Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][N:5]1[C:21](=[O:22])[C:20]2[C:19]3[C:18]4[C:13](=[CH:14][C:15]([O:25]C)=[C:16]([O:23]C)[CH:17]=4)[NH:12][C:11]=3[CH:10]=[CH:9][C:8]=2[C:6]1=[O:7].Cl.N1C=CC=CC=1.O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][N:5]1[C:21](=[O:22])[C:20]2[C:19]3[C:18]4[C:13](=[CH:14][C:15]([OH:25])=[C:16]([OH:23])[CH:17]=4)[NH:12][C:11]=3[CH:10]=[CH:9][C:8]=2[C:6]1=[O:7]
Reactant: COc1cc2[nH]c3ccc4c(c3c2cc1OC)C(=O)N(CCN(C)C)C4=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CN(C)CCN1C(=O)c2ccc3[nH]c4cc(O)c(O)cc4c3c2C1=O
Reaction time: 2 h
Yield: 29.9 %

Procedure:
A mixture of 210 mg of N-(2-dimethylaminoethyl)-6,7-dimethoxycarbazole-3,4-dicarboximide and 1.66 g of pyridine hydrochloride was sealed in a tube and stirred at 200°-210° C. for 2 hours. Then, 150 ml of water and 100 ml of ethyl acetate were added to the reaction mixture to dissolve the mixture. The solution was adjusted to pH 8.5 with potassium carbonate. The organic layer was separated, washed with an aqueous saturated sodium chloride solution, and dried over anhydrous potassium carbonate. The solvent was removed by distillation under reduced pressure. The residue was mixed with 20 ml of diethyl ether, and the mixture was stirred for 10 minutes. The resulting insoluble material was collected by filtration and recrystallized from n-propanol to obtain 58 mg (yield: 31%) of N-(2-dimethylaminoethyl)-6,7-dihydroxycarbazole-3,4-dicarboximide as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:20]2[CH:21]=[CH:22][N:23]=[C:24]([O:25]CC)[C:19]=2[C:18]2[C:13](=[CH:14][CH:15]=[N:16][CH:17]=2)[N:12]=1.ClC1C2C3C(=CC=NC=3)N=C(NC3C(F)=CC(F)=CC=3Cl)C=2C=CN=1.C[O-].[Na+].B(Br)(Br)Br>CO>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:20]2[CH:21]=[CH:22][NH:23][C:24](=[O:25])[C:19]=2[C:18]2[C:13](=[CH:14][CH:15]=[N:16][CH:17]=2)[N:12]=1
Reactant: CCOc1nccc2c(Nc3c(F)cc(F)cc3Cl)nc3ccncc3c12
Agent: BrB(Br)Br
Agent: C[O-]
Agent: Fc1cc(F)c(Nc2nc3ccncc3c3c(Cl)nccc23)c(Cl)c1
Solvent: CO
Product: O=c1[nH]ccc2c(Nc3c(F)cc(F)cc3Cl)nc3ccncc3c12
Temperature: 100 °C

Procedure:
To a solution of N-(2-chloro-4,6-difluorophenyl)-10-ethoxypyrido[4,3-c]-1,6-naphthyridin-6-amine and 10-chloro-N-(2-chloro-4,6-difluorophenyl)pyrido[4,3-c]-1,6-naphthyridin-6-amine (1.3 g) in 8 mL methanol was added sodium methoxide (5 mL, 2.06 mmol, 25% weight in methanol) and the mixture was heated to 100° C. for 1 hr. The solution was cooled to room temperature, concentrated, and redissolved with 3:1 CHCl3/i-PrOH followed by a wash with saturated NH4Cl. The organic layers were combined, dried with MgSO4, filtered, and concentrated under reduced pressure. A portion of the crude solution (540 mg) was taken up in CHCl3 (8 mL) and boron tribromide (1M in CH2Cl2, 7 mL, 7.0 mmol) and heated to 85° C. for 1 hr. The solution was cooled to room temperature, extracted with 3:1 CHCl3/i-PrOH, and washed with saturated NaHCO3. The organic layers were dried with MgSO4, filtered, and concentrated to afford the crude product. The crude residue was purified on silica gel (100% CH2Cl2 to 25% MeOH, gradient elution) which afforded the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:15][CH:14]([O:16]S(C)(=O)=O)[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[F:21][C:22]([F:32])([F:31])[O:23][C:24]1[CH:25]=[C:26](O)[CH:27]=[CH:28][CH:29]=1>>[F:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:15][CH:14]([O:16][C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([O:23][C:22]([F:21])([F:31])[F:32])[CH:25]=3)[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(F)cnc1N1CC(OS(C)(=O)=O)C1
Reactant: Oc1cccc(OC(F)(F)F)c1
Product: O=C(O)c1cc(F)cnc1N1CC(Oc2cccc(OC(F)(F)F)c2)C1
Yield: 22.1 %

