Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5]/[C:6]/2=[N:11]\[S@:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13].C1COCC1.[BH4-].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C@@H:6]2[NH:11][S@:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13]
Reactant: CC(C)(C)[S@](=O)/N=C1\CCc2c(Br)cccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)[S@](=O)N[C@H]1CCc2c(Br)cccc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a stirred suspension of crude (S,E)-N-(4-bromo-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfinamide IND INT-9 in toluene (250 mL) under N2 was added anhydrous THF (250 mL) and the reaction mixture was cooled to −78° C. Sodium borohydride (26.8 g, 710 mmol) was added in four portions over 30 min (internal temperature maintained below −65° C.). The reaction mixture was stirred at −78° C. for 30 min before it was warmed to room temperature over 1 h and continued to stir for additional 1 h. The reaction mixture was filtered through Celite pad to remove Ti salts. The filtrate was treated with EA (500 mL), saturated sodium potassium tartrate (200 mL), and brine (50 mL) and the mixture stirred at room temperature overnight. The mixture was filtered through a celite pad and the filtrate dried over MgSO4. The crude product was obtained by concentration to dryness gave 46 g (61%) of (S)-N-((S)-4-bromo-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide IND INT-11 as an off-white solid which was used in the next experiment without purification. LCMS-ESI (m/z) calculated C13H16BrNOS: 313.0; found 314.0 [M+H]+, tR=3.84 min.
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1>C(Cl)(Cl)Cl>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:11]([C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)=[O:12])=[CH:18][CH:17]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: ClC(Cl)Cl
Product: COc1ccc(NC(=O)C23CC4CC(CC(C4)C2)C3)cc1

Procedure:
Subject 6.5 g. (33.0 mmoles) of 1-adamantane carboxylic acid chloride, 4.0 g. (33.0 mmoles) of p-anisidine and 10.0 ml. of triethylamine to the process of Example 11 and crystallize the residue obtained thereby from chloroform to yield the title product, m.p. 181°-184°C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[CH:16]=[CH:15][S:14]2)=[CH:9][CH:8]=1.O>CN(C=O)C>[N:1]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[C:17](=[O:18])[CH:16]=[CH:15][S:14]2)=[CH:11][CH:12]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: O=c1ccsn1-c1ccc(CBr)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1ccc(-n2sccc2=O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 74.7 %

Procedure:
Sodium azide (6.0 mg, 0.0923 mmol) was added to a solution of 2-(4-bromomethylphenyl)isothiazol-3-one 31 (18.2 mg, 0.0674 mmol) in DMF (1 mL) and stirred for 20 h at room temperature. Water (10 mL) was added and the mixture was extracted with diethyl ether. The combined organic layer was dried (MgSO4), filtered and evaporated. The residue was purified on flash silica gel column chromatography (hexane:ethyl acetate=4:1 to 1:1), afforded the desired compound 32 (11.7 mg, 75%). 1H-NMR (CDCl3, 300 MHz) δ 4.38 (s, 2H), 6.34 (d, J=6.3 Hz, 1H), 7.41 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H), 8.17 (d, J=6.3 Hz, 1H). HRMS: Found 233.0496. Calcd for C10H9N4OS (M+H)+233.0497.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)(O)[CH:9]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[C:9]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C(C)(C)C)C(O)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)C(C)(C)C
Yield: 36.3 %

