Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.Cl[C:13]1[C:14]2[C:21]([C:22]([C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)=[O:23])=[CH:20][NH:19][C:15]=2[N:16]=[CH:17][N:18]=1>>[C:24]1([C:22]([C:21]2[C:14]3[C:13]([NH:1][C:2]4[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=4)=[N:18][CH:17]=[N:16][C:15]=3[NH:19][CH:20]=2)=[O:23])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CC(=O)Nc1cccc(N)c1
Reactant: O=C(c1cccc2ccccc12)c1c[nH]c2ncnc(Cl)c12
Product: CC(=O)Nc1cccc(Nc2ncnc3[nH]cc(C(=O)c4cccc5ccccc45)c23)c1

Procedure:
N-(3-((5-(1-Naphthoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)acetamide was synthesized using N-(3-aminophenyl)acetamide and (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(naphthalen-1-yl)methanone according to the general procedure A. A yellow solid was obtained. M.p.>300° C.; 400 MHz 1HNMR (DMSO-d6) δ 11.42 (s, 1H), 9.98 (s, 1H), 8.45 (s, 1H), 8.13 (d, J=8.4 Hz, 1H), 8.05-8.02 (m, 3H), 7.79-7.73 (m, 2H), 7.67 (s, 1H), 7.63-7.53 (m, 4H), 7.38-7.35 (m, 1H), 7.29-7.25 (m, 1H), 2.02 (s, 3H); LCMS [M+H] 422.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:17]=[C:16]([OH:28])[CH:15]=2)=[CH:9][C:8]=1[CH3:29])[CH3:2].[N:31]1([CH2:37][CH2:38]O)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:17]=[C:16]([O:28][CH2:38][CH2:37][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:15]=2)=[CH:9][C:8]=1[CH3:29])[CH3:2]
Reactant: OCCN1CCOCC1
Reactant: CCOC(=O)COc1ccc(Sc2cc(O)cc(C#Cc3ccccc3)c2)cc1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccccc3)cc(OCCN3CCOCC3)c2)cc1C
Reaction time: 16 h

Procedure:
[4-(3-Hydroxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (200 mg; 0.48 mmol), 2-morpholin-4-yl-ethanol (0.22 g; 0.67 mmol) and tributylphosphine (0.24 mL; 0.96 mmol) were dissolved in THF (15 mL) in a dried reaction flask under an atmosphere of nitrogen. 1,1′-(Azodicarbonyl)dipiperidine (0.24 g; 0.96 mmol) was dissolved in THF (10 mL) and added to the reaction mixture. After stirring for 16 h the reaction mixture was evaporated to dryness and purified by flash chromatography (ethyl acetate:heptane (1:3→1:9). Yield: 150 mg. HPLC-MS: m/z: 532.6 (M+H); Rt: 2.07 min.
Reaction SMILES: [C:1]([CH:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].Cl[C:9]([O:11][CH2:12][CH3:13])=[O:10]>>[CH2:12]([O:11][C:9](=[O:10])[C:2]#[C:1][CH:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1)[CH3:13]
Reactant: CCOC(=O)Cl
Reactant: C#CC1CCCC1
Product: CCOC(=O)C#CC1CCCC1

Procedure:
The title compound was prepared from ethynyl-cyclopentane and ethyl chloroformate in accordance with the procedures of G. Cai et al., Tetrahedron, 2006, 5697-5708.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH3:15])=[O:13])(=O)OCC)C.[CH2:16]([N:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[CH:28]=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([N:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[CH:28]=[CH:11][C:12]([O:14][CH3:15])=[O:13])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOP(=O)(CC(=O)OC)OCC
Reactant: O=Cc1cccn1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1cccn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.1 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 960 mg, 24 mmol) in DMF (20 ml) was added dropwise at an ice bath temperature a solution of diethyl(methoxycarbonylmethyl)phosphonate (5.04 g, 24 mmol) in DMF (1 ml). The mixture was stirred for 15 minutes at room temperature and cooled again. To the mixture was added dropwise a solution of 1-benzyl-2-formylpyrrole (3.7 g, 20 mmol) in DMF (2 ml). The reaction mixture was stirred for 4 hours at room temperature and poured into ice-water and extracted with ethylacetate. The extract was washed with water and dried. The solvent was evaporated. The obtained white crystal was washed with isopropylether to give 1-benzyl-2-(2-methoxycarbonylvinyl)pyrrole (3.14 g). Yield: 65%.
Reaction SMILES: [OH-].[Na+].O.Cl.[F:5][C:6]([F:20])([F:19])[C:7]1[CH:8]=[C:9]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:10]=[CH:11][CH:12]=1.Br[CH2:22][CH2:23][CH2:24][Cl:25]>CC(C)=O>[F:20][C:6]([F:5])([F:19])[C:7]1[CH:8]=[C:9]([N:13]2[CH2:18][CH2:17][N:16]([CH2:22][CH2:23][CH2:24][Cl:25])[CH2:15][CH2:14]2)[CH:10]=[CH:11][CH:12]=1
Reactant: ClCCCBr
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: FC(F)(F)c1cccc(N2CCN(CCCCl)CC2)c1
Reaction time: 18 h

