Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:59][CH3:60])[C:4]1[CH:5]=[CH:6][C:7]([NH:30][C:31](=[O:58])[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][OH:57])[CH:33]=2)=[C:8]([C:10]2[CH:11]=[C:12]([CH:27]=[CH:28][N:29]=2)[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[O:14])[CH:9]=1)[CH3:2].C(N(CC)CC)C.[C:68]1([CH3:78])[CH:73]=[CH:72][C:71]([S:74](Cl)(=[O:76])=[O:75])=[CH:70][CH:69]=1>C(Cl)Cl>[CH3:78][C:68]1[CH:73]=[CH:72][C:71]([S:74]([O:57][CH2:56][CH2:55][O:54][CH2:53][CH2:52][O:51][CH2:50][CH2:49][O:48][CH2:47][CH2:46][O:45][CH2:44][CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38][C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([C:31](=[O:58])[NH:30][C:7]3[CH:6]=[CH:5][C:4]([N:3]([CH2:1][CH3:2])[CH2:59][CH3:60])=[CH:9][C:8]=3[C:10]3[CH:11]=[C:12]([C:13](=[O:14])[NH:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=4)[CH:27]=[CH:28][N:29]=3)[CH:33]=2)(=[O:76])=[O:75])=[CH:70][CH:69]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(COCCOCCOCCOCCOCCOCCO)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)c1ccc(NC(=O)c2cccc(COCCOCCOCCOCCOCCOCCOS(=O)(=O)c3ccc(C)cc3)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reaction time: 16 h

Procedure:
To a mixture of Example 168 (500 mg, 0.595 mmol) and triethylamine (167 μL, 1.19 mmol) in DCM (3 mL) was added p-toluenesulfonyl chloride (136 mg, 0.714 mmol) in several portions and the solution stirred for 16 h. The solution was then diluted with DCM and washed with aqueous HCl and H2O, then dried over Na2SO4 and the solvent removed. The residue was purified by silica gel chromatography, using a gradient of 20% to 100% EtOAc in hexanes as eluent and the solvent removed. This gave 560 mg (95%) of the product as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16](Cl)[C:15]3[C:10](=[CH:11][C:12]([Cl:19])=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[CH2:20]([NH:27][C:16]1[C:15]2[C:10](=[CH:11][C:12]([Cl:19])=[CH:13][CH:14]=2)[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[N:17]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Clc1ccc2c(Cl)nc(-c3ccc(Br)cc3)nc2c1
Reactant: NCc1ccccc1
Solvent: C1CCOC1
Product: Clc1ccc2c(NCc3ccccc3)nc(-c3ccc(Br)cc3)nc2c1
Temperature: 25 °C

Procedure:
A solution of 2-(4-bromo-phenyl)-4,7-dichloro-quinazoline (0.085 mmol, 30 mg) [prepared analogously to example 1] in 2 ml THF is treated with benzylamine (0.174 mmol, 0.019 ml). The mixture is heated at 60° for 6 hrs. After cooling to rt, the reaction mixture is filtered through a tentacle ion exchanger (LiChrolut® SCX: Merck ChromBook, 2nd ed. page 31). Evaporation of the solvent afforded benzyl-[2-(4-bromo-phenyl)-7-chloroquinazolin-4-yl]-amine.
Reaction SMILES: C([N:8]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][C:13]=2[O:23][C@@H:24]1[CH2:28][C@@H:27]([CH2:29][O:30][Si](C(C)(C)C)(C)C)[C@@H:26]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[CH2:25]1)C1C=CC=CC=1.CO>[Pd].C(O)=O>[Si:39]([O:38][C@H:26]1[CH2:25][C@H:24]([O:23][C:13]2[N:12]=[CH:11][N:10]=[C:9]3[C:14]=2[N:15]=[C:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:8]3)[CH2:28][C@H:27]1[CH2:29][OH:30])([C:42]([CH3:43])([CH3:44])[CH3:45])([CH3:40])[CH3:41]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2ncnc3c2nc(-c2ccccc2)n3Cc2ccccc2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](Oc2ncnc3[nH]c(-c4ccccc4)nc23)C[C@H]1CO
Reaction time: 8 h

