Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(=O)[CH2:4][C@H:5]([N:9]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:11][C:12](OC)=O)[C:6]([OH:8])=O.C[O-].[Na+].CO.[C:29](N)(C)(C)[CH3:30]>C1COCC1>[CH:6]([CH:5]1[N:9]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:10][CH2:11][C:12]2([CH2:30][CH2:29]2)[CH2:4]1)=[O:8]
Reactant: CC(C)(C)N
Reactant: COC(=O)CCN(C(=O)OC(C)(C)C)[C@@H](CC(=O)OC)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CC2)CC1C=O
Temperature: 85 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
To a solution of (S)-2-[tert-Butoxycarbonyl-(2-methoxycarbonyl-ethyl)-amino]-succinic acid 4-methyl ester (intermediate 12, 420 g, 1.35 mol) in THF (2 L) under nitrogen cooled to 0° C. was added NaOMe/MeOH (1.5 L, 2.7M) in half an hour. The resulting yellow solution was stirred at 85° C. for 3 hours (after 1 hour a suspension was obtained). THF (1.5 L) was distilled off under the reduced pressure and water (2 L) was added. The resulting mixture was stirred at 110° C. for 20 hours. The mixture was washed with ethyl acetate (2×1 L). The aqueous solution was cooled to 0° C. and the value of pH was adjusted to 2.5 with concentrated HCl. The product was extracted with ethyl acetate (3×1 L) and the organic extracts were combined, washed with saturated NaCl (1 L), dried (Na2SO4) and filtered. The filtrate was cooled to 0° C. and tert-butylamine (145 ml, 1.35 mol) was added with stirring. The yellow solid was collected by filtration and dried, then boiled in isopropyl alcohol (1.5 L). The suspension was cooled to 5° C. and collected by filtration to give 180 g of intermediate 3 (light white solid, yield:45%).
Reaction SMILES: Cl[C:2]1[NH:3][C:4](=[O:12])[C:5]2[CH:10]=[CH:9][N:8]([CH3:11])[C:6]=2[N:7]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[N:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:11][N:8]1[C:6]2[N:7]=[C:2]([C:18]3[CH:19]=[N:20][C:15]([C:14]([F:25])([F:24])[F:13])=[CH:16][CH:17]=3)[NH:3][C:4](=[O:12])[C:5]=2[CH:10]=[CH:9]1
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Reactant: Cn1ccc2c(=O)[nH]c(Cl)nc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: Cn1ccc2c(=O)[nH]c(-c3ccc(C(F)(F)F)nc3)nc21
Temperature: 150 °C
Yield: 6.8 %

Procedure:
A high pressure microwave reaction vial was charged with 2-chloro-7-methyl-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one (Intermediate A) (55 mg, 0.3 mmol), 6-(trifluoromethyl)pyridin-3-ylboronic acid (68.6 mg, 0.36 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (21.9 mg, 0.03 mmol), a 2M aqueous sodium carbonate solution (0.45 mL, 0.9 mmol), and ethanol (2 mL). The vessel was sealed, degassed and flushed with nitrogen three times. The reaction was then heated at 150° C. for 10 min in a Biotage microwave reactor. At this time, the resulting black mixture was concentrated in vacuo. The residue was treated with ethyl acetate (20 mL), stirred and filtered. The filtrate was concentrated in vacuo. Reverse phase chromatography (10-100% acetonitrile/water) and lyophilization afforded 7-methyl-2-(6-trifluoromethyl-pyridin-3-yl)-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one (6 mg, 6.81%) as a white solid. LC-MS calcd. for C13H10F3N4O [(M+H)+] 295, obsd. 294.8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH:19]3[CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20]3)[CH2:15][CH:16]=1)[CH:6]=[CH:5]2.[H][H]>[Pt]=O.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH:19]3[CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20]3)[CH2:15][CH2:16]1)[CH:6]=[CH:5]2
Reactant: Clc1ccc2c(ccn2C2=CCN(CCC3Cc4ccccc4C3)CC2)c1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(=O)O
Product: Clc1ccc2c(ccn2C2CCN(CCC3Cc4ccccc4C3)CC2)c1