Procedure:
A mixture of ethyl 3,3-bis(4-fluorophenyl)-3-hydroxy-2-(1,1-dimethylethyl)propionate (1.0 g, 2.8 mmol) and p-toluenesulfonic acid (0.3 g) in 20 mL toluene was heated at reflux for 45 minutes. The mixture was cooled and concentrated in vacuo. The residue was purified by chromatography on silica eluting with 1% ethyl acetate in hexane. Concentration of the appropriate fractions gave an oil which was crystallized from petroleum ether to give 0.35 g of the title compound; m.p. =60°-62° C.
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][C:5]1[O:6][C:7]([CH3:26])=[C:8]([CH3:25])[C:9]=1[C:10]([C:12]1[CH:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[C:15]([OH:21])=[C:14]([CH:22]([CH3:24])[CH3:23])[CH:13]=1)=[O:11].Cl[S:32]([C:35]1[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[C:37]([OH:44])[CH:36]=1)(=[O:34])=[O:33]>>[Br:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][C:5]1[O:6][C:7]([CH3:26])=[C:8]([CH3:25])[C:9]=1[C:10]([C:12]1[CH:17]=[C:16]([CH:18]([CH3:19])[CH3:20])[C:15]([O:21][S:32]([C:35]2[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[C:37]([OH:44])[CH:36]=2)(=[O:34])=[O:33])=[C:14]([CH:22]([CH3:23])[CH3:24])[CH:13]=1)=[O:11]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: Cc1oc(Cc2ccccc2Br)c(C(=O)c2cc(C(C)C)c(O)c(C(C)C)c2)c1C
Product: Cc1oc(Cc2ccccc2Br)c(C(=O)c2cc(C(C)C)c(OS(=O)(=O)c3ccc(C(=O)O)c(O)c3)c(C(C)C)c2)c1C
Yield: 46.7 %

Procedure:
The title compound was prepared according to the procedure in Example 4 using [2-(2-bromo-benzyl)-4,5-dimethyl-furan-3-yl]-(3,5-diisopropyl-4-hydroxy-phenyl)-methanone (0.300 g, 0.639 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.197 g, 0.831 mmol). Purification on Dynamax C18 (90% CH3CN/H2O) gave 0.20 g (47%) of the title compound as a yellow solid, mp 90-95” C. 1H NMR (DMSO-d6) δ 1.06 (d, 12H), 1.85 (s, 3H), 2.19 (s, 3H), 3.07 (septet, 2H), 3.91 (s, 2H), 7.14-7.16 (m, 2H), 7.29 (dt, 1H), 7.44 (d, 1H), 7.47-7.52 (m, 4H), 8.05 (d, 1H). IR (KBr) 3400, 2950, 1690, 1380 and 1190 cm−1. mass spectrum (−ESI) m/z 667/669 (M−H). Anal. Calcd. for C33H33BrO8S: C, 59.19; H, 4.97; N, 0.00. Found: C, 58.82; H, 5.13; N, 0.13.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][N:7]=[C:6]([C:10]2[CH:14]=[N:13][N:12]([CH3:15])[C:11]=2[NH:16][C:17]2[CH:18]=[C:19]([NH:24][C:25](=[O:36])[C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)[CH:20]=[CH:21][C:22]=2[CH3:23])[CH:5]=1)=O.[N:37]1([CH2:43][CH2:44][NH2:45])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>CC(O)C>[CH3:23][C:22]1[CH:21]=[CH:20][C:19]([NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[CH:18][C:17]=1[NH:16][C:11]1[N:12]([CH3:15])[N:13]=[CH:14][C:10]=1[C:6]1[CH:5]=[C:4]([NH:45][CH2:44][CH2:43][N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[N:9]=[CH:8][N:7]=1
Reactant: NCCN1CCOCC1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Nc1c(-c2cc(S(C)=O)ncn2)cnn1C
Solvent: CC(C)O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Nc1c(-c2cc(NCCN3CCOCC3)ncn2)cnn1C
Temperature: 80 °C

Procedure:
The mixture of N-{3-[4-(6-Methanesulfinyl-pyrimidin-4-yl)-2-methyl-2H-pyrazol-3-ylamino]-4-methyl-phenyl}-3-trifluoromethyl-benzamide (40 mg, 0.078 mmol) and 2-Morpholin-4-yl-ethylamine (100 μL) in 2-propanol is heated to 80° C. for 3 hours. The reaction mixture is cooled to room temperature and concentrated. The crude product is then treated with 1 mL DMSO and purified by LC/MS to afford N-(4-Methyl-3-{2-methyl-4-[6-(2-morpholin-4-yl-ethylamino)-pyrimidin-4-yl]-2H-pyrazol-3-ylamino}-phenyl)-3-trifluoromethyl-benzamide.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)[C:15]([C:16](=[O:18])[CH3:17])=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.CO[CH:30](OC)[N:31]([CH3:33])[CH3:32]>>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:19]4[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=4)[C:15]([C:16](=[O:18])/[CH:17]=[CH:30]/[N:31]([CH3:33])[CH3:32])=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(OC)N(C)C
Reactant: COc1ccc(-c2nn3c(NC4CCCC4)cccc3c2C(C)=O)cc1
Solvent: O
Product: COc1ccc(-c2nn3c(NC4CCCC4)cccc3c2C(=O)/C=C/N(C)C)cc1
Temperature: 25 °C
Yield: 93 %

