Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][C:13]([OH:15])=O)(=[O:11])=[O:10])=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.Cl.[CH2:21]([O:23][C:24](=[O:30])[C@H:25]([C@@H:27]([CH3:29])[OH:28])[NH2:26])[CH3:22].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:21]([O:23][C:24](=[O:30])[CH:25]([NH:26][C:13](=[O:15])[CH2:12][S:9](=[O:10])(=[O:11])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:16]([F:19])([F:18])[F:17])[CH:27]([OH:28])[CH3:29])[CH3:22]
Reactant: O=C(O)CS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Reactant: CCOC(=O)[C@@H](N)[C@@H](C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(NC(=O)CS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F)C(C)O

Procedure:
Under the conditions of Example 2(a), 3.012 g (10 mmol) of 2-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]acetic acid, 1.736 g (10 mmol) of L-threonine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is purified by column chromatography on silica gel. The title compound is eluted with ethanol.
Reaction SMILES: [C:1](Cl)(=O)[CH:2]([CH3:4])[CH3:3].[C:7]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])([CH3:10])([CH3:9])[CH3:8].[O:16]1CCCC1>>[C:7]([NH:11][C:12](=[O:16])[C:13]([CH2:1][CH:2]([CH3:4])[CH3:3])([CH3:15])[CH3:14])([CH3:10])([CH3:9])[CH3:8]
Reactant: C1CCOC1
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)CNC(C)(C)C
Product: CC(C)CC(C)(C)C(=O)NC(C)(C)C
Reaction time: 1 h

Procedure:
Isobutyryl chloride (10.90 g, 0.1 mol) was added to a solution of tert-butylisobutylamine (25.85 g, 0.2 mol) in tetrahydrofuran (150 ml) at room temperature and stirred for 1 h. Solids were filtered off and washed with tetrahydrofuran ( 2×25 ml). N, N-tert-butylisobutyl-2-methylpropionamide was isolated by distillation to yield 18.50 g, (90%), bp 59-60° C./1.3 mm Hg. A 1 M borane-tetrahydrofuran solution (100 ml, 0,10 mol) was added dropwise to a solution of the amide (17.95 g, 90 mmol) in tetrahydrofuran (50 ml) at room temperature and the mixture refluxed for 1 h. Water (5 ml) was added after cooling, followed by a slow addition of 6 M hydrochloric acid (60 ml). Tetrahydrofuran was distilled off and solid sodium hydroxide (20.00 g, 0.5 mol) was added. The organic layer was separated and the aqueous solution was extracted with n-pentane (50 ml). The organic solutions were combined, dried over anhydrous magnesium sulfate, and the product was isolated by distillation to yield 14.24 g, (85%), bp 34-35° C./1.5 mm Hg; 1H NMR (CDCl3) δ0.84 (d, J=6.6 Hz, 12H, CH3), 1.01 (s, 9H, CH3), 1.58 (nonet, J=6.6 Hz, 2H, CH), 2.14 (d, J=6.6 Hz, 4H, CH2),
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]2[C@@H:12]([C:13]([O:15][CH3:16])=[O:14])[O:11][C:10](=[O:17])[NH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([C@H]1[C@H](C(OC)=O)OC(=O)N1)C1C=CC=CC=1>>[CH:1]1([CH2:7][C@H:8]2[C@H:12]([C:13]([O:15][CH3:16])=[O:14])[O:11][C:10](=[O:17])[NH:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)[C@H]1OC(=O)N[C@H]1CC1CCCCC1
Agent: COC(=O)[C@@H]1OC(=O)N[C@H]1Cc1ccccc1
Product: COC(=O)[C@@H]1OC(=O)N[C@H]1CC1CCCCC1
Yield: 95 %

