Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.[CH2:9](B(CC)CC)[CH3:10].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.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>[CH2:9]([C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1)[CH3:10]
Reactant: Fc1ccc(Br)cn1
Reactant: CCB(CC)CC
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: O
Solvent: CN(C)C=O
Product: CCc1ccc(F)nc1

Procedure:
A mixture of 5-bromo-2-fluoropyridine (2-a, 5.03 g, 28.6 mmol, Lancaster Synthesis, Inc., Wyndham, N.H.), triethylborane (1M in tetrahydroftiran, 42.8 mL, 42.8 mmol), K2CO3 (15.8 g, 114.2 mmol) and Pd(PPh3)4 (1.65 g, 1.43 mmol) in N,N-dimethylformamide was heated at 85 C for 4 h. The reaction mixture was diluted with water and extracted with hexanes. The organic layer was then washed with water (×2), separated, dried (MgSO4), and concentrated in vacuo. Chromatography (50%, CH2Cl2 in hexanes) afforded the desired product (2-b); 1H NMR (500 MHz, CDCl3) δ 8.04 (d, 1H, J =1.0 Hz), 7.60 (dt, 1H, J=8.0, 2.5 Hz), 6.85 (dd, 1H, J=8.3, 2.8 Hz), 2.65 (q, 2H, J=7.8 Hz), 1.21 (t, 3H, J=7.7Hz)
Reaction SMILES: [CH:1]([NH:3][C:4]([CH2:21][CH3:22])([CH2:19][CH3:20])[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)=O.[CH:23]([NH:25][C:26]([CH2:44][CH2:45][CH3:46])([CH2:41][CH2:42][CH3:43])[C:27]1[CH:32]=[CH:31][C:30]([C:33]#[C:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:29][CH:28]=1)=O>>[CH2:21]([C:4]([NH:3][CH3:1])([CH2:19][CH3:20])[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH3:22].[CH3:23][NH:25][C:26]([CH2:44][CH2:45][CH3:46])([CH2:41][CH2:42][CH3:43])[C:27]1[CH:32]=[CH:31][C:30]([C:33]#[C:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:29][CH:28]=1
Reactant: CCC(CC)(NC=O)c1ccc(C#Cc2ccccc2)cc1
Reactant: CCCC(CCC)(NC=O)c1ccc(C#Cc2ccccc2)cc1
Product: CCC(CC)(NC)c1ccc(C#Cc2ccccc2)cc1
Product: CCCC(CCC)(NC)c1ccc(C#Cc2ccccc2)cc1

Procedure:
When the above experiment is repeated using as alternate starting materials either N-formyl-α,α-diethyl-4-(phenylethynyl)-benzylamine or N-formyl-α ,α-di(n-propyl)-4-(phenylethynyl)-benzylamine there is obtained respectively α,α-diethyl-N-methyl-4-(phenylethynyl)-benzylamine or N-methyl-α,α-di(n-propyl)-4-phenylethynyl benzylamine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17]Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[Cl-:13].[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N+:10]2([CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:9][CH2:8]1
Reactant: ClCCCCCl
Reactant: c1cnc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: [Cl-]
Product: c1cnc(N2CC[N+]3(CCCC3)CC2)nc1
Temperature: 25 °C
Yield: 70 %

