Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@H:6]([CH3:19])[C@H:7]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:8]([OH:10])=O)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.Cl.Cl.[N:53]1[CH:58]=[CH:57][CH:56]=[N:55][C:54]=1[C:59]1([NH2:62])[CH2:61][CH2:60]1>CN(C=O)C.O>[C:15]([O:14][C:12](=[O:13])[NH:11][C@H:7]([C:8](=[O:10])[NH:62][C:59]1([C:54]2[N:55]=[CH:56][CH:57]=[CH:58][N:53]=2)[CH2:61][CH2:60]1)[C@H:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:19])([CH3:18])([CH3:17])[CH3:16]
Reactant: NC1(c2ncccn2)CC1
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OC(C)(C)C)C(=O)NC1(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.9 %

Procedure:
To a solution of (2S,3R)-3-tert-butoxy-2-tert-butoxycarbonylamino-butyric acid (0.20 g, 0.72 mmol) in DMF (1 mL) was added HATU (0.27 g, 0.72 mmol), Et3N (0.30 mL, 2.2 mmol) and 1-pyrimidin-2-yl-cyclopropylamine dihydrochloride (0.15 g, 0.72 mmol.). The reaction was allowed to stir at RT for 24 h. The mixture was diluted with water and extracted with EtOAc (3×50 mL). The combined extracts were washed with satd NaHCO3, 2N HCl, water and brine. The solution was dried with MgSO4, filtered and concentrated to give [(1S,2R)-2-tert-butoxy-1-(1-pyrimidin-2-yl-cyclopropylcarbamoyl)-propyl]-carbamic acid tert-butyl ester (0.23 g, 0.59 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[N:8]=[CH:7][C:6]([CH3:13])=[N:5][C:4]=2[C:3]=1[OH:14].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[K+]>CCO>[CH2:15]([O:14][C:3]1[C:2]([Cl:1])=[CH:11][C:10]([Cl:12])=[C:9]2[C:4]=1[N:5]=[C:6]([CH3:13])[CH:7]=[N:8]2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cnc2c(Cl)cc(Cl)c(O)c2n1
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cnc2c(Cl)cc(Cl)c(OCc3ccccc3)c2n1
Yield: 46.9 %

Procedure:
A mixture of 6,8-dichloro-3-methylquinoxalin-5-ol (150 mg, 0.655 mmol), benzyl bromide (0.20 mL, 1.68 mmol), KOH (0.09 g) and EtOH (10 mL) was heated under reflux for 16 h, cooled, and concentrated. Dichloromethane (20 mL) was added and the mixture washed with H2O (5 mL×2), dried and concentrated. The residue was purified via SiO2-gel chromatography (dichloromethane/MeOH, 1:0-150:1) to give 8-benzyloxy-5,7-dichloro-2-methylquinoxaline (98 mg, 47%).—1H NMR (CDCl3): δ 8.82 (s, 1H), 7.81 (s, 1H), 7.58 (m, 2H), 7.38 (m, 2H), 5.45 (s, 2H), 2.85 (s, 3H).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[Si:7](Cl)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].N1C=CN=C1.C(OCC)(=O)C>C1COCC1.O>[Si:7]([O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCCO
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCCCO
Reaction time: 2 h
Yield: 66.5 %

