Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:20]O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:8][CH2:9][C:10]([O:12][CH3:20])=[O:11])=[O:7])=[CH:13][CH:14]=1
Reactant: CO
Reactant: O=C(O)CCC(=O)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)CCC(=O)c1ccc(F)cc1

Procedure:
A solution of 3-(p-fluorobenzoyl)propionic acid (58.8 g.) in anhydrous methanol (250 ml.) was treated with concentrated sulphuric acid (3.2 ml.) and the mixture heated at reflux temperature for 10 hours. It was then concentrated to a volume of 100 ml., cooled and diluted with ice-water. The resultant solid was collected and crystallised from ligroin to yield the ester (59.7 g.), m.p. 48°-50 ° C.
Reaction SMILES: [CH3:1][N:2]([C:13]1[N:14]=[N:15][C:16](N2CCOCC2)=[CH:17][CH:18]=1)[N:3]=[C:4]1[CH2:9][CH:8]2[C:10]([CH3:12])([CH3:11])[CH:5]1[CH2:6][CH2:7]2.[ClH:25]>C(Cl)(Cl)Cl>[CH3:1][N:2]([C:13]1[N:14]=[N:15][C:16]([Cl:25])=[CH:17][CH:18]=1)[N:3]=[C:4]1[CH2:9][CH:8]2[C:10]([CH3:12])([CH3:11])[CH:5]1[CH2:6][CH2:7]2
Reactant: CN(N=C1CC2CCC1C2(C)C)c1ccc(N2CCOCC2)nn1
Reactant: Cl
Solvent: ClC(Cl)Cl
Product: CN(N=C1CC2CCC1C2(C)C)c1ccc(Cl)nn1
Yield: 65 %

Procedure:
A mixture of 32.9 g (0.1 moles) of 1,7,7-trimethyl-2-bicyclo(2,2,1)heptylidene-(6-morpholino-3-pyridazinyl)-hydrazine (prepared by the process of Example 8, Step b), 660 ml of chloroform and 660 ml of concentrated hydrochloric acid is heated at 60° while stirring under a nitrogen atmosphere for 6 hours in such a way that the chloroform layer is separated from the reaction mixture every hour and replaced by fresh solvent (660 ml). The camphor recovered can be condensed with 6-chloro-3-pyridazinylhydrazine to give pure 1,7,7-trimethyl-2-bicyclo(2,2,1)heptylidene-(6-chloro-3-pyridazinyl)-hydrazine in 65-72% yield.
Reaction SMILES: O[CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)=[O:9].[CH2:26]([C@@H:28]1[CH2:32][CH2:31][CH2:30][NH:29]1)[CH3:27]>>[CH2:26]([C@@H:28]1[CH2:32][CH2:31][CH2:30][N:29]1[CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)=[O:9])[CH3:27]
Reactant: O=C(c1ccc(-c2ccc(C(F)(F)F)cc2)cc1)N1CCC[C@H]1CO
Reactant: CC[C@@H]1CCCN1
Product: CC[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure RR starting from (2-(S)-hydroxymethyl-pyrrolidin-1-yl)-(4′-trifluoromethyl-biphenyl-4-yl)-methanone and 2-(R)-ethyl-pyrrolidine (CAS 460748-80-5) MS (M+H) 431.3.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C([O-])([O-])=O.[K+].[K+].Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC#N>[CH2:17]([N:2]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@@H:3]([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)[C@H](C)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)[C@H](C)N(Cc1ccccc1)Cc1ccccc1
Temperature: 70 °C
Reaction time: 14 h
Yield: 98.6 %

