Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].[Br:2][C:3]1[CH:14]=[C:13]([C:15]2[C:24]3[C:25]4[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=4[S:27][C:23]=3[C:22]([Br:32])=[C:21]3[C:16]=2[CH:17]=[CH:18][CH:19]=[CH:20]3)[CH:12]=[C:11]([Br:33])[C:4]=1[O:5][CH2:6][C:7](OC)=[O:8]>CO>[Br:2][C:3]1[CH:14]=[C:13]([C:15]2[C:24]3[C:25]4[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=4[S:27][C:23]=3[C:22]([Br:32])=[C:21]3[C:16]=2[CH:17]=[CH:18][CH:19]=[CH:20]3)[CH:12]=[C:11]([Br:33])[C:4]=1[O:5][CH2:6][C:7]([NH2:1])=[O:8]
Reactant: COC(=O)COc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Reactant: N
Solvent: CO
Product: NC(=O)COc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Methanol (10 mL) was purged with ammonia gas for 10 min at 0° C. [2,6-dibromo-4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-phenoxy]-acetic acid, methyl ester (0.50 g, 0.787 mmol) was added and the vessel was sealed, warmed to room temperature and stirred for two days. The reaction mixture was concentrated, diluted with ether and filtered. The solid was boiled in ethyl acetate (8 mL), hot filtered and washed with ethyl acteate and pentane and dried in vacou to provide the title compound as an off white solid (0.22 g, 45%): mp 263-265° C.: NMR (DMSO-d6); δ8.29 (d, J=8 Hz, 1 H), 8.09 (d, J=8 Hz, 1 H), 7.88 (s, 2 H), 7.80 (ddd, J=8, 7, 1 Hz, 1 H), 7.67-7.51 (m, 5 H), 7.30 (ddd, J=8, 7, 1 Hz, 1 H), 6.71 (d, J=8 Hz, 1H), 4.56 (s, 2 H); MS (EI): [M+], 3 bromine isotope pattern, 617 (30%), 619 (90%) 621 (100%) 623 (40%); Anal. Calc. for C24H14Br3NO2S: C, 46.48, H, 2.28, N, 2.26. Found: C, 45.69, H, 2.02 , N, 2.14.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]3[N:19]=[CH:20][C:21]([C:22]#[CH:23])=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:24][CH2:25][C:26]([NH:30][S:31]([C:34]1[CH:35]=[N:36][CH:37]=[C:38](Br)[CH:39]=1)(=[O:33])=[O:32])([CH2:28][OH:29])[CH3:27]>>[OH:24][CH2:25][C:26]([NH:30][S:31]([C:34]1[CH:35]=[N:36][CH:37]=[C:38]([C:23]#[C:22][C:21]2[CH:20]=[N:19][N:12]3[C:13]([C:15]([F:16])([F:17])[F:18])=[CH:14][C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)=[N:10][C:11]=23)[CH:39]=1)(=[O:33])=[O:32])([CH2:28][OH:29])[CH3:27]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12
Reactant: CC(CO)(CO)NS(=O)(=O)c1cncc(Br)c1
Product: CC(CO)(CO)NS(=O)(=O)c1cncc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)c(Cl)c4)nc23)c1

Procedure:
The title compound was prepared from 5-(3,4-dichloro-phenyl)-3-ethynyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.9) (89 mg, 0.25 mmol) and 5-bromo-pyridine-3-sulfonic acid (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide (Example B.4) (81 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (24 mg, 16%). MS (ISN) 598.2 [(M−H)−].
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH:4]=O.[O-2].[Mg+2].[CH3:9][C:10]([CH3:12])=[O:11]>[Mo](=O)=O.[O-2].[Zn+2]>[CH3:1][C:2](=[CH:3][CH:4]=[CH:9][C:10](=[O:11])[CH3:12])[CH3:6]
Reactant: CC(C)=CC=O
Reactant: CC(C)=O
Agent: O=[Mo]=O
Agent: [Mg+2]
Agent: [O-2]
Product: CC(=O)C=CC=C(C)C
Yield: 43 %

