Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[OH:19][C:20]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:21]=1[NH2:22]>>[OH:19][C:20]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:21]=1[NH:22][C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Reactant: Cc1cccc(O)c1N
Product: COc1ccc2c(c1)CCn1c-2cc(Nc2c(C)cccc2O)nc1=O

Procedure:
The title compound was prepared from 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (4) and 2-hydroxy-6-methyl-aniline as in Example 1 d. 1H-NMR (400 MHz, d6-DMSO, at 60° C.) δ 9.39 (br, 1H), 8.60 (br, 1H), 7.61 (br, 1H), 7.05-6.95 (3H), 6.75 (d, 1H), 6.73 (d, 1H), 6.34 (br, 1H), 3.95 (t, 2H), 3.83 (s, 3H), 2.95 (t, 2H), and 2.19 (s, 3H); MS (ESI) (M+H)+ 350.
Reaction SMILES: C(S([N:6]1[CH2:11][CH2:10][CH:9](C2C3C(=C(C(N)=O)C=C(C4SC(CNCC(C)CC)=CC=4)C=3)NC=2)[CH2:8][CH2:7]1)(=O)=O)C.[CH:36]([C:38]1[S:42][C:41]([B:43]([OH:45])[OH:44])=[CH:40][CH:39]=1)=O.C(N)CCCC.[BH3-]C#N.[Na+]>>[CH2:7]([NH:6][CH2:36][C:38]1[S:42][C:41]([B:43]([OH:45])[OH:44])=[CH:40][CH:39]=1)[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCC(C)CNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Reactant: O=Cc1ccc(B(O)O)s1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCCCCN
Product: CCCCCNCc1ccc(B(O)O)s1

Procedure:
Following the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), pentylamine (29 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 45 mg of crude {5-[(pentylamino)methyl]-2-thienyl}boronic acid. The crude {5-[(pentylamino)methyl]-2-thienyl}boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003 mmol) to give 20.7 mg of the title compound (20%).
Reaction SMILES: [OH-].[Na+].[P:3]([O-:20])([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:21]([O:28][C:29](=[O:32])[CH:30]=[O:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([O:28][C:29](=[O:32])[CH:30]([P:3]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:20])[OH:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=CC(=O)OCc1ccccc1
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(OCc1ccccc1)C(O)P(=O)(OCc1ccccc1)OCc1ccccc1
Temperature: 20 °C
Yield: 61 %

Procedure:
1.5 ml of a saturated methanolic sodium hydroxide solution are allowed to run rapidly into 45.5 g of dibenzyl phosphite and 28.5 g of glyoxylic acid benzyl ester. The reaction which proceeded is exothermic. The mixture is subsequently stirred at 20° C. for some hours. It is chromatographed on silica gel using methylene chloride containing 5% of methanol. The fraction with a Rf of 0.58 is evaporated, 20 ml of diethyl ether are added to the residue (55.2 g) and 45.0 g of dibenzyloxyphosphinylhydroxy-acetic acid benzyl ester are isolated. Melting point 67°-68° C. Yield: 61%.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1.[F:14][C:15]([F:25])([F:24])[C:16]1[C:17]([CH:22]=[O:23])=[N:18][CH:19]=[CH:20][CH:21]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.C1COCC1>[Br:13][C:9]1[CH:8]=[C:7]([CH:22]([C:17]2[C:16]([C:15]([F:25])([F:14])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[OH:23])[CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ncccc1C(F)(F)F
Reactant: Brc1cccc(Br)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: OC(c1cccc(Br)c1)c1ncccc1C(F)(F)F
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 55.5 %

