Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.Cl[C:29]1[N:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=1>>[OH:26][C:23]([CH3:25])([CH3:24])[CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:29]3[N:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: Cc1ccc(Cl)nn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: Cc1ccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)nn1

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 3-chloro-6-methylpyridazine in Step 4. LC-MS Method 2 tR=1.118, m/z=446; 1H NMR (CD3OD) 0.96 (s, 3H), 1.26 (s, 3H), 1.58 (d, 3H), 2.17 (s, 2H), 2.26 (m, 1H), 2.50 (m, 2H), 2.69 (s, 3H), 3.08 (m, 1H), 5.59 (m, 1H), 7.11 (m, 2H), 7.25-7.40 (5H), 7.63 (m, 1H), 7.82 (m, 2H), 7.98 (d, 1H).
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][OH:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:10](OCC)(=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(C1C=C(O)C(C(C)(C)C)=CC=1O)(C)(C)C>[C:1]([O:6][CH2:7][CH2:8][O:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:16])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCCO
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)(C)c1cc(O)c(C(C)(C)C)cc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C=C(C)C(=O)OCCOC(=O)C(=O)OCC
Reaction time: 3 h
Yield: 56.3 %

Procedure:
A 500 ml flask equipped with a decanter, a thermometer, a stirrer and an inlet for nitrogen gas was charged with 65.1 g (0.5 mol) of 2-hydroxyethyl methacrylate and 365.4 g (2.5 mol) of diethyl oxalate, to which 2 g (10 mmol) of p-toluenesulfonic acid (catalyst) and 4 g of 2,5-di-t-butylhydroquinone (polymerization inhibitor) were added. The mixture was heated to keep about 130° C. for 3 hours in nitrogen atmosphere with distilling 23.5 ml (0.40. mol) of ethanol away. The reaction mixture was evaporated to remove excess diethyl oxalate and then distilled under vacuum to obtain 64.8 g (yield 52.4%) of 2-ethoxalyloxyethyl methacrylate (bp 95°-125 ° C./0.3 mmHg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C@H:4]([OH:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].[CH3:12]I>C(#N)C.[Ag]=O>[CH3:1][O:2][C:3](=[O:11])[C@H:4]([O:10][CH3:12])[CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)C[C@@H](O)C(=O)OC
Reactant: CI
Agent: O=[Ag]
Solvent: CC#N
Product: COC(=O)C[C@@H](OC)C(=O)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 88 %

Procedure:
The above (R)-2-hydroxysuccinic acid dimethyl ester was re-dissolved in methyl iodide (100 mL), freshly prepared silver oxide (30.2 g) was added and the mixture was stirred for 24 hours at room temperature. The reaction mixture was diluted with acetonitrile (200 mL), and filtered through celite to remove silver salts and excess silver hydroxide. The filtrate was taken to dryness to leave (R)-2-methoxysuccinic acid dimethyl ester as an oil (23.2 g, 88%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:4]([O:14]COC)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2>Cl>[CH3:13][O:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4]([OH:14])=[C:3]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:2]([CH3:1])=[CH:11]2
Reactant: COCOc1c(-c2ccccc2)c(C)cc2cc(OC)ccc12
Agent: Cl
Product: COc1ccc2c(O)c(-c3ccccc3)c(C)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 162.9 %

Procedure:
3-Methyl-6-(methyloxy)-1-{[(methyloxy)methyl]oxy}-2-phenylnaphthalene (15) (1.31 g, 4.25 mmol) was dissolved in HCl (4 N in 1,4-dioxane) (10 mL) and the solution was stirred at RT under N2 for 30 min. The reaction mixture was concentrated to give 1.83 g of crude 3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenol (7) as a gold-yellow oil. Compound (7) was previously characterized and used directly in the following reaction without additional purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CCN(C(C)C)C(C)C.[CH3:21][O:22][CH2:23]Cl>C(Cl)Cl>[CH3:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([O:11][CH2:21][O:22][CH3:23])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(O)cc1OC
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccc(OC)c(OC)c1
Reaction time: 17 h

