Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:27])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:18][CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1.Cl>C(OCC)C.[BH4-].[Zn+2].[BH4-]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:27])[CH:9]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:20][CH:21]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1ccc(CC(C)(C)C)cc1)C(=O)c1cccc(Cl)c1
Agent: Cl
Agent: [BH4-]
Agent: [Zn+2]
Solvent: CCOCC
Product: CCOC(=O)C(Cc1ccc(CC(C)(C)C)cc1)C(O)c1cccc(Cl)c1
Reaction time: 0.33 h

Procedure:
While stirring zinc chloride (3.22 g, 23.6 mmol) in diethyl ether (30 ml), sodium borohydride (1.78 g, 47.2 mmol) was added at room temperature, and the mixture was stirred as it was for 2 hrs. Insoluble material in the mixture was removed by filtration and washed with diethyl ether to give a solution of zinc borohydride in diethyl ether. To the obtained solution was added a solution of ethyl 3-(3-chlorophenyl)-2-(4-neopentylbenzyl)-3-oxopropionate (4.564 g, 11.80 mmol) in diethyl ether (30 ml) under ice-cooling, and the mixture was stirred as it was for 20 min. To the reaction solution was added dilute hydrochloric acid by small portions to decompose excess zinc borohydride, and the mixture was extracted twice with ethyl acetate. The recovered organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=15/1−6/1) to give the objective substance.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][CH2:21][CH2:22][CH2:23][N:24]([CH3:32])[C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][N:26]=1>>[CH3:19][O:20][CH2:21][CH2:22][CH2:23][N:24]([CH3:32])[C:25]1[N:26]=[CH:27][C:28]([NH:31][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:29][CH:30]=1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: COCCCN(C)c1ccc(N)cn1
Product: COCCCN(C)c1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(3-methoxy-propyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N2-(3-methoxy-propyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C21H21F3N4O3 (m/e) 434, obsd 435 (M+H).
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[C:14]2[CH2:13][CH2:12][N:11]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:10][CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1>C(#N)C>[Br:1][C:7]1[C:8]2[CH2:9][CH2:10][N:11]([C:15](=[O:20])[C:16]([F:19])([F:17])[F:18])[CH2:12][CH2:13][C:14]=2[C:4]([OH:3])=[CH:5][CH:6]=1
Reactant: BrBr
Reactant: O=C(N1CCc2cccc(O)c2CC1)C(F)(F)F
Solvent: CC#N
Product: O=C(N1CCc2c(O)ccc(Br)c2CC1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
Add dropwise bromine (10.8 mL, 0.21 mol) in acetonitrile (260 mL) to a slurry of 6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (51.8 g, 0.2 mol) in acetonitrile (400 mL) at 0° C. cooling with ice-water to keep the temperature between 2-5° C. Warm the reaction to ambient temperature and stir for 30 min. Pour the mixture into ice-cold water (2 L) to obtain a white precipitate. Collect the solid by vacuum filtration, wash with water and dry under vacuum at 105° C. Recrystallize the crude material in toluene/heptane and cool the mixture in an ice bath. Collect the solid by vacuum filtration, wash with heptane and dry under vacuum at 105° C. to obtain the desired intermediate as a white solid (54.63 g, 81%). MS (ES+) m/z: 338 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[C:17]=2[F:26])=[CH:14][CH:15]=1)=O)C.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([NH2:41])=[N:39][CH:40]=2)[CH2:30][CH2:29]1>C(Cl)Cl.CO>[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([NH:41][C:4]([C:6]3[C:7]4[N:8]=[CH:9][CH:10]=[N:11][C:12]=4[C:13]([C:16]4[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[C:17]=4[F:26])=[CH:14][CH:15]=3)=[O:3])=[N:39][CH:40]=2)[CH2:30][CH2:29]1
Reactant: CN1CCN(Cc2ccc(N)nc2)CC1
Reactant: CCOC(=O)c1ccc(-c2cc(OC)cc(OC)c2F)c2nccnc12
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3nccnc23)c1
Reaction time: 1 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 143.1), 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Example 31; purified by silica gel column chromatography), and stirring the reaction mixture for 1 h at reflux. Title compound: ESI-MS: 517.1 [M+H]+; tR=3.37 min (System 1); TLC: Rf=0.11 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@H:13]([OH:14])[C@@H:12]([CH2:15]O)[O:11][C@H:10]1[N:17]1[CH:24]=[CH:23][C:21](=[O:22])[NH:20][C:18]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>CN(C=O)C>[CH2:1]([O:8][C@@H:9]1[C@H:13]([OH:14])[C@@H:12]([CH2:15][Br:26])[O:11][C@H:10]1[N:17]1[CH:24]=[CH:23][C:21](=[O:22])[NH:20][C:18]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2OCc2ccccc2)c(=O)[nH]1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=c1ccn([C@@H]2O[C@H](CBr)[C@@H](O)[C@H]2OCc2ccccc2)c(=O)[nH]1
Temperature: 20 °C
Reaction time: 2 h
Yield: 40.3 %

