Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][CH:9]2[C:14]([CH3:16])([CH3:15])[CH:13]3[CH2:17][C:10]2([CH3:18])[CH2:11][CH2:12]3)=[O:7])=[CH:4][C:3]=1[S:21]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)(=[O:23])=[O:22].[CH3:30][O:31][C:32](=[O:35])[CH2:33]Br.C(OC(=O)C)C.CCCCCC>ClCCl>[CH3:30][O:31][C:32](=[O:35])[CH2:33][N:27]1[CH2:28][CH2:29][N:24]([S:21]([C:3]2[CH:4]=[C:5]([C:6](=[O:7])[NH:8][CH:9]3[C:14]([CH3:15])([CH3:16])[CH:13]4[CH2:17][C:10]3([CH3:18])[CH2:11][CH2:12]4)[CH:19]=[CH:20][C:2]=2[CH3:1])(=[O:23])=[O:22])[CH2:25][CH2:26]1
Reactant: COC(=O)CBr
Reactant: Cc1ccc(C(=O)NC2C3(C)CCC(C3)C2(C)C)cc1S(=O)(=O)N1CCNCC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: COC(=O)CN1CCN(S(=O)(=O)c2cc(C(=O)NC3C4(C)CCC(C4)C3(C)C)ccc2C)CC1

Procedure:
Compound 30 was prepared from 117 mg 29 by stirring in 5 mL dry dichloromethane adding 100 μl N,N-diisopropylethylamine and 25 μl bromoacetic acid methylester overnight at room temperature. After aqueous work-up the product 30 was isolated by SiO2 chromatography (5-20% ethylacetate/hexane) and 23 mg of an off white solid was obtained (21% yield). MS (M+1)=492.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].CC(C)=CCCC1CCC(CCC2C=CC(OCC3CCC(CCCCC)=CC3)=CC=2)CC=1>>[CH2:1]([O:8][C:9]1[CH:14]=[N:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:19][CH:20]=2)=[N:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(-c2ncc(OCc3ccccc3)cn2)cc1
Reactant: CCCCCCCCCCBr
Agent: CCCCCC1=CCC(COc2ccc(CCC3CC=C(CCC=C(C)C)CC3)cc2)CC1
Product: CCCCCCCCCCOc1ccc(-c2ncc(OCc3ccccc3)cn2)cc1

Procedure:
The reaction between 5-benzyloxy-2-(4-hydroxyphenyl)pyrimidine (prepared essentially according to the procedure of E. P. Janulis et al., U.S. Pat. No. 5,399,291) and bromodecane is essentially that used for synthesis of ether 2H.
Reaction SMILES: [NH:1]([C:3]([C:5]1[CH:10]=[CH:9][N:8]2[C:11]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([NH:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[CH:12][N:13]=[C:7]2[CH:6]=1)=[O:4])[NH2:2].[OH-].[K+].[C:31](=[S:33])=S.[CH3:34]I>CCO>[CH3:34][S:33][C:31]1[O:4][C:3]([C:5]2[CH:10]=[CH:9][N:8]3[C:11]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([NH:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[O:22])[CH:17]=[CH:18][CH:19]=4)=[CH:12][N:13]=[C:7]3[CH:6]=2)=[N:1][N:2]=1
Reactant: S=C=S
Reactant: NNC(=O)c1ccn2c(-c3cccc(NC(=O)NCC(F)(F)F)c3)cnc2c1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CSc1nnc(-c2ccn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)o1
Temperature: 65 °C

