Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][N:14]([C:16]([N:18]3[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]3)=[O:17])[CH2:13][CH:12]([C:26](O)=[O:27])[CH2:11]2)=[CH:6][CH:5]=1.O[N:31]=[C:32]([NH2:37])[CH2:33][CH2:34][O:35][CH3:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:29][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:11][CH:12]([C:26]3[O:27][N:37]=[C:32]([CH2:33][CH2:34][O:35][CH3:36])[N:31]=3)[CH2:13][N:14]([C:16]([N:18]3[CH2:23][CH2:22][S:21](=[O:24])(=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:15]2)=[CH:8][CH:9]=1
Reactant: O=C(O)C1CC(c2ccc(OC(F)F)cc2)CN(C(=O)N2CCS(=O)(=O)CC2)C1
Reactant: COCCC(N)=NO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCc1noc(C2CC(c3ccc(OC(F)F)cc3)CN(C(=O)N3CCS(=O)(=O)CC3)C2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
300 mg (0.69 mmol) of the compound from Example 37A and 246 mg (2.08 mmol) of N′-hydroxy-3-methoxypropanimidamide were initially charged in 2.6 ml of DMF and reacted with 396 mg (1.0 mmol) of HATU and 0.36 ml (269 mg, 2.1 mmol) of N,N-diisopropylethylamine. The reaction mixture was stirred at RT for 15 minutes and then partitioned between water and ethyl acetate. The organic phase was washed repeatedly with water, dried over sodium sulphate and concentrated under reduced pressure. The residue was dissolved in 2.0 ml of DMF and converted in a microwave at 180° C. for 2 minutes. The reaction mixture was purified by means of preparative HPLC. Yield: 141 mg (38% of theory)
Reaction SMILES: [C:1]([CH2:8][C:9]([O:11][CH2:12][CH2:13][C:14]#[N:15])=[O:10])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)([O-:18])=[O:17].N1CCCCC1.C(O)(=O)C>CC(O)C>[C:14]([CH2:13][CH2:12][O:11][C:9](=[O:10])[C:8](=[CH:23][C:22]1[CH:25]=[CH:26][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=1)[C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])#[N:15]
Reactant: CCCCCC(=O)CC(=O)OCCC#N
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CCCCCC(=O)C(=Cc1ccc([N+](=O)[O-])cc1)C(=O)OCCC#N
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 2-cyanoethyl hexanoylacetate (21.1 g, 100 mmol), 4-nitrobenzaldehyde (16.6 g, 110 mmol), piperidine (430 mg, 5.00 mmol) and acetic acid (300 mg, 5.00 mmol) in 350 ml of 2-propanol was stirred at room temperature for 48 hrs. The resulting white precipitate was filtered and dried in the air. The product, 2-[(4-nitrophenyl)methylene]-3-oxooctanoic acid 2-cyanoethyl ester was obtained as a white powder (25.2 g, 73% yield).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.Cl.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:17](=[O:24])[C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1
Reactant: O=C(Cl)c1ccncc1
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Agent: Cl
Product: O=C(Nc1nc2cccc(-c3ccoc3)n2n1)c1ccncc1

