Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3([C:16]([N:18]4[CH2:22][CH2:21][C@@:20]5([C:30]6[CH:29]=[CH:28][N:27]=[CH:26][C:25]=6[C:24](=[O:31])[O:23]5)[CH2:19]4)=[O:17])[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[C:5]2[CH:32]=[CH:33][CH:34]=[CH:35][C:4]=2[NH:3]1.[CH3:36]S(C)=O.C(=O)([O-])[O-].[K+].[K+].CI>>[CH3:36][N:3]1[C:4]2[CH:35]=[CH:34][CH:33]=[CH:32][C:5]=2[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3([C:16]([N:18]4[CH2:22][CH2:21][C@@:20]5([C:30]6[CH:29]=[CH:28][N:27]=[CH:26][C:25]=6[C:24](=[O:31])[O:23]5)[CH2:19]4)=[O:17])[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[C:2]1=[O:1]
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(-n5c(=O)[nH]c6ccccc65)cc4)CC3)C2)c2ccncc21
Reactant: CS(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: Cn1c(=O)n(-c2ccc(C3(C(=O)N4CC[C@@]5(C4)OC(=O)c4cnccc45)CC3)cc2)c2ccccc21
Temperature: 25 °C

Procedure:
To a solution of (1R)-1′-({1-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one (50 mg, 0.0001 mol) in dimethyl sulfoxide (1 mL, 0.01 mol) were added potassium carbonate (16.3 mg, 0.000118 mol) and methyl iodide (6.67 μL, 0.000107 mol), and the mixture was stirred at room temperature for. 2 hours. The crude product was purified by prep-HPLC. LC/MS: 480.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[CH2:18][CH:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:16][C:15](=O)[C:14]=3[CH:13]=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:27]([NH:30][NH2:31])([NH2:29])=[NH:28].[ClH:32].Cl.O>C(O)C>[ClH:32].[NH:30]([N:31]=[C:15]1[CH2:16][CH:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][C:19]2[N:11]([S:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH:12]=[CH:13][C:14]1=2)[C:27]([NH2:29])=[NH:28]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2CC(c2ccccc2)CC3=O)cc1
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2ccc3c2CC(c2ccccc2)CC3=NNC(=N)N)cc1
Yield: 87.8 %

Procedure:
A mixture of 1-(4-methylphenyl)sulfonyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (1.0 g), aminoguanidine hydrochloride (0.32 g), concentrated hydrochloric acid (0.14 ml), water (0.14 ml) and ethanol (50 ml) was refluxed for 20 minutes. Under reduced pressure, the solvent was evaporated, and the residue was washed with water, dried and recrystallized from ethanol to give 4-guanidinoimino-1-(4-methylphenyl)sulfonyl-6-phenyl-4,5,6,7-tetrahydroindole hydrochloride (Compound 19) (1.1 g) as colorless crystals.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH3:14][N:15]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20]3[CH2:26][CH2:25][C:24](=O)[C:21]=32)=[N:16]1>O1CCCC1.O>[CH3:14][N:15]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20]3[CH2:26][CH2:25][C:24](=[CH:5][C:3]#[N:4])[C:21]=32)=[N:16]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: Cn1cc2c3c(ccc2n1)CCC3=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc2c3c(ccc2n1)CCC3=CC#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a suspension of 60% sodium hydride (116 mg, 2.90 mmol) in tetrahydrofuran (8 mL) was added diethyl cyanomethylphosphonate (516 μL, 3.19 mmol), and the mixture was stirred at room temperature for 30 min. A solution of 2-methyl-6,7-dihydrocyclopenta[e]indazol-8(2H)-one (180 mg, 0.97 mmol) in tetrahydrofuran (2 mL) was added thereto, and the mixture was stirred at 50° C. for 30 min. The reaction solution was diluted with water, extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=35/65→70/30) to give the title compound (138 mg, yield 68%).
Reaction SMILES: C([O:3][P:4]([CH2:9][C:10]1[C:14]2[CH:15]=[C:16]([N:19]3[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]([CH3:30])[C:20]3=[O:31])[CH:17]=[CH:18][C:13]=2[S:12][N:11]=1)(=[O:8])[O:5]CC)C.Br[Si](C)(C)C>C(Cl)Cl.CO>[CH3:30][N:21]1[C:22]([C:26]([F:29])([F:28])[F:27])=[CH:23][C:24](=[O:25])[N:19]([C:16]2[CH:17]=[CH:18][C:13]3[S:12][N:11]=[C:10]([CH2:9][P:4](=[O:3])([OH:5])[OH:8])[C:14]=3[CH:15]=2)[C:20]1=[O:31]
Reactant: CCOP(=O)(Cc1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12)OCC
Agent: C[Si](C)(C)Br
Solvent: CO
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CP(=O)(O)O)c3c2)c1=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 73.5 %

