Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([O:17][CH3:18])[C:11]([CH2:19][C:20]1[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=1)=[C:10]2[Cl:30].[CH3:31][N:32]1[C:36]([CH:37]=[O:38])=[CH:35][N:34]=[C:33]1[CH3:39]>C1COCC1>[Cl:30][C:10]1[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([CH:37]([C:36]3[N:32]([CH3:31])[C:33]([CH3:39])=[N:34][CH:35]=3)[OH:38])[CH:8]=2)[N:13]=[C:12]([O:17][CH3:18])[C:11]=1[CH2:19][C:20]1[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=1
Reactant: Cc1ncc(C=O)n1C
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(C(F)(F)F)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 0.9 mL, 2.25 mmol) was added dropwise by syringe to a solution of 6-bromo-4-chloro-2-methoxy-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)quinoline (1.009 g, 2.338 mmol, Intermediate 9: step c) in dry THF (12.5 mL) in a dry ice-acetone bath. After 1-2 minutes, a solution of 1,2-dimethyl-1H-imidazole-5-carbaldehyde (359.6 mg, 2.897 mmol) in dry THF (5 mL) was added dropwise. The reaction was stirred for 10 minutes, then was moved into an ice bath and allowed to warm to room temperature. The reaction was quenched with saturated aqueous ammonium chloride. Water was added and the separated aqueous layer was extracted with EtOAc/THF 10:1. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude was triturated with EtOAc/ether 1:1 and filtered, rinsing with additional ether. The collected solids were purified by flash column chromatography (silica gel, 0-5% MeOH-DCM) to provide the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 8.76 (d, J=2.0 Hz, 1H), 8.24-8.22 (m, 1H), 7.84 (d, J=8.6 Hz, 1H), 7.79-7.75 (m, 1H), 7.67-7.62 (m, 1H), 7.56 (dd, J=8.2, 0.9 Hz, 1H), 6.54 (d, J=0.7 Hz, 1H), 6.03 (s, 1H), 4.37 (s, 2H), 4.09 (s, 3H), 3.49 (s, 3H), 2.35 (s, 3H); MS m/e 477.0 [M+H]+.
Reaction SMILES: CO[C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[NH:11][C:12](=[O:21])[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>CCOC(C)=O>[Cl:10][C:7]1[CH:6]=[C:5]2[C:4]([C:3](=[O:22])[C:13]([CH3:14])([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:12](=[O:21])[NH:11]2)=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)C(C)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Product: CC1(c2ccccc2)C(=O)Nc2cc(Cl)ccc2C1=O
Yield: 60 %

Procedure:
The objective compound was prepared by the same procedure for the example 1, using a 4-chloro-2-(2-phenyl-propionyl amino)-benzoic acid methyl ester (1.00 g, 3.15 mmol) and LiHMDS (9.44 mmol, 1M solution in THF). After normal workup, the pure objective compound (0.54 g, 60%) was obtained as pale yellow solid by a flash column chromatography (Hex:EtOAc=4:1): 1H NMR (200 MHz, CDCl3) δ 1.86 (s, 3H, CH3), 6.94 (d, J=1.63 Hz, 1H, ArH), 7.06 (dd, J=8.55 Hz, 1.63 Hz, 1H, ArH), 7.26-7.32 (m, 5H, ArH), 7.83 (d, J=8.14 Hz, 1H, ArH), 9.21 (br s, 1H, NH); m.p. 174-175° C.; MS(EI) m/e 285 [M+], 153, 132, 104; HRMS m/e cacld. for C16H12NO2Cl 285.0557, found 285.0552.
Reaction SMILES: [CH2:1]([B:5]([OH:7])[OH:6])[CH2:2][CH2:3][CH3:4].O[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]O.O[C@H]([C@@H](O)C(N(C)C)=O)C(N(C)C)=O>ClCCl.[Cl-].[Na+].O>[CH2:1]([B:5]1[O:7][CH2:13][CH2:12][NH:11][CH2:10][CH2:9][O:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCB(O)O
Reactant: OCCNCCO
Agent: CN(C)C(=O)[C@H](O)[C@@H](O)C(=O)N(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCCCB1OCCNCCO1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(But-1-yl)-tetrahydro-4H-1,3,6,2-dioxazaborocine [CAS 92527-13-4] (3 g, 17.5 mmol), which was prepared from n-butylboronic acid and 2-(2-hydroxy-ethylamino)-ethanol [CAS 111-42-2] as reported in Organic Synthesis, 1998, 76, 86-96, and (2R,3R)-2,3-dihydroxy-N,N,N′,N′-tetramethyl-butanediamide [CAS 26549-65-5] (9.85 g) were dissolved in anhydrous dichloromethane (160 mL) under N2, Brine (25 mL) was added. The resulting mixture was stirred at room temperature for about 16 hours. The two layers were separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with 50 mL brine, dried over MgSO4, filtered and concentrated in vacuo to provide the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([NH2:5])=[NH:4].[Cl:8][C:9](Cl)(Cl)[S:10]Cl>>[Cl:1][C:2]([Cl:7])([Cl:6])[C:3]1[N:5]=[C:9]([Cl:8])[S:10][N:4]=1
Reactant: ClSC(Cl)(Cl)Cl
Reactant: N=C(N)C(Cl)(Cl)Cl
Product: Clc1nc(C(Cl)(Cl)Cl)ns1

