Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26]([OH:28])=O)=[CH:21][CH:20]=[CH:19]2.[F:29][C:30]([F:40])([F:39])[C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[C:33]([NH2:38])[CH:32]=1>>[NH2:38][C:33]1[CH:32]=[C:31]([C:30]([F:29])([F:39])[F:40])[CH:36]=[CH:35][C:34]=1[NH:37][C:26]([C:22]1[C:23]2[C:18](=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:25][CH:24]=2)[CH:19]=[CH:20][CH:21]=1)=[O:28]
Reactant: Nc1ccc(C(F)(F)F)cc1N
Reactant: COc1cc2ncnc(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Product: COc1cc2ncnc(Oc3ccc4c(C(=O)Nc5ccc(C(F)(F)F)cc5N)cccc4c3)c2cc1OC
Yield: 79.1 %

Procedure:
The title compound (42.3 mg, 79% yield) was prepared as a brown solid from 6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthoic acid (37.6 mg, 0.1 mmol) and 4-trifluoromethyl-o-phenylenediamine (21.1 mg, 0.12 mmol) by an analogous procedure to that described in example 16. 1H NMR (DMSO-d6) δ 4.01 (s, 6H, 2×OCH3), 5.72 (s, 2H, benzene-NH2), 6.92 (d, J=8.5 Hz, 1H, Ar—H), 7.42 (s, 1H, Ar—H), 7.59-7.65 (m, 3H, Ar—H), 7.90-7.96 (m, 2H, Ar—H), 7.98 (s, 1H, Ar—H), 8.10 (d, J=8.3 Hz, 1H, Ar—H), 8.17 (d, J=7.3 Hz, 1H, Ar—H), 8.39 (d, J=9.2 Hz, 1H, Ar—H), 8.54 (s, 1H, Ar—H), 9.90 (s, 1H, benzene-NH). LC-MS (m/z) 535 (M+1).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[C:3]#[N:4].CN1CC[O:11][CH2:10][CH2:9]1.O1C=[C:17]([C:19](Cl)=[O:20])[N:16]=[N:15]1>ClCCl>[C:3]([C:2]([NH:1][C:19]([C:17]1[O:11][C:10]([CH3:9])=[N:15][N:16]=1)=[O:20])([CH3:6])[CH3:5])#[N:4]
Reactant: CN1CCOCC1
Reactant: CC(C)(N)C#N
Reactant: O=C(Cl)c1conn1
Solvent: ClCCl
Product: Cc1nnc(C(=O)NC(C)(C)C#N)o1

Procedure:
2-Amino-2-methylpropanenitrile (90 gms) was suspended in dichloromethane (90 ml) and N-methyl morpholine (1.10 moles) was added with stirring. A mixture of oxadiazole carbonyl chloride (90 gms) in dichloromethane (100 ml) was added drop wise to the suspension at 0 to 5° C. The reaction mixture was stirred and monitored by thin layer chromatography (TLC). The reaction mass was concentrated under reduced pressure after completion of reaction. The product separated out on addition of isopropyl alcohol (500 ml), which was then filtered and dried.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][N:10]([CH2:14][CH:15]=[CH2:16])[C:9]=2[C:8](=[O:17])[NH:7][C:6]1=[O:18])[CH2:2][CH2:3][CH3:4].C1C(=O)N([Cl:26])C(=O)C1>CN(C=O)C>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:26])[N:10]([CH2:14][CH:15]=[CH2:16])[C:9]=2[C:8](=[O:17])[NH:7][C:6]1=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: C=CCn1cnc2c1c(=O)[nH]c(=O)n2CCCC
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCC
Temperature: 25 °C
Reaction time: 22 h
Yield: 63.9 %

