Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[CH2:16][C:15](=O)[NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.P(Cl)(Cl)([Cl:20])=O>CC1C=CC(C)=CC=1>[Cl:20][C:15]1[NH:14][C:11]2=[N:12][CH:13]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[CH:9]=[C:10]2[CH:16]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1Cc2cc(-c3cccc(F)c3)cnc2N1
Solvent: Cc1ccc(C)cc1
Product: Fc1cccc(-c2cnc3[nH]c(Cl)cc3c2)c1
Temperature: 102.5 °C
Reaction time: 4 h
Yield: 56.3 %

Procedure:
A suspension of 5 (16.52 g, 72.4 mmol) in neat P(O)Cl3 (21.5 mL, 0.231 mol) was stirred at 100-105° C. for 4 h. The mixture was then cooled to rt., diluted with p-xylene (100 mL) and concentrated to dryness in vacuum. The residue was separated between saturated aqueous NaHCO3— AcOEt. 10% aqueous solution of Na2CO3 was added to basify the aqueous layer to pH 9. Organic phase was separated and the aqueous layer was extracted with AcOEt (8×300 mL). Combined organic solutions were dried MgSO4, concentrated, and the residue was purified by silicagel chromatography (SGC) using CH2Cl2:AcOEt as eluent in gradient to afford recovered starting material 5 (0.76 g, 5%). The desired product was then crystallized from acetone to afford 6 (10.06 g, 56%), thin tan needles. 1H NMR (400 M CDCl3) δ 6.47 (s, 1H), 7.08 (tdd, J=8.1, 2.3, 1.5 Hz, 1H), 7.33 (ddd, J=9.9, 2.3, 1.6 Hz, 1H), 7.38-7.48 (m, 2H), 8.03 (d, J=2.1 Hz, 1H), 8.53 (d, J=2.1 Hz, 1H), 11.46 (bs, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8]C=1C#N)([O-:3])=[O:2].[C:14]([OH:17])(=[O:16])[CH3:15].S(=O)(=O)(O)O>O>[N+:1]([C:4]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:15]=1[C:14]([OH:17])=[O:16])([O-:3])=[O:2]
Reactant: CC(=O)O
Reactant: COc1ccc(C#N)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1ccc(C(=O)O)c([N+](=O)[O-])c1
Yield: 91.8 %

Procedure:
A mixture of 2-nitro-4-methoxybenzonitrile (14.0 g, 78.6 mM) in a solution of acetic acid (28 mL), sulfuric acid (28 mL) and water (28 mL) was refluxed for 11 hr, allowed to cool and diluted with water (200 mL). The resulting precipitate which formed was collected, washed with water and dried to give the title benzoic acid (14.2 g, 91.8%) as a yellow crystalline solid; MS(CI): 198 (M+H).
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH3:12])[C:5]([N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6].S(Cl)([Cl:15])=O>CN(C)C=O.CC1C=CC=CC=1>[Cl:15][CH2:2][CH2:3][N:4]([CH3:12])[C:5]([N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6]
Reactant: CN(CCO)C(=O)N1CCCC1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CN(CCCl)C(=O)N1CCCC1
Reaction time: 2 h
Yield: 100 %

Procedure:
To a stirred solution of 4 parts of N-(2-hydroxyethyl)-N-methyl-1pyrrolidinecarboxamide in 22.5 parts of methylbenzene were added 2.9 parts of thionyl chloride. After the addition of a few drops of N,N-dimethylformamide, the reaction mixture was heated slowly to reflux temperature. After stirring for 2 hours at this temperature, the mixture was cooled and the whole was evaporated, yielding 4.5 parts (100%) of N-(2-chloroethyl)-N-methyl-1-pyrrolidinecarboxamide as a residue (int. 31).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([N:20]([CH2:34][CH3:35])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=O)[NH:28][CH:27]=1)=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:34]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[NH:12][C:11]2=[O:17])[NH:28][CH:27]=1)=[O:25])[CH3:35]
Reactant: O=C1Cc2c(cccc2-c2cccc(Br)c2)N1
Reactant: CCN(CC)CCNC(=O)c1c[nH]c(C=O)c1C
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1c[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(Br)c4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 71.7 %

