Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15](OS(C(F)(F)F)(=O)=O)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:25]([OH:30])[CH2:26][CH2:27][C:28]#[CH:29]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:29]#[C:28][CH2:27][CH2:26][CH2:25][OH:30])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: C#CCCCO
Reactant: O=S(=O)(Oc1ccc2c(-c3ccc(Cl)cc3)nsc2c1)C(F)(F)F
Product: OCCCC#Cc1ccc2c(-c3ccc(Cl)cc3)nsc2c1

Procedure:
In analogy to example 14.1, Trifluoro-methanesulfonic acid 3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl ester and 4-pentyn-1-ol were converted to yield 5-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-yn-1-ol as yellow oil, MS: 327 (M, 1 Cl).
Reaction SMILES: C([O:3][C:4]1[C:13]([C:14]([O:16]CC)=[O:15])=[CH:12][C:11]2[C:6](=[CH:7][C:8]([N+:26]([O-:28])=[O:27])=[C:9]([N:19]3[CH:23]=[C:22]([CH2:24][OH:25])[N:21]=[CH:20]3)[CH:10]=2)[N:5]=1)C.[C:29]1([N:35]=[C:36]=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(OC(C)C)(C)C>ClCCl>[N+:26]([C:8]1[CH:7]=[C:6]2[C:11]([CH:12]=[C:13]([C:14]([OH:16])=[O:15])[C:4](=[O:3])[NH:5]2)=[CH:10][C:9]=1[N:19]1[CH:23]=[C:22]([CH2:24][O:25][C:36](=[O:37])[NH:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:21]=[CH:20]1)([O-:28])=[O:27]
Reactant: CCOC(=O)c1cc2cc(-n3cnc(CO)c3)c([N+](=O)[O-])cc2nc1OCC
Reactant: O=C=Nc1ccccc1
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Product: O=C(Nc1ccccc1)OCc1cn(-c2cc3cc(C(=O)O)c(=O)[nH]c3cc2[N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
To a solution of the compound of Example 1 (50.0 mg, 129 μmol) in dichloromethane (2 ml) was added phenyl isocyanate (46.2 mg, 388 μmol), and the mixture was stirred overnight at room temperature. Diisopropyl ether was added to the reaction mixture, and the precipitated crystals were collected by filtration and air-dried. These were dissolved into acetic acid (5 ml) and concentrated hydrochloric acid (1 ml) was added, which was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was washed with water and ethyl acetate in sequence and then air-dried, thereby obtaining 41.0 mg of title compound as yellow powder. Yield 71%.
Reaction SMILES: [Br-].[PH4+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=O.O.C[CH2:19][O:20][C:21]([CH3:23])=[O:22]>C1COCC1>[CH3:19][O:20][C:21](=[O:22])[CH2:23][CH2:9][CH2:4][CH2:5][CH:6]=[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=1
Reactant: CCOC(C)=O
Reactant: O=C(c1ccccn1)c1ccccn1
Agent: [Br-]
Agent: [PH4+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CCCCC=C(c1ccccn1)c1ccccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44 %

Procedure:
NHMDS (2.26 mL, 2.26 mmol) as a solution in THF was added to methyl 6-triphenylphosphonium bromide hexanoate II (1.072 g, 2.38 mmol) in THF (8 mL) at 0° C. under Ar(g). After 15 min, di-pyridin-2-yl-methanone (220 mg, 1.2 mmol) in THF (4 mL) was added; the reaction mixture was stirred for 1 h, and was then allowed to warm to rt. After 20 h stirring, water (15 mL) and EtOAc (15 mL) were added, the phases were separated, and the aqueous phase was extracted with EtOAc (2×10 mL). The organic phases were combined, dried over MgSO4, filtered, and then evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using CH2Cl2/MeOH (100:0.5 to 100:2) as eluant to furnish III as a colourless oil (155 mg, 44%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:4][CH:3]=1.Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19].C(OC(C)C)(C)C>>[NH2:9][C:8]1[C:7]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[Cl:1])[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18](=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)Nc1cccc(Cl)c1C#N
Reactant: O=C(CBr)c1ccccc1
Solvent: CC(C)OC(C)C
Product: CCOC(=O)n1c(C(=O)c2ccccc2)c(N)c2c(Cl)cccc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 6-chloro-2-(ethoxycarbonylamino)benzonitrile (step 1) and 2-bromoacetophenone. m.p.: 118-119° C. (isopropyl ether)
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9](=O)C1C=CC=CC=1>CC(C)=O>[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:8])[CH3:9]
Reactant: OCc1ccccc1
Reactant: O=Cc1ccccc1
Solvent: CC(C)=O
Product: CC(=O)c1ccccc1

