Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=[O:5].[OH2:17].[OH-].[Na+]>CO>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([CH:7]2[CH2:8][CH:6]2[C:4]([OH:17])=[O:5])=[CH:10][CH:11]=1
Reactant: O
Reactant: CON(C)C(=O)C1CC1c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CC1c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A mixture of 2-(4-chloro-phenyl)-cyclopropanecarboxylic acid methoxy-methyl-amide (9.6 g), water (20 mL), and NaOH (3.2 g) in MeOH (40 mL) was refluxed for 3 h. The reaction mixture was cooled down to room temperature and concentrated in vacuo. The residue was acidified by 6 N HCl followed by extraction with CH2Cl2. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo to give the title compound (7.3 g).
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]2[CH:27]=[C:28]([CH3:40])[C:29]3[N:33]=[C:32]([C@@H:34]4[CH2:38][CH2:37][CH2:36][O:35]4)[NH:31][C:30]=3[CH:39]=2)[CH:20]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:40][C:28]1[C:29]2[N:33]=[C:32]([C@@H:34]3[CH2:38][CH2:37][CH2:36][O:35]3)[NH:31][C:30]=2[CH:39]=[C:26]([O:25][C:21]2[N:22]=[CH:23][N:24]=[C:19]([N:14]3[CH2:13][CH2:12][C:5]4([O:4][C:3](=[O:17])[NH:2][C:7]5[N:8]=[CH:9][CH:10]=[CH:11][C:6]4=5)[CH2:16][CH2:15]3)[CH:20]=2)[CH:27]=1
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2[nH]c([C@@H]3CCCO3)nc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Oc2cc(N3CCC4(CC3)OC(=O)Nc3ncccc34)ncn2)cc2[nH]c([C@@H]3CCCO3)nc12

Procedure:
59 mg (0.23 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 70 mg (0.21 mmol) (S)-6-(6-chloropyrimidin-4-yloxy)-4-methyl-2-(tetrahydrofuran-2-yl)-1H-benzo[d]imidazole and 0.12 mL (0.70 mmol) DIPEA in 2.0 mL DMF were stirred overnight at 40° C. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were partially evaporated down i.vac. and neutralised with 4M sodium hydroxide solution. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][C@@H:40]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]1.[C:48](Cl)(=[O:55])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:48]([N:42]1[CH2:43][CH2:44][CH2:45][C@@H:40]([CH2:39][C:38]([NH:37][C:29]2[CH:30]=[CH:31][C:32]3[NH:33][C:34]4[N:35]=[C:19]([NH:20][C:21]5[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=5)[CH2:26][CH2:27][C:28]=2[CH:36]=3)[N:18]=[CH:17][C:16]=4[Cl:15])=[O:46])[CH2:41]1)(=[O:55])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(C[C@@H]1CCCNC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(C[C@@H]1CCCN(C(=O)c2ccccc2)C1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 71 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using N-[6-chloro-2,4,8,22-tetraazatetracyclo[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-[(3S)-piperidin-3-yl]acetamide bis(trifluoroacetate) and benzoyl chloride as the starting materials in 71% yield. LCMS for C32H32ClN6O2 (M+H)+: m/z=567.0.
Reaction SMILES: NC(N)=O.CN(C)C=O.Br[CH2:11][C:12](=[O:21])[C:13](=[N:19][OH:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>O>[OH:21][C:12]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:19][O:20][CH:11]=1
Reactant: CCOC(=O)C(=NO)C(=O)CBr
Agent: NC(N)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nocc1O
Temperature: 100 °C
Yield: 40 %

