Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([F:14])[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([O:19]CC)=[O:18])=[CH:5]2)[CH2:3][CH2:2]1>Cl>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([F:14])[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Agent: Cl
Product: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Temperature: 25 °C
Yield: 90.7 %

Procedure:
A suspension of 4.1 g (13.3 mmol) of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate in 150 mL of 6N hydrochloric acid was refluxed for 6 hours, then cooled to room temperature. The solids were filtered, washed with water and ether, and dried to give 3.2 g of the title compound, mp>300° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].O>CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][O:9][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:4][CH:3]=1
Reactant: CCCCCCI
Reactant: OCCOc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCOCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In DMF (195 ml) was dissolved 2-(4-bromophenoxy)-1-ethanol (19. 5 g). To the mixture was added under ice-cooling 65% sodium hydride (5.3 g), and the mixture was stirred at room temperature for 2 hours. To the mixture was added dropwise iodohexane (19.9 ml), and the mixture was stirred for 2 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=8/1) to give 1-bromo-4-(2-hexyloxyethoxy)benzene (16.2 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH:27]1[CH2:31][CH2:30][CH2:29][O:28]1)[C:4]1[C:5]2[CH2:25][NH:24][CH2:23][CH2:22][C:6]=2[N:7]=[C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[N:9]=1)[CH3:2].[C:32](O)(=[O:34])[CH3:33].C(O)C=O.C([BH3-])#N.[Na+]>CO>[CH2:1]([N:3]([CH2:26][CH:27]1[CH2:31][CH2:30][CH2:29][O:28]1)[C:4]1[C:5]2[CH2:25][N:24]([CH2:33][CH2:32][OH:34])[CH2:23][CH2:22][C:6]=2[N:7]=[C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:15][CH:16]=2)[N:9]=1)[CH3:2]
Reactant: CC(=O)O
Reactant: CCN(CC1CCCO1)c1nc(Nc2ccc(-c3cnco3)cc2)nc2c1CNCC2
Agent: O=CCO
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCN(CC1CCCO1)c1nc(Nc2ccc(-c3cnco3)cc2)nc2c1CN(CCO)CC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38.7 %

Procedure:
N4-Ethyl-N2-(4-(oxazol-5-yl)phenyl)-N4-((tetrahydrofuran-2-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (125 mg, 0.30 mmol) was dissolved in methanol (3 mL). Acetic acid (0.017 mL, 0.30 mmol) was added followed by glycoaldehyde (17.85 mg, 0.30 mmol). The reaction mixture was stirred for 15 minutes at room temperature and sodium cyanoborohydride (18.68 mg, 0.30 mmol) (MP—CNBH3) was added. The reaction was stirred overnight at room temperature, the MP—CNBH3 was filtered off, the solvent was evaporated under reduced pressure and the crude was purified by preparative HPLC yielding 2-(4-(ethyl((tetrahydrofuran-2-yl)methyl)amino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanol (54.0 mg, 34.6%) as acetate salt. MS (ES+) m/z 465.3 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10](=O)[C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:13][CH:12]=3)=[CH:7][C:6]=2[CH:26]=1.C([BH3-])#N.[Na+]>[I-].[Zn+2].[I-].ClCCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:15][CH:16]=3)=[CH:7][C:6]=2[CH:26]=1
Reactant: O=C(c1ccc(OCc2ccccc2)cc1)c1cc2cc(Br)ccc2o1
Agent: [BH3-]C#N
Agent: [I-]
Agent: [Na+]
Solvent: ClCCCl
Product: Brc1ccc2oc(Cc3ccc(OCc4ccccc4)cc3)cc2c1
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
5-Bromo-2-(4-benzyloxybenzoyl)benzofuran (9.0 g, 22 mmol), sodium cyanoborohydride (10.4 g, 0.17 mol), zinc iodide (10.5 g, 0.35 mol) and 1,2-dichloroethane (350 ml) were combined and heated to reflux for 6 hours. The mixture was cooled, quenched with saturated ammonium chloride (500 ml), acidified with concentrated HCl and stirred for 30 minutes. The layers were separated, the aqueous layer was extracted with dichloromethane (400 ml) and the combined organic layers were washed with water and brine, dried over magnesium sulfate and concentrated, leaving a white solid (8.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH:23]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.[CH2:36](I)[CH3:37]>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH:23]5[CH2:28][CH2:27][N:26]([CH2:36][CH3:37])[CH2:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1
Reactant: CCI
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C1CCNCC1
Product: CCN1CCC(N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)CC1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-(1-ethylpiperidin-4-yl)-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-piperidin-4-yl-1,3-thiazolidine-2,4-dione (Example 113) and ethyl iodide at rt following General Procedure S.
Reaction SMILES: Br.Br[CH:3]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=O.C[C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[S:25])=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[F:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]2[N:26]=[C:24]([C:23]3[CH:27]=[CH:28][CH:20]=[CH:21][CH:22]=3)[S:25][C:3]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:7][CH:8]=1
Reactant: O=C(c1ccc(F)cc1)C(Br)c1ccncc1
Reactant: Cc1ccc(C(N)=S)cc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nc(-c3ccccc3)sc2-c2ccncc2)cc1
Yield: 19.8 %

