Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=C(C=O)C=1.SCCCO.C1(C)C=CC(S(O)(=O)=O)=CC=1.CNC([C:29]1([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[S:34][CH2:33][CH2:32][CH2:31][O:30]1)=S>ClCCCl>[N:37]1[CH:38]=[CH:39][CH:40]=[C:35]([CH:29]2[S:34][CH2:33][CH2:32][CH2:31][O:30]2)[CH:36]=1
Reactant: CNC(=S)C1(c2cccnc2)OCCCS1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=Cc1cccnc1
Agent: OCCCS
Solvent: ClCCCl
Product: c1cncc(C2OCCCS2)c1
Temperature: 20 °C

Procedure:
A solution of pyridine-3-carboxaldehyde (16 g), 3-mercaptopropan-1-ol (48 g) and para-toluenesulphonic acid (2.25 g) in 1,2-dichloroethane (1500 cc) is kept at the boil for 15 hours so that the water formed is removed by azeotropic distillation. After cooling to a temperature of about 20° C., the reaction mixture is washed three times with a 5 N aqueous solution of sodium hydroxide (750 cc in total) and then three times with distilled water (1500 cc in total). The organic phase is dried over anhydrous sodium sulphate and filtered, and the filtrate is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 50° C. The product obtained (15.6 g) is chromatographed in neutral silica gel (200 g) contained in a column of diameter 3.7 cm. Elution is carried out successively with a cyclohexane/ethyl acetate mixture (80/20 by volume; 600 cc) and a cyclohexane/ethyl acetate mixture (70/30 by volume; 2700 cc), 300 cc fractions being collected. Fractions 5 to 11 are combined and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 50° C. 2-(Pyrid-3-yl)-1,3-oxathiane (8.6 g) is thus obtained in the form of a yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:6](=[O:7])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[C:4](=[O:20])[NH:3]1.[Br:22][C:23]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:24]=1[CH2:25]Br>>[Br:22][C:23]1[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][C:24]=1[CH2:25][N:3]1[C:2]([CH3:21])([CH3:1])[C:6](=[O:7])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:17])[F:18])[CH:9]=2)[C:4]1=[O:20]
Reactant: FC(F)(F)c1ccc(Br)c(CBr)c1
Reactant: CC1(C)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1Cc1cc(C(F)(F)F)ccc1Br
Yield: 96 %

Procedure:
Compound 17.2 was prepared as described for example 6.2, by reacting compound 1.1 with 2-bromo-5-trifluoromethylbenzyl bromide. 4-[3-(2-Bromo-5-trifluoromethylbenzyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-2-trifluoromethylbenzonitrile was obtained in a yield of 96%. (Molecular weight 533.01 (C21H14BrF6N3O2); retention time Rt=2.21 min. [B]; MS (ESI): 534.14 (MH+)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[C:16]([CH3:21])[C:17]([C:18](=[S:20])[NH2:19])=[C:11]2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:23]([C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[F:37])=O)[C:24]([O:26][CH2:27][CH3:28])=[O:25]>CC(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[C:16]([CH3:21])[C:17]([C:18]3[S:20][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[F:37])[N:19]=3)=[C:11]2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nn2ccc(OCc3ccccc3)cc2c1C(N)=S
Reactant: CCOC(=O)C(Cl)C(=O)c1ccccc1F
Solvent: CC(C)O
Product: CCOC(=O)c1sc(-c2c(C)nn3ccc(OCc4ccccc4)cc23)nc1-c1ccccc1F
Temperature: 25 °C
Yield: 73.3 %

