Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[CH3:29][C:30]1[S:31][C:32]([CH3:39])=[CH:33][C:34]=1[S:35](Cl)(=[O:37])=[O:36]>N.CO>[CH3:29][C:30]1[S:31][C:32]([CH3:39])=[CH:33][C:34]=1[S:35]([N:11]1[C:12]2[C:8](=[C:7]3[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]3=[CH:14][CH:13]=2)[CH:9]=[CH:10]1)(=[O:37])=[O:36]
Reactant: Cc1cc(S(=O)(=O)Cl)c(C)s1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc(S(=O)(=O)n2ccc3c4c(ccc32)OCCNC4)c(C)s1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 17.7 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. 2,5-Dimethylthiophene-3-sulfonyl chloride (21 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (3.2 mg). MS m/z 363 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][NH2:10])=[N:7][CH:8]=1.[CH:11](O)=[O:12].[OH-].[NH4+]>O>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][NH:10][CH:11]=[O:12])=[N:7][CH:8]=1
Reactant: O=CO
Reactant: NCc1ccc(Cl)cn1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: O=CNCc1ccc(Cl)cn1
Temperature: 0 °C

Procedure:
A solution of (5-chloropyridin-2-yl)methanamine hydrochloride (1.0 g, 5.31 mmol) in formic acid (5.09 g, 4.24 mL, 106 mmol) was refluxed at 110° C. After 20 h the reaction was cooled to 0° C. and 25% ammonium hydroxide in water was added until pH˜9 was reached. The mixture was diluted with water and then extracted into dichloromethane (3×). The organic layers were combined and dried (MgSO4), filtered and concentrated in vacuo. This was used directly in the next step without further purification. 1H NMR (CDCl3) δ: 8.53 (s, 1H), 8.35 (s, 1H), 7.69 (m, 1H), 7.65 (m, 1H), 4.64 (d, J=5.3 Hz, 2H), 4.0 (s, 1H).
Reaction SMILES: [O-2].[La+3].[O-2].[O-2].[La+3].[CH3:6][C:7](=[CH:9][CH2:10][CH2:11][C:12](=[CH:14][CH:15]=O)[CH3:13])[CH3:8].[CH3:17][C:18]([CH3:20])=[O:19]>>[CH3:8][C:7]([CH3:6])=[CH:9][CH2:10][CH2:11]/[C:12](/[CH3:13])=[CH:14]/[CH:15]=[CH:17]/[C:18]([CH3:20])=[O:19]
Reactant: CC(C)=CCCC(C)=CC=O
Reactant: CC(C)=O
Agent: [La+3]
Agent: [O-2]
Product: CC(=O)/C=C/C=C(\C)CCC=C(C)C

Procedure:
The following examples demonstrate the catalytic effectiveness of unsupported catalysts of pure lanthanum oxide for the aldol reaction of citral and acetone to give pseudoionone.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:4][C:3]=1[N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].[O:30]=[C:31]1[NH:35][C:34](=[O:36])[CH:33]([CH2:37][C:38]2[CH:48]=[CH:47][C:41]([O:42][CH2:43][C:44](O)=[O:45])=[CH:40][CH:39]=2)[S:32]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:30]=[C:31]1[NH:35][C:34](=[O:36])[CH:33]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:42][CH2:43][C:44]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:4][C:3]=3[N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:45])=[CH:47][CH:48]=2)[S:32]1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2-c2ccccc2)ccc1N
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2-c2ccccc2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 87 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(2-phenylphenoxy)phenyl]-N-methylcarbamate (1.60 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (1.26 g), diethyl cyanophosphonate (0.73 g), triethylamine (0.45 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified to give the desired product (2.33 g).
Reaction SMILES: Cl.C(OCC)(=O)C.[Cl:8]CCl.C([N-:18]CCC)(OC(C)(C)C)=O.[CH:22]1[CH:23]=[CH:24][C:25]([NH:32][C:33]2[C:34]([Cl:40])=[CH:35][CH:36]=[CH:37][C:38]=2[Cl:39])=[C:26]([CH2:28][C:29]([OH:31])=[O:30])[CH:27]=1>C(OCC)C>[NH2:32][C:33]([NH2:18])([CH3:34])[CH3:38].[CH:22]1[CH:23]=[CH:24][C:25]([NH:32][C:33]2[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=2[Cl:40])=[C:26]([CH2:28][C:29]([OH:31])=[O:30])[CH:27]=1.[ClH:8]
Reactant: CCC[N-]C(=O)OC(C)(C)C
Reactant: ClCCl
Agent: Cl
Agent: O=C(O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)(N)N
Reaction time: 2 h

