Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH2:9][C:10](OCC)=[O:11])=[C:6](Cl)[N:5]=[C:4](/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:3]=1.[NH4+:24].[OH-]>O1CCOCC1>[Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][C:10](=[O:11])[NH:24][C:6]=2[N:5]=[C:4](/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:3]=1
Reactant: CCOC(=O)CCc1c(Cl)nc(/C=C/c2ccccc2)nc1Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C1CCc2c(Cl)nc(/C=C/c3ccccc3)nc2N1
Temperature: 75 °C
Yield: 21 %

Procedure:
To a solution of ethyl 3-{4,6-dichloro-2-[(E)-2-phenylethenyl]-5-pyrimidinyl}propanoate (0.42 g, 1.19 mmol) in 1,4-dioxane (5 mL) was added conc. NH4OH (3.5 mL). The reaction was heated at 75° C. in a sealed tube overnight. The solution was concentrated under vacuum, diluted with water, and extracted with EtOAc/DCM. The organic layer was washed with brine, dried over Na2SO4, and concentrated under vacuum. The crude residue was then purified by column chromatography (silica gel) to yield the desired compound (0.072 g, 21%). LCMS: m/z 286.2 (MH+). Also obtained was 3-{4-amino-6-chloro-2-[(E)-2-phenylethenyl]-5-pyrimidinyl}propanamide (0.175 g).
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:27][CH2:28][CH:29]([OH:31])[CH3:30]>>[CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][CH:29]([OH:31])[CH3:30])[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S1CCN(c2nc(Cl)nc3c(SCc4ccccc4)ncnc23)CC1
Reactant: CC(O)CN
Product: CC(O)CNc1nc(N2CCS(=O)CC2)c2ncnc(SCc3ccccc3)c2n1

Procedure:
This compound was prepared analogous to Example 1 from 8-benzylthio-2-chloro-4-(1-oxido-thiomorpholino)pyrimido[5,4-d]pyrimidine and 1-amino-2-propanol.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:25])[CH:3]=1.[C:26]1([CH2:32][C:33]([N:35]=[C:36]=[O:37])=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(OCC)C>O1CCCC1.FC1C=C(NC(NC(=O)CC2C=CC=CC=2)=S)C=CC=1OC1N=CN=C(NC(N2CCCC2)=O)C=1>[F:25][C:4]1[CH:3]=[C:2]([NH:1][C:36]([NH:35][C:33](=[O:34])[CH2:32][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:37])[CH:24]=[CH:23][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]2)=[O:15])[CH:8]=1
Reactant: O=C=NC(=O)Cc1ccccc1
Reactant: CN1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3F)ccn2)CC1
Agent: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2cc(NC(=O)N3CCCC3)ncn2)c(F)c1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccccc4)cc3F)ccn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
To a solution of 4-methylpiperazine-1-carboxylic acid [4-(4-amino-2-fluorophenoxy)pyridin-2-yl]amide (80 mg) in tetrahydrofuran (2.3 ml) was added a solution of phenylacetyl isocyanate in hexane (1.4 ml, Production Example 1), followed by stirring under a nitrogen atmosphere at room temperature for 2 hrs. The reaction mixture was partitioned between ethyl acetate (100 ml) and a saturated aqueous solution of sodium hydrogencarbonate (50 ml). The organic layer was dried over anhydrous sodium sulfate, and concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (FUJI Silysia NH, eluent; hexane:ethyl acetate=1:1, ethyl acetate, then ethyl acetate:methanol=10:1). Fractions containing the target compound were concentrated to give a crude product, to which diethyl ether was then added to precipitate a solid. The solid was filtered off, washed with diethyl ether, and dried under aeration to provide the titled compound (55.2 mg, 47%) as colorless powder.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([N:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[NH2:21][CH2:22][CH2:23][CH2:24][NH2:25]>O>[NH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([N:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CN(C)c1ccc(-c2cc3ncccc3c(Cl)n2)cc1
Reactant: NCCCN
Solvent: O
Product: CN(C)c1ccc(-c2cc3ncccc3c(NCCCN)n2)cc1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of 5-chloro-7-(4-dimethylaminophenyl)-[1,6]naphthyridine (Example 2) (10 mg, 0.035 mmol) and 1,3-diaminopropane (200 microL, 2.4 mmol) was stirred at 100° C. for 5 hours. After cooling to room temperature, water was added and the resulting mixture was extracted with dichloromethane (2×3 mL). Purification by preparative thin layer chromatography afforded the title compound as a yellow film (8.5 mg). 1H NMR (CDCl3, 400 MHz) δ 8.85 (dd, 1H), 8.10 (d, 2H), 8.07 (d, 1H), 7.50 (s, 1H), 7.21 (dd, 1H), 6.81 (d, 2H), 3.87 (t, 2H), 3.02 (s, 6H), 2.97 (t, 2H), 1.90 (quint, 2H); MS (m/e) calculated for C19H23N5 321.2, found 322.4 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:22])=[C:6]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=3[NH:10][C:9]2=[O:21])[CH:7]=1.[OH-].[K+].[NH2:25]OS(O)(=O)=O.Cl>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:22])=[C:6]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]([F:18])([F:20])[F:19])=[CH:16][C:11]=3[N:10]([NH2:25])[C:9]2=[O:21])[CH:7]=1
Reactant: O=c1[nH]c2cc(C(F)(F)F)ccc2n1-c1cc(Cl)ccc1O
Reactant: NOS(=O)(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Nn1c(=O)n(-c2cc(Cl)ccc2O)c2ccc(C(F)(F)F)cc21

