Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O)(=O)=O.[CH:6]1([C:12]2[C:20]3[C:19](=[O:21])[NH:18][C:17]([C:22]4[CH:27]=[CH:26][C:25]([N:28]5CCC(O)CC5)=[CH:24][C:23]=4OC)=[N:16][C:15]=3[N:14]([CH3:37])[N:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[N+](C1C=CC(C(Cl)=O)=CC=1)([O-])=O>N1C=CC=CC=1>[NH2:28][C:25]1[CH:26]=[CH:27][C:22]([C:17]2[NH:18][C:19](=[O:21])[C:20]3[C:12]([CH:6]4[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]4)=[N:13][N:14]([CH3:37])[C:15]=3[N:16]=2)=[CH:23][CH:24]=1
Reactant: COc1cc(N2CCC(O)CC2)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Agent: CS(=O)(=O)O
Agent: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Product: Cn1nc(C2CCCCC2)c2c(=O)[nH]c(-c3ccc(N)cc3)nc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 29.7 %

Procedure:
To a pyridine solution of 2.2 g (10 mmol) of the compound obtained in Example 32, 2.2 g (13 mmol) of p-nitrobenzoyl chloride was added, and the mixture was stirred at room temperature for 1.5 hours. Then, the reaction mixture was distilled under reduced pressure, and an aqueous solution of sodium hydrogen carbonate was added to the residue, followed by extracting the mixture with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate, followed by distilling off the solvent under reduced pressure. To the residue, 30 ml of methanol and 400 mg of 10% palladium carbon were added. The mixture was stirred for 8 hours in an atmosphere of hydrogen at room temperature and atmospheric pressure. Then, the catalyst was removed by filtration, and the filtrate was distilled under reduced pressure. To the residue, 80 ml of ethanol and 40 ml of a 1M aqueous solution of sodium hydroxide were added, followed by heating the mixture under reflux for 5 hours. Then, the reaction mixture was cooled to room temperature, diluted with water, and extracted with chloroform. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=30/1) to obtain 960 mg (30%) of the captioned compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH2:18][CH3:19])=[N:11][C:12]([N+:15]([O-])=O)=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[NH4+].[Cl-]>CO.C1COCC1.[Zn]>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[N:11][C:10]=2[CH2:18][CH3:19])[CH:5]=[CH:4][N:3]=1
Reactant: CCc1nc([N+](=O)[O-])ccc1Oc1ccnc(Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1nc(N)ccc1Oc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
A suspension of Example A8 (1.3 g, 4.65 mmol) and NH4Cl (7.5 g, 140 mmol) in MeOH (24 mL) and THF (24 mL) was treated portion-wise with zinc dust (3 g, 45.9 mmol) and stirred at RT overnight. The solids were removed via filtration through diatomaceous earth and the filtrate concentrated to dryness to afford 5-((2-chloropyridin-4-yl)oxy)-6-ethylpyridin-2-amine (1.1 g, 85%). MS (ESI) m/z: 250.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:12][CH2:13][CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Br:22]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:12][CH2:13][CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:22])[N:6]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCCSc1nc(N)c2ncn(Cc3ccccc3)c2n1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCSc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 16 %

Procedure:
6-Amino-9-benzyl-2-propylthiopurine (290 mg, 0.97 mmol) and bromine (0.7 ml) were dissolved in 160 ml of methylene chloride and the solution was stirred at room temperature for 4.5 hours. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on magnesium sulfate and filtered. The solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (58 mg, yield 16%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=2)=[CH:6][C:5]([Cl:17])=[CH:4][C:3]=1[CH2:18][C:19]([OH:21])=[O:20].[Na].[CH2:23](I)[CH3:24]>CN(C)C=O.O>[NH2:1][C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=2)=[CH:6][C:5]([Cl:17])=[CH:4][C:3]=1[CH2:18][C:19]([O:21][CH2:23][CH3:24])=[O:20]
Reactant: CCI
Reactant: Nc1c(CC(=O)O)cc(Cl)cc1C(=O)c1ccc(Br)cc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1cc(Cl)cc(C(=O)c2ccc(Br)cc2)c1N
Yield: 91.3 %

