Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[N:40]([C@@H:43]([C@H:47]1[CH2:51][CH2:50][O:49][CH2:48]1)[C:44](O)=[O:45])=[N+:41]=[N-:42].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[N:40]([C@@H:43]([C@H:47]1[CH2:51][CH2:50][O:49][CH2:48]1)[C:44]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20](=[O:21])[C@H:22]([C:23]([CH3:26])([CH3:25])[CH3:24])[NH:27][C:28]([O:29][CH3:30])=[O:31])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:45])=[N+:41]=[N-:42]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: [N-]=[N+]=N[C@H](C(=O)O)[C@H]1CCOC1
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N=[N+]=[N-])[C@H]1CCOC1)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 63.6 %

Procedure:
A solution of the product of Example 2C (0.050 g, 0.094 mmol) in tetrahydrofuran (1.0 mL) was treated with 2(S)-azido 2-(3(R)-tetrahydrofuranyl)acetic acid (J. Med. Chem. 1993, 36, 2300-2310) (0.020 g, 0.117 mmol), DEPBT (0.045 g, 0.151 mmol), and N,N-diisopropylethylamine (0.080 mL, 0.459 mmol), stirred at 25° C. for 12 hours and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic layer was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with a gradient starting with chloroform and ending with 5% methanol in ethyl acetate to give the title compound (0.041 g, 64% yield).
Reaction SMILES: [S:1]1[C:5](B(O)O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.Br[C:14]1[CH:28]=[CH:27][C:17](/[CH:18]=[CH:19]/[C:20]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])=[CH:16][CH:15]=1>>[S:1]1[C:5]([C:14]2[CH:28]=[CH:27][C:17](/[CH:18]=[CH:19]/[C:20]([N:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)=[O:21])=[CH:16][CH:15]=2)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: O=C(/C=C/c1ccc(Br)cc1)N1CCCC1
Reactant: OB(O)c1cc2ccccc2s1
Product: O=C(/C=C/c1ccc(-c2cc3ccccc3s2)cc1)N1CCCC1
Yield: 43 %

Procedure:
By essentially following the procedure detailed in Example 1, Part B, the title compound was prepared from benzo[b]thiophene-2-boronic acid and 1-(trans-4-bromocinnamoyl)pyrrolidine (Part A) in 43% yield following chromatography.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:33]1[C:45]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[C:39]2[C:34]1=[CH:35][CH:36]=[CH:37][CH:38]=2.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[CH2:11][CH2:10][N:9]1[CH:33]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:39]=2[C:40]2[C:45]1=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrC1c2ccccc2-c2ccccc21
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN(C2c3ccccc3-c3ccccc32)[C@H](Cc2ccccc2)C1)C(F)(F)F
Yield: 47.4 %

Procedure:
200 mg (0.467 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 25a with 138 mg (0.561 mmol) of 9-bromofluorene and 155 mg (1.12 mmol) of potassium carbonate in 2.5 ml of acetone. The title compound (131 mg, 47%) is obtained as oil. TLC:toluene/ethyl acetate (1:1) Rf =0.43; FD-MS:M+ =591.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([OH:20])[C:5]=1[O:21][CH3:22])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33]>C(#N)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([O:20][CH2:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33])[C:5]=1[O:21][CH3:22])[CH3:2]
Reactant: CCOc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OC
Reactant: CC(C)(CO)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1ccc(-c2ccc3c(c2)COC3=O)c(OCC(C)(C)CO)c1OC
Temperature: 80 °C
Yield: 14.6 %