Procedure:
A solution of diethyl{{5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazol-3-yl}methyl}phosphonate (1.00 g, 0.00210 mol) and bromotrimethylsilane (2.20 mL, 0.0168 mol) in methylene chloride (5.0 mL) is stirred at room temperature overnight and concentrated in vacuo to obtain a residue. The residue is diluted with methanol (10.0 mL), stirred at room temperature for 3.5 hours and concentrated in vacuo to obtain a tan solid. The solid is triturated in boiling methylene chloride, filtered and dried to give the title product as a beige solid (0.650 g, mp >230° C.).
Reaction SMILES: [CH:1]1([N:7]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][CH:18]=3)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:30][O:31][C:32](=[O:36])[CH2:33][CH2:34][NH2:35]>>[CH:1]1([N:7]([CH2:25][CH:26]2[CH2:27][CH2:28]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][NH:35][CH2:34][CH2:33][C:32]([O:31][CH3:30])=[O:36])=[CH:21][CH:22]=3)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CCN
Reactant: O=Cc1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1
Agent: Cl
Product: COC(=O)CCNCc1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1

Procedure:
Following the general method as outlined in Example 73, starting from 6-[cyclohexyl(cyclopropylmethyl)amino]-N-(4-formylphenyl)pyrimidine-4-carboxamide (Intermediate 24) and beta-alanine methyl ester hydrochloride (Fluka), the title compound was obtained as a white solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:21](=[O:37])[CH2:22][C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH:25]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:14]([C:12]1[C:11]([C:16]([F:17])([F:18])[F:19])=[CH:10][C:9]2[NH:20][C:21](=[O:37])[CH2:22][C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=4)[CH:25]=3)=[N:7][C:8]=2[CH:13]=1)[CH3:15]
Reactant: CCc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cccnc3)c1)=N2

Procedure:
The title compound was prepared from {5-ethyl-2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M191) (365 mg, 0.69 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (122 mg, 43%).
Reaction SMILES: [OH-].[K+].C[O:4][C:5](=[O:18])[C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH2:13][O:14]C(=O)C)[CH:7]=1>CO.O>[OH:14][CH2:13][C:8]1[CH:7]=[C:6]([CH:11]=[C:10]([CH3:12])[CH:9]=1)[C:5]([OH:18])=[O:4]
Reactant: COC(=O)c1cc(C)cc(COC(C)=O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(CO)cc(C(=O)O)c1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
In a 5 liter flask were dissolved 380 g (5.77 mole) of 85% KOH in 2.2 liter of methanol and warmed up to 60° C. The methyl-3-acetoxymethyl-5-methylbenzoate from the previous step was added and heated with stirring at 60° C. for 2.5 hrs. The reaction mixture was cooled down to room temperature and the solvent eliminated in the rotavap. The resulting oil was dissolved in 1.5 liter of water and then washed with ethyl ether (1×1 liter). The aqueous layer was made acidic with concentrated hydrochloric acid and the resulting acidic suspension was extracted with ethyl acetate (3×350 ml). The combined organic extracts were then washed with water (2×600 ml) and then brine (2×500 ml), dried over sodium sulfate and concentrated in the rotavap to give 287.6 g of 3-hydroxymethyl-5-methylbenzoic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:11])[C:7](=[CH:9][CH:10]=1)O)([O-:3])=[O:2].CC(C)[O-:14].[Ti+4:16].CC(C)[O-:19].CC(C)[O-].CC(C)[O-]>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:10]=[CH:9][CH:7]=[C:6]([O-:11])[C:5]=1[O-:14])([O-:3])=[O:2].[Ti+4:16].[N+:1]([C:4]1[CH:10]=[CH:9][CH:7]=[C:6]([O-:11])[C:5]=1[O-:19])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)c(O)c1
Reactant: CC(C)[O-]
Agent: [Ti+4]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccc([O-])c1[O-]
Temperature: 100 °C

