Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:27][OH:28])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[S:29](Cl)([CH3:32])(=[O:31])=[O:30]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:27][O:28][S:29]([CH3:32])(=[O:31])=[O:30])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)CCCCCCCNC(=O)C(CO)NS(=O)(=O)c1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Product: COC(=O)CCCCCCCNC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
The procedure described in Example 65 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-hydroxy-N-(7-methoxycarbonylheptyl)propanamide (504 mg) was reacted with mesyl chloride to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(7-methoxycarbonylheptyl)propanamide (503.2 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1([C:16]#[N:17])[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7]1.[Br:18]N1C(=O)CCC1=O>CN(C=O)C>[Br:18][C:5]1[S:1][C:2]([C:6]2([C:16]#[N:17])[CH2:7][CH2:8][C:9]3([O:13][CH2:12][CH2:11][O:10]3)[CH2:14][CH2:15]2)=[N:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#CC1(c2nccs2)CCC2(CC1)OCCO2
Solvent: CN(C)C=O
Product: N#CC1(c2ncc(Br)s2)CCC2(CC1)OCCO2
Temperature: 50 °C
Yield: 58.1 %

Procedure:
To a solution of 8-(1,3-thiazol-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (1.78 g, 7.11 mmol) in anhydrous DMF (25 ml) was added N-bromosuccinimide (1.52 g, 8.53 mmol). The solution was heated at 50° C. for 2 h. The reaction was cooled to 23° C. then diluted with saturated aqueous NaS2O3 (175 ml) and extracted with EtOAc (2×130 ml). The combined organic layers were washed with brine (150 ml), dried over Na2SO4, filtered and concentrated. The crude yellow oil was purified via flash column chromatography (SiO2: 100% Hex to 60:40 Hex:EtOAc), to afford 8-(5-bromo-1,3-thiazol-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (1.43 g, 4.13 mmol, 58% yield) as an off-white solid. MS ESI: [M+H]+ m/z 331.1. 1H NMR (500 MHz, CDCl3): δ 7.66 (s, 1H), 4.01-3.93 (m, 4H), 2.39-2.26 (m, 4H), 2.07-2.01 (m, 2H), 1.88-1.86 (m, 2H).
Reaction SMILES: CS(Cl)(=O)=O.[N:6]1([CH2:19][C@@H:20](O)[CH3:21])[CH:10]=[CH:9][C:8]2[CH2:11][O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:7]1=2.C(N(CC)CC)C.[N-:30]=[N+:31]=[N-:32].[Na+]>ClCCl.C(OCC)C.CN(C)C=O.O>[N:30]([C@H:20]([CH3:21])[CH2:19][N:6]1[CH:10]=[CH:9][C:8]2[CH2:11][O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:7]1=2)=[N+:31]=[N-:32]
Reactant: C[C@H](O)Cn1ccc2c1-c1ccccc1OC2
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: ClCCl
Product: C[C@H](Cn1ccc2c1-c1ccccc1OC2)N=[N+]=[N-]
Yield: 79 %

Procedure:
1.15 ml of methanesulfonyl chloride were added dropwise while stirring to a solution, cooled to 0°, of 1.7 g of (S)-1-(1,4-dihydro-[1]benzopyrano[4,3-b]pyrrol-1-yl)-propan-2-ol and 4.13 ml of triethylamine in 50 ml of anhydrous dichloromethane and the mixture was stirred at this temperature for an additional 1.5 hours. The reaction mixture was subsequently diluted with 200 ml of diethyl ether, washed twice with 70 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of diethyl ether. The combined organic phases were washed with 140 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The brown solid obtained was dissolved in 50 ml of anhydrous dimethylformamide, treated with 0.88 g of sodium azide and the reaction mixture was heated to 60° while stirring for 18 hours. After cooling, the solution was poured into 140 ml of water and extracted twice with 140 ml of diethyl ether each time. The combined organic phases were washed once with 100 ml of water and once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (toluene). 1.49 g (79%) of (R)-1-(2-azido-propyl)-1,4-dihydro-[1]benzopyrano[4,3-b]-pyrrole were obtained as a colorless oil.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[N:16]([CH2:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[N:15]=[CH:14]3)=[CH:5][CH:4]=1.[ClH:28].N1C=CC=CC=1>O>[ClH:28].[OH:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[N:16]([CH2:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[N:15]=[CH:14]3)=[CH:5][CH:4]=1
Reactant: COc1ccc(/C=C/c2ccc3c(=O)n(CCCN(C)C)ncc3c2)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CN(C)CCCn1ncc2cc(/C=C/c3ccc(O)cc3)ccc2c1=O
Temperature: 180 °C
Reaction time: 7 h