Procedure:
For the manufacture of the aforementioned compound, methyl (4S,5S)-4-cyclohexylmethyl-2-oxo-oxazolidine-5-carboxylate, obtainable by hydrogenating methyl (4S,5R)-4-benzyl-2-oxo-oxazolidine-5-carboxylate, is reacted under the conditions given in Example 1. Methyl (4S,5R)-4-cyclohexylmethyl-2-oxo-oxazolidine-5-carboxylate is obtained in a yield of about 95%.
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH:7][CH3:8])=[CH:5][N:4]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[N:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[O:25]=[C:26]1[C@H:31]2[CH2:32][C@H:28]([CH:29]=[CH:30]2)[N:27]1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>C1COCC1>[C:36]([O:35][C:33](=[O:34])[NH:27][C@@H:28]1[CH2:32][C@H:31]([C:26](=[O:25])[N:7]([C:6]2[C:2]([Cl:1])=[N:3][N:4]([C:9]3[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=3)[CH:5]=2)[CH3:8])[CH:30]=[CH:29]1)([CH3:37])([CH3:38])[CH3:39]
Reactant: CNc1cn(-c2cccnc2)nc1Cl
Reactant: CC(C)(C)OC(=O)N1C(=O)[C@@H]2C=C[C@H]1C2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C(=O)[C@@H]1C=C[C@H](NC(=O)OC(C)(C)C)C1)c1cn(-c2cccnc2)nc1Cl
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A solution of 3-chloro-N-methyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine (0.20 g, 0.96 mmol) in THF (10 mL) was cooled to a temperature of about −78° C. LHMDS (1 M solution in hexanes, 1.0 mL, 1.00 mmol) was added, and the solution was stirred at a temperature of about −78° C. for 15 minutes. A solution of (1R,4S)-tert-butyl 3-oxo-2-azabicyclo[2.2.1]hept-5-ene-2- carboxylate (0.20 g, 0.96 mmol) dissolved in THF (3 mL) was added to the solution at a temperature of about −78° C. in one portion. After stirring for one hour at a temperature of about −78° C., the cooling bath was removed and the reaction warmed to a temperature of about 20° C. After stirring for an additional five minutes, acetic acid (AcOH, 0.1 mL) was added to the solution. The reaction mixture was concentrated and purified via silica gel chromatography eluting with EtOAc/hexanes to give the title compound F109 as a white solid (0.25 g, 59%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][O:7][C:8]1[CH:13]=[CH:12][N:11]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][CH:17]=2)[C:10](=[O:24])[CH:9]=1.P(Br)(Br)[Br:26]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Br:26][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][N:11]2[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[CH:9][C:10]2=[O:24])=[CH:17][CH:18]=1
Reactant: O=c1cc(OCc2ccco2)ccn1CCc1ccc(CO)cc1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1cc(OCc2ccco2)ccn1CCc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 80 mg (0.25 mmol) 4-(furan-2-ylmethoxy)-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (example 6.1a) in 3.0 mL of DCM is added at 0° C. 35 μL (0.37 mmol) phosphorus tribromide. After warming to RT, the mixture is stirred 2 h at RT and is diluted with half saturated aqueous NaHCO3-solution. The layers are separated, the aqueous phase is extracted three times with DCM/MeOH. The combined organic phase is dried over MgSO4, filtered and the solvent is evaporated to afford the product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([NH:14][C@@H:15]2[CH2:18][C@H:17]([NH:19]C(=O)OC(C)(C)C)[C:16]2([CH3:28])[CH3:27])[C:11]([C:29]#[N:30])=[CH:10][N:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:19][C@@H:17]1[CH2:18][C@H:15]([NH:14][C:12]2[C:11]([C:29]#[N:30])=[CH:10][N:9]=[C:8]([NH:7][CH2:6][CH2:5][C:4]3[CH:31]=[CH:32][CH:33]=[C:2]([Cl:1])[CH:3]=3)[N:13]=2)[C:16]1([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](Nc2nc(NCCc3cccc(Cl)c3)ncc2C#N)C1(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)[C@H](N)C[C@@H]1Nc1nc(NCCc2cccc(Cl)c2)ncc1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.8 %