Procedure:
To a stirring solution of 5-(4-ethoxy-2-hydroxy-3-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.266 mmol) in acetonitrile (7 mL) was added potassium carbonate (110 mg, 0.798 mmol) and 3-bromo-2,2-dimethylpropan-1-ol (134 mg, 0.798 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 0-25% ethyl acetate in pet ether) afforded title compound as a solid (15 mg, 14.7%).
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH3:24])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH:14]4[CH2:21][CH2:20][CH:17]([C:18]=3[CH3:19])[NH:16][CH2:15]4)=[CH:10][CH:11]=2)[N:6]([CH3:22])[C:5]1=[O:23].[O:26]1[CH:30]=[CH:29][C:28]([C:31](O)=[O:32])=[N:27]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[CH3:1][C:2]([CH3:25])([CH3:24])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH:14]4[CH2:21][CH2:20][CH:17]([C:18]=3[CH3:19])[N:16]([C:31]([C:28]3[CH:29]=[CH:30][O:26][N:27]=3)=[O:32])[CH2:15]4)=[CH:10][CH:11]=2)[N:6]([CH3:22])[C:5]1=[O:23]
Reactant: CC1=C(c2ccc3c(n2)n(C)c(=O)n3CC(C)(C)C)C2CCC1NC2
Reactant: O=C(O)c1ccon1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC1=C(c2ccc3c(n2)n(C)c(=O)n3CC(C)(C)C)C2CCC1N(C(=O)c1ccon1)C2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-(2,2-Dimethylpropyl)-3-methyl-5-(6-methyl-2-azabicyclo[2.2.2]oct-5-en-5-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (7-4, 8.6 mg, 0.03 mmol, 1.0 equiv), isoxazole-3-carboxylic acid (2-6, 4.3 mg, 0.04 mmol, 1.5 equiv), DIPEA (13 μL, 0.08 mmol, 3.0 equiv) and HATU (14.4 mg, 0.04 mmol, 1.5 equiv) were added to anhydrous acetonitrile (253 μL). After stirring for 10 min at room temperature, LCMS showed consumption of starting material. Purification by reverse-phase HPLC (10-100% CH3CN:0.1% TFA in H2O) provided 7-5 as a white solid. MS m/z (M+H): calculated=436.2343; observed=436.2351.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C@:5]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:9]([C:10](=[O:15])[C@@H:11]([O:13][CH3:14])[CH3:12])[N:8]=[C:7]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])[S:6]1.[ClH:30].[C:31](=[NH:35])(OC)[CH3:32].C(N(CC)CC)C>CO>[ClH:30].[F:23][C:17]1[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=1[C:7]1[S:6][C@@:5]([CH2:4][CH2:3][CH2:2][NH:1][C:31](=[NH:35])[CH3:32])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:9]([C:10](=[O:15])[C@@H:11]([O:13][CH3:14])[CH3:12])[N:8]=1
Reactant: CO[C@@H](C)C(=O)N1N=C(c2cc(F)ccc2F)S[C@@]1(CCCN)c1ccccc1
Reactant: COC(C)=N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CO[C@@H](C)C(=O)N1N=C(c2cc(F)ccc2F)S[C@@]1(CCCNC(C)=N)c1ccccc1
Temperature: 50 °C

Procedure:
To a solution of (S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one (Example 5, Steps A-F; 57.5 mg, 0.117 mmol) and methyl acetimidate hydrochloride (192 mg, 1.75 mmol) in methanol was added triethylamine (355 mg, 3.51 mmol). After heating at 50° C. for 16 hours, the mixture was concentrated under reduced pressure. The residue was chromatographed (15:85:1 MeOH/dichloromethane/NH4OH), and the isolated material %% as treated with excess HCl in MeOH then concentrated to afford the product. MS ESI (+) m/z 461 (M+1) detected. 1H NMR (400 MHz, CD3OD) δ 7.65-7.60 (m, 1H), 7.49-7.45 (m, 2H), 7.42-7.38 (m, 2H), 7.35-7.29 (m, 3H), 4.80 (q, 1H, J=7.1 Hz), 3.50-3.40 (m, 2H), 3.36 (s, 3H), 3.28-3.19 (m, 1H), 2.65-2.57 (m, 1H), 2.22 (s, 3H), 2.21-2.12 (m, 1H), 1.75-1.64 (m, 1H), 1.44 (d, 3H, J=7.1 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11](=O)[NH2:12])[CH2:7][CH2:6]1)=[O:4].O=C(Cl)OC(Cl)(Cl)Cl>P(OC)(OC)(OC)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]#[N:12])[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCC(C(N)=O)CC1
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: COP(=O)(OC)OC
Solvent: CCOC(C)=O
Product: COC(=O)C1CCC(C#N)CC1
Temperature: 25 °C
Yield: 35.4 %