Procedure:
50 Parts of 3,3-dimethyl-acrolein and 100 parts of acetone are heated with 12 parts of a catalyst (which has been prepared by calcining a mixture of equimolar amounts of magnesium oxide, molybdenum dioxide and zinc oxide) for 3 hours at 180° C and a pressure of 30 atmospheres and the product is subjected to fractional distillation. 27 Parts of 2-methyl-2,4-heptadien-6-one is obtained which is equivalent to a yield of 43% of theory at a conversion of 86% based on 3,3-dimethyl-acrolein.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([OH:14])[CH:8]=[N:9]2)([O-:3])=[O:2].[H-].[Na+].[CH3:17]I.O>CN(C=O)C>[CH3:17][O:14][C:7]1[CH:8]=[N:9][C:10]2[C:5]([CH:6]=1)=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=[CH:12][CH:11]=2
Reactant: O=[N+]([O-])c1cccc2ncc(O)cc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cnc2cccc([N+](=O)[O-])c2c1
Reaction time: 2 h

Procedure:
To a solution of 5-nitroquinolin-3-ol in DMF is added sodium hydride at 0° C. Then, methyl iodide is added and the mixture is stirred for 2 h. Water is added and the mixture is extracted with ethyl acetate. The organic layer is dried, filtered and concentrated under reduced pressure to give 3-methoxy-5-nitroquinoline.
Reaction SMILES: N[C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].S(=O)(=O)(O)O.[Br-:15].[K+].N([O-])=O.[Na+]>>[Br:15][CH:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[C:7]([OH:9])=[O:8]
Reactant: [Br-]
Reactant: CC(C)C[C@@H](N)C(=O)O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(C)CC(Br)C(=O)O
Temperature: 0 °C

Procedure:
A total of 50 g. of D-Leu are taken up in 1200 ml. of 2.5 N sulfuric acid containing 250 g. of potassium bromide. The mixture is cooled to 0° C. and stirred while adding 65.5 g. of sodium nitrite in small portions over a period of 11/2 hours. The solution is stirred for an additional hour at 0° C., and then heated to 25° C. and stirred another hour. The mixture is extracted with ether, the ether layer separated, washed with water, and dried over anhydrous sodium sulfate to give the desired product.
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:28]=[C:27]([CH3:29])[S:26][C:17]=2[N:18]=[C:19]([C:21]2[O:25][N:24]=[CH:23][CH:22]=2)[N:20]=1>>[O:25]1[C:21]([C:19]2[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:13][CH2:1][O:2][C:3]=4[CH:4]=3)[C:16]3[CH:28]=[C:27]([CH3:29])[S:26][C:17]=3[N:18]=2)=[CH:22][CH:23]=[N:24]1
Reactant: NCCc1ccc2c(c1)OCCO2
Reactant: Cc1cc2c(Cl)nc(-c3ccno3)nc2s1
Product: Cc1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(isoxazol-5-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.Br.Br[CH2:26][C:27]([C:29]1[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][N:30]=1)=[O:28]>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:26]=1[C:27]([C:29]1[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][N:30]=1)=[O:28]
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Reactant: Cc1cccnc1C(=O)CBr
Agent: Br
Product: COC(=O)Cc1c(C(=O)c2ncccc2C)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-4-chloro-2-(penylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 2-bromoacetyl-3-methylpyridine hydrobromide*.
Reaction SMILES: C(N(CC)CC)C.ClC(Cl)(Cl)C(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:35][C:36]1[CH:41]=[C:40]([OH:42])[CH:39]=[CH:38][C:37]=1[NH:43][C:44]([C:46]1[N:51]=[CH:50][C:49]([O:52][CH2:53][C@@H:54]([NH:56][C:57](=[O:63])[O:58][C:59]([CH3:62])([CH3:61])[CH3:60])[CH3:55])=[CH:48][C:47]=1[F:64])=O>C(#N)C.O>[F:64][C:47]1[CH:48]=[C:49]([O:52][CH2:53][C@@H:54]([NH:56][C:57](=[O:63])[O:58][C:59]([CH3:61])([CH3:60])[CH3:62])[CH3:55])[CH:50]=[N:51][C:46]=1[C:44]1[O:35][C:36]2[CH:41]=[C:40]([OH:42])[CH:39]=[CH:38][C:37]=2[N:43]=1
Reactant: C[C@@H](COc1cnc(C(=O)Nc2ccc(O)cc2O)c(F)c1)NC(=O)OC(C)(C)C
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@@H](COc1cnc(-c2nc3ccc(O)cc3o2)c(F)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 210.5 %

