Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[N+:13]([C:16]1[CH:17]=[C:18]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14].C(=O)([O-])O.[K+]>CCCCC(=O)C>[O:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4][CH:3]1[CH2:2][N:25]1[CH2:26][CH2:27][N:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=2)[CH2:23][CH2:24]1
Reactant: ClCC1COc2ccccc2O1
Reactant: O=[N+]([O-])c1cccc(N2CCNCC2)c1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCCCC(C)=O
Product: O=[N+]([O-])c1cccc(N2CCN(CC3COc4ccccc4O3)CC2)c1

Procedure:
A solution of 54.2 mmol (10 g) of 2-chloromethyl-2,3-dihydro-1,4-benzodioxin, 54.2 mmol (9.2 g) of 3-nitrophenylpiperazine and 6 g of potassium hydrogen carbonate in 100 ml of methyl-4-pentanone is heated at reflux for 72 hours. After cooling, the reaction mixture is concentrated. The residue is taken up in 200 ml of water and extracted with 200 ml of dichloromethane. The organic phase is dried over magnesium sulphate, concentrated and purified by chromatography on silica gel, using as eluant a 99/1/0.1 dichloromethane/methanol/ammonium hydroxide mixture, to yield the expected product.
Reaction SMILES: [C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[C:18](Br)=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]1([OH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC1C=CC=CC=1C.[Cu-]=O>[C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[C:18]([O:30][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3cccc(Br)c3c2CC1
Reactant: Oc1ccccc1
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1C
Product: O=C(c1ccccc1)N1CCc2[nH]c3cccc(Oc4ccccc4)c3c2CC1

Procedure:
A mixture of 3-benzoyl-10-bromo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (1.85 g, 5.00 mmol), phenol (0.94 g, 10.0 mmol), copper (I) oxide (0.036 g, 0.25 mmol), and cesium carbonate (4.89 g, 15.0 mmol) in o-xylene was reacted in a similar manner to Preparation 10 to afford 0.55 g (29%) of colorless solid as the title compound: mp 179-182° C. (CH2Cl2/hexane); IR (KBr) 1601, 3226 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.40-8.24, 7.43-7.34, 7.05-6.90, 6.55-6.50, 4.00-3.90, 3.64-3.55, 3.29-2.84; 13C NMR (75.5 MHz, CDCl3) δ 171.8, 158.1, 150.1, 137.0, 136.9, 135.0, 129.7, 129.3, 128.6, 126.5, 122.6, 122.0, 118.1, 117.6, 110.1, 109.4, 106.5, 51.2, 45.2, 28.9, 27.2; MS (EI) m/z 382 (M+); HRMS cacld for C25H22N2O2+H: 383.1759, found: 383.1749; Anal. Calcd. for C25H22N2O2.1/2H2O: C, 76.70; H, 5.92; N, 7.17. Found: C, 76.72; H, 5.79; N, 7.15.
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].[C:13]1([C:19]2[NH:20][C:21]3[CH:27]=[C:26]([S:28](Cl)(=[O:30])=[O:29])[CH:25]=[CH:24][C:22]=3[N:23]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O.C(Cl)(Cl)Cl>CN(C=O)C.CN(C)C1C=CN=CC=1>[C:13]1([C:19]2[NH:20][C:21]3[CH:27]=[C:26]([S:28]([O:12][CH2:11][C@H:9]([C@@H:7]4[C:5]([OH:6])=[C:3]([OH:4])[C:2](=[O:1])[O:8]4)[OH:10])(=[O:29])=[O:30])[CH:25]=[CH:24][C:22]=3[N:23]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccc2nc(-c3ccccc3)[nH]c2c1
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C1O[C@H]([C@H](O)COS(=O)(=O)c2ccc3nc(-c4ccccc4)[nH]c3c2)C(O)=C1O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
45.1 g of ascorbic acid (255.2 mmol; 3 eq.) are dissolved in 100 ml of DMF, 521 mg of 4-dimethylaminopyridine (4.27 mmol; 0.05 eq.) are added, and 25 g of 2-phenyl-3H-benzimidazole-5-sulfonyl chloride (85.4 mmol; 1 eq.), dissolved in 66 ml of DMF, are added dropwise at 0° C. The mixture is subsequently warmed to room temperature, and, after 6 hrs., 100 ml of water and 100 ml of chloroform are added, the mixture is extracted, dried, and the solvent is removed in vacuo. The residue is recrystallised from toluene, giving the product as a pale-beige solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[C@H:4]([CH3:12])[CH2:3]1.C(N(CC)CC)C.[CH3:21][N:22]1[CH:26]=[C:25]([C:27](Cl)=[O:28])[C:24]([CH:30]([F:32])[F:31])=[N:23]1>CN(C)C1C=CN=CC=1.C1COCC1>[CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([NH:11][C:27]([C:25]3[C:24]([CH:30]([F:32])[F:31])=[N:23][N:22]([CH3:21])[CH:26]=3)=[O:28])[CH:7]=[CH:8][CH:9]=2)[C@H:4]([CH3:12])[CH2:3]1
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: C[C@@H]1CC(C)(C)c2cccc(N)c21
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H]1CC(C)(C)c2cccc(NC(=O)c3cn(C)nc3C(F)F)c21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.1 %

