Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C@H:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[OH:26])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[H-].[Na+].[CH3:44]I.O>C1COCC1>[F:41][C:2]([F:1])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C@H:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[O:26][CH3:44])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2[C@@H](O)C2CCCCC2)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CO[C@H](c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
To a solution of (S)-(2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-cyclohexyl-methanol (1.81 g, 3.04 mmol) in THF (20 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 254.4 mg, 6.4 mmol). The mixture was stirred at room temperature for 30 minutes, cooled to 0° C. and methyl iodide (1.31 g, 9.2 mmol) was added. The mixture was stirred at room temperature for 5 hours. Water (10 mL) was added and the mixture was extracted with ethyl acetate. Combined organic layers were washed with brine, dried with sodium sulfate and concentrated in vacuo. The residue was purified by chromatography over 25+M Biotage silica column (eluted with 0-30% ethyl acetate in heptane) to afford the title compound as a colorless oil (1.77 g, 96%). 1H NMR (400 MHz, CDCl3) δ ppm 0.93-1.14(m, 5H) 1.18 (d, J=10.79 Hz, 1H) 1.43-1.54(m, 1H) 1.59-1.65(m, J=4.56 Hz, 2H) 1.68-1.74 (m, J=2.49 Hz, 1H) 1.90 (d, J=12.03 Hz, 1H) 3.06 (s, 3H) 4.08 (d, J=7.05 Hz, 1H) 4.21 (s, 3H) 4.71 (d, J=15.77 Hz, 1H) 4.71 (s, 2H) 4.88 (d, J=16.18 Hz, 1H) 7.35 (s, 1H) 7.49 (d, J=8.30 Hz, 1H) 7.55 (d, J=8.30 Hz, 1H) 7.66 (s, 2H) 7.78 (s, 1H). MS (ES+) Calc: 609.2, Found: 610.5 (M+1). [α]D20=36.49 deg (c=10.05 mg/mL, acetone) Determination of absolute configuration of (S)-(3,5-bis-trifluoromethyl-benzyl)-[2-(cyclohexyl-methoxymethyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine
Reaction SMILES: [CH3:1][S:2]([CH:5]1[CH2:8][NH:7][CH2:6]1)(=[O:4])=[O:3].F[C:10]1[C:11]([CH3:30])=[N:12][C:13]2[C:18]([N:19]=1)=[C:17]([C:20]1[NH:28][C:27]3[CH2:26][CH2:25][NH:24][C:23](=[O:29])[C:22]=3[CH:21]=1)[CH:16]=[CH:15][CH:14]=2.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH3:30][C:11]1[C:10]([N:7]2[CH2:8][CH:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6]2)=[N:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[C:20]2[NH:28][C:27]3[CH2:26][CH2:25][NH:24][C:23](=[O:29])[C:22]=3[CH:21]=2)[N:12]=1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: CS(=O)(=O)C1CNC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N1CC(S(C)(=O)=O)C1
Yield: 48.6 %

Procedure:
A solution of 3-methanesulfonyl-azetidine (10.95 mg, 0.08 mmol) (Pharmablock Co. Ltd, cat# PBJH0053), 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (126) (24 mg, 0.081 mmol) and DIEA (15.50 μL, 0.09 mmol) in 0.5 mL of NMP was heated in a microwave at 125° C. for 30 min. Purification of the crude reaction mixture on a silica gel column (1-6% MeOH in DCM) gave 2-(2-methyl-3-(3-(methylsulfonyl)azetidin-1-yl)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (16 mg, 48% yield) as a yellow crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.83 (1H, br.), 7.93 (1H, m, 7.65 (1H, m), 7.44 (1H, m), 7.14 (1H, s), 6.99 (1H, br.), 4.72 (2H, m), 4.60 (2H, m), 4.48 (1H, m), 3.43 (2H, m), 3.15 (3H, s), 2.89 (2H, m), 2.63 (3H, s). m/z (ESI, +ve) 12.1 (M+H)+.
Reaction SMILES: [CH2:1]([C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH2:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(C1C=CC(N)=CC=1)CCCCCCC.[N:32]([CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:33]=[O:34].N(CCC(OCC)=O)=C=O>>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([CH2:13][NH:14][C:33](=[O:34])[NH:32][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccc(CN)cc1
Reactant: CCOC(=O)CN=C=O
Agent: CCCCCCCCc1ccc(N)cc1
Agent: CCOC(=O)CCN=C=O
Product: CCCCCCCCc1ccc(CNC(=O)NCC(=O)OCC)cc1
Yield: 75 %

