Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[S:22]([CH3:21])(=[O:24])=[O:23])=[CH:7][CH:8]=1
Reactant: Brc1ccc(C2CCCN2)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCCC1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.9 %

Procedure:
To a suspension of 2-(4-bromophenyl)pyrrolidine hydrogen chloride (250 mg, 0.952 mmol) in anhydrous methylene chloride (5 mL) was added triethylamine (0.66 mL, 4.76 mmol) under N2. The mixture was stirred at room temperature for 15 min. under N2. After 15 min., methanesulfonyl chloride (0.31 g, 2.72 mmol) was added and the mixture was stirred at room temperature under N2 overnight. Additional methanesulfonyl chloride (0.29 g, 2.54 mmol) and triethylamine (0.35 mL, 2.38 mmol) were added and stirred at room temperature for 4 h. The reaction was concentrated, and to the residue was added water (20 mL) and methylene chloride (18 mL), and the organic phase was washed with water (10 mL×3), brine (15 mL×1), dried over sodium sulfate and concentrated to afford the desired product (240 mg, 85.2% yield) which was used without further purification in the next step.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)[CH2:3][CH2:2]1.[NH2:18][CH:19]1[CH:26]2[CH2:27][C:22]3([OH:29])[CH2:23][CH:24]([CH2:28][CH:20]1[CH2:21]3)[CH2:25]2>>[OH:29][C:22]12[CH2:27][CH:26]3[CH2:25][CH:24]([CH2:28][CH:20]([CH:19]3[NH:18][C:12](=[O:14])[C:11]3[CH:15]=[CH:16][CH:17]=[C:9]([O:8][CH2:7][CH:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[CH:10]=3)[CH2:21]1)[CH2:23]2
Reactant: NC1C2CC3CC1CC(O)(C3)C2
Reactant: O=C(O)c1cccc(OCC2CCOCC2)c1
Product: O=C(NC1C2CC3CC1CC(O)(C3)C2)c1cccc(OCC2CCOCC2)c1

Procedure:
Prepared from 3-(tetrahydro-pyran-4-ylmethoxy)-benzoic acid and 4-amino-1-hydroxyadamantane. LC-MS (m/z): 386 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=3[F:29])[CH2:16][CH2:15][CH:14]([CH2:17][S:18]([NH2:21])(=[O:20])=[O:19])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:30](O)(=[O:32])[CH3:31].CN(C1C=CC=CN=1)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[C:30]([NH:21][S:18]([CH2:17][CH:14]1[CH2:13][CH2:12][C:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:9])=[O:10])([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[F:29])[CH2:16][CH2:15]1)(=[O:20])=[O:19])(=[O:32])[CH3:31]
Reactant: NS(=O)(=O)CC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Reactant: CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: CC(=O)NS(=O)(=O)CC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of [4-(4-chloro-benzenesulfonyl)-4-(2,5-difluoro-phenyl)-cyclohexyl]-methanesulfonamide (Example 3) (64 mg, 0.14 mmol.), acetic acid (0.011 mL, 0.17 mmol.) and dimethylaminopyridine (20 mg, 0.17 mmol.) in dichloromethane was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (32 mg, 0.17 mmol.) and the mixture stirred at ambient temperature for 18 hours. After dilution with ethyl acetate (25 mL), and washing with 2N aqueous hydrochloric acid (20 mL) and brine (20 mL), drying (MgSO4) and evaporation left a residue which was purified by column chromatography on silica, eluting with ethyl acetate:dichloromethane:iso-hexane (2:1:1), to afford the desired product.
Reaction SMILES: [SH:1][C:2]1[C:7]([C:8](=[O:14])[C:9]2[S:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[O-]CC.[Na+].[CH3:19][N:20]([CH3:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Cl>CN(C)C=O>[CH3:19][N:20]([CH3:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][S:1][C:2]1[C:7]([C:8](=[O:14])[C:9]2[S:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C(c1cccs1)c1cccnc1S
Reactant: CN(C)CCCCCCCl
Agent: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCCCCCSc1ncccc1C(=O)c1cccs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 50 ml of dimethylformamide are added 4.4 g of 2-mercapto-3-(2-thenoyl)pyridine and 1.5 g of sodium ethoxide The mixture is stirred at room temperature for 30 minutes. Thereto, 4.0 g of 6-dimethylaminohexyl chloride is added, and the mixture is stirred at room temperature for 24 hours. The mixture is poured into ice-water, followed by extraction with toluene. The extract is washed with water, and the solvent is distilled. The residue is subjected to silica gel column chromatography with chloroform as the eluent, and recrystallized from isopropyl ether to give 2-(6-dimethylaminohexylthio)-3-(2-thenoyl)pyridine, m.p. 69°-71° C.
Reaction SMILES: [CH2:1]([CH:3]([OH:16])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=1)C.[CH3:17][CH:18]([OH:32])[C:19]1[CH:24]=[CH:23][C:22]([CH:25]([OH:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:21][C:20]=1[Cl:31].CC(O)C1C=C[C:38]([CH:41]([OH:46])C(C)(C)C)=CC=1>>[Cl:31][C:20]1[CH:21]=[C:22]([CH:25]([O:30][C:10](=[O:15])[CH3:7])[C:26]([CH3:27])([CH3:28])[CH3:29])[CH:23]=[CH:24][C:19]=1[CH:18]([O:32][C:41](=[O:46])[CH3:38])[CH3:17].[C:25]([O:15][CH:10]([C:7]1[CH:6]=[CH:5][C:4]([CH:3]([O:16][C:41](=[O:46])[CH3:38])[CH3:1])=[CH:9][CH:8]=1)[C:11]([CH3:12])([CH3:13])[CH3:14])(=[O:30])[CH3:22]
Reactant: CCC(O)c1ccc(C(O)C(C)(C)C)cc1
Reactant: CC(O)c1ccc(C(O)C(C)(C)C)cc1
Reactant: CC(O)c1ccc(C(O)C(C)(C)C)cc1Cl
Product: CC(=O)OC(C)c1ccc(C(OC(C)=O)C(C)(C)C)cc1
Product: CC(=O)OC(C)c1ccc(C(OC(C)=O)C(C)(C)C)cc1Cl

