Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NCC1C2C(=CC(S(O)(=O)=[O:14])=CC=2)C=CC=1.[CH:17]([C:19]1[C:28]2[C:23](=[CH:24][C:25]([S:29]([OH:32])(=[O:31])=[O:30])=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1)=[O:18].C1N2CN3CN(C2)CN1C3.[Mn]([O-])(=O)(=O)=O>>[C:17]([C:19]1[C:28]2[C:23](=[CH:24][C:25]([S:29]([OH:32])(=[O:31])=[O:30])=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1)([OH:14])=[O:18]
Reactant: O=Cc1cccc2cc(S(=O)(=O)O)ccc12
Reactant: NCc1cccc2cc(S(=O)(=O)O)ccc12
Agent: O=[Mn](=O)(=O)[O-]
Agent: C1N2CN3CN1CN(C2)C3
Product: O=C(O)c1cccc2cc(S(=O)(=O)O)ccc12

Procedure:
The 1-aminomethylnaphthalene-6-sulphonic acid can be converted into 1-formylnaphthalene-6-sulphonic acid in a manner which is known per se by a Sommelet reaction (see, for example, Houben Weyl, Methoden der Organischen Chemie (Methods of Organic Chemistry), 4th edition, volume 7/1 page 198 or Organic Reactions 8, 197 (1954)), that is to say by reaction with hexamethylenetetramine. The 1-formylnaphthalene-6-sulphonic acid is in turn oxidized by processes known for the oxidation of aldehydes to carboxylic acids (see, for example, Houben Weyl loc. cit. volume 8, pages 407-413), for example by oxidation with permanganate (see, for example, Houben Weyl, volume 4 I/b, pages 615-621), to give 1-carboxynaphthalene-6-sulphonic acid.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[N:10]=[C:11]([NH:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[S:12][CH:13]=2)=[C:4]([CH3:23])[CH:3]=1.[CH3:24][N:25]([CH3:36])[CH2:26][CH2:27][O:28][C:29]1[N:30]=[CH:31][C:32]([SH:35])=[N:33][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cu](I)I>[CH3:24][N:25]([CH3:36])[CH2:26][CH2:27][O:28][C:29]1[N:30]=[CH:31][C:32]([S:35][C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([C:9]3[N:10]=[C:11]([NH:14][C:15](=[O:22])[C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[S:12][CH:13]=3)=[C:4]([CH3:23])[CH:3]=2)=[N:33][CH:34]=1
Reactant: CN(C)CCOc1cnc(S)cn1
Reactant: Cc1cc(I)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Sc2cnc(OCCN(C)C)cn2)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Temperature: 100 °C
Yield: 46.1 %

Procedure:
A mixture of N-(4-(4-iodo-2,6-dimethylphenyl)thiazol-2-yl)isonicotinamide (0.51 g, 1.2 mmol), 5-(2-(dimethylamino)ethoxy)pyrazine-2-thiol (28-4, 0.96 g, 4.8 mmol), copper iodide (73.0 mg, 0.38 mmol), and potassium carbonate (0.64 g, 4.6 mmol) in 5.0 mL of DMF was heated at 100° C. for 16 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography on silica gel (MeOH:CH2Cl2=1:10 as eluant) to give N-(4-(4-{5-(2-(dimethylamino)ethoxy)pyrazin-2-ylthio}-2,6-dimethylphenyl)thiazol-2-yl)isonicotinamide (28, 0.28 g) as light yellow solids in 47% yield: 1H NMR (500 MHz, CD3OD) δ 8.75 (s, 2 H), 8.14 (d, J=1.1 Hz, 1 H), 8.04 (s, 1 H), 7.97 (d, J=5.9 Hz, 2 H), 7.18 (s, 2 H), 7.00 (s, 1 H), 4.58 (s, 3 H), 4.46 (t, J=5.5 Hz, 2 H), 2.81 (t, J=5.4 Hz, 2 H), 2.37 (s, 6 H), 2.10 (s, 6 H). ESI-MS: m/z 507.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][CH:24]=[O:25])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[CH3:26][Mg]Cl>C1COCC1>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][CH:24]([OH:25])[CH3:26])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12
Reactant: C[Mg]Cl
Reactant: O=CCn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Solvent: C1CCOC1
Product: CC(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21

