Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH3:13])[C:6]3[CH2:20][CH2:21][N:22]([CH3:24])[CH2:23][C:5]=3[C:4]=2[CH:3]=1.CC(C)([O-])C.[Na+].[CH:31]1([NH2:35])[CH2:34][CH2:33][CH2:32]1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:31]1([NH:35][C:2]2[CH:10]=[CH:9][C:8]3[N:7](/[CH:11]=[C:12](/[C:14]4[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=4)\[CH3:13])[C:6]4[CH2:20][CH2:21][N:22]([CH3:24])[CH2:23][C:5]=4[C:4]=3[CH:3]=2)[CH2:34][CH2:33][CH2:32]1
Reactant: NC1CCC1
Reactant: CC(=Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Product: C/C(=C\n1c2c(c3cc(NC4CCC4)ccc31)CN(C)CC2)c1ccncc1
Temperature: 100 °C
Yield: 37.3 %

Procedure:
8-Chloro-2-methyl-5-(2-pyridin-4-yl-propenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.100 g, 0.245 mmol), sodium tertbutoxide (0.283 g, 2.948 mmol), palladium acetate (0.010 g, 0.049 mmol) and 2-di-tertbutylphosphino-2′-4′-6′-triisopropylbiphenyl (0.031 g, 0.0735 mmol) were charged in a reaction bottle which was evacuated and back filled with nitrogen for 5 min. Dry toluene (2 mL) was added under nitrogen atmosphere. Finally, cyclobutylamine (24.3 mg, 0.343 mmol) was added to the reaction mixture and the contents heated to 100° C. overnight. The reaction mixture was filtered and precipitate washed with EtOAc (2×25 mL). The filtrate was concentrated under vacuum and purified by reverse phase chromatography to yield 34 mg of desired compound as the TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.80 (d, 2H), 8.10 (d, 2H), 7.62 (d, 2H), 7.44 (d, 1H), 7.30 (d, 1H), 4.50 (m, 2H), 4.18 (m, 1H), 3.85 (m, 1H), 3.70 (m, 1H), 3.26 (m, 2H), 3.18 (s, 3H), 2.38 (m, 4H), 2.10 (s, 3H), 2.02-1.85 (m, 2H).
Reaction SMILES: CO.S(=O)(=O)(O)O.[CH3:8][NH:9][S:10]([C:13]1[CH:14]=[C:15]([C:23]([OH:25])=[O:24])[C:16]2[O:21][CH2:20][CH2:19][O:18][C:17]=2[CH:22]=1)(=[O:12])=[O:11].[C:26](=O)([O-])[O-].[Na+].[Na+]>O>[CH3:26][O:24][C:23]([C:15]1[C:16]2[O:21][CH2:20][CH2:19][O:18][C:17]=2[CH:22]=[C:13]([S:10](=[O:11])(=[O:12])[NH:9][CH3:8])[CH:14]=1)=[O:25]
Reactant: O=C([O-])[O-]
Reactant: CNS(=O)(=O)c1cc2c(c(C(=O)O)c1)OCCO2
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNS(=O)(=O)c1cc2c(c(C(=O)OC)c1)OCCO2
Yield: 85 %

Procedure:
750 ml of methanol were introduced into a balloon flask provided with a condenser. Then, under cooling, 273 g of concentrated sulfuric acid and 160 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carboxylic acid were added. The mixture was heated under reflux, cooled and poured into water and sodium carbonate. The precipitate was dried off, washed and dried. 143 g of methyl-7-methylsulfamoyl-1,4-benzodioxane-5-carboxylate were obtained (M.P.: 159°-160° C.: yield: 85%).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([C:30](=[O:32])[CH3:31])[CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[C:9]2[CH:33]=[C:34](Br)[C:35]([CH3:37])=[CH:36][C:8]1=2)=[O:6])([CH3:3])[CH3:2].[CH3:39]B(O)O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([C:30](=[O:32])[CH3:31])[CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[C:9]2[CH:33]=[C:34]([CH3:39])[C:35]([CH3:37])=[CH:36][C:8]1=2)=[O:6])([CH3:3])[CH3:2]
Reactant: CB(O)O
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(C)c(Br)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(C)c(C)cc21
Yield: 38.7 %

