Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Na+:2].[Cl:3]Cl.Cl[O-].[OH:7][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].Cl[O-].[Na+].S(=O)(O)[O-].[Na+]>>[Cl:3][O-:1].[Na+:2].[Cl:3][C:14]1[CH:13]=[C:9]([C:10]([OH:12])=[O:11])[C:8]([OH:7])=[N:16][CH:15]=1
Reactant: ClCl
Reactant: O=C(O)c1cccnc1O
Reactant: [OH-]
Agent: O=S([O-])O
Agent: [Na+]
Agent: [O-]Cl
Product: O=C(O)c1cc(Cl)cnc1O
Temperature: 2 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
Sodium hypochlorite solution was prepared by first adding 40.2 kg (500 moles) of 50% sodium hydroxide solution to 50 kg of flaked ice in a jacketed vessel having external coolant; then adding 70 kg more ice and introducing 8.88 kg (125 moles) of chlorine gas below the surface, all with agitation. Temperature of the hypochlorite solution was -8° C. To the hypochlorite solution was added, portion wise, 17.04 kg (120.0 mole) of 98% purity 2-hydroxynicotinic acid. The temperature of the reaction mixture rose to 27° C. After stirring overnight, a sample was withdrawn and neutralized with 37% hydrochloric acid to give precipitate which when analyzed by 1HNMR showed 80:20 ratio of title compound to starting 2-hydroxynicotinic acid. A second solution of sodium hypochlorite prepared as above from 12 kg of 55% sodium hydroxide solution (152.4 mole), 33 kg of ice and 4.15 kg (58.5 mole) of chlorine was added to the reaction mixture and the mixture was stirred overnight at room temperature. 1HNMR analysis showed no starting material was present. Sodium bisulfite, 416 g (4.0 mole) was added and the mixture agitated for about 5 min. Eight liters of 2-isopropyl alcohol was added to reduce expected foaming. The reaction mixture was then mixed gradually with concentrated 37% hydrochloric and keeping the temperature generally at 15°-23° C. with good agitation. The temperature of the acidified mixture was then cooled to 2° C. and filtered. The filter cake was washed with 15 liters of cold water followed by 8 liters of acetone. The solids were dried for 2 days at 80° F. and pressed through an 18 mesh screen. The crystals were then dried further in a vacuum oven at 125° F. to give 18.81 kg (90.1% yield) of title compound. 1NMR analysis by the procedure of Example 3 showed only a trace of 3,5-dichloro-2-hydroxypyridine was present.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[CH:21]=[CH:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][N:24]=1)[C:15]([OH:17])=[O:16].C(N(CC)CC)C.[N+:39](C1C=CC=C2C(OC(=O)C=12)=O)([O-:41])=[O:40]>C1(C)C(C)=CC=CC=1>[NH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23](/[CH:22]=[CH:21]/[C:20]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]=2[N:3]2[C:2](=[O:1])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][C:9]=3[N+:39]([O-:41])=[O:40])[C:4]2=[O:11])=[N:24]1
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: O=C(O)c1ccc(C=Cc2n[nH]c3ccccc23)c(N2C(=O)c3ccccc3C2=O)c1
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc(/C=C/c2n[nH]c3ccccc23)c(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)c1
Temperature: 140 °C

Procedure:
To 3-amino-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (1.7 g, 6.2 mmol) obtained in Step 2 of Example 276, xylene (55 mL), triethylamine (0.45 mL, 3.1 mmol), 3-nitrophthalic anhydride (1.4 g, 7.4 mmol), molecular sieves 3A (2.0 g) were added, followed by heating at 140° C. for 4 hours. Molecular sieves 3A was filtered off and the reaction mixture was acidified by hydrochloric acid (2 mol/L). The precipitated crystal was collected by filtration to obtain (E)-4-[2-(1H-indazol-3-yl)vinyl]-3-(4-nitro-1,3-dioxo-1,3-dihydroisoindol-2-yl)benzoic acid.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])N.[C:13]1(=O)[CH2:17][CH2:16][CH2:15][CH2:14]1.OS(O)(=O)=O>O1CCOCC1>[CH2:15]1[C:14]2[C:12]3[C:4](=[C:5]([C:6]([OH:8])=[O:7])[CH:9]=[CH:10][CH:11]=3)[NH:2][C:13]=2[CH2:17][CH2:16]1
Reactant: NNc1ccccc1C(=O)O
Reactant: O=C1CCCC1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: O=C(O)c1cccc2c3c([nH]c12)CCC3
Temperature: 25 °C

