Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.C([Li])CCC.[Cl:14][SiH2:15]Cl>C1COCC1>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[N:3]1[SiH2:15][Cl:14]
Reactant: Cl[SiH2]Cl
Reactant: C[C@@H]1CCC[C@H](C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1CCCC(C)N1[SiH2]Cl
Temperature: 25 °C
Yield: 26.7 %

Procedure:
To a solution of 7.55 g (66.68 mmol) cis-2,6-dimethylpiperidine in 50 mL of THF at −78° C. was drop-wise added 28.00 mL (70.02 mmol) of a 2.5M solution of n-butyllithium in hexanes. A precipitate evolved and the reaction mixture was warmed to room temperature while stirring. After one hour this mixture was added drop-wise to a solution of 6.74 g (66.68 mmol) dichlorosilane in 30 mL xylenes and 70 mL hexanes at −40° C. and a light gray precipitate formed. The reaction mixture was stirred for 16 hours after which it was decanted from the evolved solid and subjected to distillation at ambient pressure to remove volatiles. 3.16 g of desired product was isolated with a yield of 27%. The product was confirmed by GC/MS analysis as 2,6-Dimethylpiperidinochlorosilane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]2[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:7]=1.C(N(CC)CC)C.[CH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][C:30]=1[C:39](Cl)=[O:40].C(=O)(O)[O-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH3:11][O:10][C:8]([C:6]1[CH:5]=[C:4]([NH:12][C:13]2[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:3]=[C:2]([NH:1][C:39]([C:30]2[CH:31]=[CH:32][C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:29]=2)=[O:40])[CH:7]=1)=[O:9]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: COC(=O)c1cc(N)cc(Nc2ncccc2[N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(NC(=O)c2ccc3ccccc3c2)cc(Nc2ncccc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.5 %

Procedure:
To a mixture of 2-(3-amino-5-methoxycarbonylphenylamino)-3-nitropyridine (550 mg) and triethylamine (0.3 ml) in 1,4-dioxane (10 ml) was added 2-naphthoyl chloride (0.40 g). The mixture was stirred at room temperature for 15 minutes, then poured into a mixture of ethyl acetate and aqueous sodium bicarbonate. The organic phase containing orange solid was washed with water twice and the solid was collected to give 2-[3-methoxycarbonyl-5-(2-naphthoylamino)phenylamino]-3-nitropyridine (730 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][OH:8].Cl[C:10]1[CH:11]=[N:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1>CN(C=O)C>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][O:8][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1
Reactant: FC(F)(F)c1cncc(Cl)c1
Reactant: CN1CCC[C@H]1CO
Solvent: CN(C)C=O
Product: CN1CCC[C@H]1COc1cncc(C(F)(F)F)c1

Procedure:
(S)-(-)-1-Methyl-2-pyrrolidinemethanol (Aldrich Chemical Co., 0.5 g, 4.34 mmol) was reacted with 3-chloro-5-trifluoromethylpyridine according to the method of Example 3, except using DMF in place of THF as solvent and reducing reaction time to less than 2 hours. The solvent was removed, the residue dissolved in ethyl acetate, and the product purified by chromatography over silica gel to give 170 mg of the title compound. MS (DCI/NH3) m/e: 261 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.50 (d, J=0.6 Hz, 1H), 8.49 (d, J=3.0 Hz, 1H), 7.41 (dd, J=0.6 Hz, 1H), 8.49 (d, J=3.0 Hz, 1H), 7.41 (dd, J=0.6, 3.0 Hz, 1H), 4.12-3.96 (m, 2H), 3.21-3.10 (m, 1H), 2.80-2.65 (m, 1H), 2.51 (s, 3H), 2.44 (m, 1H), 2.14-1.73 (m, 4H).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH2:13]([O:15][C:16](=[O:31])[CH:17]([C:28](=O)C)[CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])[CH3:14]>O1CCCC1>[CH2:13]([O:15][C:16](=[O:31])[C:17](=[CH2:28])[CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])[CH3:14]
Reactant: CCOC(=O)C(CCCc1ccccc1Cl)C(C)=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C=C(CCCc1ccccc1Cl)C(=O)OCC
Reaction time: 8 h
Yield: 40.2 %

