Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6](=[C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:13])[C:7]([O:9][CH2:10]C)=[O:8].C[O-].[Na+].[Br:25]N1C(=O)CCC1=O>CO>[CH3:10][O:9][C:7]([C:6]1[CH:5]=[C:4]([Br:25])[C:3](=[O:2])[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]=1[CH3:13])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C(C=CC(=O)OC)=C(C)Nc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(Br)c(=O)n(-c2ccccc2)c1C
Temperature: 25 °C
Yield: 38.4 %

Procedure:
MeOH (200 mL) was added to a flask containing 4-(1-phenylamino-ethylidene)-pent-2-enedioic acid 5-ethyl ester 1-methyl ester (5.88 g, 20.3 mmol). NaOMe solution (4.7 mL, 20.3 mmol, 4.375 M in MeOH) and N-bromosuccinimide (4.35 g, 24.4 mmol) were added, and the resulting mixture was refluxed for 1 h. After cooling to r.t., the solvent was evaporated in vacuo. The residue was partitioned between saturated NH4Cl and CH2Cl2. The aqueous layer was extracted with additional CH2Cl2 and the organic layers were combined, dried over MgSO4, and concentrated. The crude product was chromatographed (0-45% EtOAc/hexanes) to give 2.51 g of the title compound (containing about 14% of the corresponding ethyl ester) as a yellow solid. MS: (+) m/z 343.93, 346.07 (M+Na, 79/81Br).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[N:14][NH:13][C:12](=[O:16])[CH:11]=2)=[N:6][CH:7]=1.N1C=CC=CC=1COC1C=NN(C2CCCCO2)C(=O)C=1>>[N:6]1[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=1[CH2:8][O:9][C:10]1[CH:15]=[N:14][NH:13][C:12](=[O:16])[CH:11]=1
Reactant: O=c1cc(OCc2ccc(Cl)cn2)cn[nH]1
Agent: O=c1cc(OCc2ccccn2)cnn1C1CCCCO1
Product: O=c1cc(OCc2ccccn2)cn[nH]1

Procedure:
5-(Pyridin-2-ylmethoxy)-2H-pyridazin-3-one is prepared following preparation 18b from 2.40 g (8.35 mmol) 5-(pyridin-2-ylmethoxy)-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (preparation 27a).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]([S:15]([OH:18])(=[O:17])=[O:16])[CH2:11][C:12]([OH:14])=[O:13])=[O:7])(C)(C)C.Cl.O1CCOCC1.C1(=O)[O:31][C:29](=[O:30])[CH:28]=[CH:27]1>CC(N(C)C)=O>[C:12]([CH2:11][CH:10]([S:15]([OH:18])(=[O:16])=[O:17])[CH2:9][NH:8][C:6](=[O:7])/[CH:27]=[CH:28]\[C:29]([OH:31])=[O:30])([OH:14])=[O:13]
Reactant: O=C1C=CC(=O)O1
Reactant: CC(C)(C)OC(=O)NCC(CC(=O)O)S(=O)(=O)O
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: C1COCCO1
Product: O=C(O)/C=C\C(=O)NCC(CC(=O)O)S(=O)(=O)O
Reaction time: 8 h
Yield: 82.8 %

Procedure:
4-(Tert-butoxycarbonylamino)-3-sulfobutanoic acid (321 mg, 1.13 mmol) was stirred in the mixture of HCl (conc)/Dioxane (1:4, 15 ml) for 30 min, evaporated and coevaporated with EtOH/Toluene (1:1, 4×20 ml) to dryness. To the dryness material was added maleic anhydride (121 mg, 1.23 mmol) and DMA (20 ml) and the mixture was stirred overnight, evaporated and run through C-18 column eluted with water and crystallized with EtOH/Hexane to afford 263 mg (83%) of the title compound. ESI MS 279.8 (M−H). The NMR data are the same through the route with 4-azido-3-sulfobutanoic acid.
Reaction SMILES: CN(C=O)C.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[O:12][C@H:11]([CH3:18])[CH2:10]2.Br[Zn][CH2:21][CH:22]1[O:26][CH2:25][CH2:24][O:23]1>CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:23]1[CH2:24][CH2:25][O:26][CH:22]1[CH2:21][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[O:12][C@H:11]([CH3:18])[CH2:10]2
Reactant: Br[Zn]CC1OCCO1
Reactant: C[C@@H]1Cc2cc(Br)ccc2C(=O)O1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H]1Cc2cc(CC3OCCO3)ccc2C(=O)O1
Temperature: 110 °C

