Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]1([CH3:19])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N:53]1([S:58]([NH:61][C:62]([C@@:64]2([NH:69][C:70]([C@@H:72]3[CH2:83][C@:75]4([C:80]([CH3:82])([CH3:81])[C:76]54[CH2:79][CH2:78][CH2:77]5)[CH2:74][NH:73]3)=[O:71])[CH2:66][C@H:65]2[CH:67]=[CH2:68])=[O:63])(=[O:60])=[O:59])[CH2:57][CH2:56][CH2:55][CH2:54]1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([C:13]1([CH3:19])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[C:10]([N:73]1[C@H:72]([C:70](=[O:71])[NH:69][C@:64]2([C:62]([NH:61][S:58]([N:53]3[CH2:54][CH2:55][CH2:56][CH2:57]3)(=[O:60])=[O:59])=[O:63])[CH2:66][C@H:65]2[CH:67]=[CH2:68])[CH2:83][C@:75]2([C:80]([CH3:81])([CH3:82])[C:76]32[CH2:77][CH2:78][CH2:79]3)[CH2:74]1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@]2(CN1)C(C)(C)C21CCC1)C(=O)NS(=O)(=O)N1CCCC1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1(C)CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@]2(CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C1(C)CCOCC1)C(C)(C)C21CCC1)C(=O)NS(=O)(=O)N1CCCC1
Reaction time: 8 h

Procedure:
A solution of (S)-tert-Butoxycarbonylamino-(4-methyl-tetrahydro-pyran-4-yl)-acetic acid (0.306 g; 1.12 mmol) (prepared according to Tetrahedron Let. 2007, 48, 6343-6347) and HATU (0.581 g; 1.53 mmol) in DCM (20 mL) was stirred for 10 min at ambient temperature. DIPEA (1.05 mL; 6.11 mmol) and (5R,8S)-10,10-Dimethyl-7-aza-dispiro[3.0.4.1]decane-8-carboxylic acid [(1R,2S)-1-(pyrrolidine-1-sulfonylaminocarbonyl)-2-vinyl-cyclopropyl]-amide (0.57 g; 1.02 mmol) were added, the reaction mixture was stirred overnight and purified without workup by preparative HPLC (method L) to yield the title compound. LC-MS (method E): Rt=2.55 min; M/z=706 [M+]; HPLC (method A3): Rt=6.16 min
Reaction SMILES: [N:1]1([CH2:15][C:16]2[O:20][C:19]([CH2:21][OH:22])=[N:18][CH:17]=2)[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH3:30][S:31]([O:22][CH2:21][C:19]1[O:20][C:16]([CH2:15][N:1]2[CH2:6][CH2:5][C:4]3([C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH:8]=[CH:7]3)[CH2:3][CH2:2]2)=[CH:17][N:18]=1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ncc(CN2CCC3(C=Cc4ccccc43)CC2)o1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ncc(CN2CCC3(C=Cc4ccccc43)CC2)o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
To a 0° C. stirred solution of [5-(spiro[indene-1,4′-piperidine]-1′-ylmethyl)oxazol-2-yl]methanol (0.15 g, 0.51 mmol) in DCM (10.0 mL) is added triethylamine (0.18 mL, 1.26 mmol) and methane sulphonyl chloride (0.05 mL, 0.61 mmol). The reaction mixture is stirred at 0° C. for 1 hour. The reaction mixture is washed with water (20.0 mL) and brine (10.0 mL), extracted with DCM, dried over Na2SO4, and evaporated to dryness to give the crude product (0.18 g) as a brown liquid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]([CH3:12])[CH3:11])[CH:4]=1)#[N:2].Cl.[H][H]>CO.[Pd]>[NH2:2][CH2:1][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]([CH3:12])[CH3:11])[CH:4]=1
Reactant: [H][H]
Reactant: CN(C)Cc1cc(C#N)ccn1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN(C)Cc1cc(CN)ccn1
Yield: 59.9 %

