Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:11][OH:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:13]([Mg]Br)=[CH2:14].[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH:11]([OH:12])[CH:13]=[CH2:14])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: C=C[Mg]Br
Reactant: OCC1(c2ccc(Cl)cc2)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(O)C1(c2ccc(Cl)cc2)CC1
Temperature: -20 °C

Procedure:
To a stirred solution of 1-(4-chlorophenyl)-1-cyclopropanemethanol (1.8 g) in dry tetrahydrofuran (60 ml) at -78° C. is added IM vinylmagnesium bromide (12 ml) in tetrahydrofuran over 10 mins. The mixture is then allowed to warm to -20° C. and saturated aqueous ammonium chloride added (30 ml). The mixture is concentrated under reduced pressure, and extracted with ether (x3). The combined extracts are dried and the solvent evaporated under reduced pressure to the required compound, 3 g, nD 1.5523.
Reaction SMILES: C([O:4][C@H:5]([C@@H:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([CH2:22][CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:26])[CH2:17][CH2:18]2)[CH2:13][CH2:12]3)[CH2:9][CH2:8]1)[CH3:6])(=O)C>O1CCCC1.CO.O>[OH:4][C@H:5]([C@@H:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([CH2:22][CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:26])[CH2:17][CH2:18]2)[CH2:13][CH2:12]3)[CH2:9][CH2:8]1)[CH3:6]
Reactant: CC(=O)O[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C[C@H](O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 3 h
Yield: 224 %

Procedure:
—Potassium hydroxide (22.5 g) was added to a solution of (20S)-20-(acetyloxy)pregn-4-en-3-one (17.9 g) in tetrahydrofuran (418 ml), methanol (380 ml) and water (125 ml). The mixture was stirred for 3 h at room temperature and then poured into water (2 l). The product was extracted into ethyl acetate; the combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Column chromatography afforded (20S)-20-hydroxypregn-4-en-3-one (compound 7; 35.4 g).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1([CH3:24])[C:12](=[O:13])[CH:11]2[C:6](=[C:7]3[N:17]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:15]=[C:8]3[C:9](=[O:14])[CH2:10]2)[CH:5]=[N:4]1.Cl.[CH2:26]([N:28]([CH2:32][CH3:33])[CH2:29][CH2:30][Cl:31])[CH3:27]>>[ClH:31].[ClH:1].[CH3:2][C:3]1([CH3:24])[C:12](=[O:13])[CH:11]2[C:6](=[C:7]3[N:17]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:15]=[C:8]3[C:9](=[O:14])[CH:10]2[CH2:27][CH2:26][N:28]([CH2:32][CH3:33])[CH2:29][CH3:30])[CH:5]=[N:4]1
Reactant: CC1(C)N=CC2=C3N=C(c4ccccc4)N=C3C(=O)CC2C1=O
Reactant: CCN(CC)CCCl
Agent: Cl
Product: CCN(CC)CCC1C(=O)C2=NC(c3ccccc3)=NC2=C2C=NC(C)(C)C(=O)C21

Procedure:
Prepared analogous to Example 23 from 5.1 gm of 7,7-dimethyl-2-phenyl-5H,7H-imidazo[4,5-h]isoquinoline-4,6-dione hydrochloride and 3.4 gm of 2-diethylamino-ethyl chloride hydrochloride,
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH2:23][NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29](F)=[CH:28][CH:27]=2)=[CH:5][C:6]([O:21][CH3:22])=[C:7]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[N:17][C:16]([C:19]#[N:20])=[CH:15][N:14]=2)=[O:11])[CH:8]=1.CCCCC>O1CCOCC1.C(Cl)Cl>[ClH:2].[CH2:25]([NH:24][CH2:23][C:4]1[C:3]([Cl:2])=[CH:8][C:7]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[N:17][C:16]([C:19]#[N:20])=[CH:15][N:14]=2)=[O:11])=[C:6]([O:21][CH3:22])[CH:5]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1cc(CNCc2ccc(F)cc2)c(Cl)cc1NC(=O)Nc1cnc(C#N)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCCCC
Solvent: ClCCl
Product: COc1cc(CNCc2ccccc2)c(Cl)cc1NC(=O)Nc1cnc(C#N)cn1
Temperature: 5 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
A saturated solution of HCl in 1,4-dioxane (1.2 mmoL) was added to a solution of 1-(5-chloro-4-((4-fluorobenzylamino)methyl)-2-methoxyphenyl)-3-(5-cyanopyrazin-2-yl)urea (1 mmol) in DCM (50 mL) at 5° C. The reaction mixture was stirred at 5° C. for 2 hours then n-pentane (100 mL) was added and stirring continued for 15 minutes. The resulting solid was collected by filtration then washed with methanol (2×10 mL), followed by n-pentane (10 mL) and dried under reduced pressure to give the title compound (56%) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:24]([Br:25])=[CH:23][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.Cl>C(O)C>[F:1][C:2]1[C:24]([Br:25])=[CH:23][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(F)c(Br)cc32)CC1
Agent: Cl
Solvent: CCO
Product: O=c1[nH]c2cc(F)c(Br)cc2n1C1CCNCC1

