Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][CH:9]([CH3:11])[CH3:10])(=O)=O.[O:12]=[C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[N:14]1[NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(OCC)(=O)C.O>[O:22]=[C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13](=[O:12])[N:14]1[N:23]([CH2:6][CH2:7][O:8][CH:9]([CH3:10])[CH3:11])[C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29]
Reactant: CC(C)OCCOS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)NN1C(=O)c2ccccc2C1=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CC(C)OCCN(C(=O)OC(C)(C)C)N1C(=O)c2ccccc2C1=O
Temperature: 50 °C
Yield: 83 %

Procedure:
A round bottom flask charged with 2-isopropoxyethyl methanesulfonate (example 77A, 0.791 g, 4.34 mmol) in acetonitrile (21.70 mL) was stirred under an atmosphere of nitrogen. tert-Butyl 1,3-dioxoisoindolin-2-ylcarbamate (1.138 g, 4.34 mmol) was added along with potassium carbonate (2.399 g, 17.36 mmol) and benzyltriethylammonium chloride (0.198 g, 0.868 mmol). The reaction mixture was heated at 50° C. 24 h and cooled to rt over the weekend. The reaction mixture was diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organics were washed with brine, dried over anhydrous sodium sulfate, vacuum filtered through a plug of silica gel and concentrated in vacuo. The crude oil was used without additional purification (1.26 g, 83% yield).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[C:6]([O:10][C:11](=[O:24])[NH:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>C(Cl)Cl>[C:6]([O:10][C:11](=[O:24])[NH:12][CH2:13][CH2:14][N:15]([C:3](=[O:4])[CH2:2][Br:1])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: O=C(Br)CBr
Reactant: CC(C)(C)OC(=O)NCCNCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCN(CCc1ccccc1)C(=O)CBr
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
To a solution of bromoacetyl bromide (0.25 mL, 2.92 mmol) in CH2Cl2 (10 mL) at -10° C. was added a solution of 2-(phenylethylamino)ethyl carbamic acid tert-butyl ester (0.7 g, 2.65 mmol) and triethylamine (0.41 mL, 2.92 mmol) in CH2Cl2 (10 mL) dropwise. The mixture was stirred at -10° C. for 30 min, before removal of the solvent in vacuo. The residue was partitioned between EtOAc (2×30 mL) and water (30 mL). The combined organic layers were dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel, eluting with petrol:EtOAc (2:1→1:1), to afford the title amide (0.81 g, 79%) as a colourless oil. 1H NMR (250 MHz, CDCl3) δ 1.44 (9H, s), 2.86-2.94 (2H, m), 3.10-3.94 (8H, m), 4.59 and 4.92 (1H, 2×br s), 7.15-7.37 (5H, m). MS (ES+) (385/387, M+).
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([C:7]([C@H:9]2[CH2:11][C@H:10]2[C:12](O)=[O:13])=O)=[CH:5][CH:4]=1)#[N:2].O.[NH2:18][NH2:19]>C(O)C>[C:1]([C:3]1[CH:16]=[CH:15][C:6]([C:7]2[CH:9]3[CH:10]([C:12](=[O:13])[NH:18][N:19]=2)[CH2:11]3)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)[C@H]2C[C@H]2C(=O)O)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(C2=NNC(=O)C3CC23)cc1
Yield: 66.4 %

Procedure:
2.45 g (11.4 millimoles) of cis-2-(p-cyanobenzoyl)-cyclopropanecarboxylic acid, 0.57 g (11.4 millimoles) of hydrazine hydrate and 50 ml of ethanol are refluxed for 6 hours. After filtering off the product at 10° C. and drying it under reduced pressure at 50° C., 1.6 g (67% of theory) of 2-(p-cyanophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one are obtained as ocher crystals which are identical with the compound from Example 39.
Reaction SMILES: [N:1]1[NH:2][C:3]([NH:6][C:7]2[CH:12]=[C:11](Cl)[N:10]=[C:9]([S:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([CH:24]4[CH2:26][CH2:25]4)=[O:23])=[CH:17][CH:16]=3)[N:8]=2)=[N:4][CH:5]=1.Cl.[CH:28]1([C:31]2([F:35])[CH2:34][NH:33][CH2:32]2)[CH2:30][CH2:29]1.CCN(C(C)C)C(C)C>O1CCOCC1>[N:1]1[N:2]=[C:3]([NH:6][C:7]2[CH:12]=[C:11]([N:33]3[CH2:34][C:31]([CH:28]4[CH2:30][CH2:29]4)([F:35])[CH2:32]3)[N:10]=[C:9]([S:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([CH:24]4[CH2:26][CH2:25]4)=[O:23])=[CH:17][CH:16]=3)[N:8]=2)[NH:4][CH:5]=1
Reactant: O=C(Nc1ccc(Sc2nc(Cl)cc(Nc3ncn[nH]3)n2)cc1)C1CC1
Reactant: FC1(C2CC2)CNC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Sc2nc(Nc3nnc[nH]3)cc(N3CC(F)(C4CC4)C3)n2)cc1)C1CC1
Yield: 10.7 %

