Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:20]=[N:21][C:22]([CH3:25])=[CH:23][CH:24]=4)=[CH:13][C:12]3=[O:26])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:27][N:28](C(OC(C)(C)C)=O)[CH2:29][CH2:30][CH2:31][C:3]1=2.[ClH:39]>CO>[ClH:39].[CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:20]=[N:21][C:22]([CH3:25])=[CH:23][CH:24]=4)=[CH:13][C:12]3=[O:26])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:27][NH:28][CH2:29][CH2:30][CH2:31][C:3]1=2
Reactant: Cc1ccc(COc2ccn(-c3ccc4c5c(n(C)c4c3)CCCN(C(=O)OC(C)(C)C)C5)c(=O)c2)cn1
Agent: Cl
Solvent: CO
Product: Cc1ccc(COc2ccn(-c3ccc4c5c(n(C)c4c3)CCCNC5)c(=O)c2)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
tert-Butyl 6-methyl-8-(4-((6-methyl pyridine-3-yl)methoxy)-2-oxopyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (0.12 g, 0.22 mmol) was treated with 1.25 M HCl in MeOH (13 mL), and the resulting solution was stirred at ambient temperature for 18 h. The solution was concentrated to dryness to provide the title compound (0.10 g, quantitative) as a brown solid: 1H NMR (500 MHz, DMSO-d6) δ 9.17 (s, 2H), 8.89 (s, 1H), 8.51 (d, J=8.0 Hz, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.65 (d, J=8.5 Hz, 1H), 7.61 (d, J=7.5 Hz, 1H), 7.47 (d, J=1.5 Hz, 1H), 6.98 (dd, J=8.5, 1.5 Hz, 1H), 6.14 (dd, J=8.0, 2.5 Hz, 1H), 6.03 (d, J=2.0 Hz, 1H), 5.33 (s, 2H), 4.44-4.41 (m, 2H), 3.71 (s, 3H), 3.44-3.42 (m, 2H), 3.10-3.08 (m, 2H), 2.76 (s, 3H), 2.08-2.04 (m, 2H); ESI MS m/z 415 [M+H]+; HPLC (Method A)>99% (AUC), tR=9.4 min.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)(=O)=O.[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[F-].[K+]>C1(C2(C3C=CC=CC=3)CC2(P(C(C)(C)C)C(C)(C)C)C)C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:8][CH:9]=1
Reactant: COc1ccc(OS(=O)(=O)C(F)(F)F)cc1
Reactant: OB(O)c1ccccc1
Agent: CC(C)(C)P(C(C)(C)C)C1(C)CC1(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 97.1 %

Procedure:
Under a nitrogen atmosphere, 4-trifluoromethane-sulfonyloxyanisole (0.49 g, 1.9 mmol), phenylboronic acid (0.29 g, 2.4 mmol), potassium fluoride (0.24 g, 4.2 mmol), (π-allyl)palladium chloride (3.6 mg, 0.01 mmol), 2,2-diphenyl-1-(di-tert-butylphosphino)-1-methylcyclopropane (14.0 mg, 0.04 mmol) obtained in Example 4 and toluene (4 ml) were placed in a reaction flask and stirred for 1.5 hours at 80° C. The reaction mixture was cooled, washed with water, and dried over anhydrous magnesium sulfate. Then, the solvent was removed under reduced pressure, and the concentrate was purified by column chromatography to give the title compound (0.34 g, 96%) as white crystal.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:41]1[N:42]=[C:43]([NH:46]C=O)[S:44][CH:45]=1)[C:5]([NH:7][CH:8]1[C:39](=[O:40])[N:10]2[C:11]([C:23]([O:25][CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])=[C:12]([CH:15]=[CH:16][C:17]3[N:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:13][S:14][C@H:9]12)=[O:6].Cl.C(=O)(O)[O-].[Na+]>CO.O1CCCC1>[CH3:1][O:2][N:3]=[C:4]([C:41]1[N:42]=[C:43]([NH2:46])[S:44][CH:45]=1)[C:5]([NH:7][CH:8]1[C:39](=[O:40])[N:10]2[C:11]([C:23]([O:25][CH:26]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:24])=[C:12]([CH:15]=[CH:16][C:17]3[N:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=Cc3cccnn3)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=Cc3cccnn3)CS[C@H]12)c1csc(N)n1
Yield: 83.4 %