Procedure:
A mixture of 5-Chloro-1-[1-[2-(indan-2-yl)ethyl]-1,2,3,6-tetrahydropyridin-4yl]-1H-indol. 28a. (1.9 g), acetic acid (50 ml), and platinum oxide (0.1 g) was shaken for 3 h under 3 atm. hydrogen pressure. The mixture was filtered and evaporated in vacuo. The residue was dissolved in ethyl acetate and the organic phase was shaken with dilute ammonium hydroxide and then worked up in a conventional manner. Further purification was done on silica gel eluted with ethyl acetate-heptane (1:1) to give 2.0 g of crude product. The crude product was crystallized (ethyl acetate), and the title compound was collected by filtration (1.1 g, 58%).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH2:6]([NH:9][CH2:10][CH:11]=[CH2:12])[CH:7]=[CH2:8].CCN(CC)CC>C(OC(=O)C)C>[CH2:6]([N:9]([CH2:10][CH:11]=[CH2:12])[C:3](=[O:4])[CH2:2][Br:1])[CH:7]=[CH2:8]
Reactant: C=CCNCC=C
Reactant: O=C(Br)CBr
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=CCN(CC=C)C(=O)CBr
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.3 %

Procedure:
Bromoacetyl bromide (45 g, 0.22 mol) in ethylacetate (25 mL) was added dropwise to a solution of diallyl amine (9.6 g, 0.1 mol), Et3N (15 mL), in ethyl acetate (50 mL) at 0° C. The reaction was then warmed to ambient temperature, and the stirring was continued for about 3 h. The resulting mixture was washed with saturated NaHCO3 solution (3×100 mL) and dried over Na2SO4. The evaporation of the solvent gave 16.2 g of product as a light yellow oil (yield 75%). ESI-MS (m/z): 218 (M+H+). 1H NMR δD (CDCl3): 5.75 (m, 2H, CH), 5.19 (m, 4H, CH2), 3.95 (d, 4H, NCH2), 3.81 (2, 2H, BrCH2).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[O:12]1[CH2:17][CH2:16][N:15]([CH:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=2)[CH2:19][NH2:20])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([N:15]1[CH2:16][CH2:17][O:12][CH2:13][CH2:14]1)[C:21]1[CH:26]=[N:25][C:24]([C:27]([F:29])([F:30])[F:28])=[N:23][CH:22]=1)=[O:6]
Reactant: O=C(O)c1cccc(F)c1Cl
Reactant: NCC(c1cnc(C(F)(F)F)nc1)N1CCOCC1
Product: O=C(NCC(c1cnc(C(F)(F)F)nc1)N1CCOCC1)c1cccc(F)c1Cl

Procedure:
From 2-chloro-3-fluorobenzoic acid and 2-morpholino-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[CH:17][C:16]=3[CH3:30])[N:11]=2)=[CH:6][C:5]=1[CH:31]=[CH2:32])[CH3:2].[H][H]>CO.C(OCC)(=O)C.[Pd]>[CH2:31]([C:5]1[CH:6]=[C:7]([C:10]2[S:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:17][C:16]=3[CH3:30])[N:11]=2)[CH:8]=[CH:9][C:4]=1[O:3][CH2:1][CH3:2])[CH3:32]
Reactant: [H][H]
Reactant: C=Cc1cc(-c2nc(-c3ccc(CCC(=O)OC(C)(C)C)cc3C)ns2)ccc1OCC
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOc1ccc(-c2nc(-c3ccc(CCC(=O)O)cc3C)ns2)cc1CC
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.4 %

Procedure:
A solution of tert-Butyl 3-(4-(5-(4-ethoxy-3-vinylphenyl)-1,2,4-thiadiazol-3-yl)-3-methylphenyl)propanoate (0.01 g, 0.025 mmol) in methanol (1.5 mL) and ethyl acetate (1.5 mL) was degassed with nitrogen. 10% Palladium/Carbon (0.01 g) was added to the reaction mixture which was stirred under a balloon of hydrogen for 30 min. The reaction was filtered through a disposable frit and concentrated in vacuo. The resulting oil was dissolved in 20% solution of trifluoroacetic acid in dichloromethane (4 mL) and stirred at rt for 2 h after which the reaction was concentrated in vacuo. Silica gel chromatography eluting with 2% methanol/methylene chloride afforded 4.5 mg of the title compound: 1H NMR (500 MHZ, CDCl3) δ 7.86 (s, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.23 (s, 1H), 7.19 (d, J=7.5 Hz, 1H), 6.93 (d, J=8.2 Hz, 1H), 4.20-4.30 (m, 2H), 3.00-3.08 (m, 2H), 2.70-2.79 (m, 4H), 2.65 (s, 3H), 1.48-1.52 (m, 3H), 1.23-1.32 (m, 3H), ESI-MS (m/z) 453.3; HPLC A: 4.68 min.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7].[Al+3].[Cl-].[Cl-].[Cl-].[CH3:14][O:15]C(Cl)Cl>C(Cl)Cl.C[N+]([O-])=O>[CH:14]([C:4]1[CH:3]=[C:2]([C:6]([O:8][CH3:9])=[O:7])[NH:1][CH:5]=1)=[O:15]
Reactant: COC(=O)c1ccc[nH]1
Reactant: COC(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: C[N+](=O)[O-]
Product: COC(=O)c1cc(C=O)c[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.7 %

