Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[C:17]1[NH:21][C:20]2[CH:22]=[CH:23][C:24]([C:26]#[CH:27])=[CH:25][C:19]=2[N:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[C:17]1[NH:21][C:20]2[CH:22]=[CH:23][C:24]([C:26]#[C:27][C:27]#[C:26][C:24]3[CH:23]=[CH:22][C:20]4[NH:21][C:17]([C@@H:12]5[CH2:13][CH2:14][CH2:15][CH2:16][N:11]5[C:9]([O:8][CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[O:10])=[N:18][C:19]=4[CH:25]=3)=[CH:25][C:19]=2[N:18]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#Cc1ccc2[nH]c([C@@H]3CCCCN3C(=O)OCc3ccccc3)nc2c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCCC[C@H]1c1nc2cc(C#CC#Cc3ccc4[nH]c([C@@H]5CCCCN5C(=O)OCc5ccccc5)nc4c3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 38.6 %

Procedure:
To a stirring solution of (S)-2-(5-ethynyl-1H-benzoimidazol-2-yl)-piperidine-1-carboxylic acid benzyl ester (26 mg, 0.0723 mmol), CuI (3 mg) and bis(triphenylphosphine)palladium (II) dichloride (8 mg) in THF (1.5 mL) is added TEA (30 μL, 3.4 mmol). The reaction mixture is stirred at room temperature for 12 hours and filtered through celite and the filtrate is concentrated in vacuum to dryness. The residue is purified by flash column chromatography on silica gel (EtOAc/hexanes 0% to 100%) to give the title compound (S)-2-(5-{4-[2-((S)-1-benzyloxycarbonyl-piperidin-2-yl)-1H-benzoimidazol-5-yl]-buta-1,3-diynyl}-1H-benzoimidazol-2-yl)-piperidine-1-carboxylic acid benzyl ester (10 mg, 39%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([C:12]#[N:13])[CH:3]=1.C(COC)OC.O.[OH-].[Li+].Cl>O>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([C:12]#[N:13])[CH:3]=1
Reactant: COC(=O)c1ccc(Br)cc1C#N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: N#Cc1cc(Br)ccc1C(=O)O
Reaction time: 1 h
Yield: 93.5 %

Procedure:
To methyl 4-bromo-2-cyanobenzoate (4.76 g) described in Preparation Example 191 was added dimethoxyethane (78 mL), a solution obtained by dissolving lithium hydroxide monohydrate (1.25 g) in water (30 mL) under ice-cooling was added dropwise, and the mixture was stirred for 1 hr. Under ice-cooling, the mixture was neutralized with 1N hydrochloric acid and dimethoxyethane was evaporated. Water was added and the mixture was stirred under ice-cooling. The precipitated crystals were collected by filtration to give the title compound (4.19 g).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][CH2:4][CH:3]1[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(=O)(O)[O-].[Na+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CO>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:4][CH:3]1[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(C)(C)OC(=O)NC1CNc2ccccc2NC1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CN(Cc2ccccc2)c2ccccc2NC1=O
Reaction time: 8 h
Yield: 88.9 %

Procedure:
2-Oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (832 mg) was dissolved in methanol (20 ml), sodium bicarbonate (445 mg) and benzyl bromide (906 mg) were added, the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, the residue, after addition of water, was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure, the crystals were washed with isopropyl ether, to thereby obtain 980 mg of the titled compound (Yield: 86.9%).
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1)[C:10]([OH:12])=O)=[O:7])(C)(C)C.CN1CCOCC1.C(OC(Cl)=O)(C)C.[F:36][C:37]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=1[C@@H:44]([NH:51][C@H:52](C(O)=O)[CH2:53][CH:54]([CH3:56])[CH3:55])[C:45]([NH:47][CH:48]([CH3:50])[CH3:49])=[O:46]>O1CCCC1.C1(C)C=CC=CC=1.CN(C)C=O.O1CCCC1>[F:36][C:37]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=1[C@@H:44]([N:51]1[C@H:52]([CH2:53][CH:54]([CH3:56])[CH3:55])[C:6](=[O:7])[NH:8][C@H:9]([CH:13]2[CH2:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:21]2)[C:10]1=[O:12])[C:45]([NH:47][CH:48]([CH3:49])[CH3:50])=[O:46]
Reactant: CC(C)C[C@H](N[C@@H](C(=O)NC(C)C)c1ccc(F)cc1F)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C1Cc2ccccc2C1
Agent: CC(C)OC(=O)Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: Cc1ccccc1
Product: CC(C)C[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1[C@@H](C(=O)NC(C)C)c1ccc(F)cc1F
Reaction time: 0.17 h

