Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])(CC)C.[C:6]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]([O:19][CH3:20])[O:17][CH3:18])[C:11]=1[O:21][CH2:22][O:23][CH3:24])([CH3:9])([CH3:8])[CH3:7].CN(C)CCN(C)C.CN(C)[CH:35]=[O:36].Cl.[BH4-].[Na+]>C(OCC)C.CO.O>[C:6]([C:10]1[CH:15]=[CH:14][C:13]([CH2:35][OH:36])=[C:12]([CH:16]([O:19][CH3:20])[O:17][CH3:18])[C:11]=1[O:21][CH2:22][O:23][CH3:24])([CH3:9])([CH3:7])[CH3:8]
Reactant: COCOc1c(C(OC)OC)cccc1C(C)(C)C
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [BH4-]
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: COCOc1c(C(C)(C)C)ccc(CO)c1C(OC)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.9 %

Procedure:
A sec-butyl lithium-1.00M cyclohexane-n-hexane mixture solution (29.8 ml, 29.8 mmol) was added dropwise to a solution of 1-tert-butyl-3-(dimethoxymethyl)-2-(methoxymethoxy)benzene (4.00 g, 14.9 mmol) obtained in Example (10-1) and N,N,N′,N′-tetramethylethylenediamine (4.72 ml, 31.3 mmol) in diethyl ether (100 ml) at −40° C. over 20 minutes. After the reaction mixture was stirred at room temperature for 1 hour, it was cooled to −20° C. and N,N-dimethylformamide (2.30 ml, 31.3 mmol) was added thereto. After the temperature of the reaction mixture was returned to room temperature and the mixture was further stirred for 1 hour, the mixture was carefully poured into cold 0.1N hydrochloric acid and the mixture was extracted with ethyl acetate (three times). The combined organic layer was successively washed with 0.1N hydrochloric acid, water (three times) and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure to give a residue. The obtained residue was dissolved in methanol (10 ml) and sodium borohydride (111 mg, 3.00 mmol) was added thereto under ice-cooling, and the mixture was stirred at room temperature overnight. After the reaction mixture was poured into water and the mixture was extracted with ethyl acetate (four times), the organic layer was successively washed with water (twice) and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=10/1-3/1) to give [4-tert-butyl-2-(dimethoxymethyl)-3-(methoxymethoxy)phenyl]methanol (350 mg, yield: 8%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[CH2:5][NH:6][CH2:7][CH:8]1[O:12][CH2:11][CH2:10][O:9]1)[CH3:2].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:29](=[O:34])[CH:30]([Cl:33])[CH2:31][CH3:32]>O>[CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[CH2:5][N:6]([CH2:7][CH:8]1[O:12][CH2:11][CH2:10][O:9]1)[C:29](=[O:34])[CH:30]([Cl:33])[CH2:31][CH3:32])[CH3:2]
Reactant: CCOC(CNCC1OCCO1)OCC
Reactant: CCC(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(CN(CC1OCCO1)C(=O)C(Cl)CC)OCC

Procedure:
N-(2,2-Diethoxyethyl)-N-(1,3-dioxolan-2-ylmethyl)amine (0.05 mole), benzene (100 ml), water (100 ml) and sodium carbonate (2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is cooled to a temperature of from 5° to 10° C and α-chlorobutanoyl chloride (0.05 mole) is added dropwise with stirring. After the addition is completed stirring is continued until the reaction mixture has reached room temperature. After this time the organic phase is separated from the aqueous phase and is washed with water. The washed solution is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2,2-diethoxyethyl)-N-(1,3-dioxolan-2-ylmethyl)-α-chlorobutanamide as the residue.
Reaction SMILES: [CH:1]([CH:4]1[C:9](=O)[N:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[O:5]1)([CH3:3])[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21]>C1(C)C=CC=CC=1>[CH:1]([CH:4]1[C:9](=[S:21])[N:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[O:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)CN1C(=O)C(C(C)C)Oc2ccccc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: Cc1ccccc1
Product: COC(=O)CN1C(=S)C(C(C)C)Oc2ccccc21

