Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[O:30]1[CH2:33][CH:32]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:37]4[CH2:38][CH2:39][N:34]([CH:32]5[CH2:33][O:30][CH2:31]5)[CH2:35][CH2:36]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: C1CN(C2COC2)CCN1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C4COC4)CC3)n(C)c2n1
Reaction time: 18 h
Yield: 37.1 %

Procedure:
TFA (2 mL) was added to a solution of 4-oxetan-3-ylpiperazine-1-carboxylic acid tert-butyl ester (150 mg, 0.62 mmol) in DCM (10 mL) and the mixture was stirred at ambient temperature for 30 min, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo to give 1-oxetan-3-ylpiperazine as a colourless oil. A solution of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (200 mg, 0.51 mmol), 1-oxetan-3-ylpiperazine (88 mg, 0.62 mmol) and molecular sieves (4 Å, powdered, 1 g) in DCE (10 mL) was stirred at ambient temperature for 5 h. Sodium triacetoxyborohydride (162 mg, 0.76 mmol) was added and the mixture stirred for 18 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH; 100:0 to 99:1 to 98:2 to 95:5) to afford 513 as a white solid (98 mg, 37%). LCMS (Method I): RT=2.43 min, M+H+=518. 1H NMR (CDCl3, 400 MHz) δ 8.01 (dd, J=6.9, 2.4 Hz, 1 H); 7.78 (m, 1 H); 7.33-7.23 (m, 2 H); 4.70-4.60 (m, 4 H); 4.35 (m, 4 H); 3.97-3.75 (m, 7 H); 3.79 (s, 2 H); 3.57-3.49 (m, 1 H); 3.37 (q, J=7.5 Hz, 2 H); 2.66 (m, 4 H); 2.42 (m, 4 H); 1.46 (t, J=7.5 Hz, 3 H)
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[CH2:16][CH2:15]1.[OH2:30]>>[F:27][C:26]([F:29])([F:28])[C:22]1[CH:21]=[C:20]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][CH2:11][N:6]3[CH:5]=[N:4][C:3]4[C:2](=[O:30])[NH:10][CH:9]=[N:8][C:7]3=4)[CH2:15][CH2:16]2)[CH:25]=[CH:24][CH:23]=1
Reactant: FC(F)(F)c1cccc(N2CCN(CCCn3cnc4c(Cl)ncnc43)CC2)c1
Reactant: O
Product: O=c1[nH]cnc2c1ncn2CCCN1CCN(c2cccc(C(F)(F)F)c2)CC1

Procedure:
6-Chloro-9-{3-[4-(3-trifluoromethylphenyl)piperazin-1-yl]propyl}-9H-purine (200 mg) was dissolved in 3 mL of trifluoroacetic acid(TFA) and 1 mL of water and stirred for 16 hours at 25 C. The TFA was evaporated and 10 mL of 2N NaOH was added. The solution was extracted twice with 20 mL of dichloromethane. The organic layer was separated, dried with sodium sulfate and concentrated to give the title compound as an oil. The oil was dissolved in 5 mL of 50% dichloromethane in hexanes. A solution of 4N HCl in dioxane (200 uL) was added and the mixture stirred for 30 minutes followed by vacuum filtration of the suspension. A white powder of the product HCl salt was recovered.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH:6]1[O:8][CH2:7]1.[CH2:13]([N:20]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:21][C:22]([CH3:25])([NH2:24])[CH3:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH:6]([OH:8])[CH2:7][NH:24][C:22]([CH3:25])([CH3:23])[CH2:21][N:20]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(N)CN(Cc1ccccc1)Cc1ccccc1
Reactant: Cc1ccccc1OCC1CO1
Solvent: CCO
Product: Cc1ccccc1OCC(O)CNC(C)(C)CN(Cc1ccccc1)Cc1ccccc1
Yield: 64.4 %