Procedure:
A mixture of 4-cyano-2-(dimethylamino)methylpyridine (800 mg, 4.97 mmol), palladium (80 mg, 10% Pd/C) and concentrated hydrochloric acid (3 mL) in methanol (30 mL) was shaken under 60 psi of hydrogen overnight. The reaction mixture was filtered through diatomaceous earth and the filter cake rinsed with water and methanol. The filtrate was concentrated under reduced pressure and the residue partitioned between water and methylene chloride. The aqueous layer was made alkaline with 1 N sodium hydroxide and extracted with methylene chloride. The organic layer was washed with saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure to give an orange oil. Purification by flash column chromatography (97:3 2-propanol/ammonium hydroxide) gave 4-aminomethyl-2-(dimethylamino)methylpyridine 37 (492 mg): 1H NMR (500 Hz, CDCl3) δ 8.50 (d, J=5.1 Hz, 1H), 7.37 (s, 1H), 7.15 (d, J=5.1 Hz, 1H), 3.91 (s, 2H), 3.58 (s, 2H), 2.30 (s, 6H); ESI MS m/z 166 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[CH:25]=[N:26][N:27]([CH2:29][CH2:30][O:31]C5CCCCO5)[CH:28]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH:38]C(=O)C)[CH:10]=1.C(Cl)(=O)C>CO>[NH2:38][C:11]1[CH:12]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[CH:25]=[N:26][N:27]([CH2:29][CH2:30][OH:31])[CH:28]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:14]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH:10]=1
Reactant: CC(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cnn(CCOC5CCCCO5)c4)ccc32)c1
Solvent: CO
Solvent: CC(=O)Cl
Product: Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cnn(CCO)c4)ccc32)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28 %

Procedure:
To a solution of N-(2′,4′-difluoro-5-(5-(1-(2-((tetrahydro-2H-pyran-2-yl)oxy)-ethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)acetamide (0.12 g, 0.125 mmol) in methanol (5 ml) was added (1 ml) acetyl chloride at 0° C. The mixture was stirred at RT for 16 h. The mixture was quenched and extracted as in Example 1(d). The solvent was distilled off to afford the product in 28% yield (0.026 g). 1H NMR (400 MHz, DMSO-d6): δ 8.53 (s, 1H), 8.20 (s, 1H), 7.97-7.95 (d, 2H), 7.69-7.64 (m, 2H), 7.59-7.56 (dd, 1H), 7.39-7.36 (m, 1H), 6.88 (s, 2H), 6.82 (d, 1H), 5.70 (s, 2H), 4.95 (s, 1H), 4.19-4.16 (t, 2H), 3.81-3.78 (t, 2H); LC-MS (ESI): Calculated mass: 431.44; Observed mass: 432.2 [M+H]+ (rt: 0.4 min).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:19](=[O:43])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[O:33][N:32]=[C:31]([CH3:34])[C:30]=2[CH2:35][O:36]C2CCCCO2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:17][C:11]1[C:12]([N:14]([CH3:16])[CH3:15])=[CH:13][C:8]2[N:7]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[O:33][N:32]=[C:31]([CH3:34])[C:30]=4[CH2:35][OH:36])[CH:24]=3)[CH2:20][C:19](=[O:43])[NH:18][C:9]=2[CH:10]=1
Reactant: Cc1noc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)c1COC1CCCCO1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1noc(-c2cccc(C3=Nc4cc(N(C)C)c(Cl)cc4NC(=O)C3)c2)c1CO

Procedure:
The title compound was prepared from (RS)-[4-chloro-5-dimethylamino-2-(3-{3-[3-methyl-4-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-5-yl]-phenyl}-3-oxo-propionylamino)-phenyl]-carbamic acid tert.-butyl ester (Example M32) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (60 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[CH:8]=[CH:7]2.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1ccc2cccc(F)c2[nH]1
Product: Fc1cccc2ccc(Cl)nc12
Temperature: 125 °C
Yield: 73.8 %

