Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(O)C=CC=CC=1.[CH3:8][NH:9][CH2:10][C:11]1[N:12]=[C:13]([CH:16]([CH3:18])[CH3:17])[S:14][CH:15]=1.[O:19]([C:26]([NH:28][C@H:29]([C:33]([OH:35])=[O:34])[CH:30]([CH3:32])[CH3:31])=O)C1C=CC=CC=1.O>C1COCC1>[CH3:8][N:9]([C:26]([NH:28][C@H:29]([C:33]([OH:35])=[O:34])[CH:30]([CH3:32])[CH3:31])=[O:19])[CH2:10][C:11]1[N:12]=[C:13]([CH:16]([CH3:18])[CH3:17])[S:14][CH:15]=1
Reactant: CNCc1csc(C(C)C)n1
Reactant: CC(C)[C@H](NC(=O)Oc1ccccc1)C(=O)O
Solvent: O
Solvent: C1CCOC1
Solvent: Oc1ccccc1
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)cs1
Temperature: 4.5 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
To a solution of LiOH monohydrate (970 mg, 23.2 mmol) and phenol (2.18 g, 23.2 mmol) dissolved in 25 mL of THF and cooled with an ice bath to 3-6° C. was added N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amine (3.95 g, 23.2 mmol) followed by a 1 mL THF rinse. To this mixture was slowly added a solution of N-phenoxycarbonyl-L-Valine (5.0 g, 21.1 mmol) dissolved in 20 mL of THF maintaining the temperature between 3° C. and 8° C. Following the addition and a 5 mL THF rinse, the cooling bath was removed, and the reaction was allowed to warm to ambient temperature. After stirring for 3 hours at ambient temperature, an additional aliquot of LiOH monohydrate (440 mg, 10.4 mmol) was added. One hour later, the reaction was treated with 100 mL of water and the THF removed under reduced pressure. The aqueous phase was adjusted to pH 9 using concentrated HCl and then washed with MTBE (3×60 mL). Toluene (60 mL) was added to the aqueous phase which was then acidified to pH 2.5 using 4 N HCl. The toluene phase was separated, and the aqueous phase was back extracted with four 60 mL aliquots of toluene. The combined organic extracts were concentrated under reduced pressure. The oil obtained was crystallized from toluene-heptane to give the title compound (5.41 g, 82%).
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]3[CH:41]=[C:40](Br)[CH:39]=[CH:38][C:37]=3[F:43])([CH3:35])[N:26]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.[NH2:44][C:45]1[CH:52]=[CH:51][C:48]([C:49]#[N:50])=[CH:47][C:46]=1[O:53][C:54]([F:57])([F:56])[F:55]>>[NH2:24][C:25]1[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]2[CH:41]=[C:40]([NH:44][C:45]3[CH:52]=[CH:51][C:48]([C:49]#[N:50])=[CH:47][C:46]=3[O:53][C:54]([F:55])([F:56])[F:57])[CH:39]=[CH:38][C:37]=2[F:43])([CH3:35])[N:26]=1
Reactant: N#Cc1ccc(N)c(OC(F)(F)F)c1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(C)(C)C(=O)N2C)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Nc3ccc(C#N)cc3OC(F)(F)F)ccc2F)N=C1N