Procedure:
Trans-6-[2-(4-Methoxyphenyl)ethenyl]-2-[3-(dimethylamino)propyl]-phthalazin-1(2H)-one (prepared as in Example XIV) (46.6 gm, 0.122 mole) and 245 gm pyridine hydrochloride were heated together with stirring at 180° C. for 7 hours. The hot melt was added to 1200 ml water and stirred over night. The product was filtered off and washed with three 400 ml portions of water. The damp product was slurried in 350 ml of tetrahydrofuran plus 350 ml methanol, acidified with gaseous HCl, filtered and washed with ethanol. The product, which weighed 36 gm, was recrystallized from 275 ml water. Wgt=30.2 gm, mp=283°-283° C.
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.O.[CH2:13]([C:21]1[CH:30]=[CH:29][C:24]2[N:25]=[C:26](N)[S:27][C:23]=2[CH:22]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].N([O-])=O.[Na+].[K+].[Br-:36]>CC#N.O>[Br:36][C:26]1[S:27][C:23]2[CH:22]=[C:21]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:30]=[CH:29][C:24]=2[N:25]=1
Reactant: CCCCCCCCc1ccc2nc(N)sc2c1
Reactant: [Br-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCCCCCCCc1ccc2nc(Br)sc2c1
Temperature: 12.5 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
To a solution of p-TsOH.H2O (108 mg, 0.57 mmol) in MeCN (2 mL) was added compound 6-octylbenzo[d]thiazol-2-amine (50 mg, 0.19 mmol). The resulting suspension was cooled to 10-15° C. and to this was added, gradually, a solution of NaNO2 (26 mg, 0.38 mmol) and KBr (56 mg, 0.48 mmol) in H2O (0.5 mL). The mixture was then stirred at r.t. for 1 h. Then the mixture was extracted with EtOAc and purified by silica gel chromatography using PE to give product the title compound (50 mg, 82%). 1H NMR (300 MHz, CDCl3) δ 7.880 (t, 1H), 7.585 (s, 1H), 7.286 (t, 1H), 2.711 (t, 2H), 1.686-1.571 (m, 2H), 1.309-1.186 (m, 10H), 0.874 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([O:6][CH3:7])([CH3:5])[CH3:4].[I:8][C:9]1([CH2:12][C@@H](O)CO)[CH2:11][CH2:10]1>ClCCl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[I:8][C:9]1([CH2:12][C@@H:1]2[CH2:7][O:6][C:3]([CH3:5])([CH3:4])[O:2]2)[CH2:11][CH2:10]1
Reactant: OC[C@H](O)CC1(I)CC1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC1(C)OC[C@@H](CC2(I)CC2)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.8 %

Procedure:
2,2-Dimethoxypropane (140 mg, 1.337 mmol) and pyridinium p-toluenesulfonate (PPTS, 6 mg) were added to a solution of crude (R)-3-(1-iodocyclopropyl)propane-1,2-diol (step F, 0.598 mmol) dissolved in dichloromethane (3 mL) and the mixture stirred at room temperature for 2 hours. Solvents were removed under reduced pressure and the crude product purified by flash chromatography using ethyl acetate/hexane (1:10) eluant to afford (R)-4-((1-iodocyclopropyl)methyl)-2,2-dimethyl-1,3-dioxolane (84 mg, 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH3:13])[N:10]([CH:14]3[C:18](=[O:19])/[C:17](=[CH:20]\[C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=4)/[CH2:16][C:15]3=[O:28])[N:9]=2)=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH3:13])[N:10]([CH:14]3[C:18](=[O:19])[CH:17]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=4)[CH2:16][C:15]3=[O:28])[N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nn1C1C(=O)C/C(=C/c2ccc(F)cn2)C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(-c2ccc(Cl)cc2)nn1C1C(=O)CC(Cc2ccc(F)cn2)C1=O
Yield: 98.7 %

