Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:7]=3[C:8]=2[CH:9]=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)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>[CH3:29][O:30][C:31]1[CH:32]=[C:33]([C:2]2[S:3][C:4]3[CH2:5][C:6]4[C:12]([C:13]5[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=5)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:28])[CH3:27])[C:7]=4[C:8]=3[CH:9]=2)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38]
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(Br)cc2-3)cc1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(-c4ccc(OC)c(OC)c4)cc2-3)cc1
Temperature: 100 °C
Yield: 65 %

Procedure:
A mixture of the corresponding 2-Bromo-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.76 g, 1.5 mmol), 2-(3,4-Dimethoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.4 g, 2.3 mmol), Na2CO3 (2 M, 2.45 mL), and Pd(PPh3)2Cl2 (9.7 mg, 0.084 mmol) in toluene/ethanol (1:1, 8.0 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (20% EtOAc in hexane) to give 2-(3,4-Dimethoxy-phenyl)-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene as orange solid in 65% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[C:12](OC([O-])=O)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>O1CCCC1>[C:15]([O:14][C:12](=[O:13])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(=O)c1cc(N)ccc1F
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Solvent: C1CCOC1
Product: CC(=O)c1cc(NC(=O)OC(C)(C)C)ccc1F
Temperature: 25 °C
Reaction time: 28 h
Yield: 73.7 %

Procedure:
To a solution of 1.19 g (7.77 mmol) of 1-(5-amino-2-fluorophenyl)ethanone in 18 ml of dry tetrahydrofuran at room temperature under an atmosphere of nitrogen was added 1.86 g (8.54 mol) of tert-butyl dicarbonate. The solution was stirred for 28 hours at room temperature followed by 17 hours at 45° C., cooled to room temperature and evaporated under reduced pressure. The residue was dissolved in ethyl acetate and the solution washed with sodium bicarbonate solution, dried over magnesium sulphate, evaporated to dryness and the residue chromatographed on silica gel using ethyl acetate/petrol 4:1 for the elution. There was obtained 1.45 g of (3-acetyl-4-fluorophenyl)carbamic acid tert-butyl ester MS: m/e 271 [M+CH3CN]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1F)[C:5]([NH:7][CH2:8][CH:9]([CH3:11])[CH3:10])=[O:6].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([OH:26])=[O:25])=[CH:19][C:18]=1[OH:27]>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([OH:26])=[O:25])=[CH:19][C:18]=1[O:27][C:14]1[CH:13]=[CH:12][C:4]([C:5]([NH:7][CH2:8][CH:9]([CH3:11])[CH3:10])=[O:6])=[CH:3][C:2]=1[Cl:1]
Reactant: CC(C)CNC(=O)c1ccc(F)c(Cl)c1
Reactant: O=C(O)Cc1ccc(Cl)c(O)c1
Product: CC(C)CNC(=O)c1ccc(Oc2cc(CC(=O)O)ccc2Cl)c(Cl)c1

Procedure:
The title compound was prepared by the method of example 2 step (iii) using the product of step (i) and the product of example 1 step (iii).
Reaction SMILES: [Li+].[OH-].O.[OH:4][C@@:5]1([C:17]([O:19]CC)=[O:18])[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]1=[O:16]>C1COCC1.O>[OH:4][C@@:5]1([C:17]([OH:19])=[O:18])[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]1=[O:16]
Reactant: CCOC(=O)[C@]1(O)CCN(c2ccccc2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@]1(O)CCN(c2ccccc2)C1=O
Reaction time: 4 h

