Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([CH3:7])[N:6]=1.Br[CH2:16][C:17]([OH:19])=[O:18]>CN(C=O)C>[C:17]([CH2:16][S:1][C:2]1[S:3][C:4]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([CH3:7])[N:6]=1)([OH:19])=[O:18]
Reactant: O=C(O)CBr
Reactant: CCOC(=O)CCc1sc(S)nc1C
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1sc(SCC(=O)O)nc1C
Reaction time: 2 h
Yield: 152.7 %

Procedure:
2 g (8.6 mmol) of ethyl 3-(2-mercapto-4-methyl-1,3-thiazol-5-yl)propionate were initially introduced into 40 ml of dry DMF, and 1.49 g (8.6 mmol) of bromoacetic acid were added. After 2 hours, the solvent was removed in vacuo, and 3.8 g of ethyl 3-[2-(carboxymethylthio)-4-methyl-1,3-thiazol-5-yl]propionate were obtained as an oil. The crude product was taken up in 25 ml of ethanol, 33 ml of 1N sodium hydroxide solution were added, and the reaction mixture was heated at 50° C. After the reaction was complete, the ethanol was removed in vacuo, and the aqueous residue was taken up in concentrated hydrochloric acid at pH 3.0, and the solution was extracted with ethyl acetate. 1.6 g (71%) of the title compound were obtained from the organic phase after drying with MgSO4, evaporation and crystallization with diethyl ether.
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[C:6]([CH3:9])[C:5]([O:10][CH2:11][O:12][CH3:13])=[CH:4][C:3]=1[CH:14]([OH:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].[C:21]1(C)C=CC=CC=1>CN(C=O)C>[OH:20][CH:14]([C:3]1[C:2]2[O:1][CH2:21][O:8][C:7]=2[C:6]([CH3:9])=[C:5]([O:10][CH2:11][O:12][CH3:13])[CH:4]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: Cc1ccccc1
Reactant: CCOC(=O)C(O)c1cc(OCOC)c(C)c(O)c1O
Solvent: CN(C)C=O
Product: CCOC(=O)C(O)c1cc(OCOC)c(C)c2c1OCO2
Temperature: 25 °C

Procedure:
Into a clean and dry 2 L, 4-necked RB flask was charged 400 ml of N,N-dimethylformamide under nitrogen atmosphere at RT. Cesium carbonate (171 g) was added to the reaction mass under stirring at room temperature. Bromochloromethane (226 g) was added to the reaction mass under stirring at RT. Reaction mass was heated to 30-35° C. Ethyl 2-(2,3-dihydroxy-5-(methoxymethoxy)-4-methylphenyl)-2-hydroxyacetate (50 g) was dissolved in 100 ml of DMF and slowly added to the reaction mass under stirring at 30-35° C. Reaction mass was maintained at 30-35° C. for 2.5 h under stirring. Reaction mass was poured into 1 L toluene and stirred for 1.0 h at RT. Reaction mass was filtered through hyflow bed, and the bed washed with 600 mL of toluene. Filtrate was washed with 2.0 L of DM water. Aqueous layer was extracted with 2×500 mL of toluene. Combined organic layer was washed with 2×600 mL of saturated sodium chloride solution and treated with 7.5 g of activated carbon at 45-50° C. Reaction mass was filtered and distilled of solvent under vacuum at 45-55° C. to get 40 g of crude title compound as syrup. HPLC purity of the crude compound is 92.5%. The crude compound was directly used in next step. A small sample was purified by column chromatography to compare its spectral data with the literature values.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[C:8]([CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:9][CH:10]=[C:11]([Cl:12])[C:4]=2[N:3]=1.[Br:18][C:19]1[CH:25]=[C:24]([CH3:26])[C:22]([NH2:23])=[C:21]([O:27][CH3:28])[CH:20]=1>CN1CCCC1=O.C(OCC)(=O)C.O>[Br:18][C:19]1[CH:25]=[C:24]([CH3:26])[C:22]([NH:23][C:2]2[N:6]([CH3:7])[C:5]3[C:8]([CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:9][CH:10]=[C:11]([Cl:12])[C:4]=3[N:3]=2)=[C:21]([O:27][CH3:28])[CH:20]=1
Reactant: COc1cc(Br)cc(C)c1N
Reactant: CCC(CC)c1ccc(Cl)c2nc(Cl)n(C)c12
