Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([F:19])[C:16]([N:20]2[C:24](=[O:25])[N:23]([CH:26]([F:28])[F:27])[C:22]([CH3:29])=[N:21]2)=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13]C)=[O:12])=[CH:7][CH:6]=1.ClC1C=C(F)C(N2C(=O)N(C(F)F)C(C)=N2)=CC=1OC1C=CC(C(OCC)=O)=CC=1.[OH-].[Na+].Cl>O1CCCC1.O.C(O)C>[Cl:1][C:2]1[CH:18]=[C:17]([F:19])[C:16]([N:20]2[C:24](=[O:25])[N:23]([CH:26]([F:28])[F:27])[C:22]([CH3:29])=[N:21]2)=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(Oc2cc(-n3nc(C)n(C(F)F)c3=O)c(F)cc2Cl)cc1
Agent: CCOC(=O)c1ccc(Oc2cc(-n3nc(C)n(C(F)F)c3=O)c(F)cc2Cl)cc1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Cc1nn(-c2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc2F)c(=O)n1C(F)F
Temperature: 50 °C
Reaction time: 18 h
Yield: 143.9 %

Procedure:
To a stirred mixture of 1.8 g (0.0042 mole) of methyl 4-[2-chloro-4-fluoro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4 -triazol-1-yl)phenoxy]-phenylcarboxylate and 1.3 g (0.0029 mole) of ethyl 4-[2-chloro-4-fluoro-5-(4-difluoromethyl-4,5-dihydro -3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]phenylcarboxylate (prepared by the method of Step B using ethanol in place of methanol) in 20 mL of tetrahydrofuran was added a solution of 0.58 g (0.014) of sodium hydroxide in 30 mL of water. The reaction mixture was heated at 50° C. for 1.5 hour, then was stirred at room temperature for approximately 18 hours. The mixture was again heated at 50° C. for two hours and then was allowed to cool. The solvent was removed from the mixture by evaporation under reduced pressure leaving a residue. The residue was stirred in a 2N hydrochloric acid solution, and the resultant mixture was extracted successively with diethyl ether and ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to give a solid residue. The residue was purified by column chromatography on silica gel, eluting with methylene chloride:methanol (95:5) to give 2.5 g of 4-[2-chloro-4-fluoro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo 1H-1,2,4-triazol-1-yl)phenoxy]phenylcarboxylic acid as a solid, m.p. 184°-185° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([CH3:11])=[CH:4][C:3]=1[CH:12]1[CH2:21][CH2:20][C:15]2([O:19][CH2:18][CH2:17][O:16]2)[CH2:14][CH2:13]1>CO.[Pd]>[CH3:11][C:5]1[CH:4]=[C:3]([CH:12]2[CH2:21][CH2:20][C:15]3([O:19][CH2:18][CH2:17][O:16]3)[CH2:14][CH2:13]2)[C:2]([CH3:1])=[CH:7][C:6]=1[NH2:8]
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1C1CCC2(CC1)OCCO2
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C2CCC3(CC2)OCCO3)c(C)cc1N

Procedure:
A mixture of 8-(2,5-dimethyl-4-nitrophenyl)-1,4-dioxaspiro[4.5]decane (130.2 mg, 0.45 mmol) and 10% Pd—C (13.0 mg) in MeOH (20 mL) was degassed and then reacted under 1 atm. H2. Upon reaction completion, the Pd—C was removed by filtration and the filtrate was concentrated in vacuo to afford 2,5-dimethyl-4-(1,4-dioxaspiro[4.5]decan-8-yl)aniline; ESMS m/z 262.2 (M+H+).
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH2:12][N+:13]2[CH:18]=[CH:17][C:16]([C:19]([N:21]3[CH2:30][CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22]3)=[O:20])=[CH:15][CH:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]>[Pt]=O.C(O)C>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([C:19]([N:21]3[CH2:30][CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22]3)=[O:20])[CH2:17][CH2:18]2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C[n+]2ccc(C(=O)N3CCc4ccccc4C3)cc2)cc1OC
Agent: O=[Pt]
Agent: [Cl-]
Solvent: CCO
Product: COc1ccc(CN2CCC(C(=O)N3CCc4ccccc4C3)CC2)cc1OC

