Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][CH:17]([CH3:48])[C:18]([NH:20][CH:21]([CH2:38][C:39]1[CH:44]=[C:43]([F:45])[C:42]([F:46])=[CH:41][C:40]=1[F:47])[CH2:22][C:23](=[O:37])[N:24]1[CH2:29][CH2:28][N:27]2[C:30]([C:33]([F:36])([F:35])[F:34])=[N:31][N:32]=[C:26]2[CH2:25]1)=[O:19]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:10](=[O:12])[NH:16][CH:17]([C:18](=[O:19])[NH:20][CH:21]([CH2:38][C:39]1[CH:44]=[C:43]([F:45])[C:42]([F:46])=[CH:41][C:40]=1[F:47])[CH2:22][C:23](=[O:37])[N:24]1[CH2:29][CH2:28][N:27]2[C:30]([C:33]([F:35])([F:34])[F:36])=[N:31][N:32]=[C:26]2[CH2:25]1)[CH3:48])[CH:13]([CH3:15])[CH3:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(N)C(=O)NC(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=O)O
Solvent: ClCCl
Product: CC(NC(=O)C(NC(=O)OC(C)(C)C)C(C)C)C(=O)NC(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Reaction time: 0.25 h
Yield: 57.7 %

Procedure:
To a stirred solution of 2-tert-Butoxycarbonylamino-3-methyl-butyric acid (0.390 gm, 0.00179 moles) in CH2Cl2 (40 ml) was added at 0° C. The reaction mixture was then stirred for 15 minutes. To this stirred solution was added 2-Amino-N-[3-oxo-1-(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-propyl]-propionamide (0.860 gm, 0.00179 moles) at 0° C. The reaction mixture was then stirred for overnight. Dicyclohexyl urea was removed by filtration and filtrate was concentrated in vacuum. The residue was purified by silica gel chromatography using CH2Cl2/MeOH (9.7/0.3) as an eluent to yield (2-Methyl-1-{1-[3-oxo-1-(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-propylcarbamoyl]-ethylcarbamoyl}-propyl)-carbamic acid tert-butyl ester (Compound of formula 7) (Yield=0.7 gm, 58%)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[CH:9][C:8]1[CH2:19][CH2:20][CH2:21][C:7]=1[CH:6]=2.[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[N:30]=[C:31]=[O:32]>O1CCCC1>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]1[C:10]2[C:5](=[CH:6][C:7]3[CH2:21][CH2:20][CH2:19][C:8]=3[CH:9]=2)[N:4]=[CH:3][C:2]=1[NH:1][C:31]([NH:30][C:24]1[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:23]=1[F:22])=[O:32]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: Nc1cnc2cc3c(cc2c1-c1ccccc1Cl)CCC3
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)cc1F)Nc1cnc2cc3c(cc2c1-c1ccccc1Cl)CCC3
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 3-amino-4-(2-chlorophenyl)-7,8-dihydro-6H-cyclopenta[g]quinoline (2.5 g) in tetrahydrofuran (25 ml) was added 2,4-difluorophenyl isocyanate (1.2 ml) dropwise and the mixture was stirred for 5 hours at room temperature. The solvent was then distilled off to give crystals of N-[4-(2-chlorophenyl)-7,8-dihydro-6H-cyclopenta[g]quinolin-3-yl]-N'-(2,4-difluorophenyl)urea. The crystals were collected by filtration and washed with isopropyl ether (3.42 g, 89.8%). Recrystallization from acetic acid-water gave colorless needles, m.p. 247°-248° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[O:17][CH2:16][CH2:15][O:14][C:13]=2[C:12]([NH2:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](Cl)(=[O:23])[CH2:21][CH3:22]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[C:18]2[O:17][CH2:16][CH2:15][O:14][C:13]=2[C:12]([NH:19][C:20](=[O:23])[CH2:21][CH3:22])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=O)Cl
Reactant: Nc1ccc(OCc2ccccc2)c2c1OCCO2
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCC(=O)Nc1ccc(OCc2ccccc2)c2c1OCCO2
Reaction time: 17 h

Procedure:
To a solution of 30 g of 5-benzyloxy-8-amino-1,4-benzodioxane (XX); code number 760 727, in 250 ml of chloroform and 21.3 ml of triethylamine, cooled to 0° C., 12.1 cm3 of propionyl chloride were slowly added. Then, it was stirred for 17 hours, washed with a solution of diluted hydrochloric acid, with water, with an aqueous solution of sodium bicarbonate, then with water, the organic phase was evaporated and the residue recrystallized in ethyl acetate.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:20][CH2:19][CH:18]([C:21](=[O:30])[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[C:9]([O:13][C:14]([N:16]1[CH2:20][CH2:19][C:18]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)([C:21](=[O:30])[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc(Cl)c(Cl)c2)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccccc2)(C(=O)c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 23 %

Procedure:
Benzyl bromide (0.19 mL, 1.60 mmol) was added to a solution of 3-(3,4-dichloro-benzoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (138 mg, 0.40 mmol) in THF (5 mL), and then lithium bis(trimethylsilyl)amide (1.0 M, in THF, 1.2 mL, 1.20 mmol) was slowly added at room temperature. The reaction mixture was stirred at room temperature for 1.5 hours, then was quenched by addition of saturated aqueous NH4Cl, diluted with water, and extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (10% to 20% of EtOAc in hexane) to give 40 mg (23% yield) of 3-benzyl-3-(3,4-dichloro-benzoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as a colorless oil.
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][CH2:8][N:9]([S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH:23]([C:30](=[O:37])[NH:31][C:32]2[S:33][CH:34]=[N:35][N:36]=2)[CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH2:10][CH2:11][O:12][CH3:13])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:25]1([CH2:24][CH:23]([C:20]2[CH:21]=[CH:22][C:17]([S:14]([N:9]([CH2:10][CH2:11][O:12][CH3:13])[CH2:8][CH2:7][C:6]([OH:38])=[O:5])(=[O:16])=[O:15])=[CH:18][CH:19]=2)[C:30](=[O:37])[NH:31][C:32]2[S:33][CH:34]=[N:35][N:36]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COCCN(CCC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nncs2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCN(CCC(=O)O)S(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nncs2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 75 mg (0.133 mmol) of title F compound, 3-[{4-[2-cyclopentyl-1-([1,3,4]thiadiazol-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-(2-methoxy-ethyl)-amino]-propionic acid tert-butyl ester is added 2 mL of DCM and 0.5 mL of trifluoroacetic acid. The reaction mixture is stirred at ambient temperature for one hour. The reaction is evaporated to a brownish resin and subsequently dissolved in ether and decanted from some insoluble material. The organic layer is evaporated to a light orange resin which is dissolved in 2 mL methanol in a 50 mL round bottom flask. Aqueous potassium hydroxide (0.265 mL of 0.5094 M potassium hydroxide solution) is added and stirred for 30 min. The methanol is evaporated, 8 mL of water added, and the mixture lyophilized to afford 3-[{4-[2-cyclopentyl-1-([1,3,4]thiadiazol-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-(2-methoxy-ethyl)-amino]-propionic acid as a light orange-brown solid: 1H NMR (400 MHz, DMSO-d6) δ 1.1 (m, 1H), 1.4 (m, 1H), 1.6 (m, 2H), 1.7 (ddd, J=13.1, 6.9, 6.7 Hz, 2H), 2.1 (ddd, J=11.2, 8.2, 7.8, 2H), 3.2 (s, 2H), 3.2 (m, 3H), 3.7 (t, J=7.5 Hz, 1H), 7.56 (d, J=8.3, 2H), 7.63 (d, J=8.3 Hz, 2H), 8.58 (s, 1H); L/MS 511 (M+1), 509 (M−1). EC50 in primary enzyme assay 50 μM.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[N+:10]([CH3:13])([O-:12])=[O:11].[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4](/[CH:5]=[CH:13]/[N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: Cc1cccc(C=O)c1
Reactant: C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(/C=C/[N+](=O)[O-])c1
Yield: 94.9 %

Procedure:
3-Methylbenzaldehyde (21 g, 174.273 mmol) was reacted with nitro methane (967 mL, 174.273 mmol), NaOH solution (6.7 g, 174.273 mmol in 17.32 mL H2O) and ethanol (210 mL) at 0° C. for 2 hours. The reaction mass was quenched using cold 50% HCl solution (60 mL) and extracted using ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 27 g of the product (95% yield).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:23])([F:22])[C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[N:9][N:10]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:29]([O:31]CC)=[CH2:30])CCC.N1C2C(=CC(CC3N4N=C(C(=O)C)C=CC4=NN=3)=CC=2)C=CC=1>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:22][C:11]([F:23])([C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][CH:16]=[CH:15]2)[C:8]1[N:6]2[N:7]=[C:2]([C:29](=[O:31])[CH3:30])[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: FC(F)(c1ccc2ncccc2c1)c1nnc2ccc(Cl)nn12
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Solvent: C1COCCO1
Product: CC(=O)c1ccc2nnc(C(F)(F)c3ccc4ncccc4c3)n2n1
Yield: 35.2 %

Procedure:
The title compound as a light yellow oil (180 mg, 30%, 80% purity) was synthesized from 6-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)difluoromethyl)quinoline (intermediate R) (500 mg, 1.507 mmol), tributyl(1-ethoxyvinyl)stannane (2.55 mL, 7.54 mmol) and PdCl2(PPh3)2 (106 mg, 0.151 mmol) in 1,4-dioxane using the similar procedure as described in the synthesis of compound 41.2. 1H-NMR (400 MHz, MeOH-d4) δ ppm 9.17 (s, 1H), 8.91 (d, 1H), 8.65 (s, 1H), 8.43 (d, 1H), 8.28 (q, 2H), 7.96 (d, 1H), 7.92 (m, 1H), 2.61 (s, 3H). LCMS (method B): [MH]+=340.1, tR=2.16 min.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[O:4][N:3]=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.[CH2:43]([O:45][C:46](=[O:68])[C@@:47]([OH:67])([CH3:66])[CH2:48][N:49]([CH2:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[C:62]([Cl:64])[CH:61]=[CH:60][C:59]=2[F:65])=[CH:54][CH:53]=1)[NH2:50])[CH3:44]>CN(C=O)C>[CH2:43]([O:45][C:46](=[O:68])[C@@:47]([OH:67])([CH3:66])[CH2:48][N:49]([CH2:51][C:52]1[CH:53]=[CH:54][C:55]([C:58]2[CH:63]=[C:62]([Cl:64])[CH:61]=[CH:60][C:59]=2[F:65])=[CH:56][CH:57]=1)[NH:50][C:7]([C:5]1[O:4][N:3]=[C:2]([OH:1])[CH:6]=1)=[O:9])[CH3:44]
Reactant: O=C(O)c1cc(O)no1
Reactant: CCOC(=O)[C@](C)(O)CN(N)Cc1ccc(-c2cc(Cl)ccc2F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)[C@](C)(O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cc(O)no1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-Hydroxyisoxazole-5-carboxylic acid (132 mg, 1.0 mmol) and HATU (389 mg, 1.0 mmol) were combined in DMF (3.7 mL), and the resulting mixture was stirred for 10 minutes at room temperature. DIPEA (343 μL, 2.0 mmol) and (R)-3-[N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-hydrazino]-2-hydroxy-2-methyl-propionic acid ethyl ester (300 mg, 0.8 mmol) were added and the resulting mixture was stirred for 30 minutes. LC/MS showed desired product. The mixture was the evaporated under reduced pressure to yield the title compound (210 mg, 100% purity). MS m/z [M+H]+ calc'd for C23H23ClFN3O6, 492.13; Found 492.2.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].Br[CH2:15][CH2:16][CH2:17][Cl:18].C(=O)([O-])[O-].[K+].[K+].[Cl-].[K+]>CC(C)=O>[Cl:18][CH2:17][CH2:16][CH2:15][O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCCl)c(OC)c1
Temperature: 57.5 °C
Reaction time: 10 h
Yield: 97.9 %

Procedure:
In a 50 mL volume glass flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser were placed 1.02 g (5.49 mmol) of methyl 4-hydroxy-3-methoxybenzoate (purity: 98 wt. %), 2.12 g (13.2 mmol) of 3-bromo-1-chloropropane (purity: 98 wt. %), 1.16 g (8.24 mmol) of potassium carbonate (purity: 98 wt. %), 1.02 g (13.7 mmol) of potassium chloride, and 10 mL of acetone. The resulting mixture was refluxed under stirring at 55-60° C. in an argon gas atmosphere for 10 hours. After the reaction was complete, the reaction mixture was filtered. Analysis of the filtrate by high performance liquid chromatography (absolute quantitative analysis) indicated that 1.39 g (reaction yield: 98.2%) of methyl 4-(3-chloropropoxy)-3-methoxybenzoate was produced.
