Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].[C-]#N.[K+].C[CH2:28][N:29](C(C)C)C(C)C.CS(Cl)(=O)=O>O.C(OCC)C>[C:28]([C:2]1[CH2:3][CH:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][CH2:6][CH:7]=1)#[N:29]
Reactant: CC(C)(C)OC(=O)C1CCCC(=O)C1
Reactant: CCN(C(C)C)C(C)C
Agent: CS(=O)(=O)Cl
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [C-]#N
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)C1CCC=C(C#N)C1
Temperature: 25 °C

Procedure:
tert-Butyl 3-oxocyclohexanecarboxylate (1.35 g, 6.81 mmol) was taken up in water (11.4 mL) and stirred at ambient temperature. Sodium metabisulfite (0.75 g, 3.9 mmol) was added and the mixture was allowed to stir for 40 minutes. Diethyl ether (11.4 mL) was added, followed by potassium cyanide (0.70 g, 11 mmol). The resulting mixture was allowed to stir vigorously for 1 hour before it was partitioned between diethyl ether and water. The organic layer was washed with water, brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue, used without further purification, was dissolved in DCM (22.0 mL). DIPEA (1.07 g, 8.26 mmol) was added and the resulting mixture was cooled to 0° C. Methanesulfonyl chloride (0.69 g, 6.1 mmol) was added dropwise and the resulting mixture was maintained at 0° C. for 20 minutes then allowed to warm to ambient temperature. The mixture was partitioned between DCM and water. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue, used without further purification, was dissolved in pyridine (13.6 mL) and heated to 95° C. for 20 hours. The mixture was then allowed to cool to ambient temperature and was concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-45% EtOAc/hexanes). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:7]2[CH:8]=[C:9]([C:12]3[N:16]([CH3:17])[C:15]([C:18]#[N:19])=[CH:14][C:13]=3[CH3:20])[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:21])[O:3]1.[Br:23]N1C(=O)CCC1=O.N1C=CC=CC=1.O>C1COCC1>[CH3:1][C:2]1([CH3:22])[C:7]2[CH:8]=[C:9]([C:12]3[N:16]([CH3:17])[C:15]([C:18]#[N:19])=[C:14]([Br:23])[C:13]=3[CH3:20])[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:21])[O:3]1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C#N)n(C)c1-c1ccc2c(c1)C(C)(C)OC(=O)N2
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: Cc1c(Br)c(C#N)n(C)c1-c1ccc2c(c1)C(C)(C)OC(=O)N2
Reaction time: 16 h

Procedure:
To a solution of 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1,4-dimethyl-1H-pyrrole-2-carbonitrile (1 eq, 0.15 g, 0.51 mmol) in THF (5 mL) at −78° C. was added N-bromosuccinimide (1.1 eq, 0.1 g, 0.56 mmol). The solution was allowed to warm and stir for 16 hours. Pyridine (1 mL) was added and the mixture was poured into water (15 mL), the layers were separated, the aqueous layer was extracted with ethyl acetate (3×10 mL) and the combined organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The product, 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-3-bromo-1,4-dimethyl-1H-pyrrole-2-carbonitrile was obtained by crystallization from 20% ethyl acetate/hexane as a white crystalline solid. 1H NMR (300 MHz, d6-DMSO) δ 1.64 (s, 6H), 1.93 (s, 3H), 3.57 (s, 3H), 7.01 (d, 1H, J=8 Hz), 7.31 (dd, 1H, J=1.95, 8 Hz), 7.35 (s, 1 H), 10.43 (s, 1H). MS m/z (ESI (−)) 372/374 (M−H)−. Anal. calcd for C17H16N3O2, C, 54.6,H, 4.31, N, 11.2. Found, C, 54.8, H, 4.42, N, 11.1.
Reaction SMILES: [CH2:1]([C:8]1[S:9][C:10]2[CH:16]=[C:15](C3C=C(C4CCNCC4)N4C=3C(N)=NC=N4)[CH:14]=[CH:13][C:11]=2[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:33]C1C=CC2SC(SC)=NC=2C=1.[Br-].C([Zn+])C1C=CC=CC=1>>[CH2:1]([C:8]1[S:9][C:10]2[CH:16]=[CH:15][C:14]([Br:33])=[CH:13][C:11]=2[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4nc(Cc5ccccc5)sc4c3)c12
Reactant: CSc1nc2cc(Br)ccc2s1
Agent: [Br-]
Agent: [Zn+]Cc1ccccc1
Product: Brc1ccc2sc(Cc3ccccc3)nc2c1
Yield: 48 %