Procedure:
When the product of Example 6, Step C was substituted for 4-n-octylaniline and ethyl 2-isocyanatoacetate was substituted for ethyl 3-isocyanatopropionate in Example 11, Step A, the identical process afforded the title compound in 75% yield, as a colourless solid. 1H-NMR (CDCl3) 7.18 (d, 2H, J=8 Hz); 7.11 (d, 2H, J=8 Hz); 4.86 (m, 1H); 4.78 (m, 1H); 4.32 (d, 2H, J=5.6 Hz); 4.16 (q, 2H, J=7.1 Hz); 3.97 (d, 2H, J=5.3 Hz); 2.56 (t, 2H, J=8 Hz); 1.56 (m, 2H); 1.25 (m, 13H); 0.86 (t, 3H, J=6.9 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.[Cl-].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C@@H:21]([NH3+:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][C@H:21]([NH:28][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([Br:1])[CH:3]=1)[CH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[Cl:13])[CH3:27]
Reactant: CCOC(=O)C[C@H]([NH3+])Cc1ccccc1Cl
Reactant: Cc1ccc(C(=O)O)cc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C[C@@H](Cc1ccccc1Cl)NC(=O)c1ccc(C)c(Br)c1
Reaction time: 1 h

Procedure:
3-Bromo-4-methylbenzoic acid (331 mg, 1.5 mmol, 1.0 eq.) and (R)-2-(2-chloro-phenyl)-1-ethoxycarbonylmethyl-ethyl-ammonium chloride (428 mg, 1.5 mmol, 1.0 eq.) were combined with DIPEA (844 μL, 3.2 eq.) and HATU (585 mg, 1.5 mmol, 1.0 eq.) in DCM (8 mL). The resulting mixture was stirred for 1 hour, then chromatographed (0-80% EtOAc/hexanes gradient) to yield (R)-3-(3-bromo-4-methyl-benzoylamino)-4-(2-chloro-phenyl)-butyric acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[C:25](OC(=O)C)(=[O:27])[CH3:26]>CN(C)C=O>[C:25]([N:15]1[CH2:16][CH2:17][CH:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([NH2:1])[N:11]=2)[CH2:13][CH2:14]1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc(C2CCNCC2)c2ccccc2n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(c2nc(N)nc3ccccc23)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 76.3 %

Procedure:
To an ice-cold solution of 2-amino-4-(4-piperidyl)quinazoline (500 mg, 2.19 mmol) and triethylamine (233 mg, 2.3 mmol) in N,N-dimethylformamide (10 ml) was added dropwise acetic anhydride (0.22 ml, 2.30 mmol) under a nitrogen atmosphere. The reaction mixture was stirred for about 3 hours and was evaporated. The residue was partitioned between dichloromethane and saturated sodium hydrogencarbonate aqueous solution. The organic layer was washed with water and then dried over sodium sulfate and evaporated in vacuo. The residue was crystallized from ethanol. Recrystallization from methanol gave the titled compound(452 mg).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C@@H:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:27][Si:28]([CH3:33])([CH3:32])[CH2:29][CH2:30]O>>[F:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C@@H:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[C:8]([O:10][CH2:30][CH2:29][Si:28]([CH3:33])([CH3:32])[CH3:27])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)[C@H](Cc1ccc(O)cc1)Oc1ccc(F)cc1
Reactant: C[Si](C)(C)CCO
Agent: O=C(Cl)C(=O)Cl
Product: C[Si](C)(C)CCOC(=O)[C@H](Cc1ccc(O)cc1)Oc1ccc(F)cc1

