Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.ON1C(=O)CCC1=O.[C:24]([CH2:27][N:28]([CH2:38][C:39]([OH:41])=[O:40])[C@H:29]([C:35]([OH:37])=[O:36])CCCCN)([OH:26])=[O:25]>>[N:28]([CH2:27][C:24]([OH:26])=[O:25])([CH2:29][C:35]([OH:37])=[O:36])[CH2:38][C:39]([OH:41])=[O:40]
Reactant: NCCCC[C@@H](C(=O)O)N(CC(=O)O)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Product: O=C(O)CN(CC(=O)O)CC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 mg of carboxy-modified cores were washed twice with 1 ml of acetonitrile (MeCN) and then taken up in 1 ml of MeCN. To this were added 10 μmol of dicyclohexylcarbodiimide and 10 μmol of N-hydroxysuccinimide. This was followed by shaking at room temperature for two hours. Washing was then carried out once with 1 ml of cyclohexane and once with 1 ml of MeCN. The particles were then taken up in 1 ml of MeCN. 4 μmol of N,N-biscarboxymethyl-L-lysine were added thereto and shaken at room temperature for three hours. This was followed by washing once with 1 ml of acetonitrile and twice with 1 ml of 10 mM phosphate buffer (pH 7.0).
Reaction SMILES: [S:1]1(=[O:13])(=[O:12])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:14][NH:15][CH3:16]>>[CH3:14][N:15]([CH3:16])[C:10]1[CH:9]=[CH:8][C:7]2[S:1](=[O:12])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]=2[CH:11]=1
Reactant: CNC
Reactant: O=S1(=O)CCCCc2ccccc21
Product: CN(C)c1ccc2c(c1)CCCCS2(=O)=O
Temperature: 110 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To a solution of 13.00 g (28.98 mmol) of enantiomerically-enriched tetrahydrobenzothiepine-1,1-dioxide (obtained from Step 8) in 73 mL of dimethylamine (2.0 M in THF, 146 mmol) in a Parr Reactor was added about 20 mL of neat dimethylamine. The mixture was sealed and stirred at 110° C. overnight, and cooled to ambient temperature. The excess dimethylamine was evaporated. The crude oil was dissolved in 200 mL of ethyl acetate and washed with 100 mL of water, dried over MgSO4 and concentrated in vacuo. Purification on a silica gel column (Waters Prep 500) using 20% ethyl acetate/hexane gave 12.43 g (90.5%) of the enantiomerically-enriched 7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (4R,5R) as a colorless solid: 1H NMR (CDCl3) δ 0.87-0.93 (m, 6H), 1.10-1.68 (m, 12H), 2.17-2.25 (m, 1H), 2.81 (s, 6H), 2.99 (d, J=15.3 Hz, 1H), 3.15 (d, J=15.3 Hz, 1H), 3.84 (s, 3H), 4.11 (d, J=7.5 Hz, 1H), 5.49 (s, 1H), 5.99 (d, J=2.4 Hz, 1H), 6.51 (dd, J=8.7 Hz, 2.4 Hz, 1H), 6.94 (d, J=8.7 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.90 (d, J=8.7 Hz, 1H). The product was determined to have 78% e.e. by chiral HPLC on a Chiralpak AD column using 5% ethanol/hexane as the eluent. Recrystallization of this solid from ethyl acetate/hexane gave 1.70 g of the racemic product. The remaining solution was concentrated and recrystallized to give 9.8 g of colorless solid. Enantiomeric excess of this solid was determined by chiral HPLC on a Chiralpak AD column using 5% ethanol/hexane as the eluent. It showed to have 96% e.e with the first eluting peak as the major product.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:41]([CH3:42])=[CH:40][C:15]2[N:16]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]4[N:26]=[C:25]([CH3:27])[N:24]([CH:28]5[CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29]5)[C:23]=4[CH:39]=3)[S:18][C:14]=2[C:13]=1[C:43]1[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2]>Cl.CC(O)C>[NH:30]1[CH2:31][CH:28]([N:24]2[C:23]3[CH:39]=[C:19]([C:17]4[S:18][C:14]5[C:13]([C:43]6[CH:44]=[CH:45][C:46]([Cl:49])=[CH:47][CH:48]=6)=[C:12]([C@H:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:41]([CH3:42])=[CH:40][C:15]=5[N:16]=4)[CH:20]=[CH:21][C:22]=3[N:26]=[C:25]2[CH3:27])[CH2:29]1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4nc(C)n(C5CN(C(=O)OC(C)(C)C)C5)c4c3)sc2c1-c1ccc(Cl)cc1
Agent: Cl
Solvent: CC(C)O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4nc(C)n(C5CNC5)c4c3)sc2c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (S)-tert-butyl 3-(6-(6-(1-tert-butoxy-2-ethoxy-2-oxoethyl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-2-yl)-2-methyl-1H-benzo[d]imidazol-1-yl)azetidine-1-carboxylate (76 mg, 0.11 mmol) in 1.25 M HCl in i-PrOH (20 mL) was stirred at room temperature for 16 hours then at 45° C. for 3 hours. The solution was cooled to room temperature and concentrated in vacuo to provide the desired product. LCMS-ESI+: calc'd for C33H36ClN4O3S: 603.2 (M+H+); Found: 603.4 (M+H+).
