Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([CH2:11][NH:12][CH:13]([CH3:15])[CH3:14])=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[N:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[N:7]=1)=[O:5])C.Cl>[OH-].[K+].CCO>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[N:8]1[C:9]([C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[C:10]([CH2:11][NH:12][CH:13]([CH3:15])[CH3:14])[C:6]([C:4]([OH:5])=[O:3])=[N:7]1
Reactant: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1CNC(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)NCc1c(C(=O)O)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Yield: 133.7 %

Procedure:
A solution of 1-(2-chloro-phenyl)-5-(4-chloro-phenyl)-4-(isopropylamino-methyl)-1H-pyrazole-3-carboxylic acid ethyl ester I-4c (32 mg, 0.074 mmol) in a 1:4 solution of 1 M KOH/EtOH (10 ml) was stirred at 50° C. for 6 hours and at 37° C. for 72 hours. The reaction mixture was treated with conc. HCl until the pH of the solution was approximately 1 and then concentrated in vacuo. The residue was diluted with EtOH and filtered. The filtrate was concentrated under vacuum to give I-4a as a white solid (40 mg, 100%): +APCI MS (M+1) 404.1.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[CH:13]=[N:12][C:11]([O:14][CH2:15][C:16]2[N:17]([CH3:28])[N:18]=[N:19][C:20]=2[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[CH:10][N:9]=1)=[O:7]>O.C1COCC1>[F:27][C:24]1[CH:23]=[CH:22][C:21]([C:20]2[N:19]=[N:18][N:17]([CH3:28])[C:16]=2[CH2:15][O:14][C:11]2[N:12]=[CH:13][C:8]([C:6]([OH:7])=[O:5])=[N:9][CH:10]=2)=[CH:26][CH:25]=1
Reactant: COC(=O)c1cnc(OCc2c(-c3ccc(F)cc3)nnn2C)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1nnc(-c2ccc(F)cc2)c1COc1cnc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
A solution of lithium hydroxide monohydrate (107 mg, 2.55 mmol) in water (3.2 mL) was added dropwise to a suspension of 5-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyrazine-2-carboxylic acid methyl ester (438 mg, 1.27 mmol) in THF (1.8 mL). The reaction mixture was then stirred at room temperature for 1 h and was then evaporated and the residue dissolved in water, acidified with HCl (1N), and the resulting precipitate filtered off to afford the title product (403 mg, 96%) as a white solid. MS: m/e=328.1 [M−H]−.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[N:11]=[C:10]([C:12](=[C:15]2[NH:19][C:18]([CH2:20][CH3:21])=[CH:17][S:16]2)[C:13]#[N:14])[CH:9]=[CH:8][N:7]=1.CCN(CC)CC.[C:29](Cl)(=[O:31])[CH3:30]>CC(N(C)C)=O>[C:13]([C:12](=[C:15]1[NH:19][C:18]([CH2:20][CH3:21])=[CH:17][S:16]1)[C:10]1[CH:9]=[CH:8][N:7]=[C:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:1][C:29](=[O:31])[CH3:30])[N:11]=1)#[N:14]
Reactant: CC(=O)Cl
Reactant: CCC1=CSC(=C(C#N)c2ccnc(NCCCN)n2)N1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CCC1=CSC(=C(C#N)c2ccnc(NCCCNC(C)=O)n2)N1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of {2-[(3-aminopropyl)amino]pyrimidin-4-yl}(4-ethyl-1,3-thiazol-2(3H)-ylidene)acetonitrile (165 mg, 0.37 mmol) in DMA (3 mL) were added and Et3N (0.048 mL, 0.37 mmol) and acetyl chloride (0.04 mL, 0.46 mmol) at 0° C. The resulting solution was stirred at 0° C. for 3 h. The solvent was evaporated under reduced pressure (Genevac) affording the title compound as a crude yellow solid. HPLC (max plot) 92%. The solid was taken up in DCM and an excess TFA was added. The yellow precipitate formed after addition of ether was filtered off and washed with ether (×3) then dried under vacuum at 40° C. After purification by preparative HPLC then lyophilization, 148 mg of the title compound was obtained as a TFA salt (yellow powder, Y=87.3%)
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[C:6]([N+:13]([O-])=O)[CH:5]=1)=[O:3]>CO.[Pd]>[NH2:10][C:8]1[CH:9]=[C:4]([CH:2]([OH:3])[CH3:1])[CH:5]=[C:6]([NH2:13])[CH:7]=1
Reactant: CC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CC(O)c1cc(N)cc(N)c1

