Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[OH:11].[CH3:12][C:13]([Si:16](Cl)([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1>CN(C=O)C.O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[O:11][Si:16]([C:13]([CH3:15])([CH3:14])[CH3:12])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC1CCc2c(Br)cccc21
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CCc2c(Br)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-2,3-dihydro-1H-inden-1-ol INT-28 (2.56 g, 12.0 mm) in DMF (5 mL) were added TBDMSCl (2.17 g, 14.4 mmol) and imidazole (2 g, 30.0 mmol) and the reaction mixture stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with EA. The organic layers were washed with water and brine, and dried over MgSO4. The crude product was purified by chromatography (EA/hexane) to afford (4-bromo-2,3-dihydro-1H-inden-1-yloxy)(tert-butyl)dimethylsilane INT-29 (3.3 g, 84%) as a clear oil. LCMS-ESI (m/z) calculated for C15H23BrOSi: 327.3; found 195.0 [M−OTBS]+, tR=3.07 min. 1H NMR (400 MHz, CDCl3) δ 7.20 (d, J=7.8 Hz, 1H), 7.06 (d, J=7.4 Hz, 1H), 6.92 (t, J=7.7 Hz, 1H), 5.13 (t, J=7.0 Hz, 1H), 2.85 (ddd, J=16.4, 9.1, 2.9 Hz, 1H), 2.57 (dt, J=16.5, 8.3 Hz, 1H), 2.36-2.17 (m, 1H), 1.76 (dtd, J=12.8, 8.8, 7.1 Hz, 1H), 0.83-0.72 (m, 9H), 0.05-−0.06 (m, 6H).
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=2)=[CH:5][CH:4]=1)=[O:2].C([O-])([O-])=[O:23].[K+].[K+].OO.O>CS(C)=O>[CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]([NH2:19])=[O:23])=[CH:16][N:15]=2)=[CH:5][CH:4]=1)=[O:2]
Reactant: N#Cc1ccc(Oc2ccc(C=O)c3ccccc23)nc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1ccc(Oc2ccc(C=O)c3ccccc23)nc1
Temperature: 0 °C

Procedure:
To a solution of 6-(4-formylnaphthalen-1-yloxy)nicotinonitrile (Preparation 1) (3.83 g, 14.0 mmol) in DMSO (90 mL) was added K2CO3 (0.97 g, 7.0 mmol). The mixture was cooled to 0° C., H2O2 (27.5% w/v, 4.6 mL, 37.0 mmol) added dropwise and the reaction allowed to warm to rt. The mixture was poured into water (300 mL) and the resulting precipitate was filtered, washed with water and air dried to give the title compound which was used without further purification: RT=3.13 min; m/z (ES+)=292.9 [M+H]+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[ClH:51].C(NCC)C.[CH3:57][O:58][CH2:59][CH2:60][NH:61][CH2:62][CH2:63][O:64][CH3:65]>CN(C=O)C.O>[ClH:51].[CH3:57][O:58][CH2:59][CH2:60][N:61]([CH2:62][CH2:63][O:64][CH3:65])[C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:21]([C:18]2[N:17]=[C:16]3[N:12]([CH2:11][C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:1]=[CH:2][CH:3]=[CH:4]5)[N:13]=[N:14][C:15]3=[CH:20][CH:19]=2)=[CH:22][CH:23]=1
Reactant: O=C(O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Reactant: COCCNCCOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCNCC
Product: COCCN(CCOC)C(=O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Reaction time: 0.08 h
Yield: 19.1 %

