Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([N:11]3[CH2:16][N:15]([CH3:17])[CH2:14][N:13]([CH2:18][CH3:19])[C:12]3=[O:20])=[N:7][C:6]=2[CH:5]=[C:4]([C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][C:30]([CH2:38][CH3:39])([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[CH2:66]([OH:69])[C:67]#[CH:68]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C>[CH2:38]([C:30]1([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:29][CH2:28][N:27]([C:24]2[N:23]=[CH:22][C:21]([C:4]3[CH:3]=[C:2]([C:68]#[C:67][CH2:66][OH:69])[C:10]4[S:9][C:8]([N:11]5[CH2:16][N:15]([CH3:17])[CH2:14][N:13]([CH2:18][CH3:19])[C:12]5=[O:20])=[N:7][C:6]=4[CH:5]=3)=[CH:26][N:25]=2)[CH2:32][CH2:31]1)[CH3:39]
Reactant: C#CCO
Reactant: CCOC(=O)C1(CC)CCN(c2ncc(-c3cc(Br)c4sc(N5CN(C)CN(CC)C5=O)nc4c3)cn2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C1(CC)CCN(c2ncc(-c3cc(C#CCO)c4sc(N5CN(C)CN(CC)C5=O)nc4c3)cn2)CC1
Temperature: 100 °C

Procedure:
Ethyl 1-[5-[7-bromo-2-(3-ethyl-5-methyl-2-oxo-1,3,5-triazinan-1-yl)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-ethyl-piperidine-4-carboxylate (700 mg, 1.14 mmol), PdCl2(PPh3)2 (32 mg, 0.05 mmol) and triphenylphosphine (3 mg, 0.01 mmol) were placed in a 10-20 mL microwave vial and anhydrous DMF (14 mL) added, quickly followed by triethylamine (0.95 mL, 6.81 mmol) and propargyl alcohol (0.13 mL, 2.27 mmol). The solution was bubbled with argon for ˜3 minutes then CuI (4 mg, 0.02 mmol) was added. The vial was capped and mixture degassed then heated in the microwave at 100° C. for 30 minutes. More PdCl2(PPh3)2 (11 mg) and propargyl alcohol (0.05 mL) were added and argon was bubbled through the mixture then CuI (1.5 mg) added. The vial was capped and mixture degassed then heated in the microwave again at 100° C. for 15 minutes. The crude reaction mixture was filtered through a PTFE filter. The filter was rinsed with EtOAc and then water. The filtrate was diluted with water, extracted into EtOAc (4×60 mL) and the combined organic layers washed with water (2×50 mL) and brine, dried over Na2SO4 and concentrated to dryness under reduced pressure to give a brown solid. The mixture was purified by chromatography, Biotage SP4, 40 g Si cartridge, 50-80% EtOAc in cyclohexane and the relevant fractions combined to give the desired product as an off-white solid, 247 mg (37%). MS: 592.13 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH3:18])[CH2:14][C:13]([CH3:16])([CH3:15])[O:12][CH2:11][C:10](=[S:17])[NH:9]2)[CH:7]=1.[F:20][C:21]([F:29])([F:28])[C:22]1([C:25](O)=[O:26])[CH2:24][CH2:23]1>>[F:19][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:25]([C:22]2([C:21]([F:29])([F:28])[F:20])[CH2:24][CH2:23]2)=[O:26])=[CH:7][C:6]=1[C@:8]1([CH3:18])[CH2:14][C:13]([CH3:16])([CH3:15])[O:12][CH2:11][C:10](=[S:17])[NH:9]1
Reactant: CC1(C)C[C@@](C)(c2cc(N)ccc2F)NC(=S)CO1
Reactant: O=C(O)C1(C(F)(F)F)CC1
Product: CC1(C)C[C@@](C)(c2cc(NC(=O)C3(C(F)(F)F)CC3)ccc2F)NC(=S)CO1
Yield: 92 %

