Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[C@@H](O)[C@@H]1NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC2C=CC=CC=2)NC(=O)[C@H](CCN)NC(=O)[C@@H](NC([C@@H](N)CCN)=O)CCNC1=O.OS(O)(=O)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:116][C:117]([CH3:137])=[CH:118][CH2:119][CH2:120]/[C:121](/[CH3:136])=[CH:122]/[CH2:123][CH2:124]/[C:125](/[CH3:135])=[CH:126]/[CH2:127][S:128][CH2:129][C@H:130]([NH2:134])[C:131]([OH:133])=[O:132]>C(Cl)Cl>[CH2:10]([C@@H:9]([C:14](=[O:16])[NH:134][C@H:130]([C:131]([OH:133])=[O:132])[CH2:129][S:128][CH2:127]/[CH:126]=[C:125](\[CH3:135])/[CH2:124][CH2:123]/[CH:122]=[C:121](\[CH3:136])/[CH2:120][CH2:119][CH:118]=[C:117]([CH3:137])[CH3:116])[NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH:11]([CH3:12])[CH3:13]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](N)C(=O)O
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)C[C@@H]1NC(=O)[C@@H](Cc2ccccc2)NC(=O)[C@H](CCN)NC(=O)[C@@H](NC(=O)[C@@H](N)CCN)CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 100 mL round bottom flask, N-Boc-L-leucine (1.0 mmol), coupling reagent (520 mg of PBOP or 380 mg of HATU, 1 mmol) and N,N-diisopropyl-ethyl-amine (650 mg, 5 mmol) were mixed in CH2Cl2 (10 mL). The reaction mixture was stirred at room temperature for 30 minutes. S-trans, trans-farnesyl-L-cysteine (325 mg, 1 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature overnight, the CH2Cl2 was removed by rotary evaporation. The resulting residue was dissolved in ethyl acetate (50 mL). The organic solution was washed with an NH4Cl saturated solution (50 mL), dried over Na2SO4, and concentrated to afford a crude mixture. The crude mixture was purified by preparative HPLC (200 mg, 37%) to yield Compound N-58. 1H-NMR (500 MHz, CDCl3): δ 0.95 (d, J=6.5 Hz, 3H), 0.98 (d, J=6.5 Hz, 3H), 1.47 (s, 9H), 1.62 (bs, 6H), 1.51-1.59 (m, 1H), 1.69 (s, 3H), 1.72 (s, 3H), 1.99 (t, J=7.5 Hz, 2H), 2.05-2.14 (m, 8H), 2.79 (dd, J=7.5, 14.2, 1H), 3.00 (dd, J=4.8, 13.9 Hz, 1H), 3.17 (dd, J=7.6, 13.0 Hz, 1H), 3.25 (dd, J=8.2, 12.9 Hz, 1H), 4.15 (dd, J=5.4, 9.8 Hz, 1H), 4.60 (dd, J=4.9, 8.0 Hz, 1H), 5.09-5.25 (m, 2H), 5.23 (t, J=7.6 Hz, 1H). 13C-NMR (125 MHz, CDCl3): δ 16.2, 16.3, 17.8, 22.0, 23.5, 25.9, 27.4, 27.8, 28.8, 30.4, 33.6, 40.8, 40.9, 42.3, 53.3, 54.6, 80.6, 121.6, 125.2, 125.5, 132.1, 136.2, 140.6, 157.8, 173.6, 175.6; ES-MS: mass calcd for Chemical Formula: C29H50N2O5S 538.3. Found (M+Na) m/z 561.4.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][C:32]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].S(Cl)(C1C=CC(C)=CC=1)(=O)=O.Cl.[Cl:64][CH2:65][CH:66]1[NH:69][C:68](=[O:70])[CH:67]1[NH2:71].O>C(Cl)Cl>[Cl:64][CH2:65][CH:66]1[NH:69][C:68](=[O:70])[CH:67]1[NH:71][C:27](=[O:28])[C:26]([C:24]1[N:25]=[C:21]([NH:20][C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[S:22][CH:23]=1)=[N:30][O:31][C:32]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C(O)C(=NOC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: NC1C(=O)NC1CCl
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: ClCCl
Product: O=C(NC1C(=O)NC1CCl)C(=NOC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.67 h

