Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:11])([CH3:10])[C:4]([NH:6][CH:7]([CH3:9])[CH3:8])=[O:5].[H-].[Na+].[NH2:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[C:17]#[N:18]>C1COCC1>[NH2:14][C:15]1[C:16]([C:17]#[N:18])=[C:19]([CH:20]=[CH:21][CH:22]=1)[O:1][CH2:2][C:3]([CH3:10])([CH3:11])[C:4]([NH:6][CH:7]([CH3:8])[CH3:9])=[O:5]
Reactant: CC(C)NC(=O)C(C)(C)CO
Reactant: N#Cc1c(N)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)NC(=O)C(C)(C)COc1cccc(N)c1C#N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.7 %

Procedure:
To a solution of 3-hydroxy-N-isopropyl-2,2-dimethylpropanamide (Example 134c, 5.12 g, 32.15 mmol) in dry THF (100 mL) was added portion-wise NaH (60% in mineral oil, 1.41 g, 35.37 mmol) at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for about 30 minutes until bubbling ceased. 2-Amino-6-fluorobenzonitrile (4.38 g, 32.15 mmol) was added and the solution stirred at 80° C. overnight. The reaction mixture was quenched slowly with water at 0° C., and concentrated under reduced pressure. The residue was taken up in EtOAc and washed consecutively with brine and water, dried over Na2SO4 and concentrated. The residue was purified by re-crystallization from EtOAc/hexane to give the title compound as a white crystalline solid (4.4 g, 50%). 1H NMR (400 MHz, CDCl3) δ 1.18 (d, J=6.8 Hz, 6H), 1.32 (s, 6H), 3.94 (s, 2H), 4.04-4.12 (m, 1H), 4.43 (s, 2H), 5.98 (d, J=6.8 Hz, 1H), 6.21 (d, J=8.0 Hz, 1H), 6.32 (d, J=8.0 Hz, 1H), 7.21 (t, J=8.0 Hz, 1H). MS 276 (MH+).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[F:55][C:56]1[CH:61]=[CH:60][C:59]([N:62]=[C:63]=[O:64])=[CH:58][CH:57]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:63]([NH:62][C:59]2[CH:60]=[CH:61][C:56]([F:55])=[CH:57][CH:58]=2)=[O:64])[CH2:49][CH2:48]1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)Nc2ccc(F)cc2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 32 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 1-fluoro-4-isocyanatobenzene as starting materials in 32% yield. LCMS for C31H31ClFN8O2 (M+H)+: m/z=601.2.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9](O)[CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2].S(Cl)([Cl:23])=O.O>C(Cl)(Cl)Cl>[Cl:23][CH:9]([C:6]1[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][N:7]=1)[CH2:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1
Reactant: CCc1ccc(C(O)COc2ccc(C=O)cc2)nc1
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCc1ccc(C(Cl)COc2ccc(C=O)cc2)nc1
Yield: 76.7 %

Procedure:
To a stirred solution of 5 g (0.018 mol) 4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehyde dissolved in chloroform was added 2.63 g (0.022 mol) thionyl chloride at 55-60° C. Reaction mixture was refluxed for 1 hr. Progress of the reaction was monitored by TLC and after completion of reaction, subsequent work-up in alkaline water yielded 4 g (75%) of the desired product.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH3:11])[C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:12][C:13]1[CH:14]=[C:15]([NH2:20])[CH:16]=[CH:17][C:18]=1[F:19]>CN(C=O)C.C(OCC)(=O)C.[O-]S(C(F)(F)F)(=O)=O.[Ag+]>[Cl:12][C:13]1[CH:14]=[C:15]([NH:20][C:2]2[C:3]3[CH:10]=[CH:9][N:8]([CH3:11])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: Cn1ccc2c(Cl)ncnc21
Reactant: Nc1ccc(F)c(Cl)c1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1ccc2c(Nc3ccc(F)c(Cl)c3)ncnc21
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 82.7 %

