Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.Br[CH2:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13]>O1CCCC1>[CH2:15]([O:14][C:12]([C:11]1[N:1]=[C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]2[CH:10]=1)=[O:13])[CH3:16]
Reactant: Cc1cccc(N)n1
Reactant: CCOC(=O)C(=O)CBr
Solvent: C1CCOC1
Product: CCOC(=O)c1cn2c(C)cccc2n1
Yield: 58.8 %

Procedure:
2-Amino-6-methylpyridine (5 g, 0.05 mol) was dissolved in tetrahydrofuran (100 mL). Ethyl bromopyruvate (9 g, 0.05 mol) was added and the mixture was refluxed for 4 hours. The reaction was cooled and the solid that formed was filtered to give 6 grams of 5-methylimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester. Rf 0.45, 2% methanol/dichloromethane; MS m/z 205 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]2[C:13]3[C:18]([NH:19][C:4]=2[C:3]1=[O:20])=[CH:17][CH:16]=[CH:15][CH:14]=3.[H-].[Na+].C1COCC1.[Cl:28][CH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>Cl>[ClH:28].[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]2[C:13]3[C:18]([N:19]([CH2:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)[C:4]=2[C:3]1=[O:20])=[CH:17][CH:16]=[CH:15][CH:14]=3
Reactant: CN1C(=O)c2[nH]c3ccccc3c2Oc2ccccc21
Reactant: ClCCCN1CCCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C(=O)c2c(c3ccccc3n2CCCN2CCCCC2)Oc2ccccc21

Procedure:
A mixture of 1.8 g of 7-methyl-7H-indolo [3,2-b][1,5]benzoxazepin-6(5H)-one, 0.42 g of 57% sodium hydride-mineral oil dispersion and 10 ml of THF was refluxed for 15 min. and then treated with 4.0 g of 3-chloropropylpiperidine. The mixture was refluxed for 24 hrs., diluted with 2 N HCl and extracted with ether. The aqueous layer was made basic with 5% NaOH and the oil extracted with ether. The ether phase was dried and treated with dry HCl to give a white solid. The solid was recrystallized from methanol-ether to give analytical material, mp. 205°-6°.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[CH:19]=[C:18]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[O:21])[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O.Cl.[CH3:32][O:33][C:34](=[O:47])[C@H:35]([CH2:37][NH:38][C:39](=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[NH2:36].C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[C:39]([NH:38][CH2:37][C@@H:35]([C:34]([O:33][CH3:32])=[O:47])[NH:36][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:18]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[O:21])=[CH:19][C:11]=1[Cl:10])(=[O:46])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: COC(=O)[C@@H](N)CNC(=O)c1ccccc1
Reactant: O=C(NCc1cccc(O)c1)c1ccc(C(=O)O)c(Cl)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CNC(=O)c1ccccc1)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.4 %

Procedure:
Diisopropylethylamine (27 mL, 147.2 mmol) was added dropwise to a cooled (˜0° C.) solution of 2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoic acid (Example 26; 9.00 g, 29.4 mmol), 3-benzoylamino-L-alanine methyl ester hydrochloride (Example 300; 11.4 g, 44.2 mmol), HTBU (13.4 g, 35.3 mmol) and HOBT (4.8 g, 35.3 mmol) in N,N-dimethylformamide (125 mL). The reaction was allowed to warm to room temperature and to stir for 18 h. The solvent was concentrated under vacuum to remove most of the N,N-dimethylformamide. Ethyl acetate was added and the solution was washed with water (2×150 mL). 1 M HCl (3×100 mL) and brine. The solution was dried (MgSO4), filtered, evaporated, and chromatographed (0-50% acetone/dichloromethane) to give 3-benzoylamino-N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-L-alanine, methyl ester (10.7 g, 71%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:29][CH2:30][CH2:31][OH:32]>>[OH:32][CH2:31][CH2:30][CH2:29][N:22]1[CH2:21][C@@H:20]([CH3:25])[N:16]2[C:17]3[CH:18]=[CH:19][C:11]([O:10][CH:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[CH:12][C:13]=3[CH:14]=[C:15]2[C:23]1=[O:24]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CNC2=O)CC1
Reactant: OCCCBr
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CN(CCCO)C2=O)CC1
Yield: 58 %