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCC(CC)c1ccc(Cl)c2nc(Nc3c(C)cc(Br)cc3OC)n(C)c12
Temperature: 130 °C
Reaction time: 48 h
Yield: 49.1 %

Procedure:
A mixture of 2,4-dichloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole (140 mg, 0.52 mmol), 4-bromo-2-methoxy-6-methylaniline (335 mg, 1.55 mmol) and 1-methyl-2-pyrrolidone (5 drops) was stirred at 130° C. for 2 days under nitrogen atmosphere. The mixture was dissolved in ethyl acetate/water, extracted with ethyl acetate and washed with brine. The organic layer was dried over magnesium sulfate, and concentrated to give a brown oil. The oil was subjected to chromatography on a silica gel (n-hexane/ethyl acetate=10:1-1:1) and crystallized from iso-propanol to afford the title compound as colorless crystals (115 mg, 49%). mp. 218-220° C.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[H-].[Na+].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>C1COCC1.CCOCC>[CH:1]1([O:7][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: OC1C=CCCC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: C1=CC(OCc2ccccc2)CCC1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A solution of cyclohex-2-en-1-ol (10.0 g, 101.9 mmol) in anhydrous THF (100 mL) was added to a stirred suspension containing sodium hydride (8.0 g, 199.7 mmol) (60% dispersion in oil) and benzyl bromide in anhydrous THF (250 mL) maintained at 50° C. The resulting solution was stirred at 55-60° C. for 18 h. After cooling to ambient temperature, water was added to quench the reaction and the mixture was diluted with ether (500 mL). The organic phase was separated, dried (Na2SO4), filtered and concentrated in vacuo to an oil that was subjected to a short silica plug filtration to provide 16.1 g of desired product 51a that was used directly in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl[C:29]1[N:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>CCOC(C)=O.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>[C:1]([O:5][C:6](=[O:27])[CH2:7][N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:29]3[N:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=3)[CH:14]=2)[CH2:9]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CN1CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1
Reactant: Cc1ccc(Cl)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccc(-c2ccc3c(c2)CCN(CC(=O)OC(C)(C)C)C3)nn1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
To a mixture of [6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-acetic acid tert-butyl ester (1.12 g, 3 mmol), 3-chloro-6-methyl-pyridazine (501 mg, 3.9 mmol, 1.3 eq.), Pd(PPh3)4 (104 mg, 0.009 mmol, 0.03 eq.) under nitrogen, are added dioxane (30.0 ml) and sodium carbonate aqueous solution (2.0N, 3.0 ml). The resulting mixture is stirred at 90° C. for 16 hr. The reaction mixture is diluted with EtOAc (80 ml), washed with water and brine, dried over sodium sulfate, and concentrated. The crude product is purified by silica gel flash chromatography (hexane/EtOAc 1:1) to give the title compound. MS (+VE) m/z 340.20 (M++1).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:16])[C:14]=1[CH3:15])=[CH:11][CH:10]=[CH:9][CH:8]=2.C(N(CC)CC)C.[CH2:24]([N:29]=[C:30]=[O:31])[CH2:25][CH2:26][CH2:27][CH3:28]>C(Cl)(Cl)Cl>[CH3:15][C:14]1[C:13](=[O:16])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[CH2:4][NH:3][C:30]([NH:29][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:31]
Reactant: CCCCCN=C=O
Reactant: Cc1c(CN)[nH]c2ccccc2c1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCNC(=O)NCc1[nH]c2ccccc2c(=O)c1C
