Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH:15]([SH:18])([CH3:17])[CH3:16].[OH-].[Na+]>CS(C)=O>[CH:15]([S:18][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12])([CH3:17])[CH3:16]
Reactant: O=[N+]([O-])c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(C)S
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)Sc1ccc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 24 h
Yield: 99.5 %

Procedure:
To a solution containing 112.8 g (0.5 mole) of 2-chloro-5-nitrobenzotrifluoride and 46 g (0.6 mole) of isopropyl mercaptan in 400 ml of DMSO was added dropwise over 0.5 hour 40 g of 50% aqueous sodium hydroxide. This addition was exothermic to 50° C. After 24 hours, the reaction mixture was poured into ice water and extracted with 3×200 ml of methylene chloride. The combined extracts were washed with water, dried and concentrated to give 132 g (99%) of product as an orange liquid.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C(N(CC)CC)C.O.[CH:14]1([C:20](Cl)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>ClCCl>[CH3:2][N:3]([O:4][CH3:5])[C:20]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:21]
Reactant: CNOC
Reactant: O=C(Cl)C1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)C1CCCCC1
Temperature: 0 °C
Yield: 80 %

Procedure:
In a dried, flushed with nitrogen round bottom flask, N,O-dimethyl hydroxylamine hydrochloride (0.1 mol, 13.3 ml) was suspended in 200 ml anhydrous dichloromethane. To the resulting mixture triethylamine (0.22 mol, 30 ml) was added dropwise in ˜5 min while cooling by water (stirring became difficult because of salts formation). To the resulting mixture, while stirring under nitrogen and cooling by ice water, cyclohexanecarbonyl chloride was added dropwise in ˜15 min. The mixture was stirred overnight, washed with water (50 ml), saturated aqueous NH4Cl (50 ml), then brine (50 ml), dried over Na2SO4, and concentrated to give 17.8 g of crude product. Purification on 150 g silica gel, eluent hexanes-ethyl acetate, from 100:0 to 50:50, afforded 13.6 g (80%) of N-methyl-N-methoxy-cyclohexanecarboxamide as clear oil, Rf 0.44 (hexanes-EtOAc 1:1), 1H NMR (400 MHz, CDCl3) δ 3.67 (s, 3H, OCH3), 3.15 (s, 3H, NCH3), 2.65 (m, 1H, CH—CO), 1.8-1.6 (m, 5H, cyclohexyl), 1.5-1.4 (qm, 2H, cyclohexyl), 1.3-1.2 (m, 3H, cyclohexyl).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[CH2:5][C@H:6](N)[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[Br-:17].[K+].N([O-])=O.[Na+].NC(N)=O>O>[CH3:2][O:3][C:4](=[O:11])[CH2:5][C@H:6]([Br:17])[C:7]([OH:9])=[O:8]
Reactant: COC(=O)C[C@H](N)C(=O)O
Reactant: [Br-]
Agent: Cl
Agent: NC(N)=O
Agent: O=N[O-]
Solvent: O
Product: COC(=O)C[C@H](Br)C(=O)O
Reaction time: 0.33 h
Yield: 62.5 %