Procedure:
Under ice-cooling, 20 mL of 4 M hydrochloric acid/ethyl acetate was added to 1 mL dichloromethane solution of 825.0 mg (1.82 mmol) of the Boc-propylamide-diclofenac obtained above, followed by stirring for 2 hours. Diethyl ether was added thereto for precipitation, and the precipitate was dried under reduced pressure to give 714.5 mg (101%) of the titled compound. The structure was identified by 1H-NMR.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]([O:21]C)=[O:20])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:18])[N:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.[OH-].[Na+].Cl>CO.O>[NH2:1][C:2]1[C:3]([C:19]([OH:21])=[O:20])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:18])[N:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=2)=[CH:6][N:7]=1
Reactant: COC(=O)c1nc(-c2ccc(C(=O)N(C)C)cc2)cnc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C)C(=O)c1ccc(-c2cnc(N)c(C(=O)O)n2)cc1
Temperature: 60 °C
Yield: 91 %

Procedure:
To a solution of methyl 3-amino-6-[4-(dimethylcarbamoyl)phenyl]pyrazine-2-carboxylate (390 mg, 1.299 mmol) in MeOH (2.127 mL) was added a solution of NaOH (649.5 μL of 2 M, 1.299 mmol) in H2O (2.127 mL). The resulting solution was heated to 60° C. for 2 hours and then allowed to cool and neutralised with HCl. The resultant precipitate was collected and washed with ether and dried (340 mg, 91% Yield). MS (ES+) 287.08
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=3)[C:20]([NH:22][NH2:23])=[O:21])[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:27]=1.[CH:28]([N:31]=[C:32]=O)([CH3:30])[CH3:29].C(=O)(O)[O-].[Na+].C(Cl)(Cl)Cl>ClCCl>[CH:28]([NH:31][C:32]1[O:21][C:20]([C:19]2[CH:18]=[C:17]([N:14]3[CH2:13][C@H:12]4[N:8]([CH2:9][CH2:10][CH2:11]4)[C:7]4[N:27]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=4[C:15]3=[O:16])[CH:26]=[CH:25][CH:24]=2)=[N:22][N:23]=1)([CH3:30])[CH3:29]
Reactant: CC(C)N=C=O
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C(=O)NN)c1)C2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nnc(NC(C)C)o3)c1)C2=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 21 %

Procedure:
(S)-3-(9-Methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)benzoic hydrazide (300 mg, 0.780 mmol) obtained in Step 2 of Example 56 was dissolved in dichloromethane (16 mL), and the mixture was stirred at room temperature for 14 hours after adding isopropyl isocyanate (0.092 mL, 0.936 mmol). Thereafter, a saturated aqueous sodium bicarbonate solution and chloroform were added to the mixture to separate the organic layer. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Using the resulting residue, (S)-5-[3-(5-isopropylamino-1,3,4-oxadiazol-2-yl)phenyl]-9-methylthio-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (74.0 mg, 21%) was obtained in the same manner as in Step 3 of Example 52.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18](F)=[C:17]([F:23])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2].[CH3:25][CH:26]1[CH2:31][NH:30][CH2:29][CH2:28][NH:27]1.O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:30]4[CH2:29][CH2:28][NH:27][CH:26]([CH3:25])[CH2:31]4)=[C:17]([F:23])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2]
Reactant: CC1CNCCN1
Reactant: CCOC(=O)c1cn(C)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1cn(C)c2nc3c(F)c(N4CCNC(C)C4)c(F)cc3cc2c1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 64.6 %

