Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][NH:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([C:30]5[N:31]=[N:32][S:33][CH:34]=5)=[CH:26][CH:25]=4)=[CH:17][CH:16]=3)=[N:9][CH:10]=[C:11]([CH:14]=2)[C:12]#[N:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:35]=[N+:36]=[N-:37].[Na+].O>[Zn+2].[Br-].[Br-].O>[C:1]1([C:7]2[C:8]([C:15]3[CH:16]=[CH:17][C:18]([CH2:21][NH:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([C:30]5[N:31]=[N:32][S:33][CH:34]=5)=[CH:26][CH:25]=4)=[CH:19][CH:20]=3)=[N:9][CH:10]=[C:11]([C:12]3[NH:37][N:36]=[N:35][N:13]=3)[CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1cnc(-c2ccc(CNCc3ccc(-c4csnn4)cc3)cc2)c(-c2ccccc2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Br-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: O
Product: c1ccc(-c2cc(-c3nnn[nH]3)cnc2-c2ccc(CNCc3ccc(-c4csnn4)cc3)cc2)cc1

Procedure:
A mixture of 5-phenyl-6-[4({[4-(1,2,3-thiadiazol-4-yl)benzyl]amino}methyl)phenyl]nicotinonitrile (1-5; TFA salt) (69 mg, 0.1 mmol), 2M of NaN3 water solution (0.75 mL, 1.5 mmol), 2M of ZnBr2 water solution (0.5 mL, 1.0 mmol) was microwaved (Smith-Synthesizer) at 165° C. for 15 min. After this time, the solution was concentrated. The residue was re-dissolved in DMSO (1 mL) and purified by LCMS to afford the pure desired product (TFA salt) as a slightly yellow solid (1-6). Analytical LCMS: single peak (214 nm), 2.339 min. 1H NMR (500 MHz, DMSO-d6): δ 9.70 (s, 1H), 9.32 (d, J=2.1 Hz, 1H), 8.42 (d, J=2.1 Hz, 1H), 8.22 (d, J=8.2 Hz, 2H), 7.68 (d, J=8.3 Hz, 2H), 7.42-7.48 (M, 4H), 7.35-7.40 (m,3H), 7.28-7.32 (m, 2H), 4.26 (s, 2H), 4.23 (s, 2H); HRMS, calc'd for C28H22N8S (M+1), 503.1761; found 503.1769.
Reaction SMILES: [CH:1]([CH:3]([O:6][CH:7]([N:10]1[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]1=[O:17])[CH:8]=[O:9])[CH2:4][OH:5])=[O:2].[NH2:18][C:19]1[N:23]=[CH:22][NH:21][N:20]=1>CO.O>[OH:9][CH:8]1[C@H:7]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]2=[O:17])[O:6][C@H:3]([CH2:4][OH:5])[CH:1]([OH:2])[N:18]1[C:19]1[N:23]=[CH:22][NH:21][N:20]=1
Reactant: O=CC(CO)OC(C=O)n1ccc(=O)[nH]c1=O
Reactant: Nc1nc[nH]n1
Solvent: CO
Solvent: O
Product: O=c1ccn([C@@H]2O[C@H](CO)C(O)N(c3nc[nH]n3)C2O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.9 %

Procedure:
[R-(R*, R*)]-α-(1-Formyl-2-hydroxyethoxy)-3,4-dihydro-2,4-dioxo-1(2H)-pyrimidineacetaldehyde, (uridinedialdehyde), (4.84 g) was dissolved in a mixture of methanol (100 ml) and water (100 ml). To the solution was added 3-amino-1H-1,2,4-triazole (1.68 g). The mixture was stirred at ambient temperature for five hours and evaporated in vacuo. The residue was triturated with acetone to give 1-[(2R, 6R)-3,5-dihydroxy-6-hydroxymethyl-4-(1,2,4-triazol-3-yl)morpholin-2-yl]uracil (6.25 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])/[CH:4]=[CH:5]/[C:6]1[C:11]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[CH:10][CH:9]=[CH:8][C:7]=1[OH:25].Br[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>CCOCC>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][CH2:29][CH2:28][O:25][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[C:6]=1/[CH:5]=[CH:4]/[C:3]([O:2][CH3:1])=[O:26])[CH3:35]
Reactant: CCOC(=O)CCCBr
Reactant: COC(=O)/C=C/c1c(O)cccc1C#CCCCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CCOC(=O)CCCOc1cccc(C#CCCCCOC2CCCCO2)c1/C=C/C(=O)OC
Temperature: 25 °C
Reaction time: 23 h
Yield: 102.9 %