Procedure:
25 mL of anhydrous THF was placed under nitrogen and cooled to −78° C. 2.2 ml (5.5 mmol) of a 2.5 M solution of n-butyl lithium in hexanes were added. To the resulting solution was slowly added 0.7 mL (1.4 g, 5.8 mmol) of 1,3-dibromobenzene. Upon complete addition the resulting solution was stirred at −78° C. for 90 min. 1.00 g (5.71 mmol) of 3-trifluoromethyl-pyridine-2-carbaldehyde was added rapidly. The dark solution was warmed to −20° C. and stirred for 20 min at that temperature. The resulting mixture was distributed between 10% aqueous citric acid and dichloromethane. The phases were separated and the aqueous layer extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and the solvent completely evaporated. The resulting residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes to afford 1.053 g (3.171 mmol, 58%) of (3-bromo-phenyl)-(3-trifluoromethyl-pyridin-2-yl)-methanol as a yellow oil. 1H NMR (500 MHz, DMSO-d6) δ 8.84 (m, 1H), 8.18 (dd, 1H), 7.63 (m, 1H), 7.53 (dd, 1H), 7.42 (m, 1H), 7.26-7.24 (m, 2H), 6.31 (d, 1H), 6.02 (d, 1H); MS: m/z 332.0+334.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH3:10])[CH:3]=1.C([Li])(CC)C.C([Li])CCC.[I:21]I>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH3:10])[CH:5]=[CH:6][C:7]=1[I:21]
Reactant: CCCc1cccc(F)c1
Reactant: II
Agent: [Li]C(C)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCc1ccc(I)c(F)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
1-Fluoro-3-propylbenzene (30 g, 0217 mol) and dry tetrahydrofurane (300 ml) were placed in 1 L flask equipped with mechanical stirrer, nitrogen inlet and outlet, 250 ml pressure-equilibrated dropping funnel and thermometer. The mixture was cooled down to −78° C. in a dry ice/acetone bath and 1.3 mol/L sec-butyllithium solution (170 ml, 0.221 mol) was added dropwise and the reaction temperature was kept below −70° C. After addition of all butyllithium solution the mixture was stirred for 2 hours at −78° C. and iodine (55.12 g, 0.217 mol) in dry tetrahydrofurane was added dropwise. Cooling bath was removed and heating to room temperature was allowed. The tetrahydrofurane was evaporated using rotary evaporator and the oily substance was washed off in separation funnel with sodium sulfite solution. Organic phase was separated dried over magnesium sulfate and filtered. The product was distilled under reduced pressure 0.4 mmHg, collecting the fraction of the transparent liquid boiling at 60° C. 43 g of 2-fluoro-1-iodo-4-propylbenzene was obtained, 75% of theor. yield.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[C:6](=O)[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.Cl.[NH2:14][OH:15].[OH-].[Na+].C(O)C>O>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[C:6](=[N:14][OH:15])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: Cc1cnc2c(c1)CCCC2=O
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cnc2c(c1)CCCC2=NO

Procedure:
The quinoline (30g), hydroxylamine hydrochloride (14g), sodium hydroxide (9g), ethanol (165ml) and water (65ml) were stirred and refluxed for 2 hours. Water (100ml) was added and the product was allowed to crystallise overnight. The crystals were removed by filtration and washed with water and dried to give 3-methyl-8-oximino-5,6,7,8-tetrahydroquinoline (27.5g) mp 188° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[O:7][CH2:8][CH2:9]Cl.[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][CH2:25][CH2:26][NH2:27].O>CS(C)=O>[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][CH2:25][CH2:26][NH:27][CH2:9][CH2:8][O:7][C:6]1[CH:11]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:12][CH3:13]
Reactant: COc1ccc(F)cc1OCCCl
Reactant: NCCCc1c[nH]c2ccc(F)cc12
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(F)cc1OCCNCCCc1c[nH]c2ccc(F)cc12
Temperature: 90 °C
Reaction time: 12 h
Yield: 72.1 %

Procedure:
A solution of 2-(5-fluoro-2-methoxy-phenoxy)ethylchloride (0.3 g, 1.5 mmol), 3-(5-fluoro-1H-indol-3-yl)propylamine (0.56 g, 2.9 mmol) in dimethylsulfoxide (20 ml) was allowed to stir for 12 h at 90° C. The reaction mixture was poured into water (100 ml) and extracted with methylene chloride (3×100 ml). The organic layer was washed with water (3×150 ml), dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. Chromatography (10% methanol-methylene chloride) afforded 0.39 g (77%) of product as a white solid: mp 119-122° C.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Br:4][C:5]1[CH:6]=[C:7](F)[CH:8]=[C:9]([Br:11])[CH:10]=1>CN(C)C=O>[Br:4][C:5]1[CH:6]=[C:7]([O:2][CH3:1])[CH:8]=[C:9]([Br:11])[CH:10]=1
Reactant: C[O-]
Reactant: Fc1cc(Br)cc(Br)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(Br)cc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.5 %