Procedure:
To a solution of example 8 (0.150 g, 0.393 mmol) in DMF (1 ml), HOBT (0.063 g, 0.471 mmol), EDC-HCl (0.187 g, 0.983 mmol) and diethyl amine (0.16 ml, 1.17 mmol) were added and stirred for 5 min, Bis(2-methoxyethyl)amine (0.104 g, 0.786 mmol) was added at RT and the reaction mixture was stirred for 12 h. To the reaction mixture water was added and extracted with ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the amide as a yellow solid (0.04 g). The amide was dissolved in THF (2 ml), ether saturated with HCl (2 ml) was added at 0° C. and stirred for 15 min. The precipitate formed was washed with ether and dried under vacuum to afford the title compound as a yellow solid (0.035 g, 17%). M.P.: 126-129° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 9.07 (m, 1H), 8.74 (m, 1H), 8.70 (d, J=8.7 Hz, 1H), 8.29 (d, J=8.3 Hz, 2H), 8.19 (m, 3H), 8.02 (m, 1H), 7.78 (m, 1H), 7.53 (d, J=8.2 Hz, 2H), 6.27 (s, 2H), 3.64 (bs, 2H), 3.58 (br.s, 2H), 3.41 (br.s, 4H), 3.30 (s, 3H), 3.16 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]=[C:9]([CH2:11][C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:20][C:21]([F:30])([F:29])[C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[CH2:11][C:9]1[O:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:28][C:25]3[CH:26]=[CH:27][C:22]([C:21]([F:20])([F:29])[F:30])=[CH:23][CH:24]=3)[C:3]=2[N:10]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: Clc1cccc(Cl)c1Cc1nc2c(Cl)ncnc2o1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc(Nc2ncnc3oc(Cc4c(Cl)cccc4Cl)nc23)cc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
A mixture of 7-chloro-2-(2,6-dichloro-benzyl)-oxazolo[5,4-d]pyrimidine (42 mg, 0.13 mmol), 4-trifluoromethyl-phenylamine (22 mg, 0.13 mmol), and p-TsOH.H2O (51 mg, 0.27 mmol) in toluene (2 mL) was heated to 120° C. in a sealed tube. After 2 h, the solution was cooled purified by preparative reverse-phase HPLC to afford the title compound as a colorless solid (20 mg, 34%). MS (ESI): mass calcd. C19H11Cl2F3N4O, 438.0; m/z found, 439.1 [M+H]+. 1H NMR (CDCl3): 8.57 (s, 1H), 7.90 (d, J=8.6 Hz, 2H), 7.76 (s, 1H), 7.62 (d, J=8.6 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H), 7.31-7.27 (m, 1H), 4.66 (s, 2H).
Reaction SMILES: [F:1][C:2]([F:13])([C:9]([F:12])([F:11])[F:10])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].FC(F)(F)S(O[CH2:20][C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])(=O)=O.C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[F:1][C:2]([F:13])([C:9]([F:10])([F:11])[F:12])[CH2:3][C:4]([CH2:20][C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])([C:7]#[N:8])[C:5]#[N:6]
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)F
Reactant: O=S(=O)(OCC(F)(F)C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#CC(C#N)(CC(F)(F)C(F)(F)F)CC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 10 h
Yield: 1.4 %

Procedure:
In 20 ml of acetone, 2.1 g of 2-(2,2,3,3,3-pentafluoropropyl)malononitrile and 4.5 g of 2,2,3,3,3-pentafluoropropyl trifluoromethanesulfonate were dissolved, 2.2 g of potassium carbonate was added and the mixture was stirred at room temperature for 10 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture and the mixture was extracted with t-butyl methyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.05 g of 2,2-bis(2,2,3,3,3-pentafluoropropyl)malononitrile (hereinafter, referred to as the present compound (93)).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:22]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[C:23]([C:25]2([C:28]([NH2:30])=[O:29])[CH2:27][CH2:26]2)=[O:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][CH:10]=1.CS(O[CH2:43][CH2:44][CH2:45][N:46]1[CH2:52][CH:51]([OH:53])[C:48]2([CH2:50][CH2:49]2)[CH2:47]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O>[OH:53][CH:51]1[C:48]2([CH2:50][CH2:49]2)[CH2:47][N:46]([CH2:45][CH2:44][CH2:43][O:21][C:15]2[CH:14]=[C:13]3[C:18]([C:9]([O:8][C:7]4[CH:6]=[CH:5][C:4]([N:22]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=5)[C:23]([C:25]5([C:28]([NH2:30])=[O:29])[CH2:27][CH2:26]5)=[O:24])=[CH:3][C:2]=4[F:1])=[CH:10][CH:11]=[N:12]3)=[CH:17][C:16]=2[O:19][CH3:20])[CH2:52]1
Reactant: CS(=O)(=O)OCCCN1CC(O)C2(CC2)C1
Reactant: COc1cc2c(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccc(F)cc4)cc3F)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccc(F)cc4)cc3F)ccnc2cc1OCCCN1CC(O)C2(CC2)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 79.9 %

