Azzindani/Open_Reaction_Data huggingface dataset:
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].[NH:15]1[CH2:18][CH:17]([N:19]2[CH:23]=[CH:22][C:21]([C:24]3[N:36]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[CH:39]=4)[C:27]4[CH:28]=[CH:29][C:30]5[N:31]([C:32]([CH3:35])=[N:33][N:34]=5)[C:26]=4[CH:25]=3)=[N:20]2)[CH2:16]1.C(N(CC)CC)C.[CH3:52][N:53]([CH3:58])[S:54](Cl)(=[O:56])=[O:55]>C(Cl)Cl>[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:44][C:40]1[CH:39]=[C:38]([CH:43]=[CH:42][CH:41]=1)[CH2:37][N:36]1[C:27]2[CH:28]=[CH:29][C:30]3[N:31]([C:32]([CH3:35])=[N:33][N:34]=3)[C:26]=2[CH:25]=[C:24]1[C:21]1[CH:22]=[CH:23][N:19]([CH:17]2[CH2:16][N:15]([S:54]([N:53]([CH3:58])[CH3:52])(=[O:56])=[O:55])[CH2:18]2)[N:20]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Cc1nnc2ccc3c(cc(-c4ccn(C5CNC5)n4)n3Cc3cccc(Cl)c3)n12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: Cc1nnc2ccc3c(cc(-c4ccn(C5CN(S(=O)(=O)N(C)C)C5)n4)n3Cc3cccc(Cl)c3)n12
Reaction time: 0.58 h

Procedure:
A solution of 7-(1-azetidin-3-yl-1H-pyrazol-3-yl)-6-(3-chlorobenzyl)-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine bis(trifluoroacetate) salt (10.2 mg, 0.0158 mmol, prepared as in Example 156) in DCM (0.56 mL) was treated with triethylamine (11 μL, 0.079 mmol) and dimethylsulfamoyl chloride (2.5 μL, 0.024 mmol, Aldrich) and stirred for 35 minutes. Additional triethylamine (4.4 μL, 0.032 mmol) and dimethylsulfamoyl chloride (1.0 μL, 0.0093 mmol) were added. When the reaction was complete as determined by HPLC-MS, the product was purified via preparative HPLC-MS (Waters SunFire C18, eluting with a gradient of MeCN/H2O containing 0.1% TFA). Yield: (6.3 mg, 90%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[OH:32][C@@H:33]([CH2:37][CH3:38])[C:34](O)=[O:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[OH:32][C@@H:33]([CH2:37][CH3:38])[C:34]([N:22]1[CH2:23][CH2:24][N:19]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=3)[N:9]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[N:7]=2)[CH2:20][CH2:21]1)=[O:35]
Reactant: CC[C@H](O)C(=O)O
Reactant: Cc1ccc2c(N3CCNCC3)nc(-c3ccccc3O)nc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](O)C(=O)N1CCN(c2nc(-c3ccccc3O)nc3cc(C)ccc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.6 %

Procedure:
To a solution of 2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (250 mg, 0.78 mmol) in CH2Cl2 (6 mL) was added triethylamine (217 μL, 1.56 mmol) followed by the addition of (S)-2-hydroxybutanoic acid (105 mg, 1.0 mmol) and HATU (380 mg, 1.00 mmol). The reaction mixture was stirred at room temperature for 3 h and then quenched with H2O. The aqueous layer was extracted twice with CH2Cl2, dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 0-10% EtOAc in 50:50 CH2Cl2:hexanes gave (S)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)butan-1-one (300 mg, 95%). LC/MS: m/z 407.5 (M+H)+ at 2.31 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) d 8.45 (m, 1H), 8.01 (d, J=8.5 Hz, 1H), 7.70 (s, 1H), 7.39 (m, 2H), 6.95 (m, 2H), 4.92 (d, J=7.0 Hz, 1H), 4.28 (q, J=6.5 Hz, 1H), 3.89 (m, 8H), 2.52 (s, 3H), 1.67 (m, 1H), 1.51 (m, 1H), 0.91 (t, J=7.4 Hz, 3H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[C:11]#N.[H-].C([Al+]CC(C)C)C(C)C.C(OCC)(=[O:25])C.C(O)(=O)C(C(C(O)=O)O)O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[CH:11]=[O:25]
Reactant: CCOC(C)=O
Reactant: N#Cc1cc2cn[nH]c2cc1F
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: [H-]
Solvent: Cc1ccccc1
Product: O=Cc1cc2cn[nH]c2cc1F
Temperature: -40 °C
Reaction time: 3 h