Procedure:
A mixture of methyl 3,4-dihydro-2-isopropyl-3-oxo-2H-1,4-benzoxazine-4-acetate (26.0 g), phosphorus pentasulfide (44.4 g) and toluene (250 ml) was refluxed for 3 hours with heating. After cooling the insoluble matter was removed by filtration, and the solvent was evaporated off. To the residue, isopropyl ether (200 ml) was added and the insoluble matter was removed by filtration. The solvent was evaporated off, and hexane was added to the residue, to give crystals of methyl 3,4-dihydro-2-isopropyl-3-thioxo-2H-1,4-benzoxazine-4-acetate. Yield was 22.5 g (80.6%). Recrystallization from isopropyl alcohol gave yellow prisms (mp 60°-61° C.).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[C:18](B5OC(C)(C)C(C)(C)O5)[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.Br[C:33]1[CH:34]=[C:35]([C:39]2[NH:43][N:42]=[N:41][N:40]=2)[CH:36]=[CH:37][CH:38]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]([C:37]5[CH:38]=[CH:33][CH:34]=[C:35]([C:39]6[N:40]=[N:41][NH:42][N:43]=6)[CH:36]=5)[C:19]([CH3:22])=[CH:20][CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Brc1cccc(-c2nnn[nH]2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1cccc(-c2nn[nH]n2)c1
Temperature: 110 °C

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxamide (42.1 mg, 0.100 mmol), 5-(3-bromophenyl)-tetrazole (22.5 mg, 0.100 mmol), a 1 M aqueous solution of potassium carbonate (0.50 mL), Pd-FibreCat 1007 (6 mg), and ethanol (0.50 mL) were combined. The mixture was heated at 110° C. for 5 min (5 min ramp time) in a microwave reactor. After cooling, the mixture was filtered and purified by prep-HPLC to provide 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-3′-(2H-tetrazol-5-yl)-biphenyl-3-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 439.2, found 440.2 (M+1)+; Retention time 2.59 minutes.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[S:8]([CH3:10])=O.[C:17]1(S)[CH:22]=[CH:21]C=[CH:19][CH:18]=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[S:8][C:10]1[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=1
Reactant: Sc1ccccc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: Nc1nc(Sc2ccccc2)c(Br)c(-c2ccco2)n1

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, thiophenol and DBU in dioxane. EI-MS m/e (%): 349 (M{81Br}+, 40), 348 ([M{81Br}-H]+, 28), 347 (M{79Br}+, 39), 346 ([M{79Br}-H]+, 24), 268 ([M—Br]+, 100), 175 (92).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[S:12](=O)(=[O:15])([OH:14])[OH:13]>>[CH:3]1[C:2]([OH:11])=[CH:1][C:10]2[CH:9]=[CH:8][C:7]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:6][C:5]=2[CH:4]=1
Reactant: Oc1ccc2ccccc2c1
Reactant: O=S(=O)(O)O
Product: O=S(=O)(O)c1ccc2cc(O)ccc2c1

Procedure:
In the conventional method for preparing Schaeffer's Salt, 2-naphthol is heated with concentrated sulfuric acid until sulfonation is complete. The temperature and reaction time are controlled to provide a high yield of 2-naphthol-6-sulfonic acid. The sulfonation mass is then drowned in water, the resulting solution is neutralized with sodium hydroxide or sodium carbonate, and the crude Schaeffer's Salt is isolated by filtration. The Schaeffer's Salt thus obtained is not pure enough for commercial use and, therefore, must be purified. The conventional method for doing this is to recrystallize the Schaeffer's Salt by dissolving the crude salt in water, treating the solution with activated carbon and, optionally, filter aids, clarifying the solution by filtration, salting out the Schaeffer's Salt by addition of common salt to the clarified solution, and filtering off the precipitated Schaeffer's Salt. Thus, the conventional recovery and purification of the salt requires many operations, including three filtration steps. The many operations thus involved have a serious adverse effect on the cost of manufacture of Schaeffer's Salt. Not only are there high equipment and labor costs, but product losses due to the several handling operations are also encountered. This processing leaves about 2-3% of the disodium salt of DONS in the product recovered.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[N:4]([C:7]1[CH:22]=[CH:21][C:10]([O:11][C:12]2[CH:13]=[CH:14][C:15]3[S:19][N:18]=[CH:17][C:16]=3[CH:20]=2)=[CH:9][CH:8]=1)=[C:5]=[O:6]>C(OCC)C>[CH3:1][N:2]([CH3:3])[C:5]([NH:4][C:7]1[CH:22]=[CH:21][C:10]([O:11][C:12]2[CH:13]=[CH:14][C:15]3[S:19][N:18]=[CH:17][C:16]=3[CH:20]=2)=[CH:9][CH:8]=1)=[O:6]
Reactant: CNC
Reactant: O=C=Nc1ccc(Oc2ccc3sncc3c2)cc1
Solvent: CCOCC
Product: CN(C)C(=O)Nc1ccc(Oc2ccc3sncc3c2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 88 %

