Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1C=[CH:9][C:8]([CH2:11][CH2:12][C:13]([OH:15])=O)=[CH:7][N:6]=1)=[O:4].[NH2:16][CH2:17][C:18]([N:20]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([CH2:29][O:30][C:31]2[C:39]3[N:38]=[C:37]([O:40][CH3:41])[N:36]([CH2:42][C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=4)[C:35]=3[CH:34]=[CH:33][CH:32]=2)[C:23]=1[Cl:49])[CH3:21])=[O:19].ClC1C(COC2C3N=C(OC)[N:64](CC4C=CC=CN=4)C=3C=CC=2)=C(Cl)C=CC=1N(C)C(=O)CNC(=O)CCC1C=CC(C(NCCOC)=O)=CC=1>>[Cl:49][C:23]1[C:24]([CH2:29][O:30][C:31]2[C:39]3[N:38]=[C:37]([O:40][CH3:41])[N:36]([CH2:42][C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=4)[C:35]=3[CH:34]=[CH:33][CH:32]=2)=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=1[N:20]([CH3:21])[C:18](=[O:19])[CH2:17][NH:16][C:13](=[O:15])[CH2:12][CH2:11][C:8]1[CH:9]=[N:64][C:5]([C:3]([NH:2][CH3:1])=[O:4])=[N:6][CH:7]=1
Reactant: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccc2n1Cc1ccccn1
Reactant: CNC(=O)c1ccc(CCC(=O)O)cn1
Reactant: COCCNC(=O)c1ccc(CCC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c3nc(OC)n4Cc3ccccn3)c2Cl)cc1
Product: CNC(=O)c1ncc(CCC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c3nc(OC)n4Cc3ccccn3)c2Cl)cn1

Procedure:
3-(2-methylcarbamoyl-pyridine-5-yl)-propionic acid and 2-amino-N-(2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)-N-methylacetamide and coupled together as described for compound 1 above. LCMS (APCI) 691 (M+1); 1HNMR (400 MHz, MeOD) δ 2.90-3.0 (m, 5H), 3.21-3.25 (m, 5H), 3.66 (d, 1H), 3.96 (d, 1H), 4.15 (s, 3H), 5.33 (s, 2H), 5.58 (m, 2H), 6.86 (m, 2H), 7.08 (m, 2H), 7.32 (m, 1H), 7.55-762(m, 2H), 7.76 (m, 1H), 8.51 (d, 1H), 9.08 (s, 2H)
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH2:3][CH:4]([OH:6])[CH3:5].[C:8](Cl)(=[O:12])[C:9]([Cl:11])=[O:10]>>[C:9]([Cl:11])(=[O:10])[C:8]([O:6][CH:4]([CH2:3][CH:2]([CH3:7])[CH3:1])[CH3:5])=[O:12]
Reactant: CC(C)CC(C)O
Reactant: O=C(Cl)C(=O)Cl
Product: CC(C)CC(C)OC(=O)C(=O)Cl
Yield: 88.2 %

Procedure:
In this example the product was prepared in two synthetic steps. In the first step 4-methyl-2-pentanol was reacted with 50% molar excess of oxalyl chloride. Upon completion of the reaction the excess oxalyl chloride was stripped from the product at reduced pressure to produce 4-methyl-2-pentyl chlorooxalate having an assay of 96.2% and in a corrected yield of 88.2%. In the second step 4-methyl-2-pentyl chlorooxalate was reacted with 3-hydroxy-1,1-dimethylbutyl hydroperoxide in the presence of pyridine to yield the product as described below:
Reaction SMILES: O=[C:2]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][N:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]4)=[C:18]([O:28][CH3:29])[N:17]=3)[N:15]=[C:8]12)=[O:6].C(Cl)(=O)C(Cl)=O.P(Cl)(Cl)(Cl)=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:29][O:28][C:18]1[N:17]=[C:16]([C:14]2[N:15]=[C:8]3[CH:7]([C:5]4[O:6][C:2]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[CH:3][N:4]=4)[CH2:12][CH2:11][CH2:10][N:9]3[N:13]=2)[CH:21]=[CH:20][C:19]=1[N:22]1[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]1
Reactant: COc1nc(-c2nc3n(n2)CCCC3C(=O)NCC(=O)c2ccccc2)ccc1-n1cnc(C)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1nc(-c2nc3n(n2)CCCC3c2ncc(-c3ccccc3)o2)ccc1-n1cnc(C)c1
Yield: 12.8 %