Procedure:
The coupling of (S)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-6-(5-bromo-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate K) and 4-amino-3-trifluoromethoxy-benzonitrile according to procedure B followed by deprotection yielded the title compound as an off-white solid. MS (ESI): m/z=464.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([CH3:17])=[N:12][CH2:11][CH2:10]2)=[O:5])[CH3:2]>[C].[Pd].CC1C=CC(C(C)C)=CC=1>[CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([CH3:17])=[N:12][CH:11]=[CH:10]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)Nc1ccc2c(c1)CCN=C2C
Agent: [Pd]
Solvent: Cc1ccc(C(C)C)cc1
Product: CCOC(=O)Nc1ccc2c(C)nccc2c1
Temperature: 195 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
p-Cymene (100 ml) and palladium carbon (0.9 g) were added to 6-ethoxycarbonylamino-1-methyl-3,4-dihydroisoquinoline, followed by heating under stirring at 195° C. for one hour in a nitrogen atmosphere. The catalyst was filtered off and washed with ethanol, and then the filtrate was partially evaporated. After extracting with 1N hydrochloric acid, the extract was basified with potassium carbonate and then extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate anhydride. The solvent was evaporated, to give the title compound (0.629 g, 69%, 2 steps) as pale yellow crystals.
Reaction SMILES: [C:1]([CH:3](P(OCC)(OCC)=O)[N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)#[N:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH:41]=O>C1COCC1>[C:1]([C:3]([N:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:8][CH2:9]1)=[CH:41][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][N:35]=1)#[N:2]
Reactant: CCOP(=O)(OCC)C(C#N)N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=Cc1ccccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(C#N)=Cc2ccccn2)CC1
Reaction time: 0.5 h

Procedure:
In a 100 ml 3 necked round bottom flask, intermediate tert-butyl 4-(cyano(diethoxyphosphoryl)methyl)piperazine-1-carboxylate (5.5 g) was taken in dry THF (25 ml) under nitrogen. Sodium bis trimethylsilyl amide (3.3 g) was added dropwise at 0° C. and stirred for 30 min, then pyridine-2-carboxaldehyde (1.67 g) in 15 ml dry THF was added dropwise to the above reaction mixture at 0° C. Reaction mixture was stirred at room temperature for overnight. TLC was checked no starting material and the reaction mixture was quenched with saturated ammonium chloride (50 ml) and ethyl acetate was added. The organic layer was washed with brine, dried and concentrated to get crude product compound tert-butyl 4-(1-cyano-2-(pyridin-2-yl)vinyl)piperazine-1-carboxylate as yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:3]=1[CH:4]=[C:5]1[S:9]C(=S)N[C:6]1=[O:11].[OH-:18].[Na+]>>[F:1][C:2]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:3]=1/[CH:4]=[C:5](\[SH:9])/[C:6]([OH:18])=[O:11]
Reactant: [OH-]
Reactant: COc1ccc(F)c(C=C2SC(=S)NC2=O)c1
Agent: [Na+]
Product: COc1ccc(F)c(/C=C(\S)C(=O)O)c1
Temperature: 25 °C
Yield: 100 %

Procedure:
5-(2-Fluoro-5-methoxybenzylidene)-2-thioxo-1,3-thiazolidin-4-one (8.00 g, 9.7 mmol) was added in one portion to 25% w/v sodium hydroxide solution (40 mL). This was allowed stir at reflux for 1 h. After this time the reaction was allowed to cool to room temperature and poured onto water (50 mL). This was washed with dichloromethane (50 mL), and the aqueous layer acidified to pH 2 with aqueous hydrochloric acid (2 N, 50 mL) to give a white suspension. Product was extracted with ether (2×60 mL), dried (MgSO4) and solvent removed in vacuo to give a white solid (6.71 g, 100%); δH (300 M, CD3O D) 7.85 (1H, s, Ar), 7.46-7.35 (1H, m, Ar), 7.11 (1H, t, Ar), 7.01-6.75 (2H, m, CH═, and SH), 3.80 (3H, s, OCH3).
Reaction SMILES: Cl.[CH2:2]1[C:6]2([CH2:11][CH2:10][N:9]([NH2:12])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[C:30]3[N:31]([C:37]4[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:38]=4[Cl:44])[N:32]=[C:33]([C:34](Cl)=[O:35])[C:29]=3[S:28][CH2:27][C:25]=2[CH:26]=1>C(Cl)Cl>[CH2:2]1[C:6]2([CH2:11][CH2:10][N:9]([NH:12][C:34]([C:33]3[C:29]4[S:28][CH2:27][C:25]5[CH:26]=[C:21]([Cl:20])[CH:22]=[CH:23][C:24]=5[C:30]=4[N:31]([C:37]4[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:38]=4[Cl:44])[N:32]=3)=[O:35])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3]1
Reactant: NN1CCC2(CCCC2)CC1
Reactant: O=C(Cl)c1nn(-c2ccc(Cl)cc2Cl)c2c1SCc1cc(Cl)ccc1-2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NN1CCC2(CCCC2)CC1)c1nn(-c2ccc(Cl)cc2Cl)c2c1SCc1cc(Cl)ccc1-2
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.9 %

