Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:16]([OH:18])=O)[CH2:10][C:11]1[N:15]=[CH:14][NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:19]([O:21][C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23])[CH3:20].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C1COCC1.C(OCC)(=O)C>[CH2:19]([O:21][C:22]([N:24]1[CH2:25][CH2:26][N:27]([C:16]([CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:10][C:11]2[N:15]=[CH:14][NH:13][CH:12]=2)=[O:18])[CH2:28][CH2:29]1)=[O:23])[CH3:20]
Reactant: CCOC(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(C(=O)C(Cc2c[nH]cn2)NC(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
To a solution of N-t-butoxycarbonylhistidine (2 g, 7.05 mmol) in THF (30 mL) was added 1-ethoxycarbonylpiperazine (1.36 mL, 1.3 eq.), EDCI (1.65 g, 1.2 eq. ), HOBt (1.2 g, 1.1 eq.) and the reaction mixture was stirred overnight. The reaction mixture was evaporated in vacuo to afford a crude product, which was dissolved in ethyl acetate, washed with saturated NaHCO3, 1M NaHSO4 and brine. The organic layer was evaporated. Flash column chromatography with 2%–6% MeOH in CH2Cl2 afforded 4-ethoxycarbonyl-1-(1-(t-butoxycarbonyl)amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine (820 mg). 4-Ethoxycarbonyl-1-(1-(t-butoxycarbonyl)amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine (200 mg, 0.5 mmol) was treated with trifluoroacetic acid/methylene chloride (1:1, 2.0 mL) with stirring at ambient temperture for 1 hour. Evaporation gave 4-ethoxycarbonyl-1-(1-amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine, which was treated with methylene chloride and triethylamine (0.5 mL), and the solvents evaporated to again afford 4-ethoxycarbonyl-1-(1-amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine. To a solution of 2-carboxy-4-methoxyquinoline (124 mg, 0.61 mmol) in THF (4 mL) was added a mixture of 4-ethoxycarbonyl-1-(1-amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine, THF (2 mL), and triethylamine (0.1 mL), followed by addition of EDCl (136 mg, 1.4 eq.), HOBt (98 mg, 1.4 eq.). The resulting mixture was stirred overnight. The crude product (245 mg, foam) was isolated from the reaction mixture by the same methods employed above. Flash column chromatography with 25%–6% MeOH in methylene chloride afforded 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-2-(imidazol-4-yl)ethyl]aminocarbonyl-4-methoxyquinoline; NMR (CDCl3) 1.25 (t, 3), 3.10–3.30 (m, 2), 3.20–3.65 (m, 9), 4.10 (m, 5), 5.40 (m, 1), 6.90 (s, 1), 7.55–7.60 (m, 3), 7.70 (t, 1), 8.02 (d, 1), 8.20 (d, 1), 9.0 (d, 1) ppm.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11]S)=[CH:2]1.[C:13]([NH:16][CH2:17][C:18](=[O:20])[CH3:19])(=[O:15])[CH3:14]>C1C=CC=CC=1>[C:13]([NH:16][CH2:17][C:18]1([CH3:19])[C:2]2[NH:1][C:9]3[C:4]([C:3]=2[CH2:10][CH2:11][O:20]1)=[CH:5][CH:6]=[CH:7][CH:8]=3)(=[O:15])[CH3:14]
Reactant: SCCc1c[nH]c2ccccc12
Reactant: CC(=O)CNC(C)=O
Solvent: c1ccccc1
Product: CC(=O)NCC1(C)OCCc2c1[nH]c1ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tryptophol (3.86 g; II, R2, R3, R4, R5, R6 = H and X1 =OH) and acetamidoacetone (3.0 g), see R. H. Wileg and O. H. Borum, J. Amer. Chem. Soc., 70, 2005 (1948), in 300 ml of dry benzene is stirred and heated to reflux. Water is collected in a Dean-Stark trap. After removal of the water five drops of boron trifluoride-etherate is added and the mixture refluxed 30 min. using the water-separator again. After stirring at room temperature overnight, the reaction mixture is evaporated to dryness. The solid residue is dissolved in chloroform and washed successively with 10% aqueous sodium bicarbonate, water, and brine. The chloroform solution is dried over magnesium sulfate, filtered, and evaporated. The residue is crystallized from benzene to yield 1-(acetamidomethyl)-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole, m.p. 100° - 102° C. This product is dried under reduced pressure at 27° C. Spectroscopic and analytical data show that the compound is solvated with one mole of benzene which can be removed completely only be melting. Rf values of the amide and tryptophol are equal.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:24][CH:23]2[CH:21]([CH:22]2[C:25]2[NH:29][N:28]=[C:27]([C:30]3[CH:31]=[C:32]([O:37][C:38]([F:41])([F:40])[F:39])[C:33]([NH2:36])=[N:34][CH:35]=3)[CH:26]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:49][CH:50]1[CH2:52][CH2:51]1>CN(C)C=O>[Si:1]([O:18][CH:19]1[CH2:24][CH:23]2[CH:21]([CH:22]2[C:25]2[N:29]([CH2:49][CH:50]3[CH2:52][CH2:51]3)[N:28]=[C:27]([C:30]3[CH:31]=[C:32]([O:37][C:38]([F:41])([F:39])[F:40])[C:33]([NH2:36])=[N:34][CH:35]=3)[CH:26]=2)[CH2:20]1)([C:14]([CH3:16])([CH3:15])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](OC1CC2C(C1)C2c1cc(-c2cnc(N)c(OC(F)(F)F)c2)n[nH]1)(c1ccccc1)c1ccccc1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC1CC2C(C1)C2c1cc(-c2cnc(N)c(OC(F)(F)F)c2)nn1CC1CC1)(c1ccccc1)c1ccccc1
Reaction time: 16 h
Yield: 135.5 %

