Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:16]2[CH2:15][CH2:14][CH2:13][CH:12]([C:17]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2.N1C=CC=CC=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[N:19]1([C:17]([CH:12]2[C:11]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[N:4]([CH2:3][CH2:2][O:1][S:32]([CH3:31])(=[O:34])=[O:33])[C:16]=3[CH2:15][CH2:14][CH2:13]2)=[O:18])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(C1CCCc2c1c1ccccc1n2CCO)N1CCCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCn1c2c(c3ccccc31)C(C(=O)N1CCCCC1)CCC2
Temperature: 0 °C
Yield: 81.3 %

Procedure:
To a solution of [9-(2-hydroxy-ethyl)-2,3,4,9-tetrahydro-1H-carbazol-4-yl]-piperidin-1-yl-methanone (23) (260 mg, 0.8 mmol) in dichloromethane (15 mL) was added pyridine (633 mg, 8.0 mmol, 0.65 mL). The reaction was cooled to 0° C. and methanesulfonyl chloride (458 mg, 4.0 mmol, 0.31 mL) was added. The reaction was allowed to warm to room temperature overnight. The mixture was washed with 2 N HCl (2×50 mL) and water (2×50 mL), dried and concentrated in vacuo. The crude material was triturated with diethyl ether to afford 263 mg (82%) of methanesulfonic acid 2-[4-(piperidine-1-carbonyl)-1,2,3,4-tetrahydro-carbazol-9-yl]-ethyl ester as a white solid. The structure was confirmed by 13C NMR (75 MHz, CDCl3) δC 21.4, 21.8, 24.7, 25.9, 26.9, 27.4, 36.6, 36.8, 41.7, 43.3, 47.0, 67.9, 108.5, 109.5, 118.4, 119.7, 121.3, 126.9, 136.2, 172.7.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:16][C:17]2[CH:21]=[C:20]([CH:22]3[CH2:24][CH2:23]3)[NH:19][N:18]=2)=[N:4][C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[NH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:31])[CH3:30].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:29]([NH:28][CH2:27][CH2:26][NH:25][C:13]([C:11]1[S:12][C:8]([C:5]2[N:4]=[C:3]([NH:16][C:17]3[CH:21]=[C:20]([CH:22]4[CH2:23][CH2:24]4)[NH:19][N:18]=3)[C:2]([Br:1])=[CH:7][N:6]=2)=[CH:9][CH:10]=1)=[O:15])(=[O:31])[CH3:30]
Reactant: O=C(O)c1ccc(-c2ncc(Br)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Reactant: CC(=O)NCCN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)NCCNC(=O)c1ccc(-c2ncc(Br)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Temperature: 23 °C
Reaction time: 12 h
Yield: 68.1 %

Procedure:
A 100 mL round bottomed flask was charged with 5-(5-bromo-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophene-2-carboxylic acid (332.5 mg, 0.82 mmol, 1 eq), N-(2-aminoethyl)acetamide (125.3 mg, 1.23 mol, 1.5 eq), EDCI (313.0 mg, 1.6 mmol, 2 eq), HOBt (221.1 mg, 1.6 mmol, 2 eq) and DIPEA (635.4 mg, 4.9 mmol, 6 equiv) in DMF (5 mL). The mixture was stirred for 12 h at 23° C. and extracted with THF (3×70 mL). The organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (PE/EA/MeOH=1:1:0.05 as eluant) to give pale-yellow solid N-(2-acetamidoethyl)-5-(5-bromo-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophene-2-carboxamide (273.8 mg, 68.3%). LC-MS (m/z)=491.1 [M+H]+.
Reaction SMILES: [CH2:1]([C@H:8]([NH:24][C:25]([C:27]1[CH:28]=[C:29](Cl)[CH:30]=[C:31]2[C:36]=1[N:35]=[CH:34][N:33]([CH:37]([CH2:41][CH2:42][CH3:43])[CH2:38][CH2:39][CH3:40])[C:32]2=[O:44])=[O:26])[C@H:9]([OH:23])[CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].O1CCOCC1>[CH2:1]([C@H:8]([NH:24][C:25]([C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[N:35]=[CH:34][N:33]([CH:37]([CH2:41][CH2:42][CH3:43])[CH2:38][CH2:39][CH3:40])[C:32]2=[O:44])=[O:26])[C@H:9]([OH:23])[CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:21])([F:22])[F:20])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CCCC(CCC)n1cnc2c(C(=O)N[C@@H](Cc3ccccc3)[C@H](O)CNCc3cccc(C(F)(F)F)c3)cc(Cl)cc2c1=O
Agent: [Pd]
Solvent: C1COCCO1
Product: CCCC(CCC)n1cnc2c(C(=O)N[C@@H](Cc3ccccc3)[C@H](O)CNCc3cccc(C(F)(F)F)c3)cccc2c1=O
Yield: 100.2 %

