Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=[C:11]2[C:31]2[CH:32]=[N:33][C:34]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:35][C:36]=2[O:37][CH2:38][CH3:39])=[O:9])[CH2:4][CH2:3]1.[CH:44]1([N:49]=[C:50]=[O:51])[CH2:48][CH2:47][CH2:46][CH2:45]1>>[C:40]([C:34]1[N:33]=[CH:32][C:31]([C:11]2[N:10]([C:8]([N:5]3[CH2:4][CH2:3][CH:2]([NH:1][C:50]([NH:49][CH:44]4[CH2:48][CH2:47][CH2:46][CH2:45]4)=[O:51])[CH2:7][CH2:6]3)=[O:9])[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=2)=[C:36]([O:37][CH2:38][CH3:39])[CH:35]=1)([CH3:42])([CH3:41])[CH3:43]
Reactant: O=C=NC1CCCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(NC(=O)NC2CCCC2)CC1

Procedure:
In a manner similar to the method described in example 160, (4-amino-piperidin-1-yl)-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-methanone (example 204) was reacted with cyclopentyl isocyanate (Aldrich) to give the title compound. LC-MS (ES+) 733 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.[CH:16]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][CH2:26][C:27]2[CH:28]=[N:29][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:31][CH:32]=2)=[CH:21][CH:20]=1)([CH3:18])[CH3:17]>>[CH:16]([C:19]1[CH:20]=[CH:21][C:22]([N:25]([CH2:26][C:27]2[CH:28]=[N:29][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:31][CH:32]=2)[C:13]([CH:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH2:7][CH2:8][CH2:9]2)=[O:15])=[CH:23][CH:24]=1)([CH3:18])[CH3:17]
Reactant: CC(C)c1ccc(NCc2ccc(C(C)C)nc2)cc1
Reactant: COc1ccc2c(c1)C(C(=O)O)CCC2
Product: COc1ccc2c(c1)C(C(=O)N(Cc1ccc(C(C)C)nc1)c1ccc(C(C)C)cc1)CCC2
Yield: 17.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.31 g) and (4-isopropylphenyl)[(6-isopropylpyridin-3-yl)methyl]amine (0.46 g) as starting materials, N-(4-isopropylphenyl)-N-[(6-isopropylpyridin-3-yl)methyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.12 g) was obtained.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[N:10]=[C:9]([NH:11][CH3:12])[C:8]([N+:13]([O-:15])=[O:14])=[CH:7][CH:6]=1.O>CO>[CH3:1][O:2][C:5]1[N:10]=[C:9]([NH:11][CH3:12])[C:8]([N+:13]([O-:15])=[O:14])=[CH:7][CH:6]=1
Reactant: C[O-]
Reactant: CNc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNc1nc(OC)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
19 ml of a 28% methanolic solution of sodium methoxide were added dropwise to a solution of 6.00 g of 6-chloro-2-methylamino-3-nitropyridine (prepared as described in Preparation 66) in 120 ml of methanol at room temperature, and the resulting mixture was stirred at room temperature for 3 hours. At the end of this time, the reaction mixture was poured into water, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was crystallized by trituration with ethanol, to give 5.34 g of the title compound, melting at 152°-153° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:10]([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ccc(Br)cc1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Agent: [Pd+2]
Agent: CC(C)(C)[O-]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Product: CC1CN(C(=O)OC(C)(C)C)CCN1c1ccc(Cl)cc1
Temperature: 120 °C
Reaction time: 10 h
Yield: 67.6 %