Procedure:
A stirred mixture of 1,1-dimethylethyl 4-(5-fluoro-6-bromo-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinecarboxylate (D45) (0.54 g, 1.3 mmole) and 6N HCl (1 ml) in ethanol (15 ml) was heated to reflux temperature for 4 hrs. The mixture was concentrated to dryness under vacuum and the residue treated with aq. sodium carbonate and extracted with ethyl acetate. The organic extract was dried (MgSO4) and concentrated to dryness under vacuum to afford the title compound as pale buff powder, 0.35 g, 85%. LC/MS—92% 314/316 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].[F:19][C:20]([F:35])([F:34])[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[S:28][C:29]([CH2:32]O)=[CH:30][N:31]=2)=[CH:23][CH:22]=1.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:32][C:29]2[S:28][C:27]([C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:35])([F:19])[F:34])=[CH:26][CH:25]=3)=[N:31][CH:30]=2)=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Reactant: OCc1cnc(-c2ccc(C(F)(F)F)cc2)s1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)C(Cc1ccc(OCc2cnc(-c3ccc(C(F)(F)F)cc3)s2)cc1C)OCC

Procedure:
In analogy to the procedure described in example 10 c], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 10 b]) was reacted with [2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol [PCT Int. Appl. (2002), WO 02/062774 A1] in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to yield [rac]-2-ethoxy-3-{2-methyl-4-[2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-propionic acid ethyl ester as yellow crystals.
Reaction SMILES: [NH2:1][C:2]1([C:6]2[CH:7]=[C:8]([C:12]3[CH:16]=[C:15]([O:17][C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=4)[N:14]([CH2:28][C:29]([N:31]([CH3:33])[CH3:32])=[O:30])[N:13]=3)[CH:9]=[CH:10][CH:11]=2)[CH2:5][O:4][CH2:3]1.C(N(CC)CC)C.[F:41][C:42]([F:49])([F:48])[CH2:43][S:44](Cl)(=[O:46])=[O:45].O>C(Cl)Cl>[F:27][C:24]([F:25])([F:26])[C:21]1[CH:20]=[CH:19][C:18]([O:17][C:15]2[N:14]([CH2:28][C:29]([N:31]([CH3:33])[CH3:32])=[O:30])[N:13]=[C:12]([C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([C:2]4([NH:1][S:44]([CH2:43][C:42]([F:49])([F:48])[F:41])(=[O:46])=[O:45])[CH2:5][O:4][CH2:3]4)[CH:7]=3)[CH:16]=2)=[CH:23][CH:22]=1
Reactant: CN(C)C(=O)Cn1nc(-c2cccc(C3(N)COC3)c2)cc1Oc1ccc(C(F)(F)F)cc1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C)C(=O)Cn1nc(-c2cccc(C3(NS(=O)(=O)CC(F)(F)F)COC3)c2)cc1Oc1ccc(C(F)(F)F)cc1
Reaction time: 0.5 h

