Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[C:13]([NH2:18])=[N:14][CH:15]=[CH:16][CH:17]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:22][CH2:23][S:24](Cl)(=[O:26])=[O:25].O>C1COCC1>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[C:13]4=[N:18][S:24](=[O:26])(=[O:25])[CH2:23][CH2:22][N:14]4[CH:15]=[CH:16][CH:17]=3)=[CH:10][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Nc1ncccc1-c1ccc(N2CCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=CC=C(c3ccc(N4CCCC4)cc3)C2=N1
Temperature: 50 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
A mixture of 3-(4-(pyrrolidin-1-yl)phenyl)pyridin-2-amine (17.0 mg) in THF (dry) (5 ml) was added to a mixture of NaH (60%, 14.2 mg) and 2-chloroethanesulfonyl chloride (34.7 mg) in THF (dry) (5.00 mL) at room temperature. The mixture was stirred at 50° C. for 1 hr. Water and NH silica gel were added and the mixture was concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give the title compound (14.8 mg) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH:15]2[CH2:17][CH2:18][CH:12]1[C:13](=O)[CH2:14]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:21]1[CH:26]=[N:25][CH:24]=[C:23]([CH3:27])[N:22]=1>>[CH3:27][C:23]1[N:22]=[C:21]([CH:13]2[CH:12]3[CH2:18][CH2:17][CH:15]([CH2:16][N:11]3[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH2:14]2)[CH:26]=[N:25][CH:24]=1
Reactant: Cc1cncc(I)n1
Reactant: O=C1CC2CCC1N(C(=O)OCc1ccccc1)C2
Product: Cc1cncc(C2CC3CCC2N(C(=O)OCc2ccccc2)C3)n1

Procedure:
The title compound (666 mg) was prepared from 2-benzyloxycarbonyl-2-azabicyclo[2.2.2]octan-6-one and 2-iodo-6-methylpyrazine as described in Example 3. The alcohol obtained was dehydrated using potassium hydride, iodomethane and carbon disulphide as described in Example 3.
Reaction SMILES: [Mg].II.[CH3:4][CH:5]([CH3:9])[CH2:6][CH2:7]Br.[CH2:10]([Si:16](Cl)([Cl:18])[Cl:17])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>O1CCCC1.CCCCCC>[CH2:10]([Si:16]([CH2:7][CH2:6][CH:5]([CH3:9])[CH3:4])([Cl:18])[Cl:17])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CC(C)CCBr
Reactant: CCCCCC[Si](Cl)(Cl)Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCC[Si](Cl)(Cl)CCC(C)C

Procedure:
Anhydrous tetrahydrofuran (125 mL) was put into a reactor with magnesium (5.0 g, 0.21 mol) which had been dehydrated and deaerated, followed by charging of argon gas. A small amount of iodine was slowly added to the mixture. 3-Methylbutylbromide (25 g, 0.17 mol) was added dropwise to the slowly stirred mixture so that the reaction mixture was gradually refluxed. After the reaction was complete, the obtained Grignard reagent was transferred to a dropping funnel. The Grignard reagent was added dropwise to a solution being stirred containing n-hexyltrichlorosilane (38 g, 0.17 mol) in anhydrous tetrahydrofuran (100 mL) in another reactor which had been dehydrated and deaerated, followed by charging of argon gas, at 60° C.-70° C. The reaction mixture was then stirred overnight at room temperature. Hexane (500 mL) was added to the reaction mixture, and the resulting mixture was filtered under pressure, followed by fractional distillation of the filtrate to provide the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].Br[CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH3:16][CH2:15][CH:14]([O:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7])[CH2:17][CH3:18]
Reactant: COC(=O)c1ccc(O)cc1O
Reactant: CCC(Br)CC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCC(CC)Oc1ccc(C(=O)OC)c(O)c1

