Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][C:43]1[C:48]([Cl:49])=[CH:47][CH:46]=[CH:45][C:44]=1[S:50](Cl)(=[O:52])=[O:51]>C(#N)C>[Cl:42][C:43]1[C:48]([Cl:49])=[CH:47][CH:46]=[CH:45][C:44]=1[S:50]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:52])=[O:51]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3cccc(Cl)c3Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 45.7 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0280 g, 0.0607 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 2,3-dichlorobenzenesulfonyl chloride (0.0479 g, 0.195 mmol) to obtain 4-(2,3-dichlorobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0186 g, yield 37%).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:12][CH3:13])=[N+:9]([O-])[CH:10]=1)=[N+:2]=[N-:3].[CH3:14][N:15](C)C(Cl)=O.C(=O)([O-])O.[Na+].C(OCC)(=O)C>C(#N)C>[N:1]([CH2:4][C:5]1[C:10]([C:14]#[N:15])=[N:9][C:8]([CH2:12][CH3:13])=[CH:7][CH:6]=1)=[N+:2]=[N-:3]
Reactant: CCc1ccc(CN=[N+]=[N-])c[n+]1[O-]
Reactant: CN(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCc1ccc(CN=[N+]=[N-])c(C#N)n1
Temperature: 25 °C
Reaction time: 66 h
Yield: 90.5 %

Procedure:
After dissolving 5-(azidomethyl)-2-ethyl-1-pyridiniumolate (2.16 g, 12.1 mmol) in acetonitrile (25 ml), 1.77 ml of trimethylsilylnitrile (13.3 mmol) and 1.23 ml of dimethylcarbamoyl chloride (13.3 mmol) were added under a nitrogen stream and the mixture was stirred at room temperature for 66 hours. Saturated aqueous sodium hydrogencarbonate was added for treatment and extraction was performed with ethyl acetate. The extract was dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (2.05 g) as a colorless oil. (90.4% yield)
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[N:14][C:13]3[CH:25]=[CH:26][CH:27]=[N:28][C:12]2=3)[CH:8]=[CH:9][CH:10]=1)(=O)C.C(=O)(O)[O-].[Na+]>Cl>[NH2:4][C:5]1[CH:6]=[C:7]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[N:14][C:13]3[CH:25]=[CH:26][CH:27]=[N:28][C:12]2=3)[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)Nc1cccc(-n2c(=O)c(Cc3cccnc3)nc3cccnc32)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Nc1cccc(-n2c(=O)c(Cc3cccnc3)nc3cccnc32)c1
Yield: 91.5 %

