Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15])[C:8](=[O:26])[NH:7][C:6]2[CH:27]=[CH:28][C:29]([C:31]#[N:32])=[CH:30][C:5]1=2)(=[O:3])[CH3:2].Cl[CH2:34][C:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][C:36]=1[CH3:45].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+]>CN(C=O)C.CCOC(C)=O>[C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH3:15])[C:8](=[O:26])[N:7]([CH2:34][C:35]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:38]=[CH:37][C:36]=2[CH3:45])[C:6]2[CH:27]=[CH:28][C:29]([C:31]#[N:32])=[CH:30][C:5]1=2)(=[O:3])[CH3:2]
Reactant: Cc1ccc2ccccc2c1CCl
Reactant: CC(=O)N1c2cc(C#N)ccc2NC(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@@H]1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N1c2cc(C#N)ccc2N(Cc2c(C)ccc3ccccc23)C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@@H]1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a rt solution of tert-butyl(S)-1-((2S,3S)-1-acetyl-8-cyano-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (57 mg, 129 μmol) in DMF (321 μl) was added 1-(chloromethyl)-2-methylnaphthalene (29.4 mg, 154 μmol), cesium carbonate (54.4 mg, 167 μmol), and sodium iodide (25.0 mg, 167 μmol). The reaction was stirred at rt for 1 h, then diluted with EtOAc, washed with H2O and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(S)-1-((3S,4S)-5-acetyl-7-cyano-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (56.3 mg, 73%) as a white solid. MS m/z 620 (MNa)+.
Reaction SMILES: C([O:8][C@H:9]1[C@H:14]([O:15]CC2C=CC=CC=2)[C@@H:13]([O:23]CC2C=CC=CC=2)[CH:12]([C:31]2[CH:39]=[C:38]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[C:37]([Cl:49])=[C:36]3[C:32]=2[CH2:33][CH2:34][CH2:35]3)[O:11][C@@H:10]1[CH2:50][O:51]CC1C=CC=CC=1)C1C=CC=CC=1>C1COCC1.CO.[Pd]>[Cl:49][C:37]1[C:38]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=2)=[CH:39][C:31]([C@H:12]2[C@H:13]([OH:23])[C@@H:14]([OH:15])[C@H:9]([OH:8])[C@@H:10]([CH2:50][OH:51])[O:11]2)=[C:32]2[C:36]=1[CH2:35][CH2:34][CH2:33]2
Reactant: COc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)CCC3)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3c(c2Cl)CCC3)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of compound 18 (0.87 g, 1.09 mmol) in THF/MeOH (8.9 mL/8.9 mL) were added Pd/C (10% Pd, 122 mg). The mixture was stirred at rt under hydrogen atmosphere for 15 h. The catalyst removed by filtration, and then the filtrate was concentrated in vacuo. The residue was purified by prep HPLC (reverse phase) to provide the compound E005 (0.11 g, 0.25 mmol, 23%).
Reaction SMILES: [CH:1]1([CH:4]=[O:5])[CH2:3][CH2:2]1.[N+:6]([CH3:9])([O-:8])=[O:7].[OH-].[Na+].CC(O)=O>CO.O>[CH:1]1([CH:4]([OH:5])[CH2:9][N+:6]([O-:8])=[O:7])[CH2:3][CH2:2]1
Reactant: O=CC1CC1
Reactant: C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])CC(O)C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of cyclopropanecarbaldehyde (1.4 g, 20 mmol) and nitromethane (1.2 g, 20 mmol) in MeOH at 0° C. was added a solution of NaOH (840 mmol, 21 mmol) in water (8 mL). The mixture was stirred at room temperature for 1 h and then HOAc (1.3 mL) was added. Volatile solvent was removed in vacuo. The residue was diluted with water and extracted twice with EtOAc. The combined EtOAc extracted was washed with brine, dried (Na2SO4) and concentrated to give the title compound as a yellow liquid.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[C:7]1([C:13]2[CH:22]=C(C(O)=O)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl>[C:7]1([C:13]2[CH:22]=[C:1]([C:2]([Cl:4])=[O:3])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(O)c1cc(-c2ccccc2)nc2ccccc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C(Cl)c1cc(-c2ccccc2)nc2ccccc12
Temperature: -10 °C
Reaction time: 8 h

