Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:14])=[C:5]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8](=O)[CH2:7][CH2:6]2.Cl.[CH:16]([C:19]1[CH:24]=[CH:23][C:22]([NH:25]N)=[CH:21][CH:20]=1)([CH3:18])[CH3:17].Cl>C(O)C>[CH3:1][O:2][C:3]1[C:4]([CH3:14])=[C:5]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8]1[NH:25][C:22]3[CH:21]=[CH:20][C:19]([CH:16]([CH3:18])[CH3:17])=[CH:24][C:23]=3[C:7]=1[CH2:6]2
Reactant: COc1c(C)cc2c(c1C)CCC2=O
Reactant: CC(C)c1ccc(NN)cc1
Agent: Cl
Solvent: CCO
Product: COc1c(C)cc2c(c1C)Cc1c-2[nH]c2ccc(C(C)C)cc12
Temperature: 25 °C

Procedure:
A mixture of 5-methoxy-4,6-dimethyl-1-indanone (3.1 g, 16 mmol) and p-isopropylphenylhydrazine hydrochloride (3.05 g, 16 mmol), was heated to reflux in ethanol (20 cm3) containing concentrated hydrochloric acid (2 cm3). The reaction mixture was then heated at reflux for 4 hours and then allowed to cool to room temperature. The crystalline precipitate which formed, was filtered off, washed with 10% aqueous ethanol, and dried in a vacuum oven, to give the title compound as a pale green crystalline solid. Yield 3.04 g (62%). M.p. 130° C. (from ethanol). 1H NMR (CDCl3) δ: 1.33 (6H, d,), 2.34 (3H, s,), 2.35 (3H, s,), 3.02 (1H, septet,), 3.6 (1H, br,), 3.76 (2H, s,), 7.08 (1H, s,), 7.30 (1H, d,), 7.45 (1H, s,), 8.12 (1H, s,).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[C:13]([F:34])=[CH:14][C:15]([F:33])=[C:16]([NH:18][C:19](=[O:32])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4([C:29]#[N:30])[CH2:28][CH2:27]4)[C:21]=3[Cl:31])[CH:17]=1)[N:5]=2.[CH:35]1([C:38](Cl)=[O:39])[CH2:37][CH2:36]1.O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Cl:31][C:21]1[C:22]([C:26]2([C:29]#[N:30])[CH2:28][CH2:27]2)=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]([NH:18][C:16]1[CH:17]=[C:12]([O:11][C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:1][C:38]([CH:35]4[CH2:37][CH2:36]4)=[O:39])=[N:10][C:9]3=[CH:8][CH:7]=2)[C:13]([F:34])=[CH:14][C:15]=1[F:33])=[O:32]
Reactant: N#CC1(c2cccc(C(=O)Nc3cc(Oc4ccc5nc(N)sc5n4)c(F)cc3F)c2Cl)CC1
Reactant: O=C(Cl)C1CC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: N#CC1(c2cccc(C(=O)Nc3cc(Oc4ccc5nc(NC(=O)C6CC6)sc5n4)c(F)cc3F)c2Cl)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.1 %

Procedure:
To a solution of N-{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-2,4-difluorophenyl}-2-chloro-3-(1-cyanocyclopropyl)benzamide (0.17 g, 0.33 mmol) and N,N-dimethylpyridine-4-amine (0.12 g, 1.00 mmol) in pyridine (2 mL) was added dropwise cyclopropanecarbonyl chloride (0.11 g, 1.00 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added water (50 mL), and the mixture was extracted with ethyl acetate (50 mL×2). The ethyl acetate layers were combined, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in methanol (5 mL), 8N aqueous sodium hydroxide solution (1 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water (50 mL), and the mixture was extracted with ethyl acetate (50 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→100/0), and recrystallized from methanol to give the title compound (88 mg, 47%) as white crystals.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][C:11]2[C:13]([O:20][CH:21]([CH3:23])[CH3:22])=[CH:14][C:15]([C:17]([OH:19])=O)=[CH:16][C:10]=2[O:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][N:25]1[CH:29]=[CH:28][C:27]([NH2:30])=[N:26]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH3:24][N:25]1[CH:29]=[CH:28][C:27]([NH:30][C:17]([C:15]2[CH:14]=[C:13]([O:20][CH:21]([CH3:22])[CH3:23])[C:11]3[CH2:12][CH:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[O:9][C:10]=3[CH:16]=2)=[O:19])=[N:26]1
Reactant: CC(C)Oc1cc(C(=O)O)cc2c1CC(Cc1ccccc1)O2
Reactant: Cn1ccc(N)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)Oc1cc(C(=O)Nc2ccn(C)n2)cc2c1CC(Cc1ccccc1)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.7 %