Procedure:
A solution of 4-(3-acetamidophenyl)-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (0.9 g) in 4N hydrochloric acid (22 ml) was stirred under reflux for 90 minutes, and cooled. The reaction mixture was neutralized with solid sodium bicarbonate and precipitated white crystals were collected, washed with water and dried to give 4-(3-aminophenyl)-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (0.73 g).
Reaction SMILES: C(=O)(O)O.[Cl:5][C:6]1[CH:7]=[C:8]([CH:12]([OH:15])[CH2:13][NH2:14])[CH:9]=[CH:10][CH:11]=1.[CH2:16]([C:20]1[CH:29]=[CH:28][C:23]([O:24][CH2:25][C:26]#[N:27])=[CH:22][CH:21]=1)[C:17]([CH3:19])=O.O>C1C=CC=CC=1>[Cl:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[CH:12]([OH:15])[CH2:13][NH:14][CH:17]([CH3:19])[CH2:16][C:20]1[CH:29]=[CH:28][C:23]([O:24][CH2:25][C:26]#[N:27])=[CH:22][CH:21]=1
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: CC(=O)Cc1ccc(OCC#N)cc1
Agent: O=C(O)O
Solvent: c1ccccc1
Solvent: O
Product: CC(Cc1ccc(OCC#N)cc1)NCC(O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 2-(3-chlorophenyl)-2-hydroxyethylamine carbonate (3.35 g) and 4-acetonylphenoxyacetonitrile in benzene was heated under reflux for 1 h with azeotropic removal of water using a Dean and Stark head. The solution was cooled, and the solvent removed in vacuo. The residue was dissolved in methanol and treated with sodium cyanoborohydride (1.25 g) and stirred for 5 h at ambient temperature. The solvent was then evaporated under reduced pressure, the residue dissolved in ethyl acetate, washed with water (2×50 ml), brine (1×50 ml), dried (magnesium sulphate), filtered and evaporated. The residue was purified by column chromatography on silica using methanol:chloroform 2:98 as eluent to give 4-[2-[(3-chloro-β-hydroxyphenethyl)amino]propyl] phenoxyacetonitrile, (4.0 g).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=1)#[N:2].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.[ClH:17].O1CCOCC1>C(O)C>[ClH:17].[ClH:17].[NH:2]=[C:1]([N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=1
Reactant: N#Cc1ccc(C(=O)O)cn1
Reactant: C1CCNC1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: N=C(c1ccc(C(=O)O)cn1)N1CCCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
6-Cyanonicotinic acid (4.15 g, 28.0 mmol) was dissolved in anhydrous ethanol (3.2 ml) and 4N hydrochloric acid/1,4-dioxane (30 ml), and the mixture was stirred in a closed system at room temperature for two nights. The solvent was evaporated under reduced pressure, and the obtained residue was suspended in anhydrous ethanol (90 ml). Pyrrolidine (2.34 ml, 28.0 mmol) was added thereto, and the mixture was stirred at room temperature for 3 days. Pyrrolidine (3.51 ml, 42.0 mmol) was added again, and the mixture was stirred for 2.5 hours. The solvent was evaporated under reduced pressure, and water aid ethanol were added to the obtained residue. The precipitate was removed by filtration, ethanol was evaporated under reduced pressure, and the obtained aqueous solution was lyophilized to give the title compound without purification operation.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([C:16]([O:18]C)=[O:17])[CH3:15])=[CH:9][CH:8]=1)[CH3:5]>Cl>[C:3]([CH:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:15])[C:16]([OH:18])=[O:17])=[CH:9][CH:8]=1)[CH3:5])([OH:20])=[O:2]
Reactant: COC(=O)C(C)Oc1ccc(OC(C)C(=O)OC)cc1
Agent: Cl
Product: CC(Oc1ccc(OC(C)C(=O)O)cc1)C(=O)O
Temperature: 90 °C
Yield: 38.8 %

Procedure:
A mixture of 2-[4-(1-Methoxycarbonyl-ethoxy)-phenoxy]-propionic acid methyl ester 86 (20 grams, 70.9 mmol) in concentrated hydrochloric acid (100 mL) was heated to 90° C. for 8 hours. The reaction mixture was poured onto ice cold water (200 mL) and filtered the separated solid, washed with methanol and dried to give crude 87 (7 grams, 38.8%) as a white solid. M.p: 235-239.7° C.
Reaction SMILES: Br[CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[CH3:12][C:13]1[C:14]2[N:15]([N:19]=[C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH2:28])[CH:23]=3)[N:21]=2)[CH:16]=[CH:17][N:18]=1.C(N(CC)C(C)C)(C)C>C(O)C>[CH3:12][C:13]1[C:14]2[N:15]([N:19]=[C:20]([C:22]3[CH:27]=[CH:26][N:25]4[C:2]([CH3:11])=[C:3]([C:5]5[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:28]=[C:24]4[CH:23]=3)[N:21]=2)[CH:16]=[CH:17][N:18]=1
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: Cc1nccn2nc(-c3ccnc(N)c3)nc12
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nccn2nc(-c3ccn4c(C)c(-c5ccccc5)nc4c3)nc12
Temperature: 80 °C
Yield: 18 %

