Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]1[C:5](=[O:19])[C:6](=[O:18])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[OH:17])C.[CH3:20][C:21]([CH3:26])([CH3:25])[C@H:22]([NH2:24])[CH3:23].C(OCC)(=O)C>CCCCCC>[CH3:20][C:21]([CH3:26])([CH3:25])[C@H:22]([NH:24][C:4]1[C:5](=[O:19])[C:6](=[O:18])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[OH:17])[CH3:23]
Reactant: CCOc1c(Nc2ccc(C#N)cc2O)c(=O)c1=O
Reactant: C[C@@H](N)C(C)(C)C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C[C@@H](Nc1c(Nc2ccc(C#N)cc2O)c(=O)c1=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 3-ethoxy-4-(2-hydroxy-4-cyanophenyl)amino-3-cyclobutene-1,2-dione (0.395 g, 0.0015 mol) and (R)-2,2,1-trimethylpropylamine (0.2M in ethanol, 23 ml, 0.0046 mol) was stirred at room temperature for two days. TLC (2:1 ethyl acetate:hexane) indicates a loss of starting material. The ethanol is evaporated on a rotary evaporator. The reaction is taken up in ethyl acetate and extracted well with 0.25N HCl. The organic layer is washed once with distilled water, dried (Na2SO4), and evaporated to a solid. The solid is collected and washed with diethyl ether to give 3-[(R)-2,2,1-trimethylpropylamino]-4-(2-hydroxy-4-cyanophenyl)amino-3-cyclobutene-1,2-dione, 0.345 g (0.00095 mol, 72%).
Reaction SMILES: [C:1](=[N:9][NH2:10])([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2].[CH2:11]([N:14]=[C:15]=[S:16])[CH:12]=[CH2:13]>CO>[CH3:2]/[C:1](/[C:3]1[N:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)=[N:9]/[NH:10][C:15]([NH:14][CH2:11][CH:12]=[CH2:13])=[S:16]
Reactant: CC(=NN)c1ccccn1
Reactant: C=CCN=C=S
Solvent: CO
Product: C=CCNC(=S)N/N=C(/C)c1ccccn1
Yield: 53.3 %

Procedure:
A solution of 2.7 g (0.02 mol) of 2-acetylpyridine hydrazone in 5 ml of MeOH was treated with 3.1 g (0.03 mol) of allyl isothiocyanate and the solution was heated at reflux for 3 hours. The solution was cooled and the product which formed was collected. The crude material was recrystallized 3 times from MeOH, affording 2.5 g (49%) of white needles of 2-acetylpyridine 4-allyl-3-thiosemicarbazone, mp 107° C.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]([C:5]1[NH:27][C:8]2[CH2:9][C@@:10]3([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25]C)[CH:20]=4)[C@H:15]([CH2:16][C:7]=2[C:6]=1[CH3:28])[CH2:14][N:13]([CH2:17][CH3:18])[CH2:12][CH2:11]3)=[O:4].B(Br)(Br)Br.[ClH:34].CCOCC>CO>[ClH:34].[CH3:29][N:2]([CH3:1])[C:3]([C:5]1[NH:27][C:8]2[CH2:9][C@@:10]3([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=4)[C@H:15]([CH2:16][C:7]=2[C:6]=1[CH3:28])[CH2:14][N:13]([CH2:17][CH3:18])[CH2:12][CH2:11]3)=[O:4]
Reactant: CCN1CC[C@@]2(c3cccc(OC)c3)Cc3[nH]c(C(=O)N(C)C)c(C)c3C[C@@H]2C1
Agent: BrB(Br)Br
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CCN1CC[C@@]2(c3cccc(O)c3)Cc3[nH]c(C(=O)N(C)C)c(C)c3C[C@@H]2C1