Procedure:
When the above reaction is carried out using in place of α-ethyl-4-(2,2-dimethyl-1-hydroxypropyl)benzyl alcohol an equivalent amount of α-methyl-2-chloro-4-(2,2-dimethyl-1-hydroxypropyl)benzyl alcohol or α-methyl-4-(2,2-dimethyl-1-hydroxypropyl)benzyl alcohol, there is obtained 1-[2-chloro-4-(1-acetoxy-2,2-dimethylpropyl)phenyl]-1-acetoxyethane or 1-[4-(1-acetoxy- 2,2-dimethylpropyl)phenyl]-1-acetoxy ethane.
Reaction SMILES: C([CH2:4][SiH:5](Cl)[Cl:6])C=C.[CH2:8]([Mg]Cl)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].CCCCCC>O1CCCC1>[CH3:4][SiH:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[Cl:6]
Reactant: C=CCC[SiH](Cl)Cl
Reactant: CCCCCCCCCCCCCCCCCC[Mg]Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCC[SiH](C)Cl

Procedure:
[(CH3)2N--Si--(CH3)--C18H37)CH2 ]2CH2 was prepared as follows. Allylmethyldichlorosilane (0.69 moles, available from the Aldrich Chemical Co., Milwaukee, Wis., USA) was put into a reaction flask with 250 milliliters of tetrahydrofuran (THF). One molar octadecylmagnesium chloride (0.65 moles) in THF was added portionwise to the flask while the mixture was stirred and cooling to a temperature range of about -10° to +5°. The temperature of this mixture was allowed to increase to 24°. Hexane was added to the mixture, and the solid filtered off. The filtrate was evaporated on a rotary evaporator to leave an oil. The oil was vacuum-distilled, providing 134.7 g (55.8% relative to the theoretical yield) of ally methyl octadecyl-chlorosilane (compound A) as a clear, colorless oil. The boiling point of compound A was 188°/0.1-191°/0.2 mm, and gas chromatography/mass spectrometry (GC/MS) showed 100% compound A.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH2:10])=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:11][CH2:12][CH2:13][CH2:14][C:15]([F:18])([F:17])[F:16]>>[BrH:11].[C:1]([C:5]1[S:9][C:8](=[NH:10])[N:7]([CH2:12][CH2:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cnc(N)s1
Reactant: FC(F)(F)CCCBr
Product: Br
Product: CC(C)(C)c1cn(CCCC(F)(F)F)c(=N)s1
Temperature: 85 °C
Reaction time: 16 h
Yield: 63 %