Procedure:
To a round-bottomed flask charged with 5-(5-(3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexan-6-yl)-1H-pyrazol-3-yl)-3-(trifluoromethoxy)pyridin-2-amine (0.40 g, 0.35 mmol) and cesium carbonate (0.68 g, 2.1 mmol) in N,N-dimethylformamide (4 mL) was added bromomethylcyclopropane (0.28 mg, 2.1 mmol) at 20° C. After 16 h, the reaction mixture was partitioned between ethyl acetate (20 mL) and water (10 mL). The aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organics were washed with saturated aqueous sodium chloride solution (2×10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (30% ethyl acetate in petroleum ether) afforded product as an orange oil (0.30 g, 69% yield). LCMS (ESI) [MH]+=633.1.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)[C:3]=1[C:18]([OH:20])=O.Cl.C(N=C=NCCCN(C)C)C.[Cl:33][C:34]1[CH:35]=[C:36]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:37]=[CH:38][C:39]=1[Cl:40]>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:15])([F:16])[F:17])[CH:8]=2)[C:3]=1[C:18]([N:44]1[CH2:43][CH2:42][N:41]([C:36]2[CH:37]=[CH:38][C:39]([Cl:40])=[C:34]([Cl:33])[CH:35]=2)[CH2:46][CH2:45]1)=[O:20]
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: Nc1onc(-c2cccc(OC(F)(F)F)c2)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Nc1onc(-c2cccc(OC(F)(F)F)c2)c1C(=O)N1CCN(c2ccc(Cl)c(Cl)c2)CC1
Yield: 71.2 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(3-(trifluoromethoxy)phenyl)isoxazol-4-carboxylic acid (530 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(3,4-dichlorophenyl)piperazine (425 mg, 1.84 mmol), a white solid required compound (652 mg, 1.31 mmol, 71%) was obtained.
Reaction SMILES: [CH2:1]([C:3]1[S:24][C:6]2=[N:7][C:8]([CH3:23])=[C:9]([CH2:18][C:19]([O:21]C)=[O:20])[C:10]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)=[C:5]2[C:4]=1[CH3:25])[CH3:2].[O-2].[Li+].[Li+].Cl>O1CCOCC1.O>[CH2:1]([C:3]1[S:24][C:6]2=[N:7][C:8]([CH3:23])=[C:9]([CH2:18][C:19]([OH:21])=[O:20])[C:10]([C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=3)=[C:5]2[C:4]=1[CH3:25])[CH3:2]
Reactant: CCc1sc2nc(C)c(CC(=O)OC)c(-c3ccc(C)cc3)c2c1C
Agent: Cl
Agent: [Li+]
Agent: [O-2]
Solvent: O
Solvent: C1COCCO1
Product: CCc1sc2nc(C)c(CC(=O)O)c(-c3ccc(C)cc3)c2c1C
Temperature: 65 °C
Yield: 58.1 %

