Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]([C:6]1[CH:19]=[CH:18][C:9]([O:10][CH:11]([CH3:17])[C:12]([O:14][CH2:15]C)=[O:13])=[CH:8][CH:7]=1)=[O:5].Cl>CO.CCOCC>[ClH:1].[NH2:2][CH2:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH:11]([CH3:17])[C:12]([O:14][CH3:15])=[O:13])=[CH:18][CH:19]=1)=[O:5]
Reactant: CCOC(=O)C(C)Oc1ccc(C(=O)CN)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C(C)Oc1ccc(C(=O)CN)cc1

Procedure:
A solution of ethyl 2-[4-(aminoacetyl)phenoxy]-propionate hydrochloride (2.0g.) in a mixture of methanol (150ml.) and a saturated solution of hydrogen chloride in ether (1ml.) was stirred and heated under reflux for 48 hours. The reaction mixture was then evaporated in vacuo and the residue was triturated with ether (50ml.) (dried over sodium wire) to give methyl 2-[4-(aminoacetyl)phenoxy]propionate hydrochloride which was isolated as a hygroscopic solid (1.3g.) having a satisfactory analysis; found: C, 50.0%; H, 5.9%, N, 4.9%; required (+ 3/4 mole H2O): C, 50.2%; H, 6.1%; N, 4.9%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:27])[C:13]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[N:20]=3)[CH:16]=[CH:15][C:14]=2[Cl:26])[N:8]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:7]=1)=[O:5])[CH3:2].[C:34](Cl)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]>N1C=CC=CC=1>[Cl:26][C:14]1[CH:15]=[CH:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[N:20]=2)=[CH:18][C:13]=1[C:12]([NH:11][C:9]1[N:8]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:10]=1)=[O:27]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCOC(=O)c1cc(NC(=O)c2cc(-c3cccc(N)n3)ccc2Cl)n(-c2ccccc2)n1
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(NC(=O)c2cc(-c3cccc(NC(=O)C(C)(C)C)n3)ccc2Cl)n(-c2ccccc2)n1
Temperature: 25 °C
Yield: 91.6 %

Procedure:
To a solution of 5-(5-(6-aminopyridin-2-yl)-2-chlorobenzamido)-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester (Preparation 2, 4.61 g, 10 mmol) in anhydrous pyridine (50 mL) was added pivaloyl chloride (1.32 g, 11 mmol) over 10 minutes with stirring at room temperature. The reaction was stirred for 90 minutes before concentrating in vacuo to low volume. The solution was partitioned between EtOAc (250 mL) and water (100 mL). The organic layer was separated, washed with brine (10 mL), dried over magnesium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 50% EtOAc in heptanes to afford the title compound (5 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH3:15][NH:16][C:17]([C:19]1[CH:24]=[C:23]([O:25][C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)[CH:22]=[CH:21][N:20]=1)=[O:18]>>[CH3:15][NH:16][C:17]([C:19]1[CH:24]=[C:23]([O:25][C:26]2[CH:32]=[CH:31][C:29]([NH:30][C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:11]([F:12])([F:13])[F:14])[CH:4]=3)=[O:10])=[CH:28][CH:27]=2)[CH:22]=[CH:21][N:20]=1)=[O:18]
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1
Reaction time: 22 h
Yield: 93.2 %

Procedure:
A solution of 4-chloro-3-(trifluoromethyl)phenylisocyanate (14.60 g, 65.90 mmol) in CH2C12 (35 mL) was added dropwise to a suspension of 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (MethodA2, Step 4; 16.0 g, 65.77 mmol) in CH2C12 (35 mL) at 0° C. The resulting mixture was stirred at room temp. for 22 h. The resulting yellow solids were removed by filtration, then washed with CH2C12 (2×30 mL) and dried under reduced pressure to afford N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) as an off white solid (28.5 g, 93%)
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].CN(C)[CH:22]=[O:23].[OH-].[Na+]>O1CCCC1>[CH:22]([C:7]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])=[O:23]
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=Cc1ccc(C(F)(F)F)cc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.9 %