Procedure:
In a manner similar to the procedure described for Step 2 of the preparation of 5-(2-benzyl-1,3-benzothiazol-6-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine and using 5-bromo-2-(methylthio)-1,3-benzothiazole and benzylzinc bromide as starting material, 1.30 g (48%) of the desired product was isolated. 1H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.99 (d, 1H), 7.56 (d, 1H), 7.40-7.18 (m, 5H), 4.44 (s, 2H); LC-MS m/z [M+H]+304.3 & 306.3, RT 5.16 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20](F)=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O[K])(C)(C)C.[OH:31][CH2:32][CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][C:36]1=[O:40]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:31][CH2:32][CH2:33][CH2:34][N:35]4[CH2:39][CH2:38][CH2:37][C:36]4=[O:40])=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(F)ccc23)CC1
Reactant: O=C1CCCN1CCCO
Agent: CC(C)(C)O[K]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OCCCN4CCCC4=O)ccc23)CC1
Temperature: 85 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 4-(7-fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester 66.9 mg, 0.20 mmol), as prepared in Example 65b, and tert-BuOK (33.4 mg, 0.30 mmol) was added 1-(3-hydroxypropyl)-2-pyrrolidone (34.7 mg, 0.24 mmol) in anhydrous THF (3 mL). The mixture was stirred at 85° C. for 15 min and the solvent was evaporated under reduced pressure to give a light brown residue, which is used for the next step reaction without purification. 1H NMR (300 MHz, CDCl3) δ 9.10 (s, 1H), 8.03 (d, J=9.13 Hz, 1H), 7.26 (m, 1H), 7.23 (dd, J=9.05 and 2.43 Hz, 1H), 4.14 (t, J=6.08 Hz, 2H), 3.58 (m, 1H), 3.50 (t, J=6.60 Hz, 4H), 3.42 (t, J=6.98 Hz, 4H), 2.37 (t, J=8.45 Hz, 2H), 1.80-2.15 (m, 8H), 1.46 (s, 9H). LC-MS (ESI) calcd for C25H35N4O4 (MH+) 455.3, found 455.2.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8](Cl)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:11]1([CH2:17][C@H:18]2[CH2:22][O:21][C:20](=[O:23])[NH:19]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH:1]1([CH2:6][CH2:7][C:8]([N:19]2[C@@H:18]([CH2:17][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:22][O:21][C:20]2=[O:23])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)CCC1CCCC1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Product: O=C(CCC1CCCC1)N1C(=O)OC[C@@H]1Cc1ccccc1
Yield: 96.6 %

Procedure:
Following the procedure described in Example 45, 6.4 g of cyclopentane propionyl chloride and 7.1 g of (S)-4-phenylmethyl-2-oxazolidinone yielded 11.6 g of (S)-3-[3-cyclopentyl-1-oxopropyl]-4-(phenylmethyl)-2-oxazolidinone. [α]D25 =+99.61°
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[OH:9]O>C(O)(=O)C>[NH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N+:6]=1[O-:9]
Reactant: OO
Reactant: Nc1ccc(Cl)cn1
Solvent: CC(=O)O
Product: Nc1ccc(Cl)c[n+]1[O-]

