Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=3)[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([OH:21])C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.[Zn].O>[O:21]=[C:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][C:5]=2[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=[O:14])[NH:1]1
Reactant: O=C(O)c1cccc(-c2cccc3[nH]ccc23)c1
Reactant: CCO
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Solvent: O
Product: O=C1Cc2c(cccc2-c2cccc(C(=O)O)c2)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To the suspension of 3-(1H-indol-4-yl)-benzoic acid (7.58 g, 33 mmol) in t-BuOH:ethanol:acetic acid (150 mL:100 mL:50 mL) was added pyridinium tribromide (31.66 g, 99 mmol) portionwise. The mixture was stirred at room temperature for 2 hours, and then to the mixture was added with acetic acid (150 mL). Water (4 mL) and Zinc dust (13.07 g, 200 mmol) was added to the reaction mixture portionwise and stirring was continued at room temperature for 2 hours. The solvent was removed under reduced pressure. The oily residue was suspended in 1N HCl (400 mL) and stirred at room temperature overnight. The precipitate solid was collected by filtration, purified by recrystallization from ethyl acetate to give (6.4 g, 77%) of 3-(2-oxo-2,3-dihydro-1H-indol-4-yl)-benzoic acid as a pinkish white solid.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH3:13][CH:14]1[CH2:21][CH:20]([CH2:22][CH2:23][CH2:24][CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH2:19][CH2:18][O:17][C:15]1=[O:16].CI>O1CCCC1.CCCCCC>[CH3:13][C:14]1([CH3:1])[CH2:21][CH:20]([CH2:22][CH2:23][CH2:24][CH2:25][O:26][Si:27]([C:30]([CH3:32])([CH3:31])[CH3:33])([CH3:29])[CH3:28])[CH2:19][CH2:18][O:17][C:15]1=[O:16]
Reactant: CC1CC(CCCCO[Si](C)(C)C(C)(C)C)CCOC1=O
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CI
Product: CC1(C)CC(CCCCO[Si](C)(C)C(C)(C)C)CCOC1=O
Reaction time: 0.25 h

Procedure:
To a solution of 10 ml (65 mmol) diisopropylamine in 120 ml dry tetrahydrofuran is added dropwise 26 ml of a 2.5M solution of n-butyllithium in hexane and the mixture is stirred for 15 min. To this solution is added slowly a solution of 10.11 g (32 mmol) of 2-methyl-4-(4-t-butyldimethylsilyloxybutyl)-epsilon-caprolactone in 48 ml dry tetrahydrofuran. The mixture is stirred at room temperature for 35 min and 14.0 ml (0.22 mole) of methyl iodide is added rapidly while the flask is cooled in a water bath. After stirring for 3.5 h, the reaction is quenched using saturated ammonium chloride solution and is extracted with ether. The organic phase is washed with water and brine, dried, filtered and concentrated to give an amber oil which is purified by silica gel chromatography using 3:2 hexane/ether to give impure product. Further purification by a second silica gel chromatography using 4:1 hexane/ether as eluent yields 2,2-dimethyl-4-(4-t-butyldimethylsilyloxybutyl)-epsilon-caprolactone; NMR (CDCl3): delta 4.32 (t,2H), 3.6 (t,2H), 1.3 (d,6H), 0.88 (s,9H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[CH2:7][NH:8][C:9]1[CH:10]=[C:11]([NH:15]C(=O)OC(C)(C)C)[CH:12]=[CH:13][CH:14]=1)([O-:3])=[O:2].[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>ClCCl>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[N+:1]([C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)Nc1cccc(NCc2cccc([N+](=O)[O-])c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cccc(NCc2cccc([N+](=O)[O-])c2)c1
Yield: 79 %

Procedure:
A solution of tert-butyl {3-[(3-nitrobenzyl)amino]phenyl}carbamate (100 mg, 0.3 mmol) in dichloromethane (3 mL) and trifluoroacetic acid (3 mL) was stirred at 25° C. for 1 h. The reaction mixture was concentrated to a crude residue. This material was purified by preparative LCMS to give the desired product (110 mg, 79%) as a solid. LCMS for C13H14N3O2 (M+H)+: m/z=244.0.
Reaction SMILES: [C:1]1([C:7](=O)[CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C(C)=CC=CC=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:36].S>C(O)C>[C:1]1([C:7]2[S:36][C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=3)=[CH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C(CC(C(=O)c1ccccc1)c1ccccc1)c1ccc(Cl)c(Cl)c1
Agent: S
Solvent: CCO
Solvent: Cc1ccccc1C
Product: Clc1ccc(-c2cc(-c3ccccc3)c(-c3ccccc3)s2)cc1Cl
Yield: 177.8 %