Procedure:
Triethylamine (14.1 mL) was added to a solution of hexachloroethane (7.46 g) and triphenylphosphine (9.91 g) in acetonitrile (50 mL) at room temperature, and the mixture was stirred at room temperature for 10 min. Then a mixture of tert-butyl [(1S)-2-({6-[(2,4-dihydroxyphenyl)carbamoyl]-5-fluoropyridin-3-yl}oxy)-1-methylethyl]carbamate (5.31 g) and acetonitrile (50 mL) was added, and the mixture was stirred at room temperature for 2 hr. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give tert-butyl [(1S)-2-{[5-fluoro-6-(6-hydroxy-1,3-benzoxazol-2-yl)pyridin-3-yl]oxy}-1-methylethyl]carbamate (10.7 g) as a mixture with impurities. A mixture of tert-butyl [(1S)-2-{[5-fluoro-6-(6-hydroxy-1,3-benzoxazol-2-yl)pyridin-3-yl]oxy}-1-methylethyl]carbamate (4.28 g, a mixture with impurities), 2-(2,2-difluorocyclopropyl)ethyl methanesulfonate (0.531 g), potassium carbonate (0.367 g), and DMF (30 mL) was stirred at 60° C. for 1 hr. Then additional 2-(2,2-difluorocyclopropyl)ethyl methanesulfonate (0.531 g) and potassium carbonate (0.367 g) were added, and the mixture was stirred at 60° C. for 1 hr. Then additional 2-(2,2-difluorocyclopropyl)ethyl methanesulfonate (1.06 g) and potassium carbonate (0.733 g) were added, and the mixture was stirred at 60° C. for 1 hr. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.83 g) as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10](OS(C(F)(F)F)(=O)=O)[CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:31]=[N+:32]=[N-:33].[Na+].[N-]=[N+]=[N-]>CN(C)C=O>[CH2:1]([O:8][CH2:9][CH:10]([N:31]=[N+:32]=[N-:33])[CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1c2ccccc2C(=O)N1CC(COCc1ccccc1)OS(=O)(=O)C(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC(COCc1ccccc1)CN1C(=O)c2ccccc2C1=O

Procedure:
2-Benzyloxymethyl-2-(trifluoromethylsulfonyloxy)-1-phthalimido-ethane (8.5 g, 19.1 mmol) and sodium azide (2.5 g, 38.2 mmol) were stirred in dimethylformamide (80 ml) at 60° C. for 6 hours Under nitrogen. TLC in several systems was inconclusive because the Rf of the product was identical to the Rf of the starting material. A small sample was worked up and IR indicated full conversion to the azide. The reaction mixture was transferred to a 1 l extraction funnel and distributed between ethyl acetate (350 ml) and water (130 ml). The aqueous phase was extracted with ethyl acetate (80 ml); the combined organic phases were washed with water (2×120 ml), dried over magnesium sulphate, filtered and concentrated in vacuo to a pale brown oil. Crystallisation was initiated by adding ether (7 ml). Crystals were collected on a glass sinter, washed with cold ether and dried under vacuum for 28 hours. Yield: 4.5 g (70%). The mother liquors were concentrated, diluted with ether and seeded with crystals from the first crop--yielding another 1 g. Total yield: 5.5 g (85%). The structure was confirmed by NMR and IR.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH2:11][CH2:12]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:34]>C(Cl)Cl>[Br:34][CH2:12][CH2:11][C:3]1[C:4]([N+:8]([O-:10])=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: BrC(Br)(Br)Br
Reactant: O=[N+]([O-])c1cccc(Cl)c1CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(Cl)c1CCBr
Temperature: 0 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
To a solution of 2-(2-chloro-6-nitrophenyl)ethanol (33.0 g, 0.16 mole) in methylene chloride (500 mL) was added triphenylphosphine (43.0 g, 0.16 mole) and the mixture was cooled to 0° C. Carbon tetrabromide (54.4 g, 0.16 mole) in methylene chloride (100 mL) was added dropwise through an addition funnel. The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue purified by flash column chromatography (silica gel, ethyl acetate:hexanes 1:9) to provide 39.0 g of the title compound as a yellow solid. 1H NMR (CDCl3): 7.70 δ (d, 1H); 7.60 δ (d, 1H); 7.35 δ (t, 1H); 3.60 δ (t, 2H); 3.45 δ (t, 2H).
Reaction SMILES: [Br:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH:9]=[C:10](Br)Br)[CH2:5][CH2:4]1.Cl>O1CCCC1>[Br:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9]#[CH:10])[CH2:5][CH2:4]1
Reactant: BrCC1CCC(C=C(Br)Br)CC1
Agent: Cl
Solvent: C1CCOC1
Product: C#CC1CCC(CBr)CC1
Temperature: -78 °C
Reaction time: 2 h
Yield: 100.5 %