Procedure:
A solution of 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetaldehyde (128 mg, 0.29 mmol) in THF (2.9 mL) was added dropwise over 30 min to a solution of methyl magnesium chloride (290 μL, of 3 M solution diluted in 2.9 mL THF) at 0° C. The crude mixture was partitioned between CH2Cl2 and 2 M hydrochloric acid. The aqueous phase was extracted with CH2Cl2 and the combined organic layers were passed over a phase separator and concentrated under reduced pressure. The reaction was repeated with another 80 mg of starting 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetaldehyde and the combined crude mixtures were purified by column chromatography (silica gel, gradient 50 to 100% ethyl acetate/isohexane). Additional preparative HPLC purification yielded 7.2 mg of Compound 91.
Reaction SMILES: C(OCC)=O.[O-:6][CH2:7][CH3:8].[Na+].[Na].[CH3:11][O:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH2:15][CH2:16]C[C:18]2=[O:23]>C1C=CC=CC=1.C(O)C>[CH:7]([CH:8]1[CH2:16][CH2:15][C:14]2[C:19](=[CH:20][CH:21]=[CH:22][C:13]=2[O:12][CH3:11])[C:18]1=[O:23])=[O:6]
Reactant: COc1cccc2c1CCCC2=O
Reactant: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCOC=O
Solvent: c1ccccc1
Solvent: CCO
Product: COc1cccc2c1CCC(C=O)C2=O
Temperature: 0 °C

Procedure:
A solution of ethyl formate (20 ml, 0.37 mol) in anhydrous benzene (100 ml) is added to sodium ethoxide, prepared from sodium (8.34 g, 0.35 mol) and absolute ethanol, in anhydrous benzene (100 ml). The reaction mixture is cooled to about 0° C. and a solution of 5-methoxy-3,4-dihydronaphthalen-1(2H)-one (25 g, 0.14 mol) in anhydrous benzene (100 ml) is then slowly stirred in. By working up the mixture as described in J. Am. Chem. Soc., 1947, 69, 2942, the above indicated product is recovered (24.8 g); m.p. 68°-70° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.C(N(CC)CC)C.[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>ClCCl>[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:1]2[CH2:5][CH2:4][CH2:3][C@H:2]2[CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[O:25])=[CH:22][CH:21]=1
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)N1CCC[C@H]1CN1CCCC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 83.3 %

Procedure:
(S)(+)-1-(2-Pyrrolidinylmethyl)pyrrolidine (1.07 g, 6.93 mmol) and triethylamine (763 mg, 7.56 mmol) are dissolved in dichloromethane (20 mL) and cooled to 0° C. 4-Fluorobenzoyl chloride (1.00 g, 6.3 mmol) in dichloromethane (2 mL) is added to the mixture at 0° C. and stirred at room temperature for 3 h. The reaction mixture is washed with brine, dried over Na2SO4, and evaporated. The residue is purified by silica-gel column chromatography (CH2Cl2:2M NH3 in MeOH=40:1) to give 1.45 g (83%) of the title compound. MS (APCI+) 277(M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][S:12](O)(=[O:14])=[O:13].[Cl-].[Na+]>>[Cl:11][S:12]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[F:1])[C:6]([OH:8])=[O:7])(=[O:14])=[O:13]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)c1ccc(F)cc1
Agent: [Cl-]
Agent: [Na+]
Product: O=C(O)c1ccc(F)c(S(=O)(=O)Cl)c1
Temperature: 160 °C
Yield: 51.5 %