Procedure:
A solution of 2-bromo-1-(4-fluorophenyl)-2-(4-pyridyl)ethanone hydrobromide (1.6 g, 4.1 mmol) and thiobenzamide (0.57 g, 4.2 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 14 h. To the reaction mixture was poured aqueous sodium hydrogencarbonate solution and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried. The crude crystals were recrystallized from ethyl acetate to give the title compound (0.27 g, yield 19%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:11][C:12]=2[CH3:13])=[CH:4][CH:3]=1.[Br:20]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:13][C:12]1[S:11][C:10]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[N:9][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: Cc1sc(-c2ccccc2)nc1-c1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(-c2nc(-c3ccccc3)sc2CBr)cc1
Yield: 68.8 %

Procedure:
A mixture of 4-(4-chlorophenyl)-5-methyl-2-phenylthiazole (35.1 g), N-bromosuccinimide (24.0 g), azobisisobutyronitrile (4.11 g) and carbon tetrachloride (400 mL) was stirred with heating under reflux for 3 hrs. The precipitated solid was removed by filtration and the organic layer was concentrated. The residue was purified by silica gel column chromatography. 5-(Bromomethyl)-4-(4-chlorophenyl)-2-phenylthiazole (30.8 g, 69%) was obtained as crystals from a fraction eluted with hexane-ethyl acetate (19:1, volume ratio). Recrystallization from ethyl acetate gave colorless prism crystals. melting point: 108–109° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:21]1[N:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:23][N:22]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)C>[CH2:27]([C:24]1[CH:23]=[N:22][C:21]([C:14]2[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:12][CH:13]=2)=[N:26][CH:25]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCCc1cnc(Cl)nc1
Reactant: OB(O)c1ccc(CCOCc2ccccc2)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCCCCCCCc1cnc(-c2ccc(CCOCc3ccccc3)cc2)nc1
Temperature: 80 °C
Yield: 77 %

Procedure:
1.27 g (4.96 mmol) of 4-(2-benzyloxyethyl) phenylboronic acid, 1.26 g (4.96 mmol) of 2-chloro-5-decylpyrimidine, 0.19 g of tetrakis (triphenylphosphine) palladium, 8 ml of 2M sodium carbonate, 8 ml of toluene and 4 ml of ethanol were, under presence of nitrogen, heated at 80° C. for 3 hours. After the reactions had been completed, extraction with toluene was performed and the extracted solution was dried with anhydrous sodium sulfate. The solvent was removed by filtration and refining was performed by recrystallization (toluene/methanol) so that 1.65 g of 2-{4-(5-decylpyrimidine-2-yl) phenyl}ethylbenzylether was obtained (yield 77%).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[NH:3][C:2]1=O.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:2]1[N:3]=[C:4]([OH:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: O=c1[nH]c(=O)c2ccccc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Oc1nc(Cl)nc2ccccc12