Procedure:
A sealed tube was charged with aryl bromide, palladium(II) acetate (0.028 g, 0.124 mmol) and commercially available tri-t-butylphosphine-BF4 complex (0.072 g, 0.25 mmol) and sealed. The tube was evacuated and refilled with nitrogen before DMF (12 ml) and (3R)-6-bromo-3-methyl-3,4-dihydro-1H-isochromen-1-one (0.75 g, 3.1 mmol) were added followed by commercially available bromo(1,3-dioxolan-2-ylmethyl)zinc (6.2 ml, 3.1 mmol). The tube was heated to 110° C. in the microwave for 75 minutes, after which it was cooled, diluted with EtOAc, filtered, concentrated and purified via MPLC (20-50% E/H) to afford (3R)-6-(1,3-dioxolan-2-ylmethyl)-3-methyl-3,4-dihydro-1H-isochromen-1-one.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([N:8]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:10][CH2:11][CH3:12])=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[CH2:9]([N:8]([CH2:13][CH2:14][CH2:15][CH3:16])[C:7]1[CH:6]=[CH:5][C:4]([NH2:1])=[CH:18][CH:17]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCN(CCCC)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CCCCN(CCCC)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-nitro-N,N-dibutylaniline from Example 40A (1.0 g, 4.0 mmol) in methanol (10 ml) was added palladium 10 wt % on activated carbon (85 mg, 0.08 mmol) under an atmosphere of hydrogen. The reaction mixture was stirred at room temperature for 4 hours and filtered through celite. After solvent were removed under reduced pressure, the titled material was obtained as a white solid, which was used in next step without purification.
Reaction SMILES: [Cl:1][C:2]1[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[CH:12][C:3]=1[CH2:4][CH2:5][NH:6][C:7](=O)[O:8]CC.C[Si](C)(C)O[Si](C)(C)C.P(Cl)(Cl)(Cl)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>ClCCl>[Cl:1][C:2]1[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[C:12]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:8]
Reactant: CCOC(=O)NCCc1ccc(OC)c(OC)c1Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: C[Si](C)(C)O[Si](C)(C)C
Product: COc1cc2c(c(Cl)c1OC)CCNC2=O
Yield: 20.2 %

Procedure:
To ethyl 2-chloro-3,4-dimethoxyphenethylcarbamate 3 (2 g, 6.95 mmol) in 1,1,1,3,3,3-hexamethyldisiloxane (7.39 ml, 34.8 mmol) in a 20 ml microwave tube was added phosphorous oxichloride (6.48 ml, 69.5 mmol) and phosphorus pentoxide (4.93 g, 34.8 mmol). Microwaved at 150° C. (high absorption setting) for 1 hour. Solvent removed and poured on to the ice. Neutralized with 2M sodium hydroxide and extracted with dichloromethane. Dried over magnesium sulfate and chromotagraphed eluting with 0-20% methanol:dichloromethane to give 5-chloro-6,7-dimethoxy-3,4-dihydroisoquinolin-1(2H)-one (340 mg, 1.407 mmol, 20.24% yield).) LCMS (M+H)+: 242.1
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:21][CH2:22][CH2:23][C@H:24]([NH:28][CH2:29][CH:30]([O:33][CH3:34])[O:31][CH3:32])[CH2:25][O:26][CH3:27])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:11](=[O:13])[N:28]([C@H:24]([CH2:25][O:26][CH3:27])[CH2:23][CH2:22][O:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:29][CH:30]([O:31][CH3:32])[O:33][CH3:34])[CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC[C@H](CCOCc1ccccc1)NCC(OC)OC
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC[C@H](CCOCc1ccccc1)N(CC(OC)OC)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 87.3 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-L-alanine (1.12 g, 5.92 mmol) and ((S)-3-benzyloxy-1-methoxymethyl-propyl)-(2,2-dimethoxy-ethyl)-amine (1.60 g, 5.38 mmol) in N,N-dimethylformamide (16 mL) were added 4-methylmorpholine (1.63 g, 16.1 mmol) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (3.07 g, 8.06 mmol) at room temperature. The reaction mixture was stirred at room temperature was stirred at room temperature for 16 h, then partitioned between water and heptane/ethyl acetate 1:1. The organic layer was dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; heptane-ethyl acetate gradient) furnished the title compound (2.20 g, 87%). Colorless oil, MS (ISP)=469.4 (M+H)+.
Reaction SMILES: [N:1]1[N:2]([C:10]2[N:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]([NH:14][CH:15]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]([OH:20])[C:17](O)=[O:18])=[O:13])[CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2.Cl.[CH2:33]([O:35][NH2:36])[CH3:34]>>[CH2:33]([O:35][NH:36][C:17](=[O:18])[CH:16]([OH:20])[CH:15]([NH:14][C:12](=[O:13])[C:11]1[CH:28]=[CH:29][CH:30]=[N:31][C:10]=1[N:2]1[CH:3]=[C:4]2[C:9]([CH:8]=[CH:7][CH:6]=[CH:5]2)=[N:1]1)[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH3:34]
Reactant: CCON
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-n1cc2ccccc2n1
Agent: Cl
Product: CCONC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1cc2ccccc2n1

