Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][CH3:21])=[O:17])=[O:13])=[CH:7][CH:6]=1)[CH3:4].C[O-].[Na+].[CH2:25](Br)[CH:26]=[CH:27][CH3:28]>O>[CH2:25]([O:1][N:2]=[C:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([NH:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][CH3:21])=[O:17])=[O:13])=[CH:9][CH:10]=1)[CH3:4])[CH:26]=[CH:27][CH3:28]
Reactant: CCCOC(=O)CNC(=O)Nc1ccc(C(C)=NO)cc1
Reactant: CC=CCBr
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: CC=CCON=C(C)c1ccc(NC(=O)NCC(=O)OCCC)cc1

Procedure:
A solution of the N-[4-(1-hydroxyiminoethyl)phenyl]-N'-n-propoxycarbonylmethylurea in 25% methanolic sodium methoxide (1.0 equivalent) is treated at room temperature with 1.1 equivalent of crotyl bromide. The reaction mixture is stirred until the temperature falls to about 20° C. The reaction mixture is then poured into cold water and extracted with diethyl ether. The ether solution is dried over MgSO4 and filtered, and the solvent is removed by rotary evaporator to yield the product N-[4-(1-crotyloxyiminoethyl)phenyl]-N'-n-propoxycarbonylmethylurea.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.Cl.Cl.[NH2:19][CH2:20][C:21]1[CH:29]=[CH:28][C:24]([N:25]([CH3:27])[CH3:26])=[CH:23][CH:22]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[OH-].[K+]>C(O)(C)(C)C.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:26][N:25]([CH3:27])[C:24]1[CH:28]=[CH:29][C:21]([CH2:20][NH:19][C:2]2[CH:16]=[CH:15][C:5]3[C:6](=[O:14])[NH:7][C:8]4[C:13]([C:4]=3[CH:3]=2)=[CH:12][CH:11]=[CH:10][N:9]=4)=[CH:22][CH:23]=1
Reactant: CN(C)c1ccc(CN)cc1
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CN(C)C=O
Solvent: CC(C)(C)O
Product: CN(C)c1ccc(CNc2ccc3c(=O)[nH]c4ncccc4c3c2)cc1
Temperature: 170 °C
Reaction time: 0.08 h
Yield: 2 %

Procedure:
6 (200 mg, 0.87 mmol), 4-(aminomethyl)-N,N-dimethylaniline dihydrochloride (774 mg, 3.47 mmol), Pd(OAc)2 (8 mg, 0.03 mmol), X-Phos (33 mg, 0.07 mmol), and KOH (438 mg, 8 mmol) were suspended in tert-butanol (3 mL), and stirred for 5 minutes at 170° C. via microwave. The reaction mixture was diluted with DMF and filtered. The crude product was purified directly via prep-LC-MS to provide 456 (6 mg, 2% yield) as a white powder. LC-MS (M+H=345, obsd.=345). 1H NMR (400 MHz, DMSO-D6) δ 11.46 (s, 1H), 8.58 (d, J=8.0, 1H), 8.42 (d, J=3.3, 1H), 7.97 (d, J=8.8, 2H), 7.38 (s, 1H), 7.26 (t, J=7.7, 2H), 7.08 (s, 1H), 6.71 (d, J=8.6, 2H), 4.35 (d, J=5.6, 2H), 2.85 (s, 6H).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([NH:17][C:18]3[CH:19]=[N:20][N:21]([CH2:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=4[F:34])=[O:25])[CH:22]=3)=[N:12][CH:13]=[N:14]2)=[CH:9][CH:8]=1.[C:35]1(=[O:45])[NH:39][C:38](=[O:40])[C:37]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:36]12.[K].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].C(=O)([O-])O.[Na+]>CC(N(C)C)=O.C(OCC)C>[F:34][C:28]1[C:29]([F:33])=[CH:30][CH:31]=[CH:32][C:27]=1[NH:26][C:24](=[O:25])[CH2:23][N:21]1[CH:22]=[C:18]([NH:17][C:11]2[C:10]3[C:15](=[CH:16][C:7]([O:6][CH2:5][CH2:4][CH2:3][N:39]4[C:35](=[O:45])[C:36]5[C:37](=[CH:41][CH:42]=[CH:43][CH:44]=5)[C:38]4=[O:40])=[CH:8][CH:9]=3)[N:14]=[CH:13][N:12]=2)[CH:19]=[N:20]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(Cn1cc(Nc2ncnc3cc(OCCCCl)ccc23)cn1)Nc1cccc(F)c1F
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Product: O=C(Cn1cc(Nc2ncnc3cc(OCCCN4C(=O)c5ccccc5C4=O)ccc23)cn1)Nc1cccc(F)c1F
Temperature: 75 °C
Yield: 74.8 %

