Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH:13]2[CH2:15][CH2:14]2)[C:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]#[N:12].[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:11]([C:10]1[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]([CH:13]2[CH2:15][CH2:14]2)[C:2]=1[NH:1][C:16](=[O:18])[CH3:17])#[N:12]
Reactant: N#Cc1c2c(n(C3CC3)c1N)CCCC2
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1c(C#N)c2c(n1C1CC1)CCCC2
Yield: 71.5 %

Procedure:
A solution of 2-amino-1-cyclopropyl-4,5,6,7-tetrahydro-1H-indole-3-carbonitrile (3 g, 14.91 mmol) in acetic anhydride (24 ml, 254 mmol) was stirred at rt for 2.5 hours. The precipitate was filtered, washed with Ac2O, and dried to give N-(3-cyano-1-cyclopropyl-4,5,6,7-tetrahydro-1H-indol-2-yl)acetamide (2.5948 g, 10.66 mmol, 71.5% yield) as white solid. The filtrate was concentrated, suspended with Et2O, stirred, and filtered to give additional product (690 mg, 2.84 mmol, 19.03% yield) as light brown solid: 1H NMR (400 MHz, CHLOROFORM-d) δ=7.22 (br. s., 2 H), 2.98-2.86 (m, 1 H), 2.56 (t, J=5.9 Hz, 2 H), 2.49 (t, J=5.9 Hz, 2 H), 2.22 (s, 3 H), 1.88-1.65 (m, 4 H), 1.01-0.89 (m, 2 H), 0.88-0.76 (m, 2 H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[C:14]([C:20]#[N:21])[C:13]2=[O:22])[C:7]([CH3:11])=[CH:8][C:9]=1[CH3:10])([O-])=O>CN(C)C=O.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([N:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[C:14]([C:20]#[N:21])[C:13]2=[O:22])[C:7]([CH3:11])=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1cc(C)c([N+](=O)[O-])cc1-n1c(C)cc(C)c(C#N)c1=O
Agent: [Pd]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(-n2c(C)cc(C)c(C#N)c2=O)cc1N

Procedure:
48.3 g (0.165 mol) 1-(3'-nitro-4',6'-dimethylphenyl)-3-cyano-4,6-dimethyl-2-pyridone are dissolved in 1 liter of dimethylformamide and, after adding of 5 g palladium/charcoal catalyst, hydrogenated at normal pressure and 15°-20° C. The catalyst is filtered off and the filtrate is concentrated by evaporation. The residue is treated with hexane and dried. Yield: 42.0 g (95.3%) 1-(3'-amino-4',6'-dimethylphenyl)-3-cyano-4,6-dimethyl-2-pyridone, mp. 218°-219° C.
Reaction SMILES: [NH2:1][OH:2].[F:3][C:4]1[C:5]([OH:15])=[C:6]([CH:11]=[CH:12][C:13]=1[F:14])[C:7](OC)=[O:8]>O1CCOCC1>[F:3][C:4]1[C:5]([OH:15])=[C:6]([CH:11]=[CH:12][C:13]=1[F:14])[C:7]([NH:1][OH:2])=[O:8]
Reactant: NO
Reactant: COC(=O)c1ccc(F)c(F)c1O
Solvent: C1COCCO1
Product: O=C(NO)c1ccc(F)c(F)c1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 101.4 %

Procedure:
A solution of hydroxylamine (50% in water) (50 ml, 816 mmol) was added to a solution of methyl 3,4-difluoro-2-hydroxybenzoate (7.75 g, 41.2 mmol) (Intermediate 526) in dioxane (200 ml) and the mixture was stirred at room temperature for 3 days. The mixture was partitioned between water and EtOAc. The aqueous layer was acidified with concentrated HCl and extracted with EtOAc twice more. The EtOAc layers were washed with brine, combined and concentrated to give 7.9 g of a solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([NH2:11])=[C:3]([NH2:12])[CH:2]=1.N1C2C(=NC=CC=2)C(N)=[C:15](N)[CH:14]=1.C(Cl)(=O)C>C(O)(=O)C>[CH3:14][C:15]1[NH:11][C:4]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[N:1]=[CH:2][C:3]=2[N:12]=1
Reactant: Nc1cnc2ccccc2c1N
Reactant: Nc1cnc2cccnc2c1N
Solvent: CC(=O)O
Solvent: CC(=O)Cl
Product: Cc1nc2cnc3ccccc3c2[nH]1