Procedure:
To a solution of 3-Methyl-piperazine-1-carboxylic acid tert-butyl ester (1.0 g, 5 mmol) and 4-bromochlorobenzene (0.77 g, 4 mmol) was added sodium tert-butoxide (0.96 g, 10 mmol), palladium(II) dibenzylideneacetone (Pd2DBA3, 0.09 g, 0.1 mmol), and BINAP (0.19 g, 0.3 mmol). The suspension was stirred at 120° C. for 10 hours. The reaction was filtered through celite and evaporated in vacuo. The residue was purified by silica gel chromatography (hexane→ethyl acetate) to yield 0.84 g (68%) of the title compound. 1H-NMR (CDCl3): δ 1.00 (3H, m), 1.74 (9H, s), 3.10 (3H, m), 3.30 (1H, m), 3.80 (2H, m), 4.10 (1H, brs), 6.85 (2H, d), 7.20 (2H, d).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[OH:27][CH:28]([CH2:41][OH:42])[CH2:29][NH:30][C:31]([C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1)=[O:32]>>[OH:27][CH:28]([CH2:41][OH:42])[CH2:29][NH:30][C:31](=[O:32])[C:33]1[CH:40]=[CH:39][C:36]([C:37]2[NH:10][C:9]3[CH:8]=[CH:7][C:6]([NH:13][C:14](=[O:26])[C:15]4[CH:20]=[CH:19][C:18]([N:21]5[CH2:25][CH2:24][CH2:23][CH2:22]5)=[CH:17][CH:16]=4)=[CH:5][C:4]=3[N:1]=2)=[CH:35][CH:34]=1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(N2CCCC2)cc1
Reactant: O=Cc1ccc(C(=O)NCC(O)CO)cc1
Product: O=C(NCC(O)CO)c1ccc(-c2nc3cc(NC(=O)c4ccc(N5CCCC5)cc4)ccc3[nH]2)cc1

Procedure:
Compound 229 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)-4-pyrrolidinylbenzamide and 4-(2,3-dihydroxypropyl)aminocarbonylbenzaldehyde. [M+H]+ calcd for C28H29N5O4: 500.23; found: 500.56.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1Cl.[CH:10]([NH2:13])([CH3:12])[CH3:11]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[NH:13][CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)N
Reactant: Clc1cnnc(Cl)c1Cl
Solvent: Cc1ccccc1
Product: CC(C)Nc1c(Cl)cnnc1Cl

Procedure:
A solution of 3,4,5-trichloropyridazine (9.2 g) and isopropylamine (16.5 g) in toluene (25 ml) is refluxed for 18 hr. Excess isopropylamine is removed by atmospheric distillation. The residual solution is cooled and diluted with dichloromethane and aqueous sodium hydroxide solution (5%). The phases are separated. The organic phase is washed with water and then with saline. The organic phase is dried over sodium sulfate and concentrated under reduced pressure to give a liquid which contains a mixture of isomeric products. The isomers are separated by flash chromatography on silica gel eluting with ether/hexane (30/70). The appropriate fractions are pooled and concentrated to give the desired isomer, NMR (CDCl3) 1.33, 4.59, 4.87 and 8.60 δ; CMR (CDCl3) 24.2, 46.4, 117.1, 139.3, 145.5 and 151.3 δ.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]1[O:20][N:19]=[C:18]([CH2:21][NH2:22])[CH:17]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]1[O:20][N:19]=[C:18]([CH2:21][NH:22][C:8](=[O:10])[CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:17]=1
Reactant: NCc1cc(-c2ccco2)on1
Reactant: O=C(O)Cc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Cc1ccccc1)NCc1cc(-c2ccco2)on1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.5 %

Procedure:
To a solution of 7 mg of phenylacetic acid and 5 mg of C-(5-furan-2-yl-isoxazol-3-yl)-methylamine in DMF were added 8 mg of HOBt, 9 mg of EDC and 0.02 mL of TEA. After stirring at room temperature for 18 hrs, the reaction mixture was concentrated in vacuo. The concentrate was purified by preparative HPLC to produce 4 mg of the isoxazole derivative (Yield: 35%).
Reaction SMILES: [NH2:1][C:2](=[S:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl[CH2:10][C:11](=O)[CH3:12]>C(O)C>[CH3:12][C:11]1[N:1]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[S:8][CH:10]=1
Reactant: CCOC(=O)C(N)=S
Reactant: CC(=O)CCl
Solvent: CCO
Product: CCOC(=O)c1nc(C)cs1
Temperature: 25 °C

