Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][NH:9][C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)C#N)=[C:6]2[C:5](=[O:19])[N:4]([CH3:20])[C:3]1=[O:21].[F:22]C1C=C(Br)C=CC=1>>[F:22][C:13]1[CH:12]=[C:11]([C:10]2[NH:9][CH:8]=[C:7]3[C:6]=2[C:5](=[O:19])[N:4]([CH3:20])[C:3](=[O:21])[N:2]3[CH3:1])[CH:18]=[CH:17][CH:16]=1
Reactant: Cn1c(=O)c2c(-c3cccc(C#N)c3)[nH]cc2n(C)c1=O
Reactant: Fc1cccc(Br)c1
Product: Cn1c(=O)c2c(-c3cccc(F)c3)[nH]cc2n(C)c1=O

Procedure:
The title compound was prepared analogously to 3-(1,3-Dimethyl-2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-yl)benzonitrile (Example 9.0 Step 4) by replacing 3-bromobenzonitrile by 3-fluoro-1-bromobenzene in step 3;
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1.[H-].[Na+].Cl.[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18]Cl>CN(C)C=O>[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18][N:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=1)[C:9](=[O:11])[CH3:10]
Reactant: CN(C)CCCl
Reactant: CC(=O)Nc1ccc(C)cn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N(CCN(C)C)c1ccc(C)cn1
Reaction time: 0.5 h

Procedure:
N-(5-Methyl-2-pyridyl)acetamide (75.0 g, 0.5 mole) is dissolved in 1000 ml of dry dimethylformamide and a 50% suspension of sodium hydride in mineral oil (24.0 g, 0.5 mole) is added under nitrogen with stirring in two portions over 1/2 hour. The temperature rises to 40° and then is increased to 50°-55° to keep the salt in addition. Additional sodium hydride suspension (28.8 g, 0.6 mole) is added over 10 minutes followed by 2-dimethylaminoethyl chloride hydrochloride (86.5 g, 0.6 mole) added in small portions over 1/2 hour. The temperature is moderated at 70° with occasional ice bath cooling. Then the mixture is stirred overnight at steam bath temperature. The reaction mixture is cooled and filtered. Removal of the dimethylformamide under reduced pressures gives a dark liquid. The product distills as a pale yellow liquid at 124°-128° at 0.6 mm, n25D 1.5216. Weight obtained is 78 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([CH2:19]O)[CH2:15][C@H:14]1[C@@H:13]([CH3:21])[S:12][C:11]([NH:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[N:10]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:51]>ClCCl>[Br:51][CH2:19][C@@H:16]1[O:17][CH2:18][C@:9]2([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[N:10]=[C:11]([NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[S:12][C@H:13]([CH3:21])[C@@H:14]2[CH2:15]1
Reactant: C[C@H]1SC(NC(=O)c2ccccc2)=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](CO)C[C@@H]12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@H]1SC(NC(=O)c2ccccc2)=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](CBr)C[C@@H]12
Reaction time: 18 h

Procedure:
A solution of N-[(4R,4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(hydroxymethyl)-4-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (P2) (150 mg, 0.347 mmol) in dichloromethane (7.5 mL) was cooled to 0° C. Triphenylphosphine (182 mg, 0.694 mmol) was added, followed by carbon tetrabromide (70 μL, 0.69 mmol), and the reaction mixture was removed from the ice bath and stirred for 18 hours. After addition of saturated aqueous sodium chloride solution (15 mL), the mixture was extracted with dichloromethane (2×20 mL); the combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 70% ethyl acetate in heptane) provided the product as a white solid. Yield: 77.9 mg, 157 μmol, 45%. 1H NMR (400 MHz, CDCl3) δ 8.15-8.27 (br m, 2H), 7.34-7.57 (m, 4H), 6.84-6.98 (m, 2H), 4.19 (br d, J=12 Hz, 1H), 3.82-3.92 (m, 2H), 3.45-3.52 (m, 1H), 3.39 (dd, J=10.5, 5.8 Hz, 1H), 3.23-3.33 (br m, 1H), 2.89-2.98 (m, 1H), 1.93-2.02 (m, 1H), 1.6-1.73 (m, 1H), 1.28 (d, J=7 Hz, 3H).
Reaction SMILES: S(Cl)(Cl)(=O)=O.Cl[CH2:7][Cl:8].[Br:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([C:20]3[C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)=[N:23][N:22]4[CH2:31][CH2:32]C[C:21]=34)=[CH:15][CH:16]=[N:17]2)=[CH:12][CH:11]=1>N1C=CC=CC=1>[Br:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([C:20]3[C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)=[N:23][N:22]4[CH2:31][CH2:32][CH:7]([Cl:8])[C:21]=34)=[CH:15][CH:16]=[N:17]2)=[CH:12][CH:11]=1
Reactant: Brc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Reactant: ClCCl
Solvent: O=S(=O)(Cl)Cl
Solvent: c1ccncc1
Product: ClC1CCn2nc(-c3ccccn3)c(-c3ccnc4cc(Br)ccc34)c21
Reaction time: 18 h

