Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[CH2:13]([O:15][C:16]([CH:18]1[NH:23][C:22](=[O:24])[CH:21]([CH2:25][CH:26]([CH3:28])[CH3:27])[N:20]([OH:29])[C:19]1=[O:30])=[O:17])[CH3:14].[O:31]1[CH:36]=[CH:35][CH2:34][CH2:33][CH2:32]1>ClCCl>[CH2:13]([O:15][C:16]([CH:18]1[NH:23][C:22](=[O:24])[CH:21]([CH2:25][CH:26]([CH3:27])[CH3:28])[N:20]([O:29][CH:32]2[CH2:33][CH2:34][CH2:35][CH2:36][O:31]2)[C:19]1=[O:30])=[O:17])[CH3:14]
Reactant: C1=COCCC1
Reactant: CCOC(=O)C1NC(=O)C(CC(C)C)N(O)C1=O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1NC(=O)C(CC(C)C)N(OC2CCCCO2)C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.45 g of p, toluenesulfonic acid hydrate was added to 60 ml of a solution of 6.15 g of 3-ethoxycarbonyl-1-hydroxy-6-isobutylpiperazine-2,5-dione and 4 ml of 3,4-dihydro-2H-pyran in anhydrous dichloromethane. The mixture was stirred at room temperature for 4 hours. The reaction mixture was washed with an aqueous solution saturated with sodium hydrogen carbonate and then dried with anhydrous magnesium sulfate. The resulting mixture was subjected to distillation to remove the solvent to obtain 9.67 g of 3-ethoxycarbonyl-6-isobutyl-1-(2-tetrahydropyranyloxy)piperazine-2,5-dione as an orange oily substance.
Reaction SMILES: [Br-].[O:2]1[CH2:7][CH2:6][CH2:5][O:4][CH:3]1[CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.CC(C)([O-])C.[K+].[F:40][C:41]([F:56])([F:55])[C:42]1[CH:47]=[CH:46][C:45]([CH:48]2[CH2:53][CH2:52][C:51](=O)[CH2:50][CH2:49]2)=[CH:44][CH:43]=1>CCOCC>[O:4]1[CH2:5][CH2:6][CH2:7][O:2][CH:3]1[CH2:8][CH:9]=[C:51]1[CH2:50][CH2:49][CH:48]([C:45]2[CH:44]=[CH:43][C:42]([C:41]([F:40])([F:55])[F:56])=[CH:47][CH:46]=2)[CH2:53][CH2:52]1
Reactant: c1ccc([P+](CCC2OCCCO2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1CCC(c2ccc(C(F)(F)F)cc2)CC1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(C2CCC(=CCC3OCCCO3)CC2)cc1
Reaction time: 1 h

