Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([OH:21])([CH2:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH2:16])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[F:20][C:17]([F:18])([F:19])[C:15](=[CH2:16])[CH2:14][C:11]1([OH:21])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: C=C(CC1(O)CCN(C(=O)OC(C)(C)C)CC1)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C=C(CC1(O)CCNCC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl-4-hydroxy-4-(2-(trifluoromethyl)allyl)piperidine-1-carboxylate 17B (300 mg, 0.97 mmol), in DCM (5 mL) was added a solution of HCl in dioxane (3 M, 1 mL, 3 mmol), and then the mixture was stirred at room temperature for 16 hrs. The mixture was concentrated in vacuo to get the desired compound which was used directly for the next step. LC-MS: m/z 210.2 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][N:5](C(OC(C)(C)C)=O)[CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:21])[CH2:4][NH:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: COC(=O)CN(CCN1CCOCC1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CNCCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
A solution of [tert-butoxycarbonyl-(2-morpholin-4-yl-ethyl)amino]acetic acid methyl ester (0.79 g, 2.61 mmol) in CH2Cl2 (10 mL) was treated with TFA (10 mL). After stirring at room temperature for 1 h, the solution was concentrated in vacuo. The oil was dissolved in CH2Cl2 (50 mL) and the resulting solution was washed with saturated aqueous NaHCO3 (50 mL). The aqueous layer was extracted with CH2Cl2 (10×50 mL). The combined organic layers were dried over Na2SO4, filtered and the solvent was removed in vacuo to give the title compound (0.40 g, 76%) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 3.69-3.74 (m, 7H), 3.45 (s, 2H), 2.69-2.73 (m, 2H), 2.45-2.52 (m, 6H), 1.84 (s, 1H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[C:15]([CH:21]2[CH2:23][CH2:22]2)=[N:16][CH:17]=[C:18]([Cl:20])[N:19]=1.[C:24](=[O:26])=[O:25].Cl>O1CCCC1>[Cl:20][C:18]1[C:17]([C:24]([OH:26])=[O:25])=[N:16][C:15]([CH:21]2[CH2:23][CH2:22]2)=[C:14]([Cl:13])[N:19]=1
Reactant: Clc1cnc(C2CC2)c(Cl)n1
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1nc(C2CC2)c(Cl)nc1Cl
Temperature: -100 °C
Reaction time: 0.17 h
Yield: 97.9 %

Procedure:
Under an argon atmosphere, to a mixture of tetrahydrofuran (6 mL) and diisopropylamine (258 μL) was added dropwise n-butyllithium (1.62 M n-hexane solution, 1.04 mL) under ice-cooling. After cooling to −100° C., a mixture of 3,5-dichloro-2-cyclopropylpyrazine (290 mg) and tetrahydrofuran (2 mL) was added dropwise thereto, followed by stirring for 10 minutes. The obtained reactant was added to dry ice (10 g) and tetrahydrofuran (5 mL), followed by stirring for 30 minutes in a water bath. To the reactant were added 1 M hydrochloric acid and a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 3,5-dichloro-6-cyclopropylpyrazine-2-carboxylic acid (350 mg) as an oily material.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][O:13][C@H:12]([CH3:16])[CH2:11]2)=[O:9])[CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[S:19][C:20]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([OH:35])([CH3:34])[CH3:33])=[CH:28][C:27]=2[F:36])=[CH:21][C:22]=1[C:23]([NH2:25])=[O:24]>>[F:36][C:27]1[CH:28]=[C:29]([C:32]([OH:35])([CH3:33])[CH3:34])[CH:30]=[CH:31][C:26]=1[C:20]1[S:19][C:18]([NH:17][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([C:8]([N:10]3[CH2:15][CH2:14][O:13][C@H:12]([CH3:16])[CH2:11]3)=[O:9])[N:7]=2)=[C:22]([C:23]([NH2:25])=[O:24])[CH:21]=1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: C[C@@H]1CN(C(=O)c2cccc(Br)n2)CCO1
Product: C[C@@H]1CN(C(=O)c2cccc(Nc3sc(-c4ccc(C(C)(C)O)cc4F)cc3C(N)=O)n2)CCO1