Procedure:
Combine isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-7-bromo-8-methyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (0.058 g, 0.095 mmol), methylboronic acid (0.011 g, 0.190 mmol), palladium acetate (0.0009 g, 0.004 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.0036 g, 0.0087 mmol) and potassium phosphate monohydrate (0.044 g, 0.190 mmol) in toluene (2 mL) and heat in a sealed tube at 100° C. for 24 h. Dilute the cooled mixture with ethyl acetate (30 mL) and filter through Celite. Remove the filtrate solvent under reduced pressure and purify the residue using chromatography on silica gel, eluting with hexanes/ethyl acetate (60:40), to provide the title compound as a white solid (0.020 g, 38%): ESI MS 545 (M+H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.C(Cl)CCl.[Cl:26][CH2:27][C:28](O)=[O:29]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:26][CH2:27][C:28]([N:12]1[CH2:13][CH2:14][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[CH:4]=2)[CH2:10][CH2:11]1)=[O:29]
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: O=C(O)CCl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCN(c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
To solution of 1-(3-chlorophenyl)piperazine hydrochloride (1.2 g, 5.2 mmol) in DCM (10 mL) was added triethylamine (1.0 mL, 7.3 mmol), EDC (1.9 g, 10 mmol), DMAP (cat.) and chloroacetic acid (0.4 g, 5.2 mmol). The reaction was stirred at RT overnight and DCM was removed. The resultant residue was partitioned between EtOAc (50 mL) and H2O (50 mL). The organic layer was dried over Na2SO4 and concentrated to provide 1.0 g of pure 2-chloro-1-(4-(3-chlorophenyl)piperazin-1-yl)ethanone, (yield: 70%).
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH:9]([CH:13]([CH3:15])[CH3:14])[CH2:8]2)=[CH:4][CH:3]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH:13]([CH:9]1[O:10][CH2:11][CH2:12][N:7]([CH2:6][C:5]2[CH:16]=[CH:17][C:2]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[C:19]([F:30])([F:29])[F:18])=[CH:3][CH:4]=2)[CH2:8]1)([CH3:15])[CH3:14]
Reactant: CC(C)C1CN(Cc2ccc(Br)cc2)CCO1
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)C1CN(Cc2ccc(-c3ccccc3C(F)(F)F)cc2)CCO1
Temperature: 120 °C

Procedure:
The above compound could be made in the following manner: 1 eq. of 4-(4-Bromo-benzyl)-2-isopropyl-morpholine could be combined with 1.5 eq. of 2-(Trifluoromethyl)phenyl boronic acid, 10 mol % of tetrakis(triphenylphosphine)palladium(0), 6.7 eq. of 2M sodium carbonate solution, toluene and ethanol. The reaction mixture could be heated in a sealed tube at 120° C. overnight in an oil bath. The reaction mixture is filtered through Celite and concentrated in vacuo. The residue could be diluted with water and extracted with ethyl acetate. The combined organic phases could be washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material could be purified by flash chromatography to afford product.
Reaction SMILES: [C:1]1([N:7]2[C:11]3=[N:12][C:13]([Cl:17])=[N:14][C:15](Cl)=[C:10]3[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][CH:19]([NH2:28])[CH:20]([OH:27])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1.Cl.[OH-].[K+]>C(O)C.O>[C:1]1([N:7]2[C:11]3=[N:12][C:13]([Cl:17])=[N:14][C:15]([NH:28][CH:19]([CH:20]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[OH:27])[CH3:18])=[C:10]3[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(N)C(O)c1ccccc1
Reactant: Clc1nc(Cl)c2cnn(-c3ccccc3)c2n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(Nc1nc(Cl)nc2c1cnn2-c1ccccc1)C(O)c1ccccc1
Reaction time: 4 h
Yield: 90 %

