Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:45])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[CH:25]=[C:26]([O:28][CH2:29][CH3:30])[CH:27]=2)[C:10]=1[CH2:38][CH2:39][C:40]([O:42]CC)=[O:41])C.[OH-].[Na+]>>[C:40]([CH2:39][CH2:38][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:31]3[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=3)[CH:25]=[C:26]([O:28][CH2:29][CH3:30])[CH:27]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:45])=[O:3])([OH:42])=[O:41]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(OCC)cc(-c3ccc(Cl)cc3)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCOc1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc(Cl)cc2)c1
Yield: 142.9 %

Procedure:
A similar procedure as described in Example 43, step 5 was used, starting from 4-[3-[6-(4′-chloro-5-ethoxy-biphenyl-3-yloxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (150 mg, 0.24 mmol) and 1.0 N aqueous sodium hydroxide (2.4 mL) to afford 4-[2-(2-carboxy-ethyl)-3-[6-(4′-chloro-5-ethoxy-biphenyl-3-yloxy)-hexyl]-phenoxy]-butyric acid (200 mg, 98%) as a light brown waxy solid: ES(+)-HRMS m/e calcd for C33H39ClO7 (M+Na)+ 605.2276. found 605.2278.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15])=[CH:9][CH:8]=[C:7]([Br:18])[CH:6]=2.[CH2:19]([O:21][CH2:22][C:23](Cl)=[O:24])[CH3:20]>ClCCl>[Br:18][C:7]1[CH:6]=[C:5]2[C:10]([C:11]([NH:12][CH2:13][C:14]([OH:16])([CH3:15])[CH3:17])=[C:2]([NH:1][C:23](=[O:24])[CH2:22][O:21][CH2:19][CH3:20])[CH:3]=[N:4]2)=[CH:9][CH:8]=1
Reactant: CCOCC(=O)Cl
Reactant: CC(C)(O)CNc1c(N)cnc2cc(Br)ccc12
Solvent: ClCCl
Product: CCOCC(=O)Nc1cnc2cc(Br)ccc2c1NCC(C)(C)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-(3-amino-7-bromoquinolin-4-ylamino)-2-methylpropan-2-ol (158.19 g, 0.510 mol) in dichloromethane (1.2 L) was cooled to 0° C. Ethoxyacetyl chloride (62.50 g, 0.510 mol) was added dropwise, and then the reaction was allowed to warm to ambient temperature and stirred overnight. A precipitate formed and was isolated by filtration to provide N-[7-bromo-4-(2-hydroxy-2-methylpropylamino)quinolin-3-yl]-2-ethoxyacetamide as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:24])=[CH2:23])=[CH:18][C:17]=3[C:25]3[CH:26]=[CH:27][C:28]([C:31]([NH:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:32])=[N:29][CH:30]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:18][C:17]=3[C:25]3[CH:26]=[CH:27][C:28]([C:31]([NH:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:32])=[N:29][CH:30]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: C=C(C)c1ccc(CNc2ccc(-c3ccc(F)cc3)cc2)c(-c2ccc(C(=O)NCCC(=O)O)nc2)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)c1ccc(CNc2ccc(-c3ccc(F)cc3)cc2)c(-c2ccc(C(=O)NCCC(=O)O)nc2)c1
Reaction time: 1 h

Procedure:
A mixture of 3-(5-(2-(((4′-fluoro-[1,1′-biphenyl]-4-yl)amino)methyl)-5-(prop-1-en-2-yl)phenyl)picolinamido)propanoic acid (46 mg, 0.09 mmol), ammonium formate (57 mg, 0.91 mmol) and 10% Pd—C (10 mg, 0.01 mmol) in MeOH (5 mL) was refluxed. After 1 h, the resulting mixture was filtered through celite and washed with DCM-MeOH. The filtrate was concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[NH2:6].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>>[CH2:12]([N:6]([CH2:5][CH2:4][CH2:3][CH2:9][CH2:8][CH3:7])[C:5]1[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCBr
Reactant: COc1cc(N)cc(OC)c1
Product: CCCCCCN(CCCCCC)c1cc(OC)cc(OC)c1

