Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([CH:12]([CH3:27])[N:13]([S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25]C)[CH:20]=4)(=[O:18])=[O:17])[C:14]=2[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3.C1CCCCC=1.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([CH:12]([CH3:27])[N:13]([S:16]([C:19]4[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=4)(=[O:18])=[O:17])[C:14]=2[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: COc1cccc(S(=O)(=O)N2c3cc(Cl)ccc3-c3ccccc3C2C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: C1=CCCCC1
Product: CC1c2ccccc2-c2ccc(Cl)cc2N1S(=O)(=O)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A stirred suspension of 3-chloro-5-[(3-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (0.38 g, 0.95 mmol) and cyclohexene (1.73 mL, 17.1 mmol) was treated dropwise at room temperature under nitrogen with a solution of 1.0 M boron tribromide (5.7 mL, 5.7 mmol) in dichloromethane. After stirring for 20 hours at room temperature, the reaction was quenched with a saturated, aqueous sodium bicarbonate solution (50 mL), and extracted with dichloromethane (6×20 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to a crude residue. The crude residue was triturated with hexane and purified by flash column chromatography, eluting with a mixture of ethyl acetate-hexane (30:70), to afford the title compound as a homogeneous, white, crystalline solid (0.17 g, 73%), m.p. 215° C.;
Reaction SMILES: O(C[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15](=[O:18])(=[O:17])[NH2:16])C1C=CC=CC=1.C[OH:20]>[Pd]>[OH:20][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15](=[O:18])(=[O:17])[NH2:16]
Reactant: NS(=O)(=O)c1ccccc1COc1ccccc1
Reactant: CO
Agent: [Pd]
Product: NS(=O)(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
To a solution of crude 1-(phenoxymethyl)-2-sulfamoylbenzene (1.6 g, 6 mmol.) in 200 mL of methanol was added Pd/C (0.64 g). The reaction mixture was stirred at room temperature for 5 hours under H2 with a pressure of 30 psi. After the material was consumed, the reaction mixture was filtered. The solvent was evaporated to give crude 1-(hydroxy)-2-sulfamoylbenzene (800 mg, 80%) which was used directly without purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:32])[C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:34]1[CH:35]=[N:36][C:37]([O:40][CH2:41][CH2:42][N:43]2[CH2:47][CH2:46][CH2:45][CH2:44]2)=[N:38][CH:39]=1>>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:32])[C:17]1[CH:22]=[CH:21][C:20]([C:34]2[CH:39]=[N:38][C:37]([O:40][CH2:41][CH2:42][N:43]3[CH2:47][CH2:46][CH2:45][CH2:44]3)=[N:36][CH:35]=2)=[CH:19][CH:18]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Brc1cnc(OCCN2CCCC2)nc1
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(-c2cnc(OCCN3CCCC3)nc2)cc1
Yield: 28.2 %

Procedure:
Using an analogous procedure to that described in Method 44, N-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Method 13, 219 mg, 0.5 mmol) was reacted with 5-bromo-2-(2-pyrrolidin-1-ylethoxy)pyrimidine (Method 64, 136 mg, 0.5 mmol) to give the title compound (71 mg; 28%). Mass Spectrum: M+H+ 504.
Reaction SMILES: [N:1]1([C:7]2[C:11]([C:12]#[N:13])=[C:10]([N:14]=[CH:15][N:16](C)C)[NH:9][N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)N>CO>[Cl:20][C:21]1[CH:27]=[C:26]([NH:13][C:12]2[N:16]=[CH:15][N:14]=[C:10]3[NH:9][N:8]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[C:11]=23)[CH:25]=[CH:23][CH:22]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CN(C)C=Nc1[nH]nc(N2CCOCC2)c1C#N
Agent: Cl
Solvent: CO
Product: Clc1cccc(Nc2ncnc3[nH]nc(N4CCOCC4)c23)c1
Reaction time: 0.5 h