Procedure:
To a solution of 1-[3-(7-Hydrazinocarbonyl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (120 mg, 0.30 mmol) and KOH (20 mg, 0.36 mmol) in EtOH (4 ml) was added carbon disulfide (241, 0.36 mmol). The reaction mixture was heated at 65° C. for 3 h. Methyl iodide (200, excess) was added and the reaction mixture heated at 65° C. for 1 h. The mixture was then cooled, placed in an ice bath upon which a precipitate was formed. The solid was filtered off, washed with EtOAc and Et2O, then dried to afford the title compound (89 mg). MS: [M+H]+=449.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([OH:27])[CH2:19][CH2:18][CH2:17][CH:16]2[NH:20][S:21]([CH:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)Cl>[OH:27][C:15]1([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][NH:5][C:1](=[O:3])[CH3:2])=[CH:10][CH:11]=2)[CH2:19][CH2:18][CH2:17][CH:16]1[NH:20][S:21]([CH:24]([CH3:25])[CH3:26])(=[O:23])=[O:22]
Reactant: CC(C)S(=O)(=O)NC1CCCC1(O)c1ccc(OCCN)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCOc1ccc(C2(O)CCCC2NS(=O)(=O)C(C)C)cc1
Temperature: 0 °C

Procedure:
In a 100 mL 3 neck flask fitted with a stirrer and thermometer, acetyl chloride (63 mg, 1.2 eq) is added dropwise to {2-[4-(2-aminoethoxy)phenyl]-2-hydroxycyclopentyl}[(methylethyl)sulfonyl]amine (230 mg, 0.67 mmol) and triethylamine (102 mg, 1.5 eq) in CH2Cl2 (40 mL) while stirring at 0° C. under a nitrogen atmosphere. The reaction is allowed to warm to room temperature and stirred for 2 hours. The reaction is then diluted with CH2Cl2 (50 mL) and the organic layer is washed two times with H2O, dried over Na2SO4, filtered, and concentrated under reduced vacuum to yield the product. This material is purified via silica gel chromatography employing the Chromatotron® and using 2000 micron rotor while eluting with a suitable eluent, such as hexanes/ethyl acetate to provide the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:19](=[N:22][OH:23])[CH2:20][CH3:21])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:26]I>C1COCC1>[CH3:26][O:23][N:22]=[C:19]([C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:11]=1)[CH2:20][CH3:21]
Reactant: CCC(=NO)c1ccc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(=NOC)c1ccc(-c2ccccc2)c(-c2ccccc2)n1

Procedure:
Following General Procedure Q, 1-(5,6-diphenyl-pyridin-2-yl)-propan-1-one oxime (Compound 81, 30 mg, 0.1 mmol), NaH (4.8 mg, 0.20 mmol) and MeI (140 mg, 0.99 mmol) in THF were reacted to obtain the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1.[Br:25][C:26]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:27]=1[CH:28]=O>>[Br:25][C:26]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:27]=1[CH2:28][NH:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:7]2[C:6]3[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=3)[N:10]=[N:9][C:8]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:19]=1
Reactant: COc1ccc(Br)c(C=O)c1
Reactant: Nc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Product: COc1ccc(Br)c(CNc2cccc(-c3c(-c4ccccc4)nnc4c(Cl)cccc34)c2)c1

Procedure:
The title compound was prepared from 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenylamine and 2-bromo-5-methoxybenzaldehyde according to the procedure of Step 5 Example 6. MS (ES) m/z 530.0.
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.[Sm+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.C([C@@H]1COC(=O)N1[C:39]([C@H:41]1[C@H:45]([C:46]2[CH:51]=[CH:50][C:49]([F:52])=[CH:48][C:47]=2[F:53])[CH2:44][N:43]([CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH2:42]1)=[O:40])C1C=CC=CC=1.[CH3:61][OH:62]>C1CCCCC1>[CH2:54]([N:43]1[CH2:44][C@@H:45]([C:46]2[CH:51]=[CH:50][C:49]([F:52])=[CH:48][C:47]=2[F:53])[C@H:41]([C:39]([O:62][CH3:61])=[O:40])[CH2:42]1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: CO
Reactant: O=C1OC[C@@H](Cc2ccccc2)N1C(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(F)cc1F
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sm+3]
Solvent: C1CCCCC1
Product: COC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(F)cc1F
Reaction time: 24 h

