Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH2:12](Br)[CH:13]=[CH2:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N+:9]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([CH2:14][CH:13]=[CH2:12])[C:5]=1[OH:8])([O-:11])=[O:10]
Reactant: C=CCBr
Reactant: O=[N+]([O-])c1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCc1cc(Cl)cc([N+](=O)[O-])c1O
Temperature: 25 °C
Yield: 17.9 %

Procedure:
A mixture of 4-chloro-2-nitrophenol (100 g), allyl bromide (69.7 g), and potassium carbonate (95.5 g) in acetone (1 L) was refluxed for 6 hours. After cooling to room temperature and filtration, the filtrate was concentrated to give a residue. The residue was extracted with dichloromethane. The organic layer was washed with water, dried over MgSO4, and concentrated in vacuo to give a crude product (110.9 g, 90%) which was used in the next step without purification. 42 g of the crude product was heated at 180° C. for 8 hours. Purification by flash chromatography over silica gel (elution with 50% ethyl acetate in hexanes) gave 22 g (50%) of 2-nitro-4-chloro-6-allylphenol. 1H NMR (300 MHz, CDCl3) δ8.00 (d, J=2.6 Hz, 1 H), 7.44 (d, J=2.6 Hz, 1 H), 6.00-5.89 (m, 1 H), 5.20-5.12 (m, 2 H), 3.48 (d, J=6.69 Hz, 2 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[C:20]([O:30][CH3:31])[CH:19]=3)=[C:15]([C:32]3[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=3)[S:14][C:13]=2[CH:39]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:59][O:60][C:61](=[O:85])[C@H:62]([CH2:83]O)[NH:63][C:64]([C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1)([C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1)[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCN(CC)CC.CO.CCOC(C)=O.CCOC(C)=O>[CH3:59][O:60][C:61](=[O:85])[C@H:62]([CH2:83][O:38][C:35]1[CH:36]=[CH:37][C:32]([C:15]2[S:14][C:13]3[CH:39]=[C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:10]=[CH:11][C:12]=3[C:16]=2[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[C:20]([O:30][CH3:31])[CH:19]=2)=[CH:33][CH:34]=1)[NH:63][C:64]([C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1)([C:65]1[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=1)[C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1
Reactant: COc1cc(Cc2c(-c3ccc(O)cc3)sc3cc(OCc4ccccc4)ccc23)ccc1CN1CCCC1
Reactant: COC(=O)[C@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](COc1ccc(-c2sc3cc(OCc4ccccc4)ccc3c2Cc2ccc(CN3CCCC3)c(OC)c2)cc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 28 %

Procedure:
To a stirring solution of 6-benzyloxy-2-(4-hydroxyphenyl)-[3-methoxy-4-[(1-pyrrolidinyl)methyl]benzyl]benzo[b]thiophene (359 mg, 0.67 mmol), triphenylphosphine (300 mg) and N-trityl-L-serine methyl ester (392 mg) in THF (6 mL) at 0° C. was added diethyl azodicarboxylate (0.18 mL) over 5 min. The mixture was stirred at ambient temperature under argon for 24 h before concentration under reduced pressure. Chromatography with EtOAc followed by Et3N:MeOH:EtOAc (5:5:90) afforded the product (165 mg, 19%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:11]=[C:12]([C:21]4[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=4)[NH:13][C:14]=3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.C(Cl)(=O)C([Cl:33])=O>ClCCl.CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:11]=[C:12]([C:21]4[CH:29]=[CH:28][C:24]([C:25]([Cl:33])=[O:26])=[CH:23][CH:22]=4)[NH:13][C:14]=3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(-c2nc(-c3ccc4c(c3)OCO4)c(-c3ccccn3)[nH]2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(-c2nc(-c3ccc4c(c3)OCO4)c(-c3ccccn3)[nH]2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-(4-Benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-imidazol-2-yl)benzoic acid (prepared according to the method of Example 1) (379 mg; 0.98 mmol ) was suspended in dry dichloromethane (20 ml) and treated with oxalyl chloride (2 ml) and N,N-dimethylformamide (1 drop). This mixture was stirred at ambient temperature for 5 h then evaporated to dryness under reduced pressure to give the title compound as a yellow powder.
Reaction SMILES: FC[C@@H]1COC(=O)C1.N[C:10]1[CH:11]=[CH:12][CH2:13][N:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=12>>[CH:10]1[CH:11]=[CH:12][CH2:13][N:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=12
Reactant: NC1=C2c3ccccc3C=CN2CC=C1
Agent: O=C1C[C@H](CF)CO1
Product: C1=CCN2C=Cc3ccccc3C2=C1