Procedure:
To a mixture of 4-carbamoyl-cyclohexanecarboxylic acid methyl ester (2.14 g, 11.6 mmol) in trimethyl phosphate (14 mL) cooled in an ice bath was dripped in diphosgene (2.24 g 11.6 mmol) and the reaction was allowed to warm to room temperature over 2 hr. The material was diluted with ethyl acetate (200 mL) and washed with an aqueous sodium bicarbonate (saturated, 200 mL) and brine (200 mL), dried over sodium sulfate, and concentrated as a clear oil. The oil was triturated with hexanes to give 4-cyano-cyclohexanecarboxylic acid methyl ester (687 mg 36%) as a clear oil. LCMS calcd for C9H13NO2 (m/e) 167, obsd 168 (M+H).
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[C:6](=[O:31])[N:5]([CH3:32])[C:4]=2[N:3]=1.C([Li])CCC.[CH:38](=[O:42])[CH:39]([CH3:41])[CH3:40]>C1COCC1.O>[Si:24]([O:23][CH2:22][CH2:21][CH2:20][N:7]1[C:8](=[O:19])[C:9]2[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:2]([CH:38]([OH:42])[CH:39]([CH3:41])[CH3:40])=[N:3][C:4]=2[N:5]([CH3:32])[C:6]1=[O:31])([C:27]([CH3:29])([CH3:30])[CH3:28])([CH3:25])[CH3:26]
Reactant: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Reactant: CC(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(O)c1nc2c(c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C)n1Cc1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 40.5 %

Procedure:
Step 1 8-Bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.50 g, 0.923 mmol, intermediate 77) was dissolved in THF (5 mL) and cooled to −78° C. To the clear solution was slowly added drop wise 2.5 M n-butyllithium in THF (0.35 mL, 0.877 mmol) followed by the immediate addition of isobutyraldehyde (0.42 mL, 4.61 mmol). The reaction was warmed to room temperature and stirred for 1 h. The reaction was diluted with water (75 mL) and extracted with ethyl acetate (3×75 mL). The combined extracts were dried with magnesium sulfate, filtered and the solvent was removed under reduced pressure to yield an oil. The oil was purified using a 25 g silica column eluted with a gradient of 10% to 30% ethyl acetate/hexanes yielding 1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-8-(1-hydroxy-2-methylpropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.20 g, 40% yield) as a light golden oil. LCMS retention time=4.923 min and 98% purity, LCMS MH+ 535.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3]([NH2:5])=[S:4].[O-]S([O-])(=O)=O.[Mg+2].[Cl:13][CH2:14][C:15]([CH2:17]Cl)=O>CC(C)=O>[Cl:13][CH2:14][C:15]1[N:5]=[C:3]([N:2]([CH3:6])[CH3:1])[S:4][CH:17]=1
Reactant: CN(C)C(N)=S
Reactant: O=C(CCl)CCl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: CN(C)c1nc(CCl)cs1
Yield: 55 %