Procedure:
To a solution of 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (72.0 mg, 0.25 mmol) and 5-formyl-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(3-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (93.5 mg, 72%).
Reaction SMILES: [CH3:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:14][CH:13]=2)[C:10](=[O:28])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](Br)[CH:8]=2)[N:3]=1.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC>[CH3:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:14][CH:13]=2)[C:10](=[O:28])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:8]=2)[N:3]=1
Reactant: Cc1nc2ccc(Br)cc2c(=O)n1-c1ccc(OCCCN2CCCCC2)cc1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1nc2ccc(-c3ccccc3)cc2c(=O)n1-c1ccc(OCCCN2CCCCC2)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
2-methyl-6-bromo-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone synthesized in Example 34 (100 mg, 0.25 mmol) and phenylboronic acid (40 mg, 0.32 mmol) were dissolved in dimethoxyethane (1 mL), and the atmosphere in the system was replaced by nitrogen. 2M sodium carbonate aqueous solution (0.3 mL) and palladium tetrakis (triphenylphosphine) complex (10 mg, 0.012 mmol) were added, and stirred at 80° C. for 3 hours. Ethyl acetate and distilled water were added to the reaction mixture to perform an ethyl acetate extraction. The organic phase was washed with saturated brine and dried with anhydrous sodium sulfate. The product was purified by silica gel column chromatography (chloroform/methanol=20/1), and the target substance (61 mg, 61%) was obtained as a colorless solid. 1HNMR (400 MHz,CDCl3,δppm): 1.45 (2H, brs), 1.58-1.63 (4H, m), 2.00-2.04 (2H, m), 2.27 (3H, s), 2.42 (4H, brs), 2.50 (2H, t, J=7.2 Hz), 4.07 (2H, t, J=6.4 Hz), 7.04 (2H, d, J=8.8 Hz), 7.15 (2H, d, J=8.8 Hz), 7.36 (1H, t, J=7.6 Hz), 7.46 (2H, t, J=7.6 Hz), 7.67 (2H, d, J=7.2 Hz), 7.72 (1H, d, J=8.4 Hz), 7.98 (1H, d, J=2.0 Hz), 8.46 (1H, s)
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[C:16]1(C)C=CC=CC=1>>[F:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: Cc1ccc(C(=O)O)c(F)c1
Reactant: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C)cc1F
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 2-fluoro-4-methylbenzoic acid from Example D1 (6.04 g, 39.18 mmol) in toluene (80 ml) was added thionyl chloride (6.5 ml, 89.11 mmol). The mixture was heated at reflux for 2.5 h, cooled and concentrated in vacuo. The residue was dissolved in dichloromethane (50 ml) and methanol (50 ml) was added. The mixture was stirred at room temperature for 2.5 h and then concentrated in vacuo. The residue was dissolved in dichloromethane (100 ml), washed with saturated sodium bicarbonate solution and brine, dried over MgSO4, and concentrated in vacuo to give a tan solid; yield 5.07 g (77%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:12]([C:14]1[N:19]2[N:20]=[CH:21][N:22]=[C:18]2[N:17]=[CH:16][CH:15]=1)[CH3:13]>COCCOC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:12]([C:14]2[N:19]3[N:20]=[CH:21][N:22]=[C:18]3[N:17]=[CH:16][CH:15]=2)[CH3:13])=[CH:4][CH:3]=1
Reactant: CC(Br)c1ccnc2ncnn12
Reactant: Oc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(Oc1ccc(F)cc1)c1ccnc2ncnn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Fluorophenol (1.12 g) was added to a stirred suspension of sodium hydride (0.48 g) in dry 1,2-dimethoxyethane (35 ml). The mixture was stirred at room temperature for 30 minutes, then a solution of 7-(1-bromoethyl)-1,2,4-triazolo[1,5-a]pyrimidine (2.27 g, prepared in a similar manner to that described in Example 6 below) in dry 1,2-dimethoxyethane (85 ml) was added dropwise. The mixture was stirred at room temperature for 24 hours. The sodium bromide was removed from the mixture by filtration. The solvent was evaporated from the filtrate and the residue dissolved in dichloromethane and washed with 200 ml of a 5% aqueous solution of sodium hydroxide, followed by water. The organic layer was dried over magnesium sulphate. Evaporation of the solvent afforded a crude product which was purified by column chromatography on silica gel using as eluent a mixture of petroleum ether and ethyl acetate (in the ratio 6:4 respectively), followed by recrystallisation from a mixture of ethyl acetate and hexane, to give 7-[1-(4-fluorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]-pyrimidine. Yield 1.03 g, (mp 106°-108° C.).
Reaction SMILES: Cl[C:2]1[C:7]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]2[CH3:14])=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:15][N:16]([CH3:30])[CH2:17]/[CH:18]=[CH:19]\[C:20]1[C:25]([O:26][CH2:27][CH2:28][OH:29])=[CH:24][CH:23]=[CH:22][N:21]=1>>[CH3:30][N:16]([CH3:15])[CH2:17]/[CH:18]=[CH:19]\[C:20]1[C:25]([O:26][CH2:27][CH2:28][O:29][C:2]2[C:7]([N:8]3[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]3[CH3:14])=[N:6][CH:5]=[CH:4][N:3]=2)=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: CN(C)C/C=C\c1ncccc1OCCO
Reactant: C[C@@H]1CNCCN1c1nccnc1Cl
Product: C[C@@H]1CNCCN1c1nccnc1OCCOc1cccnc1/C=C\CN(C)C
Yield: 12 %

