Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=1.[C:17]([C:19]1[CH:32]=[CH:31][C:22]([CH2:23][N:24]2[C:28]([CH:29]=O)=[CH:27][N:26]=[CH:25]2)=[CH:21][C:20]=1[F:33])#[N:18].[BH3-]C#N.[Na+].CC(O)=O>CO>[F:33][C:20]1[CH:21]=[C:22]([CH2:23][N:24]2[C:28]([CH2:29][NH:2][CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=3)=[CH:27][N:26]=[CH:25]2)[CH:31]=[CH:32][C:19]=1[C:17]#[N:18]
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1F
Reactant: NCc1ccccc1-c1cccc(O)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: N#Cc1ccc(Cn2cncc2CNCc2ccccc2-c2cccc(O)c2)cc1F
Reaction time: 72 h

Procedure:
2-Aminomethyl-3′-hydroxybiphenyl hydrochloride from Step H (129 mg, 0.548 mmol) and 1-(4-cyano-3-fluorobenzyl)-5-imidazolecarboxaldehyde from Example 3, Step G (132 mg, 0.576 mmol) were stirred in MeOH (2 mL) for 30 min, then NaCNBH3 (38 mg, 0.60 mmol) was added. The reaction mixture was adjusted to pH 5 with AcOH, as judged from wetted pH paper, and stirring was continued at ambient temperature for 3 days. The reaction was quenched with 10% aq. citric acid and stirred for 20 min. Sat. aq. NaHCO3 (10 mL) was added and the mixture was extracted with CH2Cl2 (4×20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The titled product was crystallized from CH2Cl2-hexane and the first crop of white needles used for the next reaction.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)=[O:4].[CH2:16]([NH:19][C:20]([NH:22][CH2:23][CH2:24][CH3:25])=[S:21])[CH2:17][CH3:18].C(OCC)C>CO>[ClH:1].[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2([OH:4])[CH2:2][S:21][C:20](=[N:19][CH2:16][CH2:17][CH3:18])[N:22]2[CH2:23][CH2:24][CH3:25])=[CH:6][C:7]=1[S:12](=[O:15])(=[O:14])[NH2:13]
Reactant: NS(=O)(=O)c1cc(C(=O)CCl)ccc1Cl
Reactant: CCCNC(=S)NCCC
Solvent: CO
Solvent: CCOCC
Product: CCCN=C1SCC(O)(c2ccc(Cl)c(S(N)(=O)=O)c2)N1CCC
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5.3 g of 2,4'-dichloro-3'-sulfamoylacetophenone and 3.2 g of ground 1,3-dipropylthio urea were heated in 45 ml of methanol for 5 minutes to 50° C. and stirred for another 30 minutes at room temperature. After pouring the reaction mixture into 120 ml of diethyl ether the end product was obtained as a visquous mass which crystallized under mild heating rapidly with ether. Colorless solid body: melting point: 175° C. (decomposition).
Reaction SMILES: [CH2:1]([O:8][C:9](N1C(=O)CCC1=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:19][CH:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:19][CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1C(=O)OCc1ccccc1
Reactant: CCOC(=O)C(N)C(=O)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(NC(=O)OCc1ccccc1)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
N-(Benzyloxycarbonyl)succinimide (5.6 g, 22.4 mmol) was dissolved in CH2Cl2 (25 mL) and the solution was added to a cooled (0° C.) and stirred solution of diethyl aminomalonate hydrochloride (5.0 g, 23.6 mmol) and triethylamine (13.4 mL, 95 mmol) in CH2Cl2 (125 ml). The resulting solution was stirred at 0° C. for 10 min and then at rt for 1 h. The solution was washed with 10% citric acid (2×50 mL),10% sodium hydrogen carbonate (2×50 mL), and water (50 mL) and was then dried (Na2SO4) and evaporated to afford diethyl N-benzyloxycarbonylaminomalonate as a colorless oil, which crystallized upon standing at 0° C. (6.3 g) (LC/Mass + ion): 310 (M+H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([C:10]#N)=[CH:7][CH:8]=[CH:9][C:2]1=2.[CH2:12]([Mg]Cl)[CH3:13].Cl.CC[O:19]CC>>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]([C:10](=[O:19])[CH2:12][CH3:13])=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: N#Cc1cccc2sccc12
Reactant: CC[Mg]Cl
Reactant: CCOCC
Agent: Cl
Product: CCC(=O)c1cccc2sccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of benzo[b]thiophene-4-carbonitrile (24.2 g) in ether (200 ml) was added under nitrogen over 10 minutes to ethylmagnesium chloride (2M solution in ether; 250 ml), then the stirred mixture was heated under reflux for 1 hour, cooled to ambient temperature and poured into crushed ice (100 ml). The mixture was stirred for 30 minutes, then 5M hydrochloric acid (250 ml) was added. The acidic layer was separated, heated to 90° C. for 20 minutes, then allowed to cool to ambient temperature. The product was extracted into ether (500+250 ml), the combined extracts were washed with water (250 ml) and saturated aqueous sodium chloride solution (150 ml), then they were dried (MgSO4) and the solvent was removed in vacuo to give 1-(benzo[b]thiophen-4-yl)propan-1-one (18.25 g) as a colourless oil which was used without further purification.