Procedure:
A solution of ethyl amino(thioxo)acetate (500 mg, 3.75 mmol) in ethanol (9.387 ml) was stirred at room temperature under an atmosphere of argon. 1-Chloro-2-propanone (0.299 ml, 3.75 mmol) was added and the solution was heated to reflux for 48 hours. The solution was allowed to cool to room temperature and then it was concentrated under reduced pressure to give a yellow coloured oily solid. The residue was chromatographed [SiO2, 0-100% EtOAc in Hexane] to give a yellow coloured oil identified as product in 208 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:14]O>>[CH3:14][O:11][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: CO
Agent: Cl
Product: COC(=O)Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A solution of (3,4-dichlorophenyl)acetic acid (16.12 g, 78.5 mmol) in MeOH (500 mL) was bubbled with HCl gas for 5 min. The mixture was stirred at room temperature for 1 h. The solvent was removed by rotary evaporation and the. resulting residue was dissolved in EtOAc (400 mL) and washed with saturated aqueous NaHCO3 (200 mL) and saturated aqueous NaCl (200 mL). The organic extracts were dried over sodium sulfate, filtered and concentrated by rotary evaporation to give (3,4-dichlorophenyl)acetic acid methyl ester (16.22 g, 74.1 mmol, 95%). 1H NMR (300 MHz, CDCl3): δ 7.50 (m, 2H), 7.23 (dd, 1H), 3.81 (s, 3H), 3.69 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Cl[CH2:10][C:11](=O)[CH3:12].C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:10]=[C:11]([CH3:12])[N:8]=2)[N:7]=1
Reactant: CC(=O)CCl
Reactant: Nc1ccc(Cl)nn1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cn2nc(Cl)ccc2n1
Temperature: 150 °C
Yield: 80.1 %

Procedure:
To a solution of 6-chloropyridazin-3-amine (2.35 g, 18.1 mmol, 1.0 equiv) in ethanol (15 mL) was added 1-chloropropan-2-one (2.92 mL, 36.3 mmol, 2.0 equiv) and triethylamine (2.53 mL, 18.1 mmol, 1.0 equiv). The solution was heated at 150° C. for 30 min then quenched with water. Purification by column chromatography using 30% ethyl acetate in hexanes elution gave 2.43 g of the brown solid, 80%.
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:10]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]2[N:22]=[C:21]([CH3:23])[C:20]([CH:24]([CH2:29][CH2:30][CH3:31])[C:25]([O:27]C)=[O:26])=[C:19]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=3)[N:18]=2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH2:3]([N:10]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]2[N:22]=[C:21]([CH3:23])[C:20]([CH:24]([CH2:29][CH2:30][CH3:31])[C:25]([OH:27])=[O:26])=[C:19]([C:32]3[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=3)[N:18]=2)[CH2:12][CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCN(Cc3ccccc3)CC2)nc1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(N2CCCN(Cc3ccccc3)CC2)nc1-c1ccc(C)cc1
Temperature: 100 °C
Yield: 21.7 %

Procedure:
A solution of sodium hydroxide 5N (0.5 mL) was added to a mixture of methyl 2-(2-(4-benzyl-1,4-diazepan-1-yl)-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (0.083 g; 0.195 mmol) in methanol (1.5 mL). The mixture was heated in a sealed tube at 100° C. for 18 h and then concentrated under reduced pressure. The residue was dissolved in water and the pH of the solution was adjusted between 3 and 4 by addition of a solution of hydrochloric acid 6N. The precipitate was collected by filtration and dried under reduced pressure over phosphorus pentoxide to give 0.020 g (25%) of the title compound as a white solid.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[CH:27]=[C:26]([CH2:28][CH3:29])[N:25]([CH3:30])[N:24]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=2)[CH2:35][CH2:34]1>C1COCC1>[CH3:32][N:33]1[CH2:34][CH2:35][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH:45][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[CH:27]=[C:26]([CH2:28][CH3:29])[N:25]([CH3:30])[N:24]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:31])=[CH:41][CH:40]=2)[CH2:37][CH2:38]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CCc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)nn1C
Solvent: C1CCOC1
Product: CCc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(N4CCN(C)CC4)cc3)c2)nn1C
Temperature: 65 °C
Reaction time: 24 h
Yield: 12 %

