Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([NH:13][CH2:14][C:15]1[O:16][C:17]([CH3:20])=[CH:18][CH:19]=1)=[N:8]2.C(N(CC)CC)C.[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>C1COCC1>[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH:1][CH2:2][C:3]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:4]=2[CH:5]=[CH:6][C:7]([NH:13][CH2:14][C:15]2[O:16][C:17]([CH3:20])=[CH:18][CH:19]=2)=[N:8]3)=[O:34])=[CH:31][CH:30]=1
Reactant: Cc1ccc(CNc2ccc3c(CN)cccc3n2)o1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(CNc2ccc3c(CNC(=O)c4ccc(F)cc4)cccc3n2)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.5 %

Procedure:
To a cooled (ice bath) and stirred solution of (5-aminomethyl-quinolin-2-yl)-(5-methyl-furan-2-ylmethyl)-amine (95 mg, 0.355 mmol) and triethyl amine (39.6 mg, 0.39 mmol) in THF (2 ml) was added 4-fluorobenzoyl chloride (62 mg, 0.39 mmol) and the mixture was allowed to stir at room temperature for 16 h. Evaporation and purification by flash chromatography (ethyl acetate/heptane) on silica gel yielded the title compound as off-white solid (67 mg, 48%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C@H:11]([CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[C:12]([OH:14])=[O:13])(=[O:9])=[O:8])=[CH:4][CH:3]=1.[C:25]([Si:27]([CH3:30])([CH3:29])[CH3:28])#[CH:26].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.[Cu]I>[NH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([CH2:15][C@@H:11]([NH:10][S:7]([C:5]2[S:6][C:2]([C:26]#[C:25][Si:27]([CH3:30])([CH3:29])[CH3:28])=[CH:3][CH:4]=2)(=[O:9])=[O:8])[C:12]([OH:14])=[O:13])=[CH:17]1
Reactant: O=C(O)[C@@H](Cc1c[nH]c2ccccc12)NS(=O)(=O)c1ccc(Br)s1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#Cc1ccc(S(=O)(=O)N[C@H](Cc2c[nH]c3ccccc23)C(=O)O)s1
Temperature: 50 °C
Yield: 70.9 %

Procedure:
In a round bottom flask was added crude compound (R)-2-(5-Bromo-thiophene-2-sulfonylamino)-3-(1H-indol-3-yl)-propionic acid product (3) (0.25 g, 0.584 mmol) (synthesized via Example 1, Step A), commercially available ethynyltrimethylsilane (0.17 g, 1.73 mmol), PdCl2P(PPh3)2 (0.041 g, 0.061 mmol), copper(I)iodide (0.006 g, 0.0315 mmol), and triethylamine (0.177 g, 1.75 mmol) dissolved in dry DMF (3 mL) under an atmosphere of nitrogen and mixture heated at 50° C. for two hours. The reaction mixture was then diluted with ethyl acetate and washed with a solution composed of NaCl/NaHCO3/(NH4)2CO3/water (1:1:1:1) (×3), water, brine, and dried (Na2SO4) to give the desired crude (R)-3-(1H-Indol-3-yl)-2-(5-trimethylsilanylethynyl-thiophene-2-sulfonylamino)-propionic acid 115 (185 mg, 71%). LC-MS (ES+) 447; (ES−) 445.
Reaction SMILES: Br[C:2]1[C:3]([F:17])=[C:4]2[O:8][C:7]([CH:9]3[CH2:11][CH2:10]3)=[N:6][C:5]2=[C:12]([C:15]#[N:16])[C:13]=1[CH3:14].C([Sn](CCCC)(CCCC)[C:23]1[O:24][CH:25]=[CH:26][CH:27]=1)CCC>C1C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(C1(C)C(O)=C(C(C)(C)C)C=CC1)(C)(C)C>[CH:9]1([C:7]2[O:8][C:4]3[C:5](=[C:12]([C:15]#[N:16])[C:13]([CH3:14])=[C:2]([C:23]4[O:24][CH:25]=[CH:26][CH:27]=4)[C:3]=3[F:17])[N:6]=2)[CH2:11][CH2:10]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: Cc1c(Br)c(F)c2oc(C3CC3)nc2c1C#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)C1=C(O)C(C)(C(C)(C)C)CC=C1
Solvent: c1ccccc1
Product: Cc1c(-c2ccco2)c(F)c2oc(C3CC3)nc2c1C#N
Temperature: 25 °C
Reaction time: 30 h
Yield: 100 %

Procedure:
6-Bromo-2-cyclopropyl-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-77) (100 mg, 0.34 mmol) was dissolved in benzene (3 ml), then 2-tributylstannylfuran (117 μl, 0.37 mmol) and 2,6-di-tert-butylcresol (1 mg) and bis(triphenylphosphine)palladium(II) dichloride (3 mg, 0.003 mmol) were added, followed by hearing under reflux for 20 hours under nitrogen atmosphere. The reaction liquid was cooled, the insoluble matter was separated by filtration through Celite, the solvent was concentrated under reduced pressure. The resulting residue was fractionated with ethyl acetate and water, followed by washing with saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure. The resulting residue was dissolved in methylene chloride, potassium fluoride (20 mg) and water (0.1 ml) were added, followed by vigorously stirring at room temperature for 30 hours. The insoluble matter was separated by filtration through Celite, followed by fractionation with methylene chloride and water and by washing with saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure. The resulting residue was subjected to preparative silica gel column chromatography, eluted with a mixed solvent of n-hexane/ethyl acetate (3:1, v/v) to obtain 2-cyclopropyl-7-fluoro-6-(2-furyl)-5-methyl-1,3-benzoxazole-4-carbonitrile (96 mg) as a white solid. This was dissolved in dimethyl sulfoxide (2 ml), triethylamine (119 μl, 0.85 mmol) and (3S)-3-(dimethylamino)pyrrolidine (56 μl, 0.44 mmol) were added, followed by stirring at 90° C. under nitrogen atmosphere for 22 hours. After cooling to room temperature, ethyl acetate was added, followed by fractionation with water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated away, the resulting residue was subjected to preparative thin-layer silica gel column chromatography and eluted with a mixed solvent of chloroform/methanol (20:1, v/v) to obtain the entitled compound (37 mg, 29%) as a white solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]([NH:10][N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH3:20])=[CH:12]2)[CH:5]=1.Br[CH2:22][CH2:23][CH3:24].O>CN(C)C=O>[Cl:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]([N:10]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH3:20])=[CH:12]2)[CH2:22][CH2:23][CH3:24])[CH:5]=1
Reactant: CCCBr
Reactant: Cc1cn(Nc2cc(Cl)ncn2)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN(c1cc(Cl)ncn1)n1cc(C)c2ccccc21
Reaction time: 0.08 h

Procedure:
To a suspension of NaH (60% in oil, 1.52 g) in 40 ml dimethylformamide (hereafter DMF) at ice bath temperature was added 9.0 g of 6-chloro-N-(3-methyl-1H-indol-1-yl)-4-pyrimidinamine dropwise, in 50 ml DMF. After addition was complete, the reaction was stirred for 5 minutes and then 3.45 ml of 1-bromopropane was added dropwise to the cool mixture. Reaction was allowed to proceed for 4 hours at room temperature. The mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried (sat. NaCl, anhy. MgSO4).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2[C:17](OS(C(F)(F)F)(=O)=O)=[N:18][CH:19]=[C:20]([CH:25]=2)[C:21]([O:23][CH3:24])=[O:22])[CH:12]=[CH:13][C:14]=1[Cl:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2[C:17]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[CH3:34])=[N:18][CH:19]=[C:20]([CH:25]=2)[C:21]([O:23][CH3:24])=[O:22])[CH:12]=[CH:13][C:14]=1[Cl:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1B(O)O
Reactant: COC(=O)c1cnc(OS(=O)(=O)C(F)(F)F)c(-c2ccc(Cl)c(OCc3ccccc3)c2)c1
Product: COC(=O)c1cnc(-c2ccccc2C)c(-c2ccc(Cl)c(OCc3ccccc3)c2)c1
Yield: 94.9 %

Procedure:
According to the method described in example 4.5, starting from 1.5 g (2.99 mmol) of methyl 5-[3-(benzyloxy)-4-chlorophenyl]-6-{[(trifluoromethyl)sulphonyl]oxy}nicotinate and of 508 mg (3.74 mmol) of 2-methylphenyl boronic acid, we obtain 1.26 g of methyl 5-[3-(benzyloxy)-4-chlorophenyl]-6-(2-methylphenyl)nicotinate in the form of oil.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[OH:8].C(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O>[C:18]([NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[OH:8])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1ccccc1
Reaction time: 1 h

Procedure:
(±)-trans-2-Aminocyclohexanol (241 gm) was combined with chloroform (2000 ml), water (2000 ml) and sodium bicarbonate (352 gm) and stirred. Benzoyl chloride (352 gm) was added dropwise to the stirred solution and stirring was continued for 1 hr. The product was filtered and washed with water. The white solid was dried at 80° C. to provide the product (mp 172°-173° C.).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]2[N:8]([C:16]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]=[C:18]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)[C:17]=3[CH3:33])[CH2:9][C:10]3([CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.CS(C)=O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.O.[Cu]I>[F:26][C:22]1[CH:21]=[C:20]2[C:25]([C:16]([N:8]3[C:6]4[C:5](=[CH:4][CH:3]=[C:2]([N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)[CH:7]=4)[C:10]4([CH2:11][CH2:12][O:13][CH2:14][CH2:15]4)[CH2:9]3)=[C:17]([CH3:33])[C:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[N:19]2)=[CH:24][CH:23]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC2(CCOCC2)c2ccc(Br)cc21
Reactant: C1COCCN1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: O
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC2(CCOCC2)c2ccc(N3CCOCC3)cc21
Temperature: 120 °C

Procedure:
A suspension of 6-bromo-1-(7-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-yl)-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran] (100 mg, 0.198 mmol), morpholine and DMSO (2.5 mL) was degassed with argon for 15 min in a Schlenck tube. To the mixture was added copper (I) iodide (8 mg, 40 μmol), 1-(−)-proline (9 mg, 79 mmol) and potassium carbonate (82 mg, 595 μmol) and the mixture was heated at 120° C. overnight. After this time the reaction was cooled to rt and diluted with DCM (100 mL) and water (40 mL). The separated organic layer was dried over MgSO4, filtered and evaporated in vacuo. Column chromatography (hexane:EtOAc, 1:0 to 0:1) gave the desired product as a yellow oil. The product was further purified by reverse phase HPLC to give 1-(7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-6-(4-morpholinyl)-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-pyran]. 1H NMR (400 MHz, chloroform-d) δ ppm 8.76 (1H, dd, J=3.7, 1.0 Hz), 7.75-8.00 (4H, m), 7.41 (1H, ddd, J=7.1, 5.0, 1.6 Hz), 7.21-7.27 (1H, m), 7.13 (1H, d, J=8.2 Hz), 6.35 (1H, dd, J=8.2, 2.3 Hz), 5.61 (1H, d, J=2.3 Hz), 3.96-4.09 (3H, m), 3.89-3.96 (1H, m), 3.70-3.79 (4H, m), 3.49-3.60 (2H, m, J=12.2, 12.2, 2.9, 2.7 Hz), 2.91-3.04 (4H, m), 2.38 (3H, s), 2.09-2.22 (2H, m), 1.76-1.93 (2H, m). Mass Spectrum (ESI) m/e=511 (M+1).
Reaction SMILES: C([C:5]([NH:7][C:8]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([NH:16][C:17]2[C:22]([F:23])=[CH:21][N:20]=[C:19](Cl)[N:18]=2)[N:9]=1)=[O:6])(C)(C)C.[NH2:25][S:26]([C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][C:35]=1[CH3:36])[NH2:32])(=[O:28])=[O:27]>CO>[NH3:7].[CH3:5][OH:6].[NH2:25][S:26]([C:29]1[CH:30]=[C:31]([NH:32][C:19]2[N:18]=[C:17]([NH:16][C:10]3[N:9]=[C:8]([NH2:7])[C:13]([O:14][CH3:15])=[CH:12][CH:11]=3)[C:22]([F:23])=[CH:21][N:20]=2)[CH:33]=[CH:34][C:35]=1[CH3:36])(=[O:27])=[O:28]
Reactant: Cc1ccc(N)cc1S(N)(=O)=O
Reactant: COc1ccc(Nc2nc(Cl)ncc2F)nc1NC(=O)C(C)(C)C
Solvent: CO
Product: COc1ccc(Nc2nc(Nc3ccc(C)c(S(N)(=O)=O)c3)ncc2F)nc1N
Product: N
Temperature: 100 °C
Reaction time: 48 h

Procedure:
A mixture of N4-[2-(tert-butylcarbonyl)amino-3-methoxypyrid-6-yl]-2-chloro-5-fluoro-4-pyrimidineamine (65) (25 mg, 0.07 mmol) and 3-aminosulfonyl-4-methylaniline (15 mg) in methanol (1 mL) was shaken in a sealed tube at 100° C. for 48 h. The reaction mixture was then chromatographed (silica gel, CH2Cl2 then 2-4% 2N NH3/MeOH in CH2Cl2) to obtain N2-(3-aminosulfonyl-4-methylphenyl)-N4-(2-amino-3-methoxypyrid-6-yl)-5-fluoro-2,4-pyrimidinediamine (66). (Note: The N-tert-butylcarbonyl group was cleaved during this reaction to give free amine function). LCMS: purity: 90%; MS (m/z): 420 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([F:21])[C:14]=1[CH2:15]OS(C)(=O)=O)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[Cl:22][C:23]1[CH:24]=[C:25]([C:30]([C:33]2[N:37]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[C:40]([O:45][CH3:46])[CH:39]=3)[C:36]([SH:47])=[N:35][CH:34]=2)([CH3:32])[CH3:31])[CH:26]=[CH:27][C:28]=1[Cl:29].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CCOC(C)=O.O>[Cl:22][C:23]1[CH:24]=[C:25]([C:30]([C:33]2[N:37]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[C:40]([O:45][CH3:46])[CH:39]=3)[C:36]([S:47][CH2:15][C:14]3[C:13]([F:21])=[CH:12][C:4]([C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])=[CH:3][C:2]=3[F:1])=[N:35][CH:34]=2)([CH3:32])[CH3:31])[CH:26]=[CH:27][C:28]=1[Cl:29]
Reactant: COc1cc(-n2c(C(C)(C)c3ccc(Cl)c(Cl)c3)cnc2S)ccc1F
Reactant: CC(C)(C)OC(=O)c1cc(F)c(COS(C)(=O)=O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1cc(-n2c(C(C)(C)c3ccc(Cl)c(Cl)c3)cnc2SCc2c(F)cc(C(=O)OC(C)(C)C)cc2F)ccc1F
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 86.6 %

Procedure:
A mixture of tert-butyl 3,5-difluoro-4-((methylsulfonyloxy)methyl)benzoate (355 mg, 1.10 mmol) and 5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluoro-3-methoxyphenyl)-1H-imidazole-2-thiol (402 mg, 0.98 mmol)—prepared in a manner similar to that described for Example 3 from commercially available reagents—was suspended in acetone (4 mL) and treated with K2CO3 (223 mg, 1.6 mmol). The resulting white suspension was stirred at ambient temperature. The reaction mixture rapidly became a thick slurry, and acetone (5 mL) was added to facilitate stirring. After 75 min, the reaction was diluted with EtOAc and water. The aqueous layer was extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford crude product that was purified by flash chromatography (silica gel, EtOAc/Hex, 0:100 to 80:20) to afford the title compound (541 mg, 87% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.49-7.40 (m, 2H), 7.30-7.24 (m, 1H), 7.19 (s, 1H), 7.10 (d, J=2.2 Hz, 1H), 6.87 (ddd, J=10.7, 9.5, 5.4 Hz, 2H), 6.28 (ddd, J=8.5, 3.8, 2.5 Hz, 1H), 5.85 (dd, J=7.5, 2.4 Hz, 1H), 4.20-4.07 (m, 2H), 3.46 (s, 3H), 1.57 (s, 9H), 1.54 (s, 3H), 1.46 (s, 3H); MS (EI) m/z 637 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[C:5]=1[OH:11])([O-])=O.CO>C1COCC1.[Ni]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[C:5]=1[OH:11]
Reactant: O=[N+]([O-])c1cccc(Br)c1O
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cccc(Br)c1O
Reaction time: 4 h

Procedure:
5 g (22.9 mmol) 2-nitro-6-bromo-phenol (Fluka 67211) is hydrogenated in the presence of 0.1 g Ra—Ni (B113W EtOH, Degussa) in 100 ml of THF:MeOH=1:1. for 4 h. The reaction mixture is filtered (2 glass fiber filters used) and the filtrate is concentrated in vacuo. The residue is purified by chromatography (silicagel, hexane:EtOAc=2:1) to afford the title compound as a reddish oil which slowly solidifies.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([OH:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:14](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([O:13][CH3:14])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)c1ccc(C#N)c(O)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(C(C)(C)C)ccc1C#N
Temperature: 50 °C
Reaction time: 2 h
Yield: 32.4 %

Procedure:
4-t-Butyl-2-hydroxybenzonitrile (1.16 g) and potassium carbonate (376 mg) were dissolved in dimethylformamide (4 ml) and to the solution was added dropwise iodomethane (226 μl), followed by stirring at 50° C. for 2 hours. The resulting mixture was filtered to remove the remaining potassium carbonate and concentrated under reduced pressure. The obtained residue was purified by column-chromatography (hexane/ethyl acetate=10/1) to yield the compound 13-2a (167 mg, 97%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].N1C=CC=CC=1.[C:15]([O:19][C:20]([C@H:22]([C@@H:32]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:33]([NH:35][NH2:36])=[O:34])[CH2:23]/[CH:24]=[CH:25]/[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>ClCCl>[C:15]([O:19][C:20]([C@H:22]([C@@H:32]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:33]([NH:35][NH:36][S:5]([CH2:4][CH2:3][CH2:2][Cl:1])(=[O:7])=[O:6])=[O:34])[CH2:23]/[CH:24]=[CH:25]/[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)C[C@@H](C(=O)NN)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)CCCCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)NNS(=O)(=O)CCCCl)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
1.85 g of 3-chloropropylsulphonyl chloride and 0.85 g of pyridine were added to a solution of 3.0 g of (E)-2(R)-[1(S)-(tertbutoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvalerohydrazide in 40 ml of dichloromethane. After stirring at room temperature for 2 hours the solvent was evaporated and the residue was triturated with diethyl ether. The mixture was filtered and the solvent was evaporated to give 1.92 g of (E)-2(R)-[1(S)-(tertbutoxycarbonyl)-4-phenyl-3-butenyl]-2′-(3-chloropropylsulphonyl)-4-methylvalerohydrazide in the form of a pale yellow oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](=[CH2:16])[C:12]([O:14]C)=[O:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>O1CCCC1.O>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](=[CH2:16])[C:12]([OH:14])=[O:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C=C(C(=O)OC)c1ccc2ncccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=C(C(=O)O)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.7 %

Procedure:
Accordingly, as shown in step iii of Scheme 1, methyl 2-(quinolin-6-yl)acrylate (75.0 g) was dissolved in a solution containing sodium hydroxide (65.2 g, 1.63 mol) in 1.1 liters of tetrahydrofuran and 1.1 liters of water. The reaction was stirred at room temperature overnight. The organic layer was partitioned off and the aqueous layer washed with 500 mL of toluene. The aqueous layer was then cooled with an ice bath and acidified by dropwise addition of concentrated HCl until a pH of 4.5 was achieved (about 125 mL of conc. HCl, 1.508 mol), resulting in a white precipitate. After the addition was complete, the reaction was stirred for an additional 0.5 hour at 5° C. The precipitate was collected by vacuum filtration, washed with water, washed with methyl t-butyl ether, and dried under vacuum to afford 2-(quinolin-6-yl)acrylic acid (compound 1003, 36.2 g): ESMS (M+1), 200.06; 1H NMR (300.0 MHz, DMSO-d6) δ 13.01 (1H, s), 8.91 (1H, dd, J=1.8, 4.2 Hz), 8.40 (1H, d, J=7.5 Hz), 8.07 (1H, d, J=1.8 Hz), 8.01 (1H, d, J=8.7 Hz), 7.84 (1H, dd, J=1.9, 8.9 Hz), 7.55 (1H, dd, J=1.2, 8.4 Hz), 6.39 (1H, d, J=0.9 Hz), 6.17 (1H, d, J=0.9 Hz).
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[C:16]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])[C:17]4[CH2:22][NH:21][CH2:20][C:18]=4[N:19]=3)=[CH:10][CH:9]=2)=[O:6])[CH2:3][CH2:2]1.Cl.C(N(CC)CC)C.O=[CH:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:15]=[C:16]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])[C:17]4[CH2:22][N:21]([CH2:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43])[CH2:20][C:18]=4[N:19]=3)=[CH:12][CH:13]=2)[CH2:2][CH2:3]1
Reactant: O=CCCC(=O)O
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CNC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CN(CCCC(=O)O)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 4 %

Procedure:
To a solution of (S)-1-cyclopropyl-3-(4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (Example 3) as a HCl salt (100 mg, 0.23 mmol) and triethyamine (64 μL, 0.46 mmol) in DCE (3 mL, anhydrous), and DMF 0.5 mL, anhydrous) was added 4-oxobutanoic acid (45 μL, 0.46 mmol). Reaction mixture was stirred at room temperature for 30 mins. To this sodium triacetoxyborohydride (97 mg, 0.46 mmol) was added. The reaction mixture was stirred at room temperature until analysis by LCMS indicated reaction was complete. Solvent was then removed in vacuo. Purified by prep. HPLC (high pH) to afford a white solid (4.2 mg, 0.008 mmol, 4%).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12](=[CH:15]OCC)[CH:13]=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].Cl.[C:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[O:28])=[CH:25][CH:24]=1)(=[NH:22])[NH2:21].C[O-].[Na+]>CO>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]=[N:21][C:20]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[O:28])=[CH:25][CH:24]=3)=[N:22][CH:15]=2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(C(C=O)=COCC)cc1
Reactant: N=C(N)c1ccc(C(N)=O)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCCc1ccc(-c2cnc(-c3ccc(C(N)=O)cc3)nc2)cc1

Procedure:
4.46 g. of 2-(4-n-pentylphenyl)-3-ethoxy-acrolein, 3.63 g. of the 4-amidinobenzoic acid amide hydrochloride described above and 0.0254 mol of sodium methylate (obtained by dissolving 0.584 g. of sodium metal in methanol) are suspended in 250 ml. of methanol and stirred overnight at room temperature under an atmosphere of nitrogen. The yellow suspension is then filtered and the residue is washed with a little ethanol and suspended in 1.4 liters of ether for further purification. The suspension is washed with water and then filtered again. Sparingly soluble 4-[5-(4-n-pentylphenyl)-2-pyrimidinyl]benzoic acid amide is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[CH2:10][NH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClCCl.C(=O)([O-])[O-].[K+].[K+].[Br:31][CH2:32][C:33](Cl)=[O:34]>O.CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[CH2:10][NH:11][C:33](=[O:34])[CH2:32][Br:31])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)CBr
Reactant: CC(C)(C)OC(=O)N[C@@H](CN)Cc1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CNC(=O)CBr)Cc1c[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 99.7 %

Procedure:
To an ice-cooled solution of (1R)-N1 -(tert-butoxycarbonyl)-1-(1H-indol-3-ylmethyl)-1,2-ethanediamine (7.00 g) in a mixed solvent of dichloromethane (200 ml) and dimethylformamide (200 ml) was added potassium carbonate (10.03 g). To the mixture was added dropwise bromoacetyl chloride (7.61 g) for 3 minutes, and then the mixture was stirred at the same temperature for 1 hour and 40 minutes by adding further potassium carbonate (3.34 g) and bromoacetyl chloride (2.00 ml) into the mixture. The resulting mixture was poured into water, and extracted twice with dichloromethane. The extracts were combined and washed successively with 0.5N hydrochloric acid and brine, and dried over magnesium sulfate. After evaporation in vacuo, the residue was dried to give (1R)-N1 -(tert-butoxycarbonyl)-N2 -(bromoacetyl)-1-(1H-indol-3-ylmethyl)-1,2-ethanediamine (9.9 g) as crystal.