Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:8])[NH2:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[CH3:14][S:15][C:16]1[S:20][C:19]([C:21]#[N:22])=[CH:18][C:17]=1[S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:27]=1)(=[O:25])=[O:24]>C1COCC1>[C:1]([O:5][C:6](=[O:8])[NH:7][C:21](=[NH:22])[C:19]1[S:20][C:16]([S:15][CH3:14])=[C:17]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[CH:27]=2)(=[O:25])=[O:24])[CH:18]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(N)=O
Reactant: CSc1sc(C#N)cc1S(=O)(=O)c1cccc(N2CCCCC2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(N2CCCCC2)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 38.1 %

Procedure:
To a solution of carbamic acid tert-butyl ester (8 mg, 0.069 mmol, Aldrich Chemical Company) in 1 mL of THF at −78° C. was added 35 uL of n-BuLi under Ar. The mixture was stirred at −78° C. for 15 min. A solution of 5-methylsulfanyl-4-(3-piperidin-1-yl-benzenesulfonyl)-thiophene-2-carbonitrile (20 mg, 0.053 mmol, Example 286: step g) in 1 mL of THF was added. The resulting mixture was stirred at RT for 5 h, then at 50° C. overnight. Cooled to RT, the mixture was purified directly by PTLC (20% EtOAc/hexane) to give 10 mg (38%) of product as colorless oil: 1H-NMR (CDCl3; 400 MHz) δ 8.42 (s, 1H), 7.74 (dd, 1H, J=1.6, 1.6 Hz), 7.67 (s, 1H), 7.62 (ddd, 1H, J=7.5, 1.6, 1.6 Hz), 7.57 (d, 1H, J=7.5, 1.6, 1.6 Hz), 7.52 (dd, 1H, J=7.5, 7.5), 3.42–3.40 (m, 4H), 2.54 (s, 3H), 1.64 (br s, 6H), 1.61 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C22H29N3O4S3, 496.1 (M+H), found 495.9.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[N:23][N:24]([CH3:27])[C:25]=4[NH2:26])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37](=O)[CH3:38])=[CH:31][CH:30]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[N:23][N:24]([CH3:27])[C:25]=4[NH:26][CH:37]([CH3:38])[CH2:36][CH2:35][C:32]4[CH:31]=[CH:30][C:29]([Cl:28])=[CH:34][CH:33]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(=O)CCc1ccc(Cl)cc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4cnn(C)c4N)cc3)cc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4cnn(C)c4NC(C)CCc4ccc(Cl)cc4)cc3)cc2)CC1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
1-[4′-(5-Amino-1-methyl-1H-pyrazol-4-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.125 g, 0.346 mmol) and 4-(4-chloro-phenyl)-butan-2-one (0.095 g, 0.52 mmol) were dissolved in MeOH (5 mL). Acetic acid (0.030 mL, 0.52 mmol) was added along with a few molecular sieves and the reaction stirred at 30° C. overnight. Sodium cyanoborohydride (0.033 g, 0.52 mmol) was then added and the reaction was heated to 60° C. for 4 hours. An additional 0.5 equivalents of sodium cyanoborohydride was added and the reaction continued heating for 1 hour. All solvent was removed and the residue was submitted to EtOAc/H2O workup. The residue was purified twice on silica gel (0-100% EtOAc in hexanes followed by 0-10% MeOH in CH2Cl2) to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=O)[NH:8][S:9][C:5]=2[CH:4]=1.CN(C)C=O.S(Cl)([Cl:20])=O>ClC1C=CC=CC=1>[Cl:20][C:7]1[C:6]2[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[S:9][N:8]=1
Reactant: COc1ccc2c(=O)[nH]sc2c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Clc1ccccc1
Product: COc1ccc2c(Cl)nsc2c1
Reaction time: 1 h
Yield: 88 %

