Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[N:8][CH:9]=1)([CH3:3])[CH3:2].N#N.[Li][CH2:14]CCC.IC>C1COCC1.O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH3:14])=[N:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(N)nc1
Reactant: [Li]CCCC
Agent: N#N
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: CNc1ccc(C(C)C)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.3 %

Procedure:
A solution of 5-isopropyl-pyridin-2-ylamine (0.5 g, 3.67 mmol) in dry THF was purged with N2 and cooled to −78° C. n-BuLi (1.62 mL, 4.04 mmol) was added dropwise. The reaction was stirred at 0° C. for 0.5 h, and then iodomethane (0.25 mL, 4.04 mmol) was added dropwise. The resulting mixture was stirred overnight while warming to r.t. Water (20 mL) was added, and the mixture was extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated, and purified by silica gel chromatography (10% to 30% EtOAc in PE) to give 200 mg (36%) of the title compound as a brown oil. [M+H] Calc'd for C9H14N2, 151. Found, 151.
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:17][C:16]3[CH2:15][CH2:14][C:13]4=[N:18][NH:19][N:20]=[C:11]([C:12]=34)[C:10]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[N:9]2)=CC=1.FC(F)(F)C(O)=O>>[N:18]1[NH:19][N:20]=[C:11]2[C:10]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)=[N:9][NH:8][CH2:17][C:16]3[CH2:15][CH2:14][C:13]=1[C:12]2=3
Reactant: COc1ccc(CN2CC3=C4C(=NNN=C4C(N4CCOCC4)=N2)CC3)cc1
Solvent: O=C(O)C(F)(F)F
Product: C1CN(C2=NNCC3=C4C(=NNN=C24)CC3)CCO1
Temperature: 65 °C

Procedure:
To 4-(6-(4-methoxybenzyl)-6,7,8,9-tetrahydro-2H-1,2,3,5,6-pentaazabenzo[cd]azulen-4-yl)morpholine was added neat trifluoroacetic acid(1 mL). The reaction mixture was heated at 65° C. for 4-16 h. The reaction mixture was evaporated and the crude residue was dissolved in DMSO. This was then purified using reverse phase column chromatography using a Maccel AQ C18 column and a gradient of 1-95% ACN/water containing 0.05% trifluoroacetic acied, to yield 4-(6,7,8,9-tetrahydro-2H-1,2,3,5,6-pentaazabenzo[cd]azulen-4-yl)morpholine, compound 243. LC/MS. LC-Mass: 261 (M+1)
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1.[CH3:23][O:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:30]=1.B(O)O>>[CH3:23][O:24][C:25]1[CH:30]=[C:29]([C:2]2[C:3]3[CH2:16][CH2:15][N:14]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[C:4]=3[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=2)[CH:28]=[N:27][CH:26]=1
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Clc1nc(N2CCOCC2)nc2c1CCN2c1ccncc1
Agent: OBO
Product: COc1cncc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccncc2)c1

Procedure:
In the same manner as Example 1-B-10, using 4-chloro-2-morpholin-4-yl-7-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine, and 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine as a boronic acid, the desired compound was obtained.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:32])[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:21]3[N:22]=[C:23](S(C)(=O)=O)[N:24]=[C:25]([CH3:26])[C:20]=3[CH:19]=[CH:18][C:17]2=[O:31])=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[NH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>C1COCC1>[CH2:1]([NH:8][C:9](=[O:32])[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:21]3[N:22]=[C:23]([N:40]4[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]4)[N:24]=[C:25]([CH3:26])[C:20]=3[CH:19]=[CH:18][C:17]2=[O:31])=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: Cc1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccc(C(=O)NCc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc(N2CCNCC2)nc2c1ccc(=O)n2-c1ccc(C(=O)NCc2ccccc2)cc1
Reaction time: 18 h

