Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([C:16](Cl)=[O:17])=[N:6][N:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:8]=1)[CH3:2].[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][C:30]=1[O:31][CH3:32])[N:27]=[CH:26][CH:25]=[C:24]2[O:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][C:35]=1[F:41]>N1C=CC=CC=1.CCOC(C)=O>[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][C:30]=1[O:31][CH3:32])[N:27]=[CH:26][CH:25]=[C:24]2[O:33][C:34]1[CH:40]=[CH:39][C:37]([NH:38][C:16]([C:5]2[C:4]([O:3][CH2:1][CH3:2])=[CH:8][N:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[N:6]=2)=[O:17])=[CH:36][C:35]=1[F:41]
Reactant: CCOc1cn(-c2ccc(F)cc2)nc1C(=O)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOc1cn(-c2ccc(F)cc2)nc1C(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(F)c1
Reaction time: 8 h
Yield: 51.6 %

Procedure:
Acid chloride D4 (0.17 mmol, 1.0 eq.) was dissolved in dry pyridine (1.5 mL) at 0° C. and A2 (34 mg, 0.11 mmol, 0.65 eq.) was added. The reaction was allowed to reach RT overnight. The mixture was diluted with EtOAc and washed twice with aq. KOH-solution (0.5N), twice with aq. sat. NH4Cl-solution, and finally once with brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (DCM/MeOH=100:0 to 10:1) to yield the desired product D5 (31 mg, 52% over 2 steps) as a white solid. 1H NMR (400 MHz, d6-DMSO, 300K) δ 1.38 (t, J=7.0 Hz, 3H), 3.94 (s, 6H), 4.09 (q, J=7.0 Hz, 2H), 6.48 (d, J=5.3 Hz, 1H), 7.43 (m, 4H), 7.53 (s, 1H), 7.70 (d, J=9.4 Hz, 1H), 8.01 (m, 3H), 8.47 (m, 2H), 10.17 (s, 1H). MS (ES) C29H24F2N4O5 requires: 546. Found: 547 (M+H)+.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](Cl)([Cl:16])=[O:15]>ClC1C=CC=CC=1>[C:8]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:14]([Cl:16])=[O:15])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Cl)Cl
Reactant: c1ccc(Nc2ccccc2)cc1
Solvent: Clc1ccccc1
Product: O=C(Cl)N(c1ccccc1)c1ccccc1

Procedure:
By way of illustration, one mole of diphenylamine is reacted with a 10% molar excess of phosgene in a suitable solvent such as monochlorobenzene, to yield diphenylcarbamyl chloride. The carbamyl chloride thus produced is reacted further with n-propyl amine in stoichiometric amounts, in the presence of a mole of caustic soda. Diphenyl propyl urea (DPPU) is formed in essentially stoichiometric amounts. The DPPU formed may be either separated from the solvent or, if desired, supplied as a solution in its reaction solvent. DPPU pyrolyzes at 210°-220° C. to yield n-propyl isocyanate of 99% purity and greater than 90% yield. The diphenylamine remaining may be returned easily in tankcars or tankwagons for reprocessing.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[N:16][CH:17]=2)[CH2:8]1.[O:19]1[CH2:24][CH2:23][CH:22]([C:25](O)=[O:26])[CH2:21][CH2:20]1.CN1CCOCC1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.Cl>C(Cl)Cl.CN(C=O)C>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:25]([CH:22]3[CH2:23][CH2:24][O:19][CH2:20][CH2:21]3)=[O:26])=[N:16][CH:17]=2)[CH2:8]1
Reactant: O=C(O)C1CCOCC1
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2ccc(N)nc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H]1CCCN1[C@H]1CCN(c2ccc(NC(=O)C3CCOCC3)nc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 3.6 %