Procedure:
To a solution of (S)-ethyl 2-aminopropanoate hydrochloride (4.59 g, 30.0 mmol) and K2CO3 (12.4 g, 90.0 mmol) in MeCN was added (bromomethyl)benzene (12.9 g, 75.0 mmol) at RT. The mixture was stirred at 70° C. for 14 h. The reaction mixture was quenched with aq. NH4Cl. After concentration, the aqueous layer was extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (100:1) to afford 8.8 g (98%) of (S)-ethyl 2-(dibenzylamino)propanoate (26): LCMS (ESI) m/z: 298.2 [M+11]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[N:15][N:14]=[N:13]2)=[CH:8][C:4]=1[C:5](O)=[O:6].C(Cl)(=O)C([Cl:20])=O>CN(C)C=O.ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[N:15][N:14]=[N:13]2)=[CH:8][C:4]=1[C:5]([Cl:20])=[O:6]
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(-n2cnnn2)cc1C(=O)Cl
Reaction time: 4 h

Procedure:
Combine 2-methoxy-5-(1H-tetrazol-1-yl)benzoic acid (1.2 g, 5.5 mmol) and dichloromethane (40 mL). Add dropwise oxalyl chloride (0.72 mL, 8.25 mmol) followed by dimethylformamide (3 drops). After 4 hours, evaporate in vacuo and dry to give the title compound.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:13])=O>>[I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:13])=[O:5]
Reactant: O=C(O)c1ccccc1I
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccccc1I

Procedure:
Ortho-iodobenzoic acid was reacted with excess thionyl chloride for 3 hours at reflux, and thionyl chloride was distilled off under reduced pressure to obtain ortho-iodobenzoic acid chloride. This was reacted with allyl alcohol in a dichloromethane solvent in the presence of a triethyl amine catalyst to obtain allyl ortho-iodobenzoate. The yield after purification by distillation or like process was repeated was 73%.
Reaction SMILES: [CH:1]1([N:4]([CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([CH3:51])[C:46]=2[CH3:52])[C:5]([CH:7]([CH:17]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][O:34][C:35]3[C:40]([Cl:41])=[CH:39][C:38]([CH3:42])=[CH:37][C:36]=3[Cl:43])=[CH:27][CH:26]=2)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:8][NH:9]C(=O)OC(C)(C)C)=[O:6])[CH2:3][CH2:2]1.Cl>C(Cl)Cl>[NH2:9][CH2:8][CH:7]([CH:17]([C:25]1[CH:26]=[CH:27][C:28]([O:31][CH2:32][CH2:33][O:34][C:35]2[C:40]([Cl:41])=[CH:39][C:38]([CH3:42])=[CH:37][C:36]=2[Cl:43])=[CH:29][CH:30]=1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[C:5]([N:4]([CH:1]1[CH2:3][CH2:2]1)[CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([CH3:51])[C:46]=1[CH3:52])=[O:6]
Reactant: Cc1cc(Cl)c(OCCOc2ccc(C(Cc3ccccn3)C(CNC(=O)OC(C)(C)C)C(=O)N(Cc3cccc(C)c3C)C3CC3)cc2)c(Cl)c1
Agent: Cl
Solvent: ClCCl
Product: Cc1cc(Cl)c(OCCOc2ccc(C(Cc3ccccn3)C(CN)C(=O)N(Cc3cccc(C)c3C)C3CC3)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a CH2Cl2 solution (0.03 M) of tert-butyl (2-{[cyclopropyl(2,3-dimethylbenzyl)amino]carbonyl}-3-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-4-pyridin-2-ylbutyl)carbamate from the previous step (1 eq.) was added HCl (4.0 M dioxane solution, 30 eq.). The resulting solution was stirred at RT for 4 h. Following the removal of the volatiles in vacuo, the resulting residue was directly loaded onto a SiO2 column packed with 95:5 (v/v) CH2Cl2:2.0 M NH3 in MeOH. Elution with the same solvent system furnished the title compound as a white froth. Diastereomer A: MS (ESI+): 646.0. Diastereomer B: MS (ESI+): 646.0.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH2:20][CH:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)=[O:18])=[CH:12][CH:11]=2)=[C:4]([NH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[N:3]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][C:17]([O:19][CH2:20][CH:21]3[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]3)=[O:18])=[CH:14][CH:15]=2)=[C:4]([NH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[N:3]=1
Reactant: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)OCC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To the product of step (i) (237 mg) in DCM (7 ml), TFA (2 ml) was added and stirred at rt for 7 h. The solvent was removed and the crude product was partitioned between DCM/NaHCO3 (aq), dried and evaporated under reduced pressure. The residue was purified by RPHPLC to give a white solid, 54 mg.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)=[O:3].[CH2:11](Cl)[C:12]#[CH:13].C(N(C(C)C)CC)(C)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH2:13]([NH:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=1)[C:12]#[CH:11]
Reactant: C#CCCl
Reactant: CC(=O)c1ccc(N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: C#CCNc1ccc(C(C)=O)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
A mixture of 25 g (0.185 mol) of 4-aminoacetophenone, 12.7 ml (0.176 mol) of propargyl chloride, and 35 ml of diisopropylethylamine in 500 ml of dry toluene is stirred at 60° C. for eight hours then at 90° C. for twenty-four hours. The reaction is cooled to room temperature and poured into a saturated sodium bicarbonate solution. The organic portion is separated and concentrated in vacuo to an orange oil. The oil is chromatographed on silica gel eluting with a gradient of 20-50% ethyl acetate in hexane. The appropriate fractions are concentrated to leave a pale yellow solid. The solid is recrystallized from ethanol to give two crops of the desired product, 14.99 g (49% yield); mp 97°-100° C.
Reaction SMILES: [C:1]([C:4]([NH:13][C:14]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[C:18]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:17]=1)=O)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:5][CH3:6])(=[O:3])[NH2:2].CO[Na].Cl>CO>[CH2:5]([C:4]1([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:1](=[O:3])[NH:2][C:14]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[C:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:17]=2)=[N:13]1)[CH3:6]
Reactant: CCC(NC(=O)c1cc(-c2ccccc2)nc2ccccc12)(C(N)=O)c1ccccc1
Agent: CO[Na]
Agent: Cl
Solvent: CO
Product: CCC1(c2ccccc2)N=C(c2cc(-c3ccccc3)nc3ccccc23)NC1=O