Procedure:
According to still another embodiment (Scheme 3) the (S)-4-fluoromethyl-dihydro-furan-2-one is directly coupled with the amino-pyrido[2,1-a]isoquinoline derivative (VIII) to form the hydroxymethyl derivative of the pyrido[2,1-a]isoquinoline (XI), which is subsequently cyclisized to the fluoromethyl-pyrrolidin-2-one derivative (IX). The latter can be deprotected to yield the desired pyrido[2,1-a]isoquinoline derivative (II).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:10]=2[Cl:18])=[C:4]([CH3:19])[N:3]=1>C(O)(=O)C.O=[Pt]=O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:10]=2[Cl:18])=[C:4]([CH3:19])[N:3]=1
Reactant: Cc1nc(N)nc(N)c1-c1cc([N+](=O)[O-])ccc1Cl
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: Cc1nc(N)nc(N)c1-c1cc(N)ccc1Cl

Procedure:
A solution of 2,4-diamino-5-(2-chloro-5-nitrophenyl)-6-methyl pyrimidine (13.9 g) in acetic acid (500 ml) was reduced under an atmosphere of hydrogen in the presence of PtO2 (0.28 g). The mixture was filtered through hyflo and the filtrate was concentrated. The residue was neutralised with saturated NaHCO3 solution and the product was extracted with ethyl acetate, bulked, dried (MgSO4) and evaporated. Chromatography on SiO2 gel, eluting with CHCl3 40% MeOH/CHCl3, gave the desired product, 6 g, mp. 117°-121° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:41])=[N:15][CH:16]=[C:17]([C:19]2[N:20]=[N:21][N:22]([CH:24]3[CH2:27][N:26](C(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:25]3)[CH:23]=2)[CH:18]=1)[CH3:11]>CO.[OH-].[OH-].[Pd+2]>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:41])=[N:15][CH:16]=[C:17]([C:19]2[N:20]=[N:21][N:22]([CH:24]3[CH2:25][NH:26][CH2:27]3)[CH:23]=2)[CH:18]=1)[CH3:11]
Reactant: CC(Oc1cc(-c2cn(C3CN(C(c4ccccc4)c4ccccc4)C3)nn2)cnc1N)c1c(Cl)ccc(F)c1Cl
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(Oc1cc(-c2cn(C3CNC3)nn2)cnc1N)c1c(Cl)ccc(F)c1Cl

