, J=7.3, J′=1.4), 7.53 (dd, 1H, J=7.7, J′=1.1), 7.43 (td, 1H, J=7.3, J′=1.8), 7.34 (td, 1H, J=7.3, J′=1.5), 6.22 (s, 2H), 2.50 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:17]([N:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].N1CCOCC1.C(O)(C(F)(F)F)=O>CO.ClCCl>[C:20]([O:19][C:17]([N:24]1[CH2:29][CH2:28][C:27]2([NH:6][C:4](=[O:5])[C:3]3[CH:7]=[C:8]([N:11]4[CH2:12][CH2:13][O:14][CH2:15][CH2:16]4)[CH:9]=[CH:10][C:2]=3[O:1]2)[CH2:26][CH2:25]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: NC(=O)c1cc(N2CCOCC2)ccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCN1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)NC(=O)c1cc(N3CCOCC3)ccc1O2
Yield: 56.5 %

Procedure:
A mixture of 50 mg (0.23 mmol) of 2-hydroxy-5-(morpholin-4-yl)benzamide, 59 mg (0.30 mmol) of 1-Boc-4-piperidone, and 40 μL of morpholine in 3 mL of MeOH is refluxed for 6 days. Removal of solvent by rotoevaporation and purification by preparative TLC gives 53 mg (0.13 mmol, 57% yield) of 1′-(tert-butyloxycarbonyl)-6-(morpholin-4-yl)spiro[1,3-benzoxazine-2,4′-piperidine]-4(3H)-one which on treatment with 40% TFA in dichloromethane at room temperature for 2 hr. gives the bis-TFA salt of 6-(morpholin-4-yl)spiro[1,3-benzoxazine-2,4′-piperidine]-4(3H)-one in quantitative yield.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][CH:15]=[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:17]=2[OH:18])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].[CH3:24][O:25][CH2:26]Cl.[Cl-].[NH4+]>CN(C)C=O>[C:3]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:14][CH:15]=[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:17]=2[O:18][CH2:24][O:25][CH3:26])=[CH:11][CH:12]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)c1csc(-c2ccc(C(C)(C)C)cc2)c1O
Reactant: COCCl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(-c2ccc(C(C)(C)C)cc2)c1OCOC
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 92.2 %

Procedure:
60% Sodium hydride (28 mg, 0.69 mmol) was added to a solution of 2-(4-t-butylphenyl)-3-hydroxy-4-ethoxycarbonylthiophene (0.20 g, 0.66 mmol) obtained in accordance with JP-A-48-26755 in dimethylformamide (1.0 mL) at room temperature, and the reaction solution was stirred at 60° C. for 15 minutes. After the reaction solution was cooled to room temperature, chloromethyl methyl ether (0.055 mL, 0.73 mmol) was added dropwise, and the reaction solution was stirred at room temperature for another 5 hours. After addition of saturated aqueous ammonium chloride, the reaction solution was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate. The organic layer was concentrated and purified by silica gel column chromatography (chloroform) to give the desired product as a colorless oil (212 mg, yield 91%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.O>[N:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)CCCCCCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCCCCN=[N+]=[N-]
Temperature: 60 °C

Procedure:
Sodium azide (4.66 g, 72 mmol) and tetrabutylammonium iodide (66 mg, 0.18 mmol) were successively added to a solution of methyl 11-bromoundecanoate (commercially available at Aldrich, 5.00 g, 17.9 mmol) in N,N-dimethylformamide (50 ml). The reaction mixture was heated to 60° C. for 16 h and cooled to room temperature. It was diluted with water (200 ml) and extracted with ethyl acetate (200 ml). The aqueous phase was washed with water (2×200 ml). The organic phase was dried over sodium sulphate. The solvent was removed in vacuo to give 4.28 g of methyl 11-azidoundecanoate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[N:8]([C@@H:13]1[CH2:15][C@@H:14]1[F:16])[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[C:5]2=[O:20].[C@H:21]12[CH2:29][NH:28][CH2:27][C@@H:26]1[NH:25][CH2:24][CH2:23][O:22]2>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:28]1[CH2:29][C@H:21]3[C@@H:26]([NH:25][CH2:24][CH2:23][O:22]3)[CH2:27]1)[N:8]([C@@H:13]1[CH2:15][C@@H:14]1[F:16])[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[C:5]2=[O:20]
Reactant: C1CO[C@H]2CNC[C@@H]2N1
Reactant: O=C(O)c1cn([C@@H]2C[C@@H]2F)c2cc(F)c(F)cc2c1=O
Product: O=C(O)c1cn([C@@H]2C[C@@H]2F)c2cc(N3C[C@@H]4NCCO[C@H]4C3)c(F)cc2c1=O

