Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:27][CH3:28])=[CH:5][C:6]2[N:12]([C:13]([C:15]3[CH:20]=[CH:19][C:18](Br)=[C:17]([CH3:22])[CH:16]=3)=[O:14])[CH2:11][C:10]3=[CH:23][CH:24]=[CH:25][N:9]3[CH2:8][C:7]=2[CH:26]=1.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCOCC1>[CH3:1][O:2][C:3]1[C:4]([O:27][CH3:28])=[CH:5][C:6]2[N:12]([C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[C:30]([F:41])([F:40])[F:29])=[C:17]([CH3:22])[CH:16]=3)=[O:14])[CH2:11][C:10]3=[CH:23][CH:24]=[CH:25][N:9]3[CH2:8][C:7]=2[CH:26]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: COc1cc2c(cc1OC)N(C(=O)c1ccc(Br)c(C)c1)Cc1cccn1C2
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cc2c(cc1OC)N(C(=O)c1ccc(-c3ccccc3C(F)(F)F)c(C)c1)Cc1cccn1C2
Temperature: 25 °C
Yield: 87.1 %

Procedure:
The 7,8-dimethoxy-(10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-(4-bromo-3-methyl-phenyl)-methanone of Step C (1.0 g) was reacted with 2-trifluoromethylphenyl boronic acid (0.645 g, 1.5 equiv.), potassium phosphate (0.964 g, 2.0 equiv.) and a catalytic amount (0.050 g) of tetrakis(triphenylphosphine) palladium(0) in refluxing dioxane (10 mL) under nitrogen for 24 hours. The reaction was then cooled to room temperature, filtered through Celite, and the solvent removed in vacuo. The residue was dissolved in dichloromethane and the solution was washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The crude product so obtained was purified by chromatography on silica gel eluting with 5% ethyl acetate/dichloromethane to provide the title product (1.0 g) as a white crystalline solid, m.p. 187–188° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10](Cl)[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:13][S:14]([NH2:17])(=[O:16])=[O:15].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([NH:17][S:14]([CH3:13])(=[O:16])=[O:15])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Cl)nc(Cl)c1
Reactant: CS(N)(=O)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(Cl)nc(NS(C)(=O)=O)c1

Procedure:
Under a nitrogen atmosphere 10 g (49 mmol) methyl 2,6-dichloro-isonicotinate, 5.6 g (59 mmol) methanesulphonamide, 14 g (68 mmol) potassium phosphate, 1.7 g (2.9 mmol) Xantphos and 0.90 g tris(dibenzylideneacetone)dipalladium in 300 mL dioxane were stirred for 5 h at 100° C. The mixture was suction filtered through kieselguhr and evaporated down. The residue was stirred with ethanol and the solid was suction filtered.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4](I)[CH:3]=1.[C:10]([CH:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1)#[CH:11].CCN(CC)CC>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][C:4]=1[C:11]#[C:10][CH:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)C1
Reactant: Nc1ccc(Br)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C#Cc2cc(Br)ccc2N)C1
Temperature: 70 °C
Yield: 94.7 %