Procedure:
To a solution of n-butyl lithium (56.0 ml, 140 mmol) in tetrahydrofuran (100 mL) at −78° C. was added a solution of 2-bromo-5-(trifluoromethyl)benzoic acid (17.9 g, 66.7 mmol) in tetrahydrofuran (100 mL) over 0.5 hour, at which time the solution turned dark red. After stirring for 1 hour, N,N-dimethylformamide (50 mL, 646 mmol) was added dropwise and the reaction mixture was allowed to warm to room temperature over 6 hours. The mixture was cooled to 0° C. and then a solution of sodium hydroxide (2 N, 120 mL) was added. The mixture was extracted with ether (2×50 mL). The aqueous layer was separated and concentrated hydrochloric acid was added to it until the pH was acidic. The mixture was extracted with ethyl acetate (3×80 mL). The organic extracts were combined, dried with sodium sulfate, filtered, and concentrated. The residue was purified on Analogix® Intelliflash280™ (SiO2, 7-100% solvent A in hexanes; solvent A=3:1:0.1 hexane:ethyl aceate:acetic acid) over 1 hour to obtain the title compound (4.5 g, 20.6 mmol, 31% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 6.78 (br, 1H) 7.93 (d, J=8.48 Hz, 1H) 8.13-8.20 (m, 2H) 8.38 (br, 1H); MS (DCI/NH3) m/z 236 (M+NH4)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:23]([O-:25])=[O:24])[CH2:10][C@H:11]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[C:12]([O-:14])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1C=CC(S(O[C@H:37]2[CH2:42][O:41][C@@H:40]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[O:39][CH2:38]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:23]([O:25][C:11]([CH3:15])([CH3:12])[CH3:10])=[O:24])[CH2:10][C@H:11]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][C@@H:37]2[CH2:38][O:39][C@@H:40]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[O:41][CH2:42]2)=[CH:20][CH:21]=1)[C:12]([O:14][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CO[C@@H](c3ccccc3)OC2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(O)cc1)C(=O)[O-])C(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(O[C@H]2CO[C@H](c3ccccc3)OC2)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 100 °C

Procedure:
To 0.93 g (2 mmol) (4S)—N-(tert-butoxycarbonyl)-4-(4-hydroxybenzyl)-L-glutamate and 1.34 g (4 mmol) cis-2-phenyl-1,3-dioxan-5-yl 4-methylbenzenesulfonate in 18 mL was added potassium carbonate (0.55 g, 4 mmol). The mixture was heated in a microwave for 2 h at 100° C. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography to afford 0.165 g (13%) di-tert-butyl (4S)—N-(tert-butoxycarbonyl)-4-{4-[(trans-2-phenyl-1,3-dioxan-5-yl)oxy]benzyl}-L-glutamate. The benzylidene protected derivative (0.13 g, 0.2 mmoL)) was dissolved in methanol (15 mL) Palladium/C (10% Pd) was added and the mixture was stirred under hydrogen atmosphere over night. The mixture was filtered and the solvent was evaporated, yielding 0.11 g (100%) di-tert-butyl (4S)—N-(tert-butoxycarbonyl)-4-{4-[(1,3-dihydroxypropan-2-yl)oxy]benzyl}-L-glutamate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=O)=[CH:4][CH:3]=1.[F:10][C:11]1[C:16]([F:17])=[CH:15][C:14]([NH2:18])=[C:13]([I:19])[CH:12]=1.CCOC(C)=O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N:18][C:14]2[CH:15]=[C:16]([F:17])[C:11]([F:10])=[CH:12][C:13]=2[I:19])=[CH:4][CH:3]=1
Reactant: Nc1cc(F)c(F)cc1I
Reactant: O=Nc1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Fc1cc(I)c(N=Nc2ccc(Cl)cc2)cc1F
Temperature: 0 °C
Yield: 25.6 %