Procedure:
6.5 g of 1-[(3,4-dimethoxyphenyl)methyl]-4-[(1,2,3,4-tetrahydro-2-isoquinolyl)carbonyl]pyridinium chloride, 300 ml of ethanol and 0.7 g of platinum oxide are introduced into a Parr bottle.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:25])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[NH2:26][CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[O:30]1[CH2:31][CH2:32][CH:27]([NH:26][C:3]([C:5]2[N:6]([CH3:25])[N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)=[N:14][O:15][C:16]=3[CH3:17])[CH:9]=2)=[O:4])[CH2:28][CH2:29]1
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2C)nn1C
Reactant: NC1CCOCC1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)NC2CCOCC2)n(C)n1
Yield: 41 %

Procedure:
As described for example 48c, 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.29 mmol) was converted, using 4-aminotetrahydropyran instead of N,N-dimethylhydrazine, to the title compound (40 mg, 41%) which was obtained as a colorless oil. MS: m/e=415.3 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[C:11]([NH:16][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)[CH:12]=[CH:13][C:14]=1[CH3:15].[Cl:27][CH2:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:24]([C:21]1[CH:22]=[CH:23][C:18]([C:17]([NH:16][C:11]2[CH:12]=[CH:13][C:14]([CH3:15])=[C:9]([NH:8][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][C:29]([CH2:28][Cl:27])=[CH:30][CH:31]=3)[CH:10]=2)=[O:26])=[CH:19][CH:20]=1)#[N:25]
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: Cc1ccc(NC(=O)c2ccc(C#N)cc2)cc1N
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2ccc(C#N)cc2)cc1NC(=O)c1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.6 %

Procedure:
Triethylamine (0.55 ml) was added to a suspension of N-(3-amino-4-methylphenyl)-4-cyanobenzamide (0.40 g), 4-(chloromethyl)benzoyl chloride (0.45 g) and 4-dimethylaminopyridine (0.019 g) in methylene chloride (12 ml) and the mixture was stirred at ambient temperature for 16 hours. The mixture was evaporated and the residue was triturated with water. The resultant solid was isolated and washed in turn with 2N hydrochloric acid and a saturated aqueous sodium bicarbonate solution. The solid was dried under vacuum at 55° C. to give the required starting material (0.64 g); NMR Spectrum: (DMSOd6) 2.2 (s, 3H), 4.82 (s, 2H), 7.23 (d, 1H), 7.58 (m, 3H), 7.84 (s, 1H), 7.99 (m, 4H), 8.1 (d, 2H), 9.91 (s, 1H), 10.46 (s, 1H); Mass Spectrum: M−H− 402.
Reaction SMILES: O.[OH-].[Na+].[Cl:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]2([CH2:24][C:25]([O:27]C)=[O:26])[C:15]1[C:16]([O:21][CH2:22][CH3:23])=[N:17][CH:18]=[CH:19][CH:20]=1.Cl>C(O)C>[Cl:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]2([CH2:24][C:25]([OH:27])=[O:26])[C:15]1[C:16]([O:21][CH2:22][CH3:23])=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOc1ncccc1C1(CC(=O)OC)C(=O)Nc2ccc(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOc1ncccc1C1(CC(=O)O)C(=O)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 199.2 %