Procedure:
A suspension of 9-benzyl-6-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]oxy}-8-phenyl-9H-purine (0.161 g, 0.000249 mol), 10% Pd/C (0.04 g, 0.00004 mol) and formic acid (0.1 mL, 0.003 mol) in methanol (11.0 mL, 0.272 mol) was stirred under an atmosphere of nitrogen overnight. Added formic acid (0.2 mL, 0.005 mol) and 10% Pd/C (0.04 g, 0.00004 mol) to the reaction and stirred 24 h. Added 10% Pd/C (0.060 g, 0.000056 mol) and formic acid (0.2 mL, 0.005 mot) to the reaction and stirred an additional 24 h. The reaction was purged with nitrogen and filtered the mixture through celite with DCM. The filtrate was concentrated, purified by flash chromatography (30 to 50% ethyl acetate/hexane) to obtain 30 mg (27%). LC/MS: Rt=2.08 min, ES+ 441.18 (AA standard).
Reaction SMILES: CN1CCOCC1.[N:8]1([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([N:22]3[CH2:29][CH2:28][CH2:27][C@@H:23]3[C:24]([OH:26])=O)=[O:21])=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1.ClC(OCC)=O.Cl.[Br:37][C:38]1[CH:52]=[CH:51][C:50]([F:53])=[CH:49][C:39]=1[CH2:40][O:41][C:42]1[CH:48]=[CH:47][CH:46]=[CH:45][C:43]=1[NH2:44].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.O>[Br:37][C:38]1[CH:52]=[CH:51][C:50]([F:53])=[CH:49][C:39]=1[CH2:40][O:41][C:42]1[CH:48]=[CH:47][CH:46]=[CH:45][C:43]=1[NH:44][C:24]([C@H:23]1[CH2:27][CH2:28][CH2:29][N:22]1[C:20](=[O:21])[CH2:19][C:16]1[CH:15]=[CH:14][C:13]([N:8]2[CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:18][CH:17]=1)=[O:26]
Reactant: O=C(O)[C@H]1CCCN1C(=O)Cc1ccc(N2CCCC2)cc1
Reactant: Nc1ccccc1OCc1cc(F)ccc1Br
Agent: CCOC(=O)Cl
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN1CCOCC1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(Nc1ccccc1OCc1cc(F)ccc1Br)[C@H]1CCCN1C(=O)Cc1ccc(N2CCCC2)cc1
Reaction time: 2 h