Procedure:
To a solution of 5-((2S,3′S)-2-Methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-2-ylamine (0.091 g, 0.369 mmol) in DCM (3 mL) and DMF (1 mL), was added sequentially tetrahydro-2H-pyran-4-carboxlic acid (0.058 g, 0.443 mmol), N-methylmorpholine (0.122 mL, 1.11 mmol), 1-hydroxylbenzotriazole (HOBT) (0.065 g, 0.481 mmol), and EDCl.HCl (0.092 g, 0.481 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched with a saturated aqueous solution of sodium bicarbonate (3 mL) and 15 mL of dichloromethane. The aqueous layer was extracted with dichloromethane (15 mL, 2×). The combined organic layers were washed with sodium bicarbonate (15 mL), brine (15 mL), dried over Na2SO4, and concentrated under vacuum. Purification by column chromatography on silica gel (0-10%) methanol in dichloromethane afforded 4.7 mg (4.0%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:33][C:34]1[CH:43]=[CH:42][C:37]2[O:38][CH2:39][CH2:40][O:41][C:36]=2[CH:35]=1)[CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:26]3[C:21](=[C:22]([O:27][CH2:28][C:29](O)=[O:30])[CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][C:18]2=[O:32])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN.F[P-](F)(F)(F)(F)F.[N:54]1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)[C:58]2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>O.CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:33][C:34]1[CH:43]=[CH:42][C:37]2[O:38][CH2:39][CH2:40][O:41][C:36]=2[CH:35]=1)[CH:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][N:17]2[C:26]3[C:21](=[C:22]([O:27][CH2:28][C:29]([NH:54][CH3:58])=[O:30])[CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][C:18]2=[O:32])[CH2:13][CH2:14]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3c(OCC(=O)O)cccc32)CC1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CNC(=O)COc1cccc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To 5 mL of an N,N-dimethylformamide solution containing 88 mg of (1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-2-oxo-1,2-dihydroquinolin-5-yloxy)acetic acid and 41 mg of methylamine hydrochloride, 183 mg of (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate and 0.11 mL of N,N-diisopropylethylamine were added, and stirred at room temperature overnight. The reaction mixture was poured into water, and extracted with a mixture of ethyl acetate:toluene=5:1. The organic layer was washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; chloroform:methanol=10:1], to give 89 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-((methylamino)carbonylmethyloxy)-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a pale yellow foam.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[I:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH2:16])[CH3:15])=[CH:9][CH:8]=1.N1C=CC=CC=1>C(Cl)Cl>[I:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH:14]([NH:16][C:2](=[O:3])[O:4][CH3:5])[CH3:15])=[CH:11][CH:12]=1
Reactant: COC(=O)Cl
Reactant: CC(N)Cc1ccc(I)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)NC(C)Cc1ccc(I)cc1
Reaction time: 1 h

Procedure:
0.53 ml (6.89 mmol) methyl chloroformate are added to a mixture of 1.50 g (5.75 mmol) 1-(4-iodophenyl)propane-2-amine and 1.16 ml pyridine (14.3 mmol) in 30 ml DCM at 0° C. and the reaction mixture is stirred for 1 h at constant temperature. Further DCM is added and the organic solution is consecutively washed with aq. HCl-solution (0.5 mol/l) and water, dried with MgSO4 and the solvent is removed under reduced pressure. The crude product is used without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:15]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)([CH3:17])[CH3:16]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([O:31][C:28]2[CH:27]=[CH:26][C:25]([C:15]([C:18]3[CH:19]=[CH:20][C:21]([O:24][S:11]([C:8]4[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=4)(=[O:13])=[O:12])=[CH:22][CH:23]=3)([CH3:17])[CH3:16])=[CH:30][CH:29]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Oc2ccc(C(C)(C)c3ccc(OS(=O)(=O)c4ccc(C(C)(C)C)cc4)cc3)cc2)cc1
Yield: 70.4 %

Procedure:
An oven-dried 50 ml 3-necked flask is equipped with a magnetic stirring bar and reflux condenser carrying a CaCl2 drying tube and is charged with 4-tert-butylbenzenesulfonyl chloride 9.3 grams (40 mmol), 4,4'-isopropylidenediphenol (4.11 grams, 18 mmol), 4-dimethylaminopyridine (0.11 gram, 0.9 mmol), and anhydrous pyridine (20 ml), and the mixture is stirred and heated at reflux for 14 hours. Workup consists of partitioning the mixture between Et2O and H2O (50 ml each), washing the organic phase successively with 100 ml portions of H2 (2×), 5 percent HCl (2×), H2O, saturated (2×), H2O and brine, then drying (MgSO4) filtration and concentration. This gives 10.41 grams of a pale yellow sold. Three consecutive recrystallizations from EtOH-MeOH (2:1) affords 7.87 grams (70 percent yield) of the title compound as white prisms, m.p. 124° C. to 127° C.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]([NH:6][N:7]2[C:19](=[O:20])[C:18]3[C:17](=[O:21])[C:16]4[CH:15]=[CH:14][C:13]([Cl:22])=[CH:12][C:11]=4[NH:10][C:9]=3[C:8]2=[O:23])=[CH:4][CH:3]=1.CS(O)(=O)=O>CO>[Br:1][C:2]1[CH:25]=[CH:24][C:5]([N:6]2[C:8](=[O:23])[C:9]3[NH:10][C:11]4[CH:12]=[C:13]([Cl:22])[CH:14]=[CH:15][C:16]=4[C:17](=[O:21])[C:18]=3[C:19]([OH:20])=[N:7]2)=[CH:4][CH:3]=1
Reactant: O=C1c2[nH]c3cc(Cl)ccc3c(=O)c2C(=O)N1Nc1ccc(Br)cc1
Agent: CS(=O)(=O)O
Solvent: CO
Product: O=c1c2ccc(Cl)cc2[nH]c2c(=O)n(-c3ccc(Br)cc3)nc(O)c12
Temperature: 25 °C
Yield: 22.2 %

