Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[C:9]([C:15]2[CH:16]=[CH:17][C:18]3[O:22][C:21](=[O:23])[N:20]([CH3:24])[C:19]=3[CH:25]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:27])[CH:3]=1.C([O-])(=O)C.[K+].[CH3:33][O:34][C:35](=[O:43])[C:36]1[CH:41]=[CH:40][C:39](Cl)=[N:38][CH:37]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.Cl[Pd]Cl.[Fe+2].O>[CH3:33][O:34][C:35](=[O:43])[C:36]1[CH:41]=[CH:40][C:39]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[C:9]([OH:14])([C:15]3[CH:16]=[CH:17][C:18]4[O:22][C:21](=[O:23])[N:20]([CH3:24])[C:19]=4[CH:25]=3)[C:10]([F:13])([F:11])[F:12])=[C:4]([Cl:27])[CH:3]=2)=[N:38][CH:37]=1
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3ccc4oc(=O)n(C)c4c3)C(F)(F)F)c(Cl)c2)nc1
Temperature: 100 °C
Yield: 24 %

Procedure:
5-[2-(4-Bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3-methyl-3H-benzooxazol-2-one (130 mg, obtained in Example 116, step 8), bis-(pinacolato)-diboron (78 mg), potassium acetate (82 mg) and bis-(triphenylphosphine)-palladium(II)-dichloride (6 mg) was dissolved in dioxane (6 mL). The reaction mixture was heated to 100° C. for 2.5 hours. The reaction mixture was cooled to r.t. and water (1 mL), methyl-6-chloronicotinate (96 mg, [CAS Reg. No. 73781-91-6]), dichloro(1,1′-bis(diphenylphosphino)ferrocene)palladium (II) dichloromethane adduct (20 mg) and 2.0 M aqueous Na2CO3 (0.21 mL) were added and the mixture was heated to 65° C. over night. The reaction mixture was cooled, poured into ice/water and extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the title compound as a colorless foam (35 mg, 24%). MS (m/e)=521.3 [M+H+].
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([N:15]2[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=3)=[O:21])[CH2:16]2)[CH2:11][CH2:10]1.CCN(C(C)C)C(C)C.[CH2:45]([CH2:49][C:50](=O)[CH3:51])[C:46]([CH3:48])=O>CO>[CH3:51][C:50]1[N:8]([CH:9]2[CH2:10][CH2:11][CH:12]([N:15]3[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:33])[F:34])[CH:26]=4)=[O:21])[CH2:16]3)[CH2:13][CH2:14]2)[C:46]([CH3:48])=[CH:45][CH:49]=1
Reactant: CC(=O)CCC(C)=O
Reactant: NC1CCC(N2CC(NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Cc1ccc(C)n1C1CCC(N2CC(NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-{[1-(4-amino-cyclohexyl)-azetidin-3-ylcarbamoyl]-methyl}-3-trifluoromethyl-benzamide trifluoroacetic acid salt (as prepared in Example 35 Step B, 0.24 g, 0.4 mmol) in methanol (2 mL) was added DIEA (Aldrich, 0.21 mL, 1.2 mmol) and acetonylacetone (Aldrich, 0.06 mL, 0.5 mmol). The resulting mixture was stirred at rt overnight and the volatile organics were removed by evaporation. The residue was dissolved in water, extracted with EtOAc, dried over Na2SO4. Filtration and evaporation gave a crude product, which was purified by column chromatography (eluent: EtOAc) to give the cis isomer as a white solid.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]2[S:21][C:20](=[S:22])[NH:19][C:18]2=[O:23])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].C(C1C=C(C=C(C(C)(C)C)C=1O)C=O)(C)(C)C.S1CC(=O)NC1=S.CC(C1C=C(N2C(=O)CSC2=C)C=C(C(C)(C)C)C=1O)(C)C.CC(C1C=C(CC2SCNC2=O)C=C(C(C)(C)C)C=1O)(C)C.CC(N1C(=O)C(C(C)(C)C)SC1)(C)C>C(O)(=O)C>[CH3:15][C:12]([C:9]1[CH:8]=[C:7]([CH2:16][CH:17]2[S:21][C:20](=[S:22])[NH:19][C:18]2=[O:23])[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1cc(C=C2SC(=S)NC2=O)cc(C(C)(C)C)c1O
Agent: C=C1SCC(=O)N1c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: CC(C)(C)C1SCN(C(C)(C)C)C1=O
Agent: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(CC2SC(=S)NC2=O)cc(C(C)(C)C)c1O