Procedure:
A 1 L four-neck flask equipped with a stirrer, a thermometer and a condenser tube was charged with 90.6 g (0.5 mol) of 6-methoxy-1,2-benzisothiazol-3-one, 109.6 g (1.5 mol) of N,N-dimethylformamide and 150.0 g of chlorobenzene. While stirring, 89.2 g (0.75 mol) of thionyl chloride was added dropwise thereto at 80° to 90° C. over 1 hour, and the mixture was reacted at the same temperature for 5 hours. After terminating the reaction, the liquid reaction mixture was concentrated, and a crude product obtained was recrystallized from cyclohexane to give 86.9 g (0.44 mol) of 3-chloro-6-methoxy-1,2-benzisothiazole. The yield based on 6-methoxy-1,2-benzisothiazol-3-one was 87%.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)O.[CH2:9]([O:11][C:12]([O:15][CH2:16][CH3:17])([CH3:14])[CH3:13])[CH3:10].[CH2:18](O)C.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH2:9]([O:11][C:12]1([CH3:14])[CH2:13][C:1]([CH3:3])([CH3:18])[C:8]2[C:16](=[CH:17][C:4]([OH:5])=[CH:6][CH:7]=2)[O:15]1)[CH3:10]
Reactant: Oc1cccc(O)c1
Reactant: CCOC(C)(C)OCC
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCOC1(C)CC(C)(C)c2ccc(O)cc2O1
Yield: 51.2 %

Procedure:
100 ml stainless steel autoclave was charged with 2.2 g (20 mmol) of resorcin, 5.28 g (40 mmol) of acetone diethyl acetal, 9.2 g (200 mmol) of ethanol, 0.2 g (2 mmol) of conc. sulfuric acid and 40 ml of toluene, then sealed and allowed to react at 100° C. for 3 hours. After similar working up as in Example 45, 2.42 g (51.3%) of 2-ethoxy-7-hydroxy-2,4,4-trimethylchroman was obtained.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([CH3:3])C.[CH3:11]S(C)=O.Cl[C:16]1[C:21]([CH3:22])=[CH:20][C:19]([N+:23]([O-:25])=[O:24])=[CH:18][N:17]=1>>[CH3:22][C:21]1[C:16]([O:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([CH2:1][CH2:3][CH3:11])[CH:5]=2)=[N:17][CH:18]=[C:19]([N+:23]([O-:25])=[O:24])[CH:20]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Reactant: CC(C)c1cccc(O)c1
Reactant: CS(C)=O
Product: CCCc1cccc(Oc2ncc([N+](=O)[O-])cc2C)c1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
To a solution of 3-isopropylphenol (174 mg, 1.28 mmol) in DMSO (5 mL) tBuOK (143 mg, 1.28 mmol) was added and the reaction mixture was stirred at 20° C. for 30 mins. 2-chloro-3-methyl-5-nitropyridine (200 mg, 1.16 mmol) was added and the resulting mixture was stirred at 120° C. for 2 hrs. The reaction mixture was cooled to r. t., poured into ice-water (20 ml) and extracted with DCM (3×50 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated to afford the title compound (279 mg) as a light red oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(N(CC)CC)C.[CH3:17][C:18]1[N:26]([C:27]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)=[O:28])[C:25]2[CH:24]=[CH:23][C:22]([O:36][CH3:37])=[CH:21][C:20]=2[C:19]=1[CH2:38][C:39](O)=[O:40].O>C(Cl)Cl>[CH:5]([C:4]1[CH:3]=[C:2]([O:1][C:39](=[O:40])[CH2:38][C:19]2[C:20]3[C:25](=[CH:24][CH:23]=[C:22]([O:36][CH3:37])[CH:21]=3)[N:26]([C:27](=[O:28])[C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[C:18]=2[CH3:17])[CH:9]=[CH:8][CH:7]=1)=[O:6]
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: O=Cc1cccc(O)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc2c(c1)c(CC(=O)Oc1cccc(C=O)c1)c(C)n2C(=O)c1ccc(Cl)cc1