Procedure:
To a stirred solution of 2-hydrazinobenzoic acid hydrochloride (53 mmol, 10.0 g) and cyclopentanone (58 mmol, 4.9 g) in 1,4-dioxane (100 mL) was added dropwise concentrated H2SO4 (˜18M, 63 mmol, 3.5 mL). The resulting solution was heated to reflux for 2 hours. 1H NMR analysis of a crude aliquot indicated complete reaction. The reaction was allowed to cool to room temperature and then concentrated to dryness to give a red solid which was used without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:4])[CH3:3].[Cl:5][CH2:6][C@H:7]([OH:10])[CH2:8][OH:9]>>[Cl-:5].[OH:10][C@H:7]([CH2:8][OH:9])[CH2:6][N+:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: CN(C)C
Reactant: OC[C@@H](O)CCl
Product: C[N+](C)(C)C[C@H](O)CO
Product: [Cl-]
Reaction time: 2 h

Procedure:
There was added 30 ml of 30 w/v % aqueous solution of trimethylamine to 11.05 g of (R)-3-chloro-1,2-propanediol (optical purity: 100% e.e., chemical purity: 99%). After reacting for 2 hours at room temperature, the reaction mixture was concentrated. After dissolving the concentrate in 30 ml of thermal ethanol, the solution was stored over night in a refrigerator. Thus, 15.26 g of (S)-2,3-dihydroxypropyltrimethylammonium chloride was obtained.
Reaction SMILES: [CH2:1]([S:3][CH2:4][C:5](=[C:9]1[NH:14][CH2:13][CH2:12][CH2:11][S:10]1)[N+:6]([O-:8])=[O:7])[CH3:2].CC(C)=[O:17].I([O-])(=O)(=O)=O.[Na+].C(Cl)Cl>O>[CH2:1]([S:3]([CH2:4][C:5](=[C:9]1[NH:14][CH2:13][CH2:12][CH2:11][S:10]1)[N+:6]([O-:8])=[O:7])=[O:17])[CH3:2]
Reactant: CC(C)=O
Reactant: CCSCC(=C1NCCCS1)[N+](=O)[O-]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: ClCCl
Solvent: O
Product: CCS(=O)CC(=C1NCCCS1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 2.34 g of 25 and 10 ml of acetone was added all at once to a solution of 2.25 g of sodium periodate in 15 ml of water. The resulting exothermic reaction was controlled between 25° and 35° by cooling. The mixture then was stirred at room temperature for 90 minutes, then was poured into a mixture of water and methylene chloride. The separated organic phase was washed with saturated sodium thiosulfate solution, and saturated sodium chloride. It then was dried (MgSO4) and the solvent evaporated under reduced pressure to give an oil, which was triturated with ether to give a yellow solid. This was chromatographed by a preparative thin layer chromatographic technique, on silica gel and using a mixture of methanol (2%) in methylene chloride as eluent, to give 26, as a yellow solid, m.p.: 102°-104°.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6](=O)[CH2:7]Br)([O-:3])=[O:2].[C:14]([NH:17][C:18]([NH2:20])=[S:19])(=[NH:16])[NH2:15].O.[OH-].[Na+]>CN(C)C=O>[NH:17]([C:18]1[S:19][CH:7]=[C:6]([C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])[N:20]=1)[C:14]([NH2:16])=[NH:15]
Reactant: N=C(N)NC(N)=S
Reactant: O=C(CBr)c1ccccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: N=C(N)Nc1nc(-c2ccccc2[N+](=O)[O-])cs1
Yield: 95 %