Procedure:
To a solution of 3-butyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (3.34 g, 13.4 mmol) in anhydrous DMF (19 ml) was added NCS (1.97 g, 14.8 mmol) and left to stir at rt under nitrogen for 22 hours. The mixture was concentrated in vacuo to give a yellow solid which was filtered and washed with methanol. The filtrate was concentrated and the process repeated. On the final wash the filtrate was purified by SPE (Si, 20 g) cartridge eluting with 1:1; EtOAc:cyclohexane. The combined solids were dried under vacuum to afford the title compound (2.42 g, 64%); m/z 283.3 [MH+]
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][O:13][CH3:14])=[CH:7][C:6]=1[C:15]1[CH2:16][C:17]([Br:23])([CH:21]=[O:22])[CH:18]=[CH:19][CH:20]=1)C.[OH-].[K+].CCOC(C)=O>CO.O.Cl>[Br:23][C:17]1([CH:21]=[O:22])[CH:18]=[CH:19][CH:20]=[C:15]([C:6]2[CH:7]=[C:8]([O:11][CH2:12][O:13][CH3:14])[CH:9]=[CH:10][C:5]=2[C:4]([OH:24])=[O:3])[CH2:16]1
Reactant: CCOC(=O)c1ccc(OCOC)cc1C1=CC=CC(Br)(C=O)C1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: COCOc1ccc(C(=O)O)c(C2=CC=CC(Br)(C=O)C2)c1
Reaction time: 8 h

Procedure:
To a suspension of 3-bromo-3-formylphenyl-4-methoxymethoxybenzoic acid ethyl ester (1.4 g, 3.56 mmol) in 10 mL MeOH/20 mL H2O was added solid KOH (220 mg, 3.91 mmol). The reaction mixture was refluxed for 3 hours then additional solid KOH (23 mg, 0.42 mmol) was added and the temperature of the reaction was lowered to ca 50° C. after which point the reaction was stirred overnight. The workup of the reaction consisted of diluting with water and acidifying with 2N HCl to pH 1 then extracting with EtOAc (3×). The combined organic layers were dried over Na2SO4 then the solvent was removed in vacuo to give a beige solid. This solid was subjected to flash chromatography (50% EtOAc: 50% Hexanes to 100% EtOAc) to give the desired acid as a beige solid plus a fraction that contained starting ester and desired acid. This fraction was rechromatographed to give more acid for a total yield of 920 mg, 70.7%. 1H NMR (CDCl3+DMSO-d6) δ 2.91 (s, 3H); 4.67 (s, 2H); 5.2–6.6 (bs, 1H); 7.26 (t, J=8.18 Hz, 1H); 7.67 (d, J=8.18 Hz, 1H); 7.73 (d, J=8.18 Hz, 1H); 7.83–7.90 (m, 2H); 8.11 (d, J=1.64 Hz, 1H); 9.90 (s, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]([CH3:7])[CH3:6].[OH:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].C1CCN2C(=NCCC2)CC1>CC#N>[CH3:6][C:5]([CH3:7])=[CH:4][CH2:3][CH2:2][O:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)NO
Reactant: CC(C)=CCCBr
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)=CCCONC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.8 %

Procedure:
To a solution of 5-bromo-2-methylpent-2-ene (1.33 mL, 10.0 mmol) in CH3CN (25 mL) was added tert-butyl hydroxycarbamate (2.0 g, 15.0 mmol) and DBU (4.5 mL, 30 mmol) at 0° C. and the reaction mixture stirred at r.t. for overnight. Quenched with saturated NH4Cl solution and extracted with brine. Combined organic layers washed with brine and dried over anhydrous Na2SO4, filtered and concentrated to provide yellow oil, which was purified by flash chromatography (50% EtOAc-hexane) to yield tert-butyl 4-methylpent-3-enyloxycarbamate (750 mg, 70%) as a viscous oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.40 (s, 9H) 1.54 (s., 3H) 1.61 (s., 3H) 2.21-2.31 (m, 2H) 3.70-3.78 (m, 2H) 5.02-5.10 (m, 1H). MS (ES) [M+H] calculated for C11H22NO3, 216.15; found 216.10.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([O:17][CH2:18][CH2:19][OH:20])[CH2:14][CH2:13][CH2:12][C:11]([CH3:16])([CH3:15])[CH2:10]2)[C:6]=1[CH3:7].[H-].[Na+].[CH3:23]I>CN(C)C=O.CCOCC>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([O:17][CH2:18][CH2:19][O:20][CH3:23])[CH2:14][CH2:13][CH2:12][C:11]([CH3:15])([CH3:16])[CH2:10]2)[C:6]=1[CH3:7]
Reactant: CI
Reactant: Cc1c(Br)cnn1CC1(OCCO)CCCC(C)(C)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COCCOC1(Cn2ncc(Br)c2C)CCCC(C)(C)C1
Reaction time: 0.5 h