Procedure:
Into a three-necked flask equipped with a dropping funnel, a three-way cock and a thermometer was placed 2-(1,3-dioxan-2-yl)ethyltriphenylphosphonium bromide (12.2 g, 27 mmols), followed by adding tetrahydrofuran (100 ml), suspending, and stirring under ice cooling till the liquid temperature reached 10° C. The resulting reaction mixture was added potassium t-butoxide (3.0 g, 27 mmols), followed by elevating the temperature up to room temperature under ice cooling, stirring for one hour, dropwise adding a tetrahydrofuran (50 ml) solution of 4-(4-trifluoromethylphenyl) cyclohexanone (6.0 g, 25 mmols) over 30 minutes from the dropping funnel, further stirring the reaction mixture for 5 hours after completion of the dropwise addition, adding ether (100 ml), allowing to stand for one hour, filtering off deposited insoluble substance, concentrating the filtrate under reduced pressure and isolating and purifying the resulting pale brown oil by means of silica gel column chromatography, to obtain 1-(2-(1,3-dioxan-2-yl)-ethylidene)-4-(4-trifluoromethylphenyl)cyclohexane.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][C@@H:5]([N:7]2[CH:15]=[N:14][C:13]3[C:8]2=[N:9][C:10]([N:31]2[CH2:35][CH2:34][C@@H:33]([NH:36][C:37]([NH:39][C:40]4[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=4)=[O:38])[CH2:32]2)=[N:11][C:12]=3[NH:16][CH2:17][CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:4]([OH:46])[C@@H:3]1[OH:47].C([O:51][C@@H:52]([CH3:56])[C:53](Cl)=[O:54])(=O)C.C([O-])([O-])=O.[Na+].[Na+].CO>C1COCC1.CC#N>[C:25]1([CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][NH:16][C:12]2[N:11]=[C:10]([N:31]3[CH2:35][CH2:34][C@@H:33]([NH:36][C:37]([NH:39][C:40]4[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=4)=[O:38])[CH2:32]3)[N:9]=[C:8]3[C:13]=2[N:14]=[CH:15][N:7]3[C@@H:5]2[CH2:6][C@H:2]([NH:1][C:53](=[O:54])[C@@H:52]([OH:51])[CH3:56])[C@@H:3]([OH:47])[C@H:4]2[OH:46])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](O)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture comprising 1-{(R)-1-[9-((1R,2S,3R,4S)-4-amino-2,3-dihydroxy-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-pyrrolidin-3-yl}-3-pyridin-3-yl-urea (Example 26 step 2) (0.1 g, 0.16 mmol) and TEA (24 μl, 0.18 mmol) in THF (7 ml) at room temperature is treated with (S)-(−)-2-acetoxy-propionyl chloride (24 mg, 0.16 mmol) in MeCN (1 ml) at (0° C.) over 1 minute. The mixture is allowed to stir at room temperature for 18 h and then treated with sat. Na2CO3 (1 ml) and MeOH (1 ml) and then stirred for a further 2 days. The solvent is removed in vacuo and purification by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water—0.3% NH3) affords the title compound as a white solid. (MH+ 707.7)
Reaction SMILES: [F:1][C:2]([F:26])([O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[N:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[N:15]2)=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4].[OH-:27].[K+]>C(#N)C.O.O1CCOCC1>[F:26][C:2]([F:1])([O:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH:18]=[N:17][C:16]([C:19]3[CH:20]=[CH:21][C:22]([CH:25]=[O:27])=[CH:23][CH:24]=3)=[N:15]2)=[CH:12][CH:13]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Reactant: [OH-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CC#N
Product: O=Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1

Procedure:
The product from Step 1 (7.0 g, 18.7 mmol) was dissolved in 200 mL of acetonitrile and stirred at ambient temperature while ceric ammonium nitrate (32 g, 58 mmol) in 60 mL of water was added in portions over 10 min. The solution was then heated to reflux for 4 h, cooled, and diluted with 200 mL of water. The solution was extracted with 2×200 mL of ether, and the combined organic layer was dried and concentrated to give an orange oil. This material was dissolved in 40 mL of dioxane and treated with a solution of KOH (5 g, 90 mmol) in 20 mL of water. The solution was heated to reflux for 2 h, then cooled and diluted with 100 mL of water. The aldehyde precipitated and was collected by filtration. Recrystallization from MeOH/H2O gave the pure aldehyde as a white solid. 1H NMR (300 MHz, CDCl3) δ 10.1 (s, 1H), 8.65 (s, 1H), 8.40 (d, J=8.4 Hz, 2H), 8.0 (d, J=8.4 Hz, 2H), 7.85 (d, J=9 Hz, 2H), 7.45 (d, J=9 Hz, 2H); ESIMS 384.2 (M+H); mp 137-144° C.
Reaction SMILES: Cl.[NH2:2][OH:3].C[O-].[Na+].[CH3:7][O:8][CH:9]([O:18][CH3:19])[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1>CO>[CH3:7][O:8][CH:9]([O:18][CH3:19])[C:10]1[CH:17]=[CH:16][C:13]([C:14](=[N:2][OH:3])[NH2:15])=[CH:12][CH:11]=1
Reactant: COC(OC)c1ccc(C#N)cc1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(OC)c1ccc(C(N)=NO)cc1
Reaction time: 0.33 h
Yield: 931.3 %

