Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2([CH2:9][CH2:8][CH:7]([C:10](O)=O)[CH2:6]2)OCC1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:25][C:26]1[C:27](=[O:40])[N:28]([CH2:37][CH2:38][CH3:39])[C:29](=[O:36])[N:30]([CH2:33][CH2:34][CH3:35])[C:31]=1[NH2:32]>C(Cl)Cl>[CH2:37]([N:28]1[C:27](=[O:40])[C:26]2[NH:25][C:10]([CH:7]3[CH2:8][CH2:9][C:5](=[O:1])[CH2:6]3)=[N:32][C:31]=2[N:30]([CH2:33][CH2:34][CH3:35])[C:29]1=[O:36])[CH2:38][CH3:39]
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: O=C(O)C1CCC2(C1)OCCO2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CCCn1c(=O)c2[nH]c(C3CCC(=O)C3)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.9 %

Procedure:
2.4 g (0.014 mol) of 1,4-dioxaspiro[4,4]nonan-7-carboxylic acid are dissolved in 56 ml of methylene chloride and after the addition of 2.2 g (0.014 mol) of carbonyldiimidazole stirred for 1 hour at ambient temperature. Then 3.2 g (0.014 mol) of 5,6-diamino-1,3dipropyluracil are added and the mixture is stirred for a further 4 hours at ambient temperature. The solution is evaporated down in vacuo, the oily residue is mixed with 70 ml of water and 4.5 g of Ca(OH)2 and stirred for 1 hour at 70° C. 100 ml of 50% NaOH are added, the mixture is stirred for a further hour at 70° C. and for 16 hours at ambient temperature. Whilst being cooled with ice, the solution is adjusted to pH 6 with HCl and extracted with methylene chloride. After drying and evaporation in vacuo the combined organic phases yield a crystalline residue which is recrystallised from ethanol using activated charcoal. 0.8 g (16%) of white crystals are obtained, m.p. 147°-148° C.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([NH2:13])[C:7]=1[OH:14])(=[O:5])=[O:4].[Cl:15][C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[N:23]=[C:24]=[O:25]>CN(C)C=O.C(OCC)(=O)C>[Cl:12][C:11]1[CH:10]=[CH:9][C:8]([NH:13][C:24]([NH:23][C:17]2[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=2[Cl:15])=[O:25])=[C:7]([OH:14])[C:6]=1[S:3]([NH:2][CH3:1])(=[O:5])=[O:4]
Reactant: O=C=Nc1cccc(Cl)c1Cl
Reactant: CNS(=O)(=O)c1c(Cl)ccc(N)c1O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2cccc(Cl)c2Cl)c1O
Yield: 48.7 %

Procedure:
A solution of N-methyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide (70 mg, 0.29 mmol) and 2,3-dichlorophenylisocyanate (57 μL, 0.44 mmol) in 2 mL of N,N-dimethylformamide was stirred at room temperature for 66 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude material. Purification by column chromatography on silica gel, eluting with ethyl acetate/hexane (30/70, v/v), gave the desired product (60 mg, 49%, three steps). EI-MS (m/z) 422.3, 424.3, 426.3 (M−).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:18]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)([OH:20])=[O:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>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.O>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:24]2[CH:25]=[CH:26][C:21]([C:18]([OH:20])=[O:19])=[CH:22][CH:23]=2)=[CH:3][C:4]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17]
Reactant: Nc1ncc(Br)cc1OCc1ccccc1Cl
Reactant: O=C(O)c1ccc(B(O)O)cc1
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: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncc(-c2ccc(C(=O)O)cc2)cc1OCc1ccccc1Cl
Temperature: 87.5 °C
Reaction time: 0.5 h
Yield: 53.2 %