Procedure:
A slurry of 4.8 g (30 mmol) 6-fluoro-1H-indazole-5-carbonitrile [commercially available; preparation given in EP 1 510 516-A1 (production example 82)] in anhydrous toluene (150 ml) was cooled to −40° C. Under inert gas atmosphere, 48 ml (72 mmol) diisobutylaluminium hydride solution (1.5 M in toluene) were added over 30 min, and the resulting mixture was stirred at −40° C. for 3 h. Then, ethyl acetate (30 ml) was added, and the mixture was stirred for further 20 min at −40° C. followed by dropwise addition of aqueous tartaric acid (1 M, 30 ml). The mixture was allowed to warm to 0° C. and filtered at this temperature. The filtrate was extracted with ethyl acetate several times, and the combined organic phases were subsequently washed with saturated aqueous sodium hydrogencarbonate and with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product thus obtained (2.60 g, 53% of th.) was used in the next step without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([NH2:12])=[N:10][C:9]([C:13]([F:16])([F:15])[F:14])=[C:8]([Cl:17])[N:7]=1)=[O:5])C.[OH-].[Na+].O.Cl>C(O)C>[NH2:12][C:11]1[C:6]([C:4]([OH:5])=[O:3])=[N:7][C:8]([Cl:17])=[C:9]([C:13]([F:14])([F:16])[F:15])[N:10]=1
Reactant: CCOC(=O)c1nc(Cl)c(C(F)(F)F)nc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1nc(C(F)(F)F)c(Cl)nc1C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirring solution of 3-amino-6-chloro-5-trifluoromethyl-pyrazine-2-carboxylic acid ethyl ester (Intermediate 7A) (165 mg, 0.612 mmol) in dry ethanol (10 ml), 2M NaOH (0.306 ml, 0.612 mmol) was added. After stirring at RT for 10 minutes, the reaction mixture was poured into water (30 ml) and the pH taken to 6 with the addition of 1M HCl. The product was extracted with EtOAc (2×30 ml). The organics were combined and washed with brine (20 ml), dried (MgSO4) and concentrated in vacuo. The crude material was purified by preparative LC-MS using 0.1% TFA/MeCN/Water system to afford the title compound. MS m/z 244 [M+H]+
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:12]=[CH:11][C:10]2[C:9](=[O:13])[CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:16][N:17](/[CH:19]=[C:8]1/[C:9](=[O:13])[C:10]2[CH:11]=[N:12][C:3]([NH:2][CH3:1])=[N:4][C:5]=2[CH2:6][CH2:7]/1)[CH3:18]
Reactant: CNc1ncc2c(n1)CCCC2=O
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CNc1ncc2c(n1)CC/C(=C\N(C)C)C2=O
Yield: 43.1 %

