Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O:32][C:33](=[O:62])[CH:34]([C:55]1[CH:56]=[C:57]([CH3:61])[CH:58]=[CH:59][CH:60]=1)[CH2:35][C:36]1[CH:40]=[C:39]([C:41]2[CH:46]=[CH:45][C:44](Br)=[CH:43][CH:42]=2)[N:38]([C:48]2[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=2)[N:37]=1)C.[CH2:63]([NH2:66])[CH:64]=[CH2:65]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[CH2:63]([NH:66][C:44]1[CH:43]=[CH:42][C:41]([C:39]2[N:38]([C:48]3[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=3)[N:37]=[C:36]([CH2:35][CH:34]([C:55]3[CH:56]=[C:57]([CH3:61])[CH:58]=[CH:59][CH:60]=3)[C:33]([OH:62])=[O:32])[CH:40]=2)=[CH:46][CH:45]=1)[CH:64]=[CH2:65]
Reactant: CCOC(=O)C(Cc1cc(-c2ccc(Br)cc2)n(-c2ccc(C)cc2)n1)c1cccc(C)c1
Reactant: C=CCN
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCNc1ccc(-c2cc(CC(C(=O)O)c3cccc(C)c3)nn2-c2ccc(C)cc2)cc1
Temperature: 110 °C
Reaction time: 12 h
Yield: 49.8 %

Procedure:
3-[5-(4-Allylamino-phenyl)-1-β-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionic acid ethyl ester. To a mixture of Pd2(dibenzylideneacetone)3 (4 mg, 0.004 mmol, 1 mol %), 2-(di-tert-butylphosphino)biphenyl (6 mg, 0.02 mmol, 5 mol %) and K3PO4 (130 mg, 0.61 mmol, 1.5 equiv) was added a solution of 3-[5-(4-bromo-phenyl)-1-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionic acid ethyl ester (Example 77, Step C; 200 mg, 0.4 mmol) in toluene (0.6 mL) followed by allylamine (0.030 mL, 0.48 mmol, 1.2 equiv). The resulting mixture was stirred at 110° C. for 12 h and then cooled to room temperature. Ethyl acetate (2 mL) and water (3 mL) were added, and the resulting aqueous layer was back-extracted with EtOAc (3×2 mL). The combined organic layers were washed with brine (3 mL), and then dried (MgSO4). The solvent was evaporated under reduced pressure, and the residue was purified by chromatography (silica gel, 25% ethyl acetate/hexanes) to afford the desired compound (90 mg, 47%). HPLC: Rt=3.19 (Method B). MS (ESI): mass calculated for C31H33N3O2, 479.26; m/z found, 480.3 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.29 (s, 1H), 7.27-7.04 (m, 7H), 6.96 (d, J=8.5 Hz, 2H), 6.49 (d, J=8.5 Hz, 2H), 6.07 (s, 1H), 5.96-5.89 (m, 1H), 5.29-5.25 (m, 1H), 5.18-5.16 (m, 1H), 4.20-4.14 (m, 1H), 4.10-4.02 (m, 2H), 3.76-3.75 (m, 2H), 3.52-3.45 (m, 1H), 3.08 (dd, J=14.5, 6.0 Hz, 1H), 2.3 (s, 6H), 1.19 (t, J=7.1 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5]2[N:6]=[CH:7][CH:8]=[N:9][C:10]=2[CH:11]=1.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([O:12][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH:3]=1
Reactant: Oc1cc(Br)cc2nccnc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cc(Br)cc2nccnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
As shown in step 6-vi of Scheme 6, a solution of 7-bromoquinoxalin-5-ol (2.0 g, 8.89 mmol) in DCM (20 mL) was added imidazole (1.82 g, 26.7 mmol) and tert-butyldimethylsilyl chloride (1.34 g, 1.65 mL, 8.89 mmol). The reaction mixture was stirred overnight at RT, concentrated under reduced pressure, and purified by medium pressure silica gel chromatography (0 to 20% EtOAc/hexanes gradient) to provide 7-bromo-5-((tert-butyldimethylsilyl)oxy)quinoxaline (compound 1018) as a colorless oil: 1H-NMR (300 MHz, CDCL3) δ 8.69 (q, J=1.8 Hz, 2H), 7.80 (d, J=2.1 Hz, 1H), 7.22 (d, J=2.1 Hz, 1H), 0.96 (s, 9H), 0.81 (s, 7H).
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=1)(=[O:3])C.Cl[O-:18].[Na+].[OH-].[Na+].Cl>O1CCOCC1>[CH:5]1[C:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[S:8][C:7]=2[CH:15]=[CH:16][C:4]=1[C:1]([OH:3])=[O:18]
Reactant: [O-]Cl
Reactant: CC(=O)c1ccc2sc3ccccc3c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccc2sc3ccccc3c2c1
Reaction time: 5 h