Reaction SMILES: [CH:1]1([C:7]2[CH:31]=[CH:30][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27](=[O:29])[CH3:28])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O[CH:37](N(C)C)[N:38]([CH3:40])[CH3:39])(C)(C)C>ClCCl>[CH:1]1([C:7]2[CH:31]=[CH:30][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27](=[O:29])/[CH:28]=[CH:37]/[N:38]([CH3:40])[CH3:39])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CC(=O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2
Solvent: ClCCl
Product: CN(C)/C=C/C(=O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-[10-(4-cyclohexylbenzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]-ethanone of Example 6 Step B (1.0 g), tert-butoxybis(dimethylamino) methane (5 mL) and dichloromethane (25 mL) was refluxed for six hours and then allowed to stir at room temperature overnight. All volatiles were then removed at reduced pressure and the residue was dissolved in dichloromethane. The solution was washed with water, dried over anhydrous sodium sulfate and filtered through a short column of Magnesol®. The eluate was refluxed with the gradual addition of hexane to provide pale yellow crystals of the title compound (0.16 g), m.p. 237–240° C.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:13][NH:14][CH3:15].C(N(CC)C(C)C)(C)C>O1CCCC1>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:14]([CH3:15])[CH3:13])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Reactant: CNC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(Bromomethyl)benzenesulfonyl chloride (5.0 g, 18.6 mmol) was dissolved in tetrahydrofuran. N,N-dimethylamine (7.7 mL, 15.5 mmol, 2M in tetrahydrofuran) and N,N-diisopropylethylamine (3.5 mL, 20.1 mmol) were added, and the reaction was allowed to stir at ambient temperature for 2 hours. The reaction was concentrated to an oil that was partitioned between water and ethyl acetate and extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over Na2SO4, and filtered. The resulting filtrate was concentrated to an oil which deposited needles that were a mixture of the title compound and 4-chloromethyl N,N-dimethylbenzenesulfonamide The resulting needles were collected and dried (2.3 g, 44%). ES-MS m/z 534 (M+H) and 578 (M+H).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:7]([NH:8][CH2:9][CH3:10])=[CH:6][N:5]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:4]=1.[CH:17]1([C:20]([OH:22])=O)[CH2:19][CH2:18]1.Cl.CN(C)CCCN=C=NCC>ClC(Cl)C>[Cl:2][C:3]1[C:7]([N:8]([CH2:9][CH3:10])[C:20]([CH:17]2[CH2:19][CH2:18]2)=[O:22])=[CH:6][N:5]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:4]=1
Reactant: CCNc1cn(-c2cccnc2)nc1Cl
Reactant: O=C(O)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(Cl)Cl
Product: CCN(C(=O)C1CC1)c1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.2 %

Procedure:
To a solution of 3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine monohydrochloride (0.10 g, 0.0.38 mmol) in dichloroethane (0.75 ml) was added cyclopropanecarboxylic acid (0.03 g, 0.38 mmol) and 4-N,N-dimethylaminopyridine (0.14 g, 1.15 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.14 g, 0.77 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was concentrated to dryness and the crude product was purified by reverse phase silica gel chromatography eluting with 0-50% acetonitrile/water to give a white solid (0.03 g, 25%); mp 111-119° C.; 1H NMR (400 MHz, CDCl3) δ 8.96 (d, J=2.5 Hz, 1H), 8.63-8.59 (m, 1H), 8.06 (ddd, J=8.3, 2.6, 1.4 Hz, 1H), 8.01 (s, 1H), 7.46 (dd, J=8.3, 4.7 Hz, 1H), 3.73 (q, J=7.2 Hz, 2H), 1.46 (ddd, J=12.6, 8.1, 4.7 Hz, 1H), 1.16 (t, J=7.2 Hz, 3H), 1.04 (t, J=3.7 Hz, 2H), 0.71 (dd, J=7.7, 3.0 Hz, 2H); ESIMS m/z 291 ([M+H]).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9](Cl)=[O:10])[CH:3]=1.[OH2:12]>>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([OH:10])=[O:12])[CH:3]=1
Reactant: O
Reactant: Cc1nc(Cl)cc(C(=O)Cl)n1
Product: Cc1nc(Cl)cc(C(=O)O)n1