Procedure:
195 mg of N-[(1S,2R)-1-benzyl-2-hydroxy-3-{[3-(trifluoromethyl)benzyl]-amino}propyl]-6-chloro-4-oxo-3-(1-propylbutyl)-3,4-dihydroquinazoline-8-carboxamide, 5 cm3 of dioxane and 30 mg of 10% (50% wet with water) palladium on carbon are stirred under 10 bar of hydrogen in an autoclave. Since the reaction does not develop, 30 mg of 10% dry palladium on carbon are added and the reaction mixture is stirred under 15 bar of hydrogen in an autoclave. The catalyst is filtered and the filtrate is concentrated under reduced pressure (5 kPa). 185 mg of N-[(1S,2R)-1-benzyl-2-hydroxy-3-{[3-(trifluoromethyl)benzyl]amino}propyl]-4-oxo-3-(1-propylbutyl)-3,4-dihydroquinazoline-8-carboxamide are obtained.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[NH:5][CH:4]=1)=[O:2].[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:7]=2)[C:3]([CH:1]=[O:2])=[CH:4]1)(=[O:18])[CH3:17]
Reactant: COC(=O)c1ccc2c(C=O)c[nH]c2c1
Reactant: CC(=O)OC(C)=O
Product: COC(=O)c1ccc2c(C=O)cn(C(C)=O)c2c1

Procedure:
A suspension of methyl 3-formylindole-6-carboxylate (1 g, 4.93 mmol) in acetic anhydride (10 ml) was refluxed for 2 h.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[O:15])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14]([CH:16]2[CH2:17][CH2:18][N:19]([C:30](=[O:37])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:20][CH2:21]2)=[O:15])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(Nc1ccccc1Oc1ccc(Cl)cc1)C1CCNCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1Oc1ccc(Cl)cc1)C1CCN(C(=O)c2ccccc2)CC1
Temperature: 25 °C
Yield: 83.6 %