Procedure:
To a solution of (2R)-[(tert-butoxycarbonyl)amino](2,3-dihydro-1H-inden-2-yl)ethanoic acid (291 mg) in dry tetrahydrofuran (5 ml) under a nitrogen atmosphere at −20° C. was added N-methylmorpholine (101 mg) and a solution of isopropylchloroformate in toluene (1.0M, 1 ml). After 10 minutes, a solution of N-[(1R)-1-(2,4-difluorophenyl)-2-(isopropylamino)-2-oxoethyl]-L-leucine (342 mg) in N,N-dimethylformamide/tetrahydrofuran (5 ml/10 ml) was added and the resultant mixture was stirred at room temperature for 4 hours. The solvent was then removed in vacuo and the residue was treated with 4N hydrochloric acid in dioxane (2 ml). After 4 hours, methanol (5 ml) was added to the reaction mixture and this was left to stand for 18 hours. The solvent was then removed in vacuo and the residue was purified on an SPE cartridge (50 g, silica) eluting with cyclohexane/ethyl acetate (gradient from 4:1 to neat ethyl acetate), which furnished the two diastereomers as white solids (2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-isopropylethanamide; (0.137 g)
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[N:7]([CH2:11][CH2:12][N:13](CC1C=CC=CC=1)CC1C=CC=CC=1)[CH2:8][CH2:9][F:10])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:28])[N:7]([CH2:11][CH2:12][NH2:13])[CH2:8][CH2:9][F:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCF)CCN(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCN)CCF
Yield: 82.4 %

Procedure:
(2-Amino-ethyl)-(2-fluoro-ethyl)-carbamic acid tert-butyl ester (95 mg) was prepared by following General Procedure T starting from (2-dibenzylamino-ethyl)-(2-fluoro-ethyl)-carbamic acid tert-butyl ester (216 mg) and Pd—C (40 mg) in methanol (1 mL).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[N:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[C:35]([CH:43]=O)[CH:34]=1.C(O)(=O)C.[OH-].[Na+]>ClCCCl>[C:15]([O:19][C:20]([N:22]1[CH2:23][CH2:24][CH:25]([N:28]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:43][C:35]2[CH:34]=[N:33][C:42]3[C:37]([CH:36]=2)=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:26][CH2:27]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)CNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=Cc1cnc2ccccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)CN(Cc1cnc2ccccc2c1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.8 %

Procedure:
Sodium triacetoxyborohydride (1.29 g, 6.09 mmol) is added to a stirred solution of 4-isobutylamino-piperidine-1-carboxylic acid tert-butyl ester (1.09 g, 4.29 mmol), quinoline-3-carboxaldehyde (0.68 g, 4.3 mmol), acetic acid (0.25 ml, 4.37 mmol), and 1,2-dichloroethane (15 ml). The reaction is stirred for 18 h at room temperature under nitrogen. The reaction is poured into 2N NaOH (100 ml) and extracted with ethyl acetate (100 ml×3). The ethyl acetate is dried over sodium sulfate and then the sodium sulfate is filtered off. The crude product is concentrated on a rotary evaporator and purified by flash chromatography on silica gel eluting with 15% acetone/hexanes to yield (1.02 g, 60%) of 4-{isobutyl-[(quinolin-3-yl)methyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester: mass spectrum (ion spray): m/z=398.2 (M+1); 1H NMR (CDCl3): δ=8.93 (1H, d), 8.09 (1H, d), 8.02 (1H, s), 7.79 (1H, d), 7.70-7.66 (1H, m), 7.55-7.51 (1H, m), 4.16 (2H, br s), 3.79 (2H, s), 2.63-2.57 (3H, m), 2.27 (2H, d), 1.77-1.65 (3H, m), 1.52-1.48 (2H, m), 1.44 (9H, s), 0.85 (6H, d).
Reaction SMILES: [Li]CCCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.Cl[Si](CC)(CC)CC.[Cl:20][C:21]1[CH:22]=[C:23]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([C:37]([C:39]4[CH:43]=[CH:42][O:41][CH:40]=4)=[O:38])[CH:35]=3)[N:30]([CH3:44])[C:29](=[O:45])[CH:28]=2)[CH:24]=[CH:25][CH:26]=1>C1COCC1>[Cl:20][C:21]1[CH:22]=[C:23]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([C:37]([C:39]4[CH:43]=[CH:42][O:41][CH:40]=4)([OH:38])[C:11]4[N:7]([CH3:6])[CH:8]=[N:9][CH:10]=4)[CH:35]=3)[N:30]([CH3:44])[C:29](=[O:45])[CH:28]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: Cn1ccnc1
Reactant: Cn1c(=O)cc(-c2cccc(Cl)c2)c2cc(C(=O)c3ccoc3)ccc21
Agent: CC[Si](Cl)(CC)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1cncc1C(O)(c1ccoc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Temperature: -70 °C
Reaction time: 1 h
Yield: 12.2 %