Procedure:
Into a solution composed of 0.15 g of (R)-1,1,3-trimethyl-4-aminoindane (optical purity: 99% ee), 0.13 g of triethylamine, 5 mg of 4-dimethylaminopyridine and 1 mL of THF, a solution of 0.17 g of 1-methyl-3-difluoromethylpyrazole-4-carbonyl chloride in THF was dropped under ice cool. The mixture was stirred at room temperature for 15 minutes, then, to the reaction mixture was added ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium hydrogen carbonate aqueous solution and saturated saline sequentially, then, dried over magnesium sulfate and concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography to obtain 0.20 g of (R)-(−)-N-(1,1,3-trimethylindan-4-yl)-1-methyl-3-difluoromethylpyrazole-4-carboxamide (hereinafter, referred to as present carboxamide compound (2)) (optical purity: 99% ee).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:7][C:6](=[O:8])[C:5](=[C:9]([NH:11][C@@H:12]2[C@@H:25]([OH:26])[C@H:24]([OH:27])[C@@H:23]([CH2:28][OH:29])[O:22][C@@H:13]2[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:10])[C:4](=[O:30])[CH2:3]1.[C:32]1([C:38](Br)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C.N1C=CC=CC=1>[CH3:1][C:2]1([CH3:31])[CH2:7][C:6](=[O:8])[C:5](=[C:9]([NH:11][C@@H:12]2[C@@H:25]([OH:26])[C@H:24]([OH:27])[C@@H:23]([CH2:28][O:29][C:38]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[O:22][C@@H:13]2[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:10])[C:4](=[O:30])[CH2:3]1
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(N[C@H]1[C@@H](OCc2ccccc2)O[C@H](CO)[C@@H](O)[C@@H]1O)=C1C(=O)CC(C)(C)CC1=O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(N[C@H]1[C@@H](OCc2ccccc2)O[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H](O)[C@@H]1O)=C1C(=O)CC(C)(C)CC1=O
Temperature: 100 °C
Reaction time: 15 h
Yield: 66.9 %