Procedure:
390 mg of 1-phenyl-4,6-dichloropyrazolo[3,4-d]pyrimidine was suspended in 15 ml 95% ethanol. 828 mg norephedrine HCl was dissolved in 100 ml H2O, made basic with 10% KOH, and the free base extracted with 100 ml ether. The organic was dried over MgSO4, filtered, and concentrated to yield an oil which was added to the stirred reaction. After 4 hours the solution became clear and the solvent was removed under vacuum. The crude oil was then purified by radial chromatography (5-10-20% isopropyl alcohol/hexane, 4 mm plate) to yield 535 mg of [R-(S*,R*)]-α-[1-[(1-phenyl-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-yl) amino]ethyl]benzenemethanol (90%).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:3]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.ClCCl.C(Cl)(Cl)Cl.CCOCC>[O:9]1[CH:10]=[CH:11][CH:12]=[C:8]1[C:4]1[CH:5]=[N:6][CH:7]=[C:2]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[N:3]=1
Reactant: C1CNCCN1
Reactant: Clc1cncc(-c2ccco2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Solvent: CCOCC
Product: c1coc(-c2cncc(N3CCNCC3)n2)c1
Temperature: 85 °C
Yield: 64 %

Procedure:
A mixture of the product from step 1 above (0.94 g, 5.2 mmol), piperazine (1.28 g, 14.9 mmol, K2CO3 (0.87 g, 6.3 mmol) in acetonitrile (5 mL) was heated in a sealed pyrex flask at 85° C. for 3 h. The mixture was diluted with dichloromethane, filtered, and concentrated in vacuo. The oily residue was purified by silica gel chromatography (18×4 cm) to furnish a yellow oil. This material was redissolved in a small volume of CHCl3/ether (9:1) and filtered through a short (4 cm) plug of alumina eluting with ether/MeOH (96:4). The filtrate was concentrated in vacuo to afford 0.77 g (64%) of the title compound as a light yellow solid. HRMS m/z calcd for C12H14N4O (M)+ 230.1168, found 230.1170. Anal. (C12H14N4O) C, H, N.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][C@H:6]([CH2:8][OH:9])[C@@H:5]([OH:10])[C@H:4]1[OH:11].N[C:13]1[N:18]=[C:17](Cl)[CH:16]=[C:15]([Cl:20])[N:14]=1.CCN(CC)CC>C(O)(C)C>[Cl:20][C:15]1[N:14]=[CH:13][N:18]=[C:17]([NH:2][C@@H:3]2[CH2:7][C@H:6]([CH2:8][OH:9])[C@@H:5]([OH:10])[C@H:4]2[OH:11])[CH:16]=1
Reactant: N[C@@H]1C[C@H](CO)[C@@H](O)[C@H]1O
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: OC[C@H]1C[C@@H](Nc2cc(Cl)ncn2)[C@H](O)[C@@H]1O
Temperature: 90 °C
Yield: 143.3 %

