Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:13])(=O)[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH3:29][C:30]([NH2:34])([CH3:33])[CH2:31][OH:32]>C(Cl)Cl>[OH:32][CH2:31][C:30]([NH:34][C:1]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)=[O:13])([CH3:33])[CH3:29]
Reactant: CC(C)(N)CO
Reactant: O=C(O)c1ccc2ccccc2n1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(CO)NC(=O)c1ccc2ccccc2n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91 %

Procedure:
To an oven dried 250 mL round bottomed flask was weighed quinaldic acid (866 mg, 5.0 mmol). A magnetic stir bar was added and the flask was put under N2 atmosphere. The flask was charged with DCM (50 mL) and cooled to 0° C. in an ice bath. The flask was charged with N-methyl morpholine (720 μL, 7.5 mmol) and isobutlychloroformate (752 μL, 5.75 mmol) via syringe addition. The reaction was allowed to stir at 0° C. for 10 min until the solution became cloudy. At which point 2-methyl-2-aminopropanol (550 uL, 5.75 mmol) was added slowly to the flask via syringe. The reaction mixture was allowed to slowly warm to room temperature. The reaction was quenched after 2 h with 1M HCl solution (30 mL) and transferred to a separatory funnel with DCM (50 mL). The layers were partitioned and the organic phase was washed with H2O (2×30 mL) and brine (1×40 mL). After drying over Na2SO4 and filtration, the mixture was concentrated under reduced pressure. The crude mixture was purified by flash chromatography eluting with a 1:1 mixture of EtOAc and hexanes to afford N-(1-hydroxy-2-methylpropan-2-yl)quinoline-2-carboxamide as a colorless oil in 91% yield (1.112 g, 4.55 mmol) according to the following reaction
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[CH2:8]([C@@:15]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])([CH2:20][CH:21]=[CH2:22])[CH2:16][C:17]([OH:19])=[O:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCCCCC.CO>[CH2:8]([C@@:15]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])([CH2:20][CH:21]=[CH2:22])[CH2:16][C:17]([O:19][CH3:1])=[O:18])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C=CC[C@@](CC(=O)O)(Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCCCCC
Product: C=CC[C@@](CC(=O)OC)(Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A total of 5 ml of a 2 molar solution of trimethylsilyldiazomethane in hexane is added in portions to a solution of 490 mg of (S)-2-benzyl-2-tert-butoxycarbonylaminopent-4-enecarboxylic acid in 8 ml of methanol while stirring at room temperature. After the reaction is complete, the excess trimethylsilyldiazomethane is destroyed by dropwise addition of glacial acetic acid, and the volatile constituents are stripped off in a rotary evaporator at 40° C. The residue is purified on a column (silica gel, mobile phase: methylene chloride:methanol=95:5).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.Br[CH2:17][C:18]([OH:20])=[O:19].Cl>O.CN(C=O)C>[C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([O:3][CH2:17][C:18]([OH:20])=[O:19])=[CH:9][CH:8]=1
Reactant: O=C(O)CBr
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)COc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
Sodium hydride (60% dispersion in oil; 0.8 g) was added portionwise to a DMF (10 ml) solution of 4-hydroxybiphenyl (1.7 g) under ice-cooling. The reaction mixture was stirred at room temperature for 30 minutes, to which was added bromoacetic acid (1.4 g). The reaction mixture was further stirred at room temperature for 18 hours, which was poured into water. 2N hydrochloric acid was added to the mixture to adjust the pH to 4, which was extracted with ethyl acetate. The organic layer was washed with water, then dried and concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/1), and the crude crystals were recrystallized from IPE to obtain the entitled compound (1.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[NH:7][C:6]=2[CH:16]=1.[Cl:17][CH2:18][CH2:19][C:20](Cl)=[O:21].[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:17][CH2:18][CH2:19][C:20]([N:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH2:10][CH2:11][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:16][C:6]1=2)=[O:21]
Reactant: Clc1ccc2c(c1)Nc1ccccc1CC2
Reactant: O=C(Cl)CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C(CCCl)N1c2ccccc2CCc2ccc(Cl)cc21
Temperature: 95 °C
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
3-Chloro-10,11-dihydro-5H-dibenz[b,f]azepine (3.82 g, 16.6 mmol) was dissolved in toluene (20 ml). A solution of 3-chloropropionylchloride (2.53 g, 19.9 mmol) in toluene was added dropwise, and the resulting mixture was heated to 95° C. and stirred at that temperature for 30 minutes. The mixture was stirred overnight at room temperature. Further 3-chloropropionylchloride (2.53 g, 19.9 mmol) was added and the mixture was stirred at 95° C. for 1.5 h. After cooling, 0.2 M sodium hydroxide (10 ml) was added, and the phases were separated. The organic phase was diluted with more toluene (50 ml); and washed with first 0.2 M sodium hydroxide (6×10 ml) and then with more 0.2 M sodium hydroxide (3×20 ml) until the aqueous phase was alkaline. The organic phase was washed with water (3×15 ml), brine (25 ml), and dried (MgSO4). Evaporation in vacuo afforded 5.23 g (98%) of crude 3-chloro-1-(3-chloro-10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propanone as an oil. This was further purified by addition of a mixture of heptane and ethyl acetate (1:1). This afforded 3.14 g (59%) of the product as a solid.
Reaction SMILES: ClC1C(Cl)=C(C(=O)C(=C)CC)C=CC=1OCC(O)=O.[Cl:20][C:21]1[C:34]([Cl:35])=[C:33]([C:36](=[O:41])[C:37](=[CH2:40])[CH2:38][CH3:39])[CH:32]=[CH:31][C:22]=1[O:23][C:24]1([C:28](O)=[O:29])[CH2:27][CH2:26][CH2:25]1.NCC(O)=O.[NH2:47][CH2:48][CH2:49][C:50]([OH:52])=[O:51]>>[Cl:20][C:21]1[C:34]([Cl:35])=[C:33]([C:36](=[O:41])[C:37](=[CH2:40])[CH2:38][CH3:39])[CH:32]=[CH:31][C:22]=1[O:23][C:24]1([C:28]([NH:47][CH2:48][CH2:49][C:50]([OH:52])=[O:51])=[O:29])[CH2:27][CH2:26][CH2:25]1
Reactant: C=C(CC)C(=O)c1ccc(OC2(C(=O)O)CCC2)c(Cl)c1Cl
Reactant: NCCC(=O)O
Agent: C=C(CC)C(=O)c1ccc(OCC(=O)O)c(Cl)c1Cl
Agent: NCC(=O)O
Product: C=C(CC)C(=O)c1ccc(OC2(C(=O)NCCC(=O)O)CCC2)c(Cl)c1Cl

