Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C@@H:13]2[CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:12]2[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:24]([F:27])([F:26])[F:25])[C:6]=2[NH:5]1.Cl.F[C:30](F)(F)C1C2NC(=O)[C@@H]3CNC[C@@H]3C=2C=CC=1.IC>C1COCC1>[CH3:30][N:5]1[C:6]2[C:7]([C:24]([F:27])([F:25])[F:26])=[CH:8][CH:9]=[CH:10][C:11]=2[CH:12]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:14][CH:13]2[C:4]1=[O:3]
Reactant: O=C1Nc2c(cccc2C(F)(F)F)[C@H]2CNC[C@@H]12
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2c3cccc(C(F)(F)F)c3NC(=O)[C@@H]2C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CN1C(=O)C2CN(C(=O)OC(C)(C)C)CC2c2cccc(C(F)(F)F)c21
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (40 mg of 60% dispersion in mineral oil, 1.0 mmol) in 5 mL of THF was added (±)-cis-tert-butyl 4-oxo-6-(trifluoromethyl)-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]quinoline-2(9bH)-carboxylate, the intermediate from Example 3 (80 mg, 0.22 mmol) in 3 mL of THF. The mixture was stirred for 30 min and then there was added iodomethane (0.10 mL, 1.6 mmol) and the resulting mixture was allowed to stir at ambient temperature for 18 h. The reaction was filtered through a pad of silica gel and concentrated. The residue was purified by chromatography (ISCO, elution with 1-10% EtOAc in hexane) to afford tert-butyl 5-methyl-4-oxo-6-(trifluoromethyl)-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]quinoline-2(9bH)-carboxylate. To this material in 4 mL of hexane was added HCl (4 mL of a 4N solution in 1,4-dioxane, 16 mmol) and the resulting solution was allowed to stir at ambient temperature overnight. The solvents were removed in vacuo and the residue was purified by HPLC (C18 reverse phase, elution with gradient H2O/CH3CN+0.5% TFA). Pure fractions were combined and concentrated. The residue was partitioned between aq NH4OH and CHCl3, the organics were washed with brine, dried (K2CO3) and concentrated to afford 12 mg (60%) of the title compound of Example 4. 1H NMR (CDCl3): δ 7.60 (d, 1H), 7.42 (d, 1H), 7.18 (t, 1H), 3.81 (dd, 1H), 3.39 (s, 3H), 3.37-30 (m, 2H), 3.22-3.18 (m, 1H), 3.05-2.98 (m, 1H), 2.81 (t, 1H). LRMS (ESI): 271.16 (M+H)+.
Reaction SMILES: [ClH:1].Cl.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1.C([O-])(=O)C.[Na+].[Br:22]Br>C(O)(=O)C.O>[ClH:1].[Br:22][C:10]1[CH:9]=[CH:8][C:7]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:6][C:5]=1[O:4][CH3:3]
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(N2CCNCC2)ccc1Br
Reaction time: 1 h

Procedure:
To a solution of 2.33 g (8.8 mmol) of 1-(3-Methoxyphenyl)piperazine dihydrochloride and 756 mg (9.7 mmol) sodium acetate in 70 mL of acetic acid and 15 mL of water at 0° C. was added 1.55 g (9.7 mmol) bromine. After 1 hour, the reaction was concentrated to an oil in vacuo, and the oil was partitioned between ethyl acetate and 1M NaOH. The phases were separated, and the ethyl acetate phase was washed once each with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to an oil in vacuo. The oil was dissolved in a minimum volume of methanol, and the solution was acidified with 2M HCl in ether. The product was isolated by filtration. 1H NMR (D2O, 400 MHz) 7.36 (d, 1H), 6.73 (s, 1H), 6.50 (d, 1H), 3.75 (s, 3H), 3.32 (m, 8H) ppm.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]=[CH:3]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:33]1([C:39]2[CH:44]=[CH:43][N:42]=[C:41]([CH2:45][NH:46][CH2:47][CH2:48][CH3:49])[CH:40]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C)C=O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]([N:46]([CH2:45][C:41]2[CH:40]=[C:39]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:44]=[CH:43][N:42]=2)[CH2:47][CH2:48][CH3:49])=[O:9])[N:4]=[CH:3]1
Reactant: Cn1cnc(C(=O)O)c1
Reactant: CCCNCc1cc(-c2ccccc2)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCCN(Cc1cc(-c2ccccc2)ccn1)C(=O)c1cn(C)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 27.9 %

