Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6]([Cl:11])[N:5]=[C:4]([NH:12][CH:13]=[O:14])[N:3]=1.[CH2:15]([O:22][NH2:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>O1CCOCC1>[CH2:15]([O:22][NH:23][C:2]1[N:3]=[C:4]([NH:12][CH:13]=[O:14])[N:5]=[C:6]([Cl:11])[C:7]=1[NH:8][CH:9]=[O:10])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=CNc1nc(Cl)c(NC=O)c(Cl)n1
Reactant: NOCc1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=CNc1nc(Cl)c(NC=O)c(NOCc2ccccc2)n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
A mixture of 4,6-dichloro-2,5-diformamido-pyrimidine (1.9 g, 8.09 mmol), benzyloxyamine (1 g, 8.13 mmol), triethylamine (2 ml) and dioxan (20 ml) was stirred at 100° C. for 1 hour. The cooled reaction mixture was filtered and the precipitate collected and washed with dioxan (2×5 ml). The filtrate and washings were combined and evaporated to a syrup. Column chromatography on silica gel (eluted with chloroform-ethanol, 30:1) afforded the title compound (1.2 g, 46%). IR: νmax (KBr) 3242, 1694, 1588, 1472 cm-1 ; 1H NMR δH [(CD3)2SO], 4.89 (2H, s, OCH2Ph), 7.4 (5H, m, Ph), 8.15 (1H, s, CHO), 9.18, 9.42 (1H, 2×br.s, D2O exchangeable, NH), 9.25 (1H, br.s, CHO), 10.91 (2H, br.s, D2O exchangeable, 2×NH). m/e (FAB+ve ion, thioglycerol) MH+ 322.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[Cl:11][C:12]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([Cl:21])[C:13]=1[CH:14]=[O:15].[OH-].[K+].Cl>CO.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:14]([C:13]3[C:16]([Cl:21])=[CH:17][CH:18]=[C:19]([F:20])[C:12]=3[Cl:11])[OH:15])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1c(Cl)ccc(F)c1Cl
Reactant: Brc1cnc2[nH]ccc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: OC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(Br)cc12
Temperature: 25 °C

Procedure:
To a stirred mixture of 5-bromo-1H-pyrrolo[2,3-b]pyridine (0.100 g, 0.508 mmol) and 2,6-dichloro-3-fluorobenzaldehyde (0.107 g, 0.558 mmol) in MeOH (5 mL) was added potassium hydroxide (0.199 g, 3.553 mmol) at 0° C. under nitrogen atmosphere. The resulting mixture was then stirred at rt. overnight. The mixture was then poured into water (50 mL), acidified with 2N HCl and extracted with ethyl acetate (50 mL×3). The organics were combined, dried (Na2SO4) and concentrated under reduced pressure to give a crude residue which was then purified by chromatography (eluent: 20% ethyl acetate in hexane). MS (ES+): m/z=388.85, 390.84, 392.83 [MH+]. HPLC: tR=3.29 min (ZQ3, polar—5 min).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>C(Cl)(Cl)Cl.CO>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: Brc1ccccn1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: c1ccc(NCCCOc2cccc(CN3CCCCC3)c2)nc1

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (20 g) and 2-bromopyridine (12.64 g) were stirred at 125° C. for 31/2 days. The cooled reaction mixture was subjected to column chromatography on silica ((chloroform:methanol 10:1) to afford the title compound as an oil. This was treated with maleic acid in ethanol to give, on addition of diethyl ether, as a white solid 2-[3-[3-(piperidinomethyl)phenoxy]propylamino]pyridine dimaleate (11.40 g), m.p. 116°-167° C. (recrystallised from isopropanol).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:17]O>>[CH3:17][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([I:1])[CH:3]=1
Reactant: Cc1ccc(C(=O)O)cc1I
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C)c(I)c1
Temperature: 70 °C

