Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]([CH2:12][C:13]([OH:15])=O)[CH:10]=[N:11][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].[NH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2([C:28]#[N:29])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1)[CH3:18].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC#N.O>[C:1]([C:3]1[C:8]2[N:9]([CH2:12][C:13]([NH:16][CH:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4([C:28]#[N:29])[CH2:26][CH2:27]4)=[CH:21][CH:20]=3)[CH3:18])=[O:15])[CH:10]=[N:11][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1cccc2ncn(CC(=O)O)c12
Reactant: CC(N)c1ccc(C2(C#N)CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(NC(=O)Cn1cnc2cccc(C#N)c21)c1ccc(C2(C#N)CC2)cc1

Procedure:
2-(7-Cyano-1H-benzimidazol-1-yl)-N-{1-[4-(1-cyanocyclopropyl)phenyl]ethyl}acetamide is synthesized according to example 5 by mixing (7-cyano-1H-benzimidazol-1-yl)acetic acid (86.5 mg, 0.430 mmol) prepared according to scheme 3, 1-[4-(1-aminoethyl)phenyl]cyclopropanecarbonitrile (80.0 mg, 0.430 mmol) prepared according to scheme 10, Et3N (131 mg, 1.29 mmol, 0.180 mL) and HATU (163 mg, 0.430 mmol) in MeCN (10.0 mL). The product is purified by HPLC: Gilson prep pumps, Flow rate: 30 ml/min, Column: Synergi Polar (5μ) 21.2×50 mm, Mobile phase: A=water (0.05% TFA) B=MeCN, (23.0 mg, 0.0623 mmol, 14%). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.35 (dd, J=7.81, 5.47 Hz, 2H) 1.49 (d, J=7.03 Hz, 3H) 1.68 (dd, J=7.42, 5.08 Hz, 2H) 5.00-5.13 (m, 3H) 6.65 (d, J=7.42 Hz, 1H) 7.22 (d, J=8.59 Hz, 2H) 7.29 (d, J=8.20 Hz, 2H) 7.33 (d, J=7.81 Hz, 1H) 7.59 (d, J=7.62 Hz, 1H) 7.96-8.06 (m, 2H); MS [M+H], calcd: 370.0. found: 370.0.
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[N:13]=[N:14][C:15](Cl)=[CH:16][CH:17]=2)[CH:7]=1)[C:3](=[O:5])[CH3:4].[CH2:19]([NH:21][C:22](=S)[NH:23][NH2:24])[CH3:20]>C(O)C>[CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]3[N:14]([C:22]([NH:21][CH2:19][CH3:20])=[N:23][N:24]=3)[N:13]=2)[CH:7]=1)[C:3](=[O:5])[CH3:4]
Reactant: CCNC(=S)NN
Reactant: CC(=O)N(C)c1cccc(-c2ccc(Cl)nn2)c1
Solvent: CCO
Product: CCNc1nnc2ccc(-c3cccc(N(C)C(C)=O)c3)nn12

Procedure:
A solution of 6.0 g -N-methyl-N-[3-(6-chloro-3-pyridazinyl)phenyl]acetamide and 5.5 g 4-ethyl-3-thiosemicarbazide in 200 ml ethanol was refluxed for 18 hours and treated in similar fashion to Example 67. Chromatography on silica gel and recrystalization from dichloromethanehexane afforded 1.2 g yellow crystals, mp 225°-227° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH2:10]([SH:14])[CH2:11][CH2:12][CH3:13].C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[CH3:8][C:6]1[CH:7]=[C:2]([S:14][CH2:10][CH2:11][CH2:12][CH3:13])[CH:3]=[C:4]([CH3:9])[CH:5]=1
Reactant: CCCCS
Reactant: Cc1cc(C)cc(I)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: CCCCSc1cc(C)cc(C)c1
Yield: 94.7 %