Procedure:
To a solution of 7.36 g. (0.184 mole) of sodium hydroxide in 75 ml. of water and 75 ml. of acetone there is added 19.02 g. (0.074 mole) of 1-[3-(trifluoromethyl)phenyl]piperazine hydrochloride and 11.59 g. (0.074 mole) of 1-bromo-3-chloropropane, and the resulting mixture is stirred at 27° for 18 hrs. The organic layer is then separated and concentrated to an oil under reduced pressure. The oil is treated with hot (85°) 6 N HCl until solution is complete, and the resulting solution is filtered and stored at 5° for 18 hrs. The precipitate which forms is collected on a filter to afford 14.73 g. (66%) of the hydrochloride salt of the product, m.p. 190°-192°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13]CC)=[S:12])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C[Si](C)(C)[O-].[K+].C(OCC)(=O)C.Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=[S:12])=[C:5]2[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=S)c1[nH]c2ccc(Cl)cc2c1-c1ccccc1
Agent: C[Si](C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC(=S)c1[nH]c2ccc(Cl)cc2c1-c1ccccc1

Procedure:
To 57 mg of ethyl 5-chloro-3-phenylthioindole-2-carboxylate from Preparation 5 in 1.7 mL of dry tetrahydrofuran, under argon, was added 48 mg of solid potassium trimethylsilanolate. The resultant mixture was stirred at room temperature for 20 h. Ethyl acetate and 1 N HCl were then added. The organic layer was washed with brine (2×) and dried over MgSO4. Filtration and concentration gave a yellow gum which was triturated with ether-hexane to give the title compound. 1H NMR (250 MHz, CDCl3) δ 7.09-7.18 (m, 3H), 7.20-7.25 (m, 2H), 7.30 (dd, 1H, J =8.6 and 2.0 Hz), 7.43 (d, 1H, J =2.0 Hz), 7.52 (d, 1H, J =8.6 Hz).
Reaction SMILES: N1(C2N=[C:9]([CH2:14][C:15]([O-])=O)NC(=O)C=2)CCOCC1.[Na+].[N:19]1([C:25]2[N:30]=[C:29]([CH2:31][C:32](=[O:48])[N:33]3[C:41]4[C:36](=[C:37](C5C=CC=CN=5)[CH:38]=[CH:39][CH:40]=4)[CH2:35][CH2:34]3)[NH:28][C:27](=[O:49])[CH:26]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH:14]1([CH:34]2[CH2:35][C:36]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:33]2[C:32](=[O:48])[CH2:31][C:29]2[NH:28][C:27](=[O:49])[CH:26]=[C:25]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[N:30]=2)[CH2:15][CH2:9]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2c(-c3ccccn3)cccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1c2ccccc2CC1C1CC1
Yield: 160.9 %