Procedure:
A solution of 1,4-butanediol (10.54 g, 0.117 mol) in dry THF (100 mL) was treated with t-butyl dimethylsilylchloride (17.30 g, 0.114 mol) and imidazole (7.80 g, 0.114 mol). After 2 h at room temperature, work-up with ethyl acetate and water, followed by drying the organic phase and concentration, gave a crude product that was purified by silica gel flash chromatography (being eluted with 20% ethyl acetate in hexane) to yield 15.5 g (Y: 65%) of 4-(t-butyldimethylsilyloxy)-1-butanol (XXVIIa) as a colorless oil; 1H-NMR (CDCl3, 300 MHz) δ ppm: 3.58 (m, 4H) 1.58 (m, 4H) 0.84 (s, 9H) 0.01 (s, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:7]=[N:6][NH:5][C:4]=1[NH2:8])#[N:2].CN(C)[CH:11]=[CH:12][C:13]([C:15]1[CH:16]=[C:17]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[CH:18]=[CH:19][CH:20]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[C:1]([C:3]1[CH:7]=[N:6][N:5]2[C:13]([C:15]3[CH:16]=[C:17]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[CH:18]=[CH:19][CH:20]=3)=[CH:12][CH:11]=[N:8][C:4]=12)#[N:2]
Reactant: CN(C)C=CC(=O)c1cccc(N(C)S(C)(=O)=O)c1
Reactant: N#Cc1cn[nH]c1N
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CN(c1cccc(-c2ccnc3c(C#N)cnn23)c1)S(C)(=O)=O
Yield: 71.3 %

Procedure:
A mixture of 0.1 g (0.93 mmol) of 4-cyano-2H-pyrazol-3-ylamine and 0.26 g (0.93 mmol) of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-methyl-methanesulfonamide in 10 ml of glacial acetic acid was refluxed for 8 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 10 ml of dichloromethane and 10 ml of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 ml of dichloromethane. The organic layers were washed with 10 ml of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 217 mg of N-[3-(3-cyano-pyrazolo[1,5-a]pyrimidin-7-yl)-phenyl]-N-methyl-methanesulfonamide as a yellow solid (yield 71%; m.p.=193-195° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:28]2[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:27])[N:11]([C@H:22]2[CH2:25][C@H:24]([OH:26])[CH2:23]2)[C:12]2[N:13]([N:18]=[C:19]([CH3:21])[N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].[N+](=[CH:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[N-]>C([O-])(=O)C.[Rh+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[C:34]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[C:10](=[O:27])[N:11]([C@H:22]3[CH2:25][C@H:24]([O:26][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:23]3)[C:12]3[N:13]([N:18]=[C:19]([CH3:21])[N:20]=3)[C:14]=2[CH2:15][CH2:16][CH3:17])=[C:2]([F:1])[CH:3]=1)#[N:35]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@H](O)C2)c2nc(C)nn12
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@H](OCC(=O)OCC)C2)c2nc(C)nn12
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a mixture of 3′-fluoro-4′-{[4-(trans-3-hydroxycyclobutyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (899 mg), rhodium(II) acetate (dimer) (42 mg) and toluene (20 mL) was added dropwise ethyl diazoacetate (464 μL) under an argon atmosphere at 70° C., and the mixture was stirred at 70° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=70/30→55/45 (volume ratio)] to give the title compound as a colorless amorphous compound (557 mg, 53%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](OS(C2C=CC=CC=2)(=O)=O)=[C:5]([O:19][CH3:20])[CH:4]=1)#[N:2].[CH2:21]([N:23]([CH2:27][CH3:28])[CH2:24][C:25]#[CH:26])[CH3:22]>CCCCCCC.CCOC(C)=O>[CH2:21]([N:23]([CH2:27][CH3:28])[CH2:24][C:25]#[C:26][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[O:19][CH3:20])[CH3:22]
Reactant: COc1cc(C#N)ccc1OS(=O)(=O)c1ccccc1
Reactant: C#CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCN(CC)CC#Cc1ccc(C#N)cc1OC

Procedure:
This product was prepared from benzene-sulfonic acid 4-cyano-2-methoxy-phenyl ester and diethyl-prop-2-ynyl-amine following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/EtOAc 1:1; yield (90 mg, 74%); 1H NMR δ (CDCl3): 7.52 (d, J=8.35 Hz, 1H), 7.21 (d, J=8.21 Hz, 1H), 7.11 (s, 1H), 3.81 (s, 3H), 2.69 (t, J=7.22 Hz, 2H), 2.58 (t, J=7.21 Hz, 2H), 1.99 (p, J=7.11 Hz, 2H); LCMS m/z: 242.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH:5]([N:10]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]([OH:9])[CH2:7][CH3:8])C.O.[OH-].[Li+]>O1CCCC1.O>[CH2:18]([N:10]([CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH:5]([CH:6]([OH:9])[CH2:7][CH3:8])[C:4]([OH:25])=[O:3])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)C(C(O)CC)N(Cc1ccccc1)Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCC(O)C(C(=O)O)N(Cc1ccccc1)Cc1ccccc1
Temperature: 60 °C
Reaction time: 60 h