Procedure:
The title compound was synthesized in analogy to example 17, from (R)-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 8), sodium hydride and 3-bromo-1-propanol, to give the desired product as a colorless oil (58%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10]C)[CH:7]=[CH:6][C:4]=1[NH2:5].[F:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22]C)C(O)=O>>[F:12][C:13]1[CH:14]=[C:15]([C:1]2[O:2][C:3]3[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:4]=3[N:5]=2)[CH:19]=[CH:20][C:21]=1[OH:22]
Reactant: COc1ccc(N)c(OC)c1
Reactant: COc1ccc(C(=O)O)cc1F
Product: Oc1ccc2nc(-c3ccc(O)c(F)c3)oc2c1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 1, from 2,4-dimethoxyaniline, and 3-fluoro-4-methoxybenzoic acid and was obtained as a white solid, m.p. 269–271° C.; MS m/e 244 (M−H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[C:14][C:15]1[CH:19]=[C:18]([Si:20]([CH3:23])([CH3:22])[CH3:21])[O:17][CH:16]=1>C(OCC)(=O)C.[Pd]>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH:14][C:15]1[CH:19]=[C:18]([Si:20]([CH3:23])([CH3:22])[CH3:21])[O:17][CH:16]=1
Reactant: C[Si](C)(C)c1cc(C#CCCCCCCCCCCCO)co1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[Si](C)(C)c1cc(C=CCCCCCCCCCCCO)co1

Procedure:
3-(13-Hydroxy-1-tridecynyl)-5-trimethylsilylfuran, prepared as in Example 6, is hydrogenated in ethyl acetate using a poisoned palladium catalyst to give 3-(13-hydroxy-1-tridecenyl)-5-trimethylsilylfuran. Oxidizing by the procedure of Example 7 gives 4-(13-hydroxy-1-tridecenyl)-5-hydroxy-2(5H)-furanone.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH2:5][C:6]1[S:7][C:8]([CH2:11]O)=[CH:9][CH:10]=1)[CH3:4].Cl.[NH2:14][CH2:15][CH2:16][SH:17].O.[OH-].[Na+]>Cl.CCOCC.C(O)C>[ClH:1].[ClH:1].[CH3:2][N:3]([CH2:5][C:6]1[S:7][C:8]([CH2:11][S:17][CH2:16][CH2:15][NH2:14])=[CH:9][CH:10]=1)[CH3:4]
Reactant: NCCS
Reactant: CN(C)Cc1ccc(CO)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: CN(C)Cc1ccc(CSCCN)s1
Reaction time: 8 h
Yield: 144.5 %

Procedure:
A solution of 2-(dimethylaminomethyl)-5-(hydroxymethyl)thiophene hydrochloride (8.0 g) in concentrated hydrochloric acid (50 ml) was added dropwise to a stirred solution of cysteamine hydrochloride (4.37 g) in concentrated hydrochloric acid (50 ml) cooled in an ice-bath. The temperature of the mixture was maintained below 5° during the addition. The mixture was allowed to reach room temperature and was stirred overnight and poured into water. The aqueous mixture was adjusted to pH12 with 2N sodium hydroxide and was extracted with ethyl acetate (750 ml). The extract was dried and evaporated to give an oil which was dissolved in dry ether and hydrogen chloride in ethanol was added and the solid was filtered off to give 2-[5-dimethylaminomethyl-2-thienylmethylthio]ethylamine dihydrochloride (8.44 g) m.p. 190°-194°.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2([CH3:34])[CH:13]([C:14]([O:16]CC(Cl)(Cl)Cl)=[O:15])[N:12]3[C:22](=[O:33])[CH:23]([NH:24][C:25](=[O:32])[CH2:26][N:27]4[CH:31]=[N:30][N:29]=[N:28]4)[C@H:11]3[S:10]2)=[N:5][N:4]=[N:3]1.C(O)(=O)C>CN(C)C=O.[Zn]>[CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2([CH3:34])[CH:13]([C:14]([OH:16])=[O:15])[N:12]3[C:22](=[O:33])[CH:23]([NH:24][C:25](=[O:32])[CH2:26][N:27]4[CH:31]=[N:30][N:29]=[N:28]4)[C@H:11]3[S:10]2)=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1SCC1(C)S[C@@H]2C(NC(=O)Cn3cnnn3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cn1nnnc1SCC1(C)S[C@@H]2C(NC(=O)Cn3cnnn3)C(=O)N2C1C(=O)O
Temperature: -15 °C
Reaction time: 1.5 h
Yield: 54.1 %

