Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:21][CH2:20][CH2:19][N:18]([C:22](Cl)=[O:23])[CH2:17][C:16]=3[CH:25]=2)=[CH:8][CH:7]=1.C(N(C(C)C)CC)(C)C.Cl.[C:36]([CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)#[N:37]>ClCCl>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:21][CH2:20][CH2:19][N:18]([C:22]([N:41]4[CH2:42][CH2:43][CH:38]([C:36]#[N:37])[CH2:39][CH2:40]4)=[O:23])[CH2:17][C:16]=3[CH:25]=2)=[CH:8][CH:7]=1
Reactant: N#CC1CCNCC1
Reactant: O=C(Cl)N1CCOc2ccc(-c3ccc(-c4ncc[nH]4)nc3)cc2C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#CC1CCN(C(=O)N2CCOc3ccc(-c4ccc(-c5ncc[nH]5)nc4)cc3C2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
Dichloromethane (2 mL) was added to 7-[6-(1H-imidazol-2-yl)pyridin-3-yl]-2,3-dihydro-1,4-benzoxazepin-4(5H)-carbonyl chloride was obtained in step 4 followed by diisopropylethylamine (0.12 mL, 0.65 mmol) and 4-cyanopiperidine hydrochloride (25 mg, 0.16 mmol). The mixture was stirred at room temperature for 30 min and then concentrated. Purification of the residue by preparative reverse phase HPLC (0.1% aqueous ammonium acetate-acetonitrile) provided the title compound (18 mg, 32% yield) as a colorless solid. 1H NMR (400 MHz, DMSO-d6): 12.84 (br. S, 1H), 8.86 (d, 1H), 8.11 (m, 2H), 7.71 (d, 1H), 7.61 (dd, 1H), 7.25 (br. s, 1H), 7.10 (br. s, 1H), 7.06 (d, 1H), 4.49 (s, 2H), 4.23 (m, 2H), 3.61 (m, 2H), 3.30 (m, 2H), 3.00 (m, 3H), 1.87 (m, 2H), 1.73 (m, 2H); MS (EI) for C24H24N6O2: 429 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([OH:17])([CH3:16])[CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:3]=1.[Cl:18][C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1[CH2:21]Cl>>[Cl:18][C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1[CH2:21][O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:9]([OH:17])([CH3:16])[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: CC(O)(Cn1ccnc1)c1cc(F)ccc1O
Product: CC(O)(Cn1ccnc1)c1cc(F)ccc1OCc1ccc(Cl)cc1Cl
Yield: 31.6 %

Procedure:
The general procedure of Example 6 was repeated using 4-fluoro-2-(1-hydroxy-2-(1H-1-imidazolyl)-1-methylethyl)phenol [compound (2-4)] and 2,4-dichlorobenzyl chloride, to thereby yield 2-(2-((2,4-dichlorobenzyl)oxy)-5-fluorophenyl)-1-(1H-1-imidazolyl)-2-propanol as colorless crystals (yield: 31.6%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[CH2:3][CH:2]1[C:9]([O:11][CH3:12])=[O:10].[C:13]([NH:20][CH2:21][CH:22]=O)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:17][C:16]([O:15][C:13]([NH:20][CH2:21][CH2:22][N:1]1[CH2:6][CH2:5][S:4](=[O:7])(=[O:8])[CH2:3][CH:2]1[C:9]([O:11][CH3:12])=[O:10])=[O:14])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: COC(=O)C1CS(=O)(=O)CCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COC(=O)C1CS(=O)(=O)CCN1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 15.7 %

Procedure:
To a stirred solution of methyl 3-thiomorpholinecarboxylate 1,1-dioxide (D16; 1.08 g, 5.6 mmol) in 14 ml of anhydrous 1,2-dichloroethane was added N-boc-2-aminoacetaldehyde (1.1 g, 6.7 mmol) and acetic acid (0.316 ml, 5.6 mmol). After 30 min. sodium triacetoxyborohydride (1.78 g, 8.4 mmol) was added and the solution stirred at room temperature. Additional aliquots of N-boc-2-aminoacetaldehyde and sodium triacetoxyborohydride (1.0 g, 4.7 mmol) were added and the reaction continued overnight. The solvent was removed under reduced pressure and the residue was purified by SCX column, followed by chromatography (silica, cyclohexane:ethyl acetate 70:30 to 1:1) and again SCX, to give 295 mg of the target compound.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:29])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH2:26][CH3:27])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[C:8]=1[CH3:28]>C1COCC1.CO>[CH2:26]([S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:9]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:15]3[C:7]([CH2:6][C:5]([OH:29])=[O:4])=[C:8]2[CH3:28])=[CH:18][CH:19]=1)(=[O:25])=[O:24])[CH3:27]
Reactant: CCS(=O)(=O)c1ccc(Cn2c(C)c(CC(=O)OC)c3cccnc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(Cn2c(C)c(CC(=O)O)c3cccnc32)cc1