Procedure:
A mixture of 1-(2-pyrimidinyl)piperazine (32.8 g., 0.2 mole), 1,4-dichlorobutane (76.2 g., 0.6 mole) and finely powdered sodium carbonate (44.5 g., 0.42 mole) in 300 ml. of acetonitrile is stirred and refluxed for a 12-hour period. The hot reaction mixture is filtered and the filter cake washed with 50-100 ml. of hot acetonitrile. Combined filtrates are maintained at room temperature until crystallization occurs, then cooled, filtered, and collected material washed with acetone to provide a 70-90% yield of 8-(2-pyrimidinyl)-8-aza-5-azoniaspiro[4.5]decane chloride. This material is hygroscopic and after drying under vacuum at room temperature affords the monohydrate from melting about 90° C. which on continued drying under vacuum at 90° C. for several hours affords the anhydrous product having a melting point of about 210° 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[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41][NH2:42].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.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[CH:17]=[CH:18][C:19]([NH:22][C:27]([NH:42][CH2:41][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][N:35]=2)=[O:33])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: NCc1ccccn1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)NCc4ccccn4)cc3)c2cc1OC
Yield: 100 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (52 mg) was dissolved in toluene (5 ml) with heat, after the addition of triethylamine (1 ml), triphosgene (54 mg) was added, and the admixture was refluxed with heat for 2 minutes. 2-Pyridylmethylamine (0.05 ml) was added to the reaction mixture, and the admixture was refluxed with heat for 12 minutes. After the addition of aqueous sodium hydrogen carbonate, the reaction mixture was extracted 2 times with ethyl acetate, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 76 mg of the title compound (yield: 100%).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[F:17][C:18]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:19]=1[CH2:20][C:21]1[O:25][N:24]=[C:23]([C:26](O)=[O:27])[CH:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[NH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([CH:5]2[CH2:6][CH2:7][N:2]([C:26]([C:23]3[CH:22]=[C:21]([CH2:20][C:19]4[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:18]=4[F:17])[O:25][N:24]=3)=[O:27])[CH2:3][CH2:4]2)=[CH:9]1
Reactant: O=C(O)c1cc(Cc2cc(F)ccc2F)on1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(Cc2cc(F)ccc2F)on1)N1CCC(c2c[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 64.7 %

Procedure:
The mixture of 3-(piperidin-4-yl)-1H-indole hydrochloride (0.060 g; 0.253 mmol), 5-(2,5-difluorobenzyl)isoxazole-3-carboxylic acid (0.061 g; 0.253 mmol), HATU (N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate) (0.096 g: 0.253 mmol) and N,N-diisopropylethylamine (0.110 mL; 0.634 mmol) in DMF (3 mL) was stirred for 72 hours at room temperature and was concentrated under reduced pressure. The residue was dissolved in dichloromethane and the organic layer was washed with water and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent: 0 to 10% of ethyl acetate in dichloromethane) to give 0.069 g (65%) of (4-(1H-indol-3-yl)piperidin-1-yl)(5-(2,5-difluorobenzyl)isoxazol-3-yl)methanone as a white solid.
Reaction SMILES: [CH3:1][CH:2]([S:4](Cl)(=[O:6])=[O:5])[CH3:3].[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]2[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=2)=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl>[CH3:1][CH:2]([S:4]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([CH:22]=[O:23])=[CH:24][CH:25]=2)=[CH:11][CH:10]=1)(=[O:6])=[O:5])[CH3:3]
Reactant: O=Cc1ccc(OCCc2ccc(O)cc2)cc1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)S(=O)(=O)Oc1ccc(CCOc2ccc(C=O)cc2)cc1
Yield: 72.9 %