Procedure:
A solution of 1-[7-(cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone (5.56 g, 15.9 mmol) in N,N-dimethylformamide dimethyl acetal (25 mL) was heated at reflux for 5 days. The mixture was allowed to cool to room temperature. Water was added and the resulting mixture was extracted with ethyl acetate. The organic phase was dried (magnesium sulfate), filtered and concentrated. The resulting residue was purified by flash chromatography (7:3 ethyl acetate:acetone) to give (2E)-1-[7-(cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one (5.97 g, 93%) as a colored syrup: 1H NMR (CDCl3): δ 7.96-7.59 (m, 3H), 7.53 (d, 1H), 7.23 (dd, 1H), 6.93 (d, 2H), 5.97-5.94 (m, 2H), 5.07 (d, 1H), 3.95 (m, 1H), 3.81 (s, 3H), 3.0-2.3 (m, 6H), 2.07 (m, 2H), 1.76-1.60 (m, 6H); MS m/z 405 (M+1).
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1.[Cu][C:16]#[N:17]>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[N+:8]([C:7]1[C:2]([C:16]#[N:17])=[N:3][CH:4]=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Br
Reactant: N#C[Cu]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: Cc1ccccc1
Product: N#Cc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
2-Bromo-3-nitro-5-trifluoromethyl-pyridine (10.00 g, 36.87 mmol) was dissolved in toluene (250 ml) with stirring to give a pale yellow solution. Tetrabutylammonium bromide (11.90 g, 36.9 mmol) was added followed by copper(I) cyanide (9.92 g, 111 mmol) and the mixture was heated at reflux for 10 h. After cooling to RT, the reaction mixture was partitioned between water (750 ml) and EtOAc (750 ml). The organic fractions were combined, washed with water (2×250 ml) and brine (100 ml), dried (MgSO4) and concentrated in vacuo to afford the title product. 1H-NMR: [400 MHz, DMSO-d6 δH 9.55 (1H, m, ArH), 9.24 (1H, m, ArH)
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[N:21]=3)=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[CH:27]1([NH:26][C:22]2[N:21]=[C:20]([C:8]3[N:4]4[CH:5]=[CH:6][CH:7]=[C:2]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[C:3]4=[N:10][C:9]=3[C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=3)[CH:25]=[CH:24][N:23]=2)[CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1cccc(-c2nc3c(Cl)cccn3c2-c2ccnc(NC3CCCC3)n2)c1
Product: O=[N+]([O-])c1cccc(-c2nc3c(N4CCOCC4)cccn3c2-c2ccnc(NC3CCCC3)n2)c1
Temperature: 150 °C
Yield: 6 %