Procedure:
With the exclusion of air, 1.86 g (7.49 mmol) of N′-[3-(morpholin-4-yl)-4-cyano-1 H-pyrazol-5-yl]-N,N-dimethyl-formamidine in 45 ml of methanol are heated to boiling with 1.84 g (11.2 mmol) of 3-chloro-aniline hydrochloride, during which the solid temporarily dissolves. After about 30 min, a precipitate separates out again. After 8 hours the reaction mixture is cooled, filtered and washed with methanol and DIPE. Stirring the crude product in a boiling mixture of 40 ml of ethanol, 20 ml of chloroform and 20 ml of dioxane yields 4-(3-chloro-phenylamino)-3-(morpholin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine; m.p. 275-276° C.; HPLC:tRet(grad20-100/20)=11.6.
Reaction SMILES: Cl[CH2:2][C:3]([CH3:5])=[CH2:4].[C:6]1([S:12]([O-:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Na+]>CO>[CH3:5][C:3](=[CH2:4])[CH2:2][S:12]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:14])=[O:13]
Reactant: O=S([O-])c1ccccc1
Reactant: C=C(C)CCl
Agent: [Na+]
Solvent: CO
Product: C=C(C)CS(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 98128.3 %

Procedure:
A solution of 3-chloro-2-methyl-propene (80 ml, 0.81 mmol) in dry methanol (450 ml) was stirred at room temperature during the addition of sodium benzenesulfinate (200 g, 1.22 mmol). The resulting suspension was refluxed for 20 hours, cooled to room temperature and concentrated in vacuo. The residue was poured onto water (600 ml) and the resulting solid filtered, washed three times with water (200 ml) and dried under vacuum for two days to give (2-methyl-prop-2-ene-1-sulfonyl)-benzene (156 g, 99%) which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[CH3:10][Se:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([N:21]=[C:22]=[O:23])(=[O:20])=[O:19]>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:22]([NH:21][S:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[Se:11][CH3:10])(=[O:19])=[O:20])=[O:23])[N:3]=1
Reactant: C[Se]c1ccccc1S(=O)(=O)N=C=O
Reactant: Cc1cc(C)nc(N)n1
Solvent: ClCCl
Product: C[Se]c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.4 %

Procedure:
To a slurry of 4,6-dimethyl-2-pyrimidinamine (0.36 g, 29 mmol) in dry dichloromethane (5 mL) was added a solution of 2-(methylselenyl)benzenesulfonyl isocyanate (1.5 g, crude, 4.2 mmol) in dichloromethane (5 mL). The heterocycle dissolved. The solution was heated at reflux for two hours and stirred at room temperature overnight. The solution was filtered and rotary evaporated to give 1.7 g of yellow solid. This was dissolved in dichloromethane and chromatographed on a column of silica gel using as eluant 320 mL of 15:1, 220 mL of 10:1, 230 mL of 7.5:1, and finally 240 mL of 5:1 dichloromethane-ether, all with 2 mL/L acetic acid. The appropriate fractions were diluted with toluene and rotary evaporated. The residue was dissolved in dichloromethane, diluted with 1-chlorobutane, and rotary evaporated to give a white crystalline solid. This was slurried in hexanes, collected, rinsed with 1-chlorobutane, 1:1 1-chlorobutanehexanes, and hexanes and air dried. The product was isolated as 1.03 g of small white crystalline plates, melting at 205°-207° C. with decomposition.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][NH:8][N:7]=1.Cl[CH2:17][C:18]1[CH:36]=[CH:35][C:21]([O:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:27][CH:28]=2)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:29]1([C:26]2[O:27][CH:28]=[C:24]([CH2:23][O:22][C:21]3[CH:20]=[CH:19][C:18]([CH2:17][N:8]4[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([C:2]5[S:1][CH:5]=[CH:4][CH:3]=5)=[N:7]4)=[CH:36][CH:35]=3)[N:25]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOC(=O)c1c[nH]nc1-c1cccs1
Reactant: ClCc1ccc(OCc2coc(-c3ccccc3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(Cc2ccc(OCc3coc(-c4ccccc4)n3)cc2)nc1-c1cccs1
Temperature: 80 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
A mixture of ethyl 3-(2-thienyl)-1H-pyrazole-4-caboxylate (1.43 g), 4-(4-chloromethylphenoxy)methyl-2-phenyloxazole (1.88 g), potassium carbonate (1.30 g), and N,N-dimethylformamide (30 ml) was stirred at 80° C. for 8 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 1-[4-(2-phenyl-4-oxazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazole-4-carboxylate as colorless crystals (2.81 g, yield: 92%) from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 114˜115° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]3[CH:17]([C:18]([F:21])([F:20])[F:19])[CH2:16][O:15][C:14]3=[O:22])[S:11][CH:12]=2)=[CH:4][CH:3]=1.O.[CH3:24][N:25](C=O)C>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:22]=[C:14]1[N:13]([C:10]2[S:11][CH:12]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:24]#[N:25])=[CH:3][CH:4]=3)[N:9]=2)[CH:17]([C:18]([F:21])([F:20])[F:19])[CH2:16][O:15]1
Reactant: O=C1OCC(C(F)(F)F)N1c1nc(-c2ccc(Br)cc2)cs1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc(-c2csc(N3C(=O)OCC3C(F)(F)F)n2)cc1
Temperature: 120 °C
Yield: 72 %