Procedure:
The resin (A3), 0.0214 mmol) was suspended in THF (1 ml) and NEt3 (14 mg, 0.14 mmol). To this mixture was added piperazine (21 mg, 0.128 mmol) and shaking continued for 18 h. The resin was washed with THF (2×1 min), DMF (3×1 min, 60° C.) and with DCM (3×1 min) at rt.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:42])[CH:10]=[C:11]2[NH:15][C:14]([CH2:23][CH2:24]OS(C)(=O)=O)([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:13](=[O:30])[N:12]2[CH2:31][CH:32]2[CH2:37][CH:36]3[CH2:38][CH:34]([C:35]3([CH3:40])[CH3:39])[CH:33]2[CH3:41])=[CH:5][CH:4]=1)#[N:2].[NH:43]1[CH:47]=[CH:46][N:45]=[CH:44]1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[N:43]1([CH2:24][CH2:23][C:14]2([CH2:16][C:17]3[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=3)[C:13](=[O:30])[N:12]([CH2:31][CH:32]3[CH2:37][CH:36]4[CH2:38][CH:34]([C:35]4([CH3:39])[CH3:40])[CH:33]3[CH3:41])[C:11](=[CH:10][C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)=[O:42])[NH:15]2)[CH:47]=[CH:46][N:45]=[CH:44]1
Reactant: CC1C(CN2C(=O)C(CCOS(C)(=O)=O)(Cc3ccncc3)NC2=CC(=O)c2ccc(C#N)cc2)CC2CC1C2(C)C
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1C(CN2C(=O)C(CCn3ccnc3)(Cc3ccncc3)NC2=CC(=O)c2ccc(C#N)cc2)CC2CC1C2(C)C
Temperature: 80 °C
Yield: 66.5 %

Procedure:
Methanesulfonic acid 2-[2-[2-(4-cyano-phenyl)-2-oxo-ethylidene]-5-oxo-4-pyridin-4-ylmethyl-1-((+)-(2,6,6-trimethyl-bicyclo[3.1.1 ]hept-3-ylmethyl))-imidazolidin-4-yl]-ethyl ester (300 mg, 0.508 mMol) and imidazole (102 mg, 1.5 mMol) were dissolved in anhydrous dimethylformamide (2 mL) under an atmosphere of dry N2. To this mixture was added K2CO3 (207 mg, 1.5 mMol). The mixture was heated to 80° C. for 24 hours after which time it was cooled to ambient temperature and subsequently concentrated under vacuum. The residue was partitioned between CH2Cl2 and water. The CH2Cl2 layer was dried over Na2SO4, filtered and concentrated under vacuum to give a foam. The foam was chromatographed on flash silica gel using a gradient of CHCl3 --CH3OH (98:2) to CHCl3 --CH3OH (96:4) to give 190 mg of the titled compound as a 1:1 mixture of diastereomers: C.I. m/z 563.4 [M+1]; 1HNMR (CDCI3) δ8.42 (m, 4H), 7.86 (m, 4H), 7.74 (m, 4H), 7.38 (s, 1H), 7.31 (s, 1H), 7.06 (m, 4H), 7.04 (s, 1H), 7.02 (s, 1H), 6.88 (s, 1H), 6.84 (s, 1H), 5.50 (s, 1H), 5.45 (s, 1H), 3.80-4.10 (m, 4H), 2.90-3.35 (m, 8H), 2.60 (m 2H), 2.26 (m, 4H), 1.20-2.00 (m, 14H), 1.15 (s, 3H), 1.14 (s, 3H), 1.04 (m, 6H), 0.90 (s, 3H), 0.84 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.I[CH2:26][CH2:27][CH2:28][CH3:29].C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CCCC)N=2)CC1)=O)(C)(C)C>>[CH2:26]([N:14]1[C:15]2[CH2:16][CH2:17][NH:8][CH2:9][CH2:10][C:11]=2[C:12]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[N:13]1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCI
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Agent: CCCCn1nc2c(c1-c1ccc(Cl)cc1)CCN(C(=O)OC(C)(C)C)CC2
Product: CCCCn1nc(-c2ccc(Cl)cc2)c2c1CCNCC2

Procedure:
The title compound (0.033 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C, 0.1 g) using 1-iodobutane (0.038 mL) in place of benzyl chloride. The reaction sequence also yielded 2-butyl-3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C17H22ClN3, 303.15; found, m/z 304.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.39-7.34 (m, 4H), 4.07 (t, J=7.2 Hz, 2H), 3.37-3.35 (m, 2H), 3.27-3.25 (m, 2H), 3.14-3.12 (m, 2H), 2.95-2.92 (m, 2H), 1.69-1.66 (m, 2H), 1.22-1.20 (m, 2H), 0.86 (t, J=7.4 Hz, 3H).
Reaction SMILES: [F:1][CH:2]([F:18])[CH2:3][N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:17])[C:13]([O:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:28]=2[C:29]([NH:31][CH2:32][CH3:33])=[O:30])[C:23]([Cl:39])=[CH:22][N:21]=1>>[Cl:39][C:23]1[C:24]([NH:26][C:27]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:28]=2[C:29]([NH:31][CH2:32][CH3:33])=[O:30])=[N:25][C:20]([NH:17][C:12]2[C:13]([O:15][CH3:16])=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:3][CH:2]([F:1])[F:18])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:21][CH:22]=1
Reactant: CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCN(CC(F)F)CC2
Product: CCNC(=O)c1cccc(F)c1Nc1nc(Nc2cc3c(cc2OC)CCN(CC(F)F)CC3)ncc1Cl

