Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:24](=[O:26])[NH2:25])[CH:5]=[C:6]([CH3:8])[CH:7]=1.Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:24](=[O:26])[NH2:25])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(Cn2c3cccc(O)c3c3c(C(N)=O)cccc32)c1
Reactant: COC(=O)CBr
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cc(C)cc(C)c1
Reaction time: 0.05 h
Yield: 72.4 %

Procedure:
40% Methanolic Triton B (0.13 mL, 0.28 mM) was added to a solution of the 9-[(3,5-dimethylphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (80 mg, 0.23 mM) in 8 mL DMF at room temperature. After 3 minutes, methyl bromoacetate (43 mg, 0.28 mM) was added and the resultant mixture stirred at room temperature for 17 hours. The mixture was diluted with ethyl acetate, washed with H2O, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 70 mg (72%) of the {9-[(3,5-dimethylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. 1H NMR (DMSO-d6) δ 7.6 (d, 1H, J=8 Hz), 7.55 (br s, 1H), 7.45-7.3 (m, 2H), 7.25 (d, 1H, J=8 Hz), 7.2 (br s, 1H), 7.1 (d, 1H, J=8 Hz), 6.9 (s, 1H), 6.8 (s, 2H), 6.6 (d, 1H, J=8 Hz), 5.65 (s, 2H), 4.9 (s, 2H), 3.75 (s, 3H), and 2.2 (s, 6H). IR (KBr, cm−1) 3362, 3173, 1758, 1638, 1583, 1500, 1454, 1434, 1330, 1215, 1151, 1106, 772, 715, and 706. MS (FD) m/e 417.
Reaction SMILES: [NH2:1][C:2]1[CH2:6][C:5](=[O:7])[NH:4][N:3]=1.[CH3:8][O:9][C:10]1[CH:16]=[CH:15][C:13](N)=[CH:12][CH:11]=1>C(O)(=O)C>[CH3:8][O:9][C:10]1[CH:16]=[CH:15][C:13]([NH:1][C:2]2[CH2:6][C:5](=[O:7])[NH:4][N:3]=2)=[CH:12][CH:11]=1
Reactant: NC1=NNC(=O)C1
Reactant: COc1ccc(N)cc1
Solvent: CC(=O)O
Product: COc1ccc(NC2=NNC(=O)C2)cc1

Procedure:
A mixture of 3-amino-2-pyrazolin-5-one (20 mmol), 4-methoxyaniline (25 mol) in 50 ml of acetic acid was refluxed for 4 hours. The solvent was evaporated, the residue was suspended in water. The solid was filtered and crystallized from methanol.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[CH3:16][C:17]1[C:22]([O:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:21][N:20]=[C:19]([CH:30]([NH2:32])[CH3:31])[CH:18]=1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:32]([CH:30]([C:19]3[CH:18]=[C:17]([CH3:16])[C:22]([O:23][CH2:24][CH2:25][C:26]([F:29])([F:27])[F:28])=[CH:21][N:20]=3)[CH3:31])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: Cc1cc(C(C)N)ncc1OCCC(F)(F)F
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)ncc1OCCC(F)(F)F
Yield: 63 %

Procedure:
The title compound is prepared in 63% yield (400 mg, colorless amorphous solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (470 mg, 1.7 mmol, Step-1 of Intermediate-1) and 1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethanamine hydrochloride (460 mg, 1.6 mmol, Amine-62, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O)=[CH:16][CH:15]=[CH:14][C:13]=2[C:27]([F:30])([F:29])[F:28])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][CH2:38][NH2:39]>>[C:2]1([C:1]([C:9]2[CH:10]=[N:11][C:12]3[C:17]([C:18]=2[C:19]2[CH:26]=[CH:25][CH:24]=[C:21]([CH2:22][NH:39][CH2:38][CH2:37][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=4)[CH:20]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[C:27]([F:29])([F:28])[F:30])=[O:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCc1ccccn1
Reactant: O=Cc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(CNCCc2ccccn2)c1