Procedure:
1M Aqueous NaOH (1 ml) is added to a stirring solution of [1-(4-ethanesulfonyl-benzyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester (89 mg, 0.23 mmol) in 1:1 THF/MeOH (4 ml). After 1 hour the reaction is evaporated and the resulting oil is dissolved in water (8 ml) and acidified to pH 3. The resulting precipitate is collected by filtration and dried in vacuo to afford [1-(4-ethanesulfonyl-benzyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid (MH+ 373)
Reaction SMILES: [OH:1][C:2]([CH3:41])([CH3:40])[CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[C:37](C)[N:38]=[C:12]23)[CH2:7][CH2:6]1.C([Sn](=O)CCCC)CCC.[N:52]([Si](C)(C)C)=[N+:53]=[N-:54].C1(C)C=CC=CC=1>C(OCC)(=O)C>[OH:1][C:2]([CH3:41])([CH3:40])[CH2:3][O:4][C@H:5]1[CH2:6][CH2:7][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]4[NH:54][N:53]=[N:52][N:32]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[CH:37][N:38]=[C:12]23)[CH2:9][CH2:10]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2nc(C)nn12
Agent: CCCC[Sn](=O)CCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ncnn12
Temperature: 110 °C
Reaction time: 48 h

Procedure:
A mixture of 4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.2 g), dibutyltin oxide (0.046 g), azidotrimethylsilane (1.3 g) and toluene (15 mL) was stirred at 110° C. for 48 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium fluoride solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (10 mL). Tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 0.93 mL) was added and the mixture was stirred at 70° C. for 1 hr. Ethyl acetate and 1 N hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.033 g, 15%).
Reaction SMILES: C(O)C.[Cl-].[NH4+].[CH3:6][S:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:9]=1[OH:17]>[Zn].O>[CH3:6][S:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[OH:17]
Reactant: CSc1ccc([N+](=O)[O-])cc1O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: CSc1ccc(N)cc1O

Procedure:
The suspension obtained on mixing 150 ml of 96° strength ethanol, 16 ml of water, 2.3 g of ammonium chloride and 78 g of finely powdered zinc is brought to reflux. 25.1 g (0.15 mol) of 2-methylthio-5-nitrophenol are added portionwise so as to maintain the reflux without heating (exothermic reaction).
Reaction SMILES: [CH3:1][N:2]1[C:6]([N:7]2[CH2:12][CH2:11][NH:10][CH:9]([C:13]([F:16])([F:15])[F:14])[CH2:8]2)=[C:5]([NH2:17])[CH:4]=[N:3]1.[C:18]([O:22][C:23]([NH:25][C:26]1[S:30][C:29]([C:31]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=2[F:38])=[N:28][C:27]=1[C:39](O)=[O:40])=[O:24])([CH3:21])([CH3:20])[CH3:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[F:38][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([F:37])[C:31]=1[C:29]1[S:30][C:26]([NH:25][C:23](=[O:24])[O:22][C:18]([CH3:20])([CH3:19])[CH3:21])=[C:27]([C:39](=[O:40])[NH:17][C:5]2[CH:4]=[N:3][N:2]([CH3:1])[C:6]=2[N:7]2[CH2:12][CH2:11][NH:10][CH:9]([C:13]([F:16])([F:15])[F:14])[CH2:8]2)[N:28]=1
Reactant: Cn1ncc(N)c1N1CCNC(C(F)(F)F)C1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCNC(C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 37.4 %

Procedure:
To a solution of (±)-1-methyl-5-(3-(trifluoromethyl)piperazin-1-yl)-1H-pyrazol-4-amine (300 mg, 2.05 mmol), 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25 (516 mg, 1.73 mmol), HATU (0.54 g, 1.73 mmol) in DMF (15 mL) was added TEA (1.1 mL). The reaction mixture was stirred at 25° C. for 20 hours, poured into water (100 mL), and extracted with EtOAc (50 mL×2). The combined organic layers was washed with water (50 mL×2) and brine (30 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using DCM/MeOH (1:1) as eluting solvents to afford tert-butyl (±)-2-(2,6-difluorophenyl)-4-(1-methyl-5-(3-(trifluoromethyl)piperazin-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate (380 mg, 52%) as white solid. MS (ESI) m/z: 588 (M+1+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C@H:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)[CH3:11])=[O:8].[F:22][C:23]([F:34])([F:33])[O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>C(Cl)Cl>[F:22][C:23]([F:33])([F:34])[O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C@H:10]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=1)[CH3:11])=[O:8]
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCCN2)cc1
Reactant: O=Cc1cccc(OC(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCCN2Cc2cccc(OC(F)(F)F)c2)cc1
Temperature: 100 °C
Yield: 65.9 %

