Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[N+:21]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28])([O-:23])=[O:22].CO>C1COCC1.C(OCC)C>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][CH:32]=[C:24]([N+:21]([O-:23])=[O:22])[CH:25]=3)[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)c4cccc([N+](=O)[O-])c4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
To a suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.10 g, 4 mmol) in THF (30 ml) was added 3-nitrobenzoyl chloride (1.48 g, 8 mmol). The mixture was heated to reflux for 18 hours. The reaction was cooled to room temperature, methanol (2 ml) was added, and the mixture stirred for 1 hour. The solvent was evaporated in vacuo leaving a solid that was slurried in diethyl ether (30 ml) and filtered to give 1.60 g (95%) of product as an off-white solid: mp 245-247° C.; 1H NMR (DMSO-d6) d 10.85 (s, 1H), 10.53 (s, 1H), 8.76 (s, 1H), 8.50-8.37 (m, 3H), 7.95-7.87 (m, 2H), 7.70 (d, J=7.4 Hz, 1H), 5.14 (dd, J=5.7 and 12.7 Hz, 1H), 3.02-2.83 (m, 1H), 2.67-2.47 (m, 2H), 2.15-2.07 (m, 1H) 13C NMR (DMSO-d6) d 171.73, 168.79, 167.19, 166.04, 162.85, 147.84, 135.60, 134.79, 132.92, 131.21, 130.19, 126.87, 126.20, 121.69, 118.83, 48.86, 30.51, 21.63; Anal. Calcd. For C20H14N4O7: C, 56.88; H, 3.34; N, 13.27. Found: C, 56.87; H, 3.33; N, 13.05.
Reaction SMILES: [NH:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[NH:3]1.Cl.Cl.N[CH:15]([CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[C:16]([NH:18][C:19]1([C:26]#[N:27])[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)=[O:17]>C1COCC1>[C:26]([C:19]1([NH:18][C:16](=[O:17])[CH:15]([NH:1][C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[N:3]=2)[CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)#[N:27]
Reactant: N=C1NC(=O)c2ccccc21
Reactant: CN1CCC(C#N)(NC(=O)C(N)CC2CCCCC2)CC1
Agent: Cl
Solvent: C1CCOC1
Product: CN1CCC(C#N)(NC(=O)C(CC2CCCCC2)NC2=NC(=O)c3ccccc32)CC1

Procedure:
The title compound was prepared starting from 3-imino-2,3-dihydro-isoindol-1-one and 2-amino-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamide bis hydrochloride salt according to the procedure from Example 81, except that refluxing THF was used as the solvent. The compound was further purified by HPLC using a 20×250 mm C18 reverse phase column with the method being 20% acetonitrile in water to acetonitrile. MS, m/z 422.5=M+1.
Reaction SMILES: [CH3:1][S:2]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](O)=[O:14])=[CH:10][CH:11]=2)[N:6]([C:16]2[N:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:18][N:17]=2)[CH:5]=1)=[O:3].[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][C:29]1=[O:34]>>[CH3:1][S:2]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([N:31]3[CH2:32][CH2:33][NH:28][C:29](=[O:34])[CH2:30]3)=[O:14])=[CH:10][CH:11]=2)[N:6]([C:16]2[N:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:18][N:17]=2)[CH:5]=1)=[O:3]
Reactant: CS(=O)c1cn(-c2ncc(-c3ccccc3)cn2)c2cc(C(=O)O)ccc12
Reactant: O=C1CNCCN1
Product: CS(=O)c1cn(-c2ncc(-c3ccccc3)cn2)c2cc(C(=O)N3CCNC(=O)C3)ccc12

Procedure:
Synthesized from 3-(methylsulfinyl)-1-(5-phenylpyrimidin-2-yl)-1H-indole-6-carboxylic acid (200 mg, 0.53 mmol) and piperazin-2-one (64 mg, 0.63 mmol) in an analogous manner as described for example 52. White solid. Yield: 148 mg (61% of theory). HPLC-MS (method 4): Rt=2.6 min; m/z [M+H]+=460.3
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH:6](O)[C:5]=2[CH:4]=[N:3]1.[I:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[N:19][C:20]=2[NH2:22])[NH:15][N:14]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[I:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[N:19][C:20]=2[NH2:22])[N:15]([CH:6]2[CH2:7][CH2:8][CH2:9][C:10]3[N:2]([CH3:1])[N:3]=[CH:4][C:5]2=3)[N:14]=1
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: Cn1ncc2c1CCCC2O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1ncc2c1CCCC2n1nc(I)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 7.7 %