Procedure:
Compounds of the invention can also be prepared according to Reaction Scheme V, wherein Bn, E, R, R3-1, and n are as defined above; P is an amino protecting group; and Da is —(CH2)1-4—. In step (1) of Reaction Scheme V, a benzyloxy-4-chloro-3-nitroquinoline or benzyloxy-4-chloro-3-nitro[1,5]naphthyridine of Formula XLI is reacted with tert-butylamine in the presence of base, and the tert-butyl group is subsequently removed under acidic conditions to provide a 3-nitroquinolin-4-amine or 3-nitro[1,5]naphthyridin-4-amine of Formula XLII, which is reduced in step (2) to provide a quinoline-3,4-diamine or [1,5]naphthyridine-3,4-diamine of Formula XLIII. In step (3) of Reaction Scheme V, a. quinoline-3,4-diamine or [1,5]naphthyridine-3,4-diamine of Formula XLIII is reacted with acetic acid or acetyl chloride to provide a 2-methyl-1H-imidazo[4,5-c]quinoline or a 2-methyl-1H-imidazo[4,5-c][1,5]naphthyridine of Formula XLIV, which undergoes protection at the 1-position in step (4) with a suitable protecting group. In step (5) of Reaction Scheme V, the 2-methyl group of a 1H-imidazo[4,5-c]quinoline or 1H-imidazo[4,5-c][1,5]naphthyridine of Formula XLV is deprotonated with n-butyllithium and subsequently reacted with an alkylating agent of formula Br—CH2-Da-CH2—Cl, and the product of Formula XLVI is then deprotected using conventional methods to provide a 1H-imidazo[4,5-c]quinoline or 1H-imidazo[4,5-c][1,5]naphthyridine of Formula XLVII. The compound of Formula XLVII is then cyclized to provide a compound of Formula XLVIII. Steps (1) through (7) of Reaction Scheme V can be carried out using the conditions described in U.S. Pat. No. 5,482,936 (Lindstrom).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15](CC3C=CC(OC)=CC=3OC)[C:16]3[S:20][N:19]=[CH:18][N:17]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([F:32])=[CH:4][N:3]=1.[CH3:33][O:34][C:35]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][C:36]=1B(O)O>>[F:32][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([S:12]([NH:15][C:16]3[S:20][N:19]=[CH:18][N:17]=3)(=[O:13])=[O:14])[CH:7]=2)[C:2]([C:36]2[CH:37]=[CH:38][C:39]([C:41]([F:44])([F:43])[F:42])=[CH:40][C:35]=2[O:34][CH3:33])=[N:3][CH:4]=1
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Cl)ncc(F)c3c2)c(OC)c1
Product: COc1cc(C(F)(F)F)ccc1-c1ncc(F)c2cc(S(=O)(=O)Nc3ncns3)ccc12