Procedure:
A mixture of methyl 4-((S)-1-((R)-piperidine-2-carboxamido)ethyl)benzoate (D12) (50 mg, 0.17 mmol) and 3-(trifluoromethoxy)benzaldehyde (0.025 ml, 0.20 mmol), NaBH(OAc)3 (109 mg, 0.52 mmol) and catalytic CH3COOH in DCM (12 ml) was heated at 100° C. (2 cycles of 5 min each) under microwave irradiation. The resulting mixture was purified by SPE-Si (2 g) eluting with a mixture DCM/AcOEt from 100/0 to 80/20. Collected fractions after solvent evaporation afforded the title compound (D25) (52 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][C:11]2([C:16](=[O:17])[N:15]([C:18]3[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=3)[CH2:14][CH2:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][N:28]([CH3:46])[C:29]([C:31]1[N:40]([CH:41]2[CH2:45][CH2:44][CH2:43][CH2:42]2)[C:34]2[N:35]=[C:36](Cl)[N:37]=[CH:38][C:33]=2[CH:32]=1)=[O:30]>>[C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][C:11]2([C:16](=[O:17])[N:15]([C:18]3[CH:19]=[N:20][C:21]([NH:24][C:36]4[N:37]=[CH:38][C:33]5[CH:32]=[C:31]([C:29](=[O:30])[N:28]([CH3:27])[CH3:46])[N:40]([CH:41]6[CH2:45][CH2:44][CH2:43][CH2:42]6)[C:34]=5[N:35]=4)=[CH:22][CH:23]=3)[CH2:14][CH2:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCN(c3ccc(N)nc3)C2=O)CC1
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCCC5(CCN(C(=O)OC(C)(C)C)CC5)C4=O)cn3)nc2n1C1CCCC1
Yield: 93.1 %

Procedure:
Following general N—C coupling procedure 1, 2-(6-amino-pyridin-3-yl)-1-oxo-2,9-diaza-spiro[5,5]undecane-9-carboxylic acid tert-butyl ester (98 mg, 0.27 mmol) was combined with 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (80 mg, 0.27 mmol) which gave 2[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-1-oxo-2,9-diaza-spiro[5,5]undecane-9-carboxylic acid tert-butyl ester (155 mg) in 92% yield. 1H NMR (400 MHz, CD2Cl2) δ 8.92-8.70 (m, 1H), 8.63-8.53 (m, 1H), 8.25-8.13 (m, 1H), 7.75-7.36 (m, 1H), 6.59-6.46 (m, 1H), 4.93-4.70 (m, 1H), 3.93-3.78 (m 2H), 3.74-3.65 (m, 2H), 3.28-3.18 (m, 2H), 3.14 (s, 6H), 2.65-2.49 (m, 2H), 2.24-1.88 (m, 9H), 1.85-1.71 (m, 2H), 1.65-1.50 (m, 3H), 1.47 (s, 9H); HR-MS m/z 617.3583 (M+H)+
Reaction SMILES: [C:1]([P:5](Cl)[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].O1CCC[CH2:12]1.C[Mg]Br.C1(C)C=CC=CC=1>[Cu]Cl.O>[C:1]([P:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[CH3:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Reactant: C1CCOC1
Agent: Cl[Cu]
Agent: C[Mg]Br
Solvent: Cc1ccccc1
Solvent: O
Product: CP(C(C)(C)C)C(C)(C)C
Reaction time: 5 h
Yield: 91.1 %