Procedure:
Chloro-4-nitroso-benzene (9.1 g, 64 mmol; [932-98-9]) was added to a solution of 4,5-difluoro-2-iodo-phenylamine (10.9 g, 43 mmol; [847685-01-2]) in acetic acid (430 ml). The reaction mixture was heated under reflux conditions for 14 h. Ice water (1 l) and EtOAc (1 l) was added, the layers were separated and the aqueous layer was extracted two times with EtOAc. The combined extracts were washed with water and brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, CH2Cl2/heptane) to give the title compound (4.34 g, 11 mmol; 27%) as orange solid. MS: m/e=377.9 [M+].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]=[C:3]([C:7]([O:9][CH3:10])=[O:8])[CH2:2]1.C(N(CC)CC)C.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>C(Cl)Cl>[CH2:22]([O:21][C:19]([N:1]1[CH2:6][CH2:5][CH:4]=[C:3]([C:7]([O:9][CH3:10])=[O:8])[CH2:2]1)=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)C1=CCCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1=CCCN(C(=O)OCc2ccccc2)C1
Temperature: -15 °C
Reaction time: 1.5 h
Yield: 93.1 %

Procedure:
Arecoline (39.5 g, 0.25 mol) was dissolved in dry toluene (20 ml). 1-Chloroethyl chloroformate (30.5 ml) was added slowly at 0-5° C. The mixture was heated at 80° C. for 2 h, cooled to room temperature, filtered and evaporated to dryness in vacuo. The residue was dissolved in methylene chloride (400 ml) and extracted with 10% aqueous sodium carbonate. The organic layer was dried over magnesium sulfate, filtered and evaporated to dryness to give methyl 1,2,5,6-tetrahydropyridine-3-carboxylate (Yield: 30.5 g, 85%). Methyl 1,2,5,6-tetrahydropyridine-3-carboxylate (1.1 g, 7.8 mmol) was dissolved in methylene chloride (20 ml) and cooled to -15° C. Triethyl amine (2.2 ml, 15,8 mmol) and a solution of benzyl chloroformate (1.2 ml, 8,4 mmol) in methylene chloride (10 ml) were added. Stirring at room temperature for 1.5 h followed by evaporation to dryness. The residue was dissolved in methylene chloride and extracted with water two times. The organic layer separated, dried and evaporated to dryness in vacuo to give methyl 1-benzyloxycarbonyl-1,2,5,6-tetrahydropyridine-3-carboxylate as an oil (Yield: 2.0 g, 92%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH3:21])[N:15]=2)[CH:3]=1.O=[C:23]1[CH2:28][CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24]1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[CH:5]=[C:4]([C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH3:21])[N:15]=1)[CH:3]=[C:2]2[NH:1][CH:23]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]1
Reactant: CNc1nccc(-c2cc(N)c3cc(OC)ccc3c2)n1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Product: CNc1nccc(-c2cc(NC3CCCNC3)c3cc(OC)ccc3c2)n1

Procedure:
4-(6-methoxy-4-(piperidin-3-ylamino)naphthalen-2-yl)-N-methylpyrimidin-2-amine 152 was synthesized according to General Procedure E except compound 33 was used a starting material and replacing tert-butyl 4-oxopiperidine-1-carboxylate with tert-butyl 3-oxopiperidine-1-carboxylate. 1H NMR (DMSO) 400 MHz δ 9.64 (bs, 1H), 9.42 (bs, 1H), 8.42 (d, J=6.0 Hz, 1H), 8.20 (s, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.81-7.70 (m, 2H), 7.47 (bs, 1H), 7.24 (dd, JA=8.8 Hz, JB=2.0 Hz, 1H), 4.24-4.16 (m, 1H), 3.98 (s, 3H), 3.51-3.44 (m, 1H), 3.29-3.22 (m, 1H), 3.09 (bs, 3H), 3.00-2.87 (m, 2H), 2.13-2.05 (m, 1H), 2.05-1.94 (m, 1H), 1.93-1.76 (m, 2H); LCMS: 364 [M+H]. Calc. for C21H25N5O 3.1 Hydrochloric Acid 0.85 Dichloromethane 0.4 Ethyl Acetate: C, 51.45; H, 5.89; N, 12.79; Found C 51.58, H 5.71, N 12.79.
Reaction SMILES: [CH:1]([C:3]1[N:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=1)=O.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[N:12]1([CH2:1][C:3]2[N:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=Cc1cccc(C(=O)O)n1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(O)c1cccc(CN2CCCCC2)n1
Reaction time: 0.75 h
Yield: 103.5 %