Procedure:
The compound was prepared in an analogous manner as described for intermediate B14A from (S)-5-(5-amino-2-fluoro-phenyl)-5,7,7-trimethyl-[1,4]oxazepane-3-thione (intermediate A17A) (110 mg, 0.39 mmol) and commercially available 1-trifluoromethyl-cyclopropanecarboxylic acid [CAS No. 277756-46-4] (67 mg, 0.44 mmol). The compound was obtained as light yellow foam (167 mg, 92%). MS (ISP): m/z=419.2 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([F:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[NH:17][C:16]2=O)=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].P(Cl)(Cl)([Cl:30])=O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([F:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[N:17]=[C:16]2[Cl:30])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)OC(=O)c1cc(-n2c(=O)[nH]c(C(F)(F)F)c(F)c2=O)c(F)cc1Cl
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)OC(=O)c1cc(-n2c(Cl)nc(C(F)(F)F)c(F)c2=O)c(F)cc1Cl

Procedure:
using isopropyl 2-chloro-5-[3,6-dihydro-2,6-dioxo-5-fluoro-4-trifluoromethyl-1(2H) -pyrimidinyl]-4-fluorobenzoate with phosphorus oxychloride and pyridine within 1 hour at room temperature and thereafter for 1 hour at 60° C. there is obtained isopropyl 2-chloro-5-[2-chloro-5-fluoro-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]4-fluorobenzoate, 1H-NMR (CDCl3, 60 MHz): 7.88 ppm (d,1H), 7.47 ppm (d,1H), 5.30 ppm (m,1H), 1.41 ppm (d,6H);
Reaction SMILES: C(=O)(O)O.[NH2:5][NH:6][C:7]([NH2:9])=[NH:8].Cl.[OH:11][C@H:12]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@H:14]([CH2:15][CH2:16][C@@H:17]3[C@@H:29]2[CH2:28][CH2:27][C@@:26]2([CH3:34])[C@:18]3([OH:35])[CH2:19][CH2:20][C@@H:21]2/[CH:22]=[CH:23]/[CH:24]=O)[CH2:13]1>O.O1CCOCC1>[NH:6](/[N:5]=[CH:24]/[CH:23]=[CH:22]/[C@H:21]1[CH2:20][CH2:19][C@:18]2([OH:35])[C@H:17]3[C@H:29]([CH2:28][CH2:27][C@:26]12[CH3:34])[C@:30]1([CH3:33])[C@@H:14]([CH2:13][C@@H:12]([OH:11])[CH2:32][CH2:31]1)[CH2:15][CH2:16]3)[C:7]([NH2:9])=[NH:8]
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](/C=C/C=O)CC[C@]12O
Reactant: N=C(N)NN
Agent: Cl
Agent: O=C(O)O
Solvent: O
Solvent: C1COCCO1
Product: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](/C=C/C=N/NC(=N)N)CC[C@]12O
Yield: 65.4 %

Procedure:
A mixture of 1.05 g of aminoguanidine hydrogencarbonate in 23 ml of water and 70 ml of dioxane was made acid to pH 3 with 3N HCl. A solution of 2.08 g of (E)-3β,14β-dihydroxy-5β-pregn-20-ene-21-carboxaldehyde (Fullerton D. S. et al., J. Med. Chem., 1976, 19, 1330) in 20 ml of dioxane was added at room temperature. After 3 days the mixture was evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography (SiO2) using chloroform/methanol/28% ammonium hydroxide 80/20/3 as the eluant; the fractions containing the title compound were collected and evaporated to dryness. The residue was ground with diethyl ether and ethanol to give 1.58 g of the title compound (I-aa) as a white solid.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:47][C:48]1[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:47][C:48]4[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=4)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: Nc1cccnc1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)Nc2cccnc2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-Butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 3-aminopyridine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C41H47Cl2N6O3 [(M+H)+] 741.3081, observed 741.3083.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([OH:15])=O)[C:7]([CH3:16])=[CH:6]2)#[N:2].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH:29][NH2:30])=O)[CH:22]=1>>[CH3:16][C:7]1[N:8]([CH2:12][C:13]2[O:15][C:27]([C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)=[N:29][N:30]=2)[C:9]2[C:5]([CH:6]=1)=[C:4]([C:17]([F:19])([F:18])[F:20])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=2
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=O)O
Reactant: NNC(=O)c1cccnc1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1nnc(-c2cccnc2)o1

