Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:17].[C:18]1([CH2:24][C:25](=[NH:29])OCC)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C.C(Cl)(Cl)Cl>[ClH:17].[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:8][C:7]2[C:2]([NH:1][C:25](=[NH:29])[CH2:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:11][CH:12]=1
Reactant: Nc1ncccc1OCc1ccc(F)cc1
Reactant: CCOC(=N)Cc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: N=C(Cc1ccccc1)Nc1ncccc1OCc1ccc(F)cc1
Yield: 9.4 %

Procedure:
A mixture of 2-amino-3-(4-fluorobenzyloxy)pyridine (5.42 g, 24.2 mmol) and ethyl phenylacetimidate hydrochloride (6.28 g, 26.7 mmol) in ethanol (80 ml) was heated under reflux for 2 hours. Evaporation of the solvent gave an oil which was taken up in chloroform, filtered to remove an insoluble white solid, and purified by flash chromatography (chloroform/methanol) to obtain the product (0.85 g), m.p. 175°-178° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH2:15][CH2:14][NH:13][CH2:12][C:11]=2[C:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24](O)(=O)[CH3:25].C(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[CH2:1]([N:8]1[C:16]2[CH2:15][CH2:14][N:13]([CH2:24][CH3:25])[CH2:12][C:11]=2[C:10]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2cn(Cc3ccccc3)c3c2CNCC3)cc1
Reactant: CC(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CCN1CCc2c(c(-c3ccc(Cl)cc3)cn2Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 1-benzyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine (Example 25; 0.11 g) in 1,2-dichloroethane (5 mL) was added 18 μL of acetic acid, 26 μL of acetaldehyde, and 0.10 g of NaBH(OAc)3. The mixture was stirred at RT for 15 h. The mixture was diluted with CH2Cl2 and washed with satd. aq. NaHCO3 (2×). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography on SiO2 (1% 2 M NH3 in MeOH/CH2Cl2) afforded 0.02 g of the title compound. The product was dissolved in Et2O and treated with excess 1.0 M HCl in Et2O to afford 0.02 g of the corresponding HCl salt. MS (ESI): exact mass calculated for C22H23ClN2, 350.15; found, m/z 351.2 [M+H]+, 353.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.37-7.27 (m, 7H), 7.19-7.17 (m, 3H), 5.17-5.13 (m, 2H), 4.48-4.37 (m, 2H), 3.85-3.76 (m, 2H), 3.45-3.23 (m, 2H), 3.00-2.84 (m, 2H), 1.38 (t, J=7.1 Hz, 3H).
Reaction SMILES: C([O:6][CH2:7][C@@:8]([OH:22])([CH2:13][NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]([F:12])([F:11])[F:10])(=O)CCC.C(O)C>Cl>[F:10][C:9]([F:11])([F:12])[C@@:8]([CH2:13][NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([OH:22])[CH2:7][OH:6]
Reactant: CCCC(=O)OC[C@@](O)(CNCc1ccccc1)C(F)(F)F
Agent: Cl
Solvent: CCO
Product: OC[C@@](O)(CNCc1ccccc1)C(F)(F)F
Yield: 104.1 %

Procedure:
(S)-3,3,3-Trifluoro-2-hydroxy-2-{[(phenylmethyl)amino]methyl}propyl butanoate (0.32 g) was dissolved in 5M hydrochloric acid (5 ml) and ethanol (5 ml) and heated at 100° C. for 3 hours. After cooling, the ethanol was evaporated and the remaining aqueous was basified with 2M sodium hydroxide and extracted with ethyl acetate (2 times). The combined organics were dried using a hydrophobic frit and evaporated to give the title compound as a pale yellow oil (0.26 g).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:19]1[CH:26]=[CH:25][C:23](=S)[NH:22][C:20]1=[S:21].O>N1C=CC=CC=1>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:26]2[CH:25]=[CH:23][NH:22][C:20](=[S:21])[N:19]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: S=c1cc[nH]c(=S)[nH]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Solvent: O
Solvent: c1ccncc1
Product: S=c1nc(NCCCOc2cccc(CN3CCCCC3)c2)cc[nH]1

