Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.C([BH3-])#N.[Na+].[CH:22](=O)[CH2:23][CH3:24]>CO>[C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:22][CH2:23][CH3:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCC=O
Reactant: CC(C)(C)OC(=O)NCCCCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCNCCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In methanol (6.0 ml), (4-amino-butyl)-carbamic acid t-butyl ester (400.0 mg) was dissolved. After acetic acid (0.12 ml) and sodium cyanoborohydride (172.5 mg) were added to the solution, propionaldehyde (0.155 ml) was dropped thereto and the whole was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off and the residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution, followed by extraction with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off. The residue was purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (339.6 mg) as a colorless oily substance.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[N:25]([C:28]1[CH:37]=[CH:36][C:31]2[O:32][CH2:33][CH2:34][O:35][C:30]=2[CH:29]=1)=[C:26]=[O:27]>O1CCCC1>[O:32]1[C:31]2[CH:36]=[CH:37][C:28]([NH:25][C:26]([N:15]3[CH2:16][CH2:17][N:12]([C:10]4[S:9][N:8]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[N:11]=4)[CH2:13][CH2:14]3)=[O:27])=[CH:29][C:30]=2[O:35][CH2:34][CH2:33]1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C=Nc1ccc2c(c1)OCCO2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2c(c1)OCCO2)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.8 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 6-isocyanato-1,4-benzodioxan (167 ml, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was purified by high performance liquid chromatography (YMC HPLC Column eluted with 10% to 100% Liquid A; Liquid A: a 0.1% solution of trifluoroacetic acid in acetonitrile; Liquid B: an aqueous 0.1% trifluoroacetic acid solution) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 161 mg (46.9%) of the desired product as a solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[N:18])[CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C([Li])CCC.[CH:24](=[O:28])[CH:25]([CH3:27])[CH3:26].[Cl-].[NH4+]>C1COCC1>[OH:28][CH:24]([CH:25]([CH3:27])[CH3:26])[CH2:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[N:18])[CH:12]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CC(C)C=O
Reactant: CS(=O)(=O)c1ccc(-c2cccc(C#N)c2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)C(O)CS(=O)(=O)c1ccc(-c2cccc(C#N)c2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of 4′-(methylsulfonyl)biphenyl-3-carbonitrile obtained in Reference Example 102 (2.00 g, 7.77 mmol) in THF (40 mL) was added dropwise n-butyllithium (1.6M hexane solution, 5.34 mL, 8.55 mmol) at −78° C., and the mixture was stirred at −78° C. for 1 hr. Isobutyraldehyde (1.06 mL, 11.7 mmol) was added to this solution at −78° C., and the mixture was further stirred at −78° C. for 3 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, and washed with saturated sodium chloride aqueous solution. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (25%-50% ethyl acetate/hexane) to give the title compound as a pale-yellow oil (1.66 g, 65%).
Reaction SMILES: C1(COC([NH:11][C@H:12]([C:17]([O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=O)C=CC=CC=1.[H][H]>[Pd].C(OCC)(=O)C>[NH2:11][C@H:12]([C:17]([O:19][CH2:20][CH2:21][Si:22]([CH3:23])([CH3:25])[CH3:24])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: [H][H]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)OCC[Si](C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](N)C(=O)OCC[Si](C)(C)C