Procedure:
To a solution of 5-chloropyridin-2-amine (0.500 g, 3.90 mmol) in acetic acid (2.0 mL) was added 50% hydrogen peroxide (2.0 mL). The reaction mass was refluxed for 24 h. The excess of solvent was removed under vacuum to afford 0.450 g of the desired product. 1HNMR (DMSO-d6): δ 6.79 (d, J=8.7 Hz, 1H), 6.93 (s, 2H), 7.21 (d, J=8.7 Hz, 1H), 8.25 (s, 1H); MS [M+H]+: 145.23.
Reaction SMILES: [C:1](Cl)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[CH3:21])#[N:12].[OH-].[Na+].C(Cl)(Cl)Cl>CC(C)=O>[C:11]([N:13]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[CH3:21])[C:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([N:13]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[CH3:21])[C:11]#[N:12])=[O:7])#[N:12]
Reactant: Cc1ccc(NC#N)c(C)c1
Reactant: O=C(Cl)CCCCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: Cc1ccc(N(C#N)C(=O)CCCCC(=O)N(C#N)c2ccc(C)cc2C)c(C)c1

Procedure:
A solution of 10.07 g (0.055 mol) of adipyl chloride in 30 ml of acetone is added dropwise to 14.6 g (0.1 mol) of N-cyano-2,4-dimethylaniline in 60 ml of 2N NaOH (0.12 mol) at 10°-26° C. in the course of 40 minutes, while cooling and stirring rapidly, and the reaction mixture is then stirred for another 2 hours and 15 minutes at 15°-25° C. 50 ml of chloroform are then added, the mixture is stirred for 10 minutes, the two phases are separated, the organic phase is dried with anhydrous sodium sulfate, the suspension is filtered with suction and the filtrate is concentrated on a rotary evaporator at 40° C. in vacuo. The residue is recrystallised from 113 ml of ethyl acetate to give 18.7 g (93.0% of theory) of a colourless, crystalline compound with a melting point of 120°-122.2° C.
Reaction SMILES: CC(C)([O-])C.[K+].[N:7]1([CH2:12][C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=O)[CH:11]=[CH:10][N:9]=[CH:8]1.[Br-].[CH3:21][O:22][C:23]([C:25]1[CH:26]=[C:27]([CH:48]=[C:49]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:50]=1)[CH2:28][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:24].C1OCCOCCOCCOCCOCCOC1.[Cl-].[NH4+]>ClCCl>[S:16]1[CH:17]=[CH:18][N:19]=[C:15]1[C:13]([CH2:12][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1)=[CH:28][C:27]1[CH:26]=[C:25]([CH:50]=[C:49]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:48]=1)[C:23]([O:22][CH3:21])=[O:24]
Reactant: O=C(Cn1ccnc1)c1nccs1
Reactant: COC(=O)c1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc(-c2ccccc2)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Solvent: ClCCl
Product: COC(=O)c1cc(C=C(Cn2ccnc2)c2nccs2)cc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
Potassium tert-butoxide (1.05 g; 9.39 mmnol) was added to mixture of thiazol-2-yl imidazol-1-ylmethyl ketone (1.20 g; 6.25 mmol), 3-methoxycarbonyl-5-phenylbenzyl triphenyl phosphonium bromide (5.3 g; 9.39 mmol) and 18-crown-6 (0.08 g; 0.24 mmol) in dichloromethane (20 ml), at −60° C. under an argon atmosphere. After stirring overnight, at room temperature, the resulting mixture was treated with a saturated aqueous solution of ammonium chloride purified by flash chromatography eluting with dichloromethane/ethanol (95/5) to give methyl 3-[2-(thiazol-2-yl)-3-(imidazol-1-yl)prop-1-en-1-yl]-5-phenylbenzoate (Z isomer). Yield=39%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=O)[CH2:9][N:10]1[CH2:15][CH:14]=[C:13]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[CH2:12][CH2:11]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:25][C:21]1[CH:20]=[C:19]2[C:24]([C:16]([C:13]3[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][NH:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:11][CH:12]=3)=[CH:17][NH:18]2)=[CH:23][CH:22]=1
Reactant: O=C(CN1CC=C(c2c[nH]c3cc(Cl)ccc23)CC1)Nc1ccccn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Clc1ccc2c(C3=CCN(CCNc4ccccn4)CC3)c[nH]c2c1
Temperature: 25 °C
Yield: 38.5 %

