Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=O.P(Cl)(Cl)(Cl)=O.C(N(CC)CC)C.[Cl:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][C:32]=1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1)[NH2:29]>C(#N)C.C1(C)C=CC=CC=1>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:29][C:28]1[CH:30]=[CH:31][C:32]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=2)=[C:26]([Cl:25])[CH:27]=1
Reactant: O=c1[nH]cnc2ccc(I)cc12
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Fc1cccc(COc2ccc(Nc3ncnc4ccc(I)cc34)cc2Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.9 %

Procedure:
In a 200 mL-volume glass vessel equipped with a stirrer, a thermometer and a reflux condenser were placed 9.80 g (36 mmol) of 6-iodoquinazolin-4-one, 6.63 g (43 mmol) of phosphorus oxychloride, and 30 mL of toluene in a nitrogen atmosphere. While the mixture was stirred at room temperature, 4.41 g (8.8 mmol) of triethylamine was slowly added. The resulting mixture was heated to 75° C., and then reaction was carried out at 70-80° C. for 3 hours. Subsequently, the mixture was cooled to room temperature, and 40 mL of acetonitrile and 11.8 mg (43 mmol) of 3-chloro-4-(3-fluorobenzyloxy)aniline were added. The resulting mixture was stirred at 70-80° C. for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, and thus precipitated crystalline product was collected by filtration and washed with 20 mL of acetonitrile. Subsequently, the crystalline product was placed in 80 mL of aqueous sodium hydroxide (1 mol/L), and the aqueous mixture was stirred for 2 hours at room temperature. The crystalline product was collected by filtration, washed with 500 mL of water and 20 mL of acetonitrile, and dried under reduced pressure, to give 18.0 g (isolated yield: 98%, purity 100% in terms of area percentage determined by high performance liquid chromatography) of 6-iodo-4-[3-chloro-4-(3-fluorobenzyloxy)anilino]quinazoline as a yellowish crystalline product.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7]O.[CH2:9]([NH2:16])[CH2:10][S:11]S(O)(=O)=O>>[CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:11][CH2:10][CH2:9][NH2:16]
Reactant: NCCSS(=O)(=O)O
Reactant: Cc1nc[nH]c1CO
Product: Cc1nc[nH]c1CSCCN
Yield: 70.1 %

Procedure:
In the same manner as in Example 1 (i), 2.8 g of 4-methyl-5-hydroxymethylimidazole (free base) is reacted with 4.3 g of 2-aminoethanethiolsulfuric acid, yielding 3.0 g of 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole as an oily product (yield: 72.0%).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:31])[N:10]([C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:20][C:19]=2[OH:30])[CH:15]=[CH:16][CH:17]=1)[CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Br[CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(C(C)=O)C>[CH2:1]([NH:8][C:9](=[O:31])[N:10]([C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:20][C:19]=2[O:30][CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])[CH:15]=[CH:16][CH:17]=1)[CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2O)c1
Reactant: CC(C)CCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCCC(C)C)c1
Yield: 114.6 %

