Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH:9]([S:11][C:12]3[NH:16][N:15]=[N:14][N:13]=3)[CH3:10])[CH2:7][S:8][C@H:3]12.C(OC([NH:29][CH:30]([C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:41]([NH2:43])=[O:42])=[CH:36][CH:35]=1)[C:31](O)=[O:32])=O)(C)(C)C>>[CH3:10][CH:9]([S:11][C:12]1[NH:13][N:14]=[N:15][N:16]=1)[C:6]1[CH2:7][S:8][C@@H:3]2[CH:2]([NH:1][C:31](=[O:32])[CH:30]([C:34]3[CH:35]=[CH:36][C:37]([NH:40][C:41]([NH2:43])=[O:42])=[CH:38][CH:39]=3)[NH2:29])[C:20](=[O:21])[N:4]2[C:5]=1[C:17]([OH:19])=[O:18]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccc(NC(N)=O)cc1
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Product: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)C(N)c3ccc(NC(N)=O)cc3)[C@H]2SC1

Procedure:
When 7-amino-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (3.28 g, 0.01 mol) was acylated with the product of Example 1 (3.1 g, 0.01 mol) according to the procedure of Example 2, the title compound was obtained: mp > 300°.
Reaction SMILES: C(N1C2C(=CC=CC=2)C(O)(CC(=O)C2C=CC=CN=2)C1=O)CCC.[CH3:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([CH2:35][CH2:36][CH3:37])[C:30](=[O:38])[C:29]2=[O:39].[NH:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:42]([C:49](=[O:51])[CH3:50])=[CH:41]1>>[NH:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:42]([C:49](=[O:51])[CH2:50][C:29]2([OH:39])[C:28]3[C:32](=[CH:33][CH:34]=[C:26]([CH3:25])[CH:27]=3)[N:31]([CH2:35][CH2:36][CH3:37])[C:30]2=[O:38])=[CH:41]1
Reactant: CC(=O)c1c[nH]c2ccccc12
Reactant: CCCN1C(=O)C(=O)c2cc(C)ccc21
Agent: CCCCN1C(=O)C(O)(CC(=O)c2ccccn2)c2ccccc21
Product: CCCN1C(=O)C(O)(CC(=O)c2c[nH]c3ccccc23)c2cc(C)ccc21

Procedure:
This compound was made in a similar manner to 1-butyl-3-hydroxy-3-(2-oxo-2-(pyridin-2-yl)ethyl)indolin-2-one using 5-methyl-1-propylindoline-2,3-dione and commercially available 1-(1H-indol-3-yl)ethanone (purchased from Fisher Scientific). 1H-NMR δ 9.02 (bs, 1H), 8.36 (d, 1H), 7.71 (m, 1H), 7.40 (m, 1H), 7.30-7.26 (m, 3H), 7.09 (d, 1H), 6.73 (d, 1H), 5.66 (s, 1H), 3.64 (m, 2H), 3.50 (d, 1H), 3.24 (d, 1H), 2.26 (s, 3H) 1.72 (m, 2H), 0.96 (t, 3H). Calculated mass for C22H22N2O3, 362.16. Observed 385.1 (M+Na).
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:5].[CH3:20][CH:21]1[CH2:26][CH:25]([CH3:27])[CH2:24][NH:23][CH2:22]1.C(=O)([O-])[O-].[Ca+2]>C(O)C>[CH3:20][CH:21]1[CH2:26][CH:25]([CH3:27])[CH2:24][N:23]([C:2]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=2[C:4]([C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=2)=[O:5])[CH2:22]1
Reactant: O=C(c1ccc(Cl)cc1)c1cc([N+](=O)[O-])ccc1Cl
Reactant: CC1CNCC(C)C1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCO
Product: CC1CC(C)CN(c2ccc([N+](=O)[O-])cc2C(=O)c2ccc(Cl)cc2)C1
Yield: 98.1 %

Procedure:
Proceeding as indicated in example 2, with 0.035 mole (10.4 g) of 2,4'-dichloro-5-nitro-benzophenone, 0.07 mole (8 cm3) of 3,5-dimethylpiperidine and 0.035 mole (5 g) of calcium carbonate in ethanol, 12.8 g (Yield: 97%) of the expected product are obtained. M.P 159° C.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[C:13]([Si:15]([CH3:18])([CH3:17])[CH3:16])#[CH:14].C(NC(C)C)(C)C>C1COCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:16][Si:15]([C:13]#[C:14][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1)([CH3:18])[CH3:17]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C#C[Si](C)(C)C)cc1
Yield: 73 %

