Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3](=[NH:8])[NH:4][N+:5]([O-:7])=[O:6].CC#N.[CH2:12]([S:15](Cl)(=[O:17])=[O:16])[CH2:13][CH3:14].Cl>O.CCN(CC)CC>[CH3:1][S:2][C:3](=[N:8][S:15]([CH2:12][CH2:13][CH3:14])(=[O:17])=[O:16])[NH:4][N+:5]([O-:7])=[O:6]
Reactant: CSC(=N)N[N+](=O)[O-]
Reactant: CCCS(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)N=C(N[N+](=O)[O-])SC
Yield: 60.5 %

Procedure:
A mixture of S-methyl-N-nitroisothiourea (5.0 g), CH3CN (50 ml) and Et3N (11.2 g) was cooled with iced water. To the cooled mixture was added 10.6 g of n-propanesulfonyl chloride dropwise below 15° C. under stirring. After stirring at the same temperature for 1 hour, the mixture was poured into a mixed solution of conc. hydrochloric acid (20 ml) and water (180 ml) and the resulting mixture was extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo to afford 9.9 g of crude crystals. Recrystallization of the product from CCl4 (5 ml) gave 5.4 g of S-methyl-N-nitro-N'-(n-propanesulfonyl)isothiourea as a pale yellow crystal, m.p. 91°-93° C.
Reaction SMILES: C([O-])=O.[NH4+].[OH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[O:7].[OH:12][C:13]([C:15]([F:18])([F:17])[F:16])=[O:14].[C:19]1([CH2:25][CH2:26][C:27]2[CH:28]=[N:29][N:30]([CH2:45][CH3:46])[C:31]=2[CH:32]2[CH2:37][CH2:36][N:35](CC3C=CC=CC=3)[CH2:34][CH2:33]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CO.[OH-].[OH-].[Pd+2]>[OH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[O:5].[OH:14][C:13]([C:15]([F:18])([F:17])[F:16])=[O:12].[C:19]1([CH2:25][CH2:26][C:27]2[CH:28]=[N:29][N:30]([CH2:45][CH3:46])[C:31]=2[CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCn1ncc(CCc2ccccc2)c1C1CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCn1ncc(CCc2ccccc2)c1C1CCNCC1
Temperature: 60 °C

Procedure:
A mixture of ammonium formate (119 mg), 20% Pd(OH)2/C (5 mg) and 4-(4-(2-phenylethyl)-1-ethyl-(1H-pyrazol-5-yl))-1-benzylpiperidine di-TFA salt from Step F in methanol (2 mL) was heated at 60° C. for 1.5 h. The solvent was removed under reduced pressure and the residue was purified by preparative reverse-phase HPLC using a 9.4×250 mm Semi-preparative Zorbax SB-C18 column with 20-35% acetonitrile gradient in water having 0.5% (v/v) TFA over 15 min at 6.25 mL per min to give the title compound as the di-TFA salt (25 mg) as a gel.
Reaction SMILES: NC1C=C(OC)C(OC)=CC=1C(N1CCCC1COC(=O)C)=O.C([SiH2][O:29][C:30](C)(C)[CH:31]1[CH2:35][CH2:34][CH2:33][N:32]1[C:36]([C:38]1[CH:43]=[C:42]([O:44][CH3:45])[C:41]([O:46][CH3:47])=[CH:40][C:39]=1[N:48]=[C:49]=[O:50])=[O:37])(C)(C)C>>[OH:29][CH2:30][CH:31]1[CH2:35][CH2:34][CH2:33][N:32]1[C:36]([C:38]1[CH:43]=[C:42]([O:44][CH3:45])[C:41]([O:46][CH3:47])=[CH:40][C:39]=1[N:48]=[C:49]=[O:50])=[O:37]
Reactant: COc1cc(N=C=O)c(C(=O)N2CCCC2C(C)(C)O[SiH2]C(C)(C)C)cc1OC
Agent: COc1cc(N)c(C(=O)N2CCCC2COC(C)=O)cc1OC
Product: COc1cc(N=C=O)c(C(=O)N2CCCC2CO)cc1OC