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a solution of 2-(aminomethyl)-3-methylquinolin-4(1H)-one dihydrochloride (160 mg) in chloroform (5 mL) were sequentially added triethylamine (0.26 mL) and pentyl isocyanate (0.09 mL), and the mixture was stirred at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol=20/1) to obtain 1-[(3-methyl-4-oxo-1,4-dihydroquinolin-2-yl)methyl]-3-pentylurea (117 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](I)[CH:15]=3)[C:10]([C:18]([N:20]([CH3:22])[CH3:21])=[O:19])=[N:9]2)[CH:5]=[C:4]([NH:23][CH3:24])[N:3]=1.N1CCCCC1.[N:31]1[CH:36]=[CH:35][CH:34]=[N:33][C:32]=1[C:37]([OH:41])([C:39]#[CH:40])[CH3:38]>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.[Cu]I.C(OCC)(=O)C.CCCCCCC>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:40]#[C:39][C:37]([OH:41])([C:32]4[N:33]=[CH:34][CH:35]=[CH:36][N:31]=4)[CH3:38])[CH:15]=3)[C:10]([C:18]([N:20]([CH3:22])[CH3:21])=[O:19])=[N:9]2)[CH:5]=[C:4]([NH:23][CH3:24])[N:3]=1
Reactant: C#CC(C)(O)c1ncccn1
Reactant: CNc1cc(-n2nc(C(=O)N(C)C)c3ccc(I)cc32)nc(N)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCCC
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Product: CNc1cc(-n2nc(C(=O)N(C)C)c3ccc(C#CC(C)(O)c4ncccn4)cc32)nc(N)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a sealed tube was added 1-[2-amino-6-(methylamino)pyrimidin-4-yl]-6-iodo-N,N-dimethyl-1H-indazole-3-carboxamide (86 mg, 0.20 mmol), followed by piperidine (2 mL), tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol), copper(I) iodide (4 mg, 0.02 mmol) and 2-(pyrimidin-2-yl)but-3-yn-2-ol (58 mg, 0.39 mmol). The reaction mixture was purged with nitrogen gas, capped and stirred at room temperature for 1.5 hr. After cooling to RT, the reaction mixture was concentrated in vacuo. EtOAc (5 mL) was added and concentration in vacuo repeated. The residue was purified using column chromatography (Biotage, 0-10% gradient of methanol in DCM) to give a brown solid. Trituration of the solid with ethyl acetate/heptane gave the title compound. 1H NMR (DMSO, 500 MHz) delta 1.92 (3H, s), 2.80 (3H, d, J=4.1 Hz), 3.10 (3H, s), 3.31 (3H, s), 6.26 (2H, s), 6.49 (2H, s), 7.11 (1H, s), 7.30 (1H, d, J=8.4 Hz), 7.51 (1H, t, J=4.9 Hz), 7.94 (1H, d, J=8.4 Hz), 8.78-9.04 (3H, m); LC-MS: m/z=+458.10 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:17]O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:17])=[O:9])=[CH:11][CH:12]=1
Reactant: O=C(O)C=Cc1ccc(Br)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)/C=C/c1ccc(Br)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 4-bromocinnamic acid (16 g) in methanol (150 mL) was added thionyl chloride (30 mL) at 0° C. The reaction mixture was warmed to room temperature and refluxed for 3 hours. After cooling to room temperature the solvents were evaporated to dryness. The crude compound obtained was used as such for the next step.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[NH:11][C:10]3([CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.CC#N.C(=O)([O-])[O-].[Cs+].[Cs+].CC1C=CC(S(O[CH2:36][CH2:37][O:38][CH3:39])(=O)=O)=CC=1>C(OCC)(=O)C.O>[Cl:1][C:2]1[N:3]=[C:4]2[N:11]([CH2:36][CH2:37][O:38][CH3:39])[C:10]3([CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1
Reactant: COCCOS(=O)(=O)c1ccc(C)cc1
Reactant: O=c1cc(Cl)nc2n1CC1(CCCC1)N2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COCCN1c2nc(Cl)cc(=O)n2CC12CCCC2
Temperature: 65 °C
Yield: 63.6 %

Procedure:
0.200 g of 7′-chlorospiro[cyclopentane-1,2′-imidazo[1,2-a]pyrimidin]-5′-one are suspended in 7 mL de CH3CN, 0.62 g of cesium carbonate and 0.49 g of 2-methoxyethyl 4-methylbenzenesulfonate are added. The mixture is heated to 65° C. for 36 h. Water, ethyl acetate are added and then after decantation the organic phase is dried with magnesium sulfate and then evaporated. The crude is purified by flash chromatography on silica gel (CH2CL2/MeOH, 99/1). 0.16 g (yield=41%) of 7′-chloro-1′-(2-methoxyethyl)-spiro[cyclopentane-1,2′-imidazo[1,2-a]pyrimidin]-5′-one are obtained as a brown powder and including the following characteristics:
Reaction SMILES: ClS([N:5]=[C:6]=O)(=O)=O.CC(OC([N:15](C(OC(C)(C)C)=O)[C:16]1[CH:17]=[N:18][CH:19]=[C:20]([C:22]2[N:23]([CH3:32])[C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[C:26]([Cl:31])[CH:25]=3)[CH:21]=1)=O)(C)C.CN(C=O)C>C(#N)C>[NH2:15][C:16]1[CH:21]=[C:20]([C:22]2[N:23]([CH3:32])[C:24]3[C:29]([C:30]=2[C:6]#[N:5])=[CH:28][CH:27]=[C:26]([Cl:31])[CH:25]=3)[CH:19]=[N:18][CH:17]=1
Reactant: Cn1c(-c2cncc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2)cc2ccc(Cl)cc21
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cn1c(-c2cncc(N)c2)c(C#N)c2ccc(Cl)cc21
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
Chlorosulfonyl isocyanate (1.63 g, 11.5 mmol) is added to a solution of 3-[bis[[(1,1-dimethylethyl)oxy]carbonyl]amino]-5-(6-chloro-1-methyl-1H-indol-2-yl)-pyridine (0.91 g, 1.99 mmol) in acetonitrile (200 mL) and the reaction mixture is stirred for 10 min. DMF (3 mL) is added and the reaction mixture is stirred for 3 h. 20 g silica gel is added to the mixture and the solvent is removed in vacuo. The resulting solid is heated to 65° C. under high vacuum for 2 h. The mixture is cooled to room temperature and then purified by silica gel flash chromatography (dichloromethane-methanol-triethylamine, 83:8:9) to afford 2-(5-amino-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.76 (s, 3H), 5.72 (s, 2H), 7.15 (t, J=2.3 Hz, 1H), 7.35 (dd, J=8.5, 1.9 Hz, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.92 (d, J=1.8 Hz, 1H), 7.97 (d, J=1.8 Hz, 1H), 8.12 (d, J=2.5 Hz, 1H). MS (ESI) m/z 283.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([NH:21][C:22](=[O:30])[CH2:23][CH2:24][O:25]C(C)(C)C)=[CH:16][CH:15]=3)=[O:11])=[C:4]([F:31])[C:3]=1[O:32][C:33]1[CH:38]=[C:37]([C:39]#[N:40])[CH:36]=[C:35]([Cl:41])[CH:34]=1>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([NH:21][C:22](=[O:30])[CH2:23][CH2:24][OH:25])=[CH:16][CH:15]=3)=[O:11])=[C:4]([F:31])[C:3]=1[O:32][C:33]1[CH:38]=[C:37]([C:39]#[N:40])[CH:36]=[C:35]([Cl:41])[CH:34]=1
Reactant: CC(C)(C)OCCC(=O)Nc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)cc2c1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4cc(NC(=O)CCO)ccc4[nH]3)c2F)c1
Temperature: 100 °C
Yield: 19.3 %

Procedure:
N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-5-({3-[(1,1-dimethylethyl)oxy]propanoyl}amino)-1H-indole-2-carboxamide (0.040 g, 0.067 mmol) was dissolved in 4N HCl in dioxane (3 mL). The solution was heated at 100° C. overnight. The reaction mixture was cooled to room temperature and the solvent was evaporated. The residue was purified by reverse phase HPLC (acetonitrile:water with 0.1% TFA) to give the title compound (0.007 g, 19%) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.49 (br. s., 1H), 9.70 (s, 1H), 8.67-9.07 (m, 1H), 7.95 (s, 1H), 7.77 (s, 1H), 7.42-7.53 (m, 2H), 7.37 (d, 1H), 7.25-7.32 (m, 1H), 7.19-7.25 (m, 1H), 7.06 (s, 1H), 4.52 (d, 2H), 3.62-3.73 (m, 2H), 3.51-3.60 (m, 1H), 2.40 (t, 2H). ES MS: m/z 541 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-])=O)=[CH:4][N:3]=1>CCOC(C)=O.[Ni]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([NH2:9])=[C:6]([NH2:8])[CH:7]=1
Reactant: Nc1cc(Cl)ncc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCOC(C)=O