Procedure:
A small screw cap test tube was charged with 5-Ethyl-1-methyl-1H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 61 mg, 0.1465 mmol) and THF (2.0 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (27.7 mg, 0.145 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was recrystallized with ˜5 mL of i-prOH affording the title compound in 12% yield (0.010 g, 0.017 mmol).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3([C:29]4[C:20](=[CH:21][C:22]5[O:27][CH2:26][CH2:25][O:24][C:23]=5[CH:28]=4)[O:19][CH2:18]3)[C:10]2=[O:30])[CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].[C:37](=[NH:50])([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>COCCOC.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:38]1([C:37](=[N:50][C:2]2[N:7]=[C:6]([CH2:8][N:9]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11]4([C:29]5[C:20](=[CH:21][C:22]6[O:27][CH2:26][CH2:25][O:24][C:23]=6[CH:28]=5)[O:19][CH2:18]4)[C:10]3=[O:30])[CH:5]=[CH:4][CH:3]=2)[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C1N(Cc2cccc(Cl)n2)c2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: O=C1N(Cc2cccc(N=C(c3ccccc3)c3ccccc3)n2)c2ccccc2C12COc1cc3c(cc12)OCCO3
Temperature: 70 °C
Reaction time: 24 h
Yield: 67.2 %

Procedure:
A mixture of 1′-[(6-chloropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-2′(1′H)-one (0.2 g, 0.5 mmol) and sodium tert-butoxide (0.06 g, 0.67 mmol) in 1,2-dimethoxyethane (3 mL) was degassed with argon for 15 min. (R)-(−)-1′-[(S)-2-(dicyclohexylphosphino)ferrocenyl}ethyldi-tert-butylphosphine (0.006 g, 0.01 mmol), palladium(II) acetate (0.01 g, 0.05 mmol), and benzophenone imine (0.1 mL, 0.6 mmol) were added. The reaction mixture was stirred at 70° C. for 24 h, allowed to cool to ambient temperature, diluted with dichloromethane (20 mL) and filtered through a pad of diatomaceous earth. The pad was washed with dichloromethane (20 mL) and the filtrate was concentrated in vacuo. The residue was purified by column chromatography and eluted with a 25% to 35% gradient of ethyl acetate in hexanes to afford 1′-({6-[(diphenylmethylidene)amino]pyridin-2-yl}methyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.19 g, 70%) as a colorless solid: MS (ES+) m/z 565.8 (M+1).
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[F:7][C:8]([F:12])([F:11])[CH:9]=[CH2:10]>C1(C)C=CC=CC=1>[F:7][C:8]([F:12])([F:11])[CH2:9][CH2:10][S:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=C(O)CCS
Reactant: C=CC(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(O)CCSCCC(F)(F)F
Temperature: 20 °C
Reaction time: 24 h
Yield: 101 %