Procedure:
A mixture of 2-(4-{[7-(3-chloropropoxy)quinazolin-4-yl]amino}-1H-pyrazol-1-yl)-N-(2,3-difluorophenyl)acetamide hydrochloride (0.25 g, 0.49 mmol), potassium phthalimide (0.109 g, 0.59 mmol), potassium carbonate (0.081 g, 0.59 mmol) and potassium iodide (0.098 g, 0.59 mmol) in dimethylacetamide (2 ml) was heated at 75° C. for 16 hours. The reaction mixture was allowed to cool to room temperature. Aqueous sodium hydrogen carbonate was added to the mixture and the resultant precipitate was filtered and washed with water, acetonitrile then diethyl ether to give N-(2,3-difluorophenyl)-2-[4-({7-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propoxy]quinazolin-4-yl}amino)-1H-pyrazol-1-yl]acetamide (0.214 g, 75% yield):
Reaction SMILES: Cl[C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[CH2:17]1[C:26]2[C:21](=[C:22]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][C:32]=3[NH2:33])[CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][NH:18]1>COC(O)C>[NH2:33][C:32]1[CH:31]=[CH:30][N:29]=[CH:28][C:27]=1[C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:21]=1[CH2:20][CH2:19][N:18]([C:2]1[NH:11][C:10](=[O:12])[C:9]3[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=3)[N:3]=1)[CH2:17]2
Reactant: COc1cc2nc(Cl)[nH]c(=O)c2cc1OC
Reactant: Nc1ccncc1-c1cccc2c1CCNC2
Agent: COC(C)O
Product: COc1cc2nc(N3CCc4c(cccc4-c4cnccc4N)C3)[nH]c(=O)c2cc1OC
Temperature: 95 °C
Reaction time: 18 h

Procedure:
A mixture of 2-chloro-6,7-dimethoxy-3H-quinazolin-4-one 1b (0.076 g, 0.31 mmol) and 3-(1,2,3,4-tetrahydro-isoquinolin-5-yl)-pyridin-4-ylamine (0.075 g, 0.33 mmol) in methoxyethanol (5 mL) was heated to 95° C. with stirring for 18 h the volatiles were evaporated and the residue was purified by flash column eluting with 2% methanol in dichloromethane containing 0.2% of ammonium hydroxide to yield 2-[5-(4-amino-pyridin-3-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-6,7-dimethoxy-3H-quinazolin-4-one 902. The product was converted to the hydrochloric acid salt, mp. >300° C., [M+H]+=430.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10](=S)[NH:11][NH2:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH:15]([C:21]([CH3:23])=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[CH3:23][C:21]1[NH:12][N:11]=[C:10]([NH:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: NNC(=S)NCCc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1c(NCCc2ccccc2)n[nH]c1C
Temperature: 25 °C

Procedure:
A stirred slurry of 33.1 g (0.17 mole) of 4-phenylethyl-3-thiosemicarbazide in 500 mL of absolute ethanol under nitrogen atmosphere was treated with 29 g (0.17 mole) of ethyl 2-chloroacetoacetate, stirred at ambient temperature for ~72 hr, heated to reflux to dissolve most materials, and filtered hot. The filtrate was concentrated in vacuo to give a reddish oil, 71 g. The residue was chromatographed on 800 g Florosil® and eluted first with benzene to remove a yellow band (sulfur) followed by an acetone/benzene gradient which gave two main fractions. These two fractions were combined, and concentrated to give a yellow oil which solidified. Recrystallization (twice) from ligroin gave a fluffy white crystalline product, with small spots of green-yellow color, 12.1 g, mp 138°-139° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:29][C:30]1[O:31][C:32]([CH3:41])=[C:33]([CH2:35]OS(C)(=O)=O)[N:34]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:35][C:33]2[N:34]=[C:30]([CH3:29])[O:31][C:32]=2[CH3:41])=[CH:4][CH:3]=1
Reactant: Cc1nc(COS(C)(=O)=O)c(C)o1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Product: Cc1nc(Cn2cc(C(=O)N3CCC4(CC3)OC(=O)c3cc(F)ccc34)c3ccc(Cl)cc32)c(C)o1