Procedure:
To a solution of 1,3-dihydro-1-(5-chloro-2-hydroxyphenyl)-5-trifluoromethyl-2H-benzimidazol-2-one (0.2 g, 0.6 mmol) in absolute N,N-dimethylformamide (5 ml) was at room temperature added potassium hydroxide (2 pellets) and hydroxylamine-o-sulfonic acid (0.16 g, 1.3 mmol) The reaction was stirred over night, water was added (20 ml) and the mixture was acidified with 4 M hydrochloric acid. The crude crystalline product was collected by filtration and subjected to column chromatography using methylene chloride:methanol (19 1) as eluent. The fractions containing the product were concentrated in vacuo yielding the title compound as white crystals, M.p. 228°-230° C.
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]#[N:19].[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[N:20]1([C:2]2[C:10]3[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=3[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=2[C:18]#[N:19])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: N#Cc1cc([N+](=O)[O-])c2nc(C(F)(F)F)[nH]c2c1Cl
Reactant: C1CCNCC1
Product: N#Cc1cc([N+](=O)[O-])c2nc(C(F)(F)F)[nH]c2c1N1CCCCC1

Procedure:
4-Chloro-7-nitro-5-cyano-2-trifluoromethylbenzimidazole is reacted with piperidine to obtain 4-piperidino-7-nitro-5-cyano-2-trifluoromethylbenzimidazole, m.w., 339.3. This compound is reacted with calcium oxide to obtain the corresponding calcium salt, m.w., 716.6.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([C:20]4[N:24]([CH:25]([CH3:27])[CH3:26])[C:23]([CH3:28])=[N:22][CH:21]=4)[C:17]([F:29])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:3]1.[C:30](O)(=[O:34])[C@H:31]([CH3:33])[OH:32]>>[F:29][C:17]1[C:18]([C:20]2[N:24]([CH:25]([CH3:26])[CH3:27])[C:23]([CH3:28])=[N:22][CH:21]=2)=[N:19][C:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([N:4]3[CH2:5][CH2:6][C@@H:2]([NH:1][C:30](=[O:34])[C@@H:31]([OH:32])[CH3:33])[CH2:3]3)=[CH:12][CH:11]=2)=[N:15][CH:16]=1
Reactant: C[C@H](O)C(=O)O
Reactant: Cc1ncc(-c2nc(Nc3ccc(N4CC[C@@H](N)C4)cc3)ncc2F)n1C(C)C
Product: Cc1ncc(-c2nc(Nc3ccc(N4CC[C@@H](NC(=O)[C@H](C)O)C4)cc3)ncc2F)n1C(C)C