Procedure:
20 ml of water and 10 ml of 2N sodium hydroxide solution were added to a solution of 1.96 g (5.43 mmol) of methyl [5-chloro-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]acetate in 10 ml of ethanol. The reaction mixture was stirred at room temperature for 18 hours. The mixture was worked up by adjusting to pH 5 with 1N hydrochloric acid and then concentrating in a rotary evaporator. The residue was taken up in toluene and again evaporated to dryness, and the residue was dried in a vacuum drying oven. 3.75 g of crude product were obtained and were employed without further purification in the next stage.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][C:13]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)[S:18][C:12]=3[C:11]2=[O:27])=[CH:6][C:5]=1[O:28][CH3:29].O.[OH-].[Li+].Cl>O1CCOCC1.O>[CH3:29][O:28][C:5]1[CH:6]=[C:7]([N:10]2[CH2:15][CH2:14][C:13]3[CH:16]=[C:17]([C:19]4[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=4)[S:18][C:12]=3[C:11]2=[O:27])[CH:8]=[CH:9][C:4]=1[C:3]([OH:30])=[O:2]
Reactant: COC(=O)c1ccc(N2CCc3cc(-c4ccc(OC)cc4)sc3C2=O)cc1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2cc3c(s2)C(=O)N(c2ccc(C(=O)O)c(OC)c2)CC3)cc1

Procedure:
Dissolve 2-methoxy-4-[2-(4-methoxy-phenyl)-7-oxo-4,7-dihydro-5H-thieno[2,3-c]pyridin-6-yl]-benzoic acid methyl ester (0.2274 g, 0.54 mmol) in dioxane (10 mL) and add lithium hydroxide monohydrate (124 mg, 2.69 mmol) followed by water (5 mL). Stir the reaction at RT overnight, dilute with water (10 mL), and acidify with 1 N HCl. Collect the solid by filtration and wash with water (2×10 mL) and Et2O (2×10 mL). Dry the solid in a vacuum oven to give 0.145 g (66%). LC-MS/ES m/z 410.3 [M+H]+.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:11]=[C:10]2[O:12][CH2:13][CH2:14][O:15][C:9]2=[CH:8][CH:7]=1)(=O)C.[OH-].[Na+]>CO>[O:15]1[C:9]2[C:10](=[N:11][C:6]([CH2:5][OH:4])=[CH:7][CH:8]=2)[O:12][CH2:13][CH2:14]1
Reactant: CC(=O)OCc1ccc2c(n1)OCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: OCc1ccc2c(n1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
To a stirred solution of (2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)methyl acetate (75.0 g, 0.36 mol) in MeOH (500 mL) was added aqueous NaOH (2M, 350 mL, 0.72 mol) dropwise at 0° C. After the addition, the mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was diluted with water (250 mL). The aqueous solution was washed with CH2Cl2 (2×200 mL). The combined organic layers were washed with brine (2×100 mL), dried over anhydrous Na2SO4 and concentrated to yield (2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)methanol (48.0 g, 80%) as a grey solid. The crude material was used directly in the next step.
Reaction SMILES: P(=O)(O)(O)O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH3:20][NH:21][C:22]1[C:23]([NH2:28])=[CH:24][CH:25]=[CH:26][CH:27]=1.Cl.[NH:30]1[CH2:35][CH2:34][CH:33]([CH2:36][CH2:37][CH2:38][C:39](O)=O)[CH2:32][CH2:31]1.[OH-].[Na+]>O>[CH3:20][N:21]1[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N:28]=[C:39]1[CH2:38][CH2:37][CH2:36][CH:33]1[CH2:34][CH2:35][NH:30][CH2:31][CH2:32]1
Reactant: CNc1ccccc1N
Reactant: O=C(O)CCCC1CCNCC1
Agent: Cl
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: Cn1c(CCCC2CCNCC2)nc2ccccc21
Temperature: 120 °C
Yield: 86.6 %