Procedure:
Toluene (37.8 ml) and N-methylmorpholine (1.10 g, 10.8 mmol) were added to N-[(4-pyrrolidinophenyl)acetyl]-D-proline (2.90 g, 9.59 mmol). Ethyl chloroformate (1.14 g, 10.5 mmol) was added to the obtained mixture in an ice bath, and they were stirred for 2 hours. 2-(2-Bromo-5-fluorobenzyloxy)aniline hydrochloride (3.19 g, 9.59 mmol) and N-methylmorpholine (1.16 g, 11.5 mmol) were added thereto and the temperature of the obtained mixture was slowly elevated to room temperature for a period of 16 hours. Water (30 ml), citric acid (1.61 g) and toluene (10 ml) were added to the reaction mixture for the distribution. The organic layer was washed with water (10 ml), water (10 ml), 6.7% aqueous sodium hydrogencarbonate solution (10 ml), 6.7% aqueous sodium hydrogencarbonate solution (10 ml), water (10 ml) and water (10 ml). After drying over sodium sulfate, the solvent was evaporated under reduced pressure to obtain the title compound in the form of a light yellow solid (5.13 g, 93%).
Reaction SMILES: [CH:1]1([C:4]2[CH:12]=[C:11]([CH3:13])[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([F:14])[CH:5]=2)[CH2:3][CH2:2]1.[CH3:15]OC(OC)N(C)C.CC(C)([O-])C.[K+].C1COCC1.Cl>CC1CCCO1>[CH:1]1([C:4]2[CH:12]=[C:11]3[C:7](=[C:6]([F:14])[CH:5]=2)[C:8](=[O:9])[NH:10][CH:15]=[CH:13]3)[CH2:2][CH2:3]1
Reactant: COC(OC)N(C)C
Reactant: Cc1cc(C2CC2)cc(F)c1C(N)=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC1CCCO1
Product: O=c1[nH]ccc2cc(C3CC3)cc(F)c12
Temperature: 60 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of 4-cyclopropyl-2-fluoro-6-methylbenzamide (37.2 g, 0.19 mol) in 2-methyltetrahydrofuran (MeTHF; 223 ml) was added 1,1-dimethoxy-N,N-dimethylmethanamine (29.8 g, 0.25 mol). The mixture was heated to 60° C. for 2 hours, then around 100 mL of MeTHF was distilled out under vacuum in order to remove Methanol. The reaction mixture was heated to 55° C. again, and potassium tert-butoxide, 1 M solution in THF (289 ml, 0.29 mol) was added dropwise. After 1 hr stirring at 60° C., the reaction mixture was allowed to cool down to room temperature and poured into HCl, 1 M solution (289 ml, 0.29 mol), and then THF/MeTHF was distilled out at 60° C. for crystallization. During the distillation, IPA (223 ml) was added slowly. After most of THF/MeTHF was removed, the solution was cooled down to ambient temperature. The desired product was crystallized out from IPA/water, collected by filtration and washed with water and cold IPA. The filter cake was dried under vacuum at 50° C. to afford 30.1 g of the title compound (77% isolated yield) as a white solid. MS (ESI) 204 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][C@@H:9]([NH2:12])[CH2:8]1)=[O:6])[CH:2]=[CH2:3].Cl[C:14]1[N:19]=[C:18](Cl)[N:17]=[CH:16][N:15]=1.[C:21]([O:25][C:26](=[O:35])[NH:27][CH:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1)([CH3:24])([CH3:23])[CH3:22]>C(Cl)Cl>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][C@@H:9]([NH:12][C:14]2[N:19]=[C:18]([NH:34][CH:31]3[CH2:32][CH2:33][CH:28]([NH:27][C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:35])[CH2:29][CH2:30]3)[N:17]=[CH:16][N:15]=2)[CH2:8]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1CC[C@@H](N)C1
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Reactant: Clc1ncnc(Cl)n1
Solvent: ClCCl
Product: C=CCOC(=O)N1CC[C@@H](Nc2ncnc(NC3CCC(NC(=O)OC(C)(C)C)CC3)n2)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(R)-3-Amino-pyrrolidine-1-carboxylic acid allyl ester (1 eq.) is dissolved in DCM. The reaction mixture is cooled to 0° C. and a solution of 2,4-dichloro-[1,3,5]triazine (1 eq.) in DCM is added dropwise. The reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is re-cooled to 0° C. and a solution of (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (1 eq.) in DCM is added dropwise. The reaction mixture is stirred at room temperature overnight. The reaction mixture is partitioned between (0.2 M) HCl(aq) and DCM. The organics are washed with water, saturated NaHCO3(aq) and brine. The combined organics are dried (MgSO4), filtered and reduced in vacuo, to yield the title compound.
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:12]([NH:14][C@H:15]([C:41]([NH:43][C@H:44]([C:48]([NH:50][C@H:51]([C:59]([O:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)=[O:60])[CH2:52][C:53](=[O:58])[O:54][CH2:55][CH:56]=[CH2:57])=[O:49])[CH:45]([CH3:47])[CH3:46])=[O:42])[CH2:16][CH2:17][CH2:18][NH:19][C:20](=[NH:40])[NH:21][S:22]([C:25]1[C:38]([CH3:39])=[C:36]([CH3:37])[C:35]2[O:34][C:31]([CH3:33])([CH3:32])[CH2:30][CH2:29][C:28]=2[C:26]=1[CH3:27])(=[O:24])=[O:23])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].N1CCCCC1>ClCCl.CCCCCCC>[NH2:1][C@H:2]([C:12]([NH:14][C@H:15]([C:41]([NH:43][C@H:44]([C:48]([NH:50][C@H:51]([C:59]([O:61][CH2:62][C:63]1[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=1)=[O:60])[CH2:52][C:53](=[O:58])[O:54][CH2:55][CH:56]=[CH2:57])=[O:49])[CH:45]([CH3:47])[CH3:46])=[O:42])[CH2:16][CH2:17][CH2:18][NH:19][C:20](=[NH:40])[NH:21][S:22]([C:25]1[C:38]([CH3:39])=[C:36]([CH3:37])[C:35]2[O:34][C:31]([CH3:33])([CH3:32])[CH2:30][CH2:29][C:28]=2[C:26]=1[CH3:27])(=[O:23])=[O:24])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:9])[CH3:10]
Reactant: C=CCOC(=O)C[C@H](NC(=O)[C@@H](NC(=O)[C@H](CCCNC(=N)NS(=O)(=O)c1c(C)c(C)c2c(c1C)CCC(C)(C)O2)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: C1CCNCC1
Solvent: CCCCCCC
Product: C=CCOC(=O)C[C@H](NC(=O)[C@@H](NC(=O)[C@H](CCCNC(=N)NS(=O)(=O)c1c(C)c(C)c2c(c1C)CCC(C)(C)O2)NC(=O)[C@@H](N)CCC(=O)OC(C)(C)C)C(C)C)C(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
To a solution of Fmoc-Glu(OBut)-Arg(Pmc)-Val-Asp(OAllyl)-OBzl (SEQ ID NO: 37) (12.3 g, 10.3 mmol) in 105 mL of dichloromethane is added piperidine (3.5 g, 41.3 mmol) at ambient temperature. The mixture is stirred 2 hours, then diluted with heptane, concentrated to half volume, and left standing in the freezer overnight. The liquor is decanted from the oily residue, which is then taken up in dichloromethane. The solution is washed with 0.5M aqueous citric acid, water, and brine, dried (magnesium sulfate), filtered, and concentrated. The crude solid is triturated twice with heptane and filtered to give 9.0 g of Glu(OtBu)-(L)Arg(Pmc)-Val-Asp(OAllyl)-OBzl as a white powder. (Mcalc 970.2; M+1obsvd 971).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1/[CH:10]=[CH:11]/[C:12]#[N:13].[H-].[Na+].[C:16](CP(=O)(OCC)OCC)#N.F[C:28]1C=CC(OC)=[CH:32][C:29]=1[CH:30]=[O:31]>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C@@H:10]1[CH2:16][C@H:11]1[CH2:12][NH:13][C:30](=[O:31])[CH:29]([CH3:32])[CH3:28]
Reactant: COc1ccc(F)c(/C=C/C#N)c1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1ccc(F)c(C=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(F)c([C@@H]2C[C@H]2CNC(=O)C(C)C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(trans)-3-(2-Fluoro-5-methoxyphenyl)-2-propenenitrile: To a suspension of NaH (6.90 g, 60% dispersion in mineral oil, 173 mmol) in THF (500 mL) at 0° C. was added diethyl cyanomethylphosphonate (30.10 g, 170 mmol) dropwise. This was followed by the dropwise addition of a solution of 2-fluoro-5-methoxybenzaldehyde (24.5 g, 159 mmol) in THF (50 mL). The resulting suspension was allowed to warm to ambient temperature. After 18 h, H2O (200 mL) was added and the solution was extracted with EtOAc. The organics were combined, washed with brine, dried over MgSO4, and concentrated to afford a white waxy solid. The material was then purified by Kugelrohr distillation to give the title compound, 24.3 g (86%): mp 56°-57° C.;
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[OH:16].[C:17](O)(=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC(Cl)(Cl)C#N>C(#N)C>[CH3:15][CH:9]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[N:1]=[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[O:16][C:3]=3[CH:4]=2)=[N:13][NH:12][C:11](=[O:14])[CH2:10]1
Reactant: CC1CC(=O)NN=C1c1ccc(N)c(O)c1
Reactant: O=C(O)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: N#CC(Cl)(Cl)Cl
Solvent: CC#N
Product: CC1CC(=O)NN=C1c1ccc2nc(-c3ccccc3)oc2c1
Temperature: 120 °C

