Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=O)[N:5]([CH2:9][CH2:10][CH3:11])[C:4](=[O:12])[C:3]=1[NH:13][C:14]([C:16]1[CH:17]=[N:18][N:19]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=1)=O.O=P(Cl)(Cl)[Cl:30]>CN(C=O)C>[CH2:21]([N:19]1[CH:20]=[C:16]([C:14]2[NH:13][C:3]3[C:4](=[O:12])[N:5]([CH2:9][CH2:10][CH3:11])[C:6]([Cl:30])=[N:7][C:2]=3[N:1]=2)[CH:17]=[N:18]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCn1c(=O)[nH]c(N)c(NC(=O)c2cnn(Cc3ccccc3)c2)c1=O
Solvent: CN(C)C=O
Product: CCCn1c(Cl)nc2nc(-c3cnn(Cc4ccccc4)c3)[nH]c2c1=O
Temperature: 127.5 °C
Yield: 8 %

Procedure:
A mixture of 1-benzyl-1H-pyrazole-4-carboxylicacid(6-amino-2,4-dioxo-3-propyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-amide (0.5 g, 13.5 mmol), POCl3 (10 ml) and DMF (0.1 ml) were heated at 125-130° C. for 20 hours. Reaction mixture was cooled to 20-25° C. It was then concentrated under vacuum. The residue was triturated with diethyl ether, dried. The crude product was purified by column chromatography using silica gel (100-200 mesh) and 2 to 4% methanol in DCM as an eluent to obtain 8-(1-Benzyl-1H-pyrazol-4-yl)-2-chloro-1-propyl-1,7-dihydro-purin-6-one (0.04 g, 8%) as a pale brown solid.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].C[Al](C)C.[C:10]([O:14][C:15](=[O:36])[NH:16][C:17]([CH3:35])([CH3:34])[CH2:18][C:19]1[C:27]2[C:22](=[C:23]([C:28]([O:30][CH2:31]OC)=[O:29])[CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)([CH3:13])([CH3:12])[CH3:11]>ClCCl>[C:10]([O:14][C:15](=[O:36])[NH:16][C:17]([CH3:35])([CH3:34])[CH2:18][C:19]1[C:27]2[C:22](=[C:23]([C:28]([O:30][CH2:31][NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:29])[CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)([CH3:12])([CH3:13])[CH3:11]
Reactant: CS(N)(=O)=O
Reactant: COCOC(=O)c1cccc2c(CC(C)(C)NC(=O)OC(C)(C)C)c[nH]c12
Agent: C[Al](C)C
Solvent: ClCCl
Product: CC(C)(Cc1c[nH]c2c(C(=O)OCNS(C)(=O)=O)cccc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 117.8 %

Procedure:
A solution of methanesulfonamide (106 mg, 1.12 mmol) and trimethyl aluminum (2.0 M in hexanes, 0.56 ml, 1.12 mmol) in dry dichloromethane (5.0 ml) is stirred at room temperature under a nitrogen atmosphere for 20 minutes. A solution of [2-(7-(methoxycarbomethoxy)-1H-indol-3-yl)-1,1-dimethyl-ethyl]-carbamic acid tert-butyl ester (160 mg, 0.425 mmol) in dry dichloromethane (1.5 ml) is added and the mixture is heated under reflux for 15 hours. The mixture is cooled to room temperature and quenched with 1 N HCl solution (3.4 ml) and partitioned between ethyl acetate and water. The organic extracts are dried over anhydrous Na2SO4, filtered and the solvent evaporated to give 220 mg of [2-(7-(methanesulfonamidylcarbomethoxy)-1H-indol-3-yl)-1,1-dimethyl-ethyl]-carbamic acid tert-butyl ester (90%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:17]([OH:20])([CH3:19])[CH3:18])[CH2:10][CH2:11]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-]#N.[Na+]>CN1C(=O)CCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]1[CH2:10][CH2:11][O:20][C:17]1([CH3:18])[CH3:19])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(CCOS(C)(=O)=O)C(C)(C)O
Agent: [C-]#N
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)NC1CCOC1(C)C
Temperature: 85 °C
Yield: 62.2 %

