Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][C:15]1([CH3:29])[O:20][C:19]2[C:21]([CH3:28])=[C:22]([CH3:27])[C:23]([OH:26])=[C:24]([CH3:25])[C:18]=2[CH2:17][CH2:16]1>CC(C)=O>[OH:26][C:23]1[C:22]([CH3:27])=[C:21]([CH3:28])[C:19]2[O:20][C:15]([CH2:14][CH2:13][NH:12][C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[S:11])([CH3:29])[CH2:16][CH2:17][C:18]=2[C:24]=1[CH3:25]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCN)O2
Solvent: CC(C)=O
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCNC(=S)NC(=O)c1ccccc1)O2
Temperature: 25 °C
Reaction time: 15 h
Yield: 56.4 %

Procedure:
A solution of benzoylisothiocyanate (28.0 g) in acetone (200 ml) was added dropwise to a solution of amine (prepared in reference example 3, 34.3 g) in acetone (800 ml). The solution was stirred for 15 hours at room temperature. The reaction solution was evaporated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=10:1→4:1→2:1) to give the title compound (32.0 g) having the following physical data.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[N-:12]=[N+:13]=[N-:14].[Na+]>>[N:12]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[N+:13]=[N-:14]
Reactant: O=C(O)CCCCCCCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: [N-]=[N+]=NCCCCCCCC(=O)O

Procedure:
Reaction of 8-bromooctanoic acid and NaN3, as described for the synthesis of 6, gave 8-azidooctanoic acid 11. Saponification was not necessary. Used without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[CH:28][CH:27]=2)[C:8]2[C:13]([CH:14]=1)=[C:12]([NH2:15])[C:11]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:18][CH:17]=1)=[CH:10][CH:9]=2)=[O:5])C.[OH-].[Na+].[ClH:38]>C(#N)C>[ClH:38].[NH2:15][C:12]1[C:11]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH:23]([CH3:24])[CH3:25])=[CH:20][CH:21]=2)=[CH:10][CH:9]=[C:8]2[C:13]=1[CH:14]=[C:6]([C:4]([OH:5])=[O:3])[N:7]2[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:34])[CH3:35])=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1cc2c(N)c(-c3ccc(OC(C)C)cc3)ccc2n1-c1ccc(OC(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CC(C)Oc1ccc(-c2ccc3c(cc(C(=O)O)n3-c3ccc(OC(C)C)cc3)c2N)cc1
Yield: 86 %

Procedure:
A mixture of 4-amino-1,5-bis(4-isopropoxyphenyl)indole-2-carboxylic acid ethyl ester (160 mg, 340 nmol; see step (a)), acetonitrile (5 mL), and aqueous NaOH (1M, 2 mL) was heated at reflux for 3 h, and then allowed to cool. The pH was adjusted to 7 with 1 M HCl, and the mixture extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, concentrated, purified by chromatography, and dissolved in Et2O/absolute ethanol (3 mL). 4M HCl (100 μL) in dioxane was added. The precipitate was filtered off, washed with Et2O, and dried to yield the title compound (124 mg, 86%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:13])[CH:10]=NO)=[C:4]([CH2:14][CH3:15])[CH:3]=1.C(N)(=[O:18])C>>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[C:4]([CH2:14][CH3:15])[CH:3]=1)[NH:8][C:9](=[O:13])[C:10]2=[O:18]
Reactant: CC(N)=O
Reactant: CCc1cc(Br)ccc1NC(=O)C=NO
Product: CCc1cc(Br)cc2c1NC(=O)C2=O

Procedure:
Following the procedure of example 36.B. except using N-(4-Bromo-2-ethyl-phenyl)-2-hydroxyimino-acetamide as the acetamide component afforded the title compound as a solid. ESI (−) MS m/e=252 (MH−).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)[C:9](OC)=[O:10].[NH3:21]>CO>[CH3:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:9]([NH2:21])=[O:10])=[CH:15][CH:16]=1
Reactant: N
Reactant: COC(=O)C(Oc1ccc(C)cc1)c1ccccc1Cl
Solvent: CO
Product: Cc1ccc(OC(C(N)=O)c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a solution of 0.700 g (2.41 mmol) of methyl 2-(2-chlorophenyl)-2-(4-methylphenoxy)acetate (Example 4, Step B) in 10 mL of methanol, stirred at 0° C. (ice-bath) was added anhydrous NH3 for 45 minutes. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was then concentrated in vacuo and afforded 0.658 g (99%) of title compound.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]=[C:10]1[NH:16][CH2:15][CH2:14][N:13]([CH3:17])[C:12]2[CH:18]=[CH:19][CH:20]=[CH:21][C:11]1=2)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[F:22]C1C=CC(F)=CC=1C(O)=O>>[CH2:1]([O:3][P:4]([CH:9]=[C:10]1[NH:16][CH2:15][CH2:14][N:13]([CH3:17])[C:12]2[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:11]1=2)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(C=C1NCCN(C)c2ccccc21)OCC
Reactant: O=C(O)c1cc(F)ccc1F
Product: CCOP(=O)(C=C1NCCN(C)c2ccc(F)cc21)OCC

