Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH2:9]([O:11][C:12]([C:14]1[C:18]2[CH:19]=[CH:20][C:21]([OH:23])=[CH:22][C:17]=2[O:16][N:15]=1)=[O:13])[CH3:10].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN1C(=O)CCC1.C(Cl)Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:9]([O:11][C:12]([C:14]1[C:18]2[CH:19]=[CH:20][C:21]([O:23][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)=[CH:22][C:17]=2[O:16][N:15]=1)=[O:13])[CH3:10]
Reactant: Clc1ccnc(Cl)n1
Reactant: CCOC(=O)c1noc2cc(O)ccc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CCOC(=O)c1noc2cc(Oc3ccnc(Cl)n3)ccc12
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A suspension of 2.7 g (18.1 mMol) 2,4-dichloropyrimidine, 4.12 g (19.9 mMol) 6-hydroxy-benzo[d]isoxazole-3-carboxylic acid ethyl ester [preparation see: J. Am. Chem. Soc. 97 (1974), 7305] and 8.45 g (39.8 mMol) K3PO4 in 90 ml NMP is stirred for 22 h at rt. Then the mixture is diluted with 0.5 l CH2Cl2 and 0.9 l of a 5% citric acid solution. The organic phase is separated off, washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; CH2Cl2) gives the title compound: MS: [M+1]+=320; TLC(CH2Cl2/EtOAc 49:1): Rf=0.42.
Reaction SMILES: [NH:1]([C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:8])=[CH:5][N:4]=1)[NH2:2].C(=O)([O-])[O-].[K+].[K+].C([O:27][CH:28]=[C:29]([C:35](OCC)=O)[C:30]([O:32][CH2:33][CH3:34])=[O:31])C.Cl>O>[OH:27][C:28]1[N:1]([C:3]2[CH:18]=[CH:17][C:6]([C:7](=[O:8])[NH:9][CH2:10][CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:5][N:4]=2)[N:2]=[CH:35][C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: NNc1ccc(C(=O)NCC2CCOCC2)cn1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1cnn(-c2ccc(C(=O)NCC3CCOCC3)cn2)c1O
Temperature: 100 °C
Reaction time: 14 h
Yield: 74.4 %

Procedure:
Combined 6-hydrazinyl-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide (1.0 g, 4.00 mmol) and potassium carbonate (2.209 g, 15.98 mmol) in water (25 mL) and added diethyl 2-(ethoxymethylene)malonate (0.807 mL, 4.00 mmol) at 23° C. The reaction mixture was stirred at 100° C. for 14 hours, then 3N HCl (10 mL, 7.5 eq) was added to give a tan suspension. The solid was filtered, rinsed with water (3×5 mL), and dried in vacuo to give the title compound (1.114 g, 74.5% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15-1.24 (m, 2H) 1.26 (t, J=7.07 Hz, 3H) 1.56-1.68 (m, 2H) 1.81 (qdd, J=11.16, 11.16, 11.16, 6.95, 3.79 Hz, 1H) 3.19 (t, J=6.32 Hz, 2H) 3.27 (td, J=11.75, 2.02 Hz, 2H) 3.82-3.90 (m, 2H) 4.18 (q, J=7.24 Hz, 2H) 8.12 (br. s., 1H) 8.13-8.24 (m, 1H) 8.46 (dd, J=8.84, 2.27 Hz, 1H) 8.76 (t, J=5.68 Hz, 1H) 8.89 (dd, J=2.27, 0.76 Hz, 1H) 13.73 (br. s., 1H). MS m/z [M+H]+ 329.3, 375.4.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:8]([O:10][CH2:11]C)=[O:9])=[C:5]([CH3:7])[N:6]=1.[NH:13]1[C:21]2[C:16](=[C:17]([CH2:22][CH2:23][CH2:24][NH2:25])[CH:18]=[CH:19][CH:20]=2)[CH:15]=[N:14]1.C([O-])(=O)C.[K+].C(O)C>C(OCC)(=O)C.O>[CH3:11][O:10][C:8]([C:4]1[S:3][C:2]([NH:25][CH2:24][CH2:23][CH2:22][C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:16]=2[CH:15]=[N:14][NH:13]3)=[N:6][C:5]=1[CH3:7])=[O:9]
Reactant: NCCCc1cccc2[nH]ncc12
Reactant: CCOC(=O)c1sc(Cl)nc1C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1sc(NCCCc2cccc3[nH]ncc23)nc1C
Yield: 51.1 %