Procedure:
To a solution of N-(3-fluoro-4-(7-hydroxy-6-methoxyquinolin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (240 mg, 0.475 mmol) in DMA (3 mL) was added 3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propyl methanesulfonate (236 mg, 0.95 mmol) and Cs2CO3 (463 mg, 1.425 mmol). The reaction was then stirred at rt for 2 days. The solvent was removed and the residue was partioned between saturated NaHCO3 aqueous solution (15 mL) and CHCl3 (30 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (100:15:1(v/v/v) EtOAc/CH3OH/Et3N) to afford the desired compound as a white solid (250 mg, 80%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][O:12][CH2:13][CH2:14][O:15][CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[C:3]=1[Cl:18].C([N-]C(C)C)(C)C.[Li+].[Cl:27]N1C(=O)CCC1=O.[NH4+].[Cl-]>C1COCC1>[Cl:27][C:8]1[N:7]([CH2:11][O:12][CH2:13][CH2:14][O:15][CH3:16])[C:6]2[CH:5]=[C:4]([Cl:17])[C:3]([Cl:18])=[C:2]([Cl:1])[C:10]=2[N:9]=1
Reactant: COCCOCn1cnc2c(Cl)c(Cl)c(Cl)cc21
Reactant: O=C1CCC(=O)N1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCOCn1c(Cl)nc2c(Cl)c(Cl)c(Cl)cc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 4,5,6-trichloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazole (0.388 g, 1.26 mmol) and THF (6 mL) was cooled to −78° C. in an acetone/dry ice bath. Lithium diisopropylamide (1.0 M solution in THF, 2.52 mL, 2.52 mmol) was added dropwise and the reaction mixture was stirred at −78° C. for 1 h. A solution of N-chlorosuccinimide (0.336 g, 2.52 mmol) and THF (2 mL) was added. The reaction mixture was warmed to 23° C. and stirred for 2 h. Saturated aqueous NH4Cl was added and the crude product was extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) to yield the titled compound as a mixture of regioisomers (0.267 g, 62%). MS (ESI/CI): mass calcd. for C11H10Cl4N2O2, 342.0; m/z found, 343.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 8.18 (s, 1H), 8.03 (s, 1H), 5.88 (d, J=5.8 Hz, 2H), 5.71 (s, 2H), 3.71-3.66 (m, 2H), 3.64-3.61 (m, 2H), 3.44-3.38 (m, 4H), 3.17 (t, J=1.7 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[O:12][CH3:13].[F:14][CH:15]([F:19])[C:16](O)=O>O>[F:14][CH:15]([F:19])[C:16]1[NH:8][C:7]2[CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=[C:3]([O:12][CH3:13])[C:2]=2[N:1]=1
Reactant: COc1cc([N+](=O)[O-])cc(N)c1N
Reactant: O=C(O)C(F)F
Solvent: O
Product: COc1cc([N+](=O)[O-])cc2[nH]c(C(F)F)nc12
Temperature: 130 °C
Yield: 91.2 %

Procedure:
A mixture of 2,3-diamino-5-nitroanisole (Horner et al., Annalen 1953, 579, 212) (1.10 g, 6 mmol) and difluoroacetic acid (2.31 g, 24 mmol) in polyphosphoric acid (PPA) (50 g) was heated at 130° C. in an oil bath for 1 hr. The hot solution was poured into water, and the pH was adjusted to neutral with cooling to give 2-(difluoromethyl)-4-methoxy-6-nitro-1H-benzimidazole (1.33 g, 91%): mp (EtOH/H2O) 192-194° C.; 1H NMR (DMSO-d6) δ 814.18 (br, exchangeable with D2O, 1H), 8.18 (br, 1H), 7.65 (dd, J=1.4 Hz, 1H), 7.30 (t, JHF=52.9 Hz, 1H), 4.07 (s, 3H); Anal. Calcd. for C9H7F2N3O3: C, 44.45; H, 2.9; N, 17.3. Found: C, 44.75; H, 3.0; N, 17.3%.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH2:11][CH3:12])[CH:3]=1.O=S(Cl)[Cl:15]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:15])=[O:7])=[C:4]([CH2:11][CH3:12])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CCc1cc(Br)ccc1C(=O)O
Product: CCc1cc(Br)ccc1C(=O)Cl
Reaction time: 2 h
Yield: 96 %