Procedure:
5 parts of gaseous dimethylamine were passed into a solution of 26.8 parts of 5-(4'-isocyanatophenoxy)-benzisothiazole in 300 parts of diethyl ether, the reaction mixture was stirred for 12 hours at from 20 to 30° C., and the resulting precipitate was isolated. 27.6 parts (88% of theory) of 5-(4'-dimethylaminocarbonylaminophenoxy)-benzisothiazole of melting point 156° C. were obtained.
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[OH:20][C:21]([C:25]1[CH:29]=[C:28]([CH:30]=[O:31])[O:27][N:26]=1)([C:23]#[CH:24])[CH3:22]>>[F:19][C:3]1[C:2]([C:24]#[C:23][C:21]([C:25]2[CH:29]=[C:28]([CH:30]=[O:31])[O:27][N:26]=2)([OH:20])[CH3:22])=[CH:18][C:6]2[C:7]3[N:8]([CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: C#CC(C)(O)c1cc(C=O)on1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)c1cc(C=O)on1
Yield: 10 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 3-(2-hydroxybut-3-yn-2-yl)-1,2-oxazole-5-carbaldehyde to give the titled compound as a light yellow solid (14 mg, 10%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:10][CH2:9][CH2:8][C:7]=1[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=2)[N:13](S(C2C=CC(C)=CC=2)(=O)=O)[CH:12]=1)=[O:5])[CH3:2].[OH-].[Na+]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH2:10][CH2:9][CH2:8][C:7]=1[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=2)[NH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(c2cn(S(=O)(=O)c3ccc(C)cc3)c3ccc(C#N)cc23)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(c2c[nH]c3ccc(C#N)cc23)CCC1
Yield: 93.8 %

Procedure:
2-[5-Cyano-1-(toluene-4-sulfonyl)-1H-indol-3-yl]-cyclopent-1-enecarboxylic acid ethyl ester (2.0 g, 4.6 mMol) was dissolved in THF (100 mL) and sodium hydroxide (1.8 mL, 10 N, 18 mMol) was added. After refluxing for 4 h, the reaction was filtered through celite and the filtrate was evaporated. The residue was dissolved in brine (20 mL) and extracted with ethyl acetate (3×30 mL). The combined organics were dried with magnesium sulfate and evaporated in vacuo. The material was purified by chromatography on silica using ethyl acetate/hexanes (30–40%) as the eluent to provide the product as a white solid (1.21 g, 94%). 1H NMR (400 MHz, CDCl3) δ 8.59 (1H, bs), 7.93 (1H, s), 7.84 (1H, s), 7.40 (2H, s), 4.12 (2H, q, J=7.2 Hz), 3.01 (2H, m), 2.86 (2H, m), 2.02 (2H, pentet, J=7.5 Hz), 1.16 (3H, t, J=7.3 Hz); MS m/e 303.2 (M+Na).
Reaction SMILES: [N+](C1C=CC([O:10][C:11]([C:13]2[C:21]3[O:20][C:19]([N:22]4[CH2:25][CH2:24][CH2:23]4)=[N:18][C:17]=3[C:16]([O:26][CH:27]([F:29])[F:28])=[CH:15][CH:14]=2)=O)=CC=1)([O-])=O.[NH2:30][C:31]1[N:35]([CH3:36])[N:34]=[CH:33][C:32]=1[C:37]#[N:38]>>[C:37]([C:32]1[CH:33]=[N:34][N:35]([CH3:36])[C:31]=1[NH:30][C:11]([C:13]1[C:21]2[O:20][C:19]([N:22]3[CH2:25][CH2:24][CH2:23]3)=[N:18][C:17]=2[C:16]([O:26][CH:27]([F:29])[F:28])=[CH:15][CH:14]=1)=[O:10])#[N:38]
Reactant: Cn1ncc(C#N)c1N
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccc(OC(F)F)c2nc(N3CCC3)oc12
Product: Cn1ncc(C#N)c1NC(=O)c1ccc(OC(F)F)c2nc(N3CCC3)oc12
Yield: 72.7 %