Procedure:
The title compound was prepared as described Example 1 using (2R)-4-[(6-bromopyridin-2-yl)carbonyl]-2-methylmorpholine (133 mg, 0.47 mmol) and 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (137 mg, 0.47 mmol) as starting materials
Reaction SMILES: [CH:1]1([C:4]([NH:6][NH2:7])=[O:5])[CH2:3][CH2:2]1.[I:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[CH3:20])[C:12](=[NH:16])OCC>CO>[NH:16]=[C:12]([C:11]1[CH:17]=[CH:18][C:19]([CH3:20])=[C:9]([I:8])[CH:10]=1)[NH:7][NH:6][C:4]([CH:1]1[CH2:3][CH2:2]1)=[O:5]
Reactant: NNC(=O)C1CC1
Reactant: CCOC(=N)c1ccc(C)c(I)c1
Solvent: CO
Product: Cc1ccc(C(=N)NNC(=O)C2CC2)cc1I
Temperature: 75 °C
Reaction time: 1.5 h

Procedure:
Cyclopropanecarbohydrazide (0.36 g, 2.7 mmol) was added to a stirred solution of ethyl 3-iodo-4-methylbenzimidate (preparation 51b, 0.70 g, 2.4 mmol) in methanol (6 mL) and the mixture was stirred at 75° C. After 1.5 hours, the mixture was cooled to give a suspension. Methanol was added to the suspension and the precipitate was filtered and dried to give the desired compound in quantitative yield. The crude material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[C:19]([C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>>[C:19]([C:23]1[CH:24]=[CH:25][C:26]([C:27]([NH:13][CH:10]2[CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:14]=[CH:15][C:2]([Cl:1])=[C:3]([O:16][CH2:17][CH3:18])[CH:4]=3)[CH2:8][CH2:9]2)=[O:28])=[CH:30][CH:31]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Product: CCOc1cc(CN2CCC(NC(=O)c3ccc(C(C)(C)C)cc3)CC2)ccc1Cl
Yield: 30 %

Procedure:
The title compound (13 mg, 30%) was prepared analogously to example 8 by coupling of 1-(4-chloro-3-ethoxy-benzyl)piperidin-4-ylamine with 4-tert-butylbenzoic acid. MS: 429.5 (MH+)
Reaction SMILES: I[C:2]1[N:11]=[C:10]2[N:4]([CH2:5][CH2:6][C:7]3[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=3[CH:9]2[O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:43]([O:47][C:48](=[O:51])[CH:49]=[CH2:50])([CH3:46])([CH3:45])[CH3:44].CCN(CC)CC.N>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].O>[C:43]([O:47][C:48](=[O:51])[CH:49]=[CH:50][C:2]1[N:11]=[C:10]2[N:4]([CH2:5][CH2:6][C:7]3[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=3[CH:9]2[O:12][CH:13]2[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]2)[CH:3]=1)([CH3:46])([CH3:45])[CH3:44]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CN1CCC(OC2c3ccccc3CCn3cc(I)nc32)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: N
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CN1CCC(OC2c3ccccc3CCn3cc(C=CC(=O)OC(C)(C)C)nc32)CC1
Temperature: 100 °C

Procedure:
To a solution of compound 2-iodo-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 2A) (100 mg, 0.24 mmoles) in DMF (2.5 mL) in a screw-capped vial under argon are added Pd(OAc)2 (5.4 mg, 24 μmole), PPh3 (16 mg, 60 μmole), tert-butylacrylate (175 μL, 0.96 mmole) and NEt3 (140 μL, 0.88 mmole). The reaction mixture is heated at 100° C. overnight. Water is added to the reaction mixture and pH adjusted to 9-10 by adding concentrated ammonia solution. The aqueous phase is extracted three times with CH2Cl2. The organic phase is dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is pre-purified by silica gel chromatography using (CH2Cl2:MeOH:NH4OH) as eluent with a gradient from (98:2:0.1) to (96.5:3.5:0.35) and the residue is submitted to a preparative thin-layer chromatography eluting with (CH2Cl2:MeOH:NH4OH) (9:1:1) to afford 3-[4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-acrylic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1.CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:17])[C:9]([C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=1)=[CH:20][N:21]([CH3:23])[CH3:22]
Reactant: COC(OC)N(C)C
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccccc1Cl
Solvent: CN(C)C=O
Product: CN(C)C=C(C(=O)c1ccccc1Cl)c1ccc(Cl)cc1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
To a solution of the ketone product from Step A (5.48 g, 20.67 mmol) in DMF (70 mL) was added N,N-dimethylformamide dimethyl acetal (9.89 g, 82.7 mmol). The reaction was stirred at 75° C. for 16 hours. Most of the volatiles were removed in vacuo to afford the crude product as an oil which was used in the next step (Step C) without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.[CH2:10]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[CH3:11]>CN(C=O)C.O>[CH2:10]([N:12]1[CH2:17][CH2:16][N:15]([C:2]2[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=2)[CH2:14][CH2:13]1)[CH3:11]
Reactant: O=Cc1ccc(Cl)nc1
Reactant: CCN1CCNCC1
Solvent: O
Solvent: CN(C)C=O
Product: CCN1CCN(c2ccc(C=O)cn2)CC1
Yield: 89 %