Procedure:
This was prepared from (6) in the same manner as above for (7).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[N:10](CC=C)[C:9]=2[C:8](=[O:18])[NH:7][C:6]1=[O:19])[CH2:2][CH2:3][CH3:4].Br[CH2:21][CH2:22][CH2:23][N:24]1[N:28]=[N:27][C:26]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:25]1.C([O-])([O-])=O.[Cs+].[Cs+].N1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO.CN(C=O)C>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:18])[N:7]([CH2:21][CH2:22][CH2:23][N:24]2[N:28]=[N:27][C:26]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:25]2)[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCC
Reactant: BrCCCn1nnc(Cc2ccccc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: C1COCCN1
Solvent: CO
Product: CCCCn1c(=O)n(CCCn2nnc(Cc3ccccc3)n2)c(=O)c2[nH]c(Cl)nc21
Temperature: 45 °C
Reaction time: 24 h

Procedure:
A mixture of 3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (1.74 g, 6.1 mmol), crude 2-(3-bromopropyl)-5-(phenylmethyl)-2H-tetrazole) (1.9 g, 6.8 mmol), Cs2CO3 (2.2 g, 6.8 mmol) and DMF (60 ml) was stirred at 45° C. under nitrogen for 24 h. The mixture was degassed by applying a vacuum and then nitrogen was introduced. Pd(PPh3)4 (705 mg, 0.61 mmol) was added and the mixture degassed once more. Morpholine (5.4 ml, 61.4 mmol) was added and the mixture was stirred under nitrogen for 4 h, and then partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated, giving a yellow residue. MeOH was added and then passed down an aminopropyl column with the product eluting with 2% AcOH/MeOH. The product was further purified by the Companion™ system using EtOAc/cyclohexane mixtures. The resulting solid was stirred with boiling Et2O and filtered after cooling to rt. The title compound was collected as a white solid (1.01 g, 37%) and dried at 50° C. under vacuum.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:11][S:12][C:13]2[NH:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH3:10].ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH2:11][S:12]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[N:14]=2)=[O:30])=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccnc(CSc2nc3ccccc3[nH]2)c1OC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccnc(CS(=O)c2nc3ccccc3[nH]2)c1OC
Yield: 58.9 %

Procedure:
To a solution of 2-[(3,4-dimethoxypyrid-2-yl)methylthio]benzimidazole (1.08 g) in methylene chloride (30 ml) was added m-chloroperbenzoic acid (0.79 g) in small protions below 10° C. After completion of the reaction the reaction, the mixture was diluted with methylene chloride (70 ml), washed with an aqueous solution of potassium carbonate and then with water, dried, and evaporated. The residue was purified by column chromatography on silica gel (chloroform-methanol (40:1)) and crystallized from acetone-ether, to give 2-[(3,4-dimethoxypyrid-2-yl)methylsulfinyl]benzimidazole (670 mg) as light brown crystals. m.p. 149°-151° C. (decomposed).
Reaction SMILES: C(N(CC)CC)C.[S:8]1[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=[CH:9]1.Cl.[CH3:17][NH:18][O:19][CH3:20].CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:20][O:19][N:18]([CH3:17])[C:13]([C:12]1[S:8][CH:9]=[N:10][CH:11]=1)=[O:15]
Reactant: O=C(O)c1cncs1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cncs1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Triethylamine (2.77 mL, 19.9 mmol) was added slowly to a mixture of commercially available thiazole-5-carboxylic acid (1.03 g, 7.98 mmol), N,O-dimethylhydroxylamine hydrochloride (0.778 g, 7.98 mmol), and EDCI (1.83 g, 9.57 mmol) in CH2Cl2 (10 mL). The mixture was stirred at room temperature for 72 hours then quenched with saturated aqueous NaHCO3. Water (50 mL) was added followed by additional CH2Cl2. The mixture was stirred for 10 minutes and layers were separated. The CH2Cl2 layer was dried over Na2SO4 and filtered. The solvent was removed under reduced pressure and the residual oil was chromatographed (CH2Cl2/EtOAc) to provide the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=2[NH:18]C(=O)OC(C)(C)C)[CH:3]=1.Cl.C(=O)(O)[O-].[Na+].[OH-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[C:12]([NH2:18])=[CH:13][CH:14]=[C:15]([CH3:17])[CH:16]=2)[CH:3]=1
Reactant: CSc1nc(Cl)cc(Nc2cc(C)ccc2NC(=O)OC(C)(C)C)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CSc1nc(Cl)cc(Nc2cc(C)ccc2N)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
tert-Butyl (2-{[6-chloro-2-(methylsulfanyl)pyrimidin-4-yl]amino}-4-methylphenyl)carbamate (8.5 g) was dissolved in 1,4-dioxane (85 mL), and a 4 M solution (56 mL) of hydrogen chloride in 1,4-dioxane was added thereto, followed by stirring at room temperature for 8 hours. After the completion of the reaction, a saturated aqueous sodium bicarbonate solution and a 4 M aqueous sodium hydroxide solution were added thereto. The mixture was quenched, made free, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to obtain N2-[6-chloro-2-(methylsulfanyl)pyrimidin-4-yl]-4-methylbenzene-1,2-diamine (6 g) as a yellow powder.
Reaction SMILES: C(C1C=C(C=CC=1C1N[N:24]=[N:23][N:22]=1)OC1C=CC=CC=1ONC(=O)C)#N.[C:26]([C:28]1[CH:44]=[CH:43][C:31]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[NH:39][C:40](=[O:42])[CH3:41])=[CH:30][C:29]=1[C:45]1[NH:49][N:48]=[N:47][N:46]=1)#[N:27].[Cl-].[NH4+].[N-]=[N+]=[N-].[Na+].[Cl-].[Li+]>CN(C=O)C>[NH:46]1[C:45]([C:29]2[CH:30]=[C:31]([CH:43]=[CH:44][C:28]=2[C:26]2[NH:24][N:23]=[N:22][N:27]=2)[O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[NH:39][C:40](=[O:42])[CH3:41])=[N:49][N:48]=[N:47]1
Reactant: CC(=O)Nc1ccccc1Oc1ccc(C#N)c(-c2nnn[nH]2)c1
Reactant: CC(=O)NOc1ccccc1Oc1ccc(-c2nnn[nH]2)c(C#N)c1
Agent: [Cl-]
Agent: [Li+]
Agent: [N-]=[N+]=[N-]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccccc1Oc1ccc(-c2nnn[nH]2)c(-c2nnn[nH]2)c1
Temperature: 120 °C