Procedure:
2-Acetyldibenzothiophene (2.24 g.), sodium hypochlorite solution, (47 ml. containing 5.7% available chlorine), Normal sodium hydroxide solution (50 ml.) and dioxan (50 ml.), were heated on a steam bath with stirring for 5 hr. The mixture was acidified with excess hydrochloric acid, and the precipitated colourless solid filtered off, washed with water, and recrystallise twice from acetic acid to give dibenzothiophene-2-carboxylic acid, m.pt. 281°-283° C.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:5][CH:4]=1.[NH2:26][C:27]1[S:28][CH:29]=[CH:30][N:31]=1>N1C=CC=CC=1>[S:28]1[CH:29]=[CH:30][N:31]=[C:27]1[NH:26][S:20]([C:17]1[CH:18]=[CH:19][C:14]([S:11]([CH2:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:25])([F:24])[F:1])=[CH:4][CH:5]=2)(=[O:13])=[O:12])=[CH:15][CH:16]=1)(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)c1ccc(S(=O)(=O)CCc2ccc(C(F)(F)F)cc2)cc1
Reactant: Nc1nccs1
Solvent: c1ccncc1
Product: O=S(=O)(CCc1ccc(C(F)(F)F)cc1)c1ccc(S(=O)(=O)Nc2nccs2)cc1
Reaction time: 8 h
Yield: 6.4 %

Procedure:
To 4-[2-(4-Trifluoromethyl-phenyl)-ethanesulfonyl]-benzenesulfonyl chloride (1288 mg, 0.003120 mol) and 2-aminothiazole (0.31 g, 0.0031 mol) was added pyridine (20 mL). After stirring overnight, the reaction mixture was concentrated, dissolved in DMSO (4 mL) and purified by reversed phase chromatography (Phenomenex 250×30 mm 15 micron C18 column. 40 mL/min. Gradient 85% A to 100% B over 25 min. Solvent A: 7800 water/200 acetonitrile/8 TFA. Solvent B: 7200 acetonitrile/800 water/8 TFA). The compound was further purified on silica gel (CHCl3-10% MeOH in CHCl3) to give 94 mg of a light brown solid. LCMS: M+477.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(N(CC)CC)C.Cl[CH2:21][C:22]1[N:23]([CH2:35][CH2:36][CH2:37][NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C:24]2[C:33]3[N:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N:27]=[CH:26][C:25]=2[N:34]=1>CN(C=O)C.O>[O:7]=[C:6]1[C:5]2[C:4](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3](=[O:12])[N:2]1[O:1][CH2:21][C:22]1[N:23]([CH2:35][CH2:36][CH2:37][NH:38][C:39](=[O:45])[O:40][C:41]([CH3:43])([CH3:42])[CH3:44])[C:24]2[C:33]3[N:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N:27]=[CH:26][C:25]=2[N:34]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)OC(=O)NCCCn1c(CCl)nc2cnc3cccnc3c21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCn1c(CON2C(=O)c3ccccc3C2=O)nc2cnc3cccnc3c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
N-Hydroxyphthalimide (2.06 g, 12.7 mmol) and triethylamine (2.40 mL, 17.3 mmol) were added to a solution of tert-butyl 3-[2-(chloromethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]propylcarbamate (prepared as described in Parts A-D of Example 92, 11.5 mmol) in DMF (60 mL). The reaction was allowed to stir overnight at room temperature. The resulting orange suspension was diluted with water (40 mL) and the solid was isolated by filtration, washed with water (2×30 mL), and dried in a vacuum oven at 70° C. to afford 4.86 g of tert-butyl 3-(2-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)propylcarbamate as a white solid. The material was used without further purification in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:38][CH2:37][C:36]([F:40])([F:39])[CH2:35]1)(=[O:33])=[O:32]>>[F:40][C:36]1([F:39])[CH2:37][CH2:38][N:34]([S:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:6]2[CH:5]=[CH:4][C:3]([C:17]3[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=3)=[C:2]([F:1])[CH:7]=2)(=[O:33])=[O:32])[CH2:35]1
Reactant: O=S(=O)(c1ccccc1Br)N1CCC(F)(F)C1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N3CCC(F)(F)C3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 1-((2-bromophenyl)sulfonyl)-3,3-difluoropyrrolidine. MS (ESI): mass calcd. for C20H17F3N4O2S, 434.10; m/z found, 435.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.35 (d, J=1.3, 1H), 8.27 (d, J=1.4, 1H), 8.11 (d, J=7.9, 1H), 7.99 (m, 1H), 7.77-7.69 (m, 1H), 7.67-7.59 (m, 1H), 7.47-7.40 (m, 1H), 7.34-7.25 (m, 2H), 3.23 (t, J=12.9, 2H), 3.14 (t, J=7.3, 2H), 2.28-2.14 (m, 2H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]([CH3:19])[C:17](=[O:20])[C:16]3[C:11](=[C:12]([CH3:21])[CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.B(F)(F)F.[OH-].[Na+]>ClCCl.C(OCC)(=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:18]([CH3:19])[C:17](=[O:20])[C:16]3[C:11](=[C:12]([CH3:21])[CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nc3c(C)cccc3c(=O)n2C)cc1
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cccc2c(=O)n(C)c(-c3ccc(O)cc3)nc12
Temperature: -78 °C
Yield: 80.3 %