Reaction SMILES: O[C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].[C:30]([O-:33])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:18]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]([C:5]2[CH:15]=[CH:16][C:2]([O:33][CH2:30][CH2:11][CH2:10][CH2:9][CH2:8][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:16][CH3:15])=[CH:3][CH:4]=2)=[O:7])=[CH:9][CH:10]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCCBr
Reactant: O=C(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCOc1ccc(C(=O)c2ccc(OCCCCCCCCCCCC)cc2)cc1
Temperature: 120 °C
Reaction time: 60 h
Yield: 149.6 %

Procedure:
A mixture of 4,4′-dihydroxybenzophenone (21.4 g, 100 mmol), 1-bromododecane (49.8 g, 200 mmol), K2CO3 (50 g) in 500 mL of DMF were heated with stirring at 120° C. for 60 hours. After the mixture was cooled to room temperature, 1 L of water was added. The solution was extracted with CH2Cl2 (4×500 mL). The combined organic layers were dried with MgSO4 and the most of the solvent removed under reduced pressure as a white solid formed. The solids were collected by filtration, washed with cold hexanes, and air dried to give 4,4′-didodecyloxybenzophenone (41.2 g, 75%). A mixture of 4,4′didodecyloxybenzophenone (20.6 g) and hydrazine monohydrate (20 mL) in 150 mL of pentanol were heated at reflux for 24 hours. After cooling to room temperature, a white solid precipitated which is collected by vacuum filtration, washed with 20 mL cold ethanol and air dried (19.4 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10](SC)[N:11]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:11]=1
Reactant: C1COCCN1
Reactant: CSc1nc(Cc2cccc(Cl)c2)[nH]c(=O)c1C#N
Product: N#Cc1c(N2CCOCC2)nc(Cc2cccc(Cl)c2)[nH]c1=O

Procedure:
In analogy to the preparation of Example 1, 150 mg (0.51 mmol) of 2-(3-chlorobenzyl)-4-(methyl-sulphanyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile are reacted with 448 mg (5.14 mmol) of morpholine to give 109 mg (63% of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:19][CH2:18][NH:17][C:16]3=[O:20])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.Cl[CH2:24][C:25]1[NH:26][C:27](=[O:35])[C:28]2[CH2:34][O:33][CH2:32][CH2:31][C:29]=2[N:30]=1.[H-].[Na+]>C1COCC1.CN(C=O)C.CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:19][CH2:18][N:17]([CH2:24][C:25]4[NH:26][C:27](=[O:35])[C:28]5[CH2:34][O:33][CH2:32][CH2:31][C:29]=5[N:30]=4)[C:16]3=[O:20])[CH2:11][CH2:10]2)=[O:8])=[CH:21][CH:22]=1
Reactant: COc1ccc(C(=O)C2CCN(C3CCNC3=O)CC2)cc1
Reactant: O=c1[nH]c(CCl)nc2c1COCC2
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)C2CCN(C3CCN(Cc4nc5c(c(=O)[nH]4)COCC5)C3=O)CC2)cc1
Temperature: 70 °C
Yield: 107.9 %

Procedure:
To a solution of 3-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-pyrrolidin-2-one (43.7 mmol, 13.2 g) and 2-chloromethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (48 mmol, 9.6 g) in THF (400 mL) and DMF formula (20 mL) was added sodium hydride (60%, 153 mmol, 6.1 g) and heated to 70° C. for 1 hour. The reaction was allowed to cool to ambient temperature, diluted with 1 L of ether, and the resulting solid in suspension was filtered and dried under vacuum provided the title compound as an off-white solid (22 g, 95.3% yield). HRMS calculated for C25H30N4O5 466.5417. found (ESI, [M+H]+) 467.2305. 1H NMR (400 MHz, MeOD) δ ppm 1.67-1.92 (m, 4H) 2.05-2.24 (m, 2H) 2.47-2.64 (m, 3H) 2.72-2.82 (m, 1H) 2.84-2.93 (m, 1H) 3.06-3.15 (m, 1H) 3.26-3.47 (m, 10H) 3.68 (t, J=8.78 Hz, 1H) 3.83-3.99 (m, 5H) 4.16 (d, J=15.56 Hz, 1H) 4.40-4.58 (m, 3H) 7.01 (d, J=9.03 Hz, 2H) 7.97 (d, J=9.03 Hz, 2H), analytical RP-HPLC (Novapak 150×3.9 mm C18 column: mobile phase: 10-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 5 min.) retention time=2.455 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[C:11]2([CH3:23])[CH3:22])=C(N)C=1.C(OC1C=CC(CC(Cl)=O)=CC=1)C1C=CC=CC=1.[CH2:42]([O:49][C:50]1[CH:55]=[CH:54][C:53]([CH2:56][CH2:57][NH:58][C:59]2C=C(OC)C=[CH:61][C:60]=2C2CCC3C(=CC=C(OC)C=3)C2(C)C)=[CH:52][CH:51]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>>[CH2:42]([O:49][C:50]1[CH:55]=[CH:54][C:53]([CH2:56][CH2:57][NH:58][CH2:59][C:60]2[CH:61]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[C:11]2([CH3:23])[CH3:22])=[CH:52][CH:51]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NCCc1ccc(OCc3ccccc3)cc1)C2(C)C
Reactant: COc1ccc(C2CCc3cc(OC)ccc3C2(C)C)c(N)c1
Agent: O=C(Cl)Cc1ccc(OCc2ccccc2)cc1
Product: COc1ccc(C2CCc3cc(OC)ccc3C2(C)C)c(CNCCc2ccc(OCc3ccccc3)cc2)c1

Procedure:
Synthesized from 5-methoxy-2-(6-methoxy-1,1-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine and 4-benzyloxyphenylacetyl chloride according to an analogous synthetic method to Example 152, [2-(4-benzyloxyphenyl)ethyl][5-methoxy-2-(6-methoxy-1,1-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (89 mg) was used according to an analogous synthetic method to Preparation Example 18 to provide [2-(4-benzyloxyphenyl)ethyl][5-methoxy-2-(6-methoxy-1,1-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]methylamine (61 mg). This compound (60 mg) was used according to an analogous synthetic method to Example 22 to provide 4-{2-{[5-methoxy-2-(6-methoxy-1,1-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]methylamino}ethyl}phenol (50 mg). Synthesized from 4-{2-{[5-methoxy-2-(6-methoxy-1,1-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]methylamino}ethyl}phenol and 1-(2-chloroethyl)azepane according to an analogous synthetic method to Example 383 described below, {2-[4-(2-azepan-1-ylethoxy)phenyl]ethyl}[5-methoxy-2-(6-methoxy-1,1-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]methylamine (42 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (27 mg).
