Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].Cl[C:4]1[CH:5]=[C:6]([CH:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[CH2:11][CH3:12])[CH:7]=[CH:8][CH:9]=1>CO>[CH3:1][NH:2][CH2:12][CH2:11][CH:10]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:4][CH:5]=1
Reactant: CCC(Oc1ccccc1OC)c1cccc(Cl)c1
Reactant: CN
Solvent: CO
Product: CNCCC(Oc1ccccc1OC)c1ccccc1

Procedure:
A reaction mixture consisting of 200 ml. of methylamine, 225 ml. of methanol and 75 g. of 3-chloro-1-(o-methoxyphenoxy)propylbenzene was heated in an autoclave for 12 hours at 140° C. The reaction mixture was cooled, and the solvent was removed by evaporation. The semisolid residue was mixed with concentrated aqueous sodium hydroxide. The reasulting mixture was extracted several times with ether. N-methyl 3-(o-methoxyphenoxy)-3-phenylpropylamine, formed in the above reaction, was insoluble in the alkaline solution and was extracted therefrom with ether. The ether extracts were combined, and the combined extracts washed with water and dried. The ether was removed therefrom in vacuo leaving the amine as a dark colored residue. The residue was dissolved in ether and 1 equivalent of oxalic acid in methanol added slowly. N-methyl 3-(o-methoxyphenoxy)-3-phenylpropylamine oxalate formed an insoluble precipitate which was collected by filtration, and the filter cake washed with ether and dried. N-methyl 3-(o-methoxyphenoxy)-3-phenylpropylamine oxalate melted at 150°-152° C. The NMR spectrum of the compound was consistent with the expected structure.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:14]=[C:13]2[CH2:15][CH2:16][CH2:17][CH2:18][C:12]2=[C:11]2[C:7]=1[C:8]([C:27](=[O:31])[C:28]([NH2:30])=[O:29])=[C:9]([CH3:26])[N:10]2[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-].[Li+]>CO.O>[NH2:30][C:28](=[O:29])[C:27]([C:8]1[C:7]2[C:11](=[C:12]3[CH2:18][CH2:17][CH2:16][CH2:15][C:13]3=[CH:14][C:6]=2[O:5][CH2:4][C:3]([OH:32])=[O:2])[N:10]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]=1[CH3:26])=[O:31]
Reactant: COC(=O)COc1cc2c(c3c1c(C(=O)C(N)=O)c(C)n3Cc1ccccc1)CCCC2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cc3c(c2n1Cc1ccccc1)CCCC3
Yield: 95.7 %