Procedure:
A solution of 300 mg (0.703 mmol, 1 eq) of methyl 3-[3′-(3-heptyl-1-methylureido)-2-hydroxybiphenyl-4-yl]propanoate (prepared in Example 15f), 319 mg (2.11 mmol, 3 eq) of 1-bromo-3-methylbutane and 583 mg (4.22 mmol, 6 eq) of potassium carbonate in the presence of 42 mg (0.281 mmol, 0.4 eq) of sodium iodide in 10 ml of methyl ethyl ketone is refluxed for 21 hours. The insoluble matter is filtered off and the solvent is evaporated off. 400 mg of methyl 3-[3′-(3-heptyl-1-methylureido)-2-(3-methylbutoxy)biphenyl-4-yl]propanoate are obtained in the form of a yellowish oil. Quantitative yield.
Reaction SMILES: C(CCC1C=CC([C:12]2[C:13]([CH3:43])([CH3:42])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:41])([C@@:18]4([CH3:40])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([C:37]([OH:39])=[O:38])[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)=CC=1)(O)=O.B([C:47]1[S:51][C:50]([C:52]([OH:54])=[O:53])=[CH:49][CH:48]=1)(O)O.B(O)O>>[C:37]([C@:21]12[CH2:33][CH2:32][C@@H:31]([C:34]([CH3:36])=[CH2:35])[C@@H:22]1[C@@H:23]1[C@@:18]([CH3:40])([CH2:19][CH2:20]2)[C@@:17]2([CH3:41])[C@@H:26]([C@:27]3([CH3:30])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:42])([CH3:43])[C:12]([C:47]2[S:51][C:50]([C:52]([OH:54])=[O:53])=[CH:49][CH:48]=2)=[CH:29][CH2:28]3)[CH2:25][CH2:24]1)([OH:39])=[O:38]
Reactant: O=C(O)c1ccc(B(O)O)s1
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(CCC(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: OBO
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)s6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for compound (1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(2-carboxyethyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (example 4a) using 5-boronothiophene-2-carboxylic acid as the reactant boronic acid. The product was isolated as a white solid (4.15 mg, 23%). LCMS: m/e 563.53 (M−H)−, 2.94 min (method 4). 1H NMR (400 MHz, <DMSOmix>) δ ppm 0.90 (br. s., 3H), 0.96 (s, 3H), 0.98 (s, 3H), 1.04 (s, 3H), 1.06 (s, 3H), 1.09-1.76 (m, 17H), 1.68 (s, 3H), 1.80-1.94 (m, 2H), 2.10-2.23 (m, 2H), 2.25-2.40 (m, 1H), 2.91-3.05 (m, 1H), 4.58 (br. s., 1H), 4.71 (br. s., 1H), 5.75 (d, J=5.86 Hz, 1H), 6.90 (d, J=3.22 Hz, 1H), 7.51 (br. s., 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([NH:15][CH:16]([C:18]([OH:20])=[O:19])[CH3:17])[CH2:6][C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].OS(O)(=O)=O.CC(O)=O>[Pd]>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([NH:15][CH:16]([C:18]([OH:20])=[O:19])[CH3:17])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)NC(C)C(=O)O
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCOC(=O)C(CCc1ccccc1)NC(C)C(=O)O
Yield: 65.6 %

Procedure:
There was dissolved 0.4 g of ethyl-α-(1-carboxyethyl)amino-γ-oxo-γ-phenylbutyrate prepared in Example 10 into 8.0 ml of 1.6% (v/v) H2SO4 -AcOH, to which 0.1 g of 10% Pd/C was added and the hydrogenation reaction was carried out at room temperature under atmospheric pressure. After completion of the reaction, the catalyst was filtered off with suction, to which 2.5 ml of 1N NaOH solution was added and the resultant was concentrated under reduced pressure. After the residue was dissolved in water, the solution was adjusted to pH 3.0 and extracted with dichloromethane, the organic layer being washed with a saturated sodium chloride solution and concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give 0.25 g of ethyl-α-(1-carboxyethyl)amino-γ-phenylbutyrate ((αS,1S)-form/(αR,1S)-form=99/1).
Reaction SMILES: [CH3:1][C@@H:2]([C@H:7]([C:11]1[CH:16]=[CH:15][C:14]([O:17]CC2C=CC=CC=2)=[CH:13][CH:12]=1)/[CH:8]=[CH:9]\[CH3:10])[C:3]([O:5][CH3:6])=[O:4].ClB(Cl)Cl.CSC.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CCOC(C)=O>[OH:17][C:14]1[CH:13]=[CH:12][C:11]([C@H:7](/[CH:8]=[CH:9]\[CH3:10])[C@H:2]([CH3:1])[C:3]([O:5][CH3:6])=[O:4])=[CH:16][CH:15]=1
Reactant: C/C=C\[C@@H](c1ccc(OCc2ccccc2)cc1)[C@H](C)C(=O)OC
Agent: ClB(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CSC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C/C=C\[C@@H](c1ccc(O)cc1)[C@H](C)C(=O)OC
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A reaction mixture of (2S,3R,Z)-methyl 3-(4-(benzyloxy)phenyl)-2-methylhex-4-enoate 41.2 (0.45 g, 1.4 mmol), trichloroborane (0.99 g, 8.5 mmol) and dimethylsulfane (0.53 g, 8.5 mmol) in DCM (10.0 mL) was stirred at 0° C. for 5 minutes and then at room temperature for 7 hours. A saturated solution of sodium bicarbonate was added slowly at 0° C. to reach a pH of 6.5. EtOAc was added, and the organic layer was washed with brine (2×25 mL) and dried with Na2SO4. The product was purified by reverse phase HPLC to give the title compound (41.3) as the major product in a ratio of 95:5. 1H NMR (500 MHz, CDCl3) δ ppm 1.21 (d, J=6.85 Hz, 3H) 2.77 (td, J=6.97, 2.93 Hz, 1H) 3.47-3.50 (m, 3H) 3.82 (m, 1H) 5.50-5.65 (m, 2H) 6.71-6.80 (m, 2H) 7.08 (d, J=8.56 Hz, 2H). MS ESI (pos.) m/e: 235.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:24][C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=4)[C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.CO[CH:27](OC)[N:28]([CH3:30])[CH3:29].C(N(CC)CC)C>C1COCC1>[Cl:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[NH:16][C:15]1[C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:1]=[CH:27][N:28]([CH3:30])[CH3:29])=[CH:3][CH:4]=3)[NH:24][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: COC(OC)N(C)C
Reactant: Nc1ccc(-c2cc3c(Nc4cccc(Cl)c4)ncnc3[nH]2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C=Nc1ccc(-c2cc3c(Nc4cccc(Cl)c4)ncnc3[nH]2)cc1