Procedure:
A mixture of 7.16 g (20 mmol) of rac-(E)-3-[2-hydroxy-6-[6-[(tetrahydro-2H-pyran-2-yl)oxy]-1-hexynyl]phenyl]-2-propenoic acid methyl ester (preceding example), 4.37 g (22.4 mmol) of ethyl 4-bromobutyrate, 8.32 g (60.29 mmol) of anhydrous, granular potassium carbonate, and 50 mL of dry dimethyl sulfoxide was stirred at room temperature for 23 hr. The resulting mixture was diluted with ether and worked-up in the usual manner. There was obtained 9.73 g of rac-(E)-4-[2-(3-methoxy-3-oxo-1-propenyl)-3-[6-[(tetrahydro-2H-pyran-2-yl)oxy]-1-hexynyl]phenoxy]butanoic acid ethyl ester as a yellow oil containing ca. 10% of ethyl 4-bromobutyrate (NMR analysis). This material was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.I[C:10]([F:28])([F:27])[C:11]([F:26])([F:25])[C:12]([F:24])([F:23])[C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])I>[Cu].CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:10]([F:28])([F:27])[C:11]([F:26])([F:25])[C:12]([F:24])([F:23])[C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(I)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Reactant: Fc1ccc(I)cc1
Agent: [Cu]
Solvent: CS(C)=O
Product: Fc1ccc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)c2ccc(F)cc2)cc1
Temperature: 110 °C
Yield: 74.2 %

Procedure:
26.64 g of p-fluoroiodobenzene, 100 ml of DMSO and 15.24 g of copper powder were put in a flask under an atmosphere of nitrogen to be sufficiently stirred at a temperature of 110° C. Next, 30.46 g of 1,6-diiodoperfluorohexane was slowly dropped and stirred at a temperature of 120° C. for 20 hours. Then, the reaction solution was filtered so as to remove the unreacted copper, and was dropped into an aqueous solution containing a small quantity of NaCl. Then, the resulting deposits were filtered. The deposits were dissolved in acetone to be filtered and thereafter distill out the acetone. The residue was dissolved in methanol to add water and deposits were filtered. The deposits were distilled at a reduced pressure (155° C., 5 mmHg), thereby obtaining 20 g of a colorless solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:13][C:14]1[C:19](Cl)=[N:18][C:17]([Cl:21])=[CH:16][N:15]=1)[CH2:9][C@@H:10]([OH:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].O>C1COCC1>[CH2:1]([N:8]1[CH2:13][C:14]2[N:15]=[CH:16][C:17]([Cl:21])=[N:18][C:19]=2[O:12][C@@H:10]([CH3:11])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](O)CN(Cc1ccccc1)Cc1ncc(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H]1CN(Cc2ccccc2)Cc2ncc(Cl)nc2O1
Reaction time: 2 h
Yield: 51.8 %

Procedure:
To a solution of (2S)-1-{benzyl[(3,5-dichloropyrazin-2-yl)methyl]amino}propan-2-ol (3.48 g) in THF (50 mL) was added sodium hydride (513 mg) under ice-cooling, and the mixture was stirred for 2 hr under ice-cooling. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (solvent gradient: 5→20% ethyl acetate/hexane) to give the title compound (1.60 g, 52%) as a pale-yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].[O:19]([CH2:26][CH2:27][CH2:28][CH2:29]Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CS(C)=O>[O:19]([CH2:26][CH2:27][CH2:28][CH2:29][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: BrCCCCOc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1ccc(-c2ccc(OCCCCOc3ccccc3)cc2)cc1
Reaction time: 8 h
Yield: 99 %