Procedure:
2-(4-Methoxyphenyl)-3,8-dimethyl-4(3H)-quinazolinone (2.02 g, 7.20 mmol) was dissolved in dichloromethane (10 ml), stirred at −78° C., then boron trifluoride (1.0 M in CH2 Cl2, 21.6 ml) was added thereto, gradually heated up to room temperature, and stirred at that temperature for 12 hours. The reaction solution was diluted with ethyl acetate, and with cooling with ice, this was poured into aqueous 1 N sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with 1 N hydrochloric acid and saturated saline water, and dried with magnesium sulfate. The organic layer was concentrated under reduced pressure to obtain the intended compound (1.54 g, 80%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=2[CH:6]=1.[N+]([O-])([O-])=[O:12].[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>C(O)(=O)C.O.O>[Cl:1][C:2]1[S:3][C:4]2[C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:5]=2[CH:6]=1
Reactant: Clc1cc2c(s1)CCCC2
Reactant: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCCc2cc(Cl)sc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
10.0 g (57.9 mmol) of 2-chloro-4,5,6,7-tetrahydro-1-benzothiophene are dissolved in acetic acid/water (247 ml/82 ml), 127 g (231 mmol) of ammonium cerium (IV) nitrate in water (50 ml) are added and the mixture is stirred at room temperature for 5 h. The reaction mixture is added to ice-water and extracted with dichloromethane. After washing with water, the organic phase is dried over sodium sulphate and concentrated under reduced pressure. This gives 5.60 g of 2-chloro-5,6-dihydro-1-benzothiophen-7(4H)-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:21])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:21])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(F)c(F)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC1(c2ccc(F)c(F)c2)CCNC1
Reaction time: 4 h

Procedure:
Preparation according to Preparation 2: tert-Butyl 3-(3,4-difluorophenyl)-3-hydroxy-pyrrolidin-1-carboxylate (2.6 g, 8.69 mmol), dichloromethane (3 mL) and trifluoroacetic acid (3 mL). Stirred for 4 h. Yield: 1.32 g. MS m/z (relative intensity, 70 eV) 199 (M+, 876), 141 (bp), 127 (58), 113 (99), 63 (55).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1>[C].[Ru]>[CH2:1]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][NH:2]1
Reactant: c1ccc2cnccc2c1
Agent: [Ru]
Product: C1CCC2CNCCC2C1
Yield: 75.7 %