Procedure:
A solution of 2-[[3-(2-amino-1,2-dioxoethyl)-1-benzyl-2-methyl-6,7,8,9-tetrahydro-1H-benz[g]indol-4-yl]oxy]acetic acid methyl ester (285 mg, 0.671 mmol) in methanol (5 ml) was treated with 1 M lithium hydroxide solution (2.5 mL) at room temperature for 1.5 h. The reaction mixture was diluted with water, concentrated in vacuo, and treated with 1 M hydrochloric acid (1 mL). The resulting precipitate was collected via vacuum filtration and dried to provide 270 mg (96%) of the title compound as a tan powder: mp>300° C. 1H NMR (DMSO-d6) δ 8.00 (bs, 1H), 7.35 (m, 3H), 7.26 (t, J=7.0 Hz, 1H), 6.88 (d, J=7.3 Hz, 2H), 6.21 (s, 1H), 5.64 (s, 2H), 4.38 (s, 2H), 2.88 (m, 2H), 2.71 (m, 2H), 2.35 (s, 3H), 1.60 (m, 4H); MS ES+ m/e 421 (p+1); IR (KBr, cm−1) 1636, 1402.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]12[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]1)[CH2:15][N:14]1[C:21](=[O:31])[C:22]([OH:30])=[C:23]([C:25](OCC)=[O:26])[N:24]=[C:13]21)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][NH2:40])=[CH:35][CH:34]=1.CCN(CC)CC>C(O)C>[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][NH:40][C:25]([C:23]2[N:24]=[C:13]3[C:12]4([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20]4)[CH2:15][N:14]3[C:21](=[O:31])[C:22]=2[OH:30])=[O:26])=[CH:35][CH:34]=1
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CC1CCC2(NC(=O)OCc2ccccc2)CC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(NC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O)OCc1ccccc1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A mixture of ethyl 10-(((benzyloxy)carbonyl)amino)-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylate (5.00 g, 11.70 mmol), (4-fluorophenyl)methanamine (2.67 mL, 23.39 mmol) and Et3N (3.26 mL, 23.39 mmol) in ethanol (78 mL) was stirred at 90° C. for 16 h, cooled and concentrated. The resulting pale yellow foam was dissolved in ethyl acetate and washed with 1N HCl. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was taken up in hot ethyl acetate and hexane was added until the solution became slightly cloudy. After cooling, the title compound was collected by filtration as a white solid (4.8203 g, 81% yield). 1H NMR (500 MHz, DMSO-D6) δ: 10.25 (s, 1H), 7.52 (s, 1H), 7.34-7.40 (m, 8H), 7.15-7.21 (m, 2H), 5.72 (s, 1H), 4.91 (s, 2H), 4.40 (d, 2H, J=6.4 Hz), 4.15 (s, 2H), 2.48-2.52 9 m, 2H), 2.02-2.08 (m, 2H), 1.94-1.98 (m, 2H), 1.63-1.70 (m, 2H). LCMS (M+H)=507.42.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:15][CH:14]3[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:11]([CH2:12][CH2:13]3)[CH:10]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:5][CH:4]=1.[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH2:36]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:15][CH:14]3[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:11]([CH2:12][CH2:13]3)[CH:10]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:5][CH:4]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C2CCC1C(OCc1ccc3ccccc3c1)C(c1ccc(CO)cc1)C2
Product: CC(C)(C)OC(=O)N1C2CCC1C(OCc1ccc3ccccc3c1)C(c1ccc(COCc3ccccc3)cc1)C2

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (1RS,2RS,3RS,5SR)-3-(4-hydroxymethyl-phenyl)-2-(naphthalen-2-ylmethoxy)-8-aza-bicyclo[3.2.1]octane-8-carboxylate [Example 86 (eee)] with benzyl bromide there was obtained tert-butyl (1RS,2RS,3RS,5SR)-3-(4-benzyloxymethyl-phenyl)-2-(naphthalen-2-ylmethoxy)-8-aza-bicyclo[3.2.1]octane-8-carboxylate, which was used as the crude product in the reaction for BOC cleavage.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][N:21]1[C:25]([CH3:26])=[C:24]([C:27]([OH:29])=O)[C:23]([CH3:30])=[N:22]1.ClN1C(=O)CCC1=O.[CH:39]1([CH2:42][N:43]2[C:51]3[N:50]=[C:49]([CH2:52][C:53]4[CH:58]=[CH:57][C:56]([NH:59][CH2:60][CH3:61])=[CH:55][CH:54]=4)[NH:48][C:47]=3[C:46](=[O:62])[N:45]([CH2:63][C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=3[F:70])[C:44]2=[O:71])[CH2:41][CH2:40]1.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[CH:39]1([CH2:42][N:43]2[C:51]3[N:50]=[C:49]([CH2:52][C:53]4[CH:54]=[CH:55][C:56]([N:59]([CH2:60][CH3:61])[C:27]([C:24]5[C:23]([CH3:30])=[N:22][N:21]([CH3:20])[C:25]=5[CH3:26])=[O:29])=[CH:57][CH:58]=4)[NH:48][C:47]=3[C:46](=[O:62])[N:45]([CH2:63][C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=3[F:70])[C:44]2=[O:71])[CH2:41][CH2:40]1
Reactant: CCNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Reactant: Cc1nn(C)c(C)c1C(=O)O
Agent: CN(C)c1ccncc1
Agent: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(C(=O)c1c(C)nn(C)c1C)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
A suspension of triphenylphosphine (59.3 mg, 0.226 mmol) and 1,3,5-trimethyl-1H-pyrazole-4-carboxylic acid (SALOR) (26.8 mg, 0.174 mmol) in dichloromethane was cooled to 0° C. and N-chlorosuccinimide added. The mixture was stirred at 0° C. for 0.5 h then ambient temperature for an additional 0.5 h. 3-Cyclopropylmethyl-8-[4-(ethyl-amino)-benzyl]-1-(2-fluorobenzyl)-3,7-dihydro-purine-2,6-dione (93.4 mg, 0.209 mmol) was added followed by triethylamine (30.2 mg, 0.226 mmol) and 4-dimethylaminopyridine (a few crystals). The reaction was left to stir at ambient temperature overnight before washing with 1M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, drying the organic extract (sodium sulfate) and concentrating in vacuo. Purification by chromatography using silica eluted with 5:9 methanol/dichloromethane gave the product as a colorless solid (83.5 mg, 69%). MS, m/z(M+H)=584.2787.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:22])=O)=[CH:16][CH:15]=1)[C:6]([C:23](=[O:26])[CH2:24][CH3:25])=[C:5]2[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.BrC[O:35][C:36](=[O:38])[CH3:37]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20][CH2:22][O:38][C:36](=[O:35])[CH3:37])=[CH:16][CH:15]=1)[C:6]([C:23](=[O:26])[CH2:24][CH3:25])=[C:5]2[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(=O)OCBr
Reactant: CCC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(C)=O)cc1
Product: CCC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(SCOC(C)=O)cc1
Yield: 69 %