Procedure:
144 g of urea were added to 1 liter of a dimethylformamide solution containing 72 g of ethyl 4-bromo-2-hydroxyimino-3-oxobutyrate. The reaction solution was heated for 15 minutes at 100° C. and then cooled, after which water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with dilute aqueous hydrochloric acid and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and a 1:1 by volume mixture of ethyl acetate and hexane was added to the residue, to remove insoluble materials. The solution thus obtained was purified by silica gel chromatography, eluted with a 1:4 by volume mixture of ethyl acetate and hexane, to give 19 g of the title compound, melting at 59°-60° C. (after recrystallization from a mixture of ethyl acetate and hexane).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C[O:9][C:10]([C:12]1[C:16]([NH:17][C:18]([C:20]2[C:25]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:24][CH:23]=[C:22]([CH:33]3[CH2:35][CH2:34]3)[N:21]=2)=[O:19])=[CH:15][N:14]([CH3:36])[N:13]=1)=O>>[CH3:36][N:14]1[CH:15]=[C:16]([NH:17][C:18]([C:20]2[C:25]([NH:26][C:27]3[CH:32]=[N:31][CH:30]=[N:29][CH:28]=3)=[CH:24][CH:23]=[C:22]([CH:33]3[CH2:34][CH2:35]3)[N:21]=2)=[O:19])[C:12]([C:10]([N:4]2[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]2)=[O:9])=[N:13]1
Reactant: COC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Reactant: O=C1CNCCN1
Product: Cn1cc(NC(=O)c2nc(C3CC3)ccc2Nc2cncnc2)c(C(=O)N2CCNC(=O)C2)n1
Yield: 12 %

Procedure:
According to the general method described in step 5 of example 27, reaction of piperazine-2-one with 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester provided the title compound (12%) as pale yellow solid.
Reaction SMILES: [CH:1]([N:4]1[CH2:8][C:7]2([CH2:14][O:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[O:10][CH2:9]2)[O:6][C:5]1=[O:19])([CH3:3])[CH3:2].[N+:20]([O-])([OH:22])=[O:21].S(=O)(=O)(O)O>C(O)(=O)C>[CH:1]([N:4]1[CH2:8][C:7]2([CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([N+:20]([O-:22])=[O:21])=[CH:15][C:12]=3[O:13][CH2:14]2)[O:6][C:5]1=[O:19])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(C)N1CC2(COc3ccccc3OC2)OC1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(C)N1CC2(COc3ccc([N+](=O)[O-])cc3OC2)OC1=O
Reaction time: 0.33 h
Yield: 53.8 %

Procedure:
A solution of 3'-isopropyl-3,4-dihydro-2H-1,5-benzodioxepin-3-spiro-5'-oxazolidin-2'-one (24.8 g.; 94.2 mmole) in acetic acid (100 ml.) is cooled in an ice bath to the point at which freezing begins. A mixture of 90% nitric acid and concentrated sulfuric acid (54 mls., containing 1.2 ml. of nitric acid (d 1.5) to each 10 ml. of sulfuric acid, (ca. 124 mmole) is added dropwise with stirring over a period of 20 minutes, the cooling bath then is removed and stirring continued for 2 hours. A slight rise in the temperature of the reaction mixture will be noticed (to 34° C.) and the color darkens slightly. The nitration can be followed by thin layer chromatography (TLC) on silica gel using multiple development with 1:1 carbon tetrachloride/chloroform. The reaction mixture is poured into water (400 ml.) and the crude product extracted with methylene chloride (3 × 100 ml.). After washing the extract successively with water (100 ml.), 10% sodium carbonate (75 ml.) and again with water (100 ml.), it is dried over magnesium sulphate and evaporated to a syrup. The syrup is crystallized by boiling it with ethanol (50 ml.) yielding 15.58 g. (53.8%) of 3'-isopropyl-7-nitro-3,4-dihydro-2H-1,5-benzodioxepin-3-spiro-5'-oxazolidin-2'-one, m.p. 140°-144° C. and a second crop is obtained by concentrating the mother liquor to ca. 25 ml. to give an additional 3.44 g. (11.8%) of compound, m.p. 130°-140° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:29]=[CH:28][C:27]([C:30](=O)[CH:31]=[CH:32][N:33](C)C)=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.O.[NH2:38]N.Cl>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:29]=[CH:28][C:27]([C:30]3[NH:38][N:33]=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CN(C)C=CC(=O)c1ccc(-c2nc3c(cnn3-c3ccccc3)c(=O)n2-c2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: O
Solvent: CO
Product: O=c1c2cnn(-c3ccccc3)c2nc(-c2ccc(-c3ccn[nH]3)cc2)n1-c1ccc(Cl)cc1
Temperature: 80 °C