Procedure:
To a solution of 6-formyl-2-pyridinecarboxylic acid (available from Chemstep Product List, 250 mg, 1.65 mmol) in dichloromethane (5.8 ml) was added piperidine (0.428 ml, 4.33 mmol) and acetic acid (0.083 ml). The mixture was stirred at room temperature for 30 mins when sodium triacetoxyborohydride (459 mg, 2.17 mmol) was added and the mixture stirred for 45 mins. The mixture was loaded onto an aminopropyl cartridge (5 g) pre-eluted with dichloromethane. The cartridge was eluted with dichloromethane and methanol, and fractions containing product were combined and blown to dryness under a stream of nitrogen. The crude product was taken up in ethyl acetate (25 ml) and washed with sodium hydroxide solution (2M, 3×25 ml). The aqueous layer was acidified to pH6 using hydrochloric acid (5M) and concentrated under vacuum to approximately 25 ml. The solution was loaded onto an Oasis cartridge (6 g), which had been pre-eluted with methanol (1 volume) followed by water (1 volume). The cartridge was eluted with water (1 volume) followed by methanol. Fractions containing product were combined and dried to give the title compound (376 mg).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:16]O>>[CH3:16][O:9][C:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1)=[O:10]
Reactant: Cc1cccc(C(=O)O)n1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(C)n1
Temperature: 25 °C
Yield: 59 %

Procedure:
A mixture of 6-methyl-pyridine-2-carboxylic acid (10 g, 72.9 mmol) and concentrated sulfuric acid (3.5 mL) in methanol (300 mL) was heated at reflux overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was poured into saturated aqueous sodium hydrogen carbonate (250 mL), and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried (magnesium sulfate), filtered, and evaporated to give 6-methyl-pyridine-2-carboxylic acid methyl ester (6.5 g, 59%) as a colorless oil. 1HNMR (CDCl3): δ 7.97 (d, J=7.6 Hz, 1H), 7.73 (dd, J=7.6 Hz, 1H), 7.36 (d, J=7.6 Hz, 1H), 4.01 (s, 3H), 2.67 (s, 3H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][S:7][C:8]([N+]([O-])=O)=[CH:9][NH2:10].[CH3:14][S:15][C:16](SC)=[CH:17][N+:18]([O-:20])=[O:19]>O1CCOCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][S:7][CH2:8][CH2:9][NH:10][C:16]([S:15][CH3:14])=[CH:17][N+:18]([O-:20])=[O:19]
Reactant: NC=C(SCc1ccco1)[N+](=O)[O-]
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: C1COCCO1
Product: CSC(=C[N+](=O)[O-])NCCSCc1ccco1
Yield: 50.4 %

Procedure:
A solution of 2-[(2-furanylmethyl)thio]-2-nitroethenamine (3.14 g.) and 1,1-bis-(methylthio)-2-nitroethene (13.2 g.) in dioxan (100 ml.) was heated at 100° for 11/2 hours. The solution was evaporated in vacuo and the residue suspended in warm ethyl acetate (70 ml.). The cooled suspension was filtered and the filtrate evaporated in vacuo. The oily residue was suspended in ether and the solid which separated was filtered and crystallised from ethanol to give the title compound (2.17 g.), m.p. 68°-70°. TLC (silica/ether-cyclohexane, 4:1) RF 0.3
Reaction SMILES: [CH:1]1([C:6]#[N:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:18][CH2:19][CH2:20][CH2:21]I>C1COCC1>[Cl:18][CH2:19][CH2:20][CH2:21][C:1]1([C:6]#[N:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ClCCCI
Reactant: N#CC1CCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC1(CCCCl)CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of cyclopentanecarbonitrile (1.04 mL, 10 mmol) in THF (20 mL) at −78° C. was added LiHMDS (1M in THF, 11 mL) via syringe. After 30 min, 1-chloro-3-iodopropane (1.6 mL, 15 mmol) was added at once and slowly warmed to room temperature. After 20 h, the reaction mixture was quenched with saturated ammonium chloride (1 mL), diluted with EtOAc (100 mL), dried (MgSO4), filtered and concentrated to give the title compound as a yellow oil which was used in the next step without further purification.
Reaction SMILES: Cl.N[C:3]1[CH:8]=[N:7][C:6]([Br:9])=[CH:5][N:4]=1.N([O:12][CH2:13]CC(C)C)=O>CO>[Br:9][C:6]1[CH:5]=[N:4][C:3]([O:12][CH3:13])=[CH:8][N:7]=1
Reactant: CC(C)CCON=O
Reactant: Nc1cnc(Br)cn1
Agent: Cl
Solvent: CO
Product: COc1cnc(Br)cn1
Temperature: -10 °C
Reaction time: 1.5 h
Yield: 85.3 %