Procedure:
A solution of 1 M sulfuryl chloride in dichloromethane (20 mL, 20 mmol) is added to a solution of 7-bromo-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline (2.2 g, 5.62 mmol) in dry pyridine (50 mL). The mixture is stirred for 18 h and concentrated in vacuo. The residue is partitioned between chloroform and saturated sodium chloride. The organic layer is dried (sodium sulfate), filtered, concentrated in vacuo, and the residue chromatographed on SiO2 (dichloromethane to 20% methanol in dichloromethane) to yield the title compound as a red solid, 1.8 g (75%).
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([S:7]([CH2:10][CH2:11][C:12]([NH:14][NH:15][C:16]([N:18]1[CH2:24][C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[O:21][C:20]2[CH:29]=[CH:30][C:31]([O:33]C)=[CH:32][C:19]1=2)=[O:17])=[O:13])(=[O:9])=[O:8])[CH3:6]>>[CH2:5]([S:7]([CH2:10][CH2:11][C:12]([NH:14][NH:15][C:16]([N:18]1[CH2:24][C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[O:21][C:20]2[CH:29]=[CH:30][C:31]([OH:33])=[CH:32][C:19]1=2)=[O:17])=[O:13])(=[O:9])=[O:8])[CH3:6]
Reactant: CCS(=O)(=O)CCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(OC)cc21
Agent: BrB(Br)Br
Product: CCS(=O)(=O)CCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(O)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of boron tribromide (1.0M in methylene chloride, 7.2 mL) at 5° C. (ice water bath) was added under nitrogen the title compound of Example 16 (e) (1.0 g). The ice bath was removed, and the reaction was stirred at room temperature for 3 hours. The reaction was carefully quenched by the addition of 1NNaOH (10 mL), acidified by the addition of 1NHCl (15 mL), and evaporated under vacuum. The resulting solid was triturated with water, and the insoluble material was collected by filtration, washed three times with water, and then with ethyl ether. Crystallization from ethanol (3A) yielded the title compound as white crystals. Mp: 191°-194° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][C:10]2([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:18][CH:17]=3)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:3]=1.C(N(CC)CC)C>C(O)C.[Pd]>[N:26]1([CH2:25][CH2:24][CH2:23][O:22][C:19]2[CH:18]=[CH:17][C:16]([C:10]3([CH2:9][NH:8][C:4]4[CH:3]=[CH:2][N:7]=[CH:6][N:5]=4)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[CH:21][CH:20]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: Clc1cc(NCC2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)ncn1
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: c1cc(NCC2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)ncn1
Yield: 18.9 %

Procedure:
A solution of 6-chloro-N-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)pyrimidin-4-amine (50 mg, 0.12 mmol) and triethylamine (48.6 μl, 0.35 mmol) in ethanol (2 mL) was hydrogenated for 16 hours at room temperature at 50 psi in the presence of 10% Pd/C (5 mg, 10% w/w). The reaction mixture was filtered through Arbocel® and rinsed with ethanol and water. The filtrate was concentrated in vacuo. The residue was partitioned between ethyl acetate (20 ml) and saturated aqueous sodium carbonate (20 ml). The organic layer was dried over sodium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (100:0:0 to 95:5:0.5 by volume) to provide the title compound (9 mg, 20%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:3]=1[C:4]#[N:5].[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>O1CCOCC1>[C:4]([C:3]1[C:6]([C:10]([F:13])([F:12])[F:11])=[CH:7][CH:8]=[CH:9][C:2]=1[N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)#[N:5]
Reactant: N#Cc1c(F)cccc1C(F)(F)F
Reactant: C1CNCCN1
Solvent: C1COCCO1
Product: N#Cc1c(N2CCNCC2)cccc1C(F)(F)F