Procedure:
A solution of 8.36 g of 1-bromomethyl-4-(2,2-dibromovinyl)cyclohexane (trans/cis=about 3/1) in 20 mL of tetrahydrofuran was cooled to −78° C. under a nitrogen atmosphere. To the solution was added dropwise 24.3 mL of a 2.1 M methyl lithium diethyl ether solution over 30 minutes, followed by stirring for 2 hours while maintaining a temperature of −78° C. The reaction mixture was cooled in an ice bath, and 30 mL of a 1 N aqueous hydrochloric acid solution was added thereto. The reaction mixture was extracted with 30 mL of t-butyl methyl ether three times. The combined organic layer was washed sequentially with 100 mL of a saturated aqueous sodium hydrogen carbonate solution and 100 mL of a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 4.68 g of 1-bromomethyl-4-ethynylcyclohexane represented by the following formula:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:34][CH:35]=[CH2:36])=[C:5]([CH:27]=[CH:28][C:29]=1[C:30]([NH:32][CH3:33])=[O:31])[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([CH2:24][CH2:25][CH3:26])=[C:13]([CH:21]=[CH:22][CH:23]=1)[O:14][CH2:15][C:16]([O:18]CC)=[O:17].[OH-].[Li+].CO.Cl>O>[CH3:1][O:2][C:3]1[C:4]([CH2:34][CH:35]=[CH2:36])=[C:5]([CH:27]=[CH:28][C:29]=1[C:30]([NH:32][CH3:33])=[O:31])[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([CH2:24][CH2:25][CH3:26])=[C:13]([CH:21]=[CH:22][CH:23]=1)[O:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: C=CCc1c(OCCCOc2cccc(OCC(=O)OCC)c2CCC)ccc(C(=O)NC)c1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CCc1c(OCCCOc2cccc(OCC(=O)O)c2CCC)ccc(C(=O)NC)c1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The compound of Example 52 (95 mg, 0.19 mmol) and 380 μl (0.38 mmol) of 1M lithium hydroxide were added to 2.0 ml of methanol, and the reaction mixture was stirred for four hours at room temperature. The solvent was removed under vacuum to give a white solid which was suspended in 5.0 ml of water. The mixture was acidified with 10% hydrochloric acid, stirred and filtered to remove the resultant solid which was then dried at 40° C. overnight in a vacuum oven to give the product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:13][CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]2)=[CH:4][C:3]=1[F:21].C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][C:3]=1[F:21]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(Cl)c(F)c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1cc([C@@H]2CNCCO2)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(R)-tert-butyl 2-(4-chloro-3-fluorophenyl)morpholine-4-carboxylate (990 mg) was dissolved in 2 mL of dichloromethane and TFA (2 mL) was added. The solution was stirred at room temperature for 2 h. Solvents were evaporated. The residue was extracted with dichloromethane and 1N NaOH solution. The organic layer was dried and concentrated. The residue was dried in vacuum to afford (R)-2-(4-chloro-3-fluorophenyl)morpholine an oil (669 mg). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.11 (br. s., 1H) 2.72 (dd, J=12.38, 10.36 Hz, 1H) 2.86-3.04 (m, 2H) 3.07 (dd, J=12.38, 2.53 Hz, 1H) 3.79 (td, J=11.37, 3.03 Hz, 1H) 4.05 (dd, J=11.49, 2.40 Hz, 1H) 4.48 (dd, J=10.36, 2.53 Hz, 1H) 7.02-7.13 (m, 1H) 7.15-7.23 (m, 1H) 7.33-7.42 (m, 1H).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:14]=[C:13]([O:15][CH3:16])[N:12]=[C:11]([N:17]([CH3:19])[CH3:18])[N:10]=1.[N:20]1[N:21]([C:25]2[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27](O)=[O:28])[N:22]=[CH:23][CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(OCC)(=O)C.CN(C=O)C>[CH3:16][O:15][C:13]1[CH:14]=[C:9]([N:2]2[CH2:3][CH:4]3[CH:5]([CH2:6][N:7]([C:27]([C:26]4[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=4[N:21]4[N:22]=[CH:23][CH:24]=[N:20]4)=[O:28])[CH2:8]3)[CH2:1]2)[N:10]=[C:11]([N:17]([CH3:18])[CH3:19])[N:12]=1
Reactant: COc1cc(N2CC3CNCC3C2)nc(N(C)C)n1
Reactant: O=C(O)c1ccccc1-n1nccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(N2CC3CN(C(=O)c4ccccc4-n4nccn4)CC3C2)nc(N(C)C)n1
Yield: 47 %