Procedure:
Synthesized as described in Example 35C using [5-cyano-2-methyl-4-(trifluoromethyl)-1H-indol-1-yl]acetic acid and 3-pyridinecarbohydrazide: 1H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.78 (d, J=4.9 Hz, 1H), 8.27 (d, J=7.8 Hz, 1H), 8.08 (d, J=8.5 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.60 (dd, J=7.8 and 4.9 Hz, 1H), 6.65 (s, 1H), 6.00 (s, 2H), 2.57 (s, 3H); MS (ES) m/z 384 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.[CH2:23]([Mg]Cl)[CH3:24]>C1COCC1.[Cu]I>[CH2:23]([C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1)[CH3:24]
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Reactant: CC[Mg]Cl
Agent: [Cu]I
Solvent: C1CCOC1
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1CC

Procedure:
This compound is prepared from methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate and ethylmagnesium chloride in THF at −10° C. in the presence of CuI as described in the following reference: Chemistry-A European Journal, 15(29), 7167-7179, S7167/1-S7167/121; 2009.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH3:13])[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.[CH2:22]([O:24][C:25](=[O:32])[C@@:26]([F:31])([CH3:30])[C:27](O)=[O:28])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:32])[C@@:26]([F:31])([CH3:30])[C:27]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH3:13])[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2)=[O:28])[CH3:23]
Reactant: COCCN1C(=O)[C@@H](N)c2ccccc2-c2ccccc21
Reactant: CCOC(=O)[C@](C)(F)C(=O)O
Product: CCOC(=O)[C@](C)(F)C(=O)N[C@@H]1C(=O)N(CCOC)c2ccccc2-c2ccccc21

Procedure:
Using (S)-7-amino-5-(2-methoxy-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one and (R)-2-fluoro-2-methyl-malonic acid monoethyl ester, the title compound was prepared in the same manner as described for example 1c. Colorless oil (59%). MS: m/e=429(M+H+).
Reaction SMILES: [CH2:1]([NH2:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20]>CO>[CH2:1]([NH:17][CH:19]([CH3:20])[C:18]([O:22][CH3:23])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCN
Reactant: C=CC(=O)OC
Solvent: CO
Product: CCCCCCCCCCCCCCCCNC(C)C(=O)OC
Reaction time: 8 h

Procedure:
66.4 g of hexadecylamine are dissolved in 250 ml of methanol. 27 ml of methyl acrylate are added and the mixture is left to stand overnight. After removal of the solvent by distillation the residue is recrystallised from ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=O)=[CH:4][CH:3]=1.CO.[C:15]1([NH:21][NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C[O-].[Na+]>O>[C:15]1([N:21]([C:6](=[O:8])[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:12][CH:11]=2)[NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NN(C(=O)c1ccc(F)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture consisting of 101.2 g. (0.602 mole) ethyl p-fluorobenzoate, 250 ml. methanol, 70.0 g. (0.646 mole) phenylhydrazine, and 33.6 g. (0.621 mole) sodium methoxide (mixed in that order) was heated at the reflux temperature for 16 hrs. After cooling the reaction mixture to about 25°C it was poured into 1500 ml. water. The aqueous mixture was filtered, and the filter cake was washed with water and recrystallized from 95% aqueous ethanol. The crystals melted at 174° to 178°C. An analytical sample of p-fluorobenzoic acid phenylhydrazide melting at 177° to 179°C. was obtained by recrystallizing once from a mixture of ethyl acetate and Skellysolve B (essentially a mixture of isomeric hexanes boiling in the range of 146° to 156°F.), and once from 75% aqueous ethanol.
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH:15]([C:17]([CH3:19])=[O:18])=[CH2:16]>>[C:1]([CH:9]([CH2:16][CH2:15][C:17](=[O:18])[CH3:19])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: C=CC(C)=O
Reactant: CCOC(=O)CC(=O)c1ccncc1
Product: CCOC(=O)C(CCC(C)=O)C(=O)c1ccncc1