Procedure:
A mixture of N-(1-Carbamoyl-1-phenylpropyl)-2-phenyl-4-quinolinecarboxamide (100 mg, 0.24 mmol) and MeONa (13.2 mg, 0.24 mmol) in 5 mL of MeOH is refluxed for 4 hours. After cyclization is complete, the mixture is cooled and neutralized with HCl in MeOH and solvent is evaporated. The residue is washed with water and dried. Trituration with ethyl acetate affords the corresponding compound as a white solid.
Reaction SMILES: [F:1][C:2]1[C:3]([CH:8]=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[C:3](/[CH:8]=[N:18]/[C:15]2[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N)cc1
Reactant: O=Cc1ncccc1F
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(/N=C/c2ncccc2F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.7 %

Procedure:
3-Fluoro-2-formylpyridine (229 g) and paraanisidine (225 g) were dissolved in toluene (2.29 l). After adding anhydrous sodium sulfate (334 g), the mixture was stirred at room temperature for 1 hour. After filtering off the insoluble matters, the liquid reaction mixture was concentrated under reduced pressure to thereby give the title compound (449 g).
Reaction SMILES: [CH:1]([CH2:3][C:4]([OH:6])=[O:5])=[CH2:2].[CH3:7][C:8]1[CH:17]=[C:16]([CH2:18][O:19][C:20]2[CH:28]=[CH:27][C:23]([CH:24]=[N:25][OH:26])=[CH:22][CH:21]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1>C1COCC1>[CH3:7][C:8]1[CH:17]=[C:16]([CH2:18][O:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]3[CH2:2][CH:1]([CH2:3][C:4]([OH:6])=[O:5])[O:26][N:25]=3)=[CH:27][CH:28]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: Cc1cc(COc2ccc(C=NO)cc2)c2ccccc2n1
Reactant: C=CCC(=O)O
Solvent: C1CCOC1
Product: Cc1cc(COc2ccc(C3=NOC(CC(=O)O)C3)cc2)c2ccccc2n1
Reaction time: 8 h
Yield: 99.6 %

