Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[O:10][C:9](=[O:19])[C:8]=2[CH:20]=1)(=[O:3])[CH3:2].[CH2:21](O)[CH2:22][OH:23].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:18][O:17][C:13]1[CH:12]=[C:11]2[C:16]([C:7]3[CH:6]=[CH:5][C:4]([C:1]4([CH3:2])[O:23][CH2:22][CH2:21][O:3]4)=[CH:20][C:8]=3[C:9](=[O:19])[O:10]2)=[CH:15][CH:14]=1
Reactant: COc1ccc2c(c1)oc(=O)c1cc(C(C)=O)ccc12
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: COc1ccc2c(c1)oc(=O)c1cc(C3(C)OCCO3)ccc12
Yield: 60.7 %

Procedure:
The compound from Step E (5.2 g, 19 mmol), ethylene glycol (4.4 g, 71 mmol) and a catalytic amount of p-toluenesulfonic acid (0.2 g) were dissolved in benzene (300 mL) and refluxed for 28 h. The solvent was removed and the crude product chromatographed on silica gel with hexane/ethyl acetate (2:1) to yield 3.6 g (60%) of the title compound. 1H-NMR (400 MHz, CDCl3) δH 1.75 (3H, s, CH3), 3.82 (2H, t, OCH2), 3.91 (3H, s, OCH3), 4.10 (2H, t, OCH2), 6.93 (1H, s, ArH), 6.98 (1H, d, ArH), 7.47 (3H, m, ArH), 8.04 (1H, s, ArH).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[C:4]([CH3:10])[N:3]=1.[NH2:11][NH2:12]>O1CCOCC1>[CH3:10][C:4]1[N:3]=[C:2]2[NH:11][N:12]=[CH:8][C:7]2=[CH:6][CH:5]=1
Reactant: NN
Reactant: Cc1ccc(C=O)c(Cl)n1
Solvent: C1COCCO1
Product: Cc1ccc2cn[nH]c2n1
Temperature: 150 °C
Yield: 51 %

Procedure:
In a microwave vial 2-chloro-6-methylpyridine-3-carbaldehyde (1.98 g, 12.7 mmol) was dissolved in 1,4-dioxane (12 mL) and hydrazine (6.0 mL, 191 mmol) was added. The vial was sealed and heated under microwave irradiation at 150° C. for 1 h. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine then dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 50% to 100% EtOAc/heptane to provide 863 mg (41%) of 6-methyl-1H-pyrazolo[3,4-b]pyridine as a light yellow solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.06 (s, 1H), 8.03 (d, J=8.3 Hz, 1H), 7.07 (d, J=8.3 Hz, 1H), 2.79 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28](O)=[O:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH:11]=1.[NH2:32][C@H:33]([CH3:37])[C@H:34]([OH:36])[CH3:35].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CO>[OH:36][C@H:34]([CH3:35])[C@H:33]([NH:32][C:28]([C:26]1[NH:27][C:23]([C:8]2[CH:9]=[C:10]([O:12][Si:13]([CH:20]([CH3:21])[CH3:22])([CH:17]([CH3:18])[CH3:19])[CH:14]([CH3:15])[CH3:16])[CH:11]=[C:6]([O:5][C@@H:4]([CH3:31])[CH2:3][O:2][CH3:1])[CH:7]=2)=[CH:24][CH:25]=1)=[O:29])[CH3:37]
Reactant: C[C@@H](N)[C@@H](C)O
Reactant: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)O)[nH]2)c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)N[C@H](C)[C@@H](C)O)[nH]2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.9 %