Procedure:
3-(3-(Piperidinomethyl)phenoxy)propylamine (11.0 g) and dithiouracil (5.8 g) were refluxed in pyridine (100 ml; dried over potassium hydroxide) for approximately 72 hours. The solution was cooled and evaporated under reduced pressure to afford a residue. This residue was treated with water, evaporated under reduced pressure, and azeotroped thoroughly with n-propanol in an effort to remove pyridine. To the resultant residue was added further n-propanol to give the title compound as a solid which was collected by filtration and dried (13.88 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.Br[CH:14]([CH3:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][CH2:20][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:6]=[CH:5]2
Reactant: CCCCCC(C)Br
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCCCCCOc1ccc2cc(Br)ccc2c1
Temperature: 65 °C

Procedure:
A mixture of 5 g of 6-bromo-2-naphthol, 50 ml of dimethyl sulfoxide, 3.9 ml of 6-bromoheptane, 7.1 g of potassium iodide and 7.1 g of milled potassium carbonate activated at 80° C. in high vacuum is heated to 65° C. for 16 hours. It is then cooled and is partitioned between ethyl acetate and water and the organic phase is washed several times with water, dried over magnesium sulfate, filtered and evaporated down. Chromatography of the residue over 200 g of silica gel using toluene and subsequent crystallization from toluene/hexane (8:1) give 6-bromo-2-heptyloxynaphthalene.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7](=O)[CH3:8].C([O-])(=O)C.[NH4+:14]>CO.C([BH3-])#N.[Na+]>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH:7]([NH2:14])[CH3:8]
Reactant: CC(=O)c1cnccn1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(N)c1cnccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 749 %

Procedure:
To a solution of 1-pyrazin-2-yl-ethanone (2.0 g, 15.85 mmol) and ammonium acetate (19.337 g, 158.5 mmol) in methanol (50 mL) was added sodium cyanoborohydride (0.7 g, 11.1 mmol) in one portion. The reaction mixture was stirred overnight at room temperature. After removal of methanol, water (20 mL) was added to the residue and the resulting solution was basified by addition of sodium hydroxide to pH=13. The aqueous solution was extracted with dicholromethane and the combined organic phase was dried over sodium sulfate. Removal of the solvent under reduced pressure afforded 14.62 g of 1-pyrazin-2-yl-ethylamine, yield: 75%. MS (M+H)=124.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12](Cl)=[O:13])=[CH:4][N:3]=1.[OH2:15]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([OH:13])=[O:15])=[CH:4][N:3]=1
Reactant: O=C(Cl)c1cnc(Cl)nc1C(F)(F)F
Reactant: O
Product: O=C(O)c1cnc(Cl)nc1C(F)(F)F
Yield: 98 %

Procedure:
A solution of 2-chloro-4-trifluoromethylpyrimidine-5-carbonyl chloride (2.1 g, 8.6 mmol) in H2O (10 mL) was stirred at 0° C. under N2 for 0.5 h. The resulting solid was filtered and dried to give the title compound (1.91 g, 98% yield); m.p. 232°-234° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([NH:14][CH2:15][CH2:16][OH:17])[CH:6]=[CH:5]2.[C:18]([Si:22]([CH3:25])([CH3:24])Cl)([CH3:21])([CH3:20])[CH3:19].N1C=CN=C1>ClCCl>[C:18]([Si:22]([CH3:25])([CH3:24])[O:17][CH2:16][CH2:15][NH:14][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:2]([NH2:1])[CH:3]=2)[N:8]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: COc1cc2nc(NCCO)ccc2cc1N
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COc1cc2nc(NCCO[Si](C)(C)C(C)(C)C)ccc2cc1N
Temperature: 25 °C
Reaction time: 62 h
Yield: 34.5 %