Product: Nc1cnc(Cl)cc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 107.4 %

Procedure:
To a solution of 2-chloro-5-nitropyridin-4-amine (4.50 g, 25.93 mmol) in EtOAc (100 mL) was added Raney nickel (0.45 g) followed by stirring under hydrogen at RT for 2 h. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to afford 4.00 g (ca. 100%) of crude 6-chloropyridine-3,4-diamine as yellow oil. MS (ESI): m/z=144.3 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:16])=[CH:4][C:5]([OH:15])=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH3:14])[N:10]=[N:9]2)[CH:7]=1.Cl[C:18]1[N:23]=[C:22]([NH:24][C@@H:25]2[CH2:33][C@H:32]3[N:28]([CH2:29][CH2:30][CH2:31]3)[C:27]([CH3:35])([CH3:34])[CH2:26]2)[C:21]([C:36]#[N:37])=[CH:20][N:19]=1.[C:38]1([S:44]([OH:47])(=[O:46])=[O:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CC(O)C>[CH3:34][C:27]1([CH3:35])[CH2:26][C@H:25]([NH:24][C:22]2[C:21]([C:36]#[N:37])=[CH:20][N:19]=[C:18]([NH:1][C:2]3[C:3]([F:16])=[CH:4][C:5]([OH:15])=[C:6]([N:8]4[C:12](=[O:13])[N:11]([CH3:14])[N:10]=[N:9]4)[CH:7]=3)[N:23]=2)[CH2:33][C@H:32]2[N:28]1[CH2:29][CH2:30][CH2:31]2.[C:38]1([S:44]([OH:47])(=[O:46])=[O:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC1(C)C[C@H](Nc2nc(Cl)ncc2C#N)C[C@@H]2CCCN21
Reactant: Cn1nnn(-c2cc(N)c(F)cc2O)c1=O
Agent: O=S(=O)(O)c1ccccc1
Solvent: CC(C)O
Product: Cn1nnn(-c2cc(Nc3ncc(C#N)c(N[C@@H]4C[C@@H]5CCCN5C(C)(C)C4)n3)c(F)cc2O)c1=O
Temperature: 80 °C

Procedure:
A mixture of 1-(5-amino-4-fluoro-2-hydroxyphenyl)-4-methyl-1H-tetrazol-5(4H)-one (210 mg), (7R,8aS)-N-(2-chloro-5-cyanopyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine (220 mg), and benzenesulfonic acid (200 mg) in IPA (2 mL) were heated to 80° C. for overnight. After cooling to ambient temperature, the crude mixture was concentrated to dryness. The crude product was absorbed onto silica gel and purified by CombiFlash chromatography (2N NH3 in MeOH/CH2Cl2=0-30%) to give compound 1-(5-(4-((7R,8aS)-octahydro-5,5-dimethylindolizin-7-ylamino)-5-cyanopyrimidin-2-ylamino)-4-fluoro-2-hydroxyphenyl)-4-methyl-1H-tetrazol-5(4H)-one (540 mg with some benzenesulfonic acid).
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:24])[CH:9]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:10][CH2:11][C:12]([O:14]C)=[O:13].[OH-].[Na+].Cl>CO>[C:12]([CH2:11][CH2:10][CH:9]([CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:8]([NH:7][CH2:6][CH2:5][CH2:4][C:3]([OH:25])=[O:2])=[O:24])([OH:14])=[O:13]
Reactant: COC(=O)CCCNC(=O)C(CCC(=O)OC)CCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCNC(=O)C(CCC(=O)O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To the solution of 150 mg of N-(4-methoxycarbonyl-2-phenethylbutyryl)-4-aminobutyric acid methyl ester in 3 ml of methanol is added 1.0 ml of 1N sodium hydroxide and stirred for 4 hours at room temperature. The mixture is acidified with 1.5 ml of 1N hydrochloric acid, and concentrated. The solid is collected and washed with water to yield N-(4-carboxy-2-phenethyl-butyryl)-4-aminobutyric acid.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH:5]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)C.[OH-].