Procedure:
BuLi 1.6M (20.6 ml) was added dropwise at −70° C. under N2 flow to a mixture of 1-methyl-1H-imidazole (0.033 mol) in THF (60 ml). The mixture was stirred at −70° C. for 30 min. chlorotriethyl-silane (0.033 mol) was added. The mixture was brought slowly to 10° C. and cooled again to −70° C. BuLi 1.6M (20.6 ml) was added dropwise. The mixture was stirred at −70° C. for 1 hour, brought to −15° C. and cooled again to −70° C. A suspension of intermediate 27 (0.022 mol) in THF (80 ml) was added dropwise. The mixture was stirred at −70° C. for 30 min, then brought to room temperature, hydrolized, extracted with EtOAc and decanted. The organic layer was dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue (13 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 95/5/0.2; 20–45 μm). One pure fraction was collected and the solvent evaporated. The residue was crystallized from CH3CN and diethyl ether. The precipitate was filtered off and dried, yielding 1.2 g (12.2%) of 4-(3-chlorophenyl)-6-[3-furanylhydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone, melting point 248° C.
Reaction SMILES: [CH:1]([N:4](CC)C(C)C)(C)C.[Cl:10][C:11]1[CH:19]=[C:18]([C:20]2[CH:21]=[N:22][C:23]3[N:24]([C:26]([C:29]4([C:32]5[CH:33]=[C:34]6[C:39](=[CH:40][CH:41]=5)[N:38]=[CH:37][CH:36]=[CH:35]6)[CH2:31][CH2:30]4)=[CH:27][N:28]=3)[CH:25]=2)[CH:17]=[CH:16][C:12]=1[C:13](O)=[O:14].CN.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:10][C:11]1[CH:19]=[C:18]([C:20]2[CH:21]=[N:22][C:23]3[N:24]([C:26]([C:29]4([C:32]5[CH:33]=[C:34]6[C:39](=[CH:40][CH:41]=5)[N:38]=[CH:37][CH:36]=[CH:35]6)[CH2:31][CH2:30]4)=[CH:27][N:28]=3)[CH:25]=2)[CH:17]=[CH:16][C:12]=1[C:13]([NH:4][CH3:1])=[O:14]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1Cl
Agent: CN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N,N-Diisopropylethylamine (14 μL, 0.081 mmol) was added to a mixture of 2-chloro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoic acid (0.027 mmol), methylamine (2M in THF, 0.2 mL, 0.4 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (14 mg, 0.032 mmol) in N,N-dimethylformamide (0.5 mL). The mixture was stirred at RT for 2 h, and then purified by RP-HPLC (pH 10) to afford the desired product. LCMS: (M+H)=454.1/456.0.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C([O-])(=O)C.[K+].C(OC(=O)C)(=O)C.C1OCCOCCOCCOCCOCCOC1.[N:40](OCCC(C)C)=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:4]2[C:3]=1[CH:9]=[N:40][NH:5]2
Reactant: Cc1c(N)cccc1Br
Reactant: CC(C)CCON=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: Brc1cccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39.6 %