Procedure:
11.7 ml (136.3 mmol) of oxalyl chloride were dissolved in 150 ml of CH2Cl2. The solution was cooled at −10° C. and 20 g (80.2 mmol) of commercially available 2-phenylquinoline-4-carboxylic acid were added portionwise. The reaction mixture was left overnight at room temperature and then evaporated to dryness to yield 22 g of the title compound, used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH2:19][CH2:20][N:21]([CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])[CH2:22]4)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C([SiH](C(C)C)C(C)C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH2:19][CH2:20][N:21]([CH2:27][C:28]([OH:30])=[O:29])[CH2:22]4)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2noc(-c3cccc4c3CCN(CC(=O)OC(C)(C)C)C4)n2)cc1Cl
Agent: CC(C)[SiH](C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1ccc(-c2noc(-c3cccc4c3CCN(CC(=O)O)C4)n2)cc1Cl
Yield: 118.1 %

Procedure:
To a solution of tert-butyl 2-(5-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-3,4-dihydroisoquinolin-2(1H)-yl)acetate (0.1319 g, 0.273 mmol) in dichloromethane (10 ml) was added triisopropylsilane (0.056 ml, 0.273 mmol) followed by TFA (2 ml). After about 15 h reaction mixture was concentrated in vacuo. The resulting solid was triturated in ether, filtered and dried to provide 2-(5-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-3,4-dihydroisoquinolin-2(1H)-yl)acetic acid (0.138 g, 93%) as an off-white solid. LCMS (Table 1, Method c) Rt=2.00 min, m/z 428 (M+H)+.
Reaction SMILES: [I:1][C:2]1[NH:6][C:5]([C:7]2([CH3:11])[CH2:10]OC2)=[N:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[O:16]1[CH2:21]CC(C=O)C[CH2:17]1>>[I:1][C:2]1[NH:6][C:5]([CH:7]2[CH2:10][CH2:21][O:16][CH2:17][CH2:11]2)=[N:4][C:3]=1[C:12]([F:13])([F:14])[F:15]
Reactant: CC1(c2nc(C(F)(F)F)c(I)[nH]2)COC1
Reactant: O=CC1CCOCC1
Product: FC(F)(F)c1nc(C2CCOCC2)[nH]c1I

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 202.2, except tetrahydro-2H-pyran-4-carbaldehyde was used instead of 3-methyloxetane-3-carbaldehyde.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=O)[CH2:4][C:5]([O:7]CC)=O.C(O)(=O)C.[C:17]1([NH:23][NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[OH:7][C:5]1[N:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:24]=[C:3]([C:2]([F:1])([F:11])[F:12])[CH:4]=1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: NNc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: Oc1cc(C(F)(F)F)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.7 %

Procedure:
Ethyl 4,4,4-trifluoroacetoacetate (18.4 g (0.1 mol)) was dissolved in 12.0 g (0.2 mol) of acetic acid. The resulting solution was cooled to 10° C. or less with stirring, and 11.8 g (0.11 mol) of phenylhydrazine was added dropwise thereto over 0.5 hours. After the dropwise addition, the solution was stirred at room temperature for 1 hour and subsequently at 80° C. for 5 hours. When the reaction was completed, the reaction solution was cooled to room temperature, and 100 mL of water was added thereto. The produced crystal was collected by filtration, washed twice with 50 mL of water and dried by a hot air drier to obtain 22.3 g (yield: 98.0%) of the title compound as a pale yellow crystal.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([CH3:10])[N:3]=1.C(N(CC)CC)C.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][NH2:25]>C1COCC1.O>[Cl:9][C:6]1[N:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:25][CH2:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=2)[C:7]=1[F:8]
Reactant: Cc1nc(Cl)c(F)c(Cl)n1
Reactant: NCc1ccccn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1nc(Cl)c(F)c(NCc2ccccn2)n1
Reaction time: 4 h

Procedure:
4,6-Dichloro-5-fluoro-2-methylpyrimidine (0.2 g, 1.111 mmol) was dissolved in THF (1 mL). To this solution was added triethylamine (0.17 mL, 1.22 mmol), followed by commercially available (2-pyridinylmethyl)amine (0.11 mL, 1.067 mmol), which was dissolved in THF (1 mL). The reaction was left to stir for 4 hours. The reaction mixture was diluted with water and extracted with ether. The organics were dried (MgSO4) and concentrated to provide 6-chloro-5-fluoro-2-methyl-N-(2-pyridinylmethyl)-4-pyrimidinamine as a yellow wax (0.2517 g, 90%). LCMS: (M+H)+=253.3.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([O:10]C)=O)=[CH:3][CH:2]=1>C(N)CC>[CH2:2]([NH:1][C:8](=[O:10])[CH2:7][CH:4]1[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]1)[CH2:3][CH3:4]
Reactant: COC(=O)Cc1ccncc1
Solvent: CCCN
Product: CCCNC(=O)CC1CCNCC1