Procedure:
A solution of 4-nitrocatechol (10 g, 64.5 mmol) and toluene (220 ml) was dehydrated by distilling 20 mL of the solution. Thereafter, 9.15 g (32.2 mmol) of titanium(IV) isopropoxide (TTIP) was added to the solution while stirring. The mixed solution was refluxed for 1 hour, and then, while the distillation temperature was 100° C. or higher, distilled until the amount of the solution became half. After the distillation, solid content of the product was isolated by suction filtering using a membrane suction filter. The residual solid content was heated to 100° C. under vacuum using a vacuum dryer so that remaining volatile components were completely removed. The solid content (4-nitrocatechol-titanium complex) was brown in color. The yield amount was 11.0 g (31.1 mmol), and the yield percentage was 97%. 3.54 g of 4-nitrocatechol-titanium complex was dissolved into 100 mL of 1:4 acetylacetone/toluene to produce a coating liquid.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O[N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][O:15][N:19]2[C:20](=[O:29])[C:21]3=[CH:28][CH:27]=[CH:26][CH:25]=[C:22]3[C:23]2=[O:24])=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(CO)cc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(CON2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
To a suspension of 4-octyloxybenzyl alcohol (25 g), N-hydroxyphthalimide (17.15 g) and triphenylphosphine (27.74 g) in tetrahydrofuran (250 ml) was added dropwise diethyl azodicarboxylate (18.4 g) under ice-cooling. The reaction mixture was stirred at room temperature for 2 hours, and evaporated in vacuo. The residue was purified by chromatography on silica gel to give N-(4-octyloxybenzyloxy)phthalimide (33.45 g) as crystals.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[NH:4][C:3]=1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.C(N(CC)CC)C.[C:26](=O)([O:32]C(C)(C)C)[O:27][C:28]([CH3:31])([CH3:30])[CH3:29]>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:28]([O:27][C:26]([N:4]1[C:5]2[C:10](=[CH:9][C:8]([C:11]#[N:12])=[CH:7][CH:6]=2)[C:2]([CH3:1])=[C:3]1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:32])([CH3:31])([CH3:30])[CH3:29]
Reactant: Cc1c(-c2cccnc2)[nH]c2ccc(C#N)cc12
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(-c2cccnc2)n(C(=O)OC(C)(C)C)c2ccc(C#N)cc12

Procedure:
To a solution of 3-methyl-2-pyridin-3-yl-1H-indole-5-carbonitrile (Example 6, 96 mg, 0.40 mmol) in DMF (2 mL) at room temperature is added triethylamine (30 mg, 0.30 mmol), di-tert-butyl carbonate (65 mg, 0.30 mmol) and 4-(N,N-dimethylamino)pyridine (2 mg, 0.020 mmol). The mixture is stirred under N2. The mixture is purified by Xbridge RP18 with a gradient of acetonitrile in 0.1% aqueous ammonium hydroxide to give 5-cyano-3-methyl-2-pyridin-3-yl-indole-1-carboxylic acid tert-butyl ester as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.30 (s, 9H), 2.16 (s, 3H), 7.47-7.55 (m, 1H), 7.65 (dd, J=8.7, 1.6 Hz, 1H), 7.76 (d, J=7.3 Hz, 1H), 7.90 (d, J=1.0 Hz, 1H), 8.35 (d, J=8.6 Hz, 1H), 8.63 (d, J=1.8 Hz, 1H), 8.69 (dd, J=5.1, 1.5 Hz, 1H). HRMS (ESI) m/z 334.1566 [(M+H)+ Calcd for C20H20N3O2: 334.1556].
Reaction SMILES: [CH3:1][C:2]([CH3:10])=[CH:3][CH2:4][CH2:5][C:6]([CH:8]=[CH2:9])=[CH2:7].[C:11]([O:17][CH:18]=[CH2:19])(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]>CO.O>[C:11]([O:17][CH:18]=[CH:19][CH2:7][CH:6]([CH:8]=[CH2:9])[CH2:5][CH2:4][CH:3]=[C:2]([CH3:10])[CH3:1])(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: C=CC(=C)CCC=C(C)C
Reactant: C=COC(=O)C(C)(C)C
Solvent: O
Solvent: CO
Product: C=CC(CC=COC(=O)C(C)(C)C)CCC=C(C)C
Temperature: 70 °C
Reaction time: 6 h

