Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][S:14][C:15]3[C:20]([C:21]#[N:22])=[C:19]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][OH:32])=[CH:25][CH:24]=4)[C:18]([C:33]#[N:34])=[C:17]([NH:35][CH2:36][CH2:37][CH3:38])[N:16]=3)[N:12]=2)=[CH:4][CH:3]=1.[C:39]([O:43][C:44]([NH:46][C@H:47]([C:49](O)=[O:50])[CH3:48])=[O:45])([CH3:42])([CH3:41])[CH3:40].Cl.CN(C)CCCN=C=NCC.ClCCl>CN(C)C1C=CN=CC=1.CN(C=O)C.ClCCl>[C:39]([O:43][C:44]([NH:46][C@H:47]([C:49]([O:32][CH2:31][CH2:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([C:19]2[C:18]([C:33]#[N:34])=[C:17]([NH:35][CH2:36][CH2:37][CH3:38])[N:16]=[C:15]([S:14][CH2:13][C:11]3[N:12]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[S:9][CH:10]=3)[C:20]=2[C:21]#[N:22])=[CH:24][CH:25]=1)=[O:50])[CH3:48])=[O:45])([CH3:41])([CH3:42])[CH3:40]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCCNc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCNc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCOC(=O)[C@H](C)NC(=O)OC(C)(C)C)cc2)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
758 mg (1.348 mmol) of 2-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)-6-(propylamino)pyridine-3,5-dicarbonitrile (Example 12), 765 mg (4.043 mmol) of N-(tert-butoxycarbonyl)-L-alanine and 82 mg (0.674 mmol) of 4-dimethylaminopyridine were initially charged in 10.3 ml of DMF/dichloromethane (1:1). 336 mg (1.752 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added, and the reaction solution was then stirred at RT overnight. The reaction solution was freed from dichloromethane and the residue was purified by preparative HPLC (acetonitrile/water+0.1% TFA). This gave 929 mg (94% of theory) of the target compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:8]=1[C:9]([NH2:11])=[O:10]>CC(O)=O.CCOC(C)=O.[Fe]>[NH2:16][C:13]1[CH:14]=[CH:15][C:7]([O:6][CH2:5][C:4]2[CH:19]=[CH:20][CH:21]=[C:2]([F:1])[CH:3]=2)=[C:8]([CH:12]=1)[C:9]([NH2:11])=[O:10]
Reactant: NC(=O)c1cc([N+](=O)[O-])ccc1OCc1cccc(F)c1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: NC(=O)c1cc(N)ccc1OCc1cccc(F)c1
Temperature: 70 °C
Yield: 84.9 %

Procedure:
A mixture of 14A (162 mg, 0.56 mmol) and Fe powder (249 mg, 4.46 mmol) in HOAc/EtOAc (1/1) (2.4 ml) was heated at 70° C. for 2.5 h. The mixture was cooled to rt, filtered through a 1″ celite pad and rinsed with HOAc/EtOAc (1/1) (4×8 ml). The filtrate was concentrated in vacuo. The residue was diluted with 1N NaOH (25 ml), extracted with EtOAc (2×60 ml) and the combined EtOAc extracts were washed with brine (1×20 ml), dried (MgSO4), filtered and concentrated in vacuo to give 14B (123.8 mg, 67% pure).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([N:14]([CH2:37][CH3:38])[CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]1[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:24]([CH:32]=O)[NH:23][C:22]=1[CH:34]([CH3:36])[CH3:35])=[O:20])[CH3:13]>>[CH2:37]([N:14]([CH2:12][CH3:13])[CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]1[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:24]([CH:32]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[NH:23][C:22]=1[CH:34]([CH3:36])[CH3:35])=[O:20])[CH3:38]
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: CCN(CC)CCCNC(=O)c1c(C(C)C)[nH]c(C=O)c1-c1ccccc1
Product: CCN(CC)CCCNC(=O)c1c(C(C)C)[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c1-c1ccccc1
Yield: 71 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one (120 mg, 0.31 mmol) was condensed with 5-formyl-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid (3-diethylaminopropyl)amide (prepared by method C) to give 120 mg (71%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([CH3:16])[N:3]=1.[NH2:17][C:18]1[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[Se:20][C:19]=1[C:27]([NH2:29])=[O:28].CN(C=O)C.[OH-].[Na+]>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[C:4]([CH3:16])[N:3]=[C:2]2[NH:17][C:18]1[CH:22]=[C:21]([C:23]([CH3:26])([CH3:24])[CH3:25])[Se:20][C:19]=1[C:27]([NH2:29])=[O:28]
Reactant: CC(C)(C)c1cc(N)c(C(N)=O)[se]1
Reactant: COc1cc2nc(C)nc(Cl)c2cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cc2nc(C)nc(Nc3cc(C(C)(C)C)[se]c3C(N)=O)c2cc1OC