Procedure:
By carrying out the reaction essentially as described in Example 9, except that the [2,3-dichloro-4-(2-methylenebutyryl)phenoxy]acetic acid is replaced by an equimolar quantity of 1-[2,3-dichloro-4-(2-methylenebutyryl)phenoxy]cyclobutane-1-carboxylic acid and the glycine is replaced by an equimolar quantity of β-alanine, there is obtained N-{1-[2,3-dichloro-4-(2-methylenebutyryl)phenoxy]cyclobutane-1-carbonyl}3-aminopropionic acid.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[S:11]([O-:15])([O-:14])(=[O:13])=[S:12]>>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([N:2]([CH3:10])[CH3:1])=[CH:4][C:5]=1[S:12][S:11](=[O:14])(=[O:13])[OH:15]
Reactant: CN(C)c1ccc(N)cc1
Reactant: O=S([O-])([O-])=S
Product: CN(C)c1ccc(N)c(SS(=O)(=O)O)c1

Procedure:
In one embodiment, an N,N-dimethyl-1,4-diamino-benzene, 3′, is oxidized in the presence of a thiosulfate to give a thiosulfuric acid S-{2-(amino)-5-(dimethylamino)-phenyl} ester, 4′, as illustrated in the following scheme:
Reaction SMILES: [C:1](=[O:16])([O:9]C1C=CC=CC=1)[O:2]C1C=CC=CC=1.[C:17](=[N:25][OH:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:18]>C1(C)C=CC=CC=1>[C:1](=[O:2])([OH:16])[OH:9].[C:17](=[N:25][OH:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:18]
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Agent: CC(=NO)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(O)O