Procedure:
23.7 mg (0.055 mmol) of (N-2-aminomethyl-p-toluene sulfonamide) (η6-benzene) ruthenium (II) chloride obtained in the Reference Example 4 and 17.5 mg (0.068 mmol) of silver triflate were mixed in 2 ml of methanol, to which were added 2 ml (purity: 78%, 1.25 g, 9.2 mmol) of myrcene and 1.73 g (13 mmol) of vinyl pivalate. The mixture was stirred at 70° C. for 6 hours. The reaction mixture was diluted with water and the organic layer was analyzed by gas chromatography to confirm that the title compound (addition product) having a purity of 76% (regioisomer: 26%) was produced at a conversion rate of 17%.
Reaction SMILES: O.[NH2:2][NH2:3].C[O:5][C:6](=O)[CH2:7][CH:8]([C:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:27])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[C:13]([N+:28]([O-:30])=[O:29])[CH:12]=1)[CH3:9]>C(O)(=O)C>[CH3:9][CH:8]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:27])[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:13]([N+:28]([O-:30])=[O:29])[CH:12]=2)=[N:3][NH:2][C:6](=[O:5])[CH2:7]1
Reactant: NN
Reactant: COC(=O)CC(C)C(=O)c1ccc(NC(=O)c2ccc(OC)cc2)c([N+](=O)[O-])c1
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(C(=O)Nc2ccc(C3=NNC(=O)CC3C)cc2[N+](=O)[O-])cc1
Temperature: 0 °C

Procedure:
20 ml of 80% hydrazine hydrate were added dropwise to 150 ml of glacial acetic acid while stirring and ice cooling. After cooling, 10.7 gm of 3-[3-nitro-4-(4-methoxybenzoylamino)-benzoyl]-butyric acid methyl ester were added and the mixture was refluxed for 40 minutes. After cooling, 250 ml of ice water were added, and the precipitate formed was suction filtered and washed with ice water.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[CH3:20][C:21]1[C:22]([C:32](O)=[O:33])=[N:23][N:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:25]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:32]([C:22]1[C:21]([CH3:20])=[N:25][N:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:23]=1)=[O:33]
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Reactant: Cc1nn(-c2ccccc2)nc1C(=O)O
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1nn(-c2ccccc2)nc1C

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid. MS: 445.4 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:31]([O-])=O)=[CH:4][C:5]([O:29][CH3:30])=[C:6]([CH:28]=1)[C:7]([NH:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([N:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[NH:20][C:19]2=[O:27])[CH2:14][CH2:13]1)=[O:8].[H][H]>[Ni].C(O)(=O)C>[NH2:31][C:3]1[C:2]([Cl:1])=[CH:28][C:6]([C:7]([NH:9][CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][CH:15]([N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[NH:20][C:19]3=[O:27])[CH2:16][CH2:17]2)=[O:8])=[C:5]([O:29][CH3:30])[CH:4]=1
Reactant: COc1cc([N+](=O)[O-])c(Cl)cc1C(=O)NCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1
Reactant: [H][H]
Agent: [Ni]
Solvent: CC(=O)O
Product: COc1cc(N)c(Cl)cc1C(=O)NCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1

Procedure:
A mixture of 4.2 parts of 5-chloro-N-{2-[4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]ethyl}-2-methoxy-4-nitrobenzamide in 150 parts of acetic acid is hydrogenated at normal pressure and at room temperature with 1 part of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. Water is added to the residue and the whole is alkalized with a diluted sodium hydroxide solution. The precipitated product is filtered off and crystallized from methanol. The product is filtered off (the filtrate is set aside) and dried, yielding a first fraction of 0.8 parts of 4-amino-5-chloro-N-{2-[4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]ethyl}-2-methoxybenzamide; mp. 230.1° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][NH:9][CH2:10][CH2:11][OH:12]>>[CH3:8][N:9]([C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[CH2:10][CH2:11][OH:12]
Reactant: CNCCO
Reactant: Clc1ncccn1
Product: CN(CCO)c1ncccn1
Temperature: 120 °C
Yield: 88 %

