Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C@@H:25]([OH:26])[C@H:24]([OH:27])[C@@H:23]([CH2:28][OH:29])[O:22][C@@H:13]1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1.ClCCl>N1C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C@@H:25]([OH:26])[C@H:24]([OH:27])[C@@H:23]([CH2:28][O:29][S:36]([C:33]2[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=2)(=[O:38])=[O:37])[O:22][C@@H:13]1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@H]1[C@@H](OCc2ccccc2)O[C@H](CO)[C@@H](O)[C@@H]1O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@H](OCc3ccccc3)[C@H](NC(=O)OCc3ccccc3)[C@@H](O)[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 30 g of benzyl 2-benzyloxycarbonylamino-2-desoxy-α-D-glucopyranoside (Heyns and Paulsen, Chem. Ber. 88, 188 (1955)) in 116 ml of pyridine was treated at 0° C. with a solution of 19.85 g of p-tolylsulfonyl chloride in 30 ml of 30 dichloromethane and stirred at room temperature for 4 hours. Then, the mixture was poured into ice-cold 2N sulfuric acid and extracted with dichloromethane. The organic phases were washed with aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and concentrated. The residue was chromatographed over silica gel with hexane/ethyl acetate and gave benzyl 2-benzyloxycarbonylamino-2-desoxy-6-O-(p-tolyl-sulfonyl)-α-D-glucopyranoside, [α]+101.80 (c 0.5; dioxan), MS: m/z 580 ([M+Na]+).
Reaction SMILES: [C:1]([NH:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:16][C@:14]2([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)[N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:34]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[C:1]([NH:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:20])[CH2:16][C@:14]2([C:29]2[S:30][C:31]([Br:34])=[CH:32][CH:33]=2)[N:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(NC1=N[C@@]2(c3cccs3)CN(C(=O)OCc3ccccc3)C[C@H]2CS1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NC1=N[C@@]2(c3ccc(Br)s3)CN(C(=O)OCc3ccccc3)C[C@H]2CS1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 91.9 %

Procedure:
To a stirred clear and colorless solution of benzyl(4aR,7aR)-2-benzamido-7a-(2-thienyl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazine-6-carboxylate (1.67 g, 3.50 mmol) in dimethylformamide (35 mL) at room temperature, under an atmosphere of nitrogen is added N-bromosuccinimide (747 mg, 4.20 mmol). The resulting pale yellow solution is stirred at room temperature for 50 minutes. The solution is diluted with ethyl acetate (150 mL) and washed with water (3×50 mL) and brine (50 mL). The organic phase is separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel flash chromatography eluting with a hexanes/ethyl acetate, gradient from 80:20 to 0:100, to give the title compound (1.79 g, 92%) as a white solid: ES/MS (m/z): 557.8 (M+H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.Cl.[OH:12][NH2:13].C(=O)(O)[O-].[Na+]>CO>[OH:12][NH:13][C:7](=[NH:8])[C:6]1[CH:9]=[CH:10][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=1
Reactant: NO
Reactant: N#Cc1ccc(CO)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: N=C(NO)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 124.4 %

Procedure:
A solution of 25.0 g (150 mmol) of 4-(hydroxymethyl)benzonitrile, 20.8 g (300 mmol) of hydroxyamine hydrochloride and 50.4 g (600 mmol) of sodium bicarbonate in 250 mL of methanol was heated to reflux and stirred for 20 h. The reaction mixture was cooled to rt and filtered. The solid was washed with 100 mL of methanol. The combined methanol solution was concentrated to dryness to afford 31.0 g (99%) of the title compound: 1H NMR (400 Mhz, CD3OD) δ 4.63 (s, 2H), 7.39 (d, J=8.0, 2H), 7.62 (d, J=8.0, 2H).
Reaction SMILES: [Br:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([CH2:12][CH3:13])=[C:4]([OH:14])[CH:3]=1.[C:15](#[N:17])[CH3:16]>>[Br:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([CH2:12][CH3:13])=[C:4]([O:14][CH2:16][C:15]#[N:17])[CH:3]=1
Reactant: CCc1c(O)cc(Br)c2c1OCCO2
Reactant: CC#N
Product: CCc1c(OCC#N)cc(Br)c2c1OCCO2