Procedure:
(7-fluoro-1-methyl-1,2,3,4-tetrahydrobenzo[e][1,4]diazepin-5-ylidenemethyl)phosphonic acid diethyl ester was prepared in an analogous fashion to (1-methyl-1,2,3,4-tetrahydrobenzo[e][1,4]diazepin-5-ylidenemethyl)phosphonic acid diethyl ester, prepared in Example 1, by replacing 2-fluorobenzoic acid with 2,5-difluorobenzoic acid.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C@@H:4]([CH2:13][CH3:14])[C@H:5]([OH:12])[C:6]([NH:8][CH:9]1[CH2:11][CH2:10]1)=[O:7].[CH:15]1(C[C@H](NC(=O)OC(C)(C)C)CO)[CH2:20][CH2:19]C[CH2:17][CH2:16]1>>[ClH:1].[ClH:1].[NH2:3][C@@H:4]([CH2:13][CH:14]1[CH2:19][CH2:20][CH2:15][CH2:16][CH2:17]1)[C@H:5]([OH:12])[C:6]([NH:8][CH:9]1[CH2:10][CH2:11]1)=[O:7]
Reactant: CC[C@H](N)[C@H](O)C(=O)NC1CC1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC1CCCCC1
Agent: Cl
Product: N[C@@H](CC1CCCCC1)[C@H](O)C(=O)NC1CC1

Procedure:
The title compound was prepared in analogy to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide dihydrochloride, Representative Procedure A, starting with (S)-tert-butyl 1-cyclohexyl-3-hydroxypropan-2-ylcarbamate in the second step (A2).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:40])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[N:33]=[N:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:16][N:14]([CH3:15])[C:12]1[C:11]([C:17]([F:18])([F:19])[F:20])=[CH:10][C:9]2[NH:21][C:22](=[O:40])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[N:33]=[N:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=4)[CH:27]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: COc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)nn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(-c2cccc(C3=Nc4cc(N(C)C)c(C(F)(F)F)cc4NC(=O)C3)c2)nn1

Procedure:
The title compound was prepared from (5-dimethylamino-2-{3-[3-(6-methoxy-pyridazin-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M36) (282 mg, 0.49 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (214 mg).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([S:13]([NH:16][C:17]2[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]3[S:24][C:25]([C:35]#[C:36][CH2:37][OH:38])=[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=4)[C:18]=23)(=[O:15])=[O:14])[CH:10]=[CH:11][CH:12]=1.CCN(C(C)C)C(C)C>C1COCC1>[CH3:1][S:2]([O:38][CH2:37][C:36]#[C:35][C:25]1[S:24][C:19]2=[N:20][C:21]([CH3:23])=[CH:22][C:17]([NH:16][S:13]([C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([Cl:6])[CH:8]=3)(=[O:15])=[O:14])=[C:18]2[C:26]=1[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=1)(=[O:4])=[O:3]
Reactant: COc1cccc(-c2c(C#CCO)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cccc(-c2c(C#CCOS(C)(=O)=O)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 0 °C
Yield: 28.9 %

Procedure:
Methane sulfonyl chloride (7.87 μl, 0.101 mmol) was added to a mixture of 3-chloro-N-{2-(3-hydroxy-1-propyn-1-yl)-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-yl}benzenesulfonamide (Example 85) (42 mg, 0.084 mmol) and Hunig's base (17.64 μl, 0.101 mmol) in THF (395 μl) and the mixture stirred at 0° C. The mixture was slowly allowed to warm to RT, with stirring, for 2 h. The mixture was then evaporated to dryness and the residue purified on silica, eluting with a gradient of 0-100% ethyl acetate in cyclohexane, to afford the title compound (14 mg). LCMS (A) m/z: 517 [M+1]+ (displacement of OSO2Me by methanol), Rt 1.45 min (acidic).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:7][C:8]2=O.C[Si]([C:24]#[N:25])(C)C.[Cl-].[Al+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:24]([C:8]1[C:9]2[C:4](=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][CH:10]=2)[CH2:5][CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=1)#[N:25]
Reactant: C[Si](C)(C)C#N
Reactant: COc1cccc2c1CC(c1ccccc1)CC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc2c1CC(c1ccccc1)C=C2C#N
Temperature: 60 °C