Procedure:
A stirred solution of 2-{3-[3-(3-aminooxetan-3-yl)phenyl]-5-(4-trifluoromethylphenoxy)-1H-pyrazol-1-yl}-N,N-dimethylacetamide (46 mg, 0.10 mmol) in 1 mL of CH2Cl2 was cooled in an ice bath. Triethylamine (0.021 mL, 0.15 mmol) was added, followed by trifluoroethylsulfonyl chloride (0.013 mL, 0.12 mmol), and the mixture was stirred for 30 min. Water was added and the mixture was extracted with CH2Cl2. The combined organic phases were washed with water and brine, then dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. The residue was purified on a C18 reverse phase column using a gradient elution of 20-70% CH3CN:H2O with 0.1% TFA over 20 min at 20 mL/min. Fractions containing pure product were combined and the solvents were removed under reduced pressure to give 2-[5-(4-trifluoromethylphenoxy)-3-(3-{3-[(2,2,2-trifluoroethylsulfonyl)amino]oxetan-3-yl}phenyl)-1H-pyrazol-1-yl]-N,N-dimethylacetamide as a foam. Calcd (M+1)+: 607.1444. Found: 607.1468. 1H NMR (400 MHz, CDCl3) δ 7.75 (m, 2H), 7.64 (d, J=7, 2H), 7.44 (t, J=7, 1H), 7.35 (m, 2H), 7.28 (s, 1H), 6.38 (s, 1H), 6.04 (s, 1H), 5.04 (d, J=7, 2H), 4.98 (d, J=7, 2H), 4.94 (s, 2H), 3.09 (s, 3H), 2.97 (overlapping s and q, 5H).
Reaction SMILES: [Si](C=[N+]=[N-])(C)(C)[CH3:2].[OH:8][C@@H:9]1[CH2:13][O:12][C@@H:11]2[C@H:14]([O:17][C:18]3[N:19]([CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:56])([CH3:55])[CH3:54])[C:20]4[C:21]([N:48]=3)=[N:22][C:23]([C:27]3[CH:32]=[CH:31][C:30]([C:33]5[N:38]=[CH:37][C:36]([N:39]6[CH:43]=[C:42]([CH2:44][C:45]([OH:47])=[O:46])[CH:41]=[N:40]6)=[CH:35][CH:34]=5)=[CH:29][CH:28]=3)=[C:24]([Cl:26])[CH:25]=4)[CH2:15][O:16][C@H:10]12>CO.C(Cl)Cl>[OH:8][C@@H:9]1[CH2:13][O:12][C@@H:11]2[C@H:14]([O:17][C:18]3[N:19]([CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:55])([CH3:54])[CH3:56])[C:20]4[C:21]([N:48]=3)=[N:22][C:23]([C:27]3[CH:32]=[CH:31][C:30]([C:33]5[N:38]=[CH:37][C:36]([N:39]6[CH:43]=[C:42]([CH2:44][C:45]([O:47][CH3:2])=[O:46])[CH:41]=[N:40]6)=[CH:35][CH:34]=5)=[CH:29][CH:28]=3)=[C:24]([Cl:26])[CH:25]=4)[CH2:15][O:16][C@H:10]12
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(-c3ccc(-c4ccc(-n5cc(CC(=O)O)cn5)cn4)cc3)c(Cl)cc21
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)Cc1cnn(-c2ccc(-c3ccc(-c4nc5nc(O[C@@H]6CO[C@H]7[C@@H]6OC[C@H]7O)n(COCC[Si](C)(C)C)c5cc4Cl)cc3)nc2)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
TMS-Diazomethane (2 M in hexanes, 0.15 mL, 0.300 mmol) was added to a stirred solution of 2-[1-[6-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1-(2-trimethylsilylethoxymethyl)-imidazo[4,5-b]pyridin-5-yl]phenyl]-3-pyridyl]pyrazol-4-yl]acetic acid (27.3 mg, 0.039 mmol) in MeOH (0.5 mL) and DCM (0.5 mL). The reaction mixture was stirred at room temperature. After 3.5 hours, the reaction mixture was evaporated under reduced pressure to give the desired compound as a yellow residue. This material was used in the next step without further purification. LC-MS: calculated for C35H39ClN6O7Si 718.23 observed m/e: 719.31 (M+H)+ (Rt 1.26/2 min).
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:13][C:14]([F:19])([F:18])[CH:15]([OH:17])[CH3:16].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[Cl:1][C:2]1[C:3]([O:17][CH:15]([CH3:16])[C:14]([F:19])([F:18])[F:13])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cnc(Cl)c(Cl)c1
Reactant: CC(O)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cnc(OC(C)C(F)(F)F)c(Cl)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 72.2 %

