Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3](=[CH2:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:10][O-:11].[Na+]>CO.O>[CH2:7]([O:6][C:4](=[O:5])[C:3]([CH2:2][O:11][CH3:10])=[CH2:9])[CH3:8]
Reactant: C=C(CBr)C(=O)OCC
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=C(COC)C(=O)OCC
Temperature: 0 °C
Yield: 28.7 %

Procedure:
A solution of ethyl α-(bromomethyl)acrylate (0.99 g, 5.1 mmol [Villieras J., Rambaud M., Synthesis, 1982:924–926]) in methanol (10 mL) is added to an ice-cold solution of sodium methoxide (0.33 g, 6.1 mmol) in methanol (50 mL). The suspension is refluxed for 21 hours, cooled, diluted with water and extracted with dichloromethane. The organic extracts are dried over Na2SO4, filtered and concentrated under vacuum. The resulting residue is purified by flash column chromatography (1:5 ethyl acetate/hexanes) to afford the title compound (0.211 g). 1H NMR (200 MHz, CDCl3): δ 6.33–6.26 (m, 1H), 5.88–5.80 (m, 1H), 4.23 (q, 2H), 4.19–4.10 (m, 2H), 3.41 (s, 3H), 1.31 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:12][C:13]3[CH2:14][C:15]4[C:21]([C:22]5[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=5)=[N:20][N:19](COCC[Si](C)(C)C)[C:16]=4[C:17]=3[CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:12][C:13]3[CH2:14][C:15]4[C:21]([C:22]5[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=5)=[N:20][NH:19][C:16]=4[C:17]=3[CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(-c4ccc(OC)c(OC)c4)cc2-3)cc1
Agent: Cl
Solvent: CO
Product: COc1ccc(-c2n[nH]c3c2Cc2sc(-c4ccc(OC)c(OC)c4)cc2-3)cc1
Temperature: 100 °C
Yield: 88.6 %

Procedure:
2-(3,4-Dimethoxy-phenyl)-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.39 g, 0.7 mmol) was dissolved in MeOH and treated with concentrated HCl (0.22 mL, 7.3 mmol). The reaction mixture was heated at 100° C. for 4 hr. The solution was cooled to room temperature and the resultant precipitate was filtered, washed with MeOH and concentrated under reduced pressure to provide the corresponding 2-(3,4-Dimethoxy-phenyl)-6-(4-methoxy-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.25 g, 0.62 mmol) as white solid in 88% yield.
Reaction SMILES: C([Si](C)(C)[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][C@H:9]([NH:13][CH2:14][CH2:15][C:16]2[CH:31]=[CH:30][C:19]([O:20][C:21]3[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][N:22]=3)=[CH:18][CH:17]=2)[CH2:8]1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][C@H:9]([NH:13][CH2:14][CH2:15][C:16]2[CH:31]=[CH:30][C:19]([O:20][C:21]3[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][N:22]=3)=[CH:18][CH:17]=2)[CH2:8]1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CCC[C@H](NCCc2ccc(Oc3ccc(C(N)=O)cn3)cc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: NC(=O)c1ccc(Oc2ccc(CCN[C@H]3CCC[C@@H](O)C3)cc2)nc1
Reaction time: 4 h
Yield: 70.1 %

Procedure:
Treat (±)-(cis)-6-(4-{2-[3-(tert-butyldimethyl-silyloxy)cyclohexylamino]ethyl}phenoxy)nicotinamide (56.8 mg, 0.12 mmol) in THF (1.0 mL) with 1.0 M tetrabutylammonium fluoride (TBAF) in THF (0.5 eq) for 1 hour. Add another 0.5 eq of 1.0 M TBAF and stir for 4 hours. Add 1.0 eq of 1.0 M TBAF and stir for 2.5 days. Concentrate and purify by flash chromatography, eluting with 10% (2.0 M NH3 in MeOH) in CH2Cl2. Repeat the chromatography to afford the title compound (29.9 mg, 70%): MS ES+ 356.0 (M+H)+, HRMS calcd for C21H28N3O2 356.1974 (M+H)+, found 356.1965, time 0.41 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-99% over 19 min], tR=7.11 min, 100% purity; Anal. Calcd for C20H25N3O3.0.4CH2Cl2.0.4MeOH: C, 62.11; H, 6.87; N, 10.45. Found: C, 61.95; H, 6.88; N, 10.36.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][N:8]([CH3:19])[C:9]1[CH:18]=[CH:17][C:12]([CH:13]=[CH:14][CH:15]=[O:16])=[CH:11][CH:10]=1.Cl.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:19][N:8]([CH3:7])[C:9]1[CH:18]=[CH:17][C:12]([CH2:13][CH2:14][CH2:15][OH:16])=[CH:11][CH:10]=1
Reactant: CN(C)c1ccc(C=CC=O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Al+3]
Solvent: C1CCOC1
Product: CN(C)c1ccc(CCCO)cc1
Temperature: 25 °C