Procedure:
1 g. of 10% palladium on carbon catalyst is added to a solution of [(phenylmethoxy)carbonyl]-L-leucine, 2-(trimethylsilyl)ethyl ester (9.1 g., 24.9 mmole) in ethyl acetate (200 ml.) cooled in an ice-bath under nitrogen. The reaction mixture is subjected to a steady stream of hydrogen gas for 2.5 hours at room temperature, then filtered and concentrated in vacuo to remove volatiles and yield 5.8 g. of L-leucine, 2-(trimethylsilyl)-ethyl ester as a liquid product. TLC (silica gel, 3:1 hexane:ethyl acetate) Rf =0.08.
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH2:7][C:6]([CH3:10])(O)[C:5]1=[CH2:11])([CH3:3])=[CH2:2].[CH:12]([O:14]CC)=[CH2:13]>P(=O)(O)(O)O>[CH:12]([CH2:13][CH2:11][C:5]1[CH:4]([C:1]([CH3:3])=[CH2:2])[CH2:8][CH2:7][C:6]=1[CH3:10])=[O:14]
Reactant: C=COCC
Reactant: C=C(C)C1CCC(C)(O)C1=C
Agent: O=P(O)(O)O
Product: C=C(C)C1CCC(C)=C1CCC=O
Yield: 68.5 %

Procedure:
12 drops of 85% phosphoric acid were added to a mixture, cooled to -15°C in a laboratory autoclave, of 76 g of 3-isopropenyl-1-methyl-2-methylene-cyclopentan-1-ol and 72 g of ethyl vinyl ether. After gassing with argon, the autoclave was brought, in an oil bath of 180°C, to an internal temperature of 150°C (this took about 15 minutes) and held at this temperature until a distinct drop in pressure occurred (about 100 minutes). The reaction mixture was then quenched, taken up in ether, washed with aqueous bicarbonate solution and water, the solution dried over anhydrous magnesium sulphate and concentrated under reduced pressure. The crude product (110 g), obtained as a yellow oil, was fractionated and yielded 61 g (68%) of pure 2-(2-formylethyl)-3-isopropenyl-1-methyl-cyclopent-1-ene having a woody, earthy fragrance; boiling point 0.2 = 64°-65°C; nD20 = 1.4888; IRfilm : μmax = 3080, 2725, 1725, 1642, 1440, 1370, 1060 and 895 cm-1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.CCN=C=NCCCN(C)C.Cl.[F:20][C:21]([F:29])([F:28])[C:22]([F:27])([F:26])[C:23](O)=[O:24]>ClCCl.CN(C1C=CN=CC=1)C>[F:26][C:22]([F:27])([C:21]([F:29])([F:28])[F:20])[C:23]([N:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][NH:3]1)=[O:24]
Reactant: Nc1ccccn1
Reactant: O=C(O)C(F)(F)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(N=c1cccc[nH]1)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.1 %

Procedure:
In 15 ml of anhydrous dichloromethane, 300 mg (3.19 mmol) of 2-aminopyridine was dissolved. To this solution, 919 mg (4.78 mmol) of EDC-HCl, 583 mg (4.78 mmol) of DMAP, and 397 μl (628 mg, 3.83 mmol) of pentafluoropropionic acid were added in this order, followed by stirring at room temperature overnight. After completion of the reaction, the reaction liquid was diluted with dichloromethane, washed once with water, and twice with 1% hydrochloric acid, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Thus, 85 mg of 2,2,3,3,3-pentafluoro-N-(pyridin-2(1H)-ylidene)propanamide was obtained (Percentage Yield: 11%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[C:22]([NH:23][C:24]3[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[C:25]=3[O:34][CH2:35][CH2:36][CH2:37][OH:38])=[N:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[C:39](O)(=[O:41])[CH3:40].O>CN(C=O)C>[OH:38][CH2:37][CH2:36][CH2:35][O:34][C:25]1[C:26]([O:32][CH3:33])=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:24]=1[NH:23][C:22]1[C:13]([NH:12][S:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:39](=[O:41])[CH3:40])=[CH:4][CH:5]=2)(=[O:11])=[O:10])=[N:14][C:15]2[C:20]([N:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: CC(=O)O
Reactant: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2ccc(CN)cc2)c(OCCCO)c(OC)c1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2ccc(CNC(C)=O)cc2)c(OCCCO)c(OC)c1
Yield: 41 %