Procedure:
The title compound was prepared (15 mg, 6%), was prepared using a procedure analogous to Example 154 starting from N-{4-[(3R)-3-aminopyrrolidin-1-yl]phenyl}-5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidin-2-amine (Example 156; 220 mg, 0.556 mmol) and L—lactic acid (61 mg, 0.667 mmol). NMR: 1.20 (d, 3H), 1.36 (d, 6H), 1.89-2.01 (m, 1H), 2.14-2.22 (m, 1H), 2.43 (s, 3H), 3.02-3.10 (m, 1H), 3.14-3.48 (m, 3H), 3.92-4.03 (m, 1H), 4.34-4.46 (m, 1H), 5.35 (d, 2H), 5.41-5.53 (m, 1H), 6.49 (d, 2H), 7.30 (s, 1H), 7.32 (d, 2H), 8.40 (d, 1H), 9.05 (s, 1H); m/z 468.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:15][C@H:14]2[C@H:5]([C@H:6]3[C@H:11]([CH2:12][CH2:13]2)[CH2:10][C@:9]2([CH3:20])[C:16](=[O:19])[CH2:17][CH2:18][C@H:8]2[CH2:7]3)[CH2:4][CH2:3]1.[I-].[CH3:22][S+](C)C.CC(C)([O-])C.[K+].O>CS(C)=O>[CH3:20][C@@:9]12[C@:16]3([CH2:22][O:19]3)[CH2:17][CH2:18][C@H:8]1[CH2:7][C@@H:6]1[C@H:11]([CH2:12][CH2:13][C@@H:14]3[C@H:5]1[CH2:4][CH2:3][C@H:2]([OH:1])[CH2:15]3)[CH2:10]2
Reactant: C[C@]12C[C@H]3CC[C@H]4C[C@@H](O)CC[C@H]4[C@@H]3C[C@@H]1CCC2=O
Reactant: C[S+](C)C
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C[C@]12C[C@H]3CC[C@H]4C[C@@H](O)CC[C@H]4[C@@H]3C[C@@H]1CC[C@@]21CO1
Reaction time: 3 h
Yield: 71.9 %

Procedure:
To a solution of compound 14 (60 mg, 0.23 mmol) in DMSO (3 mL) was added trimethylsulfonium iodide (204 mg, 1.0 mmol) and potassium tert-butoxide (112 mg, 1.0 mmol) at room temperature. After 3 h, water (20 mL) was added and the product extracted into EtOAc (50 mL×3). The combined extracts were dried, filtered and concentrated. The residue was purified by flash column chromatography (silica gel eluted with 30% EtOAc in hexanes) to give compound 15 (48 mg, 72%) as a white solid: 160-162° C.; [α]D20 16.5 (c 0.20, CHCl3); 1H NMR (CDCl3) δ 3.64-3.50 (m, 1H), 2.91 (d, J=4.9 Hz, 1H), 2.62 (d, J=4.9 Hz, 1H), 0.87 (s, 3H); 13C NMR (CDCl3) δ 71.7, 70.6, 53.6, 47.1, 42.0, 40.3, 40.2, 38.9, 38.4, 36.3, 35.7, 31.8, 29.8, 29.6, 28.9 (2×C), 25.8, 25.5, 14.4; IR νmax 3387, 1733 cm−1. Anal. Calcd for (C19H30O2): C, 78.57; H, 10.41. Found: C, 78.36; H, 10.50.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]([CH3:12])[CH2:3]1.Cl[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].C1(O)CCCCC1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([NH:1][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]([CH3:12])[CH2:3]2)=[C:15]([N+:21]([O-:23])=[O:22])[CH:16]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: COC(=O)N1CCC(N)CC1C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: OC1CCCCC1
Product: COC(=O)N1CCC(Nc2ccc(Cl)cc2[N+](=O)[O-])CC1C
Temperature: 160 °C
Reaction time: 10 h

Procedure:
A mixture of 44 parts of methyl 4-amino-2-methyl-1-piperidinecarboxylate, 57.6 parts of 1,4-dichloro-2-nitrobenzene, 32 parts of sodium carbonate, 0.2 parts of potassium iodide and 160 parts of cyclohexanol is stirred for 10 hours at 160° C. After cooling, the reaction mixture is evaporated and water is added to the residue. The product is extracted with methylbenzene. The extract is washed successively twice with water and twice with a diluted hydrochloric acid solution. The formed precipitate is filtered off over hyflo. The filtrate is washed twice with water, dried, filtered and evaporated. The residue is stirred in 2,2'-oxybispropane with activated charcoal. The latter is filtered off and the clear filtrate is evaporated. The oily residue is purified by column-chromatography over silicagel, using trichloromethane as eluent. The pure fractions are collected and the eluent is evaporated, yielding methyl 4-(4-chloro-2-nitrophenylamino)-2-methyl-1-piperidinecarboxylate as an oily residue.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH3:19])[CH2:3][CH:4]1[CH2:7][CH:6]([C:8]([O:10]CC)=[O:9])[CH:5]1N1CCCCC1.C1(C)C=CC(S(OC)(=O)=O)=CC=1>O>[CH3:1][C:2]([CH3:20])([CH3:19])[CH2:3][CH:4]1[CH2:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5]1
Reactant: CCOC(=O)C1CC(CC(C)(C)C)C1N1CCCCC1
Agent: COS(=O)(=O)c1ccc(C)cc1
Solvent: O
Product: CC(C)(C)CC1C=C(C(=O)O)C1
Temperature: 105 °C
Reaction time: 2 h
Yield: 31.6 %