Procedure:
LiAlH4 (0.066 g, 1.71 mmol) was added to a solution of 4-(dimethylamino)cinnamaldehyde (0.10 g, 0.57 mmol) in anhydrous THF (2 mL). The reaction mixture was heated at reflux for 2 hours and cooled to rt. To the reaction mixture was added 1M HCl dropwise. The reaction mixture was stirred for 5 minutes before saturated NaHCO3 was added and the mixture was extracted with DCM. The organic phases were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with a gradient of PE:EtOAc 2:1 to provide the desired product 3-(4-(dimethylamino)phenyl)propan-1-ol (48A).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]([NH:20]C(=O)C3C=CC=CC=3)=[O:19])[CH2:13][CH2:12]2)=[CH:2]1.[OH-].[Na+]>O.CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][N:11]2[CH2:12][CH2:13][CH:14]([NH:17][C:18]([NH2:20])=[O:19])[CH2:15][CH2:16]2)=[CH:2]1
Reactant: O=C(NC(=O)c1ccccc1)NC1CCN(Cc2c[nH]c3ccccc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NC(=O)NC1CCN(Cc2c[nH]c3ccccc23)CC1
Reaction time: 3 h

Procedure:
1-[1-(Indol-3-ylmethyl)piperid-4-yl]-3-benzoylurea (0.5 g, 1.33 mmol) was added to a solution of sodium hydroxide (1 g, 0.025 mol) in water (4 ml) and methanol (16 ml). The resulting suspension was stirred for 3 hours until all the solid material had dissolved then allowed to stand at room temperature overnight, giving a blue solution. The solvents were evaporated in vacuo and the solid residue triturated thoroughly with water, collected and dried (0.32 g, 88.9%). The obtained title compound was then recrystallised from aqueous ethanol, mp--softens slowly from 122°-128° C.
Reaction SMILES: [CH3:1][C:2]1[N:23]([CH3:24])[C:5]2[CH:6]=[C:7]([C:20](O)=[O:21])[C:8]3[CH2:9][CH2:10][CH:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[NH:12][C:13]=3[C:4]=2[N:3]=1.[CH3:25][NH2:26].O>O1CCCC1.CN(C)C=O>[CH3:25][NH:26][C:20]([C:7]1[C:8]2[CH2:9][CH2:10][CH:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:12][C:13]=2[C:4]2[N:3]=[C:2]([CH3:1])[N:23]([CH3:24])[C:5]=2[CH:6]=1)=[O:21]
Reactant: CN
Reactant: Cc1nc2c3c(c(C(=O)O)cc2n1C)CCC(c1ccccc1)N3
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)c1cc2c(nc(C)n2C)c2c1CCC(c1ccccc1)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
To a suspension of 1.0 g (3.1 mmol) 2,3-dimethyl-8-phenyl-6,7,8,9-tetrahydro-3H-imidazo[4,5-h]quinoline-5-carboxylic acid in 10 ml tetrahydrofuran and 5 ml N,N-dimethylformamide were added 1.0 g (6.2 mmol) N,N′-carbonyldiimidazole. After 1 h at 60° C., the solution was cooled down and 15.6 ml (31.2 mmol) methylamine (2M in tetrahydrofuran) were added. The mixture was stirred 2 h at ambient temperature and then poured into 50 ml water. The precipitate was collected, washed with water and dried at 50° C. to yield 0.87 g (84%) of the title compound. m.p. 259° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:13][CH2:14][C@@H:15]1[O:19][C:18]([CH3:21])([CH3:20])[O:17][C@H:16]1[CH2:22][OH:23])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.O>C(Cl)Cl>[CH3:1][S:2]([O:23][CH2:22][C@H:16]1[C@H:15]([CH2:14][O:13][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:19][C:18]([CH3:20])([CH3:21])[O:17]1)(=[O:4])=[O:3]
Reactant: CC1(C)O[C@@H](CO)[C@H](COCc2ccccc2)O1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(C)O[C@@H](COCc2ccccc2)[C@H](COS(C)(=O)=O)O1
Reaction time: 0.33 h
Yield: 100 %