Procedure:
The general procedure in example 39 was followed. 5-Iodo-m-xylene (144 μL, 1.0 mmol), 1-butanethiol (107 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-propanol (1.0 mL) were used to obtain the n-butyl 3,5-dimethylphenyl sulfide (184 mg, 95% yield) as colorless oil. Column chromatographic solvent (hexane). Rf=0.5 (hexane). 1H NMR (CDCl3, 300 MHz) δ 6.92 (s, 2 H), 6.77 (s, 1 H), 2.89 (t, 2 H, J=7.2 Hz), 2.27 (s, 6 H), 1.41-1.65 (m, 4 H), 0.92 (t, 3 H, J=7.5 Hz). 13C NMR (CDCl3, 75 MHz) δ 138.5, 136.7, 127.7, 126.6, 33.5, 31.6, 22.4, 21.7, 14.1. IR (neat, cm−1) 3083, 3050, 3011, 2965, 2867. MS (EI) m/z (relative intensity) 194 (70), 138 (100). Anal Cald for C12H18S, Cald. C: 74.16, H: 9.34; Found C: 73.89, H: 9.32.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[O:9])=[C:6]([CH3:19])[CH:5]=[C:4](Cl)[N:3]=1.[NH:21]1[CH2:26][CH2:25][S:24][CH2:23][CH2:22]1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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>[Cl:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[O:9])=[C:6]([CH3:19])[CH:5]=[C:4]([N:21]2[CH2:26][CH2:25][S:24][CH2:23][CH2:22]2)[N:3]=1
Reactant: C1CSCCN1
Reactant: Cc1cc(Cl)nc(Cl)c1C(=O)NCc1cccc(F)c1
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: [Cs+]
Solvent: C1COCCO1
Product: Cc1cc(N2CCSCC2)nc(Cl)c1C(=O)NCc1cccc(F)c1
Temperature: 120 °C
Yield: 49.1 %

Procedure:
A solution of 700 mg (2.24 mmol) 2,6-dichloro-N-(3-fluorobenzyl)-4-methyl-pyridine-3-carboxylic acid amide (synthesis is described in section a) of example 2), 280 μl (2.9 mmol) thiomorpholine and 3.95 g (12.1 mmol) Cs2CO3 in dioxane (60 ml) was degassed for 30 min followed by the addition of 285 mg (0.25 mmol) Pd(PPh3)4. Subsequently the reaction solution was heated to 120° C. for 16 h. Then the mixture was filtered through celite and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 19:1) provided 420 mg (1.1 mmol, 49%) 2-chloro-N-(3-fluorobenzyl)-4-methyl-6-thiomorpholino-pyridine-3-carboxylic acid amide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[C:13]1[CH:14]=[C:15]([CH2:19][N:20]2[CH:24]=[CH:23][N:22]=[C:21]2[CH3:25])[N:16]=[N:17][CH:18]=1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:14]=[C:15]([CH2:19][N:20]3[CH:24]=[CH:23][N:22]=[C:21]3[CH3:25])[N:16]=[N:17][CH:18]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Product: Cc1nccn1Cc1cc(-c2cc(Cl)cc(Cl)c2)cnn1
Product: Cl