Procedure:
3-[4-(4-Bromophenyl)-1,3-thiazol-2-yl]-4-(trifluoromethyl)-1,3-oxazolidin-2-one, prepared in step 3 of Example 64, (0.455 g, 1.15 mmol) and zinc cyanide (81 mg, 0.69 mmol) were dissolved in 12 mL of DMF. The mixture was purged with nitrogen for 15 min and then tetrakis(triphenylphosphine)palladium(0) (66.5 mg, 0.058 mmol) was added and the mixture was heated to 120° C. for 1.5 h. The mixture was cooled and diluted with ethyl acetate and poured into 200 mL of water. The mixture was extracted with ethyl acetate, the organics were combined, washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Flash chromatography (gradient 1% acetone/hexane to 10% acetone/hexane) afforded racemic 4-{2-[2-oxo-4-(trifluoromethyl)-1,3-oxazolidin-3-yl]-1,3-thiazol-4-yl}benzonitrile (278 mg, 72%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:13][CH:12]3[CH2:14][N:15]([C:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4I)=[O:18])[CH2:16][CH:11]3[CH2:10]2)[N:3]=1.CC1C=C(C)N=C(N2CC3C[N:41]([C:43]([C:45]4[CH:50]=[CH:49][CH:48]=C(F)C=4I)=O)CC3C2)N=1>[Cu]I.COCCOC>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:13][CH:12]3[CH2:14][N:15]([C:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[C:48]4[CH:49]=[CH:50][CH:45]=[CH:43][N:41]=4)=[O:18])[CH2:16][CH:11]3[CH2:10]2)[N:3]=1
Reactant: Cc1cc(C)nc(N2CC3CN(C(=O)c4cccc(F)c4I)CC3C2)n1
Reactant: Cc1cc(C)nc(N2CC3CN(C(=O)c4ccc(F)cc4I)CC3C2)n1
Agent: [Cu]I
Solvent: COCCOC
Product: Cc1cc(C)nc(N2CC3CN(C(=O)c4ccc(F)cc4-c4ccccn4)CC3C2)n1
Temperature: 130 °C

Procedure:
The title compound was prepared in a manner analogous to Example 367 substituting (5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-fluoro-2-iodophenyl)methanone for (5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-fluoro-2-iodophenyl)methanone, with the addition of catalytic CuI, substituting dioxane for DME, heating 130° C. in microwave for 60 min. The reaction was filtered through celite, rinsed with EtOAc and then concentrated and purified on RP agilent HPLC and fractions lyophilized. MS (ESI) mass calcd. for C24H24FN5O, 417.20; m/z found, 418.2 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[C:13](Cl)[CH:14]=[CH:15][CH:16]=2)[C:11](=[O:19])[C:10]([CH2:20][OH:21])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1([CH3:33])[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[C:23]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[C:17]2[C:12](=[C:13]([C:23]3[C:24]([CH3:29])=[CH:25][C:26]([CH3:28])=[CH:27][C:22]=3[CH3:33])[CH:14]=[CH:15][CH:16]=2)[C:11](=[O:19])[C:10]([CH2:20][OH:21])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c(CO)nn(Cc2ccccc2)c2cccc(Cl)c12
Reactant: Cc1cc(C)c(B(O)O)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(-c2cccc3c2c(=O)c(CO)nn3Cc2ccccc2)c(C)c1
Temperature: 100 °C
Yield: 47.2 %