Procedure:
A mixture of Benzyl 2-Deoxy-2-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethylamino]-α-D-glucopyranoside (100 mg, 0.23 mmol), triphenylmethylbromide (149 mg, 0.46 mmol) in DMF/pyridine 1:1 (2 ml) was stirred at 100° C. for 15 h. The reaction mixture was evaporated, the residue was taken up in CHCl3 (10 ml), washed with water (3 ml), dried over MgSO4 and concentrated. The residue was purified by chromatography using CHCl3/MeOH 10:1 as the mobile phase to give Benzyl 2-Deoxy-2-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethylamino]-6-O-triphenylmethyl-α-D-glucopyranoside (14) (104 mg, 64%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:4]=1[C:5](O)=O.[OH2:15].C1[CH2:20][O:19]CC1>CN(C=O)C.O1CCOCC1.[N+]([O-])([O-])=O.[Ag+]>[CH3:1][S:2][C:3]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:4]=1[CH2:5][C:20]([OH:19])=[O:15]
Reactant: O
Reactant: CSc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: C1CCOC1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CSc1cc([N+](=O)[O-])ccc1CC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-(methylsulfanyl)-4-nitrobenzoic acid (5.3 g, 24.9 mmol) in 50 mL of THF was treated with (CoCL)2 (17.5 ml) and then DMF (2 drops). After stirring at room temperature for 2 hours, the mixture was evaporated. The residue was dissolved in 50 mL of DCM and added a solution of CH2N2 in 80 mL Et2O at 0° C. and stirred overnight. After the reaction was completed, the Et2O was partly evaporated and the product (3.7 g) filtered. A solution of the product (3.7 g, 15.6 mmol) in 90 mL dioxane was treated at 50° C. with 10 mL of water and added over 30 min with a suspension of Ag2O prepared from 3.98 g AgNO3. The mixture was stirred for 30 min at 85° C. and cooled. The precipitated product was filtered. It was decomposed with hydrochloric acid and the released acid was extracted with EtOAc. The combined organic layers were washed with 5% NaHCO3. Then the aqueous layer was acidified to pH=1˜2, extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated to afford [2-(methylsulfanyl)-4-nitrophenyl]acetic acid. 1H-NMR (400 MHz, MeOD) δ ppm 8.06˜8.07 (m, 1H), 7.93˜7.96 (m, 1H), 7.44 (d, J=8.6 Hz, 1H), 3.82 (s, 2H), 2.56 (s, 3H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:27]([Cl:26])=[CH:28][CH:29]=2)[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(Cl)cc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (110 mg, 0.45 mmol) and triethylamine (93 μL, 0.67 mmol) in methylene chloride (25 mL) was added dropwise 4-chlorobenzoyl chloride (83 mg, 0.47 mmol) in methylene chloride (5 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with diluted aqueous sodium hydrogen carbonate. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent. Yield: 97 mg (56%) of the title compound as white crystals: mp 204-205° C.; [α]21D -46° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 383 (19, M+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:19][CH2:18][C:13]3([O:17][CH2:16][CH2:15][O:14]3)[CH2:12][CH:11]2O)=[C:6]([F:21])[C:5]=1[F:22])[CH3:2].O.C(O)CO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:19][CH2:18][C:13]3([O:14][CH2:15][CH2:16][O:17]3)[CH2:12][CH:11]=2)=[C:6]([F:21])[C:5]=1[F:22])[CH3:2]
Reactant: CCOc1ccc(C2CCC3(CC2O)OCCO3)c(F)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: OCCO
Product: CCOc1ccc(C2=CCC3(CC2)OCCO3)c(F)c1F