Procedure:
A method according to claim 1 wherein the ketone is acetone and the carboxylic acid precursor is selected from the group consisting of benzyl alcohol and benzaldehyde to yield acetophenone.
Reaction SMILES: [C:1]([O:5][C:6]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(=CC)C.P([O-])([O-])(O)=[O:23].[Na+].[Na+].Cl([O-])=O.[Na+]>C(O)(C)(C)C.O>[C:1]([O:5][C:6]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[C:11]([OH:23])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Oc1ccccc1C=O
Reactant: O=P([O-])([O-])O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)Oc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.7 %

Procedure:
21.5 g (93.8 mmol) of 2-(tert-butoxycarbonyloxy)-benzaldehyde and 80 ml (750 mmol) of 2-methyl-2-butene are diluted in 250 ml of tert-butanol. A solution containing 28.1 g (234 mmol) of sodium hydrogenphosphate and 29.7 g (328 mmol) of sodium chlorite in 75 ml of water is added dropwise to the reaction medium, which is stirred at ambient temperature for 2 hours. The mixture is evaporated under reduced pressure and the residue is dissolved in dichloromethane. The organic phase is washed with water, dried over magnesium sulphate, filtered and concentrated. The white solid obtained is precipitated from heptane at 0° C. The precipitate is filtered off and then rinsed with heptane and dried. 15.8 g of 2-(tert-butoxycarbonyloxy)benzoic acid are obtained in the form of a white powder with a yield of 70%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22].Cl[C:39]1[N:44]=[CH:43][C:42]([CH3:45])=[CH:41][N:40]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][C:39]3[N:44]=[CH:43][C:42]([CH3:45])=[CH:41][N:40]=3)[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22]
Reactant: Cc1cnc(Cl)nc1
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2
Product: COc1ccc(CC2c3cc(Oc4ncc(C)cn4)c(OC)cc3CCN2CC(=O)NC2CCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide with 2-chloro-5-methyl-pyrimidine
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>C(#N)C.O>[N:12]1([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: C1COCCN1
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCOCC2)cc1O
Temperature: 50 °C
Reaction time: 40 h
Yield: 86.7 %

Procedure:
5-Fluoro-2-nitro-phenol (3.05 g, 19.4 mmol; Alfa Aesar) in Acetonitrile (20 mL) was treated with Morpholine (3.6 mL, 41 mmol) under an atmosphere of Nitrogen. After 40 h at rt, the mixture was heated at 50° C. for 6 h to drive to completion. The mixture was concentrated to ca. ½ volume, precipitate formed and the mixture was diluted with 100 mL water. The solids were collected and washed 2×50 mL water then dried to afford 5-Morpholin-4-yl-2-nitro-phenol as a yellow solid (3.77 g, 87%). 1H-NMR (DMSO): 7.88 (d, 1H, J=9.6 Hz), 6.64 (dd, 1H, J=2.4, 9.6 Hz), 6.43 (d, 1H, J=2.4 Hz), 3.70 (t, 4H, J=4.8 Hz), 3.41 (t, 4H, J=4.8 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[C:20]([C:21](=[O:29])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][N:18]=[C:17](SC)[N:16]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:40](Cl)([CH3:43])(=[O:42])=[O:41]>ClCCl>[C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[C:20]([C:21](=[O:29])[NH:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:19][N:18]=[C:17]([S:40]([CH3:43])(=[O:42])=[O:41])[N:16]=2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CSc1ncc(C(=O)Nc2ccccc2)c(Oc2cccc(NC(=O)OC(C)(C)C)c2)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cccc(Oc2nc(S(C)(=O)=O)ncc2C(=O)Nc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 117.9 %

