Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:22]([CH2:23][C:24]([OH:26])=O)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:10][CH:9]=1.Cl.Cl.[CH3:29][N:30]([CH3:38])[C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=1.C(N(CC)CC)C>CN(C)C=O.O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:22]([CH2:23][C:24]([NH:37][C:34]3[CH:35]=[CH:36][C:31]([N:30]([CH3:38])[CH3:29])=[CH:32][CH:33]=3)=[O:26])[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:12][CH:13]=1
Reactant: CN(C)c1ccc(N)cc1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C)c1ccc(NC(=O)Cn2c(-c3ccc(Cl)cc3)nc3cccnc32)cc1
Temperature: 60 °C
Yield: 12.7 %

Procedure:
Under a nitrogen atmosphere, oxalyl chloride (2.21 g, 0.0174 mole) was added slowly dropwise to a stirred and cooled (0°-10° C.) suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0174 mole) in 50 ml of dimethylformamide. After the addition was complete, the reaction solution was heated at 60° C. for 5 hrs. This acylchloride solution was added dropwise to a stirred and cooled (<10° C.) suspension of N,N-dimethyl-1,4-phenylenediamine dihydrochloride (3.64 g. 0.0174 mole), triethylamine (5.27 g, 0.052 mole), and 75 ml of dimethylformamide. The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into 1800 ml of water and refrigerated overnight. The solid was collected by filtration and dried. The solid was recrystallized twice from isopropyl alcohol, collected by filtration, washed with water, and dried under high vacuum at 98° C. overnight to give 0.9 g (12.7%) of crystals, mp 245°-246° C.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:16][CH2:17][C@@H:18]([C:20]([O:22][CH3:23])=[O:21])[N:19]=3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.C(OCC)(=O)C.O=[Pt]=O>[C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C@H:15]3[NH:19][C@H:18]([C:20]([O:22][CH3:23])=[O:21])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)[C@@H]1CCC(c2ccc(OCc3ccccc3)cc2)=N1
Agent: O=[Pt]=O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1CC[C@@H](c2ccc(OCc3ccccc3)cc2)N1
Reaction time: 6 h

Procedure:
To a solution of methyl (2S)-5-{4-[(phenylmethyl)oxy]phenyl}-3,4-dihydro-2H-pyrrole-2-carboxylate (D7, 13.7 g, 32.4 mmol) in MeOH (200 ml) was added PtO2 (240 mg) and the mixture was stirred under hydrogen atmosphere (2 atm) for 6 hours. Then the catalyst was filtered off and the solvent removed under reduced pressure to give a red oil which was dissolved in ethyl acetate and washed with NaHCO3 solution. The resulting crude material was purified by chromatography on silica gel eluting with cyclohexane/ethyl acetate (9:1 to 8:2) to afford the title compounds:
Reaction SMILES: [H-].[Na+].CN(C)[CH:5]=[O:6].[CH3:8][CH:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([OH:15])[CH3:14]>O>[CH3:14][CH:13]([O:15][CH2:8][CH2:9][CH2:10][CH2:11][CH:5]1[O:6][CH2:12][CH2:13][O:15]1)[CH2:12][CH2:11][CH2:10][CH:9]([CH3:16])[CH3:8]
Reactant: CC(C)CCCC(C)O
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)CCCC(C)OCCCCC1OCCO1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 19 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.83 g, 20 mmol) and dimethylformamide (70 mL) were charged to a 250 mL three necked flask fitted with thermocouple, magnetic stirrer, condenser and dropping funnel. To the reaction mixture was added dropwise over 10 minutes 6-methylheptan-2-ol (2.77 g, 21 mmol). The reaction mixture was stirred at room temperature for 90 minutes then water (10 mL) was added. The reaction mixture was poured into water (100 mL), extracted with methyltert-butyl ether (2×100 mL), the combined organic phase dried over magnesium sulphate and the solvent removed in vacuo. The pale yellow oil was chromatographed over silica gel to yield 2-{4-[(1,5-dimethylhexyl) oxy]butyl}-1,3-dioxolane as a colourless oil (1.4 g, 73% pure by GC RPA, 3.9 mmol, chemical yield 19%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]OS(C)(=O)=O)=[CH:4][CH:3]=1.BrC1C=CC(CCO)=CC=1.CS(Cl)(=O)=O.[O-:30][S:31]([O-:33])=[O:32].[Na+:34].[Na+]>C(O)C.O>[Na+:34].[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][S:31]([O-:33])(=[O:32])=[O:30])=[CH:6][CH:7]=1
Reactant: O=S([O-])[O-]
Reactant: CS(=O)(=O)OCCc1ccc(Br)cc1
Agent: CS(=O)(=O)Cl
Agent: OCCc1ccc(Br)cc1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=S(=O)([O-])CCc1ccc(Br)cc1