Procedure:
A mixture of 104 ml of 15% strength butyl-lithium (in hexane), 19 g of diisopropylamine and 400 ml of tetrahydrofuran is stirred together at -78°; 39 g of 5-(2-chlorophenyl)-2-acetylvaleric acid ethyl ester [prepared from 3-(2-chlorophenyl)propyltosylate and ethyl acetoacetate] are added dropwise to the resulting admixture. The mixture thus obtained is stirred for a further 20 minutes. After removing the cooling bath, 19.4 g of paraformaldehyde (anhydrous) are added in portions to the mixture. After stirring the mixture for 1 hour, it is heated under reflux for 5 hours and left to stand overnight. The solid constituents are filtered off, and the filtrate is concentrated in a rotary evaporator. 500 ml of saturated sodium bicarbonate solution are added to the residue, and the mixture is stirred for 30 minutes. Extraction with methylene chloride and evaporation of the solvent yield (after purification by distillation) 14 g of 5-(2-chlorophenyl)-2-methylenevaleric acid ethyl ester of b.p. 95° to 98° C. under 0.005 mm Hg. The title compound is obtained analogously to Example 4a by oxidation.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.Cl.[OH:10][CH:11]1[CH2:14][NH:13][CH2:12]1.[OH-].[Na+]>O>[Cl:8][C:6]1[N:7]=[CH:2][N:3]=[C:4]([N:13]2[CH2:14][CH:11]([OH:10])[CH2:12]2)[CH:5]=1
Reactant: OC1CNC1
Reactant: Clc1ccnc(Cl)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OC1CN(c2cc(Cl)ncn2)C1
Yield: 115.1 %

Procedure:
7.2 g (48.7 mmol) 2,4-dichloropyrimidine are initially introduced into 140 ml water. 5.3 g (48.7 mmol) 3-hydroxyazetidine hydrochloride and 48.7 ml 1 N sodium hydroxide solution are added and the mixture is heated at 90° C. for 72 h (the 2,4-dichloropyrimidine being detectably volatile and precipitating in crystalline form on the condenser). The solvent is removed in vacuo and the residue is dried to give 10.4 g of the crude product, which is reacted without further purification.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:44]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][C:52]=2[NH2:54])[CH:47]=[CH:46][CH:45]=1>CN(C=O)C.C([O-])(O)=O.[Na+].O>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:54][C:52]2[CH:51]=[CH:50][CH:49]=[C:48]3[C:53]=2[N:44]=[CH:45][CH:46]=[CH:47]3)=[O:8])=[CH:9][CH:10]=1
Reactant: Nc1cccc2cccnc12
Reactant: O=C(O)c1ccc(I)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc2cccnc12)c1ccc(I)cc1
Yield: 64.4 %

Procedure:
A mixture of 4-iodobenzoic acid (commercially available from Sigma-Aldrich, Milwaukee, Wis.) (9.26 g, 37.3 mmol), DIEA (13.05 mL, 74.7 mmol), HATU (7.10 g, 18.67 mmol) and quinolin-8-amine (commercially available from Sigma-Aldrich, Milwaukee, Wis.) (7 g, 48.6 mmol) in DMF (124 mL) was stirred under nitrogen overnight at room temperature. The reaction mixture was diluted with saturated NaHCO3 (100 mL) and water (300 mL) yielding a yellow/brown precipitate which was filtered, washed with water (100 mL) and dried on high vacuum to obtain 4-iodo-N-(quinolin-8-yl)benzamide (9 g, 24.05 mmol, 64.4% yield) as a yellow brown solid. 1H NMR (400 MHz, DMSO-d6) δ=10.65 (s, 1H), 8.98 (dd, J=1.6, 4.3 Hz, 1H), 8.70 (dd, J=1.4, 7.6 Hz, 1H), 8.47 (dd, J=1.7, 8.3 Hz, 1H), 8.03-7.98 (m, 2H), 7.83-7.79 (m, 2H), 7.76 (dd, J=1.3, 8.2 Hz, 1H), 7.71-7.62 (m, 2H).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([S:20]([N:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=2)[N:8]=1)=O.[F:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[NH:35]N>>[F:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[N:35]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:15]=[C:16]([S:20]([N:23]([CH3:24])[CH3:25])(=[O:21])=[O:22])[CH:17]=[CH:18][CH:19]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)N(C)C)c2)ccc1=O
Reactant: NNc1cc(F)ccc1F
Product: CN(C)S(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3cc(F)ccc3F)n2)c1

