Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:17]([C:19]1([OH:27])[CH:24]2[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]2)[CH2:20]1)#[CH:18].C(N(CC)CC)C>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:18]#[C:17][C:19]3([OH:27])[CH:24]4[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]4)[CH2:20]3)=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)[CH3:16]
Reactant: CCOc1ccc(-c2ccc(Br)cc2)cc1
Reactant: C#CC1(O)CN2CCC1CC2
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1ccc(-c2ccc(C#CC3(O)CN4CCC3CC4)cc2)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 21.8 %

Procedure:
A stirred mixture of 4-bromo-4'-ethoxybiphenyl (1.1 g), 3-ethynyl-3-hydroxyquinuclidine (600 mg), bis(triphenylphosphine)-palladium (II) chloride (140 mg), copper (I) iodide (70 mg) and dry triethylamine (5.0 ml) in dry dimethylformamide (20 ml) was stirred at 90° C. under an atmosphere of argon for 4 hours. The dimethylformamide and triethylamine were removed by evaporation and the residue was treated with saturated sodium carbomate solution (20 ml). The solid obtained was collected by filtration and crystallised from dimethylformamide to give 3-[2-(4'-ethoxybiphenyl-4-yl)ethynyl]quinuclidin-3-ol (300 mg) as a soild, m.p. 255°-256° C.; microanalysis, found C, 79.1; H, 7.3; N, 3.9; C23H25NO2 requires C, 79.5; H, 7.3; N, 4.03%; NMR (DMSO-d6): 1.2-1.4(3H, t), 1.52-1.71(1H, m), 1.8-2.0(3H, m), 2.6-2.98(5H, m), 3.05-3.2(1H, m), 4.0-4.16(2H, q), 5.51-5.62(1H, br), 6.95-7.05(2H, d), 7.4-7.5(2H, d) and 7.57-7.68(4H, m); m/z 348 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Br:12]Br>C(O)(=O)C>[Br:12][C:7]1[CH:6]=[CH:5][C:4]([OH:8])=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[CH3:1]
Reactant: BrBr
Reactant: Cc1cccc(O)c1[N+](=O)[O-]
Solvent: CC(=O)O
Product: Cc1c(Br)ccc(O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 3-methyl-2-nitrophenol (2.0 g, 13.06 mmol) in acetic acid (40 mL) was added bromine (0.70 mL, 13.71 mmol) and the mixture was stirred at RT for 5 h. The reaction was poured in to ice water and the yellow precipitate formed was filtered and washed with water and dried in vacuo to yield 4-bromo-3-methyl-2-nitrophenol. 1H NMR (400 MHz, CDCl3) δ=2.61 (s, 3H), 2.62 (s, 5H), 6.92 (d, J=8.84 Hz, 1H), 7.66 (d, J=9.09 Hz, 1H) and 9.28 (s, 1H); MS (ES+): m/z 215.00 [M-17].
Reaction SMILES: [C-:1]#[N:2].[K+].[CH:4]1[CH:9]=[C:8]2[CH:10](O)[C:11]3[C:16]([O:17][C:7]2=[CH:6][CH:5]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3.O>C(O)(=O)C>[C:1]([CH:10]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=2[O:17][C:7]2[C:8]1=[CH:9][CH:4]=[CH:5][CH:6]=2)#[N:2]
Reactant: OC1c2ccccc2Oc2ccccc21
Reactant: [C-]#N
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: N#CC1c2ccccc2Oc2ccccc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
17.5 g (0.268 mol) of potassium cyanide are added in portions to a solution, heated at 50° C., of 24.2g (0.122 mol) of xanthydrol in 420 ml of acetic acid. The reaction mixture is subsequently stirred at 60° C. for 2 hours and then cooled, poured onto 400 ml of water and extracted with ethyl acetate/hexane=1:1. The organic phases are washed with water, combined, dried over sodium sulfate and concentrated on a vacuum rotary evaporator. Chromatography of the residue over silica gel using the mobile phase system hexane/ethyl acetate=19:1 and crystallization of the pure fractions from ether/petroleum ether gives 20.2 g (80%) of 9-cyano-xanthene, melting point 101° C. (compound (102), Table 1). The compounds (111), (112), (113), (114), (115), (116) and (117) are prepared analogously to Example 2 from the corresponding substituted xanthydrols and thioxanthydrols, such as, for example, 4-cyclohexyl-xanthydrol, 2-tert-butyl-xanthydrol, 2-nonyl-xanthydrol, 2-(α,α-dimethylbenzyl)-4-methyl-xanthydrol, 2-n-propoxy-xanthydrol, 2,4-diethylthioxanthydrol or 2-dodecyl-thioxanthydrol.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][CH:9]([C:16]([C:18]2[CH:22]=[CH:21][O:20][CH:19]=2)=[O:17])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]2[O:17][C:16]([C:18]3[CH:22]=[CH:21][O:20][CH:19]=3)=[C:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(NC(=O)c1ccc(Cl)cc1)C(=O)c1ccoc1
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)Cc1nc(-c2ccc(Cl)cc2)oc1-c1ccoc1
Yield: 86 %