Procedure:
Samarium triflate (6.32 g, 10 mmol) was added to a stirred solution of (4R)-4-benzyl-3-{[(3S,4R)-1-benzyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl]carbonyl}-1,3-oxazolidin-2-one, from preparation 29 (63 g, 130 mmol) in methanol (350 mL) at room temperature. The reaction mixture was stirred for 24 hours and the solvent was removed in vacuo. Dichloromethane (290 mL) was added followed by saturated sodium hydrogen carbonate solution (140 mL) and the mixture stirred for 15 minutes. The resulting precipitate was filtered and washed with dichloromethane (250 mL) and water (25 mL). The phases were separated and the aqueous layer was extracted with dichloromethane (2×40 mL). The organic extracts were combined, dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude residue. The residue was suspended in warm cyclohexane (300 mL) and shaken till formation of a solid occurred. The mixture was allowed to stand at room temperature for 24 hours. The solid was filtered and washed with cold cyclohexane (150 mL). The filtrate was concentrated in vacuo to afford the desired compound, 38 g (87%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[C:20]([O:22]C)=O.[H-].[Na+].C([O-])(O)=O.[Na+]>C1COCC1>[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[C:20]([CH2:2][C:1](=[O:3])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:22]
Reactant: COC(=O)c1ccc2ccccc2c1
Reactant: CC(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(CC(=O)c1ccc2ccccc2c1)c1ccccc1
Reaction time: 0.17 h

Procedure:
Acetophenone (500 mg, 4.12 mmol), methyl 2-naphthoate (1.03 g, 5.36 mmol) and THF (20 mL) were added sequentially to a 50 mL round bottom flask. After stirring the mixture for 10 min, a suspension containing NaH (167 mg, 6.61 mmol) in THF (10 mL) was added dropwise at room temperature under N2. The mixture was stirred for 20 h before saturated aqueous NaHCO3 (1 mL) was added to quench the reaction. THF was removed in vacuo before 1 M HCl (20 mL) was added. The aqueous phase was extracted with CH2Cl2 (3×20 mL). The combined organic layers were washed with distilled water (2×10 mL) and brine (10 mL), and dried over Na2SO4 before concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexanes/ethyl acetate (6:1) to give 2-naphthoyl benzoylmethane, thin, as a yellow solid: 700 mg (62%). 1H NMR (300 MHz, CDCl3) δ 16.98 (s, 1H, ArCOH), 8.62 (s, 1H, 1′-ArH), 8.08-7.87 (m, 6H, 3′, 4′, 5′, 2″, 6″-ArH), 7.62-7.49 (m, 5H, 6′,7′-ArH. 3″, 4″, 5″-ArH), 7.01 (s, 1H, COCHCO); MS (MALDI) m/z 275.13 (M+H+), calcd m/z 275.11.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH2:13][CH2:12][N:11]([S:14]([C:17]2[N:18]=[N:19][NH:20][CH:21]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:5].[C:31](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Cl:1][C:2]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([CH2:22][CH:23]2[CH2:24][CH2:25]2)[CH2:13][CH2:12][N:11]([S:14]([C:17]2[N:18]=[N:19][N:20]([CH3:31])[CH:21]=2)(=[O:15])=[O:16])[CH2:10][CH2:9]1)=[O:5]
Reactant: O=C(NCC1(CC2CC2)CCN(S(=O)(=O)c2c[nH]nn2)CC1)c1ccc(Cl)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cc(S(=O)(=O)N2CCC(CNC(=O)c3ccc(Cl)cc3Cl)(CC3CC3)CC2)nn1
Temperature: 25 °C