Procedure:
The reaction was carried out in analogy to reaction step 3.1 by reacting 3-[2-(2H-indazol-2-yl)nicotinamido]-2-hydroxy-4-phenylbutanoic acid and O-ethylhydroxylamine hydrochloride.
Reaction SMILES: [CH:1]([C:4]1[N:8]2[N:9]=[C:10]([CH:13]=O)[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2].[CH3:15][NH2:16].[O-]S([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[CH:1]([C:4]1[N:8]2[N:9]=[C:10]([CH:13]=[N:16][CH3:15])[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CN
Reactant: CC(C)c1nnc2ccc(C=O)nn12
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CN=Cc1ccc2nnc(C(C)C)n2n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 66.8 %

Procedure:
To a flask was added 3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine-6-carbaldehyde (0.420 g, 2.21 mmol, Preparation #2), and methylamine (40 wt % in water, 1.33 mL, 2.65 mmol) followed by MgSO4 (0.399 g, 3.31 mmol) in DCM (2 mL) to give an orange suspension. The mixture was stirred at ambient temperature for about 17 h. The mixture was filtered and concentrated in vacuo to afford the title compound (0.300 g, 67%): 1H NMR (DMSO-d6) δ 8.43 (s, 1H), 8.31 (d, 1H), 7.74 (d, 1H), 3.59 (m, 4H), 2.5 (s, 3H), 1.45 (d, 6H).
Reaction SMILES: [S:1]([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:20]([C@@H:23]4[CH2:27][CH2:26][C@H:25]([NH:28]C(=O)OC(C)(C)C)[CH2:24]4)=[N:21][N:22]=3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[ClH:36]>O1CCOCC1>[ClH:36].[S:1]([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:20]([C@@H:23]4[CH2:27][CH2:26][C@H:25]([NH2:28])[CH2:24]4)=[N:21][N:22]=3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc([C@@H]4CC[C@H](NC(=O)OC(C)(C)C)C4)n23)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc([C@@H]4CC[C@H](N)C4)n23)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 105.9 %

