Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[N:27]1[CH:32]=[CH:31][C:30]([C:33]([C:35]2[N:36]=[CH:37][N:38]3[CH:42]=[C:41]([Sn](CCCC)(CCCC)CCCC)[S:40][C:39]=23)=[O:34])=[CH:29][CH:28]=1>>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])=[C:8]([C:41]3[S:40][C:39]4=[C:35]([C:33]([C:30]5[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=5)=[O:34])[N:36]=[CH:37][N:38]4[CH:42]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)c3ccncc3)c2s1
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)c5ccncc5)c4s3)[C@H](C)[C@H]12
Yield: 58.4 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyridin-4-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate (1.23 g) was prepared in the same manner as in step a) of Example 1, except that 1.33 g of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 2.00 g of 7-(pyridin-4-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:10])=[CH:4][C:5]([NH2:9])=[C:6]([CH3:8])[CH:7]=1.[C:11]1([S:17](Cl)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1>[F:1][C:2]1[C:3]([NH:10][S:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:19])=[O:18])=[CH:4][C:5]([NH:9][S:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:19])=[O:18])=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(F)c(N)cc1N
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: Cc1cc(F)c(NS(=O)(=O)c2ccccc2)cc1NS(=O)(=O)c1ccccc1
Temperature: 120 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
8 g 5-fluoro-2,4-diaminotoluene from Step 2 are dissolved in 250 ml pyridine, mixed with 7.9 ml benzenesulfonyl chloride, and stirred for 1 hour at 120° C. After cooling, the reaction preparation is poured over ice. The obtained precipitate is washed with water, dried in vacuum over phosphorus pentoxide, and recrystallized from methanol. 3.9 g (41% of theory) 5-fluoro-2,4-bis[(N-benzenesulfonyl)amino]toluene are obtained which melts at 146° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][N:26]1[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]2[C:27]1=[O:36].CC#N>O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:12][CH2:13][N:14]([CH2:24][CH2:25][N:26]4[C:30](=[O:31])[C:29]5=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]5[C:27]4=[O:36])[CH2:15][CH2:16]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(N3CCNCC3)n[nH]c2c1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCN1CCN(c2n[nH]c3cc(F)ccc23)CC1
Reaction time: 65 h
Yield: 56.5 %

Procedure:
A mixture of 6-fluoro-3-(4-piperazinyl)-1H-indazole (4.0 g, 18 mmol), K2CO3 (2.7 g, 20 mmole), N-(2-bromoethyl)phthalimide (4.8 g, 19 mmole) and CH3CN (100 ml) was stirred at reflux under N2 for 4 hours. After standing at ambient temperature for 65 hours, the reaction was poured into H2O. The resultant solid was collected to yield 4.0 g of a yellow powder. The product was recrystallized twice from ethanol to yield 3.5 g (50%) of a beige powder m.p.=220°-223 ° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11](Cl)=[O:12])=[C:6]2[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:3]=1.[CH3:21][S:22]([C:25]1[CH:26]=[C:27]([NH2:31])[CH:28]=[CH:29][CH:30]=1)(=[O:24])=[O:23]>>[CH3:21][S:22]([C:25]1[CH:26]=[C:27]([NH:31][C:11]([C:10]2[CH:9]=[N:8][N:7]3[C:2]([Cl:1])=[CH:3][C:4]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=4)=[N:5][C:6]=23)=[O:12])[CH:28]=[CH:29][CH:30]=1)(=[O:23])=[O:24]
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: O=C(Cl)c1cnn2c(Cl)cc(-c3ccc(Cl)cc3)nc12
Product: CS(=O)(=O)c1cccc(NC(=O)c2cnn3c(Cl)cc(-c4ccc(Cl)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-chloro-5-(4-chloro-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride and 3-methanesulfonyl-phenylamine according to general procedure II. Pale-yellow solid. MS (ISP) 461.3 [(M+H)+]; mp 253-255° C.
Reaction SMILES: Br[C:2]1[CH:6]=[C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][CH:9]=2)[S:4][C:3]=1[CH2:16][CH2:17][O:18][C:19]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([Li])CCC.[CH2:43]([O:50][CH:51]1[CH:56]([O:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[CH:55]([O:65][CH2:66][C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[CH:54]([CH2:73][O:74][CH2:75][C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)[O:53][C:52]1=[O:82])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH2:43]([O:50][CH:51]1[CH:56]([O:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[CH:55]([O:65][CH2:66][C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=2)[CH:54]([CH2:73][O:74][CH2:75][C:76]2[CH:77]=[CH:78][CH:79]=[CH:80][CH:81]=2)[O:53][C:52]1([C:2]1[CH:6]=[C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][CH:9]=2)[S:4][C:3]=1[CH2:16][CH2:17][O:18][C:19]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[OH:82])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CCc1ccc(Cc2cc(Br)c(CCOC(c3ccccc3)(c3ccccc3)c3ccccc3)s2)cc1
Reactant: O=C1OC(COCc2ccccc2)C(OCc2ccccc2)C(OCc2ccccc2)C1OCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCc1ccc(Cc2cc(C3(O)OC(COCc4ccccc4)C(OCc4ccccc4)C(OCc4ccccc4)C3OCc3ccccc3)c(CCOC(c3ccccc3)(c3ccccc3)c3ccccc3)s2)cc1
Reaction time: 0.25 h
Yield: 64.9 %