Procedure:
The title compound, MS: m/e=319.3 (M+H+), was prepared from 3,5-dichlorobenzeneboronic acid and 5-chloro-3-(2-methyl-imidazol-1-ylmethyl)-pyridazine.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]#N)[CH:5]=[C:4]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[N:3]=1.S(=O)(=O)(O)[OH:16].[OH2:20]>>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([OH:16])=[O:20])[CH:5]=[C:4]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[N:3]=1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cc(-c2ccco2)nc(N)n1
Reactant: O
Product: Nc1nc(C(=O)O)cc(-c2ccco2)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A suspension of 2-amino-6-(2-furyl)pyrimidine-4-carbonitrile (7.06 g, 37.9 mmol) in water (30 mL) was treated carefully with concentrated sulfuric acid (30 mL), stirred at 100° C. for 2 h, allowed to cool to room temperature and poured onto a mixture of ice (150 g) and water (150 mL). After standing for 1 h the crude product was filtered off, washed with water and MeCN, and dried in air to give the title compound (7.02 g, 90%) as a brown solid; NMR δH (400 MHz, DMSO) 6.71 (1H, dd, J 1.6, 3.6 Hz), 7.04 (2H, br s), 7.30 (1H, d, J 3.6 Hz), 7.36 (1H, s) and 7.94 (1H, d, J 1.2 Hz); Anal. Calc for C9H7N3O3.1.6H2O: C, 46.20; H, 4.39; N, 17.96. Found: C, 46.22; H, 4.22; N, 17.82.
Reaction SMILES: [CH:1]([NH:4]C(C)C)(C)[CH3:2].C([Li])CCC.C(#N)C.[F:16][C:17]([F:27])([F:26])[C:18]1[N:23]=[C:22]([C:24]#[N:25])[CH:21]=[CH:20][CH:19]=1>C1COCC1.O>[NH2:25][C:24]([C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([C:17]([F:26])([F:16])[F:27])[N:23]=1)=[CH:2][C:1]#[N:4]
Reactant: N#Cc1cccc(C(F)(F)F)n1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: CC#N
Solvent: C1CCOC1
Product: N#CC=C(N)c1cccc(C(F)(F)F)n1
Temperature: 25 °C
Yield: 89 %

Procedure:
A solution of 2.08 ml (13.07 mmol) diisopropylamine in dry THF (12 ml) was cooled to −70° C. under inert gas atmosphere, and 9.26 ml (14.8 mmol) n-butyllithium solution (1.6 M in hexanes) were added dropwise. Then, a solution of 688 μl (13.07 mmol) acetonitrile in dry THF (10 ml) was slowly added over 10 min. The resulting solution was stirred for further 30 min at −70° C. before a solution of 1.50 g (8.72 mmol) 6-(trifluoromethyl)pyridine-2-carbonitrile in dry THF (10 ml) was added. The mixture was allowed to warm to room temperature and stirred for 12 h before water (200 ml) was added slowly. The mixture was extracted several times with dichloromethane (100 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to yield 1.2 g (57% of th.) of the crude title compound (89% purity) which was used in the next step without further purification.
Reaction SMILES: Cl[CH2:2][CH:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][N:10]=2)[CH2:4]1.[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C)C=O.O>[N:16]([CH2:2][CH:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][N:10]=2)[CH2:4]1)=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1OC(CCl)CN1c1ccc(Cl)cn1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCC1CN(c2ccc(Cl)cn2)C(=O)O1
Yield: 66.4 %