Procedure:
To a solution of tert-butyl (1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylcarbamate (8.22 g, 16.6 mmol) in 1,4-dioxane (32 mL) was added HCl (4 N in 1,4-dioxane, 16.6 mL, 66.2 mmol), and the reaction mixture was heated at about 60° C. for about 1.5 h then stirred at ambient temperature overnight. The reaction mixture was filtered, while rinsing with Et2O (100 mL). The filter cake was dried under vacuum to give a light brown solid that was further dried in a vacuum oven at about 50° C. to give (1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine hydrochloride (7.61 g, 93%) as a beige solid: LC/MS (Table 2, Method d) Rt=1.09 min; MS m/z: 397 (M+H)+.
Reaction SMILES: OS(C(F)(F)F)(=O)=O.[C:9](=[NH:32])([O:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=2)=[CH:16][CH:15]=1)[NH2:10].[OH:33]/[CH:34]=[C:35](/[CH2:40][C:41]1[CH:42]=[N:43][CH:44]=[N:45][CH:46]=1)\[C:36](OC)=O.C([O-])(=O)C.[K+]>C1(C)C=CC=CC=1>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][C:17]2[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][O:11][C:9]3[NH:10][CH:36]=[C:35]([CH2:40][C:41]4[CH:46]=[N:45][CH:44]=[N:43][CH:42]=4)[C:34](=[O:33])[N:32]=3)=[CH:19][CH:18]=2)=[CH:22][C:23]=1[C:28]([F:31])([F:30])[F:29]
Reactant: COC(=O)/C(=C\O)Cc1cncnc1
Reactant: N=C(N)OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)C(F)(F)F
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=c1nc(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)[nH]cc1Cc1cncnc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 21.1 %

Procedure:
An alternative synthesis was provided to prepare the compound of Example 20. A suspension of 2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl imidocarbamate triflate (17.29 g, 34.0 mmol), methyl (2Z)-3-hydroxy-2-(5-pyrimidinylmethyl)-2-propenoate (5.5 g, 28.3 mmol) and potassium acetate (5.56 g, 56.6 mmol) in toluene (200 mL) was stirred at room temperature for 2 min. and then heated to reflux for 3 h. The mixture was filtered off and concentrated to dryness, which was then dissolved in DMF and purified by MDAP with TFA. The purified fractions were combined and neutrallized with ammonia. The organic solvent was removed under vacuo and the water layer was extracted with EA. The organic layer was combined and dried over Na2SO4 which was concentrated to give the white solid. The solid was recrystallized in MeCN to afford the title compound (3.0 g, 21.06% yield) LCMS: rt=3.43 min, [M+H+]=503.
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH2:6][CH2:7]Cl)[CH3:4].[N+:9]([C:12]1[O:13][C:14]2[C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=[CH:23][C:15]=2[C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O-:11])=[O:10]>>[N+:9]([C:12]1[O:13][C:14]2[C:26]([C:27]([O:29][CH2:7][CH2:6][CH2:5][N:3]([CH3:4])[CH3:2])=[O:28])=[CH:25][CH:24]=[CH:23][C:15]=2[C:16]=1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([O-:11])=[O:10]
Reactant: O=C(O)c1cccc2c(-c3ccccc3)c([N+](=O)[O-])oc12
Reactant: CN(C)CCCCl
Agent: Cl
Product: CN(C)CCCOC(=O)c1cccc2c(-c3ccccc3)c([N+](=O)[O-])oc12

Procedure:
Using the method illustrated in Example 25 N,N-dimethylamino-3-chloropropane hydrochloride is reacted with 2-nitro-3-phenyl-7-benzofurancarboxylic acid to provide N,N-dimethylaminopropyl 2-nitro-3-phenyl-7-benzofurancarboxylate, m.p. 65.5°-67.5° C., as a yellow solid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:22])[N:9]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.[CH2:23]([O:25][C:26]([C:28]1[N:29]=[C:30]([SH:33])[NH:31][CH:32]=1)=[O:27])[CH3:24]>>[CH2:23]([O:25][C:26]([C:28]1[N:29]=[C:30]([S:33][C:2]2[S:6][C:5]([NH:7][C:8]([N:9]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[O:22])=[N:4][CH:3]=2)[NH:31][CH:32]=1)=[O:27])[CH3:24]
Reactant: CCOC(=O)c1c[nH]c(S)n1
Reactant: O=C(Nc1ncc(Br)s1)N(C1CCCCC1)C1CCOCC1
Product: CCOC(=O)c1c[nH]c(Sc2cnc(NC(=O)N(C3CCCCC3)C3CCOCC3)s2)n1

Procedure:
Prepared as described in general procedure (E) using 3-(5-bromo-thiazol-2-yl)-1-cyclohexyl-1-(tetrahydro-pyran-4-yl)-urea (Example 189) and ethyl-2-mercapto-1H-imidazole-4-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]([O:11][CH2:12][CH:13]=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:16]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])[NH:17][NH2:18]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:15])[CH:4]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[O:11][CH2:12][CH:13]=[N:18][NH:17][C:16]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]
Reactant: CC(C)(C)OC(=O)NN
Reactant: COC(=O)C(OCC=O)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)C(OCC=NNC(=O)OC(C)(C)C)c1ccccc1
Temperature: 65 °C
Yield: 67.1 %

