Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][NH2:12])[CH2:5][CH2:4]1.Cl[C:14]1[N:15]=[N+:16]([O-:27])[C:17]2[CH:26]=[C:25]3[C:21]([CH2:22][CH2:23][CH2:24]3)=[CH:20][C:18]=2[N:19]=1.CCN(CC)CC>COCCOC>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][NH:12][C:14]2[N:15]=[N+:16]([O-:27])[C:17]3[CH:26]=[C:25]4[C:21]([CH2:22][CH2:23][CH2:24]4)=[CH:20][C:18]=3[N:19]=2)[CH2:5][CH2:4]1
Reactant: COC1CCN(CCCN)CC1
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCC3
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: COC1CCN(CCCNc2nc3cc4c(cc3[n+]([O-])n2)CCC4)CC1
Yield: 82.8 %

Procedure:
3-(4-Methoxy-1-piperidinyl)propylamine (304) (0.59 g, 3.4 mmol) was added to a stirred solution of chloride 21 (505 mg, 2.3 mmol) and Et3N (0.64 mL, 2.6 mmol) in DME (50 mL) and the solution stirred at reflux temperature for 16 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 58 (681 mg, 84%) as a yellow solid: mp (EtOAc/pet. ether) 120-121° C.; 1H NMR δ 8.07 (s, 1H, H-9), 7.38 (s, 1H, H-5), 6.25 (br s, 1H, NH), 3.56-3.61 (m, 2H, CH2N), 3.33 (s, 3H, OCH3), 3.24-3.30 (m, 1H, CHO), 2.97-3.03 (m, 4H, H-6, H-8), 2.71-2.78 (m, 2H, CH2N), 2.52 (br t, J=6.6 Hz, 2H, CH2N), 2.21-2.30 (m, 2H, CH2), 2.15 (br p, J=7.5 Hz, 2H, H-7), 1.91-1.98 (m, 2H, CH2), 1.85 (br p, J=6.5 Hz, 2H, CH2), 1.65-1.73 (m, 2H, CH2); 13C NMR δ 158.8, 154.4, 148.8, 143.0, 129.8, 120.5, 114.7, 75.8, 56.8, 55.5, 50.9 (2), 40.9, 33.1, 32.3, 30.5 (2), 25.7 (2). Anal. calcd for C19H27N5O2: C, 63.8; H, 7.6; N, 19.6. Found: C, 63.6; H, 7.6; N, 19.4%.
Reaction SMILES: [CH:1]([NH:3][C:4]1[C:5]([CH3:12])=[N:6][NH:7][C:8]=1[C:9]([NH2:11])=[O:10])=O.C[O-].[Na+]>CN(C)C=O>[OH:10][C:9]1[C:8]2[NH:7][N:6]=[C:5]([CH3:12])[C:4]=2[N:3]=[CH:1][N:11]=1
Reactant: Cc1n[nH]c(C(N)=O)c1NC=O
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1n[nH]c2c(O)ncnc12
Yield: 80 %

Procedure:
4-formylamino-3-methylpyrazole-5-carboxamide was cyclized in refluxing dimethylformamide with a catalytic amount of sodium methoxide to produce 7-hydroxy-3-methyl pyrazolo[4,3-d]pyrimidine in about an 80% yield. This reaction is illustrated as follows: ##STR5## Ring closure is thus achieved in this synthetic scheme by an intramolecular mechanism rather than an intermolecular mechanism as is the case in prior processes. This results in a much higher yield of product which is significantly purer than that produced by intermolecular routes.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.[Cl:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[C:21]([Cl:23])[CH:22]=1>>[CH3:13][C:7]1([CH3:14])[O:8][CH2:9][C:10](=[O:12])[NH:11][C:5]2[CH:4]=[CH:3][C:2]([C:19]3[CH:18]=[C:17]([Cl:16])[CH:22]=[C:21]([Cl:23])[CH:20]=3)=[CH:15][C:6]1=2
Reactant: CC1(C)OCC(=O)Nc2ccc(Br)cc21
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Product: CC1(C)OCC(=O)Nc2ccc(-c3cc(Cl)cc(Cl)c3)cc21