Procedure:
A thick walled glass tube was charged with N-{4-[8-chloro-2-(3-nitrophenyl)imidazo[1,2-α]pyridin-3-yl]-2-pyrimidinyl}-N-cyclopentylamine (44 mg, 0.10 mmol) and morpholine (4 mL). The vessel was sealed and heated to 150° C. for 4 days. The mixture was concentrated in vacuo and purified via flash chromatography on silica gel (2:1 to 1:1 hexanes:ethyl acetate) to provide N-cyclopentyl-4-[8-(4-morpholinyl)-2-(3-nitrophenyl)imidazo[1,2-α]pyridin-3-yl]-2-pyrimidinamine (3 mg, 6%) as a yellow solid. 1H NMR (CDCl3): δ 8.92 (m, 1H), 8.67 (s, 1H), 8.21 (d, 1H), 8.13 (m, 1H), 8.01 (d, 1H), 7.53 (t, 1H), 6.83 (t, 1H), 6.61 (d, 1H), 6.40 (d, 1H), 5.33 (m, 1H), 4.33 (m, 1H), 4.00 (m, 4H), 3.58 (m, 4H), 2.14–2.06 (m, 2H), 1.83–1.54 (m, 6H); MS m/z 486 (M+1).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([CH2:26][CH3:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:16]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:15]2[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:12]3[CH:25]=[C:24]([CH2:26][CH3:27])[S:23][C:13]=3[N:14]=2)[CH:18]=1
Reactant: CCc1cc2c(Cl)nc(-c3cccnc3)nc2s1
Reactant: NCCc1ccccc1
Product: CCc1cc2c(NCCc3ccccc3)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyridin-3-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-phenethylamino-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([CH2:7][CH2:8][CH3:9])[N:6]=1.[CH:10]1[C:23]2[CH:22]([C:24](Cl)=[O:25])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[O:15][C:14]=2[CH:13]=[CH:12][CH:11]=1>>[CH2:7]([N:5]1[N:4]=[N:3][C:2]([NH:1][C:24]([CH:22]2[C:23]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[O:15][C:16]3[C:21]2=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:25])=[N:6]1)[CH2:8][CH3:9]
Reactant: CCCn1nnc(N)n1
Reactant: O=C(Cl)C1c2ccccc2Oc2ccccc21
Product: CCCn1nnc(NC(=O)C2c3ccccc3Oc3ccccc32)n1

Procedure:
The title compound, white solid,, m.p. 208-209° and MS: (neg. ions): m/e=334.1 (M+−H) was prepared in accordance with the general method of example 1 from 5-amino-2-propyl-2H-tetrazole and 9H-xanthene-9-carbonyl chloride.
Reaction SMILES: [CH2:1]1[C:10](=O)[CH2:9][C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.C(N)CN.[N+:16]([CH3:19])([O-:18])=[O:17]>>[N+:16]([CH2:19][C:10]1[CH2:1][CH2:2][C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:9]=1)([O-:18])=[O:17]
Reactant: C[N+](=O)[O-]
Reactant: O=C1CCc2ccccc2C1
Solvent: NCCN
Product: O=[N+]([O-])CC1=Cc2ccccc2CC1

Procedure:
A solution of β-tetralone (Aldrich Chemical Co., Milwaukee, Wis. 53233) (24.5 gm) and ethylenediamine (1.75 gm) in nitromethane (250 ml) was heated at 80° for 16 hours. The reaction mixture was filtered, and the filtrate was evaporated to give a red oil. This was partially purified by elution through a short silica column, eluting with hexane/EtOAc (9:1 v/v). The product was a pink oil (26 gm) which was not purified further but was taken directly for the next reaction.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([NH2:19])[CH3:18]>>[CH2:17]([NH:19][C:8](=[O:9])[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:18]
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CCN
Product: CCNC(=O)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, off-white solid, m.p. 87° C. and MS: m/e=239 (M+) was prepared in accordance with the general method of example 1 from diphenylacetyl chloride and ethylamine.
Reaction SMILES: [ClH:1].[CH2:2]([C:9]1[N:14]=[C:13]([C:15]([C:17]2[CH:22]=[C:21]([O:23]C)[CH:20]=[C:19]([O:25]C)[CH:18]=2)=[O:16])[CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br.N>>[ClH:1].[CH2:2]([C:9]1[N:14]=[C:13]([C:15]([C:17]2[CH:22]=[C:21]([OH:23])[CH:20]=[C:19]([OH:25])[CH:18]=2)=[O:16])[CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1cc(OC)cc(C(=O)c2cccc(Cc3ccccc3)n2)c1
Agent: Br
Agent: Cl
Agent: N
Product: O=C(c1cc(O)cc(O)c1)c1cccc(Cc2ccccc2)n1