Procedure:
A mixture of ethyl 2-chloro-4-methyl-1,3-thiazole-5-carboxylate (0.28 g, 1.361 mmol), 3-(1H-Indazol-4-yl)-propylamine (300 mg, 1.712 mmol), potassium acetate (180 mg, 1.834 mmol) and ethanol (3 mL) was microwaved for 90 min. at 160° C. The reaction is diluted with ethyl acetate (150 mL) and water (30 mL). and washed with brine (2×30 mL), dried over anhydrous magnesium sulfate, filtered, concentrated to give 2-[3-(1H-Indazol-4-yl)-propylamino]-4-methyl-thiazole-5-carboxylic acid methyl ester (0.230 g, 49%)) as a yellow solid. MS m/e 331.4 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:40][C:37]1[CH:36]=[CH:35][C:34]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]2)=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(O)nc3ccc(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)cc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Oc1cc(NC2CCNCC2)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 25-mL round-bottom flask, was placed tert-butyl 4-([6-[bis(4-chlorophenyl)methyl]-2-hydroxyquinolin-4-yl]amino)piperidine-1-carboxylate (570 mg, 0.99 mmol, 1.00 equip), dichloromethane (8 mL), and CF3COOH (2 mL). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The resulting residue was recrystallized from ethyl acetate:petroleum ether in the ratio of 1:10 to yield 6-[bis(4-chlorophenyl)methyl]-4-[(piperidin-4-yl)amino]quinolin-2-ol as an off-white solid. LCMS-(ES, m/z) 478 [M+H]+
Reaction SMILES: C[O-].[Na+].[CH3:4][Si:5]([CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](=[O:25])[CH3:24])=[CH:18][CH:17]=1)([CH3:13])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[N:26](OCCC(C)C)=[O:27].C(O)(=O)C>CO>[CH3:4][Si:5]([CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22](=[N:26][OH:27])[C:23](=[O:25])[CH3:24])=[CH:20][CH:21]=1)([CH3:13])[C:6]1[CH:7]=[CH:8][C:9]([F:12])=[CH:10][CH:11]=1
Reactant: CC(=O)Cc1ccc(OC[Si](C)(C)c2ccc(F)cc2)cc1
Reactant: CC(C)CCON=O
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)C(=NO)c1ccc(OC[Si](C)(C)c2ccc(F)cc2)cc1

Procedure:
28 ml of a 30% solution of sodium methanolate in methanol are added at room temperature to 31.6 g of 1-(4-[{dimethyl-(4-fluorophenyl)-silyl}methoxy]phenyl)-propan-2-one in 300 ml of methanol, and 27 ml of isopentyl nitrite are then added dropwise. The reaction mixture is stirred for a further hour and rendered neutral with acetic acid; the solvent is evaporated off in vacuo. 200 ml of ethyl acetate are added to the residue; the organic phase is washed with water and saturated sodium chloride solution and dried over sodium sulfate; the solvent is evaporated off in vacuo. Recrystallisation from diethyl ether/hexane yields the title product having a melting point of 115-117° C.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[CH2:21]([NH2:26])[CH2:22][CH:23]([CH3:25])[CH3:24]>>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:26][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=1
Reactant: CC(C)CCN
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Product: COc1cc(CNCCC(C)C)ccc1Oc1ccc(C(N)=O)cn1
Yield: 30.4 %

Procedure:
Using a method similar to Example 405, a reaction of 6-(4-formyl-2-methoxyphenoxy)nicotinamide (0.0423 g, 0.155 mmol) and isoamylamine (0.020 g, 0.171 mmol) gives the title compound (0.0162 g, 30.3%): TOF MS ES+ 344.2 (M+H)+, HRMS calcd for C19H26N3O3 344.1974 (M+H)+, found 344.1949, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=5.9 min, 100% purity.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.Cl.Br[C:9]1[CH:14]=[CH:13][NH+:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>C(O)C>[N:12]1[CH:13]=[CH:14][C:9]([N:4]2[CH2:5][CH2:6][CH:2]([OH:1])[CH2:3]2)=[CH:10][CH:11]=1
Reactant: OC1CCNC1
Reactant: Brc1cc[nH+]cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: OC1CCN(c2ccncc2)C1
Temperature: 150 °C