Procedure:
To a solution of 3-hydroxybenzaldehyde (g 8.30) and triethylamine (g 0.824) in methylene chloride (200 ml), cooling at a temperature in the range −5° C.-0° C. indomethacin in the form of the corresponding acylchloride (g 16.50) is added under stirring. It is still maintained under stirring for 15 minutes, then water (100 ml) is added and the phases are separated. The aqueous phase is recovered and extracted with methylene chloride (300 ml). The organic phases are joined together, washed with a 5% Na2CO3 solution, the organic phase is anhydrified with sodium sulphate obtaining the expected compound.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]#[N:20])[CH:18]=[C:13]3[C:12]([C:21]3[CH:22]=[C:23]([CH:44]=[CH:45][CH:46]=3)[CH2:24][NH:25][C:26]([C:28]3[C:29](=[O:43])[N:30]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([F:41])=[C:37]([F:42])[CH:36]=4)[CH:31]=[CH:32][CH:33]=3)=[O:27])=[CH:11]2)(=O)=O)C=CC=CC=1.[N-:47]=[N+:48]=[N-:49].[Na+].[Cl-].[NH4+]>CN(C)C=O>[NH:47]1[C:19]([C:17]2[CH:18]=[C:13]3[C:12]([C:21]4[CH:22]=[C:23]([CH:44]=[CH:45][CH:46]=4)[CH2:24][NH:25][C:26]([C:28]4[C:29](=[O:43])[N:30]([CH2:34][C:35]5[CH:40]=[CH:39][C:38]([F:41])=[C:37]([F:42])[CH:36]=5)[CH:31]=[CH:32][CH:33]=4)=[O:27])=[CH:11][NH:10][C:14]3=[N:15][CH:16]=2)=[N:20][N:49]=[N:48]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cnc2c(c1)c(-c1cccc(CNC(=O)c3cccn(Cc4ccc(F)c(F)c4)c3=O)c1)cn2S(=O)(=O)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NCc1cccc(-c2c[nH]c3ncc(-c4nnn[nH]4)cc23)c1)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Temperature: 110 °C
Reaction time: 4 h

Procedure:
1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(1-benzenesulfonyl-5-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzylamide (64 mg, 0.00010 mol) was dissolved in N,N-dimethylformamide (1.0 mL, Acros) and sodium azide (11 mg, 0.00017 mol; Aldrich) and then ammonium chloride (5 mg, 0.00009 mol; Aldrich) was added. The mixture was heated at 110° C. for 1.5 hours under an atmosphere of Argon. Additional sodium azide (29 mg, 0.00045 mol; Aldrich) and ammonium chloride (19 mg, 0.00036 mol; Aldrich) were added and the reaction was heated at 110° C. under an atmosphere of Argon. After 4 h (total), the reaction was diluted with N,N-dimethylformamide, filtered and purified by preparative HPLC to yield the product in 2.0 mg yield (3%). MS m/z=539.07 M+H.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][N:5]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CC(C)=O>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:20])[CH2:4][N:5]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:15][CH:14]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: BrCc1ccccc1
Reactant: COC(=O)CN(C(=O)OC(C)(C)C)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)CN(C(=O)OC(C)(C)C)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 65.3 %

Procedure:
The N-Boc p-hydroxy phenyl glycine methyl ester from step (300a) (123.0 g, 440 mmol) was combined with benzyl bromide (90.3 g, 528 mmol), potassium carbonate (182 g, 1.3 mol) and acetone (800 mL) under a nitrogen atmosphere. The reaction was heated to reflux for 5 h, allowed to cool to rt, diluted with ethyl acetate (800 mL) filtered to remove the solids and concentrated in vacuo to give a semisolid residue. The product was crystallized from ethyl ether to give the N-Boc p-benzyloxy phenyl glycine methyl ester (106.7 g, 65%) as a white powder. MS (M+H)+ =372, (M+NH4)+ =389.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[C:15](=[O:20])[C:16](=[N:18]O)[CH3:17].O.[ClH:22]>C(O)C.[Pd]>[ClH:22].[NH2:18][CH:16]([CH3:17])[C:15]([C:4]1[CH:5]=[C:6]([O:13][CH3:14])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[O:2][CH3:1])=[O:20]
Reactant: COc1cc(C(=O)C(C)=NO)c(OC)c2ccccc12
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)C(C)N)c(OC)c2ccccc12
Reaction time: 12 h

Procedure:
To a solution of 1-(1,4-dimethoxynaphthalen-2-yl)-propane-1,2-dione 2-oxime (1 g, 3.66 mmol, Example 2, Step B) in 1 M hydrogen chloride in ethanol (50 mL) was added Pd/C 10% (100 mg), The mixture was hydrogenated on a Parr hydrogenator apparatus under 40–50 psi pressure for 12 h. The catalyst was separated by filtration and the solvent removed in vacuo to give a white solid: 1H NMR (DMSO-d) δ 1.14 (d, 3H, CH3), 3.96 (s, 3H, OH3), 4.01 (s, 3H, OCH3), 5.03 (m, 1H, CH), 7.08 (s, 1H, Ar—H), 7.73 (m, 2H, Ar—H), 8.19 (m, 2H, Ar), 8.50 (bs, 3H, NH3+); Analysis calcd. for C15H17NO3.HCl.0.2 H2O: C, 53.62; H, 5.88; N, 4.81. Found: C, 53.53; H, 5.56; N, 4.77.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][CH2:19][CH2:20][C:21]1[O:25][C:24]([NH2:26])=[N:23][N:22]=1>>[CH3:17][O:18][CH2:19][CH2:20][C:21]1[O:25][C:24]([NH:26][C:8](=[O:9])[CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:23][N:22]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: COCCc1nnc(N)o1
Product: COCCc1nnc(NC(=O)C(c2ccccc2)c2ccccc2)o1