Procedure:
About 15.5 g. of 3,5-dimethoxyphenyl 6-benzyl-2-pyridyl ketone hydrochloride in 55 ml. of constant boiling hydrobromic acid were heated under reflux for 12 hours. Removal of the solvent gave a tacky residue which was basified with ammonia solution and was extracted three times with a total of 90 ml. of boiling ethyl acetate. The extracts were washed twice with a total of 50 ml. of water, dried over magnesium sulfate and treated with charcoal. Removal of the solids and treatment of the filtrate with hydrogen chloride yielded 3.52 g. of a khaki-colored salt. Nuclear magnetic spectroscopy revealed that the methoxy groups had been removed and the product was used without further purification for the next step.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4][N:3]=1.[NH2:11][C:12]1[N:17]=[CH:16][C:15]2[C:18]([CH3:26])([CH3:25])[C:19](=[O:24])[N:20]([CH:21]3[CH2:23][CH2:22]3)[C:14]=2[CH:13]=1>>[CH:21]1([N:20]2[C:14]3[CH:13]=[C:12]([NH:11][C:8]([C:5]4[CH:6]=[N:7][C:2]([CH3:1])=[N:3][CH:4]=4)=[O:10])[N:17]=[CH:16][C:15]=3[C:18]([CH3:25])([CH3:26])[C:19]2=[O:24])[CH2:23][CH2:22]1
Reactant: Cc1ncc(C(=O)O)cn1
Reactant: CC1(C)C(=O)N(C2CC2)c2cc(N)ncc21
Product: Cc1ncc(C(=O)Nc2cc3c(cn2)C(C)(C)C(=O)N3C2CC2)cn1

Procedure:
Prepared in analogy to example 26 from 2-methylpyrimidine-5-carboxylic acid and 6-amino-1-cyclopropyl-3,3-dimethyl-1H-pyrrolo[3,2-c]pyridin-2(3H)-one (example 79c). The title compound was obtained as light yellow crystals.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:12]([CH2:13][CH2:14]Cl)=[C:11](Cl)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:17][C:18]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:19]=1[NH2:20]>CC(O)C>[CH3:17][C:18]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:19]=1[N:20]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[C:3]([CH3:2])[C:12]=2[CH2:13][CH2:14]1
Reactant: Cc1cccc(C)c1N
Reactant: Cc1nc2ccccc2c(Cl)c1CCCl
Agent: Cl
Solvent: CC(C)O
Product: Cc1cccc(C)c1N1CCc2c(C)nc3ccccc3c21
Yield: 10.5 %

Procedure:
A mixture of 2-methyl-3-(2-chloroethyl)-4-chloroquinoline hydrochloride (13.8 g, 50 mmol), 2,6-dimethylaniline (12.5 ml, 100 mmol) and 2-propanol (400 ml) was heated to 140° for 5 days in a pressure vessel, then cooled and evaporated. The crude product was converted to free base and chromatographed (silica gel, methanolic ammonia in dichloromethane). Recrystallisation from aqueous methanol followed by aqueous ethanol gave 1-(2,6-dimethylphenyl)-4-methyl- 2,3-dihydropyrrolo[3,2-c]quinoline (1.52 g), m.p. 149°-152°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([OH:19])=[CH:16]2)=[CH:11][C:10]=1[C:20]1[N:21]=[N:22][C:23]([N:26]([CH3:37])[CH:27]2[CH2:32][C:31]([CH3:34])([CH3:33])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]2)=[CH:24][CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:38]N1C(=O)CCC1=O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([OH:19])=[C:16]2[Cl:38])=[CH:11][C:10]=1[C:20]1[N:21]=[N:22][C:23]([N:26]([CH3:37])[CH:27]2[CH2:32][C:31]([CH3:33])([CH3:34])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]2)=[CH:24][CH:25]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN(c1ccc(-c2cc3ccc(O)cc3cc2OCc2ccccc2)nn1)C1CC(C)(C)NC(C)(C)C1
Solvent: CN(C)C=O
Product: CN(c1ccc(-c2cc3ccc(O)c(Cl)c3cc2OCc2ccccc2)nn1)C1CC(C)(C)NC(C)(C)C1
Reaction time: 8 h

