Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:5]([NH:8][CH:9]=O)=[N:6][CH:7]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C([O-])(O)=O.[Na+]>COCCOC.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>[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[N:3]=[C:4]3[N:11]([CH2:12][C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)[CH:9]=[N:8][C:5]3=[N:6][CH:7]=2)=[CH:24][CH:23]=1
Reactant: COc1ccc(CNc2nc(Br)cnc2NC=O)cc1
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(Cn2cnc3ncc(-c4ccc(F)cc4)nc32)cc1
Yield: 30.5 %

Procedure:
A mixture of N-[5-bromo-3-(4-methoxy-benzylamino)-pyrazin-2-yl]-formamide (160 mg, 0.47 mmol), 4-fluoro-phenyl boronic acid (200 mg, 1.44 mmol), Pd(PPh3)2Cl2 (2 mg, 0.0028 mmol), and NaHCO3 (118 mg, 1.41 mmol) in DME (1 mL) and water (0.2 mL) was put in a microwave reaction tube and reacted in a microwave reactor at 110° C. for 7 minutes. The reaction mixture was partitioned in ethyl acetate and water, and the organic layer was evaporated. The residue was purified on a C-18 reversed phase preparative HPLC eluting with Methanol/Acetontrile containing 0.1% trifluoroacetic acid to provide 6-(4-fluoro-phenyl)-1-(4-methoxy-benzyl)-1H-imidazo[4,5-b]pyrazine as a white solid (48 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][CH3:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=1.[CH3:18][N:19]=[C:20]=[O:21]>C(N(CC)CC)C.CN(C)C=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][CH3:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][O:17][C:20](=[O:21])[NH:19][CH3:18])[N:3]=1
Reactant: CN=C=O
Reactant: COCCCNc1nc(Cl)nc(NCCO)n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)OCCNc1nc(Cl)nc(NCCCOC)n1

Procedure:
A solution of 5 g 2-chloro-4-(3-methoxypropylamino)-6-(2-hydroxyethylamino)-s-triazine, 1.2 g methyl isocyanate and 10 drops triethylamine in 20 ml dimethylformamide was heated at 100° C. for 2 hours. The dimethylformamide was removed by distillation and the resulting residue was slurried with ether and filtered to give the product as a white powder. The melting point and elemental analysis on the product are tabulated in Table I.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:60][C:61]1[CH:66]=[CH:65][C:64]([OH:67])=[CH:63][CH:62]=1)[C:6]([NH:8][CH:9]([CH2:52][C:53]1[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=1)[C:10]([N:12]1[CH2:17][C:16](=[O:18])[N:15]([CH2:19][CH2:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=2)[CH2:14][CH:13]1[CH2:31][CH2:32][CH2:33][NH:34][C:35]([NH:44]C(OC(C)(C)C)=O)=[N:36]C(OC(C)(C)C)=O)=[O:11])=[O:7])(=[O:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:4][CH:5]([CH2:60][C:61]1[CH:62]=[CH:63][C:64]([OH:67])=[CH:65][CH:66]=1)[C:6]([NH:8][CH:9]([CH2:52][C:53]1[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=1)[C:10]([N:12]1[CH2:17][C:16](=[O:18])[N:15]([CH2:19][CH2:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=2)[CH2:14][CH:13]1[CH2:31][CH2:32][CH2:33][NH:34][C:35]([NH2:44])=[NH:36])=[O:11])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(Cc1ccc(O)cc1)C(=O)NC(Cc1ccc(F)cc1)C(=O)N1CC(=O)N(CCc2ccc3ccccc3c2)CC1CCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NC(Cc1ccc(O)cc1)C(=O)NC(Cc1ccc(F)cc1)C(=O)N1CC(=O)N(CCc2ccc3ccccc3c2)CC1CCCNC(=N)N
Yield: 86 %