Procedure:
2,2,2-Trichloroethyl 2-(1-methyl-1H-tetrazol-5-yl)thiomethyl-2-methyl-6-[2-(1H-tetrazol-1-yl) acetamido]-penam-3-carboxylate (0.6 g) was dissolved in dimethylformamide (5 ml). To this solution were added acetic acid (0.9 ml) and zinc powder (0.8 g) under cooling at -15°C and the mixture was stirred for 1.5 hours at the same temperature. After the reaction, zinc powder was filtered off and the filtrate was poured into 5% hydrochloric acid (20 ml) and then extracted with ethyl acetate. The extract was washed with water, dried and the solvent was distilled off. The residue was crystallized from ether to give 2-(1-methyl-1H-tetrazol-5-yl)thiomethyl-2-methyl-6-[2-(1H-tetrazol-1-yl) acetamido]-penam-3-carboxylic acid (0.25 g), mp. 152° to 154°C.
Reaction SMILES: [Cl:1][C:2]1[C:3](/[C:12](=[N:27]/[O:28][CH:29]([CH3:31])[CH3:30])/[CH2:13][NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1>C(O)(=O)C>[Cl:1][C:2]1[C:3](/[C:12](=[N:27]\[O:28][CH:29]([CH3:31])[CH3:30])/[CH2:13][NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:24])([F:25])[F:23])=[N:4][CH:5]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:7]=1
Reactant: CC(C)O/N=C(\CNC(=O)c1ccccc1C(F)(F)F)c1ncc(C(F)(F)F)cc1Cl
Solvent: CC(=O)O
Product: CC(C)O/N=C(/CNC(=O)c1ccccc1C(F)(F)F)c1ncc(C(F)(F)F)cc1Cl
Temperature: 70 °C
Reaction time: 1 h
Yield: 51.2 %

Procedure:
11.00 g of (E)-N-[2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-2-(isopropoxyimino)ethyl]-2-(trifluoromethyl)benzamide was dissolved in 30 ml of acetic acid and stirred at 70° C. for 1 hour. After completion of the reaction, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using ethyl acetate-chloroform (with a gradient of from 0:100 to 5:95) as the eluent to obtain 5.63 g of the desired product as white crystals.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:7]2=[N:6][C:5]=1[CH3:16].[C:17]1([CH3:29])[CH:22]=[CH:21][CH:20]=[C:19]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:18]=1>C1(C)C=CC=CC=1>[C:17]1([CH3:29])[CH:22]=[CH:21][CH:20]=[C:19]([N:23]2[CH2:24][CH2:25][N:26]([CH2:2][CH2:3][C:4]3[C:9](=[O:10])[N:8]4[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:7]4=[N:6][C:5]=3[CH3:16])[CH2:27][CH2:28]2)[CH:18]=1
Reactant: Cc1ccc2nc(C)c(CCCl)c(=O)n2c1
Reactant: Cc1cccc(N2CCNCC2)c1
Solvent: Cc1ccccc1
Product: Cc1cccc(N2CCN(CCc3c(C)nc4ccc(C)cn4c3=O)CC2)c1
Yield: 57.2 %

Procedure:
A mixture of 2.2 g of 3-(2-chloroethyl)-2,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one, 5 g of 1-(m-tolyl)piperazine and 25 ml of toluene was refluxed for 30 hours. After completion of the reaction, the reaction mixture was filtered while hot and the filtrate was concentrated under reduced pressure. The residue was purified by means of column chromatography using alumina and recrystallized from a mixture of ethanol and isopropyl ether to give 2 g of the desired compound as pale yellow prisms, m.p. 115 - 116°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[CH2:6][NH:7][C:8]([C:10]1([CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9].[N:31]1([C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:38]=2)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[CH2:6][NH:7][C:8]([C:10]1([CH2:23][CH2:24][CH2:25][CH2:26][N:34]2[CH2:35][CH2:36][N:31]([C:37]3[CH:46]=[CH:45][C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[N:38]=3)[CH2:32][CH2:33]2)[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9]
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Reactant: COc1cccc(CNC(=O)C2(CCCCBr)c3ccccc3-c3ccccc32)c1
Product: COc1cccc(CNC(=O)C2(CCCCN3CCN(c4ccc5ccccc5n4)CC3)c3ccccc3-c3ccccc32)c1