Procedure:
To a solution of methanesulfonic acid 3-tert-butoxycarbonylamino-4-hydroxy-4-methyl-pentyl ester (627 mg, 2.0 mmol, crude from step 2) in NMP (5 mL) was added sodium cyanide (0.98 g, 20 mmol). The reaction mixture was heated at 85° C. overnight then cooled to room temperature and partitioned between water and diethyl ether. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by SiO2 chromatography (20% to 50% EtOAc/hexanes) to afford 268 mg (62%) of (2,2-dimethyl-tetrahydro-furan-3-yl)-carbamic acid tert-butyl ester as a white solid.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([CH2:7][N:8]1[CH2:13][C:12]2[CH:14]=[C:15](/[CH:18]=[CH:19]/[C:20]([OH:22])=O)[CH:16]=[N:17][C:11]=2[NH:10][C:9]1=[O:23])=[O:6])[CH3:3].Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1.[CH3:43][NH:44][CH2:45][C:46]1[S:50][C:49]2[CH:51]=[CH:52][CH:53]=[CH:54][C:48]=2[C:47]=1[CH3:55].CNCC1C=CC2C(=CC=CC=2)C=1CCC>>[CH2:2]([O:4][C:5](=[O:6])[CH2:7][N:8]1[CH2:13][C:12]2[CH:14]=[C:15](/[CH:18]=[CH:19]/[C:20](=[O:22])[N:44]([CH3:43])[CH2:45][C:46]3[S:50][C:49]4[CH:51]=[CH:52][CH:53]=[CH:54][C:48]=4[C:47]=3[CH3:55])[CH:16]=[N:17][C:11]=2[NH:10][C:9]1=[O:23])[CH3:3]
Reactant: CCOC(=O)CN1Cc2cc(/C=C/C(=O)O)cnc2NC1=O
Reactant: CNCc1sc2ccccc2c1C
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: CCOC(=O)CN1Cc2cc(/C=C/C(=O)N(C)Cc3sc4ccccc4c3C)cnc2NC1=O
Yield: 59 %

Procedure:
According to the procedure of Example 1 (a), except substituting (E)-3-(3-ethoxycarbonylmethyl-2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-6-yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and substituting methyl-(3-methyl-benzo[b]thiophen-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, the title compound (380 mg, 59%) was prepared as a tan solid and as a mixture of amide rotomers: 1H NMR (300 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.40 (s, 1H), 8.01 (s, 1H), 7.87 (d, J=7.5 Hz, 1H), 7.43 (d, J=7.8 Hz, 1H), 7.64 (d, J=15.3 Hz, 1H), 7.42-7.16 (m, 3H), 5.11-4.88 (m, 2H), 4.53 (s, 2H), 4.18-4.11 (m, 4H), 3.14-2.93 (m, 3H), 2.42 (s, 3H), 1.21 (t, J=6.9 Hz, 3H); MS (ESI) m/e 479 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[BH4-].[Na+]>CCO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a solution of 3-bromobenzaldehyde (114.8 g, 620.4 mmol) in EtOH (650 mL), NaBH4 (7.1 g, 186.1 mmol) was added in several portions at 25° C. Then the mixture was stirred for 1 h at room temperature. The reaction was quenched with water (200 mL). After removing EtOH, the residue was dissolved in AcOEt (500 mL), and filtered. The filter was washed with water (150 mL), brine (150 mL), and dried over Na2SO4. After removing the solvent, 115.8 g of the title compound was obtained (Yield: 99.8%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28](Cl)=[N:27][N:26]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([NH:23][CH2:22][C:16]2([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:11][CH:12]=3)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[N:27][N:26]=1
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: Clc1nnc(Cl)c2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Clc1nnc(NCC2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)c2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.5 %