Procedure:
A mixture of 4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (398.8 mg, 2.4 mmol) and 3-chloro-4-fluoro-phenylamine (378 mg, 2.6 mmol) in DMF (6 mL) was stirred at room temperature for 2 minutes. To it was added silver triflate (672 mg, 2.6 mmol), the mixture was then stirred at 90° C. for 2 hours. The reaction was then diluted with ethyl acetate and filtered off the precipitate, washing the precipitate with 10% ammonia solution. The filtrate was extracted with ethyl acetate, dried and concentrated. The residue was triturated with ethyl acetate and filtered to give 549.1 mg (83%) of (3-chloro-4-fluoro-phenyl)-(7-methyl-7H-pyrrolo(2,3-d]pyrimidin-4-yl)-amine as an off-white solid. 1H NMR (300 MHz, DMSO-d6) 9.48 (s, 1H, NH), 8.35 (s, 1H), 8.29 (dd, J=2.7 & 6.8Hz, 1H), 7.75-7.80 (m, 1H), 7.37 (t, J=9.3 Hz, 1H), 7.30 (d, J=3.1 Hz, 1H), 6.77 (d, J=3.1 Hz, 1H), 3.75. (s, 3H, CH3). MS 277 [M++1].
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[C:10](=O)[C:11](=[O:13])[NH:12][C:7]=3[CH:6]=[CH:5][C:4]=2[NH:3][N:2]=1.[CH:15]1[C:20]([NH:21][NH2:22])=[CH:19][CH:18]=[C:17]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:16]=1.Cl>>[O:13]=[C:11]1[NH:12][C:7]2[CH:6]=[CH:5][C:4]3[NH:3][N:2]=[CH:1][C:9]=3[C:8]=2[C:10]1=[N:22][NH:21][C:20]1[CH:19]=[CH:18][C:17]([S:23]([NH2:26])(=[O:24])=[O:25])=[CH:16][CH:15]=1
Reactant: O=C1Nc2ccc3[nH]ncc3c2C1=O
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc4[nH]ncc4c32)cc1
Yield: 8 %

Procedure:
The title compound was prepared from 3,6-dihydro-pyrrolo[3,2-e]indazole-7,8-dione (Cuny, et al., Chemie Berichte 1981, 114, 1624-35) and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G in 8% yield: 1H NMR (DMSO-d6): δ7.02 (d, J=8.7 Hz, 1H), 7.28 Z (s, 2H), 7.51 (d, J=8.6 Hz, 2H), 7.68 (d, J=8.8 Hz, 1H), 7.82 (d, J=8.7 Hz, 2H), 8.34 (s,1H), 10.98 (s, 1H), 12.90 (s, 1H), 13.20 (s,1H); APCI−MS m/z 356 (M)−. Anal. Calcd for C15H12N6O3S.1.46H2O.0.2EtOAc: C, 47.41, H, 4.16; N, 20.99; S, 8.01. Found C, 47.40, H, 3.70; N, 21.00; S, 7.85.
Reaction SMILES: F[C:2]1[C:3]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([F:21])[CH:14]=3)[O:10][N:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:22][N:23]([CH3:38])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29]CCCCCN(C)C.[K]>CN(C)C=O>[CH3:22][N:23]([CH3:38])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:2]1[C:3]([C:8]2[N:12]=[C:11]([C:13]3[CH:14]=[C:15]([F:21])[CH:16]=[C:17]([C:19]#[N:20])[CH:18]=3)[O:10][N:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CCCCCOCCCCCN(C)C
Reactant: N#Cc1cc(F)cc(-c2nc(-c3ncccc3F)no2)c1
Agent: [K]
Solvent: CN(C)C=O
Product: CN(C)CCCCCOc1cccnc1-c1noc(-c2cc(F)cc(C#N)c2)n1

