Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[CH:11]=[CH:10][C:9]=2[C:17]([NH2:19])=[O:18])[CH2:3][CH2:2]1.[CH:20](=O)[CH3:21].C([BH3-])#N.[Na+].C(O)(=O)C>CO.O>[CH2:20]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[CH:11]=[CH:10][C:9]=2[C:17]([NH2:19])=[O:18])[CH2:3][CH2:2]1)[CH3:21]
Reactant: NC(=O)c1ccc(C(N)=O)c(NC2CCNCC2)c1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CCN1CCC(Nc2cc(C(N)=O)ccc2C(N)=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.7 %

Procedure:
To a solution of N4-[8-(5-acetylpyridin-2-yl)-8-azabicyclo[3.2.1]oct-3-endo-yl]-2-(piperidin-4-ylamino)benzene-1,4-dicarboxamide (130 mg, 0.28 mmol) in methanol were added acetaldehyde (12 mg, 0.28 mmol), sodium cyanoborohydride (18 mg, 0.28 mmol) and acetic acid (17 mg, 0.28 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. Then the reaction mixture was poured into water (250 mL), extracted with ethyl acetate (2×50 mL), dried over sodium sulfate, filtered and concentrated to a volume of 10 mL. The precipitate thus formed was collected by filtration to give N4-[8-(5-acetylpyridin-2-yl)-8-azabicyclo[3.2.1]oct-3-endo-yl]-2-[(1-ethylpiperidin-4-yl)amino]benzene-1,4-dicarboxamide (16 mg, 12% yield). 1H NMR (400 MHz, methanol-d4): 8.70 (s, 1H), 8.06 (d, J=9.2 Hz, 1H), 7.69 (d, J=8.2 Hz, 1H), 7.14 (s, 1H), 6.98 (d, J=8.2 Hz, 1H), 6.77 (d, J=9.2 Hz, 1H), 4.70 (br, s, 2H), 4.02 (m, 1H), 3.82-3.45 (m, 2H), 3.20-3.05 (m, 6H), 3.00 (s, 6H), 2.53 (s, 3H), 2.40-2.1 (m, 10H), 2.05 (m, 2H), 1.34 (t, J=7.2 Hz, 3H). MS (EI) for C29H38N6O3: 519 (MH+).
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])OC1=O.[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:17][NH2:18]>C1C=CC=CC=1>[NH2:1][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]([NH:18][CH2:17][C:16]1[CH:19]=[CH:20][C:21]([Cl:22])=[C:14]([Cl:13])[CH:15]=1)=[O:11]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: NCc1ccc(Cl)c(Cl)c1
Solvent: c1ccccc1
Product: Nc1ccccc1C(=O)NCc1ccc(Cl)c(Cl)c1

Procedure:
A mixture of 2H-3,1-benzoxazine-2,4(1H)-dione (20 g) and 3,4-dichlorobenzylamine (16.4 ml) in benzene (200 ml) was refluxed for 3 hours. After cooling, the solvent was removed under reduced pressure to give a residue, which was recrystallized from n-hexane-ethyl acetate (1:2) to afford 2-amino-N-(3,4-dichlorobenzyl)benzamide (30.5 g).
Reaction SMILES: C(=O)([O-])O[CH2:3][CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:14][C:15]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:16]=1[NH2:17]>>[C:4]([CH:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[NH:17][C:16]1[C:18]([CH3:23])=[CH:19][C:20]([CH3:22])=[CH:21][C:15]=1[CH3:14])#[CH:3]
Reactant: O=C([O-])OCC=Cc1ccccc1
Reactant: Cc1cc(C)c(N)c(C)c1
Product: C#CC(Nc1c(C)cc(C)cc1C)c1ccccc1
Reaction time: 12 h
Yield: 84.8 %