Procedure:
The reaction of 4-chloro-6,7-dimethoxy-2-methylquinazoline with 3-amino-5-tert-butylselenophene-2-carboxamide in the presence of DMF/NaOH as described in Example 1 gave title compound as an off-white color solid, mp 266-268° C. 1H NMR (400 MHz, CDCl3): δ 11.95 (1H, br s, exchangeable with D2O), 8.97 (1H, s), 7.32 (1H, s), 7.19 (1H, s), 5.38 (2H, br s, exchangeable with D2O), 4.08 (3H, s), 4.01 (3H, s), 2.70 (3H, s), 1.47 (9H, s); 13C NMR (100 MHz, CDCl3): δ 168.63, 168.60, 162.1, 154.8, 154.5, 149.2, 148.2, 148.1, 121.9, 109.0, 107.4, 107.1, 100.1, 56.2, 56.1, 37.1, 32.5, 26.3; LC-MS (negative ion mode): m/z 445, 447 (M−H)−.
Reaction SMILES: [CH2:1]([NH:5][CH3:6])[CH2:2][CH2:3][CH3:4].[CH:7]([N:10]=[C:11]=[N:12][CH:13]([CH3:15])[CH3:14])([CH3:9])[CH3:8]>>[CH2:1]([N:5]([CH3:6])[C:11]([NH:12][CH:13]([CH3:15])[CH3:14])=[N:10][CH:7]([CH3:9])[CH3:8])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC
Reactant: CC(C)N=C=NC(C)C
Product: CCCCN(C)C(=NC(C)C)NC(C)C
Yield: 100 %

Procedure:
A mixture of 32.68 g of N-butyl-N-methylamine (0.375 mol) and 23.66 g of diisopropylcarbodiimide (0.1875 mol) is heated at reflux for 3 hours. GC analysis then shows a conversion of more than 99.5% of the diisopropylcarbodiimide. The final mixture, which is colorless, is concentrated at 60° C. under 5 mbar for 2 hours, to give 40 g of a colorless and virtually odorless liquid of low viscosity, which corresponds to the expected guanidine (100% yield).
Reaction SMILES: [C:1]([O:4][CH3:5])(=[O:3])[CH3:2].[Li+].CC([N-]C(C)C)C.CN(C)P(=O)(N(C)C)N(C)C.Br[CH2:26][C:27]([CH:29]([N:31]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:30])=[O:28]>C1COCC1>[CH3:5][O:4][C:1](=[O:3])[CH2:2][CH2:26][C:27](=[O:28])[C@@H:29]([N:31]([CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH3:30]
Reactant: COC(C)=O
Reactant: CC(C(=O)CBr)N(Cc1ccccc1)Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COC(=O)CCC(=O)[C@H](C)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 0.75 h
Yield: 62 %

