Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1.O>C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.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>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:2]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH:21]=1
Reactant: OB(O)c1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2cccnc2)C1
Yield: 96.2 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.605 mmol), a solution of 3-pyridineboronic acid (112 mg, 0.912 mmol) in ethanol (0.7 ml), 2N aqueous sodium carbonate solution (2.5 ml), and tetrakis(triphenylphosphine)palladium(0) (84.0 mg, 0.0730 mmol) in toluene (5 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (190 mg, 96.4%) as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH:7]([N:8]2[CH2:12][CH2:11][C@H:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][C:15]=3[F:24])[C:9]2=[O:25])[CH2:6][CH2:5][NH:4][CH2:3]1.[Cl:27][C:28]1[CH:33]=[N:32][C:31](Cl)=[CH:30][N:29]=1.C(N(C(C)C)C(C)C)C>CN(C=O)C.[Cl-].[Na+].O>[Cl:27][C:28]1[N:29]=[CH:30][C:31]([N:4]2[CH2:5][CH2:6][CH:7]([N:8]3[CH2:12][CH2:11][C@H:10]([NH:13][C:14]4[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:16][C:15]=4[F:24])[C:9]3=[O:25])[C:2]([CH3:26])([CH3:1])[CH2:3]2)=[N:32][CH:33]=1
Reactant: CC1(C)CNCCC1N1CC[C@H](Nc2ccc(S(C)(=O)=O)cc2F)C1=O
Reactant: Clc1cnc(Cl)cn1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC1(C)CN(c2cnc(Cl)cn2)CCC1N1CC[C@H](Nc2ccc(S(C)(=O)=O)cc2F)C1=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 17.7 %

Procedure:
To a solution of (3S)-1-(3,3-dimethylpiperidin-4-yl)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)pyrrolidin-2-one (0.010 g, 0.026 mmol) in DMF (1 mL) was added 2,5-dichloropyrazine (0.0078 g, 0.052 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.018 mL, 0.10 mmol) and the reaction was stirred for 3 hours at 100° C. The reaction was cooled, poured into brine and extracted into EtOAc. The organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated under vacuum. Reverse phase HPLC purification of the crude material gave (3S)-1-(1-(5-chloropyrazin-2-yl)-3,3-dimethylpiperidin-4-yl)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)pyrrolidin-2-one (0.0023 g, 0.0046 mmol, 18% yield) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 1.02 (s, 3H), 1.03 (s, 3H), 1.81-1.91 (m 1H), 2.12-2.21 (m, 1H), 2.71-2.81 (m, 2H), 2.95-3.05 (m, 2H), 3.03 (m, 3H), 3.52 (dd, 2H), 3.97 (d, 1H), 4.15-4.23 (m, 2H), 4.47-4.51 (m, 1H), 5.12 (bs, 1H), 6.80 (t, 1H), 7.55 (d, 1H), 7.61 (d, 1H), 7.90 (s, 1H), 8.05 (s, 1H).
Reaction SMILES: C(O)CCCCCCCO.FC1C=C(C=CC=1)CBr.[F:20][C:21]1[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=1)[CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][OH:34].FC1C=C(C=CC=1)COCCCCCCCC(O)=O.Cl.Cl.[CH2:59]([O:66][C:67](=[O:75])[CH2:68][C@@H:69]([NH2:74])[CH2:70][N:71]([CH3:73])[CH3:72])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>>[CH2:59]([O:66][C:67](=[O:75])[CH2:68][C@@H:69]([NH:74][C:33](=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][O:25][CH2:24][C:23]1[CH:35]=[CH:36][CH:37]=[C:21]([F:20])[CH:22]=1)[CH2:70][N:71]([CH3:72])[CH3:73])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: OCCCCCCCCOCc1cccc(F)c1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Agent: Cl
Agent: Fc1cccc(CBr)c1
Agent: O=C(O)CCCCCCCOCc1cccc(F)c1
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCOCc1cccc(F)c1