Procedure:
To a solution of tert-butyl ((1S,3R)-3-((2-((3-chlorophenethyl)amino)-5-cyanopyrimidin-4-yl)amino)-2,2-dimethylcyclobutyl)carbamate (85 mg, 0.18 mmol) in dry DCM (2 mL) was added TFA (1.5 mL) dropwise under ice-water bath. The resulting mixture was stirred at room temperature for 30 min. After removal of the organic solvent, the residue was neutralized with ammonia and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by standard methods to afford the title compound (48.7 mg, 0.131 mmol, 73% yield). 1H NMR (400 MHz, CD3OD) δ (ppm) 8.04 (s, 1H), 7.27-7.14 (m, 4H), 4.16-3.97 (m, 1H), 3.74-3.49 (m, 2H), 2.90-2.85 (m, 3H), 2.60-2.49 (m, 1H), 1.92-1.86 (m, 1H), 1.22 (s, 3H), 0.92 (s 3H). MS (ESI) m/z 371.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](O)=O)=[CH:4][CH:3]=1.[Br:12]CCC1C=CC=CC=1F>>[Br:12][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: Fc1ccccc1CCBr
Product: Fc1ccc(CCBr)cc1

Procedure:
1-(2-Bromoethyl)-4-fluorobenzene was prepared from 4-fluorophenylacetic acid as described above for 1-(2-bromoethyl)-2-fluorobenzene.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])[CH3:3].N#N.[ClH:23]>O1CCOCC1>[NH2:1][C@H:2]([C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])[CH3:3].[ClH:23]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: Cl
Agent: N#N
Solvent: C1COCCO1
Product: C[C@H](N)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Boc-Ala-OBn was dissolved in 4N HCl in dioxane (10 mL) and stirred for three hours at room temperature. The solvent was blown off under a stream of N2. The residue was placed under high vacuum for one hour. Re-dissolved in CH2Cl2 (50 mL) and rotovap dry. Repeat the drying circle for three times till the white powder forms.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([NH:13][CH:14]([C:16]2[N:21]=[N:20][C:19]([NH:22][C:23]3[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=3)=[N:18][CH:17]=2)[CH3:15])=O)=[CH:3]1.N1C=NC=N1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[CH3:15][C:14]1[N:13]=[C:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)[N:21]2[C:16]=1[CH:17]=[N:18][C:19]([NH:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=1)=[N:20]2
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cn(C)c4ccccc34)nn2)cc(OC)c1OC
Agent: c1nc[nH]n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1cc(Nc2ncc3c(C)nc(-c4cn(C)c5ccccc45)n3n2)cc(OC)c1OC
Yield: 58.8 %

Procedure:
In a similar manner as described for Example 9, 1-methyl-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)-1H-indole-3-carboxamide (Intermediate 36) (180 mg, 0.39 mmol), and 1,2,4-triazole (165 mg, 2.34 mmol) in pyridine (3 mL) and phosphorous oxychloride (0.11 mL, 1.2 mmol) gave 5-methyl-7-(1-methyl-1H-indol-3-yl)-N-(3,4,5-trimethoxyphenyl)-imidazo[5,1-f][1,2,4]triazin-2-amine (102 mg, 59%) as a yellow solid. 1H NMR (DMSO-d6): δ9.47 (s, 1H), 9.16 (s, 1H), 8.52 (d, J=7.87 Hz, 1H), 8.40 (s, 1H), 7.54 (d, J=8.06 Hz, 1H), 7.28 (t, J=7.23 Hz, 1H), 7.20 (t, J=7.42 Hz, 1H), 7.11 (s, 2H), 3.86 (s, 3H), 3.74 (s, 6H), 3.67 (s, 3H), 2.57 (s, 3H). MS m/z 444 (M+1).
Reaction SMILES: N[C:2]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([F:20])[CH:18]=3)[N:13]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[N:12]=2)[N:8]=[C:7]2[C:3]=1[N:4]([CH2:30][C:31]([F:34])([F:33])[F:32])[C:5](=[O:29])[NH:6]2.N(OCCC(C)C)=O.C(#N)C.O.C(O)=O.[I:50]CI>>[F:20][C:17]1[CH:18]=[C:19]2[C:11]([C:9]3[N:8]=[C:7]4[C:3]([N:4]([CH2:30][C:31]([F:33])([F:34])[F:32])[C:5](=[O:29])[NH:6]4)=[C:2]([I:50])[N:10]=3)=[N:12][N:13]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[C:14]2=[N:15][CH:16]=1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncc(F)cc23)nc2[nH]c(=O)n(CC(F)(F)F)c12
Reactant: ICI
Agent: CC(C)CCON=O
Solvent: O
Solvent: CC#N
Solvent: O=CO
Product: O=c1[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncc(F)cc34)nc(I)c2n1CC(F)(F)F
Temperature: 85 °C