Procedure:
A solution of 2-acetylamino-N-[2-[2-[3-(N′,N″-di-Boc-guanidino)propyl]-4-(2-naphthalen-2-ylethyl)-5-oxo-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-3-(4-hydroxyphenyl)-propionamide, 36, (35 mg, 38 mmol), trifluoroacetic acid (1 mL) and dichloromethane (2 mL) is stirred at room temperature for 5 hours. The solution is concentrated in vacuo and the crude product purified over silica gel (acetonitrile:TFA:water) to afford 24 mg (86% yield) of the final product which corresponds to analog 227, Table IV.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[F:23][C:24]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:28][C:25]=1[C:26]#[N:27].[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[C:4]1[N:27]=[C:26]([C:25]2[CH:28]=[C:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:30]=[CH:31][C:24]=2[F:23])[N:2]([CH3:1])[N:3]=1
Reactant: CCCCCCCCCCCc1ccc(F)c(C#N)c1
Reactant: CN(N=C(Cl)c1c(F)cccc1Cl)S(=O)(=O)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: CCCCCCCCCCCc1ccc(F)c(-c2nc(-c3c(F)cccc3Cl)nn2C)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 60.9 %

Procedure:
A mixture of N-methyl-N-(benzenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (1.34 g), 2-fluoro-5-undecylbenzonitrile (1.09 g), anhydrous aluminum chloride (0.55 g) and o-dichlorobenzene (10 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, the reaction mixture is dissolved in chloroform (200 ml), washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 1.04 g of desired compound (refractive index: 1.5419).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=1.[CH:23]([Sn](CCCC)(CCCC)CCCC)=[CH2:24]>O1CCOCC1.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>[N:18]1([C:4]2[CH:5]=[C:6]([S:8]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)(=[O:10])=[O:9])[CH:7]=[C:2]([CH:23]=[CH2:24])[N:3]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(N3CCCC3)c2)cc1
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=Cc1cc(S(=O)(=O)c2ccc(N)cc2)cc(N2CCCC2)n1
Reaction time: 1 h
Yield: 48.6 %

Procedure:
0.38 g (0.001 Mol) 4-(2-Bromo-6-pyrrolidin-1-yl-pyridine-4-sulfonyl)-phenylamine, 0.116 g (0.0001 Mol) Pd(PPh3)4 and 0.292 ml (0.001 Mol) vinyl-tributylstannane were stirred at reflux for 18 h in a mixture of dioxane (10 ml) and 2N Na2CO3 (2 ml). Then the solvent was evaporated, the residue was taken up in ethyl acetate, washed with water and brine and dried over Na2SO4. After chromatography on SiO2 with ethyl acetate hexane 2:3 the product containing fractions were evaporated and the residue taken up in hexane. The suspension was stirred for 1 h and then filtered. The residue on the filter was washed with hexane (10 ml) and dried in a high vacuum. It was obtained 0.16 g (49%) 4-(2-pyrrolidin-1-yl-6-vinyl -pyridine-4-sulfonyl)-phenylamine as a yellow solid; mp.: 181-182° C.
Reaction SMILES: [CH2:1]([NH:8][S:9]([C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([N+:19]([O-:21])=[O:20])[C:13]=1C(=O)C)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[Si](C)(C)C.C([OH:32])C>S(=O)(=O)(O)O>[CH2:1]([NH:8][S:9]([C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([N+:19]([O-:21])=[O:20])[C:13]=1[OH:32])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)c1c([N+](=O)[O-])ccc(Cl)c1S(=O)(=O)NCc1ccccc1
Reactant: CCO
Agent: C[Si](C)(C)Cl
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NCc2ccccc2)c1O
Yield: 94 %

