Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:33]=[CH:32][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27](O)=[O:28])=[CH:23][C:22]=3[O:30][CH3:31])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1)[CH3:2].[NH2:34][C:35]1[S:36][CH:37]=[CH:38][N:39]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:11]1([N:10]2[C:6]3[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:33]=[CH:32][C:7]=3[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[O:28])[NH:34][C:35]4[S:36][CH:37]=[CH:38][N:39]=4)=[CH:23][C:22]=3[O:30][CH3:31])(=[O:20])=[O:19])[C:9]2=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)O)cc1OC
Reactant: Nc1nccs1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)Nc2nccs2)cc1OC
Yield: 7.7 %

Procedure:
This compound is prepared by the procedure described in EXAMPLE 100 starting from 1 g of the compound obtained in EXAMPLE 13, 0.3 g of 2-aminothiazole, 1.2 g of BOP, 1 ml of DIPEA and 20 ml of DCM. It is chromatographed on silica using a DCM/MeOH mixture (99.5/0.5; v/v) as the eluent to give 0.09 g of the expected product after crystallization from EtOH. M.p.=213° C.
Reaction SMILES: [CH3:1][N:2](C)C=O.Br[C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[C:10]([F:17])=[CH:9][N:8]=1>[C-]#N.[Zn+2].[C-]#N.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.O>[F:17][C:10]1[C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:7]([C:1]#[N:2])=[N:8][CH:9]=1
Reactant: CN(C)C=O
Reactant: Fc1cnc(Br)cc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: N#Cc1cc(C(F)(F)F)c(F)cn1
Temperature: 95 °C
Reaction time: 14 h

Procedure:
To 12 ml of N,N-dimethylformamide were added 0.8 g of 2-bromo-5-fluoro-4-trifluoromethylpyridine, 1.41 g of zinc cyanide and 0.28 g of tetrakistriphenylphosphinepalladium, and the mixture was stirred at 95° C. for 14 hours. After allowing to cool, the reaction solution was poured into water, and the resultant solution was extracted with diethyl ether three times, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.5 g of 5-fluoro-4-trifluoromethylpyridine-2-carbonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6](O)=[O:7].S(Cl)([Cl:16])=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([Cl:16])=[O:7]
Reactant: COc1ccc(C(=O)O)cc1OC
Reactant: O=S(Cl)Cl
Product: COc1ccc(C(=O)Cl)cc1OC

Procedure:
2.9 g of 3,4-dimethoxybenzoic acid and 4 ml of thionyl chloride were heated for 4 hours at reflux and concentrated under reduced pressure to obtain 3,4-dimethoxybenzoyl chloride. The 3,4-dimethoxybenzoyl chloride was dissolved in 10 ml of anhydrous benzene, and the resulting solution was added dropwise to a solution of 4.0 g of N-ethyl-N-(4-hydroxybutyl)-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine and 2.2 g of triethylamine in 50 ml of anhydrous benzene. After the addition, the resulting solution was stirred for 30 minutes at room temperature (about 25° C.) and heated for 3.5 hours at reflux. The reaction solution was washed with water, a 2 N-NaOH aqueous solution and water in this order, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was purified through silica gel chromatography to obtain N-ethyl-N-[4-(3,4-dimethoxybenzoyloxy)butyl]-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine as a colorless oily product. To this oily product was added an ethanolic solution of hydrogen chloride having a concentration of about 18% and the resulting solution was concentrated under reduced pressure to obtain a residue. The residue was dissolved in a mixed solvent of acetone and diethyl ether, and the solution was left at a temperature of about 2° to 3° C. to form crystals. By collecting the crystals through filtration and recrystallization from a mixed solvent of acetone and diethyl ether, 3.0 g of N-ethyl-N-[4-(3,4-dimethoxybenzoyloxy)butyl]-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride was obtained as colorless crystals having a melting point of 139°-140° C. The melting point, the infrared spectra and other physical data of this product corresponded to the date of the compound obtained in Example 2 (ii).
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11]1[CH:25]=[CH:24][C:14]([O:15][C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=1)C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:15][C:16]([CH3:22])([CH3:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:24][CH:25]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCOCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(CCO)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 87.7 %