Procedure:
The target compound (1.81 g) was obtained as colorless crystals by carrying out the reaction and the post-treatment according to Reference example 20(e) using the above carboxylic acid (2.30 g), oxalyl chloride (1.80 ml) and 2-trimethylsilylethanol (15.96 ml).
Reaction SMILES: CS(O[C@H:6]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[C:8](=[CH:9][CH2:10][C@@H:11]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:32])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[C@H:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:7]1)(=O)=O.[Si]([N:37]=[N+:38]=[N-:39])(C)(C)C.B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:37]([C@H:6]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[C:8](=[CH:9][CH2:10][C@@H:11]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:32])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[C@H:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:7]1)=[N+:38]=[N-:39]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OS(C)(=O)=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](N=[N+]=[N-])CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 22 °C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
To a solution of 3β-cholest-5-en-3-yl methanesulfonate (9.30 g, 20.0 mmol) in anhydrous CH2Cl2 (100 mL), TMSN3 (2.95 mL, 22.0 mmol) was added, followed by boron trifluoride etherate (5.0 mL, 40.0 mmol). The reaction was stirred at 22° C. for 2 h. When the starting material was no longer visible by TLC analysis (hexanes), the reaction was slowly poured into saturated aqueous NaHCO3 (100 mL) and vigorously stirred for 10 min. The organic layer was separated and the aqueous layer was extracted with diethyl ether (60 mL×2). The organic layers were combined, washed with deionized water (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product as light yellow solid. Flash column chromatography (hexanes) afforded the product (7.75 g, 94.1%) as white solid, mp 84-86° C.; 1H NMR (300 MHz, CDCl3) δ 5.38 (s, 1H), 3.26-3.15 (m, 1H), 2.28 (d, J=7.9 Hz, 2H), 2.05-0.85 (m, 38H), 0.68 (s, 3H); 13C NMR (75.4 MHz, CDCl3) δ 139.8, 122.5, 61.1, 56.7, 56.1, 50.1, 42.3, 39.7, 39.5, 38.1, 37.6, 36.6, 36.2, 35.8, 31.8, 31.7, 28.2, 28.0, 27.9, 24.2, 23.8, 22.8, 22.5, 21.0, 19.2, 18.7, 11.8; IR (film) ν max 2934, 2896, 2861, 2097, 1464, 1443, 1377, 1367, 1243, 1231 cm−1; APCI m/z 411.3607 (M+, C27H45N3 requires 411.3613).
Reaction SMILES: [CH:1]12[CH2:12][CH:9]([CH:10]=[CH:11]1)[CH2:8][C:7]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]2=1.[OH2:13].[OH2:14].C[N+]([O-])(C)C.C(O)(C)(C)C>ClCCl.[Os](=O)(=O)(=O)=O>[CH:1]12[CH2:12][CH:9]([CH:10]([OH:14])[CH:11]1[OH:13])[CH2:8][C:7]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]2=1
Reactant: O
Reactant: C1=CC2CC1Cc1cccnc12
Agent: O=[Os](=O)(=O)=O
Agent: C[N+](C)(C)[O-]
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: OC1C2Cc3cccnc3C(C2)C1O
Reaction time: 18 h

Procedure:
3-Aza-tricyclo[7.2.1.02,7]dodeca-2(7),3,5,10-tetraene (960 mg, 6.1 mmol) and trimethylamine N-oxide dihydrate (748 mg, 6.73 mmol) were stirred in dichloromethane (15 mL) and treated with osmium tetroxide (OsO4, 0.2 mL of a 15 mol % t-butanol solution) and the mixture was stirred vigorously. After 18 h, the residue was poured onto a silica gel column (2×6 inch) and eluted with hexanes (100 mL) then EtOAc to elute product as an oil that crystallizes on standing (1.16 g, 100%). (TLC EtOAc Rf 0.17); 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J=4.9 Hz, 1H), 7.40 (d, J=7.5 Hz, 1H), 7.07 (dd, J=7.5, 4.9 Hz, 1H), 4.19 (d, J=6.0 Hz, 1H), 3.90 (d, J=6.0 Hz, 1H), 3.45 (s, 1H), 3.00 (dd, J=17.3, 4.8 Hz, 1H), 2.67 (d, J=17.3 Hz, 1H), 2.43 (m, 2H), 1.59 (d, J=11.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 159.4, 147.6, 138.1, 130.9, 122.3, 77.1, 75.4, 51.6, 42.2, 33.9, 28.5; APCl MS m/z 192.1 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C:20](=[O:22])[CH3:21])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.I[CH2:24][C:25]1[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28].CN1CCCN(C)C1=O.C([N-]C(C)C)(C)C.[Li+]>C1COCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C:20](=[O:22])[CH2:21][CH2:24][C:25]4[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=4[C:27]([O:29][CH3:30])=[O:28])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Reactant: COC(=O)c1ccccc1CI
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)c1ccccc1CCC(=O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: -60 °C
Yield: 53.8 %

Procedure:
To a suspension of the ketone (10.0 g, 32.6 mmol) of Step 1 and the iodide (2.7 g, 47.7 mmol) of Step 2 in THF was added 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (4 mL). The ketone was dissolved by heating and the resulting solution was cooled to -60° C. A solution of 0.35M lithium diisopropylamide (89.7 mL, 30.9 mmol) was then added dropwise. After the addition was completed, the dry ice bath was removed and the reaction was allowed to warm to +10° C. The reaction was quenched by the addition of 25% aq. NH4OAc and the desired product was extracted with EtOAc, dried over Na2SO4 and evaporated under reduced pressure. The resulting mixture was purified by flash chromatography (toluene to 5% EtOAc in toluene) to yield 8 g (55%) of the title product.
Reaction SMILES: Br[C:2]1[C:3]2[O:10][CH:9]=[CH:8][C:4]=2[CH:5]=[N:6][CH:7]=1.[Cu](C#N)[C:12]#[N:13].CN(C)C=O>C(OCC)C.[Cu](I)I>[O:10]1[C:3]2[C:2]([C:12]#[N:13])=[CH:7][N:6]=[CH:5][C:4]=2[CH:8]=[CH:9]1
Reactant: N#C[Cu]C#N
Reactant: Brc1cncc2ccoc12
Agent: I[Cu]I
Solvent: CCOCC
Solvent: CN(C)C=O
Product: N#Cc1cncc2ccoc12
Temperature: 25 °C