Procedure:
The title compound, m/e=397.4 ([M+H]+), was produced in analogy with intermediate 1, steps 1 to 4. Thus, 1,8-octanediol was alkylated in step 1 with 3-fluorobenzyl bromide, leading to 8-(3-fluoro-benzyloxy)-octan-1-ol, which was oxidized in step 2 to 8-(3-fluoro-benzyloxy)-octanoic acid. This was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-3-[8-(3-fluoro-benzyloxy)-octanoylamino]-4-dimethylamino-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[H-].[Na+].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:24]=[C:23]([C:25]([NH2:27])=[O:26])[O:22][N:21]=2)=[CH:16][CH:15]=1.O>CN(C=O)C>[N:1]1([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:24]=[C:23]([C:25]([NH2:27])=[O:26])[O:22][N:21]=3)=[CH:18][CH:19]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cc(-c2ccc(Cn3nnc4ccccc43)cc2)no1
Reaction time: 0.33 h
Yield: 35.1 %

Procedure:
To a mixture of benzotriazole (13 mg, 0.11 mmol) in DMF (1 mL) was added NaH (60% dispersion; 5 mg, 0.125 mmol). The mixture was stirred for 20 min and then a solution of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 30 mg, 0.107 mmol) in DMF (1 mL) was added. The reaction mixture was stirred at room temperature overnight. H2O was added and the mixture was extracted with EtOAc (3×25 mL). The combined organic layers were washed three times with H2O/brine, dried (Na2SO4), evaporated, and purified by chromatography (10-25% acetone/CH2Cl2) to give 3-(4-benzotriazol-1-ylmethyl-phenyl)-isoxazole-5-carboxylic acid amide (12 mg, 35%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.36 (br. s., 1H) 8.06 (d, J=8.2 Hz, 1H) 7.98 (br. s., 1H) 7.81-7.91 (m, 3H) 7.49-7.59 (m, 2H) 7.34-7.48 (m, 3H) 6.06 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:23])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18]C)=[C:14]([CH:20]([CH3:22])[CH3:21])[CH:13]=1)[C:5](O)=[O:6].[C:24]1([CH3:34])[C:25]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:23])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH:20]([CH3:22])[CH3:21])[CH:13]=1)[C:5]([C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([CH3:34])[C:25]=1[S:30]([NH2:33])(=[O:32])=[O:31])=[O:6]
Reactant: COc1ccc(Oc2c(Br)cc(C(=O)O)cc2Br)cc1C(C)C
Reactant: Cc1ccccc1S(N)(=O)=O
Product: Cc1cccc(C(=O)c2cc(Br)c(Oc3ccc(O)c(C(C)C)c3)c(Br)c2)c1S(N)(=O)=O
Yield: 73.5 %

Procedure:
3,5-Dibromo-4-(4-methoxy-3-isopropylphenoxy)benzoic acid (0.035 mmol) was coupled with 2-toluenesulphonamide (0.175 mmol) using the method described in Example 58. Purification on HPLC of the residue gave 15 mg (74%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[C:11]([O:15][CH2:16][CH2:17][NH2:18])([CH3:14])([CH3:13])[CH3:12]>>[NH2:1][C:2]1[CH:9]=[C:8]([NH:18][CH2:17][CH2:16][O:15][C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: N#Cc1cnc(N)cc1F
Reactant: CC(C)(C)OCCN
Product: CC(C)(C)OCCNc1cc(N)ncc1C#N

Procedure:
From intermediate 21 and 2-(tert-butoxy)ethanamine, reacted in an analogous manner to the preparation of intermediate 102. (UPLC-MS 3) Rt=0.58 min; MS m/z [M+H]+ 235.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][CH2:9][C:10](N)=[O:11])=[C:6]([Cl:13])[N:5]=[C:4](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:3]=1.[CH3:22][CH2:23][OH:24]>>[NH2:1][C:2]1[C:7]([CH2:8][CH2:9][C:10]([O:24][CH2:23][CH3:22])=[O:11])=[C:6]([Cl:13])[N:5]=[C:4](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:3]=1
Reactant: CCO
Reactant: NC(=O)CCc1c(N)nc(/C=C/c2ccccc2)nc1Cl
Product: CCOC(=O)CCc1c(N)nc(/C=C/c2ccccc2)nc1Cl
Temperature: 25 °C