Procedure:
5-Bromo-3-(2-chloro-benzyloxy)-pyridin-2-ylamine (4.50 g, 14.3 mmol), 4-carboxybenzeneboronic acid (2.62 g, 15.8 mmol), tetrakis(triphenylphosphine)palladium(0) (0.56 g, 0.5 mmol), potassium carbonate (6.90 g, 50 mmol), dimethylformamide (36 mL), and water (18 mL) were charged to a 250 mL three neck round bottom flask equipped with a thermometer, a reflux condenser and magnetic stirring. The mixture was purged with nitrogen and gradually heated from 82 to 93° C. over a period of 4 hr. Thin layer chromatography (ethyl acetate:hexane:acetic acid 4:6:0.5) showed product at Rf 0.3 and a few small impurities. The mixture was cooled to 45° C. The solids were collected by vacuum filtration, washed with 10 mL of ethanol:water 1:1 and discarded. The combined filtrate was diluted with 216 mL of water and 4 mL of 9 N potassium hydroxide solution (to pH 12-13), cooled in an ice bath and stirred for 30 minutes with 3 g of Celite and 3 g of Norit. The solids were collected by vacuum filtration through a pad of Celite and washed with 10 mL of water. The solids were discarded. The combined filtrate was cooled in an ice bath and acidified to pH 7 with acetic acid using a pH meter. The solids were collected by vacuum filtration, washed with 20 mL of ethanol-water 1:1 and dried under vacuum to give 2.7 g (53% yield) of 4-[6-amino-5-(2-chloro-benzyloxy)-pyridin-3-yl]-benzoic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([CH3:15])([OH:14])[CH3:13].[H-].[Na+].[NH2:18]OS(O)(=O)=O>CN(C=O)C.CCOC(C)=O>[NH2:18][N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[C:5]([CH2:11][C:12]([CH3:15])([OH:14])[CH3:13])=[CH:6]1
Reactant: NOS(=O)(=O)O
Reactant: CC(C)(O)Cc1c[nH]c2ccc(F)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(O)Cc1cn(N)c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(5-fluoro-1H-indol-3-yl)-2-methyl-propan-2-ol (207 mg, 1 mmol) in DMF (10 mL) is cooled to 0° C., treated with NaH (600 mg, 15 mmol, 60% in mineral oil) and stirred for 30 min. H2NOSO3H (565 mg, 5 mmol) is added portion wise, and the mixture is warmed to rt over 2 h. The mixture is diluted with EtOAc (100 mL), quenched with water, extracted with EtOAc, dried (Na2SO4), filtered and concentrated in vacuo to afford 1-(1-amino-5-fluoroindol-3-yl)-2-methyl-propan-2-ol, which is used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[N:19]=[C:18](Cl)[CH:17]=[C:16]([NH:21][C:22]3[NH:23][N:24]=[C:25]([CH3:27])[CH:26]=3)[N:15]=2)=[CH:9][CH:8]=1)=[O:5].[NH:32]1[CH2:35][CH2:34][CH2:33]1.C(N(CC)C(C)C)(C)C>C(O)CCC>[N:32]1([C:18]2[CH:17]=[C:16]([NH:21][C:22]3[NH:23][N:24]=[C:25]([CH3:27])[CH:26]=3)[N:15]=[C:14]([S:13][C:10]3[CH:9]=[CH:8][C:7]([NH:6][C:4](=[O:5])[C:3]4[CH:28]=[CH:29][CH:30]=[CH:31][C:2]=4[Cl:1])=[CH:12][CH:11]=3)[N:19]=2)[CH2:35][CH2:34][CH2:33]1
Reactant: Cc1cc(Nc2cc(Cl)nc(Sc3ccc(NC(=O)c4ccccc4Cl)cc3)n2)[nH]n1
Reactant: C1CNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cc(Nc2cc(N3CCC3)nc(Sc3ccc(NC(=O)c4ccccc4Cl)cc3)n2)[nH]n1
Temperature: 90 °C
Reaction time: 5 h
Yield: 56.3 %