Procedure:
A solution of diphenyl carbonate (5.35g/0.025 mole) and acetophenone oxime (13.5g/0.1 mole) in 25 ml toluene was placed in a 250 ml 3-neck flask fitted with a thermometer and reflux condenser. The mixture was heated to about 116° C. for one (1) hour under nitrogen. Toluene and all low-boiling components were removed under vacuum (70°-75° C. at 2 mm Hg). The syrup gave a solid upon standing. The solid was filtered and washed with 15 ml petroleum ether. The crude product was then dissolved in 20 ml ether and hexane was added to turbidity. After filtering and drying 7.2 g of colorless crystals appeared (m.p. 110°-112° C.). Yield: 97.3%. Confirmation of the compound as acetophenone oxime carbonate was obtained through IR and NMR spectral analyses.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[C:8]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[CH:9]=[CH:10][CH:11]=2)[C:6]([O:22][C@@H:23]2[O:49][C@H:48]([CH2:50][O:51]C(=O)C(C)(C)C)[C@@H:40]([O:41]C(=O)C(C)(C)C)[C@H:32]([O:33]C(=O)C(C)(C)C)[C@H:24]2[O:25]C(=O)C(C)(C)C)=[N:5]1.O.O.[OH-].[Li+]>CO>[C@@H:23]1([O:22][C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][C:8]=3[CH2:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=3)[N:4]([CH2:3][CH2:2][OH:1])[N:5]=2)[O:49][C@H:48]([CH2:50][OH:51])[C@@H:40]([OH:41])[C@H:32]([OH:33])[C@H:24]1[OH:25]
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2nn(CCO)c3cccc(CCc4ccc(O)cc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: OCCn1nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c2c(CCc3ccc(O)cc3)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
To a solution of 1-(2-hydroxyethyl)-4-[2-(4-hydroxy-phenyl)ethyl]-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-indazole (0.31 g) in methanol (6 mL) were added water (0.6 mL) and lithium hydroxide monohydrate (0.16 g), and the mixture was stirred at room temperature for 8 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water. To the solution was added acetic acid (0.45 mL), and the resulting mixture was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (0.14 g)
Reaction SMILES: C(=O)=O.C(Cl)(Cl)(Cl)Cl.[CH:9]1[C:17]2[C:16]3[C:18]([C:26]4[C:27]([F:34])=[C:28]([OH:33])[C:29]([F:32])=[CH:30][CH:31]=4)=[C:19]4[C:24](=[CH:25][C:15]=3[S:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)[CH:23]=[CH:22][CH:21]=[CH:20]4.[Br:35]Br>C(Cl)Cl>[Br:35][C:25]1[C:15]2[S:14][C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:17]=3[C:16]=2[C:18]([C:26]2[C:27]([F:34])=[C:28]([OH:33])[C:29]([F:32])=[CH:30][CH:31]=2)=[C:19]2[C:24]=1[CH:23]=[CH:22][CH:21]=[CH:20]2
Reactant: BrBr
Reactant: Oc1c(F)ccc(-c2c3ccccc3cc3sc4ccccc4c23)c1F
Agent: O=C=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: Oc1c(F)ccc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)c1F
Reaction time: 0.47 h

Procedure:
To a cold (-23° C. dry ice/carbon tetrachloride bath) stirred solution of 3-(benzo [b]naphtho[2,3-d]thiophen-11-yl)-2,6 difluoro-phenol (1.38 g, 3.81 mmol) in methylene chloride (35 mL) was added a solution of bromine (0.22 mL, 4.19 mmol) in methylene chloride (7 mL) dropwise, very slowly, over a period of 28 minutes. After stirring an additional 1.5 h the reaction was quenched with dilute sodium bisulfite and the organics were extracted with ether. The extract was concentrated to give a yellow solid (1.64 g, 98% crude yield). A small portion was taken up in methylene chloride and combined with silica gel. The solvent was removed and the adsorbate was flash chromatographed (85/15 petroleum ether/ethyl acetate) to give the title compound as an off white solid: mp 180-182° C.; NMR (400 MHz, DMSO-d6); δ10.64 (s, 1 H), 8.30 (d, J=9 Hz, 1 H), 8.09 (d, J=9 Hz, 1 H), 7.82-7.78 (m, 1 H), 7.64-7.51 (m, 3 H), 7.42-7.37 (m, 1 H), 7.33-7.29 (m, 1 H), 6.96-6.91 (m, 1 H), 6.81-6.78 (m, 1 H); MS (FAB): (M-H): one bromine pattern observed; 439/441 (8%); Anal. Calc. for C22H11BrF2OS: C, 59.88, H, 2.51, N, 0.00%. Found: C, 59.82, H, 2.59, N, 0.06.
Reaction SMILES: F[B-](F)(F)F.C([O+](CC)CC)C.[C:13]([O:17][C:18](=[O:25])[NH:19][C@H:20]([C:22](=O)[NH2:23])[CH3:21])([CH3:16])([CH3:15])[CH3:14].[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:33]1[C:38](N)=[CH:37][CH:36]=[CH:35][N:34]=1>C1COCC1.C(O)C>[C:13]([O:17][C:18](=[O:25])[NH:19][C@H:20]([C:22]1[N:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[C:27]2=[N:26][CH:31]=[CH:30][CH:29]=[C:28]2[N:23]=1)[CH3:21])([CH3:16])([CH3:15])[CH3:14]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(N)=O
Reactant: Nc1cccnc1Nc1ccccn1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2cccnc2n1-c1ccccn1
Yield: 98.2 %

