Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C1C=CC([N:11]2C(=O)C=CC(C([O-])=O)=N2)=CC=1)(=O)=O.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([O:34][C:35]2[C:36]([C:50]([O:52]C)=O)=[N:37][N:38]([C:42]3[CH:43]=[N:44][C:45]([C:48]#[N:49])=[CH:46][CH:47]=3)[C:39](=[O:41])[CH:40]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:50]([C:36]1[C:35]([O:34][CH:31]2[CH2:32][CH2:33][N:28]([C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])[CH2:29][CH2:30]2)=[CH:40][C:39](=[O:41])[N:38]([C:42]2[CH:43]=[N:44][C:45]([C:48]#[N:49])=[CH:46][CH:47]=2)[N:37]=1)(=[O:52])[NH2:11]
Reactant: CS(=O)(=O)c1ccc(-n2nc(C(=O)[O-])ccc2=O)cc1
Reactant: COC(=O)c1nn(-c2ccc(C#N)nc2)c(=O)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(C#N)nc3)nc2C(N)=O)CC1
Yield: 77 %

Procedure:
tert-Butyl 4-(3-carbamoyl-1-(6-cyanopyridin-3-yl)-6-oxo-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylate was prepared in 77% yield according to procedures described in Example 31 (Step A) substituting methyl 441-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(4-(methylsulfonyl)phenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate for methyl 4-(1-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(6-cyanopyridin-3-yl)-6-oxo-1,6-dihydropyridazine-3-carboxylate (example 30). MS (ESI) 441 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[N:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:6]=2[CH:33]=1.[CH3:34][N:35]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[N:36]1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:29]([C:26]1[CH:25]=[CH:24][C:23]([S:20]([N:7]2[C:6]3[CH:33]=[C:2]([C:38]4[CH:37]=[N:36][N:35]([CH3:34])[CH:39]=4)[CH:3]=[CH:4][C:5]=3[NH:11][C:10]3[N:12]=[C:13]([C:16]([F:19])([F:17])[F:18])[CH:14]=[CH:15][C:9]=3[CH2:8]2)(=[O:22])=[O:21])=[CH:28][CH:27]=1)([CH3:30])([CH3:32])[CH3:31]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(Br)cc32)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cn1cc(-c2ccc3c(c2)N(S(=O)(=O)c2ccc(C(C)(C)C)cc2)Cc2ccc(C(F)(F)F)nc2N3)cn1
Temperature: 100 °C

Procedure:
A mixture of 8-bromo-6-[(4-tert-butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine (intermediate 53, 50 mg, 0.0925 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (38.5 mg, 0.185 mmol), Pd(dppf)Cl2 (22.7 mg, 0.0278 mmol), potassium carbonate (38.4 mg, 0.2775 mmol), DMSO (0.3 mL), and 3 drops of water was heated in a microwave reactor at 100° C. for 30 min. After cooling to room temperature, the reaction mixture was diluted with EtOAc, and the organic layer was separated, washed with water, brine, dried over MgSO4 and concentrated. The residue was purified via reverse phase HPLC to provide the title compound. LC/MS: m/e 542.0 (M+H)+. 1H NMR (500 MHz, CD3OD): δ 7.93 (1H, s), 7.78 (1H, s), 7.60 (2H, m), 7.40 (1H, d), 7.16 (2H, d), 7.05 (1H, d), 6.95 (1H, d), 6.90 (2H, d), 4.60-5.00 (2H, br s), 3.90 (3H, s), 1.26 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH2:13])=[CH:4][CH:3]=1.[C:16]([N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:19]([O:18][C:16]([N:23]1[CH2:28][CH2:27][CH:26]([NH:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]2[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:25][CH2:24]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1ccccc1Oc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2Oc2ccc(Cl)cc2)CC1
Temperature: 85 °C
Yield: 67.9 %

