Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2N=N1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([CH3:40])([CH3:39])[C:36](O)=[O:37])=[CH:31][CH:30]=1.CN1CCOCC1.C1(N)CCCCC1.CN(C=O)C.C(O)(C(F)(F)F)=O>CS(C)=O>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]([CH3:40])([CH3:39])[C:36]([NH:8][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:11]2)=[O:37])=[CH:33][CH:34]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CC(C)(C(=O)O)c1ccc(Cl)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: NC1CCCCC1
Solvent: CS(C)=O
Product: CC(C)(C(=O)NC1CCCCC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
BOP (200 μL, 0.25 M in DMF, 50 μmol) was added to a solution of 2-(4-chlorophenyl)-2-methylpropanoic acid (200 μL, 0.25 M in DMF, 50 μmol) at RT, followed by addition of N-methyl morpholine (40 μL). The mixture was stirred at RT for 15 min, then a solution of cyclohexylamine in DMF (200 μL, 0.25 M in DMF, 50 μmol) was added. The resulting mixture was stirred at RT for 3 h, and then was adjusted by TFA to PH=2.0, and diluted with DMSO (1100 μL). The resulting solution was purified by prep.-HPLC to afford the desired product 2-(4-chlorophenyl)-N-cyclohexyl-2-methylpropanamide. LCMS: (M+H)+=280.0/282.0.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[Cl:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[NH:17][C:18]1[C:23]([CH3:24])=[C:22]([NH:25][CH:26]2[CH2:28][CH2:27]2)[N:21]2[N:29]=[CH:30][C:31]([CH:32]=O)=[C:20]2[N:19]=1)[C:12]#[N:13].N1CCCCC1>C(O)C.O>[Cl:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[NH:17][C:18]1[C:23]([CH3:24])=[C:22]([NH:25][CH:26]2[CH2:27][CH2:28]2)[N:21]2[N:29]=[CH:30][C:31]([CH:32]=[C:7]3[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1]3)=[C:20]2[N:19]=1)[C:12]#[N:13]
Reactant: Cc1c(Nc2ccc(C#N)cc2Cl)nc2c(C=O)cnn2c1NC1CC1
Reactant: O=C1CNC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Solvent: O
Product: Cc1c(Nc2ccc(C#N)cc2Cl)nc2c(C=C3NC(=O)NC3=O)cnn2c1NC1CC1
Temperature: 80 °C
Reaction time: 10 h
Yield: 57.8 %

Procedure:
Hydantoin (2.7 mg, 0.027 mmol) and 3-chloro-4-(7-(cyclopropylamino)-3-formyl-6-methylpyrazolo[1,5-a]pyrimidin-5-ylamino)benzonitrile (10 mg, 0.027 mmol) were dissolved in ethanol (0.4 mL) along with piperidine (3 uL, 0.03 mmol). The reaction was heated at 80° C. After 10 hours, the reaction was cooled to r.t., diluted with water, and the precipitate was collected and washed with water, 1:1 ethanol:water, then ethanol. The bright yellow solid was dried in vacuo to give 3-chloro-4-(7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)-6-methylpyrazolo[1,5-a]pyrimidin-5-ylamino)benzonitrile (7 mg, 58% yield).
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:5]=2[S:4](=[O:14])(=[O:13])[N:3]=1.[CH3:15][CH:16]([NH2:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>>[Cl:12][C:9]1[CH:10]=[CH:11][C:5]2[S:4](=[O:14])(=[O:13])[N:3]=[C:2]([NH:21][CH:16]([CH3:15])[C:17]([CH3:20])([CH3:19])[CH3:18])[NH:7][C:6]=2[CH:8]=1
Reactant: CC(N)C(C)(C)C
Reactant: O=S1(=O)N=C(Cl)Nc2cc(Cl)ccc21
Product: CC(NC1=NS(=O)(=O)c2ccc(Cl)cc2N1)C(C)(C)C