Procedure:
Methyl acetate (1.0 mmol, 0.08 mL) was added dropwise to a solution of LDA (1.05 mmol) in 2.0 mL THF at -78° C., and the resulting solution was stirred for 45 minutes. Hexamethyl phosphoric triamide (1.0 mmol, 0.18 mL) was then added, and after 15 minutes a solution of α-(N,N-dibenzylamino)ethyl bromomethyl ketone (crude from the previous reaction, assumed to be 1.0 mmol) in 2.0 mL was added via syringe. The resulting solution was stirred at -78° C. for 45 minutes and then quenched with saturated solution of NaHCO3. After a work-up as described in Example 8, 0.39 g of crude product was obtained. The product was further purified by column chromatography on silica gel with 8:1 hexanes-ethyl acetate as the solvent system (Rf=0.33) to yield 0.21 g (62%) of methyl-(5S)-5-(N,N-dibenzylamino)-4-oxo-hexanoate as a colorless viscous oil. Analytical data: 1H NMR (300.15 MHz) δ 0.95 (d, J=6.6 Hz, 3H), 2.62-2.30 (m, 4H), 3.36 (q, J=6.2 Hz, 1H), 3.60 (ABq, δA =3.41, δB =3.82, J=13.5 Hz, 4H), 3.49 (s, 3H), 7.23-7.37 (m, 10H); 13C NMR 5.1, 38.9, 48.8, 51.4, 54.4, 57.5, 126.9, 128.2, 128.8, 129.2, 139.4, 170.4, 208.2.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C@@H:10]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([Cl:27])[CH:18]=2)[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:6][CH:7]=1.[CH2:29]([OH:32])[C:30]#[CH:31].C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:27][C:19]1[CH:18]=[C:17]([C@@H:10]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([NH:8][C:5]2[CH:4]=[N:3][C:2]([C:31]#[C:30][CH2:29][OH:32])=[CH:7][N:6]=2)=[O:28])[CH:22]=[CH:21][C:20]=1[S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: C#CCO
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(C#CCO)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
A solution of N-(5-bromo-pyrazin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (prepared as in Example 6, 486 mg, 1 mmol) and propargyl alcohol (84 mg, 1.5 mmol) in toluene (6 mL) was treated with copper(I) iodide (19.2 mg, 0.10 mmol), dichlorobis(triphenylphosphine)palladium(II) (36 mg, 0.05 mmol), and N,N-diisopropylethylamine (2 ml). The resulting mixture was stirred at 25° C. for 1 h and was then heated to 60° C. for 1 h. At this time, the reaction was concentrated in vacuo. The residue was extracted into ethyl acetate from a 1N aqueous hydrochloric acid solution. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 1/1 ethyl acetate/hexanes) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-hydroxy-prop-1-ynyl)-pyrazin-2-yl]-propionamide (275 mg, 57%) as a pale yellow solid: (ES)+-HRMS m/e calcd for C22H24ClN3O4S (M+H)+ 462.1249, found 462.1252.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[C:8]([Br:13])[CH:7]=1.[C:15](Cl)(=[O:18])[CH2:16][CH3:17]>C(N(CC)CC)C>[CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][N:5]([C:15](=[O:18])[CH2:16][CH3:17])[C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[C:8]([Br:13])[CH:7]=1
Reactant: CCC(=O)Cl
Reactant: CN(C)CCNc1ccc(Br)c(Br)c1
Solvent: CCN(CC)CC
Product: CCC(=O)N(CCN(C)C)c1ccc(Br)c(Br)c1

Procedure:
In the manner given in Example 2, to a solution of N,N-dimethyl-N'-(3,4-dibromophenyl)ethylenediamine and triethylamine is added propionyl chloride to give N-[2-(dimethylamino)ethyl]-3',4'-dibromopropionanilide.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C@@H:10]2[C@@H:6]([CH2:7][N:8]([C:11](=[O:22])[CH:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:13]([CH3:15])[CH3:14])[CH2:9]2)[CH2:5][CH2:4]1.[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O)(=O)C.C([BH3-])#N>ClCCl>[CH2:23]([NH:2][C@@H:3]1[C@@H:10]2[C@@H:6]([CH2:7][N:8]([C:11](=[O:22])[CH:12]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:13]([CH3:15])[CH3:14])[CH2:9]2)[CH2:5][CH2:4]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)C(C(=O)N1C[C@H]2CC[C@H](N)[C@H]2C1)c1ccccc1
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)C(C(=O)N1C[C@H]2CC[C@H](NCc3ccccc3)[C@H]2C1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-((3aR,4S,6aS)-4-aminohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-3-methyl-2-phenylbutan-1-one hydrochloric acid salt (49 mg, 0.152 mmol) and benzaldehyde (0.023 mL, 0.228 mmol) were combined in dichloromethane (1.5 mL). Acetic acid (1.5 mL) was added. The reaction was stirred at room temperature for 30 minutes, then PS-cyanoborohydride (64.9 mg, 0.152 mmol) was added. After 72 hours, 1 cms of the reaction showed no more starting material. The reaction mixture was filtered, and the solvent was removed under a stream of nitrogen. The crude material was purified using a silica gel cartridge (Analogix®, Burlington, Wis., RS-4) eluting with 1-10% methanol (2 N ammonia)/dichloromethane to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.69-7.60 (m, 2H), 7.54-7.44 (m, 2H), 7.44-7.34 (m, 5H), 7.29 (tdd, J=4.8, 7.8, 13.0, 2H), 3.90-3.36 (m, 4H), 3.29 (dd, J=3.8, 10.6, 0.5H), 2.99 (dd, J=5.7, 11.4, 0.5H), 2.93 (dd, J=6.0, 11.3, 0.5H), 2.75-2.63 (m, 1H), 2.59-2.48 (m, 1H), 2.46-2.31 (m, 1H), 2.25 (dt, J=4.1, 8.7, 0.5H), 1.97 (dt, J=9.3, 11.6, 1H), 1.93-1.85 (m, 0.5H), 1.84-1.74 (m, 1H), 1.65-1.55 (m, 0.5H), 1.51-1.35 (m, 1H), 1.33-1.21 (m, 1H), 1.18-1.10 (m, 3H), 1.01 (td, J=7.7, 13.1, 0.5H), 0.87 (dt, J=6.6, 12.9, 0.5H), 0.75 (t, J=7.2, 3H); MS (ESI+) m/z 377 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[NH:8][C:7]=2[CH:13]=1.[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>ClCCl>[O:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[NH:8][C:7]=2[CH:13]=1
Reactant: C1=COCCC1
Reactant: O=C1COc2ccc(CO)cc2N1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C1COc2ccc(COC3CCCCO3)cc2N1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The solution of 5.0 g of 6-hydroxymethyl-4H-benzo[1,4]oxazin-3-one in 60 ml of dichloromethane is admixed successively with 5.20 ml of 3,4-dihydro-2H-pyran and 0.236 g of p-toluenesulphonic acid monohydrate. The reaction mixture is stirred at room temperature over 14 hours. The solution is poured onto 1M sodium hydrogencarbonate solution (300 ml) and extracted with tert-butyl methyl ether (2×400 ml). The organic phase is washed with brine (300 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a beige solid from the residue by means of crystallization (EtOAc/heptane). Rf=0.25 (1:1 EtOAc-heptane); Rt=3.45.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([N:15]1[C:23]2[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=2)[CH:17]=[C:16]1B(O)O)(OC(C)(C)C)=O>>[CH3:25][O:24][C:20]1[CH:19]=[C:18]2[C:23](=[CH:22][CH:21]=1)[NH:15][C:16]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[CH:17]2
Reactant: COc1ccc2c(c1)cc(B(O)O)n2C(=O)OC(C)(C)C
Reactant: Brc1cccnc1
Product: COc1ccc2[nH]c(-c3cccnc3)cc2c1