Procedure:
A 100 mL stainless steel Parr reactor was charged with 3-mercaptopropionic acid (3.67 g, 34.6 mmol), toluene (30.26 g), and 2,2′-azobis(4-methoxy-2,4-dimethyl) valeronitrile (V-70, 0.543 g, 1.76 mmol) and the reactor was cooled with a dry ice/acetone bath, purged with nitrogen, and pressure checked. 3,3,3-Trifluoropropene (3.20 g, 33.3 mmol) was added via transfer cylinder and the reaction was allowed to warm to 20° C. After 24 hours, the reaction was heated to 50° C. for 1 hour to decompose any remaining V-70 initiator. The reaction was allowed to cool to room temperature. The solution was concentrated by rotary evaporation to provide the title compound (6.80 g, 77.5 wt % linear isomer by GC internal standard assay, 5.27 g active, 76%, 200:1 linear:branched by GC, 40:1 linear:branched by fluorine NMR)
Reaction SMILES: [Na+].[CH:2]1([N:5]2[C:9]([C:10]([O-])=[O:11])=[C:8]([C:13]3[CH:14]=[N:15][C:16]([N:19]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:17][CH:18]=3)[N:7]=[C:6]2[C:34]2[CH:39]=[CH:38][C:37]([O:40][C:41]([F:44])([F:43])[F:42])=[CH:36][CH:35]=2)[CH2:4][CH2:3]1.[N:45]1([CH:50]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[CH2:49][CH2:48][CH2:47][CH2:46]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:2]1([N:5]2[C:9]([C:10]([N:53]3[CH2:54][CH2:55][CH:50]([N:45]4[CH2:49][CH2:48][CH2:47][CH2:46]4)[CH2:51][CH2:52]3)=[O:11])=[C:8]([C:13]3[CH:14]=[N:15][C:16]([N:19]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:17][CH:18]=3)[N:7]=[C:6]2[C:34]2[CH:35]=[CH:36][C:37]([O:40][C:41]([F:44])([F:42])[F:43])=[CH:38][CH:39]=2)[CH2:3][CH2:4]1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: O=C([O-])c1c(-c2ccc(N(Cc3ccccc3)Cc3ccccc3)nc2)nc(-c2ccc(OC(F)(F)F)cc2)n1C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1c(-c2ccc(N(Cc3ccccc3)Cc3ccccc3)nc2)nc(-c2ccc(OC(F)(F)F)cc2)n1C1CC1)N1CCC(N2CCCC2)CC1
Reaction time: 1 h
Yield: 69.4 %

Procedure:
To a solution of 0.12 g (0.2 mmol) of 3-cyclopropyl-5-(6-dibenzylamino-pyridin-3-yl)-2-(4-trifluoromethoxy-phenyl)-3H-imidazole-4-carboxylic acid sodium salt and 0.03 g (0.2 mmol) of 4-pyrrolidin-1-yl-piperidine in 1 ml of DMF was added 83 microliters (0.6 mmol) of triethylamine and 0.08 g (0.2 mmol) of HATU. The mixture was stirred for 1 h after which time it was evaporated to dryness, the residue was partitioned between CH2Cl2 and saturated sodium hydrogen carbonate solution, the organic phase was dried with sodium sulfate and concentrated. Purification by flash column chromatography [MeOH/CH2Cl2 5:95] afforded 0.1 g (79%) of the title compound as a colorless solid. MS: 721.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:12]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1Cl
Temperature: 60 °C
Yield: 94.8 %

Procedure:
To 4-chloro-3-nitrophenol (1.74 g, 10 mmol) and benzyl bromide (2.05 g, 12 mmol) in 25 mL of acetone was added K2CO3 (2.76 g, 20 mmol). The mixture was heated at 60° C. for 4 h under Ar atmosphere and cooled to rt. It was filtered and the solid was washed with ether (80 mL) and the combined filtrate was concentrated and chromatographed (EtOAc in hexane, 3% to 30% gradient) to afford 4-(benzyloxy)-1-chloro-2-nitrobenzene as a light-yellow solid (2.5 g, 95%). 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J=2.8 Hz, 1H), 7.42-7.34 (m, 5H), 7.11 (dd, J=8.8, 2.8 Hz, 1H), 5.08 (s, 2H); MS (ESI) m/z 264 (M+H+).
Reaction SMILES: C([CH:3]([C:24]([OH:26])=[O:25])[N:4]([C:14](OCC1C=CC=CC=1)=O)[CH2:5][P:6]([CH:11]([CH3:13])[CH3:12])([CH:8]([CH3:10])[CH3:9])=[S:7])C.Br.[CH3:28]COCC>C(O)(=O)C>[CH2:14]([N:4]([CH2:5][P:6]([CH:11]([CH3:13])[CH3:12])([CH:8]([CH3:10])[CH3:9])=[S:7])[CH2:3][C:24]([OH:26])=[O:25])[CH3:28]
Reactant: CCC(C(=O)O)N(CP(=S)(C(C)C)C(C)C)C(=O)OCc1ccccc1
Reactant: CCOCC
Agent: Br
Solvent: CC(=O)O
Product: CCN(CC(=O)O)CP(=S)(C(C)C)C(C)C