Procedure:
A mixture of 300 g of the product of Step A, 150 ml of N,N-dimethyl-aniline and 1 liter of phosphoryl chloride was refluxed for 51/2 hours and was cooled and poured with vigorous stirring onto crushed ice. The mixture was filtered and the product was washed with ice water until the wash water was neutral. The product was added with stirring to 2.25 liters of 2 N aqueous sodium hydroxide and the mixture was stirred for about 3 hours until complete dissolution occured. The mixture was filtered and the filtrate was neutralized by addition of glacial acetic acid. The mixture was filtered and the product was washed with water and dried to obtain 263 g of 2-chloro-4-hydroxy-quinazoline.
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[C:3](=[O:7])[CH2:4][C:5]#[N:6].[CH2:9](O)[CH2:10][OH:11].Cl[Si](C)(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH:2]([C:3]1([CH2:4][C:5]#[N:6])[O:11][CH2:10][CH2:9][O:7]1)([CH3:8])[CH3:1]
Reactant: CC(C)C(=O)CC#N
Reactant: OCCO
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)C1(CC#N)OCCO1
Temperature: 40 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
4-Methyl-3-oxopentanenitrile was added to a mixture of ethylene glycol (4.7 mL, 84 mmol) and chlorotrimethylsilane (10.6 mL, 84 mmol) in anhydrous dichloromethane (50 mL). The mixture was stirred at 40° C. overnight. After cooling to room temperature a solution of 5% sodium bicarbonate (50 mL) was added, the layer were separated and the water phase back extracted three times with diethyl ether. The organics were combined, dried (MgSO4), filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane/ethyl acetate 8:2) to afford 2-(2-isopropyl-1,3-dioxolan-2-yl)acetonitrile (3.38 g, 78%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 4.21-4.16 (m, 2H), 4.07-3.99 (m, 2H), 2.69 (s, 2H), 2.08-2.01 (m, 1H), 0.96 (d, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][C:14]([CH3:17])([NH2:16])[CH3:15].[Cl:18][C:19]1[O:23][C:22]([CH:24]=O)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[O:23][C:22]([CH2:24][NH:16][C:14]([CH3:17])([CH3:15])[CH2:13][O:12][C:3]2[CH:4]=[CH:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]=2[Cl:1])=[CH:21][CH:20]=1
Reactant: O=Cc1ccc(Cl)o1
Reactant: CC(C)(N)COc1ccc2ccccc2c1Cl
Product: CC(C)(COc1ccc2ccccc2c1Cl)NCc1ccc(Cl)o1
Yield: 32 %

Procedure:
Prepared from 1-[(1-chloronaphthalen-2-yl)oxy]-2-methylpropan-2-amine and 5-chlorofuran-2 carbaldehyde in 32% yield as a yellow oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([CH2:29][CH3:30])=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20]Cl)=[CH:14][CH:13]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:31][NH2:32]>CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([CH2:29][CH3:30])=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:32][CH3:31])=[CH:14][CH:13]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc2ocnc2c1
Reactant: CN
Solvent: CO
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCNC)cc1)c1ccc2ocnc2c1
Yield: 25 %

Procedure:
According to the same procedure as example 1, step E described, 4-(2-(benzo[d]oxazol-5-yl)-1-(4-(2-chloroethoxy)phenyl)but-1-enyl)phenol (0.1 g, 1.0 eq) was reacted with MeNH2 (30% wt in water, 10 mL) in MeOH (20 mL) under reflux to give 20 mg desired product (25%, Z/E=1/1). 1H NMR (400 MHz, CDCl3) δ 7.08 (d, J=8.4 Hz, 2H), 7.01 (d, J=8.8 Hz, 2H), 6.82 (d, J=8.4 Hz, 2H), 6.68-6.80 (m, 6H), 6.58-6.64 (m, 4H), 6.49-6.55 (m, 4H). 6.46 (d, J=8.8 Hz, 2H), 5.89 (s, 2H), 4.09 (t, J=5.6 Hz, 2H), 3.97 (t, J=5.2 Hz, 2H), 3.00 (t, J=5.2 Hz, 2H), 2.92 (t, J=5.6 Hz, 2H), 2.54 (s, 3H), 2.50 (s, 3H), 2.39-2.49 (m, 4H), 0.80-1.00 (m, 6H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[NH2:25][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:23])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][N:19]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:18]1
Reactant: IC1CCCC1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCCNC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC3CCCN(C4CCCC4)C3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[2-(3-piperidinyl)ethyl]-9H-purin-6-amine and iodocyclopentane.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[CH2:7][C:8](=[O:10])[CH3:9]>>[N:1]1([CH2:7][C:8](=[O:10])[CH3:9])[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: CC(=O)CCl
Product: CC(=O)Cn1cccn1
Temperature: 90 °C
Yield: 37.6 %