Procedure:
The title compound was prepared from 3-[3-benzoyl-8-(trifluoromethyl)quinolin-4-yl]benzaldehyde and 2-pyridin-2-yl-ethylamine according to the procedure of Example 66. MS m/z 512.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: c1ccccc1
Reactant: C=CCCCCCC
Product: CCCCCCCCc1ccccc1
Yield: 70 %

Procedure:
The alkylation of benzene with oct-1-ene. The reaction gave a 70% yield (by GC) of three isomers of octylbenzene. The isomer ratio was determined to be 0.75:1.00:2.03, with the 4-phenyloctene as the major product and 2-phenyloctene as the minor product. During the course of the reaction, isomeration of oct-1-ene to a number of isomers of octene was observed, and the rate of this isomerisation process was considerably faster that the alkylation reaction. It was found that the ionic liquid/catalyst combination remained active on a second run. To confirm that the minor product of the reaction was an octene dimer, the same reaction was performed, but without any benzene present (shown below).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][Br:7].[Cl:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([Cl:30])[C:14]=1[NH:15][C:16]1[C:25]2[C:20](=[C:21]([OH:28])[C:22]([O:26][CH3:27])=[CH:23][CH:24]=2)[O:19][C:18](=[O:29])[CH:17]=1>>[Br:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][O:28][C:21]1[C:22]([O:26][CH3:27])=[CH:23][CH:24]=[C:25]2[C:20]=1[O:19][C:18](=[O:29])[CH:17]=[C:16]2[NH:15][C:14]1[C:13]([Cl:30])=[CH:12][N:11]=[CH:10][C:9]=1[Cl:8]
Reactant: BrCCOCCBr
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCOCCBr

Procedure:
The title compound was prepared from 2-bromoethyl ether and 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (Example 29) following the procedure outlined in Example 25. 1H NMR (400 MHz, DMSO-d6): δ 9.51 (s, 1H), 8.81 (s, 2H), 7.94 (d, 1H), 7.20 (d, 1H), 4.64 (s, 1H), 4.13 (m, 2H), 3.93 (s, 3H), 3.80-3.74 (m, 4H), 3.55 (t, 2H); MS (ESI): 502.7.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:11])=[CH:8][C:9]=1[OH:10])=O.Cl.[NH2:13][OH:14].C([O-])(=O)C.[Na+]>O.O1CCOCC1>[OH:10][C:9]1[CH:8]=[C:7]([OH:11])[CH:6]=[CH:5][C:4]=1[C:2](=[N:13][OH:14])[CH3:1]
Reactant: NO
Reactant: CC(=O)c1ccc(O)cc1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=NO)c1ccc(O)cc1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 43.6 %

Procedure:
A mixture of 2,4-dihydroxyacetophenone (25 g, 0.16 mol), hydroxylamine hydrochloride (14.8 g, 0.21 mol), sodium acetate (20 g, 0.24 mol) and water/dioxane (300 mL, 1:1) was stirred at room temperature for three days before the mixture was partitioned between chloroform and water. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo and the residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and dichloromethane to give the title compound as a white solid (11.67 g): 1H NMR (CD3OD, 200 MHz): δ=7.26 (m, 1H), 6.28 (m, 2H), 4.88 (s, 2H), 3.29 (m, 1H), 2.24 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=4)[CH2:28][CH2:27][C:26]([C:39](O)=[O:40])=[CH:25][C:24]=3[CH:42]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH3:9].S(Cl)(Cl)=O>O1CCCC1>[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=4)[CH2:28][CH2:27][C:26]([C:39]([NH:29][C:23]4[CH:24]=[CH:42][C:20]([CH2:4][N:2]([CH3:1])[CH:3]5[CH2:12][CH2:11][O:10][CH2:6][CH2:7]5)=[CH:21][CH:22]=4)=[O:40])=[CH:25][C:24]=3[CH:42]=2)=[CH:18][CH:19]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CN(C)C=O
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccc(OC)cc2)cc1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2ccc(OC)cc2)cc1
Reaction time: 1 h