Procedure:
A suspension of 5-(benzyloxy)-2-methylpyrazolo[1,5-a]pyridine-3-carbothioamide (820 mg, 2.8 mmol) obtained in Example 30-B(vi) and ethyl 2-chloro-3-(2-fluorophenyl)-3-oxopropanoate (3.1 g, 13 mmol) obtained in Example 22-B(i) in 2-propanol (50 mL) was stirred at 90° C. for 7 h. The reaction mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration. The solid was washed with EtOAc and diisopropyl ether, and dried to give the title compound (1.0 g, 75%) as a yellow solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[CH2:10](Br)[CH2:11][CH2:12][CH2:13][CH3:14].C1C=CC=CC=1>O>[C:1]1([O:7][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: CCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: CCCCCOc1ccccc1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
In a 500 ml four-neck flask, load 115 g phenol (1.223 mol) and 82.2 g (1.468 mol) of dry KOH. A mass is heated up to 90° C. while mixing. Then by dropping during 0.5 h add 184.7 g (1.223 mol) of amylbromide. Maintain the mixture at a temperature of 95-100° C. for 45 minutes while mixing. After cooling, 200 ml of benzene and 300 ml of water are added to the mixture. The water layer is decanted. Then the benzene layer is washed with 200 ml of 5% solution of NaOH The benzene layer is then washed a few times with water until the reaction mixture is neutral.
Reaction SMILES: FC(F)(F)C(O)=O.O.[Cl:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([S:20]([N:23]([CH2:30][CH:31](OCC)[O:32]CC)[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])(=[O:22])=[O:21])[CH:14]=[CH:13]2.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([S:20]([N:23]([CH2:30][CH:31]=[O:32])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])(=[O:22])=[O:21])[CH:14]=[CH:13]2
Reactant: CCOC(=O)CN(CC(OCC)OCC)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CN(CC=O)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 51.4 %

Procedure:
To a mixed solution of trifluoroacetic acid (5 ml), chloroform (1.5 ml) and water (2.5 ml) was added a solution of the compound obtained in Step 2 (560 mg) in chloroform (1 ml) under cooling with ice water. After stirring for 1.5 hours under cooling with ice water, the reaction mixture was adjusted to pH 8 with saturated aqueous solution of sodium hydrogencarbonate and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and thereafter the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=5:1–2:1) to obtain the title compound (240 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:36])[C:3]([C:5]1[N:30]([CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([N:22]4[CH2:28][CH:27]5[NH:29][CH:24]([CH2:25][CH2:26]5)[CH2:23]4)=[O:21])=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:37]([N:44]1[CH2:51][CH2:50][CH2:49][C@H:45]1[C:46](O)=[O:47])([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>>[C:40]([O:39][C:37]([N:44]1[CH2:51][CH2:50][CH2:49][CH:45]1[C:46]([N:29]1[CH:24]2[CH2:25][CH2:26][CH:27]1[CH2:28][N:22]([C:20]([C:17]1[CH:16]=[N:15][C:14]([NH:13][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:36])[CH3:1])[N:30]([CH:31]5[CH2:35][CH2:34][CH2:33][CH2:32]5)[C:8]=4[N:9]=3)=[CH:19][CH:18]=1)=[O:21])[CH2:23]2)=[O:47])=[O:38])([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5)cn3)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5C(=O)C4CCCN4C(=O)OC(C)(C)C)cn3)nc2n1C1CCCC1
Yield: 67.6 %