Procedure:
The methyl 4-[pent-3-oxy]salicylate used was prepared as follows. A mixture of methyl 4-hydroxysalicylate (74 g, 0.44 mole), 3-bromopentane (80 g, 0.53 mole), potassium iodide (20 g) and potassium carbonate (100 g) in methyl ethyl ketone (MEK, 500 mL) was heated at reflux for 65 hours. The cooled reaction mixture was then filtered and concentrated under reduced pressure. The resultant oily residue was stirred with dilute hydrochloric acid, then extracted into dichloromethane. The dichloromethane solution was washed with brine, dried over anhydrous sodium sulfate and concentrated to a clear liquid (67.0 g, 64% yield). The structure of this compound was confirmed by mass spectroscopy and by 1H and 13C NMR spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4][C:3]=1[N:11]1[C:15]([CH:16]2[CH2:18][CH2:17]2)=[C:14]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:13]=[N:12]1.[CH3:24][NH2:25]>S(Cl)(Cl)=O.C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:25][CH3:24])=[O:10])=[CH:4][C:3]=1[N:11]1[C:15]([CH:16]2[CH2:17][CH2:18]2)=[C:14]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:13]=[N:12]1
Reactant: CCOC(=O)c1cnn(-c2cc(C(=O)O)ccc2Cl)c1C1CC1
Reactant: CN
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1cnn(-c2cc(C(=O)NC)ccc2Cl)c1C1CC1
Reaction time: 6 h
Yield: 77.1 %

Procedure:
A solution of ethyl 1-(2-chloro-5-hydroxycarbonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylate (1.32 g, 3.73 mmol) in thionyl chloride (7.5 mL) was heated at reflux for 2 h under a nitrogen atmosphere. The resulting solution was concentrated in vacuo. A solution of the residue in anhydrous CH2Cl2 (10 mL) under a nitrogen atmosphere was treated with methylamine (2 M solution in THF, 9.33 mL, 18.7 mmol) followed by a catalytic amount of 4-dimethylaminopyridine. The resulting mixture was stirred for 6 h and partitioned between ethyl acetate and HCl (1 M aq). The organic layer was washed with brine, NaHCO3 (sat aq sol), and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash 40M™ chromatography (75:25 ethyl acetate/hexanes) to afford 1.00 g (77% yield) of the title compound.
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C@@H:11]([CH2:23][N:24]([CH3:26])[CH3:25])[CH2:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])(=[O:9])=[O:8])=[CH:4][CH:3]=1.[C:27]([C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:31][CH:30]=1)#[CH:28]>>[CH3:25][N:24]([CH3:26])[CH2:23][C@H:11]([NH:10][S:7]([C:5]1[S:6][C:2]([C:28]#[C:27][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:31][CH:30]=2)=[CH:3][CH:4]=1)(=[O:9])=[O:8])[CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NS(=O)(=O)c1ccc(Br)s1
Reactant: C#Cc1ccc(CCCCC)cc1
Product: CCCCCc1ccc(C#Cc2ccc(S(=O)(=O)N[C@H](CC(=O)OCc3ccccc3)CN(C)C)s2)cc1
Yield: 91 %

Procedure:
According to the method described in example S76a, (R)-benzyl 3-(5-bromothiophene-2-sulfonamido)-4-(dimethylamino)butanoate was reacted with 1-ethynyl-4-pentylbenzene to give the title compound as a black oil (68 mg, 91%). MS ESI 553.3 [M+H]+, calcd for [C30H36N2O4S2+H]+ 553.21.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8](=O)[CH2:9][O:10][C:6]=2[CH:5]=[C:4]([CH3:12])[CH:3]=1.P(Br)(Br)[Br:14]>>[CH3:1][C:2]1[C:7]2[C:8]([Br:14])=[CH:9][O:10][C:6]=2[CH:5]=[C:4]([CH3:12])[CH:3]=1
Reactant: BrP(Br)Br
Reactant: Cc1cc(C)c2c(c1)OCC2=O
Product: Cc1cc(C)c2c(Br)coc2c1
Temperature: 100 °C
Yield: 60 %

Procedure:
4,6-dimethyl-3-benzofuranone (0.09 moles) was slowly added in phosphorus tribromide (30 ml), previously heated to 100° C. The mix is cautiously treated with ice, extracted with methylenechloride. The organic phase is made anhydrous (Na2SO4) and freed from the solvent under reduced pressure to produce 4,6-dimethyl-3-bromobenzofuran (60% yield).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH3:20])[CH:14]=2)=[O:11])[CH2:6][CH2:5]1)[C:2]#[CH:3].I[C:22]1[N:23]=[C:24]([NH2:40])[C:25]2[N:26]=[CH:27][N:28]([C:38]=2[N:39]=1)[C@@H:29]1[O:37][C@H:34]([CH2:35][OH:36])[C@@H:32]([OH:33])[C@H:30]1[OH:31]>>[CH3:20][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[CH3:19])[O:12][C:10]([N:7]1[CH2:6][CH2:5][CH:4]([CH2:1][C:2]#[C:3][C:22]2[N:23]=[C:24]([NH2:40])[C:25]3[N:26]=[CH:27][N:28]([C:38]=3[N:39]=2)[C@@H:29]2[O:37][C@H:34]([CH2:35][OH:36])[C@@H:32]([OH:33])[C@H:30]2[OH:31])[CH2:9][CH2:8]1)=[O:11]
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: C#CCC1CCN(C(=O)Oc2ccc(C)c(C)c2)CC1
Product: Cc1ccc(OC(=O)N2CCC(CC#Cc3nc(N)c4ncn([C@@H]5O[C@H](CO)[C@@H](O)[C@H]5O)c4n3)CC2)cc1C