Procedure:
(±)-2-[2-(2-Cyclopropyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one is prepared by following the procedure described in example 1 using 0.90 g of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 0.60 g of (±)-2-cyclopropylindoline (reference example 12d) and 0.86 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.56 ml of pyridine and 10 ml of N,N-dimethylformamide. After purification by chromatography on a 100 g column of 20-45 μm silica, elution being carried out with a 90/10 v/v dichloromethane/methanol mixture, 0.88 g of (±)-2-[2-(2-cyclopropyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one is obtained in the form of a cream foam, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19])[CH:13]=[N:14]2)=[CH:9][CH:8]=1.[OH-].[NH4+:27]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]([CH3:22])([CH3:21])[C:18]([NH2:27])=[O:19])[CH:13]=[N:14]2)=[CH:9][CH:8]=1
Reactant: [NH4+]
Reactant: CC(C)(C(=O)Cl)c1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C(N)=O)c1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
To a solution of 2-(7-((3-chlorobenzyl)oxy)quinolin-3-yl)-2-methylpropanoyl chloride in THF (3 mL) was added ammonium hydroxide (10 mL). The reaction was stirred overnight at ambient temperature. The reaction mixture was concentrated onto silica and purification (FCC, SiO2, 0-10%, MeOH/DCM) afforded the title compound as a white solid (28 mg, 10%). 1H NMR (400 MHz, CDCl3) δ 8.88 (d, J=2.7 Hz, 1H), 8.07 (d, J=2.3 Hz, 1H), 7.73 (d, J=9.0 Hz, 1H), 7.49 (s, 1H), 7.45 (d, J=2.3 Hz, 1H), 7.39-7.27 (m, 4H), 5.34-5.22 (m, 2H), 5.19 (s, 2H), 1.71 (s, 6H). [M+H]=355.3.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:4][CH2:3]1.[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH:26]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O1CCCC1>[CH3:1][C:2]1([CH3:20])[CH2:3][CH2:4][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]2[CH2:19][CH2:18][N:17]([CH2:26][C:22]3[O:21][CH:25]=[CH:24][CH:23]=3)[CH2:16][CH2:15]2)[CH2:6][CH2:7]1
Reactant: CC1(C)CCC(c2ccccc2N2CCNCC2)CC1
Reactant: O=Cc1ccco1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)CCC(c2ccccc2N2CCN(Cc3ccco3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a mixture of 1-[2-(4,4-dimethylcyclohexyl)phenyl]piperazine (30 mg, 0.11 mmol) produced in Example (3c), furan-2-carbaldehyde (21 mg, 0.22 mmol) and tetrahydrofuran (2 mL) was added sodium triacetoxyborohydride (119 mg, 0.559 mmol), followed by stirring for 1 hour and 50 minutes at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The separated organic layer was filtered through Celite. The solvent was distilled off by nitrogen stream to the filtrate. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 1-[2-(4,4-dimethylcyclohexyl)phenyl]-4-furan-2-ylmethylpiperazine. This compound was dissolved in dichloromethane, and a 4N solution of hydrogen chloride in ethyl acetate was added. The solvent was distilled off by nitrogen stream. Hexane was added to the obtained residue to produce a solid, which was then triturated by sonication. The supernatant hexane solution was removed and the resulting solid was dried to give 38 mg of the title compound as colorless crystals.
Reaction SMILES: [Cl-].[F:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([CH2:11][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[N:8][C:7]=2[CH:31]=1.C([Li])CCC.[CH:37]([C:39]1[CH:40]=[C:41]([CH:46]=[CH:47][CH:48]=1)[C:42]([O:44][CH3:45])=[O:43])=O>CCCCCC.O1CCCC1>[F:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9](/[CH:11]=[CH:37]/[C:39]3[CH:40]=[C:41]([CH:46]=[CH:47][CH:48]=3)[C:42]([O:44][CH3:45])=[O:43])=[N:8][C:7]=2[CH:31]=1
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: Fc1ccc2sc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)c1cccc(/C=C/c2nc3cc(F)ccc3s2)c1
Yield: 76.5 %

Procedure:
Using the procedure of Preparation El and starting with 5.65 g of 5-fluorobenzothiazol-2-ylmethyl triphenyl phosphonium chloride (prepared by reacting 4.0 g of 2-chloromethyl-5-fluorobenzothiazole and 5.22 g of triphenylphosphine in 50 ml of toluene at reflux temperature for 17 hours), 7.61 ml of 1.6M n-butyl lithium solution in hexane and 2.0 g of methyl 3-formylbenzoate in 80 ml of dry tetrahydrofuran there was obtained 2.92 g of the titled product, m.p. 172°-173° C.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][CH:7]([CH2:10][OH:11])[CH2:8][O:9][C:4]=2[CH:3]=1.CN(C=O)C.[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O>[CH2:21]([O:11][CH2:10][CH:7]1[O:6][C:5]2[CH:12]=[CH:13][C:2]([Br:1])=[CH:3][C:4]=2[O:9][CH2:8]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OCC1COc2cc(Br)ccc2O1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc2c(c1)OCC(COCc1ccccc1)O2
Reaction time: 0.25 h
Yield: 72.5 %