Procedure:
Starting from 2-(azetidin-1-yl)-4-difluoromethoxybenzooxazole-7-carboxylic acid 4-nitro-phenyl ester (178 mg) and 5-amino-1-methyl-1H-pyrazole-4-carbonitrile (107 mg). Purification by column chromatography on silica eluting with 3% methanol in dichloromethane followed by trituration in diethyl ether afforded the title compound as a white solid (124 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([C:18]([O:20]C)=[O:19])[CH:12]=2.[OH-].[Na+].C(OCC)(=O)C>C(O)C>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([C:18]([OH:20])=[O:19])[CH:12]=2
Reactant: COC(=O)c1ccc2cc(-c3c(C)cccc3C)[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cccc(C)c1-c1cc2ccc(C(=O)O)cc2[nH]1
Temperature: 80 °C

Procedure:
A mixture of methyl 2-(2,6-dimethylphenyl)-1H-indole-6-carboxylate (490 mg, 1.75 mmol) and 1N sodium hydroxide (3.5 mL, 3.5 mmol) in ethanol (25 mL) was heated at 80° C. for 18 h. The solution was poured into ethyl acetate and extracted with 1N HCl. The organic phase was dried, filtered, and solvent was removed under reduced pressure to afford 2-(2,6-dimethylphenyl)-1H-indole-6-carboxylic acid.
Reaction SMILES: COC1C=CC(CN(CC2C=CC(OC)=CC=2)C2N=CC(C3C4CCNC=4N=C(N4CCOCC4)N=3)=CN=2)=CC=1.NC1C(C)=C(C(N2CCN(CC)CC2)=O)C=CC=1.C(N1CCNCC1)C.CC1C=CC(N2CCOCC2)=CC=1N.[CH2:81]([N:83]1[CH2:88][CH2:87][N:86]([C:89]([C:91]2[C:92]([CH3:140])=[C:93]([NH:97][C:98]([N:100]3[C:104]4[N:105]=[C:106]([N:134]5[CH2:139][CH2:138][O:137][CH2:136][CH2:135]5)[N:107]=[C:108]([C:109]5[CH:110]=[N:111][C:112]([N:115](CC6C=CC(OC)=CC=6)CC6C=CC(OC)=CC=6)=[N:113][CH:114]=5)[C:103]=4[CH2:102][CH2:101]3)=[O:99])[CH:94]=[CH:95][CH:96]=2)=[O:90])[CH2:85][CH2:84]1)[CH3:82]>>[CH2:81]([N:83]1[CH2:88][CH2:87][N:86]([C:89]([C:91]2[C:92]([CH3:140])=[C:93]([NH:97][C:98]([N:100]3[C:104]4[N:105]=[C:106]([N:134]5[CH2:135][CH2:136][O:137][CH2:138][CH2:139]5)[N:107]=[C:108]([C:109]5[CH:114]=[N:113][C:112]([NH2:115])=[N:111][CH:110]=5)[C:103]=4[CH2:102][CH2:101]3)=[O:99])[CH:94]=[CH:95][CH:96]=2)=[O:90])[CH2:85][CH2:84]1)[CH3:82]
Reactant: CCN1CCN(C(=O)c2cccc(NC(=O)N3CCc4c(-c5cnc(N(Cc6ccc(OC)cc6)Cc6ccc(OC)cc6)nc5)nc(N5CCOCC5)nc43)c2C)CC1
Agent: CCN1CCN(C(=O)c2cccc(N)c2C)CC1
Agent: CCN1CCNCC1
Agent: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: CCN1CCN(C(=O)c2cccc(NC(=O)N3CCc4c(-c5cnc(N)nc5)nc(N5CCOCC5)nc43)c2C)CC1
Yield: 28 %

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (150 mg), and (3-amino-2-methyl-phenyl)-(4-ethyl-piperazin-1-yl)-methanone (76 mg) obtained using 1-ethyl-piperazine instead of morpholine in the same manner as Step A and Step B in Example 1-D-243, instead of 2-methyl-5-morpholin-4-yl-phenylamine, in the same manner as Step C in Example 1-D-237, 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid [3-(4-ethyl-piperazine-1-carbonyl)-2-methyl-phenyl]-amide was obtained as a crude product. The PMB groups were removed according to Deprotection method 2, to obtain the desired compound (D-245) (45 mg, 28%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([NH2:12])=[O:11])[CH:5]=[N:4][C:3]=1[C:16]#[N:17].N[C:19]1[CH:20]=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2.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.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:16]([C:3]1[N:4]=[CH:5][C:6]([NH:8][C@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([NH2:12])=[O:11])=[N:7][C:2]=1[C:19]1[CH:20]=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2)#[N:17]
Reactant: CC(C)[C@@H](Nc1cnc(C#N)c(Cl)n1)C(N)=O
Reactant: Nc1cnc2ccccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)[C@@H](Nc1cnc(C#N)c(-c2cnc3ccccc3c2)n1)C(N)=O
Temperature: 95 °C
Yield: 82.8 %