Procedure:
To a solution of methyl-1H-imidazole-4-carboxylic acid (53 mg) in dimethylformamide (1 mL) was added 1-hydroxybenzotriazole hydrate (HOBT.H2O) (64 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl) (81 mg) and the mixture was stirred at room temperature for 10 min. A solution of N-[(4-phenylpyridin-2-yl)methyl]propan-1-amine (80 mg) in dimethylformamide (2 mL) was added thereto, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure and then saturated aqueous sodium hydrogen carbonate solution was added, followed by extraction with ethyl acetate. The organic phase was collected and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (silica gel cartridge, chloroform:methanol=98:2-82:18) and (the same column, chloroform:methanol=100:0-90:10) to afford the title compound (33 mg).
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][C:7]([CH3:10])([CH3:9])[C:6]2[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:5]=2[NH:4][C:3]1=[O:18].Cl[C:20]([O:22][CH3:23])=[O:21]>>[CH3:23][O:22][C:20](=[O:21])[NH:1][CH:2]1[CH2:8][C:7]([CH3:10])([CH3:9])[C:6]2[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:5]=2[NH:4][C:3]1=[O:18]
Reactant: COC(=O)Cl
Reactant: CC1(C)CC(N)C(=O)Nc2cc([N+](=O)[O-])ccc21
Product: COC(=O)NC1CC(C)(C)c2ccc([N+](=O)[O-])cc2NC1=O

Procedure:
(5,5-Dimethyl-8-nitro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)-carbamic acid methyl ester was prepared from 3-Amino-5,5-dimethyl-8-nitro-1,3,4,5-tetrahydro-1-benzazepin-2-one and Methyl chloroformate in an analogous manner to Example 1271d. Title compound is an off white solid. (94 mg, 38%) LCMS 308 (M+H).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=O)[CH:3]=[CH:2]1.[NH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12]>C(O)(=O)C>[O:7]=[C:1]1[CH:2]=[CH:3][C:4](=[O:6])[N:8]1[CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: O=C1C=CC(=O)O1
Reactant: NCCC(=O)O
Solvent: CC(=O)O
Product: O=C(O)CCN1C(=O)C=CC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.6 %