Procedure:
Under a nitrogen stream, to a solution of 3-bromo-5-((4-ethylphenyl)methyl)-2-(2-trityloxyethyl)thiophene (1.45 g, 2.55 mmol) in anhydrous THF (40 ml), a hexane solution of n-butyllithium (1.6 M, 1.76 ml, 2.81 mmol) was added dropwise at −78° C. and the mixture was stirred for 15 minutes. To this solution was added a solution of 3,4,5-trisbenzyloxy-6-(benzyloxymethyl)tetrahydropyran-2-one (1.50 g, 2.81 mmol) in anhydrous THF (10 ml) dropwise at −78° C. and the resulting solution was stirred at the same temperature for 10 minutes. After addition of saturated aqueous ammonium chloride, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove the solvent. The resulting residue was purified by silica gel column chromatography (developing solution=ethyl acetate:n-hexane (1:20)) to give the titled compound (1.70 g, 65%).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].F[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH:20]=2)=[CH:15][C:14]=1[N+:32]([O-:34])=[O:33].CCCCCC>CS(C)=O>[N+:32]([C:14]1[CH:15]=[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26](=[O:31])[C:27]([F:28])([F:29])[F:30])[CH:20]=2)[CH:17]=[CH:18][C:13]=1[CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])([O-:34])=[O:33]
Reactant: COC(=O)CC(=O)OC
Reactant: O=C(Nc1cccc(-c2ccc(F)c([N+](=O)[O-])c2)c1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CS(C)=O
Product: COC(=O)C(C(=O)OC)c1ccc(-c2cccc(NC(=O)C(F)(F)F)c2)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
Dimethyl malonate (9.6 mL) was added dropwise to a stirred suspension of 3.2 g of 60% sodium hydride in mineral oil in 40 mL of anhydrous dimethylsulfoxide under nitrogen. The mixture was stirred for 10 minutes and 2-fluoro-5-(3-trifluoroacetamidophenyl)nitrobenzene in 20 mL of dimethylsulfoxide was added. The resulting dark red mixture was heated to 100° C. for 2 hours. The reaction was quenched by pouring into 100 mL of saturated ammonium chloride solution and extracted twice with 50 mL of ethyl acetate each time. The organic phase was washed with 50 mL each of saturated ammonium chloride solution, water, and brine, dried over anhydrous sodium sulfate and concentrated to a yellow oil. The oil was chromatographed on a column of silica gel eluting with a 1:4 mixture of ethyl acetate:hexane to give 4.4 g (50% yield) of dimethyl 2-[2-nitro-4-(3-trifluoroacetamidophenyl)phenyl]malonate as a pale yellow solid.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[CH:9][C:10]2[N:14]=[C:13]([C@@H:15]3[CH2:21][C:18]4([CH2:20][CH2:19]4)[CH2:17][N:16]3[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[NH:12][C:11]=2[CH:29]=1)(C)C.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CO>[C:6]([C:7]1[CH:8]=[CH:9][C:10]2[N:14]=[C:13]([C@@H:15]3[CH2:21][C:18]4([CH2:19][CH2:20]4)[CH2:17][N:16]3[C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[NH:12][C:11]=2[CH:29]=1)#[CH:5]
Reactant: CC(C)(C)OC(=O)N1CC2(CC2)C[C@H]1c1nc2ccc(C#C[Si](C)(C)C)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C#Cc1ccc2nc([C@@H]3CC4(CC4)CN3C(=O)OC(C)(C)C)[nH]c2c1
Yield: 104 %

