Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][N:6]([C:16]([C:18]3[CH:27]=[CH:26][C:21](C(OC)=O)=[CH:20][CH:19]=3)=[O:17])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-:28].[Na+].[CH3:30][OH:31]>>[CH:1]1[C:11]2[CH2:10][C:15]3[CH:14]=[CH:13][CH:12]=[CH:9][C:8]=3[CH2:7][N:6]([C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:26][C:27]=3[C:30]([OH:31])=[O:28])=[O:17])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reactant: [OH-]
Reactant: CO
Agent: [Na+]
Product: O=C(O)c1ccccc1C(=O)N1Cc2ccccc2Cc2ccccc21

Procedure:
A mixture of 0.975 g of 6,11-dihydro-5H-dibenz[b,e]azepine and 0.20 g of NaH (60% in oil) in 20 ml of tetrahydrofuran is stirred at room temperature for 0.5 hr. Then 1.1 g of mono-methyl terephthalyl chloride (prepared from mono-methyl terephthalate and thionyl chloride) is added and the mixture refluxed 18 hours. The mixture is cooled, poured into ice water and filtered. The solid is triturated with dichloromethane-hexane to give 1.0 g of crystals, m.p. 182°-185° C. The preceding compound, methyl 4-[(6,11-dihydro-5H-dibenz[b,e]azepin-5-yl)carbonyl]benzoate (2.11 g), 20 ml of 2N NaOH and 20 ml of methanol is stirred overnight and then heated on a steam bath for 1 hr. The solvent is removed to give a solid. The solid is extracted with ether (discarded). The solid is dissolved in water and the solution acidified with citric acid to give a solid. The solid is filtered and washed with water to give 1.84 g of crystals, m.p. 220°-225° C.
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C([Sn](CCCC)(CCCC)[C:18]1[O:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1)CCC.O.CCOC(C)=O>CN(C=O)C.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[O:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=[C:18]1[C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cccnc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc2ccccc2o1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cccnc1-c1nc2ccccc2o1
Temperature: 110 °C
Yield: 200.6 %

Procedure:
A mixture of ethyl 2-chloronicotinate (100 mg, 0.539 mmol), 2-(tributylstannyl)benzo[d]oxazole (314 mg, 0.539 mmol) and [1,1′-bis(diphenylphosphino) ferrocene]-dichloropalladium (II) (39.4 mg, 0.054 mmol) in DMF (2 mL) was heated to 110° C. for 1 h by applying microwave radiation to the mixture. The reaction was repeated on the same scale and the thus obtained reaction mixtures obtained were combined. Excess water and EtOAc were added. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and dried over MgSO4. Purification by flash column chromatography (EtOAc/DCM, gradient: 1-10% DCM) provided the title compound (290 mg, 90%);
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:14].[CH3:16]CN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.BrC[C:36]1[CH:45]=[CH:44][C:39]2[N:40]([CH3:43])[N:41]=[N:42][C:38]=2[CH:37]=1>CN(C=O)C>[CH3:14][C:6]1[N:7]([CH2:16][C:45]2[CH:36]=[CH:37][C:38]3[N:42]=[N:41][N:40]([CH3:43])[C:39]=3[CH:44]=2)[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:13]2[C:5]=1[CH2:4][C:3]([OH:2])=[O:15]
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Reactant: Cn1nnc2cc(CBr)ccc21
Reactant: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Product: Cc1c(CC(=O)O)c2cccnc2n1Cc1ccc2nnn(C)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester ((0.025 g, 0.122 mmol) in dry DMF (1 ml) under an inert atmosphere of Argon is added dropwise, BEMP (56.6 μl, 0.196 mmol). The mixture is agitated at room temperature for 1 hour before cooling to 0° C. with an ice-bath. A solution of 5-bromomethyl-1-methyl-1H-benzotriazole (0.044 g, 0.196 mmol) in DMF (1 ml) is added to the cooled solution and the resulting mixture is agitated at room temperature for 2 days. The solvent is removed in vacuo and purification of the crude by chromatography on silica eluting with iso-hexane/ethyl acetate (0%-20% ethyl acetate) yields the titled product. (MH+ 350).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:19]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:22]=[C:21]([N:31]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N:33]=[C:32]2[CH:40]([F:42])[F:41])[N:20]=1>C1COCC1.C(O)(=O)C.O>[F:42][CH:40]([F:41])[C:32]1[N:31]([C:21]2[N:22]=[C:23]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:24]=[C:19]([NH:1][C:2]3[N:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[N:20]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: Nc1ncccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: FC(F)c1nc2ccccc2n1-c1nc(Nc2ncccn2)nc(N2CCOCC2)n1
Reaction time: 0.33 h
Yield: 30.7 %