Procedure:
To a stirred solution of 3,4-bis(methyloxy)phenol (Commercial eg Alfa Aesar) (1.0 g) and DIPEA (2.28 ml) in DCM (15 ml) was added chloromethyl methyl ether (0.74 ml) at 0 C. After stirring at 25-30 C. for 17 h, the reaction was washed with dilute hydrochloric acid and saturated aqueous sodium bicarbonate. This was dried over sodium sulphate and purified through silica eluting with 0-5% ethyl acetate in hexane, to give the title compound, 0.80 g
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:7]([CH2:16][OH:17])[CH:6]=1)[CH3:4].[C:18]([C:22]1[C:32]([F:33])=[CH:31][C:25]([O:26][CH2:27][C:28](O)=[O:29])=[CH:24][C:23]=1[F:34])([CH3:21])([CH3:20])[CH3:19].CN(C)CCCN=C=NCC>CN(C)C=O.CN(C)C1C=CN=CC=1>[C:18]([C:22]1[C:23]([F:34])=[CH:24][C:25]([O:26][CH2:27][C:28]([NH:2][C@@H:3]([C:5]2[CH:10]=[CH:9][C:8]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:7]([CH2:16][OH:17])[CH:6]=2)[CH3:4])=[O:29])=[CH:31][C:32]=1[F:33])([CH3:21])([CH3:19])[CH3:20]
Reactant: C[C@@H](N)c1ccc(NS(C)(=O)=O)c(CO)c1
Reactant: CC(C)(C)c1c(F)cc(OCC(=O)O)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)COc1cc(F)c(C(C)(C)C)c(F)c1)c1ccc(NS(C)(=O)=O)c(CO)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.4 %

Procedure:
To a solution of N-[4-[(1R)-1-aminoethyl]-2-(hydroxymethyl)phenyl]methanesulfonamide hydrochloride (40 mg, 0.14 mmol) in N,N-dimethylformamide (DMF) (2 ml), (4-tert-butyl-3,5-difluorophenoxy)acetic acid (34 mg, 0.14 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (40 mg), and 4-dimethylaminopyridine (DMAP) (0.5 mg, 0.004 mmol) were added. The solution was stirred at room temperature for 16 hours and then partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered, and evaporated. The residue obtained was purified by silica gel column chromatography, eluting with methylene chloride/ethylacetate (1:1), to give 2-(4-tert-butyl-3,5-difluorophenoxy)-N-((1R)-1-{3-(hydroxymethyl)-4-[(methylsulfonyl)amino]phenyl}ethyl)acetamide (24 mg, 36%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10](=[NH:12])[NH2:11].C[O:14][C:15](=O)/[C:16](/[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[C:17](\O)/[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C[O-].[Na+].Cl>CO>[C:21]([O:20][C:18]([C:17]1[NH:12][C:10]([CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[Br:2])=[N:11][C:15](=[O:14])[C:16]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: COC(=O)/C(OCc1ccccc1)=C(\O)C(=O)OC(C)(C)C
Reactant: N=C(N)Cc1ccccc1Br
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)c1[nH]c(Cc2ccccc2Br)nc(=O)c1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 71.3 %