Procedure:
A suspension of hydroxylamine hydrochloride (31.62 g; 45.5 mmol) in MeOH (350 ml) was treated with sodium methoxide (24.58 g; 45.5 mmol) slowly, in small portions. After stirring for 20 minutes, a solution of 4-(dimethoxymethyl)benzonitrile (67 g; 37.9 mmol) in MeOH (100 ml) was added and the mixture heated to reflux. After 12 hr, it was concentrated and partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated to afford 4-(dimethoxymethyl)-N′-hydroxybenzenecarboximidamide (74.2 g) which was used in the next step without further purification. MS: m/z 211 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C:26](=[O:27])[CH2:25][CH2:24][C@@:23]2([CH3:28])[C:3]1=[CH:4][CH2:5][C:6]1[C@H:7]3[C@:19]([CH3:29])([CH2:20][CH2:21][C:22]=12)[C@@H:10]([C@H:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:9][CH2:8]3>O1CCCC1>[CH3:30][C:2]1([CH3:1])[C@@H:26]([OH:27])[CH2:25][CH2:24][C@@:23]2([CH3:28])[C:3]1=[CH:4][CH2:5][C:6]1[C@H:7]3[C@:19]([CH3:29])([CH2:20][CH2:21][C:22]=12)[C@@H:10]([C@H:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:9][CH2:8]3
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CCC(=O)C(C)(C)C1=CC3
Solvent: C1CCOC1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CC[C@H](O)C(C)(C)C1=CC3
Reaction time: 1 h
Yield: 59.7 %

Procedure:
4,4-Dimethylcholesta-5,8-diene-3-one (100 mg) is reduced with lithiumalurninumhydride (5 mg) in 2 ml tetrahydrofuran at room temperature. The solution is stirred for one hour. After aqueous work-up and column chromatography 4,4-dimethylcholesta-5,8-diene-3β-ol (60 mg) is isolated.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:12][C:13]#[N:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOCC>[C:13]([CH2:12][O:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])#[N:14]
Reactant: Cc1cccc(C=O)c1O
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1cccc(C=O)c1OCC#N
Temperature: 55 °C

Procedure:
A mixture of 2-hydroxy-3-methylbenzaldehyde (10.2 g, 75.0 mmoles, Aldrich), bromoacetonitrile (5.70 mL, 82.5 mmoles), and potassium carbonate (11.4 g, 82.5 mmoles) in DMF (150 mL) is heated to 55° C. for 3 hours, cooled, then diluted with ether. The mixture is washed with distilled water, saturated NaCl solution, then the organic layer dried over MgSO4 and concentrated to give the title compound as a yellow solid. 1H NMR (300 MHz, CDCl3): δ10.20 (s, 1H), 7.70 (d, 1H), 7.53 (d, 1H), 7.29 (m, 1H), 4.81 (s, 2H), 2.42 (s, 3H).
Reaction SMILES: CC1C=C(N2CCN(CC3C=CC(C(F)(F)F)=CC=3)C2=O)SC=1C(OCC)=O.[CH3:29][C:30]1[N:31]=[C:32]([N:40]2[CH2:44][CH2:43][N:42]([CH2:45][C:46]3[CH:47]=[CH:48][CH:49]=[C:50]4[C:55]=3[N:54]=[CH:53][CH:52]=[CH:51]4)[C:41]2=[O:56])[S:33][C:34]=1[C:35]([O:37]CC)=[O:36]>>[CH3:29][C:30]1[N:31]=[C:32]([N:40]2[CH2:44][CH2:43][N:42]([CH2:45][C:46]3[CH:47]=[CH:48][CH:49]=[C:50]4[C:55]=3[N:54]=[CH:53][CH:52]=[CH:51]4)[C:41]2=[O:56])[S:33][C:34]=1[C:35]([OH:37])=[O:36]
Reactant: CCOC(=O)c1sc(N2CCN(Cc3cccc4cccnc34)C2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)cc1C
Product: Cc1nc(N2CCN(Cc3cccc4cccnc34)C2=O)sc1C(=O)O
Yield: 88 %