Procedure:
The title compound is prepared analogously to the procedure of Example 8 by reaction of 6,7-difluoro-1-((1R,2S)-2-fluorocyclopropyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid with (1S,6S)-2-oxa-5,8-diazabicyclo[4.3.0]nonane.
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([F:28])[CH:26]=3)[CH:21]=[CH:20]2)[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].C(O)C>[NH:14]1[CH2:17][CH:16]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([F:28])[CH:26]=3)[CH:21]=[CH:20]2)[CH2:15]1
Reactant: Fc1ccc2ccn(CC3CN(C(c4ccccc4)c4ccccc4)C3)c2c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Fc1ccc2ccn(CC3CNC3)c2c1

Procedure:
A mixture of 1-(1-benzhydryl-azetidin-3-ylmethyl)-6-fluoro-1H-indole (0.6 g, 1.6 mmol), palladium on carbon (10%, cat.amount) and ammonium formate (0.2 g, 3.2 mmol) in ethanol (20 mL) was refluxed for 30 min. The mixture was filtered through celite and the solvent removed under vacuum. Diphenylmethane was removed by triturating the residue with ether, methylene chloride and decanting. The remaining product was dried under vacuum. The crude material was directly used in next step without further purification.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[CH:8]=[N:9][C:10]2[N:11]([N:14]=[CH:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)[C:12]=1[OH:13])(=O)C.[OH-].[Na+]>CO>[OH:13][C:12]1[N:11]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[CH:19][C:20]([S:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:21][CH:22]=3)=[C:10]2[N:9]=[CH:8][C:7]=1[CH2:6][CH2:5][OH:4]
Reactant: CC(=O)OCCc1cnc2c(-c3ccc(Sc4ccccc4)cc3)cnn2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: OCCc1cnc2c(-c3ccc(Sc4ccccc4)cc3)cnn2c1O
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a methanol suspension of 180 mg of 6-(2-acetoxyethyl)-7-hydroxy-3-(4-phenylthiophenyl)pyrazolo[1,5-a]pyrimidine, 2 ml of 2N sodium hydroxide was added, and stirred for 21 hours at room temperature. Turning acidic with 10% hydrochloric acid, the precipitate was filtered, washed with-water, dried, and the title compound was obtained (150 mg, 93%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.C(=O)=O.CC(C)=O.[C:28]1([CH:34]2[CH:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:38][CH:37]=[CH:36][CH2:35]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[Cl:45][CH2:46][CH2:47][CH2:48]I>O1CCCC1.O>[CH2:43]([O:42][C:40]([C:39]1([CH2:48][CH2:47][CH2:46][Cl:45])[CH:34]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:35][CH:36]=[CH:37][CH2:38]1)=[O:41])[CH3:44]
Reactant: CCOC(=O)C1CC=CCC1c1ccccc1
Reactant: ClCCCI
Agent: CC(C)[N-]C(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: CC(C)=O
Solvent: O
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C1(CCCCl)CC=CCC1c1ccccc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 76.9 %