Procedure:
The product was obtained starting from 3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-N,N-dimethyl-benzenesulfonamide (A-12) and 2,5-difluoro-phenylhydrazine according to the method described for example 91. MS: M=458.2 (M+H)+
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:9]2[N:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11]([C@@H:13]([NH2:15])[CH3:14])=[N:12][C:8]=2[CH:7]=[CH:6][C:5]=1[F:22].Cl[C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][N:28]2[CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:3][C:4]1[C:9]2[N:10]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:11]([C@@H:13]([NH:15][C:24]3[N:32]=[CH:31][N:30]=[C:29]4[C:25]=3[N:26]=[CH:27][N:28]4[CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)[CH3:14])=[N:12][C:8]=2[CH:7]=[CH:6][C:5]=1[F:22]
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)c1nc2ccc(F)c(Cl)c2n1-c1ccccc1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c(Cl)c2n1-c1ccccc1
Temperature: 90 °C
Yield: 82.3 %

Procedure:
A mixture of (S)-1-(7-chloro-6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride (150 mg, 0.41 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (118 mg, 0.49 mmol) and DIPEA (280 μL, 1.65 mmol) in n-butanol (3 mL) was heated at 90° C. in a sealed vial for 18 h. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% MeOH in EtOAc) to afford the title compound (166 mg, 82%). LCMS (Method B): RT 3.57 min [M+H]+ 492.0/493.8.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:10][C:9](=[O:11])[NH:8][C:5]2=[N:6][CH:7]=1.[C:12]([O:15][CH:16](OCC)OCC)(=O)[CH3:13]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:16][O:15][CH2:12][CH3:13])[C:9](=[O:11])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C1Cc2cc(Br)cnc2N1
Reactant: CCOC(OCC)OC(C)=O
Product: CCOC=C1C(=O)Nc2ncc(Br)cc21

Procedure:
This compound was synthesized from 5-bromo-1H-pyrrolo[2,3-b]pyridin-2-one and and diethoxymethyl acetate according to Procedure A. 1H NMR 400 MHz (DMSO-d6): δ 11.02 (s, 1H); 8.07 (s, 1H); 7.88 (s, 1H); 7.71 (s, 1H); 4.40 (m, 2H); 1.34 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][N+:5]([O-])=[C:4]([CH3:10])[CH:3]=1.C(OP([C:19]#[N:20])(OCC)=O)C.C(N(CC)CC)C>CC#N>[Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[N:5]=[C:6]([C:19]#[N:20])[C:7]=1[CH3:8]
Reactant: Cc1c[n+]([O-])c(C)cc1Br
Reactant: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(Br)c(C)c(C#N)n1
Temperature: 80 °C
Yield: 69.8 %

Procedure:
To a Smith microwave vial was added 4-bromo-2,5-dimethyl-1-oxido-pyridin-1-ium (which may be prepared as described in Description 136), (300 mg, 1.48 mmol), diethoxyphosphorylformonitrile (0.9 mL, 5.94 mmol) and triethylamine (0.41 mL, 2.97 mmol) in anhydrous MeCN (1 mL). The reaction mixture was heated by microwave at 80° C. for 1 h. The reaction mixture was evaporated and the crude dark oil was purified on silica gel chromatography (10 g SiO2) eluting with ethyl acetate in iso-hexane (0-80%). Evaporation of desired fractions gave 4-bromo-3,6-dimethyl-pyridine-2-carbonitrile (D137) (218 mg, 1.0329 mmol, 69.6% yield) as colourless solid;
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:12][C:13]([O:15][CH3:16])=[O:14].C(=O)([O-])[O-].[K+].[K+]>[I-].[K+].CC(C)=O>[CH3:16][O:15][C:13]([CH2:12][O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1)=[O:14]
Reactant: COC(=O)CCl
Reactant: Oc1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc2cc[nH]c2c1
Temperature: 25 °C
Yield: 63.3 %

Procedure:
6-Hydroxyindole (2.9 g), methyl chloroacetate (2.7 g), potassium carbonate (5.5 g) and potassium iodide (0.2 g) are added to acetone (100 ml), and the mixture is refluxed for 8 hours. The reaction mixture is cooled to room temperature, and the insoluble materials are removed by filtration. The filtrate is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform) to give 6-methoxycarbonylmethoxyindole (2.83 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13](=[O:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:11][N:10]([CH3:21])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC1=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CC(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13](=[O:14])[CH:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:11][N:10]([CH3:21])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1cc(-c2ccccc2)c(=O)c(-c2cccc(Br)c2)c1
Agent: O=c1cccc[nH]1
Agent: [Al+3]
Agent: [H-]
Solvent: CC(C)=O
Product: CN1CC(c2ccccc2)C(=O)C(c2cccc(Br)c2)C1