Procedure:
The title compound was prepared in an analogous manner to that of EXAMPLE 228, except that 1-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide and (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid were used as the coupling partners. The final compound was purified via column chromatography (RediSep Gold 12 g silica gel column, gradient elution 0-10% MeOH:DCM) to afford 4-fluoro-1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=8.76 (s, 1H), 8.49 (d, J=9.3 Hz, 2H), 8.00 (d, J=8.4 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.64-7.42 (m, 3H), 3.75 (s, 3H). m/z (ESI) 485.0 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@@:10]([NH:36][C:37](=[O:49])[C:38]2[CH:43]=[CH:42][C:41]([F:44])=[C:40]([C:45]([F:48])([F:47])[F:46])[CH:39]=2)([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=2)[C:11]2[CH:16]=[C:15]([O:17][C:18]([F:23])([F:22])[CH:19]([F:21])[F:20])[CH:14]=[C:13]([F:24])[CH:12]=2)=[CH:5][CH:4]=1)#[N:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C@@:10]([NH:36][C:37](=[O:49])[C:38]2[CH:43]=[CH:42][C:41]([F:44])=[C:40]([C:45]([F:48])([F:47])[F:46])[CH:39]=2)([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:33])([F:34])[F:35])[CH:26]=2)[C:11]2[CH:16]=[C:15]([O:17][C:18]([F:22])([F:23])[CH:19]([F:20])[F:21])[CH:14]=[C:13]([F:24])[CH:12]=2)=[CH:7][CH:8]=1
Reactant: N#Cc1ccc(C[C@](NC(=O)c2ccc(F)c(C(F)(F)F)c2)(c2cc(F)cc(OC(F)(F)C(F)F)c2)c2ccc(F)c(C(F)(F)F)c2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1ccc(C[C@](NC(=O)c2ccc(F)c(C(F)(F)F)c2)(c2cc(F)cc(OC(F)(F)C(F)F)c2)c2ccc(F)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 36 %

Procedure:
To a solution of (R)—N-(2-(4-cyanophenyl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)-4-fluoro-3-(trifluoromethyl)benzamide, prepared as described in Procedure 56, (77% yield, 20 mg, 0.02 mmol) in THF (1.5 mL) at rt was added LAH (1.0 M in THF). The reaction mixture was stirred at rt for 5 h, then quenched by addition of 2 N LiOH. The solid was removed by filtration and the filtrate was concentrated. The resulting residue was purified by prep HPLC(YMC Sunfire 5μ C18 30×100 mm column, eluting with 20-90% MeOH/H2O containing 0.1% TFA, 10 min gradient, flow rate 40 mL/min, wavelength 220 nm) to provide (R)—N-(2-(4-(aminomethyl)phenyl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)-4-fluoro-3-(trifluoromethyl)benzamide (Example 300) as a colorless film (5 mg, 36% yield). LCMS: RT=1.8 min [M+H] 713.26 (Phenomenex Luna C18 4.6×30 mm column, eluting with 10-90% MeOH/H2O containing 0.1% TFA, 2 min gradient, flow rate 5 mL/min, wavelength 220 nm); HPLC: RT=4.31 min (Phenomenex Luna C18 4.6×50 mm column, eluting with 10-90% MeOH/H2O containing 0.2% PPA, flow rate 4 mL/min, wavelength 220 nm). 1H NMR (400 MHz, CD3OD) δ ppm 7.95 (1H, d, J=6.59 Hz), 7.46-7.48 (1H, m), 7.36 7.41 (2H, m), 7.22 (1H, t, J=9.45 Hz), 7.16 (2H, d, J=7.91 Hz), 6.99 (2H, dd, J=16.48, 9.45 Hz), 6.93 (1H, s), 6.73 (2H, d, J=7.91 Hz), 6.21H, t, J=49.7 Hz), 4.01-4.06 (1H, m), 3.93-3.99 (3H, m).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:34]([O:36][C:37]([C:39]1[O:40][C:41]2[CH:47]=[CH:46][C:45]([OH:48])=[CH:44][C:42]=2[CH:43]=1)=[O:38])[CH3:35].[F:49][C:50]1([F:59])[CH2:55][CH2:54][N:53]([CH2:56][CH2:57]O)[CH2:52][CH2:51]1>C(Cl)Cl>[CH2:34]([O:36][C:37]([C:39]1[O:40][C:41]2[CH:47]=[CH:46][C:45]([O:48][CH2:57][CH2:56][N:53]3[CH2:54][CH2:55][C:50]([F:59])([F:49])[CH2:51][CH2:52]3)=[CH:44][C:42]=2[CH:43]=1)=[O:38])[CH3:35]
Reactant: OCCN1CCC(F)(F)CC1
Reactant: CCOC(=O)c1cc2cc(O)ccc2o1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(OCCN3CCC(F)(F)CC3)ccc2o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.7 %