Procedure:
Following general amide formation method 1, 7-cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.205 mmol, 1.0 eq) was combined with BOC-Proline (48.5 mg, 0.225 mmol, 1.1 eq) which gave 2-{3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carbonyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (95 mg) in 64% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36-1.57 (m, 12H) 1.63-1.86 (m, 5H) 1.91 (br. s., 4H) 1.99-2.29 (m, 10H) 2.45-2.67 (m, 2H) 3.18 (s, 7H) 3.43 (d, J=6.57 Hz, 2H) 3.60 (br. s., 3H) 4.42 (br. s., 2H) 4.56 (br. s., 2H) 4.68-4.94 (m, 2H) 6.53 (s, 1H) 7.83 (d, J=8.08 Hz, 1H) 8.41 (br. s., 1H) 8.58 (d, J=8.59 Hz, 1H) 8.76-8.80 (m, 1H). HRMS m/z, (M+H)+: 686.3769.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([Cl:12])[N:3]=1.S(=O)(=O)(O)O.[Br:18]N1C(=O)CCC1=O>CC#N>[Br:18][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[C:4]([Cl:12])[N:3]=[C:2]2[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1cc2ccccc2c(Cl)n1
Agent: O=S(=O)(O)O
Solvent: CC#N
Product: Clc1cc2c(Br)cccc2c(Cl)n1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution of 1,3-dichloroisoquinoline (1.0 g, 5.1 mmol) in CH3CN (25 mL) was added concentrated sulfuric acid (1.0 mL, 18 mmol), followed by N-bromosuccinimide (1.1 g, 6.1 mmol). The mixture was stirred at room temperature for 60 hours. The precipitate was collected by filtration, washed with water, then dried in air to afford the title compound: 1H NMR (500 MHz, CDCl3): δ 8.35 (d, J=9.0 Hz, 1H), 8.09 (s, 1H), 8.08 (d, J=9.0 Hz, 1H), 7.57 (t, J=8.0 Hz, 1H). LC6: 3.74 min. (M+H): 278.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.[CH2:11]=O>O>[CH3:11][N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1
Reactant: C=O
Reactant: O=C(O)CC1CCNCC1
Solvent: O
Product: CN1CCC(CC(=O)O)CC1

Procedure:
4-Piperidinylacetic acid (4 grams) (28.0 mmoles) from Preparative Example 17A was dissolved in water (50 ml) and 37% formalin (2.72 ml) (33.6 mmoles) was added. The mixture was hydrogenated over 10% Pd--C at 55 psi at 25° C. for 68 hours. The catalyst was filtered off and washed with water. The combined filtrates were evaporated to dryness to give the title compound (MH+ 158).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7](/[CH:8]=[C:9]2/[C:10](=[O:15])[NH:11][C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2].[CH2:18](O)[CH2:19][OH:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7](/[CH:8]=[C:9]2/[C:10](=[O:15])[N:11]([CH2:18][CH2:19][OH:20])[C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(/C=C2\SC(=O)NC2=O)cc1
Reactant: OCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOc1ccc(/C=C2\SC(=O)N(CCO)C2=O)cc1

Procedure:
The title compound 28e was prepared from compound 2 (249 mg, 1.00 mmol), ethane-1,2-diol (111 μL, 2.00 mmol), triphenylphosphine (524 mg, 2.00 mmmol) and DIAD (394 μL, 2.00 mmol) in a manner similar to that described for 9 in 95.2% (279 mg) yield as a white solid.
Reaction SMILES: [O:1]=[P:2]([Cl:5])(Cl)[Cl:3].[CH3:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CCOCC>[CH3:6][N:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[P:2]([Cl:5])([Cl:3])=[O:1]
Reactant: CNc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: CN(c1ccccc1)P(=O)(Cl)Cl
Reaction time: 2 h
Yield: 34.4 %

Procedure:
A 500 mL three-necked flask was fitted with an N2 inlet, thermometer and dropping funnel. The flask was flushed with nitrogen and charged with 150 mL dry ether and 31.1 g (0.203 mol) POCl3. In the dropping funnel was placed a solution of 21.4 g (0.20 mol) N-methylaniline in 5 mL ether. The amine solution was added to the solution of POCL3 (at -12° to -17° C.) over 40 minutes. The temperature was allowed to rise slowly to room temperature and stirring continued for 2 h thereafter. After filtering, volatiles were removed from the filtrate at reduced pressure. The 15.4 g (69% yield) of crude product was distilled (bp 96°-98° C. at 0.05 mm).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[NH:12][C:11]([CH2:13][S:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[NH2:22])=[N:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH:26]=[C:25]1[S:33](Cl)(=[O:35])=[O:34]>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[NH:12][C:11]([CH2:13][S:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[NH:22][S:33]([C:25]2[O:24][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[CH:26]=2)(=[O:34])=[O:35])=[N:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Reactant: CC(C)(C)OC(=O)Nc1nnc(CSc2ccc(Cl)cc2N)[nH]1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1nnc(CSc2ccc(Cl)cc2NS(=O)(=O)c2cc3ccccc3o2)[nH]1