Procedure:
To an ice cooled solution of piperidine-4-carboxylic acid [2-(4-chlorophenoxy)phenyl]amide (AMR01033, 73 mg, 0.22 mmol) in dry DCM (6 mL) were added pyridine (0.036 mL, 0.44 mmol) and benzoyl chloride (0.038 mL, 0.33 mmol). The reaction mixture was stirred at room temperature until TLC showed consumption of starting material (1 h), and quenched with saturated NaHCO3. The resulting solution was extracted with DCM (3×20 mL), and the combined organic layers were washed with water, 1M HCl (3×20 mL) and brine, dried (MgSO4), filtered and evaporated. Flash chromatography on silica gel of the crude product using hexane to EtOAc gradient as eluent gave 1-benzoylpiperidine-4-carboxylic acid [2-(4-chlorophenoxy)phenyl]amide (80 mg, 83%) as a white solid, mp 158-160° C. Rf: 0.48 (EtOAc) LC/MS (APCI) tr=1.05 min, m/z 437.33 (45), 435.38 (M++H, 100) HPLC tr=2.551 min (98.36%) 1H NMR (270 MHz, CDCl3) δ 1.82 (4H, m, 2CH2), 2.51 (1H, tt, CH), 2.98 (2H, n, CH2), 3.85 (1H, m, ½CH2), 4.71 (1H, m, ½CH2), 6.82 (1H, dd, J=8.2, 1.5 Hz, ArH), 6.93 (2H, AA′BB′, ArH), 7.02 (1H, td, ArH), 7.13 (1H, td, ArH), 7.31 (1H, AA′BB′, ArH), 7.39 (5H, s, ArH,), 7.70 (1H, br s, NH) and 8.39 (1H, dd, J=8.2, 1.5 Hz, ArH). Anal. Calcd. for C25H23ClN2O3: C, 69.04; H, 5.33; N, 6.44. Found: C, 68.9; H, 5.33; N, 6.37%.
Reaction SMILES: [CH3:1][S:2]([NH:5][NH2:6])(=[O:4])=[O:3].CCN(C(C)C)C(C)C.C[O:17][C:18](=O)[C:19]1[CH:24]=[C:23]([C:25]2[N:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)[C:22]([C:31]([F:34])([F:33])[F:32])=[CH:21][C:20]=1[NH:35][C:36](OC1C=CC(Cl)=CC=1)=[O:37]>O1CCOCC1>[CH3:30][N:26]1[CH:27]=[CH:28][CH:29]=[C:25]1[C:23]1[CH:24]=[C:19]2[C:20](=[CH:21][C:22]=1[C:31]([F:32])([F:33])[F:34])[NH:35][C:36](=[O:37])[N:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:18]2=[O:17]
Reactant: CS(=O)(=O)NN
Reactant: COC(=O)c1cc(-c2cccn2C)c(C(F)(F)F)cc1NC(=O)Oc1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cn1cccc1-c1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1C(F)(F)F
Temperature: 95 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
CH3SO2NHNH2 (25.5 mg, 1.5 equiv) and i-Pr2NEt (26.5 μL, 1 equiv) were added to a solution of 2-(4-chloro-phenoxycarbonylamino)-5-(1-methyl-1H-pyrrol-2-yl)-4-trifluoromethyl-benzoic acid methyl ester (70 mg, 0.155 mmol) in dioxane (2 mL). The mixture was stirred for 2 h (TLC control) at 95° C. CH3SO2NHNH2 (25.5 mg, 1.5 equiv) and i-Pr2NEt (26.5 μL, 1 equiv) were then added. The mixture was stirred for 48 h at 95° C. The mixture was evaporated to dryness. The crude product was purified by column chromatography (silica gel 60, EtOAc/hexanes 7/3) to give N-[6-(1-methyl-1H-pyrrol-2-yl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl]-methanesulfonamide (50 mg, 80%) as a yellow solid. ESI-MS: m/z 420 [M+NH4]+, rt: 4.83 min. 1H-NMR (DMSO-d6, 400 MHz) 7.91 (s, 2H), 7.57 (s, 1H), 7.54 (s, 1H), 3.88 (s, 3H), 3.14 (s, 3H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][NH:21][OH:22].C([O-])(=O)C.[Na+]>O1CCOCC1.O>[CH3:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][N:21]([OH:22])[C:1](=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Cc1cccc(Nc2ccccc2CNO)c1C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)N(O)Cc1ccccc1Nc1cccc(C)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
Acetyl chloride (0.53 g, 6.8 mmol) is added dropwise at 0° C. to a solution of 2-[(2,3-dimethylphenyl)amino]-N-hydroxybenzenemethanamine (1.64 g, 6.8 mmol) and sodium acetate (840 mg, 10 mmol) in 2:1 dioxane/water (100 ml). The reaction mixture is stirred at room temperature for 30 minutes. The product is extracted into ethyl acetate. The organic layer is washed with brine, dried over magnesium sulfate and evaporated to a residue which is recrystallized from cyclohexane to give pure N-[[2-[(2,3-dimethylphenyl)amino]phenyl]methyl]-N-hydroxyacetamide (1.02 g, 53%); mp 93°-98° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[F:11][C:12]([F:17])([F:16])[CH:13]([OH:15])[CH3:14].[H-].[Na+]>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:15][CH:13]([CH3:14])[C:12]([F:17])([F:16])[F:11])=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(Oc1ccc([N+](=O)[O-])cn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.4 %