Procedure:
To a suspension of 5-(4-chloro-phenyl)-6-[4-(3-dimethylamino-acryloyl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (11 mg, 0.022 mmol) in MeOH (0.5 mL) is added hydrazine hydrate (2.0 mg, 0.04 mmol) and HCl (4 M in dioxane, 10 μL, 0.04 mmol), The mixture is heated to 80° C. for 2 h and cooled down to room temperature. The mixture is concentrated and purified by preparative LC/MS to provide the titled compound 5-(4-chloro-phenyl)-1-phenyl-6-[4-(2H-pyrazol-3-yl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one as white solid. HPLC-MS calculated for C26H17ClN6O (M+H1): 465.1. Found: 465.1.
Reaction SMILES: C(O)CCC.[CH2:6]([OH:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>CC(O)CC>[CH:6](=[O:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCO
Solvent: CCC(C)O
Solvent: CCCCO
Product: CCCCCCCC=O

Procedure:
Simple aliphatic alcohols such as 1-butanol and 2-butanol underwent little or no oxidation, even when heated at 100° C. (Entries 18 and 19). This observed selectivity for activated alcohols was confirmed by oxidation of a mixture of 4-methoxybenzylic alcohol (5 mmol) and 1-octanol (5 mmol), which resulted in complete oxidation of the benzylic alcohol with no formation of 1-octanal.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8](=S)[NH:9][C:10]3([O:21][C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]3.[NH3:23]>CO>[NH2:23][C:8]1[C:7]2[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=2[O:21][C:10]2([CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]2)[N:9]=1
Reactant: CCOC(=O)N1CCC2(CC1)NC(=S)c1c(F)cccc1O2
Reactant: N
Solvent: CO
Product: CCOC(=O)N1CCC2(CC1)N=C(N)c1c(F)cccc1O2
Temperature: 50 °C

Procedure:
The product of step (c) above (2.0 g, 6 mmol) was dissolved in an excess of a 7M solution of anhydrous ammonia in methanol and heated at 50° C. for 6 h. After evaporation of the solvent the residue was purified by flash chromatography on silica gel using dichloromethane/methanol (98:2) as eluent to give the title compound as a solid (1.8 g), m.p. 114-116° C. Mass spectrum (+ve CI)m /z 308 (M+ +H). Found: C, 58.63; H, 5.84; N, 13.67. Required for C15H18FN3O3 : C, 58.62; H, 5.90; N, 13.67%.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[NH2:31][C@@H:32]1[CH2:41][CH2:40][C:39]2[C:34](=[C:35]([N:42]3[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]3)[CH:36]=[CH:37][CH:38]=2)[CH2:33]1>CN(C)C=O>[CH3:48][N:45]1[CH2:46][CH2:47][N:42]([C:35]2[CH:36]=[CH:37][CH:38]=[C:39]3[C:34]=2[CH2:33][C@H:32]([NH:31][C:11](=[O:13])[C:10]2[CH:9]=[CH:8][C:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)=[CH:15][CH:14]=2)[CH2:41][CH2:40]3)[CH2:43][CH2:44]1
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(N4CCOCC4)cc2)CC3)CC1
Temperature: 75 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
To a solution of 4-morpholinobenzoic acid (0.89 g, 4.3 mmol; described in: Degutis, J.; Rasteikiene, L.; Degutiene, A. Zh. Org. Khim. 1978, 14 (10), 2060-2064) in anhydrous N,N-dimethylformamide (30 mL) was added 1,1'-carbonyldiimidazole (0.73 g, 4.3 mmol) and the reaction was heated at 75° C. When the carbon dioxide evolution had ceased (after 30 min), the reaction was cooled to room temperature and a solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (1.0 g, 4.1 mmol) in anhydrous N,N-dimethylformamide (5 mL) was added. The reaction was allowed to stir at ambient temperature for 24 h and the solvent was evaporated in vacuo. Purification on a silica gel column using chloroform/methanol/concentrated ammonium hydroxide (95:5:0.5) as the eluent gave 1.5 g (85% yield) of the title compound as white crystals: mp 230-231° C.; [α]21D -49° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 434 (10, M+).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:10])[CH2:8][N:9]=1)[CH2:2][CH2:3][CH3:4].C(O[CH:15](OC(C)C)[N:16]([CH3:18])[CH3:17])(C)C>C(Cl)Cl>[CH2:1]([C:5]1[NH:6][C:7](=[O:10])[C:8](=[CH:15][N:16]([CH3:18])[CH3:17])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1=NCC(=O)N1
Reactant: CC(C)OC(OC(C)C)N(C)C
Solvent: ClCCl
Product: CCCCC1=NC(=CN(C)C)C(=O)N1
Yield: 77.1 %