Procedure:
3-{4-Amino-6-chloro-2-[(E)-2-phenylethenyl]-5-pyrimidinyl}propanamide (0.175 g, 0.58 mmol) was dissolved in EtOH and HCl gas was bubbled through the solution until saturated. The solution was heated at reflux for 2 h, cooled to ambient temperature and concentrated under vacuum. The residue was dissolved in water, neutralised to pH9 with K2CO3 solution and extracted with EtOAc (3×). The organic layers were combined, dried over Na2SO4, filtered and concentrated under vacuum to yield ethyl 3-{4-amino-6-chloro-2-[(E)-2-phenylethenyl]-5-pyrimidinyl}propanoate as a white solid. LCMS: m/z 332.2 (MH+). This product was then dissolved in DMF (5 mL), treated with K2CO3 (0.16 g, 1.16 mmol) and heated at 75° C. for 30 minutes. The solution was cooled, diluted with water and extracted with Et2O (3×). The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was then purified by column chromatography (silica gel) with DCM/(DCM:MeOH:NH4OH) 90:10:1 to yield an additional 0.11 g of the desired compound.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:16][C:15]=3[OH:25])[C:11]=2[CH2:12]O)=[O:6])[CH2:3][CH2:2]1.C(P(CCCC)CCCC)CCC.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1.C(OCC)(=O)C>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]3[C:14]4[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:16][C:15]=4[O:25][CH2:12][C:11]=23)=[O:6])[CH2:2][CH2:3]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CO)c(O)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCNC(=O)c1ccc2c(c1)OCc1c(C(=O)NC3CC3)nnn1-2
Temperature: 25 °C
Reaction time: 7 h
Yield: 80.3 %

Procedure:
N-Cyclopropyl-1-{4-[(ethylamino)carbonyl]-2-hydroxyphenyl}-5-(hydroxymethyl)-1H-1,2,3-triazole-4-carboxamide (300 mg, 0.868 mmol) obtained in Example 317 was dissolved in THF (6.0 ml), tributylphosphine (0.300 ml, 1.13 mmol, 1.3 eq.) and ADDP (290 mg, 1.13 mmol, 1.3 eq.) were added, and the mixture was stirred at room temperature for 7 hr. The reaction mixture was diluted with ethyl acetate (10 ml), and the precipitate was collected by filtration, washed with ethyl acetate and suspended in water. The insoluble component was collected by filtration, washed with water and methanol and dried to give the title compound as a white powder (228 mg, 0.697 mmol, 80.2%).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]([Cl:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[CH2:15][C:16](=O)[CH3:17].[I-].[Na+]>CO>[NH2:12][C:10]1[N:11]2[CH:15]=[C:16]([CH3:17])[N:1]=[C:2]2[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][C:9]=1[Cl:13]
Reactant: COC(=O)c1cc(Cl)c(N)nc1N
Reactant: CC(=O)CBr
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(Cl)c(N)n2cc(C)nc12
Reaction time: 24 h
Yield: 59 %