Procedure:
1H-pyrazole (1.0 g, 15 mmol) was dissolved in chloroacetone (3.0 g, 32 mmol) and heated at 90° C. for 10 hr. Purification by silica gel column, elution with 1:1 hexanes:DCM afforded the title compound (700 mg): 1H NMR (400 MHz DMSO) delta 2.05 (s, 3H), 5.09 (s, 2H), 6.29 (t, J=2.0 Hz, 1H), 7.47 (dd, J=0.4, 1.6 Hz, 1H), 7.67 (dd, J=0.4, 2.0 Hz, 1H).
Reaction SMILES: [CH2:1]([N:4]1[C:18](=[O:19])[C:17]2[C:11]3([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:10][C:9]3[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=3[C:7]=2[NH:6][C:5]1=[S:24])[CH:2]=[CH2:3].C1(C)C=CC(S(O[CH2:35][CH2:36][O:37][CH3:38])(=O)=O)=CC=1.[OH-].[K+].O>C(O)C>[CH2:1]([N:4]1[C:18](=[O:19])[C:17]2[C:11]3([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]3)[CH2:10][C:9]3[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=3[C:7]=2[N:6]=[C:5]1[S:24][CH2:35][CH2:36][O:37][CH3:38])[CH:2]=[CH2:3]
Reactant: COCCOS(=O)(=O)c1ccc(C)cc1
Reactant: C=CCn1c(=S)[nH]c2c(c1=O)C1(CCCCC1)Cc1ccccc1-2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCn1c(SCCOC)nc2c(c1=O)C1(CCCCC1)Cc1ccccc1-2

Procedure:
A mixture of 3-allyl-2-thioxo-2,3-dihydro-1H-spiro[benzo[h]quinazoline-5,1′-cyclohexan]-4(6H)-one (5, 0.100 g, 0.295 mmol), 2-Methoxyethyl p-Toluenesulfonate (0.084 ml, 0.325 mmol), potassium hydroxide (0.025 g, 0.443 mmol) in Ethanol (1.738 ml) was refluxed ON. To the cooled solution, water (1 ml) was added and the mixture was extracted with EtOAc 2×. The organics were washed with brine, dried over sodium sulfate, filtered, and concentrated to a yellow oil. The product was purified by flash column chromatography eluting with 0 to 2.5% EtOAc in hexane. 1H NMR (500 MHz, CDCl3) δ ppm 8.08, 7.39-7.23, 5.95, 5.33-5.28, 4.71, 3.79, 3.57, 3.45, 3.06, 2.61, 1.75-1.72, 1.60-1.54, 1.42-1.39; MS (EI) m/z 397 (M+1)
Reaction SMILES: Cl.[C:2]1([CH:8]2[C:17]3[C:12](=[C:13](Cl)[CH:14]=[CH:15][CH:16]=3)[CH:11]([NH:19][C:20](=[O:22])[CH3:21])[N:10]([CH3:23])[CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.C(O)(=O)/C=C\C(O)=O>C(O)C>[C:2]1([CH:8]2[C:17]3[C:12](=[C:13]([N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[CH:14]=[CH:15][CH:16]=3)[CH:11]([NH:19][C:20](=[O:22])[CH3:21])[N:10]([CH3:23])[CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)NC1c2c(Cl)cccc2C(c2ccccc2)CN1C
Reactant: C1CCNC1
Agent: Cl
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCO
Product: CC(=O)NC1c2c(cccc2N2CCCC2)C(c2ccccc2)CN1C

