Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([C:11]1([NH2:32])[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:15]2[CH:25]=[C:26](Br)[CH:27]=[CH:28][C:14]=2[N:13]([CH3:30])[C:12]1=[O:31])=O)C1C=CC=CC=1>[Pd].CO>[NH2:32][CH:11]1[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:15]2[CH:25]=[CH:26][CH:27]=[CH:28][C:14]=2[N:13]([CH3:30])[C:12]1=[O:31]
Reactant: CN1C(=O)C(N)(C(=O)OCc2ccccc2)N=C(c2ccccc2F)c2cc(Br)ccc21
Agent: [Pd]
Solvent: CO
Product: CN1C(=O)C(N)N=C(c2ccccc2F)c2ccccc21
Reaction time: 21 h

Procedure:
A flask was charged with 3-(benzyloxycarbonyl)-amino-7-bromo-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one (1 eq.; Example 4-D, Step A) and 10% palladium on carbon. Methanol was added, and the flask was placed under a balloon of H2. The reaction was stirred for 21 hours. The mixture was filtered through celite washing with methanol. The filtrate was concentrated to a white solid.
Reaction SMILES: C([O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([OH:13])=[C:7]([C:14](=[O:16])[CH3:15])[C:6]=1[CH3:17])(=O)C.[C:18]1(=O)[CH2:21][CH2:20][CH2:19]1.N1CCCC1.Cl>C1(C)C=CC=CC=1.[OH-].[Na+].CO.O>[OH:4][C:5]1[C:6]([CH3:17])=[C:7]2[C:8](=[C:9]([CH3:12])[C:10]=1[CH3:11])[O:13][C:18]1([CH2:21][CH2:20][CH2:19]1)[CH2:15][C:14]2=[O:16]
Reactant: CC(=O)Oc1c(C)c(C)c(O)c(C(C)=O)c1C
Reactant: O=C1CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1O)C(=O)CC1(CCC1)O2
Yield: 40 %

Procedure:
To a solution of the above solid 3-acetyl-4-hydroxy-2,5,6-trimethylphenyl acetate (35 g) in 150 mL of toluene was added cyclobutanone (11.4 g) and pyrrolidine (15 mL). The reaction was allowed to reflux for 2 hours and water from the reaction was removed using a Dean-Stark apparatus. After the reaction was complete, the mixture was extracted with ethyl acetate and washed with 1N HCl and water. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to give 34 g of acetyl-protected product as a dark brown residue. This residue was hydrolyzed in 1N NaOH in MeOH/water for 3 hours. After the reaction was complete as indicated by TLC, the mixture was acidified with 1N HCl and extracted with ethyl acetate and dried over anhydrous Na2SO4. After concentration in vacuo, the resulting dark brown residue (30 g) was loaded onto a short silica gel column, and eluted with 10-40% ethyl acetate in hexane. Recrystallization of the resulting product from ethyl acetate and hexane gave 14.6 g of the desired 6-hydroxy-5,7,8-trimethylspiro[chromene-2,1′-cyclobutan]-4(3H)-one as a yellow solid. The mother liquid was concentrated to give another 4 g of crude 6-hydroxy-5,7,8-trimethylspiro[chromene-2,1′-cyclobutan]-4(3H)-one as a dark brown residue that can further be purified as described above. 1H-NMR (300 MHz, CDCl3) δ=4.61 (s, 1H), 2.86 (s, 2H), 2.56 (s, 3H), 2.30-1.70 (m, 12H) ppm. 13C-NMR (75 MHz, CDCl3) δ=195.3, 152.8, 146.2, 132.3, 124.2, 120.9, 117.3, 79.6, 47.7, 33.2, 13.4, 12.9, 12.4, 12.3 ppm. MS: m/z=247.1 (M+H+)