Procedure:
The title compound, white solid, m.p. 114-115° C. and MS: m/e=338.2 (M+H+) was prepared in accordance with the general method of example 44a from 2,2-diphenylacetic acid chloride and [5-(2-methoxy-ethyl)-[1,3,4]oxadiazol-2-yl]-amine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([NH2:8])[CH:7]=1.[CH3:19]OC(OC)OC.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>CN(C=O)C.C(O)(=O)C>[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[N:9]=[CH:19][NH:8][C:6]=2[CH:7]=1
Reactant: COC(OC)OC
Reactant: Nc1cc(Cl)c(Oc2ccccc2)cc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Clc1cc2[nH]cnc2cc1Oc1ccccc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To a solution of 5-chloro-2-nitro-4-phenoxyphenylamine (0.810 g, 3.06 mmol) in DMF (12 mL) was added trimethylorthoformate (12 mL) followed by sodium dithionite (2.66 g, 15.3 mmol), and glacial acetic acid (1.5 mL). The reaction mixture was heated in a sealed tube at 100° C. for 14 h. Additional sodium dithionite (0.5 g) and acetic acid (1 mL) were added and heating was continued at 120° C. for an additional 3 h. The reaction flask was cooled in ice, added cautiously to half-saturated sodium bicarbonate solution (300 mL) and extracted with EtOAc. Combined organic layers were washed with 5% NaHCO3, brine, dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (hexanes:EtOAc, 0% to 5% over 20 minutes) to yield the titled compound as a yellow amorphous solid (0.57 g, 76%) as a mixture of tautomers. MS (ESI/CI): mass calcd. for C13H9ClN2O, 244; m/z found, 245 [M+H]+. 1H NMR (500 MHz, CDCl3): 9.55 (s, 1H), 8.06 (s, 1H), 8.0-7.2 (m, 2H), 7.32 (t, J=7.9 Hz, 2H), 7.09 (t, J=7.3 Hz, 1H), 6.96 (d, J=8.3 Hz, 2H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([CH:12]1[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:19][C:18]3[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=3)=[O:11])[CH2:2]2.[Br:26][CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[Br-:26].[O:30]([CH2:29][CH2:28][CH2:27][N+:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([CH:12]1[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[O:19][C:20]3[C:25]1=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:11])[CH2:2]2)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrCCCOc1ccccc1
Reactant: O=C(N[C@H]1CN2CCC1CC2)C1c2ccccc2Oc2ccccc21
Solvent: C1CCOC1
Product: O=C(N[C@H]1C[N+]2(CCCOc3ccccc3)CCC1CC2)C1c2ccccc2Oc2ccccc21
Product: [Br-]
Temperature: 25 °C
Reaction time: 17 h
Yield: 98.1 %

Procedure:
0.3 g (0.00089 mol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-9H-xanthene-9-carboxamide (Example 31) were dissolved in 6 ml of THF. To this solution 0.21 ml (0.287 g, 0.001335 mol) of (3-bromopropoxy)benzene were added. The mixture was refluxed during 4 hours and then stirred 17 h at room temperature. The reaction mixture was filtered and the solid obtained washed with ether several times and dried. 0.48 g (98%) of the title product were obtained.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH3:14])[CH2:4][C:5]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)([OH:7])C.[Cl:15][C:16]1[C:23]([CH3:24])=[C:22](F)[CH:21]=[CH:20][C:17]=1[C:18]#[N:19].[CH3:26]N1C(=O)CCC1>>[Cl:15][C:16]1[C:23]([CH3:24])=[C:22]([NH:1][CH2:2][C:3]([CH3:14])([CH3:26])[CH2:4][CH:5]([OH:7])[C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:21]=[CH:20][C:17]=1[C:18]#[N:19]
Reactant: CN1CCCC1=O
Reactant: CC(CN)CC(C)(O)c1cccnc1
Reactant: Cc1c(F)ccc(C#N)c1Cl
Product: Cc1c(NCC(C)(C)CC(O)c2cccnc2)ccc(C#N)c1Cl
Yield: 51 %