Procedure:
To a solution of (1R,2S,3R,5R)-3-amino-5-(hydroxymethyl)cyclopentane-1,2-diol HCl (1.00 g, 5.44 mmol) and 2-amino-4,6-dichloropyrimidine (0.982 g, 5.99 mmol) in isopropyl alcohol (8 mL) was added Et3N (1.90 mL, 13.6 mmol). The reaction was heated to 90° C. for 1 h in an oil bath then cooled, filtered and concentrated in vacuo. The residue was dissolved in CH2Cl2 and purified by flash chromatography (20 to 50% MeOH/CH2Cl2) to afford the title compound as an off-white solid (2.025 g, >99%). LC/MS: Rt=0.81 min ES 260 (FA standard).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[NH:22][CH:21]=[C:20]([C:23](O)=[O:24])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[C:26]([O:30][C:31](=[O:40])[NH:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([NH2:39])[CH2:35][CH2:34]1)([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31](=[O:40])[NH:32][C@H:33]1[CH2:34][CH2:35][C@H:36]([NH:39][C:23]([C:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([C:7]4[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:15]=3[NH:22][CH:21]=2)=[O:24])[CH2:37][CH2:38]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c[nH]c23)c1
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c[nH]c23)c1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A75) and trans-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[C:8]([O:12][C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C@@H:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[F:30])[CH2:19][N:18]2[C:31]([C:34]([OH:36])=[O:35])=[CH:32][N:33]=[C:17]12)=[O:14])([CH3:11])([CH3:10])[CH3:9]>ClCCl.CO>[C:8]([O:12][C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C@@H:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[F:30])[CH2:19][N:18]2[C:31]([C:34]([O:36][CH3:1])=[O:35])=[CH:32][N:33]=[C:17]12)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C(=O)O)cnc21
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
(Trimethylsilyl)diazomethane (2.0 M in ether; 173 μL, 0.35 mmol) was added to a solution of (6S,9R)-9-[(tert-butoxycarbonyl)amino]-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepine-3-carboxylic acid (47 mg, 0.12 mmol) in dichloromethane (1.5 mL) and methanol (0.5 mL). After 1 h, additional (trimethylsilyl)diazomethane (2.0 M in diethyl ether; 50 μL, 0.10 mmol) was added. After 4 h, the reaction mixture was concentrated. MS 422.2 (M+1).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH:16]=[C:17](Br)[C:11]=2[N:10]([CH3:27])[C:9]1=[O:28])(=[O:3])[CH3:2].[CH3:29][Sn](C)(C)C>CN(C=O)C.CC(=O)OCC.O.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>[C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH:16]=[C:17]([CH3:29])[C:11]=2[N:10]([CH3:27])[C:9]1=[O:28])(=[O:3])[CH3:2]
Reactant: C[Sn](C)(C)C
Reactant: CC(=O)OCCCn1c(=O)c2c(c(Br)cn2Cc2ccc(Cl)cc2)n(C)c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)OCCCn1c(=O)c2c(c(C)cn2Cc2ccc(Cl)cc2)n(C)c1=O
Temperature: 25 °C
Yield: 92.6 %

Procedure:
To a solution of 3-(7-bromo-5-(4-chlorobenzyl)-1-methyl-2,4-dioxo-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (50 mg, 0.107 mmol) in DMF (2 mL) was added tetramethylstannane (38.2 mg, 0.214 mmol) and Pd(PPh3)2Cl2 (10 mg). The reaction was heated at 120° C. (MW) for 45 min, cooled to RT then diluted with EA (5 mL) and water (5 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (5:1 to 1:1) to give 3-(5-(4-chlorobenzyl)-1,7-dimethyl-2,4-dioxo-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (40 mg, 92.8% yield) as an oil. LCMS: MH+ 404 and TR=1.630 min. Used without further purification.
Reaction SMILES: O.[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])[CH2:4][CH2:3]1.[CH2:15]([O:22][C:23]1[C:24](Cl)=[N:25][C:26]([C:29]([F:32])([F:31])[F:30])=[N:27][CH:28]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[C:16]1([CH2:15][O:22][C:23]2[C:24]([N:2]3[CH2:3][CH2:4][CH:5]([CH2:8][N:9]4[CH2:13][CH2:12][CH2:11][C:10]4=[O:14])[CH2:6][CH2:7]3)=[N:25][C:26]([C:29]([F:31])([F:32])[F:30])=[N:27][CH:28]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: FC(F)(F)c1ncc(OCc2ccccc2)c(Cl)n1
Reactant: O=C1CCCN1CC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C1CCCN1CC1CCN(c2nc(C(F)(F)F)ncc2OCc2ccccc2)CC1
Yield: 79.8 %

Procedure:
A mixture of 1-[(4-piperidinyl)methyl]-2-pyrrolidinone hydrate (XXV 0.63 g, 3.46 mmol), compound XXIV (1.0 g, 3.46 mmol), and sodium carbonate (0.8 g, 6.92 mmol) in acetonitrile (20 mL) was refluxed for 18 hr. The mixture was cooled, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel using ethyl acetate as the eluent to give the desired product (1.2 g, 79.8%, mp: 155°-157°).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[CH:9][C:8]=2[C:12]([OH:14])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.Cl.[CH3:35][N:36]([CH3:50])[C:37]([C:39]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:43][CH2:42][NH:41][CH2:40]1)=[O:38]>ClCCl>[CH3:35][N:36]([CH3:50])[C:37]([C:39]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:43][CH2:42][N:41]([C:12]([C:8]2[CH:9]=[N:10][O:11][C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:14])[CH2:40]1)=[O:38]
Reactant: CN(C)C(=O)C1(c2ccccc2)CCNC1
Reactant: O=C(O)c1cnoc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)C1(c2ccccc2)CCN(C(=O)c2cnoc2-c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.1 %

