Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:10]2=[C:13]3[C:3]=1[CH2:4][N:5]([CH3:16])[S:6](=[O:15])(=[O:14])[C:7]3=[CH:8][S:9]2.[Cu][C:18]#[N:19].N1C=CC=CC=1.N>CCOCC.O>[CH3:16][N:5]1[CH2:4][C:3]2=[C:13]3[C:7](=[CH:8][S:9][C:10]3=[CH:11][CH:12]=[C:2]2[C:18]#[N:19])[S:6]1(=[O:15])=[O:14]
Reactant: N#C[Cu]
Reactant: CN1Cc2c(Br)ccc3scc(c23)S1(=O)=O
Agent: N
Solvent: CCOCC
Solvent: O
Solvent: c1ccncc1
Product: CN1Cc2c(C#N)ccc3scc(c23)S1(=O)=O
Temperature: 190 °C

Procedure:
1 g of 6-bromo-4-methyl-4,5-dihydro-1,3-dithia-4-aza-acenaphthylene-3,3-dioxide is added to 0.32 g of copper (I) cyanide and 10 ml of pyridine. The reaction mixture is heated to 190° C. for 7 h, then poured onto 10 ml of ammonia solution and combined with water and ether (30 ml of each). The aqueous phase is extracted with ether. The combined organic phases are washed with 10 ml of dilute hydrochloric acid and then dried over Na2SO4. After the solution has been evaporated down in vacuo it is purified by chromatography. Yield: 0.06 g. M.p. 238° C.
Reaction SMILES: [CH:1]([C:4]1[N:8]2[CH:9]=[C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2].O1CCCC1.[Br:23]N1C(=O)CCC1=O>CN(C)C=O>[CH:1]([C:4]1[N:8]2[CH:9]=[C:10]([C:13]3[O:17][CH:16]=[N:15][C:14]=3[Br:23])[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nnc2ccc(-c3cnco3)cn12
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)c1nnc2ccc(-c3ocnc3Br)cn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
A clean, dry, 1 liter 4 neck round bottom flask equipped with mechanical stirring, nitrogen, temperature probe, and a dry ice/acetone bath, was charged with the product from step A (45.2 gr 0.198 moles) and N,N-dimethylformamide (271 ml). The pot was cooled below −60° C. and then lithium hexamethyldisilizane, 1 molar in tetrahydrofuran (198 ml 0.198 moles), was added while keeping the temperature below −60° C. After the addition was complete, the pot was further cooled to below −70° C. and stirred for 1 hour. While stirring, a solution of N-bromosuccinimide (35.24 g 0.198 moles) and N,N-dimethylformamide (105 ml), were stirred in a separate 500 ml round bottomed flask under nitrogen. After the one hour stir at −70° C., the solution of N-bromosuccinimide and N,N-dimethylformamide was slowly added to the anion keeping the temperature below −70° C. This temperature was critical to insure proper selectivity. After the addition was complete, the pot was stirred for one hour below −70° C. The batch was warmed to room temperature and quenched into methylene chloride (452 ml) and 1N sodium hydroxide (452 ml). The extraction was repeated with a second aliquot of methylene chloride (135 ml), and the combined organic layers washed with a second 1N sodium hydroxide (452 ml) wash. The organic layer was washed with saturated brine solution (452 ml), and dried over magnesium sulfate (50 gr). The magnesium sulfate was filtered off, washed with methylene chloride (135 ml) and the filtrate and wash combined for concentration. The methylene chloride was concentrated/displaced with isopropyl ether (226 ml) to a temperature of 42° C. A thick slurry formed upon cooling. The solids were granulated at 20 to 25° C. for two hours, filtered, washed with isopropyl ether (50 ml), and dried to afford 53.0 gr of light yellow solids, 96.4% purity (HPLC), 87% of theory.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[C:15]([F:18])([F:17])[F:16])[C:8]([C:19]3[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][C:20]=3[O:27]C)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br.C1CCCCC=1>>[CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[C:15]([F:18])([F:16])[F:17])[C:8]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=3[OH:27])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(-c2nn(C3CCCC3)c3c(C(F)(F)F)cccc23)c(OC)c1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: Oc1ccc(-c2nn(C3CCCC3)c3c(C(F)(F)F)cccc23)c(O)c1
Yield: 97.5 %

