Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1CCCC1C[NH:9][C:10](=[O:25])[C:11]1[CH:16]=[C:15](NS(C)(=O)=O)[C:14](C)=[CH:13][C:12]=1OC)C.C(N(CC)CC)C.CN(C)S(Cl)(=O)=O>C(Cl)Cl>[C:10]([NH2:9])(=[O:25])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCN1CCCC1CNC(=O)c1cc(NS(C)(=O)=O)c(C)cc1OC
Agent: CN(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)c1ccccc1
Yield: 214.1 %

Procedure:
A mixture of N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-methyl-5-methanesulfonamidobenzamide (500 mg), triethylamine (823 mg), dimethylaminosulfonyl chloride (1.17 g), and methylene chloride (20 ml) is refluxed for 39 hours. The reaction mixture is washed with aqueous sodium hydrogencarbonate. The organic layer is washed with water, dried over sodium sulfate, and evaporated to remove the solvent. The residue is chromatographed on a column of alumina and eluted with 0.5-1% methanol/methylene chloride. The eluate is evaporated to give N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-methyl-5-[N-(dimethylaminosulfonyl)-methanesulfonamido[benzamide (351 mg) as an oil. This product is mixed with tetrahydrofuran (3 ml) and 10% sodium hydroxide (3 ml) and warmed at 80° C. for 1 hour. The reaction mixture is evaporated to remove the tetrahydrofuran, acidified with hydrochloric acid, made alkaline with sodium hydrogencarbonate, salted out with sodium chloride, and shaken with methylene chloride. The organic layer is washed with saturated brine, dried over sodium sulfate, and evaporated to remove the solvent. The residue is chromatographed on a column of alumina and eluted with 3% methanol/methylene chloride. The eluate is evaporated to remove the solvent. The residue is washed with ether/isopropyl ether and filtered to give N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-methyl-5-dimethylaminosulfonamidobenzamide (211 mg). The product is recrystallized from acetonitrile/isopropyl ether to give crystals melting at 129° to 129.5° C.
Reaction SMILES: [CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].CC1C=CC(S(O[CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][C:29]3[CH:34]=[C:33]([Br:35])[CH:32]=[CH:31][C:30]=3[Cl:36])=[CH:24][CH:23]=2)(=O)=O)=CC=1>O1CCCC1>[Br:35][C:33]1[CH:32]=[CH:31][C:30]([Cl:36])=[C:29]([CH2:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][CH2:20][CH2:19][O:5][CH:1]3[CH2:4][CH2:3][CH2:2]3)=[CH:23][CH:24]=2)[CH:34]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc(Cc3cc(Br)ccc3Cl)cc2)cc1
Reactant: OC1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1ccc(Br)cc1Cc1ccc(OCCOC2CCC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.3 %

Procedure:
To a solution of cyclobutanol (260 mg, 3.6 mmol) in anhydrous tetrahydrofuran (4 mL) was added sodium hydride (138 mg, 5.7 mmol) in portions at 0° C. The mixture was stirred at 0° C. for 30 min, and then 2-(4-(5-bromo-2-chlorobenzyl)phenoxy)ethyl 4-methylbenzenesulfonate (intermediate AB) (300 mg, 0.6 mmol) was added in portions. The mixture was refluxed for 3 h, whereupon TLC showed the reaction was complete. The reaction mixture was quenched with saturated ammonium chloride, extracted with ethyl acetate, washed with water and then with brine, dried over anhydrous sodium sulfate, and concentrated to a crude oil. The crude oil was purified by column chromatography (PE:EA=10:1) to get intermediate CL as an oil product (117 mg, yield: ˜49%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22](Br)[C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=1)[CH3:11].[C:28]([O-:31])(=[S:30])[CH3:29].[K+].CN(C)C=O>O>[C:28]([S:30][CH:22]([CH2:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH2:12][N:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH3:11])=[CH:16][CH:17]=1)[C:23]([O:25][CH3:26])=[O:24])(=[O:31])[CH3:29]
Reactant: CC([O-])=S
Reactant: COC(=O)C(Br)Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)SC(C)=O
Temperature: 80 °C