Procedure:
0.2 g (0.56 mmol) of 6-(4-aminophenyl)-4-(3-chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine (see stage 19.5), 0.097 ml (0.67 mmol) of N,N-dimethylformamide dimethyl acetal and 0.112 ml (0.73 mmol) of triethylamine are stirred at RT for 24 h in 10 ml of THF until all the starting material has disappeared in the TLC. The reaction solution is concentrated to dryness in vacuo and the residue is chromatographed on a silica gel column. Crystallization from THF/hexane or ethyl acetate/hexane gives 4-(3-chloroanilino)-6-(4-[dimethylamino-methylenamino]phenyl)-7H-pyrrolo[2,3-d]pyrimidine; m.p.>300° C.; MS: (M)+=390.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[S:8][CH2:9][C:10](=[O:12])[NH:11][C:6]=2[CH:5]=1)([O-:3])=[O:2].Br[CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[S:8][CH2:9][C:10](=[O:12])[N:11]([CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1CSc2ccc([N+](=O)[O-])cc2N1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)N1C(=O)CSc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Yield: 49.7 %

Procedure:
A mixture of 6-nitro-2H-benzo[b][1,4]thiazin-3(4H)-one (0.512 g, 2.436 mmol), ethyl 2-bromopropanoate (0.573 g, 3.17 mmol) and K2CO3 (1.01 g, 7.31 mmol) in acetone (40 mL) was heated at reflux for 16 h. After cooling to ambient temperature, the mixture was filtered and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 9% EtOAc in petroleum ether) to give ethyl 2-(6-nitro-3-oxo-2H-benzo[b][1,4]thiazin-4(3H)-yl)propanoate (0.376 g, 50%). TLC (eluting with 20% EtOAc/PE) Rf=0.6.
Reaction SMILES: C(O)(=O)/C=C\C(O)=O.[CH3:9][N:10]([CH2:12][C:13]1[O:17][C:16]([CH2:18][S:19][C:20](=N)N)=[CH:15][CH:14]=1)[CH3:11].ClC[CH2:25][NH:26][C:27]([NH:32][CH3:33])=[CH:28][N+:29]([O-:31])=[O:30].[OH-].[K+]>O.CO.CC(C)=O>[CH3:11][N:10]([CH2:12][C:13]1[O:17][C:16]([CH2:18][S:19][CH2:20][CH2:25][NH:26][C:27]([NH:32][CH3:33])=[CH:28][N+:29]([O-:31])=[O:30])=[CH:15][CH:14]=1)[CH3:9]
Reactant: CN(C)Cc1ccc(CSC(=N)N)o1
Reactant: CNC(=C[N+](=O)[O-])NCCCl
Agent: O=C(O)/C=C\C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)=O
Solvent: O
Product: CNC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Reaction time: 40 h
Yield: 19.6 %