Procedure:
5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[(triisopropylsilyl)oxy]phenyl}-1H-pyrrole-2-carboxylic acid (0.89 g, 1.99 mmol) synthesized in Example (106c) was dissolved in methanol (20 mL), and (2R,3R)-3-aminobutan-2-ol (0.41 g, 4.60 mmol) synthesized in Example (88a) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n hydrate (1.20 g, 4.34 mmol) were added, followed by stirring at room temperature for 3 days under nitrogen atmosphere. After the solvent was distilled off under reduced pressure, a saturated aqueous ammonium chloride solution (50 mL) was added, and extraction was carried out with methylene chloride (80 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=60%-80%) to afford the desired compound (722 mg, yield 70%) as a white foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH2:17][OH:18])=[N:9]2)=[CH:5][CH:4]=1.Br[CH2:22][C:23]([OH:25])=[O:24].[H-].[Na+]>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH2:17][O:18][CH2:22][C:23]([OH:25])=[O:24])=[N:9]2)=[CH:19][CH:20]=1
Reactant: O=C(O)CBr
Reactant: COc1ccc(Cn2nc(CO)c3ccccc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cn2nc(COCC(=O)O)c3ccccc32)cc1
Temperature: 0 °C
Yield: 62.7 %

Procedure:
A suspension containing [1-(4-methoxybenzyl)-1H-indazol-3-yl]methanol (6 g; 0.022 mol), bromoacetic acid (4 g; 0.03 mol) and 50% NaH (3 g; 0.066 mol) in THF (170 ml) was stirred at reflux for 72 hours. The reaction was then stopped by diluting with a suspension with water and ice (300 ml) and washing the aqueous phase with diethyl ether (3×150 ml). The aqueous phase was acidified with concentrated HCl. The solid thus formed was filtered off and purified by crystallization from isopropanol. 4.5 g of {[1-(4-methoxybenzyl)-1H-indazol-3-yl]methoxy}acetic acid were thus obtained.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:12][N:11]=2)=[CH:6][CH:5]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH3:37][CH:38]([CH2:43][CH2:44][CH2:45][CH3:46])[CH2:39][CH2:40][CH2:41]O>CN(C)C=O.C(OCC)C>[CH3:37][CH:38]([CH2:43][CH2:44][CH2:45][CH3:46])[CH2:39][CH2:40][CH2:41][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[CH:12][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:14][N:15]=2)=[CH:8][CH:9]=1
Reactant: CCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCCCC(C)CCCO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCCCCCCCc1cnc(-c2ccc(OCCCC(C)CCCC)cc2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.38 g of 55% sodium hydride and 10 ml of dimethylformamide were weighed out and a solution of 2 g of 2-(4-hydroxyphenyl)-5-n-decylpyrimidine in 3 ml of dimethylformamide was added dropwise thereto under ice cooling. After the completion of the addition, the resulting mixture was stirred at room temperature for one hour. Then p-toluene-sulfonate of optically active 4-methyloctanol was added dropwise thereto and the resulting mixture was stirred at 90° C. for two hours. After cooling, the reaction mixture was poured into ice/water, extractd with diethyl ether and dried followed by removal of the solvent. The residue was purified on a silica gel column to thereby give 1.5 g of optically active 2-(4-(4-methyloctoxy)phenyl)-5-n-decylpyrimidine.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][C:30]=1[CH:39]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:39][C:30]3[CH:31]=[CH:32][C:33]4[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH:29]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc2ccccc2c1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4ccc5ccccc5c4)c3)c(Cc3ccccc3)cnc12

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and naphthalene-2 carbaldehyde. MS (ESI) m/z 519.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24][CH3:25])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2C[CH2:22][CH2:21][CH2:20][NH:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].NC1N=C(OCCCC)N=C2C=1N=C(OC)N2CCC1CCCN(C(OCC2C=CC=CC=2)=O)C1>>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24][CH3:25])[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3)c2n1
Agent: CCCCOc1nc(N)c2nc(OC)n(CCC3CCCN(C(=O)OCc4ccccc4)C3)c2n1
Product: CCCCOc1nc(N)c2nc(OC)n(CCC3CCCNC3)c2n1