Reaction time: 0.5 h

Procedure:
16 g of 6-chloro-2-methylpyrimidine-4-carbonyl chloride are added dropwise at 10°-15° C. to 150 ml of water. The mixture is then stirred for 1/2 h, the solid is filtered off with suction, and the filter residue is then washed well with water and dried in vacuo at 50° C. 11.5 g of 6-chloro-2-methylpyrimidine-4-carboxylic acid of melting point 132° C. (dec.) are obtained in this way.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][NH:12]3)[N:5]=[C:4]2[N:17]([CH3:20])[N:18]=[CH:19][C:3]=12.[OH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH2:28])=[O:27])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[NH:12]1[C:13]2[C:9](=[C:8]([C:6]3[N:5]=[C:4]4[N:17]([CH3:20])[N:18]=[CH:19][C:3]4=[C:2]([O:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH2:28])=[O:27])=[CH:24][CH:23]=4)[CH:7]=3)[CH:16]=[CH:15][CH:14]=2)[CH:10]=[N:11]1
Reactant: NC(=O)c1ccc(O)cc1
Reactant: Cn1ncc2c(Cl)cc(-c3cccc4[nH]ncc34)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1ncc2c(Oc3ccc(C(N)=O)cc3)cc(-c3cccc4[nH]ncc34)nc21
Temperature: 155 °C
Yield: 18.5 %

Procedure:
4-Chloro-6-(1H-indazol-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine 7 (0.040 g, 0.141 mmoles) was dissolved in 2 mL DMF. 4-Hydroxybenzamide 8d (0.038 g, 0.281 mmol) was added followed by the addition of potassium carbonate (0.2 g, 1.41 mmol) and the resultant reaction mixture was heated in a microwave at 155° C. for 1 hour. The reaction mixture was diluted with ethyl acetate and filtered and the organic portions were washed with saturated sodium bicarbonate solution followed by brine, dried over anhydrous sodium sulfate, solvent removed and purified to obtain 109 as a white solid (10 mg, 20%). 1H NMR (400 MHz, DMSO) δ 13.25 (s, 1H), 8.72 (s, 1H), 8.04 (d, J=8.7, 3H), 7.83-7.59 (m, 3H), 7.59-7.29 (m, 4H), 7.23 (s, 1H), 4.16 (d, J=9.1, 3H). MS (ESI) m/z 385.1 (M+1)+
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[O:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH:15]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]2)[CH2:14]1.Cl[Si:33]([CH3:36])([CH3:35])[CH3:34]>CCCCCC.O1CCCC1>[O:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH:15]([CH2:23][CH2:24][N:25]2[CH2:26][CH2:27][C:28]([O:31][Si:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH2:30]2)[CH2:14]1
Reactant: O=C1CCN(CCC2COc3ccccc3C2)CC1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: C[Si](C)(C)OC1=CCN(CCC2COc3ccccc3C2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
17.4 ml of n-butyllithium in hexane are added at 0°-5° to a solution of 2.81 g of diisopropylamine in 30 ml of dry tetrahydrofuran. The whole is stirred for 30 minutes at room temperature, then cooled to -15° and a solution of 6.24 g (25 mmol) of 1-[2-(chroman-3-yl)ethyl]-4-oxopiperidine in 30 ml of tetrahydrofuran is added. After 15 minutes, a solution of 3.05 g (28 mmol) of chlorotrimethylsilane in 15 ml of tetrahydrofuran is added dropwise. The whole is stirred overnight at room temperature, the solution is filtered and the filtrate is concentrated to dryness by evaporation under reduced pressure. 1-[2-(chroman-3-yl)ethyl]-4-trimethylsilyloxy-1,2,5,6-tetrahydropyridine is thus obtained in the form of a pale yellow oil. 6.63 g (20 mmol) of the 1-[2-(chroman-3-yl)ethyl]-4-trimethylsilyloxy-1,2,5,6-tetrahydropyridine obtained are dissolved in 50 ml of dichloromethane and the solution is added dropwise to a solution, cooled to 0°, of 2.3 g (24 mmol) of chloroformic acid methyl ester and 60 mg (2.4 mmol) of anhydrous zinc bromide in 50 ml of absolute dichloromethane. After warming up to room temperature, the reaction solution is stirred for one hour and then poured onto 150 ml of saturated sodium hydrogen carbonate solution. Extraction is carried out with dichloromethane, and the combined organic phases are dried over sodium sulphate and then concentrated by evaporation. The residue is dissolved in 70 ml of ethanol and the solution is acidified with ethanolic hydrochloric acid. After adding diethyl ether and after cooling, 1-[2-(chroman-3-yl)ethyl]-4-hydroxy-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester hydrochloride or 1-[2-(chroman-3-yl)ethyl]-4-oxopiperidine-3-carboxylic acid methyl ester hydrochloride, respectively, having a melting point of 175°-177° crystallises out.