Procedure:
To a solution of 2-(4-chlorophenoxy)phenylamine (900 mg, 4.10 mmol), 1-BOC-4-piperidone (1.76 g, 8.82 mmol) and acetic acid (1.32 g, 22.05 mmol) in DCE (15 ml) was added sodium triacetoxyborohydride (2.34 g, 11.04 mmol). This solution was then split into 4 microwave tubes, which were individually heated at 85° C. for 15 minutes in a CEM discover microwave (fixed hold time set to on). The contents of each tube were added to a saturated aqueous sodium bicarbonate solution (25 ml) with extraction with ethyl acetate (3×25 ml) following. The combined organics were dried (MgSO4), filtered and concentrated in vacuo and purification by flash chromatography proceeded (eluant: 3:1 to 1:1 hexane:DCM) to provide a white solid. Recrystallisation was then carried out, which afforded the title compound as a white crystalline solid (1.122 g, 68%). M.Pt. 112-113.4° C. 1H NMR (300 MHz, CDCl3): δ 1.165-1.308 (2H, m, 2×CH), 1.380 (9H, s, t-Bu), 1.909-1.974 (2H, m, 2×CH), 2.822-2.897 (2H, ‘t’, J=11.3 Hz, CH2), 3.385-3.45 (1H, m, CH), 3.85-4.02 (3H, m, 2×CH, NH), 6.542-6.597 (1H, td, ArH), 6.674-6.842 (4H, m, ArH), 6.946-7.002 (1H, td, ArH), 7.157-7.209 ppm (2H, m, ArH). 13C NMR (67.93 MHz, CDCl3): δ 28.5, 32.3, 43.0, 49.8, 79.7, 112.2, 117.0, 118.7, 119.6, 125.3, 127.8, 129.7, 139.0, 143.0, 154.8, 156.2 ppm. LCMS: M+H, 403.46 HPLC: 99.53% (4.9411 min, isocratic, 90% acetonitrile: 10% water, 1 ml/min). CHN: Expected, N=6.95%, C=65.58%, H=6.75% Observed, N=6.82%, C=65.5%, H=6.71%
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2([OH:18])[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C-:19]#[N:20].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C>[OH:18][C:8]1([C:5]2[CH:4]=[CH:3][C:2]([C:19]#[N:20])=[N:7][CH:6]=2)[CH2:17][CH2:16][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:10][CH2:9]1
Reactant: [C-]#N
Reactant: OC1(c2ccc(F)nc2)CCC2(CC1)OCCO2
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(C2(O)CCC3(CC2)OCCO3)cn1
Yield: 36.1 %

Procedure:
To a solution of 1.7 g (6.6 mmol) of 8-(6-fluoropyridin-3-yl)-1,4-dioxaspiro[4.5]decan-8-ol in 20 mL of DMF was added KCN (430 g, 6.6 mmol) and 18-crown-6 ether (1.8 g, 6.6 mmol). The reaction mixture was refluxed for 2 days. Direct chromatography on silica gel afforded the 5-(8-hydroxy-1,4-dioxaspiro[4.5]dec-8-yl)pyridine-2-carbonitrile (620 mg, 36%): MS (m/e): 261 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[C:9](O)(=O)[CH2:10][C:11](O)=O>O>[CH2:10]([C:11]1[S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1)[C:9]1[S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: O=C(O)CC(=O)O
Reactant: Nc1ccccc1S
Solvent: O
Product: c1ccc2sc(Cc3nc4ccccc4s3)nc2c1
Reaction time: 1 h

Procedure:
To a flask were added 50 g polyphosphoric acid. After heating to 70 C under nitrogen, a mixture of 3.13 g 2-aminothiophenol and 1.3 g malonic acid was added. The reaction mixture was heated to 135 C for 1 hour, then 145 C for 1 hour. After cooling to 70 C, the mixture was poured into 100 ml water. The slurry was cooled to 22 C, filtered and the solid was washed with water. The solid was added to 50 ml ethanol and basified with aqueous ammonium hydroxide. After cooling to 5 C, the solid was filtered and washed with water. The solid was dissolved in 14 ml hot ethanol and 7 ml water was added and the solution was cooled to 5 C. Following filtration, the white solid was washed with 50% ethanol and dried, leaving 1.1 g.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:16]=3)=[CH:11][CH:10]=2)[S:3]1.N1C=CC=CC=1.[Li+].[BH4-].Cl>C1COCC1>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH:16]=3)=[CH:13][CH:14]=2)[S:3]1
Reactant: CC(C)(C)OC(=O)NCc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
3.69 g (0.009 mol) of tert-butyl [4′-(2,4-dioxothiazolidin-5-ylidenemethyl)biphenyl-3-yl]methylcarbamate, 6 ml of THF and 7.3 ml of pyridine are introduced, in order, into a 50 ml three-necked round-bottomed flask. The mixture is placed under nitrogen and 10 ml of a freshly prepared 2 M LiBH4 solution (0.02 mol) in THF are added dropwise. After stirring for 30 minutes at room temperature, the mixture is heated under reflux for 16 hours. The reaction medium is poured over 32 ml of a 1 N HCl solution and the THF is evaporated under vacuum. The precipitate obtained is filtered. After drying, the crude product (2.75 g) is chromatographed on 95 g of silica gel, eluting with a heptane/ethyl acetate=3/7 mixture. 2.45 g (66%) of tert-butyl [4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-yl]methylcarbamate are obtained.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:38]([NH2:40])=[O:39])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH3:36])[CH:31]=[C:30]([F:37])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].[CH3:41]N>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:38]([NH2:40])=[O:39])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][N:35]5[CH2:2][CH2:3][O:5][CH2:41][CH2:36]5)[CH:31]=[C:30]([F:37])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:11])=[O:12])[CH3:9]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNC)c4)cc23)CC1
Reactant: CN
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CN5CCOCC5)c4)cc23)CC1
Yield: 50.9 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(methylamino)methyl]phenyl}-1H-indole-7-carboxamide trifluoroacetate, substituting morpholine (22 mg, 0.42 mmol) for methanamine to afford 22.9 mg of the title compound (50.9%).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7]C(O)=O)=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].COC1C=CC(O)=CC=1>CN(C)C(=O)C>[OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1
Reactant: O=C(O)C=Cc1ccc(O)cc1
Agent: CC(=O)[O-]
Agent: COc1ccc(O)cc1
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: C=Cc1ccc(O)cc1
Yield: 68.07 %