Procedure:
Prepared similarly to Intermediate 32 from phenylmethyl 3-{2-[6-amino-2-(butyloxy)-8-(methyloxy)-9H-purin-9-yl]ethyl}-1-piperidinecarboxylate.
Reaction SMILES: CC([N:5]([C@@H:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH:16]2[C:20]3=[C:21]([F:29])[CH:22]=[N:23][C:24]4[CH:25]=[CH:26][C:27](=[O:28])[N:18]([C:19]=43)[CH2:17]2)[CH2:11][C@@H:10]1[OH:30])C(=O)[O-])(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:5][C@@H:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH:16]2[C:20]3=[C:21]([F:29])[CH:22]=[N:23][C:24]4[CH:25]=[CH:26][C:27](=[O:28])[N:18]([C:19]=43)[CH2:17]2)[CH2:11][C@@H:10]1[OH:30]
Reactant: CC(C)(C)N(C(=O)[O-])[C@@H]1CCN(CC2Cn3c(=O)ccc4ncc(F)c2c43)C[C@@H]1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CCN(CC2Cn3c(=O)ccc4ncc(F)c2c43)C[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
A solution of racemic 1,1-dimethylethyl{(3S,4R)-1-[(3-fluoro-7-oxo-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-4-yl)methyl]-3-hydroxy-4-piperidinyl}carbamate (15.57 g) in dichloromethane (170 ml) was cooled in ice-water, treated with trifluoracetic acid (137 ml), stirred 1 hour at room temperature and evaporated to dryness. After keeping under high vacuum for 1 hour, the crude material was dissolved in methanol and run through a column of Amberlyst A21 basic resin (500 ml) (Sigma-Aldrich Co.), eluting with methanol. The solution containing the product was evaporated and the residue chromatographed on silica gel, eluting with dichloromethane/methanol/0.88 ammonia (9:1:0.1) to give product (8.96 g, 76%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14](O)=[O:15])[C:9]2=[O:17])=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33]/[C:34](=[N:37]/[H])/[NH:35]O)=[CH:28][CH:27]=1.C(N=C=NCCCN(C)C)C>O1CCOCC1.C(OCC)(=O)C>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:32][CH2:33][C:34]2[N:35]=[C:14]([CH2:13][N:10]3[CH2:11][CH2:12][C:8]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[C:9]3=[O:17])[O:15][N:37]=2)=[CH:30][CH:31]=1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Reactant: [H]/N=C(/CCc1ccc(Cl)cc1)NO
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C1N(Cc2nc(CCc3ccc(Cl)cc3)no2)CCC1(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of the product of Example 58D (225 mg, 0.679 mmol) and the product of Example 165A (135 mg, 0.679 mmol) in 1,4-dioxane (4 mL) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.120 mL, 0.679 mmol) via syringe. The reaction was stirred at ambient temperature for 2.5 hours, then heated to 60° C. for 44 hours. The reaction was cooled to ambient temperature, diluted with ethyl acetate, and washed with 3 N aqueous HCl resulting in a homogeneous solution. Brine was added to force the phase separation. The organic layer was separated and washed with saturated aqueous NaHCO3 solution and brine, dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography on silica gel (Analogix® Intelliflash™ 280; SF15-24 g column; 50% ethyl acetate/hexanes) yielded the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.36-7.27 (m, 4H), 7.27-7.21 (m, 2H), 7.15-7.07 (m, 2H), 7.07-6.96 (m, 4H), 4.79 (s, 2H), 3.46 (t, J=6.4, 2H), 3.00 (s, 4H), 2.80 (t, J=6.4, 2H); MS (ESI+) m/z 511 (M+NH4)+.
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[OH-].[Na+:26]>C(O)(C)C>[C:1]([O-:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[Na+:26]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)[O-]