Procedure:
A solution of maleic anhydride (5.00 g, 0.0561 mol) in acetic acid (70 ml) was added dropwise to a solution of β-alanine (5.50 g, 0.0561 mol) in acetic acid (25 ml) and the mixture was stirred at room temperature for three hours. 50 mL of acetic acid was added to the white suspension and the mixture heated up to 115° C. After 1 h a limpid colourless solution was observed. The mixture was then stirred at this temperature overnight and the colour turned to orange. The solvent was then removed under reduced pressure and 30 mL of toluene was then added to the resulting orange oil. This was then evaporated under reduced pressure and this operation was repeated 3 times. The orange residue was then purified by flash chromatography (CC, SiO2, CH2Cl2/ethyl acetate 9:1) to give the product as a white solid (3.86 g, 0.0228 mol, 41%). m.p. 105-107° C. IR (neat): 3092, 2883, 2537, 1695, 1445, 1411, 1373, 1337, 1305, 1230, 1151, 1081, 1043, 924, 830, 773, 694, 618 cm−1. 1H NMR (400.03 MHz, CDCl3, 298 K) δ=2.69 (t, J=7.3 Hz, 2H, CH2), 3.82 (t, J=7.3 Hz, 2H, CH2), 6.71 (s, 2H, CHvinyl) 10.07 (bs, 1H, COOH). 13C{1H} NMR (100.59 MHz, CDCl3, 298 K) δ=32.62 (1C, CH2), 33.36 (1C, CH2), 134.38 (2C, CHvinyl) 170.48 (1C, C), 176.64 (2C, C). Anal. Calcd. for C7H7NO4: C, 49.71; H, 4.17; N, 8.28. Found C, 49.35; H, 4.19; N, 7.95.
Reaction SMILES: [CH:1]1([C@H:7]([NH:11][NH:12][C:13](=[O:23])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=2[CH3:22])[CH2:8][CH:9]=[CH2:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].O.[CH3:31][C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([CH3:41])[CH:40]=1)[C:35](Cl)=[O:36]>C(Cl)Cl>[CH:1]1([C@H:7]([N:11]([C:35](=[O:36])[C:34]2[CH:38]=[C:39]([CH3:41])[CH:40]=[C:32]([CH3:31])[CH:33]=2)[NH:12][C:13](=[O:23])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=2[CH3:22])[CH2:8][CH:9]=[CH2:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Reactant: C=CC[C@@H](NNC(=O)c1cccc(OC)c1C)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: C=CC[C@H](C1CCCCC1)N(NC(=O)c1cccc(OC)c1C)C(=O)c1cc(C)cc(C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.6 %

Procedure:
To a solution of (R)-3-methoxy-2-methyl-benzoic acid N′-(1-cyclohexyl-but-3-enyl)-hydrazide (1.3 g, 4.11 mmol) in CH2Cl2 (5 mL), was added K2CO3 (2.27 g, 16.44 mmol), H2O (5 mL), and finally 3,5-dimethylbenzoyl chloride (727 mg, 4.31 mmol). The reaction was stirred at room temperature for 24 h. Additional CH2Cl2 and H2O were added to aid manipulation, the CH2Cl2 layer was separated, and the aqueous layer was extracted with CH2Cl2. The CH2Cl2 solutions were combined and dried over anhydrous Na2SO4. The solvent was evaporated in vacuo and the residue was purified by flash chromatography to provide (R)-3,5-dimethyl-benzoic acid N-(1-cyclohexyl-but-3-enyl)-N′-(3-methoxy-2-methyl-benzoyl)-hydrazide as a white solid (1.45 g, 78% yield). Rf=0.21 (3:1 EtOAc:n-Hexane); 1H NMR (400 MHz, DMSO-d6) δ 10.47+10.39 (2 s, 1H), 7.20-7.01 (m, 5H), 6.37 (d, J=7.2 Hz, 1H), 6.22-5.89 (m, 1H), 5.18 (dd, 1H), 5.02 (dd, 1H), 4.46 (m, 1H), 3.79 (s, 3H), 2.44-2.34 (m, 2H), 2.29 (s, 3H), 2.02-1.53 (m, 8H), 1.26-1.02 (m, 3H); HRMS (ESI) m/z calcd for C28H37N2O3 [M+H]+ 449.2804, found 449.2793, calcd for C28H36N2NaO3 [M+Na]+ 471.2624, found 471.2615.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([O:9][CH3:10])[C:3]=1[O:11][CH3:12].[Cl-].[Al+3].[Cl-].[Cl-].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24].O>C(Cl)Cl>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([C:7]1[CH:6]=[C:5]([CH3:8])[C:4]([O:9][CH3:10])=[C:3]([O:11][CH3:12])[C:2]=1[CH3:1])=[O:24]
Reactant: COc1c(C)ccc(C)c1OC
Reactant: O=C(Cl)CCCCCBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COc1c(C)cc(C(=O)CCCCCBr)c(C)c1OC
Temperature: 0 °C
Reaction time: 19 h
Yield: 45.6 %