Procedure:
To a solution of 3-bromo-2-methyl aniline (0104) (0.50 g, 2.69 mmol) in chloroform (5 mL) was added potassium acetate (0.28 g, 2.82 mmol). The mixture was cooled with ice-water bath and then acetic anhydride (0.50 mL, 5.37 mmol) was added to it. Ice-water bath was then removed and the resulting mixture was stirred at room temperature for 10 minutes after which time a white gelatinous solid formed. 18-Crown-6 (0.14 g, 0.54 mmol) was then added followed by isoamyl nitrite (0.80 mL, 5.90 mmol). The mixture was then heated under reflux for 18 hours. The reaction mixture was allowed to cool, and was partitioned between chloroform (3×10 mL) and saturated aqueous sodium hydrogen carbonate (10 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SO4, filtered and evaporated to give a crude product which was purified by column chromatography (ethyl acetate in petroleum ether, 10% v/v) to give 1-(4-bromoindrazol-1-yl)-ethanone (0105) as an orange solid (0.31 g, 49%), and 4-bromo-1H-indazole (0106-3) as a pale orange solid (0.21 g, 40%). Compound 0105: LCMS: 239 [M+1]+; 1H NMR (400 Hz, CDCl3) δ 2.80 (s, 3H), 7.41 (t, J=6.8 Hz, 1H), 7.50 (d, J=6.0 Hz, 1H), 8.15 (s, 1H), 8.40 (d, J=6.8 Hz, 1H). Compound 0106: LCMS: 197 [M+1]+; 1H NMR (400 Hz, CDCl3) δ 7.25 (t, J=6.0 Hz, 1H), 7.34 (d, J=6.4 Hz, 1H), 7.46 (d, J=6.8 Hz, 1H), 8.12 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:29])[C:10]([C:12]1[S:21][C:20]2[C:19]3[CH:22]=[C:23]([C:26]([OH:28])=O)[CH:24]=[CH:25][C:18]=3[O:17][CH2:16][CH2:15][C:14]=2[CH:13]=1)=[O:11].[CH3:30][N:31]([CH3:38])[CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:29])[C:10]([C:12]1[S:21][C:20]2[C:19]3[CH:22]=[C:23]([C:26]([N:35]4[CH2:36][CH2:37][CH:32]([N:31]([CH3:38])[CH3:30])[CH2:33][CH2:34]4)=[O:28])[CH:24]=[CH:25][C:18]=3[O:17][CH2:16][CH2:15][C:14]=2[CH:13]=1)=[O:11]
Reactant: CN(C)C1CCNCC1
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(C(=O)O)ccc1OCC2)c1ccc(Cl)cc1Cl
Product: CN(C(=O)c1cc2c(s1)-c1cc(C(=O)N3CCC(N(C)C)CC3)ccc1OCC2)c1ccc(Cl)cc1Cl

Procedure:
2-[(2,4-Dichloro-phenyl)-methyl-carbamoyl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carboxylic acid and 4-(dimethylamino)piperidine were reacted by General Procedure B to give 247. NMR: (CDCl3): 1.45-1.62 (2 H, br m), 1.88-2.01 (2 H, br, m), 2.39 (6 H, s, Me), 2.50-2.61 (1 H, br m), 2.82-3.10 (2 H, br m), 3.07-3.09 (2 H, m), 3.38 (3 H, s, Me), 3.80-4.01 (1 H, br m), 4.26-4.29 (2 H, m), 4.58-4.79 (1 H, br m), 6.85 (1 H, s, Ar), 7.02 (1 H, d, J 8.3, Ar), 7.25 (1 H, dd, J 8.2 and 2.0, Ar), 7.28-7.32 (1 H, m, Ar), 7.37-7.39 (1 H, m, Ar), 7.55 (1 H, s, Ar) and 7.60 (1 H, s, Ar). MS: (ESI+) MH+=558.14
Reaction SMILES: CC1C2=CC=CC(C(O[C@H]3[C@H](O[C@H]4O[C@H](C)[C@H](O)[C@H](O)[C@H]4NC)C4=CC#C[C@H]5O[C@@]5([C@@H]5OC(=O)OC5)C#CC4=C3)=O)=C2C=C(OC)C=1.[N+:48]([C:51]1[CH:56]=[CH:55][C:54](S(O)(=O)=O)=[C:53]([N+]([O-])=O)[C:52]=1[N+]([O-])=O)([O-:50])=[O:49]>C(=O)(O)[O-].[Na+]>[N+:48]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)([O-:50])=[O:49]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)O)c([N+](=O)[O-])c1[N+](=O)[O-]
Agent: CN[C@H]1[C@@H](O[C@@H]2/C3=C/C#C[C@H]4O[C@@]4([C@H]4COC(=O)O4)C#CC3=C[C@H]2OC(=O)c2cccc3c(C)cc(OC)cc23)O[C@H](C)[C@H](O)[C@@H]1O
Agent: CN[C@H]1[C@@H](O[C@@H]2C3=CC#C[C@H]4O[C@@]4([C@H]4COC(=O)O4)C#CC3=C[C@H]2OC(=O)c2cccc3c(C)cc(OC)cc23)O[C@H](C)[C@H](O)[C@@H]1O
Agent: O=C([O-])O
Product: O=[N+]([O-])c1ccccc1