Reaction SMILES: [CH2:1]([N:3]([CH2:36][CH3:37])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:69][C:70]1[S:71][CH:72]=[CH:73][N:74]=1>CN(C=O)C>[CH2:1]([N:3]([CH2:36][CH3:37])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([NH:69][C:70]2[S:71][CH:72]=[CH:73][N:74]=2)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2]
Reactant: Nc1nccs1
Reactant: CCN(CC)CCCNc1nc(-c2cccc(C(=O)O)c2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1nc(-c2cccc(C(=O)Nc3nccs3)c2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]benzoic acid (30 mg, 0.06 mmol) in DMF (0.5 mL) were added HBTU (27 mg, 0.072 mmol), triethylamine (16.9 uL, 0.12 mmol) and 2-aminothiazole (9.01 uL, 0.09 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (20.5 mg, 58%). LC-MS m/z 590 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:14]3[CH:15]=[C:16]([NH:21][C:22](=[O:33])[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)[CH:17]=[CH:18][C:19]=3[CH3:20])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][N:3]=1.[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:42]=[C:43]([NH2:47])[CH:44]=[CH:45][CH:46]=2)[CH2:37][CH2:36]1.[Cl-].C(C1C=CC=C(CCC)C=1[N+]1C=CN(C2C(CCC)=CC=CC=2CCC)C=1)CC>O1CCOCC1>[CH3:20][C:19]1[CH:18]=[CH:17][C:16]([NH:21][C:22](=[O:33])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=2)=[CH:15][C:14]=1[C:7]1[C:8](=[O:13])[N:9]([CH3:12])[C:10]2[C:5]([CH:6]=1)=[CH:4][N:3]=[C:2]([NH:47][C:43]1[CH:44]=[CH:45][CH:46]=[C:41]([N:38]3[CH2:37][CH2:36][N:35]([CH3:34])[CH2:40][CH2:39]3)[CH:42]=1)[CH:11]=2
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cc2cnc(Cl)cc2n(C)c1=O
Reactant: CN1CCN(c2cccc(N)c2)CC1
Agent: CCCc1cccc(CCC)c1-n1cc[n+](-c2c(CCC)cccc2CCC)c1
Agent: [Cl-]
Solvent: C1COCCO1
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cc2cnc(Nc3cccc(N4CCN(C)CC4)c3)cc2n(C)c1=O
Reaction time: 14 h

Procedure:
N-[3-(7-Chloro-1-methyl-2-oxo-1,2-dihydro-[1,6]naphthyridin-3-yl)-4-methyl-phenyl]-3-trifluoromethyl-benzamide (50 mg, 0.106 mmol) is mixed with 3-(4-Methyl-piperazin-1-yl)-phenylamine (31 mg, 0.16 mmol), Pd2(dba)2 (2.4 mg, 2.5%), 1,3-Bis(2,6-di-1-propylphenyl)imidazolium chloride (2.3 mg, 5%) and potassium tert-butanoxide (17.8 mg, 0.159 mmol) under an argon environment. 6 mL of anhydrous 1,4-dioxane is added and the reaction is continued at 100° C. for 14 hours. After cooling and removal of solvent under vacuum, the crude product is dissolved in DMSO and purified by reverse phase preparative HPLC to give the final product as a pale solid: 1H NMR 400 MHz (DMSO-d6) δ 10.47 (s, 1H), 9.43 (s, 1H), 8.58 (s, 1H), 8.30 (s, 1H), 8.26 (d, 1H, J=8.1 Hz), 7.21 (d, 1H, J=7.9 Hz), 7.83 (s, 1H), 7.79 (t, 1H, J=7.8 Hz), 7.69 (m, 2H), 7.37 (s, 1H), 7.21 (m, 3H), 6.74 (s, 1H), 6.65 (d, 1H, J=6.5 Hz), 3.80 (d, 2H, J=13.9 Hz), 3.56 (s, 3H), 3.54 (d, 2H, J=13.9 Hz), 3.18 (m, 2H), 2.98 (m, 2H), 2.88 (d, 3H, J=3.8 Hz), 2.14 (s, 3H); MS m/z 627.3 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:28][C@@:26]3([CH3:27])[C@@H:22]([CH2:23][CH2:24][C:25]3=O)[C@H:21]3[C:12]2=[C:13]2[C:18]([CH2:19][CH2:20]3)=[CH:17][C:16](=[O:30])[CH2:15][CH2:14]2)=[CH:7][CH:6]=1.