Procedure:
A mixture of 3 g (15.8 mmol) of 2-fluoro-6-trifluoromethylbenzonitrile, 7.5 g (87 mmol) of piperazine and 24 mL of dioxane is heated at reflux for 5 hours.
Reaction SMILES: [S:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18][N:19]=[N+:20]=[N-:21])[O:15][C:14]3=[O:22])=[CH:9][C:8]=2[F:23])[CH2:3][CH2:2]1.[CH:24]12CC(C=C1)C=[CH:25]2>O1CCOCC1>[S:1]1[CH2:2][CH:3]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18][N:19]4[CH:25]=[CH:24][N:21]=[N:20]4)[O:15][C:14]3=[O:22])=[CH:9][C:8]=2[F:23])[CH2:5][CH2:6]1
Reactant: C1=CC2C=CC1C2
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(C3=CCSCC3)c(F)c2)C(=O)O1
Solvent: C1COCCO1
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(C2=CCSCC2)c(F)c1
Yield: 73.5 %

Procedure:
(5R)-3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-azidomethyloxazolidin-2-one (2 g, 5.7 mmol) was dissolved in dioxane (10 ml). Bicyclo[2.2.1]hepta-2,5-diene (3.1 ml, 28.7 mmol) was added and it was refluxed under nitrogen for 18 hours. The solvent was evaporated in vacuo and the residue subjected to chromatography on silica gel eluting with 25% ethylacetate in dichloromethane to give the title compound (1.51 g).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][C:22](=[O:25])[N:21]([CH2:26][CH2:27][CH2:28][OH:29])[CH2:20][C@H:19]1[CH3:30])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C.P([O-])(O)(O)=O.[K+]>ClCCl>[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][C:22](=[O:25])[N:21]([CH2:26][CH2:27][CH:28]=[O:29])[CH2:20][C@H:19]1[CH3:30])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: C[C@@H]1CN(CCCO)C(=O)CCN1C(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(CCC=O)C(=O)CCN1C(=O)OC(C)(C)C
Temperature: -6 °C
Reaction time: 0.08 h
Yield: 91.9 %

Procedure:
To a solution of 0.161 ml (1.84 mmol, 1.15 eq.) of oxalyl chloride in 9 ml dichloro-methane at −50 to −60° C. was added a solution of 0.272 ml (3.83 mmol, 2.4 eq.) dimethyl-sulfoxide in 1.5 ml dichloromethane within 5 min. The solution was stirred for 5 min and a solution of 0.457 g (1.60 mmol) of (R)-4-(3-hydroxy-propyl)-2-methyl-5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester (example 1B) in 4.5 ml dichloromethane was added within 5 min. The mixture was stirred for 15 min and 1.11 ml (7.98 mmol, 5 eq.) of triethylamine was added within 5 min. The suspension was stirred for 3.5 h and slowly warmed to −6° C. The reaction was neutralized with cold 10% aq. potassium dihydrogenphosphate solution (adjusted with solid potassium dihydrogenphosphate to pH 4-5) and extracted with ethyl acetate (3 times). The organic phases were washed with fresh sat. aq. sodium hydrogencarbonate solution and 10% aq. sodium chloride solution, dried over Na2SO4 and evaporated to give 0.418 g (92%) of the title compound as colorless oil. MS: 285.1 (MH+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=[N+]([O-])c1cccc(CNc2nc(Cl)nc3sc([N+](=O)[O-])cc23)c1
Reactant: c1c[nH]cn1
Product: O=[N+]([O-])c1cccc(CNc2nc(-n3ccnc3)nc3sc([N+](=O)[O-])cc23)c1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-nitro-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-nitro-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][NH2:2].[Cl:3][CH2:4][CH2:5][CH2:6][C:7]([C:20]#[N:21])([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:8](OCC)=[O:9].C(OCC)(=O)C.O.C(=O)(O)[O-].[Na+]>C(O)C>[Cl:3][CH2:4][CH2:5][CH2:6][C:7]([C:20]#[N:21])([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:8]([NH:1][NH2:2])=[O:9]
Reactant: CCOC(=O)C(C#N)(CCCCl)c1ccc(F)cc1
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: N#CC(CCCCl)(C(=O)NN)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Hydrazine (340 mg) was added to a solution of ethyl 5-chloro-2-cyano-2-(4-fluorophenyl)pentanoate (300 mg) in ethanol (3 mL), and the reaction solution was stirred at room temperature for 40 minutes. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was filtered through a silica gel, and the filtrate was concentrated under reduced pressure to obtain a crude product of 5-chloro-2-cyano-2-(4-fluorophenyl)pentanoic acid hydrazide.
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH3:33])=[CH:15][N:16]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24](=[O:32])[C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)[C:10]=2[N:9]=[CH:8]1)(=O)C.[OH-].[Na+].COCCOC.Cl>CO>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([C:24]([C:21]2[CH:22]=[CH:23][C:18]([CH2:17][N:16]3[C:10]4[N:9]=[CH:8][N:7]([CH2:6][CH2:5][OH:4])[C:12](=[O:13])[C:11]=4[C:14]([CH3:33])=[CH:15]3)=[CH:19][CH:20]=2)=[O:32])=[CH:30][CH:29]=1
Reactant: CC(=O)OCCn1cnc2c(c(C)cn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: CO
Product: Cc1cn(Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c2ncn(CCO)c(=O)c12
Reaction time: 4 h
Yield: 95.3 %