Procedure:
The product of the above mentioned Example 9 3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(1-(diphenylmethyl)azetidin-3-yl)-1H-1,2,3-triazol-4-yl)-2-aminopyridine (2.2 g, 3.73 mmol) was dissolved in methanol (40 mL), and palladium hydroxide/carbon (220 mg) was added to perform the hydrogenation reaction. TLC test showed that the raw materials were completely reacted. After filtration, the filtrate was concentrated under reduced pressure to yield the target product as white solid powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[Na].C1(O)C=CC=CC=1.[O:18]1[CH2:33][CH:19]1[CH2:20][N:21]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:22][CH:23]1[O:25][CH2:24]1>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:24][CH:23]2[CH2:22][N:21]([CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:20][CH:19]([CH2:33][OH:18])[O:25]2)=[CH:5][CH:4]=1
Reactant: c1ccc(CN(CC2CO2)CC2CO2)cc1
Reactant: COc1ccc(O)cc1
Agent: [Na]
Solvent: Oc1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(OCC2CN(Cc3ccccc3)CC(CO)O2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
6.21 G of p-methoxyphenol (0.05 mole Aldrich) is dissolved in 150 ml of dry dioxane and 0.4 g of finely cut sodium is added to the mixture. Stirring is continued for 1 hour after which all of the sodium is reacted with the phenol. Then 10.96 g (0.05 mole) N,N-bis(2,3-epoxypropyl)benzylamine is added and the mixture stirred for 1/2 hour under nitrogen. A flask is fitted with a reflux condenser and the mixture added and heated at reflux for 18 hours. After cooling to room temperature, the entire mixture is poured into 300 ml of water and stirred for 1/2 hour. The aqueous mixture is extracted with 3×125 ml portions of chloroform. The CHCl3 extracts are combined, washed with 200 ml of water and 200 ml of saturated NaCl solution. The CHCl3 layer is then dried over anhydrous NaSO4 and evaporated in vacuo to yield 15.4 g (90%) of crude product as a pale yellow oil. The oil is chromatographed on 300 g of neutral Alumina III to give 11.8 g of the title A compound (69%). The 11.8 g of product is dried in vacuo to give the title A as a clear colorless oil.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O)=[O:2].[CH3:12][C:13]1[CH:17]=[C:16]([NH:18][S:19]([C:22]2[S:23][C:24](Br)=[CH:25][CH:26]=2)(=[O:21])=[O:20])[O:15][N:14]=1>>[CH3:12][C:13]1[CH:17]=[C:16]([NH:18][S:19]([C:22]2[S:23][C:24]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[CH:1]=[O:2])=[CH:25][CH:26]=2)(=[O:21])=[O:20])[O:15][N:14]=1
Reactant: Cc1cc(NS(=O)(=O)c2ccc(Br)s2)on1
Reactant: O=Cc1ccccc1B(O)O
Product: Cc1cc(NS(=O)(=O)c2ccc(-c3ccccc3C=O)s2)on1
Yield: 27.5 %

Procedure:
N-(3-methyl-5-isoxazolyl)-5-(2-formylphenyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 32C from 2-formylbenzeneboronic acid (281 mg, 1.87 mmol) and N-(3-methyl-5-isoxazolyl)-5-bromothiophene-2-sulfonamide (550 mg, 1.7 mmol). Purification by column chromatography using 15% MeOH/CHCl3 gave 163 mg (28%) of the pure sulfonamide as a brown oil.
Reaction SMILES: [OH-].[Na+].[N:3]([CH:6]([O:11][CH3:12])[C:7]([O:9]C)=[O:8])=[N+:4]=[N-:5]>CO>[N:3]([CH:6]([O:11][CH3:12])[C:7]([OH:9])=[O:8])=[N+:4]=[N-:5]
Reactant: COC(=O)C(N=[N+]=[N-])OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(N=[N+]=[N-])C(=O)O
Yield: 93.4 %

