Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH:25](O)[CH2:26][CH3:27])(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[OH:30]>>[NH:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH2:25][C@@H:26]([OH:30])[CH3:27]
Reactant: CCC(O)c1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CO
Product: C[C@H](O)Cc1ncc[nH]1

Procedure:
A solution of N-tritylimidazolylpropanol (S)-(6) (2.39 g, 6.51 mmol) in 80 ml methanol containing 4.3 ml glacial acetic acid (5%) was refluxed for about 12 hours. After that time, TLC indicated disappearance of the starting materials. The mixture was concentrated in vacuo and a white precipitate appeared upon addition of 50 ml of cold distilled water. The mixture was chilled, then filtered, and the white precipitate was washed with cold distilled water (10 ml). The filtrate was then evaporated twice, and the residual yellow oil redissolved in 50 ml dry methanol and passed through the weakly basic anion exchange resin (hydroxide form) IRA-68. The solution was then evaporated to yield a solid residue that could be recrystallized from a mixture of methanol and ethyl acetate. yield: 0.80 g, 98% of pure (S)-(7). m.p. 119-121° C.; 1H NMR (200 Mhz, CD3OD) δ6.96 (s, 2H, NCHCHN); 3.96 (m, 1H, CHCH3); 2.4-2.65 (ABX, 3JH-H=6.3 Hz, 3JHb-H=6.7 Hz, 3JHa-Hb=14.5 Hz, CH2); 0.87 (d, 3H, 3JH-H=6.3 Hz, CH3); 13C NMR (50 MHz, CD3OD) δ145.8 (s, CH2CNH); 121.2 (d, NCH═CHNH); 67.1 (d, CHOH); 38.4 (t, CH2); 23.1 (q, CH3); MS (CI): [M+1]+. 127
Reaction SMILES: F[C:2]1[C:3]([CH3:15])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12](=[O:14])[CH3:13])[CH:8]=[CH:7][CH:6]=2.[NH2:16][C:17]([CH3:28])([CH3:27])[CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].CCN(C(C)C)C(C)C>CN1C(=O)CCC1.C(Cl)Cl>[C:12]([C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:11]=[C:2]([NH:16][C:17]([CH3:28])([CH3:27])[CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[C:3]([CH3:15])=[N:4]2)(=[O:14])[CH3:13]
Reactant: CC(=O)c1cccc2nc(C)c(F)nc12
Reactant: CC(C)(N)CNC(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CC(=O)c1cccc2nc(C)c(NC(C)(C)CNC(=O)OC(C)(C)C)nc12
Yield: 65.5 %

Procedure:
A solution of 1-(3-fluoro-2-methylquinoxalin-5-yl)ethanone (126g) (0.65 g, 3.19 mmol), tert-butyl (2-amino-2-methylpropyl)carbamate (1.20 g, 6.37 mmol), and DIEA (2.22 mL, 12.75 mmol) in NMP (6.37 mL) was stirred at 170° C. for 1.5 h when mostly product was observed via lcms. The reaction mixture was diluted with DCM (100 mL), added to a separatory funnel, and washed with saturated aq. brine (4×100 mL); the organic layer was separated, dried over Na2SO4, and concentrated. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 10-40% EtOAc in hexanes to give tert-butyl (2-((8-acetyl-3-methylquinoxalin-2-yl)amino)-2-methylpropyl)carbamate (339a) (0.78 g, 2.09 mmol, 65% yield) as a honey colored solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.48 (s, 9H) 1.57 (s, 6H) 2.55 (s, 3H) 2.87 (s, 3H) 3.33 (d, J=6.85 Hz, 2H) 5.25 (t, J=6.55 Hz, 1H) 6.53 (s, 1H) 7.32 (t, J=7.73 Hz, 1H) 7.73 (dd, J=7.34, 1.47 Hz, 1H) 7.88 (dd, J=8.02, 1.37 Hz, 1H). MS (ESI, pos. ion) m/z: 373.2 (M+1).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].CN1C=CN=C1.[CH3:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21].C(N(CCCC)CCCC)CCC>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[C:1]([NH:4][C@H:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:20](=[O:21])[C:19]1[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=1[CH3:17])(=[O:3])[CH3:2]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CCOC(=O)CNC(C)=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cn1ccnc1
Solvent: CCCCN(CCCC)CCCC
Solvent: ClCCl
Product: CCOC(=O)[C@@H](NC(C)=O)C(=O)c1ccccc1C
Temperature: -45 °C
Reaction time: 0.17 h

Procedure:
A solution of ethyl N-acetylglycinate (98%, 7.41 g, 50.0 mmol) and 1-methyl-1H-imidazole (99%, 4.81 mL, 60.0 mmol) in dichloromethane (100 mL) was cooled to −45° C. and treated with 2-methylbenzoyl chloride (99%, 6.59 mL, 50.0 mmol). The reaction was stirred at −45° C. for 10 minutes. Titanium(IV) chloride (19.2 mL, 175 mmol) was added, followed by tri-n-butylamine (98%, 48.6 mL, 200 mmol), and stirring was continued at the same temperature for 30 minutes. The reaction was quenched with water and extracted with diethyl ether; the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (Eluents: 1:5 ethyl acetate/heptane followed by 1:2 ethyl acetate/heptane) afforded the product. Yield: 6.00 g, 22.8 mmol, 46%. APCI m/z 264.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.93 (dd, J=7.8, 1.2 Hz, 1H), 7.44 (ddd, J=7.6, 7.5, 1.4 Hz, 1H), 7.26-7.34 (m, 2H), 6.89 (br d, J=7 Hz, 1H), 6.05 (d, J=7.2 Hz, 1H), 4.04-4.19 (m, 2H), 2.45 (br s, 3H), 2.11 (s, 3H), 1.06 (t, J=7.1 Hz, 3H).
Reaction SMILES: [H-].[Na+:2].CO.[O:5]1[CH2:11][CH:10]([OH:12])[CH2:9][O:8][C:7]2=[CH:13][S:14][CH:15]=[C:6]12.[CH2:16]1[S:20](=[O:22])(=[O:21])[O:19][CH2:18][CH2:17]1>C1(C)C=CC=CC=1.CC(C)=O>[O:12]1[CH:10]([CH2:11][O:5][CH2:18][CH2:17][CH2:16][S:20]([O-:22])(=[O:21])=[O:19])[CH2:9][O:8][C:7]2=[CH:13][S:14][CH:15]=[C:6]12.[Na+:2]
Reactant: OC1COc2cscc2OC1
Reactant: O=S1(=O)CCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: O=S(=O)([O-])CCCOCC1COc2cscc2O1
Temperature: 40 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
The monomer was formed as follows. Initially, 5.86 grams of pure NaH and 240 milliliters of toluene were added to three necks of a round bottom flask equipped with a stirrer, thermometer, and condenser placed in a heating mantle. The mixture was kept under argon. A solution of 40 grams 2,3-dihydro-thieno[3,4-b][1,4]dioxin-2-yl)-methanol (EDOT MeOH) and 3,4-dihydro-2H-thieno[3,4-b][1,4]dioxepin-3-ol (ProDOT-OH) (ratio 80:20) in 400 ml toluene were added drop wise for 15 minutes. The mixture was stirred at 40° C. for 1 hour. A solution of 28.4 grams of propane sultone in 240 milliliters toluene was added drop wise during 15 minutes. The resulting mixture was heated at reflux for an additional 2 hours. The solution was cooled to ambient temperature and 3.6 liters of acetone was added quickly. The precipitated product was filtered through a fine porosity frit and then dried under vacuum at ambient temperature for 6 days. 61 grams of sodium 3-(2,3-dihydrothieno[3,4-b][1,4]dioxin-2-ylmethoxy)-propane-1-sulfonate (EDOTSNa) was obtained (83% yield).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:14]=[C:13]([I:15])[CH:12]=[C:11]([Cl:16])[C:7]=1[C:8]([OH:10])=O.[NH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C1COCC1>[Cl:16][C:11]1[CH:12]=[C:13]([I:15])[CH:14]=[C:6]([Cl:5])[C:7]=1[C:8]([NH:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)=[O:10]
Reactant: O=C(O)c1c(Cl)cc(I)cc1Cl
Reactant: Nc1ccncc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccncc1)c1c(Cl)cc(I)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
Thionyl chloride (20 mL) was added to 2,6-dichloro-4-iodobenzoic acid (1.5 g, 4.73 mmol) and the mixture was heated to reflux for 5 h under nitrogen. After cooling the mixture was concentrated under reduced pressue. Toluene (10 mL) was added and the mixture was concentrated under reduced pressure again to remove residual thionyl chloride. The residue was dissolved in anhydrous THF (20 mL) and this was added dropwise to a cooled (0° C.) solution of 4-aminopyridine (0.53 g, 5.68 mmol) and triethylamine (1.32 mL, 9.46 mmol) in anhydrous THF (20 mL). After addition was complete, the mixture was stirred at room temperature under nitrogen overnight. The reaction was poured onto the ice water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hexanes/EtOAc=3:1) to afford the desired product (1.8 g, yield: 97%.) 1HNMR (DMSO-d6, 400 MHz): 611.14 (s, 1H), 8.47 (dd, J=1.6, 4.8 Hz, 2H), 8.03 (d, J=2.0 Hz, 2H), 7.59 (dd, J=1.6, 4.8 Hz, 2H). LCMS (ESI) m/z: 393.0 [M+H+].
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Cl[CH2:21][C:22]1[S:26][C:25]([CH3:27])=[N:24][C:23]=1[CH3:28].C([O-])([O-])=O.[K+].[K+].C1CCN2C(=NCCC2)CC1>CO>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21][C:22]1[S:26][C:25]([CH3:27])=[N:24][C:23]=1[CH3:28])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Reactant: Cc1nc(C)c(CCl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: Cc1nc(C)c(CN2C(=O)C(C)(C)c3cc(N)c([N+](=O)[O-])cc32)s1
Yield: 61.8 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (1.77 g) is alkylated using 5-chloromethyl-2,4-dimethyl-thiazole (1.09 g; 6.74 mmol) (Zh. Obshch. Khim. 1956, engl. transl. 3835) and K2CO3 (1.05 g; 7.41 mmol) at 60° C. for 3 days. After aqueous work-up the crude material is de-acetylated in MeOH (70 ml) using DBU (2.2 ml) at reflux. After aqueous work-up 5-amino-1-(2,4-dimethyl-thiazol-5-ylmethyl)-3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one (1.44 g) is obtained and used without further purification.
Reaction SMILES: C([BH3-])#N.[Na+].C(#N)C.[C:8]([C:10]1[CH:26]=[CH:25][C:13]([C:14]([C:16]2[N:24]3[C:19]([CH:20]=[CH:21][CH:22]=[CH:23]3)=[CH:18][CH:17]=2)=O)=[CH:12][CH:11]=1)#[N:9].C(OCC)(=O)C>CCCCCC>[C:8]([C:10]1[CH:11]=[CH:12][C:13]([CH2:14][C:16]2[N:24]3[C:19]([CH:20]=[CH:21][CH:22]=[CH:23]3)=[CH:18][CH:17]=2)=[CH:25][CH:26]=1)#[N:9]
Reactant: N#Cc1ccc(C(=O)c2ccc3ccccn23)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#Cc1ccc(Cc2ccc3ccccn23)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.4 %

Procedure:
Sodium cyanoborohydride (0.32 grams, 5.06 mmol) was added in portions to an acetonitrile (15 mL) solution of 3-(4-cyanobenzoyl)indolizine (13) (0.19 grams, 0.84 mmol) and chlorotrimethylsilanen (0.65 mL, 5.06 mmol) cooled in an ice-bath. The reaction mixture was stirred at room temperature for 4 hours. It was then quenched with aqueous sodium bicarbonate solution, extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with water, dried over sodium sulfate and concentrated in vacuo to give an oily residue, which was applied to the flash column chromatography using 10% ethyl acetate in hexane (Rf 0.3) to afford 3-(4-cyanobenzyl)indolizine (14) (0.11 grams, 56% yield). 1H NMR (CDCl3) δ 4.09 (s, 2H), 6.36 (m, 2H), 6.56 (m, 2H), 7.15 (d, J=8.4, 2H), 7.32 (d, J=9.3, 1H), 7.45 (m, 3H). ESMS calcd (C16H12N2): 232.1. found: 233.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH2:32]([OH:37])[CH2:33][CH2:34][C:35]#[CH:36].[NH4+].[Cl-]>CN(C=O)C.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.[Cu]I.O>[C:16]1(=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:36]#[C:35][CH2:34][CH2:33][CH2:32][OH:37])=[CH:3][CH:4]=2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Oc1ccc(C(=C2CCCCCC2)c2ccc(Br)cc2)cc1
Reactant: C#CCCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: OCCCC#Cc1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 45.1 %

Procedure:
To a degassed solution of 4-[(4-bromophenyl)(cycloheptylidene)methyl]phenol (9) (0.20 g, 0.56 mmol) in DMF (5 mL) were added Pd(PPh3)2Cl2 (40 mg, 0.06 mmol), CuI (11 mg, 0.06 mmol), N,N-diisopropylethylamine (0.45 mL, 2.52 mmol) and 4-pentyn-1-ol (0.11 mL, 1.12 mmol). The reaction mixture was stirred at 80° C. overnight, poured into saturated aqueous NH4Cl (15 mL) and water (5 mL), extracted with ethyl acetate (3×50 mL). The combined organic phase was washed with water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as brown oil. The crude product was purified by chromatography on a silica gel column eluted with a gradient from hexanes to 45% EtOAc in hexanes to give a light brown solid. The solid was triturated with hot hexanes containing 1% MeOH to afford 91 mg (45%) of the title compound (240) as beige solid. mp 125-126° C. 1H NMR (400 MHz, DMSO-d6): δ 1.49 (bs, 8H), 1.60-1.70 (m, 2H), 2.10-2.25 (m, 4H), 2.41 (t, J=7.0 Hz, 2H), 3.40-3.50 (m, 2H), 4.49 (t, J=5.2 Hz, 1H), 6.65 (d, J=8.4 Hz, 2H), 6.88 (d, J=8.4 Hz, 2H), 7.04 (d, J=8.0 Hz, 2H), 7.26 (d, J=8.2 Hz, 2H), 9.27 (s, 1H). LCMS (ESI): m/z 361 (M+H)+, 359 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[CH:13]([C:18]2[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=2)[C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].ClCCCl.CCN=C=NCCCN(C)C.Cl.Cl.[F:44][C:45]([F:53])([F:52])[CH2:46][NH:47][C:48]([NH:50][NH2:51])=[O:49]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[CH:13]([C:18]2[CH:19]=[C:20]([Cl:26])[C:21]([Cl:25])=[C:22]([Cl:24])[CH:23]=2)[C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:3]=1[C:4]([NH:51][NH:50][C:48]([NH:47][CH2:46][C:45]([F:53])([F:52])[F:44])=[O:49])=[O:5]
Reactant: NNC(=O)NCC(F)(F)F
Reactant: O=C(O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(NCC(F)(F)F)NNC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.9 %

Procedure:
To a solution containing (E)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoic acid (120 mg, 0.246 mmol), 1,2-dichloroethane (DCE) (5 mL) was added sequentially EDC.HCl (70.6 mg, 0.368 mmol), N-(2,2,2-trifluoroethyl)hydrazinecarboxamide hydrochloride (52.3 mg, 0.270 mmol) and DMAP (63.0 mg, 0.516 mmol). The reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with CH2Cl2, washed with 0.1N HCl then with aqueous NaHCO3, dried (MgSO4), filtered and evaporated to dryness. The crude product was purified by flash column chromatography afford the title compound as a glassy oil (40 mg, 26%): 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.65 (s, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.51 (d, J=6.4 Hz, 1H), 7.40 (s, 3H), 6.54 (d, J=15.8 Hz, 1H), 6.42 (dd, J=16.0, 7.7 Hz, 1H), 5.95 (s, 1H), 4.10 (s, 1H), 3.91 (m, 2H); 19F NMR (376 MHz, CDCl3) δ −68.56, −73.02; ESIMS m/z 627.9 ([M+H]+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(O)=O.CN.Cl.[BH3-][C:23]#[N:24].[Na+]>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:24][CH3:23])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNC1CCN(Cc2ccccc2)CC1
Reaction time: 2 h
Yield: 92 %

Procedure:
1-Benzylpiperidin-4-one (5.0 g, 26.315 mmol, 1.0 eq.) was dissolved in MeOH (78 ml); AcOH (0.2 ml) and CH3NH2.HCl (2.6 g, 39.47 mmol, 1.5 eq.) were added and stirring was carried out for 2 hours at RT. NaCNBH3 (3.3 g, 52.63 mmol, 2.0 eq.) was then added in portions at 0° C. and the mixture was stirred for 16 hours at RT. The reaction mixture was concentrated under reduced pressure. The residue was taken up in sat. sodium hydrogen carbonate solution (150 ml) and extracted with DCM (2×200 ml). The combined org. phases were dried over sodium sulfate, concentrated and used in the next stage without being purified further. Yield: 92% (5.0 g, 24.509 mmol)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.BrNC(=O)CCC(N)=O.NC1C(Br)=CC(C)=CN=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.CS(C)=O.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>[NH2:1][C:2]1[C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc(N)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1cnc(N)c(Br)c1
Agent: NC(=O)CCC(=O)NBr
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: Cc1cnc(N)c(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
2-amino-3-phenyl-5-methylpyridine was prepared as follows: 2-amino-5-picoline (10.8 g, 0.1 M) was dissolved in glacial acetic acid (200 ml), and N-bromosuccinamide (20 g, 0.11 M) was added. The reaction mixture was stirred at room temperature for 17 hours. The reaction mixture was poured onto ice/water and the solid removed by filtration. The filtrate was basified with solid sodium hydroxide, and the resulting precipitate was isolated by filtration (12.8 g). The product, 2-amino-3-bromo-5-methylpyridine (3.7 g, 20 mmol), was dissolved in anhydrous DMSO (100 ml) under an atmosphere of nitrogen. Phenylboronic acid (2.66 g, 22 mmol) was added, followed by the addition of potassium carbonate (9.66 g, 70 mmol) and bis(triphenylphosphine)-palladium(II) chloride (426 mg, 0.6 mmol). The reaction mixture was heated to 80° C. with stirring for 15 hours. The reaction was cooled, poured into ice/water, and the crude product was collected by filtration. The resultant material was treated with 1 M aqueous hydrochloric acid (200 ml), stirred for 10 minutes, and filtered to remove insoluble residues. The filtrate was basified with solid sodium hydroxide, and the resultant yellow precipitate was filtered and dried to provide the product, 2-amino-3-phenyl-5-methylpyridine, as a pale yellow solid (2.25 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:40][N:41]([C@@H:58]([C:66](=[O:69])[NH:67][CH3:68])[CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:42](=[O:57])[CH:43]([NH:55][CH3:56])[CH2:44][C:45]1[CH:54]=[CH:53][C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:46]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13](=[O:15])[N:55]([CH3:56])[C@@H:43]([C:42](=[O:57])[N:41]([CH3:40])[C@@H:58]([C:66](=[O:69])[NH:67][CH3:68])[CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[CH2:44][C:45]1[CH:54]=[CH:53][C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:46]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)C(Cc1ccc2ccccc2c1)NC
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 87.3 %

Procedure:
(2E)-5-(tert-Butyloxycarbonylamino)-5-methylhex-2-enoic acid (200 mg, 0.82 mmol), 1-hydroxy-7-azabenzotriazole (112 mg, 0.82 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (173 mg, 0.90 mmol) were dissolved in a mixture of methylene chloride (10 mL) and N,N-dimethylformamide (1 mL) and strirred for 15 min. N-Methyl-2-methylamino-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-3-(2-naphthyl)propionamide (332 mg, 0.82 mol) dissolved in methylene chloride (5 mL) and diisopropylethylamine (0.14 mL) were added and the mixture was stirred overnight under nitrogen atmosphere. The mixture was diluted with methylene chloride (50 mL), washed with water (50 mL), sodium hydrogen carbonate (30 mL, saturated), and sodium hydrogensulfate (30 mL, 5%). The phases were separated and the organic phase was dried with magnesium sulfate and evaporated in vacuo. The residue was chromatographed (silica, 2×40 cm) to afford 450 mg of ((3E)-1,1-dimethyl4-(N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)but-3-enyl)-carbamic acid tert-butyl ester.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:10]([CH3:11])=[C:9]([N:12]3[CH2:17][CH2:16][C:15](C)([CH3:18])[CH2:14][CH2:13]3)[N:8]=[C:7]([CH:20]3[CH2:22][CH2:21]3)[N:6]=2)[CH2:3][CH2:2]1.C1(NC2C(C)=C(N3CCC(C)CC3)N=C(C3CC3)N=2)CC1.C12CC(CC1)CN(C1N=C(C3CC3)N=C(NC3CC3)C=1C)C2.C1(NC2C(C)=C(N3CCSCC3)N=C(C3CC3)N=2)CC1.N1(C2C3CCCNC=3N=C(C3CC3)N=2)CCCCCC1.N1(C2C3CCCCNC=3N=C(C3CC3)N=2)CCCCCC1>>[N:12]1([C:9]2[N:8]=[C:7]([CH:20]3[CH2:21][CH2:22]3)[N:6]=[C:5]([NH:4][CH:1]3[CH2:2][CH2:3]3)[C:10]=2[CH3:11])[CH2:17][CH2:16][CH2:18][CH2:15][CH2:14][CH2:13]1
Reactant: Cc1c(NC2CC2)nc(C2CC2)nc1N1CCC(C)(C)CC1
Agent: C1CCCN(c2nc(C3CC3)nc3c2CCCCN3)CC1
Agent: C1CCCN(c2nc(C3CC3)nc3c2CCCN3)CC1
Agent: Cc1c(NC2CC2)nc(C2CC2)nc1N1CC2CCC(C2)C1
Product: Cc1c(NC2CC2)nc(C2CC2)nc1N1CCCCCC1

Procedure:
N,2-dicyclopropyl-6-(4,4-dimethyl-1-piperidinyl)-5-methyl-4-pyrimidinamine; N,2-dicyclopropyl-5-methyl-6-(4-methyl-1-piperidinyl)-4-pyrimidinamine; 6-(3-azabicyclo[3.2.1]oct-3-yl)-N,2-dicyclopropyl-5-methyl-4-pyrimidinamine; N,2-dicyclopropyl-5-methyl-6-(4-thiomorpholinyl)-4-pyrimidinamine; 4-azepan-1-yl-2-cyclopropyl-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidine and 4-azepan-1-yl-2-cyclopropyl-6,7,8,9-tetrahydro-pyrimido[4,5-b]azepine, or pharmaceutically acceptable salts thereof.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=4)=[O:21])=[CH:15][CH:14]=3)[C:9]([CH:11]=[CH2:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.C(O)(=O)C>C1COCC1.CCO>[NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=4)=[O:21])=[CH:15][CH:14]=3)[C:9]([CH2:11][CH3:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: C=Cc1cn2ncnc(N)c2c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccn2)cc1
Solvent: CC(=O)O
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1cn2ncnc(N)c2c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccn2)cc1

Procedure:
1-[4-(4-amino-6-vinylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-3-[4-(trifluoro-methyl)pyridin-2-yl]urea (150 mg, 0.341 mmol) was slowly dissolved in THF (100 mL) by adding acetic acid (10-20 mL). The solution was further diluted with EtOH (300 mL) and run through the H-Cube® apparatus at 20 bar, rt, 1 mL/min. The resulting solution was concentrated then washed with satd. NaHCO3. A precipitate formed and the desired product was collected by vacuum filtration to yield a tan solid. (150 mg, 99%). 1H-NMR (DMSO-d6) δ 11.89 (bs, 2H), 8.49 (d, J=5.0 Hz, 1H), 8.28 (s, 1H), 7.80 (s, 1H), 7.74 (d, J=8.8 Hz, 2H), 7.60 (s, 1H), 7.27 (m, 3H), 2.48 (q, J=7.8 Hz, 2H), 1.09 (t, J=7.5 Hz, 3H). MS [M+H]+=442.0; LCMS RT=2.95.
Reaction SMILES: [CH2:1]([N:4]1[C:8]2=[C:9]([N:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)[N:10]=[C:11]([C:13]([OH:15])=O)[CH:12]=[C:7]2[C:6]([CH3:26])=[C:5]1[CH3:27])[CH:2]=[CH2:3].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C.[CH3:60][C:61]1[CH:68]=[CH:67][C:64]([CH2:65][NH2:66])=[CH:63][CH:62]=1>ClCCl>[CH2:1]([N:4]1[C:8]2=[C:9]([N:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)[N:10]=[C:11]([C:13]([NH:66][CH2:65][C:64]3[CH:67]=[CH:68][C:61]([CH3:60])=[CH:62][CH:63]=3)=[O:15])[CH:12]=[C:7]2[C:6]([CH3:26])=[C:5]1[CH3:27])[CH:2]=[CH2:3]
Reactant: Cc1ccc(CN)cc1
Reactant: C=CCn1c(C)c(C)c2cc(C(=O)O)nc(N3CCc4ccccc4C3)c21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: C=CCn1c(C)c(C)c2cc(C(=O)NCc3ccc(C)cc3)nc(N3CCc4ccccc4C3)c21
Yield: 23.6 %

Procedure:
A solution of 1-allyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid (30 mg, 0.083 mmol) prepared in Example 732, 1-hydroxybenzotriazole hydrate (16.9 mg, 0.125 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (23.9 mg, 0.125 mmol), diisopropylethylamine (43,4 μl, 0.25 mmol), and 4-methylbenzylamine (15.9 μl, 0.125 mmol) in dichloromethane (1 ml) was stirred for 2 hours at room temperature and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/3, v/v) to give 9.1 mg of the titled compound as a white solid. (Yield: 45%).