Procedure:
A mixture of ethyl 4-bromobenzoate (1.5 g, 6.55 mmol), ethynyl trimethylsilane (965 mg, 9.82 mmol), diisopropylamine (1.39 g, 13.7 mmol), cuprous iodide(25 mg, 0.131 mmol), and bis(triphenylphosphine) palladium(II) chloride (184 mg, 0.262 mmol) was heated at 45° C. for 4 h in dry THF (10 ml) under argon atmosphere. The reaction was quenched by the addition of water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel flash column chromatography (eluent: hexane/ethyl acetate=100/1) to give ethyl 4-[(trimethylsilyl)ethynyl]benzoate (73%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=2)=[N:5][N:6]=1.[C:17](OC1C(Cl)=CC(Cl)=CC=1Cl)(=[O:22])[CH2:18][C:19]([O-])=[O:20]>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([C:4]2[S:3][C:2]3=[N:1][C:17]([OH:22])=[CH:18][C:19](=[O:20])[N:6]3[N:5]=2)=[CH:8][CH:9]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: O=C([O-])CC(=O)Oc1c(Cl)cc(Cl)cc1Cl
Reactant: CC(C)(C)c1ccc(-c2nnc(N)s2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CC(C)(C)c1ccc(-c2nn3c(=O)cc(O)nc3s2)cc1
Yield: 96.6 %

Procedure:
A mixture of 9.3 g of 2-amino-5-(4-tert-butylphenyl)-1,3,4-thiadiazole, 20 g of 2,4,6-trichlorophenyl malonate and 50 ml of Dowtherm A was heated at a temperature of 120° to 130° C. for 2 hours. After allowing the mixture to cool, the precipitate was separated by filtration, washed successively with isopropanol and diethyl ether to obtain 11.6 g of 2-(4-tert-butylphenyl)-7-hydroxy-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one as a colorless, crystalline powder having a melting point of 265° to 268° C. (decomposition).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([N:15]3[CH:20]4[CH2:21][CH2:22][CH:16]3[CH2:17][CH:18]([OH:23])[CH2:19]4)=[O:14])=[CH:12][C:7]=2[N:6]=[CH:5]1.CCN(C(C)C)C(C)C.[O:33]=[S:34]1(=[O:43])[CH2:39][CH2:38][N:37]([C:40](Cl)=[O:41])[CH2:36][CH2:35]1>C1COCC1>[OH:23][CH:18]1[CH2:19][CH:20]2[N:15]([C:13]([C:11]3[CH:10]=[CH:9][C:8]4[N:4]([CH2:3][CH2:2][NH:1][C:40]([N:37]5[CH2:38][CH2:39][S:34](=[O:43])(=[O:33])[CH2:35][CH2:36]5)=[O:41])[CH:5]=[N:6][C:7]=4[CH:12]=3)=[O:14])[CH:16]([CH2:22][CH2:21]2)[CH2:17]1
Reactant: O=C(Cl)N1CCS(=O)(=O)CC1
Reactant: NCCn1cnc2cc(C(=O)N3C4CCC3CC(O)C4)ccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCn1cnc2cc(C(=O)N3C4CCC3CC(O)C4)ccc21)N1CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 2.3 %

Procedure:
To a solution of [1-(2-aminoethyl)-1H-benzimidazol-5-yl]-(3-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-methanone (0.2 g, 0.636 mmol) in dry THF (5 mL) was added DIPEA (0.3 mL, 1.91 mmol) at 0° C. To this reaction mixture was added 1,1-dioxo-thiomorpholine-4-carbonyl chloride slowly and stirred for 2 h at ambient temperature. The solvents were evaporated and the residue purified by preparative HPLC to afford 1,1-dioxo-thiomorpholine-4-carboxylic acid {2-[5-(3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carbonyl)-benzoimidazol-1-yl]-ethyl}-amide (0.007 g, 2.3%). MS-ESI m/z 476 (M+1); 1H-NMR (300 MHz, CD3OD) δ 1.5 (t, 1H), 1.8 (m, 4H), 2.1 (brs, 3H), 2.8 (s, 4H), 3.6 (t, 2H), 3.8 (s, 4H), 4.2 (m, 2H), 4.5 (t, 2H), 4.7 (s, 1H), 7.5 (d, 1H), 7.7 (d, 1H), 7.85 (s, 1H), 8.3 (s, 1H). HPLC (VERYPOL.M): tr=6.24 min (97%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9])=[CH:6][C:5]([Br:16])=[CH:4][N:3]=1.Cl[CH2:18][C:19](=O)[CH3:20]>C(O)C>[Br:16][C:5]1[CH:6]=[C:7]([S:8]([NH:11][C:12]([CH3:13])([CH3:15])[CH3:14])(=[O:10])=[O:9])[C:2]2[N:3]([CH:18]=[C:19]([CH3:20])[N:1]=2)[CH:4]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cc(Br)cnc1N
Reactant: CC(=O)CCl
Solvent: CCO
Product: Cc1cn2cc(Br)cc(S(=O)(=O)NC(C)(C)C)c2n1
Temperature: 80 °C
Reaction time: 48 h
Yield: 65.5 %