Procedure:
To a solution of benzhydryl 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-[2-(3-pyridazinyl)vinyl]-3-cephem-4-carboxylate (syn isomer) (trans isomer) (0.85 g) in methanol (45 ml) and tetrahydrofuran (9 ml) was added conc.hydrochloric acid (0.56 ml) and the mixture was stirred at ambient temperature for 1.5 hours. The resultant solution was adjusted to pH 7.0 with 5% aqueous sodium bicarbonate and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (150 ml). The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated in vacuo to give benzhydryl 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[2-(3-pyridazinyl)vinyl]-3-cephem-4-carboxylate (syn isomer) (trans isomer) (0.68 g).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])/[C:13]/3=[CH:20]\[C:21]2[NH:22][CH:23]=[CH:24][CH:25]=2)=[CH:4][CH:3]=1.C(C1C=C2C(=CC=1)NC(=O)/C/2=C\C1NC=CC=1)#C.IC1C=CC=C([N+:51]([O-:53])=[O:52])C=1.C(N(CC)CC)C>[Cu]I.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.CN(C=O)C>[N+:51]([C:3]1[CH:4]=[C:5]([C:8]#[C:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])/[C:13]/3=[CH:20]\[C:21]2[NH:22][CH:23]=[CH:24][CH:25]=2)[CH:6]=[CH:7][CH:2]=1)([O-:53])=[O:52]
Reactant: O=C1Nc2ccc(C#Cc3ccc(O)cc3)cc2/C1=C/c1ccc[nH]1
Reactant: O=[N+]([O-])c1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#Cc1ccc2c(c1)/C(=C/c1ccc[nH]1)C(=O)N2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1Nc2ccc(C#Cc3cccc([N+](=O)[O-])c3)cc2/C1=C/c1ccc[nH]1

Procedure:
This compound was prepared in a manner analogous to the preparation of (Z)-1,3-dihydro-5-(4-hydroxyphenyl)ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Compound TTT in Example 83 above). In this example, (Z)-1,3-dihydro-5-ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (150 mg, 0.64 mmol) (from Example 82) was coupled with 1-iodo-3-nitrobenzene (175 mg, 0.70 mmol) (Aldrich) using CuI (13 mg, 0.068 mmol) and (Ph3P)2PdCl2 (22 mg, 0.031 mmol) (Aldrich) as catalyst in 3 mL DMF and 3 mL triethylamine at 70° C. for 13 hours to give (Z)-1,3-dihydro-5-(3-nitrophenyl)ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one as a red powder. (Yield 148 mg, 65%)
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9](=[N:11][O:12][C:13](=O)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH2:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1>O>[Br:8][C:5]1[N:4]=[C:3]([C:9]2[N:10]=[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:12][N:11]=2)[C:2]([NH2:1])=[N:7][CH:6]=1
Reactant: NC(=NOC(=O)c1ccccc1)c1nc(Br)cnc1N
Solvent: O
Product: Nc1ncc(Br)nc1-c1noc(-c2ccccc2)n1
Temperature: 70 °C
Yield: 87 %

