Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH:9]2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]3[O:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][CH2:37][O:38][CH3:39])[C:30]=3[CH:40]=2)=[CH:4][CH:3]=1.C1(C)C=CC(S(O[CH2:51][CH:52]([NH:61][C:62]([O:64][CH2:65][C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)=[O:63])[CH2:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)(=O)=O)=CC=1>>[CH2:65]([O:64][C:62]([NH:61][CH:52]([CH2:53][CH2:54][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)[CH2:51][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])[CH2:10][CH:9]2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]3[O:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][CH2:37][O:38][CH3:39])[C:30]=3[CH:40]=2)=[CH:4][CH:3]=1)=[O:63])[C:66]1[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(CCc2ccccc2)NC(=O)OCc2ccccc2)cc1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(O)cc3)cc21
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCC(CCc4ccccc4)NC(=O)OCc4ccccc4)cc3)cc21

Procedure:
Analogously to Method I, 0.250 g of benzyl 4-(4-hydroxyphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 259b) and 0.281 g of 2-benzyloxycarbonylamino-4-phenylbutyl toluene-4-sulphonate are reacted. The title compound is obtained as a colourless oil. Rf=0.27 (2:1 EtOAc-heptane); Rt=6.01.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[O:11][CH2:10][CH:9]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[CH2:8][C:5]2=[N:6][CH:7]=1.[F:17][C:18]([F:31])([F:30])[O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl.N1C=CC=CC=1>[F:31][C:18]([F:17])([F:30])[O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:1][C:2]2[CH:3]=[C:4]3[O:11][CH2:10][CH:9]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[CH2:8][C:5]3=[N:6][CH:7]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: CCC(=O)NC1COc2cc(N)cnc2C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)NC1COc2cc(NS(=O)(=O)c3ccc(OC(F)(F)F)cc3)cnc2C1
Temperature: 25 °C
Yield: 46.9 %

Procedure:
A portion of the raw N-(7-amino-3,4-dihydro-2H-pyrano[3,2-b]pyridin-3-yl)propionamide (100 mg, 0.45 mmol) was dissolved in CH2Cl2/pyridine 9/1 (20 ml) and 4-(trifluoromethoxy)benzenesulfonyl chloride (100 μl, 0.58 mmol) was added dropwise. After stirring at room temperature over night, the reaction mixture was concentrated and the purification of the residue by chromatography on silica gel (CH2Cl2:CH3OH, 97:3) gave the title compound (94 mg, 47% for steps 31.4 and 31.5) as a gum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.Br[C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=1.CC1C=CC(S([O-])=O)=CC=1.[Na+].[H-].[Na+]>C1COCC1.O>[C:9]([CH:8]([C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=1)[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)#[N:10]
Reactant: Cc1cccnc1Br
Reactant: N#CCc1ccc(F)cc1
Agent: Cc1ccc(S(=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccnc1C(C#N)c1ccc(F)cc1
Yield: 78.2 %

Procedure:
Under argon atmosphere, to a mixture of 4-fluorophenylacetonitrile (3.97 g), 2-bromo-3-methylpyridine (5.00 g) and sodium 4-methylphenylsulfinate (10.48 g) in THF (125 ml) was added sodium hydride (2.35 g, 60%) at 0° C. to the mixture, and the mixture was heated to reflux for 3.5 hours. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:3), to give 2-(α-cyano-4-fluorobenzyl)-3-methylpyridine (5.14 g) as brown oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]([OH:16])([C:12]([F:15])([F:14])[F:13])[C:8]([F:11])([F:10])[F:9])=[CH:5][N:6]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>N1C=CC=CC=1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:1][C:2]2[S:3][C:4]([C:7]([OH:16])([C:8]([F:9])([F:10])[F:11])[C:12]([F:15])([F:13])[F:14])=[CH:5][N:6]=2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Nc1ncc(C(O)(C(F)(F)F)C(F)(F)F)s1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ncc(C(O)(C(F)(F)F)C(F)(F)F)s1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 28.9 %