Procedure:
To a solution of 630 mg (3.06 mmol) of methyl 5,6-dichloronicotinate (from Step A) and 349 μL (3.06 mmol) of 1,1,1-trifluoro-2-propanol in 10 mL of THF at −78° C. was added 3.1 mL (3.06 mmol) of sodium bis(trimethylsilyl)amide (1.0 M in THF). After stirring at −78° C. for 30 min and at 0° C. for 5 h, the reaction was quenched by adding 10 mL of saturated NH4Cl. The mixture was poured into brine and extracted with CH2Cl2 (3×20 mL). Organic layers were combined, dried over MgSO4, and concentrated. Chromatography on a Biotage 40M cartridge using 3:97 v/v Et2O/hexanes as the eluant gave 627 mg of the title compound: 1H NMR (500 MHz, CDCl3) δ 1.56 (d, J=6.4, 3H), 3.93 (s, 3H), 5.86 (m, 1H), 8.27 (d, J=2.1, 1H), 8.67 (d, J=2.0, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:16])[C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[O:8][C:7]([CH3:18])([CH3:17])[CH:6]=[C:5]2[CH:19]([CH3:21])[CH3:20].C([Li])CCC.[CH2:27]([O:29]CC)C>>[Cl:16][C:10]1[C:11]([O:12][CH:13]([CH3:15])[CH3:14])=[C:2]([CH:27]=[O:29])[CH:3]=[C:4]2[C:9]=1[O:8][C:7]([CH3:18])([CH3:17])[CH:6]=[C:5]2[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)Oc1c(Br)cc2c(c1Cl)OC(C)(C)C=C2C(C)C
Reactant: CCOCC
Agent: [Li]CCCC
Product: CC(C)Oc1c(C=O)cc2c(c1Cl)OC(C)(C)C=C2C(C)C
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of 6-bromo-8-chloro-7-isopropoxy-4-isopropyl-2,2-dimethyl-2H-chromene, (Compound 21, 3.9 g, 10.3 mmol) in diethyl ether (100 mL) at −78° C. was added n-butyllithium (1.6 M in hexanes, 10.3 mL, 16.5 mmol). After stirring at −78° C. for 20 min, the reaction mixture was quenched with DMF (10 mL). After further stirring at −78° C. for 15 min, the reaction was allowed to warm to room temperature. The reaction mixture was poured into 1N HCl and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel, 100% hexanes to 2% ethyl acetate in hexanes) to afford the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:22])[C:5]([F:21])=[C:6]([C@:8]2([CH2:19][F:20])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.Cl[C:24]1[C:25]2[N:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:26]=2[N:27]=[CH:28][N:29]=1>CC(O)C.C(Cl)Cl>[Cl:34][C:31]1[CH:32]=[N:33][C:25]2[C:24]([NH:1][C:2]3[CH:3]=[C:4]([CH3:22])[C:5]([F:21])=[C:6]([C@:8]4([CH2:19][F:20])[CH2:13][C@@H:12]([C:14]([F:17])([F:15])[F:16])[O:11][C:10]([NH2:18])=[N:9]4)[CH:7]=3)=[N:29][CH:28]=[N:27][C:26]=2[CH:30]=1
Reactant: Cc1cc(N)cc([C@]2(CF)C[C@@H](C(F)(F)F)OC(N)=N2)c1F
Reactant: Clc1cnc2c(Cl)ncnc2c1
Solvent: CC(C)O
Solvent: ClCCl
Product: Cc1cc(Nc2ncnc3cc(Cl)cnc23)cc([C@]2(CF)C[C@@H](C(F)(F)F)OC(N)=N2)c1F
Temperature: 100 °C
Yield: 50 %