Procedure:
3-(4-Pyridinyl)-2-cyclohexen-1-one is obtained by modifying the procedure described in Example B-1 as follows: Ethyl isonicotinoylacetate and methyl vinyl ketone are reacted as in Example B-1 to yield ethyl 2-(isonicotinoyl)-5-oxohexanoate which is then reacted with 35% aqueous sodium hydroxide solution at 25°-30° C. to produce ethyl 3-(4-pyridinyl)-2-cyclohexen-1-one-4-carboxylate and the 4-carboxylate is heated with aqueous sulfuric acid at 95° C. until the evolution of carbon dioxide ceases, thereby producing 3-(4-pyridinyl)-2-cyclohexen-1-one.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[CH:19]=[CH:18][C:10]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:9]([CH2:20][CH3:21])[CH:8]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)C(C)C)(C)C.Cl[C:32]1[C:37]([CH3:38])=[C:36]([C:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=2)[N:35]=[CH:34][N:33]=1>C(Cl)Cl>[CH2:1]([N:5]([CH2:6][C:7]1[CH:19]=[CH:18][C:10]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:9]([CH2:20][CH3:21])[CH:8]=1)[C:32]1[C:37]([CH3:38])=[C:36]([C:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=2)[N:35]=[CH:34][N:33]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccc(-c2ncnc(Cl)c2C)cc1
Reactant: CCCCNCc1ccc(OCC(=O)OCC)c(CC)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCN(Cc1ccc(OCC(=O)OCC)c(CC)c1)c1ncnc(-c2ccc(C)cc2)c1C
Temperature: 100 °C
Yield: 18.6 %

Procedure:
A mixture of ethyl {4-[(butylamino)methyl]-2-ethylphenoxy}acetate (0.23 g, 0.78 mmol), N,N-diisopropylethylamine (0.18 mL, 1.05 mmol) and 4-chloro-5-methyl-6-(4-methylphenyl)pyrimidine (0.114 g, 0.52 mmol) were heated at 100° C. in a sealed reactivial for 18 h. After this time the reactivial was allowed to cool to room temperature and the residue dissolved in CH2Cl2 (50 mL) and washed with water (10 mL) and brine (10 mL). The organic extract was separated by hydrophobic frit and evaporated. Purification by Biotage™ chromatography (Silica, 40 g) eluting 9:1 cyclohexane:EtOAc afforded the title compound as a pale yellow oil (46 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1.[Br:18]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:8]([CH2:9][Br:18])=[CH:7][CH:6]=[CH:5][C:4]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1c(C)cccc1Oc1cccc(Cl)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: COc1c(CBr)cccc1Oc1cccc(Cl)c1
Yield: 104 %

Procedure:
A mixture of 3-chlorophenyl 2-methoxy-3-methylphenyl ether (14.6 g), N-bromosuccinimide (11.3 g) and 2,2'-azobisisobutyronitrile (1.1 g) in benzene (100 ml) was treated in a similar manner to that of Example 6-(3) to give oily 3-chlorophenyl 2-methoxy-3-bromomethylphenyl ether (20 g).
Reaction SMILES: C[O-].[Na+].[CH:4](OCC)=[O:5].[C:9]1([C:17]([CH2:19][C:20]2[CH:27]=[CH:26][C:23]([O:24][CH3:25])=[CH:22][CH:21]=2)=[O:18])[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[CH:11][CH:10]=1.O1CCCC1>C(O)C>[CH:4]([CH:19]([C:20]1[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[CH:26][CH:27]=1)[C:17](=[O:18])[C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[CH:15][CH:16]=1)=[O:5]
Reactant: CCOC=O
Reactant: COc1ccc(CC(=O)c2ccc(OC)cc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(C(=O)C(C=O)c2ccc(OC)cc2)cc1
Reaction time: 1 h

Procedure:
A solution of sodium methoxide (11.9 g, 0.22 mole) in 80 ml ethanol was cooled in an ice bath and treated with ethyl formate (20 ml, 0.24 mole). A solution of desoxyanisoin (51.2 g, 0.2 mole) in 275 ml warm tetrahydrofuran was then added while maintaining the reaction temperature below 5°. The reaction mixture was stirred for 1 hour at 0° and then stirred overnight at room temperature.
Reaction SMILES: IC.[Br:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[OH:14].[C:15](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:11])([CH3:13])[CH3:12])[CH:7]=[CH:6][C:5]=1[O:14][CH3:15]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)c1ccc(O)c(Br)c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc(C(C)(C)C)cc1Br
Yield: 102.3 %