Procedure:
The procedure in Example 18, Step 4, was followed starting from 2-chloro-3-[(2R)-2-methylpiperazin-1-yl]pyrazine* (0.23 g, 1.0 mmol) and 2-({2-[(1Z)-3-(dimethylamino)prop-1-enyl]pyridin-3-yl}oxy)ethanol (from Step 3; 0.24 g, 1.1 mmol). The crude product was purified on a column of silica (100 mm, i.d.=30 mm) with CHCl3/MeOH/NH4OH (80:20:0.5; 200 mL, followed by 60:40:1) as eluent to give 0.050 g (12%) of the title compound as a light brown oil. HRMS m/z calcd for C21H30N6O2 (M)+ 398.2430. found 398.2438. *Reported in WO 00/76984, Example 192, Step 2.
Reaction SMILES: C([O:3][P:4]([CH:9]=[CH:10][CH:11]1[CH:15]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]([O:25][CH3:26])[CH:13]([N:27]2[CH:35]=[N:34][C:33]3[C:32](=[O:36])[NH:31][C:30]([NH:37][C:38](=[O:42])[CH:39]([CH3:41])[CH3:40])=[N:29][C:28]2=3)[O:12]1)([O:6]CC)=[O:5])C.N1C(C)=CC=CC=1C.C[Si](Br)(C)C>CN(C=O)C>[C:38]([NH:37][C:30]1[NH:31][C:32](=[O:36])[C:33]2[N:34]=[CH:35][N:27]([CH:13]3[O:12][CH:11]([CH:10]=[CH:9][P:4]([OH:5])([OH:6])=[O:3])[CH:15]([O:16][C:17](=[O:24])[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:14]3[O:25][CH3:26])[C:28]=2[N:29]=1)(=[O:42])[CH:39]([CH3:40])[CH3:41]
Reactant: CCOP(=O)(C=CC1OC(n2cnc3c(=O)[nH]c(NC(=O)C(C)C)nc32)C(OC)C1OC(=O)c1ccccc1)OCC
Agent: C[Si](C)(C)Br
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Product: COC1C(OC(=O)c2ccccc2)C(C=CP(=O)(O)O)OC1n1cnc2c(=O)[nH]c(NC(=O)C(C)C)nc21
Temperature: 80 °C
Reaction time: 4 h
Yield: 14.4 %