Procedure:
A mixture of the product of Example 74A (0.25 g, 1.6 mmol) and 1-bromo-4,4,4-trifluorobutane (336 mg, 1.8 mmol) was warmed to 85° C. and was stirred for 16 hours. The mixture was cooled to ambient temperature and the title compound (0.35 g, 63% yield) was isolated via filtration. MS (DCI/NH3) m/z 267 (M+H)+.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][N:8]=1>C(Cl)(Cl)Cl>[ClH:3].[Cl:3][CH2:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][N:8]=1
Reactant: COc1ccnc(CO)c1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1ccnc(CCl)c1
Product: Cl
Reaction time: 2 h

Procedure:
Thionyl chloride (23 cc) was added over 25 minutes to a stirred solution of 2-hydroxymethyl-4-methoxypyridine (8.935 g) in chloroform at room temperature, and the mixture was stirred for a further 2 hours and was evaporated to dryness and the residue was triturated with ether and recrystallised from 0.9 N ethanolic hydrogen chloride/ether (7:5) to give 2-chloromethyl-4-methoxypyridine hydrochloride m.p. 142° (decomp).(12.1 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10]I)=[CH:4][CH:3]=1.C([N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)C1C=CC=CC=1>>[OH:25][C:22]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:23][CH2:24][NH:19][CH2:20][CH2:21]1
Reactant: Fc1ccc(CCCI)cc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Product: OC1(CCCc2ccc(F)cc2)CCNCC1

Procedure:
The title compound was prepared from 3-(4-fluorophenyl propyliodide and 1-benzyl-4-piperidone as described in Example 122.
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8](=O)[CH2:9]Br)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][N:16]=1>C(#N)C>[N:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]2[N:14]=[C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][N:16]3[CH:9]=2)=[CH:6][CH:5]=1)=[N+:2]=[N-:3]
Reactant: Nc1ccc(I)cn1
Reactant: [N-]=[N+]=Nc1ccc(C(=O)CBr)cc1
Solvent: CC#N
Product: [N-]=[N+]=Nc1ccc(-c2cn3cc(I)ccc3n2)cc1
Temperature: 80 °C
Yield: 65.2 %

Procedure:
218 mg (corresponding to 0.909 mmol) of 4-azidophenacylbromide and 200 mg (corresponding to 0.909 mmol) of 2-amino-5-iodopyridine were dissolved in 1.0 mL of acetonitrile. The resulting solution was heated in an oil bath at 80° C. for 3 hours. After the completion of the reaction, the reaction solution was cooled down to room temperature, and precipitates were filtered. Then, the precipitates were washed with acetonitrile and dried under reduced pressure. The resulting crude crystals were suspended in a mixed solution of 3 mL of water and 3 mL of methanol. Then, about 4 mL of a saturated sodium hydrogencarbonate solution was added thereto, and the mixture was sonicated for 5 minutes using an ultrasonic washing machine. Precipitates were filtered and recovered from the resulting mixture, sufficiently washed with water, and dried under reduced pressure, to obtain 214 mg (corresponding to 0.593 mmol) of 2-(4-azidophenyl)-6-iodoimidazo[1,2-a]pyridine (FIG. 1, step 1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19]([OH:21])=O)[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:22]([F:25])([F:24])[F:23])([O-:3])=[O:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[F:55][C:56]([F:74])([F:73])[C:57]1[CH:58]=[CH:59][C:60]2[O:64][CH:63]([CH2:65][N:66]3[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]3)[CH2:62][C:61]=2[CH:72]=1>ClCCl.O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:12][CH2:13][CH:14]([O:17][CH2:18][C:19]([N:69]3[CH2:70][CH2:71][N:66]([CH2:65][CH:63]4[CH2:62][C:61]5[CH:72]=[C:57]([C:56]([F:74])([F:55])[F:73])[CH:58]=[CH:59][C:60]=5[O:64]4)[CH2:67][CH2:68]3)=[O:21])[CH2:15][CH2:16]2)=[CH:6][C:5]=1[C:22]([F:25])([F:23])[F:24])([O-:3])=[O:2]
Reactant: FC(F)(F)c1ccc2c(c1)CC(CN1CCNCC1)O2
Reactant: O=C(O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCN(CC2Cc3cc(C(F)(F)F)ccc3O2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.6 %