Procedure:
A solution of 0.227 g (1.5 mmol) of 3,6-dimethylveratrole in 1 mL of methylene chloride was added to an ice cooled mixture of 0.245 g (1.8 mmol) of aluminum chloride and 0.416 g (1.9 mmol) of 6-bromohexanoyl chloride in 3 mL of methylene chloride. The reaction mixture was kept at 0° for 19 hours. Water was added and the organic layer was separated and washed with sodium bicarbonate solution. The dried extract was concentrated to an oil which was chromatographed on 60 g of silica gel using 10% ethyl acetate-hexane to give 0.235 g of 6-bromo-1-(3,4-dimethoxy-2,5-dimethylphenyl)-1-hexanone as an oil. The nmr spectrum was consistent with the structure and the mass spectrum gave the molecular ion at m/z 342 (C16H23BrO3)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[CH:5]=[CH:4][N:3]=1.OS(O)(=O)=O.[Br:16]N1C(=O)CCC1=O>CC(=O)OCC>[Br:16][C:5]1[C:6]([O:8][CH2:9][CH3:10])=[CH:7][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOc1ccnc(Cl)c1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOc1cc(Cl)ncc1Br
Temperature: 80 °C
Reaction time: 3 h
Yield: 41.3 %

Procedure:
2-Chloro-4-ethoxypyridine (100 g, 0.63 mol) was added to H2SO4 (500 mL) slowly. Then 1-bromopyrrolidine-2,5-dione (124.2 g, 0.70 mol) was added into above mixture at rt. The mixture was stirred at 80° C. for 3 h. TLC (PE/EA=10:1, Rf=0.5) showed the reaction was finished. The reaction mixture was poured into ice-water (2 L), and extracted with EA (1 L×3). The organic layer was washed with saturated Na2CO3 solution (1 L×2), dried over Na2SO4 and concentrated. The residue was purified by silica column chromatography (PE/EA=60:1-30:1). All fractions found to contain product by TLC (PE/EA=10:1, Rf=0.5) were combined and concentrated to yield 5-bromo-2-chloro-4-ethoxypyridine (60.9 g, 0.26 mol, 40% yield): 1H NMR (400 MHz, CD3OD) δ 8.31 (s, 1H), 7.14 (s, 1H), 4.32-4.10 (m, 2H), 1.58-1.35 (m, 3H); ES-LCMS m/z 237 (M+2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[CH2:11]([NH:15][CH2:16][C:17](O)=[O:18])[CH2:12][CH2:13][CH3:14].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:11]([N:15]1[CH2:16][C:17](=[O:18])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:9]1=[S:10])[CH2:12][CH2:13][CH3:14]
Reactant: Fc1ccc(N=C=S)cc1
Reactant: CCCCNCC(=O)O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCN1CC(=O)N(c2ccc(F)cc2)C1=S
Yield: 44.1 %

Procedure:
The title compound was prepared by the procedure described in Example 54 using 7.7 g of 4-fluorophenyl-isothiocyanate, 12.0 g of N-butyl glycine, 15.0 g of triethyl amine, and 250 mL of chloroform. Crystallization from ethanol afforded the title compound (5.9 g) as an off-white solid, m.p. 92°-93° C. Anal. Calcd. for. C13H15F N2O S: C, 58.62; H, 5.68; N, 10.52. Found: C, 58.23; H, 5.65; N, 10.56. Mass spectrum (EI, M.+) m/z 266.
Reaction SMILES: [C:1]([N+:4]1([O-:26])[CH2:9][CH2:8][C:7](=[C:10]2[C:16]3=[N:17][CH:18]=[C:19](Cl)[CH:20]=[C:15]3[CH2:14][CH2:13][C:12]3[CH:22]=[CH:23][CH:24]=[CH:25][C:11]2=3)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl[C:28]1[CH:29]=CC2C(=C3CCN(C(=O)C)CC3)C3NC(=O)C=CC=3CC[C:32]=2[CH:52]=1>>[C:1]([N+:4]1([O-:26])[CH2:9][CH2:8][C:7](=[C:10]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[CH2:14][CH2:13][C:12]3[CH:22]=[C:23]4[C:24](=[CH:25][C:11]2=3)[CH:32]=[CH:52][CH:28]=[CH:29]4)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)[N+]1([O-])CCC(=C2c3ccccc3CCc3cc(Cl)cnc32)CC1
Reactant: CC(=O)N1CCC(=C2c3ccc(Cl)cc3CCc3ccc(=O)[nH]c32)CC1
Product: CC(=O)[N+]1([O-])CCC(=C2c3cc4ccccc4cc3CCc3cccnc32)CC1

