Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:19][CH2:18][O:17][C:16]3[CH:20]=[CH:21][C:22]([N+:24]([O-])=O)=[CH:23][C:15]=3[O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H][H]>[OH-].[OH-].[Pd+2].C(OCC)(=O)C>[NH2:24][C:22]1[CH:21]=[CH:20][C:16]2[O:17][CH2:18][CH2:19][N:11]([S:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH2:12][CH2:13][O:14][C:15]=2[CH:23]=1
Reactant: [H][H]
Reactant: Cc1ccc(S(=O)(=O)N2CCOc3ccc([N+](=O)[O-])cc3OCC2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)N2CCOc3ccc(N)cc3OCC2)cc1

Procedure:
To ethyl acetate (1 L) add 4-[(4-methylphenyl)sulfonyl]-9-nitro-3,4,5,6-tetrahydro-2H-1,7,4-benzodioxazonine (7.5 g, 20 mmol) and Pd(OH)2 on carbon (1.0 g). Place the reaction mixture on a Parr hydrogenator and shake at 50 psi of hydrogen. Monitor the progress of the reaction by thin-layer chromatography. Upon completion remove the catalyst by suction filtration through celite. Remove the solvent in vacuo to obtain the title compound.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([O:9][C:10]([NH:12][C:4]2=[CH:3][CH:2]=1)=[O:11])=O.[NH:13]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)C(=O)[C:14]1=O>N1C=CC=CC=1>[CH:20]1[CH:21]=[CH:22][C:23]2[N:13]=[C:14]3[N:12]([C:4]4[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=4[C:7]3=[O:9])[C:10](=[O:11])[C:18]=2[CH:19]=1
Reactant: O=C1Nc2ccccc2C1=O
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: c1ccncc1
Product: O=C1c2ccccc2-n2c1nc1ccccc1c2=O
Yield: 38.3 %

Procedure:
11 g (0.068 mol) of the isato acid anhydride of the aforesaid formula (1a-1), and 10 g (0.068 mol) of isatine represented by the following formula: ##STR75## and 20 ml of pyridine were heated under reflux for 6 hours in a 200 ml eggplant type flask to be reacted. After the reaction solution was cooled, a crystal precipitated in the reaction solution was filtered off to give 6.46 g (yield: 38%) of tryptanthrine represented by the following formula. ##STR76##
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=2)[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[OH:34][C:35]1[C:40]([Cl:41])=[CH:39][C:38]([Cl:42])=[CH:37][C:36]=1[S:43](Cl)(=[O:45])=[O:44]>C(Cl)Cl>[Cl:41][C:40]1[C:35]([OH:34])=[C:36]([S:43]([N:11]([CH2:10][C:9]2[CH:22]=[CH:23][CH:24]=[C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:26][CH:25]=3)[CH:8]=2)[CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)(=[O:45])=[O:44])[CH:37]=[C:38]([Cl:42])[CH:39]=1
Reactant: Fc1ccc(Oc2cccc(CNCCCCc3ccccc3)c2)cc1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1cc(Cl)cc(Cl)c1O)N(CCCCc1ccccc1)Cc1cccc(Oc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 0.3 %

Procedure:
To a mixture of N-(3-(4-fluorophenoxy)benzyl)-4-phenylbutan-1-amine (100 mg, 28.6 mmol, 1.0 eq) in DCM (5 mL), was added triethylamine (86 mg, 85 mmol, 3 eq) followed by 2-hydroxy-3,5-dichlorobenzenesulfonyl chloride (75 mg, 28.6 mmol, 1.0 eq). The reaction mixture was stirred at ambient temperature for 4 h before being diluted with DCM (100 mL) and washed with water. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by preparative HPLC to afford the title compound (45 mg, 28%); 1H NMR (400 MHz, CD3OD) δ 7.67-7.66 (d, 1H), 7.58-7.57 (d, 1H), 7.30-7.26 (t, 1H), 7.23-7.20 (t, 2H), 7.15-7.00 (m, 6H), 6.97-6.94 (m, 2H), 6.88-6.84 (m, 2H), 4.47 (s, 2H), 3.26-3.22 (t, 2H), 2.46-2.43 (t, 2H), 1.42-1.34 (m, 4H). MS (ESI): 574.0 (M−H)−.
Reaction SMILES: Cl[C:2](=[CH2:5])[C:3]#[N:4].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13].[Cl-].[K+]>CC(C)=O>[O:13]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][CH2:5][CH:2]1[C:3]#[N:4]
Reactant: Nc1ccccc1O
Reactant: C=C(Cl)C#N
Agent: [Cl-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#CC1CNc2ccccc2O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.3 %