Procedure:
3-Bromopyridine and N-Boc-5-methoxy-indole-2-boronic acid are processed according to the procedure described in Example 91 to give 5-methoxy-2-pyridin-3-yl-1H-indole. HRMS (ESI) m/z 225.1026 [(M+H)+ Calcd for C14H13N2O: 225.1028]
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=2[N+:6]=1[CH3:7].CC1C=CC(S(O)(=O)=O)=CC=1.[Cl:23][C:24]([Cl:45])([Cl:44])[C:25]1[N:30]=[C:29]([C:31]([Cl:34])([Cl:33])[Cl:32])[N:28]=[C:27]([C:35]2[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=2)[N:26]=1.C1(C)C=CC=CC=1>C(N(CC)CC)C>[Cl:34][C:31]([Cl:32])([Cl:33])[C:29]1[N:30]=[C:25]([C:24]([Cl:45])([Cl:23])[Cl:44])[N:26]=[C:27]([C:35]2[CH:36]=[CH:37][C:38]([C:39]([CH:1]=[C:2]3[N:6]([CH3:7])[C:5]4[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=4[S:3]3)=[O:40])=[CH:42][CH:43]=2)[N:28]=1
Reactant: Cc1sc2ccccc2[n+]1C
Reactant: O=C(Cl)c1ccc(-c2nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN1C(=CC(=O)c2ccc(-c3nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n3)cc2)Sc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2,3-Dimethylbenzothiazolium-p-toluenesulfonate (13.4 pbw) and 4-(4,6-bis-trichloromethyl-s-triazin2-yl)-benzoylchloride (22.7 pbw) are successively suspended or dissolved, respectively, in 150 pbw of toluene. The mixture is cooled to 15° C. and with the exclusion of moisture 13.1 pbw of triethylamine are added dropwise at this temperature. The mixture discolors towards dark brown and is stirred for 3 hours at room temperature. The precipitate formed is removed by filtration with suction and washed with cold toluene. The residue is digested in 200 pbw of methanol and stirred for about 60 minutes, again filtered and dried.
Reaction SMILES: [CH3:1][CH2:2][NH:3][C:4]([CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][C@@H:12]1[C@@H:16](/[CH:17]=[CH:18]/[C@@H:19]([OH:28])[CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@H:15]([OH:29])[CH2:14][C@@H:13]1[OH:30])=[O:5].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.C(Cl)Cl>O1CCOCC1>[CH3:1][CH2:2][NH:3][C:4]([CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][C@@H:12]1[C@@H:16](/[CH:17]=[CH:18]/[C:19]([CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:28])[C@H:15]([OH:29])[CH2:14][C@@H:13]1[OH:30])=[O:5]
Reactant: CCNC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)CCc2ccccc2)[C@H](O)C[C@@H]1O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCNC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/C(=O)CCc2ccccc2)[C@H](O)C[C@@H]1O
Temperature: 40 °C
Reaction time: 24 h
Yield: 63.5 %