Procedure:
To a solution of EXAMPLE 180B (2.2 g) in N,N-dimethylformamide (20 mL) was added sodium hydride (0.38 g). After stirring for 30 minutes, methyl iodide (0.60 mL) was added. The reaction mixture was stirred for 2 hours at room temperature, diluted with ether (100 mL) and washed with water (2×75 mL) and brine (75 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with a gradient of 3% to 25% ethyl acetate/hexanes provided the title compound.
Reaction SMILES: C(C1(COC2C(C3CC3)=CC(C(OC(C)(C)C)=O)=C(F)C=2)CCCCC1)#N.[C:28]12([CH2:38][O:39][C:40]3[C:52]([CH:53]4[CH2:56][CH2:55][CH2:54]4)=[CH:51][C:43]([C:44]([O:46]C(C)(C)C)=[O:45])=[C:42]([F:57])[CH:41]=3)[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2>>[C:28]12([CH2:38][O:39][C:40]3[C:52]([CH:53]4[CH2:54][CH2:55][CH2:56]4)=[CH:51][C:43]([C:44]([OH:46])=[O:45])=[C:42]([F:57])[CH:41]=3)[CH2:29][CH:30]3[CH2:31][CH:32]([CH2:33][CH:34]([CH2:36]3)[CH2:35]1)[CH2:37]2
Reactant: CC(C)(C)OC(=O)c1cc(C2CCC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Agent: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2(C#N)CCCCC2)cc1F
Product: O=C(O)c1cc(C2CCC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F

Procedure:
Following the procedure as described in Example 373 Step 2 making non-critical variations to replace tert-butyl 4-((1-cyanocyclohexyl)methoxy)-5-cyclopropyl-2-fluorobenzoate with tert-butyl 4-(adamantan-1-ylmethoxy)-5-cyclobutyl-2-fluorobenzoate, the title compound was obtained as a yellow solid (0.65 g, 76%). The solid was carried forward without further purification and analytical characterization.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]#[N:20])=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][C:7]([CH3:15])([CH3:14])[C:8]([NH:10][CH2:11][CH2:12][CH3:13])=[O:9].O=[C:22]([CH2:28][CH3:29])[CH2:23][C:24]([O:26][CH3:27])=[O:25]>>[NH2:20][C:19]1[C:3]2[C:2](=[CH:18][CH:17]=[CH:16][C:4]=2[O:5][CH2:6][C:7]([CH3:15])([CH3:14])[C:8](=[O:9])[NH:10][CH2:11][CH2:12][CH3:13])[N:1]=[C:22]([CH2:28][CH3:29])[C:23]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: CCC(=O)CC(=O)OC
Reactant: CCCNC(=O)C(C)(C)COc1cccc(N)c1C#N
Product: CCCNC(=O)C(C)(C)COc1cccc2nc(CC)c(C(=O)OC)c(N)c12