Procedure:
To a mixture of (3S)-3-amino-3-carboxypropionic acid methyl ester hydrochloride (206 g), sulfuric acid (552 g), potassium bromide (536 g) and water (2510 ml) is added dropwise a solution of sodium nitrite (93 g) in water (200 ml) at a temperature from 10° C. to 12° C. over a period of 45 minutes. The mixture is stirred at the same temperature for 20 minutes, and thereto is added urea (40 g) in portions. The mixture is extracted with ether, and the extract is washed, dried, and concentrated under reduced pressure to give (3S)-3-bromo-3-carboxypropionic acid methyl ester (148 g) as an oily product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=1.S(Cl)([Cl:17])=O>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([C:12]([Cl:17])=[O:14])=[CH:9][CH:8]=1
Reactant: O=C(O)c1ccc(-c2ccccn2)s1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccc(-c2ccccn2)s1
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
A suspension of 5-(pyrid-2-yl)thiophene-2-carboxylic acid (48 mg) in dry toluene (10 mL) was treated with thionyl chloride (269 μL). After stirring at 100° C. for 2.5 hours the reaction mixture was allowed to cool to room temperature and then evaporated. The residue was azeotroped with toluene to give the title compound (61 mg), which was used without further purification.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][N:27]1[CH:31]=[C:30]([S:32](Cl)(=[O:34])=[O:33])[N:29]=[CH:28]1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:26][N:27]1[CH:31]=[C:30]([S:32]([N:23]2[CH2:24][CH2:25][CH:20]([C:11]3[C:10]4[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=[C:8]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[CH:9]=4)[NH:13][N:12]=3)[CH2:21][CH2:22]2)(=[O:34])=[O:33])[N:29]=[CH:28]1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)n[nH]c12
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1cnc(S(=O)(=O)N2CCC(c3n[nH]c4c(C(N)=O)cc(-c5ccccc5)cc34)CC2)c1
Yield: 60.8 %

Procedure:
This compound was prepared in a fashion analogous to the procedure described in Example 3. Thus, 5-phenyl-3-(4-piperidinyl)-1H-indazole-7-carboxamide hydrochloride (0.057 g, 0.17 mmol) was reacted with 1-methylimidazole-4-sulfonyl chloride (0.031 g, 0.17 mmol) in the presence of triethylamine (0.1 mL, 0.71 mmol) and DMAP (0.0021 g, 0.017 mmol) in DMF (3 mL) to give 0.048 g of white solid.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][N:7]1[CH2:11][C@@H:10]2[C@@H:12]([NH2:15])[CH2:13][CH2:14][C@@H:9]2[CH2:8]1.Br[CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:22]([NH:15][C@@H:12]1[C@@H:10]2[C@@H:9]([CH2:8][N:7]([CH2:6][C:5]3[CH:16]=[CH:17][CH:18]=[C:3]([C:2]([F:19])([F:1])[F:20])[CH:4]=3)[CH2:11]2)[CH2:14][CH2:13]1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: N[C@H]1CC[C@@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@@H]21
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(CN2C[C@H]3CC[C@H](NC(c4ccccc4)c4ccccc4)[C@H]3C2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
(3aR,4S,6aS)-2-(3-(Trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine (60 mg, 0.211 mmol), from Example 156 Step A was combined with (bromomethylene)dibenzene (62.6 mg, 0.253 mmol) and potassium carbonate (87 mg, 0.633 mmol) in N,N-dimethylformamide (1 mL). The reaction was stirred at room temperature for 72 hours. The reaction was quenched with water and extracted with diethyl ether. The ether extracts were washed with water (3×1 mL) and the solvent removed. The crude material was purified using a 12 g silica gel cartridge eluting with a gradient of 0-3% methanol (2 N ammonia)/dichloromethane to give (3aR,4S,6aS)-N-benzhydryl-2-(3-(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.71 (s, 1H), 7.64-7.59 (m, 4H), 7.52 (d, J=7.7, 1H), 7.44 (t, J=7.7, 1H), 7.33 (td, J=7.6, 4.7, 4H), 7.25-7.21 (m, 4H), 5.09 (s, 1H), 3.51 (q, J=13.5, 2H), 3.02 (dd, J=12.9, 5.5, 1H), 2.63-2.54 (m, 1H), 2.51 (dd, J=8.8, 2.8, 1H), 2.47-2.41 (m, 1H), 2.37 (t, J=8.0, 1H), 2.32-2.25 (m, 2H), 1.98 (td, J=11.4, 5.6, 1H), 1.89 (ddd, J=12.7, 10.4, 5.8, 1H), 1.45 (ddd, J=14.7, 11.9, 8.1, 1H), 1.32-1.23 (m, 1H); MS (ESI+) m/z 451 (M+H)+.
Reaction SMILES: C(O)=[O:2].CCN(CC)CC.C(O)=O.CCN(CC)CC.O=[C:22]([CH2:27][C:28]1[S:29][CH:30]=[CH:31][CH:32]=1)[C:23]([O:25][CH3:26])=[O:24]>ClCCl>[OH:2][C@H:27]([C:28]1[S:29][CH:30]=[CH:31][CH:32]=1)[CH2:22][C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)C(=O)Cc1cccs1
Reactant: O=CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C[C@H](O)c1cccs1
Temperature: 36 °C
Reaction time: 0.33 h