Procedure:
A 500 mL round bottom flask was charged with 2-chloro-N-{4-[4-chloro-6-(5-methyl-2H-pyrazol-3-ylamino)-pyrimidin-2-ylsulfanyl]-phenyl}-benzamide (16.0 g, 34.0 mmol), azetidine (3.87 g, 68.0 mmol), N,N-diisopropylethylamine (13.0 mL, 74.7 mmol) and n-butanol (250 mL). The reaction mixture was stirred at 90° C. for 5 h. The reaction mixture was cooled and concentrated in vacuo. Diethyl ether (200 mL) was added and a light brown solid precipitated. The solution was filtered and the solid recrystallized from ethanol to give the pure product as a white solid (9.42 g, 52%) 1H NMR (DMSO): 2.04 (3H, s), 2.32 (2H, m), 3.87 (4H, m), 5.39 (1H, s), 5.66 (1H, br s), 7.48-7.59 (6H, m), 7.82 (2H, m), 9.87 (1H, s), 10.74 (1H, s), 11.68 (1H, s); MS (ES+): 492.
Reaction SMILES: [CH2:1]([N:8](C)[C:9]1[C:10](=[O:25])[NH:11][C:12](=[O:24])[N:13]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:16])[CH:14]=1)C1C=CC=CC=1.[H][H]>CCOC(C)=O.[Pd]>[CH2:18]([NH:17][C:15]([N:13]1[CH:14]=[C:9]([NH:8][CH3:1])[C:10](=[O:25])[NH:11][C:12]1=[O:24])=[O:16])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: [H][H]
Reactant: CCCCCCNC(=O)n1cc(N(C)Cc2ccccc2)c(=O)[nH]c1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCNC(=O)n1cc(NC)c(=O)[nH]c1=O
Yield: 26.6 %

Procedure:
5-(Benzyl(methyl)amino)-N-hexyl-2,4-dioxo-pyrimidine-1-carboxamide(0.10 g, 0.28 mmol) was dissolved in EtOAc (30 mL) and hydrogenated in an H-Cube apparatus (using 10% Pd/C as catalyst, 1 bar hydrogen pressure, at 40° C.). The reaction mixture was concentrated under reduced pressure. The crude was purified by column chromatography using SI (2 g) cartridge (cyclohexane:EtOAc 85:15) to afford the title compound (0.02 g, 27%) as white powder. 1H NMR (400 MHz, DMSO-d6): δ 0.78-0.99 (m, 3H), 1.17-1.36 (m, 6H), 1.50 (dd, J=14.0, 7.0 Hz, 2H), 2.57 (s, 3H), 3.27 (dd, J=5.7, 6.9 Hz, 2H), 5.01 (s, 1H), 7.05 (s, 1H), 9.32 (t, J=5.7 Hz, 1H), 11.87 (s, 1H). 13C NMR (101 MHz, CDCl3): δ 13.85, 21.96, 25.89, 28.71, 29.70, 30.82, 40.21, 106.74, 126.49, 150.01, 150.68, 160.01. MS (ESI) m/z: 267 [M-H]−.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH:18]=4)=[CH:16][C:9]=23)[CH:5]=[CH:4][CH:3]=1.[ClH:30].O1CCOCC1>CO>[F:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH:18]=4)=[CH:16][C:9]=23)[CH:5]=[CH:4][CH:3]=1.[ClH:30]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(-c4cccc(F)n4)ccnc3[nH]2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Fc1cccc(-c2ccnc3[nH]c(C4=CCNCC4)cc23)n1