Procedure:
To a solution of 3-iodo-4-methyl-benzoic acid (10.0 g, 38.2 mmol) in methanol (70 ml) is added concentrated sulfuric acid (0.5 ml). The reaction mixture is heated at 70° C. for 48 hours, cooled to room ambient temperature and then concentrated. After that, ethyl acetate (100 ml) and aqueous NaHCO3 (saturated, 100 ml) solution are added to the residue. The organic layer is separated and washed again with aqueous NaHCO3 (saturated, 100 ml) solution. The organic layer is separated, dried over anhydrous Na2SO4 and concentrated to yield 3-iodo-4-methyl-benzoic acid methyl ester 1. It is used without further purification in the next step. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.87 (d, 1H, J=8.4 Hz), 7.48 (d, 1H, J=8.4 Hz), 3.85 (s, 3H), 3.35 (s, 3H); LC-MS m/z: 277.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:15](O)=[O:16]>>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:15]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:16]
Reactant: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: COc1ccc(N)cc1
Product: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])c(OC)c2)cc1
Yield: 92.6 %

Procedure:
Using p-anisidine (738 mg, 6.0 mmol) and 3-methoxy-4-nitrobenzoic acid (986 mg, 5.0 mmol), the procedure of Reference Example 16 was repeated to obtain 1.40 g (92.7%) of the title compound in the form of colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([C:12]([O:14][CH3:15])=[O:13])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O>CN(C=O)C.C(OCC)(=O)C>[Br:16][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[F:1])[O:9][CH2:8][CH2:7][CH:6]2[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C1CCOc2cc(F)ccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1CCOc2cc(F)c(Br)cc21
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 89.7 %

Procedure:
Methyl 7-fluoro-3,4-dihydro-2H-chromene-4-carboxylate (336 mg, 1.60 mmol) was diluted with DMF (5 mL) followed by the addition of N-bromosuccinimide (313 mg, 1.76 mmol). The reaction was heated at 50° C. and stirred for 2.5 hours. The reaction was cooled, diluted with ethyl acetate and washed with water, saturated sodium bicarbonate, water, and brine. The organic layer was dried over MgSO4, filtered and concentrated. The material was purified using a Biotage 40M cartridge, gradient 5% ethyl acetate/hexane to 50% to yield the title compound (415 mg, 89.8% yield).
Reaction SMILES: [OH-].[K+].[I-].[K+].[OH:5][C:6]1[C:11]2=[N:12][C:13]([CH3:17])=[CH:14][C:15](=[O:16])[N:10]2[CH:9]=[CH:8][C:7]=1[CH3:18].[CH2:19](Br)[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O.CO>[CH2:19]([O:5][C:6]1[C:11]2=[N:12][C:13]([CH3:17])=[CH:14][C:15](=[O:16])[N:10]2[CH:9]=[CH:8][C:7]=1[CH3:18])[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1cc(=O)n2ccc(C)c(O)c2n1
Reactant: BrCC=Cc1ccccc1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(=O)n2ccc(C)c(OCC=Cc3ccccc3)c2n1
Reaction time: 1 h

Procedure:
To a solution of 6.6 g of potassium hydroxide (85%) and 0.2 g of potassium iodide in 100 ml of water is added 150 ml of methanol and 19.0 g of 9-hydroxy-2,8-dimethyl-4H-pyrido[ 1,2-a]-pyrimidin-4-one and the whole stirred for about 1 hour. To this is added 20.1 g of cinnamyl bromide dissolved in 20 ml of methanol. The mixture is stirred at room temperature for about 18 hours and then worked up to give 9-[ (cinnamyl)oxy] -2,8-dimethyl-4H-pyrido[ 1,2-a] pyrimidin-4-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([F:10])[C:7]=1[CH:8]=[O:9].Cl[C:15]1[CH:20]=[C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:18]=[C:17]([NH2:27])[N:16]=1>>[NH2:27][C:17]1[N:16]=[C:15]([C:4]2[CH:3]=[C:2]([F:1])[C:7]([CH:8]=[O:9])=[C:6]([F:10])[CH:5]=2)[CH:20]=[C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:18]=1
Reactant: Nc1nc(Cl)cc(N2CCOCC2)n1
Reactant: O=Cc1c(F)cc(B(O)O)cc1F
Product: Nc1nc(-c2cc(F)c(C=O)c(F)c2)cc(N2CCOCC2)n1
Yield: 68 %