Procedure:
To a solution of (2-amino-1,3-thiazol-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (79.8 mg 0.3 mmol) from step 1 of example 1-1-1 in pyridine (1 ml) was added 4-chlorobenzensulfonyl chloride 63.3 mg (0.3 mmol). The reaction mixture was stirred at r.t. for 24 h. Pyridine was removed under reduced pressure to yield the residue, which was washed with 1N HCl to give a light brown solid. The solid was washed by water, saturated NaHCO3, brine, and dried by vacuum. Further purification by preparative TLC (CHCl3:CH3OH, 90:10) afforded the title compound as a white solid (38.2 mg). 1H NMR (DMSO-d6) δ7.55 (s, 1H), 7.60 (d, 2H), 7.78 (d, 2H), 9.50 (s, 1H), 13.2 (brs, 1H); ESIMS: m/z 439 (M−H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:16](=[CH:17][CH:18]=1)[O:15][C:7]1([CH2:12][O:11][C:10]([CH3:14])([CH3:13])[O:9][CH2:8]1)[CH2:6][C:5]2=[O:19].[C:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)#[N:21].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.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>[CH3:13][C:10]1([CH3:14])[O:11][CH2:12][C:7]2([CH2:6][C:5](=[O:19])[C:4]3[C:16](=[CH:17][CH:18]=[C:2]([C:26]4[CH:27]=[C:22]([CH:23]=[CH:24][CH:25]=4)[C:20]#[N:21])[CH:3]=3)[O:15]2)[CH2:8][O:9]1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CC1(C)OCC2(CO1)CC(=O)c1cc(Br)ccc1O2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)OCC2(CO1)CC(=O)c1cc(-c3cccc(C#N)c3)ccc1O2
Temperature: 100 °C
Yield: 56.9 %

Procedure:
To a solution of 6-bromo-2′,2′-dimethylspiro[chroman-2,5′-[1,3]dioxan]-4-one (498 mg, 1.5 mmol), 3-cyanophenylboronic acid (440 mg, 3.0 mmol) and Cs2CO3 (1.460 mg, 4.5 mmol) in 1,4-dioxane (4 mL) and H2O (0.5 mL) in a 10 mL CEM microwave test tube was added PdCl2(PPh3)2 (75 mg). After degassed by purging with N2, the mixture was heated to 100° C. for 5 min in a CEM microwave reactor. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (12 g, eluted with ethyl acetate in hexane 0-30%) give 3-(2′,2′-dimethyl-4-oxospiro[chroman-2,5′-[1,3]dioxane]-6-yl)benzonitrile as a yellowish solid (298 mg). MS ESI +ve m/z 350 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([O:17][C:18]1[CH:23]=[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:20][C:19]=1[CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCCC1.C(N(CC)C(C)C)(C)C>[CH2:10]([O:17][C:18]1[CH:23]=[C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:21]=[CH:20][C:19]=1[CH:32]1[CH2:37][CH2:36][N:35]([C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])[CH2:34][CH2:33]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: c1ccc(COc2ccc(C3CCNCC3)c(OCc3ccccc3)c2)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccccc1)N1CCC(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
In a 25 ml round-bottomed flask, 0.5 g of 4-(2,4-bis(benzyloxy)phenyl)piperidine in 10 ml of tetrahydrofuran is dissolved in the presence of 0.26 ml of N,N-diisopropylethylamine. 0.17 ml of benzoyl chloride is added and the mixture is then stirred for 24 hours at ambient temperature. The reaction mixture is extracted with ethyl acetate and then the organic phases are combined and dried over magnesium sulphate. The residue is chromatographed on silica gel (8/2 heptane/ethyl acetate). 0.5 g of [4-(2,4-bis(benzyloxy)phenyl)piperidin-1-yl]phenylmethanone is obtained. Yield=80%.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([CH2:6][O:7][CH3:8])=[CH2:5].B.C1C[O:13]CC1.B(O[O-])=O.[Na+]>C1COCC1.C(Cl)Cl>[CH3:1][O:2][CH2:3][CH:4]([CH2:6][O:7][CH3:8])[CH2:5][OH:13]
Reactant: C1CCOC1
Reactant: C=C(COC)COC
Agent: B
Agent: O=BO[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COCC(CO)COC
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 48 %

Procedure:
To a solution of the 3-methoxy-2-methoxymethyl-1-propene (3.5 g, 30 mmol, 1.0 eq.) in THF (10 mL) at 0° C. was added BH3.THF (1M in THF, 18 mL, 0.6 eq.) and the resulting mixture was stirred for 40 min. The reaction was quenched with water followed by sodium perborate (10.6 g, 2.3 eq.), warmed to room temperature, stirred overnight, diluted with CH2Cl2 and filtered through celite. The filtrate was diluted with brine and the separated aqueous layer was extracted with CH2Cl2. The combined extracts were dried over Na2SO4 and filtered. The filtrate was distilled at atmospheric pressure to give light yellow liquid residue. Fractional distillation of the residue at 40 milliTorr gave 3-methoxy-2-methoxymethypropan-1-ol (1.93 g, 48%). b.p.=90-110° C.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14][C:15]2([CH2:19][C:20]([OH:22])=[O:21])O)=[CH:11][CH:10]=1>ClCCl>[F:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14]/[C:15]/2=[CH:19]\[C:20]([OH:22])=[O:21])=[CH:11][CH:10]=1
Reactant: O=C(O)CC1(O)CCc2ccc(F)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)/C=C1\CCc2ccc(F)cc21
Reaction time: 0.25 h
Yield: 95.4 %