Procedure:
To a stirred solution of 1-[[5-[(Dimethylamino)methyl]-2-furanylmethyl]thio]methanimidamide maleate (1:2) (2.23 g) and N-(2-chloroethyl)-N'-methyl-2-nitro-1,1-ethenediamine (1.08 g) in water (20 ml) at 45° under an atmosphere of nitrogen was added a solution of potassium hydroxide (1.68 g) in water (3 ml). After 40 hr. at room temperature the solution was extracted with ether (2×50 ml) and the aqueous phase evaporated in vacuo. Tetrahydrofuran (70 ml), decolourising charcoal and an excess of anhydrous sodium carbonate were added to the residue and the mixture refluxed for 30 mins. After 3 hours the mixture was filtered and the filtrate evaporated in vacuo to give a semi-solid which was dissolved in a mixture of methanol and acetone and chromatographed (silica;methanol:acetone 1:1). The appropriate eluate was evaporated in vacuo to give the title compound as an oil (0.37 g), a portion of which was crystallised from 4-methylpentan-2-one, m.p. 68°-70° which was not depressed on admixture with a sample prepared according to the method of Example 15 in British Patent No. 1,565,966.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([O-])=[O:27])=[CH:24][CH:23]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].O.[OH-].[Na+]>O1CCCC1>[CH2:7]([O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:26][OH:27])=[CH:29][CH:30]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)[O-])cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCCCOc1ccc(CO)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 75.6 %

Procedure:
To about 13.61 g of lithium aluminum hydride in about 200 ml of tetrahydrofuran was added, over about 1/2 hour, a solution of about 130 g of 4-tetradecyloxybenzoate in about 400 ml of tetrahydrofuran, in an ice bath with stirring and maintaining the temperature below about 40° C. After stirring about 2 hours the mixture was cooled to about 0° C., about 9 ml of water was added dropwise followed by the dropwise addition of about 18 ml of about 15% sodium hydroxide and about 30 ml of water. This mixture was filtered through celite, the solvent was removed and the residue recrystallized from ethanol, giving about 94.5 g of the desired title compound as a white solid, mp 75°-76° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:26](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[C:46]([C:50]([O:52][CH:53]([O:55][C:56]([O:58][CH2:59][CH2:60][CH2:61][C@@H:62]([O:69][N+:70]([O-:72])=[O:71])[C@H:63]([O:65][N+:66]([O-:68])=[O:67])[CH3:64])=[O:57])[CH3:54])=[O:51])=[CH:47][CH:48]=[CH:49][C:6]=2[N:5]=1)[CH3:2]>CO>[CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:14][CH:15]=2)[C:7]2[C:46]([C:50]([O:52][CH:53]([O:55][C:56]([O:58][CH2:59][CH2:60][CH2:61][C@@H:62]([O:69][N+:70]([O-:72])=[O:71])[C@H:63]([O:65][N+:66]([O-:68])=[O:67])[CH3:64])=[O:57])[CH3:54])=[O:51])=[CH:47][CH:48]=[CH:49][C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOc1nc2cccc(C(=O)OC(C)OC(=O)OCCC[C@@H](O[N+](=O)[O-])[C@@H](C)O[N+](=O)[O-])c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: CCOc1nc2cccc(C(=O)OC(C)OC(=O)OCCC[C@@H](O[N+](=O)[O-])[C@@H](C)O[N+](=O)[O-])c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 70 °C

Procedure:
A methanol (30 mL) suspension of 1-[({[(4R,5R)-4,5-bis(nitrooxy)hexyl]oxy}carbonyl)oxy]ethyl 2-ethoxy-1-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate (2.47 g, 2.53 mmol) was heated to 70° C. for 2 hours. The reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel, eluting with 3-9% methanol/dichloromethane to give the title compound. 1H NMR (500 MHz, CD3CN) δ 7.71 (d, J=7.6 Hz, 1H), 7.61 (dt, J=1.1, 7.6 Hz, 1H), 7.48-7.56 (m, 3H), 7.42 (d, J=7.6 Hz, 1H), 7.12 (t, J=7.9 Hz, 1H), 6.96 (d, J=8.3 Hz, 2H), 6.89 (d, J=8.2 Hz, 2H), 6.78 (q, J=5.4 Hz, 1H), 5.56 (d, J=16.7 Hz, 1H), 5.53 (d, J=16.7 Hz, 1H), 5.24-5.40 (m, 2H), 4.44-4.58 (m, 2H), 4.06-4.18 (m, 2H), 1.7-1.9 (m, 4H), 1.36-1.44 (m, 6H), 1.34 (d, J=6.2 Hz, 3H); LC-MS: m/z 735.3 (M+H).
Reaction SMILES: [C:1]1([CH:7]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([O:17]CC)=[O:16])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[Li].O>C1COCC1.CO>[C:1]1([CH:7]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:22][CH:21]=2)[CH:8]2[CH2:9][CH2:10][N:11]([CH2:14][C:15]([OH:17])=[O:16])[CH2:12][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CN1CCC(C(c2ccccc2)c2ccc(C(F)(F)F)cc2)CC1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)CN1CCC(C(c2ccccc2)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 37.9 %