Procedure:
A mixture of 7.0 g (0.02 mole) of 4-phenyl-8-chloro-acetylamino-2-methyl-1,2,3,4-tetrahydro-isoquinoline-hydrochloride, 70 ml of ethanol and 20 ml (17.0 g, 0.24 mole) of pyrrolidine is refluxed for 5 hours. The reaction mixture is evaporated in vacuo, the residue is dissolved in a mixture of 100 ml of water and 100 ml of ether and the mixture is made alkaline by adding 30 ml of a 30% aqueous sodium hydroxide solution under cooling and stirring. The layers are separated, the aqueous phase is extracted five times with 100 ml of ether each, the organic phase is dried over anhydrous sodium sulfate, clarified with activated charcoal and evaporated. The residue is dissolved in 100 ml of warm ethanol and a solution of 6.6 g (0.057 mole) of maleic acid and 40 ml of ethanol is added. The product is precipitated by adding 1000 ml of ether. The sticky solid dimaleate salt is dissolved in 100 ml of water and the solution is made alkaline by adding 60 ml of a 30% aqueous sodium hydroxide solution under cooling and stirring. The aqueous layer is extracted once with 200 ml and four times with 100 ml of ether each. The ether phases are united, dried over anhydrous sodium sulfate and clarified with activated charcoal. The ether is evaporated and the residue is washed with a mixture of ether and petrolether. Thus 5.4 g of 4-phenyl-2-methyl-8-pyrrolidino-acetylamino-1,2,3,4-tetrahydro-isoquinoline are obtained in the form of white crystals (0.0154 mole). Mp.: 130° C.
Reaction SMILES: [CH3:1][C:2]12[CH2:14][CH:6]3[C:7]([CH3:13])([CH3:12])[C:8]([CH3:11])([C:9]1=[O:10])[CH:5]3[CH2:4][CH2:3]2.[CH3:15][Mg]Cl>>[CH3:1][C:2]12[CH2:14][CH:6]3[C:7]([CH3:13])([CH3:12])[C:8]([CH3:11])([C:9]1([CH3:15])[OH:10])[CH:5]3[CH2:4][CH2:3]2
Reactant: CC12CCC3C(C1)C(C)(C)C3(C)C2=O
Reactant: C[Mg]Cl
Product: CC12CCC3C(C1)C(C)(C)C3(C)C2(C)O

Procedure:
Prepared from 5,7,8,8-tetramethyl-tricyclo[3.3.1.02,7]nonan-6-one by reaction with methyl magnesium chloride.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:12])=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH2:7])=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[NH2:1][C:2]1[C:3]([F:12])=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[CH2:5][NH2:7]
Reactant: NC(=O)c1ccc(Cl)c(N)c1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NCc1ccc(Cl)c(N)c1F

Procedure:
The crude sub-title compound was prepared from 3-amino-4-chloro-2-fluoro-benzamide and LiAlH4 in analogy to step 5d.
Reaction SMILES: ClC1C(C[N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=NC=CN=1.[NH2:20]N.CO>C(Cl)Cl>[C:10]1(=[O:19])[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17](=[O:18])[NH:9][NH:20]1
Reactant: O=C1c2ccccc2C(=O)N1Cc1nccnc1Cl
Reactant: NN
Solvent: ClCCl
Solvent: CO
Product: O=c1[nH][nH]c(=O)c2ccccc12
Reaction time: 19 h

Procedure:
A solution of 2-(3-chloropyrazin-2-ylmethyl)-isoindole-1,3-dione (10.0 g, 36.5 mmol) in anhydrous CH2Cl2 (200 mL) was charged with hydrazine (2.87 mL, 2.93 g, 91.3 mmol, 2.5 eq.) at rt, under N2 atmosphere. After 2.5 b, MeOH (300 mL) was added and the reaction was heated until the solution was homogenous. The reaction mixture was allowed to stir for 19 h. The white ppt which had formed (2,3-dihydrophthalazine-1,4-dione byproduct), was filtered off and washed several times with ether. The clear filtrate was concentrated in vacuo and the concentrate was dissolved in EtOAc and filtered again to remove white ppt. All solvent was removed, giving a yellow oil which was dissolved into EtOAc and ether and charged with HCl (g). The title compound, a pale yellow solid, instantly precipitated. The title compound was dried in a 40° C. oven for 72 h, affording the title compound, as a dark yellow solid; 1H NMR (400 MHz, CD3OD) δ 4.55 (2H, s), 8.27 (1H, d, J=2.52 Hz), 8.54 (1H, d, J=2.56 Hz); MS (ES+): m/z 143.96/145.96 (100/60) [MH+]; HPLC: tR=0.41 min (OpenLynx, polar—7 min).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=1)=[O:3].[CH3:11][O:12][N:13]=[C:14]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25]Br)[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:11][O:12][N:13]=[C:14]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][O:10][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([C:2](=[O:3])[CH3:1])[CH:9]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: CC(=O)c1cccc(O)c1
Reactant: CON=C(C(=O)OC)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CON=C(C(=O)OC)c1ccccc1COc1cccc(C(C)=O)c1
Yield: 80.9 %