Procedure:
A solution of 0.83 gm (2.28 mMol) N-(2-pyridinyl)-2-(4-(6-chloro-1H-indol-3-yl)-1,2,3,6-tetrahydropyridin-1-yl)acetamide in 20 mL tetrahydrofuran was added dropwise to a slurry of 0.130 gm (3.41 mMol) lithium aluminum hydride in 10 mL tetrahydrofuran at 0° C. at such a rate as to maintain the reaction temperature >5° C. The reaction mixture was then allowed to warm to room temperature over 2 hours. The reaction mixture was then quenched by the sequential addition of water, 15% aqueous sodium hydroxide, and water with vigorous stirring. The resulting slurry was filtered through a bed of celite and the filtrate concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with a chloroform gradient containing 5-8% methanol. Fractions containing product were combined and concentrated under reduced pressure to provide 0.31 gm (39%) of the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH:4]=1.[Li]CCCC.[CH3:17][N:18]1[CH:22]2[CH2:23][C:24]([CH2:26][CH:19]1[CH2:20][CH2:21]2)=O>C(OCC)C>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]2[S:7][C:8]([C:24]3[CH2:23][CH:22]4[N:18]([CH3:17])[CH:19]([CH2:20][CH2:21]4)[CH:26]=3)=[CH:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2sccc2c1
Reactant: CN1C2CCC1CC(=O)C2
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1ccc2sc(C3=CC4CCC(C3)N4C)cc2c1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
5-Methoxy-benzo[b]thiophene (3.20 g, 19.5 mmol) was solved in diethylether (50 ml). n-BuLi (8.58 ml, 21.45 mmol) was added to the mixture at a temperature below 20° C. The cooling was removed and the mixture was allowed to stir for 30 minutes. The mixture was cooled to −70° C. Tropinone (2.71 g, 19.5 mmol) solved in diethylether (50 ml) was added during 20 minutes. The temperature was kept below −60° C. Precipitation occurred. The mixture was stirred for 2 hours. Aqueous sodium hydroxide (20 ml, 1 M) was added. The mixture was stirred for 10 minutes. The solid intermediate product (endo/exo-3-(5-methoxy-benzo-[b]thiophen-2-yl)-8-methyl-8-aza-bicyclo[3.2.1]octan-3-ol) was filtered and washed with water and diethylether. Yield 3.97 g (67%). The intermediate product was combined with acetic acid (20 ml) and hydrochloric acid (7 ml). The mixture was stirred at reflux for 1 hour. The mixture was poured out on ice. The mixture was made alkaline by adding ammonia and extracted with dichloromethane and washed with water. The crude mixture was purified by column chromatography using a mixture of dichloromethane, methanol and aqueous ammonia (6:1:1%). Yield 2.28 g, (61%).
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][C:20]([NH2:22])=[O:21])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].C1C=C(Cl)C=C(C(OO)=O)C=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[NH4+:46]>>[NH2:46][C:8]1[C:7]2[N:16]=[C:4]([CH2:1][CH2:2][CH3:3])[N:5]([CH2:17][CH2:18][CH2:19][C:20]([NH2:22])=[O:21])[C:6]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCC(N)=O
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCCC(N)=O

Procedure:
4-(2-Propyl-1H-imidazo[4,5-c]quinolin-1-yl)butanamide (2.90 g, 9.78 mmol) was treated with mCPBA (5.5 g, 25 mmol), concentrated ammonium hydroxide (100 mL of 29%), and p-toluenesulfonyl chloride (2.80 g, 14.7 mmol) according to the method described in Part E of Example 3. After the reaction solution was dried with potassium carbonate, it was decanted, and charcoal (2 g) was added. The mixture was heated at reflux for two hours, filtered through a layer of CELITE filter agent, and concentrated under reduced pressure. The crude solid was purified by column chromatography on silica gel (eluting with 90:10 dichloromethane:methanol) and combined with material from another run. The solid was recrystallized from 5:1 toluene:methanol (18 mL), dried overnight in a vacuum oven, recrystallized from ethanol:water, and dried overnight in a vacuum oven to provide 4-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butanamide as a tan solid, mp 249-251° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[N:5]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=2)[N:4]=1.C([Sn](CCCC)(CCCC)[C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:32])[F:31])=[N:28][CH:29]=1)CCC.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>CN1C(=O)CCC1>[Cl:18][C:17]1[C:12]([N:5]2[C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:7][C:3]([CH2:2][C:24]3[CH:29]=[N:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[N:4]2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C(F)(F)F)nc1
Reactant: COC(=O)c1cc(CBr)nn1-c1ncccc1Cl
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: CN1CCCC1=O
Product: COC(=O)c1cc(Cc2ccc(C(F)(F)F)nc2)nn1-c1ncccc1Cl
Reaction time: 1 h