Procedure:
Starting from 3,6-dichloro-4H-1,2,4-benzothiadiazine 1,1-dioxide (500 mg; 1.99 mmol) and 1,2,2-trimethylpropylamine (500 mg; 5.62 mmol) with the use of same procedure as in example 21 250 mg (39.8%) of the title compound was prepared; m.p. >220° C.; 1H-NMR (DMSO-d6) ppm; 10.3 (s, 1H, NH), 7.70 (d, 1H, H-8), 7.31 (dd, 1H, H-7), 7.25 (br d, 1H, H-5), 7.15 (br, 1H, NH), 3.75 (q, 1H, CH), 1.10 (d, 3H, CH3), 0.9 (s, 9H, 3×CH3). Analysis: C13H18ClN3O2S requires C, 49.44; H, 5.74; N, 13.3; (found C, 49.37; H, 6.04; N, 13.11).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:6](=O)[CH2:7][CH2:8][C:9]=2[CH:10]=1.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([F:27])=[C:17]([C@@:19]2([CH3:26])[NH:24][C:23](=[O:25])[CH2:22][O:21][CH2:20]2)[CH:18]=1.[B][B][B][B][B][B][B][B][B][B].C(=O)([O-])O.[Na+]>CO.ClCCl>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([F:27])=[C:17]([C@@:19]4([CH3:26])[NH:24][C:23](=[O:25])[CH2:22][O:21][CH2:20]4)[CH:18]=3)[CH2:7][CH2:8][C:9]=2[CH:10]=1
Reactant: C[C@@]1(c2cc(N)ccc2F)COCC(=O)N1
Reactant: O=C1CCc2cc(Cl)cnc21
Agent: O=C([O-])O
Agent: [B][B][B][B][B][B][B][B][B][B]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: C[C@@]1(c2cc(NC3CCc4cc(Cl)cnc43)ccc2F)COCC(=O)N1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A solution of 3-chloro-5,6-dihydro-[1]pyrindin-7-one (34.5 mg, 0.21 mmol) and (R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-morpholin-3-one (50.1 mg, 0.22 mmol) in a mixture of methanol (7.3 ml) and dichloromethane (0.9 ml) was treated with decaborane (6.9 mg, 0.21 mmol). The reaction mixture was stirred at room temperature for 22 hours. For the workup, the mixture was poured into a saturated aqueous solution of sodium hydrogen carbonate, thereafter extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate, then evaporated at reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 20:80 as the eluent. The (R)-5-[5-((RS)-3-chloro-6,7-dihydro-5H-[1]pyrindin-7-ylamino)-2-fluoro-phenyl]-5-methyl-morpholin-3-one was obtained as an orange solid (50 mg, 71%); (calculated) C19H19ClFN3O2 [375.83]; (found) [M]+=376, [M+2]+=378.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]2[C:6]=1[CH2:7][C:8](=[O:15])[NH:9]2.[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C)C=O>[N:16]([CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]2[C:6]=1[CH2:7][C:8](=[O:15])[NH:9]2)=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1Cc2c(OCCCl)ccc(F)c2N1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCOc1ccc(F)c2c1CC(=O)N2

Procedure:
A solution of 4-(2-chloroethoxy)-7-fluoro-1,3-dihydro-indol-2-one (2.04 g, 8.88 mmol) and sodium azide in dimethylformamide (125 mL) was heated to 70° C. for 18 hours. The reaction mixture was partitioned between methylene chloride (100 mL) and water (100 mL). The organic layer separated and washed with water (50 mL) then dried over anhydrous magnesium sulfate, filtered, and the solvent removed under vacuum. The crude product was filtered through a pad of silica to afford a yellow solid, mp 147°-148° C. MS EI m/e 261 (M+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][S:19]([CH3:18])(=[O:21])=[O:20])=[C:6]([CH:7]=[O:8])[CH:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=Cc1cc(F)ccc1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Oc1ccc(F)cc1C=O
Reaction time: 0.25 h
Yield: 97.6 %