Procedure:
A mixture of 3-hydroxypyrrolidine (9.9 g, 113.64 mmol), 4-bromopyridinium hydrochloride (22.098 g, 113.64 mmol), triethylamine (47.5 mL, 341.0 mmol) and 3:1 ethanol:water (150 mL), in a pressure tube reaction vessel, was purged with nitrogen and sealed. The mixture was heated to 150° C. for 96 hours and cooled. The solvent was evaporated and ethyl acetate (50 mL) was added. After trituration, the organic solvent was decanted off and saved. Methylene chloride (80 mL) and 2 N sodium hydroxide (60 mL) were added to the solid. The mixture was shaken vigorously and was filtered with water and methylene chloride wash to give the title compound as an off-white solid. The organic supernatant and the methylene chloride and water washes were combined. This mixture was extracted with methylene chloride. The organic layer was sodium sulfate dried and concentrated. The residue was triturated with methylene chloride and the solid was filtered. This solid was combined with the solid from above and vacuum dried (100° C. at 133 Pa for 14 hours) to give the title compound as an off-white solid (8.52 g, 46%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:27]=[C:28]([NH:37][C:38]([C@@H:40]2[NH:49][CH2:48][CH2:47][C:46]3[N:45]=[C:44]([O:50][CH3:51])[CH:43]=[CH:42][C:41]2=3)=[O:39])[CH:29]=[C:30]([F:36])[C:31]=1[Si:32]([CH3:35])([CH3:34])[CH3:33].[CH2:52]([O:59][C:60](=[O:68])[CH2:61][C@@H:62]1[CH2:64][C@H:63]1[C:65]([OH:67])=[O:66])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:36][C:30]1[CH:29]=[C:28]([NH:37][C:38]([C@@H:40]2[N:49]([C:65]([C@H:63]3[CH2:64][C@@H:62]3[CH2:61][C:60]([O:59][CH2:52][C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)=[O:68])=[O:66])[CH2:48][CH2:47][C:46]3[N:45]=[C:44]([O:50][CH3:51])[CH:43]=[CH:42][C:41]2=3)=[O:39])[CH:27]=[C:26]([F:25])[C:31]=1[Si:32]([CH3:35])([CH3:34])[CH3:33].[F:36][C:30]1[CH:29]=[C:28]([NH:37][C:38]([C@@H:40]2[N:49]([C:65]([C@@H:63]3[CH2:64][C@H:62]3[CH2:61][C:60]([O:59][CH2:52][C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)=[O:68])=[O:67])[CH2:48][CH2:47][C:46]3[N:45]=[C:44]([O:50][CH3:51])[CH:43]=[CH:42][C:41]2=3)=[O:39])[CH:27]=[C:26]([F:25])[C:31]=1[Si:32]([CH3:35])([CH3:34])[CH3:33]
Reactant: O=C(C[C@@H]1C[C@H]1C(=O)O)OCc1ccccc1
Reactant: COc1ccc2c(n1)CCN[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(n1)CCN(C(=O)[C@@H]1C[C@H]1CC(=O)OCc1ccccc1)[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Product: COc1ccc2c(n1)CCN(C(=O)[C@H]1C[C@@H]1CC(=O)OCc1ccccc1)[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %
Yield: 23 %

Procedure:
HATU (137 mg, 0.36 mmol) was added to a solution of (R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide (128 mg, 0.33 mmol), trans-2-(2-(benzyloxy)-2-oxoethyl)cyclopropanecarboxylic acid (84 mg, 0.36 mmol) and DIEA (0.065 mL, 0.36 mmol) in DMF (2 mL) at room temperature, and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 30→80% ethyl acetate/hexane) to give benzyl 2-((1R,2S)-2-((R)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)cyclopropyl)acetate (46 mg, 0.076 mmol, 23%) as a less polar compound, and benzyl 2-((1S,2R)-2-((R)-5-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)cyclopropyl)acetate (39 mg, 0.064 mmol, 20%) as a more polar compound, respectively.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][C:3]=1[N+:12]([O-])=O>CC(O)=O.[Fe]>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][C:3]=1[NH2:12]
Reactant: Cc1cc([N+](=O)[O-])c(C)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Product: Cc1cc(N)c(C)c([N+](=O)[O-])c1
Temperature: 110 °C