Procedure:
A brown opaque mixture of (S)-tert-butyl 6-(6-((trimethylsilyl)ethynyl)-1H-benzo[d]imidazol-2-yl)-5-azaspiro[2.4]heptane-5-carboxylate (0.99 kg, 2.41 mol, 1 equiv.) in methanol (5.5 L) is treated with solid potassium carbonate (340 g, 2.46 mol, 1.02 equiv.) for about 1.5 hours and the reaction was complete as indicated by TLC/MS. The mixture was rotavapped and solvent swapped to EtOAc (6 L), and then washed with 10% NaCl solution (5 L). Upon drying over Na2SO4 it was rotavapped and vacuum dried at about 25˜30° C. overnight to afford 0.845 kg (104% yield, 98% HPLC purity) of the title compound as a light brown foam. ESI MS m/z (M+H)+ 338.19.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][C:15](O)=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:18]([NH:21][NH:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:20])[CH3:19].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH:1]1[C:13]2[CH:12]([CH2:14][C:15]([N:21]([CH:18]([CH3:20])[CH3:19])[NH:22][C:23](=[O:30])[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)NNC(=O)c1ccccc1
Reactant: O=C(O)CC1c2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CC1c2ccccc2-c2ccccc21
Yield: 40.4 %

Procedure:
A solution of 9-fluoreneacetic acid (126 mg, 0.56 mmoles) and benzoic acid N′-isopropyl-hydrazide (100 mg, 0.56 mmoles) in DMF (5 mL) was treated with triethylamine (0.23 mL, 1.68 mmol), HOBT (91 mg, 0.67 mmoles) and EDCI (129 mg, 0.67 mmol) at room temperature for 72 h. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with water and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 10-30% ethyl acetate/hexanes gradient to afford the product as a solid (87 mg, 40%). LC-MS m/e 385.19 (M+H+)
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][C@H:9]3[N:21]([CH3:22])[CH2:20][CH2:19][C@@:15]4([C:16]=2[C:17]=1[OH:18])[C@@:10]3([O:24][CH3:25])[CH2:11][CH2:12][C:13](=[O:23])[CH2:14]4.Br[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>N1C=CC=CC=1>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][C@H:9]3[N:21]([CH3:22])[CH2:20][CH2:19][C@@:15]4([C:16]=2[C:17]=1[O:18][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@@:10]3([O:24][CH3:25])[CH2:11][CH2:12][C:13](=[O:23])[CH2:14]4
Reactant: Brc1ccccc1
Reactant: COc1ccc2c(c1O)[C@]13CCN(C)[C@H](C2)[C@]1(OC)CCC(=O)C3
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: COc1ccc2c(c1Oc1ccccc1)[C@]13CCN(C)[C@H](C2)[C@]1(OC)CCC(=O)C3
Yield: 59.2 %