Procedure:
To 340 ml of isopropanol, 34 g of behenic acid was dissolved at 65° C. Thereafter, while stirring, an aqueous 25N sodium hydroxide solution was added so that the pH was adjusted to 8.7. At the same time, about 400 ml of an aqueous sodium hydroxide solution were employed. Thereafter, the resulting sodium behenate solution was concentrated under reduced pressure so that the concentration of sodium behenate became 8.8 percent by weight.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]([C:13]([OH:15])=[O:14])=[CH:9][NH:8][C:6]=2[N:7]=1.C(N(CC)CC)C.ClC(OC(C)C)=O.O[N:31]1[C:35](=[O:36])[CH2:34][CH2:33][C:32]1=[O:37]>CN(C)C=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]([C:13]([O:15][N:31]3[C:35](=[O:36])[CH2:34][CH2:33][C:32]3=[O:37])=[O:14])=[CH:9][NH:8][C:6]=2[N:7]=1
Reactant: Nc1ncc2c(=O)c(C(=O)O)c[nH]c2n1
Reactant: O=C1CCC(=O)N1O
Agent: CC(C)OC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ncc2c(=O)c(C(=O)ON3C(=O)CCC3=O)c[nH]c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
A suspension of 2-amino-5,8-dihydro-5-oxopyrido[ 2,3-d]pyrimidine-6-carboxylic acid (1.70 g) and triethylamine (2.5 ml) in dried dimethylformamide (50 ml) was stirred at room temperature for 1 hour and to the suspension was added isopropyl chloroformate (1.90 ml) at 0°-5° C. The mixture was stirred at 5°-10° C. for one hour and a solution of N-hydroxysuccinimide (1.91 g) in dimethylformamide (20 ml) was added to it. The mixture was stirred at room temperature for 1.5 hours. The crystals precipitated were collected and washed with dichloromethane to give N-(2-amino-5,8-dihydro-5-oxopyrido[2,3-d]pyrimidine-6-carbonyloxy)succinimide (1.9 g) m.p. above 300° C.
Reaction SMILES: [CH2:1]([NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(O)(=O)C.[F:28][C:29]([F:38])([F:37])[C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH2:1]([NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:36][C:33]2[CH:34]=[CH:35][C:30]([C:29]([F:28])([F:37])[F:38])=[CH:31][CH:32]=2)=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCNC(=O)c1ccc(C=O)cc1
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCCCCCCCCCCCNC(=O)c1ccc(CNc2ccc(C(F)(F)F)cc2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of N-dodecyl-4-formyl-benzamide (Example 10, step a) (1.00 g, 3.115 mmol), acetic acid (0.227 g, 3.78 mmol) and 4-trifluoromethyl-phenylamine (0.609 g, 3.78 mmol) in DCE (25 mL) was added at once NaBH(OAc)3 (0.801 g, 3.78 mmol). The resulting mixture was stirred overnight at 70° C. A saturated solution of NaHCO3 (10 mL) was added to the reaction mixture, the aqueous layer was separated and extracted with DCM (3×50 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to give a colorless oil. This crude product was purified by column chromatography over silica gel (4/1 c-Hex/AcOEt to 3/1 in about 0.5 h) to give the title compound as a colorless oil (0.824 g, 63%). 1H NMR (CD3OD, 300 MHz) δ 7.74 (d, 2H, J=8.3 Hz), 7.43 (d, 2H, J=8.3 Hz), 7.29 (d, 2H, J=8.7 Hz), 6.63 (d, 2H, J=8.3 Hz), 4.42 (s, 2H), 3.35 (m, 2H), 1.58 (m, 2H), 1.27 (m, 18H), 0.88 (m, 3H). M+(LC/MS(ESI)): 463.0; M−(LC/MS(ESI)): 461.3. HPLC (Condition A), Rt: 6.84 min (HPLC purity: 98.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][CH:11]2[CH2:16][C:15]([CH3:18])([CH3:17])[NH:14][C:13]([CH3:20])([CH3:19])[CH2:12]2)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:28][CH3:29]>CN1CCCC1=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][CH:11]2[CH2:16][C:15]([CH3:18])([CH3:17])[N:14]([CH2:28][CH3:29])[C:13]([CH3:20])([CH3:19])[CH2:12]2)[CH:3]=1
Reactant: CCI
Reactant: CC1(C)CC(Nc2cc(Cl)ccc2C#N)CC(C)(C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCN1C(C)(C)CC(Nc2cc(Cl)ccc2C#N)CC1(C)C
Temperature: 90 °C