Procedure:
609 g (about 1.94 mol) of crude 8-(4-ethoxy-2,3-difluorophenyl)-1,4-dioxaspiro[4.5]decan-7-ol in 2000 ml of toluene are heated on a water separator for 2 h together with 220 ml (3.93 mol) of ethylene glycol with addition of 36.1 g (0.19 mol) of p-toluenesulfonic acid monohydrate. After cooling, the batch is washed successively with water, sat. sodium hydrogencarbonate solution and sat. sodium chloride solution. The solution is dried using sodium sulfate and concentrated to dryness. The crude product (507 g of orange oil) is crystallised from ethanol at −20° C., giving 8-(4-ethoxy-2,3-difluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene as yellow solid.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[C:6]([C:10]1[CH:15]=[C:14](C(C)(C)C)[CH:13]=[C:12]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:11]=1)([CH3:9])([CH3:8])[CH3:7]>>[C:6]([C:10]1[CH:15]=[C:14]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:13]=[C:12]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:11]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)c1cc(C(C)(C)C)cc(C(C)(C)C)c1
Reactant: O=S(=O)(O)Cl
Product: CC(C)(C)c1cc(C(C)(C)C)cc(S(=O)(=O)Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
Chlorosulfonic acid (4 mL) was added to 1,3,5-tri-tert-butyl-benzene (1.5 g, 6.1 mmol) which had been cooled to 0° C. After being stirred at 0° C. for 30 minutes, the mixture was warmed to room temperature and stirred for 1 hour. Then the mixture was poured into ice water (50 mL) and extracted with dichloromethane (20 mL×3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (gradient elution: 0-20% ethyl acetate in petroleum ether) to afford 3,5-di-tert-butyl-benzenesulfonyl chloride (880 mg, 50%) as a yellow solid (reference: Guthrie, R. D. et al. Aust. J. Chem. 40 (1987) 2133).
Reaction SMILES: [I-:1].C([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([S+:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[C:16]3[CH:23]=[CH:24][CH:25]=[CH:26][C:15]2=3)=[CH:10][CH:9]=1)(=O)C.[OH-].C[N+](C)(C)C.O.C(Cl)(Cl)Cl>CO>[I-:1].[OH:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([S+:14]2[C:15]3[CH:26]=[CH:25][CH:24]=[CH:23][C:16]=3[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]2=3)=[CH:12][CH:13]=1
Reactant: CC(=O)OCCc1ccc(-[s+]2c3ccccc3c3ccccc32)cc1
Agent: C[N+](C)(C)C
Agent: [I-]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: OCCc1ccc(-[s+]2c3ccccc3c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
While cooling with ice, 10.0 g of dibenzothiophene-S-oxide synthesized in the above step (1) is added to 30 g of diphosphorus pentoxide/methanesulfonic acid (9/1), and further 10 ml of 2-phenylethyl acetate is added thereto. The reaction solution is stirred at room temperature for 6 hours, and then poured into ice water. The obtained aqueous solution is filtered, and 23 g of potassium iodide is added. Crystals precipitated are recovered by filtration to obtain 11.1 g of 5-[(4-(2-acetoxyethyl)-phenyl]dibenzothiophenium iodide. The obtained 11.1 g of 5-[4-(2-acetoxyethyl)-phenyl]dibenzothiophenium iodide is dissolved in 200 ml of methanol, 10.7 g of a 20% aqueous solution of tetramethylammonium hydroxide is added to the solution, followed by stirring at room temperature for 2 hours. Subsequently, 100 ml of ion exchange water and 100 ml of chloroform are added to the solution to extract a chloroform layer. After the solvent is distilled off under reduced pressure, the reaction product is washed with ethyl acetate to obtain 8.5 g of the aiming 5-[4-(2-hydroxyethyl)phenyl]dibenzothiophenium iodide.
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)([O-:5])=[O:4].CS(O[CH2:16][CH:17]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29])[CH2:18][CH2:19][CH2:20][CH3:21])(=O)=O.O>CO>[Cl:29][C:23]1[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=1[CH:17]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:16][N:9]1[CH:10]=[C:6]([N+:3]([O-:5])=[O:4])[N:7]=[CH:8]1
Reactant: O=[N+]([O-])c1c[nH]cn1
Reactant: CCCCC(COS(C)(=O)=O)c1ccc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCC(Cn1cnc([N+](=O)[O-])c1)c1ccc(Cl)cc1Cl
Yield: 106.6 %