Procedure:
To a solution of 2-(methylamino)-7,8-dihydroquinazolin-5(6H)-one (0.2 g, 1 mmol) in toluene (3 mL) was added 1,1-dimethoxy-N,N-dimethylmethanamine (0.35 mL, 2.9 mmol) and triethylamine (0.15 mL, 1 mmol). The reaction mixture was refluxed for 16 hours. The reaction mixture was then concentrated under reduced pressure. The crude product was purified by flash column chromatography (SiO2, gradient from 100% chloroform to 2% methanol in chloroform) to give the desired product (0.1 g, 38%) as solid. 1H NMR (CDCl3, 400 MHz): δ 8.84 (bs, 1H), 7.62 (s, 1H), 5.68 (bs, 1H), 3.15 (s, 6H), 3.12 (d, J=6.0 Hz, 3H), 3.10-3.05 (m, 2H), 3.03-2.98 (m, 2H). LCMS [M+H]: 233.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.C(N([CH:18]([CH3:20])[CH3:19])CC)(C)C.[C:21]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:22]([C:27](Cl)=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=1>ClCCl.O>[C:23]1([C:19]2[CH:18]=[CH:20][CH:35]=[CH:30][CH:31]=2)[C:22]([C:27]([N:1]([C:27]([C:22]2[C:21]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:28])[C:2]2[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=2)=[O:28])=[CH:21][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(N(C(=O)c2ccccc2-c2ccccc2)C(=O)c2ccccc2-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a chilled (0° C.) solution of 2.64 g of methyl 6-aminopyridine-3-carboxylate and 5.5 ml of diisopropylethylamine in 30 ml of dichloromethane under argon is added 6.8 g of 2-biphenylcarbonyl chloride in 10 ml of dichloromethane. The mixture is stirred at room temperature 2 days and then diluted with 120 ml of dichloromethane and 50 ml of water. The organic layer is separated, washed with 50 ml each of 1M NaHCO3 and brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated under vacuum to give a solid. Crystallization from ethyl acetate gives 6.2 g of white crystals, m.p. 180°-188° C.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[S:6][C:7]([C:18]([OH:20])=[O:19])=[C:8]([CH2:9][N:10]([CH2:12][CH:13]([O:16][CH3:17])[O:14][CH3:15])[CH3:11])[C:4]=2[CH:3]=1.[N+](=[CH2:25])=[N-]>C(Cl)Cl.O1CCCC1.C(OCC)C>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[S:6][C:7]([C:18]([O:20][CH3:25])=[O:19])=[C:8]([CH2:9][N:10]([CH2:12][CH:13]([O:16][CH3:17])[O:14][CH3:15])[CH3:11])[C:4]=2[CH:3]=1
Reactant: COC(CN(C)Cc1c(C(=O)O)sc2ccc(Cl)cc12)OC
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1sc2ccc(Cl)cc2c1CN(C)CC(OC)OC
Temperature: 0 °C
Yield: 96 %

Procedure:
A suspension of 5-chloro-3-[N-(2,2-dimethoxyethyl)-N-methyl(aminomethyl)]benzo[b]thiophene-2-carboxylic acid (5.0 g, 14.5 mmol) in methylene chloride-tetrahydrofuran was stirred at 0° C. and treated with excess diazomethane in ethyl ether. The mixture was stirred for 2 hours at 0° C., treated with a stream of argon and concentrated to give 5.0 g (96%) of methyl 5-chloro-3-[N-(2,2-dimethoxyethyl)-N-methyl(aminomethyl)]benzo[b]thiophene-2-carboxylate.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH2:24])[CH2:12][CH2:11]2)=[N:2]1.[CH3:25][C:26]([CH3:28])=O.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)CCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][CH:26]([CH3:28])[CH3:25])[CH2:12][CH2:11]2)=[N:2]1
Reactant: Nc1ccccc1CCN1CCN(c2nsc3ccccc23)CC1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)Nc1ccccc1CCN1CCN(c2nsc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 96.4 %

