Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:13][CH2:12][NH:11][CH2:10]2)=[CH:6][C:5]([C:14]#[N:15])=[CH:4][C:3]=1[NH:16][C:17]1[N:22]=[C:21]([N:23]([CH:33]2[CH2:35][CH2:34]2)CC2C=CC(OC)=CC=2)[C:20]2=[N:36][CH:37]=[C:38]([C:39]#[N:40])[N:19]2[N:18]=1.[O:41]1[CH2:44][C:43](=O)[CH2:42]1.C(O)(=O)C.C([BH3-])#N.[Na+]>ClCCl.CO>[Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:13][CH2:12][N:11]([CH:43]3[CH2:44][O:41][CH2:42]3)[CH2:10]2)=[CH:6][C:5]([C:14]#[N:15])=[CH:4][C:3]=1[NH:16][C:17]1[N:22]=[C:21]([NH:23][CH:33]2[CH2:35][CH2:34]2)[C:20]2=[N:36][CH:37]=[C:38]([C:39]#[N:40])[N:19]2[N:18]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(OC4CCNC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: O=C1COC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(OC2CCN(C3COC3)C2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (+/−)-2-((2-chloro-5-cyano-3-(pyrrolidin-3-yloxy)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (36 mg, 0.065 mmol), oxetan-3-one (8.30 μl, 0.129 mmol), acetic acid (7.41 μl, 0.129 mmol) and molecular sieves (30 mg) in dichloromethane (1 mL)/Methanol (1 mL) was stirred at room temperature overnight. sodium cyanoborohydride (12.21 mg, 0.194 mmol) was added and the reaction mixture was stirred for 1 h. The reaction mixture was filtered through a plug of celite and the filtrate was concentrated. The crude product (38 mg) was used without purification.
Reaction SMILES: [CH2:1]([S:11]([NH:14][C:15]([C:17]1[CH:18]=[C:19]([O:26][CH3:27])[C:20]([C:23]([OH:25])=O)=[N:21][CH:22]=1)=[O:16])(=[O:13])=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH2:39]([O:43][C:44](=[O:47])[CH2:45][NH2:46])[CH2:40][CH2:41][CH3:42].NCC(O)=O.C(O)CCC>O.C1(C)C=CC=CC=1>[CH2:39]([O:43][C:44]([CH2:45][NH:46][C:23]([C:20]1[C:19]([O:26][CH3:27])=[CH:18][C:17]([C:15]([NH:14][S:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:12])=[O:13])=[O:16])=[CH:22][N:21]=1)=[O:25])=[O:47])[CH2:40][CH2:41][CH3:42]
Reactant: CCCCCCCCCCS(=O)(=O)NC(=O)c1cnc(C(=O)O)c(OC)c1
Reactant: CCCCOC(=O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: NCC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCCCO
Product: CCCCCCCCCCS(=O)(=O)NC(=O)c1cnc(C(=O)NCC(=O)OCCCC)c(OC)c1

Procedure:
The title compound was prepared from 0.5 g (1.25 mmol) of 5-[((1-decylsulfonyl)amino)carbonyl]-3-methoxypyridine-2-carboxylic acid (cf. Example 25a)) and 0.46 g (1.5 mmol) of glycine 1-butyl ester tosylate (prepared from glycine, 1-butanol, p-tos.OH using toluene in a water separator). 0.31 g of product was obtained, m.p. 82°-85° C. (from diisopropyl ether/ethyl acetate (2:1)).
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][NH:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[C:6]1([C:4]2[O:13][C:1](=[O:12])[CH2:2][N:3]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(O)CNC(=O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: O=C1CN=C(c2ccccc2)O1
Temperature: 90 °C

Procedure:
This procedure is a modification of Crawford and Little (J. Chem. Soc. 1959, 729). A flask containing hippuric acid (20 g, 0.011 mol, Aldrich) and acetic anhydride (130 mL) was placed in a boiling H2O bath (90° C.) and vigorously stirred for exactly 15 min. The solution was poured onto 200 mL of toluene, 200 mL of ice water and stirred vigorously for 5 min. The phases were separated and the organic phase was stirred with 1 L of 2% aq. NaHCO3 for 10 min., separated and dried with anhydrous Na2SO4. Filtration of the solution and rotary evaporation (bath temperature 35° C., 20 mmHg) gave a yellow white solid. The formation of a red material in this procedure is due to protect degradation and condensation. Yield 11.8 g, 66%, mp 83°-86°. 1H NMR (CDCl3): δ7.95 (d, 2H; J=7 Hz); 7.55 (t, 1H, J=7 Hz), 7.45 (t, 2H, J=7 Hz), 4.38 (s, 1H). 13C NMR (CDCl3): 175.9, 163.4, 132.7, 128.8, 127.7, 125.8, 54.9.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][N:6]1[C:10](=[O:11])[CH:9]2[CH:12]=[C:13](Br)[S:14][CH:8]2[C:7]1=[O:16])[CH3:2].[O:18]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][N:6]1[C:10](=[O:11])[CH:9]2[CH:12]=[C:13]([C:28]3[CH:29]=[CH:30][C:25]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:26][CH:27]=3)[S:14][CH:8]2[C:7]1=[O:16])[CH3:2]
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)CN1C(=O)C2C=C(Br)SC2C1=O
Product: CCOC(=O)CN1C(=O)C2C=C(c3ccc(Oc4ccccc4)cc3)SC2C1=O