Procedure:
To a solution of ethyl 2-(4-(phenyl(4-(trifluoromethyl)phenyl)methyl)piperidin-1-yl)acetate (0.2 g, 0.49 mmol) in THF/MeOH (10 mL, 1:1) was added LiOH.H2O (0.15 g, 3.7 mmol). After stirring at rt for 4 h, the solvent was removed under vacuum. The residue was diluted with water and the pH was adjusted to 3 with diluted HCl, extracted with DCM, and the combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to afford pure 2-(4-(phenyl(4-(trifluoromethyl)phenyl)methyl)piperidin-1-yl)acetic acid (0.07 g, 36% yield) as a white solid. MS (ESI, pos. ion) m/z: 378 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][S:11](Cl)(=[O:13])=[O:12])([O-:3])=[O:2].[CH3:15][NH:16][CH3:17]>O1CCOCC1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][S:11]([N:16]([CH3:17])[CH3:15])(=[O:13])=[O:12])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1CS(=O)(=O)Cl
Reactant: CNC
Solvent: C1COCCO1
Product: CN(C)S(=O)(=O)Cc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h
Yield: 85 %

Procedure:
2-Nitro-α-toluenesulfonyl chloride (0.943 g, 4.0 mmole) was dissolved in dry dioxane (7 ml) and treated with a solution of dimethylamine (4 ml 2M solution in THF, 8.0 mmole), and stirred at room temperature for a total of 6 h. The reaction mixture was transferred to a separatory funnel and partitioned between ethyl acetate and water. The organic solution was washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness to afford the pure 2-nitrobenzyl-N,N-dimethylsulfonamide, 0.829 g (85% yield).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][CH2:11][C:12]3C=CC4[C:14](=[CH:15]C=CC=4)[CH:13]=3)=[CH:9][C:4]=2[N:3]=[N:2]1.C(O[CH2:25][CH3:26])C>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][CH2:11][C:12]3[C:25]4[C:26](=[CH:9][CH:4]=[CH:5][CH:6]=4)[CH:15]=[CH:14][CH:13]=3)=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: CCOCC
Reactant: c1ccc2cc(CNc3ccc4[nH]nnc4c3)ccc2c1
Product: c1ccc2c(CNc3ccc4[nH]nnc4c3)cccc2c1
Yield: 64 %

Procedure:
As per the general procedure for compound [11]. Trituration from diethyl ether afforded [12] as a white solid (700 mg, 64%). Rf (A) 0.30 δH(400 MHz; DMSO-d6 {D2O shake}) 4.75 (2H, s, CH2) 6.49 (1H, s, BT) 6.77 (1H, s, NH, disappeared) 6.91 (1H, d, J9.0, BT) 7.43 (1H, t, Nap) 7.51-7.59 (3H, m, Nap) 7.65 (1H, d, J9.0, BT) 7.82 (1H, d, J8.1, Nap) 7.94 (1H, d, J8.4, Nap) 8.14 (1H, d, J8.1, Nap) 14.74 (1H, s, NH, disappeared); m/z (EI−HR) 274.12148 [(M) calc. for C17H14N4 274.12185]. (1H-Benzotriazol-5-yl)-(3,5-dimethoxy-benzyl)-amine [13]
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([C:28]#[N:29])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-:31].[Na+].[Na+]>S(=O)(=O)(O)O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([C:28](=[O:31])[NH2:29])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC(CC1CCN(Cc2ccccc2)CC1)(c1ccccc1)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)C(CC1CCN(Cc2ccccc2)CC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 13 %