Procedure:
A suspension of 2 g of 3-ethoxycarbonyl-7,8,9-trifluoro-1-methyl-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine in 30 cm3 of dimethyl sulphoxide and 5 g of 2-methylpiperazine is heated at a temperature close to 100° C., with stirring, for 2 hours. The solution obtained is poured, at this temperature, with stirring, into a mixture of 150 cm3 of water and 50 g of ice. 5 g of potassium carbonate are added at about 20° C. and the mixture is extracted with 3 times 50 cm3 of trichloromethane. The combined organic extracts are washed with twice 50 cm: of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 kPa) at about 50° C. The residue obtained is recrystallized from 30 cm3 of ethanol. 1.6 g of (RS)-3-ethoxycarbonyl-7,9-difluoro-1-methyl-8-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[ b][1,8]naphthyridine are obtained in the form of a yellow solid melting at 240° C.
Reaction SMILES: [CH2:1]([CH:3]([CH2:9][CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.Br[CH2:32][C:33]#[N:34]>C1COCC1>[C:33]([CH2:32][C:3]([CH2:9][CH3:10])([CH2:1][CH3:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:34]
Reactant: CCOC(=O)C(CC)CC
Reactant: N#CCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(CC)(CC)CC#N
Temperature: -78 °C
Reaction time: 1 h
Yield: 101 %

Procedure:
A solution of ethyl 2-ethylbutyrate (21.60 g, 150 mmol) in THF (25 mL) was added dropwise to a solution of lithium diisopropylamide prepared by treating diisopropylamine (16.67 g, 165 mmol) in dry THF (150 mL) with butyllithium in hexanes (2.5M, 66 mL, 165 mmol) at -78° C. for 1 h in a nitrogen atmosphere. The resulting mixture was stirred at -78° C. for 1 h, then a solution of bromoacetonitrile (21.60 g, 180 mmol) in THF (50 mL) was introduced slowly over a period of 30 minutes (the reaction mixture starts getting darker as the addition progresses). The resulting dark mixture was stirred overnight (ca. 16 h) and allowed to warm from -78° C. to room temperature. The reaction was quenched by addition of HCl (1 N, 250 mL) at 0° C. The layers were separated, and the aqueous phase was further extracted with ether (3×100 mL). The combined organic extract was washed sequentially with 75 mL portions of saturated NaHCO3, water (several times), and brine, and dried over MgSO4. The solvent was removed in vacuo to give 27.77 g of dark colored liquid. After two vacuum distillations, the nitrile (12.35 g, 45%) was obtained as a colorless liquid: bp 84-85° C. (1.3 mmHg). Analytical sample was prepared by column chromatography over silica gel (hexanes-EtOAc, 19:1) followed by bulb-to-bulb distillation (pot temp. 80° C. (1 mmHg)).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]([C:13]3[C:14]([F:27])=[C:15]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[CH:16]=[CH:17][C:18]=3[F:19])=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:27][C:14]1[C:13]([C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:30]4[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=4)[CH:3]=3)[NH:8][CH:9]=2)=[O:12])=[C:18]([F:19])[CH:17]=[CH:16][C:15]=1[NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Br)cc23)c1F
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4cccnc4)cc23)c1F
Temperature: 160 °C

Procedure:
To propane-1-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-0773, prepared as described in Example 1, 65.0 mg, 0.14 mmol) in acetonitrile (4.0 mL) was added pyridine-3-boronic acid (609, 25.0 mg, 0.20 mmol), tetrakis(triphenylphosphine)palladium(0) (11 mg, 1.0% mmol) and aqueous potassium carbonate (1.0 M, 2.0 mL). The reaction was heated to 160° C. for 10 minutes in a CEM Discover microwave instrument. The reaction was poured into water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtrated and concentrated. The desired compound was isolated by silica gel column chromatography (methylene chloride/methanol 5%) to give a white solid (P-0088, 30 mg, 46.9%). MS (ESI) [M+H+]+=457.2.
Reaction SMILES: [CH:1]1([CH:7]([NH:18][C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=2)[C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=2)[C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(NC(c2sc3cccnc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)sc2cccnc12
Reaction time: 8 h
Yield: 63.6 %