Procedure:
(2-Oxo-ethoxy)-phenyl-acetic acid methyl ester (2.7 g, 13.0 mmol) and tert-butyl carbazate (1.75 g, 13.0 mmol) were dissolved in toluene (290 mL) and heated to 65° C. over night. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, 100 g, 0% to 100% EtOAc in heptane over 60 minutes) to give the title compound as yellow viscous oil (2.81 g, 67%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([F:23])([F:22])[F:21])[CH:14]=3)[N:9]2[CH3:24])[CH:5]=[CH:6][CH:7]=1.[NH2:25][C:26]1([C:29]([OH:31])=[O:30])[CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:24][N:9]1[C:10]2[C:15](=[CH:14][C:13]([C:20]([F:23])([F:22])[F:21])=[CH:12][CH:11]=2)[C:16]([CH3:19])([CH3:18])[CH2:17][CH:8]1[C:4]1[CH:3]=[C:2]([NH:25][C:26]2([C:29]([OH:31])=[O:30])[CH2:28][CH2:27]2)[CH:7]=[CH:6][CH:5]=1
Reactant: CN1c2ccc(C(F)(F)F)cc2C(C)(C)CC1c1cccc(Br)c1
Reactant: NC1(C(=O)O)CC1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN1c2ccc(C(F)(F)F)cc2C(C)(C)CC1c1cccc(NC2(C(=O)O)CC2)c1
Temperature: 25 °C
Yield: 40.1 %

Procedure:
A solution of 2-(3-bromo-phenyl)-1,4,4-trimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinoline (398.0 mg, 1.0 mmol), copper(I) iodide (57.0 mg, 0.3 mmol), 1-amino-cyclopropanecarboxylic acid (309.0 mg, 3.0 mmol) and potassium carbonate (415.0 mg, 3.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL×2), washed with water (50 mL×2) and saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 1-[3-(1,4,4-trimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-cyclopropanecarboxylic acid (167.6 mg, 40%) as a white solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 419.2.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:16]1([C:2]2[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1ccccc1
Reactant: N#Cc1ccc(Cl)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1ccc(-c2ccccc2)cn1
Yield: 24.5 %

Procedure:
To a stirred solution of 5-chloro-2-cyanopyridine (300 mg, 2.17 mmol) in toluene: H2O (7:3) (10 mL) was added Na2CO3 (459 mg, 4.33 mmol) followed by Pd(PPh3)4 (500 mg, 0.43 mmol) and phenylboronic acid (337 mg, 2.60 mmol) at room temperature. The resulting mixture was heated to reflux for 3 hrs. The reaction mixture was then diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over sodium sulphate and concentrated. The resulting residue was purified by column chromatography (using silica gel 60-120 mesh and 4% ethylacetate in hexane as eluent) to afford 96 mg (24.6% yield) of 5-phenyl-pyridine-2-carbonitrile. LCMS Purity: 97.5%
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:32]([C:33]#[N:34])=[C:17]4[N:18]=[CH:19][CH:20]=[C:21]([C:22]5[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=5)[N:16]4[N:15]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)[OH:36]>>[C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:32]([C:33]([NH2:34])=[O:36])=[C:17]4[N:18]=[CH:19][CH:20]=[C:21]([C:22]5[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=5)[N:16]4[N:15]=3)[CH2:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1c(N2CCN(Cc3ccccc3)CC2)nn2c(-c3cccc(C(F)(F)F)c3)ccnc12
Product: NC(=O)c1c(N2CCN(Cc3ccccc3)CC2)nn2c(-c3cccc(C(F)(F)F)c3)ccnc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 7.0 g of 2-[4-(phenylmethyl)-1-piperazinyl]-7-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile (prepared as described in Example 24) and 50 ml of concentrated sulfuric acid was stirred at room temperature for 5 hours. The yellow solution was poured into ice/water. The precipitate formed was collected and washed with water, then dried in vacuo. The material was recrystallized from acetonitrile, collected and dried and gave 4.8 g of the product of the Example as a yellow solid, mp 252°-254° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]([C:17]([O:19]CC2C=CC=CC=2)=[O:18])([CH3:16])[CH3:15])[CH2:11][O:10][C:9]1([CH3:28])[CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]([C:17]([OH:19])=[O:18])([CH3:16])[CH3:15])[CH2:11][O:10][C:9]1([CH3:28])[CH3:27])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC(C)(C)C(=O)OCc2ccccc2)COC1(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1[C@@H](CC(C)(C)C(=O)O)COC1(C)C
Reaction time: 4.5 h