Procedure:
4.650 g (5.954 mmol) of the compound from example 62 were dissolved in 12 ml of diiodomethane and admixed with 12.76 ml (95.270 mmol) of isopentyl nitrite. The reaction mixture was heated to 85° C. for 16 h and, after cooling, concentrated on a rotary evaporator. 5 g of the crude product (purity 54%) were obtained. 1.2 g of the residue were by means of preparative HPLC (eluent: acetonitrile/water with 0.05% formic acid, gradient 40:60→95:5). 128 mg of the title compound were obtained (15% of theory).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]2[CH2:13][NH:12][CH2:11][C:10]3[S:14][CH:15]=[CH:16][C:9]2=3)=[CH:6][C:5]([O:17]C)=[C:4]([O:19]C)[CH:3]=1.B(Br)(Br)[Br:22].ClCCl.CO>ClCCl>[BrH:22].[F:1][C:2]1[C:7]([CH:8]2[CH2:13][NH:12][CH2:11][C:10]3[S:14][CH:15]=[CH:16][C:9]2=3)=[CH:6][C:5]([OH:17])=[C:4]([OH:19])[CH:3]=1
Reactant: BrB(Br)Br
Reactant: COc1cc(F)c(C2CNCc3sccc32)cc1OC
Solvent: ClCCl
Solvent: CO
Product: Br
Product: Oc1cc(F)c(C2CNCc3sccc32)cc1O

Procedure:
0.65 g of 4-(6-fluoro-3,4-dimethoxyphenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine was dissolved in 14 ml of dichloromethane; and to the mixture was added 1M boron tribromide-dichloromethane solution (12 ml) dropwise under an argon gas stream, while cooling -30°--60° C. (internal temperature) while stirring. The mixture was stirred for 2 hours at room temperature, and 20 ml of methanol was added dropwise thereto under ice cooling. The solvent was distilled off, and the residue obtained was crystallized by using a mixture of methanol and chloroform (1:8). The crystals were collected by filtration, and recrystallized from ethanol, giving 0.29 g of 4-(6-fluoro-3,4-dihydroxyphenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine hydrobromide.
Reaction SMILES: BrCC(N[C:6]1[CH:48]=[CH:47][C:9]([O:10][CH2:11][C:12]([NH:14][C@H:15]([C:20]([NH:22][C@@H:23]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:24]([OH:39])[C:25]([N:27]2[CH2:38][CH2:37][CH2:36][C@H:28]2[C:29]([NH:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:26])=[O:21])[CH2:16][C:17](=[O:19])[NH2:18])=[O:13])=[CH:8][CH:7]=1)=O.[CH2:49]([N:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>>[CH2:49]([N:56]1[CH2:61][CH2:60][N:59]([C:6]2[CH:48]=[CH:47][C:9]([O:10][CH2:11][C:12]([NH:14][C@H:15]([C:20]([NH:22][C@@H:23]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@H:24]([OH:39])[C:25]([N:27]3[CH2:38][CH2:37][CH2:36][C@H:28]3[C:29]([NH:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])=[O:26])=[O:21])[CH2:16][C:17](=[O:19])[NH2:18])=[O:13])=[C:8]([NH:14][C:12](=[O:13])[CH3:11])[CH:7]=2)[CH2:58][CH2:57]1)[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)COc1ccc(NC(=O)CBr)cc1
Product: CC(=O)Nc1cc(N2CCN(Cc3ccccc3)CC2)ccc1OCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)N1CCC[C@H]1C(=O)NC(C)(C)C