Procedure:
6-chloropyridine-3-carbaldehyde (5.0 g, 35.32 mmol) and 1-ethylpiperazine (20.16 g, 176.60 mmol, 22.42 mL) were heated overnight in a mixture of DMF/water (1:1, 40 mL) at 100° C. The reaction mixture was extracted with ethyl acetate (2×100 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness to provide 6-(4-ethylpiperazin-1-yl)pyridine-3-carbaldehyde, which was used in the next reaction without any further purification (6.91 g, 89% yield); 1H NMR (400 MHz, DMSO-d6): δ 0.99 (t, 3H), 2.31 (q, 2H), 2.39 (m, 4H), 3.66 (m, 4H), 6.91 (d, J=9.2 Hz, 1H), 7.82 (d, J=9.2 Hz, 1H), 8.55 (s, 1H), 9.7 (s, 1H); LRMS (ES) m/z 219.8.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:11][C:12]2[CH:13]=[C:14]([C:18](=O)[CH3:19])[CH:15]=[CH:16][CH:17]=2)[CH2:9][CH3:10])=[CH:4][C:3]=1[CH3:21].[NH:22]1[CH2:25][CH:24]([C:26]([OH:28])=[O:27])[CH2:23]1.CC(O)=O.[BH3-]C#N.[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:18]([N:22]3[CH2:25][CH:24]([C:26]([OH:28])=[O:27])[CH2:23]3)[CH3:19])[CH:15]=[CH:16][CH:17]=2)[CH2:9][CH3:10])=[CH:4][C:3]=1[CH3:21]
Reactant: CC[C@@H](Nc1cccc(C(C)=O)c1)c1ccc(Cl)c(C)c1
Reactant: O=C(O)C1CNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC[C@@H](Nc1cccc(C(C)N2CC(C(=O)O)C2)c1)c1ccc(Cl)c(C)c1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a solution of INT 11 (213 mg, 0.71 mmol) and azetidine-3-carboxylic acid (75 mg, 0.74 mmol) in MeOH (7 mL) was added HOAc (0.040 mL, 0.71 mmol) followed by NaCNBH3 (44 mg, 0.71 mmol). The reaction mixture was stirred at room temperature for 40 hours. More azetidine-3-carboxylic acid (10 mg, 0.099 mol) and NaCNBH3 (10 mg, 0.16 mmol) were added and the mixture was stirred at room temperature for an additional 4 hours. The mixture was concentrated. The residue was taken up in CH2Cl2 and washed with brine. The aqueous layer was extracted with CH2Cl2 and EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by preparative HPLC (H2O/CH3CN) to afford the title compound Example 6.
Reaction SMILES: [C:1]([CH2:3][CH2:4][P:5]([C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:10])[O:6][CH:7]([CH3:9])[CH3:8])#[N:2].N>C(O)C.[Ni]>[NH2:2][CH2:1][CH2:3][CH2:4][P:5]([C:11]([CH3:13])([CH3:12])[CH3:14])(=[O:10])[O:6][CH:7]([CH3:8])[CH3:9]
Reactant: CC(C)OP(=O)(CCC#N)C(C)(C)C
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CC(C)OP(=O)(CCCN)C(C)(C)C
Reaction time: 5 h