Procedure:
2-[6-Methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carboxylic acid (2-oxo-2-phenylethyl)amide obtained in Example 172 (35.7 mg) was suspended in toluene (0.5 mL). Oxalyl chloride (20.4 mg) was added and the mixture was stirred with heating under reflux for two hours. Toluene (3 mL) and phosphoryl chloride (60 μL) were added, followed by further stirring for two hours and 30 minutes. The reaction solution was ice-cooled. Then, chloroform and a saturated sodium bicarbonate solution were added and the organic layer was separated. The resulting organic layer was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography to obtain the title compound (4.4 mg). The compound was further purified by CHIRALPAK™ IA (2 cm×25 cm; mobile phase:hexane:ethanol=50:50) to obtain the title compound (1.2 mg, racemate). The property values of the compound are as follows.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH2:14])[CH3:13])[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[C:21]=1[O:22][CH3:23].Cl[C:25]1[N:33]=[CH:32][N:31]=[C:30]2[C:26]=1[N:27]=[CH:28][N:29]2C1CCCCO1.CCN(C(C)C)C(C)C>CC(O)C.Cl.CO>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH:14][C:25]3[N:33]=[CH:32][N:31]=[C:30]4[C:26]=3[N:27]=[CH:28][NH:29]4)[CH3:13])[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[C:21]=1[O:22][CH3:23]
Reactant: COc1c(F)ccc2nc([C@H](C)N)n(-c3ccccc3)c12
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COc1c(F)ccc2nc([C@H](C)Nc3ncnc4[nH]cnc34)n(-c3ccccc3)c12
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 63.7 %

Procedure:
To a solution of (S)-1-(6-fluoro-7-methoxy-1-phenyl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride (0.16 g, 0.44 mmol) in IPA (3 mL) was added 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (139 mg, 0.58 mmol) and DIPEA (229 μL, 1.34 mmol) and the reaction mixture heated at 90° C. for 72 hours. The reaction mixture was concentrated in vacuo and the resultant residue was subjected to flash chromatography (SiO2, eluting with 0-10% methanol in EtOAc) to give a white solid: LCMS (Method C): RT=3.13 min, [M+H]+=488. The solid was dissolved in HCl in methanol (1.25 M, 5 mL) and the reaction mixture stirred at RT for 10 min. The reaction mixture was concentrated in vacuo and the resultant residue subjected to prep. HPLC (C18 phenomonix column, 10-90% MeCN in water 0.1% formic acid, 20 min gradient) to give 338 as a white solid (113 mg, 63%). 1H NMR 400 MHz δ (d6-DMSO): 8.10-8.00 (2H, m), 7.89-7.75 (1H, m), 7.66-7.29 (7H, m), 7.13-7.02 (1H, m), 5.38-5.17 (1H, m), 3.33 (3H, s), 1.48 (3H, d, J=6.8 Hz), LCMS (Method K): RT=3.40 min, [M+H]+=404
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][CH:6]2[NH2:13].F[C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[S:22]([CH3:25])(=[O:24])=[O:23].C(N(C(C)C)CC)(C)C.O>CN(C)C=O>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][CH:6]2[NH:13][C:17]1[CH:18]=[C:19]([F:21])[CH:20]=[CH:15][C:16]=1[S:22]([CH3:25])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)c1ccc(F)cc1F
Reactant: NC1CCOc2ccc(Cl)cc21
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(F)cc1NC1CCOc2ccc(Cl)cc21
Temperature: 25 °C
Yield: 16.1 %