[Cl:31]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:31][C:17]1[C:16](=[O:30])[CH2:15][CH2:14][C:13]2[C:18]=1[CH2:19][CH2:20][C@@H:21]1[C:12]=2[C@@H:11]([C:8]2[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][CH2:2][OH:1])=[CH:10][CH:9]=2)[CH2:28][C@@:26]2([CH3:27])[C@H:22]1[CH2:23][CH2:24][CH2:25]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: C[C@]12C[C@H](c3ccc(CCCO)cc3)C3=C4CCC(=O)C=C4CC[C@H]3[C@@H]1CCC2=O
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@]12CCC[C@H]1[C@@H]1CCC3=C(Cl)C(=O)CCC3=C1[C@@H](c1ccc(CCCO)cc1)C2
Yield: 74.7 %

Procedure:
To a solution of 11.9 g of 11β-[4-(3-hydroxypropyl)phenyl]-estra-4.9-diene-3.17-dione prepared to preparation 1 in 100 ml of DMF, under inert atmosphere and at 60° C., 4.93 g of N-chloro succinimide is added and stirred for 10 mn at this temperature. It is poured into water, drawn off, washed, dried, evaporated under reduced pressure until 16.2 g of raw expected product is obtained that is purified by chromatography by eluting with the compound CH2Cl2/Acetone 85/15. 9.34 g of pure expected product is obtained.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[NH2:6].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O.[OH-].[Na+]>N1C=CC=CC=1>[C:15]([NH:6][C:5]1[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:3]([C:2]([F:13])([F:14])[F:1])[CH:4]=1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
A mixture of 3-(trifluoromethyl)-4-nitroaniline (1.00 g, 4.85 mmol) and benzoyl chloride (0.62 ml, 5.34 mmol) were heated in pyridine (20 ml) at reflux for 3 hours under an inert atmosphere. The reaction was allowed to cool to ambient temperature, poured into water (200 ml) and basified by addition of 2.0 N aqueous sodium hydroxide solution. An oily liquid separated out which crystallised on standing at 4° C. overnight. The solid was collected by suction filtration, washed with water (3×20 ml) and then purified by flash chromatography on silica gel, eluting with dichloromethane. This yielded N-benzoyl 3-(trifluoromethyl)-4-nitroaniline (1.01 g, 67% yield) as a white solid:
Reaction SMILES: [C:1]([N:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7]([N+]([O-])=O)=[CH:6][C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]1=2)#[N:2].C([O:23]CCO)C>Cl.[Fe]>[C:1]([N:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[O:23])[CH2:6][C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]1=2)#[N:2]
Reactant: CCOCCO
Reactant: N#CN1c2ccccc2C=C([N+](=O)[O-])c2ccccc21
Agent: [Fe]
Agent: Cl
Product: N#CN1c2ccccc2CC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
