Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[C:8]([CH:9]([N:13]([CH3:23])[C:14](=[O:22])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]([CH3:12])[CH3:11])=[CH:7][N:6]=[CH:5][N:4]=1)=O.Cl.[NH2:25][OH:26].C([O-])(=O)C.[K+].O>CO>[OH:26][N:25]=[CH:1][C:3]1[C:8]([CH:9]([N:13]([CH3:23])[C:14](=[O:22])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]([CH3:12])[CH3:11])=[CH:7][N:6]=[CH:5][N:4]=1
Reactant: CC(C)C(c1cncnc1C=O)N(C)C(=O)Cc1ccccc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)C(c1cncnc1C=NO)N(C)C(=O)Cc1ccccc1
Yield: 43.1 %

Procedure:
1.0 g (3.2 mmol) of N-(1-(4-formylpyrimidin-5-yl)-2-methylpropyl]-N-methylphenylacetamide was dissolved in 30 ml of methanol, and 0.45 g (6.5 mmol) of hydroxylamine hydrochloride and 0.63 g (6.4 mmol) of potassium acetate were added and reacted at room temperature for 1 hour. After completion of the reaction, the product was poured into water and extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogencarbonate solution, an aqueous citric acid solution, water and an aqueous sodium chloride solution, in this order, dried and concentrated, and the obtained oily product was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:1 to ethyl acetate) to obtain 0.45 g (yield: 43%) of N-[1-(4-hydroxyiminomethylpyrimidin-5-yl)-2-methylpropyl]-N-methylphenylacetamide as colorless crystals (melting point: 171-172° C.).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][C:9]=1[NH:19][C:20]([C:22]1[CH:23]=[N:24][C:25](Cl)=[CH:26][CH:27]=1)=[O:21])(C)(C)C.[CH2:30]([NH:32][C:33]([N:35]1[C:39]2([CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:38][CH2:37][CH2:36]1)=[O:34])[CH3:31].CCN(CC)CC>CS(C)=O>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][C:9]=1[NH:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([N:42]2[CH2:41][CH2:40][C:39]3([N:35]([C:33]([NH:32][CH2:30][CH3:31])=[O:34])[CH2:36][CH2:37][CH2:38]3)[CH2:44][CH2:43]2)=[N:24][CH:23]=1)=[O:21]
Reactant: CCNC(=O)N1CCCC12CCNCC2
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCNC(=O)N1CCCC12CCN(c1ccc(C(=O)Nc3cc(-c4cccs4)ccc3N)cn1)CC2
Reaction time: 1 h

Procedure:
A solution of intermediate F (82 mg, 0.19 mmol), N-ethyl-1,8-diazaspiro[4.5]-decane-1-carboxamide (73 mg, 0.35 mmol), and NEt3 (43 μL, 0.31 mmol) in 5 mL of DMSO was stirred at 90° C. for 12 h. The reaction mixture was partitioned between EtOAc and saturated NaHCO3, the organic layer was dried (MgSO4), filtered and concentrated. The residue was stirred in 2 mL of TFA and 2 mL of CH2Cl2 for 1 h at room temperature and concentrated. Reverse-phase chromatography (10 to 100% MeCN/water with 0.05% TFA) followed by neutralization with EtOAc/saturated NaHCO3 extraction and drying with MgSO4 gave the title compound: MS (ESI+): cal'd [M+H]+ 505.2, obs'd 505.2.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]([NH2:18])=[O:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.F[B-](F)(F)F.[CH2:24]([O+](CC)CC)[CH3:25].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH:12]1[C:10]2[C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH2:6][N:7]([C:16](=[NH:18])[O:17][CH2:24][CH3:25])[CH2:8][C:9]=2[CH:15]=[CH:14][CH:13]=1
Reactant: NC(=O)N1Cc2ccccc2-c2ccccc2C1
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1.19 g of 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboxamide are dissolved in 10 ml of methylene chloride, and the solution is treated with 1.14 g of triethyloxonium tetrafluoroborate and stirred at room temperature for 20 hours. The mixture is then poured on to 10% sodium carbonate solution/ice and the whole is extracted with methylene chloride. The combined extracts are washed with 10% sodium carbonate solution, dried over anhydrous sodium sulphate and evaporated under reduced pressure. In this manner there is obtained crude ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-caboximidate which is purified by a filtration on silica gel [eluent: n-hexane/ethyl acetate (1:1)]; m.p. 74°-76° C. (crystallized from n-hexane).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][C:15]=1[C:23]([F:26])([F:25])[F:24].O[N:28]=[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][CH3:38])[NH2:30].CCN(C(C)C)C(C)C>>[CH3:38][O:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:29]1[N:28]=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[CH3:7])=[C:15]([C:23]([F:24])([F:25])[F:26])[CH:16]=2)[O:22][N:30]=1
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1C(F)(F)F
Reactant: COc1ccccc1C(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1noc(-c2ccc(-c3ccccc3C)c(C(F)(F)F)c2)n1