Procedure:
To a solution of 4,4-difluoropiperidine hydrochloride (1 g, 6.3 mmol) in THF (20 mL) was added methylbromoacetate (0.63 mL, 6.6 mmol) and triethylamine (2.65 mL, 19.0 mmol). The reaction was heated at reflux for 4 h. The reaction was diluted with water (50 mL) and the product extracted with ethyl acetate (3×20 mL). The combined organic fractions were washed with brine, dried over magnesium sulphate and concentrated in vacuo to yield (4,4-difluoropiperidin-1-yl)acetic acid methyl ester as a brown oil (1.17 g, 96%). MS 194 (M+H)+. To a solution of (4,4-dfluompiperidin-1-yl)acetic acid methyl ester (1.17 g, 6.1 mmol) in THF (15 mL) at 0° C. was added potion wise lithium aluminium hydride (0.46 g, 12.2 mmol). Once the effervescence had ceased the reaction was heated at 60° C. for 1.5 h. The reaction was quenched with water (10 mL) followed by sodium hydroxide solution (2N, 10 mL) then water (10 mL). The reaction was filtered and the filtrate extracted with ethyl acetate (3×20 mL). The combined organic fractions were washed with brine, dried over magnesium sulphate and concentrated in vacuo to yield 2-(4,4-difluoropiperidin-1-yl)-ethanol as a brown oil (0.99 g, 99%). MS 166 (M+H)+. To a solution of diisopropylazodicarboxylate (0.36 mL, 1.82 mmol) in DCM (20 mL) was added polymer supported triphenylphosphine (728 mg, 2.18 mmol). The reaction was stirred at RT for 10 min. 5-Hydroxybenzofuran-2-carboxylic acid ethyl ester (025 g, 1.21 mmol) and 2-(4,4-difluoropiperidin-1-yl)-ethanol (210 mg, 1.27 mmol) were added and the reaction stirred at RT for 16 h. The reaction was filtered and the filtrate concentrated in vacuo. The product was purified on silica eluting with 50% tert-butyl methyl ether in n-heptane to yield 5-[2-(4,4-difluoropiperidin-1-yl)ethoxy]benzofuran-2-carboxylic acid ethyl ester as a yellow solid (375 mg, 88%). MS 354 (M+H)+. To a solution of 5-[2-(4,4-difluoropiperidin-1-yl)ethoxy]benzofuran-2-carboxylic acid ethyl ester (375 mg, 1.06 mmol) in THF (5 mL) and water (1 mL) was added lithium hydroxide (34 mg, 2.12 mmol). The reaction was stirred at RT for 16 h. The THF was removed in vacuo and the remaining aqueous solution dried overnight in a freeze dryer to yield the crude title compound as a brown solid. MS 326 (M+H. 5.3 min) and used for coupling onto H2N-Leu-P1 without any further purification.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10]C(C)C)=[CH:4][C:3]=1[C:14](=[O:17])[CH2:15][CH3:16]>C(OCC)(=O)C.CCCCCC>[OH:10][C:5]1[C:6]([O:8][CH3:9])=[CH:7][C:2]([I:1])=[C:3]([C:14](=[O:17])[CH2:15][CH3:16])[CH:4]=1
Reactant: CCC(=O)c1cc(OC(C)C)c(OC)cc1I
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCC(=O)c1cc(O)c(OC)cc1I