Procedure:
LiOH/H2O (750 mg) is added to a solution of ethyl (S)-3-hydroxy-2-oxo-1-phenylpyrrolidine-3-carboxylate (1.5 g) in THF/H2O=3:1, and the mixture is stirred for 4 h. The solvent is then removed in vacuo, and the batch is acidified using 1.5N HCl. The aqueous phase is extracted with ethyl acetate, and the combined organic phases are dried over sodium sulfate, giving (S)-3-hydroxy-2-oxo-1-phenylpyrrolidine-3-carboxylic acid;
Reaction SMILES: [C:1]([C:4]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=2[Cl:17])[C:8]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[C:7]([CH3:25])[NH:6][C:5]=1[CH2:26][CH2:27][CH2:28][CH2:29]Cl)(=[O:3])[CH3:2].[I-].[Na+].Cl.[C:34]1([C:40]2([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(O)(C)C>[ClH:16].[C:1]([C:4]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=2[Cl:17])[C:8]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])=[C:7]([CH3:25])[NH:6][C:5]=1[CH2:26][CH2:27][CH2:28][CH2:29][N:43]1[CH2:44][CH2:45][C:40]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:41][CH2:42]1)(=[O:3])[CH3:2]
Reactant: CC(=O)C1=C(CCCCCl)NC(C)=C(C(=O)OC(C)(C)C)C1c1cccc(Cl)c1Cl
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC(=O)C1=C(CCCCN2CCC(c3ccccc3)(c3ccccc3)CC2)NC(C)=C(C(=O)OC(C)(C)C)C1c1cccc(Cl)c1Cl

Procedure:
5.6 g (12.2 mmol) 3-acetyl-5-tert-butoxycarbonyl-1,4-dihydro-4-(2,3-dichlorophenyl)-2-(4-chlorobutyl)-6-methyl-pyridine are reacted first with 3.6 g (24.4 mmol) sodium iodide, as described for starting compound B, and then with 6 g (21 mmol) 4,4-diphenylpiperidine hydrochloride. Working up is carried out as described for starting compound B. The crude product is chromatographed with toluene/acetone=8/2. The product thus obtained is taken up in 30 ml isopropanol. The title compound is precipitated by addition of ethereal hydrochloric acid. Yield: 5.2 g (60%). M.p. 154°-156° C. decomp. (acetonitrile).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([F:21])[CH:20]=1)[CH:16]=O.N1CCCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:16]/[C:15]3[CH:18]=[C:19]([F:21])[CH:20]=[C:13]([Cl:12])[CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=Cc1cc(F)cc(Cl)c1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: C1CCNCC1
Solvent: CO
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1cc(F)cc(Cl)c1
Temperature: 80 °C
Yield: 93.6 %

Procedure:
To the mixture of 6-chloro-2-oxindole (4.4 g, 26 mmol) (Crescent) and 3-chloro-5-fluorobenzaldehyde (4.2 g, 26 mmol) (Aldrich) in methanol (200 mL) was added piperidine (2.3 g, 26 mmol) (Aldrich) dropwise. The mixture was then heated at 80° C. for 2 h. After cooled to 4° C., the mixture was filtered and resulting precipitate was collected, dried to give E/Z-6-chloro-3-(3-chloro-5-fluoro-benzylidene)-1,3-dihydro-indol-2-one as a yellow solid (Yield 7.5 g, 92%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)[CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10].[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH2:36][CH2:37][O:38][CH3:39])[N:31]=[CH:30][N:29]=[C:28]2[S:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][CH:47]=1)[NH2:44].C(N(C(C)C)CC)(C)C>CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]([NH:44][C:43]2[CH:45]=[CH:46][CH:47]=[C:41]([S:40][C:28]3[C:27]4[C:32](=[CH:33][C:34]([O:35][CH2:36][CH2:37][O:38][CH3:39])=[C:25]([O:24][CH3:23])[CH:26]=4)[N:31]=[CH:30][N:29]=3)[CH:42]=2)=[O:22])[CH:6]=[CH:7][C:8]=1[C:9]([F:10])([F:11])[F:12]
Reactant: COCCOc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: COc1cc(NC(=O)Oc2ccccc2)ccc1C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc2ncnc(Sc3cccc(NC(=O)Nc4ccc(C(F)(F)F)c(OC)c4)c3)c2cc1OC