Procedure:
2,4-Dichloro-N-[4-(cyclopropylmethyl)-1-(1H-[1,2,3]triazole-4-sulfonyl)piperidin-4-ylmethyl]benzamide (472 mg, 1.0 mmol) was dissolved in N,N-dimethylformamide (5 mL). Potassium carbonate (276 mg, 2 mmol) and methyl iodide (81 μL, 1.3 mmol) were added and the mixture stirred at room temperature over night.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:11]=[C:10]([CH3:12])[C:9]([OH:13])=[N:8][C:7]1=[O:14].[C:15]([C:19]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:22]=[C:21]([C:31]([F:34])([F:33])[F:32])[N:20]=1)([CH3:18])([CH3:17])[CH3:16].CCN(CC)CC.C(OCC)(=O)C>CN(C)C=O>[Cl-:1].[C:15]([C:19]1[N:24]=[C:23]([N:25]2[CH2:26][CH2:27][NH+:28]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[CH:11]=[C:10]([CH3:12])[C:9]([OH:13])=[N:8][C:7]3=[O:14])[CH2:29][CH2:30]2)[CH:22]=[C:21]([C:31]([F:32])([F:33])[F:34])[N:20]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: Cc1cn(CCCCCl)c(=O)nc1O
Reactant: CC(C)(C)c1nc(N2CCNCC2)cc(C(F)(F)F)n1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cn(CCCC[NH+]2CCN(c3cc(C(F)(F)F)nc(C(C)(C)C)n3)CC2)c(=O)nc1O
Product: [Cl-]

Procedure:
1.5 g (7.0 mmol) of 1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one from Example 5.2.1, 2.0 g (7.0 mmol) of 2-tert-butyl-4-piperazin-1-yl-6-(trifluoromethyl)pyrimidine (DE 197 35 410) and 1.4 g (14.0 mmol) of NEt3 in 100 ml of N,N-dimethylformamide (DMF) were stirred at 110° C. for 24 hours. Then ethyl acetate was added, and the mixture was washed twice with water. The combined organic phases were dried over Na2SO4, filtered to remove the desiccant and concentrated in vacuo. The oily residue was purified by chromatography on silica gel (eluent: dichloromethane:methanol 95:5 v/v), and stirred with pentane and filtered off with suction. The solid was taken up in a little methylene chloride, and a solution of HCl in diethyl ether was added, whereupon the required product precipitated as hydrochloride. The hydrochloride was filtered off with suction and washed with diethyl ether, and the title compound was dried in vacuo at 40° C. Yield: 1.1 g.
Reaction SMILES: [CH2:1]([CH:8]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9][C:10](O)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].CS(O)(=O)=[O:19].[OH:22][OH:23]>>[CH2:1]([CH:8]([CH2:13][C:14]([O:16][OH:19])=[O:15])[CH2:9][C:10]([O:22][OH:23])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CS(=O)(=O)O
Reactant: CCCCCCCC(CC(=O)O)CC(=O)O
Reactant: OO
Product: CCCCCCCC(CC(=O)OO)CC(=O)OO
Temperature: 10 °C

Procedure:
β-n-heptylglutaric acid (85 g, 0.36 mol) was added to an 800 ml beaker along with 98% methansulfonic acid (176 g, 1.84 mol) and the mixture was cooled to 10° C. 70% hydrogen peroxide was added slowly with constant stirring to maintain a reaction temperature of about 30° C. After the addition was complete, the solution was stirred at room temperature for 2 hours. Work-up as described for the alkyldiperoxyadipic acids provided β-n-heptyldiperoxyglutaric acid as an oil which solidified upon cooling to 0° C. but was found on rewarming to have a melting point of 19°-22° C. (yield 93 g; %AvO=10.7, theory=12.2; HPLC, C18ODS column, 67% methanol, retention time: 6.3 minutes, diperoxyacid, relative peak area 87%, 7.6 minutes, monoperoxyacid, relative peak area 13%.).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH2:14])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](O)=[O:22].C(Cl)CCl.C(N(CC)CC)C>C(Cl)Cl>[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH:14][C:21](=[O:22])[C:20]3[CH:24]=[CH:25][CH:26]=[C:18]([O:17][CH3:16])[CH:19]=3)[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Reactant: COc1cccc(C(=O)O)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COc1cccc(C(=O)Nc2cnn(Cc3c(C)noc3C)c2)c1
Yield: 43.6 %

