Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(=O)N[C@@H](C(C)C)C(N1[C@H](C2NC(C3C=CC(C4C=CC5C(=CC=C(C6NC([C@@H]7CCCN7[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]7[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=7)=NC=6)C=5)C=4)=CC=3)=CN=2)CC2(OCCO2)C1)=O.Cl.Cl.Cl.Cl.[CH3:70][CH:71]([CH3:116])[C@H:72]([NH:111][C:112](=[O:115])[O:113][CH3:114])[C:73](=[O:110])[N:74]1[CH2:78][CH2:77][CH2:76][C@H:75]1[C:79]1[NH:80][C:81]([C:84]2[CH:93]=[CH:92][C:91]3[C:86](=[CH:87][CH:88]=[C:89]([C:94]4[CH:99]=[CH:98][C:97]([C:100]5[NH:104][C:103]([C@H:105]6[NH:109][CH2:108][CH2:107][S:106]6)=[N:102][CH:101]=5)=[CH:96][CH:95]=4)[CH:90]=3)[CH:85]=2)=[CH:82][N:83]=1>>[CH3:60][O:59][C:57](=[O:58])[NH:56][C@H:49]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:48]([N:109]1[CH2:108][CH2:107][S:106][C@H:105]1[C:103]1[NH:104][C:100]([C:97]2[CH:96]=[CH:95][C:94]([C:89]3[CH:88]=[CH:87][C:86]4[C:91](=[CH:92][CH:93]=[C:84]([C:81]5[NH:80][C:79]([C@@H:75]6[CH2:76][CH2:77][CH2:78][N:74]6[C:73](=[O:110])[C@@H:72]([NH:111][C:112]([O:113][CH3:114])=[O:115])[CH:71]([CH3:116])[CH3:70])=[N:83][CH:82]=5)[CH:85]=4)[CH:90]=3)=[CH:99][CH:98]=2)=[CH:101][N:102]=1)=[O:61]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc([C@H]6NCCS6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(-c4ccc5cc(-c6cnc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)ccc5c4)cc3)[nH]1)OCCO2)C(C)C
Agent: Cl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc([C@@H]6SCCN6C(=O)[C@H](NC(=O)OC)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C

Procedure:
The title compound was prepared according to the method employed to prepare (S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester, except that methyl (S)-3-methyl-1-oxo-1-((S)-2-(5-(6-(4-(2-((S)-thiazolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate 4HCl salt was used instead of methyl (S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate 3HCl salt. MS (ESI) m/z 841.83 [M+H]+. (25 mg, 12%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(Cl)Cl>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:15]2[CH2:16][CH2:17][CH2:18][N:12]([CH3:11])[CH2:13][CH2:14]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CN1CCCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1CCCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
The mixture of 1 -fluoro-4-nitrobenzene (880 mg, 6.2 mmol), 1-methylhomopiperazine (2.3 mL, 18.6 mmol), Cs2CO3 (6.1 g, 18.6 mmol) in 20 mL DMF was stirred at 100° C. for 1.5 hr. It was diluted with DCM, filtered to remove the inorganic salts, washed with water, dried, evaporated in vacuuo to afford 1-(4-nitrophenyl)-4-methylhomopiperazine in quantitative yield. ES-MS: (M+H)+236.
Reaction SMILES: [CH3:1][C@@:2]([C:6]([OH:8])=[O:7])([CH2:4][SH:5])[NH2:3].[CH3:9][C:10]([CH3:12])=O>CO>[CH3:9][C:10]1([CH3:12])[NH:3][C:2]([CH3:1])([C:6]([OH:8])=[O:7])[CH2:4][S:5]1
Reactant: C[C@](N)(CS)C(=O)O
Reactant: CC(C)=O
Solvent: CO
Product: CC1(C)NC(C)(C(=O)O)CS1
Temperature: 56 °C