Procedure:
A solution of 6-chlorochroman-4-amine hydrochloride (551.0 mg, 2.50 mmol), 2,4-difluoro-1-(methylsulfonyl)benzene (496.0 mg, 2.50 mmol) and diisopropylethylamine (1.29 g, 10.0 mmol) in N,N-dimethylformamide (10 mL) was stirred at 110° C. for 16 h. The reaction was cooled to room temperature, poured over water and extracted with diethyl ether. The solvent was concentrated in vacuo and the residue was purified by silica chromatography (20% ethyl acetate in hexanes) to yield 143.0 mg (16%) of the desired product: 1H NMR (400 MHz, CDCl3) δ 7.82 (dd, 1H), 7.19 (m, 2H), 6.83 (d, 1H), 6.57 (m, 2H), 4.60 (m, 1H), 4.30 (m, 1H), 4.28 (m, 1H), 3.01 (s, 3H), 2.19 (m, 2H).
Reaction SMILES: [C:1]1([CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:8][NH:9][CH2:10][C@@H:11]([CH3:24])[CH2:12][O:13][C:14]2[CH:15]=[C:16]([CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[O:40][CH3:41])[CH:35]=O.COC(=O)CC1C=CC=C(OCC[C@H](NCC(C2C=CC=CC=2)C2C=CC=CC=2)C)C=1.[Cl:73]C1C(C(F)(F)F)=CC=CC=1C=O.Cl.CCOCC>CCOCC>[ClH:73].[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[O:40][CH3:41])[CH2:35][N:9]([CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:10][C@@H:11]([CH3:24])[CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=1
Reactant: C[C@H](CNCC(c1ccccc1)c1ccccc1)COc1cccc(CC(=O)O)c1
Reactant: COc1ccc(C=O)cc1F
Reactant: O=Cc1cccc(C(F)(F)F)c1Cl
Agent: COC(=O)Cc1cccc(OCC[C@@H](C)NCC(c2ccccc2)c2ccccc2)c1
Agent: Cl
Solvent: CCOCC
Product: COc1ccc(CN(CC(c2ccccc2)c2ccccc2)C[C@@H](C)COc2cccc(CC(=O)O)c2)cc1F

Procedure:
Following the procedure of Example 7(d) except (R)-2-(3-{3-[(2,2-diphenylethyl)amino]2-methyl-propoxy}-phenyl)acetic acid (Example 30-Step (a-b)) and 3-fluoro-4-methoxybenzaldehyde were used instead of (R)-2-(3-{3-[(2,2-diphenylethyl)amino]-3-methyl-propoxy}phenyl)acetic acid methyl ester and 2-chloro-3-trifluoromethylbenzaldehyde in step (d) the corresponding carboxylic acid was obtained. The resulting amine/carboxylic acid was dissolved in Et2O (diethylether) and acidified with 1.0 M HCl/Et2O. The reaction mixture was concentrated in vacuo and dried under reduced pressure to give the title compound as a white solid, 98 mg (97%). MS (ESI) 542.4 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C@@H:5]([N:8]1[C:13](=[O:14])[C:12]2[N:15]=[CH:16][CH:17]=[CH:18][C:11]=2[N:10]([CH2:19][C:20]2[C:24]3[C:25]([CH3:30])=[CH:26][C:27]([CH3:29])=[CH:28][C:23]=3[S:22][N:21]=2)[C:9]1=[O:31])[CH2:6][CH3:7].[OH-].[Li+].C(O)(=O)C.O>O1CCOCC1>[CH3:30][C:25]1[C:24]2[C:20]([CH2:19][N:10]3[C:11]4[CH:18]=[CH:17][CH:16]=[N:15][C:12]=4[C:13](=[O:14])[N:8]([C@@H:5]([CH2:6][CH3:7])[CH2:4][C:3]([OH:32])=[O:2])[C:9]3=[O:31])=[N:21][S:22][C:23]=2[CH:28]=[C:27]([CH3:29])[CH:26]=1
Reactant: CC[C@@H](CC(=O)OC)n1c(=O)c2ncccc2n(Cc2nsc3cc(C)cc(C)c23)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CC[C@@H](CC(=O)O)n1c(=O)c2ncccc2n(Cc2nsc3cc(C)cc(C)c23)c1=O
Reaction time: 3.5 h
Yield: 33.5 %