Procedure:
Alternatively, treatment of 3-(3-fluoropyrid-2-yl)-5-(3-fluoro-5-cyanophenyl)-1,2,4-oxadiazole with potassium 5-dimethylaminopentyloxide in N.N-dimethylformamide with a catalytic amount of 1, 4, 7, 10, 13, 16-hexaoxacyclooctadecane (18-crown-6) and heating at 110° C. affords crude product. Standard work up and purification by one or more methods, including silica gel chromatography, recystallization, trituration, and reversed-phase high-performance liquid chromatography (RP-HPLC) affords purified 3-(3-(5-dimethylaminopentyloxy)-pyrid-2-yl)-5-(3-cyano-5-fluorophenyl)-1,2,4-oxadiazole.
Reaction SMILES: CC1C=CC(S(O[CH:12]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13]2)(=O)=O)=CC=1.[C-:27]#[N:28].[Na+]>CS(C)=O.[Cl-].[Na+].O>[C:27]([CH:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[CH2:13]1)#[N:28]
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OCc3ccccc3)C2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CC1CCN(C(=O)OCc2ccccc2)C1
Temperature: 80 °C
Yield: 83 %

Procedure:
To a solution of 13.4 g (35.7 mmol) of benzyl 3-(p-methylbenzenesulfonyloxy)pyrrolidine-1-carboxylate in 49 mL of DMSO were added 2.58 g (50.6 mmol) of finely powdered sodium cyanide. The reaction mixture was heated at 80° C. for 3.5 hours and then cooled to room temperature. The crude was diluted with 100 mL of brine and extracted with diethyl ether (5×250 mL). The extracts were combined, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel with 60% ethyl acetate/hexanes to give 6.8 g (83%) of benzyl 3-cyanopyrrolidine-1-carboxylate as a clear oil. Rf=0.46 in 100% ethyl acetate; Mass Spectrum (FD+): M+=230; IR (CHCl3, cm-1): 882, 912, 986, 1030, 1119, 1169, 1292, 1347, 1362, 1424, 1451, 1468, 1486, 1498, 1702, 2891, 2962, 3021; UV (C2H5OH) λmax =206 (ε=9299), 258 (ε=214); Anal. Calcd. for C13 H14N2O2 : C,67.81; H,6.13; N,12.17; Found: C, 67.58; H. 6.26; N, 12.43; 1H NMR (300 MHz, CDC13) δ2.25-2.31 (m, 2H); 3.11 (t, J=6.5 Hz, 1H); 3.48-3.75 (m, 3H); 5.15 (s, 2H); 7.37 (s, 5H).
Reaction SMILES: Cl[CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1)[C:3](=O)[CH3:4].[C:14]([C:16]1[CH:17]=[C:18]([NH:28][C:29]([NH2:31])=[S:30])[CH:19]=[CH:20][C:21]=1[N:22]1[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]1)#[N:15]>>[Cl:13][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[CH2:6][C:2]1[S:30][C:29]([NH:28][C:18]2[CH:19]=[CH:20][C:21]([N:22]3[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]3)=[C:16]([CH:17]=2)[C:14]#[N:15])=[N:31][C:3]=1[CH3:4]
Reactant: CC(=O)C(Cl)Cc1cccc(Cl)c1
Reactant: Cc1cn(-c2ccc(NC(N)=S)cc2C#N)cn1
Product: Cc1cn(-c2ccc(Nc3nc(C)c(Cc4cccc(Cl)c4)s3)cc2C#N)cn1

Procedure:
The title compound was prepared in analogy to example 1 step e) from 54 mg (0.25 mmol) 3-chloro-4-(3-chlorophenyl)-2-butanone and 64 mg (0.25 mmol) [3-cyano-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea. The crude product was purified on silica gel with methylene chloride/methanol 9/1 yielding 50 mg (48%) 5-[5-(3-chloro-benzyl)-4-methyl-thiazol-2-ylamino]-2-(4-methyl-imidazol-1-yl)-benzonitrile as a light yellow solid. MS ISP (m/e): 420.1/422.2 (100/38) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.55 (s, 1H), 8.24 (s, 1H), 7.89 (s, 1H), 7.88 (d, 1H), 7.55 (d, 1H), 7.36-7.20 (m, 5H), 4.03 (s, 2H), 2.27 (s, 3H), 2.18 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:11])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.OS(O)(=O)=O.[Br:20]N1C(C)(C)C(=O)N(Br)C1=O>O>[Br:20][C:3]1[C:2]([F:1])=[C:7]([C:6]([CH3:11])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1)[C:8]([OH:10])=[O:9]
Reactant: Cc1c([N+](=O)[O-])ccc(F)c1C(=O)O
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c([N+](=O)[O-])cc(Br)c(F)c1C(=O)O
Reaction time: 6 h
Yield: 158 %