Procedure:
A mixture of N-{2-[3-cyano-4-(1H-tetrazol-5-yl)phenoxy]phenoxy}acetamide and N-{2-[4-cyano-3-(1H-tetrazol-5-yl)phenoxy]phenyl}acetamide (0.45 g, 1.4 mmol) was dissolved in dry DMF (20 ml). Ammonium chloride (0.17 g, 3.1 mmol), sodium azide (0.2 g, 3.1 mmol), and lithium chloride (0.13 g, 3.1 mmol) were added. The reaction mixture was heated at 120° C. for 120 hours. The reaction mixture was evaporated in vacuo and purified on a silica gel column (eluent:methylene chloride/methanol (2:1)). The yielded oil was used without any further purification in the next step.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:20]([NH:22][C@H:23]([C:26]([NH:28][C@H:29]([C:32]([OH:34])=[O:33])[CH2:30][OH:31])=[O:27])[CH2:24][OH:25])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].C(O)(=O)C>CO.[Pd]>[NH2:1][C@H:2]([C:20]([NH:22][C@H:23]([C:26]([NH:28][C@H:29]([C:32]([OH:34])=[O:33])[CH2:30][OH:31])=[O:27])[CH2:24][OH:25])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([CH3:16])=[CH:17][CH:18]=1)(=[O:10])=[O:11]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OCc2ccccc2)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)O)cc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)O)cc1

Procedure:
1.35 Grams of Z-Arg(Tos)-Ser-Ser-OH was dissolved in 50 ml of methanol and 10 ml of 10%-acetic acid, and the solution was subjected to catalytical reduction in the presence of 500 mg of palladium at 20° C. under an atmospheric pressure to obtain H-Arg(Tos)-Ser-Ser-OH.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]3[NH:14][C:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)=[C:12]([CH3:23])[C:10]3=2)[NH:5][C:4](=[O:24])[CH:3]=1.[F:25][C:26]([F:31])([F:30])[C:27](O)=O>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]3[N:14]([CH2:27][C:26]([F:31])([F:30])[F:25])[CH:13]([C:15]4[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH:12]([CH3:23])[C:10]3=2)[NH:5][C:4](=[O:24])[CH:3]=1
Reactant: COc1ccc(-c2[nH]c3ccc4[nH]c(=O)cc(Cl)c4c3c2C)cc1
Reactant: O=C(O)C(F)(F)F
Product: COc1ccc(C2C(C)c3c(ccc4[nH]c(=O)cc(Cl)c34)N2CC(F)(F)F)cc1