Reaction SMILES: C1N2CN3CN(C2)CN1C3.[OH2:11].[C:12]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>C(O)C>[C:12]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:11])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1ccc(CCl)cc1
Reactant: O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: CCO
Product: CC(C)(C)c1ccc(C=O)cc1
Temperature: 45 °C
Yield: 60 %

Procedure:
17 g of hexamethylenetetramine, 9 ml of water, 6 ml of ethanol and 21.5 g of 95% p-tert-butylbenzyl chloride are added to a three-necked flask provided with a thermometer, magnetic stirrer and reflux condenser. The mixture is now warmed slowly to 45° C. while stirring. At this temperature the mixture is initially slurry-like and thereafter thinly liquid. An exothermic reaction occurs. The temperature is held at 45° C. with the aid of an ice-bath until the reaction fades away. Thereupon the mixture is stirred with renewed warming at 45° C. for 30 minutes. The reflux condenser is now replaced by a distillation bridge and 5 ml of ethanol are distilled off from the mixture under a slight vacuum (70 Torr). Thereupon, the distillation bridge is removed and a water separator is attached, thus enabling the separated water to flow back into the reaction vessel. The water separator is filled with about 60 ml of water and 10 ml of toluene and the mixture is treated with 60 ml of water. The mixture is heated to 140° C. At the beginning of the steam distillation the pH-value is adjusted to 4.5-5 by means of 60% sulphuric acid. The liquid in the water separator is renewed several times. The organic phases are separated from the distillates and the aqueous fractions are extracted with ether. The ether extracts and organic phases are in each case combined and washed with, in each case, about 20 ml of 15% sulphuric acid, water, 10% sodium carbonate solution and finally again with water and then concentrated. There are thus obtained a total of 14.7 g of crude product which are fractionated at 17 Torr over a 5 cm Widmer column and give 11.8 g (60%) of p-tert-butylbenzaldehyde with a purity of 92% (NMR/GC).
Reaction SMILES: [NH2:1][C:2](=[O:32])[CH2:3][N:4]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=1)[CH2:5][C:6]([N:8]([C@H:10]([C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)[CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[CH3:9])=[O:7].[N:33]1([C:39]([C:41]2[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=2)=[O:40])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C([O-])([O-])=O.[Na+].[Na+].FC(F)(F)C(O)=O>O1CCOCC1.O.CS(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2](=[O:32])[CH2:3][N:4]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=1)[CH2:5][C:6]([N:8]([CH3:9])[C@H:10]([C:17]1[CH:22]=[CH:21][C:20]([C:45]2[CH:44]=[CH:43][CH:42]=[C:41]([C:39]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[O:40])[CH:46]=2)=[CH:19][CH:18]=1)[CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:7]
Reactant: CN(C(=O)CN(CC(N)=O)c1ccc(Cl)c(Cl)c1)[C@@H](CN1CCCC1)c1ccc(Br)cc1
Reactant: O=C(c1cccc(B(O)O)c1)N1CCOCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)CN(CC(N)=O)c1ccc(Cl)c(Cl)c1)[C@@H](CN1CCCC1)c1ccc(-c2cccc(C(=O)N3CCOCC3)c2)cc1
Temperature: 160 °C
Reaction time: 0.25 h
Yield: 59.1 %

Procedure:
2-[(2-amino-2-oxoethyl)(3,4-dichlorophenyl)amino]-N-[(1R)-1-(4-bromophenyl)-2-(1-pyrrolidinyl)ethyl]-N-methylacetamide (138 mg, 0.254 mmol) was dissolved in 1 mL of 1,4-Dioxane and combined with [3-(4-morpholinylcarbonyl)phenyl]boronic acid (89.8 mg, 0.382 mmol), Pd(dppf)2Cl2 (6.23 mg, 0.0076 mmol), and 400 uL of 2 M Na2CO3 in water in a glass reaction tube (0.5-2.0 mL Smith Process Vial) that was equipped with a magnetic stir bar. The tube was fitted with a rubber septum and hermetically sealed with a crimped metal foil seal. Using a Personal Chemistry Emrys Optimizer microwave unit, the reaction mixture was magnetically stirred and irradiated with microwave energy of dynamically adjusted power in order to maintain a temperature of 160° C. for 360 seconds. After allowing the mixture to cool to room temperature, it was diluted with 1.0 mL DMSO, acidified with trifluoroacetic acid and filtered through a 0.45 μm PTFE Acrodisk. The crude residue was purified by preparative HPLC (Phenomenex 75×30 mm column, 40 mL/min flow rate, A: 0.1% TFA in acetonitrile B: 0.1% TFA in water, A: 10 to 100% over 15 min, UV detection at 215 nm) to give 96 mg (0.15 mmol) of the title compound as an off-white amorphous solid. MS (ES) m/e 651 [M+H]+.