Procedure:
Prepared from 7-bromo-5,5-dimethyl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 3,5-dichloro benzeneboronic acid generally according to the coupling procedure described in example 1. 1H NMR (DMSO-d6): δ 10.02 (s, 1H), 7.76 (s, 2H), 7.55-7.64 (m, 3H), 7.18 (d, J=8.45 Hz, 1H), 4.26 (s, 2H), 1.62 (s 6H); MS (ESI) m/z 336/338/340 ([M+H]+); MS (ESI) m/z 334/336/338 ([M−H]−).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:30][CH2:29][CH2:28][C@H:27]([O:31][Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])[CH2:26]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C.O>[CH:39]([Si:32]([CH:33]([CH3:35])[CH3:34])([CH:36]([CH3:38])[CH3:37])[O:31][C@H:27]1[CH2:28][CH2:29][CH2:30][N:25]([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:26]1)([CH3:41])[CH3:40]
Reactant: CC(C)[Si](O[C@H]1CCCN(c2nnc3ccc(F)cn23)C1)(C(C)C)C(C)C
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[Si](O[C@H]1CCCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)C1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 36.9 %

Procedure:
To a solution of Intermediate A (116 mg, 0.714 mmol) in DMF (3 mL) was added NaH (60% dispersion in oil, 44 mg, 1.1 mmol) and the mixture stirred at RT for 20 min. A solution of Intermediate 63b (280 mg, 0.714 mmol) in DMF (3 mL) was added and the mixture was stirred at 60° C. for 25 min, and up to 150° C. over 20 min. The cooled mixture was diluted with water and extracted with DCM (4×20 mL). The combined organics were dried and concentrated in vacuo. The residue was purified twice by FCC, using 0-12% [2M NH3 in MeOH] in DCM, to give the title compound as a dark brown gum (141 mg, 37%). LCMS (Method 3): Rt 3.12 min, m/z 536 [MH+].
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])/[C:4](=[CH:8]/[C:9]2[CH:10]=[C:11]([CH:32]=[CH:33][CH:34]=2)[O:12][C:13]2[N:18]=[CH:17][N:16]=[C:15]([O:19][CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]3)[C:14]=2[CH3:31])/[S:3]1.[C:35]([O-])([O-])=O.[K+].[K+].CI>CC(N(C)C)=O>[CH2:29]([O:28][C:26]([N:23]1[CH2:24][CH2:25][CH:20]([O:19][C:15]2[C:14]([CH3:31])=[C:13]([O:12][C:11]3[CH:32]=[CH:33][CH:34]=[C:9](/[CH:8]=[C:4]4/[C:5](=[O:7])[N:6]([CH3:35])[C:2](=[O:1])[S:3]/4)[CH:10]=3)[N:18]=[CH:17][N:16]=2)[CH2:21][CH2:22]1)=[O:27])[CH3:30]
Reactant: CCOC(=O)N1CCC(Oc2ncnc(Oc3cccc(/C=C4\SC(=O)NC4=O)c3)c2C)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CI
Product: CCOC(=O)N1CCC(Oc2ncnc(Oc3cccc(/C=C4\SC(=O)N(C)C4=O)c3)c2C)CC1
Temperature: 27 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
To a solution (Z)-ethyl 4-((6-(3-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)-5-methylpyrimidin-4-yl)oxy)piperidine-1-carboxylate (300 mg, 0.0006198 mole) in dimethyl acetamide (10 ml), K2CO3 (171 mg, 0.001239 mole) was added followed by addition of methyl iodide (0.060 ml, 0.0009297 mole) at 0° C. and reaction mixture was stirred at 27° C. for 30 minutes. Then reaction mixture was poured into ice cold water and extracted with ethyl acetate. Organic layer was washed with water and brine, dried over sodium sulfate and evaporated on a rotavpour to yield the product as yellow solid (300 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:11](=O)[CH2:12][CH3:13])[CH:6]=[C:7]([I:10])[C:8]=1[OH:9].Cl.[NH2:16][OH:17].[OH-].[Na+].C(O)C>O>[OH2:9].[NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:11](=[N:16][OH:17])[CH2:12][CH3:13])[CH:6]=[C:7]([I:10])[C:8]=1[OH:9]
Reactant: CCC(=O)c1cc(I)c(O)c(CN)c1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCC(=NO)c1cc(I)c(O)c(CN)c1
Temperature: 25 °C
Yield: 180.5 %