Procedure:
A micture of 4.3 g of 1-(2-methylphenoxy)-2,3-epoxypropane, 7.03 g of N,N-dibenzyl-2-methyl-1,2-propanediamine and 50 ml of ethanol was refluxed for 20 hours, and the solvent was evaporated under reduced pressure. To a benzene solution of the residue was added 1N hydrochloric acid, to deposit an oily material. After removal of the benzene layer, the residue was extracted with chloroform. The organic layer was washed with 5% sodium carbonate and dried over anhydrous sodium sulfate. The solvent was evaporated to give a colorless oily product. The product was chromatographed on a column of silica gel using chloroform as an eluent. 7.3 g of 1-(2-methylphenoxy)-3-(1,1-dimethyl-2-dibenzylaminoethylamino)-2-propanol was obtained from the eluate.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>>[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8])=[O:21]
Reactant: NC(=O)c1c(N)ncn1Cc1ccccc1
Reactant: O=C(Cl)c1ccccc1F
Product: NC(=O)c1c(NC(=O)c2ccccc2F)ncn1Cc1ccccc1
Yield: 97 %

Procedure:
An amidation reaction and post-treatment were carried out according to the conditions of Example 1, using 2.2 g (10 mmol) of 4-amino-1-benzyl-5-imidazolecarboxamide prepared in Reference Example 2 and 2-fluorobenzoyl chloride instead of benzoyl chloride to obtain a crude amide product. The crude amide product was purified by suspension in hot methanol to obtain 1.69 g of 4-(2-fluorobenzoylamino)-1-benzyl-5-imidazolecarboxamide (yield 97%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[CH2:13]O)[CH2:2][CH:3]=[CH2:4].S(Cl)([Cl:17])=O>>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[CH2:13][Cl:17])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCOc1ccc(F)cc1CO
Reactant: O=S(Cl)Cl
Product: C=CCCOc1ccc(F)cc1CCl
Temperature: 25 °C
Yield: 91 %