Procedure:
3,5-Dinitroacetophenone (2.02 g, 9.5 mmol) which had been prepared according to the literature procedure (Y. Nagase et al., Macromol. Chem. Rapid Comm. (1990) 11, 185-191) was dissolved in methanol (100 ml) and hydrogenated at 60 psi using a Pd/C catalyst (5%, 100 mg). The catalyst was filtered off and the solvent was removed by evaporation. The product was used without purification in the next step. Yield: 1.22 g (84%).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[Cl:12])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[K+].Cl>C1COCC1.O.O>[Cl:12][C:6]1[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][NH2:1]
Reactant: Cc1cccc(CN=[N+]=[N-])c1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(CN)c1Cl
Reaction time: 14 h

Procedure:
1-Azidomethyl-2-chloro-3-methyl-benzene (2.99 g, 16.50 mmol) was dissolved in THF:H2O (3:1), triphenyl phosphine (4.40 g, 16.78 mmol) was added, followed by KOH (923 mg, 16.45 mmol) and the resulting mixture was stirred for 14 hours. The reaction mixture was then diluted with H2O, slowly acidified with HCl and the resulting aqueous layer was washed with Et2O (3×50 mL). The aqueous layer was then basified with NaOH (pH 14), extracted with Et2O (3×100 mL). The combined organic phases were washed with H2O (1×50 mL) and brine (1×50 mL), then dried over K2CO3 and concentrated to give the title amine.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:10][C:9]2[N:8]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([NH:19][C:20]4[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=4)[CH:12]=3)[N:7]=[C:6]([CH3:32])[C:5]=2[C:4](=[O:33])[CH2:3]1.C([OH:37])C.CS(C)=O.[OH-].[Na+].OO>O>[CH3:1][C:2]1([CH3:34])[CH2:10][C:9]2[N:8]([C:11]3[CH:18]=[CH:17][C:14]([C:15]([NH2:16])=[O:37])=[C:13]([NH:19][C:20]4[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=4)[CH:12]=3)[N:7]=[C:6]([CH3:32])[C:5]=2[C:4](=[O:33])[CH2:3]1
Reactant: CCO
Reactant: COc1cc(Nc2cc(-n3nc(C)c4c3CC(C)(C)CC4=O)ccc2C#N)cc(OC)c1OC
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(Nc2cc(-n3nc(C)c4c3CC(C)(C)CC4=O)ccc2C(N)=O)cc(OC)c1OC
Yield: 99 %