Procedure:
A stirred suspension of 2-(4-bromoanilino)-6-chloro-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-trione (1.00 g, 2.39 mM) in a solution of methanol (500 mL) and methanesulfonic acid (50 mL) was refluxed for 16 hours and cooled to room temperature. The resulting yellow suspension was filtered (the filtrate was saved for use in Example 28). The collected solids were washed with methanol and then ether to give the title compound (0.222 g, 22%) as a yellow powder, mp>400° C.; MS(CI): 420 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH2:13][O:14][C:15]3[C:16]([F:26])=[C:17]([C:22]([F:25])=[CH:23][CH:24]=3)[C:18](=[N:20]O)[NH2:19])[S:10][N:9]=2)=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.C1COCC1>CC(O)=O.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH2:13][O:14][C:15]3[C:16]([F:26])=[C:17]([C:22]([F:25])=[CH:23][CH:24]=3)[C:18](=[NH:19])[NH2:20])[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: NC(=NO)c1c(F)ccc(OCc2nc(-c3ccc(Cl)cc3)ns2)c1F
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: N=C(N)c1c(F)ccc(OCc2nc(-c3ccc(Cl)cc3)ns2)c1F
Reaction time: 4 h

Procedure:
To a solution of 3-((3-(4-chlorophenyl)-1,2,4-thiadiazol-5-yl)methoxy)-2,6-difluoro-N′-hydroxybenzimidamide (0.02 g, 0.05 mmol) in AcOH (0.50 ml) was added acetic anhydride (6 μL, 0.06 mmol) followed by addition of THF (1.0 ml) under nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 1 h after which Pd-C (10%, 2.0 mg) was added and the resulting solution was stirred under hydrogen for 4 h. After the completion of the reaction (TLC monitoring), the reaction mass was filtered through celite bed, washed the celite bed with THF (3-4 times) and concentrated the filtrate. The residue was purified over neutral alumina (40% MeOH-DCM) to get the desired product (11 mg (58%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][C:10]#[N:11].O.[NH2:14][NH2:15]>CCO>[NH2:11][C:10]1[NH:15][N:14]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])[CH:9]=1
Reactant: NN
Reactant: N#CCC(=O)c1ccccc1Br
Solvent: CCO
Solvent: O
Product: Nc1cc(-c2ccccc2Br)n[nH]1
Yield: 69.6 %

Procedure:
To a solution of 3-(2-bromo-phenyl)-3-oxo-propionitrile (1.8 g, 8.03 mmol) in absolute EtOH (25 mL) was added hydrazine hydrate (2.3 mL, 48.2 mmol). The reaction mixture was refluxed for 23 hours, then cooled and purified directly on silica gel with 0-10% MeOH in CH2Cl2 as eluent to provide 1.33 g (70% yield) of 5-amino-3-(2-bromophenyl)pyrazole as a sticky oil. 1H-NMR (d6-DMSO) δ: 11.7 (broad m, 1H, tautomers), 7.20-7.70 (broad m, 4H), 5.76 (broad m, 1H), 5.03 (broad s, 1H), 4.60 (broad s, 1H); HPLC/MS m/z: 238.0, 240.0 [MH]+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C@H:11]([CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[C:12]([OH:14])=[O:13])(=[O:9])=[O:8])=[CH:4][CH:3]=1.[C:25]1([CH3:33])[CH:30]=[CH:29][C:28]([C:31]#[CH:32])=[CH:27][CH:26]=1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.[Cu]I>[NH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([CH2:15][C@@H:11]([NH:10][S:7]([C:5]2[S:6][C:2]([C:32]#[C:31][C:28]3[CH:29]=[CH:30][C:25]([CH3:33])=[CH:26][CH:27]=3)=[CH:3][CH:4]=2)(=[O:9])=[O:8])[C:12]([OH:14])=[O:13])=[CH:17]1
Reactant: O=C(O)[C@@H](Cc1c[nH]c2ccccc12)NS(=O)(=O)c1ccc(Br)s1
Reactant: C#Cc1ccc(C)cc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C#Cc2ccc(S(=O)(=O)N[C@H](Cc3c[nH]c4ccccc34)C(=O)O)s2)cc1
Temperature: 50 °C
Yield: 55.4 %