Procedure:
A solution of 0.28 g of 8-azaspiro[4.5]dec-8-ylamine hydrochloride and 0.41 ml of triethylamine in 15 ml of DCM is cooled to 0° C., 0.6 g of the acid chloride prepared in Example 1, step A, in 10 ml of DCM is added dropwise and the mixture is left for 4 hours, with stirring, at RT. The mixture is extracted with DCM, the organic phase is washed with water, with a saturated NaCl solution, dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with the toluene/AcOEt (95/5; v/v) mixture. 0.45 g of the expected compound is obtained in amorphous form.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]=2[CH:9]=[CH:8][CH:7]=1.[NH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])[CH2:24][CH2:23]1>>[OH:1][CH:2]([CH2:3][NH:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][C:30]([F:33])([F:31])[F:32])[CH2:24][CH2:23]1)[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: O=C1c2ccccc2-c2c(OC[C@@H]3CO3)cccc21
Reactant: NCC1CCN(CCC(F)(F)F)CC1
Product: O=C1c2ccccc2-c2c(OCC(O)CNCC3CCN(CCC(F)(F)F)CC3)cccc21
Yield: 58.5 %

Procedure:
Prepared from 4-[(2S)-oxiranylmethoxy]-9-fluorenone (0.087 g, 0.34 mmol) and 4-aminomethyl-1-(3,3,3-trifluoropropyl)-piperidine (0.126 g, 0.6 mmol) of according to the procedure used for Example 2 to give 0.092 g of the title compound as a yellow solid.
Reaction SMILES: N1C=CC=CC=1.[C:7]([O:15][CH:16]([CH2:36][O:37][C:38](=[O:54])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:17][O:18][C:19](=[O:35])[CH2:20][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][CH3:34])(=[O:14])[CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].S(Cl)(Cl)=O.[CH:59]1[C:64]([Cl:65])=[CH:63][C:62](O)=[C:61]([O:67][C:68]2[CH:69]=[CH:70][C:71]([Cl:75])=[CH:72][C:73]=2[Cl:74])[CH:60]=1>C1CCCCC1>[C:11]([O:13][C:62]1[CH:63]=[C:64]([Cl:65])[CH:59]=[CH:60][C:61]=1[O:67][C:68]1[CH:69]=[CH:70][C:71]([Cl:75])=[CH:72][C:73]=1[Cl:74])(=[O:12])[CH2:10][CH2:9][CH2:8][C:7]([O:15][CH:16]([CH2:36][O:37][C:38](=[O:54])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:17][O:18][C:19](=[O:35])[CH2:20][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][CH3:34])=[O:14]
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCC(=O)O
Reactant: Oc1cc(Cl)ccc1Oc1ccc(Cl)cc1Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCCCC1
Product: CCCCCCCCCCCCCCCC(=O)OCC(COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCC(=O)Oc1cc(Cl)ccc1Oc1ccc(Cl)cc1Cl
Temperature: 35 °C
Reaction time: 1.5 h

Procedure:
A mixture of cyclohexane (60 ml.), pyridine (1.43 ml.) and 2-hexadecanoyloxy-1-(hexadecanoyloxymethyl)ethyl hydrogen glutarate (B) (11.0 g.) was warmed to 35° C. The solution obtained was added dropwise during 45 minutes to a stirred solution of thionyl chloride (1.23 ml.) in cyclohexane (25 ml.) at 35° C. The mixture was then stirred for a further 1.5 hours at 35° C., cooled to 15° C. and a solution of triclosan (4.68 g.) and pyridine (1.56 ml.) in cyclohexane (20 ml.) added during 15 minutes. The mixture was stirred at ambient temperature for 16 hours, warmed to 35° C. and washed first with 0.5 M hydrochloric acid (100 ml.) and then with water (3×100 ml.), also heated to 35° C. The mixture was then dried (MgSO4) and evaporated to give 5-chloro-2-(2,4-dichlorophenoxy)phenyl 2-hexadecanoyloxy-1-(hexadecanoyloxymethyl)ethyl glutarate as a white solid, m.p. 44°-46° C., identical with the material obtained in Example 4 as judged by its NMR and mass spectral properties.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16]CC)=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:19]([O:22][CH2:23][CH3:24])(=[O:21])[CH3:20]>>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[CH2:20][C:19]([O:22][CH2:23][CH3:24])=[O:21])[CH2:12][CH2:13]1)=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Product: CCOC(=O)CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.1 %