Procedure:
The reaction between trichloroacetamidine and trichloromethanesulfenyl chloride to produce 3-trichloromethyl-5-chloro-1,2,4-thiadiazole appears to be a complex set of reactions occurring simultaneously which may be represented as follows: ##SPC1##
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>O1CCOCC1>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([CH2:17][O:16][CH2:15][CH2:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOCc2cccnc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1cncc(COCCC2CCNCC2)c1
Reaction time: 8 h
Yield: 35.2 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-[2-(3-pyridylmethoxyl)ethyl]piperidine (413 mg, 1.29 mmol) in dioxane (0.2 mL) was added 4N HCl/dioxane (1 mL, 4.0 mmol). The solution was stirred overnight. After evaporation, the residue was dissolved in deionized water. EtOAc was used to wash the aqueous layer before the pH was altered to approx. 9-10. The aqueous layer was extracted three times with CH2Cl2, and the combined organic phases were dried over Na2SO4. After evaporation, 4-[2-(3-pyridylmethoxy)ethyl]piperidine (100 mg, 35%) was obtained as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 8.40 (m, 2H), 7.53 (d, 1H, J=7.6 Hz), 7.14 (m, 1H), 4.37 (s, 2H), 3.40 (t, 2H, J=6.0 Hz), 2.91 (d, 2H, J=12.0 Hz), 2.45 (t, 2H, J=11.6 Hz), 2.27 (s, 1H), 1.52 (d, 2H, J=12.4 Hz), 1.43 (m, 3H), 1.01 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH:5]=[O:6].[N+:14]([CH:16](S(C1C=CC(C)=CC=1)(=O)=O)[CH3:17])#[C-:15].C([O-])([O-])=O.[K+].[K+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][CH:15]=[N:14][C:16]=2[CH3:17])[CH:7]=[CH:8][C:9]=1[C:10]([F:11])([F:12])[F:13]
Reactant: O=Cc1ccc(C(F)(F)F)c(Cl)c1
Reactant: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1ncoc1-c1ccc(C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Yield: 85.4 %