Procedure:
A solution of N-benzyl-2-acetyl-6-chloro-3-nitrobenzenesulfonamide (225 mg, 0.59 mmol), 0.1 mL of chlorotrimethylsilane and 2 drops of fuming sulfuric acid in ethanol was heated to reflux for 20 hours. The solvent was evaporated. The residue was diluted with ethyl acetate and washed with water. The organic layer was then dried (Na2SO4) and concentrated to give the desired product (189 mg, 94%). 1H NMR (DMSO-d6): δ 7.92 (d, 1H), 7.18 (m, 5H), 6.93 (d, 1H), 4.15 (s, 2H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)=[CH:4][N:3]=1.CC(C)([O-])C.[K+].CN(C)C(=O)C.[CH3:31][N:32]1[CH:36]=[CH:35][C:34]([NH:37][C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[C:45]([OH:48])[CH:46]=3)[N:41]=[CH:40][N:39]=2)=[N:33]1>O>[CH3:31][N:32]1[CH:36]=[CH:35][C:34]([NH:37][C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[C:45]([O:48][C:2]4[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][O:12][CH:13]5[CH2:18][CH2:17][CH2:16][CH2:15][O:14]5)=[CH:4][N:3]=4)[CH:46]=3)[N:41]=[CH:40][N:39]=2)=[N:33]1
Reactant: Fc1ccc(OCCCOC2CCCCO2)cn1
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cn1ccc(Nc2ncnc3ccc(Oc4ccc(OCCCOC5CCCCO5)cn4)cc23)n1
Temperature: 180 °C
Reaction time: 14 h
Yield: 96.5 %

Procedure:
2-Fluoro-5-[3-(tetrahydro-2H-pyran-2-yloxy)propoxy]pyridine (305 mg, 1.10 mmol) and potassium tert-butoxide (140 mg, 1.24 mmol) were added to an N,N-dimethylacetamide solution (1 ml) of 4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol (120 mg, 0.50 mmol), and stirred at 180° C. for 14 hours under a nitrogen atmosphere in a sealed tube. The reaction solution was cooled with ice, then saline water was added, and extracted with chloroform. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Biotage, chloroform:methanol=100:3) to obtain N-(1-methyl-1H-pyrazol-3-yl)-6-({5-[3-(tetrahydro-2H-pyran-2-yloxy)prop oxy]pyridin-2-yl}oxy)quinazoline-4-amine (230 mg, yield: 97%) as a pale orange amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([CH2:18][CH2:17][N:16]([C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH2:15]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:25]1C=C(C#CC2CC3(CCN(C(OC(C)(C)C)=O)C3)ON=2)C=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([CH2:18][CH2:17][N:16]([C:19]([N:21]([CH3:22])[CH3:23])=[O:20])[CH2:15][CH2:25]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC(C#Cc3cccc(Cl)c3)=NO2)C1
Reactant: CN(C)C(=O)N1CCC2(CC(C#Cc3cccc(Cl)c3)=NO2)C1
Product: CN(C)C(=O)N1CCC2(CC1)CC(C#Cc1cccc(Cl)c1)=NO2

Procedure:
The title compound was synthesized following the method herein described for the compound of Example 95 but replacing Compound 22d for Compound 27c. After the usual work-up procedure the crude was purified by means of automated flash chromatography (Isolera®TM-Biotage; gradient Petroleum Ether-EtOAc from 3:7 to 0:1) giving pale yellow solid of the title compound. Yield: 66.2%.
Reaction SMILES: [C:1]([OH:13])(=O)[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:47][CH2:48][CH2:49][NH:50][C:51]1[N:56]=[C:55]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[N:54]=[C:53]([NH:63][CH2:64][CH2:65][NH:66][C:67](=[O:69])[CH3:68])[C:52]=1[CH3:70]>CN1C(=O)CCC1>[C:67]([NH:66][CH2:65][CH2:64][NH:63][C:53]1[N:54]=[C:55]([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[N:56]=[C:51]([NH:50][CH2:49][CH2:48][NH:47][C:1]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[O:13])[C:52]=1[CH3:70])(=[O:69])[CH3:68]
Reactant: CC(=O)NCCNc1nc(-c2ccccc2)nc(NCCN)c1C
Reactant: O=C(O)c1ccc2ccccc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCCNc1nc(-c2ccccc2)nc(NCCNC(=O)c2ccc3ccccc3n2)c1C
Reaction time: 12 h