Procedure:
To a solution of 2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]acetic acid (100 mg, 0.28 mmol) in dichloromethane (30 ml) was added EDAC.HCl (79.6 mg, 0.42 mmol, 1.5 eq), HOBt (55.9 mg, 0.41 mmol, 1.5 eq), triethylamine (55.9 mg, 0.55 mmol, 1.5 eq) and 1-[[5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl]piperazine (86.9 mg, 0.30 mmol, 1.1 eq). The solution was stirred at room temperature overnight. The reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (3×30 ml). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The crude material was purified by silica gel chromatography using 25% ethyl acetate in dichloromethane to elute. The product-containing fractions were combined and concentrated under vacuum to afford 2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]-1-(4-[[5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl]piperazin-1-yl)ethan-1-one as a yellow solid (69.9 mg, 40%); (ES, m/z): [M+H]+ 631.20; 1H NMR (300 MHz, CDCl3): δ 8.01 (d, J=9.0 Hz, 1H), 7.44 (m, 2H), 6.84 (m, 2H), 6.62 (dd, J=2.7 Hz, 9.0 Hz, 1H), 5.10 (broad s, 1H), 4.47 (d, J=8.1 Hz, 1H), 4.22 (s, 2H), 3.61-3.82 (m, 3H), 3.36-3.48 (m, 3H), 3.01-3.07 (dd, J=7.8 Hz, 16.2 Hz, 1H), 2.80-2.95 (m, 1H), 2.54-2.74 (m, 4H), 2.12-2.18 (m, 4H), 1.43-1.59 (m, 3H), 1.24-1.35 (m, 3H).
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[C:24]([CH:23]=[CH:22][CH:21]=1)[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2
Reactant: BrC=C1c2ccccc2CCc2ccccc21
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: FC(F)(F)c1cccc(C=C2c3ccccc3CCc3ccccc32)c1

Procedure:
Combine 5-bromomethylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (0.5 g, 1.75 mmol) and 3-(trifluoromethyl)phenyl boronic acid (0.33 g, 1.75 mmol) using procedures essentially as described in Example 219, below. Pass through a plug of silica gel equilibrated with hexanes. Concentrate the filtrate to give the title product. Analysis for C23H17F3: Calcd: C, 78.84 H. 4.89; Found: C, 79.03.H, 5.03. HPLC (ISO80-10M)) t=16.30 min (98%).
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][C:4]2([CH2:10][C@@H:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:8]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7]2)[O:3]1.[Cl:25][C:26]1[CH:27]=[C:28](Br)[CH:29]=[CH:30][CH:31]=1>>[Cl:25][C:26]1[CH:31]=[C:30]([N:6]2[CH2:5][C@@:4]3([CH2:10][C@@H:9]([C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[N:8]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7]3)[O:3][C:2]2=[O:1])[CH:29]=[CH:28][CH:27]=1
Reactant: Clc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)[C@@H]1CC2(CNC(=O)O2)CN1C(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)[C@@H]1C[C@@]2(CN(c3cccc(Cl)c3)C(=O)O2)CN1C(=O)OC(C)(C)C
Yield: 36.1 %

Procedure:
Following the same procedure as Example 1 step 3 using (8S)-di-tert-butyl 2-oxo-1-oxa-3,7-diazaspiro[4.4]nonane-7,8-dicarboxylate (8S)-di-tert-butyl 2-oxo-1-oxa-3,7-diazaspiro[4.4]nonane-7,8-dicarboxylate (B1) (224 mg, 0.654 mmol) and 3-chloro bromobenzene (230 μL, 1.962 mmol, 3 eq.) gave 107 mg (0.236 mmol) of (5S,8S)-di-tert-butyl 3-(3-chlorophenyl)-2-oxo-1-oxa-3,7-diazaspiro[4.4]nonane-7,8-dicarboxylate (A3). 1H NMR (300 MHz, DMSO) 7.68 (m, 1H), 7.55-7.38 (m, 2H), 7.2 (m, 1H), 4.23-4.05 (m, 3H), 3.8-3.7 (m, 1H), 3.5 (m, 1H), 2.7-2.6 (m, 1H), 2.25-2.1 (m, 1H), 1.4 (m, 18H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:25]2[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][CH2:26]2)[C:15]([NH:17][C:18]2[S:19][C:20]([CH:23]=O)=[CH:21][N:22]=2)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:33][O:34][C:35](=[O:45])[CH2:36][C:37](=[O:44])[N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:25]2[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][CH2:26]2)[C:15]([NH:17][C:18]2[S:19][C:20]([CH2:23][N:41]3[CH2:40][CH2:39][N:38]([C:37](=[O:44])[CH2:36][C:35]([O:34][CH3:33])=[O:45])[CH2:43][CH2:42]3)=[CH:21][N:22]=2)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CC(=O)N1CCNCC1
Reactant: CC1CCC(N(C(=O)Nc2ncc(C=O)s2)C2CCN(C(=O)OC(C)(C)C)CC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: COC(=O)CC(=O)N1CCN(Cc2cnc(NC(=O)N(C3CCC(C)CC3)C3CCN(C(=O)OC(C)(C)C)CC3)s2)CC1
Yield: 24.7 %