Procedure:
A solution of 40.9 g (0.1 mole) of 2-amino-3-(4-bromobenzoyl)-5-chlorobenzeneacetic acid, sodium salt, monohydrate in 400 ml of dimethylformamide was treated with 32.0 g (0.2 mole) of ethyl iodide and the solution was let stand at ambient temperature overnight. The solution was poured in 3.5 liters of cold water and a solid gradually crystallized. The solid was collected by filtration, washed with water, and recrystallized from absolute ethanol to yield 36.2 g (91%) of title compound, a yellow solid, m.p. 92°-94° C.
Reaction SMILES: [C:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[N:6]=[CH:5][C:4]=1[C:15]([O:17]CC)=[O:16])#[N:2].[OH-].[K+].C([OH:24])C>O>[C:15]([C:4]1[CH:5]=[N:6][N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[C:3]=1[C:1]([NH2:2])=[O:24])([OH:17])=[O:16]
Reactant: CCO
Reactant: CCOC(=O)c1cnn(-c2cccc(F)c2)c1C#N
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1c(C(=O)O)cnn1-c1cccc(F)c1

Procedure:
A 5.5 g. portion of ethyl 5-cyano-1-(3-fluorophenyl)-4-pyrazolecarboxylate and 4.7 g. of potassium hydroxide were dissolved in 100 ml. of ethanol at the reflux temperature and the mixture was stirred at that temperature for2 hours. The mixture was then diluted to 350 ml. with cold water, and was heated slightly to obtain a solution which was made acid with concentratedhydrochloric acid. The product was precipitated by adding small amounts of ice, and the precipitated product was then collected by filtration and crystallized from ethanol-water to obtain 3.6 g. of the desired product, m.p. 215°-216°, having the following elemental analysis.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[CH3:15][C:16]1[N:17]=[C:18]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[S:19][C:20]=1[C:21](Cl)=[O:22].C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:21]([C:20]1[S:19][C:18]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:17][C:16]=1[CH3:15])=[O:22]
Reactant: Cc1nc(-c2ccccc2)sc1C(=O)Cl
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccccc2)sc1C(=O)NCCc1c[nH]c2ccc(Cl)cc12
Yield: 75.1 %

Procedure:
This compound was obtained following Method B starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.0452 g, 0.192 mmol), 4-methyl-2-phenylthiazole-5-carbonyl chloride (0.047 g; 0.192 mmol), and triethylamine (0.067 mL; 0.479 mmol) in dichloromethane (3 mL). Flash chromatography on silica gel eluting with 3 to 30% of ethyl acetate in dichloromethane gave 0.0571 g (75%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-methyl-2-phenylthiazole-5-carboxamide as a solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([C:10]1[N:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]2=[N:12][C:11]=1[C:19]([O-])=[O:20])[CH2:8][CH3:9]>C1COCC1>[OH:20][CH2:19][C:11]1[N:12]=[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]2[C:10]=1[CH2:7][CH2:8][CH3:9]
Reactant: CCCc1c(C(=O)[O-])nc2ccccn12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCc1c(CO)nc2ccccn12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of LiAlH4 (1M in THF, 4.0 mL, 4.0 mmol) is added to a solution of 3-(1-propyl)-imidazolo[1,2-a]pyridine-2-carboxylate (1 g, 4.3 mmol) in anhydrous THF (50 mL) at 0° C. under nitrogen with magnetic stirring. The resulting pale yellow solution is stirred at 0° C. for 4 h and then quenched by addition of 75 mL of EtOAc and 2 mL saturated aqueous Na2SO4. The resulting mixture is stirred for 1 hour at ambient temperature, dried over anhydrous Na2SO4, filtered through celite and evaporated at reduced pressure to obtain 2-hydroxymethyl-3-(1-propyl)-imidazolo[1,2-a]pyridine as a colorless film. TLC (10% MeOH/CH2Cl2) Rf=0.15. Step 4. Preparation of 2-chloromethyl-3-(1-propyl)-imidazolo[1,2-a]pyridine
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](OC1C=CC=CC=1)=[N:7][CH:6]=[CH:5]2.C([O-])(=O)C.[NH4+:23].[OH-].[Na+]>>[NH2:23][C:8]1[C:9]2[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Brc1ccc2c(Oc3ccccc3)nccc2c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: Nc1nccc2cc(Br)ccc12
Temperature: 150 °C
Yield: 71.8 %

Procedure:
A mixture of 12 g of 1c and 27 g of ammonium acetate was heated at 150° C. for 14 hours. After cooling to room temperature aqueous 3N NaOH was added and the mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with brine and aqueous 2N hydrochloric acid was added until pH2-3. The acid aqueous layer was separated, made basic (pH10) with aqueous 2N NaOH and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried (MgSO4) and concentrated to give 6.4 g of 1d. 1H-NMR 200 MHz (CDCl3) δ: 5.1 (2H, br s), 6.96 (1H, dd, J=6 Hz and J=1 Hz), 7.54-7.70 (2H, m), 7.88 (1H, d, J=2 Hz), 7.98 (1H, d J=6 Hz).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([O:17]C)=O.[NH2:19][C:20]1[C:21](=[O:28])[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=1>C1(C)C(C)=CC=CC=1>[Cl:27][C:24]1[CH:23]=[CH:22][C:21](=[O:28])[C:20]([NH:19][C:15]([C:3]2[N:4]([CH3:14])[S:5](=[O:12])(=[O:13])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:2]=2[OH:1])=[O:17])=[CH:26][CH:25]=1
Reactant: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Reactant: Nc1ccc(Cl)ccc1=O
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2ccc(Cl)ccc2=O)=C(O)c2ccccc2S1(=O)=O
Temperature: 25 °C
Yield: 40.7 %