Procedure:
A mixture of 5-(chloromethyl)-3-(5-chloropyridin-2-yl)-1,3-oxazolidin-2-one (204 mg, INTERMEDIATE 1) and sodium azide (107 mg) was heated to 100° C. in 10 ml of dimethylformamide for 15 h. The sample was then diluted with 100 ml of water and extracted with 100 ml of ethyl acetate (3×). The combined organic layers were washed with water (100 ml) and brine (100 ml). They were then dried over sodium sulfate and concentrated in vacuo to provide 139 mg (67%) of the title compound in >95% purity via LC/MS. Mass spectrum (ESI) 254.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:6]=[C:5]([F:18])[C:3]=1[NH2:4].[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1[N:30]=[C:31]=[O:32]>C1COCC1>[F:18][C:5]1[CH:6]=[C:7]([B:9]2[O:13][C:12]([CH3:14])([CH3:15])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:8]=[C:2]([F:1])[C:3]=1[NH:4][C:31]([NH:30][C:21]1[CH:22]=[C:23]([C:26]([F:27])([F:29])[F:28])[CH:24]=[CH:25][C:20]=1[F:19])=[O:32]
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: CC1(C)OB(c2cc(F)c(N)c(F)c2)OC1(C)C
Solvent: C1CCOC1
Product: CC1(C)OB(c2cc(F)c(NC(=O)Nc3cc(C(F)(F)F)ccc3F)c(F)c2)OC1(C)C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a solution of 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.300 g, 1.18 mmol) in THF (2 mL) was added 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene (0.314 g, 1.53 mmol). The reaction was stirred at 45 C overnight. Solid product was present in the reaction vessel. Product was further precipitated by the addition of 1:3 ether/hexanes. The solids were collected by filtration, dried under hi vacuum and found to be clean title compound in 71% yield. 1H-NMR (DMSO-d6) δ 7.03 (dd, J=6.6, 1.8 Hz, 2H), 5.76 (s, 2H), 1.26 (s, 12H); MS [M+H]+=461.2, LCMS RT=4.11 min.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:12])[C:6]=1[CH2:7][CH2:8][C:9](O)=[O:10].[C:13](N1C=CN=C1)([N:15]1C=CN=[CH:16]1)=O.CNC.C(N(CC)C(C)C)(C)C>ClCCl.O1CCCC1>[CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:12])[C:6]=1[CH2:7][CH2:8][C:9]([N:15]([CH3:16])[CH3:13])=[O:10]
Reactant: Cc1c[nH]c(C)c1CCC(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c[nH]c(C)c1CCC(=O)N(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To the suspension of 3-(2,4-dimethyl-1H-pyrrol-3-yl)-propionic acid (10 g, 60.8 mmol) in 60 mL of dichloromethane was added 1,1′-carbonyldiimidazole (11.6 g, 71.8 mmol) followed by the addition of 2 M dimethylamine solution in tetrahydrofuran (30 mL) and N,N-diisopropylethylamine (Hunig's base, 10 mL, 60.8 mmol). The dark red reaction mixture was stirred at room temperature overnight and poured into ice water. The organic layer was washed with brine until pH of 6, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified on a silica gel column eluting with dichloromethane-methanol (98:2) to give 9.8 g (83%) of 3-(2,4-dimethyl-1H-pyrrol-3-yl)-N,N-dimethyl-propionamide as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:10][C:9](=[O:11])[CH2:8][CH:7]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5])[CH3:2].[H-].[Na+].[CH3:25]I>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:10]([CH3:25])[C:9](=[O:11])[CH2:8][CH:7]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C(=O)OCC)NC(=O)CC1c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(=O)OCC)C(c2ccccc2)CC(=O)N1C
Temperature: 25 °C
Yield: 99.6 %

Procedure:
A solution of 100 g (0.33 mole) of (±) 5,5-diethoxycarbonyl-4-phenylpyrrolidin-2-one in 500 ml of absolute dimethylformamide was added dropwise to a suspension of 9.64 g (0.36 mole) of sodium hydride in 200 ml of absolute dimethylformamide at room temperature under an N2 atmosphere. The mixture was subsequently stirred at room temperature until the evolution of gas had ended, a solution of 93.7 g (0.66 mole) of methyl iodide in 50 ml of absolute dimethylformamide was then added and the mixture was stirred at room temperature until all the starting material had reacted (about 1 hour, thin layer chromatography check). The reaction mixture was poured into 2 l of buffer solution, pH=7, and extracted five times with 600 ml of diethyl ether each time. Drying of the organic extracts (MgSO4) and stripping off of the solvent in vacuo gave 105 g (99.6%) of the title compound (95% pure according to (the 1H-NMR spectrum), which was further reacted directly. A sample was distilled in a bulb tube (boiling point0.5 : 240° C.) for analysis, Rf : 0.36 (toluene/ethyl acetate: 2/1),
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.Cl.Cl.[CH3:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([N:25]2[CH2:34][CH2:33][CH2:32][C:27]3([CH2:31][NH:30][CH2:29][CH2:28]3)[CH2:26]2)[CH:20]=1.CCOP(O)N(C(C)C)C(C)C>ClCCl>[F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5]([N:30]1[CH2:29][CH2:28][C:27]2([CH2:32][CH2:33][CH2:34][N:25]([C:21]3[CH:20]=[C:19]([CH3:18])[CH:24]=[CH:23][N:22]=3)[CH2:26]2)[CH2:31]1)=[O:6]
Reactant: O=C(O)/C=C/C(F)(F)F
Reactant: Cc1ccnc(N2CCCC3(CCNC3)C2)c1
Agent: CCOP(O)N(C(C)C)C(C)C
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1ccnc(N2CCCC3(CCN(C(=O)/C=C/C(F)(F)F)C3)C2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 9 %