Procedure:
The title compound (D134) (27 mg) was prepared according to the experimental procedure described in Description 133 starting from Methyl 5-fluoro-2-(3-((methylsulfonyl)oxy)azetidin-1-yl)nicotinate (D71) (100 mg, 0.328 mmol) and 3-(trifluoromethoxy)phenol (0.042 ml, 0.328 mmol).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[CH3:15][N:16]([CH:18](OC)OC)[CH3:17]>>[CH3:15][N:16]([CH:18]=[C:7]1[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][C:2]1=[O:1])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: COC(OC)N(C)C
Product: CN(C)C=C1CCN(C(=O)OC(C)(C)C)CC1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a stirred mixture of tert-butyl 3-oxopiperidine-1-carboxylate (1 g, 5 mmol) was added DMF-DMA (2 mL). The mixture was stirred at 100° C. for 2 hours. The mixture was concentrated by vacuum and the residue was directly for the next step (1.20 g, yield: 94%).
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12]([CH3:14])=[N:11][C:10]=2[CH:15]=1.[CH3:16][C@@H:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1>C(O)(CC)(C)C>[OH:1][C@@H:2]([CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12]([CH3:14])=[N:11][C:10]=2[CH:15]=1)[CH2:3][N:22]1[CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][C@@H:17]1[CH3:16]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: Cc1nc2cc(OC[C@H]3CO3)ccc2s1
Solvent: CCC(C)(C)O
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(C(=O)OC(C)(C)C)C[C@@H]3C)ccc2s1
Temperature: 100 °C
Reaction time: 16 h
Yield: 85.7 %

Procedure:
To a solution of 5-(((R)-oxiran-2-yl)methoxy)-2-methylbenzo[d]thiazole (3.24 g, 14.6 mmol) in tert-amyl alcohol (50 ml) was added (S)-tert-butyl 3-methylpiperazine-1-carboxylate (2.67 g, 13.3 mmol). The resulting mixture was stirred at 100° C. for 16 hours. It was then cooled, concentrated, and purified by chromatography (1:20 MeOH:CH2Cl2) to yield tert-butyl 4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl](3S)-3-methylpiperazinecarboxylate (4.8 g, 11.4 mmol).
Reaction SMILES: C[O:2][C:3](=[O:42])[CH:4]([O:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:23][NH:24][C:25]([C:27]3[O:28][C:29]([O:32][C:33]4[CH:38]=[C:37]([Cl:39])[CH:36]=[C:35]([Cl:40])[CH:34]=4)=[CH:30][CH:31]=3)=[O:26])[CH:19]=2)[C:14]=1[Br:41])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+].O>CO>[Br:41][C:14]1[C:15]2[C:20](=[CH:19][C:18]([CH2:23][NH:24][C:25]([C:27]3[O:28][C:29]([O:32][C:33]4[CH:38]=[C:37]([Cl:39])[CH:36]=[C:35]([Cl:40])[CH:34]=4)=[CH:30][CH:31]=3)=[O:26])=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[O:12][CH:4]([CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:3]([OH:42])=[O:2]
Reactant: COC(=O)C(Cc1ccccc1)Oc1ccc2cc(CNC(=O)c3ccc(Oc4cc(Cl)cc(Cl)c4)o3)ccc2c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(NCc1ccc2c(Br)c(OC(Cc3ccccc3)C(=O)O)ccc2c1)c1ccc(Oc2cc(Cl)cc(Cl)c2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.2 %