Procedure:
A mixture of methyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (1.5 g) and 2-amino-5-chloro-2,4,6-cycloheptatrien-1-one (0.87 g) in xylene (37 ml) was refluxed for 24 hours. The reaction mixture was cooled to room temperature. The crystals were collected by filtration and recrystallized from N,N-dimethylformamide to give N-(5-chloro-1-oxo-2,4,6-cycloheptatrien-2-yl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide (0.89 g).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:25]=[C:26]1[C:32]2=[CH:33][C:34]3[CH:35]=[CH:36][C:37]([C:40]([OH:42])=O)=[CH:38][C:39]=3[N:31]2[CH2:30][CH2:29][CH2:28][NH:27]1.C(N=P1N(C)CCCN1C)(C)(C)C.[F:56][C:57]([F:65])([F:64])[C:58]1[CH:62]=[C:61]([NH2:63])[O:60][N:59]=1>ClC(Cl)C>[O:25]=[C:26]1[C:32]2=[CH:33][C:34]3[CH:35]=[CH:36][C:37]([C:40]([NH:63][C:61]4[O:60][N:59]=[C:58]([C:57]([F:65])([F:64])[F:56])[CH:62]=4)=[O:42])=[CH:38][C:39]=3[N:31]2[CH2:30][CH2:29][CH2:28][NH:27]1
Reactant: Nc1cc(C(F)(F)F)no1
Reactant: O=C(O)c1ccc2cc3n(c2c1)CCCNC3=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN1CCCN(C)[PH]1=NC(C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(Cl)Cl
Product: O=C(Nc1cc(C(F)(F)F)no1)c1ccc2cc3n(c2c1)CCCNC3=O
Temperature: 60 °C
Yield: 15.5 %

Procedure:
A mixture of HATU (0.086 g, 0.225 mmol) and 1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxylic acid (Intermediate J, 0.050 g, 0.205 mmol) in dichlorethane (1 mL) in a microwave vial is heated in a microwave reactor at 60° C. for 60 minutes. Polystyrene bound 2-tert-butylimino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (0.307 g, 0.615 mmol) and 3-trifluoromethyl-isoxazol-5-ylamine (0.094 g, 0.615 mmol) are added to the mixture and the vial is heated in a microwave at 120° C. for an additional 60 minutes. The resin is filtered off and washed several times with DMF. After the removal of solvent, the residue is purified by flash column chromatography using 5% methanol/dichlorormethane to afford title compound (0.012 g, 15.5%) as a white solid.
Reaction SMILES: CC1C=CC(S(O[N:12]=[C:13]2[C:22]3[CH:21]=[N:20][CH:19]=[CH:18][C:17]=3[CH2:16][CH2:15][CH2:14]2)(=O)=O)=CC=1.C([O-])(=[O:25])C.[K+]>C(O)C.O>[NH:12]1[C:13](=[O:25])[CH2:14][CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][N:20]=[CH:21][C:22]1=2
Reactant: CC(=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)ON=C2CCCc3ccncc32)cc1
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C1CCCc2ccncc2N1
Yield: 27.6 %

Procedure:
A solution of 8-(4-methylphenylsulfonyl)oxyimino-5,6,7,8-tetrahydroisoquinoline (1.2 g) and potassium acetate (7.45 g) in ethanol (25 ml) and water (30 ml) was heated at 95° C. for 23 hours. The solvent was evaporated at reduced pressure, and the residue was basified with saturated aqueous sodium hydrogencarbonate solution and extracted with chloroform. The dried extract (dried over sodium sulfate) was evaporated at reduced pressure to give crude product. After partial purification by column chromatography (SiO2; 30 g, AcOEt/hexane=2/1, then 5% MeOH—CHCl3), the obtained solid was washed with ether to give 2,3,4,5-tetrahydro-1H-pyrido[3,4-b]azepin-2-one (170 mg).
Reaction SMILES: [F:1][C:2]([F:17])([C:13]([F:16])([F:15])[F:14])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[S:5](F)(=[O:7])=[O:6].C(N(C(C)C)C(C)C)C.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[OH:46])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>CN(C1C=CN=CC=1)C.ClCCCl>[C:27]([O:31][C:32]([N:34]1[CH2:35][CH2:36][CH:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[O:46][S:5]([C:4]([F:9])([F:10])[C:3]([F:11])([F:12])[C:2]([F:1])([F:17])[C:13]([F:16])([F:15])[F:14])(=[O:7])=[O:6])[CH2:38][CH2:39]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2O)CC1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.6 %