Procedure:
To a solution of 2-amino-5-bromo-N-tert-butylpyridine-3-sulfonamide (3.0 g, 9.7 mmol) in ethanol (6 mL) was added chloroacetone (3.0 mL, 48 mmol) and the reaction mixture was stirred at 80° C. for 48 h. The solvents were evaporated under reduced pressure and the residue was purified by flash silica gel column chromatography (5% methanol in DCM) to yield 6-bromo-N-tert-butyl-2-methylimidazo[1,2-a]pyridine-8-sulfonamide (2.2 g, 66%), which was used without further purification. LCMS Method T: retention time 1.33 min; [M+1]=346.64.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].[CH3:5][CH:6]([N:11]=[N:12][C:13](Br)([CH2:15][CH3:16])[CH3:14])[CH2:7][CH:8]([CH3:10])[CH3:9].O>CC(C)=O>[CH3:5][CH:6]([N:11]=[N:12][C:13]([N:3]=[C:2]=[O:1])([CH2:15][CH3:16])[CH3:14])[CH2:7][CH:8]([CH3:9])[CH3:10]
Reactant: N#C[O-]
Reactant: CCC(C)(Br)N=NC(C)CC(C)C
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCC(C)(N=C=O)N=NC(C)CC(C)C
Temperature: 25 °C

Procedure:
To a stirred solution of 3.25 grams (.04 moles) of potassium cyanate in 75 ml of 70% aqueous acetone in a 125 ml erlenmeyer flask was added 9.4 grams (.0377 moles) of 2-(1,3-dimethylbutylazo)2-bromobutane (from Example III) over 5 minutes while holding the reaction temperature at 15°-20° C with a cold water bath. After the addition was complete the reaction was stirred an additional hour at room temperature, poured into 200 ml of water and the product extracted with 100 ml of pentane. The pentane solution was separated, washed with 50 ml portions of water and saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure on a rotating evaporator. The product was a yellow liquid and weighed 6.4 grams (80.5% crude yield). The infrared spectrum was in agreement with the structure of 2-(1,3-dimethylbutylazo)-2-isocyanatobutane (strong broad isocyanate band at 2125-2225 cm-1).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13](O)=[O:14])[N:10]=[C:9]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:8]=2)=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1.Cl.[NH:53]1[CH2:58][CH2:57][CH:56]([N:59]2[CH2:63][CH2:62][CH2:61][C:60]2=[O:64])[CH2:55][CH2:54]1>CC(N(C)C)=O>[F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:53]3[CH2:54][CH2:55][CH:56]([N:59]4[CH2:63][CH2:62][CH2:61][C:60]4=[O:64])[CH2:57][CH2:58]3)=[O:14])[N:10]=[C:9]([C:16]3[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=3)[CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCCN1C1CCNCC1
Reactant: O=C(O)Cn1nc(-c2ccncc2)cc1Cc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CC(=O)N(C)C
Product: O=C(Cn1nc(-c2ccncc2)cc1Cc1ccc(F)cc1)N1CCC(N2CCCC2=O)CC1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
To a solution of [5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetic acid (164 mg, 0.53 mmol) in DMA (3 mL) at room temperature was added HOBt (78 mg, 0.58 mmol), EDCI (111 mg, 0.58 mmol), NMM (0.20 mL, 1.84 mmol) and 1-piperidin-4-ylpyrrolidin-2-one hydrochloride (150 mg, 0.73 mmol) and the mixture sonicated to a fine suspension and stirred for 64 hours at room temperature. The volatiles were removed under high vacuum and the residue partitioned between EtOAc (70 mL) and water (25 mL). The aqueous layer was removed and the organics washed with NaHCO3 (30 mL), brine (30 mL), dried over MgSO4, filtered and stripped to yield the title compound as an off-white solid, 123 mg, 51%. 1H NMR (400 MHz, DMSO-D6) δ ppm 8.51-8.54 (2 H, m), 7.64-7.69 (2 H, m), 7.25-7.35 (2 H, m), 7.11-7.21 (2 H, m), 6.53 (1 H, s), 5.11-5.28 (2 H, m), 4.37 (1 H, d, J=13.14 Hz), 3.90-4.05 (4 H, m), 3.23-3.31 (2 H, m), 3.08-3.20 (1 H, m), 2.57-2.70 (1 H, m), 2.22 (2 H, t, J=8.08 Hz), 1.84-1.95 (2 H, m), 1.40-1.73 (4 H, m); m/z (APCI+) for C26H28N5O2F 462.2 (M+H)+.
Reaction SMILES: [Mg].[Cl:2][C:3]1[CH:8]=[CH:7][C:6](I)=[C:5]([Cl:10])[CH:4]=1.[CH2:11]([O:13][C:14](=[O:20])[C:15](OCC)=[O:16])[CH3:12].[NH4+].[Cl-]>C(OCC)C.C(Br)C>[CH2:11]([O:13][C:14](=[O:20])[C:15]([C:6]1[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][C:5]=1[Cl:10])=[O:16])[CH3:12]
Reactant: Clc1ccc(I)c(Cl)c1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCBr
Solvent: CCOCC
Product: CCOC(=O)C(=O)c1ccc(Cl)cc1Cl
Temperature: -70 °C
Yield: 80.1 %