Procedure:
Following the procedure as described in Example 14, making variations as required to replace ethyl 3-methyl-5-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiophene-2-carboxylate with ethyl 4-methyl-2-(2-oxo-3-(quinolin-8-ylmethyl)imidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained as a colorless solid in 88% yield: MS (ES+) m/z 369.1 (M+1).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]2[N:9]([CH2:13][C:14]3[N:19]=[CH:18][N:17]=[C:16]([C:20](=O)[CH3:21])[C:15]=3[CH2:23][CH2:24][CH3:25])[CH:10]=[CH:11][N:12]=2)[CH:5]=[CH:4][CH:3]=1.C(O)=O.[CH:29]([NH2:31])=[O:30].[OH-].[Na+]>O>[F:1][C:2]1[N:7]=[C:6]([C:8]2[N:9]([CH2:13][C:14]3[N:19]=[CH:18][N:17]=[C:16]([CH:20]([NH:31][CH:29]=[O:30])[CH3:21])[C:15]=3[CH2:23][CH2:24][CH3:25])[CH:10]=[CH:11][N:12]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CCCc1c(Cn2ccnc2-c2cccc(F)n2)ncnc1C(C)=O
Reactant: NC=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Product: CCCc1c(Cn2ccnc2-c2cccc(F)n2)ncnc1C(C)NC=O
Temperature: 25 °C

Procedure:
214 (0.1 g) and formic acid (0.1 mL) are added to 2 mL of formamide at 160–180° C. The mixture is heated at 160–180° C. for an additional 3 hours. During this period, additional formic acid (0.2 mL) is added. The mixture is cooled to room temperature and poured into water (10 mL). The solution is made alkaline to at least pH 11 with concentrated sodium hydroxide. The solution is extracted with ethyl acetate. The combined organic layers are dried over MgSO4, and the solvent is removed to give the crude product. PTLC separation with 10% MeOH in methylene chloride gives the title product (215). 1H NMR δ (CDCL3) 1.06 (t, 3H, J=7.5 Hz), 1.43 (d, 3H, J=5.1 Hz), 1.55 –1.72 (m, 2H), 2.72–2.80 (m, 1H), 2.86–2.95 (m, 1H), 5.52 (p, 1H, J=5.4 Hz), 5.81 (d, 1H, J=12.3 Hz), 6.08 (d, 1H, J=12.3 Hz), 6.73 (dd, 1 H, J=6, 2.1 Hz)), 6.99 (d, 1H, J=5.7 Hz), 7.12 (d, 1H, J=2.7 Hz), 7.23 (d, 1H, J=2.7 Hz), 7.78 (q, 1H, J=6.0 Hz), 8.12 (dd, 1H, J=6.0, 2.1 Hz), 8.18 (s, 1H), 8.79 (s, 1H). LC-MS: (M+1) 369.13.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[Li][CH2:12][CH2:13][CH2:14][CH3:15].C(=O)=O.C([Li])(C)(C)C.[CH3:24][C:25]1(C)[C:29](=O)C=[CH:27][C:26]1(C)C>C1COCC1.CCCCC>[CH3:12][CH:13]1[C:24]([C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[CH2:4][CH2:3][CH2:2][NH:1]3)=[C:25]([CH3:29])[C:26]([CH3:27])=[C:14]1[CH3:15]
Reactant: CC1(C)C=CC(=O)C1(C)C
Reactant: c1ccc2c(c1)CCCN2
Reactant: [Li]CCCC
Agent: O=C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC1=C(C)C(C)C(c2cccc3c2CCCN3)=C1C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
957 mg (7.185 mmol) of 1,2,3,4-tetrahydroquinoline was dissolved in 10 ml of THF, and stirred at −78° C. for 30 minutes. 2.87m1 (7.185mmol) of nBuLi was added thereto using a syringe under a nitrogen atmosphere (yellow suspension). The mixture was sufficiently stirred for 3 hours, and the temperature was increased to −20° C. to eliminate the gas. The temperature was cooled again to −78° C. and CO2 was injected to the mixture (The color of the mixture turned to colorless white). The temperature was increased to −20° C. and the remaining CO2 was eliminated in vacuum for 1 hour. Then, 5.07 ml (8.622 mmol) of tert-butyllitium (BuLi) was added to the mixture (The color of the mixture turned to red). While the temperature was maintained at −20° C., the mixture was sufficiently stirred for 2 hours, and 26.1 ml (8.622 mmol) of 0.33 M CeCl3:2LiCl solution dissolved in THF and 1.182 g (8.622 mmol) of tetramethyl cyclopentenone were added to the mixture under a nitrogen atmosphere. While the temperature was gradually increased to room temperature, the solvents were eliminated by venting. Then, the mixture was titurated using pentane under a nitrogen atmosphere and filtered to obtain a white crystalline powder (41%).
Reaction SMILES: [NH2:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[CH3:11].Cl.S([O-])(=O)(=O)C.[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][C:20]=1[S:28](=[O:31])(=[O:30])[NH2:29]>>[NH2:29][S:28]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:19]=1[Cl:18])[C:23]([NH:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[CH3:11])=[O:24])(=[O:31])=[O:30]
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Reactant: CC1Cc2ccccc2N1N
Agent: CS(=O)(=O)[O-]
Agent: Cl
Product: CC1Cc2ccccc2N1NC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1