Procedure:
A solution of 4-(4′-hydroxyphenyl)benzoic acid (4 g) and 1N sodium hydroxide (41 ml) in dimethyl sulfoxide (40 ml) was heated for 30 minutes at 85° C., then treated with 4-phenoxybutyl bromide (6.42 g) and heating continued for 8 hours. After cooling, the reaction was poured into water and adjusted to pH 2 and the resulting precipitate was collected, washed with water, and dried to give 4-[4′-(4-phenoxybutyloxy) phenyl]benzoic acid (6.7 g).
Reaction SMILES: [N+:1]([C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:11])([O-:3])=[O:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:16](OC(=O)C)(=[O:18])[CH3:17]>[N+](C1C=CC=CC=1)([O-])=O>[OH:10][C:9]1[C:4]([N+:1]([O-:3])=[O:2])=[C:5]([OH:11])[CH:6]=[CH:7][C:8]=1[C:16](=[O:18])[CH3:17]
Reactant: O=[N+]([O-])c1c(O)cccc1O
Reactant: CC(=O)OC(C)=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(=O)c1ccc(O)c([N+](=O)[O-])c1O
Temperature: 100 °C

Procedure:
2-Nitrobenzene-1,3-diol (24.5 g) was added portionwise over 15 minutes to a vigorously stirred solution of aluminum chloride (46.3 g) in nitrobenzene (325 mL). Acetic anhydride (15.7 mL) was then added dropwise to the mixture over a further 15 minutes and the mixture then heated at 100° C. for 5 h. The reaction was cooled to ambient temperature and carefully quenched with ice'cold 2M hydrochloric acid (300 mL). The mixture was extracted with diethyl ether (2×500 mL) and the combined diethyl ether extracts then extracted with 2M aqueous sodium hydroxide (2×400 mL). The combined basic extracts were washed with diethyl ether (4×500 mL) and then acidified to pH 1 with 2M hydrochloric acid (700 mL). The resulting precipitate was filtered off, washed with water, and dried under vacuum at 40° C. to afford the subtitled compound as a yellow-brown solid. Yield 29.5 g.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.C(N(CC)CC)C.Cl[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:19]>C(Cl)(Cl)Cl>[O:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:1][C:18](=[O:19])[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:5][CH2:6]1
Reactant: CCCCCCCCCCCCCCCCOC(=O)Cl
Reactant: NCCN1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCOC(=O)NCCN1CCOCC1
Temperature: 25 °C

Procedure:
8.6 Grams of N-(2-aminoethyl)morpholine, 7.2 g of triethylamine and 120 ml of chloroform were charged in a flask equipped with a stirrer, a condenser and a calcium chloride drying tube and stirred with ice cooling. To the resulting solution was slowly added dropwise 18.2 g of hexadecyl chloroformate. After completion of the addition, the temperature of the solution was returned to room temperature, followed by refluxing with heating for 0.5 hour. The reaction mixture was cooled to room temperature, washed with water, dried over anhydrous magnesium sulfate and, then, concentrated under reduced pressure. The residue was recrystallized from acetonitrile to obtain 21.1 g of the desired product. m.p. 65° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:29][CH2:30][OH:31])[CH2:10][N:11]([CH3:28])[C:12]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[C:16]([C:24]#[N:25])[C:15]=2[O:26][CH3:27])=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8].C(Cl)(=O)C(Cl)=O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:29][CH:30]=[O:31])[CH2:10][N:11]([CH3:28])[C:12]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[C:16]([C:24]#[N:25])[C:15]=2[O:26][CH3:27])=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1c(C#N)cc2ccccc2c1C(=O)N(C)C[C@@H](CCO)c1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Product: COc1c(C#N)cc2ccccc2c1C(=O)N(C)C[C@@H](CC=O)c1ccc(Cl)c(Cl)c1

Procedure:
The alcohol from (g) was oxidized using oxalyl chloride and DMSO under standard Swern conditions to afford the aldehyde. 1H NMR (300 MHz, DMSO-d6) δ9.70-9.64 (m), 8.67-8.57 (m), 8.07-7.97 (m), 7.80 (s), 7.72-7.55 (m), 7.52-7.48 (m), 7.40-7.73 (m), 7.12-7.10 (d), 7.04-7.02 (d), 6.87-6.83 (m), 6.37-6.29 (d), 4.53-4.44 (t), 4.11-4.00 (m), 3.94 (s), 3.92 (s), 3.91-3.73 (m), 3.71 (s), 3.45-3.38 (m), 3.33 (s), 3.14 (s), 2.97-2.95 (d), 2.63 (s), 2.60 (s); MS APCI, m/z=455 (M+). This compound was characterized as a mixture of atropoisomers.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.Cl.[CH3:11][NH:12][CH3:13].C=O>C(O)CCC>[CH3:11][N:12]([CH3:13])[C:3]1[C:4]2[C:9](=[N:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: c1cnc2[nH]ccc2c1
Reactant: CNC
Agent: C=O
Agent: Cl
Solvent: CCCCO
Product: CN(C)c1c[nH]c2ncccc12
Yield: 88.2 %