Procedure:
A solution of 19.21 g of methanesulfonyl chloride (168 mmol) in methylene chloride (90 ml) was added to a solution of 35.27 g of {(4S,5S)-5-[(benzyloxy)methyl]-2,2-dimethyl-1,3-dioxolan-4-yl}methanol obtained in Reference Example (1a) (140 mmol) and 29.2 ml of triethylamine (210 mmol) in methylene chloride (270 ml) under ice-cooling over 30 minutes, and the mixture was stirred at the same temperature for 20 minutes. 0.76 ml of water (42 mmol) was added to the reaction mixture, and the mixture was further stirred at room temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure and diluted with water, followed by extraction with ethyl acetate. Then, the organic layer was washed with water, a saturated sodium bicarbonate aqueous solution and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain 46.19 g of the crude title compound.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=3)[N:7]=[C:6]([C:18]([F:21])([F:20])[F:19])[CH:5]=2)[CH2:3][CH2:2]1.[Cl:22]N1C(=O)CCC1=O.CCOC(C)=O>CN(C=O)C>[Cl:22][C:5]1[C:6]([C:18]([F:20])([F:21])[F:19])=[N:7][N:8]([C:9]2[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[C:4]=1[CH:1]1[CH2:2][CH2:3]1
Reactant: O=[N+]([O-])c1ccc(-n2nc(C(F)(F)F)cc2C2CC2)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-n2nc(C(F)(F)F)c(Cl)c2C2CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
Intermediate 13 (1 g, 3.36 mmol) was dissolved in DMF and to this N-Chlorosuccinimide (0.54 g, 4.0 mmol) was added at 0° C. Then reaction was allowed to stir at rt for 2 h. After completion of the reaction, work up (EtOAc) afforded the title compound (0.802 mg). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.39 (d, J 9, 2H), 7.82 (d, J 9, 2H), 1.91-1.80 (m, 1H), 1.10-1.00 (m, 2H), 0.80-0.72 (m, 2H).
Reaction SMILES: [C:1]([C@H:4]([NH:31]C(=O)O)[CH2:5][C:6](=[O:30])[NH:7][CH:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([C:21]3[NH:29][C:24]4[CH:25]=[N:26][CH:27]=[CH:28][C:23]=4[N:22]=3)[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)(=[O:3])[NH2:2].Cl>O1CCOCC1>[NH2:31][C@H:4]([CH2:5][C:6]([NH:7][CH:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([C:21]3[NH:29][C:24]4[CH:25]=[N:26][CH:27]=[CH:28][C:23]=4[N:22]=3)[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:30])[C:1]([NH2:2])=[O:3]
Reactant: NC(=O)[C@@H](CC(=O)NC1c2ccccc2-c2c(-c3nc4ccncc4[nH]3)cccc21)NC(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)[C@H](N)CC(=O)NC1c2ccccc2-c2c(-c3nc4ccncc4[nH]3)cccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Dissolve 144 mg of tert-butyl ester of {(R)-1-carbamoyl-2-[4-(3H-imidazo[4,5-c]pyridin-2-yl)-9H-fluoren-9(R,S)-ylcarbamoyl]-ethyl}-carbamoic acid, obtained in Example 59, in 5 ml of dioxan and add 1 ml of a 4M solution of hydrochloric acid in dioxan. After stirring for 5 hours at room temperature, dry the solid that formed. After washing successively with a saturated aqueous solution of sodium hydrogen carbonate, then with dichloromethane, we obtain 145 mg of (R)-2-amino-N4-[4-(3H-imidazo[4,5-c]pyridin-2-yl)-9H-fluoren-9(R,S)-yl]-succinamide, in the form of a pale green, crystalline solid, with the following characteristics:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=O)[C:5]2(O)[CH2:12][C:13](=[O:15])[CH3:14].C(OCC)(=O)C.O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:12][CH:13]([OH:15])[CH3:14]
Reactant: CC(=O)CC1(O)C(=O)Nc2ccc(F)cc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(O)Cc1c[nH]c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The aldol product 48 (10 mmol) was dissolved in absolute THF (20 ml) under an Ar atmosphere. BH3xTHF (30 ml, 1 M solution, 30 mmol) was then added to the mixture, while cooling with a water bath, and the mixture was stirred at room temperature for 4 h. The course of the reaction was monitored by TLC. When the reaction had ended, the reaction solution was added to a mixture of ethyl acetate (50 ml) and H2O (50 ml). After separation of the phases, the aqueous phase was extracted twice with ethyl acetate (30 ml each time). The combined organic phases were dried over Na2SO4 and concentrated under vacuo. The residue was filtered over silica gel with ethyl acetate. After removal of the solvent, the product was obtained in the form of a sufficiently pure oil and crystallizes spontaneously.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([O:28][CH3:29])[CH:22]=1>>[CH2:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([O:28][CH3:29])[CH:22]=3)[N:7]=2)=[CH:9][CH:10]=1)[CH:15]([CH3:17])[CH3:16]
Reactant: COc1cc(CCN)ccc1O
Reactant: CC(C)Cc1ccc(-c2ccnc(Cl)n2)cc1
Product: COc1cc(CCNc2nccc(-c3ccc(CC(C)C)cc3)n2)ccc1O