Procedure:
3-Acetoxyethyl-7-[4-(4-chlorobenzoyl)benzyl]-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-one (464 mg) was dissolved in methanol (12 ml) followed by addition of 1N-sodium hydroxide (2 ml). To this mixture was added DME (6 ml) to prepare a homogeneous solution. After 4 hours of stirring, 1N-HCl (2 ml) was added and the solvent was distilled off under reduced pressure. The residue was diluted with water and triturated and the resulting powder was rinsed with water and methanol and dried to provide the title compound as crystalline powder (402 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1([C:9]2[CH:10]=[C:11]([S:14][C:15]3[CH:24]=[C:23]4[C:18]([C:19](=O)[CH2:20][CH2:21][O:22]4)=[CH:17][CH:16]=3)[S:12][CH:13]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.Cl.[NH2:27][OH:28]>>[CH3:1][O:2][C:3]1([C:9]2[CH:10]=[C:11]([S:14][C:15]3[CH:24]=[C:23]4[C:18](/[C:19](=[N:27]/[OH:28])/[CH2:20][CH2:21][O:22]4)=[CH:17][CH:16]=3)[S:12][CH:13]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: COC1(c2csc(Sc3ccc4c(c3)OCCC4=O)c2)CCOCC1
Reactant: NO
Agent: Cl
Product: COC1(c2csc(Sc3ccc4c(c3)OCC/C4=N\O)c2)CCOCC1
Yield: 82 %

Procedure:
Using an analogous procedure to that described in Example 7, 7-[4-(4-methoxytetrahydropyran-4-yl)thien-2-ylthio]chroman-4-one was reacted with hydroxylamine hydrochloride to give (E)-7-[4-(4-methoxytetrahydropyran-4-yl)thien-2-ylthio]chroman-4-one oxime in 82% yield, m.p. 137°-138° C.;
Reaction SMILES: C([O:8][C:9]1[CH:37]=[CH:36][C:12]2[CH:13]=[C:14]([C:16]([C:21]3[CH:34]=[CH:33][C:24]([O:25][CH2:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[C:23]([CH3:35])[CH:22]=3)([CH2:19][CH3:20])[CH2:17][CH3:18])[O:15][C:11]=2[CH:10]=1)C1C=CC=CC=1>CCOC(C)=O.CO.[Pd]>[CH2:17]([C:16]([C:21]1[CH:34]=[CH:33][C:24]([O:25][CH2:26][C:27](=[O:32])[C:28]([CH3:29])([CH3:31])[CH3:30])=[C:23]([CH3:35])[CH:22]=1)([C:14]1[O:15][C:11]2[CH:10]=[C:9]([OH:8])[CH:37]=[CH:36][C:12]=2[CH:13]=1)[CH2:19][CH3:20])[CH3:18]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2ccc(OCc3ccccc3)cc2o1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2ccc(O)cc2o1
Reaction time: 2 h
Yield: 90.2 %

