Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([C:33]1[CH2:34][N:35]([CH3:39])[CH2:36][CH2:37][CH:38]=1)[NH2:32]>>[CH3:39][N:35]1[CH2:36][CH2:37][CH:38]=[C:33]([C:31]2[N:32]=[C:26]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[O:8])[CH2:10]3)[O:28][N:30]=2)[CH2:34]1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: CN1CCC=C(C(N)=NO)C1
Product: CN1CCC=C(c2noc(C3CC(c4ccc(OC(F)(F)F)cc4)CN(C(=O)N4CCOCC4)C3)n2)C1

Procedure:
80 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 34 mg (0.22 mmol, 1.1 eq.) of N′-hydroxy-1-methyl-1,2,5,6-tetrahydropyridine-3-carboximidamide [P. Sauerberg et al. J. Med. Chem. 1991, 34, 687-692] were reacted according to the General Method 1. Yield: 23 mg (22% of theory)
Reaction SMILES: [CH3:1][CH:2]([NH2:13])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.Cl.[CH2:15]([C:22]1([N:36]([CH3:38])[CH3:37])[CH2:27][CH2:26][CH:25](NCC2C=CC=CC=2)[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[CH2:15]([C:22]1([N:36]([CH3:37])[CH3:38])[CH2:27][CH2:26][CH:25]([NH:13][CH:2]([CH3:1])[CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CN(C)C1(Cc2ccccc2)CCC(NCc2ccccc2)CC1
Reactant: CC(N)Cc1c[nH]c2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(Cc1c[nH]c2ccccc12)NC1CCC(Cc2ccccc2)(N(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 152.4 %

Procedure:
348 mg DL-α-methyltryptamine were dissolved in dry 1,2-dichloroethane (10 ml) under argon (clear solution), 463 mg 4-benzyl-4-dimethylamino-cyclohexane (see example 3) and glacial acetic acid (229 μl) were added and the mixture was stirred for one hour at RT. 550 mg sodium triacetoxyborohydride were then added and the suspension was stirred for a further 72 hours at RT. For working up, water (20 ml) was added to the reaction mixture, the organic phase was separated off and the aqueous phase was extracted once with ether and then rendered strongly alkaline with sodium hydroxide solution (pH>10). A gelatinous precipitate which dissolved in ethyl acetate thereby precipitated out. The aqueous phase was extracted with ethyl acetate (4×10 ml). All the ethyl acetate phases were combined, dried with sodium sulfate and concentrated to dryness. 766 mg of a mixture of cis- and trans-1-benzyl-N′-[2-(1H-indol-3-yl)-1-methylethyl]-N,N-dimethylcyclohexane-1,4-diamine were obtained as a vitreous solid (m.p. 48-53° C.).
Reaction SMILES: C(NC1C=CC(C2C=C3C(=CC=2)C(=O)N([C@@H](C(C)C)C(O)=O)C3)=CC=1)(=O)C1C=CC=CC=1.[CH3:33][CH:34]([CH3:69])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][CH:44]=[C:45]([C:49]3[CH:54]=[CH:53][C:52]([NH:55][C:56](=[O:67])[C:57]4[CH:62]=[CH:61][C:60]([C:63]([F:66])([F:65])[F:64])=[CH:59][CH:58]=4)=[CH:51][CH:50]=3)[CH:46]=2)[C:41]1=[O:68])[C:36]([O:38]C)=[O:37]>>[CH3:33][CH:34]([CH3:69])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][CH:44]=[C:45]([C:49]3[CH:50]=[CH:51][C:52]([NH:55][C:56](=[O:67])[C:57]4[CH:62]=[CH:61][C:60]([C:63]([F:66])([F:64])[F:65])=[CH:59][CH:58]=4)=[CH:53][CH:54]=3)[CH:46]=2)[C:41]1=[O:68])[C:36]([OH:38])=[O:37]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)c4ccc(C(F)(F)F)cc4)cc3)ccc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=O)c4ccccc4)cc3)ccc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=O)c4ccc(C(F)(F)F)cc4)cc3)ccc2C1=O
Yield: 95 %