Procedure:
The title compound was prepared from (2-bromo-4,6-dioxo-3a,4,6,6a-tetrahydro-thieno[2,3-c]pyrrol-5-yl)-acetic acid ethyl ester, example 1-d, and 4-phenoxy-phenyl boronic acid under conditions analogous to experimental example 3-a. 1H NMR (CDCl3, 200 MHz): δ=7.58-7.54 (d, J=8.97 Hz, 2H), 7.41-7.34 (m, 3H), 7.20-7.0 (m, 4H), 4.35 (s, 2H), 4.27-4.17 (q, J=7.0, 2H), 1.32-1.25 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](Cl)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[Si]([N:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1)(C(C)(C)C)(C)C.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C(#N)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reactant: CN1CCN([Si](C)(C)C(C)(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C)CC3)cc21
Yield: 312 %

Procedure:
0.5 g (1.85 mmol) of 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (II, R1 : ethyl; X: chloro) and 1.07 g (0.50 mmol) of 4-(t-butyldimethylsilyl)-1-methyl piperazine (III, R2, R3 and R4 : methyl; R5 : t-butyl) are added to 100 ml of acetonitrile and then heated with stirring. A solution of 1.60 g (0.50 mmol) of tetrabutyl ammonium fluoride trihydrate in 5 ml of acetonitrile is added dropwise to the reaction mixture. After heating with stirring for 3 hours,the solvent is stripped off and water is added thereto to give a solid. After filtering and drying, 0.52 g (85% yield) of a solid compound is afforded.
Reaction SMILES: O=[C:2]1[NH:6][C:5]2[C:7]([Cl:25])=[CH:8][C:9]([F:24])=[C:10]([N:11]3[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]3=[O:23])[C:4]=2[O:3]1.P(Cl)(Cl)([Cl:28])=O.C(N(CC)CC)C>>[Cl:28][C:2]1[O:3][C:4]2[C:10]([N:11]3[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[N:13]([CH3:22])[C:12]3=[O:23])=[C:9]([F:24])[CH:8]=[C:7]([Cl:25])[C:5]=2[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3[nH]c(=O)oc23)c1=O
Solvent: CCN(CC)CC
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3nc(Cl)oc23)c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A stirring solution of 3.8 grams (10 mmole) of 3-(2-oxo-4-chloro-6-fluoro-2,3-dihydrobenzoxazol-7-yl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione and 7.7 grams (50 mmole) of phosphorus oxychloride is cooled in an ice bath. To this 5.0 grams (49.4 mmole) of triethylamine is added via syringe during a ten minute period. At the conclusion of this period the reaction mixture is heated to reflux where it stirs for four hours. After this period the reaction mixture is cooled to ambient temperature and poured into ice water. The resulting mixture is extracted with portions of diethyl ether. The extracts are combined, washed with an aqueous saturated sodium bicarbonate solution, dried with sodium sulfate, and filtered. The filtrate is concentrated under reduced pressure, yielding 3-(2,4-dichloro-6-fluorobenzoxazol-7-yl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione.
Reaction SMILES: C([N:8]1[CH2:25][CH2:24][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:10]=2[CH2:9]1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[F:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:15]2[C:10]3[CH2:9][NH:8][CH2:25][CH2:24][C:11]=3[N:12]=[CH:13][N:14]=2)=[CH:18][CH:19]=1
Reactant: Fc1ccc(Nc2ncnc3c2CN(Cc2ccccc2)CC3)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Fc1ccc(Nc2ncnc3c2CNCC3)cc1
Reaction time: 24 h
Yield: 101.3 %