Procedure:
A solution of 16.5 gm of 2-nitro-phenacyl bromide and 7.98 gm of amidinothiourea in 70 ml of dimethylformamide was stirred at room temperature for 16 hours, and then poured into 350 ml of water. The solution was made alkaline with 10% sodium hydroxide, and the solid which separated out after cooling was filtered, washed with water and dried, yielding 16.9 gm of the title compound, m.p. 176°-178° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[NH:10][C:11]2[S:12][CH:13]=[C:14](/[CH:16]=[CH:17]/[CH:18]=[O:19])[N:15]=2)=[CH:4][CH:3]=1.[S:21]1[CH2:27][C:25](=[O:26])[N:24]([CH2:28][C:29]([OH:31])=[O:30])[C:22]1=[S:23].[Cl-].[NH4+].N>C(O)C>[OH2:19].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[NH:10][C:11]2[S:12][CH:13]=[C:14](/[CH:16]=[CH:17]/[CH:18]=[C:27]3[S:21][C:22](=[S:23])[N:24]([CH2:28][C:29]([OH:31])=[O:30])[C:25]3=[O:26])[N:15]=2)=[CH:4][CH:3]=1.[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[NH:10][C:11]2[S:12][CH:13]=[C:14](/[CH:16]=[CH:17]/[CH:18]=[C:27]3[S:21][C:22](=[S:23])[N:24]([CH2:28][C:29]([OH:31])=[O:30])[C:25]3=[O:26])[N:15]=2)=[CH:4][CH:3]=1
Reactant: O=C/C=C/c1csc(NC(=O)Nc2ccc(Br)cc2)n1
Reactant: O=C(O)CN1C(=O)CSC1=S
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: O
Product: O=C(O)CN1C(=O)C(=C/C=C/c2csc(NC(=O)Nc3ccc(Br)cc3)n2)SC1=S

Procedure:
Following a procedure similar to that described in Example 1, the desired compound was prepared using 0.4 g of (E)-3-[2-(3-p-bromophenylureido)thiazol-4-yl]acrylaldehyde, 0.2 g of rhodanine-3-acetic acid, 0.15 g of ammonium chloride, 0.15 ml of 28% v/v aqueous ammonia and 10 ml of ethanol. The resulting product was a brownish-orange powder having the following physical properties.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[CH3:16][S:17][CH2:18][CH2:19][NH2:20].CO.C(OC(C)C)(C)C>>[CH3:16][S:17][CH2:18][CH2:19][NH:20][CH:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:9]
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Reactant: CSCCN
Solvent: CO
Solvent: CC(C)OC(C)C
Product: CSCCNC(c1ccccc1)C(O)c1ccccc1
Temperature: 140 °C
Yield: 66.7 %

Procedure:
A mixture of trans-stilbene oxide (1.18 g, 0.006 mol) and 2-(methylthio)ethylamine (0.78 g, 0.0085 mol) was heated at 140° C. in an oil bath for 15 hours. The cooled solid reaction mixture was triturated with isooctane and the red-brown solid collected. This was triturated with methanol-isopropyl ether giving an off-white solid (1.15 g, 67% yield); mp 163°-165° C.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].Br.[NH2:8][C:9]1[N:10]=[C:11]([Br:14])[S:12][CH:13]=1.C([O-])(=O)C.[Na+]>N1C=CC=CC=1>[Br:14][C:11]1[S:12][CH:13]=[C:9]([NH:8][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[N:10]=1
Reactant: CC(C)C(=O)Cl
Reactant: Nc1csc(Br)n1
Agent: Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(C)C(=O)Nc1csc(Br)n1
Reaction time: 1 h
Yield: 20 %

Procedure:
A solution of isobutyryl chloride (4.15 ml, 40 mM) in pyridine (50 ml) was cooled to 0° C. and treated portionwise with 4-amino-2-bromothiazole hydrobromide (7.8 g, 30 mM). After stirring for 1 h. the reaction mixture was poured onto 20% aqueous sodium acetate solution (500 ml) and extracted with chloroform (3×200 ml). The combined organic layers were dried and the solvents removed under reduced pressure to yield an oil which eventually crystallised. Recrystallisation from 60°-80° petroleum ether gave the title compound (2 g, 20%). mp: 95° (Found: C, 34.1; H, 3.8; N, 11.3. C7H9BrN2OS requires C, 33.7; H, 3.6; N, 11.2%).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:28][CH2:27][C:26]([CH2:32][CH3:33])([C:29]([OH:31])=[O:30])[CH2:25][CH2:24]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:34]1(C2(C(O)=O)CCNCC2)[CH:39]=CC=[CH:36][CH:35]=1.C(C1CCC(OC2C=C3C(=CC=2)C=C(C=O)C=C3)CC1)(C)(C)C.C(O)(=O)C.CO.C([BH3-])#N.[Na+]>>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:24][CH2:25][C:26]([C:32]4[CH:36]=[CH:35][CH:34]=[CH:39][CH:33]=4)([C:29]([OH:31])=[O:30])[CH2:27][CH2:28]2)[CH:16]=[CH:15]3)[CH2:9][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Reactant: CCC1(C(=O)O)CCN(Cc2ccc3cc(OC4CCC(C(C)(C)C)CC4)ccc3c2)CC1
Agent: CC(C)(C)C1CCC(Oc2ccc3cc(C=O)ccc3c2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)C1CCC(Oc2ccc3cc(CN4CCC(C(=O)O)(c5ccccc5)CC4)ccc3c2)CC1
Yield: 5 %