Procedure:
To a solution of 6-fluoro-2-methyl-3-nitrobenzoic acid (100 mg, 0.5 mmol) in concentrated H2SO4 (0.5 ml, 9.38 mmol) was added 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (79 mg, 0.28 mmol) at room temperature and under nitrogen. The reaction mixture was stirred for 6 hours during which time a precipitate formed. The reaction mixture was added slowly to deionized water (3 ml) and the resulting precipitate was filtered. The solid was washed with deionized water (2 ml) and air dried for 2 hours to give 123 mg (88%) of 3-bromo-2-fluoro-6-methyl-5-nitrobenzoic acid as a pale yellow solid. LC-MS 94%, 1.61 min (3 minute LC-MS method), m/z=275.9/277.9 (ES−), 1H NMR (500 MHz, Chloroform-d) δ ppm 8.25 (d, J=6.2 Hz, 1H), 2.58 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:17])=[CH:3][CH2:4][O:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH:12]([NH2:14])[CH3:13])=[CH:8][CH:7]=1.N1C=CC=CC=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>CCOCC>[CH3:17][C:2]([CH3:1])=[CH:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH:12]([NH:14][C:25](=[O:26])[O:27][CH2:28][CH3:29])[CH3:13])=[CH:15][CH:16]=1
Reactant: CC(C)=CCOc1ccc(OCC(C)N)cc1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCOC(=O)NC(C)COc1ccc(OCC=C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the above amine (0.86 g, 3.7 mmol) and pyridine (0.64 g, 8.0 mmol ) in 8 ml of ether at 5° is added dropwise over 10 min. ethyl chloroformate (0.43 g, 4.0 mmol) in 2 ml of ether. The mixture is stirred at 5° for 1 hour and is then allowed to warm to RT. Excess ethyl chloroformate is quenched with water and the reaction mixture is poured into water and ether and the aqueous phase is extracted with ether (3X). The combined organic layers are washed with 2N ammonium sulfate, with 10% sodium carbonate, then with water until neural and with brine. The organic layer is dried, filtered, the solvent removed and the product purified by prep. TLC to give ethyl N-{2-[4-(3-methyl-2-butenoxy)phenoxy]-1-methylethyl}carbamate m/s (M+) 307.
Reaction SMILES: [I-].[CH2:2]([O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([Zn+])=[CH:9][CH:8]=1)=[O:6])[CH3:3].[C:14](Cl)(=[O:18])[CH:15]([CH3:17])[CH3:16]>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.C1COCC1>[C:14]([C:10]1[CH:11]=[CH:12][C:7]([C:5]([O:4][CH2:2][CH3:3])=[O:6])=[CH:8][CH:9]=1)(=[O:18])[CH:15]([CH3:17])[CH3:16]
Reactant: CCOC(=O)c1ccc([Zn+])cc1
Reactant: CC(C)C(=O)Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C(=O)C(C)C)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 90.4 %