Procedure:
A mixture of methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-bromopropanoate (1.25 g), potassium thioacetate (0.5 g) and dry N,N-dimethylformamide (15 mL) was heated at 80° C. for 18 hours under a nitrogen atmosphere. The mixture was diluted with water (1 L) and extracted with ethyl acetate (3×250 mL). The combined ethyl acetate solutions were washed with water (3×250 mL) and brine (500 mL), dried (MgSO4) and evaporated. The residue was chromatographed on silica gel with 40% ethyl acetate in hexane as eluent to afford the title compound, a gum.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]1([C:12](=[CH:14][CH:15]=[CH:16][CH:17]=1)[OH:13])[OH:11]>CN(C=O)C>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[O:11][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[O:13][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5])#[N:5]
Reactant: Oc1ccccc1O
Reactant: N#Cc1ccccc1F
Solvent: CN(C)C=O
Product: N#Cc1ccccc1Oc1ccccc1Oc1ccccc1C#N
Yield: 84.6 %

Procedure:
The compound 1,2-Bis(2-cyanophenoxy)benzene was synthesized in the same manner as for 1,2-bis-(4-4-cyanophenoxy)benzene according to Example 1 above, but from 2-fluorobenzonitrile and catechol, except that the synthesis was performed in DMF at 125° C. and over a period of 10 hours. The precipitate was filtered off and washed several times with deionised water. The white product was recrystallized from methanol/water (8:1). The yield was 84.6% of the title compound with the formula: ##STR6##
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C=O)C>[Br:1][C:2]1[C:3]([Cl:11])=[C:4]2[CH:10]=[CH:9][N:8]([S:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1
Reactant: Clc1c(Br)cnc2[nH]ccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1ccc2c(Cl)c(Br)cnc21
Reaction time: 0.33 h
Yield: 99.7 %

Procedure:
5-Bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine (0.50 g, 2.160 mmol) was placed in DMF (5 mL) at 0° C. NaH (0.10 g, 2.59 mmol) was then added, and the reaction was stirred for 20 minutes. Benzenesulfonyl chloride (0.304 mL, 2.38 mmol) was then added, and the reaction was stirred for 30 minutes at 0° C. Water (50 mL) was then added. The precipitate was filtered, washed with water, washed with ether, and dried to give 5-bromo-4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.8 g, 99.6% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2(S(C3C=CC=CC=3)(=O)=O)[CH2:11][CH2:10]2)=[CH:4][N:3]=1.P([O-])([O-])[O-].[Na+].[Na+].[Na+].C(=O)([O-])O.[Na+]>CO>[CH:9]1([O:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[N:3][CH:4]=2)[CH2:11][CH2:10]1
Reactant: Cc1ccc(OC2(S(=O)(=O)c3ccccc3)CC2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-]P([O-])[O-]
Solvent: CO
Product: Cc1ccc(OC2CC2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
2-Methyl-5-(1-(phenylsulfonyl)cyclopropoxy)pyridine (540 mg, 1.87 mmol) was dissolved in methanol (5.5 mL), and sodium phosphite (671 mg, 5.598 mmol) and amalgam sodium (3.58 g, 7.47 mmol) were added thereto under ice-cold conditions, and the resultant mixture was stirred at the same temperature for 30 minutes, and then further stirred at room temperature for 3 hours. The reaction solution was added with a saturated aqueous solution of sodium hydrogen carbonate and extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by distillation, and 5-cyclopropoxy-2-methylpyridine (240 mg, yield 86%) was obtained as a yellow oil.
Reaction SMILES: [ClH:1].O[CH2:3][C:4]1[S:8][C:7]2=[CH:9][N:10]=[CH:11][N:6]2[CH:5]=1.S(Cl)([Cl:14])=O>C1COCC1>[ClH:14].[Cl:1][CH2:3][C:4]1[S:8][C:7]2=[CH:9][N:10]=[CH:11][N:6]2[CH:5]=1
Reactant: OCc1cn2cncc2s1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: C1CCOC1
Product: ClCc1cn2cncc2s1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
2-Hydroxymethylimidazo[5,1-b]thiazole hydrochloride (1.40 g) is suspended in 15 ml of THF, 0.8 ml of thionyl chloride is added thereto, and the mixture is stirred at 60° C. for 1.5 hr. The solvent is removed by evaporation to give 2-chloromethylimidazo[5,1-b]thiazole hydrochloride. This compound is dissolved in 7 ml of DMF, 1.78 g of triphenylphosphine is added thereto, and the mixture is stirred at 100° C. for 12 hr. The resultant precipitate is collected by filtration to give 2.14 g of (imidazo[5,1-b]thiazol-2-yl)methyltriphenylphosphonium chloride hydrochloride.
Reaction SMILES: [CH2:1](N1C(=O)C2N(C)C=NC=2N(C)C1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].C(O)CCCCC=C.[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(N(CC)CC)C>ClCCl.O>[CH3:29][S:30]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7])(=[O:32])=[O:31]
Reactant: C=CCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reactant: CS(=O)(=O)Cl
Agent: C=CCCCCCO
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C=CCCCCCS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 93 %

