Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)[CH:3]=[C:4]1[N:8]=[CH:7][CH:6]=[CH:5]1.CCC[CH2:13][CH3:14].ICCC.[C:19](=O)(O)[O-:20]>C1COCC1.O>[CH2:3]([C:4]1[NH:8][C:7]([CH:19]=[O:20])=[CH:6][CH:5]=1)[CH2:13][CH3:14]
Reactant: CCCCC
Reactant: O=C([O-])O
Reactant: CN(C)C=C1C=CC=N1
Solvent: C1CCOC1
Solvent: CCCI
Solvent: O
Product: CCCc1ccc(C=O)[nH]1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 60 %

Procedure:
To an anhydrous solution of 6-dimethylamino-1-azafulvene dimer (125; 12.0 g, 49.1 mmol) in THF (500 ml) at -15° C. was added dropwise a solution of 5-butyllithium in pentane (1.7M; 87 ml, 147 mmol) over 5 minutes. The yellow cloudy solution was slowly warmed to 0° C. over 10 minutes and stirred at this temperature for a further 20 minutes. The resulting deep violet colored solution was treated with 1-iodopropane (19.2 ml, 196 mmol) and allowed to warm to room temperature over 2 hours. The mixture was treated with water (20 ml) and saturated aqueous solution bicarbonate (20 ml) and refluxed for 15 hours. The mixture was extracted into methylene chloride and the organic phase was washed with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered and concentrated to a dark liquid residue (15.2 g) by rotary evaporation. Flash chromatography (silica gel, 500 g; EtOAc/hexanes, 5/95) gave 7.85 g (60%) of the title compound as a pale brown liquid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH3:15])[CH2:9]1)=O)(C)(C)C.C(Cl)[Cl:17]>>[ClH:17].[CH3:15][CH:10]1[C:11](=[O:14])[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: ClCCl
Product: CC1CNCCC1=O
Product: Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of racemic 3-methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester in anhydrous DCM at 0° C., ethanolic-HCl was added slowly and the reaction mixture was allowed to stir at 25° C. for 3 h. TLC (hexanes/EtOAc 40% EtOAc) showed complete consumption of the starting material. The reaction mixture was evaporated to give racemic 3-methyl-piperidin-4-one hydrochloride which was used crude in the next reaction.
Reaction SMILES: F.[C:2]([O:5][CH2:6][C:7]1[N:8]([CH2:28][C:29]([OH:32])([CH3:31])[CH3:30])[C:9]2[C:18]3[CH:17]=[CH:16][C:15]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:27]=1)(=[O:4])[CH3:3].C1C=C(Cl)C=C(C(OO)=[O:41])C=1.O>CN(C=O)C.CO>[C:2]([O:5][CH2:6][C:7]1[N:8]([CH2:28][C:29]([OH:32])([CH3:31])[CH3:30])[C:9]2[C:18]3[CH:17]=[CH:16][C:15]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:14][C:13]=3[N+:12]([O-:41])=[CH:11][C:10]=2[N:27]=1)(=[O:4])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)OCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)O
Agent: F
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: CC(=O)OCc1nc2c[n+]([O-])c3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)O
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 100.5 %

Procedure:
Hydrogen fluoride (7.5 g of 48%, 0.18 mol) was added to a solution of [7-benzyloxy-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl acetate (40.0 g, 0.0953 mol) in DMF (910 mL) and methanol (300 mL). mCPBA (60.6 g, 0.200 mol, 57% pure) was then added in one portion, and the reaction was stirred at ambient temperature for 5.5 hours. A mixture of ice and deionized water (4 L) was then added to the reaction mixture, and the resulting mixture was stirred vigorously for 30 minutes. The solid product was isolated by filtration, washed with deionized water, and dried under vacuum at 50° C. The solid was then triturated with diethyl ether (500 mL) for one hour, isolated by filtration, washed with diethyl ether (400 mL), and dried under vacuum at 40° C. to provide 41.7 g of [7-benzyloxy-1-(2-hydroxy-2-methylpropyl)-5-oxido-1H-imidazo[4,5-c]quinolin-2-yl]methyl acetate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH:15][C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1cnccn1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CN
Product: CC(C)(C)OC(=O)N1CCCCC1CNc1cnccn1