Procedure:
In a 300 ml four-necked flask thoroughly purged with nitrogen, 9.0 g (0.05 mol) of di-tert-butylphosphinous chloride, 0.025 g (0.25 mol (corresponding to 0.5% by mol)) of copper(I) chloride and 30 ml of tetrahydrofuran were placed. To the contents of the flask, 55 ml (0.055 mol) of a tetrahydrofuran solution of methylmagnesium bromide having a concentration of 1 mol/liter was dropwise added over a period of 1 hour with maintaining the temperature at 25° C. to 30° C. After the dropwise addition was completed, stirring was conducted at the same temperature for 5 hours. Then, disappearance of di-tert-butylphosphinous chloride was confirmed by gas chromatography. Thereafter, 40 ml of toluene and 40 ml of water were added to the reaction solution to perform liquid separation. Then, the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, followed by further distillation. Then, fractions given by distillation at 750° C. to 810° C. under reduced pressure of 20 Torr were collected. As a result, 7.4 g (purity: 98.7%) of the aimed di-tert-butylmethylphosphine was obtained as an oily substance. The yield was 91.1%.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:16][C:15]1[CH:17]=[CH:18][CH:19]=[C:13]([Cl:12])[CH:14]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: Nc1cccc(Cl)c1
Product: O=C(Nc1cccc(Cl)c1)c1cc(Br)ccc1O
Yield: 63.1 %

Procedure:
Using 5-bromosalicylic acid and 3-chloroaniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[CH:13]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>O1CCOCC1>[Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:19][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CS(=O)(=O)c1ccc(F)c(Br)c1
Reactant: NC1CCCCC1
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(NC2CCCCC2)c(Br)c1
Temperature: 110 °C
Yield: 66.7 %

Procedure:
A mixture of 2-bromo-1-fluoro-4-(methylsulfonyl)benzene (0.05 g, 0.198 mmol) and cyclohexanamine (0.059 g, 0.593 mmol) in dioxane (1 mL) in a vial was capped and heated at 110° C. for three days. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 40% ethyl acetate in hexanes to afford the title compound (0.044 g, 0.132 mmol, 67.0% yield).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)(=[O:3])=[O:4]
Reactant: Cc1ccc(S(C)(=O)=O)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1ccc(S(C)(=O)=O)cc1[N+](=O)[O-]
Temperature: 10 °C
Reaction time: 2 h

Procedure:
68 g of 4-methylsulfonyltoluene in 400 ml of concentrated sulfuric acid were admixed at 0°-10° C. with a mixture of 80 ml of concentrated sulfuric acid and 31 ml of 65% strength by weight nitric acid. The reaction mixture was stirred at 10° C. for 2 hours and at room temperature for a further 2 hours. It was then poured onto about 1 kg of ice, and the solids were filtered off with suction, washed with water and dried at 50° C. under reduced pressure, to leave 85 g of 4-methylsulfonyl-2-nitrotoluene (melting point 112°-115° C.).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([N:8]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[CH3:14])[CH:3]=1.[CH3:15][N:16]1[CH2:21][CH:20]=[C:19](B2OC(C)(C)C(C)(C)O2)[CH2:18][CH2:17]1.CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C>[CH3:14][C:9]1[N:8]([C:4]2[CH:3]=[C:2]([C:19]3[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH:18]=3)[N:6]([CH3:7])[N:5]=2)[C:12]([CH3:13])=[CH:11][CH:10]=1
Reactant: CN1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Cc1ccc(C)n1-c1cc(Br)n(C)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C)n1-c1cc(C2=CCN(C)CC2)n(C)n1
Yield: 67.7 %

Procedure:
Under argon atmosphere, to a mixture of 5-bromo-3-(2,5-dimethyl-1H-pyrrol-1-yl)-1-methyl-1H-pyrazole (100 mg), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (105 mg), and N,N-dimethylformamide (2 mL) were added a 1,1′-bis(diphenylphosphino)ferrocene-palladium (II) dichloride-dichloromethane complex (32 mg), and cesium carbonate (256 mg), followed by reacting them at 80° C. for 1 hour. After leaving to be cooled, ethyl acetate was added thereto, and the mixture was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol=1:0-9:1) to obtain 4-[3-(2,5-dimethyl-1H-pyrrol-1-yl)-1-methyl-1H-pyrazol-5-yl]-1-methyl-1,2,3,6-tetrahydropyridine (72 mg) as a brown oily substance.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10](Br)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([NH:30][C:31]([NH2:33])=[S:32])[CH:21]=[CH:22][C:23]=1[N:24]1[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]1.C(N(CC)C(C)C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:33]=[C:31]([NH:30][C:20]3[CH:21]=[CH:22][C:23]([N:24]4[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]4)=[C:18]([O:17][CH3:16])[CH:19]=3)[S:32][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(Br)C1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2nc3c(s2)CN(C(=O)OC(C)(C)C)CC3)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogy to example 1 step e) from 92 mg (0.33 mmol) 3-bromo-4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 79 mg (0.3 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea and 43 mg (0.33 mmol) N,N-diisopropyl ethyl amine. The reaction was poured onto water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulphate, filtered and the solvent was evaporated in vacuo. The crude product was purified on silica gel with methylene chloride/methanol 19/1 yielding 99 mg (75%) 2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butyl ester as a light yellow foam. MS ISP (m/e): 442.3 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.32 (s, 1H), 7.64 (s, 1H), 7.47 (s, 1H), 7.31 (d, 1H), 7.25 (d, 1H), 7.02 (d, 1H), 4.43 (s, 2H), 3.78 (s, 3H), 3.64 (t, 2H), 2.63 (m, 2H), 2.14 (s, 3H), 1.43 (s, 9H).
Reaction SMILES: [C:1]1([C:11]([OH:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]=1.[CH2:14]=[CH:15][CH:16]=[CH2:17].OC1C=CC=CC=1C>C1(C)C=CC=CC=1>[CH2:14]1[C@@H:2]2[C@@:1]([C:11]([OH:13])=[O:12])([C:10]3[C:5]([CH2:4][CH2:3]2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:17][CH:16]=[CH:15]1
Reactant: O=C(O)C1=CCCc2ccccc21
Reactant: C=CC=C
Agent: Cc1ccccc1O
Solvent: Cc1ccccc1
Product: O=C(O)[C@]12CC=CC[C@H]1CCc1ccccc12
Yield: 27 %