Procedure:
To a solution of 2 (4.50 g, 36.0 mmol) in CH2Cl2:CH3NO2 (1:1, 40 mL) at −40° C., was added AlCl3 (12.48 g, 93.6 mmol) followed by α,α-dichloromethyl methyl ether (4.15 mL, 46.8 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was slowly poured onto ice (10.00 g) and allowed to warm to room temperature. The aqueous phase was extracted with CH2Cl2 (3×50 mL). The combined organic layer was dried over anhydrous MgSO4, filtered and concentrated to give 3 as a dark brown solid (3.40 g, 62%). 1H NMR (400 MHz, CDCl3) δ 10.32 (bs, 1H), 9.83 (s, 1H), 7.59 (d, J=1.6 Hz, 1H), 7.30 (s, 1H), and 3.88 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 186.07, 161.71, 129.15, 127.71, 124.99, 114.56, and 52.34.
Reaction SMILES: C(Cl)(=O)C(C)(C)C.C(N(C(C)C)C(C)C)C.[NH:17]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:18]([C:22]([OH:24])=O)[CH:19]([CH3:21])[CH3:20].[NH:32]([CH3:52])[C@H:33]([C:38]([NH:40][C@H:41]([C:43]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:44])[CH3:42])=[O:39])[CH2:34][CH:35]([CH3:37])[CH3:36]>C(Cl)(Cl)Cl>[NH:17]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:18]([C:22]([N:32]([CH3:52])[C@H:33]([C:38]([NH:40][C@H:41]([C:43]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:44])[CH3:42])=[O:39])[CH2:34][CH:35]([CH3:37])[CH3:36])=[O:24])[CH:19]([CH3:20])[CH3:21]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CN[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)Cc1ccccc1
Agent: CC(C)(C)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@@H](C(=O)N[C@@H](C)C(=O)Cc1ccccc1)N(C)C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Reaction time: 2 h

Procedure:
12.9 ml (12.7 g=106 mMol) pivaloyl chloride and 23 g (212 mMol) N-ethyl-diisopropylamine are added to a solution of 23.2 g (106 mMol) BOC-L-Val-OH in 400 ml chloroform and the mixture stirred for 2 hrs. at room temperature under a nitrogen atmosphere. 27.37 g (89 mMol) H-MeLeu-Ala-Bzl dissolved in 100 ml chloroform are then added and the reaction mixture stirred for a further 18 hrs. at 60° C. again under a nitrogen atmosphere. The obtained solution is washed with 300 ml 1N HCl, the aqueous phase extracted with 200 ml methylene chloride and the combined organic phases washed 2× with 200 ml saturated potassium carbonate solution. The aqueous phases are extracted with 200 ml methylene chloride, the combined organic phases dried over potassium carbonate, filtered and concentrated. The residue is chromatographed on 2 kg silica gel 60 (0.065-0.2 mm) with 1% methanol in methylene chloride as eluant to yield the title compound as a colourless oil: rotation [α]D25 =-97.2 (c=1.0 in chloroform).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:7][S:8]C(=O)C.[OH-].[K+].Br[C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[CH3:21][C:15]([S:8][CH2:7][C@@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)([CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CC(=O)SC[C@@H]1CCCCO1
Reactant: CCOC(=O)C(C)(C)Br
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C)(C)SC[C@@H]1CCCCO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.9 %