Procedure:
A suspension of magnesium (6.7 g; 0.275 moles) in ethyl ether (125 ml) under stirring and nitrogen flow was added with ethyl bromide (180 mg). A solution of 1,3-dichloro-4-iodobenzene (50 g; 0.183 moles) and ethyl bromide (180 mg) in ethyl ether (100 ml) was dropped in about 1 hour keeping the temperature at 15-20° C. The suspension was stirred for further 2 hours. After decanting the magnesium in excess, the solution was dropped in about 1 hour in a solution of diethyloxalate (29.32 g; 0.2 moles) in ethyl ether (125 ml) cooled to −70° C. At the end of the addition it was stirred at −70° C. for 1 hour, then the temperature was left to rise to 10° C. and the stirring was kept on for another hour. The suspension was added with a saturated solution of NH4Cl (125 ml), the phases were separated and the aqueous one extracted with ethyl acetate (50 ml). The organic phases were washed with a solution of sodium bisulfite and treated with discolouring charcoal. After filtration, the organic solution was distilled under vacuum to give a crude which was purified by chromatography (SiO2; hexane/ethyl ether 9/1) to give 36.2 g of (2,4-dichloro-phenyl)-oxo-acetic acid ethyl ester (yield 80%) as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH3:24][O:25][CH2:26][C:27](Cl)=[O:28]>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:27](=[O:28])[CH2:26][O:25][CH3:24])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: COCC(=O)Cl
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)COC)nc3cc21

Procedure:
N-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-2-methoxy-acetamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and methoxyacetyl chloride (81 μl, 0.89 mmol). The title compound was obtained as light brown powder (171 mg, 55%).
Reaction SMILES: [CH:1]([CH:4]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1)[C:5]#[N:6])([CH3:3])[CH3:2].[NH2-].[Na+].Br[CH2:20][CH2:21][CH2:22][Cl:23]>C1(C)C=CC=CC=1>[CH3:16][O:15][C:9]1[CH:8]=[C:7]([C:4]([CH:1]([CH3:3])[CH3:2])([CH2:20][CH2:21][CH2:22][Cl:23])[C:5]#[N:6])[CH:12]=[CH:11][C:10]=1[O:13][CH3:14]
Reactant: COc1ccc(C(C#N)C(C)C)cc1OC
Reactant: ClCCCBr
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(C(C#N)(CCCCl)C(C)C)cc1OC
Temperature: 15 °C
Reaction time: 2 h

Procedure:
A solution of 2-(3,4-dimethoxyphenyl)-2-isopropylacetonitrile (6a) in toluene is slowly added to sodium amide (1.5 eq) in toluene, and the resulting mixture warmed to 80°-90° C. for one hour. The mixture was then cooled to 15° C. and 1-bromo-3-chloropropane (2 eq) slowly added and stirred for two hours at room temperature. The mixture is then carefully poured into ice water, extracted with CH2Cl2, and vacuum distilled to yield 2-(3,4-dimethoxyphenyl)-2-isopropyl-2-(3-chloropropyl)acetonitrile (21, b.p. 160°-165°/0.05 mmHg).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:10][CH2:11][CH3:12].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH2:13]([O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:10][CH2:11][CH3:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCCc1cc(C#N)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1cc(C#N)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.6 %

