Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[N:8]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.CC([O-])(C)C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.[Cl-].[Na+].O.CC([O-])=O.CC([O-])=O.[Pd+2].O>[N:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:10][CH2:9][N:8]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13][CH2:12]2)=[CH:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Brc1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccncc2)CC1
Yield: 47 %

Procedure:
To a degassed solution of 4-bromopyridine (1 equiv.), tert-butyl piperazine-1-carboxylate (16 mmol, 1.2 equiv.) and NaOtBu (3.4 equiv.) in toluene were added Pd(OAc)2 (2 mol %) and BINAP (1 mol %) and the resulting solution was refluxed for 3 h. The reaction mixture was cooled, diluted with ethyl acetate and given water and brine washes respectively. The organic layer was dried over sodium sulfate, the solvent removed in vacuo and the crude product purified by column chromatography (silica). Yield: 47%.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([Cl:21])=[CH:16][C:15]=1[NH2:22].O>C1COCC1>[Cl:20][C:18]1[C:17]([Cl:21])=[CH:16][C:15]2[NH:22][C:1](=[O:2])[NH:13][C:14]=2[CH:19]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]c2cc(Cl)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.49 g (33.9 mmol) of 1,1′-carbonyldiimidazole were added in portions to a stirred solution of 5.00 g (28.2 mmol) of 1,2-diamino-4,5-dichlorobenzene in THF (100 ml) at room temperature. The reaction solution was then stirred at room temperature overnight. The reaction mixture was mixed with water (60 ml) and cooled in an ice bath. The precipitate which separated out was filtered, washed with water and dried in vacuo.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[CH:13][CH:12]=[C:11]2[CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[C:6]([CH3:27])[CH:5]=1)(=[O:3])[NH2:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][C:36]([NH2:38])=[O:37].Cl>O.CN(C)C=O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[CH:13][CH:12]=[C:11]2[CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[C:6]([CH3:27])[CH:5]=1)(=[O:3])[NH2:2].[NH2:38][C:36](=[O:37])[CH2:35][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[N:10]([C:7]3[CH:8]=[CH:9][C:4]([C:1](=[O:3])[NH2:2])=[CH:5][C:6]=3[CH3:27])[C:11]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:12][CH:13]=2)=[CH:16][CH:17]=1
Reactant: NC(=O)CBr
Agent: Cc1cc(C(N)=O)ccc1-n1c(CCC(=O)O)ccc1-c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C(N)=O)ccc1-n1c(CCC(=O)O)ccc1-c1ccc(OCC(N)=O)cc1
Yield: 61.7 %

Procedure:
3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-hydroxyphenyl)-1H-pyrrol-2-yl)propanoic acid (7A, R1=4-carbamoyl-2-methylphenyl) was prepared according to the methodology shown in Scheme 1, R2=4-hydroxyphenyl, R1=4-carbamoyl-2-methylphenyl. A N,N-dimethylformamide solution of 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-hydroxyphenyl)-1H-pyrrol-2-yl)propanoic acid (36 mg, 0.1 mmol, 1 ml), potassium carbonate (27 mg, 0.2 mmol) and 2-bromoacetamide (18 mg, 0.12 mmol) was stirred for 18 hrs at ambient temperature, after which time the reaction was diluted with water and the pH adjusted to 2 with 1 M HCl. The aqueous layer was extracted with EtOAc (3×3 mL), dried over N2SO4, filtered and concentrated in vacuo. The residue thus obtained was triturated with hexanes and dried under high vacuum to yield the title compound as a light yellow powder (13 mg).
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([N+:31]([O-])=O)[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[C:9]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([CH:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[CH2:16][CH2:15]2)=[O:13])[N:8]=[CH:7][N:6]=1>O1CCCC1.[OH-].[Pd+2].[OH-].[C]>[NH2:31][C:29]1[CH:28]=[CH:27][C:3]([O:4][C:5]2[CH:10]=[C:9]([NH:11][C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH:20]4[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]4)[CH2:16][CH2:15]3)=[O:13])[N:8]=[CH:7][N:6]=2)=[C:2]([F:1])[CH:30]=1
Reactant: CN1CCC(N2CCN(C(=O)Nc3cc(Oc4ccc([N+](=O)[O-])cc4F)ncn3)CC2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1CCC(N2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4F)ncn3)CC2)CC1
Reaction time: 8 h
Yield: 98.9 %