Procedure:
3,4-Dimethylphenyl 4-(prop-2-ynyl)piperidine-1-carboxylate (1.430 g, 5.27 mmol) was added to a solution of 2-iodoadenosine (0.620 g, 1.577 mmol) according to general procedure 2: yield 252 mg, 30%. 1H NMR (CD3OD) δ 8.30 (s, 1H), 7.08 (d 1H, J=8.2 Hz), 6.84 (d, 1H, J=2.3 Hz), 6.78 (dd, 1H, J=2.4, J=8.1 Hz), 5.93 (d, 1H, J=6.5 Hz), 4.71 (dd, 1H, J=5.1 Hz, J=6.5 Hz), 4.38-4.27 (m, 2H), 4.25-4.14 (m, 2H), 3.89 (dd, 1H, J=2.3 Hz, J=12.6 Hz), 3.74 (dd, 1H, J=2.6, J=12.6 Hz), 3.04, 2.90 (2×br t, 2H), 2.46 (d, 2H, J=6.2 Hz), 2.23, 2.22 (2×s, 6H), 2.02-1.79, 1.52-1.26 (2×m, SH). 13C NMR (CD3OD) δ 157.3, 155.8, 150.8, 150.2, 147.5, 142.6, 138.8, 134.7, 131.1, 123.7, 120.5, 119.9, 91.4, 88.3, 86.7, 82.3, 75.5, 72.6, 63.5, 45.5, 36.5, 32.5, 26.5, 19.8, 19.1. LRMS ESI (M+H+) 537.2. HPLC rt=10.9 min.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH:11]([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][C:16]=1[C:30]1[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=1>>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([CH:11]([CH3:13])[CH3:12])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:17][C:16]=1[C:30]1[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)c1ccn2c(Br)cnc2n1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3C#N)c2)OC1(C)C
Product: CC(C)c1ccn2c(-c3ccc(F)c(-c4ccccc4C#N)c3)cnc2n1

Procedure:
3-Bromo-7-isopropylimidazo[1,2-α]pyrimidine was coupled with 2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 2′-fluoro-5′-(7-isopropylimidazo[1,2-α]pyrimidin-3-yl)biphenyl-2-carbonitrile as an off-white powder: δH (360 MHz, CDCl3) 1.38 (6H, d, J 7), 3.15 (1H, septet, J 7), 6.87 (1H, d, J 7), 7.39 (1H, t, J 9), 7.52-7.63 (4H, m), 7.71 (1H, dd, J 8 and 1), 7.83 (2H, dd, J 8 and 7), 8.74 (1H, d, J 7); m/z (ES+) 357 (M++H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C1COCC1>[C:21]([O:20][C:18]([N:25]1[CH2:30][CH2:29][N:28]([S:7]([C:5]2[S:6][C:2]([Br:1])=[CH:3][CH:4]=2)(=[O:9])=[O:8])[CH2:27][CH2:26]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(Br)s2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.9 %