Procedure:
3.77 g (13 mmole) 2-propanesulfonyl chloride dissolved in dichloromethane was slowly added to a solution of 3.2 g (13 mmole) 4-[2-(4-hydroxyphenyl)ethoxy]benzaldehyde and 2.63 g (26 mmole) triethylamine in 80 ml dichloromethane at 0° C. The temperature was slowly allowed to rise to room temperature and when the starting material was consumed the reaction mixture was poured on to ice. The phases were separated and the organic phase was washed with sodium carbonate, dried (sodium sulfate), filtered and evaporated. The residue was purified by chromatography on silica gel using dichloromethane as eluent to give 3.3 g (yield 72.8%) of 4-[2-(4-formylphenoxy)ethyl]phenyl 2-propanesulfonate.
Reaction SMILES: [OH:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:4][NH2:5].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl.N1C=CC=CC=1>[C:18]([NH:5][CH2:4][CH2:3][C:2]([OH:1])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCCC(O)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(NCCC(O)(c1ccccc1)c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
To the solution of 58.0 g of 3-hydroxy-3,3-diphenylpropylamine in 700 ml of methylene chloride and 30.5 g of pyridine, that of 37.5 g of benzoyl chloride in 300 ml of methylene chloride is added dropwise during 2 hours while stirring and cooling with an ice-bath. Stirring is continued for 1 hour at 0°-5°, the mixture washed twice with 200 ml of N hydrochloric acid, 150 ml of 5% aqueous sodium hydroxide and 25 ml of water each, dried, evaporated and the residue triturated with diethyl ether, to yield the N-benzoyl-3-hydroxy-3,3-diphenylpropylamine melting at 140°-141°.
Reaction SMILES: O.[OH-].[Li+].[O:4]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][N:14]3[CH2:18][C@H:17]([N:19]([C:29](=[O:35])[CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=4)[CH2:16][C@H:15]3[C:36]([O:38]C)=[O:37])=[CH:12][C:7]=2[O:6][CH2:5]1.CO>O>[O:4]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][N:14]3[CH2:18][C@H:17]([N:19]([C:29](=[O:35])[CH2:30][C:31]([CH3:34])([CH3:32])[CH3:33])[CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=4)[CH2:16][C@H:15]3[C:36]([OH:38])=[O:37])=[CH:12][C:7]=2[O:6][CH2:5]1
Reactant: COC(=O)[C@@H]1C[C@@H](N(Cc2cccc(OC)c2)C(=O)CC(C)(C)C)CN1Cc1ccc2c(c1)OCO2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cccc(CN(C(=O)CC(C)(C)C)[C@@H]2C[C@@H](C(=O)O)N(Cc3ccc4c(c3)OCO4)C2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
Lithium hydroxide monohydrate (17 mg, 0.405 mmol) was added to a solution of methyl(2S,4R)-1-(1,3-benzodioxol-5-ylmethyl)-4-[(3,3-dimethylbutanoyl)(3-methoxybenzyl)amino]tetrahydro-1H-2-pyrrolecarboxylate (10) (100 mg, 0.20 mmol) in 66% v/v methanol in water (1.0 mL). The mixture was stirred overnight at room temperature, then the solvent was removed under reduced pressure and the residue partitioned between dichloromethane (1.0 mL) and water (1.0 ml). The aqueous phase was acidified with 1.0 M aqueous citric acid and the two layers were vigorously stirred for 10 min at room temperature. The layers were separated and the aqueous layer was back-extracted with dichloromethane. The combined dichloromethane extracts were dried (MgSO4) and evaporated under reduced pressure to give the title acid (11) (70 mg, 72%) as an off-white solid:
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH2:18])[CH:11]=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:5]=[CH:6][CH:7]=1.[CH3:19][S:20]C1C=C(B(O)O)C=CC=1>>[CH3:19][S:20][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH2:18])[CH:11]=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:5]=[CH:6][CH:7]=1
Reactant: CSc1cccc(B(O)O)c1
Reactant: Nc1cc2cccnc2c(-c2cccc(F)c2)n1
Product: CSc1cccc(-c2nc(N)cc3cccnc23)c1

Procedure:
8-(3-Methylsulfanyl-phenyl)-[1,7]naphthyridin-6-ylamine is prepared in an analogous manner to compound D (see Example 22) using 3-methylthiophenyl boronic acid to yield the product, MS (ES+) 268.04
Reaction SMILES: FC(F)(F)[C:3]([N:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])C)=O.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21]([OH:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1>CO>[S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)([OH:24])(=[O:23])=[O:22].[CH3:3][NH:5][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12]
Reactant: C=CCCCCN(C)C(=O)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: C=CCCCCNC