Procedure:
Into a three neck 1 Liter flask equipped with a mechanical overhead stirrer and water condenser under an atmosphere of Nitrogen, was added 100 g (0.609 Mole) of p-hydroxycinnamic acid (TCI America; Portland, Oreg.) followed by 316 ml of N,N-Dimethylacetamide. The solution was stirred to form a light tan solution. To the solution was added 2.98 g of potassium acetate (Aldrich; Milwaukee, Wis.) (5 Mole %) followed by 0.1 g of 4-methoxyphenol (200 ppm; Aldrich; Milwaukee, Wis.). The flask was lowered into an oil bath preheated to 150° C. The reaction progress was monitored by HPLC as described in General Methods. The reaction mixture turned dark brown in color. Complete decarboxylation of p-hydroxycinnamic acid occurred in 4.5 h to give a solution of p-hydroxystyrene (HSM). The flask was then removed from the oil bath and allowed to cool to 40° C. To the reaction mixture was added 34.2 g finely ground potassium hydroxide, followed by rapid addition of 333.6 mL (7 equivalents) of epichlorohydrin (Aldrich). The reaction mixture turned yellow. The flask was lowered into a 90° C. oil bath. Reaction progress was monitored by HPLC. The p-hydroxystyrene was completely consumed in 80 min. with formation of p-glycidyloxystyrene, 68.07% yield based on HPLC. The reaction mixture was cooled to room temperature then filtered through a medium sintered funnel. The solids were washed with a small portion of DMAc and then with diethylether. Prostab® 5415 (1000 ppm; (bis(1-oxyl-2,2,6,6-tetramethylpiperidine-4-yl)sebacate; Ciba Specialty Chemicals, Tarrytown, N.Y.) was added and the mixture concentrated via rotovap at 40° C. The product was purified by vacuum distillation. The product fractions were collected at 98-100° C. and 2.2×10−2 Torr. Fractions were analyzed by 1H NMR in CDCl3 as described in General Methods. The fractions with good product were combined to produce total of 64.2 g of clear liquid.
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:22]2[C:23](=[O:66])[CH:24]([NH:25][C:26](=[O:65])[C:27](=[N:53][O:54][C:55]([CH3:64])([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH3:56])[C:28]3[N:29]=[C:30]([NH:33][C:34]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[S:31][CH:32]=3)[C@H:21]2[S:20][CH2:19][C:18]=1[CH2:67]Cl)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:90]([C:93]1[CH:100]=[CH:99][C:96]([CH:97]=O)=[CH:95][CH:94]=1)([O-:92])=[O:91].C(=O)([O-])O.[Na+].NC1SC=C(C(=NOC(C(O)=O)(C)C)C(NC2C(=O)N3C(C(O)=O)=C(C=CC4C=CC([N+]([O-])=O)=CC=4[N+]([O-])=O)CS[C@H]23)=O)N=1>>[CH:1]([O:14][C:15]([C:17]1[N:22]2[C:23](=[O:66])[CH:24]([NH:25][C:26](=[O:65])[C:27](=[N:53][O:54][C:55]([CH3:64])([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH3:56])[C:28]3[N:29]=[C:30]([NH:33][C:34]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[S:31][CH:32]=3)[C@H:21]2[S:20][CH2:19][C:18]=1[CH:67]=[CH:97][C:96]1[CH:99]=[CH:100][C:93]([N+:90]([O-:92])=[O:91])=[CH:94][CH:95]=1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: CC(C)(ON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C=Cc3ccc([N+](=O)[O-])cc3[N+](=O)[O-])CS[C@H]12)c1csc(N)n1)C(=O)O
Agent: O=C([O-])O
Agent: [I-]
Product: CC(C)(C)OC(=O)C(C)(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=Cc3ccc([N+](=O)[O-])cc3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 66.5 %