Procedure:
To a solution of ethyl 2-[4-(2-benzyloxyethyl)-phenoxy]-2-methylpropionate (480 mg) in ethanol (3.0ml) was added 10% palladium on activated carbon (30 mg), and the mixture was stirred for 48 hours at room temperature under a hydrogen atmosphere. The catalyst was filtered off, and the solvent of the filtrate was removed under reduced pressure. Purification of the residue by medium pressure liquid column chromatography on silica gel (eluent: hexane/diethyl ether=1/1) gave ethyl 2-[4-(2-hydroxyethyl)phenoxy]-2-methylpropionate (310 mg).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.Br[C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1[F:31]>>[F:30][C:29]1[CH:28]=[CH:27][CH:26]=[C:25]([F:31])[C:24]=1[N:17]1[CH2:16][CH2:15][C:12]2([C:11](=[O:20])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:19][CH2:18]1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: Fc1cccc(F)c1Br
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(c1c(F)cccc1F)CC2

Procedure:
The title compound was prepared in analogy to example 1 step D from a mixture of 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 1 step C) and 1-bromo-2,6-difluorobenzene. White solid. MS (ESI): 427.1 (MH+)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[CH3:30][O:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][C:33]=1[N:39]1[CH2:44][CH2:43][N:42]([CH2:45][CH2:46][S:47]([CH3:50])(=[O:49])=[O:48])[CH2:41][CH2:40]1>>[F:26][C:25]([F:28])([F:27])[C:24]([NH:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:36][C:35]4[CH:37]=[CH:38][C:32]([O:31][CH3:30])=[C:33]([N:39]5[CH2:44][CH2:43][N:42]([CH2:45][CH2:46][S:47]([CH3:50])(=[O:49])=[O:48])[CH2:41][CH2:40]5)[CH:34]=4)[N:7]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:18]=1)=[O:29]
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)C(F)(F)F
Reactant: COc1ccc(N)cc1N1CCN(CCS(C)(=O)=O)CC1
Product: COc1ccc(Nc2nccc(-c3c(-c4cccc(NC(=O)C(F)(F)F)c4)nn4ccccc34)n2)cc1N1CCN(CCS(C)(=O)=O)CC1
Yield: 42 %

Procedure:
The compound was synthesized from N-{3-[3-(2-chloro-4-pyrimidinyl)-pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,2,2-trifluoroacetamide (see Example 1, Step C) and 4-(methyloxy)-3-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}aniline to afford a yellow solid in 42% yield. ES-LC/MS m/z 695 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13](OC(=O)C)[C:14]([N:16]([CH3:27])[CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[CH3:18])=[O:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].FC(F)(F)C(O)=O>ClCCl>[CH3:18][CH:17]1[C:19]2[C:24](=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[CH:13]([C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:14](=[O:15])[N:16]1[CH3:27]
Reactant: COc1cccc(C(C)N(C)C(=O)C(OC(C)=O)c2cc(OC)c(OC)c(OC)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(c1)C(C)N(C)C(=O)C2c1cc(OC)c(OC)c(OC)c1

Procedure:
A solution of the amide from step 2 above (4.2 g) in dichloromethane (60 ml) and trifluoroacetic acid (20 ml) was refluxed for 4 hours. The reaction mixture was concentrated to dryness and the residue was submitted to chromatography on silica gel using dichloromethane-ethyl acetate (6:4) as eluent. The first fraction was concentrated to dryness and the residue was crystallized from methanol giving diastereomer I, m.p. 135-140° C. The third fraction contained diastereomer II, which was recovered as an amorphous solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)[N:7]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24].O>N1C=CC=CC=1>[C:23]([NH:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:12][CH:13]=2)[N:7]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc(-c2ccc(OCc3ccc(Cl)cc3)cc2)cs1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1nc(-c2ccc(OCc3ccc(Cl)cc3)cc2)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
In 30 ml of pyridine was dissolved 2.0 g hydrochloride of 2-amino-4-[4-(4-chlorobenzyloxy)phenyl]thiazole, and 1.0 ml of acetic anhydride was added to the solution, followed by stirring at room temperature for 2 hours. Water was added and, the precipitating crystals were recovered by filtration, thus yielding 1.9 g (95.0%) of 2-acetylamino-4-[4-(4-chlorobenzyloxy)phenyl]thiazole. m.p., 239°-240° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=1>C(#N)C>[CH3:21][O:20][C:3]1[C:2]([O:1][CH2:29][C:30]2[CH:31]=[CH:32][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:34][CH:35]=2)=[C:7]([O:8][CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[O:14][CH2:13]2
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(OC)c1O
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2ccc3c(c2)COC3=O)c(OC)c1OCc1ccc(S(C)(=O)=O)cc1
Temperature: 80 °C
Yield: 19.7 %