Procedure:
Trifluoroactic acid (100 mL) was added to a stirred, chilled (ice-methanol bath) solution of 2-(6-Fluoro-1-hydroxy-1-indanyl)acetic acid (37.5 g, 0.18 mol) in dichloromethane (900 mL). After 15 min, the mixture was concentrated in vacuo to give (E)-2-(6-fluoro-1-indanylidene)acetic acid as a yellowish-tan solid (33.0 g, 95%), m.p., 203-205° C.;
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([NH:6][CH:7]([CH3:9])[CH3:8])=[CH:4][CH:3]=1.[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.Cl.N(CC(O)=O)C.C(=O)C1C=CC=CC=1>>[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]=[CH:11][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC(C)Nc1ccc(F)cc1
Agent: CNCC(=O)O
Agent: Cl
Solvent: O=Cc1ccccc1
Product: CC(C)N(Cc1ccc(Br)cc1)c1ccc(F)cc1
Yield: 93 %

Procedure:
When the product of Step A and 4-bromobenzaldehyde were substituted for sarcosine hydrochloride salt and 4-(5-(((4-fluorophenyl)) isopropyl)amino)methyl)thiophen-2-yl)benzaldehyde, respectively, in Example 22, Step C, the similar process afforded the title compound in 93% yield, as a pale paste. 1H-NMR (CDCl3) 7.39 (d, 2H, J=8.18 Hz); 7.14 (d, 2H, J=8.08 Hz); 6.91-6.81 (m, 2H); 6.62-6.57 (m, 2H); 4.26 (s, 2H); 4.11-4.04 (m, 1H); 1.18 (d, 2H, J=5.34 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[CH:11]=[N:12][C:13]=2[O:14][CH:15]2[CH2:18][CH2:17][CH2:16]2)=[CH:4][CH:3]=1.Cl.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH:19][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=3)[CH:11]=[N:12][C:13]=2[O:14][CH:15]2[CH2:18][CH2:17][CH2:16]2)=[CH:4][CH:3]=1
Reactant: Nc1cnc(OC2CCC2)c(-c2ccc(Cl)cc2)c1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Product: O=C(Nc1cnc(OC2CCC2)c(-c2ccc(Cl)cc2)c1)c1cccnc1

