Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][NH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[Br:18]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[Br:18][C:12]1[NH:11][CH:10]=[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1c[nH]cc1-c1cccc(F)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c[nH]c(Br)c1-c1cccc(F)c1
Yield: 33.4 %

Procedure:
To a solution of 38.3 g (164 mmol) of ethyl 4-(3-fluorophenyl)-1H-pyrrole-3-carboxylate in 380 ml of tetrahydrofuran are added, over 30 minutes, 32.1 g (181 mmol) of N-bromosuccinimide (CAS 128-08-5), and the mixture is then stirred for 3 hours at reflux. After cooling, 200 ml of aqueous 5% sodium thiosulfate solution are added and the reaction product is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure, to give 17.1 g of ethyl 5-bromo-4-(3-fluorophenyl)-1H-pyrrole-3-carboxylate in the form of a white powder after recrystallizing from diisopropyl ether, filtering off and drying.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]2[S:27][C:26]3[N:28]4[C:19](=[CH:20][N:21]=[C:22]4[CH:23]=[CH:24][CH:25]=3)[CH:18]=2)=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:29].[CH3:30]O>C(O)C>[ClH:29].[ClH:29].[CH3:30][N:10]([CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]1[S:27][C:26]2[N:28]3[C:19](=[CH:20][N:21]=[C:22]3[CH:23]=[CH:24][CH:25]=2)[CH:18]=1)=[O:16])[CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(NCCCNCCCc1ccccc1)C1=Cc2cnc3cccc(n23)S1
Reactant: CO
Agent: Cl
Solvent: CCO
Product: CN(CCCNC(=O)C1=Cc2cnc3cccc(n23)S1)CCCc1ccccc1

Procedure:
To a solution of 577.3 mg (1.42 mM) of N-[3-(N-(3-phenylpropan-1-yl)amino)propan-1-yl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide in ethanol (6 ml) was added 2.0 ml (8.0 mM) of 4N-HCl/methanol at room temperature and the mixture was stirred for several minutes. The solvent was then distilled off under reduced pressure to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[N:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(OCC)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH2:10])[CH:6]=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][CH:12]=2)[N:4]=1
Reactant: COc1cc(C#N)cc(-c2ccc(C(F)(F)F)cc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COc1cc(CN)cc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 0 °C
Yield: 87.4 %

Procedure:
A solution of nitrile 26I (420 mg, 1.5 mmol) in diethyl ether (30 mL) was added in small amounts to a mixture of LiAlH4 (115 mg, 2 mol eq) in diethyl ether (20 mL) stirred at 0° C. After the addition was completed, the mixture was stirred at room temperature overnight. The excess of LiAlH4 was destroyed at 0° C. by addition of small amount of water (30 mL), the solid formed was filtered off and the organic filtrate was separated, washed with brine (50 mL) and dried over Na2SO4. The organic phase was evaporated under reduced pressure to afford 27I as a pale yellow oil (370 mg, 88% yield). 1HNMR (DMSO, 200 MHz) δ 4.13 (s, 3H), 4.22 (s, 2H), 7.56 (s, 1H), 7.88 (d, 2H, J=7.8), 8.26 (s, 1H), 8.51 (d, 2H, J=8).
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:7][CH:6]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:34][C@H:35]([C:42]#[CH:43])[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38].C(N(C(C)C)CC)(C)C.CN(C1C=CC=CN=1)C>CN(C=O)C>[NH2:2][N:3]=[CH:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:18])[CH2:13][CH2:14][C:15]([NH:34][C@H:35]([C:42]#[CH:43])[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[O:17])=[CH:9][CH:10]=1
Reactant: NN=Cc1ccc(NC(=O)CCC(=O)O)cc1
Reactant: C#C[C@@H](N)CC(=O)OCC
Agent: CC(C)COC(=O)Cl
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C#C[C@H](CC(=O)OCC)NC(=O)CCC(=O)Nc1ccc(C=NN)cc1
Reaction time: 1 h