Procedure:
Compound 16.7 (460 mg, 0.763 mmol) was dissolved in 8 mL anhydrous DMF, treated with 2,6-lutidine (0.443 mL, 3.81 mmol) and TMSBr (1.5 mL, 11.4 mmol). The mixture was stirred at 80° C. for 4 h and quenched with MeOH. The mixture was concentrated under reduced pressure and the residue was subjected to reverse phase HPLC to yield product 16.8 (60 mg, 14.4% yield).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([S:7][CH2:8][CH2:9][S:10][CH2:11][CH2:12][S:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[NH:4][N:3]=1.[C:20](OCC)(=[O:25])[CH2:21][C:22]([CH3:24])=O>C(O)(=O)C>[CH2:14]([S:13][CH2:12][CH2:11][S:10][CH2:9][CH2:8][S:7][C:5]1[N:6]=[C:2]2[N:3]([N:4]=1)[C:20]([OH:25])=[CH:21][C:22]([CH3:24])=[N:1]2)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCSCCSCCSc1nc(N)n[nH]1
Reactant: CCOC(=O)CC(C)=O
Solvent: CC(=O)O
Product: CCCCCCSCCSCCSc1nc2nc(C)cc(O)n2n1
Yield: 78.4 %

Procedure:
A mixture of Compound 12 (3.90 g, 13.3 mmole), ethyl acetoacetate (1.94 g, 14.9 mmole), and acetic acid (8.2 mL) was heated at reflux in a dry nitrogen atmosphere overnight. On cooling, the mixture solidified. The solid was collected, washed with cold ethanol and recrystallized from ethanol to yield Compound 20 (4.03 g, 74% yield), m.p. 119°-121° C. Analysis: Calculated for C10H26N4OS3 : C, 49.71; H, 6.78; N, 14.49. Found: C, 48.98; H, 6.76; N, 14.34.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])[CH2:14][CH:15]=2)=[CH:6][CH:5]=1)([O-])=O>CCOC(C)=O.[Pd]>[F:21][C:18]([F:19])([F:20])[CH2:17][CH2:16][N:13]1[CH2:14][CH2:15][CH:10]([C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=2)[CH2:11][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(C2=CCN(CCC(F)(F)F)CC2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(C2CCN(CCC(F)(F)F)CC2)cc1
Yield: 98.8 %

Procedure:
In Paar autoclave, a solution of 4-(4-nitrophenyl)-1-(3,3,3-trifluoropropyl)-1,2,3,6-tetrahydropyridine (2.6 g; 8.66 mmol; 1.0 eq.) in EtOAc (52 mL) was hydrogenated at 25 bars O/N in presence of Pd/C (moistened, 10%, 0.26 g; 2.44 mmol; 0.28 eq.). Reaction mixture was filtered through a celite pad. Filtrate was then concentrated under reduced pressure to give the title compound as a brown oil (2.33 g, 99%). UPLC/MS: (MS+) 273.4.
Reaction SMILES: Cl.[CH2:2]([O:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=O)[CH2:9][CH2:8]1)[CH3:3].[NH2:17][C@@H:18]([CH2:36][O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[CH:24][CH:23]=1)=[O:20]>>[CH2:38]([O:37][CH2:36][C@H:18]([NH:17][C:14](=[O:16])[CH2:13][N:10]1[CH2:9][CH2:8][N:7]([CH2:6][CH2:5][O:4][CH2:2][CH3:3])[CH2:12][CH2:11]1)[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[CH:24][CH:23]=1)=[O:20])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CCOCCN1CCN(CC(=O)O)CC1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: CCOCCN1CCN(CC(=O)N[C@@H](COCc2ccccc2)C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)CC1
Yield: 49.2 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-(2-ethoxyethyl)piperazin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 242, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-(2-ethoxyethyl)piperazin-1-yl)acetamido)propanamide (22.8 mg, 49.2%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.21 (s, 1H), 7.93 (d, 1H), 7.59 (d, 2H), 7.30 (m, 5H), 7.21 (t, 2H), 7.04-6.98 (m, 4H), 4.69 (m, 1H), 4.51 (s, 2H), 3.77 (m, 1H), 3.70 (m, 1H), 3.46-3.38 (m, 6H), 2.97 (s, 2H), 2.45 (t, 8H), 1.09 (t, 3H). MS (EI) for C32H39FN4O5. found 579.7 (MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([CH3:11])[S:7][C:6]1=[NH:12].CCN(CC)CC.[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([C:30](Cl)=[O:31])=[CH:22][CH:21]=1>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([CH3:11])[S:7]/[C:6]/1=[N:12]\[C:30]([C:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:20]=[CH:21][CH:22]=1)=[O:31]
Reactant: COCCn1c(C)c(C)sc1=N
Reactant: O=C(Cl)c1ccnc2ccccc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCn1c(C)c(C)s/c1=N\C(=O)c1ccnc2ccccc12
Reaction time: 18 h
Yield: 33 %