Procedure:
Triethyloxonium tetrafluoroborate (1.08 g, 5.66 mmol) was added to a solution of ((S)-1-carbamoylethyl)carbamic acid tert-butyl ester (1.00 g, 5.33 mmol) in THF (15 mL) at 20° C. under nitrogen and the resultant mixture stirred for 2 h then concentrated in vacuo. A solution of N2-pyridin-2-yl-pyridine-2,3-diamine (0.62 g, 3.33 mmol) in ethanol (15 mL) was added to the residue and the resultant solution stirred at 75° C. for 16 h. The reaction mixture was concentrated in vacuo and the residue partitioned between DCM (3×30 mL) and saturated aqueous NaHCO3 (30 mL). The combined DCM extracts were dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by chromatography (SiO2 0-5% (2M ammonia in methanol) in DCM) to give the title compound as an oil (1.11 g, 98%). LCMS (method H): Rt 2.73 min, [M+H]+ 340.
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[Cl:16][CH2:17][CH2:18]O.N1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[F:5][C:4]([F:7])([F:6])[S:1]([O:8][CH2:18][CH2:17][Cl:16])(=[O:3])=[O:2]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: OCCCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: O=S(=O)(OCCCl)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of triflic anhydride (2.0 mL, 11.9 mmol) in CCl4 (10 mL) at 0° C. was treated with a solution of 2-chloroethanol (0.8 mL, 11.9 mmol) and pyridine (0.96 mL, 11.9 mmol) in CCl4 (6.0 mL) which was pre-cooled to 0° C. The reaction mixture was stirred at 0° C. for 45 minutes and then filtered through a pad of Na2SO4. The filtrate was concentrated and used immediately in the next step.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:21])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2].[C:22](OC(=O)C)(=[O:24])[CH3:23].[C:29](Cl)(=[O:31])[CH3:30]>N1C=CC=CC=1>[C:22]([O:20][C:15]1[CH2:14][CH2:13][C@H:12]2[C:17](=[CH:18][CH2:19][C@H:8]3[C@H:7]4[C@@:3]([CH2:1][CH3:2])([CH:4]([O:21][C:29](=[O:31])[CH3:30])[CH2:5][CH2:6]4)[CH2:11][CH2:10][C@@H:9]32)[CH:16]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC[C@]12CC[C@H]3[C@@H](CC=C4C=C(OC(C)=O)CC[C@@H]43)[C@@H]1CCC2OC(C)=O

Procedure:
Reflux dl-13-ethyl-17β-hydroxygon-4-en-3-one (3.0 g) with acetic anhydride (45 cc), acetyl chloride (24 cc) and pyridine (2.4 cc) for 3 hours. Take to dryness under reduced pressure and partition the residue between benzene-ether and water. Triturate the crude product with hot ether to obtain dl-3,17-diacetoxy-13-ethylgona-3,5-diene (3.125 g), m.p. 148°-156°; λmax. KBr 5.68, 5.78, 6.0, 6.11 μ; λmax. EtOH 238 mμ (ε19,500).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:21][CH2:20][C:14]2([C:18](=[O:19])[NH:17][CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:10])=[O:9].Br[C:23]1[CH:28]=[CH:27][C:26]([C:29]2([OH:33])[CH2:32][O:31][CH2:30]2)=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:21][CH2:20][C:14]2([C:18](=[O:19])[N:17]([C:23]3[CH:24]=[CH:25][C:26]([C:29]4([OH:33])[CH2:32][O:31][CH2:30]4)=[CH:27][CH:28]=3)[CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:9])=[O:10]
Reactant: O=C1NCCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2
Reactant: OC1(c2ccc(Br)cc2)COC1
Product: O=C1N(c2ccc(C3(O)COC3)cc2)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2