Procedure:
To a solution of 2-benzyl-4-isopropoxy-2,3-dihydro-benzofuran-6-carboxylic acid (220j) (0.5 g, 1.6 mmol) in CH2Cl2 (15 mL) were added 1-methyl-1H-pyrazol-3-ylamine (0.16 g, 1.7 mmol), EDCI (0.46 g, 2.4 mmol), HOBt (0.32 g, 2.4 mmol) and N-methylmorphiline (0.81 g, 8 mmol) sequentially. The mixture was stirred at room temperature overnight. The reaction solution was washed with water (5 mL), aq. HCl (1 N, 5 mL) and sat. NaHCO3. The organic phase was dried over Na2SO4 and concentrated to give a yellow oil. The crude oil was purified by prep. HPLC to give the product as a white solid (98.6 mg, 16% yield, TFA salt). 1H NMR (400 MHz, CDCl3): δ 10.71 (s, 1H), 7.58 (s, 1H), 7.30-7.48 (m, 5H), 7.01˜7.19 (d, 2H), 6.57 (s, 1H), 5.08 (d, 1H), 4.74 (m, 1H), 3.74 (s, 3H), 2.66 (d, 2H), 2.17 (m, 1H), 1.96 (m, 1H), 1.28 (d, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11](B(O)O)=[CH:10][C:9]=2[F:17])=[CH:4][N:3]=1.Cl[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:26]=[N:27][C:28]([NH2:31])=[N:29][CH:30]=1>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[CH:26]=[N:27][C:28]([NH2:31])=[N:29][CH:30]=3)=[CH:10][C:9]=2[F:17])=[CH:4][N:3]=1
Reactant: Nc1ncc(-c2ncc(B(O)O)cc2F)cn1
Reactant: Nc1ncc(-c2ccccc2Cl)cn1
Product: Nc1ncc(-c2ccccc2-c2cnc(-c3cnc(N)nc3)c(F)c2)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 427 using (6-(2-aminopyrimidin-5-yl)-5-fluoropyridin-3-yl)boronic acid and 5-(2-chlorophenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C19H14FN7, 359.13; m/z found, 360.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.93 (s, 2H), 8.31-8.28 (m, 1H), 8.19 (s, 2H), 7.64 (dd, J=12.0, 1.9, 1H), 7.59-7.51 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:39][S:40]([CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)(=[O:42])=[O:41]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:48]3[CH2:47][CH2:46][N:45]([CH2:44][CH2:43][S:40]([CH3:39])(=[O:41])=[O:42])[CH2:50][CH2:49]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:31])([CH3:30])[C:32]#[N:33])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCN1CCNCC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1

Procedure:
2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-[4-(2-methanesulfonyl-ethyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-3-ethoxy-phenyl)-2-methyl-propionitrile was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12j) and 1-(2-methanesulfonylethyl)piperazine dihydrochloride (example 17) in an analogous manner as described in example 25. LR-MS: 696.3 [(M+H)+]
Reaction SMILES: [F:1][C:2]1([F:12])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:4]=2[O:3]1.[Br:13]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[F:12][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11][Br:13])=[CH:10][C:4]=2[O:3]1
Reactant: Cc1ccc2c(c1)OC(F)(F)O2
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: FC1(F)Oc2ccc(CBr)cc2O1
Yield: 96.6 %

