Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[C:10]([CH3:11])=[C:9]([O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[CH:8]=[C:7]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:6]=1[OH:23])([CH3:4])([CH3:3])[CH3:2].CCCCCC.C([Li])CCC.[C:35](Cl)(=[O:37])[CH3:36].[Cl-].[NH4+]>O1CCCC1>[C:35]([O:23][C:6]1[C:7]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:8][C:9]([O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)=[C:10]([CH3:11])[C:5]=1[C:1]([CH3:3])([CH3:4])[CH3:2])(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: Cc1c(OC2CCCCO2)cc(C(C)(C)C)c(O)c1C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(=O)Oc1c(C(C)(C)C)cc(OC2CCCCO2)c(C)c1C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
2,6-Di-tert-butyl-3-methyl-4-tetrahydropyranyloxyphenol (4.4 g) was dissolved in anhydrous tetrahydrofuran (50 ml) and a n-hexane solution (1.1 eq.) of n-butyllithium was added dropwise at 0° C. under a nitrogen atmosphere. After stirring the mixture for 30 min, acetyl chloride (1.08 ml, 1.1 eq.) was added and the mixture was allowed to warm to room temperature. After stirring for 3 h, the reaction mixture was poured into a saturated aqueous solution of ammonium chloride and the mixture was subjected to extraction with diethyl ether. The extract was washed with water and saturated brine, then dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by silica gel chromatography (10% ethyl acetate in n-hexane) to afford 1-acetoxy-2,6-di-tert-butyl-3-methyl-4-tetrahydropyranyloxybenzene [4.09 g (yield, 82.2%)] as a colorless crystal. Mass 362(M+)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.F[C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=1>O>[N:1]1([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: CC(=O)c1ccc(F)cc1
Solvent: O
Product: CC(=O)c1ccc(N2CCOCC2)cc1
Temperature: 120 °C
Yield: 93 %

Procedure:
A mixture of morpholine (3.2 g, 37 mmol) and 1-(4-fluorophenyl) ethanone (1.5 g, 11 mmol) is heated at 120° C. The conversion of the 1-(4-fluorophenyl) ethanone is complete after 10 hours. Water (10 ml) is than added into the reaction mixture. The precipitate is filtered off, washed with water and dried under vacuum (30° C.) to give 2.1 g of the title-compound. Yield: 93%; m.p. 95-96° C.; MS 205 (100, M+); H1 NMR (CDCl3): δ 7.99 (d, 2H), 6.86 (d, 2H), 3.86 (t, 4H), 3.30 (t, 4H), 2.53 (s, 3H); C13 NMR (CDCl3): δ 196.76, 154.43, 130.55, 128.36, 113.48, 101.16, 66.7, 47.73, 26.37.
Reaction SMILES: C(O[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=2)[N:12]=[C:11]([N:22]2[CH2:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[S:25](=[O:33])[CH2:24][CH2:23]2)[N:10]=1)C1C=CC=CC=1.[O:34]1[CH2:37][C:36]([CH2:40][NH2:41])([CH2:38][NH2:39])[CH2:35]1>>[NH2:39][CH2:38][C:36]1([CH2:40][NH:41][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=3)[N:12]=[C:11]([N:22]3[CH2:28][C:27]4[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=4[S:25](=[O:33])[CH2:24][CH2:23]3)[N:10]=2)[CH2:37][O:34][CH2:35]1
Reactant: O=C(O)c1ccc2nc(N3CCS(=O)c4ccccc4C3)nc(OCc3ccccc3)c2c1
Reactant: NCC1(CN)COC1
Product: NCC1(CNc2nc(N3CCS(=O)c4ccccc4C3)nc3ccc(C(=O)O)cc23)COC1
Temperature: 170 °C

Procedure:
A mixture of 4-(benzyloxy)-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4 (5H)-yl)quinazoline-6-carboxylic acid (170 mg, 0.37 mmol) and oxetane-3,3-diyldimethanamine (128 mg, 1.11 mmol) was heated at 170° C. for 30 minutes. Then the reaction mixture was cooled to room temperature and purified by preparative HPLC to afford 4-({[3-(Aminomethyl)oxetan-3-yl]methyl}amino)-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazoline-6-carboxylic acid, MS obsd. (ESI+) [(M+H)+] 468, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.91-8.61 (m, 2 H), 8.09-8.00 (m, 1 H), 7.77-7.74 (m, 1 H), 7.68-7.65 (m, 1 H), 7.51-7.42 (m, 2 H), 7.27-7.13 (m, 1 H), 5.26-5.17 (m, 2 H), 4.89-4.68 (m, 4 H), 452-4.45 (m, 2 H), 4.40-4.31 (m, 2 H), 4.10-3.84 (m, 2 H), 3.20-3.01 (m, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14]([C:17]([NH:19][C:20]3[S:21][C:22]4[CH2:23][NH:24][CH2:25][CH2:26][C:27]=4[N:28]=3)=[O:18])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.C([O:38][CH2:39][C:40](Cl)=[O:41])(=O)C.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CO>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:12][CH2:13][N:14]([C:17]([NH:19][C:20]3[S:21][C:22]4[CH2:23][N:24]([C:39](=[O:38])[CH2:40][OH:41])[CH2:25][CH2:26][C:27]=4[N:28]=3)=[O:18])[CH2:15][CH2:16]2)=[CH:4][CH:3]=1
Reactant: CC(=O)OCC(=O)Cl
Reactant: O=C(Nc1nc2c(s1)CNCC2)N1CCC(N2CCc3ccc(F)cc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CO
Product: O=C(CO)N1CCc2nc(NC(=O)N3CCC(N4CCc5ccc(F)cc54)CC3)sc2C1
Reaction time: 0.33 h

Procedure:
To a solution of 4-(6-fluoroindolin-1-yl)-N-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)piperidine-1-carboxamide, prepared as in Example 19 above (77.3 mg, 0.15 mmol) in CH2Cl2 (2 mL) was added pyridine (0.035 mL, 0.45 mmol, 3 equiv) and then acetoxyacetyl chloride (0.024 mL, 0.225 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred for 20 min and MeOH (2 mL) and K2CO3 (138 mg, 1.0 mmol) were added sequentially. The resulting mixture was stirred at room temperature for another 1 h. The resulting mixture was filtered and concentrated. The resulting residue was purified by column using 90-100% EtOAc/hexane as the eluent to yield an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([NH:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[N+:19]([O-])=O)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:33])[N:6]2[C@H:22]1[C:31]2[C:26](=[C:27]([F:32])[CH:28]=[CH:29][CH:30]=2)[O:25][CH2:24][CH2:23]1.C(O)(=O)C.O.[OH-].[NH4+]>[Fe].C(O)C>[NH2:19][C:13]1[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=1[NH:11][C:9]1[N:8]=[C:7]2[C:3]([NH:4][C:5](=[O:33])[N:6]2[C@H:22]2[C:31]3[C:26](=[C:27]([F:32])[CH:28]=[CH:29][CH:30]=3)[O:25][CH2:24][CH2:23]2)=[C:2]([Cl:1])[N:10]=1
Reactant: O=c1[nH]c2c(Cl)nc(Nc3cc(F)ccc3[N+](=O)[O-])nc2n1[C@@H]1CCOc2c(F)cccc21
Agent: [Fe]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1ccc(F)cc1Nc1nc(Cl)c2[nH]c(=O)n([C@@H]3CCOc4c(F)cccc43)c2n1
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