Procedure:
To a solution of 2-[3-(4-chloro-phenyl)-5-methyl-pyrazol-1-yl]-4-[1-(5-fluoro-pyridin-2-yl)-meth-(Z)-ylidene]-cyclopentane-1,3-dione (17 mg, 0.04 mmol) in methanol (0.4 ml) was added 5% palladium on activated charcoal (2 mg) and the reaction stirred for 6 hours under 1.5 bar of hydrogen. The solution was then filtered through a pad of Celite, washed with methanol (10 ml) and concentrated in vacuo to give a white solid, which was purified by column chromatography using DCM:EtOAc:AcOH (9:1:0.01%) to (3:7:0.01%) to give 2-[3-(4-chloro-phenyl)-5-methyl-pyrazol-1-yl]-4-(5-fluoro-pyridin-2-ylmethyl)-cyclopentane-1,3-dione (15.7 mg).
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:16][C:12]3([CH2:15][O:14][CH2:13]3)[CH2:11]2)(=O)=O)=CC=1.[Mg].[C:19]([OH:24])(=[O:23])[C:20]([OH:22])=[O:21]>CO>[C:19]([OH:24])(=[O:23])[C:20]([OH:22])=[O:21].[CH2:13]1[C:12]2([CH2:16][NH:10][CH2:11]2)[CH2:15][O:14]1
Reactant: Cc1ccc(S(=O)(=O)N2CC3(COC3)C2)cc1
Agent: O=C(O)C(=O)O
Agent: [Mg]
Solvent: CO
Product: C1NCC12COC2
Reaction time: 0.25 h

Procedure:
A mixture of 6-(toluene-4-sulfonyl)-2-oxa-6-aza-spiro[3.3]heptane (128) (1.27 g, 5 mmol) in MeOH (10 mL) was added magnesium chips. The mixture was reacted using ultrasound at RT for 20 mins. Oxalic acid was added and the mixture was stirred for 15 min, then concentrated to give oxalate salt (129) (1.06 g, 3.68 mmol, yield: 73.6%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([CH:12]=[N:13]O)=[C:8]2[C:3]=1[CH:4]=[N:5][CH:6]=[N:7]2.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC.O>CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[C:8]2[C:3]=1[CH:4]=[N:5][CH:6]=[N:7]2
Reactant: ON=Cc1ccc(Br)c2cncnc12
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Br)c2cncnc12
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 59.8 %