Procedure:
2.00 g of 2,2,4-trimethylthiazolidine-4-carboxamide hydrochloride prepared by the method described in Justus Liebigs Ann. Chem. (1966), 697, 140-157, was dissolved in 10 ml of 36% concentrated hydrochloric acid. The obtained solution was then heated to reflux at 105° C. for 1 hour, followed by concentration and drying. The thus obtained white solid was washed with isopropanol to obtain 1.62 g of 2-methylcysteine hydrochloride. This compound was converted into an aqueous solution, and the solution was passed through an anion exchange resin for desalinization. Thereafter, it was evaporated to dryness to obtain 1.27 g of 2-methylcysteine. The total amount of the obtained 2-methylcysteine was dissolved in 5 ml of methanol, and thereafter, 5 ml of acetone was added thereto, followed by heating to reflux at 56° C. Four hours later, the heating was terminated, and the reaction solution was concentrated and dried. The obtained white solid was then washed with acetone to obtain 1.32 g of 2,2,4-trimethylthiazolidine-4-carboxylic acid. The yield was found to be 80 mol % relative to the 2-methylcysteine hydrochloride as the raw material. The obtained 2,2,4-trimethylthiazolidine-4-carboxylic acid had the following physical properties:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[CH:9][C:10]([Cl:32])=[C:11]([CH:31]=1)[N:12]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.[B:33](OC(C)C)([O:38]C(C)C)[O:34]C(C)C>CCCCCC.C1COCC1.C(OCC)C>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:12]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:11]2[CH:31]=[C:7]([B:33]([OH:38])[OH:34])[CH:8]=[CH:9][C:10]=2[Cl:32])=[CH:15][CH:16]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(Br)ccc2Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(B(O)O)ccc2Cl)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Under argon and at −78° C., 6.1 ml (15.25 mmol) of a 2.5 M solution of n-butyllithium in hexane were slowly added dropwise to a solution of 5.2 g (11.64 mmol) of 5-bromo-2-chloro-N,N-bis(4-methoxybenzyl)aniline in 100 ml of THF/diethyl ether (1:1). The reaction solution was stirred at −78° C. for 60 min, and 4.3 ml (18.62 mmol) of triisopropyl borate were then added slowly. The reaction solution was then stirred at −78° C. for another 15 min, then slowly warmed to room temperature and stirred at this temperature for another 3 h. 150 ml of ice-water were then metered in. The organic phase was separated off, and the aqueous phase was then extracted three more times with ethyl acetate. The combined organic phases were dried over sodium sulphate. After filtration, the solvent was removed under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase: initially cyclohexane/ethyl acetate 10:1→9:1→4:1, then dichloromethane/methanol 95:5). This gave 2.54 g (6.17 mmol, 53% of theory) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[NH:15][C:14](=[O:16])[C:13]([CH:17]([NH:19][C:20](=O)[CH3:21])[CH3:18])=[N:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].P(Cl)(Cl)(Cl)=O>ClCCCl.C(=O)([O-])O.[Na+]>[CH3:18][C:17]1[N:19]=[C:20]([CH3:21])[N:12]2[C:13]=1[C:14](=[O:16])[NH:15][C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[N:11]2
Reactant: CC(=O)NC(C)c1nnc(-c2cccc([N+](=O)[O-])c2)[nH]c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: Cc1nc(C)n2nc(-c3cccc([N+](=O)[O-])c3)[nH]c(=O)c12
Temperature: 95 °C
Reaction time: 3 h