Procedure:
The process as claimed in claim 1, wherein -amino-2,3-dihydro-2-methyl-1H-indole is reacted in the form of a hydrochloride or mesylate with 4-chloro-3-sulfamoylbenzoyl chloride.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[CH2:12]([NH2:15])[CH2:13][NH2:14]>C(#N)C>[NH2:14][CH2:13][CH2:12][NH:15][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([NH2:1])[N:3]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: NCCN
Solvent: CC#N
Product: NCCNc1ccc([N+](=O)[O-])c(N)n1
Temperature: 77.5 °C
Reaction time: 20 h
Yield: 99 %

Procedure:
A mixture of 2-amino-6-chloro-3-nitropyridine (0.52 M) in acetonitrile (70 ml), and ethylene diamine (40 ml) were stirred overnight (ca. 20 h) at 75-80° C. under argon. The ethylene diamine was removed under reduced pressure. The residual solution was basified with 1M sodium hydroxide solution (50 ml). The aqueous solution was saturated with sodium chloride and extracted with a solution of 95% ethyl acetate and 5% methanol (3×150 ml) and with a solution of 95% acetonitrile and 5% methanol (3×150 ml). The organic extracts were combined and extracted with a saturated sodium chloride solution (2×75 ml). The organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure. The crude yellow solid was triturated with ether (2×25 ml) and dried overnight in vacuo resulting in 2-(2-aminoethyl)amino-6-amino-5-nitropyridine in 99% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:12])[C:8]=1[CH2:9][O:10][CH3:11])[NH2:5].C(N(CC)C1C=CC=CC=1)C.Cl[C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:25](=[O:26])[O:27][CH:28]([CH3:30])[CH3:29])[CH:6]=[C:7]([Cl:12])[C:8]=1[CH2:9][O:10][CH3:11]
Reactant: COCc1c(Cl)cc(N)cc1Cl
Reactant: CC(C)OC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)c1ccccc1
Product: COCc1c(Cl)cc(NC(=O)OC(C)C)cc1Cl
Temperature: 0 °C
Reaction time: 12 h
Yield: 89.7 %