Procedure:
A solution of 5.00 g (35.67 mmol) of 2-butyl-2-imidazolin-5-one and 7.02 g (39.24 mmol) of N,N-dimethylformamide diisopropyl acetal in 25 ml of methylene chloride was stirred at room temperature for 2.5 hours. Then, the solvent was removed on a Rotavapor, and the residue was treated with 40 ml of methylene chloride. The solution thus obtained was washed twice, each time with 10 ml of water, and dried (MgSO4) and concentrated on the Rotavapor. The residue was then dried in a high vacuum. 5.37 g of 2-butyl-4-dimethylaminomethylene-2-imidazolin-5-one was obtained; the product had a content of greater than 90 percent, according to H-NMR: This corresponds to a yield of about 71 percent, based on the 2-butyl-2-imidazolin-5-one.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)=[CH:10][C:9]=2[CH:21]=1)([CH3:4])([CH3:3])[CH3:2].Cl.N1C=CC=CC=1>O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]3[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=3)=[CH:10][C:9]=2[CH:21]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(-c2cc3cc(C(C)(C)C)ccc3o2)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc2oc(-c3ccc(O)cc3)cc2c1
Temperature: 200 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
Compound 84 was treated with Pyridine HCl (5 g) and heated to 200° C. After 1 hr, the reaction was cooled and diluted with water. The aqueous layer was extracted with EtOAc, dried over MgSO4, filtered and the crude product was purified by column chromatography (eluant 25% EtOAc/hexanes) to give a solid (0.18 g, 17%); Mp=172–174° C.; 1H NMR (DMSO-d6) δ 9.83 (s, 1 H), 7.70 (d, 2 H, J=8.9 Hz), 7.56 (d, 1 H, J=1.7 Hz), 7.45 (d, 1 H, J=9.0 Hz), 7.32 (dd, 1 H, J=9.0 Hz, 2.1 Hz), 7.11 (s, 1 H), 6.87 (d, 2 H, J=8.5 Hz); MS 265 [M−H]−
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[ClH:7].[C:8]([C:11]1[CH:15]=[CH:14][N:13]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:25]=2[N:24]=[CH:23][CH:22]=[CH:21]3)[CH:12]=1)(O)=[O:9]>ClCCl>[ClH:4].[Cl:7][C:8]([C:11]1[CH:15]=[CH:14][N:13]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:25]=2[N:24]=[CH:23][CH:22]=[CH:21]3)[CH:12]=1)=[O:9]
Reactant: O=C(O)c1ccn(-c2cccc3cccnc23)c1
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: O=C(Cl)c1ccn(-c2cccc3cccnc23)c1
Temperature: 22 °C
Reaction time: 15 h
Yield: 86.9 %