Reaction SMILES: [NH:1]1[C:6]2N=CC=[CH:10][C:5]=2[C:4](=[O:11])[O:3][C:2]1=[O:12].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:21](Br)CCC.N>>[CH2:13]([N:1]1[C:6]([CH3:21])=[C:5]([CH3:10])[C:4](=[O:11])[O:3][C:2]1=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=c1[nH]c2ncccc2c(=O)o1
Reactant: CCCCBr
Reactant: BrCc1ccccc1
Agent: N
Product: Cc1c(C)n(Cc2ccccc2)c(=O)oc1=O

Procedure:
The title compound was prepared according to the procedure of Example 1B substituting the product of Example 123A for the product of Example 1A and substituting benzyl bromide for n-butyl bromide (0.109 g, 27%). MS (DCI/NH3) m/z 249 (M+NH4)+; 1H NMR (300 MHz, DMSO-d6) δ 1.86 (s, 3 H) 2.14 (s, 3 H) 5.09 (s, 2 H) 7.32 (m, 5 H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=[C:15]3[S:19][C:18](=[S:20])[NH:17][C:16]3=[O:21])[CH:12]=2)[N:7]=[CH:6][C:5]=1[S:22]([CH3:25])(=[O:24])=[O:23])[CH3:2].IC.[CH:28](N(C(C)C)CC)(C)[CH3:29]>C(#N)C>[CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=[C:15]3[S:19][C:18]([S:20][CH2:28][CH3:29])=[N:17][C:16]3=[O:21])[CH:12]=2)[N:7]=[CH:6][C:5]=1[S:22]([CH3:25])(=[O:23])=[O:24])[CH3:2]
Reactant: CCOc1c(S(C)(=O)=O)cnc2ccc(C=C3SC(=S)NC3=O)cc12
Reactant: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CI
Product: CCOc1c(S(C)(=O)=O)cnc2ccc(C=C3SC(SCC)=NC3=O)cc12

Procedure:
Similar procedure as described in example 41b was used, starting from 5-(4-ethoxy-3-methanesulfonyl-quinolin-6-ylmethylene)-2-thioxo-thiazolidin-4-one (example 74d), iodomethane, and DIEA (diisopropylethylamine) in acetonitrile to give 5-(4-ethoxy-3-methanesulfonyl-quinolin-6-ylmethylene)-2-ethylsulfanyl-thiazol-4-one. LC-MS m/e 409 (MH+).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]([CH2:45][CH2:46][CH3:47])[CH:43]=[N:42][CH:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1.CSC.O>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]([CH2:45][CH2:46][CH3:47])[CH:43]=[N:42][CH:41]=5)=[O:57])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cncn4CCC)cc2)CCN3CC(C)C)cc1
Solvent: ClCCl
Solvent: CSC
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cncn4CCC)cc2)CCN3CC(C)C)cc1
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[1-propylimidazol-5-yl]methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (35.7 g) in dichloromethane (350 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (19.8 g) in dichloromethane (200 ml) at −78° C. Dimethylsulfide (10 ml) was added to the mixture, and the mixture was allowed to be at room temperature and stirred for 30 minutes. To the mixture was added water, and the organic layer was washed with an aqueous solution of saturated sodium bicarbonate and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate), which was recrystallized from diisopropyl ether-ethyl acetate to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[1-propylimidazol-5-yl]methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (30.5 g) (Compound 371) as yellow crystals.