Procedure:
A mixture of 0.144 g (0.479 mmol) of 1-benzyl-5-chloro-3-(hydroxymethyl)cinnolin-4(1H)-one, 0.126 g (0.766 mmol) of mesityl boronic acid, 0.111 g (0.096 mmol) of tetrakis and 0.254 g (1.20 mmol) of potassium phosphate in 8 mL of DMF was heated to 100° C. for 16 h. The reaction mixture was quenched with water and extracted with ethyl acetate containing 5% hexanes. The combined organic layers were washed with brine, dried over sodium sulfate, filtered through a plug of silica gel and concentrated in vacuo onto silica gel. The crude material was purified by flash chromatography eluting with a 25% ethyl acetate/hexanes mixture to give 0.087 g (47%) of the title compound as a tan solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[NH2:10][CH2:11][CH2:12][CH2:13][NH2:14].O>C1(C)C=CC=CC=1>[N:7]1[CH:8]=[CH:9][C:4]([CH:1]([NH:10][CH2:11][CH2:12][CH2:13][NH2:14])[CH3:2])=[CH:5][CH:6]=1
Reactant: NCCCN
Reactant: CC(=O)c1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(NCCCN)c1ccncc1
Reaction time: 16 h

Procedure:
4-Acetylpyridine (30.3 g) was added portionwise over 40 minutes to a solution of 1,3-diaminopropane (85 cm3) in toluene (250 cm3) under reflux, with continuous removal of water using a Dean and Stark trap. When no more water was observed in the toluene layer (3 hours) the mixture was concentrated in vacuo and the residue was taken into methanol (200 cm3) and treated with sodium borohydride (12.0 g) added portionwise over 20 minutes at 0° C. After stirring for 16 hours concentrated hydrochloric acid (10 cm3) was slowly added and the mixture was concentrated in vacuo. The residue was dissolved in water (100 cm3) and basified to pH11 with 5M sodium hydroxide solution. The mixture was extracted with chloroform (3×300 cm3) and the dried (MgSO4) extracts were evaporated in vacuo. Distillation gave N-[1-(4-pyridyl)ethyl]-1,3-diaminopropane (22.7 g) as a colourless oil, b.p. 108°-114°/0.03 mm.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:19][C:20]([CH2:28][CH3:29])=[C:21]([C:23]([O:25]CC)=[O:24])[N:22]=3)=[CH:14][CH:13]=2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].CO>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:19][C:20]([CH2:28][CH3:29])=[C:21]([C:23]([OH:25])=[O:24])[N:22]=3)=[CH:14][CH:13]=2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1nc(-c2ccc(NC(=O)c3nc(Cl)c(CC)[nH]3)cc2)oc1CC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1[nH]c(C(=O)Nc2ccc(-c3nc(C(=O)O)c(CC)o3)cc2)nc1Cl
Yield: 8.7 %

Procedure:
The same operation as in Example (91d) was performed using ethyl 2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}phenyl)-5-ethyl-1,3-oxazole-4-carboxylate obtained in Example (99c) (0.12 g, 2.88 mmol), 2 N lithium hydroxide (2 mL, 4 mmol), methanol (2 mL) and tetrahydrofuran (5 mL), to obtain 97 mg of the title compound as a light pink solid (87%).
Reaction SMILES: [C:1](/[C:4](/[C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:5]\[NH:6][C:7]([NH2:9])=O)(=[O:3])[CH3:2].O=P(Cl)(Cl)[Cl:18]>O>[Cl:18][C:7]1[N:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:4]([C:1](=[O:3])[CH3:2])=[CH:5][N:6]=1
Reactant: CC(=O)/C(=C\NC(N)=O)C(=O)C(F)(F)F
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: CC(=O)c1cnc(Cl)nc1C(F)(F)F
Temperature: 100 °C
Reaction time: 3 h
Yield: 41.9 %