Procedure:
To a solution of crude 16 (16 g) in dry pyridine (200 ml) was added bromobenzene (22.5 g, 143.29 mmol) and 18 g (159.178 mmol) of K2CO3 (freshly dried at 110° C. for 2 hour in a vacuum oven and quickly ground and sieved to 200 mesh). More pyridine (20 ml) followed by copper powder (1.5 g, 10 micron) was added and the mixture was refluxed (oil bath temp 140°-150° C.) for 20 hr under a N2 atmosphere with stirring. The solution was filtered hot, and the residue washed with hot pyridine. The filtrate was concentrated under reduced pressure to give crude 17 (10.5 g) as a foamy solid. The product was purified by chromatography on silia gel using graded methanol/chloroform to give 7.83 g (80% yield from 15) of 17 as a foamy solid.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:5]=[C:4]([CH3:15])[C:3]1=[O:16].[NH:17]1[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:23])[CH2:18]1>>[CH3:1][N:2]1[C:3](=[O:16])[C:4]([CH3:15])=[CH:5][C:6]([CH:8]2[CH2:13][CH2:12][CH:11]([N:17]3[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=4)=[O:23])[CH2:18]3)[CH2:10][CH2:9]2)=[CH:7]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: Cc1cc(C2CCC(=O)CC2)cn(C)c1=O
Product: Cc1cc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cn(C)c1=O

Procedure:
The title compounds were prepared as white solids from the reductive amination of 1,3-dimethyl-5-(4-oxo-cyclohexyl)-1H-pyridin-2-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.
Reaction SMILES: Br[CH:2]([CH2:8]Br)[C:3]([O:5]CC)=[O:4].C(=O)([O-])[O-].[K+].[K+].[SH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23]>CC(C)=O.C(Cl)Cl>[O:23]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[S:16][CH2:8][CH:2]1[C:3]([OH:5])=[O:4]
Reactant: Oc1ccccc1S
Reactant: CCOC(=O)C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: O=C(O)C1CSc2ccccc2O1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred mixture of 41.6 g of ethyl 2,3-dibromopropionate, 400 ml of dry acetone and 11.1 g of potassium carbonate, there was added dropwise at 27° C. a solution of 19.5 g of o-mercaptophenol in 75 ml of acetone. After the addition was complete, the reaction mixture was stirred at room temperature for 10 minutes and an additional 50.9 g of potassium carbonate was added. The reaction mixture then was refluxed for 2 hours, and allowed to stand overnight at room temperature. The mixture was filtered and the solid was washed with acetone, the washings being added to the filtrate. The acetone was stripped to leave a liquid, which was taken up in methylene chloride. The resulting solution was washed with water and dried (MgSO4), and the solvent was stripped. The resulting liquid was dry column chromatographed through silica gel, using a 4:16:80 by volume mixture of tetrahydrofuran, ethyl acetate and hexane (Solvent No. 2) as eluent, to give the ethyl ester of 2,3-dihydro-1,4-benzoxathiin-2-carboxylic acid (1A), as a light yellow liquid, boiling point not determined.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:21]=[CH:20][CH:19]=[CH:18][C:7]=1[CH2:8][N:9]1[C:13]([CH3:14])=[C:12]([CH3:15])[N:11]=[C:10]1[CH2:16]O>>[Cl:5][C:6]1[CH:21]=[CH:20][CH:19]=[CH:18][C:7]=1[CH2:8][N:9]1[C:13]([CH3:14])=[C:12]([CH3:15])[N:11]=[C:10]1[CH2:16][Cl:3]
Reactant: Cc1nc(CO)n(Cc2ccccc2Cl)c1C
Reactant: O=S(Cl)Cl
Product: Cc1nc(CCl)n(Cc2ccccc2Cl)c1C
Temperature: 50 °C