Procedure:
At room temperature, compound 31a (71.88 g, 1 eq.) and p-toluene sulfonic acid (74.4 g, 1.2 eq.) were dissolved in MeOH (640 mL). The reaction mixture was refluxed for 7 days. The solvent was then removed under vacuum, and the residue was recrystallized in acetone. The product was isolated by filtration and dried over P2O5 to give compound 32a as a white powder in 76% yield. 1H NMR (CDCl3, 400 MHz): δ (ppm) 1.38 (q, J=7.76 Hz, 2H), 1.71 (q, J=7.76 Hz, 2H), 1.99 (q, J=6.98 Hz, 2H), 2.38 (s, 3H), 2.70 (t, J=5.17 Hz, 3H), 2.87-2.93 (m, 4.92-4.99 (m, 2H), 5.67-5.73 (m, 1H), 7.20 (d, J=7.76 Hz, 2H), 7.75 (d, J=7.76 Hz, 2H), 8.62 (br s, 2H).
Reaction SMILES: ClC1C=C([N:9]2[C:13](=[O:14])[C@@]3([C@H](C4C=CC(C#N)=CC=4)CNC3)N(C)[C:10]2=[O:28])C=C(Cl)C=1.[N:29]([CH2:32][C:33]([O:35]CC)=O)=C=O.C1C[O:41][CH2:40]C1.CN(C=O)C>>[CH2:40]([OH:41])[C:32]([NH2:29])([CH2:33][OH:35])[CH2:13][OH:14].[N-:9]=[C:10]=[O:28]
Reactant: CCOC(=O)CN=C=O
Reactant: C1CCOC1
Reactant: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CNC[C@H]2c1ccc(C#N)cc1
Solvent: CN(C)C=O
Product: NC(CO)(CO)CO
Product: [N-]=C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 15 (24.9 mg, 0.06 mmol) in 1 ml THF/DMF (9/1), was added ethyl isocyanatoacetate (11.6 mg, 0.089 mmol), and the reaction mixture was stirred overnight at RT. The titled compound was obtained (33.3 mg) after treatment with PS-Trisamine (Argonaut, 73 mg, 0.267 mmol) and PS-Isocyanate (Argonaut, 85 mg, 0.122 mmol). Retention time: 1.99 min., 544 (M+1); (LCMS conditions: LC Micromass platform (APCI+, DAD (210–400 nm)), Column: TSK gel Super ODS 4.6 mm ID×5 cm, Flow rate: 2.75 mL/min, Gradient: from 100% eluent A to 100% eluent B in 2 min., with a plateau with 100% eluent B during 1 min. Eluent A: H2O (0.05% TFA), Eluent B: CH3CN/H2O/TFA (80/20/0.05)).
Reaction SMILES: [CH2:1]([N:3]([C:6]1[CH:24]=[CH:23][C:9]([CH:10]([OH:22])[C:11]2[CH:16]=[CH:15][C:14]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:13][CH:12]=2)=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].[C:25]([NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:28])[CH2:26]O.C(C(C)=O)C>CS(O)(=O)=O.CN(C)C(=N)N(C)C.CCCCCC>[CH2:18]([N:17]([CH2:20][CH3:21])[C:14]1[CH:15]=[CH:16][C:11]([CH:10]([C:9]2[CH:23]=[CH:24][C:6]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:7][CH:8]=2)[O:22][CH2:26][C:25]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:28])=[CH:12][CH:13]=1)[CH3:19]
Reactant: CCN(CC)c1ccc(C(O)c2ccc(N(CC)CC)cc2)cc1
Reactant: O=C(CO)Nc1ccccc1
Agent: CN(C)C(=N)N(C)C
Agent: CS(=O)(=O)O
Solvent: CCCCCC
Solvent: CCC(C)=O
Product: CCN(CC)c1ccc(C(OCC(=O)Nc2ccccc2)c2ccc(N(CC)CC)cc2)cc1