Procedure:
(2-(But-3-en-1-yloxy)-5-fluorophenyl)methanol (6.3 g, 32.1 mmol, 1 equiv) was taken up in thionyl chloride (107 mL) and heated to reflux for 1 h. Upon cooling to ambient temperature, the solution was concentrated in vacuo. The residue was concentrated in vacuo with benzene (×3) to remove residual thionyl chloride and provide the benzyl chloride (6.3 g, 91%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.12 (dd, J=8.7, 3.1 Hz, 1H), 6.98 (ddd, J=8.9, 8.0, 3.1 Hz, 1H), 6.82 (dd, J=9.0, 4.3 Hz, 1H), 5.93 (ddt, J=17.1, 10.3, 6.8 Hz, 1H), 5.25-5.09 (m, 2H), 4.62 (s, 2H), 4.05 (t, J=6.5 Hz, 2H), 2.58 (qt, J=6.6, 1.3 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@H:6]([NH2:11])[CH2:5]2.Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>ClCCl>[CH2:16]([O:15][C:13](=[O:14])[NH:11][C@@H:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=2)[CH2:7]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@H]1Cc2ccc(Br)cc2C1
Solvent: ClCCl
Product: O=C(N[C@H]1Cc2ccc(Br)cc2C1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(S)-5-Bromo-indan-2-ylamine (1.0 g) suspended in dichloromethane (10 ml) is cooled to 0° C. and benzyl chloroformate (0.74 ml) is added dropwise and the reaction mixture is stirred for 0.5 hour. The solution is filtered to give (S)-(5-Bromo-indan-2-yl)-carbamic acid benzyl ester. PdCl2(dppf)2 (59 mg) is placed in a dry flask under argon and isobutyl zinc bromide (50 ml, 0.5 M solution in THF) is added. (5-Bromo-indan-2-yl)-carbamic acid benzyl ester (2.50 g) is dissolved in dry THF (2 ml) and the solution is added to the reaction mixture. The reaction mixture is stirred at 50° C. for 18 hours then quenched with HCl(aq) (2M) and partitioned between ethyl acetate and water. The organic layer is dried over MgSO4, filtered and the solvent removed in vacuo. The title compound is obtained by flash column chromatography (silica, eluent ethyl acetate/iso-hexane 1:4). 1H nmr (CDCl3, 400 MHz); 7.35 (m, 5H), 7.10 (d, 1H), 7.00 (s, 1H), 6.90 (d, 1H), 5.1 (s, 2H), 4.55 (m, 1H), 3.30 (m, 2H), 2.75 (dt, 2H), 2.45 (d, 2H), 1.80 (m, 1H), 0.90 (d, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.C([Li])CCC.[CH3:27][Si:28](Cl)([CH3:30])[CH3:29]>C1(C)C=CC=CC=1.C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:10][C:11]([Si:28]([CH3:30])([CH3:29])[CH3:27])=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:7][CH:8]=1
Reactant: C[Si](C)(C)Cl
Reactant: COc1ccc(-c2ccsc2-c2ccc(OC)cc2)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cc([Si](C)(C)C)sc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,3-Bis(4-methoxyphenyl)thiophene (5.92 g, 20 mmole) was dissolved in 100 ml toluene and the volume reduced by approximately 3/4 by distillation. The cooled solution was diluted with 130 ml diethyl ether, cooled to ~10° and treated with 1.55 M n-butyl lithium (15.5 ml, 1.2 equiv.). The reaction mixture was heated at reflux for 1.5 hours, cooled to 0° and treated dropwise with a solution of trimethylsilyl chloride (3.1 ml, 1.2 equiv.) in 5 ml diethyl ether. The reaction mixture was stirred overnight at room temperature and then quenched with water.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:12]([CH3:13])=[C:11]([O:14][CH3:15])[C:10]([CH3:16])=[C:9]([CH3:17])[C:8]=1[O:18][CH3:19].[CH3:20][CH:21]([CH3:36])[C:22]([C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1)=[O:23].O>O1CCCC1>[CH3:19][O:18][C:8]1[C:9]([CH3:17])=[C:10]([CH3:16])[C:11]([O:14][CH3:15])=[C:12]([CH3:13])[C:7]=1[C:22]([C:24]1[CH:25]=[CH:26][C:27]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[CH:28][CH:29]=1)([OH:23])[CH:21]([CH3:36])[CH3:20]
Reactant: COc1c(C)c(C)c(OC)c(Br)c1C
Reactant: CC(C)C(=O)c1ccc(N2CCOCC2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1c(C)c(C)c(OC)c(C(O)(c2ccc(N3CCOCC3)cc2)C(C)C)c1C
Reaction time: 0.33 h
Yield: 76.9 %

Procedure:
n-Butyllithium (1.6 M, 18.1 mL, 29.0 mmol) was added to a solution of 1-bromo-2,5-dimethoxy-3,4,6-trimethylbenzene (7.52 g, 29.0 mmol) in tetrahydrofuran (50 mL) at −78° C., and the mixture was stirred for 20 minutes at the same temperature. To the reaction mixture was added 2-methyl-1-[4-(4-morpholinyl)phenyl] propan-1-one (6.15 g, 26.4 mmol), and the mixture was stirred for 30 minutes at room temperature. Water (40 mL) was poured into the reaction mixture, which was then extracted three times with ethyl acetate. The organic layers were combined, washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from ethanol to obtain the title compound (8.40 g, yield 90%).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:43])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([C@@H:22]2[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]2)[CH:17]=[C:16]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:15]3=[O:33])=[C:8]([C:34]2[S:35][CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[N:38]=2)[CH:7]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:52][CH2:53][N:54]([CH2:57][CH3:58])[CH2:55][CH3:56]>CN(C=O)C.CCOC(C)=O>[CH2:53]([N:54]([CH2:57][CH3:58])[CH2:55][CH2:56][N:24]1[CH2:25][CH2:26][CH2:27][C@@H:22]([N:18]2[C:19]3[C:14](=[CH:13][C:12]([C:9]4[CH:10]=[N:11][C:6]([NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:43])=[CH:7][C:8]=4[C:34]4[S:35][CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[N:38]=4)=[CH:21][CH:20]=3)[C:15](=[O:33])[C:16]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:17]2)[CH2:23]1)[CH3:52]
Reactant: CCN(CC)CCCl
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3[C@@H]2CCCNC2)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3[C@@H]2CCCN(CCN(CC)CC)C2)cn1
Temperature: 100 °C
Yield: 17.5 %