Procedure:
The compound was prepared in a manner similar as to that described for 1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-4-ethyl-piperidine-4-carboxylic acid using 4-Phenyl-piperidine-4-carboxylic acid (0.198 g, 0.967 mmol), 6-(4-tert-Butyl-cyclohexyloxy)-naphthalene-2-carbaldehyde (0.250 g, 0.805 mmol), acetic acid (0.16 mL, 2.8 mmol), Methanol (1.6 mL, 4.0E1 mmol) and sodium cyanoborohydride (75.314 mg, 1.1985 mmol) to give 21 mg of the title compound as a white solid (5%). ESI-LCMS (500 M+H). 1H NMR (DMSO-d6, 400 MHz): Shift (ppm) 7.80-7.98 (m, 3H), 7.16-7.63 (m, 8H), 4.51 (br. s., 3H), 3.45-3.64 (m, 2H), 2.96-3.18 (m, 2H), 2.68 (m, 2H), 2.13-2.31 (m, 2H), 1.74-2.09 (m, 4H), 1.00-1.53 (m, 5H), 0.89 (s, 9H)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:22]I>CN(C)C=O>[C:1]([O:5][C:6]([N:8]([CH3:22])[C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc([N+](=O)[O-])c(NC(=O)OC(C)(C)C)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 49.6 g of N-t-butoxycarbonyl-5-methoxy-2-nitroaniline [prepared as described in step (b) above] in 300 ml of dehydrated dimethylformamide was added, whilst ice-cooling, to a suspension of 12.0 g of sodium hydride (as a 55% w/w dispersion in mineral oil) in 300 ml of dehydrated dimethylformamide, and the resulting mixture was stirred at room temperature for 30 minutes, after which 17.2 ml of methyl iodide were added at room temperature. The reaction mixture was stirred for 1 hour, after which it was allowed to stand overnight at room temperature. It was then concentrated to about one-fifth of its original volume by evaporation under reduced pressure. The concentrate was mixed with ice-water and the resulting aqueous mixture was extracted with ethyl acetate. The extract was washed with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. On distilling off the solvent, there were obtained 52.1 g of the title compound, melting at 122°-124° C.
Reaction SMILES: [OH:1][C:2]1([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.CC1(C)C2C=C(C#CC3C=CC(C(OC[CH2:54][Si:55](C)([CH3:57])[CH3:56])=O)=CC=3)C=CC=2C(=O)CC1>>[OH:1][C:2]1([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH2:24][Si:55]([CH3:57])([CH3:56])[CH3:54])=[O:21])=[CH:25][CH:26]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(=O)c2ccc(C#Cc3ccc(C(=O)OCC[Si](C)(C)C)cc3)cc21
Reactant: CCOC(=O)CC1(O)CCC(C)(C)c2cc(C#Cc3ccc(C(=O)OCC)cc3)ccc21
Product: CCOC(=O)CC1(O)CCC(C)(C)c2cc(C#Cc3ccc(C(=O)OCC[Si](C)(C)C)cc3)ccc21

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethyl-5-carboethoxymethylnaphth-2-yl)ethynyl]benzoate (Compound 113), 0.38 g (0.89 mmol) of trimethylsilylethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate (Compound 116), was converted into the title compound (yellow solid) using 0.50 g (7.65 mmol) of zinc, 0.20 ml (1.78 mmol) of ethyl bromoacetate and 20 ml of dry benzene.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[NH:8][C:7](=[O:13])[CH:6]=[N:5]2.C(=O)([O-])[O-].[K+].[K+].[CH2:20](I)[CH:21]=[CH2:22]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]([CH2:22][CH:21]=[CH2:20])[C:7](=[O:13])[CH:6]=[N:5]2
Reactant: O=c1cnc2cc(F)c(F)cc2[nH]1
Reactant: C=CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCn1c(=O)cnc2cc(F)c(F)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.3 %