Procedure:
8.5 g of ethyl 3-(4-chlorobenzoylamino)-3-(3-furylcarbonyl)propionate, 50 ml of chloroform and 18.6 g of phosphorus oxychloride are treated in the same manner as described in Example 1. 6.93 g of ethyl 2-[2-(4-chlorophenyl)-5-(3-furyl)-4-oxazolyl]acetate are thereby obtained. Yield: 85.5%
Reaction SMILES: C1(NC(C)C)CCCCC1.C([Li])CCC.[I:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20].Cl.[C:27]([O:30][CH2:31][CH3:32])(=[O:29])[CH3:28]>O1CCCC1.CCCCCC>[I:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([CH2:28][C:27]([O:30][CH2:31][CH3:32])=[O:29])=[O:20]
Reactant: O=C(Cl)c1ccccc1I
Reactant: CCOC(C)=O
Agent: CC(C)NC1CCCCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1ccccc1I
Temperature: -78 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
Cyclohexyl isopropylamine (10.6 grams) is dissolved in 80 ml of tetrahydrofuran and the solution is cooled to -78° C. In a nitrogen stream, a solution of n-butyl lithium (about 15%) in hexane solution (26 ml) is added thereto, and the mixture temperature is raised to -40° C. Then it is cooled to -78° C. once again, 3.3 grams of ethyl acetate is gradually added thereto and, ten minutes thereafter, a solution of 10 grams of o-iodobenzoyl chloride in tetrahydrofuran is dropped thereinto gradually. The mixture is stirred at -78° C. for one hour, then gradually warmed up to 0° C. within two to three hours, 20 ml of 20% hydrochloric acid solution is added thereto, the mixture is poured into ice water, and extracted with ether. The extract is washed with a saturated aqueous solution of sodium bicarbonate, dried with anhydrous magnesium sulfate, ether is evaporated therefrom, and the resulting oil is purified by distilling in vacuo to give 8.5 grams of pale yellow oil, b.p. 142° C./3 mmHg.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:33]1([CH2:39][CH2:40][S:41][CH:42]([C:46](O)=[O:47])[C:43](O)=[O:44])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[OH:47][C:46]1[CH:16]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:14][CH:13]=2)[O:17][C:43](=[O:44])[C:42]=1[S:41][CH2:40][CH2:39][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccc(OCc3ccccc3)cc2)cc(O)c1SCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 4'-benzyloxyacetophenone (1.14 g, 5.06 mmol), lithium bis(trimethylsilyl)amide (0.930 g, 5.56 mmol), chlorotrimethylsilane (0.705 mL, 5.56 mmol), THF (57 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 139°-142° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.77 (t, 2 H), 2.98 (t, 2 H), 5.19 (s, 2 H), 6.68 (s, 1 H), 7.26 (m, 7 H), 7.43 (m, 5 H), 7.76 (d, 2 H).
Reaction SMILES: Cl[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[CH:4]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:3]1.[CH3:19][C:20]1([CH3:26])[CH2:25][NH:24][CH2:23][CH2:22][NH:21]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5]([C@H:4]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH2:3][C@H:2]2[N:24]2[CH2:23][CH2:22][NH:21][C:20]([CH3:26])([CH3:19])[CH2:25]2)=[CH:6][CH:7]=1
Reactant: CC1(C)CNCCN1
Reactant: Fc1ccc(C2CC(Cl)c3cc(Cl)ccc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C)CN([C@@H]2C[C@@H](c3ccc(F)cc3)c3ccc(Cl)cc32)CCN1
Yield: 75.2 %