To a round bottom flask containing (R)-6-chloro-2-(5-fluoro-2-nitrophenylamino)-9-(8-fluorochroman-4-yl)-7H-purin-8(9H)-one (310 mg, 0.65 mmol) was added glacial acetic acid (15 mL), water (37.5 mL) and ethanol (75 mL), followed by iron powder (370 mg, 6.5 mmol, 10 equiv.) and the resulting mixture heated at 90° C. for 15 min (HPLC monitoring). The reaction mixture was left to cool down to room temperature, concentrated ammonium hydroxide solution (32 mL) was added to bring the pH to basic, and the mixture was stirred for 10 min. The aqueous layer was extracted with ethyl acetate (5×100 mL), the combined organic layers were washed with brine, dried (anhydrous Na2SO4), and the solvent removed in vacuo to give the desired product as a pink solid (yield quantitative). This material was used in the next step without further purification. MS (EI) m/z 445.2 (MH)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]([CH3:40])[CH3:39])=[CH:34][CH:33]=1>>[CH:38]([C:35]1[CH:36]=[CH:37][C:32]([CH2:31][O:1][C:2]2[CH:3]=[C:4]([C:8]3[C:17]4[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=4)[N:11]=[CH:10][C:9]=3[C:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:23])[CH:5]=[CH:6][CH:7]=2)=[CH:33][CH:34]=1)([CH3:40])[CH3:39]
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Reactant: CC(C)c1ccc(CBr)cc1
Product: CC(C)c1ccc(COc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 1-Bromomethyl-4-isopropylbenzene following the procedure of Example 478: MS (ESI) m/z 526;
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[S:5][C:6]=1[CH2:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2.[C:28]([O:32][C:33](=[O:36])[CH2:34]Br)([CH3:31])([CH3:30])[CH3:29].[H-].[Na+]>CN(C=O)C>[C:28]([O:32][C:33](=[O:36])[CH2:34][N:13]1[C:14]2[C:10](=[C:9]([O:8][CH2:7][C:6]3[S:5][C:4]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][CH:19]=4)=[N:3][C:2]=3[CH3:1])[CH:17]=[CH:16][CH:15]=2)[CH:11]=[CH:12]1)([CH3:31])([CH3:30])[CH3:29]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1cccc2[nH]ccc12
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1cccc2c1ccn2CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 76.2 %

Procedure:
To a solution of 4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-1H-indole (50 mg, 130 μmol) and bromo-acetic acid tert-butyl ester (20 μl, 140 μmol) in DMF (4 ml) was added sodium hydride (55%, 8 mg, 176 μmol) under an argon atmosphere at 0° C. The mixture was naturally warmed to room temperature, stirred for 72 h, poured onto 1 N HCl/ice water 1/1 and extracted three times with dichloromethane. The combined organic layers were washed with water and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography (silica gel, heptane/AcOEt) to give 50 mg (99 μmol, 77%) of the title compound as light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[N:12]([CH:19]([CH3:29])[CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:11]=2)=[O:9])[CH:3]=1.[Cl:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:37][C:38](O)=[O:39])=[N:35][CH:36]=1>>[Si:22]([O:21][CH2:20][CH:19]([N:12]1[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:38](=[O:39])[CH2:37][C:34]3[CH:33]=[CH:32][C:31]([Cl:30])=[CH:36][N:35]=3)[CH:7]=[CH:6][N:5]=2)=[O:9])=[CH:11]1)[CH3:29])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24]
Reactant: O=C(O)Cc1ccc(Cl)cn1
Reactant: CC(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cc(N)ccn2)c2cnccc21
Product: CC(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cc(NC(=O)Cc3ccc(Cl)cn3)ccn2)c2cnccc21

Procedure:
Prepared according to Method Z (Preparation 8) using (4-aminopyridin-2-yl)[1-(2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]methanone (Preparation 30) and (5-chloropyridin-2-yl)acetic acid (Preparation 80).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C@H:10]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[S:26](Cl)(Cl)=[O:27]>ClCCl>[CH2:1]([N:8]1[CH2:9][C@H:10]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[O:11][S:26]1=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O[C@H](CNCc1ccccc1)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S1O[C@@H](c2ccc(Cl)cc2)CN1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 87.4 %

Procedure:
To a suspension of (S)-2-benzylamino-1-(4-chlorophenyl)ethanol (15.76 g, 60.21 mmol) and triethylamine (33.6 ml, 241 mmol) in dichloromethane (300 ml) was added a solution of thionyl chloride (4.83 ml, 66.2 mmol) in dichloromethane (20 ml) at −78° C. over 20 min. The resulting suspension was stirred at −78° C. for 20 min and at 0° C. for additional 20 min. The reaction mixture was partitioned between ether and water, and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 10-20% ethyl acetate-hexane) to afford (2RS,5S)-3-benzyl-5-(4-chlorophenyl)-1,2,3-oxathiazolidine 2-oxide (16.2 g 87.4%) as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[C:4]([CH2:12][CH2:13][OH:14])=[CH:5][NH:6]2.I(C1C=CC=CC=1C(O)=O)(=O)=O>CS(C)=O.O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[C:4]([CH2:12][CH:13]=[O:14])=[CH:5][NH:6]2
Reactant: OCCc1c[nH]c2c(F)ccc(Br)c12
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CS(C)=O
Solvent: O
Product: O=CCc1c[nH]c2c(F)ccc(Br)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
The mixture of 2-(4-bromo-7-fluoro-1H-indol-3-yl)-ethanol (3.00 g, 11.6 mmol) and o-iodoxybenzoic acid (IBX, 9.76 g, 34.9 mmol) in DMSO (60 mL) was stirred overnight at room temperature. The solution was diluted with H2O (100 mL) and the precipitates were filtered and the filter cake was rinsed with EtOAc. The filtrate was extracted with EtOAc (3×150 mL) and the combined organic solution was washed with brine (300 mL), dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (silica, 25% EtOAc in hexanes) to give 2.48 g (83%) of the title compound as a pale yellow solid. 1H NMR (CDCl3): 300 MHz δ 9.93 (s, 1H), 8.44 (bs, 1H), 7.20 (m, 1H), 7.17 (dd, J=8.40, 4.32 Hz, 1H), 6.80 (dd, J=10.2, 8.40 Hz, 1H), 4.12 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1(Cl)[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13].C([O-])(=O)C.[Na+].[H][H]>C(O)(=O)C.[Pd]>[Cl:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13]
Reactant: O=C1Nc2ccccc2CCC1(Cl)Cl
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1Nc2ccccc2CCC1Cl

Procedure:
A solution of 3,3-dichloro-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (20 g, 0.174 mol) and anhydrous sodium acetate (15.4 g, 0.188 mol) in glacial acetic acid (920 ml) was hydrogenated at atmospheric pressure using 5% Pd-C (1.72 g) as catalyst until the uptake of hydrogen ceased. The catalyst was filtered off and the acetic acid evaporated under reduced pressure. The residue was equilibrated between 10% NaHCO3 (900 ml) and dichloromethane (300 ml). The aqueous layer (pH 8) was further extracted with dichloromethane (3×300 ml) and the combined organic solutions were dried over anhydrous sodium sulfate and evaporated to give 3-chloro-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one, m.p. 163°-167°.