Procedure:
The title compound was synthesized in analogy to Example 48e, using 5-(4-chloro-phenyl)-6-cyclobutoxy-pyridin-3-ylamine (example 78 d) and nicotinoyl chloride hydrochloride as starting materials; MS (EI) 380.2(M+H)+.
Reaction SMILES: [Na].C([O:4][C:5](=[O:8])[CH2:6][SH:7])C.Cl/[C:10](=[C:12]1\[C@H:13]2[C@@H:15]([CH2:16][C:17]\1=O)[C:14]2([CH3:20])[CH3:19])/[CH3:11].[Li+].[OH-]>C(O)C>[CH3:19][C:14]1([CH3:20])[C@@H:15]2[CH2:16][C:17]3[C:12]([C@H:13]12)=[C:10]([CH3:11])[S:7][C:6]=3[C:5]([OH:4])=[O:8]
Reactant: CCOC(=O)CS
Reactant: C/C(Cl)=C1\C(=O)C[C@@H]2[C@H]1C2(C)C
Agent: [Li+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Product: Cc1sc(C(=O)O)c2c1[C@H]1[C@@H](C2)C1(C)C
Temperature: 30 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
Alternatively, (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid is also obtained by the following procedure: To a solution of sodium (2.80 g, 122 mmol) in ethanol (400 mL) a solution of mercaptoacetic acid ethyl ester (14.64 g, 122 mmol) in ethanol (40 mL) is added. The solution is stirred for 5 min before (1S,5R)-2-(1-chloro-(E)-ethylidene)-6,6-dimethyl-bicyclo[3.1.0]hexan-3-one (15.0 g, 81.2 mmol) in ethanol (40 mL) is added dropwise. The solution becomes slightly warm (approx. 30° C.) and turns orange to brown. A fine precipitate forms. Stirring is continued at rt for 1 h. Then, a solution of sodium (2.24 g, 97.5 mmol) in ethanol (75 mL) is added rapidly and the mixture is heated to 75° C. for 1 h. A 2N aq. solution of LiOH (75 mL) is added and stirring is continued at 75° C. for 2h, then at rt for 16 h. About ⅔ of the solvent is removed in vacuo, the remaining mixture is diluted with water (250 mL) and extracted with DCM (200 mL). The organic extract is washed twice with 1 N aq. (100 mL). The combined aqueous layers are acidified by adding 2N aq. HCl and extracted three times with diethyl ether (3×300 mL). The organic extracts are dried over MgSO4 and evaporated. The remaining residue is suspended in acetonitrile, filtered, washed with additional acetonitrile and dried under high vacuum to give the title compound (12.02 g) as a pale yellow to beige crystalline powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH3:11])=[CH:8][C:9]=1N)=[O:4].N([O-])=O.[Na+].[ClH:16]>O.[Cu]Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH3:11])=[CH:8][C:9]=1[Cl:16])=[O:4]
Reactant: Cl
Reactant: COC(=O)c1sc(C)cc1N
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1sc(C)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
A mixture of 3-Amino-5-methyl-thiophene-2-carboxylic acid methyl ester (5.0 g, 29.2 mmol) in 6N HCl (25 ml) was cooled to 0° C. (ice bath). A solution of sodium nitrite (2.01 g, 29.2 mmol) in water (5 ml) was added dropwise and the mixture was stirred at 0° C. for 60 min This mixture was then added to a solution of copper(I)chloride (2.89 g, 29.2 mmol) in conc. HCl (25 ml) at 0° C. The reaction mixture was stirred at room temperature then warmed to 65° C. until gas evolution had ceased. The reaction mixture was diluted with water and extracted with EtOAc (2×150 mL), washed with water, brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by column (0-30% EtOAc in hexane) to give 4.4 g (79%) yellow oil product.
Reaction SMILES: [CH2:1]([N:3](CC)[CH2:4][CH3:5])[CH3:2].C[Al](C)C.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[N:24]=[C:23]2[O:25][C:26]([C:35](OCC)=[O:36])=[C:27]([NH:28][C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])[C:22]2=[CH:21][C:20]=1[C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[N:24]=[C:23]2[O:25][C:26]([C:35]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[O:36])=[C:27]([NH:28][C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])[C:22]2=[CH:21][C:20]=1[C:40]1[CH:41]=[CH:42][C:43]([Cl:46])=[CH:44][CH:45]=1
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1oc2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)cc2c1NC(=O)C(F)(F)F
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCN(CC)C(=O)c1oc2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)cc2c1NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a magnetically stirred solution of 0.119 mL (1.15 mmol) of triethylamine in 5 mL toluene was added 0.575 mL (1.15 mmol) of a 2.0 M solution of trimethylaluminum in toluene at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred for 30 min. A solution of 0.300 g (0.57 mmol) of the product of Example 181 in 1 mL CH2Cl2 was added to the reaction mixture and when the addition was complete the reaction mixture was heated at 60° C. for 2 h. The reaction mixture was allowed to cool again to room temperature and was partitioned between EtOAc and 10% aq. NaHSO4. The organic extracts were combined, washed with water and brine, dried (Na2SO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 0–30% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded the titled compound. HPLC/MS: 550.0 (M+1), 551.8 (M+3); Rt=4.74 min.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:32][C@H:33]([CH2:36][CH3:37])[CH2:34][OH:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:35][CH2:34][C@H:33]([NH:32][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:31])[CH3:29])[CH:19]=1)=[O:22])[CH2:36][CH3:37]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Reactant: CC[C@@H](N)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@H](CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
A 25 mL round-bottomed flask was charged with 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.10 g, 0.22 mmol), (R)-2-aminobutan-1-ol (65 mg, 0.73 mmol), HBTU (108 mg, 0.28 mmol), and HOBT (44 mg, 0.28 mmol). Then added DMF (1 mL) followed by N,N-diisopropylethylamine (0.11 mL, 0.66 mmol). The yellow reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (30 mL). The organic layer was washed once with saturated NaHCO3 and water. The combined aqueous layers were back extracted with EtOAc (25 mL). The combined organic layers was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over SiO2 with EtOAc/hexanes (gradient: 0-50% EtOAc) to afford 70 mg (61%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-hydroxymethyl-propyl)-amide as an off-white solid.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=2)[C:8]([NH2:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][N:23]=[C:24]=[O:25]>C1(C)C=CC=CC=1>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:12]=2)[C:8]([NH:10][C:24]([NH:23][CH3:22])=[O:25])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=O)C(CC1CCCC1)c1ccc(F)c(C(F)(F)F)c1
Reactant: CN=C=O
Solvent: Cc1ccccc1
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(F)c(C(F)(F)F)c1
Yield: 99.9 %