Procedure:
A mixture of Example 309E (4.0 g, 10.14 mmol) and 4M HCl in dioxane (25.4 ml, 101 mmol) in methanol (10 mL) was stirred at room temperature for 4 hours. The mixture was concentrated and the solid was washed with ethyl acetate and vacuum dried to provide the title compound as an HCl salt. 1H NMR (400 MHz, DMSO-d6) δ 2.81 (s, 2H), 3.33 (s, 2H), 3.83 (s, 2H), 6.62 (s, 1H), 7.17 (d, J=1.6 Hz, 1H), 7.30 (dd, J=7.9, 2.6 Hz, 1H), 7.68 (d, J=5.2 Hz, 1H), 8.08-8.25 (m, 2H), 8.37 (d, J=5.2 Hz, 1H), 9.46 (s, 2H), 12.44 (s, 1H). MS (ESI+) m/z 295.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH3:17][Sn:18](Cl)([CH3:20])[CH3:19]>O1CCCC1.CCCCCC>[F:9][C:8]([F:11])([F:10])[C:4]1[CH:3]=[C:2]([Sn:18]([CH3:20])([CH3:19])[CH3:17])[CH:7]=[CH:6][CH:5]=1
Reactant: C[Sn](C)(C)Cl
Reactant: FC(F)(F)c1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[Sn](C)(C)c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To 20.0 g (88.9 mmol) of meta-bromobenzotrifluoride stirring in 200 ml of tetrahydrofuran at 78° C., 61.2 ml of 1.6M n-butyl lithium (97.9 mmol) in hexane was added dropwise. After stirring the reaction 10 minutesat -78° C., 19.5 g (97.8 mmol) of trimethyltin chloride dissolved in30 ml of tetrahydrofuran was added dropwise and the mixture stirred for 10 minutes at -78° C. before allowing to warm to room temperature. Thereaction mixture was quenched with excess saturated sodium bicarbonate and extracted with ethyl acetate (300 ml). The extract was washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated in vacuo to give a crude yield of 20.2 g of the above product, isolated as a oily semi-solid. This aryl stannane was used directly as a crude material in the coupling reactions with heterocycles of Formula II.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[O:14][C:13]([C:15]3[CH:16]=[C:17]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:18]([NH2:21])=[CH:19][CH:20]=3)=[N:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.[N:31]#[C:32]Br.C(=O)([O-])O.[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]4[N:21]=[C:32]([NH2:31])[N:22]([C:23]5[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=5)[C:17]=4[CH:16]=3)=[N:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#CBr
Reactant: COc1ccc(Nc2cc(-c3nnc(CCc4cccc(F)c4)o3)ccc2N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-n2c(N)nc3ccc(-c4nnc(CCc5cccc(F)c5)o4)cc32)cc1
Yield: 61.8 %

Procedure:
A solution of 4-[5-[2-(3-fluorophenyl)ethyl]-1,3,4-oxadiazol-2-yl]-N2-(4-methoxyphenyl)benzene-1,2-diamine (0.20 g, 0.49 mmol) and cyanogen bromide (0.11 g, 1.03 mmol) in ethanol (5 mL) was stirred at 60° C. for 4 hr. After cooling, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=1/2-1/3) to give the title compound (0.13 g, yield 62%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:37])[C:9]2[N:10]=[C:11]([C:27]3[CH:32]=[CH:31][N:30]=[C:29]([NH:33][C:34](=[O:36])[CH3:35])[CH:28]=3)[S:12][C:13]=2[C:14]2[N:15](COCC[Si](C)(C)C)[CH:16]=[CH:17][N:18]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:37])[C:9]2[N:10]=[C:11]([C:27]3[CH:32]=[CH:31][N:30]=[C:29]([NH:33][C:34](=[O:36])[CH3:35])[CH:28]=3)[S:12][C:13]=2[C:14]2[NH:18][CH:17]=[CH:16][N:15]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1cc(-c2nc(C(O)c3ccc(Cl)cc3)c(-c3nccn3COCC[Si](C)(C)C)s2)ccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1cc(-c2nc(C(O)c3ccc(Cl)cc3)c(-c3ncc[nH]3)s2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
N-{4-[4-[(4-chlorophenyl)(hydroxy)methyl]-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-1,3-thiazol-2-yl]pyridin-2-yl}acetamide (0.120 g, 0.216 mmol) was dissolved in DCM (5 mL) and trifluoroacetic acid (5.0 mL, 65 mmol) was added. The mixture was stirred at room temperature overnight. The solvent was evaporated, azeotroped with toluene and purified using column chromatography on silica gel (0 to 10% MeOH in DCM) to give the title compound (0.050 g, 50%). LCMS: (FA) ES+, 426, 428. 1H NMR (400 MHz, d4-methanol) δ: 8.68 (s, 1H), 8.38 (d, J=5.24 Hz, 1H), 7.64 (dd, J=5.25, 1.60 Hz, 1H), 7.45-7.37 (m, 2H), 7.30-7.23 (m, 2H), 7.25-7.09 (m, 2H), 6.37 (s, 1H), 2.20 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]([C:19]2[N:20]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[N:21]=[C:22]3[C:27]=2[CH:26]=[CH:25][CH:24]=[CH:23]3)[CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:6][CH:5]=1.[OH-].[Li+]>C1COCC1.CO>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([N:20]2[C:19]([CH:12]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:35])=[O:2])=[CH:5][N:6]=3)=[C:27]3[C:22]([CH:23]=[CH:24][CH:25]=[CH:26]3)=[N:21]2)=[CH:29][CH:30]=1
Reactant: COC(=O)c1ccc(OCC(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OCC(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)nc1