Procedure:
Following a procedure similar to that described in Example 38, but using 100 mg (0.137 mmol) of 1-{(2S,3S)-3-[N2 -(4-bromoacetamidophenoxy)acetyl-L-asparaginyl]amino-2-hydroxy-4-phenylbutyryl}-N-t-butyl-L-prolinamide and 1 ml of 1-benzylpiperazine, 60 mg of the title compound were obtained as a colorless powder, melting at 119°-127° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][O:7]C(C)(C)[O:5][CH2:4][C@H:3]1[OH:11].[CH:12]1[C:16]2[N:17]=[CH:18][NH:19][C:20](=[O:21])[C:15]=2[NH:14][CH:13]=1.[CH2:22]=O>O>[OH:7][CH2:8][CH:2]([NH:1][CH2:22][C:12]1[C:16]2[N:17]=[CH:18][NH:19][C:20](=[O:21])[C:15]=2[NH:14][CH:13]=1)[CH:3]([OH:11])[CH2:4][OH:5]
Reactant: C=O
Reactant: CC1(C)OC[C@@H](N)[C@H](O)CO1
Reactant: O=c1[nH]cnc2cc[nH]c12
Solvent: O
Product: O=c1[nH]cnc2c(CNC(CO)C(O)CO)c[nH]c12
Temperature: 85 °C
Yield: 27 %

Procedure:
A mixture of (5S,6R)-6-amino-2,2-dimethyl-1,3-dioxepan-5-ol (155 mg, 0.96 mmol), 9-deazahypoxanthine (100 mg, 0.74 mmol) and 37% aq formaldehyde (140 μl, 1.85 mmol) in water (2 ml) was stirred and heated in stoppered flask at 85° C. overnight. The solution was evaporated to dryness. The residue was stirred in methanolic ammonia for 10 minutes and then evaporated. The residue was chromatographed on silica (DCM-MeOH-cNH3 6:3.5:0.5) to give the racemic 7-(((2RS,3SR)-1,3,4-trihydroxybutan-2-ylamino)methyl)-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one (55 mg, 0.20 mmol, 30% yield) as a white solid 1H NMR (CDCl3) 2.76 (1H, q, J 5.2 Hz), 3.48 (1H, dd, J 6.3, 11.9 Hz), 3.60 (2H, m), 3.70 (2H, m), 3.85 (2H, ABq), 7.34 (1H, s), 7.78 (1H, s). 13C NMR (CDCl3) δ0.2, 59.8, 59.8, 63.5, 71.2, 113.1, 117.5, 129.2, 142.4, 143.5, 155.4. m/z (ESI+) 537 (2MH+, 20%), 269 (MH+, 100%). HRMS (ESI+) C11H16N4O4 requires 269.1241. found 269.1250.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH:12]([NH:16]C(=O)OCC1C=CC=CC=1)[CH2:11][CH2:10]2>[Pd].C(O)C>[NH2:16][CH:12]1[C:13]2[C:9](=[CH:8][C:7]([CH2:6][C:5]3[CH:4]=[C:3]([CH2:2][OH:1])[CH:29]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:27]=3)=[CH:15][CH:14]=2)[CH2:10][CH2:11]1
Reactant: O=C(NC1CCc2cc(Cc3cc(CO)cc(C(F)(F)F)c3)ccc21)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: NC1CCc2cc(Cc3cc(CO)cc(C(F)(F)F)c3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
A mixture of benzyl 5-(3-(hydroxymethyl)-5-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-1-ylcarbamate (1.04 g, 2.28 mmol) and 10% palladium on carbon (38 mg) in ethanol (20 mL) was placed under hydrogen (balloon) and stirred at rt for 1 h. The mixture was filtered over Celite and concentrated under reduced pressure. The white solid was triturated with diethyl ether to afford the title compound as a white solid (660 mg, 90%). MS (ESI): m/z [M+NH2]+ 305.2
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9](O)=O)=[CH:5][CH:4]=1.[CH:14]1([NH2:17])[CH2:16][CH2:15]1>>[CH:14]1([NH:17][CH2:9][CH2:8][O:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:13][CH:12]=2)[CH2:16][CH2:15]1
Reactant: COc1ccc(OCC(=O)O)cc1
Reactant: NC1CC1
Product: COc1ccc(OCCNC2CC2)cc1