Procedure:
The title compound was prepared following procedure and work up described for example 19, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 50 mg; 0.25 mmol; 1.0 eq.) and isonicotinoyl chloride hydrochloride (89 mg; 0.50 mmol; 2.0 eq.) as a white powder (39.4 mg, 51%). HPLC, Rt: 1.90 min. (purity 97.2%). LC/MS, M+(ESI): 306.4, M−(ESI): 304.4.
Reaction SMILES: C([O-])(=O)C.[Na+].Br[CH:7](Br)[C:8]([C:10]([F:13])([F:12])[F:11])=[O:9].Cl.[Br:16][C:17]1[C:22]([O:23][CH:24]([CH3:26])[CH3:25])=[CH:21][C:20]([NH:27][NH2:28])=[C:19]([F:29])[CH:18]=1>O>[Br:16][C:17]1[C:22]([O:23][CH:24]([CH3:25])[CH3:26])=[CH:21][C:20]([NH:27][N:28]=[CH:7][C:8](=[O:9])[C:10]([F:13])([F:12])[F:11])=[C:19]([F:29])[CH:18]=1
Reactant: CC(C)Oc1cc(NN)c(F)cc1Br
Reactant: O=C(C(Br)Br)C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(C)Oc1cc(NN=CC(=O)C(F)(F)F)c(F)cc1Br
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
First, 50 g (0.61 mol) of sodium acetate and 41 g (0.14 mol) of 1,1-dibromo-3,3,3-trifluoroacetone were mixed with 500 ml of water, and the mixture was stirred at 80° C. for 30 minutes and then cooled to 0° C. Then, 45 g (0.14 mol) of 4-bromo-2-fluoro-5-isopropoxyphenylhydrazine hydrochloride was added at 10° C. or lower, and the mixture was stirred at 10° C. or lower for 3 hours. The precipitated crystals were collected by filtration and dried, which afforded 35 g (94.3 mmol) of 3,3,3-trifluoro-2-oxopropanal 1-(4-bromo-2-fluoro-5-isopropoxyphenylhydrazone).
Reaction SMILES: C(N(CC1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1)C1CCCN(C(OC(C)C)=O)C2C(Br)=CC=CC1=2)(=O)C.[C:38]([N:41]([CH2:63][C:64]1[CH:69]=[C:68]([C:70]([F:73])([F:72])[F:71])[CH:67]=[C:66]([C:74]([F:77])([F:76])[F:75])[CH:65]=1)[CH:42]1[CH2:48][CH2:47][CH2:46][N:45]([C:49]([O:51][CH:52]([CH3:54])[CH3:53])=[O:50])[C:44]2[CH:55]=[C:56](Cl)[C:57]([N:59]([CH3:61])[CH3:60])=[CH:58][C:43]1=2)(=[O:40])[CH3:39]>>[C:38]([N:41]([CH2:63][C:64]1[CH:69]=[C:68]([C:70]([F:71])([F:73])[F:72])[CH:67]=[C:66]([C:74]([F:76])([F:77])[F:75])[CH:65]=1)[CH:42]1[CH2:48][CH2:47][CH2:46][N:45]([C:49]([O:51][CH:52]([CH3:53])[CH3:54])=[O:50])[C:58]2[C:57]([N:59]([CH3:60])[CH3:61])=[CH:56][CH:55]=[CH:44][C:43]1=2)(=[O:40])[CH3:39]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(Cl)c(N(C)C)cc21
Agent: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2c(Br)cccc21
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2c1cccc2N(C)C

Procedure:
This compound prepared utilizing the same methodology described in Example 50 wherein replacement of isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-7-bromo-8-chloro-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate with isopropyl 5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-9-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate following the procedure of Example 50 for the synthesis of isopropyl 5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-8-chloro-7-dimethylamino-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate. CI MS 560 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([C:15]([OH:17])=[O:16])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[Si](C)(C)C.[CH3:30][O:31][CH2:32][C:33](Cl)=[O:34]>ClCCl.CO.O>[CH3:30][O:31][CH2:32][C:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([C:15]([OH:17])=[O:16])=[CH:10][N:9]=2)=[CH:6][CH:7]=1)=[O:34]
Reactant: COCC(=O)Cl
Reactant: Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COCC(=O)Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1
Temperature: 25 °C
Yield: 90.1 %

Procedure:
A suspension of 6.9 g (30 mmol) of 2-(4-aminophenyl)-4-hydroxy-5-pyrimidine carboxylic acid and 400 ml of dichloromethane is stirred at room temperature and 16.6 ml (120 mmol) of triethylamine is added followed by 11.3 ml (90 mmol) of chlorotrimethylsilane. The mixture is stirred at room temperature for 30 min and 3.2 ml (30 mmol) of methoxyacetyl chloride in 10 ml of dichloromethane is added dropwise at 0°. The resulting mixture is stirred for 18 hrs at room temperature and 15 ml of water and 50 ml of methanol are added. The solid is filtered, washed, and dried to give 8.2 g of 2-[4-(methoxyacetylamino)phenyl]-4-hydroxy-5-pyrimidine carboxylic acid. An additional 3.2 g is obtained by evaporation of the filtrate. After recrystallization from dimethyl sulfoxide-water, the material has mp 297°-300° dec.
Reaction SMILES: [C:1]([O:5][C:6]([N:8](C(OC(C)(C)C)=O)[C:9]1[S:10][C:11]([CH3:20])=[C:12]([CH3:19])[C:13]=1[C:14]([O:16]CC)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[K+].C(O)(=O)C>O>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([CH3:20])=[C:12]([CH3:19])[C:13]=1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)sc(C)c1C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: Cc1sc(NC(=O)OC(C)(C)C)c(C(=O)O)c1C
Reaction time: 8 h