Procedure:
In a round bottom flask was added crude (R)-2-(5-Bromo-thiophene-2-sulfonylamino)-3-(1H-indol-3-yl)-propionic acid (3) (60 mg, 0.14 mmol), p-tolyl acetylene 4 (480 mg, 0.41 mmol), PdCl2P(PPh3)2 (10 mg, 0.015 mmol), copper(I)iodide (2 mg, 0.01 mmol) and triethylamine (0.025 g, 0.25 mmol) and then dissolved in dry DMF (2 mL) under an atmosphere of nitrogen. The reaction mixture was then heated at 50° C. under a nitrogen atmosphere for 2 hours. The reaction mixture was then cooled to room temperature and diluted with ethyl acetate and washed with a solution composed of NaCl/NaHCO3/(NH4)2CO3/water (1:1:1:1) (×3), water, and then dried over sodium sulfate (Na2SO4). The crude product was purified using a SAX column to provide to give the desired (R)-3-(1H-Indol-3-yl)-2-(5-p-tolylethynyl-thiophene-2-sulfonylamino)-propionic acid 5 (0.036 g, 55%).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][CH2:10][C:11]1[O:15][N:14]=[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:12]=1>C(Cl)Cl>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:13]1[CH:12]=[C:11]([CH2:10]/[N:9]=[CH:1]/[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:15][N:14]=1
Reactant: NCc1cc(-c2ccccn2)no1
Reactant: O=Cc1ccccc1
Solvent: ClCCl
Product: C(=N/Cc1cc(-c2ccccn2)no1)\c1ccccc1
Reaction time: 20 h
Yield: 97.7 %

Procedure:
Freshly distilled benzaldehyde (373 mg, 3.5 mmol) was added to a solution of 5-aminomethyl-3-(pyrid-2-yl)isoxazole (Method 70 of WO 03/048133) (0.614 mg, 3.5 mmol) in dry DCM (18 ml). 4 Å molecular sieve (1.75 g) was then added and the mixture stirred gently under nitrogen for 20 hours. The molecular sieve was removed by filtration and the filtrate evaporated. The residue was dissolved in toluene and the solution concentrated by evaporation. The product crystallised and was collected by filtration to give the title compound (900 mg, 97%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.ClC(Cl)(Cl)[C:12]([NH:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[CH:23]=[N:22][CH:21]=[CH:20]2)=[O:13].C1CCN2C(=NCCC2)CC1.O>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:12]([NH:14][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[CH:23]=[N:22][CH:21]=[CH:20]3)=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(Nc1cccc2ccncc12)C(Cl)(Cl)Cl
Reactant: NCc1ccc(Br)cc1
Solvent: O
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(NCc1ccc(Br)cc1)Nc1cccc2ccncc12

Procedure:
The title compound was prepared using 4-bromobenzylamine, the product from Example 57D, DBU and the procedure described in Example 1B. MS (ESI+) m/z 356 (M+H)+; 1H NMR (DMSO-d6) δ 9.52 (s, 1H), 9.15 (s, 1H), 8.49 (d, 1H), 8.11 (d, 1H), 7.77 (d, 1H), 7.67 (t, 1H), 7.55 (m, 3H) 7.32 (d, 2H), 7.25 (t, 1H), 4.34 (d, 2H); Anal. Calcd for C17H14BrN3O.0.25 H2O.0.16 MeOH: C, 56.34, H, 4.17, N, 11.49. Found C, 56.32, H 4.45, N 11.70.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]=1[O:16]C)([CH3:3])[CH3:2].O>C(OCC)C>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]=1[OH:16])([CH3:3])[CH3:2]
Reactant: COc1c(-c2ccccc2)cccc1C(C)C
Solvent: O
Solvent: CCOCC
Product: CC(C)c1cccc(-c2ccccc2)c1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 94 %