Procedure:
This compound was prepared using the method described in Example 23 from 9-Chloro-2-(4-methoxy-phenyl)-1-methyl-3,6-dihydro-pyrrolo[3,2-f]quinolin-7-one, and trifluoroacetic acid. Spectral data for compound 148: 1H NMR (500 MHz, acetone-d6) δ 7.48 (d, J=8.7 Hz, 2H), 7.42 (d, J=8.8 Hz, 1H), 7.33 (d, J=8.8 Hz, 1H), 7.06 (d, J=8.7 Hz, 2H), 6.74 (s, 1H), 5.01 (d, J=8.1 Hz, 1H), 4.29 (m, 1H), 4.15 (dq, J=16.3, 10.0 Hz, 1H), 3.88 (s, 3H), 3.73 (dq, J=16.3, 9.3 Hz, 1H), 0.92 (d, J=7.2 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH:9][CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].[CH3:21][O:22][C:23](=[O:30])/[CH:24]=[CH:25]/[CH2:26][C:27](O)=[O:28].C(N(CC)CC)C.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>ClCCl>[CH3:21][O:22][C:23]([CH2:24][CH:25]=[CH:26][C:27]([N:9]([CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])=[O:28])=[O:30]
Reactant: O=C(CNCc1ccccc1Br)OCc1ccccc1
Reactant: COC(=O)/C=C/CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CC=CC(=O)N(CC(=O)OCc1ccccc1)Cc1ccccc1Br
Reaction time: 2 h

Procedure:
Benzyl 2-(N-(2-bromophenylmethyl)amino)acetate was dissolved in dichloromethane (0.2 M), followed by addition of trans-glutaconic acid methyl ester (1.2 eq), triethylamine (2 eq), EDAC (1.2 eq), and HOAT (0.1 eq). After stirring for 2 hrs, the solution was washed with 10% HCl, 10% sodium carbonate, water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (50% EtOAc/Hex) afforded a viscous oil. EI-MS m/z 460, 462 (M+H)+
Reaction SMILES: O=O.[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[C:12]([C:23]([OH:25])=[O:24])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].C(N(CC)CC)C.[H][H]>COC(C)(C)C.CO>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C@@H:13]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[C@@H:12]([C:23]([OH:25])=[O:24])[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2)=C(C(=O)O)C1
Agent: O=O
Solvent: CCN(CC)CC
Solvent: CO
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(F)cc2)[C@@H](C(=O)O)C1
Temperature: 25 °C
Yield: 89 %

Procedure:
In a glove box (O2 content ≦2 ppm) a 35 ml autoclave equipped with a 15 ml glass insert and a magnetic stirring bar was charged with 4-(4-fluoro-phenyl)-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid-1-tert-butyl ester (0.300 g, 0.934 mmol), [Ru(OAc)2((S)-3,5-Xyl-4-MeO)-MeOBIPHEP] (9.67 mg, 0.00936 mmol), triethylamine (15 mg, 0.16 mmol, 0.16 eq.) and 5 ml of methanol. The asymmetric hydrogenation was run for 42 h at 80° C. under 40 bar of hydrogen. After cooling to room temperature the pressure was released from the autoclave, the methanol solution was diluted with 50 ml of tert-butyl methyl ether and extracted with two 50-ml portions of a 1 M aqueous sodium hydroxide solution. The aqueous layer was poured on ice, acidified with ice-cold 2 M aqueous hydrochloric acid solution to pH 1 and extracted with two 100-ml portions of ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give (+)-(3R,4R)-4-(4-fluoro-phenyl)-piperidine-1,3-dicarboxylic acid-1-tert-butyl ester in 89% yield (0.27 g) and with 96.6% ee.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([C:15]2[N:23]3[C:18]([C:19]([NH2:24])=[N:20][CH:21]=[N:22]3)=[CH:17][CH:16]=2)=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:25]N1C(C)(C)C(=O)N(Br)C1=O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([C:15]2[N:23]3[C:18]([C:19]([NH2:24])=[N:20][CH:21]=[N:22]3)=[C:17]([Br:25])[CH:16]=2)=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc3c(N)ncnn23)C1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2cc(Br)c3c(N)ncnn23)C1
Temperature: -20 °C
Reaction time: 2 h
Yield: 164.6 %