Procedure:
3.0 g (0.022 mol) of 3-hydroxyacetophenone and 6.0 g (0.021 mol) of methyl 2-bromomethylphenylglyoxylate O-methyloxime are dissolved in 30 ml of dimethylformamide, and 5.5 g (0.040 yol) of potassium carbonate are added. The mixture is stirred at room temperature for 24 hours, hydrolyzed with water and extracted with methyl tert-butyl ether. The organic phase is washed with water, dried and concentrated. 5.8 g (85%) of methyl 2-(3-acetylphenoxymethyl)phenylglyoxylate O-methyloxime are obtained as a colorless oil.
Reaction SMILES: OCCN(CC)CC.[NH2:9][C:10]1[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][C:11]=1[S:17]([OH:20])(=[O:19])=[O:18].[F:21][C:22]1[C:27]([C:28]#[N:29])=[C:26]([F:30])[C:25]([F:31])=[C:24]([C:32]#[N:33])[C:23]=1F>CS(C)=O>[NH2:9][C:10]1[CH:15]=[C:14]([NH:16][C:23]2[C:24]([C:32]#[N:33])=[C:25]([F:31])[C:26]([F:30])=[C:27]([C:28]#[N:29])[C:22]=2[F:21])[CH:13]=[CH:12][C:11]=1[S:17]([OH:20])(=[O:18])=[O:19]
Reactant: N#Cc1c(F)c(F)c(C#N)c(F)c1F
Reactant: Nc1ccc(S(=O)(=O)O)c(N)c1
Agent: CCN(CC)CCO
Solvent: CS(C)=O
Product: N#Cc1c(F)c(F)c(C#N)c(Nc2ccc(S(=O)(=O)O)c(N)c2)c1F
Temperature: 75 °C

Procedure:
To a mixture of N-(β-hydroxyethyl)diethylamine (5.86 g) and 2,4-diaminobenzene sulphonic acid (7.52 g) in dimethylsulphoxide (45 cm3) was added 1,2,4,5-tetrafluoro-3,6-dicyanobenzene (8.25 g) portionwise with stirring. The mixture was heated at 75° C. for 4 hours then poured into ice/water (140 cm3) to give a solution of 2-amino-4-(2,4,5-trifluoro-3,6-dicyanophenylamino)benzene sulphonic acid.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([OH:15])=[O:14])[CH2:9][CH:10]=[CH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([C@H:8]([C@@H:12]([CH2:16][CH:17]([CH3:18])[CH3:19])[C:13]([OH:15])=[O:14])[CH2:9][CH2:10][CH3:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC[C@H](C(=O)OC(C)(C)C)[C@@H](CC(C)C)C(=O)O
Agent: [Pd]
Solvent: CCO
Product: CCC[C@H](C(=O)OC(C)(C)C)[C@@H](CC(C)C)C(=O)O
Yield: 93.6 %

Procedure:
A solution of 3.0 g of 2(R)-[1(S)-(tertbutoxycarbonyl)-3-butenyl]-4-methylvaleric acid in 30 ml of ethanol was hydrogenated in the presence of 0.3 g of 5% palladium-on-carbon for 4 hours. The catalyst was removed by filtration and the solvent was evaporated. The residue was dissolved in 30 ml of toluene and the solvent was evaporated again. Repetition of this procedure gave 2.83 g of 2(R)-[1(S)-(tertbutoxycarbonyl)-butyl]-4-methyl-valeric acid as a colourless oil.