Procedure:
A solution of 1.93 g (6.36 mmol) of N-{1-[3-(3-nitrophenyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}acetamide from example 6A in 1,2-dichloroethane is treated with 2.93 g (1.78 ml, 19.09 mmol) of phosphoryl chloride. The mixture is stirred for 3 h at 95° C. After cooling, it is hydrolyzed using a couple of drops of aqueous sodium hydrogencarbonate solution. The solvent is removed in vacuo and the residue is purified by flash chromatography (eluent gradient: dichloromethane/methanol 100:1-50:1-30:1-20:1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][C:23]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:35]([CH2:37][NH2:38])[OH:36]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:38][CH2:37][CH2:35][OH:36])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][C:23]3=[O:27])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: NCCO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCC2=O)c1=O
Product: O=C(NCCO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(2-oxo-1-pyrrolidinyl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and ethanolamine employing methods similar to those described in Example 202 and was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.36 (t, J=5.7 Hz, 1 H), 8.53 (s, 1 H), 7.41 (s, 1 H), 7.18 (dd, J=8.3, 5.5 Hz, 2 H), 7.03 (t, J=8.6 Hz, 2 H), 4.16-4.11 (m, 4 H), 3.85 (t, J=5.0 Hz, 2 H), 3.63 (m, 2 H), 3.38-3.33 (m, 4 H), 2.40 (t, J=8.0 Hz, 2 H), 2.03 (m, 2 H), 1.82 (m, 2 H); HRMS C25H27FN4O5 (M+H)+ calcd 483.2044, found 483.2046.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12]Cl)(=[O:3])[CH3:2].[C-:14]#[N:15].[Na+]>CS(C)=O>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:14]#[N:15])(=[O:3])[CH3:2]
Reactant: [C-]#N
Reactant: CC(=O)OCc1ccccc1CCl
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)OCc1ccccc1CC#N
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a glass-made three-necked flask (volume: 100 ml) with a condenser, 50.0 g of [2-(chloromethyl)phenyl]methyl acetate (purity: 89%) and 50.0 g of dimethyl sulfoxide were added, and the mixture was heated to 80° C. Thereto, 50.0 g of a 34 wt % aqueous sodium cyanide solution was added dropwise while stirring over one hour. After completion of the dropwise addition, the mixed solution was continuously stirred for one hour while keeping the temperature at 80° C. The reaction mixture obtained was analyzed by the gas chromatography. As a result, the amount of [2-(cyano-methyl)phenyl]methyl acetate produced was 34.0 g (180 mmol) and the yield was 80 mol % based on [2-(chloromethyl)-phenyl]methyl acetate. Also, it was verified that 3.6 g (24 mmol) of [2-(hydroxymethyl)phenyl]acetonitrile which is a precursor of 3-isochromanone was produced.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[OH:15])[CH:5]=[CH:4][N:3]=1.[Cl:16][C:17]1[C:18](F)=[CH:19][C:20]([F:43])=[C:21]([S:23]([N:26](CC2C=CC(OC)=CC=2OC)[C:27]2[S:28][CH:29]=[N:30][N:31]=2)(=[O:25])=[O:24])[CH:22]=1>>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[O:15][C:18]2[C:17]([Cl:16])=[CH:22][C:21]([S:23]([NH:26][C:27]3[S:28][CH:29]=[N:30][N:31]=3)(=[O:24])=[O:25])=[C:20]([F:43])[CH:19]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc(-c2cc(Cl)ccc2O)ccn1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Product: Nc1cc(-c2cc(Cl)ccc2Oc2cc(F)c(S(=O)(=O)Nc3nncs3)cc2Cl)ccn1

Procedure:
The title compound was prepared from 2-(2-aminopyridin-4-yl)-4-chlorophenol, (Preparation 721) and 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (Preparation 247) using a method analogous to that used in Preparation 669. Purification by semi-preparative HPLC using 15-100% MeOH/H2O yielded the title compound.
Reaction SMILES: [CH2:1]([N+:5]([O-:7])=[O:6])/[CH:2]=[N:3]\O.Cl.N[C:10]1[C:17]([F:18])=[C:16]([Cl:19])[C:15]([F:20])=[CH:14][C:11]=1[CH:12]=O>C(O)C>[Cl:19][C:16]1[C:17]([F:18])=[C:10]2[C:11]([CH:12]=[C:1]([N+:5]([O-:7])=[O:6])[CH:2]=[N:3]2)=[CH:14][C:15]=1[F:20]
Reactant: O=[N+]([O-])C/C=N\O
Reactant: Nc1c(C=O)cc(F)c(Cl)c1F
Agent: Cl
Solvent: CCO
Product: O=[N+]([O-])c1cnc2c(F)c(Cl)c(F)cc2c1
Temperature: 35 °C
Reaction time: 16 h
Yield: 72.9 %

Procedure:
17.4 g of methazonic acid and 60 cm3 of a 37% aqueous hydrochloric acid solution were rapidly added, with stirring, to a solution of 8.7 g of 2-amino-4-chloro-3,5-difluorobenzaldehyde in 300 cm3 of ethanol, while the mixture was maintained at a temperature in the region of 35° C. The mixture was stirred for 16 hours at a temperature in the region of 20° C. The precipitate was dewatered and washed 3 times with 25 cm3 of diethyl ether. 8.1 g of 7-chloro-6,8-difluoro-3-nitroquinoline was obtained in the form of an orange-colored solid, which melted at 174° C.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[Cl:9][C:10]1[N:11]=[C:12]([N:15]2[CH2:21][CH2:20][CH2:19][NH:18][C:17](=[O:22])[CH2:16]2)[S:13][CH:14]=1>C(Cl)(Cl)Cl.C(OCC)(=O)C>[Br:8][C:14]1[S:13][C:12]([N:15]2[CH2:21][CH2:20][CH2:19][NH:18][C:17](=[O:22])[CH2:16]2)=[N:11][C:10]=1[Cl:9]
Reactant: O=C1CN(c2nc(Cl)cs2)CCCN1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C1CN(c2nc(Cl)c(Br)s2)CCCN1
Temperature: 23 °C
Reaction time: 0.13 h
Yield: 55.8 %