Procedure:
A mixture of methyl 2,6-diamino-5-chloronicotinate (EXAMPLE 1, Step 3, 15 g, 74.4 mmol), bromoacetone (10.4 mL, 112 mmol) and sodium iodide (16.7 g, 112 mmol) in methanol (700 mL) was stirred under reflux for 22 h. Another 2.5 mL (33 mmol) of bromoacetone was added and the stirring was continued for 24 h. The reaction mixture was quenched with saturated aqueous sodium carbonate and removed methanol in vacuo. The residue was extracted with ethyl acetate (250 mL×10) adding a small amount of methanol to dissolve the organic solid. The organic extracts were dried over sodium sulfate and concentrated. Purification by column chromatography on silica gel eluting with dichloromethane/methanol (20:1) gave a dark brown solid, which was washed with ethyl acetate and filtered to afford 10.5 g (43.9 mmol, 59%) of the title compound as a pale brown solid.
Reaction SMILES: C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.CS(C)=O.[Cl:18][C:19]1[C:20]([NH:25][CH2:26][C@H:27]([C@H:29]2[C@H:36]3[C@H:32]([O:33][C:34]([CH3:38])([CH3:37])[O:35]3)[C:31]([CH2:39][O:40][C:41]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:30]2)[OH:28])=[N:21][CH:22]=[CH:23][N:24]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:18][C:19]1[C:20]([NH:25][CH2:26][C:27]([C@H:29]2[C@H:36]3[C@H:32]([O:33][C:34]([CH3:38])([CH3:37])[O:35]3)[C:31]([CH2:39][O:40][C:41]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[CH:30]2)=[O:28])=[N:21][CH:22]=[CH:23][N:24]=1
Reactant: CC1(C)O[C@H]2[C@H]([C@H](O)CNc3nccnc3Cl)C=C(COC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2O1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)O[C@@H]2[C@H](O1)C(COC(c1ccccc1)(c1ccccc1)c1ccccc1)=C[C@H]2C(=O)CNc1nccnc1Cl
Reaction time: 0.5 h

Procedure:
TFAA (0.459 mL, 3.25 mmol, 3.2 equiv) in DCM (0.5 mL) was added dropwise to DMSO (0.303 mL, 4.26 mmol, 4.2 equiv) in DCM (0.5 mL) at −78° C. After 30 minutes, (S)-2-(3-chloropyrazin-2-ylamino)-1-((3aS,4S,6aR)-2,2-dimethyl-6-(trityloxymethyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)ethanol (1-6) (593 mg, 1.01 mmol, 1 equiv) in DCM (2.7 mL) was added dropwise. The resulting mixture was stirred at −78° C. for 1 hour, at which point Hunig's base (1.06 mL, 6.09 mmol, 6 equiv) was added. After 30 minutes, the reaction was partitioned between sodium bicarbonate and DCM, and the aqueous phase was extracted with DCM (3×20 mL), the combined organic extracts were washed with water, dried (MgSO4), and concentrated. The resulting yellow residue was purified via flash chromatography on silica gel column (ethyl acetate/hexanes) to yield 2-(3-chloropyrazin-2-ylamino)-1-((3aS,4R,6aR)-2,2-dimethyl-6-(trityloxymethyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)ethanone (1-7) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.93 (d, 1H, J=3 Hz), 7.64 (d, 1H, J=3 Hz), 7.21-7.49 (m, 15H), 5.94 (s, 1H), 5.62 (m, 1H), 4.97 (t, 1H, J=6 Hz), 4.60-4.77 (2 d, 1H, J=7 Hz), 3.95 (d, 1H, J=14 Hz), 3.75 (m, 2H), 3.31 (m, 1H), 1.36 (s, 3H), 1.33 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][NH:4][N:3]=1.C(O)(=O)C.O[CH:14]=[CH:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1)=O.C(O)C>C(Cl)Cl>[F:25][C:24]([F:26])([F:27])[C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:16]2[N:3]3[N:4]=[CH:5][C:6]([C:7]#[N:8])=[C:2]3[N:1]=[CH:14][CH:15]=2)[CH:19]=1
Reactant: N#Cc1c[nH]nc1N
Reactant: O=C(C=CO)c1cccc(C(F)(F)F)c1
Solvent: CCO
Solvent: ClCCl
Solvent: CC(=O)O
Product: N#Cc1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12