Procedure:
Ethyl 3-(2,2-dimethylpropyl)-2-piperidin-1-ylcyclobutanecarboxylate (1470 g) and methyl p-toluenesulfonate (417 mL) were mixed. After the mixture was stirred at 105° C. for 2 hr, water (2100 mL) was poured into the reaction mixture and the aqueous layer was extracted. The aqueous layer was washed with tert-butyl methyl ether/hexane=1/1 (800 mL) and hexane (600 mL). To the aqueous layer was added potassium hydroxide (663 g) at ice temperature and the mixture was stirred at 100° C. for 2 hr. After the reaction mixture was washed with tert-butyl methyl ether/hexane=1/1 (600 mL×2), concentrated hydrochloric acid (500 mL) and 6 N hydrochloric acid (606 mL) were added to the aqueous layer at ice temperature. The mixture was extracted with ethyl acetate (600 mL×2). The combined organic layer was washed with water (1 L×2) and brine (500 mL), then dried over magnesium sulfate. The magnesium sulfate was filtered off and the filtrate was concentrated in vacuo to give the title compound (278 g) as a crude product.
Reaction SMILES: CCC(OO)=[O:4].[C:7]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:9])[CH3:8]>CC(C)=O>[C:7]([C:15]1[CH:20]=[C:19]([OH:4])[C:18](=[CH:17][CH:16]=1)[OH:21])([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:8])[CH3:9]
Reactant: CCC(=O)OO
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)cc1
Solvent: CC(C)=O
Product: CC(C)(C)CC(C)(C)c1ccc(O)c(O)c1
Yield: 58 %

Procedure:
The procedure of Example 9 was repeated, except 10.4g (0.1 mol) of perisobutyric acid in the form of about 20 weight% acetone solution was added over 30 minutes in place of perpropionic acid. Consequently, the conversion of para-tert.-octyl phenol was 13.2%, 4-tert.-octyl pyrocatechol was formed in a yield of 58% based on the converted octyl phenol and the conversion of perisobutyric acid was 100%.
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:6][CH:5]([CH2:7][O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O>[CH2:9]([O:8][CH2:7][CH:5]1[CH2:6][C:3](=[O:2])[CH2:4]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC1(OC)CC(COCc2ccccc2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: O=C1CC(COCc2ccccc2)C1
Temperature: 25 °C
Yield: 57.2 %

Procedure:
To a stirring solution of [(3,3-dimethoxy-cyclobutyl)methoxymethyl]-benzene (13.0 g, 55.1 mmol) in 200 mL of a mixture of acetone:water (3:1) was added p-toluenesulfonic acid mono hydrate (2.1 g, 11.0 mmol). The reaction mixture was heated to 65 C for 45 minutes. Both TLC and GS/MS analysis indicated complete consumption of starting material. The reaction was cooled to room temperature and then the acetone was removed under reduced pressure. The resulting mixture was diluted with ethyl acetate and washed with an aqueous solution 5% NaOH. The layers were separated and the organic layer was dried over magnesium sulfate, filtered through a fritted funnel and then concentrated under reduced pressure. Purification of this material was accomplished by flash chromatography using a Biotage Column 75 small, eluting with a 10% EtOAc/hexanes. The product containing fractions were collected and concentrated under reduced pressure to yield the title compound (6.0 g, 58% yield) as a colorless oil.
Reaction SMILES: Br[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[C:6]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[N:5][C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].[CH:28]([N:31]([CH:34]([CH3:36])C)CC)([CH3:30])C.N1CCCC1.O>C(#N)C>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([N:7]2[C:3]([CH2:2][N:31]3[CH2:28][CH2:30][CH2:36][CH2:34]3)=[C:4]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:5]=[C:6]2[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[CH:9][CH:10]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)n(-c2ccc(Cl)cc2)c1CBr
Solvent: CC#N
Solvent: O
Solvent: C1CCNC1
Product: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)n(-c2ccc(Cl)cc2)c1CN1CCCC1
Yield: 32.3 %