Procedure:
The title compound was prepared from 3-(2,2-Difluoro-ethyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-ethyl-3-fluoro-benzamide in an analogous manner to Example 61e. Product isolated as an off-white solid (0.012 g, 14%). MP: 93-104° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 8.49 (s, 1H), 8.07 (s, 1H), 7.73 (s, 1H), 7.45 (s, 1H), 7.36-7.31 (m, 1H), 7.29-7.22 (m, 2H), 6.57 (s, 1H), 6.20-6.10 (m, 1H), 5.90 (tt, 1H, J=56.0 Hz and 3.9 Hz), 3.81 (s, 3H), 3.37 (p, 2H, J=6.7 Hz), 2.90 (dt, 2H, J=15.0 Hz and 4.1 Hz), 2.84-2.73 (m, 4H), 2.72-2.66 (m, 2H), 2.60-2.52 (m, 2H), 1.10 (t, 3H, J=7.3 Hz). MS: 549 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](S)=[N:7][C:6]=2[CH:11]=1.S(Cl)([Cl:14])=O>CN(C=O)C>[Cl:14][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:11][C:6]=2[N:7]=1
Reactant: O=S(Cl)Cl
Reactant: Sc1nc2cc(Cl)ccc2o1
Solvent: CN(C)C=O
Product: Clc1ccc2oc(Cl)nc2c1
Temperature: 65 °C

Procedure:
Subsequently, 5-chloro-2-mercaptobenzoxazole (3.1 g, 16.7 mmol) was dissolved in thionyl chloride (30 mL, 413 mmol). DMF (1.5 mL) was added and the reaction mixture was heated at 65° C. for 45 min. The solvent was removed under reduced pressure and to the residue was added toluene (2×60 mL) followed by evaporation each time to remove the excess SOCl2 (azetrope). The resultant crude product was dissolved in ethyl acetate (100 mL), washed with water (100 mL) and dried over Na2SO4. Evaporation of ethyl acetate gave 2,5-dichlorobenzoxazole, compound 19, as a red oil (3.2 g).
Reaction SMILES: Cl[C:2]1[C:3]2[S:12][CH:11]=[CH:10][C:4]=2[N:5]=[C:6]([CH2:8][Cl:9])[N:7]=1.O.[NH2:14][NH2:15]>O1CCCC1>[Cl:9][CH2:8][C:6]1[N:7]=[C:2]([NH:14][NH2:15])[C:3]2[S:12][CH:11]=[CH:10][C:4]=2[N:5]=1
Reactant: NN
Reactant: ClCc1nc(Cl)c2sccc2n1
Solvent: C1CCOC1
Solvent: O
Product: NNc1nc(CCl)nc2ccsc12
Temperature: 5 °C
Reaction time: 15 h

Procedure:
3. 8.2 g of 4-chloro-2-(chloromethyl)thieno[3,2-d]pyrimidine are dissolved in 500 ml of absolute tetrahydrofuran. The solution is cooled to 5° C. 7 ml of hydrazine hydrate are added dropwise within 5 min., whereby a solution results and the temperature rises to 15° to 20° C. The reaction mixture is stirred at room temperature for 15 h. and then evaporated in a vacuum. The residue is stirred with 100 ml of saturated aqueous sodium hydrogen carbonate solution for 30 min. and then filtered off. The crystals are washed neutral with water and dried in a vacuum. 14.7 g of 2-(chloromethyl)-4-hydrazinothieno[3,2-d]-pyrimidine are obtained. A further 1.0 g of 2-(chloromethyl)-4-hydrazinothieno[3,2-d]pyrimidine are obtained by extracting the filtrate with chloroform.
Reaction SMILES: [C:1]([N:4]([C:8]1[N:9]=[N:10][C:11]([O:14][CH2:15][C:16]2[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:18][O:19][C:20]=2[CH3:21])=[CH:12][CH:13]=1)C(=O)C)(=[O:3])[CH3:2].C(=O)(O)[O-].[Na+]>CO>[CH3:21][C:20]1[O:19][N:18]=[C:17]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:16]=1[CH2:15][O:14][C:11]1[N:10]=[N:9][C:8]([NH:4][C:1](=[O:3])[CH3:2])=[CH:13][CH:12]=1
Reactant: CC(=O)N(C(C)=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(=O)Nc1ccc(OCc2c(-c3ccccc3)noc2C)nn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.9 %