Procedure:
The title compound (0.18 g) was prepared from (RS) 2-aminomethyl-piperidine-1-carboxylic acid tert butyl ester (0.54 g) and 2-chloropyrazine according to the method of D20.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][N:8]([CH2:12][C:13]2[S:14][C:15]([C:18](=O)[CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:16][CH:17]=2)[S:7]1(=[O:26])=[O:25].[OH2:33].Cl.[NH2:35]O>CCO>[CH3:1][O:2][C:3]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][N:8]([CH2:12][C:13]2[S:14][C:15]([C:18](=[N:35][OH:33])[CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:16][CH:17]=2)[S:7]1(=[O:25])=[O:26]
Reactant: O
Reactant: COc1ccc(CN2C(=O)CN(Cc3ccc(C(=O)CCC(C)C)s3)S2(=O)=O)c(OC)c1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: COc1ccc(CN2C(=O)CN(Cc3ccc(C(CCC(C)C)=NO)s3)S2(=O)=O)c(OC)c1

Procedure:
The title D compound, 2-(2,4-dimethoxy-benzyl)-5-[5-(4-methyl-pentanoyl)-thiophen-2-ylmethyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (50 mg, 0.10 mmol) is dissolved in EtOH (5 mL) and water (1 mL) is added. Hydroxylamine hydrochloride (72 mg, 1.0 mmol) is added and the mixture is heated at reflux for 4 h. The solvent is evaporated and the residue is partitioned between EtOAc and water. The organic layer is dried over anhydrous MgSO4 and concentrated to dryness to afford 2-(2,4-dimethoxy-benzyl)-5-(5-(1-[-hydroxyimino]-4-methyl-pentyl)-thiophen-2-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one as a clear oil: [M+1]+=496.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[CH2:10][CH2:9][N:8]([C:12]3[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:7][C:6]=2[N:5]=[CH:4]1)[CH3:2].C(N1C2CN(C3C([N+]([O-])=O)=CC=CN=3)CCC=2NC1)C.[CH2:41]=[O:42]>>[CH2:1]([N:3]1[C:11]2[CH2:10][CH2:9][N:8]([C:12]3[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:7][C:6]=2[N:5]=[C:4]1[CH2:41][OH:42])[CH3:2]
Reactant: C=O
Reactant: CCn1cnc2c1CCN(c1ncccc1[N+](=O)[O-])C2
Agent: CCN1CNC2=C1CN(c1ncccc1[N+](=O)[O-])CC2
Product: CCn1c(CO)nc2c1CCN(c1ncccc1[N+](=O)[O-])C2
Temperature: 150 °C