Reaction SMILES: Cl[TeH:2]1[C:6]2[CH:7]=[C:8]([CH3:15])[C:9]3[C:14]([C:5]=2[NH:4]O1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[BH4-].[Na+].[C:18](OC(=O)C)(=O)[CH3:19].Cl>O1CCCC1.CO>[CH3:18][C:19]1[Te:2][C:6]2[CH:7]=[C:8]([CH3:15])[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:5]=2[N:4]=1
Reactant: Cc1cc2c(c3ccccc13)NO[TeH]2Cl
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc2c(cc(C)c3ccccc32)[te]1
Temperature: 5 °C
Yield: 32.8 %

Procedure:
3-Chloro-5-methylnaphth[2,1-c][1,2,5]oxatellurazole (Example 4) (16.7 g=0.05 mole) was suspended in a mixture of tetrahydrofuran (THF, 200 ml) and methanol (40 ml) in a 500 ml three necked flask fitted with a nitrogen inlet, a condenser, and a powder addition funnel. Sodium borohydride was added under a nitrogen atmosphere and in small portions until the reaction mixture was a pale orange yellow. This required about 5 to 6 g. The powder addition funnel was then removed and replaced with a stopper. The reaction mixture was then cooled to 5° C. and acetic anhydride (5.1 g=0.05 mole) added slowly through the condenser. The reaction mixture transiently turned a bright orange. Concentrated hydrochloric acid (25 ml) was then added in one portion, the ice bath removed, and the mixture stirred to room temperature. As the reaction mixture warmed up, a crystalline deposit appeared and was collected by filtration. The crystalline deposit was washed with tetrahydrofuran until the filtrate was colorless and clear. The filtrate was then heated to boiling with a mixture of isopropanol (175 ml) and concentrated ammonium hydroxide (25 ml) and filtered hot with Celite®, the cooled filtrate was diluted with water until crystallization started. A first crop of pale yellow needles (5.06 g), m.p. 110°-112° C. was obtained. A further 1.65 g of product were obtained by two further extractions with the same solvent mixture, giving a total yield of 6.71 g=43.3% of theory. For analysis, the material was recrystallized from isopropanol. This did not change the melting point. Elemental analyses were in agreement with that expected for the structural formula.