Procedure:
The title compound was prepared following the General Procedure A using: (3,5-difluoro-4-formylphenyl)boronic acid (2.17 g, 11.7 mmol) and 4-chloro-6-(4-morpholinyl)-2-pyrimidinamine (2.50 g, 11.7 mmol). The solid was dry loaded in 10 g of SiO2. Flash chromatography on SiO2 eluting from 100% CHCl3 to 90:10 CHCl3:CH3OH afforded the title compound (2.55 g, 51%) as a yellow solid. LC-MS (ES) m/z=321 [M+H]+.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].P(Cl)(Cl)(Cl)(Cl)[Cl:22]>C1C=CC=CC=1>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16]([Cl:22])=[O:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(C(=O)O)cc2)CC1
Solvent: c1ccccc1
Product: CCCCC[C@H]1CC[C@H](c2ccc(C(=O)Cl)cc2)CC1

Procedure:
In a 30 ml-reaction vessel, 2.0 g (7.3 mM) of p-(trans-4-pentylcyclohexyl)benzoic acid and 10 ml of benzene were placed. To the mixture, 1.55 g (7.4 mM) of PCl5 was added in 25 minutes to room temperature, followed by heat-refluxing for 4 hours and distilling-off of the solvent to obtain p-(trans-4-pentylcyclohexyl)benzoic acid chloride.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1.[CH2:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl.O>[F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11]([N:26]3[CH2:27][CH2:28][N:23]([CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:24][CH2:25]3)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)N1CC(Oc2ccc(F)cc2)C1
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: ClCCl
Solvent: O
Product: O=C(N1CCN(Cc2ccccc2)CC1)N1CC(Oc2ccc(F)cc2)C1
Reaction time: 18 h
Yield: 108.3 %

Procedure:
A stirred solution of 6.9 g (0.03 mole) of 3-(4-fluorophenoxy)-1-azetidinecarbonyl chloride in 60 ml of methylene chloride was treated with 10.8 g (0.06 mole) of 1-benzylpiperazine, added dropwise. After stirring for 18 hr, the reaction mixture was diluted with 200 ml of water and stirred for an additional 1 hr. The methylene chloride portion was separated and the aqueous portion was extracted with 2×25 ml of methylene chloride. The methylene chloride portions were combined, dried and concentrated in vacuo, yielding 12 g of oil residue. This oil solidified when triturated with ligroin and was recrystallized from benzene/ligroin to yield 10.1 (91%) of tan crystals. A 500 mg portion was recrystallized from benzene/ligroin to yield 250 mg of fine white crystals, m.p. 109°-111° C.
Reaction SMILES: [C:1]1([P:7](Cl)(Cl)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1([C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[OH:14])[OH:12].C(N(CC)CC)C>CCOCC>[C:1]1([P:7]2(=[O:8])[O:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[O:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1O
Reactant: O=P(Cl)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=P1(c2ccccc2)Oc2ccccc2O1
Reaction time: 0.13 h
Yield: 93.4 %

Procedure:
To a solution of 3.11 g of phenylphosphonic acid dichloride in 10 ml of ether were added 1.76 g of pyrocatechol and 20 ml of ether. The resulting solution was cooled to -25° C. to -28° C. and a solution of 3.23 g of triethylamine in 10 ml of ether was added dropwise thereto with stirring over 8 minutes. Thereafter, the reaction mixture was allowed to return to room temperature (20°-25° C.), and the precipitate was filtered off under nitrogen atmosphere and washed with 30 ml of ether. The filtrate and washings were combined and the ether was distilled off under reduced pressure to give 3.46 g (94.4% yield) of 2-phenyl-2-oxo-1,3,2-benzodioxaphosphole as a colorless oil. Upon standing in a refrigerator overnight, it crystallized.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:27])[C:7]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:8][C:9](=[N:11][C:12]2[CH:22]=[CH:21][C:15]([CH:16]=[CH:17][C:18]([OH:20])=[O:19])=[CH:14][CH:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl>[Zn].CO>[C:1]([C:5]1[CH:10]=[C:9]([CH:8]=[C:7]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:6]=1[OH:27])[NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH:16]=[CH:17][C:18]([OH:20])=[O:19])=[CH:21][CH:22]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)C1=CC(=Nc2ccc(C=CC(=O)O)cc2)C=C(C(C)(C)C)C1=O
Agent: Cl
Agent: [Zn]
Solvent: CO
Product: CC(C)(C)c1cc(Nc2ccc(C=CC(=O)O)cc2)cc(C(C)(C)C)c1O
Yield: 19.9 %