Procedure:
In the same manner as in Example 552, the title compound (190 mg, 69%) was obtained from 6-bromo-2-(4-methanesulfinylbenzyl)-4-phenyl-3-propionyl-2H-isoquinolin-1-one and acetic acid bromomethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C:22](OCC)=[O:23])[N:12]([CH3:21])[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.[CH:27]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([NH:33][C:22]([C:11]2[N:12]([CH3:21])[C:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:10]=2)=[O:23])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)n1C
Reactant: NC1CCCCC1
Product: Cn1c(C(=O)NC2CCCCC2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 90 °C

Procedure:
A mixture of ethyl 4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1-methylimidazole-2-carboxylate (20 mg, 0.05 mmol) from Step A in neat cyclohexylamine (2 mL) was heated at 90° C. for 72 hr. Most of the amine was evaporated under a stream of nitrogen and the residue was purified by Prep TLC (1 mm, silica) (25% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: C(O[CH:4]=[C:5]([CH3:12])[C:6](=O)[C:7]([F:10])([F:9])[F:8])C.O.[NH2:14][NH2:15]>C(O)C>[CH3:12][C:5]1[C:6]([C:7]([F:10])([F:9])[F:8])=[N:14][NH:15][CH:4]=1
Reactant: NN
Reactant: CCOC=C(C)C(=O)C(F)(F)F
Solvent: CCO
Solvent: O
Product: Cc1c[nH]nc1C(F)(F)F
Yield: 84.9 %

Procedure:
1.7 g (10.2 mmol) of 4-ethoxy-3-methyl-1,1,1-trifluoro-3-buten-2-on and 0.6 g (12.0 mmol) hydrazine hydrate were stirred in 50 ml of ethanol at room temperature for 2 hours. The ethanol was distilled off under reduced pressure, and the residue was separated with ethyl acetate and water. The organic layer was washed with water twice and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1.3 g of 4-methyl-3-trifluoromethylpyrazol (yield 86.7%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH2:9][OH:10])=[C:4]([F:11])[CH:3]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14]>C(Cl)Cl>[CH3:12][S:13]([O:10][CH2:9][C:5]1[C:4]([F:11])=[CH:3][C:2]([Br:1])=[CH:7][C:6]=1[F:8])(=[O:15])=[O:14]
Reactant: OCc1c(F)cc(Br)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)OCc1c(F)cc(Br)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (4-bromo-2,6-difluorophenyl)methanol (24.8 g, 112.1 mmol) in CH2Cl2 (400 mL) was added TEA (22.68 g, 224.28 mmol) and methylsulfonyl chloride (12.84 mL, 156.9 mmol) at 0° C. The reaction was stirred at 0° C. for 1 h, quenched with aqueous NH4Cl, and diluted with EtOAc. The organic layer was washed with 1N HCl (2×), H2O, brine, dried over MgSO4, and condensed to give the desired compound.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].Cl[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:16][C:15]1[C:10]([N:6]2[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]2)=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: Clc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccn(-c2ncccc2Cl)n1
Temperature: 125 °C
Reaction time: 18 h
Yield: 91.2 %