Procedure:
Methanolic hydrogen chloride (0.8 mL of a 10M methanolic solution) was added to a stirred solution of 2-amino-5-bromopyrazine (6.96 g, 0.04 mol) in anhydrous methanol (125 mL). To this cooled (-10° C.) solution was added isoamyl nitrite (16.1 mL, 0.12 mol) and the reaction mixture was stirred at -10° C. for 1.5 hours then at room temperature for 2 hours. The solvent was evaporated and the residue partitioned between aqueous saturated sodium carbonate (50 mL) and dichloromethane (4×50 mL). The combined organics were dried (sodium carbonate) and evaporated to give a brown oil which was purified by column chromatography on silica using 5% ethyl acetate in petroleum ether (60-80) to afford 2-bromo-5-methoxypyrazine as a pale yellow solid (6.45 g, 85%).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:40]=[CH:39][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C[O:43][C:44](=[O:50])[C@@H:45]1[CH2:49][CH2:48][CH2:47][NH:46]1>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][CH2:35][C:36]([N:46]3[CH2:47][CH2:48][CH2:49][C@H:45]3[C:44]([OH:43])=[O:50])=[O:37])=[CH:31][CH:32]=2)=[CH:39][CH:40]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)O)cc2)cc1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)N3CCC[C@H]3C(=O)O)cc2)cc1

Procedure:
The product from Example 100 (56 mg, 0.1 mmole) and L-Proline methyl ester hydrochloride (33 mg, 0.2 mmole) were processed as in Examples 213A and 224B to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ11.66-13.14 (br.s, 1 H), 8.95 (s, 1 H), 7.26 (m, 6 H), 7.18 (m, 3 H), 7.04 (m, 1 H), 6.96 (m, 2 H), 6.88 (m, 4 H), 4.22 (dd, 1 H), 4.03 (d, 4 H), 3.46 (m, 2 H), 2.91 (s, 3 H), 2.58 (t, 2 H), 2.39 (s, 3 H), 2.27 (t, 2 H), 1.97-2.24 (m, 2 H), 1.70-1.95 (m, 4 H); MS (APCI+) m/z 656 (M+H)+.
Reaction SMILES: [NH4+].[C:2]([C:4](=[CH2:10])[CH2:5][CH2:6][C:7]([O-:9])=[O:8])#[N:3].Cl>>[C:2]([C:4](=[CH2:10])[CH2:5][CH2:6][C:7]([OH:9])=[O:8])#[N:3]
Reactant: C=C(C#N)CCC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Product: C=C(C#N)CCC(=O)O
Temperature: -78 °C
Yield: 60 %

Procedure:
A 100-mL portion of the filtrate containing the 4-cyano-4-pentenoic acid ammonium salt product mixture described above was adjusted to pH 2.7 with 6N HCl, then saturated with sodium chloride and extracted with 4×100 mL of ethyl ether. The combined organic extracts were dried over magnesium sulfate, filtered, and the volume of the combined extracts reduced to 100 mL by rotary evaporation at reduced pressure at 28° C. To the ether solution was added 200 mL of hexane, and the resulting solution cooled to -78° C. The resulting white solid which crystallized was isolated by rapid vacuum filtration and washing with 100 mL of cold (5° C.) hexane. Residual solvent was removed under high vacuum (150 millitorr) to yield 9.80 g (60% isolated yield) of 4-cyano-4-pentenoic acid (m.p. 26.5-27.0° C., stored at -20° C.).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][CH:3]=1.CO[CH:11](OC)[N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15]>C1(C)C(C)=CC=CC=1>[CH3:15][CH2:14][CH2:13][N:12]([CH:11]=[N:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][CH:3]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCN(CCC)C(OC)OC
Reactant: Nc1cccc(O)n1
Solvent: Cc1ccccc1C
Product: CCCN(C=Nc1cccc(=O)[nH]1)CCC