Procedure:
A mixture of 2.0 g of 4-(2,6-di-tertiary-butylcyclohexadienon-4-ylideneamino)cinnamic acid, 100 ml of methanol, 0.5 ml of concentrated hydrochloric acid and 2 g of zinc powder was stirred for ten minutes. The mixture was filtered and the filtrate was evaporated to give a yellow gummy solid. This material was recrystallized from a mixture of 15 ml of benzene, 4 ml of hexane and 2 ml of cyclohexane to give 0.4 g of yellow granular 4-(3,5-di-tertiary-butyl-4-hydroxyanilino)cinnamic acid, m.p. 199°-200° C. Analysis: Calculated for C23H29NO3 2/3C6H6 : %C, 7.4; %H, 7.9; %N, 3.3; Found: %C, 77.2; %H, 7.8; %N, 3.3.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15](C)=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)[CH:5]=[CH:4][C:3]1=2.[CH3:33]C1(C)CC=C(OS(C(F)(F)F)(=O)=O)C2C=C(C#CC3C=CC(C(OCC)=O)=CC=3)C=CC1=2>>[CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[CH3:33])[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:30][CH:31]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CCC3(C)C)cc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccccc2C)=CCC3(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 1), 200.0 mg (0.418 mmol) of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(trifluoromethylsulfonyl)oxy-2-naphthalenyl)ethynyl]benzoate (Compound G) was converted into the title compound (colorless solid) using 199.4 mg (1.463 mmol) of zinc chloride, 24 mg (0.02 mmol) of tetrakis(triphenylphosphine)palladium(0) in 4.0 ml of THF, and 2-methylphenyl lithium (prepared by adding 133.9 mg (1.23 ml, 2.09 mmol) of tert-butyllithium (1.7M solution in pentane) to a cold solution (−78° C.) of 178.7 mg (1.045 mmol) of 2-methylbromobenzene in 2.0 ml of THF). 1H NMR (CDCl3): δ 7.97 (2H, d, J=8.4 Hz), 7.50 (2H, d, J=8.4 Hz), 7.49—7.19 (6H, m), 6.81 (1H, d, J=1.6 Hz), 5.89 (1H, t, J=4.5 Hz), 4.36 (2H, q, J=7.1 Hz), 2.43-2.14 (2H, dq, J=3.7, 5.4 Hz), 2.15 (3H, s), 1.39-1.34 (9H, m).
Reaction SMILES: [O:1]=[C:2]([CH2:8][N:9]1[CH:12](SC)[CH2:11][C:10]1=[O:15])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[Cl:16]Cl>C(Cl)(Cl)(Cl)Cl>[C:4](/[C:3](/[Cl:16])=[C:2]1\[CH2:8][N:9]2[CH:12]([O:1]\1)[CH2:11][C:10]2=[O:15])([O:6][CH3:7])=[O:5]
Reactant: ClCl
Reactant: COC(=O)CC(=O)CN1C(=O)CC1SC
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)/C(Cl)=C1\CN2C(=O)CC2O1
Reaction time: 0.17 h
Yield: 119.3 %