Procedure:
A mixture of 15 g (144 mmol) of N,N-dimethylthiourea and excess MgSO4 in 350 ml of acetone was heated to reflux and treated dropwise with a solution of 18.3 g (144 mmol) of 1,3-dichloroacetone in 35 ml of acetone. The resulting mixture was heated at reflux for 1.5 h, allowed to cool, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography using 20% ethyl acetate in hexane to provide 14.0 g (70%) of the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][N+:6]([O-])=[C:5]([CH3:12])[C:4]=1[CH3:13].C(OC(=O)C)(=[O:16])C>>[OH:16][CH2:12][C:5]1[C:4]([CH3:13])=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[CH:7][N:6]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1c[n+]([O-])c(C)c(C)c1OC
Product: COc1cnc(CO)c(C)c1OC
Temperature: 80 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
4.5 g of 4,5-dimethoxy-2,3-dimethylpyridine 1-oxide are warmed to 110° C. in 20 ml of acetic anhydride in the course of 30 minutes and the mixture is then concentrated on a rotary evaporator. The oily residue, which consists of the intermediate 2-acetoxymethyl-4,5-dimethoxy-3-methylpyridine, is stirred in 30 ml of 3N sodium hydroxide solution at 80° C. for 2 hours, the mixture is extracted, after cooling, five times with 30 ml of methylene chloride each time, the combined organic phases are washed twice with 2N sodium hydroxide solution, dried and concentrated and the residue is stirred with petroleum ether, filtered off with suction and dried. 4.0 g (89% of theory) of 2-hydroxymethyl-4,5-dimethoxy-3-methylpyridine of m.p. 91°-92° C. are obtained.
Reaction SMILES: [C:1]1([NH:7][C@@H:8]([CH3:12])[CH2:9][C:10]#[N:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)[OH:14]>C1(C)C=CC=CC=1.O>[C:1]1([NH:7][C@@H:8]([CH3:12])[CH2:9][C:10]([NH2:11])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](CC#N)Nc1ccccc1
Reactant: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@@H](CC(N)=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-3-phenylamino-butyronitrile (6.06 g, 0.0378 mol) in toluene (150 mL) was added a cooled solution of conc. sulfuric acid in H2O (20.12 mL H2SO4/3 mL)—(The ratio of toluene to acid/H2O is very important and should be followed strictly). Stir the biphasic mixture at room temperature for 0.5 h and warm to 35° C. and stir for 22 h. The reaction was cooled to room temperature and quenched with 13 g of Na2CO3 in water (add slowly some foaming). Separate the organic and extract 2×EtOAc. Combine all the organics and wash the organics with brine, dry over MgSO4, filter and concentrate to give the desired product in 2.11 g (90%)
Reaction SMILES: O1CCCC1.[Br:6][C:7]1[C:8]([NH:15][C@H:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)=[N:9][C:10]([S:13][CH3:14])=[N:11][CH:12]=1.N1(C2CCCCCCCCCC2)CCCCCCCCCN1.[C:44]([CH2:46][C:47](OCC)=[O:48])#[N:45]>O>[Br:6][C:7]1[C:8]([NH:15][C@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:47](=[O:48])[CH2:46][C:44]#[N:45])[CH2:17]2)=[N:9][C:10]([S:13][CH3:14])=[N:11][CH:12]=1
Reactant: CCOC(=O)CC#N
Reactant: CSc1ncc(Br)c(N[C@H]2CCCNC2)n1
Agent: C1CCCCCC(N2CCCCCCCCCN2)CCCC1
Solvent: O
Solvent: C1CCOC1
Product: CSc1ncc(Br)c(N[C@H]2CCCN(C(=O)CC#N)C2)n1

Procedure:
A tetrahydrofuran solution (6 ml) of (5-bromo-2-methylsulfanyl-pyrimidin-4-yl)-(S)-piperidin-3-yl-amine (from Example 76, step 1 above) (300 mg, 0.99 mmol), diazabicycloundecane (530 mg, 3.5 mmol) and ethyl 2-cyanoacetate was stirred at room temperature for 20 hours. The reaction was diluted with water and extracted with ethyl acetate (2×). The organics were dried and evaporated to give 3-[(S)-3-(5-bromo-2-methylsulfanyl-pyrimidin-4-ylamino)-piperidin-1-yl]-3-oxo-propionitrile as an oil. MS (ES+): 371.
Reaction SMILES: [CH3:1][C:2]1[N:3](CC2C=CC(OC)=CC=2)[C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7](O)[C:5]=2[N:6]=1.[CH3:26][N:27]1[CH:34]=[CH:33][C:31](=[O:32])[NH:30][C:28]1=[O:29]>FC(F)(F)C(O)=O>[CH3:26][N:27]1[CH:34]=[C:33]([CH:7]2[C:5]3[N:6]=[C:2]([CH3:1])[NH:3][C:4]=3[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]2=3)[C:31](=[O:32])[NH:30][C:28]1=[O:29]
Reactant: Cn1ccc(=O)[nH]c1=O
Reactant: COc1ccc(Cn2c(C)nc3c2C=Cc2ccccc2C3O)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2c([nH]1)C=Cc1ccccc1C2c1cn(C)c(=O)[nH]c1=O
Reaction time: 120 h