Procedure:
4-Bromo-2-iodoaniline (3.88 g, 19.88 mmol), tert-butyl 3-ethynylpyrrolidine-1-carboxylate (4.90 g, 16.45 mmol), CuI (65 mg, 0.34 mmol, 2 mol %) and Pd(PPh3)2Cl2 (115 mg, 0.16 mmol, 1 mol %) were mixed together under argon in a heat-gun dried flask. Acetonitrile (17 mL) and NEt3 (4.60 mL, 33.00 mmol) were added to the mixture and reaction was heated at 70° C. for 1.5 h. TLC showed complete consumption of the alkyne. Acetonitrile was concentrated under reduced pressure and EtOAc (100 mL) was added to the residue. Triethylamine salt was filtered off and washed with EtOAc. Mother liquor was concentrated and residue was purified by column chromatography using EtOAc/hexanes (gradient 0-40%) to afford tert-butyl 3-((2-amino-5-bromophenyl)ethynyl)pyrrolidine-1-carboxylate (5.69 g) in 95% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15]([OH:17])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:29][C:30]([F:33])([F:32])[F:31])[CH:27]=2)[N:22]([NH2:34])[CH:21]=1)[CH3:19].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>[CH2:18]([C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:29][C:30]([F:31])([F:33])[F:32])[CH:27]=2)[N:22]([NH:34][C:15]([C:11]2[C:12]([CH3:14])=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=2)=[O:17])[CH:21]=1)[CH3:19]
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Reactant: CCc1cn(N)c2ccc(OC(F)(F)F)cc12
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCc1cn(NC(=O)c2cnc(-c3cccc(F)c3)nc2C)c2ccc(OC(F)(F)F)cc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (250 mg, 1.1 mmol) and 3-ethyl-5-trifluoromethoxy-indol-1-ylamine (244 mg, 1 mmol) in DMF (5 mL) is stirred at 50° C. for 1 h. The mixture is treated with DMTMM (276 mg, 1 mmol) and stirred at 50° C. for 1 h. The mixture is diluted with saturated aqueous Na2CO3 (5 mL) and stirred for 10 min. The precipitate is collected by filtration, washed with H2O (50 mL) and heptane (50 mL), and dried in vacuo to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (3-ethyl-5-trifluoromethoxy-indol-1-yl)-amide (270 mg, 59%). MS: 459 (M+H); 1H NMR (300 MHz, CDCl3): δ 11.51 (s, NH, 1H), 9.08 (s, 1H), 8.35 (d, 1H), 8.24 (d, 1H), 7.48 (m, 2H), 7.22 (m, 2H), 7.11 (m, 2H), 2.85 (s, 3H), 2.80 (q, 2H), 1.35 (t, 3H).
Reaction SMILES: [CH2:1](Br)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:10]([C:13]1[CH:14]=[CH:15][C:16]2[NH:22][C:21](=[O:23])[CH2:20][N:19]=[C:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:17]=2[CH:31]=1)(=[O:12])[CH3:11]>CC(C)=O>[C:10]([C:13]1[CH:14]=[CH:15][C:16]2[N:22]([CH2:1][CH3:2])[C:21](=[O:23])[CH2:20][N:19]=[C:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:17]=2[CH:31]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)c1ccc2c(c1)C(c1ccccc1F)=NCC(=O)N2
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN1C(=O)CN=C(c2ccccc2F)c2cc(C(C)=O)ccc21
Temperature: 25 °C
Reaction time: 71 h

Procedure:
14.2 ml of ethyl bromide and 27.2 g of potassium carbonate are added to 13.6 b (45.9 mmol) of 7-acetyl-5-(o-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one in 400 ml of acetone. The mixture is stirred at room temperature for 71 hours, filtered and evaporated in vacuo. The residue is taken up in methylene chloride, the organic phase is washed with water, dried and evaporated. From methylene chloride/cyclohexane there is obtained 7-acetyl-1-ethyl-5-(o-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one of melting point 154°-156°.
Reaction SMILES: O[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=[C:4]([C:16]([CH3:19])([CH3:18])[CH3:17])[N:3]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=[C:4]([C:16]([CH3:19])([CH3:18])[CH3:17])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)c1nc(O)n(-c2c(Cl)cc(Cl)cc2Cl)n1
Product: CC(C)(C)c1nc(Cl)n(-c2c(Cl)cc(Cl)cc2Cl)n1
Yield: 84.3 %