Procedure:
To 40 ml of n-butyl alcohol was added 1.18 g of 7-azaindole, 0.88 g of dimethylamine hydrochloride and 0.33 g of paraformaldehyde, and the mixture refluxed for 30 minutes. The clear solution was then evaporated to dryness in vacuo, and 10 ml of 10% aqueous hydrochloric acid was added to the residue. The water layer was extracted with ether, and then made strongly basic with potassium carbonate. The resulting precipitate was filtered off, washed with ether and dried, yielding 1.42 g (81.1%) of 3-dimethylamino-7-azaindole, m.p. 144°-152° C.
Reaction SMILES: N[C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].[H-].[Na+].[C:17](Cl)(=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1.C(OCC)(=O)C>[CH2:19]([O:18][C:17]([C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12])=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1[nH]c(C(C)(C)C)cc1N
Reactant: O=C(Cl)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1[nH]c(C(C)(C)C)cc1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of the previously prepared methyl 3-amino-5-tert-butyl-1H-pyrrole-2-carboxylate (0.400 g, 2.0 mmol) and NaH (60% w/w, 0.760 g, 4.5 mmol) in THF (4 mL) was stirred at room temperature for 30 min. To the resulting mixture was added benzyl carbonochloridate drop wise and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution. The crude product was recrystallized from dichloromethane:hexane to afford the desired methyl 3-(benzyloxycarbonyl)-5-tert-butyl-1H-pyrrole-2-carboxylate (0.560 g) as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[C:34]([O:36][CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.[Cl:45][CH2:46][C:47]1[CH:55]=[CH:54][CH:53]=[CH:52][C:48]=1[C:49](Cl)=[O:50]>>[Cl:45][CH2:46][C:47]1[CH:55]=[CH:54][CH:53]=[CH:52][C:48]=1[C:49]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[C:34]([O:36][CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:9][CH:10]=1)=[O:50]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCO)cc2)C(OCc2cc(OCOCC[Si](C)(C)C)c3ccccc3c2)C1
Reactant: O=C(Cl)c1ccccc1CCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOC(=O)c3ccccc3CCl)cc2)C(OCc2cc(OCOCC[Si](C)(C)C)c3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 22(k), by acylating tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-[4-(2-trimethylsilanyl-ethoxymethoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate with 2-chloromethyl-benzoyl chloride there was obtained tert-butyl (3RS,4RS)-4-[4-[2-(2-chloromethyl-benzoyloxy)-ethoxy]-phenyl]-3-[4-(2-trimethylsilanyl-ethoxymethoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate as a colourless solid; MS: 776 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C([Mg]Cl)(C)C.[O:15]=[CH:16][C@@H:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:18][CH3:19].[Cl-].[NH4+]>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:16]([OH:15])[C@@H:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:18][CH3:19]
Reactant: c1ccc2ocnc2c1
Reactant: CC[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC[C@H](NC(=O)OC(C)(C)C)C(O)c1nc2ccccc2o1
Temperature: -5 °C
Reaction time: 1.5 h