Procedure:
To a solution of 3,4-dihydronaphthalene-1-carboxylic acid (29.7 g) in toluene (75 ml) was added butadiene (16 g) and a trace of butyrated hydroxy toluene (BHT). The solution was heated to 180° for 18 hours in a sealed reactor, then chromatographed twice over silica gel. Recrystallization from ethyl acetate/heptane affords the title compound as a colorless crystalline solid (10.5 g). The recovered starting material was rereacted with butadiene to afford, after workup, additional title product (8.0 g). ##STR19##
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.[I:12]I>CCCCCCC.[Hg]=O>[I:12][C:9]1[S:8][C:7]([C:5]2[S:6][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:11][CH:10]=1
Reactant: Cc1ccc(-c2cccs2)s1
Reactant: II
Agent: O=[Hg]
Solvent: CCCCCCC
Product: Cc1ccc(-c2ccc(I)s2)s1
Reaction time: 20 h

Procedure:
A solution of 12.2 grams (0.068 mole) of 5-methyl(2,2'-bithienyl) in 50 mL of heptane was stirred, and, in alternate portions, 17.8 (0.070 mole) of iodine and 12.4 grams (0.057 mole) of mercury (II) oxide were added. Upon completion of addition the reaction mixture stirred for 20 hours, and then was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to a residual solid. The solid was recrystallized from ethanol to yield 5.2 grams of 5-iodo-5'-methyl(2,2'-bithienyl).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:15]=[C:14]([O:16][CH2:17][C:18]([C:20]2[CH:29]=[CH:28][C:27]3[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[C:22]=3[CH:21]=2)=[O:19])[CH:13]=[CH:12][C:5]=1[C:6]([O:8][CH2:9][CH:10]=[CH2:11])=[O:7].[CH3:34][O:35][CH2:36][CH2:37][O:38][CH2:39]Cl.O>CN(C=O)C>[CH3:34][O:35][CH2:36][CH2:37][O:38][CH2:39][O:3][C:4]1[CH:15]=[C:14]([O:16][CH2:17][C:18]([C:20]2[CH:29]=[CH:28][C:27]3[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[C:22]=3[CH:21]=2)=[O:19])[CH:13]=[CH:12][C:5]=1[C:6]([O:8][CH2:9][C:10]1[CH:6]=[CH:5][CH:4]=[CH:15][CH:11]=1)=[O:7]
Reactant: C=CCOC(=O)c1ccc(OCC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1O
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCOc1cc(OCC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)ccc1C(=O)OCc1ccccc1

Procedure:
1.65 g (55 mmol) of sodium hydride (80% in oil) and 50 ml of DMF are introduced into a flask. A solution of 23.6 g (50 mmol) of allyl 2-hydroxy-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoyl methoxy)benzoate in 200 ml of DMF is added dropwise and the mixture is stirred until evolution of gas has ceased. 6.3 ml (55 mmol) of 2-methoxy ethoxymethyl chloride are then added dropwise and the reaction mixture is stirred for 2 hours. It is poured into water and extracted with ethyl ether, and the organic phase is separated, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column, eluted with a mixture of dichloromethane/ethyl ether (98:2). After evaporation of the solvents, 19.2 g (69%) of the expected ester are collected in the form of a slightly yellow oil.