Procedure:
To a mixture of 3,5-dichloropyrazine-2-carbonitrile (500 mg, 2.84 mmol) and D-valinamide HCl salt (476 mg, 3.12 mmol) in AcCN (10 mL) was added DIPEA (1.11 mL, 6.25 mmol). After stirring at room temperature for 4 h, it was diluted with EtOAc, washed with sat. NaHCO3, organic layer was separated and washed with brine, dried and concentrated to give (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)-3-methylbutanamide (740 mg). Step 2: To a mixture of (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)-3-methylbutanamide (100 mg, 0.394 mmol) in Dioxane (2 mL) was added 3-aminoquinoline (71 mg, 0.492 mmol), Pd(OAc)2 (18 mg, 0.079 mmol), BINAP (49 mg, 0.079 mmol) and K2CO3 (163 mg, 1.18 mmol). After heating at 95° C. for 5 h, the mixture was filtered, the filtrate was concentrated and purified by preparative HPLC to give (R)-2-(5-cyano-6-(quinolin-3-yl)pyrazin-2-ylamino)-3-methylbutanamide (113 mg).
Reaction SMILES: [F:1][C:2]1([F:37])[CH2:4][C@@H:3]1[CH2:5][O:6][C:7]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([C:15]2[O:16][C:17]3[CH:22]=[C:21]([O:23][CH2:24][C@@H:25]([NH:27][C:28](=O)[O:29]C(C)(C)C)[CH3:26])[N:20]=[CH:19][C:18]=3[N:35]=2)=[CH:9][C:8]=1[F:36].C(Cl)(=O)OC1C=CC([N+:46]([O-])=O)=CC=1>>[F:37][C:2]1([F:1])[CH2:4][C@@H:3]1[CH2:5][O:6][C:7]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([C:15]2[O:16][C:17]3[CH:22]=[C:21]([O:23][CH2:24][C@@H:25]([NH:27][C:28]([NH2:46])=[O:29])[CH3:26])[N:20]=[CH:19][C:18]=3[N:35]=2)=[CH:9][C:8]=1[F:36]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COc1cc(-c2nc3cnc(OC[C@H](C)NC(=O)OC(C)(C)C)cc3o2)cc(F)c1OC[C@H]1CC1(F)F
Product: COc1cc(-c2nc3cnc(OC[C@H](C)NC(N)=O)cc3o2)cc(F)c1OC[C@H]1CC1(F)F

Procedure:
Using tert-butyl ((2S)-1-((2-(4-(((1R)-2,2-difluorocyclopropyl)methoxy)-3-fluoro-5-methoxyphenyl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)carbamate and 4-nitrophenyl carbonochloridate, and in the same manner as in Example 59, the title compound was obtained.
Reaction SMILES: C(OC(=O)C)(=[O:3])C.C([O:10][C:11](=[O:36])[C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([C:20]2[C:29](=N)[N:28]([CH2:31][CH3:32])[C:27]3[C:22](=[CH:23][N:24]=[C:25]4[NH:35][CH:34]=[CH:33][C:26]4=3)[CH:21]=2)[CH:13]=1)C>>[CH2:31]([N:28]1[C:27]2[C:22](=[CH:23][N:24]=[C:25]3[NH:35][CH:34]=[CH:33][C:26]3=2)[CH:21]=[C:20]([C:14]2[CH:13]=[C:12]([CH:17]=[C:16]([O:18][CH3:19])[CH:15]=2)[C:11]([OH:10])=[O:36])[C:29]1=[O:3])[CH3:32]
Reactant: CCOC(=O)c1cc(OC)cc(-c2cc3cnc4[nH]ccc4c3n(CC)c2=N)c1
Reactant: CC(=O)OC(C)=O
Product: CCn1c(=O)c(-c2cc(OC)cc(C(=O)O)c2)cc2cnc3[nH]ccc3c21
Temperature: 120 °C