Procedure:
To 17.7 g (51.9 mmol) racemic (2S,3R and 2R,3S)-2-dibenzylamino-3-hydroxy-pentanoic acid ethyl ester in 245 ml tetrahydrofurane were added 8.80 g (208 mmol) lithium hydroxide monohydrate dissolved in 44 ml water. The mixture was stirred at 60° C. for 2.5 days and the organic solvent was removed by distillation. Water was added followed by extraction with diethylether. The waterphase was adjusted to pH 1. Extraction with ethylacetate yielded 14.8 g (91%) racemic (2S,3R and 2R,3S)-2-dibenzylamino-3-hydroxy-pentanoic acid, MS m/e (%): 314.1 (M+H+, 100).
Reaction SMILES: O[CH2:2][C@H:3]1[CH2:7][O:6][C:5](=[O:8])[N:4]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[H-].[Na+].[F:41][C:42]([F:58])([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:43](=[O:51])[CH2:44]P(=O)(OC)OC>ClCCl.C1COCC1>[F:41][C:42]([F:58])([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:43](=[O:51])/[CH:44]=[CH:2]/[C@H:3]1[CH2:7][O:6][C:5](=[O:8])[N:4]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16]
Reactant: COP(=O)(CC(=O)C(F)(F)c1ccccc1)OC
Reactant: N#CCCCCCCN1C(=O)OC[C@@H]1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: N#CCCCCCCN1C(=O)OC[C@@H]1/C=C/C(=O)C(F)(F)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of alcohol 2-3 (480 mg) in dichloromethane (10 mL) was added Dess-Martin periodanane (1 g) and the mixture was stirred at room temperature for 1 h and concentrated. The residue was co-evaporated with toluene several times, resuspended in ethyl acetate and was allowed to sit at 5° C. overnight. The mixture was filtered and the filtrate was concentrated to give the crude aldehyde 7-[(4S)4-formyl-2-oxo-1,3-oxazolidin-3-yl]heptanenitrile (2-5) which was used directly. To a suspension of NaH (168 mg) in THF was added dimethyl 3,3-difluoro-2-oxo-3-phenylpropylphosphonate (1.1 g) dropwise at 0° C. and the mixture was stirred at the temperature for 30 min. To the mixture was added crude aldehyde 2-5 in THF via a cannula and the mixture was stirred at room temperature for 5 h and quenched with saturated NH4Cl. The mixture was extracted with ethyl acetate and the organic layer was dried and concentrated. The residue was purified by flash chromatography to give the desired product 2-4. 1H NMR (400 MHz, acetone-d6): δ 7.70–7.55 (m, 5H), 7.08 (dd, 1H), 6.95 (d, 1H), 4.70 (m, 1H), 4.52 (t, 1H), 3.30 (m, 1H), 3.00 (m, 1H), 2.48 (t, 2H), 1.70–1.25 (m, 8H).
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([N:11]3[CH2:16][N:15]([CH3:17])[CH2:14][N:13]([CH2:18][CH3:19])[C:12]3=[O:20])=[N:7][C:6]=2[CH:5]=[C:4]([C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][C:30]([CH3:38])([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH:3]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([SiH](CC)CC)C.CN([CH:85]=[O:86])C>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:18]([N:13]1[CH2:14][N:15]([CH3:17])[CH2:16][N:11]([C:8]2[S:9][C:10]3[C:2]([CH:85]=[O:86])=[CH:3][C:4]([C:21]4[CH:22]=[N:23][C:24]([N:27]5[CH2:32][CH2:31][C:30]([CH3:38])([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:29][CH2:28]5)=[N:25][CH:26]=4)=[CH:5][C:6]=3[N:7]=2)[C:12]1=[O:20])[CH3:19]
Reactant: CCOC(=O)C1(C)CCN(c2ncc(-c3cc(Br)c4sc(N5CN(C)CN(CC)C5=O)nc4c3)cn2)CC1
Reactant: CN(C)C=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[SiH](CC)CC
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(C)CCN(c2ncc(-c3cc(C=O)c4sc(N5CN(C)CN(CC)C5=O)nc4c3)cn2)CC1
Temperature: 75 °C
Reaction time: 32 h
Yield: 29 %