Procedure:
To a solution of 5-phenylisoxazol-4-carboxylic acid (15 mg, 0.08 mmol) in dichloromethane (2 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (15 mg, 0.08 mol), triethylamine (33 μL, 0.24 mmol) and finally N,N-dimethyl-3-phenylpyrrolidine-3-carboxamide hydrochloride (15 mg, 0.06 mmol) and allowed to stir at ambient temperature overnight. The residue was purified using straight phaseHPLC (1:1 hexane/ethyl acetate) to afford the title compound (4 mg). HRMS (ESI, pos. ion) m/z calcd for C23H23N3O3: 389.1739, found 389.1744.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C@H:10]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][O:27]C2CCCCO2)[CH:21]=1)[O:11][CH2:12][C:13]1([CH2:16][C:17]([OH:19])=[O:18])[CH2:15][CH2:14]1.[CH2:34]1COCC1.N1C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C@H:10]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][OH:27])[CH:21]=1)[O:11][CH2:12][C:13]1([CH2:16][C:17]([O:19][CH3:34])=[O:18])[CH2:14][CH2:15]1
Reactant: O=C(O)CC1(CO[C@H](CCc2ccccc2Br)c2cccc(COC3CCCCO3)c2)CC1
Reactant: C1CCOC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: COC(=O)CC1(CO[C@H](CCc2ccccc2Br)c2cccc(CO)c2)CC1
Reaction time: 144 h

Procedure:
The acid of Step 7 (1.816 g, 3.51 mmol) was esterified with CH2N2 at 0° C. in ether:THF. The excess CH2N2 was quenched with AcOH and the product was concentrated and stripped with toluene twice. This ester was dissolved in 20 mL MeOH and then pyridine (7 μL) and pyridinium p-toluenesulfonate (220 mg, 0.88 mmol) were added. After 6 days of stirring, the solvent was evaporated. 25% aq. NH4OAc was then added and the product was extracted in EtOAc, dried over Na2SO4, and purified by flash chromatography on silica with EtOAc:hexane 30:70; yield: 1.53 g, (97%).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([CH2:7][CH2:8][C@H:9]([OH:28])[CH2:10][CH2:11][C@@H:12]2[C@@H:16]([CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C@@H:15]([OH:26])[CH2:14][C@H:13]2[OH:27])=[CH:5][CH:6]=1.[CH:29](I)([CH3:31])[CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+].OS([O-])(=O)=O.[Na+]>CCOCC.CN(C=O)C>[CH3:30][CH:29]([O:24][C:23]([CH2:22][CH2:21][CH2:20]/[CH:19]=[CH:18]\[CH2:17][C@@H:16]1[C@@H:12]([CH2:11][CH2:10][C@@H:9]([OH:28])[CH2:8][CH2:7][C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[C@H:13]([OH:27])[CH2:14][C@@H:15]1[OH:26])=[O:25])[CH3:31]
Reactant: O=C(O)CCC/C=C\C[C@@H]1[C@@H](CC[C@@H](O)CCc2ccccc2)[C@H](O)C[C@@H]1O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)OC(=O)CCC/C=C\C[C@@H]1[C@@H](CC[C@@H](O)CCc2ccccc2)[C@H](O)C[C@@H]1O
Temperature: 45 °C
Reaction time: 2.5 h

