Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1>>[F:12][C:2]([F:1])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([NH:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:34])[CH:31]([CH3:32])[CH3:33])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1)=[O:5]
Reactant: O=C(O)C(F)(F)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(F)(F)c3ccccc3)CC2)c1

Procedure:
Example 125 was prepared from 2,2-difluoro-2-phenylacetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.71 (s, 1H), 7.65–7.62 (m, 2H), 7.50 (s, 1H), 7.47–7.40 (m, 3H), 7.35 (d, 1H, J=7.6 Hz), 7.22 (t, 1H, J=7.2 Hz), 6.95 (d, 1H, J=7.8 Hz), 3.45 (q, 2H, J=5.3 Hz), 3.10 (d, 2H, J=10.9 Hz), 2.59–2.45 (m, 4H), 2.11–2.02 (m, 2H), 1.89–1.71 (m, 6H), 1.20 (d, 6H, J=6.9 Hz); ESMS m/e: 458.4 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH3:10])=[CH2:9])[N:3]=1.[Cl:11]N1C(=O)CCC1=O.C1C=CC=CC=1>CCCCCC>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH2:10][Cl:11])=[CH2:9])[N:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: C=C(C)c1cccc(Br)n1
Solvent: CCCCCC
Solvent: c1ccccc1
Product: C=C(CCl)c1cccc(Br)n1
Temperature: 80 °C
Reaction time: 5 h
Yield: 35.5 %

Procedure:
A mixture of 3.60 g of 2-bromo-6-isopropenylpyridine, 2.91 g of N-chlorosuccinimide and 8 ml of benzene was stirred at 80° C. for 5 hours. After the reaction mixture was cooled to room temperature, n-hexane was added thereto to remove the insoluble matter through filtration. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluted with n-hexane then n-hexane - ethyl acetate 20:1) to obtain 1.50 g of the objective compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([C:9]([NH:11][O:12][C@@H:13]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:27][CH:26]=2)[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH2:39]([N:46]=[C:47]=[O:48])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(N(CC)CC)C>ClCCl>[CH2:32]([O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][C@H:13]([O:12][NH:11][C:9]([C:3]2([CH2:2][NH:1][C:47]([NH:46][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:48])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)=[O:10])[C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])=[CH:26][CH:27]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C=NCc1ccccc1
Reactant: NCC1(C(=O)NO[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)OCc2ccccc2)CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccc1)NCC1(C(=O)NO[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)OCc2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
To a solution of (S)-benzyl 2-(1-(aminomethyl)cyclohexanecarboxamidooxy)-3-(4-(benzyloxy)phenyl)propanoate in dichloromethane 9 ml, benzyl isocyanate 143 μl (1.16 mmol) and triethylamine 271 μl (1.94 mmol) were added and the mixture was stirred at room temperature overnight. The reaction mixture was washed with water 10 ml and brine 10 ml. Then the organic phase was dried over magnesium sulfate, filtered and concentrated. The crude residue was purified on silica gel column chromatography (Merck 60N spherical, neutral elution by n-hexane:ethylacetate=100:0 to 70:30) to obtain the title compound 257 mg (41%).
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([O:5][CH2:6]1)[C:3](=[O:9])[O:2]2.O1C=CC[CH2:12][CH:11]1C([O-])=O.[Na+].C(I)C>CN(C)C=O>[O:5]1[CH:6]=[CH:1][CH2:8][CH2:7][CH:4]1[C:3]([O:2][CH2:11][CH3:12])=[O:9]
Reactant: O=C1OC2CCC1OC2
Reactant: O=C([O-])C1CCC=CO1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCI
Product: CCOC(=O)C1CCC=CO1