Procedure:
Phosphoric acid (7 ml) and diphosphorus pentoxide (14 g) were heated at 150° C. for 30 minutes, N-methylbenzene-1,2-diamine (1.3 g) and 4-piperidin-4-ylbutanoic acid hydrochloride (1.5 g) were added thereto, followed by heating at 120° C. for 3 hours. The reaction solution was poured into water, neutralized with aqueous sodium hydroxide solution, and then extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform:methanol:aqueous ammonia=10:1:0.1 (v/v/v)) to obtain 1-methyl-2-(3-piperidin-4-ylpropyl)-1H-benzimidazole (1.61 g).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:20][C:19]3[C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:17][C:16](SC)=[N:15][C:14]=3[CH:13]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[CH3:29][O:30][C:31]1[C:36]([Sn](CCCC)(CCCC)CCCC)=[CH:35][N:34]=[C:33]([NH2:50])[N:32]=1>COCCOC.C(OCC)(=O)C.CSC.[Cu]Br.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:29][O:30][C:31]1[C:36]([C:16]2[N:17]=[C:18]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[C:19]3[S:20][C:12]([CH2:11][N:8]4[CH2:7][CH2:6][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:10][CH2:9]4)=[CH:13][C:14]=3[N:15]=2)=[CH:35][N:34]=[C:33]([NH2:50])[N:32]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(N)nc1OC
Reactant: CSc1nc(N2CCOCC2)c2sc(CN3CCN(S(C)(=O)=O)CC3)cc2n1
Agent: [Cu]Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: CSC
Product: COc1nc(N)ncc1-c1nc(N2CCOCC2)c2sc(CN3CCN(S(C)(=O)=O)CC3)cc2n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-(4-methanesulfonyl-piperazin-1-ylmethyl)-2-methylsulfanyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (70 mg) in 1,2-dimethoxyethane (10 mL) was added 4-methoxy-5-tributylstannyl-pyrimidin-2-ylamine (131 mg) and copper(I)bromide-dimethyl sulfide (65 mg) and the reaction mixture was stirred at room temperature for 10 minutes. Tetrakis(triphenylphosphine)palladium (0) (9 mg) was then added and the reaction mixture was heated at reflux for 16 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (20 mL) and washed with water (2×20 mL) and brine (2×20 mL) The organic phase was dried (MgSO4), reduced in vacuo and purified by column chromatography to give 293. NMR: (CDCl3) 2.58-2.62 (4 H, m), 2.73 (3 H, s, Me), 3.18-3.22 (4 H, m), 3.76-3.80 (6 H, m), 3.89-3.94 (7 H, m), 4.98 (2 H, br s, NH), 7.24 (1 H, s, Ar) and 8.72 (1 H, s, Ar). MS: (ESI+): MH+ 521.25
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:15])[CH:11]=2)[N:6]=1)(=[O:3])[CH3:2].[Br:16]N1C(=O)CCC1=O>C1C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:15][Br:16])[CH:11]=2)[N:6]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Nc1ccc2cc(C)ccc2n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CC(=O)Nc1ccc2cc(CBr)ccc2n1
Yield: 62.6 %