Procedure:
Iodomethane (10.0 mL, 0.161 mol) was added to a mixture of 2-bromo-4-(tert-butyl)phenol [Intermediate 1, Step 1] (29.5 g, 0.129 mol) and potassium carbonate (42.7 g, 0.309 mol) in dry acetone (400 mL) and the reaction mixture refluxed under nitrogen for 22 hours. The cooled reaction mixture was then concentrated and the residue partitioned between ethyl acetate (400 mL) and 0.3 M aqueous sodium hydroxide solution (300 mL). The organic phase was separated, washed with water (300 mL) and saturated brine (300 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give 2-bromo-4-(tert-butyl)-1-methoxybenzene (32.09 g, 100% yield) as a light yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17](Cl)[N:16]=2)[CH2:10][C@@H:9]1[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23](=[NH:36])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:36]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:16]=2)[CH2:10][C@@H:9]1[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H]1C[C@@H](Oc2cccc(Cl)n2)CCN1C(=O)OC(C)(C)C
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: C[C@H]1C[C@@H](Oc2cccc(N=C(c3ccccc3)c3ccccc3)n2)CCN1C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
Combine 4-(6-chloro-pyridin-2-yloxy)-cis-2-methyl-piperidine-1-carboxylic acid tert-butyl ester isomer 2 (preparation 48, 0.725 g), benzhydrylideneamine (0.482 g), racemic-2,2′-bis(diphenylphosphino)-1,1′binaphthyl (55 mg) and sodium t-butoxide (0.299 g) in toluene (20 mL) and heat at 100° C. After 10 min., add tris(dibenzylidineacetone)-dipalladium(0) (41 mg) and heat at 100° C. After 2.5 hr., partition between ethyl acetate-hexane (1:4) and saturated aqueous NaCl, dry over anhydrous sodium sulfate, evaporate and purify on a 10 g silica gel column eluting with dichloromethane-2M NH3 in methanol, gradient) to give the crude title compound (1.19 g). Mass spectrum (electrospray): m/z=472 (M+1).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C@H:7]2[C@H:12]([OH:13])[CH2:11][CH2:10][N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8]2)[C:5](=[O:21])[CH2:4][S:3]1.[Cl:22][C:23]1[CH:40]=[CH:39][C:26]([CH2:27][N:28]2[C:36]3[C:31](=[CH:32][C:33]([CH:37]=O)=[CH:34][CH:35]=3)[CH:30]=[N:29]2)=[C:25]([C:41]([F:44])([F:43])[F:42])[CH:24]=1>>[C:17]([O:16][C:14]([N:9]1[CH2:10][CH2:11][CH:12]([OH:13])[CH:7]([N:6]2[C:5](=[O:21])/[C:4](=[CH:37]/[C:33]3[CH:32]=[C:31]4[C:36](=[CH:35][CH:34]=3)[N:28]([CH2:27][C:26]3[CH:39]=[CH:40][C:23]([Cl:22])=[CH:24][C:25]=3[C:41]([F:44])([F:42])[F:43])[N:29]=[CH:30]4)/[S:3][C:2]2=[O:1])[CH2:8]1)=[O:15])([CH3:18])([CH3:20])[CH3:19]
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H](N2C(=O)CSC2=O)C1
Product: CC(C)(C)OC(=O)N1CCC(O)C(N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)C1