Procedure:
To a mixture of 0.500 g (3.57 mmole) of 5-fluoro-2-hydroxy-benzaldehyde, 0.694 g (6.4 mmole) of triethylamine, and 5 mL of dichloromethane at 0 degrees was added dropwise, 0.444 g (3.90 mmole) of methanesulfonyl chloride. Stirring was continued for 15 minutes. The mixture was diluted with 30 mL of dichloromethane and washed with 20 mL of saturated ammonium chloride solution, 20 mL of water, 20 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 0.760 g of methanesulfonic acid 4-fluoro-2-formyl-phenyl ester as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:25](=[O:37])[NH:26][CH2:27][C:28]2[C:29](=[O:36])[NH:30][C:31]([CH3:35])=[CH:32][C:33]=2[CH3:34])[C:5]([CH3:24])=[C:6]([N:8]([CH2:22][CH3:23])[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1.B(O)O.C([O-])([O-])=O.[Na+].[Na+].O1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1.O>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:34][C:33]1[CH:32]=[C:31]([CH3:35])[NH:30][C:29](=[O:36])[C:28]=1[CH2:27][NH:26][C:25]([C:4]1[C:5]([CH3:24])=[C:6]([N:8]([CH2:22][CH3:23])[CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[CH2:13][CH2:14]2)[CH:7]=[C:2]([C:7]2[CH:6]=[CH:5][C:4]([CH2:25][N:26]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)=[CH:3][CH:2]=2)[CH:3]=1)=[O:37]
Reactant: C1COCCO1
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: OBO
Solvent: O
Product: CCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 90 °C
Yield: 68.66 %

Procedure:
To a stirred solution of tert-butyl 4-((5-bromo-3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-2-methyl-phenyl)(ethyl)amino)piperidine-1-carboxylate (2 g, 3.47 mmol) and 4-(morpholinomethyl)-phenyl)boronic acid (1.58 g, 5.21 mmol) in dioxane/water mixture, Na2CO3 (1.32 g, 12.45 mmol) was added and solution purged with argon for 15 min. Then Pd (PPh3)4 (0.4 g, 0.35 mmol) was added and argon was purged again for 10 min. The reaction mixture was heated at 90° C. for 3.5 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM. Combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford desired compound (1.6 g, 68.66%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:9].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:14][C:15]([CH3:20])=[CH:16][C:17]([OH:19])=[O:18]>Cl>[CH3:9][C:4]1[CH:5]=[C:6]([C:15]([CH3:20])([CH3:14])[CH2:16][C:17]([OH:19])=[O:18])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccccc1C
Reactant: CC(C)=CC(=O)O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(C)(C)CC(=O)O)cc1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.4 %

Procedure:
To 2-methoxytoluene (146.7 g, 1.2 mol), aluminum chloride (44 g, 0.33 mol) and 3-methylcrotonic acid (30 g, 0.3 mol) were added, and the mixture was stirred at room temperature for 24 hours, and thereafter the reaction was stopped by the addition of six normal (6-N) hydrochloric acid aqueous solution (300 ml) thereto. Subsequently, from the thus-obtained mixture, the organic material was extracted with diethyl ether (150 ml). After that, one normal (1-N) caustic soda aqueous solution (100 ml) was added to the organic layer for extraction of the carboxylic acid(s). The thus-obtained alkaline mixture was acidified by the addition of hydrochloric acid (HCl) aqueous solution, and the mixture was extracted with diethyl ether and the solvent therein was removed by distillation. The thus-obtained residue was re-crystallized with hexane to obtain 3-(3-methyl-4-methoxyphenyl)-3-methylbutyric acid (39.6 g, yield: 59%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[S:18][C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:20]([CH3:22])[N:21]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:17]2[S:18][C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:20]([CH3:22])[N:21]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: CCOC(=O)c1sc(Br)nc1C
Product: CCOC(=O)c1sc(-n2ccc(OCc3ccccc3)cc2=O)nc1C
Yield: 80 %

Procedure:
Following the procedure as described in Example 12, making variations only as required to use 4-(benzyloxy)pyridin-2(1H)-one in place of 4-phenylpyridin-2-ol to react with ethyl 2-bromo-4-methylthiazole-5-carboxylate, the title compound was obtained as a yellow solid in 80% yield: 1H NMR (300 MHz, CDCl3) δ 8.65 (d, J=7.9 Hz, 1H), 7.42-7.26 (m, 5H), 6.18 (d, J=7.9 Hz, 1H), 6.07 (s, 1H), 5.01 (s, 2H), 4.28 (q, J=7.1 Hz, 1H), 2.65 (s, 3H), 1.32 (t, J=7.1 Hz, 3H); MS (ES+) m/z 371.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH:7]=[C:6]([C:19](OCC)=[O:20])[C:5]2=[O:24].[NH3:25]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH:7]=[C:6]([C:19]([NH2:25])=[O:20])[C:5]2=[O:24]
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c2ccc(Br)cc2c1=O
Reactant: N
Solvent: CO
Product: NC(=O)c1cn(-c2ccc(F)cc2)c2ccc(Br)cc2c1=O
Temperature: 150 °C
Yield: 95 %