Procedure:
0.45 mL (5.16 mmol) of oxalyl chloride is added to a solution, cooled to a temperature in the region of 5° C., of 0.45 g (1.64 mmol) of 3-carboxy-1-(quinol-8-yl)-1H-pyrrole hydrochloride in 20 mL of dichloromethane under an argon atmosphere. After stirring at a temperature in the region of 22° C. for 15 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa), then it is placed under an argon atmosphere and 20 mL of dichloromethane and 0.45 mL (5.16 mmol) of oxalyl chloride are successively added. After stirring at a temperature in the region of 22° C. for 15 hours, concentrating the reaction medium to dryness under reduced pressure (2.7 kPa) gives 0.418 g of 3-chlorocarbonyl-1-(quinol-8-yl)-1H-pyrrole hydrochloride in the form of a cream-coloured solid which is used directly in the following step.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][SH:5].[Na].Cl.[Cl:8][CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][N:11]=1>C(O)C.CO>[ClH:8].[ClH:1].[NH2:2][CH2:3][CH2:4][S:5][CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][N:11]=1
Reactant: COc1ccnc(CCl)c1
Reactant: NCCS
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: CO
Product: COc1ccnc(CSCCN)c1
Reaction time: 8 h
Yield: 77.2 %

Procedure:
Cysteamine hydrochloride (7.62 g) was added to a solution of sodium (4.70 g) in ethanol (170 cc) and the mixture was stirred and cooled to 10° and 2-chloromethyl-4-methoxypyridine hydrochloride (11.5 g) in methanol (50 cc) was added over 35 minutes, and the mixture was left overnight at room temperature. The mixture was filtered and the filtrate was evaporated to a residue which was partitioned between chloroform and water. The chloroform extract was evaporated to an oil which was crystallised from 2.1 M ethanolic hydrogen chloride to give 2-(2-aminoethylthiomethyl)-4-methoxypyridine dihydrochloride (12.4 g) m.p. 172.5° (decomp).
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH2:21][C:22]1([CH3:27])OCC[O:23]1)[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:17])[C:7]=2[N:6]=[C:5]1[CH2:18][CH2:19][CH3:20].Cl>>[NH2:17][C:8]1[C:7]2[N:6]=[C:5]([CH2:18][CH2:19][CH3:20])[N:4]([CH2:3][C:2]([CH3:28])([CH3:1])[CH2:21][C:22](=[O:23])[CH3:27])[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: CCCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)CC1(C)OCCO1
Agent: Cl
Product: CCCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)CC(C)=O

Procedure:
By the general method of Part E of Example 30, 1-[2,2-dimethyl-3-(2-methyl-[1,3]dioxolan-2-yl)propyl]-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine was hydrolyzed with aqueous hydrochloric acid to provide 5-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-4,4-dimethylpentan-2-one as a light brown solid after recrystallization from aqueous acetonitrile, mp 178-180° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:12]=[N:11][C:10]2[O:13][CH2:14][CH2:15][CH2:16][C:9]=2[CH:8]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].O.CO[CH2:28][CH2:29]OC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:28]([C:7]1[N:12]=[N:11][C:10]2[O:13][CH2:14][CH2:15][CH2:16][C:9]=2[CH:8]=1)=[CH2:29]
Reactant: COCCOC
Reactant: O=S(=O)(Oc1cc2c(nn1)OCCC2)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C=Cc1cc2c(nn1)OCCC2
Reaction time: 0.33 h
Yield: 77 %