Procedure:
To a stirring solution of 5-(3-Hydroxy-2,4-dimethoxy-phenyl)-3H-isobenzofuran-1-one (80 mg, 0.279 mmol) in acetonitrile (10 mL) was added potassium carbonate (115 mg, 0.837 mmol) and 1-(bromomethyl)-4-(methylsulfonyl)benzene (208 mg, 0.837 mmol) and the resultant reaction mixture was heated to 80° C. for 4 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) to afford the title compound as a solid (25 mg, 19.7%).
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)(Cl)Cl>[C:29]1([NH:28][C:12]([C:9]2[C:8](=[O:15])[N:7]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]3=[N:11][CH:10]=2)=[O:14])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Reactant: Nc1ccccc1
Agent: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cccc2ncc(C(=O)Nc3ccccc3)c(=O)n12
Reaction time: 0.08 h
Yield: 78.8 %

Procedure:
A mixture containing 16.32 g (0.08 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 6.5 ml (0.08 mol) of methyl chloroformate in 40 ml of chloroform is dropped to the above mixture at a temperature between -10° C. and -13° C. during 20 minutes. After stirring for 5 minutes, 9.19 g (0.088 mol) of aniline dissolved in 80 ml of chloroform are dropped to the above solution at a temperature between -10° C. and -13° C. during 30 minutes. The reaction mixture is stirred below -10° C. for 1 hour and then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 150 ml of 5% sodium hydrogen carbonate solution each and then 3 times with 150 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to give 17.6 g (78.8%) of the named compound as yellow crystals after recrystallization from ethanol, m.p.: 186°-188° C.
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.Cl[CH2:12][C:13]([NH:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:14].C(N(CC)CC)C>C(O)C>[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([N:8]([CH2:12][C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:14])[NH2:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(NN)cc1
Reactant: O=C(CCl)NCC1CCCCC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccc(N(N)CC(=O)NCC2CCCCC2)cc1
Yield: 100 %

Procedure:
p-Tolylhydrazine hydrochloride (500 mg, 3.16 mmol), 2-chloro-N-(cyclohexylmethyl)acetamide (600 mg, 3.16 mmol), triethylamine (1.31 ml, 9.4 mmol) and ethanol (20 ml) were stirred together to obtain 870 mg of 2-(1-p-tolylhydrazinyl)-N-(cyclohexylmethyl)acetamide. The intermediate (870 mg, 3.15 mmol) and N-methyl-4-piperidone hydrochloride (471 mg, 3.16 mmol) were taken in ethanolic HCl (20 ml) and stirred at RT for 15 min, after which the solvent was removed in vacuo. The reaction mixture obtained was taken in ethanol and heated at 90 deg C. for 14 h. After completion of the reaction (monitored by LCMS), the reaction mixture was concentrated to dryness and basified with aqueous saturated sodium bicarbonate, extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate and concentrated to obtain the crude product which was purified by silica gel chromatography (Eluent: 10% MeOH in dichloromethane) to yield 70 mg (yield: 6.27%) of N-(cyclohexylmethyl)-2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetamide. The freebase obtained (70 mg, 0.19 mmol) was dissolve d in THF (10.0 ml), oxalic acid (24 mg, 0.19 mmol) in THF (10.0 ml) was added slowly, the mixture was stirred at RT for 20 min and the solid obtained was filtered, washed with ether and dried to get 70 mg (yield: 80.4%) of N-(cyclohexylmethyl)-2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetamide as oxalate salt. 1H NMR (DMSO-D2O) OXALATE SALT 8.3-8.2 (t, 1H), 7.30 (d, 1H), 7.2 (s, 1H), 7.0-6.9 (d, 1H), 4.70 (s, 2H), 4.3 (bs, 2H), 3.80-3.2 (m, 4H), 3.1 (bs, 2H), 2.90 (s, 3H), 2.30 (s, 3H), 1.70-1.50 (m, 5H), 1.40-1.30 (m, 1H), 1.20-1.0 (m, 4H), 0.90-0.70 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]3[C:16]([C:17]#[N:18])=[C:15]([CH3:19])[NH:14][C:13]([CH3:20])=[C:12]3[C:21]#[N:22])[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[O:30]=[C:31]1[CH2:35][CH2:34][C:33](=[O:36])[N:32]1[CH2:37][CH2:38][S:39](Cl)(=[O:41])=[O:40]>>[C:21]([C:12]1[CH:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[NH:1][S:39]([CH2:38][CH2:37][N:32]2[C:33](=[O:36])[CH2:34][CH2:35][C:31]2=[O:30])(=[O:40])=[O:41])[C:16]([C:17]#[N:18])=[C:15]([CH3:19])[NH:14][C:13]=1[CH3:20])#[N:22]
Reactant: O=C1CCC(=O)N1CCS(=O)(=O)Cl
Reactant: CC1=C(C#N)C(c2ccc3c(c2)c(N)nn3C(=O)OC(C)(C)C)C(C#N)=C(C)N1
Product: CC1=C(C#N)C(c2ccc3[nH]nc(NS(=O)(=O)CCN4C(=O)CCC4=O)c3c2)C(C#N)=C(C)N1