Procedure:
4-[[4-(Aminoiminomethyl)phenyl]amino]-4-oxobutanoic acid hydrochloride was added to dry DMF (35 ml) followed by N-methylmorpholine (0.39 g, 1 eq.) and isobutyl chloroformate (0.53 g, 3.9 mmol) at 25° C. The mixture was stirred for 5 min. (S)-ethyl 3-amino-4-pentynoate was added followed by diisopropylethylamine and a catalytic amount of dimethylaminopyridine. After 1 hour, the solvent was removed under reduced pressure and the product was purified by reverse phase chromatography to give (3S)-ethyl 3-[[4-[[4-(aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]amino]-4-pentynoate.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([F:13])[CH:3]=1.[CH2:14](Br)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+].CN(C)P(N(C)C)(N(C)C)=O>O>[CH2:9]([O:8][C:6](=[O:7])[C:5]1[CH:11]=[CH:12][C:2]([NH:1][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])=[CH:3][C:4]=1[F:13])[CH3:10]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: CCOC(=O)c1ccc(N)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC)c(F)c1
Temperature: 130 °C

Procedure:
A mixture of 2.6 g of ethyl 4-amino-2-fluorobenzoate 4.5 g of hexadecylbromide, 2.0 g of anhydrous potassium carbonate and 20 ml of hexamethylphosphoramide is heated to 130° C. for 22 hours. The mixture is cooled, diluted with 200 ml of water, and extracted twice with ethyl ether. The combined extracts are washed with water, dried, and the ether evaporated and the residue upon recrystallization from hexane yields ethyl-2-fluoro-4-(hexadecylamino)benzoate as a white solid.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([N:7]=[N+]=[N-])=[CH:3][CH:2]=1.[CH:11]1=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1>>[C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([N:7]2[CH:12]3[CH:11]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[CH:3][CH:2]=1
Reactant: Cc1ccc(N=[N+]=[N-])cc1
Reactant: C1=CCCCCCC1
Agent: C1=C\CCCCCC/1
Product: Cc1ccc(N2C3CCCCCCC32)cc1

Procedure:
p-Tolyl azide (0.192 g, 1.44 mmol) and cis-cyclooctene (4.230 g, 38.4 mmol), and [(Me,EtTCPh)Fe(NCCH3)2](PF6)2 (0.0020 g, 0.0014 mmol) were used in the General S4 Catalytic Reaction described above yielding 0.302 g, 97.1%. 1H NMR (CDCl3, 499.74 MHz): δ 7.02 (d, J=8.5 Hz, 2H), 6.88 (d, J=8.0 Hz, 2H), 2.32 (dd, J1=13.5 Hz, J2=2.5 Hz, 2H), 2.28 (s, 3H), 2.05 (d, J=9.5 Hz, 2H), 1.65 (m, 4H), 1.50 (m, 6H). 13C NMR (CDCl3, 125.66 MHz): δ 153.08, 131.14, 129.41, 120.15, 43.73, 27.36, 27.20, 26.59, 20.77. GC/MS (m/z): 215.1. DART HR MS (m/z): [M+H]+216.1748 (found). C15H22N, 216.1752 (calcd).
Reaction SMILES: C[O-].[Na+].[NH2:4][C:5]([NH2:7])=[S:6].C([O:10][C:11](=O)[CH2:12][C:13](=O)[CH2:14][CH2:15][CH2:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)C>CO>[CH2:18]([O:17][CH2:16][CH2:15][CH2:14][C:13]1[N:7]=[C:5]([SH:6])[N:4]=[C:11]([OH:10])[CH:12]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)CC(=O)CCCOCc1ccccc1
Reactant: NC(N)=S
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Oc1cc(CCCOCc2ccccc2)nc(S)n1
Temperature: 0 °C
Yield: 89.1 %