Procedure:
To a solution of methyl 2-(2-ethyl-3,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetate (0.077 g; 0.218 mmol) in dioxane (5 mL) and water (1.4 mL) was added a 1N lithium oxide solution (1.4 mL; 1.40 mmol). The reaction mixture was heated at 65° C. for 2 h. After cooling to room temperature, the reaction mixture was acidified with 1N HCl (pH˜2) and partially concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate/heptane to afford 0.043 g (58%) of the title compound as a white powder.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH3:13][O:14][C:15](=[O:29])[C@@H:16]1[CH2:20][C@@H:19]([OH:21])[CH2:18][N:17]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].[F:30][C:31]1[CH:32]=[CH:33][C:34]([N+:38]([O-:40])=[O:39])=[C:35](O)[CH:36]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[F:30][C:31]1[CH:36]=[CH:35][C:34]([N+:38]([O-:40])=[O:39])=[C:33]([CH:32]=1)[O:21][C@@H:19]1[CH2:18][N:17]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C@H:16]([C:15]([O:14][CH3:13])=[O:29])[CH2:20]1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](Oc2cc(F)ccc2[N+](=O)[O-])CN1C(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
Diethylazodicarboxylate (1.76 ml) was added dropwise to a solution of N-Boc-trans-4-hydroxy-L-proline methyl ester (2.74 g), 5-fluoro-2-nitrophenol (1.47 g) and triphenylphosphine (2.93 g) in dichlormethane under cooling at 0° C. The coolant was removed after 20 min and the reaction mixture was stirred at room temperature over the weekend. The solvent was evaporated and the residue war purified by chromatography to give the desired product.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=2[F:22])[CH:3]=1.[NH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][C:25]=1[CH2:30][OH:31].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:22][C:13]1[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[CH:17][C:12]=1[C:4]1[CH:3]=[C:2]([NH:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][C:25]=2[CH2:30][OH:31])[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Nc1ccncc1CO
Reactant: Fc1ccc(C(F)(F)F)cc1-c1cc(Cl)c2cccnc2n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: OCc1cnccc1Nc1cc(-c2cc(C(F)(F)F)ccc2F)nc2ncccc12
Yield: 31 %