Procedure:
A solution of lithium diisopropylamide (LDA), prepared at 0° C. under a nitrogen (N2) atmosphere from diisopropylamine (0.311 mol, 31.4 g) and n-butyllithium (0.311 mol, 2.7M, 115.3 ml) using tetrahydrofuran (400 ml) as solvent, was cooled to -78° C. employing a dry ice/acetone slurry. Ethyl 6-phenyl-3-cyclohexene-1-carboxylate (0.283 mol, 65 g) dissolved in tetrahydrofuran (100 ml) was added to the solution. After 45 min., 1-chloro-3-iodopropane (0.311 mol, 63.5 g) dissolved in tetrahydrofuran (50 ml) was added dropwise over the period of 30 min. The contents were allowed to warm to room temperature, whereupon 300 ml of water is added and the mixture was extracted three times with 200 ml of ethyl ether. The combined organic extracts were washed with 10% aqueous sodium thiosulfate and brine and dried over magnesium sulfate (MgSO4). Upon filtration, the filtrate was concentrated in vacuo to afford a yellow oil which is distilled (155°-160° C./0.05 mm) to afford ethyl-1-(3-chloropropyl)-6-phenyl-3-cyclohexene-1-carboxylate (66.75 g, 77% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH:11]([NH:13][CH:14]=[O:15])[CH3:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O>CO.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][CH:11]([NH:13][CH:14]=[O:15])[CH3:12])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(Cc1cccc([N+](=O)[O-])c1)NC=O
Agent: [Ni]
Solvent: CO
Product: CC(Cc1cccc(N)c1)NC=O

Procedure:
5.2 gm of 1-(3'-nitro-phenyl)-2-formylamino-propane was hydrogenated in methanol in the presence of Raney nickel at atmospheric pressure and room temperature. Thereafter, the catalyst was filtered off, the solvent was evaporated from the filtrate, and the residue was chromatographed on a silicagel column, using methanol/chloroform (2:8) as the flow agent. The eluate was evaporated, and the residue was recrystallized from ethyl acetate, yielding 1-(3'-aminophenyl)-2-formylamino-propane which had a melting point of 107° -108° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH2:30][CH3:31])([C:27]([OH:29])=O)[CH2:25][CH3:26])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:54][S:55]([NH2:58])(=[O:57])=[O:56].[H-].[Na+].Cl>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH2:25][CH3:26])([C:27]([NH:58][S:55]([CH3:54])(=[O:57])=[O:56])=[O:29])[CH2:30][CH3:31])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(Cl)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(Cl)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.9 %

Procedure:
A solution of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-ethyl-1-hydroxycarbonyl-propoxy)-phenyl]-2′-(5-chloro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (150 mg, 0.244 mmol) and CDI (80 mg, 0.49 mmol) in DMF (2 mL) was heated at 60° C. for 2 h, then cooled to room temperature. In a separate flask a mixture of methanesulfonamide (231 mg, 2.44 mmol) and NaH (78 mg, 60%, 1.95 mmol) was stirred in DMF (3 mL) at room temperature for 2 h, then the resulting mixture was added into the above solution. The reaction mixture was stirred at room temperature for 1 h, then poured into water and “pH” was acidified to 2-3 by addition of concentrated HCl solution. The mixture was extracted with EtOAc twice, the combined extracts were dried over anhydrous Na2SO4, concentrated and the residue was purified by flash column to give the title compound as a white solid (10 mg).
Reaction SMILES: [CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12]2.[OH:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O>>[CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2=[CH:22][C:21]1[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=1[OH:19]
Reactant: O=Cc1ccccc1O
Reactant: CC1SC(=O)NN=C1c1ccc2c(c1)CC(=O)N2
Product: CC1SC(=O)NN=C1c1ccc2c(c1)C(=Cc1ccccc1O)C(=O)N2
Yield: 62 %