Procedure:
(R)-ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-4-oxo-1-(piperidin-3-yl)-1,4-dihydroquinoline-3-carboxylate (Example 262, 0.100 g, 0.16 mmol) was taken up in DMF (2 mL), K2CO3 (0.112 g, 0.81 mmol) and 2-chloro-N,N-diethylethanamine hydrochloride (0.031 g, 0.18 mmol) were added. The mixture was heated to 100° C. overnight then the reaction was cooled to room temperature and diluted with EtOAc. The organic layer was washed with brine twice and water twice, then the solvent was removed in vacuo and the residue was purified by flash column chromatography on silica gel using (dichloromethane-methanol) to give (R)-ethyl 1-(1-(2-(diethylamino)ethyl)piperidin-3-yl)-6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (0.020 g, 17%).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:17](O)([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:9]2=[O:10])=[CH:3][CH:2]=1.S(Cl)([Cl:28])=O>CN(C=O)C>[Cl:28][C:17]1([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9](=[O:10])[N:8]1[CH2:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: O=C1c2ccccc2C(O)(c2ccc(Cl)cc2)N1Cc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(Cl)(c2ccc(Cl)cc2)N1Cc1ccccc1

Procedure:
Distilled THF (25 mL) was added to 2-benzyl-3-(4-chlorophenyl)-3-hydroxy-2,3-dihydroisoindolin-1-one (400 mg, 1.145 mmol), thionyl chloride (299.6 mg, 2.51 mmol, 0.18 mL) and catalytic DMF (3 drops) as for general procedure B1. 3-Chloro-3-(4-chlorophenyl)-2-benzylisoindolin-1-one was produced as a colourless oil (421 mg, 1.145 mmol) which was used immediately without further purification. Distilled THF (25 mL) was added to 3-chloro-3-(4-chlorophenyl)-2-benzylisoindolin-1-one (421 mg, 1.145 mmol), cis-cyclopentene diol (572 mg, 5.725 mmol) and potassium carbonate (792.9 mg, 5.725 mmol) as for general procedure B. Removal of the solvent yielded the crude product as a pink oil (354 mg). The sample was purified by flash column chromatography (EtOAc:Petrol, 40:60) to yield the title product as a cream oily solid (277.5 mg, 0.643 mmol, 56% yield). 1H NMR: (300 Hz, CDCl3) δ ppm 0.84, 1.66 (m, 1H, H16/H16′) 1.26 (m, 1H, H16/H16′) 3.85 (m, 1H, H17) 3.36 (m, 1H, H15) 4.15 (d, 1H, J=15.27 Hz, H9/H9′), 4.62 (d, 1H, J=15.31 Hz, H9/H9′), 4.68, 5.73 (dd, 1H, H18/H19), 5.21, 5.64 (dd, 1H, H18/Hl9), 7.18 (m, 10H, H1-H5, H10-H14), 7.62 (m, 2H, H6-H7), 7.83 (d, 1H, H8). Mp: 63.4-63.9° C. IR: 1489, 1683, 3061, 3379 cm−1.
Reaction SMILES: [C:1]([NH:11][C:12]1[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C([Li])CCC.[C:24]([N:34]1[CH2:39][CH2:38][C:37](=[O:40])[CH2:36][CH2:35]1)([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>O1CCCC1>[C:28]1([CH2:27][O:26][C:24]([N:34]2[CH2:35][CH2:36][C:37]([OH:40])([C:15]3[CH:16]=[CH:17][C:12]([NH:11][C:1]([O:3][CH2:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[O:2])=[CH:13][CH:14]=3)[CH2:38][CH2:39]2)=[O:25])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Nc1ccc(Br)cc1)OCc1ccccc1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C2(O)CCN(C(=O)OCc3ccccc3)CC2)cc1)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-(carbobenzyloxy)-4-bromoaniline (5.00 g) in dry tetrahydrofuran (80 mL) at -78° C. under N2 is added n-butyllithium (21.4 mL, 1.6 M in hexanes) dropwise over five minutes. The resulting yellow solution is stirred at -78° C. for 30 minutes and is then treated with a solution of N-(carbobenzyloxy)-4-piperidone (3.99 g) in dry tetrahydrofuran (17 mL). The reaction mixture is stirred for three hours, during which the reaction temperature is allowed to rise to 0° C., and is quenched with saturated aqueous ammonium chloride (30 mL). The mixture is then diluted with water (100 mL), the layers are separated, the aqueous phase is extracted with diethyl ether, and the combined organic phase is washed with saline (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is chromato-graphed on silica gel (230-400 mesh, 350 g), eluting with ethyl acetate/hexane (25/75), and those fractions with an Rf =0.38 by TLC (ethyl acetate/hexane, 50/50) are pooled and con-centrated under reduced pressure to give the title compound, mp 156° C.-158° C.
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.[CH:14]1([NH2:18])[CH2:17][CH2:16][CH2:15]1>>[Cl:11][C:9]1[S:10][C:5]2[S:4](=[O:13])(=[O:12])[N:3]=[C:2]([NH:18][CH:14]3[CH2:17][CH2:16][CH2:15]3)[NH:7][C:6]=2[CH:8]=1
Reactant: O=S1(=O)N=C(Cl)Nc2cc(Cl)sc21
Reactant: NC1CCC1
Product: O=S1(=O)N=C(NC2CCC2)Nc2cc(Cl)sc21
Temperature: 0 °C
Yield: 53 %