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (32 mg, 0.23 mmol) was dissolved in dichloromethane (0.5 ml containing one drop of dimethyl formamide), oxalyl chloride was added (20 μl, 0.23 mmol) and the solution was stirred at room temperature for 15 minutes. This solution was added to a solution of 7-(4-methyl-2-pyridyl)-2,7-diazaspiro[4.5]decane dihydrochloride (40 mg, 0.13 mmol, half of the residue from step B) and EDIPA (125 μl, 0.8 mmol) in anhydrous dichloromethane (2 ml) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and 10% to 100% acetonitrile) to yield 10 mg of a solid (0.028 mmol, 9% yield for two steps).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=1)[CH2:11]C1OCCO1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=[O:22].O>S(=O)(=O)(O)O.C(OCC)C>[CH2:1]([C:8]1[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=1)[CH:11]=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Cc2cccc(CC3OCCO3)c2)cc1
Reactant: CC(C)=O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: O
Product: O=Cc1cccc(Cc2ccccc2)c1
Reaction time: 8 h

Procedure:
A mixture of 2-(3-benzylbenzyl)-1,3-dioxolane (8.2 g), acetone (100 cm3), water (10 cm3) and concentrated sulphuric acid (20 drops) was stirred overnight, then added to diethyl ether. The resultant mixture was washed with sodium bicarbonate solution, water and brine, and dried over anhydrous magnesium sulphate. Evaporation of the solvents under reduced pressure gave 3-benzylbenzaldehyde (6.5 g), which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[N:4][C:5]2[N:6]([N:9]=[CH:10][CH:11]=2)[C:7]=1Cl.C1OCCOCCOCCOCCOCCOC1.[F-:31].[K+].O>CC#N>[Cl:1][C:2]1[C:3]([CH3:12])=[N:4][C:5]2[N:6]([N:9]=[CH:10][CH:11]=2)[C:7]=1[F:31]
Reactant: [F-]
Reactant: Cc1nc2ccnn2c(Cl)c1Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1nc2ccnn2c(F)c1Cl
Reaction time: 17 h

Procedure:
A mixture of 6,7-dichloro-5-methylpyrazolo[1,5-a]pyrimidine (1.00 equivalent), 18-crown-6 (5 mol %), and KF (3.00 equivalents) in MeCN is heated under reflux with stirring. After 17 hours, the reaction mixture is poured into water, extracted with EtOAc, dried (MgSO4), and concentrated. The product is purified by flash chromatography as necessary.
Reaction SMILES: C[N:2](/[CH:4]=[CH:5]/[C:6]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=O)C.O.[NH2:18]N>C(O)C>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][NH:2][N:18]=2)=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: NN
Reactant: CN(C)/C=C/C(=O)c1ccc([N+](=O)[O-])cc1
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2cc[nH]n2)cc1
Yield: 78.9 %