Procedure:
A 10 g. portion of 3-(3-bromophenyl)-1-methyl-5-phenyl-4(1H)-pyridinone was made from 22 g. of the corresponding 2-propanone as described in Examples 1-3. The pyridinone was reduced with 2 g. of lithium aluminum hydride as described in the examples above, and the reaction mixture was chromatographed as described above with benzene-ethyl acetate mixtures. The combined yield of the compounds of Examples 13 and 13a was 4 g., molecular weight 341 by mass spectroscopy. The yield of the compound of Example 14 was 0.5 g., molecular weight by mass spectroscopy 343.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:5]=1[CH:6]=[O:7])([OH:3])=[O:2].S(OC)(O[CH3:17])(=O)=O>C(Cl)Cl>[C:1]([C:4]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:5]=1[CH:6]=[O:7])([O:3][CH3:17])=[O:2]
Reactant: COS(=O)(=O)OC
Reactant: O=Cc1cc(F)ccc1C(=O)O
Solvent: ClCCl
Product: COC(=O)c1ccc(F)cc1C=O
Temperature: 25 °C
Yield: 68.6 %

Procedure:
A stirred mixture of 3.4 g (0.02 mole) 2-carboxy-5-fluorobenzaldehyde (the product of Example 6) and 5.0 g [3.75 ml (0.04 mole)] dimethyl sulfate in methylene chloride was heated to reflux. The heating mantle was removed; and triethylamine, 4.15 g [5.7 ml (0.04 mole)] was added dropwise at a rate which maintained a brisk reflux. After the addition was complete, the reaction mixture was allowed to cool and was stirred at room temperature over the weekend. The reaction mixture was poured into water; the layers were separated. The methylene chloride layer was washed with a sodium bicarbonate solution, dried and evaporated to give 2.5 g of the above-identified product as a yellow oil.
Reaction SMILES: NC1C=CSN=1.C([NH:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]1[CH:27]=[CH:26][S:25][N:24]=1)=[S:17])(=O)C1C=CC=CC=1>>[S:25]1[CH:26]=[CH:27][C:23]([NH:22][CH2:21][CH2:20][CH2:19][NH:18][C:16]([NH2:15])=[S:17])=[N:24]1
Reactant: O=C(NC(=S)NCCCNc1ccsn1)c1ccccc1
Agent: Nc1ccsn1
Product: NC(=S)NCCCNc1ccsn1

Procedure:
By the same procedure, using 3-aminoisothiazole, N-benzoyl-N'-[3-(3-isothiazolylamino)propyl]thiourea is prepared and the benzoyl group is removed to give N-[3-(3-isothiazolylamino)propyl]thiourea.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>CN(C)C=O.O>[CH2:37]([O:36][C:34](=[O:35])[CH2:33][O:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:4]([CH2:5][N:6]2[C:14]3[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=3)[CH:8]=[C:7]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:3]=1)[CH3:38]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc2c(c1)cc(-c1ccccc1)n2Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1cccc(Cn2c(-c3ccccc3)cc3cc(OC)ccc32)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(3-hydroxybenzyl)-5-methoxy-2-phenylindole (108 mg) in N,N-dimethylformamide (1.3 mL) was added potassium carbonate (68.2 mg) at room temperature. Then ethyl bromoacetate (0.047 mL) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (129 mg).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[C:10]1([CH:16]2[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)(Cl)(Cl)Cl>[N+:1]([C:13]1[CH:14]=[CH:15][C:10]([CH:16]2[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17]2)=[CH:11][CH:12]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)C1CCC(c2ccccc2)C1
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C1CCC(c2ccc([N+](=O)[O-])cc2)C1
Temperature: 7.5 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
A mixture of 65% nitric acid (0.95 mL) and 95% sulphuric acid (1.2 mL) in carbon tetrachloride (2.5 mL) was added dropwise to a solution of methyl 3-phenylcyclopentanecarboxylate (Journal of Organic Chemistry, 1988, 53(17), 4021) (1 g, 4.9 mmol) and the mixture was stirred at 5-10° C. for 2 h. Ice/water (30 mL) was added and the mixture was extracted with DCM (2×50 mL). The extracts were combined, washed with water and dried. The residue was adsorbed onto silica and purified by chromatography eluting with 0-30% EtOAc in hexane to give the title compound (782 mg, 64%) as an oil; 1H NMR δ3.90 (3H, s), 7.94-7.97 (2H, m), 8.03-8.06 (2H, m), 8.09-8.12 (2H, m), 8.33-8.36 (2H, m).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:19]=[CH:18][C:7]2[C:8](=[O:17])[C:9]3[C:14]([CH2:15][O:16][C:6]=2[CH:5]=1)=[CH:13][CH:12]=[CH:11][N:10]=3>C(O)C>[Cl:3][C:4]1[CH:19]=[CH:18][C:7]2[CH:8]([OH:17])[C:9]3[C:14]([CH2:15][O:16][C:6]=2[CH:5]=1)=[CH:13][CH:12]=[CH:11][N:10]=3
Reactant: O=C1c2ccc(Cl)cc2OCc2cccnc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC1c2ccc(Cl)cc2OCc2cccnc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.3 %