Procedure:
A mixture of 11.0 g of isopropyl 2-cyanoethyl(t-butyl)phosphinate, 17.0 g of ammonia and 1.7 g of Raney-Nickel in 110 ml of ethanol is hydrogenated during 5 hours. The catalyst is filtered off and the solvent removed by evaporation. The crude oil is purified by Kugelrohr-distillation to yield isopropyl 3-aminopropyl(t-butyl)phosphinate as an oil, b.p. 155°/1 Pa, n20D=1.4600.
Reaction SMILES: C[O-].[Na+].P(=O)([O-])O[C:6]([CH2:15][CH3:16])(CC)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:19][O:20][C:21]1[CH:22]=C([CH:26]=[C:27]([O:29][CH3:30])[CH:28]=1)C=O>CN(C=O)C>[CH3:19][O:20][C:21]1[CH:22]=[C:16]([CH:15]=[CH:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:26]=[C:27]([O:29][CH3:30])[CH:28]=1
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: CCC(CC)(O[PH](=O)[O-])c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C=Cc2ccccc2)cc(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
16.5 g (0.3 mol) of sodium methanolate are added at 0° C. to a solution of 60 g (0.29 mol) of crude diethylbenzyl phosphonate in 415 ml of anhydrous DMF. Then, at 0° C., a total of 50.0 g (0.3 mol) of 3,5-dimethoxybenzaldehyde is added in portions. After stirring for 1 hour at room temperature and heating for 1 hour under reflux, the product is precipitated by the addition of 660 ml of water/methanol (mixture ratio 2:1). Recrystallisation from water/methanol (2:1) yields 3,5-dimethoxystilbene in the form of colourless crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].C([Li])CCC.[CH3:16][C:17]([CH3:19])=[O:18]>C1COCC1>[F:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH3:10])=[C:2]([C:17]([OH:18])([CH3:19])[CH3:16])[CH:7]=1
Reactant: CC(C)=O
Reactant: COc1ccc(F)cc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)O
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 85 %

Procedure:
To a stirred solution of 2-bromo-4-fluoro anisole (4.1 g, 20 mmol) in anhydrous THF (40 mL) cooled to −78° C. and maintained under an atmosphere of argon was added n-butyl lithium (8.8 mL of 2.5 M solution in hexanes, 22 mmol). After stirring at −78° C. for 45 minutes, the reaction mixture was treated with anhydrous acetone (5 mL). After 15 minutes, the reaction mixture was quenched with a saturated solution of ammonium chloride and extracted with three 50 mL portions of methylene chloride. Combined extracts were washed with three 25 mL portions of water, dried over anhydrous sodium sulfate, and the solvent was evaporated to give 2-(5-fluoro-2-methoxyphenyl)propan-2-ol as a light brown thick oil (85% yield) which solidified on standing. The crude product was used for the next reaction without further purification.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2].[Cl-].[NH4+].O.O1CCCC1>C(O)C.[Fe]>[C:1]([NH:4][C:5]1[S:6][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ncc(Sc2ccc([N+](=O)[O-])cc2)s1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)Nc1ncc(Sc2ccc(N)cc2)s1
Yield: 79.5 %

Procedure:
To a mixture of 2-acetylamino-5-(4-nitrophenylthio)thiazole (2.8 g) and ammonium chloride (0.3 g) in a mixture of ethanol (60 ml), water (30 ml) and tetrahydrofuran (20 ml) was portionwise added the iron powder (3 g) at 80° C. with stirring. The mixture was refluxed for 2.5 hours with stirring. The reaction mixture was filtered by suction and the filtrate was concentrated under reduced pressure. The residue was triturated with water, the precipitates were collected by filtration, washed with water and dried in vacuo to give 2-acetylamino-5-(4-aminophenylthio)thiazole (2.0 g, yield: 79.5%).
Reaction SMILES: [CH:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([O:12][CH3:13])=[O:11])=[O:2].Br[CH2:15][CH2:16][F:17]>>[F:17][CH2:16][CH2:15][N:5]1[C:6]([CH3:9])=[C:7]([CH3:8])[C:3]([CH:1]=[O:2])=[C:4]1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1[nH]c(C)c(C)c1C=O
Reactant: FCCBr
Product: COC(=O)c1c(C=O)c(C)c(C)n1CCF