Procedure:
A mixture of 2-chloropyrimidine (20.8 g) and 2-(methylamino)ethanol (180 ml) was heated at 120° C. for 15 hours and concentrated. The residue was dissolved in ethyl acetate, washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was distilled under reduced pressure to obtain 2-(methyl-2-pyrimidylamino)ethanol (24.6 g, yield 88%) as a colorless oil. b.p. 130-132° C./1-1.5 mmHg
Reaction SMILES: [Li+].[OH-].O.[CH3:4][N:5]([C@@H:13]([CH2:18][CH:19]=[CH2:20])[C:14]([O:16]C)=[O:15])[C:6](=[O:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>C1COCC1>[CH3:4][N:5]([C@@H:13]([CH2:18][CH:19]=[CH2:20])[C:14]([OH:16])=[O:15])[C:6](=[O:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: C=CC[C@@H](C(=O)OC)N(C)C(=O)CCCCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=CC[C@@H](C(=O)O)N(C)C(=O)CCCCC
Yield: 96 %

Procedure:
Step F (3): According to the general procedure outlined in Step A (3), a solution of LiOH/H2O (2M, 2.5 mL), was added to a mixture of (S)-methyl 2-(N-methylhexanamido)pent-4-enoate (254 mg, 1.05 mmol) in THF (2.5 mL) to afford 229 mg (96% yield) of (S)-2-(N-methylhexanamido)pent-4-enoic acid as a clear viscous oil. LC-MS (M+H)+=228.2; 1H NMR (500 MHz, CDCl3) δ ppm 0.82-0.93 (m, 3H) 1.23-1.36 (m, 4H) 1.55-1.70 (m, 2H) 2.26-2.38 (m, 2H) 2.47-2.59 (m, 1H) 2.71-2.80 (m, 1H) 2.94 (s, 3H) 4.99-5.19 (m, 3H) 5.61-5.75 (m, 1H) 5.91 (br s, 1H).
Reaction SMILES: [C:1](Cl)(=[O:17])[O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl.[CH3:20][C:21]1([CH3:30])[CH2:26][CH:25]([OH:27])[CH2:24][C:23]([CH3:29])([CH3:28])[NH:22]1.[OH-].[Na+]>ClCCl.O>[C:1](=[O:17])([O:27][CH:25]1[CH2:26][C:21]([CH3:30])([CH3:20])[NH:22][C:23]([CH3:29])([CH3:28])[CH2:24]1)[O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCOC(=O)Cl
Reactant: CC1(C)CC(O)CC(C)(C)N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCOC(=O)OC1CC(C)(C)NC(C)(C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
27.7 g (0.1 mol) of tetradecyl chlorocarbonate are added slowly to a solution of 19.4 g (0.1 mol) of 2,2,6,6-tetramethyl-4-piperidinol hydrochloride in 150 ml of dichloromethane, maintaining the temperature at between 0° C. and 5° C. After the end of the addition, the mixture is stirred for 2 hours at ambient temperature, and a solution of 8.8 g (0.22 mol) of NaOH in 50 ml of water is then added slowly, with cooling to -10° C.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[O:5][C:4]2[C:13]([CH2:21][CH2:22][CH3:23])=[C:14]3[C:19](=[CH:20][C:3]1=2)[CH2:18][CH2:17][CH2:16][CH2:15]3.[N+:24]([O-])([OH:26])=[O:25].O>S(=O)(=O)(O)O>[N+:24]([C:20]1[C:3]2[C:2](=[O:1])[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[O:5][C:4]=2[C:13]([CH2:21][CH2:22][CH3:23])=[C:14]2[C:19]=1[CH2:18][CH2:17][CH2:16][CH2:15]2)([O-:26])=[O:25]
Reactant: CCCc1c2c(cc3c(=O)cc(C(=O)OCC)oc13)CCCC2
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCc1c2c(c([N+](=O)[O-])c3c(=O)cc(C(=O)OCC)oc13)CCCC2
Temperature: 25 °C
Yield: 79 %