Procedure:
A stirred solution of the product from step (iii) (0.819 g) in trifluoroacetic acid (20 ml) was heated at reflux for 1 h. 1-Methyluracil (0.311 g) was added and the reflux continued for 5 days. The solvent was evaporated under reduced pressure. The residue was purified by chromatography eluting with 10% methanol in dichloromethane to give the subtitle product as pale green glass.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[CH:17]=[C:16]([N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH3:19])[N:15]=[CH:14][N:13]=2)[C:10]=1[NH2:11])=[O:5])C.[OH-].[Li+].Cl>O1CCOCC1.O>[NH2:11][C:10]1[N:9]([C:12]2[CH:17]=[C:16]([N:18]([C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH3:19])[N:15]=[CH:14][N:13]=2)[N:8]=[CH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnn(-c2cc(N(C)C(=O)OC(C)(C)C)ncn2)c1N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CN(C(=O)OC(C)(C)C)c1cc(-n2ncc(C(=O)O)c2N)ncn1
Temperature: 85 °C

Procedure:
A mixture of 5-amino-1-[6-(tert-butoxycarbonyl-methyl-amino)-pyrimidin-4-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (5.5 g, 15.2 mmol), lithium hydroxide (1.82 g, 75.8 mmol) dissolved in a mixture of 1,4-Dioxane (20 mL) and water (5 mL) is heated to 85° C. for 8 hours. The reaction mixture is then neutralized with 2 M HCl aqueous solution until pH˜4-5 causing a white precipitate to form. After filtration, the undissolved solid is washed with small amount of water, air-dried to give 5-amino-1-[6-(tert-butoxycarbonyl-methyl-amino)-pyrimidin-4-yl]-1H-pyrazole-4-carboxylic acid as white powder: 1H NMR 400 MHz (d6-DMSO) δ 8.41 (s, 1H), 8.00-7.40 (m, 4H), 6.86-6.58 (m, 1H), 2.86 (s, 3H); MS m/z 235.10 (M+1).
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]([NH:15]C(=O)OC(C)(C)C)[CH3:14])=[CH:9][CH:8]=1)[CH3:2].CO>Cl.O1CCOCC1>[NH2:15][C@H:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH2:4][N:3]([CH2:23][CH3:24])[CH2:1][CH3:2])=[CH:8][CH:9]=1)[CH3:14]
Reactant: CCN(CC)CCOc1ccc([C@H](C)NC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCN(CC)CCOc1ccc([C@H](C)N)cc1
Temperature: 25 °C

Procedure:
A solution of 1,1-dimethylethyl [(1S)-1-(4-{[2-(diethylamino)ethyl]oxy}phenyl)ethyl]carbamate (0.912 g, 2.7 mmol) in 4N hydrogen chloride in dioxane (5 mL) and methanol (5 mL) was refluxed for 2 min. After cooling to room temperature the mixture was concentrated to afford (S)-2-[4-(1-aminoethyl)phenoxy]-N,N-diethylethylamine as the hydrochloride salt (0.830 g, 99% yield). MS (EI) for C14H24N2O: 237 (MH+).
Reaction SMILES: [H-].[Na+].[C:3]([N:22]1[CH:26]=[C:25]([CH2:27][CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)[N:24]=[N:23]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH2:39][C:40]1[N:41]=[C:42]([CH:45]=[CH:46][C:47]2[CH:52]=[CH:51][C:50]([S:53]([C:55]([F:58])([F:57])[F:56])=[O:54])=[CH:49][CH:48]=2)[O:43][CH:44]=1.O>CN(C)C=O>[F:58][C:55]([F:56])([F:57])[S:53]([C:50]1[CH:51]=[CH:52][C:47](/[CH:46]=[CH:45]/[C:42]2[O:43][CH:44]=[C:40]([CH2:39][O:37][C:34]3[CH:33]=[CH:32][C:31]([CH2:30][CH2:29][CH2:28][CH2:27][C:25]4[N:24]=[N:23][N:22]([C:3]([C:4]5[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=5)([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)[C:10]5[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=5)[CH:26]=4)=[CH:36][CH:35]=3)[N:41]=2)=[CH:48][CH:49]=1)=[O:54]
Reactant: O=S(c1ccc(C=Cc2nc(CCl)co2)cc1)C(F)(F)F
Reactant: Oc1ccc(CCCCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)nn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(c1ccc(/C=C/c2nc(COc3ccc(CCCCc4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nn4)cc3)co2)cc1)C(F)(F)F
Reaction time: 0.25 h