Procedure:
To a stirred suspension of sodium methoxide (3.48 g) in methanol (40 mL), cooled to 0° C., was added thiourea (3.56 g). The mixture was stirred until it dissolved, then 6-benzyloxy-3-oxo-hexanoic acid ethyl ester (8.52 g in 20 mL methanol) was added slowly. The solution was heated at reflux overnight, cooled to room temperature, and concentrated under vacuum. The residue was dissolved in water (50 mL), acidified to pH 6 with acetic acid, and stirred for 1 h. The precipitate was filtered, washed successively with water (2×20 mL) and isopropanol (2×20 mL), then dried to afford 6-(3-benzyloxy-propyl)-2-mercapto-pyrimidin-4-ol as a white powder (7.94 g). MS m/z 277.1 (M+1), 100%.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH:9]=O)=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([N:16]1[C:2]2[N:3]=[CH:4][N:5]=[C:6]([Cl:11])[C:7]=2[CH:8]=[CH:9]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)N
Reactant: O=CCc1c(Cl)ncnc1Cl
Product: CC(C)(C)n1ccc2c(Cl)ncnc21

Procedure:
The title compound was prepared according to the method described for Preparation 1 using (4,6-dichloropyrimidin-5-yl)acetaldehyde and tert-butylamine to afford the title compound as a yellow liquid in 77% yield, 1.61 g.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=3)=[N:9][C:10]3[N:11]([CH:13]=[CH:14][N:15]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([Br:31])C(=O)C1>C(Cl)(Cl)Cl>[Br:31][C:13]1[N:11]2[CH:12]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:8]([C:16]3[CH:17]=[CH:18][C:19]([CH:20]=[O:21])=[CH:22][CH:23]=3)=[N:9][C:10]2=[N:15][CH:14]=1
Reactant: O=Cc1ccc(-c2nc3nccn3cc2-c2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc(-c2nc3ncc(Br)n3cc2-c2ccccc2)cc1

Procedure:
1.5 g 4-(6-phenylimidazo[1,2-a]pyrimidin-7-yl)benzaldehyde (prepared as described under example 1) and 0.9 g NBS are refluxed in 30 ml chloroform for 1 h. The solvent is removed by distillation and the crude product is purified by column chromatography (dichloromethane/methanol).
Reaction SMILES: C[O:2][C@:3]1([C@@H:21]2[CH2:25][S:24][C:23](=[O:26])[N:22]2CC2C=CC(OC)=CC=2)[CH2:18][C@H:17]2[CH2:19][C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[O:20])[O:16]2)[O:4]1.CO[C@]1([C@@H]2CSC(=O)N2CC2C=CC(OC)=CC=2)C[C@H]2C[C@@H](CCCC=CCCC(C)=CC(=O)O2)O1>>[OH:2][C@:3]1([C@@H:21]2[CH2:25][S:24][C:23](=[O:26])[NH:22]2)[CH2:18][C@H:17]2[CH2:19][C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[O:20])[O:16]2)[O:4]1
Reactant: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCCCCCCCCC(=O)O3)O2)cc1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCC/C=C\CC/C(C)=C\C(=O)O3)O2)cc1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCCC=CCCC(C)=CC(=O)O3)O2)cc1
Product: O=C1CCCCCCCCC[C@@H]2C[C@H](C[C@](O)([C@@H]3CSC(=O)N3)O2)O1

Procedure:
Application of the method shown in Example 46, with the modification that (R)-4-((1R,13R,15R)-15-methoxy-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadecan-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one was substituted for (R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one, afforded the title compound.
Reaction SMILES: [CH3:1][N:2]([S:16]([CH3:19])(=[O:18])=[O:17])[C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N+:13]([O-])=O)[CH:12]=1)[C:6]([O:8]C)=[O:7].[C:20](#N)[CH2:21][CH3:22].C([O-])=O.[NH4+].[OH-].[Na+].C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O>CO.[Pd].O>[CH2:20]([NH:13][C:11]1[CH:12]=[C:3]([N:2]([CH3:1])[S:16]([CH3:19])(=[O:18])=[O:17])[CH:4]=[C:5]([CH:10]=1)[C:6]([OH:8])=[O:7])[CH2:21][CH3:22]
Reactant: CCC#N
Reactant: COC(=O)c1cc(N(C)S(C)(=O)=O)cc([N+](=O)[O-])c1
Agent: [Pd]
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: O=C[O-]
Solvent: O
Solvent: CO
Product: CCCNc1cc(C(=O)O)cc(N(C)S(C)(=O)=O)c1
Temperature: 50 °C
Reaction time: 5 h
Yield: 43 %