Procedure:
A mixture of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (300 mg, 0.94 mmol), 1,4-dichlorophthalazine (188 mg, 0.94 mmol) and N,N-diisopropylethylamine (410 μl, 2.36 mmol) in N,N-dimethylformamide (1 ml) was stirred at room temperature for 18 hours. More 1,4-dichlorophthalazine (188 mg, 0.94 mmol) was added and the reaction stirred at room temperature for 36 hours, then heated at 55° C. for 18 hours. The reaction mixture was partitioned between ethyl acetate (20 ml) and saturated aqueous sodium bicarbonate solution (20 ml). The organic layer was washed with more aqueous sodium bicarbonate, brine, dried over sodium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (100:0:0 to 92:8:0.8 by volume) to provide the title compound (183 mg, 61%). LRMS APCI+ m/z 481 [M]+.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[CH3:25][O:26][C:27]1[N:32]=[CH:31][C:30](B(O)O)=[CH:29][N:28]=1>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:30]4[CH:29]=[N:28][C:27]([O:26][CH3:25])=[N:32][CH:31]=4)=[C:4]([CH:9]=3)[C:3]([OH:2])=[O:24])[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: COc1ncc(B(O)O)cn1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: COc1ncc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cn1
Yield: 1 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with and 2-methoxypyrimidine-5-boronic acid (available from Combi-Blocks Inc.; 62 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 5-[4-(3,4-Dichloro-phenyl)-thiazol-2-yl]-2-(2-methoxy-pyrimidin-5-yl)-benzoic acid (0.9 mg, 1%). LCMS analysis indicated that the material was ˜100% pure, as measured by UV at 214 nm. LRMS m/z 457.8 and 459.8 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([Br:18])[S:17][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:19].O1CCOCC1>CCOCC>[Br:18][C:16]1[S:17][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[CH:15]=1.[ClH:19]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Br)sc2CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Brc1cc2c(s1)CCNCC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product of step g) (0.39 mmol) dissolved in ether (1 ml) was treated with 4 M HCl/dioxane (1 ml). The reaction mixture was stirred for 18 hours at ambient temperature. The resulting precipitate was filtered and washed with anhydrous diethyl ether to give the title compound as its HCl salt. 1H NMR (300 MHz, DMSO) δ 9.40 (s, 2H), 7.05 (s, 1H), 3.14-3.33 (m, 4H), 2.94-3.23 (m, 2H), 2.76-3.06 (m, 2H). MS: ESI (positive): 232, 234 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:31])[CH:9]([NH:23]C(=O)OC(C)(C)C)[CH2:10][C:11]2[O:15][N:14]=[C:13]([O:16][C:17]([F:22])([F:21])[CH:18]([F:20])[F:19])[CH:12]=2)=[CH:4][CH:3]=1.Cl.C(=O)([O-])[O-].[K+].[K+]>CO.O>[NH2:23][CH:9]([CH2:10][C:11]1[O:15][N:14]=[C:13]([O:16][C:17]([F:21])([F:22])[CH:18]([F:19])[F:20])[CH:12]=1)[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[OH:31]
Reactant: CC(C)(C)OC(=O)NC(Cc1cc(OC(F)(F)C(F)F)no1)C(O)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: NC(Cc1cc(OC(F)(F)C(F)F)no1)C(O)c1ccc(F)cc1
Yield: 100.2 %

Procedure:
A solution of tert-butyl N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[[3-(1,1,2,2-tetrafluoroethoxy)isoxazol-5-yl]methyl]ethyl]carbamate (0.291 g, 0.643 mmol) and conc. hydrochloric acid. (0.2 ml) in methanol (5 ml) was stirred at 60° C. for 0.5 hr. The reaction solution was diluted with water, alkalified with potassium carbonate, and extracted twice with ethyl acetate. The recovered organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give a crude product of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)isoxazol-5-yl]propan-1-ol as a white solid (0.227 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:10]=[CH:11][C:12]=1OS(C(F)(F)F)(=O)=O.[CH3:28][N:29]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=1)[C:30]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[O:31].[F-].[Cs+]>COCCOC.C(O)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:10]=[CH:11][C:12]=1[C:42]1[CH:41]=[CH:40][CH:39]=[C:38]([N:29]([CH3:28])[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:31])[CH:43]=1
Reactant: CCOC(=O)CCc1ccc(OS(=O)(=O)C(F)(F)F)c(OCCCOC)c1
Reactant: CN(C(=O)N1CCOCC1)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CCO
Product: CCOC(=O)CCc1ccc(-c2cccc(N(C)C(=O)N3CCOCC3)c2)c(OCCCOC)c1
Temperature: 25 °C
Yield: 19.9 %