Procedure:
The aryl-substituted rhodanine derivatives of formula I are either known in the art or may be prepared by any of a number of well-known procedures. For example, Teuber et al., Leibigs Ann. Chem., 757 (1978) disclose 5-[[3,5-bis(1,1-dimethylethyl)-4hydroxyphenyl]methylene]-2-thioxo-4-thiazolidinone (referred to in the following discussion as Compound A). The compound is prepared by reacting 3,5-di-tert-butyl-4-hydroxybenzaldehyde with rhodanine at reflux temperature in glacial acetic acid using fused sodium acetate as catalyst. 5-[[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-methylene-4-thiazolidinone (Compound B), 5-[[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]methyl]-4-thiazolidinone (Compound C) and 5-[[3,5-bis (1,1-dimethylethyl)-4-thiazolidinone (Compound D) can be prepared from Compound A as follows.
Reaction SMILES: [N:1]([N:3]([C:8]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])([CH3:10])[CH3:9])[NH:4][C:5](N)=[O:6])=[O:2].C(O)(=O)C>C(Cl)(Cl)Cl>[C:14]([NH:13][C:11]([C:8]([N:3]1[N:4]=[C:5]([O-:6])[O:2][NH2+:1]1)([CH3:10])[CH3:9])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)NC(=O)C(C)(C)N(N=O)NC(N)=O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)NC(=O)C(C)(C)N1N=C([O-])O[NH2+]1
Temperature: 25 °C

Procedure:
A mixture of 12.0 g of the compound 4c), 30 ml of glacial acetic acid and 70 ml of chloroform is heated under reflux for 3 h. After cooling to room temperature, it is washed with sodium bicarbonate solution and with water, and the chloroform solution is dried using sodium sulphate and concentrated. The residue is recrystallized from tert-butyl methyl ether.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.[CH2:25]([O:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)CO)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[CH2:25]([O:32][C:33]1[CH:40]=[C:39]([CH:38]=[CH:35][CH:34]=1)[CH2:20][Br:24])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: OCc1cccc(OCc2ccccc2)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: BrCc1cccc(OCc2ccccc2)c1
Reaction time: 0.17 h
Yield: 77.3 %

Procedure:
To a solution of triphenyl phosphine (15.7 g, 60 mmol) in THF (150 mL) was added a solution of carbon tetrabromide (20 g, 60 mmol) in THF (50 mL). A precipitation was formed and stirred for 10 min. A solution of 3-benzyloxybenzyl alcohol 50.4 (10 g, 46.7 mmol) was added. After stirred for 1.5 h, the reaction mixture was filtered and concentrated under reduced pressure. The majority of triphenyl phosphine oxide was removed by precipitation from ethyl acetate-hexane. The crude product was purified by chromatography on silica gel and precipitation from hexane to give the desired product 3-Benzyloxybenzylbromide 6.9 (10 g, 77%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)=[CH:19][CH:18]=1.Cl.[C:35]1([C:41]2([C:47]([NH2:49])=[O:48])[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][C:12]([C:14]([N:44]2[CH2:43][CH2:42][C:41]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)([C:47]([NH2:49])=[O:48])[CH2:46][CH2:45]2)=[O:16])=[CH:11][C:10]=1[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)=[CH:19][CH:18]=1
Reactant: O=C(O)c1cc(-c2ccc(OCCCOC3CCCCO3)cc2)c(-c2ccc(F)cc2Cl)s1
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)C1(c2ccccc2)CCN(C(=O)c2cc(-c3ccc(OCCCOC4CCCCO4)cc3)c(-c3ccc(F)cc3Cl)s2)CC1
Yield: 87 %