Procedure:
Methanesulfonic acid 2-(4-bromo-phenyl)-ethyl ester (1.39 g) prepared from 2-(4-bromo-phenyl)-ethanol and methanesulfonyl chloride, and Na2SO3 (816 mg) were reacted in ethanol/water (1/1), to obtain a crude product of 2-(4-bromo-phenyl)-ethanesulfonic acid sodium salt as a colorless plate-like crystal. Then, thionyl chloride (3 ml) was left to react in the presence of DMF (500 μl), to obtain 2-(4-bromo-phenyl)-ethanesulfonyl chloride, and further N-methylpiperazine (73 μl) was left to react in dichloromethane (2 ml) in the presence of triethylamine (54 μl), to obtain 1-[2-(4-bromo-phenyl)-ethanesulfonyl]-4-methyl-piperazine as a yellow solid (94 mg, 24%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[Cl:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.C(N(CC)CC)C.[C:20](Cl)(=[O:22])[CH3:21].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[NH:1][C:20](=[O:22])[CH3:21]
Reactant: Nc1cnc2ccccc2c1Cl
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cnc2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-amino-4-chloroquinoline (20.0 g, 112 mmol) in dichloromethane (125 mL) was cooled to 0° C. Triethylamine (47.0 mL, 0.336 mol) was added followed by a solution of acetyl chloride (16.0 mL, 0.224 mol) in dichloromethane (45 mL), which was added dropwise. The reaction was stirred overnight at room temperature. An analysis by LC/MS indicated the presence of starting material, and additional acetyl chloride (4 mL, 56 mmol) was added. The reaction was stirred for four hours at room temperature. Saturated aqueous sodium bicarbonate (100 mL) was added, and the mixture was stirred for three days. The organic layer was separated and washed with saturated aqueous sodium bicarbonate (2×50 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide N-(4-chloroquinolin-3-yl)acetamide as a dark red solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCOC(C)=O>CN(C=O)C>[C:22]1([S:28]([N:14]2[C:15]3[C:11](=[CH:10][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[C:17]([O:18][CH3:19])[CH:16]=3)[CH:12]=[CH:13]2)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1cc2[nH]ccc2cc1OCc1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2c(ccn2S(=O)(=O)c2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
A solution of 5-benzyloxy-6-methoxyindole (990 mg, 3.9 mmol) in DMF (3 mL) was added to a solution of NaH (234 mg, 5.9 mmol, 60% in oil) in DMF (1 mL) at 0° C. The ice bath was removed, and the reaction mixture allowed to stir at RT for 30 min. The reaction flask was cooled to 0° C. and PhSO2Cl (0.6 mL, 4.7 mmol) was added via syringe. The ice bath was removed and the reaction mixture stirred at RT for 24 h. Water (25 mL) was added and the aqueous layer extracted with Et2O (4×50 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give an oil. The residue was purified by column chromatography (25% then 40% EtOAc/hex) to furnish N-phenylsulfonyl 5-benzyloxy-6-methoxyindole as a crystalline solid (1.38 g, 90% yield).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3([CH3:20])[OH:13])[C:6]=2[N:7]=1>CCO.N1C=CC=CC=1.[Pd]>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3([CH3:20])[OH:13])[C:6]=2[N:7]=1
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(Cl)nc(N)nc21
Agent: [Pd]
Solvent: c1ccncc1
Solvent: CCO
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2cnc(N)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
A mixture of 2-amino-4-chloro-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-c]pyrimidine (Example 118, Step B) (20 mg, 0.07 mmol) in EtOH (1.0 mL), pyridine (0.1 mL) and 10% Pd/C (6 mg) under H2 (atmospheric pressure) was stirred overnight at room temperature. The mixture was filtered through a Celite pad which was thoroughly washed with EtOH. The combined filtrate was evaporated and purified on a silica gel column with CH2Cl2/MeOH, 20/1 and 10/1, as eluent to give the title compound as a white solid (16 mg).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]1([CH3:17])[CH:13]=[CH:12][C:11]([CH2:14][C:15]#[N:16])=[CH:10][CH:9]=1.[OH-].[K+]>>[C:1]1(=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([CH3:17])=[CH:9][CH:10]=2)[C:15]#[N:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCC1
Reactant: Cc1ccc(CC#N)cc1
Agent: [K+]
Agent: [OH-]
Product: Cc1ccc(C(C#N)=C2CCCCC2)cc1
Yield: 62.4 %