Procedure:
A solution of 4,4'-bis(N,N-diethylamino)benzhydrol (11.0 g, 0.034 mole), glycolanilide (5.1 g, 0.034 mole), 37.5 ml of methyl ethyl ketone, 112.5 ml of n-hexane, and 7 drops of methanesulfonic acid was refluxed for about 2 hours, removing water as formed. The solution was then treated with 5 drops of tetramethyl-guanidine and filtered hot. On cooling, the filtrate yielded a tan precipitate. The precipitate was filtered, washed with n-hexane, and dried. The pale yellow solid was recrystallized from 80 ml of methylcyclohexane and 450 ml of acetone to give a solid product, mp 123°-125° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([NH:15][C:16]3[CH:24]=[CH:23][C:19](C(O)=O)=[CH:18][CH:17]=3)[CH2:11][CH:12]([CH3:14])[CH3:13])=[C:7]([CH3:25])[C:6]=2[CH:26]=1.CNC[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[CH3:60][N:61]([CH3:64])[CH:62]=[O:63]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([NH:15][C:16]3[CH:24]=[CH:23][C:19]([C:62]([N:61]([CH3:64])[CH2:60][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:63])=[CH:18][CH:17]=3)[CH2:11][CH:12]([CH3:13])[CH3:14])=[C:7]([CH3:25])[C:6]=2[CH:26]=1
Reactant: Cc1c(C(CC(C)C)Nc2ccc(C(=O)O)cc2)oc2ccc(Cl)cc12
Reactant: CCOC(=O)CCNC
Reactant: CN(C)C=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(CC(C)C)c2oc3ccc(Cl)cc3c2C)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 85 %

Procedure:
To a mixture of 4-{[1-(5-chloro-3-methyl-1-benzofuran-2-yl)-3-methylbutyl]amino}benzoic acid (180 mg) synthesized in Example A100(3), ethyl 3-(methylamino)propanoate (95.2 mg), 1-hydroxybenzotriazole monohydrate (111 mg), triethylamine (202 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (139 mg), and the mixture was stirred at room temperature for 2.5 days. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (55% ethyl acetate/hexane) to give the title object compound (199 mg, 85%) as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:12]=[CH:11][C:10]([N:13]([C:22]([O:24]CC(Cl)(Cl)Cl)=O)C(OCC(Cl)(Cl)Cl)=O)=[CH:9][CH:8]=1.[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]1[N:41]=[C:40]([N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[S:39][N:38]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]1[N:41]=[C:40]([N:42]2[CH2:43][CH2:44][N:45]([C:22]([NH:13][C:10]3[CH:9]=[CH:8][C:7]([N:3]4[CH2:4][CH2:5][CH2:6][C:2]4=[O:1])=[CH:12][CH:11]=3)=[O:24])[CH2:46][CH2:47]2)[S:39][N:38]=1
Reactant: Fc1ccccc1-c1nsc(N2CCNCC2)n1
Reactant: O=C1CCCN1c1ccc(N(C(=O)OCC(Cl)(Cl)Cl)C(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1ccc(N2CCCC2=O)cc1)N1CCN(c2nc(-c3ccccc3F)ns2)CC1
Yield: 14.3 %

Procedure:
A solution of bis(2,2,2-trichloroethyl) [4-(2-oxopyrrolidin-1-yl)phenyl]imidodicarbonate (200 mg, 0.379 mmol), 1-[3-(2-fluorophenyl)-1,2,4-thiadiazol-5-yl]piperazine (196 mg, 0.742 mmol), diisopropylethylamine (0.132 ml, 0.758 mmol) and dimethyl sulfoxide (4 ml) was stirred at 70° C. for 24 hours, and the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to give 25.3 mg (14.3%) of the desired product as a solid.
Reaction SMILES: [OH-].[K+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:11][CH2:12][O:13][CH3:14].[Cl:15][S:16](O)(=[O:18])=[O:17]>C(Cl)Cl.CS(C)=O>[CH3:14][O:13][CH2:12][CH2:11][O:9][C:3]1[CH:8]=[CH:7][C:6]([S:16]([Cl:15])(=[O:18])=[O:17])=[CH:5][CH:4]=1
Reactant: Oc1ccccc1
Reactant: COCCBr
Reactant: O=S(=O)(O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: ClCCl
Product: COCCOc1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C