Procedure:
To a solution of 2-chloro-5-nitro-pyridine (1.74 g) and 1,1,1-trifluoro-propan-2-ol (1.097 g) in DMF (15 ml) under an argon atmosphere was added under ice cooling NaH (0.528 g, 55% suspension in oil). The mixture was stirred for 3 h at RT then partitioned between diethyl ether and water, the layers were separated dried over Na2SO4 and the solvent was evaporated off to give (rac)-5-nitro-2-(2,2,2-trifluoro-1-methyl-ethoxy)-pyridine as brown oil (2.28 g) that was used in the next step without further purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:17])[C@H:5]([CH2:7][C:8]1[CH:13]=[C:12]([I:14])[C:11]([OH:15])=[C:10]([I:16])[CH:9]=1)[NH2:6].[Cl:18][C:19]1[CH:20]=[C:21]([NH:26][CH:27]([C:29](O)=[O:30])[CH3:28])[CH:22]=[CH:23][C:24]=1[Cl:25].N[C@H](C(O)=O)C>>[CH3:2][O:3][C:4](=[O:17])[C@H:5]([CH2:7][C:8]1[CH:9]=[C:10]([I:16])[C:11]([OH:15])=[C:12]([I:14])[CH:13]=1)[NH:6][C:29](=[O:30])[CH:27]([CH3:28])[NH:26][C:21]1[CH:22]=[CH:23][C:24]([Cl:25])=[C:19]([Cl:18])[CH:20]=1
Reactant: COC(=O)[C@@H](N)Cc1cc(I)c(O)c(I)c1
Reactant: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)O
Agent: C[C@H](N)C(=O)O
Agent: Cl
Product: COC(=O)[C@H](Cc1cc(I)c(O)c(I)c1)NC(=O)C(C)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following General Procedure D and using 3,5-diiodo-L-tyrosine methyl ester hydrochloride (Bachem) and N-(3,4-dichlorophenyl)-D,L-alanine (from Example A above), the title compound was prepared as a mixture of stereoisomers about alanine. The reaction was monitored by tic (Rf=0.29 in 10% MeOH/CH2Cl2) and purification was by flash chromatography (10% methanol/methylene chloride).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([N:13]=[N+]=[N-])[CH2:10][C@@H:9]1[CH2:16][OH:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([NH2:13])[CH2:10][C@@H:9]1[CH2:16][OH:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](N=[N+]=[N-])C[C@@H]1CO
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@H](N)C[C@@H]1CO
Yield: 98.4 %

Procedure:
Hydrogenate a mixture of (2R,4R)-4-azido-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (225 g, 0.93 mol) and 10% palladium on carbon (22.5 g, pre-wetted with toluene) in methanol (2.3 L) at 15 psi of hydrogen at room temperature for 16 h. Filter off the catalyst and concentrate the filtrate to obtain the title compound as an oil (198 g, 92%). 1H NMR (400 MHz, DMSO-d6) δ 1.38 (s, 9H), 1.58 (m, 1H), 2.16 (m, 1H), 2.95 (m, 1H), 3.20-3.58 (m, 6H), 3.61 (m, 1H), 3.65 (br s, 1H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][NH:8][C:9](=[O:11])[CH3:10].CC1C=CC=C(C)N=1.[Cl:20][C:21]1[CH:22]=[N+:23]([O-])[CH:24]=[C:25]([Cl:29])[C:26]=1[CH2:27][Cl:28].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Cl:20][C:21]1[C:22]([N:8]([CH3:7])[C:9](=[O:11])[CH3:10])=[N:23][CH:24]=[C:25]([Cl:29])[C:26]=1[CH2:27][Cl:28]
Reactant: [O-][n+]1cc(Cl)c(CCl)c(Cl)c1
Reactant: CNC(C)=O
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(=O)N(C)c1ncc(Cl)c(CCl)c1Cl
Reaction time: 0.33 h