Procedure:
Add sodium borohydride (0.96 g, 25.4 mmole) to 8-chloro[1]benzoxepino[4,3-b]pyridin-11-one (10.00 g, 40.7 mmole) in ethanol (100 mL). Stir for 18 hours at room temperature. Add water (100 mL), and concentrate in vacuo. Add additional water (100 mL), and extract with dichloromethane. Wash the organic solution with saturated NaCl, dry with MgSO4, filter, and concentrate in vacuo. Dissolve the oil in dichloromethane, and chromatograph on silica gel, eluting with 50% ethyl acetate in hexane. Combine the appropriate fractions, and concentrate under reduced pressure to give a white solid (8.50 g, 84% yield): mp 105°-108° C.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:15]([CH:16]([CH3:18])[CH3:17])=[CH:14][C:13]([CH:19]([CH3:21])[CH3:20])=[N:12]3)[CH2:7][CH2:6]2)[O:4]CC1.Cl>CC(C)=O>[CH:19]([C:13]1[CH:14]=[C:15]([CH:16]([CH3:18])[CH3:17])[N:11]([CH:8]2[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]2)[N:12]=1)([CH3:20])[CH3:21]
Reactant: CC(C)c1cc(C(C)C)n(C2CCC3(CC2)OCCO3)n1
Agent: Cl
Solvent: CC(C)=O
Product: CC(C)c1cc(C(C)C)n(C2CCC(=O)CC2)n1

Procedure:
To a solution of 1-(1,4-dioxa-spiro[4.5]dec-8-yl)-3,5-diisopropyl-1H-pyrazole (40 mg) in acetone (20 ml) was added HCl (20 mL, 2M aq). The reaction was heated to reflux overnight. The reaction was cooled, concentrated and extracted with EtOAc. The organic fractions were washed with water, saturated NaHCO3 and dried over Na2SO4. The solution was concentrated and used without further purification (Yield 30.6 mg). LC-MS (C15H24N2O calculated 248) m/z 249 (M+H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[C:13]1[CH:17]=[CH:16][NH:15][CH:14]=1.[Cl:18][C:19]1[N:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>C(Cl)Cl.C(OCC)(=O)C>[Cl:18][C:19]1[C:20]([C:21]([C:14]2[NH:15][CH:16]=[CH:17][C:13]=2[C:7]2[C:6]([Cl:5])=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:12])=[O:22])=[CH:24][CH:25]=[CH:26][N:27]=1
Reactant: Clc1cccc(Cl)c1-c1cc[nH]c1
Reactant: O=C(Cl)c1cccnc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(c1cccnc1Cl)c1[nH]ccc1-c1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 4.8 %