Procedure:
4-(2-Fluoro-4-nitrophenoxy)-6-{[4-(1-methylpiperidin-4-yl)piperazin-1-yl]carbonylamino}pyrimidine (145 mg) was dissolved in tetrahydrofuran (20 ml). After adding 20% palladium hydroxide-carbon (100 mg), the mixture was stirred overnight under a hydrogen atmosphere. The catalyst was filtered and washed with tetrahydrofuran. The filtrate and the washings were combined and concentrated under reduced pressure, and the resultant residue was dried under reduced pressure to provide the title compound (134 mg, 99%) as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:5][C:6]([CH:8]([NH:17][CH:18]1[CH2:24][S:23][CH:22]([C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)[CH2:21][N:20]([CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])[C:19]1=[O:38])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([O:5][C:6]([CH:8]([NH:17][CH:18]1[CH2:24][S:23][CH:22]([C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)[CH2:21][N:20]([CH2:30][C:31]([OH:33])=[O:32])[C:19]1=[O:38])[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)C(CCc1ccccc1)NC1CSC(c2ccsc2)CN(CC(=O)OC(C)(C)C)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCOC(=O)C(CCc1ccccc1)NC1CSC(c2ccsc2)CN(CC(=O)O)C1=O

Procedure:
130 mg of isomer B of t-butyl α-[6-(1-butoxycarbonyl-3-phenylpropylamino)-5-oxo-2-(3-thienyl)perhydro-1,4-thiazepin-4-yl]acetate (prepared as described in Example 45 above) were treated with trifluoroacetic acid by the same procedure as is described in Example 43 to remove the t-butyl group and give the title compound as a crystalline powder, melting at 156° C., in a yield of 70 mg.
Reaction SMILES: C[O:2][C:3](=[O:41])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=3)[C@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[F:35])([C:26]#[N:27])[C@H:15]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[NH:14]2)=[O:12])=[CH:6][CH:5]=1.[OH-].[Na+].CO.Cl>O1CCCC1>[Cl:25][C:20]1[CH:19]=[C:18]([C@@H:17]2[C@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[F:35])([C:26]#[N:27])[C@H:15]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[NH:14][C@H:13]2[C:11]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:41])=[O:2])=[CH:9][CH:8]=2)=[O:12])[CH:23]=[CH:22][C:21]=1[F:24]
Reactant: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2ccc(F)c(Cl)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)O)cc2)[C@H](c2ccc(F)c(Cl)c2)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 80 °C
Yield: 94.7 %

Procedure:
To a solution of rac-4-{[(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid methyl ester prepared in Example 338 (0.11 g, 0.18 mmol) in tetrahydrofuran (9 mL) was added an aqueous solution (1 N) of NaOH (9 mL, 9 mmol) and methanol (3 mL). The reaction mixture was heated at 80° C. for 2 h, and the “pH” of the solution was adjusted to 5 by aqueous HCl solution. The mixture was extracted ethyl acetate twice. The combined organic extracts were washed with water, brine, dried over MgSO4, and concentrated to give rac-4-{[(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid as a white solid (0.1 g, 94%).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:23]1(N)CCCCC[CH2:24]1>>[CH:1]1([NH:6][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2][CH2:24][CH2:23]1
Reactant: NC1CCCCCC1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Product: Cc1nc(NCc2ccccn2)nc(NC2CCCCCC2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using 1-cycloheptylamine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.26-1.32 (m, 2H), 1.38-1.50 (m, 8H), 1.68 (bs, 2H), 1.81 (s, 3H), 2.07 (s, 3H), 3.80-3.88 (m, 1H), 4.49 (d, J=9.91, 2H), 5.70 (d, J=7.25, H), 6.63 (brs, 1H), 7.15-7.20 (m, 1H), 7.21-7.28 (m, 1H), 7.68 (t, J=7.25, 1H), 8.46 (bs, 1H); MS (ESI) m/z 326.9 (M+1)+.
Reaction SMILES: [Li]CCCC.[CH3:6][S:7][C:8]1[CH:12]=[CH:11][S:10][CH:9]=1.Cl[Si:14]([CH3:17])([CH3:16])[CH3:15]>CCOCC>[CH3:15][Si:14]([CH3:17])([CH3:16])[C:9]1[S:10][CH:11]=[CH:12][C:8]=1[S:7][CH3:6]
Reactant: C[Si](C)(C)Cl
Reactant: CSc1ccsc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CSc1ccsc1[Si](C)(C)C
Temperature: -70 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
A solution of n-BuLi (5.3 mL of 1.6 M in hexanes, 8.5 mmol) is added dropwise to a solution of 3-methylsulfanylthiophene (1.0 g, 7.7 mmol) in anhydrous Et2O(8 mL) under nitrogen at −70° C. The mixture is stirred at −70° C. for 2 hr. Chlorotrimethylsilane (1.5 mL) is added slowly to the reaction mixture. The mixture is warmed to room temperature and stirred for 3 hr. The reaction is quenched with water (50 mL) and Et2O (50 mL). The aqueous layer is extracted with Et2O (50 mL). The combined organic extracts are dried (Na2SO4), filtered and concentrated. The crude product is chromatographed on silica gel, eluting with hexanes to afford the title compound (0.75 g, 48%) as a colorless liquid.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[N+:4]([C:7]1[CH:14]=[CH:13][C:10]([CH2:11]Cl)=[CH:9][CH:8]=1)([O-:6])=[O:5]>C(O)C>[CH3:1][N:2]([CH2:11][C:10]1[CH:13]=[CH:14][C:7]([N+:4]([O-:6])=[O:5])=[CH:8][CH:9]=1)[CH3:3]
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: CNC
Solvent: CCO
Product: CN(C)Cc1ccc([N+](=O)[O-])cc1
Reaction time: 10 h