Procedure:
A solution of 2.79 g (13.45 mmol) of 1-{[(2S)-oxan-2-ylmethyl]sulfanyl}ethan-1-one in ethanol (60 mL) is degassed with nitrogen over 0.5 h and 1.51 g (26.91 mmol) of KOH are added. Then 3.99 mL (26.91 mmol) of ethyl α-bromoisobutyrate are added slowly. The reaction is stirred for 18 h at room temperature under a nitrogen atmosphere. The reaction mixture is filtered, the solid is rinsed with ethanol and the filtrate is concentrated under reduced pressure. The crude material is purified by column chromatography (silica, eluent: n-heptanes, 0-20% ethyl acetate) to afford 2.68 g of ethyl 2-methyl-2-{[(2S)-oxan-2-ylmethyl]sulfanyl}propanoate (purity 90%). Yield: 72%; ES-MS: m/z 247 [M+H]; 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.23-1.36 (5 H, m), 1.45-1.59 (8 H, m), 1.68 (1 H, d, J=13.12 Hz), 1.83 (1 H, d, J=10.99 Hz), 2.62-2.71 (1 H, m), 2.72-2.80 (1 H, m), 3.25-3.47 (2 H, m), 3.95-4.03 (1 H, m), 4.17 (2 H, q, J=7.12 Hz).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Br:34][C:35]1[CH:36]=[C:37]([OH:41])[CH:38]=[N:39][CH:40]=1.[C:42]([O:46][C:47]([N:49]1[CH2:54][CH2:53][CH2:52][C@H:51](O)[CH2:50]1)=[O:48])([CH3:45])([CH3:44])[CH3:43]>C1COCC1>[C:42]([O:46][C:47]([N:49]1[CH2:54][CH2:53][CH2:52][C@@H:51]([O:41][C:37]2[CH:38]=[N:39][CH:40]=[C:35]([Br:34])[CH:36]=2)[CH2:50]1)=[O:48])([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](O)C1
Reactant: Oc1cncc(Br)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2cncc(Br)c2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 66.7 %

Procedure:
To a cooled (0° C.) solution of PPh3 (1.2 g, 4.5 mmol) in THF (50 mL) is added DIAD (0.81 mL, 4.1 mmol), dropwise. After stirring at 0° C. for 15 min, 5-bromo-pyridin-3-ol (441 mg, 2.5 mmol) and (S)-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 2.5 mmol) are added and the mixture is warmed and stirred at room temperature for 16 h. The mixture is concentrated and purified by flash column chromatography to give 596 mg of (R)-3-(5-bromo-pyridin-3-yloxy)-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:13])[C:6]2[CH:7]=[CH:8][N:9]=[CH:10][C:11]=2[CH:12]=1.[F:14][C:15]([F:27])([F:26])[C:16]1[CH:25]=[CH:24][C:19]([CH2:20][N:21]=[C:22]=[O:23])=[CH:18][CH:17]=1>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N:9]=[CH:10]2)=[C:5]([NH:13][C:22]([NH:21][CH2:20][C:19]2[CH:18]=[CH:17][C:16]([C:15]([F:14])([F:27])[F:26])=[CH:25][CH:24]=2)=[O:23])[CH:4]=1
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Reactant: COc1cc(N)c2ccncc2c1
Product: COc1cc(NC(=O)NCc2ccc(C(F)(F)F)cc2)c2ccncc2c1

Procedure:
Prepared from 7-methoxyisoquinolin-5-amine (Description 82) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES+) 376 (M+H)+.
Reaction SMILES: [OH-].[K+].CC1C=C(C=CC=1)C([O:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:25])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=2)[CH2:13][CH2:12]1)=O>C(O)C.O>[CH3:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[C:17]([N:14]1[CH2:15][CH2:16][CH:11]([CH2:10][OH:9])[CH2:12][CH2:13]1)=[O:25]
Reactant: Cc1cccc(C(=O)OCC2CCN(C(=O)c3cccc(C)c3)CC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cccc(C(=O)N2CCC(CO)CC2)c1