Procedure:
Ethyl 2-bis(t-butoxycarbonyl)amino-4,5-dimethylthiophene3-carboxylate (13.6 g, 34 mmol) was hydrolysed by refluxing in 70 ml of water and 140 ml of methanol with 7.63 g of potassium hydroxide. Addition of 8.1 ml of acetic acid and stirring overnight precipitated 8.27 g (90%) of 2-t-butoxycarbonylamino-4,5-dimethylthiophene-3-carboxylic acid. M.p. 185° C. (dec.). 1H-NMR (DMSO-d6, δ): 1.5 (s, 9H), 2.15 (s, 3H), 2.2 (s, 3H), 10.4 (s, 1H), 13.1 (br.s, 1H).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:10])[CH:4]=[C:5]([CH2:8][OH:9])[O:6][CH:7]=1.CC(C)([O-])C.[K+].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>CN(C=O)C>[OH:9][CH2:8][C:5]1[O:6][CH:7]=[C:2]([O:1][CH2:23][C:22]2[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)[C:3](=[O:10])[CH:4]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=c1cc(CO)occ1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2coc(CO)cc2=O)cc1
Temperature: 50 °C
Reaction time: 21 h
Yield: 52 %

Procedure:
5-Hydroxy-2-hydroxymethyl-4H-4-pyranone (5.0 g, 35.2 mmol) was dissolved in N,N′-dimethylformamide (70 mL), and potassium tert-butoxide (4.0 g, 35.2 mmol) was added under an argon atmosphere and under ice-cold conditions. 5 minutes after, 4-methoxybenzylchloride (6.06 g, 38.7 mmol) was added at the same temperature, and stirred at 50° C. for 21 hours. Then, the reaction solution was concentrated in vacuo. After adding water and an 1N aqueous solution of sodium hydroxide, the solution was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was added diethylether for purification by recrystallization, and the title compound (4.80 g (yield 52%)) was obtained as a brown powder crystal.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][NH:14][CH:15]=3)[S:10][C:6]=2[C:5](=[O:16])[NH:4][C:3]1([CH3:18])[CH3:17].Cl.C([O-])(O)=O.[Na+].[F:25][C:26]1([F:33])[CH2:31]CC(=O)C[CH2:27]1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[O-]S([O-])(=O)=O.[Mg+2]>CCOC(C)=O.CC(N(C)C)=O.CO>[F:25][C:26]1([F:33])[CH2:31][CH2:18][C:3]2([N:2]([CH3:1])[C:7]3[CH:8]=[C:9]([C:11]4[CH:15]=[N:14][NH:13][CH:12]=4)[S:10][C:6]=3[C:5](=[O:16])[NH:4]2)[CH2:17][CH2:27]1
Reactant: O=C1CCC(F)(F)CC1
Reactant: CN1c2cc(-c3cn[nH]c3)sc2C(=O)NC1(C)C
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: CO
Product: CN1c2cc(-c3cn[nH]c3)sc2C(=O)NC12CCC(F)(F)CC2
Temperature: 50 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
A mixture of 1,2,2-trimethyl-6-(1H-pyrazol-4-yl)-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (131 mg, 0.50 mmol), 1 M aqueous HCl (2.5 mL, 2.5 mmol) and MeOH (2.5 mL) was stirred at 50° C. for 1 h. After addition of saturated aqueous NaHCO3, the organic materials were extracted with EtOAc. After removal of the solvent at reduced pressure, the residue was mixed with 4,4-difluorocyclohexanone (335 mg, 2.5 mmol), CSA (12 mg, 0.050 mmol), MgSO4 (96 mg, 1.0 mmol) and DMA (1 mL). After stirred at 80° C. for 1.5 h, saturated aqueous NaHCO3 and EtOAc were added to quench the reaction. The organic materials were extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, 90:10 hexane/EtOAc to EtOAc), then crystallized from MeOH/EtOAc/hexane to give the title compound (121 mg, 72%) as a yellow solid:
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[Br:22][C:23]1[N:24]=[C:25]([CH2:28]O)[S:26][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCCOC)=O)=NC(OCCOC)=O>C1COCC1.O>[Br:22][C:23]1[N:24]=[C:25]([CH2:28][O:20][C:17]2[CH:18]=[CH:19][N:14]([C:11]3[CH:12]=[CH:13][C:6]4[N:5]=[C:4]([CH:1]5[CH2:2][CH2:3]5)[N:8]([CH3:9])[C:7]=4[CH:10]=3)[C:15](=[O:21])[CH:16]=2)[S:26][CH:27]=1
Reactant: OCc1nc(Br)cs1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4nc(Br)cs4)cc3=O)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.2 %