Procedure:
A mixture of 1-ethyl-5-(3-nitro-pyridin-2-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine and 3-ethyl-5-(3-nitro-pyridin-2-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine in 37% formaldehyde (5 mL) in a sealed tube is heated at 150° C. overnight. The mixture is allowed to cool to ambient temperature and evaporated under reduced pressure. The resulting residue is partitioned between ethyl acetate and water and the layers are separated. The aqueous layer is further extracted with ethyl acetate and the combined organic extracts are dried over Na2SO4, filtered and the solvents removed under reduced pressure. Column chromatography of the residue on silica gel (5% MeOH in CH2Cl2 as eluent) gives [1-ethyl-5-(3-nitro-pyridin-2-yl)-4,5,6,7-tetrahydro-1H-imidazo [4,5-c]pyridin-2-yl]-methanol (80 mg). 1H NMR (CDCl3) δ: 8.33 (d, 1H), 8.15 (dd, 1H), 6.73 (q, 1H), 4.64 (s, 2H), 4.22 (s, 2H), 3.90-3.98 (m, 4H), 2.82(t, 2H) and 1.36 (t, 3H). MS: 304.2 (m+1).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]3[CH:19]=[CH:20][CH:21]=[C:11]3[CH2:10][CH2:9]2)=[O:7])=[C:4]([Cl:24])[CH:3]=1.C(N(CC)CC)C.[Cl:32][C:33]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36].[OH-].[Na+]>ClCCl>[CH:18]1[C:13]2[N:12]3[CH:19]=[CH:20][CH:21]=[C:11]3[CH2:10][CH2:9][N:8]([C:6]([C:5]3[CH:22]=[CH:23][C:2]([NH:1][C:35](=[O:36])[C:34]4[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:33]=4[Cl:32])=[CH:3][C:4]=3[Cl:24])=[O:7])[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Nc1ccc(C(=O)N2CCc3cccn3-c3ccccc32)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2CCc3cccn3-c3ccccc32)c(Cl)c1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
To a mixture of 0.10 g of 6,7-dihydro-5-(4-amino-2-chlorobenzoyl)-5H-pyrrolo[1,2-a][1,5]benzodiazepine and 0.06 g of triethylamine in 6 ml of dichloromethane is added 0.10 g of 2,4-dichlorobenzoyl chloride in 0.5 ml of dichloromethane. The mixture is stirred at room temperature for 2 hours and 2 ml of 1N NaOH is added. The volatiles are removed under vacuum and to the residue is added 2 ml of tetrahydrofuran and 1 ml of methanol. The mixture is stirred at room temperature for 2 hours and the volatiles removed. To the residue is added 2 ml of 1N NaOH and 5 ml of H2O. The mixture is extracted with ethyl acetate and the extract washed with brine and dried (Na2SO4). The solvent is removed and the solid triturated with diethyl ether-hexane to give 0.15 g of white solid, Mass Spectrum (CI):510(M+H, Cl35).
Reaction SMILES: [CH2:1]([N:5]1[C:10]([NH:11][N:12]=[CH:13][C:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[S:16][CH:15]=2)=[CH:9][C:8](=[O:23])[N:7]([CH3:24])[C:6]1=[O:25])[CH:2]([CH3:4])[CH3:3].[CH3:26][N:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[CH:32]=O.C(N(CC)CC)C>CC(N(C)C)=O>[S:16]1[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:14]([CH2:13][N:12]2[C:32]([C:28]3[N:27]([CH3:26])[CH:31]=[CH:30][CH:29]=3)=[C:9]3[C:10]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:6](=[O:25])[N:7]([CH3:24])[C:8]3=[O:23])=[N:11]2)=[CH:15]1
Reactant: Cn1cccc1C=O
Reactant: CC(C)Cn1c(NN=Cc2csc3ccccc23)cc(=O)n(C)c1=O
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cccn3C)n(Cc3csc4ccccc34)nc21
Temperature: 90 °C

Procedure:
1-Benzothiophene-3-carbaldehyde N-(3-isobutyl-1-methyl-2,6-dioxo-1,2,3,6-tetrahydro-4-pyrimidinyl)hydrazone (100 mg, 0.284 mmol) was suspended in anh. DMA (3 mL) under an atmosphere of N2 gas. To the suspension was added N-methylpyrrole-2-carboxaldehyde (37 mg, 0.34 mmol). To this suspension was added catalytic amounts of triethylamine (25 μL). The reaction mixture was placed in a preheated heating block maintained at 90° C. and heated under N2 gas for 18 h. At the end of reaction the solvent was removed in vacuo and the resulting brown oil was resuspended in DMSO (1.5 mL) and was purified by semi preparative RPHPLC eluting with MeCN/water/TFA mixtures. Yield=37 mg, Rt=2.46 min, MS: 444,(M+H).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]([CH3:39])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:24]([CH3:25])=[CH:23][N:22]=[CH:21][C:20]=2[CH3:26])=[C:15]([C:27]#[C:28][C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[N:35]=[CH:34][CH:33]=[CH:32]3)[N:14]=1)=[O:11])C)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[CH3:26][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([CH3:25])[C:19]=1[C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:10](=[O:11])[CH:9]([NH:7][CH3:6])[CH3:39])=[N:14][C:15]=1[C:27]#[C:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[CH:34][CH:33]=[CH:32]2
Reactant: Cc1cncc(C)c1-c1ccc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)nc1C#Cc1ccc2ncccc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CNC(C)C(=O)Nc1ccc(-c2c(C)cncc2C)c(C#Cc2ccc3ncccc3c2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of tert-butyl-N-[1-[[5-(3,5-dimethylpyridin-4-yl)-6-(2-quinolin-6-ylethynyl)pyridin-2-yl]amino]-1-oxopropan-2-yl]-N-methylcarbamate G1a (28 mg, 0.05 mmol) and DCM:TFA (8:2, 10 ml) is stirred at RT for 15 minutes. The mixture is diluted with toluene (10 ml) and concentrated in vacuo. The product is purified by RP HPLC. Yield: 16 mg (70%). HPLC-MS: M+H=436; tR=1.09 min (*Method—1).
Reaction SMILES: [N:1]1[C:2]([CH2:10][C:11](OCC)=[O:12])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:12][CH2:11][CH2:10][C:2]1[N:1]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[CH:3]=1
Reactant: CCOC(=O)Cc1cn2ccccc2n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCc1cn2ccccc2n1