Procedure:
6-Benzyl-N-(4-fluorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (0.64 g, 1.9 mmol) was dissolved in methanol (25 mL) and palladium hydroxide was added (0.5 g, 20% wt). The mixture was shaken on a Parr Shaker under. H2 (g) atmosphere (60 PSI) for 1 day. The mixture was filtered through celite and evaporated to give 0.47 g of material which was used as such for the next step.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[S:23](Cl)(=[O:25])=[O:24])[CH:16]=[CH:15][CH:14]=1>>[N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[S:23]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:25])=[O:24])[CH:16]=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2cccc3cccnc23)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 8-quinolinesulfonyl chloride as described in the synthetic METHOD B to give a white-yellow solid (9.2 mg) with purity >80%. LCMS (pos) m/z 378.2.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[C:13]([NH:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[C:19]([O:26][CH3:27])[CH:18]=1)(=[O:15])[CH3:14]>>[CH3:12][N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][C:17]([NH:16][C:13](=[O:15])[CH3:14])=[CH:18][C:19]=2[O:26][CH3:27])[CH2:7]1
Reactant: CN1CCc2c(N)cccc2C1
Reactant: COc1cc(NC(C)=O)ccc1C(=O)O
Product: COc1cc(NC(C)=O)ccc1C(=O)Nc1cccc2c1CCN(C)C2

Procedure:
The title compound was prepared in an analogous manner to Example 1 from 5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and 4-acetylamino-2-methoxybenzoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[O:5][CH2:6][CH2:7][OH:8].N1C=CN=C1.[CH3:17][C:18]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])[CH3:19]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[O:5][CH2:6][CH2:7][O:8][Si:21]([C:18]([CH3:20])([CH3:19])[CH3:17])([CH3:23])[CH3:22]
Reactant: OCCOc1cccc(Br)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCOc1cccc(Br)c1
Reaction time: 1 h

Procedure:
To a solution of 2-(3-Bromo-phenoxy)-ethanol (2.0 g, 9.2 mol) in dichloromethane (15 mL) at ice water bath temperature was added (1.25 g, 1.84 mmol) imidazole followed by the addition of TBSCl (1.67 g, 11 mmol) under nitrogen protection. TLC showed reaction was complete in 1 h. The reaction mixture was filtered. The filtrate was washed with water and dried over Na2SO4. The crude product was purified by column chromatography eluted with hexanes/ethyl acetate to afford titled product as a light color oil (2.65 g, 87%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][CH2:11][C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C(OC([NH:29][CH:30]([C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)[C:31](O)=[O:32])=O)(C)(C)C>>[NH2:29][C@@H:30]([C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)[C:31]([N:9]([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1)[CH2:10][CH2:11][C:12]1[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=1)=[O:32]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccc(F)cc1
Reactant: Cc1ccc(NCCc2ccc(C(F)(F)F)nc2)cc1C
Product: Cc1ccc(N(CCc2ccc(C(F)(F)F)nc2)C(=O)[C@@H](N)c2ccc(F)cc2)cc1C
Yield: 13 %

Procedure:
In analogy to example 1, (3,4-dimethyl-phenyl)-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-amine (250 mg, 0.85 mmol, prepared as per example 1, step 3) and tert-butoxycarbonylamino-(4-fluoro-phenyl)-acetic acid (343 mg, 1.27 mmol, commercially available) were coupled together and resolved by chromatography on a chiral columnto afford the title compound (48 mg, 13%) as a pale yellow oil which crystallized upon standing MS m/e: 446.2 [M+H]+.
Reaction SMILES: [C:1]([NH:5][NH:6][C:7]1([C:14]#[N:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].BrBr.C(NNC(C#N)(C1CC1)C)(C)(C)C>>[C:1]([N:5]=[N:6][C:7]1([C:14]#[N:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NNC1(C#N)CCCCCC1
Agent: BrBr
Agent: CC(C)(C)NNC(C)(C#N)C1CC1
Product: CC(C)(C)N=NC1(C#N)CCCCCC1
Reaction time: 10 h

Procedure:
1-t-Butylazo-1-cyanocycloheptane was prepared in 100% crude yield by oxidizing 1-t-butylhydrazo-1-cyanocycloheptane with bromine using the same procedure described in Example XIIIC for the oxidation of 1-t-butylhydrazo-1-cyano-1-cyclopropylethane. The crude product was chromatographed over alumina and the product eluted with pentane. The infrared spectrum of the purified product was consistent with the structure of the desired azo. The compound has a 10 hour half-life in trichlorobenzene at approximately 68°C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:5]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:6])[CH:8]=[CH:9][CH:10]=1
Reactant: C1CCNC1
Reactant: O=C(Cl)c1cccc(Br)c1
Solvent: ClCCl
Product: O=C(c1cccc(Br)c1)N1CCCC1
Reaction time: 4 h