Procedure:
In an autoclave, 120 g (0.93 mol) of the aforementioned desulfurized isoquinoline 6 g of 5% ruthenium-carbon (Ru/C) catalyst were subjected to hydrogenation at a temperature of 180° C. under a hydrogen pressure of 140 kg/cm2 ·G for 60 hours. The total amount of hydrogen absorbed during the reaction was 4.9 moles and the molar ratio of the absorbed hydrogen to isoquinoline was 5.3. The reaction mixture obtained after separation of the catalyst by filtration was analyzed by gas chromatography. It was found to contain 88% of decahydroisoquinoline. By distilling this reaction mixture, 98 g (76% in yield) of decahydroisoquinoline (197° C. to 210° C. fraction) was obtained. The trans/cis ratio of this decahydroisoquinoline was found to be 6/4.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[CH3:21][S:22][C:23]1[N:28]=[C:27]([CH:29]=[O:30])[CH:26]=[CH:25][N:24]=1.[NH4+].[Cl-]>C1COCC1>[C:17]([O:16][C:13](=[O:15])[CH2:14][CH:29]([OH:30])[C:27]1[CH:26]=[CH:25][N:24]=[C:23]([S:22][CH3:21])[N:28]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(=O)OC(C)(C)C
Reactant: CSc1nccc(C=O)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CSc1nccc(C(O)CC(=O)OC(C)(C)C)n1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 82.2 %

Procedure:
To a cold (0° C.) solution of diisopropylamine (5.7 mL, 40.5 mmol) in THF (130 mL) is added dropwise n-butyllithium (16.2 mL of a 2.5 M solution in hexanes, 40.5 mmol). The mixture is stirred for 45 min at 0° C., then the solution is cooled to −78° C. tert-Butyl acetate (5.5 mL, 40.5 mmol) is added dropwise to the reaction mixture. After stirring 40 min at −78° C., a solution of 2-methylsulfanyl-pyrimidine-4-carbaldehyde (5.0 g, 32.4 mmol) is added dropwise. After 30 min at −78° C., the solution is poured into aqueous saturated NH4Cl. The aqueous phase is extracted with EtOAc. The organic phase is dried (MgSO4), filtered and concentrated in vacuo. The crude residue is purified over silica (5% EtOAc/hexanes, followed by 20% EtOAc/hexanes) to afford 7.2 g (82% yield) of the desired product. 1H NMR (300 MHz, CDCl3) δ 8.52 (d, J=5.1 Hz, 1H), 7.22 (d, J=5.1 Hz, 1H), 5.00 (dd, J=8.4, 3.6 Hz, 1H), 2.93 (dd, J=16.5, 3.6 Hz, 1H), 2.70 (dd, J=16.5, 7.8 Hz, 1H), 2.58 (s, 3H), 1.46 (s, 9H); ESI+ MS: m/z (rel intensity) 271.1 (85, M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][CH:10](OCC)OCC>ClC1C=CC=CC=1>[Cl:1][C:2]1[C:3]2[S:8][CH:9]=[CH:10][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(CSc1ccccc1Cl)OCC
Solvent: Clc1ccccc1
Product: Clc1cccc2ccsc12
Yield: 93 %

Procedure:
Into a 2 L round bottomed flask is added 2-chlorobenzenethiol (50.0 g, 346 mmol), potassium carbonate (52.7 g, 381 mmol) and acetone (1 L). 2-Bromo-1,1-diethoxyethane (71.5 g, 363 mmol) is added and the mixture is heated to reflux for 24 hours. The cooled mixture is filtered and concentrated under reduced pressure to yield crude 2-chlorophenyl-(2,2-diethoxyethyl)sulfane as a pale pink oil (101.8 g, quantitative). A 2 L, 3-necked round-bottomed flask, fitted with a mechanical stirrer, condenser and addition funnel is charged with chlorobenzene (1 L) and polyphosphoric acid (200 g) and the mixture is heated to reflux. At reflux the crude (2-chlorophenyl)(2,2-diethoxyethyl)sulfane is added dropwise over 1.5 hours and the mixture is refluxed for a further 24 hours. The cooled organic layer is decanted and concentrated under reduced pressure. The crude material is subjected to chromatography on silica (hexane) to provide the title compound as a brown oil (54.4 g, 93% yield).
Reaction SMILES: I[CH3:2].[C:3]([O:7][C:8](=[O:23])[NH:9][C@H:10]([CH2:21][OH:22])[CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:6])([CH3:5])[CH3:4]>CN(C)C=O.[Ag-]=O>[C:3]([O:7][C:8](=[O:23])[NH:9][C@H:10]([CH2:21][O:22][CH3:2])[CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([CH3:5])([CH3:4])[CH3:6]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CCOCc1ccccc1
Reactant: CI
Agent: O=[Ag-]
Solvent: CN(C)C=O
Product: COC[C@H](CCOCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 40 °C
Yield: 99.8 %