Procedure:
To a stirred solution of p-xylene (10.4 g, 97.9 mmol) in concentrated sulfuric acid (20 mL), cooled in an ice bath, was added 90% nitric acid (12.4 mL, 264 mmol) dropwise over 50 min. The resulting mixture was heated to 80° C. for 2 h, then poured onto ice and extracted with CH2Cl2 (2×400 mL). The combined organic extracts were washed with saturated aqueous NaHCO3, then brine, then dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was partially purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—90:10 to 60:40. The resulting solid was recrystallized from CH2Cl2 to yield 2,5-dimethyl-1,3-dinitrobenzene as a white solid. 2,5-Dimethyl-1,3-dinitrobenzene (3.68 g, 18.8 mmol) was dissolved in AcOH (35 mL) and iron powder (1.95 g, 34.9 mmol) was added. The mixture was heated to 110° C. for 3 h, then filtered through a pad of Celite, washing with EtOAc and H2O. The filtrate was concentrated in vacuo to remove most of the solvent and the residue was partitioned between saturated aqueous NaHCO3 (200 mL) and EtOAc (200 mL). The organic layer was washed with brine, then dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 60:40, to give the title compound as a yellow solid. MS: m/z=167 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20][CH3:21])[C:3]=1[CH3:22].OOS([O-])=O.[K+].[O-2:29].[Al+3].[O-2:31].[O-2].[Al+3]>C(Cl)(Cl)Cl.C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([CH3:21])(=[O:31])=[O:29])[C:3]=1[CH3:22]
Reactant: CSc1ccccc1-c1nc2cc(F)cc(F)c2c(Cl)c1C
Reactant: [O-2]
Agent: O=S([O-])OO
Agent: [Al+3]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)cc(F)c2c1Cl
Temperature: 65 °C

Procedure:
The 4-chloro-5,7-difluoro-3-methyl-2-(2-(methylthio)phenyl)quinoline (300 mg, 0.893 mmol) was dissolved in chloroform (8 mL) and Oxone™ (1.65 g, 2.68 mmol) and wet aluminum(III) oxide (910 mg, 8.90 mmol) was added. The heterogeneous mixture was stirred vigorously at 65° C. and refluxed for five h. Another portion of Oxone™ (1.65 g, 2.68 mmol) and aluminum(III) oxide (910 mg, 8.90 mmol) was added and the reaction was stirred vigorously overnight at 65° C. The reaction was cooled to rt and slurried in DCM and filtered. The filtrate was concentrated and the crude product was purified by medium pressure chromatography (silica gel, 0 to 50% EtOAc:hexanes) to give 4-chloro-5,7-difluoro-3-methyl-2-(2-(methylsulfonyl)phenyl)quinoline. Mass Spectrum (ESI) m/e=368.0 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.[N+:14]([O-])([OH:16])=[O:15].N([O-])=O.[Na+]>>[OH:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2
Reactant: O=[N+]([O-])O
Reactant: COc1cc2c(cc1O)CCC2=O
Agent: O=N[O-]
Agent: [Na+]
Product: COc1cc2c(c([N+](=O)[O-])c1O)CCC2=O

Procedure:
1,4-Dihydroindeno[1,2-c]pyrazoles of general formula (13), wherein X3, R4, R5, and R6 are as defined in formula (I), can be prepared as described in Scheme 3. 5,6-Dimethoxy-1-indanone, purchased from Aldrich Chemical Co., can be treated with sodium cyanide to provide 5-hydroxy-6-methoxy-1-indanone. 5-Hydroxy-6-methoxy-1-indanone can be treated with nitric acid and sodium nitrite to provide 5-hydroxy-6-methoxy-4-nitro-1-indanone. 5-Hydroxy-6-methoxy-4-nitro-1-indanone can be treated with iodomethane and then methodology described in Scheme 2 to provide compounds of general formula (12). Compounds of general formula (12) can be treated with a reducing agent, including iron metal in the presence of acetic acid, to provide amines of general formula (13).
Reaction SMILES: C([O:8][C:9]1[CH:28]=[CH:27][C:12]([O:13][C@@H:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][C@H:15]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.O1CCCC1.[Pd]>[OH:8][C:9]1[CH:28]=[CH:27][C:12]([O:13][C@@H:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][C@H:15]2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:11][CH:10]=1
Reactant: CN1CC[C@@H](Oc2ccc(OCc3ccccc3)cc2)[C@H](c2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CN1CC[C@@H](Oc2ccc(O)cc2)[C@H](c2ccccc2)C1