Procedure:
This example illustrates the synthesis of 1-(6-Heptenyl)-3,7-dimethylxanthine (CT1534). To a solution of 6-hepten-1-ol (6.00 g, 52.6 mmol) in dichloromethane (120 ml) at 0° C. was added methanesulfonyl chloride (6.07 g, 4.0 ml, 53.0 mmol) followed by triethylamine (7.79 g, 77.0 mmol). After stirring for 10 min at 0° C., the reaction was allowed to warm to 25° C. and stirred for 2 hr. The reaction was poured into water (100 ml) and extracted with dichloromethane (2×100 ml). The organic portions were combined, dried (magnesium sulfate), and evaporated to give the 7-methanesulfonyl-1-heptene as a yellow oil (9.30 g, 93%), which was used without further purification.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[Cl-].[Mg+2].[Cl-].N1C=CC=CC=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1>C(Cl)Cl>[CH2:8]([O:7][C:1](=[O:6])[CH:2]([C:19]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)=[O:26])[C:3](=[O:4])[CH3:5])[CH3:9]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=C(Cl)c1ccncc1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C(C(C)=O)C(=O)c1ccncc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 46.7 %

Procedure:
8 g (61.5 mmol) of ethyl acetoacetate were dissolved in 280 ml of CH2Cl2, the solution was cooled at 0° C. and successively were added 6.00 g (63.3 mmol) of anhydrous magnesium chloride, 10 ml (124 mmol) of pyridine and 13.4 g (94.73 mmol) of isonicotinoyl chloride. The yellow suspension was stirred 1 h under ice cooling and 18 h at room temperature. The reaction mixture was poured into crashed ice and extracted twice with CH2Cl2. The organic phases were washed with brine, dried over magnesium sulfate, and evaporated. The residue was purified by column chromatography (n-heptane:EtOAc 1:4) to afford the title compound as light yellow oil (6.75 g, 47%). MS: 236.0 (MH+).
Reaction SMILES: O=[C:2]1[C:15]2[CH:14]=[C:13]([CH:16]([CH3:19])[CH2:17][OH:18])[CH:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.O.Cl>[Zn].C1(C)C=CC=CC=1>[CH:14]1[C:15]2[CH2:2][C:3]3[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=3)[O:9][C:10]=2[CH:11]=[CH:12][C:13]=1[CH:16]([CH3:19])[CH2:17][OH:18]
Reactant: CC(CO)c1ccc2oc3ccccc3c(=O)c2c1
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(CO)c1ccc2c(c1)Cc1ccccc1O2
Reaction time: 8 h