Procedure:
Prepared according to Method D step C from 1-cyclopentyl-3-(2,4-dimethoxyphenyl)-7-(trifluoromethyl)-1H-indazole (0.465 g, 1.2 mmol), boron tribromide (0.67 mL, 7.1 mmol) and 1.0 mL of cyclohexene to give the product (0.424 g) as an off-white solid.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([C@H:22]2[CH2:27][CH2:26][CH2:25][N:24]([C:28](=[O:30])[CH3:29])[CH2:23]2)[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:14])=[N:9][CH:8]=1)C.C1(N[C@H]2CCCN(C(=O)C)C2)CCCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[C:28]([N:24]1[CH2:25][CH2:26][CH2:27][C@H:22]([N:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:31])=[O:3])=[CH:8][N:9]=2)[CH2:23]1)(=[O:30])[CH3:29]
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(C2CCCCC2)[C@H]2CCCN(C(C)=O)C2)s1
Agent: CC(=O)N1CCC[C@H](NC2CCCCC2)C1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: CC(=O)N1CCC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCCC2)C1

Procedure:
{2-[3-(1-Acetyl-piperidin-3(S)-yl)-3-cyclohexyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester prepared as described in general procedures (A) and (B). using 1-(3(S) cyclohexylamino-piperidin-1-yl)-ethanone and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. Hydrolysis using general procedure (F) gave the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:10][C:11](O)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OC)=O.[BH4-].[Na+].Cl>O1CCCC1.C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:10][CH2:11][OH:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(CC(=O)O)c1ccccc1
Agent: COC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(CCO)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 36 %

Procedure:
To a 17.9 mmol suspension of 3-(tert-butoxycarbonylamino)-3-phenylpropanoic acid (Formula 10) in tetrahydrofuran (THF) at 0° C. was added 2.74 mL of triethyl amine and 1.52 mL of methyl chloroformate. The mixture was stirred at 0° C. for 15 minutes. Next, the white solid formed was filtered off and washed with 10 mL of THF. The filtrate was added drop-wise to 8.4 mL of 26.8 mmol sodium borohydride at 0° C. and stirred for 30 min. The mixture was then stirred at room temperature for 2 hr. Ten percent hydrochloric acid (HCl) was added until a pH of 2 was reached, and then was extracted using ethyl acetate. The resulting combined ethyl acetate layers were washed with sodium carbonate, water, brine, and concentrated. Column chromatography (50% ethyl acetate/hexane) gave 1.63 g (36%) of the title compound as a colorless oil. The aqueous phase was acidified with HCl and extracted with ethyl acetate to recover 2 g of 3-(tert-butoxycarbonylamino)-3-phenylpropanoic acid. 1H NMR (300 MHz, CDCl3) δ 1.45 (s, 9H), 1.62-1.63 (m, 1H), 1.79-1.87 (m, 1H), 3.68-3.74 (m, 2H), 5.23 (br, 1H), 5.32 (br, 1H), 7.26-7.38 (m, 5H).
Reaction SMILES: [CH3:1][CH:2]([CH:10]=[CH2:11])[CH2:3][CH2:4][CH2:5][C:6]([OH:9])([CH3:8])[CH3:7].[CH2:12]=[C:13]1[O:17][C:15](=[O:16])[CH2:14]1>CN(C)C1C=CN=CC=1>[O:17]=[C:13]([CH3:12])[CH2:14][C:15]([O:9][C:6]([CH3:7])([CH2:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH:10]=[CH2:11])[CH3:8])=[O:16]
Reactant: C=C1CC(=O)O1
Reactant: C=CC(C)CCCC(C)(C)O
Agent: CN(C)c1ccncc1
Product: C=CC(C)CCCC(C)(C)OC(=O)CC(C)=O
Temperature: 55 °C
Yield: 95 %

Procedure:
A mixture of dihydromyrcenol (37.88 g, 0.240 mol) and 4-dimethylaminopyridine (0.16 g, 1.30 mmol) in a 100 mL three-necked round-bottomed flask fitted with a condenser, argon inlet, addition funnel, magnetic stirrer and internal thermometer is heated to 50-60° C. Diketene (20.16 g, 0.240 mol) is added dropwise in the course of 15 min. The mixture has a slight exotherm and turned from yellow to red during this time. After stirring an additional hour at 50° C., the mixture is cooled to room temperature. At this point, NMR analysis indicates the reaction is complete. Purification of the product mixture by flash chromatography (elution with dichloromethane) yields the desired product in 95% yield as a nearly colorless oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[SH:7][C:8]1[N:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br.O>CN(C)C=O>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][S:7][C:8]1[N:13]=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: Sc1ncccn1
Reactant: BrCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: BrCCCCCCCSc1ncccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49 %