Procedure:
The procedure for Example 138B was used to react phenyl 3-methoxy-4-(trifluoromethyl)phenylcarbamate described in Example 190B (144 mg, 0.46 mmol) with 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline described in Example 231A (110 mg, 0.31 mmol). To this solution was added diisopropylethyl amine (80 μL, 0.46 mmol) and DMAP (4.0 mg, 0.03 mmol). The reaction was concentrated to dryness and purified by silica gel chromatography eluting with ethyl acetate/dichloromethane 0-50% over 75 minutes. The main peak collected and concentrated, then triturated with dichloromethane to give a solid weighing 43 mg. 1H (DMSO-d6) 9.19 (s, 1H), 9.04 (s, 1H), 8.70 (s, 1H), 7.84 (s, 1H), 7.6-7.40 (m, 4H), 7.35 (m, 2H), 7.25 (m, 1H), 7.00 (m, 1H), 4.34 (m, 2H), 4.00 (s, 3H), 3.84 (s, 3H), 3.78 (m, 2H). LCMS (ESI) m/z 575 (M+H)
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][CH2:4][C:5]1[N:6]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)[CH:7]=[CH:8][N:9]=1.[CH2:20]([C:22]1[NH:26][C:25](=[O:27])[NH:24][C:23]=1C(O)=O)[CH3:21]>>[CH2:20]([C:22]1[NH:26][C:25](=[O:27])[NH:24][C:23]=1[C:14](=[O:16])[C:13]1[CH:12]=[CH:11][C:10]([N:6]2[CH:7]=[CH:8][N:9]=[C:5]2[CH2:4][CH2:3][CH:2]([CH3:1])[CH3:19])=[CH:18][CH:17]=1)[CH3:21]
Reactant: CC(C)CCc1nccn1-c1ccc(C(=O)O)cc1
Reactant: CCc1[nH]c(=O)[nH]c1C(=O)O
Product: CCc1[nH]c(=O)[nH]c1C(=O)c1ccc(-n2ccnc2CCC(C)C)cc1

Procedure:
In a manner similar to that described in Example I react 4-[2-(3-methylbutyl)-1H-imidazol-1-yl]benzoic acid and 5-ethyl-2,3-dihydro-2-oxo-1H-imidazole-4-carboxylic acid to produce the title compound which can be purified by chromatography of the crude base on silica gel.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1)=O.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C1(C)C=CC=CC=1>[N:19]1([CH:1]=[C:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:5][CH2:4]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: C1CCNCC1
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)N1CCC(=CN2CCCCC2)CC1

Procedure:
To a solution of benzyl 4-formylpiperidine-1-carboxylate (12.5 g) in toluene (120 mL) was added piperidine (6.46 g). The mixture was stirred at reflux under a Dean-Stark trap overnight. The mixture was then concentrated under vacuum and the residue was used directly in the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[Cl:12].[N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15](B(O)O)[CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[Cl:12][C:7]1[C:6]2[C:11](=[C:2]([C:15]3[CH:14]=[N:13][C:22]4[C:17]([CH:16]=3)=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:3]=[CH:4][CH:5]=2)[N:10]=[CH:9][CH:8]=1
Reactant: Clc1ccnc2c(Br)cccc12
Reactant: OB(O)c1cnc2ccccc2c1
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: [Na+]
Solvent: COCCOC
Product: Clc1ccnc2c(-c3cnc4ccccc4c3)cccc12
Yield: 41.6 %

Procedure:
Pd(PPh3)4 (0.0581 g) was added to a solution of the obtained 8-bromo-4-chloroquinoline (0.242 g), 3-quinolineboronic acid (0.163 g), and an aqueous sodium carbonate solution (2 M, 1.5 mL) in ethylene glycol dimethyl ether (3.0 mL) in a nitrogen atmosphere, and the mixture was stirred at 85° C. for 3 hours. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain 4′-chloro-3,8′-biquinoline (0.114 g) as a white solid. Compound (117) was obtained as a pale yellow solid (yield based on 6 steps: 37%) according to Example 3(3) using the obtained 4′-chloro-3,8′-biquinoline instead of compound (3b) and 4-cyano-3-(4-hydroxycyclohexylamino)phenylboronic acid pinacol ester instead of 4-cyano-3-(ethylamino)phenylboronic acid pinacol ester.
Reaction SMILES: [CH3:1][N:2]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5](O)=[O:6].S(Cl)([Cl:19])=O>ClCCl>[CH3:1][N:2]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5]([Cl:19])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: CN(CCC(=O)O)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: CN(CCC(=O)Cl)c1ccc([N+](=O)[O-])cc1
Yield: 88.6 %