Procedure:
Methyl 2-(pyrid-4-yl)acetate (10 g), n-propylamine (30 ml) and 3 A molecular sieves (10 g) were heated together at 100° for 148 hours in a stainless steel bomb. Excess amine and molecular sieves were removed and the crude product in glacial acetic acid (100 ml) was hydrogenated over platinum oxide catalyst at 30°/50° p.s.i. until uptake of hydrogen ceased. The catalyst was removed by filtration, the excess acetic acid distilled off in vacuo, and the residue basified with aqueous sodium bicarbonate and extracted with ethyl acetate (100 ml). The organic layer was dried (MgSO4) and evaporated in vacuo to give crude N-n-propyl-2-(piperid-4-yl)acetamide as an oil. This was utilized without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[C:9](N)[N:10]=[C:6]2[C:5]([CH3:12])=[N:4][CH:3]=1.N([O-])=O.[Na+].C(Br)(Br)[Br:18].ClC(Cl)C(O)=O>[Br-].C([N+](CC)(CC)CC)C1C=CC=CC=1.[Al].O>[Br:18][C:9]1[N:10]=[C:6]2[C:5]([CH3:12])=[N:4][CH:3]=[C:2]([CH3:1])[N:7]2[N:8]=1
Reactant: BrC(Br)Br
Reactant: Cc1ncc(C)n2nc(N)nc12
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C(O)C(Cl)Cl
Agent: O=N[O-]
Solvent: O
Product: Cc1ncc(C)n2nc(Br)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 143.7 %

Procedure:
A mixture of 5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamine (2.4 g, 14.71 mmol), sodium nitrite (10.15 g, 147.08 mmol) and benzyltriethylammonium bromide (8 g, 29.42 mmol) in bromoform (76.2 ml, 872.17 mmol) was stirred at 25° C. for 30 minutes. To this mixture was then added dichloroacetic acid (2.43 ml, 29.42 mmol) and the reaction mixture was stirred at 25° C. for further 20 hours. (The reaction flask was wrapped in aluminum foil to protect the mixture from light). Water (100 ml) was added to the reaction mixture, which was then stirred for 30 minutes at 25° C., and finally extracted 4 times with dichloromethane. The combined organic layers were washed twice with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated. The crude material thus obtained was purified by silica gel column chromatography using hexane ethyl acetate 20% as eluent affording 2-bromo-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine (4.8 g, 74.72%) as an off white solid. MS: m/z=227 (M+H+)
Reaction SMILES: C([O-])=O.[NH4+].Cl[C:6]1[N:11]=[N:10][C:9]([NH2:12])=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[CH3:21])[CH:7]=1>CO.[Pd]>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:8]2[CH:7]=[CH:6][N:11]=[N:10][C:9]=2[NH2:12])=[C:14]([CH3:21])[CH:15]=1
Reactant: COc1ccc(-c2cc(Cl)nnc2N)c(C)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COc1ccc(-c2ccnnc2N)c(C)c1
Yield: 90.6 %