Procedure:
4-Chloro-2-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]benzonitrile was dissolved in N-methyl-2-pyrrolidinone, potassium carbonate and iodoethane were added, followed by stirring at 90° C. By post-treating the reaction liquid, 4-chloro-2-[(1-ethyl-2,2,6,6-tetramethylpiperidin-4-yl)amino]benzonitrile was obtained.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([O:18][CH3:19])(=[O:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](O)=[O:15]>>[C:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([Cl:3])=[O:15])([O:18][CH3:19])=[O:17]
Reactant: COC(=O)CCCCCCCCC(=O)O
Reactant: O=S(Cl)Cl
Product: COC(=O)CCCCCCCCC(=O)Cl
Reaction time: 2 h

Procedure:
Thionyl chloride (360 g) was added dropwise to methyl hydrogen sebacate (432.6 g, 2 moles) at 60° C. with vigorous stirring and stirring was continued for 2 h under reflux. The reaction mixture was evaporated and the residue was distilled under reduced pressure to give the title compound as a colorless oil; yield: 400 g; bp 145°-150° C./4 mmHg. (Lit. bp 166°-168° C./14 mmHg; T. D. Heyes, J. C. Roberts, J. Chem. Soc., 1952, 4935).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[F:11][C:12]([F:19])([F:18])[C@H:13]([OH:17])[CH2:14][O:15][CH3:16]>>[NH2:1][C:2]1[CH:9]=[C:8]([O:17][C@H:13]([CH2:14][O:15][CH3:16])[C:12]([F:19])([F:18])[F:11])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: N#Cc1cnc(N)cc1F
Reactant: COC[C@@H](O)C(F)(F)F
Product: COC[C@@H](Oc1cc(N)ncc1C#N)C(F)(F)F

Procedure:
From intermediate 21 and (R)-1,1,1-trifluoro-3-methoxypropan-2-ol, reacted in an analogous manner to the preparation of intermediate 68. UPLC-MS 3: Rt=0.75 min; MS m/z [M+H]+ 262.1;
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8](=[O:20])[C:9]3[C:14]([S:15](=[O:19])(=[O:18])[C:16]=2[CH:17]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3)(=O)[NH2:2].S(Cl)(Cl)=O>CN(C)C=O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8](=[O:20])[C:9]3[C:14]([S:15](=[O:18])(=[O:19])[C:16]=2[CH:17]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3)#[N:2]
Reactant: NC(=O)c1ccc2c(c1)S(=O)(=O)c1ccccc1C2=O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)S(=O)(=O)c1ccccc1C2=O
Temperature: -10 °C
Reaction time: 2 h

Procedure:
3-Carbamoylthioxanthone-10,10-dioxide (32.5 g) was dissolved in dimethyl formamide (ca. 1 litre) and cooled to -10° C in a solid carbon dioxide ethanol bath. Thionyl chloride (80 ml) was then added dropwise over 0.5 hour, maintaining the internal temperature at -5° to -10° C. Stirring was continued at this temperature for a further 2 hours. The reaction mixture was then poured into ice-water. The precipitated solid was filtered off, washed well with water, and dried at 100° C. The resulting 3-cyanothioxanthone-10,10-dioxide had a melting point of 282- 283° C.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:13][CH3:14])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.O>C1COCC1>[CH2:13]([N:12]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:11][CH2:10][CH2:9][OH:8])[CH3:14]
Reactant: CCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCN(CCCO)C(=O)OCc1ccccc1
Yield: 69.7 %