Procedure:
0.5 g of the compound obtained in stage 16G), 0.25 g of 4-phenylpiperidine-4-carboxamide hydrochloride, 0.43 ml of Et3N and 0.36 g of TBTU are added to 10 ml of CH2Cl2 and then reaction is allowed to take place at AT for 2 hours. After concentrating to dryness, taking up the residue in a water/ether mixture and filtering, 0.6 g of the expected compound is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH:13]([C:14](OC)=[O:15])[CH2:12][C:11](=[O:18])[N:10]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:7][CH:8]=1.[BH4-].[Na+]>CO>[OH:15][CH2:14][CH:13]1[CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:11](=[O:18])[CH2:12]1
Reactant: COC(=O)C1CC(=O)N(c2ccccc2)C1c1cccc(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(C2C(CO)CC(=O)N2c2ccccc2)c1

Procedure:
To 26.7 gm. of methyl 2-(3-methoxyphenyl)-5-oxo-1-phenylpyrrolidin-3-carboxylate in 200 ml of absolute methanol was added slowly at 0°-10° 24.8 gm. of sodium borohydride. The reaction was run and worked up following the procedure of example 1D. Drying (Na2SO4), filtration, and concentration in vacuo provided 17.2 gm. of colorless crystals, m.p. 123°-126°.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:12])=O>>[Cl:12][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[CH:4][N:3]=1
Reactant: CCc1cc(O)ncn1
Reactant: O=P(Cl)(Cl)Cl
Product: CCc1cc(Cl)ncn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
12.4 g (0.10 mol) of 4-hydroxy-6-ethylpyrimidine, prepared according to EP 326 389, are introduced into 25 ml of phosphorus oxychloride, the temperature rising spontaneously to 70° C. A clear solution is formed, which is kept at 70° C. for a further 2 hours and, after cooling, is stirred into ice-water. Extraction with ether yields 12.0 g of liquid crude product which is distilled in a bulb tube at 105° C. under a pressure of 26 mbar to give 11.0 g of pure substance. Analysis: C6H7ClN2 (M=142.59).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=O)[CH:5]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[F:29][C:30]1[CH:39]=[CH:38][C:33]([C:34]([NH:36]O)=[NH:35])=[CH:32][CH:31]=1>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]2[O:9][N:36]=[C:34]([C:33]3[CH:38]=[CH:39][C:30]([F:29])=[CH:31][CH:32]=3)[N:35]=2)[CH:5]=1
Reactant: N=C(NO)c1ccc(F)cc1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2nc(-c3ccc(F)cc3)no2)c1
Temperature: 115 °C
Reaction time: 2 h