Procedure:
Aqueous sodium hydroxide (30 ml. of a 2.5 N solution) is added dropwise over 15 minutes to a stirring solution of methyl 2-azido-2-methoxyacetate (10.40 g., 72 mmole) in methanol (8.5 ml.). The mixture becomes warm and cloudy during the addition. The methanol is removed under reduced pressure and the aqueous residue is acidified to pH 1 with concentrated sulfuric acid and extracted with ether. The combined ethereal extracts are dried over sodium sulfate and evaporated in vacuo to leave 2-azido-2-methoxyacetic acid (8.82 g.) as a clear liquid.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.C([O:38][C@@H:39]([CH3:43])[C:40](Cl)=[O:41])(=O)C>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:34])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:40](=[O:41])[C@@H:39]([OH:38])[CH3:43])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)[C@H](C)O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f25) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [Na].[H-].COCC[Al+2].[H-].[F:9][C:10]1[CH:25]=[CH:24][C:13]([O:14][C:15]2[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17](O)=[O:18])=[CH:12][CH:11]=1.[OH-].[Na+]>C1C=CC=CC=1>[F:9][C:10]1[CH:25]=[CH:24][C:13]([O:14][C:15]2[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=2[CH2:17][OH:18])=[CH:12][CH:11]=1
Reactant: O=C(O)c1ccccc1Oc1ccc(F)cc1
Agent: COCC[Al+2]
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: OCc1ccccc1Oc1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
36.1 mls of 70% sodium-(2-methoxyethyl)aluminum hydride in benzene are added dropwise over a one hour span to a stirring mixture of 15 g of 2-(4-fluorophenoxy)benzoic acid in 150 ml of benzene under nitrogen at ambient temperature. After total addition, the reaction mixture is stirred for an additional 30 minutes and then permitted to stand for 4 days. Thereafter, the reaction mixture is cooled to 0° C. before 100 mls of 10% sodium hydroxide are added with stirring. Following this addition, the layers separate and the aqueous layer is extracted twice with 100 ml portions of benzene. The combined benzene solutions are successively washed twice with 100 ml portions of water, washed once with 60 ml of a saturated sodium chloride solution and dried, providing a clear yellow oil. The oil is distilled at 118.5°-121.5° C. and 0.07 mm pressure to provide the clear, colorles liquid, 2-(4-fluorophenoxy)benzyl alcohol.
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[O:10][C:11]1[CH:12]=[C:13]2[O:19][C:18]([CH2:20]O)=[CH:17][C:14]2=[N:15][CH:16]=1.S(Cl)([Cl:24])=O>C(Cl)Cl>[Cl:24][CH2:20][C:18]1[O:19][C:13]2[C:14](=[N:15][CH:16]=[C:11]([O:10][C:2]3[S:1][C:9]4[C:4]([N:3]=3)=[N:5][CH:6]=[CH:7][CH:8]=4)[CH:12]=2)[CH:17]=1
Reactant: OCc1cc2ncc(Oc3nc4ncccc4s3)cc2o1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCc1cc2ncc(Oc3nc4ncccc4s3)cc2o1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98.1 %

Procedure:
To a suspension of [6-(thiazolo[4,5-b]pyridin-2-yloxy)-furo[3,2-b]pyridin-2-yl]-methanol (50 mg, 0.17 mmol) in DCM (1.6 mL) was added thionyl chloride (0.020 mL, 0.25 mmol). After 5 min, more thionyl chloride (0.020 mL, 0.25 mmol) was added to the suspension. After 2 h, additional thionyl chloride (0.020 mL, 0.25 mmol) was added. The solution was stirred (rt, 16 h) and concentrated to remove all volatiles to provide the product as a beige solid (53 mg, 99%). MS (ESI): mass calcd. for C14H8ClN3O2S, 317.00; m/z found, 317.9 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[CH:25]=[C:24](OC)[CH:23]=[C:22]([O:28][CH3:29])[CH:21]=3)=O)[CH2:14][OH:15])[CH2:8]2)=[CH:4][CH:3]=1.[N-]=C=O.[N-]=C=[S:37]>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:28][CH3:29])[CH:21]=3)=[S:37])[CH2:14][OH:15])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: [N-]=C=S
Reactant: COc1cc(NC(=O)N[C@H](CO)CCN2CC(Oc3ccc(Cl)cc3)C2)cc(OC)c1
Agent: [N-]=C=O
Product: COc1cccc(NC(=S)N[C@H](CO)CCN2CC(Oc3ccc(Cl)cc3)C2)c1

Procedure:
This compound is prepared in a manner analogous to that used to prepare 1-{(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(3,5-dimethoxy-phenyl)-urea in Example 26 except in the final step the isocyanate is replaced with the appropriate isothiocyanate.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].[NH:19]1[CH2:23][CH2:22][CH:21]([CH2:24][NH2:25])[CH2:20]1>C(#N)C>[NH2:25][CH2:24][CH:21]1[CH2:22][CH2:23][N:19]([C:2]2[N:11]=[C:10]3[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]3[CH2:12][CH3:13])=[CH:4][C:3]=2[F:18])[CH2:20]1
Reactant: NCC1CCNC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(CN)C3)nc21
Temperature: 25 °C
Reaction time: 96 h
Yield: 66.8 %