Procedure:
Intermediate 49 was coupled with 4-(2-Amino-ethyl)-2-methoxy-phenol following procedure F. LC-MS showed the product had the expected M+H+ of 378. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.3 (m, 1H) 7.99 (d, 2H) 7.25 (d, 2H) 6.95 (d, 1H) 6.85 (m, 1H) 6.74 (m, 2H) 5.5 (br s, 1H) 3.8 (s, 3H) 3.75 (m, 2H) 2.87 (t, 2H) 2.52 (t, 2H) 1.88 (m, 1H) 0.9 (d, 6H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=O.[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH2:17].C([BH3-])#N.[Na+]>CO>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[NH:17][CH2:16][CH:15]([O:18][CH3:19])[O:14][CH3:13]
Reactant: COC(CN)OC
Reactant: O=C1CCc2c(F)cc(F)cc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(CNC1CCc2c(F)cc(F)cc21)OC
Temperature: 65 °C
Reaction time: 18 h

Procedure:
A mixture of 4,6-difluoroindan-1-one (11.3 g, 67.26 mmol), 2,2-dimethoxyethylamine (7.07 g, 67.26 mmol) and sodium cyanoborohydride (4.23 g) in 75 mL of methanol was heated at gentle reflux and stirred under nitrogen for approximately 18 hours. Additional sodium cyanoborohydride (2.12 g) was added and the mixture was heated at 65° C. for 20 hours. The solvents were removed by evaporation. Purification of the residue by column chromatography on silica gel (elution: 2.5% methanol/methylene chloride) gave (4,6-difluoroindan-1-yl)-(2,2-dimethoxyethyl)amine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[O:15])=[CH:4][CH:3]=1.[CH3:16][C:17]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:21])[CH2:18][Mg]Cl>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:15])[CH2:16][C:17]([CH3:21])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:18])=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Reactant: CC(C)(C[Mg]Cl)c1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)CC(C)(C)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 114, Step 3, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and 2-methyl-2-phenylpropylmagnesium chloride.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:13][NH:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:22])C(=O)C1>C(#N)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:13][NH:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[Br:22]
Reactant: Nc1ccc(C2CCC(=O)NC2)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Nc1ncc(C2CCC(=O)NC2)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-(6-aminopyridin-3-yl)piperidin-2-one (132 mg, 0.690 mmol) in Acetonitrile (8.00 mL) was added NBS (98 mg, 0.552 mmol) at 0° C. The reaction mixture was stirred for 30 min upon warming-up to room temperature. LCMS 0.28 min, MH+270/272; 0.7 min, MH+400.1/402.1 (SEM protected one). After quenched with Na2S2O3 solution, the reaction mixture was extracted with EtOAc, which was washed with NaHCO3 solution and brine. The organic layer was dried over anhydrous Na2SO4, filtered off, concentrated in vacuo. The crude 5-(6-amino-5-bromopyridin-3-yl)piperidin-2-one was used for the next step.
Reaction SMILES: O[C:2]1[C:11]2[CH:10]=[C:9]3[N:12]=[CH:13][S:14][C:8]3=[CH:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[Cl:17][C:18]1[C:24]([O:25][CH3:26])=[CH:23][C:21]([NH2:22])=[C:20]([CH3:27])[CH:19]=1.Cl.N1C=CC=CC=1>P(Cl)(Cl)(Cl)=O.CN(C)C=O>[Cl:17][C:18]1[C:24]([O:25][CH3:26])=[CH:23][C:21]([NH:22][C:2]2[C:11]3[CH:10]=[C:9]4[N:12]=[CH:13][S:14][C:8]4=[CH:7][C:6]=3[N:5]=[CH:4][C:3]=2[C:15]#[N:16])=[C:20]([CH3:27])[CH:19]=1
Reactant: N#Cc1cnc2cc3scnc3cc2c1O
Reactant: COc1cc(N)c(C)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc(Nc2c(C#N)cnc3cc4scnc4cc23)c(C)cc1Cl
Yield: 15.5 %