Procedure:
To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (289 mg), (4-bromo-1,3-thiazol-2-yl)methanol (399 mg) and triphenylphosphine (808 mg) in THF (8 ml) was added bis(2-methoxyethyl) azodicarboxylate (722 mg), and the mixture was stirred at room temperature for 3 h. The mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated and purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH) to give the title compound (128 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH:8]([CH3:13])[C:9]2=[O:12])=[CH:5][CH:4]=1.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C1C=CC=CC=1.II>C(O)(=O)C.C(O)C.CCOCC>[C:16]([O:18][C:19]1[C:20]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH2:6][CH3:7])[CH:9]([OH:12])[C:8]=1[CH3:13])(=[O:17])[CH3:15]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc2c(c1)C(=O)C(C)C2
Agent: II
Solvent: CCO
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCc1cc(OC)cc2c1C(OC(C)=O)=C(C)C2O

Procedure:
A solution of 13.4 g of 6-methoxy-2-methylindanone and 21 g. of ethyl bromoacetate in 45 ml. benzene is added over a period of five minutes to 21 g. of zinc amalgam (prepared according to Org. Syn. Coll. Vol. 3) in 110 ml. benzene and 40 ml. dry ether. A few cyrstals of iodine are added to start the reaction, and the reaction mixture is maintained at reflux temperature (ca. 650) with external heating. At three-hour intervals, two batches of 10 g. zinc amalgam and 10 g. bromoester are added and the mixture is then refluxed for 8 hours. After addition of 30 ml. of ethanol and 150 ml. of acetic acid, the mixture is poured into 700 ml. of 50% aqueous acetic acid. The organic layer is separated, and the aqueous layer is extracted twice with ether. The combined organic layers are washed thoroughly with water, ammonium hydroxide and water. Drying over sodium sulfate, evaporation of solvent in vacuo followed by pumping at 80° (bath temperature)(l-2 mm.) gives crude ethyl-(1-hydroxy-2-methyl-6-methoxy-indenyl) acetate (ca. 18 g.).
Reaction SMILES: Br[C:2]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[Cl:13].[CH3:14][S:15]([NH:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)(=[O:17])=[O:16].C(=O)([O-])[O-].[Na+].[Na+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:6][C:5]1[CH:7]=[C:8]([C:9]([F:12])([F:11])[F:10])[C:2]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([NH:18][S:15]([CH3:14])(=[O:16])=[O:17])[CH:24]=2)=[C:3]([Cl:13])[CH:4]=1
Reactant: Nc1cc(Cl)c(Br)c(C(F)(F)F)c1
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)Nc1cccc(-c2c(Cl)cc(N)cc2C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 75.3 %