Procedure:
A solution of N-acetyl-N-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-yl]-acetamide (70 mg, 0.19 mmol) in methanol (2 mL) was treated with sodium bicarbonate (1 spatula) and stirred at room temperature for 16 h. The solvent was evaporated and the residue was extracted (dichloromethane/water). The organic phase was dried over sodium sulfate and concentrated. Crystallization of the residue from diisopropylether afforded the title compound as a light brown solid (40 mg, 65%). MS: m/e=325.4 [M+H]+.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=3)=[C:11]([NH2:14])[CH:12]=2)[N:7]([C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2].Cl[C:33]([O:35][CH3:36])=[O:34].C(OC(=O)C)(=O)C.C(NC1C=C2C(=CC=1C1C=NN(C3CC3)C=1)N(C(OC(C)C)=O)C[C@H](C)N2C(=O)C)(=O)C>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:15]3[CH:16]=[CH:17][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:19][CH:20]=3)=[C:11]([NH:14][C:33]([O:35][CH3:36])=[O:34])[CH:12]=2)[N:7]([C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2]
Reactant: COC(=O)Cl
Reactant: CC(=O)N1c2cc(N)c(-c3ccc(S(C)(=O)=O)cc3)cc2N(C(=O)OC(C)C)C[C@@H]1C
Agent: CC(=O)Nc1cc2c(cc1-c1cnn(C3CC3)c1)N(C(=O)OC(C)C)C[C@H](C)N2C(C)=O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)Nc1cc2c(cc1-c1ccc(S(C)(=O)=O)cc1)N(C(=O)OC(C)C)C[C@H](C)N2C(C)=O

Procedure:
Isopropyl (S)-4-acetyl-6-((methoxycarbonyl)amino)-3-methyl-7-(4-(methylsulfonyl)phenyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate was synthesized from isopropyl (S)-4-acetyl-6-amino-3-methyl-7-(4-(methylsulfonyl)phenyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate and methyl chloroformate (instead of acetic anhydride) according to the procedure described above for isopropyl (S)-6-acetamido-4-acetyl-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (Example 235). MS (ESI, pos. ion) m/z 504 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[OH:15][CH:16]([CH3:31])[CH2:17][S:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[C:23]([CH3:30])[CH:22]=1)(=[O:20])=[O:19]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([S:18]([CH2:17][CH:16]([OH:15])[CH3:31])(=[O:20])=[O:19])=[CH:22][C:23]=2[CH3:30])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: Cc1cc(S(=O)(=O)CC(C)O)ccc1C(=O)O
Product: Cc1cc(S(=O)(=O)CC(C)O)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
2 g of 4-bromo-2-methylbenzonitrile was reacted with 1-mercapto-2-propanol via Procedure Q to afford 4-(2-hydroxypropylthio)-2-methylbenzonitrile. 950 mg of 4-(2-hydroxypropylthio)-2-methylbenzonitrile was reacted via Procedure T to give 4-(2-hydroxypropylthio)-2-methylbenzoic acid. 1.0 g of 4-(2-hydroxypropylthio)-2-methylbenzoic acid was reacted via Procedure R to give 4-(2-hydroxypropylsulfonyl)-2-methylbenzoic acid. 100 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(2-hydroxypropylsulfonyl)-2-methylbenzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)-2-methylbenzamide. MS (Q1) 445.3 (M)+.
Reaction SMILES: O.[OH-].[Li+].[O:4]([C:11]1[N:16]=[CH:15][C:14]([C:17]2[NH:21][N:20]=[C:19]([C:22]([O:24]CC)=[O:23])[CH:18]=2)=[CH:13][N:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)C.O>[O:4]([C:11]1[N:12]=[CH:13][C:14]([C:17]2[NH:21][N:20]=[C:19]([C:22]([OH:24])=[O:23])[CH:18]=2)=[CH:15][N:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1cc(-c2cnc(Oc3ccccc3)nc2)[nH]n1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(-c2cnc(Oc3ccccc3)nc2)[nH]n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.2 %