Procedure:
Under an atmosphere of argon, benzo[d]oxazole (5 g, 42.0 mmol, Eq: 1.00) was combined with THF (100 ml) to give a light yellow solution. At −5° C. isopropylmagnesium chloride 2M in THF (21.0 ml, 42.0 mmol, Eq: 1.00) was added dropwise. The reaction was stirred for 1.5 h at −5° C. Then (S)-tert-butyl 1-oxobutan-2-ylcarbamate (4.72 g, 25.2 mmol, Eq: 0.6) diluted in 20 ml THF was added. The reaction was stirred overnight at RT. Satd. ammoniumchloride solution (6 ml) was added to the reaction. The THF was evaporated under vacuum. The reaction mixture was poured into 50 ml H2O and extracted with ethyl acetate (2×100 ml). The crude material was purified by flash chromatography (silica gel, 20 g, 0% to 40% ethyl acetate in heptane). The title compound was obtained as a brown gum (5.08 g, 39.5%, MS (m/e)=307.2 [M+H+]).
Reaction SMILES: [CH:1]([C:3]1[C:12]([Br:13])=[CH:11][C:10]2[C:9]([CH3:15])([CH3:14])[CH2:8][CH2:7][C:6]([CH3:17])([CH3:16])[C:5]=2[CH:4]=1)=[O:2].[CH2:18](O)[CH2:19][OH:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[O:2]1[CH2:18][CH2:19][O:20][CH:1]1[C:3]1[C:12]([Br:13])=[CH:11][C:10]2[C:9]([CH3:15])([CH3:14])[CH2:8][CH2:7][C:6]([CH3:17])([CH3:16])[C:5]=2[CH:4]=1
Reactant: OCCO
Reactant: CC1(C)CCC(C)(C)c2cc(C=O)c(Br)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC1(C)CCC(C)(C)c2cc(C3OCCO3)c(Br)cc21
Yield: 70.2 %

Procedure:
To a solution of 1.8 g (6.3 mmol) of 2-formyl-3-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene in 70 mL of benzene was added 3.5 mL of ethylene glycol (63 mmol) followed by p-toluenesulfonic acid monohydrate (180 mg, 0.9 mmol). The reaction mixture was heated at reflux for about 3 hours and is then concentrated under reduced pressure. The residue was partitioned between ether and saturated sodium bicarbonate solution. The ether layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography 1.4% ethyl acetate/) on a Biotage 40M SiO2 cartridge to afford 1.5 g (72%) of 2-(1,3-dioxolan-2-yl)-3-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene as a crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)(=[O:11])=[O:10])[C:5]([Cl:19])=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23]1[C:24](=O)[C:25](=[O:30])[C:26]=1[O:27]CC)[CH3:21]>C(O)C>[Cl:19][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:24]2[C:25](=[O:30])[C:26](=[O:27])[C:23]=2[O:22][CH2:20][CH3:21])=[C:7]([OH:8])[C:6]=1[S:9]([N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)(=[O:11])=[O:10]
Reactant: CN1CCN(S(=O)(=O)c2c(Cl)ccc(N)c2O)CC1
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCO
Product: CCOc1c(Nc2ccc(Cl)c(S(=O)(=O)N3CCN(C)CC3)c2O)c(=O)c1=O
Temperature: 50 °C
Yield: 73.4 %

Procedure:
A mixture of 1.98 g (6.5 mmol, 1 eq) of 6-amino-3-chloro-2-(4-methylpiperazine-1-sulfonyl)phenol and 2.20 g (48.8 mmol, 2 eq) of 3,4-diethoxy-3-cyclobutene-1,2-dione was placed in solution in 20 ml of ethanol. The reaction medium was heated at 50° C. for 16 hours. The insoluble material was filtered off, washed with ethanol and dried under vacuum at 45° C. 2.05 g of 3-[4-chloro-2-hydroxy-3-(4-methylpiperazine-1-sulfonyl)phenylamino]-4-ethoxycyclobut-3-ene-1,2-dione were obtained in the form of a yellow solid. Yield=74%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13](Cl)=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[CH:4][CH:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.[OH-].[K+].Cl>CS(C)=O.O>[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:13]2[CH:14]=[CH:15][C:10]([C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)=[O:20])=[CH:11][C:12]=2[N+:17]([O-:19])=[O:18])=[CH:24][CH:23]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=C(Nc1ccc(Br)cc1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(Oc2ccc(C(=O)Nc3ccc(Br)cc3)cc2[N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 98.1 %