Procedure:
To a cooled (−20° C.) solution of 3-(4-amino-pyrrolo[2,1-f][1,2,4]triazine-7-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.19 g, 3.59 mmol) in tetrahydrofuran (35 mL) was added THF solution of 1,3-dibromo-5,5-dimethylhydantoin (0.56 g, 1.97 mmol). The mixture was allowed to stir (−20° C.) for 2 h and then allowed to warm to rt. The reaction was quenched with the addition of 10% aqueous Na2S2O3 solution. The mixture was extracted with ethyl acetate (3×75 mL). The combined organics were washed with brine, dried (Na2SO4) and concentrated to dryness. The crude material was purified by Biotage® chromatography using a gradient of 50% to 75% ethyl acetate in hexanes to afford 1.33 g (90%) of the desired product. 1H NMR (300 MHz, CD3OD-d4) δ 8.00 (s, 1 H), 7.45 (d, 1 H), 6.94 (d, 1 H), 4.44-4.32 (m, 1 H), 3.65-3.59 (m, 2 H), 3.47-3.38 (m, 2 H), 2.31-2.11 (m, 2 H), 1.45 (s, 9 H); LC-MS [M+H]+=411.7, RT=2.98 min.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[O:7])=[C:4]([F:15])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22]([Zn]CC)[CH3:23].ClCCl>CN(C=O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:9]([N:8]([CH2:11][CH3:12])[C:6](=[O:7])[C:5]1[CH:13]=[CH:14][C:2]([CH2:22][CH3:23])=[CH:3][C:4]=1[F:15])[CH3:10]
Reactant: CCN(CC)C(=O)c1ccc(Br)cc1F
Reactant: CC[Zn]CC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1ccc(C(=O)N(CC)CC)c(F)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
To a solution of 4-bromo-N,N-diethyl-2-fluorobenzamide (5.12 g, 18.9 mmol) in 100 mL of DMF was added potassium carbonate (6.45 g, 46.7 mmol) and diethylzinc (25.5 mL of a 1.1 M solution in toluene, 28.02 mmol). The solution was degassed with a stream of argon and then there was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (305 mg, 0.37 mmol). The reaction mixture was allowed to stir at 80° C. for 3 h. The reaction mixture was allowed to cool and was diluted with ethyl acetate. The organics were washed with water and brine, dried (MgSO4) and concentrated. The residue was purified (ISCO, elution with 0-40% EtOAc/hexane, 40 min) to afford 3.70 g (88%) of the title compound as a colorless oil. LRMS (ESI): 224.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:15]=[CH:16][C:17]([OH:35])([C:31]([F:34])([F:33])[F:32])[CH2:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=2[O:29][CH3:30])([CH3:21])[CH3:20])[N:6]=1)=[O:4].C(=O)(O)[O-].[Na+]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:15][CH:16]2[C:27]3[C:22](=[C:23]([O:29][CH3:30])[C:24]([F:28])=[CH:25][CH:26]=3)[C:19]([CH3:21])([CH3:20])[CH2:18][C:17]2([OH:35])[C:31]([F:32])([F:33])[F:34])[N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(N=CC(O)(CC(C)(C)c3cccc(F)c3OC)C(F)(F)F)cccc2n1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc2c(NC3c4ccc(F)c(OC)c4C(C)(C)CC3(O)C(F)(F)F)cccc2n1
Reaction time: 3 h