Procedure:
Under argon, 0.8 g (2.36 mmol) of methyl 3-(bromomethyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylate, 1.18 g (2.60 mmol) of 5-(tributylstannyl)-2-(trifluoromethyl)pyridine, 0.11 g (0.47 mmol) of tri-2-furylphosphine and 0.07 g (0.07 mmol) of tri(dibenzylideneacetone)dipalladium were stirred in NMP at 100° C. for 2 h. The solvent was distilled off under reduced pressure, and the residue was taken up in 80 ml of ethyl acetate and stirred vigorously with 70 ml of saturated potassium fluoride solution for 60 min. The organic phase was separated off, washed once with saturated sodium chloride solution, dried over sodium sulphate and concentrated using a rotary evaporator. The desired product was obtained by chromatographic purification.
Reaction SMILES: C1C(=O)N([O:8][C:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH:15]2[S:19][CH2:18][CH:17]3[NH:20][C:21]([NH:23][CH:16]23)=[O:22])=[O:10])C(=O)C1>C(=O)([O-])O.[Na+]>[OH:10][C:9]([CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]1[C@@H:16]2[C@@H:17]([NH:20][C:21]([NH:23]2)=[O:22])[CH2:18][S:19]1)=[O:8]
Reactant: O=C1NC2CSC(CCCCC(=O)ON3C(=O)CCC3=O)C2N1
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Each 3-mg portion of the 32-clone monoclonal antibodies prepared in (1) was mixed with 10 mg of biotinyl N-hydroxysuccinimide ester (product of Zymed) and the reaction was carried out in 0.1 M sodium hydrogen carbonate (pH 8) with stirring at room temperature for 3 hours. The reaction mixture was dialyzed overnight against 5 L of PBS at 4° C. to give the biotin-labeled monoclonal antibody.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:17]=[C:16]([NH:18][C:19]([NH:21][CH2:22][C:23]([F:26])([F:25])[F:24])=S)[CH:15]=[CH:14][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:27]>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:17]=[C:16]([NH:18][C:19]([NH2:27])=[N:21][CH2:22][C:23]([F:26])([F:25])[F:24])[CH:15]=[CH:14][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)CNC(=S)Nc1ccnc(CCCOCc2ccccc2)n1
Reactant: N
Product: NC(=NCC(F)(F)F)Nc1ccnc(CCCOCc2ccccc2)n1

Procedure:
This thiourea was stirred for 18 hours with yellow mercuric oxide (10 g.) in methanolic ammonia (250 ml.). The mixture was filtered, the filtrate was evaporated to dryness and the residue was extracted with hot CH2Cl2. Evaporation of the CH2Cl2 solution gave 2-(3-benzyloxypropyl)-4-[2-(2,2,2-trifluoroethyl)guanidino]pyrimidine (9.2 g.) which was used without further purification.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][NH:13][C:12]2=[O:23])[CH2:10][CH2:9]1)=[O:7].Cl[C:36]1[N:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][N:37]=1>>[F:32][C:29]([F:31])([F:30])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:28]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][N:13]([C:36]3[N:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][N:37]=3)[C:12]2=[O:23])[CH2:24][CH2:25]1)=[O:7]
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1Cl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(c1nccc(C(F)(F)F)n1)CN2c1ccccc1Cl