Procedure:
A solution of 1-{4-[1-(6-benzyloxy-benzofuran-2-yl)-1-ethyl-propyl]-2-methyl-phenoxy}-3,3-dimethyl-butan-2-one (5.90 g, 11.8 mmol) in EtOAc (20.0 mL) is added a slurry of Pd—C (590 mg, 10%) in MeOH (20.0 mL) at RT. The resulting mixture is stirred under hydrogen balloon pressure for 2 h. The mixture is filtered through a pad of celite and the filtrate is concentrated, the residue is purified with 20-30% EtOAc/Hex to afford the title compound (4.35 g, 90%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:18][OH:19].Cl.N1C=CC=CC=1>CO>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[N:18][OH:19])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)COc1cccc(C=O)c1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)COc1cccc(C=NO)c1
Reaction time: 2 h
Yield: 91.2 %

Procedure:
To a solution of (3-formyl-phenoxy)-acetic acid tert-butyl ester (2.05 g, 8.68 mmol) in MeOH (30 mL) was added NH2OH.HCl (0.66 g, 9.54 mmol) and pyridine (3.5 mL, 43.4 mmol) and the reaction was stirred for 2 hours. The MeOH was removed in vacuo and the residue was diluted with EtOAc and 1N HCl. The layers were separated and the aqueous solution was washed with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to afford the title compound (1.99 g). 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.23-7.28 (m, 2H), 7.12 (m, 1H), 6.93 (d, 1H), 4.51 (s, 2H), 1.46 (s, 9H).
Reaction SMILES: [Na].CS(C)=O.[Cl:6][C:7]1[CH:8]=[C:9]([N:13]2[CH:17]=[N:16][C:15]([OH:18])=[N:14]2)[CH:10]=[CH:11][CH:12]=1.Br[CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CO>[Cl:6][C:7]1[CH:8]=[C:9]([N:13]2[CH:17]=[N:16][C:15]([O:18][CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH3:26])=[N:14]2)[CH:10]=[CH:11][CH:12]=1
Reactant: Oc1ncn(-c2cccc(Cl)c2)n1
Reactant: CCOC(=O)C(C)Br
Agent: [Na]
Solvent: CS(C)=O
Solvent: CO
Product: CCOC(=O)C(C)Oc1ncn(-c2cccc(Cl)c2)n1
Temperature: 0 °C
Reaction time: 4 h
Yield: 29.4 %

Procedure:
A 2.2 g portion of sodium was dissolved in 75 ml of methanol and the solution was added to 100 ml of dimethylsulfoxide. To that was added 19.2 g of 1-(3-chlorophenyl)-3-hydroxy-1,2,4-1H-triazole, and the mixture was stirred on the steam bath for 4 hours. To it was then added 17.7 g of ethyl 2-bromopropionate, and heating was continued for 2 hours more. The mixture was then cooled and poured over ice-water, and the solid was collected, dried and recrystallized from ethanol and then from toluene to obtain 8.5 g of the desired product, m.p. 70°-72°.
Reaction SMILES: [N:1]1([C:7]2[O:8][C:9]([C:16]([O:18]CC)=[O:17])=[C:10]([C:12]([F:15])([F:14])[F:13])[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C1COCC1.O.[OH-].[Na+]>[N:1]1([C:7]2[O:8][C:9]([C:16]([OH:18])=[O:17])=[C:10]([C:12]([F:14])([F:15])[F:13])[N:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)c1oc(N2CCCCC2)nc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1oc(N2CCCCC2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
To a solution of ethyl 2-(1-piperidinyl)-4-trifluoromethyloxazole-5-carboxylate (A-3) (1.28 g) in THF (20 mL) at RT was added 1 N NaOH (20 mL). The reaction mixture was stirred at RT for 3 h then diluted with H2O (100 mL) and 1 N NaOH (10 mL). The aqueous solution was washed with Et2O (2×100 mL) and then acidified to pH=1 by addition of 1 N HCl, and extracted with EtOAc (3×50 mL). The combined organic extract was dried over Na2SO4, filtered, and concentrated to yield 2-(1-piperidinyl)-4-trifluoromethyloxazole-5-carboxylic acid (A-4) as a white solid (1.16 g, 100% yield). LCMS (ESI) calcd for [M+1]+ 265.1. found 265.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7](S(C1C=CC=CC=1)(=O)=O)[CH:6]=[C:5]2[CH2:22]Br.[CH3:24][C@H:25]1[NH:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]1.C(N(CC)C(C)C)(C)C.[OH-].[Na+]>C1COCC1.CO.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[C:5]2[CH2:22][N:30]1[CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26][C@H:25]1[CH3:24]
Reactant: O=c1c2ccc(Br)cc2c(CBr)cn1S(=O)(=O)c1ccccc1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1Cc1c[nH]c(=O)c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.3 %

