Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:17]([O:20][CH2:21][C:22](Cl)=[O:23])(=[O:19])[CH3:18]>ClCCl>[C:17]([O:20][CH2:21][C:22]([NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)=[O:23])(=[O:19])[CH3:18]
Reactant: N#Cc1ccc(N)cc1
Reactant: CC(=O)OCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)Nc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.5 %

Procedure:
A solution of 4-aminobenzonitrile (5 g, 42.3 mmol) and triethylamine (7.08 mL, 50.8 mmol) in dichloromethane (DCM) (40 mL) was cooled in an ice-water bath before the dropwise addition of 2-chloro-2-oxoethyl acetate (5.46 mL, 50.8 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was diluted with DCM (50 mL) and the resulting solution washed with 2N HCl (50 mL). On mixing, precipitation occurred and the solid collected was filtered and dried under vacuum at 40° C. for 4 hours to yield a pale brown solid. The solid was dissolved in DCM (150 mL) and washed with 2N HCl (50 mL). The organic layer was collected via a hydrophobic frit and the solvent removed to yield the title compound as a cream solid (4.48 g).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[O:9]=[C:10]1[CH:16]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:15][CH2:14][C:13]2[CH:25]=[CH:26][CH:27]=[CH:28][C:12]=2[NH:11]1>CCOC(C)=O>[Br:1][C:26]1[CH:27]=[CH:28][C:12]2[NH:11][C:10](=[O:9])[CH:16]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[CH2:15][CH2:14][C:13]=2[CH:25]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)NC1CCc2ccccc2NC1=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1CCc2cc(Br)ccc2NC1=O
Yield: 203.3 %

Procedure:
472 mg of N-bromosuccinimide (2.65 mmol) are introduced at AT into a 100 ml round-bottomed flask, with stirring and under an argon atmosphere, containing 40 ml of EtOAc and 0.5 g of 2 (1.8 mmol). The medium is left stirring overnight, and is washed with 40 ml of HCl (1N), 40 ml of saturated aqueous solution of NaHCO3 and 40 ml of water. The organic phase is dried over MgSO4, filtered and then evaporated to dryness. 1.3 g of an oil are obtained, which oil is crystallized from 10 ml of isopropyl ether. After filter-drying, 450 mg of product 10 (white solid) are obtained.
Reaction SMILES: [CH2:1]=[O:2].[C:3]12[CH2:9][C:6]([CH2:7][CH2:8]1)=[CH:5]C=2.[CH:10]([OH:12])=[O:11]>OS(O)(=O)=O>[CH:10]([OH:12])=[O:11].[CH:10]([OH:12])=[O:11].[CH:6]12[CH2:7][CH:8]3[CH:1]([OH:2])[CH:5]1[CH:9]2[CH2:3]3
Reactant: C1=C2CCC(=C1)C2
Reactant: C=O
Agent: O=S(=O)(O)O
Solvent: O=CO
Product: OC1C2CC3C(C2)C13
Yield: 84 %