Procedure:
Potassium carbonate (9.95 g) was added to a solution of 2-mercaptopyrimidine (6.73 g) and 1,7-dibromoheptane (15.48 g) in N,N-dimethylformamide (85 ml). The mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), and then the solvent was distilled off under reduced pressure. The residual oil was subjected to column chromatography on silica gel and eluted with ethyl acetate-hexane (1:4, v/v) to obtain 2-(7-bromoheptylthio)pyrimidine (8.5 g) as an oil. This oil was dissolved in N,N-dimethylformamide (45 ml). Potassium phthalimide (5.44 g) was added to the solution, and the mixture was stirred at 100° C. for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4). The solvent was distilled off under reduced pressure to obtain N-[7-(2-pyrimidinylthio)heptyl]phthalimide (10.36 g, 48.6%) as an oil.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[C:11]1([C:17](C2C=CC=CC=2)=CC=O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+].Cl>O.CO>[C:11]1([CH:17]=[CH:9][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=2)=[O:10])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)c1ccccc1O
Reactant: O=CC=C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(C=Cc1ccccc1)c1ccccc1

Procedure:
A solution of 1.81 g (13.3 mmol) of 2'-hydroxyacetophenone, 2.75 g (13.2 mmol) of β-phenylcinnamaldehyde, 2.64 g NaOH (in 10 mL of water) and 100 mL MeOH was stirred for 24 hours before the solution was poured into 1000 mL water. The resulting mixture was neutralized with dilute HCl and the yellow precipitate was collected by filtration. Recrystallization from MeOH gave a pure intermediate chalcone product. Further oxidation of the above chalcone was carried out with excess H2O2 (30%) in basic (NaOH aq.) MeOH solution for 18 hours. This solution was poured into water, and neutralized with dilute HCl. The resulting light yellow precipitate was collected by filtration and the pure desired product was obtained by recrystallization from MeOH with 28% overall yield. MP: 215°-216° C. Quantum yield (relative to 3-hydroxyflavone in CH2Cl2) 0.004. Extinction coefficient εmax (M-1 cm-1) 23,000. λmax (abs)=378 nm and λmax (em)=470 nm.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:16][C@H:17]([NH:22][C:23](=[O:36])[C@@H:24]([NH:26][C:27](=[O:35])[CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH3:25])[C:18]([O:20]C)=[O:19])[CH:12]=[CH:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].O>O.C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:16][C@H:17]([NH:22][C:23](=[O:36])[C@@H:24]([NH:26][C:27](=[O:35])[CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH3:25])[C:18]([OH:20])=[O:19])[CH:12]=[CH:13][C:14]=1[CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(C)c(OCc2ccccc2)c1)NC(=O)[C@H](C)NC(=O)CN1CCOCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C[C@H](NC(=O)[C@H](C)NC(=O)CN2CCOCC2)C(=O)O)cc1OCc1ccccc1