Procedure:
To 3 l of ethanol was added 750 ml of a 40% aqueous solution of dimethylamine and 500 g. of p-nitrobenzyl chloride was added gradually thereto with stirring. After complete dissolution, the reaction was carried out at 40° C. for 10 hours. After the reaction mixture was concentrated by distilling off the ethanol, the residue was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated by distilling off the ethyl acetate. The residue thus obtained was distilled under reduced pressure to give a yellow liquid which was the desired product boiling at 102° to 104° C./2 mmHg.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH2:51][OH:52])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-:54].[Na+].[Br-].[K+].Cl[O-].[Na+].Cl>O1CCCC1>[CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([C:51]([OH:54])=[O:52])[CH2:11][O:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1F
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C(=O)O)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1F
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 117.6 %

Procedure:
To a solution of [(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl) methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-yl]methanol 20a (1.0 g, 1.38 mmol, purchased from Shanghai Caerulum Pharma Discovery Co., Ltd.) in tetrahydrofuran (20 mL) were added saturated aqueous sodium bicarbonate (20 mL), potassium bromide (33 mg, 0.28 mmol) and 2,2,6,6-tetramethylpiperidinooxy (22 mg, 0.14 mmol) in turn at 0° C., and then sodium hypochlorite (18 mL, available chlorine ≧5.5%) was added dropwise over a period of 20 min. The mixture was stirred at 0° C. for 40 min and acidified with aqueous HCl (1 N) till pH becomes 4. The resulting mixture was extracted with ethyl acetate (30 mL×2). The combined organic layers were washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 20b (1.20 g, 117.6%) as yellow oil. This material was not further purified.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH3:28])[S:16]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1[N:36]=[C:37]([NH2:40])[S:38][CH:39]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH3:28])[S:16]([C:19]2[CH:20]=[CH:21][C:22]([C:23]([NH:40][C:37]3[S:38][CH:39]=[C:35]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=4)[N:36]=3)=[O:24])=[CH:26][CH:27]=2)(=[O:18])=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nc(-c2ccccn2)cs1
Reactant: CN(c1ccc(OCc2ccccc2)cc1)S(=O)(=O)c1ccc(C(=O)O)cc1
Product: CN(c1ccc(OCc2ccccc2)cc1)S(=O)(=O)c1ccc(C(=O)Nc2nc(-c3ccccn3)cs2)cc1