Procedure:
Oxalyl chloride (109 μL; 1.28 mmol; 3 eq.), Intermediate 34 (120 mg; 0.43 mmol; 1 eq.), Intermediate 1 (71 mg; 0.43 mmol, 1 eq.) and DIEA (95 μL; 1.28 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography (c-hexane/ethyl acetate, 95/5) afforded the title compound as a white solid.
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1.[NH2:29][C@@H:30]([CH3:33])[CH2:31][OH:32].O>CO>[OH:32][CH2:31][C@@H:30]([NH:29][C:3]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:16][CH2:17]2)=[O:11])=[CH:8][CH:9]=1)=[O:28])[CH3:33]
Reactant: C[C@H](N)CO
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)cc1
Solvent: O
Solvent: CO
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)N[C@@H](C)CO)cc2)CC1
Temperature: 20 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
4-[1-[3-(Isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoic acid methyl ester (1.8 g) and (S)-(+)-2-amino-1-propanol (0.71 g) were dissolved in methanol (30 ml) and heated to reflux for 12 hours. The reaction mixture was cooled and with the slow addition of excess of water at 40° C. to precipitate the crystals, the mixture was cooled again and stirred at 20° C. for 1 hour. Following with filtration and washing with water, the filtered solid was recrystallized using isopropanol and ether, filtered and dried to give 1.66 g (yield: 83%) of the desired compound.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[S:19][C:7]2[N:8]=[C:9]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][N:10]3[C:11](=[O:12])[C:6]=2[CH:5]=1)[CH3:3].[N-:20]=[N+:21]=[N-:22].[Na+].[Cl-].[NH4+]>CN(C)C=O>[CH3:3][CH:2]([C:4]1[S:19][C:7]2[N:8]=[C:9]3[CH:16]=[CH:15][C:14]([C:17]4[NH:22][N:21]=[N:20][N:18]=4)=[CH:13][N:10]3[C:11](=[O:12])[C:6]=2[CH:5]=1)[CH3:1]
Reactant: CC(C)c1cc2c(=O)n3cc(C#N)ccc3nc2s1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1cc2c(=O)n3cc(-c4nnn[nH]4)ccc3nc2s1
Temperature: 124 °C
Yield: 55.8 %

Procedure:
A mixture of 5.1 g (0.01894 mol) of 2-(1-methylethyl)-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile (Example 16), 6.5 g (0.1 mol) of sodium azide and 5.35 g (0.1 mol) of ammonium chloride in 150 ml of dimethylformamide is stirred and heated at 124° C. for twenty-two hours under nitrogen. The reaction mixture is cooled, filtered and the filtrate evaporated. The residue is treated with 1 l water and acidified with concentrated hydrochloric acid. The resulting precipitate is collected, suspended in hot water, the suspension cooled and filtered to give 3.3 g of 2-(1-methylethyl)-7-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidin-4-one; mp 288° C. (dec) after recrystallization from pyridine-ethanol.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:13])[NH:7]2.C(=O)([O-])[O-].[K+].[K+].CC(C)=O.[CH3:24][O:25][CH2:26][CH2:27]Br>O>[OH:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:27][CH2:26][O:25][CH3:24])=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:13])[NH:7]2
Reactant: COCCBr
Reactant: O=C1CCc2c(O)ccc(O)c2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COCCOc1ccc(O)c2c1NC(=O)CC2
Yield: 52.4 %