26.3 g (0.1 mole) of 5-cyano-10-nitro-5H-dibenz[b,f]azepine are suspended in a mixture of 265 ml of ethylene glycol monoethyl ether and 75 ml of concentrated hydrochloric acid. 40 g of iron powder are added in small portions at 40° in the course of 40 minutes and the temperature is maintained at 40° by external cooling. The mixture is stirred for a further 2 hours at room temperature, is then heated to 80°, the precipitated product dissolving again, and is filtered through a heated suction filter, which is subsequently washed with ethylene glycol monoethyl ether. The crystallisation which commences in the filtrate is completed by adding 200 ml of water. After cooling for one hour in an ice-bath, filtration is carried out followed by washing with a mixture of ethylene glycol monoethyl ether and water in a ratio of 1:1. 5-cyano-10-oxo-10,11-dihydro-5H-dibenz[b,f]azepine is obtained which is identified, by comparing the IR spectra, with material from Example 27.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH3:10])[CH:5]=[CH:4][C:3]=1B(O)O.Br[C:15]1[CH:20]=[C:19]([F:21])[C:18]([C:22]([F:44])([F:43])[O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[C:34]([F:36])[C:33]([C:37]([F:40])([F:39])[F:38])=[C:32]([F:41])[CH:31]=3)=[C:26]([F:42])[CH:25]=2)=[C:17]([F:45])[CH:16]=1.[OH-].[NH3+]N>C1COCC1.O.CC(OC)(C)C.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>[F:43][C:22]([F:44])([C:18]1[C:19]([F:21])=[CH:20][C:15]([C:3]2[CH:4]=[CH:5][C:6]([CH2:8][CH2:9][CH3:10])=[CH:7][C:2]=2[F:1])=[CH:16][C:17]=1[F:45])[O:23][C:24]1[CH:25]=[C:26]([F:42])[C:27]([C:30]2[CH:35]=[C:34]([F:36])[C:33]([C:37]([F:40])([F:39])[F:38])=[C:32]([F:41])[CH:31]=2)=[CH:28][CH:29]=1
Reactant: Fc1cc(OC(F)(F)c2c(F)cc(Br)cc2F)ccc1-c1cc(F)c(C(F)(F)F)c(F)c1
Reactant: CCCc1ccc(B(O)O)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N[NH3+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CCCc1ccc(-c2cc(F)c(C(F)(F)Oc3ccc(-c4cc(F)c(C(F)(F)F)c(F)c4)c(F)c3)c(F)c2)c(F)c1

Procedure:
A mixture of 2.60 g (14.3 mmol) of 2-fluoro-4-propylbenzeneboronic acid, 7.0 g (13.1 mmol) of 4′-[(4-bromo-2,6-difluorophenyl)difluoromethoxy]-3,5,2′-trifluoro-4-trifluoromethylbiphenyl, 0.30 g (0.42 mmol) of bis(triphenyl-phosphine)palladium(II) chloride and 2.80 g (10.1 mmol) of sodium metaborate octahydrate is initially introduced in 40 ml of THF/water=3:1. 0.02 ml (0.4 mmol) of hydrazinium hydroxide is added, and the mixture is refluxed for 20 h. After cooling, the batch is diluted with MTBE, and the mixture is washed with water. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with water. The solution is dried using sodium sulfate and concentrated to dryness. The residue is purified by column chromatography (SiO2, n-heptane). The further purification is carried out by recrystallisation from ethanol and n-heptane, giving 4-[difluoro(3,5,2′-trifluoro-4′-propyl-biphenyl-4-yl)methoxy]-6,3′,5′-trifluoro-4′-trifluoromethylbiphenyl as a colourless solid.