Procedure:
The title compound, MS: m/e=651.9 (M+H+), was prepared in accordance with the general method of example 71 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-(2-chloro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one and 2-chloro-4-(trifluoromethyl)-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[N:27]=[C:28]=[S:29]>O1CCCC1.C(=O)([O-])O.[Na+]>[Cl:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])[C:2]=1[NH:1][C:28](=[S:29])[NH:27][C:20]1[C:21]([CH3:26])=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=1[Cl:18]
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCCO
Reactant: Cc1cc(Cl)cc(Cl)c1N=C=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c(NC(=S)Nc2c(C)cc(Cl)cc2Cl)c1NCCCO
Temperature: 60 °C
Reaction time: 17 h
Yield: 78.8 %

Procedure:
A mixture of methyl 3-amino-4-chloro-2-[(3-hydroxypropyl)amino]benzoate (1.50 g, 5.80 mmol) and 1,5-dichloro-2-isothiocyanato-3-methylbenzene (1.64 g, 7.52 mmol) in tetrahydrofuran (15 mL) was stirred at 60° C. for 17 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with diisopropyl ether to give the title compound as a brown powder (2.18 g, 4.57 mmol, 79%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1I)[CH:14]=[CH:13][O:12]2.C([Mg]Cl)(C)C.Cl[C:24]1[N:25]=[CH:26][C:27]2[N:28]([C:30]([CH:33]([CH3:35])[CH3:34])=[N:31][N:32]=2)[CH:29]=1>C1COCC1.CN(C=O)C.[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[C:24]1[N:25]=[CH:26][C:27]3[N:28]([C:30]([CH:33]([CH3:35])[CH3:34])=[N:31][N:32]=3)[CH:29]=1)[CH:14]=[CH:13][O:12]2
Reactant: Fc1ccc(-c2nc3occn3c2I)c(F)c1
Reactant: CC(C)c1nnc2cnc(Cl)cn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)c1nnc2cnc(-c3c(-c4ccc(F)cc4F)nc4occn34)cn12
Temperature: -35 °C
Reaction time: 0.25 h
Yield: 1.8 %

Procedure:
A 25 mL 3 necked round bottom flask with stir bar, nitrogen line, thermometer and septum was charged with 6-(2,4-difluorophenyl)-5-iodoimidazo[2,1-b]oxazole (0.458 g, 1.322 mmol, Preparation #C.1) and THF (6 mL). The solution was cooled to about −35° C. then i-PrMgCl (2.0 M in THF, 0.730 mL, 1.45 mmol) was added dropwise. After about 10 min zinc chloride (0.225 g, 1.653 mmol) in THF (2 mL) was added while maintaining the temperature of the mixture at about −30° C. The suspension was stirred at about −25 to −30° C. for about 15 min then a solution of 6-chloro-3-isopropyl-[1,2,4]triazolo[4,3-a]pyrazine (0.260 g, 1.32 mmol) and Pd(Ph3P)4 (0.076 g, 0.066 mmol) in DMF (2 mL) was added. The mixture was immediately heated in an oil bath preheated to about 85° C. for about 45 min. The reaction mixture was cooled to ambient temperature, concentrated under reduced pressure then dissolved in HOAc (approx. 0.5 mL) and DMF (such that volume was about 9 mL). The material was purified in three equal portions by RP-HPLC (Table 1, method p). The fractions containing product were combined then most of the ACN was removed under reduced pressure. The solution was basified with 2 N aqueous NaOH then extracted with DCM (25 mL then 10 mL). The organic solutions were combined and dried over MgSO4, filtered and concentrated under reduced pressure. The material was purified by flash chromatography on silica gel using DCM/MeOH (95:5) as an eluent. The fractions with product were combined then concentrated under reduced pressure. The light yellow solid was dissolved in hot ACN (about 1 mL) then added dropwise to rapidly stirring water (10 mL). The solid was collected by filtration then dried under vacuum at about 80° C. to give the title compound (0.009 g, 2%): LC/MS (Table 1, Method g) Rt=1.83 min; MS m/z: 381.1 (M+H)+.