Procedure:
The general procedure was followed with cinnamyl carbonate (0.188 g, 0.979 mmol) and 2,4,6-trimethylaniline (0.170 g, 1.25 mmol). The reaction was conducted at room temperature for 12 h. 1H NMR analysis of the crude reaction mixture indicated the ratio of regioisomers to be 97/3. The mixture was purified by flash column chromatography on silica gel (1% ethyl acetate in hexanes) to give the title compound (0.207 g, 85%). HPLC analysis indicated the enantiomeric excess of the product was 96% [Diacel CHIRALCEL OD-H (0.46 cm×25 cm); hexane/2-propanol=99.75/0.25; flow rate=0.6 mL/min; detection wavelength=254 nm; TR=17.0 (major), 19.5 (minor) min]: [α]DRT=(c, CHCl3). 1H NMR (400.13 MHz, CDCl3) δ 7.38-7.23 (m, 5H), 6.78 (s, 2H), 6.05 (ddd, J=17.2, 10.0, 6.4 Hz, 1H), 5.25 (dt, J=16.8, 1.6 Hz, 1H), 5.17 (dt, J=10.4, 1.3 Hz, 1H), 4.61 (t, J=6.4 Hz, 1H), 3.12 (br s, 1H), 2.22 (s, 3H), 2.11 (s, 6H). 13C NMR (100.59 MHz, CDCl3) δ 142.92, 141.89, 139.34, 130.89, 129.77, 129.34, 128.41, 127.10, 126.93, 115.51, 64.19, 20.56, 18.61. Anal. Calcd for C18H21N: C, 86.01; H, 8.42; N, 5.57. Found: C, 86.18; H, 8.49; N, 5.62.
Reaction SMILES: C1(P(C2CCCCC2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2C=CC=CC=2N(C)C)CCCCC1.B(O)(O)C1C=CC(C)=CC=1.[F-].[K+].Cl[C:42]1[CH:51]=[C:50]2[C:45]([NH:46][CH2:47][CH:48]3[CH2:55][N:54](C(OCC4C=CC=CC=4)=O)[CH2:53][CH2:52][N:49]32)=[CH:44][CH:43]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH3:14][C:9]1[CH:10]=[CH:11][C:12]([C:42]2[CH:51]=[C:50]3[C:45]([NH:46][CH2:47][CH:48]4[CH2:55][NH:54][CH2:53][CH2:52][N:49]43)=[CH:44][CH:43]=2)=[CH:13][CH:8]=1
Reactant: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: O=C(OCc1ccccc1)N1CCN2c3cc(Cl)ccc3NCC2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccc(B(O)O)cc1
Solvent: C1COCCO1
Product: Cc1ccc(-c2ccc3c(c2)N2CCNCC2CN3)cc1
Temperature: 100 °C
Yield: 786.3 %

Procedure:
To a two-necked round bottom flask charged with argon was added palladium (II) acetate (4 mg, 0.0195 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (10 mg, 0.02925 mmol), p-tolylboronic acid (80 mg, 0.59 mmol), potassium fluoride (68 mg, 1.17 mmol), and 9-Chloro-3-carbobenzyloxy-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxaline (140 mg, 0.39 mmol). 1 ml of degassed 1,4-dioxane was added and the reaction was degassed and heated to 100° C. for 20 h. The reaction mixture was cooled to rt and diluted with ether. 1N NaOH was added and the aqueous layer was extracted with ethyl acetate. The combined organics were washed with brine, dried over MgSO4, and concentrated to a yellow residue. The crude material was purified by radial PLC (1 mm plate, load with methylene chloride, elute with 20-40% ethyl acetate/hexanes) to give 9-(4-methylphenyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxaline as a yellow foam (0.23 mmol, 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH:14][CH3:15].C(N(C(C)C)C(C)C)C.[F:25][C:26]([F:44])([F:43])[C:27]1[CH:28]=[C:29]([C:37]([CH3:42])([CH3:41])[C:38](Cl)=[O:39])[CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1.C(=O)(O)[O-].[Na+]>ClCCl>[F:34][C:33]([F:35])([F:36])[C:31]1[CH:30]=[C:29]([C:37]([CH3:41])([CH3:42])[C:38]([N:14]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][C:8]=2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH3:15])=[O:39])[CH:28]=[C:27]([C:26]([F:43])([F:25])[F:44])[CH:32]=1
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNc1cnccc1-c1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1Cl
Temperature: 37.5 °C
Yield: 88.4 %