Procedure:
The title compound was prepared in analogy to example 148 step F) from 8-(2-chloro-benzenesulfonyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 148 step E or example 179 step A for an alternative synthesis) and 3-(4-bromo-phenyl)-oxetan-3-ol (prepared as described in WO 2008/156726). White solid. MS (ESI): 477.1 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([OH:17])(=O)=[O:15])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.CN(C=O)C.S(Cl)([Cl:25])=O>C(#N)C>[ClH:25].[N:1]1[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([Cl:25])(=[O:17])=[O:15])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)(O)c1ccc(Oc2ccncc2)cc1
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cl
Product: O=S(=O)(Cl)c1ccc(Oc2ccncc2)cc1
Yield: 100 %

Procedure:
Part C: A slurry of the sulfonic acid part B (420 g, 1.5 mol) in acetonitrile (2500 mL) and DMF (40 mL) was warmed to 75° C. under a nitrogen atmosphere and treated with thionyl chloride (243 mL, 3.3 mol) added dropwise over 3 hours. After stirring for one-half hour, the standard work-up procedure afforded 483 grams (100%) of the desired 4-[(pyrid-4-yl)oxy]benzenesulfonyl chloride hydrochloride.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[N:19]=[C:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][N:16]=3)[CH:6]=[CH:5][C:4]1=2.[OH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=O>>[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]2[CH:8]=[C:7]([C:15]3[N:19]=[C:18]([CH:20]4[CH2:25][CH2:24][N:23]([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][OH:27])[CH2:22][CH2:21]4)[O:17][N:16]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3noc(C4CCNCC4)n3)ccc21
Reactant: O=CCCCCO
Agent: Cl
Product: CC1(C)CCC(C)(C)c2cc(-c3noc(C4CCN(CCCCCO)CC4)n3)ccc21

Procedure:
The preparation was carried out as already described via a reductive amination starting from 95 mg (0.26 mmol) of 4-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2,4-oxadiazol-5-yl]piperidine hydrochloride and 52 mg (0.51 mmol) of 5-hydroxypentanal.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([CH2:19][CH2:20][NH2:21])[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.[C:23]([O:27][C:28]([NH:30][C@@H:31]([CH2:35][OH:36])[C:32](O)=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28](=[O:29])[NH:30][C@H:31]([C:32](=[O:33])[NH:21][CH2:20][CH2:19][C:16]1[S:17][CH:18]=[C:14]([C:6]2[CH:5]=[CH:4][C:3]3[C:2]([CH3:22])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=3[CH:7]=2)[N:15]=1)[CH2:35][OH:36])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(CCN)n3)ccc21
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)NCCc1nc(-c2ccc3c(c2)C(C)(C)CCC3(C)C)cs1

Procedure:
The preparation is carried out as already described starting from 186 mg (0.59 mmol) of 2-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]ethylamine from step b and 133 mg (0.65 mmol) of (S)-2-tert-butoxycarbonylamino-3-hydroxypropionic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]2[C:10](=[N:13]O)[CH2:11][O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2]>C(O)C.O1CCCC1.[Pd]>[CH2:1]([O:3][C:4]1[C:9]2[CH:10]([NH2:13])[CH2:11][O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1cccc2c1C(=NO)CO2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1cccc2c1C(N)CO2
Reaction time: 18 h
Yield: 95.1 %

Procedure:
A mixture of the above described 4-ethoxy-benzofuran-3-one oxime (4.2 g, 21.7 mmol) in ethanol (200 mL) and tetrahydrofuran (200 mL) with 10% palladium on carbon (4.0 g) was hydrogenated at 23° C. and atmospheric pressure for 18 h. Filtered the catalyst off, washed with ethanol, evaporated the filtrate totally and dried in high vacuum to give the title compound as a light brown solid (3.7 g, 1:1 mixture of product and starting material); MS: m/e=163.3 (M+H+).
Reaction SMILES: C[C:2]1([CH3:12])[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.CCO[C:16]([CH3:18])=O.[CH2:19]1COCC1>Cl[Cu]>[CH2:12]([C:2]1([CH2:16][CH3:18])[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1)[CH3:19]
Reactant: CC1(C)C=Cc2ccccc2N1
Reactant: C1CCOC1
Reactant: CCOC(C)=O
Agent: Cl[Cu]
Product: CCC1(CC)C=Cc2ccccc2N1
Yield: 50 %