Procedure:
A solution of 4-bromo-2-ethyl-benzoic acid (1.72 g, 7.51 mmol) in SOCl2 (50 mL) was heated to 90° C. and stirred for 2 hours. The volatiles were removed in vacuo to yield a brown solid (1.80 g, 96%). 1H NMR (300 MHz, CDCl3): δ 1.22 (t, J=7.4 Hz, 3 H), 2.89 (q, J=7.5 Hz, 2 H), 7.49 (m, 2 H), 8.03 (d, J=9.0 Hz, 1 H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][C:41]([NH2:44])=[N:42][CH:43]=2)O1.C([O-])([O-])=O.[Na+].[Na+].Cl>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:23][N:18]([CH:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:3][C:2]([C:38]4[CH:39]=[N:40][C:41]([NH2:44])=[N:42][CH:43]=4)=[N:7][C:6]=3[CH:8]=2)[CH2:13][CH2:14]1)[S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: CN(C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1)S(C)(=O)=O
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CN(C1CCN(Cc2cc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3s2)CC1)S(C)(=O)=O
Temperature: 140 °C

Procedure:
A suspension of N-[1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-N-methyl-methanesulfonamide (137 mg, 0.3 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (76 mg, 0.36 mmol), 1M Na2CO3 (1 ml, 1 mmol) and Pd(PPh3)2Cl2 (21 mg, 0.03 mmol) in acetonitrile was heated in a microwave at 140° C. for 25 mins. The reaction was then acidified with 2N HCl (aq) extracted with ethyl acetate, the water layer separated and basified with K2CO3 (sat. aq) resulting in 294 as a white precipitate which was filtered and dried (128 mg, 83%). NMR (DMSO, 400 MHz), 1.55-1.63 (2H, m), 1.68-1.79 (2H, m), 2.11-2.18 (2H, m), 2.70 (3H, s), 2.89 (3H, s), 2.94-2.98 (2H, m), 3.53-3.61 (1H, m), 3.79 (4H, t, J=5.2), 3.84 (2H, s), 3.95 (4H, t, J=4.4), 7.04 (2H, s), 7.32 (1H, s), 9.11 (2H, s). MS: (ESI+): MH+=519
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH2:19]([O:21][CH2:22][C:23](Cl)=[O:24])[CH3:20].O>O1CCCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:23](=[O:24])[CH2:22][O:21][CH2:19][CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: CCOCC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCOCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of (S)-4-benzyloxazolidin-2-one (4.4 g, 25 mmol) in dry tetrahydrofuran (20 ml), cooled to -78° C., was added n-butyllithium (2.5M solution in hexane, 10 ml, 25 mmol) dropwise. Another 20 ml of tetrahydrofuran was added to facilitate stirring. A solution of ethoxyacetyl chloride (3.0 g, 24 mmol) in tetrahydrofuran (5 ml) was added and the mixture was stirred at -78° C. for 30 minutes, then warmed to room temperature, poured into water and extracted with ethyl acetate (3×). The combined extracts were washed with water and brine, dried over sodium sulfate and concentrated to a yellow oil (4.3 g, [α]D =+56.7°).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][C:13]2[NH:14][N:15]=[C:16]([CH3:18])[CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:19]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([SH:29])=[CH:25][CH:24]=1)(=[O:21])[CH3:20].C(OCC)C.C([O-])([O-])=O.[K+].[K+]>C(O)(C)(C)C>[C:19]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([S:29][C:2]2[N:11]=[C:10]([NH:12][C:13]3[NH:14][N:15]=[C:16]([CH3:18])[CH:17]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:25][CH:24]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Nc1ccc(S)cc1
Reactant: Cc1cc(Nc2nc(Cl)nc3ccccc23)[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: CC(=O)Nc1ccc(Sc2nc(Nc3cc(C)n[nH]3)c3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (2-chloroquinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine (200 mg, 0.77 mmol) and 4-acetamidothiophenol (644 mg, 3.85 mmol) is refluxed in tert-butanol (3 mL) over a 20 hour period. Diethylether (10 mL) is added to the mixture and a solid forms that is collected by filtration. This solid is suspended in EtOH/H2O 1 mL/3 mL)), then K2CO3 (110 mg, 0.8 mmol) is added and the suspension is stirred for 2 h at room temperature. A solid forms and is collected and dried under vacuum to give the product [2-(4-acetamidophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([CH:13]([O:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[CH3:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CO.[Cl-].[NH4+]>O1CCCC1.O.C(OCC)(=O)C>[C:7]1([C@@H:13]([O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:20][NH2:21])=[CH:22][CH:23]=2)[CH3:14])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(Oc1ccc(C#N)cc1)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H](Oc1ccc(CN)cc1)c1ccccc1