Procedure:
A solution of Clorox® was added dropwise (1 mL) to a solution of vinyl acetic acid (0.071 g, 0.8 mmol) and 4-(2-methyl-quinolin-4-ylmethoxy)-benzaldehyde oxime (0.12 g, 0.40 mmol) in THF (4 mL) under nitrogen atmosphere at room temperature. The reaction was stirred overnight, partitioned between ethyl acetate and water saturated KH2PO4 solution. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give {3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-4,5-dihydro-isoxazol-5-yl}-acetic acid (0.15 g, 100%) as a crude solid. MS found: (M+H)+=377.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[O:8][CH2:7][C@@H:6]([N:9]2[C:13]3=[C:14]4[S:20][CH:19]=[CH:18][C:15]4=[N:16][CH:17]=[C:12]3[N:11]=[C:10]2[C@@H:21]([OH:23])[CH3:22])[CH2:5][CH2:4]1.N1C=CC=CC=1.[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:40][C:30]1[CH:35]=[CH:34][C:33]([S:36]([O:1][CH2:2][C@H:3]2[CH2:4][CH2:5][C@H:6]([N:9]3[C:13]4=[C:14]5[S:20][CH:19]=[CH:18][C:15]5=[N:16][CH:17]=[C:12]4[N:11]=[C:10]3[C@@H:21]([OH:23])[CH3:22])[CH2:7][O:8]2)(=[O:38])=[O:37])=[CH:32][CH:31]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CO)OC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H](n3c([C@H](C)O)nc4cnc5ccsc5c43)CO2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.8 %

Procedure:
To a solution of (1S)-1-{1-[(3S,6R)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}ethanol (48.0 mg, 0.144 mmol) in methylene chloride (2.09 mL) and pyridine (70.4 μL, 0.871 mmol) was added p-toluenesulfonyl chloride (35.0 mg, 0.184 mmol) and 4-dimethylaminopyridine (1.1 mg, 0.0092 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, diluted with methanol, and purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product as white solid (42 mg, 60%). LCMS calculated for C23H26N3O5S2 (M+H)+: m/z=488.1. Found: 488.1.
Reaction SMILES: ClC1C=CC2[N:6]=C(N)N=C(OCC)C=2N=1.[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:6])=[CH:19][CH:18]=1
Reactant: CCOc1nc(N)nc2ccc(Cl)nc12
Reactant: O=Cc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
A mixture of 6-chloro-4-ethoxy-pyrido[3,2-d]pyrimidin-2-ylamine (0.22 g), 4-fluorobenzaldehyde (2.0 mmol), acetic acid 5.0 mmol) and molecular sieves (10 mg) in DCE (3 mL) was stirred at room temperature for 30 minutes. NaBH(OAc)3 was added portion by portion. The mixture was stirred for 16 hours, and then quenched by adding saturated aqueous NaHCO3. The solution was partitioned with DCM. The organic layer was dried over Na2SO4 and concentrated to afford the crude product which was purified by flash chromatography using hexane/ethyl acetate as eluting solvent. 0.33 g of 6-chloro-4-ethoxy-pyrido[3,2-d]pyrimidin-2-yl)-(4-fluoro-benzyl)-amine (Example 61) was obtained (yield: 50%) as a white solid which was characterized by its mass spectrum as follows: MS (m/z) 333.1 [M+H]+.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[C:27]([O:31][C:32]([NH:34][CH2:35][C:36]([NH:38][CH2:39][C:40]1[CH:41]=[C:42]([CH:44]=[CH:45][CH:46]=1)[NH2:43])=[O:37])=[O:33])([CH3:30])([CH3:29])[CH3:28].[OH-].[Na+]>CN(C=O)C.CO>[C:27]([O:31][C:32]([NH:34][CH2:35][C:36]([NH:38][CH2:39][C:40]1[CH:41]=[C:42]([NH:43]/[C:16](=[C:6]2\[C:5](=[O:26])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:44]=[CH:45][CH:46]=1)=[O:37])=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)NCc1cccc(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)NCc1cccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)c1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 3-tert.butoxycarbonylaminomethylcarbonylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[Ca+2].[Cl-]>C(O)C>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][S:10][C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(SCc2ccccn2)cc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Product: Nc1ccc(SCc2ccccn2)cc1
Temperature: 25 °C
Yield: 66.3 %