Procedure:
Aluminum chloride (1.4 g, 10.5 mmol) was added to a mixture of 3-(2,6-dichloro-phenyl)-1H-pyrrole (2 g, prepared according to JOC, 62, 1997, 2650) and 2-chloronicotinoyl chloride (1.8 g, 10.5 mmol) in DCM (55 mL) at 0° C. The mixture was stirred at 0° C. for 30 mins and at room temperature for 1.5 hours. The reaction was diluted with ethyl acetate and washed with brine, 2N NaOH, brine, dried and concentrated. The residue was purified on silica gel column to give 160 mg of (2-chloro-pyridin-3-yl)-[3-(2,6-dichloro-phenyl)-1H-pyrrol-2-yl]-methanone.
Reaction SMILES: C1C2C(=CC=CC=2)C=CC=1C=CC(=O)CC(OC)=O.COC(OC)N(C)C.C(N)C.[CH2:31]([NH:33][CH:34]=[C:35]([C:40](=[O:53])[CH:41]=[CH:42][C:43]1[CH:52]=[CH:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=1)[C:36]([O:38]C)=[O:37])[CH3:32]>C1(C)C=CC=CC=1>[CH2:31]([N:33]1[C:42]([C:43]2[CH:52]=[CH:51][C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH:44]=2)=[CH:41][C:40](=[O:53])[C:35]([C:36]([OH:38])=[O:37])=[CH:34]1)[CH3:32]
Reactant: CCNC=C(C(=O)C=Cc1ccc2ccccc2c1)C(=O)OC
Agent: CCN
Agent: COC(=O)CC(=O)C=Cc1ccc2ccccc2c1
Agent: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CCn1cc(C(=O)O)c(=O)cc1-c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
9 G. of methyl 5-(2-naphthyl)-3-oxo-4-pentenoate and 4.7 g. of dimethylformamide dimethylacetal were dissolved in 100 ml. of toluene and stirred at 60° C. for 22 hours. After cooling, the reaction mixture was evaporated. There were obtained about 10 g. of a dark red, viscous oil, which was treated with a solution of 100 g. of ethylamine in 1 l. of toluene. The reaction mixture was stirred at room temperature for 20 hours, evaporated and the crude product was purified by column chromatography [silica gel, methylene chloride/methanol (19:1, v/v)]. After recrystallization from ether/pentane, there were obtained 6.0 g. (55%) of methyl 2-[(ethylamino)-methylene]-5-(2-naphthyl)-3-oxo-4-pentenoate in the form of light yellowish crystals, mp 80°-82° C.
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[C:48]([N:85]2[CH2:90][CH2:89][N:88]([CH2:91][C@@H:92]([OH:94])[CH3:93])[CH2:87][CH2:86]2)=[N:49][CH:50]=[C:51]([C:53]2[CH:54]=[C:55]3[C:61]([C:62]4[CH:63]=[N:64][N:65]([CH2:67][C:68]5[CH:73]=[CH:72][CH:71]=[C:70]([F:74])[CH:69]=5)[CH:66]=4)=[CH:60][N:59](S(C4C=CC(C)=CC=4)(=O)=O)[C:56]3=[N:57][CH:58]=2)[CH:52]=1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[C:48]([N:85]2[CH2:90][CH2:89][N:88]([CH2:91][C@@H:92]([OH:94])[CH3:93])[CH2:87][CH2:86]2)=[N:49][CH:50]=[C:51]([C:53]2[CH:54]=[C:55]3[C:61]([C:62]4[CH:63]=[N:64][N:65]([CH2:67][C:68]5[CH:73]=[CH:72][CH:71]=[C:70]([F:74])[CH:69]=5)[CH:66]=4)=[CH:60][NH:59][C:56]3=[N:57][CH:58]=2)[CH:52]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cnc(N5CCN(C[C@H](C)O)CC5)c(F)c4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](O)CN1CCN(c2ncc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cc2F)CC1
Yield: 54.6 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, (S)-1-(4-(3-fluoro-5-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazin-1-yl) propan-2-ol (134 mg, 0.196 mmol) was hydrolyzed with lithium hydroxide (82 mg, 1.964 mmol) in THF/methanol/water (12/4/4 mL) to yield 56 mg (54.6% yield) after purification by prep TLC using 8% methanol in chloroform as eluent. 1H NMR (CD3OD, 300 MHz): δ 8.449-8.442 (d, 1H), 8.35-8.32 (m, 2H), 8.23 (s, 1H), 7.94 (s, 1H), 7.82-7.77 (dd, 1H), 7.64 (s, 1H), 7.40-7.33 (q, 1H), 7.12-7.00 (m, 3H), 5.43 (s, 2H), 4.05-3.95 (m, 1H), 3.56-3.32 (t, 4H), 2.77-2.62 (m, 4H), 2.47-2.33 (m, 2H), 1.18-1.16 (d, 3H). MS: m/z=530.3 (M+1), HPLC: 95.33% in method A.