Procedure:
To a suspension of the product of Example 126A (0.20 g, 1.1 mmol) in 25 mL THF was added Et3N (0.3 mL, 2.2 mmol) followed by the freshly prepared quinoline-4-carbonyl chloride. This mixture was warmed to reflux and allowed to stir for 18 hours. The material was then concentrated under reduced pressure and 10 mL EtOAc, 5 mL H2O and 5 mL NH4OH were added. The layers were separated and the aqueous layer was extracted 2×5 mL EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purified via flash column chromatography (SiO2, 5% CH3OH in EtOAc) to afford the title compound (0.12 g, 0.35 mmol, 33% yield). 1H NMR (300 MHz, CD3OD) δ ppm 2.32 (d, J=0.7 Hz, 3H), 2.35 (d, J=0.7 Hz, 3H), 3.31 (s, 3H), 3.78 (t, J=5.3 Hz, 2H), 4.48 (t, J=5.1 Hz, 2H), 7.65 (ddd, J=8.5, 7.0, 1.2 Hz, 1H), 7.80 (ddd, J=8.4, 6.9, 1.4 Hz, 1H), 8.00 (d, J=4.4 Hz, 1H), 8.06-8.11 (m, 1H), 8.84 (ddd, J=8.5, 1.4, 0.7 Hz, 1H), 8.93 (d, J=4.4 Hz, 1H); MS (DCI/NH3) m/z 342 (M+H)+; Anal. calculated for C18H19N3O2S: C, 63.32; H, 5.61; N, 12.31. Found: C, 63.23; H, 5.46; N, 12.10.
Reaction SMILES: [I-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li][CH2:23][CH2:24][CH2:25][CH3:26].[NH2:27][C:28]1[C:37]2[N:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]2[CH:38]=CC(C=O)=[CH:41][C:30]=2[N:29]=1>C1COCC1>[CH:25]([C:24]1[CH:23]=[CH:38][C:31]2=[C:32]3[C:37](=[C:28]([NH2:27])[N:29]=[C:30]2[CH:41]=1)[N:36]=[CH:35][CH:34]=[CH:33]3)=[CH2:26]
Reactant: [Li]CCCC
Reactant: Nc1nc2cc(C=O)ccc2c2cccnc12
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Solvent: C1CCOC1
Product: C=Cc1ccc2c(c1)nc(N)c1ncccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl triphenyl phosphonium iodide (6.0 eq.) was added nBuLi (7.0 eq.) at −78° C. The reaction mixture was allowed to warm to 0° C. and stirred for 30 minutes (deep orange color). The reaction was again cooled down to −78° C. and 5-aminobenzo[f][1,7]naphthyridine-8-carbaldehyde (from Example 87) (1.0 eq.) in THF was introduced dropwised to the reaction. The reaction was allowed to warm to ambient temperature overnight. The reaction was quenched by saturated NH4Cl and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4 and concentrated en vacuo to obtain a crude residue. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-50% EtOAc/Hexanes to give 8-vinylbenzo[f][1,7]naphthyridin-5-amine as a white solid: 1H NMR (acetone-d6): 1H NMR (acetone-d6): δ 9.00 (dd, 1H), 8.90 (dd, 1H), 8.41 (d, 1H), 7.84 (dd, 1H), 7.65 (d, 1H), 7.52 (dd, 1H), 6.91 (dd, 1H), 6.77 (br s, 2H), 5.97 (dd, 1H), 5.34 (dd, 1H). LRMS [M+H]=222.1.
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].F[C:16](F)(F)[C:17](O)=[O:18].[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.C(Cl)(=O)C>>[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].[C:17]([N:50]1[CH2:51][CH2:52][CH:47]([CH2:46][C:45]([NH:44][C:36]2[CH:37]=[CH:38][C:39]3[NH:40][C:41]4[N:42]=[C:26]([NH:27][C:28]5[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=5)[CH2:33][CH2:34][C:35]=2[CH:43]=3)[N:25]=[CH:24][C:23]=4[Cl:22])=[O:53])[CH2:48][CH2:49]1)(=[O:18])[CH3:16]
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: CC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 43 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, 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 acetyl chloride as starting materials in 43% yield. 1H NMR (300 MHz, DMSO-d6): δ 10.02 (s, 2H), 9.40 (s, 1H), 9.01 (s, 1H), 8.31 (s, 2H), 8.20 (s, 1H), 7.65 (s, 1H), 7.31 (d, 1H), 7.08 (d, 1H), 4.38 (d, 1H), 3.81 (d, 1H), 3.00 (m, 6H), 2.52 (m, 1H), 2.32 (m, 2H), 2.00 (s, 3H), 1.75 (m, 2H), 1.20 (m, 2H). LCMS for C26H29ClN7O2 (M+H)+: m/z=506.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>C(N(CC)CC)C.[Cu]I.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>[CH2:12]([O:11][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])=[CH:3][CH:4]=2)[CH2:10][CH2:9]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C#C[Si](C)(C)C
Reactant: Brc1ccc(C2(OCc3ccccc3)CC2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(C2(OCc3ccccc3)CC2)cc1
Yield: 88.3 %