Procedure:
Following General Procedure B, the title compound was prepared from tert-butyl(5-(((2-amino-4-chlorophenyl)thio)methyl)-4H-1,2,4-triazol-3-yl)carbamate (330 mg, 0.925 mmol) and benzofuran-2-sulfonyl chloride (200 mg, 0.925 mmol) in pyridine (2 ml).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[CH:22]=[N:23][C:24](S(C)(=O)=O)=[N:25][CH:26]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:31][CH:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1.O>CN1CCCC1=O>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[CH:22]=[N:23][C:24]([NH:38][CH:35]4[CH2:36][CH2:37][CH:32]([CH3:31])[CH2:33][CH2:34]4)=[N:25][CH:26]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)c1ncc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)cn1
Reactant: CC1CCC(N)CC1
Solvent: CN1CCCC1=O
Solvent: O
Product: CC1CCC(Nc2ncc(Cc3cn(S(=O)(=O)c4ccccc4)c4ncc(Cl)cc34)cn2)CC1
Temperature: 160 °C
Yield: 80.1 %

Procedure:
In a microwave vial, to 1-benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine (37, 0.140 g, 0.302 mmol) in 2.0 mL of N-methylpyrrolidinone, 4-methylcyclohexylamine (63, 0.30 g, 2.6 mmol) is added. The reaction is heated at 160° C. for 20 minutes in a microwave, then poured into water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with 20-100% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (64, 0.120 g). MS (ESI) [M+H+]+=496.4.
Reaction SMILES: O=[C:2]1[CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14][C:13](=O)[NH:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][NH:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[O:6]1[CH2:7][CH2:8][O:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:2][NH:3][CH2:4][CH2:5]1
Reactant: O=C1COCCOCC(=O)NCCOCCOCCN1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C1COCCOCCNCCOCCOCCN1
Temperature: 25 °C
Yield: 80 %

Procedure:
A solution of 18.5 g. of the diamide obtained in Example 3 in 450 ml. anhydrous tetrahydrofurane is slowly added to a mixture of 150 ml. anhydrous tetrahydrofurane and 12 g. LiAlH4 while stirring and heating at the reflux temperature. After the addition is completed, the mixture is stirred under reflux and under a nitrogen atmosphere for 24 hours. After cooling to room temperature the excess reagent is destroyed by adding a mixture of water and THF (1:2). The mixture is filtered and the filtrate is evaporated to dryness. The residue is dissolved in benzene and the solution is passed through a column of Al2O3 with benzene as eluant. The solution is evaporated to dryness and after recrystallization from benzene/petrol ether 13.5 g. of the desired product is obtained. m.p. = 115°C-116°C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9])=[O:4].B.C1COCC1>C1COCC1>[CH3:1][O:2][C:3](=[O:4])[CH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[CH2:8][OH:9]
Reactant: COC(=O)Cc1ccccc1C(=O)O
Agent: B
Solvent: C1CCOC1
Product: COC(=O)Cc1ccccc1CO
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of 2-methoxycarbonylmethylbenzoic acid (1.84 g, 9.48 mmol) (Tetrahedron Lett. 39, 8563 (1998)) in THF (20 mL) at 0° C. is added dropwise borane THF solution (10.4 mL, 10.4 mmol) and the mixture is stirred at 0° C. for 4 h. The mixture is quenched with MeOH and the solvent is evaporated. To the residue is added EtOAc and the mixture is washed with brine. The organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure. The residue is purified by column chromatography using a gradient of 0-100% EtOAc/hexane as eluent to give the title compound as an oil.
Reaction SMILES: [C:1]1([C:11](=[O:13])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br:14]Br>O1CCOCC1>[Br:14][CH2:12][C:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)=[O:13]
Reactant: CC(=O)c1cccc2ccccc12
Reactant: BrBr
Solvent: C1COCCO1
Product: O=C(CBr)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93.2 %