Procedure:
To a solution of 5-Bromo-quinazoline-8-carbaldehyde oxime (3000.00 mg; 11.90 mmol; 1.00 eq.) in DMF (15 ml) was added 2,4,6-Tripropyl-[1,3,5,2,4,6]trioxatriphosphinane 2,4,6-trioxide (10.42 ml; 17.85 mmol; 1.50 eq.) 50% in DMF. The resulting mixture was stirred at 100° C. for 45 min, LCMS showed major peak (MS: 252/254, 234/236) and small (MS: 208/209). The reaction mixture was cooled, poured into water, extracted with EtOAc, dried and concentrated to yield sticky solid, which was washed with ether to collected the title product (1665 mg. yield 59.6%). LC-MS (232/234 and 250/252).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC(CNC(CN2C3C(=CC=CC=3)C(C=O)=C2)=O)=CC=1.[N:42]([CH2:45][C@H:46]1[O:50][C:49](=[O:51])[N:48]([C:52]2[CH:57]=[CH:56][C:55]([CH:58]([O:61][CH3:62])[O:59][CH3:60])=[C:54]([F:63])[CH:53]=2)[CH2:47]1)=[N+]=[N-].C([BH3-])#N.[Na+]>C1COCC1>[NH2:42][CH2:45][C@@H:46]1[O:50][C:49](=[O:51])[N:48]([C:52]2[CH:57]=[CH:56][C:55]([CH:58]([O:59][CH3:60])[O:61][CH3:62])=[C:54]([F:63])[CH:53]=2)[CH2:47]1
Reactant: COC(OC)c1ccc(N2C[C@@H](CN=[N+]=[N-])OC2=O)cc1F
Agent: O=Cc1cn(CC(=O)NCc2ccccc2)c2ccccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(OC)c1ccc(N2C[C@H](CN)OC2=O)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triphenylphosphine (0.130 g, 0.496 mmol) was added to a mixture of BAL aldehyde resin (0.57 g, 0.165 mmol) and 5-(S)-azidomethyl-3-[4′-dimethoxymethyl-3′-fluorophenyl]-oxazolidine-2-one (0.154 g, 0.496 mmol) in THF (3 ml) at room temperature. The mixture was stirred at room temperature for 2 h, and then at 75° C. for 16 h. The mixture was cooled to room temperature, and 1 M sodium cyanoborohydride in THF (0.99 ml, 0.992 mmol) was added in one portion. The reaction mixture was agitated for 8 h. The resulting amine resin was washed liberally with methanol and dichloromethane and dried under vacuum.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[CH2:18][NH:17][CH2:16][C:15](=[O:19])[N:14]([CH2:20][CH3:21])[C:13]=3[CH:22]=2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:42][CH2:43][OH:44]>C(O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[CH2:18][N:17]([CH2:42][CH2:43][OH:44])[CH2:16][C:15](=[O:19])[N:14]([CH2:20][CH3:21])[C:13]=3[CH:22]=2)=[N:6][CH:7]=1
Reactant: OCCBr
Reactant: CCN1C(=O)CNCc2ccc(Nc3ncc(Cl)c(Nc4c(F)cccc4C(=O)NC)n3)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCN1C(=O)CN(CCO)Cc2ccc(Nc3ncc(Cl)c(Nc4c(F)cccc4C(=O)NC)n3)cc21
Temperature: 75 °C
Yield: 44.9 %

Procedure:
A mixture of 2-[5-chloro-2-(1-ethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-methyl-benzamide (90 mg, 0.19 mmol), potassium carbonate (77 mg, 0.56 mmol) and 2-bromoethanol (47 mg, 0.37 mmol) in ethanol (5 mL) was heated at 75° C. for 16 hours. Concentration and chromatography on preparative TLC with methylene chloride and methanol (100:9) gave 45 mg of 2-{5-chloro-2-[1-ethyl-4-(2-hydroxy-ethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino]-pyrimidin-4-ylamino}-3-fluoro-N-methyl-benzamide (46%): 1H NMR (300 MHz, CD3OD) δ 8.1 (s, 1H), 7.6 (s, 1H), 7.45 (d, 1H), 7.3 (m, 3H), 7.15 (d, 1H), 3.75 (t, 2H), 3.72 (q, 2H), 3.48 (s, 2H), 3.1 (s, 2H), 2.83 (s, 3H), 2.77 (t, 2H), 1.07 (t, 3H); MS (m/e) 528.4 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)[N:4]=1.C([O:16][C:17](=[O:28])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([Cl:27])[CH:21]=1)C>>[Cl:27][C:22]1[CH:21]=[C:20]([CH2:19][CH2:18][C:17]([OH:28])=[O:16])[CH:25]=[CH:24][C:23]=1[O:26][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)[N:4]=1
Reactant: ClCc1cccc(SC2CCC2)n1
Reactant: CCOC(=O)CCc1ccc(O)c(Cl)c1
Product: O=C(O)CCc1ccc(OCc2cccc(SC3CCC3)n2)c(Cl)c1
Yield: 54.5 %