Procedure:
A mixture of Latanoprost acid [13b] (0.95 g, 2.4 mmol), isopropyl iodide (0.83 g, 4.8 mmol), cesium carbonate (1.20 g, 3.6 mmol) and DMF (20 mL) was stirred for 2-3 hours at 40-50° C. (TMC monitoring) and poured into a stirred mixture of 2 M aqueous NaHSO4 (2.5 mL, 5 mmol), ice (50 mL) and ether (50 mL). The organic layer was separated and the water phase was extracted with ether (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to give 1.05 g (100% yield) of crude product. The crude product was purified by column chromatography on silica gel (hexane/ethyl acetate 1:1 v/v) to give Latanoprost. 1H NMR (CDCl3) is compatible with literature data.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[C:4]([F:17])[C:3]=1[F:18].[NH2:19][C:20]1[N:25]=[C:24](Cl)[N:23]=[C:22]([C:27]([O:29][CH3:30])=[O:28])[CH:21]=1.[F-].[Cs+].P(C1C=C(S([O-])(=O)=O)C=CC=1)(C1C=C(S([O-])(=O)=O)C=CC=1)C1C=C(S([O-])(=O)=O)C=CC=1.[Na+].[Na+].[Na+]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[NH2:19][C:20]1[N:25]=[C:24]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:18])[C:4]=2[F:17])[N:23]=[C:22]([C:27]([O:29][CH3:30])=[O:28])[CH:21]=1
Reactant: CC1(C)OB(c2ccc(Cl)c(F)c2F)OC1(C)C
Reactant: COC(=O)c1cc(N)nc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cc(N)nc(-c2ccc(Cl)c(F)c2F)n1
Temperature: 150 °C
Yield: 68.3 %

Procedure:
2-(4-Chloro-2,3-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.4 g, 5.1 mmol, 1.2 equiv) and methyl 6-amino-2-chloropyrimidine-4-carboxylate (800 mg, 4.3 mmol, 1.0 equiv) were sequentially added to a 20 mL Biotage microwave vessel, followed by cesium fluoride (1.3 g, 8.5 mmol, 2.0 equiv), palladium(II) acetate (38 mg, 0.17 mmol, 0.04 equiv), and sodium 3,3′,3″-phosphinetriyltribenzenesulfonate (190 mg, 0.34 mmol, 0.08 equiv). A 3:1 mixture of water:acetonitrile (8.5 mL) was added and the resulting brown mixture was placed in a Biotage microwave and heated at 150° C. for 5 m. The cooled reaction mixture was diluted with water (300 mL) and extracted with dichloromethane (5×100 mL). The combined organic layers were dried (magnesium sulfate), gravity-filtered, and concentrated under vacuum. The product was purified by flash chromatography (SiO2, 40% ethyl acetate in hexane) to afford the title compound as an off-white powder (880 mg, 68% yield): mp 192-195° C.; 1H NMR (300 MHz, CDCl3) δ 7.77 (m, 1H), 7.21-7.28 (m, 2H), 7.15 (s, 1H), 5.23 (br s, 2H), 4.00 (s, 3H); IR (neat film) 3493 (w), 3393 (m), 3342 (m), 3211 (s), 1730 (m), 1649 (m); ESIMS m/z 300 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].C(N(CC)CC)C.Cl[CH2:20][C:21](Cl)=[O:22]>C(Cl)Cl>[N+:8]([C:6]1[CH:5]=[CH:4][C:3]2[O:11][CH2:20][C:21](=[O:22])[NH:1][C:2]=2[CH:7]=1)([O-:10])=[O:9]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1COc2ccc([N+](=O)[O-])cc2N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.2 %

Procedure:
A solution of 2-Amino-4-nitro phenol (6.0 g, 38.93 mmol) in methylene chloride (200 ml) was cooled to 0° C. Triethyl amine (16.3 ml, 116.9 mmol) was added followed by chloroacetyl chloride (3.42 ml, 42.8 mmol) portionwise. The mixture was stirred at room temperature for 18 hours, then diluted with methylene chloride. The organic phase was washed with water, dried over MgSO4, filtered and concentrated under reduced pressure to give 7.5 g of 6-nitro-4H-benzo[1,4]oxazin-3-one as a solid, 100%.