Procedure:
To a solution of 1-(naphthalen-1-yl)ethanone (500 mg, 2.9 mmol) in dioxane (5 mL) was added to a solution of bromine (510 mg, 3.19 mmol) in dioxane (10 mL), at room temperature, over a period of 30 minutes. The reaction mixture was then stirred at room temperature for 20 minutes and concentrated. The resulting residue was diluted with ether and washed with saturated sodium bicarbonate, water, dried over sodium sulfate and concentrated. Purification by preparative thin layer chromatography (70% DCM/30% hexanes) afforded 2-bromo-1-(naphthalen-1-yl)ethanone (673 mg, 93%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([F:15])([F:14])[F:13])[N:5]=[CH:4][CH:3]=1.[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C=O)C.O>[N:16]([C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([F:15])([F:14])[F:13])[N:5]=[CH:4][CH:3]=1)=[N+:17]=[N-:18]
Reactant: COC(=O)c1c(Cl)ccnc1C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(N=[N+]=[N-])ccnc1C(F)(F)F
Temperature: 45 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
To a stirred solution of methyl 4-chloro-2-(trifluoromethyl)nicotinate (9.75 g, 40.7 mmol) in DMF (300 mL) is added sodium azide (21.2 g, 326 mmol). The solution is warmed to 45° C. for 3 hours and then to 50° C. for 1 hour. The reaction is diluted with water (300 mL) and extracted with ether-pentane (1:1, ca. 1 L). The organic layer is back extracted with water (3×). The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford 9.50 g (95%) of the title compound as a brown oil: 1H NMR (400 MHz, CD3OD), 8.651 (d, 1H), 7.603 (d, 1H), 3.878 (s, 3H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].Cl.C(N(CC)CC)C.[O:17]=[C:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:23][C:24](O)=[O:25].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.C(O)(=O)C>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][C:24](=[O:25])[CH2:23][N:19]1[CH2:20][CH2:21][CH2:22][C:18]1=[O:17])[CH3:3]
Reactant: CCOC(=O)CN
Reactant: O=C(O)CN1CCCC1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)CN1CCCC1=O
Temperature: 0 °C
Yield: 64.8 %

Procedure:
167.4 g (1.2 mole) of glycine ethyl ester hydrochloride are suspended in 4 liters of methylene chloride, the hydrochloric acid being neutralized by adding 168 ml (1.2 mole) of triethylamine. The reaction mixture is cooled to about 0° C. and a suspension of 171.6 g (1.2 mole) of 2-oxo-1-pyrrolidineacetic acid in 1500 ml methylene chloride is added. Without allowing the temperature to rise above 5° C., a solution of 272 g (1.4 mole) of DCC in 300 ml of methylene chloride is added dropwise to this mixture. Stirring is maintained for 2 hours at the same temperature and the reaction mixture is then allowed to return to ambient temperature, while stirring for 16 hours. 80 ml of acetic acid are then added, the reaction mixture is cooled to 0° C. and the precipitate is filtered off. The filtrate is evaporated to dryness and the residue redissolved in ethyl acetate, followed by filtering to remove insoluble matter. The filtrate is treated with highly absorbing active charcoal (Norite), again filtered and the filtrate is distilled at 190° C. at a pressure of 0.01 mm Hg. There are thus obtained 256 g of a syrup which is stirred with 1500 ml of anhydrous diethyl ether and which is crystallized by cooling in an ice bath. 177.5 g of N-(2-oxo-1-pyrrolidineacetyl)-glycine ethyl ester are thus obtained (yield: 64% of theory); M.P. 63°-64° C. The melting point of a sample recrystallized from a 1:2 v/v mixture of ethyl acetate and anhydrous diethyl ether is 64°-65° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7](Cl)[S:8][C:4]=2[CH:3]=1.[CH3:12][Mg]Br.Cl.C(OCC)(=O)C>C1COCC1.CN1C(=O)CCC1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([CH3:12])[S:8][C:4]=2[CH:3]=1
Reactant: C[Mg]Br
Reactant: Clc1nc2ccc(Br)cc2s1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1nc2ccc(Br)cc2s1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77 %