Procedure:
Combine 2-chloro-2-propenenitrile (3.0 g, 34.3 mmol), 2-aminophenol (3.27 g, 29.96 mmol), acetone (50 mL), and potassium chloride (5 g, 36.18 mmol). Stir the mixture at ambient temperature for 16 hours. Filter the mixture and wash the filter cake with EtOAc. Concentrate the filtrate under reduced pressure to give a residue. Purify via flash column chromatography using a gradient of 1-50% EtOAc in petroleum ether to elute. Combine the product fractions and remove solvents under reduced pressure to provide the title compound (1.5 g, 21.6%). MS (m/z): 161 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([CH2:8][N:9]2[C:15](=[O:16])[CH:14]3[CH2:17][CH2:18][CH2:19][C:13]3=[N:12][C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]2=3)=[CH:6][CH:5]=1)([O-:3])=[O:2]>C(OCC)(=O)C.C(OCC)C>[N+:1]([C:4]1[CH:25]=[CH:24][C:7]([CH2:8][N:9]2[C:15](=[O:16])[C@H:14]3[CH2:17][CH2:18][CH2:19][C@H:13]3[NH:12][C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]2=3)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1C2CCCC2=Nc2ccccc2N1Cc1ccc([N+](=O)[O-])cc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=C1[C@H]2CCC[C@H]2Nc2ccccc2N1Cc1ccc([N+](=O)[O-])cc1
Yield: 46 %

Procedure:
Using 9-(4-nitrobenzyl)-2,3,9,10a-tetrahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one, synthesis was conducted by substantially the same procedure as in Working Example 24. The compound thus synthesized was purified by silica-gel column chromatography to afford the titled compound (yield 46%), m.p. 154°-155° C. (ethyl acetate-diethyl ether).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([C:11]2[S:12][C:13]([C:16]3[C:20]([CH3:21])=[C:19]([C:22]([F:25])([F:24])[F:23])[O:18][N:17]=3)=[CH:14][CH:15]=2)=[O:10])[CH2:4]1.Cl.[CH3:27][N:28]([CH2:30][C:31](Cl)=[O:32])[CH3:29].C(N(CC)CC)C>C1COCC1>[CH3:27][N:28]([CH3:29])[CH2:30][C:31]([NH:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([C:11]2[S:12][C:13]([C:16]3[C:20]([CH3:21])=[C:19]([C:22]([F:25])([F:24])[F:23])[O:18][N:17]=3)=[CH:14][CH:15]=2)=[O:10])[CH2:4]1)=[O:32]
Reactant: Cc1c(-c2ccc(C(=O)N3CCC[C@H](N)C3)s2)noc1C(F)(F)F
Reactant: CN(C)CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(C(=O)N3CCC[C@H](NC(=O)CN(C)C)C3)s2)noc1C(F)(F)F
Reaction time: 16 h
Yield: 77.6 %

Procedure:
A solution of ((S)-3-Amino-piperidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone, hydrochloride (Example 26, 79 mg, 0.20 mmol) in THF (3 mL) was treated with dimethylaminoacetyl chloride hydrochloride (40 mg, 0.24 mmol) followed by triethylamine (62 μL, 0.44 mmol). The resulting mixture was stirred for 16 hr, evaporated to an oil, and dissolved in water (3 mL). The solution was then basified with a saturated aqueous K2CO3 solution and the precipitated product filtered, washed with water, and air dried to afford product as a colorless solid (69 mg, 78%). 1H NMR (CDCl3) 1.62-1.72 (m, 2 H), 1.78-1.84 (m, 1 H), 1.94-2.04 (m, 1 H), 2.25 (s, 6 H), 2.32 (d, J=1.3, 3 H), 2.49 (s, 2 H), 3.24-3.40 (m, 2 H), 3.94-4.04 (m, 2 H), 4.12 (br d, J=13.2, 1 H), 7.23 (br d, J=7.5, 1 H), 7.44 (d, J=4.0, 1 H), 7.47 (br s, 1 H). 13C NMR 7.9, 23.5, 30.4, 45.6, 46.2, ˜51 (br), 63.2, 114.8, 118.8 (q, J=271), 128.3, 129.5, 131.6, 140.2, 155.1 (q, J=40), 157.9, 163.1, 170.7. 19F NMR −63.1. LC/MS 4.59 min, [M+1]+ 445.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5]([C:7]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)=[O:6]>CO.O.O>[Br:19][C:15]1[CH:14]=[C:13]([C:7]2([C:5]([OH:6])=[O:4])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)C1(c2cccc(Br)c2)CCOCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1(c2cccc(Br)c2)CCOCC1
Temperature: 65 °C
Reaction time: 5 h
Yield: 93.5 %