Procedure:
To a mixture of 4-(6,6-dimethyl-4-oxo-3-methyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(3,4,5-trimethoxyanilino)-benzonitrile (1.56 g, 3.39 mmol, 1.0 eq.) in 17 mL of a mixture of 4:1 ethanol-dimethyl sulfoxide was added 2 mL of 1 M aqueous sodium hydroxide and 2 mL of 30% hydrogen peroxide. After 3 hours the reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound, 4-(6,6-dimethyl-4-oxo-3-methyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(3,4,5-trimethoxyanilino)-benzamide, (1.61 g, 99%) as a tan solid: LC/MS (m/z): [M+H]+ 479.3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]([C@@:8]([OH:12])([CH3:11])[CH2:9]O)[CH:7]=1.S(Cl)(C)(=O)=O.Cl.CCCCCC.CCO>C(Cl)Cl.CCCCCC.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]([C@@:8]2([CH3:11])[CH2:9][O:12]2)[CH:7]=1
Reactant: C[C@@](O)(CO)c1cc(Br)ccc1F
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C[C@]1(c2cc(Br)ccc2F)CO1
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-2-(5-bromo-2-fluoro-phenyl)-propane-1,2-diol (37.35 g, 150 mmol) in CH2Cl2 (400 ml) was added under argon NEt3 (41.8 ml, 300 mmol) and dropwise mesyl chloride (12.8 ml, 165 mmol) at 0-5° C. After stirring for 0.5 h at 0-5° C. the reaction mixture was added to cold 1N HCl and extracted with CH2Cl2. Combined extracts were washed with 1N HCl, H2O and saturated NaHCO3 solution, dried over MgSO4, filtered and concentrated. The crude mesylate was dissolved in TBME (500 ml) and 200 ml 2N aqueous NaOH and after stirring for 2 h at 25° C. the mixture was extracted with TBME. Combined extracts were washed with NaH2PO4 solution and brine, dried over MgSO4, filtered and concentrated to provide the (S)-enantiomer as a colorless oil: 78% ee (Chiralpak AS-H 1218, hexane-EtOH 97:3, 0.4 mL/min); TLC (hexane-EtOAc 3:1): Rf=0.69; UPLC RtH5=1.186 min; 1H NMR (360 MHz, CDCl3): δ 7.46 (dd, 1H), 7.30 (m, 1H), 6.83 (dd, 1H), 2.88 (d, 1H), 2.72 (d, 1H), 1.59 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:14][CH2:15]Cl)(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].[C:17]([NH:25][CH:26]([P:36]([CH2:39][C:40]([N:42]1[CH2:56][CH2:55][CH2:54][C@H:43]1[C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])=[O:41])([OH:38])=[O:37])[CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O.C(OCC)(=O)C>[C:17]([NH:25][CH:26]([P:36]([CH2:39][C:40]([N:42]1[CH2:56][CH2:55][CH2:54][C@H:43]1[C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])=[O:41])([O:38][CH2:15][O:14][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[O:37])[CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: O=C(NC(CCCc1ccccc1)P(=O)(O)CC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCOP(=O)(CC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)C(CCCc1ccccc1)NC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
A equimolar mixture of triethylamine and chloromethyl pivalate are added to a solution of (±)-1-[[[1-(benzoylamino)-4-phenylbutyl]hydroxyphosphinyl]acetyl]-L-proline, phenylmethyl ester, prepared for example as set forth in Example 20 (d), in dimethylformamide under an argon atmosphere. The mixture is stirred for several hours at room temperature, diluted with ethyl acetate, washed with water, brine, dried (MgSO4), and evaporated. The crude product is chromatographed to give (±)-1-[[[1-(benzoylamino)-4-phenylbutyl][(2,2-dimethyl-1-oxopropoxy)methoxy]phosphinyl]acetyl]-L-proline, phenylmethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[OH:15].[O:16]([CH2:23][CH2:24][CH2:25]O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[O:15][CH2:25][CH2:24][CH2:23][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCCCOc1ccccc1
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCCOc2ccccc2)c(Cl)c1
Temperature: 25 °C
Yield: 81.9 %

Procedure:
To a solution of 0.30 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol, 0.16 g of 3-phenoxy-1-propanol and 0.27 g of triphenylphosphine dissolved in 10 ml of tetrahydrofuran was added dropwise a solution of 0.21 g of diisopropylazodicarboxylate dissolved in 5 ml of tetrahydrofuran, while stirring at room temperature. After stirring at room temperature for 24 hours, the reaction mixture was concentrated to obtain a residue. The residue was subjected to silica gel chromatography, which afforded 0.36 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(3-phenoxypropyloxy)benzene (82% yield), nD25.0 1.5762.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[S:32]1[CH2:35][CH:34](O)[CH2:33]1.[C:37]([O:41][C:42](=[O:50])[NH:43][CH:44]1[CH2:48][O:47][NH:46][C:45]1=[O:49])([CH3:40])([CH3:39])[CH3:38]>C1COCC1>[C:37]([O:41][C:42](=[O:50])[NH:43][C@@H:44]1[CH2:48][O:47][N:46]([CH:34]2[CH2:35][S:32][CH2:33]2)[C:45]1=[O:49])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)NC1CONC1=O
Reactant: OC1CSC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CON(C2CSC2)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 13.9 %