Procedure:
8-Fluoroquinolin-2(1H)-one (26.0 g, 159 mmol) was slurried with phosphoryl trichloride (163 ml, 1.73 mol, 11 eq) and heated to 125° C. for 2 h. The reaction was cooled to rt and poured onto 1.2 L of ice water with vigorous stirring. When the mixture had cooled to rt, the orange solid was filtered and washed with water and dried under vacuum overnight to afford 27 g of crude material. The crude material was recrystallized from hexanes by dissolving in ˜700 mL of hexanes at reflux and decanting away from residual tar. The hexane solution was cooled to 0° C. and the precipitate 2-chloro-8-fluoroquinoline was filtered. The mother liquor was concentrated in vacuo and recrystallized from hexanes to obtain a second crop of 2-chloro-8-fluoroquinoline (21.3 g, 74% total yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[NH:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=O>>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:15]([C:11]3[NH:10][CH:14]=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: O=Cc1ccc[nH]1
Product: Brc1cnc2[nH]c(-c3ccc[nH]3)nc2c1

Procedure:
The title compound was prepared from 5-bromo-2,3-diaminopyridine and pyrrole-2-carboxaldehyde.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Br:16][CH2:17][CH2:18][CH2:19][CH2:20]Br>>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: BrCCCCBr
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Product: N#Cc1ccc(-c2ccc(OCCCCBr)cc2)cc1
Yield: 31 %

Procedure:
A solution of 4'-hydroxy-4-cyanobiphenyl (11.7 g, 60 mmol) was treated with 1,4-dibromobutane (38.9 g, 0.18 mol, 216) as described in Example 1. Recrystallization of the product from ethanol gave 4'-(4-bromobutyloxy)-4-cyanobiphenyl (6.15 g, 31%): mp 62.5-64° C.; 1H NMR (CDCl3) 7.52(s, 4H), 7.41 and 6.83(2d, 4H), 3.95(t, 2H), 3.42(t, 2H), 1.97(m, 4H); IR (KBr) 2225, 1605, 1581 cm-1.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH:26]=[CH:27][N:28]=4)=[CH:20][C:19]=3[CH:29]=O)=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])[O:4][N:3]=1.[CH2:31]([NH:35][CH3:36])[CH:32]([CH3:34])[CH3:33].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH:26]=[CH:27][N:28]=4)=[CH:20][C:19]=3[CH2:29][N:35]([CH3:36])[CH2:31][CH:32]([CH3:34])[CH3:33])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:10])=[O:11])[O:4][N:3]=1
Reactant: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2C=O)c1C
Reactant: CNCC(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2CN(C)CC(C)C)c1C
Yield: 74.1 %

Procedure:
After briskly stirring a mixture of N-(3,4-dimethyl-5-isoxazolyl)-2'-formyl-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide (100 mg; 0.24 mmol; prepared as in Step (F) of Example 21), isobutylmethylamine (0.087 ml; 0.71 mmol), AcOH (0.08 ml; 1.34 mmol) and 3 Å molecular sieves (670 mg) in 2 ml of CH2Cl2 for 1 hour at room temperature, sodium triacetoxyborohydride (150 mg; 0.71 mmol) was added. After stirring 18 hours at room temperature, the reaction mixture was filtered through celite and the filtrate was partitioned between EtOAc (40 ml) and saturated NaHCO3 solution (20 ml). The organic layer was washed with water (20 ml) followed by brine (20 ml). Drying (Na2 SO4) and concentration afforded a residue that was chromatographed on a 2.5×12 cm silica gel column using a stepwise gradient of 300 ml @CH2Cl2 to 5% MeOH/CH2Cl2 in 1% increments. The pure fractions were concentrated to afford 88 mg of the title compound of this Example as a white powder.
Reaction SMILES: Br[CH2:2][C:3](=O)/[C:4](=[N:10]/[O:11][CH:12]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:20][C:21]([NH2:23])=[S:22]>>[NH2:23][C:21]1[S:22][CH:2]=[C:3](/[C:4](=[N:10]/[O:11][CH:12]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)/[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:20]=1
Reactant: CCOC(=O)/C(=N\OC1CCCCCC1)C(=O)CBr
Reactant: NC(N)=S
Product: CCOC(=O)/C(=N\OC1CCCCCC1)c1csc(N)n1
Yield: 69 %