Procedure:
A solution of 8.59 g of trans-4-(4-benzyloxyphenoxy)-1-methyl-3-phenylpiperdine in a mixture of 100 ml of absolute ethanol and 50 ml of tetrahydrofuran is hydrogenated overnight over 5% palladium-on-carbon at room temperature under 45 pounds per square inch of hydrogen. The catalyst is filtered and washed with ethanol and ether. The filtrate is concentrated in vacuo to a nearly colorless, partially solidified foam. Trituration of the foam with ether followed by recrystallization from 270 ml of chloroform gives product as a colorless solid, mps 169.5° C., 170°-172° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[OH-].[Na+].Cl[CH2:15][CH2:16][OH:17].C1(C)C=CC=CC=1>CS(C)=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:15][CH2:16][OH:17]
Reactant: OCCCl
Reactant: Oc1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: OCCOc1ccc2ccccc2c1
Yield: 70 %

Procedure:
The reaction set-up consisted of a three necked round bottom flask, equipped with a thermometer, condenser and a mechanical stirrer, and a dropping funnel. 2-Naphthol, 100 g (0.6936 moles), was dissolved in 60 mL of dimethyl sulfoxide. Sodium hydroxide, 27.7 g (0.6936 moles), was carefully added to the solution. Then 2-chloroethanol, 61.4 g (0.7629 moles), was slowly added, keeping the reaction temperature at 80° C. The reaction was followed by GC. After >>80% conversion was achieved, the reaction was worked-up by adding toluene and extracting the unreacted naphthol with 5% aqueous NaOH. The product was then recrystallized in ethanol or distilled under vacuum (70-80% yield).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:33])[CH2:31][CH3:32])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:33])[CH2:31][CH3:32])=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCC(c1ccccc1)c1ccccc1
Reactant: CCC(=O)Nc1ccc(C2CCNCC2)cc1
Product: CCC(=O)Nc1ccc(C2CCN(CCC(c3ccccc3)c3ccccc3)CC2)cc1

Procedure:
Prepared by Procedure O and Scheme W using 3,3-diphenyl-1-propanol and N-[4-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 427.0 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH2:4].[CH:5]1([CH2:12]Br)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>>[CH:5]1([CH2:12][NH:4][CH2:3][CH2:2][OH:1])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: BrCC1CCCCCC1
Reactant: NCCO
Product: OCCNCC1CCCCCC1

Procedure:
2-Hydroxyethylamine was reacted with cycloheptylmethyl bromide according to Method B2a to give N-cycloheptylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cycloheptylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate to give 2-(2-methyl-4-nitrophenylimino)-3-(cycloheptylmethyl)-1,3-thiazolidine.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Si](C)(C)C)=[C:10]([F:18])[C:9]=2[F:19])[N:5]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[C:3]=1[O:24][CH3:25].[Br:26]Br.S(=O)(O)[O-].[Na+]>ClCCCl.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Br:26])=[C:10]([F:18])[C:9]=2[F:19])[N:5]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[C:3]=1[O:24][CH3:25]
Reactant: COC(=O)c1nc(-c2ccc([Si](C)(C)C)c(F)c2F)nc(N)c1OC
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COC(=O)c1nc(-c2ccc(Br)c(F)c2F)nc(N)c1OC
Temperature: 60 °C
Yield: 21.1 %