Procedure:
4-(N-(4-(benzyloxy)phenyl)sulfamoyl)benzoic acid (15) (493 mg, 1.24 mmol) was treated with 4-(pyridin-2-yl)thiazol-2-amine (200 mg, 1.13 mmol) using method C. The residue was purified using flash chromatography eluting with 0-8% MeOH in dichloromethane. The resulting solid was triturated with diethyl ether to give 4-(N-(4-(benzyloxy)phenyl)-N-methylsulfamoyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide as an off white solid. Yield: 289 mg (46%). 1H-NMR: 8.62 (d, J=5.0 Hz, 1H), 8.29 (d, J=8.5 Hz, 2H), 8.02 (d, J=8.0 Hz, 1H), 7.94-7.88 (m, 2H), 7.67 (d, J=8.5 Hz, 2H), 7.46-7.31 (m, 6H), 7.04-6.96 (m, 4H), 5.10 (s, 2H), 3.16 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]([CH2:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19])[C:9]2=[O:14])([O-])=O.C(O)C>[Pd]>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]([CH2:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19])[C:9]2=[O:14]
Reactant: CC(=O)NCCn1ccc2c([N+](=O)[O-])cccc2c1=O
Agent: [Pd]
Solvent: CCO
Product: CC(=O)NCCn1ccc2c(N)cccc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a round bottom flask was combined N-(2-(5-nitro-1-oxoisoquinolin-2(1H)-yl)ethyl)acetamide (3.27 g, 0.0119 mol), palladium on C (1.6 g, 0.015 mol) and ethanol (250 mL, 4.2 mol). The reaction mixture was stirred under hydrogen at room temperature overnight. The mixture was filtered over celite, volatiles were removed under vacuum producing the title compound as a yellow solid. The compound was taken to the next step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:16]=[C:10]3[CH:11]=[CH:12][C:13]([NH2:15])=[CH:14][N:9]3[N:8]=2)[CH:2]=1.[CH2:17]([O:19][C:20]([C:22]1[CH:23]=[N:24][N:25]([CH3:30])[C:26]=1[C:27](O)=[O:28])=[O:21])[CH3:18].CCCP(=O)=O.C(OCC)(=O)C.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH2:17]([O:19][C:20]([C:22]1[CH:23]=[N:24][N:25]([CH3:30])[C:26]=1[C:27](=[O:28])[NH:15][C:13]1[CH:12]=[CH:11][C:10]2[N:9]([N:8]=[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[N:16]=2)[CH:14]=1)=[O:21])[CH3:18]
Reactant: CCOC(=O)c1cnn(C)c1C(=O)O
Reactant: Nc1ccc2nc(-c3cccnc3)nn2c1
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccc2nc(-c3cccnc3)nn2c1
Temperature: 70 °C
Reaction time: 18 h
Yield: 92.9 %

Procedure:
A mixture of 2-(pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-ylamine (480 mg, 2.27 mmol), 4-(ethoxycarbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (495 mg, 2.5 mmol), propylphosphonic anhydride in ethyl acetate 50% (3.62 g, 3.35 ml, 5.68 mmol) and N,N-diisopropylethylamine (1.17 g, 1.55 ml, 9.09 mmol) in tetrahydrofuran (10 ml) was stirred for 18 hours at 70° C. The solvent was evaporated under reduced pressure, the residue was triturated with saturated aqueous sodium hydrogencarbonate. The precipitated solid was filtered off, washed with water and dried in vacuo, affording 1-methyl-5-(2-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid ethyl ester (825 mg, 93%) as light brown solid. Mp.: 217° C. MS: m/z=392.1 (M+H+).
Reaction SMILES: [P:1]([O:19][CH2:20][C@H:21]([C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[C:44]([F:49])[CH:43]=1)[N:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][N:31]=[C:30]([NH:34][CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[N:29]=2)=[CH:24][C:23]1=[O:41])([O:11]CC1C=CC=CC=1)([O:3]CC1C=CC=CC=1)=[O:2]>[Pd].CO>[P:1]([OH:3])([OH:11])([O:19][CH2:20][C@H:21]([C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[C:44]([F:49])[CH:43]=1)[N:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][N:31]=[C:30]([NH:34][CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[N:29]=2)=[CH:24][C:23]1=[O:41])=[O:2]
Reactant: O=c1cc(-c2ccnc(NC3CCOCC3)n2)ccn1[C@H](COP(=O)(OCc1ccccc1)OCc1ccccc1)c1ccc(Cl)c(F)c1
Agent: [Pd]
Solvent: CO
Product: O=c1cc(-c2ccnc(NC3CCOCC3)n2)ccn1[C@H](COP(=O)(O)O)c1ccc(Cl)c(F)c1
Reaction time: 8 h
Yield: 0.5 %