Procedure:
A solution of quinaldic acid (30 μl of a 0.3M solution in NMP), HATU (30 μl of a 0.3M solution in NMP) and diisopropylethylamine (30 μl of a 0.3M solution in NMP) was shaken at ambient temperature in a well of a 96 position microtitre plate for 45 min. N-[2-({6-[(2-aminoethyl)amino]-5-methyl-2-phenylpyrimidin-4-yl}amino)ethyl]acetamide (30 μl of a 0.3M solution in NMP) was then added and the mixture shaken for a further 12 hrs. Purification via ion exchange silica (SCX) yields the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH:6]([CH2:7][CH2:8][C:9]([O:11]CC)=[O:10])[CH2:5][CH2:4][S:3]1.[OH-:14].[Na+]>C1COCC1>[SH:3][CH2:4][CH2:5][CH:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[C:2]([OH:1])=[O:14]
Reactant: CCOC(=O)CCC1CCSC1=O
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)CCC(CCS)C(=O)O
Reaction time: 48 h
Yield: 20 %

Procedure:
To a solution of ethyl 3-(2-oxotetrahydro-3-thiophenyl)propanoate (0.77 g, 3.81 mmol) in THF (5 ml) was added sodium hydroxide (1 M in water, 5 ml). The mixture was allowed to stir for two days, then the THF was removed under reduced pressure, the aqueous layer was washed with ether, then acidified to pH 1 with HCl and extracted with ethyl acetate. The combined ethyl acetate extracts were dried over magnesium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by column chromatography yielding a 150 mg of clear oil (20%). 1H NMR (d6-DMSO) δ 1.7 (m, 3H), 1.8 (m, 1H), 2.2 (m, 2H), 2.3-2.5 (m, 4H). Analysis calculated for C7H12SO4: C, 43.74; H, 6.29; S, 16.68. Found: C, 43.61; H, 6.39; S, 16.55.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[OH:9].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:10]([O:9][C:3]1[C:2]([Br:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Br:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Oc1c(Br)cccc1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Brc1cccc(Br)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.1 %

Procedure:
2,6-Dibromophenol (29.30 g, 116 mmol) and benzyl bromide (33.14 g, 194 mmol) were dissolved in 2-butanone (300 mL). Potassium carbonate (29.47 g, 213 mmol) was added, and the mixture was stirred for 1.5 hr at reflux temperature. The reaction mixture was cooled to room temperature, filtered, and evaporated to dryness. The remaining viscous oil was subjected to silicagel column chromatography, flushing with n-pentane to remove benzyl bromide, then DCM/n-pentane=1:1 to elute the product, yielding the product as a white crystalline solid (39.32 g, 99%). 1H-NMR (CDCl3): δ=7.61 (dd, 2H), 7.54 (d, 2H), 7.41 (m, 3H), 6.90 (t, 1H), 5.04, (s, 2H) ppm.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH:9]1([C:12]2[CH:16]=[C:15]([NH2:17])[NH:14][N:13]=2)[CH2:11][CH2:10]1.CCN(C(C)C)C(C)C>CS(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:17][C:15]2[NH:14][N:13]=[C:12]([CH:9]3[CH2:11][CH2:10]3)[CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Nc1cc(C2CC2)n[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Temperature: 60 °C
Reaction time: 16 h
Yield: 80.8 %

Procedure:
A dried 5-L, three-necked round bottom flask fitted with an overhead stirrer and reflux condenser was charged with a solution of 2,4-dichloropyrimidine (250 g, 1.68 mol) in anhydrous DMSO (2300 mL). 3-Cyclopropyl-1H-pyrazol-5-amine (227.4 g, 1.85 mol) and DIPEA (438 mL, 2.52 mol) were added sequentially at RT. The resulting solution was stirred at 60° C. for 16 h, cooled to RT, and poured into ice water. The precipitated yellow solid was collected by vacuum filtration, washed with water, 1.5 N HCl (3×1 L), and finally with water (4×500 mL). The precipitate was dried by air suction overnight to give 320 g (81%) of 20 as yellow solid: 1H NMR (400 MHz, DMSO-d6): δ 12.19 (s, 1H), 10.29 (s, 1H), 8.15 (s, 1H), 7.0 (br s, 1H), 6.0 (br s, 1H), 1.85-1.92 (m, 1H), 0.91-0.95 (m, 2H), 0.7 (m, 2H); MS (ESI+) m/z: 236 [M+1]+.
Reaction SMILES: [H-].[Na+].CS(C)=O.[I-].[CH3:8][S+](C)(C)=O.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:28]3[N:27]=[C:26]4[CH2:29][CH2:30][CH2:31][CH:32]5[CH2:37][C:36](=[O:38])[CH2:35][CH2:34][C:33]5([CH2:39][C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=5)[C:25]4=[CH:24][C:23]=3[CH:22]=[N:21]2)=[CH:16][CH:15]=1>C1COCC1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:28]3[N:27]=[C:26]4[CH2:29][CH2:30][CH2:31][CH:32]5[CH2:37][C:36]6([CH2:8][O:38]6)[CH2:35][CH2:34][C:33]5([CH2:39][C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=5)[C:25]4=[CH:24][C:23]=3[CH:22]=[N:21]2)=[CH:16][CH:15]=1
Reactant: C[S+](C)(C)=O
Reactant: O=C1CCC2(Cc3ccccn3)c3cc4cnn(-c5ccc(F)cc5)c4nc3CCCC2C1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Fc1ccc(-n2ncc3cc4c(nc32)CCCC2CC3(CCC42Cc2ccccn2)CO3)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.2 %