Procedure:
In a 1 l multinecked flask equipped with a sparging stirrer, reflux condenser and internal thermometer, an HCOOH/Et3N mixture (molar ratio 1:1) is prepared by gradually adding 41 ml of HCOOH dropwise within 20 min to 152 ml of Et3N with stirring and ice cooling. 190 g of methyl 2-oxo-3-(2-thienyl)propionate are added to this biphasic mixture, the homogeneous yellow solution is admixed with 0.1 l of dichloromethane and the entire mixture is degassed by passing through argon for 20 min. It is heated to 36° C. and the dark red catalyst solution is added all at once to the reaction mixture with vigorous stirring. Stirring is effected at 800 rpm while passing argon through the reaction mixture for 14 h.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].[O:19]1[CH2:21][CH:20]1[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:21][CH:20]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[OH:19])[C:6]3[CH2:11][CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: c1cc(C2CO2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCCc2c(c3cc(Cl)ccc3n2CC(O)c2ccncc2)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 9-chloro-2-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indole (1 g, 4.273 mmol) in DMF was added NaH (512 mg, 12.81 mmol) in portions at 0° C. After stirring the reaction mixture at 0° C. for 15 min, a solution of 4-(oxiran-2-yl)pyridine (775 mg, 6.409 mmol) in DMF (1 mL) was added dropwise into the mixture at the same temperature and stirring continued at RT overnight. The progress of reaction was monitored by TLC and LCMS. After completion, ice water was added into the reaction mixture and extracted with EtOAc (3×50 mL). The organic layer was washed with water (5×50 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography using 10% MeOH/DCM as eluent followed by recrystallization with MeOH and acetonitrile to yield 2-(9-chloro-2-methyl-2,3,4,5-tetrahydroazepino[4,3-b]indol-6(1H)-yl)-1-(pyridin-4-yl)ethanol. 1H NMR (CDCl3, Free base) δ (ppm): 8.5 (d, 2H), 7.4 (s, 1H), 7.3 (d, 2H), 7.19 (d, 1H), 7.05 (d, 1H), 4.85 (dd, 1H), 4.18 (m, 2H), 3.8 (d, 1H), 3.65 (d, 1H), 3.0 (m, 2H), 2.8 (m, 1H), 2.69 (m, 1H), 2.42 (s, 3H), 1.85 (m, 2H). Separation by chiral HPLC provides enantiomers II-71a-b.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].[Cl:15][C:16]1[CH:21]=[C:20](I)[CH:19]=[CH:18][N:17]=1>>[Cl:15][C:16]1[CH:21]=[C:20]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=2)[CH:19]=[CH:18][N:17]=1
Reactant: Clc1cc(I)ccn1
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Product: COC(=O)CCc1ccc(C#Cc2ccnc(Cl)c2)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (104 mg, 0.55 mmol) and 2-chloro-4-iodopyridine (141 mg, 0.59 mmol) according to the general procedure IC to give 96 mg (58%) of a pale yellow solid after purification by flash chromatography (SiO2, EtOAc/hexanes, 1:5). Rf: 0.22 (EtOAc:hexanes, 1:5); 1HNMR (CDCl3) δ 8.36-8.35 (m, 1H), 7.48-7.45 (m, 2H), 7.42-7.41 (m, 1H), 7.29-7.26 (m, 1H), 7.24-7.21 (m, 2H), 3.67 (s, 3H), 3.01-2.96 (t, 2H, J=7.8 Hz), 2.67-2.62 (t, 2H, J=7.8 Hz); 13CNMR (CDCl3) δ 172.9, 151.7, 149.5, 142.4, 134.4, 132.1, 128.6, 125.9, 124.1, 95.4, 85.3, 51.8, 35.2, 30.8; EI-MS calcd for C17H15ClNO2 (M+): 299. found: 299.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[C:15](=[O:26])[N:16]([CH2:21][CH2:22][CH2:23][CH2:24]Br)[C:17](=[O:20])[CH2:18][O:19][C:13]=2[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[N:29][C:28]=1[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>O1CCOCC1>[CH2:1]([O:8][C:9]1[C:14]2[C:15](=[O:26])[N:16]([CH2:21][CH2:22][CH2:23][CH2:24][N:36]3[CH2:37][CH2:38][N:33]([C:28]4[N:27]=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:34][CH2:35]3)[C:17](=[O:20])[CH2:18][O:19][C:13]=2[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1COc2cccc(OCc3ccccc3)c2C(=O)N1CCCCBr
Reactant: c1cnc(N2CCNCC2)nc1
Solvent: C1COCCO1
Product: O=C1COc2cccc(OCc3ccccc3)c2C(=O)N1CCCCN1CCN(c2ncccn2)CC1
Yield: 79 %