Procedure:
8-Bromo-5-ethyl-2,3-dihydro-benzo[1,4]dioxin-6-ol (3.182 g, 12.3 mmol), as described in the procedure of Step 6 of Example 21, was converted to cyanomethyl ether 8-Bromo-5-ethyl-2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-acetonitrile (2.30 g, 63%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[CH:3]=1.[Cl:11]Cl.CCOC(C)=O.CCCCCC>CCOC(C)=O>[Cl:11][C:3]1[C:4]2[S:8][CH:7]=[N:6][C:5]=2[CH:9]=[CH:10][C:2]=1[NH2:1]
Reactant: Nc1ccc2ncsc2c1
Reactant: ClCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Nc1ccc2ncsc2c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of 6-aminobenzothiazole (2.0 g, 13.4 mmol) in 100 mL of ACOH was added a solution of Cl2 saturated AcOH and the resulting reaction mixture was stirred for 1 h at 25° C. Reaction mixture was concentrated in vacuo, yielding a yellow solid which was dissolved in EtOAc and washed with aq. NaHCO3. Organic layer was dried over Na2SO4 and concentrated in vacuo, yielding an oil which was subjected to column chromatography (10-50% EtOAc/n-Hexane) to obtain 7.8 g (34 mmol, 80% ) of the desired product.
Reaction SMILES: Cl.[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3].[CH3:17][N:18]([CH3:28])[C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23]>>[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][CH:27]=[C:19]([N:18]([CH3:17])[CH3:28])[CH:20]=2)=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3]
Reactant: CN(C)c1cccc(C(=O)Cl)c1
Reactant: CC(C)NCC(=O)c1ccc(O)c(O)c1
Agent: Cl
Product: CC(C)NCC(=O)c1ccc(OC(=O)c2cccc(N(C)C)c2)c(O)c1

Procedure:
Following the procedure described above in Example 58A, but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride and m-dimethylaminobenzoyl chloride instead of isovaleryl chloride, there is obtained 3-hydroxy-4-(m-dimethylaminobenzoyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-hydroxy-4-(m-dimethylaminobenzoyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride.
Reaction SMILES: CC(C)([O-])C.[Na+].Br[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[C:18]([O:20][C:21]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=3)[C:17]3=[C:33]([CH3:37])[N:34]=[C:35]([CH3:36])[N:16]3[N:15]=2)=[CH:10][CH:9]=1.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>C1(C)C=CC=CC=1>[CH3:37][C:33]1[N:34]=[C:35]([CH3:36])[N:16]2[C:17]=1[C:18]([O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=1)=[N:19][C:14]([C:11]1[CH:12]=[CH:13][C:8]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[CH:9][CH:10]=1)=[N:15]2
Reactant: COc1cc(Oc2nc(-c3ccc(Br)cc3)nn3c(C)nc(C)c23)cc(OC)c1OC
Reactant: C1COCCN1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc(Oc2nc(-c3ccc(N4CCOCC4)cc3)nn3c(C)nc(C)c23)cc(OC)c1OC
Temperature: 100 °C
Reaction time: 8 h

Procedure:
28 mg (0.29 mmol) of sodium tert-butoxide are introduced into a second Schlenk tube under argon. Subsequently, 100 mg (0.21 mmol) of 2-(4-bromophenyl)-5,7-dimethyl-4-(3,4,5-trimethoxyphenoxy)imidazo[5,1-f][1,2,4]triazine from Exam-ple 16A, 22 mg (0.25 mmol) of morpholine and 2 ml of anhydrous toluene are added. Solution A is likewise added, and the whole is stirred overnight at 100° C. After cooling, the mixture is then filtered off with suction through a glass frit. The filtrate is concentrated to dryness under reduced pressure and purified by flash chromatography (cyclohexane/ethyl acetate 10:1-4:1-3:2-1:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15](O)[C:10]3[N:11]=[C:12]([CH3:14])[S:13][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:17]=1.[NH:18]1[CH:25]=[CH:24][C:22](=[O:23])[NH:21][C:19]1=[O:20]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15]([C:24]3[C:22](=[O:23])[NH:21][C:19](=[O:20])[NH:18][CH:25]=3)[C:10]3[N:11]=[C:12]([CH3:14])[S:13][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:17]=1
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: Cc1nc2c(s1)C=Cc1cc(Cl)ccc1C2O
Solvent: CC(=O)O
Product: Cc1nc2c(s1)C=Cc1cc(Cl)ccc1C2c1c[nH]c(=O)[nH]c1=O