Procedure:
A mixture of 2-[1-bromo-6-({[5-(3,5-dichloro-phenoxy)-furan-2-carbonyl]-amino}-methyl)-naphthalen-2-yloxy]-3-phenyl-propionic acid methyl ester (0.34 g, 0.508 mmol), prepared in the previous step, 1N NaOH (1.50 mL, 1.5 mmol), 5 mL of water and 50 mL of methanol was stirred under nitrogen at room temperature for 18 h (overnight). The methanol was removed under reduced pressure. The solid that formed was collected by filtration and identified as the sodium salt salt of 2-[1-bromo-6-({[5-(3,5-dichloro-phenoxy)-furan-2-carbonyl]-amino}-methyl)-naphthalen-2-yloxy]-3-phenyl-propionic acid (0.1537 g, 46%). The clear filtrate was acidified with 1N HCl. The solid that precipitated was collected by filtration and dried under reduced pressure to give the title compound (0.0905 g, 27%) as a white solid, mp 86-100° C.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[F:33][C:34]1[CH:66]=[C:65]([F:67])[CH:64]=[CH:63][C:35]=1[C:36]([NH:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:53]=[C:52]3[C:48]([CH2:49][N:50]([C@@H:55]([CH:60]([CH3:62])[CH3:61])[C:56]([O:58]C)=[O:57])[C:51]3=[O:54])=[CH:47][CH:46]=2)=[CH:41][CH:40]=1)=[O:37]>>[F:33][C:34]1[CH:66]=[C:65]([F:67])[CH:64]=[CH:63][C:35]=1[C:36]([NH:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:53]=[C:52]3[C:48]([CH2:49][N:50]([C@@H:55]([CH:60]([CH3:62])[CH3:61])[C:56]([OH:58])=[O:57])[C:51]3=[O:54])=[CH:47][CH:46]=2)=[CH:41][CH:40]=1)=[O:37]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(F)cc4F)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(F)cc4F)cc3)cc2C1=O
Yield: 84 %

Procedure:
The compound of example 110 was prepared analogous to compound of example 98 by hydrolysis of compound of example 109.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](/[CH:19]=C/C)=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:22]=[O+][O-].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:18]([CH:19]=[O:22])=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C/C=C/c1ccc2ncccc2c1OCc1ccccc1
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=Cc1ccc2ncccc2c1OCc1ccccc1

Procedure:
Treatment of 5-(benzyloxy)-6-[(1E)-prop-1-enyl]quinoline in methylene chloride with excess ozone at −78° C. followed by addition of diisopropylethylamine, aqueous work-up, and subsequent purification by flash column chromatography provides 5-(benzyloxy)quinoline-6-carbaldehyde.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:20][C:21]([NH2:23])=[O:22])=[C:8]([CH3:19])[N:9]2[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.O>C(Cl)Cl>[OH:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:20][C:21]([NH2:23])=[O:22])=[C:8]([CH3:19])[N:9]2[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(CC(N)=O)c(C)n(Cc3ccccc3)c2c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cc1c(CC(N)=O)c2ccc(O)cc2n1Cc1ccccc1
Reaction time: 3 h
Yield: 44.7 %

Procedure:
To a solution of 1.53 g (5 mmol) of 6-methoxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetamide was added 20 mL (20 mmol) of 1M BBr3 in methylene chloride and the mixture stirred for 3 hours. Water was added and the mixture extracted with EtOAc. The EtOAc solution was washed with a NaCl solution, dried (MgSO4), and concentrated at reduced pressure. The residue was chromatographed on silica and the product eluted with 5% MeOH/methylene chloride to give 658 mg (45% yield) of 6-hydroxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetamide, mp, 174°-179° C.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9](Cl)[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:19][N:20]([CH3:25])[CH2:21][CH2:22][NH:23][CH3:24]>O>[CH3:19][N:20]([CH3:25])[CH2:21][CH2:22][N:23]([CH3:24])[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([N:23]([CH2:22][CH2:21][N:20]([CH3:25])[CH3:19])[CH3:24])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2cccc(Cl)c2C(=O)c2cccc(Cl)c21
Reactant: CNCCN(C)C
Solvent: O
Product: CN(C)CCN(C)c1cccc2c1C(=O)c1cccc(N(C)CCN(C)C)c1C2=O
Temperature: 25 °C