Procedure:
Concentration of fraction B (Rf 0.7 in 1:1 v/v ethyl acetate/hexane) afforded the starting ether 11 (98 mg, 21% recovery) as a pale-yellow oil that was identical, as judged by 1H NMR spectroscopic analysis, with authentic material.
Reaction SMILES: [NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:12]([OH:14])=O)[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.Cl.[CH3:48][O:49][C:50](=[O:54])[C@@H:51]([CH3:53])[NH2:52].CCN(CC)CC>CCOC(C)=O>[NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:12]([NH:52][C@@H:51]([C:50]([O:49][CH3:48])=[O:54])[CH3:53])=[O:14])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)[C@@H](C)N
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](C)NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a solution of Boc-Ser(OBn) (4.12 g, 13.95 mmol) in EtOAc (100 mL) at 0° C. was added HOBT (2.35 g, 15.35 mmol) and DCC (3.17 g, 15.35 mmol). D-Alanine methyl ester hydrochloride (1.95 g, 13.95 mmol) was added followed by Et3N (2.14 mL, 15.35 mmol). The mixture was allowed to warm to room temperature and stirred overnight. The mixture was filtered, and the filtrate was washed with saturated aqueous NaHCO3, brine, dried (MgSO4), and concentrated. Flash chromatography (40% EtOAc/hexane) gave 2.60 g of the title compound as a colorless oil; CI-MS 381 (m+1).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][CH2:6][C@H:7]([OH:18])[C:8]([NH:10][C:11]1[CH:16]=[N:15][C:14]([CH3:17])=[CH:13][N:12]=1)=[O:9])[CH3:4].Cl[C:20]1[N:25]=[CH:24][N:23]=[C:22]2[N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]([F:38])([F:37])[F:36])[N:27]=[CH:28][C:21]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH2:3]([O:5][CH2:6][C@H:7]([O:18][C:20]1[C:21]2[CH:28]=[N:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]([F:37])([F:38])[F:36])[C:22]=2[N:23]=[CH:24][N:25]=1)[C:8]([NH:10][C:11]1[CH:16]=[N:15][C:14]([CH3:17])=[CH:13][N:12]=1)=[O:9])[CH3:4]
Reactant: CCOC[C@H](O)C(=O)Nc1cnc(C)cn1
Reactant: FC(F)(F)c1ccccc1-n1ncc2c(Cl)ncnc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC[C@H](Oc1ncnc2c1cnn2-c1ccccc1C(F)(F)F)C(=O)Nc1cnc(C)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 90.3 %

Procedure:
60% Sodium hydride (60.0 mg, 1.50 mmol) was added in one portion to (S)-3-ethoxy-2-hydroxy-N-(5-methylpyrazin-2-yl)propanamide (Intermediate H1) (225 mg, 1.00 mmol) in anhydrous THF (5 mL) and the mixture was cooled to 0° C. under nitrogen. The resulting suspension was stirred at 0° C. for 10 minutes and then 4-chloro-1-(2-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate P1) (298.6 mg, 1.00 mmol) as suspension in dry THF (4 mL) added dropwise over 1 minute. The mixture was stirred at 0° C. for 15 mins, allowed to warm to ambient temperature and stirred for 2 hours. 1M Citric acid (2 mL) was added and the mixture extracted with ethyl acetate (2×20 mL). The organic extracts were washed with water (15 mL) and brine (15 mL), dried (MgSO4) and evaporated. The residue was purified by flash silica chromatography, eluting with 60 to 100% ethyl acetate in isohexane to give the product (440 mg, 88%).
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]2[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)([N:23]1[CH:27]=[CH:26]N=C1)=O.C(N(CC)CC)C.Cl.C(N)C>C(#N)C>[C:1]1([CH:7]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:8]2[CH2:9][CH:10]([C:12]([NH:23][CH2:27][CH3:26])=[O:14])[CH2:11]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCNC(=O)C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 60 °C
Yield: 114 %