Procedure:
2-Bromopropiophenone (0.034 ml, 0.221 mmol) was added to a solution of 4-(8-methyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)pyridin-2-amine (0.025 g, 0.111 mmol) in Ethanol (2.2 ml) and the mixture was heated at 80° C. for 40 hours. LC/MS analysis of the reaction mixture indicates reaction approximately 40% complete. The reaction mixture was transferred to a microwave reaction tube and N,N-diisopropylethylamine (0.059 ml, 0.332 mmol) was added. The reaction mixture was heated at 110° C. under standard microwave conditions for 2 hours. LC/MS analysis indicates reaction completion. The reaction mixture was concentrated in vacuo. The crude product was purified by flash chromatography (silica gel; 30-100% EtOAc/hexanes) to afford a tan solid (0.007 g, 0.020 mmol, 18.05% yield). 1H NMR (400 MHz, METHANOL-d4) δ 8.76 (d, J=4.5 Hz, 1H), 8.51 (s, 1H), 8.42 (d, J=6.5 Hz, 1H), 8.08 (d, J=4.5 Hz, 1H), 7.90 (dd, J=7.2, 1.6 Hz, 1H), 7.82-7.75 (m, 2H), 7.52 (t, J=7.5 Hz, 2H), 7.42 (s, 1H), 2.97 (s, 3H), 2.73 (s, 3H), LC/MS: (Method 2) Anal. Calcd. for [M+H]+C20H17N6: 341.15. Found: 341.07.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:13][CH:12]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[CH3:22])[C:11]2[C:10](=[O:23])[CH2:9][CH2:8][CH2:7][C:6]=2[N:5]1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>O1CCCC1>[CH3:22][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:14]=1[CH:12]1[C:11]2[C:10](=[O:23])[CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=2)[C:4](=[O:3])[N:13]1[S:35]([CH3:34])(=[O:37])=[O:36])[C:18]#[N:19]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C#N)ccc1C1C2=C(CCCC2=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (60% in mineral oil, 15 mg, 0.38 mmol) is added to a solution of 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-3-methylbenzonitrile (example 55, 60 mg, 0.13 mmol) in tetrahydrofuran (3 mL), and the mixture is stirred at room temperature for 20 min. Methanesulfonyl chloride (22 μL, 0.28 mmol) is added, and the mixture is stirred at room temperature over night. Another portion of sodium hydride (60% in mineral oil, 5 mg, 0.13 mmol) and methanesulfonyl chloride (10 μL, 0.13 mmol) is added, and the mixture is stirred for 1 h and purified by preparative HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 28 mg; ESI mass spectrum [M+H]+=504; Retention time HPLC: 0.71 min (X012_S01).
Reaction SMILES: [CH2:1]([C:3]1([CH3:23])[CH:8]([CH3:9])[C:7](=O)[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[N:4]1[O:14][CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[CH3:2].Cl.[NH2:25][NH:26][C:27]([NH2:29])=[O:28]>CO.[OH-].[K+].O>[CH2:1]([C:3]1([CH3:23])[CH:8]([CH3:9])[C:7](=[N:25][NH:26][C:27]([NH2:29])=[O:28])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[N:4]1[O:14][CH:15]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH3:16])[CH3:2]
Reactant: CCC1(C)CC(=O)C(C)C(C)(CC)N1OC(C)c1ccccc1
Reactant: NNC(N)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC1(C)CC(=NNC(N)=O)C(C)C(C)(CC)N1OC(C)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.8 %

Procedure:
2,6-diethyl-2,3,6-trimethyl-1-(1-phenyl-ethoxy)-4-oxopiperidine prepared according to DE 199 09 767 A1 is dissolved in methanol containing 10% by weight of KOH and stirred for 5 hours at room temperature. Methanol is evaporated, the residue is washed with water and dried in vacuo. To a solution of 6.4 g (0.02 mol) 2,6-diethyl-2,3,6-trimethyl-1-(1-pheyl-ethoxy)-piperidine-4-one in 20 ml methanol are added 3.3 g (0.03 mol) semicarbazide hydrochloride and 1.67 g (0.025 mol) KOH (85%). The mixture is stirred under reflux 5 h and then diluted with 200 ml water. The precipitate is extracted into 100 ml of dichloromethane, the organic layer is washed with water, dryied over MgSO4 and evaporated to give 7.8 g (98.8%) of the title compound as a slightly yellow resin.
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][C:14]([C:16]2[C:17]3[CH:18]=[N:19][N:20]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[C:21]=3[CH:22]=[CH:23][CH:24]=2)=[O:15])=[CH:8][N:7]=1)=[O:5])C.[NH3:32].CO>>[C:4]([C:6]1[N:7]=[CH:8][C:9]([CH2:12][NH:13][C:14]([C:16]2[C:17]3[CH:18]=[N:19][N:20]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[C:21]=3[CH:22]=[CH:23][CH:24]=2)=[O:15])=[CH:10][CH:11]=1)(=[O:5])[NH2:32]
Reactant: CCOC(=O)c1ccc(CNC(=O)c2cccc3c2cnn3-c2ccc(F)cc2)cn1
Reactant: N
Solvent: CO
Product: NC(=O)c1ccc(CNC(=O)c2cccc3c2cnn3-c2ccc(F)cc2)cn1
Temperature: 25 °C