Procedure:
n-bromosuccinimide (80 mg, 0.449 mmol) was combined with a solution of 4-(4-chloro-1,3-thiazol-2-yl)-1,4-diazepan-2-one (100 mg, 0.432 mmol) in CHCl3 (6 ml) and stirred at 23° C. for 8 minutes. The solution became dark was immediately diluted with ethyl acetate, and washed successively with aq. sodium thiosulfate (sat.), aq. NaHCO3 (sat.) and brine. The organic fraction was dried (Na2SO4), filtered and concentrated to afford 4-(5-bromo-4-chloro-1,3-thiazol-2-yl)-1,4-diazepan-2-one (75 mg, 0.241 mmol, 55.9% yield) as a yellow oil of sufficient purity for subsequent transformations.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.[Li]CCCC.CCCCCC.[F:34][C:35]1([F:46])[C:39]([F:40])=[C:38](F)[C:37]([F:43])([F:42])[C:36]1([F:45])[F:44]>C1COCC1>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]2[S:5][C:4]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)=[CH:3][C:2]=2[C:38]2[C:37]([F:43])([F:42])[C:36]([F:44])([F:45])[C:35]([F:34])([F:46])[C:39]=2[F:40])=[CH:8][CH:9]=1
Reactant: FC1=C(F)C(F)(F)C(F)(F)C1(F)F
Reactant: COc1ccc(-c2sc(-c3ccc(C#N)cc3)cc2Br)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(-c2sc(-c3ccc(C#N)cc3)cc2C2=C(F)C(F)(F)C(F)(F)C2(F)F)cc1
Temperature: -50 °C
Reaction time: 0.25 h
Yield: 61.3 %

Procedure:
To a solution of (57) (5.0 g, 13.50 mmol) in dry THF (300 mL) was slowly added n-BuLi hexane solution (2.0 M, 7.43 mL, 14.85 mmol) at −50° C. under an argon atmosphere. The solution was stirred for 15 minutes at −50° C. After the addition of octafluorocyclopentene (5.44 mL, 40.5 mmol), the reaction mixture was stirred for 2 h. The reaction was quenched by the addition of methanol and warmed to RT. The solvents were removed by rotary evaporation and flash chromatography (10% EtOAc in hexanes) afforded a dark yellow oil (4.0 g, 61.3%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]([CH3:31])[C:16]([C:18]3[N:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=4)=[CH:20][CH:19]=3)=[O:17])=[CH:11][CH:10]=2)[CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.FC1C=C(C2N=CC(C(N(C)C3C=CC(CN4CCN[C@@H](C)C4)=CC=3)=O)=CC=2)C=CC=1>C(Cl)Cl.CO>[CH3:31][N:15]([C:12]1[CH:11]=[CH:10][C:9]([CH2:8][N:6]2[CH2:5][CH2:4][NH:3][C@@H:2]([CH3:1])[CH2:7]2)=[CH:14][CH:13]=1)[C:16]([C:18]1[N:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=2)=[CH:20][CH:19]=1)=[O:17]
Reactant: Cc1cc(-c2ccc(C(=O)N(C)c3ccc(CN4CCN(C(=O)OC(C)(C)C)[C@@H](C)C4)cc3)nc2)ccn1
Agent: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(-c4cccc(F)c4)nc3)cc2)CCN1
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(-c2ccc(C(=O)N(C)c3ccc(CN4CCN[C@@H](C)C4)cc3)nc2)ccn1