Procedure:
To a mixture of 100 mg (0.44 mmol) of 8-hydroxy[1,3]thiazolo[4,5-g]quinoline-7-carbonitrile in 5 mL of phosphoryl chloride is added five drops of N,N-dimethylformamide. The mixture is heated at reflux temperature for 30 minutes and then concentrated in vacuo. To the residue at 0° C. is added 50 mL of water. The solids are collected, washed with water, and dried in vacuo. To a mixture of this compound in 2 mL of 2-ethoxyethanol are added 76 mg (0.44 mmol) of 4-chloro-5-methoxy-2-methylaniline and 20 mg of pyridine hydrochloride. The mixture is refluxed for one hour and concentrated. The residue is chromatographed by silica gel chromatography, eluting with 9:1 methylene chloride/methanol to yield 26 mg (16%) of product as a dark oil.
Reaction SMILES: [C:1]1([C:11](OCC)=[O:12])([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[CH2:3][CH2:2]1.[H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+]>C1COCC1>[OH:12][CH2:11][C:1]1([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[CH2:2][CH2:3]1
Reactant: CCOC(=O)C1(C(=O)OC(C)(C)C)CC1
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1(CO)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Step 2 To a stirred solution of 1-tert-butyl 1-ethyl cyclopropane-1,1-dicarboxylate (0.5 g, 2.33 mmol) in THF (11.7 mL) at −78° C. was added lithium tri-tert-butoxyaluminum hydride solution (11.7 mL, 11.7 mmol) dropwise. The mixture was warmed to room temperature and stirred overnight before it was quenched at 0° C. by the addition of a saturated solution of potassium sodium tartrate. EtOAc was added the phases were separated and the aqueous phase was extracted into EtOAc (×2). Combined organic extracts were dried (Na2SO4), filtered and concentrated providing tert-butyl 1-(hydroxymethyl)-cyclopropane-1-carboxylate which was used without further purification, 0.438 g.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=1)(=[O:3])[CH3:2].Cl[C:15]([O:17][CH2:18][CH3:19])=[O:16].O>N1C=CC=CC=1>[C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:8]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: CC(=O)NCCc1cccc(N)c1
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)Nc1cccc(CCNC(C)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
N-Acetyl-N-(3-aminophenethyl)amine (1.7 g, Production Example 29b) was dissolved in pyridine (5 ml). Under ice-cooling, ethyl chloroformate (1.4 ml) was added dropwise thereinto, followed by stirring at room temperature for one hour. Then, the mixture was ice-cooled again and water was added thereto. The mixture was extracted with ethyl acetate, and the extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, to give the title compound (2.358 g, 97%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH:28]=[CH:29][CH:30]=3)[CH2:18][O:19][CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH3:37]>Cl.O1CCOCC1>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH:28]=[CH:29][CH:30]=3)[CH2:18][O:19][CH2:20][C:21]([OH:23])=[O:22])[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH3:37]
Reactant: COCc1cc(-c2nc(-c3cccc(COCC(=O)OC(C)(C)C)c3)no2)ccc1-c1ccccc1C
Agent: Cl
Solvent: C1COCCO1
Product: COCc1cc(-c2nc(-c3cccc(COCC(=O)O)c3)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 81.8 %