Procedure:
A solution of 0.54 g. of 3-aminopyrazole-4-carbonitrile and 1.29 g. of 3-hydroxy-3'-(trifluoromethyl)acrylophenone acetate in 25 ml. of absolute ethanol is refluxed for 15 hours. The mixture is cooled and filtered giving a solid which is dissolved in methylene chloride and treated as described in Example 1, giving the desired product, m.p. 141°-142.5° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.[CH2:25]([Mg]Cl)[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>C1COCC1>[C:14]([C:11]1[CH:10]=[C:7]([CH:8]([OH:9])[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:12]=1[OH:13])([CH3:17])([CH3:16])[CH3:15]
Reactant: Cl[Mg]CCc1ccccc1
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(O)CCc2ccccc2)cc(C(C)(C)C)c1O
Temperature: 80 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
To a 5-liter, 4-neck round-bottom flask fitted with a mechanical stirrer, reflux condenser, thermometer, and addition funnel were charged 238.5 grams (1.02 moles) of 3,5-di-t-butyl-4-hydroxybenzaldehyde and 979 grams of toluene. To this suspension, a one molar solution of phenethylmagnesium chloride in THF was slowly added such that the pot temperature slowly rose to 40° C. After the addition of several hundred milliliters of Grignard reagent solution a green sticky solid formed. The addition was halted, an additional 859 mL of toluene was added, and the solution was warmed to 80° C. The remaining Grignard reagent was slowly added while maintaining the pot temperature between 50° C. and 70° C. After the addition was complete, the reaction mixture was stirred at 70° C. for one hour. During this time, the green solids dissolved and the reaction mixture formed two liquid phases. After this time, the reaction was cooled and then quenched by slowly adding 80 mL of deionized water. The quenched reaction mixture was then poured into six liters of water. The organic phase was separated and the solvent removed in vacuo. The resulting crude product was then dissolved in warm hexane and filtered. The filtrate was washed with hexane (2×100 mL). The hexane portions were combined and solvent removed producing 242 grams (69.8 percent) of a viscous amber oil.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@@H:6]([CH2:7][OH:8])[O:5][C@H:4]1[N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[NH2:18].N1C=CC=CC=1.[C:25]([Si:29](Cl)([CH3:31])[CH3:30])([CH3:28])([CH3:27])[CH3:26]>C(OCC)(=O)C>[O:8]([CH2:7][C@H:6]1[O:5][C@@H:4]([N:9]2[CH:17]=[N:16][C:15]3[C:10]2=[N:11][CH:12]=[N:13][C:14]=3[NH2:18])[C@@H:3]1[CH2:2][OH:1])[Si:29]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:31])[CH3:30]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@H]1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]1CO
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In a round-bottom flask were placed 10 g of 9-((2R,3R,4S)-3,4-bis-hyroxymethyl-oxetan-2-yl)adenine and 100 mL of pyridine. To the system was added 6.4 g of tert-butylchlorodimethylsilane, and the reaction mixture was stirred under nitrogen at room temperature for 1 day. The mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine, dried (sodium sulfate) and concentrated with a rotary evaporator. The residue was purified by column chromatography to afford 9-((2R, 3R, 4S)-4-t-butyldimethylsiloxymethyl-3-hydroxymethyl -oxetan-2-yl)adenine.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4]([S:13](Cl)(=[O:15])=[O:14])=[CH:3]1.[CH3:17][NH2:18]>>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4]([S:13]([NH:18][CH3:17])(=[O:15])=[O:14])=[CH:3]1
Reactant: Cn1cc(S(=O)(=O)Cl)c(=O)c2ccccc21
Reactant: CN
Product: CNS(=O)(=O)c1cn(C)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-methyl-4-oxo-1,4-dihydroquinoline-3-sulphonyl chloride (3.56 g) and aqueous methylamine (30% w/v; 100 ml) was stirred at room temperature for 1 hour. The precipitated solid was filtered off, washed with water and crystallised from aqueous acetic acid to give the compound 1,N-dimethyl-4-oxo-1,4-dihydroquinoline-3-sulphonamide, m.p. 248°-250°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:8][C:9]([F:19])([F:18])[C:10](=O)[CH2:11][C:12](OCC)=[O:13]>>[F:8][C:9]([F:19])([F:18])[C:10]1[CH:11]=[C:12]([OH:13])[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:1]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Product: Oc1cc(C(F)(F)F)nc2ccccc12