Procedure:
To a solution of 1-methyl-4,5,6,7-tetrahydro-1H-indazol-4-ol (400 mg, 2.63 mmol) and 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (684 mg, 2.63 mmol) and Ph3P (1.03 g, 3.94 mmol) in THF (40 mL) was added DIAD (798 mg, 3.94 mmol) dropwise at 0° C. After the addition was completed, the mixture was allowed to warm to room temperature and stirred for 3 hours. The mixture was extracted with EA, the combined the organic layers were washed with brine and dried over anhydrous Na2SO4. The volatiles were concentrated in vacuo and the residue was purified by silica gel chromatography (DCM/methanol=40/1 v/v %) to give 3-iodo-1-(1-methyl-4,5,6,7-tetrahydro-1H-indazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (80 mg, 8%). MS-ESI (m/z): 396 (M+1)+ (Acq Method: 10-80AB_2 min_220 &254.1 cm; Rt: 0.82 min)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.Cl[CH2:21]Cl.CO>O.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:4]=1[C:5]([O:7][CH3:21])=[O:6]
Reactant: COc1cc(OC)c(C(=O)O)cc1OC
Reactant: ClCCl
Solvent: CO
Solvent: O=S(Cl)Cl
Solvent: O
Product: COC(=O)c1cc(OC)c(OC)cc1OC
Reaction time: 1 h
Yield: 65 %

Procedure:
To 21.2 g of 2,4,5-trimethoxybenzoic acid, 30 ml of thionyl chloride were added at room temperature, followed by heating under reflux for 4 hours. The reaction mixture was thereafter distilled off under reduced pressure. To the residue so obtained, 50 ml of dichloromethane, 10 ml of methanol and 20 ml of triethylamine were added, followed by stirring under ice cooling for one hour. After the completion of the reaction, water was added to the reaction mixture, followed by extraction with chloroform. The extract was washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, whereby a crude product was obtained. The crude product so obtained was washed with methanol, whereby 14.6 g of methyl 2,4,5-trimethoxybenzoate were obtained (yield: 65%).
Reaction SMILES: [Cl-].[Cl:2][CH2:3][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[NH2-].[Na+].[Cl:25][C:26]1[C:31]2[C:32](=[O:43])[N:33]([CH3:42])[CH2:34][C:35]3[N:36]([CH:37]=[N:38][C:39]=3[CH:40]=O)[C:30]=2[CH:29]=[CH:28][CH:27]=1>O1CCCC1>[Cl:25][C:26]1[C:31]2[C:32](=[O:43])[N:33]([CH3:42])[CH2:34][C:35]3[N:36]([CH:37]=[N:38][C:39]=3/[CH:40]=[CH:3]\[Cl:2])[C:30]=2[CH:29]=[CH:28][CH:27]=1
Reactant: CN1Cc2c(C=O)ncn2-c2cccc(Cl)c2C1=O
Reactant: ClC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1Cc2c(/C=C\Cl)ncn2-c2cccc(Cl)c2C1=O
Reaction time: 1 h