Procedure:
Oxalyl dichloride (45 μL, 0.47 mmol) was added dropwise to a solution of N-methylacetamide (36 μL, 0.47 mmol) and 2,6-dimethyl-pyridine (55 μL, 0.47 mmol) in anhydrous DCM (10 mL) at 0° C. After stirring for 20 min, 3,5-dichloro-4-chloromethyl-pyridine 1-oxide (10 mg, 0.047 mmol) was added to it and stirring was continued overnight at 45° C. Saturated aqueous Na2CO3 solution (20 mL) and DCM (40 mL) were added to the reaction mixture. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography over silica gel (elution with EA/hexane 1:3) to give the title compound. MS (m/z): 267.4 [M+H+].
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].[CH2:9](O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1CCC(N=C=NC2CCCCC2)CC1>>[CH2:9]([CH:3]([CH2:2][C:1]([OH:8])=[O:7])[C:4]([OH:6])=[O:5])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)CCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: O=C(O)CC(Cc1ccccc1)C(=O)O

Procedure:
Succinic acid can be protected with benzyl alcohol in the presence of DCC to obtain mono benzyl succinic acid. The product can then be purified via silica gel chromatography. Mono benzyl succinic acid can then be activated with HOSU in the presence of DCC and then coupled to Tris to obtain benzyl-succinate. This compound can then be acylated with lauric acid in the presence of DCC to give a mixture of the title compound. The three compounds can then be separated by silica gel chromatography with elution by organic solvents.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[C:11]([CH:13]2[C:22]3[C:17](=[C:18]([OH:23])[CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1.Cl.Cl[CH2:36][CH2:37][N:38]([CH3:40])[CH3:39]>>[CH3:39][N:38]([CH3:40])[CH2:37][CH2:36][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:17]=1[CH2:16][CH2:15][CH2:14][CH:13]2[C:11]([N:10]([CH2:9][C:6]1[CH:7]=[CH:8][C:3]([N:2]([CH3:33])[CH3:1])=[CH:4][CH:5]=1)[C:24]1[CH:29]=[CH:28][C:27]([CH:30]([CH3:31])[CH3:32])=[CH:26][CH:25]=1)=[O:12]
Reactant: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3c(O)cccc32)cc1
Reactant: CN(C)CCCl
Agent: Cl
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3c(OCCN(C)C)cccc32)cc1
Yield: 70.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 106 using N-[(4-dimethylaminophenyl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.66 g) and 2-chloro-N,N-dimethylethylamine hydrochloride (0.32 g) as starting materials, 5-[2-(dimethylamino)ethoxy]-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.54 g) was obtained. This compound was dissolved in ethyl acetate, and oxalic acid was added. The precipitated solid was subjected to recrystallization from ethyl acetate to give 5-[2-(dimethylamino)ethoxy]-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide oxalate ¼ hydrate (93.8 mg).
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH3:10])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[CH2:11]([O:13][C:14]1[O:15][C:16](=[O:28])[C:17]2[CH:27]=[C:26]3[C:21]([CH2:22][CH2:23][CH2:24][CH2:25]3)=[CH:20][C:18]=2[N:19]=1)[CH3:12]>C1C=CC=CC=1>[C:5](/[C:4](=[C:16](\[C:17]1[C:18]([NH:19][C:14]([O:13][CH2:11][CH3:12])=[O:15])=[CH:20][C:21]2[CH2:22][CH2:23][CH2:24][CH2:25][C:26]=2[CH:27]=1)/[OH:28])/[C:3]([O:9][CH3:10])=[O:8])(=[O:6])[CH3:7]
Reactant: COC(=O)CC(C)=O
Reactant: CCOc1nc2cc3c(cc2c(=O)o1)CCCC3
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCOC(=O)Nc1cc2c(cc1/C(O)=C(\C(C)=O)C(=O)OC)CCCC2
Temperature: 23 °C
Reaction time: 1 h