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]#[CH:8])(=[O:4])[CH:2]=[CH2:3].[CH2:9]([N:25]=[N+:26]=[N-:27])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].O>CN(C=O)C>[CH2:9]([N:25]1[CH:8]=[C:7]([CH2:6][O:5][C:1](=[O:4])[CH:2]=[CH2:3])[N:27]=[N:26]1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCCCCCN=[N+]=[N-]
Reactant: C#CCOC(=O)C=C
Solvent: CN(C)C=O
Solvent: O
Product: C=CC(=O)OCc1cn(CCCCCCCCCCCCCCCC)nn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
Propargyl acrylate (1.10 g, 10 mmoles), hexadecyl azide (2.37 g, 10 mmoles) and tetrakis(acetonitrile)copper (I) hexafluorophosphate (74 mg, 0.2 mmoles) are dissolved in DMF (20 ml) and stirred at room temperature under nitrogen for 24 hours. The reaction mixture is poured into water wherefrom the product precipitated as a white crystalline solid (2.95 g; yield 85%; mp 72-73° C.). 1H NMR (CDCl3, δ ppm) 7.61 (s, 1H), 6.44 (d, 1H), 6.14 (dd, 1H), 5.85 (d, 1H), 5.31 (s, 2H), 4.34 (t, 2H), 1.92 (q, 2H), 1.26 (m, 28H), 0.88 (t, 3H). 13C NMR (CDCl3, δ ppm) 166.00, 142.73, 131.39, 128.04, 123.64, 57.75, 50.43, 31.89, 30.22, 29.66, 29.65, 29.64, 29.62, 29.61, 29.56, 29.47, 29.33, 29.32, 28.95, 26.46, 22.66, 14.08. MS for C12H39N3O2 calculated 377.58; found 377.20.
Reaction SMILES: C[N:2](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[O:23]=[S:24]1(=[O:49])[C:29]2[CH:30]=[C:31]([O:34][C:35]3[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][C:43](O)=[O:44])=[CH:37][CH:36]=3)[CH:32]=[CH:33][C:28]=2[N:27]2[CH2:46][CH2:47][CH2:48][C:26]2=[N:25]1.C(N(C(C)C)CC)(C)C.N.Cl>C(Cl)Cl.CCOC(C)=O>[O:23]=[S:24]1(=[O:49])[C:29]2[CH:30]=[C:31]([O:34][C:35]3[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][C:43]([NH2:2])=[O:44])=[CH:37][CH:36]=3)[CH:32]=[CH:33][C:28]=2[N:27]2[CH2:46][CH2:47][CH2:48][C:26]2=[N:25]1
Reactant: O=C(O)CCc1ccc(Oc2ccc3c(c2)S(=O)(=O)N=C2CCCN23)cc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NC(=O)CCc1ccc(Oc2ccc3c(c2)S(=O)(=O)N=C2CCCN23)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
415 mg (1.30 mmol) of TBTU are added to a suspension (500 mg, 1.30 mmol) of the compound obtained in Step B of Example 2 in 25 ml of CH2Cl2. The suspension is stirred at ambient temperature for 10 minutes and 293 μl (1.68 mmol) of diisopropylethylamine are added. The reaction mixture becomes a solution and stirring is continued for 10 minutes. The solution is then saturated with ammonia gas and stirring is continued for 30 minutes. Thin-layer chromatography (AcOEt) indicates that all the starting material has disappeared. The reaction mixture is then acidified by adding 1N HCl; the organic phase is decanted off, washed (water and then saturated NaCl solution), dried (MgSO4) and evaporated. The residue is triturated in Et2O and the white solid formed is filtered off to yield the title product.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[CH:12]4[CH2:18][CH2:17][NH:16][CH2:15][CH2:14][CH:13]4[N:5]([C:6]=23)[CH2:4][CH2:3]1.Cl[CH2:20][CH2:21][CH2:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)=[O:24].CCN(C(C)C)C(C)C>O1CCOCC1>[CH3:1][N:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[CH:12]4[CH2:18][CH2:17][N:16]([CH2:20][CH2:21][CH2:22][C:23]([C:25]5[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=5)=[O:24])[CH2:15][CH2:14][CH:13]4[N:5]([C:6]=23)[CH2:4][CH2:3]1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: CN1CCN2c3c(cccc31)C1CCNCCC12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CN1CCN2c3c(cccc31)C1CCN(CCCC(=O)c3ccc(F)cc3)CCC12