Procedure:
5-[4-(3-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylidenamino]-quinoline-2-carboxylic acid methyl ester (120 mg, 0.243 mmol) is dissolved in 2.0 ml of dichloromethane. Titanium tetrachloride (1 M solution in dichloromethane, 0.73 ml, 0.73 mmol) is added in drops within 15 minutes at −30° C. Then, the reaction mixture is allowed to stir for 3 hours at −30° C. to −15° C. By adding saturated sodium bicarbonate solution at −30° C., the reaction is brought to a halt. It is extracted with ethyl acetate, the combined organic phases are washed with water and saturated sodium chloride solution. After drying on sodium sulfate and after the solvent is removed in a vacuum as well as subsequent purification on silica gel with dichloromethane/methanol (0-3% methanol), 70 mg (58% of theory) of the product is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][C:3]=1[NH:18][C:19]([CH3:38])([CH2:21][CH2:22][N:23]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH3:20].[C:39]([O:43][CH2:44]C)(=[O:42])[CH:40]=O.C1(C)C=CC=CC=1>CO>[CH3:44][O:43][C:39]([C:40]1[N:18]([C:19]([CH3:38])([CH2:21][CH2:22][N:23]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH3:20])[C:3]2[CH:4]=[C:5]([C:6]([O:8][CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:7])[CH:16]=[CH:17][C:2]=2[N:1]=1)=[O:42]
Reactant: CC(C)(CCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)Nc1cc(C(=O)OCc2ccccc2)ccc1N
Reactant: CCOC(=O)C=O
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1nc2ccc(C(=O)OCc3ccccc3)cc2n1C(C)(C)CCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 99 %

Procedure:
To a stirred solution of crude benzyl 4-amino-3-({4-[bis(tert-butoxycarbonyl)amino]-2-methylbutan-2-yl}amino)benzoate (250 mg, 0.47 mmol) in methanol (10 mL) is added a 50% solution of ethyl glyoxalate in toluene (0.38 mL, 1.90 mmol). After 16 h, the solvent is evaporated to afford the title compound (295 mg, >99%), which is used in the next step without purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([N:27]([C@@H:34]([CH3:37])[CH2:35]O)[CH2:28][C@H:29]([OH:33])[CH2:30][O:31][CH3:32])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl:38]C(Cl)(Cl)Cl>>[CH2:20]([N:27]([CH2:28][C@H:29]([OH:33])[CH2:30][O:31][CH3:32])[C@@H:34]([CH3:37])[CH2:35][Cl:38])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: COC[C@@H](O)CN(Cc1ccccc1)[C@@H](C)CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC[C@@H](O)CN(Cc1ccccc1)[C@@H](C)CCl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Triphenylphosphine (10.09 g) was added to a solution of (2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-methoxypropyl]amino]-1-propanol (8.86 g) in tetrachloromethane (4.06 ml) at room temperature. After being stirred at room temperature for 2 days, the solution was concentrated under reduced pressure. The residue was triturated with diisopropyl ether (200 ml) three times, and the soluble portions were separated by decantation and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using mixed solvents of dichloromethane and methanol (40:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give (2S)-1-[N-benzyl-N-[(1S)-2-chloro-1-methylethyl]amino]-3-methoxy-2-propanol (4.90 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[C:13]([Cl:18])[CH:12]=3)=[CH:9][S:10][C:6]=2[CH:5]=[CH:4][N:3]=1.C1C(=O)N([Br:26])C(=O)C1.[O-]S([O-])=O.[Na+].[Na+].C(OCC)(=O)C>C1COCC1>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[C:13]([Cl:18])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([Br:26])=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1nccc2scc(-c3ccc(F)c(Cl)c3)c12
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ncc(Br)c2scc(-c3ccc(F)c(Cl)c3)c12
Temperature: 0 °C
Reaction time: 1 h
Yield: 108.3 %

Procedure:
To the solution of 4-amino-3-(3-chloro-4-fluoro-phenyl)thieno[3,2-c]pyridine (240 mg, 0.86 mmol) in 10 ml of THF cooled at 0° C. was added NBS (153 mg, 0.86 mmol) and the reaction mixture was stirred for 1 hour at 0° C. The resultant mixture was poured into 10% Na2SO3 and ethyl acetate, the organic phase was collected, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on a silica gel column to afford the titled compound (333 mg). 1H NMR (400 MHz, DMSO-d6) ppm 7.97 (s, 1H), 7.73 (dd, J=2.1, 7.2 Hz, 1H), 7.69 (s, 1H), 7.55 (dd, J=8.8 Hz, 1H), 7.48 (ddd, J=2.2, 4.7, 8.4 Hz, 1H), 5.66 (s, 2H). MS: m/z 357, 359, 361 (M+H)+.