Procedure:
3-[Methyl-(4-nitro-phenyl)-amino]-propionic acid (1.2 g, 5.35 mmol) in dichloromethane (10 mL) was cooled to 0° C. and thionyl chloride (1.55 mL, 21.4 mmol) was added. The mixture was heated to reflux for 4 h. The solvent was evaporated to give the crude compound which was azeotroped with toluene to remove the traces of thionyl chloride, affording 3-[methyl-(4-nitro-phenyl)-amino]-propionyl chloride (1.15 g, 88%) as a yellow solid.
Reaction SMILES: Br[CH:2]([C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)[C:3](=O)[CH3:4].[NH2:14][C:15]1[S:16][CH:17]=[CH:18][N:19]=1.C(N(CC)CC)C>C(O)CCC>[C:10]([C:9]1[CH:12]=[CH:13][C:6]([C:2]2[N:19]3[C:15]([S:16][CH:17]=[CH:18]3)=[N:14][C:3]=2[CH3:4])=[CH:7][CH:8]=1)#[N:11]
Reactant: Nc1nccs1
Reactant: CC(=O)C(Br)c1ccc(C#N)cc1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: Cc1nc2sccn2c1-c1ccc(C#N)cc1
Reaction time: 2 h
Yield: 35 %

Procedure:
A solution of 4-(1-bromo-2-oxopropyl)benzonitrile (1 g, 4 mmol) in n-butanol (3 ml) was added in a single portion to a hot (110° C.), stirred solution of 2-aminothiazole in n-butanol (3 ml). After refluxing for 2 hours, triethylamine (0.5 ml, 4 mmol) was added and heating was resumed for a further 2 hours. All volatiles were evaporated and the residue was chromatographed on silica gel, eluting with ethyl acetate:hexane:diethylamine (5:14:1) to afford an off-white solid (0.34 g, 35%), m.p. 88°-91° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.CO[C:12]1[C:13](=[O:19])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1>CO>[O:19]=[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=[C:12]1[N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]1
Reactant: OCCN1CCNCC1
Reactant: COc1cccccc1=O
Solvent: CO
Product: O=c1cccccc1N1CCN(CCO)CC1
Yield: 51.1 %

Procedure:
A mixture of 1-(2-hydroxyethyl)piperazine (10.0 g) and 2-methoxy-2,4,6-cycloheptatrien-1-one (10.9 g) in methanol (50 ml) was refluxed for 24 hr and evaporated. The residue was chromatographed on silica gel (100 g) using methanol-ethyl acetate (1:4). The eluates were evaporated and crystallized from ethyl acetate-hexane to give the title compound (9.2 g): mp 85°-86° C.; ir (CHCl3) 3440, 1616 and 1555 cm1 ; nmr(CDCl3) δ2.55 (t, 2H), 2.63 (m, 4H), 3.30 (m, 4H), 3.60 (t, 2H) and 6.40-7.65 (m, 5H); and Anal. Calcd for C13H18N2O2 : C, 66.64% H, 7.74% N, 11.96% and Found: C, 66.12% H, 7.83% N, 11.99%.
Reaction SMILES: [OH-].[K+].CN(C=O)C.[CH2:8]([O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[CH:19]2)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1>O>[CH2:8]([O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:30][C:29]1[CH:32]=[CH:33][C:26]([F:25])=[CH:27][CH:28]=1)[CH:20]=[CH:19]2)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Reactant: Fc1ccc(CCl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(Cn2ccc3cc(OCc4ccccc4)ccc32)cc1
Temperature: 10 °C
Reaction time: 0.08 h