Procedure:
The compound of example 309 was prepared analogous to compound of example 305 by hydrolysis of compound of example 308.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[CH:9]=[N:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.O[NH:28][C:29]([C:31]1[S:32][C:33]([S:36](=[O:39])(=[O:38])[NH2:37])=[CH:34][CH:35]=1)=[NH:30]>>[F:26][C:2]([F:1])([F:25])[C:3]1[N:8]2[CH:9]=[N:10][C:11]([C:12]3[O:14][N:30]=[C:29]([C:31]4[S:32][C:33]([S:36]([NH2:37])(=[O:39])=[O:38])=[CH:34][CH:35]=4)[N:28]=3)=[C:7]2[N:6]=[C:5]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=2)[CH:4]=1
Reactant: O=C(O)c1ncn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)s1
Product: NS(=O)(=O)c1ccc(-c2noc(-c3ncn4c(C(F)(F)F)cc(-c5ccc(C(F)(F)F)cc5)nc34)n2)s1

Procedure:
The title compound was prepared from 4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine-8-carboxylic acid (example C.30) (188 mg, 0.5 mmol) and N-hydroxy-5-sulfamoyl-thiophene-2-carboxamidine (example B.2) (166 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography (ethyl acetate/heptane) and crystallization (dichloromethane/ethyl acetate) as a yellow solid (199 mg, 71%). MS (ISN) 559.1 [(M−H)−]; mp 295° C.
Reaction SMILES: [CH:1]1([CH2:7][S:8][C:9]2[CH:22]=[CH:21][C:12]3[NH:13][C:14]([NH:16][C:17](=[O:20])[O:18][CH3:19])=[N:15][C:11]=3[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26]CO.O>C1(C)C=CC=CC=1>[CH:5]1[CH2:4][CH2:3][CH2:2][CH:1]([CH2:7][S:8][C:9]2[CH:22]=[CH:21][C:12]3[NH:13][C:14]([NH:16][C:17](=[O:20])[O:18][CH2:19][CH2:26][CH2:25][N:24]([CH3:29])[CH3:23])=[N:15][C:11]=3[CH:10]=2)[CH:6]=1
Reactant: COC(=O)Nc1nc2cc(SCC3CCCCC3)ccc2[nH]1
Reactant: CN(C)CCCO
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C)CCCOC(=O)Nc1nc2cc(SCC3C=CCCC3)ccc2[nH]1

Procedure:
A mixture of 0.01 mole of the methyl ester of Example 4 and 0.02 mole of 3-dimethylamino-1-propanol is refluxed in 20 ml of toluene until all the H2O present has been azeotroped off. The heating mantle is removed and 0.25 g of aluminum isopropoxide is added. The mixture is then refluxed overnight. After cooling the solid present is filtered off, washed with water and crystallized.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:21]2[CH2:25][CH2:24][C@@H:23]([OH:26])[CH2:22]2)[C:8]2[N:13]=[N:12][N:11](CC3N(C)N=NN=3)[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C([N:34]1[C:38]2[N:39]=[C:40](C(C)(C)C)N=C(N3CCC(O)C3)[C:37]=2[N:36]=[N:35]1)C1C=CC=CC=1.ClCC1N(C)N=NN=1>>[C:1]([C:5]1[N:6]=[C:7]([N:21]2[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22]2)[C:8]2[C:9](=[N:11][N:12]([CH2:37][C:38]3[N:39]([CH3:40])[N:36]=[N:35][N:34]=3)[N:13]=2)[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(N2CCC(O)C2)c2nnn(Cc3ccccc3)c2n1
Reactant: Cn1nnnc1Cn1nnc2c(N3CC[C@@H](O)C3)nc(C(C)(C)C)nc21
Agent: Cn1nnnc1CCl
Product: Cn1nnnc1Cn1nc2nc(C(C)(C)C)nc(N3CCC(O)C3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of (R)-1-(5-tert-butyl-3-((1-methyl-1H-tetrazol-5-yl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)pyrrolidin-3-ol (example 113, b) 1-(3-Benzyl-5-tert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-pyrrolidin-3-ol was hydrogenated and subsequently reacted with 5-(chloromethyl)-1-methyl-1H-tetrazole and isolated as light yellow oil. MS (m/e): 359.3 (MH+).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:13])[CH2:10][C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>>[CH2:1]([NH:8][C:9](=[O:13])[C:10]([C:11]#[N:12])=[CH:16][N:17]([CH3:18])[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCC(=O)NCc1ccccc1
Reactant: COC(OC)N(C)C
Product: CN(C)C=C(C#N)C(=O)NCc1ccccc1