Procedure:
Compound I-6 was prepared according to the procedure of compound I-1 using N-(4-(4-(2H-1,2,4-Triazol-3-ylamino)-6-chloropyrimidin-2-ylthio)phenyl)cyclopropanecarboxamide (140 mg, 0.36 mmol), 3-cyclopropyl-3-fluoroazetidine hydrochloride (62 mg), DiPEA (0.14 mL) in 1,4-dioxane (5 mL). After purification by column chromatography, the obtained material was further purified by preparative HPLC to yield 18 mg of desired product after evaporation and lyophilization, purity: 99+% (HPLC method A, Rf=8.466 minutes).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[C:14]([N:22]3[CH:26]=[N:25][N:24]=[N:23]3)[CH:13]=2)[S:5][C:6]=1[C:7]([O:9]CC)=[O:8].[OH-].[Na+].Cl.O>O1CCCC1.CO>[CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[C:14]([N:22]3[CH:26]=[N:25][N:24]=[N:23]3)[CH:13]=2)[S:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1sc(-c2ccc(OC(C)C)c(-n3cnnn3)c2)nc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-c2ccc(OC(C)C)c(-n3cnnn3)c2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
A reaction mixture solution prepared by dissolving 1.13 g of ethyl 4-methyl-2-[4-(propan-2-yloxy)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-1,3-thiazole-5-carboxylate in 15 mL of a mixed solution of tetrahydrofuran/methanol=1/1 and adding 3.0 mL of 2 M sodium hydroxide aqueous solution to the mixture was stirred at room temperature for 3 hours. After the addition of 3.0 mL of 2 M hydrochloric acid to the reaction solution under stirring, 7 mL of water was added and extraction was performed using 30 mL of ethyl acetate. The organic layer was concentrated, followed by purifying by a conventional method to obtain 920 mg of 4-methyl-2-[4-(propan-2-yloxy)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-1,3-thiazole-5-carboxylic acid.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([OH:9])[CH2:5][C:6]([CH3:8])=[CH2:7].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([C@@H:23]([NH2:25])[CH3:24])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([C@@H:23]([NH:25][CH2:2][CH2:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([OH:9])[CH2:5][C:6]([CH3:8])=[CH2:7])[CH3:24])=[CH:19][CH:18]=1
Reactant: C=C(C)CC(O)(CCCl)c1ccccc1
Reactant: C[C@H](N)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=C(C)CC(O)(CCN[C@@H](C)c1ccc(Br)cc1)c1ccccc1
Temperature: 96 °C
Yield: 60.1 %

Procedure:
1-chloro-5-methyl-3-phenylhex-5-en-3-ol (1.28 g, 5.7 mmol), (S)-1-(4-bromophenyl)ethanamine (1.37 g, 1.2 equiv), KI (995 mg, 1.05 equiv), K2CO3 (1.57 g, 2 equiv) were mixed with acetonitrile (15 mL) and heated to reflux (oil bath 96° C.) for overnight. After being cooled to rt, the mixture was filtered, concentrated, and purified by chromatography on a 40-g silica gel column, eluted with 0˜8% MeOH in CH2Cl2, to afford 1-((S)-1-(4-bromophenyl)ethylamino)-5-methyl-3-phenylhex-5-en-3-ol (1.33 g, 60%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([Cl:16])=[C:14]3[O:17][CH2:18][O:19][C:13]3=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:20].[C:21]1([CH2:27][C:28](=[NH:32])OCC)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[ClH:16].[Cl:20][C:11]1[CH:12]=[C:13]2[O:19][CH2:18][O:17][C:14]2=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:28](=[NH:32])[CH2:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=N)Cc1ccccc1
Reactant: Nc1ncccc1OCc1ccc2c(c1Cl)OCO2
Agent: Cl
Solvent: CCO
Product: N=C(Cc1ccccc1)Nc1ncccc1OCc1cc2c(cc1Cl)OCO2
Yield: 10.7 %