Procedure:
Acetic anhydride (0.123 mL, 1.3 mmol) is added to (3-(9-ethyl-8-imino-8,9-dihydro-3H-3,4,9-triaza-cyclopenta[a]naphthalen-7-yl)-5-methoxy-benzoic acid ethyl ester (100 mg, 0.26 mmol) in sealed tube and heated at 120° C. for 2.5 hr. The acetic anhydride is evaporated and 6N HCl (3 mL) is added and the mixture is again heated at 105° C. for 1 hr. The reaction mixture is brought to room temperature and poured in ice cold water. The acid is crystallized out and filtered. It is washed with water and dried to give the desired product. MS m/z 364.2 (M+1).
Reaction SMILES: C(N(CC)CC)C.C(O)=O.[CH3:11][C@H:12]1[C:20]2[C:19]([N:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)=[N:18][CH:17]=[N:16][C:15]=2[C:14](=[O:34])[CH2:13]1.O[C@H]1C2N=CN=C(N3CCN(C(OC(C)(C)C)=O)CC3)C=2[C@H](C)C1>C(Cl)Cl>[OH:34][C@@H:14]1[C:15]2[N:16]=[CH:17][N:18]=[C:19]([N:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)[C:20]=2[C@H:12]([CH3:11])[CH2:13]1
Reactant: C[C@@H]1CC(=O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=CO
Product: C[C@@H]1C[C@H](O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Reaction time: 0.08 h
Yield: 95.4 %

Procedure:
Triethylamine (4.33 mL, 31.1 mmol) (degassed with nitrogen 30 minutes prior to use) and formic acid (1.36 mL, 36.1 mmol) (degassed with nitrogen 30 minutes prior to use) were added to a solution of (R)-tert-butyl 4-(5-methyl-7-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (9.75 g, 29.3 mmol) in DCM (210 mL; degassed with nitrogen 30 minutes prior to use). The reaction mixture was stirred for 5 minutes, and then a Ru catalyst (0.0933 g, 0.147 mmol) was added. The reaction was stirred under positive nitrogen pressure overnight (18 hours). The reaction mixture was concentrated to dryness and dried on a high vacuum. 1H NMR of the crude looked like 85% diastereoselectivity. The crude was flashed on Biotage 65M (loaded 1:1 DCM:ethyl acetate 500 mL flushed, then 1:4 DCM:ethyl acetate until product (2nd spot), then gradient to neat ethyl acetate, then 25:1 DCM:MeOH eluted rest of product. The fractions were combined and concentrated on a rotary evaporator. The residue was concentrated again from DCM/hexanes to give a mixture of tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (major) and tert-butyl 4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (minor) (9.35 g, 95.3% yield) as a beige foam. LC/MS (APCI+) m/z 335 [M+H]+. 1H NMR (CDCl3) shows 88% diastereoselectivity by integration of carbinol methine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH2:12]([CH2:14][NH2:15])[OH:13]>C(O)C.CO>[Cl:1][C:2]1[N:7]=[C:6]([NH:15][CH2:14][CH2:12][OH:13])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: NCCO
Solvent: CO
Solvent: CCO
Product: O=[N+]([O-])c1cnc(Cl)nc1NCCO
Reaction time: 18 h
Yield: 81 %

Procedure:
19.40 g (0.1 mole) of 2,4-dichloro-5-nitropyrimidine was completely dissolved in 60 ml of ethanol and maintained below 15° C. To this solution, a solution of 12.22 g (0.2 mole) of ethanolamine in 20 ml of methanol was added slowly while maintaining the temperature of a reactor below 20° C. The mixture was stirred below 15° C. for 18 hours. After completion of the reaction, the reaction product was maintained below 5° C., and the resulting crystal was filtered, washed and dried, thereby giving 17.71 g (81% yield) of light yellow-colored 2-chloro-4-(2-hydroxyethylamino)-5-nitropyrimidine.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]>O1CCCC1.CN(C)C1C=CN=CC=1.O.Cl>[Br:1][C:2]1[CH:10]=[C:6]([C:7]([O:9][C:6]([CH3:10])([CH3:7])[CH3:5])=[O:8])[CH:5]=[N:4][C:3]=1[Cl:11]
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)c1cnc(Cl)c(Br)c1
Reaction time: 16 h
Yield: 154.8 %

Procedure:
To a solution of 5-bromo-6-chloronicotinic acid (25.0 g, 106 mmol) in tetrahydrofuran (1.06 L) was added di-tort-butyl dicarbonate (69.2 g, 317 mmol) followed by 4-dimethylaminopyridine (12.9 g, 106 mmol). After 16 h, the mixture was diluted with water and aqueous hydrochloric acid was added (106 mL, 1 M, 106 mmol). The mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with brine (3×), dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→10% methanol/dichloromethane) gave the title compound (24.0 g). MS 292.96 (M).