Procedure:
100 mg of 4-aminomethyl-N-{3-[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]-quinoxalin-2-yl}benzenesulfonamide (content 82%), 37 mg of DAPECI and 8.7 l of acetic acid in 1 ml of DMF are stirred at RT overnight in a screw-cap vial. The reaction solution is poured into water, and the deposited precipitate is filtered off with suction. Purification by preparative HPLC on silica gel RP18 (acetonitrile, water) gives a total of 39 mg of N-(4-{3-[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-ylsulfamoyl}benzyl)acetamide (yield 41%); MS-FAB (M+H+)=582.2; Rf (polar method): 2.19 min.
Reaction SMILES: [F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3].[Cl:17][C:18]1[CH:19]=[C:20]([C:24]2[O:28][C:27]([CH3:29])=[N:26][C:25]=2[C:30](O)=[O:31])[CH:21]=[CH:22][CH:23]=1>>[F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:30]([C:25]3[N:26]=[C:27]([CH3:29])[O:28][C:24]=3[C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[CH:19]=3)=[O:31])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3]
Reactant: Cc1nc(C(=O)O)c(-c2cccc(Cl)c2)o1
Reactant: CC(F)(F)c1csc(Cn2ncc(N)n2)n1
Product: Cc1nc(C(=O)Nc2cnn(Cc3nc(C(C)(F)F)cs3)n2)c(-c2cccc(Cl)c2)o1

Procedure:
Following general procedure Z2, starting from 2-[4-(1,1-difluoro-ethyl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-chloro-phenyl)-2-methyl-oxazole-4-carboxylic acid.
Reaction SMILES: [C:1]([N:3]1[C:11]2[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[C:5]2[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][C:4]1=2)#[CH:2].Br[C:19]1[CH:23]=[CH:22][S:21][CH:20]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][N:14]1[CH2:15][CH2:16][C:4]2[N:3]([C:1]#[C:2][C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)[C:11]3[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=3[C:5]=2[CH2:13]1
Reactant: Brc1ccsc1
Reactant: C#Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2C#Cc2ccsc2)CCN(C)C1
Yield: 6.5 %

Procedure:
A mixture of 5-ethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (165 mg, 0.736 mmol), 3-bromothiophene (100 mg, 0.613 mmol), TBAF.3H2O (580 mg, 1.84 mmol), and dichlorobis(triphenylphosphine)palladium (II) (13 mg, 0.018 mmol) were heated by microwave at 80° C. for 5 min. The reaction was monitored by TLC and LCMS. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (2×50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product obtained was purified by HPLC to yield 12.2 mg of 2,8-dimethyl-5-thiophen-3-ylethynyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CDCl3, freebase) δ (ppm): 7.50 (s, 1H), 7.40 (d, 1H), 7.38 (d, 1H), 7.20 (m, 2H), 7.10 (d, 1H), 3.68 (s, 2H), 2.98 (t, 2H), 2.90 (t, 2H), 2.58 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:26])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12](=[O:25])(=[O:24])[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([F:23])([F:22])[F:21].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>CN(C=O)C>[CH3:3][O:4][C:5](=[O:26])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12](=[O:25])(=[O:24])[N:13]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([F:23])([F:21])[F:22]
Reactant: COC(=O)c1ccccc1S(=O)(=O)Nc1ccccc1C(F)(F)F
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CN(c1ccccc1C(F)(F)F)S(=O)(=O)c1ccccc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.4 %