Procedure:
A mixture of 1,6-dichloro-3-(4-fluorophenyl)-2,3-dihydro-1H-indene (28 g, 0.1 mol), 2,2-dimethylpiperazine (15 g, 0.13 mol) and potassium carbonate (30 g) in acetone (250 mL) was refluxed for 18 h. The reaction mixture was evaporated in vacuo and treated with water and ether. The ether phase was separated and extracted with 1M methane sulfonic acid. The base was liberated with 10M sodium hydroxide, extracted with ether and dried (MgSO4). After filtration and evaporation in vacuo the residue was dissolved in acetone and treated with fumaric acid. The fumarate salt was filtered to give 27 g of 1 as the hemifumarate salt, mp 240°-241° C. A sample recrystallized from ethanol had mp 242°-244° C. Isomeric purity (TLC): 95% trans isomer (racemate).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH:32]([OH:35])([CH3:34])[CH3:33]>>[CH:32]([O:35][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1)([CH3:34])[CH3:33]
Reactant: CC(C)O
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(Nc2nc(NC3CCCCCC3)nc(OC(C)C)n2)cc1Cl

Procedure:
To a portion of 6-chloro-N-(3-chloro-4-methoxyphenyl)-N′-cycloheptyl-[1,3,5]triazine-2,4-diamine (5 g) in isopropanol was added K2CO3 (3.2 g) and refluxed for about 10-12 h. TLC was monitored. After the completion of the reaction, the reaction mass was filtered through vacuum and the filtrate was evaporated to yield the title compound. (Wt. 3.7 g Y: 70%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:9](=[O:10])[N:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][C:13]=2[CH3:22])[C:7]2[CH:23]=[CH:24][C:25]([C:27]#[N:28])=[CH:26][C:6]=2[N:5]([C:29](=[O:35])[CH2:30][S:31]([CH3:34])(=[O:33])=[O:32])[C@H:4]1[CH3:36].[C:37]([O:41][C:42]([N:44]([CH2:50][CH3:51])[C@@H:45]([CH3:49])[C:46](O)=[O:47])=[O:43])([CH3:40])([CH3:39])[CH3:38].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:27]([C:25]1[CH:24]=[CH:23][C:7]2[N:8]([CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][C:13]=3[CH3:22])[C:9](=[O:10])[C@@H:3]([NH:2][C:46](=[O:47])[C@@H:45]([N:44]([CH2:50][CH3:51])[C:42](=[O:43])[O:41][C:37]([CH3:38])([CH3:40])[CH3:39])[CH3:49])[C@H:4]([CH3:36])[N:5]([C:29](=[O:35])[CH2:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:6]=2[CH:26]=1)#[N:28]
Reactant: Cc1ccc2ccccc2c1CN1C(=O)[C@@H](N)[C@H](C)N(C(=O)CS(C)(=O)=O)c2cc(C#N)ccc21
Reactant: CCN(C(=O)OC(C)(C)C)[C@@H](C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(C(=O)OC(C)(C)C)[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2c(C)ccc3ccccc23)c2ccc(C#N)cc2N(C(=O)CS(C)(=O)=O)[C@H]1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.1 %

Procedure:
To a rt solution of (3S,4S)-3-amino-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile hydrochloride (100 mg, 190 μmol) in DMF (632 μl) was added (S)-2-(tert-butoxycarbonyl(ethyl)amino)propanoic acid (45.3 mg, 209 μmol), N,N-diisopropylethylamine (131 μl, 759 μmol), and HBTU (79.2 mg, 209 μmol). The reaction was stirred at rt for 30 min, then purified by reverse phase preparative HPLC to provide tert-butyl(S)-1-((3S,4S)-7-cyano-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(ethyl)carbamate (105 mg, 80%) as a white solid. MS m/z 712 (MNa)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH2:12][CH2:13][OH:14])[C:5]#[N:6].[N:15]([O-])=O.[Na+]>Cl.O>[OH:14][CH2:13][CH2:12][CH2:11][N:10]1[C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[N:1]=[N:15]1
Reactant: O=N[O-]
Reactant: N#Cc1ccc(NCCCO)c(N)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc2c(c1)nnn2CCCO
Yield: 98.9 %