Procedure:
219 mg (1 mmol) 6-(4-amino-3-hydroxy-phenyl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one, 122 mg (1 mmol) benzoic acid, 1.7 g (3 mmol) polymer-bound triphenylphosphine, 289 mg (2 mmol) trichloroacetonitrile and 7.5 ml acetonitrile are placed in a microwave vial and heated to 120° C. for 15 min at 200 W. The resin is filtered off and washed with methanol as well as acetonitrile. The solv. is eliminated by rotary evaporation i.V. and the residue is purified by RP-HPLC.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:14]([O:16]C)=[O:15])=[O:10])=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:14]([OH:16])=[O:15])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C)c(C(=O)Nc2ccc(N)nc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)O)cc1C(=O)Nc1ccc(N)nc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To methyl 3-((6-aminopyridin-3-yl)carbamoyl)-4-methylbenzoate (0.11 g, 0.39 mmol) dissolved in tetrahydrofuran (1.5 mL) was added a solution of lithium hydroxide, monohydrate (24 mg, 0.58 mmol) in water (1.5 mL). The reaction mixture was stirred at RT for 4 h. THF was removed in vacuo and to the aqueous layer was added 2N HCl until pH 4-5. The precipitate formed was collected by filtration, washed with water, dried to give 3-((6-aminopyridin-3-yl)carbamoyl)-4-methylbenzoic acid as a tan solid, MS (ESI, pos. ion) m/z: 272.1 (M+1).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[C:6]1([N:12]2[C:16](=O)[CH2:15][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+].CN(C)[CH:28]=[O:29]>>[Cl:3][C:16]1[N:12]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:13]=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]=1[CH:28]=[O:29]
Reactant: CN(C)C=O
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1CC(c2ccccc2)=NN1c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=Cc1c(-c2ccccc2)nn(-c2ccccc2)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
At 5° to 10° 97.3 g of phosphorus oxytrichloride are added dropwise to 92.7 g of dimethylformamide and the mixture is stirred for completion of the complex formation for 30 minutes at room temperature. Following this 30 g of 1,3-diphenyl-2-pyrazoline-5-one are added and while stirring heating is carried out for 1 hour at 55°C and for 20 hours at 70°. The product is poured on to approximately 600 g of ice neutralised with concentrated sodium hydroxide solution to pH 3-4, vacuum filtered and washed with water. 5-Chloro-1,3-diphenyl-pyrazole-4-carboxaldehyde is obtained with a yield of 93 %; F 109°-110° (from petroleum ether).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[O:12][CH3:13].C(=O)([O-])[O-].[K+].[K+]>S(=O)(=O)(O)O>[CH3:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([N+:1]([O-:4])=[O:2])[C:11]=1[O:12][CH3:13]
Reactant: COc1ccncc1C
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COc1c(C)cncc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 30 %