Procedure:
3,5-Dichloro-4-methoxymethylaniline (2.06 g) and N,N-diethylaniline (1.49 g) were dissolved in toluene (15 ml). To the resultant solution was dropwise added isopropyl chloroformate (1.24 g) in 5 minutes under ice-cooling. The resultant mixture was allowed to stand at room temperature for 12 hours, poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixture of toluene and ethyl acetate as the eluent to give isopropyl N-(3,5-dichloro-4-methoxymethylphenyl)carbamate (Compound No. 1) (2.62 g) in a yield of 89.6% nD26.2 1.5283.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][NH2:10].Cl[CH2:12][CH2:13][N:14]=[C:15]=[S:16]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][NH:10][C:15]1[S:16][CH2:12][CH2:13][N:14]=1
Reactant: S=C=NCCCl
Reactant: Cc1cccc(NN)c1C
Solvent: Cc1ccccc1
Product: Cc1cccc(NNC2=NCCS2)c1C
Temperature: 0 °C

Procedure:
13.6 g (0.1 mol) of 2,3-dimethylphenylhydrazine were dissolved in 50 ml of toluene, and a solution of 12.8 (5% excess) of 2-chloroethyl isothiocyanate in 25 ml of toluene was added in the course of 15 minutes, while stirring and cooling with ice water, and the mixture was further stirred for 2 hours at room temperature and for 2 hours under reflux. The product was filtered off with suction when cold and was recrystallised from isopropanol. Mp. 220° to 221° (decomposition) (hydrochloride), 13.5 g (52.5% of theory).
Reaction SMILES: C([N:4](C(C)C)CC)(C)C.[CH3:10][S:11]([C:14]1[CH:15]=[C:16]([NH:20][C:21](=[O:29])OC2C=CC=CC=2)[CH:17]=[CH:18][CH:19]=1)(=[O:13])=[O:12].N[C:31]1[CH:54]=[CH:53][C:34]([O:35][C:36]2[C:45]3[C:40](=[CH:41][C:42]([O:48][CH2:49][CH2:50][O:51][CH3:52])=[C:43]([C:46]#[N:47])[CH:44]=3)[N:39]=[CH:38][CH:37]=2)=[CH:33][CH:32]=1>>[C:46]([C:43]1[CH:44]=[C:45]2[C:40](=[CH:41][C:42]=1[O:48][CH2:49][CH2:50][O:51][CH3:52])[N:39]=[CH:38][CH:37]=[C:36]2[O:35][C:34]1[CH:53]=[CH:54][C:31]([N:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([S:11]([CH3:10])(=[O:12])=[O:13])[CH:15]=2)[C:21]([NH2:4])=[O:29])=[CH:32][CH:33]=1)#[N:47]
Reactant: CCN(C(C)C)C(C)C
Reactant: COCCOc1cc2nccc(Oc3ccc(N)cc3)c2cc1C#N
Reactant: CS(=O)(=O)c1cccc(NC(=O)Oc2ccccc2)c1
Product: COCCOc1cc2nccc(Oc3ccc(N(C(N)=O)c4cccc(S(C)(=O)=O)c4)cc3)c2cc1C#N
Yield: 75.5 %

Procedure:
Diisopropylethylamine (0.057 ml, 0.328 mmol) and phenyl N-[3-(methylsulfonyl)phenyl]carbamate (96 mg, 0.328 mmol) were reacted with 4-(4-aminophenoxy)-7-(2-methoxyethoxy)-6-cyanoquinoline (100 mg, 0.298 mmol), and the title compound (120 mg, 0.225 mmol, 75.6%) was obtained as white crystals by the same procedure as in Example 34.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.[S:30](=O)(=[O:33])([OH:32])[OH:31]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([S:30]([OH:33])(=[O:32])=[O:31])=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(-c2ccsc2-c2ccc(F)cc2)cc1
Reactant: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2cc(S(=O)(=O)O)sc2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]thiophene (5 g), acetic anhydride (4.3 ml) and sulfuric acid (0.97 ml) in dichloromethane (47 ml) was stirred at ambient temperature overnight. The mixture was concentrated to give a crude blue oil of 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]thiophene-2-sulfonic acid (10.5 g).
Reaction SMILES: C[O:2][C:3](=[O:34])/[C:4](/[NH:12][C:13](=[O:33])[C:14]1[C:19]([CH3:20])=[CH:18][C:17]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])=[CH:16][C:15]=1[Cl:32])=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.[OH-].[Li+]>CO.O1CCCC1.O>[Cl:32][C:15]1[CH:16]=[C:17]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])[CH:18]=[C:19]([CH3:20])[C:14]=1[C:13]([NH:12]/[C:4](=[CH:5]\[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)/[C:3]([OH:34])=[O:2])=[O:33]
Reactant: COC(=O)/C(=C/c1ccccc1)NC(=O)c1c(C)cc(C(=O)NCc2cccc(O)c2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cc(C(=O)NCc2cccc(O)c2)cc(Cl)c1C(=O)N/C(=C\c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 17 h
Yield: 42.6 %