Procedure:
A round bottomed flask was charged with 4.9 g (0.015 mol) 2-[2-(4-1,2-Benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-phenylamine, 50 mL ClCH2CH2Cl, 1.2 mL (0.016 mol) acetone, 0.93 mL (0.016 mol) HOAc, and 5.2 g (0.024 mol) NaBH(OAc)3. After stirring for 15 h at rt the reaction was quenched with 50 mL 2M K2CO3. The organic layer was separated, dried and concentrated in vacuo to give 5.5 g (100% yield) of the desired material as a yellow-orange oil. MS (APCI): 381 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J=8 Hz, 1H), 7.70 (d, J=8 Hz, 1H), 7.47–7.42 (m, 1H), 7.35–7.31 (m, 1H), 7.03–7.00 (m, 2H), 6.54–6.50 (m, 2H), 3.61–3.55 (m, 5H), 2.75–2.71 (m, 6H), 2.65–2.60 (m, 2H), 1.18 (d, J=6 Hz, 6H).
Reaction SMILES: [Cl:1][CH:2]([Cl:5])[C:3]#[N:4].C[O-].[Na+].Cl.N[C@H:11]([C:14]([O:16][CH2:17]C)=[O:15])[CH2:12][OH:13].ClCCl>CO.O>[Cl:1][CH:2]([Cl:5])[C:3]1[O:13][CH2:12][CH:11]([C:14]([O:16][CH3:17])=[O:15])[N:4]=1
Reactant: CCOC(=O)[C@@H](N)CO
Reactant: N#CC(Cl)Cl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COC(=O)C1COC(C(Cl)Cl)=N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of dichloroacetonitrile (215 g, 1.96 mol) in methanol (200 mL) was added drop-wise to a −5° C. solution of sodium methoxide (15.4 g, 0.285 mol) in methanol (500 mL). A solution of ethyl serinate, hydrochloride salt (382 g, 2.45 mol) in methanol (300 mL) was then added to the −5° C. reaction mixture, which was subsequently allowed to stir at room temperature for 16 hours. Dichloromethane (1 L) and water (800 mL) were added, and the aqueous layer was extracted with dichloromethane (1 L); the combined organic layers were concentrated in vacuo to provide the product as a yellow oil, which was used in the next step without additional purification. Yield: 300 g, 1.4 mol, 71%. 1H NMR (400 MHz, CDCl3) δ 6.29 (s, 1H), 4.90 (dd, J=10.8, 8.3 Hz, 1H), 4.74 (dd, J=8.8, 8.3 Hz, 1H), 4.66 (dd, J=10.8, 8.9 Hz, 1H), 3.82 (s, 3H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([O:11][C:12](=[O:21])[C@H:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[OH:14])[CH3:10].Br[CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25].C(O)(=O)[CH2:35][C:36](CC(O)=O)(C(O)=O)[OH:37]>O1CCCC1.C1CCCCC1>[C:36]([O:14][C@H:13]([C:12]([O:11][CH2:9][CH3:10])=[O:21])[C@H:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])(=[O:37])[CH3:35]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CCOC(=O)C[C@H](O)C(=O)OCC
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)=O)[C@@H](CC(=O)OCc1ccccc1)C(=O)OCC
Temperature: -20 °C
Reaction time: 1 h

Procedure:
5.2 ml of a 2M cyclohexane solution of lithium diisopropylamide was dissolved in 10 ml of tetrahydrofuran, and 5 ml of a tetrahydrofuran solution containing 2 g of (S)-malic acid diethyl ester, was dropwise added at -78° C. under a nitrogen atmosphere. The reaction solution was gradually heated to -20° C. over a period of one hour and then again cooled to -78° C. Then, 5 ml of a tetrahydrofuran solution containing 1.32 g of benzyl bromoacetate was added thereto, followed by stirring for one hour at -78° C. to -20° C. 10 ml of a 1N citric acid aqueous solution was added thereto and extracted with ethyl ether. Then, the ether layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1→3/1). The obtained (1S,2R)-1-hydroxy-1,2,3-propanetricarboxylic acid 3-benzyl 1,2-diethyl ester was dissolved in 6 ml of pyridine, and 3 ml of acetic anhydride was added thereto, followed by stirring at room temperature for 12 hours. The reaction solution was evaporated to dryness under reduced pressure, and then residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to obtain 966 mg of the above-identified compound as colorless oily substance.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2C=N[CH:14]=[CH:13][N:12]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].ClC1N=C(C)[CH:21]=[CH:20][N:19]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[N:12]=[C:13]([CH3:14])[CH:21]=[CH:20][N:19]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1ccnc(Cl)n1
Reactant: Cc1ccc(-c2cnccn2)c(C(=O)O)c1
Product: Cc1ccc(-c2nccc(C)n2)c(C(=O)O)c1

Procedure:
The title compound was prepared following the same general protocol as described for 5-methyl-2-(pyrazin-2-yl)benzoic acid in Example A19, starting from 2-chloro-4-methylpyrimidine. ESI-MS (m/z): 229 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:14][Si:15]([CH2:18][CH2:19][O:20][CH2:21]Cl)([CH3:17])[CH3:16].[CH2:23]([Sn](CCCC)(CCCC)CCCC)[CH:24]=[CH2:25]>CN(C=O)C>[CH3:14][Si:15]([CH2:18][CH2:19][O:20][CH2:21][N:13]1[C:9]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH2:25][CH:24]=[CH2:23])[CH:3]=2)=[N:10][N:11]=[N:12]1)([CH3:17])[CH3:16]
Reactant: Cc1ccc(-c2nnn[nH]2)cc1Br
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: C[Si](C)(C)CCOCCl
Solvent: CN(C)C=O
Product: C=CCc1cc(-c2nnnn2COCC[Si](C)(C)C)ccc1C
Temperature: 70 °C