Procedure:
As for Example 1, N-benzyl-2-cyanoacetamide, m.p. 122°-123° C., is heated with N,N-dimethylformamide dimethylacetal to give N-benzyl-2-cyano-3-dimethylaminoacrylamide as colorless needles, m.p. 160.5°-161° C.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.O([C:14]([NH:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)=[O:15])C1C=CC=CC=1.[Cl:23]CCCl>>[ClH:23].[N:20]1[CH:19]=[CH:18][C:17]([NH:16][C:14]([N:1]2[CH2:2][CH:3]=[CH:4][CH2:5][CH2:6]2)=[O:15])=[CH:22][CH:21]=1
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Reactant: C1=CCNCC1
Reactant: ClCCCl
Product: Cl
Product: O=C(Nc1ccncc1)N1CC=CCC1

Procedure:
A solution of 1,2,3,6-tetrahydropyridine (0.25 g) and 4-phenoxycarbonylaminopyridine (0.64 g) in 1,2-dichloroethane (5 ml) was heated to 75° C. for 6 hours. Evaporation of the solvent gave a residue, which was chlomatographed on silica gel (50 ml) eluting with 0-5% methanol in dichloromethane, and taken up into a solution of hydrogen chloride in ethyl acetate (4N, 2 ml). Evaporation under reduced pressure and trituration with diisopropyl ether gave 1-(pyridin-4-ylcarbamoyl)-1,2,3,6-tetrahydropyridine hydrochloride (0.43 g).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH3:11])=[C:5]([Cl:12])[C:4]=1[F:13].[CH:14]([CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1)=[CH2:15].Cl>C1COCC1.C1(C)C=CC=CC=1>[Cl:12][C:5]1[C:4]([F:13])=[C:3]([C:19]2([OH:22])[CH2:20][CH2:21][CH:16]([CH:14]=[CH2:15])[CH2:17][CH2:18]2)[CH:8]=[CH:7][C:6]=1[O:9][CH2:10][CH3:11]
Reactant: C=CC1CCC(=O)CC1
Reactant: CCOc1ccc(Br)c(F)c1Cl
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=CC1CCC(O)(c2ccc(OCC)c(Cl)c2F)CC1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 133 %

Procedure:
1.5 g of well dried magnesium and 30 mL of THF were placed in a reactor under nitrogen atmosphere, and heated to 40° C. 15.3 g of the compound (1) dissolved in 30 mL of THF was slowly added dropwise thereto at a temperature range of from 35 to 49° C., followed by stirring for 30 minutes. Thereafter, 5.0 g of the compound (23) dissolved in 5 mL of THF was slowly added dropwise thereto at a temperature range of from 30 to 40° C., followed by stirring for 30 minutes. After cooling the resulting reaction mixture to 25° C., the reaction mixture was poured into and mixed with a mixture of 100 mL of 1N hydrochloric acid and 100 mL of toluene. The mixture was separated into an organic layer and an aqueous layer by standing still, so as to attain extraction to the organic layer. The resulting organic layer was fractionated and washed with water, a 2N sodium hydroxide aqueous solution, a saturated sodium bicarbonate aqueous solution and water, followed by drying over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure to obtain 16.0 g of 1-(3-chloro-4-ethoxy-2-fluorophenyl)-4-vinylcyclohexanol (24) as a yellow liquid.
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.CC(C)=[O:13].[O:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH:17]=[C:16]1[C:24](=O)[CH3:25]>C1(C)C=CC=CC=1.O.C(O)(=O)C>[CH2:8]([O:7][C:3](=[O:10])[CH:24]([C:16]1[O:15][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH:17]=1)[CH:25]=[O:13])[CH3:9]
Reactant: CC(=O)c1cc2ccccc2o1
Reactant: CC(C)=O
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C=O)c1cc2ccccc2o1
Temperature: 25 °C