Temperature: 96 °C
Reaction time: 18 h
Yield: 30.7 %

Procedure:
3-Methyl-2,3,7,8,9,10,11,11a-octahydro-1H,6bH-azepino[4′,5′:4,5]pyrrolo[1,2,3-de]quinoxaline (72 mg, 0.3 mmol), 4-chloro-4′-flourobutyrophenone (119 mg, 0.6 mmol), KI (49 mg, 0.3 mmol), and DIEA (383 mg, 3 mmol) were added to dioxane (2.5 mL). The suspension was stirred at 96° C. for 18 hrs. The reaction was cooled to rt and then concentrated. The residue was purified by column chromatography (5–10% MeOH/CH2Cl2), to afford the title compound (37.5 mg, 31%) as an oil. The enantiomers of the title compound were separated on a Chiracel OD column using 8% EtOH-Hexane as the eluent. 1H NMR (CDCl3, 300 MHz) δ 7.9–8.1 (2H, m), 7.1–7.2 (2H, m), 6.6–6.7 (1H, m), 6.3–6.5 (2H, m), 2.7–3.8 (19 H, m), 1.9–2.3 (4H, m) ppm. MS (ESI): 408.3 (base, M+H)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.[NH2:8][C:9]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:10]=1[CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[Cl:22][C:20]1[CH:19]=[CH:18][C:10]([CH2:11][N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[C:9]([N:8]=[C:2]2[CH2:3][CH2:4][CH2:5][CH2:6][NH:1]2)[CH:21]=1
Reactant: Nc1cc(Cl)ccc1CN1CCOCC1
Reactant: O=C1CCCCN1
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ccc(CN2CCOCC2)c(N=C2CCCCN2)c1

Procedure:
A mixture of 2-piperidone (6 g) in benzene (50 ml), 4-(2-amino-4-chlorobenzyl)morpholine (6.8 g) in benzene (50 ml) and phosphorus oxychloride (5.5 ml) was heated at 60°-65° C. for 5 hours to give 4-[4-chloro-2-(2-piperidinylideneamino)benzyl]morpholine (m.p. 121°-122° C.) which was recrystallised from hexane.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[Cl:9].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C1COCC1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:4][C:3]=1[Cl:9]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(Br)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccc(Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 21.1 %

Procedure:
To a solution of Intermediate 62A (0.843 g, 4.08 mmol) in THF (20.41 mL) was added triethylamine (5.69 mL, 40.8 mmol) followed by methanesulfonyl chloride (0.414 mL, 5.31 mmol). The reaction mixture was allowed to stir at room temperature for 3 days, then quenched with a saturated aqueous solution of NaHCO3 and diluted with EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (2×). The organic phases were combined, dried over Na2SO4, filtered, and concentrated to afford the title compound (245 mg, 0.861 mmol, 21.09% yield) as a white solid. HPLC Ret timej: 1.32 min. MS (ES): m/z=284.2 [M+H]−. Intermediate 62 was used in the synthesis of Example 212.
Reaction SMILES: Br[C:2]1[C:3]([CH3:28])=[C:4]([C:15]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)(=[O:21])=[O:20])=[CH:16][CH:17]=1)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].[CH:29](B(OCCCC)OCCCC)=[CH2:30].[F-].[Cs+]>COCCOC.CO.[Cl-].[Na+].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>[CH3:28][C:3]1[C:2]([CH:29]=[CH2:30])=[CH:17][CH:16]=[C:15]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)(=[O:21])=[O:20])[C:4]=1[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: C=CB(OCCCC)OCCCC
Reactant: Cc1c(Br)ccc(NS(=O)(=O)c2ccccn2)c1C(=O)OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Cs+]
Solvent: CO