Procedure:
To a mixture of 2'-O-benzyluridine [Wagner et al. (1974), J. Org. Chem. 39, 24-30] (334 mg 1 mM) carbon tetrabromide (500 mg) and DMF (4 ml) at 20° C. under Argon was added over 5 mins a solution of triphenylphosphine (340 mg) in DMF (2 ml). The mixture was stirred at 20° C. for 2 hrs, poured into water (60 ml) and extracted twice with ethyl acetate. The combined organic extracts were washed with water, dried, and evaporated to an oil. This oil was chromatographed on 20 g of Merck silica gel (Art. 9385). Elution with 5% methanol in toluene gave 2'-O-benzyl-5'-bromo-5'-deoxyuridine (160 mg, 40%).
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:14])[NH:6][C:7]1[O:11][N:10]=[C:9]([CH3:12])[C:8]=1[CH3:13].[C:17]1([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[CH:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[CH3:12][C:9]1[C:8]([CH3:13])=[C:7]([NH:6][C:5]([N:32]2[CH2:33][CH2:34][N:29]([C:25]3[CH:24]=[C:23]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:28]=[CH:27][N:26]=3)[CH2:30][CH2:31]2)=[O:14])[O:11][N:10]=1
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Reactant: c1ccc(-c2ccnc(N3CCNCC3)c2)cc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1noc(NC(=O)N2CCN(c3cc(-c4ccccc4)ccn3)CC2)c1C
Yield: 36.8 %

Procedure:
A solution of 2,2,2-trichloroethyl(3,4-dimethylisoxazol-5-yl)carbamate (120 mg, 0.418 mmol), 1-(4-phenylpyridin-2-yl)piperazine (100 mg, 0.418 mmol), diisopropylethylamine (0.146 ml, 0.836 mmol) and dimethylsulfoxide (2 ml) was stirred at 70° C. for 3 hours, then the reaction solution was poured into water, and extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduce pressure, and the residue was recrystallized from ethyl acetate to give the titled compound 58.0 mg (36.7%) as solid product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[CH:12]2.[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[S:28](Cl)(=[O:30])=[O:29]>>[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[S:28]([NH:19][C:4]1[CH:5]=[N:6][C:7]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[CH:12]3)=[C:2]([Cl:1])[CH:3]=1)(=[O:30])=[O:29]
Reactant: Nc1cnc(Oc2ccc3ncccc3c2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Product: O=S(=O)(Nc1cnc(Oc2ccc3ncccc3c2)c(Cl)c1)c1ccc(Cl)cc1Cl