Procedure:
To a vigorously stirred suspension of NaH (60% dispersion in mineral oil, 2.6 g, 65 mmol, 3.32 equiv.) and diethyl carbonate (4.7 mL, 38.83 mmol, 1.99 equiv.) in dry toluene (30 mL) was added drop wise (over a period of 1 h) a solution of the methyl ketone, 1-benzofuran-2-yl-ethanone (1 g, 7.87 mmol) in toluene (5 mL) under reflux. After addition, the mixture was stirred at reflux for 0.5 h. The mixture was cooled to RT and was acidified with glacial acetic acid. After adding cold water, the mixture was extracted 3 times with ethyl acetate. Combined organic extract was washed with water and brine. After drying over MgSO4, solvent was evaporated to furnish the crude βketoester, 3-benzofuran-2-yl-3-oxo-propionic acid ethyl ester. To the crude product was added absolute ethanol (10 mL) and hydrazine hydrate (1.5 mL, excess). The mixture was kept under reflux for 4 h. A solid separated, which was filtered and washed with EtOH. Upon drying, a 1.87 g (48%) of the pyrazolone (VId) was isolated. 1H-NMR (DMSO-d6) δ 12.5 (br s, 1H), 10.1 (br s, 1H), 7.62-7.18 (series of multiplets, 4H), 7.10 (s, 1H), 5.87 (s, 1H). MS: 201(M+H)
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:24])=[C:11]([N:16]4[CH2:21][CH:20]([CH3:22])[NH:19][CH:18]([CH3:23])[CH2:17]4)[C:12]=3[O:14][CH3:15])[C:7](=[O:25])[C:6]([C:26]([NH:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[Cl:37])=[O:27])=[CH:5]2)[CH2:3][CH2:2]1.C([O:43][CH2:44][C@@H:45]1[O:47][CH2:46]1)(=O)CCC.C([O-])(=O)CCC.[OH-].[Li+]>>[ClH:36].[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:24])=[C:11]([N:16]4[CH2:17][CH:18]([CH3:23])[N:19]([CH2:46][C@@H:45]([OH:47])[CH2:44][OH:43])[CH:20]([CH3:22])[CH2:21]4)[C:12]=3[O:14][CH3:15])[C:7](=[O:25])[C:6]([C:26]([NH:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[Cl:37])=[O:27])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCCC(=O)OC[C@H]1CO1
Reactant: COc1c(N2CC(C)NC(C)C2)c(F)cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3Cl)cn(C3CC3)c12
Agent: CCCC(=O)[O-]
Agent: [Li+]
Agent: [OH-]
Product: COc1c(N2CC(C)N(C[C@@H](O)CO)C(C)C2)c(F)cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3Cl)cn(C3CC3)c12
Product: Cl

Procedure:
The title compound is prepared in analogy to Example 89 from Example 12 with (2R)-3-butanoyloxy-1,2-epoxypropane and subsequent hydrolysis of the butyrate with 1 equivalent of a 1M lithium hydroxide solution at 70° C. for 1 h. For the work-up the solvent is removed on a rotary evaporator, the residue is adjusted to a neutral pH using 1N hydrochloric acid and buffer pH 7 and extracted with dichloromethane. Purification takes place by RP-HPLC (Method 6).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][C@H:3]1[CH2:4][OH:5].[OH-].[Na+].Cl[C:12]1[N:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([Cl:27])[CH:20]=2)[N:15]=[C:14]([NH:28][CH:29]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[N:13]=1>C1C=CC=CC=1>[Cl:27][C:21]1[CH:20]=[C:19]([NH:18][C:16]2[N:15]=[C:14]([NH:28][CH:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)[N:13]=[C:12]([O:5][CH2:4][CH:3]3[CH2:6][CH2:7][CH2:8][N:2]3[CH3:1])[N:17]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Reactant: CN1CCC[C@H]1CO
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: COc1ccc(Nc2nc(NC3CCCCCC3)nc(OCC3CCCN3C)n2)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of N-methyl prolinol (0.226 g, 1.96 mmol) and sodium hydroxide (79 mg, 1.96 mmol) in benzene (10 mL) was heated to reflux for 2 hours with stirring under nitrogen atmosphere and then cooled to 25° C. followed by the addition of compound 133 (0.25 g, 0.65 mmol) at same temperature. The mixture was heated to reflux for 6 hours, concentrated under vacuum and diluted with water (3 mL). The gum which separated was collected (by decanting out the liquid portion) and purified by column chromatography (1-3% MeOH—CHCl3) to afford the title compound E25 as a semi-solid (0.06 g, 20%). HPLC: Symmetry shield RP18 (250×4.6 mm) 5 microns [solvent A=0.01 M KH2PO4 (pH 3.0); solvent B=CH3CN], Gradient elution program: T/% B=0/35, 10/35, 40/80, 50/80, 55/35, 60/35; 270 nm, Rt 15.51 min, 99.55% purity; MS (CI): m/z 461 (M+H, 100).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:27][CH3:28])=[C:10]([CH2:19][NH:20][C:21](=[O:26])[CH2:22][C:23](O)=[O:24])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Br:29][C:30]1[CH:31]=[C:32]([CH2:37][NH2:38])[CH:33]=[CH:34][C:35]=1[F:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[Br:29][C:30]1[CH:31]=[C:32]([CH2:37][NH:38][C:23](=[O:24])[CH2:22][C:21]([NH:20][CH2:19][C:10]2[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]3[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]3=[N:8][C:9]=2[CH2:27][CH3:28])=[O:26])[CH:33]=[CH:34][C:35]=1[F:36]
Reactant: NCc1ccc(F)c(Br)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1ccc(F)c(Br)c1
Yield: 106.3 %