Procedure:
A solution of 6,7-difluoro-2(1H)-quinoxalinone (0.57 g; 3.13 mmol) in dry DMF (10 ml) containing anhydrous potassium carbonate (1.3 g; 9.4 mmol) was treated with allyl iodide (0.31 ml; 3.45 mmol) and the mixture was stirred at rt for 2 h. The solvents were evaporated, water was added and the mixture was extracted (3×) with DCM. The extracts were dried and evaporated, and the residue was chromatographed on silica gel, eluting with 0-50% ethyl acetate/hexane to give the product (0.44 g, 63%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([I:14])[C:11]=1[O:12][CH3:13])[C:6](O)=[O:7])#[N:2].C1(C)C=CC=CC=1.S(Cl)([Cl:24])=O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([I:14])[C:11]=1[O:12][CH3:13])[C:6]([Cl:24])=[O:7])#[N:2]
Reactant: COc1c(I)cc(C(=O)O)cc1C#N
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1c(I)cc(C(=O)Cl)cc1C#N
Temperature: 60 °C
Reaction time: 15 h

Procedure:
To 3-cyano-5-iodo-4-methoxybenzoic acid (512 mg), toluene (5 mL), N,N-dimethylformamide (1 droplet) and thionyl chloride (0.15 mL) were added, and the mixture was stirred at 60° C. for 15 hours. The solvent was distilled off under reduced pressure and then azeotroped with toluene to obtain the title compound (527 mg) as a pale yellow solid.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[S:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)(=[O:15])=[O:14].CS([C:26]1[N:31]=[CH:30][C:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:28][N:27]=1)(=O)=O.O>C1COCC1>[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[S:13]([N:16]1[CH2:21][CH2:20][N:19]([C:26]2[N:27]=[CH:28][C:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][N:31]=2)[CH2:18][CH2:17]1)(=[O:15])=[O:14]
Reactant: CCOC(=O)c1cnc(S(C)(=O)=O)nc1
Reactant: O=S(=O)(c1ccc2ccccc2c1)N1CCNCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(N2CCN(S(=O)(=O)c3ccc4ccccc4c3)CC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
NaH 60% (0.0217 mol) was added portionwise at room temperature to a solution of 1-(2-naphtalenesulfonyl)-piperazine (0.011 mol) in THF (50 ml) under N2 flow. The mixture was stirred at room temperature for 1 hour, then cooled to 0° C. A solution of 2-(methylsulfonyl)-5-pyrimidinecarboxylic acid, ethyl ester (0.014 mol) in THF (30 ml) was added quickly. The mixture was stirred at room temperature for 2 hours, poured out into water and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue was taken up in diethyl ether. The precipitate was filtered off and dried, yielding 3.92 g (84%) of 2-[4-(2-naphthalenylsulfonyl)-1-piperazinyl]-5-pyrimidinecarboxylic acid, ethyl ester (interm. 8), melting point>260° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:15])[NH:9][C:10]1[CH:14]=[CH:13][O:12][N:11]=1)([CH3:6])([CH3:5])[CH3:4].[F:16][C:17]1[CH:18]=[C:19]([N:24]2[CH2:28][C@H:27]([CH2:29]OS(C)(=O)=O)[O:26][C:25]2=[O:35])[CH:20]=[CH:21][C:22]=1[I:23]>CN(C)C=O.C(=O)(O)[O-].[Na+]>[C:3]([O:7][C:8](=[O:15])[N:9]([CH2:29][C@@H:27]1[O:26][C:25](=[O:35])[N:24]([C:19]2[CH:20]=[CH:21][C:22]([I:23])=[C:17]([F:16])[CH:18]=2)[CH2:28]1)[C:10]1[CH:14]=[CH:13][O:12][N:11]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CS(=O)(=O)OC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Reactant: CC(C)(C)OC(=O)Nc1ccon1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(C[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1)c1ccon1
Yield: 57.1 %