Procedure:
One droplet of DMF was added to a solution of 7-(4-butoxyethoxyphenyl)-1-(4-methoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (140 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (100 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were evaporated under reduced pressure, the resulting residue was suspended in tetrahydrofuran (25 ml), and the suspension was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (74 mg) and triethylamine (344 mg) in tetrahydrofuran (10 ml) at 0° C. The suspension was stirred under nitrogen atmosphere at room temperature for 3.5 hours, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:8), which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-(4-methoxybenzyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 56) (89 mg) as yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[N:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[S:9][C:10]=1[CH2:11][CH3:12])[CH3:2].[CH:24]([N-]C(C)C)(C)C.[Li+].CI>O1CCCC1>[CH2:1]([O:3][C:4](=[O:23])[CH:5]([C:6]1[N:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][CH:14]=2)[S:9][C:10]=1[CH2:11][CH3:12])[CH3:24])[CH3:2]
Reactant: CCOC(=O)Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CC
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C(C)c1nc(-c2ccc(C(F)(F)F)cc2)sc1CC
Temperature: 25 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-acetic acid ethyl ester (2.02 g, 6.13 mmol) is dissolved into anhydrous tetrahydrofuran (THF) (10 mL) and lithium diisopropylamide (LDA) is slowly added at room temperature. This solution is allowed to stir at room temperature and monitored by TLC. After complete conversion, methyl iodide (582 mg, 4.00 mmol) is added slowly and the reaction is followed by TLC. After 18 h., the reaction is not complete, but is quenched with saturated ammonium chloride solution and diluted with diethyl ether. The two phases are separated and the organic layer is washed with water and brine, dried over anhydrous sodium sufate, then concentrated and purified using flash column chromatography (10% EtOAc/Hexanes). The pure 2-[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propionic acid ethyl ester (1.30 g, 3.64 mmol) is obtained in 59% yield.
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:18])[CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:17].[CH:19](=[C:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[CH2:20][CH2:21][CH3:22]>CCCCCCC.CCOC(C)=O>[CH:19](=[C:23]1[CH2:28][CH2:27][N:26]([CH2:2][C@@H:3]([CH3:18])[CH2:4][N:5]2[C:10]3[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=3[O:8][CH2:7][C:6]2=[O:17])[CH2:25][CH2:24]1)[CH2:20][CH2:21][CH3:22]
Reactant: COc1ccc2c(c1)N(C[C@H](C)CI)C(=O)CO2
Reactant: CCCC=C1CCNCC1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCCC=C1CCN(C[C@@H](C)CN2C(=O)COc3ccc(OC)cc32)CC1
Yield: 87.5 %

Procedure:
The compound (S)-4-(3-Iodo-2-methylpropyl)-6-methoxy-4H-benzo[1,4]oxazin-3-one (111MF36) (0.612 g, 1.69 mmol) and 4-butylidenepiperidine (0.212 g, 1.5 mmol) were mixed according to GP16. CC (SiO2; Heptane/EtOAc 4:1-4) gave the title compound (111MF39) (0.489 g, 77%). 1H NMR (CDCl3) δ 6.90 (d, J=8.4 Hz, 1H), 6.73 (d, J=2.8 Hz, 1H), 6.50 (dd, J=8.4 Hz, J=2.8 Hz, 1H), 5.11 (t, J=7.6 Hz, 1H), 4.54 (q, J=14.4 Hz, 2H), 3.97-3.94 (d, J=6.8 Hz, 2H), 3.78 (s, 3H), 2.48-2.41 (m, 2H), 2.33-2.23 (m, 5H), 2.20-2.13 (m, 4H), 1.96 (q, J=7.4 Hz, 2H), 1.40-1.29 (m, 2H), 0.91-0.86 (m, 6H); 13C NMR (CDCl3) δ 165.3, 155.5, 139.8, 136.5, 129.8, 122.5, 117.2, 107.0, 103.4, 68.1, 63.8, 56.5, 56.0, 55.7, 45.5, 36.2, 29.3, 29.2, 28.4, 23.3, 16.9, 13.9; HPLC-MS; (ammonium acetate) [M+H]+=373.3.
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11](Cl)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[NH:24]1[CH2:29][CH2:28][S:27][CH2:26][CH2:25]1.O>CN1CCCC1=O>[C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]([N:24]3[CH2:29][CH2:28][S:27][CH2:26][CH2:25]3)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(Cl)c([N+](=O)[O-])cc2s1
Reactant: C1CSCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)c1nc2cc(N3CCSCC3)c([N+](=O)[O-])cc2s1