Procedure:
100 g of an equimolar mixture of chloromethyltriphenylphosphonium chloride and sodium amide were stirred for 45 minutes in 450 ml of tetrahydrofuran, whereby the temperature rose to 37°. 62.23 g (229.7 mmol) of 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxaldehyde were then added portionwise thereto at room temperature and, after completion of the addition, the mixture was stirred for a further 1 hour. The reaction mixture was subsequently filtered and the filtrate was evaporated. After chromatography of the residue on silica gel while eluting with cyclohexane/ether/wasopropanol (3:3:1) there was obtained 7-chloro-3-[(Z)-2-chlorovinyl]-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 205°-207°.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:13](OCC)C.S(=O)(=O)(O)O>C(O)C>[CH3:13][C:4]([C:3]1[C:2]([F:1])=[CH:10][C:9]([F:11])=[C:8]([F:12])[CH:7]=1)=[O:5]
Reactant: O=C(Cl)c1cc(F)c(F)cc1F
Reactant: CCOCC
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CC(=O)c1cc(F)c(F)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
194.5 g (1 mol) of 2,4,5-trifluorobenzoyl chloride were initially introduced into 100 ml of diethyl ether and heated to boiling under reflux. 1.1 mol of ethoxymagnesium malonic ester dissolved in 100 ml of ethanol and 125 ml of diethyl ether were then allowed to drop in in the course of 30 minutes and the mixture was stirred for 1 hour under reflux. After cooling, the reaction mixture was stirred into 500 ml of ice water and adjusted to a pH of 1 with concentrated sulphuric acid, and the organic material (345 g) was separated off. This organic material was dissolved in 300 ml of acetic acid and, after adding 37.5 ml of concentrated sulphuric acid, heated to reflux until evolution of CO2 had ended, which took 6 hours. The reaction mixture was then cooled and poured into water, and the organic phase was separated off and distilled. 83 g of product having a boiling point at 10 mbar of 63° to 64° C. were obtained. This corresponds to a yield of 47% of theory.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])#[N:2].[N-:10]=[N+:11]=[N-:12].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[OH:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]1[NH:12][N:11]=[N:10][N:2]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccccc1O
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Oc1ccccc1-c1nnn[nH]1
Yield: 98 %

Procedure:
Into the same device as used in Example 1 were placed 5.96 g (0.050 mole) of orthocyanophenol, 9.76 g (0.150 mole) of sodium azide, 20.65 g (0.150 mole) of triethylamine hydrochloride and 60 ml of toluene. The mixture was reacted for 5 hours in the same manner as in Example 1, giving 7.95 g (0.049 mole) of 5-(2-hydroxyphenyl)-1H-tetrazole (yield 98.0% based on orthocyanophenol).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)(OC)O[CH2:12][CH:13]=[CH2:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Pd]>[CH2:14]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH:13]=[CH2:12]
Reactant: C=CCOC(=O)OC
Reactant: O=Cc1ccc(O)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C=CCOc1ccc(C=O)cc1

Procedure:
A mixture of p-hydroxybenzaldehyde (4.0 g, 33 mmoles), allyl methyl carbonate (16.0 g, 138 mmoles), 5 percent palladium on charcoal (1.3 g, 0.6 mmole palladium) and triphenyl phosphine (0.086 g, 0.32 mmole) is refluxed overnight. After removal of the catalyst and distillation (90° C., 0.6 mm Hg), 4.54 g, 85 percent of substantially pure p-allyloxybenzaldehyde is obtained.
Reaction SMILES: CC([O-])(C)C.[K+].C1COCC1.[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[C:15]([CH2:22][C:23]([NH2:25])=[O:24])=[CH:16][NH:17]2.C[O:27][C:28](=O)[C:29]([C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:39]=1[N:38]([CH3:40])[CH:37]=[CH:36]2)=O>CN(C=O)C>[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[C:15]([C:22]1[C:23](=[O:24])[NH:25][C:28](=[O:27])[C:29]=1[C:31]1[CH:32]=[CH:33][CH:34]=[C:35]3[C:39]=1[N:38]([CH3:40])[CH:37]=[CH:36]3)=[CH:16][NH:17]2
Reactant: COC(=O)C(=O)c1cccc2ccn(C)c12
Reactant: NC(=O)Cc1c[nH]c2cccc(F)c12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1ccc2cccc(C3=C(c4c[nH]c5cccc(F)c45)C(=O)NC3=O)c21
Reaction time: 4 h
Yield: 54.6 %