Procedure:
4.8 g (0.015 mol) of 5-hydroxy-3-(tert-butyl)-1-(2,4,6-trichlorophenyl)-1H-1,2,4-triazole was added to 20 ml of phosphorus oxychloride, and stirred under reflux for 24 hours. The reaction mixture was cooled, and excess phosphorus oxychloride was distilled off under reduced pressure. To the residue, 100 ml of dichloromethane was added, and the mixture was washed with water. Then, the dichloromethane layer was dried, and the solvent was distilled off. The residue thereby obtained was purified by silica gel column chromatography to obtain 4.3 g (yield: 84.3%) of the desired compound as white needle like crystals. Melting point 98°-98.5° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:15]2[CH:16]=[C:17](Br)[CH:18]=[CH:19][C:14]=2[O:13][CH2:12][C:11]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:22]=[C:23]1[NH:27][CH2:26][C@H:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:24]1.C(=O)([O-])[O-].[Cs+].[Cs+].CNCCNC>C(Cl)(Cl)Cl.CO.[Cu]I.O1CCOCC1>[CH2:1]([O:8][CH2:9][N:10]1[C:15]2[CH:16]=[C:17]([N:27]3[C:23](=[O:22])[CH2:24][C@@H:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:26]3)[CH:18]=[CH:19][C:14]=2[O:13][CH2:12][C:11]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1COc2ccc(Br)cc2N1COCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CNC(=O)C1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@@H]1CC(=O)N(c2ccc3c(c2)N(COCc2ccccc2)C(=O)CO3)C1
Temperature: 100 °C
Yield: 79.8 %

Procedure:
In a reaction vessel were weighed and charged 4-[(Benzyloxy)methyl]-6-bromo-2H-1,4-benzoxazin-3(4H)-one (366 mg, 1.05 mmol), tert-butyl [(3R)-5-oxopyrrolidin-3-yl]carbamate (200 mg, 1.00 mmol), cesium carbonate (652 mg, 2.00 mmol) and 1,4-dioxane (5 ml), which was purged with nitrogen gas, subsequently copper (I) iodide (190 mg, 1.00 mmol) and N,N′-dimethylethylenediamine (0.107 ml, 1.00 mmol) were added thereto, and the mixture was stirred with heating for 9 hours on an oil bath at 100° C. After lowering the temperature to room temperature, the reaction solution was diluted with a mixed solvent of chloroform-methanol (9:1) to remove insoluble material by filtration using celite. The filtrate was concentrated under reduced pressure. The residue was roughly purified by silica gel column chromatography (chloroform/methanol), subsequently crystallized in a mixed solvent of n-hexane-ethyl acetate (1:1) and collected by filtration to yield 373 mg (80%) of the title compound in the form of a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:13]([C:12]1[CH:15]=[CH:16][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]([O:17][CH3:18])[CH:11]=1)[OH:14])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: ClCCCCCCCCCCOCc1ccccc1
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Product: COc1cc(C(O)CCCCCCCCCCOCc2ccccc2)ccc1OCc1ccccc1

Procedure:
By following the procedure as in Reference Example 17(c) using 4-benzyloxy-3-methoxybenzaldehyde and 10-benzyloxy-1-chlorodecane, 11-benzyloxy-1-(4-benzyloxy-3-methoxyphenyl)-1-undecanol was obtained.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]#[N:6].[I-:7].CS[C:10]1[S:14][CH:13]=[CH:12][S+:11]=1>O1CCCC1>[I-:7].[S:11]1[CH:12]=[CH:13][S:14][C:10]1=[CH:1][NH2+:2][CH2:3][CH2:4][C:5]#[N:6]
Reactant: CSc1scc[s+]1
Reactant: CNCCC#N
Agent: [I-]
Solvent: C1CCOC1
Product: N#CCC[NH2+]C=C1SC=CS1
Temperature: 25 °C
Yield: 79.6 %