Procedure:
A solution of 3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionamide (303 mg, 1.0 mmol) in toluene (5 mL) was treated with methyl isocyanate (0.59 mL, 10 5 mmol). The resulting solution was heated to reflux for 24 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl afforded 1-[3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionyl]-3-methyl-urea (360 mg, 49.2%) as a pale yellow oil: FAB-HRMS m/e calcd for C17H20F4N2O2 (M+H)+361.1539, found 361.1534.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:17])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.C(O)(=[O:20])C>>[Br:1][C:2]1[C:3]([OH:17])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([CH3:16])=[O:20])=[CH:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: CC(=O)O
Reactant: CSc1ccc(Nc2ncc(Br)c(O)n2)cc1
Product: CS(=O)c1ccc(Nc2ncc(Br)c(O)n2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
11 g of 5-bromo-2-[4-(methylsulfanyl)phenylamino]pyrimidin-4-ol is suspended in 110 ml of glacial acetic acid. While being cooled with ice water, 4.6 ml of a 30% solution of hydrogen superoxide is added in drops. The mixture is stirred for 18 hours at room temperature and then suctioned off. The filter cake is washed twice with water and once with ethanol and dried at 60° C. in a vacuum. 8.75 g (75.7% of theory) of the product with a melting point of 240° C. (decomposition) is obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:24]([N:31]=[C:32]=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[CH2:24]([NH:31][C:32]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:8][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:11][CH2:12]1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C=NCc1ccccc1
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCNCC1
Solvent: ClCCl
Product: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(C(=O)NCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95.3 %

Procedure:
To a cold (0° C.), stirred solution of COMPOUND 249 (69 mg, 0.22 mmol) in CH2Cl2 (2 mL) was added benzyl isocyanate (35 μL, 0.28 mmol). After 15 minutes, the cooling bath was removed and the reaction mixture was warmed to room temperature. After an additional 45 minutes, the mixture was concentrated under reduced pressure. Purification of the crude material by radial chromatography on silica gel (1 mm plate, 25:1:1 CH2Cl2-MeOH—NH4OH) provided 93 mg (87%) of COMPOUND 271 as a white solid. 1H NMR (CDCl3) δ 1.60-1.71 (m, 2H), 1.88-1.93 (m, 2H), 2.08 (s, 6H), 2.61-2.69 (m, 3H), 3.81 (s, 4H), 4.05 (d, 2H, J=12.9 Hz), 4.42 (d, 2H, J=5.4 Hz), 4.74 (br t, 1H, J=5.4 Hz), 7.08 (dd, 2H, J=7.5, 5.1 Hz), 7.25-7.38 (m, 7H), 8.34 (d, 2H, J=3.6 Hz); 13C NMR (CDCl3) δ 18.36, 27.35, 44.58, 45.30, 54.99, 57.83, 122.81, 127.47, 128.03, 128.87, 133.82, 138.45, 140.13, 146.20, 157.52, 157.83; ES-MS m/z 444 (M+H). Anal. Calcd. For C27H33N5O.0.4.CH2Cl2: C, 68.91; H, 7.13; N, 14.66. Found: C, 69.19; H, 7.37; N, 14.64.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[I:12]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C>[CH3:11][O:10][C:8]([C:3]1[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([I:12])[N:4]=1)=[O:9]
Reactant: COC(=O)c1nccnc1N
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1nc(I)cnc1N
Temperature: 70 °C
Reaction time: 15 h
Yield: 61.5 %

Procedure:
Methyl 3-amino-2-pyrazinecarboxylate (10 g, 65.3 mmol) and N-iodosuccinimide (24 g, 106.7 mmol) were dissolved in anhydrous DMF (150 mL) and the mixture was stirred at 70° C. for 15 hours under a nitrogen atmosphere. The mixture was then cooled to room temperature and a saturated aqueous solution of sodium thiosulfate (400 mL) was added. The suspension was sonicated for 15 minutes, concentrated under vacuum and dispersed in water. The crude product was filtered off and washed with cold ethanol. The residue was crystallized from ethanol, using decolorizing charcoal to afford 3-amino-6-iodo-pyrazine-2-carboxylic acid methyl ester (11.2 g, 61% yield) as orange needles. 1H-NMR (d6-DMSO) δ: 8.57 [1H] s, 7.59 [2H] s, br, 3.93 [3H] s. MS: m/z 280 [MH+].