Procedure:
Combine 7-bromofuro[3,2-c]pyridine (4.673 g, 23.5 mmol), copper cyanide (4.21 g, 47.1 mmol), copper iodide (8.96 g, 47.1 mmol), and anhydrous dimethylformamide (100 mL) and at 130° C. for 30 hours. Cool to room temperature, dilute with diethyl ether and wash with 15% aqueous ammonium hydroxide. Extract combined aqueous layers with diethyl ether, wash combined organic layers with 15% aqueous ammonium hydroxide, and brine, dry over magnesium sulfate, and concentrate. Purification using flash chromatography, eluting with hexane: ethyl acetate gives the tide compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.C(OC([N:70]1[CH2:74][CH2:73][CH2:72][NH:71]1)=O)(C)(C)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:70]1[CH2:74][CH2:73][CH2:72][NH:71]1)=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCCN1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCCN3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and N-tert.-butyloxycarbonyl-pyrazolidine in DMSO at ambient temperature.
Reaction SMILES: CS[C:3](SC)=[C:4](C(OC)=O)[C:5]#[N:6].CC1N=CNC=1CSCCN.[C:24]([C:28]([C:43]#[N:44])=[C:29](SC)[NH:30][CH2:31][CH2:32][S:33][CH2:34][C:35]1[NH:39][CH:38]=[N:37][C:36]=1[CH3:40])([O:26][CH3:27])=[O:25].C(N)C#C>>[C:24]([C:28]([C:43]#[N:44])=[C:29]([NH:6][CH2:5][C:4]#[CH:3])[NH:30][CH2:31][CH2:32][S:33][CH2:34][C:35]1[NH:39][CH:38]=[N:37][C:36]=1[CH3:40])([O:26][CH3:27])=[O:25]
Reactant: COC(=O)C(C#N)=C(SC)SC
Reactant: COC(=O)C(C#N)=C(NCCSCc1[nH]cnc1C)SC
Agent: C#CCN
Agent: Cc1nc[nH]c1CSCCN
Product: C#CCNC(NCCSCc1[nH]cnc1C)=C(C#N)C(=O)OC

Procedure:
When 1,1-bis(methylthio)-2-carbomethoxy-2-cyanoethylene [prepared according to the procedure described in Chem. Ber., 95, 2861 (1962)] is reacted with 2-[(4-methyl-1H-imidazol-5-yl)methylthio]ethylamine according to the procedure of Example 6, Step A, and the resultant 1-carbomethoxy-1-cyano-2-methylthio-2-{2-[(4-methyl-1H-imidazol-5-yl)-methylthio]ethylamino}ethylene treated with propargylamine by the procedure of Example 6, Step B, there is produced 1-carbomethoxy-1-cyano-2-(2-propynylamino)-2-{2-[(4-methyl-1H-imidazol-5-yl)methylthio]ethylamino}ethylene.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1.[Na]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCOS(C)(=O)=O
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCCC1CCn1ccnc1
Temperature: 70 °C
Yield: 69 %

Procedure:
The title compound from Step B above (2.68 g, 8.72 mmoles) (crude product, prior to chromatography) was dissolved in anhydrous DMF (30 mL) and sodium imidazole (1.18 g, 13.1 mmoles) was added. The mixture was heated at 70° C. for 2 h and then evaporated to dryness. The product was directly chromatographed on silica gel using 1% (10% conc. NH4OH in methanol)-dichloromethane as the eluant to give the title compound (1.69 g, 69%): ESMS: m/z 280.1 (MH+); dH (CDCl3) 1.48 ppm (9H, s, CH3); dC (CDCl3) CH3: 28.5, 28.5, 28.5; CH2: 19.1, 25.5, 28.9, 31.8, ˜39.1, 44.3; CH: 48.1, 118.9, 129.5, 137.1; C: 80.1, carbonyl not visible.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([CH:22]=[O:23])[CH:19]=[C:18]([CH2:24][O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[C:31]1([Mg]Br)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CO.[Cl-].[NH4+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([CH:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[OH:23])[CH:19]=[C:18]([CH2:24][O:25][CH2:26][C:27]([F:29])([F:30])[F:28])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(Nc2nc(C=O)cc(COCC(F)(F)F)n2)ccc1-n1cnc(C)c1
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(Nc2nc(COCC(F)(F)F)cc(C(O)c3ccccc3)n2)ccc1-n1cnc(C)c1