Procedure:
100 mg (0.52 mmol) of 3-amino-4-[(3-hydroxypropyl)amino]benzonitrile (Intermediate 12) are suspended in 0.5 ml of 5N aqueous HCl. After cooling externally with an ice/water bath, a solution of 54.12 mg (0.78 mmol) of sodium nitrite in 0.4 ml water is added dropwise with stirring. After 3.5 hr excess water is added and the solid is extracted with dichloromethane, washed with water, dried and concentrated to give 104 mg of pure title compound (96% yield).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:21]2[C:20](=[O:22])[NH:19][C:18](=[O:23])[N:17]([CH3:24])[C:16]=2[N:15]=[CH:14]1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].Cl[CH2:26][CH2:27][CH2:28][CH2:29][P:30]([O:35][CH2:36][CH3:37])(=[O:34])[O:31][CH2:32][CH3:33].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:7]([O:6][P:4]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:21]2[C:20](=[O:22])[N:19]([CH2:26][CH2:27][CH2:28][CH2:29][P:30](=[O:34])([O:35][CH2:36][CH3:37])[O:31][CH2:32][CH3:33])[C:18](=[O:23])[N:17]([CH3:24])[C:16]=2[N:15]=[CH:14]1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(CCCCn1cnc2c1c(=O)[nH]c(=O)n2C)OCC
Reactant: CCOP(=O)(CCCCCl)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOP(=O)(CCCCn1c(=O)c2c(ncn2CCCCP(=O)(OCC)OCC)n(C)c1=O)OCC
Temperature: 70 °C

Procedure:
8 g (0.022 mol) of 7-(4-diethylphosphonobutyl)-3-methylxanthine (according to Example 24) were suspended in 100 ml of DMF, treated with 6.13 g (0.027 mol) of diethyl 4-chlorobutanephosphonate and 3.7 g (0.028 mol) of activated potassium carbonate and heated at 70° C. for 4 hours. The product was then filtered, the filtrate was concentrated under reduced pressure and the oily residue which remained was chromatographed on a silica gel column (eluent: ethyl acetate/methanol 10:1).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[N:11]2[N:12]=[C:13]([CH3:16])[C:14](I)=[C:10]2[N:9]=[C:8]([CH3:17])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[Cl:18][C:19]1[S:20][CH:21]=[C:22]([Cl:24])[N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.CC1OCCC1>CC(N(C)C)=O>[CH2:1]([CH:3]([C:6]1[N:11]2[N:12]=[C:13]([CH3:16])[C:14]([C:21]3[S:20][C:19]([Cl:18])=[N:23][C:22]=3[Cl:24])=[C:10]2[N:9]=[C:8]([CH3:17])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)c1cc(C)nc2c(I)c(C)nn12
Reactant: Clc1csc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CC(=O)N(C)C
Solvent: CC1CCCO1
Product: CCC(CC)c1cc(C)nc2c(-c3sc(Cl)nc3Cl)c(C)nn12
Temperature: 70 °C
Yield: 87.3 %