Procedure:
A mixture of 1.527 g of the syn isomer of sodium 2-(2-tritylamino-4-thiazolyl)-2-trityloxyimino-acetic acid, 419 mg of tosyl chloride and 15 ml of methylene chloride was stirred for 40 minutes and then a solution of 342 mg of 4-chloromethyl-3-amino-2-oxo-azetidine hydrochloride in 15 ml of methylene chloride and 0.6 ml of triethylaime was added thereto. The mixture was stirred for 2 hours and water was added thereto with stirring. The decanted aqueous phase was extracted with methylene chloride and the combined organic phases were dried, filtered and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with ether to obtain 736 mg of syn isomer of 4-chloromethyl-3-[2-(2-tritylamino-4-thiazolyl)-2-trityloxyimino-acetamido]-2-oxo-azetidine.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH:14]([CH3:17])[CH2:15][F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:18][C:19]([CH:25]1[CH2:27][CH2:26]1)([CH3:24])[CH2:20][C:21]([NH2:23])=[O:22]>>[NH2:23][C:21](=[O:22])[CH2:20][C:19]([NH:18][C:10](=[O:12])[C:7]1[CH:6]=[C:5]([O:13][CH:14]([CH3:17])[CH2:15][F:16])[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)([CH:25]1[CH2:27][CH2:26]1)[CH3:24]
Reactant: CC(N)(CC(N)=O)C1CC1
Reactant: CC(CF)Oc1cc(C(=O)O)ncc1C1CC1
Product: CC(CF)Oc1cc(C(=O)NC(C)(CC(N)=O)C2CC2)ncc1C1CC1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-cyclopropyl-4-(1-fluoropropan-2-yloxy)picolinic acid (enantiomer B) (example 289b) and 3-amino-3-cyclopropyl-butanamide (example 270c) as starting materials and isolated (85.4 mg, 80%); MS (ESI, m/z): 364.4 (M+H+).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[C:10]([C:18]4[CH:23]=[CH:22][C:21]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=4)=[C:11]4[C:16](=[CH:17][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1)[CH:15]=[CH:14][CH:13]=[CH:12]4.II.[I:31](O)(=O)=O.S(=O)(O)[O-].[Na+]>O1CCCC1.C(O)(=O)C.S(=O)(=O)(O)O>[I:31][C:17]1[C:7]2[S:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:9]=3[C:8]=2[C:10]([C:18]2[CH:23]=[CH:22][C:21]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=2)=[C:11]2[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]2
Reactant: [O-][I+2]([O-])O
Reactant: CS(=O)(=O)Oc1ccc(-c2c3ccccc3cc3sc4ccccc4c23)cc1
Agent: II
Agent: O=S(=O)(O)O
Agent: O=S([O-])O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CS(=O)(=O)Oc1ccc(-c2c3ccccc3c(I)c3sc4ccccc4c23)cc1
Temperature: 25 °C
Reaction time: 88 h
Yield: 373 %

Procedure:
To a solution of methanesulfonic acid 4-benzo[b]naphtho[2,3-d]thiophen-11-yl-phenyl ester (2.24 g, 5.54 mmole) in tetrahydrofuran (22.4 mL), 80% aqueous acetic acid (11.2 mL) and sulfuric acid (0.6 mL) was added iodine (0.984 g, 3.87 mmol) and iodic acid (0.244 g, 1.39 mmol). The reaction mixture was stirred for 88 h at room temperature then combined with an aqueous solution of sodium bisulfite (100 mL). The organics were extracted with ether (500 mL). The extracts were concentrated and chased with benzene and pet ether to provide the title compound as a yellow solid (2.75 g, 94%): mp 176-186° C.; NMR (CDCl3); δ 8.24 (ddd, J=8, 1, 1 Hz, 1H), 7.81 (ddd, J=8, 1, 1 Hz, 1H), 7.65-7.58 (m, 3H), 7.52-7.38 (m, 5H), 7.11-7.07 (ddd, J=8, 7, 1 Hz, 1H), 6.57 (ddd, J=8, 1, 1 Hz, 1H), 3.33 (s, 3H); MS (+FAB): [M+] m/z 530 (65%), [M+H]+m/z 531 (25%); Anal. calc. for C23H15IO3S2: C, 52.08, H, 2.85, N, 0.00. Found: C, 51.75, H, 2.75, N, 0.06.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([C:10](O)([CH3:12])[CH3:11])=[N:6][C:5]=12.C(N(S(F)(F)[F:20])CC)C>ClCCl>[F:20][C:10]([C:7]1[CH:8]=[CH:9][N:4]2[CH:3]=[CH:2][N:1]=[C:5]2[N:6]=1)([CH3:12])[CH3:11]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(O)c1ccn2ccnc2n1
Solvent: ClCCl
Product: CC(C)(F)c1ccn2ccnc2n1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 17.3 %