Procedure:
To a suspension of 8.8 g (35 mmol) of 5-methoxy-3-phenyl-1,2,3,4-tetrahydro-1-naphthalenone, the product of Example 1, is added 7.5 g (75.6 mmol) of trimethylsilyl cyanide (commercially available from Aldrich Chemical Company) and approximately 50 mg of anhydrous aluminum chloride (AlCl3). The reaction mixture is heated at 60° C. for 3 h then cooled to ambient temperature and diluted with 150 mL of toluene. The volume of the reaction mixture is reduced in vacuo to approximately 50 mL. The resultant trimethylsilyl adduct is dehydrated by treatment with 15 mL of trifluroacetic acid and 100 mg of p-toluenesulfonic acid in 200 mL of toluene at reflux temperature for 1 h. The reaction mixture is cooled to ambient temperature, the layers separated and the organic layer washed with water, aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound.
Reaction SMILES: C1(C)C=C(C)C=C(C)C=1[C:9]1[C:10](=[O:24])[C:11](=[O:23])[C:12]2[C:21]([CH:22]=1)=[N:20][C:19]1[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH:13]=2.CN1C(=O)N(C)CCC1>C1COCC1>[C:11]1(=[O:23])[C:12]2[C:21](=[N:20][C:19]3[C:14]([CH:13]=2)=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:22]=[CH:9][C:10]1=[O:24]
Reactant: Cc1cc(C)c(C2=Cc3nc4ccccc4cc3C(=O)C2=O)c(C)c1
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: O=C1C=Cc2nc3ccccc3cc2C1=O
Yield: 95 %

Procedure:
Under an atmosphere of argon, 151.4 mg (2.45×10−4 mol) of mesityl-acridine-quinone 43 was dissolved in 30 mL of 0.1M SmI2 in THF. Then, 2.2 mL (18.2 mmol) of DMPU were added dropwise. The reaction mixture was refluxed for 24 hr. Filtration to remove a precipitate and evaporation of solvent yielded an orange oil, which was purified by column chromatography on silica gel with 5% MeOH in CH2Cl2 to afford 48.7 mg (45%) of acridine-quinone 44 as an orange glassy solid: 1H NMR (300 MHz, DMSO-d6, TMS) δ8.54 (d, J=8 Hz, 2H), 7.96 (t, J=7 Hz, 2H), 7.92 (d, J=7 Hz, 1H), 7.79 (d, J=8 Hz, 2H), 7.7-7.6 (m, 3H), 7.51 (t, J=8 Hz, 2H), 6.01 (s, 1H), 4.20 (t, J=6 Hz, 2H), 4.13 (t, J=7 Hz, 2H), 2.1-1.9 (m, 4H), 1.7-1.6 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([N:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[NH:12][C:11]3[CH:21]=[CH:22][CH:23]=[N:24][C:10]2=3)=[O:8])=[CH:3][CH:2]=1.[BH4-].[Na+].[CH3:27]O>>[CH3:27][N:1]1[CH2:6][CH2:5][C:4]([C:7]([N:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[NH:12][C:11]3[CH:21]=[CH:22][CH:23]=[N:24][C:10]2=3)=[O:8])=[CH:3][CH2:2]1
Reactant: O=C1Nc2cccnc2N(C(=O)c2ccncc2)c2ccccc21
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: CN1CC=C(C(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1
Temperature: 0 °C