Procedure:
A procedure similar to that described in Preparation 2 was repeated, except that 2. 65 g of ethyl imidazo-[1,2-a]pyridin-2-ylacetate (prepared as described in Preparation 25), 0.5 g of lithium aluminum hydride and 100 ml of tetrahydrofuran were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and ethanol in ratios ranging from 20:1 to 4:1 by volume as the eluent, to give 1.32 g of the title compound, melting at 120.3-126.9° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClC(Cl)C>[Cl:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[N:5]=[C:4]([NH:18][CH:19]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[N:3]=[C:2]([C:31]3[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][C:30]=3[O:34][CH3:35])[N:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: COc1cccc(OC)c1
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: COc1ccc(-c2nc(Nc3ccc(OC)c(Cl)c3)nc(NC3CCCCCC3)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A mixture of compound 133 (0.5 grams), 1,3-dimethoxybenzene (0.18 g) and AlCl3 (0.2 grams) in dichloroethane (10 mL) was stirred under nitrogen atmosphere at room temperature for 30 min. It was then heated at 80° C. for 3 hours with stirring. The reaction mixture was poured into ice-cold water (50 mL), extracted with chloroform (3×30 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. The residue thus obtained was purified by column chromatography using petroleum ether-ethyl acetate to afford the expected product (yield 64%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([F:18])=[C:12]([CH:17]=2)[C:13]([O:15][CH3:16])=[O:14])[CH2:4][C@H:3]1[O:19][CH3:20].[Cl:21][C:22]1[N:23]=[C:24]([C:29](O)=[O:30])[NH:25][C:26]=1[CH2:27][CH3:28].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:21][C:22]1[N:23]=[C:24]([C:29]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:9]=[CH:10][C:11]([F:18])=[C:12]([CH:17]=3)[C:13]([O:15][CH3:16])=[O:14])[CH2:4][C@H:3]2[O:19][CH3:20])=[O:30])[NH:25][C:26]=1[CH2:27][CH3:28]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: COC(=O)c1cc(N2CC[C@H](N)[C@H](OC)C2)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3ccc(F)c(C(=O)OC)c3)C[C@H]2OC)nc1Cl
Yield: 39 %

Procedure:
The same operation as in Example (1g) was performed using methyl cis(±)-5-(4-amino-3-methoxypiperidin-1-yl)-2-fluorobenzoate obtained in Example (176b) (20.1 mg, 0.07 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained by the method described in Example (1d) (11.3 mg, 0.06 mmol), WSC hydrochloride (37.2 mg, 0.19 mmol) and HOBt (8.7 mg, 0.06 mmol), to obtain 11 mg of the title compound as a pale yellow solid (39%).
Reaction SMILES: [CH2:1]([C:11]1[C:18]2[S:17][C:16]3[CH:19]=[CH:20][S:21][C:15]=3[C:14]=2[S:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Br:22]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:22][C:12]1[S:13][C:14]2[C:15]3[S:21][CH:20]=[CH:19][C:16]=3[S:17][C:18]=2[C:11]=1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCCCCCCc1csc2c1sc1ccsc12
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCc1c(Br)sc2c1sc1ccsc12
Temperature: 0 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
3-decanyldithieno[3,2-b:2′,3′-d]thiophene (91) (9.03 g, 0.027 mol) was dissolved in DMF (100 mL). To this solution, N-bromosuccinimide (NBS) (4.78 g, 0.027 mol) in DMF (50 mL) was added dropwise in the dark under argon. The resulting mixture was stirred at 0° C. for three hours. GC/MS showed a single peak at 415. This solution was poured into water (500 mL). Organic solution was extracted with hexane (3×100 mL). The combined organic solutions were washed with brine (2×50 mL) and water (50 mL). After drying over MgSO4, the hexane was evaporated. The crude product was purified by column chromatography and eluted with hexane to yield the target compound (10.1 g, 90.2%). 1HNMR: solvent, CD2Cl2. δ 7.39 (d, 1H), 7.29 (d, 1H), 2.74 (t, 2H), 1.74-1.33 (m, 16H), 0.89 (t, 3H). 13CNMR: 140.89, 140.63, 136.00, 131.55, 129.22, 126.58, 121.04, 108.89, 32.31, 29.94, 29.73 (overlap), 29.35, 28.49, 23.09, 14.27.
Reaction SMILES: [NH:1]1[C:6]2N=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[O:3][C:2]1=[O:12].[CH3:13][C:14]1[S:15][C:16]([CH2:19]Cl)=[CH:17][N:18]=1.[CH2:21](Br)CCC>>[CH3:13][C:14]1[S:15][C:16]([CH2:19][N:1]2[C:6]3[CH:21]=[CH:8][CH:9]=[CH:10][C:5]=3[C:4](=[O:11])[O:3][C:2]2=[O:12])=[CH:17][N:18]=1
Reactant: CCCCBr
Reactant: Cc1ncc(CCl)s1
Reactant: O=c1[nH]c2ncccc2c(=O)o1
Product: Cc1ncc(Cn2c(=O)oc(=O)c3ccccc32)s1