Procedure:
A mixture of [4-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-6-methoxy-pyrimidin-2-yl]-dimethyl-amine (60.0 mg, 0.23 mmol), 2-[1,2,3]triazol-2-yl-benzoic acid (47.4 mg, 0.25 mmol), HATU (130.0 mg, 0.34 mmol) and DIPEA (0.12 mL, 0.68 mmol) was stirred into DMF (4.0 mL) at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (60.0 mL) and washed with water (2×100 mL). The organic phase was dried (Na2SO4), filtered and concentrated to dryness. The crude product was purified using Agilent HPLC (Basic system) to yield pure title compound (47.0 mg, 47.5%). MS (ESI) mass calcd. for C22H26N8O2, 434.5; m/z found [M+H]+. 1H NMR (CDCl3): 7.98 (d, J=8.1, 1H), 7.73 (s, 2H), 7.75 (s, 2H), 7.55-7.47 (m, 1H), 7.45-7.37 (m, 2H), 5.00-4.90 (m, 1H), 3.91-3.80 (m, 5H), 3.70 (dd, J=12.5, 3.9, 2H), 3.60-3.29 (m, 4H), 3.19-3.04 (m, 8H).
Reaction SMILES: [S-:1][C:2]#[N:3].[Na+].[C:5]([N:9]=[N:10][C:11](Cl)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12])([CH3:8])([CH3:7])[CH3:6].O>C(O)(C)C>[C:5]([N:9]=[N:10][C:11]([N:3]=[C:2]=[S:1])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH3:12])([CH3:6])([CH3:7])[CH3:8]
Reactant: N#C[S-]
Reactant: CC(C)(C)N=NC(C)(Cl)c1ccccc1
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)N=NC(C)(N=C=S)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 26.0 grams (0.32 moles) of sodium thiocyanate in 150 ml of 75% aqueous isopropanol cooled to 5° C. in a 500 ml erlenmeyer flask was added 71.4 grams (0.32 moles) of 1-t-butylazo-1-chloro-1-phenylethane over 3 minutes holding the temperature at 5°-10° C. with an ice bath. The reaction mixture was stirred for 90 minutes at room temperature, poured into 300 ml water and the product extracted with 100 ml of pentane. The pentane extract was washed twice with 100 ml water, once with 10% NaHCO3 solution, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure. The product was a light brown liquid which weighed 43.3 grams (54.6% crude yield). The infrared spectrum of the product had a very strong broad band at 1960-2175 cm-1 which is indicative of the α-isothiocyanate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14](OCC)=[O:15])[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][OH:15])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)c1cnoc1-c1ccc(Cl)c(Br)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cnoc1-c1ccc(Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
To a solution of ethyl 5-(3-bromo-4-chlorophenyl)isoxazole-4-carboxylate (6.19 g) in tetrahydrofuran (100 ml) was gently added diisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 40 ml) at 0° C. and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give 5-(3-bromo-4-chlorophenyl)-4-isoxazolylmethanol (5.10 g, yield 94%) as a colorless oil. NMR (CDCl3) δ: 4.73 (2H, d, J=4.8 Hz), 7.59 (1H, d, J=8.4 Hz), 7.72 (1H, dd, J=2.2, 8.4 Hz), 8.10 (1H, d, J=2.2 Hz), 8.37 (1H, s).
Reaction SMILES: C1(C)C=CC=CC=1.O1CCCC1.[CH2:13]([NH:16][C:17](=O)[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=1)[CH2:14][CH3:15].CSC.B>CO>[C:26]([C:23]1[CH:22]=[CH:21][C:20]([O:19][CH2:18][CH2:17][NH:16][CH2:13][CH2:14][CH3:15])=[CH:25][CH:24]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CCCNC(=O)COc1ccc(C(C)(C)C)cc1
Agent: B
Solvent: Cc1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: CCCNCCOc1ccc(C(C)(C)C)cc1
Yield: 94.4 %