Procedure:
Compound 45 (0.300 g, 1.50 mmol) was diluted in anhydrous benzene (10 mL). N-Bromosuccinimide (0.280 g, 1.57 mmol) and a catalytic amount (˜0.020 g) of benzoyl peroxide were added, and the mixture was heated to reflux under nitrogen until an orange tint was no longer visible in the solution refluxing in the condenser (around 2 h 40 min). The mixture was cooled, concentrated, and purified by flash column chromatography (SiO2), eluting with a gradient of 10% to 12% EtOAc in CH2Cl2 to yield the product (0.262 g, 63%) as a flocculent yellow solid. The 1H NMR chemical shifts for this compound are identical to those previously reported in the literature. 1H-NMR (500 MHz; CDCl3): δ 8.44 (br d, J=8.6 Hz, 1 H), 8.30 (br s, 1 H), 8.17 (d, J=9.0 Hz, 1 H), 7.82 (m, J=9.1 Hz, 2 H), 7.72 (dd, J=8.6, 2.1 Hz, 1 H), 4.67 (s, 2 H), 2.29 (s, 3 H).
Reaction SMILES: C([O:4][C@H:5]([CH3:50])[C:6]([N:8]([C@@H:25]([C:30]1[N:31]=[C:32]([C:42]2[CH:47]=[C:46]([F:48])[CH:45]=[CH:44][C:43]=2[F:49])[S:33][C:34]=1[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:9][CH2:10][C@H:11]([N:14]1C(=O)C2C(=CC=CC=2)C1=O)[CH2:12][F:13])=[O:7])(=O)C.NN>CCO>[NH2:14][C@H:11]([CH2:12][F:13])[CH2:10][CH2:9][N:8]([C@@H:25]([C:30]1[N:31]=[C:32]([C:42]2[CH:47]=[C:46]([F:48])[CH:45]=[CH:44][C:43]=2[F:49])[S:33][C:34]=1[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:26]([CH3:28])([CH3:27])[CH3:29])[C:6](=[O:7])[C@@H:5]([OH:4])[CH3:50]
Reactant: CC(=O)O[C@H](C)C(=O)N(CC[C@@H](CF)N1C(=O)c2ccccc2C1=O)[C@@H](c1nc(-c2cc(F)ccc2F)sc1Cc1ccccc1)C(C)(C)C
Agent: NN
Solvent: CCO
Product: C[C@H](O)C(=O)N(CC[C@H](N)CF)[C@@H](c1nc(-c2cc(F)ccc2F)sc1Cc1ccccc1)C(C)(C)C
Temperature: 60 °C
Yield: 30.8 %

Procedure:
To a solution of (R)-1-(((R)-1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropyl)((S)-3-(1,3-dioxoisoindolin-2-yl)-4-fluorobutyl)amino)-1-oxopropan-2-yl acetate (10 mg, 0.014 mmol) in EtOH (1 mL) was added anhydrous hydrazine (45 μL). The reaction was heated at 60° C. for 14 h. After cooled the reaction mixture, the white precipitate was filtered through Celite® pad with EtOH washes. The filtrate was concentrated and purified by preparative reverse phase HPLC. The pure fractions were combined and lyophilized to yield (S)-N-((S)-3-amino-4-fluorobutyl)-N-((R)-1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropyl)-2-hydroxypropanamide (2.3 mg, 25%) as TFA salt. LC/MS (uplc) MH+ 543.2, 1.05 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[C:26]([F:29])[C:27]=3[CH3:28])[C:22]([OH:24])=O)[C:13]=2[CH2:12][NH:11][C:10]1=[O:36].CN.[CH2:39]([N:41](CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[C:26]([F:29])[C:27]=3[CH3:28])[C:22]([NH:41][CH3:39])=[O:24])[C:13]=2[CH2:12][NH:11][C:10]1=[O:36]
Reactant: Cc1c(F)cc(C(=O)O)cc1-c1nc(NCCN(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Reactant: CCN(CC)CC
Agent: CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CNC(=O)c1cc(F)c(C)c(-c2nc(NCCN(C)C)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Yield: 54.5 %

Procedure:
To the solution of 3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]-amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-5-fluoro-4-methylbenzoic acid (25 mg, 0.05 mmol) in CH2Cl2 (2 mL) were added methylamine (2.0 M soln. in THF, 0.13 mL, 0.26 mmol), triethylamine (0.05 mL, 0.36 mmol) and HBTU (20 mg, 0.053 mmol). The reaction mixture was stirred over night. The reaction mixture was concentrated. Separation via a HPLC with TFA followed by treatment with t-amino SPE cartridge then provided the title compound as a white solid (14 mg, 54%). LC-MS m/z 514 (M+H)+; 1H-NMR (MeOD) δ 2.24 (s, 3H), 2.78 (s, 6H), 2.94 (s, 3H), 3.15 (m, 2H), 3.55 (m, 2H), 4.22 (s, 2H), 7.18 (m, 2H), 7.56 (m, 2H), 7.39 (m, 1H).
Reaction SMILES: [C:1]([C:5]1[NH:14][C:8]2=[CH:9][N:10]=[C:11]([NH2:13])[CH:12]=[C:7]2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3([C:27](O)=[O:28])[CH2:26][CH2:25]3)=[CH:23][C:18]=2[O:17][CH2:16]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3([C:27]([NH:13][C:11]4[CH:12]=[C:7]5[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[NH:14][C:8]5=[CH:9][N:10]=4)=[O:28])[CH2:25][CH2:26]3)=[CH:23][C:18]=2[O:17][CH2:16]1
Reactant: CC(C)(C)c1cc2cc(N)ncc2[nH]1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ncc2[nH]1
Reaction time: 16 h
Yield: 665.7 %