Procedure:
To a solution of 0.214 g (2.25 mmol) of 2-aminopyrimidine in THF (4 mL) at 0° C. was added 1.25 mL of NaHMDS (2 M solution in THF) and the mixture was stirred for 20 min. A solution of 0.275 g (0.75 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole in THF (4 mL) was added, and the resulting mixture was stirred for 1 hr at RT. After neutralization with acetic acid, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed sequentially with water and aq. NH3, dried and concentrated. Chromatography on alumina, eluting first with hexanes/EtOAc (4:1), then with CH2Cl2/EtOAc (1:3) gave an orange powder. Recrystallization from ethanol gave 0.098 g (31% yield) of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(2-pyrimidinyl)-1,3,5-triazin-2-amine: mp 261-263° C.; 1H NMR (CDCl3) δ8.69-8.67 (m, 3H), 8.34 (t, JHF=53.3 Hz, 1H), 8.07 (br s, 1H), 7.91 (dd, J=7.9, 0.9 Hz, 1H), 7.49-7.40 (m, 2H), 7.05 (t, J=4.8 Hz, 1H), 3.96 (m, 4H), 3.83 (m, 4H); Anal. Calcd. for C19H17F2N9O: C, 53.65; H, 4.0; N, 29.6. Found: C, 53.6; H, 4.1; N, 29.4%.
Reaction SMILES: ClC(OCC(C)C)=O.[O:9]([CH2:17][C:18]#[C:19][C:20]([OH:22])=O)[Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].CN1CCOCC1.N#N.[NH2:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[N:39]=[CH:38][C:37]([C:43]#[N:44])=[C:36]2[NH:45][C:46]1[CH:51]=[CH:50][CH:49]=[C:48]([Br:52])[CH:47]=1>O1CCCC1.N1C=CC=CC=1>[Br:52][C:48]1[CH:47]=[C:46]([NH:45][C:36]2[C:35]3[C:40](=[CH:41][CH:42]=[C:33]([NH:32][C:20](=[O:22])[C:19]#[C:18][CH2:17][O:9][Si:10]([C:13]([CH3:14])([CH3:15])[CH3:16])([CH3:11])[CH3:12])[CH:34]=3)[N:39]=[CH:38][C:37]=2[C:43]#[N:44])[CH:51]=[CH:50][CH:49]=1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Reactant: CC(C)(C)[Si](C)(C)OCC#CC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: N#N
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)[Si](C)(C)OCC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 34.8 %

Procedure:
Isobutyl chloroformate (0.214 g, 1.57 mmol) was dropwise added into an ice cold solution of 4-t-butyldimethylsiloxy-2-butynoic acid (0.336 g, 1.57 mmol) and N-methylmorpholine (0.19 g, 1.88 mmol) in 15 mL of tetrahydrofuan under N2. After stirring for 30 min, the reaction mixture was added dropwise into a solution of 0.4 g (1.18 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 3 mL of tetrahydrofuran and 1.5 mL of pyridine and stirred at 0° C. for 1 hr. The reaction was quenched with ice water, poured into saturated sodium bicarbonate and brine, and extracted with ethyl acetate. The ethyl acetate layer was concentrated and purified by column chromatography eluted with 60% ethyl acetate in hexane. The product was collected, and dried in vacuo to give 0.22 g (35%) of yellow solid;: mass spectrum (electrospray, m/e,): 535.1189 (M+.).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(Cl)Cl>O>[CH3:16][S:17]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:19])=[O:18]
Reactant: OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccccc1
Temperature: -5 °C
Yield: 85 %