Procedure:
The synthesis of 2,5-dioxabicyclo[2.2.2]octan-3 one was achieved through a three step reaction sequence as illustrated below: ##STR3## Sodium 3,4-dihydro-2H-Pyran-2-carboxylate was esterified with ethyl iodide in dimethylformamide to afford ethyl 3,4-dihydro-2H-pyran-2-carboxylate. Subsequent hydroboration with a borane solution in tetrahydropyran at 0° C., followed by oxidation with a sodium dichromate-sulfuric acid aqueous solution and subsequent treatment with sodium hydrogen sulfite gave ethyl 5-hydroxytetrahydropyran-2-carboxylate as a stereoisomer mixture. The hydroxytetrahydropyran ester was heated in a dilute solution in the presence of a catalytic amount of p-toluenesulfonic acid, any ethyl alcohol being liberated was removed through a Soxhlet extractor containing type 5A molecular sieves. Column chromatographic separation of the reaction products and subsequent repeated recrystallization gave the bicyclic lactone as colorless crystals; the overall yield was approximately 20%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:28]=[CH:29][C:30]([CH2:33][CH3:34])=[CH:31][CH:32]=3)[O:24][C:25]=2[CH3:26])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Reactant: CCc1ccc(-c2nc(CCl)c(C)o2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCOC(=O)C(Cc1ccc(OCc2nc(-c3ccc(CC)cc3)oc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 120 f], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 129 c]) was reacted with 4-chloromethyl-2-(4-ethyl-phenyl)-5-methyl-oxazole (example 122 a]) in the presence of potassium carbonate and potassium iodide to yield [rac]-2-ethoxy-3-{4-[2-(4-ethyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 120 f] to yield [rac]-2-ethoxy-3-{4-[2-(4-ethyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic acid as light yellow solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:23]3[C:18]([CH2:19][CH:20]=[CH:21][CH:22]=3)=[CH:17][NH:16][C:15]2=[O:24])[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl.O.[H][H]>[Pd].CO>[N:14]1([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][NH:16][C:15]1=[O:24]
Reactant: O=C1NC=C2CC=CC=C2N1C1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: O=C1NCc2ccccc2N1C1CCNCC1
Temperature: 40 °C
Yield: 44.3 %

Procedure:
In this reference example, 16.0 g of 1-benzyl-4-[3,5-dihydro-2(1H)-quinazolinon-1-yl]-piperidine, 4.0 g of 10% Pd-C, 50 ml of 1 N hydrochloric acid, 150 ml of water and 300 ml of methanol are mixed and stirred at 40° C. Hydrogen gas is introduced to the mixture for 5 hours with stirring. Then, the Pd-C is removed by filtration and the filtrate is concentrated. The white crystalline residue is dissolved in 50 ml of water. The solution is adjusted to pH 10 with aqueous 5 N sodium hydroxide and extracted with chloroform. The extract is washed with water, dried and thereafter concentrated. Then, 50 ml of a mixture of ethyl acetate and n-hexane (1:1 by volume) is added to the residue. After trituration, the solid is separated by filtration, washed with the same mixed solvent to obtain 9.9 g of a crude product. The crude product is recrystallized from water-ethanol to obtain 5.1 g of the desired product.
Reaction SMILES: [C:1]([C:5]1[CH:48]=[CH:47][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][CH2:18][N:19]([CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]([O:45]C)=[O:44])=[CH:39][CH:38]=2)[CH:20]2[CH2:29][CH2:28][CH2:27][C:26]3[N:25]=[C:24]([C:30]([O:32]CC)=[O:31])[CH:23]=[CH:22][C:21]2=3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.O>[C:1]([C:5]1[CH:48]=[CH:47][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][CH2:18][N:19]([CH2:35][CH2:36][C:37]2[CH:38]=[CH:39][C:40]([C:43]([OH:45])=[O:44])=[CH:41][CH:42]=2)[CH:20]2[CH2:29][CH2:28][CH2:27][C:26]3[N:25]=[C:24]([C:30]([OH:32])=[O:31])[CH:23]=[CH:22][C:21]2=3)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1ccc(C(=O)OC)cc1)CCc1ccccc1OCc1ccc(C(C)(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(COc2ccccc2CCN(CCc2ccc(C(=O)O)cc2)C2CCCc3nc(C(=O)O)ccc32)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
35 mg (0.05 mmol) of ethyl 5-[(2-{2-[(4-tert-butylbenzyl)oxy]phenyl}ethyl){2-[4-(methoxycarbo-nyl)phenyl]ethyl}amino]-5,6,7,8-tetrahydroquinoline-2-carboxylate (Example 43A) were taken up in 1 ml of THF and 1 ml of water, and 7 mg (0.16 mmol) of lithium hydroxide monohydrate were added. The reaction was stirred at 50° C. overnight. After the reaction had gone to completion, the THF was removed on a rotary evaporator and the mixture that remained was diluted with water. The mixture was then acidified with 1 M hydrochloric acid and extracted repeatedly using a 1:1 mixture of ethyl acetate and dichloromethane. The combined organic phases were dried over magnesium sulphate, filtered and concentrated to dryness. This gave 29 mg (0.04 mmol, content 91%, 81% of theory) of the title compound as a yellowish solid.
Reaction SMILES: O.CC1C=CC(S(O)(=O)=O)=CC=1.[OH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16](O)[C:15]=1[NH:21][C:22](=[O:37])[CH2:23][C:24]1[NH:25][C:26](=[O:36])[CH:27]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:29]=1>C1(C)C(C)=CC=CC=1>[OH:13][C:14]1[C:15]2[N:21]=[C:22]([CH2:23][C:24]3[NH:25][C:26](=[O:36])[CH:27]=[C:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[N:29]=3)[O:37][C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1c(O)cccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: O=c1cc(N2CCOCC2)nc(Cc2nc3c(O)cccc3o2)[nH]1
Temperature: 0 °C
Yield: 79.3 %