Procedure:
To 2-[[(4-nitrophenyl)sulfanyl]methyl]pyridine (6.7 g) were added 85% ethanol solution (203 ml), and to this mixture was added calcium chloride (1.53 g) and reduced iron (7.68 g), and the mixture was heated to reflux for 16 hours. After allowing the mixture to be cooled to room temperature, ethanol was removed under reduced pressure, and the obtained residue was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 4-[(2-pyridinylmethyl)sulfanyl]aniline (3.9 g).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[CH:11]=[CH:10][C:4]=1[C:5](=[NH:9])OCC.Cl.N[CH2:24][C:25]([NH:31]Cl)([CH3:30])[C:26]([O:28][CH3:29])=[O:27].CCN(CC)CC>CO>[OH:2][C:3]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[CH:11]=[CH:10][C:4]=1[C:5]1[NH:9][CH2:24][C:25]([CH3:30])([C:26]([O:28][CH3:29])=[O:27])[N:31]=1
Reactant: CCOC(=N)c1ccc(OCCOCCOC)cc1O
Reactant: COC(=O)C(C)(CN)NCl
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COCCOCCOc1ccc(C2=NC(C)(C(=O)OC)CN2)c(O)c1
Yield: 49.7 %

Procedure:
To a solution of ethyl 2-hydroxy-4-(2-(2-methoxyethoxy)ethoxy)benzimidate hydrochloride (0.35 g, crude, ˜1.0 mmol) in MeOH (10 mL) was added methyl 3-amino-2-(chloroamino)-2-methylpropanoate hydrochloride (0.24 g, crude, ˜1.0 mmol) followed by dropwise addition of Et3N (1 mL) at 0° C. The resulting solution was refluxed overnight. The solvent was evaporated under vacuum and the residue was purified by prep-HPLC to obtain the title compound as colorless oil (175 mg, 50%). LC-MS (ES, m/z): 353 [M+H]+.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([CH3:22])[CH2:7][CH:8]([NH:18][C:19](=[O:21])[CH3:20])[C:9]1[S:10][C:11]([C:14]#[C:15][CH2:16][OH:17])=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[Cl:23][C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1.C(OC(N=NC(OCC)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[C:1]([O:4][CH2:5][C@H:6]([CH3:22])[CH2:7][CH:8]([NH:18][C:19](=[O:21])[CH3:20])[C:9]1[S:10][C:11]([C:14]#[C:15][CH2:16][O:17][C:27]2[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=2)=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(=O)NC(C[C@@H](C)COC(C)=O)c1ccc(C#CCO)s1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)NC(C[C@@H](C)COC(C)=O)c1ccc(C#CCOc2ccc(Cl)cc2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.1 %