Procedure:
Sodium methoxide (4.5M solution in methanol, 8.80 ml, 41.0 mmol) was added dropwise to a stirred solution of 3,5-dibromofluorobenzene (5.00 g, 19.0 mmol, Aldrich) in N,N-dimethylformamide (95 ml) at 0° C. under a nitrogen atmosphere. The reaction was warmed to room temperature, stirred for 1 hour and then evaporated under reduced pressure. The residue was dissolved in diethyl ether and was washed with water (3×300 ml) and brine (300 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure to give the title compound as a white solid (5.13 g).
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[F:11][C:12]1[CH:13]=[C:14]([C:18]2[C:19]([CH:28]([NH2:30])[CH3:29])=[CH:20][CH:21]=[C:22]3[C:27]=2[N:26]=[CH:25][CH:24]=[CH:23]3)[CH:15]=[N:16][CH:17]=1.C(N(CC)C(C)C)(C)C>C(O)C>[F:11][C:12]1[CH:13]=[C:14]([C:18]2[C:19]([CH:28]([NH:30][C:2]3[N:10]=[CH:9][N:8]=[C:7]4[C:3]=3[N:4]=[CH:5][NH:6]4)[CH3:29])=[CH:20][CH:21]=[C:22]3[C:27]=2[N:26]=[CH:25][CH:24]=[CH:23]3)[CH:15]=[N:16][CH:17]=1
Reactant: CC(N)c1ccc2cccnc2c1-c1cncc(F)c1
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2[nH]cnc12)c1ccc2cccnc2c1-c1cncc(F)c1

Procedure:
A mixture of 6-bromo-9H-purine (0.1072 g, 0.54 mmol), 1-[8-(5-fluoropyridin-3-yl)quinolin-7-yl]ethanamine (0.072 g, 0.27 mmol), and N,N-diisopropylethylamine (0.05630 mL, 0.32) in ethanol (0.9 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resultant residue was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/minute) to give the desired product as a tris-TFA salt. LCMS calculated for C21H17FN7(M+H)+: m/z=386.2; found: 386.1. 1H NMR (DMSO-d6, 400 MHz) δ 9.40 (1H, s), 8.81 (1H, m), 8.65 (1H, s), 8.62 (1H, s), 8.50 (1H, s), 8.41 (2H, m), 8.11 (1H, d, J=8.8 Hz). 7.97˜7.84 (2H, m), 7.55 (1H, dd, J=8.4 and 4.4 Hz), 5.25 (1H, m), 1.58 (3H, d, J=6.8 Hz) ppm. 19F NMR (DMSO-d6, 376.28 MHz) δ −75.0 ppm.
Reaction SMILES: C(O)(=O)C.[NH2:5][CH2:6][C@@H:7]([C:9]1[CH:10]=[CH:11][C:12]([OH:20])=[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=1)[OH:8].O=[C:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:41]=[CH:40][C:31]([CH2:32][N:33]3[C:37](=[O:38])[NH:36][C:35](=[O:39])[O:34]3)=[CH:30][CH:29]=2)[CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C>[O:38]=[C:37]1[NH:36][C:35](=[O:39])[O:34][N:33]1[CH2:32][C:31]1[CH:30]=[CH:29][C:28]([N:25]2[CH2:26][CH2:27][CH:22]([NH:5][CH2:6][C@@H:7]([C:9]3[CH:10]=[CH:11][C:12]([OH:20])=[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=3)[OH:8])[CH2:23][CH2:24]2)=[CH:41][CH:40]=1
Reactant: O=C1CCN(c2ccc(Cn3oc(=O)[nH]c3=O)cc2)CC1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(Cn4oc(=O)[nH]c4=O)cc3)CC2)ccc1O
Reaction time: 0.33 h
Yield: 71.2 %