Procedure:
A solution of 12.2 g (55.8 mmol) [4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amine and 15.3 ml (89 mmol) N-ethyldiisopropylamine in 130 ml dichloromethane was cooled in an ice bath and a solution of 19 g (59.6 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride in 30 ml dichloromethane was added dropwise. The reaction mixture was warmed to 35-40° C. for 20 h, cooled to room temperature again and was stirred with 250 ml saturated sodium bicarbonate solution. The organic layer was separated and the aqueous phase was extracted with dichloromethane. The combined organic layers were dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography to give 24.7 g (88%) of the title compound as white crystals.
Reaction SMILES: [CH2:1]([NH:9][C:10]([C@@H:12]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][N:13]1C(OC(C)(C)C)=O)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([NH:9][C:10]([C@@H:12]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13]1)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCNC(=O)[C@@H]1CCCCCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCNC(=O)[C@@H]1CCCCCN1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
(S)-(−)-1-(tert-Butoxycarbonyl)-2-azepanecarboxylic acid n-octyl amide (2) (1.00 g; 2.82 mmol) is dissolved in methylene chloride (40 mL) at ambient temperature. Trifluoroacetic acid (20 mL) is added and the solution is stirred for 7 hours at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is dissolved in methylene chloride (200 mL) and poured onto saturated sodium bicarbonate solution. The pH is adjusted to 9 with saturated potassium carbonate solution. The mixture is shaken and the layers separated. The water layer is extracted with methylene chloride (3 times, 50 mL each). The combined organic extracts are washed with water, dried over MgSO4, filtered, and concentrated in vacuo affording the desired product (3).
Reaction SMILES: [C:1]([C:3]1([C:8](OC)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2].[BH4-].[Li+]>C1COCC1>[OH:9][CH2:8][C:3]1([C:1]#[N:2])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC(=O)C1(C#N)CCCC1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC1(CO)CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 103.1 %

Procedure:
A mixture of methyl 1-cyanocyclopentanecarboxylate (prepared in Example 740, Step 1) (500 mg, 3.0 mmol) in THF (7 mL) was treated with lithium tetrahydroborate (100 mg, 6.0 mmol). The resulting solution was heated to reflux for 3 hours, then stirred at ambient temperature for 16 hours. The mixture was quenched by the addition of water, and was extracted with ethyl acetate. The combined organic extracts were dried over Na2SO4, then filtered and the solvent was removed in vacuo to afford the product (387 mg, 95%). 1H NMR (300 MHz, CDCl3): δ3.62 (s, 2H), 2.39-1.60 (m, 8H).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:12])=[CH:4][C:5]([F:11])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.O[CH2:14][NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18].S(=O)(=O)(O)O>>[Br:1][C:2]1[C:3]([Cl:12])=[C:4]([CH2:14][NH:15][C:16]([C:17]([F:20])([F:19])[F:18])=[O:21])[C:5]([F:11])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)c(Cl)cc1F
Reactant: O=C(NCO)C(F)(F)F
Agent: O=S(=O)(O)O
Product: O=C(NCc1c(F)c([N+](=O)[O-])cc(Br)c1Cl)C(F)(F)F
Temperature: 80 °C
Reaction time: 10 h

Procedure:
A mixture of the compound (204 mg) obtained in Example 519a, N-hydroxymethyl-2,2,2-trifluoroacetamide (115 mg) and 10% fuming sulfuric acid (1.6 ml) was stirred at 80° C. for 10 h. The reaction mixture was cooled, put into ice water and subjected to extraction with ether. The organic layer was washed with water and a saturated aqueous sodium chloride solution sequentially, then dried with anhydrous sodium sulfate and concentrated under reduced pressure.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:19]=3)[N:14]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH:13]=2)=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.Cl>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:19]=3)[N:14]([S:27]([C:30]3[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=3)(=[O:29])=[O:28])[CH:13]=2)=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C(=O)c3cccc([N+](=O)[O-])c3)c3cc(-c4cccnc4)cnc32)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2cc(C(=O)c3cccc(N)c3)c3cc(-c4cccnc4)cnc32)cc1
Reaction time: 8 h

Procedure:
To (3-nitro-phenyl)-[5-pyridin-3-yl-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (537, 180 mg, 0.361 mmol) in methanol (4 mL) was added 10% palladium on carbon (20 mg) and few drops of concentrated aqueous hydrochloric acid. The resulting mixture was stirred under an atmosphere of hydrogen overnight and the catalyst was filtered out through a bed of celite. The filtrate was concentrated and purified by silica gel column chromatography eluting with 90% ethyl acetate in hexane to give the compound (538, 58 mg, 34%). MS (ESI) [M+H+]+=469.3.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Si:9]([O:16][CH2:17][C@@H:18]([N:20]1[C:24]2[N:25]=[CH:26][N:27]=[CH:28][C:23]=2[CH:22]=[CH:21]1)[CH3:19])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[Si:9]([O:16][CH2:17][C@@H:18]([N:20]1[C:24]2[N:25]=[CH:26][N:27]=[CH:28][C:23]=2[C:22]([I:1])=[CH:21]1)[CH3:19])([C:12]([CH3:13])([CH3:14])[CH3:15])([CH3:10])[CH3:11]
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)n1ccc2cncnc21
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)n1cc(I)c2cncnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 66 %