Procedure:
A solution of 12.76 g (0.23 mol) of potassium hydroxide in 75 ml of ethanol and 75 ml of water is added to a solution of 80 g (0.23 mol) of [1-(3-methylbenzoyl)-4-piperidyl]methyl 3-methylbenzoate in 400 ml of ethanol. The mixture is stirred at 20° C. for 3h, the solvent evaporated off under reduced pressure and the aqueous phase extracted with ethyl acetate. The organic phase is washed with water and then with saturated aqueous sodium chloride solution, and dried over magnesium sulphate. The solvent is evaporated off under reduced pressure and 53 g of alcohol are obtained, this being used without further treatment in the following stage.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[CH2:5]([O:7][C:8]([CH3:18])([CH3:17])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:16])[CH2:13][CH:14]=O)[CH3:6]>CN(C)C=O>[CH2:5]([O:7][C:8]([CH3:18])([CH3:17])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:16])[CH2:13][CH:14]=[CH:9][C:8]([CH3:17])=[CH:3][C:2]([O:7][CH2:5][CH3:6])=[O:1])[CH3:6]
Reactant: CCOC(C)(C)CCCC(C)CC=O
Reactant: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C=C(C)C=CCC(C)CCCC(C)(C)OCC
Reaction time: 1.5 h

Procedure:
Sodium ethoxide (prepared from 0.2 g. of sodium and 12 ml. of ethanol) is slowly added to a mixture of 1.1 g. of 7-ethoxy-3,7-dimethyloctan-1-al, diethyl 3-ethoxycarbonyl-2-methylprop-2-enyl phosphonate and 50 ml. of dimethylformamide, with stirring, under nitrogen, at 0°. The reaction is stirred for 1.5 hours after addition is complete and then worked up by extraction with ether to yield ethyl 11-ethoxy-3,7,11-trimethyldodeca-2,4-dienoate, mostly trans(2), trans(4), which can be further purified by chromatography and distillation.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:35][CH2:36][CH3:37])=[C:8]([N:10]=[C:11]2[N:15]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14](=[O:23])[C:13](=[C:24]3[N:28]([CH2:29]C)[C:27]4[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=4[S:25]3)[S:12]2)[CH:9]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO.C1COCC1>[CH2:16]([N:15]1[C:14](=[O:23])[C:13](=[C:24]2[N:28]([CH3:29])[C:27]3[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=3[S:25]2)[S:12][C:11]1=[N:10][C:8]1[CH:9]=[C:4]([CH:1]([OH:3])[CH3:2])[CH:5]=[CH:6][C:7]=1[NH:35][CH2:36][CH3:37])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCNc1ccc(C(C)=O)cc1N=C1SC(=C2Sc3ccccc3N2CC)C(=O)N1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCNc1ccc(C(C)O)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
The product of Example 38 was reduced with sodium borohydride in 1:1 MeOH/THF and chromatographed (TEA-washed silica gel, 0-10% MeOH/DCM) to afford the title compound. 1H-NMR (CDCl3): δ 7.47-7.54 (3H, m), 7.28-7.37 (4H, m), 7.17 (1H, m), 6.99-7.06 (3H, m), 6.57 (1H, d), 5.19 (2H, s), 4.80 (1H, q), 3.76 (3H, s), 3.01 (2H, q), 1.48 (3H, d), 1.04 (3H, s); MS(ESI): 517 (MH+).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([NH2:16])=[C:9]2[C:4]=1[CH2:5][CH2:6][NH:7][CH2:8]2.[CH:17](=O)[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([BH3-])#N.[Na+]>CO.O>[Br:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([NH2:16])=[C:9]2[C:4]=1[CH2:5][CH2:6][N:7]([CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:8]2
Reactant: O=CCCc1ccccc1
Reactant: Nc1c([N+](=O)[O-])cc(Br)c2c1CNCC2
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1c([N+](=O)[O-])cc(Br)c2c1CN(CCCc1ccccc1)CC2
Reaction time: 6 h
Yield: 93.3 %

Procedure:
A solution of the product from Example 5 (1 g, 3.24 mmol) and hydrocinnamaldehyde (0.94 g, 7 mmol) in 2:1 MeOH/H2O (50 mL) was treated with sodium cyanoborohydride (0.56 g, 9 mmol) portionwise under nitrogen and stirred for six hours. The solvent was decanted and the semi-solid was dissolved in dichloromethane, dried over magnesium sulfate, filtered and concentrated under vacuum. The crude compound was chromatographed on silica gel (eluted with 25% ethyl acetate in hexane) to give the title compound (1.18 g, 94% yield) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[N:21]1([CH2:27][C:28]2[CH:29]=[C:30]([NH2:34])[CH:31]=[CH:32][CH:33]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:34][C:30]2[CH:31]=[CH:32][CH:33]=[C:28]([CH2:27][N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[CH:29]=2)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2c(n1)CCS2
Reactant: Nc1cccc(CN2CCOCC2)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nc2c(c(Nc3cccc(CN4CCOCC4)c3)n1)SCC2
Reaction time: 20 h
Yield: 70.6 %