Procedure:
Methyl 3-oxo-4-(2-oxo-4-methylthioazetidin-1-yl)butyrate (120 mg, 0.52 mmole) was dissolved in dry carbon tetrachloride (15 ml) and the solution was stirred and ice-cooled while chlorine (75 mg, 1.05 mmole) in carbon tetrachloride (1.4 ml) was added in one portion. The cooling bath was removed and stirring was continued for 10 minutes. The solvent was then evaporated under reduced pressure to yield a pale yellow gum (135 mg).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]2[CH:13]=[C:14]([C:16]([O-:18])=O)[CH:15]=[C:5]2[C:4]1=[O:19])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:32][C:33]1[NH:37][N:36]=[N:35][N:34]=1>CN(C)C=O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]2[CH:13]=[C:14]([C:16]([NH:32][C:33]3[NH:37][N:36]=[N:35][N:34]=3)=[O:18])[CH:15]=[C:5]2[C:4]1=[O:19])[CH3:2]
Reactant: Nc1nnn[nH]1
Reactant: CCn1c(=O)c2cc(C(=O)[O-])cn2c2ccccc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CCn1c(=O)c2cc(C(=O)Nc3nnn[nH]3)cn2c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
A mixture of 1.2 g (4.7 mmole) of 4,5-dihydro-5-ethyl-4-oxo-pyrrolo-[1,2-a]-quinoxaline-2-carboxylate acid (prepared by the process of French application No. 2,387,230), 0.81 g (5.0 mmole) of carbonyldiimidazole and 25 ml of anhydrous dimethylformamide was stirred until a clear solution was obtained and 0.425 g (5.0 mmole) of anhydrous 5-amino-tetrazole were added thereto. The mixture was stirred at room temperature for 30 minutes and was then filtered. The recovered product was washed with ethyl acetate and dried over P2O5 under vacuum to obtain 1.4 g of 4,5-dihydro-5-ethyl-4-oxo-N-(1H-tetrazol-5-yl)-pyrrolo-[1,2-a]-quinoxaline-2-carboxamide in the form of white crystals melting at 315°-318° C.
Reaction SMILES: Br[CH:2]([CH2:20][CH3:21])[C:3]([C:5]1[CH:19]=[CH:18][C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:11][C:7]=2[CH:6]=1)=O.[NH:22]([NH:24][C:25](=[S:33])[O:26]C1C=CC=CC=1)N.C(#N)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH2:20]([CH:2]1[S:33][C:25](=[O:26])[NH:24][N:22]=[C:3]1[C:5]1[CH:19]=[CH:18][C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:11][C:7]=2[CH:6]=1)[CH3:21]
Reactant: CCC(Br)C(=O)c1ccc2nc(-c3ccccc3)oc2c1
Reactant: NNNC(=S)Oc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Product: CCC1SC(=O)NN=C1c1ccc2nc(-c3ccccc3)oc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
50 mg (145 μmol) 2-bromo-1-(2-phenyl-benzoxazol-6-yl)-butan-1-one, 60 mg (293 μmol) O-phenyl hydrazinethiocarbamate, 50 μl (363 μmol) TEA, 2 ml acetonitrile and 200 μl water are stirred together at 80° C. for 1 h. The reaction mixture is extracted with water and DCM. The org. phase is dried and the solv. is eliminated completely in vacuo. The residue is combined with 1 ml acetonitrile and 2 drops of water. 10 mg (53 μmol) para-toluenesulphonic acid monohydrate are added under argon and the mixture is also stirred for 1 h at RT under argon. Then it is left to react for 30 min under argon at 100° C. in the microwave. The reaction mixture is purified by RP-HPLC.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19]O)[O:16][C:15]2=[O:21])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[N:9]1.[CH3:22][C:23]1[N:24]=[N:25][NH:26][N:27]=1.CO>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][N:25]3[N:26]=[N:27][C:23]([CH3:22])=[N:24]3)[O:16][C:15]2=[O:21])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[N:9]1
Reactant: Cc1cn(-c2ccc(N3C[C@H](CO)OC3=O)cc2F)nn1
Reactant: Cc1nn[nH]n1
Solvent: ClCCl
Solvent: CO
Product: Cc1cn(-c2ccc(N3C[C@H](Cn4nnc(C)n4)OC3=O)cc2F)nn1
Yield: 44.1 %

Procedure:
This compound was prepared from (5R)-3-[3-Fluoro-4-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl]-5-(hydroxymethyl)oxazolidin-2-one (Intermediate 19) (1.054 g, 3.61 mmol) and 5-methyl-2H-tetrazole (0.608 g, 7.23 mmol), as described for Example 29. Chromatography on silica gel with 5% methanol in dichloromethane gave the crude product (0.72 g) which was purified further by trituration with dichloromethane and diethyl ether to afford the title product (0.571 g). The regioisomeric product (5R)-3-[3-fluoro-4-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl]-5-[(5-methyl-1H-tetrazol-1-yl)methyl]-1,3-oxazolidin-2-one was also isolated (0.228 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[N:10]([C:18](=[O:21])[CH2:19]Cl)[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1Cl.Cl>O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[N:10]1[C:11]2[C:16](=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[CH2:19][C:18]1=[O:21]
Reactant: Cc1ccc(N(C(=O)CCl)c2c(F)cc(F)cc2Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: Clc1ccccc1Cl
Product: Cc1ccc2c(c1)CC(=O)N2c1c(F)cc(F)cc1Cl
Temperature: 25 °C