Procedure:
A mixture of (Z)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]-6-methylbenzoyl]amino]-3-phenylpropenoic acid methyl ester (Example 212; 23 mg, 0.048 mmol) and lithium hydroxide monohydrate (6 mg, 0.144 mmol) in methanol/tetrahydrofuran/water (2:2:1; 0.25 mL) was stirred at room temperature for 17 h. An second portion of lithium hydroxide monohydrate (2 mg, 0.05 mmol) was added and the solution was stirred for an additional 4 h. The volatiles were removed in vacuo and the residue was taken up in a mixture of chloroform/methanol/water/acetic acid (150:30:10:6) and evaporated to dryness. The residue was re-dissolved in the same solvent mixture (1 mL) and applied to a silica gel column. The column was eluted with in turn with chloroform, chloroform/methanol/water/acetic acid (300:30:10:6) and chloroform/methanol/water/acetic acid (150:30:10:6). The appropriate fractions were combined, evaporated and then lyophilized to give (Z)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]-6-methylbenzoyl]amino]-3-phenylpropenoic acid (9.5 mg, 43% yield) as a colorless powder.
Reaction SMILES: Cl[C:2]1[C:13]2=[C:14]3[N:9]([CH2:10][CH2:11][CH2:12]2)[CH:8]=[C:7]([C:15]([OH:17])=[O:16])[C:6](=[O:18])[C:5]3=[CH:4][CH:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.Cl>CS(C)=O>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:2]2[C:13]3=[C:14]4[N:9]([CH2:10][CH2:11][CH2:12]3)[CH:8]=[C:7]([C:15]([OH:17])=[O:16])[C:6](=[O:18])[C:5]4=[CH:4][CH:3]=2)[CH2:22][CH2:21]1
Reactant: O=C(O)c1cn2c3c(c(Cl)ccc3c1=O)CCC2
Reactant: CN1CCNCC1
Agent: Cl
Solvent: CS(C)=O
Product: CN1CCN(c2ccc3c(=O)c(C(=O)O)cn4c3c2CCC4)CC1
Yield: 20.1 %

Procedure:
4.0 g of 8-chloro-6,7-dihydro-1-oxo-1H,5H-benzo-[ij]quinolizine-2-carboxylic acid and 4.6 g of N-methylpiperazine was added to 10 ml of anhydrous dimethylsulfoxide and the mixture was heated on an oil bath at 150° to 160° C. for 8 hours while stirring. After completion of the reaction, the solvent and excessive methylpiperazine were removed under reduced pressure and a mixture of methanol and diethyl ether was added to form precipitates which were separated by filtration and washed with diethyl ether. The crystals thus obtained were suspended in 20 ml of a 10% aqueous hydrochloric acid solution and insoluble materials were removed by filtration. The filtrate was purified through column chromatography using Amberlite LH-20 (a trade name for a product of Tokyo Organic Chemical Industries Ltd.) (eluent: water, ethanol). Recrystallization of the eluate from dimethylformamide gave 1.0 g of 8-(4-methyl-1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo-[ij]quinolizine-2-carboxylic acid light yellow plates having a melting point of 278° to 280.5° C.