Procedure:
To 1.3g (0.0307 mole) of sodium hydroxide in 150 ml of methanol is added 3.5g (0.0307 mole) of 4-nitroimidazole, and the solution is heated and the methanol distilled off. To the concentrate is added 100 ml of dimethyl formamide and the solution is heated up to 120° to remove the excess methanol and water. This dimethyl formamide solution is then cooled to less than 90° and 10.0g (of 0.0307 mole) of 2-(2,4-dichlorophenyl)hexyl methane sulfonate is added. The reaction mixture is heated up to 145° for 2 hours and then cooled and poured into water. The organic material is extracted out with ether and after drying, the extract is stripped to give 11.2g of residue. The concentrate is triturated with hexane and then dissolved in 25 ml of methanol. The methanol solution is poured slowly into water and a gummy solid forms. This solid is separated by filtration, dried and recrystallized from acetone-hexane to give 4.2g (41%) of the product, m.p. 67°-69°.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[N:4]=[CH:3]1.C(O)(C(F)(F)F)=O.C1C(=O)N([I:31])C(=O)C1>C(Cl)Cl>[I:31][C:6]1[N:2]([CH3:1])[CH:3]=[N:4][C:5]=1[C:7]1[CH:8]=[CH:9][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:11][CH:12]=1
Reactant: Cn1cnc(-c2ccc(S(C)(=O)=O)cc2)c1
Reactant: O=C1CCC(=O)N1I
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cnc(-c2ccc(S(C)(=O)=O)cc2)c1I
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.5 %

Procedure:
To the solution of 1-methyl-4-[4-(methylsulfonyl)phenyl]-1H-imidazole (2.3 g, 9.73 mmol) in CH2Cl2 (6 ml) was added TFA (3.0 ml, 38.9 mmol), and NIS (2.41 g, 10.71) at rt. After being stirred at rt for 3 h, the reaction mixture was diluted with CH2Cl2, quenched with NaHCO3 (aq), washed with aq Na2S2O3, water and brine. Dried over Na2SO4, filtered and concentrated to afford 5-iodo-1-methyl-4-[4-(methylsulfonyl)phenyl]-1H-imidazole (3.4 g) which was used in the next step without further purification. LCMS: [M+1]+=363.0
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].Cl.Cl.[NH2:34][C:35]1([CH3:39])[CH2:38][NH:37][CH2:36]1.CN1CCCC1>C(O)C>[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20]([N:37]4[CH2:38][C:35]([NH2:34])([CH3:39])[CH2:36]4)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31]
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: CC1(N)CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: CC1(N)CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4nc(N)c(F)cc4F)c3c2Cl)C1
Temperature: 90 °C
Reaction time: 0.67 h
Yield: 68.3 %

Procedure:
To 350 mg of N,N-dimethylformamide were added 80 mg of 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 60 mg of 3-amino-3-methylazetidine dihydrochloride, and 150 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 40 minutes. After adding 0.5 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol to obtain 64 mg of the title compound as a pale yellow powder.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=3)[C:19](=[O:28])[N:18]([CH3:29])[C:17]2=[O:30])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=[O:35].NC1CCN(CCN2C3C=C(OC)C=CC=3COC2=O)CC1>>[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=3)[C:19](=[O:28])[N:18]([CH3:29])[C:17]2=[O:30])[C:10](=[O:35])[CH2:9]1
Reactant: COc1ccc2c(=O)n(C)c(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Reactant: O=C(O)C(F)(F)F
Agent: COc1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)OC2
Product: COc1ccc2c(=O)n(C)c(=O)n(CCN3CCC(N)CC3=O)c2c1