Procedure:
Compound D (1.00 g, 2.56 mmol, 1.00 eq) was suspended in 7N ammonia in methanol (30 mL) in a microwave vial and the reaction was heated in a microwave reactor at 150° C. for 60 minutes. The reaction was concentrated to afford 881 mg (95%) of the title compound as a brown solid that was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 9.08 (d, J=4.0 Hz, 1H), 8.57 (s, 1H), 8.43 (d, J=2.4 Hz, 1H), 7.85 (dd, J=9.1, 2.4 Hz, 1H), 7.77-7.73 (m, 2H), 7.66 (d, J=4.1 Hz, 1H), 7.56-7.50 (m, 2H), 7.02 (d, J=9.1 Hz, 1H); ES-MS [M+1]+: 361.2.
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:15]2[N:14]=[CH:13][N:12]3[CH:16]=[N:17][C:18]([CH:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[O:26])[CH2:21][CH2:20]4)=[C:11]3[C:10]=2[CH:9]=[CH:8]1.C[Si](C)(C)CCOCN1C2N=CN3C=NC(C4CCCN(C(OCC5C=CC=CC=5)=O)C4)=C3C=2C=C1>>[C:18]1([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:26])[CH2:21][CH2:20]2)[N:17]=[CH:16][N:12]2[C:11]=1[C:10]1[CH:9]=[CH:8][NH:7][C:15]=1[N:14]=[CH:13]2
Reactant: C[Si](C)(C)CCOCn1ccc2c1ncn1cnc(C3CCN(C(=O)OCc4ccccc4)CC3)c21
Agent: C[Si](C)(C)CCOCn1ccc2c1ncn1cnc(C3CCCN(C(=O)OCc4ccccc4)C3)c21
Product: O=C(OCc1ccccc1)N1CCC(c2ncn3cnc4[nH]ccc4c23)CC1
Yield: 2 %

Procedure:
The reactions in Synthetic Examplea 3 were carried out in substantially the same manners except that benzyl 4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-imidazo[1,5-c]pyrrolo[3,2-e]pyrimidin-1-yl)piperidine-1-carboxylate obtained in Reference Synthetic Examplea 78 was used instead of benzyl 3-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-imidazo[1,5-c]pyrrolo[3,2-e]pyrimidin-1-yl)piperidine-1-carboxylate to give the title compound as a yellow solid (4.6 mg, yield 2%).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[C:8]1(B(O)O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:8]1([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][C:1]2=[O:7])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1C=CCCC1
Reactant: OB(O)c1ccccc1
Product: O=C1CCCCC1c1ccccc1