Procedure:
2-Amino-3-(6-chloro-4,5-methylenedioxybenzyloxy)pyridine (6 g, 21.6 mmol) and ethyl phenylacetimidate hydrochloride (5.17 g, 26 mmol) in ethanol (150 ml) were heated under reflux for 3 hrs. The solvent was evaporated and the residue purified by flash chromatography (silica, 1% methanol/dichloromethane), trituration with ether and recrystallisation from ethanol to give the tire compound (1.0 g), m.p. 189° C. (softening 170° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[C:20]([CH2:22][C:23](O)=[O:24])#[N:21].CCN=C=NCCCN(C)C.Cl>O.CN(C=O)C>[C:20]([CH2:22][C:23]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:18][CH:19]=2)=[CH:6][CH:7]=1)=[O:24])#[N:21]
Reactant: N#CCC(=O)O
Reactant: COC(=O)c1ccc(CCc2ccc(N)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCc2ccc(NC(=O)CC#N)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.8 %

Procedure:
To a mixture of 43.9 g of methyl 4-[2-(4-aminophenyl)ethyl]benzoate, 22.3 g of cyanoacetic acid, and 150 mL of DMF was added 49.5 g of WSC.hydrochloride under ice cooling. After the reaction mixture was stirred for 24 hours at room temperature, 450 mL of water was added thereto at room temperature, followed by stirring for 30 minutes at room temperature. Thereafter, the precipitate was collected by filtration, thereby obtaining 54.2 g of methyl 4-(2-{4-[(cyanoacetyl)amino]phenyl}ethyl)benzoate.
Reaction SMILES: [C:1]1([C:7]([NH:20][CH:21]2[C:37](=[O:38])[N:23]3[CH:24]([C:29](=O)[NH:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:25]([CH3:28])([CH3:27])[S:26][C@H:22]23)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.[N-:51]=[N+:52]=[N-:53].CN(C)C(=[NH2+])N(C)C>O.C(Cl)(Cl)Cl.C(Cl)Cl>[C:1]1([C:7]([NH:20][CH:21]2[C:37](=[O:38])[N:23]3[CH:24]([C:29]4[N:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:53]=[N:52][N:51]=4)[C:25]([CH3:27])([CH3:28])[S:26][C@H:22]23)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)NC(=O)C1N2C(=O)C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2SC1(C)C
Reactant: [N-]=[N+]=[N-]
Agent: CN(C)C(=[NH2+])N(C)C
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)n1nnnc1C1N2C(=O)C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2SC1(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 529 mg. (1 mmole) of 6-(triphenylmethylamino)-2,2-dimethyl-3-(N-[ethoxycarbonyl]carbamoyl)penam and 240 mg. (3 mmole) of pyridine, in 25 ml. of methylene chloride, is added 208 mg. (1 mmole) of phosphorus pentachloride, at 0° C. The reaction mixture is stirred at 0° C. for 0.5 hour and then at ca. 25° C. for 2 hours. The solvents and the excess pyridine are then removed by evaporation in vacuo, and the residue is re-dissolved in 15 ml. of chloroform. The latter chloroform solution is cooled to 0° C., and 0.47 g. (3 mmole) of tetramethylguanidinium azide is added in several small portions with stirring. Stirring is continued for 2 hours at ambient temperature, and then to the reaction mixture is added a further 15 ml. of chloroform followed by 30 ml. of water. The pH is adjusted to 6.5, and then the chloroform layer is removed. The chloroform solution is washed with water followed by brine, and then it is dried using anhydrous sodium sulfate. Removal of the solvent by evaporation in vacuo affords crude 6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[ethoxycarbonyl]tetrazol-5-yl)penam. The crude product is purified further by chromatography using silica gel.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([O:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([F:26])[C:23](Cl)=[N:24][C:17]=2[N:16]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)[C:15]1=[O:37])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(#N)C>[CH2:6]([O:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([F:26])[C:23]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:24][C:17]=2[N:16]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)[C:15]1=[O:37])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C1CCNC1
Reactant: O=c1c2cc(F)c(Cl)nc2n(-c2cccc(C(F)(F)F)c2)c(=O)n1OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=c1c2cc(F)c(N3CCCC3)nc2n(-c2cccc(C(F)(F)F)c2)c(=O)n1OCc1ccccc1
Yield: 76.1 %