Procedure:
In a 50 ml flask, 1.17 g (6.5 mmol) of isophtalic acid monomethyl ester are dissolved in 10 ml of DMF. To this solution, 1.16 g (7.2 mmol, 1.1 eq.) of 1,1′-carbonyl-diimidazole is added at room temperature under nitrogen. The mixture is stirred until carbon dioxide formation stops. Then, 1.00 g (6.5 mmol) of 4-fluoro-N-hydroxy-benzamidine is added and the resulting yellow solution stirred for 2 h. Now, another 1.16 g (7.2 mmol, 1.1 eq.) of 1,1′-carbonyl-diimidazole are added and the mixture is heated to 115° C. After 2 h at this temperature, the reaction mixture is cooled to room temperature and the solvent removed in vacuo. After chromatographical purification (160 g SiO2;eluent: hexane/CH2Cl2 6:4 to 1:1) the title compound is obtained as a white solid. Mass spectrum: m/z (M+H)+: 299.0
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:32])[C@@H:15]([NH:24]C(OC(C)(C)C)=O)[CH2:16][C:17]2[C:18]([OH:23])=[N:19][O:20][C:21]=2[CH3:22])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:32])[C@@H:15]([NH2:24])[CH2:16][C:17]2[C:18]([OH:23])=[N:19][O:20][C:21]=2[CH3:22])[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](Cc2c(O)noc2C)NC(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)Cc2c(O)noc2C)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 146 mg 4-[(S)-2-tert-Butoxycarbonylamino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)-propionyl]-piperazine-1-carboxylic acid butyl ester in 5 ml dichloromethane were added 0.4 ml TFA. After 12 h stirring at RT the solvents were removed and the residue was codistilled twice with toluene. Yield: 156 mg.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[NH2:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15](F)[C:12]=1[C:13]#[N:14]>CS(C)=O>[O:7]([C:15]1[CH:16]=[CH:17][CH:18]=[C:11]([NH2:10])[C:12]=1[C:13]#[N:14])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1c(N)cccc1F
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#Cc1c(N)cccc1Oc1ccccc1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
Phenol (2.06 g, 22 mmol) was dissolved in dry dimethyl sulfoxide (25 mL), and sodium hydride (0.53 g, 22 mmol) was added in portions, and the mixture stirred for 1 hour under argon. 2-Amino-6-fluorobenzonitrile (2.72 g, 20 mmol) was added and the mixture heated to 110° C. overnight. The solvent was evaporated in vacuo, and the residue was partitioned between ethyl acetate and water. The organic phase was washed with water (5×), brine (1×) dried over anhydrous Na2SO4 filtered, and evaporated to give the crude product which was then chromatographed on silica gel eluted with 0–20% ethyl acetate in hexane to give the title compound as a white amorphous solid. Recrystallization from carbon tetrachloride, hexane gave a white crystalline solid. mp 66–67° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:6][CH:7]=1)=O.[CH3:13][NH:14][CH3:15].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:13][N:14]([CH2:1][C:3]1[CH:4]=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:6][CH:7]=1)[CH3:15]
Reactant: CNC
Reactant: CCOC(=O)c1cc(C=O)c[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCOC(=O)c1cc(CN(C)C)c[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the compound obtained in Step C and dimethylamine (1.1 eq.) there is added, in portions, NaBH(OAc)3 (952 mg). The mixture is stirred overnight at ambient temperature. After evaporation to dryness, the residue is taken up in CH2Cl2 and water. The aqueous phase is extracted with CH2Cl2. The organic phases are combined and then extracted with aqueous 1N HCl solution. The aqueous phase is made alkaline and is then extracted with CH2Cl2. The organic phase is dried over magnesium sulphate, filtered and evaporated to dryness to yield the title product, which is used directly in the next Step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH:10][C:11]1[N:16]=[C:15]([NH:17][CH3:18])[C:14]([C:19]([F:22])([F:21])[F:20])=[CH:13][N:12]=1)[C:5]#[N:6].[N-:23]=[N+:24]=[N-:25].[Na+].[Cl-].[NH4+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[N:23]=[N:24][NH:25][N:6]=2)[CH:7]=[CH:8][C:9]=1[NH:10][C:11]1[N:16]=[C:15]([NH:17][CH3:18])[C:14]([C:19]([F:20])([F:21])[F:22])=[CH:13][N:12]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CNc1nc(Nc2ccc(C#N)cc2Cl)ncc1C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1nc(Nc2ccc(-c3nn[nH]n3)cc2Cl)ncc1C(F)(F)F
Temperature: 125 °C
Yield: 28.3 %