Procedure:
To a stirred solution of 6 (0.35 g, 0.7 mmol) and triethylamine (0.2 mL, 1.4 mmol) in dichloromethane (10 mL) at 0° C. was added mesyl chloride (0.12 g, 1.05 mmol) and then the reaction mixture stirred at room temperature for 1 h. It was quenched with water; the organic layer was separated, dried over anhydrous Na2SO4 and concentrated to obtain 7 as colorless oil (0.4 g, crude).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2].CS(C)=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C>>[N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[O:21])=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1NCCCCCCO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=CCCCCCNc1c([N+](=O)[O-])cnc2ccccc12
Yield: 99.6 %

Procedure:
The alcohol from Step 1, 6-(3-nitro-quinolin-4-ylamino)hexan-1-ol (10.0 g, 34.6 mmol), was oxidized by the general method described in Step 6 of Example 1 with DMSO (4.05 g, 51.8 mmol), oxalyl chloride (4.83 g, 38.0 mmol), and triethylamine (10.5 g, 104 mmol) to provide 6-(3-nitroquinolin-4-ylamino)hexanal (9.9 g) as a bright yellow solid that was used directly in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[O:18])[C:5]([C:8]2[C:9]([CH:15]=[O:16])=[CH:10][C:11]([Br:14])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1.[BH4-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:9]=2[CH2:15][OH:16])=[C:4]([CH2:17][OH:18])[CH:3]=1
Reactant: O=Cc1cc(Br)ccc1-c1ccc(Br)cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1cc(Br)ccc1-c1ccc(Br)cc1CO
Temperature: 25 °C
Reaction time: 12 h
Yield: 87 %

Procedure:
The solution of 2,7-dibromo-phenanthrene (3.8 g) in DCM/MeOH (120 ml/1 ml) was cooled to −78° C., and it became a suspension. Ozone was bubbled thorough for 20 minutes, and the mixture became blue. Oxygen was bubbled for 5 minutes and dimethyl sulfide (3 ml) was added. The mixture was warmed to 25° C. and stirred for 12 hours. Concentration and purification by flash column chromatography (hexanes/EtOAc) gave 4,4′-dibromo-biphenyl-2,2′-dicarbaldehyde (600 mg). To the solution of 4,4′-dibromo-biphenyl-2,2′-dicarbaldehyde (600 mg, 1.7 mmol) in THF/MeOH (10 ml/10 ml) at 0° C. was added sodium borohydride (320 mg, 8.2 mmol). The mixture was warmed to 25° C. and stirred for 12 hours. The mixture was quenched with water, and extracted with EtOAc. The organic phase was washed with water and brine, and was dried with sodium sulfate. Concentration gave (4,4′-dibromo-2′-hydroxymethyl-biphenyl-2-yl)-methanol (550 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][O:16][C:15]3=[O:24])[CH2:10][CH2:9]2)=[C:4]([Cl:25])[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:38]([C:40]1([C:43](O)=[O:44])[CH2:42][CH2:41]1)#[N:39]>>[Cl:25][C:4]1[CH:3]=[C:2]([NH:1][C:43]([C:40]2([C:38]#[N:39])[CH2:42][CH2:41]2)=[O:44])[CH:7]=[CH:6][C:5]=1[N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][O:16][C:15]2=[O:24])[CH2:12][CH2:13]1
Reactant: N#CC1(C(=O)O)CC1
Reactant: Nc1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(Cl)c1
Agent: O=C(n1ccnc1)n1ccnc1
Product: N#CC1(C(=O)Nc2ccc(N3CCC(N4C(=O)OCc5ccccc54)CC3)c(Cl)c2)CC1