Procedure:
In a 1-liter stainless steel autoclave equipped with electrically-driven stirrer were placed 38.3 g. (0.100 mole) of 1,2-diphenyl-4-(3,4-dichlorophenyl)butane-1,4-dione, 100 ml of xylene, 20 g of phosphorus pentasulfide and 140 g of hydrogen sulfide. The reactor was heated for three hours at 160°-164° C. The crude product remaining after cooling and venting the reactor was stirred with ethanol. Filtration gave 30.5 g (80%) of solid m.p. 101°-103° C. Recrystallization from 30 ml of dioxane and 60 ml of ethanol gave 22.5 g (59%) of pure product, m.p. 106.2°-107.8° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.[C:25]1(C)C=C[CH:28]=[CH:27][CH:26]=1.ClC(Cl)([O:35][C:36](=O)[O:37]C(Cl)(Cl)Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)CCC.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:36](=[O:35])[O:37][CH2:28][CH2:27][CH2:26][CH3:25])=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOC(=O)Nc1cc(C)c(Oc2ccnc3cc(OC)c(OC)cc23)cc1C
Yield: 94 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-butanol (17 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (65 mg, yield 94%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[OH:31])[CH2:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[F:38][C:39]([F:46])([F:45])[CH2:40][CH2:41][CH2:42][CH2:43]Br>C(#N)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH2:43][CH2:42][CH2:41][CH2:40][C:39]([F:46])([F:45])[F:38])[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: FC(F)(F)CCCCBr
Reactant: COC(=O)c1ccc(CC(/C=C/c2ccccc2O)CCc2ccc(C#N)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CC(/C=C/c2ccccc2OCCCCC(F)(F)F)CCc2ccc(C#N)cc2)cc1

Procedure:
A solution of 200 mg (0.486 mmol) of methyl 4-[(3E)-2-[2-(4-cyanophenyl)ethyl]-4-(2-hydroxyphenyl)but-3-en-1-yl]benzoate in 10 ml of acetonitrile is mixed with 101 mg (0.73 mmol) of potassium carbonate and 149 mg (0.73 mmol) of 1,1,1-trifluoro-5-bromopentane [CAS Reg. No. 54932-74-00] and stirred under reflux for 12 h. After conversion is complete, the salts are filtered off and the mother liquor is evaporated. 205 mg (0.28 mmol, 79% of theory) of the title compound are obtained.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:19])C=1>ClCCl>[O:1]1[C:10]2[C:5](=[N+:6]([O-:19])[CH:7]=[CH:8][CH:9]=2)[O:4][CH2:3][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1cnc2c(c1)OCCO2
Solvent: ClCCl
Product: [O-][n+]1cccc2c1OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
2,3-Dihydro-[1,4]dioxino[2,3-b]pyridine (121 mg, 790 μmol) was dissolved in dichloromethane (4.0 mL), added 3-chloroperbenzoic acid (234 mg, 950 μmol), and stirred at room temperature for 1 hour. The reaction solution was concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (chloroform/methanol), and the title compound (102 mg (yield 84%)) was obtained as a white solid.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:33])[CH2:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[C:18]1[N:19]=[N:20][C:21]([NH:24][NH:25]C(OC(C)(C)C)=O)=[CH:22][CH:23]=1)([CH3:4])([CH3:3])[CH3:2].[S:34](=[O:38])(=[O:37])([OH:36])[OH:35]>>[C:1]([NH:5][CH2:6][CH:7]([OH:33])[CH2:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[C:18]1[N:19]=[N:20][C:21]([NH:24][NH2:25])=[CH:22][CH:23]=1)([CH3:4])([CH3:2])[CH3:3].[S:34]([O-:38])([O-:37])(=[O:36])=[O:35]
Reactant: COc1ccc(-c2ccc(NNC(=O)OC(C)(C)C)nn2)c(OCC(O)CNC(C)(C)C)c1
Reactant: O=S(=O)(O)O
Product: COc1ccc(-c2ccc(NN)nn2)c(OCC(O)CNC(C)(C)C)c1
Product: O=S(=O)([O-])[O-]