Procedure:
239 mg of 4-methylbenzenesulphonic acid hydrate are added to a solution of 870 mg of N-(2,6-dihydroxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide in 60 ml of ortho-xylene. The reaction mixture is brought to reflux for 4 hours. After cooling to 0° C., the insoluble material formed is filtered off. The filtrate is concentrated to dryness under reduced pressure and then the residue is chromatographed on a silica gel column, elution being carried out with 90/10 CH2Cl2/MeOH. 654 mg of 2-[(4-hydroxy-1,3-benzoxazol-2-yl)methyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are thus obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [I-].[Na+:2].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1>CC(C)=O>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([O-:13])=[O:12])=[CH:9][CH:10]=1.[Na+:2]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(S(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
Sodiumiodide (21.76 grams, 145.2 mmol) and 4-methoxybenzenesulfonyl chloride (10.0 grams, 48.39 mmol) were combined in dry acetone (dried over MgSO4 and filtered) (200 ml) and stirred at room temperature overnight. Collected fine white solids via suction filtration. Dried on high vacuum giving 9.11 grams of sodium 4-methoxybenzenesulfinate as a pale yellow fine powder (97% yield).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:16]2[CH:20]=[C:19]([C:21](=[O:24])[CH2:22][CH3:23])[N:18]([CH2:25][CH3:26])[CH:17]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:34][CH2:35][CH3:36]>CN(C=O)C>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:16]2[CH:20]=[C:19]([C:21](=[O:24])[CH2:22][CH3:23])[N:18]([CH2:25][CH3:26])[CH:17]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:34][CH2:35][CH3:36])[CH:10]=2)[N:3]=1
Reactant: CCCI
Reactant: CCC(=O)c1cc(C2(c3cccc(O)c3)N=C(N)N(C)C2=O)cn1CC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCOc1cccc(C2(c3cc(C(=O)CC)n(CC)c3)N=C(N)N(C)C2=O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 44.8 %

Procedure:
Under a nitrogen atmosphere, a solution of 2-amino-5-(1-ethyl-5-propionyl-1-H-pyrrol-3-yl)-5-(3-hydroxy-phenyl)-3-methyl-3,5-dihydro-imidazol-4-one (0.08 g, 0.225 mmol) in DMF (5 mL) was treated with Cs2CO3 (0.15 g, 0.45 mmol) and iodopropane (0.046 g, 0.27 mmol). The reaction mixture was sealed and stirred at room temperature for 20 hours. The solvent was removed in vacuo and the residue was dissolved in CHCl3 and filtered. The filtrate was evaporated. The resultant residue was purified by combi flash chromatography (ethyl acetate/methylene chloride/methyl alcohol/triethyl amine, 5/4.4/0.5/0.1) to give the title compound as a white solid (0.04 g, 45% yield), mp 95° C., 1H NMR (400 MHZ, DMSO-d6) δ 0.89-0.99 (dt, 6H), 1.15 (t, 3H), 1.64-1.66 (m, 2H), 2.64-2.68 (m, 2H), 2.9 (s, 3H), 3.81 (m, 2H), 4.20 (m, 2H), 6.50 (bs, 2H), 6.72-6.74 (m, 1H), 6.87 (s, 1H), 7.0-7.02 (m, 3H), 7.14 (m, 1H), MS m/e (M+H)+ 397.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[NH2:33])[C:27]([OH:29])=[O:28].Cl>C(O)(C)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:33][C:32]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=4[O:23][CH3:22])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cl
Solvent: CC(C)(C)O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 53 °C
Reaction time: 60 h