Procedure:
A solution of 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (257 mg, 1.0 mmol) in cyclobutylamine (1.0 ml) was stirred for 18 h at 90° C. in a sealed flask. The cooled solution was concentrated in vacuo and the residue was stirred with water (10 ml) at 0° C. followed by adjustment to pH 2 with 4M hydrochloric acid. The product was isolated by filtration, washed with water, and recrystallised from methanol/ethyl acetate followed by drying in vacuo at room temperature to give 155 mg (53%) of the pure title compound; mp 315-317° C. dec.; 1H-NMR (DMSO-d6): δ1.58-1.75 (m, 2H), 1.89-2.05 (m, 2H), 2.19-2.30 (m, 2H), 4.16 (m, 1H), 7.06 (s, 1H), 7.62 (br s, 1H), 10.83 (br s, 1H); MS: m/e 291/293 (M+); (C9H10N3Cl1O2S2) calc C, 37.05; H, 3.45; N, 14.40; found C, 37.18; H, 3.48; N, 14.19.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[C:17]([CH:21]3[C:30]([CH3:32])([CH3:31])[CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([C:33](O)=[O:34])[CH:27]=4)[NH:22]3)[CH:18]=[CH:19][CH:20]=2)[CH2:11][CH2:10]1.[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[C:17]([CH:21]3[C:30]([CH3:31])([CH3:32])[CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([C:33]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[O:34])[CH:27]=4)[NH:22]3)[CH:18]=[CH:19][CH:20]=2)[CH2:11][CH2:10]1
Reactant: CS(N)(=O)=O
Reactant: Cc1ccc(N2CCN(c3cccc(C4Nc5ccc(C(=O)O)cc5CC4(C)C)c3)CC2)c(C)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(N2CCN(c3cccc(C4Nc5ccc(C(=O)NS(C)(=O)=O)cc5CC4(C)C)c3)CC2)c(C)c1
Yield: 29.6 %