Procedure:
0.5 g (1.25 mmol) of (±)trans-2-dimethylaminocarbonyl-6-ethyl-8a-(3-methoxyphenyl)-3-methyl-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrrolo[2,3-g] isoquinoline were treated with 0.725 ml (7.5 mmol) of boron tribromide as described in example 2. The etude product was dissolved in MeOH and the solution brought to acidic pH with HCl/Et2O. The solvent was evaporated in vacuo and the solid crystallized from EtOH, yielding 0.15 g of the title compound. M.p.=305° C. dec.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([CH2:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)=[N:2]1.C([N-]C(C)C)(C)C.[Li+].[C:23]1(=[O:28])[CH2:27][CH2:26][CH2:25][CH2:24]1.O>O1CCCC1>[OH:28][C:23]1([CH:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[C:3]2[N:4]=[CH:5][NH:1][N:2]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C1CCCC1
Reactant: N#Cc1ccc(Cc2nc[nH]n2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(C(c2nc[nH]n2)C2(O)CCCC2)cc1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
5 g of 4-[1-(1,2,4-triazolyl)methyl]benzonitrile is dissolved in 100 ml of tetrahydrofuran and combined at -50° with 20 ml of 1.5-molar solution of lithium diisopropylamide in tetrahydrofuran, stirred for 0.5 hour, further stirred for 1 hour with 2.4 g of cyclopentanone at -70°, and heated to 25°. Then water is added, the mixture is extracted twice with ethyl acetate, washed neutral with water, dried over sodium sulfate, and concentrated to dryness under vacuum, thus obtaining 7.21 g of crude 4-[1-hydroxycyclopent-1-yl-1-(1,2,4-triazolyl)methyl]benzonitrile.
Reaction SMILES: Br[C:2]1[C:3]([CH2:10][O:11][CH2:12][O:13][CH3:14])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.CC(C)([O-])C.[Na+].[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>C1(C)C=CC=CC=1>[CH3:9][O:8][C:5]1[N:4]=[C:3]([CH2:10][O:11][CH2:12][O:13][CH3:14])[C:2]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:7][CH:6]=1
Reactant: COCOCc1nc(OC)ccc1Br
Reactant: C1CCNC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COCOCc1nc(OC)ccc1N1CCCC1
Yield: 13.6 %

Procedure:
A solution of 3-bromo-6-methoxy-2-(methoxymethyloxy)methylpyridine (324.6 mg, 1.24 mmol), tris(dibenzylideneacetone)(chloroform)dipalladium(0) (32.7 mg, 0.03 mmol), (2-biphenyl)di-t-butylphosphine (18.5 mg, 0.06 mmol), sodium t-butoxide (357 mg, 3.71 mmol) and pyrrolidine (640 mg, 3.74 mmol) in toluene (4.5 mL) was stirred at 135° C. for 3 hours in a sealed tube. The reaction mixture was extracted with chloroform/water, and the organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by preparative silica gel thin layer chromatography (hexane:ethyl acetate=3:1) to obtain 6-methoxy-2-(methoxymethyloxy)methyl-3-(pyrrolidin-1-yl)pyridine (42.7 mg, 14%) as yellow oil.
Reaction SMILES: FC(F)(F)C(OC1C(OC(=O)C(F)(F)F)=C(I)C=CC=1)=O.C([C:25]1[CH:30]=[C:29]([O:31][C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39]([NH:41][C:42](=[O:51])[CH2:43][C:44]3[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=3)=[O:40])=[CH:34][C:33]=2[F:52])[CH:28]=[CH:27][N:26]=1)(=O)N.O.[N:54]1C=CC=CC=1.[ClH:60]>CN(C=O)C>[ClH:60].[NH2:54][C:25]1[CH:30]=[C:29]([O:31][C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39]([NH:41][C:42](=[O:51])[CH2:43][C:44]3[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=3)=[O:40])=[CH:34][C:33]=2[F:52])[CH:28]=[CH:27][N:26]=1
Reactant: c1ccncc1
Reactant: NC(=O)c1cc(Oc2ccc(NC(=O)NC(=O)Cc3ccc(F)cc3)cc2F)ccn1
Agent: Cl
Agent: O=C(Oc1cccc(I)c1OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(Oc2ccc(NC(=O)NC(=O)Cc3ccc(F)cc3)cc2F)ccn1
Temperature: 0 °C
Reaction time: 5 h
Yield: 61.7 %