Procedure:
The title compound was prepared following the procedure described for Example 1 using 100 mg (0.256 mmol) tert-butyl 3-amino-5-(3,5-dicyano-2,6-dimethyl-1,4-dihydropyridin-4-yl)-1H-indazole-1-carboxylate (Example 3A) and 173 mg (0.77 mmol) 2-(2,5-dioxopyrrolidin-1-yl)ethane-sulfonyl chloride. Yield: 20 mg (17% of th.).
Reaction SMILES: [OH:1][CH:2]([C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1)[C:3]1[CH:4]=[C:5]([C:24]([OH:26])=[O:25])[C:6]2[O:10][C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:8][C:7]=2[CH:23]=1>CC(C)=O.CS(C)=O>[C:17]1([C:9]2([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[O:8][C:7]3[CH:23]=[C:3]([C:2]([C:27]4[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=4)=[O:1])[CH:4]=[C:5]([C:24]([OH:26])=[O:25])[C:6]=3[O:10]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)c1cc(C(O)c2ccncc2)cc2c1OC(c1ccccc1)(c1ccccc1)O2
Solvent: CC(C)=O
Solvent: CS(C)=O
Product: O=C(c1ccncc1)c1cc2c(c(C(=O)O)c1)OC(c1ccccc1)(c1ccccc1)O2
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of 6-(hydroxy-pyridin-4-yl-methyl)-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid (128 mg, 0.324 mmol, 1 eq.) in a mixture of 10 mL acetone and 3 mL DMSO, IBX (273 mg, 0.973 mmol, 3 eq.) was added and the reaction mixture was stirred 3 h at 50° C. The mixture was partitioned between H2O and EtOAc, and the organic layer was washed with saturated NaCl solution before being dried over MgSO4 and evaporated under reduced pressure to yield the title compound as a yellowish solid.
Reaction SMILES: [H-].[Na+].[BH4-].[Na+].O.[NH2:6][C:7]1[N:12]=[C:11]([SH:13])[N:10]=[C:9]([OH:14])[CH:8]=1.Cl[C@@H:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17]>CN(C=O)C>[NH2:6][C:7]1[N:12]=[C:11]([S:13][C@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])[N:10]=[C:9]([OH:14])[CH:8]=1
Reactant: C[C@@H](Cl)c1ccccc1
Reactant: Nc1cc(O)nc(S)n1
Agent: [BH4-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](Sc1nc(N)cc(O)n1)c1ccccc1
Reaction time: 0.5 h
Yield: 46.5 %

Procedure:
NaH (60% in oil) (0.5 g, 12.5 mmol) followed by NaBH4 (40 mg, 1 mmol) was added to 6-amino-2-mercaptopyrimidin-4-ol monohydrate (1.6 g, 10 mmol) in DMF (20 mL). After 30 min, [(1R)-1-chloroethyl]benzene (1.4 g, 10 mmol) was added and the reaction mixture was stirred for 16 h. The reaction was concentrated in vacuo to ca. 10 mL volume and then poured into water (ca. 50 mL). The precipitated solid material was filtered off and washed with water and ether to give the title compound (1.15 g, 46% yield).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].O[CH2:6][C:7]1[N:12]=[CH:11][CH:10]=[CH:9][N:8]=1.S(Cl)(Cl)=O>>[N:8]1[CH:9]=[CH:10][CH:11]=[N:12][C:7]=1[CH2:6][NH:3][CH2:2][CH2:1][NH2:4]
Reactant: OCc1ncccn1
Reactant: NCCN
Solvent: O=S(Cl)Cl
Product: NCCNCc1ncccn1