Procedure:
Ethyl 1-[5-[7-bromo-2-(3-ethyl-5-methyl-2-oxo-1,3,5-triazinan-1-yl)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate (Intermediate 9) (2.58 g, 4.28 mmol) was dissolved in DMF (50 mL). Triethylamine (1.19 mL, 8.56 mmol), 1,3-bis(diphenylphosphino)propane (200 mg, 0.4 mmol), triethylsilane (2.05 mL, 12.8 mmol), Pd(OAc)2 (100 mg, 0.4 mmol) and Pd(dppf)Cl2DCM (200 mg, 0.2 mmol) were added and the mixture stirred at 75° C. for 32 h under an atmosphere of carbon monoxide (160 psi). The reaction mixture was cooled to rt, concentrated to dryness and the solid residue purified by flash column chromatography (80 g GraceResolv silica cartridge—dry loaded) eluting with 0-20% MeOH/CH2Cl2 to afford a brown solid. This solid was washed with EtOAc to afford the desired compound (690 mg, 29%) as an off-white solid. MS: 552.08 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@H:10]([CH2:24][C:25]([OH:27])=O)[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH2:42]([CH2:44][NH2:45])[OH:43]>O1CCCC1.O.CN(C)C=O>[OH:43][CH2:42][CH2:44][NH:45][C:25](=[O:27])[CH2:24][C@@H:10]1[N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:14]2[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]12
Reactant: NCCO
Reactant: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@@H](CC(=O)O)c1nnc(C)n1-2
Agent: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@@H](CC(=O)NCCO)c1nnc(C)n1-2
Temperature: -5 °C
Reaction time: 2 h
Yield: 29.5 %

Procedure:
(S)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetic acid (7.0 g) and triethylamine (2.73 ml) are added to a mixed solvent of dimethylformamide (70 ml) and tetrahydrofuran (30 ml). The mixture is cooled to -5° C., and pivaloyl chloride (2.38 ml) is dropwise added at said temperature. Ten minutes later, a solution of ethanolamine (1.17 g) in tetrahydrofuran (10 ml) is dropwise added at said temperature, and the mixture is stirred at room temperature for 2 hours. Water is added to the reaction mixture, and the mixture is extracted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled away, and the residue is purified by column chromatography (chloroform: methanol =50: 1) and recrystallized from ethyl acetate to give 2.29 g of (S)-N-(2-hydroxyethyl)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetamide 1/4 hydrate, melting point 254°-255° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][C:19]=4[F:21])[N:14]=[C:13]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[C:12]=3[CH3:28])[CH2:9][C:8]([CH3:30])([CH3:29])[C:5]2=[N:6][CH:7]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:30][C:8]1([CH3:29])[C:5]2=[N:6][CH:7]=[C:2]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:3]=[C:4]2[N:10]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[F:21])[N:14]=[C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:12]=2[CH3:28])[CH2:9]1
Reactant: Cc1c(-c2ccccn2)nc2cccc(F)c2c1N1CC(C)(C)c2ncc(Br)cc21
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C2CCCCC2)C2CCCCC2)C1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2cccc(F)c2c1N1CC(C)(C)c2ncc(N3CCOCC3)cc21
Temperature: 100 °C
Reaction time: 14 h