Procedure:
10% Pd—C (hydrous product; 7.89 g) and ammonium formate (11.96 g) were added to a solution of 6-chloro-4-(4-methoxy-2-methylphenyl)-3-pyridazineamine (7.89 g) in methanol (100 mL), and the mixture was heated under reflux for 1.5 hours. The reaction mixture was filtered through Celite, and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:ethanol=10:1) to give the title compound (6.16 g) as white crystals.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[NH:10][NH2:11].CN([CH:15]=[C:16]1[C:22]2[CH:23]=[N:24][CH:25]=[CH:26][C:21]=2[NH:20][C:19]2[N:27]=[CH:28][CH:29]=[CH:30][C:18]=2[C:17]1=O)C>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[N:10]1[CH:15]=[C:16]2[C:17]([C:18]3[CH:30]=[CH:29][CH:28]=[N:27][C:19]=3[NH:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=32)=[N:11]1
Reactant: NNc1c(Cl)cccc1Cl
Reactant: CN(C)C=C1C(=O)c2cccnc2Nc2ccncc21
Agent: Cl
Solvent: CCO
Product: Clc1cccc(Cl)c1-n1cc2c(n1)-c1cccnc1Nc1ccncc1-2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2,6-Dichlorophenyl)hydrazine hydrochloride (168 mg, 0.788 mmol) was added to a solution of 6-[(dimethylamino)methylene]-6,11-dihydro-5H-dipyrido[2,3-b:3′,4′-f]azepin-5-one (105 mg, 0.394 mmol, Intermediate E-1) in ethanol (4 mL) and stirred at room temperature. After 30 minutes, the mixture was heated to 60° C. overnight. The reaction was then cooled to room temperature and the major product from the reaction mixture was isolated using preparative LC/MS to provide the desired product as a white powder. 1H NMR (DMSO-d6) δ 8.77 (bs, 1H), 8.45 (bs, 1H), 8.40 (bs, 1H), 8.04 (m, 2H), 7.94 (d, 1H), 7.75 (m, 2H), 7.62 (m, 1H), 6.95 (m, 1H), 6.87 (m, 1H). LC/MS: 380 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:18]([O-:20])=[O:19])=[C:6]([CH:17]=1)[O:7][C@H:8]1[C@H:12]2[O:13][CH2:14][C@@H:15]([OH:16])[C@H:11]2[O:10][CH2:9]1.[CH2:21](I)[CH3:22].[H-].[Na+].O>CN(C=O)C.CCOC(C)=O>[CH2:21]([O:16][C@@H:15]1[CH2:14][O:13][C@@H:12]2[C@H:8]([O:7][C:6]3[CH:17]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N+:18]([O-:20])=[O:19])[CH2:9][O:10][C@H:11]12)[CH3:22]
Reactant: O=[N+]([O-])c1ccc(F)cc1O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCO[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 1.1 g (3.8 mmol) (3R,3aR,6R,6aR)-6-(5-fluoro-2-nitro-phenoxy)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol (III.1), 0.88 g (5.6 mmol) ethyl iodide in DMF, 0.2 g (4.1 mmol) NaH (55% in mineral oil) are added and the temperature is kept below 35° C. The mixture is stirred at RT for 1 h. Water and EtOAc are added and the organic layer is separated, washed with water, dried and evaporated. The residue was purified by FC.
Reaction SMILES: O1CCCC1.[OH:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH:8]1[C:20]([O:22]C)=[O:21].[OH-].[Li+].Cl>O>[C:16]([O:15][C:13]([N:10]1[CH2:11][CH2:12][CH:7]([OH:6])[CH:8]([C:20]([OH:22])=[O:21])[CH2:9]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(O)C(C(=O)O)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a flask, tetrahydrofuran (1.01 mL) was added to 1-tert-butyl 3-methyl 4-hydroxypiperidine-1,3-dicarboxylate (0.079 g, 0.303 mmol). A solution of lithium hydroxide (0.0254 g, 0.607 mmol) in water (0.505 mL) was added to the reaction. The reaction was allowed to stir at room temperature for 4 hrs. Using 1N hydrochloric acid, the reaction was neutralized to pH 6 and was concentrated in vacuo. The crude product was purified using prep LC/MS. LC-MS: 190.1 [M−t-butyl]. LC/MS RT=2.58 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([CH3:11])=[CH:9][S:8][C:7]=2[CH:12]=1.[O:13]1CCOCC1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([CH:11]=[O:13])=[CH:9][S:8][C:7]=2[CH:12]=1
Reactant: COc1ccc2c(C)csc2c1
Reactant: C1COCCO1
Product: COc1ccc2c(C=O)csc2c1
Yield: 80 %