Reaction SMILES: ClCC1C=CC(C(Cl)=O)=CC=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1.[Cl:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]([N:44]=[C:45]=[S:46])=[O:43])=[CH:38][CH:37]=1>C1(C)C=CC=CC=1.C(O)C>[Cl:34][CH2:35][C:36]1[CH:37]=[CH:38][C:39]([C:42]([N:44]=[C:45]=[S:46])=[O:43])=[CH:40][CH:41]=1.[Cl:34][CH2:35][C:36]1[CH:37]=[CH:38][C:39]([C:42]([NH:44][C:45]([NH:31][C:30]2[CH:32]=[CH:33][C:27]([O:26][C:17]3[C:16]4[C:21](=[CH:22][C:23]([O:24][CH3:25])=[C:14]([O:13][CH3:12])[CH:15]=4)[N:20]=[CH:19][CH:18]=3)=[CH:28][CH:29]=2)=[S:46])=[O:43])=[CH:40][CH:41]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1ccc(CCl)cc1
Agent: O=C(N=C=S)c1ccc(CCl)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(CCl)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
4-(Chloromethyl)-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-(chloromethyl)-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-(chloromethyl)-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (54 mg, yield 63%).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([CH3:18])[C:9]([C:11]3[N:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=3)=[CH:10][C:5]=2[O:4][N:3]=1.[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:21]=1[C:22](Cl)=[O:23].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:21]=1[C:22]([NH:17][C:14]1[CH:13]=[N:12][C:11]([C:9]2[C:8]([CH3:18])=[CH:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH:10]=2)=[CH:16][N:15]=1)=[O:23]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Cc1cc2c(C)noc2cc1-c1cnc(N)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc2c(C)noc2cc1-c1cnc(NC(=O)c2c(F)cccc2F)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
To a solution of 5-(3,5-dimethylbenz[d]isoxazol-6-yl)pyrazine-2-ylamine (109) (7.5 mg, 0.03 mmol) in 1 ml DCM was added 2,6-difluorobenzoyl chloride (11 μl, 0.09 mmol) followed by addition of DIEA (47 μl). The resulting solution was stirred at r.t. for 2 h. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 2 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (90 μl) at r.t. for 1 h before worked up with EA/aq. NaHCO3. Silica gel flash chromatography furnished 7.3 mg (yield: 63.8%, purity>95%) (2,6-difluorophenyl)-N-[5-(3,5-dimethylbenzo[d]isoxazol-6-yl)pyrazin-2-yl]carboxamide (110) as white solid.
Reaction SMILES: C(OCC)(=O)C.N1C=CC=CC=1CC(O)=O.O.[CH2:18]1[CH:23]([C:24]([NH:26][CH:27]([C:34]([OH:36])=[O:35])[CH2:28][C:29]2[NH:33][CH:32]=[N:31][CH:30]=2)=[O:25])[NH:22][C:20](=[O:21])[CH2:19]1.[CH:37]1[CH:42]=[C:41]2[C:43]([CH2:46][CH:47]([NH2:57])[C:48]([NH:50][CH:51]([C:54]([OH:56])=O)[CH2:52][OH:53])=[O:49])=[CH:44][NH:45][C:40]2=[CH:39][CH:38]=1.[CH3:58][O:59][C:60]([C@@H:62]([NH2:71])[CH2:63][C:64]1[CH:69]=[CH:68][C:67]([OH:70])=[CH:66][CH:65]=1)=[O:61]>>[CH2:18]1[CH:23]([C:24]([NH:26][CH:27]([C:34]([OH:36])=[O:35])[CH2:28][C:29]2[NH:33][CH:32]=[N:31][CH:30]=2)=[O:25])[NH:22][C:20](=[O:21])[CH2:19]1.[NH2:57][C@H:47]([C:48]([NH:50][C@H:51]([C:54]([NH:71][C@H:62]([C:60]([O:59][CH3:58])=[O:61])[CH2:63][C:64]1[CH:65]=[CH:66][C:67]([OH:70])=[CH:68][CH:69]=1)=[O:56])[CH2:52][OH:53])=[O:49])[CH2:46][C:43]1[C:41]2[C:40](=[CH:39][CH:38]=[CH:37][CH:42]=2)[NH:45][CH:44]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: NC(Cc1c[nH]c2ccccc12)C(=O)NC(CO)C(=O)O
Agent: O=C(O)Cc1ccccn1
Agent: O=C1CCC(C(=O)NC(Cc2cnc[nH]2)C(=O)O)N1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12

Procedure:
The reaction solution containing pyroglu-his azide, prepared as described in Example 22, is cooled to a temperature of -40°C., and to this is added a solution of 1.1 g. of trp-ser-tyr-OMe trifluoroacetate, as prepared in Example 4, 5, 6 and 7, in 4 ml. of degassed dimethylformamide. The pH of the resulting solution is adjusted to 8.0 by the addition of diisopropylethylamine, and the mixture is maintained at a temperature of -5°C. (with periodic adjustment of the pH to 8.0 by addition of diisopropylethylamine) for a period of 18 hours, at the end of which time the reaction to form the pentapeptide is substantially complete as shown by thin layer chromatography on silica gel G using the solvent system ethyl acetate-pyridine-acetic acid-water (10:5:1:3). The reaction solution is evaporated in vacuo; the residual material is dissolved in 50 ml. butanol; the butanol solution is washed with three 25 ml.-portions of water; the combined water washings are extracted with six 10 ml.-portions of butanol; and the combined butanol solutions are evaporated to a small volume. The crystalline material which precipitates is recovered by filtration, dried and further purified by chromatography on a silica gel column to give 0.5 g. of substantially pure pyroglu-his-trp-ser-tyr-OMe.