Procedure:
7-(1-ethyl-propyl)-3-iodo-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (10 g, 29.17 mmoles), 2,4-dichlorothiazole (5.2 g, 33.76 mmoles), cesium carbonate (19.9 g, 61.07 mmoles) and 1,10-phenanthroline (1 g, 5.5 mmoles) are charged into a 250 mL 3-necked round bottomed flask, followed by 2-MeTHF (36 mL, 3.6 volumes). The reaction mixture is degassed with nitrogen and then evacuated. Cuprous chloride (0.57 g, 5.7 mmoles), DMAC (10 mL, 1 volume) and 2-MeTHF (4 mL, 0.4 volumes) are added in succession. The reaction mixture is degassed with nitrogen and then evacuated. The contents are refluxed for 20 hr. The reaction mixture is cooled to ˜70° C. and 2-MeTHF (100 mL, 10 volumes) is added. The contents are filtered at ˜70° C. and the residual cake is washed with 2-MeTHF (80 mL, 8 volumes) at about 65-72° C. The filtrate is transferred into a separatory funnel and extracted with water. The organic layer is separated and washed with dilute HCl. The resulting organic layer is treated with Darco G60, filtered hot (60° C.). The filtrate is concentrated at atmospheric pressure to ˜2.8 volumes. 25 mL 2-propanol is added, followed by re-concentration to ˜2.8 volumes. An additional 25 mL 2-propanol is added, followed again by re-concentration to ˜2.8 volumes. Finally, 48 mL 2-propanol is added. The contents are cooled to −7° C., maintained at −7° C. for 1 hr., filtered and rinsed with 20 mL chilled 2-propanol. Product is suction dried and then vacuum dried at 60° C. to afford 9.41 g 7-(1-ethyl-propyl)-3-(2,4-dichloro-thiazol-5-yl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (purity of product by HPLC assay is 95.88%). MS (ES)=369 (M+1).
Reaction SMILES: [C:1]([CH2:8][N:9]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16][N:15]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:14][CH2:13][N:12]([CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-])=O)=[CH:33][CH:32]=2)[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCOCC>C(O)C.[Pd]>[C:1]([CH2:8][N:9]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16][N:15]([CH2:21][C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:14][CH2:13][N:12]([CH2:29][CH2:30][C:31]2[CH:32]=[CH:33][C:34]([NH2:37])=[CH:35][CH:36]=2)[CH2:11][CH2:10]1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)CN1CCNCCN(CC(=O)OC(C)(C)C)CCN(CCc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CCOCC
Solvent: CCO
Product: CC(C)(C)OC(=O)CN1CCNCCN(CC(=O)OC(C)(C)C)CCN(CCc2ccc(N)cc2)CC1
Yield: 97.8 %

Procedure:
To a solution of compound (25) (1.35 g, 2.46 mmol) in absolute ethanol (100 ml) was added 10% Pd/C (0.41 g). The resultant mixture was stirred at an ambient temperature in the presence of H2 (g) for 12 hours. The reaction mixture was filtered through a celite pad and washed with ethanol (2×20 ml). The filtrate was evaporated in vacuo to give an oily residue, which was then treated with Et2O to obtain a white solid of compound (26) (1.25 g, 98% yield).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH:15]([F:17])[F:16])C=O)[CH2:3][CH2:2]1.[BH4-].[Na+].[OH-:20].[Na+]>C(O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([OH:20])[CH:11]=[CH:12][C:13]=2[O:14][CH:15]([F:17])[F:16])[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: [OH-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Oc1ccc(OC(F)F)c(OCC2CC2)c1

Procedure:
Crude 3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde (26.4 g) in absolute ethanol (200 mL) was treated with sodium borohydride (8.23 g, 217 mmol) under an argon atmosphere at room temperature for 0.33 h. Ten percent aqueous sodium hydroxide (150 mL) was added, the ethanol was removed in vacuo and the aqueous residue was extracted three times with ether. The organic extract was washed twice with brine, was dried (sodium sulfate), was filtered and was evaporated to a pale yellow oil (24.4 g).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[CH:10][N:9]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[F:27])[CH2:16][CH2:15]3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33]([NH:35][NH2:36])=[O:34]>CN1C(=O)CCC1>[NH2:8][C:6]1[N:7]=[C:2]([NH:36][NH:35][C:33]([C:29]2[O:28][CH:32]=[CH:31][CH:30]=2)=[O:34])[C:3]2[CH:11]=[CH:10][N:9]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[F:27])[CH2:16][CH2:15]3)[C:4]=2[N:5]=1
Reactant: NNC(=O)c1ccco1
Reactant: Nc1nc(Cl)c2ccn(CCN3CCN(c4ccc(F)cc4F)CC3)c2n1
Solvent: CN1CCCC1=O
Product: Nc1nc(NNC(=O)c2ccco2)c2ccn(CCN3CCN(c4ccc(F)cc4F)CC3)c2n1
Temperature: 25 °C