Procedure:
A mixture of bimatoprost 1 (0.33 g, 0.8 mmol), DDQ (0.68 g, 3.0 mmol), CH2Cl2 (5 mL) and 1,4-dioxane (5 mL) was stirred for 24 h at 40° C. and evaporated in vacuo. The residue was purified by chromatography on a silica gel (20 g, eluent EtOAc then EtOAc/MeOH 20:1) to give 0.21 g (63%) of 15-keto bimatoprost 1c as yellow oil.
Reaction SMILES: [CH3:1]OP(CC(=O)C)(=O)OC.C([O-])([O-])=O.[K+].[K+].O=[CH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:23][CH:22]=1>CC#N.CO>[CH2:20]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:23][CH:22]=1)[CH2:19][C:18]#[CH:1]
Reactant: COC(=O)Cc1ccc(CCC=O)cc1
Reactant: COP(=O)(CC(C)=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: C#CCCc1ccc(CC(=O)OC)cc1
Reaction time: 2 h

Procedure:
Dimethyl-2-oxopropylphosphonate (1.2 equiv, 1.5 g, 9.1 mmol) was added to a suspension of K2CO3 (3 equiv, 3.1 g, 23 mmol) and p-TsN3 (1.2 equiv, 1.8 g, 9.1 mmol) in MeCN (144 mL). The mixture was then stirred for 2 h. A solution of the methyl 2-(4-(3-oxopropyl)phenyl)acetate (1 equiv, 1.56 g, 7.6 mmol) in MeOH was then added in one portion and the reaction was stirred overnight. The solvent was evaporated under reduced pressure. The residue was partitioned between Et2O (100 mL) and water (100 mL). The aqueous phase was separated and extracted with Et2O (25 mL) twice. The organic phases were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash column eluting with 0-30% EtOAc in hexanes to afford methyl 2-(4-(but-3-ynyl)phenyl)acetate in 980 mg (64%). LRMS: 202.5 (calc) 225.1 (found)(MNa)+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:21][CH3:22])[C:4]1[C:13]([CH2:14][NH:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1.CCN(CC)CC.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH3:22][O:21][CH:3]([O:2][CH3:1])[C:4]1[C:13]([CH2:14][N:15]([CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[S:31]([CH3:30])(=[O:33])=[O:32])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1
Reactant: COC(OC)c1nc2c(cc1CNCCN(C)C)CCCN2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(OC)c1nc2c(cc1CN(CCN(C)C)S(C)(=O)=O)CCCN2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N1-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-N2,N2-dimethylethane-1,2-diamine (intermediate 199, 780 mg, 2.53 mmol) and NEt3 (0.705 mL, 5.06 mmol) in DCM (20 ml) at 0° C. was added dropwise methanesulfonyl chloride (0.215 ml, 2.78 mmol) and the solution was allowed to stir for 2 h at room temperature. The reaction mixture was quenched by the addition of NaHCO3 and diluted. Phases were separated and the water phase was extracted with DCM (2×), organic phases were combined, dried using Na2SO4, filtered and concentrated. The crude product was purified by reversed phase preparative HPLC eluting with a gradient of MeCN and water (RP 6, H2O/MeCN 95:05 to 40:60 in 25 min). Fractions containing the product were collected, diluted with water and basified with NaHCO3. The mixture was concentrated and extracted with DCM, dried using Na2SO4, filtered and dried to yield the title compound as a colorless waxy solid. (UPLC-MS 3) tR 0.34 min, ESI-MS 387.2 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 7.26 (s, 1H), 6.56-6.52 (m, 1H), 5.01 (s, 1H), 4.33 (s, 2H), 3.32 (s, 6H), 3.28-3.23 (m, 2H), 3.11 (t, 2H), 3.06 (s, 3H), 2.66 (t, 2H), 2.24 (t, 2H), 2.08 (s, 6H), 1.80-1.73 (m, 2H).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Cl)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=1>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([O:26][C:22]2[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=2)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: Oc1cccnc1
Reactant: CCCCOC(=O)c1nc(Cl)c2ccccc2c1O
Product: CCCCOC(=O)c1nc(Oc2cccnc2)c2ccccc2c1O