Procedure:
30 ml of 100% nitric acid is added to 150 ml of 98% sulphuric acid with stirring and cooling. To this solution is added dropwise 3.2 g (26 mmol) of 3-methyl-4-methoxy pyridine. The mixture is stirred at 80° C. for 2.5 hours, cooled down and added cautiously to a mixture of 400 g of crushed ice and 300 g of potassium carbonate with external cooling. 125 g more of potassium carbonate is added, and the suspension is filtered. The cake is washed with around 1 l of diethyl ether. The filtrate layers are separated, the ethereal layer is dried, filtered off and concentrated to give 2.9 g (30% yield) of a yellow oil (M+1 =169) (purity #80%, used with no further purification).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Si:8]([CH3:11])([CH3:10])[CH3:9])[CH:3]=1.[Li]CCCC.CN([CH:20]=[O:21])C.Cl>CCOCC.O>[CH3:9][Si:8]([CH3:11])([CH3:10])[C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH:20]=[O:21]
Reactant: C[Si](C)(C)c1cccc(Br)c1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: C[Si](C)(C)c1cccc(C=O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46.6 %

Procedure:
To a solution of 5 g (21.89 mmol) of 1-bromo-3-trimethylsilylbenzene prepared according to the protocol described in the preceding step, in 40 mL of anhydrous Et2O, cooled to 0° C. and maintained under a nitrogen atmosphere, are added dropwise, with stirring and over 30 minutes, 16.36 mL (26.18 mmol) of BuLi (1.6M/hexane). Stirring is continued at 0° C. for a further 30 minutes, and the mixture is then maintained at room temperature for 90 minutes. 2.69 mL (34.91 mmol) of DMF, diluted with 17 mL of anhydrous Et2O, are then introduced into the reaction mixture. After stirring for 3 hours at room temperature, the reaction mixture is hydrolysed at 0° C. by successive addition of 10 mL of concentrated HCl solution and 100 mL of water. The product is extracted with 3×50 mL of CH2Cl2. The combined organic phases are washed with 100 mL of water, dried over Na2SO4, filtered and evaporated under reduced pressure. The crude reaction product is purified by flash chromatography on a column of silica gel, eluting with a gradient of from 10 to 20% of CH2Cl2 in heptane to give 1.82 g of the expected 3-trimethylsilylbenzaldehyde in the form of a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1C)=[O:10].ClC1C=CC2N=[C:24](C3C=CC=CC=3)[O:25]C(=O)C=2C=1>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:25][CH3:24])=[O:10]
Reactant: Cc1ccccc1C(=O)c1cc(Cl)ccc1N
Reactant: O=c1oc(-c2ccccc2)nc2ccc(Cl)cc12
Product: COc1ccccc1C(=O)c1cc(Cl)ccc1N
Yield: 84 %