Procedure:
Ethyl N-carbobenzoxy-N-(diisopropylthiophosphinylmethyl)glycine (2 g., 0.0044 mole) was reacted with 36% hydrogen bromide (8 ml) in glacial acetic acid. Ether was added and the oily precipitate was isolated by decanting the ether layer. The oil was washed with ether twice, then suspended in benzene and treated with propylene oxide. The solution was concentrated in vacuo to yield ethyl N-(diisopropylthiophosphinylmethyl)glycine (0.7 g., 0.0022 mole) as an oil, ND22 =1.5066.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].CN(C)CCN(C)C.[C:27]1([CH3:34])[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[Li].C([Li])(C)(C)C.BrC1C=CC=CC=1C>C1COCC1.CCCCC.C(OCC)C>[CH3:7][NH:6][C:4]([C:3]1[C:2]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH3:34])=[CH:11][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1)=[O:5]
Reactant: CNC(=O)c1ccc(N2CCN(C)CC2)cc1Cl
Reactant: [Li]c1ccccc1C
Agent: CN(C)CCN(C)C
Agent: Cc1ccccc1Br
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCC
Product: CNC(=O)c1ccc(N2CCN(C)CC2)cc1-c1ccccc1C
Temperature: -25 °C
Yield: 36 %

Procedure:
To a solution of 125 mg (0.467 mmol)2-chloro-N-methyl-4-(4-methyl-piperazin-1-yl)-benzamide and 0.22 ml (1.5 mmol) N,N,N′,N′-tetramethylethylenediamine in 2 ml THF a solution of o-tolyllithium, prepared by addition of 2.5 ml (3.8 mmol) of a 1.5 M solution of tert.-butyllithium in pentane to a solution of 0.23 ml (1.9 mmol)2-bromotoluene in 2 ml diethyl ether at −78°, was added dropwise at −78°. The reaction mixture was allowed to warm to −25° C. over a period of 2 h. After quenching with 1 ml water at −25° the mixture was warmed to room temperature followed by dilution with 10 ethyl acetate and washing with 10 ml 1 N NaOH solution. The layers were separated and the aqueous layer was extracted with 2 10ml portion of ethyl acetate. The combined organic layers were dried (Na2SO4) and evaporated. Chromatography, (SiO2, CH2Cl2/methanol 19:1) afforded 55 mg (36%) 2′-Methyl-5-(4methyl-piperazin-1-yl)-biphenyl-2-carboxylic acid methylamide as a colorless oil MS (EI): 324(M+).
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:17][C:18]([F:32])([F:31])[C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:22]O.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C)C1C=CN=CC=1>[F:17][C:18]([F:31])([F:32])[C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:26]=1)[CH2:22][O:11][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=1[O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1Oc1ccccc1
Reactant: OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1Oc1ccccc1
Reaction time: 8 h
Yield: 31.8 %

Procedure:
To a solution of 118 mg (0.55 mmol) 2-phenoxybenzoic acid and 122 mg (0.50 mmol) 3,5 bis(trifluoromethyl)benzyl alcohol in 1.5 ml dichloromethane at 0° C. was added a solution of 124 mg (0.60 mmol) 1,3-dicyclohexylcarbodiimide and 7 mg (0.06 mmol) 4-dimethylaminopyridine in 1 ml dichloromethane. The ice bath was removed and stirring was continued at room temperature overnight. The solvent was removed in vacuo and the residue re-dissolved in diethyl ether, filtered and evaporated. The residue was purified by flash chromatography to give 70 mg (32%) of the title compound as white crystals.