Procedure:
To 3 ml of thionyl chloride is added 2.39 g (9.5 mmol) of 1-(2′-chlorobenzyl)-4,5-dimethyl-2-hydroxymethyl-imidazole. The mixture is heated at 50° C. for about 5 min., and the thionyl chloride is evaporated in vacuo. The residue is dissolved in 10 ml of dichloromethane, then evaporated in vacuo. This is repeated twice to give 1-(2′-chlorobenzyl)-4,5-dimethyl-2-chloromethylimidazole as a cream colored foam which is used in next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[C:35]5[C:30](=[CH:31][CH:32]=[C:33]([O:36]C)[N:34]=5)[N:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)=[N:10][N:9]=2)=[CH:4][CH:3]=1.Br.C(O)(=O)C.[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][C:26]4[CH:27]=[CH:28][N:29]=[C:30]5[C:35]=4[NH:34][C:33](=[O:36])[CH:32]=[CH:31]5)=[CH:23][CH:24]=3)=[N:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc2nccc(Oc3ccc(Nc4nnc(-c5ccc(Cl)cc5)c5ccccc45)cc3)c2n1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=c1ccc2nccc(Oc3ccc(Nc4nnc(-c5ccc(Cl)cc5)c5ccccc45)cc3)c2[nH]1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
In a 48 mL sealed pressure vessel, was added 4-(4-chlorophenyl)-N-(4-(6-methoxy-1,5-naphthyridin-4-yloxy)phenyl)phthalazin-1-amine (0.280 g, 0.553 mmol), HBr (6.01 mL, 11.1 mmol), and acetic acid (6.34 mL, 11.1 mmol). The mixture was stirred at 85° C. for 1 hour. The reaction was monitored and found complete by LC/MS. The reaction mixture was cooled to RT, carefully basified with 6 N NaOH. Light yellow solids crashed out, which were filtered, rinsed with water and dried in vacuum oven to yield 8-(4-(4-(4-chlorophenyl)phthalazin-1-ylamino)phenoxy)-1,5-naphthyridin-2(1H)-one. The product was used without further purification. MS:[M+H]=492.1; Calc'd 491.9 for C28H18ClN5O2
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9](OCC)(=O)[CH:10]=[O:11].C1(C)C=CC=CC=1>C(O)C>[NH:7]1[C:2]2[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:8]=[CH:9][C:10]1=[O:11]
Reactant: Nc1ccccc1N
Reactant: CCOC(=O)C=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=c1cnc2ccccc2[nH]1
Temperature: 45 °C
Yield: 93 %

Procedure:
To a stirred suspension of o-phenylenediamine (50 g, 462.9 mmol) in ethanol (200 mL), at rt was added a solution of ethyl glyoxalate in toluene (50%; 113 mL, 555.48 mmol) over a period of 45 min. After heating to 45° C. for 10 h, the mixture was left at rt under stirring. The precipitate was filtered and the residue was washed with water and dried to give 1H-quinoxalin-2-one as an off-white powder (63 g, 93%): 1H-NMR (300 MHz, d6-DMSO): δ=12.44 (1H, s), 8.19 (1H, s), 7.78 (1H, d), 7.55 (1H, dd), 7.32 (2H, m) ppm.
Reaction SMILES: C(O[C:4]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6](=[O:11])[CH:5]=1)C.[CH2:12]([Mg]Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.OS(O)(=O)=O>C1COCC1>[CH2:12]([C:4]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6](=[O:11])[CH:5]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CCOC1=CC(=O)CCCC1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: O=C1C=C(Cc2ccccc2)CCCC1
Reaction time: 6 h
Yield: 65 %

Procedure:
A solution of 3-ethoxy-2-cyclohepten-1-one(5 g, 0.89 mol) in THF (70 mL) was added at room temperature to a solution of 2M benzyl magnesium chloride (800 ml) under N2 and stirred for 6 h. The resulting mixture was poured into a solution of 30% H2SO4 and stirred for 5 h. The resulting organic layer was separated, and the aqueous layer was extracted with several portions of ether. The combined organic layer was dried (MgSO4), and concentrated in vacuo to give 3-benzyl-2-cyclohepten-1-one (3.1 g, 65%) as a colorless oil. NMR (CDCl3); 3.45(s,2H1benzylic protons), 5.97 (bs, 1H, olefinic proton), 7.22 (m, 5H, aromatic protons).
Reaction SMILES: Br[CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[C:7]([C:14](O)=[O:15])[CH:8]=[CH:9][CH:10]=2)[O:5][C:4]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:23][NH:24][CH3:25]>>[CH3:23][N:24]([CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[C:7]([CH2:14][OH:15])[CH:8]=[CH:9][CH:10]=2)[O:5][C:4]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:25]
Reactant: CNC
Reactant: O=C(O)c1cccc2c(=O)c(CBr)c(-c3ccccc3)oc12
Product: CN(C)Cc1c(-c2ccccc2)oc2c(CO)cccc2c1=O