Procedure:
1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (Example 4-1a) (300 mg, 1.3 mmol), 3-methoxybenzoic acid (172 mg, 1.3 mmol), EDC (386 mg, 2 mmol), and triethyl amine (303 mg, 3 mmol) were stirred in DCM (5 mL) at ambient temperature for 6 hours. The reaction was diluted with DCM (50 mL) and the organic phase was washed with aqueous 0.1 N HCL (150 mL) followed by aqueous 1N NaOH (150 mL). The organic layer was dried over sodium sulfate, filtered and concentrated on the rotovap. The crude product was purified by silica gel chromotography (40% ethyl acetate in hexanes) to afford 225 mg of an off white solid. The solid was triturated with ethyl acetate/hexanes (1/9) and the white solid was collect by filtration. The pure product was dissolved in absolute ethanol and concentrated on the rotovap (4×, 25 mL) to afford N-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-3-methoxybenzamide (185 mg, 43%) as a white solid. NMR (CDCl3, 400 MHz): b 2.20 (s, 3H), 2.42 (s, 3H), 3.85 (s, 3H), 5.03 (s, 2H), 7.09-7.06 (m, 1H), 7.37-7.35 (m, 2H), 7.41 (m, 1H), 7.51 (s, 1H), 7.93 (bs, 1H), 8.03 (s, 1H). LC/MS; [M+H] calculated for C17H18N4O3; expected 327.14. Found 327.30. Melting point: 127-129° C.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]3[CH:14]=[N:13][NH:12][C:10]3=2)[NH:5][CH:4]=1)[CH3:2].[H-].[Na+].[S:17](Cl)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18].[CH3:28]N(C=O)C>>[CH2:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]3[CH:14]=[N:13][N:12]([CH3:28])[C:10]3=2)[N:5]([S:17]([C:20]2[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH:4]=1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCc1c[nH]c2ncc3cn[nH]c3c12
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CCc1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc3cnn(C)c3c12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 78 %

Procedure:
8-Ethyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (10.5 g, 56.3 mmol) in DMF (200 mL) was cooled to about 0° C. then treated with 60 wt % NaH (2.36 g, 59.1 mmol). After about 20 min, TsCl (11.3 g, 59.1 mmol) was added in portions. After about 40 min the mixture was poured slowly into ice water (300 mL) and stirred. The solids were collected by filtration then the material was dissolved in DCM (300 mL). The water layer was separated then the organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The material was triturated with Et2O then the solids were collected by filtration and dried to constant weight to provide 8-ethyl-1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (14.8 g, 78%): LC/MS (Table 2, Method c) Rt=1.55 min; MS m/z 355 (M+H)+.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])[N:10]=2)[CH:7]=1.C([Sn](CCCC)(CCCC)[C:25]([O:27][CH2:28][CH3:29])=[CH2:26])CCC>C1(C)C=CC=CC=1.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>[CH2:28]([O:27][C:25]([C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])[N:10]=2)[CH:7]=1)=[CH2:26])[CH3:29]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: O=C(Nc1ccccc1)c1cn2cc(I)ccc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=C(OCC)c1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Temperature: 150 °C
Reaction time: 16 h
Yield: 61.4 %

Procedure:
To a suspension of 1 g of 6-iodo-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in 50 mL of toluene are added 159 mg of tetrakis(triphenylphosphine)palladium and 1.09 g of tributyl(1-ethoxyvinyl)tin. The reaction mixture is heated for 9 hours at 150° C. and then for 16 hours at 130° C., and concentrated to dryness. The residue is taken up in dichloromethane and washed with aqueous 10% potassium fluoride solution. The organic phase is dried and concentrated to dryness and the residue is chromatographed on a silica cartridge, eluting with a mixture of cyclohexane and ethyl acetate. The fractions containing the expected product are combined and evaporated to dryness under reduced pressure to give 0.52 g of 6-(1-ethoxyvinyl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in the form of a beige-coloured solid.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:28].C1COCC1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)=[CH:37][CH:36]=1>CCOC(C)=O>[N:41]1([C:38]2[CH:37]=[CH:36][C:35]([NH:34][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]6[S:24][CH:25]=[CH:26][CH:27]=6)=[O:22])=[CH:16][CH:15]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:28])=[CH:40][CH:39]=2)[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: O=C1Nc2cc(C(=O)c3ccc(NC(=O)c4cccs4)cc3)ccc2C1=CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1Nc2cc(C(=O)c3ccc(NC(=O)c4cccs4)cc3)ccc2C1=CNc1ccc(N2CCOCC2)cc1
Temperature: 65 °C
Reaction time: 24 h
Yield: 70.4 %