Procedure:
A mixture of compound (E)-1-(2-acetyl-4,4,4-trifluoro-3-oxobut-1-en-1-yl)urea (55 g, 0.25 mol) and POCl3 (240.7 g, 1.57 mol) was stirred at 100° C. for 3 h. The mixture was added dropwise to water (1.5 L) at rt and extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography eluting with PE/EtOAc 3/1 to give compound 1-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)ethanone (23.5 g, 42.7% yield) as a pale-yellow oil. 1H NMR (CDCl3 300 MHz): δ 8.80 (s, 1H), 2.58 (s, 3H). 19F NMR (920-083-1A CDCl3 400 MHz): δ −65.5 ppm. 13C NMR (903-158-1A CDCl3 400 MHz): δ 195.9, 162.3, 160.1, 153.8 (dd, J=50 Hz), 130.9, 119.5 (dd, J=366 Hz), 30.7.
Reaction SMILES: C[O-].[Na+].[N+](C(C)C)([O-])=[O:5].[CH3:10][C:11]1[C:18]([CH2:19]Br)=[CH:17][CH:16]=[C:15]([NH:21][C:22](=[O:24])[CH3:23])[C:12]=1[C:13]#[N:14]>CO>[C:22]([NH:21][C:15]1[CH:16]=[CH:17][C:18]([CH:19]=[O:5])=[C:11]([CH3:10])[C:12]=1[C:13]#[N:14])(=[O:24])[CH3:23]
Reactant: CC(C)[N+](=O)[O-]
Reactant: CC(=O)Nc1ccc(CBr)c(C)c1C#N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)Nc1ccc(C=O)c(C)c1C#N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.8 %

Procedure:
To a solution of sodium methoxide, 0.43 g, in 100 ml of methanol, was added 0.84 g of 2-nitropropane. After 15 min, 2 g of 2-methyl-3-bromomethyl-6-acetamidobenzonitrile was added and the resulting solution was stirred for 2.5 h at ambient temperature. The solvent was then evaporated at reduced pressure and the residue dissolved in chloroform. The chloroform solution was filtered, washed with H2O, dried and the solvent removed at reduced pressure. The residue was crystallized from chloroform-carbon tetrachloride to yield 0.8 g (53%) of product, m.p. 170°-173° C. NMR (CDCl3) 2.30 (3H, s, CH3CO--N), 2.90 (3H, s, CH3), 8.00 (1H, d, C--5H), 8.6 (1H, d, C--6H), 10.20 (1H, s, (CHO)d. Anal. calc'd for CH11H10N2O2.1/3H2O: C, 63.5; H, 4.84; N, 13.5. Found: C, 63.4; H, 5.00; N, 13.7.
Reaction SMILES: [C:1]1([C:7]2([OH:12])[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]2[C:55]([C:56](O)=[O:57])=[CH:54][O:53][N:52]=2)=[CH:47][CH:46]=1>CN(C=O)C>[CH3:44][C:45]1[CH:46]=[CH:47][C:48]([C:51]2[C:55]([C:56]([N:9]3[CH2:10][CH2:11][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)([OH:12])[CH2:8]3)=[O:57])=[CH:54][O:53][N:52]=2)=[CH:49][CH:50]=1
Reactant: OC1(c2ccccc2)CCNC1
Reactant: Cc1ccc(-c2nocc2C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2nocc2C(=O)N2CCC(O)(c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.9 %