Procedure:
To a mixture of (4S,6S)-4-(5-amino-2-fluoro-3-methylphenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (0.044 g, 0.136 mmol) and 4,7-dichloropyrido[3,2-d]pyrimidine (0.030 g, 0.150 mmol) in iPrOH (2 mL) was added a catalytic amount of concentrated H2 SO4 and the resulting mixture was heated in microwave at 100° C. for 45 min. The mixture was diluted with DCM, washed with 1 N NaOH and extracted with DCM. The combined organics were dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using 0-4% MeOH/DCM to afford a light brown solid as (4S,6S)-4-(5-((7-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2-fluoro-3-methylphenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (0.033 g, 0.068 mmol, 49.8% yield). MS m/z=486.9 [M+H]+. Calculated for C20H16ClF5N6O: 486.10.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10](=[O:29])[C@@H:11]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:20]([Cl:28])[CH:19]=2)[CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:7][CH:8]=1.[CH3:30][S-:31].[Na+]>CC(C)=O.C(OCC)(=O)C>[Cl:28][C:20]1[CH:19]=[C:18]([CH:11]([CH2:12][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17]2)[C:10]([NH:9][C:6]2[CH:5]=[N:4][C:3]([CH2:2][S:31][CH3:30])=[CH:8][N:7]=2)=[O:29])[CH:23]=[CH:22][C:21]=1[S:24]([CH3:27])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(CBr)cn2)cc1Cl
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CSCc1cnc(NC(=O)C(CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 61.6 %

Procedure:
A solution of N-(5-bromomethyl-pyrazin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (95.1 mg, 0.19 mmol) in acetone (1 mL) was cooled to 0° C. and then treated with sodium thiomethoxide (12.9 mg, 0.18 mmol). The reaction stirred at 0° C. for 1.5 h and then was treated with a second aliquot of sodium thiomethoxide (3.6 mg, 0.051 mmol). The reaction was stirred at 0° C. and then slowly warmed to 25° C. over 1.5 h. A third aliquot of sodium thiomethoxide (3–4 mg, 0.042–0.057 mmol) was added, and the reaction mixture was stirred at 25° C. for 1.5 h, at which point, APCI-LRMS indicated the reaction had gone to completion. The reaction was then diluted with ethyl acetate (50 mL), washed with water (2×25 mL) and a saturated aqueous sodium chloride solution (25 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/2 ethyl acetate/hexanes) afforded racemized 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-methylsulfanylmethyl-pyrazin-2-yl)-propionamide (51.9 mg, 58%) as a white foam: mp 70–75° C. (foam to gel); (ES)+-HRMS m/e calcd for C21H26ClN3O3S2 (M+H)+ 468.1177, found 468.1179.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:8]([F:33])=[C:9]([N:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16](=[O:21])[C:15]([C:22]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[N:25]=[CH:24][CH:23]=4)=[N:14]3)[CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1>CO.[Pd]>[F:33][C:8]1[C:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[CH:12][CH:11]=[CH:10][C:9]=1[N:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16](=[O:21])[C:15]([C:22]2[N:26]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:25]=[CH:24][CH:23]=2)=[N:14]1
Reactant: COc1cn(-c2cccc(C3=CCOCC3)c2F)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: [Pd]
Solvent: CO
Product: COc1cn(-c2cccc(C3CCOCC3)c2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.7 %

Procedure:
A mixture of 1-[3-(3,6-dihydro-2H-pyran-4-yl)-2-fluorophenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (190 mg, 0.427 mmol) and Pd/C (10% Pd, 50% wet, 19 mg) in MeOH (10 mL) was stirred at room temperature for 16 h under H2. The mixture was filtered through a pad of Celite, concentrated in vacuo, purified by column chromatography on basic silica gel (hexane/AcOEt=50/50 to 0/100) and recrystallized with EtOH/hexane to yield the title compound (152 mg, 79% yield) as a pale yellow solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 1.60-1.85 (4H, m), 3.39-3.56 (3H, m), 3.77 (3H, s), 3.91-4.04 (2H, m), 6.92-7.04 (2H, m), 7.21 (1H, t, J=8.1 Hz), 7.27-7.54 (6H, m), 7.78 (1H, d, J=1.9 Hz), 8.49 (1H, d, J=1.9 Hz).
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([NH2:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:15]1(=O)[O:21][C:19](=[O:20])[CH:18]=[C:16]1[CH3:17].C([O-])([O-])=O.[K+].[K+]>C(O)(=O)C>[CH3:17][C:16]1[C:15](=[O:21])[N:14]([C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:19](=[O:20])[CH:18]=1
Reactant: CC1=CC(=O)OC1=O
Reactant: Nc1ccc([N+](=O)[O-])c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CC1=CC(=O)N(c2ccc([N+](=O)[O-])c3ccccc23)C1=O
Temperature: 115 °C
Reaction time: 0.25 h
Yield: 121 %