Procedure:
To a dispersion of sodium hydride (95%) (0.80 g, 33 mmol, 2.1 equiv) in anhydrous benzene (100 mL) under nitrogen was added dropwise methyl acetoacetate (5.0 mL, 5.4 g, 46 mmol, 2.9 equiv) and the resulting mixture was stirred at 23° C. for 1 h. 2-ethoxy-6,7,8,9-tetrahydro-4H-naphtho[2,3-d][1,3]oxazin-4-one (1-3) (3.8 g, 16 mmol, 1 equiv) was added and the reaction mixture was stirred for 20 h. The excess sodium hydride was quenched with water and the organic layer was separated, extracted three times with water and the combined aqueous layers were made acidic with concentrated hydrochloric acid solution. The resulting precipitate was filtered and dried to yield methyl (2Z)-2-acetyl-3-{3-[(ethoxycarbonyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-3-hydroxyprop-2-enoate (1-4) as a yellow oil. LRMS m/z (M+H) 362.5 found, 362.2 required.
Reaction SMILES: [CH2:1]([S:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)[CH3:2].[CH3:11]I>C(#N)C>[CH2:1]([S:3][CH2:4][C:5]1[CH2:6][CH2:7][N:8]([CH3:11])[CH2:9][CH:10]=1)[CH3:2]
Reactant: CI
Reactant: CCSCc1ccncc1
Solvent: CC#N
Product: CCSCC1=CCN(C)CC1
Yield: 47.6 %

Procedure:
8.2 g (0.054 mol) of 4-[(ethylthio)methyl]pyridine are dissolved in 60 ml of acetonitrile and then 9.1 g of methyliodide are added. After 12 hours the reaction mixture is evaporated down in vacuo. The residue is reacted analogously to Example 1 b) with sodium borohydride in methanol and worked up. The crude product obtained is distilled (5.2 g; 56.3% of theory; b.p. 118°-120° C./20 mbar) and then chromatographed on neutral aluminium oxide using chloroform as eluant. 4.4 g of 4-[(ethylthio)methyl]-1-methyl-1,2,3,6-tetrahydropyridine are obtained, which is converted with one equivalent of maleic acid into the maleate (m.p. 102°-105° C., from ethyl acetate).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25]([O:27]C)=O)[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:13]=[N:14][CH:15]=[N:16][CH:17]=3)[NH:9]2)=[CH:5][CH:4]=1.[NH3:29]>CO.O1CCCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25]([NH2:29])=[O:27])[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:17]=[N:16][CH:15]=[N:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1
Reactant: N
Reactant: COC(=O)c1cccc(Cc2c(-c3cncnc3)[nH]c3cc(OC)ccc23)n1
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(Cc3cccc(C(N)=O)n3)c(-c3cncnc3)[nH]c2c1