Procedure:
A mixture of 9.48 g of 4(S)-(2-benzyloxycarbonyl-2-methyl-propyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester and 2.58 g of 10% Pd/C in 100 ml of ethyl acetate is hydrogenated at room temperature for 4.5 hours. The solid is removed by filtration over Hyflo®. The mixture is concentrated and re-dissolved in ethyl acetate and 2N NaOH. The layers are separated and the aqueous layer is extracted with ethyl acetate (2×). The aqueous layer is acidified to pH 3 with 4M HCl and extracted with ethyl acetate (3×). The combined organic layers from the second extraction are dried over sodium sulphate, filtered and concentrated. The crude title compound is obtained as a colourless oil. Rf=0.43 (EtOAc-heptane 1:1); Rt=4.23 (gradient I).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:6]=[CH:5]2.C([Li])(C)(C)C.C[O:27][C:28]([C@:30]1([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:34][CH2:33][CH2:32][N:31]1[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=O>C1COCC1>[C:38]([O:37][C:35]([N:31]1[CH2:32][CH2:33][CH2:34][C:30]1([CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[C:28]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:11]([CH:15]([CH3:16])[CH3:17])([CH:18]([CH3:19])[CH3:20])[CH:12]([CH3:13])[CH3:14])[CH:6]=[CH:5]2)=[O:27])=[O:36])([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)ccc21
Reactant: COC(=O)[C@]1(Cc2ccccc2)CCCN1C(=O)OC(C)(C)C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(C(=O)C3(Cc4ccccc4)CCCN3C(=O)OC(C)(C)C)ccc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 16.5 %

Procedure:
To a stirred solution of 5-bromo-1-triisopropylsilanyl-1H-indole (0.55 g, 1.57 mmol) in THF (10 mL) at −78° C. under nitrogen atmosphere was added tert-butyllithium (2.02 mL of 1.55 M solution in pentanes, 3.13 mmol) dropwise. After one hour, the reaction mixture was added rapidly to a cold (−78° C.) solution of (R)-2-benzyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (0.50 g, 3.13 mmol) in THF (10 mL). The reaction mixture was stirred at −78° C. for one hour, then warmed to room temperature and stirred for two hours. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl (20 mL) then extracted with EtOAc. The combined extracts were washed with brine then dried (MgSO4), filtered and concentrated in vacuo. Purification by chromatography (silica, 0-20% EtOAc in hexanes) gave 2-benzyl-2-(1-triisopropylsilanyl-1H-indole-5-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.145 g, 0.259 mmol, 16%) as a colourless gum.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH3:11])=O.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[C:22](=[S:24])[NH2:23]>>[CH3:11][C:10]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[C:3]1[N:23]=[C:22]([C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[CH3:12])[S:24][CH:2]=1
Reactant: Cc1ccncc1C(=O)CBr
Reactant: Cc1ccc([N+](=O)[O-])cc1C(N)=S
Product: Cc1ccncc1-c1csc(-c2cc([N+](=O)[O-])ccc2C)n1

Procedure:
By the reaction in the same manner as in Example 25-ii) using 2-methyl-5-nitrobenzonitrile (1.25 g), 2-methyl-5-nitrobenzenecarbothioamide was obtained as a yellow powder. Then, by the reaction in the same manner as in Example 25-iii) using 2-bromo-1-(4-methylpyridin-3-yl)ethanone hydrobromate (1.35 g) and 2-methyl-5-nitrobenzenecarbothioamide, the title compound (460 mg) was obtained as colorless needle crystals.