Procedure:
4-nitro-1-naphthalamine (2.00 g, 10.63 mmol) and citraconic anhydride (1.05 mL, 11.69 mmol) were dissolved in acetic acid (10 mL) and heated to 115° C. for 14 h. The reaction was then cooled to 25° C. and transferred to cold sat K2CO3 with vigorous stirring. After 15 min, the solution was filtered, rinsed with water and dried under vacuum to yield 3.63 g of compound 16A as a yellow solid. This material was taken on to the next step without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][CH:11]([O:17][CH:18]([CH3:20])[CH3:19])[C:12]([O:14]CC)=[O:13])[CH:7]=[CH:8][CH:9]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>>[CH:18]([O:17][CH:11]([CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][CH2:2][O:1][C:30]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)=[O:31])[CH:5]=1)[C:12]([OH:14])=[O:13])([CH3:19])[CH3:20]
Reactant: COc1ccc(N=C=O)cc1
Reactant: CCOC(=O)C(Cc1cccc(CCO)c1)OC(C)C
Product: COc1ccc(NC(=O)OCCc2cccc(CC(OC(C)C)C(=O)O)c2)cc1

Procedure:
Using ethyl 3-[3-(2-hydroxyethyl)phenyl]-2-isopropoxypropanoate and 4-methoxyphenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[C:22]([CH3:24])[CH:21]=[N:20]1)=[O:11].Cl[C:26]1[N:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[N:23]=[C:22]([CH3:24])[CH:21]=[N:20]2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:26]1[N:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1
Reactant: FC(F)(F)c1ccc(Cl)nn1
Reactant: Cc1ccc(-n2ncc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-n2ncc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)nn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(4-methyl-2H-1,2,3-triazol-2-yl)phenyl)methanone and 3-chloro-6-(trifluoromethyl)pyridazine. ESI-MS (m/z): 474 [M+1]+.
Reaction SMILES: [CH2:1]([PH:5](=[O:7])[OH:6])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.C[Si](Cl)(C)C.[CH2:20]=[C:21]([CH2:32][CH2:33][C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>ClCCl>[CH2:1]([P:5]([CH2:20][CH:21]([C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])[CH2:32][CH2:33][C:34]([O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:35])(=[O:6])[OH:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[PH](=O)O
Reactant: C=C(CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCP(=O)(O)CC(CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 40.6 %

Procedure:
Butylphosphinic acid (2.0 g, 16 mmol) in 80 mL of dry dichloromethane was cooled to 0° C. under an atmosphere of nitrogen. Triethylamine (6.7 g, 66 mmol) was added followed by trimethylsilyl chloride (58 mL, 58 mmol, 1.0 M in dichloromethane). The mixture was stirred at 0° C. for 10 minutes and dibenzyl 2-methylenepentanedioate (2) (6.4 g, 20 mmol) in 20 mL of dichloroemthane was added. The cold bath was removed and the reaction warmed to room temperature and stirred overnight. The mixture was then cooled to 0° C. and quenched by the slow addition of 5% hydrochloric acid. The dichloromethane layer was then removed and washed with 5% hydrochloric acid and with brine. The organic layer was dried (MgSO4) and evaporated to give a clear light golden liquid. The liquid was purified by flash chromatography and eluted with 3:1 hexane/ethyl acetate containing 5% acetic acid. The desired fractions were combined and evaporated to give butyl[2,4-di(benzyloxycarbonyl)butyl]phosphinic acid (3,R=-butyl, R1=H) (2.9 g, 40%) as a clear and colorless oil. Rf 0.12 (3:1, Hex./EtOAc 5% AcOH).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1([C:7](O)=O)[CH2:6][CH2:5][CH2:4]1.[NH2:12][NH:13][C:14]([NH2:16])=[S:15].P(Cl)(Cl)(Cl)=O>>[F:1][C:2]([F:11])([F:10])[C:3]1([C:7]2[S:15][C:14]([NH2:16])=[N:13][N:12]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: O=C(O)C1(C(F)(F)F)CCC1
Reactant: NNC(N)=S
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1nnc(C2(C(F)(F)F)CCC2)s1

Procedure:
Commercially available, 1-(trifluoromethyl)cyclobutanecarboxylic acid (Oakwood), thiosemicarbazide (Aldrich) and phosphorus oxychloride (Aldrich) were processed as described for Example 1A to obtain the title compound. MS (ESI+) m/z 224 (M+H)+.