Procedure:
A mixture of the appropriate aniline and ethyl 4,4,4-trifluoro-3-oxobutanoate may be treated with polyphosphoric acid to afford the requisite 2-(trifluoromethyl)quinolin-4-ol (see British Pat. Appl. GB 1419789 A 19751231).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2C(OC(C)(C)C)=O)=[CH:6][C:5]([F:20])=[CH:4][N:3]=1.[ClH:21]>O1CCOCC1>[ClH:1].[ClH:21].[Cl:1][C:2]1[C:7]([C@H:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:6][C:5]([F:20])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1c1cc(F)cnc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: Fc1cnc(Cl)c([C@H]2CCCN2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a dioxane (5 mL) solution of (R)-tert-butyl 2-(2-chloro-5-fluoropyridin-3-yl)pyrrolidine-1-carboxylate (500 mg, 1.66 mmol) was added HCl (4 N dioxane, 20 mL), followed by stirring at ambient temperature overnight. The mixture was concentrated and treated with Et2O, then vacuum-dried, to provide the product as a white solid (0.36 g, 80%). MS (apci pos) m/z=201.1 (M+H). The enantiomeric excess (ee %) of the product was determined to be >92% according to the method described in Preparation A.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([CH2:7][C:8]#[N:9])=[O:6].[C:13]1([N:19](C2C=CC=CC=2)[CH:20]=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1.CCOCC>[I:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([C:7](=[CH:20][NH:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]#[N:9])=[O:6]
Reactant: N#CCC(=O)c1cccc(I)c1
Reactant: O=CN(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: N#CC(=CNc1ccccc1)C(=O)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
A mixture of 2-(3-iodobenzoyl)acetonitrile (36.2 g, 133.5 mmol) and N,N-diphenylformamide (26.2 g, 133.5 mmol) in toluene (200 ml) was heated at reflux under a nitrogen atmosphere. After 8 h, the reaction mixture was cooled to room temperature and diluted with ether (200 ml) to give 2-(3-iodobenzoyl)-3-phenylaminoacrylonitrile (31.2 g) as a solid.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:14][C:13]=2[CH3:21])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CS(C)=O>[CH3:11][S:8]([C:7]1[CH:6]=[CH:5][C:4]([C:12]2[S:16][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:14][C:13]=2[CH3:21])=[CH:3][C:2]=1[N:26]1[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]1)(=[O:10])=[O:9]
Reactant: CN1CCNCC1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(F)c2)s1
Solvent: CS(C)=O
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(N3CCN(C)CC3)c2)s1
Temperature: 115 °C

Procedure:
A stirred mixture of N-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 64) (0.05 g, 0.15 mmol) and 1-methylpiperazine (0.1 ml, 0.9 mmol) in dry DMSO (1 ml) is heated under argon at 115° C. for 1 hour. The solvent is removed and water (30 ml) is added. The product is extracted with ethyl acetate (2×30 ml) and the combined organic extracts are washed with brine (20 ml) and dried (MgSO4). Removal of the solvent and trituration with diethyl ether affords the title compound as a yellow solid.
Reaction SMILES: COC([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[N:7]([CH3:15])[CH:6]=1)=O.[CH3:16][O:17][C:18](C1NC2C(C=1)=CC=C(Br)C=2)=[O:19]>>[CH3:16][O:17][C:18]([C:6]1[N:7]([CH3:15])[C:8]2[C:13]([CH:5]=1)=[CH:12][CH:11]=[C:10]([Br:14])[CH:9]=2)=[O:19]
Reactant: COC(=O)c1cn(C)c2cc(Br)ccc12
Reactant: COC(=O)c1cc2ccc(Br)cc2[nH]1
Product: COC(=O)c1cc2ccc(Br)cc2n1C

Procedure:
The title compound is prepared essentially as described in the preparation of 6-bromo-1-methyl-1H-indole-3-carboxylic acid methyl ester utilizing 6-bromo-1H-indole-2-carboxylic acid methyl ester, ES/MS m/e 270.0 (M+2).