Procedure:
A solution of 1.0 mmol of this tetrazole, 2.0 mmol of SEMCl in 10 mL DMF was stirred for 1 h. 2.0 mmol of allyltributyltin and 0.1 mmol of Pd(Ph3)4 was added and heated at 70° C. for 14 h. Chromatography provided N-trimethylsilylethoxymethyl-5-(3'-allyl-4'-methylphenyl)tetrazole.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.[H-].[Na+].CS(O[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24][CH2:23]1)(=O)=O.C(OC(=O)NC1CCN(CCN2C3C(=CC=C(OC)C=3)C=CC2=O)CC1)(C)(C)C>ClCCl.CO>[C:32]([O:31][C:29](=[O:30])[NH:28][CH:25]1[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][N:7]2[C:6]3[CH:12]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=3[O:10][CH2:9][C:8]2=[O:11])[CH2:23][CH2:24]1)([CH3:35])([CH3:34])[CH3:33]
Reactant: Cc1ccc2c(c1)NC(=O)CO2
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Agent: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc2c(c1)N(CCN1CCC(NC(=O)OC(C)(C)C)CC1)C(=O)CO2
Yield: 66 %

Procedure:
Commercially available 6-methyl-2H-1,4-benzoxazin-3(4H)-one (326 mg, 2.0 mmol) was deprotonated with sodium hydride and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6) (2.2 mmol) as described for Intermediate 2. Chromatography on silica gel with dichloromethane/methanol (20:1) gave the product in 66% yield as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5](O)=O.[NH2:12][NH:13][C:14]([NH2:16])=[S:15].P(Cl)(Cl)(Cl)=O.C(=O)(O)[O-].[Na+]>O1CCOCC1>[CH:2]1([NH:16][C:14]2[S:15][C:5]([C:4]3[CH:3]=[C:2]([OH:1])[C:10]([OH:11])=[CH:9][CH:8]=3)=[N:12][N:13]=2)[CH2:3][CH2:4][CH2:8][CH2:9][CH2:10]1
Reactant: O=C(O)c1ccc(O)c(O)c1
Reactant: NNC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: Oc1ccc(-c2nnc(NC3CCCCC3)s2)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a mixture of 3,4-dihydroxybenzoic acid (2.885 mmol, 0.445 g), thiosemicarbazide (5b) (2.885 mmol, 0.500 g) in anhydrous dioxane (10 mL) was added phosphorus oxychloride (3.751 mmol, 0.350 mL) at 90° C., and the mixture of sodium bicarbonate to pH 7 then stirred at RT overnight. The precipitate was filtered, washed with hexane, then dried to give the title compound. Yield: 71%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C:10](=[CH:18][N:19]([CH3:22])[C:20]=2[CH3:21])[N:11]([CH3:17])[C:12](=[O:16])[CH:13]([OH:15])[N:14]=1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C.O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C:10](=[CH:18][N:19]([CH3:22])[C:20]=2[CH3:21])[N:11]([CH3:17])[C:12](=[O:16])[CH:13]([O:15][C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:30])[N:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1c2c(cn1C)N(C)C(=O)C(O)N=C2c1ccccc1Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1c2c(cn1C)N(C)C(=O)C(OC(=O)c1ccccc1)N=C2c1ccccc1Cl

Procedure:
A mixture of 5-(2-chlorophenyl)-1,7-dihydro-3-hydroxy-1,6,7-trimethyl-pyrrolo[3,4-e][1,4]diazepin-2(3H)-one (4.75 g, 0.0149 mole), benzoyl chloride (2.45 g, 0.0174 mole) and triethylamine (4.5 g, 0.0445 mole) in benzene (100 ml) is refluxed for about 2 hours. Benzene is then boiled off under vacuum and the residue is taken up with a small amount of water and filtered. The raw material thus obtained is crystallized from ethanol yielding 4.9 g of the compound of the title. M.p. 228°-29° C.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[O:14][CH3:15])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[O-:18][Mn](=O)(=O)=O.[K+]>O1CCOCC1>[C:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]([OH:18])=[O:11])=[CH:8][C:7]=1[O:14][CH3:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: COc1cc(C=O)ccc1OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cc(C(=O)O)ccc1OC(C)(C)C
Reaction time: 16 h
Yield: 48.9 %