Procedure:
Nonafluoro-butane-1-sulfonyl fluoride (2.71 mL; 15.1 mmol) was added to a mixture of ethyl-diisopropyl-amine (2.87 mL; 16.5 mmol), 4-(N,N-dimethylamino)-pyridine (25 mg) and 4-(2-hydroxy-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (3.81 g; 13.7 mmol) in 50 ml 1,2-dichloro-ethane at 0° C. under argon. The reaction mixture was allowed to warm to room temperature and stirred 16 hours. The reaction mixture was extracted with water (100 mL) and brine (100 mL). The combined aqueous phases were extracted with ethyl acetate (100 mL). The combined organic phases were washed with brine (100 mL), dried with MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (silica gel; ethyl acetate/heptane) to give 4.34 g 4-[2-(nonafluorobutane-1-sulfonyloxy)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester (7.76 mmol; 57%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]2[C:19](=[O:20])[O:18][C@H:17]3[C:21]4[C@@:26]([CH3:29])([CH2:27][CH2:28][C:16]23[OH:31])[CH2:25][CH2:24][CH2:23][C:22]=4[CH3:30])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.CC(C[AlH]CC(C)C)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]2[CH:19]([OH:20])[O:18][C@H:17]3[C:21]4[C@@:26]([CH3:29])([CH2:27][CH2:28][C:16]23[OH:31])[CH2:25][CH2:24][CH2:23][C:22]=4[CH3:30])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1=C2[C@@H]3OC(=O)C(CN4CCN(Cc5ccccc5)CC4)C3(O)CC[C@@]2(C)CCC1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC1=C2[C@@H]3OC(O)C(CN4CCN(Cc5ccccc5)CC4)C3(O)CC[C@@]2(C)CCC1
Reaction time: 3 h