Procedure:
A mixture of 2 g of 2-tert-butyl-5-chloro-6-nitrobenzothiazole, described in Example 5, 2 g of anhydrous potassium carbonate and 1.5 ml of thiomorpholine in 7 ml of 1-methyl-2-pyrrolidinone is heated in a sealed glass tube at 120° for 12 hours, poured into water, the solid filtered, washed with water and isopropyl alcohol to give 2-tert-butyl-6-nitro-5-[thiomorpholin-4-yl]benzothiazole, melting at 117°-120°.
Reaction SMILES: I[C:2]1[CH:20]=[CH:19][C:5]([O:6][CH2:7][CH2:8][N:9]2[C:14]([CH3:16])([CH3:15])[CH2:13][CH2:12][CH2:11][C:10]2([CH3:18])[CH3:17])=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[CH:30][C:31]([C:34]#[CH:35])=[N:32][CH:33]=2)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:29]=[CH:30][C:31]([C:34]#[C:35][C:2]3[CH:20]=[CH:19][C:5]([O:6][CH2:7][CH2:8][N:9]4[C:14]([CH3:16])([CH3:15])[CH2:13][CH2:12][CH2:11][C:10]4([CH3:18])[CH3:17])=[CH:4][CH:3]=3)=[N:32][CH:33]=2)=[CH:26][CH:27]=1
Reactant: CC1(C)CCCC(C)(C)N1CCOc1ccc(I)cc1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: CC1(C)CCCC(C)(C)N1CCOc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1

Procedure:
Prepared according to general working method I from 1-[2-(4-iodo-phenoxy)-ethyl]-2,2,6,6-tetramethyl-piperidine (260 mg, 0.67 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (155 mg, 0.73 mmol).
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([CH:24]4[CH2:28][CH2:27][C:26](=O)[CH2:25]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH2:3]1.C[CH2:32][N:33](CC)[CH2:34]C.CNC.C1COCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:30][C:2]1([F:1])[CH2:3][CH2:4][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([CH:24]4[CH2:28][CH2:27][CH:26]([N:33]([CH3:34])[CH3:32])[CH2:25]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:6][CH2:7]1
Reactant: O=C1CCC(c2ccc3c(C(=O)NCC4(O)CCC(F)(F)CC4)c(Cl)ccc3n2)C1
Reactant: CCN(CC)CC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CNC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)C1CCC(c2ccc3c(C(=O)NCC4(O)CCC(F)(F)CC4)c(Cl)ccc3n2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.4 %