Procedure:
A quantity of 2.3 gm (0.005 mol) of 5,11-dihydro-11-[(4-pyridinyl)-carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one methoiodide was suspended in 200 ml of methanol, and at 0° C. 0.25 gm (0.006 mol) of sodium borohydride were added thereto in portions. The resulting mixture was stirred for a further hour in an ice bath. Then, the mixture was stirred into 1 liter of ice-cold water and extracted exhaustively with methylene chloride. The combined extracts were washed with water, dried over sodium sulphate, and concentrated by evaporation in vacuo. After being recrystallized from diisopropyl ether/methanol, the colorless crystals melted at 226°-227° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([S:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:9]([O:17]CC2C=CC(OC)=CC=2)=[CH:8][N:7]=1)(=[O:3])[CH3:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([S:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:9]([OH:17])=[CH:8][N:7]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(COc2cnc(COC(C)=O)cc2SC(C)(C)C)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCc1cc(SC(C)(C)C)c(O)cn1
Reaction time: 0.17 h
Yield: 83.2 %

Procedure:
A solution of [4-[(1,1-dimethylethyl)thio]-5-({[4-(methoxy)phenyl]methyl}oxy)-2-pyridinyl]methyl acetate (9 g, 24 mmol) in dichloromethane (100 mL) was treated with triethylsilane (3.86 mL, 24 mmol). The reaction mixture was stirred for 10 minutes before adding trifluoroacetic acid (10 mL). The reaction mixture was stirred at room temperature for 3 hours under argon atmosphere. The solvents were evaporated under vacuum. The residue was taken up in dichloromethane and chromatographed on silica gel eluting with 10%-30% ethyl acetate in hexane to afford the product as an oil (5.1 g, 83%); MS (+ve ion electrospray) m/z 256 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:12]=[CH:11][S:10][C:9]=1[C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1)(C)(C)C.Cl.CC(O)C.[OH-].[Na+]>CCOC(C)=O>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([C:9]2[S:10][CH:11]=[CH:12][C:8]=2[NH2:7])=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)Nc1ccsc1-c1ccc(Br)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: Nc1ccsc1-c1ccc(Br)cc1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 98.2 %

Procedure:
Charge a 10 L double jacketed reactor equipped with mechanical stirring, set under inert atmosphere of argon with [2-(4-bromo-phenyl)-thiophen-3-yl]-carbamic acid tert-butyl ester (800 g, 2.25 mol) and EtOAc (3.2 L). Cool the yellow solution is down to 16.9° C. and add a solution of 5-6N HCl/IPA (1600 mL) in 10 minutes via a dropping funnel between 10° C. and 25° C. Heat the reaction mixture to 50° C. Stir the resulting suspension for 90 minutes at 50° C. Cool the suspension below 10° C. and add 2N NaOH solution (2773 mL) over 25 minutes, maintaining the temperature below 20° C. Add 2N NaOH (450 mL) to reach a pH of 12-13. Separate the two layers by decantation. Re-extract the aqueous phase with EtOAc (500 mL). Dry the combined organic layers over MgSO4 (200 g) and evaporate to dryness to yield 2-(4-Bromo-phenyl)-thiophen-3-ylamine (562.3 g, 2.21 mol) as a beige solid. 1H NMR (250 MHz, CDCl3): 3.70(s (broad), 2 H) 6.65(d,1 H, J=5.4 Hz), 7.06(d, 1 H, J=5.2 Hz), 7.32(d, 2 H, J=8.9 Hz), 7.45 (d, 2H, J=8.8 Hz).
Reaction SMILES: C([S:9][CH2:10][CH2:11][C:12]([N:14]1[C@@H:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])=[O:13])(=O)C1C=CC=CC=1.CO.N>O>[SH:9][CH2:10][CH2:11][C:12]([N:14]1[C@@H:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])=[O:13]
Reactant: O=C(SCCC(=O)N1[C@@H](c2ccccc2)CC[C@H]1C(=O)O)c1ccccc1
Agent: N
Solvent: CO
Solvent: O
Product: O=C(O)[C@@H]1CC[C@H](c2ccccc2)N1C(=O)CCS
Temperature: 25 °C
Reaction time: 2 h