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:10][CH2:9][NH:8][C:7]1=[O:11].[C:12]1(=O)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[BH4-].[Na+]>C(O)(=O)C>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:10][CH2:9][N:8]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:7]1=[O:11]
Reactant: O=C1NCCN1CCCCCl
Reactant: O=C1CCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1N(CCCCCl)CCN1C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-(4-chloro-1-butyl)-2-imidazolidinone (50 g) and cyclohexanone (83.3 g) in glacial acetic acid (1000 ml) was stirred for one hour at room temperature. The mixture was cooled to 10-15° C. and NaBH4 (42.4 g) was added in small portions during 5 hours. After stirring overnight at room temperature, acetic acid was evaporated in vacuo. Water (500 ml) and dichloromethane (300 ml) were added and pH adjusted to >9 by addition of aqueous diluted NH4OH. The organic phase was separated, dried with anhydrous MgSO4, filtered and the solvent evaporated in vacuo. The remaining crude product was purified by column chromatography on silica gel (eluted with ethyl acetate). The pure title compound 1a crystalized upon standing. Yield: 33 g, mp: 30-35° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12](C(OCC)=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>O.C(O)C.[Cl-].[Na+]>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)N1CCC(NC(=O)OC(C)(C)C)CC1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
19.91 g (0.073 mol) of the compound from Example 20A are added to a mixture of 32.33 g (0.576 mol) of KOH in 175 ml of water and 175 ml of ethanol and heated to reflux for 4 h. The reaction solution is then stirred at room temperature overnight, diluted with 350 ml of conc. sodium chloride solution and extracted four times with a total of 1500 ml of ethyl acetate. The organic extract is washed four times with 100 ml of sodium chloride solution each time, dried over sodium acetate, concentrated and dried under-high vacuum.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH2:29][CH3:30])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].CN(C)C=O.[O:36]1[CH2:39][C:38](=O)[CH2:37]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH2:29][CH3:30])[C:16]3[CH2:22][CH2:21][N:20]([CH:38]4[CH2:39][O:36][CH2:37]4)[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4CC)n2)CCNC3)cc1
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4CC)n2)CCN(C2COC2)C3)cc1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
(S)-1-ethyl-3-(4-(4-(3-ethylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.0500 g, 0.122 mmol) in dry N,N-Dimethylformamide (0.593 mL, 7.66 mmol) at 0° C. was added 3-oxetanone (0.00881 mL, 0.122 mmol). The reaction mixture was stirred at 50° C. for 10 minutes then cooled at 0° C. and added Sodium triacetoxyborohydride (0.05163 g, 0.2436 mmol). The reaction mixture was allowed to warm slowly to room temperature and stirred overnight. The reaction mixture was filtered through a disc filter and purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.61 (s, 1H), 8.14 (d, J=8.7, 2H), 7.46 (d, J=8.7, 2H), 6.15 (t, J=5.5, 1H), 4.64 (t, J=6.2, 2H), 4.59-4.50 (m, 2H), 3.97 (s, 1H), 3.86 (d, J=10.7, 1H), 3.78 (d, J=11.2, 1H), 3.74-3.60 (m, 4H), 3.55 (t, J=10.9, 1H), 3.43 (d, J=10.4, 1H), 3.35 (d, J=17.0, 1H), 3.18-3.05 (m, 2H), 2.76 (s, 1H), 2.68 (d, J=11.2, 1H), 2.60 (d, J=15.2, 1H), 2.41-2.30 (m, 1H), 1.87-1.67 (m, 2H), 1.06 (t, J=7.2, 3H), 0.83 (t, J=7.4, 3H). LC/MS-m/z+467.2 (M+H)+.