Procedure:
To a stirred solution of 6-chloro-2-(3-oxo-cyclopentyl)-quinoline-5-carboxylic acid (4,4-difluoro-1-hydroxycyclohexylmethyl)-amide (0.30 g, 0.28 mmol, 1.00 eq) in DCM (15.00 ml, 50.00 V) were added Et3N (0.09 g, 0.84 mmol, 3.00 eq) and dimethylamine solution 2.0 M in THF (0.70 mL, 1.40 mmol, 5.00 eq) at 0° C., and warmed to room temperature. The reaction mixture was stirred at RT for 1 h and sodium triacetoxyborohydride (0.09 g, 0.42 mmol, 1.50 eq) was added and the reaction mixture was stirred at RT for 16 h and the solvent was removed under vacuum. The crude product was purified by prep HPLC to provide 6-chloro-2-(3-dimethylaminocyclopentyl)-quinoline-5-carboxylic acid (4,4-difluoro-1-hydroxy-cyclohexyl methyl)-amide (0.03 g, 0.06 mmol, 22.3%, Brown solid). 1H NMR (400 MHz, DMSO-d6): δ 8.81 (t, J=5.82 Hz, 1H), 8.01-7.96 (m, 2H), 7.76-7.74 (m, 1H), 7.60-7.56 (m, 1H), 7.56-3.28 (m, 1H), 3.27-3.25 (m, 2H), 2.68-2.57 (m, 1H), 2.56-2.48 (m, 1H), 2.25-2.16 (m, 1H), 2.15-2.07 (m, 6H), 2.06-1.96 (m, 5H), 1.96-1.90 (m, 4H), 1.88-1.83 (m, 2H), 1.78-1.72 (m, 1H), 1.30-1.24 (m, 2H). m/z: 450.2 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Si:8]([CH3:11])([CH3:10])[CH3:9])[C:3]=1[N:12]=[C:13]=[O:14].[CH2:15]([OH:17])[CH3:16]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Si:8]([CH3:10])([CH3:11])[CH3:9])[C:3]=1[NH:12][C:13](=[O:14])[O:17][CH2:15][CH3:16]
Reactant: C[Si](C)(C)c1cccc(Cl)c1N=C=O
Reactant: CCO
Product: CCOC(=O)Nc1c(Cl)cccc1[Si](C)(C)C

Procedure:
A mixture of the compound of Example h (10 mmol) and ethanol (75 mL) was refluxed for 1 h. The mixture was concentrated and the residue dissolved in ethyl acatate. The solution was washed twice with water and the solvent removed to yield the crude product, which was recrystallized from hexane. GC/MS showed some remaining isocyanate so the solid was dissolved in ethanol and refluxed again with approx. 0.1 g diazobisbicyclooctane. FID/GC indicated a complete reaction and the ethanol was removed and the title compound recovered. m.p. 109-110° C.
Reaction SMILES: [CH3:1][C:2]([CH3:44])([CH2:6][C:7]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[C:10]2[CH:28]=[CH:29][C:30]([O:32][CH2:33][C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)=[CH:31][C:9]=2[N:8]=1)[C:3]([OH:5])=[O:4].Br[C:46]1[S:50][CH:49]=[N:48][CH:47]=1>>[CH3:1][C:2]([CH3:44])([CH2:6][C:7]1[N:11]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:46]3[S:50][CH:49]=[N:48][CH:47]=3)=[CH:17][CH:18]=2)[C:10]2[CH:28]=[CH:29][C:30]([O:32][CH2:33][C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)=[CH:31][C:9]=2[N:8]=1)[C:3]([OH:5])=[O:4]
Reactant: CC(C)(Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)O
Reactant: Brc1cncs1
Product: CC(C)(Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(-c2cncs2)cc1)C(=O)O