Procedure:
To a solution of 7.5 g (28 mmole) of 1-(diphenylmethyl)azetidine-3-carboxylic acid in 75 ml of acetonitrile was added 6.0 g (37 mmole) of 1,1'-carbonyldiimidazole. The reaction was heated at 60° C. for two hours and successively treated with 3.1 g (30.8 mmole) of triethylamine and 2.52 g (30.8 mmole) of ethylamine hydrochloride. The reaction was stirred at 60° C. for an additional hour, the solvent evaporated in vacuo and the residue dissolved in chloroform. After washing with water and drying over magnesium sulfate, the chloroform layer was evaporated in vacuo to give 9.4 g of 1-(diphenylmethyl)-N-ethyl-3-azetidinecarboxamide, mp 91°-93° C.
Reaction SMILES: C(OC([N:6]1[C:11]2[CH:12]=[C:13]([C:16]([N:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]([N:28]([C:36](=[O:38])[CH3:37])[C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)[CH2:20][CH:19]3[CH3:39])=[O:17])[CH:14]=[CH:15][C:10]=2[O:9][CH2:8][CH2:7]1)=O)C>C(Cl)Cl.I[Si](C)(C)C>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([N:28]([C@H:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:18]([C:16]([C:13]3[CH:14]=[CH:15][C:10]4[O:9][CH2:8][CH2:7][NH:6][C:11]=4[CH:12]=3)=[O:17])[C@@H:19]([CH3:39])[CH2:20]2)[C:36](=[O:38])[CH3:37])=[CH:30][CH:31]=1
Reactant: CCOC(=O)N1CCOc2ccc(C(=O)N3c4ccccc4C(N(C(C)=O)c4ccc(Cl)cc4)CC3C)cc21
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc3c(c2)NCCO3)c2ccccc21
Reaction time: 96 h

Procedure:
6-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid ethyl ester was dissolved in methylene chloride (3 mL) and iodotrimethylsilane (1 mL). After 4 days, the reaction was quenched with sat. aq. NaHCO3. The residue was partitioned between methylene chloride and water, then extracted three times with methylene chloride, dried over MgSO4, filtered and concentrated. The crude residue was purified by silica gel chromatography (ethyl acetate) to afford the product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])=[O:18])[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.NN>[Ni]>[NH2:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:12][CH2:13][N:14]([C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])=[O:18])[CH2:15][CH2:16]2)[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: Nc1cc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)ccc1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Product: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)cc1N
Temperature: 25 °C
Reaction time: 5 h
Yield: 88 %

Procedure:
To a mixture of [4-(3-amino-4-nitrophenyl)piperazin-1-yl](2-trifluoromethylphenyl)methanone (2.000 g, 5.070 mmol) and Raney Ni (0.5 mL) was added hydrazine (3 mL). The mixture was allowed to stir at room temperature for 5 h. The mixture was then filtered through celite, washed with ethyl acetate. The organic extracts were combined, washed with water and brine, concentrated, and purified by column chromatography to obtain the title compound in 88% yield (1.830 g). 1H NMR (300 MHz, CDCl3) 7.70 (d, 1H, J=7.7 Hz), 7.59 (t, 1H, J=7.3 Hz), 7.50 (t, 1H, J=7.4 Hz), 7.33 (d, 1H, J=7.5 Hz), 6.61 (d, 1H, J=8.3 Hz), 6.34 (d, 1H, J=2.5 Hz), 6.28 (dd, 1H, J=2.6, 8.3 Hz), 3.92 (dd, 1H, J=3.4, 6.1 Hz), 3.28 (t, 1H, J=5.1 Hz), 3.12-3.02 (m, 2H), 2.94-2.80 (m, 2H). MS (ES+) m/z 365.2 (M+1).
Reaction SMILES: [C:1]([CH2:3][C@@H:4]1[CH2:8][C@@H:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[CH2:6][N:5]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])#[N:2]>C1COCC1>[NH2:2][CH2:1][CH2:3][C@@H:4]1[CH2:8][C@@H:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[CH2:6][N:5]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]
Reactant: CC(C)(C)OC(=O)N1C[C@H](Cc2ccc(Cl)c(Cl)c2)C[C@H]1CC#N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](Cc2ccc(Cl)c(Cl)c2)C[C@H]1CCN
Temperature: 45 °C
Reaction time: 16 h
Yield: 68.7 %

Procedure:
To a solution of (2S,4R)-2-(cyanomethyl)-4-(3,4-dichloro-benzyl)-1-tert-butoxycarbonyl-pyrrolidine (6.34 g, 17.2 g) in dry THF (65 mL) was added a 1.0 M solution of BH3 in THF (110 mL, 110 mmol) and the mixture was warmed at 45° C. for 1.5 hrs. The mixture was then cooled in ice and quenched by adding water dropwise until frothing ceased. The cold mixture was acidified with 2N HCl and then another 100 mL of 1N HCl was added, the mixture then being stored at 6° C. for 16 hrs. The clear solution was made basic with aqueous Na2CO3 and the resulting emulsion then extracted with CH2Cl2, completion of the workup then affording 7.3 g of crude product. Purification by chromatography on silica gel eluting with 0.5% conc. NH4OH and 10-15% CH3OH in CH2Cl2 gave pure (2S,4R)-2-(2-aminoethyl)-4-(3,4-dichloro-benzyl)-1-tert-butoxycarbonylpyrrolidine (4.40 g, 11.8 mm) as a clear oil.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:12]2[N:13]([CH3:23])[C:14]([CH2:17][C:18]([CH3:22])([CH3:21])[CH2:19][CH3:20])=[CH:15][N:16]=2)=[CH:6][CH:5]=1.[CH3:35]I>O1CCCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH:11]([N:24]([CH3:35])[C:25](=[O:34])[O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:12]2[N:13]([CH3:23])[C:14]([CH2:17][C:18]([CH3:21])([CH3:22])[CH2:19][CH3:20])=[CH:15][N:16]=2)=[CH:8][CH:9]=1
Reactant: CI
Reactant: CCC(C)(C)Cc1cnc(C(Cc2ccc(Br)cc2)NC(=O)OCc2ccccc2)n1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(C)(C)Cc1cnc(C(Cc2ccc(Br)cc2)N(C)C(=O)OCc2ccccc2)n1C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (60 wt % in mineral oil) (20 mg, 0.47 mmol) was added to a solution of benzyl {2-(4-bromophenyl)-1-[5-(2,2-dimethylbutyl)-1-methyl-1H-imidazol-2-yl]ethyl}carbamate (70 mg, 0.14 mmol) in tetrahydrofuran. After stirring at 0° C. for 10 min, methyl iodide (20 μL, 0.31 mmol) was added and the reaction allowed to warm to ambient temperature. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo to afford benzyl {2-(4-bromophenyl)-1-[5-(2,2-dimethylbutyl)-1-methyl-1H-imidazol-2-yl]ethyl}methylcarbamate which was used in the subsequent step without further purification.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:14]([CH2:15][C@@H:16]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][C:12]([Cl:28])=[C:11]2[C:7]=1[CH:8]=[N:9][NH:10]2)(=[O:3])[CH3:2].[Cl:29]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:4][CH2:5][C:6]1[C:14]([CH2:15][C@@H:16]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][C:12]([Cl:28])=[C:11]2[C:7]=1[C:8]([Cl:29])=[N:9][NH:10]2)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)C[C@H](Cc1cc(Cl)c2[nH]ncc2c1COC(C)=O)C(=O)OCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@H](Cc1cc(Cl)c2[nH]nc(Cl)c2c1COC(C)=O)C(=O)OCC
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
(S)-Diethyl 2-((4-(acetoxymethyl)-7-chloro-1H-indazol-5-yl)methyl)succinate (1.12 g, 2.73 mmol) was dissolved in N,N-dimethylformamide (30 ml). Mixture was warmed to 70° C. N-Chlorosuccinimide (400 mg, 3.00 mmol) was added to the solution. Mixture was warmed to 150° C. and held with stirring for 30 minutes. Mixture was cooled to room temperature and then diluted with ethyl acetate. Material was washed twice with 1N sodium thiosulfate and the aqueous phase was discarded. Material was washed successively with water and brine and the aqueous phases were discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as dark amber oil in quantitative yield. MS (M−H)−=443.0.