Procedure:
Methyl 6-amino-2-(2,3-difluoro-4-(trimethylsilyl)phenyl)-5-methoxypyrimidine-4-carboxylate (350 mg, 0.95 mmol) was stirred in 4 mL 1,2-dichloroethane, treated with bromine (1.0 g, 6.3 mmol) and heated to 60° C. for 6 h. After cooling, the mixture was stirred with 15% sodium bisulfite solution until negative to starch-iodine paper. The mixture was diluted with ethyl acetate, washed with saturated NaCl, dried (Na2SO4), and evaporated. Purification by flash chromatography (SiO2, eluting with 0-30% ethyl acetate in hexanes) provided the title compound as white solid (75 mg, 23%).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:5][CH:4]([C:6]([NH2:8])=[O:7])[CH2:3]1.C(Cl)(=O)[C:11](Cl)=[O:12].[CH3:16][N:17]1[CH:21]=[C:20]([C:22]2[CH:27]=[C:26]([O:28][C:29]3[CH:30]=[CH:31][C:32]([NH2:35])=[N:33][CH:34]=3)[CH:25]=[CH:24][N:23]=2)[CH:19]=[N:18]1.N1C=CC=CC=1>ClCCCl.C1COCC1>[CH3:1][C:2]1([CH3:9])[CH2:5][CH:4]([C:6]([NH:8][C:11](=[O:12])[NH:35][C:32]2[CH:31]=[CH:30][C:29]([O:28][C:26]3[CH:25]=[CH:24][N:23]=[C:22]([C:20]4[CH:19]=[N:18][N:17]([CH3:16])[CH:21]=4)[CH:27]=3)=[CH:34][N:33]=2)=[O:7])[CH2:3]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1(C)CC(C(N)=O)C1
Reactant: Cn1cc(-c2cc(Oc3ccc(N)nc3)ccn2)cn1
Solvent: c1ccncc1
Solvent: ClCCCl
Solvent: C1CCOC1
Product: Cn1cc(-c2cc(Oc3ccc(NC(=O)NC(=O)C4CC(C)(C)C4)nc3)ccn2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
A suspension of Example B1 (0.074 g, 0.584 mmol) in DCE (6 mL) was treated with oxalyl chloride (0.051 mL, 0.584 mmol), stirred at RT for 30 min, then warmed to 83° C. for 3 h. The mixture was cooled to RT and added drop-wise to a solution of Example A2 (0.13 g, 0.486 mmol) in THF (6.0 mL) and pyridine (0.197 mL, 2.43 mmol). The mixture was stirred at RT for 1 h, treated with satd. NaHCO3, extracted with EtOAc (3×) and the combined organics were dried over MgSO4 and concentrated to dryness. The residue was triturated with MeCN, sonicated for 5 min and the solid was collected via filtration and dried to afford 3,3-dimethyl-N-((5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)cyclobutanecarboxamide (125 mg, 61%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.11 (s, 1H), 10.70 (s, 1H), 8.37 (d, J=5.7 Hz, 1H), 8.27-8.25 (m, 2H), 8.07 (d, J=9.0 Hz, 1H), 7.96 (d, J=0.7 Hz, 1H), 7.72 (dd, J=9.0, 2.9 Hz, 1H), 7.23 (d, J=2.4 Hz, 1H), 6.70 (dd, J=5.7, 2.4 Hz, 1H), 3.84 (s, 3H), 3.24 (m, 1H), 2.03-1.87 (m, 4H), 1.13 (s, 3H), 1.05 (s, 3H); MS (ESI) m/z: 421.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][CH2:20][OH:21])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24].N1C=CC=CC=1.OS([O-])(=O)=O.[K+]>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][CH2:20][O:21][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: OCCC#Cc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)OCCC#Cc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Temperature: 25 °C
Yield: 100.2 %

Procedure:
365 mg (1.02 mmol) 4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-but-3-yn-1-ol in 7 ml CH2Cl2 were treated with 94 μl (1.21 mmol) methane sulfonic acid chloride, 0.13 ml (1.53 mmol) pyridine and 135 mg (1.2 mmol) DMAP at 0° C. The solution was stirred at RT over night, was diluted with water and acidified with 10% aq. KHSO4. The inorganic phase was extracted with CH2Cl2. The combined organic phases were washed with NaHCO3 solution, brine and dried over Na2SO4. Evaporation gave 446 mg crude Methanesulfonic acid 4-[3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl]-but-3-ynyl ester, MS: 436 (MH+).