Procedure:
A mixture of 3-amino-N′-(benzoyloxy)-6-bromopyrazine-2-carboximidamide (575 mg, 1.711 mmol) and polyphosphonic acid (2.300 mL) was heated at 70° C. for 3.5 hours. The resultant solution was diluted with water (20 mL), quenched with NaHCO3 and the resultant product isolated by filtration (475 mg, 87% Yield) as a fawn solid.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[CH:21]1[C:29]2[C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[O:26][C:25]=2[CH:24]=[CH:23][C:22]=1[CH:34]=O>>[CH:21]1[C:29]2[C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[O:26][C:25]=2[CH:24]=[CH:23][C:22]=1[CH2:34][N:1]1[CH:2]([C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1=[O:9]
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1ccc2oc3ccccc3c2c1
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1ccc2oc3ccccc3c2c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with commercially available dibenzo[b,d]furan-2-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions I): tR=1.53 min.; [M+H]+: 430.13 g/mol.
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH2:14][C:15]3[C:16]4[C@:28]([CH3:36])([CH2:29][CH2:30][C:31]=32)[C@@H:19]([C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:18][CH:17]=4)[C:11]1([CH3:38])[CH3:37])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:47])C=1>C(OCC)C.C(=O)(O)[O-].[Na+]>[C:1]([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@H:12]([CH2:13][CH2:14][C:15]3[C@H:16]4[C@:28]([CH3:36])([CH2:29][CH2:30][C:31]=32)[C@@H:19]([C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:18][C:17]4=[O:47])[C:11]1([CH3:38])[CH3:37])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](OC(=O)c2ccccc2)C(C)(C)[C@@H]1CC3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)CCC[C@@H](C)[C@H]1CC(=O)[C@H]2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](OC(=O)c2ccccc2)C(C)(C)[C@H]1CC3
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
To a solution of 3β-benzoyloxy-4,4-dimethyl-5α-cholest-8,14-diene (5.0 g, 10.2 mmol) in diethyl ether solution (300 mL) and 0.5M aqueous sodium bicarbonate (300 mL) was added meta-chloro-perbenzoic acid (2.44 g, 11.3 mmol) (Aldrich). After 30 min, the ether fraction was separated from the sodium bicarbonate layer and the aqueous fraction was repeatedly extracted with diethyl ether (5×500 mL). The organic fractions were combined, washed with brine (1×100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to about 150 ml. This ether solution of 38a was promptly cooled (0°) and treated dropwise with boron trifluoride etherate (26 mL, 22.5 mmol (Aldrich). After 30 min, the reaction was quenched with ice water (200 mL) and the aqueous phase was reextracted with ether (3×100 mL). The combined ether fractions were extracted with saturated sodium bicarbonate solution (1×200 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was crystallized from isopropanol (75 mL) to afford 4.10 g of 3β-benzoyloxy-4,4-dimethyl-5β-cholest-8-en-15-one (Compound 40a) in 75% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([CH:23]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([NH:17][C:18]([CH:20]3[CH2:22][CH2:21]3)=[O:19])[N:16]=2)[N:13]=1.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](Cl)=[O:32]>CN1CCCC1=O.Cl>[CH:20]1([C:18]([NH:17][C:15]2[N:16]=[C:11]3[CH:10]=[CH:9][C:8]([O:7][C:6]4[CH:23]=[C:2]([NH:1][C:31](=[O:32])[C:30]5[CH:34]=[CH:35][CH:36]=[C:28]([C:27]([F:26])([F:37])[F:38])[CH:29]=5)[CH:3]=[CH:4][C:5]=4[O:24][CH3:25])=[N:13][N:12]3[CH:14]=2)=[O:19])[CH2:21][CH2:22]1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: COc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Agent: Cl
Solvent: CN1CCCC1=O
Product: COc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80 %

Procedure:
To a solution of N-[6-(5-amino-2-methoxyphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.44 mmol) in N-methylpyrrolidone (6.0 mL) was added 3-(trifluoromethyl)benzoyl chloride (92 mg, 0.44 mmol) under ice-cooling, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with 1N hydrochloric acid and extracted with ethyl acetate, and the organic layer was washed with 5% aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate/hexane=50/50→100/0), and precipitated from ethyl acetate/diisopropyl ether to give the title compound (180 mg, 80%) as a white powder.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([NH:18]C=O)/[CH:6]=[C:7](\[CH2:15][CH2:16][CH3:17])/[CH2:8][P:9]([O:13]C)([O:11]C)=[O:10])C>O>[NH2:18][CH:5](/[CH:6]=[C:7](\[CH2:15][CH2:16][CH3:17])/[CH2:8][P:9]([OH:13])([OH:11])=[O:10])[C:4]([OH:21])=[O:3]
Reactant: CCC/C(=C\C(NC=O)C(=O)OCC)CP(=O)(OC)OC
Solvent: O
Product: CCC/C(=C\C(N)C(=O)O)CP(=O)(O)O