Procedure:
A mixture of 1,5-dichloroanthraquinone (5.5 g, 20 mmol) and N,N,N′-trimethylethylenediamine (40 ml) was refluxed for 18 h. The mixture was cooled to room temperature, diluted with water (400 mL) and extracted with chloroform (2×200 mL). The combined organic layer was washed with water, brine, dried over MgSO4 and evaporated to dryness. The residue thus obtained was purified by silica gel flash chromatography [CHCl3/MeOH/Et3N (44:5:1)] to provide Compound 9. Abs (max, PBS pH 7.4)=508 nm. The structure of Compound 9 is given below:
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.[CH3:20][O:21]C1C=C(C=CC=1)C(Cl)=O>>[CH3:20][O:21][C:8]1[CH:7]=[C:6]([C:9]2[S:10][C:11]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: COc1ccc(-c2nc3ccc(OC)cc3s2)cc1
Product: COc1cccc(-c2nc3ccc(OC)cc3s2)c1
Yield: 91 %

Procedure:
The same method as described for 2-(p-methoxyphenyl)-6-methoxybenzothiazole can be used to obtain the corresponding meta isomer by replacing p-methoxybenzoyl chloride with m-methoxybenzoyl chloride. Yield: 91%; melting point: 155°-157° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10](=[O:12])[CH2:9][C:8]=2[CH:13]=1)([O-:3])=[O:2].[C:14](O)(=[O:19])[CH2:15][CH2:16][CH2:17][CH3:18].C(OC(=O)CCCC)(=O)CCCC>>[OH:19][C:14](=[C:9]1[C:8]2[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[O:11][C:10]1=[O:12])[CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C1Cc2cc([N+](=O)[O-])ccc2O1
Reactant: CCCCC(=O)O
Agent: CCCCC(=O)OC(=O)CCCC
Product: CCCCC(O)=C1C(=O)Oc2ccc([N+](=O)[O-])cc21

Procedure:
In a further process disclosed in EP-A 1 116 719, 5-nitro-2(3H)-benzofuranone is reacted in the presence of pentanoic acid and pentanoic anhydride to give 3-(1-hydroxypentylidene)-5-nitro-2(3H)-benzofuranone which reacts under acidic conditions to give 2-(n-butyl)-5-nitrobenzofuran. The disadvantage of this process is that 5-nitro-2(3H)-benzofuranone is used as precursor, which makes industrial application uneconomic.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:19])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[N:7]=1.[CH3:20][O:21][C:22]1[CH:28]=[C:27]([N:29]2[CH2:34][CH2:33][CH:32]([N:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)[CH2:31][CH2:30]2)[CH:26]=[CH:25][C:23]=1[NH2:24].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(O)C.ClCCl>[Cl:19][C:5]1[N:4]=[N:3][C:2]([NH:24][C:23]2[CH:25]=[CH:26][C:27]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]4)[CH2:31][CH2:30]3)=[CH:28][C:22]=2[O:21][CH3:20])=[N:7][C:6]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=1
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1N
Reactant: CP(C)(=O)c1ccc(Nc2nc(Cl)nnc2Cl)cc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1nnc(Cl)c(Nc2ccc(P(C)(C)=O)cc2)n1
Temperature: 25 °C

Procedure:
A mixture of 3,6-dichloro-N-[4-(dimethylphosphoryl)phenyl]-1,2,4-triazin-5-amine (0.7 mmol), 2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]aniline (0.7 mmol) and camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 hours in 2-propanol. The reaction mixture is allowed to cool to room temperature, dissolved in dichloromethane and washed with an aqueous solution of Na2CO3. The dichloromethane extract is dried over MgSO4 and evaporated. The crude product is purified by Prep-HPLC.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.CSC>O1CCCC1.C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[CH2:13][OH:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: B
Solvent: ClC(Cl)Cl
Solvent: CSC
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC[C@H]1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To a stirred solution of 1(benzyloxycarbonyl)-L-proline (15 g) in tetrahydrofuran (150 ml) at 0° C., borane-methylsulfide complex (9 ml, 95% in dimethyl sulfide) was added and the reaction mixture was stirred at room temperature for 8 h. At the end of this time the reaction was quenched with 10% AcOH in methanol and the solvent was removed under reduced pressure. The crude product thus obtained was diluted with CHCl3 and washed with water, dried (CaCl2) and the solvent was removed under reduced pressure to get 11.5 g (81%) of the title compound as a thick liquid.
Reaction SMILES: C(O[C:6]([N:8](C)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]#[C:16][CH2:17][O:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH2:11][CH2:10]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:6][NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]#[C:16][CH2:17][O:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH2:13][CH2:14]1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C#CCOS(C)(=O)=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H]1CC[C@H](C#CCOS(C)(=O)=O)CC1
Reaction time: 0.5 h