Procedure:
To a solution of 4-hydroxy-3-propylbenzonitrile (0.97 g, 6 mmol) (Example 29) in DMF (20 mL) were added 10 drops of water, benzyl bromide (2.05 g, 12 mmol), and Cs2CO3 (2.93 g, 9 mmol), and the mixture was stirred for 12 h at rt. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in EtOAc and filtered. The precipitate was washed with more EtOAc. The combined filtrates were concentrated and purified by silica gel chromatography (EtOAc/hexanes (v/v)=1:19) to give 1.23 g (82%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 7.48-7.32 (m, 7H), 6.92 (d, 1H), 5.13 (s, 2H), 2.67 (t, 2H), 1.72-1.60 (m, 2H), 0.98 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].CN(C(/N=N/C(N(C)C)=O)=O)C.C(OC([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[C:36]([O:41][CH2:42][CH2:43]O)=[N:37][CH:38]=[CH:39][N:40]=2)[CH2:31][CH2:30]1)=O)(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[N:32]1([C:35]2[C:36]([O:41][CH2:42][CH2:43][O:9][C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])=[N:37][CH:38]=[CH:39][N:40]=2)[CH2:33][CH2:34][NH:29][CH2:30][CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCO)CC1
Reactant: Oc1c(F)cccc1F
Agent: CN(C)C(=O)/N=N/C(=O)N(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Fc1cccc(F)c1OCCOc1nccnc1N1CCNCC1

Procedure:
The title compound was prepared according to the procedure of Example 77 starting from 2,6-difluorophenol (239 mg, 1.84 mmol), TMAD (384 mg, 2.25 mmol), 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (600 mg, 1.86 mmol; prepared in Example 52, Step 2), and triphenylphosphine (969 mg, 3.69 mmol) to give 279 mg (45%) of a solid: mp 101-102° C. HRMS m/z calcd for C16H18F2N4O2 (M)+336.1398, found 336.1403.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[N+:14]([C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19])([O-:16])=[O:15].Cl.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N+:14]([O-:16])=[O:15])=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: CSc1ncnc2cc(N)ncc12
Reactant: Nc1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Nc1cc2ncnc(Nc3ccccc3[N+](=O)[O-])c2cn1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 33.3 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (220 mg, 1.15 mmole) and 2-nitroaniline (2.00 g, 14.5 mmole) is heated to 100° C., then excess dry HCl gas is added to the hot stirred solution, and the mixture stirred at 160° C. for 20 min. The resulting product is neutralized with excess NaHCO3, dissolved in MeOH/CHCl3, dried onto silica gel and chromatographed over silica gel (2-4% MeOH/CH2Cl2) to give 7-amino-4-(2-nitroanilino)pyrido[4,3-d]pyrimidine (108 mg, 33%) as a yellow brown solid. 1H NMR (DMSO) δ 10.40 (1H, brs), 9.24 (1H, brs), 8.20 (1H, brs), 8.12 (1H, brs), 8.01 (2H, brs), 7.75 (1H, brs), 6.70 (2H, brs), 6.43 (1H, brs)
Reaction SMILES: [CH2:1]([N:6]1[CH2:11][CH2:10][C:9]2([C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[NH:26][C:27]([NH:29]C(=O)C3C=CC=CC=3)=[S:28])[CH2:12]2)[CH2:8][CH2:7]1)[C:2]([CH3:5])([CH3:4])[CH3:3].[Li+].[OH-]>C1COCC1.CO>[CH2:1]([N:6]1[CH2:7][CH2:8][C:9]2([C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[NH:26][C:27]([NH2:29])=[S:28])[CH2:12]2)[CH2:10][CH2:11]1)[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)CN1CCC2(CC1)CN(c1ccccc1NC(=S)NC(=O)c1ccccc1)c1ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)CN1CCC2(CC1)CN(c1ccccc1NC(N)=S)c1ccccc12
Temperature: 50 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
A mixture of 20g (138 mg, 0.27 mmol) and 1 N LiOH (0.5 mL) in THF/MeOH (2:1, 3 mL) was stirred at 50° C. for 2 h. The reaction was concentrated and the residue was extracted with EtOAc. The combined organic layers were dried over magnesium sulfate, concentrated and purified by flash chromatography (silica gel, 0-10% MeOH/DCM) to give 20h as yellow solid (83 mg). LC-MS m/z 409.0 [M+H]+.
Reaction SMILES: [CH:1]([NH:4][C:5]([N:7]1[CH2:12][CH2:11][N:10](C(OCC2C=CC=CC=2)=O)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[CH:1]([NH:4][C:5]([N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)NC(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)NC(=O)N1CCNCC1
Yield: 130.4 %