Procedure:
Ethyl 4-bromo-(Z)-2-(cycloheptyloxyimino)-3-oxobutyrate (6.3 g) was treated with thiourea as described in Example 4d. Crystallisation from dichloromethane/hexane gave the title compound as a white solid (4.1 g, 69%), m.p. 107°-8° C. (Found: C: 54.24, H: 6.72, N: 13.33. C14H21N3O3S requires C: 54.00, H: 6.80, N:13.49%). νmax (KBr) 3433, 2930, 1723, 1611, 1540 cm -1 ; δH (CDCl3) 1.33 (3H, t) 1.4-2.0 (12H, m), 4.35 (3H, q+m) 5.60 (2H, br s, exch. D2O), 6.64 (1H,ss).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2=[CH2:14])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:26])C=1.[OH-].[Ca+2].[OH-]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]32[O:26][CH2:14]3)=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C1C(C)(C)CCC1(C)Cc1ccc(Cl)cc1
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC1(C)CCC(C)(Cc2ccc(Cl)cc2)C12CO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.8 %

Procedure:
2-(4-Chlorobenzyl)-2,5,5-trimethyl-1-methylenecyclopentane (6.1 g) was dissolved in 60 ml of chloroform, followed by the addition of 8.5 g of m-chloroperbenzoic acid. The resultant mixture was stirred for 5 hours under ice cooling. Calcium hydroxide (4.0 g) was added, followed by stirring at room temperature for 30 minutes. A solid thus precipitated was filtered off. From the chloroform layer as the filtrate, chloroform was distilled off under reduced pressure to obtain a colorless oily substance. The substance was subjected to and purified by chromatography on a silica gel column (eluent: 6:1 mixed solvent of n-hexane and methylene chloride), thereby obtaining 2.0 g of 4-(4-chlorobenzyl)-4,7,7-trimethyl-1-oxaspiro[2.4]heptane used in the above Preparation Example.
Reaction SMILES: [P:1]([OH:4])([OH:3])[OH:2].C(O)(=O)CC.[C:10](#[N:12])[CH3:11]>>[NH2:12][C:10]([P:1]([OH:4])(=[O:2])[OH:3])([P:1]([OH:4])(=[O:3])[OH:2])[CH3:11]
Reactant: OP(O)O
Reactant: CC#N
Solvent: CCC(=O)O
Product: CC(N)(P(=O)(O)O)P(=O)(O)O
Yield: 85 %

Procedure:
Into a reactor similar to the above were charged 174 g phosphorous acid and 92 g propionic acid. 41.5 g acetonitrile was introduced slowly for 72 minutes at 135°-140° C. into the agitated mixture which was maintained for an additional 10 hours at that temperature. The 1-aminoethane-1, 1-diphosphonic acid produced was isolated from the reaction mixture in the same manner as described in Example 1. The yield was 85% of the theory calculated on the acetonitrile employed.
Reaction SMILES: C([O:3][C:4](=[O:27])[C@@H:5]([O:25][CH3:26])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)C.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1>>[CH3:26][O:25][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([C:30]3[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=3)=[CH:22][CH:23]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:27]
Reactant: OB(O)c1cccnc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCOc2ccc(I)cc2)cc1)OC
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(-c3cccnc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-{4-[3-(4-iodo-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid ethyl ester (Example 270, Step A) and 3-pyridyl boronic acid by following the procedure described for Example 270 (Steps B and C). 1H-NMR (MeOD, 300.15 MHz): δ 8.76 (s, 1H), 8.46 (s, 1H), 8.05 (d, 1H, J=8.1), 7.60 (d, 2H, J=8.7), 7.49 (dd, 1H, J=7.7, 4.8), 7.19 (d, 2H, J=8.5), 7.09 (d, 2H, J=8.7), 6.85 (d, 2H, J=8.5), 4.24 (t, 2H, J=6.1), 4.17 (t, 2H, J=6.3), 3.74 (dd, 1H, J=8.7, 3.8), 3.27 (s, 3H), 2.97 (dd, 1H, J=14.3, 3.8), 2.81 (dd, 1H, J=14.1, 8.5), 2.26 (qn, 2H, J=6.0).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:35])[CH2:13][NH:14][C:15]([C:17]1[CH:18]=[C:19]([CH:23]2[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24]2)[CH:20]=[CH:21][CH:22]=1)=[O:16].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:35])[CH2:13][NH:14][C:15](=[O:16])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(C(=O)NCC(O)CN3CCc4ccccc4C3)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1cccc(C2CCNC2)c1
Temperature: 29 °C
Reaction time: 2 h
Yield: 25.1 %