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19 above) with methanesulfonic acid 2,5-dimethyl-oxazol-4-ylmethyl ester (prepared by mesylation of (2,5-dimethyl-oxazol-4-yl)-methanol, described in Organic Letters (1999), 1(1), 87-90) gave the title compound.
Reaction SMILES: [S:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].C(N(CC)CC)C.[C:29](Cl)(=[O:38])[C:30]1[C:31]([O:36][CH3:37])=[CH:32][CH:33]=[CH:34][CH:35]=1.O>CN(C)C1C=CN=CC=1.C(#N)C>[CH3:37][O:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:29]([NH:2][S:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])=[CH:7][CH:6]=1)(=[O:3])=[O:4])=[O:38]
Reactant: NS(=O)(=O)c1ccc(NC(=O)c2ccc(Cl)cc2Cl)cc1
Reactant: COc1ccccc1C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccccc1C(=O)NS(=O)(=O)c1ccc(NC(=O)c2ccc(Cl)cc2Cl)cc1
Reaction time: 2 h

Procedure:
5 g (15 mmol) of N-(4-sulfamoylphenyl)-2,4-dichlorobenzamide are introduced into 80 ml of acetonitrile at 0° C., and 2.93 g (30 mmol) of triethylamine and a catalytic amount of DMAP (4-dimethylaminopyridine) are added. 2.47 g (15 mmol) of o-anisoyl chloride—dissolved in 20 ml of acetonitrile—are subsequently added dropwise. After a further 2 hours at room temperature, the mixture is transferred into water and the precipitate is filtered off with suction; Yield: 4.2 g (60%); M.p.: 140-146° C.
Reaction SMILES: C([C@H]1CC[C@H](OC2C=C3C(=CC=2)N=C(CN2CC(C(O)=O)C2)C=C3C(F)(F)F)CC1)(C)(C)C.C[O:35][C:36]([CH:38]1[CH2:41][N:40]([CH2:42][C:43]2[CH:44]=[C:45]3[C:50](=[CH:51][CH:52]=2)[N:49]=[C:48]([O:53][C@H:54]2[CH2:59][CH2:58][C@H:57]([C:60]([CH3:63])([CH3:62])[CH3:61])[CH2:56][CH2:55]2)[CH:47]=[CH:46]3)[CH2:39]1)=[O:37]>>[C:60]([C@H:57]1[CH2:56][CH2:55][C@H:54]([O:53][C:48]2[CH:47]=[CH:46][C:45]3[C:50](=[CH:51][CH:52]=[C:43]([CH2:42][N:40]4[CH2:41][CH:38]([C:36]([OH:37])=[O:35])[CH2:39]4)[CH:44]=3)[N:49]=2)[CH2:59][CH2:58]1)([CH3:63])([CH3:61])[CH3:62]
Reactant: COC(=O)C1CN(Cc2ccc3nc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)C1
Agent: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3nc(CN4CC(C(=O)O)C4)cc(C(F)(F)F)c3c2)CC1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(CN4CC(C(=O)O)C4)ccc3n2)CC1