Procedure:
A solution of triphenylphosphine (0.79 g) in THF (22 ml) was cooled under argon to −10° C. Diethylazodicarboxylate (DEAD, 1.57 g) was added dropwise then thietan-3-ol (0.4 g) and (3-oxo-isoxazolidin-4-yl)-carbamic acid tert-butyl ester (0.27 g, prepared from (D)-cycloserine as described in Chem. Pharm. Bull. 2002, 50(4) 554-557). The reaction mixture was stirred at room temperature for 24 hours then the solvent was removed in vacuo. The crude product was purified by column chromatography (eluent cyclohexane/ethyl acetate) to afford the title product as a white solid (51 mg). 1H-NMR (CDCl3, 400 MHz): 5.45 (q, 1H), 5.05 (m, 1H), 4.90 (m, 1H), 4.50 (t, 1H), 4.10 (dd, 1H), 3.55 (m, 2H), 3.40 (m, 2H), 1.50 (s, 9H).
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[C:20]3=[N:21][S:22](=[O:26])(=[O:25])[CH2:23][CH2:24][N:19]3[CH2:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.Cl>CC(O)=O>[O:26]=[S:22]1(=[O:25])[CH2:23][CH2:24][N:19]2[CH2:18][CH2:17][CH2:16][CH:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=3)[C:20]2=[N:21]1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C2CCCN3CCS(=O)(=O)N=C23)cc1
Agent: Cl
Solvent: CC(=O)O
Product: O=S1(=O)CCN2CCCC(c3ccc(O)cc3)C2=N1
Temperature: 60 °C
Reaction time: 2 h
Yield: 101.2 %

Procedure:
A mixture of 9-(4-((tert-butyldimethylsilyl)oxy)phenyl)-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (6.97 g) and 6 M HCl aq. (10.0 mL) in AcOH (100 mL) was stirred at 60° C. for 2 hr. After cooling to room temperature, the solvent was removed in vacuo. The residual solid was recrystallized from MeOH—IPE to give the title compound (5.01 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[C:3]=1[CH3:10].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl[CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH3:25]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH3:25])=[C:4]([CH3:9])[C:3]=1[CH3:10]
Reactant: Cc1c(O)ccc(Br)c1C
Reactant: CCCOCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOCCOc1ccc(Br)c(C)c1C
Temperature: 25 °C
Reaction time: 10 h

Procedure:
In DMF (82 ml) was dissolved 4-bromo-2,3-dimethylphenol (8.2 g). To the mixture were added potassium carbonate (7.3 g) and sodium iodide (6.1 g) and then was added dropwise 2-chloroethylpropylether (6.2 ml), and the mixture was stirred at 90 for 10 hours and cooled to room temperature. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, 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 (hexane/ethyl acetate=12/1) to give 4-bromo-2,3-dimethyl-1-(2-propoxyethoxy)benzene (7.5 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][C:3]=1[O:13][CH3:14].CS(O)(=O)=O.[OH-].[Na+]>>[F:1][C:2]1[CH:7]=[C:6]2[C:5]([CH2:8][CH2:9][C:10]2=[O:12])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: COc1cc(CCC(=O)O)ccc1F
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2c(cc1F)C(=O)CC2
Temperature: 90 °C
Yield: 94.4 %