Procedure:
The title compound was prepared according to the procedure of Example 1B substituting isatoic anhydride for the product of Example 1A and 2-methyl-5-chloromethylthiazole for n-butyl bromide to give (0.410 g, 73%).
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[N:12]1([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CC(=O)OCC>>[N:11]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[CH2:2][N:15]1[CH2:14][CH2:13][N:12]([C:18]2[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=2)[CH2:17][CH2:16]1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: ClCc1nc2cccnc2s1
Solvent: CCOC(C)=O
Product: Oc1ccc(N2CCN(Cc3nc4cccnc4s3)CC2)cc1

Procedure:
The product from Example 38A (150 mg, 0.81 mmol), 4-(1-piperazinyl)phenol (160 mg, 0.98 mmol), and D1 EA (280 μL, 1.6 mmol) were processed as described in Example 38B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.73 (m, 4H) 3.02 (m, 4H) 4.03 (s, 2H) 6.72 (m, 4H) 7.56 (dd, J=8.14, 4.75 Hz, 1H) 8.33 (dd, J=8.14, 1.70 Hz, 1H) 8.59 (dd, J=4.58, 1.53 Hz, 1H): (ESI) m/z 327 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)=[CH:4][CH:3]=1.Cl.[CH3:26][C:27]1([NH:31][C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])[CH2:30][NH:29][CH2:28]1.C(N(CC)CC)C>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([N:29]4[CH2:30][C:27]([CH3:26])([NH:31][C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])[CH2:28]4)[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)=[CH:4][CH:3]=1
Reactant: CC1(NC(=O)C(F)(F)F)CNC1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC1(NC(=O)C(F)(F)F)CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4)c3c2F)C1

Procedure:
A mixture of 1 g (3 mmoles) of 1-(4-fluorophenyl)-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.98 g (4.5 mmoles) of 3-methyl-3-trifluoroacetamidoazetidine hydrochloride and 0.6 g (6 mmoles) of triethylamine is heated under reflux for 3 hours in 10 ml of pyridine.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]([C:13]([O:15][CH3:16])=[O:14])=[C:7]([C:9]([O:11][CH3:12])=[O:10])[N:8]=1)[CH2:2][CH3:3].[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:12][O:11][C:9]([C:7]1[N:8]=[C:4]([CH2:1][CH2:2][CH3:3])[N:5]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([Br:17])=[CH:19][CH:20]=2)[C:6]=1[C:13]([O:15][CH3:16])=[O:14])=[O:10]
Reactant: BrCc1ccc(Br)cc1
Reactant: CCCc1nc(C(=O)OC)c(C(=O)OC)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1nc(C(=O)OC)c(C(=O)OC)n1Cc1ccc(Br)cc1
Yield: 88.3 %