Procedure:
To a solution of benzyl 4-(isopropylcarbamoyl)piperazine-1-carboxylate (3, 3.94 g, 12.9 mmol) in methanol (100 mL) was added 10% Pd/C (50% wet, 0.400 g) and the mixture was stirred under 1 atmosphere of hydrogen for 16 h. After this time, the mixture was filtered through Celite and the filtrate concentrated to afford the title compound (2.88 g, >99%): 1H NMR (300 MHz, CD3OD) δ 4.00-3.80 (m, 1H), 3.45-3.35 (m, 4H), 2.88-2.78 (m, 4H), 1.13 (d, J=6.5 Hz, 6H); Multimode MS m/z 172 [M+H]+.
Reaction SMILES: [Br-].[CH3:2][Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:12]([O:19][C:20](=[O:37])[CH2:21][CH2:22][C:23](=O)[CH2:24][CH2:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1.O>[CH2:12]([O:19][C:20](=[O:37])[CH2:21][CH2:22][C:23](=[CH2:2])[CH2:24][CH2:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(CCC(=O)OCc1ccccc1)CCC(=O)OCc1ccccc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(CCC(=O)OCc1ccccc1)CCC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.9 %

Procedure:
Methyltriphenylphsphonium bromide (536 mg, 1.5 mmol) was suspended in anhydrous THF (1.0 mL) at −5° C. A THF solution of NaHMDS (1.0 M, 1.5 mL, 1.5 mmol) was added dropwise to keep the temperature below 0° C. The mixture was stirred at 0° C. for 0.5 h before cooled to −78° C. To this ylid solution was added a solution of dibenzyl-4-oxopimelate (354 mg, 1.0 mmol) in THF (1.0 mL) dropwise to keep the temperature below −50° C. The temperature was allowed to rise to room temperature in 1.5 h with stirring after addition. The reaction mixture was then poured in icy water (25 mL) and extracted with Et2O (2×25 mL). The organic layer was washed with brine (20 mL) and dried over Na2SO4. The solvent was removed under vacuum and the residue was subjected to silica chromatography (EtOAc/hexanes, up to 1/10) to give compound B4 (197 mg). The yield was 56%. 1H NMR (200 MHz, CDCl3) δ 7.37 (m, 10H), 5.11 (s, 4H), 4.78 (d, 2H, J=1.1 Hz), 2.53 (m, 4H), 2.39 (m, 4H); 13C NMR (50 MHz, CDCl3) δ 173.3, 146.6, 136.4, 129.0, 128.7, 110.5, 66.9, 33.2, 31.6; MS (MALDI-TOF) calcd (M+Na+) 375.4, found 375.6.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[O:5][CH2:6][CH2:7][NH2:8].I.CS[C:16]1[NH:25][CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1>C(#N)C.C(O)(C(F)(F)F)=O>[N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:24][NH:25][C:16]=1[NH:8][CH2:7][CH2:6][O:5][C:4]1[CH:9]=[CH:10][CH:11]=[CH:12][C:3]=1[O:2][CH3:1]
Reactant: COc1ccccc1OCCN
Reactant: CSC1=Nc2ccccc2CN1
Agent: I
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1OCCNC1=Nc2ccccc2CN1
Temperature: 80 °C
Yield: 61.4 %

Procedure:
2-(2-Methoxy-phenoxy)-ethylamine (42 mg, 0.25 mmol) was added to a solution of 2-methylsulfanyl-3,4-dihydro-quinazoline hydroiodide (70 mg, 0.23 mmol) in acetonitrile (1 ml), and the mixture was heated overnight (80° C.) in a screw-capped vial. The title compound (42 mg, 62%) was then isolated from the reaction mixture by preparative, reverse-phase HPLC (YMC CombiPrep C18 column 50×20 mm, solvent gradient 5-95% CH3CN in 0.1% TFA(aq) over 6.0 min, λ=230 nm, flow rate 40 ml/min).