Procedure:
7-[2-(1-methyl-1-tert-butoxycarbonylethoxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester (775 mg, 0.8 mmol), sodium iodide (120 mg, 0.8 mmol), triphenylphosphine (210 mg, 0.8 mmol), 4-nitrobenzaldehyde (483 mg, 3.2 mmol) and sodium hydrogen carbonate (200 mg, 2.4 mmol) were used to conduct the procedure similar to that shown in (1) of Example 1 to obtain 568 mg (yield: 66%) of 7-[2-(1-methyl-1-tert-butoxycarbonylethoxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-(4-nitrostyryl)-3-cephem-4-carboxylic acid benzhydryl ester as yellow powder.
Reaction SMILES: [C:1]([C:5]1[CH:16]=[CH:15][C:8]([CH2:9][O:10][CH2:11][CH:12]2[CH2:14][O:13]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:17]#[C:18][NH2:19].[Na]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][O:10][CH2:11][CH:12]2[O:13][C:18]([NH2:19])=[N:17][CH2:14]2)=[CH:15][CH:16]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(COCC2CO2)cc1
Reactant: N#CN
Agent: [Na]
Product: CC(C)(C)c1ccc(COCC2CN=C(N)O2)cc1

Procedure:
The title compound was prepared from 2-(4-tert-butyl-benzyloxymethyl)-oxirane and sodium hydrogen cyanamide according to the procedures employed for the preparation of the compound in Step 2 of Example 1.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([CH:8]1[NH:13][C:12](=[O:14])[CH:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:10]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[C:9]1=[O:26])=[O:7])[CH3:4].[CH3:27]I.[Cl-].[NH4+]>CN(C)C=O>[CH2:3]([O:5][C:6]([C:8]1([CH3:27])[NH:13][C:12](=[O:14])[CH:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:10]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[C:9]1=[O:26])=[O:7])[CH3:4]
Reactant: CI
Reactant: CCOC(=O)C1NC(=O)C(CC(C)C)N(OC2CCCCO2)C1=O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C)NC(=O)C(CC(C)C)N(OC2CCCCO2)C1=O
Reaction time: 0.17 h

Procedure:
1.04 g of 60% sodium hydride was added to 100 ml of 9.67 g of 3-ethoxycarbonyl-6-isobutyl-1-(2-tetrahydropyranyloxy)piperazine-2,5-dione in anhydrous N,N-dimethylformamide, on ice cooling, and the mixture was stirred for 10 minutes. Thereto was added 3.5 ml of methyl iodide. The mixture was stirred at room temperature for 5 hours. The reaction mixture was ice-cooled and poured into an aqueous solution saturated with ammonium chloride. The mixture was extracted with ethyl acetate. The extract was washed three times with an aqueous solution saturated with sodium chloride, dried with anhydrous magnesium sulfate, and subjected to distillation to remove the solvent to obtain 8.53 g of (3RS,6SR)-3-ethoxycarbonyl-6-isobutyl-3-methyl-1-(2-tetrahydropyranyloxy)piperazine-2,5-dione as a brown oily substance.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[CH:23]([CH3:25])[CH3:24].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[N:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[CH:23]([CH3:24])[CH3:25]
Reactant: C1COCCN1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(C(C)C)cc3c(=O)[nH]2)c1
Product: CC(C)c1cc2c(N3CCOCC3)nc(-n3cc(C(=O)O)cn3)nc2cc1F