Procedure:
Lithium hydroxide (0.21 g, 5.01 mmol) is added to a solution of 4-(3-bromo-phenyl)-tetrahydro-pyran-4-carboxylic acid methyl ester (0.5 g, 1.67 mmol) in methanol/water (8 mL, 3:1) and the reaction mixture is stirred for 5 hours at 65° C. The mixture is diluted with water and the volatiles are removed in vacuo. The aqueous is extracted once with diethyl ether, acidified to pH 2, and extracted twice with ethyl acetate. The combined extracts is dried over magnesium sulfate, filtered and concentrated in vacuo to afford 4-(3-bromo-phenyl)-tetrahydro-pyran-4-carboxylic acid (445 mg) sed in the next step without further purification. LCMS: RT=1.9 minutes; MS: 283 (M−H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]3[C:14]([NH:25][C@@H:26]4[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]4)=[N:15][C:16](S(C)(=O)=O)=[N:17][C:18]=3[O:19][CH3:20])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[N:39]1[CH:44]=[CH:43][CH:42]=[C:41]([N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH:40]=1.C(N(C(C)C)C(C)C)C>CC#N>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]3[C:14]([NH:25][C@@H:26]4[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:37])([CH3:38])[CH3:36])=[O:33])[CH2:27]4)=[N:15][C:16]([N:48]4[CH2:49][CH2:50][N:45]([C:41]5[CH:40]=[N:39][CH:44]=[CH:43][CH:42]=5)[CH2:46][CH2:47]4)=[N:17][C:18]=3[O:19][CH3:20])[S:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: COc1nc(S(C)(=O)=O)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1-c1nc(-c2ccc(F)cc2)cs1
Reactant: c1cncc(N2CCNCC2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1nc(N2CCN(c3cccnc3)CC2)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1-c1nc(-c2ccc(F)cc2)cs1

Procedure:
A solution of tert-butyl (3R)-3-([5-[4-(4-fluorophenyl)-1,3-thiazol-2-yl]-2-methanesulfonyl-6-methoxypyrimidin-4-yl]amino)piperidine-1-carboxylate (45.0 mg, 0.08 mmol, 1.00 equiv), 1-(pyridin-3-yl)piperazine (15.6 mg, 0.10 mmol, 1.20 equiv) and N-ethyl-N-isopropylpropan-2-amine (20.7 mg, 0.16 mmol, 2.00 equiv) in CH3CN (6.0 mL) was heated for 15 h at 100° C. in an oil bath. Concentration under reduced pressure gave 80.0 mg (crude) of the title compound, which was used directly for next step without further purification. MS m/z [M+H]+ (ESI): 647.
Reaction SMILES: C1(=[O:8])NCCCCC1.[CH2:9]([C:11]([CH2:16][OH:17])([CH2:14][OH:15])[CH2:12]C)[OH:10].O>>[OH:10][CH2:9][C:11]([CH2:16][OH:17])([CH2:14][OH:15])[CH2:12][OH:8]
Reactant: O=C1CCCCCN1
Reactant: CCC(CO)(CO)CO
Solvent: O
Product: OCC(CO)(CO)CO