Procedure:
2-(2-Bromophenyl)acetimidamide hydrochloride (2 g, 8.01 mmol, Eq: 1.00) and 4-tert-butyl 1-methyl 2-(benzyloxy)-3-hydroxyfumarate (4) (3.44 g, 11.2 mmol, Eq: 1.39) were dissolved in methanol (40.0 ml) and cooled down to 0° C. At that temperature sodium methoxide (1.37 g, 24.0 mmol, Eq: 3) was added. After another 15 minutes at this temperature, the resulting suspension was allowed to warm to room temperature overnight. A little methanol (˜5 ml) was added and the yellow suspension was cooled to 0° C. 1M HCl (˜50 ml) was added and a precipitate formed. The suspension was stirred for −20 minutes. The solid was collected by filtration, washed with water and a little methanol/water 9/1 and dried to afford 5-(benzyloxy)-2-(2-bromobenzyl)-6-oxo-3,6-dihydro-pyrimidine-4-carboxylic acid tert-butyl ester (2.69 g, 5.71 mmol, 71.2% yield) (67) as an off-white solid.
Reaction SMILES: Br[C:2]1[C:3]([NH:21][C:22]2[CH:26]=[C:25]([CH:27]3[CH2:29][CH2:28]3)[NH:24][N:23]=2)=[N:4][C:5]([C:8]2[S:12][C:11]([S:13]([NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])=[O:14])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH2:30]([Sn](CCCC)(CCCC)C=C)[CH2:31]CC>[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].O1CCOCC1>[C:17]([NH:16][S:13]([C:11]1[S:12][C:8]([C:5]2[N:4]=[C:3]([NH:21][C:22]3[CH:26]=[C:25]([CH:27]4[CH2:29][CH2:28]4)[NH:24][N:23]=3)[C:2]([CH:30]=[CH2:31])=[CH:7][N:6]=2)=[CH:9][CH:10]=1)(=[O:15])=[O:14])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2ncc(Br)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: C1COCCO1
Product: C=Cc1cnc(-c2ccc(S(=O)(=O)NC(C)(C)C)s2)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
The mixture of 5-(5-bromo-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)-N-tert-butylthiophene-2-sulfonamide (1 g, 2.0 mmol, 1.0 eq), tributyl(vinyl)stannane (956 mg, 3.01 mmol, 1.5 eq), Pd (PPh3)2Cl2 (200 mg, 0.28 mmol, 0.14 eq) and Bu4NBr (642 mg, 2.0 mmol, 1.0 eq) in 1,4-dioxane (30 mL) was stirred at 100° C. for 2 h under N2, cooled to room temperature and partitioned between EtOAc and water. The organic layer was concentrated and purified by silica gel chromatography to afford N-tert-butyl-5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-vinylpyrimidin-2-yl)thiophene-2-sulfonamide (755 mg, 80%). LC-MS (m/z)=444 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.I[C:13]1[CH:14]=[C:15]([CH3:20])[CH:16]=[C:17]([CH3:19])[CH:18]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[C@@H]1(N)CCCC[C@H]1N>[Cu]I.CCCCCC.C(OCC)(=O)C.O1CCOCC1>[CH3:20][C:15]1[CH:14]=[C:13]([N:8]2[C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[CH:6]=[CH:7]2)[CH:18]=[C:17]([CH3:19])[CH:16]=1
Reactant: Cc1cc(C)cc(I)c1
Reactant: COc1ccc2[nH]ccc2c1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc2c(ccn2-c2cc(C)cc(C)c2)c1
Yield: 99.5 %

Procedure:
Using the general procedure outlined in Example 63, 5-methoxyindole (0.177 g, 1.20 mmol) was coupled with 5-iodo-m-xylene (144 μL, 1.00 mmol) using CuI (2.0 mg, 0.010 mmol, 1.0 mol %), K3PO4 (2.1 mmol), trans-1,2-cyclohexanediamine (12 μL, 0.10 mmol, 10 mol %) and dioxane (1.0 mL) to give the crude product. Column chromatography (2×15 cm, hexane:ethyl acetate 50:1) provided 0.250 g (100% yield) of the product as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.66 (d, 1H, J=8.9 Hz), 7.43 (d, 1H, J=3.2 Hz), 7.32 (d, 1H, J=3.3 Hz), 7.27 (bs, 2H), 7.12 (bs, 1H), 7.07 (dd, 1H, J=2.4 Hz and J=9.0 Hz), 6.75 (d, 1H, J=2.2 Hz), 4.02 (s, 3H), 2.54 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 154.33, 139.68, 139.20, 130.93, 129.71, 128.26, 127.78, 121.58, 112.20, 111.37, 102.80, 102.45, 55.58, 21.20.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([C:26]([C:29]([NH:31]C(C)(C3C=CC=CC=3)C)=[O:30])=[CH:27][N:28]=2)[C:21]([O:23]CC)=[O:22])[CH2:14][C@H:13]1[O:41][CH3:42])=[O:10].Cl>CO.O>[NH2:31][C:29]([C:26]1[C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]([N:15]2[CH2:16][CH2:17][C@H:12]([NH:11][C:9]([C:3]3[NH:4][C:5]([CH3:8])=[C:6]([Cl:7])[C:2]=3[Cl:1])=[O:10])[C@H:13]([O:41][CH3:42])[CH2:14]2)=[N:28][CH:27]=1)=[O:30]
Reactant: CCOC(=O)c1cc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)ncc1C(=O)NC(C)(C)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: O
Product: CO[C@@H]1CN(c2cc(C(=O)O)c(C(N)=O)cn2)CC[C@@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Temperature: 120 °C
Yield: 10 %

Procedure:
A mixture of 85 mg (0.17 mmol) of Cis(±)-ethyl 5-(aminocarbonyl)-2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)isonicotinate (Example 198) and 86 mg (0.50 mmol) Ba(OH)2 in 3 ml MeOH and 2 ml water was heated at 120° C. for 1 h. The mixture was acidified to about pH=4 with 1N HCl and extracted 4 times with EtOAc. The EtOAc was concentrated and the residue was purified by reverse phase HPLC (20-40% CH3CN gradient in water with 0.1% TFA) to afford 8 mg of product as a white solid. MS (ES) MH+: 470 for C19H21Cl2N5O5; NMR: 1.5-1.8, (m, 3H), 2.2 (s, 3H), 3.0-3.2 (m, 2H), 3.3 (s, 3H), 3.5 (m, 2H), 4.2-4.5 (m, 2H), 4.9 (d, 1H), 6.9 (s, 1H), 7.1-7.3 (m, 2H), 7.8 (s, 1H), 8.4 (s, 1H), 12.1 (s, 1H), 13.1 (s, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]2[CH2:9][CH2:10][O:11][C:12]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:13]=3[C:14]=2[N:15]=1)=[O:5])C.[OH-].[Li+]>C1COCC1>[F:20][C:17]1[CH:18]=[CH:19][C:12]2[O:11][CH2:10][CH2:9][C:8]3[S:7][C:6]([C:4]([OH:5])=[O:3])=[N:15][C:14]=3[C:13]=2[CH:16]=1
Reactant: CCOC(=O)c1nc2c(s1)CCOc1ccc(F)cc1-2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1nc2c(s1)CCOc1ccc(F)cc1-2
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
Dissolved 9-fluoro-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid ethyl ester (0.75 g, 2.6 mmol) in 30 mL THF and added 1 M Lithium Hydroxide (10 mL, 10 mmol). Allowed reaction mixture to stir for 2 hours at room temperature. Reaction was complete by LCMS. THF was removed by rotovap and the aqueous layer was acidified with 1 M HCl. The product was extracted by DCM and concentrated in vacuo to give 0.68 g (100% yield unpurified) of 9-fluoro-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].C1C(=O)N([Br:28])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:28][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:18])[F:19]
Reactant: Cc1ccc(-c2nc3ccccc3o2)cc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1cc(-c2nc3ccccc3o2)ccc1CBr
Temperature: 25 °C

Procedure:
A mixture of 2-[4-methyl-3-(trifluoromethyl)phenyl]-1,3-benzoxazole (600 mg, 2.2 mmol), n-bromosuccinimide (579 mg, 3.25 mmol), benzoyl peroxide (26 mg, 0.11 mmol) in carbon tetrachloride (15 mL) was refluxed for 3 h and then cooled to rt. The white precipitate was filtered and the filtrate was concentrated to dryness. The crude was purified by flash chromatography on silica gel eluting with EtOAc:hexanes (1:1) to afford 2-[4-(bromomethyl)-3-(trifluoromethyl)phenyl]-1,3-benzoxazole.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[N:4]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:3]1[C:17]1[C:21]2[N:22]=[CH:23][N:24]=[C:25]([OH:26])[C:20]=2[NH:19][CH:18]=1.Cl.C(N(CC)CC)C.I([O-])(=O)(=O)=O.[Na+].[BH4-].[Na+]>CO.O>[OH:9][CH2:8][CH:5]([N:4]([C@@H:3]([C:17]1[C:21]2[N:22]=[CH:23][NH:24][C:25](=[O:26])[C:20]=2[NH:19][CH:18]=1)[CH2:2][OH:1])[C:10](=[O:11])[O:12][C:13]([CH3:15])([CH3:16])[CH3:14])[CH2:6][OH:7]
Reactant: CC(C)(C)OC(=O)N1[C@H](CO)[C@@H](O)[C@@H](O)[C@@H]1c1c[nH]c2c(O)ncnc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(C(CO)CO)[C@H](CO)c1c[nH]c2c(=O)[nH]cnc12
Reaction time: 0.25 h
Yield: 91.8 %

Procedure:
Di-tert-butyl Bicarbonate (0.091 g, 0.416 mmol) was added to a solution of (2S,3S,4R,5R)-2-(4-hydroxy-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-5-(hydroxymethyl)pyrrolidine-3,4-diol hydrochloride (0.07 g, 0.231 mmol, synthesized according to G. B. Evans, R. N. Furneaux, G. J. Gainsford, V. L. Schramm and P. C. Tyler, Tetrahedron, 2000, 56, 3053) and triethylamine (0.065 ml, 0.462 mmol) in a mixture of water (1 ml) and MeOH (3 ml). The solution was stirred for 30 mins., then the solvent evaporated to give 116 mg of a colourless solid which consisted, as estimated by 1H NMR, of about 78 mg, 0.213 mmol of (2S,3S,4R,5R)-tert-butyl 3,4-dihydroxy-2-(4-hydroxy-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-5-(hydroxymethyl)pyrrolidine-1-carboxylate with the rest being triethylamine hydrochloride. This mixture was dissolved in MeOH (4 ml) and water (3 nil) and sodium periodate (0.055 g, 0.255 mmol) added. After stirring for 15 mins a precipitate formed. Sodium borohydride (0.024 g, 0.639 mmol) was added and the mixture stirred for 15 mins then filtered through Celite and the solvent evaporated. The residue was chromatographed on silica gel (CH2Cl2-MeOH, 85:15) to give (S)-tert-butyl 1,3-dihydroxypropan-2-yl(2-hydroxy-1-(4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-7-yl)ethyl)carbamate (0.072 g, 92%) as a colourless solid. 1H NMR (CD3OD) δ 7.89 (s, 1H), 7.50 (br.s 1H), 5.32 (br. s, 0.5 H), 5.08 (br. s, 0.5H), 4.28 (br.s 1H), 4.17-3.50 (br. m, 6H), 1.39 (br. d, 9H). +ESMS Found 369.1760 (M+H)+ C16H25N4O6 requires 369.1774. [α]D20 +35.8 (c, 0.505, MeOH).
Reaction SMILES: [CH3:1][C:2]([NH:5][CH2:6][CH:7]([OH:26])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[CH:20][NH:21]2)([CH3:4])[CH3:3].[C:27](O)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:27]([O:26][CH:7]([CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[CH:20][NH:21]2)[CH2:6][NH:5][C:2]([CH3:1])([CH3:3])[CH3:4])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)(C)NCC(O)COc1ccccc1Cc1cccc2[nH]ccc12
Product: CC(C)(C)NCC(COc1ccccc1Cc1cccc2[nH]ccc12)OC(=O)c1ccccc1
Yield: 39.3 %