Procedure:
(S)-Methyl 3-(3-(benzyloxy)-4-methylphenyl)-2-((S)-2-(2-morpholinoacetamido) propanamido)propanoate (1.2 g, 2.4 mmol) was treated with a solution of lithium hydroxide-H2O (300 mg, 7.2 mmol) in water/THF (10 mL/10 mL) for 30 min. The THF was removed and the aqueous phase was acidified to pH=3-4 with 1 N HCl and then concentrated to dryness to afford (S)-3-(3-(benzyloxy)-4-methylphenyl)-2-((S)-2-(2-morpholinoacetamido)propanamido)propanoic acid, which was used directly without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][N:5]1[C:11](=O)[CH2:10][CH2:9][CH2:8][C:7]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:6]1=2.B.C1COCC1>>[CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:6]1=2
Reactant: CN(C)CCN1C(=O)CCCc2cc([N+](=O)[O-])ccc21
Agent: B
Solvent: C1CCOC1
Product: CN(C)CCN1CCCCc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
A solution of 1-(2-(dimethylamino)ethyl)-7-nitro-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (0.8 g, 2.88 mmol) was treated with a solution of 1M borane in THF (28.8 mL, 28.80 mmol). The solution was heated at reflux for 6 hours then stirred at room temperature overnight. After this time, the mixture was cooled to 0° C. and quenched with methanol (20 mL). The mixture was concentrated, dissolved in methanol (20 mL), and heated at reflux for 4 hours. The reaction was concentrated and the residue was subjected to silica gel chromatography using a gradient of 1.5-5% 2M NH3 in MeOH/CH2Cl2 to give a yellow oil (565 mg, 74.6%). 1H-NMR (CDCl3) δ 7.96 (dd, J=2.7, 8.7 Hz, 1H), 7.91 (d, J=2.7 Hz, 1H), 6.75 (d, J=9.0 Hz, 1H), 3.44-3.39 (m, 2H), 3.37-3.33 (m, 2H), 2.88-2.85 (m, 2H), 2.55-2.51 (m, 2H), 2.29 (s, 6H), 1.85-1.78 (m, 4H). MS (ESI): 264.2 (M+1).
Reaction SMILES: [CH:1]1([CH:6]([C:11]2(O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:7]([O:9][CH3:10])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH:1]1([CH:6]([C:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=2)[C:7]([O:9][CH3:10])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)C(C1CCCC1)C1(O)CCCCC1
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: COC(=O)C(C1=CCCCC1)C1CCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 105.8 %

Procedure:
The product of Example R (16.25 g, 0.068 mole) was dissolved in pyridine (100 mls) containing 3 g of 4-dimethylaminopyridine at 25° C. Trifluoromethane sulfonic anhydride (20.0 g, 0.068 moles) was added dropwise under N2 over 10 minutes. The temperature was increased to +50° C. for 15 minutes. After cooling the mixture to room temperature and stirring for 15 minutes, the reaction mixture was poured into 600 mls of 2N HCL and extracted with 1:1 ethyl acetate/ether. The organic phase was washed with brine and dried over Na2SO4. The filtration of the drying agent and removal of solvent gave 16 g of the title compound (99% yield).
Reaction SMILES: [BH3-]C#N.[Na+].[N:5]1([C:10]2[N:15]=[C:14]([CH:16]3[CH:20]([C:21]([NH:23][CH3:24])=[O:22])[CH2:19][CH2:18][NH:17]3)[CH:13]=[C:12]([CH3:25])[N:11]=2)[CH:9]=[CH:8][N:7]=[CH:6]1.[O:26]1[C:30]2[CH:31]=[CH:32][C:33]([CH2:35][N:36]([CH2:44][CH:45]=O)[C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:34][C:29]=2[O:28][CH2:27]1.C(OC)(OC)OC>C(O)(=O)C.O>[N:5]1([C:10]2[N:15]=[C:14]([CH:16]3[CH:20]([C:21](=[O:22])[NH:23][CH3:24])[CH2:19][CH2:18][N:17]3[CH2:45][CH2:44][N:36]([CH2:35][C:33]3[CH:32]=[CH:31][C:30]4[O:26][CH2:27][O:28][C:29]=4[CH:34]=3)[C:37](=[O:43])[O:38][C:39]([CH3:41])([CH3:40])[CH3:42])[CH:13]=[C:12]([CH3:25])[N:11]=2)[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: CC(C)(C)OC(=O)N(CC=O)Cc1ccc2c(c1)OCO2
Reactant: CNC(=O)C1CCNC1c1cc(C)nc(-n2ccnc2)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: COC(OC)OC
Product: CNC(=O)C1CCN(CCN(Cc2ccc3c(c2)OCO3)C(=O)OC(C)(C)C)C1c1cc(C)nc(-n2ccnc2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 22.2 %