Procedure:
2-tert-Butyl-1H-pyrrolo[2,3-c]pyridin-5-amine (325 mg, 0.158 mmol) and 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (300 mg, 1.58 mmol) were dissolved in acetonitrile (10 mL) containing triethylamine (659 μL, 0.470 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (608 mg, 1.60 mmol) was added to the mixture and the resulting solution was allowed to stir for 16 hours during which time a large amount of precipitate formed. The reaction mixture was filtered and the filtercake was washed with acetonitrile and then dried to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropanecarboxamide (397 mg, 67%). ESI-MS m/z calc. 377.2, found; 378.5 (M+1)+; Retention time 1.44 minutes. 1H NMR (400 MHz, DMSO) 11.26 (s, 1H), 8.21 (s, 1H), 8.06 (s, 1H), 7.83 (s, 1H), 7.13 (d, J=1.5 Hz, 1H), 7.04-6.98 (m, 2H), 6.20 (d, J=1.0 Hz, 1H), 6.09 (s, 2H), 1.49-1.45 (m, 2H), 1.38 (s, 9H), 1.12-1.08 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:9][CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1.[ClH:17].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:17].[CH3:1][O:2][CH2:3][C@@H:4]1[CH2:9][CH2:8][CH2:7][NH:6][CH2:5]1
Reactant: COC[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl (R)-3-methoxymethylpiperidine-1-carboxylate (13.00 g, 56.6 mmol) in ethyl acetate (26 ml) was added 4N HCl-ethyl acetate solution (26 ml), and the mixture was stirred at room temperature for 3 hr. The solvent was evaporated under reduced pressure to give (R)-3-methoxymethylpiperidine hydrochloride as a crude product. A mixed solvent (100 ml) of hexane:ethyl acetate=1:4 was added to the obtained solid, and the mixture was stirred. The solid was collected by filtration to give (R)-3-methoxymethylpiperidine hydrochloride (7.82 g, yield 84%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][S:12]([N:15]2CCOC[CH2:16]2)(=[O:14])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].CN>CO>[CH3:16][NH:15][S:12]([CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(CCS(=O)(=O)N2CCOCC2)cc1
Agent: CN
Solvent: CO
Product: CNS(=O)(=O)CCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 19.4 %

Procedure:
A suspension of 2.12 g (8.49 mmol) of 2-(4-nitro-phenyl)-ethanesulfonyl chloride (as prepared in Example 26, step (c)) in MeOH (40 mL) was cooled to 0° C. and treated with 21.2 mL (42.4 mmol) of methylamine (2.0 M in MeOH). The mixture was slowly warmed to RT, stirred for 16 h, and warmed to 40° C. for 3 days. Solvents were evaporated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 50% EtOAc-hexane afforded 402 mg (19%) of the title compound as a white solid: 1H-NMR (CD3CN; 400 MHz): δ 8.19 (d, 2H, J=8.8 Hz), 7.54 (d, 2H, J=8.8 Hz), 5.15-5.05 (br s, 1H), 3.39-3.32 (m, 2H), 3.22-3.15 (m, 2H), 2.70 (d, 3H, J=5.2 Hz).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:19][P:20]([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])=[O:21])([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11](=[O:16])[CH2:10][C:9]2([CH3:18])[CH3:17])=[O:5])[CH3:2].[OH-:28].[K+]>CO>[OH:12][C:13]1[CH:14]=[CH:15][C:6]([P:4]([O:3][CH2:1][CH3:2])([CH2:19][P:20]([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])=[O:21])=[O:5])=[CH:7][C:8]=1[C:9]([CH3:18])([CH3:17])[CH2:10][C:11]([OH:16])=[O:28]
Reactant: [OH-]
Reactant: CCOP(=O)(CP(=O)(OCC)c1ccc2c(c1)C(C)(C)CC(=O)O2)OCC
Agent: [K+]
Solvent: CO
Product: CCOP(=O)(CP(=O)(OCC)c1ccc(O)c(C(C)(C)CC(=O)O)c1)OCC
Yield: 105 %