Procedure:
To a mixture of ethyl N-Boc-piperidine-4-carboxylate (0.5 mol) and ethyl acetate (3 mol) t-BuOK (1.5 mol) was added in some portions at 0 C. The mixture was stirred at room temperature for 3 h (monitored by TLC), concentrated up to a half of volume, diluted with water (200 mL) and extacted with ether. Organic layer was dried over sodium sulfate and evaporated in vacuo. Purification by column chromatography (silica gel, ethyl acetate/hexane) afforded 4-(2-ethoxycarbonyl-acetyl)-piperidine-1-carboxylic acid tert-butyl ester (78 g, 52%)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([Li])CCC.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=[O:22])[CH:16]=1.[Cl-].[NH4+]>CCCCCC.CCOCC.O>[CH3:9][O:8][C:5]1[CH:4]=[CH:3][C:2]([CH:21]([C:17]2[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=2)[OH:22])=[CH:7][N:6]=1
Reactant: O=Cc1cccnc1
Reactant: COc1ccc(Br)cn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: O
Product: COc1ccc(C(O)c2cccnc2)cn1
Temperature: -50 °C
Yield: 23.6 %

Procedure:
5-Bromo-2-methoxypyridine (188 g) was added over 30 minutes to a 1.55 molar solution of n-butyllithium in hexane (770 ml) and ether (1200 ml) stirred at -50° C. The suspension was stirred for 1 hour when pyridine-3-carboxaldehyde (112 g) in ether (200 ml) was added over 30 minutes. The solution was stirred for 3.5 hr and then allowed to warm to ambient temperature. Saturated ammonium chloride solution (100 ml) and water (2 L) was added and the solution was concentrated to ca. 2.5 L in vacuo. Chloroform (3 L) was added and the title compound (41.3 g) was collected by filtration. The chloroform layer was separated, dried over magnesium sulphate and the solvent was removed under reduced pressure. The residue was treated with chloroform (200 ml) and filtered to give a second crop of the product (51.01 g). Recrystallisation from isopropanol/ether gave the title compound, m.p. 129°-130° C.
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][CH:16]2[CH2:21][CH2:20]N(CC)CC2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].C(OC1NC(N)=C2C(N=1)=NC(OC)=N2)CCC.[CH2:44]([N:46]1[CH2:51]CC(CCO)[CH2:48][CH2:47]1)[CH3:45]>>[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:21]2[CH2:20][CH2:51][N:46]([CH2:47][CH3:48])[CH2:44][CH2:45]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCN1CCC(CCO)CC1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCN(CC)CC3)c2n1
Agent: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Product: CCCCOc1nc(N)c2nc(OC)n(CCC3CCN(CC)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 19 from 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine and 2-(1-ethyl-4-piperidinyl)ethanol.
Reaction SMILES: [C:1]1([C:7]2[NH:19][C:18]3[CH:17]=[CH:16][C:15]4[C:10](=[C:11]([NH2:21])[N:12]=[C:13]([NH2:20])[N:14]=4)[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:24]I>CN(C)C=O>[CH3:24][N:19]1[C:18]2[CH:17]=[CH:16][C:15]3[C:10](=[C:11]([NH2:21])[N:12]=[C:13]([NH2:20])[N:14]=3)[C:9]=2[CH:8]=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1nc(N)c2c(ccc3[nH]c(-c4ccccc4)cc32)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(-c2ccccc2)cc2c3c(N)nc(N)nc3ccc21