Procedure:
20 g of neocarzinostatin (NCS) was dissolved in 5.0 ml of 0.8M aqueous solution of sodium bicarbonate under ice-cooling in the dark. The powdery H-SMA stepwise was added in a total amount of 0.5 g in several times and dissolved thereinto. During the reaction,, the pH of the solution was kept around 8.5. The conversion of such an unreacted primary amino group originating from NCS can be determined by a method (hereinafter referred to as "TNBS" method) in which a small amount of a sample taken out from the reaction mixture 24 hours after the addition was started was diluted, and was reacted with trinitrobenzene sulfonic acid to produce a nitrobenzene derivative, which was determined based on the amount of the primary amino group spectrophotometrically by a visible absorption spectrometer at 420 nm. It was learned that the primary amino groups completely disappeared.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:3]=1[O:4][CH2:5][CH:6]([NH:8][C:9](=O)[CH3:10])[CH3:7].O1CCCC1>C(O)C.CCOCC>[CH3:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:3]=1[O:4][CH2:5][CH:6]([NH:8][CH2:9][CH3:10])[CH3:7]
Reactant: CC(=O)NC(C)COc1c(C)cccc1C
Solvent: CCOCC
Solvent: CCO
Solvent: C1CCOC1
Product: CCNC(C)COc1c(C)cccc1C

Procedure:
Step 2 involves the reduction of the N-[2-(2,6-dimethylphenoxy)-1-methylethyl]-acetamide to the amine. The product from step 1 is heated to reflux temperature in the presence of an aprotic solvent such as tetrahydrofuran, and an effective reducing agent such as borane-dimethylsulfide complex. The reaction temperature is maintained at reflux for about 5-40 hours, preferably about 24 hours, and is preferably performed under an inert atmosphere, e.g., nitrogen. When the reaction is substantially complete, the product is isolated and purified by conventional techniques, for example converting to an acid salt, preferably the hydrochloride salt, then crystallizing from an organic solvent, for example ethanol/ether, yielding racemic [2-(2,6-dimethylphenoxy)-1-methylethyl]-ethylamine salt, preferably the hydrochloride salt.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[N:16]=[C:15]([O:17]C)[C:14]([CH2:19][N:20]([CH3:31])[C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24][CH2:23][CH2:22]2)=[C:13]([CH3:32])[N:12]=1)[CH3:2].CCO.Cl.[OH-].[Na+]>CCOC(C)=O>[CH2:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[C:11]1[N:16]=[C:15]([OH:17])[C:14]([CH2:19][N:20]([CH3:31])[C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24][CH2:23][CH2:22]2)=[C:13]([CH3:32])[N:12]=1)[CH3:10]
Reactant: CCc1cccc(CC)c1-c1nc(C)c(CN(C)[C@H]2CCCc3ccccc32)c(OC)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCc1cccc(CC)c1-c1nc(C)c(CN(C)[C@H]2CCCc3ccccc32)c(O)n1
Temperature: 90 °C

Procedure:
To a flask containing (1S)—N-{[2-(2,6-diethylphenyl)-4-methoxy-6-methylpyrimidin-5-yl]methyl}-N-methyl-1,2,3,4-tetrahydronaphthalen-1-amine (3.5 g, 8.15 mmol) is added EtOH (50 mL) and HCl (12 N, 50 mL) and the solution is heated at 90° C. for 16 h. The solution is cooled to 0° C. and basified using 5N NaOH slowly, followed by addition of EtOAc (100 mL). The organic layer is washed with sat. NaHCO3 (100 mL), brine (100 mL) and dried over Na2SO4. Concentration and vacuum drying affords the title compound as a white gummy foam. [mass expected (415.57); mass found (415.33)]
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].I[CH2:34][CH2:35][CH:36](Br)[CH2:37][CH3:38].C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH:36]([CH2:37][CH3:38])[CH2:35][CH3:34])[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCNC2)c1
Reactant: CCC(Br)CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(C(CC)CC)C2)c1
Temperature: 78 °C
Yield: 75 %