Procedure:
A mixture of methyl 6-(6-methoxy-2-pyrimidin-5-yl-1H-indol-3-ylmethyl)pyridine-2-carboxylate (466 mg), a solution of ammonia in methanol (about 7 mol/L, 18.6 mL) and tetrahydrofuran (6.2 mL) was stirred at room temperature for 48 hours. The precipitate was collected by filtration, washed with methanol, and then dried under reduced pressure to obtain the title compound (370 mg). 1H-NMR (DMSO-d6) δ ppm: 3.79 (3H, s), 4.44 (2H, s), 6.70 (1H, dd, J=2.3, 8.5 Hz), 6.89 (1H, d, J=2.3 Hz), 7.34-7.41 (1H, m), 7.51 (1H, d, J=8.5 Hz), 7.63-7.77 (2H, m), 7.79-7.86 (2H, m), 9.13 (1H, s), 9.14 (2H, s), 11.45 (1H, s).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[NH:15]1[CH2:20][CH2:19][C:18]2([C:25]3=[CH:26][CH:27]=[CH:28][CH2:29][CH:24]3[CH2:23][CH2:22][O:21]2)[CH2:17][CH2:16]1.[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].CO>C(OCC)(=O)C>[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:15]3[CH2:20][CH2:19][C:18]4([C:25]5=[CH:26][CH:27]=[CH:28][CH2:29][CH:24]5[CH2:23][CH2:22][O:21]4)[CH2:17][CH2:16]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: C1=CCC2CCOC3(CCNCC3)C2=C1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC2(CC1)OCCC1CC=CC=C12

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 1,5-dihydrospiro[4H-2-benzopyran-1,4′-piperidine]. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 58% overall yield. FDMS m/e=392 (M+ of free base). α[D]589=−23.56 (c=0.51, methanol).
Reaction SMILES: [CH3:1][CH2:2][CH:3](P(OCC)(OCC)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:17][C:18]1[CH2:23][CH2:22][CH2:21][C:20]([CH3:25])([CH3:24])[C:19]=1/[CH:26]=[CH:27]/[C:28](/[CH3:37])=[CH:29]/[CH:30]=[CH:31]/[C:32](/[CH3:36])=[CH:33]/[CH:34]=O>>[CH3:36][C:32]([CH:31]=[CH:30][CH:29]=[C:28]([CH3:37])[CH:27]=[CH:26][C:19]1[C:20]([CH3:25])([CH3:24])[CH2:21][CH2:22][CH2:23][C:18]=1[CH3:17])=[CH:33][CH:34]=[C:3]([CH2:2][CH3:1])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=O)C(C)(C)CCC1
Reactant: CCOC(=O)C(CC)P(=O)(OCC)OCC
Product: CCOC(=O)C(=CC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C)CC

Procedure:
In analogy to the procedure given in Example 1: Triethyl 2-phosphonobutyrate was reacted with retinal to give ethyl 5,9-dimethyl-2-ethyl-11-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8,10-undecapentaenoate, which was converted by the procedure of Example 2 to 5,9-dimethyl-2-ethyl-11-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8,10-undecapentaenoic acid, m.p.=164°-165° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([NH:9][CH2:10][CH2:11][CH3:12])[N:3]=1.Cl.[CH3:14][NH:15][O:16][CH3:17].CCN(C(C)C)C(C)C>CCO>[NH2:1][C:2]1[N:7]=[C:6]([N:15]([CH3:14])[O:16][CH3:17])[N:5]=[C:4]([NH:9][CH2:10][CH2:11][CH3:12])[N:3]=1
Reactant: CCCNc1nc(N)nc(Cl)n1
Reactant: CNOC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCCNc1nc(N)nc(N(C)OC)n1
Temperature: 100 °C
Yield: 88.4 %

Procedure:
A mixture of 6-amino-2-chloro-4-n-propylamino-[1,3,5]triazine (XXXVIII) (5 g, 26.65 mmol), N,O-dimethylhydroxylamine hydrochloride (13 g, 133.24 mmol) and DIPEA (27.5 g, 213.2 mmol) in EtOH (100 mL) was heated at 100° C. for 16 h, after which time the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (400 mL), which was washed with water (200 mL) and then with a brine solution (200 mL) and finally dried over Na2SO4. The solvent was removed under reduced pressure to yield N-(6-amino-4-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXXIX) as a white solid (5 g, 89% yield). LCMS (ESI) m/z=213 (M+H)+.