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-3-methoxy-benzylamide and 2-piperazin-1-yl-quinoline.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:14])([CH3:13])[CH:7]([CH3:12])[N:8]2[CH3:11])=[CH:4][CH:3]=1.[F:15][C:16]([F:26])([F:25])[C:17](=O)[CH2:18][C:19](OCC)=[O:20]>>[O:20]=[C:19]1[CH:18]=[C:17]([C:16]([F:26])([F:25])[F:15])[C:3]2[C:2](=[CH:10][C:9]3[N:8]([CH3:11])[CH:7]([CH3:12])[C:6]([CH3:13])([CH3:14])[C:5]=3[CH:4]=2)[NH:1]1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: CC1N(C)c2cc(N)ccc2C1(C)C
Product: CC1N(C)c2cc3[nH]c(=O)cc(C(F)(F)F)c3cc2C1(C)C
Reaction time: 1 h

Procedure:
6-Amino-1,2,3,3-tetramethylindoline (6.9 g, 0.036 mole) was treated with 6.8 g of ethyl trifluoroacetoacetate. There was an immediate reaction with heat evolution and formation of a solid. The mixture was heated in an oil bath under a reflux condenser for 16 hrs at 135°-140° C., then for 1 hr at 145°-150° C. The cooled cake was broken up, triturated with 10 ml of diethyl ether, filtered and washed twice with cold ether; 7.7 g (69%). When recrystallized from 275 ml of 95% ethanol, the compound was obtained as felted, yellow needles; m.p. 248°-249° C., shrinking at 244° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:15]([CH:16]([CH3:18])[CH3:17])=[C:14]([CH:19]=[O:20])[N:13]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[N:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[BH4-].[Na+]>C1COCC1>[CH2:1]([NH:8][C:9]([C:11]1[C:15]([CH:16]([CH3:18])[CH3:17])=[C:14]([CH2:19][OH:20])[N:13]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[N:12]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1c(C(=O)NCc2ccccc2)nn(-c2ccc(F)cc2)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1c(C(=O)NCc2ccccc2)nn(-c2ccc(F)cc2)c1CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
To a solution of 1-(4-fluoro-phenyl)-5-formyl-4-isopropyl-1H-pyrazole-3-carboxylic acid benzylamide (0.620 g, 1.70 mmol) in THF:MeOH (40 mL) at 0° C. was added sodium borohydride (96.3 mg, 2.55 mmol; commercially available from Sigma Aldrich). The reaction was stirred for 30 min at 0° C. at which point TLC analysis indicated the reaction was complete and the solvent was removed under reduced pressure. To the reaction residue was added ethyl acetate (50 mL) and saturated NaHCO3 (15 mL), and the organic layer was separated, dried (Na2SO4) and concentrated. The resulting oil was purified by silica gel chromatography (40% EtOAc/Hex) to afford 1-(4-fluoro-phenyl)-5-hydroxymethyl-4-isopropyl-1H-pyrazole-3-carboxylic acid benzylamide (0.540 g, 87%): MS(APCI+): m/z368.1 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[N:16]([C:28]4[CH:33]=[CH:32][C:31]([N:34]5[S:38](=[O:40])(=[O:39])[NH:37][C:36](=[O:41])[CH2:35]5)=[CH:30][CH:29]=4)[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=4[Cl:27])[N:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[Cl:27][C:21]1[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:15]([CH2:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:42]4[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]4)=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)[N:16]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[S:38](=[O:40])(=[O:39])[NH:37][C:36](=[O:41])[CH2:35]3)=[CH:30][CH:29]=2)[CH:17]=1
Reactant: C1CNCCN1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Br)cc4)cc3)cc2)S(=O)(=O)N1
Product: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(N5CCNCC5)cc4)cc3)cc2)S(=O)(=O)N1