Procedure:
NaBH3CN (76 mg, 1.2 mmol) was added all at once to a stirred solution of 2-(2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl)-N-methylpyrrolidine-3-carboxamide (230 mg, 0.80 mmol), tert-butyl benzo[d][1,3]dioxol-5-ylmethyl(2-oxoethyl)carbamate (280 mg, 0.95 mmol), acetic acid (100 μL, 1.59 μmol) and trimethyl orthoformate (20 ml). The reaction mixture stirred at rt for 16 h then water (20 mL) was added. The solution was extracted with EtOAc (2×20 mL), the combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified using column chromatography (20:1 CHCl3/MeOH) to afford 100 mg (22%) of tert-butyl 2-(2-(2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl)-3-(methylcarbamoyl)pyrrolidin-1-yl)ethyl(benzo[d][1,3]dioxol-5-ylmethyl)carbamate as a colorless oil.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:19]=[C:9]2[N:10]=[C:11]([C:15](OC)=[O:16])[CH:12]=[C:13]([SH:14])[N:8]2[N:7]=1)(=O)C.[NH2:20][OH:21]>CO>[OH:21][NH:20][C:15]([C:11]1[CH:12]=[C:13]([SH:14])[N:8]2[N:7]=[C:6]([CH2:5][OH:4])[N:19]=[C:9]2[N:10]=1)=[O:16]
Reactant: COC(=O)c1cc(S)n2nc(COC(C)=O)nc2n1
Reactant: NO
Solvent: CO
Product: O=C(NO)c1cc(S)n2nc(CO)nc2n1
Yield: 74 %

Procedure:
Methyl 2-(acetoxymethyl)-7-mercapto-s-triazolo[1,5-a]pyrimidine-5-carboxylate (80 mg) (0.28 mmol) are dissolved in 3 ml of absolute methanol. 188 mg (5.7 mmol) of hydroxylamine are added within 4 days while stirring. The product is precipitated (pH 6) with 3N aqueous hydrochloric acid, filtered off under suction and washed with methanol. After crystallization from methanol there are obtained 50 mg of N-hydroxy-2-(hydroxymethyl)-7-mercapto-s-triazolo[1,5-a]pyrimidine-5-carboxamide as a yellow powder.
Reaction SMILES: Br[C:2]1[C:3]([NH:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[CH2:16]([N:19]1[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]1)[C:17]#[CH:18].C(N(CC)CC)C>CN(C=O)C.[Cu]I>[CH3:13][C:12]([CH3:15])([CH3:14])[CH2:11][N:10]1[C:3]2[N:4]=[C:5]([C:8]#[N:9])[N:6]=[CH:7][C:2]=2[CH:18]=[C:17]1[CH2:16][N:19]1[CH2:20][CH2:21][S:22](=[O:25])(=[O:26])[CH2:23][CH2:24]1
Reactant: CC(C)(C)CNc1nc(C#N)ncc1Br
Reactant: C#CCN1CCS(=O)(=O)CC1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)Cn1c(CN2CCS(=O)(=O)CC2)cc2cnc(C#N)nc21
Temperature: 80 °C
Reaction time: 31 h
Yield: 1.4 %

Procedure:
To a solution of 0.54 g (2 mmoles) of 5-bromo-4-(2,2-dimethyl-propylamino)-pyrimidine-2-carbonitrile and 0.75 g (4.3 mmoles) of 4-propargylthiomorpholine-1,1-dioxide in 5 ml of DMF are added 0.841 ml (6 mmoles) of triethylamine, 0.38 g (2 mmoles) of copper(I) iodide and 0.14 g (0.2 mmoles) of Pd(PPh3)2Cl2under nitrogen atmosphere. The mixture is stirred for 31 hours at 80° C. The mixture is filtered through celite, diluted with AcOEt, washed with H2O and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by HPLC(H2O—0.1% TFA/CH3CN—0.1% TFA). Fractions are collected, basified with 5% aqueous NaHCO3, extracted with AcOEt, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting residue is then purified by HPLC (n-Hexane/AcOEt) to give 0.01 g of desired 7-(2,2-dimethyl-propyl)-6-(1,1-dioxo-1λ6-thiomorpholin-4-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 1.4% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C:13]3[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=3)[C:6]=2[CH:19]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][N:25]2C1CCCCO1.CCN(C(C)C)C(C)C.Cl.O1CCOCC1>CC(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:12][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:11])[N:7]([C:13]3[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=3)[C:6]=2[CH:19]=1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1cnn(C)c1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1cnn(C)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 63.1 %