Procedure:
To a mixture of methyl 3-[methyl(methylsulfonyl)amino]-5-nitrobenzoate obtained in Reference Example 92.88 g (10 mmol), 10% Pd/C (50% wet) (0.60 g), methanol (30 mL), propionitrile (10 mL) and H2O (10 mL) was added ammonium formate 12.6 g (200 mmol) and the mixture was stirred at 50° C. for 5 hours. The reaction solution was filtered on Celite and the solvent was evaporated and the mixture was dissolved in ethyl acetate, washed with water and dried on magnesium sulfate. The solvent was evaporated and the residue was purified by a column chromatography on silica gel (eluted with chloroform). The resulting methyl ester 1.90 g (6.33 mmol) was dissolved in methanol (20 mL) and thereto was added 2.5N aqueous sodium hydroxide solution 7.60 mL (18.99 mmol) and the mixture was stirred at 40° C. for 1 hour. To the reaction solution was added 5% aqueous citrate and the mixture was extracted with ethyl acetate and washed with 5% aqueous sodium chloride solution and dried on magnesium sulfate. The solvent was evaporated and the residue was recrystallized from n-hexane to give 1.28 g (4.3 mmol) of the title compound (yield: 43%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[CH:7][N:8]2[CH2:11][CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)=[CH:4][CH:3]=1.C([O:26][C:27](=[O:38])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH2:35][CH2:36]Cl)C>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:18]3[CH2:19][CH2:20][N:21]([CH2:36][CH2:35][O:34][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[C:27]([OH:38])=[O:26])[CH2:22][CH2:23]3)=[CH:7][N:8]2[CH2:11][CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccccc1OCCCl
Reactant: Fc1ccc2c(C3CCNCC3)cn(CCc3ccsc3)c2c1
Product: O=C(O)c1ccccc1OCCN1CCC(c2cn(CCc3ccsc3)c3cc(F)ccc23)CC1
Yield: 6.5 %

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 0.1 g (0.31 mmol) of 6-fluoro-3-piperidin-4-yl-1-(2-thiophen-3-yl-ethyl)-1H-indole (example 78, part B) and 0.09 g (0.42 mmol) of 2-(2-chloro-ethoxy)-benzoic acid ethyl ester. After purification by HPLC-MS using a C-18 column, 0.01 g (99% of purity) of 2-(2-{4-[6-fluoro-1-(2-thiophen-3-yl-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([N:27]5[C:31]([CH3:32])=[CH:30][CH:29]=[C:28]5[CH3:33])(=[O:26])=[O:25])[CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)=[CH:4][CH:3]=1.[NH2:49][C:50]1[CH:51]=[CH:52][C:53](Br)=[N:54][CH:55]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:49][C:50]1[CH:51]=[CH:52][C:53]([C:37]2[CH:38]=[CH:39][C:34]([C:9]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[C:13](=[O:14])[C:12]4[CH:15]=[N:16][N:17]([C:18]5[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([N:27]6[C:31]([CH3:32])=[CH:30][CH:29]=[C:28]6[CH3:33])(=[O:25])=[O:26])[CH:19]=5)[C:11]=4[N:10]=3)=[CH:35][CH:36]=2)=[N:54][CH:55]=1
Reactant: Nc1ccc(Br)nc1
Reactant: Cc1ccc(C)n1S(=O)(=O)c1cccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)nc32)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1ccc(C)n1S(=O)(=O)c1cccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5ccc(N)cn5)cc4)nc32)c1
Temperature: 100 °C