Procedure:
1-acetyl-4-(3-chloro-5,6-dihydro-11 H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine N-oxide, i.e., ##STR9## 8-chloro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-2(1 H)-one;
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C(O)C.[CH2:15]([NH:17]CC)C.[CH3:20][CH2:21][CH2:22][CH2:23]CC.C(O)C>>[CH:8]1([N:3]2[CH2:4][CH2:5][CH2:15][NH:17][CH2:2][CH2:1]2)[C:7]2[C:20](=[CH:21][CH:22]=[CH:23][CH:6]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: CCCCCC
Reactant: CCNCC
Solvent: CCO
Product: c1ccc2c(c1)CCCC2N1CCCNCC1

Procedure:
R(−) N-(1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine was obtained as the second material to elute on subjecting racemic material (5.3 g), prepared as in Example 2, to preparative Chiral Pak AD HPLC resolution using a hexane/ethanol mixture with modification with diethylamine. The enantiomeric purity was determined on an analytical scale using hexane:ethanol:diethylamine (90:5:.05, v/v) and detection at 220 nm. The solution containing this enantiomer was concentrated using a rotary evaporator to give the title compound (2.65 g), [α]D22−94° (c=0.64, methanol); 98.5% ee.
Reaction SMILES: [Si](Cl)(Cl)(Cl)Cl.[N-:6]=[N+:7]=[N-:8].[Na+].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([NH2:20])=O)=[CH:13][CH:12]=1>C(#N)C>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[N:6]=[N:7][NH:8][N:20]=2)=[CH:13][CH:12]=1
Reactant: [N-]=[N+]=[N-]
Reactant: NC(=O)Cc1ccc(Br)cc1
Agent: Cl[Si](Cl)(Cl)Cl
Agent: [Na+]
Solvent: CC#N
Product: Brc1ccc(Cc2nn[nH]n2)cc1
Temperature: 85 °C
Yield: 75.3 %

Procedure:
Stir a mixture of SiCl4 (1.7 g, 10 mmol, 2 eq.) and NaN3 (1.95 g, 30 mmol, 6 eq.) in 50 mL of acetonitrile for 2 hours. Add 1.07 g of 2-(4-bromophenyl) acetamide (5 mmol, 1 eq.) and heat to 85° C. for 5 hour. Cool to room temperature and filter off the solid wash the solid with EtOAc. Wash the ester layer with water, saturated aq. sodium chloride, dry over MgSO4 and evaporate the solvent to afford 900 mg title compound (80%). MS (m/e): 237.0.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[NH:10][C@@H:11]([CH3:14])[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:13][CH2:12][C@@H:11]([NH:10][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:15])[CH3:14])(=[O:26])=[O:25]
Reactant: C[C@@H](CO)NC(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](COS(C)(=O)=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.6 %