Procedure:
Similar viscosities are obtained by initially heating the polyalcohols (a) to (d) with polyphosphoric acid (= phosphoric acid dehydrated above 200° C.), resulting once again in the formation of acid semi-esters and diester mixtures through cleavage of the anhydridic phosphorus-oxygen-phosphorus bond. These acid semi-ester and di-ester mixtures are mixed with the multicomponent mixture of 1 mol of ε-caprolactam, 1 mol of trimethylol propane and 1 mol of water.
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[C:3]1[CH:4]=[C:5]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[N:34]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:35][CH3:36])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:10][N:9]=1.[OH-].[Na+].C(OCC)(=O)C>C(O)C>[F:49][C:2]([F:1])([F:48])[C:3]1[CH:4]=[C:5]([CH:41]=[C:42]([C:44]([F:45])([F:46])[F:47])[CH:43]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[N:34]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:35][CH3:36])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][N:13]=1
Reactant: CCCCN(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)OCC)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCN(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(butyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (110 mg) is dissolved in ethanol (2 ml) and thereto is added a 2N-aqueous sodium hydroxide solution (233 μl) and the mixture is stirred at room temperature overnight. Thereto are added ethyl acetate and a saturated aqueous citric acid solution, and the mixture is separated and the organic layer is washed with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to 7:3) to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(butyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid (69 mg). The resulting carboxylic acid is dissolved in ethanol (0.2 mL) and thereto is added 2N-aqueous sodium hydroxide solution (50 μl) and the reaction solution is concentrated under reduced pressure to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(butyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid sodium salt (70 mg). MS (m/z): 679 [M−Na]−
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][C:12](=[O:14])[CH3:13])[CH:5]=[C:4]([Cl:15])[N:3]=1.[N:16]1[C:25]2[C:20](=[CH:21][C:22]([CH2:26][NH2:27])=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.CCN(CC)CC>CC#N>[Cl:15][C:4]1[N:3]=[C:2]([NH:27][CH2:26][C:22]2[CH:21]=[C:20]3[C:25](=[CH:24][CH:23]=2)[N:16]=[CH:17][CH:18]=[CH:19]3)[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][C:12](=[O:14])[CH3:13])[CH:5]=1
Reactant: NCc1ccc2ncccc2c1
Reactant: CC(=O)Nc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(Cl)nc(NCc2ccc3ncccc3c2)c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 1 h
Yield: 61.6 %

Procedure:
To a mixture of N-(2,6-dichloro-3-nitropyridin-4-yl)acetamide (240 mg, 0.96 mmol) and quinolin-6-ylmethanamine (150 mg, 0.96 mmol) in CH3CN (10 mL) was added Et3N (0.5 mL). The reaction mixture was stirred at 80° C. for 1 h. After being cooled to room temperature, the mixture was purified by chromatography on silica gel eluting with DCM/MeOH=50/1 to afford the title compound (220 mg). MS (m/z): 372 (M+1)+.
Reaction SMILES: [CH2:1]([C:3]1[N:11]=[C:10]([O:12][CH3:13])[C:9]([NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:8][C:4]=1[C:5]([OH:7])=O)[CH3:2].[CH:30]1[C:43]2[C:34](=[N:35][C:36]3[C:41]([C:42]=2[NH:44][C:45]2[CH:46]=[C:47]([CH2:52][OH:53])[CH:48]=[C:49]([NH2:51])[CH:50]=2)=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:33]=[CH:32][CH:31]=1>>[CH:30]1[C:43]2[C:34](=[N:35][C:36]3[C:41]([C:42]=2[NH:44][C:45]2[CH:50]=[C:49]([NH:51][C:5]([C:4]4[CH:8]=[C:9]([NH:14][C:15]([N:17]5[CH2:18][CH2:19][N:20]([C:23]6[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=6)[CH2:21][CH2:22]5)=[O:16])[C:10]([O:12][CH3:13])=[N:11][C:3]=4[CH2:1][CH3:2])=[O:7])[CH:48]=[C:47]([CH2:52][OH:53])[CH:46]=2)=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:33]=[CH:32][CH:31]=1
Reactant: Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Reactant: CCc1nc(OC)c(NC(=O)N2CCN(c3cccc(F)c3)CC2)cc1C(=O)O
Product: CCc1nc(OC)c(NC(=O)N2CCN(c3cccc(F)c3)CC2)cc1C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Yield: 72.1 %

Procedure:
The same reaction procedure to the example 18 were carried out using 2-ethyl-5-{[4-(3-fluorophenyl)-piperazine-1-carbonyl]-amino}-6-methoxynicotinic acid and [3-(acridine-9-yl-amino)-5-aminophenyl]-methanol to give the titled compound.
Reaction SMILES: C[Al](C)C.[Cl-].[NH4+:6].C[O:8][C:9]([C:11]1[C:12]([S:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[N:13][S:14][C:15]=1[NH:16][C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1)=O>>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][S:23][C:12]2[C:11]([C:9]([NH2:6])=[O:8])=[C:15]([NH:16][C:17]3[N:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[S:14][N:13]=2)=[CH:26][CH:27]=1
Reactant: COC(=O)c1c(SCc2ccc(Cl)cc2)nsc1Nc1ncccn1
Reactant: [NH4+]
Agent: C[Al](C)C
Agent: [Cl-]
Product: NC(=O)c1c(SCc2ccc(Cl)cc2)nsc1Nc1ncccn1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 16.5 %