Procedure:
Ethyl 3-[3-(3-methoxypropoxy)-4-{[(trifluoromethyl)sulfonyl]oxy}phenyl]propanoate (1.0 g, 2.40 mmol) was, dissolved in 1,2-dimethoxyethane (14.4 ml) and ethanol (1.6 ml). N-methyl-N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]morpholine-4-carboxamide (0.914 g, 2.64 mmol) was added and argon was bubbled in the solution for 10 minutes. Cesium fluoride (0.80 g, 5.28 mmol) and palladium tetrakistriphenylphosphine (0.139 g, 0.12 mmol) were added and the mixture was heated to reflux under an argon atmosphere for 14 hours. After cooling to room temperature, solvents were evaporated under reduced pressure and the residue was dissolved in ethyl acetate and water. The organic phase was washed with saturated aqueous ammonium chloride and brine, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate, 7/3) giving 0.232 g (20%) of the desired product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[C:23]4[CH:24]=[N:25][C:26]([NH2:40])=[C:27]([O:28][C@@H:29]([C:31]5[C:36]([Cl:37])=[CH:35][CH:34]=[C:33]([F:38])[C:32]=5[Cl:39])[CH3:30])[C:22]=4[O:21][C:20]=3[Br:41])[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.C(OCC)C>[Br:41][C:20]1[O:21][C:22]2[C:27]([O:28][C@@H:29]([C:31]3[C:36]([Cl:37])=[CH:35][CH:34]=[C:33]([F:38])[C:32]=3[Cl:39])[CH3:30])=[C:26]([NH2:40])[N:25]=[CH:24][C:23]=2[C:19]=1[C:17]1[CH:16]=[N:15][N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:18]=1
Reactant: C[C@@H](Oc1c(N)ncc2c(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)c(Br)oc12)c1c(Cl)ccc(F)c1Cl
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@@H](Oc1c(N)ncc2c(-c3cnn(C4CCNCC4)c3)c(Br)oc12)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4-{6-amino-2-bromo-7-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-furo[3,2-c]pyridin-3-yl}-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (2.0 mg, 0.0030 mmol) in DCM (0.1 mL) was added 1N HCl in diethyl ether (0.2 mL). The resulting mixture was stirred at rt overnight. Evaporation afforded the title compound as a light-yellow gum. LC-MS (ES+): 567.97/569.97/571.99 [MH+].
Reaction SMILES: [CH:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:23][C:24]3[CH:32]=[CH:31][C:27]([C:28]([OH:30])=O)=[CH:26][CH:25]=3)=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.O.[NH2:44][C:45]1[NH:49][N:48]=[N:47][N:46]=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH:1]1([N:7]2[C:11]([C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]([F:20])([F:22])[F:21])=[CH:16][CH:17]=3)=[CH:10][C:9]([CH2:23][C:24]3[CH:32]=[CH:31][C:27]([C:28]([NH:44][C:45]4[NH:49][N:48]=[N:47][N:46]=4)=[O:30])=[CH:26][CH:25]=3)=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1ccc(Cc2cc(-c3ccc(OC(F)(F)F)cc3)n(C3CCCCC3)n2)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1nnn[nH]1)c1ccc(Cc2cc(-c3ccc(OC(F)(F)F)cc3)n(C3CCCCC3)n2)cc1
Reaction time: 22 h

Procedure:
A solution of 55.6 mg product from Step E above, 28.8 mg EDC, 20.3 mg HOBt in 1 mL DMF was stirred at room temperature for 45 minutes. 5-Aminotetrazole monohydrate (15.5 mg) was added and the mixture stirred for additional 22 hours. DIEA (26 μL) and more EDC (13.8 mg) were added and the reaction continued for another day. The title compound was isolated on preparative HPLC using 75˜90% MeCN gradient over 10 minutes at 8.0 mL per minute with 0.1% TFA as a white solid following lyophilization. LC-MS: 2.26 min. (M+H=512.1).
Reaction SMILES: [NH2:1][C:2](=[O:28])[C@@H:3]([NH:20]C(=O)OC(C)(C)C)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:20][C@@H:3]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)[C:2]([NH2:1])=[O:28]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(S(=O)(=O)c2ccccc2)cc1)C(N)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)[C@@H](N)Cc1ccc(S(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.9 %