Procedure:
A 202 mg amount of the compound of Example 13 was dissolved in 20 ml of dioxane, and 242 mg (3 equivalents) of 1-(2-pyrimidinyl)piperazine was added, followed by heating under reflux for 7 hours. The reaction treatment and purification were conducted as in Example 75, to give 195 mg of the desired compound (yield 79%). The maleic acid salt was obtained in a conventional manner.
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50].C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+].[Cl-].[C:70]([O:77][CH2:78][CH3:79])(=[O:76])[CH2:71][CH2:72][C:73]([O-])=[O:74].[Br-].C(OCC)(=O)CCC([O-])=O>CCOCC.O>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:42])[CH3:43])[C@H:35]2[O:44][C:73]([CH2:72][CH2:71][C:70]([O:77][CH2:78][CH3:79])=[O:76])=[O:74])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50]
Reactant: CCOC(=O)CCC(=O)[O-]
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)CCC(=O)O[C@H]1[C@H](O[C@@H]2[C@@H](C)[C@H](O[C@H]3C[C@@](C)(OC)[C@@H](O)[C@H](C)O3)[C@@H](C)C(=O)O[C@H](CC)[C@@](C)(O)[C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@]2(C)O)O[C@H](C)C[C@@H]1N(C)C
Temperature: 25 °C