Procedure:
A 1.0 M solution of KOtBu in THF (10.6 mL, 10.6 mmol) was added to a solution of 2-(4-fluoro-1H-indol-3-yl)-acetamide (595 mg, 3.10 mmol) and (1-methyl-1H-indol-7-yl)-oxo-acetic acid methyl ester (646 mg, 2.98 mmol) in DMF (40 mL). The initially light yellow solution turned red-orange over 4 h and was then stirred 4 h at 60–70° C. The heating bath was removed, 1N HCl added and the mixture poured into EtOAc. The EtOAc layer was separated and washed with water (2×), saturated aq NaHCO3 (2×) and brine (3×), dried (MgSO4), filtered and concentrated onto SiO2. Flash chromatography (1:1 EtOAc:hexanes) afforded a red glass that was dried at 70° C. overnight giving the title compound (585 mg, 55%) as a bright red solid. 1H NMR (400 MHz, DMSO-6) 11.83 (br s, 1H), 11.21 (s, 1H), 7.53 (dd, J=7, 1 Hz, 1H), 7.40 (d, J=3 Hz, 1H), 7.25 (d, J=3 Hz, 1H), 7.21 (d, J=8 Hz, 1H), 7.0–7.08 (m, 1H), 7.86–7.04 (m, 2H), 6.65 (dd, J=11, 8 Hz, 1H), 6.44 (d, J=3 Hz, 1H), 3.71 (s, 3H). IR (CHCl3, cm−1) 1726. MS (electrospray, m/z) 360 (M++1), 358 (M−−1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24](OS(C(F)(F)F)(=O)=O)=[CH:23][CH:22]=1.[C:35]([C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1)#[CH:36]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:36]#[C:35][C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)=[CH:25][CH:26]=1
Reactant: O=S(=O)(Oc1ccc(Cc2cc([C@@]3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1)C(F)(F)F
Reactant: C#Cc1ccncc1
Product: OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(C#Cc4ccncc4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
The compound was obtained starting from 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-trifluoromethylsulfonyloxy-benzyl)-benzene and 4-ethynyl-pyridine.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:13])[C:10](Cl)=[O:11].[F:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[C:22]1[CH2:26][NH:25][CH:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=1>ClCCl>[F:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[C:22]1[CH2:26][N:25]([C:10]([N:9]([CH3:13])[CH3:8])=[O:11])[CH:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=1
Reactant: Fc1ccc(F)c(C2=CC(c3ccccc3)NC2)c1
Reactant: CN(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)N1CC(c2cc(F)ccc2F)=CC1c1ccccc1
Reaction time: 2 h

Procedure:
Triethylamine (1.37 mL, 9.79 mmol, 5.00 equiv) and dimethylcarbamoyl chloride (0.180 mL, 1.96 mmol, 1.00 equiv) were added to a solution of 4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrole (24, 1.96 mmol) in dichloromethane (50 mL) at 23° C., and the resulting mixture was stirred for 2 hours, then concentrated. The residue was partitioned between saturated aqueous sodium bicarbonate solution (75 ml) and ethyl acetate (100 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by reverse-phase LC (H2O/CH3CN gradient w/0.1% TPA present) to provide 4-(2,5-difluorophenyl)-N,N-dimethyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide (2-5) as an off-white solid. 1H NMR (500 MHz, CDCl3) δ 7.35-7.29 (m, 4H), 7.25 (m, 1H), 7.05 (m, 1H), 7.00 (m, 1H), 6.96 (m, 1H), 6.40 (br s, 1H), 6.13 (m, 1H), 4.88 (ddd, 1H, J=13.7, 5.6, 2.0 Hz), 4.52 (d, 1H, J=13.7 Hz), 2.88 (s, 6H). LRMS m/z (M+H) 329.1 found, 329.1 required.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:11]=1)[C:5](OC)=[O:6]>O1CCCC1.C1C=CC=CC=1.Cl>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:11]=1)[CH2:5][OH:6]
Reactant: COC(=O)c1cc(C)ccc1Sc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: Cc1ccc(Sc2ccccc2)c(CO)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
322.5 g of methyl 3-methyl-6-(phenylthio)-benzoate in 3 litres of absolute tetrahydrofuran are treated dropwise over a period of 30 minutes under argon and under reflux with 420 ml of a 70% sodium-dihydro-bis(2-methoxyethoxy)-aluminate solution in benzene and the mixture is boiled for a further 3 hours under reflux. Then the mixture is cooled to ca 4° C, diluted with 1 litre of benzene, hydrolysed with 700 ml of 2-N hydrochloric acid, then poured on to ice-water and treated with a further 400 ml of concentrated hydrochloric acid in order to obtain a clear solution. The organic phase is washed with water, dried over sodium sulphate, filtered and evaporated. There is obtained 3-methyl-6-(phenylthio)-benzyl alcohol as a red-brown oil.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([F:13])([F:12])[C:6]1[N:11]=[CH:10][CH:9]=[CH:8][N:7]=1)C.[BH4-].[Na+]>CCO>[F:13][C:5]([F:12])([C:6]1[N:7]=[CH:8][CH:9]=[CH:10][N:11]=1)[CH2:4][OH:3]
Reactant: CCOC(=O)C(F)(F)c1ncccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCC(F)(F)c1ncccn1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 50.3 %