Procedure:
A mixture of 10 g. of 2-(9-oxo-2-xanthenyl)-propanol, 12 g. of amalgamized zinc, 15 ml. of water, 40 ml. of concentrated hydrochloric acid, and 20 ml. of toluene is refluxed for 48 hours. At 8 hour intervals, another 10 ml. of concentrated hydrochloric acid is added. After filtration over active carbon and removal of the solvent mixture by evaporation, 2-(2-xanthenyl)-propanol is obtained, m.p. 86°-89°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:17]([C:18](O)=[O:19])[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)=[CH:27][CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:42][O:43][C:44](=[O:61])[C@@H:45]([NH2:60])[CH2:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]2[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=2)=[CH:49][CH:48]=1>>[C:1]([O:5][C:6]([N:8]1[CH:17]([C:18](=[O:19])[NH:60][C@H:45]([C:44]([O:43][CH3:42])=[O:61])[CH2:46][C:47]2[CH:52]=[CH:51][C:50]([C:53]3[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=3)=[CH:49][CH:48]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)=[CH:27][CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(F)cc2)cc1
Reactant: CC(C)(C)OC(=O)N1Cc2cc3c(cc2CC1C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(F)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Yield: 72.5 %

Procedure:
(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]-isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester (50 mg) was coupled with (S)-2-amino-3-(4′-fluoro-biphenyl-4-yl)-propionic acid methyl ester hydrochloride (29 mg) according to General Procedure L to give (S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-8-[(S)-2-(4′-fluoro-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester (52 mg). This intermediate was deprotected as described in General Procedure C to give (S)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-fluoro-biphenyl-4-yl)-propionic acid methyl esterhydrochloride. This compound was further reacted with 2-acetylamino-4-methyl-thiazole-5-sulfonyl chloride to furnish (S)-2-({(S)-7-(2-acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-fluoro-biphenyl-4-yl)-propionic acid methyl ester as described in General Procedure E. This compound, upon reaction with ethyl iodide and K2CO3 in DMF, gave (S)-2-({(S)-7-[2-(acetyl-ethyl-amino)-5-methyl-thiazole-4-sulfonyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-fluoro-biphenyl-4-yl)-propionic acid methyl ester according to General Procedure O. This product (15 mg) was hydrolyzed according to General Procedure B to furnish the title compound. LCMS (m/z): 934.
Reaction SMILES: [OH:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.Cl[CH:29]([OH:31])[CH3:30].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[OH:31][CH2:29][CH2:30][O:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: COc1ccc2nc(-c3ccc(NC(=O)c4ccc(O)cc4)cc3)sc2c1
Reactant: CC(O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2nc(-c3ccc(NC(=O)c4ccc(OCCO)cc4)cc3)sc2c1
Temperature: 25 °C
Yield: 76.3 %