Procedure:
A solution of 5-({[1-(4-fluoro-phenyl)-1H-indazole-4-carbonyl]-amino}-methyl)-pyridine-2-carboxylic acid ethyl ester (Example 5) (60 mg, 0.1 mmol) in a 7 N solution of ammonia in methanol (0.65 mL, 4.6 mmol) was stirred at 100° C. in a sealed tube for 16 hours. The mixture was cooled to room temperature and filtered. The solid was washed with MeOH (3×3 mL) and dried. The solid was then triturated with ethyl acetate (2 mL), sonicated, filtered and air dried to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C1C(=O)N([Br:23])C(=O)C1>CC#N.CC(N=NC(C#N)(C)C)(C#N)C>[Br:23][CH2:12][C:5]1[CH:4]=[C:3]([N+:13]([O-:15])=[O:14])[C:2]([Cl:1])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(Cl)c([N+](=O)[O-])cc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC#N
Product: COC(=O)c1cc(Cl)c([N+](=O)[O-])cc1CBr
Temperature: 70 °C
Yield: 88.3 %

Procedure:
A mixture of methyl 5-chloro-2-methyl-4-nitrobenzoate (862 mg, 4 mmol) and NBS (854 mg, 4.8 mmol) in MeCN (16 mL) was degassed and then AIBN (14 mg, 0.08 mmol) was added. The mixture was heated to 70° C. for 18 h. The solvent was removed in vacuo and the residue was partitioned between DCM (50 mL) and water (50 mL). The organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo. Purification of the residue via silica gel column chromatography (0-100% EtOAc in iso-hexane) in order to remove baseline impurities gave methyl 2-(bromomethyl)-5-chloro-4-nitrobenzoate (1.09 g, 89%) as a brown oil. 1H NMR (400 MHz, CDCl3): δ 8.14 (s, 1H), 7.98 (s, 1H), 4.91 (s, 2H), 4.00 (s, 3H).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([I:8])[C:5]([CH3:9])=[CH:4][N:3]=1.[OH-].[NH4+:11]>>[I:8][C:6]1[C:5]([CH3:9])=[CH:4][N:3]=[C:2]([NH2:11])[CH:7]=1
Reactant: [NH4+]
Reactant: Cc1cnc(F)cc1I
Agent: [OH-]
Product: Cc1cnc(N)cc1I
Temperature: 110 °C

Procedure:
In a 500 mL sealed tube 2-fluoro-4-iodo-5-methylpyridine (4.0 g, 16.81 mmol) in 12N ammonium hydroxide (300 mL) was heated to 110° C. for 72 hours. Upon cooling to room temperature a white solid separated. The solid was collected, washed with water and dried in vacuo to afford 4-iodo-5-methylpyridin-2-amine (I-28A) as an off-white solid which was carried on to the next step without purification. 1H-NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.04 (s, 1H), 4.27 (bs, 2H), 2.24 (s, 3H). MS m/z 235.0 (M+1).
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@@H:5]3[C@@H:21]([C@@:22]4([CH3:28])[CH2:23][CH2:24][C@H:25]([OH:27])[CH2:26][C:2]124)[CH2:20][CH2:19][C@@:18]1([CH3:29])[C@H:6]3[CH2:7][CH2:8][C@@H:9]1[C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15].[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH2:35].C(O)CCC>COC(C)(C)C>[OH:1][C@:2]12[CH2:26][C@@H:25]([OH:27])[CH2:24][CH2:23][C@:22]1([CH3:28])[C@@H:21]1[C@H:5]([C@H:6]3[C@:18]([CH3:29])([CH2:19][CH2:20]1)[C@@H:9]([C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:8][CH2:7]3)[CH2:4][C@H:3]2[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][NH2:35]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@@H]4OC45C[C@@H](O)CC[C@]5(C)[C@H]3CC[C@]12C
Reactant: NCCCCN
Solvent: CCCCO
Solvent: COC(C)(C)C
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@@H](NCCCCN)[C@@]4(O)C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 60.8 %