Procedure:
Heat a solution of 5-amino-4-methyl-2-pyridin-3-yl-pentan-2-ol (630 mg, 3.24 mmol) and 2-chloro-4-fluoro-3-methyl-benzonitrile (493 mg, 2.92 mmol) in NMP (2 mL) at 120° C. for 2 h in a microwave reactor. Purify the crude product by SCX to obtain 570 mg (51%) of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([F:13])=[CH:8][C:7]=1[F:14])=[O:4].[CH2:15]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]2[N:38]([C:39]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:37]=[N:36][N:35]=2)=[CH:24][CH:23]=1)[CH2:16][CH2:17][CH2:18][CH3:19].[I-].[K+].C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[CH2:15]([N:20]([CH2:2][C:3]([NH:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([F:13])=[CH:8][C:7]=1[F:14])=[O:4])[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]2[N:38]([C:39]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)([C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)[C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)[N:37]=[N:36][N:35]=2)=[CH:26][CH:27]=1)[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=C(CCl)Nc1c(F)cc(F)cc1F
Reactant: CCCCCNCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCCN(CC(=O)Nc1c(F)cc(F)cc1F)Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 80 °C
Yield: 41.9 %

Procedure:
N-(Chloroacetyl)-2,4,6-trifluoroaniline (313.0 mg), N-pentyl-N-[[2′-[N-(triphenylmethyl)tetrazol-5-yl]-1,1′-biphenyl-4-yl]methyl]amine (780.0 mg), potassium iodide (230 mg) and triethylamine (2.1 g) were suspended in dimethylformamide (12 mL). The resulting mixture was heated to about 80° C., and then stirred at that temperature. Three hours later, the reaction mixture was cooled, ethyl acetate (100 mL) was added, and the mixture was washed four times with brine (200 mL, each). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column (hexane/ethyl acetate) to afford N-pentyl-N-[[[(2,4,6-trifluorophenyl)amino]carbonyl]methyl]-N-[[2′-[N-(triphenylmethyl)tetrazol-5-yl]-1,1′-biphenyl-4-yl]methyl]amine (434.8 mg). Yield: 42%.
Reaction SMILES: C([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1)(=O)C.[Se](=O)=[O:15].[O:17]1[CH2:22][CH2:21][O:20]CC1>O>[OH:15][CH:21]([OH:20])[C:22]([C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[CH:12][CH:13]=[CH:4][CH:5]=2)[CH:10]=1)=[O:17]
Reactant: CC(=O)c1ccc2ccccc2c1
Reactant: O=[Se]=O
Reactant: C1COCCO1
Solvent: O
Product: O=C(c1ccc2ccccc2c1)C(O)O