Procedure:
Hydrolysis of E-2-formylamino-4-propyl-5-dimethylphosphono-3-pentenoic acidethyl ester in a manner analogous to that described in Example 11 yields E-2-amino-4-propyl-5-phosphono-3-pentenoic acid, m.p. 193° (H2O).
Reaction SMILES: [C:1]1([N:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:23][C:24]1[CH:29]=[N:28][C:27](Br)=[CH:26][N:25]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[Br:23][C:24]1[N:25]=[CH:26][C:27]([C:11]2[CH:12]=[CH:13][C:8]([N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:9][CH:10]=2)=[N:28][CH:29]=1
Reactant: Brc1cnc(Br)cn1
Reactant: OB(O)c1ccc(N(c2ccccc2)c2ccccc2)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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Brc1cnc(-c2ccc(N(c3ccccc3)c3ccccc3)cc2)cn1
Temperature: 85 °C
Yield: 68.2 %

Procedure:
A mixture of (4-(diphenylamino)phenyl)boronic acid (3.26 g, 11.3 mmol), 2,5-dibromopyrazine (5.82 g, 22.6 mmol), Pd(PPh3)4 (0.635 g, 0.55 mmol), K2CO3 (3.45 g, 25 mmol) in dioxane/water (100 mL/16 mL) was degassed and heated at about 85° C. for about 20 hours. The resulting mixture was poured into ethyl acetate (250 mL), washed with brine, dried over Na2SO4, loaded on silica gel and purified by flash column using eluents of hexanes to hexanes/dichloromethane 4:1. After removal of solvent, a yellow solid (Compound 19) was obtained (3.1 g, in 68.2% yield).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[C:9]([Cl:10])=[N:8][C:7]([Cl:11])=[N:6][C:5]=2[N:12]=1.Cl.[OH-:14].[Na+]>>[Cl:11][C:7]1[N:8]=[C:9]([Cl:10])[C:4]2[S:3][C:2](=[O:14])[NH:12][C:5]=2[N:6]=1
Reactant: Clc1nc(Cl)c2sc(Cl)nc2n1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: O=c1[nH]c2nc(Cl)nc(Cl)c2s1
Temperature: 60 °C
Yield: 50 %

Procedure:
A suspension of the trichloro compound (22: 3.0 g, 12 mmol) in 1N NaOH (35 mL) was heated at 60° C. for 1 h. The solution was treated with decolorizing carbon and then acidified with 10% aqueous HCl. The resulting precipitate was collected and reprecipitated from dilute base with glacial acetic acid to provide 24 as orange needles (1.38 g, 50%): mp. 191°-192° C.: UV λmax (pH 1) 254 nm (ε5,300), 290 (11,400): UV λmax (pH 7, 11) 226 nm (ε28,900), 300 (14,100). Anal. Calcd. for C5HCl2N3OS: C, 27.04: H, 0.45: Cl, 31.93: N, 18.93. Found: C, 26.78: H, 0.61: Cl, 32.15: N, 18.66.
Reaction SMILES: O1CCOCC1.Cl.[CH2:8]([O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N:23]#[C:24][NH2:25].O>CCOCC>[CH2:8]([O:15][C:16]1[CH:17]=[C:18]([NH:19][C:24]([NH2:25])=[NH:23])[CH:20]=[CH:21][CH:22]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: N#CN
Reactant: Nc1cccc(OCc2ccccc2)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CCOCC
Product: N=C(N)Nc1cccc(OCc2ccccc2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A 4 N HCl dioxane suspension of 3-benzyloxyaniline (1.0 equivalent) and cyanamide (1.0 equivalent) was stirred at 100° C. overnight. To the reaction mixture was added water and ether. The aqueous layer was washed with ether twice. The aqueous layer was adjusted to a pH greater 10 with 1M NaOH, and the desired guanidine was extracted to methylene chloride, precipitated and filtered. The filtration cake was N-(3-benzyloxy-phenyl)-guanidine (greater than 80% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]#[N:38])[CH:32]=1)=[O:30])C>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][C:9]=1[NH:22][C:27](=[O:26])[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]#[N:38])[CH:32]=1)=[O:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(=O)c1cccc(C#N)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)c2ccccc2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(C(=O)c2ccccc2)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Yield: 29.3 %