Procedure:
A mixture of Example 45A (2.84 g, 13.6 mmol), 1-(1-isocyanoethylsulfonyl)-4-methylbenzene (2.85 g, 13.6 mmol), and K2CO3 (2.26 g, 16.3 mmol) in MeOH (70 mL) was heated to reflux. After 2 hr the reaction mixture was cooled to ambient temperature, and the volatiles were evaporated at reduced pressure. The residue was partitioned between Et2O and H2O. The separated aqueous layer was extracted with Et2O, and the combined organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Flash chromatography (Analogix® Intelliflash 280; 10% to 30% EtOAc/hexanes eluant; SF40-150 g column) yielded 3.04 g (85%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.48 (s, 1H), 7.96 (d, J=8.4, 1H), 7.87 (s, 1H), 7.78 (dd, J=8.3, 0.8, 1H), 2.43 (s, 3H). MS (DCI+) m/z 262 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH:11]([CH3:13])[C:10]([NH:14][CH:15]=[O:16])=[N:9]2)=[CH:4][CH:3]=1.[C:17](OC(=O)C)(=O)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH:11]([CH3:13])[C:10]([NH:14][C:15](=[O:16])[CH3:17])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC1CN(c2ccc(Cl)cc2)N=C1NC=O
Product: CC(=O)NC1=NN(c2ccc(Cl)cc2)CC1C
Reaction time: 0.25 h

Procedure:
A 9.0 g. amount of 3-amino-1-(p-chlorophenyl)-4-methyl-2-pyrazoline (prepared as described in Example 23) is dissolved in 54.0 ml. of acetic anhydride. The warm solution is allowed to stand for 16 hours at room temperature with some solid separation. The solid is collected by filtration and is dissolved in methanol. Then 1 N potassium hydroxide in methanol is added to make basic. After 15 minutes at room temperature, the solvent is removed in vacuo and water is added to separate a solid. The solid is collected and recrystallized from dichloromethane-hexane to give 6.5 g. of the desired product as white crystals, m.p. 172°-173° C.
Reaction SMILES: ClC(OCC)=O.O1CCCC1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21]([N:29]3[CH:33]=[CH:32][N:31]=[C:30]3[CH3:34])[O:22][C:23]=2[CH2:24][CH2:25][C:26]([OH:28])=O)=[CH:15][CH:14]=1.Cl.[Cl:36][CH2:37][CH2:38][NH2:39]>O.CN(C)C=O.C(N(CC)CC)C>[Cl:36][CH2:37][CH2:38][NH:39][C:26](=[O:28])[CH2:25][CH2:24][C:23]1[O:22][C:21]([N:29]2[CH:33]=[CH:32][N:31]=[C:30]2[CH3:34])=[N:20][C:19]=1[C:16]1[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][CH:17]=1
Reactant: NCCCl
Reactant: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCC(=O)O)o1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCC(=O)NCCCl)o1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
Ethyl chloroformate (590 mg) was dropwise added to a tetrahydrofuran (40 ml) solution of 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropionic acid (1.50 g) and triethylamine (550 mg), at −30° C. After stirring for 30 minutes, the reaction mixture was poured into a solution as prepared from 2-chloroethylamine hydrochloride (2.62 g), triethylamine (2.29 g) and N,N-dimethylformamide (20 ml), at 0° C., and then stirred at room temperature for 1 hour. The reaction mixture was poured into water, and the crystals thus precipitated were collected by filtration to obtain N-(2-chloroethyl)-4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropionamide (1.53 g, 86%). This was recrystallized from ethyl acetate-hexane to give colorless needles. mp 155-156° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:20][C:21]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:22]=1[CH2:23]Cl>CN(C=O)C.C(OCC)(=O)C>[CH3:20][C:21]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:22]=1[CH2:23][O:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1cccc(O)c1
Reactant: Cc1ccc(CCl)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cccc(OCc2ccc(C)cc2C)c1
Reaction time: 16 h