Procedure:
Prepared as in Example 2a from 3-(3-amino-2-cyanophenoxy)-2,2-dimethyl-N-propylpropan-amide (Tachdjian, C. et al. PCT Int. Appl. 2008, WO 2008154221) and methyl 3-oxopentanoate as a yellow solid (17%). 1H NMR (400 MHz, DMSO-d6) δ 0.75 (t, J=8.0 Hz, 3H), 1.17 (t, J=8.0 Hz, 3H), 1.26 (s, 6H), 1.40 (m, 2H), 2.84 (q, J=8.0 Hz, 2H), 3.04 (q, J=8.0 Hz, 2H), 3.85 (s, 3H), 4.13 (s, 2H), 6.88 (d, J=8.0 Hz, 1H), 7.27 (dd, J=8.0 Hz, 1H), 7.51 (t, J=8.0 Hz, 1H), 7.81 (m, 3H). MS 388 (MH+).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[N:7]=1)=[O:5].[CH3:13][O:14][C:15]([C@H:17]1[CH2:22][CH2:21][C@H:20]([C:23](Cl)=[O:24])[CH2:19][CH2:18]1)=[O:16].C(N(CC)CC)C>C(#N)C>[CH3:13][O:14][C:15]([C@H:17]1[CH2:22][CH2:21][C@H:20]([C:23](=[O:24])[NH:2][CH2:3][C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[N:7]=2)=[O:5])[CH2:19][CH2:18]1)=[O:16]
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)Cl)CC1
Reactant: NCC(=O)c1cccc(Br)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)[C@H]1CC[C@H](C(=O)NCC(=O)c2cccc(Br)n2)CC1

Procedure:
To a suspension of 2-amino-1-(6-bromopyridin-2-yl)ethanone hydrochloride (10.00 g, 39.8 mmol) obtained in Step 1, trans-4-chlorocarbonylcyclohexanecarboxylic acid methyl ester (9.00 g, 44.0 mmol) in acetonitrile (200 ml), a solution of triethylamine (13.9 ml, 100 mmol) in acetonitrile (60 ml) was added dropwise while ice-cooled for 2 hours. After the reaction solution was concentrated, water was added and extracted with ethyl acetate. The organic layer was sequentially washed with 10% aqueous citric acid, a saturated aqueous sodium bicarbonate, a saturated brine and dried over magnesium sulfate. After concentrated, the residue was purified by flash chromatography on silica gel (n-hexane:ethyl acetate=1:2) and the title compound (7.38 g, 48%) was obtained.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1NC.Cl[C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][N:17]=1.[CH:26]([N:29](CC)C(C)C)(C)C.CS(C)=O>C(OCC)(=O)C>[CH3:23][O:22][C:20](=[O:21])[C:19]1[CH:24]=[CH:25][C:16]([NH:29][CH2:26][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:17][CH:18]=1
Reactant: CNc1c(-c2ccccc2)noc1C
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(NCc2c(-c3ccccc3)noc2C)nc1
Temperature: 160 °C
Yield: 46.1 %

Procedure:
A mixture of (5-methyl-3-phenyl-4-isoxazolyl)-methylamine (200 mg, 1.06 mmol), methyl 6-chloronicotinate (182 mg, 1.06 mmol), N,N-diisopropyl ethyl amine (364 μL, 2.13 mmol) and DMSO (2 mL) was heated in the microwave to 160° C. for 0.5 h. It was diluted with ethyl acetate (8 mL) and washed with aqueous sodium carbonate (saturated, 8 mL), water (8 mL) and brine (8 mL). The combined aqueous layers were extracted with ethyl acetate (10 mL) and the combined organic layers were dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 50:50) afforded the title compound (158 mg, 46%) as a light yellow oil. MS: m/e=324.3 [M+H]+.
Reaction SMILES: [Cl-].[Li+].C[C:4](P(OC)(O)=O)([C:6]([O-:8])=[O:7])C.[CH2:14]1CCN2C(=NCCC2)CC1.[F:25][C:26]([F:38])([F:37])[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=1)=O>CC#N>[F:25][C:26]([F:38])([F:37])/[C:27](/[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=1)=[CH:4]\[C:6]([O:8][CH3:14])=[O:7]
Reactant: COc1cccc(C(=O)C(F)(F)F)c1
Reactant: C1CCC2=NCCCN2CC1
Reactant: COP(=O)(O)C(C)(C)C(=O)[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Product: COC(=O)/C=C(/c1cccc(OC)c1)C(F)(F)F
Reaction time: 8 h
Yield: 97.6 %