Procedure:
To a solution of 80 mg of (S)-3-[1-(4,6-dimethyl-benzo[d]isothiazol-3-ylmethyl)-2,4-dioxo-1,4-dihydro-2H-pyrido[3,2-d]pyrimidin-3-yl]-pentanoic acid methyl ester in 1,4-dioxane (2.5 mL) is added lithium hydroxide solution (11 mg of lithium hydroxide monohydrate in 0.5 mL of water) at room temperature. The solution is stirred at the same temperature for 3.5 h. Then 0.5 mL of acetic acid is added along with 25 mL of water. The mixture is extracted with ethyl acetate (3×50 mL). The combined organic layers are dried over sodium sulfate and concentrated. The residue is purified by flash chromatography on silica gel to give 26 mg (34%) of (S)-3-[1-(4,6-dimethyl-benzo[d]isothiazol-3-ylmethyl)-2,4-dioxo-1,4-dihydro-2H-pyrido[3,2-d]pyrimidin-3-yl]-pentanoic acid; LCMS (ESMS): m/z 439.12 (M+H+).
Reaction SMILES: FC(F)(F)C([O-])=O.[CH2:8]([O:15][C:16]([NH:18][C@H:19]([C:28]1[NH:29][C:30]([C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[C:38]([O:43][CH3:44])[CH:39]=3)[CH:34]=2)=[CH:31][NH+:32]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](O)=[O:26])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:45][N:46](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CN>CN(C=O)C.CCOC(C)=O>[CH3:44][O:43][C:38]1[CH:39]=[C:40]2[C:35](=[CH:36][CH:37]=1)[CH:34]=[C:33]([C:30]1[NH:29][C:28]([C@@H:19]([NH:18][C:16](=[O:17])[O:15][CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([NH:46][CH3:45])=[O:26])=[N:32][CH:31]=1)[CH:42]=[CH:41]2
Reactant: COc1ccc2cc(-c3c[nH+]c([C@H](CCCCCC(=O)O)NC(=O)OCc4ccccc4)[nH]3)ccc2c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CNC(=O)CCCCC[C@H](NC(=O)OCc1ccccc1)c1ncc(-c2ccc3cc(OC)ccc3c2)[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of E2 in DMF (0.1 M) were added HATU (1.5 eq.) and DIPEA (2.0 eq.) followed after 10 min by methylamine (2.0 M solution in THF, 5 eq.). Reaction mixture was stirred at room temperature for 16 h, then it was diluted with EtOAc, washed with sat. aq. NaHCO3 sol., brine, dried over Na2SO4, filtered and concentrated to give a dark brown residue. The resulting crude was purified by column chromatography (eluent: petroleum ether/EtOAc from 9:1 to 100% EtOAc, then EtOAc/MeOH=95:5) to give the title compound as a colorless oil. MS (ES+) C30H34N4O4: 515 (M+H)+.
Reaction SMILES: [CH:1]([NH:4][C:5]([CH2:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH2:20][C@@H:21]([CH3:28])[CH2:22]OS(C)(=O)=O)[CH:15]=2)[N:10]=[C:9]1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=1)=[O:6])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:43]([NH:45][CH2:46][CH3:47])[CH3:44].CCCCCC>C(#N)C>[CH2:43]([N:45]([CH2:46][CH3:47])[CH2:22][C@H:21]([CH3:28])[CH2:20][O:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=1)[N:8]([CH2:7][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[C:17]2=[O:18])[CH3:44]
Reactant: COc1cccc(-c2nc3ccc(OC[C@@H](C)COS(C)(=O)=O)cc3c(=O)n2CC(=O)NC(C)C)c1
Reactant: CCNCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CC#N
Product: CCN(CC)C[C@H](C)COc1ccc2nc(-c3cccc(OC)c3)n(CC(=O)NC(C)C)c(=O)c2c1
Temperature: 80 °C
Yield: 64.2 %