Procedure:
A solution of (S)-benzyl(1-hydroxypropan-2-yl)carbamate (400 g, 1.91 mol) and triethylamine (270 g, 2.67 mol) in methylene chloride (2.4 L) was cooled to 0° C. To this mixture was added methanesulfonyl chloride (263 g, 2.30 mol) at an internal temperature of 5° C. or below. Subsequently, the resulting reaction mixture was stirred at room temperature for 16 hours. After confirming the disappearance of the starting materials by TLC, to the reaction mixture was added purified water. The resulting organic layer was partitioned, washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the target product as a yellow solid (519 g, yield 94.5%).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([CH:13]([OH:15])[CH3:14])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:16]1[N:20]=[CH:19][N:18]([C:21](N2C=NC=C2)=[O:22])[CH:17]=1>C(#N)C>[N:18]1([C:21]([O:15][CH:13]([C:10]2[CH:11]=[N:12][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][CH:9]=2)[CH3:14])=[O:22])[CH:17]=[CH:16][N:20]=[CH:19]1
Reactant: CC(O)c1ccc(-c2ccccc2)nc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: CC(OC(=O)n1ccnc1)c1ccc(-c2ccccc2)nc1

Procedure:
Synthesized using compound 45a (170 mg, 0.85 mmol), CDI (692 mg, 4.27 mmol) and acetonitrile (10 mL) according to Method E. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (2:1) as eluent. White solid. Yield: 107 mg, 43%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=1.82 (d, J=6.9 Hz, 3H), 6.16 (q, J=6.6 Hz, 1H), 7.08 (dd, J=1.7, 0.8 Hz, 1H), 7.41-7.53 (m, 4H), 7.76-7.85 (m, 2H), 7.98-8.03 (m, 2H), 8.17 (d, J=1.3 Hz, 1H), 8.78 (d, J=1.9 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=21.5, 74.9, 117.1, 120.4, 126.9, 128.8, 129.3, 130.8, 133.3, 134.7, 137.0, 138.6, 147.9, 148.0, 158.0; MS (ESI): m/z=294.28 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH:7]([O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH2:6][N:5]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:4]1.Cl[C:25]1[C:34]2[C:29](=[N:30][CH:31]=[CH:32][N:33]=2)[CH:28]=[C:27]([Cl:35])[N:26]=1.CCN(C(C)C)C(C)C>C1COCC1>[Si:10]([O:9][CH:7]1[CH2:8][CH:3]([CH2:2][NH:1][C:25]2[C:34]3[C:29](=[N:30][CH:31]=[CH:32][N:33]=3)[CH:28]=[C:27]([Cl:35])[N:26]=2)[CH2:4][N:5]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:6]1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC(CN)CC(O[Si](C)(C)C(C)(C)C)C1
Reactant: Clc1cc2nccnc2c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(CNc2nc(Cl)cc3nccnc23)CC(O[Si](C)(C)C(C)(C)C)C1

Procedure:
A solution of tert-butyl 3-(aminomethyl)-5-(tert-butyldimethylsilyloxy)piperidine-1-carboxylate (4.74 g, 13.7 mmol), 5,7-dichloropyrido[4,3-b]pyrazine (2.75 g, 13.7 mmol) and DIPEA (2.12 g, 16.4 mmol) in THF (20 mL) was stirred at room temperature for 48 hours. The volatiles were removed under reduced pressure and the residue was treated with ethyl acetate, washed with brine, dried over Na2SO4, filtered, and concentrated to give the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[CH3:32].Cl>C(O)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=4[CH3:32])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1cc(C(=O)O)ccc1N
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cl
Solvent: CCO
Product: Cc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Yield: 23.9 %