Procedure:
The title compound was prepared by reacting 5-chloro-6-(quinolin-6-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 3) and 2,4-dichlorobenzene-1-sulfonyl chloride.
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:4]1=[O:21].[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]([C:32]([O-])=[O:33])[N:23]=1.[Na+].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[F:20][C:17]1[CH:18]=[CH:19][C:14]([N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=3)[CH:3]([NH:2][C:32]([C:24]3[N:23]=[CH:22][C:31]4[C:26]([CH:25]=3)=[CH:27][CH:28]=[CH:29][CH:30]=4)=[O:33])[C:4]2=[O:21])=[CH:15][CH:16]=1
Reactant: O=C([O-])c1cc2ccccc2cn1
Reactant: COc1ccc2c(c1)N(c1ccc(F)cc1)C(=O)C2N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)N(c1ccc(F)cc1)C(=O)C2NC(=O)c1cc2ccccc2cn1
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
To a stirred suspension of 2.00 g of 3-amino-1-(4-fluorophenyl)-2,3-dihydro-6-methoxy-1H-indol-2-one hydrochloride, 1.33 g of sodium isoquinoline-3-carboxylate and 0.88 g of 1-hydroxybenzotriazole in 10 ml of anhydrous dimethylformamide was added 1.49 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride under ice cooling. The whole was stirred for 30 minutes. The reaction mixture was extracted by pouring a mixed solvent of ethyl acetate-tetrahydrofuran (2:1). The extract was washed with water, dried and evaporated. The residue was triturated with a mixed solvent of ethyl acetate and tetrahydrofuran to afford 2.60 g of N-[1(4-fluorophenyl)-2,3-dihydro-6-methoxy-2-oxo-1H-indol-3-yl]-3-isoquinolinecarboxamide as a powder. Melting point: 219° to 220° C.
Reaction SMILES: [O:1]1[CH:7]2[CH:2]1[C:3]([CH3:17])([CH3:16])[O:4][C:5]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:6]=12.[C:18]([N:20]=[C:21]1[NH:25][CH2:24][CH2:23][S:22]1)#[N:19].C(N(CC)CC)C.CN(C)C=O>O>[C:18]([N:20]=[C:21]1[N:25]([C@@H:7]2[C:6]3[CH:8]=[C:9]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=[CH:11][C:5]=3[O:4][C:3]([CH3:17])([CH3:16])[C@H:2]2[OH:1])[CH2:24][CH2:23][S:22]1)#[N:19]
Reactant: N#CN=C1NCCS1
Reactant: CC1(C)Oc2ccc(S(C)(=O)=O)cc2C2OC21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(C)Oc2ccc(S(C)(=O)=O)cc2[C@@H](N2CCSC2=NC#N)[C@@H]1O
Temperature: 100 °C
Reaction time: 5 h
Yield: 71.1 %

Procedure:
A mixture of 3,4-dihydro-3,4-epoxy-6-mesyl-2,2-dimethyl-2H-1-benzopyran (1.5 g), 2-(cyanoimino)-thiazolidine (1.1 g), triethylamine (3 ml) and N,N-dimethylformamide (6 ml) was stirred at 100° C. for 5 hours. After cooling, the reaction mixture was poured into water. The precipitate was collected by filtration, washed well with water and dried in vacuo to give trans-4-(2-cyanoiminothiazolidin-3-yl)-3,4-dihydro-3-hydroxy-6-mesyl-2,2-dimethyl-2H-1-benzopyran (1.6 g).
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].C(OC([N:14]([C:22]1[C:27]([C:28]2[N:32]=[C:31]([CH3:33])[O:30][N:29]=2)=[N:26][C:25]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[CH:24][N:23]=1)C(=O)OC(C)(C)C)=O)(C)(C)C.C(N(CC)CC)C.Cl.O1CCOCC1>ClCCl>[CH2:1]([S:3]([N:37]1[CH2:38][CH2:39][N:34]([C:25]2[N:26]=[C:27]([C:28]3[N:32]=[C:31]([CH3:33])[O:30][N:29]=3)[C:22]([NH2:14])=[N:23][CH:24]=2)[CH2:35][CH2:36]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)Cl
Reactant: Cc1nc(-c2nc(N3CCNCC3)cnc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)no1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(-c3noc(C)n3)n2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 19.2 %