Procedure:
In a flask charged with 2-bromo-6-isopropylanisole (1.98 g, 8.64 mmol), phenylboronic acid (2.10 g, 17.28 mmol), palladium acetate (96 mg, 0.43 mmol), triphenylphosphine (0.225 g, 0.86 mmol) and potassium phosphate (11 g, 51.84 mmol), mixture of water (8 mL) and dimethoxyethane (32 mL) was added, and the resultant mixture was heated under reflux for 12 hours. After cooling to ambient temperature, aqueous ammonium chloride (15 mL) and diethyl ether (30 mL) were charged thereto. The organic layer was isolated, and the residue was extracted with diethyl ether. Combined organic layer was dried over magnesium sulfate, and evaporated to remove the volatiles to obtain 2-isopropyl-6-phenylanisole as grey solid (2 g). The anisole obtained (without further purification) was dissolved in methylene chloride (15 mL), and 12 mL of boron tribromide solution (1 M in methylene chloride) was added dropwise thereto at −78° C. Reaction was carried out for 12 hours while slowly raising the temperature to ambient temperature. When the reaction was completed, mixture of water (15 mL) and diethyl ether (30 mL) was added thereto. After isolating the organic layer, the aqueous layer was extracted with diethyl ether (15 mL×3). The combined organic layer was dried, and evaporated under reduced pressure to remove the volatiles. The residue was purified via silica gel column by using mixed solvent of hexane and methylene chloride to obtain 2-isopropyl-6-phenylphenol (1.72 g) as white solid.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[Br:7][C:8]1[CH:9]=C(C)[CH:11]=[CH:12][C:13]=1[Br:14].[C:16]([OH:19])(=[O:18])[CH3:17]>>[Br:7][C:8]1[CH:9]=[C:17]([CH:11]=[CH:12][C:13]=1[Br:14])[C:16]([OH:19])=[O:18]
Reactant: CC(=O)O
Reactant: Cc1ccc(Br)c(Br)c1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: O=C(O)c1ccc(Br)c(Br)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 37 %

Procedure:
A saturated aqueous solution of potassium permanganate (61.3 g, 388 mmol) was added in portions to a well stirred solution of 3,4-dibromotoluene (40.4 g, 162 mmol) in acetic acid (700 mL) while maintaining the temperature between 70 and 80° C. After addition, the suspension was stirred for an additional 4 hours at 80° C. The solution was concentrated on a rotary evaporator, the residue treated with 5 N NaOH (700 mL) and heated under reflux for 2 hours. The MnO2 cake was filtered from solution and washed thoroughly with hot water. The filtrate was extracted with hexane (2×100 mL) and acidified with concentrated HCl pH 2. Collected white precipitate by filtration. Washed precipitate with water and dried under high vacuum. Obtained 16.59 gram (37% yield) of 3,4-dibromobenzoic acid. 1H NMR (300 MHz, DMSO-d6): δ13.47 (singlet, 1H), 8.14 (singlet, 1H), 7.88 (doublet, J=8.1 Hz, 1H), 7.99 (doublet, J=8.1 Hz, 1H). 13C NMR (300 MHz, DMSO-d6): δ165.72, 134.42, 134.18, 132.07, 129.96, 129.32, 124.40.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([C:29]1[S:30][CH:31]=[C:32]([C:34]([OH:36])=O)[N:33]=1)([CH3:28])([CH3:27])[CH3:26].[Si:37]([O:44][CH2:45][CH2:46][C:47]1[CH:48]=[C:49]([CH2:52][N:53]2[CH2:63][CH2:62][C:56]3([O:61][CH2:60][CH2:59][NH:58][CH2:57]3)[CH2:55][CH2:54]2)[S:50][CH:51]=1)([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38].C(N(CC)CC)C>CN(C=O)C>[CH3:52][CH2:49][CH2:48][CH:47]([CH3:51])[CH3:46].[Si:37]([O:44][CH2:45][CH2:46][C:47]1[CH:48]=[C:49]([CH2:52][N:53]2[CH2:63][CH2:62][C:56]3([O:61][CH2:60][CH2:59][N:58]([C:34]([C:32]4[N:33]=[C:29]([C:25]([CH3:26])([CH3:27])[CH3:28])[S:30][CH:31]=4)=[O:36])[CH2:57]3)[CH2:55][CH2:54]2)[S:50][CH:51]=1)([C:40]([CH3:41])([CH3:42])[CH3:43])([CH3:39])[CH3:38]
Reactant: CC(C)(C)c1nc(C(=O)O)cs1
Reactant: CC(C)(C)[Si](C)(C)OCCc1csc(CN2CCC3(CC2)CNCCO3)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cc(CCO[Si](C)(C)C(C)(C)C)cs4)CC3)C2)cs1
Product: CCCC(C)C
Reaction time: 1 h