Procedure:
Using the procedure of Step G of Example 3, 16.3 g of the product of Step C and 5.65 g of the benzoic acid were reacted to obtain 8.29 g of the desired product melting at 195° C. (ethanol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][CH:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]2=[O:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][S:11][CH2:10][CH2:9]1.[CH3:25][C:26]1[CH:27]=[CH:28][C:29]([S:32]([NH:35]Cl)(=[O:34])=[O:33])=[CH:30][CH:31]=1.CO.C(Cl)(Cl)Cl>C(Cl)Cl.[Br-].C([P+](CCCC)(CCCC)CCCC)CCCCCCCCCCCCCCC.ClCl>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]2=[O:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][S:11](=[N:35][S:32]([C:29]2[CH:30]=[CH:31][C:26]([CH3:25])=[CH:27][CH:28]=2)(=[O:33])=[O:34])[CH2:12][CH2:13]1
Reactant: CC(=O)NCC1CN(c2ccc(N3CCSCC3)c(F)c2)C(=O)O1
Reactant: Cc1ccc(S(=O)(=O)NCl)cc1
Agent: CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC
Agent: ClCl
Agent: [Br-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCS(=NS(=O)(=O)c4ccc(C)cc4)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
The N-[[3-[3-fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (213 mg, 0.603 mmol) was dissolved in dry CH2Cl2 (11.5 mL) and then treated with hexadecyl-tributylphosphonium bromide (138 mg, 0.271 mmol). To this clear, colorless solution, the chloramine-T (165 mg, 0.723 mmol) was added. The resultant cloudy solution was stirred at room temperature for three hours. At this time, the reaction was determined to be complete by TLC (10% MeOH/CHCl3, UV short wave). The reaction mixture was transferred to a separatory funnel and diluted with CH2 Cl2 (10 mL). This solution was washed with cold 5% NaOH (20 mL), water (20 mL), and brine (20 mL). The aqueous portions were combined and then back-extracted with more CH2Cl2 (3×20 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resultant material was chromatographed on silica gel (100 g), eluting with a gradient of 0-6% MeOH in 10% CH3CN/CHCl3 to give 314 mg (99%) of the title compound as a white solid which decomposes at 79° C. and has a HRMS (FAB) calculated for C23H28FN4O5S2 (M+H)+, 523.1485, found 523.1477.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1([C:14]2[NH:18][C:17]([CH:19]3[CH2:21][CH2:20]3)=[N:16][N:15]=2)[CH2:13][CH2:12]1)C1C=CC=CC=1>CO.[Pd]>[CH:19]1([C:17]2[NH:18][C:14]([C:11]3([NH2:10])[CH2:12][CH2:13]3)=[N:15][N:16]=2)[CH2:21][CH2:20]1
Reactant: O=C(NC1(c2nnc(C3CC3)[nH]2)CC1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NC1(c2nnc(C3CC3)[nH]2)CC1
Reaction time: 1.5 h
Yield: 98.6 %

Procedure:
[1-(5-Cyclopropyl-4H-[1,2,4]triazol-3-yl)-cyclopropyl]-carbamic acid benzyl ester (220 mg, 0.74 mmol) was dissolved in MeOH (40 mL) followed by the addition of 10% Pd/C. The solution mixture was stirred under H2 balloon for 1.5 hours. The reaction mixture was filtered through celite. The solvent was concentrated under high vacuum pump to afford 1-(5-Cyclopropyl-4H-[1,2,4]triazol-3-yl)-cyclopropylamine (120 mg, 0.73 mmol, 99.1%) as off-white solids.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:19])[C@H:7]([CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)[NH2:8])([CH3:4])[CH3:3].Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>CC#N>[CH3:4][C:2]([O:5][C:6](=[O:19])[C@H:7]([CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)[NH:8][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC(C)(C)C
Yield: 81.6 %

Procedure:
To a solution of L-tryptophan 1,1-dimethylethyl ester (17.10 g; 65.68 mmol) in CH3CN (150 mL) 2M phosphate. buffer (pH 8; 150 mL) was added. Tert-butyl bromoacetate (10.7 mL; 72.25 mmol) was dropped into the mixture and vigorous mechanical stirring set on. The reaction was monitored by HPLC (Chromatographic method of Example 3, A)). After 23 h the organic layer was separated and concentrated to dryness to give a crude oil (26.62 g), which was purified by flash chromatography (silica gel; n-hexane/ethyl acetate, 8:2 v/v) to give the desired product (20.07 g; 53.59 mmol). Yield 54.5% starting from L-tryptophan.
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:21][C:22]([F:32])([F:31])[C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=O>>[F:20][C:17]([F:18])([F:19])[C:14]1[N:12]2[N:13]=[C:8]([N:1]3[CH2:7][CH2:6][CH2:5][N:4]([CH2:26][C:25]4[CH:28]=[CH:29][CH:30]=[C:23]([C:22]([F:21])([F:31])[F:32])[CH:24]=4)[CH2:3][CH2:2]3)[CH:9]=[CH:10][C:11]2=[N:16][N:15]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCCNCC3)nn12
Reactant: O=Cc1cccc(C(F)(F)F)c1
Product: FC(F)(F)c1cccc(CN2CCCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1

Procedure:
Reductive amination of 6-(1,4-diazepan-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-(trifluoromethyl)benzaldehyde was carried out according to General Synthetic Method 8. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 3-(trifluoromethyl)-6-[4-[[3-(trifluoromethyl)phenyl]methyl]-1,4-diazepan-1-yl]-[1,2,4]triazolo[4,3-b]pyridazine.