Procedure:
Bis-(trifluoroacetoxy)-iodobenzene (Aldrich, 3.09 g, 7.20 mmol, 1.4 eq) was added to a solution of 1-(4-(2-carbamoylpyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea (2.19 g, 5.14 mmol, 1.0 eq), water (0.241 mL, 13.4 mmol, 2.6 eq) and pyridine (1.62 mL, 20 mmol, 3.9 eq) in DMF (20 mL) at room temperature and the reaction mixture was stirred for 5 h. The reaction mixture was quenched with 1 N HCl and the aqueous solution extracted with Et2O, discarding the organic layer. The aqueous layer was neutralized with 1 N NaOH and extracted with EtOAc. The combined organic layers were washed with 10% aq LiCl, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with 0-5% MeOH in CHCl3) and the appropriate fractions were concentrated in vacuo. The residue was dissolved in THF (50 mL) cooled to 0° C. and treated with anhydrous HCl (4N, 10 mL, 40 mmol, 7.8 eq). The reaction mixture was allowed to warm to room temperature and stirred for 2 h resulting in a heterogeneous solution. The solution was filtered and the solid washed with Et2O and dried in vacuo to afford the title compound (1.38 g, 63%) as a solid. 1H NMR (DMSO-d6)
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([CH3:5])=O.[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[CH:3]([NH:15][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:5]
Reactant: NCc1ccccc1
Reactant: CC(=O)C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(NCc1ccccc1)C(F)(F)F
Yield: 98.4 %

Procedure:
After briskly stirring a mixture of 1,1,1-trifluoroacetone (1.0 ml; 11.2 mmol), benzylamine (1.1 ml; 10 mmol), AcOH (2 ml) and 3 Å molecular sieves (5 g) in 30 ml of CH2Cl2 for 2 hour at room temperature, sodium triacetoxyborohydride (4.25 g; 20 mmol) was added. After stirring 48 hours at room temperature, the reaction mixture was filtered through celite. After removing the volatiles in vacuo the residue was partitioned between ether (100 ml) and 1N NaOH (100 ml). The organic layer was washed with brine (50 ml), dried (MgSO4) and filtered through a 5×5 cm pad of silica gel. The pad was rinsed with ether and the filtrate was concentrated to afford 2.0 g (99%) of the title compound of this step as a colorless liquid.
Reaction SMILES: N1C=CC=[CH:3][C:2]=1[O:7]C(=S)OC1C=CC=CN=1.[Na].[OH:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:28]=1[NH:27][CH2:26][CH:25]([N:29]([CH3:31])[CH3:30])[CH2:24]2.C(N(CCC)C1CC2C(=C(N)C=CC=2)NC1)CC>>[CH3:30][N:29]([CH3:31])[CH:25]1[CH2:26][N:27]2[C:2](=[O:7])[CH2:3][O:18][C:19]3[C:28]2=[C:23]([CH:22]=[CH:21][CH:20]=3)[CH2:24]1
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Reactant: CN(C)C1CNc2c(O)cccc2C1
Agent: CCCN(CCC)C1CNc2c(N)cccc2C1
Agent: [Na]
Product: CN(C)C1Cc2cccc3c2N(C1)C(=O)CO3