Procedure:
To a stirred solution of commercially available 5-bromo-thiophene-2-sulfonyl chloride (1.0 g, 3.82 mmol) in THF (8 ml) was added at room temperature triethylamine (0.59 ml, 4.21 mmol), the mixture was cooled (ice-water) and a solution of commercially available 1-BOC-piperazine (2.14 g, 11.5 mmol) in THF (8 ml) was added drop wise. The reaction mixture was stirred at room temperature for 16 h and evaporated. The crude product was further purified by flash chromatography (ethyl acetate/heptane) and subsequent crystallization from dichloromethane/hexane to yield the title compound (1.35 g, 86%) as a white solid. MS (ISP) 413.2 [(M+H)+], mp 127° C.
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[F:29][C:30]([F:39])([F:38])[C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[CH3:20][CH:19]([CH3:21])[C:18]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C@@H:2]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[O:1][C:34]3[CH:35]=[CH:36][C:31]([C:30]([F:39])([F:38])[F:29])=[CH:32][CH:33]=3)[CH2:6][CH2:7]2)[CH:12]=1)=[O:22]
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](Oc3ccc(C(F)(F)F)cc3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 38.9 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (9.53 mg, 0.0250 mmol), 4-trifluoromethylphenol (8.100 mg, 0.050 mmol), triphenylphosphine (9.8 mg, 0.0375 mmol) and diethyl azodicarboxylate (5.22 mg, 0.0300 mmol) in THF (1.0 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (5.10 mg, 38.9% yield) as a thick oil: 1H NMR δ 8.06 (s, 1H), 7.49 (s, 1H), 7.44 (apparent d, 2H, J=0.6 Hz), 7.38-7.30 (m, 4H), 7.30-7.20 (m, 3H), 6.96 (apparent d, 1H, J=7.6 Hz), 6.91 (apparent d, 2H, J=8.6 Hz), 5.34 (m, 1H), 3.19 (m, 2H), 2.72 (m, 2H), 2.53 (m, 2H), 2.40-1.80 (m, 8H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 525.4 (M+H)+.
Reaction SMILES: [C:1]([N:5]([C:7]([C:9]1[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=1)=[O:8])[NH2:6])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:26]=[C:27]=[O:28])(=[O:25])=[O:24])=[CH:19][CH:18]=1.CCOCC>C(Cl)Cl>[C:1]([N:5]([C:7]([C:9]1[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=1)=[O:8])[NH:6][C:27]([NH:26][S:23]([C:20]1[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=1)(=[O:24])=[O:25])=[O:28])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Reactant: Cc1cccc(C(=O)N(N)C(C)(C)C)c1
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1cccc(C(=O)N(NC(=O)NS(=O)(=O)c2ccc(Cl)cc2)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N'-t-butyl-N'-3-toluoyl hydrazine (4.03 g, 0.02 mol) in methylene chloride (25 ml) under nitrogen was added 4-chlorobenzenesulfonyl isocyanate (5 g, 80%, 0.02 mol) at room temperature. The exothermic reaction mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure to give an oil. A precipitate appeared after treating with ether. The pure product was collected by suction-filtration and washed with a small amount of ether affording 4.8 g of 1-t-butyl-1-(3-toluoyl)-4-(4-chlorobenzenesulfonyl)semicarbazide as a white solid: m.p. 184°-188° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]2[S:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([NH2:21])[CH3:20])=[CH:15][CH:14]=3)=[CH:11][N:12]=2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[C:33](OC(=O)C)(=[O:35])[CH3:34]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]2[S:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([NH:21][C:33](=[O:35])[CH3:34])[CH3:20])=[CH:15][CH:14]=3)=[CH:11][N:12]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Oc2ncc(-c3ccc(C(C)N)cc3)s2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Oc2ncc(-c3ccc(C(C)NC(C)=O)cc3)s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of Example 11D ((110 mg, 0.337 mmol) and diisopropylethylamine (0.5 mL) in methylene chloride (1 mL) cooled to 0° C. was added acetic anhydride (100 μL, 1.06 mmol, 3.1 eq.). The mixture was stirred at room temperature overnight. The reaction mixture was purified directly on silica gel eluting with ethyl acetate:hexane gradient (0-80%) to give the title compound (109 mg, 88%). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.30 (d, J=8.09 Hz, 1 H), 7.66 (s, 1 H), 7.45-7.54 (m, 2 H), 7.33-7.40 (m, 2 H), 7.27-7.32 (m, Hz, 2 H), 6.99-7.10 (m, 2 H), 4.77-4.96 (m, 1 H), 3.79 (s, 3 H), 1.83 (s, 3 H), 1.32 (d, J=6.99 Hz, 3 H); MS (DCl) m/e 369 (M+H).
Reaction SMILES: C([NH:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16]Cl)=[C:7]([O:19][CH2:20][C:21]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[CH:22]=2)[CH:6]=1)(=O)C.N1CCCCC1.[CH3:37][CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[NH2:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][N:41]2[CH2:42][CH2:43][CH:38]([CH3:37])[CH2:39][CH2:40]2)=[C:7]([O:19][CH2:20][C:21]2[CH:22]=[C:23]([O:29][CH3:30])[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=2)[CH:6]=1
Reactant: COc1cc(COc2cc(NC(C)=O)c(Cl)cc2C(=O)CCCCCl)cc(OC)c1
Reactant: CC1CCNCC1
Solvent: C1CCNCC1
Product: COc1cc(COc2cc(N)c(Cl)cc2C(=O)CCCCN2CCC(C)CC2)cc(OC)c1