Procedure:
A mixture of (6-bromo-2,3-dihydro-1,4-benzodioxin-2-yl)methanol (3.94 g, 16.1 mmol) and DMF (35 mL) at rt is treated with a 60% dispersion of NaH in mineral oil (0.706 g, 17.7 mmol). After 15 min, the mixture is treated with benzyl bromide (2.10 mL, 17.7 mmol). After 2 h, the mixture is poured into H2O and extracted with EtOAc (2×125 mL). The combined organics are washed with H2O (3×100 mL), brine, dried (MgSO4), filtered, and concentrated. The resulting oil is adsorbed onto SiO2 and chromatographed (Biotage 40M+SIM, 5% EtOAc/Hexane). The product fractions are pooled and concentrated to give an oil which solidified (upon standing) to give 3.91 g (73%) of 2-[(benzyloxy)methyl]-6-bromo-2,3-dihydro-1,4-benzodioxine: 1H NMR (400 MHz, CDCl3) δ 7.30-7.45, 7.06, 6.99, 6.81, 4.60-4.70, 4.30-4.40, 4.05-4.15, 3.65-3.85; MS (EI) m/z 244 (M+).
Reaction SMILES: [H-].[Na+].[CH:3]1([NH:9][C:10]2[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][N:13]=[C:12]3[NH:21][CH:22]=[CH:23][C:11]=23)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:24][Si:25]([CH2:28][CH2:29][O:30][CH2:31]Cl)([CH3:27])[CH3:26]>CN(C=O)C>[CH:3]1([NH:9][C:10]2[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][N:13]=[C:12]3[N:21]([CH2:31][O:30][CH2:29][CH2:28][Si:25]([CH3:27])([CH3:26])[CH3:24])[CH:22]=[CH:23][C:11]=23)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)c1cnc2[nH]ccc2c1NC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2c(ccn2COCC[Si](C)(C)C)c1NC1CCCCC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 102.4 %

Procedure:
A suspension of NaH (60 wt % in mineral oil, 0.077 g, 1.9 mmol) in DMF (15 mL) was cooled to about 0° C. Ethyl 4-(cyclohexylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.52 g, 1.8 mmol) was added and the resulting mixture was stirred for about 20 min at about 0° C. SEMCl (0.308 g, 1.84 mmol) was added and the resulting mixture was stirred for about 2 h while warming to rt. The solvent was removed under reduced pressure and the residue partitioned between EtOAc (120 mL) and saturated aqueous NH4Cl (40 mL). The organic phase was isolated, washed with brine (50 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give ethyl 4-(cyclohexylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.77 g, 100%): LC/MS (Table 2, Method b) Rt=3.29 min.; MS m/z: 418 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]([Cl:23])[CH:16]=1)[CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[N+]=[N-]>CCO.O=[Pt]=O>[NH2:1][CH2:4][C@@H:5]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]([Cl:23])[CH:16]=1)[CH2:6][C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8]
Reactant: CC(C)(C)OC(=O)C[C@@H](CN=[N+]=[N-])Nc1ccc(C#N)c(Cl)c1
Agent: O=[Pt]=O
Solvent: CCO
Product: CC(C)(C)OC(=O)C[C@@H](CN)Nc1ccc(C#N)c(Cl)c1
Reaction time: 2.5 h
Yield: 84.1 %