Procedure:
In analogy to the procedure described in example 7.2, [rac]-6-{2-[2-(4-chloro-phenyl)-2H-indazol-3-yl]-2-cyclohexyl-ethoxy}-nicotinic acid methyl ester was treated with 1 N aqueous lithium hydroxide solution in THF and MeOH to give the title compound as colorless oil. MS: m/e=476.1 [M+H+].
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[NH:4][N:5]=[CH:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][C@@H:13]2[CH2:15][C@@H:11]([C:12]2([CH3:17])[CH3:16])[C@H:10]1[CH3:18].Cl.Cl[CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[Br:1][C:2]1[C:3](=[O:19])[N:4]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[N:5]=[CH:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][C@@H:13]2[CH2:15][C@@H:11]([C:12]2([CH3:16])[CH3:17])[C@H:10]1[CH3:18]
Reactant: ClCCCCc1ccncc1
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cn[nH]c(=O)c1Br)C2(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CCCCc3ccncc3)c(=O)c1Br)C2(C)C
Temperature: 80 °C
Reaction time: 6.5 h
Yield: 12.2 %

Procedure:
4-Bromo-5-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-3(2H)-one (221 mg, 0.677 mmol) in N,N-dimethylformamide (4 mL) was mixed with 4-(4-chlorobutyl)pyridine hydrochloride (278 mg, 1.35 mmol) and potassium carbonate (375 mg, 2.71 mmol) at room temperature and stirred at 80° C. for 6.5 hours. After cooling, ethyl acetate was added, and the organic layer was washed with saturated aqueous ammonium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform/methanol=50/1) to give the desired product (38 mg, 12% yield).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:13]1(B(O)O)[CH2:15][CH2:14]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].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.O>[CH:13]1([C:2]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH2:15][CH2:14]1
Reactant: OB(O)C1CC1
Reactant: COC(=O)c1c(F)cccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1c(F)cccc1C1CC1
Yield: 98.8 %

Procedure:
Methyl 2-bromo-6-fluorobenzoate (2, 11.29 g, 48.5 mmol), cyclopropylboronic acid (6.24 g, 72.7 mmol), K3PO4 (30.85 g, 145.4 mmol) and Pd(PPh3)4 (2.80 g, 2.4 mmol) were mixed under argon in a degassed mixture of toluene and water (20:1, 160 mL). The resulting brown suspension was heated at reflux for 2.5 h, cooled, filtered through Celite, and evaporated. The residue was partitioned between ethyl acetate (150 mL) and brine (150 mL). The layers were separated and organic layer was dried over magnesium sulfate and evaporated. The oily residue was suspended in hexane and the solid was removed by filtration. Evaporation of the filtrate afforded the title compound (9.30 g, 47.9 mmol, 99%) as a light brown oil.
Reaction SMILES: Cl.[NH:2]1[CH2:13][S:12][CH2:11][C@H:3]1[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].C(N(CC)CC)C.[CH2:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH:22]1[CH2:30][CH2:31][C:32](O)=[O:33].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH2:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:21][CH:22]1[CH2:30][CH2:31][C:32]([CH:11]1[S:12][CH2:13][NH:2][C@@H:3]1[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])=[O:33]
Reactant: O=C([C@@H]1CSCN1)N1CCCC1
Reactant: O=C(O)CCC1Cc2ccccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCC1Cc2ccccc2C1)C1SCN[C@@H]1C(=O)N1CCCC1
Reaction time: 0.17 h
Yield: 71.2 %

Procedure:
0.89 g of 1-L-thioprolylpyrrolidine hydrochloride was suspended in 20 ml of methylene chloride. To the suspension were added 0.40 g of triethylamine and 0.76 g of 3-(indan-2-yl)propionic acid under ice-cooling with stirring. After 10 minutes, 0.92 g of WSC.HCl was added to the mixture under ice-cooling while stirring. The mixture was sirred for 16 hours at room temperature. The reaction mixture was washed with diluted hydrochloric acid, water, and saturated sodium hydrogen carbonate in this order. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was recrystallized from ethyl acetate/isopropyl ether to produce 1.02 g of 1-{3-[3-(indan-2-yl)proprionyl]-L-thioprolyl]pyrrolidine as colorless crystals (yield: 71%).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]O)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(Cl)([Cl:20])=O>C(Cl)(Cl)Cl>[CH2:1]([O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][Cl:20])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCOc1ccc(CO)cc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCOc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.6 %