Procedure:
A solution of 5-(4-chloro-phenyl)-1-[3-(2,5-dimethyl-pyrrole-1-sulfonyl)-phenyl]-6-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (0.950 g, 1.393 mmol) in N,N-dimethylformamide (40 mL) is degassed with argon for 0.5 h. Then 5-amino-2-bromopyridine (0.43 g, 2.507 mmol), cesium carbonate (0.907 g, 2.78 mmol), Pd(dppf)2Cl2 (0.122 g, 0.167 mmol) is added and the resultant mixture is degassed with argon for 0.5 h. The reaction mixture is then heated at 100° C. for 6 h. The reaction mixture is cooled to rt and diluted with water and extracted with ethyl acetate (3×). The combined organic layer is washed with brine, dried over Na2SO4, concentrated, and purified by column chromatography (silica gel 60-120 mesh) to afford 6-[4-(5-amino-pyridin-2-yl)-phenyl]-5-(4-chloro-phenyl)-1-[3-(2,5-dimethyl-pyrrole-1-sulfonyl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C@@H:7]1([NH2:14])[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[NH2:13].I[C:16]1[CH:17]=[C:18]([CH3:23])[CH:19]=[C:20]([CH3:22])[CH:21]=1>[Cu]I>[CH3:23][C:18]1[CH:17]=[C:16]([NH:13][C@@H:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C@H:7]2[NH2:14])[CH:21]=[C:20]([CH3:22])[CH:19]=1
Reactant: Cc1cc(C)cc(I)c1
Reactant: N[C@@H]1CCCC[C@H]1N
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(C)cc(N[C@@H]2CCCC[C@H]2N)c1
Temperature: 100 °C
Reaction time: 23 h
Yield: 40.8 %

Procedure:
An oven-dried resealable Schlenk tube was charged with CuI (40 mg, 0.210 mmol), K2CO3 (850 mg, 6.15 mmol), evacuated and backfilled with argon. trans-1,2-Cyclohexanediamine (240 μL, 2.00 mmol) and 5-iodo-m-xylene (900 μL, 6.24 mmol) were added under argon. The Schlenk tube was sealed and the reaction mixture was stirred magnetically at 100° C. for 23 h. The resulting purple-blue suspension was cooled to room temperature and filtered through a 2×1 cm pad of Celite eluting with 50 mL of dichloromethane. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (2×20 cm; dichloromethane saturated with aq NH3-methanol 40:1; 15 mL fractions). Fractions 9-13 provided 178 mg (41% yield) of the product as a tan solid. 1H NMR (400 MHz, CDCl3): δ 6.39 (s, 1H), 6.34 (s, 2H), 3.36 (br s, 1H), 3.03-2.92 (m, 1H), 2.56-2.46 (m, 1H), 2.25 (s, 6H), 2.20-2.10 (m, 1H), 2.08-1.95 (m, 1H), 1.83-1.70 (m, 2H), 1.55-1.20 (m, 5H), 1.10-1.00 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:3]=1[CH2:4][N:5]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([O:22][CH2:23][CH3:24])[C:17]([O:19]CC)=[O:18])=[CH:11][CH:10]=1.[Li+].[OH-]>C1COCC1>[F:1][C:2]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:3]=1[CH2:4][N:5]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([O:22][CH2:23][CH3:24])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1
Reactant: CCCCCCCCCN(Cc1ccc(F)cc1F)C(=O)COc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCCCCN(Cc1ccc(F)cc1F)C(=O)COc1ccc(C[C@H](OCC)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
To a solution of ethyl(2S)-3-(4-{2-[(2,4-difluorobenzyl)(nonyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate (0.038 g, 0.070 mmol) in THF (3 mL) was added aqueous 0.10 M LiOH (2 mL) and the reaction mixture was stirred at room temperature overnight. After acidification with 5% HCl, the mixture was extracted with ethyl acetate (3×25 mL) and the combined organic phase was washed with brine (25 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to afford 0.034 g (94%) of a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[O:8][C:7](=[O:13])[C:6]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])=[C:5]2[OH:21].O=S(Cl)Cl.[CH2:26](O)[CH3:27]>>[CH2:26]([O:19][C:18](=[O:20])[CH2:17][NH:16][C:14]([C:6]1[C:7](=[O:13])[O:8][C:9]2[C:4]([C:5]=1[OH:21])=[CH:3][C:2]([Cl:1])=[CH:11][C:10]=2[Cl:12])=[O:15])[CH3:27]
Reactant: CCO
Reactant: O=C(O)CNC(=O)c1c(O)c2cc(Cl)cc(Cl)c2oc1=O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CNC(=O)c1c(O)c2cc(Cl)cc(Cl)c2oc1=O