Procedure:
Sodium hydride (60 wt % in oil, 0.454 g, 11.35 mmol) and DMSO (25 mL) were heated to about 65° C. for about 30 min then cooled to rt. THF (50 mL) was added then the mixture was cooled to about 0° C. Trimethylsulfoxonium iodide (2.56 g, 11.63 mmol) was added then after about 30 min rac-(4aR,12bR)-9-(4-fluorophenyl)-12b-(pyridin-2-ylmethyl)-1,4,4a,5,6,7,9,12b-octahydrobenzo[3,4]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-3 (2H)-one (118, R1=4-Fluorophenyl, R2=Pyridin-2-ylmethyl) (2.5 g, 5.68 mmol) was added. The mixture was allowed to warm to rt and stir for about 12 h. The mixture was concentrated under reduced pressure then the material was partitioned between water (100 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (25 mL) then the organic solutions were combined and washed with water (75 mL) then brine (30 mL), dried over MgSO4 then filtered. The filtrate was concentrated under reduced pressure and the material was purified on silica gel (120 g) using a gradient from 0-10% MeOH in DCM. Product fractions were combined and concentrated under reduced pressure to yield rac-(2′R,4aS,12bS)-9-(4-fluorophenyl)-12b-(pyridin-2-ylmethyl)-2,4,4a,5,6,7,9,12b-octahydro-1H-spiro[benzo[3,4]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridine-3,2′-oxirane] (119, R1=4-Fluorophenyl, R2=Pyridin-2-ylmethyl) (1.865 g, 72.3%); LC/MS, method 3, Rt=2.65 min, MS m/z 455 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.42-8.34 (m, 2H), 8.32-8.28 (m, 1H), 8.20 (s, 1H), 7.75-7.72 (m, 1H), 7.49-7.37 (m, 3H), 7.06 (ddd, J=5.2, 4.5, 0.9 Hz, 1H), 6.72-6.67 (m, 1H), 3.73 (d, J=12.8 Hz, 1H), 3.59-3.47 (m, 1H), 3.42-3.33 (m, 1H), 3.02 (d, J=12.9 Hz, 1H), 2.70-2.56 (m, 1H), 2.44-2.34 (m, 2H), 2.13-2.00 (m, 1H), 1.96-1.81 (m, 2H), 1.79-1.58 (m, 3H), 1.35-1.21 (m, 3H), 1.21-1.10 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH:3]=1.CCN=C=N[CH2:16][CH2:17][CH2:18][N:19](C)C.Cl.C1C=C2N=NN(O)C2=CC=1.O.C1(N)CC1>CN(C=O)C>[CH:18]1([NH:19][C:8](=[O:10])[C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)[CH2:16][CH2:17]1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1ccc(O)cc1
Agent: Cl
Agent: NC1CC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC1CC1)c1ccc(O)cc1