Procedure:
Acetic acid (0.09 mL, 1.6 mmol) was added to a mixture of N-{5-[(1R)-2-amino-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide (197 mg, 0.8 mmol) (which was obtained in Example 10), 2-[4-(4-oxo-1-piperidinyl)benzyl]-1,2,4-oxadiazolidine-3,5-dione (231 mg, 0.8 mmol) (which was obtained in Example 55), and DMF(5 mL). The mixture was stirred for 20 minutes and then, sodium triacetoxyborohydride (203 mg, 0.96 mmol) was added, and the new mixture was stirred at room temperature for 24 hours. The volatiles were removed in vacuo and the residue was purified by flash chromatography (dichloromethane/methyl alcohol 4/1) to produce an off-white solid (296 mg, 71% yield); mp 193–195° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.58–1.62 (m, 2H), 1.96–2.07 (m, 2H), 2.60–2.70 (m, 2H), 2.86–3.17 (m, 6H), 3.72–3.8 (m, 2H), 4.28 (s, 2H), 2.70–2.74 (m, 1H), 6.83–6.87 (m, 3H), 7.03–7.13 (m, 3H), 7.23 (m, 1H), 8.60 (brs, 2H); MS (ES) m/z: 518 (M−H)−.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH3:17])[C:9](=[O:18])[C:8]1=[O:19]>>[CH3:17][N:10]1[C:11]2[C:16](=[CH:15][C:14]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:13][CH:12]=2)[N:7]([CH3:6])[C:8](=[O:19])[C:9]1=[O:18]
Reactant: Cn1c(=O)c(=O)n(C)c2ccccc21
Reactant: O=S(=O)(O)Cl
Product: Cn1c(=O)c(=O)n(C)c2cc(S(=O)(=O)Cl)ccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Chlorosulfonic acid (3 mL) was heated to 65° C. and 1,4-dimethylquinoxaline-2,3(1H,4H)-dione (example 6-3b, 1 g, 5.5 mmol) was added in portions over 0.5 hour. The reaction mixture was stirred for 4 hours then cooled to ambient temperature and poured slowly onto ice. The resulting precipitate was filtered and washed with water to give 1,4-dimethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-sulfonyl chloride as a white solid. 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.50 (s, 6H), 7.25 (m, 2H), 7.38 (m, 4H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[C:15]3[CH2:23][N:22]([C:24]4[CH:25]=[N:26][C:27]([O:34][CH3:35])=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=4)[CH2:21][CH2:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:9]1)=[O:7])(C)(C)C.[CH2:36](N(CC)CC)[CH3:37].C(Cl)(=O)CC>Cl>[CH3:35][O:34][C:27]1[N:26]=[CH:25][C:24]([N:22]2[CH2:21][CH2:20][C:16]3[N:17]=[CH:18][N:19]=[C:14]([NH:13][C@H:10]4[CH2:11][CH2:12][N:8]([C:6](=[O:7])[CH2:36][CH3:37])[CH2:9]4)[C:15]=3[CH2:23]2)=[CH:29][C:28]=1[C:30]([F:33])([F:31])[F:32]
Reactant: COc1ncc(N2CCc3ncnc(N[C@H]4CCN(C(=O)OC(C)(C)C)C4)c3C2)cc1C(F)(F)F
Reactant: CCN(CC)CC
Agent: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CC[C@H](Nc2ncnc3c2CN(c2cnc(OC)c(C(F)(F)F)c2)CC3)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
A solution of (S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 24) (29.04 g, 58.73 mmol) in 2-Me-THF (100 mL) was dropwise added into aqueous HCl solution (150 mL, 31%) over 15 min. The reaction mixture was partitioned between water (300 mL) and isopropyl acetate (100 mL) and the upper organic phase was discarded. The aqueous phase was partitioned between 25% NaOH (aq) (200 g) and 2-Me-THF (200 mL), and the organic phase was collected and dried. Triethylamine (16.32 mL, 117.48 mmol) was added into the organic phase followed by dropwise addition of propionyl chloride (6.0 g, 64.6 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 1 h. The reaction mixture was washed with water (110 mL) and the resulting organic phase was concentrated in vacuo to give a brown gum. The residue was recrystallized with isopropanol and methyl tert-butyl ether to give 1-{(S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1-yl}-propan-1-one as a colourless solid (17.2 g, 65% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([NH:16][C:17]1[S:18][CH2:19][C@@H:20]2[CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][C@:21]2([C:33]2[CH:38]=[N:37][CH:36]=[CH:35][N:34]=2)[N:22]=1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl>[N:34]1[CH:35]=[CH:36][N:37]=[CH:38][C:33]=1[C@:21]12[CH2:23][NH:24][CH2:25][C@H:20]1[CH2:19][S:18][C:17]([NH:16][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[N:22]2
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2cnccn2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC1=N[C@@]2(c3cnccn3)CNC[C@H]2CS1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 100.1 %