Reaction SMILES: C(C1N=C(C2[CH:18]=[C:17](Cl)[C:16]3[C:11](=[C:12]([CH3:22])[C:13]([O:20][CH3:21])=[CH:14][CH:15]=3)[N:10]=2)SC=1)(C)C.C[O:24]C1C(C)=C(C=CC=1)N.B(Cl)(Cl)Cl.[Cl-].[Cl-].[Cl-].[Al+3]>C(#N)C>[CH3:22][C:12]1[C:13]([O:20][CH3:21])=[CH:14][CH:15]=[C:16]([C:17](=[O:24])[CH3:18])[C:11]=1[NH2:10]
Reactant: COc1ccc2c(Cl)cc(-c3nc(C(C)C)cs3)nc2c1C
Reactant: COc1cccc(N)c1C
Agent: ClB(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC#N
Product: COc1ccc(C(C)=O)c(N)c1C

Procedure:
Optionally substituted 2-(thiazol-2-yl)-4-chloro-7-alkoxy-8-alkyl-quinoline 2-phenyl-4-chloro-7-alkoxy-quinolines, such as 2-(4-isopropylthiazol-2-yl)-4-chloro-7-methoxy-8-methyl-quinoline, can be synthesized as shown in Scheme XIII. 3-Alkoxy-2-alkyl-anilines, such as 3-methoxy-2-methyl-aniline, can react with acetonitrile (CH3CN) in the presence of Lewis acids, for example boron trichloride and aluminum trichloride, to provide 2-alkyl-3-alkoxy-6-acetyl-anilines such as 2-methyl-3-methoxy-6-acetyl-aniline. The 2-alkyl-3-alkoxy-6-acetyl-anilines, such as 2-methyl-3-methoxy-6-acetyl-aniline, can be coupled to an an optionally substituted thiazole-2-carboxylic acid chloride, such as 4-isopropylthiazole-2-carbonyl chloride to provide an optionally substituted 1-acetyl-2-[(thiazol-2-yl)-carbonylamino]-3-alkyl-4-alkoxy-benzene, such as 1-acetyl-2-[(4-isopropyl-thiazol-2-yl)-carbonylamino]-3-methyl-4-methoxy-benzene. The optionally substituted 1-acetyl-2-[(thiazol-2-yl)-carbonylamino]-3-alkyl-4-alkoxy-benzene, such as 1-acetyl-2-[(4-isopropyl-thiazol-2-yl)-carbonylamino]-3-methyl-4-methoxy-benzene, can be cyclized under basic conditions, for example sodium tert-butoxide in tert-butanol, to provide an optionally substituted 2-(thiazol-2-yl)-4-hydroxy-7-alkoxy-8-alkyl-quinoline, such as 2-(4-isopropylthiazol-2-yl)-4-hydroxy-7-methoxy-8-methyl-quinoline. Finally, an optionally substituted 2-(thiazol-2-yl)-4-hydroxy-7-alkoxy-8-alkyl-quinoline, such as 2-(4-isopropylthiazol-2-yl)-4-hydroxy-7-methoxy-8-methyl-quinoline can be reacted with a chlorinating agent, for example phosphorous oxychloride, oxalyl chloride, thionyl chloride and the like, to provide an optionally substituted 2-(thiazol-2-yl)-4-chloro-7-alkoxy-8-alkyl-quinoline 2-phenyl-4-chloro-7-alkoxy-quinolines, such as 2-(4-isopropylthiazol-2-yl)-4-chloro-7-methoxy-8-methyl-quinoline.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].Cl.[NH2:8][C:9]1[CH:38]=[CH:37][C:12]2[NH:13][C:14]([C:19]3[C:20](=[O:36])[C@:21]([CH3:35])([CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[C:22]4[C:27]([C:28]=3[OH:29])=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:15][S:16](=[O:18])(=[O:17])[C:11]=2[CH:10]=1.N1C=CC=CC=1>CC(C)=O>[OH:29][C:28]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@@:21]([CH3:35])([CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[C:20](=[O:36])[C:19]=1[C:14]1[NH:13][C:12]2[CH:37]=[CH:38][C:9]([NH:8][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:10][C:11]=2[S:16](=[O:18])(=[O:17])[N:15]=1
Reactant: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CCS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)c3ccccc3[C@@](C)(CCC(C)C)C1=O)N2