Procedure:
Prepared from (2-amino-4-benzoyl-phenyl)-carbamic acid tert.-butyl ester (Example G24) (375 mg, 1.20 mmol) and 3-(3-cyano-phenyl)-3-oxo-propionic acid ethyl ester (Pol. J. Chem. 1978, 25) (313 mg, 1.44 mmol) according to the general procedure K. Obtained as a light yellow solid (170 mg).
Reaction SMILES: C([Si](C)(C)[N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[CH:8]=[CH:7]1)(C)(C)C.Cl[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH:25]2[CH2:30][C:29]([CH3:32])([CH3:31])[NH:28][C:27]([CH3:34])([CH3:33])[CH2:26]2)[N:19]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[NH:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8]([C:22]2[CH:23]=[CH:18][N:19]=[C:20]([NH:24][CH:25]3[CH2:30][C:29]([CH3:32])([CH3:31])[NH:28][C:27]([CH3:34])([CH3:33])[CH2:26]3)[N:21]=2)=[CH:7]1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Reactant: CC(C)(C)[Si](C)(C)n1ccc2cccnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC1(C)CC(Nc2nccc(-c3c[nH]c4ncccc34)n2)CC(C)(C)N1

Procedure:
The title compound was prepared as described in Example 215, starting from 1-(tert-butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridine (prepared by TBDMS protection of 1H-pyrrolo[2,3-b]pyridine) and (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine, followed by in situ cleavage of the TBDMS protecting group with catalytic amounts of TBAF.
Reaction SMILES: Cl.[F:2][C:3]([F:12])([F:11])[C:4]1[CH:5]=[C:6]([NH2:10])[CH:7]=[CH:8][CH:9]=1.[C:13](#[N:16])[CH:14]=[CH2:15].C(NCC)C.[OH-].[Na+]>>[F:2][C:3]([F:11])([F:12])[C:4]1[CH:5]=[C:6]([NH:10][CH:14]([CH3:15])[C:13]#[N:16])[CH:7]=[CH:8][CH:9]=1
Reactant: C=CC#N
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCNCC
Product: CC(C#N)Nc1cccc(C(F)(F)F)c1
Temperature: 180 °C
Reaction time: 2.5 h

Procedure:
A mixture of 70 parts of 3-(trifluoromethyl)benzeneamine hydrochloride, 26.5 parts of 2-propenenitrile and 36.5 parts of N-ethylethanamine was stirred for 2.5 hours at 180° C. After cooling to 0° C., the whole was treated with a sodium hydroxide solution. The product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated, yielding 34.5 parts (45%) of 3-[[(3-(trifluoromethyl)phenyl]amino]propanenitrile as a residue (int. 105).
Reaction SMILES: C1(S[CH2:8][N:9]2[C:13](=[O:14])[CH:12]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[N:11]([CH3:20])[S:10]2(=[O:22])=[O:21])C=CC=CC=1.C(Cl)[Cl:24]>>[Cl:24][CH2:8][N:9]1[C:13](=[O:14])[CH:12]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[N:11]([CH3:20])[S:10]1(=[O:22])=[O:21]
Reactant: ClCCl
Reactant: CC(C)CCC1C(=O)N(CSc2ccccc2)S(=O)(=O)N1C
Product: CC(C)CCC1C(=O)N(CCl)S(=O)(=O)N1C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 70 %