Procedure:
A solution of 3-bromo-benzoyl chloride (2.7 g, 12 mmol) in DCM (40 mL) was chilled to zero degrees and treated with pyrrolidine (3 mL, 36.8 mmol). Reaction was allowed to come to room temperature and stir for 4 h. Mixture was then poured onto water and washed once. Organic phase then washed with brine, dried over sodium sulfate, filtered and evaporated to amber oil (3.1 g, 100%).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)=O.ClCC(Cl)=O.C([SiH](CC)CC)C.O>FC(F)(F)C(O)=O>[Cl:1][CH2:2][CH2:3][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2
Reactant: O=C1Cc2cc(C(=O)CCl)ccc2N1
Agent: CC[SiH](CC)CC
Agent: O=C(Cl)CCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C1Cc2cc(CCCl)ccc2N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
5-Chloroacetyl-2-oxindole (prepared by the same procedure used for the preparation of O-53, except starting from chloroacetyl chloride) (4.18 g) in 30 mL of trifluoroacetic acid in an ice bath was treated with 4.65 g of triethylsilane and stirred at room temperature for 3 hours. The mixture was poured into 150 mL of water and the precipitate collected by vacuum filtration, washed with 50 mL of water and dried to give 2.53 g (65% yield) of 5-(2-chloroethyl)-2-oxindole as a reddish-brown solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH2:10]([OH:13])[CH:11]=[CH2:12].[OH-].[Na+].C(=O)([O-])[O-].[K+].[K+]>O>[OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:12][CH2:11][CH2:10][OH:13])[CH2:6][CH2:5]1
Reactant: OCCN1CCNCC1
Reactant: C=CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: OCCCN1CCN(CCO)CC1

Procedure:
1-(2-hydroxyethyl)-piperazine, 26 grams, freshly distilled allyl alcohol, 36 g and sodium hydroxide, 8 g are heated to 118°-120° C. for 36 hours. The viscous reaction mixture is taken up into 250 ml water, and solid potassium carbonate is added to saturate the warmed solution. A yellow oil, the product, rises to the top. It is extracted with tetrahydrofuran, the solvent evaporated, the residue dissolved in ethanol, the solution filtered, and the ethanol evaporated under vacuum to a thick oil, which solidifies on standing to give the isolated product, [I], above.
Reaction SMILES: [CH3:1][O-:2].[Na+].C1(C)C=CC=CC=1.[CH3:11][O:12][C:13]1[C:31]([O:32][CH3:33])=[C:30]([O:34][CH3:35])[CH:29]=[C:28]([CH3:36])[C:14]=1[C:15]([C:17]1[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][N:20]=[CH:19][C:18]=1Cl)=[O:16].CN(C)P(=O)(N(C)C)N(C)C>O>[CH3:11][O:12][C:13]1[C:31]([O:32][CH3:33])=[C:30]([O:34][CH3:35])[CH:29]=[C:28]([CH3:36])[C:14]=1[C:15]([C:17]1[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][N:20]=[CH:19][C:18]=1[O:2][CH3:1])=[O:16]
Reactant: C[O-]
Reactant: COc1cc(C)c(C(=O)c2c(Cl)cncc2C(F)(F)F)c(OC)c1OC
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(C)c(C(=O)c2c(OC)cncc2C(F)(F)F)c(OC)c1OC
Yield: 63.9 %

Procedure:
16.4 g (304 mmol) of sodium methoxide was added to a toluene 150 ml solution of 18.5 g (47.5 mmol) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-3-chloro-5-trifluoromethylpyridine obtained in step (c) and 16.6 ml (95.4 mmol) of hexamethylphosphoric triamide, followed by stirring under reflux by heating for 30 minutes. Water was added thereto to terminate the reaction, the aqueous layer was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The crude product thus obtained was purified by silica gel column chromatography to obtain 11.7 g (yield 64%) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-3-methoxy-5-trifluoromethylpyridine (compound No. 122; m.p. 103-106° C.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]([CH3:27])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15](Br)=[C:14]([C:19]#[C:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:13]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].Br[Zn][CH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]([CH3:27])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[C:14]([C:19]#[C:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:13]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Br)c(C#Cc2ccccc2)n1
Reactant: Br[Zn]C1CCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CC(NC(=O)OC(C)(C)C)C(=O)Nc1ccc(C2CCCC2)c(C#Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
A mixture of tert-butyl-N-[1-[[5-bromo-6-(2-phenylethynyl)pyridin-2-yl]amino]-1-oxopropan-2-yl]carbamate C2d (60 mg, 0.14 mmol), bromo(cyclopentyl)zinc (0.5 M solution in THF, 1.6 ml, 0.81 mmol), Palladium(II) acetate (1.5 mg, 0.01 mmol), 2-Dicyclohexyl-phosphino-2′,4′,6′-triisopropylbiphenyl (6.4 mg, 0.01 mmol) in toluene (0.25 ml) is stirred at RT for 6 days. The reaction mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 18 mg (31%). HPLC-MS: M+H=434; tR=1.97 min (*Method—5).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([O:12]C)=[O:11])=[CH:4][CH:3]=1.Cl.[NH2:16]O.[OH-].[Na+].O>CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([OH:12])[O:11][N:16]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)CC(=O)c1ccc(C)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(-c2cc(O)on2)cc1