Procedure:
A mixture of 4-hydroxy-N-[4-(6-methoxybenzothiazol-2-yl)-phenyl]-benzamide (0.20 g, 0.53 mmol), chloroethanol (0.064 g, 0.80 mmol) and potassium carbonate (0.26 g, 1.86 mmol) was heated at 100° C. in dry DMF (10 ml) for 18 h. On cooling to room temperature, water (30 ml) was added and the reaction mixture was extracted with EtOAc (7×40 ml). The combined organic extracts were washed with brine (80 ml) and dried (Na2SO4). The solvent was removed under reduced pressure to give the title compound (0.17 g, 76%) as a colourless solid.
Reaction SMILES: C(O[C:5]([CH3:8])([CH3:7])[CH3:6])(=O)C.[CH2:9]([O:11][C:12](=[O:36])[CH:13]([OH:35])[C:14]1[C:15]([CH3:34])=[N:16][C:17]2[S:18][C:19]3[CH2:20][O:21][CH2:22][CH2:23][C:24]=3[C:25]=2[C:26]=1[C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1)[CH3:10].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:9]([O:11][C:12](=[O:36])[CH:13]([O:35][C:5]([CH3:8])([CH3:7])[CH3:6])[C:14]1[C:15]([CH3:34])=[N:16][C:17]2[S:18][C:19]3[CH2:20][O:21][CH2:22][CH2:23][C:24]=3[C:25]=2[C:26]=1[C:27]1[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=1)[CH3:10]
Reactant: CC(=O)OC(C)(C)C
Reactant: CCOC(=O)C(O)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCOC3
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCOC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
Tert-Butyl acetate (0.8 mL) was added to a solution of hydroxy-(2-methyl-4-p-tolyl-5,8-dihydro-6H-7-oxa-9-thia-1-aza-fluoren-3-yl)-acetic acid ethyl ester (100 mg, 0.252 mmol) in dichloromethane (0.8 mL) followed by concentrated sulphuric acid (40 μL) and the reaction stirred at room temperature for 2 hours. Sodium bicarbonate solution (10% aqueous, 2 mL) was added and the reaction evaporated in vacuo until only the aqueous remained. The aqueous was extracted with ethyl acetate (2 mL) and the organic layer washed with brine (1 mL), dried and concentrated in vacuo. The residue was purified by flash chromatography on silica eluting with 0-30% ethyl acetate/heptanes to afford a colourless solid (66 mg, 45%). LCMS (12 min acidic) 7.25 min, ES+/AP+ 454 (MH+)
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1>Br.CC(O)=O>[F:17][C:15]([F:16])([F:18])[C:14]1[C:9]([C:6]2[CH:5]=[CH:4][C:3](=[O:2])[NH:8][CH:7]=2)=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: COc1ccc(-c2ncccc2C(F)(F)F)cn1
Agent: Br
Solvent: CC(=O)O
Product: O=c1ccc(-c2ncccc2C(F)(F)F)c[nH]1
Reaction time: 1 h
Yield: 93.7 %

Procedure:
Heat 6′-methoxy-3-trifluoromethyl-[2,3′]bipyridinyl (41 g, 0.16 mol) in 30% HBr/AcOH (100 mL) to reflux for 1 hour. Cool the mixture and filter, and wash the precipitate with ether (100 mL). Transfer the precipitate into 10M sodium hydroxide (500 mL) and stir for 1 hour, and treat the solution with hydrochloric acid until the solution is pH 7. Collect the white solid by filtration and air dry to give the title compound (36 g, 93%) as a white solid.
Reaction SMILES: C([O:3][C:4]1(OCC)[CH2:9][CH2:8][C:7]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:13]=2)([CH2:10][F:11])[CH2:6][CH2:5]1)C.Cl>C(OCC)(=O)C>[CH:21]1([O:20][C:14]2[CH:13]=[C:12]([C:7]3([CH2:10][F:11])[CH2:6][CH2:5][C:4](=[O:3])[CH2:9][CH2:8]3)[CH:17]=[CH:16][C:15]=2[O:18][CH3:19])[CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CCOC1(OCC)CCC(CF)(c2ccc(OC)c(OC3CCCC3)c2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc(C2(CF)CCC(=O)CC2)cc1OC1CCCC1
Yield: 24.6 %

Procedure:
4-(3-Cyclopentyloxy-4-methoxyphenyl)-4-(fluoromethyl)cyclohexan-1-one diethyl ketal (0.35 g, 0.95 mmol) in ethyl acetate (2 mL) was treated with 1N hydrochloric acid (2 mL) and the mixture was stirred vigorously and gently heated for 10 min. The mixture was extracted with ethyl acetate, the organic extract was washed with 5% aqueous sodium carbonate, dried (magnesium sulfate) and the solvent was removed in vacuo. Purification by flash chromatography, eluting with 25% ethyl acetate/hexanes, followed by trituration with ether/hexanes, provided a white solid (0.075 g, 24%): m.p. 72°-74° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][N:5]=[C:4](Cl)[CH:3]=1.S(=O)(=O)(O)[OH:15]>>[Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[C:4]([OH:15])[CH:3]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Reactant: O=S(=O)(O)O
Product: O=C(O)c1cnc(O)cc1Cl