Procedure:
A mixture of 2,2-difluoro-5-methyl-1,3-benzodioxole (29.0 g, 0.169 mole), N-bromosuccinimide (30.1 g, 0.169 mole), benzoyl peroxide (0.5 g) and carbon tetrachloride (50 ml) is refluxed for 2.5 hours. Carbon tetrachloride (50 ml) is then added to the hot reaction mixture and the solids are filtered off. The filtrate and washings are evaporated to yield 41.0 g of product as a brown oil; nmr (CCl4) δ 4.38 (S, 2H), 6.8-7.4 (m, 3H). The product is used without purification in the next step.
Reaction SMILES: [NH:1]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:2]1.Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=1)=[O:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:2]([CH2:17][C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=2)=[O:19])[N:1]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)c1cc(C(=O)OCC)[nH]n1
Reactant: CC(C)(C)c1ccc(C(=O)CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc(C(=O)OCC)n(CC(=O)c2ccc(C(C)(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 849 mg (4.00 mmol) diethyl pyrazole-3,5-dicarboxylate and 1.02 g (4.00 mmol) 2-bromo-1-(4-tert-butyl-phenyl)-ethanone in 4 ml acetone is treated with 663 mg (4.80 mmol) potassium carbonate. The resulting suspension is stirred overnight at room temperature. The reaction mixture is partitioned between water and dichloromethane. The organic phase is dried over sodium sulfate and evaporated to give 1-[2-(4-tert-butyl-phenyl)-2-oxoethyl]-1H-pyrazole-3,5-dicarboxylic acid diethyl ester as light yellow foam; HPLC/MS 2.77 (A), [M+H] 387.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([NH:15][CH:16]([CH:21]([CH3:23])[CH3:22])[C:17]([O:19][CH3:20])=[O:18])=[O:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:31]1[S:32][C:33]2[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:34]=2[N:35]=1>>[F:40][C:38]1[CH:37]=[CH:36][C:34]2[N:35]=[C:31]([O:1][C:2]3[CH:7]=[CH:6][C:5]([C:8]4[CH:12]=[C:11]([C:13]([NH:15][CH:16]([CH:21]([CH3:23])[CH3:22])[C:17]([O:19][CH3:20])=[O:18])=[O:14])[O:10][N:9]=4)=[CH:4][CH:3]=3)[S:32][C:33]=2[CH:39]=1
Reactant: COC(=O)C(NC(=O)c1cc(-c2ccc(O)cc2)no1)C(C)C
Reactant: Fc1ccc2nc(Cl)sc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)C(NC(=O)c1cc(-c2ccc(Oc3nc4ccc(F)cc4s3)cc2)no1)C(C)C
Reaction time: 0.29 h

Procedure:
To methyl 2-(3-(4-hydroxyphenyl)isoxazole-5-carboxamido)-3-methylbutanoate (200 mg) in N,N′-Dimethyl formamide (4 ml), cesium carbonate (245 mg) was added and stirred for 15-20 minutes. To this 2-chloro-6-fluorobenzo[d]thiazole (141 mg) was added and the reaction mixture was stirred at RT for 18 hours. Solvent was evaporated to obtain pale brown solid, which was purified by column chromatography (silica gel, EtOAc—CHCl3) to obtain off white solid, which was crystallized using DCM-Petroleum ether to obtain the title compound as white solid. Yield: 240 mg (81%); MS (ES+): m/z 470 (M+1); 1HNMR (DMSO-d6, 300 MHz): δ 9.27 (d, 1H), 8.08 (d, 2H), 7.93 (dd, 1H), 7.8 (s, 1H), 7.74 (dd, 1H), 7.67 (d, 2H), 7.31 (m, 1H), 4.33 (m, 1H), 3.69 (s, 3H), 2.23 (m, 1H), 0.98 (d, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:13]([C:14]([NH2:16])=[O:15])=[CH:12][NH:11][N:10]=2)=[CH:4][CH:3]=1.O=[S:18]1(=O)[CH2:23][CH2:22][C:21](=[CH:24][C:25]#[N:26])[CH2:20][CH2:19]1.C1CCN2C(=NCCC2)CC1>CC#N>[C:25]([CH2:24][C:21]1([N:11]2[CH:12]=[C:13]([C:14]([NH2:16])=[O:15])[C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:10]2)[CH2:22][CH2:23][S:18][CH2:19][CH2:20]1)#[N:26]
Reactant: NC(=O)c1c[nH]nc1Nc1ccc(F)cc1
Reactant: N#CC=C1CCS(=O)(=O)CC1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: N#CCC1(n2cc(C(N)=O)c(Nc3ccc(F)cc3)n2)CCSCC1
Temperature: 80 °C