Procedure:
A solution of 1-benzyl-4-(2-cyano-2,2-diphenylethyl)piperidine (7.57 g, 19.9 mmol) (Example 23) in 90% sulphuric acid (45 ml) was heated at 100° C. for one hour, allowed to cool to room temperature, poured into ice, basified with saturated aqueous sodium carbonate solution and extracted into dichloromethane. The combined organic extracts were dried over magnesium sulphate and evaporated. The residue was purified by chromatography on silica using dichloromethane plus 0-10% methanol as eluant. Appropriate fractions were combined and evaporated to give the title compound (1.06 g, 13%) as a colourless foam which was characterised as a hemihydrate.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]([CH3:11])[C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:24](OC)(=[O:29])[C:25]([O:27][CH3:28])=[O:26].Cl>C1COCC1>[CH3:28][O:27][C:25](=[O:26])[C:24]([OH:29])=[CH:9][C:8](=[O:10])[N:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:13][CH:12]=1)[CH3:11]
Reactant: COC(=O)C(=O)OC
Reactant: CC(=O)N(C)Cc1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
N-(4-Fluoro-benzyl)-N-methyl-acetamide (3.6 grams, 20 mmol) was dissolved in 20 mL of THF and cooled to −78° C. To this was added 40 mL of 1M LiHMDS (in THF) and the resulting solution stirred for 30 min. Next dimethyl oxalate (3.5 grams, 30 mmol) dissolved in 8 mL of THF is added and the reaction stirred for 2 h at −78° C., then warmed to 0° C. and stirred an additional 30 min. To this was added 1N HCl and the mixture then extracted with EtOAc. The organic layer was washed with saturated NaCl, dried over Na2SO4, filtered and the solvent removed. The crude product was purified by column chromatography (4×4 cm SiO2, 80:20 Hex/EtOAc) to yield 4.3 grams solid (80% yield). HRMS (M+H) calcd for C13H15NO4F: 268.0985; found: 268.0983. Anal calcd for C13H14NO4F: C, 58.42; H, 5.28; N, 5.24. found: C, 58.48; H, 5.21; N, 5.26. 1H NMR and 13C NMR show a mixture of rotamers at room temperature. 1H NMR (500 MHz, CDCl3) δ: 3.00 (s), 3.86 (s), 3.89 (s), 4.55 (s), 6.29 (s), 6.31 (s), 7.00–7.24 (overlapping m, 4). 13C NMR δ; 33.43, 34.79, 49.97, 52.63, 52.97, 93.27, 93.55, 115.63, 115.80, 115.95, 116.13, 128.36, 128.42, 129.71, 129.78, 131.32, 132.03, 159.70, 161.40, 163.25, 163.35, 170.93, 171.16.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[N:5][C:6]([C@@H:9]([NH2:11])[CH3:10])=[N:7][CH:8]=1.[CH3:12][O:13][C:14]1[NH:18][N:17]=[C:16]([NH:19][C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[N:23]=[C:22](S(C)(=O)=O)[N:21]=2)[CH:15]=1.CCN(C(C)C)C(C)C>CCCCO>[F:2][C:3]1[CH:4]=[N:5][C:6]([C@@H:9]([NH:11][C:22]2[N:21]=[C:20]([NH:19][C:16]3[CH:15]=[C:14]([O:13][CH3:12])[NH:18][N:17]=3)[CH:25]=[C:24]([C:26]([F:29])([F:27])[F:28])[N:23]=2)[CH3:10])=[N:7][CH:8]=1
Reactant: COc1cc(Nc2cc(C(F)(F)F)nc(S(C)(=O)=O)n2)n[nH]1
Reactant: C[C@H](N)c1ncc(F)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COc1cc(Nc2cc(C(F)(F)F)nc(N[C@@H](C)c3ncc(F)cn3)n2)n[nH]1
Temperature: 90 °C
Yield: 5.2 %

Procedure:
A mixture of (S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7, 139 mg), N-(5-methoxy-1H-pyrazol-3-yl)-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-amine (Method 45, 265 mg) and DIPEA (0.35 ml) in n-BuOH (5.0 ml) was heated at 90° C. for 6 hours. The solvent was removed under reduced pressure and the residue was purified by Gilson (10-50% MeCN/H2O, 15 minutes) to give the titled compound as solid (16.3 mg). 1H NMR δ 12.11 (s, 1H) 10.47 (s, 1H) 8.86 (s, 2H) 8.29 (s, 1H) 6.27 (s, 1H) 5.30 (s, 1H) 5.13-5.25 (m, 1H) 3.77 (s, 3H) 1.51 (d, 3H); m/z 399.