Procedure:
4-Fluoro-benzoic acid (8 g, 57 mmol) is added carefully to chlorosulfonic acid (58 g, 498 mmol) then sodium chloride (10 g, 169 mmol) is added in small portions. After complete addition, the reaction is heated at 160° C. for 5 h. The reaction mixture is cooled down and poured into ice-water. A white solid precipitate is collected and redissolved in ethyl acetate. The organic layer is washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered, and the solvent is removed in vacuo. The residue is triturated with hexane to give 7 g (51% yield) of the title compound as a white solid. 1H NMR (CDCl3): δ 8.78 (m, 1H), 8.52 (m, 1H), 7.5 (t, 1H). MS (m/z): 308 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11]([OH:14])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18]([C:20]1([CH2:36]I)[CH2:24][CH2:23][N:22]([C:25](=[O:35])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH2:33][CH3:34])[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1([CH2:36][O:14][C:11]2[CH:10]=[N:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:13][N:12]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:35])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH2:33][CH3:34])[CH2:21]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccccc2OCC)C1
Reactant: Oc1cnc(-c2ccc(Cl)cc2)cn1
Product: CCOC(=O)C1(COc2cnc(-c3ccc(Cl)cc3)cn2)CCN(C(=O)c2ccccc2OCC)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 5-(4-chloro-phenyl)-pyrazin-2-ol (Preparation 25) and 1-(2-ethoxy-benzoyl)-3-iodomethyl-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 16) to afford the racemate as a white solid (86 mg, 30%)
Reaction SMILES: O1CCCC1.COP([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])(OC)=O.[H-].[Na+].[CH:22]1([C:27]2[CH2:28][CH:29]3[CH:32]([CH:33]=2)[C:31](=O)[CH2:30]3)[CH2:26][CH2:25][CH2:24][CH2:23]1>O>[CH:22]1([C:27]2[CH2:33][C@@H:32]3[C@H:29]([CH:28]=2)[C:30](=[CH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:31]3)[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: O=C1CC2CC(C3CCCC3)=CC12
Reactant: COP(=O)(CC(=O)OC(C)(C)C)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C=C1C[C@@H]2CC(C3CCCC3)=C[C@H]12
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
A tetrahydrofuran (15 mL) solution of tert-butyl dimethylphosphonoacetate (3.21 g, 14.4 mmol) was added dropwise at 0° C. over 15 minutes to a tetrahydrofuran (15 mL) suspension of sodium hydride (0.59 g, 63%, 15.7 mmol), and the mixture was stirred at 0° C. for 25 minutes. To this solution, a tetrahydrofuran (15 mL) solution of 3-cyclopentylbicyclo[3.2.0]hept-3-en-6-one (2.30 g, 13.1 mmol) was added dropwise at 0° C. over 10 minutes, and the mixture was stirred at room temperature for 16 hours. The mixture was treated with water, followed by extraction with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the compound of interest as a yellow oil substance (3.30 g, 92%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[N:7]1[C:11]([NH2:12])=[C:10]([C:13]([NH2:15])=[O:14])[C:9]([CH3:16])=[N:8]1.[N:17]1[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][CH:18]=1>>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[N:7]1[C:11]2=[N:12][C:23]([C:20]3[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=3)=[N:15][C:13](=[O:14])[C:10]2=[C:9]([CH3:16])[NH:8]1
Reactant: Cc1nn(C2CCCC2C)c(N)c1C(N)=O
Reactant: O=Cc1ccncc1
Product: Cc1[nH]n(C2CCCC2C)c2nc(-c3ccncc3)nc(=O)c1-2
Temperature: 120 °C
Reaction time: 1 h
Yield: 32.6 %

Procedure:
To a solution of 1-(2-methylcyclopentyl)-3-methyl-5-amino-1H-pyrazole-4-carboxamide (2.3 g, 10.4 mmol) in xylenes (8.0 ml) under argon was added 4-pyridinecarboxaldehyde (1.5 ml, 15.5 mmol). The reaction mixture was warmed to 120° C. and stirred for 1 hour at which time the mixture became homogeneous. The reaction mixture was then heated to 160° C. for 24 hours and then cooled to room temperature. A solid precipitated which was collected by filtration through a glass frit. The solid was washed with ether, saturated NaHCO3 then water and was recrystallized from DMF. The solid was collected on a glass frit and was washed with methanol, then ether and dried at 110° C. for 72 hours in high vacuum to afford 1.05 g (33%) of 1-(2-methyl-cyclopentyl)-3-methyl-6-(4-pyridyl)-pyrazolo [3,4-d]pyrimidin-4-one as white crystals, m.p. 290°-291° C.
Reaction SMILES: C([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][C@@H:13]([C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[CH2:12][CH2:11][C@@H:10]1[NH:20][C:21]([C:23]1[N:24]=[CH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[C:28]([Cl:33])[CH:27]=2)=[O:22])=O)(C)(C)C.Cl.[CH3:35][N:36]1[CH2:41][CH2:40][C:39]2[N:42]=[C:43](C([O-])=O)[S:44][C:38]=2[CH2:37]1.[Li+]>C(O)C>[ClH:33].[Cl:33][C:28]1[CH:27]=[C:26]2[C:31]([CH:32]=[C:23]([C:21]([NH:20][C@H:10]3[CH2:11][CH2:12][C@H:13]([C:15](=[O:19])[N:16]([CH3:17])[CH3:18])[CH2:14][C@H:9]3[NH:8][C:6]([C:43]3[S:44][C:38]4[CH2:37][N:36]([CH3:35])[CH2:41][CH2:40][C:39]=4[N:42]=3)=[O:5])=[O:22])[N:24]=[CH:25]2)=[CH:30][CH:29]=1
Reactant: CN(C)C(=O)[C@H]1CC[C@H](NC(=O)c2cc3ccc(Cl)cc3cn2)[C@H](NC(=O)OC(C)(C)C)C1
Reactant: CN1CCc2nc(C(=O)[O-])sc2C1
Agent: Cl
Agent: [Li+]
Solvent: CCO
Product: CN1CCc2nc(C(=O)N[C@@H]3C[C@@H](C(=O)N(C)C)CC[C@@H]3NC(=O)c3cc4ccc(Cl)cc4cn3)sc2C1