Procedure:
To a stirred solution of Ethyl 2-(3-hydroxyphenyl)acetate (3 g, 16.6 mmol) in DMF (20 ml) was added potassium carbonate (2.99 g, 21.6 mmol) at room temperature followed by drop wise addition of 2,4-Dimethylbenzyl chloride (3.11 g, 18.3 mmol). The reaction mixture was stirred for 16 hours and taken in ethyl acetate, washed with water (2×), brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (hex:ethyl acetate 4:1) to give the title compound.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C[Al](C)C.[CH3:17][C:18]1[N:23]=[C:22]([C:24]#[N:25])[CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([C:24](=[NH:25])[NH:10][C:9]2[CH:11]=[CH:12][C:6]([S:3]([CH3:2])(=[O:4])=[O:5])=[CH:7][CH:8]=2)[N:23]=1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: Cc1cccc(C#N)n1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cccc(C(=N)Nc2ccc(S(C)(=O)=O)cc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline hydrochloride (4.2 g, 20.3 mmol) in toluene (100 ml) at 0° C., was added trimethylaluminum (2M solution in toluene, 12 ml, 24 mmol) over 10 minutes. The reaction mixture was warmed to room temperature and stirred for 2 hours. A solution of 6-methyl-2-cyanopyridine (3.6 g, 30.5 mmol) in toluene (100 ml) was added over 10 minutes and the mixture was heated to 85–90° C. After 24 hours, the reaction mixture was cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue was washed with a mixture of methylene chloride/methanol and later with methanol. The combined filtrates were concentrated and the resulting yellowish solid was stirred with hexane and ethyl acetate (1000 ml) and filtered. The white solid (5.1 g, 87%) was used in the next reaction without further purification. Anal. Calc'd. for C14H16N3SClO20.2H2O: C, 51.05; H, 5.02; N, 12.76. Found: C, 50.97; H, 4.78; N, 12.80.
Reaction SMILES: [CH3:1][Si:2]([CH3:54])([CH3:53])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:35][CH:34]3[N:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:31]([CH2:32][CH2:33]3)[CH2:30]2)[C:9]=1Br.C([Sn](CCCC)(CCCC)[C:60]([O:62][CH2:63][CH3:64])=[CH2:61])CCC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][Si:2]([CH3:54])([CH3:53])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:35][CH:34]3[N:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:31]([CH2:32][CH2:33]3)[CH2:30]2)[C:9]=1[C:60]([O:62][CH2:63][CH3:64])=[CH2:61]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(c1nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c1Br)C2
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=C(OCC)c1c(C2CC3CCC(C2)N3C(=O)OC(C)(C)C)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N(COCC[Si](C)(C)C)COCC[Si](C)(C)C
Temperature: 100 °C

Procedure:
A mixture of compound tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (834 mg, 0.49 mmol), tributyl(1-ethoxyvinyl)tin (356 mg, 0.98 mmol), tetrakis(triphenylphosphine)palladium (56.9 mg, 0.049 mmol) in dioxane (6 mL) was degassed with argon for five minutes. It was then heated at 100° C. in a sealed tube for 16 h, at which time LC/MS analysis confirmed full consumption of starting material. On cooling, the solvent was rotoevaporated, and the crude residue was redissolved in EtOAc, washed with 0.5 M KF solution, brine (1×25 mL), and dried over MgSO4. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel. Elution with EtOAc/Hexanes gave tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-(1-ethoxyvinyl)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate. The enol ether was then treated with 20% TFA/CH2Cl2 (10 mL) for 2 h at room temperature. Concentration afforded 5-(8-azabicyclo[3.2.1]octan-3-yl)-3-(6-phenylpyridin-3-yl)-8,9-dihydropyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-6(7H)-one as an TFA salt. LCMS tR=0.67 Min (5 min run, UV254nm). Mass calculated for, M+ 450.2, observed LC/MS m/z 451.0 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C1(C)C=CC=CC=1.Cl[CH2:15][CH2:16][CH2:17][C:18]#[N:19]>C(Cl)(Cl)Cl>[N:1]1([CH2:15][CH2:16][CH2:17][C:18]#[N:19])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: N#CCCCCl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: N#CCCCN1CCOCC1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
196.9 ml morpholine, 500 ml toluol and 100 ml chloroform were stirred in a round-bottomed flask under N2 atmosphere and at 80° C. After one hour 100 g 4-chlorobutyronitrile was added dropwise within one hour. The reaction was stirred one day at 80° C. and another day at room temperature. The mixture was fritted and the residue was washed two times with ether. The filtrate was concentrated and finally distilleed under vacuum. The product fractions were collected at 95-100° C. and 1.2-0.89 Torr. The purity of the colourless oil was judged by gas chromatography and 1H-NMR.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([F:26])[CH:19]=3)=[N:6]2)[CH2:3][CH2:2]1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:8][C:7]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([F:26])[CH:19]=3)=[N:6]2)[CH2:2][CH2:3]1
Reactant: C1CCNC1
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1F
Product: COc1ccc(-c2cc(CN3CCCC3)c(=O)n(CC3CC3)n2)cc1F
Yield: 75.9 %