Procedure:
3-[2-(3-t-Butylamino-2-hydroxypropoxy)-4-methoxyphenyl]-6-(2-t-butyloxycarbonylhydrazino)pyridazine (0.01 mole) was treated with dilute sulphuric acid (0.01 mole) and the solution evaporated to dryness to give the title compound as its sulphate salt.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])(C)(C)C.C(O[C:23](=[O:40])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([CH3:39])[CH:34]=2)[CH:28]=1)=O)(C)(C)C>>[Cl:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[N:7]=[C:25]([C:27]3[CH:32]=[CH:31][N:30]=[C:29]([C:33]4[CH:38]=[CH:37][N:36]=[C:35]([CH3:39])[CH:34]=4)[CH:28]=3)[CH2:24][C:23](=[O:40])[NH:16][C:9]=2[CH:10]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: Cc1cc(-c2cc(C(=O)CC(=O)OC(C)(C)C)ccn2)ccn1
Product: Cc1cc(-c2cc(C3=Nc4cc(C)c(Cl)cc4NC(=O)C3)ccn2)ccn1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (67 mg, 0.26 mmol) and 3-(2′-methyl-[2,4′]bipyri-dinyl-4-yl)-3-oxo-propionic acid tert-butyl ester (Example K59) (81 mg, 0.26 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (69 mg).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[CH2:10]([O:12][C:13]([C:15]1([CH2:29]I)[CH2:19][CH2:18][N:17]([C:20](=[O:28])[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:16]1)=[O:14])[CH3:11]>>[CH2:10]([O:12][C:13]([C:15]1([CH2:29][O:9][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[CH2:19][CH2:18][N:17]([C:20](=[O:28])[C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[CH2:16]1)=[O:14])[CH3:11]
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccc(F)cc2)C1
Reactant: Oc1cccc(F)c1F
Product: CCOC(=O)C1(COc2cccc(F)c2F)CCN(C(=O)c2ccc(F)cc2)C1

Procedure:
The title compound was prepared according to the method described for Preparation using 2,3-difluoro-phenol and 1-(4-fluoro-benzoyl)-3-iodomethyl-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 12) to afford the racemate as a white solid (167 mg, 68%) ES m/z 408 [MH]+
Reaction SMILES: [O:1]1[CH2:6][C:5](=O)[CH2:4][C:3](=[O:8])[CH2:2]1.[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][C:11]=1[I:18].[NH2:19]/[C:20](/[CH3:26])=[CH:21]\[C:22]([O:24][CH3:25])=[O:23]>CO>[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]2[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([CH3:26])[NH:19][C:5]3[CH2:6][O:1][CH2:2][C:3](=[O:8])[C:4]2=3)=[CH:12][C:11]=1[I:18]
Reactant: COC(=O)/C=C(/C)N
Reactant: O=C1COCC(=O)C1
Reactant: O=Cc1ccc(F)c(I)c1
Solvent: CO
Product: COC(=O)C1=C(C)NC2=C(C(=O)COC2)C1c1ccc(F)c(I)c1
Yield: 45.1 %

Procedure:
The product from Example 1C (0.34 g, 3.0 mmol), the product from Example 2C (0.74 g, 3.0 mmol) and methyl 3-aminocrotonate (0.35 g, 3.0 mmol) in methanol (8 mL) were processed as described in Example 5A to provide the title compound (0.60 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[N:5]([CH3:7])[CH:6]=1.[C:12]([O:16][C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13].CCO.C([O-])([O-])=O.[K+].[K+]>O.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.C1(C)C=CC=CC=1>[C:12]([O:16][C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[N:5]([CH3:7])[CH:6]=2)=[CH:22][CH:21]=1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)c1cc(Br)cn1C
Reactant: CC(C)(C)OC(=O)Nc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cc(-c2ccc(NC(=O)OC(C)(C)C)cc2)cn1C
Temperature: 100 °C
Yield: 96.8 %