Procedure:
To 30 ml of tetrahydrofuran, 0.8 g of N-methyl-(2-cyanoethyl)amine was dissolved, and 2.0 g of 2-methylthio-1,3-dithiolium iodide was gradually added thereto under stirring at room temperature. The mixture was stirred at room temperature for 1 hour, and then the precipitated crystals were collected by filtration and recrystallized from acetone-ethyl ether, whereby 1.8 g (yield: 80%) of 1-(1,3-dithiol-2-ylidene)-N-methyl-N-(2-cyanoethyl)ammonium iodide (Compound No. 4) was obtained as crystals having a melting point of 203° C.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5]([Cl:6])=[N:4][C:2]=1[Cl:3].[C:10]1([CH3:19])[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=1[OH:18]>C1(C)C=CC=CC=1>[Cl:3][C:2]1[N:4]=[C:5]([Cl:6])[N:7]=[C:8]([O:18][C:11]2[C:12]([CH3:17])=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=2[CH3:19])[N:1]=1
Reactant: Cc1cc(C)c(O)c(C)c1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(Oc2nc(Cl)nc(Cl)n2)c(C)c1

Procedure:
Reference is now made to the drawing, which is a flow chart of an exemplary completely integrated process of the present invention for conversion of cyanuric chloride to capped polymer. Cyanuric chloride (CYCI) dissolved in a suitable solvent, preferably toluene, is introduced into the system via line 1, and phase transfer catalyst (PTC) is added at 2. Mesitol and aqueous base are added from vessels 3 and 4, the rates of addition being controlled by valves 5 and 6 respectively. The reactant mixture then passes into static mixer 7, the residence time therein being effective to produce a toluene solution of the desired 2,4-dichloro-6-mesitoxy-1,3,5-triazine (DCMT).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[C:5]([CH3:10])[C:6]=1[C:7]([NH2:9])=[O:8].ClC(Cl)(Cl)[C:20]([N:22]=C=O)=[O:21].N>C(#N)C.CO>[NH2:22][C:20]([NH:1][C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[C:5]([CH3:10])[C:6]=1[C:7]([NH2:9])=[O:8])=[O:21]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: Cc1c(-c2ccc(Cl)cc2)sc(N)c1C(N)=O
Agent: N
Solvent: CC#N
Solvent: CO
Product: Cc1c(-c2ccc(Cl)cc2)sc(NC(N)=O)c1C(N)=O
Reaction time: 0.17 h

Procedure:
2-Amino-4-methyl-5-(4-chlorophenyl)-3-thiophencarboxamide (0.44 g) was suspended in acetonitrile (25 mL) and trichloroacetylisocyanate (0.2 mL) added dropwise with stirring over 10 minutes. Stirring was continued for a further 3 h at room temperature and then a 2M solution of ammonia in methanol (10 mL) was added and stirring continued for a further 2 h. The solvent was evaporated and the residue treated with water. The resultant solid was filtered off and washed with more water. The crude product was chromatographed on silica gel eluting with dichloromethane/methanol mixtures. Trituration with ether gave the title urea (0. 1 g).
Reaction SMILES: C(OC([NH:7][C@H:8]([C:15]([NH:17][C:18]1[CH:19]=[C:20]([CH2:25][C@H:26]([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:21]=[CH:22][C:23]=1[Cl:24])=[O:16])[CH:9]([C:11]([F:14])([F:13])[F:12])[CH3:10])=O)C=C.CC1(C)CC(=O)CC(=O)C1>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.C1COCC1>[Cl:24][C:23]1[CH:22]=[CH:21][C:20]([CH2:25][C@H:26]([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:19][C:18]=1[NH:17][C:15](=[O:16])[C@H:8]([CH:9]([C:11]([F:14])([F:13])[F:12])[CH3:10])[NH2:7]
Reactant: C=CCOC(=O)N[C@H](C(=O)Nc1cc(C[C@H](C)C(=O)OCC)ccc1Cl)C(C)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)CC(=O)CC(=O)C1
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](C)Cc1ccc(Cl)c(NC(=O)[C@@H](N)C(C)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.24 g (4.68 mmol) of ethyl (2S)-3-[3-({N-[(allyloxy)carbonyl]-4,4,4-trifluorovalyl}amino)-4-chlorophenyl]-2-methylpropanoate (Example 39A, mixture of 4 isomers) and 5.25 g (37.4 mmol) of dimedone were initially charged in 25 ml of abs. THF. At RT, the solution was deoxygenated by passing through argon for 30 min Subsequently 108.1 mg (0.094 mmol) of tetrakis(triphenylphosphine)palladium(0) were added and the mixture was stirred at RT overnight. After dilution with ethyl acetate, the mixture was washed twice with sat. sodium bicarbonate solution and once with sat. sodium chloride solution. The organic phase was dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 40:1→20:1) and separated. This gave 1.65 g of the target compound as diastereomer mixture 1 (89.4% of theory).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11][C:12](=O)[C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[C:19]([F:22])([F:21])[F:20])[CH3:2].[NH2:23][C:24]1[C:28]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)=[CH:27][NH:26][N:25]=1>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([C:13]([F:16])([F:15])[F:14])[N:25]3[N:26]=[CH:27][C:28]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)=[C:24]3[N:23]=2)=[CH:6][C:5]=1[C:19]([F:22])([F:21])[F:20])[CH3:2]
Reactant: CCOc1ccc(C(=O)CC(=O)C(F)(F)F)cc1C(F)(F)F
Reactant: Nc1n[nH]cc1-c1ccncc1
Product: CCOc1ccc(-c2cc(C(F)(F)F)n3ncc(-c4ccncc4)c3n2)cc1C(F)(F)F
Yield: 56.6 %