Procedure:
21.6 g of 5,8-dihydroxy-3,4-dihydrocarbostyril and 19.9 g of potassium carbonate were added to a mixture comprising 480 ml of acetone and 120 ml of water, and the resulting mixture was stirred while refluxing for 30 minutes. 76 g of 2-methoxyethyl bromide was then added thereto followed by stirring while refluxing for 8 hours. The solvent was evaporated, and water was added to the residue. The mixture was extracted with diethyl ether. The aqueous layer was rendered acidic with hydrochloric acid and then extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate, and the chloroform evaporated to obtain 15 g of 5-hydroxy-8-(2-methoxyethoxy)-3,4-dihydrocarbostyril as a black oily substance.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[CH:7]=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])([O-])=O.O.O.Cl[Sn]Cl>CCO>[CH2:12]([O:11][C:9](=[O:10])[CH:8]=[CH:7][C:6]1[CH:14]=[CH:15][CH:16]=[C:4]([NH2:1])[CH:5]=1)[CH3:13]
Reactant: CCOC(=O)C=Cc1cccc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)C=Cc1cccc(N)c1

Procedure:
Ethyl 3-nitrocinnamate (1) (2.0 g, 9.04 mmol) was reduced using method A, except that SnCl2.2H2O (10.2 g, 45.20 mmol) in EtOH (20 mL) was used and after the reaction the solvent was concentrated in vacuo, Rochelle's salt and saturated NaHCO3 (1:1, 80 mL) were added, and the aqueous basified with 1N NaOH. The aqueous was extracted with EtOAc (3×40 mL), washed with Rochelle's salt/saturated NaHCO3 solution (2×40 mL), dried (MgSO4) and the solvent was concentrated in vacuo to give the title compound. Yield: 1.77 g, >100%; LC/MS tr 0.89 min; MS (ES+) m/z 192 (M+H)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]2)=[C:4]([O:14][CH3:15])[CH:3]=1.[Cl:16][C:17]1[CH:29]=[CH:28][C:20]([CH2:21][N:22]2[CH:26]=[CH:25][C:24]([NH2:27])=[N:23]2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:29]=[CH:28][C:20]([CH2:21][N:22]2[CH:26]=[CH:25][C:24]([NH:27][C:2]3[CH:7]=[CH:6][C:5]([N:8]4[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]4)=[C:4]([O:14][CH3:15])[CH:3]=3)=[N:23]2)=[CH:19][CH:18]=1
Reactant: COc1cc(Br)ccc1-n1cnc(C)c1
Reactant: Nc1ccn(Cc2ccc(Cl)cc2)n1
Product: COc1cc(Nc2ccn(Cc3ccc(Cl)cc3)n2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 43 starting with 1-(4-bromo-2-methoxy-phenyl)-4-methyl-1H-imidazole and 1-(4-chloro-benzyl)-1H-pyrazol-3-yl amine. The title compound was obtained as a yellow liquid (Yield=41%). MS ISP (m/e): 394.1 (100) [(M+H)+].
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]([CH3:11])[CH2:9][N:8](CC3C=CC(OC)=CC=3)[C:4]=2[N:5]=[CH:6][N:7]=1.[C:21]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(O[K])(C)(C)C.C(OCC)(=O)C>CN1C(=O)CCC1>[C:24]([O:23][C:21]([N:28]1[CH2:33][CH2:32][N:31]([C:2]2[C:3]3[CH:10]([CH3:11])[CH2:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:30][CH2:29]1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: COc1ccc(CN2CC(C)c3c(Cl)ncnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(C)(C)O[K]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC1CNc2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 128 °C
Yield: 50 %