Procedure:
A mixture of 4-bromo-3-chloro-5-(trifluoromethyl)aniline (573 mg, 2.09 mmol, Eq: 1.00), 3-(methylsulfonamido)phenylboronic acid (529 mg, 2.46 mmol, Eq: 1.18) and tetrakis(triphenylphosphine)palladium (0) (211 mg, 183 μmol, Eq: 0.0875) was degassed (vacuum/nitrogen cycles) then degassed dioxane (6.87 ml) (nitrogen bubbling with sonication) and a degassed (nitrogen bubbling with sonication) 2M solution of sodium carbonate in water (1.83 ml, 3.66 mmol, Eq: 1.75) were added. The mixture was stirred at 100° C. for 18 h. The reaction mixture was adsorbed unto silica (2 g), concentrated and purified on silica gel (silica 40 g, dichloromethane/ethyl acetate 100:0 to 80:20) to give 574 mg (75%) of the desired product as a yellow solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][CH2:12][C:13]([OH:15])=[O:14].O1CCCC1.[C:21](=O)([O:27]C(C)(C)C)[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]>[OH-].[Na+]>[C:23]([O:22][C:21]([N:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[CH2:12][C:13]([OH:15])=[O:14])=[O:27])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: O=C(O)CNc1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CC(=O)O)c1ccc2ccccc2c1
Temperature: 24 °C
Reaction time: 4 h
Yield: 85.5 %

Procedure:
To a stirred solution of 10 g (50 mM) of 2-naphthylglycine (from Preparation 1) in 100 ml of 1N sodium hydroxide were added 50 ml of tetrahydrofuran followed by 30 g (140 mM) of di-tert.-butyl carbonate. The reaction mixture was stirred at 24° C. for four hours. The product was isolated by first washing the reaction mixture three times with 50 ml portions of diethyl ether, and then the mixture was made acidic to pH 2.0 by the addition of conc. hydrochloric acid. The aqueous acid mixture was extracted several times with ethyl acetate, and the extracts were combined, washed with water, dried and the solvent was removed by evaporation under reduced pressure to provide 12.8 g (85% yield) of N-tert.-butoxycarbonyl-2-naphthylglycine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([Cl:12])[CH:6]=1)=[O:4].[CH3:13][C:14]([O:17][C:18]([N:20]1[CH2:26][CH2:25][C:24]2[CH:27]=[CH:28][C:29](B(O)O)=[CH:30][C:23]=2[CH2:22][CH2:21]1)=[O:19])([CH3:16])[CH3:15]>>[Cl:12][C:7]1[CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:10]=[CH:9][C:8]=1[O:11][C:28]1[CH:29]=[CH:30][C:23]2[CH2:22][CH2:21][N:20]([C:18]([O:17][C:14]([CH3:13])([CH3:15])[CH3:16])=[O:19])[CH2:26][CH2:25][C:24]=2[CH:27]=1
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(B(O)O)cc2CC1
Product: COC(=O)c1ccc(Oc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)c(Cl)c1

Procedure:
The title compound was prepared from methyl 3-chloro-4-hydroxy benzoate (320 mg, 1.72 mmol) and (3-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)boronic acid (E264, Step 2) using the method outlined in Example 264 Step 3 (211 mg, 29%); NMR (CDCl3) δ 1.49 (9H, s), 2.88 (4H, m), 3.56 (4H, m), 3.91 (3H, s), 6.78-6.89 (3H, m), 7.12 (H, m), 7.84 (H, m), 8.14 (H, s)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Br[C:10]([CH3:19])([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:10]([CH3:19])([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: Sc1ccc(Br)cc1
Product: CC(C)(C)OC(=O)C(C)(C)Sc1ccc(Br)cc1
Yield: 80 %

Procedure:
As above, tert-butyl 2-[4-(2-aminoethyl)phenylthio]-2-methylpropionate was obtained in 86% yield by reacting 4-bromothiophenol (1) as a starting material with tert-butyl 2-bromoisobutyrate to obtain tert-butyl 2-(4-bromophenylthio)-2-methylpropionate (2) in 80% yield, reacting it with N-vinyl phthalimide in presence of palladium catalyst for 24 hours to obtain tert-butyl 2-[4-(2-phthalimidoethenyl)phenylthio]-2-methylpropionate (3) in 84% yield, reducing the resulted compound (3) under Wilkinson catalyst to obtain tert-butyl 2-[4-(2-phthalimidoethyl)phenylthio]-2-methylpropionate (4) in 91% yield and then reacting the resulted compound (4) with hydrazine.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]([N:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[O:14])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[C:1]1([C:7]2[N:8]=[CH:9][C:10]([C:13]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:14])=[CH:11][N:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cnc(-c3ccccc3)nc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cnc(-c2ccccc2)nc1)N1CCNCC1
Reaction time: 1 h
Yield: 93.6 %