Procedure:
The KOH pellets are added to the mixture of DMF and water, and the mixture is vigorously stirred for 5 minutes. After addition of the 5-benzyloxyindole, the mixture is stirred at room temperature for a further 45 minutes. Then, at an internal temperature of 10–20° C., 4-fluorobenzyl chloride is added dropwise while stirring. The mixture is then stirred at room temperature for a further 90 minutes. The mixture is cooled to 10° C., and 300 ml of water are added. It is cooled during this so that the internal temperature does not exceed 20° C. The mixture is stirred for 2 hours, and then the precipitate is filtered off with suction, washed with water and dried at 30° C. initially in circulating air and then in vacuo. The resulting product is very pure so that no additional purification operation is necessary.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[OH:14])=[CH:4][CH:3]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][C:15](=[O:17])[CH3:16])=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccccc2O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccccc1-c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
A solution of 1.0 g (5.4 mmol) of 4-methyl-2'-hydroxy-1,1'-biphenyl in 2.0 mL of pyridine was treated with 2 mL of acetic anhydride. The reaction mixture was stirred at room temperature for 5 hours. The solvent was removed under vacuum to yield 1.11 g (4.9 mmol, 90%) of the product as an oil. 1H NMR (200 MHz, CDCl3): δ 2.07 (s, 3H), 2.36 (s, 3H), 7.07 (dd; 3, 8 Hz; 1H), 7.15 (d, 8 Hz, 2H), 7.2-7.4 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[S:10][C:11]2[CH:12]=[N:13][CH:14]=[C:15]([F:18])[C:16]=2[N:17]=1.C1C=C(Cl)C=C(C(OO)=[O:27])C=1>C(Cl)Cl>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[S:10][C:11]2[CH:12]=[N+:13]([O-:27])[CH:14]=[C:15]([F:18])[C:16]=2[N:17]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1cncc2sc(-c3c(Cl)cccc3Cl)nc12
Solvent: ClCCl
Product: [O-][n+]1cc(F)c2nc(-c3c(Cl)cccc3Cl)sc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 120.6 %

Procedure:
To an ice-cooled solution of 2-(2,6-dichlorophenyl)-7-fluorothiazolo[5,4-c]pyridine (5.1 g, 17.1 mmol) in DCM (70 mL), was added m-CPBA (11.77 g, 68.2 mmol) over 3 minutes, at 0° C. under argon. The reaction mixture was slowly warmed to room temperature over 1 hour and then stirred at room temperature for 4 hours. The resultant mixture was diluted with DCM (150 mL) and washed with a saturated solution of potassium carbonate (100 mL). Additional amounts of DCM and water were added, followed by MeOH (50 mL). The organic layer was separated, washed with water (300 mL), dried (Na2SO4) and concentrated under reduced pressure. The resultant residue was triturated with water, dried under reduced pressure to afford the title compound as a white solid (6.50 g, quantitative). LCMS (Method F): RT=2.76 min, m/z: 315 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:5]=[CH:6][C:7]=1[N:8]1[C:16](=[O:17])[C:15]2[C:14](O)=[C:13]3[CH:19]=[CH:20][CH:21]=[CH:22][C:12]3=[C:11]([O:23][CH2:24][CH3:25])[C:10]=2[C:9]1=[O:26].C(=O)([O-])[O-].[Na+].[Na+].FC(F)(F)S([O:44][CH2:45][C:46]([F:49])([F:48])[F:47])(=O)=O.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:5]=[CH:6][C:7]=1[N:8]1[C:16](=[O:17])[C:15]2[C:14]([O:44][CH2:45][C:46]([F:49])([F:48])[F:47])=[C:13]3[CH:19]=[CH:20][CH:21]=[CH:22][C:12]3=[C:11]([O:23][CH2:24][CH3:25])[C:10]=2[C:9]1=[O:26]
Reactant: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC)c4ccccc4c3O)C2=O)c(Cl)c1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC(F)(F)F)c4ccccc4c3OCC)C2=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 36.4 %

Procedure:
To a solution of ethyl {3-chloro-4-[4-(ethyloxy)-9-hydroxy-1,3-dioxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl]phenyl}acetate (0.60 g, 1.32 mmol) in DMF (6 ml), was added sodium carbonate (0.280 g, 2.65 mmol) followed by 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.460 g, 1.98 mmol). This was stirred at room temperature for 5 hours. Water was added to the reaction mixture and the resulting brown solid was collected by filtration. This was purified by chromatography on silica gel eluting with 5-60% ethylacetate in hexane to give the title compound (0.258 g, 0.48 mmol). LC/MS: Rt=3.85, [MH]+ 536.
Reaction SMILES: O.[NH2:2][NH2:3].C([O:6][C:7](=O)[C:8]([CH3:12])([CH3:11])[CH2:9][CH3:10])C>>[CH3:11][C:8]([CH3:12])([CH2:9][CH3:10])[C:7]([NH:2][NH2:3])=[O:6]
Reactant: CCOC(=O)C(C)(C)CC
Reactant: NN
Solvent: O
Product: CCC(C)(C)C(=O)NN
Yield: 61.8 %