Procedure:
6-Bromo-4-(bromomethyl)-2-(phenylsulfonyl)isoquinolin-1(2H)-one (Example 11d, 2.0 g), tert-butyl (3R)-3-methylpiperazine-1-carboxylate (0.946 g) and N,N-diisopropylethylamine (1.143 mL) were dissolved in THF (10 mL) and stirred at room temperature under nitrogen for 16 h. The reaction mixture was diluted with methanol (10 mL) and treated with sodium hydroxide (0.35 g), after stirring at room temperature for 1 h, water (200 mL) was added and the reaction mixture extracted into ethyl acetate (250 mL). The separated organic layer was dried (MgSO4) filtered and evaporated, the residue was purified (SiO2 chromatography, elution with ethyl acetate) to give the subtitle compound (0.75 g) as a solid.
Reaction SMILES: [Cl-].[CH3:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[C:8]([O-:10])=[O:9].C1COCC1.CN>C(OCC)(=O)C>[CH3:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: Cc1sccc1C(=O)[O-]
Agent: CN
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1sccc1C(=O)O
Yield: 89.3 %

Procedure:
2-Methyl-3-thiophenecarboxylate chloride (60.5 g)/THF (300 ml) solution was added dropwise to a 40% aqueous solution of methylamine (400 ml) at 0° C. Ethyl acetate (2 l) was added thereto, and then the organic layer was washed sequentially with water, a 5N aqueous solution of hydrochloride acid, an aqueous solution of saturated of saturated sodium bicarbonate, water and brine, dried and evaporated. The resulting residue was crystallized from n-hexane, to give the title compound as a white powder (43.5 g, yield; 71.8%).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[C:6]([CH:21]2[CH2:23][CH2:22]2)=[N:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:9][CH:10]=1.ClCC1C(C2CC2)=NC(C2C=CC(C(F)(F)F)=CC=2)=NC=1.CC(C[AlH]CC(C)C)C>C1COCC1>[CH:21]1([C:6]2[C:5]([CH2:4][CH2:3][OH:2])=[CH:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:15][CH:16]=3)[N:7]=2)[CH2:23][CH2:22]1
Reactant: COC(=O)Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Agent: CC(C)C[AlH]CC(C)C
Agent: FC(F)(F)c1ccc(-c2ncc(CCl)c(C3CC3)n2)cc1
Solvent: C1CCOC1
Product: OCCc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.60 g (1.78 mmol) of [4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-acetic acid methyl ester (prepared from 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 9E]) in analogy to the sequences described in examples 4H] to 4J]) was dissolved in 10 ml of abs. THF and cooled down to 0° C. It was then reacted with 3.18 nml of DIBAL-H-solution (1.2 M in toluene) and the mixture stirred for 2 h at room temperature. Careful quenching with ice/THF/H2O, twofold extraction with AcOEt, washing with diluted HCl solution and brine, drying over sodium sulfate, and evaporation of the solvents left a crude product which was purified by crystallization from dichloromethane/n-heptane to deliver finally 0.53 g of the title compound as light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[CH:15]([NH:17][NH2:18])=O>C(O)CCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]3[N:10]([CH:15]=[N:17][N:18]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2ccc(Br)cc2)nn1
Reactant: NNC=O
Solvent: CCCCO
Product: Brc1ccc(-c2ccc3nncn3n2)cc1

Procedure:
A mixture of 3.76 g. of 3-(p-bromophenyl)-6-chloropyridazine, 1.80 g. of formylhydrazine and 50 ml. of butyl alcohol is heated to reflux and allowed to reflux overnight. The reaction mixture is allowed to cool and the precipitated product is washed with water, air dried and recrystallized from methyl alcohol, m.p. 209°-211° C.