Procedure:
A solution of the title A compound, 4-chloro-7-(2-(4-(2,4-difluorophenyl)piperazin-1-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (75 mg, 0.19 mmol) and 2-furoic acid hydrazide (49 mg, 0.39 mmol) in 1 mL of NMP is heated at 150° C. for 3 h. After cooling to RT, the crude reaction is purified by column chromatography on silica gel, eluting with a gradient of 5% to 10% of MeOH in EtOAc. Fractions containing the product are combined and evaporated to dryness to 4-yl)furan-2-carbohydrazide as a yellow solid: LC/MS (M+1=483.2).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[H-].[Na+].Br[CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1>CN(C=O)C.O>[Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]([CH2:18][CH2:19][O:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:25][CH:26]=3)[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)c1cc2c(Cl)nccc2[nH]1
Reactant: FC(F)(F)Oc1ccc(OCCBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(Cl)nccc2n1CCOc1ccc(OC(F)(F)F)cc1
Temperature: 60 °C
Yield: 71.4 %

Procedure:
To a solution of Methyl 4-chloro-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (350 mg, 1.662 mmole) in DMF (6 mL) was added NaH (60% dispersion in mineral oil, 86 mg, 2.160 mmole) portionwise at RT. After gas evolution had ceased a solution of 1-(2-bromoethoxy)-4-(trifluoromethoxy)benzene (616 mg, 2.160 mmole) in DMF (1 mL) was added. After the addition was complete the mixture was heated to 60° C. After 4 hr the mixture was cooled to RT. The mixture was diluted with water and extracted with EtOAc (3×). The combined organic layers were washed with H2O and brine, dried (MgSO4), filtered, and concentrated. Flash column (Biotage-SNAP-25 g SiO2, 30% EtOAc/hexanes) gave the title compound (492 mg, 71%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.21 (d, J=6.0 Hz, 1 H); 7.45 (s, 1 H); 7.42 (d, J=6.0 Hz, 1 H); 7.07 (d, J=8.6 Hz, 2 H); 6.76-6.70 (m, 2 H); 4.93 (t, J=5.13 Hz, 2 H); 4.34 (t, J=5.0 Hz, 3 H); 3.95 (s, 3 H).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[N:9]2[C:10]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[C:24]([Br:32])[C:11]=3[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=3)=[N:13][CH2:14][C:8]2=[N:7][N:6]=1.[CH3:34][NH2:35]>>[CH3:34][NH:35][C:3](=[O:2])[CH2:4][C:5]1[N:9]2[C:10]3[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[C:24]([Br:32])[C:11]=3[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=3)=[N:13][CH2:14][C:8]2=[N:7][N:6]=1
Reactant: COC(=O)Cc1nnc2n1-c1ccc(C(F)(F)F)c(Br)c1C(c1cccc([N+](=O)[O-])c1)=NC2
Reactant: CN
Product: CNC(=O)Cc1nnc2n1-c1ccc(C(F)(F)F)c(Br)c1C(c1cccc([N+](=O)[O-])c1)=NC2

Procedure:
In the manner given in Preparation 3, 7-bromo-8-trifluoromethyl-6-(m-nitrophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine-1-acetic acid methyl ester is reacted with methylamine in diemethylformamide to give N-methyl-7-bromo-8-trifluoromethyl-6-(m-nitrophenyl)-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine-1-acetamide.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[O:7][CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=1)(=[O:4])=[O:3].[C:16](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[CH3:16][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[C:6]1[O:7][CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1coc(NS(C)(=O)=O)n1
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CCOC(=O)c1coc(N(C)S(C)(=O)=O)n1
Reaction time: 3 h

Procedure:
To a 25 ml round bottom flask under N2 was added (101.8mg, 0.4346 mmoles) ethyl 2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxylate, (180.2 mg, 1.3038 mmoles, 3.0 eq.) potassium carbonate, and (5 ml) acetonitrile. The mixture was then agitated at ambient temperature while (33.8 μl, 0.5429 mmoles, 1.25 eq.) iodomethane was added. The reaction was allowed to run at ambient temperature for 3 hours. An electrospray mass spec indicated mostly starting material. The N2 line was removed and an additional (40 μl, 0.6425 mmoles, 1.5 eq.) iodomethane were added. The reaction was left at ambient temperature overnight. The reaction was quenched with (5 ml) 1N HCl and was extracted with dichloromethane. The organic layer was washed with water and then evaporated to dryness. The resulting oil was purified by preparative HPLC, yielding (70 mg) of ethyl 2-[methyl(methylsulfonyl)amino]-1,3-oxazole-4-carboxylate.