Procedure:
A mixture of 45.1 g of 2'-acetonaphthone, 29.4 g of selenium dioxide, 350 ml of dioxane and 7.0 ml of water was stirred, heated carefully to reflux and maintained at reflux for 3 hours. The mixture was cooled, filtered through diatomaceous earth and the filtrate evaporated in vacuo. The residue was treated with 300 ml of water and the resulting white solid collected and recrystallized from aqueous acetone giving the desired product as white crystals, mp 103°-120° C.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:14][CH3:15])=[C:9]([N+:16]([O-])=O)[CH:8]=1)=[O:5].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:31]([N:38]1[C:42](=[O:43])[C:41](=[C:44]2[N:48]([CH3:49])[C:47]3[CH:50]=[CH:51][CH:52]=[CH:53][C:46]=3[S:45]2)[S:40][CH2+:39]1SC)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([N:38]1[C:42](=[O:43])[C:41](=[C:44]2[N:48]([CH3:49])[C:47]3[CH:50]=[CH:51][CH:52]=[CH:53][C:46]=3[S:45]2)[S:40][C:39]1=[N:16][C:9]1[CH:8]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][N:2]([CH3:19])[CH3:1])[CH:12]=[CH:11][C:10]=1[NH:13][CH2:14][CH3:15])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CS[CH2+]1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Reactant: CCNc1ccc(NC(=O)CN(C)C)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(NC(=O)CN(C)C)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to Example 30, intermediate 2-dimethylamino-4′-ethylamino-3′-nitroacetanilide was hydrogenated and then condensed with 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate to afford the title compound. 1H-NMR (CDCl3): δ 8.85 (1H, s), 7.43 (3H, t), 7.18-7.28 (5H, m), 7.10 (2H, t), 6.95 (1H, d), 6.48 (1H, d), 5.10 (2H, s), 3.71 (3H, s), 3.03 (2H, s), 2.93 (2H, q), 2.33 (6H, s), 0.97 (3H, t); MS(ESI): 584(MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.Cl[C:24]([O:26][CH2:27]C(C)C)=[O:25].[N+](=C)=[N-]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][C:24]([O:26][CH3:27])=[O:25])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Reactant: CC(C)COC(=O)Cl
Agent: C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)CC1CCCN1C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a stirred solution of pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 35 (10 g, 46.46 mmol) in dry THF were added drop wise N-methyl morpholine (6.4 mL, 58.1 mmol) and isobutyl chloroformate (6.7 mL, 65.1 mmol) at −30° C. The reaction mixture was stirred at same temperature for one hour and diazomethane solution (prepared in situ) was added at −30° C. The resulting mixture was allowed to stir at rt overnight. Excess diazomethane was quenched with acetic acid (15 mL) and evaporated under reduced pressure. The residue was dissolved in ether and washed with water and brine. The organic layer was dried over anhydrous Na2SO4, filtered and evaporated. The residue was dissolved in methanol (100 mL) and Ag2O (5.5 g) was added portion-wise at ice-cold conditions, and then allowed to stir at rt for 2 hours. Chloroform was added, filtered through Celite® reagent and washed with methanol. The filtrate was concentrated and the crude material was purified by chromatography on silica-gel (230-400 mesh) eluting with 1-5% of ethyl acetate-hexane to get light yellow liquid compound 36.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH2:11][CH3:12])=[N:7][C:6]=2[CH:13]=1.[C:14]1([CH3:26])[CH:19]=[CH:18][C:17]([S:20]([O:23]CC)(=[O:22])=[O:21])=[CH:16][CH:15]=1.[CH3:27][CH2:28]OCC>CC(C)=O>[S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH3:26])=[CH:15][CH:16]=1)([O-:23])(=[O:22])=[O:21].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH2:11][CH3:12])=[N+:7]([CH2:27][CH3:28])[C:6]=2[CH:13]=1
Reactant: CCSc1nc2cc(Cl)ccc2s1
Reactant: CCOCC
Reactant: CCOS(=O)(=O)c1ccc(C)cc1
Solvent: CC(C)=O
Product: CCSc1sc2ccc(Cl)cc2[n+]1CC
Product: Cc1ccc(S(=O)(=O)[O-])cc1

Procedure:
5-Chloro-2-(ethylthio)benzothiazole (11.5 g, 0.05 mol) and 10.55 g ethyl p-toluenesulfonate were heated at 150°-160° C. for 2 hours. After cooling, the product was dissolved in acetone and poured into 400 ml stirred anhydrous ether. The resulting precipitated oil crystallized upon scraping with a spatula. The ether was decanted, the solid triturated with ether, and the ether again decanted to yield 11.04 g (51%) after air drying.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH:6]=[N:7][OH:8].CN(C=O)C.[Cl:14]N1C(=O)CCC1=O>[Cl-].[Na+].O>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6](=[N:7][OH:8])[Cl:14]
Reactant: ON=CC1CCCO1
Reactant: O=C1CCC(=O)N1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: ON=C(Cl)C1CCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.3 %

Procedure:
A 250 mL round-bottomed flask was charged with tetrahydrofuran-2-carbaldehyde oxime (2.0 g, 17 mmol) and DMF (100 mL). 1-chloropyrrolidine-2,5-dione (2.3 g, 17 mmol) was added and stirred at ambient temperature overnight. The reaction was poured into 1:1 brine:water (800 mL) and extracted with EtOAc (500 mL). The organic layer was washed twice with water, dried over sodium sulfate, filtered and concentrated to afford the title compound (2.6 g, 100%).