Procedure:
Reaction of 1-(4-ethoxy-3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (1164 mg, 0.5 mmol), prepared from 4-ethoxy-3-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from 4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (128 mg, 57%). MS (ISP) 453.5 [(M+H)+]; mp 233° C.
Reaction SMILES: [H-].[Na+].C[O:4][C:5](=O)[C:6]([CH3:27])([CH3:26])[CH2:7][O:8][Si:9]([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:29](#[N:31])[CH3:30].Cl>C1(C)C=CC=CC=1>[C:22]([Si:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[O:8][CH2:7][C:6]([CH3:27])([CH3:26])[C:5](=[O:4])[CH2:30][C:29]#[N:31])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC#N
Reactant: COC(=O)C(C)(C)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)CC#N
Yield: 24.5 %

Procedure:
A suspension of sodium hydride (60% dispersion in oil) (2.12 g, 52.9 mmol) in toluene (65 mL) at reflux under N2 was added over 55 mins a solution of Intermediate 153a (15.93 g, assumed 37.8 mmol) and acetonitrile (2.87 mL, 54.9 mmol) in toluene (31 mL). The mixture was heated at reflux for 67 h. The cooled reaction mixture was slowly acidified to pH 5 with aqueous 1N HCl and extracted with EtOAc. The aqueous layer was extracted with EtOAc (×2) and the combined organic phase was washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by FCC, using 0-50% ether in pentane, to give the title compound (3.52 g, 25%) as a yellow oil. LCMS (Method 3): Rt 4.94 min, m/z 402.3 [M+Na+].
Reaction SMILES: C(OC(O[CH2:10][CH3:11])OCC)(=O)C.[NH:12]([C:14]1[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:18]C=[CH:16][N:15]=1)[NH2:13]>>[C:20]1([C:19]2[C:14]3[N:15]([CH:16]=[N:13][N:12]=3)[CH:10]=[CH:11][N:18]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NNc1nccnc1-c1ccccc1
Reactant: CCOC(OCC)OC(C)=O
Product: c1ccc(-c2nccn3cnnc23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 10 ml. of stirred diethoxymethyl acetate at room temperature is added, in portions, 2.0 g. of 2-hydrazino-3-phenylpyrazine. The reaction mixture is stirred at room temperature and after one hour the precipitated product is collected, washed with ethanol and air dried. The crude product is recrystallized from acetonitrile to yield 1.1 g. of the product of the example as tan needles, m.p. 238°-239° C.
Reaction SMILES: [NH:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2].[CH3:7][CH:8]([CH3:27])[C:9]([O:11][CH:12]([O:16][C:17](ON1C(=O)CCC1=O)=[O:18])[CH:13]([CH3:15])[CH3:14])=[O:10]>>[CH3:2][N:1]([C:17]([O:16][CH:12]([O:11][C:9](=[O:10])[CH:8]([CH3:27])[CH3:7])[CH:13]([CH3:15])[CH3:14])=[O:18])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CC(C)C(=O)OC(OC(=O)ON1C(=O)CCC1=O)C(C)C
Reactant: CNCC(=O)O
Product: CC(C)C(=O)OC(OC(=O)N(C)CC(=O)O)C(C)C
Yield: 55.8 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, sarcosine (0.108 g, 1.19 mmol) and 1-(2,5-dioxoazolidinyloxycarbonyloxy)-2-methylpropyl 2-methylpropanoate (0.3 g, 0.99 mmol) were reacted to provide 0.152 g (55% yield) of the title compound (37) as a colorless liquid after work-up and mass-guided preparative HPLC purification. 1H NMR (CD3OD, 400 MHz): δ=6.57 (dd, 1H), 4.19 (m, 2H), 3.03 (2s, 3H), 2.6 (m, 1H), 2.01 (br m, 1H), 1.18 (m, 6H), 1.0-0.98 (2m, 6H). MS (ESI) nm/z 298.14 (M+Na)+, 274.13 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[C:4]([CH3:11])[CH:3]=1.Br[C:13]1C=C(C)C(C=C)=C(C)C=1.B1C2CCCC1CCC2>>[Br:1][C:2]1[CH:7]=[C:6]([CH3:13])[C:5]([CH2:8][CH2:9][OH:10])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1CCO
Reactant: C=Cc1c(C)cc(Br)cc1C
Agent: B1C2CCCC1CCC2
Product: Cc1cc(Br)cc(C)c1CCO
Yield: 62 %