Procedure:
5,6α-epoxicholestan-3β-ol (8.9 g, 22.1 mmol, 1 eq) and putrescine (3.9 g, 44.1 mmol, 2 eq) were charged in a round-bottomed flask equipped with a magnetic stirrer bar. 1-Butanol (70 ml, 5 vol) was added and the mixture heated to reflux for 40 h. The reaction mixture was cooled at r.t., diluted with methyl-tertbutyl-ether (5 vol) and washed with water (5 vol) and with brine (5 vol). The organic layer was passed through a silica pad (40 g) eluted with methyl-tertbutyl-ether (3 vol) then 10% Methanol/ethyl acetate (60 vol). Fractions of interest were pooled and the solvent was removed under reduced pressure to give 5α-Hydroxy-6β-(4-aminobutylamino)-cholestan-3β-ol as a white solid (6.6 g, 61%). In same conditions, use of ethanol as solvent (40 vol) and Ca(OTf)2 as catalyst gave a 19% yield.
Reaction SMILES: C[N+]1([O-])CCOCC1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][C:19](=[O:21])[CH3:20])=[CH:12][C:11]=1[CH2:22][OH:23]>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][C:19](=[O:21])[CH3:20])=[CH:12][C:11]=1[CH:22]=[O:23]
Reactant: CC(=O)NCCc1ccc(Cl)c(CO)c1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC(=O)NCCc1ccc(Cl)c(C=O)c1
Reaction time: 0.5 h
Yield: 50.5 %