Procedure:
To a suspension of lithium chloride (0.623 g, 14.7 mmol) in MeCN (20 mL), were added trimethylphosphonoacetate (available from Aldrich) (1.70 mL, 11.8 mmol), DBU (1.76 mL, 11.8 mmol), and 2,2,2-trifluoro-1-(3-methoxyphenyl)ethanone (available from Oakwood Products Inc.) (2.0 g, 9.80 mmol) at room temperature. The pale yellow mixture was heated to reflux and stirred overnight. The mixture was partitioned between water and EtOAc. The layers were separated, and the aqueous phase was extracted with additional EtOAc. The combined organic layers were washed with 1 N HCl and brine, dried over Na2SO4, and concentrated. The crude product was purified by silica gel flash chromatography (0-10% EtOAc/hexane) to afford 6.1 (2.49 g, 97.7% yield) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:6]([N:7]([CH2:13][C:14]#[CH:15])[C:8](=[O:12])[CH2:9][NH:10][CH3:11])=[CH:5][N:4]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:6]([N:7]([CH2:13][C:14]#[CH:15])[C:8](=[O:12])[CH2:9][N:10]([CH3:11])[S:23]([CH3:22])(=[O:25])=[O:24])=[CH:5][N:4]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: C#CCN(C(=O)CNC)c1cn(-c2cccnc2)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C#CCN(C(=O)CN(C)S(C)(=O)=O)c1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.3 %

Procedure:
To a solution of N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-2-(methylamino)-N-(prop-2-yn-1-yl)acetamide (0.100 g, 0.329 mmol) in DCM (0.65 ml) was added methanesulfonyl chloride (0.057 g, 0.494 mmol) followed by diisopropylethylamine (0.11 ml, 0.658 mmol) and the reaction was stirred at room temperature for 24 h. The reaction mixture was poured into a solution of saturated NaHCO3 and subsequently extracted with DCM. The organic layers were combined and concentrated, and the residue was purified using silica gel chromatography (50-100% EtOAc/hexanes) to afford the title compound as a yellow solid (0.091 g, 0.238 mmol, 72%): (IR thin film) 1678 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.97 (d, J=2.6 Hz, 1H), 8.65 (dd, J=4.8, 1.3 Hz, 1H), 8.15 (s, 1H), 8.04 (ddd, J=8.3, 2.7, 1.4 Hz, 1H), 7.48 (dd, J=8.4, 4.7 Hz, 1H), 3.77 (hept, J=6.9 Hz, 2H), 3.05 (s, 2H), 3.01 (s, 3H), 2.87 (s, 3H), 2.31 (t, J=2.5 Hz, 1H); ESIMS m/z 382 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:22](=[O:23])[NH:21][CH2:20][CH2:19][C:6]3=[C:7]([C:11]4[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=4)[CH:14]=O)[NH:8][C:9]([CH:10]=1)=[C:5]23.C1([C:30]2[NH:31]C3C=CC=C4C(=O)NCCC=2C=34)C=CC=CC=1.BrC1NC2C=C(F)C=C3C(=O)NCCC=1C=23.C(C1C=C(B(O)O)C=CC=1)=O.CN>>[F:1][C:2]1[CH:3]=[C:4]2[C:22](=[O:23])[NH:21][CH2:20][CH2:19][C:6]3=[C:7]([C:11]4[CH:18]=[CH:17][CH:16]=[C:13]([CH2:14][NH:31][CH3:30])[CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23
Reactant: O=Cc1cccc(-c2[nH]c3cc(F)cc4c3c2CCNC4=O)c1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Agent: CN
Agent: O=C1NCCc2c(Br)[nH]c3cc(F)cc1c23
Agent: O=Cc1cccc(B(O)O)c1
Product: CNCc1cccc(-c2[nH]c3cc(F)cc4c3c2CCNC4=O)c1