Procedure:
Silver(I) oxide (4.49 g, 19.4 mmol) and iodomethane (2.75 g, 19.4 mmol) were added at room temperature to a solution or ((S)-3-benzyloxy-1-hydroxymethyl-propyl)-carbamic acid tert-butyl ester (2.60 g, 8.81 mmol) in N,N-dimethylformamide (8 mL). The reaction mixture was heated at 40° C. for 2.5 h, then insoluble material was removed by filtration through diatomaceous earth. After evaporation of the filtrate, the residue was taken up in ethyl acetate and washed with water. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated to afford the title compound (2.72 g, 100%), which was used without further purification. Colorless liquid, MS (ISP)=310.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[CH2:10][C@H:11]([NH2:29])[C:12](=[O:28])[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][S:32]([NH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([NH:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][C:49](O)=[O:50])=[O:42])(=[O:34])=[O:33].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:30])[CH2:10][C@H:11]([NH:29][C:49](=[O:50])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][NH:43][C:41](=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][NH:35][S:32]([CH3:31])(=[O:33])=[O:34])[C:12](=[O:28])[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)NCCCCCC(=O)NCCCCCC(=O)O
Reactant: CCCCCCCCCCCCCCNC(=O)[C@@H](N)CC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCNC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCNC(=O)CCCCCNS(C)(=O)=O
Yield: 7.7 %

Procedure:
1.05 g of (S)-3-amino-3-tetradecylcarbamoylpropionic acid benzyl ester and 1.00 g of 6-(6-methanesulfonamidohexanamido)hexanoic acid were mingled in 20 ml of methylenechloride and after adding thereto 500 mg of DCC and treating the mixuture in the same manner as in Example 26, 140 mg of (S)-3-[6-(6-methanesulfonamidohexanamido)hexanamido]-3-tetradecylcarbamoylpropionic acid benzyl ester was obtained.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[CH:12][C:11]([C:14]2[N:19]=[C:18]([NH2:20])[CH:17]=[N:16][CH:15]=2)=[CH:10][N:9]=1.[CH3:23][N:24]1[C:32](=[O:33])[C:31]2[N:30]([C@@H:34]([CH3:38])[C:35](O)=[O:36])[CH:29]=[N:28][C:27]=2[N:26]([CH3:39])[C:25]1=[O:40].C1CCC(N=C=NC2CCCCC2)CC1.N1C=CC=CC=1>C(Cl)Cl>[CH3:23][N:24]1[C:32](=[O:33])[C:31]2[N:30]([C@@H:34]([CH3:38])[C:35]([NH:20][C:18]3[CH:17]=[N:16][CH:15]=[C:14]([C:11]4[CH:10]=[N:9][C:8]([N:4]5[CH2:5][CH2:6][CH2:7][C@H:3]5[C:2]([F:21])([F:1])[F:22])=[N:13][CH:12]=4)[N:19]=3)=[O:36])[CH:29]=[N:28][C:27]=2[N:26]([CH3:39])[C:25]1=[O:40]
Reactant: C[C@@H](C(=O)O)n1cnc2c1c(=O)n(C)c(=O)n2C
Reactant: Nc1cncc(-c2cnc(N3CCC[C@H]3C(F)(F)F)nc2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@@H](C(=O)Nc1cncc(-c2cnc(N3CCC[C@H]3C(F)(F)F)nc2)n1)n1cnc2c1c(=O)n(C)c(=O)n2C
Reaction time: 0.08 h