Procedure:
Using the method of Example N-4, pyrrolidine (0.04 mL, 0.52 mmol), 3-benzyloxy-7-chloro-6-fluoro-1-(3-trifluoromethylphenyl)-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example V-2, 0.19 g, 0.42 mmol) and triethylamine (0.36 mL, 2.6 mmol) were combined in 20 mL of acetonitrile to give 0.16 g of the title compound as a solid, mp>250° C.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O-:16])[N:10]=[CH:9]2)C=CC=CC=1.[Na+].[Cl-].[CH3:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[CH2:31]([O:16][CH2:15][CH2:14][CH2:13][C:11]1[N:10]=[CH:9][NH:8][CH:12]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCC
Reactant: [O-]CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Cl-]
Agent: [Na+]
Product: CCCCCCCOCCCc1c[nH]cn1

Procedure:
5 mmol of sodium 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanolate and 5 mmol of heptane chloride are treated as described in Example 5.
Reaction SMILES: [CH:1]1([C:4]2[S:5][C:6]3[C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=[C:9]([O:16][CH3:17])[C:7]=3[N:8]=2)[CH2:3][CH2:2]1.[CH:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[C:20](O)[CH:19]=1.Cl.CN(C)CCCN=C=NCC.C(OCC)C>ClCCl>[N+:24]([C:23]1[CH:18]=[CH:19][C:20]([O:14][C:13]([C:12]2[C:6]3[S:5][C:4]([CH:1]4[CH2:2][CH2:3]4)=[N:8][C:7]=3[C:9]([O:16][CH3:17])=[CH:10][CH:11]=2)=[O:15])=[CH:21][CH:22]=1)([O-:26])=[O:25]
Reactant: COc1ccc(C(=O)O)c2sc(C3CC3)nc12
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2sc(C3CC3)nc12
Yield: 72.3 %