Procedure:
3-(8-fluoro-6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)-benzaldehyde (247 mg, 0.80 mmol; prepared in a manner similar to that described for compound 12 from 2-bromo-8-fluoro-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one and 3-formylphenylboronic acid) was reacted with methylamine (4.91 mmol) as described for Compound PPP to yield 8-fluoro-2-(3-methylaminomethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 193 mg (74%) as an off-white solid: m.p. 270-272° C. (dec); 1H NMR (300 MHz, d6-DMSO) δ 2.34 (s, 3H), 3.05 (m, 2H), 3.39 (m, 2H), 3.78 (s, 2H), 7.42 (m, 5H), 7.61 (br s, 1H), 8.26 (br t, 1H), 11.70 (br s, 1H). HRMS (MALDI, MH+) Calcd for C19H18N3OF: 324.1512. Found: 324.1498. Anal. (C19H18N3OF.1.5 H2O.0.35 CHCl3) C, H, N.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(N(CC)CC)C.[C:20]([O:24][C:25]([NH:27][CH2:28][CH2:29]OS(C)(=O)=O)=[O:26])([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C.C(OCC)(=O)C>[C:20]([O:24][C:25](=[O:26])[NH:27][CH2:28][CH2:29][O:1][N:2]1[C:3](=[O:12])[C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:7])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCCOS(C)(=O)=O
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCON1C(=O)c2ccccc2C1=O
Temperature: 50 °C

Procedure:
Added N-hydroxyphthalimide (1.12 g, 6.87 mmol) and triethylamine (0.96 mL, 6.87 mmol) to a solution of methanesulfonic acid 2-tert-butoxycarbonylaminoethyl ester (1.37 g, 5.73 mmol) in DMF (20 mL). The solution was heated to 50° C. for 16 hours after which time it was cooled to room temperature. The solution was diluted with ethyl acetate, washed with water (2×), saturated K2CO3, dried over Na2SO4 and concentrated to an orange solid (747 mg, 43%) which was taken on without purification.
Reaction SMILES: [O:1]1[C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:9][CH2:10][C:4]=2[CH:3]=[CH:2]1.[CH3:24][NH:25][CH3:26].[CH2:27]=O>C(O)(=O)C>[CH3:24][N:25]([CH2:27][C:2]1[O:1][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:9][CH2:10][C:4]=2[CH:3]=1)[CH3:26]
Reactant: CNC
Reactant: C=O
Reactant: O=C(CCCCCc1ccccc1)N1CCc2ccoc2CC1
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CCN(C(=O)CCCCCc1ccccc1)CC2
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.230 g (0.739 mmol) of 1-(4,5,7,8-tetrahydrofuro[2,3-d]azepin-6-yl)-6-phenylhexan-1-one in 20 ml of acetic acid, 80 mg (0.89 mmol) of 50% aqueous dimethylamine and 72 mg (0.89 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 30 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=4/1) to yield the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](I)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:18]1([CH2:21][OH:22])[CH2:20][CH2:19]1>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:22][CH2:21][CH:18]3[CH2:20][CH2:19]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OCC1CC1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(I)cc2C1
Product: CC(C)(C)OC(=O)N1Cc2ccc(OCC3CC3)cc2C1

Procedure:
Prepared in analogy to Example A6(a) from 5-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A38(b)) and cyclopropylmethanol. Off-white solid. MS (m/e): 234.1 ([M+H-Me2C═CH2]+, 100%)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([O:26]C)=[O:25])=[C:12]2[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[F:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].O.Cl>CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([OH:26])=[O:25])=[C:12]2[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[F:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1c(-c2ccccc2F)c2cc(OCc3ccccc3)ccc2c(=O)n1CC(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)Cn1c(C(=O)O)c(-c2ccccc2F)c2cc(OCc3ccccc3)ccc2c1=O
Yield: 92 %