Procedure:
A round bottom flask was charged with (S)-6-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyrazin-2-amine (5.097 g, 16.43 mmol) and (S)-2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propanoic acid (Intermediate 8) (4.97 g, 19.71 mmol). The reagents were suspended in DCM (Volume: 36.5 ml, Ratio: 4), sonicated and allowed to stir for 5 minutes. To the yellow heterogenous mixture was added DCC (5.76 g, 27.9 mmol) and finally pyridine (Volume: 18.25 ml, Ratio: 2) was added and the mixture was allowed to stir for 3 hours. The reaction mixture was diluted with CH2Cl2 and filtered over Celite®. The filtrate was then concentrated and redissolved in a minimal amount of and added dropwise to stirring hexanes to precipitate out crude 2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6-(2-((S)-2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyrazin-2-yl)propanamide, which was dried overnight. The mixture of diasteromers was resolved using SFC purification to give the (S,S)-isomer in 2.58 g (retention time: 2.5 min, de: 98%); and the (R,S)-isomer in 0.208 g (retention time: 2.2 min, de: 99%); 1H NMR, (S,S)-isomer (300 MHz, DMSO-d6) δ 11.40 (s, 1H), 9.16 (d, J=3.5 Hz, 3H), 8.97 (s, 1H), 8.36 (s, 1H), 5.86 (d, J=7.3 Hz, 1H), 5.20-5.03 (m, 1H), 3.73 (t, J=6.5 Hz, 2H), 3.46 (s, 3H), 3.19 (s, 3H), 2.29-2.04 (m, 4H), 1.89 (d, J=7.3 Hz, 3H); m/z found [M+H]+=545.19
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9][CH:8]=2)[CH:4]=[N:3]1.S(Cl)([Cl:18])=O>>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[CH:11][C:10]([C:13]([Cl:18])=[O:15])=[CH:9][CH:8]=2)[CH:4]=[N:3]1
Reactant: O=S(Cl)Cl
Reactant: Cn1cc(-c2ccc(C(=O)O)cn2)cn1
Product: Cn1cc(-c2ccc(C(=O)Cl)cn2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 6-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxylic Acid (0.48 g) in thionyl chloride (5.0 ml) was stirred at room temperature for 2 hours. The volatile material was removed under reduced pressure to afford 6-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carbonyl chloride as a solid, which was utilized without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:16]C)=[C:4]([C:8]2[CH:9]=[C:10]([C:13]([OH:15])=[O:14])[NH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.B(Br)(Br)Br>ClCCl>[NH2:1][C:2]1[C:3]([OH:16])=[C:4]([C:8]2[CH:9]=[C:10]([C:13]([OH:15])=[O:14])[NH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(N)cccc1-c1c[nH]c(C(=O)O)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1cccc(-c2c[nH]c(C(=O)O)c2)c1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 114.6 %

Procedure:
To a solution of 4-(3-amino-2-methoxy-phenyl)-1H-pyrrole-2-carboxylic acid 57h (130 mg, 0.56 mmol) in 2 mL of dichloromethane was added boron tribromide (1.12 mL, 2.24 mmol). The reaction mixture was stirred at room temperature for 6 hours. The reaction was monitored by TLC until the disappearance of the starting materials and quenched with methanol. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound 4-(3-amino-2-hydroxy-phenyl)-1H-pyrrole-2-carboxylic acid 57i (140 mg, yield 99%) as a grey solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[CH:9][C:10](=O)[NH:11][N:12]=2)=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:10]1[N:11]=[N:12][C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:8][CH:9]=1
Reactant: O=c1ccc(-c2ccncc2)n[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc(-c2ccncc2)nn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 64.6 %

Procedure:
75.6 g 6-Pyridin-4-yl-2H-pyridazin-3-one is added in small portions to 234.5 g phosphorus oxychloride and the resulting mixture is stirred for 1 h at 100° C. Diluting into ice cold water, adjusting the pH 7 with aqueous sodium hydroxide and extraction with dichloromethane yielded 54 g 3-Chloro-6-pyridin-4-yl-pyridazine which is used without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:6](=[O:7])[NH:5][C:3]1=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH:15]([O:17][CH2:18][CH2:19]Cl)=[CH2:16].CN(C)C=O>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:8][C:6](=[O:7])[N:5]([CH2:19][CH2:18][O:17][CH:15]=[CH2:16])[C:3]1=[O:4]
Reactant: C=COCCCl
Reactant: CN1CC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C=COCCN1C(=O)CN(C)C1=O

Procedure:
A mixture of 82.6 g (0.72 mol) of 1-methylhydantoin, 50.7 g (0.37 mol) of anhydrous potassium carbonate, 89.6 g (0.84 mol) of 2-chloroethyl vinyl ether, 700 ml of dimethylformamide and 100 ml of toluene is reacted for 2 hours and 30 minutes at 130°-138° C., whilst removing the water of reaction. The mixture is then worked up as described in Example 1, and 128.5 g of a clear, reddish brown, viscous crude product (96.9% of theory) are obtained. The crude product is distilled (boiling point 133° C.-134° C./0.2 mm Hg) and 108.5 g (81.8% of theory) of a colourless, viscous distillate are obtained; this crystallises and melts at 54°-56° C.