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-fluoro-6-isopropyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and morpholine in step E. MS (ESI): predicted mass calcd. for C19H20FN5O3, 385.2
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH3:13].C([O-])([O-])=O.[K+].[K+].[CH3:21][C:22]([CH3:24])=O>>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:24][C:22]#[CH:21])=[CH:8][C:7]=1[CH3:13]
Reactant: COC(=O)COc1ccc(O)cc1C
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C#CCOc1ccc(OCC(=O)OC)c(C)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (4-hydroxy-2-methyl-phenoxy)-acetic acid methyl ester (5.1 g, 25.8 mmol) and K2CO3 (7.1 g, 51.5 mmol) in acetone (85 ml) was added propagylbromide (3.1 g, 25.7 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 days, and then filtered and evaporated in vacuo. The residue was purified on column chromatography using methylene chloride as eluent to give the title compound in 6.0 (100%) yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:27][S@@](C(C)(C)C)=O)([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([F:26])[CH:17]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.Cl>CO.O1CCOCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:23])[F:24])[CH:19]=[C:18]([F:26])[CH:17]=2)([NH2:27])[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)[S@@](=O)N[C@@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: N[C@@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Reaction time: 0.33 h

Procedure:
(R)-N-((S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide (0.765 g, 1.53 mmol) was dissolved in anhydrous MeOH (4 mL). At RT, 4.0M HCl in dioxane (1.5 mL) was added and the reaction mixture stirred for 20 min. The reaction mixture was diluted with EtOAc (50 mL), transferred to a separation funnel and washed with 1.0M NaOH (ca. 20 mL). The organic portion was dried over anhydrous Na2SO4, decanted and concentrated yielding (S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine as a pale yellow oil, (0.745 g, crude quantitative yield). LCMS: 1.51 min [M+1] 395.2 (2 min gradient, MeOH/H2O 0.1% TFA).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[NH:11]1[CH:15]=[N:14][C:13]([C:16]([O:18]C)=[O:17])=[N:12]1.ClC1C=C(N2C=NC(C(O)=O)=N2)C=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([N:11]2[CH:15]=[N:14][C:13]([C:16]([OH:18])=[O:17])=[N:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: COC(=O)c1nc[nH]n1
Agent: O=C(O)c1ncn(-c2cccc(Cl)c2)n1
Product: O=C(O)c1ncn(-c2cccc(F)c2)n1

Procedure:
This intermediate was prepared from 3-fluorophenylboronic acid and methyl 1,2,4-triazole-3-carboxylate in two steps according to the preparation of 1-(3-chloro-phenyl)-1H-[1,2,4]-triazole-3-carboxylic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:60][C:61]1[CH:62]=[C:63]2[C:67](=[CH:68][CH:69]=1)[C:66](=[O:70])[N:65]([CH2:71][CH2:72][CH2:73][CH3:74])[CH2:64]2.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.O>[CH2:71]([N:65]1[CH2:64][C:63]2[C:67](=[CH:68][CH:69]=[C:61]([NH:60][C:2]3[CH:3]=[N:4][CH:5]=[CH:6][C:7]=3[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:62]=2)[C:66]1=[O:70])[CH2:72][CH2:73][CH3:74]
Reactant: CCCCN1Cc2cc(N)ccc2C1=O
Reactant: Brc1cnccc1-c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCCN1Cc2cc(Nc3cnccc3-c3ccccc3)ccc2C1=O
Temperature: 120 °C
Yield: 29.3 %

Procedure:
3-Bromo-4-phenylpyridine (125 mg, 0.534 mmol) was added to a suspension of 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (33 mg, 0.053 mmol) and tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) (49 mg, 0.053 mmol) in toluene (5 mL). 5-Amino-2-butylisoindolin-1-one (120 mg, 0.587 mmol) and sodium tert-butoxide (128 mg, 1.335 mmol) were added and the mixture was stirred and heated in the microwave (120° C., 300 W, 75 min). Water and ethyl acetate were added, the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and dried over MgSO4. Purification by flash chromatography (dichloromethane/methanol, gradient 1-5% methanol) provided 2-butyl-5-(4-phenylpyridin-3-ylamino)isoindolin-1-one (56 mg, 46%). ESI-MS [M+H]+=358.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([OH:15])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[CH3:17][C:18]1[C:23]([CH2:24][CH2:25]O)=[CH:22][CH:21]=[C:20]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[N:19]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([O:15][CH2:25][CH2:24][C:23]3[C:18]([CH3:17])=[N:19][C:20]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:29][CH:28]=4)=[CH:21][CH:22]=3)[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCO
Reactant: CCOC(=O)Cn1ccc2c(O)cccc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)Cn1ccc2c(OCCc3ccc(-c4ccc(C(F)(F)F)cc4)nc3C)cccc21

Procedure:
In analogy to the procedure described in example 5 f], (4-hydroxy-indol-1-yl)-acetic acid ethyl ester was reacted with 2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethanol (example 8 e]) in the presence of di-tert-butyl azodicarboxylate and triphenylphosphine in tetrahydrofuran to yield the title compound as white solid.