Procedure:
Prepared according to procedure N using 4-(6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-5-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (98.2 mg, 0.21 mmol) (described herein), morpholine (37 mg, 0.42 mmol), Pd2dba3 (29.1 mg, 0.032 mmol), 2-(dicyclohexylphosphino)-2,4,6-tri-i-propyl-1,1-biphenyl (30.3 mg, 0.064 mmol), and sodium tert-butoxide (50.9 mg, 0.53 mmol) in toluene (2.1 mL). The reaction mixture was stirred at 100° C. for 14 h. Purification afforded 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-5-fluoro-3-methyl-2-(2-pyridinyl)quinoline as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.75 (1H, dt, J=4.8, 1.5 Hz), 8.03 (1H, dd, J=8.5, 1.3 Hz), 7.85-7.97 (2H, m), 7.58-7.68 (1H, m), 7.50-7.57 (1H, m), 7.36-7.45 (1H, m), 7.10-7.22 (1H, m), 5.70-5.80 (1H, m), 3.86 (1H, dd, J=8.8, 1.6 Hz), 3.66-3.78 (5H, m), 2.92-3.05 (4H, m), 2.40-2.50 (3H, m), 1.54-1.65 (3H, m), 1.45-1.54 (3H, m). Mass Spectrum (ESI) m/e=470 (M+1).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]1([N:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C)C=O>[CH:25]1[CH:24]=[CH:23][C:22]([N:15]([C:9]2[CH:10]=[CH:11][C:12]([Br:1])=[CH:13][CH:14]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:27][CH:26]=1
Reactant: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
Into a 200 ml three-necked flask, 8.0 g (45 mmol) of N-bromosuccinimide and 10.0 g (41 mmol) of triphenylamine were placed, followed by 150 ml of N,N-dimethylformamide. The mixture was stirred overnight at room temperature. Next, N,N-dimethylformamide was removed from the reaction, and the resulting solid matter was extracted with carbon tetrachloride. Then, carbon tetrachloride was removed, and the reaction product was recrystallized twice from ethanol to give a white solid, 4-bromotriphenylamine in an amount of 8.2 g (yield: 61.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][S:13]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#[N:33])[CH:27]=4)=[O:24])=[CH:18][CH:17]=3)(=[O:15])=[O:14])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH2:34]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)[CH2:35][CH2:36][CH3:37]>>[CH2:34]([N:38]1[CH2:43][CH2:42][N:41]([C:32](=[NH:33])[C:28]2[CH:27]=[C:26]([NH:25][C:23](=[O:24])[NH:22][C:19]3[CH:20]=[CH:21][C:16]([S:13]([NH:12][C:6]4[C:5]5[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=5)[N:9]=[CH:8][CH:7]=4)(=[O:14])=[O:15])=[CH:17][CH:18]=3)[CH:31]=[CH:30][CH:29]=2)[CH2:40][CH2:39]1)[CH2:35][CH2:36][CH3:37]
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)Nc3ccnc4cc(Cl)ccc34)cc2)c1
Reactant: CCCCN1CCNCC1
Product: CCCCN1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)Nc4ccnc5cc(Cl)ccc45)cc3)c2)CC1
Yield: 25 %

Procedure:
The title compound was prepared from N-(7-chloroquinolin-4-yl)-4-(3-(3-cyanophenyl)ureido)benzenesulfonamide following procedure C and using 2.2 equivalents of n-butylpiperazine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [Cl:1][C:2]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2C)[CH2:6][CH2:5]1)=[O:3].[F:17]C1C=CC=CC=1N1CCNCC1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1>ClCCl>[Cl:1][C:2]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])[CH2:6][CH2:5]1)=[O:3]
Reactant: Cc1ccccc1N1CCN(C(=O)Cl)CC1
Reactant: Fc1ccccc1N1CCNCC1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Cl)N1CCN(c2ccccc2F)CC1
Yield: 88 %