Procedure:
To a solution of methyl 6-benzyloxy-4-(2-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (0.46 g, 1 mmol) in methanol (30 mL) was added an aqueous solution (3 mL) of lithium hydroxide monohydrate (0.42 g, 10 mmol). The obtained mixture was refluxed under heating for 12 h. The reaction mixture was poured into water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give 6-benzyloxy-4-(2-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylic acid (0.41 g, 93.2%) as crystals.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].Cl.C(OCC)(=O)C>O1CCOCC1.[OH-].[Na+]>[CH2:1]([S:3]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)Cl
Reactant: NCCCCCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)NCCCCCC(=O)O
Temperature: 25 °C
Yield: 38.3 %

Procedure:
A solution of ethanesulfonyl chloride (3.9 ml, 41.1 mmol) in dioxane (10 ml) was added to a solution of 6-aminohexanoic acid (2 g, 15.2 mmol) in 1N NaOH (56 ml) and dioxane (10 ml), while stirring at 0–5° C. The pH of the reaction mixture was adjusted to 8–9 by addition of 25% sodium hydroxide solution. The mixture was allowed to warm to room temperature and stirred for 30 minutes. Further 25% NaOH solution was added to adjust the pH to about 11. After 3.5 h 1N hydrochloric acid (15 ml) and ethyl acetate (60 ml) were added. The organic layer was dried over sodium sulfate and concentrated. The residue was triturated with a mixture of diethyl ether (5 ml) and hexane (15 ml). The solid was collected by filtration and dried affording 1.3 g of the title compound (40% yield). 1H NMR (DMSO-d6): 11.9 (1H, s); 6.97 (1H, t, J=5.7 Hz); 2.97 (2H, q, J=7.1); 2.88 (2H, q, J=6.6); 2.2 (2H, t, J=7.3); 1.47 (4H, m); 1.29 (2H, m); 1.18 (3H, t, J=7.3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].C(OC1C=CC(N)=CC=1)C.Br[CH:21]([CH:39]([CH3:41])[CH3:40])[C:22]([O:24]CC1C=CC=C(OC2C=CC=CC=2)C=1)=[O:23]>>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][C@H:21]([C:22]([OH:24])=[O:23])[CH:39]([CH3:41])[CH3:40]
Reactant: CC(C)C(Br)C(=O)OCc1cccc(Oc2ccccc2)c1
Reactant: COc1ccccc1N
Agent: CCOc1ccc(N)cc1
Product: COc1ccccc1N[C@H](C(=O)O)C(C)C

Procedure:
Using the procedure of Example 1, each of 2-methoxyaniline and 4-ethoxyaniline is reacted with m-phenoxybenzyl α-bromoisovalerate to yield the m-phenoxybenzyl ester of N-(2-methoxyphenyl)valine, MS m/e 405.2 (M+), and the m-phenoxybenzyl ester of N-(4-ethoxyphenyl)valine, MS m/e 419.1 (M+).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:26][CH2:27][NH2:28].CN1CCOCC1>C(Cl)(Cl)Cl>[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:26][CH2:27][NH:28][S:17]([C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([C:3]3[C:4]([CH3:7])=[N:5][NH:6][C:2]=3[NH2:1])[S:9][C:10]=2[CH:16]=1)(=[O:19])=[O:18]
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Reactant: NCCc1cccs1
Solvent: CN1CCOCC1
Solvent: ClC(Cl)Cl
Product: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)NCCc3cccs3)cc2s1
Yield: 8.3 %

Procedure:
the title compound (8 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonyl chloride (75 mg, 0.23 mmol), 2-thiophen-2-ylethylamine (29 μL, 0.25 mmol) and PS-NMM (0.22 g, 0.45 mmol) in 4 mL of chloroform. MS (m/z, ES+): 420.4 (M+1, 100): 1H NMR (500 MHz, ppm, DMSO-d6): δ 11.8-12.2 (br s, 1H), 8.5 (s, 1H), 8.0 (d, 1H), 7.8 (m, 2H), 7.32 (d, 1H), 6.93 (dd, 1H), 6.86 (d, 1H), 6.0 (br s, 2H), 3.03 (q, 2H), 2.92 (t, 2H), 2.43 (br s, 3H). Yield=8%.