Procedure:
Synthesized according to typical procedures C and D from (4-methoxyphenoxy)-acetic acid and cyclopropylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][C:22]1([CH3:31])[CH2:27][CH:26]([NH2:28])[CH2:25][C:24]([CH3:30])([CH3:29])[NH:23]1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:28][CH:26]2[CH2:27][C:22]([CH3:31])([CH3:21])[NH:23][C:24]([CH3:30])([CH3:29])[CH2:25]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CC1(C)CC(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)CC(C)(C)N1

Procedure:
Prepared according to the procedure described for example 70 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (150 mg, 0.43 mmol) and 2,2,6,6-tetramethylpiperidin-4-amine (81.0 mg, 0.51 mmol). The title compound was obtained as a solid (35.0 mg, 17% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.99 (2H, m), 8.81 (1H, m), 8.47 (1H, s), 7.81 (1H, m), 4.18 (1H, m), 1.96 (2H, m), 1.51 (2H, m), 1.39 (12H, m). MS m/z: 487.25, 489.27 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([NH2:4])[CH3:3].[Cl:5][C:6]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C@H:28]([OH:35])[CH2:29]OS(C)(=O)=O)=[CH:22][C:7]=1[C:8]([NH:10][CH2:11][C:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2)=[O:9]>C(#N)C>[ClH:5].[Cl:5][C:6]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C@H:28]([OH:35])[CH2:29][NH:4][CH:2]([CH3:3])[CH3:1])=[CH:22][C:7]=1[C:8]([NH:10][CH2:11][C:12]12[CH2:21][CH:16]3[CH2:15][CH:14]([CH2:20][CH:18]([CH2:17]3)[CH2:19]1)[CH2:13]2)=[O:9]
Reactant: CS(=O)(=O)OC[C@@H](O)CCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Reactant: CC(C)N
Solvent: CC#N
Product: CC(C)NC[C@@H](O)CCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Product: Cl
Temperature: 50 °C

Procedure:
1-Methylethylamine (3 mL) was added to a solution of 2-chloro-5-[(3S)-3-hydroxy-4-[(methylsulfonyl)oxy]butyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)benzamide (Example 1c) (0.22 g) in acetonitrile (10 mL) and heated at 50° C. for 18 hours. On cooling the reaction mixture was concentrated and purified by solid phase extraction on Waters' SCX resin, eluting with ammonia in methanol (7M). Further purification by reverse phase HPLC (gradient 25–95% acetonitrile in 0.2% aqueous trifluoroacetic acid on Symmetry™ column). The residue was dissolved in methanol (5 mL) and hydrochloric acid in dioxane (4M, 1 mL) was added, evaporation and recrystallisation from MeCN, gave the titled compound as the hydrochloric acid salt (30 mg).
Reaction SMILES: N[C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[CH:3]=1.N1C=CC(=O)NC1=O.[N:18]([O-])=[O:19].[Na+]>C(O)(=O)C.O>[N:18]([C:3]1[C:4](=[O:9])[NH:5][C:6](=[O:8])[NH:7][CH:2]=1)=[O:19]
Reactant: O=N[O-]
Reactant: Nc1cc(=O)[nH]c(=O)[nH]1
Agent: O=c1cc[nH]c(=O)[nH]1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=Nc1c[nH]c(=O)[nH]c1=O
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 132 %