Procedure:
Part B: To a magnetically stirred solution of ethyl 5-bromomethyl-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate (11.69 g, 23.9 mmol) in acetonitrile (40 ml) is added diisopropylethylamine (DIPEA) (5.2 ml, 30 mmol) and pyrrolidine (1.7 g, 23.9 mmol) and the resulting solution is reacted at room temperature for 2 hours. Water (250 ml) is added and the resulting mixture is extracted three times with dichloromethane. The collected dichloromethane layers are dried over Na2SO4, filtered and concentrated in vacuo. Subsequent purification with flash chromatography (petroleum ether/EtOAc=20/80 (v/v)) gives ethyl 1-(4-chlorophenyl)-2-(2,4-dichloro-phenyl)-5-(pyrrolidin-1-ylmethyl)-1H-imidazole-4-carboxylate (3.7 gram, 32% yield). 1H-NMR (200 MHz, CDCl3): δ 1.42 (t, J=7 Hz, 3H), 1.62-1.72 (m, 4H), 2.42-2.50 (m, 4H), 3.83 (s, 2H), 4.43 (q, J=7 Hz, 2H), 7.17-7.40 (m, 7H).
Reaction SMILES: [CH2:1]1[C:5]2=[CH:6][C:7]3[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][C:12]=3[N:4]2[CH2:3][CH2:2]1.[H-].[Na+].[CH2:16](I)[CH3:17]>CN(C)C=O>[CH2:16]([O:13][C:9]1[CH:10]=[CH:11][C:12]2[N:4]3[CH2:3][CH2:2][CH2:1][C:5]3=[CH:6][C:7]=2[CH:8]=1)[CH3:17]
Reactant: Oc1ccc2c(c1)cc1n2CCC1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc2c(c1)cc1n2CCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
a solution of 64.00 g 2,3-dihydro-1H-3a-aza-cyclopenta[a]inden-6-ol in 240 mL N,N-dimethylformamide was added over 10 min to a cooled (0° C.) suspension of 17.73 g (0.406 mol) sodium hydride (55% in oil) in 400 mL N,N-dimethylformamide. The mixture was stirred at 0° C. for 30 min. To the resulting mixture was added 32.84 mL (63.39 g, 0.406mol) ethyl iodide dropwise over 10 min. The mixture was stirred at room temperature for 1 h. The mixture was partitioned between ice-water and ethyl acetate. The phases were separated and the organic phase was washed with 10% citric acid, 10% sodium bicarbonate solution and brine. The aqueous phases were re-extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate and evaporated to dryness. The solid residue was stirred with 600 mL n-hexane for 1 h and the product collected by filtration. The filtrate was concentrated to obtain a second crop of product, to afford a combined yield of 66.4 g (89.3%) of the title compound as white crystals melting at 101-102° C.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH3:5])=[CH2:2].[C:6]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])[C@@H:7]([CH3:9])[OH:8]>P(Cl)(Cl)(Cl)=O.C(OCC)(=O)C>[CH2:1]([O:3][CH:4]([O:8][C@H:7]([CH3:9])[C:6]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])[CH3:5])[CH3:2]
Reactant: C=COCC
Reactant: CC(C)COC(=O)[C@@H](C)O
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(C)O[C@H](C)C(=O)OCC(C)C
Temperature: 25 °C
Yield: 82.1 %

Procedure:
17.2 g of dehydrated ethyl vinyl ether was dropwise added to a mixture of 32.7 g of isobutyl (R)-(+)-lactate and 0.3 g of phosphorus oxychloride which was being stirred at room temperature, so that the internal temperature of the reaction system could be kept at 40° C. or less. Then, the resulting mixture was stirred at room temperature overnight. After the reaction, thereto was added 200 ml of ethyl acetate, followed by washing with a saturated aqueous sodium hydrogen carbonate solution, water and a saturated aqueous sodium chloride solution in this order. The washed material was dried over anhydrous sodium sulfate and then subjected to vacuum distillation to remove the solvent. The resulting concentrate was subjected to distillation to obtain 40.1 g (yield: 91.8%) of an oily title compound (diastereomixture).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:15]2=[N:16][C:17]([C:20]#[N:21])=[CH:18][CH:19]=[C:14]2[N:13](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:12]=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:15]2=[N:16][C:17]([C:20]#[N:21])=[CH:18][CH:19]=[C:14]2[NH:13][N:12]=1
Reactant: N#Cc1ccc2c(n1)c(-c1ccc3ccccc3c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc2[nH]nc(-c3ccc4ccccc4c3)c2n1
Reaction time: 2 h
Yield: 94.8 %