Procedure:
4-tert-Butoxy-3-methoxybenzaldehyde (130 mg, 0.62 mmol) was suspended in a mixture of dioxane (520 μL) and potassium hydroxide (6.5 mL of 0.20 M, 1.3 mmol). KMnO4 (150 mg, 0.93 mmol) was added and the reaction was stirred vigorously for 16 hours. The reaction mixture was filtered and then concentrated in vacuo to 3 mL. Hydrochloric acid (1M, 4 mL) was added and the resulting precipitate was filtered and washed with 1M HCl and a small amount of water to yield 4-tert-butoxy-3-methoxy-benzoic acid (68 mg, 49%) as a white solid. ESI-MS m/z calc. 224.1. found 225.2 (M+1)+. Retention time: 1.66 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 12.80 (s, 1H), 7.66-7.41 (m, 2H), 7.09 (d, J=8.8 Hz, 1H), 3.78 (s, 3H), 1.32 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C@H:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:25][N:26]([CH3:30])[C:27](Cl)=[O:28]>CN(C=O)C>[CH3:25][N:26]([CH3:30])[C:27](=[O:28])[NH:14][C@H:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:15]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)[C@H](N)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)N[C@@H](C(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (R)-tert-butyl-2-amino-2-phenylacetate (1.0 g, 4.10 mmol) and Hunig's base (1.79 mL, 10.25 mmol) in DMF (40 mL) was added dimethylcarbamoyl chloride (0.38 mL, 4.18 mmol) dropwise over 10 minutes. After stirring at room temperature for 3 hours, the reaction was concentrated under reduced pressure and the resulting residue was dissolved in ethyl acetate. The organic layer was washed with H2O, 1N aq. HCl and brine, dried (MgSO4), filtered and concentrated under reduced pressure. (R)-tert-butyl 2-(3,3-dimethylureido)-2-phenylacetate was obtained as a white solid (0.86 g; 75%) and used without further purification. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.33 (s, 9H) 2.82 (s, 6H) 5.17 (d, J=7.63 Hz, 1H) 6.55 (d, J=7.32 Hz, 1H) 7.24-7.41 (m, 5H). LCMS: Anal. Calcd. for C15H22N2O3 278.16 found 279.23 (M+H)+. HPLC Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 4 minutes, 1 minutes hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, RT=2.26 min, 97% homogeneity index.
Reaction SMILES: Br.Br[CH2:3][C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5].[CH3:12][O:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([NH2:22])[CH:16]=1.C([O-])(O)=O.[Na+]>CCO>[CH3:12][O:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([NH:22][CH2:3][C:4](=[O:5])[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:16]=1
Reactant: O=C(CBr)c1cccnc1
Reactant: COC(=O)c1ccc(C)c(N)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1ccc(C)c(NCC(=O)c2cccnc2)c1
Reaction time: 2 h
Yield: 16.7 %

Procedure:
To a solution of 2-bromo-1-pyridin-3-yl-ethanone hydrobromide (Barlin, G. B. et al. Australian J. Chem, 1989, 1735) (500 mg, 1.78 mmol) in 2 ml of EtOH was added 3-amino-4-methyl-benzoic acid methyl ester (Lancaster; 294 mg, 1.78 mmol) and NaHCO3 (750 mg, 8.9 mmol), and the mixture was stirred for 2 h. The mixture was then filtered and washded with MeOH, then the filtrated was concentrated to a small volume and dissolved in EtOAc. The EtOAc slurry was washed with water and brine, and the washes were extracted once more with EtOAc. The combined organic portions were dried with Na2SO4, filtered, concentrated, and chromatographed (0-5% MeOH in dichloromethane) to provide 84.5 mg of 4-methyl-3-(2-oxo-2-pyridin-3-yl-ethylamino)-benzoic acid methyl ester.