Procedure:
A solution of 6.02 g (17.43 mmol) of trans-Methanesulfonic acid 3-[4-(tert-butoxycarbonyl-methyl-amino)-cyclohexyl]-prop-2-ynyl ester in 95 ml CH2Cl2 was treated at 0° C. with 45 ml TFA (for 20 min). After 30 min at this temperature, the reaction was evaporated and evaporated again with toluene (4 times) to give 8.17 g (quantitative) of crude trans-Methanesulfonic acid 3-(4-methylamino-cyclohexyl)-prop-2-ynyl ester.trifluoroacetate, MS: 245 (M).
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:28](O)=[O:29])=[C:21]5[C:25]=4[O:24][C:23]([CH3:27])([CH3:26])[CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:31])[C:8](=[O:32])[C@H:7]2[CH2:33][CH3:34])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:35]1([CH2:38][N:39]2[CH2:44][CH2:43][N:42]([C@@H:45]3[CH2:50][CH2:49][C@H:48]([NH2:51])[CH2:47][CH2:46]3)[CH2:41][CH2:40]2)[CH2:37][CH2:36]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:28]([NH:51][C@H:48]5[CH2:47][CH2:46][C@@H:45]([N:42]6[CH2:41][CH2:40][N:39]([CH2:38][CH:35]7[CH2:36][CH2:37]7)[CH2:44][CH2:43]6)[CH2:50][CH2:49]5)=[O:29])=[C:21]5[C:25]=4[O:24][C:23]([CH3:27])([CH3:26])[CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:31])[C:8](=[O:32])[C@H:7]2[CH2:33][CH3:34])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N[C@H]1CC[C@@H](N2CCN(CC3CC3)CC2)CC1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OC(C)(C)C4)nc2N1C1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)N[C@H]4CC[C@@H](N5CCN(CC6CC6)CC5)CC4)c4c3OC(C)(C)C4)nc2N1C1CCCC1
Reaction time: 3 h
Yield: 78.8 %

Procedure:
7-[[(7R)-8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,2-dimethyl-3H-benzofuran-4-carboxylic acid 4f (116 mg, 0.25 mmol) was dissolved in 15 mL of dichloromethane followed by the addition of (cis)-4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexanamine 12e (65 mg, 0.28 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetra methyluronium tetrafluoroborate (80 mg, 0.25 mmol) and diisopropylethylamine (97 mg, 0.75 mmol). The reaction solution was stirred for 3 hours. The resulting solution was added with 20 mL of saturated sodium bicarbonate solution and extracted with dichloromethane (50 mL×3). The combined organic phase was washed with water (50 mL), saturated sodium chloride solution (50 mL) successively, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-N-[(cis)-4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexyl]-2,2-dimethyl-3H-benzofuran-4-carboxamide 23 (135 mg, yield: 78.9%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[O:5][CH:6]=1.[CH2:9](OB(C=C)OCCCC)[CH2:10]CC.ClC1C=CC(CC2C=C(C=O)SC=2)=CC=1>CN(C=O)C>[CH:9]([C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[O:5][CH:6]=1)=[CH2:10]
Reactant: C=CB(OCCCC)OCCCC
Reactant: O=Cc1cc(Br)co1
Agent: O=Cc1cc(Cc2ccc(Cl)cc2)cs1
Solvent: CN(C)C=O
Product: C=Cc1coc(C=O)c1