Procedure:
10.0 g (88.4 mmol) of 3-nitropyrazole and 14.4 g (97.2 mmol) of 2,3-dichloropyridine were initially charged in 50 ml of dimethylformamide, 23.9 g (173 mmol) of potassium carbonate were added and the reaction mixture was stirred at 125° C. for 18 hours. After cooling, the mixture was poured into water and the precipitated solid was filtered off. Recrystallization from isopropanol/water gave 18.1 g (90% of theory) of 3-chloro-2-(3-nitro-1H-pyrazol-1-yl)pyridine (log P: 1.83; MH+: 225.1; 1H-NMR (400 MHz, CD3CN, δ, ppm): 7.15 (s, 1H), 7.56 (d, 1H), 8.15 (d, 1H), 8.23 (d, 1H), 8.53 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)([CH3:4])([CH3:3])[CH3:2].[C:13]([NH:23][C:24]([CH3:29])([C:26](O)=[O:27])[CH3:25])([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[C:1]([O:5][C:6]([CH:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:26](=[O:27])[C:24]([NH:23][C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])([CH3:29])[CH3:25])=[O:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)C1CCCN1C(=O)C(C)(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
To a solution of proline-tert-butyl ester (47) (2.00 g, 12 mmol, in CH2Cl2 (15 ml) was added N-carbobenzyloxy-2-methylalanine (3.05 g, 13 mmol), HOBT (2.36 g, 17 mmol) and EDC (3.43 g, 18 mmol) and the solution was stirred at room temperature under N2 for 48 hours. The solvent was evaporated, the crude material dissolved in EtOAc and washed with 0.5N NaHSO4 (2×), saturated NaHCO3 (2×) and brine and was dried over anhydrous Na2SO4, filtered and evaporated to give a white solid (4.68 g, 100%). 1H-NMR (500 MHz, CDCl3) δ 1.20-2.15 (m, 4H), 1.43 (s, 9H), 1.59 (d, 6H), 3.21-3.79 (m, 2H), 4.35 (br s, 1H), 4.82-5.19 (m, 3H), 5.74 (br s, 1H), 7.17-7.49 (m, 5H). Analytical HPLC (C18 column) 10.66 min. LC-MS (ES+) m/e=391.3 (M+H).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Cl:26])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[N+:27]([O-])([O-:29])=[O:28].[K+]>S(=O)(=O)(O)O>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Cl:26])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][C:23]([N+:27]([O-:29])=[O:28])=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Cl)c2ccc(Oc3ccccc3)cc2c1O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCCCOC(=O)c1nc(Cl)c2ccc(Oc3ccc([N+](=O)[O-])cc3)cc2c1O
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 45.9 %

Procedure:
200 mg of 1-Chloro-4-hydroxy-6-phenoxy-isoquinoline-3-carboxylic acid butyl ester, Example D-10a, was dissolved in 3 ml of concentrated sulfuric acid. The reaction mixture was cooled to −20° C. and 60 mg of potassium nitrate was added slowly to the stirring solution. The reaction was kept between −10 to −20° C. while stirring for 15 min, and poured into ice-water. The aqueous mixture was extracted twice with ethyl acetate. The organic fractions were washed successively with saturated bicarbonate and brine solutions, dried over anhydrous magnesium sulfate, and concentrated to a residue under reduced pressure. The resultant solid was triturated with ethyl acetate followed by methanol to produce 103 mg of white solid; MS (+): m/z 417.07 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH:10]1([C:13]2[NH:17][N:16]=[C:15]([NH2:18])[CH:14]=2)[CH2:12][CH2:11]1.C(N(C(C)C)CC)(C)C>C(O)CCC>[Cl:1][C:2]1[N:3]=[C:4]([NH:18][C:15]2[CH:14]=[C:13]([CH:10]3[CH2:12][CH2:11]3)[NH:17][N:16]=2)[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: Nc1cc(C2CC2)[nH]n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cc(Nc2cc(C3CC3)[nH]n2)nc(Cl)n1
Temperature: 80 °C
Yield: 92.4 %