Procedure:
Proceeding as in Example 4, Step (c), but replacing 1-(4-acetylamino-5-chloro-2-methoxyphenyl)-5-chloropentan-1-one with 1-[4-acetylamino-5-chloro-2-(3,5-dimethoxybenzyloxy)phenyl]-5-chloropentan-1-one and piperidine with 4-methylpiperidine, gave 1-[4-amino-5-chloro-2-(3,5-dimethoxybenzyloxy)phenyl]-5-(4-methylpiperidin-1-yl)pentan-1-one, m.p. 136-137° C.
Reaction SMILES: [CH2:1]1[N:6]2[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[NH:9][C:10](=[O:12])[CH2:11][CH:5]2[CH2:4][NH:3][CH2:2]1.[Br:17]N1C(=O)CCC1=O>C(O)(=O)C.O>[Br:17][C:14]1[CH:15]=[CH:16][C:7]2[N:6]3[CH2:1][CH2:2][NH:3][CH2:4][CH:5]3[CH2:11][C:10](=[O:12])[NH:9][C:8]=2[CH:13]=1
Reactant: O=C1CC2CNCCN2c2ccccc2N1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: O
Product: O=C1CC2CNCCN2c2ccc(Br)cc2N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Example 1D (1.54 g, 6.07 mmol) in acetic acid/water (1:1, 20 mL) was added N-bromosuccinimide (1.08 g, 6.07 mmol). The reaction mixture was stirred at room temperature for 2 hours. Product precipitated. The precipitate was collected to afford the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 7.36 (d, J=8.54 Hz, 1H), 7.16 (s, 1H), 7.11 (d, J=8.85 Hz, 1H), 3.54-3.63 (m, 1H), 3.22-3.40 (m, 4H), 2.93-3.07 (m, 2H), 2.65-2.72 (m, 1H), 2.08 (d, J=13.73 Hz, 1H); MS (ESI) m/z 297.8 (M+H)+.
Reaction SMILES: [N:1]1([C:6]2([C:10]#[N:11])[CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:10]([NH2:11])[C:6]2([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:7][CH2:8][CH2:9]2)=[CH:15][CH:14]=1
Reactant: Clc1ccc(I)cc1
Reactant: N#CC1(N2CCCC2)CCC1
Product: NC(c1ccc(Cl)cc1)C1(N2CCCC2)CCC1

Procedure:
The title compound, yellow oil, MS: m/e=265.2 [(M+H)+], was prepared in accordance with the general method of intermediate K from 1-pyrrolidin-1-yl-cyclobutanecarbonitrile (intermediate F) and 1-chloro-4-iodobenzene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.N[CH:13]([CH2:21][NH:22][C:23]1[C:28]([CH2:29][CH3:30])=[C:27]([N:31]2[CH2:36][CH2:35][CH:34]([C:37]3[CH:46]=[CH:45][C:44]4[CH2:43][CH2:42][CH2:41][NH:40][C:39]=4[N:38]=3)[CH2:33][CH2:32]2)[N:26]=[CH:25][N:24]=1)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>ClCCl.N1C=CC=CC=1>[CH2:29]([C:28]1[C:23]([NH:22][CH2:21][CH:13]([C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])=[N:24][CH:25]=[N:26][C:27]=1[N:31]1[CH2:36][CH2:35][CH:34]([C:37]2[CH:46]=[CH:45][C:44]3[CH2:43][CH2:42][CH2:41][NH:40][C:39]=3[N:38]=2)[CH2:33][CH2:32]1)[CH3:30]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CCc1c(NCC(N)C(=O)OC(C)(C)C)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1c(NCC(C(=O)OC(C)(C)C)C(=O)c2ccc(OC)cc2)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
40 mg (0.233 mmoles) of 4-methoxy-benzoyl chloride in solution in 3 ml of dichloromethane is added to a mixture of 112.5 mg (0.233 mmoles) of tert-butyl 2-amino-3-{5-ethyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-piperidin-1-yl]-pyrimidin-4-ylamino}-propionate in solution in 6 ml of dichloromethane and 650 μl of pyridine. The reaction mixture is stirred at ambient temperature for 1 hour. Then, the solvent is evaporated off under reduced pressure (2 kPa) and the residue is chromatographed on silica gel with the following eluent: ethyl acetate-dichloromethane (50-50), ethyl acetate-dichloromethane/methanol (95/5) 50-50 then finishing with ethyl acetate-dichloromethane/methanol (9/1) 50-50. 98 mg of expected product is obtained.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:20](=[O:21])[C:19]2[CH:22]=[CH:23][S:24][C:18]=2[S:17][CH2:16][CH2:15]1.O>C(Cl)Cl>[C:5]([C:23]1[S:24][C:18]2[S:17][CH2:16][CH2:15][N:14]([CH2:13][CH2:12][CH2:11][CH2:10][Cl:9])[C:20](=[O:21])[C:19]=2[CH:22]=1)(=[O:7])[CH3:6]
Reactant: O=C1c2ccsc2SCCN1CCCCCl
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC(=O)c1cc2c(s1)SCCN(CCCCCl)C2=O
Reaction time: 0.25 h