Procedure:
To 250 ml of a 1:1 mixture of toluene: tetrahydrofuran, 35.0 gm N-(n-propyl)-4-t-butylphenoxy-acetamide, the product of Example 16, was added. The resulting mixture was heated to reflux and then 42.8 ml borane methylsulfide was added slowly. The reaction mixture was maintained at reflux for 48 hours at which time completion of the reaction was checked by IR spectroscopy. The reaction mixture was then cooled and 200 ml methanol was added slowly to the system. The system was then acidified by bubbling hydrogen chloride gas through it, and then heated to reflux and refluxed for 1 hour. The solvent was removed by stripping; the resulting oil was redissolved in methanol and the methanol stripped. The residue was dissolved in methylene chloride and basified with sodium hydroxide. The methylene chloride solution was then washed with water. The methylene chloride was stripped to give 31.2 gm of the N-(n-propyl) ethanolamine 4-t-butylphenylether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:46]=[CH:45][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13](B4OC(C)(C)C(C)(C)O4)=[CH:14][CH:15]=3)[C:10]([C:26]3[N:27]=[N:28][N:29]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([N:39]5[CH2:44][CH2:43][O:42][CH2:41][CH2:40]5)=[O:38])=[CH:33][CH:32]=4)[CH:30]=3)=[N:9]2)=[CH:5][CH:4]=1.[OH:47]O>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:47])=[CH:14][CH:15]=3)[C:10]([C:26]3[N:27]=[N:28][N:29]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([N:39]5[CH2:44][CH2:43][O:42][CH2:41][CH2:40]5)=[O:38])=[CH:33][CH:32]=4)[CH:30]=3)=[N:9]2)=[CH:45][CH:46]=1
Reactant: OO
Reactant: COc1ccc(Cn2nc(-c3cn(-c4ccc(C(=O)N5CCOCC5)cc4)nn3)c3cc(B4OC(C)(C)C(C)(C)O4)ccc32)cc1
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2nc(-c3cn(-c4ccc(C(=O)N5CCOCC5)cc4)nn3)c3cc(O)ccc32)cc1
Yield: 67.8 %

Procedure:
A solution of 1-(4-methoxybenzyl)-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (239 mg; 0.39 mmol; 1.0 eq.) and hydrogen peroxide (52 mg, 1.54 mmol, 4 eq.) in EtOAc (4.8 mL) was stirred O/N at RT. Solvent was removed under reduced pressure and the crude was purified by preparative HPLC to give the title compound as a white powder (135 mg, 69%). UPLC/MS: (MS+) 511.1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)[CH3:2].[H-].[Na+].[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[CH:27][N:26]=[C:25](Cl)[N:24]=1>CN(C=O)C>[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[CH:27][N:26]=[C:25]([NH:14][CH:11]2[CH2:10][CH2:9][N:8]([CH2:7][C:6]3[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)[CH2:13][CH2:12]2)[N:24]=1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1OC
Reactant: N#Cc1cnc(Cl)nc1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc(CN2CCC(Nc3ncc(C#N)c(N)n3)CC2)ccc1OC
Temperature: 25 °C
Yield: 34 %

Procedure:
To a solution of 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (39.7 mg, 0.15 mmol, 1.5 equiv; intermediate A1) in dry DMF (1.5 mL) under Ar was added sodium hydride (6.6 mg, 0.15 mmol, 1.5 equiv; 55% free-flowing powder moistened with oil) and the reaction mixture stirred at rt. After 2 h 4-amino-2-chloro-pyrimidine-5-carbonitrile (15.5 mg, 0.10 mmol, 1.0 equiv; commercially available) was added and the mixture heated by microwave irradiation to 140° C. for 1 h. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 19.7 mg (34%) of the title compound. MS (ISP): 383.4 [M+H]+.