Procedure:
The product from step (iii) (1 g) and uracil (3 g) were heated at 100° C. in acetic acid (200 ml) for 16 h. The solvent was evaporated under reduced pressure and the residue partitioned between ethyl acetate and brine. The organic phase was collected, dried (MgSO4), and evaporated under reduced pressure to leave a beige solid. The solid was triturated with isohexane/ethyl acetate mixtures and filtered to leave a cream solid. Yield. 1.35 g Used directly in the next step.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.C=O.[CH:18](O)=O>CO>[CH3:8][C@H:6]1[N:7]([CH3:18])[C@@H:2]([CH3:1])[CH2:3][N:4]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:5]1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1
Reactant: O=CO
Agent: C=O
Solvent: CO
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1C
Temperature: 70 °C
Yield: 73.2 %

Procedure:
(3R,5S)-tert-Butyl 3,5-dimethylpiperazine-1-carboxylate (1.50 g, 7.00 mmol) was dissolved in 70 mL of methanol. To this was added 37% aqueous formaldehyde (1.17 mL, 14.0 mmol) and formic acid (1.14 mL, 24.5 mmol). The reaction mixture was heated to 70° C. for 24 hours, then concentrated under reduced pressure. The resulting oil was taken up in EtOAc, washed with 10% aqueous potassium carbonate, dried over sodium sulfate and concentrated to give 1.17 g (73%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH3:44])[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH3:44])[CH:39]=2)[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(-c4ccccc4F)ccc3NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
The title compound was prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert-butyl ester [CAS 335255-65-7] (302 mg, 1.0 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (311 mg, 1.0 mmol) according to the general procedure M. Obtained as an off-white foam (480 mg, 89%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1.[Cl:13][C:14]([Cl:38])([Cl:37])[CH2:15][O:16][C:17](=[O:36])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][S:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][C:33](O)=[O:34])[CH:27]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:38][C:14]([Cl:13])([Cl:37])[CH2:15][O:16][C:17](=[O:36])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][S:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][C:33]([O:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:8][CH:7]=2)=[O:34])[CH:27]=1
Reactant: OCc1ccc(C(F)(F)F)cc1
Reactant: O=C(O)Cc1cccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(Cc1cccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)c1)OCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
(4-Trifluoromethyl-phenyl)-methanol (58 mg, 0.332 mmol) was added to a stirred mixture of 2-(3-carboxymethyl-phenylsulfanylmethyl)-benzoic acid 2,2,2-trichloro-ethyl ester (120 mg, 0.277 mmol), EDCxHCl (80 mg, 0.415 mmol), DMAP (3.4 mg, 0.028 mmol) and DCM (4 mL). The reaction mixture was stirred at rt overnight. More DCM was added and the mixture was washed with 0.25M HCl, the organic phase was dried through a phase separator and concentrated. The crude was submitted to flash chromatography using heptane and EtOAc (90/10) as the eluent to yield the titled compound (105 mg, 64%) as a colourless oil; 1H NMR (400 MHz, CDCl3): δ 3.62 (s, 2H), 4.54 (s, 2H), 4.96 (s, 2H), 5.18 (s, 2H), 7.09-7.15 (m, 1H), 7.18-7.24 (m, 4H), 7.30-7.43 (m, 4H), 7.60 (d, 2H), 8.08 (d, 1H); Mass spectrum: M−H+ 590.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:11]([F:14])([F:13])[F:12])=[CH:9][N:10]=1)[C:5](O)=[O:6].S(Cl)([Cl:17])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:11]([F:14])([F:13])[F:12])=[CH:9][N:10]=1)[C:5]([Cl:17])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Cl)ncc1C(F)(F)F
Product: O=C(Cl)c1cc(Cl)ncc1C(F)(F)F
Temperature: 25 °C

Procedure:
A mixture of 0.66 g of 2-chloro-5-trifluoromethyl isonicotinic acid and 4 ml of thionyl chloride was heated to reflux for 2.5 hours. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure to give 2-chloro-5-trifluoromethyl isonicotinic acid chloride. A mixture of the resultant 2-chloro-5-trifluoromethyl isonicotinic acid chloride and 4 ml of DMF was added dropwise to a mixture of 0.48 g of 2-amino-4-tert-butylphenol, 0.59 g of triethylamine and 4 ml of DMF while ice-cooling. The reaction mixture was stirred at room temperature for one hour, and stirred while heating at 50° C. for one hour. The mixture was cooled to room temperature, and water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.75 g of N-(5-tert-butyl-2-hydroxyphenyl)-2-chloro-5-trifluoromethylisonicotinamide.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][N:9]=1.[OH-].[Na+]>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:9][CH:10]=1
Reactant: C1CNCCN1
Reactant: Clc1ccc(Cl)nc1
Agent: [Na+]
Agent: [OH-]
Product: Clc1ccc(N2CCNCC2)nc1
Temperature: 145 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
To piperazine (29.0 g) dissolved at 115° C. was added 2,5-dichloropyridine (5.1 g) and the mixture was stirred at 140-150° C. for 1 hr. The reaction mixture was poured into a 1N aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give the title compound (5.0 g) as a pale-brown solid.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][C@@H:29]([C:37]([CH3:40])([CH3:39])[CH3:38])/[CH:30]=[CH:31]/[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:9]=2)=[N:6][CH:7]=1.CCOC(C)=O.[H][H]>CO.[Pd]>[F:1][C:2]1[C:3]([NH:28][C@@H:29]([C:37]([CH3:38])([CH3:40])[CH3:39])[CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:25])=[CH:26][CH:27]=3)(=[O:20])=[O:19])[CH:9]=2)=[N:6][CH:7]=1
Reactant: [H][H]
Reactant: CCOC(=O)/C=C/[C@@H](Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)ncc1F)C(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)CC[C@@H](Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)ncc1F)C(C)(C)C

Procedure:
To a nitrogen purged flask charged with 10% Pd/C (0.033 g, 0.310 mmol) was added enough methanol to cover the catalyst. To this mixture was added a solution of (R,E)-ethyl 4-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-5,5-dimethylhex-2-enoate, 38a, (0.330 g, 0.579 mmol) in MeOH. Note, a small amount of EtOAc was added to fully solubilize the starting material. The reaction mixture was then stirred under 1 atmosphere of hydrogen for 3 hours. LCMS shows presence of significant amounts of starting material. The contents of the reaction mixture were transferred to a pressure vessel containing a fresh source of palladium (0.033 g, 0.310 mmol). The reaction mixture was stirred in a Parr hydrogenation flask under 46 psi of hydrogen overnight. The mixture was diluted with methanol and filtered through celite. The filtrate was concentrated in vacuo to afford 331 mg of the desired product that was used without further purification: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=3.75 minutes (M+H) 572.35.
Reaction SMILES: Cl/[C:2](=[N:15]\[OH:16])/[C:3]1[CH:8]=[CH:7][C:6]([P:9]([CH3:14])(=[O:13])[O:10][CH2:11][CH3:12])=[CH:5][CH:4]=1.[C:17]([C:19]1[C:20]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)=[N:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)=[N:23][CH:24]=1)#[CH:18].C(N(CC)CC)C>C1COCC1>[CH3:40][O:39][C:36]1[CH:35]=[CH:34][C:33]([CH2:32][O:31][C:20]2[C:19]([C:17]3[O:16][N:15]=[C:2]([C:3]4[CH:8]=[CH:7][C:6]([P:9]([CH3:14])(=[O:13])[O:10][CH2:11][CH3:12])=[CH:5][CH:4]=4)[CH:18]=3)=[CH:24][N:23]=[C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[N:21]=2)=[CH:38][CH:37]=1
Reactant: C#Cc1cnc(-c2ccccn2)nc1OCc1ccc(OC)cc1
Reactant: CCOP(C)(=O)c1ccc(/C(Cl)=N/O)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOP(C)(=O)c1ccc(-c2cc(-c3cnc(-c4ccccn4)nc3OCc3ccc(OC)cc3)on2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 55.3 %