Procedure:
A mixture of the product from Example 49A (3.55 g, 10 mmol), 4-aminophenol (1.09 g, 10 mmol), and potassium hydroxide (1.12 g, 20 mmol) were dissolved in dimethyl sulfoxide (15 mL) and heated at 100° C. in a CEM Discover microwave for 25 minutes. The mixture was then cooled to room temperature, poured into water (300 mL), the pH of the solution adjusted to 6 with 1N aqueous hydrochloric acid, the resultant solution stirred for 30 minutes and the resultant solid collected and dried to provide the title compound as a yellow solid (4.2 g, 98%).
Reaction SMILES: [Cl-].[Li+].[C:3](=[C:6]([CH2:24][CH2:25]Cl)[CH2:7][C:8]1(C(OC)=O)[CH:13]([CH3:14])[CH2:12][C:11]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:10][C:9]1=[O:19])([CH3:5])[CH3:4].O>CN(C)P(=O)(N(C)C)N(C)C>[C:3](=[C:6]1[CH2:24][CH2:25][C:8]2([CH:13]([CH3:14])[CH2:12][C:11]([O:15][CH:16]([CH3:17])[CH3:18])=[CH:10][C:9]2=[O:19])[CH2:7]1)([CH3:4])[CH3:5]
Reactant: COC(=O)C1(CC(CCCl)=C(C)C)C(=O)C=C(OC(C)C)CC1C
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)=C1CCC2(C1)C(=O)C=C(OC(C)C)CC2C
Temperature: 130 °C
Yield: 81.9 %

Procedure:
Dry lithium chloride (3.8 g, 0.09 mol) and methyl 1-(2-isopropylidene-4-chlorobutyl)-2-oxo-4-isopropoxy-6-methyl-3-cyclohexene carboxylate (21.3 g, 0.06 mol) were mixed in anhydrous hexamethylphosphoric triamide (120 mL) under nitrogen. The solution was heated at 130° C. for 40 minutes and after cooling was poured into water (300 mL). The mixture was extracted with ether and the extract dried (Na2SO4). Solvent removal gave 15.2 g of crude spiroketones 1 and 2 (glc purity of 93%, spiroketones separated on HPLC). Crystallization from petroleum ether gave 12.9 g of 2-isopropylidene-8-isopropoxy-10-methylspiro[4.5]dec-7-en-6-one isomer 1 exclusively, mp 77°-77.5° C.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH2:15][NH2:16])=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[O:17]1CCOCC1>O.Cl>[NH2:16][CH2:15][C:11]1[CH:12]=[C:13]([CH3:14])[C:8]([C:6]2[CH:5]=[CH:4][NH:3][C:2](=[O:17])[CH:7]=2)=[N:9][CH:10]=1
Reactant: Cc1cc(CN)cnc1-c1ccnc(F)c1
Reactant: C1COCCO1
Agent: Cl
Solvent: O
Product: Cc1cc(CN)cnc1-c1cc[nH]c(=O)c1
Temperature: 90 °C
Reaction time: 10 h

Procedure:
To a mixture of (2′-fluoro-3-methyl-2,4′-bipyridin-5-yl)methanamine 66-1 (65 mg, 0.30 mmol) in dioxane (0.6 mL) and H2O (0.2 mL) was added a few drops of aqueous concentrated HCl solution. The mixture was stirred at 90° C. for 10 hours, and then concentrated to dryness by rotary evaporation to give 4-(5-(aminomethyl)-3-methylpyridin-2-yl)pyridin-2(1H)-one 66-2 as yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31](OCC)=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:29])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:37][CH2:38][CH2:39][CH2:40][OH:41]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31]([NH:37][CH2:38][CH2:39][CH2:40][OH:41])=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:29])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: NCCCO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCCC2=O)c1=O
Product: O=C(NCCCO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(2-oxohexahydro-1H-azepin-1-yl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 3-amino-1-propanol using methods similar to Example 563 to provide an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.54 (d, J=4.42 Hz, 4 H), 1.60-1.76 (m, 6 H), 2.36-2.44 (m, 2 H), 3.33-3.39 (m, 4 H), 3.39-3.52 (m, 4 H), 4.15-4.24 (m, 4 H), 4.60 (t, J=5.05 Hz, 1 H), 7.14 (ddd, J=9.00, 6.69, 2.00 Hz, 2 H), 7.38-7.44 (m, 2 H), 7.99 (d, J=1.47 Hz, 1 H), 8.56 (d, J=1.47 Hz, 1 H), 10.33 (t, J=5.90 Hz, 1 H), 17.23 (s, 1 H); ES+ MS: 525 (M+H+).