Procedure:
To a solution of 3-chloro-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)benzonitrile (135 mg, 6.41 mmol) in DMF (2 mL) was added sodium azide (80 mg, 1.24 mmol) and ammonium chloride (66 mg, 1.24 mmol). The mixture was heated at 125° C. for 18 h. The mixture was cooled, filtered and the solid washed with ethyl acetate. The filtrated was concentrated under reduced pressure and the crude residue was diluted with water (5 mL) and diethyl ether (5 mL). A precipitate formed which was filtered and washed with further portions of water and diethyl ether. The solid was co-evaporated with dichloromethane and methanol and then dried in a vacuum oven to yield N2-(2-chloro-4-(2H-tetrazol-5-yl)phenyl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (130 mg, 85%). LCMS (ESCI_Formic_MeCN): [MH+]=371 at 3.11 min. 1H NMR (400 MHz, DMSO): δ 8.94 (s, 1H); 8.26-8.19 (m, 2H); 8.14 (d, J=2.0, 1H); 8.03-7.96 (m, 1H); 7.30-7.22 (m, 1H); 2.89 (t, J=4.4, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19](OS(C(F)(F)F)(=O)=O)[CH:20]=3)[CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:32]([Mg]Br)=[CH2:33]>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH:32]=[CH2:33])[CH:20]=3)[CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Oc1ccc2cc(C3CCN(Cc4ccccc4)CC3)ccc2c1)C(F)(F)F
Reactant: C=C[Mg]Br
Product: C=Cc1ccc2cc(C3CCN(Cc4ccccc4)CC3)ccc2c1
Yield: 63.3 %

Procedure:
Beginning with 0.839 gm (1.9 mMol) 1-benzyl-4-(6-trifluoromethanesulfonyloxynaphth-2-yl)piperidine and 3.73 mL (3.7 mMol) vinylmagnesium bromide (1M in tetrahydrofuran), 0.394 gm (65%) of the desired compound were prepared as a waxy white solid substantially by the procedure of EXAMPLE 7.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:9][CH3:10])[C:6]([OH:8])=O)(=[O:3])[CH3:2].N1C=CC=CC=1.ClC(=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20]>O1CCCC1>[C:1]([NH:4][CH:5]([CH2:9][CH3:10])[C:6](=[O:8])[C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:3])[CH3:2]
Reactant: CCC(NC(C)=O)C(=O)O
Reactant: CCOC(=O)C(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C(CC)NC(C)=O
Temperature: 25 °C

Procedure:
9.2 g (63.4 mmol) 2-(acetylamino)butanoic acid are suspended in 120 ml tetrahydrofuran and heated to reflux together with 15.0 g (190 mmol) pyridine and a bit of N,N-dimethylaminopyridine. While heating at reflux, 17.3 g (127 mmol) ethyl chloro(oxo)acetate are added dropwise. The reaction mixture is heated at reflux until no more evolution of gas can be observed. After cooling down to room temperature, the reaction mixture is added to ice water and the organic phase extracted with ethyl acetate. The dried organic phase is evaporated to dryness in vacuo, dissolved in ethanol and the solution directly used for the next reaction.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([F:14])[C:11]([Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][C:9]=2[F:19])[N:5]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[C:3]=1[Cl:24].[Br:25]Br.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[C:7]([Br:25])=[C:6]([C:8]2[CH:13]=[C:12]([F:14])[C:11]([Si:15]([CH3:17])([CH3:18])[CH3:16])=[CH:10][C:9]=2[F:19])[N:5]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[C:3]=1[Cl:24]
Reactant: COC(=O)c1nc(-c2cc(F)c([Si](C)(C)C)cc2F)cc(N)c1Cl
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1nc(-c2cc(F)c([Si](C)(C)C)cc2F)c(Br)c(N)c1Cl
Temperature: 20 °C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
To a solution of methyl 4-amino-3-chloro-6-(2,5-difluoro-4-(trimethylsilyl)phenyl)picolinate (0.210 g, 0.566 mmol) in CH2Cl2 (2.265 mL) at 20° C. was added bromine (0.117 mL, 2.265 mmol). The reaction mixture was stirred at 20° C. overnight. The mixture was then poured into a saturated aqueous solution of Na2S2O3 and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (SiO2, hexanes/EtOAc gradient) to provide the title compound as a white solid (0.125 g, 49.1%): mp 165-166° C.; 1H NMR (400 MHz, CDCl3) δ 7.10 (dd, J=8.9, 4.0 Hz, 1H), 7.03 (dd, J=7.6, 5.1 Hz, 1H), 5.43 (s, 2H), 3.96 (s, 3H), 0.33 (d, J=0.7 Hz, 9H); ESIMS m/z 450 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[NH2:8].[C:10](=O)([O-])[O-:11].[K+].[K+].C(=O)=O>O>[CH3:9][C:4]1[CH:5]=[CH:6][C:7]2=[N:8][C:10](=[O:11])[N:1]=[C:2]2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(N)c(N)c1
Agent: O=C=O
Agent: [K+]
Solvent: O
Product: Cc1ccc2c(c1)=NC(=O)N=2
Temperature: 230 °C
Yield: 473.8 %