Procedure:
A solution of difluoro-pyrimidin-2-yl-acetic acid ethyl ester (1.75 g, 8.65 mmol), as prepared in the previous step (and containing undissolved green precipitate), in anhydrous absolute EtOH (18 mL) was stirred at 0° C. for 5 min, and was then treated with solid NaBH4 (655 mg, 17.3 mmol) in one slow steady portion at 0° C. Bubbles immediately formed, and the solution turned light amber. Stirring continued at 0° C. for 2 h, and the reaction was then quenched with half-saturated NH4Cl (40 mL) and extracted with EtOAc (2×15 mL). The organic phases were combined, washed with saturated NaCl (1×10 mL), dried (Na2SO4), and concentrated to give the title compound as a yellow oil (696 mg, 50%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[CH:10]([CH3:12])[CH3:11])[CH:7]=1.FC1N=CC(C(C)C)=CC=1[C:16]#[N:17]>>[CH3:11][CH:10]([CH3:12])/[CH:9]=[CH:8]/[C:6]1[CH:5]=[N:4][CH:3]=[C:2]([CH:7]=1)[C:16]#[N:17]
Reactant: CC(C)c1cnc(F)c(C#N)c1
Reactant: CC(C)/C=C/c1cncc(Br)c1
Product: CC(C)/C=C/c1cncc(C#N)c1

Procedure:
(E)-5-(3-methylbut-1-enyl)nicotinonitrile was synthesized from (E)-3-bromo-5-(3-methylbut-1-enyl)pyridine following the general procedure as described for the 2-fluoro-5-isopropylnicotinonitrile.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@@H:33]6[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N:49]1([C:55](Cl)=[O:56])[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>N1C=CC=CC=1>[N:49]1([C:55]([O:39][C@H:36]2[CH2:37][CH2:38][C@@H:33]([C:30]3[CH:31]=[CH:32][C:27]([C:23]4[N:22]=[C:21]5[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:18]([O:17][C@@H:16]6[CH2:15][O:14][C@@H:13]7[C@H:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[CH2:10][O:11][C@H:12]67)=[N:19][C:20]5=[CH:25][C:24]=4[Cl:26])=[CH:28][CH:29]=3)[CH2:34][CH2:35]2)=[O:56])[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@@H](O)CC4)cc3)nc2n1COCC[Si](C)(C)C
Reactant: O=C(Cl)N1CCOCC1
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@@H](OC(=O)N5CCOCC5)CC4)cc3)nc2n1COCC[Si](C)(C)C
Temperature: 50 °C
Reaction time: 6 h