Procedure:
This compound was prepared by following the procedure of Example 56 part B, but substituting ethyl bromoacetate for di (2-pyridyl)thiocarbonate and the sodium salt of 1,2,3,4-tetrahydro-8-hydroxy-N,N-dimethyl-3-quinolinamine for 1,2,3,4-tetrahydro-N3,N3 -dipropyl-3,8-quinolinediamine.
Reaction SMILES: [CH2:1]([C:3]1([CH2:16][CH3:17])[C:8]2[CH:9]=[C:10]([OH:13])[CH:11]=[CH:12][C:7]=2[N:6]([CH3:14])[C:5](=[O:15])[O:4]1)[CH3:2].[C:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[C:24]([F:26])[CH:25]=1)#[N:19]>>[CH2:16]([C:3]1([CH2:1][CH3:2])[O:4][C:5](=[O:15])[N:6]([CH3:14])[C:7]2[CH:12]=[CH:11][C:10]([O:13][C:22]3[CH:21]=[C:20]([CH:25]=[C:24]([F:26])[CH:23]=3)[C:18]#[N:19])=[CH:9][C:8]1=2)[CH3:17]
Reactant: N#Cc1cc(F)cc(B(O)O)c1
Reactant: CCC1(CC)OC(=O)N(C)c2ccc(O)cc21
Product: CCC1(CC)OC(=O)N(C)c2ccc(Oc3cc(F)cc(C#N)c3)cc21

Procedure:
Prepared from 4,4-diethyl-6-hydroxy-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 3-cyano-5-fluorobenzeneboronic acid according to the coupling procedure described in example 69. A white solid, 1H NMR (DMSO-d6): δ 7.61 (m, 1H), 7.29 (s, 1H), 7.23 (dt, J=10.3, 2.3 Hz, 1H), 7.17 (m, 2H), 7.13 (m, 1H), 3.30 (s, 3H), 2.02 (m, 2H), 1.89 (m, 2H), 0.79 (t, J=7.2 Hz, 6H). MS (ESI) m/z 355 ([M+H]+); HRMS: calcd for C20H19FN2O3, 354.1380. found (ESI+), 355.14578.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([NH:14][S:15]([CH2:18][CH:19](O)[CH2:20][CH2:21][CH3:22])(=[O:17])=[O:16])([CH3:13])([CH3:12])[CH3:11].C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>O1CCCC1>[C:10]([NH:14][S:15]([CH2:18][CH:19]([O:8][C:1](=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:20][CH2:21][CH3:22])(=[O:17])=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CCCC(O)CS(=O)(=O)NC(C)(C)C
Reactant: O=C(O)c1ccccc1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: C1CCOC1
Product: CCCC(CS(=O)(=O)NC(C)(C)C)OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 106.7 %

Procedure:
Under nitrogen atmosphere, benzoic acid (92.8 g) was added gradually to a mixture of N,N′-carbonyldiimidazole (123.3 g) and tetrahydrofuran (500 ml) taking 10 minutes at room temperature. After stirring for 1 hour at room temperature, a solution of N-t-butyl-2-hydroxy-1-pentanesulfonamide (84.9 g) in tetrahydrofuran (300 ml) was added dropwise thereto taking 15 minutes. Then, a solution of diazabicycloundecene (57.9 g) in tetrahydrofuran (200 ml) was added dropwise thereto taking 35 minutes and the resulting solution was stirred for 17 hours at room temperature. The reaction mixture was decanted to ice-water, made acidic by adding dilute hydrochloric acid, and extracted with chloroform. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and water, dried over sodium sulfate, and concentrated under reduced pressure to obtain N-t-butyl-2-benzoyloxy-1-pentanesulfonamide (132.8 g) as yellowish brown oil.
Reaction SMILES: P([O-])([O-])([O-])=O.[B+3].[OH:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1.[NH3:19]>>[OH:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]#[N:19])=[CH:10][CH:9]=1.[OH:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:17][CH:18]=1
Reactant: N
Agent: CCOC(=O)c1ccc(O)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [B+3]
Product: N#Cc1ccc(O)cc1
Reaction time: 0 h