Procedure:
A solution of 3-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-3-oxopropanoic acid (0.600 g, 1.541 mmol), 1-(3-bromo-4-fluorophenyl)methanamine (0.432 g, 1.796 mmol), HATU (0.760 g, 1.999 mmol) and triethylamine (0.600 mL, 4.30 mmol) in dichloromethane (35 mL) was stirred overnight at room temperature. The solution was diluted with DCM, washed with saturated NaHCO3, water followed by saturated NaCl, and dried over Na2SO4. The organic layer was evaporated to a pale amber residue. This was purified on 80 g. Combi-Flash column with DCM [0-8% MeOH] to give N-[(3-bromo-4-fluorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}propanediamide (942.9 mg, 106%, containing 12% impurities). LC-MS m/z 575.3 (M+H)+, 0.84 min (ret time).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.Cl.[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:22][NH2:23].C(N(CC)CC)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:23][CH2:22][C:21]1[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:19]([F:18])[CH:20]=1
Reactant: COc1ccc(CN)cc1F
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc1F
Reaction time: 0.25 h
Yield: 69.6 %

Procedure:
To a suspension of (4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (0.11 g, 0.39 mmol) and 3-fluoro-4-methoxy-benzylamine hydrochloride (75 mg, 0.39 mmol) in tetrahydrofuran (5 mL) is added triethylamine (0.13 mL, 0.98 mmol). After 15 minutes of stirring, the solvent is evaporated under reduced pressure. The solid material is collected by Buchner filtration, washed successively with diethyl ether, water, and methanol, and then dried under house vacuum to give (4Z)-6-bromo-4-{[(3-fluoro-4-methoxybenzyl)amino]methylene}isoquinoline-1,3(2H,4H)-dione as an off-white solid (0.11 g, 69%).
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:6])[CH2:4][Br:5].N1C=CN=C1.[C:12]([Si:16](Cl)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:15])([CH3:14])[CH3:13]>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)C>[Br:1][CH2:2][CH:3]([CH2:4][Br:5])[O:6][Si:16]([C:12]([CH3:15])([CH3:14])[CH3:13])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OC(CBr)CBr
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)[Si](OC(CBr)CBr)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 100.3 %