Procedure:
To a solution of 4-Chloro-7-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (0.55 g, 1.88 mmol) in NMP (20 mL) were added 1-Boc-piperazine (1.0 g, 5.40 mmol) and tBuOK (0.21 g, 1.88 mmol). The mixture was heated to 128° C. for 30 hours. After cooling, the mixture was diluted by ethyl acetate (500 mL) and washed with water (5×150 mL). The organic phase was dried and concentrated. The residue was subject to column chromatography, eluted by hexane/ethyl acetate (1:1) to give 4-(5-Methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.30 g, 36%). 1H NMR (CDCl3, 400 MHz) δ 8.19 (s, 1H), 7.18 (d, J=8.4 Hz, 2H), 6.84 (d, J=8.4 Hz, 2H), 4.52 (dd, J=27.6 Hz, J=14.8 Hz, 2H), 3.79 (s, 3H), 3.58 (m, 12H), 3.34 (m 1H), 2.95 (m, 1H), 1.48 (s, 9H), 1.15 (d, J=6.8 Hz, 3H). MS (APCI+) [M+H]+440.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]=O)=[CH:15][C:14]=2[CH3:22])=[N:4][CH:5]=[N:6][C:7]=1[CH3:8].Cl.[NH2:24][OH:25].[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[C:3]([NH:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]=[N:24][OH:25])=[CH:15][C:14]=2[CH3:22])=[N:4][CH:5]=[N:6][C:7]=1[CH3:8]
Reactant: NO
Reactant: Cc1cc(CC=O)ccc1OCCNc1ncnc(C)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(CC=NO)ccc1OCCNc1ncnc(C)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
6.0 g of 5-chloro-4-[2-(4-formylmethyl-2-methylphenoxy)ethylamino]-6-methylpyrimidine were dissolved in 50 ml of ethanol, and a solution of 1.4 g of hydroxylamine hydrochloride in 5 ml of water was added thereto. Subsequently, a solution of 0.8 g of sodium hydroxide in 5 ml of water was added dropwise to the mixture. After completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours. It was then poured into water. Crystals precipitated, and these were collected by filtration, washed with water and dried to obtain 5.2 g of 5-chloro-4-{2-[4-(2-hydroxyiminoethyl)-2-methylphenoxy]ethylamino}-6-methylpyrimidine as an intermediate.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:8]=[C:9]([N+:17]([O-:19])=[O:18])[C:10]([Cl:16])=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].[CH3:20]O>>[CH3:20][O:13][C:12](=[O:14])[C:11]1[CH:15]=[C:7]([Br:6])[CH:8]=[C:9]([N+:17]([O-:19])=[O:18])[C:10]=1[Cl:16]
Reactant: O=C(O)c1cc(Br)cc([N+](=O)[O-])c1Cl
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1Cl

Procedure:
20 ml of concentrated sulfuric acid are added dropwise to 51.0 g (0.182 mol) of 5-bromo-2-chloro-3-nitrobenzoic acid and 500 ml of methanol. The mixture is then boiled under reflux for 16 hours and subsequently cooled with an ice bath and the resulting precipitate is isolated by filtration. The mother liquor is concentrated, water is added and the resulting precipitate is isolated by filtration.
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][N:16]1[C:24]2[C:23]([CH3:25])=[C:22]([CH3:26])[N:21]=[C:20]([NH2:27])[C:19]=2[N:18]=[C:17]1[CH3:28]>>[NH2:27][C:20]1[C:19]2[N:18]=[C:17]([CH3:28])[N:16]([CH2:15][CH2:14][O:13][CH2:12][CH2:11][NH:10][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[C:24]=2[C:23]([CH3:25])=[C:22]([CH3:26])[N:21]=1
Reactant: Cc1nc(N)c2nc(C)n(CCOCCN)c2c1C
Reactant: O=C(Cl)N1CCOCC1
Product: Cc1nc(N)c2nc(C)n(CCOCCNC(=O)N3CCOCC3)c2c1C