Procedure:
This product from Example 3 was added to a solution of methanol saturated with ammonia and was stirred at 25° C. for 2 hours. The solvent was evaporated off, leaving a solid which was stirred in water and filtered. The filtrate was extracted five times with diethyl ether and was acidified. The acidified solution was then extracted with methylene chloride, washed with brine, dried over magnesium sulfate and concentrated to a solid. This residue was extracted with hot hexane from which the title compound crystallized, m.p. 61°-64° C.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1>C(O)(=O)CC>[CH:5]1[CH:6]=[CH:7][C:2]([C:1]2[C:13]3=[N:9][C:10]([CH:11]=[CH:12]3)=[C:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:10]3=[N:9][C:13]([CH:12]=[CH:11]3)=[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:10]3[NH:9][C:13](=[CH:12][CH:11]=3)[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:10]3[NH:9][C:13]=2[CH:12]=[CH:11]3)=[CH:3][CH:4]=1
Reactant: c1cc[nH]c1
Reactant: O=Cc1ccccc1
Solvent: CCC(=O)O
Product: C1=Cc2nc1c(-c1ccccc1)c1nc(c(-c3ccccc3)c3ccc([nH]3)c(-c3ccccc3)c3ccc([nH]3)c2-c2ccccc2)C=C1
Reaction time: 24 h
Yield: 20 %

Procedure:
In a 4-liter flask equipped with a cooling tube, 80 ml (84.8 g) of benzaldehyde, 56 ml (53.6 g) of pyrrol, and 3 liters of propionic acid were placed and reacted for 30 minutes under reflux. Then, the flask was allowed to stand for one day. After filtering the reaction mixture, recrystallization from a mixed solvent of methanol and chloroform (1:1 by weight) was carried out for purification. Thus, α,β,γ,δ-tetraphenylporphine was obtained in 20% yield.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]2[S:16][CH2:15][C:14]3([CH2:20][CH2:19][CH2:18][CH2:17]3)[NH:13]2)=[C:7]([CH3:21])[CH:6]=1)=[O:4].[CH:22]1(Br)[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]2[S:16][CH2:15][C:14]3([CH2:20][CH2:19][CH2:18][CH2:17]3)[N:13]2[CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:7]([CH3:21])[CH:6]=1)=[O:4]
Reactant: BrC1CCCC1
Reactant: COC(=O)c1ccc(N=C2NC3(CCCC3)CS2)c(C)c1
Product: COC(=O)c1ccc(N=C2SCC3(CCCC3)N2C2CCCC2)c(C)c1

Procedure:
Methyl 4-amino-3-methylbenzoate was converted to 4-methoxycarbonyl-2-methylphenyl isothiocyanate according to Method A2b. 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was sequentially reacted with SOCl2 and 4-methoxycarbonyl-2-methylphenyl isothiocyanate according to Method C2a to give 2-(4-methoxycarbonyl-2-methylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2h to give 2-(4-methoxycarbonyl-2-methylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][N:24]=4)[CH2:19][CH2:18]3)=[N:9][N:8]=2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:67][NH:68][CH2:69][CH2:70][OH:71]>CN(C=O)C>[F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([N:17]3[CH2:18][CH2:19][N:20]([C:23]4[CH:31]=[CH:30][C:26]([C:27]([N:68]([CH2:69][CH2:70][OH:71])[CH3:67])=[O:28])=[CH:25][N:24]=4)[CH2:21][CH2:22]3)=[N:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: CNCCO
Reactant: O=C(O)c1ccc(N2CCN(c3nnc(Cc4ccc(F)cc4)c4ccccc34)CC2)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCO)C(=O)c1ccc(N2CCN(c3nnc(Cc4ccc(F)cc4)c4ccccc34)CC2)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.6 %

Procedure:
6-{4-[4-(4-Fluoro-benzyl)-phthalazin-1-yl]-piperazin-1-yl}-nicotinic acid (100 mg, 0.225 mmol), DMF (0.5 mL), Diisopropylethylamine (195 μL, 1.125 mmol), HBTU (102 mg, 0.270 mmol), and 2-(methylamino)ethanol (18 μL, 0.225 mmol) are combined in a 10 mL flask and stirred for 4 h at room temperature. Concentrate to remove DMF in vacuo. The residue is purified by flash chromatography on silica gel (0-25% MeOH/CH2Cl2 with 5% TEA) to afford the title compound (68.2 mg, 61%).
Reaction SMILES: C[O:2][C:3](=[O:20])[C@@H:4]1[C:8]([CH3:10])([CH3:9])[C:7]([F:12])([F:11])[CH2:6][N:5]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[Li+].[OH-]>CO.O>[F:12][C:7]1([F:11])[CH2:6][N:5]([C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[C@H:4]([C:3]([OH:20])=[O:2])[C:8]1([CH3:10])[CH3:9]
Reactant: COC(=O)[C@H]1N(C(=O)OC(C)(C)C)CC(F)(F)C1(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(F)(F)C(C)(C)[C@H]1C(=O)O
Temperature: 50 °C