Procedure:
N-Iodosuccinimide (124 g, 553 mmol) was added to 7-[(1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl]-7H-pyrrolo[2,3-d]pyrimidine (153.4 g, 526 mmol) (see Preparation 8) in acetonitrile (700 mL). The mixture was stirred at room temperature for 16 hours then saturated aqueous sodium thiosulfate (700 mL) was added. The mixture was extracted with EtOAc (800 mL) then the organic extract was dried over magnesium sulfate and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (gradient of pentane:EtOAc 90:10 to 80:20) to afford the title compound as a yellow solid in 66% yield, 145 g. 1H NMR (400 MHz, CDCl3) δ: −0.90 (d, 6H) 0.80 (s, 9H) 1.58 (d, 3H) 3.84 (m, 2H) 5.07 (m, 1H) 7.48 (s, 1H) 8.73 (s, 1H) 8.86 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[C:6]([CH:8]1[CH2:12][CH2:11][NH:10][CH2:9]1)=[O:7].[O:18]([CH2:25][CH2:26][CH2:27]Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:18]([CH2:25][CH2:26][CH2:27][N:10]1[CH2:11][CH2:12][CH:8]([C:6](=[O:7])[C:5]2[CH:13]=[CH:14][CH:15]=[C:3]([C:2]([F:1])([F:16])[F:17])[CH:4]=2)[CH2:9]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCCCOc1ccccc1
Reactant: O=C(c1cccc(C(F)(F)F)c1)C1CCNC1
Product: O=C(c1cccc(C(F)(F)F)c1)C1CCN(CCCOc2ccccc2)C1

Procedure:
Following the procedure of Preparation 9, the title compound is prepared from 3-(3-trifluoromethylbenzoyl)pyrroldine (U.S. Pat. No. 3,489,769) and 3-phenoxypropyl bromide.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:26]([O:60][CH3:61])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:58][CH3:59])[C@@H:36]([CH3:57])[C:37]([NH:39][C@@:40]1([C:49]([N:51]2[CH2:56][CH2:55][CH2:54][CH2:53][O:52]2)=[O:50])[CH2:42][C@@H:41]1[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH:11]([CH3:13])[CH3:12].[CH:66]([C:68]1[CH:76]=[CH:75][C:71]([C:72]([OH:74])=[O:73])=[CH:70][CH:69]=1)=O>>[C:72]([C:71]1[CH:75]=[CH:76][C:68]([CH2:66][N:9]([CH3:8])[C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:26]([O:60][CH3:61])[CH2:27][C:28]([N:30]2[CH2:34][CH2:33][CH2:32][C@H:31]2[C@H:35]([O:58][CH3:59])[C@@H:36]([CH3:57])[C:37]([NH:39][C@@:40]2([C:49]([N:51]3[CH2:56][CH2:55][CH2:54][CH2:53][O:52]3)=[O:50])[CH2:42][C@@H:41]2[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:19])[CH3:20])=[O:15])[CH:11]([CH3:12])[CH3:13])=[CH:69][CH:70]=1)([OH:74])=[O:73]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@]1(C(=O)N2CCCCO2)C[C@@H]1c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@]1(C(=O)N2CCCCO2)C[C@@H]1c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)Cc1ccc(C(=O)O)cc1)C(C)C

Procedure:
The title compound was prepared in analogy to the synthesis of Intermediate 61, by reaction of 15 mg of N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-{[(1S,2R)-1-(1,2-oxazinan-2-ylcarbonyl)-2-phenylcyclopropyl]amino}-3-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide trifluoroacetate (Intermediate 16) with 4-formylbenzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([NH:16][NH:17][CH:18]=O)=O)=[C:12]([C:20]2[CH:21]=[N:22][N:23]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=3)[C:24]=2[C:25]([F:28])([F:27])[F:26])[O:11][N:10]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:45])=CC=1>O1CCOCC1.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]2[S:45][CH:18]=[N:17][N:16]=2)=[C:12]([C:20]2[CH:21]=[N:22][N:23]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=3)[C:24]=2[C:25]([F:28])([F:27])[F:26])[O:11][N:10]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=CNNC(=O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2cccc(Cl)c2)c1C(F)(F)F
Solvent: C1COCCO1
Solvent: ClCCl
Product: Fc1cccc(Cl)c1-c1noc(-c2cnn(-c3cccc(Cl)c3)c2C(F)(F)F)c1-c1nncs1
Yield: 31 %