Procedure:
Using a procedure analogous to that used to prepare 30B, 32A was heated in a pressure vessel with 9-BBN at 100° C. for 10 h to yield 32B (6.7 g, 62%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ ppm 2.31 (s, 6 H) 2.89 (t, J=7.33 Hz, 2 H) 3.73 (t, J=7.33 Hz, 2 H) 7.16 (s, 2 H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[N:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:12]=3)[C:5]2=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1)CCC>C1(C)C(C)=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:9]2[N:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:12]=3)[C:5]3[C:6]([N:8]=2)=[N:7][C:2]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)=[CH:3][CH:4]=3)=[CH:24][CH:25]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: Fc1ccc(-c2nc3nc(Cl)ccc3n2-c2ccnc(NC3CCCC3)n2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1C
Product: Fc1ccc(-c2nc3nc(-c4cccnc4)ccc3n2-c2ccnc(NC3CCCC3)n2)cc1
Yield: 58.8 %

Procedure:
5-Chloro-2-(4-fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)imidazo[4,5-b]pyridine (2 g 4.9 mmol), 3-tributylstannylpyridine (3.6 g 9.8 mmol) and PdCl2(PPh3)2 (340 mg 0.48 mmol) are heated in xylene (50 ml) for 3 h at 150° C. under argon. The reaction mixture is filtered at 60° C. and chromatographed over SiO2 (acetone/hexanes 3/7 to 6/4) to yield pale yellow crystals (1.3 g). Recrystallisation from THF/hexanes renders the title compound as colorless crystals (985 mg 45%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:6].Cl[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1>>[CH3:1][NH:2][CH2:3][CH2:4][C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[O:6][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1
Reactant: CNCC[C@H](O)c1ccccc1
Reactant: FC(F)(F)c1ccc(Cl)cc1
Product: CNCC[C@H](Oc1ccc(C(F)(F)F)cc1)c1ccccc1

Procedure:
A process according to claim 4 comprising the additional step, following all preceding steps, of reacting (S)-3-(methylamino)-1-phenylpropanol with a strong base followed by 4-chlorobenzotrifluoride to provide (S)-N-methyl-3-phenyl-3-[(α,α,α-trifluoro-p-tolyl)oxy]propylamine.