Procedure:
This compound was prepared in a manner similar to that described for 1,2-Dihydro-2,2-dimethylquinoline (structure 17 of Scheme III, where R1=R2=Me) from 2-ethyl-1-pentyn-3-yl(phenyl)amine (3.00 g, 16.0 mmol) and CuCl (0.190 g, 1.92 mmol) in THF to afford 1.51 g (50%) of 2,2-diethyl-1,2-dihydroquinoline after flash chromatography (hexanes:EtOAc, 16:1). Data for 2,2-diethyl-1,2-dihydroquinoline: Rf 0.44 (16:1 hexanes:EtOAc; 1H NMR (400 MHz, CDCl3) 6.85-6.95 (m, 1H), 6.81 (d, J=7.3, 1H), 6.48 (t, J=7.3, 1H), 6.36 (d, J=9.9, 1H), 5.21 (d, J=9.9, 1H), 3.39 (broad s, 1H), 1.35-1.55 (m, 4H), 0.93 (t, J=7.5, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]([C:19]3[C:20](=[O:32])[N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:22]([CH3:25])[C:23]=3[CH3:24])=[O:18])=[N:14][CH:15]=2)[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[C:40](Cl)(=[O:42])[CH3:41].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.C1COCC1>[C:40]([NH:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]([C:19]3[C:20](=[O:32])[N:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:22]([CH3:25])[C:23]=3[CH3:24])=[O:18])=[N:14][CH:15]=2)[CH:5]=[CH:4][N:3]=1)(=[O:42])[CH3:41]
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3Cl)cn2)c(=O)n(-c2ccccc2)n1C
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nccc(Oc2ccc(NC(=O)c3c(C)n(C)n(-c4ccccc4)c3=O)nc2)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 23.4 %

Procedure:
To a solution of N-(5-((2-amino-3-chloropyridin-4-yl)oxy)pyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (60 mg, 0.13 mmol), and Et3N (26.3 mg, 0.26 mmol) in CH2Cl2 (1 mL) and THF (2 mL) was added acetyl chloride (20 mg, 0.26 mmol). The reaction was stirred at rt for 3 hours, then treated with saturated Na2CO3 aqueous solution (2 mL). The resulted mixture was continued to stir at rt for 5 minutes, then concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/CH3OH (v/v)=50/1) to give the title compound as a light beige solid (15 mg, 22.7%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([C:18](=[O:20])[CH3:19])=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15](Cl)[N:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH2:21]([NH2:25])[CH2:22][CH2:23][CH3:24]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([C:18](=[O:20])[CH3:19])=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([NH:25][CH2:21][CH2:22][CH2:23][CH3:24])[N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCCCN
Reactant: CC(=O)c1c(-c2ccc(Br)cc2)nn2c(Cl)cccc12
Product: CCCCNc1cccc2c(C(C)=O)c(-c3ccc(Br)cc3)nn12
Yield: 76 %

Procedure:
In a similar manner as described in Example 1, from 1-[2-(4-bromophenyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]ethanone (2.55 g, 7.3 mmol) and butylamine, 1-[2-(4-bromophenyl)-7-(butylamino)pyrazolo[1,5-a]pyridin-3-yl]ethanone (2.15 g, 76%) was obtained as a yellow oil. 1H NMR (CDCl3): δ 7.61 (m, 3 H), 7.43 (m, 3 H), 6.08 (d, 1 H), 6.02 (broad s, 1 H), 3.33 (q, 2 H), 2.12 (s, 3 H), 1.70 (m, 2 H), 1.44 (m, 2 H), 0.94 (t, 3 H); MS m/z 386 (M+1).
Reaction SMILES: [SH:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[O-]Cl.[Na+].[OH-].[NH4+:19]>[OH-].[Na+].O>[CH3:14][O:13][C:9]1[CH:8]=[C:7]([C:4]2[N:3]=[C:2]([S:1][NH2:19])[S:6][N:5]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: COc1cccc(-c2nsc(S)n2)c1
Reactant: [NH4+]
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: O
Product: COc1cccc(-c2nsc(SN)n2)c1
Reaction time: 0.25 h

Procedure:
A solution of 2.2 g of 5-mercapto-3-(3-methoxyphenyl)-1,2,4-thiadiazole in 35 ml of 5% sodium hydroxide and a solution prepared by diluting 22 ml of 5.25% NaOCl solution to 35 ml with water were added dropwise simultaneously to 95 ml of ammonium hydroxide solution while maintaining the mixture at 0°. The resulting mixture was stirred for 15 minutes and the precipitated solid was collected, washed with water and dried (P2O5 /high vacuum) to give 1.76 g of solid, m.p. 157°-160° C. dec.