Procedure:
To a stirred solution of (S)-tert-butyl 1-amino-1-oxo-3-(4-(phenylsulfonyl)phenyl)propan-2-ylcarbamate (440 mg) in DCM (10 mL) at 0° C. was added TFA (2.51 mL). The mixture was allowed to warm to RT and stirred for 1 h. The mixture was concentrated in vacuo and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate, dried over sodium sulfate, filtered and concentrated in vacuo to leave the subtitle compound (175 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15][CH3:16])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([O:13][CH3:14])[CH:7]=1.N1C=CC=CC=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH3:16][O:15][CH:3]([O:2][CH3:1])[CH2:4][N:5]([S:24]([CH3:23])(=[O:26])=[O:25])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([O:13][CH3:14])[CH:7]=1
Reactant: COc1cc(NCC(OC)OC)ccc1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(N(CC(OC)OC)S(C)(=O)=O)ccc1F
Yield: 97.6 %

Procedure:
N-(2,2-dimethoxyethyl)-4-fluoro-3-methoxyaniline (1.46 g, 6.37 mmol) in dichloromethane (20 ml) was treated with pyridine (0.5 g 6.37 mmol) and methanesulphonyl chloride (766 mg, 6.69 mmol) and the mixture stirred until the reaction was complete by tlc. Aqueous work up and removal of solvent in vacuo gave N-(2,2-dimethoxyethyl)-N-methanesulphonyl-4-fluoro-3-methoxyaniline 1.91 g
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:20])[C:5]2[S:10][C:9](=[O:11])[N:8]([CH2:12][CH:13]3[CH2:17][O:16]C(C)(C)[O:14]3)[C:6]=2[N:7]=1.Cl>CO>[NH2:1][C:2]1[NH:3][C:4](=[O:20])[C:5]2[S:10][C:9](=[O:11])[N:8]([CH2:12][CH:13]([OH:14])[CH2:17][OH:16])[C:6]=2[N:7]=1
Reactant: CC1(C)OCC(Cn2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Agent: Cl
Solvent: CO
Product: Nc1nc2c(sc(=O)n2CC(O)CO)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 5-amino-3-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)thiazolo[4,5-d]pyrimidine-2,7(3H,6H)-dione(200 mg, 0.67 mmol) and a solution of hydrogen chloride in MeOH (10%, 20 mL) was protected from moisture and stirred at ambient temperature for 45 min. The solution was evaporated and the residue was stirred with H2O (20 mL). The mixture was immediately made basic (pH=9) by the addition of cone. NH4OH and then acidified (pH=6) withAcOH. The mixture was allowed to stand for 2 h and then the solid was collected by filtration, washed with H2O (50 mL) and dried in vacuumat 95° C. for 16 h.; 100 mg (0.387 mmol, 57%), mp 248°-254° C. Ir (KBr): ν 3360 broad (OH, NH, NH2), and 1600 broad (C=O, C=C, C=N) cm-1. Uv, λ max (nm), (ε×10-3): pH 1, 302 (10.4), 250 (9.59), 222 (29.3); MeOH, 302 (9.16), 250 (8.71), 222 (26.9); pH 11, 292 (7.62), 250 (7.67), 224 1H nmr (DMSO-d6): δ3.68-3.73 (m, 2 H, CH2), 3.80-3.92 (m, 3 H, CH2 and OH), 4.63 (t, 1 H, CH), 4.87 (d, 1 H, OH), 6.90 (br s, 2 H, NH2) and (br s, 1 H, NH). Anal. Calc'dfor C8H10N4O4S (258.26): C, 37.21; H, 3.90; N, 21.69. Found: C, 36.81; H, 4.02; N, 21.26.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]1[N:24]=[C:23]2[C:19]([NH:20][C:21](=[O:33])[N:22]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])=[C:18]([C:34]([O:36]CC)=O)[N:17]=1)(C(C)(C)C)(C)C.[NH2:39]C1C(C(OCC)=O)=NC(NC2C=CC=CC=2O[Si](C(C)(C)C)(C)C)=NC=1NC1C=CC=CC=1OC.C(N1C=CN=C1)(N1C=CN=C1)=O>C(Cl)Cl>[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]1[N:24]=[C:23]2[C:19]([NH:20][C:21](=[O:33])[N:22]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])=[C:18]([C:34]([NH2:39])=[O:36])[N:17]=1
Reactant: CCOC(=O)c1nc(Nc2ccccc2O[Si](C)(C)C(C)(C)C)nc(Nc2ccccc2OC)c1N
Reactant: CCOC(=O)c1nc(Nc2ccccc2O[Si](C)(C)C(C)(C)C)nc2c1[nH]c(=O)n2-c1ccccc1OC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(Nc3ccccc3O)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
Ethyl 2-(2-(tert-butyldimethylsilyloxy)phenylamino)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxylate. Ethyl 5-amino-2-(2-(tert-butyldimethylsilyloxy)phenyl amino)-6-(2-methoxyphenylamino)pyrimidine-4-carboxylate (232.6 mg, 0.456 mmol) was dissolved in methylene chloride (5 mL) and 1,1′-carbonyldiimidazole (740 mg, 4.56 mmol) was added. The reaction was refluxed for 1H and then stirred at room temperature overnight. Solvent was removed under reduced pressure and crude was purified by column chromatography (50% ethyl acetate in hexanes). Fractions containing product were combined and the solvent evaporated to provide the title compound (235.2 mg, 0.439 mmol, 96% yield) as a yellow solid. MS (ESI) m/z 536.4 [M+1]+.
Reaction SMILES: [OH:1][C@:2]1([C:16]2[S:17][CH:18]=[CH:19][N:20]=2)[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][CH2:3]1.C1C(=O)N([Br:28])C(=O)C1.[O-]S([O-])=O.[Na+].[Na+]>CN(C=O)C.O>[Br:28][C:18]1[S:17][C:16]([C@@:2]2([OH:1])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:4][CH2:3]2)=[N:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@](O)(c2nccs2)CC1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@](O)(c2ncc(Br)s2)CC1
Temperature: 40 °C
Yield: 94.7 %