Procedure:
A mixture of 2-{3-[4-(2,4-dimethyl-phenyl)-piperazin-1-yl]-phenyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 0.21 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (61 mg, 0.32 mmol), 4-dimethylaminopyridine (39 mg, 0.32 mmol), methane sulfonamide (60 mg, 0.63 mmol) in dichloromethane (10 mL) was refluxed for 12 hours. Removal of the solvent afforded an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded N-(2-{3-[4-(2,4-Dimethyl-phenyl)-piperazin-1-yl]-phenyl}-3,3-dimethyl-1,2,3,4tetrahydro-quinoline-6-carbonyl)-methanesulfonamide (34 mg, 30%) as a light yellow solid: LC/MS m/e calcd for C31H38N4O3S (M+H)+: 547.7, observed: 547.2.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:8]=2)[CH:5]=[N:4][C:3]=1[C:20]#N.CC(C[AlH]CC(C)C)C.[OH2:31].Cl>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:8]=2)[CH:5]=[N:4][C:3]=1[CH:20]=[O:31]
Reactant: Cc1c(C#N)ncn1-c1cccc(Oc2ccccc2)c1
Reactant: O
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1c(C=O)ncn1-c1cccc(Oc2ccccc2)c1
Temperature: -70 °C
Reaction time: 2 h

Procedure:
4.13 g of 5-methyl-1-(3-phenoxyphenyl)-imidazole-4-carbonitrile is dissolved in 200 ml of toluene. At -60° C. to -70° C., 15 ml of Dibah, 1.2 mol in toluene is instilled. It is stirred for 2 hours at -70° C., 2.5 ml of water is instilled at -70° C. and the mixture is allowed to come to room temperature. It is adjusted to pH 4 with 2N hydrochloric acid solution and the mixture is extracted with toluene and ethyl acetate. The organic phases are combined and dried on MgSO4. After purification by column chromatography, 2.46 g (59% of theory) of the title compound is obtained as oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([O:13]C)=O)[C:5]([C:6]([OH:8])=O)=[C:4]([CH3:15])[C:3]=1[N+:16]([O-])=O.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.[N:52]1([CH2:57][CH2:58][NH2:59])[CH2:56][CH2:55][CH2:54][CH2:53]1>C1COCC1>[NH2:16][C:3]1[C:4]([CH3:15])=[C:5]2[C:9](=[CH:10][C:2]=1[NH2:1])[C:11](=[O:13])[N:59]([CH2:58][CH2:57][N:52]1[CH2:56][CH2:55][CH2:54][CH2:53]1)[C:6]2=[O:8]
Reactant: COC(=O)c1cc(N)c([N+](=O)[O-])c(C)c1C(=O)O
Reactant: NCCN1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(N)c(N)cc2c1C(=O)N(CCN1CCCC1)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 104 %

Procedure:
To a solution of 4-amino-6-(methoxycarbonyl)-2-methyl-3-nitrobenzoic acid (380 mg, 1.0 mmol), HATU (114 mg, 1.0 mmol) and DIPEA (129 mg, 1.0 mmol) in THF (20 mL) was added 2-(pyrrolidin-1-yl)ethanamine (114 mg, 1.0 mmol) and stirred at RT for overnight. The reaction mixture was evaporated in vacuo and the residue was triturated with MeOH (10 mL). The yellow precipitate was isolated by filtration and dried to afford the title compound (300 mg) as a yellow solid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([F:15])[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20]CC)=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.C(O)(=O)C.S(=O)(=O)(O)O>O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([F:15])[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Yield: 103.9 %

Procedure:
A mixture of 94 g of ethyl 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 600 ml of glacial acetic acid, 450 ml of water and 70 ml of concentrated sulphuric acid is heated to reflux for 1.5 hours. The hot suspension is then poured onto ice, and the precipitate is filtered off with suction, thoroughly washed with water, and dried in vacuo at 100° C. In this manner, 88.9 g of pure 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid II (X1 =X2 =F) of melting point 228°-230° C. (decomposition) are obtained.