Procedure:
To a solution consisting of lithium hydroxide monohydrate (0.13 g, 3.0 mmol) dissolved in ethanol (10 mL)/water (5 mL) was added ethyl 5-(2-phenoxypyrimidin-5-yl)-1H-pyrazole-3-carboxylate (Example 54, 90 mg, 0.29 mmol) and the mixture was stirred at room temperature for 18 hours. Ethanol was removed under reduced pressure and the solution diluted with water and subsequently was acidified with acetic acid to precipitate product. The solid precipitate was filtered, washed with water, and dried under high vacuum to afford the title compound as a white solid (64 mg, 79% yield); Rf 0.15 with 2% methanol in dichloromethane; 1H-NMR (300 MHz; DMSO-d6) δ 9.12 (s, 2H), 7.49 (dd, 2H), 7.25-7.43 (m, 4H); MS (ESI−) m/z 281 (M−1); H-PGDS FPBA IC50: 5 μM.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[Cl:28][C:29]1[C:34]([F:35])=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1.C([O-])(O)=O.[Na+]>COCCOC.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:28][C:29]1[N:30]=[CH:31][C:32]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:18])([F:20])[F:19])=[CH:14][CH:15]=3)=[O:8])[CH:21]=2)=[CH:33][C:34]=1[F:35]
Reactant: CC1(C)OB(c2cnc(Cl)c(F)c2)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cnc(Cl)c(F)c2)c1
Temperature: 95 °C
Reaction time: 2 h

Procedure:
(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1, 300 mg, 0.672 mmol) and 2-chloro-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (346 mg, 1.345 mmol) were dissolved in DME (2.7 mL). A solution of 2 M NaHCO3 (1.01 mL, 2.03 mmol) was added, the RM was flushed with argon and Pd(PPh3)2Cl2 (56.6 mg, 0.081 mmol) was added. The RM was stirred under argon at 95° C. for 2 h in a capped pressure safe tube. After cooling to RT, the RM was dissolved in EtOAc, and washed with brine. The organic phase was dried over Na2SO4 and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH from 2% to 5% MeOH), followed by a second purification (RediSep® Silica gel column, n-hexane/EtOAc, 50 to 100% EtOAc) and treatment with Si-Thiol (200 mg) in MeOH to afford the title compound as a white powder. HPLC (Condition 4) tR=5.63 min, UPLC-MS (Condition 7) m/z=497.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.65-1.80 (m, 1H) 1.80-1.91 (m, 1H) 2.87 (d, J=10.56 Hz, 1H) 3.18-3.28 (m, 2H) 3.33-3.50 (m, 1H) 4.20 (br. s, 1H) 4.86 (d, J=3.52 Hz, 1H) 7.34 (d, J=8.99 Hz, 2H) 7.84 (d, J=8.99 Hz, 2H) 7.99-8.11 (m, 2H) 8.34 (s, 1H) 8.77 (d, J=2.35 Hz, 1H) 10.16 (s, 1H).
Reaction SMILES: [NH2:1][CH:2]1[C:15](=[O:16])[N:4]2[CH:5]([C:10]3[NH:14][N:13]=[N:12][N:11]=3)[C:6]([CH3:9])([CH3:8])[S:7][C@H:3]12.[N:17]([CH2:20][C:21]1[CH:25]=[CH:24][S:23][C:22]=1[CH2:26][C:27](O)=[O:28])=[N+:18]=[N-:19].Cl.C(N=C=NCCCN(C)C)C>O1CCCC1.O>[N:17]([CH2:20][C:21]1[CH:25]=[CH:24][S:23][C:22]=1[CH2:26][C:27]([NH:1][CH:2]1[C:15](=[O:16])[N:4]2[CH:5]([C:10]3[NH:11][N:12]=[N:13][N:14]=3)[C:6]([CH3:8])([CH3:9])[S:7][C@H:3]12)=[O:28])=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=NCc1ccsc1CC(=O)O
Reactant: CC1(C)S[C@@H]2C(N)C(=O)N2C1c1nnn[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)S[C@@H]2C(NC(=O)Cc3sccc3CN=[N+]=[N-])C(=O)N2C1c1nnn[nH]1
Reaction time: 2.5 h
Yield: 88 %