Procedure:
To a mixture of methyl 4-{[cyclohexyl(3-methylthieno[3,2-b]pyridin-2-yl)methyl]amino}benzoate (1.31 g) synthesized above, tetrahydrofuran (10 mL) and ethanol (10 mL) was added 1N aqueous sodium hydroxide solution (10 mL), and the mixture was stirred overnight with heating under reflux. 1N Aqueous sodium hydroxide solution (5 mL) was additionally added, and the mixture was further stirred with heating under reflux for 7 hr, and concentrated under reduced pressure. The residue was dissolved in water (20 mL), and 1N hydrochloric acid (15 mL) was added at 0° C. The resulting precipitate was collected by filtration, and the obtained brown solid was dissolved in ethyl acetate. The solution was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with diisopropyl ether to give the title object compound (804 mg, 64%) as a brown solid.
Reaction SMILES: [C:1]([C:5]1[CH:26]=[CH:25][C:8]([C:9]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:30]>CN(C=O)C.CCOC(C)=O>[C:1]([C:5]1[CH:26]=[CH:25][C:8]([C:9]([N:11]([C@@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)[CH3:30])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)c2ccc(C(C)(C)C)cc2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C(=O)c1ccc(C(C)(C)C)cc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (R)-tert-butyl 3-aminopiperidine-1-carboxylate (8) (6.27 g, 33.5 mmol) in DCM (100 mL) was added DIEA (8.75 mL, 50.3 mmol) and then 4-tert-butylbenzoyl chloride (8.0 mL, 43.6 mmol) in drop-wise manner. The mixture was stirred for 3 h at RT, diluted with DCM, washed with 1N NaOH, dried, and concentrated. The residue was subjected to flash column chromatography with 0 to 10% EtOAc in DCM to give (R)-tert-butyl 3-(4-tert-butylbenzamido)piperidine-1-carboxylate (11.0 g, 91%). To a solution of (R)-tert-butyl 3-(4-tert-butylbenzamido)piperidine-1-carboxylate (850 mg, 2.36 mmol) in DMF (10 mL) was added NaH (60% in mineral oil, 190 mg, 4.72 mmol). The mixture was stirred at RT for 10 min and then iodomethane (0.44 mL, 7.08 mmol) was added. The mixture was stirred at RT for 1 h, and diluted with 150 mL EtOAc. The mixture was washed with water ×2, dried, and concentrated. The residue was subjected to flash column with 0 to 3% MeOH in DCM to afford (R)-tert-butyl 3-(4-tert-butyl-N-methylbenzamido)piperidine-1-carboxylate (9) in quantitative yield. It was treated with 15 mL 4N HCl in dioxane at RT for 1 h. The mixture was concentrated in vacuo to dryness to afford (R)-4-tert-butyl-N-methyl-N-(piperidin-3-yl)benzamide (10) HCl salt in quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[CH3:15][O-:16].[Na+].O>CO>[Cl:1][C:2]1[N:11]=[C:10]([O:16][CH3:15])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: COc1ccc2nc(Cl)nc(Cl)c2c1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc2nc(Cl)nc(OC)c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 61.8 %

Procedure:
A solution of 2,4-dichloro-6-methoxyquinazoline (0.33 g) in methanol (5 mL) was added sodium methoxide (0.086 g), and the mixture was stirred at room temperature for 6 h. Water was added to the reaction mixture, and the aqueous layer was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel, chloroform/methanol=50:1) to obtain 2-chloro-4,6-dimethoxyquinazoline (0.20 g).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4]O.[CH2:6]([NH:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH3:9].CS(C)=O>O>[CH2:6]([N:10]([CH2:4][CH2:3][CH2:2][Cl:1])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH3:9]
Reactant: OCCCCl
Reactant: CCCCNCCCC
Solvent: O
Solvent: CS(C)=O
Product: CCCCN(CCCC)CCCCl
Reaction time: 8 h
Yield: 58 %