Procedure:
The product of Step 2 (14.5 g, 48.6 mmol) was dissolved in DMF (58 mL) and then treated with NBS (11.24 g, 63.2 mmol) and warmed to 40° C. for 3 hours. The reaction was quenched with Na2SO3 (3.0 g, 24.30 mmol) in H2O (50 mL) and the solution was then extracted with EtOAc (100 mL), washed with brine (50 mL) and then chromatographed on silica gel to afford tert-butyl (4R)-4-(5-bromo-1,3-thiazol-2-yl)-4-hydroxyazepane-1-carboxylate (18.3 g, 46 mmol). MS ESI: [M+H-tBu]+ m/z 320.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[Cl:7][C:8]1[CH:9]=[C:10]([C@@H:14]2[C@@H:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:18]([C@@H:27]([CH:36]3[CH2:38][CH2:37]3)[CH2:28][NH:29][S:30]([CH:33]3[CH2:35][CH2:34]3)(=[O:32])=[O:31])[C:17](=[O:39])[C@:16]([CH2:42][CH:43]([OH:46])CO)([CH2:40][CH3:41])[CH2:15]2)[CH:11]=[CH:12][CH:13]=1.CO>O.C1COCC1.[Na+].[Cl-]>[Cl:7][C:8]1[CH:9]=[C:10]([C@@H:14]2[C@@H:19]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[N:18]([C@@H:27]([CH:36]3[CH2:38][CH2:37]3)[CH2:28][NH:29][S:30]([CH:33]3[CH2:34][CH2:35]3)(=[O:32])=[O:31])[C:17](=[O:39])[C@@:16]([CH2:40][CH3:41])([CH2:42][CH:43]=[O:46])[CH2:15]2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC[C@]1(CC(O)CO)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CNS(=O)(=O)C2CC2)C2CC2)C1=O
Agent: [Cl-]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC[C@]1(CC=O)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CNS(=O)(=O)C2CC2)C2CC2)C1=O
Reaction time: 0.5 h
Yield: 116.3 %

Procedure:
Sodium periodate (89 mg, 0.418 mmol) was added to a clear solution of N-((2S)-2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2,3-dihydroxypropyl)-3-ethyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)cyclopropanesulfonamide (Example 254, Step B, 85 mg, 0.14 mmol) in water (0.5 mL) and THF (1 mL). After several minutes, a solid formed. Methanol (1 ml) was added and the resulting emulsion was stirred for 30 min. The reaction was diluted with sat. aq. NaCl solution and extracted twice with ethyl acetate. The combined organic layers were washed with sat. aq. NaCl solution, dried over sodium sulfate and concentrated under the reduced pressure to provide the title compound (94 mg) which was used without purification in the next step. Mass Spectrum (ESI) m/z=577.0 (M+1)