Procedure:
Argon was bubbled for 15 minutes through a solution of 6,7-dihydro-5H-pyrano[2,3-c]pyridazin-3-yl trifluoromethanesulfonate (228 mg, 0.8 mmol) in 1,2-dimethoxyethane (6.5 ml). Tetrakis(triphenylphosphine)palladium(0) (50 mg, 0.0475 mmol) was added and the solution stirred for 20 minutes under argon. The mixture was then treated with potassium carbonate (111 mg, 0.8 mmol), water (1.9 ml) and triethenylboroxin pyridine complex (180 mg, 0.75 mmol). After stirring for 2 hours at 80° C., the mixture was cooled and partitioned between DCM and saturated aqueous sodium bicarbonate solution. Layers were separated and the aqueous was extracted twice with 20% MeOH/DCM. The combined organic solution was dried over magnesium sulfate, evaporated and the residue chromatographed on silica, eluting with ethyl acetate to give the product as a white solid (100 mg, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:19][CH2:18]3)[C:14](O)=[O:15])[C:11]3[CH:20]=[C:21]([F:25])[C:22]([F:24])=[CH:23][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:19][CH2:18]3)[CH2:14][OH:15])[C:11]3[CH:20]=[C:21]([F:25])[C:22]([F:24])=[CH:23][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)C(C1CC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC(C1CC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To an ice-cold suspension of 3.0 g (8.27 mmol) [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclopropyl-acetic acid in 105 ml tetrahydrofuran were added in portions 0.47 g (12.4 mmol) lithium aluminium hydride. After removal of the cooling bath the reaction mixture was stirred for 1 h at room temperature. The reaction mixture was poured onto 200 ml potassium sodium tartrate solution wan was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated to give a yellow solid which was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane:ethyl acetate (100:0 to 50:50). The product containing fractions were pooled and evaporated until precipitation started. The suspension was filtered and washed with n-heptane to give the desired compound as an off-white solid (56%). MS (Turbo Spray): m/z=349.2 [M+H].
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1.O1C=CCC[CH2:23]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:21])([C:15]1[CH:16]=[CH:17][C:18]([CH3:23])=[CH:19][CH:20]=1)[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1
Reactant: CC(CCCCBr)(COC1CCCCO1)c1ccccc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(C(C)(CCCCBr)COC2CCCCO2)cc1
Yield: 93 %

Procedure:
According to the method described for the synthesis of 207d, 206e (18.2 g, 63.8 mmol) was reacted with 3,4-dihydro-2H-pyran (6.4 g, 76.0 mmol) and p-toluenesulfonic acid hydrate (0.43 g, 2.3 mmol) in CH2Cl2 (300 mL) to give 207e (22.0 g, 93%) as an oil, which was used without further purification. 1H NMR (CDCl3): δ 7.25-7.05 (m, 4H), 4.60-4.48 (m, 1H), 3.82 (m, 2H), 3.48-3.37 (m, 2H), 3.35-3.26 (m, 2H), 2.30 (s, 3H), 1.90-1.40 (m, 11H), 1.34 (s, 3H), 1.40-1.08 (m, 1H). 13C NMR (CDCl3): δ 142.78, 135.22, 128.81, 126.39, 99.09, 99.01, 61.93, 61.85, 41.67, 41.56, 38.12, 37.87, 33.68, 33.64, 30.62, 25.96, 22.89, 20.97, 19.41, 19.37. HRMS (LSIMS, nba): Calcd for C19H30O2Br (MO: 369.1429, found: 369.1451.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:15]2[CH:16]=[C:12]([CH3:11])[N:13]=[CH:14]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: Cc1c[nH]cn1
Reactant: N#Cc1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Temperature: 90 °C
Reaction time: 16 h
Yield: 59.1 %

Procedure:
A mixture of 5-bromo-2-fluorobenzonitrile (25.0 g, 125 mmol), 4-methylimidazole (12.5 g, 152 mmol), potassium carbonate (34.55 g, 250 mmol) in DMSO (500 mL) was stirred at 90° C. for 16 h. Water (1.5 L) was added and the resulting suspension was stirred with ice-bath cooling for 1 h. The precipitate was then filtered off, washed with water (0.5 L) and dried at 50° C. over KOH. The resulting raw material (25.6 g) was dissolved in boiling ethyl acetate (300 mL). After addition of diisopropylether (300 mL) the solution was allowed to cool to room temperature. Filtration and drying afforded the title compound (19.35 g, 59%) as a white solid. Mp 166° C.