Procedure:
Compound of example 27 (200 mg, 0.47 mmol) was dissolved in anhydrous DCM and toluene (1:1) (2 mL) and solution was cooled to −78° C. DIBAL in toluene (1.0 M, 1.4 mL, 1.2 equivalents) was added dropwise at −78° C. and mixture was stirred for 3 hours. Saturated sodium sulphate solution was added and reaction mixture was extracted by DCM (3×50 mL), dried over sodium sulphate and was concentrated to obtain the title compound.
Reaction SMILES: CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH3:32][O:33][C:34]1[CH:39]=[C:38]([CH3:40])[C:37]([S:41]([N:44]2[CH2:49][CH2:48][CH2:47][CH2:46][C@H:45]2[CH2:50][O:51][CH2:52][C:53]([OH:55])=O)(=[O:43])=[O:42])=[C:36]([CH3:56])[CH:35]=1.[N:57]1[CH:62]=[CH:61][C:60]([C:63]2([O:76][CH2:77][CH2:78][N:79]3[CH2:83][CH2:82][CH2:81][CH2:80]3)[CH2:68][CH2:67][N:66](C(OC(C)(C)C)=O)[CH2:65][CH2:64]2)=[CH:59][CH:58]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:32][O:33][C:34]1[CH:39]=[C:38]([CH3:40])[C:37]([S:41]([N:44]2[CH2:49][CH2:48][CH2:47][CH2:46][C@H:45]2[CH2:50][O:51][CH2:52][C:53]([N:66]2[CH2:67][CH2:68][C:63]([C:60]3[CH:59]=[CH:58][N:57]=[CH:62][CH:61]=3)([O:76][CH2:77][CH2:78][N:79]3[CH2:83][CH2:82][CH2:81][CH2:80]3)[CH2:64][CH2:65]2)=[O:55])(=[O:43])=[O:42])=[C:36]([CH3:56])[CH:35]=1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCC[C@H]2COCC(=O)O)c(C)c1
Reactant: CC(C)(C)OC(=O)N1CCC(OCCN2CCCC2)(c2ccncc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C)c(S(=O)(=O)N2CCCC[C@H]2COCC(=O)N2CCC(OCCN3CCCC3)(c3ccncc3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
DIPEA (4 eq.), EDCl (1.2 eq.) and HOBt (1 eq.) were added to a solution of (S)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetic acid [acid D] (0.65 mmol) in methylene chloride (5 ml). tert-Butyl 4-(pyridin-4-yl)-4-(2-(pyrrolidin-1-yl)ethoxy)piperidine-1-carboxylate [amine J] (0.78 mmol) [Boc-deprotected in the presence of TFA (10-13 eq.) in methylene chloride (see e.g. stage (iii)/amine H)] and DIPEA (2 eq.) were added dropwise in methylene chloride (3 ml) to the reaction mixture, while cooling with ice, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride and washed with saturated ammonium chloride solution, saturated sodium chloride solution, saturated sodium bicarbonate solution and finally with sat. sodium chloride solution again. The organic phase was dried over sodium sulfate and concentrated to dryness on a rotary evaporator. The crude product was purified by means of column chromatography (silica gel, methanol/methylene chloride) to obtain the desired product. Yield: 36%. MS, Rt=2.6 min, m/z=629.4 [MH]+
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([S:7]([O:10][CH2:11][C@H:12]([C:14]2([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH3:13])(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(N(CC)CC)C.C1(S)C=CC=CC=1.O>CN(C)C=O>[C:1]1([CH3:20])[CH:2]=[CH:3][C:4]([S:7]([O:10][CH2:11][C@@H:12]([C:14]2([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH3:13])(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](C)C2(O)CCCC2)cc1
Agent: Sc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)OC[C@H](C)C2(O)CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
To a mixture of 4a (3.65 g, 11.9 mmol) and triethylamine (2.5 mL) in N, N-dimethylformamide (18 mL) was added thiophenol (1.8 mL) in one portion. The mixture was stirred at ambient temperature overnight. The mixture was poured into water, and extracted with diethyl ether. The combined organic layers were washed with sodium bicarbonate solution and brine, and dried over sodium sulfate. Filtration and concentration gave 3.26 g of an oily material, which was purified by column chromatography (silica gel 40 g, ethyl acetate in n-hexane, 2.5-20%) to give 2.06 g (73.3%) of 5a, as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=1[CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.CN([CH:29]=[O:30])C.Cl>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:29]=[O:30])=[CH:11][C:10]=1[CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(OCc2ccccc2)c(C2CCCC2)c1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(OCc2ccccc2)c(C2CCCC2)c1
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
A stirred solution of 1-benzyloxy-4-bromo-2-cyclopentyl-benzene (1500 mg, 4.53 mmol) in tetrahydrofuran (13.4 mL) was cooled to −65° C. n-BuLi (3.11 mL of 1.6 M, 4.98 mmol) was added dropwise over several minutes. After 30 min, DMF (497 mg, 526.0 μL, 6.79 mmol) was added dropwise over a period of 10 min. Stirring at −65° C. was maintained for 20 min, and then the reaction was quenched by the addition of HCl (9.06 mL of 1 M, 9.06 mmol). The aqueous and organic layers were separated. The organic layer was washed with saturated NaHCO3 (10 mL) and water (10 mL), dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (0-10% ethyl acetate/hexanes) provided 4-benzyloxy-3-cyclopentyl-benzaldehyde (800 mg, 63% yield) white solid. 1H NMR (400.0 MHz, DMSO-d6) δ 9.86 (s, 1H), 7.76 (dd, J=2.1, 6.6 Hz, 2H), 7.49-7.29 (m, 5H), 7.26-7.20 (m, 1H), 5.26 (s, 2H), 3.37-3.26 (m, 1H), 2.00-1.90 (m, 2H), 1.73-1.50 (m, 6H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[C:18]([F:27])[CH:17]=1)[C:10]([CH3:29])([CH3:28])[CH2:9]2)=[O:5])C.O.[OH-].[Li+].O.Cl>CO.O1CCCC1>[F:27][C:18]1[CH:17]=[C:16]([CH:11]2[C:10]([CH3:28])([CH3:29])[CH2:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=3)[NH:12]2)[CH:21]=[C:20]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:19]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(F)cc(N3CCCC3)c1)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cc(F)cc(N2CCCC2)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 60.3 %

Procedure:
A mixture of 2-(3-fluoro-5-pyrrolidin-1-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.18 g, 0.45 mmol), lithium hydroxide hydrate (0.19 g, 4.5 mmol), water (1 mL) in methanol (3 mL) and tetrahydrofuran (10 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(3-fluoro-5-pyrrolidin-1-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 60%) as a white solid which was used for next step without further purification: LC/MS m/e calcd for C22H25FN2O2 (M+H)+: 369.5, observed: 369.2.