Procedure:
A mixture of 6-methoxy-3-methylbenzo[b]thiophene (2.753 g, 15.5 mmol) and SeO2 (2.06 g, 18.55 mmol) in 1,4-dioxane (30 mL) was refluxed for 2 days and then filtered. The filtrate was concentrated in vacuo, and the residue was purified on a silica gel column eluting with EtOAc/hexane (1:10) to give 6-methoxybenzo[b]thiophene-3-carbaldehyde (2.3 g, 80%).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]([C:20]2[CH:21]=[N:22][C:23]([NH2:26])=[CH:24][CH:25]=2)=[O:19])[C:12]=1[F:27])[CH2:9][CH3:10])(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[NH2:7][C@@H:8]([C:11]1[C:12]([F:27])=[C:13]([C:18]([C:20]2[CH:21]=[N:22][C:23]([NH2:26])=[CH:24][CH:25]=2)=[O:19])[C:14]([Cl:17])=[CH:15][CH:16]=1)[CH2:9][CH3:10]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(C(=O)c2ccc(N)nc2)c1F
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC[C@@H](N)c1ccc(Cl)c(C(=O)c2ccc(N)nc2)c1F
Reaction time: 18 h
Yield: 98.2 %

Procedure:
Step 3 To a solution of {(R)-1-[3-(6-amino-pyridine-3-carbonyl)-4-chloro-2-fluoro-phenyl]-propyl}-carbamic acid tert-butyl ester (2.18 g, 4.43 mmol) in DCM (50 mL) was added 4M HCl in dioxane (7.75 mL, 31 mmol, 7 eq) and the reaction stirred for 18 h. Complete conversion. Mixture was concentrated and then triturated with diethyl ether (50 mL) and the solid filtered off and dried in a vacuum oven to give [3-((R)-1-amino-propyl)-6-chloro-2-fluoro-phenyl]-(6-amino-pyridin-3-yl)-methanone (1.54 g, 4.35 mmol, 98%) as a beige solid and the HCl salt
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([SH:9])[S:8][C:4]=2[CH:3]=1.[C:12](=O)([O-])[O-].[K+].[K+].CI>O1CCCC1>[I:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([S:9][CH3:12])[S:8][C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Sc1nc2ccc(I)cc2s1
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CSc1nc2ccc(I)cc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred, room temperature mixture of 6-iodobenzo[d]thiazole-2-thiol (Reference Example 6a, 1.5 g, 5.1 mmol) and potassium carbonate (0.707 g, 5.1 mmol) in tetrahydrofuran (30 mL) was added methyl iodide (0.35 mL, 5.6 mmol). The reaction mixture was stirred at room temperature overnight, then volatiles were removed under reduced pressure to give a solid. The solid was partitioned between saturated aqueous sodium carbonate and chloroform. The chloroform layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to provide 6-iodo-2-(methylthio)benzo[d]thiazole. 1H NMR (300 MHz, CDCl3) δ ppm 2.78 (s, 3H), 7.58 (d, J=9 Hz, 1H), 7.69 (dd, J=2, 9 Hz, 1H), 8.07 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 308 (M+H)+.
Reaction SMILES: C[Si](I)(C)C.[CH:6]([C@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([CH2:26][C:27]3[CH:28]=[N:29][C:30]([O:33]C)=[CH:31][CH:32]=3)=[CH:18][N:17]=2)[CH2:11][CH2:10]1)([CH3:8])[CH3:7]>C(Cl)(Cl)Cl>[CH:6]([C@H:9]1[CH2:10][CH2:11][C@H:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([CH2:26][C:27]3[CH:28]=[N:29][C:30]([OH:33])=[CH:31][CH:32]=3)=[CH:18][N:17]=2)[CH2:13][CH2:14]1)([CH3:8])[CH3:7]
Reactant: COc1ccc(Cc2cnc(N[C@H]3CC[C@H](C(C)C)CC3)c3ccccc23)cn1
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: CC(C)[C@H]1CC[C@H](Nc2ncc(Cc3ccc(O)nc3)c3ccccc23)CC1
Temperature: 60 °C
Reaction time: 14 h