[Li+]>O1CCCC1>[C:20]([O:19][C:17]([NH:16][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)[C:4]([OH:24])=[O:3])=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CCOC(=O)C(Cc1cccc([N+](=O)[O-])c1)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(Cc1cccc([N+](=O)[O-])c1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of crude 2-tert-butoxycarbonylamino-3-(3-nitro-phenyl)-propionic acid ethyl ester (1.00 g , ≈2.96 mmol) in tetrahydrofuran (10 mL) was added 3M aqueous lithium hydroxide solution (3 mL, 9 mmol) and the mixture was stirred at ambient temperature overnight. The reaction mixture was concentrated to dryness, the residue taken up in water (20 mL) and extracted with ether (2×10 mL). The aqueous layer was filtered through Celite®, cooled in ice and adjusted to pH=2 with 0.1M aqueous hydrochloric acid. The mixture was then extracted with dichloromethane (3×15 mL), dried over sodium sulfate and concetrated in vacuo to give crude 2-tert-butoxycarbonylamino-3-(3-nitro-phenyl)-propionic acid as a pale yellow solid which was used without further purification (0.63 g, ≈69%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([CH3:11])[C:8](/[CH:12]=[CH:13]/[C:14]([OH:16])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22]([CH2:27][OH:28])=[CH:21]2>>[C:1]([C:5]1[N:10]=[C:9]([CH3:11])[C:8](/[CH:12]=[CH:13]/[C:14]([NH:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22]([CH2:27][OH:28])=[CH:21]3)=[O:16])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1nc(C(C)(C)C)ccc1/C=C/C(=O)O
Reactant: Nc1ccc2[nH]c(CO)cc2c1
Product: Cc1nc(C(C)(C)C)ccc1/C=C/C(=O)Nc1ccc2[nH]c(CO)cc2c1

Procedure:
Analogous to the procedure used to prepare Example 1, (2E)-3-[6-(tert-butyl)-2-methyl(3-pyridyl)]prop-2-enoic acid, Example 75(c), (10 mg, 0.50 mmol) and (5-aminoindol-2-yl)methan-1-ol, Example 74(b), (81, 0.50 mmol) provided, after purification by silica gel chromatography (25:75 hexane:EtOAc), the title compound as a pale yellow solid. MP 213° C. MS (ESI, pos. ion) m/z: 364 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.C(Cl)(=O)C(Cl)=O.N1C=CC=CC=1.[NH2:25][N:26]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=[C:27]1[N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>C(Cl)Cl.CN(C=O)C.CCOC(C)=O>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:25][N:26]2[C:35](=[O:36])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=[C:27]2[N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: Nn1c(N2CCCC2)nc2ccccc2c1=O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1cc(F)cc(F)c1)Nn1c(N2CCCC2)nc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 15 %

Procedure:
3,5-Difluorophenylacetic acid (0.227 g, 1.30 mmol) was dissolved in DCM (5 mL), followed by addition of oxalyl chloride (137 μL, 1.56 mmol) and 2 drops of dry DMF. After 1 hour gas evolution had stopped and pyridine (106 μL, 1.30 mmol) was added, followed by addition of 3-amino-2-pyrrolidin-1-yl-3H-quinazolin-4-one. After stirring at RT for 5 minutes additional pyridine (212 μL, 2.60 mmol) was added. The reaction mixture was stirred overnight at RT. The mixture was diluted with EtOAc (20 mL), washed with 1 M HCl (20 mL), dried (MgSO4) and evaporated in vacuo. The crude product was subjected to column chromatography (EtOAc/Heptane) giving the title compound (0.073 g, 15%). LC-ESI-HRMS of [M+H]+shows 385,1485 Da. Calc. 385,147607 Da.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([O:8][CH2:9][C:10]([CH2:15][O:16][C:17](=[O:19])[CH3:18])([CH3:14])[C:11](O)=[O:12])(=[O:7])[CH3:6]>>[C:5]([O:8][CH2:9][C:10]([CH2:15][O:16][C:17](=[O:19])[CH3:18])([CH3:14])[C:11]([Cl:3])=[O:12])(=[O:7])[CH3:6]
Reactant: CC(=O)OCC(C)(COC(C)=O)C(=O)O
Reactant: O=S(Cl)Cl
Product: CC(=O)OCC(C)(COC(C)=O)C(=O)Cl
Temperature: 100 °C

Procedure:
182 ml (2.5 moles) of thionyl chloride are poured over 218 g (1 mole) of 2,2-bis-acetonxymethyl propionic acid (step 1), followed by refluxing for 8 hours at a batch temperature of approximately 100° C. Excess thionyl chloride is distilled off in a water jet vacuum, leaving a pale yellow, oily product. Yield 236 g (100% of the theoretical).