Procedure:
Ethyl 6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylate (9.4 g) was dissolved in concentrated sulphuric acid (100 ml) and cooled to room temperature, and fuming nitric acid (3 ml) was added dropwise, with stirring. The resulting mixture was stirred for a further 3 hours and then poured into water (2 l). The resulting yellow semi-solid was extracted into ether. The organic layer was washed with water, dried (sodium sulphate) and evaporated to give a yellow solid of moderately pure ethyl 6,7,8,9-tetrahydro-5-nitro-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylate (3.5 g; 79%). An analytically pure sample (5 g) was obtained on recrystallisation from cyclohexane, mp 140°-2°.
Reaction SMILES: Cl.[C:2]([CH2:5][N:6]1[CH2:11][CH2:10][C:9]2([CH:16]=[C:15]([C:17]3[CH:22]=[C:21](F)[C:20]([O:24]CC)=[C:19](F)[CH:18]=3)[C:14]3[CH:28]=[CH:29][CH:30]=[CH:31][C:13]=3[O:12]2)[CH2:8][CH2:7]1)([OH:4])=[O:3].C(=O)([O-])O.[Na+].[CH2:37](I)[CH3:38]>CN(C)C=O.C(OCC)(=O)C>[OH:24][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[C:14]3[CH:28]=[CH:29][CH:30]=[CH:31][C:13]=3[O:12][C:9]3([CH2:8][CH2:7][N:6]([CH2:5][C:2]([O:4][CH2:37][CH3:38])=[O:3])[CH2:11][CH2:10]3)[CH:16]=2)=[CH:18][CH:19]=1
Reactant: CCI
Reactant: CCOc1c(F)cc(C2=CC3(CCN(CC(=O)O)CC3)Oc3ccccc32)cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CN1CCC2(C=C(c3ccc(O)cc3)c3ccccc3O2)CC1
Temperature: 80 °C
Yield: 51.1 %

Procedure:
To a mixture of 1′-Carboxymethyl-4-(4-hydroxyphenyl)spiro[2H-1-benzopyran-2,4′-piperidine]-1′-acetate (432 mg, 1 mmol., prepared according to Example 42), sodium hydrogen carbonate (176 mg, 2.1 mmol) in dry N,N-dimethylformamide (25 cm3) was added ethyl iodide (0.088 cm3, 1.1 mmol) and the mixture was heated to 80° C. for 2 h. Upon cooling, it was diluted with ethyl acetate (100 cm3) and washed with water (5×100 cm3). The organic solution was then dried over sodium sulfate before the solvent was removed in vacuo. The crude material was then passed through a short pad of silica first with dichloromethane (which was discarded) and then with ethyl acetate. The solvent was removed to afford the desired product (194 mg, 51%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:16]1[CH:20]=[CH:19][CH:18]=[N:17]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:16]2[CH:20]=[CH:19][CH:18]=[N:17]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1cn[nH]c1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Product: CC(C)(C)OC(=O)N1CCC(Cn2cccn2)CC1

Procedure:
By a similar manner to Reference Example 29, 1-tert-butoxycarbonyl-piperidin-4-methanol (1.08 g, 5.0 mmol) was reacted with pyrazole (1.02 g, 1.5 mmol) to give the titled compound as pale yellow oily substance (980 mg, 74%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[C@H:7]([CH2:9][CH:10]([CH3:12])[CH3:11])[NH2:8])([CH3:4])([CH3:3])[CH3:2].[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH:19]=O>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:13])[CH:7]([N:8]=[CH:19][C:15]1[S:14][CH:18]=[CH:17][CH:16]=1)[CH2:9][CH:10]([CH3:11])[CH3:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Reactant: O=Cc1cccs1
Solvent: Cc1ccccc1
Product: CC(C)CC(N=Cc1cccs1)C(=O)OC(C)(C)C
Temperature: 90 °C

Procedure:
To a stirred solution of leucine t-butyl ester (10 g) in toluene (100 mL) is added thiophene-2-carboxaldehyde (5.0 mL) and the mixture is heated to 90° C. for 2 hours. The mixture was cooled, washed with water, dried over magnesium sulfate, filtered, and evaporated to an oil (14.5 g).