Procedure:
5-{4-[2-(4′-Bromo-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (268 mg, 0.4 mmol) was treated as described in general procedure R using excess piperazine (346 mg, 4 mmol) to give the desired compound 5-{4-[4-(2,4-dichloro-phenyl)-2-(4′-piperazin-1-yl-biphenyl-4-ylmethyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5]3[C:6](=[CH:11][CH:12]=[CH:13][C:4]=3[C:3]1=[O:14])[CH:7]=[CH:8][CH:9]=2>[Ni].C(O)C>[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]3[CH2:11][CH2:12][CH2:13][CH:4]([C:5]=23)[C:3]1=[O:14]
Reactant: CN1C(=O)c2cccc3cccc1c23
Agent: [Ni]
Solvent: CCO
Product: CN1C(=O)C2CCCc3cccc1c32

Procedure:
Ethanol and Raney nickel slurry (Aldrich) were added to 1-methyl-1H-benz[cd]indol-2-one (4.5 g, 25 mmol), and catalytic reduction was carried out under ordinary pressure. The reaction was completed when 1.15 L of hydrogen absorption was observed, and then Raney nickel was removed by filtration, the filtrate was concentrated and the resulting material was separated and purified by a silica gel column chromatography to obtain 3.8 g (20 mmol, 80% in yield) of the title compound.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:32](=[O:33])[N:13]3[C:14]([C:20]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)=[O:21])=[C:15]([CH2:18]Cl)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-:34].[Na+].[C:36]([C:39]12[CH2:46][CH2:45][N:42]([CH2:43][CH2:44]1)[CH2:41][CH2:40]2)(=[O:38])[NH2:37]>CC(C)=O>[I-:34].[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:32](=[O:33])[N:13]3[C:14]([C:20]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)=[O:21])=[C:15]([CH2:18][N+:42]45[CH2:45][CH2:46][C:39]([C:36](=[O:38])[NH2:37])([CH2:44][CH2:43]4)[CH2:40][CH2:41]5)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)C12CCN(CC1)CC2
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(COC(=O)C2=C(C[N+]34CCC(C(N)=O)(CC3)CC4)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.9 %

Procedure:
p-Methoxybenzyl 7β-phenylacetamido-3-chloromethyl-3-cephem-4-carboxylate (980 mg) was suspended in acetone (20 ml), and sodium iodide (362 mg) was added to the suspension and stirred at room temperature for 1 hour. To the resulting suspension was added 4-carbamoylquinuclidine (313 mg) under ice-cooled condition, and the mixture was stirred for 2 hours. The reaction mixture was filtered, and diethyl ether (70 ml) was added to the filtrate. The deposited solid was filtered to obtain the desired product (500 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:6]([CH:14]=1)[CH:7]=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[H][H]>C(OCC)(=O)C.[Pt](=O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:6]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:14]=1
Reactant: CCOC(=O)C=Cc1cc(Cl)ccc1OCCc1ccccc1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cc(Cl)ccc1OCCc1ccccc1
Yield: 93.9 %

Procedure:
570 mg of platinum dioxide was suspended in a solution of 11.39 g of the crude ethyl 5-chloro-2-(2-phenylethoxy)cinnamate in 80 ml of ethyl acetate and stirred in a hydrogen gas stream at room temperature for 4.5 hours. Filtering through Celite and evaporating under reduced pressure gave 10.76 g of crude ethyl 3-[5-chloro-2-(2-phenylethoxy)phenyl]propionate. This compound was not purified any more but used in the subsequent reaction as such.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][C@@H:7]([OH:10])[CH2:8][OH:9])=[O:4].CC(C)([O-])C.[K+].CO.O>C(O)(CC)(C)C>[OH:9][CH2:8][C@H:7]1[CH2:6][NH:5][C:3](=[O:4])[CH2:2][O:10]1
Reactant: O=C(CCl)NC[C@@H](O)CO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CCC(C)(C)O
Product: O=C1CO[C@@H](CO)CN1
Reaction time: 1 h
Yield: 54.9 %