Procedure:
To the suspension of NaH (60% in mineral oil, 2.0 g, 50 mmol) in 45 mL of DMF at 0° C. was added a solution of 2-(2-trifluoromethyl-phenylsulfamoyl)-benzoic acid methyl ester (12.0 g, 33.3 mmol) in 22 mL of DMF dropwise. After about 10 minutes, 11.22 g (66.8 mmol) of methyl bromoacetate was added, and reaction solution was warmed to room temperature in 3 hours. The light yellow reaction mixture was poured into ice water. The mixture was then extracted with EtOAc 3×(˜400 mL) and washed with brine. The organic layer was dried over MgSO4 and evaporated down to a sick light orange oil. White crystals were formed upon treatment with Et2O and hexane. It was collected and dried over the vacuum oven to give pure 2-[methoxycarbonylmethyl-(2-trifluoromethyl-phenyl)-sulfamoyl]-benzoic acid methyl ester (13.85 g, 96%).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[CH3:12][N:13]1[C:17]([CH3:18])=[C:16](B2OC(C)(C)C(C)(C)O2)[C:15]([CH3:28])=[N:14]1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O>[CH3:12][N:13]1[C:17]([CH3:18])=[C:16]([C:2]2[CH:10]=[C:9]3[C:5]([CH2:6][CH2:7][C:8]3=[O:11])=[CH:4][CH:3]=2)[C:15]([CH3:28])=[N:14]1
Reactant: O=C1CCc2ccc(Br)cc21
Reactant: Cc1nn(C)c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1nn(C)c(C)c1-c1ccc2c(c1)C(=O)CC2
Temperature: 100 °C
Reaction time: 3 h

Procedure:
6-Bromo-indan-1-one (0.94 mmol) was dissolved in DME/H2O 1/1 (10 mL) under argon atmosphere. 1,3,5-Trimethyl-1H-pyrazole-4-boronic acid pinacol ester (1.42 mmol), K2CO3 (2.82 mmol), and tetrakis-(triphenylphosphine)palladium (5 mol %, 0.047 mmol) were added and the reaction mixture was stirred at 100° C. for 3 h. The reaction mixture was evaporated to dryness, then dissolved in CHCl3 and filtered through Celite® to give the crude product 6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-indan-1-one. The crude was purified by flash column chromatography (AcOEt-Cyclohexane as eluents) by using a CombiFlash Companion™ system to yield the title compound (84%). MS [MH]+=240
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:7]=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=1)[C:2]#[C:3][CH3:4].[CH3:15][C:16]1[C:17]([NH2:31])=[N:18][C:19]2([C:29]3[C:24](=[CH:25][CH:26]=[C:27]([NH2:30])[CH:28]=3)[O:23][CH2:22][CH2:21]2)[N:20]=1>>[NH2:31][C:17]1[C:16]([CH3:15])=[N:20][C:19]2([C:29]3[C:24](=[CH:25][CH:26]=[C:27]([NH:30][C:12]([C:9]4[CH:8]=[N:7][C:6]([O:5][CH2:1][C:2]#[C:3][CH3:4])=[CH:11][N:10]=4)=[O:14])[CH:28]=3)[O:23][CH2:22][CH2:21]2)[N:18]=1
Reactant: CC#CCOc1cnc(C(=O)O)cn1
Reactant: CC1=NC2(CCOc3ccc(N)cc32)N=C1N
Product: CC#CCOc1cnc(C(=O)Nc2ccc3c(c2)C2(CCO3)N=C(C)C(N)=N2)cn1
Yield: 25.6 %