Procedure:
A mixture of 2-(6-amino-7-methoxy-quinolin-2-ylamino)-ethanol (0.4 g, 1.72 mmol), tert-butyldimethylchlorosilane (0.8 g, 5.15 mmol) and imidazole (0.4 g, 5.15 mmol) in dichloromethane (20 mL) was stirred at room temperature for 62 hours. The resulting mixture was washed with water and the organic layer was separated, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (EtOAc/hexane, 3/7) to afford 206 mg of N2-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-7-methoxy-quinoline-2,6-diamine as a brown oil. MS=348 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][C:5]1[S:9][C:8]2[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:7]=2[C:6]=1[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)(O)[CH3:16]>C(O)(C(F)(F)F)=O.S(=O)(=O)(O)O>[CH3:24][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[S:9][C:8]2[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:7]=2[C:6]=1[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=[CH2:16]
Reactant: Cc1ccc2c(C(C)(O)c3ccccn3)c(CCN(C)C)sc2c1
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: C=C(c1ccccn1)c1c(CCN(C)C)sc2cc(C)ccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a cooled solution of 1-[2-(2-dimethylamino-ethyl)-6-methyl-benzo[b]thiophen-3-yl]-1-pyridin-2-yl-ethanol (Compound 4-5) (220 mg, 0.65 mmol) in TFA (2 mL), conc. sulfuric acid (500 uL) was added dropwise and the reaction was allowed to warm up to room temperature. After stirring for 4 hours the mixture was concentrated slightly, made basic with 1N NaOH and extracted with EtOAc (4 times). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. Purification using mass triggered preparative HPLC afforded dimethyl-{2-[6-methyl-3-(1-pyridin-2-yl-vinyl)-benzo[b]thiophen-2-yl]-ethyl}-amine (Compound 4-6). (MH+=323.0, tR=40.15, Method 2)
Reaction SMILES: [P:1]([O-:38])([O:34][CH2:35][CH2:36]Br)([O:3][CH2:4][CH:5]([O:28][C:29]1[CH:33]=[CH:32][O:31][N:30]=1)[CH2:6][O:7][C:8](=[O:27])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:2].[CH3:39][N:40]1[CH:44]=[CH:43][N:42]=[CH:41]1>C1(C)C=CC=CC=1>[P:1]([O-:38])([O:34][CH2:35][CH2:36][N+:42]1[CH:43]=[CH:44][N:40]([CH3:39])[CH:41]=1)([O:3][CH2:4][CH:5]([O:28][C:29]1[CH:33]=[CH:32][O:31][N:30]=1)[CH2:6][O:7][C:8](=[O:27])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:2]
Reactant: Cn1ccnc1
Reactant: CCCCCCCCCCCCCCCCCNC(=O)OCC(COP(=O)([O-])OCCBr)Oc1ccon1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCNC(=O)OCC(COP(=O)([O-])OCC[n+]1ccn(C)c1)Oc1ccon1
Reaction time: 15 h

Procedure:
A mixture of 0.900 g of (2RS)-3-(N-heptadecylcarbamoyloxy)-2-(3-isoxazolyloxy)propyl 2-bromoethyl phosphate [prepared as described in Example 11(a)], 1.14 ml of N-methylimidazole and 1.0 ml of toluene was heated on an oil bath kept at 80° C. for 15 hours, whilst stirring. The toluene was then distilled off, and the resulting residue was dissolved in 10 ml of a 95:5 by volume mixture of tetrahydrofuran and water. The resulting solution was passed through a column of 14 ml of Amberlite MB-3 resin. The eluate wa repeatedly passed two times through the same column and the column was finally washed with a 95:5 by volume mixture of tetrahydrofuran and water. The eluates and the washings were combined and concentrated by evaporation under reduced pressure. The residue was purified by medium pressure liquid chromatography using a Lobar B column. 0.656 g of the title compound was obtained as a white powder melting at 45°-46° C. from the fractions eluted with a 160:35:5 by volume mixture of methylene chloride, methanol and water.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[C:27]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:39][S:40]([CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)(=[O:42])=[O:41]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:48]3[CH2:47][CH2:46][N:45]([CH2:44][CH2:43][S:40]([CH3:39])(=[O:41])=[O:42])[CH2:50][CH2:49]3)=[O:21])[C:10]([C:23]3[CH:28]=[C:27]([C:29]([CH3:30])([CH3:31])[C:32]#[N:33])[CH:26]=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)CCN1CCNCC1
Reactant: CCOc1ccc(C(C)(C)C#N)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1ccc(C(C)(C)C#N)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1