Procedure:
3,5-dimethoxyaniline was bromided with n-hexylbromide so as to obtain 1-di-n-hexylamino-3,5-dimethoxybenzene. This was nitrosoized so as to obtain 1-di-n-hexylamino-3,5-dimethoxy-4-nitrobenzene.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])=[CH:11][CH:10]=2)[N:5]=[N:6][CH:7]=1.[C:23]([C:27]1[CH:28]=[C:29]2[C:34](=[C:35]([F:37])[CH:36]=1)[C:33](=[O:38])[N:32]([C:39]1[CH:49]=[CH:48][CH:47]=[C:46](B3OC(C)(C)C(C)(C)O3)[C:40]=1[CH2:41][O:42][C:43](=[O:45])[CH3:44])[N:31]=[CH:30]2)([CH3:26])([CH3:25])[CH3:24].C([O-])([O-])=O.[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:23]([C:27]1[CH:28]=[C:29]2[C:34](=[C:35]([F:37])[CH:36]=1)[C:33](=[O:38])[N:32]([C:39]1[CH:49]=[CH:48][CH:47]=[C:46]([C:2]3[CH:3]=[C:4]([NH:8][C:9]4[CH:10]=[CH:11][C:12]([C:15]([N:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)=[O:16])=[CH:13][N:14]=4)[N:5]=[N:6][CH:7]=3)[C:40]=1[CH2:41][O:42][C:43](=[O:45])[CH3:44])[N:31]=[CH:30]2)([CH3:24])([CH3:25])[CH3:26]
Reactant: O=C(c1ccc(Nc2cc(Cl)cnn2)nc1)N1CCOCC1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)OCc1c(-c2cnnc(Nc3ccc(C(=O)N4CCOCC4)cn3)c2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 25 °C

Procedure:
[6-(5-Chloro-pyridazin-3-ylamino)-pyridin-3-yl]-morpholin-4-yl-methanone (200 mg, 0.63 mmol), acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-benzyl ester (470 mg, 1.25 mmol) and K2CO3 (173 mg, 1.25 mmol) were dissolved in dioxane/H2O (10:1, 11 ml). Under N2 atmosphere, Pd2(dba)3 (58 mg, 0.063 mmol) and X-phos (120 mg, 0.25 mmol) were added and the mixture was stirred at reflux temperature overnight. After the completion of the reaction, the mixture was cooled to room temperature and filtered. The organic layer was washed with saturated brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column (petroleum ether:ethyl acetate=2:1). The desired product was obtained as a yellow solid (240 mg, yield 59%). LC-MS: 652[M+1]+, tR=1.459 min.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C(S)C.[N:8]1([CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:27]([C:28]4[CH:33]=[CH:32][C:31]([O:34]C)=[CH:30][CH:29]=4)=[CH:26][CH:25]=[C:24]([CH3:36])[N:23]=3)=[CH:18][CH:17]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1>ClCCCl>[N:8]1([CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[C:27]([C:28]4[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=4)=[CH:26][CH:25]=[C:24]([CH3:36])[N:23]=3)=[CH:20][CH:21]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COc1ccc(-c2ccc(C)nc2-c2ccc(OCCN3CCCC3)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCCl
Product: Cc1ccc(-c2ccc(O)cc2)c(-c2ccc(OCCN3CCCC3)cc2)n1
Reaction time: 0.25 h
Yield: 89 %