Procedure:
A small screw cap test tube was charged with Thiophene-2-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (100 mg, 0.257 mmol) and THF (2 mL). To the resulting solution was added N-(4-aminophenyl)morpholine (50.2 mg, 0.282 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. EtOAc and Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 71% (100 mg, 0.181 mmol) of the title compound.
Reaction SMILES: C(N(CC)[C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([C:20]3[C:21]4[C:26]([CH:27]=[C:28]5[C:33]=3[CH:32]=[CH:31][CH:30]=[CH:29]5)=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:19])[CH2:14][CH2:13]2)[CH2:7]1)=[O:5])C.[CH2:36]([Mg]Br)[CH3:37].O1CC[CH2:42][CH2:41]1>>[CH:22]1[C:21]2[C:26](=[CH:27][C:28]3[C:33]([C:20]=2[C:18]([N:15]2[CH2:16][CH2:17][CH:12]([N:8]4[CH2:9][CH2:10][CH2:11][CH:6]([C:4]([CH2:36][CH3:37])([OH:5])[CH2:41][CH3:42])[CH2:7]4)[CH2:13][CH2:14]2)=[O:19])=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:25]=[CH:24][CH:23]=1
Reactant: CC[Mg]Br
Reactant: C1CCOC1
Reactant: CCN(CC)C(=O)[C@@H]1CCCN(C2CCN(C(=O)c3c4ccccc4cc4ccccc34)CC2)C1
Product: CCC(O)(CC)C1CCCN(C2CCN(C(=O)c3c4ccccc4cc4ccccc34)CC2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 15 %

Procedure:
To a solution of (3R)-1′-(anthracene-9-carbonyl)-[1,4′]bipiperidinyl-3-carboxylic acid diethylamide (Intermediate 22, 22.2 mg, 47 μmol) in anhydrous tetrahydrofuran (0.5 mL) under nitrogen at −25° C. was added a solution of ethylmagnesium bromide (1M in tetrahydrofuran, 2.1 eq., 0.1 mL). The solution was allowed to warm to ambient temperature and after 30 min a further addition of ethylmagnesium bromide (1M in tetrahydrofuran, 4.2 eq., 0.2 mL) was made. The mixture was stirred for 16 hr at ambient temperature before quenching with methanol. The mixture was diluted with dichloromethane, washed with a mixture of sodium hydroxide and sodium hydrogen carbonate solutions, dried over anhydrous sodium sulfate and the solvent was removed by evaporation under vacuum. The crude product was purified by chromatography on silica gel eluting with a 1%-10% methanol-dichloromethane gradient to give the title compound (3.2 mg, 15%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:13]OS(C)(=O)=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C-:19]#[N:20].[Na+].O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:13][C:19]#[N:20])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: CS(=O)(=O)OCC1(c2ccc(Cl)cc2)CCCC1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCC1(c2ccc(Cl)cc2)CCCC1
Temperature: 130 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
To a stirred solution of methanesulfonic acid 1-(4-chlorophenyl)-cyclopentylmethyl ester (320) (14 g, 48.48 mmol) in dimethyl sulfoxide (50 mL) were added KI (805 mg, 4.85 mmol) and NaCN (3.6 g, 72.72 mmol) and stirred for 130° C. for 4 h. After completion of reaction, cold water (200 mL) was added. After extraction with ethyl acetate (3×100 mL), the combined organic parts were washed with saturated ferrous sulphate solution (2×100 mL), water (2×100 mL) and brine (100 mL) and dried and concentrated. The crude product was purified by CombiFlash column (10-20% ethyl acetate in hexane was used as eluent) to get [1-(4-chlorophenyl)-cyclopentyl]-acetonitrile (321) (8.2 g, 77%) as a light yellow liquid.