Procedure:
(5Z)-3-{5-[1-(4-chloro-2-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]-2,4-dioxothiazolidin-3-yl}-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester was prepared from 1,1-dimethylethyl trans-3-(2,4-dioxo-1,3-thiazolidin-3-yl)-4-hydroxypiperidine-1-carboxylate (from Example 270) and [4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-carbaldehyde (from Example 1) following General Procedure F1.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:48]=[CH:47][C:9]([CH2:10][NH:11][C:12]2[CH:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]3[CH:46]=[CH:45][C:28]([C:29]([NH:31][CH2:32][C:33]([CH3:44])([CH3:43])[CH2:34][NH:35]C(=O)OC(C)(C)C)=[O:30])=[CH:27][CH:26]=3)[N:13]=2)=[CH:8][CH:7]=1.[C:49]([OH:55])([C:51]([F:54])([F:53])[F:52])=[O:50].C(Cl)Cl>>[C:49]([OH:55])([C:51]([F:54])([F:53])[F:52])=[O:50].[NH2:35][CH2:34][C:33]([CH3:44])([CH3:43])[CH2:32][NH:31][C:29](=[O:30])[C:28]1[CH:45]=[CH:46][C:25]([NH:24][C:14]2[N:13]=[C:12]([NH:11][CH2:10][C:9]3[CH:47]=[CH:48][C:6]([O:5][CH2:4][CH2:3][CH2:2][Br:1])=[CH:7][CH:8]=3)[CH:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:21])[F:22])[N:15]=2)=[CH:26][CH:27]=1
Reactant: CC(C)(CNC(=O)OC(C)(C)C)CNC(=O)c1ccc(Nc2nc(NCc3ccc(OCCCBr)cc3)cc(OCC(F)(F)F)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(CN)CNC(=O)c1ccc(Nc2nc(NCc3ccc(OCCCBr)cc3)cc(OCC(F)(F)F)n2)cc1
Yield: 84 %

Procedure:
tert-butyl (3-(4-((4-((4-(3-bromopropoxy)benzyl)amino)-6-(2,2,2-trifluoroethoxy)pyrimidin-2-yl)amino)benzamido)-2,2-dimethylpropyl)carbamate (35 mg, 0.047 mmol) was stirred in TFA/DCM (1:1) solution (2 mL) for 1 h. The solution was concentrated and free TFA to give N-(3-amino-2,2-dimethylpropyl)-4-((4-((4-(3-bromopropoxy)benzyl)amino)-6-(2,2,2-trifluoroethoxy)pyrimidin-2-yl)amino)benzamide (31 mg, 84%) which was carried to the next step without purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[Br:31][C:32]1[C:40]2[O:39][C:38]([CH2:41]O)=[CH:37][C:36]=2[CH:35]=[C:34]([Cl:43])[CH:33]=1>C1(C)C=CC=CC=1.O>[Br:31][C:32]1[C:40]2[O:39][C:38]([CH2:41][N:24]3[C:20](=[O:30])[C:21]4[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:23]3=[O:25])=[CH:37][C:36]=2[CH:35]=[C:34]([Cl:43])[CH:33]=1
Reactant: OCc1cc2cc(Cl)cc(Br)c2o1
Reactant: O=C1NC(=O)c2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1Cc1cc2cc(Cl)cc(Br)c2o1
Reaction time: 0.17 h
Yield: 84.8 %

Procedure:
To a solution of triphenylphoshine (1.44 g, 5.48 mmol) in toluene (50 mL) cooled to 0° C. was added the diisopropylazadicarboxylate (1.11 g, 5.48 mmol) followed by the phthalimide (0.81 g, 5.48 mmol) and the reaction mixture allowed to stir for 10 min. The (7-bromo-5-chloro-1-benzofuran-2-yl)methanol (1.37 g, 5.22 mmol) was then added and the reaction was allowed to stir at 0° C. an additional 1 h. The reaction mixture was then quenched with water (1 mL) and the solvent was removed in vacuo to provide a crude solid. The solid was suspended in water (100 mL) and the aqueous layer was extracted with ethyl acetate (3×100 mL), the combined organic extracts were washed with saturated aqueous sodium chloride (50 mL), dried (magnesium sulfate), and the solvent removed in vacuo to provide a crude residue. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:5) provided 1.73 g (85%) of 2-[(7-bromo-5-chloro-1-benzofuran-2-yl)methyl]-1H-isoindole-1,3(2H)-dione as a white solid. mp 194-198° C.; HRMS-ESI (m/z). [M+H]+ calcd for C17H9BrClNO3, 388.94545; found, 389.9553.