Procedure:
(cis)-4-(4-(2-((3R,3aR,6R,6aS)-6-(tert-Butyldimethylsilyloxy)hexahydrofuro[3,2-b]furan-3-yloxy)-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)phenyl)cyclohexanol (50 mg) is dissolved in pyridine (1 mL), treated with morpholine-4-carbonyl chloride (25 μL) and stirred for 6 hours at 50° C. Morpholine-4-carbonyl chloride (75 μL) is added and the mixture is stirred for 12 hours at 70° C. Morpholine-4-carbonyl chloride (75 μL) is added and the mixture is stirred for 6 hours at 70° C. Again morpholine-4-carbonyl chloride (250 μL) is added and the mixture is stirred for 12 hours at 70° C. The mixture is partitioned between ethylacetate and hydrochloric acid (1 M). The organic phase is dried (MgSO4) and concentrated. The crude product is used directly in the next step.
Reaction SMILES: C[O:2][C:3](=[O:37])[C@@H:4]([NH:17][C:18]([C:20]1[S:24][C:23]([NH:25][C:26](=[O:35])[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=2)=[N:22][C:21]=1[CH3:36])=[O:19])[CH2:5][NH:6][C:7](=[O:16])[C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[CH:9]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[F:15][C:10]1[CH:9]=[C:8]([CH:13]=[C:12]([F:14])[CH:11]=1)[C:7]([NH:6][CH2:5][C@H:4]([NH:17][C:18]([C:20]1[S:24][C:23]([NH:25][C:26](=[O:35])[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=2)=[N:22][C:21]=1[CH3:36])=[O:19])[C:3]([OH:37])=[O:2])=[O:16]
Reactant: COC(=O)[C@H](CNC(=O)c1cc(F)cc(F)c1)NC(=O)c1sc(NC(=O)Cc2cccc(O)c2)nc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(NC(=O)Cc2cccc(O)c2)sc1C(=O)N[C@@H](CNC(=O)c1cc(F)cc(F)c1)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 59 %

Procedure:
To a mixture of (S)-3-(3,5-Difluoro-benzoylamino)-2-({2-[2-(3-hydroxy-phenyl)-acetylamino]-4-methyl-thiazole-5-carbonyl}-amino)-propionic acid methyl ester (89.9 mg, 0.169 mmol) in THF (4 mL) and water (2 mL) was added lithium hydroxide monohydrate (80 mg, 1.91 mmol) The reaction was stirred at 25° C. for 1.5 h. The reaction mixture was acidified with concentrated HCl and concentrated under reduced pressure. The resulting crude compound was purified by HPLC to give (S)-3-(3,5-Difluoro-benzoylamino)-2-({2-[2-(3-hydroxy-phenyl)-acetylamino]-4-methyl-thiazole-5-carbonyl}-amino)-propionic acid (51.7 mg, 59%) as a white solid. MS m/e 519.5 (M+H+)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11](S)=[CH:10][C:8]=2[CH:9]=1)=[O:4].ClCC1SC(C2C=CC(C(F)(F)F)=CC=2)=NC=1C.C(=O)([O-])[O-:34].[Cs+].[Cs+]>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([OH:34])=[CH:10][C:8]=2[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc2cc(S)ccc2o1
Reactant: O=C([O-])[O-]
Agent: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1cc2cc(O)ccc2o1
Temperature: 60 °C
Reaction time: 2 h
Yield: 152.4 %

Procedure:
A mixture of 5-mercapto-benzofuran-2-carboxylic acid methyl ester (300 mg, 1.4 mmol) and 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole (550 mg, 1.9 mmol) was dissolved in 5 ml anhydrous acetonitrile followed by addition of cesium carbonate (700 mg, 2.1 mmol). The reaction was then stirred at 60° C. for 2 hours, filtered and concentrated in vacuo. Purification by flash column chromatography (gradient elution: 5% EtOAc/hexanes to 45% EtOAc/hexanes), gave the title compound (410 mg, 61%) as a pale yellow solid. M.p. 132-133° C.; IR (thin film) cm−1: 1731; 400 MHz 1H NMR (DMSO-d6) δ 7.95 (d, 2H, J=8.1 Hz), 7.79 (s, 1H), 7.74 (d, 2H, J=8.1 Hz), 7.65 (m, 2H), 7.51 (d, 1H, J=9.0 Hz), 4.44 (s, 2H), 3.82 (s, 3H); MS m/z 464 (M+1); Anal. Calc'd for C22H16F3N1O3S2 C, 57.01; H, 3.48; N, 3.02, found: C, 56.94; H, 3.44; N, 2.84.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[N:21]1([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)[CH:25]=[CH:24][CH:23]=[N:22]1>>[N:21]1([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH2:29][N:1]2[CH:2]([C:11]3[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=3[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]2=[O:9])[CH:25]=[CH:24][CH:23]=[N:22]1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(-n2cccn2)c1
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1cccc(-n2cccn2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with commercially available 3-(1H-pyrazol-1-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.86 min.; [M+H]+: 406.12 g/mol.