Procedure:
8.1 mg (0.20 mmol) 95% sodium hydride were given at 0° C. to a solution of 90 mg (0.20 mmol) 4-[4-(1-trityl-1H-[1,2,3]triazol-4-yl)-butyl]-phenol in 3.0 ml N,N-dimethylformamide and stirred for 15 min. 66 mg (0.20 mmol) 4-chloromethyl-2-[2-(4-trifluoromethanesulfinyl-phenyl)-vinyl]-oxazole were added and stirring continued at 25° C. for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was dried over sodium sulphate and the solvents distilled off in vacuo. Yield 146 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C@H:10]([CH2:10][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:12])[C:11]([O:13][CH2:9][C:6]2[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=2)=[O:12])=[CH:7][CH:8]=1
Reactant: C1COCCN1
Reactant: COc1ccc(CCC(=O)O)cc1
Product: COc1ccc(C[C@H](CC(=O)N2CCOCC2)C(=O)OCc2ccccc2)cc1

Procedure:
A procedure similar to those described in Preparations 12-14 was repeated, but using 3-(4-methoxyphenyl)propionic acid as one of the starting materials and morpholine as the amine, to afford benzyl 2(R)-(4-methoxybenzyl)-3-(morpholinocarbonyl)propionate. 1.62 g (4.08 mmole) of this compound was dissolved in 50 ml of ethanol, and the solution was stirred at room temperature for 4 hours under an atmosphere of hydrogen and in the presence of 160 mg of 10% w/w palladium-on-charcoal. At the end of this time, the catalyst was removed by filtration and the filtrate was concentrated by distillation under reduced pressure, to afford 1.25 g of the title compound as a colorless oily substance.
Reaction SMILES: O1CCCC1.[OH:6][C:7]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][CH:14]=2)[CH2:10][C:9](=[O:24])[C:8]=1[C:25](=O)[CH2:26][CH3:27].[CH3:29][O:30][NH2:31].C[O-].[Na+]>CO>[CH3:29][O:30][N:31]=[C:25]([C:8]1[C:9](=[O:24])[CH2:10][CH:11]([C:13]2[CH:14]=[CH:15][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:17][CH:18]=2)[CH2:12][C:7]=1[OH:6])[CH2:26][CH3:27]
Reactant: CCC(=O)C1=C(O)CC(c2ccc(NS(C)(=O)=O)cc2)CC1=O
Reactant: CON
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(=NOC)C1=C(O)CC(c2ccc(NS(C)(=O)=O)cc2)CC1=O
Reaction time: 15 h

Procedure:
Into 10 ml of tetrahydrofuran was dissolved 1.2 g of 3-hydroxy-5-(4-methanesulfonamidophenyl)-2-propionyl-2-cyclohexen-1-one and to the solution were added 0.6 g of methoxyamine hydrocholorate salt and 1.4 g of methanol containing 28% of sodium methylate. Then, the mixture was kept for 15 hours at room temperature and an insoluble material was filtered off from it and the resulting filtrate solution was concentrated under reduced pressure. Its residue was dissolved in chloroform and the solution was washed with a dilute hydrochloric acid solution and water, and it was dried with anhydrous magnesium sulfate. The chloroform was distilled off from it under a reduced pressure and ethyl ether was add in it. Thus, the crystal sedimented is collected with a filtering step and 1.2 g of the desired compound as colorless crystals having a melting point of 150°-151° C. was obtained.