Procedure:
Compound 41A is prepared according to the procedure described for compound 15A, using the following reactants: 1-(2-fluorophenyl)piperazine (1.54 g, 8.06 mmol); triphosgene (850 mg, 2.85 mmol); pyridine (0.69 ml, 8.6 mmol); dichloromethane (60 ml).
Reaction SMILES: [CH:1](=[C:5]1[CH2:10][CH2:9][CH:8]([CH:11]2[CH2:16][CH2:15][CH:14]([CH:17]=[CH2:18])[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)[CH2:2][CH:3]=[CH2:4].[FH:19].C(=O)([O-])O.[Na+]>ClCCl.N1C=CC=CC=1>[CH2:1]([C:5]1([F:19])[CH2:6][CH2:7][CH:8]([CH:11]2[CH2:12][CH2:13][CH:14]([CH:17]=[CH2:18])[CH2:15][CH2:16]2)[CH2:9][CH2:10]1)[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCC=C1CCC(C2CCC(C=C)CC2)CC1
Reactant: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCCC1(F)CCC(C2CCC(C=C)CC2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
20.6 g of 4'-but-3-enylidene-4-vinylbicyclohexyl in 40 ml of dichloromethane were cooled to -25° C. 7.523 ml of a 70% solution of hydrogen fluoride in pyridine were then added dropwise with stirring, and the mixture was stirred at -25° C. for 30 minutes and then at RT for a further 8 hours. The reaction solution was poured into a suspension of 40 g of sodium hydrogencarbonate and 800 g of ice-water. The mixture was extracted with three times 150 ml of hexane. The combined organic extracts were washed once with 50 ml of sodium chloride solution, dried using sodium sulphate, filtered and evaporated to a residue. Crystallization from pentane at -25° C. gave 4-but-3-enyl-4-fluoro-4'-vinylbicyclohexyl (C 13 SmB 37 N 80 I, Δn=0.049, Δε=-1.8, viscosity=13 mm2).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([S:29](C)(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH3:33]>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([NH2:33])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N
Reactant: CC(C)=CCCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O
Product: CC(C)=CCCOc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 384 substituting 2-(3,4-difluorophenyl)-4-(4-methyl-3-pentenyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone. mp 70-73° C. 1H NMR (300 MHz, DMSO-d6) δ 1.5 (d, 6H), 2.27 (m, 2H) 4.43 (t, 2H), 4.5 (m, 1H), 7.5 (m, 2H), 7.6 (m, 1H), 7.8 (m, 2H), 7.92 (d, J=2 H, 2H), 8.2 (s, 1H). MS (DCI/NH3) m/z 462 (M+H)+, 479 (M+NH4)+. Anal. calc. for C22H21F2N3O4S: C, 57.26; H, 4.59; N, 9.11. Found,: C, 56.96; H, 4.70; N, 9.01.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[NH:34][C:35](=[O:42])[C:36]([CH3:41])([CH3:40])[CH:37](Cl)C)[CH2:24][CH:23]2[OH:43])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[N:34]3[CH2:37][C:36]([CH3:41])([CH3:40])[C:35]3=[O:42])[CH2:24][CH:23]2[OH:43])=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)=[O:11]
Reactant: CC(Cl)C(C)(C)C(=O)Nc1ccccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)CN(c2ccccc2N2CCC(NC(=O)C3(NC(=O)c4cc5ccccc5o4)CCCCC3)C(O)C2)C1=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
The solution of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-[2-(3-chloro-2,2-dimethylbutyryl)aminophenyl]piperidin-3-ol (4.1 g) obtained in Step 3 in 50 ml of dimethylformamide was cooled to 0° C. Sodium hydride (NaH, 60%; 640 mg) was added to the reaction mixture, which was then stirred overnight at 50° C., diluted with ethyl acetate, washed with a brine, and then dried and concentrated on sodium sulfate. The resulting residue was purified with column chromatography to give 2.1 g of the titled compound.