Procedure:
A solution of 40.0 g (0.177 mole) of 2-propyl-4,5-bis(methoxycarbonyl)-imidazole and 44.6 g (0.178 mole) of 4-bromobenzyl bromide in 350 mL of DMF was stirred in the presence of 37.5 g (0.271 mole) of K2CO3 overnight at room temperature. The reaction mixture was then poured into 1200 mL of water and extracted with 3×300 mL of ether. The combined ether extracts were washed with 8×1000 mL of water and once with brine, then dried over MgSO4. The solvent was removed under reduced pressure to yield 61.8 g (88%) of the title compound as a solid. 1H NMR (300 MHz, CDCl3): δ0.94 (t, J=7.6 Hz, 3H); 1.73 (m, 2H); 2.63 (t, J=7.9 Hz, 2H); 3.81 (s, 3H); 3.93 (s, 3H); 5.37 (s, 2H); 6.86 (d, J=8.8 Hz, 2H); 7.45 (d, J=8.8 Hz, 2H). MS [DCI (NH3)]: m/z 395/397 (M+H, 1 Br).
Reaction SMILES: C1(P(=[N:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2/[CH:27]=[CH:28]/[C:29]([O:31][CH3:32])=[O:30])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][C:35]=1[N:44]=[C:45]=O.[F:47][C:48]1[CH:53]=[CH:52][C:51]([N:54]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)=[CH:50][CH:49]=1>>[F:47][C:48]1[CH:49]=[CH:50][C:51]([N:54]2[CH2:59][CH2:58][N:57]([C:45]3[N:44]([C:35]4[CH:36]=[C:37]([C:40]([F:43])([F:42])[F:41])[CH:38]=[CH:39][C:34]=4[F:33])[CH:27]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:22]4[C:21](=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:20]=3)[CH2:56][CH2:55]2)=[CH:52][CH:53]=1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: COC(=O)/C=C/c1ccccc1N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: COC(=O)CC1c2ccccc2N=C(N2CCN(c3ccc(F)cc3)CC2)N1c1cc(C(F)(F)F)ccc1F

Procedure:
Starting with 150 mg (0.34 mmol) of the iminophosphorane from Example 3A, 74 mg (0.34 mmol) of 2-fluoro-5-(trifluoromethyl)phenyl isocyanate and 61 mg (0.34 mmol) of N-(4-fluorophenyl)piperazine, the general procedure [E] and chromatographic purification (method 2) give 34 mg (17% of theory) of product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@:12]([CH3:16])([C:13](O)=O)[CH2:11][O:10][C:9]1([CH3:18])[CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:53][CH2:54][C:55]([C:57]1[CH:62]=[CH:61][C:60]([O:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])=[C:59]([C:72]([F:75])([F:74])[F:73])[CH:58]=1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:85])=CC=1>C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:17][C:9]1([CH3:18])[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@@:12]([CH3:16])([C:13]2[S:85][C:55]([C:57]3[CH:62]=[CH:61][C:60]([O:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])=[C:59]([C:72]([F:75])([F:74])[F:73])[CH:58]=3)=[CH:54][N:53]=2)[CH2:11][O:10]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCCCCCCCOc1ccc(C(=O)CN)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1C(C)(C)OC[C@]1(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCCCCCCCOc1ccc(-c2cnc([C@@]3(C)COC(C)(C)N3C(=O)OC(C)(C)C)s2)cc1C(F)(F)F
Yield: 40.9 %

Procedure:
To a solution of (R)-3-(tert-Butoxycarbonyl)-2,2,4-trimethyloxazolidine-4-carboxylic acid (D3) (100 mg, 1 equiv), HATU (220 mg, 1.5 equiv), and DIEA (0.67 mL, 10 equiv) in DCM (5 mL) was added 2-amino-1-(4-(octyloxy)-3-(trifluoromethyl)phenyl)ethanone hydrochloride (D2) (142 mg, 1.0 equivalents). The solvent removed in vacuo and the product was purified with silica gel column chromatography using the Combi-Flash system (Hex:EtOAc). This resulted in a colourless, thick oil which was dissolved in toluene (5 mL) with Lawesson's reagent (280 mg, 3 equiv). The resultant mixture was heated at 120° C. for 2 hours to produce the title product as a colourless oil 41% yield (90 mg). TLC (1:2 EtOAc:Hex), Rf=0.3; MS (ESI, M+Na)=572.99; 1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 8.11 (d, 1H, J=8.4 Hz), 7.05 (d, 1H, J=8.4 Hz), 4.62-4.79 (m, 2H), 4.13 (t, 2H, J=6.4 Hz), 3.28 (br s, 1H), 1.22-1.90 (m, 30H), 0.89 (t, 3H, J=6.4 Hz).