Procedure:
To a solution of 2-phenylthiomethyl-4-(3-methylbutyl)-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (8.15 g, 24.66 mmol) in 200 ml of methylene chloride was added in one portion under nitrogen sulfuryl chloride (2.36 ml, 29.6 mmol) and the mixture was stirred for 3.5 hours at room temperature. The mixture was concentrated in vacuo and the residue was triturated in hexane to afford 4.64 g (70%) of 2-chloromethyl-4-(3-methylbutyl)-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula II: R1 =H; R2 =(CH2)2CH(CH3)2 ; R3 =CH3 ; X'=Cl) as a solid, m.p. 59°-60° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[C@H:6](/[CH:7]=[CH:8]/[C:9](/[CH3:16])=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C@@:5]1([CH3:31])[C:17]1[CH:26]=[CH:25][C:24]2[C:23]([CH3:28])([CH3:27])[CH2:22][CH2:21][C:20]([CH3:30])([CH3:29])[C:19]=2[CH:18]=1.COC[C@H]1[C@H](C=O)[C@]1(C)C1C=CC2C(C)(C)CCC(C)(C)C=2C=1>>[CH3:1][O:2][CH2:3][C@H:4]1[C@H:6](/[CH:7]=[CH:8]/[C:9](/[CH3:16])=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C@@:5]1([CH3:31])[C:17]1[CH:26]=[CH:25][C:24]2[C:23]([CH3:28])([CH3:27])[CH2:22][CH2:21][C:20]([CH3:30])([CH3:29])[C:19]=2[CH:18]=1
Reactant: CCOC(=O)/C=C(C)/C=C/[C@H]1[C@@H](COC)[C@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: COC[C@H]1[C@H](C=O)[C@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: CCOC(=O)/C=C(C)/C=C/[C@H]1[C@H](COC)[C@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 76 %

Procedure:
Following a procedure similar to that for the preparation of Compound 16a but using Intermediate 14a as the starting material afforded the title compound (32 mg, 76% yield) as a white solid:
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[C:18](C1C=CC=CC=1)(=[O:25])[C:19]1C=CC=C[CH:20]=1.C(Cl)(=O)C=C>O>[C:18]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1)(=[O:25])[CH:19]=[CH2:20]
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Agent: C=CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CC(=O)Oc1ccc(C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 100 g quantity of 4-hydroxybenzophenone was added to 500 ml of water containing 22.0 g of sodium hydroxide. The solution was stirred until all of the benzophenone had dissolved. After the solution had cooled to 5°-10° C., there was added 45.5 g of acrylyl chloride over a period of 30 minutes, to yield a white solid which was recovered by filtration after the solution had been stirred for 2 hours at 5°-10° C. and an additional hour at room temperature. The white solid was recrystallized from ethanol and found to have m.p. 44°-46° C. Infrared and NMR spectra confirmed the structure of 4-acryloxybenzophenone.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18](Br)[CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[CH3:32][C:33]1[CH:38]=[C:37]([CH3:39])[CH:36]=[CH:35][C:34]=1[N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:43]3[CH2:44][CH2:45][N:40]([C:34]4[CH:35]=[CH:36][C:37]([CH3:39])=[CH:38][C:33]=4[CH3:32])[CH2:41][CH2:42]3)[CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(Br)c1)N2
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N3CCN(c4ccc(C)cc4C)CC3)c1)N2
Temperature: 120 °C
Reaction time: 12 h
Yield: 40.2 %

Procedure:
To a mixture of 2-(3-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (388 mg, 1 mmol), palladium acetate (6.73 mg, 0.03 mmol), cesium carbonate (0.65 g, 2 mmol), xantphos (23 mg, 0.04 mmol) and 1-(2,4-dimethyl-phenyl)-piperazine hydrochloride (285 mg, 1.5 mmol) in toluene (10 mL) was stirred at 120° C. for 12 hours. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×100 mL), washed with saturated aqueous sodium chloride (2×50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (20% ethyl acetate/hexanes) to afford 2-{3-[4-(2,4-dimethyl-phenyl)-piperazin-1-yl]-phenyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.20 g, 40%) as a white solid: LC/MS m/e calcd for C32H39N3O2 (M+H)+: 498.7, observed: 498.9.