Procedure:
Trifluoroacetic acid (1.5 mL) is added to a stirred solution of tert-butyl(4aR,7aR)-2-benzamido-7a-pyrazin-2-yl-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazine-6-carboxylate (299 mg, 0.680 mmol) in dichloromethane (6 mL) at room temperature. The reaction is stirred at room temperature for 80 minutes and the solvent is evaporated under reduced pressure. The resulting residue is dissolved in methanol (20 mL) and this solution is loaded onto an ion exchange column and eluted with methanol then with 7 M ammonia/methanol solution. The basic fraction is collected and concentrated under reduced pressure to give the title compound (231 mg, quantitative). ES/MS (m/e): 340 (M+1).
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][C@@H:8]([OH:10])[CH2:9][C@H:2]12.C(N(CC)CC)C.[F:18][C:19]([F:31])([F:30])[C:20]1[CH:21]=[C:22]([S:26](Cl)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1>ClCCl>[F:31][C:19]([F:18])([F:30])[C:20]1[CH:21]=[C:22]([S:26]([N:6]2[CH2:5][CH2:4][N:3]3[CH2:7][C@@H:8]([OH:10])[CH2:9][C@@H:2]3[CH2:1]2)(=[O:27])=[O:28])[CH:23]=[CH:24][CH:25]=1
Reactant: O[C@H]1C[C@@H]2CNCCN2C1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1cccc(C(F)(F)F)c1)N1CCN2C[C@@H](O)C[C@@H]2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To (7S,8aR)-2-benzyloctahydropyrrolo[1,2-a]pyrazin-7-ol (Example 17D, 5 g, 21.52 mmol) and solvent 2,2,2-trifluoroethanol (50 mL) were added to 20% palladium hydroxide on carbon, wet (0.500 g) in a pressure bottle. The mixture was stirred at 50° C. for 16 hours under 30 psi of hydrogen. The mixture was filtered through a nylon membrane to give a crude (7S,8aR)-octahydropyrrolo[1,2-a]pyrazin-7-ol. To a solution of the above crude (7S,8aR)-octahydropyrrolo[1,2-a]pyrazin-7-ol (1.0 g, 7 mmol) and triethylamine (1.13 g, 11.2 mmol) in dichloromethane (40 mL) was slowly added a solution of 3-(trifluoromethyl)benzene-1-sulfonyl chloride (1.712 g, 7 mmol) in dichloromethane (2 mL). The solution was stirred at room temperature for 4 hours. The solution was concentrated, diluted with ethyl acetate (100 mL), washed with water (20 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (dichloromethane/methanol=10:1) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43-1.58 (m, 2H), 1.97 (m, 2H), 2.10-2.35 (m, 3H), 2.90 (m, 1H), 3.20 (m, 1H), 3.62 (m, 1H), 3.77 (m, 1H), 4.14 (m, 1H), 4.80 (m, 1H), 7.92 (m, 2H), 8.10 (m, 2H); MS (ESI) m/z 351 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([OH:19])=[CH:16]2)=[CH:11][C:10]=1[C:20]1[S:21][C:22]([N:25]([CH3:36])[CH:26]2[CH2:31][C:30]([CH3:33])([CH3:32])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]2)=[N:23][N:24]=1)C1C=CC=CC=1.B(Br)(Br)Br.CO>C(Cl)Cl>[CH3:36][N:25]([CH:26]1[CH2:31][C:30]([CH3:33])([CH3:32])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]1)[C:22]1[S:21][C:20]([C:10]2[C:9]([OH:8])=[CH:18][C:17]3[C:12]([CH:11]=2)=[CH:13][CH:14]=[C:15]([OH:19])[CH:16]=3)=[N:24][N:23]=1
Reactant: CN(c1nnc(-c2cc3ccc(O)cc3cc2OCc2ccccc2)s1)C1CC(C)(C)NC(C)(C)C1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CN(c1nnc(-c2cc3ccc(O)cc3cc2O)s1)C1CC(C)(C)NC(C)(C)C1
Temperature: 25 °C
Yield: 44.6 %