Procedure:
To a solution of methyl ester F4 (4.7 g, 16 mmol) in methanol (100 mL) was added a solution of LiOH (6.8 g, 160 mmol) in water (50 mL) and the solution was heated at 50° C. for 14 h. The methanol was removed in vacuo and the remaining solution was diluted with water (200 mL). The aqueous solution was extracted with ether (2×200 mL), acidified with 1N HCl (200 mL) and extracted again with ether (2×200 mL). The combined organics were washed with brine (1×200 mL), dried with magnesium sulfate and concentrated in vacuo. The while solid was dried overnight at 40° C. under vacuum. Isolated yield: 4.3 g (95%). 1H NMR (400 MHz, DMSO-d6): □ 12.95 (bs, 1H), 3.93 (s, 1H), 3.84–3.74 (m, 2H), 1.38 (s)+1.33 (s) (9H), 1.19 (s, 3H), 1.01 (s, 3H); 19F NMR (376 MHz, DMSO-d6): □ −111.4 (dt, J=227, 13 Hz)+−112.4 (dt, J=227, 13 Hz) (1F), −113.5 (dt, J=227, 14 Hz) +−113.9 (dt, J=227, 15 Hz) (1F); MS-APCI (m/z+): 180.1, (m/z−): 278.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:6]([O:8][CH3:9])=[O:7])#[N:2].[NH2:14][OH:15].Cl.C(N(CC)C(C)C)(C)C>O1CCCC1>[OH:15][N:14]=[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:6]([O:8][CH3:9])=[O:7])[NH2:2]
Reactant: COC(=O)c1ccc(C)c(C#N)c1
Reactant: NO
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(C)c(C(N)=NO)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 30.6 %

Procedure:
A mixture of methyl 3-cyano-4-methylbenzoate (compound 1.7, 8 g, 43.38 mmol, 1.00 equiv, 95%), NH2OH.HCl (3.785 g, 54.86 mmol, 1.20 equiv), and N,N-Diisopropylethylamine (DIEA, 17.7 g, 136.95 mmol, 3.00 equiv) in tetrahydrofuran (100 mL) was stirred overnight at 70° C. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was taken up in water and the pH was adjusted to 2-3 with hydrogen chloride (aqueous, 1 M). After washing the mixture with 3×40 mL of ethyl acetate, the pH of the aqueous layer was adjusted to 8-9 with NaOH (aqueous, 2 M) followed by extraction with 3×30 mL of ethyl acetate. The combined organic layers were dried over (Na2SO4) and concentrated under reduced pressure to yield 2.76 g (29%) of the title compound as a white solid.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH3:9][C:10]([CH3:12])=O.C(OC(=O)C)(=O)C>C(Cl)Cl.[Cl-].[Cl-].[Zn+2]>[C:3]([C:2](=[C:10]([CH3:12])[CH3:9])[C:1]([O:7][CH3:8])=[O:6])(=[O:4])[CH3:5]
Reactant: CC(C)=O
Reactant: COC(=O)CC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: COC(=O)C(C(C)=O)=C(C)C
Temperature: 50 °C

Procedure:
To a mixture of 9.54 g (70 mmol) of anhydrous ZnCl2, 53.9 mL (500 mmol) of methyl acetoacetate and 55 mL (750 mmol) of acetone are added 64 mL of acetic anhydride. The reaction medium is then heated for 3 days at 50° C., and then diluted with 1 L of DCM and washed with water (3×100 mL). The organic phase is dried over Na2SO4, filtered and then concentrated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, eluting with a cyclohexane/EtOAc gradient of 0 to 10% EtOAc. After concentrating under reduced pressure, 51.5 g of methyl 2-acetyl-3-methylbut-2-enoate are obtained in the form of a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH:20]=O)[CH:8]=[C:9]([Cl:11])[CH:10]=1.[CH2:23]([NH2:25])[CH3:24]>>[CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH2:20][NH:25][CH2:23][CH3:24])[CH:8]=[C:9]([Cl:11])[CH:10]=1
Reactant: COC(=O)Cc1cc(Cl)cc(-c2cc(OC)ccc2C=O)c1
Reactant: CCN
Product: CCNCc1ccc(OC)cc1-c1cc(Cl)cc(CC(=O)OC)c1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using the following starting materials: (5-chloro-2′-formyl-5′-methoxy biphenyl-3-yl)-acetic acid methyl ester and ethylamine (2M in THF).