Procedure:
5% Pd/C (0.15 g) was added to (S)-dibenzyl (2-(4-chloro-3-fluorophenyl)-2-(2-oxo-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-1(2H)-yl)ethyl) phosphate (978 mg) under nitrogen. MeOH (8 mL) was added, and the mixture was purged with a hydrogen balloon. The mixture was left under hydrogen overnight. The mixture was filtered through Celite®, and the solvent was removed to leave a solid. The solid was purified by HPLC to obtain (S)-2-(4-chloro-3-fluorophenyl)-2-(2-oxo-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-1(2H)-yl)ethyl dihydrogen phosphate (3.8 mg). MS=525.0.
Reaction SMILES: [CH3:1][N:2](C(OC(C)(C)C)=O)[C:3](N1C=CC=N1)=[N:4]C(OC(C)(C)C)=O.C(N(C(C)C)C(C)C)C.[ClH:33].Cl.[NH2:35][CH2:36][CH2:37][N:38]1[C:46]2[C:45]([NH:47][C:48]3[CH:53]=[CH:52][C:51]([O:54][C:55]4[CH:60]=[CH:59][CH:58]=[C:57]([C:61]([F:64])([F:63])[F:62])[CH:56]=4)=[C:50]([Cl:65])[CH:49]=3)=[N:44][CH:43]=[N:42][C:41]=2[CH:40]=[CH:39]1.O>C(#N)C>[ClH:65].[ClH:33].[Cl:65][C:50]1[CH:49]=[C:48]([NH:47][C:45]2[C:46]3[N:38]([CH2:37][CH2:36][NH:35][C:3]([NH:2][CH3:1])=[NH:4])[CH:39]=[CH:40][C:41]=3[N:42]=[CH:43][N:44]=2)[CH:53]=[CH:52][C:51]=1[O:54][C:55]1[CH:60]=[CH:59][CH:58]=[C:57]([C:61]([F:64])([F:63])[F:62])[CH:56]=1
Reactant: NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Reactant: CN(C(=O)OC(C)(C)C)C(=NC(=O)OC(C)(C)C)n1cccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC#N
Product: CNC(=N)NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 96 h
Yield: 88.5 %

Procedure:
To a solution of N-methyl-N,N′-bis(tert-butoxy carbonyl)-1H-pyrazole-1-carboxamidine (138 mg) and ethyldiisopropylamine (0.16 mL) in acetonitrile (4 mL) was added 5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (200 mg), and the mixture was stirred at room temperature for 4 days. Under ice-cooling, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane=80:20→100:0). The obtained product was dissolved in ethyl acetate, 4N hydrochloric acid/ethyl acetate was added, and the mixture was stirred at room temperature for 22 hrs. The precipitate was collected by filtration, and washed with ethyl acetate and diisopropyl ether to give the title compound (98 mg) as a powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][C:3]=1[C:10]1[CH:34]=[C:33]([CH3:35])[C:13]2[N:14]=[C:15]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH2:26][CH2:27][N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)[CH:20]=3)[N:16]=[N:17][C:12]=2[CH:11]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:10]1[CH:34]=[C:33]([CH3:35])[C:13]2[N:14]=[C:15]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH2:26][CH2:27][N:28]4[CH2:29][CH2:30][CH2:31][CH2:32]4)[CH:20]=3)[N:16]=[N:17][C:12]=2[CH:11]=1
Reactant: COc1ccc(Cl)c(-c2cc(C)c3nc(Nc4cccc(SCCN5CCCC5)c4)nnc3c2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(-c2cc(O)ccc2Cl)cc2nnc(Nc3cccc(SCCN4CCCC4)c3)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.2 %

Procedure:
[7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[1,2,4]triazin-3-yl]-[3-(2-pyrrolidin-1-yl-ethylsulfanyl)-phenyl]-amine (1.0 equiv., 0.62 mmol) was dissolved in anhydrous DCM, purged of air using house vacuum, and placed under an argon blanket. Neat BBr3 (4.0 equiv., 2.5 mmol) was then added via syringe and allowed to stir at room temperature for 2 h. The reaction was quenched using saturated NaHCO3; the precipitate was filtered and washed with water and Et2O to afford a dark orange/brown solid. The compound was purified by flash chromatography using 90:10 DCM/MeOH to recover a burnt orange solid (64.6 mg, 22% yield). Rf=0.32 1H NMR (DMSO-d6): δ 1.68 (bs, 4H), 2.68 (s, 3H), 2.73 (bs, 2H), 3.14 (t, J=6.87 Hz, 2H), 6.87 (d, J=8.10 Hz, 1H), 6.93 (s, 1H), 7.03 (d, J=7.42 Hz, 1H), 7.34 (t, J=7.58 Hz, 1H), 7.40 (d, J=8.65 Hz, 1H), 7.77 (d, J=7.95 Hz, 1H), 8.16 (s, 2H), 9.93 (s, 1H), 11.01 (s, 1H). MS (ES+): m/z=493