Procedure:
A catalytic amount of tetrakis(triphenylphosphine)palladium, Pd(PPh3)4 (0.477 g, 0.413, 0.06 eq) was added to a solution of 4 (1.5 g, 6.88 mmol, 1 eq) and (4-((tert-butoxycarbonyl)amino)phenyl)boronic acid (1.57 g, 6.88 mmol, 1.20 eq) in a 9:3:1 combination (13.5 ml) of EtOH, toluene and water in the presence of K2CO3 (2.856 g, 3 eq.) in a 10-20 mL microwave vial containing a magnetic stirrer. The reaction vessel was flushed with nitrogen during each addition. The reaction mixture was sealed in an inert N2 atmosphere and heated with microwave radiation in an EMRYS™ Optimizer Microwave Station (Personal Chemistry) at 100° C. for 12 minutes. After LCMS and TLC analysis revealed completion of the reaction, the cooled reaction mixture was diluted with water (50 mL), extracted with EtOAc (3×40 mL), the filtrates combined, dried over MgSO4 and concentrated under vacuum. The resulting oil was subjected to flash chromatography (n-hexane/EtOAc 9:1) to give 5 (Yield—2.2 g, 97%). IR (FTIR, vmax/cm−1): 3353, 2975, 1696, 1521, 1441, 1366, 1264, 1235, 1209, 1058, 822, 799, 657; 1H-NMR (400 MHz, CDCl3): δ 7.40 (d, 2H, J=8.8 Hz), 7.33 (d, 2H, J=8.8 Hz), 7.16 (d, 1H, J=2.0 Hz), 7.02 (d, 1H, J=2.0), 6.45 (br s, 1H), 3.95 (s, 3H), 3.83 (s, 3H), 1.52 (s, 9H); 13C-NMR (100 MHz, CDCl3): δ 161.7, 152.8, 136.5, 129.5, 125.9, 125.6, 123.7, 123.0, 119.0, 114.6, 80.5, 51.1, 36.9, 28.4; EIMS m/z (+EI) calc. for C18H22N2O4 (M)+ 330.38. found 330.46 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16](Cl)[N:15]=[C:14]([NH:19][CH3:20])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[N:15]=[C:14]([NH:19][CH3:20])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CNc1nc(Cl)cc(NS(=O)(=O)c2ccc(N)cc2)n1
Reactant: C1CCNC1
Solvent: CCO
Product: CNc1nc(NS(=O)(=O)c2ccc(N)cc2)cc(N2CCCC2)n1
Yield: 63.1 %

Procedure:
0.314 g (0.001 mol) of 4-amino-N-(6-chloro-2-methylamino-pyrimidin-4-yl)-benzenesulfonamide and 2.5 ml (0.15 mol) of pyrrolidine were stirred in 20 ml of ethanol in an autoclave at 130° C. for 4 hours. The reaction mixture was freed from solvent, the residue was suspended in 5 ml of ethanol and treated in an ultrasound bath for 15 min. The precipitate was filtered off, dissolved in 150 ml of 1N NaOH and filtered. The filtrate was adjusted to pH 6 with 1N HCl. The precipitate was filtered off under suction, washed with water and dried. There was obtained 0.22 g (63%) of 4 -amino-N-(2-methylamino-6-pyrrolidin-1-yl-pyrimidin-4-yl)-benzenesulfonamide as beige crystals; m.p.: >300° C.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:11][C@@H:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=3)=[N:19][N:20]=2)[C@@H:13]([OH:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl>[C:35]([O:15][C@@H:13]([CH3:14])[C@@H:12]([NH:11][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=1[CH3:10])[C:16]1[O:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]#[N:28])=[CH:25][CH:26]=2)=[N:19][N:20]=1)(=[O:37])[CH3:36]
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(C#N)cc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)O[C@@H](C)[C@@H](Nc1ccc(C#N)c(Cl)c1C)c1nnc(-c2ccc(C#N)cc2)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.5 %

Procedure:
To a 50 mL round bottomed flask was added 2-chloro-4-((1R,2S)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)-3-methylbenzonitrile (200 mg, 0.508 mmol), pyridine (1 mL, 12.41 mmol) and methylene chloride (15 mL). Acetyl chloride (0.18 mL, 2.54 mmol) was then added dropwise and the mixture was stirred at room temperature for 18 h. The reaction mixture was then quenched with 10% aq HCl (15 mL) and methylene chloride (30 mL) was added. The phases were partitioned and the aqueous phase extracted with methylene chloride (30 mL) (×2). The combined organics were washed with a saturated solution of sodium hydrogen carbonate, dried (Na2SO4) and concentrated to furnish a yellow oil (0.052 g, 24%). 1H NMR (Acetone d6, 400 MHz) δ 8.23 (d, J=9 Hz, 2 H), 8.02 (d, J=9 Hz, 2 H), 7.54 (d, J=9 Hz, 1 H), 7.01 (d, J=9 Hz, 1 H), 5.74 (d, J=9 Hz, 1 H), 5.68-5.62 (m, 1H), (dd, J=9 and 5 Hz, 1H), 2.37 (s, 3 H), 2.04 (s, 3H), 1.47 (d, J=6 Hz, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:20]=[C:21]([CH3:23])[CH:22]=1)[O:16][CH2:17][CH2:18][OH:19])(=[O:11])=[O:10].C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:20]=[C:21]([CH3:23])[CH:22]=1)[O:16][CH2:17][CH:18]=[O:19])(=[O:11])=[O:10]
Reactant: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCO)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(OCC=O)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 61 %