Procedure:
To a reaction mixture of 7-(benzyloxy)-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol (100 mg, 0.201 mmol) in DMF (2 mL) was added N-chlorosuccinimide (32.3 mg, 0.242 mmol) at room temperature. The reaction mixture was stirred overnight then loaded onto an SCX column, washed with MeOH, and eluted with 2 M NH3 in MeOH. The product-containing fractions were concentrated and purified via silica gel flash column chromatography to give the title compound as a light brown solid product (25 mg, 23% yield). MS (M+1)=531.6.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:14][CH2:13]1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH:15]1[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][CH2:9][NH2:8])[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)NCCCN1CCC(c2ccccn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCN1CCC(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
To 1-Benzyl-4-(2-pyridyl)-piperidine (3.26 g, 12.9 mmol) in dry methanol (25 ml), 10% palladium hydroxide (1.9 g) was added and the solution was hydrogenated at 200 psi for 24 hours. The solution was filtered over celite, concentrated to give 2.1 g (99%) of 4-(2-pyridyl)-piperidine which was used as such for the subsequent step. A mixture of 3-bromopropylamine hydrobromide (20 g, 91.3 mmol), potassium carbonate (37.85 g, 273.9 mmol) and di-tert-butyldicarbonate (21.90 g, 100 mmol) in methanol was stirred at room temperature for 24 hours. The reaction mixture was concentrated and partitioned between 250 ml EtOAc and 50 ml water, dried over sodium sulfate, filtered and concentrated. Purification of the crude product by column chromatography (Hexane: EtOAc, 4.5:0.5) gave 17.5 g (80%) of the product as a pale yellow oil. To a stirred solution of the 4-(2-pyridyl)-piperidine (1.86 g, 11.4 mmol) in dioxane (20 ml), N-(tert-butoxycarbonyl)-3-bromopropylamine (2.82 g, 11.4 mmol) and potassium carbonate (3.16 g, 22.9 mmol) were added and the solution refluxed for 24 hours. The reaction mixture was cooled to room temperature, concentrated and partitioned between 40 ml chloroform and 5 ml water. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (ethyl acetate: methanol, 4:1) to yield 1.86 g (49%) of the required product as a colorless oil; 1H-NMR (CDCl3): δ 1.45 (s, 9 H),1.54-1.69 (m, 8 H), 2.21-2.68 (m, 2 H), 2.74-2.80 (m, 1 H), 3.02-3.22 (m, 4 H), 5.41 (s, 1H), 7.13-7.17 (m, 1 H), 7.33 (d, J=7.93 Hz, 1 H).7.63 (t, J=7.6 Hz, 1 H), 8.54 (d, J=4.6 Hz, 1 H). To N-(tert-butoxycarbonyl)-3-[4-(2-pyridyl)-piperidin-1-yl]propylamine (0.15g, 0.45 mmol) in 5 ml of dichloromethane, 1 ml of trifluoroacetic acid was added and the solution stirred at room temperature for 1 hour. The solution was concentrated, neutralized with 10% KOH solution and extracted into 25 ml of dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated to give 0.098 g (100w) of 3-[4-(2-pyridyl)-piperidin-1-yl]propylamine which was used as such for the subsequent step (step h).
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:13][C:12]([C:14]2[N:15]=[CH:16][N:17]([C:19]3[N:24]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)[CH:22]=[C:21]([CH3:32])[N:20]=3)[CH:18]=2)=[N:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[CH:22]=[C:21]([CH3:32])[N:20]=[C:19]([N:17]3[CH:18]=[C:14]([C:12]4[S:13][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:10][N:11]=4)[N:15]=[CH:16]3)[N:24]=2)=[CH:26][CH:27]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(-c3ncc(S(=O)(=O)NC(C)(C)C)s3)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(-c3ncc(S(N)(=O)=O)s3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 18.1 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-2-{1-[4-(4-chloro-phenyl)-6-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiazole-5-sulfonamide (0.1 g) in dichloromethane (2 mL) was added TFA (2 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and purified by flash-chromatography on silica gel (ethyl acetate/hexane) and crystallization (dichloromethane) to yielded the title compound as a light brown solid (0.016 g, 5%). MS (ISP) 433.2 [(M+H)+]; mp 255.5° C.