Procedure:
To a solution of tert-butyl 3-(3-((3-(3, 4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl) carbamoyl)phenyl)pyrrolidine-1-carboxylate (400 mg, 0.83 mmol) in CH2Cl2 (5 mL) was added TFA (1 mL) at 29° C. The mixture was stirred for 2 h at 29° C. The mixture was concentrated and the residue was purified by prep-HPLC to give the title compound (79.1 mg, Yield 25.0%). 1H NMR (CD3OD, 400 MHz): δ 7.75-7.93 (m, 2H), 7.45-7.62 (m, 2H), 7.17-7.37 (m, 4H), 4.45-4.74 (m, 2H), 4.40 (dd, J=6.3, 3.3 Hz, 1H), 3.71-4.04 (m, 2H), 3.49-3.70 (m, 5H), 3.35-3.49 (m, 3H), 3.08-3.32 (m, 3H), 2.52 (qd, J=6.6, 4.2 Hz, 1H), 2.09-2.27 (m, 1H). LCMS (m/z): 380.2 (M+1).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[C:13]([OH:22])(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[NH2:16]>C1COCC1>[C:14]12[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[NH:16][C:2](=[O:4])[O:22][C:13]2=[O:21]
Reactant: Nc1ccccc1C(=O)O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=c1[nH]c2ccccc2c(=O)o1
Temperature: 0 °C
Yield: 70 %

Procedure:
An ice-cold solution of triphosgene (3.0 g, 10 mmol, 0.4 eq) in 10 mL of anhydrous THF was added to a mixture or solution of anthranilic acid (or 2-amino-benzoic acid) (25 mmol) in 15 mL of dry THF and cooled slowly. The mixture as then stirred or shaken for 24-48 h at room temperature nd cooled in a refrigerator (0° C. to −10° C.) for 12-24 h. The resulting solid was collected by filtration and washed with cold methyl t-butyl ether (MTBE) and dried to give the isatoic anhydride in 70-98% yield. About 30 isatoic anhydrides were prepared in this manner.
Reaction SMILES: [C:1]([C:3]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])OC(C)(C)C)#[N:2].Cl.N1C=CC=CC=1.[C:34]([O:37][C:38](C)([CH3:42])[C:39](Cl)=O)(=[O:36])[CH3:35]>O1CCOCC1>[C:34]([O:37][C:38]([CH3:42])([CH3:39])[C:13]([NH:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][C:4]1[CH:20]=[CH:21][CH:22]=[C:23]([N+:24]([O-:26])=[O:25])[C:3]=1[C:1]#[N:2])=[O:19])(=[O:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)NCCCCCCOc1cccc([N+](=O)[O-])c1C#N
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CC(=O)OC(C)(C)C(=O)NCCCCCCOc1cccc([N+](=O)[O-])c1C#N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 22.4 %