Procedure:
PtO2 (0.98 g) in EtOH (100 mL) was reduced with H2 (40 psi) on a Parr shaker for 20 minutes. To this mixture was added a solution of 1,1-dimethylethyl (3S)-4-azido-3-[(3-chloro-4-cyanophenyl)amino]butanoate (25.5 g, 76 mmol) in EtOH (100 mL) and the reaction was shaken on a Parr shaker under H2 (35 psi) for 2.5 h. The reaction mixture was filtered through a pad Celite and concentrated. The residue was dissolved in CH2Cl2, washed with H2O, dried over MgSO4, filtered and the solvent removed. The residue was triturated with Et2O (75 mL), chilled, and filtered to afford the titled product (19.8 g, 84%). 1H-NMR (CD3OD) δ: 1.39 (9H, s), 2.39 (1H, m), 2.58 (1H, m), 2.73 (1H, m), 2.79 (1H, m), 3.97 (1H, m), 6.68 (1H, d, J=8 Hz), 6.84 (1H, s), 7.44 (1H, d, J=8.8 Hz). LC-MS (ES) m/e 310.6 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O.[N+:17]([CH3:20])([O-:19])=[O:18].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[N+:17](/[CH:20]=[CH:12]/[C:11]1[CH:10]=[C:9]([CH:16]=[CH:15][CH:14]=1)[O:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)([O-:19])=[O:18]
Reactant: O=Cc1cccc(OCc2ccccn2)c1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1cccc(OCc2ccccn2)c1
Temperature: 100 °C
Reaction time: 6 h
Yield: 71.4 %

Procedure:
A mixture of 3-(pyridin-2-ylmethoxy)-benzaldehyde (2.98 g, 14 mmol) described in Manufacturing Example 60-1-1, nitromethane (1.51 mL, 28 mmol), ammonium acetate (1.62 g, 21 mmol) and acetic acid (30 mL) was stirred for 6 hours at 100° C. This mixture was cooled to room temperature, concentrated under a reduced pressure, and diluted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=4:1-2:1-1:1) to obtain the title compound (2.56 g, 71%).
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.Cl.[O:24]1[CH2:27][CH:26]([NH2:28])[CH2:25]1.CCN(C(C)C)C(C)C>>[CH3:22][C:3]1[C:2]([NH:28][CH:26]2[CH2:27][O:24][CH2:25]2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:4]=1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: NC1COC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC1COC1
Temperature: 100 °C
Yield: 66 %

Procedure:
Prepared similarly to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 41 mg, 0.138 mmol), oxetan-3-amine hydrochloride (30.3 mg, 0.277 mmol, Frontier Scientific), and DIPEA (121 μl, 0.692 mmol), heating at 100° C. for 30 min. Purification by silica gel (100% DCM to 8% MeOH/DCM) provided 2-(2-methyl-3-(oxetan-3-ylamino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (66% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.60 (s, 3H) 2.92 (t, J=6.85 Hz, 2H) 3.45 (td, J=6.85, 2.35 Hz, 2H) 4.74 (t, J=6.16 Hz, 2H) 4.98 (t, J=6.16 Hz, 2H) 5.04-5.15 (m, 1H) 6.98 (br. s., 1H) 7.10 (d, J=2.15 Hz, 1H) 7.37 (t, J=7.73 Hz, 1H) 7.60 (dd, J=8.02, 1.17 Hz, 1H) 7.70 (d, J=4.69 Hz, 1H) 7.85 (dd, J=7.63, 1.17 Hz, 1H) 11.80 (br. s., 1H). MS (ESI, pos. ion) m/z: 350.1 (M+1).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[N+:12]([O-])([OH:14])=[O:13]>>[N+:12]([C:9]1[CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=[CH:7][C:8]=1[Br:11])([O-:14])=[O:13]
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Reactant: O=[N+]([O-])O
Product: CS(=O)(=O)c1ccc(Br)c([N+](=O)[O-])c1

Procedure:
4-methylsulfonyl-bromobenzene was reacted with nitric acid to obtain 2-nitro-4-methylsulfonyl-bromobenzene melting at 126° C. which was reacted with N-hydroxy-phthalimide to obtain 0-(4-methylsulfonyl-2-nitro-phenoxy)-phthalimide melting at 215° C. The latter was reacted to obtain 0-(4-methylsulfonyl-2-nitro-phenyl)-hydroxylamine melting at 190° C.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])N.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[CH3:31][O:30][C:26]1[CH:25]=[C:23]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)[CH:22]=[C:21]([O:20][CH3:19])[C:27]=1[O:28][CH3:29]
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Reactant: COc1cc(N)cc(OC)c1OC
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(Nc2ncnc3ccc4nc(C#N)sc4c23)cc(OC)c1OC
Yield: 94 %