Procedure:
Synthesized as per 1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-trifluoromethyl-quinolin-2-ylmethyl]-azetidine-3-carboxylic acid using 1-[2-(trans-4-tert-Butyl-cyclohexyloxy)-quinolin-6-ylmethyl]-azetidine-3-carboxylic acid methyl ester as starting material. ESI-MS (M+H+): 397.39; 1H NMR (400 MHz, METHANOL-d4) Shift 8.15 (d, J=8.78 Hz, 1H), 7.89-7.94 (m, 1H), 7.86 (d, J=8.78 Hz, 1H), 7.67 (dd, J=1.88, 8.66 Hz, 1H), 6.96 (d, J=8.78 Hz, 1H), 5.10-5.22 (m, 1H), 4.55 (s, 2H), 4.20-4.47 (m, 4H), 3.71 (quin, J=8.28 Hz, 1H), 2.28 (d, J=9.54 Hz, 2H), 1.92 (d, J=14.31 Hz, 2H), 1.36-1.52 (m, 2H), 1.19-1.36 (m, 2H), 1.06-1.19 (m, 1H), 0.92 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([NH2:20])[CH3:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH3:2].C([O-])([O-])=O.[Na+].[Na+].Cl[C:28]([O:30][CH3:31])=[O:29]>CC(C)=O>[CH3:31][O:30][C:28](=[O:29])[NH:20][CH:18]([C:15]1[CH:14]=[CH:13][C:12]([C:11]#[C:10][C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)=[CH:17][CH:16]=1)[CH3:19]
Reactant: COC(=O)Cl
Reactant: CCOc1ccc(C#Cc2ccc(C(C)N)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOc1ccc(C#Cc2ccc(C(C)NC(=O)OC)cc2)cc1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To 26.5 mg (0.10 mmol) 1-[4-(4-ethoxy-phenylethynyl)-phenyl]-ethylamine (I63) in 2.00 mL acetone are added 47.7 mg (0.45 mmol) Na2CO3 and 10.2 μL methyl chloroformate. The reaction mixture is stirred at 40° C. for 3 h. After cooling down to r.t. the reaction mixture is filtered and the solvent is removed in vacuo. The residue is purified by HPLC (MeOH/H2O/TFA).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.F[B-](F)(F)F.[O:17]=[N+:18]=[O:19].O>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([N+:18]([O-:19])=[O:17])[C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1O
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)cc([N+](=O)[O-])c1O
Reaction time: 2 h

Procedure:
A solution of 4-chloro-2-nitrophenol (4 g, 23 mmol) in acetonitrile (100 ml) was cooled to −25 C.°, and gradually added with nitronium tetrafluoroborate powder (4.9 g). The reaction mixture was stirred for 2 hours while the temperature was raised to −10 C.°, and the reaction was stopped by adding 10 ml of water. The acetonitrile was evaporated under reduced pressure, and the residue was diluted with diethyl ether. The ether layer was washed with water, then washed twice with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated by vacuum concentration to obtain the title compound as yellow plate crystals (5.1 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[BH4-].[Na+]>COC(O)C.C(OCC)(=O)C>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:2]2
Reactant: CCOC(=O)c1cnc2ccc(Cl)cc2c1Cl
Agent: COC(C)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2ccc(Cl)cc2c1
Temperature: 25 °C

Procedure:
Ethyl 4,6-Dichloroquinoline-3-carboxylate [prepared as described in C. C. Price and R. M. Roberts J. Amer. Chem. Soc. 68, 1204 (1964); C. J. Ohnmacht, Jr. J. Med. Chem. 14, 17 (1971)](2.0 g, 7.4 mmol) was added portionwise to a solution of sodium borohydride (1.2 g, 31 mmol) in 15 ml of methoxyethanol at about 0° C. The reaction mixture was warmed to room temperature over 3 hours then diluted with ethyl acetate. After standard aqueous workup (dil HCl; saturated NaHCO3) the organic layer was dried (NaSO4) and concentrated to a residue. The residue was exposed to air oxidation (about 14 days) and extracted repeatedly with boiling heptane. The heptane was removed in vacuo to yield ethyl 6-chloroquinoline-3-carboxylate as a beige solid. 1H NMR [(CDCl3), 300 MHz]: δ 9.38 (bs, 1H), 8.68 (s, 1H), 8.05 (d, 1H), 7.83 (s, 2H), 7.69 (d, 1H), 4.40 (q, 2H), 1.39 (t, 3H). MS(EI): 236(M++H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=3)[C:12]([C:20](O)=[O:21])=[CH:11]2)[C:4]=1[CH3:23].[CH3:24][O:25][CH2:26][CH2:27][NH2:28].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>>[CH3:1][O:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=3)[C:12]([C:20]([NH:28][CH2:27][CH2:26][O:25][CH3:24])=[O:21])=[CH:11]2)[C:4]=1[CH3:23]
Reactant: COc1ncnc(Cn2cc(C(=O)O)c3ncc(C)cc32)c1C
Reactant: COCCN
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Product: COCCNC(=O)c1cn(Cc2ncnc(OC)c2C)c2cc(C)cnc12
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
See FIG. 18(c). 1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (0.100 g, 0.32 mmol) and 2-methoxyethanamine (0.048 g, 0.64 mmol), TEA (0.134 mL, 0.96 mmol) was added. After 3 min, 1-Propanephosphonic acid cyclic anhydride (0.255 g, 0.80 mmol) was added. The resulting reaction mixture was stirred at rt for 50 min. LCMS analysis showed formation of required product. Reaction was diluted with DCM and water. DCM layer was extracted and washed with brine and dried over sodium sulphate and concentrated. Purification was done on Waters RP system to get product 1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-N-(2-methoxyethyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (0.045 g, 38.0%). ES+MS m/z: 370.21. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.17-2.28 (s, 3H ) 2.40 (s, 3 H ) 3.30 (s, 13 H ) 3.50 (d, J=4.52 Hz, 2 H ) 3.55 (t, J=5.18 Hz, 2 H ) 3.94 (s, 3 H ) 5.63 (s, 2 H ) 7.74 (s, 1 H ) 8.12 (s, 1 H ) 8.34 (s, 1 H ) 8.42 (s, 1 H) 8.78 (t, J=5.46 Hz, 1H ).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:21]4[CH2:22][C:23]5[S:24][CH:25]=[CH:26][C:27]=5[C:20]=4[N:19](COCC[Si](C)(C)C)[N:18]=3)=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([O-])=O.Cl>CO.[Fe]>[S:24]1[CH:25]=[CH:26][C:27]2[C:20]3[NH:19][N:18]=[C:17]([C:14]4[CH:13]=[CH:12][C:11]([NH:10][C:7]5[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=5)=[CH:16][CH:15]=4)[C:21]=3[CH2:22][C:23]1=2
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Nc3ccc([N+](=O)[O-])cc3)cc2)c2c1-c1ccsc1C2
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: Nc1ccc(Nc2ccc(-c3n[nH]c4c3Cc3sccc3-4)cc2)cc1
Temperature: 100 °C
Yield: 80 %