Procedure:
The title compound was prepared with similar methods to those in Example 147 using 2,2-dimethyl-3-(5-(quinolin-2-ylmethoxy)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-benzo[d]imidazol-2-yl)propanoic acid and 5-bromothiazole. MS (ESI): mass calcd. for C32H28N4O3S, 548.19; m/z found, 549.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.83 (d, J=9.1, 1H), 8.32-8.28 (m, 2H), 8.18 (d, J=8.8, 1H), 8.01-7.93 (m, 2H), 7.79 (t, J=7.5, 1H), 7.68-7.59 (m, 3H), 7.49 (s, 1H), 7.34 (d, J=7.8, 3H), 5.84 (s, 2H), 5.69 (s, 2H), 3.54 (s, 2H), 1.31 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][C:14]([C:20]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([CH2:29][N:30]([CH3:37])[CH:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[CH:25][CH:24]=4)=[O:21])=[CH:13][C:12]=3[CH:38]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48].O>CN(C=O)C>[C:50]([O:49][C:47]([CH2:46][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][C:14]([C:20]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([CH2:29][N:30]([CH3:37])[CH:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[CH:25][CH:24]=4)=[O:21])=[CH:13][C:12]=3[CH:38]=2)=[CH:4][CH:3]=1)=[O:48])([CH3:53])([CH3:52])[CH3:51]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(O)cc4)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(OCC(=O)OC(C)(C)C)cc4)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In DMF (4.8 ml) was dissolved 7-(4-hydroxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (320 mg). To the mixture was added potassium carbonate (96 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added t-butyl bromoacetate (0.093 ml), and the mixture was stirred at room temperature for 4 hours. The mixture was added to water, and the mixture was extracted with ethyl acetate/THF, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1) and recrystallized from ethanol to give 7-[4-(t-butoxycarbonylmethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 90) (274 mg).
Reaction SMILES: [C:1]([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[OH:23])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[Br:29]Br.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)(Cl)Cl.O>[Br:29][C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([OH:23])=[C:12]([CH:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:21]=1[CH3:22]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccccc2c1O
Reactant: BrBr
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(OC(C)(C)C)c1c(C)c(Br)c2ccccc2c1O
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
A solution of ethyl 2-tert-butoxy-2-(1-hydroxy-3-methylnaphthalen-2-yl)acetate (1.24 g, 3.92 mmol) in CHCl3 (20 mL) was treated with solid NaHCO3 (843 mg, 9.80 mmol). Then a solution of Br2 (750 mg, 4.70 mmol) in CHCl3 (5.0 mL) was added dropwise over 2 min at 23° C. After 30 min, the reaction was treated with 10% Na2S2O3 solution (10 mL). After maximum decolorization was achieved, the reaction was diluted with H2O (10 mL) and extracted with DCM (3×10 mL). Combined organic phases were dried (Na2SO4), filtered, and concentrated. The residue was treated with DCM and wet-loaded onto a silica gel column and purified by flash chromatography (ethyl acetate/hexanes) giving the desired product (1.50 g, 97% yield). 1H NMR (400 MHz, CDCl3) δ 9.18 (s, 1H), 8.28 (d, J=8.6 Hz, 1H), 8.20 (d, J=8.6 Hz, 1H), 7.56 (dd, J=8.6, 8.6 Hz, 1H), 7.45 (dd, J=8.6, 8.6 Hz, 1H), 5.60 (s, 1H), 4.24-4.06 (m, 2H), 2.77 (s, 3H), 1.31 (s, 9H), 1.20 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+].Cl[C:14]1[N+:19]([O-:20])=[C:18]2[CH2:21][CH2:22][CH2:23][C:17]2=[C:16]([Cl:24])[CH:15]=1>CN1C(=O)CCC1.C(Cl)Cl>[Cl:24][C:16]1[CH:15]=[C:14]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N+:19]([O-:20])=[C:18]2[CH2:21][CH2:22][CH2:23][C:17]=12
Reactant: [O-][n+]1c(Cl)cc(Cl)c2c1CCC2
Reactant: OC1CCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: [O-][n+]1c(OC2CCCC2)cc(Cl)c2c1CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 112.6 %

Procedure:
To a solution of cyclopentanol (0.050 g, 0.59 mmol) in NMP (3 mL) at rt was added potassium tert-butoxide (0.060 g, 0.54 mmol). The mixture was stirred at rt for 1 h. 2,4-Dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide (0.100 g, 0.49 mmol) in NMP (1 mL) was added and the mixture was heated to 80° C. for 1 h. The mixture was diluted with methylene chloride and washed with water. The organic layer were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, dichloromethane/methanol) to afford crude product (0.140 g) as a brown oil. MW=253.72. 1H NMR (CDCl3, 300 MHz) δ 6.69 (s, 1H), 5.04 (s, 1H), 3.23 (t, J=7.6 Hz, 2H), 2.99 (t, J=7.6 Hz, 2H), 2.20 (quin, J=7.6 Hz, 2H), 2.00-1.56 (m, 8H); APCI MS m/z 254 [M+H]+.