Procedure:
2-(3-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-[4-(2-methanesulfonyl-ethyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-4-ethoxy-phenyl)-2-methyl-propionitrile was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[5-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12e) and 1-(2-methanesulfonylethyl)piperazine dihydrochloride (example 17) in an analogous manner as described in example 25. LR-MS: 696.3 [(M+H)+]
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]2[C:16](=[CH:17][CH:18]=1)[C:10]1=[N:11][NH:12][C:13](=[O:15])[CH2:14][CH:9]1[CH2:8]2)(=O)C.C(O)C>O.NN>[NH2:4][C:5]1[CH:6]=[C:7]2[C:16](=[CH:17][CH:18]=1)[C:10]1=[N:11][NH:12][C:13](=[O:15])[CH2:14][CH:9]1[CH2:8]2
Reactant: CC(=O)Nc1ccc2c(c1)CC1CC(=O)NN=C21
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(c1)CC1CC(=O)NN=C21
Yield: 33 %

Procedure:
7-Acetamido-4,4a-dihydro-[5H]-indeno[1,2-c]pyridazin-3[2H]-one (1.50 g) was suspended in hydrazine hydrate (30 ml ) and heated under reflux with ethanol (5 ml ) for 2 hours. The solution was filtered through diatomaceous earth, allowed to cool, then extracted into chloroform. The combined organic extracts were dried over magnesium sulphate and concentrated. Recrystallisation of the crude product from n-propanol gave 7-amino-4,4a-dihydro-[5H]-indeno[1,2-c]pyridazin-3[2H]-one (0.41 g, m.p. 244°-245° C.) as a pale yellow powder; ν(Nujol mull) 3400, 3320, 3220, 1652, 1635, 1600, and 1580cm-1 ; δ(DMSO-d6) 2.50 (3H,m,4-H,5-H2), 3.05 (1H,m,4a-H), 5.67 (2H,s(br),NH2), 6.55 (2H,m,6,H-H), 7.27 (1H,d,9-H).
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].[OH:10][CH2:11][CH2:12][NH:13][CH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[C:18]#[N:19]>CN(C=O)C.O>[C:18]([C:17]1[CH:16]=[C:15]([CH:22]=[CH:21][CH:20]=1)[CH2:14][N:13]([CH2:12][CH2:11][OH:10])[CH2:3][CH2:2][C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])#[N:19]
Reactant: N#Cc1cccc(CNCCO)c1
Reactant: C=CC(=O)OC(C)(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCN(CCO)Cc1cccc(C#N)c1
Temperature: 80 °C

Procedure:
Tert-butyl acrylate (3.56 ml, 29 mmol) was added into a solution of 3-{[(2-hydroxyethyl)amino]methyl}benzonitrile (4.9 g, 28 mmol) in anhydrous DMF (5 mL) under nitrogen atmosphere. The resulting mixture was heated at 80° C. for 12 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford the title compound as colorless liquid. 1H NMR (DMSO-d6, 400 MHz) δ 7.75 (s, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.62 (d, J=7.9 Hz, 1H), 7.50 (m, 1H), 4.36 (t, 1H), 3.62 (s, 2H), 3.43 (m, 2H), 2.69 (t, 2H), 2.47 (m, 2H), 2.34 (t, 2H), 1.38 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:10][CH3:11])=[N:4][CH:3]=1.Cl.Cl[CH2:14][C:15]1[C:16]([C:21]2[CH:25]=[CH:24][N:23]([CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[N:22]=2)=[N:17][CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:8]([C:7]1[CH:6]=[C:5]([O:10][CH3:11])[N:4]=[CH:3][C:2]=1[O:1][CH2:14][C:15]1[C:16]([C:21]2[CH:25]=[CH:24][N:23]([CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[N:22]=2)=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:9]
Reactant: COc1cc(C=O)c(O)cn1
Reactant: COC(=O)CCn1ccc(-c2ncccc2CCl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCn1ccc(-c2ncccc2COc2cnc(OC)cc2C=O)n1
Temperature: 70 °C
Yield: 111 %