Solvent: COCCOC
Solvent: O
Product: C=Cc1ccc(NS(=O)(=O)c2ccccn2)c(C(=O)OCc2ccccc2)c1C
Temperature: 80 °C
Reaction time: 36 h
Yield: 46.5 %

Procedure:
A solution of Example 110A (1.38 g, 3.0 mmol), dibutyl vinylboronate (0.83 g, 4.5 mmol), CsF (1.36 g, 9.0 mmol), and Pd(PPh3)4 (0.17 g, 0.15 mmol) in DME (12 mL) and methanol (6 mL) was purged with argon and stirred at 80° C. for 36 hours. The mixture was treated with brine (30 mL) and extracted with ethyl acetate. The ethyl acetate solution was dried (MgSO4), filtered and concentrated. The residue was purified by flash column chromatography on a silica gel with 30% ethyl acetate/hexanes to provide the desired product (0.57 g, 46.6%). 1H NMR (DMSO-d6) δ 2.12 (s, 3H), 5.26 (s, 2H), 5.34 (d, 1H), 5.65 (d, 1H), 6.86-6.91 (dd, 1H), 6.98 (d, 1H), 7.31-7.47 (m, 6H), 7.65 (m, 1H), 9.87 (d, 1H), 8.04 (dt, 1H), 8.74 (d, 1H), 10.04 (s, 1H); MS (ESI(+)) m/e 409 (M+H)+. Further elution of the column with 5% methanol in ethyl acetate with 0.1% acetic acid provided another white solid (0.125 g) which was identified as Example 172B.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[C:15]([O:37][CH3:38])=[C:16]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([N:30]3[CH2:33][CH:32]([C:34]#[N:35])[CH2:31]3)=[O:29])=[C:24]([F:36])[CH:23]=2)[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:20][C:18]1[C:17]([CH3:21])=[C:16]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([N:30]3[CH2:33][CH:32]([C:34]#[N:35])[CH2:31]3)=[O:29])=[C:24]([F:36])[CH:23]=2)[C:15]([O:37][CH3:38])=[C:14]([CH:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:13])[CH:19]=1
Reactant: Brc1ncnc2[nH]cnc12
Reactant: COc1c(C(C)N)cc(Cl)c(C)c1-c1ccc(C(=O)N2CC(C#N)C2)c(F)c1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1-c1ccc(C(=O)N2CC(C#N)C2)c(F)c1
Temperature: 90 °C

Procedure:
A mixture of 6-bromo-9H-purine (11 mg, 0.057 mmol), 1-{[3′-(1-aminoethyl)-5′-chloro-3-fluoro-2′-methoxy-6′-methylbiphenyl-4-yl]carbonyl}azetidine-3-carbonitrile (21 mg, 0.052 mmol), and N,N-diisopropylethylamine (0.018 mL, 0.10 mmol) in isopropyl alcohol (0.2 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C26H24ClFN7O2 (M+H)+: m/z=520.2. found: 520.1.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][CH:6]1[C:13]2[CH:12]=[CH:11][S:10][C:9]=2[C:8](=[O:14])[CH:7]1[CH3:15].[Br:16]Br.Cl>C(Cl)(Cl)Cl>[Br:16][C:12]1[C:13]2[CH:6]([CH3:5])[CH:7]([CH3:15])[C:8](=[O:14])[C:9]=2[S:10][CH:11]=1
Reactant: CC1C(=O)c2sccc2C1C
Reactant: BrBr
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CC1C(=O)c2scc(Br)c2C1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 29.3 g (220 mmol) of AlCl3 in 40 ml of chloroform a solution of 16.4 g (100 mmol) of 4,5-dimethyl-4,5-dihydro-6H-cyclopenta[b]thiophen-6-one in 15 ml of chloroform was added while vigorously stirring for 30 min at 0° C. This mixture was stirred for 15 min; then, a solution of 5.48 ml (17.1 g, 107 mmol) of bromine in 10 ml of chloroform was added dropwise over 1 h at 0° C. The resulting mixture was stirred for 1.5 h at room temperature and then poured on 200 cm3 of ice. The mixture was acidified with 4 M HCl to pH 1. The organic layer was separated, and the aqueous layer was washed with 3×100 ml of dichloromethane. The combined organic fractions were dried over K2CO3 and evaporated to dryness. The product was isolated by vacuum distillation, bp 110-112° C./2 mm Hg. Yield 22.1 g (91%).