Procedure:
A mixture of 2,4,6-trichloropyrimidine (30 g, 163 mmol), 5-cyclopropyl-1H-pyrazol-3-ylamine (20 g, 163 mmol), diisopropylethylamine (50 mL, 300 mmol) and 1-butanol (100 mL) was heated to 80° C. for 2 h. The solvents were removed on a rotary evaporator and the residue was taken up in ethyl acetate. The organic solution was washed with water and brine and dried over magnesium sulfate. The residue was concentrated on a rotary evaporator to give the desired product (40.7 g, 92%) as a light yellow solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([O:12][CH:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[C:10]=2[N:11]=1.[Cl:20][C:21]1[C:26]([NH:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[F:38])(=[O:30])=[O:29])=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][N:22]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[Cl:20][C:21]1[C:26]([NH:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[F:38])(=[O:30])=[O:29])=[CH:25][C:24]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]=[CH:7][N:8]=[C:9]([O:12][CH:13]4[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]4)[C:10]=3[N:11]=2)=[CH:23][N:22]=1
Reactant: CN1CCC(Oc2ncnc3ccc(Cl)nc23)CC1
Reactant: CC1(C)OB(c2cnc(Cl)c(NS(=O)(=O)c3ccc(F)cc3F)c2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CN1CCC(Oc2ncnc3ccc(-c4cnc(Cl)c(NS(=O)(=O)c5ccc(F)cc5F)c4)nc23)CC1
Temperature: 25 °C
Yield: 33.9 %

Procedure:
A mixture of 6-chloro-4-(1-methylpiperidin-4-yloxy)pyrido[3,2-d]pyrimidine (Intermediate 6) (0.03 g, 0.108 mmol), N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide (Intermediate 3) (0.046 g, 0.108 mmol), PdCl2(dppf)-CH2Cl2Adduct (8.79 mg, 10.76 μmol) and sodium bicarbonate (0.215 ml, 0.215 mmol) in dioxane (0.538 ml) was refluxed for 3 hours. After cooling to room temperature, the reaction mixture was filtered through a Celite pad and washed with CH2Cl2. The filtrate was concentrated in vacuo. The residue was purified by prep TLC (EtOAc:MeOH=10:1) to give N-(2-chloro-5-(4-(1-methylpiperidin-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzene-sulfonamide (0.02 g, 34%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 2.10-2.22 (2H, m), 2.37 (2H, s), 2.62 (3H, s), 2.88-2.95 (2H, m), 3.13-3.17 (2H, m), 5.64 (1H, brs), 6.86-6.94 (2H, m), 7.86-7.92 (1H, m), 8.21 (1H, d, J=9.2 Hz), 8.34 (1H, d, J=8.8 Hz), 8.79 (1H, d, J=2.0 Hz), 8.82 (1H, s), 8.91 (1H, brs). m/z=547.4 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][CH2:11][C:12]#[N:13])=[CH:5][CH:4]=1.[N:14](OC)=[O:15]>CO>[OH:15][N:14]=[C:11]([CH:10]=[CH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:12]#[N:13]
Reactant: COc1ccc(C=CCC#N)cc1
Reactant: CON=O
Solvent: CO
Product: COc1ccc(C=CC(C#N)=NO)cc1
Reaction time: 8 h
Yield: 35606.7 %