Procedure:
4-Hydroxybenzenecarboxylic acid was stirred with WSC hydrochloride, HOBt hydrate and cyclopropylamine in DMF at room temperature to obtain N-cyclopropyl-4-hydroxybenzamide.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:12]2[C:7](=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]=[CH:10][CH:11]=2)[O+:6]=[C:5]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:4]=1.[O-:25][CH2:26][CH3:27].[Na+].C(O)C>C(Cl)(Cl)Cl>[Cl-:2].[CH2:26]([O:25][C:3]1[C:12]2[C:7](=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]=[CH:10][CH:11]=2)[O+:6]=[C:5]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:4]=1)[CH3:27]
Reactant: Clc1cc(N2CCOCC2)[o+]c2c(-c3ccccc3)cccc12
Reactant: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCOc1cc(N2CCOCC2)[o+]c2c(-c3ccccc3)cccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A vial was charged with a magnetic stirring bar, 4-chloro-2-morpholino-8-phenylchromenylium chloride (78) (50 mg, 138 μmol), chloroform (1.0 mL), and a solution of sodium ethoxide in ethanol (21%, 108 μL, 290 μmol). The mixture was magnetically stirred at room temperature for 1 hour to give 4-ethoxy-2-morpholino-8-phenylchromenylium chloride (80).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([OH:10])=[O:9].[ClH:11].[CH3:12]O>>[ClH:11].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10][CH3:12])=[O:9]
Reactant: CO
Reactant: O=C(O)Cc1ccccn1
Agent: Cl
Product: COC(=O)Cc1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A solution of 2-(2-pyridinyl)acetic acid (0.50 g, 3 mmol; prepared according to J. Prakt. Chem. 1961, 285, 118) in MeOH (20 mL) was saturated with HCl gas at 0° C., then was allowed to warm to RT. After stirring overnight, the reaction was concentrated under vacuum to afford the title compound (0.54 g, 100%) as a colorless solid: 1H NMR (CDCl3) δ8.90 (br s, 1H), 7.89 (m, 2H), 6.89 (t, J=6.5 Hz, 1H), 6.79 (d, J=8 Hz, 1H), 4.21 (m, 2H), 3.81 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][NH2:12])=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.Cl.Cl.[NH2:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](N)=[NH:20].CC[O-].[Na+].O>CN(C=O)C>[NH2:15][C:16]1[CH:17]=[C:18]([C:19]2[NH:20][C:9]([C:3]3[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([Br:8])[N:4]=3)=[N:11][N:12]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: NNC(=O)c1nc(Br)cnc1N
Reactant: N=C(N)c1cccc(N)c1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cccc(-c2nnc(-c3nc(Br)cnc3N)[nH]2)c1
Temperature: 100 °C
Yield: 100 %

Procedure:
A mixture of 3-amino-6-bromo-pyrazine-2-carbohydrazide (5 g, 21.55 mmol), 3-aminobenzamidine dihydrochloride (4.484 g, 21.55 mmol) and NaOEt (4.399 g, 64.65 mmol) were combined in DMF (50.00 mL) and heated to 100° C. in the microwave for 20 min. Water was added and the precipitate collected. Used without further purification. Assumed 100% Yield.
Reaction SMILES: [Cl:1][CH2:2][C:3](O)=[O:4].[CH3:6][O:7][C:8](=[O:13])[C:9]([NH2:12])([CH3:11])[CH3:10].C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:6][O:7][C:8](=[O:13])[C:9]([NH:12][C:3](=[O:4])[CH2:2][Cl:1])([CH3:11])[CH3:10]
Reactant: O=C(O)CCl
Reactant: COC(=O)C(C)(C)N
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)(C)NC(=O)CCl
Reaction time: 0.5 h

Procedure:
To a solution of 0.95 g chloro acetic acid in 20 ml of dry THF 1.78 g N,N′-carbonyl-diimidazole were added. After 0.5 h at room temperature and under argon atmosphere 1.69 g 2-amino-2-methyl-propionic acid methyl ester and 1.29 g N,N-diisopropyl-ethyl-amine were added and it was stirred for 3 h. Then the solvent was evaporated, the residue taken up in ethyl acetate and washed with 2 M hydrochloric acid, water and sat. aqueous sodium hydrogen carbonate solution. The combined organic fractions were dried over sodium sulphate, filtrated and concentrated. The resulting residue was crystallized from diethylether to yield 2-(2-chloro-acetylamino)-2-methyl-propionic acid methyl ester.