Procedure:
NMO (184 mg, 1.32 mmol) was added to a sol. of N-[2-(4-chloro-3-hydroxymethyl-phenyl)-ethyl]-acetamide (100 mg, 0.439 mmol) in CH2Cl2 (9.22 mL). The mixture was stirred for 30 min, and tetrapropylammonium perruthenate (15.5 mg, 0.044 mmol) was added. The mixture was stirred for 1 h at rt, and was filtered over celite. The filtrate was evaporated under reduced pressure. Purification of the crude by FC(CH2Cl2/MeOH 49:1) yielded the title compound (50 mg, 50%). LC-MS: tR=0.75 min; ES+: 267.10.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O>COCCOC>[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11]
Reactant: OB(O)c1ccccc1F
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CSc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CSc1ccccc1-c1ccccc1F
Yield: 69.3 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-phenylsulfanyl)-acetyl]-N′-isopropyl-hydrazide (100 mg, 0.246 mmol) in DME (5 ml)/2M Na2CO3 (0.43 ml, 0.86 mmoles) was treated with 2-fluorophenylboronic acid (69 mg, 0.49 mmol) and Pd[PPh3]4 (28 mg, 0.025 mmol) for 12 hours at 90° C. The reaction mixture was partitioned between water and DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was adsorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexane gradient to afford the product as a solid (72 mg, 68%). MS m/e 423.22 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C@@H:17]([CH:19]2[CH2:21][CH2:20]2)[CH3:18])[C:11]=1[NH2:22].[C:23](OCC)(=[O:27])[C:24]([CH3:26])=O>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[C:11]2[N:22]=[C:24]([CH3:26])[C:23](=[O:27])[N:16]([C@@H:17]([CH:19]3[CH2:20][CH2:21]3)[CH3:18])[C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: CCOC(=O)C(C)=O
Reactant: COc1ccc(-c2ncnc(N[C@H](C)C3CC3)c2N)c(Cl)c1
Solvent: CCO
Product: COc1ccc(-c2ncnc3c2nc(C)c(=O)n3[C@H](C)C2CC2)c(Cl)c1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
(R)-6-(2-Chloro-4-methoxy-phenyl)-N4-(1-cyclopropyl-ethyl)-pyrimidine-4,5-diamine (0.20 g, 0.52 mmol) was diluted in ethanol (5 ml) and ethyl pyruvate was added (0.58 ml, 5.2 mmol). The mixture was stirred for 18 hours at which time the solution was concentrated. The residue was diluted in glacial acetic acid (10 ml) and warmed to 100° C. for 1 hour. After concentrating the solution the product was purified by reverse phase HPLC to yield 2.0 mg of (R)-4-(2-chloro-4-methoxy-phenyl)-8-(1-cyclopropyl-ethyl)-6-methyl-8H-pteridin-7-one (Example 565a). 1H NMR (300 MHz, CDCl3) δ ppm 9.04 (s, 1 H), 7.45 (d, J=8.42 Hz, 1 H), 7.09 (d, J=2.56 Hz, 1 H), 6.98 (dd, J=8.42, 2.56 Hz, 1 H), 4.26 (m, 1 H), 3.91 (s, 3 H), 2.54 (d, J=7.32, 3 H), 2.18 (m, 3 H), 0.87 (m, 2 H), 0.45 (m, 2 H), 0.26 (m, 1 H). MS (AP) 371.3 [(M+H)+, 100].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[CH:18]1([NH2:21])[CH2:20][CH2:19]1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([NH:21][CH:18]1[CH2:20][CH2:19]1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1Cl
Reactant: NC1CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NC1CC1)c1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
To a suspension of 5-bromo-2-chlorobenzoic acid (17.6 g, 75 mmol) in CH2Cl2 (180 mL) was added oxalyl chloride (7.0 mL, 83 mmol). DMF (8 drops) was added, and the mixture was stirred for 2 h at rt (gas evolution). The mixture was reduced under reduced pressure, and the crude residue was diluted with CH2Cl2 (530 mL). The mixture was cooled to 0° C., and a sol. of cyclopropylamine (5.8 mL, 83 mmol) in CH2Cl2 (45 mL) was added dropwise. The mixture was stirred for 10 min at 0° C., and was allowed to warm to rt. DIPEA (14.3 mL, 84 mmol) was added, and the mixture was stirred for 2 h at rt. The mixture was diluted with more CH2Cl2, and was washed with aq. 10% HCl, water, and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. The residue was triturated with hexane, filtered, and dried under high vacuum to yield the title compound (19.3 g, 94%). LC-MS: tR=0.84 min; ES+: 316.89.
Reaction SMILES: [C:1]([CH2:4][C:5]1([CH2:10][C:11](O)=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6]1)(O)=[O:2].B.C1COCC1>>[OH:2][CH2:1][CH2:4][C:5]1([CH2:10][CH2:11][OH:12])[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: O=C(O)CC1(CC(=O)O)CCCC1
Agent: B
Solvent: C1CCOC1
Product: OCCC1(CCO)CCCC1
Reaction time: 8 h
Yield: 95.4 %

Procedure:
To a stirred solution of (1-carboxymethyl-cyclopentyl)-acetic acid (1.0 g, 5.3 mmol) at 0° C. was added borane in THF (20 mL, 1.0 M; 20 mmol) and the resultant reaction mixture was stirred and allowed to come to RT overnight. The reaction mixture was cooled in an ice bath and quenched by dropwise addition of methanol (about 5 mL). The solvent was evaporated under reduced pressure and the residue was partitioned between aqueous sodium bicarbonate and ethyl acetate (about 50 mL, 1:1). The organic phase was dried over Na2SO4, concentrated under reduced pressure and filtered through a bed of silica gel to afford 2-[1-(2-hydroxy-ethyl)-cyclopentyl]-ethanol (800 mg) after evaporation of the eluent.