Procedure:
2-Chloromethyl-6-cyclobutylsulfanyl-pyridine (34 mg, 0.17 mmol) obtained in Step C of Preparation Example 37 and 3-(3-chloro-4-hydroxy-phenyl)-propionic acid ethyl ester (43 mg, 0.19 mmol) obtained in Step C of Preparation Example 42 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (35 mg, 63%).
Reaction SMILES: [F:1][C:2]([F:53])([F:52])[C:3]1[CH:4]=[C:5]([C:13]([CH3:51])([CH3:50])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:31]3[C@H:40]([CH2:41][O:42][Si](C(C)(C)C)(C)C)[CH2:39][N:38]4[C@H:33]([CH2:34][O:35][CH2:36][CH2:37]4)[CH2:32]3)=[CH:22][C:23]=2[C:24]2[CH:25]=[N:26][CH:27]=[CH:28][C:29]=2[CH3:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl>CO>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C:13]([CH3:51])([CH3:50])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:31]3[C@H:40]([CH2:41][OH:42])[CH2:39][N:38]4[C@H:33]([CH2:34][O:35][CH2:36][CH2:37]4)[CH2:32]3)=[CH:22][C:23]=2[C:24]2[CH:25]=[N:26][CH:27]=[CH:28][C:29]=2[CH3:30])[CH3:17])=[O:15])[CH:4]=[C:3]([C:2]([F:1])([F:53])[F:52])[CH:8]=1
Reactant: Cc1ccncc1-c1cc(N2C[C@H]3COCCN3C[C@H]2CO[Si](C)(C)C(C)(C)C)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Solvent: CO
Product: Cc1ccncc1-c1cc(N2C[C@H]3COCCN3C[C@H]2CO)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
2-[3,5-bis(trifluoromethyl)phenyl]-N-{6′-[(7S,9aS)-7-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-4-methyl-3,4′-bipyridin-3′-yl}-N,2-dimethylpropanamide (D53, 86 mg) was dissolved in dry MeOH (4 mL), cooled in an ice/salt bath to ˜0° C. before adding c.HCl solution. The mixture was stirred at ˜0° C. for 45 mins before allowing to warm up to R.T. and stirring for a further 2 hrs. Placed on a 5 g SCX column, washed with MeOH ×3, before eluting compound off with NH3 in MeOH. Solvent evaporated. Residue purified on a 5 g sek pak column eluting with Pent to EtOAc to 10% MeOH/EtOAc. Solvent evaporated to dryness in vacuo to afford a colourless gum of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4](C([O-])=O)[C:5]([C:8]([O:10]C)=[O:9])=[CH:6][CH:7]=1.C(N(CC)CC)C.C1(C)C=CC=CC=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CC(C)=O.O>[C:8]([OH:10])(=[O:9])[C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: COC(=O)c1ccc(Br)cc1C(=O)[O-]
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1ccccc1
Temperature: 80 °C

Procedure:
To a solution of the mixture from Example 11 (2.07 g; 8 mmol), triethylamine (6.0 ml; 0.043 mol), and toluene (80 ml) was added diphenylphosphoryl azide (5.0 g; 0.018 mol) and the reaction mixture was heated at 80° C. for 2 hours. The reaction mixture was diluted with acetone (200 ml) and water (40 ml), heated further at 80° C. for 8 hours, cooled to room temperature and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with 15% ethyl acetate/hexane) to provide benzoic acid, 2-amino-4-bromo, methyl ester (0.514 g) as a white solid and benzoic acid, 2-amino-5-bromo, methyl ester (0.930 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:43]=[C:44]([CH2:48][C:49]([N:51]2[CH2:56][CH2:55][N:54]([CH2:57][CH3:58])[CH2:53][CH2:52]2)=[O:50])[CH:45]=[CH:46][CH:47]=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:43]=[C:44]([CH2:48][C:49]([N:51]6[CH2:52][CH2:53][N:54]([CH2:57][CH3:58])[CH2:55][CH2:56]6)=[O:50])[CH:45]=[CH:46][CH:47]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: CCN1CCN(C(=O)Cc2cccc(Br)c2)CC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: CCN1CCN(C(=O)Cc2cccc(N3CCc4c(-c5cnc(N(Cc6ccc(OC)cc6)Cc6ccc(OC)cc6)nc5)nc(N5CCOCC5)nc43)c2)CC1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (200 mg) and 2-(3-bromo-phenyl)-1-(4-ethyl-piperazin-1-yl)-ethanone (137 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of 2-[3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-phenyl]-1-(4-ethyl-piperazin-1-yl)-ethanone was obtained, and further PMB group was removed according to the above Deprotection method 2, to obtain the desired compound (D-184) as a pale yellow powder (112 mg, 60%).
Reaction SMILES: [Li+].[Cl-].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22][CH3:23])[CH:18]=3)[CH:13]([C:24]3[CH:29]=[CH:28][C:27]4[O:30][CH2:31][O:32][C:26]=4[CH:25]=3)[CH:12]2[C:33]([O:35][CH3:36])=[O:34])=[C:7](OS(C(F)(F)F)(=O)=O)[CH:6]=1.C([Sn]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)(CCCC)CCCC)CCC>O1CCOCC1.C(OCC)(=O)C.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>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22][CH3:23])[CH:18]=3)[CH:13]([C:24]3[CH:29]=[CH:28][C:27]4[O:30][CH2:31][O:32][C:26]=4[CH:25]=3)[CH:12]2[C:33]([O:35][CH3:36])=[O:34])=[C:7]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[CH:6]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OS(=O)(=O)C(F)(F)F)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1-c1ccccc1)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Temperature: 25 °C