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][C:12]([O:14]C)=[O:13].[OH-].[Na+].Cl>>[C:12]([CH2:11][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([OH:16])=[O:2])([OH:14])=[O:13]
Reactant: COC(=O)COc1ccccc1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)COc1ccccc1C(=O)O
Temperature: 80 °C
Yield: 78.2 %

Procedure:
2-Methoxycarbonylmethoxybenzoic acid methyl ester 1 (95 g, 424 mmol) was added to a 10% aqueous NaOH solution (475 ml) and heated at 80° C. for 4 hrs. The reaction mixture was cooled to room temperature and pH adjusted to 2 with dilute HCl. Crude 91 was purified by dissolving in 10% aqueous NaOH and precipitated by acidifying with HCl, to get pure 91 (65 g, 78.2%) as a white powder. M.p: 189-192° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:10][C@H:9]1[CH3:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of (2R,4R)-1-(tert-butoxycarbonyl)-4-hydroxy-2-methylpyrrolidine (1.92 g) and methanesulfonyl chloride (955 μl) in dichloromethane (30 ml) was added dropwise triethylamine (1.99 ml) at 0° C. After one hour, the reaction mixture was washed in turn with 1N-hydrochloric acid and brine and the organic layer was dried over magnesium sulfate. Evaporation of the solvent gave an oil, which was chromatographed on silica gel (200 ml) eluting with a mixture of hexane and ethyl acetate (1:1, V/V) to give (2R,4R)-1-(tert-butoxycarbonyl)-4-methanesulfonyloxy-2-methylpyrrolidine (2.49 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[N:6][C:7]=1Cl.[NH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.C(N(CC)C(C)C)(C)C>CN1C(=O)CCC1>[NH2:9][C:3]1[N:4]=[CH:5][N:6]=[C:7]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[C:2]=1[Cl:1]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: Nc1ncnc(Cl)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC(CNc2ncnc(N)c2Cl)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 10-mL vial was placed 5,6-dichloropyrimidin-4-amine (250.00 mg; 1.52 mmol), tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (653.40 mg; 3.05 mmol), and N,N-diisopropylethylamine (1.01 ml; 6.10 mmol) suspended in NMP (2.50 ml). The reaction mixture was run in the microwave at 150° C. for 2 hours. The reaction mixture was allowed to cool to rt. The mixture was purified using Biotage column chromatography eluting from 50-100% EtOAc/Hexanes. Fractions containing the desired product were combined and concentrated under reduced pressure to afford tert-butyl 4-{[(6-amino-5-chloropyrimidin-4-yl)amino]methyl}piperidine-1-carboxylate as a yellow viscous oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([NH:7][CH2:8][C:9]1[CH:18]=[C:17]([Br:19])[CH:16]=[C:15]2[C:10]=1[N:11]=[C:12]([O:22]C)[C:13]([O:20]C)=[N:14]2)=[O:6])[CH3:2]>Br.C(O)(=O)C.C(OCC)C>[CH2:1]([O:3][C:4](=[O:24])[C:5]([NH:7][CH2:8][C:9]1[CH:18]=[C:17]([Br:19])[CH:16]=[C:15]2[C:10]=1[NH:11][C:12](=[O:22])[C:13](=[O:20])[NH:14]2)=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)NCc1cc(Br)cc2nc(OC)c(OC)nc12
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)C(=O)NCc1cc(Br)cc2[nH]c(=O)c(=O)[nH]c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
254 mg (0.79 mmol) of N-(7-bromo-2,3-dimethoxy-quinoxalin-5-ylmethyl)-oxalamic acid ethyl ester are dissolved in 6 ml of an approximately 25% solution of hydrogen bromide in acetic acid, and the solution is stirred at room temperature for 16 hours. The mixture is diluted with diethyl ether, and the solid is filtered off and washed with diethyl ether. After drying under a high vacuum, the title compound is obtained in the form of a beige solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10].C(=O)([O-])[O-].[K+].[K+].[Cl:32][C:33]([CH2:35]Cl)=[CH2:34]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH2:35][C:33]([Cl:32])=[CH2:34])=[C:6]([CH:24]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10]
Reactant: CCCCOC(=O)c1ccc(N(CC)Cc2cc(Br)ccc2O)nn1
Reactant: C=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(Cl)COc1ccc(Br)cc1CN(CC)c1ccc(C(=O)OCCCC)nn1
Temperature: 25 °C
Yield: 72 %

Procedure:
Butyl 6-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino]pyridazine-3-carboxy late (reference example 11) (0.28 g, 0.69 mmol) in DMF (4 ml) was treated with potassium carbonate (0.28 g, 2.05 mmol) followed by 2,3-dichloro-1-propene (168 mg, 140 μl, 1.4 mmol) and the mixture stirred at ambient temperature over the weekend. The mixture was evaporated, in vacuo, to dryness, presorbed to 1.5 g silica and purified by MPLC to give the title compound as a colourless gum (0.24 g, 72%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N:6]1[N:7]([CH2:15][CH2:16][C:17]#[C:18][C:19]2[N:24]=[C:23]([NH2:25])[CH:22]=[CH:21][CH:20]=2)[N:8]=[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=12.CCN(CC)CC>C(Cl)Cl>[CH3:1][S:2]([N:25]([C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([C:18]#[C:17][CH2:16][CH2:15][N:7]2[N:8]=[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]3=[N:6]2)[N:24]=1)[S:2]([CH3:1])(=[O:4])=[O:3])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc(C#CCCn2nc3ccccc3n2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N(c1cccc(C#CCCn2nc3ccccc3n2)n1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
A solution of methanesulfonyl chloride (98 mg, 0.85 mmol) in DCM was added to a solution of 6-(4-benzotriazol-2-yl-but-1-ynyl)-pyridin-2-ylamine (100 mg, 0.38 mmol, Example 169(A)) and Et3N (0.12 mL, 0.85 mmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 2 hours and then the solvent was evaporated. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 3:2) to yield 140 mg (0.33 mmol, 88%) of N-methylsulfonyl-N-[6-(4-benzo[d][1,2,3]triazol-2-yl-but-1-ynyl)-pyridin-2-yl]-methylsulfonamide as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]([OH:14])[C:12]([CH3:16])([CH3:15])[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].O.S(=O)(=O)(O)O>C(O)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(C2=NOC(C)(C)C2O)cc1Br
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(C2=NOC(C)(C)C2=O)cc1Br
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
To a solution 3-(3-bromo-4-methylphenyl)-5,5-dimethyl-4,5-dihydroisoxazol-4-ol (1.80 g, 6.42 mmol) in glacial acetic acid (70 mL), chromium trioxide (640 mg, 6.42 mmol, 1.0 eq), water (4 mL) and concentrated sulfuric acid (0.8 mL) were successively added and the resulting mixture was stirred at 100° C. for 30 min. The reaction was cooled to room temperature and poured into water (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water (10 mL), brine (10 mL) dried (Na2SO4) and filtered. The filtrate was concentrated under vacuum. The crude product was purified by flash column chromatography (silica gel, 2% ethyl acetate in hexane) to afford the 800 mg of the desired product as a white solid. 1HNMR (400 MHz, CDCl3) δ 8.29 (d, J=1.0 Hz, 1H), 7.94 (dd, J=1.0, 8.0 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 2.44 (s, 3H), 1.46 (s. 3H), 1.24 (s, 3H); ESI-MS (m/z) 282, 284 [(MH)+, Br79,81].
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][OH:23])=[CH:17][CH:16]=1.C([O-])(O)=O.[Na+].O>CN(C=O)C>[OH:23][CH2:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=2[N+:11]([O-:13])=[O:12])=[CH:16][CH:17]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: CC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccc(Nc2ccc(CCO)cc2)c([N+](=O)[O-])c1
Yield: 45 %

Procedure:
A mixture of 2-chloro-5-acetylnitrobenzene (Oelschlaeger, H.; Schreiber, O. Liebigs Ann. Chem., 1961, 641, 81., 2 g, 10 mmol), 4-aminophenylethyl alcohol (1.64 g, 12 mmol) and NaHCO3 (1 g, 12 mmol) in DMF (60 mL) was heated at 150° C. for 3 h. After cooling, the mixture was poured into water (100 mL) and extracted with ethyl acetate (300 mL). The organic layer was washed with 2N aqueous NaOH (100 mL) and brine (100 mL), then dried (Na2SO4), and concentrated. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1:1) to afford 1.36 g (45%) of the title compound as an orange oil; 1H-NMR (CDCl3) δ 9.83 (1H, br.s), 8.20 (1H, d, J=2.1 Hz), 7.94 (1H, dd, J=2.1 Hz, 9.3 Hz), 7.34 (2H, d, J=8.2 Hz), 7.24 (2H, d, J=8.2 Hz), 7.16 (1H, d, J=9.3 Hz), 3.91 (2H, t, J=6.6 Hz), 2.92 (2H, t, J=6.6 Hz), 2.57 (3H, s).