Procedure:
The title compound was prepared from the product of example 120 step (ii) (0.05 g), carbonyldiimidazole (0.025 g) and 1-cyano-1-cyclopropane carboxylic acid (0.019 g) using the method of example 115 step (i). Yield 0.003 g.
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.B(Br)(Br)Br.O>C(Cl)Cl>[CH:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)=[O:7])[CH2:2][CH:3]=[CH:4][CH2:5]1
Reactant: COc1ccc(-c2ccc(C(=O)C3CC=CC3)cc2)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccc(-c2ccc(O)cc2)cc1)C1CC=CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
A solution of (3-cyclopenten-1-yl)(4'-methoxy-[1,1'-biphenyl]-4-yl)-methanone (42 g) in methylene dichloride (400 ml) was added over 1 h. to a solution of boron tribromide (30 ml) in methylene dichloride (200 ml) at -70° C. under an atmosphere of nitrogen. The reaction mixture was allowed to warm up slowly at room temperature and was stirred overnight. The solution was poured into water and the mixture was stirred for 10 min. The organic layer was washed twice with water, once with brine and dried (MgSO4). Removal of the solvent gave (3-cyclopenten-1-yl) (4'-hydroxy-[1,1'-biphenyl]-4-yl)-methanone (38.5 g). A small sample recrystallised from ethanol had m.p. 153°-155° C.
Reaction SMILES: [C:1]([N:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)[CH3:5])(=[O:3])[CH3:2].C(C1(C2C=CC(OC)=C(C=2)[CH:27]=[O:28])CC1)#N>>[C:1]([N:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[C:13]([CH:14]=2)[CH:27]=[O:28])[CH2:7][CH2:8]1)[CH3:5])(=[O:3])[CH3:2]
Reactant: COc1ccc(C2(C#N)CC2)cc1C=O
Reactant: COc1ccc(C2(N(C)C(C)=O)CC2)cc1
Product: COc1ccc(C2(N(C)C(C)=O)CC2)cc1C=O

Procedure:
This compound was prepared from Compound 9 in the same manner of Compound 2.
Reaction SMILES: CC1N=C(C#CC(C2CCNCC2)O)C=CC=1.[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[C:26]/[CH:27]=[C:28]2\[CH2:29][NH:30][CH2:31][CH2:32][CH2:33]\2)[N:20]=1.Cl[C:35]1[C:40]([N+:41]([O-:43])=[O:42])=[CH:39][CH:38]=[C:37]([CH3:44])[N:36]=1>>[CH3:44][C:37]1[N:36]=[C:35]([N:30]2[CH2:31][CH2:32][CH2:33]/[C:28](=[CH:27]\[C:26]#[C:25][C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([CH3:18])[N:20]=3)/[CH2:29]2)[C:40]([N+:41]([O-:43])=[O:42])=[CH:39][CH:38]=1
Reactant: Cc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: Cc1cccc(C#C/C=C2/CCCNC2)n1
Agent: Cc1cccc(C#CC(O)C2CCNCC2)n1
Product: Cc1cccc(C#C/C=C2\CCCN(c3nc(C)ccc3[N+](=O)[O-])C2)n1