Procedure:
Trimethyl aluminum (2M/toluene, 2.55 mL, 5.1 mmol) is added to a dry flask containing ammonium chloride (272.3 mg, 5.1 mmol). The solution is then allowed to stir for 30 min and is added to a dry flask containing compound 21 (100 mg, 0.26 mmol). The reaction is then heated to 80° C. for 4 hours and then cooled to room temperature. The reaction is then carefully quenched with 1 N HCl and extracted with EtOAc (×3). The combined organics are dried over sodium sulfate, filtered and concentrated in vacuo. Column chromatography (20%→50% EtOAc/methylene chloride) provides 3-(4-Chloro-benzylsulfanyl)-5-(pyrimidin-2-ylamino)-isothiazole-4-carboxylic acid amide (16.2 mg, 17%) in addition to the starting material 21 (36.6 mg). 1H NMR (d6 DMSO): δ 11.61 (1H, br. s), 8.73 (2H, d, J=5.0 Hz), 7.43 (2H, d, J=8.4 Hz), 7.34 (2H, d, J=8.4 Hz), 7.15 (1H, dd, J=5.0, 5.0 Hz), 4.46 (2H, s). LRMS (M+): 378.1, (M−): 376.0.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[OH:7][C@@H:8]1[C:13]2=[C:14]3[C:23](=[C:24]([O:26][CH3:27])[CH:25]=[C:12]2[O:11][C:10]([CH3:35])([CH3:34])[C@@H:9]1[OH:36])[C:22](=[O:28])[C:21]1[C:16](=[CH:17][CH:18]=[C:19]2[CH:32]=[CH:31][CH:30]=[CH:29][C:20]2=1)[N:15]3[CH3:33]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:1]([O:36][C@H:9]1[C:10]([CH3:34])([CH3:35])[O:11][C:12]2[C:13](=[C:14]3[C:23](=[C:24]([O:26][CH3:27])[CH:25]=2)[C:22](=[O:28])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]4[CH:32]=[CH:31][CH:30]=[CH:29][C:20]4=2)[N:15]3[CH3:33])[C@H:8]1[OH:7])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: COc1cc2c(c3c1c(=O)c1c4ccccc4ccc1n3C)[C@@H](O)[C@@H](O)C(C)(C)O2
Reactant: CCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCCC(=O)O[C@@H]1[C@H](O)c2c(cc(OC)c3c(=O)c4c5ccccc5ccc4n(C)c23)OC1(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Add 2 equivalents of butyryl chloride to a solution of 0.74 mmol of the compound of Example 4 in the presence of 4-dimethylaminopyridine in 7 ml of anhydrous pyridine. Stir at ambient temperature for 72 hours and then add 5 equivalents of butyryl chloride and resume stirring for 72 hours; then evaporate to dryness. Chromatography over silica gel allows the expected product to be isolated.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[CH:9][C:8]=1[Cl:17].C[O:19][B:20](OC)[O:21]C.Cl>C1COCC1>[Cl:17][C:8]1[CH:9]=[C:10]([O:13][CH:14]([CH3:16])[CH3:15])[CH:11]=[CH:12][C:7]=1[B:20]([OH:21])[OH:19]
Reactant: COB(OC)OC
Reactant: CC(C)Oc1ccc(Br)c(Cl)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(B(O)O)c(Cl)c1
Temperature: 25 °C
Yield: 43.7 %