Procedure:
A mixture of 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (2.542 kg, 8.05 mol), 3-methoxy-4-aminobenzoic acid (1.50 kg) in t-butyl alcohol (23 L) and heat to about 53° C. Add conc. HCl (951 g) over about 10 minutes, heat to 80° C. and stir for 60 hours. The temperature was adjusted to 15° C. and stirred for 40 hours to give a solid which was collected by filtration, rinsed with isopropyl alcohol/water (1:1, 2×2.5 L) and dried under a stream of nitrogen for about 1.5 hours, then in a vacuum oven at 40° C. for 4 days to give 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH:21]([O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O)([CH3:23])[CH3:22]>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([O:24][CH:21]([CH3:23])[CH3:22])[CH:26]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: CC(C)Oc1cccc(C=O)c1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cccc(OC(C)C)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with 3-isopropoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.91 min.; [M+H]+: 384.08 g/mol.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].FC(F)(F)C(O)=O.[N:17]([O-:19])=[O:18].[Na+]>O>[CH3:8][C:7]1[C:2]([CH3:1])=[CH:3][C:4]([OH:9])=[C:5]([N+:17]([O-:19])=[O:18])[CH:6]=1
Reactant: O=N[O-]
Reactant: Cc1ccc(O)cc1C
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cc(O)c([N+](=O)[O-])cc1C
Temperature: 25 °C
Reaction time: 14 h
Yield: 80 %

Procedure:
To 3,4-dimethylphenol(12.1 g, 0.1 mol), trifluoroacetic acid(250 ml) was added, and in water bath sodium nitrite(12.4 g, 0.18 mol) was added slowly. The resulting mixture was stirred at room temperature for 14 hours and concentrated under the reduced pressure to remove trifluoroacetic acid, followed by addition of water(150 ml), extracted with ether and purified by column chromatography to obtain the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5](Cl)=[O:6].[NH2:15][C:16]([CH3:32])([CH2:19][N:20]1[CH:28]=[C:27]2[C:22]([C:23]([Cl:31])=[C:24]([Cl:30])[CH:25]=[C:26]2[Cl:29])=[N:21]1)[C:17]#[N:18]>C1COCC1>[C:17]([C:16]([NH:15][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([C:11]([F:14])([F:13])[F:12])=[C:2]([F:1])[CH:3]=1)([CH3:32])[CH2:19][N:20]1[CH:28]=[C:27]2[C:22]([C:23]([Cl:31])=[C:24]([Cl:30])[CH:25]=[C:26]2[Cl:29])=[N:21]1)#[N:18]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)c(F)c1
Reactant: CC(N)(C#N)Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1
Solvent: C1CCOC1
Product: CC(C#N)(Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1)NC(=O)c1ccc(C(F)(F)F)c(F)c1

Procedure:
Using a procedure similar to that described in Example 60, except using a solution of 3-fluoro-4-trifluoromethylbenzoyl chloride (0.16 mmole) in THF and a solution of 2-amino-2-methyl-3-(4,6,7-trichloro-2H-indazol-2-yl)propionitrile (0.075 mmole, described in Example 147) in THF mixed with TEA (3% v./v.), the title compound was isolated as solid residue (13.9 mg). It was dissolved in DMSO for further biological evaluation and analyzed by LCMS. MS (ES): M/Z [M+H]=493, RT=0.76 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.O[CH2:13][C@@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:22]([O:21][C:19]([N:15]1[CH2:16][CH2:17][CH2:18][C@H:14]1[CH2:13][N:8]1[C:4]2[N:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]=2[C:10]([I:11])=[CH:9]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: Clc1ncnc2[nH]cc(I)c12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1Cn1cc(I)c2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.9 %