Procedure:
The AlCl3 (3.6 g, 27 mmol) was stirred in 100 mL of DCE at 0° C., ethanethiol (3 mL, 38 retool) was added, and the mixture stirred for 15 min. The 2-[4-[2-(1-pyrrolidinyl) ethoxy]phenyl]-3- (4-methoxyphenyl) -6-methylpyridine (1.5 g, 3.9 mmol) in 50 mL DCE was added dropwise to the reaction mixture and stirred for 2 h as it was allowed to come to rt, then quenched with 75 mL THF at 0° C., followed by 50 mL 1N HCl and worked up. The crude product was triturated with Et2O, filtered, and dried in vacuo to give 1.3 g (90 % yield) of an off-white solid: mp 159°-161° C.; 1H NMR (CDCl3) d 1.80-184 (bs, 4H, pyrrolidine), 2.61 (s, 3H, pyr-CH3), 2.67-2.69 (bs, 4H, pyrrolidine), 2.93-2.97(m, 2H, CH2N), 4.08-4.10 (m, 2H, OCH2), 6.60-6.65 (m, 4H, ArH), 6.90-6.93 (d, 2H, J=8 Hz, ArH), 7.08-7.11 (d, 1H, J=8 Hz, ArH), 7.23-7.26 (m, 2H, ArH), 7.50-7.53 (d, 1H, J=8 Hz, ArH); MS(FD) 374(M+). Anal. Calcd for C24H26N2O2 : C, 76.98; H, 7.00; N, 7.48. Found: C, 76.70; H, 7.07; N, 7.36.
Reaction SMILES: [C:1]1(C)[CH:6]=CC(S(Cl)(=O)=O)=C[CH:2]=1.[C:12]1([CH3:40])[CH:17]=[CH:16][C:15]([S:18]([N:21]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25][N:24]([S:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH2:23][CH2:22]2)(=[O:20])=[O:19])=[CH:14][CH:13]=1.ICCCI.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:12]1([CH3:40])[CH:17]=[CH:16][C:15]([S:18]([N:21]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25][N:24]([S:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)(=[O:31])=[O:32])[CH2:23][CH2:22]2)(=[O:20])=[O:19])=[CH:14][CH:13]=1.[CH3:2][CH2:1][CH3:6].[C:12]1([CH3:40])[CH:17]=[CH:16][C:15]([S:18]([N:21]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25][N:24]([S:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)(=[O:31])=[O:32])[CH2:23][CH2:22]2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cc1ccc(S(=O)(=O)N2CCNCCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Agent: ICCCI
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CCC

Procedure:
N,N′-bis(p-toluenesulfonyl)-1,4,7-triazacyclononane(1.1.20) was prepared by reacting(1.1.3) with two equivalents of p-toluenesulfonyl chloride. Two equivalents of N,N′-bis(p-toluenesulfonyl)-1,4,7-triazacyclononane(1.1.20) hydrobromide were reacted with one equivalent of 1,3-diiodopropane in acetonitrile with excess potassium carbonate. 1,3-Bis[N,N′-bis(p-toluenesulfonyl)-1,4,7-triazacyclononane propane(1.1.21) was isolated and purified by chromatography. The p-toluenesulfonyl groups were removed using sulfuric acid and HBr to yield the title compound (1.1.19).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].[C:10]1([CH3:19])[CH:15]=[CH:14][C:13]([C:16](Cl)=[O:17])=[CH:12][CH:11]=1>>[CH3:4][C@H:3]([CH2:5][CH3:6])[C@@H:2]([NH:1][C:16](=[O:17])[C:13]1[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Reactant: Cc1ccc(C(=O)Cl)cc1
Product: CC[C@@H](C)[C@@H](NC(=O)c1ccc(C)cc1)C(=O)O

Procedure:
(L)-Isoleucine and p-toluoyl chloride were processed as described in Example 26A to provide the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([CH2:13][CH2:14]O)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:16][NH:17][CH3:18]>C(O)C.ClCCl>[CH3:16][N:17]([CH3:18])[CH2:14][CH2:13][S:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:12])=[O:11]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)CCO)c1
Reactant: CNC
Solvent: ClCCl
Solvent: CCO
Product: CN(C)CCS(=O)(=O)c1cccc([N+](=O)[O-])c1
Yield: 59.6 %

Procedure:
2-(3-Nitro-phenylsulfonyl)-ethanol (0.5 g; 2.6 mmol) was dissolved in 3 mL ethanol and 2 mL of dichloromethane. Then 1 mL of (7.8 mmol) dimethylamine (33% in ethanol) was added, the reaction mixture was subsequently concentrated in vacuo, dissolved in dichloromethane, and the product was precipitated by adding diethyl ether and petrol ether. 0.4 g (1.55 mmol; 59% yield) of dimethyl-[2-(3-nitro-benzenesulfonyl)-ethyl]-amine were obtained as a yellow solid.
Reaction SMILES: [C:1]1([CH2:11][C:12]#[N:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.ClC1C=CC=CC=1CS[C:19]#[N:20].C([N-]C(C)C)(C)C.[Li+].[OH-].[Na+]>C1C=CC=CC=1>[C:1]1([CH:11]([C:19]#[N:20])[C:12]#[N:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: N#CCc1cccc2ccccc12
Reactant: N#CSCc1ccccc1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Na+]
Solvent: c1ccccc1
Product: N#CC(C#N)c1cccc2ccccc12
Reaction time: 1 h