Procedure:
The procedure outlined in example 1 is repeated with cyclohexanone (22.34 g, 0.29 mol), p-tolylacetonitrile (20.96 g, 0.16 mol) and KOH (1.79 g, 0.032 mol). Short path distillation of the crude at 0.05 mbar/115-130° C. followed by recrystallization from hexane yields 21.1 g (63% yield) of product as white crystals, m.p. 50.5-51.3° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7]([OH:9])=O.[NH:13]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:6]/[C:7]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][CH2:15][CH2:14]2)=[O:9])[CH:10]=[CH:11][CH:12]=1
Reactant: O=C(O)/C=C/c1cccc(Cl)c1
Reactant: O=C1CCNCCN1
Product: O=C1CCN(C(=O)/C=C/c2cccc(Cl)c2)CCN1

Procedure:
In analogy to the procedure described in intermediate 1A, (E)-3-chlorocinnamic acid and 2,3,6,7-tetrahydro-(1H)-1,4-diazepin-5(4H)-one gave the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([O:4][C:5]([NH:7][C@@H:8]([C:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][C:14]([OH:22])([CH2:15]3)[CH2:13]1)[CH2:19]2)[C:9](O)=[O:10])=[O:6])[CH3:3].CS(Cl)(=O)=O.C(N(C(C)C)CC)(C)C.Cl.[C@H:39]12[CH2:44][C@H:43]1[CH2:42][C@@H:41]([C:45]([NH2:47])=O)[NH:40]2.OC1C2N=NNC=2C=CC=1>C1COCC1>[C:45]([C@@H:41]1[CH2:42][C@H:43]2[C@H:39]([CH2:44]2)[N:40]1[C:9](=[O:10])[C@H:8]([C:12]12[CH2:19][CH:18]3[CH2:17][CH:16]([CH2:15][C:14]([OH:22])([CH2:20]3)[CH2:13]1)[CH2:21]2)[NH:7][C:5]([O:4][C:2]([CH3:23])([CH3:1])[CH3:3])=[O:6])#[N:47]
Reactant: NC(=O)[C@@H]1C[C@@H]2C[C@@H]2N1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C12CC3CC(CC(O)(C3)C1)C2
Agent: CS(=O)(=O)Cl
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1[C@H](C#N)C[C@@H]2C[C@@H]21)C12CC3CC(CC(O)(C3)C1)C2
Temperature: -6 °C
Reaction time: 8 h

Procedure:
A 2 L three-necked flask equipped with a thermometer, a mechanical stirrer and a gas inlet was charged with (αS)-α[[(1,1-dimethylethoxy)carbonyl]amino]-3-hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid (Formula 3) (50 grams, 153.8 mmol). THF (200 ml) was added and stirred to produce a clear solution. The solution was cooled to −6° C. in an acetone-dry ice-water bath. Methanesulfonyl chloride (Mes-C1) (13.1 ml, 169 mmol, 1.1 equivalents) was then added as a single portion followed by diisopropylethylamine (94 ml, 539 mmol, 1.1 equivalents). The diisopropylethylamine was added slowly over a period of about 4 minutes to keep the internal temperature below 8° C. The reaction mixture was stirred at 0° C. until all acid was converted to mixed anhydride. (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride salt (32.5 grams, 200 mmol, 1.1 equivalents) and hydroxybenzotriazole (HOBT) (1.04 grams, 7.6 mmol, 0.05 equivalents) were then added in a single portion and the flask was removed from the cooling bath. The reaction mixture was stirred at room temperature for 2 hours and then left overnight at room temperature.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6]C)=O)#N.[CH2:8]([CH:10]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:11]N)[CH3:9].C(OCC)(=O)CC(C)=O.[NH:26]1CCC[CH2:28][CH2:27]1.Cl>CO>[CH2:8]([CH:10]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:11][C:3]1[C:4](=[O:6])[NH:26][CH:27]=[CH:28][CH:1]=1)[CH3:9]
Reactant: C1CCNCC1
Reactant: COC(=O)CC#N
Reactant: CCCCC(CC)CN
Agent: Cl
Solvent: CO
Solvent: CCOC(=O)CC(C)=O
Product: CCCCC(CC)Cc1ccc[nH]c1=O
Temperature: 100 °C
Yield: 82 %