Procedure:
A solution of 5.48 g. (0.0228 mole) of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam in 200 m.l of 1:1 tetrahydrofuran-water is adjusted to pH 7.5, and then 4.5 g. (0.0228 mole) of 2-(3-azidomethyl-2-thienyl)acetic acid is added. The mixture is cooled to 0°-5° C., and 4.37 g. (0.0288 mole) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride is added. The reaction mixture is stirred at pH 6 and at 0°-5° C. for 2.5 hours. At this point, the tetrahydrofuran is removed by evaporation in vacuo and the pH is adjusted to 7.5. The aqueous residue is washed with ethyl acetate and then the pH is lowered to 2.2. The product is extracted into ethyl acetate. The ethyl acetate is dried and evaporated in vacuo. This affords 8.1 g. (88% yield) of the title compound as a foam. IR (KBr disc): 2100, 1800, 1666, 1529 and 1250 cm-1. NMR (CDCl3): 7.3 (d, 1H), 7.0 (d, 1H), 5.7 (m, 2H), 5.3 (s, 1H), 4.4 (s, 2H), 3.9 (s, 2H), 1.6 (s, 3H) and 1.1 ppm (s, 3H).
Reaction SMILES: [NH2:1][C:2]([C:4]1[O:8][C:7]([S:9]([N:12]2[C:16]([C:17]3[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=3)=[C:15]([F:24])[C:14]([CH2:25][N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:13]2)(=[O:11])=[O:10])=[CH:6][CH:5]=1)=O.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1>[C:2]([C:4]1[O:8][C:7]([S:9]([N:12]2[C:16]([C:17]3[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=3)=[C:15]([F:24])[C:14]([CH2:25][N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[CH:13]2)(=[O:11])=[O:10])=[CH:6][CH:5]=1)#[N:1]
Reactant: CN(Cc1cn(S(=O)(=O)c2ccc(C(N)=O)o2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CN(Cc1cn(S(=O)(=O)c2ccc(C#N)o2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
To a solution of tert-butyl {[1-{[5-(aminocarbonyl)-2-furyl]sulfonyl}-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (285 mg) in tetrahydrofuran (2.5 mL) were added pyridine (181 mg) and trifluoroacetic anhydride (211 mg) under ice-cooling, and the mixture was stirred for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica-gel column chromatography (eluent: hexane-ethyl acetate=6:1→3:2) to give the title compound as a pale-yellow oil (yield 258 mg, 94%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][N:12]=[C:11]([C:14]([F:17])([F:16])[F:15])[C:10]=1[CH2:18][OH:19].O[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:23]([CH3:34])[C:22]=1[CH3:35].C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.P(CCCC)(CCCC)CCCC>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][N:12]=[C:11]([C:14]([F:17])([F:16])[F:15])[C:10]=1[CH2:18][O:19][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:23]([CH3:34])[C:22]=1[CH3:35]
Reactant: Cc1ccc(-c2snc(C(F)(F)F)c2CO)c(C)c1
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Product: CCOC(=O)CCc1ccc(OCc2c(C(F)(F)F)nsc2-c2ccc(C)cc2C)c(C)c1C
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed [5-(2,4-dimethylphenyl)-3-(trifluoromethyl)-1,2-thiazol-4-yl]methanol (100 mg, 0.35 mmol, 1.00 equiv), tol (3 mL), ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate (154 mg, 0.69 mmol, 1.99 equiv), ADDP (174 mg, 0.70 mmol, 2.00 equiv), n-Bu3P (140 mg, 0.69 mmol, 1.99 equiv). The resulting solution was stirred overnight at 60° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a TLC plate with ethyl acetate/petroleum ether (1/5). This resulted in 90 mg (crude) of ethyl 3-(4-[[5-(2,4-dimethylphenyl)-3-(trifluoromethyl)-1,2-thiazol-4-yl]methoxy]-2,3-dimethylphenyl) propanoate as colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C@@H:9]([OH:12])[C@H:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7]1)=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1O.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1>[Cl:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[O:12][C@H:9]1[CH2:10][CH2:11][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][C@H:8]1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)N1CC[C@@H](O)[C@H](c2ccccc2)C1
Reactant: Oc1ccccc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CCOC(=O)N1CC[C@H](Oc2ccccc2Cl)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of 6.23 g of trans-1-ethoxycarbonyl-3-phenyl-4-piperidinol, 7.21 g of triphenylphosphine, 2.85 g of 2-chlorophenol and 250 ml of benzene is added dropwise at 5° C. under nitrogen, a solution of 4.79 g of diethyl azodicarboxylate in 250 ml of benzene. After the addition is complete, the mixture is stirred overnight at room temperature. The reaction mixture is processed according to the procedure of Example 75 to give product as a gum.