Procedure:
Starting from 5-(3,6-dihydro-6-methyl-2-oxo-2H-1,3,4-thiadiazin-5-yl)-1,3-dihydro-2H-indol-2-one and 2-hydroxy benzaldehyde and following the method described in Example 10, the desired compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][CH2:30][O:31][C:24]=3[CH:23]=2)[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][CH2:30][O:31][C:24]=4[CH:23]=3)[C:11]3[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: O=[N+]([O-])c1cc2c(NCc3ccc4c(c3)OCCO4)nc(Cl)nc2s1
Product: Cc1nccn1-c1nc(NCc2ccc3c(c2)OCCO3)c2cc([N+](=O)[O-])sc2n1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-nitro-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-nitro-4-(3,4ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[CH3:9][P:10]([O-:16])[O:11][CH2:12][CH:13]([CH3:15])[CH3:14].C(N(CC)CC)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:9][PH:10](=[O:16])[O:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:3][CH:4]=1
Reactant: CC(C)COP(C)[O-]
Reactant: Fc1ccc(Br)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC(C)CO[PH](=O)Cc1ccc(F)cc1
Temperature: 100 °C
Yield: 82.1 %

Procedure:
A mixture of 50.0 g (289 mmol) of 4-bromofluorobenzene, 43.3 g (318 mmol) of isobutyl methanephosphonite, 43.8 ml (318 mmol) of triethylamine, 1.64 g (0.29 mmol,1 mol %) of bis(dibenzylideneacetone)-palladium and 1.50 g (0.58 mmol, 2 mol %) of triphenylphosphine was heated for 20 hours at 100° C. under an inert gas atmosphere. At 23° C., the solution was filtered off from the ammonium salt formed and the filtrate was evaporated under reduced pressure. Fractional distillation under reduced pressure gave 54.60 g (83% of theory) of isobutyl 4-fluorophenylmethylphosphinate having a boiling point of 83° C./0.08 mbar.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.Cl[C:12]([O-])=O.O=S(Cl)Cl.C1(OC(Cl)=O)C=CC=CC=1.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.N=C=N.C1N=CN(C(N2C=NC=C2)=O)C=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.ON1C(=O)CCC1=O>CO.CN1C(=O)CCC1.CN(C=O)C.ClCCCl.C(Cl)Cl>[CH3:12][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: O=C([O-])Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N=C=N
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(Cl)nc1

Procedure:
6-Chloronicotinic acid 51 is activated by reacting with a chloroformate activating agent such as SOCl2, phenylchloroformate, or p-nitrophenyl chloroformate, or a carbodiimide activating agent such as CDI, DCC, or EDC in the presence of HOBt and N-hydroxysuccinimide in a polar aprotic solvent such as CH2Cl2, 1,2-dichloroethane, DMF, or NMP, and heating. An alcohol such as methanol is then added to form 6-chloronicotinic acid methyl ester 52.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH2:7].[C:8]1(=O)[O:13][C:11](=[O:12])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12>C1(C)C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11](=[O:12])[C:10]2[C:9](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]1=[O:13]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCc1cccs1
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1Cc1cccs1
Yield: 94.7 %

Procedure:
A solution of thiophene-2-methylamine (4.203 g, 37.13 mmol) and of phtalic anhydride (5.00 g, 33.76 mmol) in toluene (100 mL) was stirred and heated at reflux for 3 h to remove the formed water by azeotropic distillation (Dean-Stark). The solvent was then evaporated under vacuum. The residue was dissolved in DCM (100 mL), washed with water (3×30 mL), dried over MgSO4, filtered and concentrated to afford the title compound as a white solid (7.78 g, 95%). 1H NMR (CDCl3, 300 MHz) δ 7.84 (d, 1H. J=5.4 Hz), 7.83 (d, 1H. J=5.4 Hz), 7.69 (d, 1H, J=5.4 Hz), 7.68 (d, 1H, J=5.4 Hz), 7.20 (d, 0.5H, J=5.2 Hz), 7.19 (d, 0.5H, J=5.2 Hz), 7.14 (m, 1H), 6.92 (d, 0.5H, J=5.1 Hz), 6.91 (d, 0.5H, J=5.1 Hz), 5.01 (s, 2H). HPLC (Condition A), Rt: 4.11 min (HPLC purity: 99.2%).