Procedure:
To a stirred solution of 39.9 g paraformaldehyde in formic acid (800 ml) and conc. H2SO4 (15 ml) under nitrogen and at 20°C was added dropwise 132 g norbornadiene while keeping the temperature between 20°-25°C. After 1.5 hr the reaction was quenched by adding to 800 ml of ice-water. Extraction with ether (3 × 750 ml), washing the organic layer with water (1 × 250 ml), brine (3 × 250 ml) and drying (Na2SO4) afforded the crude 3-hydroymethyl tricyclo [2.2.1.02,6 ]heptan-5-ol bisformate (1') as an oil. Distillation, after a forerum of bp. 40°C/15mm, gave 235 g pure tricyclenebisformate, bp. 104°C/0.3 mm (84% yield).
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]2[O:16][C:15]([C:17](=[O:19])[CH3:18])=[CH:14][CH:13]=2)[CH:10]=1)([O-:5])=[O:4].[CH2:20](O)[CH2:21][OH:22].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CC(=O)OCC.O>[CH3:18][C:17]1([C:15]2[O:16][C:12]([CH2:11][N:9]3[CH:10]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=[N:8]3)=[CH:13][CH:14]=2)[O:22][CH2:21][CH2:20][O:19]1
Reactant: OCCO
Reactant: CC(=O)c1ccc(Cn2cc([N+](=O)[O-])cn2)o1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#N
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(c2ccc(Cn3cc([N+](=O)[O-])cn3)o2)OCCO1
Temperature: 25 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and a Dean-Stark apparatus under inert atmosphere (N2), a solution of 1-[5-(4-nitro-pyrazol-1-ylmethyl)-furan-2-yl]-ethanone (3.40 g, 14.46 mmol), ethylene glycol (8.1 mL, 144.84 mmol) and TsOH (28 mg, 0.15 mmol) in toluene (150.0 mL) was heated to reflux for 4 h. The reaction mixture was allowed to cool to rt. Water (200 mL) and EA (40 mL) were added and the aq. phase was extracted with EA (2×80 mL). The combined org. extracts were washed with sat. aq. NaHCO3 (200 mL), dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (60:40 hept-EA) gave the title compound as a yellow oil. TLC: rf (60:40 hept-EA)=0.31. LC-MS-conditions 02: tR=0.91 min. 1H NMR (400 MHz, CDCl3) δ 1.72 (s, 3H), 3.99 (dd, J=4.5, 2.5 Hz, 2H), 4.06 (dd, J=4.4, 2.5 Hz, 2H), 5.31 (s, 2H), 6.35 (d, J=3.3 Hz, 1H), 6.42 (d, J=3.3 Hz, 1H), 8.09 (s, 1H), 8.12 (s, 1H).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])=[C:16]([C:27]([N:29]3[CH2:34][CH2:33][CH:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH2:31][CH2:30]3)=[O:28])[CH:15]=[N:14][C:13]=12)(=[O:8])=[O:7])(C)(C)C.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[F:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:17]2[N:12]3[N:11]=[CH:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[C:13]3[N:14]=[CH:15][C:16]=2[C:27]([N:29]2[CH2:34][CH2:33][CH:32]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:31][CH2:30]2)=[O:28])=[C:20]([CH3:26])[CH:21]=1
Reactant: Cc1cc(F)ccc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(S(=O)(=O)NC(C)(C)C)cnn12
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Cc1cc(F)ccc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(S(N)(=O)=O)cnn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
N-tert-Butyl-7-(4-fluoro-2-methylphenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-sulfonamide (0.874 g, 1.548 mmol) obtained in step 4 was dissolved in trifluoroacetic acid (13 mL), anisole (0.4 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography (chloroform/methanol=10/1) to give the title compound (0.442 g, 56%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:55][N:56]1[CH:60]=[C:59]([S:61](Cl)(=[O:63])=[O:62])[N:58]=[C:57]1[CH3:65]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([S:61]([C:59]2[N:58]=[C:57]([CH3:65])[N:56]([CH3:55])[CH:60]=2)(=[O:63])=[O:62])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: Cc1nc(S(=O)(=O)Cl)cn1C
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(S(=O)(=O)N2CCC(CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)cn1C
Yield: 24 %

Procedure:
The desired compound was prepared according to the procedure of Example A42 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 1,2-dimethyl-1H-imidazole-4-sulfonyl chloride as starting materials in 24% yield. LCMS for C29H33ClN9O3S (M+H)+: m/z=622.2.
Reaction SMILES: FC1C=C(F)C=CC=1[C@@H](NCCC1(O)CCC2(OCC(C)(C)CO2)CC1)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[F:40][C:41]1[CH:46]=[C:45]([F:47])[CH:44]=[CH:43][C:42]=1[C@@H:48]([N:50]1[CH2:55][CH2:54][C:53]2([CH2:67][CH2:66][C:58]3(OCC(C)(C)C[O:59]3)[CH2:57][CH2:56]2)[O:52][C:51]1=[O:68])[CH3:49]>>[F:40][C:41]1[CH:46]=[C:45]([F:47])[CH:44]=[CH:43][C:42]=1[C@@H:48]([N:50]1[CH2:55][CH2:54][C:53]2([CH2:67][CH2:66][C:58](=[O:59])[CH2:57][CH2:56]2)[O:52][C:51]1=[O:68])[CH3:49]
Reactant: C[C@@H](c1ccc(F)cc1F)N1CCC2(CCC3(CC2)OCC(C)(C)CO3)OC1=O
Agent: C[C@H](NCCC1(O)CCC2(CC1)OCC(C)(C)CO2)c1ccc(F)cc1F
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: C[C@@H](c1ccc(F)cc1F)N1CCC2(CCC(=O)CC2)OC1=O