Procedure:
In a manner similar to that recorded in Example 2 (Method A), 6.88 g. 8-phenyl-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine in 300 ml. dry dimethylformamide is treated with 1.44 g. ca. 50% sodium hydride-mineral oil dispersion and the salt is reacted with 4.26 g. methyl iodide for 3 hours. The crude product is recrystallized from methanol (twice) and from acetonitrile to give 3.54 g. title compound, m.p. 295.0-296.5 (dec., softens 288°).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:29][O:30][CH2:31][CH3:32])[N:14]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.B1([C:40]2[CH:45]=[CH:44][CH:43]=[N:42][CH:41]=2)OCCCO1>>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:29][O:30][CH2:31][CH3:32])[N:14]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:40]3[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: c1cncc(B2OCCCO2)c1
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 85.4 %

Procedure:
tert-Butyl 4-[(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidine-1-carboxylate (12.79 g, 24.67 mmol) and pyrdine-3-boronic acid 1,3-propanediol cyclic ester (4.42 g, 27.14 mmol) were coupled according to the method described in Examples 118-121. The work-up procedure described in Part F of Examples 125-135 was followed. The crude product was recrystallized twice from ethyl acetate to provide 10.89 g of tert-butyl 4-{[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}piperidine-1-carboxylate as an off-white solid, mp 197-198° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[C:21](OCC)(=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1COCC1>[OH:27][C:21]1([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:15][C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: Cc1cccnc1NC(=O)OC(C)(C)C
Reactant: CCOC(=O)C(=O)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1(O)Cc2cccnc2N1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 41.2 %

Procedure:
To a stirred solution of 2-tert-butoxycarbonylamino-3-methylpyridine (1.0 g, 4.8 mmol) in THF (10 mL) at −10° C. under Ar was added dropwise a solution of n-butyllithium (1.6 M, 6.0 mL, 9.6 mmol). The mixture was stirred for 30 min then added dropwise via cannula to a stirred solution of diethyl oxalate (2.1 g, 14.4 mmol) in THF (10 mL) at 0° C. under Ar. The mixture was stirred for 1 h and partitioned between water (50 mL) and ethyl acetate (30 mL). The aqueous layer was extracted with ethyl acetate (20 mL). The combined organic extracts were washed (water, brine), dried (sodium sulfate), concentrated in vacuo and purified by column chromatography [SiO2; ethyl acetate-heptane (1:1)] to give the product as a clear oil (0.61 g, 47%). IR νmax (film)/cm−1 3475, 2982, 2935, 2237, 1740, 1695, 1606, 1592, 1433, 1371, 1310, 1248, 1209, 1188, 1159, 1099, 1065, 1023, 912, 855, 785, 770, 732 and 645; NMR δH (400 MHz, CDCl3) 1.27 (3H, t, J 7Hz), 1.53 (9H, s), 3.18 (1H, d, J 17 Hz), 3.40 (1H, d, J 17 Hz), 4.27 (2H, q, J 7 Hz), 6.90 (1H, dd, J, 2.5,5 Hz), 7.43 (1H, d, J 7 Hz), 8.26 (1H, d, J 3.5 Hz).
Reaction SMILES: [CH2:1]([Sn:5](=O)[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[C:11]([OH:20])(=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].C1(C)C=CC=CC=1>O>[C:11]([O-:20])(=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O-:18])=[O:17].[CH2:1]([Sn+2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Sn](=O)CCCC
Reactant: O=C(O)CCCCC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCC[Sn+2]CCCC
Product: O=C([O-])CCCCC(=O)[O-]
Yield: 99.1 %