Procedure:
3-(4-Fluoro-3-methoxy-phenyl)-propionic acid (2 g, 10 mmol) and Methanesulfonic acid (15 ml) were sealed in process vial (20 ml) and it was heated at 90° C. for 10 minutes under microwave irradiation. The mixture was poured into ice and neutralized with NaOH. The solid was collected and dried to give 1.7 g of product (93.5% yield). LC-MS: m/e 181 (MH+)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([NH2:30])=[CH:11][C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:14]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:13]=2[CH:29]=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([NH:30][S:39]([C:36]2[CH:37]=[CH:38][C:33]([Cl:32])=[CH:34][CH:35]=2)(=[O:41])=[O:40])=[CH:11][C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:14]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:13]=2[CH:29]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)CCCCOc1cc2c(cc1N)nc(-c1ccccc1)n2-c1ccccc1
Product: COC(=O)CCCCOc1cc2c(cc1NS(=O)(=O)c1ccc(Cl)cc1)nc(-c1ccccc1)n2-c1ccccc1

Procedure:
5-[(5-Amino-1,2-diphenyl-1H-benzimidazol-6-yl)oxy]pentanoic acid methyl ester was reacted with 4-chlorobenzenesulfonic acid chloride according to general operating instructions 13.
Reaction SMILES: O1CCCC1.[C:6]([O:10][C:11](=[O:51])[N:12]([CH2:40][C:41]1[CH:50]=[CH:49][C:44]2[O:45][CH2:46][CH2:47][O:48][C:43]=2[CH:42]=1)[CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][N:21]2[C:30]3[C:25](=[C:26]([C:33](=[O:38])N(OC)C)[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=3)[CH:24]=[CH:23][C:22]2=[O:39])[CH2:15][CH2:14]1)([CH3:9])([CH3:8])[CH3:7].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[Cl-].[NH4+]>C(OCC)(=O)C>[C:6]([O:10][C:11](=[O:51])[N:12]([CH2:40][C:41]1[CH:50]=[CH:49][C:44]2[O:45][CH2:46][CH2:47][O:48][C:43]=2[CH:42]=1)[CH:13]1[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][N:21]2[C:30]3[C:25](=[C:26]([CH:33]=[O:38])[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=3)[CH:24]=[CH:23][C:22]2=[O:39])[CH2:17][CH2:18]1)([CH3:9])([CH3:7])[CH3:8]
Reactant: COc1cc(C(=O)N(C)OC)c2ccc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1cc(C=O)c2ccc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Reaction time: 1 h
Yield: 68.2 %

Procedure:
To 20 mL of a tetrahydrofuran solution containing 1.05 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-methoxy-5-((methoxy)(methyl)carbamoyl)-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 4.95 mL of 1 mol/L diisobutyl aluminum hydride/toluene was added at −78° C. and stirred for 1 hour. To the reaction mixture, aqueous saturated ammonium chloride solution and ethyl acetate were added. The organic layer was separated, washed sequentially with aqueous saturated sodium hydrogen carbonate solution and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; chloroform:methanol=10:1], to give 0.65 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-formyl-7-methoxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a colorless oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3](/[CH:6]=[CH:7]/[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:2]1.O.NN.C(O)(=O)C.I([O-])(=O)(=O)=O.[Na+]>C(O)C.O.[Cu]=S>[O:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:2]1
Reactant: CCOC(=O)/C=C/c1ccoc1
Agent: S=[Cu]
Agent: NN
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCc1ccoc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 8.186 g (49.26 mmol) of ethyl (E)-3-(3-furyl)acrylate, 24.7 g (493 mmol) of hydrazine monohydrate, 5 ml of acetic acid and 5 ml of saturated aqueous copper sulfide in 500 ml of ethanol, a solution of 52.7 g (246 mmol) of sodium periodate in 300 ml of water was added dropwise over a period of 1 hour, followed by stirring at room temperature for 1 day. The reaction mixture was extracted with ether 3 times. The combined organic layer was washed with dilute hydrochloric acid and then aqueous sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=15/1) to yield the desired product.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:19][CH2:18][C@H:17]([OH:20])[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[CH2:10]1.FC1C(F)=CC=CC=1[C@H]1CC[C@@H](O)C2=NC=CC=C2C1>CO>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1=[CH:10][C:11]2[C:12]([CH:17]([OH:20])[CH2:18][CH2:19]1)=[N:13][CH:14]=[CH:15][CH:16]=2
Reactant: O[C@H]1CC[C@H](c2cccc(F)c2F)Cc2cccnc21
Agent: O[C@@H]1CC[C@H](c2cccc(F)c2F)Cc2cccnc21
Solvent: CO
Product: OC1CCC(c2cccc(F)c2F)=Cc2cccnc21