Procedure:
Using the method of Examples 54-68, 4-morpholinecarbonyl chloride was reacted with 1-[2-(2-aminoethoxy)ethyl]-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The product was purified using Method A. The observed accurate mass was 377.2295.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[C:8]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH:22](O)[C:23]4[S:24][CH:25]=[C:26]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[N:27]=4)[CH:20]=3)[NH:15][C:14](=[O:35])[C:13]=2[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:9]=[CH:10][CH:11]=1>C(Cl)Cl>[Cl:5][C:6]1[CH:7]=[C:8]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH:22]([Cl:3])[C:23]4[S:24][CH:25]=[C:26]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:27]=4)[CH:20]=3)[NH:15][C:14](=[O:35])[C:13]=2[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)c1c(-c2cccc(Cl)c2)c2cc(C(O)c3nc(-c4ccccc4)cs3)ccc2[nH]c1=O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1c(-c2cccc(Cl)c2)c2cc(C(Cl)c3nc(-c4ccccc4)cs3)ccc2[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thionyl chloride (30 ml) was added dropwise to a mixture of intermediate (19) (0.0245 mol) in DCM (150 ml), previously cooled on an ice bath. The mixture was stirred at a low temperature for 1 hour and at room temperature overnight. The solvent was evaporated till dryness. The product was used without further purification, yielding (quant.) of ethyl 4-(3-chlorophenyl)-6-[chloro(4-phenyl-2-thiazolyl)methyl]-1,2-dihydro-2-oxo-3-quinolinecarboxylate (intermediate 20).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[N:3]=1.[Br:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([Br:25])[C:19]=1[NH2:26].Cl>C(OCC)C.O1CCOCC1>[Br:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([Br:25])[C:19]=1[NH:26][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[N:3]=1
Reactant: N#Cc1ccc(Nc2nccc(Cl)n2)cc1
Reactant: Cc1cc(Br)c(N)c(Br)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1cc(Br)c(Nc2ccnc(Nc3ccc(C#N)cc3)n2)c(Br)c1
Temperature: 170 °C
Yield: 16 %

Procedure:
4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile (0.003 mol), 2,6-dibromo-4-methyl-benzenamine (0.006 mol) and 1 M HCl in diethyl ether (4.5 ml) in 1,4-dioxane (10 ml) were combined in a tube and heated under Ar until all diethyl ether had evaporated. The tube was sealed and heated at 170° C. for 2.5 days. Silica gel was added, and the solvent was evaporated. The residue was purified by flash column chromatography over silica gel (eluent gradient: CH2Cl2:CH3OH:NH4OH 100:0:0 to 99:0.9:0.1). The desired fractions were collected and the solvent was evaporated. The residue was recrystallized from acetonitrile, filtered off and dried, yielding 0.22 g (15.9%) of 4-[[4-[(2,6-dibromo-4-methylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile (compound 61).
Reaction SMILES: [CH3:1][C:2]1([CH3:40])[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@:5]([CH3:39])([C:14](=O)[NH:15][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[C:21]([C:34]([F:37])([F:36])[F:35])[CH:20]=2)=O)[CH2:4][O:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:50])=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:40])[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@:5]([CH3:39])([C:14]2[S:50][C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[C:21]([C:34]([F:37])([F:36])[F:35])[CH:20]=3)=[CH:16][N:15]=2)[CH2:4][O:3]1
Reactant: CCCCCCCCOc1ccc(C(=O)CNC(=O)[C@@]2(C)COC(C)(C)N2C(=O)OC(C)(C)C)cc1C(F)(F)F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCOc1ccc(-c2cnc([C@@]3(C)COC(C)(C)N3C(=O)OC(C)(C)C)s2)cc1C(F)(F)F
Temperature: 100 °C
Yield: 67 %

Procedure:
A suspension of protected oxazolidine-amide 6 (180 mg, 1.0 equivalent) and Lawesson's Reagent (390 mg, 3.0 equivalents) in toluene (5 mL) was sealed and heated at 100° C. for 1 hour. After cooling to room temperature, the reaction mixture was purified by silica gel column chromatography using the Combi-Flash system (Hex:EtOAc) as a thick colourless oil in 67% yield (120 mg). TLC (1:2 EtOAc:Hex), Rf=0.8; MS (ESI, M+H+)=571.11; 1H NMR (400 MHz, CDCl3) δ 7.73 (br s, 1H), 7.70 (s, 1H), 7.61 (d, 1H, J=6.8 Hz), 7.01 (d, 1H, J=6.8 Hz), 3.96-4.28 (m, 4H), 1.21-1.99 (m, 30H), 0.89 (t, 3H, J=7.6 Hz).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[C:18]([O:22][C:23](=[O:43])[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:27]=1[CH2:33][NH:34][C:35](=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([CH3:21])([CH3:20])[CH3:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[C:18]([O:22][C:23](=[O:43])[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][CH:7]=2)=[CH:28][C:27]=1[CH2:33][NH:34][C:35](=[O:42])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)CCc1ccc(O)cc1CNC(=O)c1ccccc1
Reactant: BrCCCOc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CCc1ccc(OCCCOc2ccc(-c3ccccc3)cc2)cc1CNC(=O)c1ccccc1
Temperature: 60 °C
Yield: 88.4 %