Procedure:
To a solution of compound 33b, 4-Methyl-2-(5-piperidin-3-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (42 mg, 0.093 mmol) in CH3CN (0.5 ml) was added 1-iodo-3-Bromopentane (21.0 mg, 0. 14 mmol) and cesium carbonate (61.0 mg, 0.186 mmol). The reaction was heated to 78° C. overnight. The subsequent addition of the reactants as described above and allowing the reaction to continue over a second night, resulted in ˜75% product: starting material. The reaction was cooled to room temperature, concentrated in vacuo, diluted with EtOAc, washed with NaHCO3, and brine. The solution was filtered, and concentrated, then purified via silica gel chromatography to give the product as a clear oil. (32.7 mg, 68% ) Calculated for C31H42F3NO2 (M+H) 517.67, Found 518.4.
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]([N+:12]([O-:14])=[O:13])=[C:5]2Cl.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]([O:31][CH3:32])=[O:30])[CH2:25][CH2:24]2)=[C:19]([C:33]([F:36])([F:35])[F:34])[CH:18]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2[NH:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]([O:31][CH3:32])=[O:30])[CH2:25][CH2:24]2)=[C:19]([C:33]([F:36])([F:34])[F:35])[CH:18]=1
Reactant: COC(=O)C1CCN(c2ccc(N)cc2C(F)(F)F)CC1
Reactant: O=[N+]([O-])c1cnc2ccc(Br)cc2c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)C1CCN(c2ccc(Nc3c([N+](=O)[O-])cnc4ccc(Br)cc34)cc2C(F)(F)F)CC1
Temperature: 25 °C
Yield: 90.4 %

Procedure:
To a solution of compound 8.0 6-bromo-4-chloro-3-nitroquinoline (0.29 g, 1.0 mmol, 1 equiv.) in dioxane (5 mL) at room temperature was added 8.1 methyl 1-(4-amino-2-(trifluoromethyl)phenyl)piperidine-4-carboxylate (0.3 g, 1.0 mmol, 1 equiv.). The resulting mixture was heated overnight to 85° C. under argon. Upon cooling to room temperature, the mixture was neutralized with aqueous NaHCO3, diluted with EtOAc (50 mL), and washed with water (50 mL) and brine (50 mL). The organic phase was dried over Na2SO4. After removal of solvent under vacuum, the resulting residue was purified via flash chromatography (Hexanes:EtOAc=4:1) to afford desired product 8.2 methyl 1-(4-(6-bromo-3-nitroquinolin-4-ylamino)-2-(trifluoromethyl)phenyl)piperidine-4-carboxylate (0.50 g; 90%). LC-MS (M+H): 555.10
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18](O)=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH2:30][NH:29][CH2:28][CH2:27]2>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([N:29]3[CH2:28][CH2:27][C:26]4[C:31](=[CH:32][CH:33]=[C:24]([O:23][CH3:22])[CH:25]=4)[CH2:30]3)=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)CCNC2
Reactant: O=C(O)c1nc(-c2ccc(F)cc2)nc2ccccc12
Agent: Cl
Product: COc1ccc2c(c1)CCN(C(=O)c1nc(-c3ccc(F)cc3)nc3ccccc13)C2
Yield: 23.5 %

Procedure:
Reaction of 2-(4-fluorophenyl)quinazoline-4-carboxylic acid with 6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 7 (23.5% yield): 1H NMR (400 MHz, CDCl3) δ 2.87 and 3.11 (2t, 2H), 3.58 and 4.19 (2t, 2H), 3.81 and 3.84 (2s, 3H), 4.47 and 5.08 (2s, 2H), 6.68-6.90 (m, 2H), 7.20-7.25 (m, 3H), 7.57-7.66 (m, 1H), 7.93-8.06 (m, 2H), 8.19-8.21 (d, 8.65-8.71 (m, 2H); 19F (282 MHz, CDCl3) δ −109.5; MS (ESI) m/z 414 ([M+H]+).