Procedure:
With stirring and cooling, 0.3 mol of 1-naphthylaceto-nitrile and then, dropwise, 0.6 mol of 2-chlorobenzyl thiocyanate are added to a solution of 0.65 mol of lithium diisopropylamide in benzene. After one hour, the reaction mixture is introduced into 1 l of 0.3 molar NaOH, and the mixture is allowed to stand for a while and then the two phases which are formed are separated. The aqueous solution is neutralized by adding hydrochloric acid and allowed to stand overnight. The precipitated product is filtered off with suction, dried and purified by recrystallization from ethanol.
Reaction SMILES: Cl.[CH2:2]([C:4]1[N:9]([CH2:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8](=[O:19])[C:7]2[C:20]([O:33][CH3:34])=[C:21]([C:24]([NH:26][CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[O:25])[N:22]([CH3:23])[C:6]=2[CH:5]=1)[CH3:3].C(N(CC)CC)C.C1COCC1.C([O:50][CH2:51][C:52](Cl)=[O:53])(=O)C>C(OCC)(=O)C>[CH2:2]([C:4]1[N:9]([CH2:10][C:11](=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:8](=[O:19])[C:7]2[C:20]([O:33][CH3:34])=[C:21]([C:24]([NH:26][CH:27]3[CH2:28][CH2:29][N:30]([C:51](=[O:50])[CH2:52][OH:53])[CH2:31][CH2:32]3)=[O:25])[N:22]([CH3:23])[C:6]=2[CH:5]=1)[CH3:3]
Reactant: CCc1cc2c(c(OC)c(C(=O)NC3CCNCC3)n2C)c(=O)n1CC(=O)c1ccccc1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCc1cc2c(c(OC)c(C(=O)NC3CCN(C(=O)CO)CC3)n2C)c(=O)n1CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 65 %

Procedure:
To a mixture of the compound of Example 130 (90.0 mg, 0.185 mmol), triethylamine (76.9 μL, 0.555 mmol) and THF (5 mL) was added acetoxyacetyl chloride (23.8 μL, 0.221 mmol) at 0° C., and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; ethyl acetate), and the obtained solid was dissolved in THF (1.2 mL)-ethanol (2.5 mL). 8N Aqueous sodium hydroxide solution (250 μL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with water, acidified with 6N hydrochloric acid (0.5 mL), and extracted twice with ethyl acetate. The extract was combined, washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; ethyl acetate/methanol=10/0-9/1), and the obtained solid was recrystallized from ethyl acetate to give the title compound (61.2 mg, 65%) as white crystals.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][C:27]([C:34]([O:36][CH2:37][CH3:38])=[O:35])([CH2:31][CH2:32][CH3:33])[CH2:28][CH2:29][CH3:30])/[C:9]1=[O:39])=O)(C)(C)C.[F:40][C:41]1[CH:42]=[CH:43][C:44]([CH3:56])=[C:45]([CH:47]=[N:48][C:49]([O:51][Si](C)(C)C)=[CH2:50])[CH:46]=1>C1(C)C=CC=CC=1>[Cl:25][C:23]1[CH:22]=[CH:21][C:20]([O:26][C:27]([C:34]([O:36][CH2:37][CH3:38])=[O:35])([CH2:28][CH2:29][CH3:30])[CH2:31][CH2:32][CH3:33])=[C:19]([CH:18]2[CH2:51][C:49](=[O:50])[NH:48][CH:47]([C:45]3[CH:46]=[C:41]([F:40])[CH:42]=[CH:43][C:44]=3[CH3:56])[C:10]32[C:11]2[C:16](=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[NH:8][C:9]3=[O:39])[CH:24]=1
Reactant: CCCC(CCC)(Oc1ccc(Cl)cc1/C=C1\C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)ccc21)C(=O)OCC
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CCCC(CCC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)OCC
Yield: 9.9 %

Procedure:
In a manner similar to the method described in Example 10d, E/Z-6-chloro-3-[5-chloro-2-(1-ethoxycarbonyl-1-propyl-butoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (1.3 g, 2.3 mmol) was reacted with 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (10 mmol) prepared in Example 1d in toluene to give the title compound as a white solid (150 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]3[C:15]4[C:16](=[C:20]([C:24]([O:26]CC)=[O:25])[N:21]([CH3:23])[N:22]=4)[CH2:17][CH2:18][CH2:19][C:12]3=[CH:11][N:10]=2)=[C:4]([O:29][CH3:30])[CH:3]=1.[OH-].[Na+]>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]3[C:15]4[C:16](=[C:20]([C:24]([OH:26])=[O:25])[N:21]([CH3:23])[N:22]=4)[CH2:17][CH2:18][CH2:19][C:12]3=[CH:11][N:10]=2)=[C:4]([O:29][CH3:30])[CH:3]=1
Reactant: CCOC(=O)c1c2c(nn1C)-c1nc(Nc3ccc(Br)cc3OC)ncc1CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(Br)ccc1Nc1ncc2c(n1)-c1nn(C)c(C(=O)O)c1CCC2
Yield: 80.7 %