Procedure:
A mixture of 5-hydroxy-2-methoxyisonicotinaldehyde (30 mg, 0.20 mmol, 1 eq.), methyl 3-(3-(3-(chloromethyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoate hydrochloride (63 mg, 0.20 mmol, 1 eq.), and K2CO3 (100 mg, 10.32 mmol, 4 eq.) in DMF (5.0 mL) was heated at 70° C. for 2 h. The mixture was cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give methyl 3-(3-(3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoate (88 mg, quantitative yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.50 (s, 1H), 8.65 (dd, J=4.7, 0.9 Hz, 1H), 8.09 (s, 1H), 8.02 (dd, J=7.8, 0.8 Hz, 1H), 7.53 (d, J=2.3 Hz, 1H), 7.31 (dd, J=7.9, 4.8 Hz, 1H), 7.12 (s, 1H), 6.96 (d, J=2.3 Hz, 1H), 5.71 (s, 2H), 4.46 (t, J=6.6 Hz, 2H), 3.93 (s, 3H), 3.69 (s, 3H), 2.91 (t, J=6.6 Hz, 2H). LRMS (M+H+) m/z 397.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([C:15]([OH:17])=O)=[N:11][N:10]([CH:18]([CH3:20])[CH3:19])[C:9]2=[O:21])=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[N:30]=[CH:29][CH:28]=[C:27]2[O:36][C:37]1[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][C:38]=1[F:44].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[N:30]=[CH:29][CH:28]=[C:27]2[O:36][C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:15]([C:12]2[C:13](=[O:14])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:9](=[O:21])[N:10]([CH:18]([CH3:20])[CH3:19])[N:11]=2)=[O:17])=[CH:39][C:38]=1[F:44]
Reactant: CC(C)n1nc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4nn(C(C)C)c(=O)n(-c5ccc(F)cc5)c4=O)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-(4-fluorophenyl)-2-isopropyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid (500 mg, 2 mmol), 4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenylamine (535 mg, 1.70 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (639 mg, 1.68 mmol) and N,N-diisopropylethylamine (279 uL, 1.60 mmol) in N,N-dimethylformamide (8 mL) was stirred at rt for 3 h. The solvent was removed and the residue dissolved in EtOAc and washed with saturated NaHCO3 solution water and brine. After drying over magnesium sulfate, solvent was evaporated and the product was purified by ISCO silica gel chromatography (hexane: EtOAc 1:4) to give 835 mg (83%), which triturated with ether and dried. mp=225-226° C.; LCMS m/z=590 (M+1); 1H NMR DMSO) δ: 10.87 (s, 1H), 8.49 (d, 1H, J=5.2 Hz), 7.97 (dd, 1H, J=12.6, 2.2 Hz), 7.59-7.36 (m, 8H), 6.50 (d, 1H, J=4.9 Hz), 4.90 (m, 1H), 3.95 (s, 6H), 3.32 (s, 3H), 1.38 (d, 6H, J=6.6 Hz).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:11]([C:12]([OH:14])=[O:13])=[C:10]([C:15]([OH:17])=[O:16])[C:9]3[CH2:18][O:19][CH2:20][CH2:21][C:8]2=3)=[CH:4][CH:3]=1.[C:24](OC(C(F)(F)F)=O)(C(F)(F)F)=O>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]([C:12]([OH:14])=[O:13])=[C:10]([C:15]([O:17][CH3:24])=[O:16])[C:9]3[CH2:18][O:19][CH2:20][CH2:21][C:8]2=3)=[CH:22][CH:23]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C(O)c1c2c(n(Cc3ccc(F)cc3)c1C(=O)O)CCOC2
Solvent: ClCCl
Product: COC(=O)c1c2c(n(Cc3ccc(F)cc3)c1C(=O)O)CCOC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
An ice cooled suspension of 1-(4-fluorobenzyl)-1,4,6,7-tetrahydropyrano[4,3-b]pyrrole-2,3-dicarboxylic acid (3.1 g, 9.71 mmol) in Dichloromethane (DCM) (50 mL) was treated with TFAA (2.70 mL, 19.42 mmol) and warmed to ambient temperature. After 2 h, the reaction mixture was concentrated in vacuo, dissolved in MeOH (5 mL) and heated to reflux (90° C. bath). After 2 h, the reaction mixture was concentrated in vacuo to afford 1-(4-fluorobenzyl)-3-(methoxycarbonyl)-1,4,6,7-tetrahydropyrano[4,3-b]pyrrole-2-carboxylic acid. The crude acid was dissolved in DMF (25 mL) and treated with N-methyl sarcosine methyl ester HCl (2.033 g, 14.56 mmol), DIPEA (2.54 mL, 14.56 mmol) and HATU (4.43 g, 11.65 mmol). After 20 min, the reaction mixture was partitioned between water and EtOAc. The layers were separated and the organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by ISCO (0-50% EtOAc-hexanes) to afford methyl 1-(4-fluorobenzyl)-2-((2-methoxy-2-oxoethyl)(methyl)carbamoyl)-1,4,6,7-tetrahydropyrano[4,3-b]pyrrole-3-carboxylate (3.2 g, 7.65 mmol, 79% yield) as a white solid. LCMS (m/z) ES+=419 (M+1).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH:9]([C:15]([OH:17])=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])=[O:7])([CH3:4])[CH3:3].[CH3:18][C:19]([O:22][C:23]([NH:25]/[C:26](/N1N=CC=C1)=[N:27]/[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:24])([CH3:21])[CH3:20].C(N(CC)CC)C>C(Cl)Cl>[C:31]([O:30][C:28]([N:27]=[C:26]([NH:25][C:23]([O:22][C:19]([CH3:21])([CH3:20])[CH3:18])=[O:24])[NH:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([NH:8][C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[C:15]([OH:17])=[O:16])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)NC(CCCCN)C(=O)O
Reactant: CC(C)(C)OC(=O)/N=C(/NC(=O)OC(C)(C)C)n1cccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N=C(NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 111 %