Procedure:
1.25 g 2,4-dichloro-6,7-dihydro-thieno[3,2-d]pyrimidine are placed in 5 ml dimethylformamide, first 1.05 ml diisopropylethylamine, then 0.960 g 3-morpholin-4-ylmethyl-phenylamine (J. Med. Chem. 1990, 33, 327) are added. The reaction mixture is sf 20 hours at 60° C., then after cooling evaporated down. The residue is extracted with dichloromethane and water, the organic phase is dried and evaporated to dryness. The residue is crystallised with petroleum ether/ethyl acetate. 1.28 g of the product are obtained as a powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[N:3]=1.Cl.[NH:19]1[C@@H:23]([CH2:24][OH:25])[CH2:22][CH2:21][C@H:20]1[CH2:26][OH:27].C(=O)([O-])O.[Na+]>CC(C)=O.CC(C)=O.O.O>[Cl:8][C:6]1[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[N:3]=[C:2]([N:19]2[C@@H:23]([CH2:24][OH:25])[CH2:22][CH2:21][C@H:20]2[CH2:26][OH:27])[N:7]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc(Cl)nc(Cl)n2)cc1
Reactant: OC[C@@H]1CC[C@H](CO)N1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(-c2nc(Cl)nc(N3[C@H](CO)CC[C@@H]3CO)n2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of 2,4-dichloro-6-(4-nitrophenyl)-1,3,5-triazine (2.2 g, 8.0 mmol) in acetone (40 mL) was added to magnetically stirred ice water (60 mL). The mixture was treated with a solution of (2S,5R)-pyrrolidine-2,5-diyldimethanol hydrochloride (1.0 g, 6.0 mmol) in acetone/water (20 mL, 3:1), followed by a suspension of sodium hydrogen carbonate (1.0 g, 12 mmol) in water (12 mL). After 30 minutes of stirring at 0° C., the mixture was treated with an additional quantity of (2S,5R)-pyrrolidine-2,5-diyldimethanol hydrochloride (0.26 g, 1.6 mmol) in water (3 mL), followed by sodium hydrogen carbonate (0.35 g) in water (5 mL). The suspension was allowed to stir overnight while regaining room temperature. The title compound was isolated by Buchner filtration, washed with water, and dried under house vacuum. Compound identification by mass spectrometry was achieved via the analysis of the product reaction product of ((2S,5R)-1-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)pyrrolidine-2,5-diyl)dimethanol with excess morpholine in ethanol. MS (ES+)=417.2 (M+morpholine−Cl)+
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.O>COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]3=[N:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Cc1ccn2c(Br)cnc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cccc(-c2cnc3cc(C)ccn23)c1
Temperature: 25 °C
Yield: 92.7 %

Procedure:
A mixture of 3-bromo-7-methylimidazo[1,2-α]pyridine (18.0 g, 86 mmol) and 3-methoxyphenylboronic acid (17.0 g, 112 mmol) in 1,2-dimethoxyethane (250 ml) and sodium carbonate (120 ml of a 2M aqueous solution) was degassed for 25 minutes. Tetrakis(triphenylphosphine)pallidum(0) (500 mg, 0.4 mmol) was then added and the mixture heated at reflux for 17 hours. After cooling to ambient temperature the reaction was poured into water (400 ml), extracted with ethyl acetate (3×400 ml) and the combined organics dried over anhydrous magnesium sulphate. Filtration and evaporation to dryness afforded 3-(3-methoxyphenyl)-7-methylimidazo[1,2-α]pyridine as a colourless oil (19 g, 93%). 1H NMR (360 MHz, CDC3) δH 2.40 (3H, s), 3.84 (3H, s), 6.63-6.65 (1H, m), 6.91-6.95 (1H, m), 7.05-7.07 (1H, m), 7.10-7.12 (1H, m), 7.30-7.38 (1H, m), 7.42 (1H, s), 7.66 (1H, s), 8.22 (1H, d, J 7); m/z (ES+) 239 (M++H).