Procedure:
Ethanesulfonyl chloride (41.38 mg, 30.49 μL, 0.3218 mmol) was added to a solution of tert-butyl N-tert-butoxycarbonyl-N-[3-(5-methyl-1,2,4-oxadiazol-3-yl)-5-piperazin-1-yl-pyrazin-2-yl]carbamate (150 mg, 0.2925 mmol) and triethylamine (59.20 mg, 81.54 μL, 0.5850 mmol) in dichloromethane (5.818 mL) at 0° C. and the resulting solution stirred at ambient temperature for 1.5 hours. The reaction was treated with HCl in dioxane (365.8 μL of 4 M, 1.463 mmol) and allowed to stir at ambient temperature overnight. The reaction was concentrated in vacuo and the resultant residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound (19.8 mg, 12% Yield). 1H NMR (DMSO) d 1.23 (3H, t), 2.70 (3H, s), 3.08-3.13 (2H, q), 3.31 (4H, m), 3.48 (4H, m), 6.50 (2H, br s), 8.17 (1H, s) ppm; MS (ES+) 353.99
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:15]([CH3:31])([CH3:30])[CH2:14]2)[N:5]=[C:4]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]2[CH2:42][C:41]([CH3:44])([CH3:43])[N:40]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:39]([CH3:55])([CH3:54])[CH2:38]2)[N:3]=1.[NH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][C:62]([O-:64])=[O:63].[Na+]>>[CH2:22]([O:21][N:16]1[C:17]([CH3:20])([CH3:19])[CH2:18][CH:13]([CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]2[N:5]=[C:4]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]3[CH2:42][C:41]([CH3:43])([CH3:44])[N:40]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:39]([CH3:54])([CH3:55])[CH2:38]3)[N:3]=[C:2]([NH:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][C:62]([OH:64])=[O:63])[N:7]=2)[CH2:14][C:15]1([CH3:30])[CH3:31])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: NCCCCCC(=O)[O-]
Reactant: CCCCCCCCON1C(C)(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)n2)CC1(C)C
Agent: [Na+]
Product: CCCCCCCCON1C(C)(C)CC(CCCCNc2nc(NCCCCCC(=O)O)nc(NCCCCC3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)n2)CC1(C)C

Procedure:
The title compound, a colorless glass, is prepared from 2-chloro-4,6-bis[N-(1-octyloxy-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-1,3,5-triazine and sodium 6-aminohexanoate according to the procedure of Example 15.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([C:20]2([CH2:25][NH2:26])[CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:12]1.C(N(CC)CC)C>C(OCC)C>[CH3:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([C:20]2([CH2:25][NH:26][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:12]1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cn1cc(C2(CN)CCCC2)c2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cn1cc(C2(CNC(=O)c3ccccc3)CCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The reaction is performed under a dry nitrogen atmosphere. 9.8 g (0.07 mol) of benzoyl chloride dissolved in 70 cm3 of diethyl ether are added dropwise to a solution of 16 g (0.07 mol) of 1-(1-methyl-3-indolyl)-cyclopentylmethylamine and 7.08 g (0.07 mol) of triethylamine in 70 cm3 of diethyl ether so as to maintain a gentle reflux of the ether, and the mixture is then stirred for 2 hours at room temperature. The precipitate formed is thereafter drained, the ether solution is washed with water, dried over sodium sulphate and filtered and the ether is evaporated off from the filtrate. The residue thereby obtained is crystallised by washing with cold diisopropyl ether.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)([CH3:5])[C:3]#[CH:4].C(C1(C2C=CC(OC)=C(C=2)[CH:24]=[O:25])CC1)#N>>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([C:2]([CH3:1])([CH3:5])[C:3]#[CH:4])=[CH:7][C:8]=1[CH:24]=[O:25]
Reactant: C#CC(C)(C)c1ccc(OC)cc1
Reactant: COc1ccc(C2(C#N)CC2)cc1C=O
Product: C#CC(C)(C)c1ccc(OC)c(C=O)c1