Procedure:
To a slurry of anhydrous LiCl (46 mg, 1.1 mmol) and tetrakis(triphenylphosphine)palladium(0) (24 mg, 0.02 mmol) in dry dioxane (3 mL) was added a solution of Methyl(1RS,2RS,3RS)-3-(4-Methoxy-2-trifluoromethanesulfonyloxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (95 mg, 0.16 mmol) and tri(but-1-yl)stannylbenzene (319 mg, 0.87 mmol) in dioxane (1 mL). The mixture was refluxed under Argon for 17 h, cooled to room temperature, diluted with ethyl acetate (5 ml) and the resulting solution washed sequentially with brine and water. The organic layer was dried (MgSO4 anhydrous), filtered through a short pad of silica gel and concentrated in vacuo to yield an oil. The product was purified by flash column chromatography (silica gel, gradient elution from hexanes to 10% ethyl acetate/hexanes) to afford the title compound as a white solid. (92 mg, 86%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[F:16])[C:5]([OH:7])=O)[CH3:2].[NH2:17][CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=1[O:27][CH3:28]>>[C:23]([C:22]1[CH:25]=[CH:26][C:19]([CH2:18][NH:17][C:5](=[O:7])[CH:4]([O:3][CH2:1][CH3:2])[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[F:16])=[C:20]([O:27][CH3:28])[CH:21]=1)#[N:24]
Reactant: COc1cc(C#N)ccc1CN
Reactant: CCOC(C(=O)O)c1ccc(OC)cc1F
Product: CCOC(C(=O)NCc1ccc(C#N)cc1OC)c1ccc(OC)cc1F

Procedure:
(RS)-Ethoxy-(2-fluoro-4-methoxy-phenyl)-acetic acid, described in example 63.1 was coupled with 4-aminomethyl-3-methoxy-benzonitrile (CAS 182159-14-4) according to general procedure B to give (RS)-N-(4-cyano-2-methoxy-benzyl)-2-ethoxy-2-(2-fluoro-4-methoxy-phenyl)-acetamide. Yellow oil. MS 373.2 ([M+H]+)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[Cl:30][C:31]1[CH:36]=[C:35](I)[C:34]([Cl:38])=[CH:33][N:32]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:30][C:31]1[CH:36]=[C:35]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[C:34]([Cl:38])=[CH:33][N:32]=1
Reactant: Clc1cc(I)c(Cl)cn1
Reactant: OB(O)c1cccc(F)c1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: Fc1cccc(-c2cc(Cl)ncc2Cl)c1
Temperature: 95 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-fluorophenylboronic acid (0.776 g, 5.5 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.140 g, 0.15 mmol), tricyclohexylphosphine (0.087 g, 0.31 mmol), and 2,5-dichloro-4-iodopyridine 20 (1.5 g, 5.6 mmol) was added dioxane (15 mL) and a solution of potassium phosphate (2.0 g, 9.6 mmol) in water (7.5 mL). The reaction mixture was degassed by bubbling nitrogen through the solution for 10 min, and the reaction mixture was heated to 95° C. After 2 h, the reaction mixture was diluted with EtOAc, washed with water (1×), brine (1×), dried over MgSO4, filtered through a pad of silica gel (1.5 cm), and concentrated. Purification by flash column chromatography on silica gel (5% to 10% EtOAc in hexanes) gave 2,5-dichloro-4-(3-fluorophenyl)pyridine.