Procedure:
A reaction tube having an inside diameter of 5 cm was filled with 293 g of a supported catalyst composed of boron phosphate (P2O5 /B2O3 mole ratio=2) deposited in an amount of 2.51% by weight on the same silica carrier as used in Example 1. Ethyl p-hydroxybenzoate and ammonia were introduced into the reaction tube at a rate of 72.3 g/hr and 148 g/hr, and reacted in the vapor phase at 385° C. The mole ratio of ammonia to ethyl p-hydroxybenzoate in the gaseous mixture was 20:1, and the contact time was 10 seconds. When the reaction was continued for 8 hours, 388.9 g of p-hydroxybenzonitrile was obtained from 578.4 g of ethyl p-hydroxybenzoate. The yield was 93.8% by weight. Gas chromatographic analysis showed that the amount of by-product phenol was only 0.5% by weight.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH:14]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:15]([NH:17][OH:18])=[O:16])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].CO.C1C[O:30]CC1>O>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([CH:14]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:15]([NH:17][OH:18])=[O:16])(=[O:30])=[O:13])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: C1CCOC1
Reactant: CC#CCOc1ccc(S(=O)C(C(=O)NO)C2CCCCC2)cc1
Solvent: CO
Solvent: O
Product: CC#CCOc1ccc(S(=O)(=O)C(C(=O)NO)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 2-{[4-(2-butynyl oxy)phenyl]sulfinyl}-2-cyclohexyl-N-hydroxyacetamide (180 mg, 0.52 mmol) in MeOH/THF at room, wxone (5.0 g, excess) was added in water (20 ml). Reaction mixture was stirred at room temperature for 6 hrs and filtered. Methanol-THF layer was concentrated and extracted with chloroform. The organic layer was washed well with water, dried, filtered and concentrated. The product was purified by silica gel column chromatography by eluting it with 4:1 ethyl acetate; hexane and 2-{[4-(2-butynyl oxy)phenyl]sulfonyl}-2-cyclohexyl-N-hydroxyacetamide was isolated as a white solid. mp: 191° C.; Yield: 45 mg (24%); MS: 366.3 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ 0.95-1.12 (band, 5H), 1.58 (m, 5H), 1.85 (t, J=2.22 Hz, 3H), 2.05 (m, 1H), 3.63 (d, J=9.1 Hz, 1H), 4.87 (d, J=2.34 Hz, 2H), 7.16 (d, J=9 Hz, 2H), 7.76 (d, J=9 Hz, 2H), 9.01 (s, 1H), 10.7 (s, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1.[F:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>C(O)C>[F:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][CH2:2][C:3]2[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:15][CH:14]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=[N+]([O-])c1cccnc1CBr
Solvent: CCO
Product: O=[N+]([O-])c1cccnc1CNc1ccc(F)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 115.2 %

Procedure:
A solution of 2-bromomethyl-3-nitropyridine (2 g, 9.13 mmol) prepared in Step 2 of Preparation 1 and 4-fluoroaniline (0.87 ml, 9.13 mmol) in ethanol (15 ml) was stirred for 2 hours at 40° C. The reaction mixture was concentrated under reduced pressure to give 2.6 g of the titled compound as a brown solid. The product was used in the subsequent step without further purification.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH:14]([C:16]3[CH:17]=[C:18]([Cl:30])[C:19]([C:28]#[N:29])=[C:20]4[C:26]=3[O:25][CH:24]([CH3:27])[CH2:23][NH:22][CH2:21]4)[CH3:15])[N:11]=[C:12]([CH3:13])[C:5]=12.C(N(CC)CC)C.Br.Br[CH2:40][C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1>CN(C)C=O>[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH:14]([C:16]3[CH:17]=[C:18]([Cl:30])[C:19]([C:28]#[N:29])=[C:20]4[C:26]=3[O:25][CH:24]([CH3:27])[CH2:23][N:22]([CH2:40][C:41]3[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=3)[CH2:21]4)[CH3:15])[N:11]=[C:12]([CH3:13])[C:5]=12
Reactant: BrCc1cccnc1
Reactant: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OC(C)CNC3)c2ncnc(N)c12
Agent: Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OC(C)CN(Cc2cccnc2)C3)c2ncnc(N)c12
Temperature: 85 °C