Procedure:
Under nitrogen methylene chloride (1.4 liter), benzyl alcohol (129.6 g., 1.2 moles) and triethylamine (182 g., 1.8 moles) were combined, stirred and cooled to -5° C. in an ice-water-acetone bath. A solution of methanesulfonyl chloride (150 g., 1.31 moles) in 100 ml. of methylene chloride was added over 49 minutes, maintaining the temperature between -5° and 2° C. After stirring for 10 minutes at 0°-2° C., the reaction was diluted with 500 ml. of water, precooled to 5° C. The organic layer was separated, washed 2×500 ml. of cold water, dried over MgSO4, filtered and evaporated in vacuo to yield title product as a light yellow oil [190 g.; 85%; 1H--NMR (CDCl3) delta (ppm): 2.9 (s, 3H), 5.2 (s, 2H), 7.4 (m, 5H); Rf 0.75 (CH2Cl 2)]. This product was refrigerated until used in the next step.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[NH:14][C:15]([NH2:24])=[C:16]2[C:20]([N:21]=1)=[N:19][C:18]([O:22][CH3:23])=[N:17]2)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH:34]1[CH2:39][CH2:38][O:37][C:36]([CH3:41])([CH3:40])[CH2:35]1>CN(C=O)C>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH:34]2[CH2:39][CH2:38][O:37][C:36]([CH3:41])([CH3:40])[CH2:35]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: CC1(C)CC(CCBr)CCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCC3CCOC(C)(C)C3)c2n1
Temperature: 60 °C
Yield: 13.5 %

Procedure:
A mixture of 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate (0.2 g, 0.569 mmol) and anhydrous potassium carbonate (0.315 g, 2.277 mmol) in DMF was heated at 60° C. for 1 hour. The mixture was cooled to room temperature and 4-(2-bromoethyl)-2,2-dimethyltetrahydro-2H-pyran (0.151 g, 0.683 mmol) was added and the mixture heated at 50° C. for 18 hours. The mixture was quenched with water (2 ml) and extracted with DCM (2×5 ml). The DCM was separated through a hydrophobic frit and evaporated by blowing down under a stream of nitrogen. Addition of DMSO:MeOH (1:1) gave a precipitate which was collected by filtration, washed with methanol and dried in vacuo to give the title compound (29 mg).
Reaction SMILES: [CH3:1][C:2]([O:4][C:5]([CH3:7])=[O:6])=O.[F:8][C@@H:9]1[C@@H](CO)[O:12][C@@H:11]([N:16]2[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:10]1>N1C=CC=CC=1>[C:5]([O:4][CH2:2][C@H:1]1[O:12][C@@H:11]([N:16]2[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:10][C@@H:9]1[F:8])(=[O:6])[CH3:7]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]c1=O
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
56 mMol acetanhydride is added at 0° C. to a solution of 50 mMol 3'-deoxy-3'-fluorothymidine in 50 ml pyridine. The reaction solution stands overnight at room temperature and is subsequently poured into ice water. The aqueous phase is decanted. The oily product is purified in a chromatographic column on silica gel with chloroform eluent. The fractions obtained from the product are isolated as a solid material which is recrystallized from ethanol. M.P.97°-98° C.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:17][CH2:18][CH:19]([CH2:23][CH2:24][CH2:25][F:26])[C:20]([OH:22])=[O:21])[C:10]([O:12]C(C)(C)C)=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C@@H:9]([CH2:17][CH2:18][CH:19]([CH2:23][CH2:24][CH2:25][F:26])[C:20]([O-:22])=[O:21])[C:10]([OH:12])=[O:11].[NH4+:8]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(CCCF)C(=O)O)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](CCC(CCCF)C(=O)[O-])C(=O)O
Product: [NH4+]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-tert-Butyl 6-hydrogen (2S)-2-[(tert-butoxycarbonyl)amino]-5-(3-fluoropropyl)-hexanedioate (57.0 mg, 0.15 mmol) and trifluoroacetic acid (0.5 mL) and dichloromethane (0.5 mL) was stirred at r.t. for 30 min. Then the mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (ZIC HILIC, 5 μm 100×4.6 mm, acetonitrile/0.1 M aqueous ammonium formate solution gradient, 10 mL/min).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:24]3[CH:29]=[C:28]([F:30])[C:27]([NH:31][C:32]([NH:34][C:35]4[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][C:36]=4[F:45])=[O:33])=[CH:26][C:25]=3[F:46])[CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O.C(OCC)(=O)C>ClCCCl>[NH2:1][C:2]1[C:7]2=[C:8]([C:24]3[C:25]([F:46])=[CH:26][C:27]([NH:31][C:32]([NH:34][C:35]4[CH:40]=[C:39]([C:41]([F:43])([F:44])[F:42])[CH:38]=[CH:37][C:36]=4[F:45])=[O:33])=[C:28]([F:30])[CH:29]=3)[CH:9]=[C:10]([CH:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(-c3cc(F)c(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3F)c3c(N)ncnn23)CC1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Nc1ncnn2c(C3CCNCC3)cc(-c3cc(F)c(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3F)c12
Reaction time: 0.17 h
Yield: 42.1 %