Procedure:
Racemic trans-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol and cis-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol. In a 500 mL round-bottomed flask was (E)-6-(2,3-difluorophenyl)-8,9-dihydro-7H-cyclohepta[b]pyridin-9-ol (660 mg, 2.415 mmol) in MeOH (20 mL) to give a colorless solution. Pd/C (257 mg, 0.242 mmol) was added, and the mixture was stirred under hydrogen balloon for 4 h. LCMS showed complete conversion. Filtered and concentrated to a colorless oil. Purification by FCC up to 80% EtOAc/hexane afforded two products: trans-alcohol (104.3 mg, 16%), and cis-alcohol (492.8 mg, 74%), both as white solids. Analytical data of both alcohols matched that of previously described.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][C:6]([O:24][CH3:25])=[C:7]([O:22][CH3:23])[CH:8]=2)[N:3]=1.[N:26]1([CH2:32][CH2:33][NH2:34])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:23][O:22][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[O:24][CH3:25])[N:3]=[C:2]([NH:34][CH2:33][CH2:32][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[N:11]=[C:10]2[N:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH3:13]
Reactant: COc1ccc(N(C)c2nc(Cl)nc3cc(OC)c(OC)cc23)cc1
Reactant: NCCN1CCOCC1
Product: COc1ccc(N(C)c2nc(NCCN3CCOCC3)nc3cc(OC)c(OC)cc23)cc1

Procedure:
The title compound was prepared from (2-chloro-6,7-dimethoxyquinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (50 mg, 0.139 mmol) and 2-morpholin-4-yl-ethylamine (25 μL, 0.167 mmol) by a procedure similar to example 10 and was isolated as white powder (27 mg, 54%). 1H NMR (CDCl3): 7.21 (d, J=8.4 Hz, 2H), 7.00 (d, J=8.4 Hz, 2H), 6.93 (s, 1H), 6.13 (s, 1H), 3.95 (s, 3H), 3.84 (s, 3H), 3.77-3.74 (m, 4H), 3.71-3.66 (m, 2H), 3.60 (s, 3H), 3.25 (s, 3H), 2.70 (t, J=7.2 Hz, 2H), 2.59-2.56 (m, 4H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mg].[CH3:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH:16]=[O:17]>C1COCC1>[CH3:12][C:13]1[CH:14]=[C:15]([CH:16]([OH:17])[CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1ccc(C=O)cc1C
Reactant: BrCCCc1ccccc1
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(C(O)CCCc2ccccc2)cc1C
Temperature: 25 °C
Yield: 58.7 %

Procedure:
3-Phenyl-1-1-propyl magnesium bromide was prepared from the reaction of 3-phenyl-1-bromopropane (8.0 mL. 52.6 mmol) and magnesium turnings (1.40 g, 57.6 mmol) in THF. This solution was added dropwise to an ice-water cooled solution of 3-methyl-para-anisaldehyde (7.70 mL. 52.6 mmol) in THF. The resulting reaction was allowed to warm to room temperature, and after 1h was partitioned between aqueous ammonium chloride and ether. The organic phase was dried over magnesium sulfate, concentrated, and purified by chromatography over silica gel eluted with 15% ethyl acetate in hexanes to afford 8.35 g of 2-methyl-4-(1-hydroxy-4-phenyl-1-butyl) anisole as a clear oil.