Procedure:
To a 100-mL round-bottom flask was added THF (25 mL). The solvent was bubbled with nitrogen for a few minutes then cooled to 0° C. and added bis(triphenylphosphine)palladium(II) chloride (0.44 g, 0.63 mmol) followed by 4-(ethoxycarbonyl)phenylzinciodide (25.0 mL, 12.5 mmol; 0.50 M in THF). After stirred at at 0° C. for 15 min, isobutyryl chloride (1.32 mL, 12.5 mmol) was added and the resulting mixture was stirred at 0° C. for 2 h. The reaction was quenched with slow addition of 1 N HCl and extracted with EtOAc (3×100 mL). After separation, combined organic extracts were washed with sat. NaHCO3, water, brine, dried (MgSO4), and concentrated. Flash column chromatography (EtOAc:hexanes, 0:1 to 1:9) afforded ethyl 4-isobutyrylbenzoate (2.49 g, 90%) as a slight-brown oil. LC-MS: (FA) ES+ 221; 1H NMR (CDCl3, 400 MHz) δ8.13 (d, J=8.5 Hz, 2H), 7.99 (d, J=8.5 Hz, 2H), 4.40 (q, J=7.2 Hz, 2H), 3.56 (m, 1H), 1.42 (t, J=7.2 Hz, 3H), 1.23 (d, J=7.2 Hz, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=O)=[CH:9][CH:8]=1)[CH3:2].[C:16]([O:20][C:21](=[O:42])[CH:22]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:19])([CH3:18])[CH3:17]>ClCCl>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10](/[CH:13]=[CH:22]/[C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:42])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CSc1ccc(C=O)cc1
Solvent: ClCCl
Product: CCOC(=O)CSc1ccc(/C=C/C(=O)OC(C)(C)C)cc1
Yield: 78.6 %

Procedure:
A solution of 2.24 g of (4-formyl-phenylsulfanyl)-acetic acid ethyl ester and 4.72 g of (triphenylphosphoranylidene)-acetic acid tert-butyl ester in 50 ml of dichloromethane was kept at 20° for 15 h. The solvent was evaporated in vacuo and the remaining oil was chromatographed on silica gel using dichloromethane/hexane (1:1) as eluent to give 2.53 g of (E)-2-[4-(2-tert-butoxycarbonyl-vinyl)-phenylsulfanyl]-acetic acid ethyl ester as a colorless oil. To a solution of this material in 20 ml of tetrahydrofuran were added 8 ml of 2N aqueous sodium hydroxide, and the mixture was stirred for 2 h at 20°. The clear solution was diluted with 20 ml of ethyl acetate and then extracted with 30 ml of water. The aqueous layer was cooled with ice, acidified to pH 2.8 by the addition of 3N HCl, and the mixture was extracted with 60 ml of ethyl acetate. The organic layer was dried over sodium sulfate, evaporated in vacuo, and the residue was crystallized from ethyl acetate/hexane to give 1.78 g (E)-2-[4-(2-tert-butoxycarbonyl-vinyl)-phenylsulfanyl]-acetic acid as white crystals.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]#[N:12])[CH:8]=2)[NH:3]1.[N:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]2[C:29]3[C:24](=[CH:25][C:26]([CH:30]=O)=[CH:27][CH:28]=3)[N:23](COCC[Si](C)(C)C)[N:22]=2)=[CH:15][CH:14]=1>>[O:1]=[C:2]1[C:10](=[CH:30][C:26]2[CH:25]=[C:24]3[C:29]([C:21](/[CH:20]=[CH:19]/[C:16]4[CH:15]=[CH:14][N:13]=[CH:18][CH:17]=4)=[N:22][NH:23]3)=[CH:28][CH:27]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]#[N:12])[CH:8]=2)[NH:3]1
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Reactant: C[Si](C)(C)CCOCn1nc(/C=C/c2ccncc2)c2ccc(C=O)cc21
Product: N#Cc1ccc2c(c1)C(=Cc1ccc3c(/C=C/c4ccncc4)n[nH]c3c1)C(=O)N2