Procedure:
A suspension of Example 274 (498 mg, 0.77 mmol) in 10 mL 1,2-dichloroethane was treated with 3 mL TFA at rt. The reaction quickly became homogeneous and at 10 min no starting material remained by RP-HPLC. The reaction mixture was concentrated in vacuo, and the residue taken up again in fresh 1,2-dichloroethane and concentrated again; this was repeated 2 times. The residue was taken up in THF (5 mL) and EtOAc (35 mL) and washed with aq. sodium carbonate. The organic layer was dried with sodium sulfate and concentrated in vacuo to provide a tan solid. Trituration with ethyl acetate provided the title compound (178 mg, 42%) as a tan solid. Concentration of the mother liquor provided an additional the title compound (201 mg, 48 mmol) of similar purity. 1H-NMR (DMSO-d6) δ 9.54 (bs, 2H), 8.70 (dd, 1H), 8.21 (dd, 1H), 7.96 (s, 1H), 7.60 (dd, 1H), 7.30-7.46 (m, 1H), 7.38 (dd, 1H), 6.57 (s, 1H), 3.16-3.31 (m, 1H), 3.02-3.12 (m, 2H), 2.60-2.74 (m, 2H), 1.89-2.02 (m, 2H), 1.60 (ddd, 2H), 1.42 (s, 9H); MS [M+H]+=550.2; LCMS RT=2.43
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][N:14]1[C:20](=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C[O:23][C:24]1[CH2:29][CH2:28][CH2:27][C:26](=O)[CH:25]=1.Cl>O1CCCC1>[CH3:13][N:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([C:26]2[CH2:27][CH2:28][CH2:29][C:24](=[O:23])[CH:25]=2)[C:20]1=[O:21]
Reactant: CN1CCCCCC1=O
Reactant: COC1=CC(=O)CCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CN1CCCCC(C2=CC(=O)CCC2)C1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 85.8 %

Procedure:
Diisopropylamine (12.14 g, 17.0 ml) in dry tetrahydrofuran (THF 20 ml) was added dropwise to a stirred cooled (-10° C.) solution of butyl lithium (86 ml of 1.4 molar solution in hexane) under nitrogen. After 10 minutes Gilman test was negative. 1-Methylcaprolactam (14.19 g) in THF (20 ml) was added, also at -10° C. Reaction was stirred for 10 minutes at 0° C. and 3-methoxy-2-cyclohexenone (12.6 g, 0.1 mole) in THF (20 ml) was added. The mixture was allowed to warm to room temperature and stirred at room temperature for 1.5 hours, then cooled to -10° C. and decomposed by addition of 2 N HCl (125 ml) rapidly but not allowing temperature to exceed 0° C. The mixture was stirred at room temperature for 30 minutes. The aqueous layer was separated and extracted with dichloromethane. The combined organic extracts were dried over anhydrous magnesium sulphate and evaporated to an oil which crystallised from toluene-light petroleum (b.p. 60°-80° C.) affording the title compound (18.99 g), m.p. 109°-110° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:11]2[CH:16]3[CH2:17][CH2:18][CH:12]2[CH2:13][O:14][CH2:15]3)[N:3]=1.CI.[C:21]([O-])([O-])=O.[K+].[K+]>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:21])=[C:4]([N:11]2[CH:12]3[CH2:18][CH2:17][CH:16]2[CH2:15][O:14][CH2:13]3)[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Clc1nc(N2C3CCC2COC3)c2nc[nH]c2n1
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: Cn1cnc2c(N3C4CCC3COC4)nc(Cl)nc21
Reaction time: 65 h
Yield: 98.2 %