Procedure:
By the procedure of Example 34, ethylenediamine is reacted with 2-chloroemethylpyrimidine, prepared by treating 2-hydroxymethylpyrimidine with thionyl chloride, to give N-(2-pyrimidylmethyl)ethylenediamine.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][C:27]1[C:28]([C:33](O)=[O:34])=[N:29][CH:30]=[CH:31][CH:32]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:33]([C:28]4[C:27]([CH3:26])=[CH:32][CH:31]=[CH:30][N:29]=4)=[O:34])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: Cc1cccnc1C(=O)O
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ncccc4C)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 3-methylpyridine-2-carboxylic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) to yield the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[CH:10]([OH:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:3]=1.C([Li])CCC.[CH3:25][O:26][C:27](=[O:38])[C:28]1[CH:37]=[CH:36][CH:35]=[C:30]([C:31](OC)=[O:32])[CH:29]=1>O1CCCC1>[CH3:25][O:26][C:27]([C:28]1[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=1)[C:31]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[CH:10]([OH:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:3]=1)=[O:32])=[O:38]
Reactant: COC(=O)c1cccc(C(=O)OC)c1
Reactant: CCCCCCCCC(O)/C=C/c1cccc(Br)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCC(O)/C=C/c1cccc(C(=O)c2cccc(C(=O)OC)c2)n1
Yield: 15.9 %

Procedure:
Under the conditions of example 1B, 652 mg of 2-bromo-6[(1E)-(3RS)-3-hydroxy-1-undecenyl]-pyridine in 3 ml of tetrahydrofuran is mixed with 2.75 ml of n-butyllithium (1.6 molar in hexane) and 427 mg of isophthalic acid dimethyl ester in 3 ml of tetrahydrofuran, worked up and chromatographed on silica gel with hexane/ethyl acetate=95/5 to 75/25. 130 mg of an oily crude product is obtained, which is subjected to complete purification of the high-pressure liquid chromatography on silanized silica gel (RP 18 material) with methanol/H2O=85/15. 58 mg of the title compound is thus obtained as colorless oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.[Cl:16][CH2:17][CH2:18][NH2:19].C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:16][CH2:17][CH2:18][NH:19][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: NCCCl
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cnc2ccccc2c1NCCCl
Reaction time: 8 h
Yield: 87.8 %

Procedure:
Using the general method of Example 1 Part A, 4-chloro-3-nitroquinoline (15.0 g, 71.90 mol) was reacted with 2-chloroethylamine monohydrochloride (8.3 g, 71.90 mmol). The crude product was suspended in water (300 mL) and solid sodium carbonate was added to adjust the pH to 10. The suspension was stirred overnight and then cooled in an ice bath. The solid was then isolated by filtration and washed with chilled water to provide 15.88 g of N-(2chloroethyl)-3-nitroquinolin-4-amine as a bright yellow fluffy solid.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:11]([C@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3[C:17](Cl)=[O:18])=[N:10][CH:9]=[N:8]2)=[CH:4][CH:3]=1.[NH2:22][C@@H:23]1[C:32]2[C:27](=[CH:28][C:29]([C:33]([F:36])([F:35])[F:34])=[CH:30][CH:31]=2)[O:26][CH2:25][CH2:24]1.CCN(C(C)C)C(C)C>CC#N>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:11]([C@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3[C:17]([NH:22][C@@H:23]3[C:32]4[C:27](=[CH:28][C:29]([C:33]([F:36])([F:34])[F:35])=[CH:30][CH:31]=4)[O:26][CH2:25][CH2:24]3)=[O:18])=[N:10][CH:9]=[N:8]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)N1CCC[C@@H]1c1ncnn1Cc1ccc(Cl)cc1
Reactant: N[C@H]1CCOc2cc(C(F)(F)F)ccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1CCOc2cc(C(F)(F)F)ccc21)N1CCC[C@@H]1c1ncnn1Cc1ccc(Cl)cc1

Procedure:
A solution of (R)-1-(4-chlorobenzyl)-5-(1-chlorocarbonylpyrrolidin-2-yl)-1H-1,2,4-triazole (60 mg), (S)-4-amino-7-trifluoromethylchroman and DIEA in dry MeCN was stirred overnight at RT. The solvent was removed and the residue was partitioned between water and EtOAc. The EtOAc layer was washed with water and evaporated after drying over Na2SO4. The residue was purified by chromatography (silica gel, hexane:EtOAc (1:1)→EtOAc) to give 40 mg of the desired product.