Procedure:
To a mixture of [(6,8-dichloro-4-hydroxy-2-oxo-2H-chromene-3-carbonyl)-amino]-acetic acid (100 mg, 0.30 mmol) in ethanol (6 mL) was added SOCl2 dropwise. Resulting mixture was refluxed for 1.5 h. After cooled, white precipitate was collected, rinsed with ethanol and dried to give the title compound (94 mg). MS ESI(+) m/e: 362, 360 (M+1).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:24]=[CH:23][C:15]([C:16]([O:18][C:19](C)(C)C)=[O:17])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:19][O:18][C:16]([C@H:15]1[CH2:23][CH2:24][C@H:12]([O:11][C:8]2[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][CH:9]=2)[CH2:13][CH2:14]1)=[O:17]
Reactant: COC(=O)[C@H]1CC[C@H](Oc2ccc(C(=O)OC(C)(C)C)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@H]1CC[C@H](Oc2ccc(C(=O)O)cc2)CC1
Temperature: 4 °C

Procedure:
1.6 g of tert-butyl trans-4-(4-methoxycarbonylcyclohexyloxy)benzoate (4.78 mmol, 1 eq.) are placed in dichloromethane. The reaction medium is cooled to a temperature of 4° C. with stirring in an ice bath. 3 mL of trifluoroacetic acid (40.39 mmol, 8.44 eq.) are added and the ice bath is removed. After stirring for 17 hours at room temperature, the medium is concentrated, taken up in diethyl ether and filtered to give 1.0 g of trans-4-(4-methoxycarbonylcyclohexyloxy)benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C@H:23]3[CH2:27][CH2:26][NH:25][CH2:24]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:11]3)=[N:8][C:4]=2[CH:3]=1.FC(F)(F)S(O[CH2:36][C:37]([F:40])([F:39])[F:38])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C@H:23]3[CH2:27][CH2:26][N:25]([CH2:36][C:37]([F:40])([F:39])[F:38])[CH2:24]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:20])=[O:21])=[N:11]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2[C@H]2CCNC2)c2cnccc12
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2[C@H]2CCN(CC(F)(F)F)C2)c2cnccc12
Reaction time: 8 h
Yield: 20.9 %

Procedure:
A mixture of (S)-1-((5-chloro-1-(pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)methyl)-3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine (120 mg, 0.28 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (64 mg, 0.28 mmol) and Cs2CO3 (182 mg, 0.56 mmol) in 5 mL of DMF was stirred overnight. The mixture was filtered and purified by prep-HPLC to give 1-({5-chloro-1-[(3S)-(1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]-1H-benzimidazol-2-yl}methyl)-3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine (30 mg, yield: 21%) as an off-white solid.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=CC=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.C1(CN)CC1>C(O)(=O)C>[CH:6]1([CH2:1][N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH2:4][CH2:5]1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: COC(=O)c1scc(-c2ccccc2)c1N
Agent: NCC1CC1
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: O=c1c2scc(-c3ccccc3)c2ncn1CC1CC1
Yield: 62.6 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1.0 ml), cyclopropanemethylamine (0.086 ml, 0.99 mmol), and acetic acid (0.1 ml) were used to give 76 mg (0.27 mmol, 62.6% yield) of the title compound.