Procedure:
9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile bishydrochloride (0.020 g, 0.05 mmol) was taken up in N,N-dimethylformamide (2.0 mL) and triethylamine (0.034 mL, 0.24 mmol), and the 3-(bromomethyl)pyridine hydrobromide was added. The reaction was heated to 85° C. for 2 h and was allowed to cool. The product was purified by prep HPLC on C-18 column eluting water:acetonitrile gradient buffered pH 10 to give two diastereomers: Peak #1 (Example 59): LCMS calculated for C25H26ClN8O (M+H)+: m/z=489.2; found: 489.2; Peak #2 (Example 60): LCMS calculated for C25H26ClN8O (M+H)+: m/z=489.2; found: 489.2.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:26](O)=[O:27])=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2].[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([C:26]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:20])[O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: Nc1ccccc1
Reactant: CC(=O)Nc1nc(CCc2ccc(NC(=O)OC(C)(C)C)cc2)c(C(=O)O)s1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1nc(CCc2ccc(NC(=O)OC(C)(C)C)cc2)c(C(=O)Nc2ccccc2)s1
Temperature: 55 °C
Reaction time: 3 h

Procedure:
A mixture of 2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,3-thiazole-5-carboxylic acid (80.mg), aniline (0.019 ml), benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (113 mg) and N,N-diisopropylethylamine (0.076 ml) in N,N-dimethylformamide (2 ml) was stirred at ambient temperature for 21 hours and at 55 ° C. for 3 hours. The reaction mixture was poured into 1N hydrochloric acid, and extracted with chloroform. The organic layer was washed with water, saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residual solid was washed with ethyl ether to give tert-butyl 4-{2-[2-(acetylamino)-5-(anilinocarbonyl)-1,3-thiazol-4-yl]ethyl}phenylcarbamate (57.2 mg) as a colorless solid.
Reaction SMILES: [C:1]([O:5][NH:6][C:7]([C:9]1[CH:18]=[C:17]2[C:12]([C:13]([CH3:21])=[CH:14][C:15]([CH3:20])([CH3:19])[NH:16]2)=[CH:11][CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(OCC)(=O)C.C(O)C>[C:1]([O:5][NH:6][C:7]([C:9]1[CH:18]=[C:17]2[C:12]([CH:13]([CH3:21])[CH2:14][C:15]([CH3:20])([CH3:19])[NH:16]2)=[CH:11][CH:10]=1)=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1=CC(C)(C)Nc2cc(C(=O)NOC(C)(C)C)ccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC1CC(C)(C)Nc2cc(C(=O)NOC(C)(C)C)ccc21
Reaction time: 4 h
Yield: 100.3 %