Procedure:
Prepared as described in general procedure (P) using 4-[3-(5-formyl-thiazol-2-yl)-1-(4-methyl-cyclohexyl)-ureido]-piperidine-1-carboxylic acid tert-butyl ester (68 mg, 0.15 mmol), 3-oxo-3-piperazin-1-yl-propionic acid methyl ester hydrochloride (54 mg, 0.19 mmol) and sodium triacetoxyborohydride (38 mg, 0.18 mmol) to afford 23 mg (25%) of the desired product after purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:6][N:5]=[C:4]2[S:15][CH:16]=[CH:17][C:3]=12.[N-:18]=[C:19]=[O:20].[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=1N=C=O.C(N(C(C)C)CC)(C)C>CO.C(N(CC)CC)C>[NH2:1][C:2]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([N:14]([C:23]3[CH:24]=[C:25]([C:28]([F:30])([F:31])[F:29])[CH:26]=[CH:27][C:22]=3[F:21])[C:19]([NH2:18])=[O:20])=[CH:12][CH:13]=2)[CH2:6][N:5]=[C:4]2[S:15][CH:16]=[CH:17][C:3]=12
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: [N-]=C=O
Reactant: NC1=c2ccsc2=NCN1c1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)N(c1ccc(N2CN=c3sccc3=C2N)cc1)c1cc(C(F)(F)F)ccc1F

Procedure:
4-Amino-3-(4-aminophenyl)thieno[2,3-d]pyrimidine (0.2 mmoles) was dissolved in 1 mL amine-free DMF and treated with 0.3 mmoles of the isocyanate of choice (2-fluoro-5-trifluoromethyl-phenyl isocyanate) and 0.6 mmoles of diisopropylethylamine for 2 hours at room temperature. The reaction mixture was treated with 0.5 mL 1:1 methanol-triethylamine for half an hour and concentrated to dryness in a Speedvac system, reconstituted in 1 mL DMSO and purified by prep HPLC. The fraction containing the desired product was collected and concentrated to dryness. MH+=448.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6]Br)(=[O:3])[CH3:2].[Li].[C:9]([C:13]1[CH:28]=[CH:27][C:16]([C:17]([C:19](=[C:22](SC)[S:23][CH3:24])[C:20]#[N:21])=O)=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].[Cl-].[NH4+].C1C[O:34]CC1>CCOC(C)=O>[CH2:5]([O:4][C:1]([C:2]1[O:34][C:22]([S:23][CH3:24])=[C:19]([C:20]#[N:21])[C:17]=1[C:16]1[CH:27]=[CH:28][C:13]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:14][CH:15]=1)=[O:3])[CH3:6]
Reactant: C1CCOC1
Reactant: CC(=O)OCCBr
Reactant: CSC(SC)=C(C#N)C(=O)c1ccc(C(C)(C)C)cc1
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1oc(SC)c(C#N)c1-c1ccc(C(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 38 %