Procedure:
(4-Nitro-phenyl)-{4-[4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl]-phenyl}-amine (0.25 g, 0.5 mmol) was dissolved in MeOH and treated with concentrated HCl (0.16 mL, 5 mmol) and iron powder (0.34 g, 6.0 mmol). The reaction mixture was heated at 100° C. for 4 hr. The solution was cooled to room temperature and the resultant precipitate was filtered, washed with MeOH and concentrated under reduced pressure to provide the corresponding N-[4-(4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-phenyl]-benzene-1,4-diamine (0.14 g, 0.4 mmol) as yellow solid in 80% yield.
Reaction SMILES: [F:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][N:6]=1.C([O-])(O)=O.[Na+]>CCO>[NH2:11][C:8]1[CH:9]=[CH:10][C:5]([NH:4][CH2:3][CH2:2][F:1])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(NCCF)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1ccc(NCCF)nc1
Temperature: 75 °C

Procedure:
A stirred mixture of the product from Step 1 (2.08 g, 0.0112 mol) and EtOH (25 ml), under nitrogen, was treated with stannous chloride dihydrate (12.6 g, 0.056 mol). The mixture was warmed at 75° C. for 30 minutes, cooled and mixed with ice water. This mixture was made alkaline (pH 8-9) with saturated NaHCO3 and extracted with EtOAc. The extract was concentrated to give the titled product which was used without further purification in Step 3.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]([C:9]2[N:13](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:12]=[N:11][CH:10]=2)O)=[CH:3][CH:2]=1.[CH3:33][CH:34](O)[CH3:35].[OH-].[Na+]>C(Cl)(Cl)Cl>[NH:13]1[C:9]([CH:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[CH2:33][C:34]2[CH:35]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:10][N:11]=[CH:12]1
Reactant: OC(c1ccncc1)c1cncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: c1ccc(CC(c2ccncc2)c2cnc[nH]2)cc1
Temperature: 160 °C