Procedure:
A mixture of 2-chloro-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-9H-purine (650 mg, 2.45 mmol), methyl iodide (183 μL, 2.94 mmol) and K2CO3 (473 mg, 3.43 mmol) in THF (15 mL) was stirred at r.t. for 18 h before further methyl iodide (50 μL, 0.80 mmol) was added. The resulting mixture was allowed to stir for 65 h then concentrated in vacuo. The resulting residue was partitioned between EtOAc and H2O, the organic phase washed with brine, then dried (Na2SO4) and concentrated in vacuo affording the title compound as an off-white solid (673 mg, 98%). LCMS (method H): RT 2.63 min [M+H]+ 280.3
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:3]=[N:2]1.[H-].[Na+].[CH2:15]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1CCl)[CH2:16][CH2:17][CH3:18].[CH3:29]N(C)C=O>>[CH2:15]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:29][N:1]2[CH:5]=[C:4]([C:6]3[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=3)[CH:3]=[N:2]2)=[CH:25][CH:26]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCOCc1ccccc1CCl
Reactant: Nc1ncccc1-c1cn[nH]c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CCCCOCc1ccc(Cn2cc(-c3cccnc3N)cn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a mixture of 3-(1H-pyrazol-4-yl)-pyridin-2-ylamine (20 mg, 0.13 mmol) described in Manufacturing Example 32-1-4 and N,N-dimethylformamide (1 mL) was added sodium hydride (6.8 mg, 0.19 mmol, 66% in oil), which was stirred for 30 minutes at room temperature. 1-Butoxymethylchloromethyl-benzene (29 mg, 0.14 mmol) described in Manufacturing Example 33-1-4 was added to the reaction mixture at room temperature, and stirred for 1.5 hours at 40° C. The reaction mixture was cooled and partitioned into water and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1) to obtain the title compound (33 mg, 78%).
Reaction SMILES: C[O-].[Na+].[Si]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([NH:40][S@@:41]([C:43]([CH3:46])([CH3:45])[CH3:44])=[O:42])([C:26]2[CH:31]=[C:30]([O:32][C:33]([F:38])([F:37])[CH:34]([F:36])[F:35])[CH:29]=[C:28]([F:39])[CH:27]=2)[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][C:13]=1[F:47])(C(C)(C)C)(C)C>>[F:47][C:13]1[CH:14]=[C:15]([C:18]([NH:40][S@@:41]([C:43]([CH3:46])([CH3:45])[CH3:44])=[O:42])([C:26]2[CH:31]=[C:30]([O:32][C:33]([F:37])([F:38])[CH:34]([F:35])[F:36])[CH:29]=[C:28]([F:39])[CH:27]=2)[CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:16]=[CH:17][C:12]=1[OH:11]
Reactant: CC(C)(C)[S@@](=O)NC(Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(O[Si](C)(C)C(C)(C)C)c(F)c1
Agent: C[O-]
Agent: [Na+]
Product: CC(C)(C)[S@@](=O)NC(Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(O)c(F)c1
Reaction time: 0.25 h
Yield: 86.8 %

Procedure:
At room temperature a solution of NaOMe (5 mL, 0.5 M solution in MeOH) was added to the 4:1 diastereomeric mixture of (R)—N-(1-(4-(tert-butyldimethylsilyloxy)-3-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide (801 mg, 1.22 mmol). The reaction mixture was stirred for 15 minutes, MeOH was removed then the residue dissolved in EtOAc (50 mL) and transferred to a separation funnel HCl (20 mL, 1.0 N solution) was added and the EtOAc layer was separated. The aqueous layer was extracted with EtOAc (2×10 mL) and the combined organic layers were dried over Na2SO4, filtered and concentrated to yield (R)—N-(1-(3-fluoro-4-hydroxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide as a white foam (578 mg, 87% yield). LCMS: RT=1.987 min [M+H] 546.35 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH2:11]([NH2:14])[CH2:12][NH2:13].O>C(Cl)Cl>[NH2:13][CH2:12][CH2:11][NH:14][S:7]([C:5]1[S:6][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:9])=[O:8]
Reactant: NCCN
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Solvent: O
Solvent: ClCCl
Product: NCCNS(=O)(=O)c1ccc(Br)s1
Temperature: 0 °C
Yield: 91.7 %