Procedure:
3-[(4-Fluorophenyl)amino]-1H-pyrazole-4-carboxamide (Intermediate 31-7) (100 mg, 0.45 mmol) was added to a mixture of 2-(1,1-dioxidodihydro-2H-thiopyran-4(3H)-ylidene)acetonitrile (160 mg, 0.91 mmol) in MeCN (1.51 mL). DBU (0.068 mL, 0.45 mmol) was then added, the reaction vessel was capped and the reaction mixture was heated to 80° C. for 4 hours. The reaction mixture was cooled to ambient temperature, and purified by reverse phase preparative HPLC (using a gradient elution of MeCN/water, with 0.1% v/v TFA modifier). Desired fractions were combined, basified with saturated aqueous NaHCO3, and extracted with EtOAc. The organic layer was dried over anhydrous NaSO4, filtered, and concentrated in vacuo to afford the title compound, Example #7.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([C:27]4[CH:32]=[CH:31][C:30]([CH2:33][CH2:34]O)=[C:29]([C:36]5[NH:37][C:38]6[C:43]([C:44]=5[CH3:45])=[CH:42][CH:41]=[CH:40][CH:39]=6)[N:28]=4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.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>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:23])=[O:24])[C:18]([C:27]4[CH:32]=[CH:31][C:30]5[CH2:33][CH2:34][N:37]6[C:38]7[CH:39]=[CH:40][CH:41]=[CH:42][C:43]=7[C:44]([CH3:45])=[C:36]6[C:29]=5[N:28]=4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(CCO)c(-c4[nH]c5ccccc5c4C)n3)cc12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3c(C)c5ccccc5n3CC4)cc12

Procedure:
To a mixture of 2-(4-fluorophenyl)-5-(5-(2-hydroxyethyl)-6-(3-methyl-1H-indol-2-yl)pyridin-2-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (43 mg, 0.069 mmol) and triphenylphosphine (90 mg, 0.343 mmol) in THF (4 mL) was diisopropyl azodicarboxylate (0.067 mL, 0.343 mmol). The resultant mixture was stirred at ambient temperature for 16 h, diluted with EtOAc and washed successively with H2O (2×) and brine (1×). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography using a step gradient of 0-40-90% EtOAc/Hexanes as eluent. Further purification by silica gel column chromatography with a gradient of 0-10% EtOAc/CH2Cl2 as eluent, followed by lyophilization from CH3CN/H2O provided the title compound. 1H NMR δ (ppm) (CHCl3-d): 8.16 (1H, s), 8.07˜8.03 (2H, m), 7.70˜7.66 (3H, m), 7.47 (1H, d, J=7.77 Hz), 7.37 (1H, d, J=8.24 Hz), 7.32 (1H, D, J=7.1 Hz), 7.26˜7.22 (2H, m), 7.16 (1H, t, J=7.40 Hz), 5.95 (1H, br s), 4.34 (2H, t, J=6.37 Hz), 3.32 (3H, s), 3.28 (2H, t, J=6.4 Hz), 3.05 (3H, d, J=4.91 Hz), 2.83 (3H, s), 2.75 (3H, s). MS (M+H): 609.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:19]=3)[N:14]=2)[CH2:9][CH2:8]1)[C:3]([OH:5])=O.CCN=C=NCCCN(C)C.Cl.N1(O)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[N+:56]([C:59]1[CH:64]=[CH:63][C:62]([NH:65][CH:66]2[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]2)=[CH:61][C:60]=1[C:72]([F:75])([F:74])[F:73])([O-:58])=[O:57]>ClCCl>[CH3:1][CH:2]([CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:23]([F:25])([F:24])[F:26])[CH:19]=3)[N:14]=2)[CH2:9][CH2:8]1)[C:3]([N:69]1[CH2:70][CH2:71][CH:66]([NH:65][C:62]2[CH:63]=[CH:64][C:59]([N+:56]([O-:58])=[O:57])=[C:60]([C:72]([F:73])([F:74])[F:75])[CH:61]=2)[CH2:67][CH2:68]1)=[O:5]
Reactant: CC(CN1CCN(c2ccc3cc(C(F)(F)F)ccc3n2)CC1)C(=O)O
Reactant: O=[N+]([O-])c1ccc(NC2CCNCC2)cc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(CN1CCN(c2ccc3cc(C(F)(F)F)ccc3n2)CC1)C(=O)N1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
To a solution of 2-methyl-3-[4-[6-(trifluoromethyl) quinolin-2-yl]piperazin-1-yl]propanoic acid (100 mg, 0.27 mmol) in dichloromethane (20 ml) was added EDAC.HCl (79 mg, 0.41 mmol, 1.5 eq.), 1H-1,2,3-benzotriazol-1-ol (55.2 mg, 0.41 mmol, 1.5 eq.), triethylamine (82.6 mg, 0.82 mmol, 3 eq.) and N-[4-nitro-3-(trifluoromethyl)phenyl]piperidin-4-amine (94.5 mg, 0.33 mmol, 1.2 eq.). The resulting solution was stirred overnight at room temperature and then quenched by the addition of water (50 ml) and extracted with dichloromethane (3×30 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue, which was purified by Prep-TLC with 5% methanol in dichloromethane to afford of 2-methyl-1-(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]piperidin-1-yl)-3-[4-[6-(trifluoromethyl)quinolin-2-yl]piperazin-1-yl]propan-1-one as a yellow solid (111.2 mg, 64%). (ES, m/z): [M+H]+ 639.40; 1H NMR (300 MHz, CDCl3): δ 7.95-8.08 (m, 1H), 7.72 (overlapping m, 2H), 7.01 (d, J=9.3 Hz, 1H), 6.89 (m, 1H), 6.65 (m, 1H), 4.49-4.70 (m, 2H), 4.08 (m, 1H), 3.72-3.85 (br m, 5H), 3.65 (m, 1H), 3.08 (br s, 1H), 2.88 (br m, 2H), 2.68 (br s, 3H), 2.38 (m, 1H), 2.07-2.20 (overlapping m, 2H), 1.47 (m, 2H), 1.13 (br s, 3H).
Reaction SMILES: CC(C)=[O:3].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:8]=1[CH2:16][CH2:17][OH:18].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>>[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:8]=1[CH2:16][C:17]([OH:3])=[O:18]
Reactant: CC(C)=O
Reactant: COc1cccc([N+](=O)[O-])c1CCO
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: COc1cccc([N+](=O)[O-])c1CC(=O)O
Temperature: 0 °C
Yield: 98.4 %