Procedure:
A solution of N-α-Boc-L-lysine 18 (5.00 g, 20.3 mmol) in CH2Cl2 (100 mL) was charged with N,N′-bis-Boc-1-guanylpyrazole (5.10 g, 16.6 mmol) and triethylamine (5.54 mL, 40.6 mmol). The reaction mixture was stirred at room temperature for 48 h. The reaction mixture was washed with 10% aqueous citric acid (2×80 mL) and the solvent was removed under reduced pressure. The residue was dissolved in 1 N NaOH (200 mL), the pH of solution was adjusted to 5-6 with 1 N HCl, and the mixture was extracted with CH2Cl2 (300 ml). The CH2Cl2 layer was separated and the aqueous layer was extracted with CH2Cl2 (2×200 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to afford compound 10 (9.00 g, 91%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 4.10-4.02 (m, 1H), 3.36 (t, J=6.8 Hz, 2H), 1.90-1.78 (m, 1H), 1.73-1.56 (m, 3H), 1.52 (s, 9H), 1.45-1.31 (m, 2H), 1.47 (s, 9H), 1.43 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][NH:11][C:12](=[O:32])[C@H:13]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:14][N:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=[O:17])[C:3]=1[F:33].Cl.[NH2:35][C@@H:36]([CH2:42][CH3:43])[C:37]([N:39]([CH3:41])[CH3:40])=[O:38].C(N(C(C)C)CC)(C)C>CS(C)=O>[CH:27]1([CH2:26][C@H:13]([CH2:14][N:15]([CH:16]=[O:17])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12]([NH:11][NH:10][C:4]2[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([NH:35][C@@H:36]([CH2:42][CH3:43])[C:37]([N:39]([CH3:41])[CH3:40])=[O:38])[C:3]=2[F:33])=[O:32])[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: COc1nc(Cl)c(F)c(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)n1
Reactant: CC[C@H](N)C(=O)N(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC[C@H](Nc1nc(OC)nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c1F)C(=O)N(C)C
Temperature: 80 °C
Reaction time: 168 h
Yield: 22.4 %

Procedure:
[(2R)-3-{2-[6-Chloro-5-fluoro-2-(methyloxy)-4-pyrimidinyl]hydrazino}-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamide (0.133 g, 0.28 mmol), (2S)-2-amino-N,N-dimethylbutanamide, hydrochloride salt (Example 83) (0.075 g, 0.45 mmol) and diisopropylethylamine (0.1 mL, 0.62 mmol) were stirred in DMSO (2 mL) overnight at 65° C. Then additional diisopropylethylamine (0.2 mL) was added, and the reaction was stirred for 7 days at 80° C. Purified by RP-HPLC to provide (2S)-2-{[6-{2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]hydrazino}-5-fluoro-2-(methyloxy)-4-pyrimidinyl]amino}-N,N-dimethylbutanamide (0.036 g, 23%). LCMS: (M+H)+=574.3.