Procedure:
(1S,2R,4S)—N2-(tert-Butoxycarbonyl)-N1-[(7-chloroisoquinolin-3-yl)carbonyl]-4-(N,N-dimethyl-carbamoyl)-1,2-cyclohexanediamine was treated with a saturated ethanol solution of hydrochloric acid and then condensed with lithium 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate in a similar manner to Example 118 to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH:18]=[C:17]3[CH:12]([CH2:13][CH2:14][N:15]([CH3:19])[CH2:16]3)[CH:11]3[C:20](=O)[N:21]([CH3:24])[C:22](=O)[CH:10]23)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH:18]=[C:17]3[CH:12]([CH2:13][CH2:14][N:15]([CH3:19])[CH2:16]3)[CH:11]3[CH2:20][N:21]([CH3:24])[CH2:22][CH:10]23)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2C=C3CN(C)CCC3C3C(=O)N(C)C(=O)C23)cc1
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Product: COc1ccc(C2C=C3CN(C)CCC3C3CN(C)CC23)cc1
Yield: 88 %

Procedure:
A solution of 6.7 g (0.02 moles) of 3a,4,6,7,8,9,9a,9b-octahydro-4-(p-methoxyphenyl)-2,7-dimethyl-2H-pyrrolo[3,4-f]-isoquinoline-1,3-dione in 100 ml of dichloromethane-ether (1:1) is added to a slurry of 3 g (0.08 moles) lithium aluminum hydride in 300 ml dichloromethane-ether (1:1) under nitrogen. This is refluxed for 18 hours. Saturated sodium carbonate solution is added at room temperature until the reaction is white. The salts are filtered and washed with dichloromethane. The combined filtrates are evaporated to yield 5.5 g (90%) 1,3,3a,4,6,7,8,9,9a,9b-decahydro-4-(p-methoxyphenyl)-2,7-dimethyl-2H-pyrrolo[3,4-f]isoquinoline. This is dissolved in isorpopanol-ether, and hydrochloric acid in isopropanol is added until the solution is acidic to pH paper. Excess ether is added and the white solid product is filtered.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[CH3:9][C:10](O)([CH2:13][CH2:14][CH2:15][CH:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:11][CH3:12].S(=O)(=O)(O)O>COCCO>[CH2:11]([C:10]([C:3]1[CH:4]=[C:5]([OH:6])[C:7]([C:10]([CH3:9])([CH2:11][CH3:12])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:21])[CH3:22])=[CH:8][C:1]=1[OH:2])([CH3:9])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH3:12]
Reactant: Oc1ccc(O)cc1
Reactant: CCC(C)(O)CCCC(C)CCCC(C)C
Agent: O=S(=O)(O)O
Solvent: COCCO
Product: CCC(C)(CCCC(C)CCCC(C)C)c1cc(O)c(C(C)(CC)CCCC(C)CCCC(C)C)cc1O
Temperature: 0 °C