Procedure:
A mixture of 5-bromothiophene-2-sulfonyl chloride (2.5 g, 9.6 mmol, 1.0 eq) in CH2Cl2 (100 mL) was stirred at 0° C., ethane-1, 2-diamine (2.3 g, 38.24 mmol, 4 eq) was added drop-wise. Then, the mixture was stirred at 0° C. for 0.5 h. Water was added and extracted with EA (6×80 ml). The combined organic layers were dried (Na2SO4), filtered and concentrated to give N-(2-aminoethyl)-5-bromothiophene-2-sulfonamide (2.51 g, 92.0%). LC-MS (m/z)=284.1 [M+H]+.
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([N+:28]([O-:30])=[O:29])[C:26]=1[OH:27])[CH:22]=O)[CH3:17].[NH2:31][C:32]([NH2:34])=[O:33].Cl>C(O)C>[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:22]2[C:8]([C:9]3[CH:14]=[N:13][CH:12]=[CH:11][N:10]=3)=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[NH:34][C:32](=[O:33])[NH:31]2)[CH:24]=[C:25]([N+:28]([O-:30])=[O:29])[C:26]=1[OH:27])[CH3:17]
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: O=C(Cc1cnccn1)c1ccccc1
Reactant: NC(N)=O
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2cnccn2)cc([N+](=O)[O-])c1O
Yield: 21.9 %

Procedure:
To a solution of 1-phenyl-2-(pyrazin-2-yl)ethanone (Intermediate 26) (150 mg, 0.76 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (149 mg, 0.76 mmol), and urea (137 mg, 2.28 mmol) in 20 mL of ethanol was added 0.2 mL of concentrated HCl solution, the reaction mixture was stirred at reflux for 2 days. After the solvent was removed under reduced pressure, the residue was purified by reverse-phase preparatory HPLC (26-53% acetonitrile+0.1% trifluoroacetic acid in water+0.1% trifluoroacetic acid, over 15 min.) to give Compound 58 (72 mg, yield 21.9%). 1H NMR (DMSO-d6300 MHz): δ10.27 (S, 1H), 9.22 (s, 1H), 8.43 (s, 1H), 8.15 (s, 1H), 7.84 (s, 1H), 7.65 (s, 1H), 7.44 (m, 4H), 7.32 (d, J=7.2 Hz, 3H), 5.45 (d, J=2.1 Hz, 1H), 4.10 (m, 2H), 1.35 (t, J=6.9 Hz, 3H); MS (ESI): m/z 434.0 [M+1]+.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6]([Cl:11])[N:5]=[C:4]([NH:12][CH:13]=[O:14])[N:3]=1.[CH2:15]([O:22][CH2:23][CH:24]([CH2:28][O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:25][O:26][NH2:27])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>O1CCOCC1>[CH2:30]([O:29][CH2:28][CH:24]([CH2:23][O:22][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:25][O:26][NH:27][C:2]1[N:3]=[C:4]([NH:12][CH:13]=[O:14])[N:5]=[C:6]([Cl:11])[C:7]=1[NH:8][CH:9]=[O:10])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=CNc1nc(Cl)c(NC=O)c(Cl)n1
Reactant: NOCC(COCc1ccccc1)COCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=CNc1nc(Cl)c(NC=O)c(NOCC(COCc2ccccc2)COCc2ccccc2)n1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 70 %

Procedure:
A mixture of 4,6-dichloro-2,5-diformamidopyrimidine (from Description 1a) (3.3 g, 14.0 mmol), 3-benzyloxy-2-benzyloxymethylprop-1-oxyamine (4.2 g, 14.0 mmol), triethylamine (5.8 ml, 41.6 mmol) and dioxan (100 ml) was stirred at 100° C. for 2.5 hours. The cooled reaction mixture was filtered and the precipitate collected and washed with dioxan (2×25 ml). The filtrate and washings were combined and evaporated to a syrup. Column chromatography on silica gel (eluted with chloroform-ethanol, 50:1) afforded the title compound (4.9 g, 70%). IR: υmax (KBr) 3240, 2910, 2860, 1690, 1585, 1565, 1475, 1420 cm-1. 1H NMR: δH [(CD3)2SO] 2.29 (1H, quintet, J=6.0, 5.6 Hz, CH), 3.56 (4H, d, J=5.6 Hz, 2×CH2OCH2Ph), 3.94 (2H, d, J=6.0 Hz, CH2ON) 4.46 (4H, s, 2×CH2Ph), 7.30 (10H, m, 2 ×Ph), 9.28 (1H, br.s, NCHO), 9.42 (1H, br.s, NCHO), 10.86 (2H, br.s, D2O exchangeable, 2×NHCHO).