Procedure:
HATU (0.306 g) was added to stirred solution of 2-tert-butylthiazole-4-carboxylic acid (0.16 g), 9-((4-(2-(tert-butyldimethylsilyloxy)ethyl)thiophen-2-yl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecane (example 43, step b) (0.300 g) and triethylamine (0.41 mL) in DMF (3 mL). After 1 h, the reaction mixture was partitioned between water and ethyl acetate. The ethyl acetate layer was washed twice with water and brine, dried over magnesium sulphate, filtered and evaporated in vacuo. Purification by silica gel chromatography eluting with ethyl acetate:isohexane:triethylamine, 12:90:10 gave the subtitled compound as a gum. Yield 0.3 g.
Reaction SMILES: [F:1][CH:2]([F:20])[O:3][C:4]1[C:9]2[O:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[C:8]=2[C:7]([C:17]([OH:19])=[O:18])=[CH:6][CH:5]=1.[CH:21]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][CH:24]=[C:23](O)[CH:22]=1.CCN=C=NCCCN(C)C.Cl.CC1(C)C=CN=C(N)C1>CN(C=O)C>[F:20][CH:2]([F:1])[O:3][C:4]1[C:9]2[O:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[C:8]=2[C:7]([C:17]([O:19][C:23]2[CH:22]=[CH:21][C:26]([N+:27]([O-:29])=[O:28])=[CH:25][CH:24]=2)=[O:18])=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccc(OC(F)F)c2oc3ccncc3c12
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CC1(C)C=CN=C(N)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccc(OC(F)F)c2oc3ccncc3c12
Temperature: 72.5 °C

Procedure:
A mixture of 6-Difluoromethyloxybenzo[4,5]furo[3,2-c]pyridine-9-carboxylic acid (5.5 g, 0.0197 moles), p-nitro phenol (4.1 g, 0.0295 moles), EDCl (5.7 g, 0.295 moles), 4,4-dimethyl amino pyridine (250 mg, 0.00197 moles) in DMF (603.0 mL) was heated to 70-75° C. for 4-5 hours. The residue obtained after removal of solvent under vacuo was triturated with water (50.0 mL) to give intermediate-18 (6.0 mg) as yellow solid.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].S1(C[CH2:10][CH2:9][CH2:8]1)(=O)=O.BrCCC.[C:16]([CH2:18][CH2:19][N:20]([CH2:27][CH2:28][OH:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)#[N:17]>O>[C:16]([CH2:18][CH2:19][N:20]([CH2:27][CH2:28][O:29][C:2](=[O:1])[NH:3][CH2:8][CH2:9][CH3:10])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)#[N:17]
Reactant: N#C[O-]
Reactant: N#CCCN(CCO)c1ccccc1
Reactant: O=S1(=O)CCCC1
Agent: [K+]
Solvent: CCCBr
Solvent: O
Product: CCCNC(=O)OCCN(CCC#N)c1ccccc1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 4 g. (.05 mole) of potassium cyanate and 25 ml. of sulfolane at 90° C. are added dropwise 9 ml. (12.3 g, 0.1 mole) of 1-bromopropane over a one-hour period. After 10 minutes of stirring at the same temperature, a solution of 6 g. (0.027 mole) of N-(2-cyanoethyl)-N-(2-hydroxyethyl)aniline in 5 ml. sulfolane is added. The resulting mixture is stirred at 90°-100° C. for three hours and then allowed to cool to 50° C. The mixture is poured into 1 liter of water under agitation, and the resulting layers separated. TLC of the organic layer in 4:1 benzene: acetone shows the absence of starting alcohol with the product of the above formula.