Procedure:
A solution of 2-[3-(2-methoxyphenylsulfonyloxy)-5-methylphenoxy]-ethanol (322 mg, 0.95 mmol, as prepared in the preceding step), N,N-diisopropylethylamine (0.35 mL, 2.0 mmol), anhydrous dimethyl sulfoxide (0.20 mL, 2.9 mmol) and anhydrous dichloromethane (2.5 mL) was cooled to 0° C. under nitrogen. Sulfur trioxide pyridine complex (308 mg, 1.9 mmol) was added in portions over 10 minutes. The solution was stirred at 0° C. for 5 hours, then the reaction was quenched with 5% aqueous citric acid (25 mL). Diethyl ether (25 mL) was added, and the mixture was extracted. The aqueous layer was extracted with diethyl ether (25 mL), and the combined organic layers were washed with 5% aqueous citric acid (25 mL). The aqueous layer was extracted with diethyl ether (25 mL), and the combined organic layers were washed with pH 7 buffer (0.5M, 2×40 mL) and brine (40 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to an oil. Crude product was purified by flash column chromatography through silica gel (0% to 5% acetone in dichloromethane) to give the title compound as a colorless oil (195 mg, 61%). 1H-NMR (300 MHz, CDCl3) δ 9.76 (t, 1H, J=1 Hz), 7.81 (dd, 1H, J=1.7, 7.9 Hz), 7.60-7.65 (m, 1H), 7.09 (d, 1H, J=8 Hz), 7.00-7.05 (m, 1H), 6.63 (br s, 1H), 6.59 (br s, 1H), 6.41 (t, 1H, J=2.2 Hz), 4.45 (d, 2H, J=1 Hz), 4.03 (s, 3H), 2.27 (s, 3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C16H16O6S: 359.1 (M+Na). Found: 358.8.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:25]=[CH:24][C:18]([CH2:19][C:20]4([NH2:23])[CH2:22][CH2:21]4)=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[N+](C1C=CC([CH:37]2[S:41]/[C:40](=[N:42]\[C:43](=O)[O-:44])/[N:39]([C:46]3[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:47]=3[CH:53]([CH3:55])[CH3:54])[C:38]2=[O:56])=CC=1)([O-])=O>>[CH:53]([C:47]1[CH:48]=[CH:49][C:50]([CH3:52])=[CH:51][C:46]=1[N:39]1[C:38](=[O:56])[CH2:37][S:41]/[C:40]/1=[N:42]\[C:43]([NH:23][C:20]1([CH2:19][C:18]2[CH:24]=[CH:25][C:15]([C:12]3[N:13]=[CH:14][N:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:26])[F:27])=[CH:9][CH:8]=4)[N:11]=3)=[CH:16][CH:17]=2)[CH2:21][CH2:22]1)=[O:44])([CH3:55])[CH3:54]
Reactant: NC1(Cc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)CC1
Reactant: Cc1ccc(C(C)C)c(N2C(=O)C(c3ccc([N+](=O)[O-])cc3)S/C2=N\C(=O)[O-])c1
Product: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)NC2(Cc3ccc(-c4ncn(-c5ccc(OC(F)(F)F)cc5)n4)cc3)CC2)c1

Procedure:
The title compound was prepared as described in Example 95 using 1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzyl)cyclopropanamine (CB30) and (Z)-4-nitrophenyl(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)carbamate (CA50), purified by flash column chromatography using 0-100% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent and isolated as red oil (0.104 g, 37%).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[F:24].CN([CH:28]=[O:29])C>C1COCC1.O>[Cl:16][C:17]1[C:18]([F:24])=[C:19]([C:20]([CH3:23])=[CH:21][CH:22]=1)[CH:28]=[O:29]
Reactant: CN(C)C=O
Reactant: Cc1ccc(Cl)c(F)c1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(Cl)c(F)c1C=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 7.2 %

Procedure:
(Reference: E. J. Org. Chem. 2005, 2116-2123) To a solution of 2,2,6,6-tetramethylpiperidine (0.642 mL, 3.80 mmol) in THF (15 mL) at −78° C. was added n-BuLi (2.162 mL, 3.46 mmol) dropwise. The resulting solution was stirred at −78° C. for 1 h and added 1-chloro-2-fluoro-4-methylbenzene (0.5 g, 3.46 mmol) dropwise. The solution was stirred for additional 0.5 h and then added DMF (0.536 mL, 6.92 mmol). The reaction was stirred at −78° C. for 1.5 h and at ambient temperature for 12 h. The mixture was diluted with water and extracted with EtOAc (3×). The combined organic layer was washed with brine and concentrated. The residue was purified by silica gel chromatography to yield the desired product (43 mg, 7%).