Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[CH:11][C:10](B2OC(C)(C)C(C)(C)O2)=[CH:9][N:8]=1.Cl[C:23]1[N:28]=[C:27]([NH2:29])[CH:26]=[N:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:8]=[CH:9][C:10]([C:23]2[N:28]=[C:27]([NH2:29])[CH:26]=[N:25][CH:24]=2)=[CH:11][N:12]=1
Reactant: C[C@H]1CCCN1c1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Nc1cncc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H]1CCCN1c1ncc(-c2cncc(N)n2)cn1
Temperature: 90 °C
Yield: 59.1 %

Procedure:
A flask was charged with (S)-2-(2-methylpyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (7.1 g, 24.55 mmol), 6-chloropyrazin-2-amine (2.89 g, 22.32 mmol), Pd(PPh3)4 (2.58 g, 2.232 mmol) and 1,4-dioxane (74.4 mL). The reaction mixture was purged with nitrogen for several minutes before aqueous 2M sodium carbonate (22.32 mL, 44.6 mmol) solution was added. The reaction mixture was then purged with nitrogen for another 10 minutes at 25° C. before it was heated to 90° C. under nitrogen overnight. 1,4-Dioxane was removed in vacuo and the crude mixture was diluted with EtOAc. The product was washed with water and brine. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified on silica gel chromatography to yield 3.38 g (13.2 mmol, 84%) of the title product as a light brown solid. ESI-MS (EI+, m/z): 258.26, 1H NMR (Chloroform-d) δ: 8.92 (d, J=5.3 Hz, 2H), 8.25 (s, 1H), 7.88 (s, 1H), 4.60 (s, 2H), 4.39 (d, J=5.8 Hz, 1H), 3.81-3.68 (m, 1H), 3.68-3.55 (m, 1H), 2.24-1.95 (m, 3H), 1.78 (s, 1H), 1.31 (d, J=6.3 Hz, 3H)
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[NH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1>ClCCl.N1C=CC=CC=1>[C:26]([C:25]1[CH:28]=[CH:29][C:22]([NH:21][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:21][C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)=[O:13])=[CH:23][CH:24]=1)#[N:27]
Reactant: N#Cc1ccc(N)cc1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1ccc(NC(=O)c2ccccc2SSc2ccccc2C(=O)Nc2ccc(C#N)cc2)cc1
Yield: 12.5 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and 4-aminobenzonitrile (1.38 g, 11.7 mmol) in 11 mL of pyridine. The crude product was triturated with a hot mixture of ethyl acetate and ethanol (1:1), filtered, and recrystallized from ethanol-DMF-water to yield 0.37 g of the title compound, mp 239°-241° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:42][O:43][C:44]1[C:45]2[N:58]=[C:57]([NH2:59])[S:56][C:46]=2[C:47]([N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[N:48][CH:49]=1>C1COCC1>[CH3:42][O:43][C:44]1[C:45]2[N:58]=[C:57]([NH:59][C:8](=[O:10])[CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[S:56][C:46]=2[C:47]([N:50]2[CH2:51][CH2:52][O:53][CH2:54][CH2:55]2)=[N:48][CH:49]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)Cc3ccccc3)nc12

Procedure:
From phenylacetic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 385 (M+H+, 100).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[C:15]3[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=3[O:13][N:12]=2)[CH2:7][CH2:6]1.[C@@H:21]12[C:30](=O)[O:29][C:27](=[O:28])[C@@H:22]1[CH2:23][CH2:24][CH2:25][CH2:26]2.[ClH:32]>N1C=CC=CC=1.C(O)C>[ClH:32].[F:20][C:18]1[CH:17]=[CH:16][C:15]2[C:11]([CH:8]3[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][N:1]4[C:27](=[O:28])[C@H:22]5[C@H:21]([CH2:26][CH2:25][CH2:24][CH2:23]5)[C:30]4=[O:29])[CH2:6][CH2:7]3)=[N:12][O:13][C:14]=2[CH:19]=1
Reactant: NCCCN1CCC(c2noc3cc(F)ccc23)CC1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: O=C1[C@H]2CCCC[C@H]2C(=O)N1CCCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of 1-(3-aminopropyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (3.01 g, 10.8 mmol) and cis-1,2-cyclohexane-dicarboxylic anhydride (1.9 g, 12.3 mmol) in dry pyridine (30 ml) was heated at reflux for 16 hours. The dark brown solution was concentrated to dryness on a rotary evaporator. The crude residue was purified twice by flash chromatography over a silica gel column. The pure product thus obtained weighed 2.5 g (67%). This was converted to the hydrochloride salt by treatment with HCl in ethanol (50 ml). The cis-2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]-hexahydro-1H-isoindole-1,3-dione hydrochloride crystals so obtained weighed 3.0 g, m.p.=242°-245° C.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[C:21](=[C:22]([C:24](=[O:26])[NH2:25])[CH:23]=2)[NH:20][C:19]2[CH:18]=[C:17]([N:27]4[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]4)[CH:16]=[CH:15][C:14]3=2)=[CH:7][C:6]=1[Cl:40].[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:24]([C:22]1[CH:23]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)=[C:6]([Cl:40])[CH:7]=2)[CH:12]=[C:13]2[C:21]=1[NH:20][C:19]1[CH:18]=[C:17]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)[CH:16]=[CH:15][C:14]2=1)(=[O:26])[NH2:25]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)[nH]c2c(C(N)=O)cc(-c4ccc(OCCBr)c(Cl)c4)cc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)[nH]c2c(C(N)=O)cc(-c4ccc(OCCN5CCOCC5)c(Cl)c4)cc23)CC1
Temperature: 75 °C
Yield: 89.4 %

Procedure:
tert-Butyl 4-(6-(4-(2-bromoethoxy)-3-chlorophenyl)-8-carbamoyl-9H-carbazol-2-yl)piperazine-1-carboxylate (342 mg, estimated purity 55%, ˜0.30 mmol, Example 409C) was dissolved in DMF (6 ml). Morpholine (0.5 ml, 5.7 mmol) and K2CO3 (160 mg, 1.16 mmol) were added and the mixture heated to 75° C. for 2 hour. The reaction mixture was poured into a separating funnel that was loaded with 100 ml water+25 ml saturated aq. NH4Cl solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated to dryness. Purification by prep HPLC gave 170 mg tert-butyl 4-(8-carbamoyl-6-(3-chloro-4-(2-morpholinoethoxy)phenyl)-9H-carbazol-2-yl)piperazine-1-carboxylate. MS (ESI) m/e+=634/636, m/e−=632/634 [1 Cl isotope pattern]. HPLC retention time 16.96 min. (Sunfire C18 3.5 μm, 3.0×150 mm column, 15 min gradient, 10-100% B, 0.5 mL/min. Solvent A: 5% CH3CN—95% H2O—0.1% TFA; Solvent B: 95% CH3CN—5% H2O—0.1% TFA), then isocratic at 100% B. 1H NMR (DMSO-d6) δ ppm 11.14 (s, 1H), 8.50 (d, 1H, J=1.3), 8.33 (b, 1H), 8.14 (d, 1H, J=1.5), 8.07 (d, 1H, J=8.8), 7.98 (d, 1H, J=2.3), 7.82 (dd, 1H, J=8.8, 2.3), 7.51 (b, 1H), 7.31 (d, 1H, J=8.8), 7.25 (d, 1H, J=2.0), 6.95 (dd, 1H, J=8.8, 2.0), 4.26 (t, 2H, J=5.8), 3.63-3.59 (m, 4H), 3.53 (b, 4H), 3.21-3.17 (m, 4H), 2.79 (t, 2H, J=5.8), 2.58-2.54 (m, 4H), 1.46 (s, 9H).
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:11][C@H:12]1[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:15]([N:21]2[CH:29]=[N:28][C:27]3[C:22]2=[N:23][C:24]([C:31]#[N:32])=[N:25][C:26]=3Cl)[O:14][C@@H:13]1[CH2:33][O:34][C:35](=[O:37])[CH3:36])(=[O:10])[CH3:9].[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([CH:45]([C:48]2[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=2)[CH2:46][NH2:47])=[CH:41][CH:40]=1>C(#N)C>[C:8]([O:11][C@H:12]1[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:15]([N:21]2[CH:29]=[N:28][C:27]3[C:22]2=[N:23][C:24]([C:31]#[N:32])=[N:25][C:26]=3[NH:47][CH2:46][CH:45]([C:42]2[CH:43]=[CH:44][C:39]([Cl:38])=[CH:40][CH:41]=2)[C:48]2[CH:49]=[CH:50][C:51]([Cl:54])=[CH:52][CH:53]=2)[O:14][C@@H:13]1[CH2:33][O:34][C:35](=[O:37])[CH3:36])(=[O:10])[CH3:9]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NCC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccc(Cl)cc4)c4ccc(Cl)cc4)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 16 h
Yield: 91.7 %

Procedure:
Triethylamine (0.2 ml, 1.14 mmol) was added to a stirred solution of (2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-(6-chloro-2-cyano-9H-purin-9-yl)tetrahydro-3-furanyl acetate (500 mg, 1.14 mmol) (Preparation 45) and 2,2-bis(4-chlorophenyl)ethanamine (919 mg, 1.2 mmol) (J. Am. Chem. Soc., 1983, 105 (10), 3138) in acetonitrile (5 ml) at room temperature. The reaction mixture was stirred for 16 hours. The solvent was then removed under reduced pressure and the residue was dissolved in dichloromethane (20 ml). The solution was washed with water (10 ml) and saturated sodium chloride solution (10 ml), dried over anhydrous magnesium sulphate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:(99:1 by volume) increasing in polarity to dichloromethane:methanol (98.5:1.5 by volume). The solvent was removed under reduced pressure to give the title compound (698 mg) as a foam.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C@@H:5]([C:6]2[N:10]=[CH:9][N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[N:7]=2)[CH2:4][C@H:3]1[NH2:17].Cl[C:20]1[C:25]([C:26]#[N:27])=[CH:24][N:23]=[C:22]([S:28][CH3:29])[N:21]=1.CCN(C(C)C)C(C)C>C(O)(C)C>[CH3:1][C:2]1([CH3:18])[C@@H:5]([C:6]2[N:10]=[CH:9][N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[N:7]=2)[CH2:4][C@H:3]1[NH:17][C:20]1[C:25]([C:26]#[N:27])=[CH:24][N:23]=[C:22]([S:28][CH3:29])[N:21]=1
Reactant: CC1(C)[C@H](N)C[C@@H]1c1ncn(C2CCCCO2)n1
Reactant: CSc1ncc(C#N)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CSc1ncc(C#N)c(N[C@@H]2C[C@H](c3ncn(C4CCCCO4)n3)C2(C)C)n1
Temperature: 90 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
A mixture of (1R,3S)-2,2-dimethyl-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)cyclobutanamine (340 mg, crude) and 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile (210 mg, 1.14 mmol) and DIEA (450 mg, 3.50 mmol) in isopropanol (5 mL) was stirred at 90° C. for 1 h. After removal of the solvent, the residue was purified by silica gel column chromatography (10%-30% ethyl acetate in petroleum ether) to afford the title compound (290 mg, 0.727 mmol, 65% yield for two steps). MS (ESI) m/z 400.2 [M+H]+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]12[CH2:16][CH:15]1[C:14](=O)[CH2:13][CH2:12]2.CN.[C:20]([BH3-])#[N:21].[Na+].[ClH:24].[CH3:25][OH:26]>>[ClH:24].[CH3:20][NH:21][CH:14]1[CH2:13][CH2:12][C:11]2([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)[CH:15]1[CH2:16]2.[ClH:24].[CH2:25]([O:26][CH2:1][CH3:2])[CH3:20]
Reactant: [BH3-]C#N
Reactant: CO
Reactant: O=C1CCC2(c3ccc4ccccc4c3)CC12
Agent: CN
Agent: Cl
Agent: [Na+]
Product: CCOCC
Product: CNC1CCC2(c3ccc4ccccc4c3)CC12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(naphthalen-2-yl)bicyclo[3.1.0]hexan-2-one (0.72 g, 3.24 mmol) in methanol (50 mL) was added methylamine (33% in ethanol, 6.05 mL, 48.6 mmol, 15.0 eq.) and sodium cyanoborohydride (0.26 g, 4.21 mmol, 1.3 eq.). The mixture was stirred at room temperature overnight. The reaction mixture was cooled to 10° C., and acidified with 1N HCl (25 mL). The reaction mixture was concentrated at 30° C. and the resulting aqueous layer diluted with water (25 mL). The aqueous layer was then extracted with ethyl acetate (125 mL) to remove non-polar impurities. The aqueous layer was then adjusted to pH 9 with 1N NaOH (25 mL), and the aqueous layer extracted with ethyl acetate (3×25 mL). The combined organic layers were dried over magnesium sulphate, filtered and concentrated in vacuo. The residue was then dissolved in diethyl ether (20 mL) and the HCl salt was formed by slowly adding HCl/diethyl ether solution (10 mL). The slurry was stirred for 30 mins before filtration. The solids were rinsed with ice cold diethyl ether (10 mL) and the compound was quickly transferred to a vacuum oven and dried for 12 hours to afford the desired compound (0.36 g, 47%) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 1.12-1.15 (1H, m, CH), 1.37-1.39 (1H, m, CH), 1.42-1.54 (1H, m, CH), 2.11-2.13 (1H, m, CH), 2.25-2.37 (2H, m, CH2), 2.34-2.37 (1H, m, CH), 3.98-4.05 (1H, m, CH), 7.33 (1H, dd, J 1.6, 8.4, ArH), 7.40-7.47 (2H, m, ArH), 7.71-7.72 (1H, m, ArH), 7.78-7.80 (3H, m, ArH). 13C NMR (400 MHz, CD3OD); δ ppm 13.41 (s, 1C), 24.40 (s, 1C), 24.50 (s, 1C), 30.55 (s, 1C), 31.69 (s, 1C), 33.3 (s, 1C), 61.44 (s, 1C), 124.75 (s, 1C), 125.28 (s, 1C), 125.91 (s, 1C), 127.25 (s, 1C), 127.28 (s, 1C), 127.85 (s, 1C), 132.32 (s, 1C), 133.59 (s, 1C), 140.18 (s, 1C). LCMS (M+1) 238.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([CH3:10])=[CH:8][N:7]=[C:6]([CH2:11]O)[C:5]=1[CH3:13])[CH3:2].S(Cl)([Cl:16])=O.CCOCC>C(Cl)Cl>[ClH:16].[Cl:16][CH2:11][C:6]1[C:5]([CH3:13])=[C:4]([O:3][CH2:1][CH3:2])[C:9]([CH3:10])=[CH:8][N:7]=1
Reactant: CCOc1c(C)cnc(CO)c1C
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CCOc1c(C)cnc(CCl)c1C
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
21.0 g of 4-ethoxy-3,5-dimethyl-2-pyridylmethanol, dissolved in 110 ml of methylene chloride, were added dropwise at 0° to 10 ml of thionyl chloride in 220 ml of methylene chloride. After stirring at room temperature for 16 hours 890 ml of ether were added dropwise thereto while cooling and the mixture was stirred at room temperature for a further 2 hours. The separated crystals were filtered off under suction and washed with ether. There was obtained 2-chloromethyl-4-ethoxy-3,5-dimethylpyridine hydrochloride of melting point 156°-158°.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[N:7][C:8]([C:15]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])=[CH:9][C:10]=1[CH2:11][CH:12]([CH3:14])[CH3:13])=O.O.[NH2:24][NH2:25]>C(O)C>[CH2:11]([C:10]1[CH:9]=[C:8]([C:15]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])[N:7]=[N:6][C:5]=1[C:3]([NH:24][NH2:25])=[O:2])[CH:12]([CH3:14])[CH3:13]
Reactant: COC(=O)c1nnc(C(=O)N2CCCCC2)cc1CC(C)C
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)Cc1cc(C(=O)N2CCCCC2)nnc1C(=O)NN
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
The mono-methyl ester 5 (10 mg, 0.033 mmol) was dissolved in 3.5 mL anhydrous ethanol (dried over 4 Å molecular sieves). Hydrazine hydrate was added (55 μL, 1.65 mmol, 53 mg), and the reaction was stirred for 5.5 hours at room temperature under an atmosphere of nitrogen. The volatiles were evaporated under reduced pressure, and the product oil was triturated three times with ca. 3 mL diethyl ether. The bright yellow oil was dried under high vacuum to produce a 10 mg (quant.) of a pale yellow solid. MS: (ESI-TOF) MH+ expected: 306.1924, found: 306.1923.
Reaction SMILES: [O:1]1[CH2:4][CH:3]([NH2:5])[CH2:2]1.[Cl:6][C:7]1[N:12]=[C:11](Cl)[CH:10]=[C:9]([CH2:14][O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[N:8]=1>CO.C(#N)C>[Cl:6][C:7]1[N:12]=[C:11]([NH:5][CH:3]2[CH2:4][O:1][CH2:2]2)[CH:10]=[C:9]([CH2:14][O:15][CH2:16][C:17]([F:20])([F:18])[F:19])[N:8]=1
Reactant: NC1COC1
Reactant: FC(F)(F)COCc1cc(Cl)nc(Cl)n1
Solvent: CO
Solvent: CC#N
Product: FC(F)(F)COCc1cc(NC2COC2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.7 %

Procedure:
A solution of oxetan-3-amine (77 mg, 1.06 mmol) in MeOH (2 mL) was added dropwise to an ice-cold solution of 2,4-dichloro-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine (92 mg, 0.35 mmol) in acetonitrile (2 mL). The mixture stirred at rt overnight. The mixture was separated by preparative chromatography to give the title compound (58 mg, 55%).
Reaction SMILES: [CH:1]1([NH:7][C:8](=[N:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[O:9][N:10]=[C:11]([CH2:13][CH3:14])[CH3:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][C:23](OC(C)=O)=[O:24]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:23]([N:15]([CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)[C:8](=[N:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[O:9][N:10]=[C:11]([CH2:13][CH3:14])[CH3:12])(=[O:24])[CH3:22]
Reactant: CCC(C)=NOC(=NC1CCCCC1)NC1CCCCC1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCC(C)=NOC(=NC1CCCCC1)N(C(C)=O)C1CCCCC1
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of 1,3-dicyclohexyl-O—(N-2-butylideneamino)-isourea (Cmpd. 2) (10.5 g, 35.7 mmol) and 4-dimethylaminopyridine (100 mg) in pyridine (25 ml) is dropwise added acetanhydride (5 ml, 52.9 mmol). The mixture is stirred 2 h and evaporated. The residue is dissolved in toluene (100 ml), washed with water (5×20 ml), dried over MgSO4 and evaporated to afford 9.58 g of the title compound as a light yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])#[CH:2].[CH3:20][Si:21]([CH2:24][N:25]=[N+:26]=[N-:27])([CH3:23])[CH3:22]>C1C=CC=CC=1.C[C]1[C](C)[C](C)[C](C)[C]1C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ru]>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[CH:10]=[C:5]([CH:4]=[C:3]([C:1]3[N:25]([CH2:24][Si:21]([CH3:23])([CH3:22])[CH3:20])[N:26]=[N:27][CH:2]=3)[CH:12]=2)[C:6]([O:8][CH3:9])=[O:7])=[N:14][CH:15]=1
Reactant: C#Cc1cc(C(=O)OC)cc(-c2ccc(C)cn2)c1
Reactant: C[Si](C)(C)CN=[N+]=[N-]
Agent: Cl[Ru]
Agent: C[C]1[C](C)[C](C)[C](C)[C]1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: COC(=O)c1cc(-c2ccc(C)cn2)cc(-c2cnnn2C[Si](C)(C)C)c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a degassed solution of methyl 3-ethynyl-5-(5-methylpyridin-2-yl)benzoate (124 mg, 0.493 mmol) in benzene (12 mL) were added trimethylsilylmethylazide (96 mg, 0.740 mmol) and pentamethylcyclopentadienylbis(triphenylphosphine)ruthenium(II) chloride (59 mg, 0.074 mmol) and the mixture heated to 80° C. in a sealed tube. After 16 h, the title compound was showed as the major isomer (10:1 isomeric ratio) in the reaction. The reaction was concentrated and purified by reverse-phase HPLC gave the title compound (120 mg). MS 381.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:14]1[CH:18]=[CH:17][S:16][CH:15]=1)[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[NH2:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[N:29][CH:28]=[CH:27]2>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH:30]1[C:31]2[C:26](=[CH:25][C:24]([NH:23][C:11](=[O:13])[CH2:10][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:14]3[CH:18]=[CH:17][S:16][CH:15]=3)=[CH:33][CH:32]=2)[CH:27]=[CH:28][N:29]=1
Reactant: CC(C)(C)OC(=O)NC(CC(=O)O)c1ccsc1
Reactant: Nc1ccc2cnccc2c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NC(CC(=O)Nc1ccc2cnccc2c1)c1ccsc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To 3-(tert-butyoxcarbonylamino)-3-(thiophen-3-yl)propanoic acid (E4) in pyridine was added EDC, DMAP, and 6-aminoisoquinoline. The solution was stirred for 10 hours at room temperature. The mixture was poured into NaHCO3(sat) and extracted with EtOAc, dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 5% MeOH/CH2Cl2) gave pure tert-butyl 3-(isoquinolin-6-ylamino)-3-oxo-1-(thiophen-3-yl)propylcarbamate (E5).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:7])[CH:5]=[O:6].[CH3:8][O:9][C:10]1[CH:18]=[C:17]2[C:13]([CH2:14][C:15](=O)N2)=C[CH:11]=1.[CH3:20]I>O>[CH3:8][O:9][C:10]1[CH:11]=[C:3]2[C:13]([C:14]([CH3:15])([CH3:20])[C:5](=[O:6])[N:4]2[CH3:7])=[CH:17][CH:18]=1
Reactant: CI
Reactant: CN(C)C=O
Reactant: COc1ccc2c(c1)NC(=O)C2
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COc1ccc2c(c1)N(C)C(=O)C2(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 45 %

Procedure:
In a flame-dried flask under nitrogen, 490 mg of 60% sodium hydride (12.26 mmol) was slurried three times with Hexanes, and the Hexanes were syringed off. Added 6.25 ml of N,N-dimethylformamide, followed by 500 mg of 6-Methoxy-1,3-dihydro-indol-2-one (3.06 mmol) and stirred at room temperature for 5 minutes. Chilled in ice-H2O bath and added 763 μl of methyl iodide (12.26 mmol) dropwise. After 10 minutes, warmed to room temperature and stirred for 1.5 hours. Chilled in ice-H2O bath and added 20 ml of H2O dropwise. Extracted three times with 2:1 EtOAc/toluene. The combined organics were washed with sodium thiosulfate, H2O and brine, dried (MgSO4) and the solvent removed in vacuo to crude red oil. Purified on Biotage Flash 40, eluting with 4:1 Hexanes/EtOAc to give 285 mg of a white solid (45%). 1H NMR (400 MHz, CDCl3) δ 1.31 (6H, s), 3.16 (3H, s), 3.80 (3H, s), 6.41 (1H, d, J=2.28 Hz), 6.53 (1H, m), 7.06 (1H, d, J=8.1 Hz). M/z (APCI+) 206.0 (M+1).
Reaction SMILES: [Cl:1][CH:2]([CH2:6][CH:7]([C:9]([O:11][CH3:12])=[O:10])C)[C:3](O)=[O:4].S(Cl)([Cl:15])=O>>[Cl:1][CH:2]([CH2:6][CH2:7][C:9]([O:11][CH3:12])=[O:10])[C:3]([Cl:15])=[O:4]
Reactant: COC(=O)C(C)CC(Cl)C(=O)O
Reactant: O=S(Cl)Cl
Product: COC(=O)CCC(Cl)C(=O)Cl

Procedure:
A mixture of 6.2 g of 2-chloro-4-methoxycarbonyl valeric acid and 12.6 ml of thionyl chloride was refluxed for 30 minutes, then the solvent was distilled off under reduced pressure to leave 2-chloro-4-methoxycarbonyl butyryl chloride. A mixture of this product, 5.0 g of 2-benzylaminodiphenyl methanol, 100 ml of ethyl acetate and 100 ml of a saturated aqueous solution of sodium hydrogencarbonate was stirred for one hour at room temperature. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate. then the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (eluent, hexane:ethyl acetate=2:1) to give 5.3 g of 2-[N-benzyl-N-(2-chloro-4-methoxycarbonyl)butyryl]amino-diphenyl methanol as an oily product.
Reaction SMILES: [I:1][C:2]1[C:3]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:4][C:5]([S:13][CH3:14])=[C:6]([CH:12]=1)[C:7](OCC)=[O:8].[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[OH:8][CH2:7][C:6]1[C:5]([S:13][CH3:14])=[CH:4][C:3]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])=[C:2]([I:1])[CH:12]=1
Reactant: CCOC(=O)c1cc(I)c(NS(C)(=O)=O)cc1SC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CSc1cc(NS(C)(=O)=O)c(I)cc1CO
Temperature: 0 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
To a solution of ethyl 5-iodo-4-(methylsulfonamido)-2-(methylthio)benzoate (crude, from step 2) in dry toluene (200 mL) at 0° C. was added diisobutylaluminium hydride (1.0 M in toluene, 100 mL, 100 mmol) slowly. After addition, the mixture was stirred at 0° C. for 3 h and quenched with methanol/H2O (1/1). The reaction mixture was poured into a vigorously stirred solution of potassium sodium tartrate (1M, 300 mL) and stirred vigorously for 2 h, after which time it settled to two clear phases. The organic layer was separated, and the aqueous layer was extracted with EtOAc (3×200 mL). The combined organic solution was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-40% EtOAc/Hexanes) to afford N-(4-(hydroxymethyl)-2-iodo-5-(methylthio)phenyl)methanesulfonamide (11.9 g, 80% yield for two steps). LC-MS m/z 356 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 7.82 (s, 1H), 7.49 (s, 1H), 4.67 (s, 2H), 2.99 (s, 3H), 2.50 (s, 3H).