Procedure:
To a mixture consisting of tert-butyl 4-(2-phenylpyrimidine-5-carbonyl)piperazine-1-carboxylate (587 mg) in dichloromethane (8 mL) at 0° C. was added trifluoroacetic acid (7 mL). The mixture was stirred cold for one hour and was subsequently concentrated under reduced pressure to provide a residue, which was purified by flash silica column chromatography. Elution with 95:5 dichloromethane-methanol with 0.5% concentrated ammonium hydroxide afforded the title compound (400 mg, 94% yield); MS (ESI+) m/z 269 (M+1); HPLC (Column: 2.1×150 mm, 3μGeminiC18; detection wavelength: 210 nm; mobile phase A: 90/10H2O/CH3CN 10 mM NH4OAc; mobile phase B: 10/90H2O/CH3CN 10 mM NH4OAc; gradient: 0-6 minutes 0-100% B, 6-10 minutes 100% B, 10.1-15 minutes 0% B; flow rate: 0.25 mL/min) purity: 98.5%, retention time: 9.7 minutes.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1)=[O:4].[CH3:12][C:13]1[N:14]=[CH:15][NH:16][CH:17]=1>C(#N)C>[I:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][N:16]2[CH:17]=[C:13]([CH3:12])[N:14]=[CH:15]2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(I)cc1
Reactant: Cc1c[nH]cn1
Solvent: CC#N
Product: Cc1cn(CC(=O)c2ccc(I)cc2)cn1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 2.50 g (7.69 mmol) 2-bromo-1-(4-iodo-phenyl)-ethanone in 30 mL ACN are added 1.90 g (23.1 mmol) 4-methylimidazole and the mixture is stirred at rt for 48 h. After that time, the solvent is evaporated and the residue is taken up in EtOAc. The mixture is washed with water and brine (2×) and the organic layer is dried over magnesium sulphate. The solvent is evaporated and the residue is recrystallized from diethyl ether to yield the desired product.
Reaction SMILES: [Cl:1][CH:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4](C)[N:3]1N.ClC1N=C(Cl)N=C(N)N=1.ClC1N=C(Cl)N=[C:23]([NH:28][C:29]([NH2:31])=[O:30])N=1>>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:28]([CH3:23])[C:29]([NH2:31])=[O:30])[N:3]=1
Reactant: CC1=NC(Cl)=NC(Cl)N1N
Reactant: NC(=O)Nc1nc(Cl)nc(Cl)n1
Agent: Nc1nc(Cl)nc(Cl)n1
Product: CN(C(N)=O)c1nc(Cl)nc(Cl)n1

Procedure:
By using 89 parts of 2,4-dichloro-6-methyl-amino-s-triazine instead of 82.5 parts of 2,4-dichloro-6-amino-s-triazine and otherwise carrying out the procedure as described in Example 1 for the manufacture of N-(2,4-dichloro-s-triazin-6-yl)-urea, there are obtained 79.5 parts of N-(2,4-dichloro-s-triazin-6-yl)-N-methyl-urea with a melting point of 172°-174°C.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Br:7][C:8]1[CH:9]=[CH:10][C:11]([F:16])=[C:12]([CH:15]=1)[CH:13]=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([F:16])=[C:12]([CH:15]=1)[CH:13]=[CH2:1]
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1cc(Br)ccc1F
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=Cc1cc(Br)ccc1F
Temperature: 25 °C
Yield: 89.5 %

Procedure:
A mixture of methyltriphenylphosphonium bromide (2.14 g, 6 mmol) and potassium t-butoxide (672 mg, 6 mmol) in 50 mL of THF was refluxed for 30 minutes under N2 and then cooled to room temperature. 5-Bromo-2-fluorobenzaldehyde (1.02 g, 5 mmol) was added and the resulting mixture was refluxed for 2 hours (until the TLC showed the disappearance of starting aldehyde). The reaction was concentrated in vacuo and partitioned between water and ethyl acetate. The acetate layer was washed with water and brine. The solution was dried over MgSO4 and concentrated in vacuo. The residue was purified by chromatography (silica gel, 15:1 hexanes-diethyl ether) to provide 900 mg (90%) of 5-bromo-2-fluorostyrene.