Procedure:
Following the procedure of Example 1(10), 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and pyrrolidine were reacted to yield the title compound as a yellow oil (yield: 75.9%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.S(Cl)(Cl)=O.[CH2:15](O)[CH3:16]>>[NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:15][CH3:16])=[O:9])[CH2:4][CH2:3]1
Reactant: CCO
Reactant: NC1CCC(C(=O)O)CC1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C1CCC(N)CC1
Temperature: 80 °C

Procedure:
To an ice-cold solution of 4-aminocyclohexanecarboxylic acid (5.0 g, 34.92 mmol) in ethanol (20 mL) was added thionyl chloride (7.60 ml, 104.76 mmol) and the mixture heated up to 80° C. for 2-3 h. After the completion of reaction (by TLC), the solvent was evaporated under reduced pressure to give the desired product in quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[C:17]([Cl:24])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH:14]([CH3:16])[CH3:15].O.O.[Sn](Cl)Cl>CN1C(=O)CCC1>[Cl:24][C:17]1[CH:18]=[C:19]([CH:20]=[C:2]([Cl:1])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH:14]([CH3:15])[CH3:16])[NH2:21]
Reactant: CC(C)c1c[nH]c2ccc(Oc3c(Cl)cc([N+](=O)[O-])cc3Cl)cc12
Agent: Cl[Sn]Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)c1c[nH]c2ccc(Oc3c(Cl)cc(N)cc3Cl)cc12

Procedure:
500 mg of 5-(2,6-dichloro-4-nitrophenoxy)-3-isopropyl-1H-indole (Example I) are stirred with 6.18 g of tin(II) chloride dihydrate in 5 ml of NMP for 17 hours at 50° C. The solvent is removed in vacuo and the residue is taken up in ethyl acetate. The mixture is washed with saturated ammonium chloride solution and saturated sodium chloride solution, the organic phase is dried and the solvent is removed in vacuo. The product is precipitated with diethyl ether. By chromatographic purification (cyclohexane/ethyl acetate) of the solid, 174 mg of 3,5-dichloro-4-[(3-isopropyl-1H-indol-5-yl)oxy]aniline are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([NH:11][NH:12]C(OC(C)(C)C)=O)=[O:10])[CH:6]=[CH:5][CH:4]=1.Cl>O1CCOCC1>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([NH:11][NH2:12])=[O:10])[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc(C(=O)NNC(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cccc(C(=O)NN)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 167.1 %