Procedure:
N-Ethyl 3-benzyloxycarbonylamino-1-propanol t-butyldimethylsilyl ether (8.5 g) was dissolved in THF (120 ml), and to the resulting solution was added under ice-cooling a solution of 1N tetra-butylammonium fluoride in THF (48 ml). The resultant mixture was stirred at room temperature for 1 hour. Ethyl acetate and water were added to the reaction solution obtained. The organic layer so sepasated was washed with water and then dried over magnesium sulfate. The solvent was evaporated off from the solution, and the residue was purified by a silica gel chromatography, thus affording the titled compound (4.0 g; 71%)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:23])[C:10]([CH3:22])([CH3:21])[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.[Cl:35][C:36]1[CH:37]=[CH:38][C:39]2[N:40]([CH:42]=[C:43]([CH2:45]Cl)[N:44]=2)[N:41]=1>O>[Cl:35][C:36]1[CH:37]=[CH:38][C:39]2[N:40]([CH:42]=[C:43]([CH2:45][O:1][C:2]3[CH:3]=[CH:4][C:5]([C:8]4[C:9](=[O:23])[C:10]([CH3:21])([CH3:22])[O:11][C:12]=4[C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)=[CH:6][CH:7]=3)[N:44]=2)[N:41]=1
Reactant: COc1ccc(C2=C(c3ccc(O)cc3)C(=O)C(C)(C)O2)cc1
Reactant: ClCc1cn2nc(Cl)ccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C2=C(c3ccc(OCc4cn5nc(Cl)ccc5n4)cc3)C(=O)C(C)(C)O2)cc1
Temperature: 80 °C
Yield: 59.1 %

Procedure:
4-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (200 mg, 0.64 mmol) was added to a mixture of cesium carbonate (838 mg, 2.5 mmol) and DMF (5 mL) at RT under an atmosphere of nitrogen. The reaction mixture was stirred at RT for 30 min upon which 6-chloro-2-(chloromethyl)imidazo[1,2-b]pyridazine (196 mg, 9.6 mmol) was added. The mixture was heated at 80° C. for 4 h (the reaction was monitored by TLC). The reaction mixture was diluted with water and extracted with EtOAc; the combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The organic residue was purified by flash column chromatography using 30% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 4-(4-((6-chloroimidazo[1,2-b]pyridazin-2-yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (180 mg, 63.0%,) as an off-white solid. 1H NMR, 500 MHz, DMSO-d6: δ 8.45 (s, 1H), 8.2 (d, 1H), 7.55 (d, 2H), 7.4 (d, 1H), 7.15 (d, 2H), 7.1 (d, 2H), 7.0 (d, 2H), 5.25 (s, 2H) 3.8 (s, 3H), 1.25 (s, 6H). MS: [M+H]+: m/z=476.7. HPLC: (96.7%, Condition-A).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([Cl:27])[CH:25]=2)[CH:20]=[CH:19][CH:18]=1>>[Cl:27][C:24]1[CH:25]=[C:26]2[C:21]([CH:20]=[CH:19][CH:18]=[C:17]2[CH2:16][N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=[C:6]2[C:4]([OH:3])=[O:5])=[CH:22][CH:23]=1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: Clc1ccc2cccc(CBr)c2c1
Product: O=C(O)c1cc2ccccc2n1Cc1cccc2ccc(Cl)cc12

Procedure:
Using general procedure B, 1H-indole-2-carboxylic acid ethyl ester was coupled with 1-bromomethyl-7-chloro-naphthalene and the product obtained was hydrolyzed to give 1-(7-chloro-naphthalen-1-ylmethyl)-1H-indole-2-carboxylic acid as a white solid. MS: 334.0 ([M−H]).