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1.[CH2:11](I)[CH:12]([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[N:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1
Reactant: Cn1c(=O)cc(Cl)[nH]c1=O
Reactant: CC(C)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Cn1c(Cl)cc(=O)n(C)c1=O
Temperature: 50 °C
Yield: 51.6 %

Procedure:
A mixture of 6-chloro-3-methylpyrimidine-2,4(1H,3H)-dione (3 g, 18.8 mmol), isobutyl iodide (5 mL, 43.5 mmol) and potassium carbonate (5.3 g, 38.4 mmol) in anhydrous DMF (200 mL) is heated at 50° C. for 8 hours. Additional isobutyl iodide (4.3 mL, 37.5 mmol) is added, and the reaction mixture heated at 50° C. for 24 hours. After hot filtration, the filtrate is evaporated to dryness under reduced pressure. The obtained oil is further purified by silica-gel flash chromatography to give 2.1 g of pure product (Yield: 52%).
Reaction SMILES: CC1CCC[O:3]1.[CH:7]12[N:13]([C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:15]=3)[CH:10]([CH2:11][CH2:12]1)[CH2:9][CH2:8]2.O=C1C2C(=CC=CC=2C(F)(F)F)NC=C1C(O)=O.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.N1C=CC=CC=1.[OH2:67]>>[N+:18]([C:17]1[CH:19]=[CH:20][C:14]([N:13]2[CH:10]3[CH2:9][CH2:8][CH:7]2[CH2:12][CH2:11]3)=[CH:15][C:16]=1[C:21]([F:24])([F:22])[F:23])([O-:3])=[O:67]
Reactant: Nc1ccc(N2C3CCC2CC3)cc1C(F)(F)F
Reactant: O
Reactant: CC1CCCO1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C(O)c1c[nH]c2cccc(C(F)(F)F)c2c1=O
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(N2C3CCC2CC3)cc1C(F)(F)F
Temperature: 45 °C

Procedure:
2-Methyltetrahydrofuran (1 vol) was charged into a 30 L jacketed reactor vessel followed by the addition of the hydrochloride salt of 4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(trifluoromethyl)aniline (3-HCl) (1.2 eq) and 4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxylic acid (2) (573 g, 2.228 mol). Additional 2-methyltetrahydrofuran (9 vol) was charged into the vessel and stirring commenced. T3P in 2-methyltetrahydrofuran (2 eq) was added to the reaction mixture over a period of 15 min. Pyridine (3 eq) was added rapidly in a dropwise fashion using an addition funnel. Under stirring, the mixture was then heated to 45° C. over a period of about 30 min and this temperature was maintained for about 5 h. The mixture was cooled to room temperature. 2-methyltetrahydrofuran (4 vol) was added followed by the slow addition of water (6.9 vol), and the temperature of the reaction was kept below 30° C. The water layer was removed and the organic layer was washed twice with NaHCO3 saturated aqueous solution. The organic layer was then carefully washed with 10% w/w citric acid (5 vol) and washed with water (7 vol), and polished filtered and transferred into another dry vessel. 2-methyltetrahydrofuran (10 vol) was added and stirring commenced. Heptane (10 vol) was rapidly added in a dropwise fashion with stirring. The mixture was stirred for a period of about 12 h, and then vacuum filtered. The solid filter cake was introduced into another vessel. Water (15 vol) was charged into the vessel and the suspension was stirred vigorously for 48 h, then filtered. The solid cake was washed with water (5 vol) and dried at 45° C. to constant weight to produce Compound 1 Form B.