Procedure:
1-Propyl, 3-cyclopropyl, 6-aminouracil (2) (12.8 g, 61.2 mmol) was dissolved in acetic acid (25 ml) in 200 ml of water and the mixture was cooled to 10° C. To the uracil solution, NaNO2 (7.6 g, 110.1 mmol) in 50 ml of water was added dropwise at 10° C. The mixture was stirred at 10° C. for 30 min and then at room temperature for 1 h. The solvent was removed under reduced pressure and the residue was dissolved in the mixture of absolute ethanol and CH2Cl2 (1:1) and boiled for 20 min. The hot mixture was filtered through a layer of Celite 545 to remove the insoluble inorganic salts. The mother liquid was evaporated under reduced pressured to remove the solvent to give 1-propyl, 3-cyclopropyl, 6-amino, 5-nitrosouracil (4) (11.4 g, 78%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[C:20]([N:39]1[CH:43]=[C:42]([C:44](=[O:46])[CH3:45])[N:41]=[CH:40]1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[NH4+]>C1COCC1.CCCCCC>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:44]([C:42]3[N:41]=[CH:40][N:39]([C:20]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH:43]=3)([OH:46])[CH3:45])[CH:3]=2)=[CH:9][CH:10]=1
Reactant: Fc1ccc(-c2cccc(Br)c2)cc1
Reactant: CC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(O)(c1cccc(-c2ccc(F)cc2)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 0.33 h
Yield: 55.2 %

Procedure:
To a solution of 3-bromo-4′-fluoro-1,1′-biphenyl (1.50 g) in THF (20 ml) was added dropwise a solution (1.6 M; 3.73 ml) of n-butyllithium in hexane at −78° C., and the mixture was stirred for 20 min. A solution of 1-(1-trityl-1H-imidazol-4-yl)-1-ethanone (1.91 g) in THF (25 ml) was added dropwise at −78° C., and the mixture was stirred at −78° C. for 1 h, at −35 to −10° C. for 1 h and at 0° C. for 1 h. Saturated aqueous ammonium chloride solution was added to the reaction mixture and the mixture was extracted with ethyl acetate, washed with saturated brine and dried. The solvent was evaporated under reduced pressure and the residue was purified by column chomatography (eluent, hexane:ethyl acetate=3:1→1:1) and recrystallized from ethyl acetate-hexane to give the title compound (1.57 g) as colorless prism crystals.
Reaction SMILES: [C:1](I)([F:4])([F:3])[F:2].[CH2:6]([N:13]1[CH:17]=[C:16]([CH3:18])[C:15]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:14]1[C:26]([OH:28])=[O:27])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.OO>CS(C)=O.O>[CH2:6]([N:13]1[C:17]([C:1]([F:4])([F:3])[F:2])=[C:16]([CH3:18])[C:15]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:14]1[C:26]([OH:28])=[O:27])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: FC(F)(F)I
Reactant: Cc1cn(Cc2ccccc2)c(C(=O)O)c1-c1ccc(F)cc1
Agent: OO
Solvent: O
Solvent: CS(C)=O
Product: Cc1c(-c2ccc(F)cc2)c(C(=O)O)n(Cc2ccccc2)c1C(F)(F)F
Reaction time: 16 h

Procedure:
CF3I (10 g) gas was bubbled through a solution of 1-benzyl-3-(4-fluorophenyl)-4-methyl-1H-pyrrole-2-carboxylic acid (4.0 g, 12.94 mmol) in DMSO (40 mL) and FeSO4.7H2O (2.15 g, 7.76 mmol) at RT for 5 min. 30% Aqueous H2O2 (8.7 mL, 77.64 mmol) was then added at 0° C. and stirring was continued at room temperature for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (1×100 mL) and brine (50 mL), dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; 60-120 mesh); it eluted with 10-12% EtOAc in petroleum ether to yield ACI-09 (1.7 g, 35%) as a white solid.