Procedure:
Lastly, to examine the utility of the catalyst on a somewhat larger scale, the reaction of cyclohexenone with phenylboronic acid was performed on a 20 mmol scale and the product 2-phenyl cyclohexanone was isolated in identical yield (83%) to the small-scale reaction (Table 1, entry 5). Thus, the ligands described herein may have practical application in larger scale reactions.
Reaction SMILES: N1C=CN=C1.[Cl:6][C:7]1[N:8]=[C:9]([CH2:21][OH:22])[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:11]=1[Cl:12].Cl[Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].[NH4+].[Cl-]>C(Cl)Cl>[Cl:6][C:7]1[N:8]=[C:9]([CH2:21][O:22][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:18])([CH3:19])[CH3:20])[C:11]=1[Cl:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[Si](C)(C)CCOCn1c(CO)nc(Cl)c1Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1nc(Cl)c(Cl)n1COCC[Si](C)(C)C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
Imidazole (282 mg, 4.14 mmol) was added to a solution of [4,5-dichloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazol-2-yl]methanol (614 mg, 2.07 mmol) and chloro(1,1-dimethylethyl)dimethylsilane (345 mg, 2.28 mmol) in DCM (8 mL) at RT under N2. The mixture was stirred overnight. Aqueous NH4Cl was then added. Extracted with DMC and the extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography (0-10% EtOAc in hexane) to give the title compound (845 mg, 99%) as a colorless oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 5.42 (2H, s) 4.74 (2H, s) 3.53-3.59 (2H, m) 0.87-0.95 (11H, m) 0.09 (6H, s) 0.00 (9H, s). LCMS: m/z 411 (M+1).
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[C:34]([CH2:35][CH2:36][OH:37])=[C:33]([F:38])[CH:32]=[CH:31][C:10]=1[CH2:11][N:12]1[CH2:30][CH2:29][C:15]2([O:20][CH2:19][CH2:18][N:17]([C:21]([C:23]3[S:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[O:22])[CH2:16]2)[CH2:14][CH2:13]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[F:8][C:9]1[C:10]([CH2:11][N:12]2[CH2:30][CH2:29][C:15]3([O:20][CH2:19][CH2:18][N:17]([C:21]([C:23]4[S:24][C:25]([CH3:28])=[CH:26][CH:27]=4)=[O:22])[CH2:16]3)[CH2:14][CH2:13]2)=[CH:31][CH:32]=[C:33]([F:38])[C:34]=1[CH2:35][CH:36]=[O:37]
Reactant: Cc1ccc(C(=O)N2CCOC3(CCN(Cc4ccc(F)c(CCO)c4F)CC3)C2)s1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)N2CCOC3(CCN(Cc4ccc(F)c(CC=O)c4F)CC3)C2)s1
Reaction time: 0.08 h

Procedure:
TFA (0.05 mL) was added to a solution of (9-(2,4-difluoro-3-(2-hydroxyethyl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(5-methylthiophen-2-yl)methanone (example 34, step a) (0.27 g) in DCM (5 mL) at 0° C. and the resulting mixture stirred for 5 min. Dess-Martin periodinane (0.38 g) was then added and the mixture stirred at RT for 45 min. Saturated sodium thiosulphate solution (5 mL), saturated sodium bicabonate solution (5 mL) and ethyl acetate (20 mL) were then added and the mixture stirred vigorously for 10 min. The aqueous phase was separated and extracted with ethyl acetate (20 mL). The combined organic solutions were washed with brine (20 mL), acidified with a few drops of acetic acid, dried over sodium sulphate, filtered and evaporated to give the subtitled compound as a clear gum. Yield 0.27 g.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)=[O:5].[CH:20]1[C:30]2[CH2:29][CH2:28][C:27]3[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=3[NH:25][C:24]=2[CH:23]=[CH:22][CH:21]=1.[H-].[Na+]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.ClCCl.O>[CH:20]1[C:30]2[CH2:29][CH2:28][C:27]3[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=3[N:25]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([NH:6][C:4](=[O:5])[C:3]4[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=4[CH3:1])=[CH:8][CH:9]=3)=[O:12])[C:24]=2[CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc2c(c1)CCc1ccccc1N2
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2c3ccccc3CCc3ccccc32)cc1
Temperature: 80 °C
Yield: 3.2 %

Procedure:
To a mixture of 1.37 g (5 mmol) of 4-[(2-methylbenzoyl)amino]benzoyl chloride and 0.061 g of 4-(dimethylamino)pyridine in 4 ml of pyridine is added 0.975 g (5 mmol) of 10,11-dihydro-5H-dibenz[b,f]azepine. The mixture is heated at 80° C. for 18 hours and then 0.2 g of sodium hydride (60% in oil) (5 mmol) is added. The mixture is refluxed for 2 hours, diluted with dichloromethane and water and then filtered. To the filtrate is added 1N HCl and the mixture filtered. The filtrate is dried (Na2 SO4) and the solvent removed to give a solid. The solid (1.1 g) is chromatographed on thick layer silica gel plates to give 70 mg of yellow solid, m.p. 112°-118° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][NH:10][CH3:11])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:12][C:13]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])[CH3:14].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:9][NH:10][CH3:11])=[CH:3][C:2]=1[C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([CH2:25][N:22]2[CH2:23][CH2:24][N:19]([C:17]([O:16][C:13]([CH3:15])([CH3:14])[CH3:12])=[O:18])[CH2:20][CH2:21]2)[CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(B(O)O)c2)CC1
Reactant: CNCc1ccc(F)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CNCc1ccc(F)c(-c2cccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c2)c1
Temperature: 150 °C
Yield: 65.8 %