Procedure:
2-(3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-6-((2,2,2-trifluoroethoxy)methyl)-pyrimidine-4-carbaldehyde (0.10 g, 0.24 mmol) was dissolved in THF (5 mL). The mixture was cooled on an ice bath and phenylmagnesium bromide (3 M, 0.79 mL, 2.37 mmol) was added over 30 min. MeOH and ammonium chloride (aq, sat) were added. The mixture was extracted with EtOAc (×2). The organic phase was filtered through a pad of silica and sodium sulfate. The solvents were evaporated and the residue was purified by preparative HPLC to give the title compound as a dry film, 50 mg (22%).
Reaction SMILES: Cl.[CH2:2]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1)[CH:3]=[CH2:4].C(Cl)Cl.[Cl:19][CH:20]([Cl:24])[C:21](Cl)=[O:22]>C(N(CC)CC)C>[CH2:2]([N:5]([C:21](=[O:22])[CH:20]([Cl:24])[Cl:19])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:13])([F:14])[F:15])[CH:7]=1)[CH:3]=[CH2:4]
Reactant: C=CCNc1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)C(Cl)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCN(C(=O)C(Cl)Cl)c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
Twenty-three and eight tenths grams of N-allyl m-trifluoromethyl aniline hydrochloride was suspended in 200 ml. of methylene chloride, 21 g. of triethylamine was added and the mixture stirred in a water bath at room temperature while 15 g. of dichloroacetyl chloride was added dropwise. After stirring about 30 minutes, after addition was complete, the mixture was washed with dilute ~1% sodium hydroxide, dilute ~1% hydrochloric acid and water, separated and dried over magnesium sulfate and the solvent stripped under vacuum. The product was dissolved in ether and treated with 10 g. of 20% ethereal hydrochloric acid, the precipitate filtered off and the ether stripped under vacuum to give 25 g. of product, nD30 1.4740.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:23]#[N:24])[CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O.C(C1C=CC=CC=1B1OC(C)(C)C(C)(C)O1)(C)C>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:23]#[N:24])[CH:20]=[C:21]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[CH3:25])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C#N)cc(Br)c3O2)cc1
Reactant: Cc1ccccc1B(O)O
Agent: CC(C)c1ccccc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C#N)cc(-c4ccccc4C)c3O2)cc1
Yield: 99 %

Procedure:
Treatment of 3-bromo-4-hydroxybenzonitrile (10.0 g, 50.0 mmol) with potassium carbonate (27.9 g, 200 mmol) and allyl bromide (7.96 g, 66.0 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 3-allyl-5-bromo-4-hydroxybenzonitrile. Treatment of 3-allyl-5-bromo-4-hydroxybenzonitrile (4.63 g, 19.0 mmol) with 3-chloroperoxybenzoic acid (6.2 g, 35.93 mmol, 77%) followed by potassium carbonate (6.56 g, 47.5 mmol) generally according to the procedure described for Intermediate 9 afforded 1.30 g (426) of (±)-7-bromo-2-(hydroxymethyl)-2,3-dihydro-1-benzofuran-5-carbonitrile. Treatment of (±)-7-bromo-2-(hydroxymethyl)-2,3-dihydro-1-benzofuran-5-carbonitrile (1.3 g, 5.0 mmol) with p-toluenesulfonyl chloride (1.02 g, 5.4 mol) generally according to the procedure described for Intermediate 10 gave 1.5 g (72%) of (±)-(7-bromo-5-cyano-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. Treatment of (±)-(7-bromo-5-cyano-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.30 g, 0.73 mmol) and 2-methylphenylboronic acid (0.3 g, 2.20 mmol) generally according to the procedure described for Intermediate 35 afforded 0.33 g, (99%) of (±)-[5-cyano-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.26 g, 4.0 mmol) generally according to the procedure described for Intermediate 98 afforded 0.17 g (74%) of (±)-2-(azidomethyl)-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-5-carbonitrile. Treatment of the azide with polymer-supported triphenylphosphine (0.24 g, 0.67 mmol) according to the procedure described in Example 154 afforded 0.118 g (53%) of (±)-2-(aminomethyl)-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-5-carbonitrile as a white solid, hydrochloride salt. mp 127-129° C.