Procedure:
The title compound was synthesized according to the method described in Example A57 from 2-oxoindoline-5-carbonitrile (10 mg, 0.063 mmol) and (E)-3-(2-(pyridin-4-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (25 mg, 0.063 mmol) with a modified purification procedure. The product was precipitated with EtOAc and filtered washing with EtOAc to give 4.5 mg, 30% of a yellow powder which was a 65:35 mixture of (E)/(Z) isomers. 1H NMR (400 MHz, d6-DMSO) δ 14.04, 13.94 (s, 1H), 11.24, 11.22 (s, 1H), 9.01, 8.42 (s, 1H), 8.83 (d, J=5.5 Hz, 2H), 8.50-8.17 (m, 3H), 8.03 (s, 1H), 7.99 (s, 1H), 7.86 (s, 1H), 7.81-7.65 (m, 3H), 7.07, 7.01 (d, J=8.4 Hz, 1H); MS ESI 390.1 [M+H]+, calcd for [C24H15N5O+H]+ 390.14.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[O:11][C:12]2[C:17]([C:18](=[O:20])[CH:19]=1)=[C:16]([O:21]C)[CH:15]=[C:14]([O:23]C)[C:13]=2[C@@H:25]1[CH2:29][CH2:28][N:27]([CH3:30])[C@H:26]1[CH2:31][OH:32])[C:5]#[N:6].Cl.N1C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[O:11][C:12]2[C:17]([C:18](=[O:20])[CH:19]=1)=[C:16]([OH:21])[CH:15]=[C:14]([OH:23])[C:13]=2[C@@H:25]1[CH2:29][CH2:28][N:27]([CH3:30])[C@H:26]1[CH2:31][OH:32])[C:5]#[N:6]
Reactant: COc1cc(OC)c2c(=O)cc(-c3ccc(C#N)cc3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Solvent: c1ccncc1
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4ccc(C#N)cc4Cl)oc23)[C@@H]1CO

Procedure:
Compound of example 97 (0.3 g, 0.6 mmol) was demethylated using pyridine hydrochloride (3 g, 26.0 mmol) as described in example 17 to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][N:15]=1)[C:12]1[N:8]([CH:9]=[C:10]([C:16](/[N:18]=[CH:19]/[N:20](C)C)=O)[N:11]=1)[CH2:7][CH2:6][O:5]2.[CH:23]([NH:26]N)([CH3:25])[CH3:24]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][N:15]=1)[C:12]1[N:8]([CH:9]=[C:10]([C:16]3[N:26]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:19][N:18]=3)[N:11]=1)[CH2:7][CH2:6][O:5]2
Reactant: CN(C)/C=N/C(=O)c1cn2c(n1)-c1cnc(Cl)cc1OCC2
Reactant: CC(C)NN
Solvent: CC(=O)O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(Cl)cc1OCC2
Temperature: 100 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
To a solution of 12-chloro-N-[(1E)-(dimethylamino)methylidene]-9-oxa-3,6,13-triazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene-4-carboxamide (0.25 mmol, 80 mg) in acetic acid (3 mL) was added hydrochloric isopropylhydrazine (0.50 mmol, 5 mg). The mixture was stirred at 100° C. for 1 h under nitrogen atmosphere. After removal of the solvent, the residue was purified by reverse phase combiflash eluting with a 0-50% gradient of CH3CN in 0.3% NH4HCO3 to give 12-chloro-4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6,13-triazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene (50 mg, 61% yield). LCMS (ESI) m/z: 331.1 [M+H+]. 1H NMR (500 MHz, DMSO-d6): δ 9.29 (s, 1H), 8.02 (s, 1H), 7.94 (s, 1H), 7.24 (s, 1H), 5.86 (t, J=13.5 Hz, 1H), 4.68-4.65 (m, 2H), 4.61-4.59 (m, 2H), 1.49 (d, J=6.5 Hz, 6H)
Reaction SMILES: IC.[C:3](=O)([O-])[O-].[K+].[K+].[C:9]([O:13][C:14]([N:16]([CH3:26])[C@H:17]([C:22]([NH:24][CH3:25])=[O:23])[C:18](=[O:21])[O:19][CH3:20])=[O:15])([CH3:12])([CH3:11])[CH3:10]>C(#N)C>[C:9]([O:13][C:14]([N:16]([CH3:26])[C@:17]([CH3:3])([C:22]([NH:24][CH3:25])=[O:23])[C:18](=[O:21])[O:19][CH3:20])=[O:15])([CH3:11])([CH3:10])[CH3:12]
Reactant: O=C([O-])[O-]
Reactant: CNC(=O)[C@H](C(=O)OC)N(C)C(=O)OC(C)(C)C
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CNC(=O)[C@](C)(C(=O)OC)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.2 %