Procedure:
Into a 1 liter round-bottom flask equipped with stirrer and Dean Stark trap was charged methyl cyanoacetate (99 grams, 1 mol; obtained from Sigma-Aldrich Co., Milwaukee, Wis.), followed with methanol solvent (150 milliliters), and the mixture was stirred briefly. 2-Ethylhexylamine (130 grams, 1 mol) was slowly added into this mixture, followed with the sequential addition of ethyl acetoacetate (130 grams, 1 mol; obtained from Sigma-Aldrich Co.), and then piperidine (85 grams, 1 mol; obtained from Sigma-Aldrich Co.). The solution was stirred and heated at 100° C. for 12 hours, and then was cooled to room temperature. The mixture was diluted with 2,500 milliliters of methanol and acidified carefully with concentrated hydrochloric acid until a large amount of precipitate had formed. The precipitate was filtered by vacuum and repeatedly washed with deionized water and filtered until the filtrate was of neutral pH. The crude material was recrystallized in warm methanol to afford 170 grams (65 percent yield) of 2-ethylhexyl pyridone as a white solid.
Reaction SMILES: CS(O[CH2:6][C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=2)[O:9][N:8]=1)(=O)=O.[N:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:30]3[CH2:31][CH2:32][CH2:33][NH:34][C:29]3=[N:28][N:27]=2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[N:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:30]3[CH2:31][CH2:32][CH2:33][N:34]([CH2:6][C:7]4[N:11]=[C:10]([C:12]5[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=5)[C:18]#[N:19])[O:9][N:8]=4)[C:29]3=[N:28][N:27]=2)=[CH:22][CH:21]=1
Reactant: c1cc(-c2nnc3n2CCCN3)ccn1
Reactant: CS(=O)(=O)OCc1noc(-c2cccc(C#N)c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: N#Cc1cccc(-c2nc(CN3CCCn4c(-c5ccncc5)nnc43)no2)c1
Temperature: 25 °C
Yield: 1.4 %

Procedure:
[5-(3-cyanophenyl)-1,2,4-oxadiazol-3-yl]methyl methanesulfonate (0.278 g; 0.99 mmol) and 3-pyridin-4-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine (0.220 g; 1.09 mmol) were dissolved in butanone (20 ml) and potassium carbonate (0.275 g; 1.99 mmol) was added portionwise. The mixture was heated at reflux for 18 h before cooling to r.t. This mixture was concentrated in vacuo and DCM (20 ml) was added. The mixture was washed with water, dried (Na2SO4), evaporated and purified using prep. HPLC chromatography to give the title compound (5.4 mg). 1H NMR: 8.77 (m, 2H), 8.41 (s, 1H), 8.34 (d, 1H), 7.87 (d, 1H), 7.68 (t, 1H), 7.56 (m, 2H) 5.51 (s, 2H), 4.09 (m, 2H), 3.62 (m, 2H), 2.19 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1)[CH2:27]Cl.C(N1N=C(C2C=CC(OC)=C(OC)C=2)[C@H]2[C@H](CCCC2)C1=O)C1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:27][C:26]3[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=[C:24]([O:23][CH3:22])[CH:25]=3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1cc(CCl)cc(OC)c1
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Agent: COc1ccc(C2=NN(Cc3ccccc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1cc(CN2N=C(c3ccc(OC)c(OC)c3)[C@@H]3CCCC[C@@H]3C2=O)cc(OC)c1