Procedure:
2.5 g of 4-octyloxybenzyl alcohol were dissolved in 20 ml of chloroform, and the resultant solution was further fed dropwise with 1.48 g of thionyl chloride and then stirred for 1 hour at room temperature. The solution reacted was poured into ice-water and extracted with chloroform. The organic layer resulted was then dried with anhydrous magnesium sulfate, and the solvent used was removed by distillation under reduced pressure, thereby affording 2.2 g of 4-octyloxybenzyl chloride.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(C(NC1N=C([N:23]2[CH2:27][CH2:26][C@@H:25]([NH:28][C:29]([NH:31][C@@H:32]3[CH2:36][CH2:35][NH:34][CH2:33]3)=[O:30])[CH2:24]2)N=C2C=1N=CN2[C@@H]1C[C@H](NC(=O)CC)[C@@H](O)[C@H]1O)CC)C.FC(F)(F)C(O)=O.Cl[C:57]1[N:65]=[C:64]2[C:60]([N:61]=[CH:62][N:63]2[C@@H:66]2[CH2:70][C@H:69]([NH:71][C:72](=[O:75])[CH2:73][CH3:74])[C@@H:68]([OH:76])[C@H:67]2[OH:77])=[C:59]([NH:78][CH2:79][CH2:80][C:81]([CH3:84])([CH3:83])[CH3:82])[N:58]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:82][C:81]([CH3:84])([CH3:83])[CH2:80][CH2:79][NH:78][C:59]1[N:58]=[C:57]([N:23]2[CH2:27][CH2:26][C@@H:25]([NH:28][C:29]([NH:31][C@@H:32]3[CH2:36][CH2:35][NH:34][CH2:33]3)=[O:30])[CH2:24]2)[N:65]=[C:64]2[C:60]=1[N:61]=[CH:62][N:63]2[C@@H:66]1[CH2:70][C@H:69]([NH:71][C:72](=[O:75])[CH2:73][CH3:74])[C@@H:68]([OH:76])[C@H:67]1[OH:77]
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NC(CC)CC)nc(N4CC[C@@H](NC(=O)N[C@@H]5CCNC5)C4)nc32)[C@H](O)[C@@H]1O
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCCC(C)(C)C)nc(Cl)nc32)[C@H](O)[C@@H]1O
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCCC(C)(C)C)nc(N4CC[C@@H](NC(=O)N[C@@H]5CCNC5)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
This compound is prepared analogously to N-((1S,2R,3S,4R)-4-{6-(1-ethyl-propylamino)-2-[(R)-3-((R)-3-pyrrolidin-3-ylureido)-pyrrolidin-1-yl]-purin-9-yl}-2,3-dihydroxy-cyclopentyl)-propionamide trifluoroacetate by replacing N-{(1S,2R,3S,4R)-4-[2-chloro-6-(1-ethyl-propylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide with N-{(1S,2R,3S,4R)-4-[2-chloro-6-(3,3-dimethyl-butylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide trifluoroacetate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](Cl)=[O:18]>O1CCCC1>[Cl:11][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:17]([C:13]2[O:12][CH:16]=[CH:15][CH:14]=2)=[O:18])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Reactant: O=C(Cl)c1ccco1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1ccco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
To a suspension of 5-amino-2-chlorobenzoic acid (13.7 g, 79.85 mmol, 1.00 equiv) in tetrahydrofuran (100 mL) was added furan-2-carbonyl chloride (11.5 g, 88.10 mmol, 1.10 equiv) in a bath of ice and stirred overnight at room temperature. The resulting mixture was concentrated under vacuum and diluted with DCM. The solid was collected by filtration to give 17 g (80%) of 2-chloro-5-(furan-2-amido)benzoic acid as a gray solid.