Procedure:
3-(2-chloro-6-fluorophenyl)-5-(1-(3-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carbohydrazide (85 mg, 0.2 mmol) was treated with formic acid (6.4 μL, 0.2 mmol). The mixture was stirred at r.t. for 72 h. To the reaction mixture was added water, the resulting precipitate was collected, washed with water and dried in vacuum to give 61 mg of the intermediate as a colorless solid. To a solution of the intermediate 3-(2-chloro-6-fluorophenyl)-5-(1-(3-chlorophenyl)-5-(tri fluoromethyl)-1H-pyrazol-4-yl)-N′-formyl isoxazole-4-carbohydrazide (20 mg, 0.038 mmol) in dioxane (2 mL) was added Lawesson's Reagent (0.033 mL, 0.1 mmol). The mixture was stirred at reflux for 3 h. The mixture was diluted with dichloromethane and washed with water (3×), dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by pTLC (EE/PE 1:1) to give 6 mg of example IB-8 as a colorless solid (yield 31%). Result of LC/MS MH+: 525.72; 1H NMR (MeOD): δ 7.35 (t, 1H), 7.49 (d, 1H), 7.59-7.71 (m, 5H), 8.37 (s, 1H), 9.38 (s, 1H)
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[F:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][CH:26]=[C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[C:24]=2[CH:34]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[F:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][CH:15]([N:31]3[CH2:32][CH2:33][N:28]([C:25]4[C:24]5[CH:34]=[C:20]([F:19])[CH:21]=[CH:22][C:23]=5[O:27][CH:26]=4)[CH2:29][CH2:30]3)[CH2:14][CH2:13]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=C1CCN(c2ccc(F)c3cccnc23)CC1
Reactant: Fc1ccc2occ(N3CCNCC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Fc1ccc2occ(N3CCN(C4CCN(c5ccc(F)c6cccnc56)CC4)CC3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.2 %

Procedure:
To a solution of 0.200 g of 1-(5-fluoro-quinolin-8-yl)-piperidin-4-one (Example C, Step 3, 0.20 g) and 5-fluoro-3-piperazino benzofuran (Step 2, 0.20 g) in CH2Cl2 (10 mL) was added sodium triacetoxyborohydride (0.224 g) and 0.02 mL acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH, and the product was extracted with CH2Cl2. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ML of silica gel using 50% Ethyl acetate/Hexanes then 100% Ethyl acetate to give 0.100 g of the desired product. Mp: 187-189° C.; MS (ES) m/z (relative intensity): 449 (M++−H, 100).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH2:25][CH:26]([CH3:28])[CH3:27])=[N:5][C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])=[CH:10][C:9]([O:20][CH2:21][C:22]([NH2:24])=[O:23])=[CH:8][CH:7]=2)#[N:2].N.O1CCCC1.[ClH:35]>C(OCC)(=O)C.[Ni].CO>[ClH:35].[ClH:35].[NH2:2][CH2:1][C:3]1[C:4]([CH2:25][CH:26]([CH3:28])[CH3:27])=[N:5][C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])=[CH:10][C:9]([O:20][CH2:21][C:22]([NH2:24])=[O:23])=[CH:8][CH:7]=2
Reactant: CC(C)Cc1nc2ccc(OCC(N)=O)cc2c(-c2ccccc2F)c1C#N
Agent: [Ni]
Agent: Cl
Agent: N
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)Cc1nc2ccc(OCC(N)=O)cc2c(-c2ccccc2F)c1CN
Temperature: 25 °C
Reaction time: 6 h
Yield: 59 %

