Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[C:6]([NH2:11])[C:7]([NH2:10])=[CH:8][CH:9]=1)[CH3:3].C(OC([NH:19][C@H:20]([C:25](O)=O)[C@@H:21]([CH3:24])[O:22][CH3:23])=O)(C)(C)C>>[CH3:23][O:22][C@H:21]([CH3:24])[C@@H:20]([C:25]1[NH:10][C:7]2[CH:8]=[CH:9][C:4]([CH:2]([CH3:1])[CH3:3])=[CH:5][C:6]=2[N:11]=1)[NH2:19]
Reactant: CC(C)c1ccc(N)c(N)c1
Reactant: CO[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CO[C@H](C)[C@H](N)c1nc2cc(C(C)C)ccc2[nH]1

Procedure:
The title compound was prepared according to Method 4 using 4-(1-methylethyl)-1,2-benzenediamine and N-(tert-butoxycarbonyl)-O-methyl-L-threonine (Preparation 51). The residue was purified by elution through an SCX cartridge.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N+:11]=2[O-:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:25])C=1>C(Cl)(Cl)Cl>[C:1]1([CH2:7][CH2:8][S:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N+:11]=2[O-:16])=[O:25])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: [O-][n+]1ccccc1SCCc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=S(CCc1ccccc1)c1cccc[n+]1[O-]

Procedure:
The procedure employed is identical to that of Example 68 using 2.8 gm (0.012 mol) 2-(2-phenylethylthio)pyridine N-oxide in 25 ml of chloroform with 2.4 gm (0.012 mol) MCPBA in 50 ml chloroform.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]2[C:11]=1[NH:10][C:9](=O)[CH:8]=[C:7]2[CH2:13][CH2:14]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.P(Cl)(Cl)([Cl:52])=O>O1CCCC1>[Br:1][C:2]1[C:11]2[C:6]3=[C:7]([CH2:13][CH2:14][O:16][C:5]3=[CH:4][CH:3]=1)[CH:8]=[C:9]([Cl:52])[N:10]=2
Reactant: O=c1cc(CCO)c2c(O)ccc(Br)c2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1cc2c3c(ccc(Br)c3n1)OCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.2 %

Procedure:
To a stirred solution of 8-bromo-5-hydroxy-4-(2-hydroxyethyl)quinolin-2(1H)-one (0.560 g; 1.971 mmol) in tetrahydrofuran (25 ml) was added triphenylphosphine (0.775 g; 2.96 mmol) followed by the dropwise addition of diisopropyl azodicarboxylate (0.582 ml; 2.96 mmol). The reaction mixture was stirred at room temperature for 2 h, concentrated under reduced pressure and the remaining crude residue was slowly added to phosphorus oxychloride (2.5 ml; 26.7 mmol) at room temperature. The reaction mixture was heated at 100° C. for 1 h and then cooled to room temperature before removing of the volatiles under reduced pressure. The residue was dissolved in dichloromethane, washed with a solution of sodium hydroxide 1N, water and brine, dried over magnesium sulphate and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-40%) in heptane furnished 0.220 g (39%) of 7-bromo-5-chloro-2,3-dihydropyrano[4,3,2-de]quinoline as a white solid.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:31][C:32]1[C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:35]=[CH:34][C:33]=1[NH2:47]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[NH2:47][C:33]1[C:32]([CH3:31])=[C:37]([C:2]2[N:3]=[C:4]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])=[CH:13][CH:12]=3)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: Cc1c(N)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: Cn1cc(Br)nc(Nc2ccc(C(=O)N3CCOCC3)cc2)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1c(N)cccc1-c1cn(C)c(=O)c(Nc2ccc(C(=O)N3CCOCC3)cc2)n1
Temperature: 100 °C
Yield: 84.3 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 101d (9.23 g, 23.5 mmol), 1,4-dioxane (250 mL) and aqueous 0.71M sodium carbonate (50 mL, 35.5 mmol). After bubbling argon through the resulting solution for 15 minutes, 101f (6.58 g, 28.2 mmol) and tetrakis(triphenylphosphine)palladium (4.06 g, 3.51 mmol) were added and the reaction mixture then heated at 100° C. for 38 h. After this time the reaction was cooled to room temperature and partitioned between water (1 L) and methylene chloride (300 mL). The aqueous phase was separated and re-extracted with methylene chloride (2×300 mL). A white precipitate of the product present in the combined organic extracts was filtered and retained. The organic phase was extracted with 2N hydrochloric acid (2×200 mL) and then discarded. The acidic aqueous phase was made basic with 2N sodium hydroxide to pH 8-10 and extracted with methylene chloride (3×300 mL). The combined organic extracts were dried over sodium sulfate, filtered, then combined with the white precipitate (vide supra) and concentrated under reduced pressure. The resulting white solid was triturated with hot ethanol (100 mL), filtered, and washed with ethanol (2×40 mL). The filter cake was dissolved in chloroform, the solution was concentrated under reduced pressure and dried to a constant weight under high vacuum at 50° C. to afford an 84% yield of 101g (8.31 g) as an off-white solid: mp 274-275° C.; 1H NMR (500 MHz, CDCl3) δ 9.40 (s, 1H), 8.09 (d, 2H, J=8.5 Hz), 7.34 (d, 2H, J=8.5 Hz), 7.14 (s, 1H), 6.93 (t, 1H, J=7.5 Hz), 6.66 (d, 1H, J=7.5 Hz), 6.57 (d, 1H, J=7.5 Hz), 4.92 (bs, 2H), 3.58 (bs, 4H), 3.54 (s, 3H), 3.48 (bs, 4H), 2.09 (s, 3H); MS (ESI+) m/z 420 (M+H).
Reaction SMILES: NC1N(C(OC(C)(C)C)=O)N=C(C2C=CC(OCC3C=CC(C4SC(N5CCC6C(=C(C(=O)N(C7SC8C=CC=CC=8N=7)COCC[Si](C)(C)C)C=CC=6)C5)=NC=4C(OCC)=O)=CC=3)=CC=2)C=1C#N.NC1N(C(OC(C)(C)C)=O)N=C(C2C=CC(O)=CC=2)C=1C#N.O[CH2:93][C:94]1[S:98][C:97]([N:99]2[CH2:108][CH2:107][C:106]3[C:101](=[C:102]([C:109](=[O:128])/[N:110]=[C:111]4/[S:112][C:113]5[CH:127]=[CH:126][CH:125]=[CH:124][C:114]=5[N:115]/4[CH2:116][O:117][CH2:118][CH2:119][Si:120]([CH3:123])([CH3:122])[CH3:121])[CH:103]=[CH:104][CH:105]=3)[CH2:100]2)=[N:96][C:95]=1[C:129]([O:131][CH3:132])=[O:130].[OH:133][C:134]1[CH:139]=[CH:138][C:137]([C:140]2[C:141]([C:145]#[N:146])=[CH:142][S:143][CH:144]=2)=[CH:136][CH:135]=1>>[C:145]([C:141]1[C:140]([C:137]2[CH:136]=[CH:135][C:134]([OH:133])=[C:139]([CH:138]=2)[CH2:93][C:94]2[S:98][C:97]([N:99]3[CH2:108][CH2:107][C:106]4[C:101](=[C:102]([C:109](=[O:128])/[N:110]=[C:111]5/[S:112][C:113]6[CH:127]=[CH:126][CH:125]=[CH:124][C:114]=6[N:115]/5[CH2:116][O:117][CH2:118][CH2:119][Si:120]([CH3:121])([CH3:123])[CH3:122])[CH:103]=[CH:104][CH:105]=4)[CH2:100]3)=[N:96][C:95]=2[C:129]([O:131][CH3:132])=[O:130])=[CH:144][S:143][CH:142]=1)#[N:146]
Reactant: N#Cc1cscc1-c1ccc(O)cc1
Reactant: COC(=O)c1nc(N2CCc3cccc(C(=O)/N=c4/sc5ccccc5n4COCC[Si](C)(C)C)c3C2)sc1CO
Agent: CC(C)(C)OC(=O)n1nc(-c2ccc(O)cc2)c(C#N)c1N
Agent: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1-c1ccc(COc2ccc(-c3nn(C(=O)OC(C)(C)C)c(N)c3C#N)cc2)cc1
Product: COC(=O)c1nc(N2CCc3cccc(C(=O)/N=c4/sc5ccccc5n4COCC[Si](C)(C)C)c3C2)sc1Cc1cc(-c2cscc2C#N)ccc1O

Procedure:
The title compound 60A was prepared in a similar manner to the synthesis of compound 35A by substituting compound 34D and compound 31F with compound 45D and compound 51A, respectively: ESI (+)/LC/MS: 892 (M+NH4—H2O)+: 1H NMR (DMSO-d6): δ 9.99 (s, 1H), 8.58 (s, 1H), 8.21 (d, J=6.71 Hz, 1H), 7.92 (d, J=7.32 Hz, 1H), 7.66-7.68 (m, 2H), 7.52-7.55 (m, 1H), 7.32-7.41 (m, 5H), 6.92 (d, J=8.24 Hz, 1H), 5.97 (s, 2H), 5.08 (s, 2H), 4.35 (s, 2H), 3.78 (s, 3H), 3.64-3.68 (m, 2H), 2.98 (t, J=5.8 Hz, 2H), 0.84-0.87 (m, 2H), −0.22 (s, 9H). ESI (+)/MS: 794 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1CCN(Cc2ccccc2)C1
Reactant: Brc1ccccc1
Product: c1ccc(CN2CC[C@H](Nc3ccccc3)C2)cc1

Procedure:
((S)-1-benzylpyrrolidin-3-yl)-phenylamine was synthesized using (S)-1-benzylpyrrolidin-3-ylamine and bromobenzene in the same manner as in Reference Example 3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[NH2:12].Cl[CH2:14][C:15]1[C:16]([NH:25][CH3:26])=[CH:17][C:18]([N:21]([O:23][CH3:24])[CH3:22])=[N:19][CH:20]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[NH:12][CH2:14][C:15]1[C:16]([NH:25][CH3:26])=[CH:17][C:18]([N:21]([O:23][CH3:24])[CH3:22])=[N:19][CH:20]=1
Reactant: CNc1cc(N(C)OC)ncc1CCl
Reactant: Nc1cc([N+](=O)[O-])c(F)cc1Cl
Solvent: c1ccncc1
Product: CNc1cc(N(C)OC)ncc1CNc1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 50 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
2-Chloro-4-fluoro-5-nitro-phenylamine (1.4 g, 7.4 mmol) was added to a solution of 5-(chloromethyl)-N2-methoxy-N2,N4-dimethylpyridine-2,4-diamine from example A16 (1.6 g, 7.4 mmol) in pyridine (30 mL) and the mixture was stirred at 50° C. for 8 hours. The reaction mixture was concentrated under reduced pressure and the solid residue was thoroughly washed with water to give 5-((2-chloro-4-fluoro-5-nitrophenylamino)methyl)-N2-methoxy-N2,N4-dimethylpyridine-2,4-diamine (1.5 g, 56% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.01 (s, 1H), 7.76 (d, J=8.4 Hz, 1 H), 7.71 (s, 1 H), 7.34 (d, J=8 Hz, 1 H), 6.56 (m, 1 H), 5.98 (s, 1 H), 4.36 (d, J=4 Hz, 2 H), 3.71 (s, 3 H), 3.31 (s, 3 H), 2.91-2.92 (d, J=4 Hz, 3 H); MS (ESI) m/z: 369.9 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C:5]([NH2:7])=[S:6])(=[NH:3])[NH2:2].Br[CH2:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(O)C>[NH:4]([C:5]1[S:6][CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:7]=1)[C:1]([NH2:2])=[NH:3]
Reactant: CCOC(=O)C(=O)CBr
Reactant: N=C(N)NC(N)=S
Solvent: CCO
Product: CCOC(=O)c1csc(NC(=N)N)n1
Reaction time: 2.5 h
Yield: 84.1 %

Procedure:
A suspension of guanylthiourea (2.36 g) and ethyl 3-bromopyruvate (4.8 g) in dry ethanol (50 ml) is refluxed under stirring for 2.5 hours. The reaction mixture is concentrated in vacuum to dryness, and the residue is dissolved in water (about 100 ml). The aqueous solution is washed with ethyl acetate and made alkaline with 5% sodium hydrogencarbonate solution. The precipitated crystals are filtered, washed with water and dried to give 2-guanidino-4-ethoxycarbonylthiazole (3.6 g) as crystals. The yield is 84%.
Reaction SMILES: C(OC([N:8]1[CH2:32][CH2:31][C:12]2[C:13]3[C:14](O)([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])[C:15]([F:21])([F:20])[CH2:16][C:17]=3[CH:18]=[CH:19][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:21][C:15]1([F:20])[CH:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])[C:13]2[C:12]3[CH2:31][CH2:32][NH:8][CH2:9][CH2:10][C:11]=3[CH:19]=[CH:18][C:17]=2[CH2:16]1
Reactant: COc1ccccc1C1(O)c2c(ccc3c2CCN(C(=O)OC(C)(C)C)CC3)CC1(F)F
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccccc1C1c2c(ccc3c2CCNCC3)CC1(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.9 %

Procedure:
Into a glass vial, the product from step (c) (112 mg, 0.251 mmol) dissolved in 2 ml DCM was added. To this stirred solution, triethylsilane (603 μL, 3.77 mmol) was added, followed by TFA (290 μL, 3.77 mmol). After stirring at room temperature for 16 hours, additional triethylsilane (603 μL, 3.77 mmol) and TFA (290 μL, 3.77 mmol) were added. The reaction mixture was stirred for an additional 16 hours. The volatiles were then evaporated in vacuo and the residue diluted with 2M HCl (20 ml). The aqueous mixture was washed with diethyl ether (2×), basified with 2M NaOH to pH 10, and extracted with DCM (3×). The combined DCM extracts were washed with brine, dried over Na2SO4, and solvent evaporated in vacuo to give the title compound as a white semi-solid (52 mg). 1H NMR (300 MHz, CDCl3) δ 7.23-7.20 (m, 1H); 7.08-7.02 (m, 2H); 6.95-6.91 (m, 1H); 6.78 (t, J=7.5 Hz, 1H); 6.51 (bs, 1H); 5.15 (d, J=21.0 Hz, 1H); 3.91 (s, 3H); 3.47-3.28 (m, 2H); 2.97-2.81 (m, 4H); 2.72-2.62 (m, 2H); 2.51-2.46 (2H); 1.68 (bs, 1H); MS: ESI (positive): 330 (M+1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]([CH3:26])[C:9]([CH:11]1[CH2:13][C:12]1([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O.[OH-].[Na+]>CCOCC>[CH3:26][N:8]([CH2:9][CH:11]1[CH2:13][C:12]1([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH3:7]
Reactant: CN(C)C(=O)C1CC1(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CN(C)CC1CC1(c1ccccc1)c1ccccc1
Yield: 91 %

Procedure:
To a solution of lithium aluminum hydride (0.30 g) in ether (10 ml) was added a solution of 2,2-diphenylcyclopropanecarboxylic acid N,N-dimethylamide (0.813 g) in ether (15 ml) under ice-cooling, and the resulting mixture was stirred under reflux for 2 hours. The reaction mixture was cooled, admixed with a 10% aqueous solution of sodium hydroxide (20 ml) and extracted with ether. The ether extract was dried over anhydrous magnesium sulfate and evaporated to afford N,N-dimethyl-2,2-diphenylcyclopropylmethylamine (0.701 g) as an oily substance. M.P. 231°-233° C (hydrochloride).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].CCN(CC)CC.[C:22]([C:24]1[C:25]([C:38]([F:41])([F:40])[F:39])=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH2:33][C:34](=[NH:37])[NH:35]O)[CH:28]=[CH:27]2)#[N:23]>CC#N>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]1[O:5][N:37]=[C:34]([CH2:33][N:29]2[C:30]3[C:26](=[C:25]([C:38]([F:41])([F:39])[F:40])[C:24]([C:22]#[N:23])=[CH:32][CH:31]=3)[CH:27]=[CH:28]2)[N:35]=1
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3cc(C(F)(F)F)ccc3Cl)n2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.8 %

Procedure:
2-Chloro-5-(trifluoromethyl)benzoyl chloride (0.017 g, 0.071 mmol), Et3N (0.008 g. 0.078 mmol) and 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (0.020 g, 0.071 mmol) were combined in CH3CN (1.5 mL). After stirring at rt for 1 h, the mixture was heated to 150° C. in a microwave for 10 min. Purification (SiO2, EtOAc/hexanes) afforded the title compound (0.025 g): MS (ESI): m/z 469 (M−1).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]2[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=2)=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([O:31][C:32]([NH:34][C:35]1[C:44]([N+:45]([O-:47])=[O:46])=[CH:43][CH:42]=[CH:41][C:36]=1[C:37]([O:39][CH3:40])=[O:38])=[O:33])([CH3:30])([CH3:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:27]([O:31][C:32]([N:34]([C:35]1[C:44]([N+:45]([O-:47])=[O:46])=[CH:43][CH:42]=[CH:41][C:36]=1[C:37]([O:39][CH3:40])=[O:38])[CH2:25][C:22]1[CH:23]=[CH:24][C:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12]2[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:9]=[N:10][N:11]=2)=[CH:20][CH:21]=1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1NC(=O)OC(C)(C)C
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2Cc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cccc([N+](=O)[O-])c1N(Cc1ccc(-c2ccccc2-c2nnnn2Cc2ccccc2)cc1)C(=O)OC(C)(C)C
Yield: 81.7 %

Procedure:
A mixture of 1-benzyl-5-[4′-(bromomethyl)biphenyl-2-yl]-1H-tetrazole (compound 5b, 9.82 g, 24 mmol), methyl 2-(tert-butoxycarbonylamino)-3-nitrobenzoate (compound 19a, 7.32 g, 24.7 mmol) and potassium carbonate (3.68 g, 26.7 mmol) in acetonitrile (100 mL) was heated under reflux for 6 hr under argon stream. To the reaction mixture was added potassium carbonate (1.34 g), and the mixture was heated under reflux for 3 hr. The reaction mixture was cooled and filtered. The insoluble material was washed with chloroform. The filtrate and washing were combined, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column (hexane→hexane:AcOEt=5:1→4:1→3:1→2:1→3:2) to give methyl 2-(N-tert-butoxycarbonyl-N-{(2′-[1-benzyl-1H-tetrazol-5-yl]biphenyl-4-yl)methyl}amino)-3-nitrobenzoate (compound 20b) (12.17 g, 81%) as a yellow amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:3]=1[CH2:4][NH:5][S:6]([CH3:9])(=[O:8])=[O:7]>O1CCCC1.C(O)C.[Pd]>[NH2:14][C:12]1[CH:11]=[CH:10][C:3]([CH2:4][NH:5][S:6]([CH3:9])(=[O:8])=[O:7])=[C:2]([F:1])[CH:13]=1
Reactant: CS(=O)(=O)NCc1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CS(=O)(=O)NCc1ccc(N)cc1F
Reaction time: 15 h
Yield: 86.5 %

Procedure:
To a stirred solution of N-(2-fluoro-4-nitrobenzyl)methanesulfonamide (250 mg, 1.007 mmol) in tetrahydrofuran and ethanol as co-solvent were added 10% Pd/C (25 mg). The mixture was charged with H2 (gas) balloon. The resulting mixture was stirred for 15 h, then filtered by using celite. The filtrate was removed in vacuo. The crude was purified by column chromatography. N-(4-Amino-2-fluorobenzyl)methanesulfonamide (190 mg) was obtained as 86% yield.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[BH4-].[Na+].Cl.C(=O)(O)[O-].[Na+]>C1COCC1.O>[CH3:1][C:2]1[CH:10]=[C:6]([CH2:7][OH:8])[CH:5]=[N:4][C:3]=1[N:11]1[CH:15]=[CH:14][CH:13]=[N:12]1
Reactant: Cc1cc(C(=O)O)cnc1-n1cccn1
Agent: Cl
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(CO)cnc1-n1cccn1
Temperature: 25 °C
Reaction time: 14 h
Yield: 57.7 %

Procedure:
To a solution of 5-methyl-6-(1H-pyrazol-1-yl)nicotinic acid (2.20 g, 10.8 mmol, Step-2) in THF (50 mL) is added 1,1′-carbonyldiimidazole (2.63 g, 16.2 mmol). After stirring at rt for 14 hours, the mixture is cooled to 0° C., and a solution of sodium borohydride (2.05 g, 54.1 mmol) in cold water (15 mL) is slowly added. After stirring at 0° C. for 15 min, 2 M hydrochloric acid (25 mL) is added carefully. The resulting mixture is poured onto saturated aqueous sodium bicarbonate solution (200 mL), and the aqueous layer is extracted with EtOAc (200 mL). The separated organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by chromatography on silica gel eluting with n-hexane/EtOAc (4:1-2:1) to give 1.18 g (58% yield) of the title compound as a pale yellow oil.
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][CH:9]1[NH:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=2)[CH2:10]1.[F:24][C:25]([F:38])([F:37])[C:26]1[O:30][N:29]=[C:28]([CH2:31][CH2:32][CH2:33][C:34](O)=[O:35])[N:27]=1>>[CH3:8][CH:9]1[N:14]([C:34](=[O:35])[CH2:33][CH2:32][CH2:31][C:28]2[N:27]=[C:26]([C:25]([F:37])([F:38])[F:24])[O:30][N:29]=2)[CH2:13][CH2:12][N:11]([CH2:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=2)[CH2:10]1
Reactant: CC1CN(Cc2ccc(C#N)cn2)CCN1
Reactant: O=C(O)CCCc1noc(C(F)(F)F)n1
Solvent: O=C(O)C(F)(F)F
Product: CC1CN(Cc2ccc(C#N)cn2)CCN1C(=O)CCCc1noc(C(F)(F)F)n1
Yield: 16 %

Procedure:
This compound was synthesized from 6-((3-methylpiperazin-1-yl)methyl)nicotinonitrile TFA salt and 4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)butanoic acid as described for example 37 step 3 (16 mg, yield 16%) pale yellow viscous liquid. 1H NMR (400 MHz, MeOD) δ 8.82-8.81 (dd, J=2.0 Hz, 0.8 Hz, 1H), 8.15-8.12 (dd, J=8.2 Hz, 2.1 Hz, 1H), 7.77-7.75 (d, J=8.0 Hz, 1H), 3.78-3.66 (m, 2H), 2.96-2.92 (t, J=7.4 Hz, 2H), 2.89-2.85 (m, 1H), 2.73-2.69 (dt, J=11.5 Hz, 1.7 Hz, 1H), 2.51 (m, 2H), 2.34-2.30 (m, 1H), 2.22-2.17 (m, 1H), 2.14-2.06 (m, 2H), 1.35-1.32 (m, 3H), 1.30 (s, 3H). MS (ESI) m/z: Calculated for C19H21F3N6O2: 422.17. found: 423.2 (M+H)+
Reaction SMILES: [I:1][C:2]1[C:6]2[C:7]([O:11][CH3:12])=[N:8][CH:9]=[CH:10][C:5]=2[NH:4][CH:3]=1.[H-].[Na+].CC1C=CC(S(O[CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)(=O)=O)=CC=1>CN(C=O)C>[I:1][C:2]1[C:6]2[C:7]([O:11][CH3:12])=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CCOCC2)cc1
Reactant: COc1nccc2[nH]cc(I)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nccc2c1c(I)cn2C1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
To a solution of 3-iodo-4-methoxy-1H-pyrrolo[3,2-c]pyridine (0.150 g) in DMF (10 mL) was added sodium hydride (60% dispersion in mineral oil, 55.0 mg), and the mixture was stirred at room temperature for 1 hr. Tetrahydro-2H-pyran-4-yl 4-methylbenzenesulfonate (0.351 g) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (120 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCCC)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[CH2:33]([C:35]1([OH:41])[CH2:40][CH2:39][CH2:38][NH:37][CH2:36]1)[CH3:34]>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:37]5[CH2:38][CH2:39][CH2:40][C:35]([CH2:33][CH3:34])([OH:41])[CH2:36]5)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:31])([F:30])[F:32])[CH:3]=1
Reactant: CCC1(O)CCCNC1
Reactant: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CCC1(O)CCCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)C1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-ethyl-3-hydroxy-piperidin-1-yl)-thiazol-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one and 3-Ethyl-piperidin-3-ol following General Procedure B.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([CH2:8][NH:9]C(=O)OC(C)(C)C)[CH:5]=[CH:4][N:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>O1CCOCC1>[NH2:9][CH2:8][C:6]1[CH:5]=[CH:4][N:3]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:2](=[O:1])[CH:7]=1
Reactant: CC(C)(C)OC(=O)NCc1ccn(-c2ccccc2)c(=O)c1
Agent: Cl
Solvent: C1COCCO1
Product: NCc1ccn(-c2ccccc2)c(=O)c1

Procedure:
Tert-butyl (2-oxo-1-phenyl-1,2-dihydropyridin-4-ylmethyl)-carbamate (83 mg, 0.28 mmol) is treated with 4N hydrogen chloride in dioxane in order to remove the Boc protecting group. The hydrochloride salt of 4-aminomethyl-1-phenyl-1H-pyridin-2-one, obtained after concentration of the reaction mixture, is dissolved in N,N-dimethylformamide (5 mL) and is coupled to (4E)-6-iodo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (92 mg, 0.28 mmol) in the presence of triethylamine (200 μL). After one hour, the reaction mixture is concentrated under reduced pressure and purified by flash silica gel chromatography (methanol/chloroform) to provide (4Z)-6-iodo-4-({[(2-oxo-1-phenyl-1,2dihydropyridin-4-yl)methyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione as a pale yellow solid (8.8 mg, 6.3%).