Procedure:
A mixture of (S)-1-[6-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-1H-benzoimidazol-2-yl]ethylamine, (0.055 g, 0.21 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (0.070 g, 0.30 mmol) and DIPEA (0.07 mL, 0.38 mmol) in IPA (1.5 mL) was stirred at 80° C. in a sealed tube for 16 h. After cooling, the reaction mixture was concentrated in vacuo and the residue purified by chromatography (SiO2, 0-10% (2M ammonia in methanol) in DCM). The product was dissolved in methanol (4 mL) and treated with HCl/dioxane (4M, 0.5 mL, 2.0 mmol) then stirred for 15 minutes. The resulting mixture was concentrated in vacuo and the residue loaded onto an Isolute® SCX-2 cartridge and washed with MeOH then the product eluted with 2M NH3/MeOH and concentrated in vacuo to give 419 as a white solid (0.050 g, 63%). LCMS (Method K): RT 2.65 min [M+H]+ 378.0. 1H NMR (DMSO-d6, 400 MHz): δ 12.90 (1H, s), 8.22-8.03 (3H, m), 7.89-7.81 (1H, m), 7.76 (1H, s), 7.66-7.62 (1H, m), 7.09-7.05 (1H, m), 7.00-6.91 (1H, m), 5.61-5.42 (1H, m), 3.86 (3H, s), 1.57 (3H, d, J=6.84 Hz)
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])=[N:6][C:7]=1[CH3:8].Cl.[NH2:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21][CH2:20]1.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O.COC(C)(C)C>[Br:1][C:2]1[C:3]([NH:18][C@H:19]2[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21][CH2:20]2)=[N:4][C:5]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(-n2c(C)ccc2C)nc(Cl)c1Br
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: COC(C)(C)C
Solvent: CC(=O)N(C)C
Product: Cc1nc(-n2c(C)ccc2C)nc(N[C@H]2CC[C@H](O)CC2)c1Br
Temperature: 160 °C

Procedure:
A mixture of 5-bromo-4-chloro-2-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methyl pyrimidine (1.50 g, 4.99 mmol), trans-4-aminocyclohexanol hydrochloride (1.17 g, 6.24 mmol), and diisopropylethyl amine (2.61 mL, 15.0 mmol) in dimethylacetamide (25.0 mL) was heated at 160° C. in a sealed tube overnight. The reaction mixture was diluted with methyltertbutyl ether (400 mL), washed with saturated ammonia chloride (2×) and brine, dried (MgSO4), filtered, and concentrated. The combined aqueous layers were extracted with dichloromethane (3×150 mL), dried (MgSO4), filtered, and concentrated. The crude product was purified by flash chromatography eluting with chloroform/methanol (0.5-3%) to afford trans-4-(5-bromo-2-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methylpyrimidin-4-ylamino)cyclohexanol (1.76 g, 93%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH:21]([N:24]1[C:28]([C:29]2[N:38]=[C:37]3[N:31]([CH2:32][CH2:33][O:34][C:35]4[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][C:36]=43)[CH:30]=2)=[N:27][CH:26]=[N:25]1)([CH3:23])[CH3:22]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:43]([C:40]2[CH:41]=[CH:42][C:35]3[O:34][CH2:33][CH2:32][N:31]4[C:37](=[N:38][C:29]([C:28]5[N:24]([CH:21]([CH3:22])[CH3:23])[N:25]=[CH:26][N:27]=5)=[CH:30]4)[C:36]=3[CH:39]=2)(=[O:45])=[O:44])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)Cl)ccc1OCC2
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)N3CCN(C(=O)OC(C)(C)C)CC3)ccc1OCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
To a solution of piperazine-1-carboxylic acid tert-butyl ester (216 mg, 1.16 mmol) and NEt3 (272 μL, 1.93 mmol) in DCM (30 mL) at 0° C. was added a suspension of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene-9-sulfonyl chloride from Example 121 (270 mg, 0.39 mmol) in DCM (20 mL) and the resulting mixture warmed to RT after 10 min then stirred for 30 min. The reaction mixture was diluted with DCM, washed with a saturated aqueous NaHCO3 solution then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-5% MeOH in DCM) affording 4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene-9-sulfonyl]piperazine-1-carboxylic acid tert-butyl ester (196 mg, 93%) as a white solid. LCMS: RT 4.72 min [M+H]+ 544.3. 1H NMR (DMSO, 400 MHz): δ 8.77 (1H, d, J=2.43 Hz), 8.01 (1H, s), 7.94 (1H, d, J=0.61 Hz), 7.63 (1H, dd, J=8.64, 2.44 Hz), 7.28 (1H, d, J=8.64 Hz), 5.75-5.71 (1H, m), 4.67-4.57 (4H, m), 3.44-3.38 (4H, m), 2.91 (4H, t, J=4.83 Hz), 1.50 (6H, d, J=6.62 Hz), 1.32 (9H, s)