Procedure:
Starting from 2-cyclopropyl-4-methoxybenzothiazole-7-carboxylic acid (270 mg), p-nitrophenol (165 mg), and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (228 mg) in dichloromethane (35 ml). Trituration ofthe residue with diethyl ether yielded the title compound as a bright yellow solid (290 mg). TLC Rf 0.60 (ethyl acetate).
Reaction SMILES: [OH-].[Li+].C[O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH:15](/[CH:28]=[CH:29]/[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[O:36][CH2:37][CH2:38][CH2:39][N:40]2[CH2:44][CH2:43][CH2:42][C:41]2=[O:45])[CH2:16][CH2:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)=[O:6].Cl>C1COCC1.O>[C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH:15](/[CH:28]=[CH:29]/[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[O:36][CH2:37][CH2:38][CH2:39][N:40]2[CH2:44][CH2:43][CH2:42][C:41]2=[O:45])[CH2:16][CH2:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)([OH:6])=[O:4]
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCN2CCCC2=O)CCc2ccc(C(=O)OC)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(CCC(/C=C/c2ccccc2OCCCN2CCCC2=O)CCc2ccc(C(=O)O)cc2)cc1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
18.5 mg (0.75 mmol) of lithium hydroxide are added to a solution of 150 mg (0.26 mmol) of methyl 4-[(4E)-3-{2-[4-(methoxycarbonyl)phenyl]ethyl}-5-{2-[3-(2-oxopyrrolidin-1-yl)propoxy]-phenyl}pent-4-en-1-yl]benzoate in 10 ml of THF and 10 ml of water, and the mixture is stirred at 50° C. for 12 h. The mixture is then adjusted to pH 2 using 1 M hydrochloric acid and concentrated. The residue obtained is purified directly by preparative HPLC. This gives 104 mg (content 97%, 0.18 mmol, 71% of theory) of the title compound.
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[N:24]=[C:23]([NH:25]C(=O)OC(C)(C)C)[S:22][N:21]=4)[CH:18]=3)[N:13]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:12]=2)[CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[N:24]=[C:23]([NH2:25])[S:22][N:21]=4)[CH:18]=3)[N:13]([S:33]([C:36]3[CH:37]=[CH:38][C:39]([CH3:40])=[CH:41][CH:42]=3)(=[O:35])=[O:34])[CH:12]=2)[CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cccc(OC(C)C)n3)c3cc(-c4nsc(NC(=O)OC(C)(C)C)n4)ccc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cccc(OC(C)C)n3)c3cc(-c4nsc(N)n4)ccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
To a mixture of tert-butyl (3-(3-(6-isopropoxypyridin-2-yl)-1-tosyl-1H-indol-5-yl)-1,2,4-thiadiazol-5-yl)carbamate (0.35 g, 0.577 mmol) in DCM (10 mL) was added TFA (4 mL) at 0° C. The reaction was stirred for 2 h at RT. The solvent was then removed in vacuo and the residue was triturated with Et2O to give 3-(3-(6-isopropoxypyridin-2-yl)-1-tosyl-1H-indol-5-yl)-1,2,4-thiadiazol-5-amine (0.25 g, 85.6%). MS (ESI, pos. ion) m/z: 506.1 (M+1).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[O:11][C:10]=2[CH3:20])O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:23])=O>C1(C)C=CC=CC=1>[Cl:23][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[O:11][C:10]=1[CH3:20]
Reactant: Cc1oc(-c2ccncc2)cc1C(O)C1CCCCC1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccncc2)cc1C(Cl)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of cyclohexyl[2-methyl-5-(pyridin-4-yl)furan-3-yl]methanol (0.9 g) in toluene (10 mL) was added thionyl chloride (0.7 mL), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure to give the title compound (0.9 g, 100%) as a yellow crystal.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[C:26]2=[CH:27][CH:28]=[N:29][CH:30]=[C:25]2[C:5]2[C:6]([OH:24])=[CH:7][C:8]([CH:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:11])=[CH:9][C:4]=2[O:3]1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>N1C=CC=CC=1>[C:32]([O:24][C:6]1[C:5]2[C:25]3[C:26]([C:2]([CH3:1])([CH3:31])[O:3][C:4]=2[CH:9]=[C:8]([CH:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:11])[CH:7]=1)=[CH:27][CH:28]=[N:29][CH:30]=3)(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCCCCC(C)c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Solvent: c1ccncc1
Product: CCCCCCCCCCCCC(C)c1cc(OC(C)=O)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
10-Acetoxy-5,5-dimethyl-8-(2-tetradecyl)-5H-[1]benzopyrano[3,4-d]pyridine is prepared by reacting 5,5-dimethyl-10-hydroxy-8-(2-tetradecyl)-5H-[1]benzopyrano[3,4-d]pyridine and acetic anhydride in the presence of pyridine according to the method of Example 12.
Reaction SMILES: C[O-].[Na+].C(O)(=O)C.[CH:8]([NH2:10])=[NH:9].C[O:12][C:13]([CH:15]1[CH2:20][C:19]([C:36]#[N:37])([C:21]2[C:29]3[C:28]4[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=4[O:26][C:25]=3[C:24]([O:34][CH3:35])=[CH:23][CH:22]=2)[CH2:18][CH2:17][C:16]1=O)=O>CO>[CH3:35][O:34][C:24]1[C:25]2[O:26][C:27]3[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=3[C:29]=2[C:21]([C:19]2([C:36]#[N:37])[CH2:18][CH2:17][C:16]3[N:10]=[CH:8][NH:9][C:13](=[O:12])[C:15]=3[CH2:20]2)=[CH:22][CH:23]=1
Reactant: COC(=O)C1CC(C#N)(c2ccc(OC)c3oc4ccccc4c23)CCC1=O
Reactant: N=CN
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(C2(C#N)CCc3nc[nH]c(=O)c3C2)c2c1oc1ccccc12
Temperature: 65 °C
Reaction time: 18 h