Procedure:
To a solution of tert-butyl 6-(2-cyano-3-nitrophenoxy)hexylcarbamate (333 mmol, 121 mg) (Example 225c) in dioxane (2 mL) was added con. HCl (1 mL). After 15 minutes, the solution was concentrated in vacuo and dried on high vacuum. The crude HCl salt was suspended in DCM (dry, 10 mL) and treated with pyridine (2.664 mmol, 62 μL) and 1-chloro-2-methyl-1-oxopropan-2-yl acetate (1.332 mmol, 193 μL). The reaction mixture was refluxed under a nitrogen atmosphere until clear (6 h), then cooled to room temperature and the volatiles removed in vacuo. The residue was purified on silica gel (40% to 100% EtOAc in hexanes) to give the product (117 mg, 90%) as a light yellow heavy oil. MS 392 (MH+).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[C:10]([C:11]2[NH:15][CH:14]=[C:13]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:12]=2)=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:4].[CH3:26][O:27][C:28]1[N:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>O1CCCC1.C1OCCOCCOCCOCCOC1>[C:3]([C:5]1[C:10]([C:11]2[N:15]([S:34]([C:31]3[CH:32]=[N:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=3)(=[O:35])=[O:36])[CH:14]=[C:13]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH:12]=2)=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:4]
Reactant: CN(Cc1c[nH]c(-c2cccnc2C#N)c1)C(=O)OC(C)(C)C
Reactant: COc1ccc(S(=O)(=O)Cl)cn1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2cccnc2C#N)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To a suspension of sodium hydride (60% in oil, 26 mg) in tetrahydrofuran (4 mL) were added dropwise a solution of tert-butyl {[5-(2-cyanopyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (156 mg) in tetrahydrofuran (2 mL), 15-crown-5 (0.13 mL) and 6-methoxypyridine-3-sulfonyl chloride (135 mg) under ice-cooling, and the mixture was stirred for 30 min. The reaction mixture was diluted with ice water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→2:3) to give the title compound as a pale-yellow oil (yield 235 mg, 97%).
Reaction SMILES: Cl[CH2:2][Si:3]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)([CH3:5])[CH3:4].[Na].[NH:14]1[CH:18]=[N:17][CH:16]=[N:15]1>CN(C)C=O.O>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([Si:3]([CH3:5])([CH3:4])[CH2:2][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)=[CH:7][CH:8]=1
Reactant: c1nc[nH]n1
Reactant: C[Si](C)(CCl)c1ccc(Cl)cc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(Cn1cncn1)c1ccc(Cl)cc1
Yield: 39.7 %

Procedure:
A mixture of 2.2 g (0.010 mol) of chloromethyl(4-chlorophenyl)dimethylsilane and 1.1 g (0.012 mol) of 1,2,4-triazole sodium salt in 5 ml of dimethylformamide was warmed to 80°-90° for 2 hours, diluted with water, and extracted with ether. The ether solution was washed with water and brine, dried over magnesium sulfate, and evaporated to leave 2:1 g (83%) of the title compound as a yellow liquid: nD21 1.5428; ir (neat) 1555, 1470, 1245, 1130, 1080, 1010, 835, 805, 795, 735 cm-1 ; nmr (CDCl3) 0.4 (6H, s), 3.8 (2H, s), 7.4 (4H, broad s), 7.8 (1H, s), 7.9 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([S:11](N)(=[O:13])=[O:12])=[CH:4][C:3]=1[Br:15].[Cl:16]S(O)(=O)=O>>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([S:11]([Cl:16])(=[O:13])=[O:12])=[CH:4][C:3]=1[Br:15]
Reactant: O=S(=O)(O)Cl
Reactant: Nc1c(Br)cc(S(N)(=O)=O)cc1[N+](=O)[O-]
Product: Nc1c(Br)cc(S(=O)(=O)Cl)cc1[N+](=O)[O-]

Procedure:
4-Amino-3-bromo-5-nitrobenzenesulfonamide ((U.S. Pat. No. 3,987,199) 1 g, 3.17 mmol) was heated at 95° C. for 3 h in chlorosulfonic acid (10 mL). The solution was cooled then poured onto ice and then filtered. The solid was redissolved in DCM and dried over sodium sulfate. Removal of the solvent yielded the product (960 mg) which was used without further purification.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH:18]([C:20]2[N:21]([S:31]([N:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])[CH:22]=[C:23]([CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][CH3:28])[N:24]=2)O)=[CH:13][CH:12]=1>C(Cl)Cl>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH:18]([C:20]2[N:21]([S:31]([N:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])[CH:22]=[C:23]([CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][CH3:28])[N:24]=2)[F:7])=[CH:13][CH:12]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(O)Cc2ccc(Br)cc2)n1
Solvent: ClCCl
Product: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(F)Cc2ccc(Br)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diethylaminosulfur trifluoride (7.01 mL, 53.5 mmol) was added to an ambient temperature solution of 2-[2-(4-bromophenyl)-1-hydroxyethyl]-4-(2,2-dimethylbutyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (4.89 g, 10.7 mmol) in methylene chloride (100 mL). After stirring at ambient temperature overnight, the reaction mixture was quenched with saturated aqueous sodium bicarbonate and extracted with methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-30% ethyl acetate/hexane afforded 2-[2-(4-bromophenyl)-1-fluoroethyl]-4-(2,2-dimethylbutyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide.