Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[C:5]([Cl:8])=[N:6][CH:7]=1.[CH:12]([Mg]Br)=[CH:13][CH3:14]>O1CCCC1.CCOCC>[Br:1][C:2]1[CH:7]=[N:6][C:5]([Cl:8])=[C:4]2[NH:9][CH:12]=[C:13]([CH3:14])[C:3]=12
Reactant: CC=C[Mg]Br
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1c[nH]c2c(Cl)ncc(Br)c12
Temperature: -40 °C

Procedure:
To a solution of 5-bromo-2-chloro-3-nitro-pyridine, (10.28 g) in dry tetrahydrofuran (450 ml) at −78° C. under an atmosphere of nitrogen was added dropwise, a solution of 1-propenylmagnesium bromide (0.5M in tetrahydrofuran; 305 ml), keeping the internal temperature below −70° C. The solution was allowed to warm to −40° C. over 1 h then quenched with saturated ammonium chloride (350 ml). The aqueous was extracted twice with ethyl acetate (2×200 ml) and the combined organics were dried (MgSO4), filtered and evaporated to give a brown oil. The mixture was dissolved in ether, a solid filtered off then evaporated. The residue was dissolved in ether, loaded onto four Biotage silica samplets and purified by Biotage chromatography over silica gel (4×100 g), eluting with 10% ethyl acetate/isohexane (1 L) followed by 15% ethyl acetate/isohexane (1 L). The fractions containing product from the four columns were combined and evaporated to afford an orange solid. The orange solid was triturated with isohexane, filtered and washed with isohexane and dried to give the title compound as an off white solid. (1.07 g).
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Br[C:40]1[CH:41]=[C:42]([CH:49]=[CH:50][CH:51]=1)[C:43]([NH:45][CH:46]([CH3:48])[CH3:47])=[O:44]>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>[OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:50]2[CH:51]=[CH:40][CH:41]=[C:42]([C:43]([NH:45][CH:46]([CH3:48])[CH3:47])=[O:44])[CH:49]=2)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)NC(=O)c1cccc(Br)c1
Reactant: CC(C)C(O)(c1ccc(B(O)O)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(C)NC(=O)c1cccc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)c1
Yield: 44.8 %

Procedure:
By the reaction in the same manner as in Example 33-(ii) using 4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronic acid (3.40 g), 3-bromo-N-isopropylbenzamide (1.70 g) and tetrakis(triphenylphosphine)palladium(0) (0.220 g), the title compound (1.88 g) was obtained as a colorless amorphous powder.
Reaction SMILES: [C:1]([C:3]1[C:4]([F:24])=[CH:5][C:6]([O:22]C)=[C:7]([CH:21]=1)[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)=[O:9])#[N:2].B(Br)(Br)Br>ClCCl>[C:1]([C:3]1[C:4]([F:24])=[CH:5][C:6]([OH:22])=[C:7]([CH:21]=1)[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)=[O:9])#[N:2]
Reactant: COc1cc(F)c(C#N)cc1C(=O)NCc1cccc([N+](=O)[O-])c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#Cc1cc(C(=O)NCc2cccc([N+](=O)[O-])c2)c(O)cc1F
Temperature: 25 °C
Yield: 58.6 %

Procedure:
To a stirring solution of [5-cyano-4-fluoro-2-methoxy-N-(3-nitro-benzyl)-benzamide (1.5 g, 4.6 mmol) in dichloromethane (200 mL, 0.3 M) at −78° C. was added BBr3 (21.5 mL, 21.4 mmol). the mixture was allowed to'stir for 45 min at −78° C. and the dry ice/acetone bath was then removed and the solution was allowed to warm to room temperature. Then, the solution was cooled down again to −78° C. and was then quenched with 100 mL of methanol. The mixture was allowed to warm to room temperature and concentrated. Purification by MPLC (10-100% ethyl acetate, 23 mL/min, 75 min) provided 5-cyano-4-fluoro-2-hydroxy-N-(3-nitro-benzyl)-benzamide (0.85 g, 59%) as a beige powder: Rf 0.37 (70% ethyl acetate in heptane); 1H NMR (DMSO-d6, 300 MHz) δ 9.50 (bd s, 1H), 8.39 (d, J=7.5 Hz, 1H), 8.20 (s, 1H), 8.12 (d, J=9.3 Hz, 1H), 7.80 (d, J=7.2 Hz, 1H), 7.63 (t, J=7.8 Hz, 1H), 7.04 (d, J=11.1 Hz, 1H), 4.62 (s, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:32]([CH3:34])[CH3:33])[C:6]2[O:10][C:9]([C:11]3[CH:30]=[CH:29][C:14]([C:15]([NH:17][CH2:18]OC(N4CCCOCC4)=O)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:31]=1)#[N:2].[CH3:35][OH:36]>[Pd]>[C:1]([C:3]1[CH:4]=[C:5]([CH:32]([CH3:34])[CH3:33])[C:6]2[O:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([NH:17][CH2:18][C@H:5]4[O:36][CH2:35][CH2:9][NH:8][CH2:7][CH2:6]4)=[O:16])=[CH:29][CH:30]=3)=[N:8][C:7]=2[CH:31]=1)#[N:2]
Reactant: CO
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCOC(=O)N4CCCOCC4)cc3)oc12
Agent: [Pd]
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@@H]4CCNCCO4)cc3)oc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a solution of benzyl(7S)-7-({[4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoyl]amino}methyl-1,4-oxazepane-4-carboxylate (211 mg) in 30 ml methanol was added 10% palladium on carbon (40 mg). The mixture was stirred under an atmosphere of hydrogen (via balloon) overnight at room temperature. The mixture was then filtered through a small plug of Celite and concentrated in vacuo to provide the title compound (133 mg, 83%). Mass spectrum (ESI) 419.3 (M+1).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19]>>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[NH:1][C:2](=[O:11])[CH2:3][CH2:4]2)=[O:19]
Reactant: O=C(Cl)CCCCCBr
Reactant: O=C1CCc2ccccc2N1
Product: O=C1CCc2cc(C(=O)CCCCCBr)ccc2N1

Procedure:
Using 3,4-dihydroquinolin-2(1H)-one (2.94 g) and 6-bromohexanoyl chloride (5.1 g) according to the same method as that of Reference Example 1, the title compound was obtained as colorless crystals (1.62 g) having a melting point of 116 to 117° C.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4](Br)=[N:5][N:6]=1.[C:8]1([OH:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.C(Cl)(Cl)Cl>[Br:1][C:2]1[S:3][C:4]([O:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][N:6]=1
Reactant: Oc1ccccc1
Reactant: Brc1nnc(Br)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: Brc1nnc(Oc2ccccc2)s1
Temperature: 25 °C

Procedure:
A solution of 2,5-dibromo-1,3,4-thiadiazole (1.00 g, 4.10 mmol; prepared as described in Yasuda, T.; Imase, T.; Sasaki, S.; Yamamoto, T. Macromolecules 2005, 38, 1500) and phenol (188 mg, 2.00 mmol; Aldrich) in anhydrous tetrahydrofuran (4 mL) was treated with cesium carbonate (2.0 g, 6.0 mmol) and heated to reflux for 5 hours. The mixture was cooled to room temperature, diluted with chloroform, filtered through Celite, and the residue was purified by flash chromatography (Analogix 40×120 mm 80 g silica gel column, chloroform) to afford the title compound: 1H NMR (300 MHz, chloroform-D) δ ppm 7.28-7.35 (m, 3H), 7.41-7.49 (m, 2H). MS (+ESI) m/z=257/259 (M+H)+.
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]1([N:13]=[C:14]=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[CH2:16]([NH2:19])[CH2:17][NH2:18]>CCCCC>[CH2:16]([NH:19][C:14]([NH:13][C:7]1([N:6]=[N:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:15])[CH2:17][NH:18][C:14]([NH:13][C:7]1([N:6]=[N:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:15]
Reactant: NCCN
Reactant: CC(C)(C)N=NC1(N=C=O)CCCCC1
Solvent: CCCCC
Product: CC(C)(C)N=NC1(NC(=O)NCCNC(=O)NC2(N=NC(C)(C)C)CCCCC2)CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 8.4 grams (0.0402 moles) of 1-t-butylazo-1-isocyanatocyclohexane stirred with a magnetic stirrer in a 50 ml erlenmeyer flask was added 1.57 grams (0.0201 moles) of ethylenediamine. Solids formed and the reaction mixture was diluted with pentane and stirred for 3 hours at room temperature. The pentane was stripped from the reaction mixture leaving a semi-solid. The semi-solid was slurried in cold pentane and filtered. The white solid filter cake was air dried and weighed 10.0 grams (75% crude yield). The product melted at 165°-167° C. with decomposition. The infrared spectrum of the product contained a strong carbonyl band at 1670 cm-1 and NH bands at 3300 and 3340 cm-1. The isocyanate band at 2225 cm-1 was absent.
Reaction SMILES: I[C:2]1[S:6][C:5]([C:7]2([O:11][CH2:12][C:13]([O:15][CH2:16]C)=[O:14])[CH2:10][CH2:9][CH2:8]2)=[N:4][CH:3]=1.[F-].[Cs+].CC1(C)C(C)(C)OB([C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=2)O1.C(COC)OC>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.CO>[NH2:32][C:31]1[CH:33]=[CH:34][C:28]([C:2]2[S:6][C:5]([C:7]3([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:8][CH2:9][CH2:10]3)=[N:4][CH:3]=2)=[CH:29][CH:30]=1
Reactant: CCOC(=O)COC1(c2ncc(I)s2)CCC1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: COCCOC
Product: COC(=O)COC1(c2ncc(-c3ccc(N)cc3)s2)CCC1
Temperature: 90 °C

Procedure:
A solution of Example 24A (0.750 g, 2/04 mmol), CsF (0.930 g, 6.12 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.447 g, 2.04 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.231 g, 0.200 mmol) in a solvent mixture of dimethoxyethane (5 mL) and methanol (5 mL) was heated to 90° C. for 16 h. The reaction was cooled to room temperature and partitioned between H2O (10 mL) and ethyl acetate (10 mL). The layers were separated, and the aqueous was extracted with additional ethyl acetate (2×10 mL). The combined organics were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 gel, eluting with a gradient of 10% ethyl acetate in hexane to 50% ethyl acetate in hexane, to give the title compound. MS (ESI) m/z 319 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([Si](C)(C)C)[Si](C)(C)C)=[CH:4][CH:3]=1.[Li]CCCC.[O:22]=[C:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1>O1CCCC1>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:23]2([OH:22])[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[CH2:27][CH2:28]2)=[CH:3][CH:4]=1
Reactant: C[Si](C)(C)N(c1ccc(Br)cc1)[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(N)cc2)CC1
Temperature: -78 °C

Procedure:
N-(4-Bromophenyl)-1,1,1-trimethyl-N-(trimethylsilyl)silanamine (7 g, 22.12 mmol) in tetrahydrofuran (100 mL) was treated with a solution of n-BuLi (1M, 22 mL) at −78° C. The reaction mixture was stirred an additional hour at −78° C. and then treated with a solution of tert-butyl 4-oxopiperidine-1-carboxylate (3.97 g, 19.91 mmol) in tetrahydrofuran (20 mL). The reaction mixture was stirred at −78° C. for 30 minutes and then warmed to room temperature. The reaction was quenched by addition of saturated ammonium chloride solution (100 mL) and then was extracted with ethyl acetate. The combined organics were washed with water, brine, dried with magnesium sulfate, filtered and concentrated. The crude tert-butyl 4-(4-(bis(trimethylsilyl)amino)phenyl)-4-hydroxypiperidine-1-carboxylate was treated with a solution of tetrabutylammonium fluoride (1M THF, 40 mL) at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The organics were washed with water and brine, dried with magnesium sulfate, filtered and concentrated. Purification by normal phase chromatography provided the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]3[NH:20][N:19]=[N:18][N:17]=3)[CH2:15][C@@:9]1([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@H:10]([O:21][C@H:22]([C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=1)[CH2:23][O:24][CH3:25])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:48](=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]3[NH:17][N:18]([CH3:48])[NH:19][N:20]=3)[CH2:15][C@@:9]1([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@H:10]([O:21][C@H:22]([C:26]1[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[C:28]([C:36]([F:38])([F:39])[F:37])[CH:27]=1)[CH2:23][O:24][CH3:25])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC[C@H](O[C@@H]1CC[C@H]2[C@H](c3nnn[nH]3)C[C@]1(c1ccccc1)N2Cc1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COC[C@H](O[C@@H]1CC[C@H]2[C@H](C3=NNN(C)N3)C[C@]1(c1ccccc1)N2Cc1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
(1R*,2R*,5S*,6R*)-8-Benzyl-2-{(1R*)-1-[3,5-bis(trifluoromethyl)phenyl]-2-methoxyethoxy}-1-phenyl-6-(tetrazol-5-yl)-8-azabicyclo[3.2.1]octane (Example 199; 0.05 g, 0.1 mmol), methyl iodide (0.04 g 0.02 ml, 0.3 mmol) and potassium carbonate (0.04 g, 0.3 mmol) in acetonitrile were heated at 60° C. for 1.5 hours. The mixture was quenched with water and concentrated in vacuo, the residue was partitioned between water and dichloromethane using a bond elute cartridge. The organics were collected and concentrated in vacuo and the residue purified by preparative thin layer chromatography eluting with 5% methanol/dichloromethane. The title compound was isolated as a white solid (33 mg, 58%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[Cl:9].[NH2:10][C:11]1[CH:12]=[C:13]2[C:17]3=[C:18]([CH2:20][S:21][CH2:22][CH2:23][N:16]3[C@H:15]3[CH2:24][CH2:25][N:26](C(OC(C)(C)C)=O)[CH2:27][C@@H:14]23)[CH:19]=1>>[Cl:9][C:3]1[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=1[NH:10][C:11]1[CH:12]=[C:13]2[C:17]3=[C:18]([CH2:20][S:21][CH2:22][CH2:23][N:16]3[C@H:15]3[CH2:24][CH2:25][NH:26][CH2:27][C@@H:14]23)[CH:19]=1
Reactant: Clc1cccc(Br)c1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCSC3
Product: Clc1cccc(Nc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCSC3)c1Cl

Procedure:
Using 1-bromo-2,3-dichlorobenzene and following the procedures described in EXAMPLE 33, Parts C and D, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 33, Part B was converted into the title compound of EXAMPLE 37 as a powder. 1H NMR(CDCl3, 300 MHz) δ 1.79-1.89 (m, 2H), 2.58-2.69 (m, 1H), 2.79-3.25 (m, 7H), 3.41-3.50 (m, 1H), 3.60-3.68 (m, 2H), 3.74 (s, 2H), 6.01 (s, 1H), 6.73 (d, 1H, J=2 Hz), 6.81-6.85 (m, 3H), 6.95-6.98 (m 1H). LRMS (ES)+: 406 (M+H)+.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C-:12]#[N:13].[K+].C1OCCOCCOCCOCCOCCOC1.Cl>CS(C)=O>[C:12]([C:2]1[S:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1)#[N:13]
Reactant: [C-]#N
Reactant: Oc1ccc2nc(Cl)sc2c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1nc2ccc(O)cc2s1
Temperature: 120 °C

Procedure:
4 g. of the mixture of 2-chloro-6-hyroxybenzothiazole and 2-iodo-6-hydroxybenzothiazole obtained in Example 2 are added to a suspension of 3 g. potassium cyanide and 100 mg. 18-crown-6 in 150 ml. dimethyl sulphoxide heated to 120° C. and stirred at a bath temperature of 120° C. After a reaction time of 3 hours, the reaction mixture is poured in 1 liter of ice water and the solution obtained is acidified with dilute hydrochloric acid. Subsequently, it is extracted twice with 500 ml. amounts of diethyl ether and the extracts are washed with water, dried over anhydrous sodium sulphate, mixed with charcoal, filtered and the filtrate evaporated in a vacuum. 2.5 g. Crude 2-cyano-6-hydroxybenzothiazole are obtained.
Reaction SMILES: C([N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=O)=CCC.C(OC)(=O)[C:12]1[CH:17]=[CH:16][CH:15]=[N:14][CH:13]=1>CN(C=O)C>[CH:16]1[CH:15]=[N:14][CH:13]=[C:12]([C:6]2[CH2:7][CH2:8][CH2:9][N:5]=2)[CH:17]=1
Reactant: COC(=O)c1cccnc1
Reactant: CCC=CN1CCCC1=O
Solvent: CN(C)C=O
Product: c1cncc(C2=NCCC2)c1
Temperature: 90 °C
Yield: 76.9 %

Procedure:
Sodium hydride (17.26 g, 072 mol of 60% dispersion in a mineral oil) was washed with toluene (25 ml×2) to remove mineral oil and added to 25 ml of DMF. To this a solution containing 1-(but-1-enyl)-pyrrolidin-2-one (I, 50 g, 0.3597 mol) and methyl nicotinate (41.8 g, 0.3057 mol) in 50 ml of DMF was added. The reaction mixture was heated to 90° C. for 2 hrs. DMF was partially removed under reduced pressure and 100 ml water and HCl (165 ml) were added. The reaction mixture was heated to 110° C. for 12 hr, cooled and washed with ethyl acetate (50 ml×2). The aqueous layer was cooled to 0° C., pH adjusted to about 14 using NaOH, extracted with dichloromethane (100 ml×4), the extract dried over Na2SO4, the solvent removed completely and the crude solid was purified by high vacuum distillation to get myosmine (34.38 g, 77.2% yield, 98.5% purity by GC).
Reaction SMILES: CO[C:3]1[CH:4]=[C:5](CCCCCCCCC2C=CC(N)=CC=2)[C:6]2[C:11]([C:12]=1OC)=[CH:10][CH:9]=[CH:8][CH:7]=2.CCN(CC)CC.Cl[C:38]1[C:39]2[C:44]([N:45]=[C:46]3[C:51]=1[CH:50]=[CH:49][CH:48]=[CH:47]3)=[CH:43][CH:42]=[CH:41][CH:40]=2>CO>[C:10]1([C:40]2[C:39]3[C:44](=[N:45][C:46]4[C:51]([CH:38]=3)=[CH:50][CH:49]=[CH:48][CH:47]=4)[CH:43]=[CH:42][CH:41]=2)[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][CH:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cc(CCCCCCCCc2ccc(N)cc2)c2ccccc2c1OC
Reactant: Clc1c2ccccc2nc2ccccc12
Solvent: CO
Solvent: CCN(CC)CC
Product: c1ccc2nc3cccc(-c4cccc5ccccc45)c3cc2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 153 %

Procedure:
To a solution of 99 mg (2.53×10−4 mol) of 1-(3,4-dimethoxy-1-naphthyl)-8-(4-aminophenyl)-octane 37 and 35 mL (2.51×10−4 mol) of Et3N in 4 mL of MeOH were added 54 mg (2.53×10−4 mol) of 9-chloroacridine. The reaction mixture was stirred at room temperature for 20 hr. Evaporation of solvent and column chromatography on silica gel with first 1% MeOH in CH2Cl2 and then 3% MeOH in CH2Cl2 afforded 118.2 mg (82%) of acridine 38: 1H NMR (250 MHz, CDCl3, TMS) δ8.14 (d, J=8 Hz, 1H), 8.0-7.9 (m, 5H), 7.66 (br t, 2H), 7.46 (t, J=8 Hz), 7.37 (t, J=8 Hz, 1H), 7.3-7.2 (m, 2H), 7.12 (s, 1H), 7.06 (d, J=8.4 Hz, 2H), 6.82 (d, J=8.4 Hz, 2H), 3.1-3.0 (m, 2H), 2.6-2.5 (m, 2H), 1.8-1.3 (m, 12H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:22][N:23]([CH3:31])[CH2:24]/[CH:25]=[C:26](\[CH3:30])/[C:27]([O-])=[O:28].[Li+].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>O1CCCC1>[CH3:22][N:23]([CH3:31])[CH2:24]/[CH:25]=[C:26](\[CH3:30])/[C:27]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1)=[O:28]
Reactant: C/C(=C\CN(C)C)C(=O)[O-]
Reactant: CCOC(=O)c1c[nH]c2ncnc(-c3cccc(N)c3)c12
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c[nH]c2ncnc(-c3cccc(NC(=O)/C(C)=C/CN(C)C)c3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To ethyl 4-(3-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (100 mg, 0.354 mmol) was added tetrahydrofuran (3.54 mL), TEA (74 μl, 0.53 mmol), lithium (2E)-4-(dimethylamino)-2-methylbut-2-enoate (137 mg, 0.920 mmol) and 1-propanephosphonic acid cyclic anhydride (211 μL, 0.354 mmol). The reaction was stirred at 25° C. overnight and then extracted from aqueous sodium hydrogen carbonate (5%) using ethyl acetate (×3). The organic layers were combined and dried with Na2SO4, filtered, and evaporated in vacuo. The crude product was then taken up in 2 mL of methanol and purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA modifier. Lyophilization of the desired fractions afforded the title compound as a colorless solid. LRMS (ESI) calc'd for C22H26N5O3 [M+H]+: 408, found 408. 1H NMR (600 MHz, DMSO-D6) 13.06 (bs, 1H), 10.04 (s, 1H), 9.76 (bs, 1H), 8.96 (s, 1H), 8.36 (d, 1H, J=2.8 Hz), 8.08 (s, 1H), 7.85 (dm, 1H, J=9.0 Hz), 7.47 (t, 1H, J=7.8 Hz), 7.36 (dm, 1H, J=7.8 Hz), 6.33 (t, 1H, J=7.2 Hz), 3.98 (apparent t, 1H, J=7.2 Hz), 3.91 (q, 2H, J=7.2 Hz), 2.89 (s, 3H), 2.88 (s, 3H), 2.02 (s, 3H), 0.90 (t, 3H, J=7.2 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH:4]=[CH:5][CH2:6]O.P(Br)(Br)[Br:13]>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH:4]=[CH:5][CH2:6][Br:13]
Reactant: BrP(Br)Br
Reactant: OCC=Cc1ccccc1Br
Solvent: ClC(Cl)(Cl)Cl
Product: BrCC=Cc1ccccc1Br
Temperature: 0 °C
Yield: 85 %

Procedure:
All of the o-bromocinnamylalcohol (159 mM) from Step A was dissolved in 300 ml of carbon tetrachloride under nitrogen and chilled to 0°. Then 100 ml of carbon tetrachloride containing phosphorous tribromide (5.62 ml; 59.8 mM) was added dropwise. After stirring at 0° for an additional hour the reaction was poured into ice water and partitioned. The aqueous layer was extracted once with methylene chloride and the combined organic layers were washed with cold 1.5 N aqueous sodium hydroxide. Drying over magnesium sulfate followed by solvent removal gave a pale yellow oil, which was purified by short path distillation at 0.2 ton. The o-bromocinnamyl bromide was distilled at 105° and 37.3 g (85% yield) was isolated. NMR (CDCl3): δ6.8-7.7 (m; 5H); 6.33 (AB:1H); 4.15 (d; 2H).
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:6]([O:8]N1C(=O)CCC1=O)=O)[CH:3]([CH3:5])[CH3:4].[NH2:23][C@H:24]([C:40]([O:42][CH3:43])=[O:41])[CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].Cl.C(N(CC)CC)C>C1COCC1>[NH:1]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[C@H:2]([C:6]([NH:23][C@H:24]([C:40]([O:42][CH3:43])=[O:41])[CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])=[O:8])[CH:3]([CH3:4])[CH3:5]
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Reaction time: 17 h
Yield: 99.3 %

Procedure:
A mixture of t-Boc-Val-OSu (3.14 g, 10 mmol) and H-Lys(CBZ)-OCH3.HCl (3.31 g, 10 mmol) in THF (300 ml) was treated at room temperature with triethylamine (1.38 ml) and left stirring for 17 hr. The resulting solution was evaporated in vacuo and the residue was dissolved in EtOAc (500 ml). The organic solution was washed successively with water (2×200 ml), 5% citric acid (2×200 ml), water (2×200 ml) and dried over Na2SO4. The dried solution was filtered and evaporated in vacuo to give (VI) (4.9 g; 99%) as a foam. T.l.c. RfE4 =0.64.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].CO[CH:18]1[CH2:22][CH2:21][CH:20](OC)O1>C(O)(=O)C>[N:1]1([C:2]2[N:6]([C:7]([CH3:8])([CH3:9])[CH3:10])[N:5]=[CH:4][C:3]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:18]=[CH:22][CH:21]=[CH:20]1
Reactant: COC1CCC(OC)O1
Reactant: CCOC(=O)c1cnn(C(C)(C)C)c1N
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn(C(C)(C)C)c1-n1cccc1
Yield: 85.6 %

Procedure:
8.45 g of ethyl 5-amino-1-t-butyl-1H-pyrazole-4-carboxylate was dissolved in 60 ml of acetic acid, and 7.93 g of 2,5-dimethoxytetrahydrofuran was then added. The mixture was heated to reflux for 2 hours. The reaction mixture was concentrated under reduced pressure. After water was added, the residue was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 8.95 g of ethyl 5-(1H-pyrrol-1-yl)-1-t-butyl-1H-pyrazole-4-carboxylate.