Procedure:
4-(4-Methoxy-phenyl)-but-3-enenitrile (5.0 g; 0.025 mmol) dissolved in 90 ml of methanol is treated with ca 0.050 mol of gaseous methyl nitrite in the same way as described in example 2.2. After stirring overnight at ca 25° C., the reaction mixture is rotary evaporated and partitioned between 200 ml of 0.5 N HCl and 200 ml ethyl acetate. The aqueous phase is extracted with 50 ml of ethyl acetate. The combined organic extracts are evaporated and purified by flash chromatography (150 g SiO2; hexane:ethyl acetate 80:20 v:v); to yield 2-hydroxyimino-4-(4-methoxy-phenyl)-but-3-enenitrile 1.8 g (36%) as a yellow solid which is used for the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[C:4]([N:14]2[CH:18]=[CH:17][C:16]([CH3:19])=[N:15]2)[CH:3]=1.[NH2:20][C:21]1[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][C@H:34]([NH:38]C(OC(C)(C)C)=O)[C:35]([OH:37])=[O:36])=[CH:29][CH:28]=2)[CH:24]=[C:23](Cl)[N:22]=1.O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[NH2:38][C@@H:34]([CH2:33][C:30]1[CH:31]=[CH:32][C:27]([C:25]2[CH:24]=[C:23]([O:13][C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[N:14]3[CH:18]=[CH:17][C:16]([CH3:19])=[N:15]3)[C:9]([F:12])([F:11])[F:10])[N:22]=[C:21]([NH2:20])[N:26]=2)=[CH:28][CH:29]=1)[C:35]([OH:37])=[O:36]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(Cl)nc(N)n2)cc1)C(=O)O
Reactant: Cc1ccn(-c2cc(Cl)ccc2C(O)C(F)(F)F)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(-c3ccc(C[C@H](N)C(=O)O)cc3)nc(N)n2)C(F)(F)F)n1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
1-[4-Chloro-2-(3-methyl-pyrazol-1-yl)-phenyl]-2,2,2-trifluoro-ethanol (0.120 g, 0.41 mmol), (S)-3-[4-(2-amino-6-chloro-pyrimidine-4-yl)-phenyl]-2-tert-butoxycarbonylamino-propionic acid (0.176 g, 0.45 mmol), 1,4-dioxane (4 ml), and Cs2CO3 (0.533 g, 1.64 mmol) were combined in a 20 ml sealed tube, and the mixture was heated at 100° C. for 12 hours. The mixture was concentrated. To the residue, 10% methanol in DCM (50 ml) was added and the mixture was filtered. The filtrate was concentrated to give a crude product, which was taken in THF/3N HCl (30 ml/15 ml) and the resulting mixture was stirred at 40-45° C. for 12 hours. LCMS indicated the completion of reaction with desired product. The mixture was concentrated to give a crude product, which was dissolved in MeOH and H2O (1:1) and purified by preparative HPLC using MeOH/H2O/TFA as solvent system to give (S)-2-amino-3-[4-(2-amino-6-{1-[4-chloro-2-(3-methyl-pyrazol-1-yl)-phenyl]-2,2,2-trifluoro-ethoxy}-pyrimidine-4-yl)-phenyl]-propionic acid as a TFA salt. LCMS: M+1=547. 1H-NMR (400 MHz, CD3OD): δ (ppm) 2.30 (s, 3H), 3.10-3.30 (m, 2H), 4.20 (t, 1H), 6.32 (d, 1H), 6.74 (s, 1H), 7.0 (q, 1H), 7.38 (d, 2H), 7.50 (m, 2H), 7.72 (m, 1H), 7.90 (m, 3H).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:8]=2)[CH:6]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[C:30]=1[OH:37].B(O)O>O1CCOCC1.CC(N(C)C)=O>[CH3:36][O:35][C:31]1[CH:32]=[C:33]([C:6]2[N:5]([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[N:8]=3)[CH:4]=[N:3][CH:2]=2)[CH:34]=[C:29]([O:28][CH3:27])[C:30]=1[OH:37]
Reactant: Brc1cn(-c2ccnc(N3CCOCC3)n2)cn1
Reactant: COc1cccc(OC)c1O
Agent: O=P([O-])([O-])[O-]
Agent: OBO
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: C1COCCO1
Product: COc1cc(-c2cncn2-c2ccnc(N3CCOCC3)n2)cc(OC)c1O
Temperature: 170 °C
Yield: 96.3 %

Procedure:
To a solution of 4-[4-(4-Bromo-imidazol-1-yl)-pyrimidin-2-yl]-morpholine (0.20 g, 0.65 mmol) in anhydrous dioxane (6 ml) and anhydrous DMA (0.6 m) was added tripotassium phosphate (0.28 g, 1.3 mmol) and 2,6-dimethoxy-phenol-boronic acid (0.18 g, 0.91 mmol). The resultant mixture was degassed with sonication for 10 minutes before the addition of bis(tri-butylphospine)palladium (0.017 g, 0.033 mmol) and degassing for a further 5 minutes. The reaction vessel was sealed and heated under the influence of microwave radiation (170° C., 11 min, low absorption setting). Upon completion, the reaction was filtered through a thin silica plug which was then washed with 10% methanol/CH2Cl2. The filtrate was concentrated in vacuo and the crude residue purified by flash chromatography (SiO2) (1:1—EtOAc:Hexanes) to give the desired product (0.24 g, 96%) as a white crystalline solid in analytically pure form. m/z (LC-MSW, ESP):384.4 [M+H]+, R/T=2.90 mins.