Procedure:
A mixture of compound 38-e (750 mg, 2.8 mmol), compound 37-j (820 mg, 2.6 mmol) and triethylamine (780 mg, 7.8 mmol) in THF (20 mL) was stirred at room temperature for 12 h. The resulting mixture was concentrated under reduce pressure, purified by column chromatography on silica gel (DCM:MeOH=30:1) to give compound 38-f (780 mg). LC-MS 543 [M+H]+
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[SH:6].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:14][C:15](=[O:26])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>CC(C)=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6][CH2:14][C:15](=[O:26])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCC(=O)CCl
Reactant: Sc1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCC(=O)CSc1cccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
To a solution of thiophene-2-thiol (2.0 g, 17.2 mmol) in dry acetone (100 ml) is added anhydrous potassium carbonate (2.8 g; 20 mmol), followed by 1-chlorododecan-2-one (3.8 g, 17.2 mmol) dropwise. The reaction is stirred for 30 min and RT, filtered and concentrated under reduced pressure. The crude product is further purified by column chromatography (eluent: petrol/ethyl acetate 100:0 to 95:5) to afford the product as a colourless oil (3.66 g, 71%). M/Z 298 (M+). 1H NMR (300 MHz, CDCl3) δ 7.36 (1H, dd), 7.15 (1H, dd), 6.96 (1H, dd), 3.55 (2H, s), 2.55 (2H, t), 1.57 (2H, m), 1.35-1.20 (14H, m), 0.88 (3H, t). 13C NMR (75 MHz, CDCl3) δ 205.1, 134.6, 132.5, 130.3, 127.7, 48.2, 41.1, 31.9, 29.6, 29.5, 29.4, 29.3, 29.1, 23.8, 22.7, 14.1.
Reaction SMILES: Br[CH:2]([CH3:16])[C:3]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)=[O:4].[CH3:17][NH2:18].O>C(Cl)(Cl)Cl>[CH3:17][NH:18][CH:2]([CH3:16])[C:3]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)=[O:4]
Reactant: CC(Br)C(=O)c1ccc(OCC(=O)O)cc1
Reactant: CN
Solvent: O
Solvent: ClC(Cl)Cl
Product: CNC(C)C(=O)c1ccc(OCC(=O)O)cc1
Reaction time: 1.5 h
Yield: 65 %

Procedure:
4-(2-bromopropionyl)phenoxyacetic acid (5 g, 17.5 mmol) in chloroform (50 ml) was stirred vigorously at 35-40° C. and a solution of 40% methylamine in water (4.05 ml, 52 mmol) was added dropwise over 30 mins. Stirring was continued at this temperature for a further 1.5 h after addition. The mixture was evaporated to dryness and the crude residue was purified by column chromatography (silica gel: 10% methanol in chloroform) to give the title product (2.7 g, 65%) as a white foam.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6]([S:12][CH3:13])[N:5]=1.[C:14]([O:18][CH3:19])(=[O:17])[CH2:15][OH:16].CN(C)C=O>O>[CH3:11][O:10][C:8]1[N:7]=[C:6]([S:12][CH3:13])[N:5]=[C:4]([O:16][CH2:15][C:14]([O:18][CH3:19])=[O:17])[CH:9]=1
Reactant: COC(=O)CO
Reactant: COc1cc(Cl)nc(SC)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1cc(OC)nc(SC)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 59.9 %

Procedure:
0.4 g of sodium hydride was added to a mixture of 1.59 g of 4-chloro-6-methoxy-2-methylthiopyrimidine, 0.98 g of methyl glycolate and 10 ml of N,N-dimethylformamide at 0° C. The mixture was stirred at room temperature for 5 hours, then, the reaction solution was poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 1.22 g of 6-methoxy-4-(methoxycarbonyl)methoxy-2-methylthiopyrimidine.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[CH2:14][CH2:13]2)[CH:5]=1.Br[CH2:29][CH:30]1[O:34][CH2:33][CH2:32][O:31]1>>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:27])=[CH:5][C:6]=1[CH2:11][N:12]1[CH2:13][CH2:14][CH:15]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH2:29][CH:30]3[O:34][CH2:33][CH2:32][O:31]3)[CH:19]=2)[CH2:16][CH2:17]1
Reactant: COC(=O)c1ccc(Br)c(CN2CCC(c3c[nH]c4ccccc34)CC2)c1
Reactant: BrCC1OCCO1
Product: O=C(O)c1ccc(Br)c(CN2CCC(c3cn(CC4OCCO4)c4ccccc34)CC2)c1

Procedure:
This compound was prepared following the procedure described in example 1 (part E) starting with 0.055 g (0.13 mmol) 4-bromo-3-[4-(1H-indol-3-yl)-piperidin-1-ylmethyl]-benzoic acid methyl ester and 0.034 mg (0.16 mmol) 2-bromomethyl-[1,3]dioxolane. After the described purification, 0.021 g (32% of yield) of the expected acid was obtained.