Procedure:
ethyl 4,6-dichloronicotinate (17 g) is boiled for 4 hours with 24% sulfuric acid (400 ml). The white crystals that separate are filtered from the boiling solution and 4-chloro-6-hydroxynicotinic acid (6 g, m.p. 299°-300° C.) is obtained; the acidic solution is left overnight in the refrigerator. The crystallized solid is collected by filtration and dried under vacuum, thus obtaining 6-chloro-4-hydroxynicotinic acid (4.6 g) m.p. 231°-233° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([OH:14])=O.[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH2:22][CH2:21][CH2:20]2>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([N:23]1[C:24]2[C:19](=[CH:18][C:17]([O:16][CH3:15])=[CH:26][CH:25]=2)[CH2:20][CH2:21][CH2:22]1)=[O:14]
Reactant: O=C(O)CSc1nc2ccccc2s1
Reactant: COc1ccc2c(c1)CCCN2
Product: COc1ccc2c(c1)CCCN2C(=O)CSc1nc2ccccc2s1

Procedure:
The title compound was synthesized according to General Procedure B using 2-(benzo[d]thiazol-2-ylthio)acetic acid and 6-methoxy-1,2,3,4-tetrahydroquinoline to yield 39 (245 mg, 1.5 mmol). MS (APCI: m/z 371 [M+H]+. Anal. Calcd. for C19H18N2O2S2: C, 61.60; H, 4.90; N, 7.56. Found: C, 61.49; H, 4.87; N, 7.59.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[C:10]=1[OH:11])[C:5]([OH:7])=[O:6].Cl.[CH2:16](Cl)Cl>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[C:10]=1[OH:11])[C:5]([O:7][CH3:16])=[O:6]
Reactant: ClCCl
Reactant: O=C(O)c1cc(O)c(O)c([N+](=O)[O-])c1
Agent: Cl
Product: COC(=O)c1cc(O)c(O)c([N+](=O)[O-])c1
Reaction time: 3 h

Procedure:
1.0 g of 3,4-dihydroxy-5-nitrobenzoic acid is treated with 20 ml of methanolic hydrochloric acid, stirred at 45° for 3 hours and, after removing the solvent, the residue is taken up in methylene chloride. The organic phase is washed with sodium chloride solution, dried over sodium sulfate and evaporated. The crystalline product obtained is taken up in methylene chloride and filtered over a ten-fold amount of silica gel. The material obtained is recrystallized from ethyl acetate/n-hexane. There is obtained methyl 3,4-dihydroxy-5-nitrobenzoate in the form of yellow crystals of m.p. 144°-145°.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH:28]([CH3:32])[C:29](O)=[O:30])[CH:27]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[NH2:35][CH2:36][CH:37]([OH:39])[CH3:38]>>[OH:39][CH:37]([CH3:38])[CH2:36][NH:35][C:29](=[O:30])[CH:28]([N:26]1[CH:27]=[C:23]([C:21]2[CH:20]=[N:19][N:18]3[C:14]([C:10]4[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:33])([F:1])[F:34])=[O:6])[CH:9]=4)=[CH:15][N:16]=[C:17]3[CH:22]=2)[CH:24]=[N:25]1)[CH3:32]
Reactant: CC(O)CN
Reactant: CC(C(=O)O)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1
Product: CC(O)CNC(=O)C(C)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 54, Step 3 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanoic acid and 1-amino-2-propanol. LCMS (M+H)+: m/z=531.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:18][C:19]#[N:20]>>[CH3:13][O:14][C:15]1[CH:16]=[C:17](/[C:18](=[CH:6]/[C:5]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=2)/[C:19]#[N:20])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: COc1ccc(C=O)cc1OC
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(/C=C(\C#N)c2ccc(OC)c(OC)c2)cc1OC
Yield: 89.4 %

Procedure:
3,4-Dimethoxybenzaldehyde (1.00 g) and 3,4-dimethoxybenzyl cyanide (1.07 g) were subjected to condensation in accordance with process A of (production process 2), to thereby produce the target product (1.75 g, yield: 89%).