Procedure:
n-Butyllithium (1.6 M solution in hexanes, 23.5 mmol, 14.7 mL) was added to 1-bromo-2-chloro-4-iso-propoxybenzene (19.4 mmol, 4.85 g) in THF (120 mL) at −78° C. under an atmosphere of nitrogen. After stirring for thirty minutes the trimethylborate (76.6 mmol, 8.7 mL) was added over twenty minutes. The reaction was allowed to warm to room temperature overnight while stirring. The solution was then acidified with HCl (3 M, 200 mL), and extracted into EtOAc. The EtOAc was then extracted with NaOH (1 N, 4×100 mL), which was subsequently acidified with concentrated HCl forming (2-Chloro-4-iso-propoxyphenyl)boronic acid (1.82 g, 44%) as a white precipitate, which was filtered and dried. 1H NMR (CD3OD, 300 MHz): 7.19 (1H, d, J 8.4 Hz), 6.87 (1H, d, J 2.2 Hz), 6.82 (1H, dd, J 8.4 and 2.2 Hz), 4.58 (1H, m), 1.28 (6H, d, J 5.9 Hz.)
Reaction SMILES: [NH:1]([C:5]1[CH:27]=[CH:26][C:8]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[C:2]([CH3:4])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH2:2]([NH:1][C:5]1[CH:27]=[CH:26][C:8]([CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][CH:14]([N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18]3)[CH2:15][CH2:16]2)=[CH:7][CH:6]=1)[CH3:4]
Reactant: CC(=O)Nc1ccc(CCN2CCC(N3CCc4ccccc43)CC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCNc1ccc(CCN2CCC(N3CCc4ccccc43)CC2)cc1
Yield: 30.8 %

Procedure:
1-[1-(4-Acetaminophenethyl)piperidin-4-yl]indoline (135 mg) was dissolved in tetrahydrofuran (5 ml). After adding lithium aluminum hydride (28 mg) at room temperature, the resultant mixture was heated under reflux for 2 hr. After adding water, the reaction solution was extracted with ethyl acetate. Then the organic layer was washed with brine and dried over magnesium sulfate. After evaporating the solvent, the obtained residue was purified by NH-silica gel column chromatography (hexane/ethyl acetate system) to give the title compound (40 mg) as an oil.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:25]=[CH:24][C:6]([C:7]([NH:9][C:10](=S)[NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[O:8])=[CH:5][CH:4]=1.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH2:35])[N:30]=1>CN(C=O)C.C(OCC)(=O)C>[NH2:28][C:29]1[N:30]=[C:31]([NH:35]/[C:10](/[NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:9]\[C:7](=[O:8])[C:6]2[CH:24]=[CH:25][C:3]([C:2]([F:27])([F:26])[F:1])=[CH:4][CH:5]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: O=C(NC(=S)NCc1ccccc1C(F)(F)F)c1ccc(C(F)(F)F)cc1
Reactant: Nc1cccc(N)n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1cccc(N/C(=N\C(=O)c2ccc(C(F)(F)F)cc2)NCc2ccccc2C(F)(F)F)n1
Temperature: 25 °C
Yield: 55.3 %

Procedure:
A solution of 4-(trifluoromethyl)-N-((2-(trifluoromethyl)benzyl)carbamothioyl) benzamide (2.0 g, 4.92 mmol), 2,6-diaminopyridine (591 mg, 5.41 mmol), and 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (EDC hydrochloride) (1.13 g, 5.91 mmol) in DMF (49 mL) was heated to 65° C. for 30 minutes, then allowed to cool to room temperature. The mixture was then diluted with ethyl acetate, washed with aqueous sodium bicarbonate solution, washed with brine, dried over sodium sulfate, and concentrated to provide the crude product. The crude product was purified by chromatography (gradient: 9:1 hexanes:EtOAc to 6:4 hexanes:EtOAc) to provide (Z)-N-(((6-aminopyridin-2-yl)amino)((2-(trifluoromethyl) benzyl)amino)methylene)-4-(trifluoromethyl)benzamide as a yellow solid (1.31 g, 55% yield).
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[Cl:28])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:30][CH3:31].C(N(CC)C(C)C)(C)C>C1COCC1>[CH2:30]([N:13]1[CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[Cl:28])=[CH:17][CH:16]=2)[CH2:9][C@@H:8]1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:31]
Reactant: CCBr
Reactant: Cc1ccc(Cl)c(-c2ccc(CN3CCN[C@@H](Cc4ccccc4)C3)cc2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCN1CCN(Cc2ccc(-c3cc(C)ccc3Cl)cc2)C[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
This compound was made in the following manner: 50 mg of 3-(S)-benzyl-1-(2′-chloro-5′-methyl-biphenyl-4-ylmethyl)-piperazine was dissolved in THF, 2 equ. of bromoethane and 2 equ. of N,N-diisopropylethylamine were added. The reaction was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was diluted with DCM, washed with saturated aqueous sodium bicarbonate solution, then dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography to afford the title compound as the free base. Treatment with 1 equ. 1M HCl in dioxane and concentration in vacuo afforded 29.5 mg of the corresponding hydrochloride salt. Yield 51%, ES MS m/z 419/421.