Procedure:
A mixture of 2 00 g (7.39 mmole) of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8 -napthyridine-3-carboxylic acid, 250 mL acetonitrile and 2.22 g (22.17 mmole) 3-pyrrolidinemethanamine [J. Org. Chem., 26, 4955 (1961)], was stirred at room temperature for four days. The reaction was filtered and the precipitate dissolved in 500 mL ammonium hydroxide at pH 10.5. This solution was filtered and the solvent removed at reduced pressure. The product was washed in 2×10 mL of water, then with ethanol/ether (1:1) until dry to give 1.65 g of 7-[3-(aminomethyl)-1-pyrrolidinyl]-1-ethyl-6-fluoro-1,4-dihydro-4-oxo -1,8-naphthyridine-3-carboxylic acid, mp 217°-218.5° C. Analysis calculated for C16H19FN4O3.1/2H2O:
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[CH:8]2[CH2:9][CH:10]=[CH:11][CH2:12][CH:7]2[C:5]1=[O:6])[CH:2]=[CH2:3].[Na].[OH:16]O>S([O-])(O)(=O)=O.C[N+](CCCCCCCC)(CCCCCCCC)CCCCCCCC.NCP(=O)(O)O>[O:16]1[CH:11]2[CH:10]1[CH2:9][CH:8]1[C:13](=[O:14])[N:4]([CH2:1][CH:2]=[CH2:3])[C:5](=[O:6])[CH:7]1[CH2:12]2
Reactant: C=CCN1C(=O)C2CC=CCC2C1=O
Reactant: OO
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: NCP(=O)(O)O
Agent: O=S(=O)([O-])O
Product: C=CCN1C(=O)C2CC3OC3CC2C1=O
Reaction time: 4 h

Procedure:
100.0 g of N-allyl-4-cyclohexene-1,2-dicarboximide, 2.44 g of methyltrioctylammonium hydrogen sulfate, 3.45 g of sodium tungstenate dihydrate and 0.58 g of aminomethylphosphonic acid were charged into a 500 mL three-mouth flask provided with a reflux condenser, thermometer, stirring apparatus, dropping funnel and oil bath. After heating using the oil bath maintained at a temperature of 90° C., 80 ml of 30% aqueous hydrogen peroxide were dropped in over the course of 180 minutes through the dropping funnel followed by aging for 4 hours. After cooling with an ice bath and removing the excess hydrogen peroxide with 300 ml of saturated aqueous sodium thiosulfate solution, the reaction mixture was extracted twice with 200 ml of ethyl acetate. The resulting ethyl acetate solution was dried overnight with anhydrous sodium sulfate followed by removing the solvent ethyl acetate using a rotary evaporator and purifying by column chromatography using a column packed with 25% aqueous silica gel to obtain 78.9 g of 4,5-epoxy-N-allylcyclohexane-1,2-dicarboximide.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]#[C:10][CH2:11][CH3:12].CN1CCOCC1.C([O-])([O-])=O.[Ca+2]>CO.[Pd].[Zn]>[CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH3:12]
Reactant: CCC#CCCCCCCCCO
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CN1CCOCC1
Solvent: CO
Product: CCC=CCCCCCCCCO
Yield: 96.7 %