Procedure:
To a solution of (R)-(−)-methanesulfonic acid 3-[3-(isopropylcarbamoylmethyl)-2-(3-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-6-yloxy]-2-methylpropyl ester (1.13 g, 2.18 mmol) in anhydrous acetonitrile (40 mL) was added potassium carbonate (1.51 g, 10.95 mmol) followed by diethyl amine (3.20 g, 4.53 mL, 43.80 mmol) and the reaction mixture was heated at 80° C. in a pressure tube. After 2 days (reaction complete by HPLC), the reaction mixture was concentrated in vacuo to dryness and the residue was partitioned between water (100 mL) and ethyl acetate (150 mL). The aqueous layer was extracted with ethyl acetate (5×150 mL) and with dichloromethane (5×100 mL). The combined organic phase was dried (Na2SO4), solvent evaporated in vacuo, and the resulting residue purified by chromatography on silica gel with a gradient of methanol:dichloromethane (1:19, v/v) to methanol:dichloromethane (1:4, v/v) as eluent. The resultant solid was recrystallised from diethyl ether:hexane to afford (S)-(+)-2-[6-(3-diethylamino-2-methylpropoxy)-2-(3-methoxyphenyl)-4-oxo-4H-quinazolin-3-yl]-N-isopropy-acetamide (EXAMPLE 4a) (0.69 g, 1.40 mmol, 65% from (S)-(+)-2-[6-(3-hydroxy-2-methylpropoxy)-2-(3-methoxyphenyl)-4-oxo-4H-quinazolin-3-yl]-N-isopropylacetamide) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.N1(C(N2C=CN=C2)=S)C=CN=[CH:10]1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[C:29]1[NH:30][C:31]2[CH:37]=[C:36]([C:38]([NH:40][NH2:41])=[O:39])[CH:35]=[CH:34][C:32]=2[N:33]=1.CCN=C=NCCCN(C)C>CN(C=O)C.CCOC(C)=O>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[C:29]1[NH:30][C:31]2[CH:37]=[C:36]([C:38]3[O:39][C:10]([NH:1][C:2]4[CH:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=4)=[N:41][N:40]=3)[CH:35]=[CH:34][C:32]=2[N:33]=1
Reactant: Cc1ccc(N)cn1
Reactant: NNC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(Nc2nnc(-c3ccc4nc(-c5c(Cl)cccc5Cl)[nH]c4c3)o2)cn1
Temperature: 4 °C
Reaction time: 72 h

Procedure:
Combine 3-amino-6-methyl-pyridine (66 mg, 0.606 mmol) and di-imidazol-1-yl-methanethione (108 mg, 0.606 mmol) in DMF (1.5 mL) and stir for 4 hr. Add 2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid hydrazide (150 mg, 0.466 mmol) and DMF (1 mL). Stir for 3 days. Add EDCI (179 mg, 0.932 mmol) and heat to 80° C. for 45 min. Upon cooling, dilute the reaction with EtOAc (50 mL) and extract with water (10 mL) and 1 N NaOH (10 mL). Combine the aqueous layers and allow to stand overnight. Filter the combined aqueous layers and wash the collected solid with Et2O. Suspend the solid in boiling toluene/EtOAc. Allow the suspension to cool to 4° C. and collect the solid. Wash with Et2O. Purify the solid by reverse phase HPLC (20-65% ACN/H2O+5 mM NH4OH) to afford the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 2.46 (s, 3H) 7.33 (d, J=8.34 Hz, 1H) 7.64-7.68 (m, 1H) 7.71 (s, 1H) 7.73 (d, J=2.02 Hz, 1H) 7.86 (br. s., 2H) 8.04 (dd, J=8.40, 2.46 Hz, 1H) 8.13 (br. s., 1H) 8.70 (d, J=2.53 Hz, 1H) 10.88 (br. s., 1H); MS m/z=437.0 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[N:9]([CH2:14][C:15]#[CH:16])[C:8]=2[CH:17]=1)([O-])=O>C(O)(=O)C.CCOC(C)=O.O.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[N:9]([CH2:14][C:15]#[CH:16])[C:8]=2[CH:17]=1
Reactant: C#CCN1C(=O)COc2ccc([N+](=O)[O-])cc21
Agent: [Fe]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C#CCN1C(=O)COc2ccc(N)cc21
Temperature: 25 °C
Yield: 74.2 %