Procedure:
Prepared from VII and 3,4,5-trimethoxyaniline. Flash chromatography eluent (DCM-EtOAc, 5:5). Yield: 94%; pale yellow solid, mp 230° C.; IR (KBr) νmax/cm−1 3255, 3089, 3001, 2947, 2837, 2230, 1735, 1637, 1613, 1581, 1498, 1458, 1412, 1381, 1352, 1307, 1270, 1229, 1193, 1165, 1122, 1037, 1002, 991, 970, 952, 852, 830; 1H NMR (300 MHz, DMSO-d6) δ 8.51 (d, 1H, J=9.0 Hz), 8.05 (s, 1H), 7.80 (d, 1H, J=9.0 Hz), 6.46 (s, 2H), 3.77 (s, 6H), 3.67 (s, 3H); HRMS calcd for C19H16N5O3S (M+H+): 394.0974, found 394.0987.
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][C:6]([NH2:8])=[S:7])[CH3:4].[C:9]1(=[O:27])[N:13]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([CH2:20]Br)=O)[C:12](=[O:22])[C:11]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:10]12>C(O)C>[CH3:2][N:3]([CH2:5][C:6]1[S:7][CH:20]=[C:18]([CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[C:12](=[O:22])[C:11]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:10]3[C:9]2=[O:27])[N:8]=1)[CH3:4]
Reactant: O=C(CBr)CCCCN1C(=O)c2ccccc2C1=O
Reactant: CN(C)CC(N)=S
Agent: Cl
Solvent: CCO
Product: CN(C)Cc1nc(CCCCN2C(=O)c3ccccc3C2=O)cs1

Procedure:
Following the procedure of Example 1, a stirred solution containing 3.2 g. of dimethylaminothioacetamide hydrochloride, and 6.48 g of bromomethyl 4-phthalimidobutyl ketone [prepared by the procedure of Chem. Listy., 49, 1385 (1955); C.A., 50, 5573c (1956)]; in 50 ml. of ethanol was heated at refluxing temperature for about 5 hours and was then cooled. Volatile constituents were removed by evaporation in vacuo leaving 2-(dimethylaminomethyl)-4-(phthalimido-1-butyl)thiazole as a semi-solid residue. The compound was utilized without further purification.
Reaction SMILES: [CH2:1]([CH:8]([CH2:11][N:12]([CH3:14])[CH3:13])[CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[F:30][C:31]([F:40])([F:39])[C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1.O.O.[C:43]([OH:48])(=[O:47])[C:44]([OH:46])=[O:45]>CCOCC>[C:43]([OH:48])(=[O:47])[C:44]([OH:46])=[O:45].[CH3:13][N:12]([CH2:11][CH:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][O:10][C:35]1[CH:36]=[CH:37][C:32]([C:31]([F:40])([F:39])[F:30])=[CH:33][CH:34]=1)[CH3:14]
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: CN(C)CC(CO)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CCOCC
Product: CN(C)CC(COc1ccc(C(F)(F)F)cc1)Cc1ccccc1

Procedure:
A mixture of 2-benzyl-3-dimethylaminopropanol (4.2 g), dicyclohexylcarbodiimide (4.6 g) and cuprous chloride (0.2 g) is maintained at 80° for 40 hours. 4-Trifluoromethylphenol (5.0 g) is added, and the mixture maintained at 130° for 12 hours. The reaction mixture is cooled and ether (100 ml) is added. The insoluble material is filtered off and the filtrate extracted with 2N hydrochloric acid (3×100 ml). The acidic solutions are combined and made basic by the addition of concentrated aqueous ammonia. The aqueous solution is extracted with ether (3×150 ml), and the combined extracts dried over magnesium sulfate and evaporated under reduced pressure to give the ether as a yellow oil. This material is converted to the oxalate salt by dissolving in ether and adding the calculated quantity of oxalic acid dihydrate in ether. Filtration gives N,N-dimethyl-2-benzyl-3-(4-trifluoromethylphenoxy)propylamine oxalate, m.p. 147°-149°.