Procedure:
Ethyl 9-[(4-bromo-2-methoxyphenyl)amino]-2-methyl-2,4,5,6-tetrahydropyrazolo[4′,3′:6,7]cyclohepta[1,2-d]pyrimidine-3-carboxylate (0.250 g, 0.530 mmol) was suspended in anhydrous EtOH (5 mL) and treated with a 2 M solution of NaOH (0.260 mL, 0.5 eq.) at reflux temperature for 1 hour. Solvent was evaporated to dryness and the residue dissolved in water. After treatment with AcOH, the resulting precipitate was collected by filtration to give the title compound (190 mg, 80% yield) as a white solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([OH:13])=[CH:5][CH:4]=1.C([Li])CCC.C(OC(NC1C2C(=CC=CC=2)C(O)=CC=1)=O)(C)(C)C.Cl.Cl[CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C1COCC1>[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)=[CH:5][CH:4]=1
Reactant: Nc1ccc(O)c2ccccc12
Reactant: ClCCN1CCOCC1
Agent: CC(C)(C)OC(=O)Nc1ccc(O)c2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CC#N
Product: Nc1ccc(OCCN2CCOCC2)c2ccccc12

Procedure:
4-Amino-1-naphthol hydrochloride (40) can be neutralized with a base, such as n-butyl lithium, in a non-protic solvent, such as THF, and reacted with di-tert-butyl dicarbonate (BOC)2O) at temperatures between −78-25° C. The product, 4-tert-butyloxycarbonylamino-1-naphthol (41) can be alkylated with 4-(2-chloroethyl)morpholine hydrochloride in a non-protic solvent, such as acetonitrile, wit a base, such as powdered potassium carbonate, at temperatures between 60-80° C. Purification of the product 4-tert-butyloxycarbonylamino-1-(2-(morpholin-4-yl)ethoxy)naphthalene (42) can be accomplished by silica gel chromatography. Removal of the BOC-protecting group can be accomplished with HCl in a non-protic solvent, such as dioxane, to furnish 1-amino-4-(2-(morpholin-4-yl)ethoxy)naphthalene (39) as the hydrochloride salt.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][NH:8][N:7]=1)=[O:5])[CH3:2].Br[CH2:12][CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Li+]>CN1CCCC1=O.C(OCC)(=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[N:8]=[CH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: BrCCOC1CCCCO1
Reactant: CCOC(=O)c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1ccnn1CCOC1CCCCO1
Temperature: 80 °C

Procedure:
Ethyl-pyrazole-3-carboxylate (980 mg, 7.0 mmol), 2-(2-bromoethoxy)-tetrahydro-2H-pyran (1.57 g, 7.5 mmol), potassium carbonate (1.01 g, 7.3 mmol) and lithium iodide (46.8 mg, 0.35 mmol) were dissolved in 1-methyl-2-pyrrolidinone (10 mL) and the reaction mixture heated to 80° C. for 24 hours. The reaction mixture was allowed to cool for 17 hours and then diluted with a mixture of ethyl acetate:water 1:1 (500 mL). The organic layer was washed with water (3×250 mL), dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with cyclohexane:ethyl acetate 90:10 to 80:20 to 75:25 to 50:50. The appropriate fractions were combined and concentrated in vacuo to yield the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10](=O)[CH3:11].Cl.[NH2:14][OH:15].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10](=[N:14][OH:15])[CH3:11]
Reactant: CC(=O)/C=C/c1ccccc1Cl
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C=Cc1ccccc1Cl)=NO
Yield: 58.1 %