Procedure:
In a manner similar to that described above for compound 1m, 6-chloro-2-phenyl-benzo[d][1,3]oxazin-4-one was converted to 1n (84% yield) MS m/z=262 (M+H).
Reaction SMILES: COC1C=CC(NC(N)=O)=CC=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1.[CH2:24]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>C1(C)C=CC=CC=1>[CH2:33]([N:32]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:22]([NH:21][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH3:13])=[CH:20][CH:19]=1)=[O:23])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCCCCCCCNCCCCCCCC
Reactant: COc1ccc(N=C=O)cc1
Agent: COc1ccc(NC(N)=O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCN(CCCCCCCC)C(=O)Nc1ccc(OC)cc1
Yield: 60 %

Procedure:
To study the reaction mechanism, 4-methoxyphenylurea was heated in boiling toluene. It was expected that 4-methoxyphenyl isocyanate would be formed, but instead the 4-methoxyphenylurea remained completely unchanged. On heating 4-methoxyphenylurea in boiling toluene with the addition of one equivalent of dioctylamine, N,N-dioctyl-N'-4-methoxyphenylurea was formed in 60% yield after one hour, no by-products, in particular no isocyanates or by-products derived from them, being produced. Proof that the reaction does not proceed via isocyanates was obtained using 1H-NMR and 13C-NMR spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(=O)(O)O.[NH:15]([C:17](=[NH:19])[NH2:18])[NH2:16].ClCCl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:16][NH:15][C:17](=[NH:18])[NH2:19])=[O:5]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: N=C(N)NN
Agent: O=C(O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: N=C(N)NNC(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-chlorobenzoyl chloride (10 g, 60 mmol, 1.00 equiv) and hydrazinecarboximidamide carbonic acid salt (11.6 g, 85 mmol, 1.49 equiv) in pyridine (10 mL) and dichloromethane (100 g, 1.18 mol, 41.21 equiv) was stirred for 3 h at 25° C. After the reaction was completed, the resulting mixture was concentrated under vacuum. The residue was purified via silica gel column (ethyl acetate/petroleum ether (10/1)) resulting in 3 g (22%) of 2-(2-chlorobenzoyl)hydrazinecarboximidamide as yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:4]([CH:5]=[C:6]([Br:8])[Br:7])[CH:3]1[C:9](Cl)=[O:10].N1C=CC=CC=1.[O:19]([C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=1)[CH:29]([OH:32])[CH:30]=[CH2:31])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CCOCC>[O:19]([C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=1)[CH:29]([O:32][C:9]([CH:3]1[CH:4]([CH:5]=[C:6]([Br:7])[Br:8])[C:2]1([CH3:12])[CH3:1])=[O:10])[CH:30]=[CH2:31])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC1(C)C(C=C(Br)Br)C1C(=O)Cl
Reactant: C=CC(O)c1cccc(Oc2ccccc2)c1
Solvent: CCOCC
Solvent: c1ccncc1
Product: C=CC(OC(=O)C1C(C=C(Br)Br)C1(C)C)c1cccc(Oc2ccccc2)c1

Procedure:
15.8 g (0.05 mole) of 2,2-dimethyl-3-(2',2'-dibromovinyl)-cyclopropanecarboxylic acid chloride are added dropwise, whilst stirring, to 5.1 g (0.05 mole) of pyridine, 100 ml of absolute ether and 11.4 g (0.05 mole) of 3-phenoxy-α-vinyl-benzyl alcohol at 0°-5° C.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[C:4]([C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][C:10](=[O:16])[NH:11]2)(O)=[O:5].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH2:1]([NH:3][C:4]([C:7]1[C:8]2[CH2:9][C:10](=[O:16])[NH:11][C:12]=2[CH:13]=[CH:14][CH:15]=1)=[O:5])[CH3:2]
Reactant: CCN
Reactant: O=C1Cc2c(cccc2C(=O)O)N1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: CCNC(=O)c1cccc2c1CC(=O)N2
Temperature: 25 °C
Reaction time: 6 h
Yield: 65.3 %

Procedure:
Ethylamine (2.1 mL of 2.0M solution in tetrahydrofuran, 4.2 mmol) was added dropwise to a suspension of 4-carboxy-2-oxindole (380 mg, 2.1 mmol) in dimethylformamide (8 mL), followed by 4-dimethylaminopyridine (385 mg, 3.15 mmol) and PyBOP (2.185 g, 4.2 mmol). The mixture was stirred at room temperature for 6 hrs. The reaction was concentrated. The residue was dissolved in dichloromethane, washed with saturated sodium bicarbonate and brine, dried, concentrated and recrystallized to give 280 mg (65%) of 2-oxo-2,3-dihydro-1H-indole-4-carboxylic acid ethylamide.