Procedure:
To an oven-dried 100 mL round-bottomed flask containing 7-tert-butyloxycarbamoyl-1,2-dihydro-2,2,4-trimethylquinoline (EXAMPLE 147) (200 mg, 0.69 mmol) in 50 mL 2:1 ethyl acetate/ethanol at rt was added 10% Pd on C (approx 1 mol %), and the mixture was stirred under an atmosphere of H2 for 4 h. The reaction mixture was then filtered, and concentrated under diminished pressure to give 201 mg (quant) of 7-tert-butyloxycarbamoyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline as a white oily solid. Data for (R/S)-7-tert-butyloxycarbamoyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline: 1H NMR (400 MHz, CDCl3) 7.02 (d, J=8.7, 1H, 5-H), 6.73 (br s, 1H, HNBoc), 6.39 (dd, J=8.3, 2.2, 1H, 6-H), 6.29 (br s, 1H, 8-H), 3.62 (br s, 1H, NH), 2.85 (ddq, J=12.5, 12.3, 6.4, 1H, 4-H), 1.70 and 1.39 [d of ABq, JAB=12.8, JA=5.5 Hz (3-Hequiv), JB=12.6 Hz (3-Hax)2H], 1.49 [s, 9H, (CH3)3CO)], 1.29 (d, J=6.7, 3H, 4-CH3), 1.21 (s, 3H, 2-CH3), 1-14 (s, 3H, 2-CH3).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:18]4([NH:21][CH3:22])[CH2:19][CH2:20][CH:15]([CH2:16][CH2:17]4)[CH2:14][N:13]3[C:23](=[O:26])[C:24]=2[OH:25])=[O:9])=[CH:4][CH:3]=1.[O:29]=[C:30]([N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)[C:31]([OH:33])=O.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C1C=CN=CC=1.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:18]4([N:21]([CH3:22])[C:31](=[O:33])[C:30](=[O:29])[N:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[CH2:19][CH2:20][CH:15]([CH2:16][CH2:17]4)[CH2:14][N:13]3[C:23](=[O:26])[C:24]=2[OH:25])=[O:9])=[CH:27][CH:28]=1
Reactant: CNC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Reactant: O=C(O)C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C(=O)C(=O)N1CCCC1)C12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.1 %

Procedure:
To a stirred solution of N-(4-fluorobenzyl)-3-hydroxy-10-(methylamino)-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxamide (50 mg, 0.100 mmol) in (DMF (2 mL) was added 2-oxo-2-(pyrrolidin-1-yl)acetic acid (57.2 mg, 0.400 mmol), diisopropyl-ethylamine (0.105 mL, 0.599 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (152 mg, 0.400 mmol) and 4-(dimethylamino)pyridine (DMAP) (1.221 mg, 9.99 μmol) and the resulting mixture was stirred at room temperature for 3 h. The crude was then purified by preparative HPLC and recrystallized from methanol to afford the title compound as a glassy white crystals (20 mg, 40% yield). 1H NMR (500 MHz, CDCl3) δ: 12.1 (1 H, s), 9.6 (1 H, brs), 7.4-7.4 (2 H, m), 7.0-7.0 (2 H, m), 4.8-4.9 (1 H, m), 4.6-4.7 (1 H, m), 4.4-4.5 (1 H, m), 3.6-3.7 (2 H, m), 3.5 (2 H, t, J=6.71 Hz), 3.3-3.4 (2 H, m), 3.0 (3 H, s), 2.5 (1 H, brs), 1.9-2.1 (9 H, m), 1.7-1.8 (2 H, m). LCMS (M+H)=512.24. HPLC purity: >95%.
Reaction SMILES: [C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])(=[O:3])[CH3:2].C(NC(C)C)(C)C.[Li].[O:17]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:21](=[O:28])[O:20][CH2:19][CH2:18]1.C([O-])(O)=O.[Na+]>C1COCC1>[OH:20][CH2:19][CH2:18][O:17][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:21](=[O:28])[CH2:2][C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3]
Reactant: CC(=O)OC(C)(C)C
Reactant: O=C1OCCOc2ccccc21
Agent: O=C([O-])O
Agent: [Li]
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)c1ccccc1OCCO
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 34.4 %

Procedure:
To a solution of tert-butyl acetate (7.96 g, 68.5 mmol) in anhydrous THF (100 mL) was added freshly prepared lithium diisopropyl amine (37 mL, 1.85 M in THF) dropwise over 15 min at −78° C., and the mixture was stirred at −78° C. for 30 min. 2H-benzo[e][1,4]dioxepin-5(3H)-one (10.2 g, 62.3 mmol) was added dropwise as a solution in THF (50 mL) at −78 C, and stirring was continued for 30 min. Saturated NaHCO3 solution was added and the mixture was extracted with EtOAc. The organic layer was dried (Na2SO4), and concentrated under reduced pressure to give the title compound (6.0 g, 77.9%) as a yellow oil, which was used directly in the next step without further purification.