Procedure:
To a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (4.0 g, 14.34 mmol, 1.0 eq), (S)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (4.04 g, 20.08 mmol, 1.4 eq), and PPh3 (7.5 g, 28.68 mmol, 2.0 eq) in dry THF (30 mL), DIAD (5.80 g, 28.68 mmol, 2.0 eq) was added dropwise at 0° C. The mixture was stirred at RT for 5 h. The reaction mixture was concentrated and purified by silica gel chromatography (eluted with PE:EtOAc 1:1) to afford (S)-2-(4-chloro-5-iodo-pyrrolo[2,3-d]pyrimidin-7-ylmethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (5.1 g, 77% in yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12]([OH:14])[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.Cl[CH2:17][C:18]([NH2:20])=[O:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[C:12]([O:14][CH2:17][C:18](=[O:19])[NH2:20])[CH:13]=[C:4]([C:3]([O:2][CH3:1])=[O:15])[CH:5]=1
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Reactant: NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(OCC(N)=O)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of 5-hydroxyisophthalic acid dimethyl ester (500 mg, 2.38 mmol) and chloroacetamide (245 mg, 2.62 mmol) in DMF (7 mL) is added potassium carbonate (986 mg, 7.14 mmol) and the mixture is stirred at room temperature for 2 days. Water is added to the mixture and then it is extracted with ethyl acetate. The organic phase is washed with water and brine and is dried over sodium sulfate. The organic solution is concentrated to one fourth volume to give a precipitate. The solid is filtered, washed with ethyl acetate and dried under reduced pressure to give 5-carbamoylmethoxyisophthalic acid dimethyl ester. MS 268.2 (M+1);); 1H-NMR (400 MHz, CDCl3); δ ppm 3.96 (s, 6H), 4.59 (s, 2H), 5.87 (s, broad, 1H), 6.55 (s, broad, 1H), 7.79 (s, 2H), 8.37 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[C:6]([O:9][CH3:10])[C:5]([O:11][CH:12]([F:14])[F:13])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[CH2:22][CH3:23]>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH:12]([F:13])[F:14])=[C:6]([O:9][CH3:10])[C:7]=1[O:8][CH2:21][CH2:22][CH3:23]
Reactant: COc1c(OC(F)F)ccc(Br)c1O
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCOc1c(Br)ccc(OC(F)F)c1OC
Temperature: 80 °C
Yield: 86.5 %

Procedure:
To a stirring solution of 6-bromo-3-(difluoromethoxy)-2-methoxyphenol (300 mg, 1.115 mmol) in acetonitrile (10 mL) was added potassium carbonate (495 mg, 2.334 mmol) and propyl bromide (411 mg, 3.34 mmol) and the resultant reaction mixture was heated to 80° C. for 3 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure to afford 300 mg of 1-Bromo-4-(difluoromethoxy)-3-methoxy-2-propoxybenzene (Int14-F2) as a solid. A stirring solution of 1-bromo-4-(difluoromethoxy)-3-methoxy-2-propoxybenzene (300 mg, 0.964 mmol) in dimethylformamide (5 mL) was purged with argon for 1 h, to this cesium carbonate (625 mg, 1.926 mmol), tetrakis(triphenylphosphine) palladium(0) (37 mg, 0.032 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (199 mg, 0.771 mmol) were added and the resultant reaction mixture was heated to 80-90° C. for 3 h. The reaction mixture was cooled to RT, filtered and the filtrate was diluted with water and extracted with ethyl acetate (3×). The combined ethyl acetate layer was washed with brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) afforded the title compound as a solid (40 mg, 11%).
Reaction SMILES: [F:1][C:2]([S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12]C)([F:4])[F:3].Br.C(O)(=O)C>O>[F:1][C:2]([S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])([F:4])[F:3]
Reactant: COc1ccccc1SC(F)(F)F
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccccc1SC(F)(F)F
Yield: 46 %

Procedure:
A mixture of 4.69 g of 2-methoxyphenyl trifluoromethyl sulfide, obtained according to Example 3, 20 ml of 48% strength by weight aqueous hydrobromic acid, and 20 ml of 96% strength by weight acetic acid was boiled under reflux for 24 hours. The completion of the reaction was then checked by gas chromatography. After cooling, the reaction mixture was poured into water. The organic phase was separated off and the aqueous phase was extracted with dichloromethane. The extract was combined with the organic phase. Drying over magnesium sulfate, concentration, and vacuum distillation gave 2.01 g (46% of theory) of 2-hydroxyphenyl trifluoromethyl sulfide (boiling point 65-66° C. at 26 mbar, melting point 35-37° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][C@H:14]2[CH2:23][O:24][CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])(=[O:12])=[O:11])=[C:5]([CH3:33])[CH:4]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][C@H:14]2[CH2:23][O:24][CH2:25][C:26]([OH:28])=[O:27])(=[O:12])=[O:11])=[C:5]([CH3:33])[CH:4]=1
Reactant: COc1cc(C)c(S(=O)(=O)N2c3ccccc3CC[C@H]2COCC(=O)OC(C)(C)C)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N2c3ccccc3CC[C@H]2COCC(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-tert-Butyl 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydroquinoline-2-yl)methoxy)acetate (1 g, 2.103 mmol) was dissolved in dichloromethane (15 ml) and trifluoroacetic acid (3.24 ml, 42.05 mmol) was added slowly. After stirring at room temperature for 2 h, the solvent was removed in vacuo and the residue was co-evaporated twice more with 20 ml of toluene each time. Yield: 0.84 g (95%).