Procedure:
The title compound was prepared as pale brown crystals in 77.4% yeild in a similar procedure to that described in Referential Example 9 by using methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate and 1-bromo-2-fluoroethane.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=1[CH2:9]O.N1C(C)=CC(C)=CC=1C>C(Cl)Cl>[CH3:5][O:6][C:7]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=1[CH2:9][Cl:3]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(OC)c(CO)c1
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: COc1ccc(OC)c(CCl)c1
Reaction time: 0.5 h

Procedure:
Thionyl chloride (108 g) is slowly added during 1 hour to a stirred mixture of 2,5-dimethoxybenzyl alcohol (150 g), 2,4,6-collidine (108 g), and methylene chloride (750 ml) at room temperature. The reaction is slightly exothermic. After stirring for another 30 minutes, the mixture is washed with hydrochloric acid (2 N) and water and then dried (MgSO4). Evaporation gives a residue of 2,5-dimethoxybenzyl chloride which crystallizes (127 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.B.O1CCCC1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccc(Cl)cc1
Agent: B
Solvent: C1CCOC1
Product: OCCCc1ccc(Cl)cc1
Reaction time: 15 h
Yield: 84.7 %

Procedure:
To a stirred solution of 5.0 g (27 mmol) of 3-(4-chlorophenyl)propionic acid in 30 ml of tetrahydrofuran at 0° C., 30 ml (1M in THF, 30 mmol) of borane-tetrahydrofuran solution was added dropwise. The reaction was stirred for 15 hours. The reaction mixture was concentrated in vacuo. The residue was quenched with water and partitioned between diethyl ether and saturated sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted twice with 40 ml of diethyl ether. The organic layers were combined and washed with brine, dried over MgSO4 and concentrated in vacuo to obtain 3.9 g of a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([CH3:12])[CH2:6][CH2:5]2.N1C=CC=CC=1.[C:26](Cl)(=[O:28])[CH3:27]>ClCCl>[Br:1][C:2]1[C:3]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:26](=[O:28])[CH3:27])[CH:7]([CH3:12])[CH2:6][CH2:5]2
Reactant: CC(=O)Cl
Reactant: CC1CCc2c(ccc(Br)c2Oc2ccccc2)N1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1c2ccc(Br)c(Oc3ccccc3)c2CCC1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.6 %

Procedure:
A solution of rac-6-bromo-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline (0.022 g, 0.069 mmol) in dichloromethane (1 mL), and pyridine (0.017 mL, 0.207 mmol) was cooled to 0° C. and treated with acetyl chloride (5.41 μL, 0.076 mmol). The reaction mixture was then stirred at rt. After 10 min, additional acetyl chloride (3.93 μL, 0.055 mmol) was added and stirring was continued at rt. After 75 min, the reaction mixture was diluted with dichloromethane and washed with 1 N aqueous hydrochloric acid solution (2×0.5 mL) and 5% aqueous sodium chloride solution (0.5 mL). The dichloromethane layer was concentrated to afford crude rac-1-(6-bromo-2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.024 g, 96%) as a nearly colorless gum that solidified upon standing. The crude product was used without further purification. MS (ESI, pos. ion) m/z 360, 362 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:24][CH:23]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[C:14](=[O:34])[N:13]1[CH:9]([CH2:10][CH:11]([O:35][C:36]3[CH:41]=[C:40]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[N:39]=[C:38]([O:48][CH3:49])[N:37]=3)[CH2:12]1)[C:8](=[O:50])[NH:7]2)=[O:5])C.CO.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.C(Cl)Cl.O>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:15]2[C:14](=[O:34])[N:13]3[CH:9]([CH2:10][CH:11]([O:35][C:36]4[CH:41]=[C:40]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[N:39]=[C:38]([O:48][CH3:49])[N:37]=4)[CH2:12]3)[C:8](=[O:50])[NH:7][C:6]3([C:4]([OH:5])=[O:3])[CH:23]([CH2:24]3)[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:27][CH:28]=1
Reactant: CCOC(=O)C12CC1C=CCCCCCN(Cc1ccc(OC)cc1)C(=O)N1CC(Oc3cc(-c4ccccc4)nc(OC)n3)CC1C(=O)N2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN2CCCCCC=CC3CC3(C(=O)O)NC(=O)C3CC(Oc4cc(-c5ccccc5)nc(OC)n4)CN3C2=O)cc1
Temperature: 25 °C