Procedure:
Ethyl ester of 3-bromomethylflavone-8-carboxylic acid was reacted with dimethylamine in a conventional manner and the resultant product was reduced to give 3-dimethylaminomethylflavone-8-methanol.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[CH2:6][N:7]=[C:8]=[O:9])[CH3:2].[Br:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:28]=1[C:22]1([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH2:21][CH:20]2[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[Br:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:28]=1[C:22]1([CH2:23][CH2:24][N:25]([C:8](=[O:9])[NH:7][CH2:6][C:5]3[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=3[O:3][CH2:1][CH3:2])[CH2:26][CH2:27]1)[CH2:21][CH:20]2[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOc1ccccc1CN=C=O
Reactant: CCOC(=O)CC1CC2(CCNCC2)c2c(Br)cccc21
Product: CCOC(=O)CC1CC2(CCN(C(=O)NCc3ccccc3OCC)CC2)c2c(Br)cccc21

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 19 using 2-ethoxybenzyl isocyanate and ethyl 2-(7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate. 1H NMR (CDCl3) [selected resonances] 1.28 (t, 3H), 1.44 (t, 3H), 4.11 (q, 2H), 4.19 (q, 2H), 4.45 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH2:18][CH:19]=[C:20]([Cl:22])[Cl:21])[CH:14]=[C:13]([Cl:23])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH2:10][CH:11]=[O:12].[Cl:24][C:25](Cl)([Cl:28])[C:26]#[N:27].Cl>[Zn].CN(C)C=O>[Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH2:18][CH:19]=[C:20]([Cl:22])[Cl:21])[CH:14]=[C:13]([Cl:23])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH2:10][CH:11]([OH:12])[C:25]([C:26]#[N:27])([Cl:28])[Cl:24]
Reactant: O=CCOCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: N#CC(Cl)(Cl)Cl
Agent: Cl
Agent: [Zn]
Solvent: CN(C)C=O
Product: N#CC(Cl)(Cl)C(O)COCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Yield: 246.7 %

Procedure:
To a mixture of 0.60 g of 4-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)butyloxyacetaldehyde, 0.29 g of zinc dust and 10 ml of N,N-dimethylformamide was added 0.040 g of trichloroacetonitrile with stirring at room temperature. After stirring at room temperature for 2 hours, the reaction mixture was poured into 10 ml of diluted hydrochloric acid and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water; dried over magnesium sulfate and then evaporated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.35 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(4-(3-cyano-3,3-dichloro-2-hydroxypropyloxy)butyloxy)benzene (yield, 46%), nD24.0 1.5460.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH:19]C(=O)OCC3C=CC=CC=3)[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1>[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH2:19])[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(NCC1Cc2cccc(-c3ccc(F)cc3F)c2O1)OCc1ccccc1
Agent: [Pd]
Product: NCC1Cc2cccc(-c3ccc(F)cc3F)c2O1
Yield: 43 %

Procedure:
Treatment of (+)-benzyl {[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (1.1 g, 2.78 mmol) with palladium on carbon (0.135 g, 10 wt. %) generally according to the procedure described for Example 1 gave 0.312 g (43%) of (+)-1-[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. [α]D25=+3.58 (c 10.0 in dimethylsulfoxide); mp 222-224° C.; Anal. calcd. for C15H13F2NOHCl: C, 60.51; H, 4.74; N, 4.7. Found: C, 59.98; H, 4.7; N, 4.64.