Procedure:
The title compound was prepared as described for the compound of Example 237 but starting from Compound 310c or 311c instead of compound 237a and using 2-chloro-6-methyl-3-nitropyridine instead of 2-bromo-3-nitropyridine. After the work-up, the residue was purified by automated flash liquid chromatography (SP1™-Biotage) eluting with PE-EtOAc gradient from PE-EtOAc 7:3 to 6:4 affording the title products. Example 310:18%. Example 310: 11%
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:8]=[C:9]([CH:17]=[C:18](Br)[CH:19]=1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:3]([F:6])([F:5])[F:4].Br[Zn][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][N:24]=1>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[NH2:1][CH:2]([C:7]1[CH:8]=[C:9]([CH:17]=[C:18]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][N:24]=2)[CH:19]=1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:3]([F:6])([F:5])[F:4]
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc(C(N)C(F)(F)F)c1
Reactant: Cc1ccc([Zn]Br)nc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Product: Cc1ccc(-c2cc(C(=O)OC(C)(C)C)cc(C(N)C(F)(F)F)c2)nc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a solution of tert-butyl 3-(1-amino-2,2,2-trifluoroethyl)-5-bromobenzoate (1.4 g, 3.95 mmol) in dioxane (20 mL) was added bis(tri-t-butylphosphine)palladium(0) (0.06 g, 0.12 mmol). The mixture was degassed with nitrogen and bromo(5-methylpyridin-2-yl)zinc (0.5 M in THF; 23.7 mL, 11.9 mmol) was added. The mixture was heated to 70° C. After 1 h, the mixture was cooled to ambient temperature and filtered with Celite. The filtrate was concentrated to remove dioxane and saturated NaHCO3 was added. The mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→60% dichloromethane/ethyl acetate) gave the title compound (1.39 g). MS 367.1 (M+1).
Reaction SMILES: [C:1]1([CH2:10][C:11]#[N:12])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]#[N:9])[CH:2]=1.N[CH:14]([CH2:17][CH3:18])[CH2:15][OH:16]>CC1C=CC=CC=1C.O.O.O.O.[N+]([O-])([O-])=O.[Cd+2].[N+]([O-])([O-])=O>[CH2:17]([CH:14]1[CH2:15][O:16][C:11]([CH2:10][C:1]2[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]3[O:16][CH2:15][CH:14]([CH2:17][CH3:18])[N:9]=3)[CH:2]=2)=[N:12]1)[CH3:18]
Reactant: CCC(N)CO
Reactant: N#CCc1cccc(CC#N)c1
Agent: O=[N+]([O-])[O-]
Agent: [Cd+2]
Solvent: Cc1ccccc1C
Solvent: O
Product: CCC1COC(Cc2cccc(CC3=NC(CC)CO3)c2)=N1
Temperature: 130 °C
Reaction time: 72 h
Yield: 66.4 %

Procedure:
In a one liter four-necked round-bottom flask equipped with a condenser, N2 inlet/outlet, magnetic stirrer, and thermometer, was charged with 52.65 g of 1,3-phenylene-diacetonitrile (0.337 mol, Aldrich), 78.13 g of 2-amino-1-butanol (0.876 mol, Aldrich), and 3.38 g of cadmium nitrate tetrahydrate (0.011 mol, Aldrich) in 300 mL of o-xylene. The mixture was heated to 130° C. and the reaction was run for 72 hours. The cooled mixture was washed with de-ionized water (2×200 mL). The organic layer was dried over sodium sulfate and acidic alumina gel. After removal of solvent in vacuo, 67.21 g of an amber liquid resin was obtained in a yield of 67%. The viscosity of this resin at room temperature is 250 mPa.·. 1H NMR (CDCl3, 400 MHz): δ 7.11-7.19 (m, 4H), 4.20 (t, 2H), 3.91-3.97 (m, 2H), 3.77 (t, 2H), 3.52 (s, 4H), 1.53-1.61 (m, 2H), 1.40-1.47 (m, 2H), 0.86 (t, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=O)=[CH:4][C:3]=1[O:31][CH3:32].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[CH:4][C:3]=1[O:31][CH3:32]
Reactant: COc1cc(/C=C/C(=O)N2CCC(c3ccc(Oc4ccccc4)cc3)CC2)ccc1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(/C=C/CN2CCC(c3ccc(Oc4ccccc4)cc3)CC2)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To an 8 ml tetrahydrofuran solution of 400 mg of the compound (5) synthesized in Reference Example 5 was added under ice cooling 60 mg of lithium aluminum hydride, then the resulting mixture was stirred at room temperature for two hours. A 10% aqueous solution of sodium hydroxide solution was added, then the product was extracted with methylene chloride. The extract was dried, filtered, then concentrated under reduced pressure to obtain a residue which was then purified by silica gel column chromatography (methylene chloride:methanol=20:1) to obtain the above-referenced compound (19) in an amount of 273 mg (yield 72%).
Reaction SMILES: [NH2:1][C:2]1([C:16]2[S:17][CH:18]=[C:19]([Br:21])[CH:20]=2)[CH:6]([CH2:7][OH:8])[CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.[C:22]([N:30]=[C:31]=[S:32])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[C:22]([NH:30][C:31]([NH:1][C:2]1([C:16]2[S:17][CH:18]=[C:19]([Br:21])[CH:20]=2)[CH:6]([CH2:7][OH:8])[CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1)=[S:32])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CC(CO)C(N)(c2cc(Br)cs2)C1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(CO)C(NC(=S)NC(=O)c2ccccc2)(c2cc(Br)cs2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 3-amino-3-(4-bromo-2-thienyl)-4-(hydroxymethyl)pyrrolidine-1-carboxylate (8.5 g, 22.5 mmol) in tetrahydrofuran (100 mL) at 0° C. is added benzoyl isothiocyanate (3.24 mL, 24 mmol). The resulting solution is warmed to room temperature, and stirred under nitrogen at room temperature for 2 hours. The solution is concentrated and the residue is purified by silica gel flash chromatography eluting with hexanes/ethyl acetate (gradient from 100:0 to 0:100 over 30 min) to give the title compound. ES/MS (m/e): (79Br/81Br) 538/540 (M+H).
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]2[C:12](=[O:13])[NH:11][C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])=[N:9][C:7]=2[N:8]=1.[CH3:24][NH2:25]>C(Cl)(Cl)Cl>[CH3:24][NH:25][C:3]1[N:4]=[N:5][C:6]2[C:12](=[O:13])[NH:11][C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])=[N:9][C:7]=2[N:8]=1
Reactant: CCCOc1ccccc1-c1nc2nc(SC)nnc2c(=O)[nH]1
Reactant: CN
Solvent: ClC(Cl)Cl
Product: CCCOc1ccccc1-c1nc2nc(NC)nnc2c(=O)[nH]1