Reaction SMILES: NC1C=CC(C2C3C(=NC=NC=3N)N([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)N=2)=CC=1.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:33]=1[OH:39].[NH2:40][C:41]1[N:46]=[CH:45][N:44]=[C:43]2[N:47]([C@H:67]3[CH2:72][CH2:71][C@@H:70]([N:73]4[CH2:78][CH2:77][N:76]([CH3:79])[CH2:75][CH2:74]4)[CH2:69][CH2:68]3)[N:48]=[C:49]([C:50]3[CH:55]=[CH:54][C:53]([NH:56][C:57]4OC5C=CC=C(C)C=5N=4)=[CH:52][CH:51]=3)[C:42]=12>>[NH2:40][C:41]1[N:46]=[CH:45][N:44]=[C:43]2[N:47]([C@H:67]3[CH2:72][CH2:71][C@@H:70]([N:73]4[CH2:74][CH2:75][N:76]([CH3:79])[CH2:77][CH2:78]4)[CH2:69][CH2:68]3)[N:48]=[C:49]([C:50]3[CH:55]=[CH:54][C:53]([NH:56][C:57]4[O:39][C:33]5[C:34]([CH3:38])=[CH:35][CH:36]=[CH:37][C:32]=5[N:31]=4)=[CH:52][CH:51]=3)[C:42]=12
Reactant: Cc1cccc2oc(Nc3ccc(-c4nn([C@H]5CC[C@@H](N6CCN(C)CC6)CC5)c5ncnc(N)c45)cc3)nc12
Reactant: Cc1cccc(N)c1O
Agent: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(N)cc4)c4c(N)ncnc43)CC2)CC1
Product: Cc1cccc2nc(Nc3ccc(-c4nn([C@H]5CC[C@@H](N6CCN(C)CC6)CC5)c5ncnc(N)c45)cc3)oc12

Procedure:
Cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-7-methyl-1,3-benzoxazol-2-amine was prepared from cis-3-(4-aminophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.100 g, 0.245 mmol) and 2-amino-6-methylphenol (0.030 g, 0.245 mmol) in a manner similar to that used in the synthesis of cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-4-methyl-1,3-benzoxazol-2-amine (PH4052419F). The compound was formed as an off-white solid (0.018 g, 14%): RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 100 Å, 5 μm, 250×4.6 mm column) tr=7.37 min., 85%; m/z 539 (MH+).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][NH:11][C:12](=[O:27])[C:13](=[N:15][NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH3:14])=[CH:6][CH:5]=1.CI.[C:30](OCC)(=O)C>CN(C)C=O>[Cl:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][NH:11][C:12](=[O:27])[C:13](=[N:15][N:16]([CH3:30])[C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][CH:18]=2)[CH3:14])=[CH:6][CH:5]=1
Reactant: CC(=NNc1ccc(C(F)(F)F)cc1)C(=O)NCc1ccc(Cl)nc1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(=NN(C)c1ccc(C(F)(F)F)cc1)C(=O)NCc1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
60% sodium hydride (0.12 g, 3.0 mmol) was added to a solution of N-(6-chloro-3-pyridylmethyl)-2-(4-trifluoromethylphenyl hydrazono) propionic acid amide (Compound No. 63) (1.0 g, 2.7 mmol) in N,N-dimethylformamide (5 ml) and stirred for 10 minutes. Methyl iodide (0.40 g, 2.8 mmol) was gradually added thereto, and stirred at room temperature for 2 hours. To the reaction mixture, ice water and ethyl acetate were added, and subjected to extraction. The organic phase was washed with a saturated brine, then dried on anhydrous sodium sulfate and concentrated. The resulting residue was purified with a silica gel chromatography to obtain N-(6-chloro-3-pyridylmethyl)-2-[N-methyl-N-(4-trifluoromethylphenyl) hydrazono]propionic acid amide (Compound No. 110) (0.80 g, 2.1 mmol, 77%).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>N1C=CC=CC=1>[CH3:13][S:14]([O:1][CH:2]1[CH2:3][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5]1)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
To a solution of tert-butyl 3-hydroxy-1-azetanecarboxylate (4.0 g, 0.023 mol) in anhydrous pyridine (50 mL), methanesulfonyl chloride (5.3 g, 0.046 mol) was added at −20° C. under an atmosphere of nitrogen. The yellow heterogeneous mixture was stirred between −20° C. to −30° C. for one hour, then between 0° C. to −5° C. for two hours. The mixture was poured into ice water (50 mL). The water phase was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with water (1×50 mL), 5% aquoeus citric acid (4×50 mL), water (1×50 mL), saturated sodium bicarbonate (1×50 mL), and brine (1×50 mL) and dried over sodium sulfate. The solvent was removed under reduced pressure to yield tert-butyl 3-[(methylsulfonyl)oxy]-1-azetanecarboxylate as brownish oil (4.85 g, 0.019 mol).