Procedure:
To a solution of [(3-bromo-4-fluorophenyl)methyl]methylamine (0.52 g, 2.39 mmol) in p-dioxane/H2O (15/5 mL) was added {3-[(4-{[(1,1-dimethylethyl)oxy]carbonyl}-1-piperazinyl)methyl]phenyl}boronic acid (1.15 g, 3.60 mmol), Pd(PPh3)4 (139 mg, 0.12 mmol), and K2CO3 (1.33 g, 9.6 mmol). The mixture was heated with a microwave at 150° C. for 15 min. The organic layer was separated, concentrated. The residue was redissolved in EtOAc (˜70 mL), which was washed with H2O (20 mL), brine (20 mL), dried over Na2SO4, filtered, concentrated and purified by CombiFlash chromatograph to afford the title compound 0.65 g (66%). LC-MS m/z 414 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[N:7][C:8]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28]C(=O)OC(C)(C)C)[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:10]=2)[CH2:5][O:4][CH2:3]1>C(O)(C(F)(F)F)=O>[NH2:28][C:24]1([C:21]2[CH:20]=[CH:19][C:18]([C:8]3[N:7]=[C:6]4[CH2:5][O:4][CH2:3][C:2](=[O:1])[C:11]4=[CH:10][C:9]=3[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:23][CH:22]=2)[CH2:25][CH2:26][CH2:27]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=O)COC4)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=O)COC4)cc2)CCC1
Reaction time: 0.01 h
Yield: 103.8 %

Procedure:
tert-Butyl (1-(4-(5-oxo-3-phenyl-6,8-dihydro-5H-pyrano[3,4-b]pyridin-2-yl)phenyl)cyclobutyl)carbamate (12 mg, 0.026 mmol) was dissolved in TFA (1 mL) and stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜3 mL) and concentrated to dryness under reduced pressure three times. The residue was then slurried in diethyl ether (3 mL) and after settling the supernatant solvent removed by pipette. This was repeated three times. The remaining solvent was removed by freeze drying overnight to give the desired compound as an off-white solid (10 mg, 77% yield). 1H-NMR (500 MHz, MeOD) δ 8.19 (1H, s), 7.41 (2H, d), 7.32 (2H, d), 7.20-7.24 (3H, m), 7.11-7.15 (2H, m), 4.94 (2H, s), 4.37 (2H, s), 2.59-2.68 (2H, m), 2.39-2.49 (2H, m), 2.06-2.16 (1H, m), 1.79-1.95 (1H, m). LCMS (Method D) RT=0.86 min, M+H+=371.00.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13]C=2C)[N:4]=1.C(OCC)(=[O:23])C.O=[O+][O-]>O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]([C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH2:13])=[O:23])[N:4]=1
Reactant: CCOC(C)=O
Reactant: COc1cc(OC)nc(-c2c(C)[nH]c3ccccc23)n1
Agent: O=[O+][O-]
Solvent: O
Product: COc1cc(OC)nc(C(=O)c2ccccc2N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
In a reactor were placed 0.60 g (22 m moles) of 3-(4,6-dimethoxypyrimidine-2-yl)-2-methylindole and 20 ml of ethyl acetate. Thereinto was blown ozone at 0° C. to 10° C. for 4 hours. Thin-layer chromatography was conducted to confirm the disappearance of 3-(4,6-dimethoxypyrimidine-2-yl)-2-methylindole and complete a reaction. Then, the reaction mixture was heated to room temperature and concentrated. To the concentrate were added 20 ml of methanol and 5 ml of 6 N hydrochloric acid, and refluxing was made for 1 hour with heating. After the completion of the reaction, the reaction mixture was cooled to room temperature. 100 ml of water was added. The mixture was made alkaline with an aqueous sodium hydroxide solution, and extraction was made with ethyl acetate. The organic layer was concentrated. The concentrate was subjected to column chromatography separation to obtain 0.26 g (10 m moles) of 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)aniline. Yield: 46%