Procedure:
In a mixed solvent of THF (200 mL) and NMP (20 mL) were dissolved 6-bromo-2-chlorobenzothiazole 1 (15 g, 60.4 mmol) and Fe(acac)3 (1.07 g, 3.02 mmol). To the obtained mixture was added at 0° C. 3M methyl magnesium bromide ethereal solution (24.14 ml, 72.4 mmol). It was stirred at room temperature for 1.5 hours. To the reaction mixture was added at 0° C. 3M methyl magnesium bromide ethereal solution (10.1 ml, 30.2 mmol). It was stirred at room temperatures for 1 hour. To the reaction mixture 1N aqueous hydrochloric acid and ethyl acetate. After extraction, the organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified with column chromatography to give Compound 53 (10.6 g, 46.5 mmol).
Reaction SMILES: [C:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][CH2:9][C:10]2[N:15]3[CH:16]=[N:17][CH:18]=[C:14]3[CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(O)=[O:2].C(O)(=O)C.CO>O1CCCC1>[OH:2][CH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH2:9][C:10]2[N:15]3[CH:16]=[N:17][CH:18]=[C:14]3[CH:13]=[CH:12][CH:11]=2)=[CH:19][CH:20]=1
Reactant: O=C(O)c1ccc(CCc2cccc3cncn23)cc1
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: OCc1ccc(CCc2cccc3cncn23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-(p-carboxyphenethyl)-imidazo[1,5-a]pyridine (2.66 g) is dissolved in 100 ml of dry tetrahydrofuran at 0° and 20 ml of 1M borane tetrahydrofuran complex in tetrahydrofuran (20 ml) is added dropwise. The reaction mixture is stirred at room temperature for two hours, and 20 ml of acetic acid and 20 ml of methanol are added carefully. The mixture is refluxed for 1 hour, cooled and evaporated, the resulting oil is partitioned between ether and 1N sulfuric acid. The aqueous phase is separated, adjusted to pH=8 and extracted with ethyl acetate the extract is dried over sodium sulfate and evaporated to yield 5-[p-(hydroxymethyl)phenethyl]imidazo[1,5-a]pyridine.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH2:34][CH2:33][CH:32]([OH:35])[CH2:31][CH2:30]1>>[CH3:22][N:20]1[CH:21]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[N:7]=[C:2]([N:29]5[CH2:34][CH2:33][CH:32]([OH:35])[CH2:31][CH2:30]5)[CH:3]=[CH:4][CH:5]=4)=[N:9][NH:10][C:11]3=[CH:12][N:13]=2)[CH:18]=[N:19]1
Reactant: OC1CCNCC1
Reactant: Cn1cc(-c2cc3c(-c4cccc(F)n4)nn(C4CCCCO4)c3cn2)cn1
Product: Cn1cc(-c2cc3c(-c4cccc(N5CCC(O)CC5)n4)n[nH]c3cn2)cn1
Yield: 56.1 %

Procedure:
Following the procedures as described in Example 189, 3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and piperidin-4-ol were reacted. The product was deprotected and purified to give 294 as a white solid (56.1% over two steps). 1H NMR (400 MHz, DMSO) δ 13.69 (broad s, 1H), 9.03 (s, 1H), 8.53 (s, 1H), 8.11 (s, 1H), 7.82 (s, 1H), 7.64 (t, J=7.9 Hz, 1H), 7.42 (d, J=7.4 Hz, 1H), 6.87 (d, J=8.5 Hz, 1H), 4.73 (d, J=3.2 Hz, 1H), 4.24-4.15 (m, 2H), 3.91 (s, 3H), 3.6-3.76 (m, 1H), 3.37-3.29 (m, 2H), 1.97-1.86 (m, 2H), 1.58-1.44 (m, 2H). LC/MS: m/z 376.2 [M+1]