Procedure:
Tert-butyl [(3-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzyl)oxy]acetate (411 mg, 0.82 mmol) was dissolved in a 4M solution of HCl in dioxane (5 mL). The resulting mixture was stirred at RT for 5 hours. The reaction mixture was concentrated under reduced pressure to give the title compound as a colorless oil (298 mg, 82%). 1H NMR (DMSO-d6, 300 MHz): d=12.75 (brs, 1H), 8.33 (d, J=1.5 Hz, 1H), 8.18 (dd, J=7.9, 1.8 Hz, 1H), 8.13 (brs, 1H), 8.06 (m, 1H), 7.61 (m, 2H), 7.43 (d, J=8.0H, 1H), 7.37-7.26 (m, 3H), 7.15 (d, J=7.0 Hz, 1H), 4.68 (s, 2H), 4.23 (d, 2H), 4.17 (d, J=12.7 Hz, 1H), 4.17 (d, J=12.7 Hz, 1H), 4.16 (s, 2H), 3.25 (s, 3H), 2.04 (s, 3H). LC/MS (Method A): 445.3 (M+H)+. 443.4 (M−H)−. HPLC (Method A) Rt: 5.18 min (purity: 97.5%).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][NH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:14][CH2:15][C:16](Cl)=[O:17].C(OCC)(=O)C.CCCCCCC>C(OCC)(=O)C>[Cl:14][CH2:15][C:16]([N:11]1[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=2)[CH2:8][CH2:9][CH2:10]1)=[O:17]
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCC2
Reactant: O=C(Cl)CCl
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: O=C(CCl)N1CCCc2ccc([N+](=O)[O-])cc21
Temperature: 60 °C
Reaction time: 2 h

Procedure:
1.78 g of 7-nitro-1,2,3,4-tetrahydroquinoline (0.01 mol) are dissolved in 15 ml of ethyl acetate. This solution is run into a mixture of 15 ml of ethyl acetate and 0.80 ml of chloroacetyl chloride. A white precipitate forms immediately, and stirring is continued at 30° C. for 2 h (the reaction is monitored by thin layer chromatography (90/10 ethyl acetate/heptane)). After 2 h, since the reaction is incomplete, 0.2 equivalent of chloroacetyl chloride is added and the temperature is raised to 60° C.; the solid formed undergoes dissolution. When the reaction has finished, the medium is cooled and the solvent is evaporated off. 2.46 g of a beige product which corresponds to the expected compound are recovered.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[C:8]2[CH:15]=[N:14][N:13]([CH2:16][CH3:17])[C:9]2=[N:10][C:11]=1[CH3:12])=[O:5])[CH3:2].[OH:19][CH:20]([CH3:24])[CH2:21][CH2:22][NH2:23]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:23][CH2:22][CH2:21][CH:20]([OH:19])[CH3:24])=[C:8]2[CH:15]=[N:14][N:13]([CH2:16][CH3:17])[C:9]2=[N:10][C:11]=1[CH3:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)nc2c(cnn2CC)c1Cl
Reactant: CC(O)CCN
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)nc2c(cnn2CC)c1NCCC(C)O
Temperature: 45 °C

Procedure:
2.75 each of 4-chloro-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester and 3-hydroxy-n-butylamine are combined with 15.6 ml of dry toluene under N2 and heated at 45° C. for 48 hours. The mixture was cooled to room temperature and the toluene layer was decanted from the oil that separated out. The toluene layer was washed with water and then dried and concentrated in vacuo to yield 3.7 g of product which crystallized on trituration with hexane. This was recrytallized from hexane to yield 1.91 g of white product mp 94.5°-96.5° C.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][NH:6][CH2:7][CH2:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1.Cl.O1CCO[CH2:20]1>>[ClH:1].[CH3:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:7][CH2:8][C:9]2[S:10][CH:11]=[CH:12][C:13]=2[CH2:20]1
Reactant: C1COCO1
Reactant: Cc1ccccc1CNCCc1cccs1
Agent: Cl
Product: Cc1ccccc1CN1CCc2sccc2C1
Temperature: 10 °C
Yield: 62.7 %

Procedure:
N-[(2-methylbenzyl)]-2-(2-thienyl)ethylamine HCl (26.8 g, 0.1 moles) is suspended in 75 ml of 1,3-dioxolane. 0.25 ml of 37% hydrochloride acid is added. The reaction mixture is refluxed for 24 hours. Thereafter, the mixture is cooled to 10° C. and the crystalline precipitate is filtered and washed twice with 5 ml of isopropanol. The product is dried at 60° C. under vacuum to yield 17.4 g (62.7%) of 5-(2-methylbenzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine HCl having a m.p. of 207-210° C.