Procedure:
55 g of hydroquinone and 120 ml of 3,7,11-trimethyldodecan-3-ol were dissolved in 120 ml of methyl Cellosolve. Then, 50 ml of concentrated sulfuric acid (36 N) was added dropwise thereto under stirring and cooling so as to maintain the temperature at 40° C. or less. Subsequently, the reaction mixture was maintained at 50° to 55° C. for 4 hours. The resulting reaction mixture was added to ice-water, and extracted with 500 ml of benzene. The benzene layer was washed with water and, after drying over anhydrous sodium sulfate, benzene and unreacted 3,7,11-trimethyldodecan-3-ol were distilled off under reduced pressure. The residual oil was chromatographed on silica gel using benzene as a developing solvent. Thus, 41 g of 2,5-bis(1-ethyl-1,5,9-trimethyldecyl)hydroquinone (the same compound as obtained in Synthesis Example 1) was first eluted, and then 20 g of 2-(1-ethyl-1,5,9-trimethyldecyl)hydroquinone was eluted. The results of elemental analysis of the above-described monoalkyl hydroquinone are shown below.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17](O)[C:16]3[C:11](=[C:12]([CH3:22])[C:13]([O:20][CH3:21])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].[OH-].[Na+].O=P(Cl)(Cl)[Cl:27]>>[Cl:27][C:17]1[C:16]2[C:11](=[C:12]([CH3:22])[C:13]([O:20][CH3:21])=[CH:14][CH:15]=2)[N:10]=[C:9]([C:6]2[S:7][CH:8]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=2)[CH:18]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1C
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2c(Cl)cc(-c3nc(C(C)C)cs3)nc2c1C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 96 %

Procedure:
2-(4-Isopropyl-thiazol-2-yl)-7-methoxy-8-methyl-quinolin-4-ol (526 mg, 1.67 mmol) was taken up in POCl3 (4.0 mL) and placed in a 85° C. oil bath. The reaction was monitored by LC/MS and determined to be complete after 40 min. The reaction was cooled to rt, and poured into ice water. Adjust pH=10 with 10N NaOH. The mixture was extracted with CH2Cl2, dried with Na2SO4, filtered and was concentrated to afford analytically clean 4-chloro-2-(4-isopropyl-thiazol-2-yl)-7-methoxy-8-methyl-quinoline (532 mg, 96%) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH:12]2[CH2:17][CH2:16][CH:15]([NH:18]C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[CH:8]=[CH:7][C:6]=1[CH2:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([N:35]2[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=3[CH2:38][O:37][C:36]2=[O:45])[CH2:31][CH2:30]1)=[O:28].Cl>CCOC(C)=O>[F:47][C:2]([F:1])([F:46])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH:12]2[CH2:13][CH2:14][CH:15]([NH2:18])[CH2:16][CH2:17]2)[CH:8]=[CH:7][C:6]=1[CH2:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([N:35]2[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=3[CH2:38][O:37][C:36]2=[O:45])[CH2:31][CH2:30]1)=[O:28]
Reactant: CC(C)(C)OC(=O)NC1CCC(Oc2ccc(CC(=O)N3CCC(N4C(=O)OCc5ccccc54)CC3)c(OCC(F)(F)F)c2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: NC1CCC(Oc2ccc(CC(=O)N3CCC(N4C(=O)OCc5ccccc54)CC3)c(OCC(F)(F)F)c2)CC1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Into a stirred solution of 1-(1-(2-(2,2,2-trifluoroethoxy)-4-(1-(tert-butyloxycarbonylamino)cyclohex-4-yloxy)phenyl-acetyl) piperidin-4-yl)-4H-3,1-benzoxazin-2(1H)-one (0.20 g, 0.30 mmol) from Step 3 above in EtOAc (10 mL) at 0° C. was bubbled HCl gas for 15 min. The resulting suspension was stirred at 0° C. for 45 min. Excess HCl was removed by bubbling argon though the mixture for 15 min. Ether (25 mL) was added and the cold suspension was filtered. The solids were washed with additional ether and dried under reduced pressure for 18 h to give the hydrochloride salt of the title compound as an amorphous white powder.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:20]#[N:21])([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:22][NH:23][CH2:24][CH2:25][C:26]1[CH:36]=[CH:35][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][CH:27]=1>>[C:20]([C:5]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)([C:6]([O:8][CH3:9])=[O:7])[CH2:4][CH2:3][CH2:2][N:23]([CH3:22])[CH2:24][CH2:25][C:26]1[CH:36]=[CH:35][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][CH:27]=1)#[N:21]
Reactant: CCOC(=O)c1ccc(CCNC)cc1
Reactant: COC(=O)C(C#N)(CCCBr)c1ccc(OC)c(OC)c1
Product: CCOC(=O)c1ccc(CCN(C)CCCC(C#N)(C(=O)OC)c2ccc(OC)c(OC)c2)cc1