Procedure:
To a solution of 1,3-dibromo-2-propanol (20.00 g, 91.79 mmol) in methylene chloride (DCM) (100 mL) cooled to 0° C. was added 1H-imidazole (6.56 g, 96.4 mmol) followed by tert-butylchlorodiphenylsilane (25.1 mL, 96.4 mmol) and 4-dimethylaminopyridine (1.12 g, 9.18 mmol). The reaction was stirred with warming to room temperature overnight. The reaction mixture was diluted with diethyl ether, washed with water, and the aqueous layer was again extracted once with ether. The combined organic extracts were washed with water, followed by brine, dried over sodium sulfate, decanted and concentrated. Flash chromatography (eluting with a gradient from 0-15% ethyl acetate/hexanes) afforded desired product (42 g, 100%). 1H NMR (300 MHz, CDCl3): δ 7.72-7.66 (m, 4H), 7.51-7.37 (m, 6H), 4.00-3.91 (m, 1H), 3.49-3.45 (m, 4H), 1.09 (s, 9H).
Reaction SMILES: [O:1]=[C:2]([C@H:4]([CH2:6][C:7]1[CH:14]=[C:12]([OH:13])[C:10]([OH:11])=[CH:9][CH:8]=1)[NH2:5])[OH:3].S(Cl)([Cl:17])=O.[CH3:19]O>>[ClH:17].[CH3:19][O:1][C:2](=[O:3])[C@H:4]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:11])=[C:12]([OH:13])[CH:14]=1)[NH2:5]
Reactant: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Reactant: CO
Reactant: O=S(Cl)Cl
Product: COC(=O)[C@@H](N)Cc1ccc(O)c(O)c1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.97 g (10 mmol) of L-DOPA 15 in 100 ml of MeOH at 0° C. was added 6.57 ml (90 mmol) of thionyl chloride via addition funnel. The mixture was stirred overnight while the temperature was slowly warmed to room temperature. The solvent was evaporated and the thick oil was treated with toluene (3×15 ml) and evaporated. The yield of white solid was 3.26 g (100%); NMR (DMSQ-d6) δ 2.90 (m, 2H), 3.38 (bs, 2H), 3.61 (s, 3H), 4.08 (m, 1H), 6.40 (d, 1H, J=7 Hz), 6.59 (s, 1H), 6.65(d, 2H, J=7 Hz), 8.59 (bs, 1H), 8.90 (d, 1H, J=10 Hz). MS: 212 m/z (M+H)+.
Reaction SMILES: [ClH:1].[CH:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[OH:19][C:20]1[CH:29]=[CH:28][C:23]([O:24][CH2:25][CH2:26]Br)=[CH:22][CH:21]=1.C([O-])(O)=O.[Na+]>>[ClH:1].[CH:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:26][CH2:25][O:24][C:23]2[CH:28]=[CH:29][C:20]([OH:19])=[CH:21][CH:22]=2)[CH2:15][CH2:14]1
Reactant: Oc1ccc(OCCBr)cc1
Reactant: c1cc2c(cc1CC1CCNCC1)CCCC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Oc1ccc(OCCN2CCC(Cc3ccc4c(c3)CCCC4)CC2)cc1

Procedure:
The title compound was prepared from 4-((5,6,7,8-tetrahydro-2-naphthyl)methyl)piperidine hydrochloride (250 mg, 940 μmol), 2-(4-hydroxyphenoxy)ethyl bromide (204 mg, 940 μmol) and NaHCO3 (162 mg, 1.93 mmol) as a pale beige solid (152 mg): 1H NMR (CD3OD) 1.55-1.65 (m, 2H), 1.70-1.96 (m, 7H), 2.54 (d, J=6.3 Hz, 2H), 2.62-2.78 (m, 4H), 3.05 (t, J=12 Hz, 2H), 3.43-3.68 (m, 4H), 4.25 (t, J=4.8 Hz, 2H), 6.72 (d, J=9.0 Hz, 2H), 6.80-6.90 (m, 4H), 6.95 (d, J=7.5 Hz, 1H); Anal. Calcd for C24H32ClNO2 ·H2O: C, 68.64; H, 8.16; N, 3.33. Found: C, 68.39; H, 7.99; N, 3.36.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH:12]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](N1C=CN=C1)([N:27]1[CH:31]=[CH:30]N=C1)=[O:26].C(CN)[OH:38]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:25]([NH:27][CH2:31][CH2:30][OH:38])=[O:26])[CH2:13][CH:12]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCO
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1ccccc1C1CC(O)CCN1C(=O)OCc1ccccc1
Solvent: Cc1ccccc1
Product: Cc1ccccc1C1CC(OC(=O)NCCO)CCN1C(=O)OCc1ccccc1
Temperature: 60 °C

Procedure:
In 21 ml of toluene was dissolved 1.63 g of 1-benzyloxycarbonyl-4-hydroxy-2-(2-methylphenyl)piperidine, added thereto was 973 mg of 1,1′-carbonyldiimidazole, and the mixture was stirred at 60° C. for an hour. To the solution was added 1.21 ml of ethanolamine, and the mixture was stirred at 60° C. for 6 hours. To the reaction mixture was added distilled water, and extracted with chloroform. The organic layer was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:acetone=9:1→chloroform:methanol=19:1), to give 1.34 g of 1-benzyloxycarbonyl-4-(2-hydroxyethylaminocarbonyloxy)-2-(2-methylphenyl)piperidine.