Procedure:
Under a N2 atmosphere, 122 μl (0.90 mmol) of trimethylsilyl iodide are added to a solution of 351 mg (0.90 mmol) of trans 1-(4-isopropyl-cyclohexylamino)-4-[(6-methoxy-pyridin-3-yl)-methyl]-isoquinoline in 8 ml of chloroform, and stirred for 14 h at 60° C., then a further 122 μl of trimethylsilyl iodide are added and stirring is again effected for 3 h at 60° C. The mixture is cooled, the supernatant solution decanted from the solid, rinsed with a little chloroform and the chloroform phases discarded. The residue is dissolved by stirring in 40 ml of methylene chloride, 10 ml of methanol, 5 ml of EtOAc, 5 ml of saturated NaHCO3 solution and 5 ml of water. After adding more water, the organic phase is separated and washed with water and brine. The aqueous phases are extracted 3 more times with EtOAc. Drying (Na2SO4), concentrating by evaporation and crystallisation from hexane yield trans 1-(4-isopropyl-cyclohexylamino)-4-[(6-hydroxy-pyridin-3-yl)-methyl]-isoquinoline from the organic phases; FAB-MS: (M+H)+=376; TLC(acetone/CH2Cl2 3:2): Rf=0.13.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[F:19][C@@H:20]1[C@@H:24]([CH2:25][OH:26])[O:23][C@@H:22](N2C=CC(=O)NC2=O)[CH2:21]1.[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:22]2[O:23][C@H:24]([CH2:25][OH:26])[C@@H:20]([F:19])[CH2:21]2)=[C:4]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1
Reactant: Nc1nc(OCc2ccccc2)c2nc[nH]c2n1
Reactant: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Nc1nc(OCc2ccccc2)c2ncn([C@H]3C[C@H](F)[C@@H](CO)O3)c2n1
Temperature: 37 °C
Reaction time: 24 h
Yield: 62 %

Procedure:
2-Amino-6-benzyloxy-9H-purine (0.60 g 2.5 mmoles) and 2',3'-dideoxy-3'-fluorouridine (0.5 g 2.2 mmoles) were suspended in potassium phosphate buffer (10 mM) 50 ml, pH 6.8, containing 0.04% potassium azide. Purified purine nucleoside phosphorylase (1070) I.U.) and thymidine phosphorylase (400 I.U.) (Krenitsky et al, Biochemistry, 20, 3615 (1981) and U.S. Pat. No. 4,381,344) were added to the reaction mixture and the suspension stirred at 37° C. After 24 hours, additional thymidine phosphorylase (2000 I.U.) was added and, after 14 days, an additional 10 mM potassium phosphate buffer 25 ml, pH 6.8, containing 0.04% potassium azide was added. Additional purine nucleoside phosphorylase (5400 I.U.) and thymidine phosphorylase (2000 I.U.) were added after 17 days. After a total reaction time of 33 days, denatured protein was removed by filtration. The precipitate was washed with methanol until all the UV absorbing material was eluted from the precipitate. The filtrate was diluted with water until the methanol content was <10% and this diluted sample was applied to a series of coupled columns. The initial column contained AG1-X2 (2.5×10 cm, OH form) while the second column contained XAD-2 (2.5×20 cm). After sample application, the columns were washed with water 800 ml and the product eluted with methanol. Product-containing fractions were flash chromatographed on silica gel (2.5×20 cm) using dichloromethane:methanol (9:1). Solvent was removed and lyophilization yielded 2-amino-6-benzyloxy-9-(2,3-dideoxy-3-fluoro-β-D-erythro-pentofuranosyl)-9H-purine (0.49 g).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[SH:7][C:8]1[N:22]=[CH:21][CH:20]=[CH:19][C:9]=1[C:10]([NH:12][CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)=[O:11].Br[CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1>CN(C=O)C>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][CH2:25][CH2:24][S:7][C:8]2[C:9]([C:10]([NH:12][CH2:13][C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)=[O:11])=[CH:19][CH:20]=[CH:21][N:22]=2)=[CH:28][CH:29]=1
Reactant: O=C(NCc1cccs1)c1cccnc1S
Reactant: Fc1ccc(CCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NCc1cccs1)c1cccnc1SCCCc1ccc(F)cc1
Reaction time: 1 h
Yield: 73.3 %

Procedure:
227 mg (1.65 mmol) of K2CO3 were added to a solution of 375 mg (1.5 mmol) of 2-mercapto-N-(thiophen-2-ylmethyl)nicotinamide in DMF (6 ml) and stirring was carried out for 1 h at RT. 325 mg (1.5 mmol) of 1-(3-bromopropyl)-4-fluorobenzene were then added and stirring was carried out for a further 16 h at RT. The mixture was then concentrated in vacuo and the residue was taken up in an EA/water mixture. The organic phase was separated off and the aqueous phase was extracted again with EA. The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by means of CC (EA/hex 1:2), yielding 428 mg (1.1 mmol, 74%) of 2-[3-(4-fluorophenyl)-propylsulfanyl]-N-(thiophen-2-yl-methyl) -pyridine-3-carboxylic acid amide. MS: m/z 3871 [M+H]+.