Procedure:
Prepared from compound 1 and 3,5-dimethoxybenzylchloride as described for compound 78. Purified by chromatography (dichloromethane). Crystallized from methanol. M.p. 114°-117° C.
Reaction SMILES: [NH2:1][CH:2]1[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.C1N=CN([C:17]([N:19]2[CH:23]=N[CH:21]=[CH:20]2)=[O:18])C=1.CCN(C(C)C)C(C)C.[Cl:33][C:34]1[CH:47]=[C:46]2[C:37]([CH:38]([CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH2:39][C:40]32CCNC[CH2:41]3)=[CH:36][CH:35]=1>>[CH:9]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]([CH2:4]3)[CH:2]1[NH:1][C:17]([N:19]1[CH2:20][CH2:21][C:40]3([C:46]4[C:37](=[CH:36][CH:35]=[C:34]([Cl:33])[CH:47]=4)[CH:38]([CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH2:39]3)[CH2:41][CH2:23]1)=[O:18])[CH2:8]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)CC1CC2(CCNCC2)c2cc(Cl)ccc21
Reactant: NC1C2CC3CC(C2)CC1C3
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC1CC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
A solution of 2-aminoadamantane (123 mg, 0.66 mmol), CDI (107 mg, 0.66 mmol), DIEA (232 mg, 0.18 mmol) was stirred at 0° C. for 1 h. Then (±)-ethyl 2-(6-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate (180 mg, 0.60 mmol) was added to the solution and the mixture was stirred at rt overnight. The solvent was removed and the residue was purified by preparative TLC to give (±)-ethyl 2-(1′-((2-adamantyl)carbamoyl)-6-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate (250 mg, 86%). LC-MS Method 6 tR=1.492 min, m/z=485.2; 1H NMR (CDCl3): δ=1.29 (t, 3H), 1.56-1.66 (m, 4H), 1.66-1.80 (m, 6H), 1.85 (m, 5H), 1.93 (m, 2H), 2.04-2.16 (m, 1H), 2.37-2.49 (m, 1H), 2.56-2.65 (m, 1H), 2.88-2.92 (m, 1H), 3.00-3.20 (m, 2H), 3.55-3.66 (m, 1H), 3.81-3.90 (m, 1H), 3.90-4.00 (m, 2H), 4.20 (q, 2H), 5.26-5.50 (m, 3H), 7.07-7.14 (m, 2H), 7.19 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]1.[CH3:18][C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:22]=[C:21]([CH:30]=O)[CH:20]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][CH2:30][C:21]2[CH:20]=[C:19]([CH3:18])[N:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:22]=2)[CH2:11][CH2:10]1
Reactant: Cc1cc(C=O)nn1-c1ccccc1
Reactant: Cc1ccc(N2CCN(CCN)CC2)c(C)c1
Product: Cc1ccc(N2CCN(CCNCc3cc(C)n(-c4ccccc4)n3)CC2)c(C)c1
Yield: 39.3 %

Procedure:
Compound 25 was prepared using the same method as that of Example 1 except that 4-(2,4-dimethylphenyl)piperazin-1-ylethylamine and 5-methyl-1-phenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: Cl.[C:2]([O:5][C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][C:25]=1[CH3:26])[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([OH:22])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)(=[O:4])[CH3:3].Cl.Cl[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1>>[C:2]([O:5][C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][C:25]=1[CH3:26])[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)(=[O:4])[CH3:3]
Reactant: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1O
Reactant: ClCc1ccccn1
Agent: Cl
Product: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1OCc1ccccn1
Yield: 39.5 %