Procedure:
A solution of 4.3 g of 2-(2-methoxy-6-nitrophenyl)-1-ethanol acetone (117 mL) is slowly treated with a solution of Jones Reagent (31 mL). The volatiles are removed under reduced pressure, diluted with 5M sodium hydroxide, cooled to 0° C., and treated slowly with concentrated H2SO4. This solution is extracted four times with ethyl acetate with the combine organics washed with brine, dried over NaSO4, filtered, and concentrated. The crude material is purified by LC (10% MeOH/CH2Cl2) to give 3.5 g of 2-(2-methoxy-6-nitrophenyl)acetic acid as a yellow/gold solid. 1H NMR (300 MHz, DMSO-d6) δ3.84 (s, 3H), 3.87 (s, 2H), 7.42 (d, J=7 Hz, 1H), 7.52 (t, J=8 Hz, 1H), 7.59 (dd, J=1, 8 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ157.9, 150.7, 127.5, 120.1, 115.3, 114.8, 56.4, 11.1; IR (drift) 3020, 2983, 2945, 2888, 2840, 1710, 1531, 1471, 1434, 1353, 1274, 1256, 1229, 1058, 799 cm−1. HRMS (FAB) calculated for C9H9NO5+H1 212.0559, found 212.0555.
Reaction SMILES: [C:1]([N:4]([CH2:6][C:7]([OH:9])=[O:8])[CH3:5])(=O)C.[P:10]([OH:13])([OH:12])[OH:11].S(=O)(=O)(O)O.C=O>O>[P:10]([CH2:1][N:4]([CH3:5])[CH2:6][C:7]([OH:9])=[O:8])([OH:13])([OH:12])=[O:11]
Reactant: OP(O)O
Reactant: CC(=O)N(C)CC(=O)O
Agent: C=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CN(CC(=O)O)CP(=O)(O)O
Temperature: 120 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
N-acetyl sarcosine (XX)(2.0 g, 15.3 mmole), phosphorous acid (1.25 g, 15.3 mmole) were mixed with concentrated sulfuric acid (3.1 g) and water (1.7 g) then refluxed in a 120° C. oil bath. Formalin, 37% (1.4 g, 16.7 mmole) was added dropwise over 20 min. and the reaction was continued for an additional 18 h. 31P NMR analysis indicated 98% yield of (XXI) based on mmoles of (XX) charged.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([CH2:8][C:9]([OH:11])=[O:10])=[C:5]([CH3:7])[N:6]=1.[C:12]([O:16][C:17](=[O:22])[C:18](Br)([CH3:20])[CH3:19])([CH3:15])([CH3:14])[CH3:13]>CO.[OH-].[Na+]>[C:12]([O:16][C:17](=[O:22])[C:18]([S:1][C:2]1[S:3][C:4]([CH2:8][C:9]([OH:11])=[O:10])=[C:5]([CH3:7])[N:6]=1)([CH3:20])[CH3:19])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: Cc1nc(S)sc1CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc(SC(C)(C)C(=O)OC(C)(C)C)sc1CC(=O)O
Temperature: 60 °C
Reaction time: 6 h
Yield: 95.2 %