Procedure:
To a suspension of 13 g of aluminum chloride in 150 ml of methylene chloride was added 4.6 ml of acetyl chloride under ice-cooling and the mixture was stirred for 15 minutes. To the mixture was added a solution of 9.0 g of 4-(4-chlorobutyl)-2,3-dihydrothieno[3,2-f]-1,4-thiazepin-5(4H)-one in 20 ml of methylene chloride and the mixture was stirred at room temperature of 2 hours. Then, the mixture was poured into chilled water and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and the solvent was distilled off. The resulting crystals were recrystallized from ethyl acetate to give 6.9 g of 7-acetyl-4-(4-chlorobutyl)-2,3-dihydrothieno-[3,2-f]-1,4-thiazepin-5(4H)-one as white crystals, melting at 132°-134° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][C@@H:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][N:17]=2)[CH3:15])=[O:12])=[CH:6][CH:5]=1)([CH3:3])=[CH2:2].C1C[O:31]CC1.[OH-].[Na+].OO>C(Cl)Cl.O>[OH:31][CH2:2][CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([NH:13][C@@H:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:25])[F:26])=[CH:18][N:17]=2)[CH3:15])=[O:12])=[CH:8][CH:9]=1)[CH3:3]
Reactant: C1CCOC1
Reactant: C=C(C)c1ccc(CC(=O)N[C@H](C)c2ccc(OCC(F)(F)F)cn2)cc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(CO)c1ccc(CC(=O)N[C@H](C)c2ccc(OCC(F)(F)F)cn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
A microwave vial was charged with 2-(4-isopropenylphenyl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide (300 mg, 0.793 mmol) and THF (500 uL). The solution was cooled to 0° C. and borane tetrahydrofuran complex (1.19 mL, 1.19 mmol) was added via syringe. The reaction was warmed to room temperature over 1.5 h., then NaOH (5M, 634 uL, 3.17 mmol) was added dropwise, followed by the slow addition of hydrogen peroxide (30 wt. % in water, 991 uL, 8.72 mmol). After stirring for 30 min, the mixture was diluted with CH2Cl2 (30 mL) and water (30 mL), and the layers were separated. The aqueous layer was washed with CH2Cl2 (2×15 mL) and the combined organic layer was dried over MgSO4, filtered, and concentrated. The resulting crude material was purified by normal phase chromatography (20-100% EtOAc/Hexanes) to give 133 mg (42%) of 2-[4-(2-hydroxy-1-methylethyl)phenyl]-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 8.20 (d, J=2.57 Hz, 1H), 7.21 (m, 6H), 6.69 (d, J=6.96 Hz, 1H), 5.10 (quint. J=6.96 Hz, 1H), 4.38 (q, J=8.00, 2H), 3.71 (m, 2H), 3.57 (s, 2H), 2.96 (m, 1H), 1.40 (d, J=6.67 Hz, 3H), 1.28 (d, J=6.96 Hz, 3H); MS (Electrospray): m/z 397.4 (M+H). The two diastereomers were separable by chiral HPLC under the following conditions: Column: ChiralPak AD (4.6 mm×250 mm, 10 u), Solvent: Hex/EtOH/MeOH (85/7.5/7.5), 1 mL/L diethylamine, Flow rate: 1 mL/min, Retention times: 11.3 and 12.8 min