Procedure:
The title compound was synthesized from 4-bromo-furan-2-carbaldehyde (1.1 g, 6.29 mmol) and vinylboronic acid dibutyl ester (1.67 mL, 7.54 mmol) using the same conditions used to synthesize 4-(4-chlorobenzyl)thiophene-2-carbaldehyde, with the exception that the reaction was run in DMF (20 mL). Purification by flash chromatography (0-30% EtOAc in heptane) provided 4-vinylfuran-2-carbaldehyde as an orange oil; Yield 282 mg (37%). 1H NMR (400 MHz, CDCl3) δ ppm 5.31 (dd, J=10.88, 0.93 Hz, 1H), 5.61 (dd, J=17.57, 0.54 Hz, 1H), 6.56 (dd, J=17.55, 10.91 Hz, 1H), 7.37 (s, 1H), 7.67 (s, 1H), 9.66 (d, J=0.59 Hz, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[NH:6][N:5]=1)(=[O:3])[CH3:2].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:42][C@@H:43]([CH3:59])[CH2:44][N:45]1[CH:49]=[CH:48][C:47]([C:50]2[CH:57]=[CH:56][C:53]([C:54]#[N:55])=[C:52]([Cl:58])[CH:51]=2)=[N:46]1>C(Cl)Cl>[C:1]([C:4]1[CH:8]=[C:7]([C:9]([NH:42][C@@H:43]([CH3:59])[CH2:44][N:45]2[CH:49]=[CH:48][C:47]([C:50]3[CH:57]=[CH:56][C:53]([C:54]#[N:55])=[C:52]([Cl:58])[CH:51]=3)=[N:46]2)=[O:11])[NH:6][N:5]=1)(=[O:3])[CH3:2]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)[nH]n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.6 %

Procedure:
3-Acetyl-1H-pyrazole-5-carboxylic acid (0.59 g; 3.84 mmol) and DIPEA (1.0 ml; 5.75 mmol) were dissolved in 4 ml of dry DCM. Anhydrous HOBt (0.78 g; 5.75 mmol) and EDCI (1.10 g; 5.75 mmol) were added at RT. (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (1.00 g; 3.84 mmol) was dissolved in 4 ml of DCM and the reaction was stirred for overnight at RT. 40 ml of DCM was added and organic layer washed with 3×15 ml of water. Combined water phases were washed with 2×20 ml of DCM. Both organic phases were dried over Na2SO4, filtered and evaporated to dryness. Both crude product fractions were combined and purified by CombiFlash (2% MeOH in DCM). Product fractions were combined and evaporated to give 497 mg of product. 1H-NMR (400 MHz; d6-DMSO): δ 1.16 (d, 3H, J=6.7 Hz), 2.49 (s, 3H), 4.31 (m, 2H), 4.46 (sept, 1H, J=6.7 Hz), 6.93 (d, 1H, J=2.4 Hz), 7.31 (s, 1H), 7.81 (d, 1H, J=2.4 Hz), 7.92 (d, 1H, J=7.9 Hz), 7.97 (d, 1H, J=8.1 Hz), 8.03 (d, 1H, J=1.3 Hz), 8.48 (d, 1H, J=8.5 Hz), 14.16 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[C:11]([O:24][CH3:25])=[N:12][CH:13]=[CH:14][C:15]=1[C:16]1([CH2:22][CH3:23])OCCC[O:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CCCCCCC>C(O)C.O>[CH2:1]([O:8][CH2:9][C:10]1[C:11]([O:24][CH3:25])=[N:12][CH:13]=[CH:14][C:15]=1[C:16](=[O:17])[CH2:22][CH3:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC1(c2ccnc(OC)c2COCc2ccccc2)OCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCCC
Solvent: O
Solvent: CCO
Product: CCC(=O)c1ccnc(OC)c1COCc1ccccc1
Temperature: 80 °C
Reaction time: 6.25 h
Yield: 96.5 %

Procedure:
To stirred solution of 4.120 g 3-benzyloxymethyl-4-(2-ethyl-[1,3]dioxan-2-yl)-2-methoxy-pyridine as obtained from Example 6 (12.00 mmol) in 96 mL ethanol and 24 mL water were added at room temperature 461 mg para-toluenesulfonic acid monohydrate (2.40 mmol, 0.2 eq). The mixture was subsequently heated to 80° C. and the reaction was monitored by HPLC and after 6.25 h at 80° C. (<0.2% area starting material as obtained from Example 6), the solution was cooled down to room temperature and poured into 600 mL heptane. The organic phase was washed with 600 mL water, subsequently with 600 mL aqueous NaHCO3 solution (0.1 M) and again with 600 mL water. The organic phase was dried over 20 g Na2SO4 (30 min) and filtered. The solid was washed with 40 mL heptane. After evaporation of solvent in a rotary evaporator (40° C./10 mbar), the title compound (3.302 g, 96% by weight) was obtained as a light yellow oil.