Procedure:
1,1-dimethylethyl 2-{[6-(methyloxy)-2-pyridinyl]carbonyl}hydrazinecarboxylate (194)(1.685 g, 6.30 mmol) was dissolved in 1,4-dioxane (21.01 ml) and HCl (4M in 1,4-dioxane) (15.76 ml, 63.0 mmol) was added. The solution was stirred at room temperature for 5 hours. LCMS showed that no starting material remained and the product had formed. The solvent was removed under reduced pressure to afford 1.76 g of the crude material. The crude material was loaded onto two 10 g SCX columns and these were washed with methanol. The product was eluted off using 2M ammonia in methanol and the solvent was removed under reduced pressure to afford the purified desired product in 0.954 g.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][CH:11]([CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)[CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.O1CCOCC1>C(Cl)(Cl)Cl>[C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][CH:11]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH3:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(N[C@@H]1C[C@H]1c1ccccc1)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: CC(N[C@@H]1C[C@H]1c1ccccc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Chloroform (5 mL) was added to a 200 mL round-bottomed flask containing 1,1-dimethylethyl 4-(1-{[trans-2-phenylcyclopropyl]amino}ethyl)-1-piperidinecarboxylate (67 mg, 0.194 mmol) to give a suspension. HCl/1,4-Dioxane (1.5 mL, 6.00 mmol) was added and the mixture stirred 18 hours at room temperature. The Upon completion, the solvents were removed, MeOH (1 mL) added and the mixture purified via reverse phase column chromatography on Gilson ((C18 column: 0.1% Formic acid H2O/CH3CN, 95-5%) affording the title compound as a white solid LC-MS (ES) m/z=245 (M+H)+, 1H NMR (400 MHz, MeOD-d4) δ ppm 1H NMR (400 MHz, MeOD) d 7.93 (s, 1H), 7.31-7.39 (m, 2H), 7.17-7.30 (m, 3H), 3.46-3.59 (m, 3H), 2.95-3.14 (m, 3H), 2.50-2.63 (m, 1H), 2.17-2.28 (m, 1H), 1.94-2.05 (m, 3H), 1.59-1.76 (m, 3H), 1.48 (t, J=7.71 Hz, 1H), 1.39 (d, J=6.82 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([C:16]=1[NH:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)=[C:14]([F:24])[CH:13]=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCC[CH2:26]1>CN(C)C=O>[C:1]([O:5][C:6]([C:8]1[N:9]([CH3:26])[C:10]2[C:15]([C:16]=1[NH:17][C:18]1[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=1)=[C:14]([F:24])[CH:13]=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)c1[nH]c2cccc(F)c2c1Nc1ccncc1
Solvent: CN(C)C=O
Product: Cn1c(C(=O)OC(C)(C)C)c(Nc2ccncc2)c2c(F)cccc21

Procedure:
Follow the procedure of Example 24 but start with 4-fluoro-3-(4-pyridinylamino)-1H-indole-2-carboxylic tert-butyl ester, but substitute tetrahydrofuran for dimethylformamide to obtain the title compound: ESI/MS 342 (M+H); HPLC: Rt=1.41 min.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([O:12]CC)=O)[C:3]1=[O:15].[NH2:16][C:17]1[CH:21]=[C:20]([CH3:22])[O:19][N:18]=1.BrC1C=CC=CC=1>>[CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[O:19][N:18]=2)=[O:12])[C:3]1=[O:15]
Reactant: Cc1cc(N)no1
Reactant: CCOC(=O)c1c(O)cc(C)n(C)c1=O
Solvent: Brc1ccccc1
Product: Cc1cc(NC(=O)c2c(O)cc(C)n(C)c2=O)no1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 66.5 %

Procedure:
213 mg of ethyl 1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxyl ate and 79 mg of 3-amino-5-methylisooxazole were added to 2.5 ml of bromobenzene, then, the mixture was stirred for 6.5 hours under heat refluxing condition. The reaction mixture was cooled to room temperature. The resulting solid was collected by filtration, and washed with a mixed solvent of t-butyl methyl ether and hexane and dried to obtain 141 mg of 1,6-dimethyl-4-hydroxy-N-(5-methylisooxazol-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide (hereinafter, referred to as present compound 27) represented by the formula:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[CH2:11]([O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1)[CH3:12]>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:18][C:17]2[CH:19]=[CH:20][C:14]([O:13][CH2:11][CH3:12])=[CH:15][C:16]=2[N+:21]([O-:23])=[O:22])=[O:7])=[CH:9][CH:10]=1
Reactant: CCOc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Product: CCOc1ccc(NC(=O)c2ccc(Cl)nc2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared from 6-chloronicotinoyl chloride and 4-ethoxy-2-nitroaniline and was obtained as a yellow solid as described in Example 1. 1H NMR (CDCl3): 11.13 (s, 1H), 9.01 (d, J=2.4, 1H), 8.82 (d, J=9.3, 1H), 8.24-8.20 (m, 1H), 7.74 (d, J=3.0, 1H), 7.51 (d, J=7.8, 1H), 7.34-7.30(m, 1H), 4.11 (q, J=6.9, 2H), 1.47 (t, J=6.9, 3H).