Procedure:
tert-Butyl{1-[2-(7-methoxy-3-methyl-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 111, 350 mg, 0.83 mmol) was reacted as described for Intermediate 106. The crude trifluoro acetate of the title compound was obtained as a black oil, 395 mg (quantitative), and used without further purification for the next step.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[O:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[C:10]([O:12][CH3:13])=[O:11].[C:14](Br)([CH3:17])([CH3:16])[CH3:15].Cl>C(=S)=S>[C:14]([C:9]1[O:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)Br
Reactant: COC(=O)c1ccco1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COC(=O)c1ccc(C(C)(C)C)o1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
AlCl3 (25.4 g, 190 mmol) is added batchwise to methyl furan-2-carboxylate (20.0 g, 159 mmol) and tert.-butylbromide (21.4 mL, 190 mmol) in CS2 (200 mL) while cooling with ice and the mixture is stirred for 6 h at RT. The reaction mixture is poured onto ice water, mixed with conc. hydrochloric acid (25 mL) and stirred for 10 min. Then the aqueous phase is extracted 2× with 200 mL EA. The combined organic phase is dried on Na2SO4, filtered and evaporated down using the rotary evaporator. The methyl 5-tert.-butyl-furan-2-carboxylate thus obtained is used further without any additional purification steps.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH:12]=[N:11][C:10]=3[O:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:22]Br>CN(C=O)C.CCOC(C)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>[Br:22][C:8]1[O:9][C:10]2[N:11]=[CH:12][N:13]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:14](=[O:16])[C:15]=2[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrBr
Reactant: O=c1c2c(-c3ccccc3)coc2ncn1CC(F)(F)F
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1c2c(-c3ccccc3)c(Br)oc2ncn1CC(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 5-phenyl-3-(2,2,2-trifluoroethyl)furo[2,3-d]pyrimidin-4(3H)-one (730 mg, 2.48 mmol) in DMF (10 ml) at 0° C. was added bromine (0.153 ml, 2.98 mmol). The reaction mixture was stirred at 0° C. for 1 h and then 3 h at RT. The reaction mixture was diluted with EtOAc (50 ml) and 20% w/w aq. sodium thiosulfate solution (50 ml) and the layers were separated. The organic layer was further washed with brine (2×50 ml), dried (Na2SO4) and concentrated in vacuo affording the title compound as an orange solid. LCMS RT=1.40 min, M+H+=373/375.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[NH2:9][NH:10][C:11]([NH:13][NH2:14])=[O:12]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[N:9][NH:10][C:11]([NH:13][N:14]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:12])[CH:2]=1
Reactant: NNC(=O)NN
Reactant: O=Cc1cccnc1
Solvent: CO
Product: O=C(NN=Cc1cccnc1)NN=Cc1cccnc1
Reaction time: 1 h

Procedure:
32.2 g of pyridine-3-carbaldehyde are added in the course of approx. 10 minutes, at room temperature, to a suspension of 13.5 g of carbohydrazide in 200 ml of methanol, the temperature rising to more than 35°. The reaction mixture is further stirred for 1 hour and then cooled to 5°. The crystals that precipitate are filtered off with suction and dried in vacuo at 70°. 40 g of the title compound having a melting point of 202°-204° are thus obtained.
Reaction SMILES: C(=O)C1C=CC=CC=1.[CH3:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:34]3[C:29](=[CH:30][C:31]([F:41])=[C:32]([N:35]4[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36]4)[CH:33]=3)[C:28](=[O:42])[C:27]([C:43]([OH:45])=[O:44])=[CH:26]2)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:34]3[C:29](=[CH:30][C:31]([F:41])=[C:32]([N:35]4[CH2:39][CH2:38][CH:37]([N:40]=[CH:9][C:10]5[CH:17]=[CH:16][C:13]([CH3:14])=[CH:12][CH:11]=5)[CH2:36]4)[CH:33]=3)[C:28](=[O:42])[C:27]([C:43]([OH:45])=[O:44])=[CH:26]2)=[CH:21][CH:20]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: NC1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3-c2ccc(F)cc2)C1
Solvent: O=Cc1ccccc1
Product: Cc1ccc(C=NC2CCN(c3cc4c(cc3F)c(=O)c(C(=O)O)cn4-c3ccc(F)cc3)C2)cc1

Procedure:
In the described fashion of Example 1 replacing benzaldehyde with p-methylbenzaldehyde and using the acid (1) (R=ethyl) described in example 13 one obtains 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-p-methylbenzylidene)amino-1-pyrrolidinyl)-quinoline-3-carboxylic acid (3) (R=ethyl-Z=p-methylphenyl).