Procedure:
To a stirred solution of sodium methoxide (185.3 mg, 3.5 mmol) in 10 ml of methanol was added formamidine acetate (290 mg, 2.78 mmol) and the compound obtained in example 1. The reaction mass was allowed to stir at 60-70° C. for 18 hrs under nitrogen atmosphere. Most of the methanol was evaporated under vacuum and residue was purified by column chromatography to get 200 mg (67.3% yields) of the product.
Reaction SMILES: C([O:4][C@@H:5]([CH3:28])[C:6]([NH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[NH:11][C:10]=1[C:19]([C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][N:22]=1)=[O:20])=[O:7])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O.C(OCC)C>[Cl:18][C:14]1[CH:13]=[C:12]2[C:17]([C:9]([NH:8][C:6](=[O:7])[C@@H:5]([OH:4])[CH3:28])=[C:10]([C:19]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][N:22]=3)=[O:20])[NH:11]2)=[CH:16][CH:15]=1
Reactant: CC(=O)O[C@@H](C)C(=O)Nc1c(C(=O)c2cc(Cl)ccn2)[nH]c2cc(Cl)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: O
Product: C[C@H](O)C(=O)Nc1c(C(=O)c2cc(Cl)ccn2)[nH]c2cc(Cl)ccc12
Reaction time: 30 h
Yield: 74.7 %

Procedure:
To a suspension of 3-[(S)-2-acetoxypropionylamino]-6-chloro-2-(4-chloropyridine-2-carbonyl)indole (Example 362, 316.7 mg, 0.7536 mmol) in DMSO (10 ml) was added potassium carbonate (104.2 mg, 0.7536 mmol) in water (1 ml) at room temperature. After stirring for 30 h, the mixture was diluted with diethyl ether (200 ml), and then washed with water (50 ml×3), brine (50 ml), and dried (MgSO4). Removal of solvent gave a crystalline residue, which was recrystallized from ethyl acetate to afford 213.0 mg (74.7%) of the title compound. m.p.: 244-246° C. (recrystallized from ethyl acetate) IR(KBr)ν: 3483, 3288, 1690, 1570, 1553, 1533, 1481, 1348, 1240, 1186, 737 cm−1. 1H-NMR (DMSO-d6) δ: 12.07 (1 H, br s), 11.43 (1 H, br s), 8.82 (1 H, dd, J=5.3 and 0.5 Hz), 8.26 (1 H, d, J=9.1 Hz), 8.20 (1 H, dd, J=2.1, 0.5 Hz), 7.91 (1 H, dd, J=5.4, 2.1 Hz), 7.67 (1 H, dd, J=2.0, 0.5 Hz), 7.07 (1 H, dd, J=8.9, 2.0 Hz), 6.18 (1H, d, J=4.9 Hz), 4.23 (1 H,dd, J=6.8, 4.9 Hz), 134 (3 H, d, J=6.8 Hz).
Reaction SMILES: [CH2:1]([C:8]1[N:12]=[C:11]([CH2:13][CH2:14][C:15]([OH:17])=O)[O:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:30][NH2:31]>C1COCC1>[CH2:1]([C:8]1[N:12]=[C:11]([CH2:13][CH2:14][C:15]([NH:30][NH2:31])=[O:17])[O:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCc1nc(Cc2ccccc2)no1
Reactant: NN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: NNC(=O)CCc1nc(Cc2ccccc2)no1
Temperature: 25 °C

Procedure:
To a solution of 3-(3-benzyl-1,2,4-oxadiazol-5-yl)propanoic acid (1.0 g, 4.3 mmol) in THF (15 mL) was added N,N-carbonyldiimidazole (0.77 g, 4.7 mmol). After refluxing for 2 hours, hydrazine (0.6 g, 20 mmol) was added to the reaction mixture slowly with syringe at 0° C. The reaction mixture was allowed to warm to room temperature slowly and then concentrated to yield the desired product as white solid. LCMS calculated for C12H15N4O2 (M+H): 247.1. found: 247.1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.I[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18]>>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COc1ccccc1I
Reactant: c1ccc2[nH]ccc2c1
Product: COc1ccccc1-n1ccc2ccccc21

Procedure:
Prepared by Procedure C and Scheme O using 1H-indole and 1-iodo-2-methoxybenzene: ESMS m/e: 224.0 (M+H)+.