Procedure:
150 mg 4-chloro-2-(2-fluoro-5-trifluoromethyl-phenyl)-[1,8]naphthyridine and 57 mg 4-amino-3-hydroxymethylpyridine in 6 ml dioxane containing 299 mg Cs2CO3, 8 mg Pd2 (dba)3 and 10 mg xantphos were incubated under argon gas at 90° C. for 18 hrs. After evaporation to dryness the crude sample was flashed on SiO2 with a MeOH gradient in DCM. A pooled fraction was evaporated to give 59 mg product {4-[2-(2-fluoro-5-trifluoromethyl-phenyl)-[1,8]naphthyridin-4-ylamino]-pyridin-3-yl}-methanol with Rt˜1.48 min and correct mass found M+H˜415.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:23][CH2:22][CH:11]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH2:38]Br>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:34][C:35]2[CH:42]=[CH:41][CH:40]=[C:37]([CH3:38])[CH:36]=2)([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:22][CH2:23]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)OCc2ccccc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc(CC2(C(=O)OCc3ccccc3)CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cold (−78° C.) solution of benzyl N-tert-butoxycarbonyl-isonipecotate (8.02 g, 25.11 mmol) in anhydrous THF (80 mL), a solution of sodium bis(trimethysilyl)amide (35 mL, 35 mmol; 1 M) in THF was added over a period of 10 min. The resulting orange solution was stirred at −78° C. for 1 h. and then treated dropwise with 3-methylbenzyl bromide (4.1 mL, 30.6 mmol). The reaction mixture was allowed to warm to room temp., and stirred overnight. The reaction was quenched with saturated aqueous ammonium chloride, diluted with water, and extracted with ethyl acetate. The organic extracts were combined, washed with brine, and concentrated under vacuum. The residual oil was subjected to column chromatography on silica eluting with 20% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title product.
Reaction SMILES: COC1C=CC([CH:9]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=2)[OH:10])=CC=1[N+]([O-])=O.COC1C=C(Br)C=C(OC)C=1OC.[Mg].[CH3:40][O:41][C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][C:49]=1[N+:50]([O-:52])=[O:51])C=O>>[CH3:40][O:41][C:42]1[CH:43]=[C:44]([CH:9]([C:11]2[CH:12]=[C:13]([O:21][CH3:22])[C:14]([O:19][CH3:20])=[C:15]([O:17][CH3:18])[CH:16]=2)[OH:10])[CH:47]=[CH:48][C:49]=1[N+:50]([O-:52])=[O:51]
Reactant: COc1ccc(C(O)c2cc(OC)c(OC)c(OC)c2)cc1[N+](=O)[O-]
Reactant: COc1cc(C=O)ccc1[N+](=O)[O-]
Agent: COc1cc(Br)cc(OC)c1OC
Agent: [Mg]
Product: COc1cc(C(O)c2cc(OC)c(OC)c(OC)c2)ccc1[N+](=O)[O-]
Yield: 60 %

Procedure:
(3-Methoxy-4-nitro-phenyl)-(3,4,5-trimethoxy-phenyl)-methanol was prepared analogously to (4-methoxy-3-nitro-phenyl)-(3,4,5-trimethoxy-phenyl)-methanol using 3,4,5-trimethoxy-bromobenzene (3.0 g, 12.1 mmol), magnesium turning (1.0 g, 24.3 mmol) and 3-methoxy-4-nitro-benzaldehyde (1.8 g, 10.1 mmol). The crude product was purified by flash chromatography (silica gel, Hexane:EtOAc 7:3) to afford (3-methoxy-4-nitro-phenyl)-(3,4,5-trimethoxy-phenyl)-methanol (2.1 g, 60%): 1H NMR (CDCl3) δ 7.82 (d, J=8 Hz, 1H), 7.23 (s, 1H), 6.97 (d, J=8 Hz, 1H), 6.54 (s, 2H), 5.76 (s, 1H), 4.76 (s, 1H), 3.96 (s, 3H), 3.85 (s, 9H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:6]=1)=[O:4].C(OC(=O)C)C.[N:22]12CN3CN(CN(C3)C1)C2.C(O)C.[ClH:35]>>[ClH:35].[NH2:22][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:6]=1)=[O:4]
Reactant: O=C(CBr)c1ccc(F)c(C(F)(F)F)c1
Reactant: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: NCC(=O)c1ccc(F)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 2-bromo-1-(4-fluoro-3-(trifluoromethyl)phenyl)ethanone (60.00 g 1.00 equiv; 210.50 mmoles (mmol)) in ethylacetate (EA) (450 mL; 4.60 moles (mol)), add 1,3,5,7-tetraazatricyclo-[3.3.1.13,7]decane (Methenamine, 1.10 equiv; 231.55 mmol; 32.46 g) and stir at RT overnight. Remove the solvent in vacuo and triturate the solid with methyl-t-butylether (MTBE), filter and dry in vacuo. Add ethanol (450 mL; 7.73 mol) followed by hydrogen chloride (36.5 wt/wt % in water) (150 mL; 8.30 equiv; 1.75 mol) and stir the mixture overnight. Remove the solvent in vacuo and dry the solid in vacuo at 50° C. for 1 week to give the title compound (54.23 g; 100% yield) as a white solid with some amount of ammonium salt. 1H NMR (300 MHz, DMSO): 8.69-8.59 (m, 4H), 8.07-8.01 (m, 1H), 4.95 (d, J=5.2 Hz, 2H). Use the solid as is.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)=[CH:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][CH:8]=1.Cl[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:24][O:23][C:19]1[CH:18]=[C:17]([C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]3[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=3)[CH2:13][CH2:12]2)[CH:22]=[CH:21][CH:20]=1
Reactant: ClCCCCCCCCc1cccnc1
Reactant: COc1cccc(C(=CC2CCNCC2)c2cccc(OC)c2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(C(=CC2CCN(CCCCCCCCc3cccnc3)CC2)c2cccc(OC)c2)c1
Reaction time: 16 h
Yield: 70.1 %