Procedure:
The title compound is prepared from 9-{2-[(S)-1-(2,4-difluoro-phenyl)-ethylamino]-ethyl}-3,3-dimethyl-1,5-dioxa-spiro[5.5]undecan-9-ol and triphosgene following a procedure analogous to that described in Step 4 of Intermediate 2; the crude product, a mixture of the title compound and 3-[(S)-1-(2,4-difluoro-phenyl)-ethyl]-12,12-dimethyl-1,10,14-trioxa-3-aza-dispiro[5.2.5.2]hexadecan-2-one, obtained after that is treated as described in Step 10 of Intermediate 2 to convert the intermediate to the title compound as well. Yield: 30% of theory; LC (method 6): tR=1.10 min; Mass spectrum (ESI+): m/z=324 [M+H]+.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[CH3:9][NH2:10]>O>[CH3:9][NH:10][C:3]([CH3:5])=[CH:2][C:1]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CC(C)=O
Reactant: CN
Solvent: O
Product: CNC(C)=CC(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
To a mixture of methyl acetoacetate (23.2 g, 0.2 mol) in water (15 mL) at 10° C. was added dropwise methylamine (40% aqueous solution, 18.6 g, 0.24 mol). The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The resulting solid precipitate was collected by filtration and washed with ice water (2×), and then dried in a vacuum oven at 55° C. overnight to provide the title compound as a white solid (20.9 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:18]([CH:19]=2)[C:17]2[CH2:16][CH2:15][N:14](C(OCC)=O)[CH2:13][C:12]=2[S:11]3)=[CH:4][CH:3]=1.[BrH:25]>C(O)(=O)C>[BrH:25].[BrH:25].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:18]([CH:19]=2)[C:17]2[CH2:16][CH2:15][NH:14][CH2:13][C:12]=2[S:11]3)=[CH:4][CH:3]=1
Reactant: CCOC(=O)N1CCc2c(sc3nc(-c4ccc(Cl)cc4)cn23)C1
Agent: Br
Solvent: CC(=O)O
Product: Clc1ccc(-c2cn3c4c(sc3n2)CNCC4)cc1

Procedure:
A mixture of 9 g of the product of Example 5 and 100 ml of a solution of hydrobromic acid in acetic acid (20% (w/w) hydrobromic acid) was heated on a boiled water bath for one hour. The precipitated crystals were filtered off and washed with n-hexane to give 9.3 g of 2-(4-chlorophenyl)-5,6,7,8-tetrahydroimidazo[2',1':2,3]thiazolo[5,4-c]pyridine dihydrobromide, melting at 304°-307° C. with decomposition.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]=[C:6]2[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=1.[Na].[SH:22][C:23]1[NH:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1>>[N:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[NH:27][C:23]=1[S:22][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]=[C:6]2[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: Cc1cccc(Nc2ncnc3ccc(CBr)cc23)c1
Agent: [Na]
Product: Cc1cccc(Nc2ncnc3ccc(CSc4nc5ccccc5[nH]4)cc23)c1
Yield: 59 %