Procedure:
Reaction of 1b with 2c produced 3n. MS found M+H=483. The oxalate salt of 3n was recrystallized from ethyl acetate; mp 88-89° C.
Reaction SMILES: [Mg].Cl[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[Cl:11].II.[CH:14](=[O:19])[CH2:15][CH2:16][CH2:17][CH3:18]>CCOCC>[Cl:11][C:5]1[CH:6]=[C:7]([Cl:10])[CH:8]=[CH:9][C:4]=1[CH2:3][CH:14]([OH:19])[CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: CCCCC=O
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: CCCCC(O)Cc1ccc(Cl)cc1Cl
Yield: 23 %

Procedure:
To 7.5 g (0.384 mole) of magnesium turnings in 150 ml of ether is added a 10.0 g (0.051 mole) portion of α,2,4-trichlorotoluene and a few crystals of iodine. When the iodine color has dissipated, the reaction is warmed to reflux, and 58.0 g (0.297 mole) of additional α,2,4-trichlorotoluene in 50 ml of ether is added at such a rate that the refluxing is maintained. When the addition is complete, the reaction is stirred at reflux for 2 hours and cooled. To this reaction mixture is added 17.0 g (0.197 mole) of valeraldehyde, and the reaction is heated again at reflux for 2 hours. The reaction is cooled and poured into ice cold dilute hydrochloric acid, and the organic phase is separated. The aqueous solution is extracted with ether, and the extract is combined with the organic phase. After a water wash, the organic solution is dried over anhydrous magnesium sulfate and stripped of solvent to give 57.2 g of crude product. A distillation provides 11.3 g (23%) of the product. Purity is determined by glc.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:14][S:15]([C:18]1[CH:19]=[C:20]([C:30](O)=[O:31])[C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:22][CH:23]=1)(=[O:17])=[O:16]>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:30]([C:20]3[CH:19]=[C:18]([S:15]([CH3:14])(=[O:17])=[O:16])[CH:23]=[CH:22][C:21]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:31])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: CS(=O)(=O)c1ccc(-c2ccccc2)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(-c2ccccc2)c(C(=O)N2CCN(c3ccc(O)cc3)CC2)c1

Procedure:
The title compound was prepared according to the procedure E described for Example 9 from ′1-(4-hydroxyphenyl)-piperazine [56621-48-8] and 4-Methanesulfonyl-biphenyl-2-carboxylic acid (Example V). MS (ISP): 437.4 MH+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([NH:15][CH:16]1[CH2:20][CH2:19][NH:18][CH2:17]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH3:21][C:22]([CH3:24])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C(OCC)(=O)C.O.C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([NH:15][CH:16]1[CH2:20][CH2:19][N:18]([CH:22]([CH3:24])[CH3:21])[CH2:17]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CC(C)=O
Reactant: CCOC(=O)c1cc2cc(NC3CCNC3)ccc2[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2cc(NC3CCN(C(C)C)C3)ccc2[nH]1
Yield: 53.9 %

Procedure:
A mixture of 0.2 g (1 mmol) 5-(pyrrolidin-3-ylamino)-1H-indole-2-carboxylic acid ethyl ester, 0.042 g (1 mmol) acetone and 0.1 ml acetic acid in 10 ml THF was treated after 1 h with 0.233 g (1 mmol) sodium trisacetoxyborohydride at 0° C. The mixture was allowed to react for 39 h at room temperature. The mixture was treated with 5 ml water, 15 ml Na2CO3 aq. and 15 ml ethyl acetate and the aqueous phase was extracted with 40 ml ethyl acetate. The combined organic phases were dried over Na2SO4, filtered and evaporated to dryness. The residue was purified over silica eluting with a gradient formed from DCM/2N NH3 in methanol to yield 0.17 g (74%) of the title compound and light brown solid. MS (m/e): 316.3 (MH+, 100%).
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([NH2:11])[CH:3]=1.[CH3:12]N(C=O)C.C[Sn](C)(C)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CO.C(Cl)(Cl)Cl>[CH3:12][C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([NH2:11])[CH:3]=1
Reactant: CN(C)C=O
Reactant: Nc1cc(Br)c2[nH]cnc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Sn](C)(C)C
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1cc(N)cc2nc[nH]c12
Temperature: 140 °C
Reaction time: 12 h
Yield: 45 %

Procedure:
To the solution of 4-bromo-6-aminobenzimidazole (0.85 g, 6.0 mmol) in sealed tube with 10 ml of DMF was added tetramethyltin (1.7 ml, 12 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.20 g). The resulting reaction mixture was stirred for 12 h at 140° C. and concentrated in vacuo, yielding oily residue which was subjected to column chromatography (5% MeOH/CHCl3)to produce 0.28 g (45%) of the desired product.