Procedure:
The title compound was prepared from 1,1-dimethylethyl (2S)-2-methyl-4-[(4-{methyl[(2′-methyl-3,4′-bipyridin-6-yl)carbonyl]amino}phenyl)methyl]-1-piperazinecarboxylate (D130) using a procedure similar to that described for E1 in Example 1 although hydrochloride salt preparation was carried out in DCM/MeOH (1:1). δH (MeOD, 400 MHz) 8.96 (1H, br.m), 8.76 (1H, d), 8.39 (1H, br.m), 8.33 (1H, s), 8.23 (1H, d), 7.81 (1H, br.d), 7.58 (2H, br.s), 7.36 (2H, br.s), 3.86 (1H, br.s), 3.58-3.71 (4H, m), 3.54 (3H, s), 3.44 (1H, m), 3.34 (2H, s), 3.30 (1H, m), 2.85 (3H, s), 1.40 (3H, d), NH not observed. MS (ES+): 316.1, no molecular ion (MH+) observed.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:20][CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:14](N(OC)C)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH:27]([Mg]Br)=[CH:28][CH3:29].Cl>O1CCCC1>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:14](=[O:15])[CH:27]=[CH:28][CH3:29])[CH2:20][CH:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CON(C)C(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: CC=C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CC=CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
To a solution of 2-[4-(cyclopropylsulfonyl)phenyl]-N-methoxy-N-methyl-3-(tetrahydro-2H-pyran-4-yl)propanamide (1.00 g) in tetrahydrofuran (10 mL) was added 1-propenylmagnesium bromide (0.5M tetrahydrofuran solution, 17.2 mL) under ice-cooling, and the mixture was warmed to room temperature and stirred for 3 hr. The reaction mixture was poured into a mixture of concentrated hydrochloric acid (5 mL) and ice (100 g), and the mixture was stirred for 15 min. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (632 mg, yield 61%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (4:1, volume ratio). MS: 363 (MH+).
Reaction SMILES: [C:1]1([O:7][C:8]([N:10]2[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([CH:24]4[C:30]5=[N:31][CH:32]=[C:33]([Br:35])[CH:34]=[C:29]5[CH2:28][CH2:27][C:26]5[CH:36]=[C:37]([Cl:41])[CH:38]=[C:39]([Cl:40])[C:25]4=5)[CH2:20][CH2:19]3)=[O:17])[CH2:11]2)=[NH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:42][N:43]([CH3:48])[S:44](Cl)(=[O:46])=[O:45]>CC#N.C1C=CC=CC=1.C1(C)C=CC=CC=1>[C:1]1([O:7][C:8]([N:10]2[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([CH:24]4[C:30]5=[N:31][CH:32]=[C:33]([Br:35])[CH:34]=[C:29]5[CH2:28][CH2:27][C:26]5[CH:36]=[C:37]([Cl:41])[CH:38]=[C:39]([Cl:40])[C:25]4=5)[CH2:20][CH2:19]3)=[O:17])[CH2:11]2)=[N:9][S:44](=[O:46])(=[O:45])[N:43]([CH3:48])[CH3:42])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N=C(Oc1ccccc1)N1CCC(CC(=O)N2CCC(C3c4ncc(Br)cc4CCc4cc(Cl)cc(Cl)c43)CC2)C1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: c1ccccc1
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CN(C)S(=O)(=O)N=C(Oc1ccccc1)N1CCC(CC(=O)N2CCC(C3c4ncc(Br)cc4CCc4cc(Cl)cc(Cl)c43)CC2)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Dissolve the product of Example 9 (1 equivalent) in an inert anhydrous solvent such as CH3CN, benzene or toluene and add Et2N (2 equivalents). Cool the solution to 0° C. and add N,N-dimethylsulfamoyl chloride (1.2 equivalents). Stir the mixture at 0° C. to25° C. for 3 h, extract, filter and evaporate to give the title compound.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[OH2:7].[Br:8][C:9]1[O:13][C:12]([CH:14]([S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:15][NH:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[O:18])=[CH:11][CH:10]=1>CO>[C:26]1([S:25]([CH:14]([C:12]2[O:13][C:9]([Br:8])=[CH:10][CH:11]=2)[CH2:15][NH:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[O:18])=[O:7])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(NCC(Sc1ccccc1)c1ccc(Br)o1)c1ccccn1
Reactant: O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Product: O=C(NCC(c1ccc(Br)o1)S(=O)c1ccccc1)c1ccccn1
Reaction time: 4.5 h

Procedure:
Sodium periodate (57 mg, 0.2677 mmol) in a small amount of water was added to pyridine-2-carboxylic acid [2-(5-bromofuran-2-yl)-2-phenylsulfanylethyl]-amide (90 mg, 0.2231 mmol) in methanol (13 ml). After refluxing for 4 h another 57 mg (0.2677 mmol) of sodium periodate was added and refluxing was continued for 4.5 h. Water (30 ml) was added and the product was extracted into EtOAc. The organic phase was washed with water, dried with Na2SO4 and evaporated. The crude product was used as such in the next step.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([O:25][CH:26]([CH3:31])[C:27]([F:30])([F:29])[F:28])=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][CH:10]=2)=[O:5])C.[OH-].[Na+]>>[Cl:24][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:25][CH:26]([CH3:31])[C:27]([F:28])([F:30])[F:29])[C:6]([C:4]([OH:5])=[O:3])=[C:15]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23]
Reactant: CCOC(=O)c1c(OC(C)C(F)(F)F)nc2ccc(Cl)cc2c1Cc1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(Oc1nc2ccc(Cl)cc2c(Cc2ccccc2Cl)c1C(=O)O)C(F)(F)F