Reaction time: 4 h
Yield: 94.7 %

Procedure:
Ethane sulfonylchloride (75.6 mg, 0.588 mmol) was added carefully dropwise to a solution of Example 39H (70.0 mg, 0.147 mmol) and pyridine (93.1 mg, 1.18 mmol) in acetone (7 mL). The reaction mixture was stirred for 4 h and then concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with a 0-25% ethyl acetate/hexane gradient to give the title compound (74 mg, 95%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.42 m, 1 H) 0.69 (d, J=6.62 Hz, 3H) 0.72 (d, J=6.62 Hz, 3 H) 0.80 m, 1 H) 1.22 (t, J=7.35 Hz, 3 H) 1.33 (m, 1 H) 1.57 (s, 3 H) 2.07 m, 1 H) 2.22 m, 1 H) 3.19 m, 2 H) 5.76 (s, 1 H) 7.53 (dd, J=7.91, 4.23 Hz, 1H) 7.57 (dd, J=8.82, 2.21 Hz, 1 H) 7.63 (d, J=2.21 Hz, 1 H) 7.71 (d, J=8.82 Hz, 1 H) 7.76 (d, J=3.68 Hz, 2 H) 8.16 (d, J=7.72 Hz, 1 H) 10.31 (s, 1 H) 13.77 (s, 1 H).). MS (ESI+) m/z 532.0 (M+H)+, 549.1 (M+NH4)+ (ESI−) m/z 530.1 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:15])[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:7]=1[CH3:8].Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][CH:18]=1>CN(C1C=CN=CC=1)C.ClC1C=CC=CC=1Cl>[CH3:28][O:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][C:23]=1[O:29][CH3:30])[N:20]=[CH:19][CH:18]=[C:17]2[O:15][C:4]1[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc(O)c(-c2cccnc2)nc1C
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc(C)c(C)nc3-c3cccnc3)c2cc1OC
Temperature: 140 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
5,6-Dimethyl-[2,3′]-bipyridin-3-ol (50 mg), 4-chloro-6,7-dimethoxyquinoline (168 mg), and 4-(N,N-dimethylamino)pyridine (92 mg) were dissolved in 1,2-dichlorobenzene (2.5 ml), and the mixture was stirred at 140° C. overnight. The reaction solution was cooled to room temperature, and the solvent was then removed by distillation under the reduced pressure. The residue was purified by thin layer chromatography using hexane-acetone to give the title compound (81 mg, yield 84%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:26]=[CH:25][C:9]([CH2:10][O:11][C:12]2[C:13]3[N:14]([C:18]([CH2:22][C:23]#[CH:24])=[C:19]([CH3:21])[N:20]=3)[CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:7]=1)=[O:5])C>C(O)C.S(=O)(=O)(O)O>[C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH2:10][O:11][C:12]2[C:13]3[N:14]([C:18]([CH2:22][C:23]#[CH:24])=[C:19]([CH3:21])[N:20]=3)[CH:15]=[CH:16][CH:17]=2)=[CH:25][CH:26]=1)([OH:5])=[O:3]
Reactant: C#CCc1c(C)nc2c(OCc3ccc(C(=O)OCC)cc3)cccn12
Agent: O=S(=O)(O)O
Solvent: CCO
Product: C#CCc1c(C)nc2c(OCc3ccc(C(=O)O)cc3)cccn12
Yield: 69 %

Procedure:
A mixture of 8-(4-ethoxycarbonylbenzyloxy)-2-methyl-3-(2-propynyl)imidazo[1,2-a]pyridine (1.04 g) in ethanol (15 ml) and 20% sulfuric acid (40 ml) was refluxed for 5 hours and then ethanol was evaporated in vacuo. The mixture was cooled and the resulting precipitates were collected by filtration. The obtained sulfate was treated with an aqueous solution of sodium bicarbonate and then the mixture was adjusted to pH 4.5 with acetic acid. The resulting precipitates were collected by filtration and air-dried to give 8-(4-carboxybenzyloxy)-2-methyl-3-(2-propynyl)imidazo[1,2-a]pyridine (0.66 g).