Procedure:
Iodomethane (1.4 mL) and potassium carbonate (1.6 g) were added to an acetonitrile (5.0 mL) solution of N2-(t-butoxycarbonyl)-N,N2,O-trimethyl-3-oxoserinamide (Intermediate 4-2, 2.0 g), and the mixture was stirred for 20 hours at room temperature under closed conditions. Iodomethane (2.8 mL) was added, and the mixture was stirred for 3 days at room temperature under closed conditions. Further, iodomethane (2.8 mL) was added, and the mixture was stirred for 1 day at room temperature under closed conditions, and then stirred for 9 hours at 50° C. After the reaction mixture was stirred for 14 hours at room temperature, potassium carbonate was filtered out. Then, the system was washed with ethyl acetate, and the reaction mixture was concentrated. The resulting residue was purified by OH type silica gel column chromatography (gradient elution with hexane/ethyl acetate=70/30→100/0) to obtain N2-(t-butoxycarbonyl)-N,N2,O,2-tetramethyl-3-oxoserinamide (Intermediate 8-2, yellow oil) (1.5 g, 78%).
Reaction SMILES: Cl[C:2]1[C:3](=[O:14])[N:4]([CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.Cl.[Br:16][C:17]1[CH:18]=[C:19]([O:26][CH3:27])[CH:20]=[C:21]2[C:25]=1[NH:24][CH2:23][CH2:22]2>>[Br:16][C:17]1[CH:18]=[C:19]([O:26][CH3:27])[CH:20]=[C:21]2[C:25]=1[N:24]([C:2]1[C:3](=[O:14])[N:4]([CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1)[CH2:23][CH2:22]2
Reactant: COc1cc(Br)c2c(c1)CCN2
Reactant: CCC(CC)n1cc(Cl)nc(Cl)c1=O
Agent: Cl
Product: CCC(CC)n1cc(Cl)nc(N2CCc3cc(OC)cc(Br)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-(1-ethylpropyl)-2(1H)-pyrazinone and 7-bromo-5-methoxyindoline hydrochloride as the starting materials. mp 130-132° C.; 1H NMR (300 MHz, CDCl3): δ 6.92 (d, J=2.6 Hz, 1 H), 6.78 (d, J=2.2 Hz, 1 H), 6.73 (s, 1 H), 4.81 (brs, 1 H), 4.35 (t, J=7.7 Hz, 2 H), 3.78 (s, 3 H), 3.11 (t, J=7.7 Hz, 2 H), 1.87-1.73 (m, 2 H), 1.70-1.60 (m, 2 H), 0.89 (s, 6 H); HRMS (ESI) calcd for C18H22N3O2BrCl (M+H)+: 426.0584; found m/z 426.0606.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-])=O)[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[NH4+].[Cl-]>CCO.O.[Fe]>[NH2:12][C:4]1[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: CC(=O)c1cc(Br)cc([N+](=O)[O-])c1O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(=O)c1cc(Br)cc(N)c1O

Procedure:
A mixture of 1-(5-bromo-2-hydroxy-3-nitrophenyl)ethanone (25 g, 96 mmol), iron (27 g, 481 mmol), and NH4Cl (5.1 g, 96 mmol) in EtOH/H2O (5:1, 300 ml) was heated at reflux in 2 h, the mixture was cooled filtered the solid, the filtrate was concentrated, taken up in H2O, extracted with DCM (3×), dried over MgSO4, concentrated and purified by ISCO (10% EtOAc/Hexanes) to give the title compound as a yellow solid. MS (m+2): 232.1.