Procedure:
6212 g (34.8 moles) of dodec-9-yn-1-ol and 316 g of N-methylmorpholine are dissolved in 46 l of methanol in a 100 l glass flask, and 62 g of a catalyst (0.7% Pd and 3.1% of Zn on a CaCO3 carrier) are suspended in the solution. Thereafter, the stirred suspension is flushed with nitrogen, and hydrogenation is carried out at from 0° to 5° C. and under a hydrogen pressure of 0.1 bar above atmospheric pressure until the absorption of hydrogen is complete. The methanol and morpholine are stripped off to give 6,200 g of dodec-9-en-1-ol containing 96.6% of the cis compound and 2.1% of the trans compound.
Reaction SMILES: [Cl:1][C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:14])[C:7](=[O:13])[CH2:8][CH2:9][NH:10]2)=[CH:4][N:3]=1.[H-].[Na+].Cl[CH:18]1[CH2:22][CH2:21][CH2:20][C:19]1=[O:23].[Cl-].[NH4+]>CC(N(C)C)=O>[Cl:1][C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:14])[C:7](=[O:13])[CH2:8][CH2:9][N:10]2[CH:18]2[CH2:22][CH2:21][CH2:20][C:19]2=[O:23])=[CH:4][N:3]=1
Reactant: CN1C(=O)CCNc2nc(Cl)ncc21
Reactant: O=C1CCCC1Cl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CC(=O)N(C)C
Product: CN1C(=O)CCN(C2CCCC2=O)c2nc(Cl)ncc21
Temperature: 100 °C
Yield: 59.7 %

Procedure:
10-chloro-6-methyl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 100; 256 mg, 1.20 mmol) was taken up in DMA (10 mL) and cooled on an ice-bath, with stirring, under nitrogen. Sodium hydride (60% in mineral oil; 232 mg, 5.8 mmol) was carefully added portionwise and the reaction mixture left to stir for 5 minutes, before removing cooling bath and stirring for a further 30 minutes. A solution of 2-chlorocyclopentanone (Aldrich; 600 uL, 6.00 mmol) in DMA (5 mL) was then added. The reaction mixture was heated to 100° C. and stirred for 3.5 hours and then allowed to cool, before addition of saturated aqueous ammonium chloride solution (1 mL). The mixture was partitioned between DCM (40 mL) and water (40 mL). Phases were separated and the aqueous phase re-extracted with DCM (40 mL). Combined extracts were washed with brine, dried over magnesium sulphate, filtered and evaporated. The residue was purified on a silica column eluting with ethyl acetate. Product containing fractions were combined and evaporated to yield the title compound as a sticky brown gum (211 mg, 60%)
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH:21]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22]1.C(Br)(Br)(Br)[Br:34]>C1COCC1>[Br:34][CH:21]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Br)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Triphenylphosphine (727 mg, 2.77 mmol) was added to a stirred solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (173 mg, 0.924 mmol) and carbon tetrabromide (919 mg, 2.77 mmol) in THF (3.00 mL) at 0° C., and the resulting mixture was allowed to warm slowly to rt. After 20 h, the reaction was filtered and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (gradient elution; 10%-40% EtOAc/hexanes as eluent) afforded the title compound i-4-a. m/z (ES) 250 (MH)+. 1H NMR (500 MHz, CDCl3): δ 4.49 (m, 1H), 3.81 (m, 2H), 3.63 (m, 1H), 3.53 (m, 1H), 2.33 (m, 1H), 2.26 (m, 1H), 1.49 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)[N:5]=[C:4]([NH:15][C@H:16]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH3:17])[CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[CH2:67]([OH:70])[CH2:68][OH:69]>O1CCOCC1>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C@@H:16]([NH:15][C:4]2[CH:3]=[C:2]([O:69][CH2:68][CH2:67][OH:70])[CH:7]=[C:6]([NH:8][C:9]3[CH:14]=[N:13][CH:12]=[CH:11][N:10]=3)[N:5]=2)[CH3:17])=[CH:19][CH:20]=1
Reactant: OCCO
Reactant: C[C@H](Nc1cc(Cl)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C[C@H](Nc1cc(OCCO)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 13 h

Procedure:
To 150 mg of (S)-4-chloro-N2-[1-(4-fluorophenyl)ethyl]-N6-(pyrazin-2-yl)pyridine-2,6-diamine, 187 mg of tripotassium phosphate, 84 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl and 46 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added 3 ml of ethylene glycol and 1.5 ml of 1,4-dioxane, and the mixture was degassed, and substituted by argon gas, and the mixture was stirred at 100° C. for 13 hours. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 62 mg of (S)-2-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino) pyridin-4-yloxy}ethanol as pale brown powder. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain 52 mg of the objective compound as yellow powder.