Procedure:
To a cooled (−78° C.) suspension of 2-(imidazo[1,2-α]pyrimidin-7-yl)propan-2-ol (1.02 mg, 5.8 mmol) in dichloromethane (25 ml) was added (diethylamino)sulfur trifluoride (1.22 mg, 7.5 mmol) dropwise over 5 min. The mixture was stirred at −78° C. for 40 min then quenched with methanol (1 ml). The mixture was warmed to ambient temperature, made basic with saturated sodium hydrogencarbonate solution (25 ml) and extracted with dichloromethane (2×25 ml). The combined organics were washed with brine (50 ml), dried over anhydrous sodium sulfate and evaporated to dryness. Purification of this material by chromatography on silica eluting with dichloromethane (containing 0.5% conc. ammonia) on a gradient of methanol (1-3%) gave 7-(1-fluoro-1-methylethyl)imidazo[1,2-α]pyrimidine (180 mg, 17%) as a yellow solid: δH (360 MHz, CDCl3) 1.78 (6H, d, J 22), 7.21 (1H, dd, J 7 and 1), 7.54 (1H, d, J 1), 7.79 (1H, d, J 1), 8.45 (1H, d, J 7).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]([CH2:45][CH2:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH:42]=[CH:43][N:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:53]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:62])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38]([CH2:39][C:40]5[N:41]([CH2:45][CH2:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH:42]=[CH:43][N:44]=5)=[O:62])=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:53]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4CCCC(=O)OCC)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nccn4CCCC(=O)OCC)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
To a solution of ethyl 4-[2-[[[4-[[[7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepin-4-yl]carbonyl]amino]phenyl]thio]methyl]-1H-imidazol-1-yl]butanoate (1.0 g) in dichloromethane (10 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.50 g) in dichloromethane (10 ml) at −78° C. The mixture was stirred for 1 hour at −78° C., an aqueous solution of sodium thiosulfate was added to the mixture, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica gel, ethyl acetate), to give ethyl 4-[2-[[[4-[[[7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-yl]carbonyl]amino]phenyl]sulfinyl]methyl]-1H-imidazol-1-yl]butanoate (Preparation of Compound 414) (911 mg) as yellow crystals.
Reaction SMILES: [Li]C(CC)C.C1CCCCC1.C(=O)=O.CC(C)=O.CN(CCN(C)C)C.[CH2:27]([NH:29][C:30](=[O:38])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:37])[CH3:28].[CH2:39]([Si:42]([CH3:45])([CH3:44])Cl)[CH:40]=[CH2:41]>C1COCC1>[Cl:37][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([Si:42]([CH3:45])([CH3:44])[CH2:39][CH:40]=[CH2:41])[C:31]=1[C:30]([NH:29][CH2:27][CH3:28])=[O:38]
Reactant: C=CC[Si](C)(C)Cl
Reactant: CCNC(=O)c1ccccc1Cl
Agent: CN(C)CCN(C)C
Agent: O=C=O
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: C=CC[Si](C)(C)c1cccc(Cl)c1C(=O)NCC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.3M s-BuLi in cyclohexane (10.5 mL, 13.6 mmol) was added dropwise to a dry-ice/acetone cooled solution of TMEDA (1.0 mL, 6.5 mmol) in THF (10 mL), followed by the dropwise addition of a solution of the compound of example f (1.0 g, 5.45 mmol) in THF (10 mL). The reaction mixture was stirred at -78° C. for 30 min, then allyldimethylchlorosilane (10.9 mmol) was added and the mixture was stirred for 2.5 h at -78° C. The resulting reaction was warmed to -30° C., quenched with dilute aq citric acid, diluted with water, and extracted with EtOAc (2×). The combined organic extracts were dried (MgSO4), concentrated, and purified by HPLC with 1:19 EtOAc/cyclohexane to give the desired compound as a white solid. m.p. 61-63° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:11]2[C:6](=[C:7]([C:12](OC)=[O:13])[CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:16])[CH2:3]1.[BH4-].[Li+].C(=O)(O)[O-].[Na+]>O1CCCC1.COC(C)(C)C>[OH:13][CH2:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[NH:5][C:4](=[O:16])[CH2:3][C:2]2([CH3:17])[CH3:1]
Reactant: COC(=O)c1cccc2c1NC(=O)CC2(C)C
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CC1(C)CC(=O)Nc2c(CO)cccc21
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A solution of 3.72 g of methyl 4,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinoline-8-carboxylate in 100 ml of tetrahydrofuran is admixed with 1.83 g of lithium borohydride and then stirred at 50° C. over 1 hour. The reaction mixture is cooled to room temperature, diluted with tert-butyl methyl ether and stirred with saturated aqueous sodium bicarbonate solution until no more gas is formed. The phases are separated—the organic phase is washed with water, dried over sodium sulphate and concentrated by evaporation. The crude title compound is obtained as a brown-yellow oil from the residue. Rt=3.02.
Reaction SMILES: [CH2:1]([N:8]([C:22](=[O:26])[CH2:23][C:24]#[N:25])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>ClCCl>[NH2:25][C:24]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH:13]=2)[C:9](=[O:10])[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:22](=[O:26])[CH:23]=1
Reactant: COC(=O)c1cccc(NC(=O)N(Cc2ccccc2)C(=O)CC#N)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(-n2c(N)cc(=O)n(Cc3ccccc3)c2=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Benzyl-1-(cyanoacetyl)-3-[3-(methoxycarbonyl)phenyl]urea (3.51 g) was dissolved in dichloromethane (50 ml) and triethylamine (1.52 g) added. The mixture was stirred for one hour at room temperature and the product filtered off and washed with dichloromethane. Yield=3.16 g.
Reaction SMILES: [F:1][C:2]1[C:3]([F:24])=[CH:4][C:5]2[CH:6]=[C:7]3[C:22](=[O:23])[NH:21][CH2:20][CH2:19][N:8]3[C:9]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[CH3:25]OC1C=CC(B(O)O)=CC=1>>[F:1][C:2]1[C:3]([F:24])=[CH:4][C:5]2[CH:6]=[C:7]3[C:22](=[O:23])[NH:21][CH2:20][CH2:19][CH2:25][N:8]3[C:9]=2[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COc1ccc(-c2c(F)c(F)cc3cc4n(c23)CCNC4=O)cc1
Product: COc1ccc(-c2c(F)c(F)cc3cc4n(c23)CCCNC4=O)cc1