Procedure:
A mixture of pyridin-4-yl(1-trityl-1H-imidazol-5-yl)methanol, (Intermediate 4) (526 g, 1.03 mmol) in 57% aqueous Hl (10 mL) and iPrOH (2 mL) was added red phosphorus (318 mg, 10.3 mmol) in a resealable tube was heated at 160° C. for 16 h. The mixture was then cooled to room temperature and poured into ice-water, which was then basified with NaOH and diluted with CHCl3. The residue was isolated in a typical aqueous workup using CHCl3 and purified by MPLC with 5 to 15% MeOH: CH2Cl2 to give 4-(1-(1H-imidazol-5-yl)-2-phenylethyl)pyridine (AGN214418) as a solid, 36 mg. 1HNMR (CD3OD, 300 MHz) δ 6.98 (s, 1H), 7.20-7.11, (m, 9H), 7.61 (s, 1H), 4.38 (t, J=9 Hz, 1H), 3.43 (dd, J=6 Hz, 12 Hz, 1H), 3.19 (dd, J=9 Hz, 15 Hz, 1H).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[C:14]([O:16][CH2:17][C:18]3[CH:19]=[C:20]([CH:24]([CH:31]4[CH2:33][CH2:32]4)[CH2:25][C:26]([O:28]CC)=[O:27])[CH:21]=[CH:22][CH:23]=3)[CH:13]=[CH:12][C:11]=2[C:34]2[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:35]=2[F:42])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.Cl>CO.C1COCC1>[C:1]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[C:14]([O:16][CH2:17][C:18]3[CH:19]=[C:20]([CH:24]([CH:31]4[CH2:33][CH2:32]4)[CH2:25][C:26]([OH:28])=[O:27])[CH:21]=[CH:22][CH:23]=3)[CH:13]=[CH:12][C:11]=2[C:34]2[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:35]=2[F:42])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(-c3nnc(C(C)(C)C)s3)c2)c1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(OCc3cccc(C(CC(=O)O)C4CC4)c3)cc2-c2nnc(C(C)(C)C)s2)c1
Temperature: 25 °C
Reaction time: 9 h
Yield: 99.3 %

Procedure:
To a solution of ethyl 3-(3-(((2-(5-(tert-butyl)-1,3,4-thiadiazol-2-yl)-2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-yl)oxy)methyl)phenyl)-3-cyclopropylpropanoate (129 mg) in methanol (1.5 mL) and THF (1.5 mL) was added 1N aqueous sodium hydroxide solution (0.66 mL), and the mixture was stirred at room temperature for 9 hr. Water and hydrochloric acid were added, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (122 mg) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:18][C:19]([O:21]C(C)(C)C)=[O:20].N#N>CC#N>[NH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([O:1][CH2:18][C:19]([OH:21])=[O:20])[CH:10]=2)[CH:6]=[CH:7]1
Reactant: Oc1ccc2cc[nH]c2c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(O)COc1ccc2cc[nH]c2c1

Procedure:
6-Hydroxyindole (1.0 g, 7.51 mmol) in degassed MeCN (10 mL) was added K2CO3 (1.14 g, 8.26 mmol) followed by tert-butyl bromoacetate (1.16 g, 8.26 mmol) and the reaction mixture was stirred for 20 hous under N2. The precipitate was filtered off and the solvent was removed in vacuo to give (1-H-indole-6-yloxy)-acetic acid. This was converted to [1-Cyclopropylmethyl-3-(thiazol-2-ylcarbamoyl)-1H-indol-6-yloxy]-acetic acid tert-butyl ester follwing general procedure (A). [1-Cyclopropylmethyl-3-(thiazol-2-ylcarbamoyl)-1H-indol-6-yloxy]-acetic acid was obtained by treating the intermediate with TFA-DCM (1:1) (2 mL) for 90 min before the solvent was removed in vacuo.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH2:9][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:7][CH:8]=1)([OH:3])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.CCN(CC)CC.Cl.Cl.[NH2:44][CH2:45][CH2:46][CH2:47][NH:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=1>C(Cl)Cl>[C:17]1([CH:10]([CH2:9][C:6]2[O:7][CH:8]=[C:4]([C:1]([NH:44][CH2:45][CH2:46][CH2:47][NH:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=3)=[O:3])[N:5]=2)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)CC(Cc1nc(C(=O)O)co1)c1ccccc1
Reactant: NCCCNc1ccccn1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CC(Cc1nc(C(=O)NCCCNc2ccccn2)co1)c1ccccc1
Reaction time: 2 h
Yield: 90.9 %

Procedure:
To a solution of ethyl (±)-4-(4-carboxy-1,3-oxazol-2-yl)-3-phenylbutanoate (100 mg, 0.33 mmole) in CH2Cl2 (2 mL) was added 1,1′-carbonyldiimidazole (80 mg, 0.49 mmole). After 2 hr, Et3N (0.14 mL, 0.98 mmole) and 2-[(3-amino-1-propyl)amino]pyridine dihydrochloride (110 mg, 0.49 mmole) were added. After 4 h, the mixture was concentrated under reduced pressure. The residue was chromatographed on silica gel (75% EtOAc/hexanes) to give the title compound (131 mg, 91%) as a yellow oil: MS (ES) m/e 437 (M+H)+.