Procedure:
The process for preparing erythromycin ethylsuccinate hydrate comprises: method A. in a reaction vessel, one or more of a C1-C6 lower alcohol, a C2-C6 lower nitrile, a C3-C8 lower ketone or C2-C8 lower ether is used as a solvent, to the solvent is added erythromycin, stirred at a temperature of 0-50° C. to dissolve erythromycin; to the solution is added sodium bicarbonate or sodium carbonate or potassium carbonate, and water, stirred, and cooled to 20° C. or below; to the cooled mixture is added monoethyl succinate halide, including monoethyl succinate chloride or monoethyl succinate bromide, allowed to react, and monitored by TLC until the reaction is complete; to the resultant is added an acid or a base to control the pH value at about 7.0-8.5; the organic phase is precipitated and separated; to the organic phase is added water, cooled to −20° C.-10° C.; upon the solid is precipitated completely, the mixture is filtered, the resulting solid is recrystalized with water and one or more of a C1-C6 lower alcohol, a C2-C6 lower nitrile, a C2-C8 lower ether, a C3-C8 lower ketone or C1-C6 lower halogenated hydrocarbons as solvent once or more times, cooled to −20° C.-10° C., filtered, dried to obtain erythromycin ethylsuccinate crystalline hydrate;
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][N:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][C:17]([O:19]CC2C=CC=CC=2)=[O:18])[C:10]1=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[C:1]([O:5][C:6]([CH2:8][N:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][C:17]([OH:19])=[O:18])[C:10]1=[O:27])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1c(=O)ccn(CC(=O)OCc2ccccc2)c1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Cn1c(=O)ccn(CC(=O)O)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of phenylmethyl 2-(3-{[(tert-butyl)oxycarbonyl]methyl}-2,4-dioxo-1,3-dihydropyrimidinyl)acetate (1.2) in ethyl acetate (20 ml) was added 20 wt. % palladium hydroxide (50 mg). After stirring the mixture at room temperature under a hydrogen atmosphere for 1 hour, the catalyst was removed by filtration. The filtrate was evaporated under reduced pressure to give 2-(3-{[(tert-butyl)oxycarbonyl]methyl}-2,4-dioxo-1,3-dihydropyrimidinyl)acetic acid as a white powder.
Reaction SMILES: C([NH:4][CH:5]([CH:9]1[CH2:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:6]([OH:8])=[O:7])(=O)C.[ClH:17]>>[ClH:17].[NH2:4][CH:5]([CH:9]1[CH2:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:6]([OH:8])=[O:7]
Reactant: CC(=O)NC(C(=O)O)C1Cc2ccccc21
Agent: Cl
Product: NC(C(=O)O)C1Cc2ccccc21
Yield: 100.1 %

Procedure:
A mixture of #100 (200 mg, 0.912 mmol, 1 eq.) and 6 N aqueous hydrochloric acid (12.3 mL, 73.8 mmol, 81 eq.) was heated at reflux overnight. The reaction mixture was concentrated in vacuo to give the single enantiomer #101 (195 mg) as an off-yellow solid, which was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:30])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]23[CH2:29][CH:24]4[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]4)[CH2:21]2)[CH2:27]3)=[CH:16][CH:15]=1.Cl.C(OCC)(=O)C>O1CCOCC1.O>[C:20]12([C:17]3[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:11]([NH:10][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[C:3]([OH:31])=[O:2])=[O:30])=[CH:15][CH:16]=3)[CH2:29][CH:24]3[CH2:23][CH:22]([CH2:28][CH:26]([CH2:25]3)[CH2:27]1)[CH2:21]2
Reactant: COC(=O)c1ccccc1NC(=O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1ccccc1C(=O)O
Reaction time: 8 h
Yield: 65.2 %

Procedure:
A solution of 2-[2-(4-Adamantan-1-yl-phenoxy)-acetylamino]-benzoic acid methyl ester (30.5 mg, 0.07 mmol) in 1,4-dioxane/H2O (3:1, 3 mL) added LiOHH2O (8.4 mg, 0.2 mmol) at room temperature. The resulting mixture was stirred overnight, and then acidified with 10% HCl to PH 2. Ethyl acetate was added and the organic layer was separated. The organic layer was washed with water, and dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (n-Hexane:EtOAc:MeOH=6:3:1) to gave 2-[2-(4-Adamant-1-yl-phenoxy)-acetylamino]-benzoic acid as a white solid (18.5 mg, 62.5% yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12](C2C=CC=C(Cl)C=2)=[C:11]2[C:6]([N:7]([CH3:23])[C:8](=[O:22])[N:9]([CH3:21])[C:10]2=[O:20])=[CH:5]1.Br[C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[CH:26]=1>>[NH2:1][CH2:2][CH2:3][N:4]1[C:12]([C:25]2[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[CH:26]=2)=[C:11]2[C:6]([N:7]([CH3:23])[C:8](=[O:22])[N:9]([CH3:21])[C:10]2=[O:20])=[CH:5]1
Reactant: Cc1cc(C)cc(Br)c1
Reactant: Cn1c(=O)c2c(-c3cccc(Cl)c3)n(CCN)cc2n(C)c1=O
Product: Cc1cc(C)cc(-c2c3c(=O)n(C)c(=O)n(C)c3cn2CCN)c1