Procedure:
The title compound (28 mg, 24% yield) was prepared as described for Example 13a starting from 5-(but-2-ynyloxy)pyrazine-2-carboxylic acid (Intermediate 36, 58 mg, 0.30 mmol) and 5′-methylspiro[chroman-4,2′-imidazole]-4′,6-diamine (Intermediate 30, 63 mg, 0.27 mmol). The crude product was purified by flash chromatography (4 g silica, gradient elution of (EtOAc/MeOH/conc. NH3 (80/20/1) in heptane) followed by preparative chromatography. The pure fractions were combined and evaporated. The residual oil was solidified by evaporation with EtOAc and heptanes: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.85 (t, 3H), 1.88-1.96 (m, 2H), 2.23 (s, 3H), 4.28-4.48 (m, 2H), 5.07 (q, 2H), 6.55 (s, 2H), 6.79 (d, 1H), 7.02-7.10 (m, 1H), 7.55-7.64 (m, 1H), 8.39 (d, 1H), 8.84 (d, 1H), 10.26 (s, 1H); MS (APCI+) m/z 405 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]=O.[CH:12]([CH:14]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:13]>C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1/[CH:10]=[CH:14]/[CH:12]=[O:13]
Reactant: O=Cc1cc2ccccc2o1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: O=C/C=C/c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
A solution of benzofuran-2-carboxaldehyde (2.2 g, 15.1 mmol) and formylmethylenetriphenylphosphorane (4.6 g, 15.1 mmoles) in CH2Cl2 (150 mL) was refluxed for 6 hours. Another aliquot of formylmethylenetriphenylphosphorane (1.5 g, 4.93 mmol) was then added and the reflux continued overnight. The reaction mixture was cooled to RT, the solvent concentrated at reduced pressure and the residue was chromatographed on silicagel (n-heptane/EtOAc 4/1). The collected fractions were pooled and concentrated and the residue triturated with isopropyl ether to give, after drying, pure title compound (1.3 g, 7.55 mmol, yield 50.0%) as pale yellow crystals, m.p.=67°.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:34]([NH:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[CH2:38]([NH:37][S:34]([C:30]1[CH:29]=[C:28]([NH:27][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:26])([F:1])[F:25])=[CH:4][C:5]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=4)=[N:6][C:7]=23)=[O:13])[CH:33]=[CH:32][CH:31]=1)(=[O:36])=[O:35])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: Nc1cccc(S(=O)(=O)NCc2ccccc2)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=C(Nc1cccc(S(=O)(=O)NCc2ccccc2)c1)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-amino-N-benzyl-benzenesulfonamide [CAS No. 303780-52-1] according to general procedure II. Yellow solid. MS (ISP) 618.1 [(M−H)−]; mp 227° C.
Reaction SMILES: [CH3:1]/[C:2](=[CH:7]\[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)/[CH2:3][CH2:4][CH:5]=O.Cl.[NH2:16]O>C(O)C>[CH3:1]/[C:2](=[CH:7]\[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)/[CH2:3][CH2:4][C:5]#[N:16]
Reactant: C/C(=C\c1ccc(C)cc1)CCC=O
Reactant: NO
Agent: Cl
Solvent: CCO
Product: C/C(=C\c1ccc(C)cc1)CCC#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
(4E)-4-methyl-5-(4-methylphenyl)-4-pentenal (3.2 g, 0.017 mol) and hydroxylamine hydrochloride (1.77 g, 0.025 mol) were heated together in 95% ethyl alcohol (55 ml) at reflux for 4 hours. After cooling to room temperature, ethanol was removed on the rotavapor. The residue was stirred in diethyl ether (250 ml) for 30 minutes. The solid was filtered off, rinsed with diethyl ether and discarded. The filtrate was evaporated under vacuum. The product was purified by column chromatography on silica gel (eluent: heptane/ethyl acetate 11:1) followed by bulb-to-bulb distillation. 2.18 g of the desired compound were obtained (0.012 mol, 70% yield).
Reaction SMILES: [C:1]([N:8]1[CH2:16][C@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][C@H:9]1[C:10]([O:12][CH3:13])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Li+].[CH3:24][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[C:1]([N:8]1[CH2:16][C@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][C@@:9]1([CH3:24])[C:10]([O:12][CH3:13])=[O:11])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)[C@@H]1C[C@@H](c2ccccc2)CN1C(=O)OC(C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)[C@]1(C)C[C@@H](c2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-BOC-4-(S)-phenyl-(L)-proline, methyl ester from Step A (2.0 g, 6.56 mmol) in anhydrous THF (20 mL) at −78° C. was added over a 30 min period 1M LiHMDS in hexanes (9.83 mL, 9.83 mmol) and allowed to stir for 30 mins at −78° C. The reaction was then allowed to stir for 1 hr at 0° C. The reaction was then cooled to −78° C. and MeI (4.65 g, 32.79 mmol) was added dropwise. The reaction was allowed to warm to rt overnight. The reaction was quenched with NH4Cl. The organic layer was collected and washed with 1M HCl, NaHCO3, brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluted with 75% Et2O/hexanes to give 1.85 g of desired product.
Reaction SMILES: [CH3:1][C:2]1[N:3]([S:9]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])[CH:4]=[CH:5][C:6]=1[CH:7]=[O:8].[Br:18]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:18][C:4]1[N:3]([S:9]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)(=[O:10])=[O:11])[C:2]([CH3:1])=[C:6]([CH:7]=[O:8])[CH:5]=1
Reactant: Cc1c(C=O)ccn1S(=O)(=O)c1cccnc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C=O)cc(Br)n1S(=O)(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.7 %