Procedure:
Next, to a solution of lithium aluminum hydride (68 mg, 1.78 mmol) in tetrahydrofuran (5.0 mL) was added a solution of the resulting 4-(1-phenyl-ethoxy)-benzonitrile (159 mg, 0.712 mmol) in tetrahydrofuran (1 mL) on an ice bath, which was stirred under reflux for 2 hours. The reaction solution was allowed to room temperature, a mixture solvent of methanol and water (9:1) was added, an aqueous solution of saturated ammonium chloride was further added, then, ethyl acetate and water were added for partitioning, the organic layer was dried over anhydrous magnesium sulfate, then, the solvent was evaporated to obtain the title compound (172 mg, quantitatively) as a yellow oily substance.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.ClCl.CS(C)=O.[OH:13][CH2:14][C@@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>CCCCCC.CCOC(C)=O>[CH:14]([C@@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:13]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: ClCl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 84 %

Procedure:
To a solution of oxalyl chloride (28 mL, 56.2 mmol) in 14 mL dry CH2 Cl2 cooled at -78° C. (a dry ice acetone bath) was added 12 mL dry DMSO over 40 minutes. The reaction was stirred at -74° C. for additional 40 minutes and (S)-2-(hydroxymethyl)-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester, (5.40 g, 26.86 mmol) in 14 mL CH2 Cl2 was added dropwise at -65° C. over 30 minutes. The reaction stirred additional 20 minutes at room temperature and partitioned between Et2O and H2O. The Et2O layer was washed with more H2O (50 mL×4) and the H2O layers was extracted with Et2O (40 mL×3). All the Et2O layers was combined, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The crude product was isolated by a silica-gel column using EtOAc and hexane (1:5 ratio) as an eluting solvent to give title compound (84% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:18]([CH3:20])=[O:19])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1.[C:21](=O)([O-])[O-].[K+].[K+].CI.O>CS(C)=O>[CH3:21][O:16][C:15](=[O:17])[CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[CH:9][CH:10]=1)[S:18]([CH3:20])=[O:19]
Reactant: CS(=O)C(C(=O)O)c1ccc(-c2ccccc2F)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)C(c1ccc(-c2ccccc2F)cc1)S(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 11.5 gm (39.3 millimols) of (2'-fluoro-4-biphenylyl)-methyl-sulfinyl-acetic acid in 60 ml of dimethyl sulfoxide, was admixed with 8.2 gm of dry potassium carbonate and 8.4 gm of methyl iodide, and the mixture was stirred at room temperature for 3 hours. Thereafter, water was added, whereupon the reaction product crystallized out and was suction-filtered off, dried and recrystallized from carbon tetrachloride and isopropanol Yield: 3.8 gm (32% of theory); m.p. 79°-80° C
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([Br:9])=[N:7][CH:8]=1)#N.[H-].C([Al+]CC(C)C)C(C)C.[OH:20]S(O)(=O)=O>C1(C)C=CC=CC=1.C(Cl)Cl.CO>[Br:9][C:6]1[N:7]=[CH:8][C:3]([CH:1]=[O:20])=[N:4][CH:5]=1
Reactant: N#Cc1cnc(Br)cn1
Reactant: O=S(=O)(O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: O=Cc1cnc(Br)cn1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 28 %