Procedure:
To a mixture of 100 g (0.3 mol) of N-(2′-chloro-4′,6′-difluorophenyl)-N-chloroacetyl-4-methylaniline and 103 g (0.78 mol) of aluminum chloride is added 400 ml of 1,2-dichlorobenzene. The reaction is heated to 140° for 2 hours. The reaction is cooled to room temperature and added to a mixture of 100 ml of concentrated HCl and 700 ml water (cooled to 0-5° in a dry ice/acetone bath). The mixture is extracted twice with 400 ml of methylene chloride. The combined organic layers are washed with 600 ml of 3N HCl. The organic layer is stirred with 66 g of magnesium sulfate and 33 g of charcoal (DARCO G-60). The solids are filtered off and the solvents are evaporated under reduced pressure to give a tan solid which is recrystallized from ethanol to give N-(2′-chloro-4′,6′-difluorophenyl)-5-methyloxindole, mp 137-140°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH3:16])[C:10]=1[CH:17]([OH:22])[C:18]([F:21])([F:20])[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH3:16])[C:10]=1[CH:17]([O:22][S:31]([CH3:30])(=[O:33])=[O:32])[C:18]([F:20])([F:21])[F:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cn1ccc(=O)c(OCc2ccccc2)c1C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1ccc(=O)c(OCc2ccccc2)c1C(OS(C)(=O)=O)C(F)(F)F
Reaction time: 3 h
Yield: 19.4 %

Procedure:
To a suspension of 3-benzyloxy-1-methyl-2-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one (4 g) in CH2Cl2 (80 mL) was added Et3N (2.40 mL, 17.5 mmol), followed by methanesulfonyl chloride (1.25 mL, 16.2 mmol) at ice-water bath temperature. The resulting mixture was then stirred for 3 h. The reaction mixture was quenched with water and extracted twice with CH2Cl2 (2×50 mL). The combined organic fractions were washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The residue was purified by flash column chromatography on silica gel using a mixture of CH2Cl2 and MeOH (95/5, v/v) as eluant, thereby affording the product, methanesulfonic acid 1-(3-benzyloxy-1-methyl-4-oxo-1,4-dihydro-pyridin-2-yl)-2,2,2-trifluoro-ethyl ester (0.97 g, 19.4% yield). MS-ESI (m/z): 391.9 [M+1]+, 206, 91.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[C:6]#[N:7])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:32][C:33]1([CH3:41])[O:38][CH2:37][CH:36]([CH2:39]O)[CH2:35][O:34]1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C1(C)C=CC=CC=1>[CH3:32][C:33]1([CH3:41])[O:38][CH2:37][CH:36]([CH2:39][O:11][C:10]2[C:9]([CH3:12])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[CH2:1][CH3:2])[CH2:35][O:34]1
Reactant: CCc1cc(C#N)cc(C)c1O
Reactant: CC1(C)OCC(CO)CO1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCc1cc(C#N)cc(C)c1OCC1COC(C)(C)OC1
Reaction time: 0.25 h
Yield: 27.8 %

Procedure:
To a solution of 3-ethyl-4-hydroxy-5-methyl-benzonitrile (480 mg, 2.98 mmol) in THF (10 mL), triphenylphosphine (1.17 g, 4.47 mmol) and (2,2-dimethyl-[1,3]dioxan-5-yl)-methanol (478 mg, 3.28 mmol) is added. The mixture is cooled to 4° C. before DEAD (1.94 g, 4.47 mmol, 2.05 mL of a 40% solution in toluene) is added. Stirring is continued at 4° C. for 15 min, then at rt for 1 h. The solvent is removed in vacuo and the crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to give 4-(2,2-dimethyl-[1,3]dioxan-5-ylmethoxy)-3-ethyl-5-methyl-benzonitrile (240 mg) as a yellow oil; LC-MS: tR=1.04 min; [M+1+CH3CN]+=330.97. To a solution of this material (240 mg, 829 μmol) in methanol (5 mL), hydroxylamine hydrochloride (86 mg, 1.24 mmol) and NaHCO3 (104 mg, 1.24 mmol) is added. The mixture is stirred at 60° C. for 5 h before it is diluted with EA and washed with water. The org. extract is dried over MgSO4, filtered, concentrated and dried to give the title compound (280 mg) as a pale yellow oil; LC-MS: tR=0.72 min; [M+1+CH3CN]+=323.01.