Procedure:
A solution of 3-phenylpyrrolidin-3-ol (8 mg, 0.039 mmol), TBTU (15 mg, 0.047 mmol, 1.2 equ.) and N-ethyl-N-isopropylpropan-2-amine (14 μL, 0,079 mmol, 2 equ.) in DMF (0.3 mL) was added to 3-(4-methylphenyl)isoxazole-4-carboxylic acid (8 mg, 0.039 mmol) and the reaction mixture was stirred at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (8 mg). MS (ESI, pos. ion) m/z Calcd for C21H20N2O3: 348.1474, found 348.1465.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([C:13]1[CH:17]=[CH:16][NH:15][CH:14]=1)=[O:12].[Cl:18][CH2:19][C:20](Cl)=[O:21].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[Cl:18][CH2:19][C:20]([C:16]1[NH:15][CH:14]=[C:13]([C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[O:12])[CH:17]=1)=[O:21]
Reactant: O=C(c1cc[nH]c1)c1ccc2ccccc2c1
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(c1c[nH]c(C(=O)CCl)c1)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
A mixture of 12.82 g (0.058 mole) of 3-(2-naphthalenoyl)-1H-pyrrole, 7 mL (0.087 mole) of chloroacetyl chloride and 7.7 g (0.12 mole) of aluminum chloride in 500 mL of 1,2-dichloroethane was stirred at room temperature for 1 h. The reaction mixture was heated to reflux for 3 h. Another 7 g of aluminum chloride was added and refluxing continued for 1 h. After cooling, the reaction mixture was poured into 2 N HCl/ice, the organics were separated, washed with water, NaHCO3, water, brine and dried (Na2SO4). The solvent was evaporated in vacuo and recrystallized from toluene to give 13.9 g (81%) of 2-chloro-1-[4-(2-naphthalenoyl)-1H-pyrrol-2-yl]ethanone. mp 175-177° C. CIMS m/z 299 (MH+). 1H NMR (300 MHz, CDCl3) δ 8.4 (Ar, 1H); 8.0-7.85 (Ar, 4H); 7.7-7.5 (Ar, 4H); 4.6 (s, 2H).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]([NH:13][CH:14]([C:17]2[C:18](=[O:26])[NH:19][C:20]([CH:23]3[CH2:25][CH2:24]3)=[N:21][N:22]=2)[CH2:15][CH3:16])=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)=O>>[C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[N:22]3[C:17]([C:18](=[O:26])[NH:19][C:20]([CH:23]4[CH2:25][CH2:24]4)=[N:21]3)=[C:14]([CH2:15][CH3:16])[N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(NC(=O)C1CCC(C(C)(C)C)CC1)c1nnc(C2CC2)[nH]c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1nc(C2CCC(C(C)(C)C)CC2)n2nc(C3CC3)[nH]c(=O)c12

Procedure:
In analogy to the procedure for Example 1, 464 mg (1.29 mmol) crude 4-tert-butyl-N-[1-(3-cyclopropyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)propyl]cyclohexanecarboxamide, 200 mg (1.29 mmol) phosphoric trichloride are stirred at reflux for 3 hours, and proportionate amounts of the solvents are used. The resulting mixture is separated into the isomers via silica gel chromatography with eluent cyclohexane/ethylacetate 5/1, 2/1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.O.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[C:24](#[N:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>[Cu]Cl>[Cl:8][C:6]1[CH:5]=[CH:4][N:3]2[N:31]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:1]=[C:2]2[CH:7]=1
Reactant: N#Cc1ccccc1
Reactant: Nc1cc(Cl)ccn1
Agent: Cl[Cu]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: O
Product: Clc1ccn2nc(-c3ccccc3)nc2c1
Temperature: 130 °C
Yield: 79 %

Procedure:
A mixture of 2-amino-4-chloropyridine (5.00 g, 38.9 mmol), copper (I) chloride (195 mg, 1.97 mmol), 1,10-phenanthroline monohydrate (390 mg, 1.97 mmol) and benzonitrile (65 mL) was heated in a 100 mL 4-necked flask to 130° C. During 23 h a gentle flow of O2/N2 (5:95) was bubbled through the reaction mixture (>99% conversion, HPLC method see below). The dark brown suspension was then cooled to 0-5° C. and filtered. The filter cake was washed with TBME (50 mL) and dried to yield crude 7-chloro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine (7.09 g, 79%) as a green solid with 100% purity (HPLC area-%, method see below).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1>C(O)C>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH2:10])[CH2:5][CH2:4]1
Reactant: COc1ccc(CN)cc1
Solvent: CCO
Product: COC1CCC(CN)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
(4-Methoxyphenyl)methanamine (1 g) in ethanol (10 mL) was treated with 5% Rh—Al2O3 (99.8 mg) under a H2 atmosphere (500 psi) at 50° C. for 16 hours. Additional 5% Rh—Al2O3 (0.4 g) was added. The resulting mixture was stirred under H2 atmosphere (500 psi) at 60° C. for 2 hours. The insoluble material was filtered off and the filtrate was concentrated to provide a mixture of cis and trans product as an oil, which was used for next step without further purification.