Procedure:
To a mixture of 2-{[3-cyano-4-(2-fluorophenyl)-2-isobutylquinolin-6-yl]oxy}acetamide (0.11 g, 0.29 mmol), 25% aqueous ammonia (2 ml), tetrahydrofuran (2 ml) and methanol (10 ml) was added Raney-nickel (1 ml), and the mixture was stirred under a hydrogen (0.5 MPa) atmosphere at room temperature for 6 hrs. The reaction mixture was filtered, and the filtrate was partitioned between ethyl acetate (50 ml) and 10% aqueous potassium carbonate solution (25 ml). The organic layer was washed with saturated brine (10 ml) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give a colorless oil. This was dissolved in ethyl acetate (2 ml) and 4N solution of hydrogen chloride in ethyl acetate (1 ml) was added. The reaction mixture was concentrated and the obtained crude crystals were recrystallized from diisopropyl ether-methanol to give the title compound (0.078 g, yield 59%) as pale-yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][CH:7]([C:9]([OH:11])=[O:10])[NH2:8])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:18]O>>[CH3:18][O:10][C:9](=[O:11])[CH:7]([NH2:8])[CH2:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=1
Reactant: NC(Cc1ccc(Cl)cc1)C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C(N)Cc1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
4-Chloro-DL-phenylalanine (1.00 g, 5.00 mmol) was dissolved in methanol (30 mL) and cooled to 0° C. Thionyl chloride (2.92 mL, 40.0 mmol) was added dropwise. The mixture was allowed to warm to room temperature and was heated at reflux for 4 h. The solvent and reagents were removed in vacuo to yield the hydrochloride salt 1-1 as a white powder in quantitative yield (1.25 g, 5.00 mmol). 1H NMR (300 MHz, CD3OD): δ=7.37 (d, 2H, J=6.6 Hz), 7.27 (d, 2H, J=6.6 Hz), 4.34 (t, 1H, J=6.9 Hz), 3.81 (s, 3H), 3.26 (dd, 1H, J=14.4, 6.4 Hz), 3.18 (dd, 1H, J=14.4, 7.3 Hz); 13C NMR (75 mHz, CD3OD): δ=170.28, 134.87, 134.18, 132.11, 130.19, 54.99, 53.85, 38.81; ESI-MS calcd for C10H13ClNO2 [M+H]+: 214.0635. found 214.0638.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([NH:13][C:14](=[O:22])[C:15]3[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=3)[S:12][C:8]=2[C:7]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:36](OC(=O)C)(=[O:38])[CH3:37].C(=O)(O)[O-].[Na+]>C1COCC1.O>[C:36]([N:26]1[CH2:27][CH2:28][CH:23]([C:7]2[C:8]3[S:12][C:11]([NH:13][C:14](=[O:22])[C:15]4[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=4)=[N:10][C:9]=3[C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)[CH2:24][CH2:25]1)(=[O:38])[CH3:37]
Reactant: COc1ccc(C2CCNCC2)c2sc(NC(=O)c3ccnc(C)c3)nc12
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(C2CCN(C(C)=O)CC2)c2sc(NC(=O)c3ccnc(C)c3)nc12
Reaction time: 1 h
Yield: 74.2 %

Procedure:
To a solution of 0.75 g (0.165 mMol) N-(4-methoxy-7-piperidin-4-yl-benzothiazol-2-yl)-2-methyl-isonicotinamide hydrochloride (1:2) in 4 ml THF were added 0.05 ml triethyl amine. At 0° C. 0.019 ml (0.2 mMol) acetic anhydride was added dropwise and stirred for 1 h. Then a mixture of 5 ml sat. aqueous sodium bicarbonate and 10 ml water were added. A precipitation formed, which was filtered. The residue on the filter was triturated in water. Upon isolation and drying in vacuo one obtained 0.052 g (74%) N-[7-(1-acetyl-piperidin-4-yl)-4-methoxy-benzothiazol-2-yl]-2-methyl-isonicotinamide as a white solid. F.p.: 213-215° C.
Reaction SMILES: P(Br)(Br)[Br:2].[Cl:5][C:6]1[C:17]2[CH:16]=[C:15]3[C:11]([O:12][CH2:13][O:14]3)=[CH:10][C:9]=2[S:8][C:7]=1[CH2:18]O>CCOCC>[Br:2][CH2:18][C:7]1[S:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][C:17]=2[C:6]=1[Cl:5])[O:14][CH2:13][O:12]3
Reactant: BrP(Br)Br
Reactant: OCc1sc2cc3c(cc2c1Cl)OCO3
Solvent: CCOCC
Product: Clc1c(CBr)sc2cc3c(cc12)OCO3
Temperature: 25 °C
Yield: 95 %

Procedure:
Add a solution of phosphorous tribromide (1.5 equivalents) in ether (10 mL/g) to a solution of (7-chloro-1,3-dioxa-5-thia-s-indacen-6-yl)-methanol (1.64 g, 6.8 mmol) in ether (20 mL/g) at 0° C. Stir to room temp for an hour. Pour onto ice water, wash with water, saturated sodium bicarbonate, brine, dry, and concentrate to afford the title compound as a white powder (1.96 g, 95%): 1H NMR (CDCl3) δ 7.17 (s, 1H), 7.13 (s, 1H), 6.05 (s, 2H), 4.72 (d, 2H).