Procedure:
A solution of 1-(4-nitrophenyl)-3-N,N-dimethylamino-2-propen-1-one (27.3 g) and 85% hydrazine hydrate (23.6 g) in ethanol was heated at 60° C. for one hour. The crystallized solid was filtered to give 18.5 g of 3-(4-nitrophenyl)-pyrazole; M.p. 196°-197° C.
Reaction SMILES: C(OC[N:10]1[N:14]=[N:13][C:12]([C:15]2[N:20]=[C:19]([NH:21][C@H:22]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH3:23])[N:18]=[C:17]([NH:31][C:32]3[CH:37]=[N:36][CH:35]=[CH:34][N:33]=3)[CH:16]=2)=[N:11]1)C1C=CC=CC=1.Cl.C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C>[F:30][C:27]1[CH:26]=[CH:25][C:24]([C@@H:22]([NH:21][C:19]2[N:18]=[C:17]([NH:31][C:32]3[CH:37]=[N:36][CH:35]=[CH:34][N:33]=3)[CH:16]=[C:15]([C:12]3[N:11]=[N:10][NH:14][N:13]=3)[N:20]=2)[CH3:23])=[CH:29][CH:28]=1
Reactant: C[C@H](Nc1nc(Nc2cnccn2)cc(-c2nnn(COCc3ccccc3)n2)n1)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(-c2nn[nH]n2)n1)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 39.5 %

Procedure:
50 mg of (S)-6-[2-(Benzyloxymethyl)-2H-tetrazol-5-yl]-N2-[1-(4-fluorophenyl)ethyl]-N4-(pyrazin-2-yl)pyrimidine-2,4-diamine was dissolved in 1.5 ml of methanol, and 1.5 ml of 10% hydrochloric acid was added thereto, and the mixture was stirred at 80° C. for 20 hours. The reaction solution was air-cooled to room temperature, and then diluted with ethyl acetate, and the pH of the mixture was adjusted to 4 by using saturated sodium bicarbonate aqueous solution. The organic layer was subjected to extraction, and washed in turn with water and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was washed with methanol and filtered and dried under reduced pressure to obtain 15 mg of the objective compound as white powder.
Reaction SMILES: Cl.O1C2C=C[C:9]([C:11](=[N:13]O)[CH3:12])=[CH:10]C=2CC1.[CH3:15][C:16]([O:18][C:19]([CH3:21])=O)=O.[CH3:22][C:23](O)=[O:24]>>[O:18]1[C:19]2[CH:21]=[CH:12][C:11]([NH:13][C:23](=[O:24])[CH3:22])=[CH:9][C:10]=2[CH2:15][CH2:16]1
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)O
Reactant: CC(=NO)c1ccc2c(c1)CCO2
Agent: Cl
Product: CC(=O)Nc1ccc2c(c1)CCO2
Temperature: 0 °C
Reaction time: 24 h
Yield: 51.8 %

Procedure:
NH2OH.HCl (7.3 g, 105 mmol) was added to a stirred solution of ketone 191 (14.2 g, 87.7 mmol) and pyridine (9.2 mL, 114 mmol) in MeOH (100 mL) and the mixture stirred at 20° C. for 16 h. The solvent was evaporated and the residue partitioned between brine and EtOAc. The organic fraction was dried and the solvent evaporated to give crude 1-(2,3-dihydro-1-benzofuran-5-yl)ethanone oxime (15.3 g, 99%). HCl gas was bubbled through a solution of the oxime (15.3 g, 86.5 mmol) in Ac2O (16.3 mL, 173 mmol) and HOAc (54 mL, 865 mmol), and the solution stood at 20° C. for 24 h. The precipitate was poured into ice/water, stirred for 2 h, the solid filtered and washed with water and dried. The aqueous fraction was extracted with DCM (2×50 mL), the combined organic extract dried and the solvent evaporated. The slurry was treated with water (20 mL) and evaporated several times to remove Ac2O. The combined solids were purified by chromatography, eluting with a gradient (50-100%) of EtOAc/pet. ether, to give acetamide 192 (7.94 g, 52%) as a white solid: mp 92-93° C. [lit. (Blade-Font, A.; de Mas Rocabayera, T. J. Chem. Soc. P1, 1982, 814848) mp 93° C.]; 1H NMR δ 7.47 (br s, 1H, H-4), 7.21 (br s, 1H, NH), 6.99 (dd, J=8.5, 2.1 Hz, 1H, H-6), 6.69 (d, J=8.5 Hz, 1H, H-7), 4.55 (t, J=8.7 Hz, 2H, H-2), 3.18 (br t, J=8.7 Hz, 2H, H-3), 2.13 (s, 3H, CH3).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][C:10]=2Br)=[CH:5][CH:4]=1.[N+:19]([O-:24])([N+]([O-])=O)=[O:20].C1CCC(C(O)=O)CC=1>C(O)(=O)C>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][C:10]=2[N+:19]([O-:24])=[O:20])=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: BrCc1ccc(-c2c(Br)oc3ccccc23)cc1
Agent: O=C(O)C1CC=CCC1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1oc2ccccc2c1-c1ccc(CBr)cc1