Procedure:
A mixture of 2.0 g of 3'-aminomethyl-4'-hydroxy-5'-iodopropiophenone and 1.2 g of hydroxylamine hydrochloride is added to 10 ml of 4N sodium hydroxide solution and 3.5 ml of ethanol, and then the mixture is refluxed with heating for 45 minutes. After cooling to room temperature, 15 ml of water is added to the reaction mixture. After filtration of the mixture, the filtrate is stirred under ice cooling and adjusted to pH 7.5 with concentrated hydrochloric acid. The white fine powder precipitated is collected by filtration, washed with cold water and dried to give 2.0 g of 3'-aminomethyl -4'-hydroxy-5'-iodopropiophenone oxime monohydrate, melting at 167°-168° C. with decomposition.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]3[CH2:27][O:26]3)[CH:20]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH2:27][OH:26])[CH:20]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: O=S(=O)(Nc1cccc(C2CO2)c1)c1ccc(-c2ccc(F)cc2F)cc1
Reactant: C1COCCN1
Solvent: CO
Product: O=S(=O)(Nc1cccc(C(CO)N2CCOCC2)c1)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
Using a method analogous to Method D, using 2′,4′-difluoro-N-(3-(oxiran-2-yl)phenyl)biphenyl-4-sulfonamide and 1 M morpholine in methanol, a mixture of regioisomers was obtained. Reverse-phase HPLC was used to purify the mixture and the title compound was obtained as a pale orange powder from the mixture of isomers as gave ABD785. 1H NMR (300 MHz, CDCl3): δ 2.75-2.81 (3H, m), 3.30 (1H, m), 3.60-3.95 (8H, m), 4.10-4.20 (1H, m), 6.80-7.10 (3H, m), 7.20-7.30 (2H, m), 7.35-7.45 (2H, m), 7.57 (2H, d, J=8 Hz) and 7.91 (2H, d, J=8 Hz). MS, m/z: Calcd, 474.142. Found, 474.58 (M).
Reaction SMILES: Br[C:2]1[C:3]([N:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)=[C:4]([C@H:10]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[CH2:29]([O:36][C:37]1[N:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.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>[CH2:29]([O:36][C:37]1[N:42]=[CH:41][C:40]([C:2]2[C:7]([CH3:8])=[N:6][C:5]([CH3:9])=[C:4]([C@H:10]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:3]=2[N:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)=[CH:39][CH:38]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)nc1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(Br)c1N1CCC(C)(C)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCc3ccccc3)nc2)c1N1CCC(C)(C)CC1
Reaction time: 2 h
Yield: 24 %

Procedure:
A mixture of (S)-ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (0.0553 g, 0.121 mmol), (6-(benzyloxy)pyridin-3-yl)boronic acid (0.042 g, 0.182 mmol) and 2M Na2CO3 (0.152 ml, 0.304 mmol) in DMF (2 mL) was degassed for 10 min. Then, Pd(Ph3P)4 (0.014 g, 0.012 mmol) added, degassed for 5 min and placed in a pre-heated oil bath at 110° C. After 2 h, cooled and purified by prep-HPLC to afford (S)-ethyl 2-(6′-(benzyloxy)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-[3,3′-bipyridin]-5-yl)-2-(tert-butoxy)acetate (0.016 g, 0.029 mmol, 23.54% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 8.08-8.10 (m, 0.5H), 8.00 (d, J=1.9 Hz, 0.5H), 7.51-7.54 (m, 2.5H), 7.39-7.44 (m, 2.5H), 7.34-7.38 (m, 1H), 6.92-6.96 (m, 1H), 6.05 (s, 1H), 5.41-5.55 (m, 2H), 4.23-4.30 (m, 1H), 4.15-4.22 (m, 1H), 3.26 (d, J=12.3 Hz, 0.5H), 3.19 (d, J=11.5 Hz, 0.5H), 2.87-2.96 (m, 0.5H), 2.75-2.83 (m, 0.5H), 2.63 (s, 1.5H), 2.62 (s, 1.5H), 2.38 (d, J=11.2 Hz, 0.5H), 2.26-2.31 (m, 0.5H), 2.25 (s, 1.5H), 2.23 (s, 1.5H), 2.05-2.18 (m, 1H), 1.50-1.57 (m, 1H), 1.35-1.44 (m, 1H), 1.27 (dt, J=2.2, 7.1 Hz, 3H), 1.22 (s, 4.5H), 1.21 (s, 4.5H), 1.06-1.16 (m, 2H), 0.92 (s, 3H), 0.67 (br. s., 3H). LCMS (M+H)=560.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].N1C=CN=C1.[CH:15]([Si:18](Cl)([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16]>CN(C)C=O.O>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][Si:18]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:15]([CH3:17])[CH3:16])=[C:2]([Cl:1])[CH:7]=1
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[Si](Oc1ccc(Cl)cc1Cl)(C(C)C)C(C)C
Reaction time: 3 h
Yield: 81.7 %