Procedure:
A mixture of 1.0 g (3.15 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-20), 0.572 g (3.78 mmole) of 4-amino-3-methylbenzoic acid, 10 mL of ethanol and 40 mL of 1M hydrochloric acid was heated at reflux for 14 hours. The mixture was cooled and the white precipitate was collected by filtratration, washed with cold water and dried in vacuum to give 0.3251 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methyl-benzoic acid (I-184) as off-white solid.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([CH2:22][N:23]2C[CH:25]([C:27]([OH:29])=[O:28])[CH2:24]2)[CH:16]=[C:15]3[CH:30]2[CH2:32][CH2:31]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C([C@H]1CC[C@H](OC2C=C3C(=CC=2)N=C(CNCCC(O)=O)C=C3C)CC1)(C)(C)C>>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([CH2:22][NH:23][CH2:24][CH2:25][C:27]([OH:29])=[O:28])[CH:16]=[C:15]3[CH:30]2[CH2:31][CH2:32]2)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3nc(CN4CC(C(=O)O)C4)cc(C4CC4)c3c2)CC1
Agent: Cc1cc(CNCCC(=O)O)nc2ccc(O[C@H]3CC[C@H](C(C)(C)C)CC3)cc12
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3nc(CNCCC(=O)O)cc(C4CC4)c3c2)CC1

Procedure:
Synthesized as per 1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-cyclopropyl-quinolin-2-ylmethyl]-azetidine-3-carboxylic acid using the appropriate intermediate available from the synthesis of 3-{[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-methyl-quinolin-2-ylmethyl]-amino}-propionic acid.) ESI-MS(M+H+): 425.3; 1H NMR (400 MHz, METHANOL-d4) Shift 8.00 (d, J=9.29 Hz, 1H), 7.72 (d, J=2.51 Hz, 1H), 7.43 (dd, J=2.64, 9.16 Hz, 1H), 7.14 (s, 1H), 4.50 (s, 2H), 4.40-4.49 (m, 1H), 3.44 (t, J=6.78 Hz, 2H), 2.87 (t, J=6.65 Hz, 2H), 2.44-2.54 (m, 1H), 2.32 (d, J=11.04 Hz, 2H), 1.91-1.99 (m, 2H), 1.42-1.54 (m, 2H), 1.21-1.36 (m, 4H), 1.07-1.21 (m, 1H), 0.94 (s, 9H), 0.84-0.92 (m, 2H).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12](S(O)(=O)=O)=[CH:11][CH:10]=1>O1CCCC1.CN(C)C=O>[CH2:1]([O:8][CH2:19][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCc1ccccc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: c1ccc(COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In a manner similar to that described in Example I, 0.68 ml of benzyl alcohol and 7 mg of p-toluenesulfonic acid are added to a solution of 350 mg of Compound Z-1(DMTD) in a mixture of 7 ml of tetrahydrofuran and 3 ml of dimethylformamide and the mixture stirred at room temperature for 24 hours. At the end the volatiles are removed in vacuo to obtain a residue which is purified on a preparative HPLC column using water/acetonitrile (40/60) as eluant. The appropriate fractions are combined and lyophilized to obtain benzyl ether of Z-1(DMTD).
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5]([Cl:6])=[N:4][C:2]=1[Cl:3].C(=O)(O)[O-].[K+].[CH:15]1([CH2:21][OH:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>C1(C)C=CC=CC=1.C1OCCOCCOCCOCCOCCOC1>[Cl:3][C:2]1[N:4]=[C:5]([Cl:6])[N:7]=[C:8]([O:22][CH2:21][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:1]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: OCC1CCCCC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Product: Clc1nc(Cl)nc(OCC2CCCCC2)n1
Yield: 99.4 %

Procedure:
To cyanuric chloride (3.76 g, 20.0 mmol) dissolved in toluene (20 mL) was added potassium bicarbonate (2.80 g, 20.0 mmol) and 18-crown-6 (0.1614 g, 0.6 mmol) followed by dropwise addition of cyclohexylmethanol (2.5 mL, 20 mmol) in 15 mL of toluene (15 mL). The reaction mixture was allowed to stir at reflux for about 18 hours under nitrogen. The reaction mixture was passed through a plug of Celite and concentrated using a rotary evaporator and dried over night under vacuum to give 113 as an oil (5.212 g, 99% recovery).