Procedure:
To a solution of 5-cyano-2-bromopyrazine (1.02 g, 5.54 mmol) in anhydrous toluene (15 mL) at −78° C. was added 1 M diisobutyl aluminum hydride (8.32 mmol) in CH2Cl2 (8.3 mL). The reaction mixture was stirred at −78° C. for 15 min, warmed to room temperature, stirred for 26 h, and then diluted with MeOH (4 mL) and stirred for 30 min at room temperature before addition of 10% H2SO4 (55 mL). The resulting solution was stirred for 1.75 h and extracted with EtOAc (100 mL, 50 mL). After solvent removal at reduced pressure, the residue was chromatographed (11% to 14% EtOAc/hexane) to give 289 mg (28%) of 5-bromo-pyrazine-2-carbaldehyde as an orange solid, mp 56-58° C. IR 2960, 1654, 1546, 1111 cm−1; 1H NMR (CDCl3) δ 8.83 (d, J=1.24 Hz, 1H, 6-PyrH), 8.91 (d, J=1.24 Hz, 1H, 3-PyrH), 10.13 ppm (s, 1H, CHO). HRMS calcd C5H3BrN2O [M+H]+ 186.9501. found 186.9496.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([O:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=3)=[CH:7][CH:6]=[CH:5][C:4]1=2.[O:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1.[BH3-]C#N.[Na+]>>[O:23]1[CH2:28][CH2:27][CH:26]([NH:1][CH2:2][CH:3]2[CH2:12][CH2:11][CH2:10][C:9]3[C:8]([O:13][C:14]4[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=4)=[CH:7][CH:6]=[CH:5][C:4]2=3)[CH2:25][CH2:24]1
Reactant: O=C1CCOCC1
Reactant: NCC1CCCc2c(Oc3ccc(C(N)=O)cn3)cccc21
Agent: [BH3-]C#N
Agent: [Na+]
Product: NC(=O)c1ccc(Oc2cccc3c2CCCC3CNC2CCOCC2)nc1
Yield: 45.2 %

Procedure:
Using a method similar to Example 204, using 6-(5-aminomethyl-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-nicotinamide (intermediate 20, 238 mg, 0.800 mmol), tetrahydro-4H-pyran-4-one (160 mg, 1.60 mmol), and NaBH3CN (100 mg, 1.60 mmol) gives the title compound (138 mg) as a white foam. Mass spectrum (ion spray): m/z=382 (M+1); 1HNMR (CDCl3): 8.57 (s, 1H), 8.16 (d, 1H), 7.23-7.16 (m, 2H), 6.94-6.90 (m, 2H), 5.86 (br. s, 2H), 4.00 (d, 2H), 3.40 (t, 2H), 3.15-2.78 (m, 3H), 2.65-2.41 (m, 2H), 1.97-1.46 (m, 9H).
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])[CH3:3].[Na+].[I-:17].[OH-].[Na+].[O-]Cl.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+].Cl>CO>[I:17][C:11]1[CH:10]=[C:9]([C:2]([CH3:1])([CH2:4][C:5]([CH3:6])([CH3:7])[CH3:8])[CH3:3])[CH:14]=[CH:13][C:12]=1[OH:15]
Reactant: [I-]
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)cc1
Agent: Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)CC(C)(C)c1ccc(O)c(I)c1
Temperature: 0 °C

Procedure:
To a stirred solution of 10.30 g (50.00 mmol) of 4-(2,4,4-trimethylpentan-2-yl)phenol in 125 mL of methanol at 0° C., add 7.48 g (50.00 mmol) of NaI and 2.00 g (50 mmol) of NaOH. To the resulting mixture add 86 mL of 5% aqueous NaOCl solution (commercial bleach) over a one hour period. Stir the resulting slurry for one more hour at 0° C. Then add 30 mL of aqueous 10% Na2S2O3 solution, and acidify the resulting reaction mixture with addition of dilute hydrochloric acid. Extract the resulting mixture with methylene chloride, wash the resulting organic layer with brine, and dry it over anhydrous magnesium sulfate. Remove volatiles and purify the resulting residue by flash chromatography on silica gel eluting with 5 volume percent (vol %) ethyl acetate in hexanes to yield 11.00 g (66%) of (P2) as a viscous oil.