Procedure:
This compound was prepared from Compound 21 in the same manner of Compound 2.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][CH2:7][OH:8])(=[O:4])=[O:3].[H-].[Na+].[Br:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([CH2:18]Br)[CH:17]=1.[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O.O>[Br:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([CH2:18][O:8][CH2:7][CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:17]=1
Reactant: CS(=O)(=O)CCCO
Reactant: BrCc1cncc(Br)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)CCCOCc1cncc(Br)c1
Reaction time: 0.25 h
Yield: 99 %

Procedure:
3-Methanesulfonyl-propan-1-ol (69 mg, 0.50 mmol) is dissolved in 2.0 mL of DMF and 60% sodium hydride (20 mg, 0.50 mmol) is added at 0° C. The mixture is stirred for 15 min and 3-bromo-5-bromomethyl-pyridine (50 mg, 0.20 mmol) is added. The mixture is stirred for 2 hrs and saturated aqueous NH4Cl solution (3 mL) is added along with water (10 mL) and EtOAc (10 mL). The mixture is stirred for 10 min and the aqueous layer is separated and extracted with EtOAc (2×15 ml). The organic layers are combined and concentrated to give the crude product. Purification by flash column chromatography affords 61 mg of 3-bromo-5-(3-methanesulfonyl-propoxymethyl)-pyridine.
Reaction SMILES: [CH2:1]([C:3]1([C:16]([O:18]CC)=[O:17])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)[CH3:2].[OH-].[K+].Cl>C(O)C.O>[C:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][C:3]([CH2:1][CH3:2])([C:16]([OH:18])=[O:17])[CH2:4][CH2:5]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CCOC(=O)C1(CC)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Yield: 90.9 %

Procedure:
To a stirred solution of 1-tert-butyl 4-ethyl 4-ethylpiperidine-1,4-dicarboxylate (Intermediate 21-step 2, 10.0 g, 63.69. mmol) in 50 ml ethanol was added potassium hydroxide (8.0 g, 95.5 mmol) and the contents were refluxed for 16 hours. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with water, acidified with 5% HCl and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to furnish the title compound (8.2 g) as a light yellow liquid. 1H NMR (300 MHz, CDCl3): 1.44 (s, 9H); 2.07-2.11 (m, 2H); 2.28 (s, 1H); 2.82 (s, 2H); 2.92-2.95 (m, 1H); 3.46-3.52 (m, 3H); ES Mass: 280 (100%), [M+Na].
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[C@H:30]12[CH2:36][C@H:33]([NH:34][CH2:35]1)[CH2:32][N:31]2[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38].C(N(CC)C(C)C)(C)C.CC#N>CN1C(=O)CCC1>[C:40]([O:39][C:37]([N:31]1[CH2:32][CH:33]2[CH2:36][CH:30]1[CH2:35][N:34]2[C:2]1[CH:29]=[CH:28][C:5]([C:6](=[O:7])[NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:11]=2)=[CH:4][N:3]=1)=[O:38])([CH3:43])([CH3:41])[CH3:42]
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC2CC1CN2c1ccc(C(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)cn1
Temperature: 115 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
A mixture of 6-chloro-N-((7-chloro-4-oxo-1-phenyl-1,4-dihydroquinolin-3-yl)methyl)nicotinamide (intermediate E) (30 mg, 0.071 mmol), (1S,4S)-tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (43 mg, 0.212 mmol) and N,N-diisopropylethylamine (59.2 mg, 80.0 μL, 0.456 mmol) in NMP (500 μL) was stirred at 115° C. in a sealed tube overnight. The reaction mixture was transferred to a vial with CH3CN, then concentrated under a stream of nitrogen. The crude product was purified using preparative reverse-phase HPLC. The product 5-{5-[(7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-carbamoyl]-pyridin-2-yl}-2,5-diaza-bicyclo-[2.2.1]-heptane-2-carboxylic acid tert-butyl ester (28 mg, 68%) was obtained as a white solid. MS calcd. for C32H32ClN5O4 [(M+H)+] 586.2, obsd. 586.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=2)=[CH:4][CH:3]=1.[CH2:14]1[CH2:20][S:17](=[O:19])(=[O:18])[O:16][CH2:15]1>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([CH2:15][CH2:14][CH2:20][S:17]([OH:19])(=[O:18])=[O:16])[CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCCO1
Reactant: Fc1ccc(C2=CCNCC2)cc1
Solvent: CC(C)=O
Product: O=S(=O)(O)CCCN1CC=C(c2ccc(F)cc2)CC1
Temperature: 25 °C