Procedure:
To a mixture of 2,4-dichlorophenol (3.20 g) and imidazole (2.67 g) in dimethylformamide (30 ml) was added triisopropylsilyl chloride (3.97 g) in water bath under nitrogen atmosphere, and the mixture was stirred for 3 hours under the same condition. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane) to give 1,3-dichloro-4-triisopropylsilyloxybenzene (5.12 g).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH2:35][CH2:36][CH3:37])=[C:7]([CH:29]=[CH:30][C:31]=1[C:32](=[O:34])[CH3:33])[O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:27]=[CH:26][C:16]([C:17]([O:19]C2CCCCO2)=[O:18])=[CH:15][C:14]=1[Br:28])(=[O:3])[CH3:2].Cl.C(Cl)(Cl)Cl>O1CCCC1>[C:1]([O:4][C:5]1[C:6]([CH2:35][CH2:36][CH3:37])=[C:7]([CH:29]=[CH:30][C:31]=1[C:32](=[O:34])[CH3:33])[O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:27]=[CH:26][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=1[Br:28])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCOc2ccc(C(=O)OC3CCCCO3)cc2Br)ccc(C(C)=O)c1OC(C)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CCCc1c(OCCCOc2ccc(C(=O)O)cc2Br)ccc(C(C)=O)c1OC(C)=O
Reaction time: 1 h
Yield: 63 %

Procedure:
In tetrahydrofuran (10 ml) was dissolved tetrahydropyranyl 4-[3-(3-acetoxy-4-acetyl-2-propylphenoxy)propoxy]-3-bromobenzoate (1.3 g). To the solution was added 1N HCl (1 ml), which was left standing at room temperature for one hour, followed by addition of chloroform (60 ml). The mixture was washed with water sufficiently and dried with sodium sulfate. Then, the solvent was evaporated off. The residue was crystallized with isopropyl ether, followed by recrystallization from aqueous alcohol to give 0.7 g of 4-[3-(3-acetoxy-4-acetyl-2-propylphenoxy)propoxy]-3-bromobenzoic acid as crystals, m.p. 155°-156° C.
Reaction SMILES: [F:1][C:2]1[C:3]2[N:10]([C:11]([CH3:15])([CH3:14])[CH2:12][OH:13])[CH:9]=[C:8]([I:16])[C:4]=2[CH:5]=[N:6][CH:7]=1.N1C(C)=CC=CC=1C.[CH3:25][C:26]([Si:29](OS(C(F)(F)F)(=O)=O)([CH3:31])[CH3:30])([CH3:28])[CH3:27]>C(Cl)Cl>[C:26]([Si:29]([CH3:31])([CH3:30])[O:13][CH2:12][C:11]([N:10]1[C:3]2[C:2]([F:1])=[CH:7][N:6]=[CH:5][C:4]=2[C:8]([I:16])=[CH:9]1)([CH3:14])[CH3:15])([CH3:28])([CH3:27])[CH3:25]
Reactant: CC(C)(CO)n1cc(I)c2cncc(F)c21
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(I)c2cncc(F)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(7-fluoro-3-iodo-pyrrolo[3,2-c]pyridin-1-yl)-2-methyl-propan-1-ol (Preparation 72, 4.5 gm, 13.47 mmol) in DCM (90 mL) were added 2,6-lutidine (3.91 mL, 33.65 mmol) and tert-butyl dimethylsilyl trifluoromethanesulfonate (4.62 gm, 17.51 mmol) at 0° C. The resulting mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with DCM. The organic layer was washed with water, brine, dried over sodium sulphate, and evaporated in vacuo. The crude material was purified by silica gel column chromatography eluting with 10-12% EtOAc in Hexane to afford the title compound as off white solid (45%, 2.7 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[C:6](Cl)(=[O:9])[CH:7]=[CH2:8]>C(#N)C>[OH:5][CH2:4][CH2:3][CH2:2][NH:1][C:6](=[O:9])[CH:7]=[CH2:8]
Reactant: C=CC(=O)Cl
Reactant: NCCCO
Solvent: CC#N
Product: C=CC(=O)NCCCO