Procedure:
3-Methylthio-8-oxo-6-(2-propoxyphenyl)-7,8-dihydropyrimido[4,5-e][1,2,4]triazine (2.0 g) was treated with a solution of methylamine in industrial methylated spirit (33%, 30 ml) at 75° C. in a pressure vessel for 20 hours. The cooled reaction mixture was evaporated under reduced pressure to afford an oily solid which was dissolved in chloroform. The organic solution was washed with water, dried and evaporated under reduced pressure to afford a yellow oily solid which was eluted from a silica column with chloroform/methanol (5%). The fractions containing product were combined and evaporated under reduced pressure to afford a yellow solid (180 mg) which together with another sample (50 mg), similarly prepared, was recrystallized from ethanol to afford the title compound, 140 mg, m.p. 261-263° C.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][C:6]1[N:7]([CH3:20])[C:8]([C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:9][CH:10]=1)C.[OH-].[Na+]>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]([C:8]2[N:7]([CH3:20])[C:6]([CH2:5][C:4]([OH:21])=[O:3])=[CH:10][CH:9]=2)=[O:19])=[CH:13][CH:14]=1
Reactant: CCOC(=O)Cc1ccc(C(=O)c2ccc(Cl)cc2)n1C
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(CC(=O)O)ccc1C(=O)c1ccc(Cl)cc1

Procedure:
A suspension of 3.06 g. (0.01 mole) of ethyl-5-(p-chlorobenzoyl)-1-methylpyrrole-2-acetate in 25 ml. of 0.5 N sodium hydroxide is refluxed for 30 minutes. About two-thirds of this solution is cooled, washed with ether, and then acidified with dilute hydrochloric acid. The resulting solid precipitate is collected by filtration, dried and recrystallized from ethanol-water to give the product, 5-(p-chlorobenzoyl)-1-metylpyrrole-2-acetic acid; m.p. 189-191° C. Upon recrystallization from ethanol-water, the melting point is 188-190° C. Analysis: Calcd. for C14H12ClNO3 : C, 60.54;H, 4.36; N, 5.05%. Found: C, 60.54;H, 4.37; N, 5.14%.