Procedure:
Synthesized from 1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester and pyridin-3-ol in analogy to Example D-20 d); MS-(+)-ion: M+1=339.1.
Reaction SMILES: C(O)(=O)C.S(=O)(=O)(O)O.[CH:10]1[C:18]2[C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[S:15](=[O:24])(=[O:23])[C:14]=2[CH:13]=[CH:12][CH:11]=1.[N+:25]([O-])([OH:27])=[O:26]>O>[N+:25]([C:21]1[CH:20]=[CH:19][C:17]2[C:18]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[S:15](=[O:24])(=[O:23])[C:16]=2[CH:22]=1)([O-:27])=[O:26]
Reactant: O=[N+]([O-])O
Reactant: O=S1(=O)c2ccccc2-c2ccccc21
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)c1ccccc1-2
Temperature: 4 °C

Procedure:
To a mixture of acetic acid (77 ml) and sulphuric acid (77 ml) was added dibenzothiophene-5,5-dioxide (35.0 g), and the mixture cooled to 4° C. Addition of a total of 197 g. (131 ml) fuming nitric acid was begun, but in a short time the resulting paste became too thick to stir efficiently, and a further 77 ml, acetic acid was added. Local heating due to inefficient stirring was observed to occur, but the temperature of the reaction mixture was maintained at 4° C. as far as was possible. When the addition was complete (ca. 20 min.), the mixture was stirred at 4° C. for a further 30 min., and then poured into water. The crude nitrocompound was filtered off and recrystallised from dimethylformamide, m.p. 259° C.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH:17]=2)=[C:10]([CH3:32])[CH:9]=1)=[O:6]>CCO.CCOC(C)=O.[Ni]>[F:30][C:27]1[CH:28]=[CH:29][C:24]([CH:23]([OH:31])[C:18]2[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=2[OH:22])[O:15][C:11]2[C:12]([CH3:14])=[CH:13][C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([OH:33])=[O:2])=[CH:9][C:10]=2[CH3:32])=[CH:25][CH:26]=1
Reactant: COC(=O)CC(=O)Nc1cc(C)c(Oc2ccc(O)c(C(=O)c3ccc(F)cc3)c2)c(C)c1
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(NC(=O)CC(=O)O)cc(C)c1Oc1ccc(O)c(C(O)c2ccc(F)cc2)c1
Reaction time: 1 h
Yield: 73.8 %

Procedure:
To a solution of N-{4-[3-(4-fluoro-benzoyl)-4-hydroxy-phenoxy]-3,5-dimethyl-phenyl}-malonamic acid methyl ester (222 mg, 0.49 mmol) in a mixture of EtOH/EtOAc (4:1, 25 mL) was added nickel catalyst (2 mL, water and methanol washed). The mixture was hydrogenated under 50 psi at room temperature for 1 h. The catalyst was filtered off and the filtrate was concentrated. The residue was purified by preparative TLC to give the title compound of Step A (159 mg) as a white solid. MS (APCl−) Calc.: 453.2, Found: 452.2 (M−1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:21]COC)=[C:9]([C:11]2[N:16]=[CH:15][C:14]([C:17](F)(F)F)=[CH:13]N=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:25]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([OH:21])=[C:9]([C:11]2[CH:25]=[CH:13][C:14]([CH3:17])=[CH:15][N:16]=2)[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COCOc1ccc(C(C)(C)C)cc1-c1ncc(C(F)(F)F)cn1
Solvent: CO
Product: Cc1ccc(-c2cc(C(C)(C)C)ccc2O)nc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 1427.1 %

Procedure:
To a solution of 2-(5-(tert-butyl)-2-(methoxymethoxy)phenyl)-5-(trifluoromethyl)pyrimidine (0.23 g, 0.68 mmol) in methanol (10 mL) was added a catalytic amount of para-toluenesulfonic acid (10 mg) and the reaction mixture stirred at 40° C. open to air for 30 minutes. The reaction mixture was concentrated under reduced pressure to give 4-(tert-butyl)-2-(5-methylpyridin-2-yl)phenol (0.20 g, 100% yield) as a colorless oil.