Procedure:
In a 250 ml single neck flask was charged 5.4 g (29.9 mmoles, 1.0 eq.) of (E)-4-(2-chlorophenyl)-3-buten-2-one and 5.2 g (75.4 mmoles, 2.5 eq) of hydroxylamine hydrochloride and 6 g of 50% sodium hydroxide (75 mmoles, 2.5 eq) and 100 ml of methanol. The reaction mixture was stirred at reflux for 2 hours. The reaction mixture was concentrated, diluted with water (50 ml), and then extracted with ethyl acetate (2×50 ml). The organic phase was dried and concentrated, to obtain 3.4 g of 4-(2-chlorophenyl)-3-buten-2-one 2-oxime (E/Z mixture of oximes) as an oil in 58.1% yield.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([CH2:23][NH:24][C:25](=O)OC(C)(C)C)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1.ClCCl.CO>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([CH2:23][NH:24][CH3:25])[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(Oc2ccc(C3(CNC(=O)OC(C)(C)C)CCOCC3)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CNCC1(c2ccc(OC3CCN(C(C)C)CC3)cc2)CCOCC1
Temperature: 40 °C
Yield: 93.6 %

Procedure:
To a stirred solution of tert-butyl [4-(4-[(1-isopropylpiperidin-4-yl)oxy]phenyl)tetrahydro-2H-pyran-4-yl]methylcarbamate (532 mg, 1.23 mmol) in THF (3.5 ml) at 0° C. was added dropwise a solution of LiAlH4 (1.0M solution in Et2O, 3.69 ml, 3.69 mmol). Reaction stirred for 60 hours at ambient temperature before a further dropwise addition of LiAlH4 (1.0M solution in Et2O, 0.6 ml, 0.6 mmol). Heated at 40° C. until reaction complete. The reaction was then cooled to 0° C., water (0.2 ml) was added dropwise followed by sodium hydroxide (2.0M, 0.2 ml) and water (0.6 ml). 1% methanol in dichloromethane (10 ml) was added and the mixture filtered through a short pad of arbocel, eluting with 1% methanol in dichloromethane (25 ml). The organic washings were dried over Na2SO4 and concentrated in vacuo to give the title compound as a solid (399 mg, 94%). 1H NMR (400 MHz, CDCl3) δ 7.20 (d, 2H), 7.88 (d, 2H), 4.22-4.34 (m, 1H), 3.70-3.80 (m, 2H), 3.60-4.01 (d, 2H), 2.70-2.88 (m, 3H), 2.64 (s, 2H), 2.32-2.44 (m, 2H) 2.24 (s, 3H), 2.10-2.18 (M, 2H), 1.99-2.08 (m, 2H), 1.79-1.96 (m, 4H), 1.03 (d, 6H).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[S:7][C:6]2[C:17]3[C:22]([CH:23]=[CH:24][C:5]=2[NH:4][C:3]1=[O:25])=[CH:21][CH:20]=[CH:19][CH:18]=3.C(=O)([O-])[O-].[K+].[K+].[CH2:32]([N:34]([CH2:38][CH3:39])[CH2:35][CH2:36]Cl)[CH3:33].O>C(OCC)(=O)C>[CH2:32]([N:34]([CH2:38][CH3:39])[CH2:35][CH2:36][N:4]1[C:3](=[O:25])[C@H:2]([OH:1])[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[S:7][C:6]2[C:17]3[C:22]([CH:23]=[CH:24][C:5]1=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:33]
Reactant: CCN(CC)CCCl
Reactant: COc1ccc([C@@H]2Sc3c(ccc4ccccc34)NC(=O)[C@@H]2O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCN(CC)CCN1C(=O)[C@H](O)[C@H](c2ccc(OC)cc2)Sc2c1ccc1ccccc21
Yield: 86.9 %

Procedure:
A mixture of 4.4 g of (±)-cis-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)naphtho[1,2-b]-1,4-thiazepin-4(5H)-one, 2.0 g of potassium carbonate and 1.8 g of 2-diethylaminoethyl chloride in 100 mL ethyl acetate was stirred and heated at reflux for 2 hours then an additional 0.5 g of 2-diethylaminoethyl chloride was added four times at 2 hour intervals. The mixture was heated at reflux for a total of 12 hours, then cooled to room temperature and to the mixture ethyl acetate and water were added. The organic phase was separated, washed with brine and dried (magnesium sulfate). Removal of the solvent gave the product which after crystallization from ether afforded 4.9 g (87%) (±)-cis-5-[2-(diethylamino)ethyl]-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)naphtho[1,2-b]-1,4-thiazepin-4(5H)-one, mp 124°-125°.