Procedure:
Compound 2c (0.680 mg, 0.996 mmol) was dissolved in a 2:1:1 mixture of THF:MeOH:H2O (144 ml). LiOH (1 M, 10 ml) was added and the reaction mixture was stirred at RT over night. 5% Citric acid was added, followed by DCM. The organic layer was separated, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography, DCM: MeOH 9:1 which the title compound (380 mg, 58%), MS (M+H)+656.
Reaction SMILES: I[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH3:13][C:14]([CH:17]=[O:18])([CH3:16])[CH3:15].[Cl-].[NH4+]>C(OCC)C>[CH3:13][C:14]([CH3:16])([CH3:15])[CH:17]([C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1)[OH:18]
Reactant: Ic1cnccn1
Reactant: CC(C)(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)(C)C(O)c1cnccn1
Temperature: 25 °C

Procedure:
A solution of 2-iodopyrazine (1.0 g, 4.85 mmol) in dry diethylether (10 ml) was added to a solution of n-butyl lithium (4.04 ml of 1.5M, 6.06 mmol) in dry diethylether (20 ml) at -50° C. over a period of 5 minutes under a nitrogen atmosphere. This was followed immediately by the addition of a solution of pivaldehyde (0.65 g, 7.58 mmol) in dry diethylether (10 ml). The reaction mixture was allowed to warm to room temperature over 4 hours and then poured into a mixture of ice and 10% ammonium chloride solution. The aqueous solution was extracted with diethylether (3×50 ml). The combined extracts were washed with water, dried over magnesium sulphate and concentrated under reduced pressure. The residue was taken up in diethylether and filtered through a bed of silica gel. The filtrate was concentrated under reduced pressure to give the product as a clear oil. (0.76 g, 94%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH3:8])[N:5]=[CH:4][CH:3]=1.Cl[C:10]([CH:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][CH3:12].ClC(=C(C(OCC)=O)C(OCC)=O)CC.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:7]([N:6]1[C:2]([NH:1][C:10](=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][CH3:12])=[CH:3][CH:4]=[N:5]1)[CH3:8]
Reactant: CCn1nccc1N
Reactant: CC=C(Cl)C(C(=O)OCC)C(=O)OCC
Agent: CCOC(=O)C(C(=O)OCC)=C(Cl)CC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C(=O)OCC)=C(CC)Nc1ccnn1CC
Temperature: 90 °C

Procedure:
5-Amino-1-ethylpyrazole (5.85 g, 0.0526 moles, 1.06 equivalents) was added in one portion to 31.35 g of a solution at room temperature, wherein the solution is of diethyl (1-chloro-1-propen-1-yl)propanedioate and/or diethyl (1-chloropropylidene)propanedioate (about 11.65 g, 0.0496 moles, 1.0 equivalent) in toluene (about 19.70 g). Triethylamine (14 ml, 10.05 g, 0.0993 moles, 2.0 equivalents) was added slowly to the reaction mixture ensuring Tint<30° C. by use of an ice bath. The reaction mixture was then heated at 90° C. for approximately 15.5 hours and then was allowed to cool to room temperature. The reaction mixture was filtered, the filter cake washed with toluene (23 ml), and then the filter cake was pulled dry. Toluene (12 ml) was added to the filtrate, and the solution was concentrated in vacuo to about 55 ml volume. Toluene (12 ml) was added to the solution which was then concentrated down to about 55 ml, and this toluene (12 ml) addition and evaporation was repeated. The toluene solution (about 55 ml) washed with 2M aqueous sodium hydroxide solution (55 ml), and the two layers were separated. The organic layer was concentrated to dryness to yield diethyl {1-[(1-ethyl-1H-pyrazol-5-yl)amino]propylidene}propanedioate as a brown liquid (11.11 g, about 72% theory yield). HPLC (5 min generic solvent gradient): TRET about 3.05. Mass Spectrum: Found: MH+ 310.1, (M-H)− 308.1.