Procedure:
Add a solution of the bromoethyl acetate (2.13 ml, 19.17 mmol) in THF (10 ml) dropwise to a −78 ° C. solution of the lithium hexamethylsillylamide (1M, 21 ml, 20.7 mmol) in THF. Stir the mixture at −78° C. for 10 minutes and treat with a dropwise solution of 2-(4-tert-butyl-benzoyl)-3,3-bis-methylsulfanyl-acrylonitrile (2.25 g, 7.67 mmol) in THF (20 ml). Stir the mixture at −78° C. for 30 minutes and at RT for 6 h. Pour into a saturated solution of ammonium chloride (100 ml). Extract organic with EtOAc (3×100 ml). Combine the organics wash with water (3×100 ml), brine (100 ml), dry over magnesium sulfate, filter and concentrate under reduced pressure. Purification by flash chromatography, eluting with ethyl acetate:hexanes (1:9) provides the title compound (1 g, 38%): Mass spectrum (M+1)=344.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([CH2:9][NH:10][C:11]([C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]2)=O)=[N:4][N:3]=1.O=P(Cl)(Cl)Cl>ClCCCl>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]2=[CH:9][N:10]=[C:11]([C@H:13]3[CH2:18][CH2:17][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]3)[N:4]2[N:3]=1
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)NCc2nnc(N)[nH]c2=O)CC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COC(=O)[C@H]1CC[C@H](c2ncc3c(=O)[nH]c(N)nn32)CC1

Procedure:
A solution of methyl trans-4-{[(3-amino-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)methyl]carbamoyl}cyclohexanecarboxylate (2.00 g, 0.00646 mol) in 1,2-dichloroethane (130 mL) was charged with POCl3 (4.2 mL, 0.045 mol) and heated to reflux for 3 h. The reaction mixture was concentrated in vacuo then partitioned between EtOAc and sat. NaHCO3 and separated. The aqueous was re-extracted with EtOAc (3×) and the combined organic fractions were dried over Na2SO4, filtered, and concentrated in vacuo resulting in 1.43 g, (76% yield) of the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43 (q, J=11.79 Hz, 2H), 1.61 (q, J=12.55 Hz, 2H), 1.85-2.11 (m, 4H), 2.38 (t, J=11.87 Hz, 1H), 2.98 (t, J=11.75 Hz, 1H), 3.61 (s, 3 H), 6.17 (br. s., 2 H), 7.49 (s, 1H) and 10.90 (br. s., 1H); MS (ES+): m/z 292.25 [MH+].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].CC(C)=O.C(=O)=O.[Li]CCCC.[C:22]([N:26]1[C:30]2[NH:31][C:32](=[O:44])[CH2:33][CH:34]([C:35]3[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=3[F:43])[C:29]=2[C:28]([CH:45]2[CH2:48][C:47](=[O:49])[CH2:46]2)=[N:27]1)([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[C:22]([N:26]1[C:30]2[NH:31][C:32](=[O:44])[CH2:33][CH:34]([C:35]3[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=3[F:43])[C:29]=2[C:28]([CH:45]2[CH2:48][C:47]([C:2]3[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=3)[C:5]#[N:6])([OH:49])[CH2:46]2)=[N:27]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)n1nc(C2CC(=O)C2)c2c1NC(=O)CC2c1cc(F)c(F)cc1F
Reactant: N#Cc1cccc(Br)c1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)n1nc(C2CC(O)(c3cccc(C#N)c3)C2)c2c1NC(=O)CC2c1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38.9 %

Procedure:
To a stirring solution of 3-bromobenzonitrile (3.7 g, 20.4 mmol) in 50 mL of THF at −78° C. (acetone/CO2 bath) was added a solution of n-BuLi (8.2 mL, 20.4 mmol, 2.5 M in hexanes). After 15 min, a solution of 1-tert-butyl-3-(3-oxo-cyclobutyl)-4-(2,4,5-trifluoro-phenyl)-1,4,5,7-tetrahydro-pyrazolo[3,4-b]pyridin-6-one (2.0 g, 5.1 mmol in 10 mL of THF) was added. After one hr, the reaction mixture was quenched cold by the addition of a saturated NH4Cl solution, and was then allowed to warm to room temperature. The reaction mixture was diluted with CH2Cl2, and the layers were separated. The organic layer was dried over MgSO4, filtered through a pad of diatomaceous earth, and concentrated under reduced pressure to give a tan solid. Purification of this material was accomplished by MPLC using a 35 g ISCO cartridge on a Biotage® system eluting with a gradient of 25-50% EtOAc/hexanes. The product-containing fractions were collected and concentrated to yield the title compound (0.98 g, 40% yield) as a tan solid. Rf=0.29 (50% EtOAc/hexanes).