Procedure:
Using an analogous procedure to that described in Example 34, 6-bromomethyl-4-(3-methylanilino)quinazoline was reacted with 2-mercaptobenzimidazole sodium salt to give 6-(2-benzimidazolylthiomethyl)4-(3-methylanilino)quinazoline in 59% yield, m.p. 123-129° C.; NMR Spectrum: 2.34 (s, 3H), 4.77 (s, 2H), 6.96 (d, 1H), 7.13 (m, 2H), 7.28 (t, 1H), 7.46 (broad s, 2H), 7.68 (m, 3H), 7.96 (m, 1H), 8.57 (s, 1H), 8.65 (d, 1H), 9.79 (broad s, 1H); Elemental Analysis: Found C, 64.9; H, 5.3; N, 15.9; C23H19N5S 1.6H2O 0.1CH3OH requires C, 64.5; H, 5.3; N, 16.3%.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH2:7]P(OC)(OC)=O)=[O:6].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH:23]2[CH2:25][CH2:24]2)=O)=[CH:17][CH:16]=1.O>O1CCCC1.CN(C)C=O.C(OCC)C>[CH:23]1([C:21]([C:18]2[CH:17]=[CH:16][C:15]([Cl:14])=[CH:20][CH:19]=2)=[CH:7][C:5]([O:4][CH3:3])=[O:6])[CH2:24][CH2:25]1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: O=C(c1ccc(Cl)cc1)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)C=C(c1ccc(Cl)cc1)C1CC1
Temperature: 80 °C
Reaction time: 5 h
Yield: 921.8 %

Procedure:
A 50% suspension of 5.7 grams (0.012 mole) of sodium hydride in mineral oil was washed with three portions of tetrahydrofuran, and to this was added 21.7 grams (0.012 mole) of trimethyl phosphonoacetate in 300 mL of tetrahydrofuran. To the resultant thick mixture was added 150 ml of dimethylformamide. This was followed by the addition of a solution of 19.6 grams (0.011 mole) of cyclopropyl 4-chlorophenyl ketone in 50 ml of dimethylformamide. Upon completion of addition, the reaction mixture was heated to 80° C. and it was stirred for five hours. Gas chromatography of the reaction mixture indicated the presence of unreacted ketone. The reaction mixture was cooled, and an additional 1.0 gram of 97% sodium hydride was added. Upon completion of addition, the reaction mixture was again warmed to 80° C. and stirred for about 18 hours. Gas chromatography analysis of the reaction mixture indicated that unreacted ketone was still present. An additional 0.8 gram of 97% sodium hydride and 4.0 grams of trimethyl phosphonoacetate were added, and the reaction mixture was heated at 80° C. for an additional six hours. After this time the reaction mixture was cooled and poured into 500 ml of water and 300 ml of diethyl ether. The diethyl ether layer was separated, and the aqueous layer was extracted with five portions of diethyl ether. The ether layer and the extracts were combined and were washed with four portions of water. The aqueous layer and the water washes were combined and extracted with two portions of diethyl ether. The two ether extracts were combined and were washed with four portions of water. All of the organic layers and diethyl ether washes were combined and dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure, yielding 24.0 grams of methyl 3-cyclopropyl-3-(4-chlorophenyl)propenoate.
Reaction SMILES: [BrH:1].Br.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1.[OH-].[Na+]>CS(C)=O>[Br:1][C:10]1[CH:9]=[CH:8][C:7]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:6][C:5]=1[O:4][CH3:3]
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1cc(N2CCNCC2)ccc1Br
Temperature: 65 °C

Procedure:
A solution of 1-(3-methoxyphenyl)piperazine dihydrobromide (3.5 g, 10 mmol) is dissolved in DMSO (30 mL) and heated at 65° C. for 4 h in a flask which is open to the atmosphere. After cooling, the mixture is poured into a separatory funnel containing 100 mL of 1 N sodium hydroxide solution and extracted with ethyl ether (3×100 mL). The organic extracts are dried (Na2SO4), filtered, and concentrated to provide 1-(4-bromo-3 -methoxyphenyl)piperazine as a solid. 1H NMR (400 MHz, CDCl3) 7.34-7.36 (d, J=2.2 Hz, 1H,), 6.47 (s, 1H), 6.38-6.41 (d, J=2.8 Hz, 1H), 3.87 (s, 3H, OMe), 3.11 -3.13 (m, 4H), 3.01 -3.03 (m, 4H)
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([OH:15])=[O:14])[N:8]=1.[CH2:16](O)[CH3:17]>C1(C)C=CC=CC=1>[CH2:16]([O:14][C:13]([C:9]1[N:8]=[C:7]([Br:6])[CH:12]=[CH:11][CH:10]=1)=[O:15])[CH3:17]
Reactant: CCO
Reactant: O=C(O)c1cccc(Br)n1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccc(Br)n1