Procedure:
The title compound was prepared in analogy to example 12 step B from 6-chloro-4-(2-chloro-benzyl)-2-(2,2,2-trifluoro-1-methyl-ethoxy)-quinoline-3-carboxylic acid ethyl ester (35 mg, 0.074 mmol) and 1N NaOH. Pale brown solid (21 mg, 64%). LC-MS (ESI): 442 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=3[O:14][N:13]=2)=[CH:8][CH:7]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+].Cl>C(#N)C>[F:21][C:19]1[CH:18]=[CH:17][C:16]2[C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:7][CH:8]=3)=[N:13][O:14][C:15]=2[CH:20]=1
Reactant: Fc1ccc2c(-c3ccc(OCCCBr)cc3)noc2c1
Reactant: C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc2c(-c3ccc(OCCCN4CCCCC4)cc3)noc2c1

Procedure:
Combine 3-[4-(3-bromo-propoxy)-phenyl]-6-fluoro-benzo[d]isoxazole (0.727 g, 2.08 mmol), piperidine (0.707 g, 8.30 mmol), potassium carbonate (0.575 g, 4.16 mmol) and acetonitrile (7.0 mL) and heat (75° C.) overnight. Cool (45° C.) reaction, filter through a Waters Sep-Pak 1 g Silica cartridge (ethyl acetate) and concentrate (in vacuo). Purify the crude product by column (silica) chromatography with a graded solvent mixture of 5% methanol in dichloromethane to 10% methanol in dichloromethane. Concentrate to give a colorless oil and dry under vacuum (0.6 mm Hg, room temperature) for 3 hours to obtain a waxy, off-white solid. Acidify the free base with ethereal HCl, recrystallize (ethanol:ethyl acetate) and dry (in vacuo, 0.6 mm Hg, 60° C.) for 3 hours to give the title compound as the salt (0.336 g, 41% Yield). Microanalysis (C, H, N) is consistent with the final, desired compound. mp=202-205° C.
Reaction SMILES: [H-].[Na+].[CH3:3]N(C=O)C.[F:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C@H:19]2[CH2:38][N:23]3[C:24]4[C:29]([C:30]([CH2:31][C:32]([O:34][CH2:35][CH2:36][CH3:37])=[O:33])=[C:22]3[CH2:21][CH2:20]2)=[CH:28][CH:27]=[CH:26][CH:25]=4)(=[O:17])=[O:16])=[CH:11][CH:10]=1>[NH4+].[Cl-]>[F:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]([CH3:3])[C@H:19]2[CH2:38][N:23]3[C:24]4[C:29]([C:30]([CH2:31][C:32]([O:34][CH2:35][CH2:36][CH3:37])=[O:33])=[C:22]3[CH2:21][CH2:20]2)=[CH:28][CH:27]=[CH:26][CH:25]=4)(=[O:16])=[O:17])=[CH:11][CH:10]=1
Reactant: CN(C)C=O
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NS(=O)(=O)c1ccc(F)cc1)CC2
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Product: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](N(C)S(=O)(=O)c1ccc(F)cc1)CC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
Sodium hydride (1.05 equiv.) was added to a 0° C. DMF solution (0.14 M) of propyl {(7R)-7-{[(4-fluorophenyl)sulfonyl]amino}-6,7,8,9-tetrahydropyrido [1,2-α]indol-10-yl }acetate from Step 7 and the mixture was stirred at 0 ° C. for 30 min. lodomethane (3 equiv.) was added and the reaction was stirred at 0° C. for 2 h. The mixture was poured in aqueous NH4Cl and extracted with Et2O (2×). The combined organic extracts were washed with water (3×), brine and then dried with MgSO4, filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel using a CombiFlashRF (Teledyne ISCO) eluting with EtOAc/Hex (5:95 to 50:50) to give the title compound (98%) as a colorless oil.