Procedure:
To a slurry of 5.1 g (91 mmol) of iron powder in 42.5 ml of 5% aqueous acetic acid was added dropwise a solution of 4 g (17 mmol) of 6-nitro-4-propargyl-2H-1,4-benzoxazin-3(4H)-one dissolved in 42.5 ml of glacial acetic acid and 42.5 ml of EtOAc. The reaction mixture was heated to gentle reflux for 1 hour then cooled to room temperature. The iron was removed by suction filtration. EtOAc (50 ml) was added to the filtrate and the layers were separated. The aqueous phase was extracted with EtOAc (2×50 ml) and the organic layers were combined, washed with saturated aqueous sodium bicarbonate solution (100), and dried (MgSO4). The solvent was removed in vacuo to yield a thin brown oil which was taken up in 50 ml of water and reextracted with EtOAc (3×50 ml). The organic layers were combined, washed with water (2×50 ml) and then dried (MgSO4). The solvent was removed in vacuo to yield 2.55 g (75% yield) of 6-amino-4-propargyl-2H-1,4-benzoxazin-3 (4H)-one, a dark brown solid, m.p. 136°-140° C.
Reaction SMILES: [Cl-].[NH4+].O.[N+:4]([C:7]1[CH:8]=[CH:9][C:10]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH:16]2CCO)=[C:11]([CH:14]=1)[C:12]#[N:13])([O-])=O.[CH2:24]([OH:26])[CH3:25]>[Fe]>[NH2:4][C:7]1[CH:8]=[CH:9][C:10]([N:15]2[CH2:16][CH2:17][N:18]([CH2:25][CH2:24][OH:26])[CH2:19][CH2:20]2)=[C:11]([CH:14]=1)[C:12]#[N:13]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N1CCNCC1CCO
Reactant: CCO
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: N#Cc1cc(N)ccc1N1CCN(CCO)CC1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
Ammonium chloride (1.5 g) and iron powder (13.8 g) were added to a mixed solvent of water (51 ml) and ethanol (170 ml), and the mixture was heated to 65° C. Then, 5-nitro-2-(2-hydroxyethylpiperazin-1-yl)benzonitrile (17 g) was added in parts over 20 min and the mixture was stirred at a refluxing temperature for 30 min. The reaction mixture was ice-cooled and filtrated. The solvent was evaporated under reduced pressure. To the residue was added aqueous sodium hydroxide solution and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give the title compound (13 g), melting point: 137–138° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[N:11]=[N:10]1)#[N:2].S(=O)(=O)(O)[OH:19].[OH-].[NH4+]>>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[N:11]=[N:10]1)(=[O:19])[NH2:2]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccccc1-n1nnc2cccnc21
Agent: [NH4+]
Agent: [OH-]
Product: NC(=O)c1ccccc1-n1nnc2cccnc21
Reaction time: 7 h

Procedure:
The cyano compound (from Example 7) (600 mg.) was dissolved in 8 ml. of concentrated sulfuric acid with ice cooling. After standing at room temperature for 7 hours it was poured onto ice. The cold solution was treated with an excess of ammonium hydroxide. The precipitate was collected, air dried and recrystallized from dimethylformamide and water to give 3-(2-carbamoylphenyl)-3H-1,2,3-triazolo[4,5-b]pyridine, m.p. >340° C.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:14]=[C:13]2[CH2:15][CH2:16][CH2:17][C:12]2=[C:11]2[C:7]=1[C:8]([C:27](=[O:31])[C:28]([NH2:30])=[O:29])=[C:9]([CH3:26])[N:10]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Br:25].[OH-].[Li+].Cl>CO.O>[NH2:30][C:28](=[O:29])[C:27]([C:8]1[C:7]2[C:11](=[C:12]3[CH2:17][CH2:16][CH2:15][C:13]3=[CH:14][C:6]=2[O:5][CH2:4][C:3]([OH:32])=[O:2])[N:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Br:25])[C:9]=1[CH3:26])=[O:31]
Reactant: COC(=O)COc1cc2c(c3c1c(C(=O)C(N)=O)c(C)n3Cc1ccccc1Br)CCC2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cc3c(c2n1Cc1ccccc1Br)CCC3
Temperature: 25 °C
Yield: 35.3 %