Procedure:
Reflux a mixture of hydrazine monohydrate (0.97 g, 19.4 mmol) and 2,2-dimethyl-butyric acid ethyl ester (1.4 g, 9.7 mmol) for 72 hours. Purify the crude material by flash chromatography (silica gel) using 5% (7 M ammoniated methanol) in dichloromethane to afford the title compound (0.78 g). 1H NMR (CDCl3) δ 0.81 (t, 3H), 1.13 (s, 6H), 1.53 (q, 2H), 3.88 (s, 2H), 7.05 (bs, 1H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([CH:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[O:19][CH2:18][CH:17]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][O:15]3)[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.[BH4-].[Na+].O>C(O)C>[OH:1][CH:2]1[CH2:3][CH2:4][CH:5]([CH:8]2[CH2:9][CH2:10][CH:11]([CH:14]3[O:15][CH2:16][CH:17]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:18][O:19]3)[CH2:12][CH2:13]2)[CH2:6][CH2:7]1
Reactant: CCCCC1COC(C2CCC(C3CCC(=O)CC3)CC2)OC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCC1COC(C2CCC(C3CCC(O)CC3)CC2)OC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 37.4 %

Procedure:
In 50 ml of ethanol was dissolved 3.2 g (9.9 mmol) of the 2-(4-(4-oxocyclohexyl)cyclohexyl)-5-n-butyl-1,3-dioxane, and the solution was cooled down to 0° C. To this solution was added gradually 0.19 g (5.0 mmol) of sodium borohydride such that the liquid temperature did not exceed 15° C., and the mixture was stirred for 1 hour. Water in an amount of 50 ml was added to the reaction mixture, the product thus formed was extracted with ether, the extract was washed with 1N-hydrochloric acid and water in this turn, and the solvent was distilled off. After the residue was purified by column chromatography on silica gel (eluent: heptane/ethyl acetate=2/1), the solvent was distilled off. The residue was recrystallized from ethanol to give 1.2 g (3.7 mmol) of 2-(4-(4-hydroxy-cyclohexyl)cyclohexyl)-5-n-butyl-1,3-dioxane. Yield of this compound based on 2-(4-(4-oxocyclohexyl)cyclohexyl-5-n-butyl-1,3-dioxane was 37%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[OH:9]O>C(O)(=O)C>[NH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N+:6]=1[O-:9]
Reactant: Nc1ccc(Cl)cn1
Reactant: OO
Solvent: CC(=O)O
Product: Nc1ccc(Cl)c[n+]1[O-]

Procedure:
To a solution of 5-chloropyridin-2-amine (0.500 g, 3.90 mmol) in acetic acid (2.0 mL) was added 50% hydrogen peroxide (2.0 mL). The reaction mass was refluxed for 24 h. The excess of solvent was removed under vacuum to afford 0.450 g of the desired product. 1HNMR (DMSO-d6): δ 6.79 (d, J=8.7 Hz, 1H), 6.93 (s, 2H), 7.21 (d, J=8.7 Hz, 1H), 8.25 (s, 1H); MS [M+H]+: 145.23.
Reaction SMILES: [CH:1]([NH:4][S:5]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[NH2:14])(=[O:7])=[O:6])([CH3:3])[CH3:2].[CH:15]([O-])([O-])OCC>>[CH:1]([N:4]1[CH:15]=[N:14][C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[S:5]1(=[O:7])=[O:6])([CH3:3])[CH3:2]
Reactant: CCOC([O-])[O-]
Reactant: CC(C)NS(=O)(=O)c1cnccc1N
Product: CC(C)N1C=Nc2ccncc2S1(=O)=O
Temperature: 120 °C

Procedure:
A mixture of 0.5 g of N-isopropyl-4- aminopyridine-3-sulfonamide (Preparation 7) and 5 cm3 of ethyl orthoformate is maintained in an open vessel at 120° C. for 4 hours. After concentrating the solution under partial vacuum, the oily residue obtained is triturated with 10 cm3 of ice-cold water. The crystalline precipitate which appears is collected on a filter and washed with water. It is recrystallized from a methanol/water (1/2) mixture.