Procedure:
(R)-2-Chloro-N-(2,3-dihydroxypropyl)acetamide (1.31 g, 8.20 mmol) in tert-amyl alcohol (34 mL) was added dropwise over 2 h to a stirred solution of potassium tert-butoxide (2.30 g, 20.6 mmol) in tert-amyl alcohol (16 mL) at room temperature under nitrogen. After 1 hr, MeOH (8 mL) and water (0.5 mL) were added and the reaction mixture was stirred for an additional 20 min. The mixture was concentrated under vacuum and purified by flash column chromatography on silica gel, eluting with methanol/ethyl acetate (2/8) to give the title compound as a white solid (0.59 g, 54%).
Reaction SMILES: COC1C=CC(C[O:10][CH:11]2[CH2:15][CH:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]([NH:24][C:25](=[O:37])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:32]3[N:36]=[CH:35][CH:34]=[N:33]3)[CH2:12]2)=CC=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C(Cl)Cl.O>[OH:10][CH:11]1[CH2:15][CH:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]([NH:24][C:25](=[O:37])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N:32]2[N:33]=[CH:34][CH:35]=[N:36]2)[CH2:12]1
Reactant: COc1ccc(COC2CC(NC(=O)OC(C)(C)C)C(NC(=O)c3ccccc3-n3nccn3)C2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CC(O)CC1NC(=O)c1ccccc1-n1nccn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl N-{4-[(4-methoxyphenyl)methoxy]-2-[2-(2H-1,2,3-triazol-2-yl)benzamido]cyclopentyl}carbamate (1.85 g, 3.64 mmol) in DCM (36 ml) and water (0.364 ml) at 0° C. under an atmosphere of nitrogen was added 4,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile (CAS number 84-58-2; 1.655 g, 7.29 mmol). The reaction was stirred at 0° C. for 1 hour, then was partitioned between a saturated solution of sodium bicarbonate and DCM. The organics were filtered through a hydrophobic frit and concentrated in vacuo. The crude material was purified by column chromatography (silica, 0-100% ethyl acetate/petrol then 0-30% methanol/ethyl acetate) to afford the title compound.
Reaction SMILES: CCN=C=NCCCN(C)C.[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:24](=[O:25])[C:23]([C:26]([OH:28])=O)=[CH:22][CH:21]=[N:20]2)=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C.[CH3:38][O:39][C:40]1[CH:75]=[CH:74][C:43]([CH2:44][N:45]2[C:49]3=[N:50][CH:51]=[CH:52][C:53]([O:54][C:55]4[CH:60]=[CH:59][C:58]([NH2:61])=[CH:57][C:56]=4[F:62])=[C:48]3[C:47]([NH:63][CH:64]3[CH2:69][CH2:68][N:67]([CH2:70][CH2:71][O:72][CH3:73])[CH2:66][CH2:65]3)=[N:46]2)=[CH:42][CH:41]=1>C(Cl)Cl>[CH3:38][O:39][C:40]1[CH:41]=[CH:42][C:43]([CH2:44][N:45]2[C:49]3=[N:50][CH:51]=[CH:52][C:53]([O:54][C:55]4[CH:60]=[CH:59][C:58]([NH:61][C:26]([C:23]5[C:24](=[O:25])[N:19]([C:16]6[CH:15]=[CH:14][C:13]([F:12])=[CH:18][CH:17]=6)[N:20]=[CH:21][CH:22]=5)=[O:28])=[CH:57][C:56]=4[F:62])=[C:48]3[C:47]([NH:63][CH:64]3[CH2:65][CH2:66][N:67]([CH2:70][CH2:71][O:72][CH3:73])[CH2:68][CH2:69]3)=[N:46]2)=[CH:74][CH:75]=1
Reactant: COCCN1CCC(Nc2nn(Cc3ccc(OC)cc3)c3nccc(Oc4ccc(N)cc4F)c23)CC1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCN1CCC(Nc2nn(Cc3ccc(OC)cc3)c3nccc(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)c23)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76 %

Procedure:
EDCI (47 mg, 0.24 mmol) was added to a stirred mixture of 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (57 mg, 0.24 mmol, prepared according to the procedure for Example 19, Step C), HOBt-hydrate (38 mg, 0.24 mmol), and DIEA (0.070 mL, 0.404 mmol) in DCM (1 mL) at ambient temperature, and the reaction was stirred for 15 minutes at ambient temperature. 1-(4-Methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-N-(1-(2-methoxyethyl)piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine (42 mg, 0.0807 mmol) was added, and the resulting solution was stirred for 2 days at ambient temperature. The crude reaction mixture was loaded directly on to a preparative TLC plate (2 mm thickness) and eluted with 10% MeOH/DCM. The product was obtained as a waxy solid (45 mg, 76%). LRMS (APCI+): 100% purity, 220 nm, m/z 737 (M+1) detected.