Procedure:
To 10 mL of a solution containing 360 mg of 3-naphthalen-2-yl-1-trityl-1H-pyrazolo[4,3-b]pyridine-5-carbonitrile obtained by Production example 15 in dichloromethane, 3 mL of trifluoroacetic acid was added at room temperature and stirred for 2 hours. The reaction solution was added with aqueous sodium hydrogen carbonate, extracted with ethyl acetate, washed with water, and dried over magnesium sulfate. After evaporating, the residue was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=3:1), to afford 180 mg of the title compound as a colorless powder.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:10]1[CH2:15][CH:14]=[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.B(F)(F)F.CC[O:30]CC.[OH-].[Na+].OO.Cl>COCCOCCOC.O>[CH2:3]([N:10]1[CH2:11][CH2:12][CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[CH:14]([OH:30])[CH2:15]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOCC
Reactant: COc1ccccc1C1=CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: FB(F)F
Agent: OO
Solvent: O
Solvent: COCCOCCOC
Product: COc1ccccc1C1CCN(Cc2ccccc2)CC1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
Sodium borohydride (0.590 g, 15.94 mmol) was added at once to a solution of 1-benzyl-4-(2-methoxyphenyl)-1,2,3,6-tetrahydropyridine (2.0 g, 7.16 mmol) in (7 mL) anhydrous diglyme at 0° C. The reaction mixture was warmed to room temperature and a solution of borontrifluoride etherate (2.0 g 14.2 mmol) in (2 mL) diglyme was added dropwise under a N2. The reaction mixture was stirred at room temperature for 2 h. Water (0.8 mL) was then added to the reaction mixture slowly followed by 6N NaOH (1.8 mL). The reaction mixture was heated to 50° C. for another 45 min. and then 30% H2O2 (1.7 mL, 14.7 mmol) was added. The reaction mixture was stirred for another 45 min., Concentrated HCl (1.7 mL) was added and the solvents were evaporated in vacuum. Water (7 mL) was added to the residue and the solvent again evaporation. The residue was quenched with saturated ammonium hydroxide solution and extracted with DCM (2×50 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 1-benzyl-4-(2-methoxyphenyl)piperidin-3-ol (1.0 g, 50%); 1H NMR (200 MHz, CDCl3): δ 1.79-2.18 (m, 5H), 2.91-3.045 (m, 2H), 3.184-3.256 (dd, J=10.4, 4.0 Hz, 2H), 3.615 (s, 2H), 3.827 (s, 3H), 3.785-3.949 (m, 1H), 6.892 (d, J=8.5 Hz, 2H), 6.974 (t, J=7.5 Hz, 1H), 7.188-7.416 (m, 7H); m/e=297 (M+1).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH:7]=[CH:8][N+:9]([O-])=O)=[CH:5][CH:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:1][C:2]1[S:3][C:4]([CH2:7][CH2:8][NH2:9])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C=C[N+](=O)[O-])s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1ccc(CCN)s1
Yield: 85 %

Procedure:
In close analogy to the procedure described above, 2-Methyl-5-(2-nitro-vinyl)-thiophene is reacted with lithium aluminium hydride to provide the title compound.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].C([O-])(O)=O.[Na+].[CH3:14][O:15][C:16](Cl)=[O:17].Cl>O1CCCC1.O>[CH3:14][O:15][C:16]([NH:1][C@@H:2]([CH:3]([CH3:5])[CH3:4])[C:6]([OH:8])=[O:7])=[O:17]
Reactant: COC(=O)Cl
Reactant: CC(C)[C@H](N)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)N[C@H](C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
L-Valine (S) (0.213 mol) was dissolved in anhydrous tetrahydrofuran (645 mL) with NaHCO3 (0.640 mol) in water (645 mL). Methylchloroformate (0.235 mol) was added and the reaction mixture was stirred at room temperature overnight. The mixture was acidified to pH 3 with 1N HCl. The aqueous layer was extracted with EtOAc. The organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give compound 1 as a white solid in 98% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 0.93 (d, J=7.00 Hz, 3H), 1.00 (d, J=7.00 Hz, 3H), 2.23 (m, 1H), 3.70 (s, 3H), 4.33 (m, 1H), 5.26 (brs, 1H), 8.50 (brs, 1H); and MS (ESI, EI+) m/z=176 (MH+).