Procedure:
A solution of 2-[[3-(2-amino-1,2-dioxoethyl)-2-methyl-1-(2-bromobenzyl)-1,6,7,8-tetrahydrocyclopent[g]indol-4-yl]oxy]acetic acid methyl ester (106 mg, 0.21 mmol) in methanol (3 mL) was treated with 1 N lithium hydroxide solution (1 mL). The solution was heated to reflux then allowed to cool to room temperature. The mixture was diluted with water and acidified with 1 N hydrochloric acid. The resulting precipitate was collected via vacuum filtration and washed carefully with ethyl acetate to provide 36 mg (35%) of the title compound as a tan solid: mp 261-262° C. (dec). 1H NMR (DMSO-d6) δ 12.88 (bs, 1H), 7.72 (m, 2H), 7.43 (bs, 1H), 7.26 (m, 2H), 6.46 (s, 1H), 6.18 (m, 1H), 5.48 (s, 2H), 4.62 (s, 2H), 2.80 (m, 4H), 2.43 (s, 3H), 1.93 (quintet, J=7.3 Hz, 2H); IR (KBr, cm−1) 3431, 1735, 1628, 1213.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:11](=[O:14])[CH:12]=[CH2:13])=[CH:4][C:3]=1[N:15]1[N:19]=[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]2=[N:16]1.[CH3:24][O-:25].[Na+].[CH3:27][OH:28]>C1(C)C(C)=CC=CC=1>[N:19]1[N:15]([C:3]2[C:24]([OH:25])=[C:7]([CH2:2][C:7]3[CH:6]=[C:5]([CH3:8])[CH:4]=[C:3]([N:15]4[N:16]=[C:17]5[CH:23]=[CH:22][CH:21]=[CH:20][C:18]5=[N:19]4)[C:27]=3[OH:28])[CH:6]=[C:5]([CH2:8][CH2:9][O:10][C:11](=[O:14])[CH:12]=[CH2:13])[CH:4]=2)[N:16]=[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=12
Reactant: CO
Reactant: C=CC(=O)OCCc1ccc(O)c(-n2nc3ccccc3n2)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: C=CC(=O)OCCc1cc(Cc2cc(C)cc(-n3nc4ccccc4n3)c2O)c(O)c(-n2nc3ccccc3n2)c1
Temperature: 25 °C
Yield: 69.1 %

Procedure:
Ten grams (30.9 mmols) of crude 2-(3'-N,N-diethylaminomethyl-2'-hydroxy-5'-methylphenyl)-2H-benzotriazole obtained following the procedures of Synthesis Example 1 and 9.57 g (30.9 mmols) of 2-(2'-hydroxy-5'-acryloyloxyethylphenyl)-2H-benzotriazole were dissolved in 64 ml of xylene, and 1.5 ml of a 28% sodium methylate-methanol solution were added thereto. The mixture was then refluxed in a nitrogen stream for 10 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature. Yellow crystals precipitated at this stage were separated through filtration, and recrystallized from chloroform to obtain 11.8 g of 6-(2H-benzotriazol-2-yl)-4-acryloyloxyethyl-2-[3'-(2H-benzotriazol-2-yl)-2'-hydroxy-5'-methylphenyl]methylphenol (hereinafter abbreviated as "RUVA-4") as white crystals (yield 69.1%, purity 99.0%).