Procedure:
A solution of 120 (0.99 g, 2.4 mmol) and KOH (0.095 g, 2.4 mmol) in methanol was stirred at room temperature for 2 hr. The solvent was removed removed under reduced pressure and the product was resuspended in water, the pH was adjusted to 4 by the addition of HCl, and the product was extracted with CH2Cl2. The organics were dried over Na2SO4, filtered and concentrated, resulting in 121 as a pale yellow oil (1.1 g, 105%) which was used without purification. 1H NMR (400 MHz, CDCl3) δ 1.26 (t, J=7.2, 3H), 1.29-1.37 (m, 6H), 1.45 (s, 3H), 1.48 (s, 3H), 2.63 (dd, J=17.7, 20.9, 2H), 2.93 (AB q, J=14.2, 2H), 4.00-4.20 (m, 6H), 6.74 (bs, 1H), 7.56 (ddd, J=1.6, 8.5, 12.2, 2H), 7.63 (d, J=13.3, 1H).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:21])[C:5]2[S:10][C:9](=[O:11])[N:8]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])[C:6]=2[N:7]=1.[OH-].[Na+]>CC(O)=O>[NH2:1][C:2]1[NH:3][C:4](=[O:21])[C:5]2[S:10][C:9](=[O:11])[N:8]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:6]=2[N:7]=1
Reactant: CCOC(=O)CCCCn1c(=O)sc2c(=O)[nH]c(N)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1nc2c(sc(=O)n2CCCCC(=O)O)c(=O)[nH]1
Reaction time: 1.5 h

Procedure:
A mixture of 5-amino-3-[4-(ethoxycarbonyl)butyl]thiazolo[4,5-d]pyrimidine-2,7(3H,6H)-dione (312 mg, 1 mmol) and 1 N NaOH (5 mL) was stirred at ambient temperaturefor 1.5 h. The mixture was acidified (pH=4) with AcOH and then refrigeratedfor 16 h. The solid was collected by filtration, crystallized from a MeOH:H2O mixture and dried under vacuum at 80° C. for 16 h; 220 mg (0.774 mmol, 77%), mp 263°-265° C. Ir (KBr): v 3410, 3315 and 3180 (NH, NH2), 1725 (C=O) and 1640 (C=O), and 1640 (C=O, C=N) cm-3. Uv, λ max (nm), (ε×10-3): pH 1, 302 (9.79), 250 (8.52), 222 (31.0); MeOH, 302 (9.48), 250 (8.79), 222 (30.40); pH 11, 292 (8.26), 250 (8.15), 224 (12.20). 1H nmr (DMSO-d6): δ 1.43-1.50 (m, 2 H, CH2), 1.60-1.67 (m, 2 H, CH2), 2.24 (t, 2 H, CH2), 3.76 (t,2 H, NCH2), 6.91 (br s, 2 H, NH2) 11.1 (br s, 1 H, NH), and 12.0 (br s, 1 H, COOH) Anal. Calc'd for C10H12N4O4S (284.30): C, 42.25; H, 4.25; N, 19.71. Found: C, 42.32; H, 4.22; N, 19.69.