Procedure:
Using General Procedure D; 1-bromo-4-(1-benzyloxycyclopropyl)-benzene (Intermediate 69, 160.0 mg, 0.53 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (10.0 mg, 0.05 mmol) and then sparged with argon for 5 minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis-(triphenylphosphine)palladium(II) (37.0 mg, 0.05 mmol). The resulting reaction mixture was heated to 70° C. for 5d. The title compound (150.0 mg, 83%) was isolated by chromatography (0-3% EtOAc-hexanes) as a pale-yellow oil.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[C:5]1([CH2:15][NH2:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:5]1([CH2:15][N:16]=[C:1]=[O:2])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)Cl
Reactant: NCc1cccc2ccccc12
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C=NCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of phosgene (20% in toluene, 5 ml) was diluted with toluene (10 ml). A mixture of 1-naphthalenemethylamine (500 μl, 3.41 mmol), triethylamine (0.95 ml, 6.82 mmol) in toluene (5 ml) was added dropwise. The reaction mixture was heated at reflux overnight. The mixture was cooled to room temperature, and the solvent was removed. The residue was stirred with ether (50 ml) for 10 minutes and filtered. The filtrate was concentrated to give the crude product which was purified by flash chromatography (silica gel, methylene chloride) to give the desired product (518 mg) as a colorless oil. IR 2260 cm−1.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH2:17][S:18]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)(=[O:20])=[O:19]>CCOC(C)=O>[CH3:13][C:12]([CH3:15])([CH3:14])[C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:25]3[CH:26]=[C:21]([S:18]([NH2:17])(=[O:20])=[O:19])[CH:22]=[CH:23][CH:24]=3)[N:3]=2)[NH:8][CH:9]=1)=[O:16]
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Reactant: NS(=O)(=O)c1cccc(B(O)O)c1
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3cccc(S(N)(=O)=O)c3)nc12

Procedure:
3-[7-(2,2-Dimethyl-propionyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-benzenesulfonamide was prepared starting from 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one and (3-aminosulfonylphenyl)Boronic Acid following general procedures as described in these Examples. Silica gel chromatography using 20-100% EtOAc in hexanes as eluant provided 60 mg (37%) of a pale yellow solid. MP 275-277° C., M+H=359.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:12])#[C:2][CH2:3][CH2:4][CH3:5].CC(C)([O-])C.[K+].O>CN1CCCC1=O>[CH2:3]([C:2]1[NH:12][C:7]2[C:6]([CH:1]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:4][CH3:5]
Reactant: CCCC#Cc1ccccc1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The reaction was carried out under an argon atmosphere. 2.7 g (10 mmol) 2-pent-1-ynyl-phenylamine were added to 2.3 g (20 mmol) potassium tert.butoxide in 50 mL of N-methyl-2-pyrrolidinone and the mixture was stirred overnight at RT. The reaction mixture was mixed with water and extracted with ethyl acetate. The organic phase was dried and evaporated down. The residue was purified on silica gel.