Procedure:
Methylsulfoxide (400 mL) is cooled with an ice/water bath with mechanical stirring and charged with potassium hydroxide pellets (118.2 g, 2.11 mole) followed by phenol (94.1 g, 0.70 mole) and then 2-bromoethylmethyl ether (86 mL, 0.9 mole) is added at a rapid dripping rate. The mixture is stirred for 15 min., warmed to room temperature and then stirred for 2 hrs. It is then diluted with 1 L of ice/water and extracted 2 times with CH2Cl2. The combined organic layers were then dried over MgSO4, filtered and evaparated The yield is in excess of 100% so it is taken in CHCl3 and washed 2 times with water and 1 time with brine. This organic layer was processed similarly and the concentrate was taken in 1.1 L of CH2Cl2 in a mechanically stirred flask 5 L flask. Chlorosulfonic acid (140 mL, 2.1 mole) is added dropwise causing slight warming A heavy precipitate is observed after addition of half of the reagent, so the mixture is diluted with 1.1 L of additional CH2Cl2. The resulting mixture is allowed to stir at rt for 16 hrs. It is then poured onto ˜2 L of ice/water. The layers are separated and the aqueous layer is extracted two times with CH2Cl2. The combined organic layers are then combined, dried over MgSO4, filtered and evaparated to give the desired material which is sufficiently pure to carry forward without purification. ESI MS: m/z (rel intensity) 247.1 (M++H, 35), 264.1 (M++NH3, 100), 269.0 (M++Na, 45).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.C(=O)(O)[O-].[Na+].[CH3:15][C@H:16]1[CH2:20][CH2:19][CH2:18][NH:17]1>CO>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([N:17]2[CH2:18][CH2:19][CH2:20][C@@H:16]2[CH3:15])[N:3]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: C[C@H]1CCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: C[C@H]1CCCN1c1nc(Cl)cc(Cl)n1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Dissolve 2,4,6-trichloropyrimidine (23.5 g, 0.13 mol) in anhydrous MeOH (220 mL), and add solid sodium bicarbonate (28.3 g, 0.33 mol). Cool to 0° C. and add 2-(S)-methylpyrrolidine (12 g, 0.14 mol) dropwise. Let stir at room temperature for 16 h. Filter off the excess sodium bicarbonate, and evaporate under reduced pressure. Purify by SiO2 flash chromatography, using 50:1 hexanes:EtOAc, increasing to 30:1 hexanes:EtOAc, to provide the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21](C(O)=O)=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([F:36])([F:35])[F:34].[OH:37][N:38]1[C:42]2C=[CH:44][CH:45]=[CH:46][C:41]=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.[CH3:68][N:69]([CH3:72])[CH:70]=[O:71]>C(OCC)(=O)C>[CH3:68][N:69]([CH2:72][C:45]1[CH:44]=[N+:38]([O-:37])[CH:42]=[CH:41][CH:46]=1)[C:70]([C:21]1[N:13]2[C:12]([CH2:11][N:10]([C:8]([C:6]3[CH:5]=[CH:4][C:3]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]([F:36])([F:34])[F:35])=[C:2]([CH3:1])[CH:7]=3)=[O:9])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14]2)=[CH:23][CH:22]=1)=[O:71]
Reactant: On1nnc2ccccc21
Reactant: CN(C)C=O
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)O)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)N(C)Cc4ccc[n+]([O-])c4)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Reaction time: 8 h

Procedure:
To a stirred solution of the 10-(2-methyl-2′-trifluoromethyl-biphenyl-4-carbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Example 1, Step F (0.50 g, 1.02 mmol), methyl-(1-oxy-pyridin-3-ylmethyl)-amine dihydrochloride of Step C (0.26 g, 1.23 mmol) and 1-hydroxybenzotriazole (0.16 g, 1.18 mmol) in N,N-dimethylformamide (4 mL) was added 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (0.21 g, 1.10 mmol) followed by N,N-diisopropylethyl amine (0.73 mL, 4.10 mmol). The reaction mixture was stirred overnight, diluted with ethyl acetate and washed with water and saturated aqueous sodium bicarbonate. The organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a yellow foam. Purification by flash chromatography eluting with 2% methanol in chloroform provided 0.52 g of the title compound, which was redissolved in dichloromethane and concentrated in vacuo to give a white foam.