Procedure:
Commercially available (2-mercapto-4-methyl-1,3-thiazol-5-yl)acetic acid (15 g) was dissolved in methanol (360 mL) and 1N aqueous sodium hydroxide solution (174 mL), 2-bromo-2-methylpropionic acid tert-butyl ester (19.4 g) was added, and the mixture was stirred at 60° C. for 6 hr. The reaction mixture was concentrated, the residue was dissolved in water, and the mixture was acidified with 10% aqueous citric acid solution. The precipitated solid was collected by filtration, and dried under reduced pressure to give the title compound (25 g) as a white solid.
Reaction SMILES: [N:1]1([C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:14](Cl)(Cl)=[S:15].O>O1CCOCC1>[N:1]1([C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=[C:14]=[S:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccccc1N1CCCCC1
Reactant: S=C(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Product: S=C=Nc1ccccc1N1CCCCC1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of 2-piperidinoaniline (17.6 g) in dioxane (100 ml) was added over 25 minutes to a mixture of thiophosgene (10.2 ml) and water (200 ml) which had been cooled to 0° C. The temperature of the mixture was allowed to rise to ambient and the mixture was stirred for 4 hours. Ice (200 g) and water (200 ml) were added and the mixture extracted with ether (6×50 ml). The combined extracts were washed with water (100 ml) and brine (100 ml), dried and evaporated to give a residue which purified by chromatography on a silica column eluted with hexane to give 2 -piperidinophenyl isothiocyanate as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[CH:3]=1.CN.C=O.[CH3:21][N:22]1[CH2:27]COC[CH2:23]1>O.C(O)C>[Br:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([N:9]3[CH2:23][N:22]([CH3:27])[CH2:21][N:12]([CH2:13][CH3:14])[C:10]3=[O:11])[S:8][C:4]=2[CH:3]=1
Reactant: CN1CCOCC1
Reactant: CCNC(=O)Nc1nc2ccc(Br)cc2s1
Agent: C=O
Agent: CN
Solvent: O
Solvent: CCO
Product: CCN1CN(C)CN(c2nc3ccc(Br)cc3s2)C1=O
Yield: 88 %

Procedure:
A mixture of 1-(6-bromo-2-benzothiazolyl)-3-ethylurea, methylamine, formaldehyde, and N-methyl morpholine in a mixed solvent of ethanol and water was reacted to give the desired compound 1.56 g (88%).
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9]([Si:13]([O:16][CH2:17][CH2:18][C:19]#[CH:20])([CH3:15])[CH3:14])([CH3:12])([CH3:11])[CH3:10]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Si:13]([O:16][CH2:17][CH2:18][C:19]#[C:20][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4])([C:9]([CH3:10])([CH3:11])[CH3:12])([CH3:15])[CH3:14]
Reactant: C#CCCO[Si](C)(C)C(C)(C)C
Reactant: Nc1ccccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCC#Cc1ccccc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Iodoaniline (1.76 g, 8 mmol) was dissolved in triethylamine (50 mL) and placed under N2. tert-Butylbut-3-ynyloxydimethylsilane (2.58 g, 14 mmol) was added, followed by bis(triphenylphosphine)palladium(II) chloride (30 mg, 0.042 mmol) and copper(I) iodide (7 mg, 0.036 mmol), and the reaction was stirred overnight at room temperature. Triethylamine was evaporated, and the residue was diluted with ether and filtered through Celite. The filtrate was concentrated, and the residue was purified by SiO2 chromatography (5-20% ethyl acetate/hexanes) to give the desired product. The reaction was assumed to be quantitative.