Procedure:
8.3 g (76 mmol) of 6-amino-2-hydroxypyridine and 20 g (114 mmol) of N,N-di-n-propylformamide dimethyl acetal are placed in 70 ml of xylene under argon. .The whole is heated at 100° for 1/2 hour while stirring It is then allowed to cool, is concentrated by evaporation under a water-jet vacuum and the residue is filtered over 10 times the amount of Florisil using methylene chloride. The fractions containing the product are concentrated by evaporation and then crystallised from n-hexane. N-(2-hydroxy-6-pyridyl)-N',N'-di-n-propylformamidine and N-(2-pyridon-6-yl)-N',N'-di-n-propylformamidine having a melting point of 102°-104° are obtained.
Reaction SMILES: Br[C:2]1[C:7]2[NH:8][C:9]3[CH:10]=[CH:11][C:12]([F:15])=[CH:13][C:14]=3[C:6]=2[C:5]([NH:16][CH3:17])=[N:4][CH:3]=1.[Cu][C:19]#[N:20]>CN1C(=O)CCC1.C(OCC)(=O)C>[F:15][C:12]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[C:2]([C:19]#[N:20])=[CH:3][N:4]=[C:5]([NH:16][CH3:17])[C:6]=3[C:14]=2[CH:13]=1
Reactant: N#C[Cu]
Reactant: CNc1ncc(Br)c2[nH]c3ccc(F)cc3c12
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CNc1ncc(C#N)c2[nH]c3ccc(F)cc3c12
Temperature: 225 °C

Procedure:
4-Bromo-8-fluoro-N-methyl-5H-pyrido[4,3-b]indol-1-amine (150 mg, 0.501 mmol) was combined with copper(I) cyanide (114 mg, 1.275 mmol) and dissolved in NMP (2.55 mL). The reaction was heated to 225° C. in a microwave for one hr. The solution was cooled to ambient temperature, diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated. The crude residue was purified on silica gel (EtOAc/hexanes).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C@@H:8]([CH2:11][CH3:12])[CH2:9][OH:10].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>O>[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([O:10][CH2:9][C@@H:8]([CH3:7])[CH2:11][CH3:12])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC[C@H](C)CO
Solvent: c1ccncc1
Solvent: O
Product: CC[C@H](C)COS(=O)(=O)c1ccc(C)cc1
Yield: 95.1 %

Procedure:
In 300 ml flask were charged 100 ml of pyridine and 40 g of (S)-2-methylbutanol (98 ee %) (produced by Tokyo Chemical Industry Co., Ltd.), and the mixture was cooled to 15° C. or less. To the mixture was added 104 g of p-toluenesulfonyl chloride at that temperature over 10 minutes. The inner temperature was returned to room temperature, at which the mixture was allowed to react for 2 hours. Water was added thereto, and the reaction mixture was extracted with ethyl acetate. The extract was washed twice with a saturated sodium chloride aqueous solution. The solvent was removed by distillation under reduced pressure to obtain 104.6 g of (S)-2-methylbutyl p-toluenesulfonate. The resulting compound was put in a 1 l flask, and 300 ml of dimethylformamide (hereinafter abbreviated as DMF) and 47.7 g of lithium bromide (monohydrate) were added thereto, followed by allowing the mixture to react at 60° C. for 5 hours. Water was added thereto, and the reaction mixture was extracted with diethyl ether. The extract was washed twice with water, and diethyl ether was removed by distillation to obtain 60.2 g of a crude product. The crude product was purified by distillation to obtain 45.45 g (66.2%) of the titled compound (b.p.: 55° C./100 mmHg).