Procedure:
Using an analogous procedure to that described for the starting material in Example 1, 4-(3-acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (376 mg) was reacted with 2-(chloromethyl)pyridine hydrochloride (328 mg) to give 4-(3-acetoxy-4-methylanilino)-6-methoxy-7-(2-pyridylmethoxy)quinazoline (170 mg, 40%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[N:11]=[C:12]([NH:15][C:16]3[N:21]=[CH:20][C:19]([S:22]CCC(OC)=O)=[CH:18][C:17]=3[O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[S:13][CH:14]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl:36][C:37]1[CH:42]=[CH:41][N:40]=[C:39]2[CH:43]=[CH:44][S:45][C:38]=12.CC([O-])(C)C.[K+].[NH4+].[Cl-:53]>CS(C)=O>[ClH:36].[ClH:53].[O:29]([C:17]1[C:16]([NH:15][C:12]2[S:13][CH:14]=[C:10]([CH:7]3[CH2:6][CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:9][CH2:8]3)[N:11]=2)=[N:21][CH:20]=[C:19]([S:22][C:37]2[CH:42]=[CH:41][N:40]=[C:39]3[CH:43]=[CH:44][S:45][C:38]=23)[CH:18]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: [Cl-]
Reactant: Clc1ccnc2ccsc12
Reactant: COC(=O)CCSc1cnc(Nc2nc(C3CCN(C(C)=O)CC3)cs2)c(Oc2ccccc2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [NH4+]
Solvent: CS(C)=O
Product: CC(=O)N1CCC(c2csc(Nc3ncc(Sc4ccnc5ccsc45)cc3Oc3ccccc3)n2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
A mixture of methyl 3-(6-(4-(1-acetylpiperidin-4-yl)thiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)propanoate (20.2 g, 39.3 mmol) and 7-chlorothieno[3,2-b]pyridine (7.34 g, 43.3 mmol) in DMSO (500 mL) was purged with nitrogen for 30 minutes and then KOtBu (13.9 g, 118.0 mmol) was added and the reaction was stirred at ambient temperature for 2 hrs. The mixture was poured into saturated aqueous NH4Cl (1 L) and extracted with EtOAc (1 L). The organics were washed with water (3×500 mL), dried over Na2SO4 and concentrated to a residue that was purified on silica eluting with 3-5% MeOH/EtOAc. The purified free base was dissolved in CH2Cl2 (300 mL) and 1N HCl in Et2O (300 mL) was added the slurry was concentrated to dryness to afford 1-(4-(2-(3-phenoxy-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)thiazol-4-yl)piperidin-1-yl)ethanone dihydrochloride (19.5 g, 78%) as a yellow solid which was dried in a high vacuum oven at 45° C. overnight. 1H NMR (d6-DMSO) δ 8.65 (d, 1H), 8.48 (d, 1H), 8.46 (d, 1H), 7.77 (d, 1H), 7.54 (d, 1H), 7.41 (m, 2H), 7.18 (m, 4H), 6.82 (s, 1H), 4.43 (m, 1H), 3.88 (m, 1H), 3.14 (m, 1H), 2.89 (m, 1H), 2.64 (m, 1H), 2.01 (s, 3H), 1.96 (m, 2H), 1.58 (m, 1H), 1.45 (m, 1H). Mass spectrum (apci) m/z=560.4 (M+H-2HCl).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH:9]([CH3:11])[CH3:10])[CH:3]=1.O.[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:13](=[O:15])[CH3:14])=[C:4]([CH:9]([CH3:11])[CH3:10])[CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)c1cc(Br)ccc1N
Solvent: O
Product: CC(=O)Nc1ccc(Br)cc1C(C)C
Yield: 83 %

Procedure:
A solution of 4-bromo-2-iso-propyl-phenylamine (780 mg, 3.64 mmol) in acetic anhydride (4 mL) was stirred at room temperature over night. The reaction was poured into water and the resulting white precipitate was filtered off and dried under vacuum to give N-(4-bromo-2-iso-propyl-phenyl)-acetamide as a light pink solid (0.770 g, 83%); 1H NMR (300 MHz, DMSO-d6): δ 9.39(s, 1H), 7.43(d, 1H, J=2.4 Hz), 3.16(m, 1H), 2.04(s, 3H), 1.13(d, 6H, J=7 Hz); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=dichloromethane; Rf=0.21
Reaction SMILES: [CH:1]([P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6])=[CH2:2].CO[CH2:13][N:14]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:15][Si](C)(C)C>C(Cl)Cl>[CH2:20]([N:14]1[CH2:13][CH2:2][CH:1]([P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6])[CH2:15]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C=CP(=O)(OCC)OCC
Solvent: ClCCl
Product: CCOP(=O)(OCC)C1CCN(Cc2ccccc2)C1
Yield: 86.7 %

Procedure:
A solution of 6.0 g (36.6 mmol) of diethyl vinylphosphonate and 11 mL (44 mmol) of N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine in 150 mL of CH2Cl2 at 0° C. was stirred for 30 min. The reaction mixture was washed with 150 mL of 1N NaHCO3 and 150 mL of sat'd NaCl. The organic layer was dried over Na2SO4 and concentrated. The residue was purified on a 40L Biotage column using 3:2 and 1:1 v/v hexane/acetone as the gradient to afford 9.44 g (87%) of the title compound as a pale yellow oil: RF: 0.24 (3:2 v/v hexane/acetone); 1H-NMR (500 MHz) δ 1.32 (t, J=7.0, 6H), 2.04-2.12 (m, 2H), 2.39-2.58 (m, 3H), 2.83 (m, 1H), 2.97 (m, 1H), 3.64 (s, 2H), 4.06-4.16 (m, 4H), 7.24-7.34 (m, 5H); ESI-MS 298 (M+H); LC-1: 1.2 min.