Procedure:
According to method of U.S. Pat. No. 3,781,438, 2 g of methyl 3-(4-methylphenyl)-3-oxopropanoate was dissolved in methanol, slightly excessive hydroxylamine hydrochloride and equivalent amount of sodium hydroxide were added, the mixture was heated to reflux. 3 hr later, the reaction was traced by Thin-Layer Chromatography, after the reaction, water was added to the reaction mixture, extracted with ethyl acetate, The combined organic extracts were dried and concentrated to obtain 3-(4-methylphenyl)isoxazol-5-ol as solid (compound III-3).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([F:17])([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:31][NH:32][O:33][CH3:34].O>ClCCl.C(OCC)(=O)C>[CH3:34][O:33][N:32]([CH3:31])[C:14]([C:11]1([F:17])[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCC(F)(C(=O)O)CC1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CON(C)C(=O)C1(F)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.6 %

Procedure:
After dissolving 2.19 g of 1-(tert-butoxycarbonyl)-4-fluoropiperidine-4-carboxylic acid in 30 ml of dichloromethane, 2.16 g of 1,1′-carbonyldimidazole was added and the mixture was stirred at room temperature for 1.5 hours. Next, 1.30 g of N-methyl-O-methylhydroxylamine hydrochloride was added and the mixture was stirred overnight at room temperature. Water was added to the reaction solution, and extraction was performed with ethyl acetate. The organic layer was washed with aqueous sodium carbonate solution, water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (2.33 g, 90% yield).
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[O:15])[CH2:10][CH2:9]2)=O)=[CH:4][CH:3]=1.N(C(OCC)=O)=NC(OCC)=O.[Cl:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[CH2:41][OH:42].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)(Cl)Cl.C1COCC1>[Cl:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[C:41]([O:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)=[O:42]
Reactant: O=C(Oc1cccnc1)N1CCN(C(=O)c2ccc(O)cc2)CC1
Reactant: OCc1cccc(Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: O=C(Oc1ccc(CN2CCN(C(=O)Oc3cccnc3)CC2)cc1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 62.8 %

Procedure:
A THF (5 ml) solution containing 3-pyridyl 4-(4-hydroxybenzoyl)-1-piperazinecarboxylate (300 mg) and diethyl azodicarboxylate (0.62 ml, 40% Tol solution) was dropwise added to a THF (5 ml) solution containing 3-chlorobenzyl alcohol (200 mg) and triphenylphosphine (360 mg), at 0° C., followed by stirring at room temperature for 3 days. The reaction solution was diluted with chloroform, washed with an aqueous saturated sodium hydrogencarbonate solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform:methanol=95:5 (v/v)), and the resulting solid was recrystallized from 2-propanol to obtain 3-pyridyl 4-{4-[(3-chlorobenzoyl)oxy]benzyl}-1-piperazinecarboxylate (260 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:19]1[N:20]=[N:21][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:23][CH:24]=1.C(OCC)(=O)C>CN1C(=O)CCC1.O>[CH:26]([O:25][C:22]1[N:21]=[N:20][C:19]([O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[CH:6][CH:7]=2)=[CH:24][CH:23]=1)([CH3:28])[CH3:27]
Reactant: CC(C)Oc1ccc(Cl)nn1
Reactant: CC(=O)NC(C)CCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)NC(C)CCc1ccc(Oc2ccc(OC(C)C)nn2)cc1
Temperature: 150 °C
Reaction time: 0.25 h

Procedure:
N-[3-(4-Hydroxyphenyl)-1-methylpropyl]acetamide (311 mg, 1.5 mmol) was dissolved in 3 ml of NMP, admixed with sodium hydride (55% in oil) (120 mg, 3 mmol) and, after addition of 3-chloro-6-isopropoxypyridazine (259 mg, 1.5 mmol) stirred in a microwave reactor at 150° C. for 15 min. Following addition of ethyl acetate and water, the organic phase was separated off, concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 40mg (8%), M+H+: 344.2.