Procedure:
The title compound, light yellow solid (46 mg, 54%), MS (ISP) m/z=343.2 [(M+H)+], mp 182.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-8,9-difluoro-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 7) (78.8 mg, 0.25 mmol) and commercially available 4-methoxy-phenylboronic acid (49.4 mg, 0.325 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4].[CH3:32][Sn](C)(C)C.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.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>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13]([CH3:32])[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4]
Reactant: C[Sn](C)(C)C
Reactant: COC(=O)c1nc(Br)c2c(cc(Cc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1nc(C)c2c(cc(Cc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 62.3 %

Procedure:
A mixture of 1,3-dibenzyl-8-bromo-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (150 mg, 0.31 mmol), tetramethyltin (0.22 mL, 1.57 mmol) and PdCl2(PPh3)2 (44 mg, 0.063 mmol) in 5 mL of DMF was heated at 120° C. for 2 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc (50 mL) and brine (10 mL) were added. 1M HCl was added with stirring until pH was about 2. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was chromatographed (0-40% EtOAc/hexanes+2% AcOH) to give 80 mg of the title compound. MS: (+) m/z 415.12 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH2:18][CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Product: CC(C)(C)OC(=O)N1CCC(CNc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Yield: 10.2 %

Procedure:
Following general procedure B, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (500 mg, 1.60 mmol) was reacted with tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (516 mg, 2.41 mmol) to afford the desired product (80 mg, >99%) as an orange foam: ESI MS m/z 489 [C24H30BrN3O3+H]+.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3](Cl)([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH3:28])=[CH:22][CH:21]=1)[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1.C([SnH](CCCC)CCCC)CCC.O>C1(C)C=CC=CC=1>[F:1][C:2]([F:30])([F:31])[CH:3]([C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH3:28])=[CH:24][CH:25]=1)[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1
Reactant: CCOc1ccc(C(Cl)(COCc2cccc(Oc3ccccc3)c2)C(F)(F)F)cc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: O
Solvent: Cc1ccccc1
Product: CCOc1ccc(C(COCc2cccc(Oc3ccccc3)c2)C(F)(F)F)cc1
Yield: 90.2 %