Procedure:
To a solution of 2-methyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (974 mg) in N,N-dimethylformamide (10 mL) was added N-bromosuccinimide (1.17 g) at 0° C., and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:1) to give the title compound as white crystals (yield 675 mg, 53%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)[CH2:19][C:20]([OH:22])=[O:21].N1CCCCC1>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:10]=1/[CH:11]=[CH:19]\[C:20]([OH:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CC(=O)O
Reactant: Cc1cccc(C=O)c1OCc1ccccc1
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: Cc1cccc(/C=C\C(=O)O)c1OCc1ccccc1

Procedure:
Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-(benzyloxy)-3-methylbenzaldehyde (20 g, 88.39 mmol, 1.00 equiv), propanedioic acid (27.6 g, 265.23 mmol, 3.00 equiv), piperidine (1.5 g, 17.62 mmol, 0.20 equiv) and pyridine (200 mL). The resulting solution was heated to reflux for 2 h in an oil bath. The reaction was then quenched by the addition of 1.5 L of water/ice. The pH value of the solution was adjusted to 2-3 with hydrogen chloride. The solids were collected by filtration. The filter cake was washed with 2×500 mL of water and 2×500 mL of hexane. This resulted in 21 g (89%) of (2Z)-3-[2-(benzyloxy)-3-methylphenyl]prop-2-enoic acid as a white solid. MS (ESI) m/z 269 ([M+H]+).
Reaction SMILES: [F:1][C:2](Br)([F:4])[F:3].[CH3:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[CH3:16])[C:10](Cl)=[O:11].CCCCCC>C(Cl)Cl>[CH3:6][C:7]1[CH:8]=[C:9]([C:10](=[O:11])[C:2]([F:4])([F:3])[F:1])[CH:13]=[CH:14][C:15]=1[CH3:16]
Reactant: Cc1ccc(C(=O)Cl)cc1C
Reactant: FC(F)(F)Br
Solvent: ClCCl
Solvent: CCCCCC
Product: Cc1ccc(C(=O)C(F)(F)F)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.2 %

Procedure:
Under protective gas, 41 g (0.27 mol) of trifluoromethyl bromide are condensed into a solution of 42 g (0.25 mol) of 3,4-dimethylbenzoyl chloride in 150 ml of CH2Cl2 in a round-bottomed flask at about -70° C. A solution of 66.7 g (0.27 mol) of phosphorous acid trisdiethylamide in 50 ml of CH2Cl2 are then metered in at about -70° C., the first 90% of the solution being added rapidly and the last 10% of the solution being metered in slowly (during the course of about 2 hours). The mixture is subsequently stirred for one hour more at this temperature and then warmed to room temperature. After addition of the same volume of hexane, 2 phases are formed. After phase separation, the lower phase is carefully extracted using hexane; the combined hexane phases are concentrated and distilled under reduced pressure. 20.8 g (41% yield) of 1-(3,4-dimethylphenyl)- 2,2,2-trifluoroethan-1-one of b.p. 98°-99° C./22 mbar are obtained.