Procedure:
(2R)-Acetylamino-2-methyl-4-[5-(3-hydroxypropynyl)thiophen-2-yl]butyl acetate (285 mg, 0.88 mmol) obtained in Example 52(a) and 4-chlorophenol (136 mg, 1.06 mmol) were dissolved in anhydrous tetrahydrofuran (5 ml), and then azodicarboxylic acid diethylester (230 mg, 1.32 mmol) and triphenylphosphine (346 mg, 1.32 mmol) were added thereto in an ice bath followed by stirring for 4 hours at room temperature. Into the reaction mixture was poured water, and the resulting solution was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a silica gel column (elution solvent; hexane:ethyl acetate=2:1-1:3) to give (2R)-acetylamino-2-methyl-4-{5-[3-(4-chlorophenoxy)propynyl]thiophen-2-yl}butyl acetate (195 mg, 51% yield) as a yellow oil. This product was dissolved in 6 ml of a mixture solvent (tetrahydrofuran:methanol:water=1:1:1), and lithium hydroxide monohydrate (370 mg, 8.82 mmol) was added thereto followed by stirring for 6 hours at 50° C. The reaction solution was poured into water, extracted with dichloromethane, and after the dichloromethane layer was dried over anhydrous sodium sulfate, the solvent was evaporated in vacuo. The residue (175 mg, 0.50 mmol) was dissolved in ethyl acetate (5 ml), and oxalic acid (45 mg, 0.50 mmol) was added thereto to precipitate crystals. The crystals were filtered off to afford the title compound (198 mg, 86% yield) as white crystals.
Reaction SMILES: C(N[C:6]([NH:8][S:9]([CH2:12][C:13]1[C:22]([S:23]([N:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])=[CH:21][CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16])(=[O:11])=[O:10])=[O:7])CCC.N12CCN(CC1)CC2.C(Cl)(Cl)=O>>[CH3:27][N:26]([S:23]([C:22]1[CH:21]=[CH:20][CH:19]=[C:14]([C:15]([O:17][CH3:18])=[O:16])[C:13]=1[CH2:12][S:9]([N:8]=[C:6]=[O:7])(=[O:11])=[O:10])(=[O:25])=[O:24])[CH3:28]
Reactant: CCCCNC(=O)NS(=O)(=O)Cc1c(C(=O)OC)cccc1S(=O)(=O)N(C)C
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)Cl
Product: COC(=O)c1cccc(S(=O)(=O)N(C)C)c1CS(=O)(=O)N=C=O

Procedure:
A suspension of 7.4 g of the product from Example 15 and 0.1 g of 1,4-diazabicyclo[2.2.2]octane in 100 ml xylenes was heated to reflux temperature. To this solution was added 1.5 ml of phosgene at a rate that maintained the temperature above 130°. When the addition was complete, the turbid solution was heated at reflux temperature for about one hour, allowed to cool, and then filtered under an atmosphere of nitrogen. Removal of the solvent from the filtrate gave the product as a dark oil which was dissolved in dry methylene chloride and carried on to the next step without purification. The infrared spectrum of this intermediate displayed a characteristic isocyanate absorption at 2240 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:27]=[CH:28][C:29]=2[CH3:30])[CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([NH:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[CH:25]=[C:26]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:27]=[CH:28][C:29]=3[CH3:30])[CH2:20][CH2:19]2)=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C)(C(=O)O)c1ccc(Cl)cc1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C(C)(C)c2ccc(Cl)cc2)CC1

Procedure:
Example 91 was prepared from 2-(4-chlorophenyl)-2-methylpropanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.41–7.27 (m, 7H), 7.09 (d, 1H, J=8.0 Hz), 6.59 (br s, 1H), 3.34 (dd, 2H, J=6.4, 12.0 Hz), 2.93 (d, 2H, J=11.6 Hz), 2.64 (m, 1H), 2.54 (m, 1H), 2.37 (t, 2H, J=6.4 Hz), 2.28 (s, 3H), 1.98 (t, 2H, J=12.4 Hz), 1.71–1.64 (m, 4H), 1.59 (s, 6H), 1.61–1.55 (m, 2H), 1.28 (d, 6H, J=6.8 Hz); ESMS m/e: 498.3 (M+H)+.
Reaction SMILES: C[CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1F)[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[C:22](=O)([O-])[O-].[Na+].[Na+]>CO>[C:10]1([C:3]2([C:7]([O:9][CH3:22])=[O:8])[CH2:4][CH2:5][CH2:6][CH2:2]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: CC1CCCC1(C(=O)O)c1ccccc1F
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1(c2ccccc2)CCCC1

Procedure:
To a solution of methyl 1-(2-fluorophenyl)cyclopentanecarboxylic acid (10 g, 52.56 mmol) in anhydrous methanol was added 1 mL of the concentration of sulfuric acid. The mixture was refluxed for overnight. The mixture was neutralized to pH 4-5 with sodium carbonate. The solvent was evaporated. The residue was dissolved in ethyl acetate (50 mL), washed with brine (3×10 mL), dried over MgSO4. The crude product was used for the next reaction without further purification.