Procedure:
A few crystals of α,α'-azoisobutyronitrile (AIBN) were added to a solution of 1,1,1-trifluoro-2-chloro-2-(4-ethoxyphenyl)-3-(3-phenoxybenzyloxy)propane (0.36 g) in toluene (15 cm3), and the mixture was cooled in an ice bath whilst tri-n-butyl tin hydride (0.25 cm3) was added. The reaction mixture was heated at the reflux temperature for 1.5 hours under an atmosphere of nitrogen. Analysis by gas liquid chromatography at this time showed no trace of the starting chloro compound. The mixture was cooled, poured into water (50 cm3), and extracted with diethyl ether (4×30 cm3). The combined organic layers were dried over anhydrous sodium sulphate and the residual oil after evaporation of the solvent under reduced pressure was purified by column chromatography on a silica gel support, eluting with n-hexane containing 6% by volume diethyl ether, to give 1,1,1-trifluoro-2-(4-ethoxyphenyl)-3-(3-phenoxybenzyloxy)-propane (0.3 g) as an oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N+:12]([O-])=O)[C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1>CCO.[Pd]>[NH2:12][C:4]1[C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=[CH:2][CH:3]=1
Reactant: O=c1[nH]c2cc(Cl)cc([N+](=O)[O-])c2o1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc2[nH]c(=O)oc12
Reaction time: 18 h

Procedure:
To a solution of 5-chloro-7-nitro-1,3-benzoxazol-2(3H)-one from Step A (1.10 g, 5.13 mmol) in EtOH (50 mL) was added 10% Pd/C (300 mg). The reaction mixture was shaken in a Parr apparatus under a hydrogen atmosphere (40 p.s.i.) for 18 h, then filtered through a Celite pad, washing with EtOH, and the filtrate was concentrated under reduced pressure to give the title compound. MS: m/z=151 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C.[H-].[Na+].Br[C:29]1[CH:30]=[C:31]([CH:52]=[CH:53][N:54]=1)[C:32]([NH:34][C:35]1[S:36][C:37]2[C:43]([CH:44]3[CH2:49][O:48][CH2:47][CH2:46][O:45]3)=[CH:42][CH:41]=[C:40]([O:50][CH3:51])[C:38]=2[N:39]=1)=[O:33]>O1CCOCC1.CN(C=O)C>[O:45]1[CH2:46][CH2:47][O:48][CH2:49][CH:44]1[C:43]1[C:37]2[S:36][C:35]([NH:34][C:32](=[O:33])[C:31]3[CH:52]=[CH:53][N:54]=[C:29]([O:1][CH2:2][CH2:3][N:4]4[CH2:9][CH2:8][O:7][CH2:6][CH2:5]4)[CH:30]=3)=[N:39][C:38]=2[C:40]([O:50][CH3:51])=[CH:41][CH:42]=1
Reactant: OCCN1CCOCC1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(OCCN4CCOCC4)c3)nc12
Temperature: 50 °C
Yield: 72.6 %

Procedure:
To a solution of 437 mg (3.33 mmol) N-(2-hydroxyethyl)morpholine and 20 mg (0.09 mmol) 2,6-di-tert-butyl-para-cresol in 5 ml dioxane and 1 ml DMF was added portionwise 194 mg (4.44 mmol) sodium hydride (55% dispersion in oil) and the mixture heated at 50° C. for 30 min. 200 mg (0.44 mmol) (+)-2-bromo-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide was then added and the mixture heated at 80° C. for 16 h. The reaction mixture was then poured onto water and extracted three times with ethyl acetate. The organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (5/95 methanol/ethyl acetate) followed by trituration in ether and hexane afforded 160 mg (72%) (+)-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-2-(2-morpholin-4-yl-ethoxy)-isonicotinamide as a white solid. [α]D20=+51.2° (c=1.04, CHCl3), ES-MS m/e (%): 501 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-])=O)=[C:6]([CH:20]=1)[O:7][C@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH2:9]1.Cl[Sn]Cl>CCOC(C)=O.C([O-])([O-])=O.[K+].[K+]>[NH2:21][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:20][C:6]=1[O:7][C@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14](=[O:19])[C:15]([F:17])([F:16])[F:18])[CH2:9]1
Reactant: O=C(N1CCC[C@H](Oc2cc(Cl)ccc2[N+](=O)[O-])C1)C(F)(F)F
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: Nc1ccc(Cl)cc1O[C@H]1CCCN(C(=O)C(F)(F)F)C1

Procedure:
(S)-1-(3-(5-chloro-2-nitrophenoxy)piperidin-1-yl)-2,2,2-trifluoroethanone (465.0 mg) and SnCl2*H2O (1.49 g) was dissolved in EtOAc (10.0 ml) and heated at reflux for 3.5 h. The reaction mixture was diluted with EtOAc an 10% aq. K2CO3. The mixture was separated and the organic layer washed with water and brine. The organic phase was dried and poured through an hydrophobic frit. The solvent was evaporated to give the intended product.