Procedure:
Starting with 3-(4'-bromomethyl phenyl)-2-bromobenzofuran, nitration with dinitrogen tetraoxide in acetic acid in the presence of cyclohexene-4-carboxylic acid provides 3-(4'bromomethyl phenyl)-2-nitrobenzofuran which is reacted according to the method of Example 1 with N,N'-dimethylaminoethylamine. The product obtained is 3-[4'-(N,N'-dimethylaminoethylaminomethyl)phenyl]-2-nitrobenzofuran having the structure ##STR35##
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[CH3:7][C@:8]12[C@@:25]3([CH3:26])[C@@H:16]([C@:17]4([CH3:30])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:28])([CH3:27])[C:20](=[O:29])[CH2:19][CH2:18]4)[CH2:15][CH2:14][C@@H:13]1[C@H:12]1[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:11]1([C:37](Cl)=[O:38])[CH2:10][CH2:9]2>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:37]([C@:11]12[CH2:33][CH2:32][C@@H:31]([C:34]([CH3:36])=[CH2:35])[C@@H:12]1[C@@H:13]1[C@@:8]([CH3:7])([CH2:9][CH2:10]2)[C@@:25]2([CH3:26])[C@@H:16]([C@:17]3([CH3:30])[C@@H:22]([CH2:23][CH2:24]2)[C:21]([CH3:28])([CH3:27])[C:20](=[O:29])[CH2:19][CH2:18]3)[CH2:15][CH2:14]1)=[O:38]
Reactant: CN(C)CCN
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)Cl)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CCC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CCC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reaction time: 16 h

Procedure:
To a mixture of N1,N1-dimethylethane-1,2-diamine (74.5 mg, 0.845 mmol), Hunig'sBase (0.369 mL, 2.114 mmol) and DMAP (5.16 mg, 0.042 mmol) in dichloromethane (2 mL) was added (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-9-oxo-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carbonyl chloride (200 mg, 0.423 mmol). The reaction mixture was stirred for 16 h. LCMS indicated the formation of desired product. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol and the clear solution was purified by prep HPLC to provide the title compound as a colorless oil (150 mg, 68%). LCMS: m/e 525.56 (M+H)+, 2.27 min (method 1). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 6.89 (t, J=5.04 Hz, 1H), 4.72 (d, J=2.14 Hz, 1H), 4.58 (s, 1H), 3.59-3.34 (m, 2H), 3.12 (td, J=11.06, 4.12 Hz, 1H), 2.67 (t, J=5.80 Hz, 2H), 2.53-2.43 (m, 2H), 2.41 (s, 6H), 2.40-2.32 (m, 1H), 2.07-2.03 (m, 1H), 1.97-1.84 (m, 2H), 1.78 (dd, J=11.60, 7.93 Hz, 1H), 1.71 (dd, J=13.12, 2.44 Hz, 1H), 1.67 (s, 3H), 1.62-1.22 (m, 14H), 1.21-1.11 (m, 1H), 1.06 (s, 3H), 1.01 (s, 3H), 1.04-0.97 (m, 1H), 0.97 (s, 6H), 0.91 (s, 3H).