Procedure:
To a stirred, ice-bath cooled suspension of 7-(benzyloxy)-6-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)naphthalen-2-ol (49 mg, 0.112 mmol) in DCM (2 ml) under nitrogen was added BBr3 (1M solution in DCM, 0.56 mL, 0.56 mmol). The reaction mixture was quenched by addition of MeOH (2 mL) and the resulting solution was warmed to room temperature, then loaded onto a 1 g SCX cartridge (pre-wet with MeOH). The cartridge was washed with MeOH (˜15 mL) then flushed with 7M NH3 in MeOH (˜10 mL). The MeOH/NH3 was removed in vacuo to afford the crude product. The crude product was taken up in 1:1 MeOH:DMSO (2 mL), filtered via syringe filter, and the filtrate purified by preparative HPLC, under neutral conditions, running a gradient from 10-90% MeCN/water over 15 minutes. The relevant fractions were combined and concentrated in vacuo to afford the title compound as a dark green/brown solid (20.6 mg, 49.2% yield). LC-MS: Rt 0.85 min; MS m/z 413.3 [M+H]+ [Method B]. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.92 (br. s., 1H) 9.81 (br. s., 1H) 8.31 (s, 1H) 7.74 (d, J=9.09 Hz, 1H) 7.07 (s, 1H) 6.87-6.94 (m, 2H) 4.25-4.34 (m, 1H) 3.01 (s, 3H) 1.64 (dd, J=12.13, 3.03 Hz, 2H) 1.45 (t, J=12.13 Hz, 2H) 1.22 (s, 6H) 1.10 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[N:12][C:11]([C:14]([OH:16])=O)=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].C(OC([N:24]1[CH2:29][CH2:28][NH:27][C:26]([CH3:31])([CH3:30])[CH2:25]1)=O)(C)(C)C.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].CC1(C)CNCCN1C(C1N=CN(C2C=CC=CC=2)N=1)=O>>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[CH3:30][C:26]1([CH3:31])[CH2:25][NH:24][CH2:29][CH2:28][N:27]1[C:14]([C:11]1[N:12]=[CH:13][N:9]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([F:1])[CH:3]=2)[N:10]=1)=[O:16]
Reactant: CC1(C)CN(C(=O)OC(C)(C)C)CCN1
Reactant: Cc1ccc(-n2cnc(C(=O)O)n2)cc1F
Agent: CC1(C)CNCCN1C(=O)c1ncn(-c2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-n2cnc(C(=O)N3CCNCC3(C)C)n2)cc1F

Procedure:
This intermediate was prepared from 1-(3-fluoro-4-methyl-phenyl)-1H-[1,2,4]-triazole-3-carboxylic acid and 3,3-dimethyl-piperazine-1-carboxylic acid tert-butyl ester in two steps according to the preparation of (2,2-dimethyl-piperazin-1-yl)-(1-phenyl-1-H-[1,2,4]-triazol-3-yl)-methanone trifluoroacetate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:8](Cl)=[N:7]2.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+]>CC#N.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:8]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N:7]2
Reactant: CC(C)(C)Nc1nc2c(Br)cccc2nc1Cl
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)Nc1nc2c(Br)cccc2nc1-c1ccccc1
Temperature: 80 °C
Reaction time: 17.5 h
Yield: 61.6 %

Procedure:
A suspension of 8-bromo-N-(tert-butyl)-3-chloroquinoxalin-2-amine (Example 304a (˜2.5:1 mixture with 5-bromo-N-(tert-butyl)-3-chloroquinoxalin-2-amine); 119.0 mg, 0.378 mmol), phenylboronic acid (Aldrich; 46.1 mg, 0.378 mmol), Na2CO3 (200 mg, 1.891 mmol), and Pd(PPh3)4 (Strem Chemicals, Inc.; 21.85 mg, 0.019 mmol) in a mixture of MeCN (3.0 mL) and water (1.000 mL) was stirred under argon at 80° C. for 17.5 h. The reaction mixture was cooled to RT and concentrated onto silica gel. Chromatographic purification (silica gel, 0-10% EtOAc/hexanes) furnished 8-bromo-N-(tert-butyl)-3-phenylquinoxalin-2-amine (83.0 mg, 0.233 mmol, 62% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.85 (1H, dd, J=4.5, 1.2 Hz), 7.83 (1H, dd, J=5.1, 1.4 Hz), 7.67-7.72 (2H, m), 7.51-7.59 (3H, m), 7.20 (1H, t, J=7.8 Hz), 5.23 (1H, br. s.), 1.57 (9H, s). m/z (ESI, +ve) 355.9/358.0 (M+H)+.