Procedure:
To a 250 mL, four-neck round bottom flask equipped with a mechanical stirrer, a thermometer, a 100 mL dropping fuel, and a nitrogen inlet/outlet, 30.0 g of 1-amino-3-propanol (0.4 mole), and 100 mL of acetonitrile were added. The mixture was cooled below 0° C. with an ice/water bath. To this solution, 18.1 g of freshly distilled acryloyl chloride (0.2 mole) in 50 mL of acetonitrile was added through the dropping funnel. The addition rate was controlled so that the reaction temperature was kept below 0° C. After the addition was finished and the agitation was turned off, the reaction solution separated into two liquid phases. The bottom layer viscous salt solution phase was discarded. 100 mL of deionized water was added to the top layer acetonitrile solution phase. After removing all acetonitrile by vacuum distillation, the aqueous solution was passed through a mixed bed ion-exchange column packed with 20 g of Dowex MR-3C resin. A total of 76 grams of eluate was collected. The final solution has the following properties: HPLC and FT-IR analysis indicates there is no ester formation; HPAA concentration: 7.2% (wt/wt); pH=5.6 at 25° C.; Conductivity=56.6 μS/cm at 25° C.; Viscosity=1.1 cPs at 25° C. The relative low yield of HPAA is due to the fact that HPAA is soluble in the salt phase. HPAA in the salt phase can be recovered by acetone extraction since HPAA is soluble in acetone, and the salt is insoluble.
Reaction SMILES: [CH3:1][C:2]1[S:23][C:5]2=[N:6][C:7]([CH3:22])=[C:8]([CH2:17][C:18]([O:20]C)=[O:19])[C:9]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)=[C:4]2[C:3]=1[CH3:24].[O-2].[Li+].[Li+].Cl>O1CCOCC1.O>[CH3:1][C:2]1[S:23][C:5]2=[N:6][C:7]([CH3:22])=[C:8]([CH2:17][C:18]([OH:20])=[O:19])[C:9]([C:10]3[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=3)=[C:4]2[C:3]=1[CH3:24]
Reactant: COC(=O)Cc1c(C)nc2sc(C)c(C)c2c1-c1ccc(C)cc1
Agent: Cl
Agent: [Li+]
Agent: [O-2]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(-c2c(CC(=O)O)c(C)nc3sc(C)c(C)c23)cc1
Temperature: 60 °C
Yield: 36.3 %

Procedure:
To a solution of methyl 2-(2,3,6-trimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetate (0.049 g; 0.144 mmol) in dioxane (3.5 mL) and water (0.9 mL) was added a 1N lithium oxide solution (0.9 mL; 0.90 mmol). The reaction mixture was heated at 60° C. for 2 h. After cooling to room temperature, the reaction mixture was acidified with 1N HCl (pH˜2) and partially concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate/heptane to afford 0.017 g (37%) of the title compound as a white powder.
Reaction SMILES: C[Sn]([N:5]=[N+:6]=[N-:7])(C)C.[Cl:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([CH2:19][O:20][C:21]3[CH:40]=[CH:39][C:24]4[O:25][CH2:26][C:27]5[CH:38]=[CH:37][CH:36]=[CH:35][C:28]=5[CH:29]([S:30][CH2:31][CH2:32][C:33]#[N:34])[C:23]=4[CH:22]=3)=[N:16]2)=[CH:11][CH:10]=1.Cl.[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[Cl:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([CH2:19][O:20][C:21]3[CH:40]=[CH:39][C:24]4[O:25][CH2:26][C:27]5[CH:38]=[CH:37][CH:36]=[CH:35][C:28]=5[CH:29]([S:30][CH2:31][CH2:32][C:33]5[NH:34][N:7]=[N:6][N:5]=5)[C:23]=4[CH:22]=3)=[N:16]2)=[CH:11][CH:10]=1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: N#CCCSC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: Clc1ccc2ccc(COc3ccc4c(c3)C(SCCc3nnn[nH]3)c3ccccc3CO4)nc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 4.6 %