Procedure:
To sodium hydride (60% in oil, 9.04 mM) suspended in dry N,N-dimethylformamide (10 ml) under nitrogen, N-isoxazol-3-yl-carbamic acid tert-butyl ester (1.66 g, 9.04 mM) in N,N-dimethylformamide (10 ml) was added dropwise at ambient temperature. Methanesulfonic acid (5R)-3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl ester (2.5 g, 6.02 mM) in N,N-dimethylformamide (10 ml) was added slowly, and the mixture heated to 75° for 2 hours. After cooling, the mixture was diluted with aqueous sodium bicarbonate (5%, 300 ml), and extracted with ethyl acetate (3×100 ml). The organic phase was washed with water (100 ml) and brine (100 ml), dried (magnesium sulfate), evaporated and crude product purified by chromatography on a 50 g silica Mega Bond Elut® column, eluting with dichloromethane. Relevant fractions were combined to give the title compound (1.73 g).
Reaction SMILES: [O:1]([C:8]1[C:17]2[N:18]=[CH:19][N:20]([CH2:21][CH2:22][O:23][CH2:24][C:25]#[CH:26])[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[N:30](C)[CH3:31]>>[CH3:31][N:30]1[C:29]2[C:28](=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:26]=[C:25]1[CH2:24][O:23][CH2:22][CH2:21][N:20]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:17]=2[N:18]=[CH:19]1
Reactant: CN(C)c1ccccc1I
Reactant: C#CCOCCn1cnc2c(Oc3ccccc3)nc3ccccc3c21
Product: Cn1c(COCCn2cnc3c(Oc4ccccc4)nc4ccccc4c32)cc2ccccc21
Yield: 24.2 %

Procedure:
Using the general method of Example 30 Part D, 4-phenoxy-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-c]quinoline (3.16 g, 9.20 mmol) was reacted with 2-iodo-N,N-dimethylaniline (2.5 g, 10.1 mmol) to provide a 1.0 g of 1-{2-[(1-methyl-1H-indol-2-yl)methoxy]ethyl }-4-phenoxy-1H-imidazo[4,5-c]quinoline as a pale yellow crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]O)=[N:6][CH:7]=1.O=S(Cl)[Cl:12]>>[ClH:12].[Cl:12][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(CO)nc1
Product: Cc1ccc(CCl)nc1
Product: Cl
Yield: 91.3 %

Procedure:
A solution of (5-methylpyridin-2-yl)methanol in SOCl2(10 mL) was refluxed 30 min. The mixture was concentrated and dried in vacuo to give 2-(chloromethyl)-5-methylpyridine hydrochloride (2.1 g, 91.3% yield) as white solid. LCMS MH+ 142.
Reaction SMILES: O=P(Cl)(Cl)Cl.[Cl:6][C:7]1[C:8]([CH:13]([NH:30][C:31]([CH:33]2[CH2:36][CH2:35][CH2:34]2)=O)[C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[CH:19][C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:21]3)=[CH:16][CH:15]=2)=[N:9][CH:10]=[CH:11][N:12]=1.N.CC(O)C>>[Cl:6][C:7]1[C:8]2[N:9]([CH:31]([CH:33]3[CH2:36][CH2:35][CH2:34]3)[NH:30][C:13]=2[C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[CH:19][C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:21]3)=[CH:16][CH:15]=2)[CH:10]=[CH:11][N:12]=1
Reactant: O=C(NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl)C1CCC1
Agent: N
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(C)O
Product: ClC1=NC=CN2C1=C(c1ccc3ccc(-c4ccccc4)nc3c1)NC2C1CCC1
Temperature: 70 °C

Procedure:
A mixture of POCl3 (5 mL, 8 g, 55 mmol) and cyclobutanecarboxylic acid [(3-chloropyrazin-2-yl)-(2-phenylquinolin-7-yl)methyl]-amide [275 mg, 0.583 mmol] is heated to 70° C. for 21.5 h. POCl3 is evaporated, a cold solution of NH3 in iPrOH (2M, 11 mL, 22 mmol) is added, the suspension is sonicated, the solid is filtered off and washed with iPrOH. The solid is suspended in CHCl3 and filtered, and the filtrate is concentrated to obtain the title compound as yellow solid. 1H NMR (CDCl3, 400 MHz) δ 2.04-2.15 (m, 1H), 2.15-2.28 (m, 1H), 2.50-2.60 (m, 2H), 2.64-2.76 (m, 2H), 3.89 (quint, J=8.4 Hz, 1H), 7.35 (d, J=4.8 Hz, 1H), 7.44-7.50 (m, 1H), 7.51-7.57 (m, 3H), 7.89-7.93 (m, 3H), 8.17-8.22 (m, 2H), 8.27 (dd, J=0.8, 8.8 Hz, 1H), 8.53 (d, J=0.8 Hz, 1H). MS (ES+): m/z 410.9/412.9 (100/39) [MH+].