Procedure:
24.4 g (0.2 mol) of 3,4-diaminotoluene, 18 g of water and 5.5 g (0.04 mol) of potassium carbonate were introduced into a 200 ml reactor. After sealing, CO2 was injected up to a pressure of 35 bar. The mixture was then heated to 230° C., and this temperature maintained for 12 hours. During the heating period, the pressure rose to up to 80 bar. After the reaction was completed, the mixture was cooled, the excess CO2 pressure was let down, and the aqueous slurry of crystals was removed. The aqueous catalyst solution was separated off through a filter, the solid was washed with water until it no longer contained carbonate, and was dried. 27.7 g (93.7% of theory) of 5-methylbenzimidazolone of m.p. = 301-303° C. were isolated.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]=[C:11]([NH:13][NH2:14])[CH2:10][N:9]=[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]=2[CH:21]=1.[Br:24][CH2:25][C:26](=O)[CH2:27][OH:28]>O1CCCC1>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]=[C:11]([NH:13][N:14]=[C:26]([CH2:27][OH:28])[CH2:25][Br:24])[CH2:10][N:9]=[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]=2[CH:21]=1
Reactant: NNC1=Nc2ccc(C(F)(F)F)cc2C(c2ccccc2)=NC1
Reactant: O=C(CO)CBr
Solvent: C1CCOC1
Product: OCC(CBr)=NNC1=Nc2ccc(C(F)(F)F)cc2C(c2ccccc2)=NC1

Procedure:
In the manner given in Example 1, 7-(trifluoromethyl)-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in tetrahydrofuran can be treated with 1-bromo-3-hydroxypropanone under nitrogen to give 7-(trifluoromethyl)-2-[[2-bromo-1-(hydroxymethyl)ethylidene]hydrazino]-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:15]3/[C:16](=[O:22])[N:17]=[C:18](SC)[S:19]/3)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:23]#[N:24])[CH3:2].[OH:25][CH:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:27][NH2:28].CCN(C(C)C)C(C)C>>[CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:15]3/[C:16](=[O:22])[N:17]=[C:18]([NH:28][CH2:27][CH:26]([OH:25])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[S:19]/3)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:23]#[N:24])[CH3:2]
Reactant: CCOc1c(C#N)cnc2ccc(/C=C3\SC(SC)=NC3=O)cc12
Reactant: NCC(O)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1c(C#N)cnc2ccc(/C=C3\SC(NCC(O)c4ccccc4)=NC3=O)cc12

Procedure:
Similar procedure as described in example 14h was used, starting from 4-ethoxy-6-[2-methylsulfanyl-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carbonitrile (example 14g), 2-hydroxy-2-phenyl-ethylamine and DIEA to give 4-ethoxy-6-[2-(2-hydroxy-2-phenyl-ethylamino)-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carbonitrile. LC-MS m/e 445 (MH+).