Procedure:
A mixture of 1000 grams of dibutyltin oxide, 587.2 grams adipic acid and 500 ml. of toluene were refluxed for 3 hours. There was obtained 72 grams of water by azeotropic distillation. The reaction mixture was then hot filtered and the solvent was removed in vacuo from resulting light yellow filtrate. After drying, there was obtained 1501 grams of a dibutyltin adipate or a 99.1% yield. The product has a melting point of 128°-130° C. The identity of the product was further confirmed by its NMR spectrum.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:16])([C:12]([F:15])([F:14])[F:13])[O:7][CH2:6][CH2:5]2.C(N(CC)CC)C.[C:24](Cl)(=[O:26])[CH3:25]>C1COCC1>[C:24]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:16])([C:12]([F:15])([F:13])[F:14])[O:7][CH2:6][CH2:5]2)(=[O:26])[CH3:25]
Reactant: CC1(C(F)(F)F)OCCc2cc(O)ccc21
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc2c(c1)CCOC2(C)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a stirred solution of 6-hydroxy-1-methyl-1-trifluoromethylisochroman (79 g, 0.34 mol) and triethylamine (120 mL, 0.88 mol) in THF (680 mL) was added acetyl chloride (31 mL, 0.44 mol) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction was quenched by adding aqueous 1 N-HCl (400 mL), and extracted with ethyl acetate (500 mL). The extracts were washed with aqueous saturated NaHCO3 (100 mL) and brine (100 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography (Silica-gel, 15×20 cm, 6% ethyl acetate/hexane) to afford 6-acetoxy-1-methyl-1-trifluoromethylisochroman (83 g, 89%) as a colorless oil. 1H-NMR(CDCl3): 7.36 (d, J=7.2 Hz, 1H), 6.98 (dd, J=7.2, 2.5 Hz, 1H), 6.91 (d, J=2.5 Hz, 1H), 4.18-4.08 (m, 1H), 3.92 (dt, J=11, 5.4 Hz, 1H), 2.86 (t, J=5.4 Hz, 2H), 2.30 (s, 1H), 1.66 (s, 3H).
Reaction SMILES: [NH3:1].[C:2]1([S:8]([C:11]2[C:12]([S:22][CH3:23])=[N:13][N:14]3[C:19](Cl)=[CH:18][C:17]([CH3:21])=[N:16][C:15]=23)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.CN(C=O)C>[C:2]1([S:8]([C:11]2[C:12]([S:22][CH3:23])=[N:13][N:14]3[C:19]([NH2:1])=[CH:18][C:17]([CH3:21])=[N:16][C:15]=23)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccccc1
Reactant: N
Solvent: CO
Solvent: CN(C)C=O
Product: CSc1nn2c(N)cc(C)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
10 ml of a 50% solution of NH3 in MeOH were added to a solution of 0.40 g (1.13 mmol) of 3-benzenesulphonyl-7-chloro-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine in 10 ml of DMF and stirred at RT for 2 hrs. The reaction solution was evaporated in a high vacuum and the residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2, and the combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (SiO2, CH2Cl2/AcOEt 7:1) and crystallization from EtOH yielded 0.25 g (66%) of (3-benzenesulphonyl-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-yl)amine as colorless crystals, m.p. >230°.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[C:13]([CH3:16])=[CH:14][S:15][C:3]=12.[CH3:17]N(C=O)C.C(=O)([O-])[O-].[K+].[K+].IC>O>[CH3:16][C:13]1[C:4]2[N:5]([CH3:17])[CH:6]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2](=[O:1])[C:3]=2[S:15][CH:14]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cnc2c(C)csc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: CCOC(=O)c1cn(C)c2c(C)csc2c1=O
Temperature: 0 °C

Procedure:
A 500 mL three-necked flask fitted with an overhead stirrer and argon inlet is charged with 21.9 g of ethyl 7-hydroxy-3-methylthieno[3,2-b]pyridine-6-carboxylate and 150 mL of DMF. The mixture is stirred while 25.5 g of powdered potassium carbonate is added in portions, then is cooled to 0° C. Iodomethane (15 mL) is added dropwise over 45 min, and the completed mixture is stirred vigorously and allowed to warm slowly as the ice in the bath melts. The following day, the mixture is diluted slowly with water to a final volume of 800 ml, and the resulting solid is filtered, washed well with water, and dried under vacuum to provide 17.2 g of the title compound as a brown crystalline solid. Flash chromatography of 12.2 g using 2-4% MeOH in CH2Cl2 affords 11.43 g of tan solid.