Procedure:
1.25 g of trimethyltin azide was added to 1.4 g of 2-(7-chloroquinolin-2-yl)methoxy-11-(2-cyanoethylthio)-6,11-dihydrodibenz[b,e]oxepine dissolved in 40 ml of xylene and the mixture was refluxed under heating for 8.5 hours. After cooling, 1.5 ml of conc. hydrochloric acid was added to the mixture and the mixture was stirred at room temperature for 15 minutes and then adjusted to about pH 4 with a 1N-sodium hydroxide aqueous solution. Crystals precipitated were applied to silica gel column chromatography to obtain 70 mg of the title compound as light orange powder.
Reaction SMILES: [OH:1][C:2]1([CH:5]2[CH2:9][CH:8]([O:10][CH3:11])[CH2:7][N:6]2[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:4][CH2:3]1.[CH3:22]I.[H-].[Na+]>C1COCC1>[CH3:11][O:10][CH:8]1[CH2:7][N:6]([C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[CH:5]([C:2]2([O:1][CH3:22])[CH2:3][CH2:4]2)[CH2:9]1
Reactant: COC1CC(C2(O)CC2)N(C(=O)OCc2ccccc2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1CC(C2(OC)CC2)N(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of benzyl 2-(1-hydroxycyclopropyl)-4-methoxypyrrolidine-1-carboxylate (312 mg, 1.07 mmol) dissolved in THF (3.6 mL) at 0° C. was added methyl iodide (0.23 mL, 3.68 mmol) followed by sodium hydride (56.5 mg, 2.36 mmol). The mixture was stirred for 2 hours at room temperature. The reaction was quenched with ice, and diluted with diethyl ether. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-20% methanol/dichloromethane, linear gradient) to afford benzyl 4-methoxy-2-(1-methoxycyclopropyl)pyrrolidine-1-carboxylate. MS ESI calc'd. for C17H23NO4 [M+H]+ 306. found 306.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[S:9][C:10]([C:14]([OH:16])=O)=[C:11]([CH3:13])[N:12]=2)[C:4](=[O:17])[CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][NH2:27])=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][NH:27][C:14]([C:10]2[S:9][C:8]([N:5]3[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][C:4]3=[O:17])=[N:12][C:11]=2[CH3:13])=[O:16])=[CH:21][CH:20]=1
Reactant: NCCc1ccc(F)cc1
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)O
Product: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCCc1ccc(F)cc1
Yield: 69 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid in place of 4-methyl-2-(2-oxo-4-phenylpyridin-1(2H)-yl)thiazole-5-carboxylic acid to react with 2-(4-fluorophenyl)ethanamine, the title compound was obtained as a colorless solid in 69% yield: mp 225-227° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 11.47 (s, 1H), 8.57 (d, J=8.0 Hz, 1H), 8.23 (t, J=5.5 Hz, 1H), 7.25-7.18 (m, 2H), 7.12-7.04 (m, 2H), 6.25 (dd, J=8.0, 2.6 Hz, 1H), 5.81 (d, J=2.5 Hz, 1H), 3.42-3.35 (m, 2H), 2.78 (t, J=7.2 Hz, 2H), 2.50 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 167.8, 161.9, 161.6, 159.6, 154.1, 149.6, 136.0, 132.6, 130.9, 124.0, 115.5, 104.3, 98.0, 41.2, 34.5, 17.3; MS (ES+) m/z 374.2 (M+1).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[O:21][CH2:20][CH2:19][NH:18][CH2:17]2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:22]([O:26][C:27](=[O:32])[CH2:28][CH:29](Br)[CH3:30])([CH3:25])([CH3:24])[CH3:23].[I-].[Na+].C1CCN2C(=NCCC2)CC1>CC#N>[C:22]([O:26][C:27](=[O:32])[CH2:28][CH:29]([N:18]1[CH2:19][CH2:20][O:21][CH:16]([C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:15][CH:14]=2)[CH2:17]1)[CH3:30])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(Br)CC(=O)OC(C)(C)C
Reactant: CCCCCCCCOc1ccc(C2CNCCO2)cc1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCCCCCCCOc1ccc(C2CN(C(C)CC(=O)OC(C)(C)C)CCO2)cc1
Temperature: 120 °C
Yield: 31.4 %

Procedure:
A mixture of 2-(4-octyloxy-phenyl)-morpholine (0.24 gram, 1.1 mmol), 3-bromobutyric acid tert-butyl ester (0.24 g; 1.1 mmol), sodium iodide (27.4 mg; 0.2 mmol), and DBU (0.4 mL; 2.7 mmol) in CH3CN (10 mL) was heated in a closed vessel at 120° C. After cooling to RT the reaction mixture was partitioned between 5% aqueous NaHCO3 solution and EtOAc. The layers were separated and the organic layer was dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (SiO2, Et2O) to afford 3-[2-(4-octyloxy-phenyl)-morpholin-4-yl]-butyric acid tert-butyl ester (0.15 g).