Procedure:
A mixture of 4-[2,2-bis(3-methoxyphenyl)ethenyl]piperidine (1.65 g), 3-(8-chloroctyl)pyridine (1.13 g), sodium iodide (0.75 g) and anhydrous sodium carbonate (0.53 g) in dimethylformamide (10 ml) was stirred under argon at 75° for 16 hours. The solvent was removed in vacuo and the residue was taken up in a mixture of ethyl acetate and 1N sodium hydroxide solution. The separated aqueous layer was reextracted with three portions of ethyl acetate. The organic layers were washed in turn with water and brine, then were combined, dried over sodium sulfate, decolorized with charcoal and evaporated to give 2.5 g of crude product as an oil. The oil was purified by HPLC (hexane:ethyl acetate:triethylamine; 34:17:1) to give 1.8 g of 3-[8-[4-[2,2-bis(3-methoxyphenyl)ethenyl]-1-piperidinyl]octyl]pyridine, as an oil.
Reaction SMILES: O.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[C:11]1(=[O:17])[O:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[OH-].[K+]>CC1C=CC(C(C)C)=CC=1>[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:15][CH2:14][CH2:13][CH2:12][C:11]([OH:17])=[O:16])=[CH:3]1
Reactant: O=C1CCCCO1
Reactant: c1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccc(C(C)C)cc1
Solvent: O
Product: O=C(O)CCCCc1c[nH]c2ccccc12
Reaction time: 96 h

Procedure:
In a water separator, indole (50 g, 0.43 mol.), δ-valerolactone (tetrahydropyran-2-one, 49.2 g, 0.49 mol.), potassium hydroxide (35.9 g, 0.64 mol.) in p-cymene (1-isopropyl-4-methylbenzene, 250 ml) were heated at boiling for 4 d, with stirring. For working up, water (200 ml) was added to the mixture, the phases were separated, and the aqueous phase was adjusted to pH 4 with 2M HCl and stored for 2 d at 4° C. in a refrigerator. The resulting solid was filtered off with suction and washed with water (3×20 ml). Recrystallisation from ether (50 ml) yielded 5-(1H-indol-3-yl)pentanoic acid in the form of a white solid having a melting point of 80–83° C. in a yield of 38.8 g.
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].[Li]CCCC.[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1)([O-:14])=[O:13]>C1COCC1>[CH3:1][C:2]([OH:6])([CH3:3])[C:4]#[C:5][CH:19]([C:18]1[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:22][CH:21]=1)[OH:20]
Reactant: C#CC(C)(C)O
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(O)C#CC(O)c1ccc([N+](=O)[O-])cc1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 64.3 %

Procedure:
To a stirred −78° C. solution of 2-methylbut-3-yn-2-ol (6.1 mL, 63.5 mmol, 1.2 eq) in dry THF (250 mL), n-BuLi (62 mL, 2.3 M in hexane, 142 mmol, 2.7 eq) was added dropwise over 10 minutes under an inert atmosphere. After being stirred for 40 min at −78° C., a solution of 4-nitrobenzaldehyde (8 g, 52.9 mmol, 1 eq) in dry THF (50 mL) was added to the reaction mixture and stirring was continued for an additional 1 h at −78° C. The reaction mixture was then quenched with a saturated NH4Cl solution and extracted with EtOAc (2×200 mL). The combined organic layers were washed with water (200 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography (30% ethyl acetate in hexanes) to afford 4-methyl-1-(4-nitrophenyl)pent-2-yne-1,4-diol (8 g, 65%) as a yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:17])[C:5]([S:8]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)(=[O:10])=[O:9])([CH3:7])[CH3:6])C.O.[OH-].[Li+]>C1COCC1.O.O>[CH:11]1([S:8]([C:5]([CH3:7])([CH3:6])[C:4]([OH:17])=[O:3])(=[O:10])=[O:9])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CCOC(=O)C(C)(C)S(=O)(=O)C1CCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C(=O)O)S(=O)(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.7 %