Procedure:
A mixture of 9.5 g of 3-chloropropanol, 37 ml of dibutylamine and 50 ml of dimethylsulfoxide was stirred at 70°-80° C. for 8 hours. After cooling, water was added to the mixture and the mixture was extracted with ethyl acetate. The extract was washed and dried, and the solvent was removed from the mixture under reduced pressure. The residue was dissolved in 50 ml of chloroform, and under ice-cooling, 8 ml of thionyl chloride was added dropwise to the solution. After stirring at 50° C. for 3 hours, the solvent was removed from the reaction mixture under reduced pressure. Water was added to the residue and the mixture was washed with diethyl ether. The mixture was made alkaline with potassium carbonate and extracted with ethyl acetate. The extract was washed and dried, and the solvent was removed from the extract under reduced pressure. The residue was purified by silica gel column chromatography (solvent; chloroform:ethanol=20:1) to give 12 g of N,N-dibutyl-3-chloropropylamine (yield: 58%, oily product).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.[CH2:12](Br)[CH:13]=[CH2:14]>C(=O)([O-])[O-].[K+].[K+].CC(C)=O>[CH2:14]([O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:7]=1[O:8][CH3:9])[CH:2]=[O:1])[CH:13]=[CH2:12]
Reactant: C=CCBr
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(C=O)ccc1OC
Yield: 88.5 %

Procedure:
Isovanillin (76 g) was dissolved in a stirred mixture of potassium carbonate (104 g) and acetone (450 mls) followed by the dropwise addittion of allyl bromide (67 g) over ca. 20 mins. The mixture was refluxed for 5 hours, cooled and filtered. The solvent was removed from the filtrate under reduced pressure and the residue was distilled under vacuum to yield 3-allyloxy-4-methoxybenzaldehyde (85 g), b.p. 137°-150° C. at 1.5 mbar.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[N+:25]([C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1)([O-:27])=[O:26]>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:32][C:31]3[CH:34]=[CH:35][C:28]([N+:25]([O-:27])=[O:26])=[CH:29][CH:30]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Product: O=[N+]([O-])c1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)cc1
Yield: 1.2 %

Procedure:
The title compound (0.004 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C, 0.3 g) using 4-nitrobenzyl bromide (0.3 g) in place of benzyl chloride. MS (ESI): exact mass calculated for C20H19ClN4O2, 382.12; found, m/z 383.1 [M+H]+. 1H NMR (400 MHz, CD3OD): 8.23-8.19 (m, 2H), 7.51-7.47 (m, 2H), 7.45-7.47 (m, 2H), 7.32 (d, J=8.6 Hz, 2H), 5.52 (s, 2H), 2.98-2.95 (m, 4H), 2.89-2.85 (m, 2H), 2.83-2.79 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]#[C:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:18]=[C:17]([OH:30])[CH:16]=2)=[CH:9][C:8]=1[CH3:31])[CH3:2].[F:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40]OC)=[CH:36][CH:35]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]#[C:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:18]=[C:17]([O:30][CH2:40][C:37]3[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=3)[CH:16]=2)=[CH:9][C:8]=1[CH3:31])[CH3:2]
Reactant: COCc1ccc(F)cc1
Reactant: CCOC(=O)COc1ccc(SCc2cc(O)cc(C#CCN3CCOCC3)c2)cc1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(SCc2cc(C#CCN3CCOCC3)cc(OCc3ccc(F)cc3)c2)cc1C
Reaction time: 16 h

Procedure:
{4-[3-Hydroxy-5-(3-morpholin-4-yl-prop-1-ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (250 mg; 0.55 mmol), 1-fluoro-4-methoxymethyl-benzene (103.8 mg; 0.82 mmol), tributylphosphine (0.33 mg; 1.65 mmol) and 1,1′-(azodicarbonyl)dipiperidine (0.414 g; 1.65 mmol) were dissolved in THF (15 mL) in a dried reaction flask under an atmosphere of nitrogen. The reaction mixture was stirred for 16 h and purified by prep. HPLC (method A). Yield: 160 mg. HPLC-MS: m/z: 564.1 (M+H); Rt: 1.99 min.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][C@H:21]([CH3:25])[NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:26][O:27][CH2:28][CH2:29]Br.[H-].[Na+]>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][C@H:21]([CH3:25])[N:22]([CH2:29][CH2:28][O:27][CH3:26])[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: COCCBr
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3C[C@H](C)NC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: COCCN1C(=O)c2cc3cc(OC4CCN(C(C)C)CC4)ccc3n2C[C@@H]1C
Yield: 30 %

Procedure:
The title compound was synthesized in analogy to example 17, from (S)-8-(1-isopropyl-piperidin-4-yloxy)-3-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 13), 2-bromoethyl methyl ether and sodium hydride, to give the desired product as a colorless oil (30%).