Procedure:
To a solution of 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine (1.96 g, 13.7 mmol) in acetone (30 mL) was added 1,3-propane sultone (1.74 g, 14.5 mmol). The mixture was stirred at reflux overnight. Only a small amount of compound precipitated. The resulting suspension was cooled to room temperature with stirring and a larger amount of solid precipitated. The suspension was heated with the addition of a small amount of MeOH until complete dissolution of the solid. The resulting solution was stirred at reflux for a few minutes and was cooled to room temperature with stirring. The solid was collected by filtration, washed with MeOH and dried in vacuo. This allowed the isolation of compound F, 1.33 g (32%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:10])=[CH:5][CH:4]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.C(OCC)C.C(OCC)(=O)C.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>[CH:2]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:10])=[CH:17][CH:18]=1)=[O:1]
Reactant: O=C(NCc1ccc(CO)cc1)c1ccccn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCOCC
Product: O=Cc1ccc(CNC(=O)c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
To a stirred solution of pyridine-2-carboxylic acid-4-hydroxymethyl-benzylamide (360 mg, 1.48 mmol) in anhydrous CH2Cl2 (10 mL) was added Dess-Martin periodiane (690 mg, 1.63 mmol) and the reaction stirred at room temperature for 1 h. The mixture was diluted with diethyl ether (25 mL), ethyl acetate (25 mL), saturated aqueous sodium bicarbonate (15 mL) and saturated aqueous sodium thiosulfate (15 mL) and stirred for 30 minutes. The phases were separated and the aqueous phase washed with ethyl acetate (1×15 mL). The combined organic layers were washed with brine (1×20 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. Purification of the crude oil by column chromatography on silica gel (CH2Cl2) gave the desired aldehyde as a pale yellow oil (300 mg, 85%). 1H NMR (300 MHz, CDCl3) δ 4.76 (d, 2H, J=6.0 Hz), 7.42-7.44 (m, 1H), 7.53 (d, 2H, J=6.0 Hz), 7.87 (d, 2H, J=6.0 Hz), 7.85-7.88 (m, 1H), 8.24 (d, 1H, J=6.0 Hz), 8.55 (br s, 1H), 8.57 (d, 1H, J=3.0 Hz), 10.00 (s, 1H).
Reaction SMILES: [F:1][CH:2]([F:23])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([CH3:22])[CH:16]=2)[CH:4]=1.[CH3:24][S:25]([C:28]1[CH:29]=[C:30]([NH2:34])[CH:31]=[CH:32][CH:33]=1)(=[O:27])=[O:26].Cl>>[CH3:24][S:25]([C:28]1[CH:29]=[C:30]([NH:34][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:23])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([CH3:22])[CH:16]=4)=[N:6][C:7]=23)=[O:14])[CH:31]=[CH:32][CH:33]=1)(=[O:26])=[O:27]
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: Cc1cc(-c2cc(C(F)F)n3ncc(C(=O)O)c3n2)ccc1Cl
Agent: Cl
Product: Cc1cc(-c2cc(C(F)F)n3ncc(C(=O)Nc4cccc(S(C)(=O)=O)c4)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(3-methyl-4-chloro-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Example C.14) and 3-methanesulfonyl-phenylamine [commercially available as hydrochloride] according to general procedure II. Yellow solid. MS (ISP) 488.9 [(M−H)−]; mp 270° C.