Procedure:
To a solution of 3.47 g (13.2 mmol) of 2-cyclohexanesulfonyl-2-methyl-propionic acid ethyl ester in THF/water (4/1, 50 mL) were added 1.11 g (26.4 mmol) of lithium hydroxide monohydrate. The reaction was stirred at room temperature for 18 h. The reaction was further diluted with water (20 mL) and then washed with DCM (2×15 mL). The basic aqueous layer was cooled in an ice bath and then acidified with 1M aqueous HCl solution to pH 2. The acidic aqueous layer was extracted with DCM (3×20 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and filtered. Concentration of the filtrate under reduced pressure afforded 2.96 g of 2-cyclohexanesulfonyl-2-methyl-propionic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:30])=[CH:11][C:12]([F:29])=[C:13]([CH:28]=1)[NH:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([OH:27])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][N:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:32][CH2:33][OH:34].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[C:10]([CH3:30])=[CH:11][C:12]([F:29])=[C:13]([CH:28]=1)[NH:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH2:32][CH2:33][OH:34])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][N:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCBr
Reactant: COc1cc2c(Nc3cc(OCc4ccccc4)c(C)cc3F)ncnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Nc3cc(OCc4ccccc4)c(C)cc3F)ncnc2cc1OCCO
Temperature: 50 °C
Yield: 44.5 %

Procedure:
A mixture of 4-(5-benzyloxy-2-fluoro4-methylanilino)-7-hydroxy-6-methoxyquinazoline (440 mg, 1 mmol), 2-bromoethanol (77 ml, 1 mmol) and potassium carbonate (150 mg, 1.1 mmol) in DMF (5 ml) was heated at 50° C. for 1 hour, further 2-bromoethanol (42 ml, 0.6 mmol) and potassium carbonate (150 mg, 1.1 mmol) was added and the mixture was maintained at 50° C. for 2 hours. The reaction mixture was diluted with water, neutralised with 2M hydrochloric acid and extracted with ethyl acetate. The extracts were dried (MgSO4), the solvent removed by evaporation and the residue triturated with ether and hexane to give 4-(5-benzyloxy-2-fluoro-4-methylanilino)-7-(2-hydroxyethoxy)-6-methoxyquinazoline (200 mg, 41%).
Reaction SMILES: [NH2:1][C:2]1([C:7]#[N:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:16](Cl)(=[O:21])[CH2:17][CH2:18][CH2:19][CH3:20]>ClCCl>[C:7]([C:2]1([NH:1][C:16](=[O:21])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3]1)#[N:8]
Reactant: N#CC1(N)CCCC1
Reactant: CCCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(=O)NC1(C#N)CCCC1
Temperature: 32.5 °C
Reaction time: 2 h

Procedure:
To 11.0 g (0.1 mol) of 1-amino-1-cyanocyclopentane dissolved in 100 ml of dichloromethane, 15 ml 10.9 g (0.1 mol) of triethylamine was added, then dropwise 13 ml, 13 g (0.1 mol) of valeroyl chloride, while keeping the temperature at 25-35° C. The reaction mixture was stirred at 30-35° C. for 2 hours, then it was washed with water. The phases were separated, the organic phase was evaporated to obtain the pure title compound as an oil. The compound was identified by elementary analysis, IR, NMR and GC-MS spectomety.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[N:31]=[C:32]=[O:33]>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[NH:31][C:32](=[O:33])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1Cl
Reactant: NC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Product: NC(=O)c1[nH]c2cnccc2c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2Cl)cc1

Procedure:
76 mg of solid yellow 3-{4-[3-(2-chloro-5-trifluoromethylphenyl)ureido]phenyl}-1H-pyrrolo[2,3-c]pyridine-2-carboxamide are prepared as described in Example 1 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide and 2-chloro-5-trifluoromethylphenyl isocyanate.