Procedure:
Sulfuric acid (1.46 mL) was added to a mixture of 2-bromo-6-pyridine-carboxylic acid, ethanol (15 mL) and toluene (30 mL). The reaction heated to reflux for 16 h. The mixture was partitioned between chloroform and a saturated aqueous solution of sodium bicarbonate. The aqueous layer was extracted with chloroform (2 x) and the combined organic layers were dried over sodium sulfate, filtered and concentrated to yield a cloudy orange oil. The oil was purified by silica gel chromatography with 9:1 hexane:ethyl acetate. The title product was obtained as an oily white solid (1.31 g).
Reaction SMILES: [OH:1][C@H:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:3][C:4]([OH:6])=[O:5].N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].ClCCl>CO>[Si:23]([O:1][C@H:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:3][C:4]([OH:6])=[O:5])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CCCCCCCCCCC[C@@H](O)CC(=O)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CO
Solvent: ClCCl
Product: CCCCCCCCCCC[C@H](CC(=O)O)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 22 h
Yield: 79.2 %

Procedure:
A mixture of 2.44 g (R)-3-hydroxytetradecanoic acid (0.01 mole), 2.72 g imidazole (0.04 mole), 3.03 g t-butyldimethylsilyl chloride (0.02 mole), and 50 mL dichloromethane was stirred at room temperature for 22 hours. 5 mL Methanol was added and the resultant mixture was stirred at room temperature for 15 minutes after which it was concentrated to dryness on a rotary evaporator (ca. 100 mm Hg, 35° C.). The residue was chromatographed on a 1" column slurry packed with silica gel in chloroform. The product was eluted with 5% methanol in chloroform. The chromatography was monitored by TLC (silica gel, 5% methanol in chloroform, phosphomolybdic acid visualization, product Rf ca. 0.6) and fractions containing only product were pooled and concentrated on a rotary evaporator (ca. 1 mm Hg, 30° C.) to a clear oil (2.84 g, 79% yield).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([O:18][CH2:19][CH2:20][NH:21]C(=O)OC(C)(C)C)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].ClC1C=CC=C(C(OO)=O)C=1.[OH-].[NH4+:41].C1(S(Cl)(=O)=O)C=CC=CC=1.C(=O)(O)[O-].[Na+].Cl.[OH-].[Na+]>ClCCl.C(O)C.O>[NH2:21][CH2:20][CH2:19][O:18][N:6]1[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:41])[C:8]=2[N:17]=[C:5]1[CH2:4][O:3][CH2:1][CH3:2]
Reactant: CCOCc1nc2cnc3ccccc3c2n1OCCNC(=O)OC(C)(C)C
Reactant: [NH4+]
Agent: Cl
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: CCOCc1nc2c(N)nc3ccccc3c2n1OCCN
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of tert-butyl 2-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]oxy}ethylcarbamate (6.0 g) from several batches of Part C in dichloromethane (100 mL) was added m-chloroperbenzoic acid (7.0 g). After about 2 hours, concentrated ammonium hydroxide (35 mL) and water (10 mL) were added. The mixture was cooled in an ice bath and a solution of benzenesulfonyl chloride (3.5 mL) in dichloromethane (25 mL) was added dropwise. The mixture was stirred for 2 hours at room temperature; then dichloromethane (75 mL) and saturated aqueous sodium bicarbonate (35 mL) were added. The aqueous layer was separated and extracted with dichloromethane (2×25 mL). The organic layers were combined, dried over potassium carbonate, filtered, and evaporated to afford an oil. The oil was dissolved in ethanol (50 mL). Concentrated hydrochloric acid (4 mL) was added and the mixture was heated at reflux for 2 days. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (10 mL) and added to stirred toluene (125 mL) causing an oil to form. The oil was stirred in dichloromethane (75 mL) and 15% sodium hydroxide solution (75 mL) for 2 hours. The layers were separated and the aqueous layer was extracted with dichloromethane (25 mL). The organic layers were combined, dried over potassium carbonate, filtered, and concentrated under reduced pressure to afford 1.3 g of 1-(2-aminoethoxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9](Cl)(=[O:11])=[O:10].[N-:13]=[N+:14]=[N-:15].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9]([N:13]=[N+:14]=[N-:15])(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: [N-]=[N+]=NS(=O)(=O)c1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 15.0 g (0.61 mole) 2,6-dichlorobenzenesulfonyl chloride in 100 ml ethanol was added a solution of 5.2 g (0.79 mole) of sodium azide dissolved in a minimum amount of water. The solution was stirred 30 minutes and then poured into a 2 liter Erlenmeyer flask containing 500 ml of ice water. The resultant white solid was recrystallized from ethanol; yield 14.29 g (93% of theory). The purified product melted at 63°-64° C. (lit. 63°-64° C.).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH2:3][C:4]1[O:5][CH:6]=[CH:7][C:8]=1[CH3:9].C([Li])CCC.[CH2:16]=[O:17].O>O1CCCC1.CCCCCC>[CH3:1][N:2]([CH2:3][C:4]1[O:5][C:6]([CH2:16][OH:17])=[CH:7][C:8]=1[CH3:9])[CH3:10]
Reactant: C=O
Reactant: Cc1ccoc1CN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(CO)oc1CN(C)C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
A solution of N,N,3-trimethyl-2-furanmethanamine (10.3 g) in dry tetrahydrofuran (200 ml) under nitrogen was treated over 2 hr with 1.6 M n-butyl lithium in hexane 846.2 ml) at -40° to -45° C. After stirring for 2 hr at room temperature paraformaldehyde (2.3 g) in dry tetrahydrofuran (100 ml) was added and the solution stirred overnight. Water (10 ml) was added and the solvent evaporated. Ethyl acetate (200 ml) and sodium sulphate were added and the organic phase was evaporated giving an oily residue which was distilled (85°/0.1 mm) affording the title compound (8 g).
Reaction SMILES: [CH3:1][C:2]1[C:14]([CH:15]([CH2:20][CH2:21][CH3:22])[C:16]([O:18]C)=[O:17])=[C:13]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)[N:5]2[N:6]=[C:7]3[C:12]([CH:11]=[CH:10][CH:9]=[CH:8]3)=[C:4]2[N:3]=1.[OH-].[Na+]>CO.C(O)C>[CH3:1][C:2]1[C:14]([CH:15]([CH2:20][CH2:21][CH3:22])[C:16]([OH:18])=[O:17])=[C:13]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)[N:5]2[N:6]=[C:7]3[C:12]([CH:11]=[CH:10][CH:9]=[CH:8]3)=[C:4]2[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc2c3ccccc3nn2c1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: CCCC(C(=O)O)c1c(C)nc2c3ccccc3nn2c1-c1ccc(C)cc1
Temperature: 60 °C
Yield: 29.9 %

Procedure:
To a solution of methyl 2-(2-methyl-4-p-tolylpyrimido[1,2-b]indazol-3-yl)pentanoate (0.264 g; 0.68 mmol) in a mixture methanol-ethanol (2:1) (21 mL) was added a 5% sodium hydroxide solution (16.3 mL; 20.4 mmol) and the reaction mixture was heated to 60° C. for 18 h. The organic volatiles were removed under reduced pressure and the remaining basic solution was acidified till pH 2 with a 1N hydrochloric acid solution and the aqueous layer was extracted with ethyl acetate. The organics were combined, dried over magnesium sulfate and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol (1-20%) in dichloromethane and by preparative HPLC (method 2) furnished 0.076 g (30%) of 2-(2-methyl-4-p-tolylpyrimido[1,2-b]indazol-3-yl)pentanoic acid as a white solid. ESI/APCI(+): 374 (M+H). ESI/APCI(−): 372 (M−H).