Procedure:
The title compound was prepared analogously to Intermediate B by replacing 1-bromo-3-chlorobenzene with 1-bromo-3,5-dimethylbenzene;
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:15]2[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:14]=2[N:13]=[C:12]1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([NH2:30])[CH:23]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[S:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[S:42](Cl)(=[O:44])=[O:43]>O>[CH2:1]([O:8][C:9]([N:11]1[C:15]2[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:14]=2[N:13]=[C:12]1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([NH:30][S:42]([C:38]2[S:37][CH:41]=[CH:40][CH:39]=2)(=[O:44])=[O:43])[CH:23]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: COc1ccc(-c2nc3cc(Cl)c(Cl)cc3n2C(=O)OCc2ccccc2)cc1N
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(-c2nc3cc(Cl)c(Cl)cc3n2C(=O)OCc2ccccc2)cc1NS(=O)(=O)c1cccs1
Reaction time: 8 h

Procedure:
2-(3-Amino-4-methoxy-phenyl)-5,6-dichloro-benzoimidazole-1-carboxylic acid benzyl ester from Step C was mixed with pyridine (5 mL) and 2-thienylsulfonyl chloride (0.1283 g, 0.7 mmol) was added. The mixture was allowed to stand overnight. Water (100 mL) was added to the reaction mixture and the product crystallized within 5 hours. The solid was then collected by filtration and triturated with 1/1, hexanes/ethyl acetate (0.2 g), mp 195-198° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21]4[C:22](=O)[CH2:23][N:24]([CH3:28])[S:25](=[O:27])(=[O:26])[C:20]=4[CH:19]=[CH:18]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.[NH2:31][OH:32]>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21]4[C:22](=[N:31][OH:32])[CH2:23][N:24]([CH3:28])[S:25](=[O:27])(=[O:26])[C:20]=4[CH:19]=[CH:18]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CN1CC(=O)c2c(ccn2CCCN2CCN(c3ccc(F)cc3)CC2)S1(=O)=O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CN1CC(=NO)c2c(ccn2CCCN2CCN(c3ccc(F)cc3)CC2)S1(=O)=O
Temperature: 60 °C
Reaction time: 21 h
Yield: 82.7 %

Procedure:
A suspension of 168 mg (0.4 mmol) of Compound 25 and 111 mg (1.6 mmol) of hydroxylamine hydrochloride in 10 ml of pyridine was stirred for 21 hours over an oil bath of 60° C. Post-treatment was conducted in a similar manner as in Example 18. The residue was purified by chromatography on a silica gel column (eluent: methanol/chloroform=1/99), whereby 144 mg of the title compound were obtained (yield: 83%).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([CH3:29])=[C:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[C:10]([O:17][CH:18]([CH3:20])[CH3:19])=[N:11]2.CO.[OH-].[Na+]>C(O)=O>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:30])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([O:17][CH:18]([CH3:20])[CH3:19])[C:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[C:8]2[CH3:29]
Reactant: COC(=O)COc1ccc(Cl)c2nc(OC(C)C)c(Cc3ccc(F)cc3)c(C)c12
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: CO
Product: Cc1c(Cc2ccc(F)cc2)c(OC(C)C)nc2c(Cl)ccc(OCC(=O)O)c12

Procedure:
A solution of [8-chloro-3-(4-fluorobenzyl)-2-isopropoxy-4-methylquinolin-5-yloxy]acetic acid methyl ester (0.020 g), methanol (1.0 mL) and 1.0 M aqueous sodium hydroxide solution (0.25 mL) was stirred at room temperature for 3 hours. The pH of the solution was adjusted to 5 by the addition of formic acid and the solvent removed under reduced pressure. Purification of the residue by preparative reverse-phase HPLC using a gradient over 30 minutes of acetonitrile in water (30% to 90% of organic modifier) gave title compound as a white solid, 0.0085 g.