Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([Mg]Br)=[CH:9][CH:8]=1.[CH3:15][C:16]1([CH3:35])[CH2:21][CH2:20][C:19](=[O:22])/[C:18](=[CH:23]/[O:24][Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])/[CH2:17]1>C1(C)C=CC=CC=1>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:19]2([OH:22])[CH2:20][CH2:21][C:16]([CH3:15])([CH3:35])[CH2:17]/[C:18]/2=[CH:23]\[O:24][Si:25]([CH:26]([CH3:28])[CH3:27])([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30])=[CH:9][CH:8]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CC(C)[Si](O/C=C1\CC(C)(C)CCC1=O)(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)[Si](O/C=C1\CC(C)(C)CCC1(O)c1ccc(Cl)cc1)(C(C)C)C(C)C
Temperature: -2.5 °C
Reaction time: 1 h

Procedure:
To EXAMPLE 2 (26 g, as a solution in toluene) was added to anhydrous tetrahydrofuran (65 mL). The resulting mixture was cooled to −5 to 0° C. A separate flask was charged with anhydrous tetrahydrofuran (65 mL) and a 1 M solution of (4-chlorophenyl)magnesium bromide (172 mL, 2.05 equiv). The reagent mixture was cooled to −5 to 0° C. The mixture of EXAMPLE 2 in toluene was slowly added to the Grignard reagent, maintaining a reaction temperature below 5° C. The reaction was monitored by HPLC and was determined to be complete in about one hour. The reaction mixture was quenched slowly with methanol (91 mL), maintaining an internal temperature below 5° C.
Reaction SMILES: [CH3:1][N:2]([C@@H:16]([C:31]1[CH:36]=[CH:35][C:34]([O:37]CC2C=CC=CC=2)=[CH:33][CH:32]=1)[CH2:17][N:18]1[CH2:22][CH2:21][C@H:20]([O:23]CC2C=CC=CC=2)[CH2:19]1)[C:3](=[O:15])[CH2:4][C:5]1[CH:14]=[CH:13][C:8]2[NH:9][C:10](=[O:12])[NH:11][C:7]=2[CH:6]=1.[H][H]>C(OCC)(=O)C>[CH3:1][N:2]([C@@H:16]([C:31]1[CH:32]=[CH:33][C:34]([OH:37])=[CH:35][CH:36]=1)[CH2:17][N:18]1[CH2:22][CH2:21][C@H:20]([OH:23])[CH2:19]1)[C:3](=[O:15])[CH2:4][C:5]1[CH:14]=[CH:13][C:8]2[NH:9][C:10](=[O:12])[NH:11][C:7]=2[CH:6]=1
Reactant: [H][H]
Reactant: CN(C(=O)Cc1ccc2[nH]c(=O)[nH]c2c1)[C@H](CN1CC[C@H](OCc2ccccc2)C1)c1ccc(OCc2ccccc2)cc1
Solvent: CCOC(C)=O
Product: CN(C(=O)Cc1ccc2[nH]c(=O)[nH]c2c1)[C@H](CN1CC[C@H](O)C1)c1ccc(O)cc1

Procedure:
A solution of 1 g of N-methyl-N-[(1S)-1-(p-benzyloxyphenyl)-2-((3S)-3-benzyloxypyrrolidino)ethyl]-2-(2-oxo-2,3-dihydrobenzimidazol-5-yl)acetamide in 25 ml of ethyl acetate is hydrogenated on 0.5 g of 5% Pd--C at 20° and under 1 bar until hydrogen uptake ceases, the mixture is filtered, the filtrate is evaporated, and N-methyl-N-[(1S)-1-(p-hydroxyphenyl)-2-((3S)-3-hydroxypyrrolidino)ethyl]-2-(2-oxo-2,3-dihydrobenzimidazol-5-yl)acetamide is obtained.
Reaction SMILES: [CH:1]1(B(O)O)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.Br[C:43]1[C:48]([C:49]2[CH:54]=[CH:53][C:52]([F:55])=[CH:51][C:50]=2[F:56])=[C:47]([F:57])[C:46]([O:58][CH2:59][CH3:60])=[C:45]([CH:61]=[O:62])[CH:44]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C1(C)C=CC=CC=1>[CH:1]1([C:43]2[C:48]([C:49]3[CH:54]=[CH:53][C:52]([F:55])=[CH:51][C:50]=3[F:56])=[C:47]([F:57])[C:46]([O:58][CH2:59][CH3:60])=[C:45]([CH:61]=[O:62])[CH:44]=2)[CH2:3][CH2:2]1
Reactant: OB(O)C1CC1
Reactant: CCOc1c(C=O)cc(Br)c(-c2ccc(F)cc2F)c1F
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOc1c(C=O)cc(C2CC2)c(-c2ccc(F)cc2F)c1F
Reaction time: 15 h
Yield: 94.7 %

Procedure:
Cyclopropylboronic acid (0.77 g), a 2 M aqueous sodium carbonate solution (5.94 mL), tris(dibenzylideneacetone)dipalladium(0) (0.272 g), and dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (0.244 g) were added at room temperature to a toluene (20 mL) solution of 6-bromo-3-ethoxy-2,2′,4′-trifluorobiphenyl-4-carbaldehyde (1.07 g), and the mixture was stirred at 100 C for 15 hours in an argon atmosphere. Water was added to the reaction mixture at room temperature, and then, the mixture was filtered through celite. The filtrate was subjected to extraction with ethyl acetate. The organic layer was separated, then washed with water and saturated saline in this order, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (904 mg).
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][N:9]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:10](B(O)O)=[C:6]2[C:5](=[O:22])[N:4]([CH3:23])[C:3]1=[O:24].Br[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[C:29]#[N:30].C(=O)([O-])[O-].[K+].[K+]>C(OCCCC)(=O)C.O>[CH3:1][N:2]1[C:7]2=[CH:8][N:9]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:10]([C:26]3[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=3)[C:29]#[N:30])=[C:6]2[C:5](=[O:22])[N:4]([CH3:23])[C:3]1=[O:24]
Reactant: N#Cc1cccc(Br)c1
Reactant: Cn1c(=O)c2c(B(O)O)n(COCC[Si](C)(C)C)cc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCOC(C)=O
Product: Cn1c(=O)c2c(-c3cccc(C#N)c3)n(COCC[Si](C)(C)C)cc2n(C)c1=O
Temperature: 80 °C

Procedure:
A mixture of 1,3-dimethyl-2,4-dioxo-6-((2-(trimethylsilyl)ethoxy)methyl)-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-ylboronic acid (step 2) (2.0 g, 5.7 mmol), 3-bromobenzonitrile (937 mg, 5.2 mmol), Pd-118 (168 mg, 0.26 mmol) and potassium carbonate (1.42 g, 10.3 mmol) in n-butyl acetate (40 mL) was heated to 80° C., then water (2.23 mL, 124.0 mmol) was added and the mixture was heated at 80° C. for 90 minutes. The reaction mixture was diluted with water (100 mL), the layers were separated as much as possible, and the aqueous phase (and residual organic portion) was extracted with DCM (1×100 mL, 2×50 mL). The combined organic extracts were washed with brine (1×100 mL), dried with magnesium sulfate and the solvent was removed under vacuum.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH:7]([OH:10])[CH2:8][OH:9])[N:6]=1.[C:11]([O:15][C:16]([N:18]1[CH:22]=[CH:21][CH:20]=[C:19]1B(O)O)=[O:17])([CH3:14])([CH3:13])[CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O>[OH:10][CH:7]([C:5]1[N:6]=[C:2]([C:19]2[N:18]([C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])[CH:22]=[CH:21][CH:20]=2)[S:3][CH:4]=1)[CH2:8][OH:9]
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: OCC(O)c1csc(Br)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)n1cccc1-c1nc(C(O)CO)cs1
Temperature: 100 °C
Reaction time: 14 h
Yield: 57 %

Procedure:
1-(2-Bromo-1,3-thiazol-4-yl)ethane-1,2-diol (1.10 g, 4.91 mmol) synthesized in Example (9b) and commercially available 1-(t-butoxycarbonyl)pyrrole-2-boronic acid (1.55 g, 7.35 mmol) were dissolved in 1,2-dimethoxyethane (40 mL), and palladium (II) acetate (55.0 mg, 0.245 mmol), triphenylphosphine (260 mg, 0.991 mmol) and an aqueous potassium carbonate solution (3M, 4.9 mL, 14.7 mmol) were added, followed by stirring at 100° C. for 14 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (30 mL) and ethyl acetate (40 mL) were added, and the solution was separated. The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=50%-100%) to afford the desired compound (868 mg, yield 59%) as a brown oil.
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:25][C:26]1[O:30][C:29]([C:31]2([CH3:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[N:28][C:27]=1[CH2:38][CH2:39]OS(C1C=CC(C)=CC=1)(=O)=O>>[F:23][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[F:22])[O:15][C:5]([CH3:14])([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:39][CH2:38][C:27]2[N:28]=[C:29]([C:31]3([CH3:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[O:30][C:26]=2[CH3:25])=[CH:9][CH:8]=1)[C:4]([OH:3])=[O:24]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(F)c(F)c1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3(C)CCCCC3)oc2C)cc1
Product: Cc1oc(C2(C)CCCCC2)nc1CCOc1ccc(CC(C)(Oc2ccc(F)c(F)c2)C(=O)O)cc1

Procedure:
The title compound was prepared from 2-(3,4-difluoro-phenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-[5-methyl-2-(1-methylcyclohexyl)oxazol-4-yl)-ethyl ester using the method of Example 56. 1H NMR (400 MHz, CDCl3) δ 7.15 (d, 2H, J=8.60 Hz), 7.00 (q, 1H, J=8.99 Hz), 6.79 (d, 2H, J=8.60 Hz), 6.77-6.74 (m, 1H), 6.63-6.61 (m, 1H), 4.12 (t, 2H, J=6.25 Hz), 3.19 (d, 1H, J=14.08 Hz), 3.09 (d, 1H, J=14.08 Hz), 2.97 (t, 2H, J=6.25 Hz), 2.31 (s, 3H), 2.16-2.08 (m, 2H), 1.61-1.35 (m, 8H), 1.39 (s, 3H), 1.29 (s, 3H); MS (ES+) calcd for C29H34NO5F2: Found m/e 514.3 (M+1, 100%).
Reaction SMILES: C([O:3][C:4]([C:6]1(C(OCC)=O)[CH2:14][C:13]2[N:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:7]1)=[O:5])C.[ClH:20]>>[ClH:20].[N:12]1[C:13]2[CH2:14][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)C1(C(=O)OCC)Cc2cccnc2C1
Agent: Cl
Product: O=C(O)C1Cc2cccnc2C1

Procedure:
5,7-Dihydro-[1]pyrindine-6,6-dicarboxylic acid diethyl ester (0.953 g, 3.62 mmol) is taken into concentrated hydrochloric acid, heated to reflux for 4 hours and evaporated to afford 6,7-dihydro-5H-[1]pyrindine-6-carboxylic acid hydrochloride. δc (DMSO-d6) 33.9 (t), 34.5 (t) 41.2 (d), 124.8 (d), 140.1 (d), 140.8 (d), 141.2 (s), 158.4 (s), 175.2 (s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1.[B-](F)(F)(F)[CH3:22].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O.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]>[CH3:22][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1
Reactant: C[B-](F)(F)F
Reactant: Cc1ccc(S(=O)(=O)n2ccc3cc(Br)cnc32)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3cc(C)cnc32)cc1
Yield: 46.5 %

Procedure:
A solution of 5-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (5 g, 14.29 mmol), potassium trifluoro(methyl)borate (2.62 g, 21.43 mmol), cesium carbonate (12.56 g, 38.57 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.16 g, 1.43 mmol) in THF (150 mL) and water (15 mL) was heated at reflux for 18 hours. The reaction mixture was cooled down to ambient and partitioned between EtOAc (100 mL) and water (100 mL). The organic phase was separated, washed with 1N HCl (100 mL) and brine (100 mL), then, dried over magnesium sulfate and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to give the title compound as a white solid (1.903 g, 47% yield).
Reaction SMILES: O[CH2:2][C:3]1[O:4][C:5]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1.C([BH3-])#N.[Na+].C(Cl)(Cl)Cl.O>ClC(Cl)C.[I-].[Zn+2].[I-]>[CH3:13][O:12][C:11]1[C:5]2[O:4][C:3]([CH3:2])=[CH:7][C:6]=2[CH:8]=[CH:9][CH:10]=1
Reactant: COc1cccc2cc(CO)oc12
Agent: [BH3-]C#N
Agent: [I-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(Cl)Cl
Product: COc1cccc2cc(C)oc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.8 %

Procedure:
A mixture of 2-hydroxymethyl-7-methoxybenzofuran (300 mg), sodium cyanoborohydride (796 mg) and zinc iodide (809 mg) in dichloroethane (10 ml) was stirred for 2 hours at ambient temperature and then refluxed overnight. Chloroform and water were added to the reaction mixture, and the separated organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash chromatography (n-hexane:ethyl acetate 15:1, v/v) to give 7-methoxy-2-methylbenzofuran (95 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH:16]([OH:21])[C:17]([F:20])([F:19])[F:18])[N:11]([CH3:22])[C:10]=1[CH2:23]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:27])=O>C(#N)C>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH:16]([OH:21])[C:17]([F:20])([F:19])[F:18])[N:11]([CH3:22])[C:10]=1[CH2:23][Cl:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(C(O)C(F)(F)F)cc(=O)c(OCc2ccccc2)c1CO
Reactant: O=S(Cl)Cl
Solvent: CC#N
Product: Cn1c(C(O)C(F)(F)F)cc(=O)c(OCc2ccccc2)c1CCl
Reaction time: 0.17 h

Procedure:
To a suspension of 3-benzyloxy-2-hydroxymethyl-1-methyl-6-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one (0.31 g, 0.90 mmol) in acetonitrile (8 mL) was added thionyl chloride (0.33 mL, 4.5 mmol) at room temperature. A clear solution resulted. The reaction was completed in 10 min. The reaction mixture was evaporated to dryness to give crude 3-benzyloxy-2-chloromethyl-1-methyl-6-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one as an oil. The crude oil obtained was taken up in ethanol (10 mL) to give a clear solution. To the solution was added sodium borohydride (380 mg, 10 mmol) in several portions. The reaction was completed within a few min. The reaction mixture was diluted with methanol. The resulting clear solution was evaporated to dryness to give a solid. The solid was repeatedly extracted with dichloromethane. The combined dichloromethane solutions were combined and evaporated to dryness. Purification of the residue by column chromatography on silica gel (methanol/dichloromethane, 5/100 to 8/100 v/v) afforded the title compound (0.20 g, 67% yield, HPLC Method 1 (Example 24), RT=14.4 min). 1H NMR (DMSO-d6+D2O) δ ppm: 7.36 (m, 5H), 6.53 (s, 1H), 5.50 (q, J=6.5 Hz, 1H), 5.00 (s, 2H), 3.56 (s, 3H), 2.24 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[C:20]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:24][C:23]([C:26](Cl)=[O:27])=[CH:22][CH:21]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:26](=[O:27])[C:23]3[CH:24]=[CH:25][C:20]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:21][CH:22]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)c1ccc(-c2ccccc2)cc1

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and 4-biphenylcarbonyl chloride were combined to provide N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-4-phenylbenzamide as a white powder, m.p. 215.4° C. (decomposition). 1H NMR (300 MHz, DMSO-d6) δ8.54 (t, J=5.7 Hz, 1H), 8.22 (s, 1H), 8.05 (d, J=7.2 Hz, 1H), 7.88 (d, J=5.4 Hz, 2H), 7.75-7.70 (m, 4H), 7.62 (dd, J=8.4, 1.5 Hz, 1H), 7.52-7.38 (m, 4H), 7.22 (dt, J=7.5, 1.2 Hz, 1H), 6.61 (s, 2H), 4.65 (t, J=7.2 Hz, 2H), 3.30 (m, 2H), 1.93 (quintet, J=7.5 Hz, 2H), 1.60 (quintet, J=7.5 Hz, 2H); MS (EI) m/e 435.2054 (435.2059 calcd for C27H25N5O).
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[OH:20][C@@H:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[NH2:26].CCN(C(C)C)C(C)C>>[OH:20][C@@H:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[NH:26][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: N[C@@H]1CCC[C@H]1O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(N[C@@H]2CCC[C@H]2O)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, (1R,2R)-2-hydroxy-cyclopentylamine and DIEA to give 2-((1R,2R)-2-hydroxy-cyclopentylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 340 (MH+).
Reaction SMILES: [C:1](=[O:6])([O:4][CH3:5])OC.[H-].[Na+].[C:9]1(=[O:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C([O-])(O)=O.[Na+]>C1COCC1>[O:17]=[C:9]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[C:1]([O:4][CH3:5])=[O:6]
Reactant: O=C1CCCCCCC1
Reactant: COC(=O)OC
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1CCCCCCC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of dimethyl carbonate (30 mL, 0.36 mol) in dry THF (600 mL) was added sodium hydride (15 g, 0.36 mol) by portion at 5-10° C. The resulting mixture was stirred at this temperature for 30 min and then was added a solution of cyclooctanone (15.0 g, 0.12 mol) in THF (100 mL) dropwise over 30 min. The resultant mixture was stirred at refluxed for 4 h before cooling to room temperature. The reaction mixture was poured into saturated NaHCO3 solution (100 mL) and ice (500 g), and then the mixture was extracted with PE/EA (4:1, 400 mL×2). The organic layer was washed with brine (400 mL), dried over Na2SO4 and concentrated to give crude product. Then the target product (19.3 g, 88%) was purified by distilling at 60° C. in vacuum.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.Br[C:27]1[CH:28]=[N:29][CH:30]=[C:31]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:32]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([NH:1][C:27]3[CH:28]=[N:29][CH:30]=[C:31]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:32]=3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:15])([CH3:16])[CH3:17]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(N)nc12
Reactant: CS(=O)(=O)c1cncc(Br)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3cncc(S(C)(=O)=O)c3)nc12
Temperature: 150 °C
Yield: 95.3 %

Procedure:
To a mixture of 2-amino-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (92 mg, 253 mol), 3-bromo-5-(methylsulfonyl)pyridine (77.7 mg, 329 mol), xantphos (43.9 mg, 75.9 mol), Pd2(dba)3 (23.2 mg, 25.3 mol) and cesium carbonate (165 mg, 506 mol) in dioxane (2 mL) was heated in a microwave at 150° C. for 20 min. The mixture was cooled then filtered through a pad of celite. The filtrate was concentrated in vacuo then purified by chromatography (silica, 30-70% ethyl acetate in hexanes) to give N-tert-butyl-2-(5-(methylsulfonyl)pyridin-3-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (125 mg, 241 mol, 95%) as a yellow gum. (EI/CI) m/z: 519.3 [M+H].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH2:11])=[S:10])[CH:5]=[CH:6][CH:7]=1.Br[CH2:13][C:14](=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>CN(C=O)C>[OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[S:10][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=S)Nc1cccc(O)c1
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(Nc2cccc(O)c2)n1
Yield: 81 %

Procedure:
Following the general procedure for the synthesis of derivatives 6 and 7, a solution of 3-hydroxyphenylthiourea (150 mg, 0.89 mmol) and ethyl 3-bromopyruvate (0.11 mL, 0.89 mmol) in dry DMF (3.6 mL) was heated at 60° C. for 6 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 6/4) in 81% yield (189 mg).
Reaction SMILES: [Br:1][CH2:2][C:3]1[S:7][C:6]([CH2:8][OH:9])=[C:5]([O:10][CH3:11])[CH:4]=1.N1C=CN=C1.[C:17]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])([CH3:19])[CH3:18]>ClCCl>[Br:1][CH2:2][C:3]1[S:7][C:6]([CH2:8][O:9][Si:21]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:23])[CH3:22])=[C:5]([O:10][CH3:11])[CH:4]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1cc(CBr)sc1CO
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COc1cc(CBr)sc1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.5 %

Procedure:
To a solution of (5-bromomethyl-3-methoxy-thiophen-2-yl)-methanol (0.6 g, 2.5 mmol) in anhydrous dichloromethane (10 mL) is added imidazole (0.516 g, 7.59 mmol) and tert-butylchlorodimethylsilane (0.412 g, 2.75 mmol) at 0° C. The reaction mixture is allowed to warm to room temperature and stirred for 1 hour. The reaction mixture is quenched with water and concentrated. The residue is dissolved in DCM, washed with water (25 mL) and brine (25 mL), dried over Na2SO4, filtered, and concentrated to give the title compound (0.9 g). ESI/MS m/z (79Br/81Br) 351/353.1 [M+H]+.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[F:12][C:13]1([CH2:26][OH:27])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[F:12][C:13]1([CH2:26][O:27][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:17][CH2:18]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(CO)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2(F)CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
p-Toluenesulfonyl chloride (230 mg, 1.209 mmol) was added portionwise to tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (188 mg, 0.806 mmol), triethylamine (227 μL, 1.612 mmol), and DMAP (9.85 mg, 0.081 mmol) in dichloromethane (2015 μL) at 0° C. The solution was stirred at room temperature overnight and then partitioned between dichloromethane and water. The organic layer was washed with 0.2M HCl and then dried (MgSO4) and concentrated. The residue was dissolved in dichloromethane and loaded onto a 25+M Biotage silica column. Chromatography, eluting with a gradient of EtOAc in hexanes, gave tert-butyl 4-fluoro-4-(tosyloxymethyl)piperidine-1-carboxylate (251 mg, 0.648 mmol, 80%) as a clear semi-solid.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([O:7][C:8](Cl)=[S:9])=[CH:3][CH:2]=1.[N-:11]=[N+:12]=[N-:13].[Na+]>CC(C)=O.O>[O:7]([C:8]1[S:9][N:13]=[N:12][N:11]=1)[C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: S=C(Cl)Oc1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: c1ccc(Oc2nnns2)cc1
Reaction time: 0.75 h

Procedure:
Phenyl chlorothionoformate (3.44 grams, 0.02 mole) was dissolved in 5 ml of dry acetone. Sodium azide (1.4 grams, 0.22 mole) was dissolved in 12 ml of deionized water with 8 ml of acetone and slowly added to the phenyl chlorothionoformate solution over a 5 minute period. The reaction was kept at 5° C. in an ice bath and stirred an additional 45 minutes before adding 12 ml of water. The solution was filtered to collect the product; m.p. 35°-36° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[NH2:17].[C:19](Cl)(Cl)=[O:20]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[N:17]=[C:19]=[O:20]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(C(F)(F)F)cc1N
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1cc([N+](=O)[O-])c(C(F)(F)F)cc1N=C=O
Temperature: 25 °C
Yield: 100 %

Procedure:
To a suspension of 2-amino-5-nitro-4-trifluoromethyl-benzoic acid methyl ester (100 mg, 0.379 mmol) in dry toluene (1.5 mL) was added a solution of phosgene in toluene (20%, 1.5 mL) at −15° C. After warming to r.t., a stream of phosgene was introduced into the suspension and simultaneously heating was started. At reflux, the stream of phosgene was maintained for one hour, then replaced by a stream of argon for an additional hour. The toluene was distilled off leaving 2-isocyanato-5-nitro-4-trifluoromethyl-benzoic acid methyl ester (110 mg, 100%) as a beige solid. IR (CHCl3): 2260 cm−1 (s). 1H-NMR (CDCl3, 360 MHz): 4.05 (s, 3H), 7.55 (s, 1H), 8.65 (s, 1H).