Procedure:
A solution of 4-(3-bromo-propoxy)-biphenyl (291 mg, 1.00 mmol; Preparation 12) and 3-[2-(benzoylamino-methyl)-4-hydroxy-phenyl]-propionic acid tert-butyl ester (320 mg, 0.90 mmol; Preparation 21) in DMF (5 mL) was treated with K2CO3 (100 mg) and heated at 60° C. for 48 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3×20 mL). The combined organics were dried (Na2SO4), concentrated, and purified using silica gel chromatography (10-30% EtOAc/hexanes) to give 3-{2-(benzoylaminomethyl)-4-[3-(biphenyl-4-yloxy)propoxy]phenyl}propionic acid tert-butyl ester (450 mg). This material was treated with a mixture of CH2Cl2 (1.0 mL)/TFA (0.8 mL)/water (0.1 mL) at ambient temperature for 2 h. The reaction mixture was concentrated and dried under vacuum to afford the title product as a white solid (380 mg, 75%). MS (ES) m/e 510.1 (M+1).
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:15])([F:14])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C@H:11]([NH2:13])[CH3:12])[CH:6]=1.C(N(CC)C(C)C)(C)C.[F:25][C:26]1[CH:34]=[C:33]2[C:29]([C:30]([C:36]3[N:37]=[C:38]4[C:44]([C:45](O)=[O:46])=[CH:43][N:42]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[C:39]4=[N:40][CH:41]=3)=[N:31][N:32]2[CH3:35])=[CH:28][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:15][C:4]([F:14])([F:3])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C@H:11]([NH:13][C:45]([C:44]2[C:38]3[C:39](=[N:40][CH:41]=[C:36]([C:30]4[C:29]5[C:33](=[CH:34][C:26]([F:25])=[CH:27][CH:28]=5)[N:32]([CH3:35])[N:31]=4)[N:37]=3)[N:42]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[CH:43]=2)=[O:46])[CH3:12])[CH:6]=1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Reactant: C[C@@H](N)c1cc(C(F)(F)F)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1cc(C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
To a solution of (R)-1-(4-trifluoromethyl-pyridin-2-yl)-ethylamine dihydrochloride (89 mg, 0.34 mmol) in DMF (2 mL) was added N,N-diisopropylethylamine (0.20 mL, 1.13 mmol), 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.23 mmol), and HATU (95 mg, 0.25 mmol). The yellow reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (3×). The combined organics were washed with water (3×) and brine then dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 50% to 100% EtOAc/hexanes to give 122 mg (88%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-trifluoromethyl-pyridin-2-yl)-ethyl]-amide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([C:11]([NH2:13])=[O:12])[NH2:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.O.[C:15]1([C:21]([CH:23]=O)=O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:11](=[O:12])[N:13]=[C:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:23]=[N:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=CC(=O)c1ccccc1
Reactant: NC(=O)N(N)c1cc(Cl)cc(Cl)c1
Solvent: C1COCCO1
Solvent: O
Product: O=c1nc(-c2ccccc2)cnn1-c1cc(Cl)cc(Cl)c1
Yield: 42.2 %

Procedure:
In 50 ml of dioxane was dissolved 2.20 g of 2-(3,5-dichlorophenyl)semicarbazide followed by addition of 1.52 g of phenylglyoxal monohydrate, and the mixture was refluxed for 5 hours. The reaction mixture was then concentrated and the residue was recrystallized from acetonitrile to provide 1.34 g of the title compound. m.p. 160-161° C.